Comparison	O
with	O
alkaline	B-GENE
phosphatases	I-GENE
and	O
5	B-GENE
-	I-GENE
nucleotidase	I-GENE

Pharmacologic	O
aspects	O
of	O
neonatal	O
hyperbilirubinemia	O
.	O

When	O
CSF	O
[	O
HCO3	O
-	O
]	O
is	O
shown	O
as	O
a	O
function	O
of	O
CSF	O
PCO2	O
the	O
data	O
of	O
K	O
-	O
depleted	O
rats	O
are	O
no	O
longer	O
displaced	O
when	O
compared	O
to	O
controls	O
but	O
still	O
have	O
a	O
significantly	O
greater	O
slope	O
(	O
1	O
.	O
21	O
+	O
/	O
-	O
0	O
.	O
23	O
vs	O
.	O

Flurazepam	O
thus	O
appears	O
to	O
be	O
an	O
effective	O
hypnotic	O
drug	O
with	O
the	O
optimum	O
dose	O
for	O
use	O
in	O
general	O
practice	O
being	O
15	O
mg	O
at	O
night	O
.	O

Beta	O
blocking	O
agents	O
.	O

When	O
extracorporeal	O
CO2	O
removal	O
approximated	O
CO2	O
production	O
(	O
VCO2	O
)	O
,	O
alveolar	O
ventilation	O
almost	O
ceased	O
.	O

Intravenous	O
administration	O
(	O
25	O
mg	O
/	O
kg	O
)	O
of	O
carbonic	B-GENE
anhydrase	I-GENE
inhibitors	O
(	O
acetazolamide	O
,	O
methazolamide	O
,	O
dichlorphenamide	O
,	O
sulthiame	O
)	O
induced	O
an	O
early	O
important	O
rise	O
of	O
cortical	O
p	O
O2	O
,	O
which	O
is	O
not	O
dependent	O
on	O
increase	O
of	O
p	O
O2	O
and	O
p	O
CO2	O
and	O
decrease	O
of	O
pH	O
in	O
arterial	O
blood	O
.	O

Teratological	O
study	O
of	O
etoperidone	O
in	O
the	O
rat	O
and	O
rabbit	O
.	O

Colorectal	O
polyps	O
should	O
be	O
removed	O
endoscopically	O
whenever	O
possible	O
.	O

The	O
variable	O
HMG	B-GENE
dosage	O
regimen	O
was	O
found	O
to	O
offer	O
no	O
advantages	O
when	O
compared	O
with	O
our	O
standard	O
daily	O
dosage	O
regimen	O
.	O

When	O
the	O
CO2	O
content	O
reached	O
9	O
Vol	O
%	O
the	O
animals	O
became	O
apathic	O
and	O
lost	O
body	O
weight	O
.	O

Serum	B-GENE
gamma	I-GENE
glutamyltransferase	I-GENE
in	O
the	O
diagnosis	O
of	O
liver	O
disease	O
in	O
cattle	O
.	O

By	O
contrast	O
,	O
secretory	B-GENE
HI	I-GENE
antibodies	I-GENE
were	O
not	O
demonstrated	O
at	O
the	O
onset	O
of	O
illness	O
in	O
any	O
of	O
the	O
patients	O
,	O
but	O
their	O
formation	O
started	O
early	O
and	O
the	O
antibodies	O
reached	O
maximal	O
levels	O
about	O
10	O
days	O
after	O
onset	O
of	O
illness	O
.	O

With	O
the	O
exception	O
of	O
virus	O
assay	O
and	O
quantitation	O
,	O
these	O
methods	O
are	O
simple	O
and	O
inexpensive	O
enough	O
to	O
be	O
done	O
in	O
typical	O
shellfish	O
microbiology	O
laboratories	O
.	O

Characteristics	O
of	O
lipase	B-GENE
activity	O
.	O

Takayasu	O
'	O
s	O
disease	O
:	O
association	O
with	O
HLA	B-GENE
-	I-GENE
B5	I-GENE
.	O

SGPT	B-GENE
,	O
SGOT	B-GENE
,	O
and	O
alkaline	B-GENE
phosphatase	I-GENE
concentrations	O
were	O
essentially	O
normal	O
in	O
all	O
subjects	O
.	O

Gamma	B-GENE
glutamyl	I-GENE
transpeptidase	I-GENE
(	O
GGTP	B-GENE
)	O
activity	O
in	O
the	O
seminal	O
fluid	O

Patients	O
with	O
Parkinson	O
'	O
s	O
disease	O
showed	O
a	O
relatively	O
high	O
incidence	O
to	O
psychoses	O
during	O
drug	O
treatment	O
(	O
51	O
.	O
47	O
%	O
)	O
.	O

Selective	O
stimulation	O
of	O
central	O
alpha	B-GENE
-	I-GENE
autoreceptors	I-GENE
following	O
treatment	O
with	O
alpha	O
-	O
methyldopa	O
and	O
FLA	O
136	O
.	O

Anti	O
-	O
anxiety	O
action	O
of	O
diazepam	O
after	O
intra	O
-	O
amygdaloid	O
application	O
in	O
the	O
rat	O
.	O

Abstracts	O
.	O

Removal	O
of	O
thick	O
,	O
permanently	O
altered	O
mucoas	O
is	O
recommended	O
even	O
in	O
the	O
absence	O
of	O
squamous	O
epithelium	O
.	O

An	O
IgG	B-GENE
monoclonal	O
gammopathy	O
was	O
present	O
in	O
the	O
serum	O
of	O
4	O
patients	O
and	O
Bence	O
-	O
Joanes	O
proteinuria	O
was	O
found	O
in	O
1	O
patient	O
.	O

Studies	O
on	O
immunoglobulin	B-GENE
E	I-GENE
:	O
the	O
impact	O
of	O
a	O
sojourn	O
with	O
Professor	O
Dan	O
H	O
.	O

Peroxydase	B-GENE
reaction	O
stains	O
were	O
negative	O
,	O
chloroacetate	B-GENE
esterase	I-GENE
were	O
strongly	O
positive	O
.	O

Ten	O
out	O
-	O
patients	O
with	O
pustulosis	O
palmaris	O
et	O
plantaris	O
were	O
examined	O
with	O
direct	O
immunofluorescence	O
(	O
IF	O
)	O
technique	O
for	O
deposition	O
of	O
fibrinogen	B-GENE
,	O
fibrin	B-GENE
or	O
its	O
degradation	O
products	O
(	O
FR	B-GENE
-	I-GENE
antigen	I-GENE
)	O
in	O
affected	O
and	O
unaffected	O
skin	O
,	O
together	O
with	O
heparin	O
-	O
precipitable	O
fraction	O
(	O
HPF	O
)	O
,	O
cryoglobulin	B-GENE
and	O
total	O
plasma	O
fibrinogen	B-GENE
in	O
the	O
blood	O
.	O

Of	O
600	O
mediastinoscopies	O
carried	O
out	O
from	O
1966	O
to	O
1973	O
,	O
479	O
were	O
performed	O
to	O
assess	O
the	O
operability	O
of	O
a	O
pulmonary	O
carcinoma	O
.	O

A	O
mixture	O
of	O
human	B-GENE
albumin	I-GENE
5	O
%	O
and	O
hydroxy	O
-	O
ethyl	O
-	O
starch	O
was	O
used	O
as	O
a	O
solution	O
for	O
dilution	O
.	O

In	O
the	O
matched	O
control	O
group	O
the	O
acquisition	O
-	O
rate	O
of	O
both	O
symptomatic	O
and	O
asymptomatic	O
0acteriuria	O
was	O
over	O
12	O
%	O
,	O
a	O
figure	O
similar	O
to	O
the	O
percentage	O
of	O
women	O
present	O
in	O
the	O
practice	O
population	O
during	O
one	O
year	O
with	O
transient	O
,	O
symptomatic	O
,	O
and	O
persistent	O
A	O
.	O
B	O
.	O

Late	O
complications	O
of	O
catheterisation	O
for	O
intravenous	O
nutrition	O
.	O

Prenatal	O
diagnosis	O
of	O
galactosaemia	O
.	O

Sings	O
which	O
are	O
indicative	O
of	O
metaplastic	O
erythropoiesis	O
are	O
absent	O
.	O

False	O
positive	O
amniotic	B-GENE
fluid	I-GENE
alpha	I-GENE
fetoprotein	I-GENE
levels	O
resulting	O
from	O
contamination	O
with	O
fetal	O
blood	O
:	O
results	O
of	O
an	O
experiment	O
.	O

Serum	O
-	O
ferritin	B-GENE
in	O
diagnosis	O
of	O
haemochromatosis	O
.	O

In	O
2	O
subjects	O
the	O
phytomitogen	O
reactivity	O
of	O
the	O
lymphocytes	O
was	O
improved	O
after	O
treatment	O
.	O

Patients	O
at	O
risk	O
of	O
hypothyroidism	O
.	O

Albumin	B-GENE
and	O
cyclic	O
AMP	O
levels	O
in	O
peritoneal	O
fluids	O
in	O
the	O
child	O

Preface	O
.	O

Thirty	O
-	O
five	O
strains	O
of	O
Legionnaires	O
'	O
disease	O
bacteria	O
were	O
shown	O
to	O
belong	O
in	O
four	O
distinct	O
serologic	O
groups	O
on	O
the	O
basis	O
of	O
findings	O
obtained	O
with	O
direct	O
fluorescent	O
antibody	O
testing	O
.	O

On	O
the	O
other	O
hand	O
factor	B-GENE
IX	I-GENE
activity	O
is	O
decreased	O
in	O
coumarin	O
treatment	O
with	O
factor	B-GENE
IX	I-GENE
antigen	O
remaining	O
normal	O
.	O

The	O
concentration	O
of	O
alpha	B-GENE
2	I-GENE
-	I-GENE
macroglobulin	I-GENE
,	O
alpha	B-GENE
1	I-GENE
-	I-GENE
antitrypsin	I-GENE
,	O
plasminogen	B-GENE
,	O
C3	B-GENE
-	I-GENE
complement	I-GENE
,	O
fibrinogen	B-GENE
degradation	I-GENE
products	I-GENE
(	O
FDP	B-GENE
)	O
and	O
fibrinolytic	O
activity	O
,	O
were	O
studied	O
in	O
the	O
aqueous	O
humour	O
and	O
serum	O
from	O
nine	O
patients	O
with	O
Fuchs	O
'	O
endothelial	O
dystrophy	O
,	O
17	O
patients	O
with	O
uncomplicated	O
senile	O
cataract	O
and	O
in	O
the	O
secondary	O
aqueous	O
from	O
six	O
cataract	O
patients	O
.	O

Only	O
17	O
%	O
of	O
all	O
patients	O
admitted	O
it	O
at	O
all	O
times	O
.	O

Prazosin	O
alone	O
was	O
effective	O
in	O
volume	O
responsive	O
patients	O
at	O
a	O
dose	O
of	O
5	O
+	O
/	O
-	O
1	O
.	O
0	O
mg	O
daily	O
.	O

T4	O
and	O
FT4I	O
followed	O
parallel	O
courses	O
in	O
both	O
groups	O
;	O
during	O
the	O
first	O
45	O
days	O
,	O
however	O
,	O
the	O
values	O
were	O
significantly	O
lower	O
in	O
premature	O
infants	O
under	O
34	O
weeks	O
'	O
EGA	O
than	O
in	O
term	O
infants	O
(	O
P	O
less	O
than	O
0	O
.	O
001	O
)	O
.	O

A	O
three	O
-	O
phased	O
analysis	O
of	O
treatment	O
plans	O
for	O
45	O
patients	O
was	O
undertaken	O
.	O

Aspirin	O
intolerance	O
:	O
unaltered	O
susceptibility	O
of	O
platelet	B-GENE
cyclo	I-GENE
-	I-GENE
oxygenase	I-GENE
to	O
inhibition	O
by	O
aspirin	O
in	O
vitro	O
.	O

These	O
results	O
indicate	O
that	O
cynomolgus	O
monkeys	O
are	O
either	O
less	O
sensitive	O
or	O
respond	O
differently	O
than	O
rhesus	O
monkeys	O
to	O
some	O
of	O
the	O
pharmacological	O
effects	O
of	O
norcocaine	O
.	O

59	O
cases	O
of	O
surgically	O
resectable	O
cancers	O
(	O
T1	O
,	O
T2	O
,	O
T3	O
,	O
N0	O
,	O
N1	O
)	O
had	O
a	O
minimum	O
followup	O
of	O
two	O
years	O
(	O
average	O
4	O
years	O
+	O
/	O
-	O
3	O
months	O
)	O
.	O

The	O
effect	O
of	O
CBZ	O
and	O
DPH	O
can	O
be	O
explained	O
by	O
interference	O
with	O
thyroid	O
hormone	O
binding	O
to	O
TBG	B-GENE
combined	O
with	O
enzyme	O
-	O
induced	O
increased	O
metabolic	O
clearance	O
rate	O
of	O
thyroid	O
hormones	O
without	O
homeostatic	O
maintenance	O
of	O
premedication	O
levels	O
of	O
FT4	O
and	O
FT3	O
.	O

The	O
present	O
research	O
evaluated	O
the	O
possibility	O
that	O
polyethylene	O
glycol	O
400	O
(	O
PEG	O
400	O
)	O
might	O
be	O
efficacious	O
,	O
toxic	O
,	O
or	O
both	O
.	O

According	O
to	O
their	O
functional	O
properties	O
the	O
latter	O
neurons	O
were	O
subdivided	O
into	O
:	O
(	O
a	O
)	O
neurons	O
responding	O
to	O
stimuli	O
near	O
the	O
eyes	O
;	O
(	O
b	O
)	O
neurons	O
triggered	O
by	O
complex	O
visual	O
stimuli	O
;	O
(	O
c	O
)	O
neurons	O
inhibited	O
by	O
visual	O
stimuli	O
.	O

Pentobarbital	O
(	O
1	O
,	O
3	O
,	O
10	O
,	O
and	O
17	O
.	O
5	O
mg	O
/	O
kg	O
)	O
was	O
also	O
tested	O
in	O
combination	O
with	O
rate	O
-	O
decreasing	O
doses	O
of	O
normeperidine	O
(	O
17	O
.	O
5	O
mg	O
/	O
kg	O
)	O
,	O
anileridine	O
(	O
10	O
mg	O
/	O
kg	O
)	O
,	O
alphaprodine	O
(	O
10	O
mg	O
/	O
kg	O
)	O
,	O
and	O
fentanyl	O
(	O
0	O
.	O
3	O
mg	O
/	O
kg	O
)	O
.	O

Pb	O
foil	O
(	O
0	O
.	O
55	O
gcm	O
-	O
2	O
)	O
provided	O
the	O
best	O
overall	O
improvement	O
.	O

An	O
anatomical	O
and	O
histochemical	O
study	O
has	O
been	O
undertaken	O
and	O
as	O
a	O
result	O
emphasis	O
is	O
given	O
to	O
recent	O
hypotheses	O
that	O
suggest	O
there	O
are	O
similarities	O
with	O
Type	O
IV	O
glycogen	O
storage	O
disease	O
(	O
Andersen	O
'	O
s	O
disease	O
)	O
which	O
,	O
although	O
clinically	O
distinct	O
,	O
has	O
the	O
same	O
enzyme	O
defect	O
.	O

All	O
groups	O
were	O
tested	O
in	O
a	O
Hebb	O
-	O
Williams	O
maze	O
at	O
100	O
approximately	O
10	O
days	O
of	O
age	O
.	O

Erythromycin	O
and	O
clindamycin	O
resistance	O
in	O
Corynebacterium	O
diphtheriae	O
from	O
skin	O
lesions	O
.	O

Imposed	O
angular	O
displacements	O
of	O
monkey	O
'	O
s	O
wrist	O
produce	O
three	O
major	O
peaks	O
of	O
activity	O
(	O
terms	O
M1	O
,	O
M2	O
,	O
and	O
M3	O
peaks	O
)	O
in	O
the	O
averaged	O
gross	O
EMG	O
activity	O
ot	O
the	O
stretched	O
muscles	O
.	O

Hemolytic	O
disease	O
of	O
African	O
newborn	O
.	O

In	O
this	O
animal	O
,	O
infected	O
with	O
what	O
was	O
judged	O
previously	O
to	O
be	O
the	O
less	O
virulent	O
of	O
the	O
two	O
T	O
.	O
cruzi	O
stocks	O
used	O
(	O
'	O
strain	O
7	O
'	O
)	O
,	O
there	O
was	O
severe	O
myocarditis	O
,	O
with	O
myofibre	O
degeneration	O
,	O
and	O
lesions	O
of	O
the	O
oesophagus	O
.	O

The	O
majority	O
of	O
MRF	O
units	O
were	O
behaviorally	O
incongruent	O
;	O
in	O
the	O
most	O
frequently	O
observed	O
case	O
,	O
their	O
activity	O
failed	O
to	O
change	O
reliably	O
when	O
behavior	O
habituated	O
.	O

Variability	O
within	O
Down	O
'	O
s	O
syndrome	O
(	O
trisomy	O
-	O
21	O
)	O
:	O
empirically	O
observed	O
sex	O
differences	O
in	O
IQs	O
.	O

VII	O
.	O

Several	O
demographic	O
indices	O
of	O
isolated	O
populations	O
in	O
Uzbekistan	O

2	O
.	O
-	O
-	O
concepts	O
of	O
higher	O
nervous	O
function	O
in	O
the	O
USSR	O
.	O

The	O
maintenance	O
of	O
increased	O
myocardial	O
capillary	O
density	O
required	O
a	O
similar	O
amount	O
of	O
exercise	O
,	O
and	O
at	O
least	O
1	O
h	O
of	O
exercise	O
once	O
a	O
week	O
was	O
necessary	O
to	O
maintain	O
the	O
enlargement	O
of	O
ECA	O
.	O
20	O

These	O
observations	O
have	O
led	O
us	O
to	O
conclude	O
that	O
an	O
elevated	O
VIII	O
-	O
ratio	O
is	O
a	O
very	O
sensitive	O
indicator	O
of	O
intravascular	O
coagulation	O
.	O

Eight	O
hours	O
after	O
the	O
administration	O
of	O
colchicine	O
,	O
the	O
serum	B-GENE
ceruloplasmin	I-GENE
level	O
began	O
to	O
rise	O
again	O
in	O
female	O
rats	O
,	O
but	O
not	O
in	O
male	O
rats	O
.	O

Radioimmunoassays	O
of	O
pregnenolone	O
,	O
progesterone	O
,	O
dehydroepiandrosterone	O
(	O
DHA	O
)	O
16	O
alpha	O
-	O
hydroxy	O
-	O
DHA	O
,	O
estriol	O
,	O
and	O
cortisol	O
were	O
performed	O
on	O
a	O
total	O
of	O
0	O
;	O
1	O
ml	O
;	O
of	O
fetal	O
plasma	O
,	O
collected	O
during	O
the	O
course	O
of	O
normal	O
vaginal	O
delivery	O
.	O

In	O
only	O
two	O
patients	O
were	O
we	O
able	O
to	O
demonstrate	O
changes	O
suggestive	O
of	O
pulmonary	O
metastases	O
any	O
earlier	O
with	O
a	O
99mTc	O
-	O
EHDP	O
scan	O
than	O
with	O
chest	O
radiographs	O
and	O
one	O
of	O
these	O
resolved	O
spontaneously	O
.	O

The	O
majority	O
of	O
tumors	O
occurred	O
in	O
the	O
nasal	O
cavities	O
,	O
although	O
significant	O
incidences	O
were	O
also	O
found	O
in	O
the	O
larynx	O
,	O
trachea	O
and	O
stem	O
bronchi	O
.	O

Prediction	O
of	O
the	O
times	O
of	O
sandfly	O
development	O

Native	O
human	B-GENE
fibrinogen	I-GENE
was	O
brought	O
to	O
coagulation	O
by	O
adding	O
thrombin	B-GENE
.	O

No	O
post	O
-	O
operative	O
haemorrhages	O
from	O
the	O
prostheses	O
were	O
observed	O
.	O

The	O
Southern	O
technique	O
allowed	O
a	O
further	O
localization	O
of	O
the	O
region	O
of	O
most	O
extensive	O
transcription	O
to	O
a	O
1	O
.	O
8	O
kb	O
HindIII	B-GENE
-	O
EcoRI	B-GENE
fragment	O
.	O

Accepting	O
arbitrarily	O
chosen	O
limits	O
of	O
maximized	O
errors	O
of	O
+	O
/	O
-	O
10	O
%	O
,	O
it	O
could	O
be	O
shown	O
that	O
the	O
system	O
did	O
not	O
work	O
acceptably	O
when	O
the	O
mean	O
carbon	O
dioxide	O
concentration	O
was	O
below	O
1	O
.	O
5	O
vol	O
.	O
%	O
within	O
the	O
fresh	O
gas	O
flow	O
rates	O
(	O
2	O
.	O
2	O
-	O
-	O
7	O
.	O
7	O
1	O
min	O
-	O
1	O
)	O
and	O
the	O
range	O
of	O
minute	O
ventilation	O
(	O
4	O
-	O
-	O
10	O
1	O
min	O
-	O
1	O
)	O
employed	O
.	O

SV	O
increased	O
less	O
in	O
SHR	O
,	O
mainly	O
reflecting	O
the	O
reduced	O
diastolic	O
compliance	O
of	O
the	O
hypertrophied	O
SHR	O
left	O
ventricle	O
and	O
the	O
consequent	O
rightward	O
shift	O
of	O
its	O
Frank	O
-	O
Starling	O
curve	O
.	O

The	O
carcass	O
of	O
a	O
great	O
horned	O
owl	O
(	O
Bubo	O
virginianus	O
)	O
,	O
which	O
had	O
been	O
found	O
moribund	O
in	O
southern	O
Ontario	O
,	O
was	O
presented	O
for	O
necropsy	O
.	O

The	O
inner	O
ears	O
were	O
exposed	O
by	O
microdissection	O
,	O
and	O
the	O
vestibular	O
sensory	O
regions	O
were	O
either	O
sectioned	O
and	O
studied	O
with	O
light	O
or	O
electron	O
microscopy	O
,	O
or	O
prepared	O
and	O
studied	O
with	O
the	O
surface	O
specimen	O
technique	O
.	O

Patulin	O
is	O
extracted	O
from	O
apple	O
butter	O
samples	O
with	O
ethyl	O
acetate	O
and	O
the	O
extract	O
is	O
cleaned	O
up	O
on	O
a	O
silica	O
gel	O
column	O
,	O
using	O
benzene	O
-	O
ethyl	O
acetate	O
(	O
75	O
+	O
25	O
)	O
as	O
the	O
eluant	O
.	O

Steroid	O
glucuronides	O
in	O
amniotic	O
fluid	O
at	O
term	O
.	O

The	O
matrix	O
surrounding	O
the	O
clusters	O
either	O
showed	O
a	O
normal	O
morphology	O
or	O
a	O
homogeneous	O
appearance	O
,	O
within	O
which	O
faint	O
cross	O
striations	O
but	O
no	O
distinctly	O
fibrillar	O
outlines	O
could	O
be	O
identified	O
.	O

Riboflavin	O
did	O
not	O
affect	O
the	O
percentage	O
of	O
aflatoxin	O
-	O
treated	O
animals	O
with	O
abnormal	O
urinary	O
excretion	O
patterns	O
,	O
but	O
did	O
increase	O
the	O
magnitude	O
of	O
the	O
disturbances	O
in	O
elimination	O
of	O
kynurenic	O
and	O
xanthurenic	O
acids	O
.	O

Polyglactin	O
910	O
suture	O
absorption	O
and	O
the	O
role	O
of	O
cellular	O
enzymes	O
.	O

The	O
incidence	O
of	O
DNCB	O
reactions	O
was	O
78	O
per	O
cent	O
for	O
Stage	O
I	O
and	O
II	O
cancers	O
(	O
37	O
patinets	O
)	O
,	O
73	O
per	O
cent	O
for	O
resectable	O
Stage	O
III	O
cancer	O
(	O
22	O
patients	O
)	O
,	O
and	O
66	O
per	O
cent	O
in	O
patients	O
with	O
unresectable	O
or	O
inoperable	O
Stage	O
III	O
cancer	O
.	O

Studies	O
of	O
lipoproteins	O
should	O
,	O
however	O
,	O
be	O
made	O
in	O
children	O
from	O
families	O
known	O
to	O
have	O
FH	O
or	O
early	O
coronary	O
heart	O
disease	O
.	O

Sixteen	O
other	O
normal	O
subjects	O
with	O
2	O
g	O
of	O
Metyrapone	O
are	O
best	O
responses	O
.	O

EEG	O
theta	O
waves	O
and	O
psychological	O
phenomena	O
:	O
a	O
review	O
and	O
analysis	O
.	O

REM	O
dream	O
content	O
was	O
scored	O
for	O
categories	O
suggesting	O
the	O
predominant	O
influence	O
of	O
the	O
left	O
hemisphere	O
,	O
e	O
.	O
g	O
.	O
,	O
good	O
ego	O
functioning	O
,	O
verbalization	O
,	O
or	O
the	O
right	O
hemisphere	O
,	O
e	O
.	O
g	O
.	O
,	O
music	O
,	O
spatial	O
salience	O
,	O
bizarreness	O
.	O

Innervation	O
of	O
the	O
ventral	O
diaphragm	O
of	O
the	O
locust	O
(	O
Locusta	O
migratoria	O
)	O
.	O

Ectopic	O
ACTH	B-GENE
syndrome	O
and	O
medullary	O
thyroid	O
carcinoma	O
.	O

A	O
striking	O
finding	O
in	O
all	O
of	O
the	O
studies	O
was	O
a	O
positive	O
correlation	O
between	O
PI	O
ACTH	B-GENE
and	O
MSH	B-GENE
contents	O
.	O

Chronic	O
hypophosphatemia	O
is	O
the	O
most	O
common	O
type	O
of	O
"	O
resistant	O
"	O
rickets	O
.	O

There	O
was	O
no	O
correlation	O
between	O
serum	B-GENE
LH	I-GENE
and	O
chronological	O
or	O
bone	O
age	O
in	O
this	O
age	O
group	O
,	O
which	O
suggests	O
that	O
the	O
correlation	O
found	O
is	O
not	O
due	O
to	O
age	O
-	O
related	O
parallel	O
phenomena	O
.	O

Molecular	O
neurochemistry	O
of	O
addictive	O
drugs	O
.	O

Efforts	O
were	O
made	O
to	O
determine	O
the	O
amount	O
of	O
time	O
required	O
for	O
kidney	O
lesions	O
to	O
develop	O
and	O
,	O
if	O
possible	O
,	O
to	O
delineate	O
the	O
potential	O
site	O
of	O
action	O
of	O
PBB	O
.	O

Effect	O
of	O
succimer	O
on	O
the	O
intensity	O
of	O
tricarboxylic	B-GENE
acid	I-GENE
dehydrogenase	I-GENE
reactions	O
in	O
the	O
brain	O
of	O
rats	O
poisoned	O
with	O
mercuric	O
chloride	O

Distribution	O
and	O
correlations	O
of	O
serum	O
uric	O
-	O
acid	O
in	O
two	O
French	O
adult	O
populations	O
:	O
13	O
,	O
885	O
men	O
and	O
6	O
,	O
861	O
women	O

The	O
incidence	O
of	O
hepatitis	B-GENE
B	I-GENE
antigen	I-GENE
following	O
transfusion	O
was	O
about	O
2	O
.	O
8	O
per	O
cent	O
.	O

Technetium	O
-	O
99m	O
stannous	O
pyrophosphate	O
myocardial	O
scintigrams	O
were	O
obtained	O
in	O
138	O
clinically	O
stable	O
patients	O
32	O
.	O
7	O
+	O
/	O
-	O
47	O
.	O
3	O
weeks	O
(	O
range	O
6	O
to	O
260	O
)	O
after	O
acute	O
myocardial	O
infarction	O
.	O

A	O
similar	O
phenomenon	O
has	O
been	O
reported	O
in	O
a	O
few	O
humans	O
.	O

The	O
decline	O
in	O
the	O
activity	O
of	O
cytochrome	B-GENE
oxidase	I-GENE
,	O
peroxidase	B-GENE
and	O
in	O
the	O
lipid	O
content	O
of	O
peripheral	O
neutrophils	O
was	O
followed	O
by	O
a	O
decrease	O
in	O
the	O
phagocytic	O
activity	O
.	O

Treatment	O
of	O
2	O
patients	O
with	O
pseudohypoparathyroidism	O
type	O
I	O
with	O
vitamin	O
-	O
D	O
-	O
3	O
and	O
1	O
alpha	O
-	O
Hydroxycholecalciferol	O
consecutively	O
resulted	O
in	O
a	O
nonuniform	O
response	O
with	O
regard	O
to	O
the	O
normalisation	O
of	O
serum	O
-	O
calcium	O
.	O

Workers	O
with	O
"	O
sensitivity	O
"	O
to	O
toluene	O
diisocyanate	O
(	O
TDI	O
)	O
studied	O
in	O
depth	O
in	O
an	O
attempt	O
to	O
determine	O
mechanisms	O
of	O
bronchial	O
hyperreactivity	O
.	O

Total	O
VO2	O
was	O
decreased	O
in	O
both	O
groups	O
during	O
severe	O
hypoxia	O
but	O
limb	O
VO2	O
was	O
maintained	O
in	O
the	O
beta	O
-	O
block	O
group	O
.	O
beta	O
-	O
Block	O
prevented	O
the	O
fall	O
in	O
total	O
and	O
limb	O
peripheral	O
resistance	O
seen	O
in	O
severe	O
hypoxia	O
but	O
did	O
not	O
alter	O
the	O
consistently	O
more	O
efficient	O
utilization	O
of	O
total	O
O2	O
delivery	O
shown	O
by	O
the	O
limb	O
in	O
comparison	O
to	O
the	O
whole	O
body	O
by	O
higher	O
O2	O
extraction	O
ratios	O
and	O
lower	O
venous	O
O2	O
pressure	O
.	O
beta	B-GENE
-	I-GENE
Vasodilator	I-GENE
receptors	I-GENE
evidently	O
played	O
an	O
active	O
part	O
in	O
the	O
vasodilatation	O
seen	O
during	O
severe	O
hypoxia	O
.	O

Phenobarbital	O
-	O
induced	O
alterations	O
in	O
the	O
metabolism	O
of	O
[	O
3H	O
]	O
vitamin	O
D3	O
by	O
the	O
perfused	O
rachitic	O
rat	O
liver	O
in	O
vitro	O
.	O

Modulation	O
of	O
25	B-GENE
-	I-GENE
hydroxyvitamin	I-GENE
D3	I-GENE
-	I-GENE
24	I-GENE
-	I-GENE
hydroxylase	I-GENE
by	O
aminophylline	O
:	O
a	O
cytochrome	B-GENE
P	I-GENE
-	I-GENE
450	I-GENE
monooxygenase	I-GENE
system	O
.	O

In	O
both	O
these	O
respects	O
,	O
however	O
,	O
the	O
DBP	B-GENE
mRNA	I-GENE
resembles	O
the	O
late	O
messengers	O
of	O
SV40	O
and	O
polyoma	O
viruses	O
.	O

Effect	O
of	O
corticosteroid	O
-	O
containing	O
antirheumatic	O
combination	O
drugs	O
on	O
endogenous	O
ACTH	B-GENE
and	O
cortisol	O
production	O
.	O

Serum	B-GENE
ACTH	I-GENE
did	O
not	O
respond	O
to	O
insulin	B-GENE
and	O
metyrapone	O
.	O

Anatomy	O
of	O
the	O
RNA	O
and	O
gene	O
products	O
of	O
MC29	O
and	O
MH2	O
,	O
two	O
defective	O
avian	O
tumor	O
viruses	O
causing	O
acute	O
leukemia	O
and	O
carcinoma	O
:	O
evidence	O
for	O
a	O
new	O
class	O
of	O
transforming	O
genes	O
.	O

Bertioga	O
(	O
Guama	O
group	O
)	O
and	O
Anhembi	O
(	O
Bunyamwera	O
group	O
)	O
,	O
two	O
new	O
arboviruses	O
isolated	O
in	O
Sao	O
Paulo	O
,	O
Brazil	O
.	O

Gamma	B-GENE
glutamyl	I-GENE
transpeptidase	I-GENE
activity	O
was	O
increased	O
up	O
to	O
15	O
times	O
above	O
the	O
upper	O
normal	O
limit	O
in	O
children	O
,	O
who	O
received	O
aminopyrine	O
for	O
two	O
weeks	O
or	O
longer	O
.	O

XXI	O
.	O

A	O
gas	O
-	O
liquid	O
chromatographic	O
method	O
for	O
the	O
determination	O
of	O
p	O
-	O
chlorophenoxyisobutyric	O
(	O
CPIB	O
)	O
acid	O
in	O
blood	O
plasma	O
is	O
described	O
.	O

Dopamine	B-GENE
receptor	I-GENE
blockade	O
and	O
the	O
neuroleptics	O
,	O
a	O
crystallographic	O
study	O
.	O

V	O
.	O

A	O
rapid	O
fluorimetric	O
procedure	O
for	O
the	O
determination	O
of	O
the	O
fungicide	O
5	O
-	O
fluorocytosine	O
in	O
serum	O
is	O
described	O
.	O

The	O
'	O
field	O
of	O
stress	O
'	O
of	O
the	O
supervisory	O
nurse	O

How	O
do	O
graduates	O
of	O
different	O
types	O
of	O
programs	O
perform	O
on	O
state	O
boards	O
?	O

Similarly	O
,	O
maternal	B-GENE
serum	I-GENE
somatomedin	I-GENE
A	I-GENE
was	O
significantly	O
reduced	O
in	O
rats	O
nursing	O
large	O
litters	O
.	O

The	O
sequences	O
following	O
the	O
X	O
.	O
borealis	O
oocyte	O
and	O
somatic	O
5S	B-GENE
genes	I-GENE
are	O
identical	O
in	O
12	O
of	O
the	O
first	O
14	O
residues	O
and	O
contain	O
two	O
or	O
more	O
T	O
clusters	O
,	O
as	O
does	O
the	O
corresponding	O
region	O
of	O
X	B-GENE
.	I-GENE
laevis	I-GENE
oocyte	I-GENE
5S	I-GENE
DNA	I-GENE
.	O

This	O
mechanism	O
is	O
not	O
due	O
to	O
the	O
observed	O
grain	O
boundary	O
precipitates	O
.	O

This	O
report	O
has	O
reviewed	O
some	O
of	O
the	O
reasons	O
for	O
treatment	O
failures	O
and	O
has	O
presented	O
a	O
philosophy	O
for	O
their	O
management	O
.	O

Diagnosis	O
and	O
treatment	O
planning	O
in	O
Class	O
II	O
,	O
division	O
2	O

Because	O
of	O
serious	O
infections	O
(	O
fever	O
larger	O
than	O
or	O
equal	O
to	O
101	O
degrees	O
F	O
.	O
granulocytes	O
less	O
than	O
1	O
,	O
000	O
/	O
mm	O
,	O
3	O
and	O
hospitalization	O
)	O
and	O
1	O
drug	O
death	O
in	O
the	O
first	O
4	O
patients	O
,	O
oral	O
calcium	O
leucovorin	O
,	O
20	O
to	O
30	O
mg	O
/	O
m2	O
orally	O
,	O
was	O
given	O
2	O
days	O
after	O
methotrexate	O
in	O
subsequent	O
treatment	O
cycles	O
.	O

It	O
seems	O
that	O
the	O
way	O
in	O
which	O
drugs	O
modify	O
a	O
patient	O
'	O
s	O
serum	O
chemistry	O
may	O
be	O
used	O
to	O
assess	O
the	O
efficacy	O
with	O
which	O
they	O
control	O
the	O
inflammatory	O
process	O
.	O

Here	O
the	O
conventional	O
tests	O
clearly	O
pointed	O
to	O
the	O
presence	O
of	O
retrocochlear	O
disease	O
.	O

The	O
end	O
-	O
stage	O
or	O
involutional	O
phase	O
of	O
proliferative	O
diabetic	O
retinopathy	O
may	O
result	O
in	O
stabilization	O
of	O
vision	O
for	O
long	O
periods	O
of	O
time	O
.	O

On	O
the	O
basis	O
of	O
serum	B-GENE
alpha1AT	I-GENE
quantitation	O
,	O
newborn	O
infants	O
may	O
be	O
separated	O
into	O
two	O
groups	O
,	O
characterized	O
respectively	O
by	O
concentrations	O
above	O
or	O
below	O
150	O
mg	O
%	O
.	O

In	O
patients	O
who	O
were	O
not	O
vented	O
,	O
there	O
was	O
overall	O
significant	O
depression	O
of	O
function	O
(	O
67	O
+	O
/	O
-	O
5	O
%	O
of	O
control	O
;	O
range	O
,	O
91	O
-	O
-	O
45	O
%	O
,	O
p	O
less	O
than	O
0	O
.	O
01	O
)	O
.	O

Changes	O
in	O
body	O
weight	O
and	O
agonistic	O
behavior	O
were	O
also	O
recorded	O
.	O

The	O
uterine	O
response	O
to	O
prostaglandin	O
E2	O
(	O
PGE2	O
)	O
and	O
prostaglandin	O
F2alpha	O
(	O
administered	O
by	O
intravenous	O
and	O
intrauterine	O
routes	O
)	O
was	O
evaluated	O
during	O
different	O
phases	O
of	O
the	O
menstrual	O
cycle	O
in	O
five	O
functionally	O
infertile	O
women	O
.	O

A	O
total	O
of	O
26	O
BCG	O
strains	O
,	O
out	O
of	O
them	O
10	O
Czechoslovak	O
strains	O
(	O
2	O
lyophilized	O
cultures	O
of	O
BCG	O
of	O
different	O
batch	O
,	O
6	O
strains	O
isolated	O
from	O
abscesses	O
of	O
children	O
after	O
BCG	O
-	O
vaccination	O
and	O
2	O
strains	O
from	O
fatal	O
cases	O
after	O
BCG	O
-	O
vaccination	O
)	O
and	O
16	O
strains	O
obtained	O
from	O
foreign	O
laboratories	O
,	O
were	O
used	O
.	O

High	O
levels	O
of	O
serum	O
calcitonin	B-GENE
were	O
found	O
in	O
patients	O
with	O
chronic	O
renal	O
failure	O
.	O

Detection	O
of	O
anti	O
-	O
lymphocyte	O
antibodies	O
using	O
the	O
immunoperoxidase	B-GENE
antiglobulin	B-GENE
technic	O
.	O

The	O
response	O
of	O
serum	B-GENE
GH	I-GENE
to	O
arginine	O
infusion	O
was	O
normal	O
,	O
while	O
that	O
to	O
insulin	B-GENE
-	O
induced	O
hypoglycemia	O
was	O
poor	O
.	O

The	O
mortality	O
rate	O
and	O
histopathological	O
features	O
of	O
Nocardia	O
asteroides	O
and	O
Nocardia	O
brasiliensis	O
infections	O
in	O
congenitally	O
athymic	O
(	O
nude	O
)	O
mice	O
of	O
ICR	O
and	O
C3H	O
/	O
eB	O
origins	O
were	O
quite	O
different	O
from	O
what	O
we	O
found	O
for	O
Swiss	O
white	O
mice	O
and	O
other	O
inbred	O
mouse	O
strains	O
(	O
namely	O
,	O
C57	O
/	O
BL	O
/	O
6J	O
,	O
New	O
Zealand	O
Black	O
,	O
BALB	O
/	O
c	O
,	O
CBA	O
/	O
LAC	O
,	O
and	O
C3H	O
/	O
eB	O
)	O
.	O

Williams	O
,	O
2	O
August	O
1977	O
.	O

Use	O
of	O
radioactive	O
isotopes	O
in	O
the	O
chemistry	O
of	O
proteins	O

(	O
Emeritus	O
)	O
John	O
Henri	O
Roosegaarde	O
Bisschop	O

Disrupted	O
vaccines	O
and	O
whole	O
-	O
virus	O
vaccines	O
containing	O
type	B-GENE
B	I-GENE
antigen	I-GENE
only	O
did	O
not	O
cause	O
significant	O
reactivity	O
.	O

255	O
-	O
61	O
.	O

Antenatal	O
diagnosis	O
of	O
haematological	O
disorders	O
-	O
-	O
'	O
1978	O
'	O
.	O

Hepatic	O
oxygen	O
supply	O
and	O
selected	O
blood	O
parameters	O
were	O
recorded	O
in	O
fasted	O
male	O
rates	O
given	O
20	O
-	O
-	O
30	O
mg	O
/	O
kg	O
Escherichia	B-GENE
coli	I-GENE
endotoxin	I-GENE
intraperitoneally	O
.	O

Gonadal	O
dysfunction	O
in	O
patients	O
with	O
ataxia	O
telangiectasia	O
.	O

The	O
maximum	O
period	O
of	O
treatment	O
was	O
73	O
(	O
oral	O
)	O
,	O
73	O
(	O
intraperitoneal	O
)	O
or	O
75	O
(	O
dermal	O
)	O
weeks	O
.	O

A	O
study	O
of	O
the	O
comparative	O
efficacy	O
of	O
diflucortolone	O
valerate	O
0	O
.	O
3	O
%	O
ointment	O
and	O
clobetasol	O
propionate	O
0	O
.	O
05	O
%	O
ointment	O
.	O

Most	O
of	O
the	O
phenomena	O
of	O
azotaemic	O
osteodystrophy	O
are	O
encountered	O
in	O
simple	O
vitamin	O
D	O
deficiency	O
;	O
as	O
in	O
that	O
condition	O
,	O
deficiency	O
of	O
1	O
,	O
25	O
-	O
dihydroxycholecalciferol	O
may	O
be	O
of	O
primary	O
significance	O
in	O
causing	O
secondary	O
hyperparathyroidism	O
in	O
renal	O
failure	O
.	O

Basal	O
FSH	B-GENE
and	O
LH	B-GENE
levels	O
were	O
significantly	O
lower	O
in	O
addicts	O
;	O
after	O
GnRH	B-GENE
stimulation	O
the	O
addicts	O
'	O
FSH	B-GENE
and	O
LH	B-GENE
values	O
increased	O
but	O
not	O
significantly	O
compared	O
to	O
controls	O
.	O

Adriamycin	O
:	O
comparison	O
of	O
a	O
5	O
-	O
week	O
schedule	O
with	O
a	O
3	O
-	O
week	O
schedule	O
in	O
the	O
treatment	O
of	O
breast	O
cancer	O
.	O

Follow	O
-	O
up	O
controls	O
of	O
luteinizing	B-GENE
hormone	I-GENE
(	O
LH	B-GENE
)	O
,	O
follicle	B-GENE
stimulating	I-GENE
hormone	I-GENE
(	O
FSH	B-GENE
)	O
,	O
prolactin	B-GENE
(	O
HPRL	B-GENE
)	O
,	O
oestradiol	O
(	O
E2	O
)	O
,	O
progesterone	O
(	O
P	O
)	O
and	O
testosterone	O
(	O
T	O
)	O
in	O
the	O
catabolic	O
and	O
healing	O
phase	O
of	O
burn	O
disease	O
.	O

Renin	B-GENE
studies	O
performed	O
in	O
34	O
hypertensive	O
patients	O
and	O
in	O
a	O
control	O
group	O
of	O
11	O
recipients	O
showed	O
that	O
elevation	O
of	O
plasma	B-GENE
renin	I-GENE
activity	O
and	O
of	O
plasma	O
aldosterone	O
level	O
is	O
frequent	O
but	O
difficult	O
to	O
interpret	O
,	O
particularly	O
when	O
a	O
renal	O
artery	O
stenosis	O
is	O
observed	O
.	O

A	O
randomized	O
clinical	O
trial	O
in	O
sixty	O
-	O
two	O
adult	O
patients	O
suffering	O
from	O
typhoid	O
fever	O
,	O
proved	O
by	O
blood	O
and	O
marrow	O
culture	O
,	O
showed	O
that	O
amoxycillin	O
in	O
a	O
dosage	O
schedule	O
of	O
1	O
g	O
8	O
-	O
hourly	O
orally	O
for	O
fourteen	O
days	O
was	O
better	O
than	O
chloramphenicol	O
with	O
regard	O
to	O
clinical	O
and	O
temperature	O
response	O
and	O
in	O
respect	O
of	O
carriers	O
and	O
relapse	O
rates	O
.	O

202	O
-	O
8	O
.	O

Bone	O
marrow	O
transplantation	O
-	O
1979	O
.	O

In	O
this	O
article	O
,	O
the	O
clinical	O
actions	O
of	O
the	O
principal	O
dopamine	B-GENE
receptor	I-GENE
stimulating	O
agents	O
(	O
apomorphine	O
and	O
its	O
derivatives	O
;	O
piribedil	O
,	O
rye	O
-	O
ergot	O
derivatives	O
)	O
are	O
discussed	O
on	O
the	O
basis	O
of	O
their	O
biochemical	O
and	O
pharmacological	O
properties	O
.	O

The	O
unilateral	O
vestibular	O
hypofunction	O
.	O

Thus	O
,	O
the	O
inhibition	O
of	O
pepsin	B-GENE
in	O
human	O
gastric	O
juice	O
does	O
not	O
appear	O
to	O
have	O
a	O
major	O
influence	O
on	O
the	O
healing	O
of	O
duodenal	O
ulcer	O
.	O

The	O
IDF	O
standard	O
method	O
for	O
the	O
detection	O
of	O
penicillin	O
in	O
milk	O
is	O
not	O
suitable	O
for	O
the	O
detection	O
of	O
sulphonamide	O
residues	O
in	O
milk	O
.	O

Capsular	O
antigens	O
of	O
Staphylococcus	O
aureus	O

The	O
course	O
of	O
endotoxin	O
fever	O
remained	O
uninfluenced	O
by	O
ALS	O
.	O

2	O
new	O
Algerian	O
cases	O

Seventy	O
-	O
one	O
percent	O
of	O
patients	O
treated	O
with	O
ticarcillin	O
alone	O
responded	O
favorably	O
.	O

Accurate	O
pathologic	O
staging	O
identifies	O
patients	O
who	O
are	O
potentially	O
curable	O
with	O
radiotherapy	O
.	O

Inherent	O
hematology	O
of	O
old	O
age	O

Neomycin	O
is	O
fairly	O
effective	O
against	O
staphylococci	O
,	O
less	O
effective	O
against	O
streptococci	O
,	O
and	O
fairly	O
effective	O
against	O
gram	O
-	O
negative	O
intestinal	O
organisms	O
.	O

It	O
was	O
concluded	O
,	O
that	O
on	O
a	O
given	O
section	O
,	O
75	O
,	O
7	O
per	O
cent	O
of	O
the	O
trabeculae	O
were	O
in	O
contact	O
with	O
vascular	O
cavities	O
.	O

2	O
.	O

Changes	O
in	O
tissue	O
PCO2	O
were	O
less	O
dramatic	O
and	O
did	O
not	O
vary	O
significantly	O
from	O
those	O
recorded	O
in	O
venous	O
blood	O
.	O

Ultrasonic	O
evaluation	O
of	O
renal	O
calculi	O
.	O

Recognition	O
of	O
emphysema	O
was	O
poor	O
when	O
radiographs	O
of	O
inadequate	O
quality	O
were	O
included	O
(	O
anteroposterior	O
films	O
or	O
films	O
from	O
patients	O
with	O
acute	O
or	O
chronic	O
lung	O
disease	O
)	O
.	O

Isolation	O
of	O
T	O
.	O
gambiense	O
strains	O
in	O
Zaire	O
and	O
their	O
adaptation	O
to	O
laboratory	O
animals	O

Pharmacokinetic	O
profile	O
of	O
clonazepam	O
in	O
rhesus	O
monkeys	O
.	O

Immunologic	O
mechanisms	O
in	O
chronic	O
brucellosis	O
in	O
humans	O
.	O

Intestinal	O
adaptation	O
(	O
first	O
of	O
two	O
parts	O
)	O
.	O

In	O
patients	O
who	O
had	O
received	O
no	O
previous	O
drug	O
treatment	O
,	O
log	O
baseline	O
plasma	B-GENE
renin	I-GENE
activity	O
and	O
change	O
in	O
mean	O
blood	O
pressure	O
after	O
SQ	O
20881	O
correlated	O
significantly	O
(	O
r	O
=	O
0	O
.	O
651	O
,	O
P	O
less	O
than	O
0	O
.	O
05	O
)	O
.	O

These	O
techniques	O
have	O
been	O
used	O
by	O
many	O
people	O
for	O
many	O
years	O
and	O
no	O
claim	O
is	O
being	O
made	O
for	O
any	O
innovation	O
in	O
this	O
regard	O
.	O

40	O
patients	O
with	O
chronic	O
osteomyelitis	O
were	O
treated	O
per	O
os	O
with	O
the	O
bactericidal	O
beta	O
-	O
lactam	O
-	O
antibiotic	O
cephalexin	O
during	O
3	O
to	O
60	O
weeks	O
.	O

A	O
total	O
of	O
57	O
patients	O
with	O
Hodgkin	O
'	O
s	O
disease	O
limited	O
to	O
above	O
the	O
diaphragm	O
(	O
Stages	O
I	O
and	O
II	O
,	O
A	O
and	O
B	O
)	O
were	O
treated	O
with	O
radiation	O
therapy	O
alone	O
at	O
the	O
University	O
of	O
Florida	O
between	O
1964	O
and	O
1974	O
.	O

Year	O
one	O
of	O
the	O
first	O
general	O
practitioner	O
medical	O
unit	O
in	O
the	O
greater	O
Glasgow	O
area	O
.	O

This	O
multiple	O
-	O
electrode	O
array	O
for	O
round	O
window	O
cochlear	O
implantation	O
is	O
a	O
robust	O
,	O
reliable	O
system	O
for	O
inserting	O
20	O
mm	O
along	O
the	O
scala	O
tympani	O
with	O
a	O
minimum	O
of	O
trauma	O
and	O
can	O
provide	O
for	O
bipolar	O
stimulation	O
.	O

As	O
authorized	O
by	O
the	O
World	O
Health	O
Organization	O
29th	O
Expert	O
Committee	O
on	O
Biological	O
Standardization	O
,	O
the	O
preparation	O
of	O
human	B-GENE
prolactin	I-GENE
in	O
ampoules	O
coded	O
75	O
/	O
504	O
has	O
been	O
established	O
as	O
the	O
International	O
Reference	O
Preparation	O
(	O
IRP	O
)	O
of	O
human	B-GENE
prolactin	I-GENE
for	O
immunoassay	O
.	O

i	O
.	O

Biliary	O
-	O
enteric	O
fistulas	O

Plasma	O
ion	O
changes	O
in	O
venous	O
blood	O
incubated	O
with	O
beta	B-GENE
receptor	I-GENE
blockers	O
and	O
subjected	O
to	O
tonometry	O
in	O
vitro	O
.	O

Such	O
marked	O
differences	O
are	O
found	O
occasionally	O
in	O
the	O
literature	O
:	O
heterophile	O
antibodies	O
against	O
bovine	B-GENE
gammaglobulin	I-GENE
are	O
regarded	O
as	O
responsible	O
for	O
the	O
interference	O
in	O
the	O
Sephadex	O
system	O
of	O
RIST	O
.	O

"	O
Let	O
the	O
hundred	O
flowers	O
bloom	O
"	O
.	O

Various	O
treatment	O
modalities	O
are	O
reviewed	O
in	O
the	O
context	O
of	O
the	O
psychology	O
as	O
well	O
as	O
the	O
physiology	O
of	O
severe	O
intractable	O
pain	O
.	O

Lethal	O
Tachmalcor	O
(	O
4	O
-	O
(	O
3	O
'	O
-	O
diethylamino	O
-	O
2	O
'	O
-	O
hydroxypropyl	O
)	O
-	O
ajmaline	O
)	O
poisoning	O
in	O
childhood	O

Ophthalmosonographic	O
evaluation	O
of	O
blood	O
flow	O
velocity	O
in	O
arteriocavernous	O
fistula	O

Serum	O
ferritin	B-GENE
concentration	O
and	O
bone	O
marrow	O
iron	O
stores	O
.	O

The	O
systolic	O
pressure	O
gradient	O
(	O
SPG	O
)	O
between	O
the	O
left	O
ventricle	O
(	O
LV	O
)	O
and	O
left	O
atrium	O
(	O
LA	O
)	O
was	O
obtained	O
from	O
high	O
-	O
fidelity	O
pressure	O
transducers	O
.	O

A	O
prospective	O
trail	O
comparing	O
hysterectomy	O
,	O
hysterectomy	O
plus	O
vaginal	O
radium	O
,	O
and	O
uterine	O
radium	O
plus	O
hysterectomy	O
in	O
stage	O
I	O
endometrial	O
carcinoma	O
.	O

On	O
the	O
basis	O
of	O
a	O
patient	O
'	O
s	O
report	O
of	O
one	O
inaccurate	O
Clinitemp	O
,	O
we	O
undertook	O
to	O
investigate	O
the	O
accuracy	O
of	O
this	O
thermometer	O
.	O

Cryoglobulinemia	O
in	O
Raynaud	O
'	O
s	O
syndrome	O

Data	O
were	O
processed	O
with	O
a	O
semi	O
-	O
automatic	O
computer	O
program	O
which	O
develops	O
an	O
averaged	O
-	O
volume	O
curve	O
from	O
an	O
assigned	O
LV	O
region	O
-	O
of	O
-	O
interest	O
.	O

The	O
preferential	O
serum	B-GENE
IgA	I-GENE
response	O
observed	O
in	O
the	O
patient	O
population	O
suggests	O
that	O
bronchial	O
associated	O
lymphoid	O
tissue	O
in	O
the	O
diseased	O
lung	O
is	O
an	O
important	O
source	O
of	O
circulating	O
IgA	B-GENE
.	O

Ultimate	O
strengthes	O
seem	O
to	O
be	O
reached	O
for	O
cast	O
cobalt	O
alloys	O
,	O
whereas	O
titanium	O
alloys	O
,	O
such	O
as	O
Ta	O
6	O
V	O
,	O
present	O
very	O
high	O
fatigue	O
limit	O
under	O
corrosion	O
.	O

The	O
effects	O
of	O
intracisternal	O
injection	O
(	O
i	O
.	O
c	O
.	O
i	O
.	O
)	O
of	O
clonidine	O
(	O
1	O
microgram	O
kg	O
-	O
1	O
)	O
on	O
blood	O
pressure	O
and	O
heart	O
rate	O
were	O
studied	O
in	O
conscious	O
rabbits	O
with	O
an	O
implanted	O
catheter	O
in	O
the	O
cisterna	O
magna	O
.	O

Platelet	O
number	O
and	O
life	O
span	O
were	O
determined	O
in	O
the	O
last	O
trimester	O
of	O
pregnancy	O
in	O
22	O
women	O
who	O
were	O
delivered	O
of	O
small	O
-	O
for	O
-	O
gestational	O
age	O
(	O
SGA	O
)	O
infants	O
and	O
in	O
21	O
women	O
with	O
infants	O
having	O
normal	O
birth	O
weights	O
.	O

Serial	O
measurements	O
of	O
total	O
serum	O
IgE	B-GENE
appears	O
to	O
be	O
a	O
useful	O
index	O
of	O
disease	O
activity	O
in	O
ABPA	O
.	O

A	O
rise	O
of	O
hemoglobin	B-GENE
concentration	O
accompanied	O
by	O
an	O
increase	O
of	O
the	O
total	O
iron	O
in	O
the	O
blood	O
serum	O
of	O
white	O
mice	O
was	O
found	O
under	O
oxygen	O
pressure	O
of	O
4	O
atm	O
for	O
an	O
hour	O
(	O
preconvulsive	O
state	O
)	O
and	O
6	O
atm	O
(	O
convulsive	O
state	O
)	O
.	O

Nernst	O
-	O
-	O
Planck	O
analog	O
equations	O
and	O
stationary	O
state	O
membrane	O
electric	O
potentials	O
.	O

Effects	O
of	O
methylene	O
chloride	O
,	O
trichloroethane	O
,	O
trichloroethylene	O
,	O
tetrachloroethylene	O
and	O
toluene	O
on	O
the	O
development	O
of	O
chick	O
embryos	O
.	O

Effect	O
of	O
intraventricular	O
administration	O
of	O
streptolysin	B-GENE
O	I-GENE
on	O
the	O
electroencephalogram	O
of	O
rabbits	O
.	O

In	O
this	O
situation	O
the	O
convlusion	O
threshold	O
for	O
the	O
8	O
substances	O
is	O
as	O
follows	O
:	O
pethidine	O
20	O
mg	O
.	O
kg	O
-	O
1	O
I	O
.	O
V	O
.	O
,	O
piritramide	O
30	O
,	O
morphine	O
180	O
,	O
phenoperidine	O
4	O
,	O
R	O
39	O
209	O
5	O
,	O
fentanyl	O
4	O
,	O
sufentanil	O
4	O
and	O
R	O
34	O
995	O
10	O
mg	O
.	O
kg	O
-	O
1	O
I	O
.	O
V	O
.	O

Roentgenographically	O
,	O
the	O
lesion	O
was	O
usually	O
a	O
well	O
-	O
defined	O
and	O
benign	O
appearing	O
one	O
,	O
either	O
purely	O
lytic	O
(	O
3	O
cases	O
)	O
or	O
with	O
central	O
radiodensity	O
(	O
2	O
cases	O
)	O
.	O

Effects	O
of	O
chronic	O
descending	O
tractotomy	O
on	O
the	O
response	O
patterns	O
of	O
neurons	O
in	O
the	O
trigeminal	O
nuclei	O
principalis	O
and	O
oralis	O
.	O

Efficacy	O
of	O
a	O
three	O
-	O
versus	O
a	O
five	O
-	O
week	O
alcohol	O
treatment	O
program	O
.	O

Isolated	O
calcaneal	O
tuberculous	O
osteomyelitis	O
.	O

It	O
is	O
concluded	O
that	O
opiate	B-GENE
receptors	I-GENE
bordering	O
the	O
fourth	O
cerebral	O
ventricle	O
mediate	O
the	O
cardiovascular	O
and	O
hypnotic	O
action	O
of	O
fentanyl	O
.	O

In	O
case	O
of	O
a	O
pathologically	O
convoluted	O
internal	O
carotid	O
the	O
common	O
carotid	O
artery	O
was	O
resected	O
with	O
an	O
end	O
-	O
to	O
-	O
end	O
anastomosis	O
.	O

These	O
data	O
confirm	O
the	O
existence	O
of	O
hyperlipemic	O
abdominal	O
crisis	O
as	O
a	O
distinct	O
entity	O
and	O
testify	O
to	O
the	O
importance	O
of	O
recognizing	O
this	O
syndrome	O
in	O
order	O
to	O
avoid	O
the	O
occurrence	O
of	O
acute	O
pancreatitis	O
and	O
the	O
performance	O
of	O
unnecessary	O
and	O
potentially	O
harmful	O
surgery	O
.	O

In	O
addition	O
a	O
significant	O
Treatment	O
X	O
Strain	O
interaction	O
was	O
due	O
to	O
the	O
larger	O
defecation	O
numbers	O
displayed	O
by	O
the	O
taurine	O
-	O
injected	O
MR	O
rats	O
relative	O
to	O
the	O
saline	O
-	O
injected	O
MR	O
rats	O
.	O

The	O
failures	O
frequently	O
were	O
related	O
to	O
patient	O
intolerance	O
or	O
poor	O
mechanical	O
fit	O
and	O
occurred	O
in	O
the	O
first	O
few	O
days	O
or	O
first	O
few	O
months	O
after	O
insertion	O
.	O

These	O
characteristics	O
indicated	O
the	O
pronounced	O
activity	O
of	O
collagenous	O
fiber	O
synthesis	O
and	O
the	O
matrix	O
of	O
the	O
osteoid	O
tissue	O
.	O

Carbohydrate	O
metabolism	O
and	O
the	O
semen	O
profile	O
:	O
glucose	O
,	O
insulin	B-GENE
,	O
and	O
sperm	O
studies	O
.	O

It	O
has	O
come	O
out	O
that	O
CAEC	O
is	O
between	O
CC	O
and	O
CIEC	O
and	O
that	O
attacks	O
of	O
biliary	O
fever	O
and	O
high	O
levels	O
of	O
alkaline	B-GENE
phosphatase	I-GENE
and	O
transaminases	O
in	O
the	O
serum	O
are	O
the	O
helpful	O
findings	O
for	O
preoperative	O
diagnosis	O
.	O

The	O
sub	O
-	O
acute	O
inhalation	O
toxicity	O
of	O
furfural	O
was	O
studied	O
in	O
Syrian	O
golden	O
hamsters	O
.	O

A	O
study	O
of	O
the	O
E	O
.	O
O	O
.	O
R	O
.	O
T	O
.	O
C	O
.	O

An	O
intravenous	O
preparation	O
of	O
doxycycline	O
(	O
DOTC	O
,	O
Vibramycin	O
'	O
Pfizer	O
'	O
)	O
,	O
a	O
long	O
-	O
lasting	O
tetracycline	O
,	O
was	O
administered	O
mainly	O
by	O
drip	O
infusion	O
for	O
a	O
series	O
of	O
study	O
in	O
the	O
pediatrics	O
field	O
,	O
and	O
the	O
results	O
were	O
as	O
follows	O
:	O
1	O
)	O
DOTC	O
(	O
100	O
mg	O
)	O
was	O
dissolved	O
in	O
a	O
100	O
ml	O
of	O
glucose	O
solution	O
and	O
2	O
-	O
-	O
3	O
mg	O
/	O
kg	O
was	O
administered	O
intravenously	O
.	O

5	O
)	O
Before	O
and	O
ten	O
days	O
after	O
DOTC	O
infusion	O
,	O
laboratory	O
tests	O
for	O
liver	O
and	O
renal	O
functions	O
and	O
blood	O
were	O
performed	O
.	O

Structural	O
characteristics	O
of	O
the	O
erythrocyte	O
membrane	O
,	O
peroxidation	O
processes	O
and	O
antioxidant	O
function	O
in	O
children	O
with	O
diffuse	O
glomerulonephritis	O

The	O
enteric	O
route	O
is	O
the	O
principal	O
mode	O
of	O
transmission	O
for	O
hepatitis	O
A	O
,	O
but	O
maximal	O
levels	O
of	O
hepatitis	O
A	O
virus	O
excretion	O
occur	O
before	O
the	O
onset	O
of	O
jaundice	O
.	O

All	O
13	O
patients	O
showed	O
endoscopic	O
evidence	O
of	O
oesophagitis	O
,	O
moderate	O
in	O
4	O
and	O
severe	O
in	O
9	O
.	O

Urinary	O
excretion	O
of	O
oestrone	O
,	O
oestradiol	O
-	O
17	O
beta	O
and	O
oestriol	O
in	O
pregnancies	O
complicated	O
by	O
steroid	B-GENE
sulphatase	I-GENE
deficiency	O
.	O

Both	O
reduced	O
spontaneous	O
locomotor	O
activity	O
in	O
mice	O
,	O
protected	O
them	O
from	O
death	O
from	O
amphetamine	O
induced	O
toxicity	O
,	O
prolonged	O
hexobarbitone	O
sleeping	O
time	O
and	O
caused	O
a	O
depletion	O
of	O
catecholamines	O
from	O
various	O
organs	O
of	O
the	O
rat	O
.	O

On	O
the	O
role	O
of	O
transferrin	B-GENE
in	O
the	O
uptake	O
of	O
gallium	O
by	O
tumor	O
cells	O
.	O

Irradiation	O
of	O
human	O
blood	O
platelets	O
with	O
UV	O
-	O
A	O
in	O
vitro	O
impairs	O
their	O
ability	O
to	O
aggregate	O
after	O
challenge	O
with	O
collagen	B-GENE
.	O

Following	O
the	O
satisfactory	O
results	O
and	O
taking	O
into	O
account	O
that	O
the	O
complications	O
had	O
reduced	O
to	O
a	O
very	O
low	O
rate	O
(	O
in	O
2	O
cases	O
lead	O
tip	O
displacement	O
and	O
pouch	O
haematoma	O
occurred	O
respectively	O
)	O
,	O
the	O
Authors	O
consider	O
the	O
adopted	O
method	O
an	O
useful	O
approach	O
for	O
PMK	O
implantation	O
particularly	O
when	O
the	O
use	O
of	O
the	O
vena	O
cephalica	O
is	O
deemed	O
impossible	O
.	O

When	O
two	O
determinations	O
were	O
performed	O
on	O
12	O
samples	O
of	O
plasma	O
taken	O
from	O
normal	O
adults	O
in	O
October	O
,	O
the	O
values	O
were	O
22	O
.	O
6	O
+	O
/	O
-	O
4	O
.	O
8	O
and	O
21	O
.	O
0	O
+	O
/	O
-	O
3	O
.	O
6	O
(	O
mean	O
+	O
/	O
-	O
SD	O
)	O
ng	O
/	O
ml	O
,	O
respectively	O
.	O

The	O
six	O
commonest	O
causes	O
of	O
death	O
varied	O
in	O
the	O
three	O
ethnic	O
groups	O
.	O

Although	O
Grice	O
'	O
s	O
operation	O
has	O
been	O
used	O
all	O
over	O
the	O
world	O
,	O
no	O
systematic	O
account	O
of	O
it	O
has	O
been	O
found	O
in	O
the	O
literature	O
(	O
including	O
publications	O
dealing	O
with	O
technique	O
)	O
,	O
which	O
presents	O
it	O
in	O
terms	O
related	O
to	O
the	O
basic	O
"	O
classical	O
"	O
principles	O
on	O
which	O
the	O
operation	O
was	O
conceived	O
.	O

(	O
5	O
)	O
No	O
changes	O
were	O
observed	O
in	O
the	O
gastric	O
venous	O
blood	O
flow	O
by	O
continuous	O
intravenous	O
injection	O
of	O
cimetidine	O
,	O
but	O
by	O
rapid	O
injection	O
both	O
the	O
flow	O
was	O
augmented	O
and	O
the	O
systemic	O
blood	O
pressure	O
decreased	O
transiently	O
.	O

Study	O
on	O
re	O
-	O
establishment	O
of	O
ovulation	O
after	O
termination	O
of	O
sex	O
-	O
steroidal	O
treatment	O
-	O
-	O
compared	O
with	O
re	O
-	O
appearance	O
of	O
ovulation	O
after	O
abortion	O
and	O
premature	O
delivery	O
.	O

Pharmacokinetics	O
of	O
Carbamazepine	O
in	O
man	O
:	O
a	O
review	O
.	O

Of	O
the	O
compounds	O
tested	O
,	O
alpha	O
-	O
(	O
3	O
-	O
methyl	O
-	O
2	O
-	O
quinoxalinyl	O
)	O
-	O
N	O
-	O
methylnitrone	O
1	O
,	O
4	O
-	O
dioxide	O
(	O
2	O
)	O
was	O
the	O
most	O
active	O
agent	O
in	O
vivo	O
against	O
the	O
gram	O
-	O
negative	O
and	O
the	O
gram	O
-	O
positive	O
organisms	O
.	O

Changes	O
in	O
ionic	O
content	O
of	O
the	O
mucous	O
suggest	O
that	O
cholinergic	O
mechanisms	O
affect	O
pressure	O
in	O
the	O
excretory	O
duct	O
of	O
the	O
gland	O
.	O

Calves	O
fed	O
MCT	O
-	O
milk	O
had	O
significantly	O
lower	O
blood	O
cholesterol	O
than	O
calves	O
fed	O
T	O
-	O
or	O
SBO	O
-	O
milk	O
.	O

Under	O
halothane	O
anesthesia	O
,	O
the	O
flow	O
pneumocardiogram	O
(	O
PnCG	O
)	O
and	O
its	O
time	O
derivative	O
(	O
acceleration	O
pneumocardiogram	O
or	O
dPn	O
/	O
dt	O
)	O
were	O
transduced	O
during	O
apnea	O
by	O
a	O
small	O
high	O
-	O
gain	O
pneumotachograph	O
.	O

Sensory	O
kindling	O
:	O
implications	O
for	O
development	O
of	O
sensory	O
prostheses	O
.	O

It	O
is	O
concluded	O
that	O
stereotypy	O
can	O
be	O
evoked	O
also	O
in	O
the	O
case	O
when	O
the	O
striatal	O
dopaminergic	O
tone	O
is	O
normal	O
or	O
even	O
below	O
normal	O
:	O
it	O
is	O
the	O
equilibrium	O
of	O
the	O
striatal	O
cholinergic	O
-	O
dopaminergic	O
systems	O
which	O
must	O
be	O
shifted	O
towards	O
dopamine	O
,	O
which	O
is	O
necessary	O
for	O
the	O
development	O
of	O
this	O
behavioral	O
manifestation	O
.	O

In	O
the	O
duodenum	O
a	O
small	O
part	O
of	O
the	O
administered	O
dose	O
was	O
transformed	O
to	O
3H	O
-	O
alpha	O
-	O
acetyldigoxin	O
.	O

Functional	O
effects	O
following	O
subacute	O
administration	O
.	O

Although	O
it	O
has	O
been	O
shown	O
that	O
it	O
is	O
possible	O
to	O
use	O
orally	O
administered	O
testosterone	O
to	O
maintain	O
se	O
-	O
T	O
levels	O
in	O
the	O
normal	O
male	O
range	O
,	O
the	O
convenience	O
to	O
the	O
patient	O
must	O
be	O
balanced	O
against	O
the	O
cost	O
and	O
possible	O
side	O
effects	O
of	O
the	O
large	O
doses	O
required	O
.	O

Contrary	O
to	O
1	O
,	O
8	O
-	O
dihydroxy	O
-	O
9	O
-	O
anthrone	O
,	O
1	O
,	O
8	O
,	O
9	O
-	O
triacetoxyanthracene	O
and	O
1	O
,	O
8	O
-	O
diacetoxy	O
-	O
9	O
-	O
anthrone	O
are	O
effective	O
against	O
psoriatic	O
lesions	O
without	O
accompanying	O
inflammations	O
of	O
the	O
skin	O
.	O

Etiopathogenetic	O
and	O
therapeutic	O
problems	O
in	O
acute	O
orbital	O
inflammation	O

Nursing	O
of	O
patients	O
with	O
gynecological	O
diseases	O

We	O
measured	O
basal	O
plasma	O
prolactin	B-GENE
concentrations	O
(	O
in	O
samples	O
obtained	O
during	O
the	O
early	O
follicular	O
phase	O
)	O
in	O
25	O
normal	O
(	O
control	O
)	O
women	O
and	O
in	O
a	O
similar	O
group	O
of	O
40	O
patients	O
with	O
a	O
long	O
-	O
standing	O
history	O
of	O
infertility	O
.	O

Ovarian	O
allotransplantation	O
in	O
human	O
.	O

Screening	O
of	O
asthma	O
patients	O
by	O
determination	O
of	O
IgE	B-GENE
and	O
by	O
comprehension	O
of	O
spectrum	O
of	O
allergospecific	B-GENE
IgE	I-GENE
antibodies	I-GENE

The	O
induction	O
of	O
seizures	O
in	O
"	O
Papio	O
papio	O
"	O
following	O
allylglycine	O
alone	O
or	O
in	O
combination	O
with	O
intermittent	O
photic	O
stimulation	O

A	O
highly	O
significant	O
correlation	O
was	O
found	O
between	O
the	O
presence	O
of	O
fibrinolytic	O
degradation	O
products	O
(	O
FDP	O
)	O
and	O
the	O
incidence	O
of	O
nephropathy	O
and	O
renal	O
insufficiency	O
,	O
as	O
well	O
as	O
between	O
the	O
presence	O
of	O
fibrin	B-GENE
monomers	I-GENE
(	O
Godal	O
'	O
s	O
ethanol	O
-	O
gelification	O
test	O
)	O
and	O
the	O
evolutive	O
signs	O
of	O
the	O
primary	O
disease	O
(	O
fever	O
,	O
accelerated	O
ESR	O
)	O
.	O

In	O
girls	O
prolactin	B-GENE
levels	O
rise	O
at	O
stage	O
2	O
,	O
and	O
are	O
higher	O
after	O
menarche	O
;	O
in	O
boys	O
there	O
is	O
no	O
change	O
in	O
prolactin	B-GENE
levels	O
.	O

2	O
cases	O
of	O
toxic	O
lymphomononucleosis	O

Such	O
an	O
hemoglobin	B-GENE
solution	O
was	O
shown	O
to	O
exhibit	O
a	O
high	O
affinity	O
for	O
oxygen	O
and	O
a	O
low	O
Bohr	O
effect	O
(	O
assessed	O
from	O
the	O
delta	O
log	O
Po2	O
/	O
delta	O
pH	O
ratio	O
)	O
.	O

A	O
one	O
-	O
week	O
ulcer	O
therapy	O
with	O
atropine	O
and	O
Vikalin	O
(	O
Roter	O
)	O
led	O
to	O
a	O
significant	O
(	O
p	O
less	O
than	O
0	O
.	O
01	O
)	O
reduction	O
of	O
the	O
nocturnal	O
proteolytic	O
activity	O
.	O

In	O
one	O
patient	O
with	O
severe	O
diarrhea	O
the	O
estriol	O
concentration	O
in	O
serum	O
was	O
low	O
until	O
the	O
intestinal	O
function	O
normalised	O
and	O
the	O
estriol	O
concentration	O
went	O
up	O
exactly	O
when	O
the	O
diarrhea	O
stopped	O
.	O

Serum	O
levels	O
of	O
IgG	B-GENE
and	O
IgM	B-GENE
were	O
also	O
raised	O
,	O
but	O
contrary	O
to	O
the	O
findings	O
of	O
other	O
observers	O
IgA	B-GENE
levels	O
were	O
normal	O
.	O

Experimental	O
ischemic	O
heart	O
disease	O
induced	O
by	O
thromboxane	O
A2	O
in	O
rabbits	O
.	O

Vitrectomy	O
in	O
ocular	O
traumatology	O

To	O
study	O
the	O
sensitivity	O
of	O
some	O
central	O
brain	O
structures	O
to	O
the	O
action	O
of	O
an	O
electromagnetic	O
field	O
of	O
decimeter	O
waves	O
(	O
EMF	O
of	O
DW	O
)	O
a	O
dynamic	O
investigation	O
of	O
single	O
unit	O
activity	O
was	O
undertaken	O
.	O

No	O
systematic	O
L	O
-	O
R	O
differences	O
were	O
observed	O
.	O

A	O
decrease	O
of	O
the	O
lysozyme	B-GENE
activity	O
coincided	O
with	O
the	O
clinical	O
improvement	O
of	O
the	O
bacterial	O
meningitis	O
.	O

1	O
The	O
effects	O
in	O
normal	O
subjects	O
of	O
a	O
single	O
oral	O
dose	O
of	O
Motival	O
(	O
one	O
tablet	O
,	O
containing	O
fluphenazine	O
0	O
.	O
5	O
mg	O
and	O
nortriptyline	O
10	O
mg	O
)	O
on	O
the	O
contingent	O
negative	O
variation	O
(	O
CNV	O
)	O
,	O
reaction	O
time	O
,	O
heart	O
rate	O
,	O
blood	O
pressure	O
and	O
self	O
-	O
rating	O
scales	O
for	O
alertness	O
,	O
anxiety	O
,	O
tension	O
,	O
detachment	O
and	O
depression	O
were	O
compared	O
with	O
those	O
of	O
diazepam	O
(	O
5	O
mg	O
and	O
7	O
.	O
5	O
mg	O
)	O
and	O
placebo	O
or	O
propranolol	O
(	O
60	O
mg	O
)	O
.	O

Stress	O
effects	O
on	O
affiliation	O
preferences	O
among	O
subjects	O
possessing	O
the	O
type	O
A	O
coronary	O
-	O
prone	O
behavior	O
pattern	O
.	O

These	O
show	O
that	O
the	O
collagen	B-GENE
in	O
this	O
tissue	O
is	O
modified	O
compared	O
with	O
that	O
in	O
tendon	O
.	O

Smoking	O
was	O
regarded	O
as	O
the	O
major	O
contribution	O
to	O
pulmonary	O
dysfunction	O
.	O

The	O
malignity	O
of	O
nevoid	O
lentigo	O
.	O

These	O
responses	O
were	O
compared	O
with	O
others	O
in	O
the	O
same	O
subjects	O
under	O
the	O
same	O
conditions	O
and	O
it	O
was	O
concluded	O
that	O
the	O
antihypertensive	O
effect	O
of	O
labetalol	O
is	O
explained	O
by	O
concurrent	O
blockade	O
of	O
alpha	B-GENE
-	I-GENE
and	I-GENE
beta	I-GENE
-	I-GENE
adrenoceptors	I-GENE
.	O

Diuretics	O
:	O
basic	O
clinical	O
pharmacology	O
and	O
therapeutic	O
use	O
.	O

Three	O
patients	O
with	O
four	O
renoureteral	O
units	O
have	O
undergone	O
single	O
-	O
stage	O
reconstruction	O
involving	O
ureteroureterostomy	O
and	O
ipsilateral	O
ureteroneocystostomy	O
following	O
temporary	O
loop	O
cutaneous	O
ureterostomy	O
.	O

Internally	O
oriented	O
patients	O
'	O
scores	O
on	O
Rotter	O
'	O
s	O
Internal	O
-	O
External	O
Locus	O
of	O
Control	O
Scale	O
remained	O
the	O
same	O
over	O
treatment	O
but	O
those	O
of	O
externally	O
oriented	O
patients	O
shifted	O
toward	O
greater	O
internal	O
control	O
.	O

Action	O
of	O
strontium	O
-	O
90	O
and	O
metaphos	O
on	O
Cyprinus	O
carpio	O

Kodak	O
XV	O
-	O
2	O
film	O
is	O
wrapped	O
around	O
a	O
cylindrical	O
water	O
-	O
filled	O
phantom	O
and	O
the	O
dose	O
distribution	O
is	O
recorded	O
.	O

Diagnosis	O
and	O
differential	O
diagnosis	O

The	O
multiple	O
factors	O
affecting	O
plasma	O
renin	B-GENE
activity	O
in	O
essential	O
hypertension	O
.	O

Cortisone	O
induced	O
bone	O
changes	O
and	O
its	O
response	O
to	O
lipid	O
clearing	O
agents	O
.	O

When	O
blood	O
samples	O
of	O
patients	O
with	O
hyperbilirubinemia	O
were	O
analyzed	O
,	O
direct	O
measurement	O
of	O
ZPP	O
by	O
this	O
fluorimeter	O
yielded	O
significantly	O
higher	O
levels	O
than	O
did	O
an	O
alternate	O
extraction	O
method	O
.	O

Delayed	O
hypersensitivity	O
in	O
man	O
:	O
effects	O
of	O
systemic	O
anticoagulation	O
.	O

Experimental	O
studies	O
on	O
virus	O
excretion	O
and	O
non	O
-	O
arthropod	O
transmission	O
.	O

Prevention	O
of	O
acute	O
paraquat	O
toxicity	O
in	O
rats	O
by	O
superoxide	B-GENE
dismutase	I-GENE
.	O

Increased	O
urinary	O
riboflavin	O
excretion	O
resulting	O
from	O
boric	O
acid	O
ingestion	O
.	O

Radionuclide	O
angiography	O
and	O
static	O
whole	O
body	O
imaging	O
performed	O
with	O
technetium	O
-	O
99m	O
-	O
labeled	O
particulates	O
can	O
clearly	O
demonstrate	O
differential	O
shunting	O
in	O
patients	O
with	O
patent	O
ductus	O
arteriosus	O
(	O
PDA	O
)	O
with	O
Eisenmenger	O
physiology	O
.	O

Looming	O
detectors	O
in	O
the	O
human	O
visual	O
pathway	O
.	O

Escherichia	O
of	O
a	O
single	O
sero	O
-	O
anzymatic	O
type	O
(	O
06a6b	O
:	O
K13	O
:	O
H1	O
)	O
were	O
isolated	O
in	O
a	O
group	O
affection	O
.	O

The	O
method	O
described	O
may	O
prove	O
useful	O
in	O
studying	O
the	O
physiology	O
of	O
the	O
nasal	O
cycle	O
.	O

At	O
the	O
same	O
time	O
we	O
obtained	O
easily	O
understandable	O
EEG	O
-	O
information	O
which	O
has	O
never	O
previously	O
been	O
available	O
to	O
us	O
.	O

Analysis	O
of	O
liver	O
biopsy	O
specimens	O
from	O
patients	O
with	O
hepatitis	O
showed	O
a	O
large	O
variation	O
in	O
the	O
mean	O
iron	O
content	O
of	O
the	O
liver	O
ferritin	B-GENE
molecules	O
.	O

Angiotensin	B-GENE
effect	O
in	O
the	O
human	O
kidney	O
.	O

Procion	O
yellow	O
dye	O
was	O
injected	O
intracellularly	O
into	O
large	O
auditory	O
fibers	O
of	O
goldfish	O
to	O
investigate	O
the	O
relationship	O
between	O
the	O
response	O
type	O
of	O
these	O
fibers	O
and	O
their	O
site	O
of	O
termination	O
in	O
the	O
saccular	O
macula	O
.	O

Incidental	O
findings	O
in	O
the	O
epidermis	O
and	O
in	O
the	O
intraepidermal	O
eccrine	O
sweat	O
duct	O
units	O
.	O

Silicosis	O
mortality	O

These	O
consisted	O
of	O
beading	O
and	O
strictures	O
mainly	O
of	O
the	O
intrahepatic	O
biliary	O
tree	O
(	O
IHB	O
)	O
.	O

Pentane	O
and	O
ethane	O
,	O
which	O
arise	O
during	O
lipid	O
peroxidation	O
in	O
vivo	O
,	O
were	O
measured	O
by	O
gas	O
chromatography	O
in	O
breath	O
samples	O
of	O
rats	O
fed	O
for	O
8	O
weeks	O
a	O
vitamin	O
E	O
-	O
deficient	O
diet	O
to	O
which	O
had	O
been	O
added	O
0	O
,	O
11	O
,	O
or	O
40	O
IU	O
vitamin	O
E	O
acetate	O
per	O
kg	O
.	O

The	O
effect	O
of	O
pure	O
natural	O
porcine	B-GENE
secretin	I-GENE
on	O
endocrine	O
and	O
exocrine	O
pancreatic	O
secretion	O
was	O
studied	O
in	O
the	O
totally	O
isolated	O
perfused	O
porcine	O
pancreas	O
.	O

Biometric	O
analysis	O
of	O
intraocular	O
lens	O
power	O
required	O
to	O
produce	O
emmetropia	O
:	O
results	O
of	O
450	O
implants	O
.	O

Althoug	O
RBF	O
tended	O
to	O
increase	O
after	O
the	O
therapy	O
,	O
there	O
was	O
no	O
statistically	O
significant	O
change	O
in	O
RBF	O
,	O
GFR	O
and	O
cardiac	O
output	O
.	O

Six	O
patients	O
with	O
glomerulonephritis	O
in	O
association	O
with	O
a	O
ventriculovascular	O
shunt	O
were	O
treated	O
with	O
three	O
basic	O
modes	O
of	O
therapy	O
.	O

The	O
mass	O
of	O
UO2	O
in	O
the	O
extrapulmonary	O
bronchi	O
and	O
first	O
bifurcation	O
decreased	O
more	O
slowly	O
over	O
0	O
-	O
-	O
8	O
d	O
after	O
inhalation	O
than	O
the	O
corresponding	O
mass	O
on	O
the	O
trachea	O
.	O

Synovial	O
cysts	O
of	O
the	O
hip	O
joint	O

A	O
sharp	O
outbreak	O
of	O
influenza	O
A	O
occurred	O
on	O
the	O
base	O
during	O
February	O
that	O
was	O
due	O
to	O
an	O
A	O
/	O
Texas	O
/	O
1	O
/	O
77	O
-	O
like	O
virus	O
,	O
a	O
variant	O
of	O
the	O
A	O
/	O
Victoria	O
/	O
3	O
/	O
75	O
prototpye	O
.	O

Because	O
decreases	O
in	O
the	O
disfluency	O
rates	O
of	O
stutterers	O
were	O
observed	O
during	O
the	O
presentation	O
of	O
all	O
three	O
stimulus	O
words	O
,	O
the	O
data	O
failed	O
to	O
support	O
the	O
operant	O
model	O
.	O

Effect	O
of	O
time	O
and	O
dose	O
on	O
alterations	O
following	O
inhalation	O
of	O
plutonium	O
-	O
239	O
dioxide	O
aerosol	O
in	O
rat	O
.	O

In	O
biopsies	O
CK	B-GENE
-	I-GENE
MB	I-GENE
fraction	O
of	O
total	O
myocardial	O
CPK	B-GENE
was	O
37	O
%	O
,	O
the	O
total	B-GENE
-	I-GENE
CPK	I-GENE
activity	O
of	O
human	O
skeletal	O
muscles	O
still	O
shows	O
a	O
5	O
%	O
fraction	O
of	O
CK	B-GENE
-	I-GENE
MB	I-GENE
.	O

Value	O
of	O
determination	O
of	O
alkaline	B-GENE
phosphatase	I-GENE
isoenzymes	I-GENE
for	O
differential	O
diagnosis	O
of	O
obstructive	O
jaundice	O
and	O
biliary	O
liver	O
cirrhosis	O

Several	O
free	O
2nd	O
-	O
generation	O
schizonts	O
,	O
which	O
varied	O
in	O
diameter	O
from	O
11	O
to	O
21	O
.	O
6	O
micrometer	O
,	O
were	O
found	O
on	O
the	O
epithelial	O
surface	O
of	O
the	O
cecum	O
.	O

The	O
calculated	O
pD2	O
values	O
were	O
8	O
.	O
8	O
for	O
E	O
,	O
8	O
.	O
6	O
for	O
DHE	O
and	O
6	O
.	O
6	O
for	O
M	O
.	O

Newcastle	O
disease	O
virus	O
surveillance	O
in	O
Hong	O
Kong	O
on	O
local	O
and	O
imported	O
poultry	O
.	O

It	O
was	O
postulated	O
that	O
persistent	O
challenge	O
by	O
M	O
.	O
leprae	O
or	O
its	O
antigens	O
to	O
the	O
IgA	B-GENE
immunocytes	O
of	O
the	O
intestinal	O
epithelium	O
might	O
have	O
induced	O
tolerance	O
leading	O
to	O
IgA	B-GENE
deficiency	O
and	O
subsequent	O
subtotal	O
atrophy	O
of	O
the	O
intestinal	O
villi	O
in	O
the	O
patients	O
with	O
lepromatous	O
leprosy	O
.	O

Treatment	O
of	O
hypertension	O
with	O
a	O
combination	O
of	O
the	O
adrenergic	B-GENE
beta	I-GENE
receptor	I-GENE
blockader	O
,	O
obsidan	O
,	O
and	O
the	O
vasodilator	O
,	O
apressin	O

Orthop	O
.	O

Thyroid	O
disease	O
and	O
pregnancy	O
.	O

To	O
minimize	O
reflux	O
into	O
the	O
blind	O
loop	O
,	O
a	O
number	O
of	O
technical	O
steps	O
are	O
considered	O
indispensable	O
:	O
1	O
)	O
fluted	O
section	O
of	O
the	O
jejunal	O
stump	O
;	O
2	O
)	O
isoperistaltic	O
construction	O
of	O
the	O
anastomosis	O
and	O
,	O
particularly	O
,	O
3	O
)	O
the	O
creation	O
of	O
a	O
single	O
or	O
double	O
valve	O
system	O
upstream	O
from	O
the	O
anastomosis	O
by	O
spiral	O
introflexion	O
of	O
the	O
mucosa	O
using	O
seroserous	O
stitches	O
parallel	O
and	O
perpendicular	O
to	O
the	O
ileal	O
lumen	O
.	O

At	O
this	O
stage	O
,	O
the	O
eventual	O
high	O
mortality	O
of	O
acute	O
ischemia	O
is	O
established	O
whatever	O
the	O
urgency	O
of	O
the	O
operation	O
or	O
the	O
skill	O
with	O
which	O
it	O
is	O
performed	O
.	O

Pathogens	O
(	O
Staphylococcus	O
aureus	O
or	O
Gram	O
-	O
negative	O
bacilli	O
)	O
were	O
isolated	O
from	O
only	O
one	O
member	O
of	O
staff	O
in	O
small	O
numbers	O
and	O
irregularly	O
and	O
rarely	O
in	O
large	O
numbers	O
from	O
patients	O
.	O

Reaction	O
times	O
to	O
tachistoscopically	O
presented	O
stimuli	O
in	O
diabetics	O

Two	O
out	O
of	O
five	O
patients	O
undergoing	O
selective	O
spinal	O
arteriography	O
developed	O
transient	O
neurological	O
complications	O
during	O
the	O
injection	O
of	O
Urografin	O
310	O
M	O
.	O

The	O
data	O
indicate	O
a	O
three	O
-	O
phase	O
reaction	O
after	O
B1	O
injection	O
:	O
Phase	O
1	O
-	O
-	O
shortly	O
after	O
injection	O
there	O
is	O
a	O
drop	O
of	O
all	O
parameters	O
lasting	O
for	O
30	O
sec	O
.	O

Serum	B-GENE
relaxin	I-GENE
levels	O
in	O
prostaglandin	O
E2	O
induced	O
abortions	O
.	O

A	O
-	O
-	O
A	O
natural	O
hydrostatic	O
phenomenon	O
,	O
at	O
the	O
level	O
of	O
the	O
ends	O
of	O
the	O
plantar	O
arcs	O
,	O
diffuses	O
body	O
weight	O
,	O
as	O
PAIN	O
plays	O
the	O
role	O
of	O
outsentry	O
(	O
fig	O
.	O
-	O
-	O
1	O
)	O
(	O
5	O
)	O
;	O
B	O
-	O
-	O
Plantar	O
perforating	O
ulceration	O
(	O
PPU	O
)	O
is	O
caused	O
by	O
a	O
combination	O
of	O
INSENSITIVITY	O
and	O
TRAUMATIS	O
(	O
1	O
)	O
;	O
C	O
-	O
-	O
The	O
patient	O
reposing	O
,	O
as	O
body	O
weight	O
(	O
traumatism	O
)	O
effects	O
disappear	O
,	O
cicatrization	O
process	O
can	O
be	O
easily	O
observed	O
;	O
D	O
-	O
-	O
PNEUMATIC	O
INSOLE	O
,	O
being	O
elastic	O
,	O
diffuses	O
localized	O
compression	O
at	O
the	O
ends	O
of	O
the	O
plantar	O
arcs	O
,	O
reduces	O
attrition	O
,	O
makes	O
easier	O
blood	O
circulation	O
,	O
as	O
well	O
as	O
cure	O
and	O
prophylaxis	O
of	O
PPU	O
(	O
fig	O
.	O
-	O
-	O
6	O
)	O
(	O
3	O
)	O
.	O

Effect	O
of	O
indoramin	O
in	O
small	O
doses	O
on	O
the	O
central	O
vasomotor	O
loci	O
has	O
been	O
studied	O
in	O
chloralose	O
anesthetized	O
cats	O
by	O
localizing	O
it	O
to	O
the	O
central	O
sites	O
.	O

Contingency	O
contracting	O
between	O
clients	O
and	O
their	O
parents	O
/	O
caregivers	O
was	O
used	O
to	O
specify	O
consequences	O
for	O
daily	O
self	O
-	O
monitoring	O
,	O
reduced	O
caloric	O
intake	O
,	O
weight	O
loss	O
,	O
and	O
exercise	O
.	O

Dietetics	O
of	O
childhood	O
-	O
and	O
juvenile	O
diabetes	O

The	O
results	O
of	O
a	O
quantitative	O
study	O
of	O
vasculosyncytial	O
membranes	O
in	O
123	O
placentas	O
are	O
presented	O
.	O

The	O
micromethod	O
uses	O
microcuvettes	O
and	O
substitutes	O
ferrozine	O
for	O
the	O
bathophenanthroline	O
chromogen	O
of	O
the	O
ICSH	O
.	O

Platelet	O
serotonin	O
(	O
5	O
-	O
HT	O
)	O
and	O
5	B-GENE
-	I-GENE
HT	I-GENE
releasing	I-GENE
factor	I-GENE
in	O
plasma	O
of	O
migrainous	O
patients	O
.	O

The	O
vigilance	O
task	O
and	O
the	O
measurement	O
of	O
attentional	O
deficits	O
.	O

The	O
December	O
armed	O
revolt	O
in	O
Moscow	O
and	O
the	O
paramedical	O
personnel	O

The	O
motor	O
unit	O
viewed	O
from	O
above	O
.	O

Avian	O
reproductive	O
system	O
:	O
daily	O
variations	O
in	O
responses	O
to	O
hormones	O
.	O

Biological	O
properties	O
of	O
sumithion	O
.	O

Serological	O
studies	O
of	O
antibodies	O
to	O
Epstein	O
-	O
Barr	O
virus	O
in	O
infectious	O
mononucleosis	O

Carcinoembryonic	B-GENE
antigen	I-GENE
(	O
CEA	B-GENE
)	O
procedures	O
and	O
clinical	O
evaluation	O
.	O

On	O
the	O
basis	O
of	O
a	O
global	O
assessment	O
patients	O
showed	O
a	O
highly	O
significant	O
preference	O
for	O
imipramine	O
compared	O
with	O
placebo	O
as	O
adjunctive	O
therapy	O
.	O

39	O
-	O
47	O
.	O

Absorption	O
varied	O
between	O
65	O
and	O
95	O
per	O
cent	O
,	O
with	O
a	O
mean	O
absorption	O
of	O
80	O
per	O
cent	O
,	O
in	O
both	O
pregnant	O
and	O
non	O
-	O
pregnant	O
subjects	O
.	O

Advances	O
in	O
the	O
management	O
of	O
gynecologic	O
cancer	O
-	O
-	O
radiation	O
therapy	O
.	O

The	O
clinico	O
-	O
pathological	O
data	O
from	O
a	O
patient	O
with	O
irreversible	O
post	O
-	O
partum	O
renal	O
failure	O
(	O
IPRF	O
)	O
are	O
presented	O
.	O

Dialyzable	O
transfer	B-GENE
factor	I-GENE
.	O

19	O
-	O
32	O
.	O

Rheumatoid	B-GENE
factor	I-GENE
and	O
antinuclear	O
antibody	O
tests	O
were	O
frequently	O
positive	O
,	O
and	O
reactions	O
to	O
gold	O
therapy	O
were	O
more	O
frequent	O
than	O
in	O
other	O
rheumatoid	O
populations	O
.	O

This	O
report	O
presents	O
an	O
analysis	O
of	O
the	O
vocal	O
repertoire	O
of	O
howler	O
monkeys	O
(	O
Alouatta	O
palliata	O
)	O
observed	O
during	O
a	O
field	O
study	O
in	O
southwestern	O
Panama	O
.	O

Up	O
to	O
now	O
the	O
number	O
of	O
patients	O
examined	O
is	O
about	O
300	O
,	O
additionally	O
6	O
persons	O
who	O
underwent	O
binephrectomy	O
.	O

Deflunia	O
was	O
well	O
tolerated	O
by	O
25	O
patients	O
,	O
very	O
well	O
tolerated	O
by	O
2	O
.	O

III	O
.	O

A	O
new	O
instrument	O
has	O
been	O
designed	O
for	O
freeze	O
-	O
fracturing	O
of	O
biological	O
material	O
in	O
ultra	O
high	O
vacuum	O
.	O

Pancreatic	O
and	O
biliary	O
secretion	O
and	O
gastric	O
emptying	O
rates	O
of	O
a	O
liquid	O
test	O
meal	O
(	O
LTM	O
)	O
were	O
determined	O
in	O
normal	O
persons	O
,	O
in	O
patients	O
with	O
subtotal	O
gastrectomy	O
with	O
gastroduodenostomy	O
(	O
STG	O
-	O
BI	O
)	O
or	O
with	O
gastrojejunostomy	O
(	O
STG	O
-	O
BII	O
)	O
,	O
and	O
in	O
patients	O
with	O
truncal	O
vagotomy	O
and	O
pyloroplasty	O
(	O
V	O
&	O
P	O
)	O
.	O

Also	O
,	O
except	O
in	O
one	O
patient	O
who	O
developed	O
gallstones	O
following	O
institution	O
of	O
colestipol	O
,	O
saturation	O
of	O
gallbladder	O
bile	O
with	O
cholesterol	O
was	O
not	O
markedly	O
increased	O
by	O
this	O
drug	O
alone	O
.	O

A	O
diagnosis	O
of	O
MS	O
was	O
made	O
based	O
on	O
subtle	O
neurologic	O
signs	O
,	O
spinal	O
fluid	O
gamma	B-GENE
globulin	I-GENE
elevations	O
,	O
and	O
abnormalities	O
in	O
neuropsychological	O
testing	O
.	O

If	O
,	O
however	O
,	O
the	O
mean	O
temperature	O
rise	O
was	O
higher	O
(	O
0	O
.	O
57	O
degrees	O
C	O
or	O
0	O
.	O
69	O
degrees	O
C	O
)	O
,	O
such	O
a	O
selection	O
practically	O
resulted	O
in	O
the	O
disappearance	O
of	O
'	O
passable	O
'	O
qualifications	O
in	O
the	O
triplet	O
groups	O
and	O
a	O
great	O
predominance	O
of	O
'	O
to	O
be	O
rejected	O
'	O
qualifications	O
in	O
the	O
large	O
groups	O
.	O

The	O
elevated	O
Viso	O
V	O
in	O
the	O
RDS	O
group	O
suggests	O
an	O
increase	O
in	O
small	O
airway	O
resistance	O
secondary	O
to	O
the	O
disease	O
or	O
to	O
its	O
therapy	O
.	O

The	O
psychological	O
tests	O
consisted	O
of	O
a	O
free	O
-	O
recall	O
task	O
,	O
a	O
test	O
for	O
visuomotor	O
coordination	O
and	O
a	O
recognition	O
task	O
.	O

Selective	O
bronchial	O
intubation	O
in	O
the	O
management	O
of	O
unilateral	O
pulmonary	O
interstitial	O
emphysema	O
.	O

The	O
background	O
processes	O
depending	O
on	O
the	O
etiological	O
factor	O
and	O
the	O
character	O
of	O
lesion	O
of	O
the	O
epithelium	O
are	O
divided	O
into	O
dyshormonal	O
,	O
inflammatory	O
,	O
and	O
posttraumatic	O
.	O

The	O
sense	O
of	O
self	O
.	O

Eleven	O
strains	O
of	O
Fusarium	O
poae	O
and	O
F	O
.	O
sporotrichioides	O
from	O
the	O
U	O
.	O
S	O
.	O
S	O
.	O
R	O
.	O
and	O
7	O
strains	O
of	O
these	O
species	O
and	O
one	O
of	O
F	O
.	O
sporotrichioides	O
var	O
.	O
tricinctum	O
from	O
U	O
.	O
S	O
.	O
A	O
.	O
and	O
France	O
have	O
been	O
compared	O
as	O
to	O
their	O
capacity	O
to	O
yield	O
T	B-GENE
-	I-GENE
2	I-GENE
toxin	I-GENE
.	O

Current	O
diagnostic	O
uses	O
of	O
computerized	O
tomography	O
in	O
clinical	O
medicine	O
.	O

A	O
follow	O
-	O
up	O
study	O
of	O
22	O
patients	O
with	O
Ebstein	O
'	O
s	O
anomaly	O
has	O
been	O
performed	O
.	O

Deaths	O
stopped	O
11	O
hours	O
after	O
copper	O
concentrations	O
decreased	O
below	O
0	O
.	O
2	O
ppm	O
and	O
signs	O
of	O
distress	O
stopped	O
in	O
surviving	O
pinfish	O
by	O
approximately	O
6	O
hours	O
after	O
the	O
last	O
death	O
.	O

Recurrence	O
of	O
bladder	O
tumors	O
among	O
the	O
original	O
9	O
cases	O
has	O
occurred	O
only	O
among	O
the	O
5	O
whose	O
properdin	B-GENE
levels	O
remained	O
below	O
the	O
median	O
.	O

Adaptation	O
of	O
taurocholate	O
transport	O
maximum	O
to	O
increased	O
secretory	O
load	O
in	O
the	O
rat	O
.	O

Dangers	O
in	O
use	O
of	O
live	O
-	O
virus	O
vaccines	O
.	O

Treatment	O
with	O
heparin	O
,	O
plasminogen	B-GENE
activators	O
and	O
fibrinogenolytic	O
agents	O
was	O
disappointing	O
although	O
renal	O
function	O
has	O
stabilized	O
in	O
one	O
patient	O
on	O
long	O
term	O
oral	O
anticoagulant	O
therapy	O
.	O

In	O
diethyl	O
ether	O
solution	O
the	O
main	O
peak	O
is	O
that	O
of	O
2	O
-	O
benzylidenamio	O
-	O
1	O
-	O
phenylpropane	O
,	O
which	O
has	O
a	O
retention	O
time	O
of	O
23	O
,	O
2	O
minutes	O
under	O
the	O
condition	O
delineated	O
.	O

Amikacin	O
was	O
used	O
in	O
the	O
treatment	O
of	O
56	O
serious	O
gram	O
-	O
negative	O
infections	O
in	O
54	O
patients	O
of	O
whom	O
47	O
survived	O
.	O

The	O
data	O
normally	O
available	O
are	O
insufficient	O
and	O
take	O
no	O
account	O
of	O
the	O
direction	O
of	O
recirculation	O
,	O
which	O
may	O
be	O
a	O
determining	O
factor	O
.	O

The	O
acids	O
were	O
obtained	O
by	O
hydrolysis	O
of	O
the	O
corresponding	O
esters	O
,	O
and	O
their	O
anti	O
-	O
inflammatory	O
activity	O
was	O
tested	O
.	O

Unrecognized	O
amnionitis	O
and	O
prematurity	O
:	O
a	O
preliminary	O
report	O
.	O

Evaluation	O
of	O
the	O
new	O
Gravigard	O
IUCD	O
inserter	O
.	O

Bacterial	O
meningitis	O
secondary	O
to	O
abscess	O
of	O
the	O
nasal	O
septum	O
.	O

Serum	B-GENE
amylase	I-GENE
became	O
markedly	O
elevated	O
(	O
2	O
,	O
624	O
CU	O
/	O
100	O
ml	O
)	O
,	O
as	O
did	O
the	O
serum	O
FFA	O
(	O
29	O
.	O
19	O
mEq	O
/	O
liter	O
)	O
.	O

In	O
the	O
control	O
preparation	O
before	O
weight	O
was	O
allowed	O
to	O
increase	O
,	O
isogravimetric	O
capillary	O
pressure	O
(	O
Pci	O
)	O
averaged	O
8	O
mmHg	O
lower	O
than	O
colloid	O
osmotic	O
pressure	O
of	O
the	O
plasma	O
(	O
IIp	O
)	O
.	O

The	O
morphological	O
effects	O
of	O
two	O
snake	O
venoms	O
,	O
N	O
.	O
naja	O
and	O
A	O
.	O
piscivorus	O
,	O
and	O
of	O
the	O
Direct	B-GENE
Lytic	I-GENE
Factor	I-GENE
and	O
Phospholipase	B-GENE
-	I-GENE
A	I-GENE
,	O
compounds	O
purified	O
from	O
N	O
.	O
naja	O
crude	O
venom	O
,	O
were	O
investigated	O
on	O
lung	O
and	O
cremaster	O
vessels	O
of	O
rats	O
.	O

Since	O
GAGs	O
are	O
the	O
components	O
of	O
cartilage	O
matrix	O
,	O
the	O
depletion	O
of	O
which	O
is	O
associated	O
with	O
osteoarthrosis	O
,	O
a	O
method	O
for	O
measuring	O
sulphated	O
GAG	O
synthesis	O
in	O
culture	O
has	O
been	O
investigated	O
.	O

The	O
length	O
scales	O
of	O
the	O
turbulence	O
were	O
also	O
estimated	O
:	O
at	O
a	O
Reynolds	O
number	O
near	O
4	O
,	O
000	O
the	O
macroscale	O
is	O
about	O
1	O
.	O
25	O
mm	O
,	O
the	O
Taylor	O
microscale	O
is	O
about	O
0	O
.	O
85	O
mm	O
,	O
and	O
the	O
Kolmogoroff	O
scale	O
is	O
near	O
0	O
.	O
075	O
mm	O
.	O

Well	O
-	O
visualised	O
arteriograms	O
of	O
the	O
limbs	O
can	O
be	O
obtained	O
by	O
xeroradiography	O
after	O
rapid	O
manual	O
injection	O
of	O
contrast	O
-	O
medium	O
into	O
an	O
arm	O
vein	O
,	O
as	O
demonstrated	O
in	O
28	O
patients	O
.	O

No	O
hypotension	O
was	O
noted	O
in	O
patients	O
with	O
toxemia	O
and	O
only	O
2	O
ran	O
a	O
fever	O
above	O
37	O
.	O
5	O
degrees	O
C	O
.	O

The	O
sera	O
and	O
nasal	O
secretions	O
of	O
142	O
patients	O
,	O
who	O
were	O
positive	O
in	O
HD	O
or	O
mites	O
skin	O
test	O
,	O
were	O
subjected	O
to	O
a	O
radioallergosorbent	O
test	O
(	O
RAST	O
)	O
for	O
estimating	O
the	O
specific	O
IgE	B-GENE
antibody	I-GENE
activity	O
to	O
mites	O
.	O

Diallylnitrosamine	O
(	O
DAN	O
)	O
,	O
one	O
of	O
the	O
few	O
nitrosamines	O
tested	O
thus	O
far	O
that	O
has	O
not	O
induced	O
neoplasms	O
in	O
rats	O
,	O
caused	O
a	O
high	O
incidence	O
of	O
respiratory	O
tract	O
tumors	O
in	O
Syrian	O
golden	O
hamsters	O
treated	O
sc	O
with	O
single	O
or	O
weekly	O
doses	O
of	O
the	O
compound	O
.	O

Haemodynamic	O
responses	O
to	O
antagonism	O
of	O
bocurarine	O
block	O
with	O
atropine	O
-	O
neostigmine	O
mixture	O
in	O
children	O
.	O

The	O
mechanism	O
by	O
which	O
large	O
molecules	O
,	O
such	O
as	O
the	O
diphosphonate	O
99mTc	O
-	O
labeled	O
EHDP	O
or	O
99mTc	O
-	O
labeled	O
pyrophosphate	O
,	O
pass	O
through	O
capillaries	O
in	O
bone	O
is	O
by	O
passive	O
diffusion	O
.	O

Twenty	O
-	O
nine	O
days	O
after	O
injection	O
of	O
5	O
.	O
8	O
mCi	O
of	O
Tc	O
-	O
99m	O
,	O
which	O
gives	O
28	O
rads	O
to	O
the	O
testis	O
,	O
the	O
number	O
of	O
sperm	O
hads	O
decreased	O
to	O
70	O
%	O
of	O
control	O
.	O

Self	O
-	O
emasculation	O
is	O
the	O
end	O
result	O
of	O
an	O
unusual	O
psychiatric	O
disorder	O
,	O
which	O
initially	O
requires	O
surgical	O
treatment	O
.	O

Possibility	O
of	O
a	O
TSH	B-GENE
-	O
Screening	O
method	O
for	O
detection	O
of	O
hypothyroidism	O
in	O
the	O
newborn	O

Thus	O
analysis	O
indicated	O
no	O
reliable	O
evidence	O
that	O
conscious	O
presleep	O
suggestions	O
become	O
incorporated	O
into	O
dream	O
content	O
.	O

The	O
prevalence	O
of	O
hepatitis	B-GENE
B	I-GENE
surface	I-GENE
antigen	I-GENE
(	O
HBsAg	B-GENE
)	O
and	O
anti	B-GENE
-	I-GENE
HBs	I-GENE
was	O
determined	O
by	O
a	O
sensitive	O
double	O
-	O
antibody	O
radio	O
-	O
immunoassay	O
technique	O
in	O
a	O
series	O
of	O
patients	O
with	O
chronic	O
liver	O
diseases	O
.	O

Decreased	O
cardiac	O
glycogen	O
following	O
phenformin	O
injection	O
in	O
hyperglycemic	O
,	O
hyperinsulinemic	O
anaesthetized	O
rats	O
.	O

Biological	O
evaluation	O
of	O
mibolerone	O
in	O
the	O
female	O
Beagle	O
.	O

Levels	O
of	O
both	O
PGF	O
and	O
PGFM	O
were	O
significantly	O
higher	O
during	O
early	O
spontaneous	O
labour	O
,	O
at	O
a	O
cervical	O
dilatation	O
of	O
less	O
than	O
4	O
cm	O
,	O
than	O
before	O
the	O
onset	O
of	O
labour	O
.	O

Propranolol	O
(	O
Inderal	O
)	O
administered	O
in	O
a	O
dose	O
which	O
blocks	O
the	O
beta	O
-	O
adrenergic	O
apparatus	O
of	O
the	O
heart	O
prevents	O
the	O
development	O
of	O
the	O
positive	O
inotropic	O
effect	O
of	O
therapeutic	O
doses	O
of	O
strophanthin	O
K	O
on	O
a	O
hypodynamic	O
left	O
ventricular	O
myocardium	O
.	O

Recent	O
studies	O
have	O
shown	O
the	O
rat	O
larynx	O
to	O
be	O
an	O
important	O
organ	O
in	O
the	O
evaluation	O
of	O
irritancy	O
of	O
inhaled	O
materials	O
.	O

Scanning	O
electron	O
microscopic	O
investigations	O
on	O
the	O
formation	O
of	O
Reissner	O
'	O
s	O
fiber	O
in	O
Rattus	O
rattus	O

Feeding	O
behavior	O
,	O
circannual	O
body	O
weight	O
and	O
hibernation	O
rhythms	O
in	O
European	O
hamsters	O
lesioned	O
in	O
the	O
noradrenergic	O
ascending	O
bundles	O

Role	O
of	O
the	O
infectious	O
-	O
disease	O
specialist	O
of	O
a	O
polyclinic	O
in	O
reducing	O
the	O
incidence	O
of	O
communicable	O
diseases	O

These	O
observed	O
drug	O
interactions	O
,	O
plus	O
the	O
known	O
effect	O
of	O
probenecid	O
to	O
block	O
secretion	O
of	O
PZA	O
,	O
have	O
to	O
be	O
considered	O
in	O
evaluating	O
the	O
effect	O
of	O
the	O
two	O
drugs	O
given	O
together	O
,	O
compared	O
to	O
the	O
effect	O
of	O
each	O
drug	O
given	O
separately	O
.	O

At	O
a	O
systolic	O
blood	O
pressure	O
(	O
BP	O
)	O
of	O
60	O
mmHg	O
,	O
C02	O
responsiveness	O
was	O
abolished	O
,	O
but	O
was	O
maintained	O
at	O
higher	O
levels	O
of	O
BP	O
.	O

On	O
cessation	O
of	O
steroid	O
therapy	O
the	O
patient	O
was	O
noted	O
to	O
have	O
radiologic	O
manifestations	O
of	O
hypertrophic	O
osteoarthropathy	O
(	O
HOA	O
)	O
as	O
well	O
as	O
clinical	O
and	O
laboratory	O
features	O
of	O
rheumatoid	O
arthritis	O
(	O
RA	O
)	O
.	O

The	O
effect	O
of	O
food	O
on	O
procainamide	O
absorption	O
.	O

After	O
giving	O
a	O
survey	O
on	O
the	O
situation	O
of	O
antibiotic	O
resistance	O
in	O
the	O
region	O
of	O
Northern	O
Bavaria	O
during	O
1973	O
/	O
74	O
and	O
comparing	O
the	O
activity	O
of	O
a	O
sulfamethoxazole	O
(	O
SMZ	O
)	O
trimethoprim	O
(	O
TMP	O
)	O
combination	O
to	O
other	O
commonly	O
used	O
antibiotics	O
and	O
chemotherapeutic	O
agents	O
,	O
the	O
results	O
of	O
tests	O
with	O
the	O
new	O
combination	O
of	O
N1	O
-	O
(	O
4	O
,	O
5	O
-	O
dimethyl	O
-	O
2	O
-	O
oxazolyl	O
)	O
-	O
sulfanilamide	O
)	O
(	O
sulfamoxole	O
)	O
and	O
2	O
,	O
4	O
-	O
diamino	O
-	O
5	O
-	O
(	O
3	O
,	O
4	O
,	O
5	O
-	O
trimethoxy	O
-	O
benzyl	O
)	O
-	O
pyrimidine	O
(	O
trimethoprim	O
)	O
at	O
a	O
ratio	O
of	O
5	O
:	O
1	O
(	O
CN	O
3123	O
;	O
Nevin	O
,	O
Supristol	O
)	O
are	O
compared	O
to	O
those	O
of	O
tests	O
with	O
TMP	O
/	O
SMZ	O
.	O

RESULTS	O
:	O
Total	O
IgE	B-GENE
levels	O
showed	O
a	O
tendency	O
to	O
diminish	O
.	O

Does	O
afferent	O
loop	O
syndrome	O
exist	O
?	O
]	O
It	O
is	O
the	O
author	O
'	O
s	O
opinion	O
that	O
diagnosis	O
of	O
the	O
"	O
adducent	O
loop	O
syndrome	O
"	O
is	O
unlikely	O
to	O
be	O
correct	O
in	O
patients	O
subjected	O
to	O
Billroth	O
-	O
II	O
gastrectomy	O
.	O

Letter	O
:	O
Is	O
actinic	O
(	O
solar	O
)	O
damage	O
the	O
provoking	O
cause	O
of	O
'	O
post	O
-	O
inflammatory	O
elastolysis	O
and	O
cutis	O
laxa	O
(	O
PECL	O
)	O
'	O
?	O

These	O
data	O
suggest	O
that	O
spontaneous	O
recovery	O
of	O
central	O
respiratory	O
function	O
after	O
intoxication	O
with	O
Soman	O
or	O
Sarin	O
may	O
not	O
be	O
related	O
to	O
the	O
return	O
of	O
AChE	B-GENE
activity	O
.	O

Batch	O
cultures	O
of	O
S	O
.	O
mutans	O
serotype	O
a	O
demonstrated	O
no	O
growth	O
on	O
MSB	O
agar	O
.	O

Crisis	O
of	O
the	O
therapeutic	O
community	O
in	O
Great	O
Britain	O

Pregnant	O
women	O
at	O
term	O
had	O
the	O
lowest	O
levels	O
of	O
antithrombin	B-GENE
III	I-GENE
.	O

Hematology	O
problem	O
of	O
the	O
month	O
:	O
band	O
or	O
seg	O
?	O

It	O
is	O
possible	O
that	O
cyclic	O
variations	O
in	O
heme	O
turnover	O
are	O
related	O
to	O
changes	O
in	O
erythrocyte	O
characteristics	O
during	O
the	O
progesterone	O
phase	O
.	O

Haemodilution	O
in	O
cardiopulmonary	O
bypass	O
using	O
a	O
gelatine	O
derivative	O
for	O
priming	O
.	O

I	O
.	O

The	O
performance	O
of	O
three	O
commonly	O
used	O
chemical	O
cartridge	O
respirators	O
for	O
SO2	O
was	O
measured	O
under	O
working	O
conditions	O
in	O
a	O
copper	O
smelter	O
.	O

The	O
neuroleptic	O
-	O
induced	O
increase	O
in	O
central	O
DA	O
turnover	O
(	O
an	O
indicator	O
for	O
the	O
degree	O
of	O
DA	B-GENE
receptor	I-GENE
blocking	O
)	O
was	O
found	O
to	O
be	O
positively	O
correlated	O
with	O
the	O
therapeutic	O
effect	O
of	O
neuroleptics	O
and	O
the	O
development	O
of	O
hypokinetic	O
-	O
rigid	O
symptoms	O
.	O

Rainbow	O
trout	O
were	O
obtained	O
from	O
a	O
commercial	O
trout	O
farm	O
,	O
kept	O
in	O
running	O
water	O
and	O
feeding	O
in	O
experimental	O
pellets	O
for	O
4	O
to	O
8	O
weeks	O
.	O

Stimulation	O
of	O
macrophage	O
function	O
by	O
killed	O
Bordetella	O
pertussis	O
cells	O
did	O
not	O
show	O
any	O
beneficial	O
effect	O
as	O
an	O
increased	O
susceptibility	O
became	O
apparent	O
.	O

Primary	O
amenorrhoea	O
in	O
a	O
phenotypically	O
female	O
individual	O
with	O
a	O
karyotype	O
46	O
,	O
xy	O
and	O
bilateral	O
gonadoblastoma	O

Toward	O
absolute	O
methods	O
in	O
clinical	O
chemistry	O
:	O
application	O
of	O
mass	O
fragmentography	O
to	O
high	O
-	O
accuracy	O
analyses	O
.	O

Application	O
of	O
the	O
2	O
-	O
deoxy	O
-	O
D	O
-	O
glucose	O
method	O
to	O
the	O
coupling	O
of	O
cerebral	O
metabolism	O
and	O
blood	O
flow	O
.	O

Serum	O
gastrin	B-GENE
levels	O
did	O
not	O
change	O
in	O
either	O
group	O
;	O
however	O
,	O
background	O
serum	O
gastrin	B-GENE
concentrations	O
were	O
significantly	O
greater	O
for	O
V	O
&	O
P	O
patients	O
than	O
V	O
&	O
A	O
patients	O
throughout	O
the	O
study	O
.	O

Efferent	O
projections	O
of	O
the	O
ventral	O
portion	O
of	O
the	O
putamen	O
to	O
the	O
frontal	O
,	O
parietal	O
and	O
temporal	O
regions	O
of	O
the	O
cat	O
cerebral	O
cortex	O

Preflight	O
,	O
inflight	O
,	O
and	O
postflight	O
exercise	O
response	O
tests	O
were	O
conducted	O
on	O
the	O
astronauts	O
of	O
the	O
second	O
Skylab	O
mission	O
(	O
Skylab	O
3	O
)	O
as	O
part	O
of	O
an	O
evaluation	O
of	O
physiological	O
adaptation	O
to	O
long	O
-	O
term	O
weightlessness	O
.	O

Mean	O
corpuscular	B-GENE
hemoglobin	I-GENE
concentrations	O
remained	O
normal	O
for	O
48	O
h	O
and	O
then	O
decreased	O
in	O
both	O
groups	O
,	O
the	O
CO2	O
group	O
showing	O
the	O
larger	O
decrease	O
.	O

All	O
Cu	O
values	O
obtained	O
from	O
the	O
organs	O
investigated	O
had	O
reached	O
a	O
saturation	O
level	O
at	O
8	O
mug	O
Cu	O
/	O
g	O
diet	O
with	O
the	O
exception	O
of	O
the	O
values	O
for	O
body	O
Cu	O
found	O
in	O
the	O
dams	O
that	O
were	O
killed	O
on	O
the	O
day	O
of	O
delivery	O
.	O

The	O
effect	O
of	O
calcitonin	B-GENE
,	O
a	O
large	O
amount	O
of	O
calcium	O
given	O
orally	O
,	O
pentagastrin	O
and	O
glucagon	B-GENE
on	O
plasma	O
47Ca	O
radioactivity	O
curves	O
in	O
subjects	O
pretreated	O
with	O
47Ca	O
was	O
examined	O
.	O

State	O
of	O
the	O
body	O
in	O
disorders	O
of	O
diurnal	O
physiological	O
rhythms	O
and	O
long	O
-	O
term	O
hypokinesia	O

The	O
response	O
of	O
the	O
plasma	B-GENE
fibrinogen	I-GENE
level	O
to	O
the	O
subucutaneous	O
injection	O
of	O
turpentine	O
and	O
to	O
the	O
intravenous	O
injection	O
of	O
endotoxin	O
was	O
measured	O
in	O
normal	O
rabbits	O
and	O
in	O
rabbits	O
made	O
granulocytopenic	O
and	O
thrombocytopenic	O
with	O
busulfan	O
.	O

Constantly	O
rectilinear	O
pressure	O
curves	O
without	O
uterine	O
activities	O
are	O
interpreted	O
as	O
characteristic	O
tocographic	O
criteria	O
of	O
an	O
advanced	O
ectopic	O
gravidity	O
.	O

Since	O
myoglobin	B-GENE
is	O
co	O
-	O
extracted	O
with	O
the	O
hemoglobin	B-GENE
,	O
the	O
2	O
heme	O
pigments	O
are	O
separated	O
in	O
one	O
portion	O
of	O
the	O
extract	O
by	O
precipitating	O
the	O
hemoglobin	B-GENE
in	O
an	O
85	O
%	O
(	O
NH4	O
)	O
2SO4	O
solution	O
.	O

Considering	O
these	O
sources	O
of	O
error	O
some	O
of	O
the	O
variability	O
in	O
the	O
present	O
investigation	O
might	O
be	O
avoided	O
by	O
systematic	O
instructions	O
.	O

E	O
50	O
,	O
843	O
(	O
1994	O
)	O
]	O
.	O

Six	O
patients	O
with	O
the	O
diagnosis	O
of	O
acute	O
mania	O
were	O
treated	O
with	O
high	O
doses	O
of	O
the	O
beta	O
-	O
adrenergic	O
blocking	O
agent	O
propranolol	O
.	O

Effect	O
of	O
trauma	O
on	O
plasma	B-GENE
glucagon	I-GENE
and	O
insulin	B-GENE
concentrations	O
in	O
sheep	O
.	O

With	O
the	O
help	O
of	O
a	O
nomogram	O
one	O
can	O
read	O
off	O
the	O
refraction	O
,	O
when	O
axis	O
length	O
and	O
corneal	O
curvature	O
are	O
known	O
.	O

This	O
up	O
-	O
grading	O
of	O
the	O
final	O
score	O
by	O
the	O
CA	O
component	O
is	O
greater	O
(	O
3	O
-	O
8	O
%	O
)	O
in	O
the	O
less	O
able	O
students	O
with	O
scores	O
below	O
the	O
mean	O
level	O
.	O

Compared	O
to	O
controls	O
,	O
both	O
UB	O
and	O
OCS	O
rats	O
showed	O
a	O
small	O
but	O
significant	O
post	O
-	O
operative	O
reduction	O
in	O
the	O
nocturnality	O
of	O
drinking	O
.	O

Effect	O
of	O
indomethacin	O
on	O
coronary	O
circulation	O
:	O
effect	O
on	O
ECG	O
tracing	O

Dual	O
innervation	O
of	O
fast	O
fibers	O
in	O
trunk	O
muscles	O
of	O
lamprey	O
larvae	O

The	O
feed	O
consumed	O
which	O
was	O
lowered	O
by	O
25	O
%	O
initially	O
,	O
did	O
not	O
alter	O
later	O
.	O

Certain	O
characteristics	O
of	O
eye	O
changes	O
in	O
patients	O
with	O
pheochromocytoma	O
including	O
Sipple	O
'	O
s	O
syndrome	O

The	O
color	O
-	O
word	O
interference	O
effect	O
previously	O
reported	O
with	O
normal	O
populations	O
when	O
given	O
the	O
Stroop	O
test	O
was	O
demonstrated	O
for	O
this	O
retarded	O
sample	O
using	O
a	O
special	O
format	O
.	O

It	O
was	O
found	O
that	O
under	O
the	O
selected	O
conditions	O
a	O
linear	O
dependence	O
exists	O
between	O
the	O
betaI	O
%	O
value	O
and	O
lgC	O
within	O
the	O
range	O
of	O
0	O
.	O
5	O
-	O
-	O
10	O
mug	O
ruscogenin	O
.	O

The	O
influence	O
of	O
adrenergic	O
nerves	O
of	O
the	O
response	O
of	O
blood	O
vessels	O
in	O
the	O
rabbit	O
ear	O
to	O
2	B-GENE
-	I-GENE
-	I-GENE
phenylalanine	I-GENE
-	I-GENE
8	I-GENE
-	I-GENE
lysine	I-GENE
vasopressin	I-GENE
(	O
Octapressin	B-GENE
)	O
.	O

Potscoital	O
test	O

When	O
a	O
tumour	O
is	O
present	O
nipple	O
discharge	O
is	O
of	O
little	O
importance	O
for	O
the	O
diagnosis	O
and	O
treatment	O
.	O

Studies	O
of	O
biochemical	O
and	O
morphological	O
changes	O
(	O
between	O
normal	O
and	O
treated	O
animals	O
)	O
show	O
that	O
chrysotile	O
induces	O
an	O
increase	O
in	O
the	O
lung	O
free	O
cell	O
population	O
and	O
pulmonary	O
surfactant	O
levels	O
.	O

Infrared	O
measurements	O
of	O
temperature	O
changes	O
and	O
estimates	O
of	O
the	O
heating	O
produced	O
at	O
the	O
mical	O
.	O

Who	O
says	O
'	O
National	O
Health	O
Dis	O
-	O
service	O
'	O
.	O

Is	O
criticism	O
of	O
patient	O
care	O
justified	O
and	O
does	O
it	O
have	O
educational	O
value	O
?	O
Patients	O
'	O
criticism	O
contributes	O
to	O
improved	O
patient	O
care	O

Critique	O
of	O
"	O
Interactive	O
Effects	O
of	O
Test	O
Anxiety	O
and	O
Credit	O
/	O
No	O
Credit	O
or	O
A	O
-	O
F	O
Grade	O
Condition	O
upon	O
Short	O
-	O
term	O
and	O
Long	O
-	O
term	O
Recall	O
of	O
Course	O
Information	O
.	O

These	O
studies	O
have	O
shown	O
that	O
the	O
majority	O
of	O
tested	O
staphylococci	O
were	O
resistant	O
to	O
penicillin	O
G	O
,	O
erythromycin	O
,	O
and	O
produced	O
beta	B-GENE
-	I-GENE
lactamase	I-GENE
.	O

Improvement	O
of	O
nursing	O
instruction	O
to	O
be	O
given	O
at	O
the	O
time	O
of	O
discharge	O
from	O
the	O
ward	O
for	O
premature	O
infants	O

No	O
difference	O
in	O
the	O
clinical	O
acceptability	O
could	O
be	O
ascertained	O
between	O
the	O
two	O
groups	O
.	O

After	O
90	O
d	O
a	O
subsurface	O
,	O
radiolucent	O
caries	O
-	O
like	O
lesion	O
was	O
observed	O
in	O
two	O
specimens	O
only	O
.	O

Plethysmographic	O
technique	O
and	O
indirect	O
blood	O
pressure	O
recordings	O
were	O
used	O
.	O

The	O
second	O
and	O
third	O
responded	O
similarly	O
to	O
either	O
a	O
combined	O
cyclophosphamide	O
+	O
antilymphocyte	B-GENE
globulin	I-GENE
(	O
ALG	B-GENE
)	O
treatment	O
or	O
to	O
ALG	B-GENE
administration	O
preceded	O
by	O
a	O
small	O
dosage	O
of	O
cyclophosphamide	O
,	O
which	O
had	O
proved	O
ineffective	O
when	O
administered	O
alone	O
.	O

Evidence	O
is	O
presented	O
that	O
Leber	O
'	O
s	O
military	O
aneurysm	O
retinitis	O
is	O
not	O
a	O
separate	O
entity	O
but	O
a	O
special	O
form	O
of	O
Coats	O
'	O
disease	O
.	O

Fibrin	B-GENE
cloaking	O
along	O
the	O
catheter	O
was	O
found	O
in	O
20	O
patients	O
studied	O
by	O
pull	O
-	O
out	O
arteriography	O
and	O
was	O
unassociated	O
with	O
clinical	O
symptoms	O
.	O

The	O
influence	O
of	O
a	O
mobile	O
pupil	O
on	O
the	O
response	O
in	O
the	O
DC	O
-	O
ERG	O
is	O
demonstrated	O
.	O

A	O
newly	O
synthesized	O
anti	O
-	O
inflammatory	O
agent	O
,	O
Y	O
-	O
8004	O
demonstrated	O
a	O
greater	O
inhibition	O
than	O
did	O
indomethacin	O
(	O
IM	O
)	O
.	O
on	O
inflammatory	O
response	O
such	O
as	O
ultraviolet	O
erythema	O
in	O
guinea	O
pigs	O
,	O
carrageenin	O
edema	O
,	O
evans	O
blue	O
and	O
carrageenin	O
-	O
induced	O
pleuritis	O
and	O
acetic	O
acid	O
-	O
induced	O
peritonitis	O
in	O
rats	O
.	O

As	O
stands	O
shifted	O
in	O
dominance	O
from	O
pine	O
to	O
fir	O
with	O
age	O
,	O
subalpine	O
fir	O
appeared	O
to	O
maintain	O
gradually	O
increasing	O
rates	O
of	O
whole	O
-	O
forest	O
productivity	O
until	O
stands	O
were	O
approximately	O
400	O
years	O
old	O
.	O

Alpha	B-GENE
-	I-GENE
1	I-GENE
antitrypsin	I-GENE
and	O
Indian	O
childhood	O
cirrhosis	O
.	O

Lymphocyte	O
subpopulations	O
,	O
serum	B-GENE
IgE	I-GENE
and	O
total	O
eosinophil	O
counts	O
in	O
patients	O
with	O
bronchial	O
asthma	O
.	O

A	O
range	O
of	O
normal	O
ventricular	O
measurements	O
for	O
the	O
EMI	O
scan	O
is	O
suggested	O
.	O

A	O
comparison	O
of	O
physical	O
and	O
cytogenetic	O
estimates	O
of	O
radiation	O
dose	O
in	O
patients	O
treated	O
with	O
iodine	O
-	O
131	O
for	O
thyroid	O
carcinoma	O
.	O

Technique	O
for	O
obtaining	O
refined	O
ceramics	O
with	O
dense	O
mass	O

Mean	O
total	O
lung	O
capacity	O
,	O
functional	O
residual	O
capacity	O
,	O
and	O
residual	O
volume	O
increased	O
significantly	O
,	O
and	O
the	O
mean	O
closing	O
volume	O
,	O
the	O
lung	O
volume	O
above	O
residual	O
volume	O
at	O
which	O
phase	O
IV	O
begins	O
,	O
decreased	O
significantly	O
with	O
11	O
cm	O
H20	O
continuous	O
positive	O
airway	O
pressure	O
;	O
differences	O
at	O
5	O
cm	O
H20	O
were	O
not	O
significant	O
.	O

Current	O
status	O
of	O
zinc	O
deficiency	O
in	O
the	O
pathogenesis	O
of	O
neurological	O
,	O
dermatological	O
and	O
musculoskeletal	O
disorders	O
.	O

Calcium	O
and	O
phosphorus	O
metabolism	O
in	O
chronic	O
uremia	O
.	O

Modern	O
studies	O
,	O
conducted	O
with	O
Delta	O
-	O
9	O
-	O
THC	O
,	O
in	O
healthy	O
voluntaries	O
,	O
again	O
suggest	O
the	O
comparison	O
or	O
even	O
the	O
identity	O
of	O
the	O
modifications	O
caused	O
by	O
cannabis	O
with	O
sleep	O
and	O
dream	O
.	O

The	O
correcting	O
action	O
of	O
tropatepine	O
hydrochloride	O
upon	O
the	O
extrapyramidal	O
effects	O
induced	O
by	O
neuroleptics	O
has	O
been	O
studied	O
in	O
32	O
acute	O
psychotic	O
states	O
.	O

Epididymal	O
growth	O
was	O
retarded	O
in	O
animals	O
maintained	O
solely	O
on	O
chickpea	O
haulm	O
and	O
improved	O
with	O
supplementation	O
.	O

Two	O
patients	O
were	O
treated	O
with	O
both	O
regimens	O
.	O

Results	O
obtained	O
for	O
chloramphenicol	O
-	O
containing	O
preparations	O
are	O
presented	O
,	O
and	O
both	O
dissolution	O
curves	O
and	O
cup	O
-	O
plate	O
assays	O
demonstrate	O
that	O
chloramphenicol	O
has	O
far	O
superior	O
release	O
(	O
and	O
hence	O
activity	O
)	O
from	O
creams	O
than	O
from	O
ophthalmic	O
ointments	O
.	O

IgG	B-GENE
levels	O
of	O
1	O
/	O
100	O
were	O
present	O
in	O
only	O
four	O
out	O
of	O
ten	O
samples	O
obtained	O
150	O
days	O
after	O
the	O
clinical	O
onset	O
.	O

Letter	O
:	O
Perspectives	O
in	O
bone	O
marrow	O
transplantation	O
.	O

Assessment	O
of	O
the	O
carcinogenicity	O
of	O
non	O
-	O
nutritive	O
sweetners	O
II	O
:	O
Cyclamates	O
and	O
cyclohexylamine	O
.	O

The	O
discordant	O
behaviour	O
in	O
weakly	O
infected	O
mice	O
was	O
due	O
to	O
the	O
occurrence	O
in	O
some	O
animals	O
of	O
a	O
second	O
phase	O
of	O
more	O
rapid	O
increase	O
of	O
the	O
parasitemia	O
.	O

Residual	O
amphotericin	O
B	O
was	O
detected	O
in	O
the	O
feces	O
of	O
the	O
mice	O
only	O
while	O
they	O
were	O
receiving	O
the	O
0	O
.	O
3	O
mg	O
/	O
ml	O
dose	O
level	O
.	O

There	O
was	O
a	O
slight	O
increase	O
in	O
total	O
transferrin	B-GENE
2	O
hr	O
after	O
1	O
tablet	O
and	O
values	O
remained	O
high	O
throughout	O
the	O
experiment	O
.	O

Following	O
intravenous	O
administration	O
,	O
the	O
myocardial	O
concentration	O
of	O
tracer	O
thallium	O
-	O
201	O
,	O
potassium	O
-	O
43	O
,	O
and	O
rubidium	O
-	O
81	O
were	O
determined	O
in	O
mice	O
;	O
thallium	O
was	O
present	O
in	O
the	O
greatest	O
concentration	O
in	O
the	O
myocardium	O
(	O
2	O
.	O
08	O
%	O
compared	O
1	O
.	O
25	O
%	O
for	O
potassium	O
and	O
1	O
.	O
15	O
%	O
for	O
rubidium	O
at	O
10	O
minutes	O
)	O
.	O

Thromboplastin	B-GENE
time	O
,	O
partial	O
thromboplastin	B-GENE
time	O
,	O
thrombin	B-GENE
time	O
,	O
heat	O
-	O
dependent	O
fibrin	B-GENE
,	O
clot	O
retraction	O
,	O
and	O
clotting	B-GENE
factors	I-GENE
II	I-GENE
,	I-GENE
V	I-GENE
,	I-GENE
VIII	I-GENE
,	I-GENE
IX	I-GENE
,	I-GENE
X	I-GENE
,	O
and	O
the	O
platelet	O
count	O
were	O
determined	O
.	O

The	O
data	O
support	O
the	O
notion	O
that	O
suppression	O
of	O
images	O
during	O
binocular	O
rivalry	O
is	O
independent	O
in	O
both	O
eyes	O
.	O

Glycogen	O
utilization	O
was	O
increased	O
,	O
but	O
tissue	O
levels	O
of	O
creatine	O
phosphate	O
,	O
ATP	O
,	O
and	O
lactate	O
were	O
similar	O
to	O
those	O
in	O
hearts	O
receiving	O
normal	O
flow	O
.	O

The	O
records	O
from	O
1948	O
through	O
1967	O
of	O
344	O
previously	O
untreated	O
patients	O
with	O
squamous	O
cell	O
carcinoma	O
of	O
the	O
oral	O
cavity	O
,	O
oropharynx	O
,	O
supraglottic	O
larynx	O
and	O
hypopharynx	O
who	O
had	O
clinically	O
positive	O
cervical	O
lymph	O
node	O
metastases	O
staged	O
N1	O
,	O
N2A	O
,	O
or	O
N2B	O
,	O
and	O
whose	O
initial	O
neck	O
treatment	O
consisted	O
of	O
external	O
radiation	O
therapy	O
alone	O
were	O
reviewed	O
.	O

With	O
0	O
.	O
5	O
vol	O
.	O
-	O
%	O
,	O
the	O
corresponding	O
values	O
were	O
345	O
mumol	O
/	O
1	O
(	O
5	O
.	O
72	O
mg	O
/	O
100	O
ml	O
)	O
and	O
137	O
mumol	O
/	O
1	O
(	O
2	O
.	O
25	O
mg	O
/	O
100	O
ml	O
)	O
respectively	O
.	O

The	O
authors	O
describe	O
the	O
technique	O
of	O
transverse	O
axial	O
tomography	O
of	O
the	O
spine	O
and	O
give	O
a	O
detailed	O
description	O
of	O
the	O
axial	O
anatomy	O
of	O
the	O
normal	O
lumbar	O
spine	O
from	O
L	O
-	O
4	O
to	O
the	O
sacrum	O
.	O

Owing	O
to	O
parental	O
attitude	O
,	O
a	O
low	O
protein	O
diet	O
(	O
1	O
-	O
5	O
g	O
/	O
kg	O
)	O
was	O
introduced	O
only	O
late	O
.	O

In	O
none	O
of	O
the	O
44	O
type	O
I	O
attacks	O
and	O
29	O
type	O
II	O
attacks	O
which	O
were	O
recorded	O
did	O
circulatory	O
changes	O
;	O
the	O
latter	O
were	O
different	O
in	O
the	O
two	O
groups	O
.	O

A	O
clinically	O
useful	O
diagnostic	O
method	O
has	O
been	O
developed	O
for	O
detecting	O
and	O
quantitating	O
periods	O
of	O
apnea	O
in	O
pediatric	O
patients	O
.	O

The	O
other	O
hypoglycaemic	O
patient	O
showed	O
an	O
exaggerated	O
insulin	B-GENE
release	O
in	O
response	O
to	O
tolbutamide	O
.	O

Effect	O
of	O
ingestion	O
of	O
Norbiogest	O
during	O
the	O
quiescent	O
period	O
of	O
the	O
genital	O
organs	O

Bulbar	O
pouches	O
were	O
perfused	O
with	O
solutions	O
of	O
0	O
.	O
9	O
%	O
Na	O
C1	O
,	O
0	O
.	O
1	O
N	O
HC1	O
,	O
40	O
%	O
glucose	O
,	O
40	O
%	O
NaC1	O
,	O
and	O
40	O
%	O
peptone	O
or	O
with	O
0	O
.	O
1	O
%	O
solutions	O
of	O
acetylcholine	O
chloride	O
.	O

Liver	O
microsomes	O
of	O
the	O
shag	O
showed	O
smaller	O
than	O
8	O
%	O
of	O
the	O
epoxide	B-GENE
hydrase	I-GENE
activity	O
and	O
smaller	O
than	O
14	O
%	O
of	O
the	O
hydroxylating	O
capacity	O
of	O
liver	O
microsomes	O
from	O
the	O
rat	O
.	O

A	O
clinical	O
,	O
serological	O
and	O
prognostic	O
study	O

The	O
American	O
Burkitt	O
Lymphoma	O
Registry	O
:	O
a	O
progress	O
report	O
.	O

Vitrectomy	O
with	O
an	O
alternative	O
instrument	O
system	O
.	O

The	O
metabolic	O
clearance	O
rate	O
of	O
progesterone	O
was	O
295	O
+	O
/	O
-	O
49	O
(	O
S	O
.	O
E	O
.	O
)	O
1	O
/	O
day	O
.	O

The	O
mean	O
plasma	O
sodium	O
concentration	O
which	O
was	O
135	O
.	O
95	O
(	O
+	O
/	O
-	O
SD	O
4	O
.	O
14	O
)	O
mEq	O
/	O
kg	O
before	O
diuretic	O
treatment	O
was	O
significantly	O
decreased	O
during	O
treatment	O
to	O
129	O
.	O
19	O
(	O
+	O
/	O
-	O
SD	O
2	O
.	O
77	O
)	O
mEq	O
/	O
kg	O
,	O
P	O
less	O
than	O
0	O
.	O
001	O
.	O

Editorial	O
:	O
Low	O
-	O
dose	O
heparin	O
and	O
the	O
prevention	O
of	O
venous	O
thromboembolic	O
disease	O
.	O

Effects	O
of	O
perceptual	O
salience	O
on	O
the	O
matrix	O
task	O
performance	O
of	O
four	O
-	O
and	O
six	O
-	O
year	O
-	O
old	O
children	O
.	O

Glucose	B-GENE
-	I-GENE
6	I-GENE
-	I-GENE
phosphate	I-GENE
dehydrogenase	I-GENE
(	O
G	B-GENE
-	I-GENE
6	I-GENE
-	I-GENE
PD	I-GENE
)	O
deficiency	O
in	O
the	O
newborn	O
.	O

The	O
eluting	O
solvent	O
was	O
methanol	O
-	O
chloroform	O
(	O
10	O
+	O
90	O
)	O
at	O
a	O
flow	O
rate	O
of	O
2	O
.	O
0	O
ml	O
/	O
min	O
.	O

The	O
bronchial	O
epithelia	O
of	O
all	O
smoke	O
-	O
exposed	O
animals	O
were	O
hyperplastic	O
,	O
and	O
their	O
ultrastructure	O
showed	O
invaginations	O
,	O
tilt	O
of	O
nuclear	O
axes	O
,	O
an	O
increase	O
in	O
the	O
number	O
and	O
size	O
of	O
lysosomes	O
and	O
multivesiculated	O
bodies	O
,	O
and	O
increased	O
numbers	O
of	O
enlarged	O
intramitochondrial	O
granules	O
.	O

The	O
routine	O
administration	O
of	O
fat	O
-	O
soluble	O
vitamins	O
appears	O
unnecessary	O
but	O
it	O
is	O
prudent	O
to	O
measure	O
prothrombin	B-GENE
time	O
and	O
serum	O
vitamins	O
A	O
and	O
E	O
at	O
intervals	O
.	O

Prostaglandins	O
F	O
(	O
PGF	O
)	O
were	O
measured	O
in	O
uterine	O
vein	O
,	O
ovarian	O
artery	O
,	O
and	O
jugular	O
vein	O
plasma	O
and	O
in	O
the	O
endometrial	O
tissues	O
at	O
various	O
times	O
during	O
the	O
bovine	O
estrous	O
cycle	O
,	O
and	O
were	O
compared	O
to	O
peripheral	O
plasma	O
progesterone	O
levels	O
.	O

Before	O
this	O
date	O
,	O
the	O
drug	O
directly	O
inhibits	O
fetal	O
weight	O
gain	O
,	O
whereas	O
the	O
sensitivity	O
of	O
the	O
placenta	O
is	O
only	O
transient	O
at	O
day	O
16	O
resulting	O
in	O
maximum	O
weight	O
decrease	O
of	O
this	O
organ	O
24	O
h	O
later	O
.	O

Groups	O
of	O
ten	O
dependent	O
and	O
ten	O
saline	O
mice	O
were	O
singly	O
tested	O
in	O
both	O
light	O
and	O
dark	O
conditions	O
in	O
each	O
of	O
five	O
covered	O
cylinders	O
(	O
2	O
-	O
23	O
in	O
high	O
)	O
.	O

The	O
effects	O
initiated	O
from	O
the	O
nucleus	O
accumbens	O
septi	O
were	O
most	O
marked	O
.	O

The	O
appearance	O
of	O
dyskinetic	O
movement	O
disorders	O
in	O
humans	O
following	O
the	O
chronic	O
use	O
of	O
levodopa	O
or	O
amphetamine	O
may	O
be	O
a	O
manifestation	O
of	O
similarly	O
increased	O
dopamine	B-GENE
receptor	I-GENE
site	I-GENE
sensitivity	O
within	O
the	O
striatum	O
.	O

Association	O
with	O
HL	B-GENE
-	I-GENE
A	I-GENE
W	I-GENE
-	I-GENE
27	I-GENE
.	O

Letter	O
:	O
Lactose	O
tolerance	O
tests	O
as	O
a	O
predictor	O
of	O
milk	O
tolerance	O
.	O

Retinoblastoma	O
:	O
a	O
study	O
of	O
natural	O
history	O
and	O
prognosis	O
of	O
268	O
cases	O
.	O

Like	O
pineal	O
melatonin	O
,	O
serum	O
melatonin	O
was	O
high	O
at	O
mid	O
-	O
dark	O
and	O
low	O
at	O
mid	O
-	O
light	O
.	O

D	O
.	O

Atherosclerosis	O

The	O
authors	O
concluded	O
that	O
ultrasonic	O
Doppler	O
-	O
cardiography	O
can	O
be	O
used	O
for	O
measuring	O
the	O
relative	O
changes	O
in	O
the	O
stroke	O
volume	O
.	O

The	O
attainment	O
of	O
sexual	O
maturity	O
in	O
terms	O
of	O
secondary	O
sexual	O
characteristics	O
,	O
the	O
production	O
of	O
spermatozoa	O
in	O
the	O
male	O
,	O
and	O
the	O
cyclical	O
female	O
pattern	O
with	O
release	O
of	O
ova	O
are	O
end	O
-	O
points	O
of	O
the	O
developmental	O
process	O
.	O

Caution	O
should	O
be	O
exercised	O
in	O
the	O
use	O
of	O
these	O
dyes	O
for	O
lymphograms	O
.	O

This	O
reveals	O
a	O
new	O
test	O
for	O
short	O
saphenous	O
incompetence	O
and	O
shows	O
that	O
14	O
per	O
cent	O
of	O
varices	O
stem	O
from	O
a	O
saphenopopliteal	O
reflux	O
.	O

Three	O
groups	O
of	O
patients	O
who	O
had	O
undergone	O
subtotal	O
thyroidectomy	O
for	O
Graves	O
'	O
s	O
disease	O
,	O
toxic	O
multinodular	O
goitre	O
,	O
or	O
euthyroid	O
multinodular	O
goitre	O
12	O
to	O
15	O
years	O
before	O
and	O
in	O
whom	O
a	O
normal	O
serum	O
thyroxine	O
(	O
T	O
-	O
4	O
)	O
level	O
was	O
found	O
were	O
each	O
divided	O
into	O
two	O
subgroups	O
on	O
the	O
basis	O
of	O
a	O
normal	O
or	O
a	O
raised	O
serum	O
thyrotrophin	B-GENE
concentration	O
.	O

Routine	O
isotope	O
cystography	O
using	O
99M	O
Tc	O
sulfur	O
colloid	O
for	O
detection	O
and	O
follow	O
-	O
up	O
of	O
vesico	O
-	O
ureteral	O
reflux	O

Air	O
ion	O
action	O
on	O
bacteria	O
.	O

The	O
interpretation	O
of	O
antibiotic	O
disc	O
sensitivities	O
.	O

Following	O
retransfusion	O
,	O
the	O
affected	O
epithelial	O
lining	O
appeared	O
greatly	O
distended	O
over	O
the	O
oedematous	O
lamina	O
propria	O
,	O
with	O
almost	O
complete	O
loss	O
of	O
structural	O
detail	O
.	O

Characteristics	O
of	O
anesthesia	O
and	O
resuscitation	O
in	O
emergency	O
lung	O
surgery	O

Tobramycin	O
60	O
mg	O
did	O
not	O
show	O
any	O
remarkable	O
effect	O
,	O
but	O
dibecacin	O
100	O
mg	O
produced	O
a	O
slight	O
potentiating	O
effect	O
on	O
the	O
action	O
of	O
d	O
-	O
tubocurarine	O
.	O

In	O
about	O
one	O
third	O
of	O
the	O
cases	O
this	O
operation	O
results	O
in	O
tonal	O
and	O
vocal	O
improvement	O
for	O
patients	O
suffering	O
from	O
progressive	O
perceptive	O
deafness	O
.	O

The	O
specific	O
electrical	O
resistance	O
of	O
the	O
cerebrospinal	O
fluid	O
was	O
measured	O
by	O
means	O
of	O
conductometry	O
in	O
14	O
cases	O
of	O
meningitis	O
purulenta	O
,	O
17	O
cases	O
of	O
meningitis	O
serosa	O
,	O
10	O
cases	O
of	O
encephalitis	O
and	O
in	O
32	O
control	O
subjects	O
.	O

2	O
-	O
Chemical	O
occlusion	O
of	O
vas	O
is	O
quite	O
effective	O
in	O
producing	O
a	O
block	O
in	O
the	O
vas	O
deferens	O
of	O
dogs	O
.	O

Besides	O
,	O
we	O
found	O
in	O
3	O
patients	O
increased	O
serum	B-GENE
immunoglobulins	I-GENE
,	O
chiefly	O
IgG	B-GENE
,	O
as	O
first	O
Russe	O
,	O
Busey	O
and	O
Barbeau	O
demonstrated	O
in	O
a	O
large	O
French	O
-	O
Canadian	O
family	O
.	O

We	O
suggest	O
that	O
such	O
occlusions	O
occurred	O
at	O
the	O
time	O
of	O
the	O
infarction	O
.	O

Streptococcal	O
preparation	O
(	O
OK	O
-	O
432	O
)	O
,	O
a	O
new	O
type	O
of	O
anti	O
-	O
cancer	O
agent	O
,	O
was	O
given	O
to	O
the	O
patients	O
with	O
advanced	O
cancer	O
in	O
combination	O
with	O
Mitomycin	O
-	O
C	O
,	O
5	O
-	O
FU	O
and	O
Cytosine	O
arabinoside	O
.	O

Generally	O
,	O
a	O
correlation	O
was	O
observed	O
between	O
highest	O
concentrations	O
of	O
CSF	B-GENE
immunoglobulins	I-GENE
and	O
degree	O
of	O
meningeal	O
inflammatory	O
response	O
,	O
even	O
if	O
this	O
was	O
a	O
component	O
of	O
other	O
neurological	O
diseases	O
.	O

Experimental	O
cardiotoxicity	O
of	O
adriamycin	O

Muscular	O
pathology	O

Demonstration	O
of	O
the	O
agent	O
was	O
performed	O
from	O
the	O
6th	O
to	O
the	O
11th	O
day	O
p	O
.	O
i	O
.	O
by	O
direct	O
microscopic	O
methods	O
(	O
Stamp	O
and	O
auramine	O
staining	O
,	O
fluorescent	O
antibody	O
technique	O
)	O
;	O
the	O
Coxiella	O
content	O
was	O
determined	O
by	O
titration	O
in	O
embryonated	O
hen	O
'	O
s	O
eggs	O
.	O

The	O
patients	O
were	O
divided	O
into	O
4	O
groups	O
receiving	O
NLA	O
II	O
with	O
or	O
without	O
nalorphine	O
,	O
morphine	O
or	O
Micoren	O
.	O

The	O
alterations	O
of	O
5	O
-	O
HT	O
and	O
5	O
-	O
HIAA	O
levels	O
in	O
several	O
regions	O
of	O
the	O
brain	O
under	O
the	O
conditions	O
examined	O
may	O
indicate	O
that	O
IDPN	O
'	O
s	O
neurotoxicity	O
primarily	O
affects	O
5	O
-	O
HT	O
-	O
containing	O
neurones	O
.	O

(	O
5	O
)	O
An	O
increase	O
in	O
leukocyte	O
-	O
counts	O
occurred	O
on	O
the	O
administration	O
of	O
serum	O
obtained	O
from	O
rabbit	O
during	O
phase	O
-	O
2	O
.	O

The	O
results	O
obtained	O
tend	O
to	O
prove	O
that	O
the	O
reticuloendothelial	O
system	O
mainly	O
participated	O
in	O
beryllium	O
retention	O
.	O

The	O
calcium	O
ratio	O
(	O
mean	O
ratio	O
of	O
the	O
predicted	O
to	O
measured	O
TBCa	O
)	O
in	O
men	O
was	O
1	O
.	O
000	O
+	O
/	O
-	O
7	O
.	O
8	O
%	O
and	O
in	O
women	O
0	O
.	O
996	O
+	O
/	O
-	O
7	O
.	O
1	O
%	O
.	O

Total	O
cholesterol	O
was	O
measured	O
in	O
amniotic	O
fluids	O
collected	O
at	O
different	O
stages	O
of	O
gestation	O
.	O

Her	O
serum	O
FT3	O
concentration	O
was	O
,	O
however	O
,	O
much	O
higher	O
than	O
the	O
ranges	O
in	O
normal	O
pregnancy	O
or	O
in	O
GTD	O
patients	O
without	O
clinical	O
hyperthyroidism	O
.	O

The	O
authors	O
found	O
that	O
except	O
for	O
fear	O
and	O
pugnacity	O
all	O
husband	O
-	O
wife	O
trait	O
correlations	O
were	O
positive	O
,	O
in	O
contrast	O
to	O
Winch	O
'	O
s	O
principle	O
of	O
type	O
I	O
complementarity	O
.	O

A	O
note	O
on	O
the	O
phase	O
-	O
plane	O
technique	O
representation	O
of	O
cardiac	O
action	O
potentials	O
.	O

3	O
activities	O
of	O
the	O
factor	B-GENE
II	I-GENE
molecule	O
in	O
the	O
newborn	O
infant	O
at	O
term	O

However	O
,	O
we	O
did	O
detect	O
lot	O
-	O
to	O
-	O
lot	O
variation	O
and	O
differences	O
in	O
performance	O
between	O
narrow	O
bandpass	O
and	O
wide	O
bandpass	O
spectrophotometers	O
.	O

The	O
cochlear	O
compromise	O
.	O

A	O
case	O
observed	O
in	O
Saigon	O

Hypertonic	O
glucose	O
administered	O
intrajejunally	O
in	O
Heidenhain	O
pouch	O
dogs	O
resulted	O
in	O
an	O
equal	O
inhibition	O
of	O
pentagastrin	O
-	O
induced	O
acid	O
secretion	O
from	O
the	O
pouch	O
and	O
the	O
main	O
stomach	O
,	O
whereas	O
hypertonic	O
saline	O
had	O
no	O
effect	O
.	O

Biohydrogenation	O
of	O
linoleic	O
acid	O
into	O
octadecenoic	O
acid	O
was	O
observed	O
.	O

Chlamydial	O
agents	O
were	O
isolated	O
from	O
the	O
semen	O
near	O
the	O
end	O
of	O
the	O
chlamydemic	O
phase	O
.	O

Because	O
of	O
the	O
increased	O
CPK	B-GENE
activity	O
found	O
in	O
normal	O
newborns	O
,	O
screening	O
for	O
Duchenne	O
-	O
type	O
muscular	O
dystrophy	O
should	O
be	O
postponed	O
for	O
a	O
few	O
weeks	O
after	O
delivery	O
.	O

In	O
contrast	O
,	O
the	O
insulin	B-GENE
response	O
had	O
returned	O
to	O
the	O
non	O
-	O
pregnant	O
value	O
by	O
the	O
second	O
day	O
of	O
the	O
puerperium	O
.	O

The	O
authors	O
report	O
the	O
results	O
of	O
a	O
series	O
of	O
toxicological	O
tests	O
conducted	O
on	O
plastic	O
materials	O
(	O
polyethylene	O
)	O
activated	O
with	O
tetraphenylbutadiene	O
(	O
TPB	O
)	O
an	O
additive	O
recently	O
proposed	O
as	O
a	O
sensitizer	O
capable	O
of	O
photodegrading	O
plastic	O
materials	O
.	O

Mutational	O
analysis	O
of	O
the	O
major	O
homology	O
region	O
of	O
Mason	O
-	O
Pfizer	O
monkey	O
virus	O
by	O
use	O
of	O
saturation	O
mutagenesis	O
.	O

One	O
site	O
,	O
PAL	B-GENE
,	O
occurs	O
within	O
the	O
10	O
bp	O
sequence	O
GGGGAGGAGG	O
.	O

Nuclear	O
extracts	O
prepared	O
from	O
both	O
neural	O
and	O
non	O
-	O
neural	O
cell	O
lines	O
,	O
mouse	O
brain	O
,	O
and	O
mouse	O
liver	O
contain	O
proteins	O
that	O
recognize	O
and	O
bind	O
to	O
the	O
PROX	O
and	O
PAL	O
sequences	O
indicating	O
that	O
proteins	O
which	O
bind	O
to	O
these	O
target	O
sequences	O
are	O
widespread	O
.	O

To	O
determine	O
if	O
the	O
NF	B-GENE
(	I-GENE
H	I-GENE
)	I-GENE
promoter	I-GENE
can	O
be	O
activated	O
in	O
a	O
tissue	O
specific	O
manner	O
during	O
development	O
transgenic	O
mice	O
containing	O
the	O
promoter	O
region	O
linked	O
to	O
a	O
beta	B-GENE
-	I-GENE
galactosidase	I-GENE
reporter	I-GENE
gene	I-GENE
were	O
generated	O
.	O

Here	O
we	O
describe	O
and	O
map	O
two	O
more	O
new	O
genes	O
identified	O
as	O
allele	O
-	O
specific	O
suppressors	O
that	O
compensate	O
for	O
carboxy	O
-	O
terminal	O
truncation	O
of	O
PET122	B-GENE
.	O

Previous	O
studies	O
have	O
shown	O
[	O
Hisanaga	O
,	O
S	O
.	O
,	O
Kusubata	O
,	O
M	O
.	O
,	O
Okumura	O
,	O
E	O
.	O
&	O
Kishimoto	O
,	O
T	O
.	O

Treatment	O
and	O
staining	O
of	O
smears	O
and	O
sections	O
for	O
detection	O
of	O
microorganisms	O

The	O
apparent	O
Kd	O
of	O
the	O
MetRS	B-GENE
/	I-GENE
CAU	I-GENE
operator	I-GENE
complex	I-GENE
is	O
one	O
order	O
magnitude	O
higher	O
than	O
that	O
of	O
the	O
ThrRS	B-GENE
/	I-GENE
CGU	I-GENE
operator	I-GENE
complex	I-GENE
.	O

A	O
significant	O
direct	O
relationship	O
was	O
observed	O
between	O
the	O
percent	O
area	O
density	O
of	O
smooth	O
muscle	O
and	O
the	O
percent	O
change	O
in	O
peak	O
urinary	O
flow	O
rate	O
.	O

Rabbit	B-GENE
skeletal	I-GENE
muscle	I-GENE
glycogenin	I-GENE
.	O

Characterization	O
of	O
the	O
human	B-GENE
gene	I-GENE
encoding	I-GENE
cytokeratin	I-GENE
17	I-GENE
and	O
its	O
expression	O
pattern	O
.	O

Animals	O
that	O
received	O
DSP	O
-	O
4	O
were	O
significantly	O
retarded	O
in	O
motor	O
recovery	O
compared	O
with	O
the	O
saline	O
group	O
.	O

The	O
prophylactic	O
use	O
of	O
new	O
medication	O
for	O
patients	O
between	O
the	O
first	O
and	O
second	O
cycle	O
of	O
chemotherapy	O
,	O
in	O
agreement	O
with	O
the	O
estimates	O
calculated	O
,	O
does	O
not	O
save	O
health	O
care	O
costs	O
but	O
may	O
improve	O
the	O
quality	O
of	O
life	O
in	O
these	O
patients	O
and	O
permit	O
the	O
continuation	O
of	O
a	O
therapeutic	O
schedule	O
without	O
interruption	O
which	O
may	O
improve	O
the	O
life	O
expectancy	O
of	O
the	O
patient	O
.	O

The	O
isolation	O
of	O
this	O
gene	O
was	O
based	O
on	O
the	O
identification	O
of	O
the	O
Y	O
-	O
231	O
cosmid	O
that	O
contains	O
CpG	O
rich	O
sequences	O
(	O
HTF	O
islands	O
)	O
in	O
its	O
human	O
insert	O
.	O

Gene	O
constructs	O
consisting	O
of	O
human	B-GENE
growth	I-GENE
hormone	I-GENE
(	O
hGH	B-GENE
)	O
gene	O
driven	O
by	O
promoter	O
/	O
regulatory	O
sequence	O
of	O
mouse	B-GENE
metallothionein	I-GENE
(	O
mMT	B-GENE
)	O
,	O
viral	B-GENE
thymidine	I-GENE
kinase	I-GENE
(	O
vTK	B-GENE
)	O
,	O
rat	B-GENE
cholecystokinin	I-GENE
(	O
rCCK	B-GENE
)	O
,	O
or	O
chicken	B-GENE
beta	I-GENE
-	I-GENE
actin	I-GENE
(	O
cBA	B-GENE
)	O
gene	O
were	O
injected	O
into	O
the	O
cytoplasm	O
of	O
fertilized	O
medaka	O
eggs	O
via	O
the	O
micropyle	O
.	O

Serum	O
gastrin	B-GENE
and	O
AFP	B-GENE
levels	O
had	O
the	O
same	O
evolution	O
and	O
appear	O
to	O
have	O
the	O
same	O
interest	O
to	O
follow	O
the	O
course	O
of	O
the	O
disease	O
.	O

Prospects	O
for	O
controlled	O
-	O
delivery	O
systems	O
.	O

Though	O
hepatomegaly	O
and	O
mild	O
elevation	O
of	O
enzymes	O
can	O
be	O
observed	O
in	O
a	O
significant	O
proportion	O
of	O
patients	O
,	O
involvement	O
of	O
liver	O
leading	O
to	O
acute	O
hepatitis	O
or	O
liver	O
cell	O
necrosis	O
is	O
a	O
relatively	O
uncommon	O
complication	O
in	O
P	O
.	O
falciparum	O
malaria	O
.	O

For	O
the	O
first	O
group	O
,	O
the	O
maximal	O
decrease	O
in	O
plasma	O
potassium	O
elicited	O
by	O
salbutamol	O
was	O
0	O
.	O
80	O
+	O
/	O
-	O
0	O
.	O
19	O
,	O
0	O
.	O
48	O
+	O
/	O
-	O
0	O
.	O
22	O
,	O
and	O
0	O
.	O
78	O
+	O
/	O
-	O
0	O
.	O
46	O
mmol	O
/	O
l	O
,	O
and	O
for	O
the	O
second	O
group	O
,	O
maximal	O
decrement	O
was	O
1	O
.	O
31	O
+	O
/	O
-	O
0	O
.	O
37	O
,	O
0	O
.	O
70	O
+	O
/	O
-	O
0	O
.	O
24	O
,	O
and	O
0	O
.	O
84	O
+	O
/	O
-	O
0	O
.	O
17	O
mmol	O
/	O
l	O
for	O
the	O
iv	O
,	O
po	O
,	O
and	O
it	O
routes	O
,	O
respectively	O
.	O

A	O
statistically	O
significant	O
improvement	O
due	O
to	O
the	O
administration	O
of	O
Bromergon	O
was	O
observed	O
in	O
symptoms	O
associated	O
with	O
overreactiveness	O
to	O
normal	O
prolactin	B-GENE
levels	O
,	O
i	O
.	O
e	O
.	O
abdominal	O
tension	O
,	O
edema	O
,	O
weight	O
gain	O
and	O
breast	O
tenderness	O
.	O

The	O
magnitude	O
of	O
the	O
early	O
response	O
was	O
241	O
+	O
/	O
-	O
51	O
%	O
in	O
A	O
(	O
%	O
baseline	O
RL	O
;	O
mean	O
+	O
/	O
-	O
SE	O
)	O
,	O
and	O
significantly	O
less	O
in	O
B	O
(	O
119	O
+	O
/	O
-	O
7	O
%	O
)	O
and	O
C	O
(	O
131	O
+	O
/	O
-	O
16	O
%	O
)	O
(	O
p	O
<	O
0	O
.	O
01	O
)	O
.	O

Most	O
of	O
the	O
patients	O
presented	O
with	O
Transient	O
Ischemic	O
Attacks	O
(	O
64	O
%	O
)	O
or	O
Reversible	O
Ischemic	O
Neurologic	O
Deficits	O
(	O
19	O
%	O
)	O
.	O

This	O
analysis	O
,	O
together	O
with	O
a	O
consideration	O
of	O
the	O
SCBs	O
found	O
upstream	O
of	O
known	O
SWI4	B-GENE
,	I-GENE
6	I-GENE
-	O
dependent	O
genes	O
,	O
leads	O
to	O
the	O
proposal	O
of	O
a	O
revised	O
consensus	O
sequence	O
for	O
this	O
important	O
regulatory	O
element	O
.	O

Mutational	O
analysis	O
of	O
a	O
DNA	O
sequence	O
involved	O
in	O
linking	O
gene	O
expression	O
to	O
the	O
cell	O
cycle	O
.	O

The	O
natural	O
history	O
of	O
these	O
lesions	O
,	O
locoregional	O
efficiency	O
of	O
the	O
different	O
treatments	O
used	O
,	O
the	O
part	O
played	O
by	O
chemotherapy	O
,	O
survival	O
,	O
causes	O
of	O
death	O
and	O
therapeutic	O
modalities	O
used	O
as	O
a	O
last	O
measure	O
,	O
have	O
been	O
analysed	O
.	O

The	O
method	O
was	O
adapted	O
for	O
the	O
determination	O
of	O
nadolol	O
racemate	O
A	O
by	O
a	O
change	O
in	O
mobile	O
phase	O
composition	O
.	O

In	O
general	O
,	O
however	O
,	O
this	O
study	O
provided	O
little	O
evidence	O
of	O
any	O
effect	O
of	O
supplementation	O
to	O
athletic	O
performance	O
for	O
athletes	O
consuming	O
the	O
dietary	O
RDIs	O
.	O

In	O
7	O
of	O
9	O
cases	O
,	O
the	O
enhancer	O
is	O
fused	O
to	O
the	O
c	B-GENE
-	I-GENE
myc	I-GENE
bearing	I-GENE
sequences	I-GENE
of	O
chromosome	O
8	O
.	O

These	O
components	O
both	O
had	O
a	O
median	O
R2	O
of	O
0	O
.	O
84	O
,	O
compared	O
to	O
median	O
R2s	O
ranging	O
from	O
0	O
.	O
37	O
to	O
0	O
.	O
83	O
for	O
five	O
commonly	O
used	O
ad	O
hoc	O
EEG	O
components	O
.	O

The	O
obtained	O
results	O
were	O
compared	O
with	O
control	O
group	O
(	O
10	O
female	O
volunteers	O
)	O
.	O

100	O
years	O
of	O
dentistry	O
at	O
the	O
Friedrich	O
Schiller	O
University	O
in	O
Jena	O

The	O
target	O
contained	O
between	O
positions	O
-	O
403	O
and	O
-	O
125	O
acts	O
independently	O
of	O
orientation	O
,	O
in	O
different	O
cell	O
types	O
and	O
species	O
,	O
and	O
in	O
the	O
context	O
of	O
a	O
heterologous	O
promoter	O
.	O

Synergistic	O
transactivation	O
of	O
the	O
BMRF1	B-GENE
promoter	I-GENE
by	O
the	O
Z	B-GENE
/	O
c	B-GENE
-	I-GENE
myb	I-GENE
combination	O
appears	O
to	O
involve	O
direct	O
binding	O
by	O
the	O
Z	B-GENE
protein	I-GENE
but	O
not	O
the	O
c	B-GENE
-	I-GENE
myb	I-GENE
protein	I-GENE
.	O

The	O
UCR	O
core	O
sequence	O
,	O
CGCCATTTT	O
,	O
binds	O
a	O
ubiquitous	O
nuclear	O
factor	O
and	O
mediates	O
negative	O
regulation	O
of	O
MuLV	O
promoter	O
activity	O
.	O

These	O
studies	O
show	O
that	O
UCRBP	B-GENE
binds	O
to	O
various	O
target	O
motifs	O
that	O
are	O
distinct	O
from	O
the	O
UCR	O
motif	O
:	O
the	O
adeno	B-GENE
-	I-GENE
associated	I-GENE
virus	I-GENE
P5	I-GENE
promoter	I-GENE
and	O
elements	O
in	O
the	O
immunoglobulin	B-GENE
light	I-GENE
-	I-GENE
and	I-GENE
heavy	I-GENE
-	I-GENE
chain	I-GENE
genes	O
,	O
as	O
well	O
as	O
elements	O
in	O
ribosomal	B-GENE
protein	I-GENE
genes	I-GENE
.	O

The	O
cellular	O
sequences	O
5	O
'	O
to	O
the	O
viral	O
integration	O
site	O
exhibited	O
85	O
to	O
97	O
%	O
identity	O
to	O
several	O
sequences	O
belonging	O
to	O
the	O
mouse	B-GENE
L1	I-GENE
family	I-GENE
of	O
long	O
interspersed	O
repetitive	O
sequences	O
.	O

These	O
results	O
indicate	O
that	O
both	O
N	O
-	O
and	O
C	O
-	O
terminal	O
mutations	O
are	O
required	O
to	O
inhibit	O
transrepression	O
by	O
FBR	B-GENE
protein	I-GENE
and	O
that	O
multiple	O
structural	O
mutations	O
accompanied	O
by	O
posttranslational	O
protein	O
modification	O
alter	O
gene	O
regulation	O
by	O
FBR	B-GENE
protein	I-GENE
.	O

The	O
JS78	O
mutation	O
changes	O
Gln243	O
in	O
gp0	O
.	O
7	O
to	O
an	O
amber	O
codon	O
,	O
which	O
explains	O
the	O
production	O
of	O
the	O
truncated	O
,	O
30	B-GENE
-	I-GENE
kDa	I-GENE
gp0	I-GENE
.	I-GENE
7	I-GENE
-	I-GENE
related	I-GENE
polypeptide	I-GENE
,	O
and	O
implicates	O
the	O
11	O
-	O
kDa	O
C	O
-	O
terminal	O
domain	O
in	O
host	O
transcription	O
shut	O
-	O
off	O
.	O

The	O
predicted	O
receptor	O
structure	O
includes	O
a	O
cysteine	O
-	O
rich	O
extracellular	O
domain	O
,	O
a	O
single	O
hydrophobic	O
transmembrane	O
domain	O
,	O
and	O
a	O
predicted	O
cytoplasmic	B-GENE
serine	I-GENE
/	I-GENE
threonine	I-GENE
kinase	I-GENE
domain	I-GENE
.	O

Drosophila	B-GENE
UbcD1	I-GENE
encodes	O
a	O
highly	O
conserved	O
ubiquitin	B-GENE
-	O
conjugating	O
enzyme	O
involved	O
in	O
selective	O
protein	O
degradation	O
.	O

Analysis	O
of	O
the	O
entire	O
16	O
.	O
7	O
-	O
kb	O
mt	O
genome	O
determined	O
that	O
a	O
MDP1	B-GENE
mediates	O
cleavage	O
of	O
chick	O
mtDNA	O
in	O
vitro	O
at	O
three	O
H	O
-	O
and	O
two	O
L	O
-	O
strand	O
sequence	O
-	O
specific	O
target	O
sites	O
located	O
within	O
a	O
90	O
-	O
bp	O
A	O
+	O
T	O
-	O
rich	O
genomic	O
tract	O
,	O
theoretically	O
capable	O
of	O
forming	O
stable	O
secondary	O
structures	O
,	O
approximately	O
200	O
bases	O
upstream	O
from	O
the	O
H	O
-	O
strand	O
origin	O
(	O
OH	O
)	O
of	O
replication	O
.	O

The	O
goal	O
of	O
the	O
present	O
study	O
was	O
to	O
determine	O
the	O
feasibility	O
of	O
retrovirus	O
mediated	O
expression	O
of	O
rp47phox	B-GENE
in	O
the	O
HL60	O
and	O
U937	O
human	O
hematopoietic	O
cell	O
lines	O
,	O
and	O
in	O
an	O
Epstein	O
-	O
Barr	O
virus	O
transformed	O
B	O
-	O
lymphocyte	O
cell	O
line	O
(	O
EBV	O
-	O
BCL	O
)	O
derived	O
from	O
a	O
p47phox	B-GENE
-	O
deficient	O
CGD	O
patient	O
.	O

A	O
rather	O
similar	O
pattern	O
of	O
results	O
was	O
obtained	O
with	O
respect	O
to	O
LMP2B	B-GENE
mRNA	I-GENE
expression	O
,	O
such	O
transcripts	O
being	O
detectable	O
only	O
in	O
a	O
subset	O
of	O
tumors	O
,	O
and	O
then	O
at	O
apparently	O
low	O
levels	O
.	O

Analysis	O
of	O
nucleotide	O
sequence	O
of	O
the	O
rightmost	O
43	O
kbp	O
of	O
herpesvirus	O
saimiri	O
(	O
HVS	O
)	O
L	O
-	O
DNA	O
:	O
general	O
conservation	O
of	O
genetic	O
organization	O
between	O
HVS	O
and	O
Epstein	O
-	O
Barr	O
virus	O
.	O

Treatment	O
with	O
MK	O
-	O
801	O
induced	O
a	O
burst	O
suppression	O
in	O
the	O
EEG	O
and	O
a	O
transient	O
drop	O
(	O
11	O
.	O
4	O
+	O
/	O
-	O
6	O
.	O
5	O
mm	O
Hg	O
)	O
in	O
the	O
mean	O
arterial	O
pressure	O
.	O

Myogenic	O
differentiation	O
can	O
be	O
inhibited	O
by	O
the	O
adenovirus	O
E1a	B-GENE
protein	I-GENE
in	O
the	O
rat	O
L6	O
muscle	O
cell	O
line	O
.	O

Acad	O
.	O

Both	O
in	O
vitro	O
-	O
synthesized	O
S2	B-GENE
protein	I-GENE
and	O
synthetic	O
peptides	O
corresponding	O
to	O
S2	B-GENE
are	O
shown	O
to	O
react	O
positively	O
with	O
sera	O
obtained	O
from	O
EIAV	O
-	O
infected	O
horses	O
,	O
providing	O
the	O
first	O
direct	O
evidence	O
of	O
expression	O
of	O
this	O
protein	O
in	O
infected	O
animals	O
.	O

Many	O
canonical	O
TATA	O
sequences	O
are	O
present	O
upstream	O
from	O
these	O
VZV	O
transcriptional	O
start	O
sites	O
but	O
,	O
apparently	O
,	O
are	O
not	O
used	O
.	O

The	O
ORF	O
4	O
gene	O
was	O
minimally	O
active	O
,	O
whereas	O
the	O
ORF	O
62	O
gene	O
gave	O
twofold	O
induction	O
;	O
both	O
genes	O
,	O
acting	O
together	O
,	O
gave	O
fivefold	O
induction	O
.	O

Interestingly	O
,	O
the	O
IR5	B-GENE
ORF	I-GENE
of	O
EHV	O
-	O
1	O
possesses	O
a	O
sequence	O
of	O
13	O
amino	O
acids	O
(	O
CAYWCCLGHAFAC	O
)	O
that	O
is	O
a	O
perfect	O
match	O
to	O
the	O
consensus	O
zinc	O
finger	O
motif	O
(	O
C	O
-	O
X2	O
-	O
4	O
-	O
C	O
-	O
X2	O
-	O
15	O
-	O
C	O
/	O
H	O
-	O
X2	O
-	O
4	O
-	O
C	O
/	O
H	O
)	O
.	O

The	O
DNA	O
sequence	O
of	O
the	O
sulfate	B-GENE
activation	I-GENE
locus	I-GENE
from	O
Escherichia	O
coli	O
K	O
-	O
12	O
has	O
been	O
determined	O
.	O

Plasma	O
membranes	O
of	O
cultured	O
cells	O
contain	O
high	O
affinity	O
receptors	O
for	O
high	B-GENE
density	I-GENE
lipoprotein	I-GENE
(	O
HDL	B-GENE
)	O
that	O
appear	O
to	O
mediate	O
removal	O
of	O
excess	O
intracellular	O
cholesterol	O
.	O

After	O
the	O
first	O
28	O
patients	O
vincristine	O
was	O
replaced	O
by	O
teniposide	O
(	O
VM	O
-	O
26	O
)	O
due	O
to	O
neurotoxicity	O
.	O

These	O
results	O
indicate	O
that	O
an	O
internal	O
short	O
element	O
located	O
at	O
the	O
very	O
5	O
'	O
terminal	O
of	O
L1	B-GENE
sequence	I-GENE
and	O
the	O
nuclear	O
factor	O
binding	O
to	O
the	O
element	O
play	O
a	O
crucial	O
role	O
in	O
the	O
transcription	O
of	O
human	B-GENE
L1	I-GENE
.	O

Tumor	O
cells	O
were	O
focally	O
immunoreactive	O
for	O
neuron	B-GENE
-	I-GENE
specific	I-GENE
enolase	I-GENE
,	O
insulin	B-GENE
,	O
glucagon	B-GENE
and	O
VIP	B-GENE
.	O

A	O
recombinant	O
with	O
a	O
5	O
'	O
end	O
from	O
src	B-GENE
and	O
a	O
3	O
'	O
end	O
from	O
ros	B-GENE
,	O
called	O
SRC	B-GENE
x	O
ROS	B-GENE
,	O
transformed	O
chicken	O
embryo	O
fibroblasts	O
(	O
CEF	O
)	O
to	O
a	O
spindle	O
shape	O
morphology	O
,	O
mimicking	O
that	O
of	O
UR2	B-GENE
.	O

ROS	B-GENE
x	O
SRC	B-GENE
(	O
R	B-GENE
)	O
contains	O
a	O
16	O
-	O
amino	O
-	O
acid	O
deletion	O
that	O
includes	O
the	O
3	O
'	O
half	O
of	O
the	O
transmembrane	O
domain	O
of	O
ros	B-GENE
.	O

To	O
define	O
the	O
number	O
and	O
nature	O
of	O
the	O
E6	B-GENE
and	O
E7	B-GENE
gene	I-GENE
products	O
expressed	O
in	O
BPV	O
-	O
1	O
-	O
transformed	O
cells	O
,	O
we	O
performed	O
immunoprecipitation	O
experiments	O
with	O
antisera	O
raised	O
to	O
bacterially	O
expressed	O
BPV	B-GENE
-	I-GENE
1	I-GENE
E6	I-GENE
and	O
E7	B-GENE
fusion	I-GENE
proteins	I-GENE
.	O

Transient	O
transfection	O
assays	O
showed	O
that	O
site	O
A	O
is	O
necessary	O
and	O
sufficient	O
for	O
RXR	B-GENE
alpha	I-GENE
-	O
mediated	O
transactivation	O
of	O
the	O
apoAI	B-GENE
gene	I-GENE
basal	I-GENE
promoter	I-GENE
in	O
human	O
hepatoma	O
HepG2	O
cells	O
in	O
the	O
presence	O
of	O
RA	O
and	O
that	O
this	O
transactivation	O
is	O
abolished	O
by	O
increasing	O
amounts	O
of	O
cotransfected	O
ARP	B-GENE
-	I-GENE
1	I-GENE
.	O

A	O
third	O
prominent	O
component	O
of	O
apparent	O
molecular	O
mass	O
16	O
kDa	O
displayed	O
several	O
properties	O
,	O
including	O
ability	O
to	O
bind	O
45Ca2	O
+	O
,	O
that	O
are	O
characteristic	O
of	O
the	O
regulatory	O
(	O
B	O
)	O
subunit	O
of	O
mammalian	B-GENE
calcineurin	I-GENE
and	O
was	O
recognized	O
by	O
an	O
antiserum	O
raised	O
against	O
bovine	B-GENE
calcineurin	I-GENE
.	O

As	O
was	O
observed	O
previously	O
for	O
MATa	B-GENE
cna1	B-GENE
cna2	B-GENE
double	O
mutants	O
,	O
MATa	B-GENE
cnb1	B-GENE
mutants	I-GENE
were	O
defective	O
in	O
their	O
ability	O
to	O
recover	O
from	O
alpha	B-GENE
-	I-GENE
factor	I-GENE
-	O
induced	O
growth	O
arrest	O
.	O

Antibodies	O
against	O
this	O
purified	O
protein	O
localize	O
RIM1	B-GENE
to	O
mitochondria	O
.	O

METHODS	O
:	O
IgG	B-GENE
antibodies	I-GENE
vs	O
HHV	O
-	O
6	O
(	O
anti	B-GENE
-	I-GENE
HHV	I-GENE
-	I-GENE
6	I-GENE
-	I-GENE
IgG	I-GENE
)	O
were	O
determined	O
by	O
indirect	O
immunofluorescence	O
in	O
100	O
IVDA	O
(	O
29	O
seronegative	O
and	O
71	O
seropositive	O
for	O
HIV	O
-	O
1	O
of	O
which	O
45	O
were	O
in	O
stage	O
II	O
and	O
26	O
in	O
IV	O
-	O
C1	O
of	O
CDC	O
)	O
as	O
well	O
as	O
in	O
100	O
healthy	O
subjects	O
of	O
a	O
similar	O
age	O
(	O
control	O
group	O
)	O
.	O

A	O
position	O
-	O
independent	O
activation	O
domain	O
which	O
contained	O
conserved	O
regions	O
II	O
and	O
III	O
was	O
identified	O
at	O
the	O
carboxyl	O
terminus	O
of	O
the	O
HNF	B-GENE
-	I-GENE
3	I-GENE
beta	I-GENE
protein	I-GENE
(	O
amino	O
acids	O
361	O
to	O
458	O
)	O
.	O

HNF	B-GENE
-	I-GENE
3	I-GENE
beta	I-GENE
amino	I-GENE
-	I-GENE
terminal	I-GENE
sequences	I-GENE
defined	O
by	O
conserved	O
region	O
IV	O
also	O
contributed	O
to	O
transactivation	O
,	O
but	O
region	O
IV	O
activity	O
required	O
the	O
participation	O
of	O
the	O
region	O
II	O
-	O
III	O
domain	O
.	O

Possible	O
roles	O
of	O
RAD5	B-GENE
putative	O
ATPase	B-GENE
/	O
DNA	B-GENE
helicase	I-GENE
activity	O
in	O
DNA	O
repair	O
and	O
in	O
the	O
maintenance	O
of	O
wild	O
-	O
type	O
rates	O
of	O
instability	O
of	O
simple	O
repetitive	O
sequences	O
are	O
discussed	O
.	O

Susceptibilities	O
of	O
540	O
anaerobic	O
gram	O
-	O
negative	O
bacilli	O
to	O
amoxicillin	O
,	O
amoxicillin	O
-	O
BRL	O
42715	O
,	O
amoxicillin	O
-	O
clavulanate	O
,	O
temafloxacin	O
,	O
and	O
clindamycin	O
.	O

Nocodazole	O
arrest	O
of	O
DU249	O
cells	O
was	O
exploited	O
for	O
the	O
detection	O
of	O
an	O
M	O
-	O
phase	O
-	O
activated	O
MBP	B-GENE
kinase	I-GENE
that	O
was	O
resolved	O
from	O
p41	B-GENE
MAP	I-GENE
kinase	I-GENE
by	O
phenyl	O
-	O
Superose	O
chromatography	O
.	O

The	O
hit1	B-GENE
-	I-GENE
1	I-GENE
mutation	O
caused	O
a	O
defect	O
in	O
synthesis	O
of	O
a	O
74	B-GENE
-	I-GENE
kD	I-GENE
heat	I-GENE
shock	I-GENE
protein	I-GENE
.	O

The	O
319	O
base	O
pair	O
region	O
immediately	O
upstream	O
of	O
the	O
CAP	O
site	O
is	O
characterized	O
by	O
the	O
lack	O
of	O
a	O
proximal	O
TATA	O
box	O
and	O
the	O
presence	O
of	O
sequences	O
similar	O
to	O
GC	O
boxes	O
,	O
CACCC	O
boxes	O
,	O
CCAAT	O
boxes	O
,	O
activator	B-GENE
protein	I-GENE
2	I-GENE
(	O
Ap	B-GENE
-	I-GENE
2	I-GENE
)	O
sites	O
,	O
partial	O
glucocorticoid	O
response	O
elements	O
(	O
GREs	O
)	O
,	O
and	O
partial	O
cyclic	O
AMP	O
response	O
elements	O
(	O
CREs	O
)	O
.	O

In	O
rats	O
anaesthetized	O
with	O
+	O
-	O
chloralose	O
the	O
changes	O
in	O
extracellular	O
pH	O
and	O
K	O
+	O
in	O
spinal	O
cord	O
dorsal	O
horn	O
were	O
studied	O
using	O
pH	O
and	O
K	O
+	O
ion	O
-	O
selective	O
electrodes	O
.	O

Replication	O
of	O
bovine	O
papillomavirus	O
-	O
1	O
(	O
BPV	O
-	O
1	O
)	O
DNA	O
requires	O
two	O
viral	O
gene	O
products	O
,	O
the	O
E1	B-GENE
protein	I-GENE
and	O
the	O
full	B-GENE
-	I-GENE
length	I-GENE
E2	I-GENE
protein	I-GENE
.	O

Insertional	O
inactivation	O
of	O
sms	B-GENE
led	O
to	O
increased	O
sensitivity	O
to	O
the	O
alkylating	O
agent	O
methylmethane	O
sulfonate	O
,	O
but	O
not	O
to	O
a	O
requirement	O
for	O
serine	O
or	O
other	O
metabolites	O
.	O

These	O
findings	O
suggest	O
that	O
the	O
MAP	B-GENE
kinase	I-GENE
activator	I-GENE
/	O
MAP	B-GENE
kinase	I-GENE
system	O
may	O
be	O
the	O
downstream	O
components	O
of	O
ras	B-GENE
signal	O
transduction	O
pathways	O
.	O

NSCL	B-GENE
-	I-GENE
1	I-GENE
is	O
expressed	O
in	O
a	O
larger	O
number	O
of	O
these	O
cell	O
lines	O
.	O

Labile	O
LTR	B-GENE
-	I-GENE
binding	I-GENE
proteins	I-GENE
appear	O
to	O
be	O
essential	O
for	O
c	B-GENE
-	I-GENE
myc	I-GENE
hyperexpression	O
,	O
since	O
both	O
LTR	O
-	O
enhanced	O
transcription	O
and	O
the	O
activities	O
of	O
LTR	B-GENE
-	I-GENE
binding	I-GENE
proteins	I-GENE
are	O
specifically	O
decreased	O
after	O
inhibition	O
of	O
protein	O
synthesis	O
(	O
A	O
.	O

Ruddell	O
,	O
M	O
.	O

A	O
single	O
MEF	B-GENE
-	I-GENE
2	I-GENE
site	I-GENE
is	O
a	O
major	O
positive	O
regulatory	O
element	O
required	O
for	O
transcription	O
of	O
the	O
muscle	O
-	O
specific	O
subunit	O
of	O
the	O
human	B-GENE
phosphoglycerate	I-GENE
mutase	I-GENE
gene	I-GENE
in	O
skeletal	O
and	O
cardiac	O
muscle	O
cells	O
.	O

Truncation	O
variants	O
of	O
peptides	O
isolated	O
from	O
MHC	B-GENE
class	I-GENE
II	I-GENE
molecules	I-GENE
suggest	O
sequence	O
motifs	O
.	O

Although	O
the	O
E	O
-	O
box	O
consensus	O
is	O
minimally	O
defined	O
as	O
CANNTG	O
,	O
the	O
adjacent	O
nucleotides	O
of	O
functional	O
E	O
-	O
boxes	O
are	O
variable	O
for	O
genes	O
regulated	O
by	O
the	O
bHLH	B-GENE
proteins	I-GENE
.	O

Intermediate	O
levels	O
of	O
gene	O
activity	O
were	O
observed	O
for	O
TnI	B-GENE
enhancers	I-GENE
containing	O
E	O
-	O
boxes	O
derived	O
from	O
the	O
MCK	B-GENE
left	I-GENE
E	I-GENE
-	I-GENE
box	I-GENE
site	I-GENE
or	O
from	O
the	O
Ig	B-GENE
kappa	I-GENE
E2	I-GENE
E	I-GENE
-	I-GENE
box	I-GENE
.	O

T	B-GENE
-	I-GENE
cell	I-GENE
receptor	I-GENE
beta	I-GENE
(	O
TCR	B-GENE
beta	I-GENE
)	O
gene	O
rearrangements	O
occur	O
in	O
a	O
third	O
of	O
early	O
B	O
-	O
cell	O
acute	O
lymphoblastic	O
leukemias	O
(	O
ALLs	O
)	O
.	O

The	O
CANNTG	O
motifs	O
were	O
found	O
to	O
bind	O
MyoD	B-GENE
and	O
myogenin	B-GENE
fusion	I-GENE
proteins	I-GENE
and	O
to	O
interact	O
with	O
proteins	O
in	O
nuclear	O
extracts	O
from	O
cultured	O
myotubes	O
.	O

Peripheral	O
polyneuropathy	O
associated	O
with	O
multiple	O
myeloma	O
.	O

We	O
have	O
cloned	O
and	O
sequenced	O
COX12	B-GENE
,	O
the	O
nuclear	O
gene	O
for	O
subunit	B-GENE
VIb	I-GENE
of	O
Saccharomyces	B-GENE
cerevisiae	I-GENE
cytochrome	I-GENE
c	I-GENE
oxidase	I-GENE
.	O

The	O
structure	O
of	O
the	O
calcineurin	B-GENE
A	I-GENE
gene	I-GENE
was	O
determined	O
by	O
comparison	O
of	O
the	O
genomic	O
and	O
cDNA	O
sequences	O
.	O

The	O
basal	O
promoter	O
elements	O
of	O
murine	B-GENE
cytochrome	I-GENE
c	I-GENE
oxidase	I-GENE
subunit	I-GENE
IV	I-GENE
gene	I-GENE
consist	O
of	O
tandemly	O
duplicated	O
ets	B-GENE
motifs	O
that	O
bind	O
to	O
GABP	B-GENE
-	I-GENE
related	I-GENE
transcription	I-GENE
factors	I-GENE
.	O

Lastly	O
,	O
there	O
are	O
multiple	O
instances	O
in	O
which	O
short	O
oligonucleotide	O
direct	O
repeats	O
flank	O
a	O
region	O
absent	O
from	O
either	O
variola	O
or	O
vaccinia	O
virus	O
.	O

Here	O
we	O
show	O
that	O
short	O
synthetic	O
peptides	O
containing	O
the	O
pRB	B-GENE
-	I-GENE
binding	I-GENE
sequences	I-GENE
of	O
E1A	B-GENE
are	O
sufficient	O
for	O
interaction	O
with	O
p107	B-GENE
,	O
cyclin	B-GENE
A	I-GENE
,	O
and	O
p130	B-GENE
.	O

These	O
mutants	O
grow	O
normally	O
in	O
3T6	O
mouse	O
fibroblast	O
cells	O
,	O
and	O
they	O
do	O
not	O
complement	O
the	O
wild	O
-	O
type	O
virus	O
in	O
coinfection	O
experiments	O
of	O
C2	O
myoblasts	O
.	O

The	O
MICs	O
of	O
this	O
compound	O
against	O
90	O
%	O
of	O
these	O
organisms	O
,	O
except	O
for	O
methicillin	O
-	O
resistant	O
S	O
.	O
aureus	O
,	O
ranged	O
from	O
less	O
than	O
or	O
equal	O
to	O
0	O
.	O
006	O
to	O
3	O
.	O
13	O
micrograms	O
/	O
ml	O
.	O

The	O
minimal	O
promoter	O
of	O
the	O
RII	B-GENE
beta	I-GENE
gene	I-GENE
was	O
composed	O
of	O
two	O
adjacent	O
functional	O
elements	O
.	O

Mapping	O
the	O
cAMP	B-GENE
receptor	I-GENE
protein	I-GENE
contact	I-GENE
site	I-GENE
on	O
the	O
alpha	O
subunit	O
of	O
Escherichia	B-GENE
coli	I-GENE
RNA	I-GENE
polymerase	I-GENE
.	O

Here	O
we	O
show	O
that	O
epidermal	B-GENE
growth	I-GENE
factor	I-GENE
or	O
platelet	B-GENE
-	I-GENE
derived	I-GENE
growth	I-GENE
factor	I-GENE
stimulation	O
of	O
intact	O
human	O
or	O
murine	O
cells	O
leads	O
to	O
phosphorylation	O
of	O
Nck	B-GENE
protein	I-GENE
on	O
tyrosine	O
,	O
serine	O
,	O
and	O
threonine	O
residues	O
.	O

A	O
major	O
mechanism	O
whereby	O
steroid	B-GENE
hydroxylase	I-GENE
gene	I-GENE
transcription	O
is	O
regulated	O
in	O
the	O
adrenal	O
cortex	O
requires	O
the	O
pituitary	O
peptide	O
hormone	O
,	O
ACTH	B-GENE
,	O
which	O
acts	O
via	O
cAMP	O
.	O

A	O
combination	O
of	O
comparative	O
sequence	O
analysis	O
and	O
thermodynamic	O
methods	O
reveals	O
the	O
conservation	O
of	O
tertiary	O
structure	O
elements	O
in	O
the	O
5	O
'	O
untranslated	O
region	O
(	O
UTR	O
)	O
of	O
human	O
enteroviruses	O
and	O
rhinoviruses	O
.	O

Km	O
and	O
Vmax	O
for	O
two	O
substrates	O
,	O
src	B-GENE
-	I-GENE
related	I-GENE
peptide	I-GENE
and	O
poly	O
(	O
Glu	O
,	O
Tyr	O
)	O
(	O
4	O
:	O
1	O
)	O
,	O
were	O
2	O
.	O
4	O
mM	O
and	O
2	O
.	O
5	O
mumol	O
min	O
-	O
1	O
mg	O
-	O
1	O
and	O
0	O
.	O
26	O
mM	O
and	O
1	O
.	O
2	O
mumol	O
min	O
-	O
1	O
mg	O
-	O
1	O
,	O
respectively	O
.	O

Strategies	O
for	O
blood	O
screening	O
for	O
the	O
hepatitis	O
C	O
virus	O
and	O
for	O
the	O
human	O
immunodeficiency	O
virus	O
in	O
high	O
risk	O
groups	O
.	O

Comparison	O
of	O
data	O
obtained	O
with	O
the	O
results	O
of	O
chronic	O
treatment	O
with	O
the	O
opioid	O
antagonist	O
permits	O
to	O
conclude	O
that	O
the	O
chronic	O
blockade	O
increases	O
the	O
fatiguability	O
to	O
a	O
great	O
extent	O
than	O
chronic	O
activation	O
of	O
opioid	O
system	O
.	O

Laboratory	O
studies	O
using	O
Ca45	O
labeled	O
teeth	O
and	O
biologically	O
stained	O
teeth	O
confirmed	O
that	O
the	O
dentifrice	O
did	O
not	O
decalcify	O
enamel	O
or	O
bleach	O
teeth	O
.	O

Structure	O
and	O
expression	O
of	O
a	O
gene	O
from	O
Arabidopsis	O
thaliana	O
encoding	O
a	O
protein	O
related	O
to	O
SNF1	B-GENE
protein	O
kinase	O
.	O

We	O
have	O
cloned	O
and	O
characterized	O
a	O
55	O
-	O
kb	O
region	O
of	O
DNA	O
surrounding	O
HRAS1	B-GENE
.	O

The	O
ORF1	O
protein	O
was	O
found	O
to	O
be	O
highly	O
homologous	O
to	O
the	O
putative	O
potexvirus	B-GENE
RNA	I-GENE
replicases	I-GENE
;	O
ORF2	O
,	O
-	O
3	O
,	O
-	O
5	O
and	O
-	O
6	O
proteins	O
also	O
have	O
analogues	O
among	O
the	O
potex	O
-	O
and	O
/	O
or	O
carlavirus	O
-	O
encoded	O
proteins	O
.	O

A	O
total	O
of	O
281	O
patients	O
were	O
divided	O
into	O
groups	O
according	O
to	O
their	O
clinical	O
diagnosis	O
and	O
were	O
examined	O
using	O
capnography	O
,	O
spirometry	O
and	O
blood	O
-	O
gas	O
analysis	O
.	O

The	O
relationships	O
between	O
the	O
partial	O
pressures	O
of	O
O2	O
and	O
CO2	O
as	O
well	O
as	O
between	O
their	O
gradients	O
,	O
become	O
stronger	O
with	O
the	O
increase	O
of	O
the	O
ventilation	O
-	O
perfusion	O
ratio	O
.	O

No	O
significant	O
correlations	O
of	O
peak	O
VO2	O
were	O
observed	O
between	O
the	O
3	O
tests	O
.	O

An	O
RNA	B-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
gene	I-GENE
(	O
rbp1	B-GENE
)	O
from	O
Drosophila	O
melanogaster	O
,	O
encoding	O
an	O
RNA	O
recognition	O
motif	O
and	O
an	O
Arg	O
-	O
Ser	O
rich	O
(	O
RS	O
)	O
domain	O
,	O
has	O
been	O
characterized	O
.	O

A	O
comparative	O
study	O
of	O
the	O
total	O
protein	O
profiles	O
of	O
wild	O
-	O
type	O
S	O
.	O
entomophila	O
UC9	O
and	O
mutant	O
UC21	O
revealed	O
that	O
the	O
mutant	O
lacked	O
an	O
approximately	O
44	O
-	O
kDa	O
protein	O
and	O
overexpressed	O
an	O
approximately	O
20	O
-	O
kDa	O
protein	O
.	O

Characterization	O
of	O
the	O
regulon	O
controlled	O
by	O
the	O
leucine	B-GENE
-	I-GENE
responsive	I-GENE
regulatory	I-GENE
protein	I-GENE
in	O
Escherichia	O
coli	O
.	O

Mapping	O
of	O
the	O
mouse	B-GENE
ornithine	I-GENE
decarboxylase	I-GENE
-	I-GENE
related	I-GENE
sequence	I-GENE
family	I-GENE
.	O

This	O
mutation	O
also	O
results	O
in	O
markedly	O
decreased	O
levels	O
of	O
CAD	B-GENE
mRNA	I-GENE
and	O
protein	O
in	O
the	O
mutant	O
.	O

Mutational	O
studies	O
revealed	O
that	O
it	O
was	O
the	O
homeodomain	B-GENE
binding	I-GENE
site	I-GENE
II	I-GENE
sequence	I-GENE
that	O
was	O
required	O
for	O
this	O
regulation	O
.	O

Thus	O
,	O
the	O
pol	B-GENE
alpha	I-GENE
-	O
primase	B-GENE
complex	O
appears	O
to	O
act	O
processively	O
for	O
only	O
a	O
short	O
distance	O
.	O

Interestingly	O
,	O
the	O
positions	O
of	O
these	O
introns	O
have	O
been	O
conserved	O
in	O
comparison	O
with	O
the	O
genes	O
of	O
two	O
other	O
transglutaminase	O
-	O
like	O
activities	O
described	O
in	O
the	O
literature	O
,	O
but	O
the	O
TGM1	B-GENE
gene	I-GENE
is	O
by	O
far	O
the	O
smallest	O
characterized	O
to	O
date	O
because	O
its	O
introns	O
are	O
relatively	O
smaller	O
.	O

In	O
a	O
retrospective	O
analysis	O
of	O
data	O
from	O
35	O
cases	O
with	O
malignant	O
lymphoma	O
from	O
a	O
cohort	O
of	O
2017	O
HIV	O
-	O
infected	O
patients	O
,	O
the	O
stage	O
of	O
HIV	O
-	O
disease	O
,	O
the	O
CD4	B-GENE
counts	O
at	O
the	O
time	O
of	O
diagnosis	O
,	O
and	O
the	O
use	O
of	O
antineoplastic	O
agents	O
or	O
radiotherapy	O
were	O
correlated	O
with	O
outcome	O
.	O

1	O
.	O

Effects	O
of	O
dioxins	O
on	O
thyroid	O
function	O
in	O
newborn	O
babies	O
.	O

cDNA	O
clones	O
encoding	O
Arabidopsis	O
thaliana	O
and	O
Zea	B-GENE
mays	I-GENE
mitochondrial	I-GENE
chaperonin	I-GENE
HSP60	B-GENE
and	O
gene	O
expression	O
during	O
seed	O
germination	O
and	O
heat	O
shock	O
.	O

The	O
single	O
site	O
of	O
glycosylation	O
is	O
located	O
near	O
the	O
C	O
-	O
terminus	O
in	O
the	O
N	O
-	O
glycosylation	O
sequon	O
-	O
Asn	O
-	O
Cys	O
-	O
Ser	O
-	O
in	O
which	O
Cys	O
forms	O
part	O
of	O
a	O
disulphide	O
bridge	O
.	O

The	O
pulmonary	O
toxic	O
events	O
induced	O
by	O
acute	O
nitrogen	O
dioxide	O
(	O
NO	O
)	O
2	O
exposure	O
were	O
studied	O
in	O
the	O
rat	O
to	O
develop	O
an	O
inhalation	O
model	O
to	O
investigate	O
therapeutic	O
measures	O
.	O

The	O
pulmonary	O
effects	O
observed	O
,	O
became	O
more	O
pronounced	O
with	O
increasing	O
NO2	O
concentrations	O
(	O
0	O
,	O
25	O
,	O
75	O
,	O
125	O
,	O
175	O
or	O
200	O
ppm	O
,	O
1	O
ppm	O
NO2	O
=	O
1	O
.	O
88	O
mg	O
m	O
-	O
3	O
NO2	O
)	O
and	O
exposure	O
times	O
(	O
5	O
,	O
10	O
,	O
20	O
or	O
30	O
min	O
)	O
.	O

Interaction	O
of	O
H	B-GENE
-	I-GENE
2Eb	I-GENE
with	O
an	O
IAP	B-GENE
retrotransposon	I-GENE
in	O
the	O
A20	O
/	O
2J	O
B	O
cell	O
lymphoma	O
.	O

Gestational	O
trophoblastic	O
diseases	O
:	O
recent	O
advances	O
in	O
the	O
understanding	O
of	O
cytogenetics	O
,	O
histopathology	O
,	O
and	O
natural	O
history	O
.	O

With	O
the	O
exception	O
of	O
mutants	O
that	O
remove	O
the	O
membrane	O
anchor	O
domain	O
,	O
all	O
of	O
the	O
mutant	O
glycoproteins	O
retained	O
the	O
ability	O
to	O
cause	O
fusion	O
of	O
CD4	B-GENE
-	O
bearing	O
cells	O
.	O

The	O
subunit	O
protein	O
of	O
curli	B-GENE
was	O
highly	O
homologous	O
at	O
its	O
amino	O
terminus	O
to	O
SEF	B-GENE
-	I-GENE
17	I-GENE
,	O
the	O
subunit	O
protein	O
of	O
thin	O
,	O
aggregative	O
fimbriae	O
of	O
Salmonella	O
enteritidis	O
27655	O
strain	O
3b	O
,	O
suggesting	O
that	O
these	O
fibres	O
form	O
a	O
novel	O
class	O
of	O
surface	O
organelles	O
on	O
enterobacteria	O
.	O

Substitution	O
of	O
the	O
DR1	B-GENE
beta	I-GENE
chain	I-GENE
with	O
H	B-GENE
-	I-GENE
2E	I-GENE
beta	I-GENE
k	I-GENE
led	O
to	O
a	O
dramatic	O
loss	O
of	O
recognition	O
;	O
alpha	O
chain	O
substitution	O
had	O
a	O
less	O
marked	O
effect	O
.	O

This	O
negative	O
regulatory	O
pathway	O
may	O
be	O
important	O
for	O
determining	O
cell	O
fate	O
or	O
maintaining	O
an	O
inducible	O
state	O
in	O
the	O
ventroposterior	O
region	O
of	O
the	O
embryo	O
.	O

The	O
distal	O
portion	O
of	O
the	O
rat	B-GENE
insulin	I-GENE
I	I-GENE
gene	I-GENE
5	I-GENE
'	I-GENE
-	I-GENE
flanking	I-GENE
DNA	I-GENE
contains	O
two	O
sequence	O
elements	O
,	O
the	O
Far	O
and	O
FLAT	O
elements	O
,	O
that	O
can	O
function	O
in	O
combination	O
,	O
but	O
not	O
separately	O
,	O
as	O
a	O
beta	O
-	O
cell	O
-	O
specific	O
transcriptional	O
enhancer	O
.	O

The	O
deduced	O
amino	O
acid	O
sequence	O
exhibited	O
98	O
%	O
identity	O
to	O
the	O
human	O
cellular	O
transglutaminase	O
sequence	O
.	O

Repeated	O
efforts	O
to	O
isolate	O
recombinant	O
baculoviruses	O
containing	O
a	O
wild	O
-	O
type	O
kinase	O
failed	O
,	O
whereas	O
recombinants	O
expressing	O
a	O
nonfunctional	O
kinase	O
with	O
a	O
catalytic	O
domain	O
II	O
mutation	O
were	O
readily	O
isolated	O
.	O

Finally	O
,	O
we	O
determined	O
that	O
the	O
P68	B-GENE
amino	O
terminus	O
was	O
both	O
necessary	O
and	O
sufficient	O
for	O
binding	O
dsRNA	O
as	O
we	O
were	O
able	O
to	O
transfer	O
dsRNA	O
-	O
binding	O
properties	O
to	O
a	O
reporter	O
gene	O
product	O
previously	O
unable	O
to	O
bind	O
RNA	O
.	O

From	O
August	O
1989	O
to	O
October	O
1990	O
,	O
83	O
pregnant	O
Chinese	O
women	O
were	O
the	O
subjects	O
for	O
measuring	O
the	O
levels	O
of	O
plasma	O
functional	O
antithrombin	B-GENE
III	I-GENE
(	O
AT	B-GENE
III	I-GENE
)	O
activity	O
.	O

Visual	O
acuity	O
may	O
be	O
decreased	O
by	O
transient	O
changes	O
in	O
refractive	O
error	O
caused	O
by	O
sulfonamides	O
,	O
the	O
antifungal	O
agent	O
metronidazole	O
,	O
thiazide	O
diuretics	O
,	O
and	O
carbonic	B-GENE
anhydrase	I-GENE
inhibitors	O
.	O

Currents	O
aspects	O
of	O
H2	B-GENE
receptor	I-GENE
antagonists	O
in	O
the	O
treatment	O
of	O
ulcers	O

In	O
addition	O
,	O
a	O
21	O
-	O
mer	O
subrepeat	O
structure	O
is	O
also	O
present	O
in	O
each	O
unit	O
.	O

Sequencing	O
revealed	O
one	O
large	O
open	O
reading	O
frame	O
encoding	O
a	O
39	O
-	O
kDa	O
protein	O
.	O

These	O
sites	O
are	O
also	O
potential	O
keratan	O
sulfate	O
attachment	O
sites	O
.	O

We	O
propose	O
that	O
plasmids	O
of	O
the	O
pLS1	O
family	O
(	O
pE194	O
,	O
pADB201	O
,	O
and	O
pLB4	O
)	O
share	O
functional	O
and	O
structural	O
characteristics	O
for	O
the	O
regulation	O
of	O
their	O
copy	O
numbers	O
.	O

Perturbation	O
of	O
dNTP	O
pools	O
also	O
affected	O
the	O
frameshift	O
fidelity	O
of	O
the	O
replicative	O
yeast	B-GENE
DNA	I-GENE
polymerase	I-GENE
alpha	I-GENE
.	O

Differential	O
expression	O
of	O
the	O
"	O
B	O
"	O
subunit	O
of	O
the	O
vacuolar	B-GENE
H	I-GENE
(	I-GENE
+	I-GENE
)	I-GENE
-	I-GENE
ATPase	I-GENE
in	O
bovine	O
tissues	O
.	O

In	O
addition	O
,	O
the	O
hGCSFR	B-GENE
gene	I-GENE
was	O
chromosomally	O
localized	O
by	O
Southern	O
blot	O
analysis	O
of	O
its	O
segregation	O
pattern	O
in	O
a	O
panel	O
of	O
rodent	O
-	O
human	O
hybrid	O
DNAs	O
using	O
the	O
radiolabeled	O
cDNA	O
probe	O
.	O

We	O
have	O
isolated	O
and	O
characterised	O
a	O
differentially	O
-	O
regulated	O
gene	O
family	O
in	O
the	O
protozoan	O
parasite	O
Leishmania	O
major	O
.	O

At	O
some	O
sites	O
,	O
%	O
T	O
is	O
greatly	O
increased	O
by	O
Cl	O
-	O
concentrations	O
up	O
to	O
1	O
M	O
,	O
while	O
at	O
other	O
sites	O
%	O
T	O
is	O
reduced	O
or	O
unaffected	O
by	O
these	O
conditions	O
.	O

Necrosis	O
appears	O
6	O
h	O
after	O
TA	O
infusion	O
,	O
being	O
5	O
.	O
77	O
%	O
in	O
extent	O
after	O
12	O
h	O
,	O
14	O
.	O
9	O
%	O
after	O
24	O
h	O
and	O
animals	O
die	O
with	O
an	O
area	O
of	O
29	O
.	O
5	O
%	O
necrosis	O
.	O

In	O
summary	O
,	O
the	O
segments	O
of	O
C3	B-GENE
represented	O
by	O
amino	O
acid	O
residues	O
1082	O
-	O
1118	O
,	O
1117	O
-	O
1155	O
,	O
1234	O
-	O
1294	O
and	O
1312	O
-	O
1404	O
accommodate	O
C3	B-GENE
(	I-GENE
D	I-GENE
)	I-GENE
epitopes	I-GENE
that	O
are	O
expressed	O
by	O
erythrocyte	O
-	O
bound	O
C3	B-GENE
fragments	I-GENE
,	O
but	O
not	O
by	O
the	O
corresponding	O
fluid	O
-	O
phase	O
fragment	O
,	O
whereas	O
the	O
segments	O
spanning	O
residues	O
973	O
-	O
1026	O
and	O
1477	O
-	O
1510	O
contain	O
C3	B-GENE
(	I-GENE
D	I-GENE
)	I-GENE
epitopes	I-GENE
that	O
are	O
exposed	O
exclusively	O
in	O
denatured	O
C3	B-GENE
and	O
therefore	O
hidden	O
in	O
physiological	O
fragments	O
of	O
the	O
protein	O
.	O

These	O
exons	O
,	O
further	O
identified	O
as	O
exons	O
9	O
,	O
10	O
,	O
and	O
11	O
,	O
together	O
encode	O
the	O
37	O
amino	O
acid	O
residues	O
present	O
in	O
alpha	B-GENE
s1	I-GENE
-	I-GENE
casein	I-GENE
variant	I-GENE
A	I-GENE
but	O
missing	O
in	O
variant	O
F	O
.	O

We	O
also	O
report	O
here	O
the	O
complete	O
structural	O
organization	O
of	O
the	O
goat	B-GENE
alpha	I-GENE
s1	I-GENE
-	I-GENE
casein	I-GENE
transcription	I-GENE
unit	I-GENE
,	O
deduced	O
from	O
polymerase	O
chain	O
reaction	O
experiments	O
.	O

Homodimers	O
of	O
the	O
three	O
proteins	O
specifically	O
recognize	O
the	O
G	O
-	O
box	O
motif	O
,	O
with	O
GBF1	B-GENE
and	O
GBF3	B-GENE
binding	O
symmetrically	O
to	O
this	O
palindromic	O
sequence	O
.	O

The	O
hydrophobicity	O
plot	O
of	O
NHE	B-GENE
-	I-GENE
3	I-GENE
is	O
very	O
similar	O
to	O
that	O
of	O
NHE	B-GENE
-	I-GENE
1	I-GENE
and	O
NHE	B-GENE
-	I-GENE
2	I-GENE
.	O

The	O
initial	O
translation	O
protein	O
encoded	O
by	O
the	O
cDNA	O
is	O
53	O
,	O
932	O
kDa	O
and	O
possesses	O
a	O
hydrophilic	O
amino	O
acid	O
composition	O
with	O
glutamic	O
acid	O
comprising	O
22	O
%	O
of	O
the	O
total	O
amino	O
acid	O
residues	O
.	O

Each	O
group	O
received	O
15	O
ml	O
/	O
kg	O
of	O
either	O
6	O
%	O
pentafraction	O
,	O
6	O
%	O
pentastarch	O
,	O
or	O
plasma	O
followed	O
two	O
hours	O
later	O
by	O
1	O
.	O
5	O
micrograms	O
/	O
kg	O
/	O
0	O
.	O
5	O
hr	O
E	O
.	O

Genetic	O
and	O
biochemical	O
evidence	O
suggests	O
that	O
v	B-GENE
-	I-GENE
Crk	I-GENE
can	O
induce	O
transformation	O
of	O
chicken	O
embryo	O
fibroblasts	O
by	O
influencing	O
the	O
activity	O
of	O
cellular	O
proteins	O
involved	O
in	O
growth	O
regulation	O
.	O

We	O
have	O
constructed	O
,	O
using	O
synthetic	O
DNA	O
oligonucleotides	O
,	O
a	O
U14	B-GENE
snRNA	I-GENE
gene	I-GENE
which	O
has	O
been	O
positioned	O
behind	O
a	O
T7	B-GENE
RNA	I-GENE
polymerase	I-GENE
promoter	I-GENE
site	I-GENE
and	O
then	O
inserted	O
into	O
a	O
plasmid	O
.	O

The	O
carcinoma	O
was	O
restricted	O
within	O
the	O
epithelium	O
in	O
one	O
,	O
the	O
mucosal	O
layer	O
in	O
five	O
,	O
and	O
the	O
submucosal	O
layer	O
in	O
two	O
.	O

In	O
addition	O
,	O
C	B-GENE
/	I-GENE
EBP	I-GENE
beta	I-GENE
and	O
C	B-GENE
/	I-GENE
EBP	I-GENE
gamma	I-GENE
readily	O
heterodimerize	O
with	O
each	O
other	O
as	O
well	O
as	O
with	O
C	B-GENE
/	I-GENE
EBP	I-GENE
alpha	I-GENE
.	O

In	O
contrast	O
,	O
tobacco	B-GENE
GS	I-GENE
-	I-GENE
2	I-GENE
is	O
composed	O
of	O
subunits	O
of	O
identical	O
size	O
in	O
all	O
organs	O
examined	O
.	O

Between	O
acoR	B-GENE
and	O
acoXABC	B-GENE
,	O
two	O
different	O
types	O
of	O
sequences	O
with	O
dual	O
rotational	O
symmetry	O
[	O
CAC	O
-	O
(	O
N11	O
to	O
N18	O
)	O
-	O
GTG	O
and	O
TGT	O
-	O
(	O
N10	O
to	O
N14	O
)	O
-	O
ACA	O
]	O
were	O
found	O
;	O
these	O
sequences	O
are	O
similar	O
to	O
NtrC	B-GENE
and	O
NifA	B-GENE
upstream	I-GENE
activator	I-GENE
sequences	I-GENE
,	O
respectively	O
.	O

Although	O
the	O
effects	O
of	O
the	O
calcium	O
supplement	O
or	O
calcium	O
antagonist	O
alone	O
were	O
significant	O
,	O
such	O
hypotensive	O
responses	O
were	O
not	O
optimal	O
or	O
predictable	O
or	O
clearly	O
dose	O
-	O
dependent	O
.	O

C	O
.	O
,	O
Sun	O
,	O
J	O
.	O
,	O
Hsu	O
,	O
M	O
.	O
-	O
Y	O
.	O
,	O
Vallejo	O
-	O
Ramirez	O
,	O
J	O
.	O
,	O
Inouye	O
,	O
S	O
.	O
,	O
and	O
Inouye	O
,	O
M	O
.	O

Surprisingly	O
,	O
the	O
full	O
-	O
deletion	O
mutant	O
showed	O
a	O
strong	O
block	O
in	O
virus	O
release	O
,	O
suggesting	O
that	O
NC	B-GENE
is	O
involved	O
in	O
virus	O
assembly	O
.	O

Furthermore	O
it	O
was	O
suggested	O
that	O
FK506	O
plasma	O
levels	O
were	O
concerned	O
with	O
the	O
appearance	O
of	O
side	O
effect	O
.	O

Thirty	O
percent	O
of	O
patients	O
were	O
tapered	O
off	O
all	O
steroids	O
,	O
and	O
the	O
average	O
steroid	O
dose	O
in	O
the	O
group	O
who	O
received	O
steroids	O
was	O
8	O
.	O
6	O
mg	O
of	O
prednisone	O
per	O
day	O
.	O

Thus	O
,	O
cibenzoline	O
is	O
an	O
effective	O
antiarrhythmic	O
agent	O
with	O
a	O
favourable	O
pharmacokinetic	O
profile	O
that	O
may	O
be	O
considered	O
with	O
other	O
class	O
I	O
drugs	O
in	O
patients	O
requiring	O
therapy	O
for	O
high	O
risk	O
arrhythmias	O
.	O

T	B-GENE
antigen	I-GENE
contains	O
four	O
H	O
-	O
2Db	O
-	O
restricted	O
cytotoxic	O
T	O
lymphocyte	O
(	O
CTL	O
)	O
recognition	O
epitopes	O
that	O
are	O
targets	O
for	O
CTL	O
clones	O
Y	O
-	O
1	O
,	O
Y	O
-	O
2	O
,	O
Y	O
-	O
3	O
,	O
and	O
Y	O
-	O
5	O
.	O

The	O
method	O
requires	O
a	O
reversed	O
-	O
phase	O
column	O
and	O
a	O
paired	O
-	O
ion	O
technique	O
to	O
separate	O
docusate	O
sodium	O
from	O
other	O
components	O
.	O

Here	O
we	O
demonstrate	O
that	O
the	O
protein	O
product	O
of	O
the	O
ref	B-GENE
-	I-GENE
1	I-GENE
gene	I-GENE
stimulates	O
the	O
DNA	O
binding	O
activity	O
of	O
Fos	B-GENE
-	O
Jun	B-GENE
heterodimers	O
,	O
Jun	B-GENE
-	O
Jun	B-GENE
homodimers	O
and	O
Hela	O
cell	O
AP	B-GENE
-	I-GENE
1	I-GENE
proteins	I-GENE
as	O
well	O
as	O
that	O
of	O
several	O
other	O
transcription	O
factors	O
including	O
NF	B-GENE
-	I-GENE
kappa	I-GENE
B	I-GENE
,	O
Myb	B-GENE
and	O
members	O
of	O
the	O
ATF	B-GENE
/	O
CREB	B-GENE
family	O
.	O

The	O
pulpal	O
tissues	O
of	O
the	O
permanent	O
mandibular	O
molars	O
were	O
amputated	O
and	O
then	O
dressed	O
with	O
calcium	O
hydrate	O
.	O

Northern	O
blot	O
analyses	O
demonstrate	O
that	O
3	O
.	O
9	O
-	O
and	O
5	O
-	O
kilobase	O
mRNAs	O
corresponding	O
to	O
the	O
cDNA	O
were	O
present	O
in	O
all	O
tissues	O
examined	O
,	O
suggesting	O
that	O
the	O
protein	O
it	O
encodes	O
performs	O
a	O
housekeeping	O
function	O
.	O

The	O
ARG	B-GENE
SH2	B-GENE
domain	I-GENE
exhibited	O
relatively	O
weak	O
affinity	O
for	O
BCR	B-GENE
and	O
was	O
determined	O
to	O
bind	O
about	O
10	O
-	O
fold	O
less	O
strongly	O
than	O
the	O
ABL	B-GENE
SH2	B-GENE
domain	I-GENE
.	O

We	O
analyzed	O
an	O
EBV	O
B	O
-	O
cell	O
clone	O
,	O
E29	O
.	O
1	O
,	O
derived	O
from	O
an	O
11	O
week	O
-	O
old	O
embryo	O
,	O
and	O
secreting	O
both	O
IgM	B-GENE
kappa	I-GENE
and	O
IgM	B-GENE
lambda	I-GENE
.	O

Interestingly	O
,	O
this	O
activation	O
occurred	O
only	O
when	O
the	O
regions	O
were	O
cloned	O
in	O
the	O
same	O
relative	O
orientation	O
in	O
which	O
they	O
exist	O
on	O
wild	O
-	O
type	O
pCF10	O
.	O

In	O
rats	O
,	O
we	O
examined	O
the	O
effect	O
of	O
an	O
omentum	O
wrapping	O
on	O
the	O
vascularization	O
of	O
the	O
trachea	O
and	O
on	O
regeneration	O
of	O
the	O
mucosal	O
epithelium	O
in	O
the	O
very	O
early	O
stage	O
after	O
free	O
tracheal	O
grafting	O
.	O

To	O
study	O
a	O
possible	O
functional	O
role	O
of	O
this	O
putative	O
chicken	O
ICS	B-GENE
,	O
an	O
oligonucleotide	O
spanning	O
the	O
upstream	O
sequences	O
of	O
the	O
BF	B-GENE
-	I-GENE
IV	I-GENE
gene	I-GENE
(	O
-	O
174	O
/	O
-	O
194	O
)	O
was	O
cloned	O
singly	O
or	O
in	O
multiple	O
copies	O
before	O
the	O
herpes	O
TK	B-GENE
promoter	I-GENE
controlling	O
the	O
chloramphenicol	B-GENE
acetyl	I-GENE
transferase	I-GENE
(	O
CAT	B-GENE
)	O
gene	O
(	O
pBLCAT2	B-GENE
)	O
.	O

In	O
general	O
,	O
two	O
separate	O
high	O
-	O
performance	O
liquid	O
chromatographic	O
runs	O
were	O
performed	O
,	O
one	O
for	O
the	O
gamma	O
-	O
aminobutyric	O
acid	O
determination	O
and	O
one	O
for	O
the	O
determination	O
of	O
the	O
monoamines	O
.	O

We	O
report	O
the	O
successful	O
use	O
of	O
electroconvulsive	O
therapy	O
for	O
treatment	O
of	O
severe	O
depression	O
in	O
a	O
young	O
man	O
with	O
adult	O
GM2	O
gangliosidosis	O
.	O

Through	O
Southern	O
blot	O
analyses	O
of	O
DNA	O
from	O
backcross	O
and	O
cogenic	O
mice	O
,	O
recombinant	O
inbred	O
strains	O
,	O
and	O
somatic	O
cell	O
hybrids	O
,	O
the	O
genetic	O
loci	O
that	O
produce	O
the	O
cyclin	B-GENE
B1	I-GENE
-	I-GENE
related	I-GENE
sequences	I-GENE
(	O
designated	O
loci	B-GENE
Cycb1	I-GENE
-	I-GENE
rs1	I-GENE
to	O
Cycb1	B-GENE
-	I-GENE
rs9	I-GENE
)	O
were	O
mapped	O
on	O
mouse	O
chromosomes	O
5	O
,	O
1	O
,	O
17	O
,	O
4	O
,	O
14	O
,	O
13	O
,	O
7	O
,	O
X	O
,	O
and	O
8	O
,	O
respectively	O
.	O

Again	O
residue	O
Glu	O
-	O
381	O
of	O
beta	O
was	O
notably	O
reduced	O
and	O
no	O
missing	O
residue	O
from	O
the	O
epsilon	O
peptide	O
could	O
be	O
identified	O
,	O
but	O
the	O
peptide	O
sequence	O
limited	O
the	O
possible	O
choices	O
to	O
Ser	O
-	O
106	O
,	O
Ser	O
-	O
107	O
,	O
or	O
Ser	O
-	O
108	O
.	O

Porcelain	O
to	O
dentin	O
bond	O
strength	O
with	O
a	O
dentin	O
adhesive	O
.	O

TBPf	O
is	O
defined	O
as	O
a	O
quotient	O
of	O
the	O
difference	O
of	O
the	O
first	O
and	O
the	O
second	O
measurement	O
:	O
TBPf	O
=	O
(	O
P1	O
-	O
P2	O
)	O
/	O
(	O
A1	O
-	O
A2	O
)	O
.	O

It	O
was	O
concluded	O
that	O
Scotchbond	O
2	O
and	O
Prisma	O
Universal	O
Bond	O
2	O
are	O
effective	O
and	O
are	O
the	O
dentine	O
bonding	O
agents	O
of	O
choice	O
.	O

The	O
neurohypophysial	O
vasopressin	B-GENE
and	O
oxytocin	B-GENE
content	O
was	O
bioassayed	O
by	O
pressor	O
effect	O
following	O
Dekanski	O
or	O
milk	O
-	O
ejection	O
activity	O
in	O
vitro	O
following	O
van	O
Dongen	O
and	O
Hays	O
,	O
respectively	O
.	O

Comments	O
are	O
given	O
on	O
the	O
present	O
status	O
of	O
regulations	O
concerning	O
water	O
in	O
swimming	O
pools	O
and	O
baths	O
-	O
-	O
1991	O
-	O
-	O
(	O
in	O
connection	O
with	O
the	O
KOK	O
regulations	O
-	O
-	O
1972	O
-	O
-	O
and	O
the	O
Federal	O
German	O
standard	O
[	O
DIN	O
]	O
No	O
.	O

If	O
no	O
reply	O
was	O
received	O
,	O
telephone	O
contact	O
or	O
home	O
visits	O
were	O
made	O
.	O

The	O
treatment	O
group	O
also	O
showed	O
in	O
vivo	O
T	O
-	O
cell	O
activation	O
with	O
an	O
initial	O
lymphopenia	O
followed	O
by	O
a	O
rebound	O
lymphocytosis	O
and	O
upregulation	O
of	O
the	O
subset	O
markers	O
CD25	B-GENE
(	O
interleukin	B-GENE
2	I-GENE
receptor	I-GENE
)	O
and	O
CD45RO	B-GENE
(	O
T	O
-	O
memory	O
cells	O
)	O
.	O

Urease	B-GENE
activity	O
,	O
judged	O
as	O
the	O
amount	O
of	O
ammonia	O
production	O
from	O
urea	O
,	O
could	O
be	O
measured	O
at	O
25	O
ng	O
per	O
tube	O
(	O
S	O
/	O
N	O
=	O
1	O
.	O
5	O
)	O
with	O
Jack	B-GENE
bean	I-GENE
meal	I-GENE
urease	I-GENE
.	O

Although	O
a	O
wide	O
range	O
of	O
cognitive	O
functions	O
had	O
been	O
tested	O
,	O
all	O
but	O
one	O
seizure	O
occurred	O
during	O
assessment	O
of	O
memory	O
performance	O
.	O

The	O
experiments	O
show	O
that	O
it	O
is	O
the	O
micromilieu	O
of	O
the	O
alveoli	O
and	O
the	O
condition	O
of	O
the	O
AM	O
(	O
certain	O
physiological	O
activation	O
states	O
,	O
such	O
as	O
phagocytic	O
activity	O
)	O
that	O
essentially	O
determine	O
the	O
degree	O
of	O
recovery	O
.	O

A	O
cDNA	O
library	O
of	O
tumour	O
cells	O
was	O
screened	O
with	O
an	O
interleukin	B-GENE
2	I-GENE
gene	O
-	O
specific	O
probe	O
.	O

Our	O
experiments	O
suggest	O
that	O
the	O
SCL	B-GENE
gene	I-GENE
can	O
be	O
a	O
target	O
for	O
the	O
erythroid	B-GENE
transcription	I-GENE
factor	I-GENE
GATA	I-GENE
-	I-GENE
1	I-GENE
and	O
that	O
the	O
SCL	B-GENE
gene	I-GENE
product	I-GENE
serves	O
as	O
a	O
positive	O
regulator	O
of	O
erythroid	O
differentiation	O
.	O

Complexes	O
containing	O
wild	O
-	O
type	O
and	O
either	O
his175	B-GENE
or	I-GENE
his273	I-GENE
mutant	I-GENE
p53	I-GENE
proteins	I-GENE
are	O
completely	O
unable	O
to	O
bind	O
to	O
the	O
RGC	B-GENE
DNA	I-GENE
sequence	I-GENE
.	O

These	O
temperature	O
-	O
and	O
cold	O
-	O
sensitive	O
strains	O
were	O
used	O
to	O
prepare	O
extracts	O
deficient	O
in	O
BRF1	B-GENE
activity	O
and	O
were	O
tested	O
for	O
transcriptional	O
activity	O
by	O
RNA	B-GENE
polymerases	I-GENE
I	I-GENE
,	I-GENE
II	I-GENE
,	I-GENE
and	I-GENE
III	I-GENE
in	O
vitro	O
.	O

These	O
results	O
lead	O
us	O
to	O
hypothesize	O
that	O
a	O
single	O
multisubunit	B-GENE
TFIID	I-GENE
protein	I-GENE
supports	O
transcriptional	O
stimulation	O
by	O
diverse	O
activation	O
domains	O
and	O
from	O
a	O
TATA	O
-	O
less	O
promoter	O
.	O

Clone	O
pSRc200	O
hybrid	O
selected	O
an	O
mRNA	O
that	O
on	O
cell	O
-	O
free	O
translation	O
produced	O
a	O
38	O
-	O
kDa	O
polypeptide	O
.	O

From	O
these	O
results	O
,	O
CBF	B-GENE
-	I-GENE
A	I-GENE
is	O
a	O
novel	O
CArG	O
box	O
-	O
,	O
ssDNA	B-GENE
-	I-GENE
and	I-GENE
RNA	I-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
,	O
as	O
well	O
as	O
a	O
repressive	O
transcriptional	O
factor	O
.	O

Cleavage	O
by	O
the	O
intron	O
-	O
encoded	O
enzyme	O
(	O
I	B-GENE
-	I-GENE
CreI	I-GENE
)	O
occurs	O
5	O
bp	O
and	O
1	O
bp	O
3	O
'	O
to	O
the	O
intron	O
insertion	O
site	O
(	O
in	O
the	O
3	O
'	O
-	O
exon	O
)	O
in	O
the	O
top	O
(	O
/	O
)	O
and	O
bottom	O
(	O
,	O
)	O
strands	O
,	O
respectively	O
,	O
resulting	O
in	O
4	O
-	O
nt	O
single	O
-	O
stranded	O
overhangs	O
with	O
3	O
'	O
-	O
OH	O
termini	O
.	O

Surprisingly	O
,	O
the	O
Xenopus	B-GENE
U7	I-GENE
gene	I-GENE
contains	O
two	O
adjacent	O
octamer	O
-	O
binding	O
motifs	O
located	O
only	O
12	O
and	O
24	O
bp	O
upstream	O
from	O
the	O
PSE	B-GENE
,	O
instead	O
of	O
the	O
usual	O
location	O
around	O
150	O
-	O
200	O
bp	O
upstream	O
.	O

The	O
results	O
support	O
earlier	O
reports	O
that	O
collagenase	B-GENE
inhibitors	O
are	O
useful	O
in	O
controlling	O
blister	O
formation	O
in	O
recessive	O
dystrophic	O
epidermolysis	O
bullosa	O
.	O

In	O
humans	O
,	O
four	O
AMP	B-GENE
deaminase	I-GENE
variants	I-GENE
,	O
termed	O
M	B-GENE
(	O
muscle	O
)	O
,	O
L	B-GENE
(	O
liver	O
)	O
,	O
E1	B-GENE
,	O
and	O
E2	B-GENE
(	O
erythrocyte	O
)	O
can	O
be	O
distinguished	O
by	O
a	O
variety	O
of	O
biochemical	O
and	O
immunological	O
criteria	O
.	O

Western	O
blot	O
analyses	O
detect	O
anti	B-GENE
-	I-GENE
E	I-GENE
-	O
specific	O
immunoreactivity	O
in	O
affinity	O
-	O
purified	O
extracts	O
derived	O
from	O
the	O
bacterial	O
expression	O
of	O
a	O
truncated	B-GENE
AMPD3	I-GENE
cDNA	I-GENE
.	O

These	O
results	O
demonstrate	O
that	O
endogenous	O
N	O
-	O
methylation	O
of	O
salsolinol	O
into	O
N	O
-	O
methylsalsolinol	O
occurs	O
in	O
the	O
brain	O
in	O
vivo	O
.	O

DR1	B-GENE
molecules	I-GENE
purified	O
from	O
human	O
lymphoblastoid	O
cell	O
lines	O
could	O
specifically	O
bind	O
to	O
these	O
peptide	O
sequences	O
expressed	O
on	O
the	O
phage	O
surface	O
.	O

This	O
article	O
describes	O
the	O
collaborative	O
care	O
of	O
the	O
woman	O
participating	O
in	O
maternal	O
blood	O
donation	O
for	O
intrauterine	O
transfusion	O
.	O

Chronic	O
hepatitis	O
B	O
in	O
adopted	O
Romanian	O
children	O
.	O

Behind	O
the	O
ATPase	B-GENE
cluster	I-GENE
,	O
two	O
open	O
reading	O
frames	O
were	O
detected	O
that	O
are	O
not	O
homologous	O
to	O
any	O
known	O
chloroplast	O
gene	O
.	O

Therefore	O
,	O
recombinant	O
human	O
Ads	O
that	O
express	O
noninfectious	O
HIV	O
or	O
other	O
microbial	O
proteins	O
are	O
attractive	O
vaccine	O
candidates	O
.	O

Alignment	O
of	O
the	O
selected	O
sequences	O
allowed	O
us	O
to	O
predict	O
a	O
consensus	O
sequence	O
for	O
binding	O
of	O
the	O
individual	O
homodimeric	O
Rel	B-GENE
-	I-GENE
related	I-GENE
proteins	I-GENE
,	O
and	O
DNA	O
-	O
protein	O
binding	O
analysis	O
of	O
the	O
selected	O
DNA	O
sequences	O
revealed	O
sequence	O
specificity	O
of	O
the	O
proteins	O
.	O

Using	O
either	O
a	O
p50	B-GENE
-	O
or	O
p65	B-GENE
-	I-GENE
selected	I-GENE
kappa	I-GENE
B	I-GENE
motif	I-GENE
,	O
which	O
displayed	O
differential	O
binding	O
with	O
respect	O
to	O
the	O
other	O
protein	O
,	O
little	O
to	O
no	O
binding	O
was	O
observed	O
with	O
the	O
heterodimeric	B-GENE
NF	I-GENE
-	I-GENE
kappa	I-GENE
B	I-GENE
complex	I-GENE
.	O

However	O
,	O
a	O
cosmid	O
clone	O
containing	O
the	O
entire	O
mouse	B-GENE
alpha	I-GENE
1	I-GENE
(	I-GENE
I	I-GENE
)	I-GENE
gene	I-GENE
,	O
including	O
3	O
.	O
7	O
kb	O
of	O
5	O
'	O
-	O
and	O
4	O
kb	O
of	O
3	O
'	O
-	O
flanking	O
DNA	O
,	O
was	O
expressed	O
at	O
reduced	O
levels	O
in	O
fibroblasts	O
overexpressing	O
oncogenic	B-GENE
ras	I-GENE
.	O

To	O
define	O
transcriptional	O
control	O
elements	O
responsible	O
for	O
muscle	O
-	O
specific	O
expression	O
of	O
the	O
human	B-GENE
myoglobin	I-GENE
gene	I-GENE
,	O
we	O
performed	O
mutational	O
analysis	O
of	O
upstream	O
sequences	O
(	O
nucleotide	O
positions	O
-	O
373	O
to	O
+	O
7	O
relative	O
to	O
the	O
transcriptional	O
start	O
site	O
)	O
linked	O
to	O
a	O
firefly	B-GENE
luciferase	I-GENE
gene	I-GENE
.	O

Sequencing	O
analysis	O
has	O
shown	O
that	O
each	O
rap1t	B-GENE
allele	I-GENE
contains	O
a	O
nonsense	O
mutation	O
within	O
a	O
discrete	O
region	O
between	O
amino	O
acids	O
663	O
and	O
684	O
.	O

By	O
screening	O
a	O
Y1	O
cell	O
cDNA	O
library	O
with	O
the	O
DNA	O
-	O
binding	O
region	O
of	O
the	O
H	B-GENE
-	I-GENE
2RIIBP	I-GENE
nuclear	I-GENE
hormone	I-GENE
receptor	I-GENE
cDNA	I-GENE
,	O
we	O
isolated	O
a	O
cDNA	O
that	O
is	O
selectively	O
expressed	O
in	O
steroidogenic	O
cells	O
.	O

Autopsy	O
demonstrated	O
good	O
survival	O
of	O
the	O
transplanted	O
cells	O
with	O
good	O
integration	O
with	O
the	O
brain	O
of	O
the	O
recipient	O
and	O
traces	O
of	O
positive	O
immunocytochemical	O
reaction	O
for	O
tyrosine	B-GENE
hydroxylase	I-GENE
.	O

The	O
technique	O
of	O
the	O
TEE	O
visualization	O
of	O
the	O
proximal	O
coronary	O
arteries	O
is	O
described	O
.	O

The	O
sequence	O
of	O
this	O
region	O
shows	O
high	O
G	O
+	O
C	O
content	O
(	O
62	O
%	O
)	O
,	O
which	O
is	O
particularly	O
emphasized	O
in	O
the	O
200	O
bp	O
upstream	O
from	O
the	O
mRNA	O
start	O
(	O
80	O
%	O
G	O
+	O
C	O
)	O
.	O

PaO2	O
threshold	O
was	O
determined	O
through	O
an	O
indwelling	O
O2	O
sensor	O
catheter	O
.	O

By	O
using	O
lambda	O
gt11	O
expression	O
cloning	O
with	O
oligonucleotides	O
corresponding	O
to	O
the	O
human	O
immunodeficiency	O
virus	O
1	O
TATA	O
element	O
,	O
we	O
report	O
the	O
identification	O
of	O
a	O
cellular	O
protein	O
with	O
a	O
calculated	O
molecular	O
mass	O
of	O
123	O
kDa	O
that	O
we	O
designate	O
TATA	B-GENE
element	I-GENE
modulatory	I-GENE
factor	I-GENE
(	O
TMF	B-GENE
)	O
.	O

Blood	O
levels	O
of	O
melatonin	O
,	O
serotonin	O
,	O
cortisol	O
,	O
and	O
prolactin	B-GENE
in	O
relation	O
to	O
the	O
circadian	O
rhythm	O
of	O
platelet	O
serotonin	O
uptake	O
.	O

We	O
couldn	O
'	O
t	O
detect	O
any	O
effect	O
of	O
n	O
-	O
3	O
FA	O
supplementation	O
on	O
total	O
cholesterol	O
,	O
HDL	B-GENE
cholesterol	I-GENE
,	O
LDL	B-GENE
cholesterol	I-GENE
,	O
apo	B-GENE
A1	I-GENE
,	O
Lp	B-GENE
(	I-GENE
a	I-GENE
)	I-GENE
,	O
HbA1C	B-GENE
,	O
glucose	O
,	O
fibrinogen	B-GENE
,	O
factor	B-GENE
VIII	I-GENE
,	O
antithrombin	B-GENE
III	I-GENE
,	O
plasminogen	B-GENE
activator	I-GENE
inhibitor	I-GENE
,	O
tissue	B-GENE
plasminogen	I-GENE
activator	I-GENE
and	O
von	B-GENE
Willebrand	I-GENE
factor	I-GENE
concentration	O
,	O
on	O
bleeding	O
time	O
or	O
on	O
systolic	O
or	O
diastolic	O
blood	O
pressure	O
.	O

In	O
8	O
healthy	O
volunteers	O
there	O
were	O
no	O
significant	O
differences	O
in	O
AUC	O
,	O
peak	O
plasma	O
concentrations	O
or	O
time	O
to	O
peak	O
concentration	O
when	O
OXC	O
was	O
administered	O
either	O
with	O
or	O
without	O
ERY	O
.	O

Using	O
5	O
ng	O
/	O
mL	O
as	O
the	O
cutoff	O
,	O
the	O
sensitivity	O
of	O
CEA	B-GENE
was	O
68	O
%	O
.	O

Rolandic	O
spikes	O
and	O
cognitive	O
function	O
.	O

The	O
effect	O
of	O
sodium	O
18	O
beta	O
-	O
glycyrrhetate	O
(	O
SGA	O
)	O
on	O
experimental	O
arrhythmia	O
was	O
investigated	O
.	O

Thus	O
,	O
chronic	O
hematocrit	O
decrease	O
induced	O
by	O
H	O
or	O
P	O
resulted	O
in	O
a	O
significant	O
fall	O
in	O
blood	O
pressure	O
compared	O
to	O
control	O
(	O
201	O
+	O
/	O
-	O
3	O
v	O
175	O
+	O
/	O
-	O
4	O
,	O
167	O
+	O
/	O
-	O
4	O
mm	O
Hg	O
,	O
respectively	O
;	O
P	O
<	O
.	O
05	O
)	O
.	O

The	O
effects	O
of	O
diltiazem	O
were	O
stereoselective	O
,	O
thus	O
the	O
potentiation	O
induced	O
by	O
d	O
-	O
cis	O
diltiazem	O
was	O
significantly	O
greater	O
in	O
all	O
cases	O
than	O
that	O
induced	O
by	O
l	O
-	O
cis	O
diltiazem	O
,	O
which	O
suggests	O
that	O
calcium	O
channel	O
blockade	O
plays	O
a	O
role	O
in	O
these	O
interactions	O
.	O

Substitution	O
of	O
either	O
Val33	O
(	O
by	O
Gly	O
)	O
or	O
Gly28	O
(	O
by	O
Ser	O
)	O
,	O
two	O
of	O
the	O
most	O
conserved	O
residues	O
in	O
all	O
protein	O
kinases	O
,	O
resulted	O
in	O
enzyme	O
with	O
marginally	O
detectable	O
activity	O
.	O

Significance	O
of	O
the	O
biopsy	O
site	O
of	O
the	O
latissimus	O
dorsi	O
muscle	O
for	O
fiber	O
typing	O
.	O

The	O
TIMP	B-GENE
(	O
-	O
59	O
/	O
-	O
53	O
)	O
AP1	B-GENE
site	O
is	O
a	O
promiscuous	O
motif	O
that	O
binds	O
c	B-GENE
-	I-GENE
Fos	I-GENE
/	O
c	B-GENE
-	I-GENE
Jun	I-GENE
AP1	B-GENE
translated	O
in	O
vitro	O
and	O
is	O
an	O
effective	O
competitor	O
for	O
binding	O
of	O
nuclear	B-GENE
AP1	I-GENE
factors	I-GENE
to	O
the	O
consensus	O
TRE	O
,	O
but	O
in	O
addition	O
it	O
binds	O
factors	O
that	O
do	O
not	O
associate	O
with	O
the	O
consensus	O
TRE	O
.	O

Involvement	O
of	O
AP1	B-GENE
and	O
PEA3	B-GENE
binding	I-GENE
sites	I-GENE
in	O
the	O
regulation	O
of	O
murine	B-GENE
tissue	I-GENE
inhibitor	I-GENE
of	I-GENE
metalloproteinases	I-GENE
-	I-GENE
1	I-GENE
(	O
TIMP	B-GENE
-	I-GENE
1	I-GENE
)	O
transcription	O
.	O

Of	O
the	O
serum	B-GENE
neutralizing	I-GENE
(	I-GENE
SN	I-GENE
)	I-GENE
antibody	I-GENE
negative	O
calves	O
89	O
.	O
7	O
%	O
(	O
26	O
/	O
29	O
)	O
and	O
92	O
.	O
8	O
%	O
(	O
90	O
/	O
97	O
)	O
developed	O
SN	B-GENE
antibody	I-GENE
1	O
month	O
after	O
intranasal	O
and	O
intramuscular	O
vaccination	O
,	O
respectively	O
.	O

Fractionation	O
of	O
crude	O
nuclear	O
extracts	O
by	O
heparin	O
-	O
agarose	O
chromatography	O
indicates	O
that	O
PCAT	B-GENE
-	I-GENE
1	I-GENE
is	O
more	O
prevalent	O
in	O
extracts	O
prepared	O
from	O
salt	O
-	O
stressed	O
leaf	O
tissue	O
.	O

A	O
controlled	O
trial	O
of	O
recombinant	B-GENE
human	I-GENE
granulocyte	I-GENE
-	I-GENE
macrophage	I-GENE
colony	I-GENE
-	I-GENE
stimulating	I-GENE
factor	I-GENE
after	O
total	O
body	O
irradiation	O
,	O
high	O
-	O
dose	O
chemotherapy	O
,	O
and	O
autologous	O
bone	O
marrow	O
transplantation	O
for	O
acute	O
lymphoblastic	O
leukemia	O
or	O
malignant	O
lymphoma	O
.	O

These	O
data	O
demonstrate	O
that	O
DMVA	O
does	O
not	O
cause	O
more	O
myocardial	O
trauma	O
than	O
CPB	O
when	O
used	O
to	O
provide	O
resuscitative	O
circulatory	O
support	O
.	O

The	O
IgG	B-GENE
subclass	O
profile	O
of	O
untreated	O
coeliac	O
disease	O
was	O
found	O
to	O
be	O
the	O
same	O
as	O
in	O
healthy	O
controls	O
(	O
IgG1	B-GENE
approximately	O
IgG2	B-GENE
>	O
IgG3	B-GENE
>	O
IgG4	B-GENE
)	O
,	O
with	O
only	O
the	O
magnitude	O
of	O
the	O
individual	O
subclass	O
responses	O
being	O
increased	O
in	O
coeliac	O
patients	O
.	O

Examination	O
of	O
ANCA	B-GENE
is	O
not	O
only	O
a	O
significant	O
contribution	O
towards	O
a	O
more	O
accurate	O
diagnosis	O
of	O
renal	O
vasculitis	O
,	O
but	O
also	O
an	O
indicator	O
of	O
the	O
activity	O
of	O
the	O
disease	O
and	O
thus	O
of	O
the	O
effectiveness	O
of	O
immunosuppressive	O
treatment	O
.	O

On	O
the	O
other	O
hand	O
,	O
total	O
pinealectomy	O
in	O
these	O
already	O
sympathectomized	O
blinded	O
rabbits	O
always	O
resulted	O
in	O
a	O
substantial	O
deceleration	O
of	O
the	O
rhythms	O
(	O
mean	O
delta	O
tau	O
=	O
+	O
0	O
.	O
23	O
h	O
)	O
.	O

Cicatricial	O
pemphigoid	O
is	O
an	O
autoimmune	O
systemic	O
disease	O
characterized	O
by	O
chronic	O
conjunctival	O
cicatrization	O
.	O

The	O
effects	O
of	O
two	O
levels	O
of	O
caffeine	O
ingestion	O
on	O
excess	O
postexercise	O
oxygen	O
consumption	O
in	O
untrained	O
women	O
.	O

The	O
distinguishing	O
features	O
involved	O
eight	O
amino	O
acid	O
changes	O
,	O
including	O
a	O
single	O
lysine	O
deletion	O
relative	O
to	O
a	O
primate	O
consensus	O
sequence	O
in	O
the	O
first	O
complementary	O
-	O
determing	O
region	O
of	O
V1J1	B-GENE
.	O

4	O
.	O

The	O
in	O
vivo	O
profile	O
of	O
ZFH	B-GENE
-	I-GENE
2	I-GENE
in	O
the	O
larval	O
CNS	O
shows	O
intriguing	O
overlap	O
with	O
DDC	B-GENE
in	O
specific	O
serotonin	O
and	O
dopamine	O
neurons	O
.	O

Unlike	O
the	O
introns	O
of	O
other	O
duplicated	O
ribosomal	B-GENE
protein	I-GENE
genes	I-GENE
which	O
are	O
highly	O
diverged	O
,	O
the	O
duplicated	O
S13	B-GENE
genes	I-GENE
have	O
two	O
nearly	O
identical	O
DNA	O
sequences	O
of	O
25	O
and	O
31	O
bp	O
in	O
length	O
within	O
their	O
introns	O
.	O

In	O
a	O
prospective	O
,	O
randomized	O
clinical	O
trial	O
we	O
compared	O
the	O
efficacy	O
of	O
subcutaneously	O
(	O
SC	O
)	O
administered	O
(	O
every	O
8	O
h	O
)	O
calcium	O
heparin	O
to	O
intravenous	O
(	O
IV	O
)	O
sodium	O
heparin	O
in	O
the	O
treatment	O
of	O
proximal	O
deep	O
-	O
vein	O
thrombosis	O
(	O
DVT	O
)	O
.	O

The	O
highest	O
prevalence	O
of	O
reported	O
pet	O
allergy	O
,	O
chronic	O
cough	O
,	O
wheeze	O
,	O
attacks	O
of	O
shortness	O
of	O
breath	O
with	O
wheezing	O
,	O
and	O
doctor	O
-	O
diagnosed	O
asthma	O
was	O
found	O
in	O
children	O
who	O
had	O
pets	O
in	O
the	O
past	O
but	O
not	O
anymore	O
.	O

Therefore	O
,	O
it	O
would	O
be	O
advantageous	O
to	O
identify	O
such	O
persons	O
and	O
treat	O
them	O
preferentially	O
.	O

On	O
the	O
basis	O
of	O
these	O
unique	O
properties	O
,	O
the	O
newly	O
characterized	O
hemagglutinin	B-GENE
has	O
been	O
termed	O
Limulus	B-GENE
18K	I-GENE
agglutination	I-GENE
-	I-GENE
aggregation	I-GENE
factor	I-GENE
(	O
18K	B-GENE
-	I-GENE
LAF	I-GENE
)	O
.	O

The	O
shift	O
to	O
the	O
nonpermissive	O
temperature	O
is	O
accompanied	O
by	O
the	O
loss	O
of	O
guanyl	O
nucleotide	O
-	O
dependent	O
activity	O
of	O
adenylylcyclase	B-GENE
in	O
vitro	O
.	O

Clin	O
.	O

The	O
data	O
indicate	O
that	O
the	O
minimal	O
catalytic	O
domain	O
of	O
Nmt1p	B-GENE
is	O
located	O
between	O
Ile59	O
-	O
-	O
>	O
Phe96	O
and	O
Gly451	O
-	O
-	O
>	O
Leu455	O
.	O

It	O
corresponds	O
to	O
the	O
complete	O
mitochondrial	O
presequence	O
and	O
the	O
lipoyl	O
-	O
bearing	O
domain	O
that	O
are	O
encoded	O
by	O
exons	O
I	O
through	O
IV	O
of	O
the	O
functional	O
E2	B-GENE
gene	I-GENE
.	O

Human	O
neutrophil	O
response	O
to	O
short	O
-	O
term	O
exposure	O
to	O
F	O
-	O
75	O
cobalt	O
-	O
based	O
alloy	O
.	O

Disruption	O
of	O
microtubules	O
did	O
not	O
affect	O
the	O
fidelity	O
or	O
kinetics	O
of	O
vacuolar	O
protein	O
sorting	O
,	O
indicating	O
that	O
Vps1p	B-GENE
function	O
is	O
not	O
dependent	O
on	O
microtubules	O
.	O

A	O
mutant	O
form	O
of	O
Vps1p	B-GENE
lacking	O
the	O
entire	O
GTP	O
-	O
binding	O
domain	O
interfered	O
with	O
vacuolar	O
protein	O
sorting	O
in	O
wild	O
-	O
type	O
cells	O
.	O

According	O
to	O
out	O
field	O
research	O
,	O
the	O
tick	O
fauna	O
was	O
very	O
rich	O
throughout	O
that	O
area	O
,	O
and	O
it	O
was	O
permissible	O
enough	O
to	O
determine	O
ticks	O
as	O
the	O
vectors	O
,	O
based	O
on	O
arising	O
of	O
anti	B-GENE
-	I-GENE
SF	I-GENE
group	I-GENE
rickettsiae	I-GENE
(	O
SFGR	B-GENE
)	O
antibody	O
in	O
mice	O
inoculated	O
with	O
some	O
tick	O
emulsions	O
,	O
findings	O
of	O
rickettsiae	O
reactive	O
to	O
patient	O
sera	O
or	O
a	O
species	O
-	O
specific	O
monoclonal	O
antibody	O
to	O
JSFR	B-GENE
in	O
the	O
hemolymph	O
cells	O
of	O
some	O
ticks	O
,	O
and	O
electron	O
microscopical	O
observations	O
of	O
SFGR	B-GENE
in	O
various	O
internal	O
organs	O
including	O
the	O
salivary	O
gland	O
of	O
ticks	O
.	O

Nucleotide	O
sequence	O
and	O
transcriptional	O
analysis	O
of	O
the	O
polyhedrin	B-GENE
gene	I-GENE
of	O
Spodoptera	O
exigua	O
nuclear	O
polyhedrosis	O
virus	O
.	O

Validation	O
of	O
automated	O
systems	O
-	O
-	O
system	O
definition	O
.	O

As	O
a	O
consequence	O
of	O
dark	O
rearing	O
,	O
the	O
numerical	O
density	O
of	O
cortical	O
neurons	O
in	O
area	O
17	O
amounted	O
to	O
about	O
double	O
of	O
the	O
value	O
observed	O
in	O
normally	O
reared	O
kittens	O
and	O
was	O
also	O
significantly	O
higher	O
in	O
area	O
18	O
.	O

These	O
results	O
suggest	O
that	O
decreased	O
class	O
I	O
enhancer	O
activity	O
in	O
Ad12	O
-	O
transformed	O
cells	O
may	O
,	O
at	O
least	O
in	O
part	O
,	O
be	O
due	O
to	O
the	O
higher	O
levels	O
of	O
an	O
enhancer	O
-	O
specific	O
factor	O
,	O
possibly	O
acting	O
as	O
a	O
repressor	O
.	O

A	O
second	O
domain	O
,	O
located	O
in	O
the	O
C	O
-	O
terminal	O
437	O
amino	O
acids	O
of	O
IE1	B-GENE
,	O
is	O
required	O
for	O
inhibitory	O
and	O
DNA	O
-	O
binding	O
activities	O
.	O

In	O
order	O
to	O
investigate	O
the	O
blood	O
compatibility	O
of	O
autogenous	O
vein	O
graft	O
(	O
AVG	O
)	O
,	O
changes	O
in	O
prostacyclin	O
(	O
PGI2	O
)	O
production	O
following	O
harvesting	O
and	O
arterial	O
implantation	O
were	O
studied	O
experimentally	O
.	O

Subcutaneous	O
administration	O
of	O
the	O
somatostatin	B-GENE
analogue	O
,	O
octreotide	O
,	O
100	O
micrograms	O
thrice	O
daily	O
,	O
resulted	O
in	O
a	O
sustained	O
improvement	O
in	O
diarrhoea	O
and	O
disappearance	O
of	O
faecal	O
incontinence	O
without	O
reducing	O
calcitonin	B-GENE
levels	O
.	O

205	O
,	O
285	O
-	O
290	O
]	O
and	O
was	O
subsequently	O
cloned	O
and	O
sequenced	O
[	O
J	O
.	O

Nonreplicating	O
vaccinia	O
vector	O
efficiently	O
expresses	O
recombinant	O
genes	O
.	O

Interferon	B-GENE
type	I-GENE
I	I-GENE
in	O
protective	O
body	O
reactions	O
in	O
an	O
experimental	O
Klebsiella	O
infection	O

No	O
other	O
changes	O
in	O
hematopoietic	O
differentiation	O
status	O
were	O
observed	O
in	O
association	O
with	O
Id	B-GENE
-	I-GENE
SCL	I-GENE
expression	O
.	O

For	O
pressure	O
greater	O
than	O
121	O
atm	O
abs	O
,	O
an	O
increased	O
excitability	O
of	O
the	O
tadpoles	O
made	O
it	O
difficult	O
to	O
distinguish	O
the	O
righting	O
reflex	O
from	O
involuntary	O
movements	O
.	O

One	O
air	O
embolism	O
occurred	O
;	O
this	O
was	O
the	O
only	O
filter	O
-	O
or	O
retrieval	O
-	O
related	O
complication	O
.	O

The	O
5	O
'	O
region	O
of	O
ADH5	B-GENE
contains	O
consensus	O
binding	O
sites	O
for	O
the	O
transcriptional	O
regulatory	O
proteins	O
,	O
Sp1	B-GENE
,	O
AP2	B-GENE
,	O
LF	B-GENE
-	I-GENE
A1	I-GENE
,	O
NF	B-GENE
-	I-GENE
1	I-GENE
,	O
NF	B-GENE
-	I-GENE
A2	I-GENE
,	O
and	O
NF	B-GENE
-	I-GENE
E1	I-GENE
.	O

These	O
data	O
indicate	O
that	O
RNK	B-GENE
-	I-GENE
Met	I-GENE
-	I-GENE
1	I-GENE
is	O
a	O
serine	B-GENE
protease	I-GENE
with	O
unique	O
activity	O
that	O
is	O
expressed	O
in	O
the	O
granules	O
of	O
large	O
granular	O
lymphocytes	O
.	O

Purification	O
and	O
cloning	O
of	O
a	O
novel	O
serine	B-GENE
protease	I-GENE
,	O
RNK	B-GENE
-	I-GENE
Met	I-GENE
-	I-GENE
1	I-GENE
,	O
from	O
the	O
granules	O
of	O
a	O
rat	O
natural	O
killer	O
cell	O
leukemia	O
.	O

We	O
describe	O
here	O
17	O
dominant	B-GENE
GCN2	I-GENE
mutations	I-GENE
that	O
lead	O
to	O
derepression	O
of	O
GCN4	B-GENE
expression	O
in	O
the	O
absence	O
of	O
amino	O
acid	O
starvation	O
.	O

Administration	O
of	O
growth	B-GENE
hormone	I-GENE
leads	O
to	O
faster	O
growth	O
,	O
but	O
also	O
faster	O
bone	O
maturation	O
.	O

Comparisons	O
with	O
the	O
available	O
amino	O
acid	O
residue	O
(	O
aa	O
)	O
sequence	O
information	O
from	O
the	O
complete	O
CPMV	B-GENE
RNA	I-GENE
1	I-GENE
sequence	I-GENE
and	O
the	O
partial	O
sequence	O
of	O
red	B-GENE
clover	I-GENE
mottle	I-GENE
virus	I-GENE
RNA	I-GENE
1	I-GENE
suggest	O
that	O
CPSMV	B-GENE
RNA	I-GENE
1	I-GENE
specifies	O
the	O
expected	O
set	O
of	O
five	O
mature	O
proteins	O
:	O
32K	B-GENE
proteinase	I-GENE
cofactor	I-GENE
,	O
58K	B-GENE
presumed	I-GENE
helicase	I-GENE
,	O
VPg	B-GENE
5	I-GENE
'	I-GENE
-	I-GENE
linked	I-GENE
protein	I-GENE
of	O
the	O
genomic	O
RNAs	O
,	O
24K	B-GENE
proteinase	I-GENE
,	O
and	O
87K	B-GENE
presumed	I-GENE
polymerase	I-GENE
,	O
separated	O
by	O
four	O
cleavage	O
sites	O
.	O

In	O
addition	O
,	O
the	O
utility	O
of	O
beta	B-GENE
2	I-GENE
transferrin	I-GENE
assay	O
in	O
the	O
diagnosis	O
of	O
cerebrospinal	O
fluid	O
otorrhea	O
is	O
presented	O
.	O

The	O
addition	O
of	O
diatrizoate	O
to	O
the	O
IPRK	O
led	O
to	O
a	O
dose	O
-	O
dependent	O
biphasic	O
change	O
in	O
RPF	O
and	O
GFR	O
characterized	O
by	O
an	O
initial	O
transient	O
increase	O
followed	O
by	O
a	O
marked	O
and	O
sustained	O
decrease	O
.	O

To	O
prepare	O
for	O
analyses	O
with	O
the	O
family	O
variables	O
,	O
we	O
next	O
present	O
descriptive	O
data	O
based	O
on	O
separate	O
principal	O
components	O
analysis	O
(	O
PCA	O
)	O
and	O
multidimensional	O
scaling	O
analysis	O
(	O
MDS	O
)	O
of	O
14	O
self	O
-	O
reported	O
health	O
scores	O
for	O
husbands	O
and	O
for	O
wives	O
.	O

The	O
structural	O
genes	O
encoding	O
glyceraldehyde	B-GENE
-	I-GENE
3	I-GENE
-	I-GENE
phosphate	I-GENE
dehydrogenase	I-GENE
(	O
GAPDH	B-GENE
)	O
,	O
3	B-GENE
-	I-GENE
phosphoglycerate	I-GENE
kinase	I-GENE
(	O
PGK	B-GENE
)	O
and	O
the	O
N	O
-	O
terminal	O
part	O
of	O
triosephosphate	B-GENE
isomerase	I-GENE
(	O
TIM	B-GENE
)	O
from	O
mesophilic	O
Bacillus	O
megaterium	O
DSM319	O
have	O
been	O
cloned	O
as	O
a	O
gene	O
cluster	O
(	O
gap	B-GENE
operon	I-GENE
)	O
by	O
complementation	O
of	O
an	O
Escherichia	O
coli	O
gap	B-GENE
amber	I-GENE
mutant	I-GENE
.	O

Pseudomonas	B-GENE
aeruginosa	I-GENE
exotoxin	I-GENE
A	I-GENE
:	O
its	O
role	O
in	O
retardation	O
of	O
wound	O
healing	O
:	O
the	O
1992	O
Lindberg	O
Award	O
.	O

Laboratory	O
studies	O
showed	O
that	O
the	O
direct	O
fluorescent	O
-	O
antibody	O
kits	O
were	O
the	O
least	O
sensitive	O
in	O
this	O
case	O
and	O
did	O
not	O
detect	O
fewer	O
than	O
10	O
(	O
4	O
)	O
elementary	O
bodies	O
per	O
ml	O
,	O
while	O
most	O
ELISA	O
kits	O
detected	O
between	O
130	O
and	O
600	O
elementary	O
bodies	O
per	O
ml	O
.	O

To	O
study	O
the	O
significance	O
of	O
these	O
domains	O
and	O
the	O
overall	O
evolutionary	O
conservation	O
of	O
the	O
gene	O
,	O
the	O
homolog	O
from	O
Drosophila	O
melanogaster	O
was	O
isolated	O
by	O
low	O
stringency	O
hybridizations	O
using	O
two	O
flanking	O
probes	O
of	O
the	O
human	B-GENE
ERCC3	I-GENE
cDNA	I-GENE
.	O

Mono	O
-	O
ADP	O
-	O
ribosylation	O
is	O
a	O
reversible	O
modification	O
of	O
proteins	O
,	O
with	O
NAD	O
:	O
arginine	B-GENE
ADP	I-GENE
-	I-GENE
ribosyltransferases	I-GENE
(	O
EC	B-GENE
2	I-GENE
.	I-GENE
4	I-GENE
.	I-GENE
2	I-GENE
.	I-GENE
31	I-GENE
)	O
and	O
ADP	B-GENE
-	I-GENE
ribosylarginine	I-GENE
hydrolases	I-GENE
(	O
EC	B-GENE
3	I-GENE
.	I-GENE
2	I-GENE
.	I-GENE
2	I-GENE
.	I-GENE
19	I-GENE
)	O
catalyzing	O
the	O
opposing	O
reactions	O
in	O
an	O
ADP	O
-	O
ribosylation	O
cycle	O
.	O

For	O
this	O
reason	O
,	O
the	O
particle	O
forming	O
capacity	O
of	O
derivatives	O
of	O
the	O
HIV	B-GENE
-	I-GENE
1	I-GENE
group	I-GENE
specific	I-GENE
core	I-GENE
antigen	I-GENE
p55	I-GENE
gag	I-GENE
was	O
assayed	O
and	O
compared	O
dependent	O
on	O
various	O
expression	O
systems	O
:	O
recombinant	O
bacteria	O
,	O
vaccinia	O
-	O
and	O
baculoviruses	O
were	O
established	O
encoding	O
the	O
entire	O
core	B-GENE
protein	I-GENE
p55	I-GENE
either	O
in	O
its	O
authentic	O
sequence	O
or	O
lacking	O
the	O
myristylation	O
consensus	O
signal	O
.	O

The	O
tramtrack	B-GENE
(	O
ttk	B-GENE
)	O
gene	O
of	O
Drosophila	O
encodes	O
69	O
-	O
kDa	O
and	O
88	O
-	O
kDa	O
proteins	O
through	O
alternative	O
splicing	O
of	O
the	O
primary	O
ttk	B-GENE
transcript	I-GENE
.	O

Removal	O
of	O
beta	B-GENE
2	I-GENE
-	I-GENE
microglobulin	I-GENE
by	O
hemodialysis	O
and	O
hemofiltration	O
:	O
a	O
four	O
year	O
follow	O
up	O
.	O

Removal	O
of	O
beta	B-GENE
2	I-GENE
-	I-GENE
microglobulin	I-GENE
by	O
hemodialysis	O
and	O
hemofiltration	O
:	O
a	O
four	O
year	O
follow	O
up	O
.	O

Adapromine	O
was	O
established	O
to	O
evoke	O
a	O
decrease	O
of	O
the	O
amplitude	O
of	O
the	O
dominant	O
peak	O
and	O
dominant	O
theta	O
-	O
activity	O
in	O
power	O
spectra	O
of	O
the	O
EEG	O
in	O
the	O
cortex	O
and	O
hippocamp	O
,	O
with	O
an	O
increase	O
of	O
rapid	O
wave	O
activity	O
in	O
the	O
beta	O
2	O
range	O
in	O
the	O
right	O
cortex	O
and	O
hippocamp	O
.	O

These	O
sequences	O
were	O
then	O
used	O
to	O
clone	O
the	O
full	O
-	O
length	O
genes	O
from	O
a	O
yeast	O
genomic	O
library	O
.	O

GAL4	B-GENE
-	O
VP16	B-GENE
-	O
mediated	O
antirepression	O
required	O
an	O
auxiliary	O
factor	O
,	O
denoted	O
as	O
a	O
co	O
-	O
antirepressor	O
,	O
which	O
was	O
partially	O
purified	O
from	O
Drosophila	O
embryos	O
.	O

After	O
28	O
days	O
of	O
haloperidol	O
treatment	O
,	O
similar	O
changes	O
were	O
observed	O
for	O
delta	O
,	O
together	O
with	O
an	O
increase	O
of	O
alpha	O
1	O
,	O
and	O
a	O
decrease	O
of	O
fast	O
beta	O
.	O

Four	O
ruminally	O
and	O
duodenally	O
cannulated	O
Hampshire	O
wethers	O
were	O
used	O
in	O
a	O
4	O
x	O
4	O
Latin	O
square	O
experiment	O
to	O
determine	O
whether	O
linoleoyl	O
methionine	O
and	O
calcium	O
linoleate	O
would	O
increase	O
duodenal	O
flow	O
of	O
unsaturated	O
fatty	O
acids	O
(	O
C18	O
:	O
2	O
+	O
cis	O
C18	O
:	O
1	O
)	O
.	O

Truncated	B-GENE
ICSBP	I-GENE
lacking	O
the	O
first	O
33	O
amino	O
-	O
terminal	O
amino	O
acids	O
fails	O
to	O
bind	O
to	O
the	O
ICS	B-GENE
,	O
indicating	O
that	O
at	O
least	O
part	O
of	O
the	O
DNA	O
binding	O
domain	O
is	O
located	O
within	O
the	O
well	O
conserved	O
amino	O
terminus	O
.	O

Therefore	O
,	O
ICSBP	B-GENE
may	O
be	O
involved	O
in	O
maintaining	O
submaximal	O
transcriptional	O
activity	O
of	O
IFN	B-GENE
-	O
inducible	O
genes	O
in	O
hematopoietic	O
cells	O
.	O

A	O
case	O
of	O
chronic	O
hepatitis	O
C	O
with	O
primary	O
hypothyroidism	O
manifested	O
during	O
interferon	B-GENE
treatment	O

Dynamic	O
decision	O
making	O
:	O
human	O
control	O
of	O
complex	O
systems	O
.	O

A	O
coiled	B-GENE
-	I-GENE
coil	I-GENE
related	I-GENE
protein	I-GENE
specific	O
for	O
synapsed	O
regions	O
of	O
meiotic	O
prophase	O
chromosomes	O
.	O

Abstracts	O
.	O

These	O
results	O
indicate	O
a	O
possible	O
involvement	O
of	O
endogenous	O
opioid	O
peptides	O
in	O
the	O
cardiac	O
effects	O
due	O
to	O
myocardial	O
ischaemia	O
and	O
reperfusion	O
,	O
mediated	O
by	O
opiate	B-GENE
receptors	I-GENE
through	O
opiate	O
antagonism	O
.	O

Since	O
CENP	B-GENE
-	I-GENE
B	I-GENE
gene	I-GENE
is	O
conserved	O
in	O
mammalian	O
species	O
and	O
CENP	B-GENE
-	I-GENE
B	I-GENE
boxes	I-GENE
are	O
found	O
also	O
in	O
mouse	O
centromere	O
satellite	O
DNA	O
(	O
minor	O
satellite	O
)	O
,	O
this	O
sequence	O
-	O
specific	O
DNA	O
-	O
protein	O
interaction	O
may	O
be	O
important	O
for	O
some	O
kind	O
of	O
common	O
centromere	O
function	O
.	O

Interestingly	O
,	O
a	O
portion	O
of	O
the	O
tail	O
domain	O
(	O
aa	O
,	O
1	O
,	O
094	O
-	O
1	O
,	O
830	O
)	O
shares	O
58	O
%	O
amino	O
acid	O
sequence	O
identity	O
with	O
a	O
723	O
-	O
aa	O
protein	O
from	O
mouse	O
brain	O
reported	O
to	O
be	O
a	O
glutamic	B-GENE
acid	I-GENE
decarboxylase	I-GENE
.	O

However	O
,	O
in	O
the	O
subgroup	O
with	O
normal	O
Ht	O
(	O
<	O
0	O
.	O
45	O
l	O
/	O
l	O
;	O
n	O
=	O
201	O
)	O
there	O
was	O
a	O
significant	O
reduction	O
(	O
p	O
<	O
0	O
.	O
05	O
)	O
of	O
the	O
mortality	O
after	O
3	O
months	O
(	O
27	O
%	O
and	O
16	O
%	O
,	O
respectively	O
)	O
and	O
an	O
increase	O
of	O
independence	O
at	O
home	O
(	O
35	O
%	O
and	O
48	O
%	O
,	O
respectively	O
)	O
due	O
to	O
a	O
reduction	O
of	O
the	O
viscosity	O
by	O
means	O
of	O
haemodilution	O
with	O
albumin	B-GENE
(	O
a	O
specific	O
viscosity	O
effect	O
in	O
the	O
normovolaemic	O
group	O
)	O
.	O

Distribution	O
and	O
changing	O
morphological	O
course	O

The	O
appropriate	O
use	O
and	O
benefits	O
of	O
bile	O
acid	O
sequestrants	O
,	O
nicotinic	O
acid	O
,	O
fibric	O
acids	O
,	O
3	B-GENE
-	I-GENE
hydroxy	I-GENE
-	I-GENE
3	I-GENE
-	I-GENE
methylglutaryl	I-GENE
coenzyme	I-GENE
A	I-GENE
(	I-GENE
HMG	I-GENE
-	I-GENE
CoA	I-GENE
)	I-GENE
reductase	I-GENE
inhibitors	O
,	O
and	O
probucol	O
are	O
individually	O
discussed	O
,	O
whereas	O
nonpharmacologic	O
approaches	O
used	O
in	O
conjunction	O
with	O
the	O
drugs	O
are	O
recommended	O
emphatically	O
.	O

This	O
may	O
result	O
in	O
more	O
reabsorption	O
and	O
hence	O
reduced	O
renal	O
clearance	O
.	O

The	O
major	O
pathological	O
findings	O
of	O
the	O
placenta	O
were	O
prematuration	O
and	O
hypoplasia	O
.	O

Green	O
pepper	O
significantly	O
inhibited	O
N	O
-	O
nitrosothiazolidine	O
-	O
carboxylic	O
acid	O
formation	O
relative	O
to	O
ascorbic	O
acid	O
alone	O
.	O

A	O
genomic	O
clone	O
,	O
pTt21	O
,	O
containing	O
DNA	O
apparently	O
transcribed	O
specifically	O
in	O
Trypanosoma	O
cruzi	O
trypomastigotes	O
,	O
was	O
obtained	O
by	O
differentially	O
screening	O
a	O
genomic	O
library	O
with	O
trypomastigote	O
and	O
epimastigote	O
cDNA	O
.	O

Brucellosis	O
-	O
-	O
1990	O

Assay	O
of	O
urea	O
by	O
immobilized	O
urease	B-GENE
coupled	O
to	O
a	O
differential	O
pH	O
-	O
meter	O
.	O

RESULTS	O
:	O
In	O
the	O
AGA	O
group	O
,	O
both	O
fetal	O
and	O
maternal	O
serum	O
prolactin	B-GENE
concentration	O
increased	O
significantly	O
with	O
gestation	O
(	O
P	O
<	O
0	O
.	O
001	O
and	O
P	O
<	O
0	O
.	O
01	O
,	O
respectively	O
)	O
.	O

One	O
phage	O
clone	O
contains	O
a	O
junction	O
between	O
alpha	O
satellite	O
DNA	O
and	O
a	O
novel	O
low	O
-	O
copy	O
repeated	O
sequence	O
.	O

The	O
5	O
'	O
-	O
flanking	O
region	O
of	O
the	O
human	B-GENE
lactoferrin	I-GENE
gene	I-GENE
was	O
isolated	O
from	O
a	O
human	O
placental	O
genomic	O
library	O
.	O

Therefore	O
,	O
the	O
molecular	O
mechanisms	O
of	O
the	O
estrogen	O
action	O
that	O
govern	O
the	O
lactoferrin	B-GENE
gene	I-GENE
expression	O
differ	O
between	O
mouse	O
and	O
human	O
.	O

The	O
CEM	O
receives	O
registration	O
updates	O
via	O
an	O
HL7	O
message	O
and	O
evaluates	O
data	O
dependencies	O
in	O
rules	O
via	O
an	O
interface	O
to	O
the	O
relational	O
database	O
.	O

Magnetic	O
resonance	O
spectroscopy	O
(	O
MRS	O
)	O
and	O
imaging	O
(	O
MRI	O
)	O
are	O
now	O
well	O
established	O
techniques	O
for	O
the	O
study	O
of	O
cellular	O
metabolism	O
and	O
gross	O
structure	O
of	O
muscle	O
.	O

Simultaneously	O
a	O
greater	O
NA	O
was	O
found	O
with	O
no	O
change	O
in	O
plasma	O
epinephrine	O
response	O
.	O

We	O
investigated	O
the	O
diagnostic	O
value	O
of	O
a	O
new	O
in	O
vitro	O
test	O
,	O
Pharmacia	O
CAP	O
System	O
(	O
Pharmacia	O
Diagnostics	O
AB	O
,	O
Uppsala	O
,	O
Sweden	O
)	O
,	O
for	O
the	O
quantitative	O
measurement	O
of	O
allergen	B-GENE
-	I-GENE
specific	I-GENE
IgE	I-GENE
antibodies	I-GENE
by	O
comparison	O
with	O
RAST	O
in	O
2	O
groups	O
of	O
patients	O
,	O
71	O
atopic	O
and	O
48	O
non	O
-	O
atopic	O
.	O

Patients	O
receiving	O
VPA	O
showed	O
differences	O
in	O
attention	O
,	O
visuomotor	O
performance	O
,	O
verbal	O
span	O
and	O
sensory	O
discrimination	O
tasks	O
at	O
T1	O
,	O
in	O
visuomotor	O
performance	O
at	O
T2	O
and	O
in	O
spatial	O
span	O
at	O
T3	O
,	O
whereas	O
no	O
differences	O
were	O
detected	O
at	O
T4	O
.	O

We	O
found	O
that	O
the	O
gene	O
segment	O
containing	O
the	O
mu	O
m	O
poly	O
(	O
A	O
)	O
signals	O
,	O
along	O
with	O
536	O
bp	O
of	O
downstream	O
flanking	O
sequence	O
,	O
acted	O
as	O
a	O
transcription	O
terminator	O
in	O
both	O
myeloma	O
cells	O
and	O
L	O
cell	O
fibroblasts	O
.	O

Alena	O
is	O
a	O
nurse	O
in	O
Prague	O
-	O
-	O
she	O
dreams	O
of	O
higher	O
wages	O
and	O
a	O
trip	O
across	O
the	O
ocean	O

Dopamine	O
neurons	O
in	O
subjects	O
that	O
received	O
6	O
-	O
OHDA	O
were	O
protected	O
by	O
pre	O
-	O
treatment	O
with	O
GBR	O
-	O
12909	O
.	O

The	O
results	O
of	O
this	O
study	O
demonstrate	O
that	O
strongyloidiasis	O
was	O
the	O
cause	O
of	O
sudden	O
death	O
.	O

A	O
second	O
large	O
group	O
of	O
disorders	O
in	O
pregnancy	O
is	O
caused	O
by	O
effects	O
of	O
infections	O
of	O
the	O
mother	O
without	O
pathogens	O
being	O
transmitted	O
to	O
the	O
embryo	O
or	O
the	O
placenta	O
.	O

Four	O
short	O
nucleotide	O
sequences	O
(	O
boxes	O
I	O
to	O
IV	O
)	O
contribute	O
to	O
the	O
light	O
responsiveness	O
of	O
the	O
parsley	B-GENE
chalcone	I-GENE
synthase	I-GENE
promoter	I-GENE
.	O

The	O
case	O
described	O
is	O
that	O
of	O
a	O
72	O
-	O
year	O
-	O
old	O
man	O
with	O
ochronosis	O
who	O
suffered	O
a	O
hyperextension	O
injury	O
to	O
his	O
spine	O
in	O
a	O
fall	O
,	O
resulting	O
in	O
a	O
fracture	O
through	O
an	O
ankylosed	O
L2	O
-	O
L3	O
disk	O
space	O
.	O

The	O
mean	O
blood	O
flow	O
in	O
the	O
penile	O
foreskin	O
was	O
estimated	O
to	O
be	O
15	O
ml	O
/	O
min	O
/	O
100	O
g	O
and	O
it	O
increased	O
to	O
150	O
-	O
200	O
%	O
after	O
the	O
induction	O
of	O
anesthesia	O
,	O
and	O
then	O
decreased	O
to	O
72	O
%	O
at	O
the	O
tip	O
of	O
the	O
created	O
parameatal	O
foreskin	O
flap	O
.	O

Exogenous	O
LHRH	B-GENE
is	O
also	O
known	O
to	O
facilitate	O
mating	O
behavior	O
in	O
several	O
species	O
.	O

The	O
first	O
146	O
consecutive	O
patients	O
treated	O
with	O
EVL	O
during	O
the	O
period	O
from	O
August	O
,	O
1986	O
to	O
July	O
,	O
1989	O
are	O
reported	O
.	O

Replacing	O
the	O
aspartic	O
acid	O
with	O
a	O
lysine	O
but	O
not	O
with	O
an	O
alanine	O
or	O
valine	O
residue	O
allowed	O
formation	O
of	O
disulfide	O
-	O
linked	O
dimers	O
.	O

During	O
V	O
-	O
A	O
bypass	O
,	O
hemodynamics	O
were	O
stable	O
.	O

Greater	O
rupture	O
force	O
was	O
required	O
in	O
the	O
adult	O
pigs	O
than	O
in	O
the	O
young	O
pigs	O
.	O

At	O
rest	O
AFF	O
was	O
significantly	O
higher	O
in	O
UT	O
(	O
29	O
%	O
)	O
as	O
compared	O
to	O
AT	O
(	O
25	O
%	O
)	O
and	O
UEA	O
(	O
25	O
%	O
)	O
.	O

We	O
investigated	O
the	O
smoking	O
habits	O
of	O
relapsers	O
1	O
year	O
after	O
quitting	O
in	O
a	O
smoking	O
cessation	O
trial	O
using	O
nicotine	O
or	O
placebo	O
patches	O
.	O

Exposure	O
to	O
hepatitis	O
B	O
virus	O
in	O
the	O
general	O
population	O
of	O
Hisayama	O
,	O
Japan	O
:	O
significance	O
of	O
isolated	O
antibody	O
to	O
hepatitis	B-GENE
B	I-GENE
surface	I-GENE
antigen	I-GENE
in	O
general	O
population	O
.	O

Because	O
of	O
this	O
latter	O
phenomenon	O
,	O
we	O
were	O
able	O
to	O
identify	O
a	O
particular	O
cysteine	O
motif	O
that	O
was	O
repeated	O
multiple	O
times	O
in	O
Dfurin2	B-GENE
but	O
present	O
only	O
twice	O
in	O
mammalian	B-GENE
furin	I-GENE
.	O

On	O
the	O
other	O
hand	O
,	O
neither	O
phosphate	O
buffered	O
saline	O
injection	O
into	O
the	O
ES	O
nor	O
primary	O
KLH	B-GENE
challenges	O
of	O
the	O
ES	O
were	O
capable	O
of	O
elevating	O
the	O
threshold	O
level	O
and	O
changing	O
the	O
latency	O
.	O

A	O
newly	O
developed	O
broad	O
-	O
spectrum	O
fluoroquinolone	O
,	O
levofloxacin	O
(	O
LVFX	O
,	O
DR	O
-	O
3355	O
)	O
,	O
was	O
evaluated	O
in	O
vitro	O
and	O
in	O
vivo	O
in	O
comparison	O
with	O
ciprofloxacin	O
(	O
CPFX	O
)	O
,	O
ofloxacin	O
(	O
OFLX	O
)	O
and	O
norfloxacin	O
(	O
NFLX	O
)	O
.	O

The	O
mean	O
serum	O
creatinine	O
levels	O
were	O
similar	O
at	O
one	O
year	O
(	O
SPK	O
1	O
.	O
8	O
,	O
KTA	O
1	O
.	O
9	O
mg	O
/	O
d	O
)	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
250	O
WORDS	O
)	O

Model	O
predictions	O
were	O
in	O
accord	O
with	O
the	O
nine	O
-	O
year	O
survival	O
experience	O
of	O
women	O
in	O
the	O
HIP	O
trial	O
,	O
and	O
,	O
with	O
the	O
exception	O
of	O
women	O
40	O
-	O
44	O
years	O
old	O
,	O
with	O
HIP	O
data	O
on	O
18	O
-	O
year	O
survival	O
.	O

High	O
-	O
resolution	O
computed	O
tomography	O
in	O
the	O
diagnosis	O
of	O
miliary	O
tuberculosis	O
.	O

Previously	O
,	O
we	O
showed	O
that	O
SNF2	B-GENE
,	O
SNF5	B-GENE
,	O
and	O
SNF6	B-GENE
function	O
interdependently	O
in	O
transcriptional	O
activation	O
,	O
possibly	O
forming	O
a	O
heteromeric	O
complex	O
.	O

We	O
show	O
that	O
LexA	B-GENE
-	O
GAL4	B-GENE
and	O
LexA	B-GENE
-	O
Bicoid	B-GENE
fusion	O
proteins	O
are	O
both	O
dependent	O
on	O
SNF2	B-GENE
,	O
SNF5	B-GENE
,	O
and	O
SNF6	B-GENE
for	O
activation	O
of	O
target	O
genes	O
containing	O
one	O
or	O
multiple	O
lexA	B-GENE
operators	I-GENE
.	O

George	O
T	O
.	O

A	O
lambda	O
gt10	O
cDNA	O
library	O
was	O
constructed	O
from	O
poly	O
(	O
A	O
)	O
+	O
RNA	O
of	O
young	O
green	O
leaves	O
of	O
spinach	O
.	O

NE	B-GENE
and	O
PR3	B-GENE
assist	O
in	O
the	O
destruction	O
of	O
phagocytosed	O
microorganisms	O
,	O
cleave	O
the	O
important	O
connective	B-GENE
-	I-GENE
tissue	I-GENE
protein	I-GENE
elastin	I-GENE
,	O
and	O
generate	O
chemotactic	O
activities	O
by	O
forming	O
alpha	B-GENE
1	I-GENE
-	I-GENE
proteinase	I-GENE
inhibitor	I-GENE
complexes	I-GENE
and	O
elastin	B-GENE
peptides	I-GENE
.	O

Selected	O
topics	O
in	O
pediatric	O
ultrasonography	O
-	O
-	O
1992	O
.	O

Methods	O
included	O
24	O
-	O
hour	O
dietary	O
recall	O
,	O
menu	O
weights	O
,	O
and	O
recipe	O
analysis	O
.	O

Factors	O
associated	O
with	O
afterdrop	O
included	O
age	O
,	O
end	O
-	O
of	O
-	O
surgery	O
temperature	O
(	O
both	O
positively	O
)	O
and	O
body	O
mass	O
(	O
negatively	O
)	O
.	O

Both	O
GH	B-GENE
deficiency	O
and	O
impaired	O
spinal	O
growth	O
may	O
result	O
in	O
short	O
stature	O
,	O
whereas	O
the	O
occurrence	O
of	O
early	O
puberty	O
in	O
association	O
with	O
GH	B-GENE
deficiency	O
reduces	O
the	O
time	O
available	O
for	O
GH	B-GENE
therapy	O
.	O

By	O
contrast	O
,	O
d	B-GENE
(	I-GENE
T2AG3T	I-GENE
)	I-GENE
and	O
d	B-GENE
(	I-GENE
T2G4T	I-GENE
)	I-GENE
form	O
only	O
the	O
G	O
-	O
quadruplex	O
monomer	O
structures	O
independent	O
of	O
K	O
cation	O
concentration	O
as	O
reported	O
previously	O
[	O
Sen	O
,	O
D	O
.	O
,	O
&	O
Gilbert	O
,	O
W	O
.	O

Differentiating	O
among	O
renal	O
stones	O
.	O

IFI	B-GENE
16	I-GENE
mRNA	I-GENE
was	O
found	O
to	O
be	O
constitutively	O
expressed	O
in	O
lymphoid	O
cells	O
and	O
in	O
cell	O
lines	O
of	O
both	O
the	O
T	O
and	O
B	O
lineages	O
.	O

Mitochondria	O
-	O
lytic	O
action	O
of	O
warfarin	O
in	O
lymphocytes	O
.	O

Exon	O
-	O
intron	O
junctions	O
in	O
the	O
human	O
and	O
rat	B-GENE
AdoMet	I-GENE
decarboxylase	I-GENE
genes	I-GENE
were	O
in	O
identical	O
positions	O
except	O
that	O
exons	O
6	O
and	O
7	O
of	O
the	O
human	O
gene	O
formed	O
a	O
single	O
exon	O
in	O
the	O
rat	O
gene	O
.	O

Interferon	B-GENE
-	I-GENE
alpha	I-GENE
-	O
induced	O
gene	O
expression	O
:	O
evidence	O
for	O
a	O
selective	O
effect	O
of	O
ouabain	O
on	O
activation	O
of	O
the	O
ISGF3	B-GENE
transcription	I-GENE
complex	I-GENE
.	O

Moreover	O
,	O
LD50	O
in	O
mice	O
of	O
RP	O
-	O
170	O
(	O
4	O
.	O
3	O
g	O
/	O
kg	O
on	O
i	O
.	O
v	O
.	O
)	O
was	O
increased	O
to	O
5	O
.	O
2	O
g	O
/	O
kg	O
by	O
oral	O
administration	O
.	O

Among	O
the	O
few	O
proteins	O
of	O
the	O
eukaryotic	O
nucleolus	O
that	O
have	O
been	O
characterized	O
,	O
four	O
proteins	O
,	O
nucleolin	B-GENE
,	O
fibrillarin	B-GENE
,	O
SSB1	B-GENE
and	O
NSR1	B-GENE
,	O
possess	O
a	O
common	O
structural	O
motif	O
,	O
the	O
GAR	O
domain	O
,	O
which	O
is	O
rich	O
in	O
glycine	O
and	O
arginine	O
residues	O
.	O

Thus	O
,	O
this	O
study	O
provides	O
evidence	O
that	O
a	O
novel	O
,	O
ubiquitous	O
factor	O
(	O
HF	B-GENE
-	I-GENE
1a	I-GENE
)	O
and	O
a	O
muscle	O
factor	O
(	O
HF	B-GENE
-	I-GENE
1b	I-GENE
/	O
MEF	B-GENE
-	I-GENE
2	I-GENE
)	O
can	O
form	O
a	O
novel	O
,	O
E	O
-	O
box	O
-	O
independent	O
pathway	O
for	O
muscle	O
-	O
specific	O
expression	O
in	O
ventricular	O
cardiac	O
muscle	O
cells	O
.	O

Mutations	O
in	O
either	O
gene	O
block	O
some	O
crucial	O
late	O
step	O
in	O
assembly	O
of	O
F1	B-GENE
,	O
causing	O
the	O
alpha	O
and	O
beta	O
subunits	O
to	O
accumulate	O
in	O
mitochondria	O
as	O
inactive	O
aggregates	O
(	O
Ackerman	O
,	O
S	O
.	O

Expense	O
limits	O
the	O
use	O
of	O
hepatitis	O
B	O
vaccines	O
,	O
but	O
low	O
-	O
dose	O
intradermal	O
immunization	O
has	O
been	O
evaluated	O
as	O
a	O
cost	O
-	O
saving	O
strategy	O
in	O
numerous	O
studies	O
.	O

Estrogen	O
replacement	O
therapy	O
and	O
risk	O
of	O
breast	O
cancer	O
:	O
results	O
of	O
two	O
meta	O
-	O
analyses	O
.	O

Switching	O
FDC	O
-	O
P1	O
/	O
MAC	O
cells	O
from	O
growth	O
in	O
M	B-GENE
-	I-GENE
CSF	I-GENE
to	O
GM	B-GENE
-	I-GENE
CSF	I-GENE
caused	O
the	O
selective	O
degradation	O
of	O
c	B-GENE
-	I-GENE
fms	I-GENE
mRNA	I-GENE
within	O
6	O
h	O
after	O
factor	O
switching	O
.	O

There	O
was	O
however	O
,	O
no	O
significant	O
difference	O
in	O
the	O
prevalence	O
of	O
chronic	O
respiratory	O
symptoms	O
between	O
animal	O
food	O
workers	O
with	O
positive	O
and	O
negative	O
skin	O
tests	O
to	O
house	O
dust	O
or	O
to	O
fish	O
flour	O
or	O
among	O
those	O
with	O
increased	O
or	O
normal	O
IgE	B-GENE
(	O
except	O
for	O
dyspnea	O
)	O
.	O

An	O
unexpected	O
finding	O
was	O
the	O
presence	O
at	O
position	O
-	O
403	O
to	O
-	O
385	O
of	O
a	O
putative	O
dioxin	O
responsive	O
element	O
,	O
a	O
sequence	O
found	O
to	O
be	O
responsible	O
for	O
the	O
induction	O
of	O
transcription	O
of	O
the	O
cytochrome	B-GENE
P450IA1	I-GENE
gene	I-GENE
(	O
CYPIA1	B-GENE
)	O
and	O
other	O
genes	O
involved	O
in	O
detoxification	O
/	O
activation	O
of	O
polycyclic	O
aromatic	O
hydrocarbons	O
.	O

Using	O
bovine	B-GENE
and	I-GENE
murine	I-GENE
c	I-GENE
-	I-GENE
myb	I-GENE
clones	O
,	O
no	O
change	O
in	O
the	O
rate	O
of	O
c	B-GENE
-	I-GENE
myb	I-GENE
gene	I-GENE
transcription	O
or	O
mRNA	O
stability	O
was	O
detected	O
during	O
the	O
cell	O
cycle	O
.	O

A	O
13	O
base	O
-	O
pair	O
oligonucleotide	O
spanning	O
nucleotides	O
+	O
80	O
to	O
+	O
92	O
of	O
the	O
5	B-GENE
S	I-GENE
RNA	I-GENE
gene	I-GENE
retained	O
specific	O
and	O
high	O
-	O
affinity	O
binding	O
,	O
although	O
the	O
latter	O
was	O
reduced	O
sixfold	O
relative	O
to	O
longer	O
DNA	O
fragments	O
.	O

Moreover	O
,	O
the	O
reconstitution	O
of	O
eUSF	B-GENE
and	O
TFIID	B-GENE
-	O
depleted	O
transcription	O
complexes	O
with	O
purified	O
protein	O
fractions	O
demonstrate	O
that	O
not	O
only	O
TFIID	B-GENE
but	O
also	O
eUSF	B-GENE
essentially	O
participates	O
in	O
complex	O
formation	O
even	O
on	O
H5	B-GENE
promoter	I-GENE
mutations	O
lacking	O
the	O
TATA	O
-	O
box	O
.	O

Radiolabelled	O
palmitate	O
was	O
not	O
incorporated	O
into	O
the	O
mutated	O
protein	O
,	O
showing	O
that	O
lipid	O
modification	O
occurs	O
at	O
the	O
Cys	O
-	O
22	O
residue	O
.	O

17	O
volunteer	O
deaf	O
Ss	O
were	O
compared	O
with	O
18	O
volunteer	O
hearing	O
Ss	O
on	O
the	O
Stanford	O
Hypnotic	O
Clinical	O
Scale	O
(	O
SHCS	O
)	O
of	O
Morgan	O
and	O
J	O
.	O

Mature	B-GENE
tobacco	I-GENE
L12	I-GENE
protein	I-GENE
has	O
44	O
%	O
amino	O
acid	O
identity	O
with	O
ribosomal	O
protein	O
L7	B-GENE
/	O
L12	B-GENE
of	O
Escherichia	O
coli	O
.	O

Nuclear	B-GENE
-	I-GENE
encoded	I-GENE
chloroplast	I-GENE
ribosomal	I-GENE
protein	I-GENE
L12	I-GENE
of	I-GENE
Nicotiana	I-GENE
tabacum	I-GENE
:	O
characterization	O
of	O
mature	O
protein	O
and	O
isolation	O
and	O
sequence	O
analysis	O
of	O
cDNA	O
clones	O
encoding	O
its	O
cytoplasmic	O
precursor	O
.	O

The	O
gene	O
encoding	O
IFN	B-GENE
-	I-GENE
gamma	I-GENE
was	O
previously	O
found	O
to	O
contain	O
an	O
intronic	O
enhancer	O
element	O
that	O
was	O
not	O
tissue	O
-	O
specific	O
in	O
its	O
activity	O
,	O
despite	O
the	O
restricted	O
expression	O
of	O
the	O
intact	O
IFN	B-GENE
-	I-GENE
gamma	I-GENE
-	I-GENE
encoding	I-GENE
gene	I-GENE
.	O

Molecular	O
cloning	O
of	O
the	O
polypeptide	O
component	O
of	O
the	O
Rel	B-GENE
-	I-GENE
related	I-GENE
human	I-GENE
p75	I-GENE
nucleoprotein	I-GENE
complex	I-GENE
has	O
revealed	O
its	O
identity	O
with	O
the	O
65	O
-	O
kDa	O
(	O
p65	B-GENE
)	O
subunit	O
of	O
NF	B-GENE
-	I-GENE
kappa	I-GENE
B	I-GENE
.	O

Of	O
the	O
drugs	O
orally	O
administered	O
,	O
WR	O
-	O
168643	O
was	O
the	O
best	O
protector	O
with	O
a	O
DMF	O
of	O
1	O
.	O
51	O
.	O

Characterization	O
of	O
these	O
R	O
subunits	O
by	O
their	O
8	O
-	O
azido	O
-	O
cAMP	O
photoaffinity	O
labeling	O
and	O
immunoreactivity	O
,	O
as	O
well	O
as	O
by	O
a	O
phosphorylation	O
-	O
dependent	O
mobility	O
shift	O
on	O
sodium	O
dodecyl	O
sulfate	O
-	O
polyacrylamide	O
gel	O
electrophoresis	O
(	O
SDS	O
-	O
PAGE	O
)	O
,	O
indicated	O
subunit	O
sizes	O
of	O
RII	B-GENE
beta	I-GENE
(	O
53	O
kDa	O
)	O
greater	O
than	O
RII	B-GENE
alpha	I-GENE
dephosphoform	O
(	O
51	O
kDa	O
)	O
greater	O
than	O
RI	B-GENE
alpha	I-GENE
(	O
49	O
kDa	O
)	O
.	O

Comparison	O
of	O
the	O
genomic	O
DNA	O
sequence	O
with	O
that	O
of	O
the	O
four	O
different	O
mRNAs	O
indicates	O
that	O
these	O
transcripts	O
are	O
produced	O
by	O
alternative	O
splicing	O
of	O
the	O
murine	O
pre	O
-	O
mRNA	O
according	O
to	O
a	O
cassette	O
model	O
.	O

During	O
the	O
1980	O
'	O
s	O
,	O
quantifications	O
of	O
immunoserological	O
testings	O
,	O
especially	O
C	B-GENE
reactive	I-GENE
protein	I-GENE
,	O
rheumatoid	B-GENE
factor	I-GENE
and	O
antistreptolysin	B-GENE
O	I-GENE
,	O
progressed	O
rapidly	O
.	O

Within	O
the	O
human	O
enhancer	O
,	O
these	O
two	O
sites	O
are	O
located	O
within	O
the	O
previously	O
defined	O
DNase	B-GENE
I	I-GENE
footprints	I-GENE
,	O
NFAT	B-GENE
-	I-GENE
1	I-GENE
and	O
NFIL	B-GENE
-	I-GENE
2B	I-GENE
,	O
respectively	O
.	O

The	O
cardiac	B-GENE
myosin	I-GENE
light	I-GENE
chain	I-GENE
-	I-GENE
2	I-GENE
(	O
MLC	B-GENE
-	I-GENE
2	I-GENE
)	O
gene	O
promoter	O
contains	O
several	O
positive	O
and	O
negative	O
cis	O
-	O
acting	O
sequences	O
that	O
are	O
involved	O
in	O
the	O
regulation	O
of	O
its	O
expression	O
.	O

Deletion	O
mutagenesis	O
demonstrated	O
that	O
these	O
two	O
elements	O
are	O
involved	O
in	O
the	O
positive	O
regulation	O
of	O
MLC	B-GENE
-	I-GENE
2	I-GENE
gene	I-GENE
transcription	O
.	O

Disruption	O
mutations	O
have	O
been	O
constructed	O
in	O
the	O
SLK1	B-GENE
gene	I-GENE
.	O
slk1	B-GENE
null	I-GENE
mutants	I-GENE
cannot	O
grow	O
at	O
37	O
degrees	O
C	O
,	O
but	O
many	O
cells	O
can	O
grow	O
at	O
30	O
,	O
24	O
,	O
and	O
17	O
degrees	O
C	O
.	O

Molecular	O
and	O
genetic	O
analysis	O
of	O
the	O
yeast	B-GENE
early	I-GENE
meiotic	I-GENE
recombination	I-GENE
genes	I-GENE
REC102	I-GENE
and	O
REC107	B-GENE
/	O
MER2	B-GENE
.	O

Probable	O
progressive	O
multifocal	O
leukoencephalopathy	O
(	O
PML	O
)	O
was	O
diagnosed	O
on	O
the	O
basis	O
of	O
clinical	O
picture	O
and	O
magnetic	O
resonance	O
imaging	O
in	O
a	O
63	O
-	O
year	O
-	O
old	O
man	O
with	O
a	O
complete	O
remission	O
of	O
a	O
non	O
-	O
Hodgkin	O
'	O
s	O
lymphoma	O
.	O

Proprotein	O
processing	O
occurs	O
intracellularly	O
.	O

A	O
32P	O
-	O
labeled	O
LAP	B-GENE
DNA	O
-	O
binding	O
and	O
dimerization	O
domain	O
"	O
zipper	O
probe	O
"	O
was	O
used	O
to	O
isolate	O
a	O
clone	O
that	O
encodes	O
a	O
new	O
C	B-GENE
/	I-GENE
EBP	I-GENE
-	I-GENE
homologous	I-GENE
protein	I-GENE
:	O
CHOP	B-GENE
-	I-GENE
10	I-GENE
.	O

Using	O
a	O
degenerate	O
oligodeoxyribonucleotide	O
(	O
oligo	O
)	O
based	O
on	O
the	O
N	O
-	O
terminal	O
aa	O
sequence	O
,	O
plus	O
an	O
internal	O
oligo	O
homologous	O
to	O
a	O
conserved	O
region	O
within	O
the	O
portion	O
of	O
CYP1	B-GENE
and	O
CYP2	B-GENE
that	O
had	O
been	O
deleted	O
in	O
the	O
genome	O
,	O
a	O
CYP3	B-GENE
-	I-GENE
specific	I-GENE
DNA	I-GENE
fragment	I-GENE
was	O
generated	O
by	O
the	O
polymerase	O
chain	O
reaction	O
(	O
PCR	O
)	O
using	O
GL81	O
genomic	O
DNA	O
as	O
a	O
substrate	O
.	O

Stringent	O
hybridization	O
of	O
EHS	B-GENE
-	I-GENE
1	I-GENE
back	O
to	O
primate	O
genomic	O
DNA	O
indicates	O
two	O
distinct	O
EHS	B-GENE
-	I-GENE
1	I-GENE
loci	I-GENE
in	O
normal	O
human	O
DNA	O
,	O
an	O
identical	O
band	O
pattern	O
in	O
chimpanzee	O
DNA	O
,	O
and	O
a	O
single	O
locus	O
in	O
rhesus	O
monkey	O
DNA	O
.	O

The	O
level	O
of	O
carboxyl	B-GENE
-	I-GENE
terminal	I-GENE
parathyroid	I-GENE
hormone	I-GENE
in	O
the	O
patients	O
with	O
thyroid	O
carcinoma	O
was	O
higher	O
than	O
that	O
in	O
the	O
patients	O
without	O
thyroid	O
carcinoma	O
(	O
P	O
less	O
than	O
0	O
.	O
05	O
)	O
.	O

The	O
Caenorhabditis	B-GENE
elegans	I-GENE
vitellogenin	I-GENE
genes	I-GENE
are	O
subject	O
to	O
sex	O
-	O
,	O
stage	O
-	O
,	O
and	O
tissue	O
-	O
specific	O
regulation	O
:	O
they	O
are	O
expressed	O
solely	O
in	O
the	O
adult	O
hermaphrodite	O
intestine	O
.	O

The	O
functions	O
of	O
isolated	O
portions	O
of	O
the	O
insulin	B-GENE
,	O
IAPP	B-GENE
,	O
and	O
beta	B-GENE
GK	I-GENE
promoters	I-GENE
were	O
studied	O
by	O
using	O
transient	O
expression	O
and	O
DNA	O
binding	O
assays	O
.	O

The	O
c	B-GENE
-	I-GENE
Ets	I-GENE
-	I-GENE
1	I-GENE
oncoprotein	I-GENE
is	O
a	O
transcription	O
activator	O
that	O
specifically	O
binds	O
to	O
DNA	O
.	O

Previous	O
transactivation	O
experiments	O
indicated	O
that	O
three	O
amino	O
acids	O
residing	O
in	O
this	O
region	O
,	O
Gly	O
,	O
Ser	O
and	O
Val	O
,	O
appear	O
to	O
be	O
critical	O
for	O
target	O
-	O
site	O
discrimination	O
.	O

GR63178A	O
is	O
a	O
water	O
-	O
soluble	O
analogue	O
of	O
mitoquidone	O
,	O
a	O
pentacyclic	O
pyrroloquinone	O
.	O

Marker	O
rescue	O
analysis	O
has	O
localized	O
ts8	B-GENE
to	O
a	O
910	O
-	O
bp	O
internal	O
segment	O
of	O
rpoB	B-GENE
that	O
encodes	O
the	O
Rif	B-GENE
domain	I-GENE
.	O

This	O
vector	O
transfected	O
into	O
the	O
yeast	O
Saccharomyces	O
cerevisiae	O
directs	O
expression	O
of	O
a	O
secreted	O
mature	O
protein	O
at	O
levels	O
up	O
to	O
200	O
mg	O
of	O
LAPP	O
/	O
liter	O
of	O
culture	O
medium	O
.	O

Competition	O
analysis	O
by	O
gel	O
mobility	O
shift	O
electrophoresis	O
indicates	O
that	O
this	O
DNA	O
-	O
protein	O
interaction	O
is	O
novel	O
and	O
not	O
related	O
to	O
many	O
transcription	O
factors	O
previously	O
reported	O
.	O

This	O
DNA	O
motif	O
represents	O
a	O
novel	O
protein	O
-	O
binding	O
sequence	O
.	O

OBJECTIVE	O
:	O
The	O
study	O
was	O
designed	O
to	O
investigate	O
the	O
frequency	O
of	O
alterations	O
in	O
serum	O
creatinine	O
in	O
patients	O
with	O
psoriasis	O
receiving	O
5	O
mg	O
/	O
kg	O
/	O
day	O
of	O
cyclosporine	O
.	O

Intrapocket	O
chemotherapy	O
in	O
adult	O
periodontitis	O
using	O
a	O
new	O
controlled	O
-	O
release	O
insert	O
containing	O
ofloxacin	O
(	O
PT	O
-	O
01	O
)	O
.	O

Electromagnetic	O
blood	O
flow	O
(	O
BF	O
)	O
probe	O
was	O
applied	O
on	O
the	O
left	O
anterior	O
descending	O
artery	O
(	O
LAD	O
)	O
.	O

Hence	O
temperature	O
and	O
virF	B-GENE
are	O
both	O
required	O
for	O
the	O
induction	O
of	O
the	O
yop	B-GENE
regulon	I-GENE
.	O

Problems	O
remain	O
to	O
be	O
resolved	O
in	O
the	O
area	O
of	O
quantitative	O
risk	O
assessment	O
.	O

The	O
Klebsiella	B-GENE
aerogenes	I-GENE
gene	I-GENE
maoA	I-GENE
,	O
which	O
is	O
involved	O
in	O
the	O
synthesis	O
of	O
monoamine	B-GENE
oxidase	I-GENE
,	O
was	O
induced	O
by	O
tyramine	O
and	O
the	O
related	O
compounds	O
,	O
subjected	O
to	O
catabolite	O
and	O
ammonium	O
ion	O
repression	O
,	O
and	O
cloned	O
.	O

Eight	O
of	O
14	O
infectious	O
or	O
inflammatory	O
lesions	O
could	O
be	O
detected	O
in	O
the	O
early	O
scan	O
(	O
4	O
-	O
6	O
h	O
p	O
.	O
i	O
.	O
)	O
.	O

Similar	O
observations	O
have	O
been	O
made	O
previously	O
for	O
other	O
genes	O
.	O

Preceptorship	O
of	O
CNS	O
students	O
:	O
an	O
exploratory	O
study	O
.	O

To	O
determine	O
the	O
genetic	O
basis	O
for	O
the	O
differences	O
between	O
the	O
cardiac	O
and	O
brain	B-GENE
AE3	I-GENE
variants	I-GENE
,	O
we	O
isolated	O
and	O
characterized	O
the	O
rat	O
gene	O
.	O

The	O
1	O
.	O
7	O
kb	O
cloned	O
fragment	O
was	O
sequenced	O
and	O
shown	O
to	O
contain	O
the	O
entire	O
fliA	B-GENE
gene	I-GENE
.	O

Institution	O
of	O
both	O
intravenous	O
and	O
intracisternal	O
administration	O
of	O
amphotericin	O
B	O
and	O
possibly	O
concomitant	O
intravenous	O
administration	O
of	O
dexamethasone	O
may	O
be	O
warranted	O
in	O
situations	O
in	O
which	O
the	O
association	O
of	O
C	O
.	O
immitis	O
with	O
CNS	O
vasculitis	O
or	O
encephalitis	O
appears	O
likely	O
before	O
serologic	O
or	O
cultural	O
confirmation	O
of	O
C	O
.	O
immitis	O
infection	O
involving	O
the	O
CNS	O
is	O
available	O
.	O

Lac	B-GENE
operators	O
were	O
introduced	O
into	O
several	O
positions	O
within	O
the	O
CAB	B-GENE
promoter	I-GENE
and	O
operator	O
-	O
free	O
plasmid	O
was	O
used	O
as	O
control	O
.	O

Overproduction	O
,	O
purification	O
and	O
characterization	O
of	O
M	B-GENE
.	I-GENE
HinfI	I-GENE
methyltransferase	I-GENE
and	O
its	O
deletion	O
mutant	O
.	O

Various	O
companies	O
produce	O
this	O
type	O
of	O
lens	O
.	O

From	O
March	O
5	O
through	O
October	O
26	O
,	O
1991	O
,	O
eight	O
persons	O
were	O
diagnosed	O
with	O
elevated	O
blood	O
lead	O
levels	O
(	O
BLLs	O
)	O
at	O
a	O
local	O
hospital	O
and	O
were	O
reported	O
to	O
the	O
notifiable	O
disease	O
surveillance	O
system	O
maintained	O
by	O
the	O
Alabama	O
Department	O
of	O
Public	O
Health	O
(	O
ADPH	O
)	O
.	O

According	O
to	O
the	O
changes	O
of	O
perfusion	O
defects	O
between	O
Ex	O
,	O
RD	O
and	O
ReI	O
images	O
,	O
they	O
were	O
classified	O
into	O
3	O
types	O
:	O
Type	O
I	O
;	O
perfusion	O
defect	O
on	O
the	O
RD	O
image	O
was	O
identical	O
to	O
ReI	O
image	O
(	O
75	O
%	O
)	O
Type	O
I	O
was	O
divided	O
into	O
2	O
subgroups	O
whether	O
perfusion	O
defect	O
at	O
Ex	O
was	O
unchanged	O
(	O
Ia	O
,	O
42	O
%	O
)	O
or	O
improved	O
(	O
Ib	O
,	O
33	O
%	O
)	O
on	O
the	O
RD	O
image	O
.	O

Keck	O
,	O
C	O
.	O
J	O
.	O

Twenty	O
-	O
eight	O
(	O
7	O
.	O
0	O
%	O
)	O
infants	O
without	O
periventricular	O
hemorrhage	O
were	O
revealed	O
as	O
having	O
spastic	O
cerebral	O
palsy	O
by	O
neurodevelopmental	O
evaluation	O
in	O
later	O
infancy	O
.	O

A	O
possible	O
mechanism	O
is	O
that	O
elevated	O
alveolar	O
pressure	O
and	O
decreased	O
cardiac	O
output	O
eliminate	O
blood	O
flow	O
from	O
corner	O
vessels	O
in	O
nondependent	O
high	O
VA	O
/	O
Q	O
regions	O
.	O

In	O
both	O
cities	O
,	O
HTLV	O
-	O
I	O
/	O
II	O
prevalence	O
increased	O
significantly	O
with	O
age	O
,	O
and	O
the	O
New	O
Orleans	O
age	O
-	O
and	O
sex	O
-	O
adjusted	O
HTLV	O
-	O
I	O
/	O
II	O
prevalence	O
was	O
significantly	O
higher	O
than	O
that	O
of	O
Baltimore	O
(	O
P	O
less	O
than	O
.	O
001	O
)	O
.	O

Hybridization	O
data	O
indicate	O
that	O
6F6	B-GENE
.	I-GENE
2	I-GENE
corresponds	O
to	O
the	O
previously	O
characterized	O
m6F6	B-GENE
cDNA	I-GENE
clone	I-GENE
and	O
that	O
6F6	B-GENE
.	I-GENE
1	I-GENE
and	O
6F6	B-GENE
.	I-GENE
3	I-GENE
,	O
but	O
not	O
6F6	B-GENE
.	I-GENE
2	I-GENE
,	O
are	O
adjacent	O
to	O
alpha	B-GENE
-	I-GENE
type	I-GENE
genes	I-GENE
.	O

The	O
SEN1	B-GENE
gene	I-GENE
corresponds	O
to	O
a	O
6	O
,	O
336	O
-	O
bp	O
open	O
reading	O
frame	O
coding	O
for	O
a	O
2	O
,	O
112	O
-	O
amino	O
-	O
acid	O
protein	O
(	O
molecular	O
mass	O
,	O
239	O
kDa	O
)	O
.	O

Protein	B-GENE
tyrosine	I-GENE
kinases	I-GENE
(	O
PTKs	B-GENE
)	O
are	O
implicated	O
in	O
the	O
control	O
of	O
cell	O
growth	O
by	O
virtue	O
of	O
their	O
frequent	O
appearance	O
as	O
products	O
of	O
retroviral	O
oncogenes	O
,	O
as	O
intracellular	O
signal	O
transducers	O
,	O
and	O
as	O
growth	B-GENE
factor	I-GENE
receptors	I-GENE
or	O
components	O
thereof	O
.	O

The	O
IA4	B-GENE
mAb	I-GENE
was	O
identified	O
among	O
a	O
series	O
of	O
antibodies	O
raised	O
in	O
BALB	O
/	O
c	O
mice	O
after	O
immunization	O
against	O
a	O
HLA	B-GENE
class	O
I	O
-	O
deficient	O
,	O
lymphokine	O
-	O
activated	O
killer	O
(	O
LAK	O
)	O
-	O
susceptible	O
EBV	O
-	O
B	O
lymphocyte	O
line	O
.	O

In	O
a	O
randomized	O
double	O
-	O
blind	O
cross	O
-	O
over	O
study	O
,	O
the	O
subjects	O
received	O
theophylline	O
5	O
mg	O
.	O
kg	O
-	O
1	O
per	O
day	O
with	O
omeprazole	O
20	O
mg	O
per	O
day	O
or	O
identical	O
placebo	O
during	O
two	O
periods	O
,	O
each	O
of	O
7	O
days	O
,	O
separated	O
by	O
a	O
washout	O
period	O
of	O
7	O
days	O
.	O

Primer	O
extension	O
and	O
mung	B-GENE
bean	I-GENE
and	I-GENE
S1	I-GENE
nuclease	I-GENE
mapping	O
indicated	O
multiple	O
transcription	O
initiation	O
sites	O
and	O
were	O
consistent	O
with	O
Northern	O
analyses	O
.	O

Two	O
variant	O
PRP	B-GENE
-	I-GENE
precursor	I-GENE
alleles	I-GENE
occur	O
which	O
slightly	O
differ	O
in	O
the	O
number	O
of	O
repeats	O
in	O
domain	O
C	O
.	O

Unlike	O
the	O
typical	O
enhancer	O
element	O
,	O
this	O
region	O
functions	O
in	O
an	O
orientation	O
-	O
dependent	O
manner	O
.	O

Allagille	O
'	O
s	O
syndrome	O
associated	O
with	O
antenatal	O
ascites	O

Sensitivity	O
and	O
specificity	O
was	O
established	O
for	O
the	O
Pharmacia	O
CAP	O
System	O
and	O
the	O
DPC	O
AlaSTAT	O
System	O
by	O
comparison	O
with	O
results	O
of	O
the	O
skin	O
prick	O
test	O
.	O

PSI	B-GENE
-	I-GENE
G	I-GENE
and	O
PSI	B-GENE
-	I-GENE
K	I-GENE
probably	O
have	O
evolved	O
from	O
a	O
gene	O
duplication	O
of	O
an	O
ancestral	O
gene	O
.	O

Site	O
-	O
directed	O
mutagenesis	O
revealed	O
that	O
two	O
clusters	O
of	O
basic	O
amino	O
acids	O
within	O
a	O
conserved	O
basic	O
region	O
and	O
two	O
amphipathic	O
helices	O
within	O
the	O
adjacent	O
HLH	O
domain	O
are	O
essential	O
for	O
sequence	O
-	O
specific	O
DNA	O
binding	O
and	O
hetero	O
-	O
oligomerization	O
,	O
respectively	O
.	O

Dimerization	O
of	O
Myf	B-GENE
-	I-GENE
5	I-GENE
with	O
the	O
ubiquitously	O
expressed	O
bHLH	O
protein	O
E12	B-GENE
not	O
only	O
increases	O
the	O
affinity	O
for	O
DNA	O
but	O
also	O
stimulates	O
transactivation	O
independently	O
of	O
DNA	O
binding	O
.	O

SEA	O
was	O
recorded	O
with	O
bidirectional	O
filters	O
at	O
25	O
-	O
250	O
HZ	O
and	O
40	O
-	O
250	O
Hz	O
using	O
Simson	O
method	O
.	O

Neural	O
-	O
specific	O
expression	O
,	O
genomic	O
structure	O
,	O
and	O
chromosomal	O
localization	O
of	O
the	O
gene	O
encoding	O
the	O
zinc	B-GENE
-	I-GENE
finger	I-GENE
transcription	I-GENE
factor	I-GENE
NGFI	I-GENE
-	I-GENE
C	I-GENE
.	O

An	O
experiment	O
examined	O
the	O
effects	O
of	O
treatment	O
with	O
gonadotrophin	B-GENE
releasing	I-GENE
hormone	I-GENE
(	O
100	O
micrograms	O
GnRH	B-GENE
injected	O
24	O
h	O
after	O
progestagen	O
sponge	O
removal	O
)	O
,	O
season	O
of	O
treatment	O
(	O
autumn	O
v	O
.	O
spring	O
)	O
,	O
the	O
effect	O
of	O
supplementary	O
feeding	O
with	O
lupin	O
grain	O
(	O
in	O
autumn	O
only	O
,	O
from	O
12	O
days	O
before	O
until	O
8	O
days	O
after	O
sponge	O
removal	O
)	O
on	O
the	O
time	O
of	O
ovulation	O
in	O
182	O
mature	O
Merino	O
ewes	O
superovulated	O
with	O
a	O
combination	O
of	O
400	O
I	O
.	O
U	O
.	O
pregnant	B-GENE
mare	I-GENE
serum	I-GENE
gonadotrophin	I-GENE
(	O
PMSG	B-GENE
)	O
and	O
12	O
mg	O
follicle	B-GENE
stimulating	I-GENE
hormone	I-GENE
(	O
FSH	B-GENE
-	I-GENE
P	I-GENE
)	O
.	O

Drug	O
-	O
drug	O
interactions	O
are	O
most	O
likely	O
to	O
occur	O
in	O
patients	O
receiving	O
multiple	O
medications	O
and	O
with	O
drugs	O
that	O
have	O
a	O
narrow	O
therapeutic	O
window	O
.	O

Total	O
body	O
irradiation	O
was	O
delivered	O
according	O
to	O
a	O
hyperfractionated	O
scheme	O
of	O
12	O
fractions	O
given	O
three	O
per	O
day	O
5	O
hr	O
apart	O
for	O
4	O
days	O
.	O

A	O
reduction	O
in	O
blood	O
pressure	O
was	O
only	O
observed	O
at	O
the	O
end	O
of	O
the	O
study	O
,	O
from	O
142	O
+	O
/	O
-	O
17	O
/	O
86	O
.	O
6	O
+	O
/	O
-	O
9	O
.	O
1	O
to	O
139	O
+	O
/	O
-	O
13	O
/	O
82	O
.	O
9	O
+	O
/	O
-	O
8	O
.	O
9	O
mmHg	O
(	O
P	O
less	O
than	O
0	O
.	O
05	O
for	O
DBP	O
)	O
.	O

A	O
gene	O
homologous	O
to	O
the	O
Escherichia	B-GENE
coli	I-GENE
dnaA	I-GENE
gene	I-GENE
was	O
isolated	O
from	O
Pseudomonas	O
putida	O
and	O
its	O
transcription	O
was	O
investigated	O
in	O
E	O
.	O
coli	O
as	O
well	O
as	O
in	O
P	O
.	O
putida	O
.	O

STP1	B-GENE
is	O
an	O
unessential	O
yeast	O
gene	O
involved	O
in	O
the	O
removal	O
of	O
intervening	O
sequences	O
from	O
some	O
,	O
but	O
not	O
all	O
,	O
families	O
of	O
intervening	O
sequence	O
-	O
containing	O
pre	O
-	O
tRNAs	O
.	O

Using	O
these	O
antibodies	O
,	O
we	O
were	O
able	O
to	O
define	O
the	O
conditions	O
to	O
completely	O
solubilize	O
the	O
Cdc25	B-GENE
protein	I-GENE
.	O

GCR1	B-GENE
gene	I-GENE
function	O
is	O
required	O
for	O
high	O
-	O
level	O
glycolytic	O
gene	O
expression	O
in	O
Saccharomyces	O
cerevisiae	O
.	O

The	O
decay	O
curves	O
of	O
chlorophyll	O
fluorescence	O
showed	O
a	O
superposition	O
of	O
three	O
exponentially	O
decaying	O
components	O
with	O
time	O
constants	O
of	O
T1	O
=	O
100	O
-	O
200	O
ps	O
,	O
T2	O
=	O
300	O
-	O
500	O
ps	O
and	O
T3	O
=	O
2	O
.	O
0	O
-	O
3	O
.	O
5	O
ns	O
.	O

After	O
tilting	O
,	O
systolic	O
blood	O
pressure	O
fell	O
an	O
average	O
of	O
17	O
%	O
in	O
patients	O
who	O
cramped	O
infrequently	O
(	O
p	O
=	O
0	O
.	O
0031	O
)	O
but	O
only	O
10	O
%	O
in	O
frequently	O
cramping	O
patients	O
.	O

Most	O
apneic	O
events	O
occurred	O
during	O
Stages	O
I	O
and	O
II	O
,	O
and	O
REM	O
,	O
but	O
this	O
proportion	O
was	O
less	O
during	O
the	O
gamma	O
OH	O
study	O
(	O
77	O
.	O
9	O
+	O
/	O
-	O
8	O
.	O
9	O
%	O
)	O
than	O
during	O
the	O
control	O
studies	O
(	O
92	O
.	O
3	O
+	O
/	O
-	O
1	O
.	O
9	O
and	O
95	O
.	O
9	O
+	O
/	O
-	O
2	O
.	O
2	O
%	O
)	O
,	O
apneas	O
occurring	O
even	O
during	O
SWS	O
with	O
gamma	O
OH	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
250	O
WORDS	O
)	O

Eight	O
rabbits	O
were	O
exposed	O
to	O
0	O
.	O
7	O
+	O
/	O
-	O
0	O
.	O
4	O
mg	O
/	O
m3	O
Co2	O
+	O
as	O
CoCl2	O
and	O
1	O
.	O
2	O
+	O
/	O
-	O
0	O
.	O
7	O
mg	O
/	O
m3	O
Cr3	O
+	O
as	O
Cr	O
(	O
NO3	O
)	O
3	O
(	O
group	O
Co	O
+	O
Cr	O
)	O
,	O
eight	O
to	O
0	O
.	O
6	O
+	O
/	O
-	O
0	O
.	O
5	O
mg	O
/	O
m3	O
Co2	O
+	O
(	O
group	O
Co	O
)	O
,	O
and	O
eight	O
to	O
filtered	O
air	O
(	O
control	O
group	O
)	O
,	O
for	O
4	O
months	O
,	O
5	O
days	O
/	O
week	O
,	O
and	O
6	O
hr	O
/	O
day	O
.	O

16	O
women	O
were	O
treated	O
with	O
methadone	O
to	O
prevent	O
withdrawal	O
symptoms	O
.	O

Disruption	O
demonstrates	O
that	O
CDC14	B-GENE
is	O
an	O
essential	O
gene	O
.	O

Coronary	O
flow	O
was	O
reduced	O
by	O
10	O
%	O
in	O
the	O
phosphocreatine	O
and	O
by	O
18	O
%	O
in	O
the	O
control	O
group	O
.	O

The	O
60A	B-GENE
transcripts	I-GENE
and	O
protein	O
are	O
first	O
detected	O
at	O
the	O
onset	O
of	O
gastrulation	O
,	O
primarily	O
in	O
the	O
mesoderm	O
of	O
the	O
extending	O
germ	O
band	O
.	O

Influence	O
of	O
neural	O
regulation	O
on	O
anti	O
-	O
arrhythmic	O
effects	O
of	O
GABA	O
in	O
rats	O

Recent	O
investigations	O
have	O
detailed	O
a	O
selective	O
dye	O
release	O
technique	O
in	O
which	O
a	O
pulse	O
of	O
laser	O
light	O
induces	O
the	O
release	O
of	O
a	O
fluorescent	O
dye	O
from	O
temperature	O
-	O
sensitive	O
liposomes	O
circulating	O
in	O
the	O
retinal	O
vasculature	O
.	O

And	O
the	O
natural	O
barriers	O
?	O

Three	O
pyridoxine	O
derivatives	O
have	O
been	O
isolated	O
from	O
the	O
fresh	O
stem	O
bark	O
of	O
Albizzia	O
julibrissin	O
DURAZZ	O
.	O
.	O

The	O
coating	O
materials	O
were	O
poloxamine	O
904	O
,	O
poloxamine	O
908	O
,	O
poloxamine	O
1508	O
,	O
poloxamer	O
338	O
,	O
and	O
Brij	O
35	O
.	O

The	O
eating	O
and	O
drinking	O
patterns	O
of	O
pygmy	O
goats	O
fed	O
ad	O
lib	O
and	O
kept	O
on	O
a	O
12	O
h	O
light	O
/	O
12	O
h	O
dark	O
cycle	O
were	O
recorded	O
and	O
analyzed	O
.	O

The	O
present	O
study	O
highlights	O
the	O
improvement	O
in	O
sputum	O
amoxycillin	O
(	O
amoxy	O
)	O
levels	O
when	O
a	O
combination	O
tablet	O
,	O
amoxy	O
500	O
mg	O
plus	O
bromhexeine	O
8	O
mg	O
,	O
is	O
administered	O
as	O
compared	O
to	O
plain	O
amoxy	O
500	O
mg	O
.	O

His	O
HC	B-GENE
II	I-GENE
activity	O
and	O
antigen	O
levels	O
were	O
49	O
%	O
and	O
50	O
%	O
,	O
respectively	O
,	O
and	O
his	O
daughter	O
also	O
showed	O
similar	O
low	O
levels	O
.	O

Argatroban	O
may	O
be	O
more	O
effective	O
under	O
low	O
HC	B-GENE
II	I-GENE
conditions	O
because	O
of	O
its	O
potent	O
inhibition	O
of	O
thrombin	B-GENE
activity	O
at	O
sites	O
of	O
vascular	O
wall	O
damage	O
.	O

Because	O
the	O
adrenergic	O
nervous	O
system	O
influences	O
cardiac	O
arrhythmias	O
and	O
myocardial	O
infarction	O
can	O
directly	O
affect	O
sympathetic	O
innervation	O
in	O
the	O
heart	O
,	O
we	O
investigated	O
the	O
role	O
of	O
the	O
sympathetic	O
nervous	O
system	O
on	O
reentry	O
in	O
the	O
canine	O
heart	O
4	O
days	O
after	O
infarction	O
.	O

Furthermore	O
,	O
no	O
transcripts	O
of	O
the	O
same	O
size	O
and	O
having	O
the	O
same	O
developmental	O
profile	O
as	O
those	O
generated	O
by	O
the	O
wild	B-GENE
-	I-GENE
type	I-GENE
E10	I-GENE
fragment	I-GENE
were	O
identified	O
by	O
probes	O
covering	O
the	O
remainder	O
of	O
the	O
cloned	O
region	O
.	O

Intravenous	O
amine	O
pressor	O
tests	O
in	O
healthy	O
volunteers	O
.	O

The	O
mean	O
minimum	O
steady	O
-	O
state	O
concentration	O
after	O
the	O
oral	O
regimen	O
(	O
23	O
micrograms	O
.	O
l	O
-	O
1	O
)	O
was	O
78	O
%	O
of	O
that	O
after	O
the	O
intramuscular	O
regime	O
(	O
29	O
micrograms	O
.	O
l	O
-	O
1	O
)	O
.	O

In	O
an	O
ongoing	O
study	O
the	O
performance	O
of	O
the	O
SMSP	O
is	O
being	O
compared	O
with	O
that	O
of	O
the	O
Mini	O
Speech	O
Processor	O
(	O
MSP	O
)	O
.	O

These	O
mutant	O
proteins	O
retained	O
the	O
ability	O
to	O
competitively	O
inhibit	O
kappa	B-GENE
B	I-GENE
-	O
mediated	O
transcriptional	O
activation	O
of	O
the	O
human	B-GENE
immunodeficiency	I-GENE
virus	I-GENE
long	I-GENE
terminal	I-GENE
repeat	I-GENE
but	O
failed	O
to	O
efficiently	O
transform	O
chicken	O
lymphoid	O
cells	O
both	O
in	O
vitro	O
and	O
in	O
vivo	O
.	O

The	O
sequence	O
-	O
specific	O
interaction	O
of	O
nuclear	B-GENE
factor	I-GENE
HiNF	I-GENE
-	I-GENE
D	I-GENE
with	O
this	O
key	O
proximal	O
promoter	O
element	O
of	O
the	O
H4	B-GENE
-	I-GENE
FO108	I-GENE
gene	I-GENE
is	O
cell	O
cycle	O
regulated	O
in	O
normal	O
diploid	O
cells	O
(	O
J	O
.	O

In	O
conclusion	O
,	O
to	O
study	O
and	O
overcome	O
TI	O
region	O
-	O
based	O
expression	O
problems	O
it	O
is	O
worthwhile	O
to	O
start	O
out	O
with	O
a	O
versatile	O
vector	O
containing	O
exhaustive	O
mutations	O
in	O
the	O
periShine	O
-	O
Dalgarno	O
sequences	O
;	O
as	O
a	O
rule	O
the	O
coding	O
MTI	O
subregion	O
can	O
be	O
kept	O
unchanged	O
.	O

Four	O
of	O
these	O
five	O
subjects	O
also	O
performed	O
mixed	O
sequences	O
under	O
conditional	O
control	O
of	O
the	O
words	O
(	O
e	O
.	O
g	O
.	O
,	O
A1	O
-	O
-	O
-	O
-	O
B2	O
-	O
-	O
-	O
-	O
A3	O
-	O
-	O
-	O
-	O
B4	O
-	O
-	O
-	O
-	O
A5	O
and	O
its	O
reversal	O
)	O
,	O
verifying	O
that	O
the	O
stimuli	O
which	O
occupied	O
the	O
same	O
position	O
in	O
each	O
sequence	O
were	O
members	O
of	O
the	O
same	O
class	O
.	O

While	O
blood	O
pressure	O
and	O
noradrenergic	O
activity	O
,	O
assessed	O
as	O
changes	O
in	O
the	O
plasma	O
levels	O
and	O
urinary	O
excretion	O
of	O
norepinephrine	O
,	O
remained	O
unaffected	O
in	O
the	O
Pl	O
group	O
,	O
a	O
significant	O
drop	O
in	O
the	O
supine	O
systolic	O
and	O
diastolic	O
blood	O
pressures	O
,	O
as	O
well	O
as	O
in	O
the	O
resting	O
venous	O
norepinephrine	O
level	O
and	O
in	O
urinary	O
norepinephrine	O
excretion	O
was	O
found	O
after	O
the	O
first	O
month	O
of	O
dF	O
administration	O
.	O

Wild	O
-	O
type	O
protein	O
bound	O
azido	O
-	O
ATP	O
well	O
,	O
but	O
mutants	O
with	O
substitutions	O
in	O
the	O
consensus	O
amino	O
acids	O
were	O
unable	O
to	O
bind	O
azido	O
-	O
ATP	O
.	O

Therefore	O
,	O
with	O
a	O
biopsy	O
from	O
the	O
stoma	O
site	O
there	O
is	O
a	O
risk	O
of	O
missing	O
early	O
rejection	O
.	O

Whole	O
blood	O
serotonin	O
levels	O
were	O
investigated	O
in	O
a	O
control	O
group	O
(	O
n	O
=	O
35	O
)	O
and	O
in	O
a	O
group	O
of	O
chronic	O
renal	O
failure	O
patients	O
(	O
n	O
=	O
127	O
)	O
on	O
various	O
treatment	O
regimen	O
i	O
.	O
e	O
.	O
conservative	O
treatment	O
(	O
n	O
=	O
39	O
)	O
,	O
maintenance	O
haemodialysis	O
(	O
n	O
=	O
35	O
)	O
and	O
after	O
renal	O
transplantation	O
(	O
n	O
=	O
53	O
)	O
.	O

Tissues	O
and	O
exudates	O
contain	O
sufficient	O
thymidine	O
for	O
growth	O
of	O
anaerobic	O
bacteria	O
in	O
the	O
presence	O
of	O
inhibitory	O
levels	O
of	O
trimethoprim	O
-	O
sulfamethoxazole	O
.	O

The	O
homologies	O
between	O
RAD16	B-GENE
,	O
RAD54	B-GENE
and	O
SNF2	B-GENE
are	O
also	O
shared	O
by	O
several	O
additional	O
,	O
recently	O
isolated	O
yeast	O
and	O
Drosophila	O
genes	O
.	O

But	O
the	O
application	O
solutions	O
of	O
instrument	O
disinfectants	O
should	O
not	O
be	O
used	O
longer	O
than	O
one	O
day	O
.	O

In	O
the	O
Rett	O
syndrome	O
we	O
,	O
therefore	O
,	O
suspect	O
there	O
are	O
disturbances	O
in	O
the	O
brain	O
stem	O
functions	O
especially	O
in	O
the	O
ascending	O
reticular	O
activating	O
system	O
which	O
is	O
related	O
to	O
elevation	O
of	O
the	O
conscious	O
level	O
.	O

In	O
a	O
similar	O
experiment	O
,	O
simultaneous	O
nitrofurazone	O
administration	O
and	O
S	O
.	O
enteritidis	O
challenge	O
resulted	O
in	O
no	O
significant	O
differences	O
in	O
S	O
.	O
enteritidis	O
isolation	O
frequency	O
.	O

In	O
agreement	O
with	O
this	O
southern	O
blotting	O
of	O
mouse	O
DNA	O
with	O
SmN	B-GENE
probes	O
reveals	O
bands	O
,	O
additional	O
to	O
those	O
derived	O
from	O
the	O
pseudogene	O
,	O
which	O
are	O
characteristic	O
of	O
an	O
intron	O
-	O
containing	O
SmN	B-GENE
gene	I-GENE
.	O

Two	O
cDNAs	O
encoding	O
casein	B-GENE
kinase	I-GENE
-	I-GENE
1	I-GENE
have	O
been	O
isolated	O
from	O
a	O
yeast	O
cDNA	O
library	O
and	O
termed	O
CKI1	B-GENE
and	O
CKI2	B-GENE
.	O

Incidence	O
rate	O
ranging	O
between	O
122	O
/	O
100	O
,	O
000	O
/	O
year	O
and	O
190	O
/	O
100	O
,	O
000	O
/	O
year	O
were	O
found	O
(	O
minimum	O
,	O
estimated	O
and	O
raw	O
datasets	O
)	O
.	O

The	O
observed	O
sequence	O
variation	O
disrupts	O
the	O
first	O
ORF	O
in	O
many	O
Y	B-GENE
'	O
s	O
while	O
most	O
of	O
the	O
second	O
ORF	O
including	O
the	O
putative	O
helicase	B-GENE
region	I-GENE
is	O
unaffected	O
.	O

The	O
final	O
screening	O
yielded	O
a	O
clone	O
containing	O
a	O
2	O
kilobase	O
(	O
kb	O
)	O
insert	O
.	O

Lesions	O
were	O
made	O
by	O
pressure	O
injection	O
of	O
kainic	O
acid	O
into	O
the	O
SOC	O
through	O
a	O
stereotaxically	O
positioned	O
glass	O
micropipette	O
.	O

A	O
38	O
-	O
bp	O
poly	O
(	O
dA	O
-	O
dT	O
)	O
region	O
was	O
found	O
to	O
be	O
a	O
positive	O
regulator	O
of	O
Act1	B-GENE
promoter	I-GENE
activity	O
.	O

We	O
identified	O
a	O
protein	O
,	O
termed	O
NFIL	B-GENE
-	I-GENE
1	I-GENE
beta	I-GENE
A	I-GENE
(	O
NF	B-GENE
beta	I-GENE
A	I-GENE
)	O
,	O
that	O
binds	O
to	O
a	O
highly	O
conserved	O
12	O
-	O
bp	O
DNA	O
sequence	O
(	O
-	O
49	O
to	O
-	O
38	O
)	O
located	O
upstream	O
of	O
the	O
TATA	O
box	O
motif	O
in	O
both	O
the	O
human	B-GENE
and	I-GENE
murine	I-GENE
IL	I-GENE
-	I-GENE
1	I-GENE
beta	I-GENE
genes	I-GENE
.	O

We	O
tried	O
amphotericin	O
B	O
(	O
AmB	O
)	O
,	O
and	O
remission	O
of	O
the	O
tumor	O
was	O
obtained	O
.	O

Cutis	O
aplasia	O
.	O

The	O
DRF	B-GENE
-	I-GENE
2	I-GENE
nuclear	I-GENE
protein	I-GENE
has	O
characteristics	O
similar	O
to	O
those	O
of	O
the	O
muscle	O
-	O
specific	O
regulatory	O
factor	O
,	O
MEF	B-GENE
-	I-GENE
2	I-GENE
(	O
Buskin	O
and	O
Hauschka	O
1989	O
;	O
Gossett	O
et	O
al	O
.	O
,	O
1989	O
)	O
.	O

From	O
the	O
15	O
-	O
kb	O
clone	O
a	O
4	B-GENE
-	I-GENE
kb	I-GENE
EcoRI	I-GENE
fragment	I-GENE
containing	O
the	O
first	O
two	O
exons	O
and	O
2	O
.	O
6	O
kb	O
of	O
the	O
5	O
'	O
flanking	O
region	O
of	O
the	O
opn	B-GENE
gene	I-GENE
was	O
sequenced	O
,	O
and	O
the	O
transcriptional	O
start	O
site	O
determined	O
by	O
primer	O
extension	O
analysis	O
and	O
S1	B-GENE
nuclease	I-GENE
mapping	O
.	O

Cardiovascular	O
risk	O
factors	O
were	O
measured	O
by	O
standardized	O
techniques	O
.	O

Production	O
costs	O
included	O
feed	O
,	O
non	O
-	O
feed	O
operating	O
,	O
fixed	O
,	O
and	O
replacement	O
stock	O
costs	O
.	O

We	O
report	O
a	O
patient	O
developing	O
factor	B-GENE
VII	I-GENE
inhibitor	I-GENE
possibly	O
as	O
a	O
reaction	O
to	O
penicillin	O
administration	O
;	O
it	O
gave	O
rise	O
to	O
fatal	O
haemorrhage	O
.	O

Account	O
was	O
taken	O
of	O
noncellular	O
and	O
nonhuman	O
elements	O
in	O
the	O
smears	O
;	O
they	O
included	O
mucus	O
,	O
Charcot	O
-	O
Layden	O
crystals	O
,	O
pollen	O
grains	O
,	O
vegetal	O
fragments	O
and	O
fungi	O
.	O

The	O
results	O
indicate	O
that	O
the	O
carbon	O
-	O
perfused	O
areas	O
and	O
MBF	O
in	O
the	O
liver	O
,	O
renal	O
cortex	O
,	O
spleen	O
,	O
and	O
small	O
intestinal	O
serosa	O
(	O
only	O
MBF	O
)	O
increased	O
significantly	O
5	O
h	O
after	O
CLP	O
.	O

Lewis	O
,	O
N	O
.	O

This	O
accurate	O
and	O
rapid	O
method	O
makes	O
the	O
MLPA	O
test	O
logistically	O
feasible	O
for	O
large	O
-	O
scale	O
screening	O
.	O

The	O
modalities	O
for	O
using	O
reference	O
values	O
for	O
individual	O
subjects	O
as	O
well	O
as	O
for	O
groups	O
are	O
then	O
discussed	O
and	O
the	O
main	O
points	O
of	O
research	O
which	O
must	O
be	O
faced	O
in	O
the	O
near	O
future	O
regarding	O
reference	O
values	O
are	O
highlighted	O
.	O

The	O
clinical	O
application	O
of	O
the	O
antibody	O
-	O
targeted	O
Phthalocyanine	O
was	O
performed	O
in	O
3	O
patients	O
suffering	O
from	O
an	O
advanced	O
ovarian	O
carcinoma	O
(	O
FIGO	O
III	O
)	O
.	O

We	O
found	O
that	O
lung	O
cancer	O
tissues	O
of	O
positive	O
67Ga	O
scan	O
expressed	O
TFR	B-GENE
,	O
but	O
those	O
of	O
a	O
negative	O
scan	O
did	O
not	O
.	O

This	O
open	O
reading	O
frame	O
was	O
confirmed	O
the	O
correct	O
one	O
by	O
direct	O
amino	O
-	O
terminal	O
sequence	O
analysis	O
of	O
the	O
overproduced	O
msgB	B-GENE
gene	I-GENE
product	I-GENE
.	O

In	O
this	O
study	O
,	O
we	O
purified	O
and	O
characterized	O
the	O
recombinant	B-GENE
furin	I-GENE
from	O
the	O
conditioned	O
medium	O
of	O
these	O
cells	O
.	O

The	O
virus	O
encodes	O
a	O
40	O
-	O
kDa	O
protein	O
,	O
tax	B-GENE
,	O
that	O
is	O
important	O
for	O
the	O
immortalization	O
of	O
T	O
cells	O
.	O

However	O
,	O
butyrate	O
was	O
at	O
least	O
2	O
-	O
fold	O
more	O
effective	O
in	O
stimulating	O
CAT	B-GENE
activity	O
of	O
fusion	O
genes	O
containing	O
upstream	O
sequences	O
(	O
-	O
834	O
to	O
-	O
576	O
)	O
than	O
those	O
containing	O
proximal	O
sequences	O
(	O
-	O
456	O
to	O
-	O
172	O
)	O
,	O
suggesting	O
two	O
regions	O
in	O
the	O
PSG1	B-GENE
-	I-GENE
I	I-GENE
gene	I-GENE
that	O
mediate	O
the	O
butyrate	O
response	O
.	O

An	O
examination	O
of	O
the	O
role	O
of	O
the	O
carboxyl	O
terminus	O
in	O
regulating	O
NGFI	B-GENE
-	I-GENE
B	I-GENE
transcriptional	O
activity	O
revealed	O
that	O
,	O
in	O
accordance	O
with	O
other	O
nuclear	O
receptors	O
,	O
mutants	O
lacking	O
portions	O
of	O
the	O
carboxyl	O
terminus	O
had	O
greatly	O
decreased	O
activity	O
.	O

Altogether	O
these	O
results	O
indicate	O
that	O
the	O
Syn	B-GENE
5	I-GENE
locus	I-GENE
segregates	O
from	O
the	O
gene	O
specifying	O
gH	B-GENE
,	O
to	O
a	O
region	O
encompassing	O
portions	O
of	O
the	O
TK	B-GENE
and	O
UL	B-GENE
24	I-GENE
genes	I-GENE
,	O
and	O
that	O
the	O
syn	B-GENE
mutation	I-GENE
does	O
not	O
affect	O
the	O
expression	O
or	O
activity	O
of	O
TK	B-GENE
.	O

Nucleoprotein	O
(	O
N	O
)	O
expressed	O
by	O
both	O
recombinant	O
vaccinia	O
virus	O
and	O
TGEV	O
had	O
a	O
relative	O
molecular	O
mass	O
(	O
Mr	O
)	O
of	O
47	O
,	O
000	O
and	O
was	O
susceptible	O
to	O
degradation	O
at	O
the	O
C	O
-	O
terminus	O
yielding	O
discrete	O
breakdown	O
products	O
.	O

Recently	O
,	O
the	O
3	B-GENE
.	I-GENE
6	I-GENE
-	I-GENE
kb	I-GENE
full	I-GENE
-	I-GENE
length	I-GENE
alpha	I-GENE
-	I-GENE
GalNAc	I-GENE
cDNA	I-GENE
sequence	I-GENE
was	O
isolated	O
and	O
found	O
to	O
have	O
remarkable	O
nucleotide	O
and	O
predicted	O
amino	O
acid	O
homology	O
(	O
55	O
.	O
8	O
and	O
46	O
.	O
9	O
%	O
,	O
respectively	O
)	O
with	O
the	O
human	B-GENE
alpha	I-GENE
-	I-GENE
galactosidase	I-GENE
A	I-GENE
(	O
alpha	B-GENE
-	I-GENE
Gal	I-GENE
A	I-GENE
)	O
cDNA	O
.	O

The	O
reason	O
that	O
nitrous	O
oxide	O
does	O
not	O
produce	O
hydroxyl	O
radicals	O
readily	O
might	O
be	O
that	O
the	O
one	O
-	O
electron	O
reduction	O
proceeds	O
through	O
an	O
N2O	O
-	O
intermediate	O
which	O
is	O
energetically	O
very	O
unfavourable	O
:	O
EO	O
(	O
N2O	O
/	O
N2O	O
-	O
)	O
=	O
-	O
1	O
.	O
1	O
V	O
.	O

All	O
mutant	B-GENE
JCV	I-GENE
T	I-GENE
antigens	I-GENE
bound	O
to	O
JCV	O
and	O
SV40	O
origins	O
of	O
DNA	O
replication	O
.	O

Since	O
each	O
transcript	O
appears	O
to	O
encode	O
the	O
same	O
protein	O
,	O
this	O
complexity	O
may	O
reflect	O
the	O
need	O
for	O
lineage	O
-	O
specific	O
or	O
differentiation	O
-	O
dependent	O
control	O
of	O
expression	O
.	O

In	O
patients	O
with	O
limited	O
disease	O
,	O
the	O
survival	O
in	O
the	O
alternating	O
arm	O
was	O
significantly	O
superior	O
to	O
the	O
survival	O
in	O
the	O
CAV	O
arm	O
(	O
P	O
=	O
.	O
014	O
)	O
or	O
the	O
survival	O
in	O
the	O
PE	O
arm	O
(	O
P	O
=	O
.	O
023	O
)	O
.	O

We	O
identify	O
the	O
"	O
M	O
region	O
"	O
of	O
the	O
muscle	B-GENE
-	I-GENE
specific	I-GENE
Xenopus	I-GENE
cardiac	I-GENE
actin	I-GENE
gene	I-GENE
promoter	I-GENE
from	O
-	O
282	O
to	O
-	O
348	O
as	O
necessary	O
for	O
the	O
embryonic	O
expression	O
of	O
a	O
cardiac	O
actin	B-GENE
-	O
beta	B-GENE
-	I-GENE
globin	I-GENE
reporter	O
gene	O
injected	O
into	O
fertilized	O
eggs	O
.	O

In	O
addition	O
to	O
the	O
previously	O
identified	O
and	O
characterized	O
attenuator	B-GENE
1	I-GENE
situated	O
93	O
nucleotides	O
downstream	O
from	O
the	O
major	O
late	O
transcription	O
start	O
site	O
,	O
a	O
second	O
attenuator	O
,	O
attenuator	B-GENE
2	I-GENE
,	O
situated	O
55	O
nucleotides	O
downstream	O
from	O
it	O
,	O
has	O
been	O
identified	O
.	O

EBNA	B-GENE
-	I-GENE
2	I-GENE
and	O
the	O
cis	O
-	O
acting	O
CD23	B-GENE
element	I-GENE
increased	O
TK	B-GENE
-	O
promoted	O
mRNA	O
and	O
did	O
not	O
alter	O
the	O
herpes	B-GENE
simplex	I-GENE
virus	I-GENE
TK	I-GENE
promoter	I-GENE
transcription	I-GENE
start	I-GENE
site	I-GENE
.	O

These	O
experiments	O
delineate	O
a	O
186	O
-	O
bp	O
,	O
EBNA	B-GENE
-	I-GENE
2	I-GENE
-	O
responsive	O
cell	O
DNA	O
fragment	O
and	O
provide	O
firm	O
evidence	O
that	O
EBNA	B-GENE
-	I-GENE
2	I-GENE
transactivates	O
transcription	O
of	O
cell	O
genes	O
.	O

Plasma	O
vitamin	O
E	O
,	O
total	O
lipids	O
and	O
myeloperoxidase	B-GENE
levels	O
during	O
spinal	O
surgery	O
.	O

Transfecting	O
the	O
cloned	O
bovine	O
PBR	B-GENE
/	O
IBP	B-GENE
cDNA	O
into	O
COS	O
-	O
7	O
cells	O
resulted	O
in	O
an	O
11	O
-	O
fold	O
increase	O
in	O
the	O
density	O
of	O
high	O
affinity	O
[	O
3H	O
]	O
PK	O
11195	O
binding	O
sites	O
which	O
had	O
only	O
low	O
affinity	O
for	O
Ro5	O
-	O
4864	O
.	O

The	O
initial	O
phase	O
of	O
increased	O
vascular	O
permeability	O
in	O
the	O
peritoneal	O
cavity	O
and	O
LTB4	O
production	O
was	O
dose	O
dependently	O
inhibited	O
by	O
the	O
5	O
-	O
LO	O
inhibitors	O
phenidone	O
,	O
BW	O
A4C	O
,	O
A63162	O
,	O
and	O
ICI	O
207	O
968	O
but	O
not	O
by	O
dexamethasone	O
or	O
colchicine	O
.	O

Discrepant	O
results	O
with	O
a	O
latex	O
agglutination	O
test	O
in	O
the	O
assessment	O
of	O
cytomegalovirus	O
antibody	O
status	O
of	O
cardiac	O
transplant	O
donors	O
.	O

Each	O
mRNA	O
contained	O
five	O
or	O
six	O
internal	O
uridine	O
residues	O
,	O
which	O
were	O
transcribed	O
using	O
a	O
mixture	O
of	O
UTP	O
and	O
thio	O
-	O
UTP	O
.	O

We	O
have	O
isolated	O
and	O
sequenced	O
two	O
overlapping	O
cDNA	O
fragments	O
which	O
could	O
encode	O
the	O
complete	O
amino	O
acid	O
sequence	O
of	O
rat	B-GENE
testis	I-GENE
fructose	I-GENE
-	I-GENE
6	I-GENE
-	I-GENE
phosphate	I-GENE
,	I-GENE
2	I-GENE
-	I-GENE
kinase	I-GENE
:	O
fructose	B-GENE
-	I-GENE
2	I-GENE
,	I-GENE
6	I-GENE
-	I-GENE
bisphosphatase	I-GENE
.	O

We	O
have	O
identified	O
SWI5	B-GENE
'	O
s	O
nuclear	O
localization	O
signal	O
(	O
NLS	O
)	O
and	O
show	O
that	O
it	O
can	O
confer	O
cell	O
cycle	O
-	O
dependent	O
nuclear	O
entry	O
to	O
a	O
heterologous	O
protein	O
.	O

In	O
contrast	O
to	O
behavioral	O
deviation	O
(	O
the	O
avoidance	O
conditioning	O
lost	O
)	O
,	O
the	O
haloperidol	O
intrastriatal	O
microinjections	O
did	O
not	O
affect	O
the	O
DA	O
synaptic	O
level	O
in	O
rostral	O
neostriatum	O
.	O

In	O
similar	O
transient	O
transfection	O
experiments	O
in	O
HeLa	O
cells	O
,	O
overexpression	O
of	O
the	O
wt	B-GENE
human	I-GENE
retinoblastoma	I-GENE
susceptibility	I-GENE
gene	I-GENE
product	I-GENE
,	O
RB	B-GENE
,	O
was	O
found	O
to	O
repress	O
the	O
serum	O
-	O
induced	O
IL	B-GENE
-	I-GENE
6	I-GENE
(	O
-	O
225	O
to	O
+	O
13	O
)	O
,	O
c	B-GENE
-	I-GENE
fos	I-GENE
(	O
-	O
711	O
to	O
+	O
42	O
)	O
,	O
and	O
beta	B-GENE
-	I-GENE
actin	I-GENE
(	O
-	O
3400	O
to	O
+	O
912	O
)	O
promoters	O
but	O
not	O
the	O
PRV	O
-	O
induced	O
IL	B-GENE
-	I-GENE
6	I-GENE
(	O
-	O
110	O
to	O
+	O
13	O
)	O
or	O
the	O
serum	O
-	O
induced	O
MHC	B-GENE
(	O
-	O
528	O
to	O
-	O
38	O
)	O
promoters	O
.	O

This	O
repression	O
was	O
mediated	O
through	O
binding	O
to	O
the	O
E2	B-GENE
DNA	I-GENE
-	I-GENE
binding	I-GENE
site	I-GENE
immediately	O
upstream	O
of	O
the	O
P105	B-GENE
promoter	O
TATA	O
box	O
and	O
could	O
be	O
abrogated	O
by	O
preincubation	O
of	O
the	O
HPV	B-GENE
-	I-GENE
18	I-GENE
P105	I-GENE
promoter	I-GENE
template	O
with	O
the	O
nuclear	O
extract	O
allowing	O
the	O
formation	O
of	O
the	O
preinitiation	O
complex	O
.	O

We	O
did	O
not	O
detect	O
p50	B-GENE
in	O
association	O
with	O
native	B-GENE
glucocorticoid	I-GENE
receptor	I-GENE
in	O
L	O
cells	O
or	O
with	O
the	O
overexpressed	O
glucocorticoid	B-GENE
receptor	I-GENE
in	O
Chinese	O
hamster	O
ovary	O
cells	O
.	O

Two	O
putative	O
12	O
-	O
O	O
-	O
tetradecanoyl	O
-	O
phorbol	O
-	O
13	O
-	O
acetate	O
(	O
TPA	O
)	O
response	O
elements	O
,	O
that	O
might	O
serve	O
as	O
binding	O
sites	O
for	O
the	O
transcription	B-GENE
factor	I-GENE
AP	I-GENE
-	I-GENE
1	I-GENE
and	O
a	O
consensus	O
sequence	O
of	O
a	O
transforming	B-GENE
growth	I-GENE
factor	I-GENE
beta	I-GENE
1	I-GENE
(	O
TGF	B-GENE
-	I-GENE
beta	I-GENE
1	I-GENE
)	O
inhibitory	O
element	O
were	O
found	O
in	O
the	O
promoter	O
region	O
.	O

TPA	O
and	O
TGF	B-GENE
-	I-GENE
beta	I-GENE
1	I-GENE
did	O
not	O
markedly	O
affect	O
the	O
activities	O
of	O
the	O
72	O
-	O
kDa	O
enzyme	O
.	O

They	O
were	O
almost	O
regularly	O
excited	O
by	O
pressure	O
to	O
the	O
ipsilateral	O
cornea	O
or	O
to	O
both	O
corneas	O
at	O
a	O
strength	O
well	O
above	O
the	O
human	O
corneal	O
pain	O
threshold	O
.	O

Feed	O
intake	O
was	O
not	O
affected	O
by	O
dietary	O
KCl	O
or	O
NaHCO3	O
supplementation	O
,	O
but	O
average	O
daily	O
gain	O
increased	O
with	O
increased	O
K	O
and	O
tended	O
to	O
be	O
reduced	O
by	O
dietary	O
NaHCO3	O
.	O

Extraction	O
procedure	O
for	O
the	O
measurement	O
of	O
butyltin	O
compounds	O
in	O
biological	O
tissues	O
using	O
toluene	O
,	O
HBr	O
,	O
and	O
tropolone	O
.	O

In	O
this	O
study	O
,	O
we	O
have	O
cloned	O
a	O
region	O
that	O
complements	O
the	O
exoenzyme	B-GENE
S	I-GENE
-	O
deficient	O
phenotype	O
of	O
strain	O
388	O
exs1	B-GENE
:	O
:	O
Tn1	B-GENE
,	O
a	O
chromosomal	B-GENE
Tn1	I-GENE
insertional	I-GENE
mutation	I-GENE
.	O

Alignment	O
of	O
the	O
amino	O
acid	O
sequences	O
surrounding	O
Tyr	O
-	O
766	O
with	O
corresponding	O
regions	O
of	O
other	O
FGFRs	B-GENE
revealed	O
conserved	O
tyrosine	O
residues	O
in	O
all	O
known	O
members	O
of	O
the	O
FGFR	B-GENE
family	I-GENE
.	O

The	O
transcription	O
initiation	O
site	O
was	O
determined	O
to	O
occur	O
66	O
bp	O
upstream	O
of	O
the	O
initiating	O
Met	O
.	O

All	O
anti	B-GENE
-	I-GENE
I	I-GENE
and	O
anti	B-GENE
-	I-GENE
i	I-GENE
CA	I-GENE
were	O
shown	O
to	O
express	O
VH4	B-GENE
heavy	I-GENE
chains	I-GENE
,	O
and	O
14	O
of	O
17	O
CA	B-GENE
expressed	O
a	O
previously	O
described	O
VH4	B-GENE
second	O
hypervariable	O
region	O
determinant	O
,	O
termed	O
VH4	B-GENE
-	I-GENE
HV2a	I-GENE
.	O

Intron	O
K1	B-GENE
cox1	I-GENE
.	I-GENE
2	I-GENE
is	O
not	O
found	O
in	O
S	O
.	O
cerevisiae	O
and	O
appears	O
at	O
an	O
unique	O
location	O
in	O
K	O
.	O
lactis	O
.	O

We	O
have	O
determined	O
that	O
the	O
mutants	O
define	O
two	O
complementation	O
groups	O
,	O
designated	O
cgs1	B-GENE
+	I-GENE
and	O
cgs2	B-GENE
+	I-GENE
(	O
continues	O
to	O
grow	O
in	O
stationary	O
)	O
.	O

The	O
results	O
of	O
induced	O
coexpression	O
were	O
also	O
supported	O
by	O
rapid	O
generation	O
of	O
FeLV	O
recombinants	O
when	O
FeLV	O
-	O
C	O
was	O
used	O
to	O
infect	O
the	O
feline	O
3201B	O
cell	O
line	O
that	O
constitutively	O
expresses	O
high	O
levels	O
of	O
endogenous	O
FeLV	O
-	O
specific	O
mRNAs	O
.	O

Recombination	O
between	O
feline	O
leukemia	O
virus	O
subgroup	O
B	O
or	O
C	O
and	O
endogenous	O
env	B-GENE
elements	O
alters	O
the	O
in	O
vitro	O
biological	O
activities	O
of	O
the	O
viruses	O
.	O

The	O
nucleotide	O
sequences	O
at	O
the	O
5	O
'	O
and	O
3	O
'	O
ends	O
of	O
these	O
introns	O
are	O
characteristic	O
of	O
spliced	O
transcripts	O
from	O
eukaryotic	O
protein	O
-	O
encoding	O
genes	O
,	O
with	O
one	O
significant	O
difference	O
;	O
i	O
.	O
e	O
.	O
,	O
the	O
5	O
'	O
end	O
of	O
the	O
LAT	B-GENE
intron	I-GENE
is	O
GC	O
instead	O
of	O
the	O
consensus	O
sequence	O
GT	O
.	O

At	O
1	O
,	O
5	O
,	O
and	O
9	O
months	O
after	O
initial	O
isolation	O
of	O
C	O
.	O
kutscheri	O
from	O
the	O
oral	O
cavity	O
,	O
hamsters	O
were	O
euthanatized	O
,	O
and	O
attempts	O
were	O
made	O
to	O
culture	O
C	O
.	O
kutscheri	O
from	O
13	O
additional	O
sites	O
.	O

The	O
strategy	O
has	O
been	O
used	O
to	O
determine	O
2	O
.	O
6	O
kilobases	O
of	O
nucleotide	O
sequence	O
in	O
the	O
Saccharomyces	B-GENE
cerevisiae	I-GENE
ADE	I-GENE
1	I-GENE
locus	I-GENE
.	O

Two	O
independent	O
promoters	O
as	O
well	O
as	O
5	O
'	O
untranslated	O
regions	O
regulate	O
Dd	B-GENE
ras	I-GENE
expression	O
in	O
Dictyostelium	O
.	O

The	O
results	O
suggested	O
that	O
,	O
depending	O
upon	O
the	O
cell	O
type	O
,	O
gene	O
cotransfer	O
using	O
aminoglycoside	O
resistance	O
as	O
a	O
selectable	O
marker	O
may	O
seriously	O
perturb	O
important	O
cellular	O
control	O
mechanisms	O
such	O
as	O
the	O
PKC	B-GENE
pathway	O
leading	O
to	O
activation	O
of	O
gene	O
expression	O
.	O

Therefore	O
,	O
the	O
strD	B-GENE
and	O
strE	B-GENE
genes	I-GENE
could	O
serve	O
as	O
universal	O
probes	O
indicative	O
of	O
the	O
presence	O
of	O
biosynthetic	O
capacity	O
for	O
6	O
-	O
deoxyhexose	O
moieties	O
.	O

The	O
two	O
genes	O
code	O
for	O
polypeptides	B-GENE
of	I-GENE
420	I-GENE
amino	I-GENE
acids	I-GENE
(	I-GENE
M	I-GENE
.	I-GENE
HgiCI	I-GENE
)	I-GENE
and	O
345	B-GENE
amino	I-GENE
acids	I-GENE
(	I-GENE
R	I-GENE
.	I-GENE
HgiCI	I-GENE
)	I-GENE
.	O

Expression	O
of	O
the	O
wt1	B-GENE
gene	I-GENE
via	O
transient	O
transfection	O
in	O
COS	O
-	O
1	O
cells	O
revealed	O
a	O
52	O
kDa	O
protein	O
which	O
was	O
immunoprecipitated	O
by	O
both	O
the	O
N	O
-	O
terminal	O
-	O
and	O
C	O
-	O
terminal	O
-	O
specific	O
antisera	O
.	O

The	O
factor	O
which	O
binds	O
to	O
the	O
TR	B-GENE
promoter	I-GENE
co	O
-	O
sedimented	O
with	O
SV40	O
chromosomes	O
extracted	O
late	O
in	O
infection	O
.	O

Temafloxacin	O
400	O
mg	O
b	O
.	O
i	O
.	O
d	O
.	O
administered	O
orally	O
for	O
28	O
days	O
represents	O
a	O
safe	O
and	O
effective	O
treatment	O
for	O
chronic	O
bacterial	O
prostatitis	O
.	O

Its	O
neuromuscular	O
effects	O
are	O
similar	O
to	O
a	O
single	O
ED90	O
dose	O
of	O
vecuronium	O
.	O

The	O
patient	O
with	O
a	O
prolonged	O
fever	O
caused	O
by	O
dissecting	O
aneurysm	O
of	O
the	O
aorta	O
in	O
whom	O
pleuropneumonia	O
masked	O
the	O
real	O
diseases	O
has	O
been	O
presented	O
.	O

The	O
resulting	O
clone	O
pKB11	B-GENE
,	O
which	O
has	O
a	O
1369	O
-	O
base	O
pair	O
(	O
bp	O
)	O
cDNA	O
insert	O
,	O
overlapping	O
pCAD142	B-GENE
by	O
781	O
bp	O
,	O
was	O
identified	O
by	O
hybridization	O
methods	O
and	O
sequence	O
analysis	O
and	O
found	O
to	O
contain	O
the	O
entire	O
cDNA	O
sequence	O
for	O
the	O
amino	O
end	O
of	O
the	O
CAD	B-GENE
polypeptide	I-GENE
.	O

This	O
conclusion	O
was	O
confirmed	O
by	O
Northern	O
blotting	O
analysis	O
of	O
the	O
5	O
'	O
-	O
flanking	O
region	O
of	O
CAD	B-GENE
gene	I-GENE
.	O

We	O
report	O
the	O
isolation	O
of	O
genomic	O
and	O
cDNA	O
clones	O
of	O
the	O
light	O
-	O
independent	O
Sn	B-GENE
:	I-GENE
bol3	I-GENE
allele	I-GENE
.	O

Its	O
clearance	O
has	O
been	O
found	O
to	O
be	O
decreased	O
(	O
typically	O
by	O
around	O
25	O
%	O
,	O
but	O
often	O
by	O
far	O
more	O
)	O
by	O
erythromycin	O
,	O
troleandomycin	O
(	O
triacetyloleandomycin	O
)	O
,	O
roxithromycin	O
,	O
enoxacin	O
,	O
ciprofloxacin	O
,	O
pefloxacin	O
,	O
norfloxacin	O
,	O
ofloxacin	O
,	O
fluoroquinolone	O
T	O
-	O
3262	O
,	O
pipemidic	O
acid	O
,	O
cimetidine	O
,	O
etintidine	O
,	O
propranolol	O
,	O
verapamil	O
,	O
diltiazem	O
,	O
nifedipine	O
,	O
furosemide	O
(	O
frusemide	O
)	O
,	O
at	O
least	O
some	O
anovulent	O
agents	O
,	O
viloxazine	O
,	O
allopurinol	O
,	O
ticlopidine	O
,	O
idrocilamide	O
,	O
thiabendazole	O
,	O
disulfiram	O
,	O
influenza	O
-	O
and	O
BCG	O
-	O
vaccination	O
,	O
interferon	B-GENE
,	O
and	O
caffeine	O
(	O
half	O
-	O
life	O
increase	O
)	O
.	O

We	O
enrolled	O
253	O
HIV	B-GENE
-	I-GENE
antibody	I-GENE
positive	O
heroin	O
addicts	O
without	O
HIV	O
-	O
related	O
disease	O
(	O
n	O
=	O
81	O
)	O
or	O
with	O
persistent	O
generalized	O
lymphadenopathy	O
(	O
n	O
=	O
172	O
)	O
in	O
a	O
prospective	O
study	O
to	O
evaluate	O
clinical	O
progression	O
to	O
AIDS	O
related	O
complex	O
(	O
ARC	O
)	O
or	O
AIDS	O
and	O
to	O
identify	O
factors	O
of	O
possible	O
prognostic	O
relevance	O
.	O

No	O
homology	O
was	O
found	O
between	O
RNA14	B-GENE
and	O
RNA15	B-GENE
or	O
between	O
RNA14	B-GENE
and	O
other	O
proteins	O
contained	O
in	O
data	O
banks	O
.	O

Mutations	O
in	O
the	O
yeast	B-GENE
RNA14	I-GENE
and	O
RNA15	B-GENE
genes	I-GENE
result	O
in	O
an	O
abnormal	O
mRNA	O
decay	O
rate	O
;	O
sequence	O
analysis	O
reveals	O
an	O
RNA	O
-	O
binding	O
domain	O
in	O
the	O
RNA15	B-GENE
protein	I-GENE
.	O

Myocardial	O
infarction	O
in	O
patients	O
with	O
previous	O
bypass	O
surgery	O
.	O

The	O
most	O
striking	O
difference	O
in	O
the	O
birch	B-GENE
NAD	I-GENE
(	I-GENE
P	I-GENE
)	I-GENE
H	I-GENE
-	I-GENE
NR	I-GENE
sequence	I-GENE
in	O
comparison	O
to	O
NADH	B-GENE
-	I-GENE
NR	I-GENE
sequences	I-GENE
was	O
found	O
at	O
the	O
putative	O
pyridine	O
nucleotide	O
binding	O
site	O
.	O

A	O
single	O
amino	O
acid	O
difference	O
in	O
the	O
C	O
-	O
terminal	O
region	O
influences	O
dominant	O
negative	O
activity	O
and	O
receptor	O
dimer	O
formation	O
.	O

The	O
95	O
%	O
confidence	O
values	O
(	O
2SD	O
)	O
for	O
the	O
change	O
in	O
Ros	O
required	O
to	O
exclude	O
natural	O
variability	O
were	O
0	O
.	O
39	O
,	O
0	O
.	O
50	O
and	O
0	O
.	O
53	O
cmH2O	O
l	O
-	O
1	O
s	O
,	O
respectively	O
.	O

Among	O
953	O
infants	O
in	O
22	O
neonatal	O
care	O
units	O
studied	O
,	O
23	O
%	O
(	O
median	O
value	O
,	O
range	O
0	O
-	O
78	O
)	O
were	O
found	O
to	O
be	O
faecally	O
colonized	O
with	O
one	O
of	O
21	O
distinct	O
nosocomial	O
strains	O
of	O
Escherichia	O
coli	O
,	O
Klebsiella	O
or	O
Enterobacter	O
spp	O
.	O

Biochemical	O
studies	O
revealed	O
the	O
expected	O
loss	O
of	O
ChAT	B-GENE
activity	O
in	O
the	O
dorsal	O
and	O
ventral	O
hippocampi	O
of	O
lesioned	O
animals	O
along	O
with	O
elevated	O
levels	O
of	O
norepinephrine	O
(	O
NE	O
)	O
in	O
the	O
dorsal	O
hippocampus	O
of	O
MS	O
/	O
HSI	O
animals	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
250	O
WORDS	O
)	O

The	O
localization	O
of	O
this	O
proteoglycan	O
locus	O
in	O
the	O
human	O
genome	O
and	O
the	O
availability	O
of	O
new	O
RFLPs	O
provide	O
the	O
tools	O
for	O
future	O
studies	O
of	O
human	O
diseases	O
where	O
the	O
HSPG2	B-GENE
proteoglycan	I-GENE
gene	I-GENE
is	O
suspected	O
to	O
be	O
involved	O
.	O

After	O
2	O
min	O
of	O
dobutamine	O
injection	O
,	O
or	O
after	O
20	O
min	O
of	O
pimobendan	O
injection	O
,	O
the	O
myocardium	O
was	O
removed	O
,	O
and	O
used	O
for	O
determination	O
of	O
the	O
tissue	O
levels	O
of	O
metabolites	O
of	O
energy	O
and	O
carbohydrate	O
metabolism	O
.	O

During	O
coronary	O
stenosis	O
,	O
on	O
the	O
contrary	O
,	O
intracoronary	O
procaterol	O
at	O
the	O
same	O
dose	O
significantly	O
deteriorated	O
regional	O
myocardial	O
dysfunction	O
without	O
changing	O
LCX	O
flow	O
,	O
global	O
hemodynamics	O
and	O
cardiac	O
lactate	O
metabolism	O
.	O

Here	O
we	O
present	O
evidence	O
that	O
major	B-GENE
IE	I-GENE
proteins	I-GENE
IE86	B-GENE
,	O
IE72	B-GENE
,	O
and	O
IE55	B-GENE
are	O
capable	O
of	O
trans	O
-	O
activating	O
the	O
HIV	B-GENE
LTR	I-GENE
in	O
a	O
T	O
-	O
cell	O
line	O
,	O
HUT	O
-	O
78	O
.	O

In	O
a	O
country	O
where	O
general	O
HIV	O
prevalence	O
is	O
low	O
,	O
the	O
strategy	O
is	O
cost	O
-	O
effective	O
for	O
location	O
and	O
counselling	O
of	O
unknowingly	O
seropositive	O
individuals	O
.	O

The	O
cis	O
-	O
acting	O
element	O
mediating	O
glucocorticoid	O
inducibility	O
of	O
the	O
chicken	B-GENE
glutamine	I-GENE
synthetase	I-GENE
gene	I-GENE
has	O
been	O
identified	O
.	O

However	O
,	O
the	O
increase	O
in	O
biliary	O
excretion	O
did	O
not	O
compensate	O
for	O
the	O
reduced	O
elimination	O
of	O
bretylium	O
and	O
hexylsalicylic	O
acid	O
via	O
the	O
kidney	O
.	O

Diagnostic	O
value	O
of	O
cerebrospinal	B-GENE
fluid	I-GENE
immunoglobulin	I-GENE
G	I-GENE
(	O
IgG	B-GENE
)	O
in	O
pediatric	O
neurological	O
diseases	O
.	O

Expression	O
of	O
six	O
genes	O
,	O
ipaB	B-GENE
,	O
ipaC	B-GENE
,	O
invE	B-GENE
,	O
invG	B-GENE
,	O
invJ	B-GENE
,	O
and	O
invK	B-GENE
,	O
was	O
apparently	O
regulated	O
by	O
the	O
positive	O
regulator	O
virF	B-GENE
.	O

Inducible	O
VT	O
was	O
suppressed	O
entirely	O
in	O
one	O
patient	O
.	O

The	O
presence	O
of	O
the	O
corresponding	O
mature	O
mRNA	O
transcripts	O
(	O
3	O
.	O
2	O
-	O
3	O
.	O
5	O
kilobase	O
pairs	O
(	O
kb	O
]	O
in	O
human	O
fibroblasts	O
was	O
shown	O
by	O
Northern	O
blot	O
hybridization	O
,	O
S1	B-GENE
nuclease	I-GENE
protection	O
assay	O
,	O
and	O
the	O
polymerase	O
chain	O
reaction	O
.	O

Approximately	O
50	O
%	O
of	O
the	O
ribosomal	O
DNA	O
(	O
rDNA	O
)	O
units	O
of	O
Drosophila	O
melanogaster	O
are	O
inactivated	O
by	O
two	O
different	O
28	B-GENE
S	I-GENE
RNA	I-GENE
ribosomal	I-GENE
gene	I-GENE
insertions	O
(	O
type	O
I	O
and	O
type	O
II	O
)	O
.	O

Gap	B-GENE
b3	I-GENE
consists	O
of	O
two	O
polypeptide	O
chains	O
(	O
Mr	O
=	O
110	O
,	O
000	O
and	O
30	O
,	O
000	O
)	O
,	O
which	O
seem	O
to	O
be	O
proteolytic	O
cleavage	O
products	O
connected	O
by	O
disulfide	O
bonds	O
from	O
a	O
precursor	O
protein	O
.	O

However	O
,	O
the	O
rtFc	B-GENE
gamma	I-GENE
R	I-GENE
alpha	I-GENE
cDNA	I-GENE
clone	O
is	O
complementary	O
to	O
at	O
least	O
two	O
different	O
-	O
sized	O
mRNAs	O
expressed	O
by	O
CRNK	O
-	O
16	O
cells	O
,	O
contrasting	O
the	O
single	O
Fc	B-GENE
gamma	I-GENE
R	I-GENE
-	I-GENE
related	I-GENE
mRNA	I-GENE
species	O
expressed	O
by	O
human	O
and	O
mouse	O
natural	O
killer	O
cells	O
.	O

Both	O
genes	O
comprise	O
three	O
exons	O
,	O
two	O
introns	O
and	O
an	O
unusually	O
long	O
3	O
'	O
-	O
untranslated	O
region	O
(	O
3	O
.	O
2	O
kilobase	O
pairs	O
)	O
,	O
specificying	O
a	O
mRNA	O
of	O
approximately	O
4	O
.	O
1	O
kilobases	O
.	O

This	O
exon	O
,	O
here	O
named	O
exon	O
0	O
,	O
contained	O
the	O
entire	O
5	O
'	O
untranslated	O
region	O
and	O
the	O
N	O
-	O
terminal	O
signal	O
sequence	O
of	O
the	O
polypeptide	O
.	O

Treatment	O
of	O
human	O
myeloid	O
cell	O
lines	O
HL	O
-	O
60	O
and	O
U937	O
with	O
phorbol	O
12	O
-	O
myristate	O
13	O
-	O
acetate	O
(	O
PMA	O
)	O
increased	O
within	O
2	O
h	O
cellular	O
levels	O
of	O
the	O
RNA	O
hybridizable	O
to	O
LD78	B-GENE
cDNA	I-GENE
.	O

A	O
new	O
,	O
flexible	O
fiberoptic	O
ventriculoscope	O
for	O
observation	O
of	O
the	O
ventricles	O
and	O
major	O
cisterns	O
is	O
reported	O
.	O

Isopenicillin	B-GENE
N	I-GENE
isomerase	I-GENE
(	O
epimerase	B-GENE
)	O
has	O
been	O
purified	O
from	O
Streptomyces	O
clavuligerus	O
,	O
and	O
the	O
amino	O
acid	O
sequence	O
of	O
the	O
N	O
-	O
terminus	O
has	O
been	O
determined	O
.	O

Serum	O
IgG	B-GENE
was	O
initially	O
elevated	O
in	O
6	O
patients	O
.	O

The	O
patient	O
initially	O
attained	O
complete	O
remission	O
(	O
CR1	O
)	O
with	O
conventional	O
chemotherapy	O
and	O
then	O
relapsed	O
14	O
months	O
later	O
.	O

157	O
+	O
/	O
-	O
16	O
mg	O
/	O
dl	O
;	O
NS	O
)	O
,	O
glucose	O
levels	O
,	O
and	O
basal	O
(	O
17	O
+	O
/	O
-	O
4	O
vs	O
.	O

Platelet	O
aggregation	O
and	O
metabolic	O
control	O
are	O
not	O
affected	O
by	O
calcium	O
antagonist	O
treatment	O
in	O
type	O
II	O
diabetes	O
mellitus	O
.	O

Wnt	B-GENE
-	I-GENE
1	I-GENE
(	O
int	B-GENE
-	I-GENE
1	I-GENE
)	O
is	O
a	O
cellular	O
oncogene	O
often	O
activated	O
by	O
insertion	O
of	O
proviral	O
DNA	O
of	O
the	O
mouse	O
mammary	O
tumor	O
virus	O
.	O

Induction	O
of	O
Jurkat	O
leukemic	O
T	O
cells	O
with	O
phorbol	O
12	O
-	O
myristate	O
13	O
-	O
acetate	O
and	O
ionomycin	O
did	O
not	O
affect	O
the	O
level	O
of	O
FKBP	B-GENE
mRNA	I-GENE
.	O

GLUT5	B-GENE
mRNA	I-GENE
is	O
expressed	O
at	O
highest	O
levels	O
in	O
small	O
intestine	O
and	O
at	O
much	O
lower	O
levels	O
in	O
kidney	O
,	O
skeletal	O
muscle	O
,	O
and	O
adipose	O
tissue	O
.	O

e	O
.	O

We	O
speculate	O
that	O
these	O
tumors	O
may	O
represent	O
congenital	O
hamartomatous	O
growths	O
.	O

Identification	O
and	O
characterization	O
of	O
the	O
promoter	O
for	O
the	O
cytotactin	B-GENE
gene	I-GENE
.	O

(	O
1988	O
)	O
J	O
.	O

These	O
results	O
strongly	O
suggested	O
that	O
similar	O
,	O
if	O
not	O
identical	O
,	O
the	O
CArG	B-GENE
box	I-GENE
binding	I-GENE
proteins	I-GENE
interact	O
with	O
the	O
functionally	O
different	O
promoter	O
element	O
in	O
the	O
VLC1	B-GENE
,	O
cardiac	B-GENE
alpha	I-GENE
-	I-GENE
actin	I-GENE
,	O
and	O
c	B-GENE
-	I-GENE
fos	I-GENE
genes	I-GENE
.	O

Polyadenylation	O
of	O
B4	B-GENE
RNA	I-GENE
,	O
which	O
occurs	O
very	O
early	O
during	O
maturation	O
,	O
is	O
limited	O
to	O
150	O
residues	O
,	O
and	O
it	O
is	O
this	O
number	O
that	O
is	O
required	O
for	O
polysomal	O
recruitment	O
.	O

Co	O
-	O
existence	O
of	O
these	O
regulatory	O
elements	O
with	O
other	O
elements	O
,	O
such	O
as	O
the	O
AP	B-GENE
-	I-GENE
2	I-GENE
element	I-GENE
or	O
CCAAT	O
box	O
,	O
was	O
also	O
found	O
.	O

Recently	O
,	O
studies	O
of	O
agents	O
that	O
disrupt	O
collagen	B-GENE
synthesis	O
and	O
deposition	O
have	O
yielded	O
several	O
new	O
angiogenesis	O
inhibitors	O
.	O

Since	O
the	O
5	O
'	O
-	O
flanking	O
region	O
of	O
this	O
gene	O
is	O
likely	O
involved	O
in	O
hormonal	O
regulation	O
of	O
its	O
expression	O
,	O
we	O
have	O
isolated	O
and	O
partially	O
characterized	O
an	O
avian	O
fatty	B-GENE
acid	I-GENE
synthase	I-GENE
gene	O
.	O

A	O
new	O
set	O
of	O
cDNA	O
clones	O
spanning	O
approximately	O
3	O
.	O
2	O
kb	O
was	O
isolated	O
from	O
a	O
lambda	O
-	O
ZAP	O
goose	O
liver	O
cDNA	O
library	O
using	O
the	O
5	O
'	O
-	O
most	O
exon	O
-	O
containing	O
fragment	O
of	O
the	O
5	O
'	O
-	O
most	O
genomic	O
DNA	O
clone	O
.	O

Northern	O
blotting	O
analysis	O
indicates	O
that	O
expression	O
of	O
the	O
genes	O
corresponding	O
to	O
these	O
clones	O
is	O
confined	O
to	O
pollen	O
tissue	O
.	O

Whereas	O
cDNA	O
hybridization	O
to	O
genomic	O
DNA	O
blots	O
indicated	O
a	O
small	O
subfamily	O
of	O
G0S19	B-GENE
genes	I-GENE
,	O
simple	O
patterns	O
of	O
bands	O
indicated	O
that	O
most	O
cDNAs	O
,	O
including	O
G0S30	B-GENE
cDNA	I-GENE
,	O
corresponded	O
to	O
single	O
-	O
copy	O
genes	O
.	O

Lymphoproliferative	O
disorders	O
arising	O
under	O
immunosuppression	O
with	O
FK	O
506	O
:	O
initial	O
observations	O
in	O
a	O
large	O
transplant	O
population	O
.	O

The	O
Drosophila	B-GENE
suppressor	I-GENE
of	I-GENE
sable	I-GENE
gene	I-GENE
encodes	O
a	O
polypeptide	O
with	O
regions	O
similar	O
to	O
those	O
of	O
RNA	O
-	O
binding	O
proteins	O
.	O

2	O
:	O
121	O
-	O
133	O
,	O
1988	O
)	O
.	O

Using	O
avidin	B-GENE
-	I-GENE
biotin	I-GENE
complex	O
DNA	O
binding	O
assays	O
,	O
a	O
series	O
of	O
overlapping	O
alpha	B-GENE
promoter	I-GENE
DNA	I-GENE
sequences	I-GENE
between	O
-	O
170	O
to	O
29	O
basepairs	O
were	O
tested	O
,	O
but	O
each	O
failed	O
to	O
bind	O
GR	B-GENE
,	O
whereas	O
a	O
control	O
GRE	O
avidly	O
bound	O
receptor	O
.	O

Sequence	O
determination	O
of	O
isolated	O
peptides	O
suggested	O
that	O
Asn120	O
is	O
glycosylated	O
,	O
Asn65	O
and	O
Asn109	O
glycosylated	O
in	O
some	O
molecules	O
but	O
not	O
in	O
others	O
,	O
and	O
Asn72	O
not	O
glycosylated	O
.	O

The	O
DNA	O
sequence	O
conferring	O
AP	B-GENE
-	I-GENE
1	I-GENE
activity	O
was	O
located	O
in	O
the	O
proximal	O
promoter	O
region	O
.	O

The	O
murine	B-GENE
mutation	I-GENE
dominant	I-GENE
white	I-GENE
spotting	I-GENE
(	O
W	B-GENE
)	O
is	O
in	O
the	O
proto	O
-	O
oncogene	O
,	O
c	B-GENE
-	I-GENE
kit	I-GENE
.	O

The	O
proteins	O
differ	O
in	O
the	O
presence	O
or	O
absence	O
of	O
a	O
21	O
-	O
amino	O
-	O
acid	O
sequence	O
located	O
24	O
amino	O
acids	O
C	O
terminal	O
of	O
the	O
translational	O
initiation	O
codon	O
.	O

Our	O
results	O
also	O
indicate	O
the	O
existence	O
of	O
sequences	O
downstream	O
of	O
-	O
0	O
.	O
11	O
kb	O
which	O
can	O
influence	O
the	O
pattern	O
of	O
tissue	O
-	O
specific	O
expression	O
of	O
the	O
HLA	B-GENE
-	I-GENE
B7	I-GENE
gene	I-GENE
and	O
the	O
ability	O
of	O
this	O
gene	O
to	O
respond	O
to	O
gamma	B-GENE
interferon	I-GENE
.	O

The	O
SH2	B-GENE
and	O
SH3	B-GENE
domains	I-GENE
of	O
pp60src	B-GENE
direct	O
stable	O
association	O
with	O
tyrosine	O
phosphorylated	O
proteins	O
p130	B-GENE
and	O
p110	B-GENE
.	O

These	O
clones	O
overlapped	O
and	O
contained	O
the	O
structural	O
gene	O
encoding	O
the	O
complete	O
C5	B-GENE
alpha	I-GENE
-	I-GENE
chain	I-GENE
and	O
90	O
%	O
of	O
the	O
beta	O
-	O
chain	O
.	O

The	O
C5	B-GENE
alpha	I-GENE
-	I-GENE
chain	I-GENE
was	O
encoded	O
by	O
49	O
kilobases	O
containing	O
26	O
exons	O
;	O
the	O
beta	O
-	O
chain	O
was	O
encoded	O
by	O
29	O
kilobases	O
containing	O
16	O
exons	O
.	O

Heterozygous	O
mutation	O
in	O
the	O
G	O
+	O
5	O
position	O
of	O
intron	O
33	O
of	O
the	O
pro	B-GENE
-	I-GENE
alpha	I-GENE
2	I-GENE
(	I-GENE
I	I-GENE
)	I-GENE
gene	I-GENE
(	O
COL1A2	B-GENE
)	O
that	O
causes	O
aberrant	O
RNA	O
splicing	O
and	O
lethal	O
osteogenesis	O
imperfecta	O
.	O

The	O
nucleotide	O
sequences	O
of	O
these	O
genes	O
differ	O
at	O
only	O
nine	O
positions	O
,	O
resulting	O
in	O
three	O
amino	O
acid	O
differences	O
.	O

The	O
protein	O
predicted	O
by	O
the	O
sequence	O
of	O
the	O
human	B-GENE
pim	I-GENE
-	I-GENE
1	I-GENE
proto	I-GENE
-	I-GENE
oncogene	I-GENE
shares	O
extensive	O
homology	O
with	O
known	O
serine	B-GENE
/	I-GENE
threonine	I-GENE
protein	I-GENE
kinases	I-GENE
,	O
and	O
yet	O
the	O
human	B-GENE
Pim	I-GENE
-	I-GENE
1	I-GENE
enzyme	I-GENE
has	O
previously	O
been	O
reported	O
to	O
exhibit	O
protein	B-GENE
tyrosine	I-GENE
kinase	I-GENE
activity	O
both	O
in	O
vitro	O
and	O
in	O
vivo	O
.	O

A	O
full	B-GENE
-	I-GENE
length	I-GENE
human	I-GENE
pim	I-GENE
-	I-GENE
1	I-GENE
cDNA	I-GENE
was	O
subcloned	O
into	O
the	O
bacterial	O
vector	O
pGEX	O
-	O
2T	O
and	O
the	O
Pim	B-GENE
-	I-GENE
1	I-GENE
protein	I-GENE
expressed	O
as	O
a	O
fusion	O
product	O
with	O
bacterial	B-GENE
glutathione	I-GENE
S	I-GENE
-	I-GENE
transferase	I-GENE
(	O
GST	B-GENE
)	O
.	O

The	O
10	O
kDa	O
polypeptide	O
was	O
phosphorylated	O
in	O
vitro	O
by	O
incubating	O
wheat	O
etioplast	O
membranes	O
with	O
[	O
gamma	O
32P	O
]	O
ATP	O
.	O

Homology	O
with	O
the	O
human	O
protein	O
is	O
only	O
34	O
%	O
in	O
the	O
tandem	O
repeat	O
domain	O
,	O
mainly	O
showing	O
conservation	O
of	O
serines	O
and	O
threonines	O
,	O
presumed	O
sites	O
of	O
O	O
-	O
linked	O
carbohydrate	O
attachment	O
.	O

In	O
addition	O
to	O
targeting	O
partially	O
assembled	O
Ti	B-GENE
alpha	I-GENE
-	I-GENE
beta	I-GENE
CD3	B-GENE
gamma	I-GENE
delta	I-GENE
epsilon	I-GENE
TCR	B-GENE
complexes	I-GENE
to	O
the	O
cell	O
surface	O
,	O
CD3	B-GENE
zeta	I-GENE
appears	O
to	O
be	O
essential	O
for	O
interleukin	B-GENE
-	I-GENE
2	I-GENE
production	O
after	O
TCR	B-GENE
stimulation	O
with	O
antigen	B-GENE
/	I-GENE
major	I-GENE
histocompatibility	I-GENE
complex	I-GENE
.	O

When	O
desipramine	O
was	O
injected	O
16	O
hrs	O
after	O
fluoxetine	O
injection	O
,	O
brain	O
levels	O
of	O
desipramine	O
were	O
no	O
longer	O
elevated	O
.	O

Opposite	O
effects	O
of	O
CYP1	B-GENE
are	O
observed	O
in	O
aerobic	O
,	O
heme	O
-	O
sufficient	O
cells	O
.	O

A	O
segmental	O
analysis	O
of	O
the	O
key	O
regions	O
of	O
HLA	B-GENE
-	I-GENE
DR1	I-GENE
that	O
control	O
T	O
cell	O
allorecognition	O
was	O
performed	O
by	O
using	O
a	O
series	O
of	O
transfected	O
cell	O
lines	O
expressing	O
the	O
products	O
of	O
recombinant	O
DRB	B-GENE
/	O
H	B-GENE
-	I-GENE
2Eb	I-GENE
genes	O
,	O
paired	O
with	O
either	O
DR	B-GENE
alpha	I-GENE
or	O
H	B-GENE
-	I-GENE
2E	I-GENE
alpha	I-GENE
.	O

We	O
characterized	O
cDNA	O
clones	O
specific	O
for	O
the	O
extracellular	O
matrix	O
glycoprotein	O
undulin	B-GENE
.	O

The	O
alpha	B-GENE
inhibin	I-GENE
promoter	I-GENE
containing	O
a	O
mutated	O
CRE	O
was	O
not	O
regulated	O
by	O
forskolin	O
in	O
granulosa	O
cells	O
and	O
did	O
not	O
bind	O
the	O
CREB	B-GENE
protein	I-GENE
.	O

Regulation	O
of	O
the	O
alpha	B-GENE
inhibin	I-GENE
gene	I-GENE
by	O
cyclic	O
adenosine	O
3	O
'	O
,	O
5	O
'	O
-	O
monophosphate	O
after	O
transfection	O
into	O
rat	O
granulosa	O
cells	O
.	O

Comparison	O
of	O
the	O
nucleotide	O
sequences	O
between	O
the	O
human	O
and	O
bovine	O
DNA	O
showed	O
that	O
the	O
sequence	O
similarity	O
extended	O
2400	O
bp	O
downstream	O
from	O
the	O
coding	O
region	O
.	O

In	O
patients	O
with	O
osteomyelitis	O
and	O
joint	O
empyema	O
(	O
n	O
=	O
48	O
)	O
PMN	B-GENE
elastase	I-GENE
had	O
a	O
sensitivity	O
of	O
77	O
%	O
,	O
which	O
was	O
only	O
exceeded	O
by	O
that	O
of	O
the	O
unspecific	O
erythrocyte	O
sedimentation	O
rate	O
(	O
sensitivity	O
89	O
%	O
)	O
.	O

These	O
results	O
indicate	O
that	O
the	O
sulfhydryl	O
group	O
of	O
certain	O
angiotensin	B-GENE
converting	I-GENE
enzyme	I-GENE
inhibitors	O
can	O
potentiate	O
their	O
effect	O
on	O
the	O
endogenous	O
nitrovasodilator	O
EDRF	B-GENE
.	O

Pharmacokinetics	O
of	O
FK	O
506	O
in	O
transplant	O
patients	O
.	O

A	O
second	O
even	O
more	O
significant	O
match	O
to	O
this	O
E	O
.	O
coli	O
region	O
was	O
found	O
in	O
the	O
retroviral	B-GENE
ribonuclease	I-GENE
H	I-GENE
(	O
RNase	B-GENE
H	I-GENE
)	O
domain	O
,	O
and	O
corresponds	O
precisely	O
to	O
a	O
region	O
that	O
has	O
been	O
aligned	O
by	O
previous	O
investigators	O
with	O
the	O
E	B-GENE
.	I-GENE
coli	I-GENE
RNase	I-GENE
H	I-GENE
,	O
suggesting	O
that	O
Pol	B-GENE
I	I-GENE
helices	O
O	O
and	O
P	O
are	O
homologous	O
to	O
helices	O
A	O
and	O
D	O
of	O
the	O
RNase	B-GENE
H	I-GENE
crystal	O
structure	O
,	O
respectively	O
.	O

Analysis	O
of	O
the	O
deduced	O
amino	O
acid	O
sequence	O
suggests	O
that	O
CHIP28	B-GENE
protein	I-GENE
contains	O
six	O
bilayer	O
-	O
spanning	O
domains	O
,	O
two	O
exofacial	O
potential	O
N	O
-	O
glycosylation	O
sites	O
,	O
and	O
intracellular	O
N	O
and	O
C	O
termini	O
.	O

The	O
qualitative	O
concentrations	O
of	O
HCG	B-GENE
had	O
a	O
sensitivity	O
of	O
37	O
.	O
5	O
%	O
and	O
a	O
specificity	O
of	O
100	O
%	O
.	O

The	O
reduced	O
rate	O
of	O
F	O
absorption	O
and	O
slower	O
rise	O
in	O
plasma	O
F	O
concentration	O
accompanying	O
delayed	O
gastric	O
emptying	O
indicate	O
that	O
passage	O
of	O
F	O
into	O
the	O
small	O
intestine	O
is	O
the	O
major	O
factor	O
in	O
rapid	O
F	O
absorption	O
.	O

The	O
activity	O
of	O
serum	B-GENE
lipase	I-GENE
and	O
amylase	B-GENE
distinctly	O
increased	O
at	O
3	O
h	O
and	O
went	O
up	O
to	O
the	O
maximum	O
at	O
12	O
h	O
after	O
injection	O
of	O
Na	O
-	O
Tc	O
.	O

They	O
were	O
checked	O
for	O
anti	B-GENE
-	I-GENE
HCV	I-GENE
(	O
anti	B-GENE
-	I-GENE
C100	I-GENE
-	I-GENE
3	I-GENE
)	O
with	O
HCV	O
EIA	O
kit	O
(	O
Abbott	O
Lab	O
.	O
,	O
North	O
Chicago	O
,	O
IL	O
)	O
.	O

Diltiazem	O
resulted	O
in	O
a	O
significant	O
increase	O
in	O
epicardial	O
diameter	O
(	O
+	O
10	O
%	O
;	O
p	O
=	O
0	O
.	O
001	O
)	O
and	O
in	O
coronary	O
blood	O
flow	O
(	O
CBF	O
)	O
(	O
+	O
30	O
%	O
;	O
p	O
=	O
0	O
.	O
0001	O
)	O
.	O

The	O
first	O
transfusion	O
resulted	O
in	O
a	O
platelet	O
increment	O
to	O
32	O
Gpt	O
/	O
l	O
(	O
CCI	O
11	O
)	O
.	O

These	O
risk	O
factors	O
can	O
be	O
divided	O
into	O
2	O
groups	O
:	O
local	O
vessel	O
wall	O
-	O
related	O
factors	O
,	O
and	O
local	O
(	O
focal	O
action	O
)	O
systemic	O
factors	O
.	O

Epidemiology	O
and	O
prevention	O
of	O
hospital	O
infections	O
in	O
the	O
Local	O
Health	O
Unit	O
of	O
Sassari	O
:	O
profile	O
of	O
bacterial	O
resistance	O
and	O
antimicrobial	O
agents	O
of	O
large	O
usage	O
.	O

PRDII	B-GENE
-	I-GENE
BF1	I-GENE
-	I-GENE
derived	I-GENE
cDNAs	I-GENE
did	O
not	O
result	O
in	O
stimulation	O
of	O
either	O
basal	O
or	O
tat	B-GENE
-	O
induced	O
activated	O
gene	O
expression	O
.	O

Vaccinia	O
virus	O
(	O
VV	O
)	O
is	O
a	O
potent	O
immunogen	O
,	O
but	O
the	O
nature	O
of	O
VV	O
proteins	O
involved	O
in	O
the	O
activation	O
of	O
the	O
immune	O
response	O
of	O
the	O
host	O
is	O
not	O
yet	O
known	O
.	O

Max	B-GENE
:	O
functional	O
domains	O
and	O
interaction	O
with	O
c	B-GENE
-	I-GENE
Myc	I-GENE
.	O

86	O
:	O
3199	O
-	O
3203	O
)	O
or	O
G1	O
to	O
S	O
phase	O
(	O
Reilly	O
,	O
C	O
.	O

Substitutions	O
introduced	O
at	O
bases	O
surrounding	O
the	O
ICR2	B-GENE
motif	I-GENE
yielded	O
levels	O
of	O
pRNA	O
replication	O
that	O
differed	O
,	O
depending	O
on	O
the	O
maintenance	O
of	O
a	O
putative	O
5	O
'	O
stem	O
-	O
loop	O
structure	O
in	O
the	O
positive	O
strand	O
of	O
the	O
viral	O
genome	O
.	O

Zn	O
(	O
II	O
)	O
coordination	O
domain	O
mutants	O
of	O
T4	O
gene	B-GENE
32	I-GENE
protein	O
.	O

Zn	O
(	O
II	O
)	O
coordination	O
domain	O
mutants	O
of	O
T4	B-GENE
gene	I-GENE
32	I-GENE
protein	I-GENE
.	O

The	O
tissue	O
specificity	O
of	O
gene	O
expression	O
was	O
identical	O
to	O
that	O
described	O
previously	O
for	O
the	O
CaMV	B-GENE
35S	I-GENE
domain	I-GENE
B	I-GENE
enhancer	I-GENE
element	I-GENE
.	O

The	O
pathophysiology	O
and	O
clinical	O
management	O
of	O
acute	O
brain	O
injury	O
in	O
infancy	O
and	O
childhood	O
are	O
presented	O
using	O
acute	O
traumatic	O
brain	O
injury	O
as	O
a	O
model	O
.	O

Transcripts	O
from	O
a	O
second	O
POU	B-GENE
-	I-GENE
domain	I-GENE
gene	I-GENE
,	O
Oct	B-GENE
-	I-GENE
25	I-GENE
,	O
were	O
present	O
at	O
low	O
levels	O
in	O
oocytes	O
and	O
early	O
embryos	O
and	O
were	O
dramatically	O
upregulated	O
during	O
early	O
gastrulation	O
.	O

The	O
genome	O
of	O
Thogoto	O
virus	O
comprises	O
six	O
segments	O
of	O
single	O
-	O
stranded	O
,	O
negative	O
sense	O
RNA	O
.	O

These	O
tumors	O
were	O
classified	O
into	O
three	O
broad	O
groups	O
:	O
I	O
,	O
cystadenoma	O
;	O
II	O
,	O
cystadenocarcinoma	O
;	O
and	O
III	O
,	O
adenocarcinoma	O
with	O
mucin	B-GENE
production	O
or	O
an	O
associated	O
cyst	O
.	O

Immunostaining	O
of	O
cells	O
transfected	O
with	O
these	O
constructs	O
revealed	O
that	O
both	O
the	O
myristoylated	O
and	O
nonmyristoylated	O
mutants	O
were	O
localized	O
in	O
nuclei	O
,	O
whereas	O
wild	B-GENE
-	I-GENE
type	I-GENE
PKC	I-GENE
alpha	I-GENE
was	O
primarily	O
cytoplasmic	O
and	O
perinuclear	O
.	O

We	O
have	O
partially	O
sequenced	O
the	O
RAP74	B-GENE
protein	I-GENE
from	O
purified	O
HeLa	O
cells	O
,	O
cloned	O
its	O
complementary	O
DNA	O
and	O
shown	O
that	O
its	O
translation	O
product	O
can	O
interact	O
with	O
RAP30	B-GENE
in	O
vitro	O
as	O
well	O
as	O
in	O
vivo	O
.	O

Effects	O
of	O
thromboxane	B-GENE
synthetase	I-GENE
inhibition	O
on	O
postburn	O
mesenteric	O
vascular	O
resistance	O
and	O
the	O
rate	O
of	O
bacterial	O
translocation	O
in	O
a	O
chronic	O
porcine	O
model	O
.	O

The	O
primary	O
pancreatic	O
insult	O
seemed	O
to	O
be	O
unaffected	O
by	O
the	O
treatment	O
,	O
because	O
neither	O
the	O
rise	O
in	O
plasma	B-GENE
lipase	I-GENE
nor	O
the	O
development	O
of	O
ascites	O
or	O
the	O
extension	O
of	O
the	O
pancreatic	O
necrosis	O
were	O
diminished	O
.	O

The	O
size	O
of	O
the	O
mutant	O
molecule	O
corresponds	O
to	O
the	O
unprocessed	O
cytoplasmic	O
precursor	O
(	O
pre	B-GENE
-	I-GENE
super	I-GENE
-	I-GENE
pro	I-GENE
-	I-GENE
PrB	I-GENE
)	O
,	O
as	O
detected	O
in	O
sec61	B-GENE
mutants	I-GENE
,	O
when	O
translocation	O
into	O
the	O
endoplasmic	O
reticulum	O
is	O
blocked	O
.	O

Thus	O
,	O
the	O
active	O
-	O
site	O
mutation	O
prevents	O
the	O
wild	O
-	O
type	O
processing	O
of	O
the	O
N	O
-	O
glycosylated	O
73	O
-	O
kDa	O
precursor	O
of	O
PrB	B-GENE
to	O
the	O
41	B-GENE
.	I-GENE
5	I-GENE
kDa	I-GENE
pro	I-GENE
-	I-GENE
PrB	I-GENE
in	O
the	O
endoplasmic	O
reticulum	O
.	O

The	O
predicted	O
amino	O
acid	O
sequence	O
exhibited	O
70	O
%	O
identity	O
to	O
that	O
of	O
Bacillus	B-GENE
stearothermophilus	I-GENE
TyrTS	I-GENE
and	O
55	O
%	O
identity	O
to	O
that	O
of	O
E	B-GENE
.	I-GENE
coli	I-GENE
TyrTS	I-GENE
,	O
while	O
identity	O
to	O
a	O
second	O
cryptic	O
B	B-GENE
.	I-GENE
subtilis	I-GENE
TyrTS	I-GENE
gene	I-GENE
,	O
designated	O
tyrZ	B-GENE
,	O
was	O
only	O
27	O
%	O
.	O

Heat	O
-	O
inducible	O
CAT	B-GENE
activity	O
was	O
detectable	O
when	O
additional	O
sequences	O
from	O
the	O
native	O
promoter	O
containing	O
three	O
CCAAT	O
boxes	O
and	O
a	O
single	O
HSE	O
were	O
present	O
in	O
the	O
constructions	O
.	O

SETTING	O
-	O
-	O
Women	O
,	O
Infants	O
,	O
and	O
Children	O
clinics	O
in	O
Minneapolis	O
,	O
Minn	O
.	O

BACKGROUND	O
:	O
The	O
effectiveness	O
of	O
monoamine	B-GENE
oxidase	I-GENE
inhibitors	O
(	O
MAOIs	O
)	O
in	O
tricyclic	O
resistant	O
depression	O
has	O
received	O
surprisingly	O
little	O
systematic	O
study	O
.	O

The	O
upstream	O
delta	O
-	O
alpha	O
breakpoint	O
is	O
flanked	O
by	O
the	O
direct	O
repeats	O
of	O
the	O
acceptor	O
splice	O
site	O
,	O
whereas	O
the	O
down	O
-	O
stream	O
alpha	O
-	O
delta	O
breakpoint	O
is	O
located	O
in	O
the	O
adjacent	O
intron	O
.	O

Patients	O
with	O
moderate	O
PDDAT	O
were	O
impaired	O
on	O
all	O
serial	O
positions	O
for	O
both	O
spatial	O
order	O
and	O
spatial	O
recognition	O
memory	O
.	O

Bone	O
and	O
bones	O
.	O

Management	O
often	O
involves	O
beta	O
-	O
and	O
calcium	O
channel	O
blocking	O
drugs	O
or	O
type	O
IC	O
antiarrhythmic	O
drugs	O
.	O

To	O
overcome	O
this	O
problem	O
,	O
we	O
have	O
overexpressed	O
Kex2p	B-GENE
using	O
the	O
baculovirus	O
/	O
insect	O
cell	O
expression	O
system	O
.	O

J	O
.	O

The	O
major	B-GENE
49	I-GENE
-	I-GENE
kDa	I-GENE
core	I-GENE
protein	I-GENE
in	O
the	O
liver	O
HSPG	B-GENE
preparation	O
was	O
found	O
to	O
be	O
reactive	O
to	O
an	O
antibody	O
that	O
specifically	O
recognizes	O
the	O
cytoplasmic	O
domain	O
of	O
fibroglycan	B-GENE
.	O

While	O
no	O
obvious	O
transmembrane	O
regions	O
were	O
identified	O
,	O
several	O
short	O
hydrophobic	O
amino	O
acid	O
stretches	O
were	O
found	O
to	O
be	O
localized	O
in	O
and	O
around	O
the	O
Pro	O
II	O
region	O
,	O
and	O
these	O
may	O
be	O
responsible	O
for	O
attachment	O
of	O
precursors	O
to	O
membranes	O
.	O

Toxicity	O
was	O
mild	O
,	O
mainly	O
consisting	O
of	O
emesis	O
(	O
81	O
%	O
of	O
the	O
patients	O
;	O
66	O
%	O
of	O
the	O
courses	O
)	O
,	O
leukopenia	O
of	O
World	O
Health	O
Organization	O
(	O
WHO	O
)	O
grade	O
1	O
to	O
2	O
(	O
47	O
%	O
of	O
the	O
patients	O
;	O
18	O
%	O
of	O
the	O
courses	O
)	O
,	O
and	O
thrombocytopenia	O
(	O
12	O
%	O
of	O
the	O
patients	O
;	O
3	O
%	O
of	O
the	O
courses	O
)	O
.	O

This	O
study	O
confirms	O
,	O
although	O
individual	O
reaction	O
is	O
remarkably	O
different	O
,	O
transportation	O
as	O
a	O
potent	O
stressor	O
for	O
Beagle	O
dogs	O
.	O

RESULTS	O
:	O
Plasma	B-GENE
AVP	I-GENE
responses	O
to	O
osmotic	O
stimulation	O
,	O
and	O
non	O
-	O
osmotic	O
inhibition	O
by	O
drinking	O
,	O
were	O
normal	O
in	O
patients	O
with	O
compulsive	O
water	O
drinking	O
.	O

The	O
fragments	O
of	O
each	O
region	O
were	O
amplified	O
by	O
polymerase	O
chain	O
reaction	O
and	O
analyzed	O
by	O
gel	O
electrophoresis	O
to	O
detect	O
single	O
-	O
strand	O
conformation	O
polymorphism	O
.	O

The	O
csbA	B-GENE
fusion	I-GENE
was	O
maximally	O
expressed	O
during	O
early	O
stationary	O
phase	O
in	O
cells	O
grown	O
in	O
Luria	O
broth	O
containing	O
5	O
%	O
glucose	O
and	O
0	O
.	O
2	O
%	O
glutamine	O
.	O

The	O
constraints	O
of	O
primase	B-GENE
recognition	I-GENE
sequences	I-GENE
,	O
nucleotide	O
substrate	O
requirements	O
,	O
and	O
the	O
effects	O
of	O
additional	O
proteins	O
on	O
oligoribonucleotide	O
synthesis	O
by	O
the	O
63	B-GENE
-	I-GENE
kDa	I-GENE
gene	I-GENE
4	I-GENE
protein	I-GENE
have	O
been	O
examined	O
using	O
templates	O
of	O
defined	O
sequence	O
.	O

Thrombolytic	O
therapy	O
in	O
spontaneous	O
coronary	O
artery	O
dissection	O
.	O

A	O
prospective	O
trial	O
was	O
carried	O
out	O
in	O
156	O
unselected	O
patients	O
(	O
41	O
men	O
,	O
mean	O
age	O
67	O
.	O
5	O
years	O
,	O
115	O
women	O
,	O
mean	O
age	O
71	O
.	O
4	O
years	O
)	O
who	O
had	O
undergone	O
total	O
hip	O
joint	O
replacement	O
because	O
of	O
degenerative	O
or	O
inflammatory	O
arthritis	O
or	O
fracture	O
of	O
the	O
neck	O
of	O
the	O
femur	O
.	O

When	O
both	O
lesions	O
were	O
complete	O
lateral	O
hemisections	O
in	O
weanling	O
operates	O
,	O
little	O
behavioral	O
recovery	O
was	O
observed	O
,	O
similar	O
to	O
complete	O
spinal	O
cord	O
transection	O
(	O
N	O
=	O
3	O
)	O
.	O

Human	O
SRF	B-GENE
-	I-GENE
related	I-GENE
proteins	I-GENE
:	O
DNA	O
-	O
binding	O
properties	O
and	O
potential	O
regulatory	O
targets	O
.	O

We	O
have	O
isolated	O
cDNAs	O
for	O
a	O
gene	O
coding	O
for	O
a	O
G	B-GENE
protein	I-GENE
alpha	I-GENE
subunit	I-GENE
from	I-GENE
tomato	I-GENE
(	O
Lycopersicon	O
esculentum	O
,	O
cv	O
.	O

Growth	O
factor	O
stimulation	O
of	O
cells	O
causes	O
the	O
phosphorylation	O
of	O
the	O
c	B-GENE
-	I-GENE
Myc	I-GENE
transcriptional	I-GENE
activation	I-GENE
domain	I-GENE
at	O
Ser62	O
within	O
a	O
proline	O
-	O
rich	O
region	O
that	O
is	O
highly	O
conserved	O
among	O
members	O
of	O
the	O
Myc	B-GENE
family	I-GENE
(	O
Alvarez	O
,	O
E	O
.	O
,	O
Northwood	O
,	O
I	O
.	O
C	O
.	O
,	O
Gonzalez	O
,	O
F	O
.	O

The	O
authors	O
evaluated	O
the	O
potential	O
for	O
thrombotic	O
complications	O
arising	O
from	O
implantation	O
of	O
a	O
ventricular	O
assist	O
device	O
(	O
Sarns	O
/	O
3M	O
-	O
VAD	O
)	O
in	O
four	O
calves	O
.	O

Cardiac	O
output	O
(	O
CO	O
)	O
was	O
significantly	O
higher	O
(	O
p	O
less	O
than	O
0	O
.	O
0005	O
)	O
in	O
the	O
MBBF	O
group	O
.	O

Amino	O
acid	O
residues	O
147	O
-	O
167	O
of	O
the	O
previously	O
reported	O
sequence	O
are	O
replaced	O
by	O
new	O
residues	O
147	O
to	O
150	O
.	O

Transcriptional	O
activation	O
by	O
the	O
HIV	B-GENE
-	I-GENE
1	I-GENE
Tat	I-GENE
protein	I-GENE
requires	O
specific	O
residues	O
in	O
the	O
hexanucleotide	O
loop	O
and	O
trinucleotide	O
bulge	O
of	O
the	O
TAR	B-GENE
RNA	O
stem	O
-	O
loop	O
structure	O
found	O
in	O
the	O
5	O
'	O
-	O
untranslated	O
leader	O
of	O
all	O
viral	O
transcripts	O
.	O

These	O
results	O
strongly	O
suggest	O
that	O
locally	O
-	O
applied	O
TTC	O
in	O
combination	O
with	O
FDBA	O
enhances	O
new	O
bone	O
formation	O
in	O
experimental	O
alveolar	O
bone	O
defects	O
.	O

As	O
an	O
initial	O
step	O
towards	O
the	O
characterization	O
of	O
replicative	O
DNA	B-GENE
polymerases	I-GENE
of	I-GENE
trypanosomes	I-GENE
,	O
we	O
have	O
cloned	O
,	O
sequenced	O
and	O
examined	O
the	O
expression	O
of	O
the	O
Trypanosoma	O
(	O
Trypanozoon	O
)	O
brucei	O
brucei	O
gene	O
that	O
encodes	O
the	O
DNA	B-GENE
polymerase	I-GENE
alpha	I-GENE
catalytic	I-GENE
core	I-GENE
(	O
pol	B-GENE
alpha	I-GENE
)	O
.	O

In	O
addition	O
,	O
there	O
was	O
a	O
significant	O
increase	O
in	O
postdexamethasone	O
cortical	O
concentrations	O
with	O
age	O
(	O
p	O
less	O
than	O
0	O
.	O
01	O
;	O
r	O
=	O
0	O
.	O
31	O
)	O
.	O

The	O
volume	O
fraction	O
(	O
Vv	O
)	O
and	O
number	O
/	O
mm2	O
(	O
Na	O
)	O
of	O
all	O
capillaries	O
(	O
perfused	O
and	O
nonperfused	O
)	O
in	O
a	O
given	O
area	O
of	O
brain	O
were	O
determined	O
after	O
staining	O
for	O
alkaline	B-GENE
phosphatase	I-GENE
.	O

Airway	O
pressure	O
and	O
air	O
flow	O
were	O
measured	O
at	O
the	O
endotracheal	O
tube	O
in	O
13	O
children	O
on	O
a	O
variety	O
of	O
ventilators	O
.	O

Appl	O
.	O

Issues	O
of	O
distribution	O
of	O
kinetic	O
energy	O
of	O
traumatizing	O
object	O
in	O
direct	O
contact	O
interaction	O
with	O
head	O
during	O
impact	O
are	O
discussed	O
from	O
position	O
of	O
biomechanics	O
.	O

CONCLUSION	O
:	O
Monitoring	O
SpO2	O
at	O
the	O
nasal	O
septum	O
site	O
is	O
more	O
reliable	O
than	O
monitoring	O
it	O
at	O
the	O
finger	O
site	O
in	O
hypothermic	O
patients	O
.	O

The	O
granules	O
grew	O
as	O
the	O
melted	O
material	O
immersed	O
into	O
the	O
void	O
space	O
among	O
the	O
adhered	O
particles	O
.	O

Hence	O
,	O
the	O
uPA	B-GENE
promoter	I-GENE
contains	O
multiple	O
weak	O
cis	O
-	O
acting	O
elements	O
distributed	O
over	O
7	O
.	O
0	O
kb	O
5	O
'	O
to	O
the	O
translation	O
start	O
site	O
.	O

Substituting	O
a	O
Ser	O
for	O
Gly69	O
or	O
a	O
Glu	O
for	O
Lys	O
71	O
in	O
the	O
conserved	O
TGEK	B-GENE
tetrapeptide	I-GENE
in	O
finger	O
II	O
of	O
TFIIIA	B-GENE
resulted	O
in	O
the	O
loss	O
of	O
DNA	O
binding	O
.	O

P	O
.	O

In	O
one	O
,	O
exploratory	O
behavior	O
(	O
assessed	O
by	O
hole	O
pokes	O
)	O
and	O
locomotion	O
were	O
assessed	O
during	O
a	O
10	O
-	O
min	O
test	O
session	O
.	O

12	O
-	O
O	O
-	O
Tetradecanoylphorbol	O
13	O
-	O
acetate	O
was	O
found	O
to	O
inhibit	O
rapidly	O
and	O
potently	O
the	O
expression	O
of	O
mRNAs	O
coding	O
for	O
the	O
myogenic	O
regulators	O
CMD1	B-GENE
and	O
myogenin	B-GENE
.	O

In	O
Xenopus	O
laevis	O
,	O
the	O
gene	O
encoding	O
the	O
elongation	B-GENE
factor	I-GENE
1	I-GENE
-	I-GENE
alpha	I-GENE
variant	I-GENE
EF	B-GENE
-	I-GENE
1	I-GENE
alpha	I-GENE
O	I-GENE
,	O
where	O
O	O
stands	O
for	O
oocyte	O
,	O
is	O
expressed	O
in	O
oocytes	O
and	O
early	O
embryos	O
.	O

These	O
introns	O
belong	O
to	O
the	O
class	O
of	O
nuclear	O
pre	O
-	O
mRNA	O
introns	O
and	O
contain	O
typical	O
5	O
'	O
-	O
and	O
3	O
'	O
-	O
consensus	O
sequences	O
,	O
as	O
well	O
as	O
unique	O
features	O
.	O

The	O
mRNA	O
identified	O
in	O
both	O
human	O
and	O
rat	O
cells	O
with	O
the	O
human	B-GENE
clathrin	I-GENE
clone	O
revealed	O
transcripts	O
of	O
approximately	O
6	O
.	O
5	O
kb	O
,	O
which	O
is	O
consistent	O
with	O
the	O
predicted	O
180	O
kDa	O
molecular	O
weight	O
of	O
the	O
clathrin	B-GENE
heavy	I-GENE
chain	I-GENE
.	O

In	O
this	O
report	O
,	O
almost	O
6	O
kb	O
of	O
DNA	O
sequence	O
is	O
presented	O
,	O
including	O
1251	O
bp	O
5	O
'	O
to	O
the	O
gene	O
,	O
over	O
4	O
kb	O
of	O
exon	O
and	O
exon	O
-	O
intron	O
junctions	O
,	O
and	O
583	O
bp	O
3	O
'	O
to	O
the	O
gene	O
.	O

Antibodies	O
specific	O
to	O
rE12	B-GENE
and	O
rNFIL	B-GENE
-	I-GENE
6	I-GENE
disrupt	O
nucleoprotein	O
complexes	O
with	O
these	O
DNA	O
-	O
binding	O
sites	O
,	O
confirming	O
the	O
interaction	O
of	O
native	O
in	O
vivo	O
factors	O
.	O

A	O
method	O
is	O
described	O
for	O
detecting	O
targeted	O
events	O
at	O
the	O
mu	B-GENE
heavy	I-GENE
chain	I-GENE
gene	I-GENE
which	O
relies	O
on	O
co	O
-	O
conversion	O
(	O
or	O
co	O
-	O
exchange	O
)	O
of	O
a	O
point	O
mutation	O
with	O
a	O
selectable	O
marker	O
contained	O
on	O
a	O
replacement	O
vector	O
.	O

Allergenic	O
activity	O
of	O
allergen	O
extract	O
Ambrosia	O
elatior	O
(	O
AE	O
)	O
was	O
tested	O
in	O
fifteen	O
volunteers	O
extremely	O
sensitive	O
to	O
the	O
allergen	O
.	O

This	O
study	O
was	O
aimed	O
at	O
assessing	O
whether	O
c	O
-	O
DDP	O
administration	O
immediately	O
before	O
radiotherapy	O
could	O
increase	O
frequency	O
and	O
duration	O
of	O
objective	O
responses	O
,	O
as	O
well	O
as	O
survival	O
,	O
in	O
patients	O
affected	O
with	O
locally	O
advanced	O
stages	O
of	O
squamous	O
carcinomas	O
of	O
the	O
head	O
and	O
neck	O
.	O

Two	O
potential	O
regulatory	O
sequences	O
for	O
DNA	O
binding	O
proteins	O
were	O
found	O
in	O
the	O
non	O
-	O
coding	O
5	O
'	O
region	O
:	O
a	O
HAP2	B-GENE
/	O
HAP3	B-GENE
consensus	O
recognition	O
sequence	O
at	O
nucleotide	O
-	O
154	O
and	O
a	O
BAF1	B-GENE
consensus	I-GENE
recognition	I-GENE
sequence	I-GENE
at	O
nucleotide	O
-	O
136	O
.	O

We	O
exploit	O
the	O
properties	O
of	O
LexA	B-GENE
fusion	I-GENE
proteins	I-GENE
to	O
study	O
the	O
dimerization	O
and	O
DNA	O
-	O
contacting	O
domains	O
of	O
cRel	B-GENE
.	O

Plasma	O
lipid	O
and	O
lipoprotein	O
profiles	O
were	O
compared	O
in	O
elderly	O
female	O
runners	O
(	O
RU	O
:	O
n	O
=	O
15	O
,	O
aged	O
66	O
+	O
/	O
-	O
5	O
years	O
,	O
body	O
fat	O
20	O
+	O
/	O
-	O
4	O
%	O
,	O
training	O
distance	O
35	O
+	O
/	O
-	O
15	O
km	O
week	O
-	O
1	O
,	O
VO2max	O
36	O
+	O
/	O
-	O
4	O
ml	O
kg	O
-	O
1	O
min	O
-	O
1	O
,	O
mean	O
+	O
/	O
-	O
SD	O
)	O
and	O
age	O
-	O
matched	O
untrained	O
women	O
(	O
UT	O
:	O
n	O
=	O
28	O
,	O
66	O
+	O
/	O
-	O
4	O
years	O
,	O
body	O
fat	O
26	O
+	O
/	O
-	O
6	O
%	O
,	O
VO2max	O
26	O
+	O
/	O
-	O
3	O
ml	O
kg	O
-	O
1	O
min	O
-	O
1	O
)	O
.	O

Fundamental	O
and	O
clinical	O
evaluation	O
of	O
equilibrium	O
dialysis	O
-	O
-	O
radioimmunoassay	O
system	O
for	O
measurement	O
of	O
serum	O
free	O
thyroxine	O

We	O
conclude	O
that	O
TA	O
caused	O
a	O
specific	O
decrease	O
in	O
AGD	O
on	O
GD	O
20	O
that	O
was	O
largely	O
reversed	O
by	O
PCD	O
23	O
.	O

When	O
examined	O
as	O
adults	O
(	O
8	O
weeks	O
old	O
)	O
,	O
the	O
external	O
genitalia	O
of	O
TA	O
-	O
exposed	O
offspring	O
were	O
normal	O
.	O

After	O
PTCA	O
,	O
ejection	O
fraction	O
increased	O
from	O
54	O
+	O
/	O
-	O
8	O
%	O
to	O
59	O
+	O
/	O
-	O
8	O
%	O
(	O
p	O
less	O
than	O
0	O
.	O
05	O
)	O
and	O
regional	O
function	O
improved	O
significantly	O
(	O
maximal	O
standard	O
deviation	O
before	O
PTCA	O
:	O
2	O
.	O
8	O
+	O
/	O
-	O
0	O
.	O
8	O
;	O
after	O
PTCA	O
:	O
1	O
.	O
9	O
+	O
/	O
-	O
0	O
.	O
9	O
-	O
segments	O
below	O
the	O
first	O
standard	O
deviation	O
before	O
PTCA	O
:	O
31	O
+	O
/	O
-	O
16	O
;	O
after	O
PTCA	O
:	O
19	O
+	O
/	O
-	O
17	O
)	O
.	O

The	O
alcoholic	O
patient	O
,	O
his	O
work	O
and	O
the	O
subjectivity	O
of	O
the	O
period	O

These	O
data	O
suggest	O
that	O
the	O
combined	O
treatment	O
with	O
a	O
thromboxane	B-GENE
synthetase	I-GENE
inhibitor	O
and	O
a	O
thromboxane	B-GENE
receptor	I-GENE
antagonist	O
provides	O
a	O
better	O
protection	O
against	O
digoxin	O
intoxication	O
than	O
with	O
either	O
agent	O
alone	O
.	O

A	O
330	O
-	O
kb	O
YAC	O
,	O
A148A7	O
,	O
spanned	O
from	O
the	O
HLA	B-GENE
-	O
DQA1	B-GENE
locus	O
through	O
the	O
Y3	B-GENE
/	O
Ring	B-GENE
4	I-GENE
locus	O
and	O
extended	O
at	O
least	O
130	O
kb	O
centromeric	O
of	O
YAC	O
B1D12	O
.	O

Adverse	O
foetal	O
outcome	O
in	O
specific	O
IgM	B-GENE
positive	O
Chlamydia	O
trachomatis	O
infection	O
in	O
pregnancy	O
.	O

Using	O
an	O
image	O
-	O
processing	O
computer	O
,	O
regional	O
LV	O
time	O
-	O
density	O
curves	O
were	O
constructed	O
for	O
one	O
cardiac	O
cycle	O
.	O

In	O
a	O
second	O
patient	O
the	O
VT	O
became	O
nonsustained	O
.	O

The	O
possible	O
mechanisms	O
underlying	O
differences	O
in	O
post	O
-	O
tetanic	O
effects	O
from	O
muscle	O
and	O
cutaneous	O
afferents	O
in	O
adults	O
and	O
neonates	O
are	O
discussed	O
.	O

We	O
examined	O
behavioral	O
alterations	O
in	O
the	O
brown	O
cockroach	O
,	O
Periplaneta	O
brunnea	O
,	O
infected	O
with	O
the	O
acanthocephalan	O
,	O
Moniliformis	O
moniliformis	O
.	O

First	O
,	O
the	O
finding	O
of	O
a	O
monomeric	O
Alu	B-GENE
family	O
repeat	O
at	O
the	O
junction	O
between	O
nonhomology	O
block	O
I	O
and	O
homology	O
block	O
Y	O
of	O
the	O
alpha	B-GENE
2	I-GENE
gene	I-GENE
-	I-GENE
containing	I-GENE
unit	I-GENE
in	I-GENE
rhesus	I-GENE
macaque	I-GENE
suggests	O
that	O
the	O
dimeric	O
Alu	B-GENE
family	O
repeat	O
,	O
Alu	B-GENE
3	I-GENE
,	O
at	O
the	O
orthologous	O
position	O
in	O
human	O
was	O
generated	O
by	O
insertion	O
of	O
a	O
monomeric	O
Alu	B-GENE
family	O
repeat	O
into	O
the	O
3	O
'	O
end	O
of	O
another	O
preexisting	O
Alu	B-GENE
family	O
repeat	O
.	O

The	O
sequence	O
of	O
the	O
repressor	O
locus	O
,	O
c	O
,	O
of	O
the	O
Streptomyces	O
temperate	O
phage	O
,	O
phi	O
C31	O
,	O
was	O
shown	O
previously	O
to	O
contain	O
an	O
open	O
reading	O
frame	O
encoding	O
a	O
74	O
kDa	O
protein	O
.	O

This	O
differential	O
sensitivity	O
to	O
DB	O
,	O
as	O
measured	O
by	O
a	O
lower	O
concentration	O
of	O
DB	O
which	O
caused	O
loss	O
of	O
righting	O
in	O
LS	O
,	O
was	O
accompanied	O
by	O
an	O
equal	O
rate	O
of	O
water	O
-	O
soluble	O
barbiturate	O
brain	O
distribution	O
and	O
elimination	O
in	O
the	O
two	O
lines	O
.	O

The	O
existence	O
of	O
threshold	O
concentrations	O
,	O
above	O
which	O
certain	O
phenomena	O
may	O
occur	O
,	O
strengthens	O
the	O
role	O
of	O
sentinels	O
.	O

However	O
,	O
it	O
was	O
synthesized	O
at	O
both	O
temperatures	O
after	O
addition	O
of	O
A23187	O
.	O

Ten	O
out	O
of	O
10	O
patients	O
with	O
progressive	O
disease	O
had	O
mast	O
cells	O
greater	O
than	O
or	O
equal	O
to	O
0	O
.	O
5	O
%	O
,	O
hyaluronan	O
greater	O
than	O
or	O
equal	O
to	O
50	O
micrograms	O
.	O
l	O
-	O
1	O
and	O
fibronectin	B-GENE
greater	O
than	O
or	O
equal	O
to	O
350	O
micrograms	O
.	O
l	O
-	O
1	O
compared	O
to	O
eight	O
out	O
of	O
41	O
patients	O
with	O
stable	O
or	O
regressive	O
disease	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
250	O
WORDS	O
)	O

Our	O
mapping	O
results	O
did	O
not	O
suggest	O
involvement	O
of	O
this	O
gene	O
in	O
previously	O
mapped	O
genetic	O
disorders	O
or	O
in	O
known	O
neoplasia	O
-	O
associated	O
translocation	O
breakpoints	O
.	O

These	O
changes	O
weren	O
'	O
t	O
so	O
significant	O
in	O
the	O
group	O
of	O
obese	O
children	O
who	O
didn	O
'	O
t	O
lose	O
weight	O
.	O

Arsenic	O
contents	O
in	O
native	O
copper	O

In	O
ten	O
other	O
experiments	O
(	O
5	O
experimental	O
and	O
5	O
control	O
rats	O
)	O
99mTc	O
-	O
sulfur	O
colloid	O
was	O
injected	O
intravenously	O
.	O

Magnetotherapy	O
of	O
hepatitis	O
A	O
and	O
B	O
in	O
children	O

These	O
results	O
were	O
superior	O
to	O
those	O
in	O
24	O
patients	O
with	O
conventional	O
end	O
-	O
to	O
-	O
end	O
sutures	O
on	O
clinical	O
testing	O
.	O

Mutational	O
analysis	O
supports	O
a	O
role	O
for	O
multiple	O
structural	O
features	O
in	O
the	O
C	O
-	O
terminal	O
secretion	O
signal	O
of	O
Escherichia	B-GENE
coli	I-GENE
haemolysin	I-GENE
.	O

Among	O
blood	O
donors	O
in	O
the	O
Republic	O
of	O
Serbia	O
,	O
regardless	O
the	O
number	O
of	O
blood	O
donations	O
,	O
the	O
percentage	O
of	O
female	O
donors	O
is	O
significantly	O
lower	O
compared	O
to	O
the	O
percentage	O
of	O
male	O
blood	O
donors	O
.	O

Extramedullary	O
relapse	O
in	O
childhood	O
leukemia	O
.	O

Mycoplasma	O
pneumoniae	O
was	O
isolated	O
from	O
the	O
pleural	O
fluid	O
of	O
this	O
patient	O
.	O

RU486	O
and	O
ONO	O
802	O
in	O
combination	O
have	O
been	O
shown	O
to	O
be	O
effective	O
in	O
early	O
termination	O
of	O
pregnancy	O
.	O

The	O
presence	O
of	O
local	O
abnormalities	O
in	O
both	O
patients	O
can	O
support	O
the	O
hypothesis	O
that	O
the	O
cortex	O
,	O
especially	O
of	O
the	O
temporal	O
anterior	O
lobe	O
,	O
is	O
involved	O
in	O
the	O
origin	O
of	O
the	O
laughing	O
seizures	O
.	O

In	O
line	O
with	O
the	O
small	O
values	O
for	O
QS	O
/	O
QC	O
,	O
our	O
results	O
further	O
indicate	O
that	O
even	O
large	O
,	O
well	O
-	O
perfused	O
,	O
occluded	O
air	O
spaces	O
in	O
the	O
lung	O
will	O
hardly	O
affect	O
the	O
recovered	O
ventilation	O
/	O
perfusion	O
distribution	O
obtained	O
from	O
inert	O
gas	O
data	O
when	O
CDCSF6	O
exceeds	O
0	O
.	O
1	O
ml	O
.	O
min	O
-	O
1	O
.	O
mmHg	O
-	O
1	O
.	O

Many	O
cells	O
were	O
negative	O
for	O
endothelial	O
-	O
cell	O
markers	O
,	O
and	O
they	O
reacted	O
with	O
a	O
monoclonal	O
antibody	O
against	O
muscle	O
actin	B-GENE
.	O

CT	O
abnormalities	O
noted	O
in	O
term	O
babies	O
included	O
hemorrhage	O
(	O
subarachnoid	O
5	O
.	O
8	O
%	O
,	O
intracerebral	O
11	O
.	O
6	O
%	O
)	O
,	O
hypodensity	O
(	O
mild	O
23	O
.	O
2	O
%	O
,	O
moderate	O
11	O
.	O
6	O
%	O
severe	O
5	O
.	O
8	O
%	O
)	O
;	O
hypodensity	O
with	O
hemorrhage	O
5	O
.	O
8	O
%	O
and	O
cerebral	O
atrophy	O
5	O
.	O
8	O
%	O
.	O

The	O
effects	O
of	O
contrast	O
media	O
on	O
coagulation	B-GENE
factor	I-GENE
XII	I-GENE
.	O

Pigs	O
were	O
switched	O
from	O
the	O
growing	O
to	O
the	O
finishing	O
diet	O
at	O
57	O
and	O
61	O
kg	O
in	O
Exp	O
.	O

In	O
sixteen	O
patients	O
with	O
moderate	O
essential	O
hypertension	O
the	O
effects	O
of	O
10	O
-	O
day	O
nifedipine	O
treatment	O
on	O
serum	O
uric	O
acid	O
and	O
renal	O
excretion	O
of	O
uric	O
acid	O
were	O
evaluated	O
.	O

TPTA	O
produced	O
brain	O
congestion	O
,	O
and	O
hepatic	O
and	O
pulmonary	O
petechial	O
and	O
generalized	O
hemorrhages	O
.	O

Examples	O
are	O
using	O
more	O
subjects	O
or	O
an	O
improved	O
research	O
design	O
,	O
developing	O
consensus	O
statements	O
or	O
using	O
meta	O
-	O
analysis	O
.	O

A	O
two	O
phase	O
slug	O
flow	O
tubular	O
heat	O
exchanger	O
was	O
used	O
for	O
the	O
thermal	O
inactivation	O
of	O
Listeria	O
monocytogenes	O
in	O
natural	O
infected	O
milk	O
from	O
seven	O
cows	O
.	O

So	O
far	O
15	O
children	O
have	O
been	O
studied	O
.	O

Regional	O
cerebral	O
blood	O
flow	O
(	O
rCBF	O
)	O
measurements	O
and	O
psychiatric	O
ratings	O
were	O
performed	O
on	O
seven	O
schizophrenic	O
patients	O
(	O
mean	O
age	O
=	O
41	O
.	O
4	O
years	O
)	O
who	O
had	O
been	O
examined	O
18	O
years	O
previously	O
in	O
a	O
study	O
that	O
used	O
similar	O
psychiatric	O
ratings	O
and	O
a	O
comparable	O
rCBF	O
technique	O
.	O

In	O
the	O
present	O
study	O
,	O
we	O
identified	O
a	O
strong	O
positive	O
cis	O
-	O
regulatory	O
element	O
at	O
-	O
70	O
bp	O
to	O
-	O
75	O
bp	O
in	O
the	O
LpS1	B-GENE
beta	I-GENE
promoter	I-GENE
with	O
the	O
sequence	O
(	O
G	O
)	O
6	O
and	O
a	O
similar	O
,	O
more	O
distal	O
cis	O
-	O
element	O
at	O
-	O
721	O
bp	O
to	O
-	O
726	O
bp	O
.	O

No	O
case	O
of	O
SMF	O
demonstrated	O
expansive	O
tumorous	O
growth	O
.	O

Different	O
doses	O
of	O
15	O
-	O
methyl	O
-	O
PGF2	O
alpha	O
(	O
0	O
.	O
125	O
-	O
10	O
mg	O
)	O
were	O
used	O
to	O
induce	O
luteolysis	O
and	O
oestrus	O
in	O
7	O
heifers	O
with	O
28	O
treatments	O
on	O
day	O
8	O
-	O
12	O
of	O
the	O
oestrous	O
cycle	O
.	O

Review	O
of	O
the	O
literature	O
and	O
report	O
of	O
a	O
case	O
of	O
a	O
dermoid	O
cyst	O
.	O

Resolution	O
of	O
thermographic	O
asymmetry	O
and	O
/	O
or	O
decrease	O
in	O
Delta	O
T	O
was	O
demonstrated	O
in	O
approximately	O
81	O
%	O
of	O
the	O
post	O
-	O
treatment	O
population	O
.	O

Maize	B-GENE
rbcS	I-GENE
promoter	I-GENE
activity	O
depends	O
on	O
sequence	O
elements	O
not	O
found	O
in	O
dicot	B-GENE
rbcS	I-GENE
promoters	I-GENE
.	O

Measurements	O
were	O
done	O
with	O
a	O
commercial	O
haematofluorometer	O
Buchler	O
ZF	O
which	O
was	O
calibrated	O
to	O
the	O
average	O
haematocrit	O
value	O
of	O
0	O
.	O
42	O
.	O

The	O
relatively	O
scanty	O
number	O
of	O
examples	O
,	O
which	O
could	O
be	O
justified	O
by	O
the	O
variety	O
and	O
complexity	O
of	O
combined	O
exposure	O
,	O
allows	O
to	O
conclude	O
that	O
life	O
-	O
style	O
factors	O
have	O
considerable	O
influence	O
on	O
interindividual	O
differences	O
in	O
susceptibility	O
to	O
xenobiotics	O
toxicity	O
.	O

The	O
12S	B-GENE
E1A	I-GENE
product	I-GENE
does	O
not	O
activate	O
a	O
TRE	O
sequence	O
,	O
but	O
cotransfection	O
with	O
c	B-GENE
-	I-GENE
jun	I-GENE
circumvents	O
this	O
lack	O
of	O
stimulation	O
.	O

After	O
treatment	O
with	O
tunicamycin	O
,	O
the	O
transfectants	O
secreted	O
unglycosylated	O
18	O
-	O
kDa	O
polypeptides	O
which	O
could	O
also	O
bind	O
IgE	B-GENE
.	O

PAS1	B-GENE
,	O
a	O
yeast	O
gene	O
required	O
for	O
peroxisome	O
biogenesis	O
,	O
encodes	O
a	O
member	O
of	O
a	O
novel	O
family	O
of	O
putative	O
ATPases	B-GENE
.	O

The	O
pp90rsk	B-GENE
-	I-GENE
protein	I-GENE
kinase	I-GENE
activity	O
(	O
referred	O
to	O
as	O
rsk	B-GENE
-	I-GENE
kinase	I-GENE
)	O
is	O
also	O
not	O
related	O
to	O
cofactor	O
-	O
dependent	O
signal	O
transducing	O
protein	O
kinases	O
such	O
as	O
the	O
cyclic	B-GENE
AMP	I-GENE
-	I-GENE
dependent	I-GENE
protein	I-GENE
kinases	I-GENE
,	O
members	O
of	O
the	O
protein	B-GENE
kinase	I-GENE
C	I-GENE
family	I-GENE
,	O
or	O
other	O
Ca2	B-GENE
(	I-GENE
+	I-GENE
)	I-GENE
-	I-GENE
dependent	I-GENE
protein	I-GENE
kinases	I-GENE
.	O

Human	B-GENE
GATA	I-GENE
-	I-GENE
3	I-GENE
:	O
a	O
lineage	O
-	O
restricted	O
transcription	O
factor	O
that	O
regulates	O
the	O
expression	O
of	O
the	O
T	B-GENE
cell	I-GENE
receptor	I-GENE
alpha	I-GENE
gene	I-GENE
.	O

Like	O
many	O
eukaryotic	O
transcription	O
factors	O
,	O
these	O
proteins	O
bind	O
to	O
DNA	O
as	O
dimers	O
.	O

Furthermore	O
,	O
the	O
UvrA	B-GENE
protein	I-GENE
interacts	O
with	O
the	O
UvrB	B-GENE
protein	I-GENE
to	O
modulate	O
its	O
activities	O
,	O
both	O
in	O
solution	O
and	O
in	O
association	O
with	O
DNA	O
,	O
where	O
the	O
UvrAB	B-GENE
complex	I-GENE
possesses	O
a	O
helicase	B-GENE
activity	O
.	O

The	O
ED30	O
values	O
were	O
2	O
.	O
4	O
and	O
2	O
.	O
2	O
mg	O
/	O
kg	O
and	O
similar	O
to	O
the	O
respective	O
values	O
of	O
nifedipine	O
(	O
ED	O
30	O
:	O
2	O
.	O
4	O
,	O
2	O
.	O
1	O
mg	O
/	O
kg	O
)	O
.	O

Southwestern	O
blot	O
analysis	O
demonstrated	O
that	O
this	O
phosphoprotein	O
can	O
bind	O
the	O
kappa	B-GENE
B	I-GENE
element	I-GENE
directly	O
and	O
specifically	O
.	O

The	O
minus	O
-	O
end	O
-	O
directed	O
microtubule	O
motors	O
,	O
the	O
dyneins	B-GENE
,	O
may	O
also	O
constitute	O
a	O
superfamily	O
of	O
force	O
-	O
generating	O
proteins	O
with	O
distinct	O
attachment	O
domains	O
.	O

The	O
incompatibility	O
group	O
W	O
plasmid	O
pSa	O
suppresses	O
Agrobacterium	O
tumefaciens	O
oncogenicity	O
(	O
J	O
.	O

Potential	O
translational	O
start	O
signals	O
are	O
upstream	O
of	O
ORF1	O
and	O
ORF2	O
.	O

Imaging	O
of	O
D2	B-GENE
dopamine	I-GENE
receptor	I-GENE

The	O
abundance	O
of	O
transcripts	O
from	O
several	O
unrelated	O
genes	O
is	O
decreased	O
in	O
cdc68	B-GENE
-	I-GENE
1	I-GENE
mutant	I-GENE
cells	O
after	O
transfer	O
to	O
the	O
restrictive	O
temperature	O
,	O
while	O
at	O
least	O
one	O
transcript	O
,	O
from	O
the	O
HSP82	B-GENE
gene	I-GENE
,	O
persists	O
in	O
an	O
aberrant	O
fashion	O
.	O

The	O
murine	B-GENE
Mov	I-GENE
-	I-GENE
34	I-GENE
gene	I-GENE
:	O
full	O
-	O
length	O
cDNA	O
and	O
genomic	O
organization	O
.	O

CREB	B-GENE
was	O
identified	O
as	O
one	O
of	O
the	O
protein	O
components	O
in	O
several	O
of	O
the	O
gel	O
shift	O
complexes	O
formed	O
with	O
the	O
variant	O
CRE	O
.	O

The	O
spectrum	O
of	O
histologically	O
diagnosed	O
malignant	O
neoplasms	O
in	O
Sabah	O
,	O
1983	O
-	O
1988	O
.	O

When	O
transfected	O
into	O
Drosophila	O
SL	O
-	O
2	O
cells	O
,	O
pCAT	O
plasmid	O
containing	O
2	O
,	O
090	O
bp	O
of	O
5	O
'	O
-	O
flanking	O
region	O
shows	O
a	O
3	O
.	O
0	O
-	O
to	O
3	O
.	O
5	O
-	O
fold	O
increase	O
in	O
chloramphenicol	B-GENE
acetyltransferase	I-GENE
activity	O
after	O
induction	O
with	O
retinoic	O
acid	O
and	O
/	O
or	O
8	O
-	O
bromo	O
-	O
cAMP	O
.	O

Two	O
alternatively	O
spliced	O
5	O
'	O
UTRs	O
,	O
designated	O
type	O
I	O
and	O
type	O
II	O
,	O
of	O
222	O
and	O
115	O
bp	O
,	O
respectively	O
,	O
were	O
found	O
associated	O
with	O
PFP	B-GENE
.	O

The	O
N	O
-	O
terminus	O
of	O
another	O
open	O
reading	O
frame	O
was	O
found	O
3	O
'	O
from	O
nifA	B-GENE
and	O
tentatively	O
identified	O
as	O
nifB	B-GENE
by	O
amino	O
acid	O
sequence	O
comparison	O
.	O

The	O
RNA	O
genome	O
of	O
rabbit	O
hemorrhagic	O
disease	O
virus	O
(	O
RHDV	O
)	O
was	O
molecularly	O
cloned	O
.	O

Therefore	O
,	O
we	O
have	O
developed	O
a	O
system	O
to	O
study	O
nuclear	O
targeting	O
in	O
plants	O
and	O
have	O
established	O
that	O
the	O
nuclear	O
transport	O
machinery	O
is	O
similar	O
in	O
monocots	O
and	O
dicots	O
.	O

A	O
novel	O
cDNA	O
clone	O
termed	O
R2	O
was	O
isolated	O
by	O
subtractive	O
hybridization	O
of	O
a	O
cDNA	O
library	O
of	O
phytohemagglutinin	B-GENE
(	O
PHA	B-GENE
)	O
/	O
phorbol	O
myristate	O
acetate	O
-	O
stimulated	O
Jurkat	O
cells	O
and	O
by	O
rescreening	O
a	O
cDNA	O
library	O
of	O
PHA	O
-	O
stimulated	O
peripheral	O
blood	O
lymphocytes	O
.	O

Chagas	O
'	O
disease	O
,	O
visceral	O
leishmaniasis	O
,	O
anti	B-GENE
-	I-GENE
nuclear	I-GENE
factor	I-GENE
,	O
schistosomiasis	O
,	O
rheumatoid	B-GENE
factor	I-GENE
and	O
normal	O
controls	O
.	O

The	O
second	O
transcriptional	O
unit	O
,	O
designated	O
UL26	B-GENE
.	I-GENE
5	I-GENE
,	O
predicted	O
to	O
specify	O
a	O
protein	O
of	O
329	O
amino	O
acids	O
,	O
encodes	O
the	O
family	B-GENE
35	I-GENE
proteins	I-GENE
;	O
it	O
is	O
transcribed	O
by	O
an	O
mRNA	O
which	O
initiates	O
at	O
approximately	O
nucleotide	O
+	O
1000	O
of	O
the	O
UL26	B-GENE
transcription	O
initiation	O
site	O
and	O
is	O
translated	O
from	O
the	O
methionine	O
initiation	O
codon	O
located	O
at	O
position	O
+	O
1099	O
of	O
the	O
UL26	B-GENE
transcriptional	I-GENE
unit	I-GENE
.	O

The	O
adeno	B-GENE
-	I-GENE
associated	I-GENE
virus	I-GENE
(	I-GENE
AAV	I-GENE
)	I-GENE
rep	I-GENE
gene	I-GENE
encodes	O
four	O
proteins	O
(	O
Rep78	B-GENE
,	O
Rep68	B-GENE
,	O
Rep52	B-GENE
,	O
and	O
Rep40	B-GENE
)	O
required	O
for	O
AAV	O
DNA	O
replication	O
and	O
AAV	O
gene	O
regulation	O
.	O

A	O
larger	O
region	O
upstream	O
of	O
human	B-GENE
CMV	I-GENE
dbp	I-GENE
also	O
mediated	O
replication	O
in	O
transient	O
assays	O
.	O

It	O
also	O
contains	O
a	O
picornaviral	B-GENE
3C	I-GENE
-	I-GENE
like	I-GENE
protease	I-GENE
domain	I-GENE
and	O
two	O
papain	B-GENE
-	I-GENE
like	I-GENE
protease	I-GENE
domains	I-GENE
.	O

However	O
,	O
the	O
relative	O
positions	O
of	O
the	O
VV	O
genes	O
(	O
genus	O
Orthopoxvirus	O
)	O
are	O
different	O
than	O
those	O
of	O
the	O
corresponding	O
ORFs	O
in	O
SFV	O
(	O
genus	O
Leporipoxvirus	O
)	O
,	O
indicating	O
complex	O
rearrangements	O
of	O
DNA	O
in	O
the	O
genome	O
of	O
one	O
or	O
both	O
of	O
these	O
viruses	O
subsequent	O
to	O
their	O
divergence	O
from	O
a	O
common	O
ancestor	O
.	O

This	O
result	O
suggests	O
that	O
phosphorylation	O
of	O
Thr	O
14	O
and	O
/	O
or	O
Tyr	O
15	O
inhibits	O
p34cdc2	B-GENE
kinase	I-GENE
activity	O
,	O
in	O
line	O
with	O
the	O
location	O
of	O
these	O
residues	O
within	O
the	O
putative	O
ATP	O
binding	O
site	O
of	O
the	O
kinase	O
.	O

In	O
short	O
-	O
term	O
cotransfections	O
,	O
a	O
pFRTK	B-GENE
-	O
CAT	B-GENE
target	O
containing	O
EBNA	B-GENE
-	I-GENE
1	I-GENE
-	I-GENE
binding	I-GENE
sites	I-GENE
from	O
the	O
EBV	O
origin	O
of	O
plasmid	O
replication	O
,	O
ori	B-GENE
-	I-GENE
P	I-GENE
,	O
was	O
transactivated	O
by	O
a	O
carboxy	B-GENE
-	I-GENE
terminal	I-GENE
EBNA	I-GENE
-	I-GENE
1	I-GENE
construction	I-GENE
(	O
amino	O
acids	O
450	O
to	O
641	O
)	O
that	O
also	O
carried	O
a	O
c	B-GENE
-	I-GENE
myc	I-GENE
nuclear	I-GENE
localization	I-GENE
signal	I-GENE
.	O

The	O
findings	O
are	O
compatible	O
with	O
the	O
idea	O
that	O
the	O
genes	O
encoding	O
PDGF	B-GENE
receptors	I-GENE
in	O
glioma	O
cells	O
are	O
regulated	O
in	O
concert	O
with	O
other	O
genes	O
,	O
the	O
expression	O
of	O
which	O
may	O
reflect	O
the	O
developmental	O
program	O
of	O
normal	O
glia	O
cell	O
lineages	O
.	O

Suggestive	O
evidence	O
was	O
obtained	O
that	O
cstA	B-GENE
is	O
involved	O
in	O
peptide	O
utilization	O
.	O

This	O
study	O
tested	O
the	O
hypothesis	O
that	O
sodium	O
channel	O
blocking	O
drugs	O
selectively	O
prolong	O
the	O
late	O
potential	O
,	O
or	O
terminal	O
low	O
amplitude	O
signal	O
,	O
portion	O
of	O
the	O
signal	O
-	O
averaged	O
QRS	O
complex	O
and	O
that	O
prolongation	O
of	O
the	O
late	O
potential	O
would	O
correlate	O
with	O
slowing	O
of	O
ventricular	O
tachycardia	O
.	O

Identification	O
and	O
nucleotide	O
sequence	O
of	O
Rhizobium	B-GENE
meliloti	I-GENE
insertion	I-GENE
sequence	I-GENE
ISRm3	I-GENE
:	O
similarity	O
between	O
the	O
putative	O
transposase	B-GENE
encoded	O
by	O
ISRm3	B-GENE
and	O
those	O
encoded	O
by	O
Staphylococcus	B-GENE
aureus	I-GENE
IS256	I-GENE
and	O
Thiobacillus	B-GENE
ferrooxidans	I-GENE
IST2	I-GENE
.	O

To	O
determine	O
the	O
relationship	O
of	O
these	O
viruses	O
,	O
the	O
complete	O
DNA	O
sequence	O
of	O
KV	O
consisting	O
of	O
4754	O
bp	O
was	O
determined	O
.	O

Whereas	O
a	O
PR55	B-GENE
beta	I-GENE
transcript	I-GENE
of	O
about	O
2	O
.	O
3	O
kb	O
was	O
detected	O
at	O
high	O
levels	O
in	O
the	O
neuroblastoma	O
derived	O
cell	O
line	O
LA	O
-	O
N	O
-	O
1	O
,	O
the	O
level	O
of	O
the	O
mRNA	O
was	O
very	O
low	O
in	O
the	O
other	O
human	O
cell	O
lines	O
analyzed	O
.	O

Heterodimers	O
of	O
myogenin	B-GENE
and	O
E12	B-GENE
(	O
or	O
MyoD	B-GENE
and	O
E12	B-GENE
)	O
specifically	O
bound	O
a	O
restriction	O
fragment	O
extending	O
from	O
-	O
200	O
to	O
-	O
103	O
relative	O
to	O
the	O
start	O
of	O
cardiac	B-GENE
alpha	I-GENE
-	I-GENE
actin	I-GENE
transcription	O
.	O

The	O
effects	O
of	O
c	B-GENE
-	I-GENE
myc	I-GENE
were	O
further	O
dissected	O
by	O
showing	O
that	O
c	B-GENE
-	I-GENE
myc	I-GENE
can	O
inhibit	O
differentiation	O
independently	O
of	O
Id	B-GENE
,	O
a	O
negative	O
regulator	O
of	O
muscle	O
differentiation	O
.	O

Stable	O
association	O
of	O
U2	B-GENE
snRNP	I-GENE
with	O
the	O
branchpoint	O
sequence	O
of	O
mammalian	O
pre	O
-	O
mRNAs	O
requires	O
binding	O
of	O
a	O
non	O
-	O
snRNP	O
protein	O
to	O
the	O
polypyrimidine	O
tract	O
.	O

The	O
Italian	O
Lung	O
Cancer	O
Task	O
Force	O
(	O
FONICAP	O
)	O
.	O

The	O
promoter	O
activity	O
of	O
the	O
gene	B-GENE
encoding	I-GENE
Alzheimer	I-GENE
beta	I-GENE
-	I-GENE
amyloid	I-GENE
precursor	I-GENE
protein	I-GENE
(	O
APP	B-GENE
)	O
is	O
regulated	O
by	O
two	O
blocks	O
of	O
upstream	O
sequences	O
.	O

This	O
element	O
was	O
used	O
to	O
screen	O
an	O
EMBL3	O
mouse	O
genomic	O
library	O
.	O

The	O
MVV	O
-	O
value	O
is	O
under	O
the	O
predicted	O
level	O
in	O
the	O
case	O
of	O
67	O
-	O
76	O
percent	O
.	O

The	O
rad9	B-GENE
.	I-GENE
192	I-GENE
DNA	I-GENE
repair	I-GENE
mutant	I-GENE
from	I-GENE
the	I-GENE
fission	I-GENE
yeast	I-GENE
,	I-GENE
Schizosaccharomyces	I-GENE
pombe	I-GENE
,	O
is	O
sensitive	O
to	O
both	O
UV	O
and	O
ionising	O
radiation	O
.	O

Review	O
:	O
deterioration	O
of	O
glucose	O
tolerance	O
with	O
age	O
:	O
the	O
role	O
of	O
insulin	B-GENE
resistance	O
.	O

The	O
5	O
'	O
region	O
shows	O
strong	O
sequence	O
similarity	O
to	O
Escherichia	O
coli	O
consensus	O
promoters	O
and	O
ribosome	O
-	O
binding	O
sequences	O
and	O
allows	O
high	O
levels	O
of	O
expression	O
in	O
E	O
.	O
coli	O
.	O

Premature	O
initiation	O
of	O
mitosis	O
in	O
yeast	O
lacking	O
RCC1	B-GENE
or	O
an	O
interacting	O
GTPase	B-GENE
.	O

The	O
method	O
has	O
been	O
routinely	O
used	O
in	O
our	O
laboratory	O
for	O
1	O
year	O
and	O
has	O
proven	O
to	O
be	O
a	O
reliable	O
procedure	O
for	O
the	O
biological	O
control	O
of	O
occupational	O
exposure	O
to	O
toluene	O
and	O
/	O
or	O
xylene	O
.	O

The	O
patient	O
was	O
a	O
78	O
-	O
year	O
-	O
old	O
male	O
in	O
whom	O
skin	O
lesions	O
preceded	O
the	O
diagnosis	O
of	O
myelofibrosis	O
.	O

Oculus	O
-	O
500	O
is	O
a	O
group	O
of	O
high	O
resolution	O
imaging	O
boards	O
for	O
use	O
with	O
IBM	O
-	O
AT	O
and	O
compatible	O
computers	O
.	O

After	O
resection	O
of	O
the	O
proximal	O
fragment	O
,	O
all	O
scaphoid	O
contact	O
area	O
and	O
pressure	O
was	O
born	O
by	O
the	O
distal	O
scaphoid	O
fragment	O
.	O

Plate	O
luting	O
,	O
a	O
technique	O
that	O
uses	O
polymethylmethacrylate	O
(	O
PMMA	O
)	O
interposed	O
between	O
the	O
plate	O
and	O
the	O
bone	O
,	O
as	O
well	O
as	O
between	O
the	O
screw	O
heads	O
and	O
the	O
plate	O
,	O
to	O
improve	O
the	O
stability	O
of	O
internal	O
fixation	O
was	O
tested	O
in	O
vitro	O
using	O
20	O
paired	O
equine	O
third	O
metacarpal	O
bones	O
with	O
mid	O
-	O
diaphyseal	O
osteotomies	O
plated	O
with	O
six	O
-	O
hole	O
broad	O
ASIF	O
compression	O
plates	O
.	O

These	O
features	O
were	O
considered	O
consistent	O
with	O
a	O
diagnosis	O
of	O
Rothmund	O
-	O
Thomson	O
syndrome	O
.	O

Thyroid	O
lymphoma	O
and	O
its	O
management	O
.	O

The	O
protein	O
encoded	O
by	O
ORF113	B-GENE
contains	O
a	O
transmembrane	O
domain	O
.	O

Space	O
limitations	O
prevent	O
an	O
exhaustive	O
review	O
of	O
all	O
biologic	O
pharmaceuticals	O
,	O
such	O
as	O
tissue	B-GENE
plasminogen	I-GENE
activating	I-GENE
substance	I-GENE
,	O
hormones	O
(	O
e	O
.	O
g	O
.	O
,	O
thyroid	O
,	O
insulin	B-GENE
,	O
growth	B-GENE
hormone	I-GENE
,	O
erythropoietin	B-GENE
)	O
,	O
clotting	O
factors	O
,	O
and	O
blood	O
products	O
.	O

The	O
various	O
forms	O
of	O
sickle	O
cell	O
disease	O
share	O
the	O
common	O
feature	O
of	O
an	O
abnormal	O
globin	B-GENE
chain	I-GENE
that	O
,	O
under	O
certain	O
conditions	O
such	O
as	O
hypoxia	O
,	O
results	O
in	O
the	O
sickling	O
of	O
red	O
blood	O
cells	O
and	O
obstruction	O
of	O
blood	O
vessels	O
.	O

The	O
primary	O
structure	O
of	O
each	O
of	O
the	O
three	O
proteins	O
has	O
about	O
70	O
%	O
homology	O
with	O
that	O
of	O
mouse	B-GENE
contrapsin	I-GENE
,	O
in	O
contrast	O
to	O
43	O
-	O
46	O
%	O
homology	O
with	O
that	O
of	O
rat	B-GENE
alpha	I-GENE
1	I-GENE
-	I-GENE
protease	I-GENE
inhibitor	O
.	O

Patterns	O
of	O
connections	O
underlying	O
cross	O
-	O
modality	O
integration	O
were	O
studied	O
by	O
injecting	O
distinguishable	O
,	O
retrograde	O
tracers	O
(	O
Fluoro	O
-	O
Gold	O
and	O
diamidino	O
yellow	O
)	O
in	O
pairwise	O
manner	O
into	O
different	O
sensory	O
representations	O
(	O
visual	O
,	O
somatosensory	O
,	O
and	O
auditory	O
)	O
in	O
the	O
cerebral	O
cortex	O
of	O
the	O
rat	O
.	O

The	O
across	O
-	O
fiber	O
pattern	O
of	O
the	O
responses	O
to	O
hypotonic	O
NaCl	O
solutions	O
correlated	O
strongly	O
to	O
that	O
elicited	O
by	O
distilled	O
H2O	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
400	O
WORDS	O
)	O

Human	B-GENE
immunodeficiency	I-GENE
virus	I-GENE
type	I-GENE
1	I-GENE
(	I-GENE
HIV	I-GENE
-	I-GENE
1	I-GENE
)	I-GENE
IN	I-GENE
,	O
expressed	O
in	O
Escherichia	O
coli	O
,	O
was	O
purified	O
to	O
near	O
homogeneity	O
.	O

Thigh	O
girth	O
correlated	O
positively	O
with	O
HDL	B-GENE
and	O
HDL2	B-GENE
-	I-GENE
C	I-GENE
and	O
mass	O
,	O
and	O
with	O
LDL	B-GENE
particle	O
size	O
among	O
women	O
.	O

Contributions	O
from	O
pairs	O
of	O
source	O
and	O
target	O
volume	O
elements	O
are	O
summed	O
for	O
the	O
S	O
values	O
between	O
the	O
tumor	O
and	O
itself	O
,	O
between	O
the	O
remaining	O
healthy	O
host	O
organ	O
and	O
itself	O
,	O
and	O
between	O
the	O
tumor	O
and	O
the	O
remaining	O
healthy	O
host	O
organ	O
,	O
with	O
the	O
reciprocity	O
theorem	O
assumed	O
for	O
the	O
last	O
.	O

Tests	O
showed	O
that	O
an	O
overall	O
impression	O
of	O
the	O
force	O
applied	O
could	O
be	O
obtained	O
from	O
a	O
laboratory	O
simulation	O
,	O
but	O
that	O
clearing	O
cement	O
and	O
testing	O
cement	O
were	O
not	O
modelled	O
by	O
this	O
method	O
.	O

The	O
cDNA	O
contained	O
an	O
open	O
reading	O
frame	O
of	O
1392	O
bp	O
that	O
predicted	O
a	O
protein	O
of	O
464	O
amino	O
acids	O
and	O
a	O
molecular	O
mass	O
of	O
52	O
kDa	O
;	O
this	O
protein	O
has	O
97	O
%	O
identity	O
to	O
rat	B-GENE
liver	I-GENE
glucokinase	I-GENE
.	O

Analysis	O
of	O
viral	O
mutants	O
in	O
vivo	O
demonstrated	O
that	O
the	O
NFIII	B-GENE
/	O
OCT	B-GENE
-	I-GENE
1	I-GENE
binding	O
site	O
and	O
a	O
conserved	O
ATF	B-GENE
motif	I-GENE
were	O
important	O
for	O
efficient	O
viral	O
growth	O
.	O

Recovery	O
of	O
radiolabelled	O
BA	O
through	O
urine	O
(	O
28	O
%	O
)	O
and	O
faeces	O
(	O
22	O
%	O
)	O
up	O
to	O
96	O
hrs	O
averaged	O
50	O
%	O
,	O
whereas	O
residual	O
radioactivity	O
in	O
liver	O
and	O
testis	O
experienced	O
a	O
recovery	O
of	O
29	O
%	O
in	O
scorbutic	O
animals	O
.	O

Paradoxically	O
,	O
however	O
,	O
the	O
GH	B-GENE
receptor	I-GENE
cloned	O
from	O
liver	O
exhibits	O
no	O
sequence	O
similarity	O
to	O
receptors	O
with	O
known	O
signal	O
transduction	O
mechanisms	O
,	O
including	O
those	O
exhibiting	O
ligand	O
-	O
activated	O
tyrosine	B-GENE
kinase	I-GENE
activity	O
.	O

This	O
indicates	O
that	O
under	O
certain	O
experimental	O
conditions	O
cdc2	B-GENE
/	O
p58	B-GENE
and	O
cdc2	B-GENE
/	O
p62	B-GENE
may	O
express	O
some	O
differences	O
in	O
their	O
catalytic	O
activity	O
.	O

Mutation	O
analysis	O
implicated	O
multiple	O
segments	O
of	O
the	O
5	O
'	O
untranslated	O
region	O
as	O
contributing	O
to	O
the	O
inhibitory	O
effect	O
.	O

Identification	O
of	O
Ets	B-GENE
-	O
and	O
notch	B-GENE
-	O
related	O
subunits	O
in	O
GA	B-GENE
binding	I-GENE
protein	I-GENE
.	O

The	O
enzymatic	O
response	O
of	O
neutrophils	O
and	O
monocytes	O
was	O
similar	O
although	O
the	O
magnitude	O
of	O
the	O
NADPH	B-GENE
oxidase	I-GENE
activity	O
was	O
significantly	O
higher	O
in	O
neutrophils	O
than	O
in	O
monocytes	O
.	O

In	O
the	O
ileum	O
,	O
enterotoxin	O
increased	O
the	O
luminal	O
disappearance	O
(	O
P	O
less	O
than	O
0	O
.	O
05	O
)	O
and	O
peripheral	O
blood	O
appearance	O
(	O
P	O
less	O
than	O
0	O
.	O
001	O
)	O
of	O
chloroquine	O
.	O

It	O
is	O
concluded	O
that	O
attention	O
to	O
these	O
issues	O
can	O
substantially	O
improve	O
the	O
quality	O
of	O
research	O
on	O
AIDS	O
related	O
behaviors	O
on	O
Black	O
communities	O
.	O

The	O
effectiveness	O
of	O
alpha	O
-	O
mercapto	O
-	O
beta	O
-	O
(	O
2	O
-	O
furyl	O
)	O
acrylic	O
acid	O
(	O
MFA	O
)	O
and	O
N	O
-	O
benzyl	O
-	O
N	O
-	O
dithiocarboxy	O
-	O
D	O
-	O
glucamine	O
(	O
NaB	O
)	O
,	O
used	O
in	O
combination	O
,	O
in	O
the	O
mobilization	O
and	O
excretion	O
of	O
lead	O
was	O
investigated	O
in	O
rats	O
.	O

These	O
results	O
suggest	O
that	O
beta	B-GENE
-	I-GENE
1	I-GENE
may	O
act	O
as	O
a	O
tissue	O
-	O
specific	O
,	O
trans	O
-	O
acting	O
regulator	O
of	O
the	O
expression	O
of	O
the	O
beta	B-GENE
-	I-GENE
zein	I-GENE
gene	I-GENE
in	O
developing	O
maize	O
endosperm	O
.	O

This	O
study	O
examines	O
the	O
effects	O
of	O
hypovolemia	O
on	O
the	O
extracellular	O
ptO2	O
and	O
ptH	O
distributions	O
at	O
multiple	O
tissue	O
sites	O
using	O
a	O
recently	O
developed	O
multipoint	O
microelectrode	O
,	O
that	O
provides	O
simultaneous	O
measurements	O
of	O
ptO2	O
and	O
ptH	O
.	O

All	O
members	O
are	O
also	O
capable	O
of	O
activating	O
in	O
vivo	O
transcription	O
from	O
promoters	O
that	O
contain	O
a	O
C	B-GENE
/	I-GENE
EBP	I-GENE
-	I-GENE
binding	I-GENE
site	I-GENE
.	O

The	O
domains	O
involved	O
in	O
superactivation	O
appear	O
to	O
be	O
a	O
subset	O
of	O
those	O
necessary	O
to	O
achieve	O
synergistic	O
activation	O
.	O

Information	O
on	O
conserved	O
noncoding	O
sequences	O
will	O
help	O
in	O
studies	O
on	O
the	O
regulation	O
of	O
the	O
pro	B-GENE
alpha	I-GENE
1	I-GENE
(	I-GENE
II	I-GENE
)	I-GENE
collagen	I-GENE
gene	I-GENE
.	O

Chlamydia	O
trachomatis	O
and	O
Chlamydia	O
psittaci	O
were	O
not	O
affected	O
by	O
methanol	O
fixation	O
.	O

Although	O
human	O
infections	O
with	O
bacteraemia	O
due	O
to	O
Pasteurella	O
multocida	O
are	O
not	O
uncommon	O
,	O
endocarditis	O
associated	O
with	O
P	O
.	O
haemolytica	O
is	O
rare	O
.	O

For	O
SMX	O
at	O
pH	O
7	O
.	O
0	O
,	O
a	O
1	O
:	O
1	O
complex	O
is	O
formed	O
,	O
but	O
at	O
pH	O
7	O
.	O
5	O
HPCD	O
has	O
little	O
effect	O
on	O
the	O
solubility	O
of	O
the	O
highly	O
ionized	O
SMX	O
,	O
presumably	O
since	O
only	O
un	O
-	O
ionized	O
molecules	O
can	O
form	O
inclusion	O
complexes	O
with	O
the	O
HPCD	O
.	O

PO2	O
measurements	O
using	O
a	O
double	O
barrelled	O
recess	O
type	O
microelectrodes	O
were	O
measured	O
in	O
the	O
optic	O
nerve	O
head	O
of	O
miniature	O
pigs	O
in	O
normoxia	O
and	O
hyperoxia	O
.	O

POU	B-GENE
-	O
specific	O
and	O
POU	B-GENE
-	O
homeo	O
domains	O
of	O
Oct3	B-GENE
were	O
produced	O
in	O
Echerichia	O
coli	O
for	O
characterization	O
of	O
DNA	O
binding	O
to	O
the	O
octamer	O
sequence	O
.	O

The	O
nucleotide	O
(	O
nt	O
)	O
sequences	O
of	O
the	O
exons	O
,	O
exon	O
/	O
intron	O
boundaries	O
and	O
5	O
'	O
-	O
and	O
3	O
'	O
-	O
untranslated	O
regions	O
were	O
determined	O
.	O

Out	O
of	O
40	O
patients	O
,	O
who	O
initially	O
did	O
not	O
show	O
eye	O
complications	O
due	O
to	O
leprosy	O
,	O
37	O
patients	O
were	O
essentially	O
the	O
same	O
10	O
years	O
later	O
.	O

Thus	O
,	O
two	O
very	O
different	O
regulatory	O
elements	O
are	O
used	O
to	O
mediate	O
estrogen	O
induction	O
of	O
related	O
genes	O
in	O
chickens	O
and	O
amphibians	O
.	O

Experimentally	O
in	O
green	O
monkeys	O
,	O
Syrian	O
hamsters	O
and	O
white	O
mice	O
the	O
authors	O
studied	O
the	O
pathogenic	O
properties	O
of	O
a	O
new	O
virus	O
Issyk	O
-	O
Kul	O
.	O

Increasing	O
mean	O
arterial	O
pressure	O
by	O
phenylephrine	O
infusion	O
to	O
levels	O
much	O
greater	O
than	O
produced	O
by	O
NMA	O
and	O
NNA	O
caused	O
only	O
small	O
reductions	O
in	O
cardiac	O
output	O
.	O

J	O
.	O

With	O
stepwise	O
reductions	O
in	O
flow	O
,	O
the	O
peak	O
(	O
S	O
)	O
and	O
trough	O
(	O
D	O
)	O
points	O
of	O
the	O
maximum	O
shifted	O
-	O
frequency	O
envelope	O
fell	O
in	O
parallel	O
in	O
a	O
linear	O
fashion	O
until	O
D	O
reached	O
zero	O
.	O

The	O
IE0	B-GENE
gene	I-GENE
product	O
also	O
transactivated	O
the	O
IE1	B-GENE
promoter	I-GENE
but	O
did	O
not	O
affect	O
expression	O
from	O
its	O
own	O
promoter	O
.	O

Evaluation	O
of	O
left	O
ventricular	O
function	O
using	O
gated	O
planar	O
myocardial	O
imaging	O
with	O
Tc	O
-	O
99m	O
-	O
MIBI	O

Bone	O
marrow	O
abnormalities	O
in	O
Hodgkin	O
'	O
s	O
disease	O
are	O
reviewed	O
and	O
the	O
current	O
understanding	O
of	O
the	O
pathological	O
mechanisms	O
leading	O
to	O
aplastic	O
anemia	O
is	O
discussed	O
.	O

The	O
smaller	O
uptake	O
rate	O
and	O
faster	O
clearance	O
rate	O
resulted	O
in	O
the	O
lower	O
BCF	O
for	O
SWA	O
killifish	O
.	O

Increases	O
in	O
the	O
perfusate	O
PCO2	O
but	O
not	O
in	O
the	O
perfusate	O
H	O
+	O
were	O
highly	O
correlated	O
with	O
decreases	O
in	O
both	O
myocardial	O
contractility	O
and	O
oxygen	O
consumption	O
(	O
r2	O
=	O
.	O
88	O
)	O
.	O

Expression	O
was	O
cell	O
cycle	O
controlled	O
,	O
with	O
steady	O
-	O
state	O
RNA	O
levels	O
significantly	O
higher	O
in	O
growth	O
-	O
arrested	O
than	O
in	O
growth	O
-	O
stimulated	O
cells	O
.	O

Determinants	O
of	O
recurrent	O
ischaemia	O
and	O
revascularisation	O
procedures	O
after	O
thrombolysis	O
with	O
recombinant	O
tissue	B-GENE
plasminogen	I-GENE
activator	I-GENE
in	O
primary	O
coronary	O
occlusion	O
.	O

Therefore	O
,	O
the	O
rbcL	B-GENE
-	O
rbcS	B-GENE
locus	O
seems	O
to	O
be	O
barely	O
expressed	O
under	O
a	O
standard	O
condition	O
for	O
photoautotrophic	O
growth	O
.	O

Relationship	O
between	O
mitochondrial	B-GENE
NADH	I-GENE
-	I-GENE
ubiquinone	I-GENE
reductase	I-GENE
and	O
a	O
bacterial	B-GENE
NAD	I-GENE
-	I-GENE
reducing	I-GENE
hydrogenase	I-GENE
.	O

Analysis	O
of	O
mRNA	O
expression	O
shows	O
that	O
AT	B-GENE
-	I-GENE
BP1	I-GENE
and	O
AT	B-GENE
-	I-GENE
BP2	I-GENE
are	O
expressed	O
in	O
all	O
the	O
tissues	O
examined	O
.	O

3	O
cases	O

Sequence	O
requirements	O
for	O
premature	O
transcription	O
arrest	O
within	O
the	O
first	O
intron	O
of	O
the	O
mouse	B-GENE
c	I-GENE
-	I-GENE
fos	I-GENE
gene	I-GENE
.	O

Infarct	O
regional	O
ejection	O
fraction	O
improved	O
by	O
10	O
.	O
1	O
+	O
/	O
-	O
2	O
.	O
1	O
%	O
between	O
early	O
and	O
late	O
studies	O
when	O
the	O
infarct	O
-	O
related	O
artery	O
was	O
patent	O
and	O
by	O
4	O
.	O
8	O
+	O
/	O
-	O
1	O
.	O
4	O
%	O
if	O
it	O
was	O
occluded	O
(	O
p	O
=	O
0	O
.	O
048	O
)	O
;	O
changes	O
in	O
global	O
and	O
noninfarct	O
regional	O
ejection	O
fraction	O
were	O
similar	O
irrespective	O
of	O
perfusion	O
status	O
.	O

One	O
of	O
its	O
lysine	O
residues	O
is	O
modified	O
by	O
spermidine	O
to	O
form	O
hypusine	O
,	O
a	O
posttranslational	O
modification	O
unique	O
to	O
eIF	B-GENE
-	I-GENE
5A	I-GENE
.	O

The	O
plasmid	O
shuffle	O
technique	O
was	O
used	O
to	O
replace	O
the	O
wild	O
-	O
type	O
gene	O
with	O
the	O
mutant	O
form	O
,	O
resulting	O
in	O
failure	O
of	O
the	O
yeast	O
cells	O
to	O
grow	O
.	O

If	O
this	O
is	O
the	O
case	O
,	O
identification	O
and	O
characterization	O
of	O
transcripts	O
from	O
the	O
Ig	B-GENE
loci	I-GENE
should	O
permit	O
a	O
better	O
understanding	O
of	O
the	O
gene	O
rearrangement	O
process	O
.	O

Transcription	O
of	O
the	O
metH	B-GENE
gene	I-GENE
in	I-GENE
Salmonella	I-GENE
typhimurium	I-GENE
and	I-GENE
Escherichia	I-GENE
coli	I-GENE
is	O
positively	O
regulated	O
by	O
the	O
metR	B-GENE
gene	I-GENE
product	I-GENE
,	O
a	O
DNA	O
binding	O
protein	O
.	O

Disruption	O
of	O
the	O
chromosomal	B-GENE
AAR1	I-GENE
gene	I-GENE
in	O
alpha	O
and	O
a	O
/	O
alpha	O
cells	O
conferred	O
the	O
nonmating	O
phenotype	O
,	O
and	O
the	O
a	O
/	O
alpha	O
diploids	O
could	O
not	O
sporulate	O
.	O

The	O
effect	O
of	O
ICRF	O
-	O
187	O
on	O
the	O
antitumor	O
response	O
induced	O
by	O
the	O
combination	O
of	O
ADR	O
and	O
WBH	O
was	O
also	O
investigated	O
in	O
order	O
to	O
assess	O
alterations	O
in	O
the	O
therapeutic	O
index	O
of	O
this	O
combined	O
therapeutic	O
modality	O
treatment	O
.	O

The	O
ORF	O
was	O
analyzed	O
for	O
secondary	O
structural	O
features	O
,	O
and	O
the	O
sequence	O
data	O
bases	O
were	O
searched	O
for	O
homologies	O
.	O

Mitomycin	O
-	O
C	O
can	O
cause	O
severe	O
necrosis	O
and	O
ulceration	O
when	O
extravasated	O
inadvertently	O
into	O
skin	O
and	O
soft	O
tissues	O
following	O
IV	O
drug	O
administration	O
.	O

In	O
this	O
study	O
,	O
we	O
have	O
cloned	O
the	O
5	O
'	O
-	O
flanking	O
region	O
of	O
the	O
human	B-GENE
nidogen	I-GENE
gene	I-GENE
.	O

Consistent	O
with	O
the	O
in	O
vivo	O
result	O
,	O
the	O
pseudorevertant	O
endonucleases	O
in	O
the	O
crude	O
cell	O
extract	O
display	O
site	O
-	O
specific	O
partial	O
DNA	O
cleavage	O
activity	O
.	O

Additionally	O
,	O
I	B-GENE
kappa	I-GENE
B	I-GENE
beta	I-GENE
,	O
but	O
not	O
I	B-GENE
kappa	I-GENE
B	I-GENE
alpha	I-GENE
,	O
also	O
prevented	O
the	O
binding	O
of	O
Rel	B-GENE
to	O
the	O
kappa	B-GENE
B	I-GENE
site	I-GENE
.	O

Sequence	O
analysis	O
reveals	O
that	O
the	O
DNA	O
binding	O
domain	O
of	O
ILF	B-GENE
has	O
strong	O
homology	O
to	O
the	O
recently	O
described	O
fork	B-GENE
head	I-GENE
DNA	I-GENE
binding	I-GENE
domain	I-GENE
found	O
in	O
the	O
Drosophila	B-GENE
homeotic	I-GENE
protein	I-GENE
fork	I-GENE
head	I-GENE
and	O
a	O
family	O
of	O
hepatocyte	B-GENE
nuclear	I-GENE
factors	I-GENE
,	O
HNF	B-GENE
-	I-GENE
3	I-GENE
.	O

Lengthy	O
and	O
repeated	O
hemodialyses	O
were	O
required	O
to	O
lower	O
lithemia	O
to	O
nontoxic	O
ranges	O
.	O

A	O
single	O
i	O
.	O
p	O
.	O
injection	O
of	O
d	O
,	O
l	O
-	O
baclofen	O
10	O
mg	O
/	O
kg	O
both	O
reduced	O
noradrenaline	O
(	O
NA	O
)	O
biosynthesis	O
in	O
vivo	O
(	O
31	O
%	O
)	O
and	O
the	O
endogenous	O
concentration	O
of	O
normetanephrine	O
(	O
NMN	O
)	O
(	O
32	O
%	O
)	O
and	O
increased	O
NA	O
levels	O
(	O
28	O
%	O
)	O
.	O

Fufang	O
wuzi	O
yanzong	O
pills	O
have	O
strong	O
leukogenic	O
effect	O
on	O
cyclophosphamide	O
induced	O
leukopenia	O
in	O
mice	O
.	O

Mutations	O
in	O
the	O
small	O
subunit	O
of	O
ribulosebisphosphate	B-GENE
carboxylase	I-GENE
affect	O
subunit	O
binding	O
and	O
catalysis	O
.	O

The	O
structural	O
changes	O
in	O
intra	O
-	O
acinar	O
artery	O
manifested	O
mainly	O
by	O
an	O
increase	O
in	O
number	O
of	O
muscular	O
artery	O
resulting	O
from	O
muscularization	O
of	O
precursor	O
cells	O
(	O
pericytes	O
and	O
intermediate	O
cells	O
)	O
located	O
within	O
partially	O
muscular	O
and	O
nonmuscular	O
arterial	O
wall	O
to	O
smooth	O
muscle	O
cell	O
,	O
and	O
by	O
the	O
medial	O
wall	O
thickened	O
due	O
to	O
hypertrophy	O
and	O
hyperplasia	O
of	O
smooth	O
muscle	O
cells	O
as	O
well	O
as	O
accumulation	O
of	O
a	O
large	O
amount	O
of	O
collagen	B-GENE
,	O
especially	O
the	O
type	B-GENE
1	I-GENE
collagen	I-GENE
.	O

These	O
results	O
suggest	O
that	O
NZ	O
-	O
107	O
may	O
be	O
a	O
useful	O
drug	O
for	O
the	O
treatment	O
of	O
bronchial	O
asthma	O
by	O
reducing	O
late	O
-	O
phase	O
airway	O
responses	O
and	O
airway	O
hyperreactivity	O
.	O

In	O
study	O
2	O
,	O
the	O
correlation	O
coefficients	O
between	O
the	O
ISO2	O
measurements	O
obtained	O
at	O
the	O
ulcer	O
margin	O
and	O
at	O
the	O
adjacent	O
normal	O
mucosa	O
,	O
and	O
delta	O
ISO2	O
obtained	O
by	O
the	O
experienced	O
observer	O
and	O
one	O
of	O
the	O
three	O
learners	O
were	O
0	O
.	O
94	O
,	O
0	O
.	O
97	O
,	O
and	O
0	O
.	O
94	O
,	O
respectively	O
.	O

Bronchial	O
mucosa	O
tattooing	O
in	O
persons	O
exposed	O
to	O
different	O
industrial	O
aerosols	O
did	O
not	O
depend	O
on	O
the	O
forms	O
of	O
PC	O
,	O
DB	O
and	O
the	O
diseases	O
'	O
stages	O
.	O

Anti	B-GENE
-	I-GENE
HBc	I-GENE
production	O
of	O
PBMC	O
was	O
enhanced	O
remarkably	O
in	O
this	O
case	O
.	O

Lipoprotein	B-GENE
lipase	I-GENE
(	O
LPL	B-GENE
)	O
,	O
a	O
key	O
enzyme	O
in	O
normal	O
lipoprotein	O
metabolism	O
,	O
has	O
a	O
complex	O
pattern	O
of	O
regulation	O
and	O
tissue	O
-	O
specific	O
expression	O
.	O

Deletion	O
of	O
the	O
proximal	O
octanucleotide	O
motif	O
from	O
the	O
plasmid	O
containing	O
the	O
-	O
461	O
fragment	O
of	O
the	O
LPL	B-GENE
promoter	I-GENE
,	O
resulted	O
in	O
a	O
79	O
and	O
76	O
%	O
decrease	O
in	O
the	O
level	O
of	O
expression	O
in	O
transfected	O
3T3	O
-	O
L1	O
adipocytes	O
and	O
HepG2	O
hepatocytes	O
,	O
respectively	O
.	O

We	O
examined	O
the	O
binding	O
of	O
purified	O
T3	B-GENE
receptor	I-GENE
alpha	I-GENE
(	O
T3R	B-GENE
alpha	I-GENE
)	O
,	O
overexpressed	O
in	O
Escherichia	O
coli	O
,	O
to	O
wild	O
-	O
type	O
and	O
up	O
and	O
down	O
mutations	O
of	O
the	O
rGH	B-GENE
T3RE	B-GENE
to	O
evaluate	O
whether	O
transcriptional	O
potency	O
correlates	O
with	O
changes	O
in	O
T3R	B-GENE
binding	O
.	O

Comparison	O
of	O
the	O
cDNA	O
-	O
predicted	O
avian	B-GENE
TnIcardiac	I-GENE
amino	I-GENE
acid	I-GENE
sequences	I-GENE
with	O
known	O
TnI	B-GENE
sequences	I-GENE
indicated	O
1	O
)	O
that	O
the	O
presence	O
of	O
an	O
N	O
-	O
terminal	O
extension	O
sequence	O
carrying	O
a	O
dual	O
protein	B-GENE
kinase	I-GENE
A	I-GENE
phosphorylation	O
target	O
site	O
and	O
an	O
adjacent	O
proline	O
-	O
rich	O
segment	O
is	O
an	O
ancient	O
cardiac	O
-	O
specific	O
feature	O
of	O
TnI	B-GENE
which	O
has	O
been	O
conserved	O
since	O
the	O
bird	O
/	O
mammal	O
divergence	O
,	O
2	O
)	O
that	O
features	O
of	O
the	O
near	O
-	O
N	O
-	O
terminal	O
troponin	B-GENE
C	I-GENE
(	O
TnC	B-GENE
)	O
-	O
binding	O
site	O
sequence	O
suggest	O
isoform	O
-	O
specific	O
adaptation	O
of	O
TnI	B-GENE
and	O
TnC	B-GENE
,	O
and	O
3	O
)	O
that	O
the	O
avian	O
TnIcardiac	B-GENE
internal	O
actin	B-GENE
/	I-GENE
TnC	I-GENE
-	I-GENE
binding	I-GENE
,	I-GENE
actomyosin	I-GENE
-	I-GENE
inhibitory	I-GENE
,	I-GENE
domain	I-GENE
shows	O
significant	O
sequence	O
divergence	O
from	O
mammalian	B-GENE
TnIcardiac	I-GENE
sequences	I-GENE
,	O
including	O
the	O
absence	O
of	O
a	O
protein	B-GENE
kinase	I-GENE
C	I-GENE
target	O
site	O
which	O
is	O
a	O
cardiac	O
-	O
specific	O
feature	O
of	O
TnI	B-GENE
in	O
mammals	O
.	O

Ventilatory	O
management	O
casebook	O
.	O

An	O
ASSEMBLER	O
routine	O
for	O
on	O
-	O
line	O
graphic	O
display	O
and	O
averaging	O
of	O
data	O
acquired	O
on	O
a	O
personal	O
microcomputer	O
.	O

Expression	O
of	O
the	O
mouse	B-GENE
TSH	I-GENE
beta	I-GENE
gene	I-GENE
,	O
therefore	O
,	O
gives	O
rise	O
to	O
multiple	O
mRNAs	O
,	O
each	O
with	O
a	O
unique	O
5	O
'	O
-	O
untranslated	O
region	O
.	O

It	O
was	O
found	O
that	O
the	O
ROSP	O
undergoes	O
a	O
number	O
of	O
fluctuations	O
in	O
the	O
negative	O
and	O
positive	O
directions	O
with	O
a	O
gradually	O
decreasing	O
amplitude	O
in	O
the	O
course	O
of	O
5	O
-	O
25	O
days	O
following	O
the	O
operation	O
,	O
after	O
which	O
relatively	O
stable	O
negative	O
values	O
of	O
the	O
ROSP	O
are	O
established	O
on	O
the	O
average	O
in	O
electrodes	O
implanted	O
to	O
the	O
level	O
of	O
the	O
dura	O
mater	O
,	O
and	O
positive	O
values	O
in	O
electrodes	O
implanted	O
to	O
the	O
level	O
of	O
the	O
pia	O
mater	O
.	O

Blood	O
flow	O
velocity	O
waveforms	O
were	O
recorded	O
by	O
pulsed	O
Doppler	O
examination	O
of	O
the	O
fetal	O
internal	O
carotid	O
and	O
middle	O
cerebral	O
arteries	O
using	O
the	O
established	O
transabdominal	O
route	O
as	O
well	O
as	O
a	O
new	O
transvaginal	O
approach	O
.	O

Quantitative	O
analysis	O
of	O
DNA	O
using	O
flow	O
cytometry	O
and	O
immunocytochemical	O
findings	O
in	O
16	O
cases	O
of	O
cardiac	O
myxomas	O

Sequence	O
analysis	O
revealed	O
that	O
in	O
addition	O
to	O
the	O
non	O
-	O
spliced	O
variant	O
,	O
multiple	O
mRNA	O
species	O
were	O
generated	O
by	O
alternative	O
splicing	O
resulting	O
in	O
the	O
exclusion	O
of	O
92	O
,	O
166	O
,	O
170	O
,	O
174	O
and	O
263	O
nucleotides	O
(	O
nt	O
)	O
,	O
respectively	O
,	O
from	O
exon	O
1	O
.	O

Position	O
22	O
is	O
an	O
isoleucine	O
in	O
the	O
complete	B-GENE
SsoL12	I-GENE
protein	I-GENE
sequence	I-GENE
,	O
coded	O
by	O
an	O
AUA	O
codon	O
.	O

Symptoms	O
due	O
to	O
the	O
action	O
of	O
mastocyte	O
mediators	O
were	O
observed	O
.	O

In	O
the	O
yeast	O
Saccharomyces	O
cerevisiae	O
,	O
copper	O
levels	O
exert	O
some	O
control	O
over	O
the	O
level	O
of	O
SOD1	B-GENE
expression	O
.	O

Of	O
these	O
179	O
samples	O
,	O
Mobiluncus	O
SP	O
was	O
observed	O
in	O
35	O
(	O
19	O
.	O
6	O
%	O
)	O
using	O
Gram	O
staining	O
and	O
in	O
18	O
(	O
10	O
.	O
1	O
%	O
)	O
this	O
microorganism	O
was	O
isolated	O
in	O
agar	O
RLK	O
and	O
anaerobic	O
atmosphere	O
.	O

Previous	O
investigators	O
have	O
suggested	O
that	O
subretinal	O
blood	O
damages	O
the	O
retina	O
in	O
part	O
because	O
of	O
its	O
solid	O
fibrin	B-GENE
meshwork	O
.	O

Twenty	O
-	O
four	O
hours	O
later	O
,	O
the	O
animals	O
were	O
randomized	O
to	O
subretinal	O
treatment	O
with	O
2	O
.	O
5	O
micrograms	O
of	O
tissue	B-GENE
plasminogen	I-GENE
activator	I-GENE
or	O
a	O
similar	O
volume	O
of	O
physiologic	O
saline	O
.	O

Neuro	O
-	O
otological	O
examinations	O
revealed	O
spontaneous	O
downbeat	O
nystagmus	O
,	O
bilateral	O
gaze	O
nystagmus	O
and	O
rebound	O
nystagmus	O
.	O

Since	O
the	O
morphology	O
of	O
the	O
lesions	O
can	O
mimic	O
that	O
of	O
other	O
cutaneous	O
disorders	O
,	O
Bowen	O
'	O
s	O
disease	O
is	O
often	O
not	O
recognized	O
initially	O
.	O

Equine	O
amnion	O
and	O
live	O
yeast	O
cell	O
derivative	O
were	O
evaluated	O
as	O
a	O
biological	O
dressing	O
and	O
as	O
a	O
topical	O
wound	O
medicament	O
respectively	O
,	O
in	O
the	O
treatment	O
of	O
granulating	O
wounds	O
of	O
the	O
distal	O
portion	O
of	O
the	O
limbs	O
of	O
horses	O
.	O

To	O
lower	O
the	O
current	O
high	O
incidence	O
of	O
NANB	O
-	O
induced	O
PTH	O
,	O
in	O
1986	O
,	O
the	O
American	O
Association	O
of	O
Blood	O
Banks	O
(	O
AABB	O
)	O
recommended	O
testing	O
for	O
these	O
PTH	O
-	O
associated	O
"	O
surrogate	O
"	O
markers	O
on	O
all	O
donated	O
units	O
of	O
blood	O
.	O

Fusion	O
of	O
ubiquitin	B-GENE
to	O
pADPRP	B-GENE
increased	O
the	O
yield	O
of	O
pADPRP	B-GENE
approximately	O
10	O
-	O
fold	O
compared	O
to	O
that	O
of	O
the	O
unfused	O
enzyme	O
.	O

In	O
group	O
III	O
,	O
patients	O
also	O
received	O
their	O
own	O
mediastinal	O
drainage	O
blood	O
,	O
shed	O
for	O
6	O
hours	O
after	O
operation	O
,	O
after	O
concentration	O
and	O
washing	O
in	O
a	O
MBRS	O
.	O

The	O
effect	O
of	O
salmon	B-GENE
calcitonin	I-GENE
nasal	O
spray	O
in	O
women	O
with	O
established	O
osteoporosis	O
has	O
also	O
been	O
studied	O
.	O

Skeletal	O
muscle	O
metaboreceptor	O
responses	O
are	O
impaired	O
in	O
heart	O
failure	O
.	O

Skeletal	O
muscle	O
metaboreceptor	O
exercise	O
responses	O
are	O
attenuated	O
in	O
heart	O
failure	O
.	O

Evaluation	O
of	O
antiepileptic	O
drug	O
effect	O
on	O
membrane	O
fluidity	O
.	O

The	O
examinations	O
were	O
performed	O
on	O
two	O
groups	O
of	O
20	O
(	O
using	O
AmF	O
/	O
SnF2	O
)	O
-	O
,	O
resp	O
.	O

The	O
vaccine	O
used	O
was	O
known	O
to	O
be	O
immunogenic	O
for	O
older	O
children	O
and	O
adults	O
.	O

Both	O
groups	O
then	O
underwent	O
hypnotic	O
induction	O
,	O
and	O
completed	O
the	O
test	O
again	O
(	O
R2	O
)	O
.	O

Applications	O
of	O
three	O
-	O
dimensional	O
analysis	O
to	O
the	O
auditory	O
P300	O
.	O

The	O
construct	O
was	O
introduced	O
into	O
BW2001	O
(	O
xth	O
-	O
11	O
,	O
nfo	O
-	O
2	O
)	O
strain	O
cells	O
of	O
Escherichia	O
coli	O
.	O

Recombinant	B-GENE
human	I-GENE
TFIID	I-GENE
supported	O
weak	O
basal	O
transcription	O
in	O
heat	O
-	O
treated	O
nuclear	O
extracts	O
whereas	O
a	O
partially	O
purified	O
TFIID	B-GENE
fraction	O
from	O
HeLa	O
cells	O
reconstituted	O
a	O
maximal	O
level	O
of	O
transcription	O
.	O

Only	O
after	O
a	O
pretreatment	O
aimed	O
at	O
increasing	O
its	O
oxide	O
surface	O
layer	O
was	O
titanium	O
powder	O
found	O
to	O
accelerate	O
the	O
precipitation	O
from	O
solutions	O
containing	O
2	O
mmol	O
/	O
L	O
CaCl2	O
,	O
2	O
mmol	O
/	O
L	O
KH2PO4	O
,	O
50	O
mmol	O
/	O
L	O
Hepes	O
,	O
pH	O
7	O
.	O
2	O
,	O
and	O
to	O
induce	O
precipitation	O
from	O
metastable	O
solutions	O
containing	O
1	O
.	O
2	O
mmol	O
/	O
L	O
CaCl2	O
,	O
1	O
.	O
2	O
mmol	O
/	O
L	O
KH2PO4	O
,	O
50	O
mmol	O
/	O
L	O
Hepes	O
,	O
pH	O
7	O
.	O
2	O
,	O
at	O
37	O
degrees	O
C	O
.	O

We	O
conclude	O
that	O
solidification	O
could	O
occur	O
in	O
all	O
feeds	O
containing	O
casein	B-GENE
and	O
that	O
alternative	O
feeds	O
should	O
be	O
considered	O
in	O
patients	O
with	O
increased	O
gastric	O
acidity	O
.	O

Neither	O
model	O
,	O
as	O
applied	O
,	O
provided	O
a	O
satisfactory	O
account	O
of	O
the	O
effects	O
of	O
the	O
main	O
variables	O
of	O
number	O
of	O
tones	O
and	O
amount	O
of	O
perturbation	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
400	O
WORDS	O
)	O

Determination	O
of	O
an	O
RNA	O
structure	O
involved	O
in	O
splicing	O
inhibition	O
of	O
a	O
muscle	O
-	O
specific	O
exon	O
.	O

Endothelial	O
cells	O
stored	O
with	O
University	O
of	O
Wisconsin	O
solution	O
excluded	O
trypan	O
blue	O
better	O
(	O
1	O
.	O
0	O
%	O
+	O
/	O
-	O
0	O
.	O
5	O
%	O
cells	O
stained	O
,	O
p	O
less	O
than	O
0	O
.	O
001	O
.	O

The	O
effect	O
of	O
diffusion	O
limitation	O
was	O
quantified	O
in	O
terms	O
of	O
the	O
ratio	O
O2	O
uptake	O
/	O
O2	O
requirement	O
(	O
=	O
fraction	O
of	O
cross	O
-	O
sectional	O
area	O
supplied	O
with	O
O2	O
)	O
,	O
assuming	O
local	O
O2	O
requirement	O
per	O
unit	O
volume	O
to	O
be	O
constant	O
and	O
independent	O
of	O
PO2	O
at	O
PO2	O
greater	O
than	O
0	O
.	O

(	O
2	O
)	O
Diffusion	O
limitation	O
in	O
the	O
heterogeneous	O
model	O
sets	O
in	O
at	O
a	O
lower	O
O2	O
requirement	O
value	O
,	O
and	O
increases	O
more	O
gradually	O
with	O
increasing	O
O2	O
requirement	O
,	O
than	O
in	O
the	O
corresponding	O
homogeneous	O
models	O
with	O
the	O
same	O
average	O
cylinder	O
diameter	O
.	O

The	O
antihypertensive	O
effect	O
of	O
Estulic	O
has	O
been	O
examined	O
over	O
a	O
12	O
-	O
month	O
period	O
in	O
101	O
hypertensive	O
patients	O
.	O

At	O
the	O
time	O
of	O
the	O
seizure	O
,	O
the	O
patient	O
was	O
asked	O
to	O
read	O
a	O
test	O
phrase	O
aloud	O
until	O
it	O
was	O
read	O
correctly	O
and	O
clearly	O
.	O

Monitoring	O
patients	O
with	O
acute	O
leukemia	O
for	O
IL	B-GENE
-	I-GENE
1	I-GENE
and	O
TNF	B-GENE
levels	O
throughout	O
the	O
clinical	O
course	O
of	O
disease	O
may	O
help	O
clarify	O
the	O
causes	O
of	O
febrile	O
episodes	O
.	O

Echinococcus	O
granulosus	O
was	O
diagnosed	O
by	O
fine	O
-	O
needle	O
aspiration	O
cytology	O
of	O
a	O
lung	O
cyst	O
in	O
a	O
6	O
-	O
yr	O
-	O
old	O
white	O
female	O
in	O
central	O
Missouri	O
.	O

The	O
sequence	O
was	O
determined	O
of	O
6493	O
nucleotides	O
encompassing	O
the	O
bet	B-GENE
genes	I-GENE
of	I-GENE
Escherichia	I-GENE
coli	I-GENE
which	O
encode	O
the	O
osmoregulatory	O
choline	O
-	O
glycine	O
betaine	O
pathway	O
.	O

A	O
7	O
-	O
day	O
treatment	O
of	O
amphotericin	O
B	O
(	O
5	O
mg	O
/	O
kg	O
/	O
day	O
i	O
.	O
p	O
.	O
)	O
significantly	O
reduced	O
the	O
glomerular	O
filtration	O
rate	O
(	O
GFR	O
)	O
measured	O
as	O
inuline	O
clearance	O
and	O
creatinine	O
clearance	O
(	O
0	O
.	O
74	O
+	O
/	O
-	O
0	O
.	O
29	O
and	O
0	O
.	O
16	O
+	O
/	O
-	O
0	O
.	O
04	O
ml	O
/	O
min	O
,	O
respectively	O
)	O
in	O
comparison	O
to	O
vehicle	O
-	O
treated	O
rats	O
(	O
2	O
.	O
04	O
+	O
/	O
-	O
0	O
.	O
23	O
and	O
1	O
.	O
29	O
+	O
/	O
-	O
0	O
.	O
19	O
ml	O
/	O
min	O
,	O
respectively	O
)	O
.	O

Confocal	O
fluorescence	O
microscopy	O
in	O
modern	O
cell	O
biology	O
.	O

Toluene	O
is	O
the	O
chemical	O
most	O
frequently	O
present	O
in	O
cases	O
involving	O
volatile	O
solvents	O
.	O

Fortunately	O
DDT	O
-	O
,	O
HCH	O
-	O
and	O
HCB	O
-	O
levels	O
decreased	O
in	O
breast	O
milk	O
during	O
the	O
last	O
years	O
.	O

A	O
herpesvirus	O
proteinase	O
activity	O
has	O
been	O
identified	O
and	O
partially	O
characterized	O
by	O
using	O
the	O
cloned	O
enzyme	O
and	O
substrate	O
genes	O
in	O
transient	O
transfection	O
assays	O
.	O

Adult	O
H	O
,	O
but	O
not	O
R	O
,	O
manifested	O
the	O
burrowing	O
preference	O
whenever	O
offered	O
the	O
opportunity	O
.	O

The	O
rear	O
silver	O
liquid	O
chamber	O
was	O
threefold	O
thick	O
to	O
17	O
MeV	O
protons	O
in	O
water	O
and	O
it	O
efficiently	O
produced	O
either	O
13N	O
by	O
the	O
16O	O
(	O
p	O
,	O
alpha	O
)	O
13N	O
reaction	O
or	O
[	O
18F	O
]	O
fluoride	O
ion	O
by	O
the	O
18O	O
(	O
p	O
,	O
n	O
)	O
18F	O
reaction	O
.	O

Heterogeneous	O
electron	O
transfer	O
of	O
cytochrome	B-GENE
c	I-GENE
facilitated	O
by	O
polypyrrole	O
and	O
methylene	O
blue	O
polypyrrole	O
film	O
modified	O
electrodes	O
.	O

Selective	O
activation	O
of	O
adrenaline	O
secretion	O
by	O
the	O
rat	O
adrenal	O
in	O
neuroglycopenia	O
detected	O
via	O
microdialysis	O

The	O
1489	O
-	O
base	O
pair	O
EFIA	B-GENE
cDNA	O
encodes	O
a	O
322	O
-	O
amino	O
acid	O
protein	O
which	O
is	O
nearly	O
identical	O
to	O
two	O
previously	O
described	O
human	O
DNA	O
binding	O
proteins	O
.	O

Four	O
putative	O
positive	O
cDNA	O
clones	O
were	O
isolated	O
,	O
and	O
the	O
largest	O
insert	O
(	O
pASB	B-GENE
-	I-GENE
1	I-GENE
)	O
was	O
sequenced	O
in	O
both	O
orientations	O
.	O

Sci	O
.	O

Dose	O
standardisation	O
of	O
botulinum	B-GENE
toxin	I-GENE
.	O

The	O
coding	O
sequence	O
for	O
a	O
260	O
-	O
amino	O
-	O
acid	O
residue	O
polypeptide	O
was	O
interrupted	O
by	O
a	O
single	O
short	O
intron	O
of	O
60	O
base	O
pairs	O
(	O
bp	O
)	O
,	O
and	O
about	O
70	O
%	O
of	O
the	O
deduced	O
amino	O
acid	O
sequence	O
of	O
the	O
Drosophila	B-GENE
PCNA	I-GENE
was	O
identical	O
to	O
the	O
rat	O
and	O
human	B-GENE
PCNA	I-GENE
polypeptides	I-GENE
,	O
with	O
conserved	O
unique	O
repeats	O
of	O
leucine	O
in	O
the	O
C	O
-	O
terminal	O
region	O
.	O

Translational	O
fusions	O
of	O
the	O
aroF	B-GENE
regulatory	I-GENE
regions	I-GENE
to	O
lacZ	B-GENE
were	O
constructed	O
and	O
then	O
introduced	O
in	O
single	O
copy	O
into	O
the	O
E	O
.	O
coli	O
chromosome	O
.	O
beta	B-GENE
-	I-GENE
Galactosidase	I-GENE
assays	O
for	O
tyrR	O
-	O
mediated	O
regulation	O
of	O
aroF	B-GENE
-	O
lacZ	B-GENE
expression	O
revealed	O
that	O
the	O
E	B-GENE
.	I-GENE
coli	I-GENE
TyrR	I-GENE
repressor	I-GENE
apparently	O
recognizes	O
the	O
operators	O
of	O
both	O
organisms	O
with	O
about	O
equal	O
efficiency	O
.	O

During	O
exercise	O
K	O
+	O
is	O
released	O
from	O
contracting	O
muscle	O
and	O
plasma	O
K	O
+	O
concentration	O
rises	O
.	O

Following	O
treatment	O
,	O
serum	O
estradiol	O
levels	O
were	O
higher	O
in	O
groups	O
E	O
+	O
T	O
and	O
E	O
than	O
in	O
group	O
C	O
.	O

We	O
conclude	O
that	O
the	O
beta	O
-	O
adrenergic	O
agonist	O
,	O
isoproterenol	O
,	O
has	O
little	O
influence	O
on	O
vascular	O
capacitance	O
or	O
liver	O
volume	O
of	O
dogs	O
,	O
unless	O
the	O
hepatic	O
outflow	O
resistance	O
is	O
elevated	O
by	O
agents	O
such	O
as	O
histamine	O
.	O

DNA	O
sequence	O
and	O
evolution	O
of	O
the	O
CPS	B-GENE
domain	I-GENE
of	O
the	O
Syrian	B-GENE
hamster	I-GENE
multifunctional	I-GENE
protein	I-GENE
CAD	I-GENE
.	O

A	O
high	O
-	O
frequency	O
restriction	O
fragment	O
length	O
polymorphism	O
was	O
evident	O
in	O
the	O
DNA	O
from	O
29	O
unrelated	O
individuals	O
using	O
the	O
enzyme	O
BglII	B-GENE
.	O

The	O
antilog	O
transformation	O
of	O
pH	O
did	O
not	O
improve	O
the	O
results	O
.	O

Telomeres	O
prevent	O
end	O
-	O
to	O
-	O
end	O
fusions	O
and	O
exonucleolytic	O
degradation	O
,	O
enable	O
the	O
end	O
of	O
the	O
linear	O
DNA	O
molecule	O
to	O
replicate	O
,	O
and	O
function	O
in	O
cell	O
division	O
.	O

One	O
of	O
these	O
is	O
located	O
in	O
the	O
5	O
'	O
-	O
untranslated	O
region	O
,	O
and	O
may	O
encode	O
regulatory	O
sequences	O
.	O

The	O
native	O
enzyme	O
purified	O
from	O
protease	B-GENE
-	I-GENE
B	I-GENE
-	O
deficient	O
URA2	B-GENE
-	O
transformed	O
cells	O
,	O
was	O
phosphorylated	O
in	O
vitro	O
using	O
catalytic	O
subunits	O
of	O
pure	O
cAMP	B-GENE
-	I-GENE
dependent	I-GENE
protein	I-GENE
kinase	I-GENE
.	O

A	O
bovine	O
abomasum	O
lambda	O
gt11	O
cDNA	O
library	O
was	O
screened	O
with	O
a	O
monoclonal	O
antibody	O
raised	O
against	O
the	O
rabbit	B-GENE
H	I-GENE
,	I-GENE
K	I-GENE
-	I-GENE
ATPase	I-GENE
beta	I-GENE
subunit	I-GENE
.	O

Judicious	O
use	O
of	O
laboratory	O
testing	O
,	O
including	O
monitoring	O
of	O
CD4	B-GENE
cell	O
counts	O
,	O
is	O
recommended	O
.	O

There	O
is	O
no	O
TATA	O
box	O
appropriately	O
spaced	O
upstream	O
from	O
the	O
transcription	O
initiation	O
site	O
.	O

Characterization	O
of	O
the	O
5	O
'	O
end	O
of	O
the	O
growth	O
-	O
regulated	O
Syrian	B-GENE
hamster	I-GENE
CAD	I-GENE
gene	I-GENE
.	O

Early	O
cirrhosis	O
,	O
an	O
early	O
modality	O
of	O
the	O
evolution	O
of	O
acute	O
hepatitis	O
.	O

Combined	O
therapy	O
with	O
MK	O
-	O
801	O
and	O
nimodipine	O
for	O
protection	O
of	O
ischemic	O
brain	O
damage	O
.	O

Initial	O
screening	O
of	O
a	O
rat	O
liver	O
cDNA	O
library	O
with	O
an	O
oligonucleotide	O
probe	O
derived	O
from	O
the	O
rat	O
SCP2	B-GENE
protein	O
sequence	O
revealed	O
an	O
825	O
-	O
base	O
pair	O
cDNA	O
clone	O
coding	O
for	O
the	O
complete	O
SCP2	B-GENE
protein	O
sequence	O
.	O

Cloning	O
,	O
expression	O
,	O
and	O
nucleotide	O
sequence	O
of	O
rat	B-GENE
liver	I-GENE
sterol	I-GENE
carrier	I-GENE
protein	I-GENE
2	I-GENE
cDNAs	I-GENE
.	O

The	O
addition	O
of	O
an	O
equimolar	O
complex	O
of	O
the	O
fourth	O
and	O
seventh	O
largest	O
subunits	O
,	O
purified	O
from	O
pol	B-GENE
II	I-GENE
holoenzyme	I-GENE
by	O
ion	O
-	O
exchange	O
chromatography	O
in	O
the	O
presence	O
of	O
urea	O
,	O
restored	O
promoter	O
-	O
directed	O
initiation	O
activity	O
to	O
pol	B-GENE
II	I-GENE
delta	I-GENE
4	I-GENE
/	I-GENE
7	I-GENE
.	O

We	O
report	O
here	O
the	O
identification	O
of	O
HSF	B-GENE
in	O
the	O
fission	O
yeast	O
Schizosaccharomyces	O
pombe	O
.	O

Induction	O
requires	O
the	O
ACE1	B-GENE
gene	I-GENE
product	I-GENE
,	O
which	O
binds	O
to	O
specific	O
sites	O
in	O
the	O
promoter	O
region	O
of	O
the	O
CUP1	B-GENE
gene	I-GENE
.	O

Gel	O
mobility	O
shift	O
assays	O
using	O
a	O
synthetic	O
E6	B-GENE
motif	I-GENE
detected	O
a	O
B	O
-	O
cell	O
-	O
specific	O
complex	O
in	O
addition	O
to	O
a	O
ubiquitous	O
band	O
found	O
also	O
in	O
T	O
cells	O
and	O
HeLa	O
cells	O
.	O

The	O
sequence	O
of	O
four	O
clones	O
was	O
sufficient	O
to	O
construct	O
a	O
3018	B-GENE
-	I-GENE
bp	I-GENE
BAL	I-GENE
cDNA	I-GENE
structure	O
.	O

The	O
application	O
of	O
these	O
instruments	O
allows	O
occlusion	O
of	O
the	O
ascending	O
aorta	O
traversed	O
by	O
the	O
perfusion	O
cannula	O
inserted	O
directly	O
or	O
through	O
the	O
apex	O
of	O
the	O
heart	O
as	O
well	O
as	O
simultaneous	O
left	O
ventricular	O
venting	O
.	O

Adenylosuccinate	B-GENE
synthetase	I-GENE
(	O
IMP	O
:	O
L	B-GENE
-	I-GENE
aspartate	I-GENE
ligase	I-GENE
(	O
GDP	O
)	O
,	O
EC	B-GENE
6	I-GENE
.	I-GENE
3	I-GENE
.	I-GENE
4	I-GENE
.	I-GENE
4	I-GENE
)	O
plays	O
an	O
important	O
role	O
in	O
purine	O
biosynthesis	O
catalyzing	O
the	O
GTP	O
-	O
dependent	O
conversion	O
of	O
IMP	O
to	O
AMP	O
.	O

Immunophenotyping	O
in	O
four	O
cases	O
,	O
demonstrated	O
non	O
-	O
B	O
,	O
non	O
-	O
T	O
cell	O
origin	O
in	O
three	O
and	O
pre	O
-	O
B	O
cell	O
origin	O
in	O
one	O
.	O

The	O
results	O
strengthen	O
the	O
conclusion	O
that	O
predominantly	O
dynamic	O
activity	O
increases	O
the	O
G4	B-GENE
content	O
of	O
mature	O
innervated	O
fast	O
muscles	O
.	O

We	O
reviewed	O
the	O
records	O
of	O
151	O
patients	O
with	O
optic	O
neuritis	O
examined	O
over	O
an	O
eight	O
-	O
year	O
period	O
.	O

Cut	O
-	O
off	O
levels	O
that	O
define	O
abnormality	O
are	O
rather	O
arbitrary	O
and	O
this	O
decreases	O
the	O
specificity	O
of	O
the	O
test	O
in	O
apparently	O
healthy	O
patients	O
.	O

Alanine	B-GENE
aminotransferase	I-GENE
in	O
clinical	O
practice	O
.	O

Nucleotide	O
sequence	O
analysis	O
of	O
the	O
Pseudomonas	B-GENE
putida	I-GENE
PpG7	I-GENE
salicylate	I-GENE
hydroxylase	I-GENE
gene	I-GENE
(	O
nahG	B-GENE
)	O
and	O
its	O
3	O
'	O
-	O
flanking	O
region	O
.	O

All	O
six	O
ARF	B-GENE
cDNAs	I-GENE
are	O
more	O
similar	O
to	O
each	O
other	O
than	O
to	O
other	O
approximately	O
20	B-GENE
-	I-GENE
kDa	I-GENE
guanine	I-GENE
nucleotide	I-GENE
-	I-GENE
binding	I-GENE
proteins	I-GENE
.	O

The	O
long	O
terminal	O
repeat	O
(	O
LTR	O
)	O
of	O
the	O
human	O
immunodeficiency	O
virus	O
(	O
HIV	O
)	O
contains	O
three	O
binding	O
sites	O
for	O
the	O
transcriptional	O
factor	O
Sp1	B-GENE
.	O

DNA	O
from	O
PCR	O
was	O
labeled	O
and	O
used	O
to	O
isolate	O
several	O
lambda	O
gt11	O
cDNA	O
clones	O
,	O
including	O
one	O
full	O
-	O
length	O
one	O
(	O
Dd	B-GENE
kinase	I-GENE
-	I-GENE
2	I-GENE
)	O
.	O

A	O
.	O

Perilunar	O
luxation	O
-	O
-	O
an	O
unusual	O
injury	O
demanding	O
immediate	O
and	O
correct	O
treatment	O

Landsberg	O
(	O
La	O
-	O
O	O
)	O
and	O
cv	O
.	O

In	O
summary	O
,	O
at	O
equianesthetic	O
concentrations	O
,	O
desflurane	O
and	O
isoflurane	O
produced	O
similar	O
hemodynamic	O
effects	O
;	O
however	O
,	O
in	O
the	O
absence	O
of	O
drugs	O
that	O
inhibit	O
autonomic	O
reflexes	O
,	O
desflurane	O
had	O
less	O
negative	O
inotropic	O
activity	O
and	O
produced	O
less	O
decrease	O
in	O
arterial	O
pressure	O
.	O

We	O
report	O
here	O
the	O
isolation	O
of	O
a	O
full	O
-	O
length	O
cDNA	O
clone	O
coding	O
for	O
a	O
hitherto	O
undiscovered	O
isoform	O
of	O
the	O
bovine	B-GENE
C	I-GENE
-	I-GENE
subunit	I-GENE
.	O

Isoform	B-GENE
C	I-GENE
beta	I-GENE
2	I-GENE
,	O
an	O
unusual	O
form	O
of	O
the	O
bovine	O
catalytic	O
subunit	O
of	O
cAMP	B-GENE
-	I-GENE
dependent	I-GENE
protein	I-GENE
kinase	I-GENE
.	O

Salient	O
applications	O
of	O
PB	O
-	O
PK	O
modeling	O
to	O
toxicological	O
problems	O
are	O
illustrated	O
with	O
examples	O
.	O

Patients	O
with	O
apparently	O
minor	O
CT	O
abnormalities	O
may	O
have	O
significant	O
epidural	O
disease	O
.	O

The	O
cdr1	B-GENE
sequence	I-GENE
includes	O
an	O
additional	O
237	O
amino	O
acids	O
of	O
the	O
contiguous	O
fragment	O
and	O
encodes	O
a	O
product	O
of	O
predicted	O
Mr	O
67	O
,	O
000	O
.	O

Armed	O
with	O
a	O
clear	O
understanding	O
of	O
the	O
pathophysiologic	O
pathways	O
that	O
may	O
cause	O
and	O
/	O
or	O
contribute	O
to	O
the	O
development	O
of	O
unconjugated	O
hyperbilirubinemia	O
and	O
the	O
associated	O
jaundice	O
,	O
the	O
practitioner	O
will	O
be	O
successful	O
in	O
helping	O
the	O
family	O
understand	O
their	O
child	O
'	O
s	O
illness	O
.	O

Displacement	O
thresholds	O
of	O
peripheral	O
sites	O
in	O
monocular	O
human	O
vision	O
were	O
obtained	O
.	O

The	O
authors	O
report	O
a	O
case	O
in	O
which	O
stereotactic	O
irrigation	O
of	O
a	O
brain	O
cyst	O
was	O
temporally	O
associated	O
with	O
respiratory	O
distress	O
.	O

ELISA	O
was	O
found	O
to	O
make	O
a	O
contribution	O
to	O
the	O
diagnosis	O
of	O
tuberculosis	O
similar	O
to	O
that	O
of	O
sputum	O
smear	O
.	O

In	O
this	O
paper	O
,	O
we	O
report	O
a	O
detailed	O
study	O
of	O
the	O
structure	O
and	O
the	O
functional	O
role	O
of	O
the	O
MalT	B-GENE
binding	I-GENE
sites	I-GENE
located	O
in	O
the	O
adjacent	O
and	O
divergent	O
pulAp	B-GENE
and	O
pulCp	B-GENE
promoters	I-GENE
.	O

Despite	O
the	O
small	O
number	O
of	O
patients	O
,	O
on	O
the	O
basis	O
of	O
this	O
report	O
,	O
we	O
can	O
confirm	O
that	O
1	O
.	O
5	O
MU	O
/	O
day	O
of	O
alpha	B-GENE
-	I-GENE
IFN	I-GENE
is	O
an	O
adequate	O
treatment	O
for	O
patients	O
with	O
hairy	O
cell	O
leukemia	O
.	O

Paroxysmal	O
fluctuations	O
in	O
observed	O
parasitemia	O
in	O
Plasmodium	O
falciparum	O
malaria	O
.	O

No	O
positive	O
family	O
history	O
was	O
obtained	O
.	O

Occupational	O
asthma	O
and	O
rhinoconjunctivitis	O
from	O
inhalation	O
of	O
crystalline	O
bovine	B-GENE
serum	I-GENE
albumin	I-GENE
powder	O
.	O

A	O
further	O
subdivision	O
of	O
Category	O
pN1	O
into	O
pN1a	O
(	O
metastasis	O
in	O
single	O
node	O
)	O
and	O
pN1b	O
(	O
two	O
or	O
more	O
nodes	O
)	O
is	O
recommended	O
.	O

Amino	O
acid	O
sequence	O
comparisons	O
of	O
the	O
E74A	B-GENE
protein	I-GENE
reveal	O
a	O
highly	O
conserved	O
C	O
-	O
terminal	O
region	O
that	O
is	O
rich	O
in	O
basic	O
amino	O
acid	O
residues	O
and	O
which	O
has	O
been	O
proposed	O
to	O
possess	O
sequence	O
-	O
specific	O
DNA	O
binding	O
activity	O
.	O

We	O
found	O
that	O
the	O
relative	O
strengths	O
of	O
the	O
promoters	O
were	O
similar	O
in	O
different	O
contexts	O
.	O

Grasso	O
,	O
and	O
A	O
.	O

After	O
6	O
months	O
,	O
definite	O
improvement	O
in	O
strength	O
occurred	O
in	O
4	O
of	O
7	O
carnitine	O
-	O
treated	O
patients	O
and	O
in	O
none	O
of	O
7	O
controls	O
.	O

Age	O
at	O
POI	O
and	O
asymptote	O
were	O
achieved	O
later	O
for	O
Line	O
RBC2	O
than	O
for	O
Line	O
F	O
.	O

To	O
identify	O
the	O
DNA	O
sequences	O
that	O
cis	O
-	O
regulate	O
the	O
expression	O
of	O
the	O
rat	B-GENE
liver	I-GENE
pyruvate	I-GENE
kinase	I-GENE
(	O
L	B-GENE
-	I-GENE
PK	I-GENE
)	O
genes	O
,	O
a	O
series	O
of	O
constructs	O
in	O
which	O
the	O
chloramphenicol	B-GENE
acetyltransferase	I-GENE
reporter	I-GENE
genes	I-GENE
is	O
driven	O
by	O
various	O
deleted	O
fragments	O
of	O
the	O
3200	O
base	O
pairs	O
(	O
bp	O
)	O
upstream	O
of	O
the	O
L	B-GENE
-	I-GENE
PK	I-GENE
gene	I-GENE
cap	I-GENE
site	I-GENE
have	O
been	O
assayed	O
for	O
transient	O
expression	O
after	O
introduction	O
into	O
hepatoma	O
HepG2	O
cells	O
,	O
rat	O
hepatocytes	O
in	O
primary	O
culture	O
,	O
fibroblast	O
LTK	O
-	O
cells	O
,	O
myogenic	O
C2C12	O
cells	O
,	O
and	O
CHO	O
cells	O
.	O

The	O
disturbance	O
of	O
pulmonary	O
gas	O
exchange	O
,	O
as	O
revealed	O
by	O
the	O
high	O
value	O
of	O
AaDO2	O
,	O
existed	O
without	O
left	O
ventricular	O
dysfunction	O
,	O
and	O
AaDO2	O
had	O
no	O
significant	O
relationship	O
with	O
any	O
of	O
the	O
hemodynamic	O
parameters	O
including	O
the	O
difference	O
between	O
plasma	O
colloid	O
osmotic	O
pressure	O
and	O
PCW	O
.	O

A	O
dose	O
of	O
3	O
and	O
6	O
micrograms	O
/	O
kg	O
/	O
day	O
GM	B-GENE
-	I-GENE
CSF	I-GENE
reduces	O
the	O
severity	O
of	O
neutropenia	O
and	O
thrombocytopenia	O
after	O
carboplatin	O
-	O
cyclophosphamide	O
chemotherapy	O
,	O
which	O
may	O
lead	O
to	O
more	O
effective	O
chemotherapy	O
for	O
ovarian	O
cancer	O
in	O
the	O
future	O
.	O

These	O
differences	O
involve	O
specific	O
hydrogen	O
-	O
bonding	O
interactions	O
between	O
the	O
protein	O
and	O
DNA	O
,	O
including	O
guanine	O
N7	O
sites	O
in	O
the	O
major	O
groove	O
of	O
DNA	O
,	O
and	O
alterations	O
in	O
DNA	O
phosphodiester	O
conformation	O
induced	O
by	O
protein	O
binding	O
.	O

Biochemical	O
analysis	O
demonstrates	O
that	O
the	O
BJ1	B-GENE
protein	I-GENE
is	O
associated	O
with	O
nucleosomes	O
and	O
is	O
released	O
from	O
chromatin	O
by	O
agents	O
which	O
intercalate	O
into	O
DNA	O
,	O
as	O
previously	O
shown	O
for	O
the	O
high	B-GENE
mobility	I-GENE
group	I-GENE
proteins	I-GENE
(	O
HMGs	B-GENE
)	O
.	O

I	O
propose	O
that	O
their	O
gene	O
products	O
bind	O
to	O
the	O
chromatin	O
to	O
establish	O
or	O
maintain	O
a	O
proper	O
higher	O
order	O
structure	O
as	O
a	O
prerequisite	O
for	O
a	O
regulated	O
gene	O
expression	O
.	O

The	O
C4BP	B-GENE
alpha	I-GENE
gene	I-GENE
is	O
organized	O
as	O
follows	O
:	O
the	O
first	O
exon	O
codes	O
for	O
the	O
first	O
198	O
nucleotides	O
of	O
the	O
5	O
'	O
UTR	O
.	O

The	O
human	B-GENE
immunodeficiency	I-GENE
virus	I-GENE
type	I-GENE
1	I-GENE
(	I-GENE
HIV	I-GENE
-	I-GENE
1	I-GENE
)	I-GENE
Rev	I-GENE
protein	I-GENE
is	O
a	O
positive	O
posttranscriptional	O
regulator	O
of	O
viral	O
structural	O
gene	O
expression	O
and	O
essential	O
for	O
virus	O
replication	O
.	O

The	O
CDC7	B-GENE
gene	I-GENE
has	O
two	O
in	O
-	O
frame	O
AUG	O
codons	O
as	O
possible	O
translation	O
start	O
sites	O
,	O
which	O
would	O
produce	O
58	O
-	O
and	O
56	O
-	O
kDa	O
proteins	O
,	O
respectively	O
.	O

Differences	O
in	O
the	O
clinical	O
presentation	O
and	O
the	O
gross	O
appearance	O
of	O
the	O
two	O
cases	O
are	O
described	O
,	O
and	O
similarities	O
in	O
the	O
microscopic	O
features	O
are	O
discussed	O
.	O

MEASUREMENTS	O
AND	O
MAIN	O
RESULTS	O
:	O
The	O
two	O
groups	O
were	O
similar	O
on	O
entry	O
into	O
the	O
study	O
,	O
including	O
mean	O
FEV1	O
measurements	O
(	O
0	O
.	O
70	O
L	O
atropine	O
/	O
0	O
.	O
60	O
L	O
metaproterenol	O
,	O
P	O
greater	O
than	O
.	O
05	O
)	O
.	O

Using	O
an	O
ELISA	O
,	O
we	O
found	O
that	O
surfactant	B-GENE
protein	I-GENE
A	I-GENE
(	O
SP	B-GENE
-	I-GENE
A	I-GENE
)	O
was	O
markedly	O
elevated	O
in	O
the	O
pneumonia	O
patients	O
.	O

In	O
view	O
of	O
the	O
short	O
t1	O
/	O
2	O
,	O
we	O
used	O
three	O
doses	O
/	O
day	O
.	O

Temporal	O
control	O
of	O
GUS	B-GENE
expression	O
was	O
found	O
to	O
involve	O
two	O
negative	O
regulatory	O
sequences	O
,	O
NRS1	O
(	O
-	O
391	O
to	O
-	O
295	O
)	O
and	O
NRS2	O
(	O
-	O
518	O
to	O
-	O
418	O
)	O
,	O
as	O
well	O
as	O
the	O
positive	O
domain	O
UAS1	O
.	O

We	O
purified	O
a	O
Ca2	B-GENE
+	I-GENE
/	I-GENE
calmodulin	I-GENE
(	I-GENE
CaM	I-GENE
)	I-GENE
-	I-GENE
dependent	I-GENE
protein	I-GENE
kinase	I-GENE
(	O
CaM	B-GENE
kinase	I-GENE
)	O
from	O
the	O
yeast	O
Saccharomyces	O
cerevisiae	O
with	O
properties	O
similar	O
to	O
mammalian	B-GENE
type	I-GENE
II	I-GENE
CaM	I-GENE
kinases	I-GENE
.	O

In	O
most	O
cases	O
,	O
DR4	B-GENE
-	O
homozygous	O
,	O
DRB1	B-GENE
-	O
heterozygous	O
individuals	O
could	O
be	O
genotyped	O
with	O
the	O
panel	O
of	O
probes	O
.	O

The	O
prevalence	O
of	O
opportunistic	O
infection	O
among	O
surviving	O
AIDS	O
patients	O
and	O
the	O
probability	O
of	O
being	O
in	O
tumour	O
response	O
following	O
cancer	O
therapy	O
conditional	O
on	O
being	O
alive	O
are	O
two	O
examples	O
of	O
such	O
functions	O
.	O

Genomic	O
clones	O
encompassing	O
the	O
human	B-GENE
ETS1	I-GENE
gene	I-GENE
were	O
isolated	O
and	O
utilized	O
to	O
define	O
its	O
molecular	O
organization	O
.	O

Polymerase	O
chain	O
reaction	O
analysis	O
of	O
ETS1	B-GENE
cDNA	I-GENE
identified	O
several	O
amplified	O
products	O
,	O
indicating	O
alternative	O
splicing	O
.	O

Most	O
of	O
the	O
expressed	O
human	B-GENE
E3	I-GENE
polypeptides	I-GENE
(	O
five	O
bands	O
)	O
were	O
found	O
in	O
the	O
insoluble	O
pellet	O
while	O
primarily	O
full	B-GENE
-	I-GENE
length	I-GENE
mature	I-GENE
E3	I-GENE
was	O
found	O
in	O
the	O
soluble	O
fraction	O
.	O

To	O
test	O
promotor	O
function	O
,	O
chimeric	O
genes	O
were	O
constructed	O
linking	O
fragments	O
of	O
chicken	O
IGF	B-GENE
-	I-GENE
I	I-GENE
5	O
'	O
-	O
flanking	O
DNA	O
to	O
a	O
promoterless	O
reporter	O
plasmid	O
.	O

The	O
alpha	B-GENE
4	I-GENE
gene	I-GENE
5	O
'	O
flanking	O
region	O
acted	O
as	O
a	O
promoter	O
in	O
transfection	O
assays	O
.	O

Characterization	O
of	O
the	O
alpha	B-GENE
4	I-GENE
integrin	I-GENE
gene	I-GENE
promoter	I-GENE
.	O

Only	O
the	O
3	O
.	O
0	O
-	O
kb	O
transcript	O
was	O
detected	O
in	O
adult	O
tissues	O
,	O
where	O
its	O
expression	O
was	O
restricted	O
almost	O
exclusively	O
to	O
the	O
central	O
nervous	O
system	O
.	O

Two	O
homologues	O
of	O
the	O
rhombotin	B-GENE
gene	I-GENE
have	O
now	O
been	O
isolated	O
.	O

Angina	O
haemorrhagica	O
bullosa	O
causing	O
respiratory	O
obstruction	O
postoperatively	O
.	O

We	O
examined	O
the	O
effects	O
of	O
long	O
-	O
term	O
perfusion	O
with	O
pyridoxalated	O
hemoglobin	B-GENE
polyoxyethylene	O
conjugate	O
(	O
PHP	O
)	O
solution	O
on	O
cardiac	O
function	O
of	O
isolated	O
rat	O
hearts	O
.	O

The	O
gcd2	B-GENE
-	I-GENE
503	I-GENE
mutation	O
also	O
results	O
in	O
polysome	O
runoff	O
,	O
accumulation	O
of	O
inactive	O
80S	B-GENE
ribosomal	I-GENE
couples	I-GENE
,	O
and	O
accumulation	O
of	O
at	O
least	O
one	O
of	O
the	O
subunits	O
of	O
the	O
general	B-GENE
translation	I-GENE
initiation	I-GENE
factor	I-GENE
2	I-GENE
(	O
eIF	B-GENE
-	I-GENE
2	I-GENE
alpha	I-GENE
)	O
in	O
43S	B-GENE
-	O
48S	B-GENE
particles	O
following	O
a	O
shift	O
to	O
the	O
restrictive	O
temperature	O
.	O

Eight	O
patients	O
with	O
ARC	O
and	O
renal	O
failure	O
were	O
recently	O
evaluated	O
.	O

To	O
measure	O
the	O
enhancer	O
activity	O
of	O
DR60	B-GENE
,	O
a	O
reporter	O
plasmid	O
was	O
constructed	O
that	O
contained	O
DR60	B-GENE
cloned	O
upstream	O
of	O
the	O
reporter	O
chloramphenicol	B-GENE
acetyltransferase	I-GENE
gene	I-GENE
under	O
the	O
control	O
of	O
the	O
delayed	O
-	O
early	O
39K	O
promoter	O
.	O

A	O
single	O
case	O
of	O
an	O
adenocarcinoma	O
,	O
arising	O
in	O
a	O
retroperitoneal	O
enterogenous	O
cyst	O
and	O
which	O
presented	O
as	O
a	O
left	O
renal	O
cyst	O
,	O
is	O
reported	O
.	O

Using	O
the	O
polymerase	O
chain	O
reaction	O
,	O
we	O
analyzed	O
the	O
U6	B-GENE
RNA	I-GENE
genes	I-GENE
of	O
52	O
organisms	O
.	O

Both	O
tear	O
volume	O
and	O
tear	O
flow	O
were	O
found	O
to	O
be	O
significantly	O
(	O
P	O
less	O
than	O
0	O
.	O
001	O
)	O
decreased	O
up	O
to	O
6	O
h	O
after	O
instillation	O
,	O
reaching	O
a	O
minimum	O
90	O
min	O
after	O
application	O
(	O
tear	O
volume	O
:	O
-	O
63	O
%	O
;	O
tear	O
flow	O
:	O
-	O
71	O
%	O
)	O
.	O

Hydrophobicity	O
analysis	O
indicated	O
that	O
the	O
KlaA	B-GENE
and	O
KlaB	B-GENE
polypeptides	I-GENE
are	O
likely	O
to	O
be	O
soluble	O
,	O
whereas	O
the	O
KlaC	B-GENE
polypeptide	I-GENE
was	O
predicted	O
to	O
have	O
four	O
potential	O
membrane	O
-	O
spanning	O
domains	O
.	O

To	O
facilitate	O
the	O
availability	O
of	O
important	O
new	O
therapeutic	O
agents	O
,	O
the	O
Food	O
and	O
Drug	O
Administration	O
(	O
FDA	O
)	O
in	O
the	O
mid	O
-	O
1970s	O
began	O
assigning	O
therapeutic	O
ratings	O
to	O
investigational	O
new	O
drugs	O
and	O
holding	O
end	O
-	O
of	O
-	O
phase	O
II	O
conferences	O
with	O
drug	O
sponsors	O
.	O

In	O
contrast	O
,	O
similar	O
rates	O
of	O
B	O
.	O
sphaericus	O
products	O
,	O
ABG	O
-	O
6184	O
technical	O
powder	O
and	O
BSP	O
-	O
2	O
flowable	O
concentrate	O
,	O
produced	O
no	O
significant	O
reduction	O
.	O

Furthermore	O
,	O
the	O
DNA	B-GENE
polymerase	I-GENE
II	I-GENE
complex	I-GENE
was	O
difficult	O
to	O
obtain	O
from	O
dpb2	B-GENE
-	I-GENE
1	I-GENE
mutant	O
cells	O
,	O
suggesting	O
that	O
a	O
stable	O
DNA	B-GENE
polymerase	I-GENE
II	I-GENE
complex	I-GENE
requires	O
DPB2	B-GENE
and	O
is	O
essential	O
for	O
chromosomal	O
replication	O
.	O

To	O
determine	O
whether	O
mononuclear	O
cell	O
secretory	O
products	O
contribute	O
to	O
the	O
changes	O
in	O
bone	O
turnover	O
that	O
characterize	O
the	O
development	O
of	O
postmenopausal	O
osteoporosis	O
,	O
we	O
evaluated	O
the	O
effects	O
of	O
oophorectomy	O
and	O
subsequent	O
estrogen	O
replacement	O
on	O
the	O
spontaneous	O
secretion	O
of	O
interleukin	B-GENE
1	I-GENE
(	O
IL	B-GENE
-	I-GENE
1	I-GENE
)	O
and	O
tumor	B-GENE
necrosis	I-GENE
factor	I-GENE
alpha	I-GENE
(	O
TNF	B-GENE
-	I-GENE
alpha	I-GENE
)	O
and	O
on	O
the	O
phytohemagglutinin	B-GENE
A	I-GENE
-	O
induced	O
secretion	O
of	O
granulocyte	B-GENE
-	I-GENE
macrophage	I-GENE
colony	I-GENE
-	I-GENE
stimulating	I-GENE
factor	I-GENE
(	O
GM	B-GENE
-	I-GENE
CSF	I-GENE
)	O
from	O
peripheral	O
blood	O
mononuclear	O
cells	O
.	O

There	O
were	O
45	O
to	O
56	O
nt	O
differences	O
between	O
the	O
virulent	O
and	O
avirulent	O
groups	O
while	O
there	O
were	O
6	O
to	O
14	O
nt	O
differences	O
among	O
four	O
avirulent	O
strains	O
.	O

The	O
standard	O
principles	O
of	O
surgical	O
management	O
must	O
be	O
adhered	O
to	O
when	O
using	O
Sandostatin	O
to	O
treat	O
patients	O
with	O
these	O
disorders	O
.	O

Some	O
of	O
the	O
PCR	O
products	O
contained	O
mutations	O
in	O
ATG1	B-GENE
and	O
/	O
or	O
ATG2	B-GENE
.	O

These	O
data	O
suggest	O
that	O
the	O
levels	O
of	O
oxygen	O
free	O
radicals	O
were	O
increased	O
in	O
hepatocytes	O
and	O
mitochondria	O
.	O

The	O
sequence	O
of	O
the	O
pMxL1	O
plasmid	O
containing	O
the	O
invertible	O
region	O
contains	O
a	O
perfect	O
tandem	O
repeat	O
of	O
19	O
bp	O
in	O
the	O
orientation	O
1	O
nonexpressed	O
pilin	B-GENE
gene	I-GENE
at	O
the	O
middle	O
of	O
the	O
recombination	O
junction	O
site	O
.	O

No	O
evidence	O
for	O
the	O
presence	O
of	O
introns	O
within	O
the	O
acvA	B-GENE
gene	I-GENE
has	O
been	O
found	O
.	O

These	O
observations	O
,	O
together	O
with	O
the	O
occurrence	O
of	O
putative	O
4	O
'	O
-	O
phosphopantetheine	O
-	O
attachment	O
sites	O
and	O
a	O
putative	O
thioesterase	B-GENE
site	I-GENE
,	O
are	O
discussed	O
with	O
reference	O
to	O
the	O
reaction	O
sequence	O
leading	O
to	O
production	O
of	O
the	O
ACV	B-GENE
tripeptide	I-GENE
.	O

Pargyline	O
,	O
a	O
monoamine	B-GENE
oxidase	I-GENE
inhibitor	O
,	O
reduces	O
peak	O
3	O
transiently	O
(	O
max	O
.	O

When	O
given	O
the	O
choice	O
between	O
an	O
estrous	O
female	O
and	O
a	O
sexually	O
active	O
male	O
in	O
the	O
AOF	O
,	O
flutamide	O
females	O
,	O
as	O
well	O
as	O
controls	O
,	O
preferred	O
the	O
male	O
partner	O
.	O

Hypoxic	O
ventilatory	O
responses	O
were	O
-	O
1	O
.	O
99	O
+	O
/	O
-	O
0	O
.	O
37	O
L	O
/	O
min	O
/	O
%	O
SaO2	O
in	O
the	O
relatives	O
and	O
-	O
1	O
.	O
54	O
+	O
/	O
-	O
0	O
.	O
25	O
L	O
/	O
min	O
/	O
%	O
SaO2	O
in	O
the	O
control	O
subjects	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
250	O
WORDS	O
)	O

Very	O
small	O
deletions	O
within	O
the	O
conserved	O
region	O
completely	O
abolished	O
transforming	O
activity	O
of	O
dbl	B-GENE
,	O
while	O
extensive	O
deletion	O
outside	O
of	O
this	O
region	O
had	O
no	O
effect	O
.	O

This	O
computerized	O
list	O
was	O
linked	O
to	O
the	O
central	O
files	O
of	O
the	O
Massachusetts	O
Cancer	O
Registry	O
and	O
cases	O
diagnosed	O
between	O
1982	O
and	O
1988	O
were	O
identified	O
.	O

We	O
also	O
present	O
evidence	O
for	O
a	O
negative	O
regulatory	O
element	O
in	O
the	O
5	O
'	O
flanking	O
region	O
of	O
the	O
Mlu	B-GENE
I	I-GENE
upstream	I-GENE
activation	I-GENE
sequence	I-GENE
.	O

Mechanism	O
of	O
activation	O
of	O
the	O
vav	B-GENE
protooncogene	I-GENE
.	O
vav	B-GENE
is	O
a	O
human	O
locus	O
that	O
appears	O
to	O
be	O
specifically	O
expressed	O
in	O
cells	O
of	O
hematopoietic	O
origin	O
regardless	O
of	O
their	O
differentiation	O
lineage	O
.	O

Endothelial	O
cell	O
seeding	O
.	O

Menetrier	O
disease	O
in	O
a	O
child	O
.	O

After	O
hemodynamic	O
stabilization	O
,	O
the	O
goal	O
of	O
therapy	O
is	O
to	O
diminish	O
the	O
chance	O
that	O
an	O
ulcer	O
will	O
continue	O
to	O
bleed	O
or	O
will	O
rebleed	O
.	O

Thirty	O
seven	O
patients	O
(	O
amitriptyline	O
n	O
=	O
16	O
,	O
moclobemide	O
n	O
=	O
21	O
)	O
completed	O
the	O
six	O
week	O
protocol	O
,	O
which	O
was	O
conducted	O
under	O
double	O
blind	O
conditions	O
.	O

The	O
stimulus	O
threshold	O
for	O
EER	O
showed	O
a	O
less	O
individual	O
variation	O
than	O
amplitude	O
.	O

Analysis	O
of	O
electrically	O
evoked	O
response	O
(	O
EER	O
)	O
in	O
relation	O
to	O
the	O
central	O
visual	O
pathway	O
of	O
the	O
cat	O
(	O
1	O
)	O
.	O

Furthermore	O
,	O
plasma	O
fibrinogen	B-GENE
levels	O
increased	O
by	O
a	O
mean	O
of	O
17	O
.	O
6	O
%	O
,	O
a	O
potentially	O
adverse	O
effect	O
of	O
gemfibrozil	O
that	O
has	O
not	O
been	O
previously	O
reported	O
.	O

Gemfibrozil	O
in	O
hyperlipidaemic	O
patients	O
with	O
peripheral	O
arterial	O
disease	O
:	O
some	O
undiscovered	O
actions	O
.	O

An	O
RME1	B-GENE
-	O
independent	O
pathway	O
for	O
sporulation	O
control	O
in	O
Saccharomyces	O
cerevisiae	O
acts	O
through	O
IME1	B-GENE
transcript	I-GENE
accumulation	O
.	O

The	O
role	O
of	O
pharmacological	O
profiling	O
in	O
safety	O
assessment	O
.	O

Its	O
application	O
in	O
Madagascar	O
:	O
advantages	O
and	O
disadvantages	O

The	O
authors	O
evaluate	O
the	O
clinical	O
efficacy	O
of	O
EMB	O
AZS	O
in	O
recurrent	O
ulcer	O
after	O
operation	O
on	O
the	O
stomach	O
caused	O
by	O
a	O
high	O
level	O
of	O
acid	O
production	O
and	O
ulcerative	O
gastroduodenal	O
bleeding	O
.	O

To	O
investigate	O
the	O
regulation	O
of	O
Spec	B-GENE
gene	I-GENE
activity	O
,	O
the	O
region	O
around	O
the	O
Spec1	B-GENE
transcriptional	I-GENE
initiation	I-GENE
site	I-GENE
was	O
analyzed	O
for	O
sites	O
of	O
protein	O
-	O
DNA	O
interaction	O
.	O

Phosphopeptide	O
mapping	O
revealed	O
the	O
same	O
autophosphorylation	O
sites	O
utilized	O
by	O
EGFR	B-GENE
-	I-GENE
IC	I-GENE
as	O
those	O
identified	O
in	O
wild	B-GENE
-	I-GENE
type	I-GENE
EGFR	I-GENE
.	O

The	O
encoded	O
sequence	O
revealed	O
a	O
typical	O
signal	O
peptide	O
,	O
a	O
predominantly	O
hydrophilic	O
707	O
amino	O
acid	O
residue	O
domain	O
with	O
8	O
N	O
-	O
glycosylation	O
sites	O
,	O
a	O
transmembrane	O
domain	O
,	O
and	O
a	O
C	O
-	O
terminal	O
domain	O
of	O
52	O
amino	O
acids	O
.	O

The	O
TCF	B-GENE
-	I-GENE
1	I-GENE
alpha	I-GENE
binding	I-GENE
site	I-GENE
was	O
also	O
required	O
for	O
TCR	B-GENE
alpha	I-GENE
enhancer	I-GENE
activity	O
in	O
transcriptionally	O
active	O
extracts	O
from	O
Jurkat	O
but	O
not	O
HeLa	O
cells	O
,	O
confirming	O
that	O
TCF	B-GENE
-	I-GENE
1	I-GENE
alpha	I-GENE
is	O
a	O
T	B-GENE
-	I-GENE
cell	I-GENE
-	I-GENE
specific	I-GENE
transcription	I-GENE
factor	I-GENE
.	O

A	O
new	O
semi	O
-	O
automatic	O
method	O
for	O
quantifying	O
regional	O
cerebral	O
uptake	O
of	O
99m	O
technetium	O
-	O
hexamethylpropylene	O
amine	O
oxime	O
(	O
99mTc	O
-	O
HMPAO	O
)	O
was	O
used	O
to	O
assess	O
single	O
photon	O
emission	O
tomograms	O
from	O
5	O
normal	O
subjects	O
,	O
14	O
patients	O
with	O
Alzheimer	O
'	O
s	O
disease	O
,	O
14	O
patients	O
with	O
dementia	O
of	O
frontal	O
lobe	O
type	O
and	O
4	O
patients	O
with	O
dementia	O
with	O
motor	O
neurone	O
disease	O
.	O

The	O
results	O
showed	O
that	O
fog	O
,	O
up	O
to	O
a	O
level	O
of	O
base	O
plus	O
fog	O
of	O
0	O
.	O
6	O
optical	O
density	O
units	O
,	O
had	O
no	O
influence	O
on	O
the	O
diagnostic	O
accuracy	O
in	O
the	O
absence	O
of	O
any	O
compensation	O
.	O

IdB	O
1031	O
was	O
first	O
extracted	O
by	O
liquid	O
-	O
solid	O
partition	O
and	O
the	O
extracts	O
were	O
evaporated	O
and	O
analysed	O
on	O
a	O
reversed	O
-	O
phase	O
column	O
under	O
isocratic	O
conditions	O
,	O
using	O
either	O
an	O
electrochemical	O
or	O
a	O
UV	O
detector	O
.	O

In	O
this	O
model	O
,	O
eltoprazine	O
has	O
a	O
very	O
specific	O
anti	O
-	O
aggressive	O
(	O
serenic	O
)	O
profile	O
,	O
inhibiting	O
aggression	O
while	O
social	O
interaction	O
and	O
exploration	O
are	O
not	O
decreased	O
but	O
even	O
enhanced	O
;	O
inactivity	O
,	O
a	O
measure	O
for	O
sedation	O
,	O
is	O
not	O
affected	O
.	O

A	O
new	O
method	O
for	O
the	O
in	O
vitro	O
transfer	O
of	O
delayed	O
hypersensitivity	O
by	O
dialysed	O
transfer	B-GENE
factor	I-GENE
.	O

Effect	O
of	O
separate	O
and	O
combined	O
effects	O
of	O
plutonium	O
-	O
239	O
,	O
hexachlorobutadiene	O
and	O
tributyl	O
phosphate	O
on	O
the	O
thymus	O
gland	O
of	O
rats	O

Data	O
collection	O
was	O
made	O
with	O
a	O
query	O
language	O
,	O
and	O
data	O
analysis	O
performed	O
with	O
an	O
interactive	O
knowledge	O
-	O
based	O
statistical	O
tool	O
,	O
MAXITAB	O
,	O
employing	O
a	O
multivariate	O
tabular	O
analysis	O
technique	O
.	O

ARPIA	O
has	O
been	O
implemented	O
by	O
using	O
a	O
relational	O
DBMS	O
,	O
very	O
cheap	O
and	O
highly	O
diffused	O
on	O
personal	O
computers	O
.	O

Diuresis	O
was	O
induced	O
by	O
scheduled	O
drinking	O
of	O
tea	O
(	O
150	O
ml	O
/	O
h	O
)	O
.	O

Diagnostic	O
value	O
of	O
adenosine	B-GENE
deaminase	I-GENE
activity	O
in	O
tuberculous	O
effusions	O
.	O

Femoral	O
strain	O
adaptation	O
after	O
total	O
hip	O
replacement	O
:	O
a	O
comparison	O
of	O
cemented	O
and	O
porous	O
ingrowth	O
components	O
in	O
canines	O
.	O

Immuno	O
-	O
cytochemistry	O
,	O
using	O
antisera	O
against	O
Campylobacter	O
jejuni	O
,	O
showed	O
that	O
the	O
positive	O
staining	O
in	O
altered	O
epithelial	O
cells	O
were	O
restricted	O
to	O
intracellular	O
organisms	O
having	O
a	O
structure	O
resembling	O
Campylobacter	O
spp	O
.	O

Promoter	O
activities	O
were	O
estimated	O
using	O
beta	B-GENE
-	I-GENE
glucuronidase	I-GENE
and	O
neomycin	B-GENE
phosphotransferase	I-GENE
II	I-GENE
reporter	I-GENE
gene	I-GENE
systems	I-GENE
.	O

The	O
5	O
'	O
regions	O
of	O
these	O
two	O
soybean	B-GENE
actin	I-GENE
genes	I-GENE
contain	O
many	O
unusual	O
features	O
including	O
(	O
CT	O
)	O
repeats	O
and	O
long	O
stretches	O
of	O
pyrimidine	O
-	O
rich	O
DNA	O
.	O

All	O
8	O
(	O
100	O
%	O
)	O
patients	O
with	O
fulminant	O
hepatic	O
failure	O
who	O
received	O
grafts	O
survived	O
,	O
including	O
3	O
who	O
received	O
ABO	O
-	O
incompatible	O
grafts	O
,	O
though	O
2	O
of	O
these	O
subsequently	O
required	O
retransplantation	O
.	O

No	O
patient	O
had	O
a	O
history	O
of	O
excess	O
alcohol	O
intake	O
,	O
or	O
prolonged	O
intake	O
of	O
hepatotoxic	O
drugs	O
and	O
steroids	O
,	O
and	O
were	O
not	O
obese	O
or	O
malnourished	O
.	O

An	O
evolutionary	O
comparison	O
of	O
amino	O
acid	O
sequences	O
of	O
34	O
HSP70	B-GENE
proteins	I-GENE
from	O
17	O
species	O
suggests	O
that	O
BiP	B-GENE
genes	I-GENE
share	O
a	O
common	O
ancestor	O
,	O
which	O
diverged	O
from	O
other	O
HSP70	B-GENE
genes	I-GENE
near	O
the	O
time	O
when	O
eukaryotes	O
first	O
appeared	O
.	O

Spore	O
inocula	O
(	O
approximately	O
10	O
(	O
6	O
)	O
/	O
coupon	O
)	O
were	O
dried	O
onto	O
0	O
.	O
5	O
-	O
in	O
.	O

However	O
,	O
overexpression	O
of	O
both	O
the	O
STE4	B-GENE
and	O
STE18	B-GENE
proteins	I-GENE
did	O
not	O
generate	O
a	O
stronger	O
pheromone	O
response	O
than	O
overexpression	O
of	O
STE4	B-GENE
in	O
the	O
presence	O
of	O
wild	O
-	O
type	O
levels	O
of	O
STE18	B-GENE
.	O

Reverse	O
transcription	O
-	O
PCR	O
was	O
then	O
used	O
to	O
clone	O
from	O
human	O
poly	O
(	O
A	O
)	O
+	O
RNA	O
the	O
cDNA	O
corresponding	O
to	O
the	O
expressed	O
homolog	O
of	O
psi	B-GENE
ARF	I-GENE
4	I-GENE
,	O
referred	O
to	O
as	O
human	B-GENE
ARF	I-GENE
4	I-GENE
.	O

To	O
evaluate	O
the	O
cost	O
and	O
benefits	O
of	O
screening	O
tests	O
for	O
Chlamydia	O
trachomatis	O
in	O
adolescent	O
males	O
,	O
we	O
developed	O
a	O
decision	O
analysis	O
model	O
and	O
compared	O
the	O
leukocyte	B-GENE
esterase	I-GENE
urine	O
dipstick	O
test	O
with	O
culture	O
,	O
with	O
direct	O
-	O
smear	O
fluorescent	O
antibody	O
(	O
DFA	O
)	O
,	O
and	O
with	O
the	O
option	O
of	O
no	O
screening	O
(	O
no	O
treatment	O
)	O
.	O

Sequencing	O
the	O
gene	O
for	O
an	O
imipenem	O
-	O
cefoxitin	O
-	O
hydrolyzing	O
enzyme	O
(	O
CfiA	B-GENE
)	O
from	O
Bacteroides	O
fragilis	O
TAL2480	O
reveals	O
strong	O
similarity	O
between	O
CfiA	B-GENE
and	O
Bacillus	B-GENE
cereus	I-GENE
beta	I-GENE
-	I-GENE
lactamase	I-GENE
II	I-GENE
.	O

The	O
cloned	O
HindIII	B-GENE
fragment	I-GENE
,	O
which	O
was	O
shown	O
by	O
DNA	O
sequence	O
analysis	O
to	O
encode	O
the	O
N	O
-	O
terminal	O
half	O
of	O
the	O
B	B-GENE
.	I-GENE
subtilis	I-GENE
IF2	I-GENE
protein	I-GENE
and	O
0	O
.	O
2	O
kb	O
of	O
upstream	O
flanking	O
sequence	O
,	O
was	O
utilized	O
as	O
a	O
homologous	O
probe	O
to	O
clone	O
an	O
overlapping	O
2	B-GENE
.	I-GENE
76	I-GENE
-	I-GENE
kb	I-GENE
ClaI	I-GENE
chromosomal	I-GENE
fragment	I-GENE
containing	O
the	O
entire	B-GENE
IF2	I-GENE
structural	I-GENE
gene	I-GENE
.	O

Maternal	O
seizures	O
had	O
occurred	O
during	O
pregnancy	O
in	O
52	O
per	O
cent	O
.	O

It	O
encodes	O
a	O
protein	O
with	O
three	O
zinc	O
fingers	O
similar	O
to	O
those	O
of	O
the	O
transcription	B-GENE
factor	I-GENE
Sp1	I-GENE
.	O

Krox	B-GENE
-	I-GENE
24	I-GENE
is	O
therefore	O
a	O
sequence	O
-	O
specific	O
transcriptional	O
activator	O
.	O

The	O
interindividual	O
variability	O
of	O
the	O
parameters	O
is	O
taken	O
into	O
consideration	O
by	O
interactively	O
determining	O
the	O
threshold	O
levels	O
.	O

Inspired	O
CO2	O
causing	O
changes	O
from	O
hypo	O
-	O
to	O
normocapnia	O
has	O
previously	O
been	O
shown	O
to	O
improve	O
arterial	O
O2	O
tension	O
(	O
PaO2	O
)	O
and	O
to	O
reduce	O
alveolar	O
-	O
arterial	O
O2	O
difference	O
.	O

Expression	O
,	O
nucleotide	O
sequence	O
and	O
mutational	O
analysis	O
of	O
two	O
open	O
reading	O
frames	O
in	O
the	O
nif	B-GENE
gene	I-GENE
region	I-GENE
of	I-GENE
Anabaena	I-GENE
sp	I-GENE
.	I-GENE
strain	I-GENE
PCC7120	I-GENE
.	O

Our	O
results	O
suggest	O
that	O
a	O
sequence	O
match	O
between	O
enhancers	O
and	O
certain	O
promoter	O
elements	O
is	O
critical	O
.	O

This	O
Mr	O
is	O
similar	O
to	O
those	O
of	O
the	O
purified	B-GENE
smg	I-GENE
p25A	I-GENE
GDI	I-GENE
estimated	O
by	O
sodium	O
dodecyl	O
sulfate	O
-	O
polyacrylamide	O
gel	O
electrophoresis	O
and	O
sucrose	O
density	O
gradient	O
ultracentrifugation	O
,	O
which	O
are	O
about	O
54	O
,	O
000	O
and	O
65	O
,	O
000	O
,	O
respectively	O
.	O

Yeast	O
mutants	O
assigned	O
to	O
the	O
pet	B-GENE
complementation	O
group	O
G104	O
were	O
found	O
to	O
lack	O
alpha	B-GENE
-	I-GENE
ketoglutarate	I-GENE
dehydrogenase	I-GENE
activity	O
as	O
a	O
result	O
of	O
mutations	O
in	O
the	O
dihydrolipoyl	B-GENE
transsuccinylase	I-GENE
(	O
KE2	B-GENE
)	O
component	O
of	O
the	O
complex	O
.	O

Critical	O
residues	O
required	O
for	O
repression	O
are	O
located	O
within	O
the	O
C	O
-	O
terminal	O
27	O
amino	O
acids	O
of	O
c	B-GENE
-	I-GENE
Fos	I-GENE
,	O
since	O
v	B-GENE
-	I-GENE
Fos	I-GENE
and	O
C	O
-	O
terminal	O
truncations	O
of	O
c	B-GENE
-	I-GENE
Fos	I-GENE
did	O
not	O
down	O
regulate	O
.	O

We	O
also	O
discovered	O
a	O
V	B-GENE
lambda	I-GENE
pseudogene	I-GENE
,	O
called	O
psi	B-GENE
V	I-GENE
lambda	I-GENE
1	I-GENE
,	O
3	O
kb	O
upstream	O
of	O
the	O
U266	B-GENE
lambda	I-GENE
gene	I-GENE
.	O

In	O
this	O
paper	O
,	O
we	O
have	O
analyzed	O
the	O
structure	O
of	O
human	O
gene	O
for	O
Gx	B-GENE
alpha	I-GENE
,	O
which	O
spans	O
more	O
than	O
60	O
kilobases	O
.	O

A	O
long	O
follow	O
-	O
up	O
study	O
revealed	O
that	O
convalescent	O
stage	O
children	O
still	O
have	O
the	O
potency	O
to	O
have	O
an	O
immediate	O
type	O
hypersensitivity	O
reaction	O
on	O
exposure	O
to	O
mite	O
antigen	O
,	O
with	O
a	O
high	O
titer	O
of	O
mite	B-GENE
specific	I-GENE
IgE	I-GENE
in	O
their	O
sera	O
,	O
but	O
they	O
are	O
free	O
from	O
asthmatic	O
attacks	O
because	O
of	O
the	O
reduction	O
in	O
the	O
amount	O
of	O
mite	O
antigen	O
in	O
the	O
body	O
,	O
as	O
shown	O
by	O
the	O
reduction	O
in	O
the	O
amount	O
of	O
mite	B-GENE
specific	I-GENE
IgG	I-GENE
.	O

But	O
no	O
influence	O
was	O
observed	O
at	O
lower	O
concentrations	O
than	O
1	O
/	O
4	O
MIC	O
of	O
AMK	O
.	O

Furthermore	O
,	O
we	O
notice	O
two	O
potential	O
consensus	O
motifs	O
which	O
are	O
also	O
found	O
in	O
corresponding	O
positions	O
in	O
the	O
genes	O
for	O
the	O
nerve	B-GENE
growth	I-GENE
factor	I-GENE
receptor	I-GENE
and	O
the	O
68	B-GENE
-	I-GENE
kDa	I-GENE
neurofilament	I-GENE
protein	I-GENE
.	O

In	O
addition	O
,	O
the	O
-	O
119	O
to	O
-	O
81	O
fragment	O
of	O
the	O
CCK	B-GENE
promoter	I-GENE
contains	O
a	O
transcriptional	O
enhancer	O
that	O
potentiates	O
the	O
transcription	O
from	O
the	O
herpes	O
simplex	O
virus	O
thymidine	B-GENE
kinase	I-GENE
promoter	I-GENE
in	O
a	O
position	O
-	O
and	O
orientation	O
-	O
independent	O
manner	O
.	O

Thirty	O
minutes	O
of	O
supine	O
restraint	O
decreased	O
DOPAC	O
concentrations	O
in	O
the	O
median	O
eminence	O
of	O
female	O
rats	O
that	O
were	O
not	O
exposed	O
to	O
ether	O
,	O
and	O
brief	O
exposure	O
to	O
ether	O
enhanced	O
this	O
effect	O
.	O

Influence	O
of	O
metoprolol	O
treatment	O
on	O
sympatho	O
-	O
adrenal	O
activation	O
of	O
fibrinolysis	O
.	O

Five	O
of	O
10	O
scars	O
studied	O
decreased	O
at	O
least	O
50	O
%	O
in	O
linear	O
dimensions	O
.	O

Managing	O
dysphagia	O
in	O
a	O
chronic	O
care	O
setting	O
:	O
an	O
introduction	O
.	O

Gel	O
-	O
mobility	O
-	O
shift	O
assays	O
confirmed	O
that	O
the	O
Raji	O
nuclear	O
proteins	O
that	O
bound	O
to	O
W	O
and	O
V	O
elements	O
were	O
competed	O
with	O
by	O
an	O
HLA	B-GENE
-	I-GENE
DRA	I-GENE
X	I-GENE
-	I-GENE
box	I-GENE
oligonucleotide	I-GENE
.	O

The	O
NF1	B-GENE
locus	I-GENE
encodes	O
a	O
protein	O
functionally	O
related	O
to	O
mammalian	B-GENE
GAP	I-GENE
and	O
yeast	B-GENE
IRA	I-GENE
proteins	I-GENE
.	O

A	O
second	O
isotype	O
of	O
Raja	B-GENE
immunoglobulin	I-GENE
heavy	I-GENE
chain	I-GENE
genes	I-GENE
has	O
been	O
detected	O
by	O
screening	O
a	O
spleen	O
cDNA	O
library	O
with	O
homologous	O
Raja	B-GENE
VH	I-GENE
-	O
and	O
CH1	B-GENE
-	O
specific	O
probes	O
complementing	O
the	O
respective	O
regions	O
of	O
the	O
mu	B-GENE
-	I-GENE
like	I-GENE
isotype	I-GENE
.	O

Petko	O
,	O
and	O
S	O
.	O

Disruption	O
of	O
ARF2	B-GENE
causes	O
no	O
detectable	O
phenotype	O
.	O

Human	O
recombinant	O
DNA	O
-	O
derived	O
antihemophilic	B-GENE
factor	I-GENE
(	O
factor	B-GENE
VIII	I-GENE
)	O
in	O
the	O
treatment	O
of	O
hemophilia	O
A	O
.	O
recombinant	O
Factor	B-GENE
VIII	I-GENE
Study	O
Group	O
.	O

Like	O
other	O
members	O
of	O
this	O
family	O
,	O
the	O
AP	B-GENE
-	I-GENE
4	I-GENE
HLH	O
motif	O
and	O
the	O
adjacent	O
basic	O
domain	O
are	O
necessary	O
and	O
sufficient	O
to	O
confer	O
site	O
-	O
specific	O
DNA	O
binding	O
.	O

Furthermore	O
,	O
expression	O
of	O
the	O
promoter	O
in	O
embryonic	O
Drosophila	O
melanogaster	O
cells	O
that	O
lack	O
MyoD1	B-GENE
and	O
Sp1	B-GENE
is	O
strictly	O
dependent	O
on	O
all	O
three	O
sites	O
remaining	O
intact	O
and	O
on	O
the	O
presence	O
of	O
exogenously	O
supplied	O
Sp1	B-GENE
and	O
MyoD1	B-GENE
.	O

Effects	O
of	O
a	O
selective	O
monoamine	B-GENE
oxidase	I-GENE
(	I-GENE
MAO	I-GENE
)	I-GENE
-	I-GENE
-	I-GENE
A	I-GENE
inhibitor	O
,	O
clorgyline	O
,	O
a	O
selective	O
MAO	B-GENE
-	I-GENE
B	I-GENE
inhibitor	O
,	O
deprenyl	O
,	O
and	O
a	O
non	O
-	O
selective	O
MAO	B-GENE
inhibitor	O
,	O
nialamide	O
,	O
were	O
investigated	O
on	O
footshock	O
-	O
induced	O
aggression	O
(	O
FIA	O
)	O
in	O
paired	O
rats	O
.	O

To	O
identify	O
structural	O
features	O
of	O
residues	O
flanking	O
the	O
c	O
-	O
region	O
that	O
influence	O
the	O
fidelity	O
and	O
efficiency	O
of	O
signal	O
peptidase	O
cleavage	O
as	O
well	O
as	O
co	O
-	O
translational	O
translocation	O
,	O
we	O
introduced	O
six	O
amino	O
acid	O
substitutions	O
into	O
the	O
COOH	O
terminus	O
of	O
the	O
hydrophobic	O
core	O
and	O
seven	O
substitutions	O
at	O
the	O
NH2	O
terminus	O
of	O
the	O
mature	O
region	O
(	O
the	O
+	O
1	O
position	O
)	O
of	O
a	O
model	O
eukaryotic	B-GENE
preprotein	I-GENE
-	I-GENE
human	I-GENE
pre	I-GENE
(	I-GENE
delta	I-GENE
pro	I-GENE
)	I-GENE
apoA	I-GENE
-	I-GENE
II	I-GENE
.	O

Additionally	O
,	O
although	O
c	B-GENE
-	I-GENE
fos	I-GENE
and	O
egr	B-GENE
-	I-GENE
1	I-GENE
mRNAs	I-GENE
are	O
expressed	O
at	O
elevated	O
levels	O
in	O
stimulated	O
liver	O
cells	O
,	O
fos	B-GENE
-	I-GENE
B	I-GENE
,	O
fra	B-GENE
-	I-GENE
1	I-GENE
,	O
and	O
egr	B-GENE
-	I-GENE
2	I-GENE
are	O
not	O
,	O
which	O
suggests	O
that	O
factors	O
in	O
addition	O
to	O
the	O
serum	B-GENE
response	I-GENE
factor	I-GENE
participate	O
in	O
the	O
regulation	O
of	O
immediate	B-GENE
-	I-GENE
early	I-GENE
gene	I-GENE
induction	O
.	O

Of	O
848	O
patients	O
,	O
819	O
cases	O
with	O
complete	O
description	O
of	O
patient	O
'	O
s	O
background	O
were	O
evaluable	O
:	O
Group	O
A	O
(	O
surgery	O
+	O
MMC	O
+	O
5	O
-	O
FU	O
:	O
chemotherapy	O
)	O
253	O
cases	O
,	O
group	O
B	O
(	O
surgery	O
+	O
MMC	O
+	O
5	O
-	O
FU	O
+	O
OK	O
-	O
432	O
or	O
PSK	O
:	O
immunochemotherapy	O
)	O
282	O
and	O
group	O
C	O
(	O
surgery	O
alone	O
)	O
284	O
.	O

The	O
nuclear	O
proteins	O
encoded	O
by	O
the	O
c	B-GENE
-	I-GENE
fos	I-GENE
and	O
c	B-GENE
-	I-GENE
jun	I-GENE
protooncogenes	I-GENE
are	O
expressed	O
during	O
the	O
proliferation	O
period	O
of	O
osteoblast	O
phenotype	O
development	O
.	O

This	O
model	O
is	O
further	O
supported	O
by	O
binding	O
of	O
the	O
Fos	B-GENE
-	O
Jun	B-GENE
complex	O
at	O
an	O
AP	B-GENE
-	I-GENE
1	I-GENE
site	I-GENE
in	O
the	O
type	B-GENE
alpha	I-GENE
I	I-GENE
collagen	I-GENE
promoter	I-GENE
that	O
is	O
contiguous	O
with	O
,	O
but	O
not	O
overlapping	O
,	O
the	O
VDRE	O
.	O

PBSX	B-GENE
is	O
induced	O
by	O
agents	O
which	O
elicit	O
the	O
SOS	O
response	O
.	O

A	O
bacteriological	O
relapse	O
requiring	O
treatment	O
occurred	O
by	O
5	O
years	O
in	O
16	O
.	O
8	O
%	O
of	O
113	O
R3	O
,	O
5	O
.	O
2	O
%	O
of	O
97	O
R5	O
,	O
and	O
20	O
.	O
0	O
%	O
of	O
115	O
Z5	O
patients	O
with	O
organisms	O
sensitive	O
to	O
streptomycin	O
and	O
isoniazid	O
initially	O
.	O

In	O
the	O
controls	O
,	O
it	O
was	O
found	O
that	O
all	O
right	O
-	O
handed	O
and	O
10	O
out	O
of	O
14	O
left	O
-	O
handed	O
control	O
subjects	O
showed	O
a	O
right	O
VHF	O
(	O
i	O
.	O
e	O
.	O
,	O
left	O
hemisphere	O
)	O
advantage	O
.	O

Although	O
no	O
Rh	B-GENE
-	I-GENE
antibodies	I-GENE
were	O
demonstrable	O
,	O
a	O
similar	O
mechanism	O
can	O
be	O
postulated	O
for	O
the	O
Rh	O
-	O
system	O
.	O

This	O
study	O
was	O
performed	O
to	O
clarify	O
the	O
location	O
of	O
a	O
transesophageal	O
echocardiographic	O
(	O
TEE	O
)	O
transducer	O
when	O
obtaining	O
the	O
short	O
-	O
axis	O
view	O
of	O
the	O
left	O
ventricle	O
(	O
S	O
-	O
LV	O
)	O
.	O

From	O
S3	O
(	O
CBF	O
:	O
79	O
-	O
60	O
%	O
)	O
to	O
S5	O
(	O
CBF	O
:	O
39	O
-	O
0	O
%	O
)	O
,	O
%	O
WTh	O
,	O
1	O
/	O
TPC	O
and	O
1	O
/	O
T	O
were	O
significantly	O
decreased	O
from	O
those	O
of	O
the	O
control	O
levels	O
(	O
all	O
p	O
less	O
than	O
0	O
.	O
01	O
)	O
.	O

In	O
that	O
case	O
,	O
the	O
ratio	O
of	O
brush	O
abrasion	O
was	O
0	O
.	O
268	O
,	O
compressive	O
and	O
transverse	O
strength	O
,	O
124	O
.	O
3	O
and	O
86	O
.	O
3	O
MPa	O
respectively	O
,	O
hardness	O
,	O
43	O
.	O
2	O
Hk	O
,	O
water	O
absorption	O
14	O
.	O
2	O
micrograms	O
/	O
mm3	O
and	O
thermal	O
expansion	O
coefficient	O
,	O
47	O
.	O
4	O
x	O
10	O
(	O
-	O
6	O
)	O
/	O
degrees	O
C	O
.	O

9	O
,	O
1498	O
-	O
1506	O
)	O
.	O

In	O
a	O
highly	O
select	O
group	O
of	O
stable	O
hypertensive	O
patients	O
,	O
we	O
have	O
assessed	O
the	O
strength	O
of	O
association	O
between	O
various	O
blood	O
pressure	O
measurements	O
(	O
24	O
h	O
average	O
automated	O
ambulatory	O
blood	O
pressure	O
,	O
4	O
h	O
automated	O
ambulatory	O
morning	O
average	O
blood	O
pressure	O
,	O
multiple	O
office	O
visit	O
average	O
blood	O
pressure	O
,	O
and	O
a	O
single	O
office	O
visit	O
average	O
blood	O
pressure	O
)	O
and	O
various	O
echocardiographic	O
indices	O
of	O
hypertensive	O
cardiac	O
target	O
organ	O
damage	O
(	O
left	O
atrial	O
diameter	O
,	O
left	O
ventricular	O
end	O
diastolic	O
diameter	O
,	O
posterior	O
wall	O
thickness	O
,	O
combined	O
wall	O
thickness	O
,	O
relative	O
wall	O
thickness	O
,	O
left	O
ventricular	O
mass	O
and	O
mass	O
index	O
,	O
and	O
combined	O
wall	O
thickness	O
/	O
left	O
ventricular	O
diastolic	O
diameter	O
ratio	O
)	O
.	O

The	O
p36	B-GENE
gene	I-GENE
is	O
at	O
least	O
22	O
kb	O
in	O
length	O
and	O
has	O
a	O
coding	O
sequence	O
of	O
approximately	O
1	O
kb	O
,	O
representing	O
only	O
4	O
.	O
5	O
%	O
of	O
the	O
gene	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
250	O
WORDS	O
)	O

This	O
multimodality	O
treatment	O
for	O
locally	O
advanced	O
gynecologic	O
tumors	O
appears	O
feasible	O
with	O
modification	O
,	O
and	O
continued	O
work	O
exploring	O
this	O
approach	O
is	O
encouraged	O
.	O

With	O
the	O
modified	O
fingertip	O
-	O
to	O
-	O
floor	O
(	O
MFTF	O
)	O
method	O
,	O
patients	O
stand	O
on	O
a	O
stool	O
and	O
forward	O
bend	O
so	O
that	O
measurements	O
can	O
be	O
taken	O
on	O
patients	O
who	O
are	O
able	O
to	O
touch	O
the	O
floor	O
or	O
reach	O
beyond	O
the	O
level	O
of	O
the	O
floor	O
.	O

No	O
significant	O
differences	O
could	O
be	O
seen	O
in	O
response	O
rates	O
according	O
to	O
the	O
concentration	O
of	O
estrogen	B-GENE
receptors	I-GENE
or	O
presence	O
of	O
progesteron	B-GENE
receptors	I-GENE
in	O
this	O
group	O
of	O
patients	O
.	O

Teicoplanin	O
was	O
given	O
most	O
often	O
because	O
of	O
persistent	O
fever	O
or	O
initial	O
Gram	O
-	O
positive	O
bacteraemia	O
and	O
only	O
one	O
-	O
third	O
of	O
these	O
cases	O
responded	O
.	O

In	O
Experiments	O
1	O
and	O
2	O
,	O
infants	O
,	O
like	O
adults	O
,	O
initially	O
categorized	O
novel	O
objects	O
on	O
the	O
basis	O
of	O
physical	O
appearance	O
,	O
but	O
only	O
if	O
trained	O
with	O
multiple	O
exemplars	O
,	O
after	O
delays	O
of	O
1	O
and	O
7	O
days	O
.	O

The	O
clinical	O
picture	O
of	O
the	O
disease	O
was	O
significantly	O
different	O
from	O
anthropogenic	O
cutaneous	O
leishmaniasis	O
caused	O
by	O
L	O
.	O
tropica	O
but	O
similar	O
to	O
cutaneous	O
patterns	O
caused	O
by	O
L	O
.	O
infantum	O
which	O
was	O
a	O
prevalent	O
pattern	O
in	O
the	O
southern	O
France	O
.	O

In	O
comparison	O
with	O
the	O
16	O
introns	O
reported	O
in	O
AHA3	B-GENE
,	O
AHA2	B-GENE
is	O
missing	O
one	O
intron	O
in	O
the	O
5	O
'	O
-	O
untranslated	O
region	O
and	O
a	O
second	O
intron	O
in	O
the	O
C	O
-	O
terminal	O
coding	O
region	O
.	O

Northern	O
blot	O
analysis	O
indicates	O
that	O
AHA2	B-GENE
mRNA	I-GENE
relative	O
to	O
total	O
cellular	O
RNA	O
is	O
expressed	O
at	O
significantly	O
higher	O
levels	O
in	O
root	O
tissue	O
as	O
compared	O
with	O
shoot	O
tissue	O
.	O

Impaction	O
of	O
gastrostomy	O
tube	O
in	O
the	O
abdominal	O
wall	O
.	O

Both	O
antidepressants	O
elevated	O
the	O
pain	O
threshold	O
acutely	O
,	O
while	O
pretreatment	O
with	O
pCPA	O
largely	O
blocked	O
the	O
analgesia	O
.	O

Sci	O
.	O

A	O
needs	O
assessment	O
of	O
these	O
families	O
was	O
also	O
done	O
.	O

TCR	B-GENE
alpha	I-GENE
and	I-GENE
beta	I-GENE
gene	I-GENE
expression	O
may	O
be	O
regulated	O
by	O
a	O
common	O
set	O
of	O
T	B-GENE
-	I-GENE
cell	I-GENE
nuclear	I-GENE
proteins	I-GENE
in	O
that	O
the	O
T	B-GENE
beta	I-GENE
2	I-GENE
element	I-GENE
binding	O
a	O
set	O
of	O
cyclic	B-GENE
AMP	I-GENE
response	I-GENE
element	I-GENE
-	I-GENE
binding	I-GENE
proteins	I-GENE
that	O
are	O
also	O
bound	O
by	O
the	O
T	B-GENE
alpha	I-GENE
1	I-GENE
element	I-GENE
of	O
the	O
human	O
TCR	B-GENE
alpha	I-GENE
enhancer	O
and	O
the	O
decamer	O
element	O
present	O
in	O
a	O
large	O
number	O
of	O
human	O
and	O
murine	O
TCR	B-GENE
beta	I-GENE
promoters	O
.	O

The	O
3	O
'	O
stem	O
-	O
loop	O
is	O
highly	O
divergent	O
in	O
structure	O
among	O
species	O
and	O
lies	O
immediately	O
upstream	O
of	O
the	O
binding	O
site	O
for	O
Sm	B-GENE
proteins	I-GENE
.	O

The	O
deleted	O
nucleotide	O
sequence	O
corresponded	O
to	O
sequences	O
that	O
,	O
by	O
analogy	O
to	O
the	O
organization	O
of	O
the	O
type	B-GENE
I	I-GENE
collagen	I-GENE
genes	I-GENE
,	O
should	O
be	O
precisely	O
encoded	O
by	O
exon	O
41	O
of	O
the	O
COL3A1	B-GENE
gene	I-GENE
.	O

These	O
losses	O
account	O
for	O
the	O
resistance	O
of	O
EDS	O
-	O
IV	O
collagen	B-GENE
to	O
cyanogen	O
bromide	O
and	O
mammalian	B-GENE
collagenase	I-GENE
digestion	O
.	O

Two	O
other	O
peptides	O
,	O
either	O
partially	O
or	O
totally	O
lacking	O
the	O
basic	O
region	O
,	O
but	O
containing	O
the	O
intact	O
leucine	O
zipper	O
domain	O
,	O
readily	O
form	O
dimers	O
but	O
do	O
not	O
bind	O
to	O
the	O
CRE	O
.	O

In	O
contrast	O
,	O
the	O
CRE	O
of	O
the	O
human	B-GENE
c	I-GENE
-	I-GENE
fos	I-GENE
promoter	I-GENE
located	O
at	O
-	O
60	O
was	O
weakly	O
induced	O
by	O
cAMP	O
and	O
E1a	B-GENE
in	O
both	O
HeLa	O
and	O
PC12	O
cells	O
.	O

We	O
have	O
isolated	O
and	O
sequenced	O
the	O
gene	O
encoding	O
the	O
human	B-GENE
U1	I-GENE
-	I-GENE
70K	I-GENE
snRNP	I-GENE
protein	I-GENE
.	O

Although	O
popular	O
this	O
hypothesis	O
is	O
far	O
from	O
explaining	O
all	O
the	O
clinical	O
facts	O
,	O
namely	O
that	O
rigidity	O
is	O
equal	O
in	O
extensor	O
and	O
flexor	O
,	O
proximal	O
and	O
distal	O
muscles	O
.	O

Fluid	O
(	O
AVLF	O
)	O
31	O
.	O

The	O
results	O
supported	O
the	O
therapeutic	O
principle	O
of	O
TCM	O
:	O
Treating	O
patients	O
according	O
to	O
their	O
pathophysiological	O
patterns	O
.	O

The	O
nmr	B-GENE
gene	I-GENE
is	O
the	O
major	O
negative	O
regulatory	O
gene	O
in	O
the	O
nitrogen	O
control	O
circuit	O
of	O
Neurospora	O
crassa	O
,	O
which	O
,	O
together	O
with	O
positive	O
regulatory	O
genes	O
,	O
governs	O
the	O
expression	O
of	O
multiple	O
unlinked	O
structural	O
genes	O
of	O
the	O
circuit	O
.	O

The	O
4	O
days	O
dexamethasone	O
suppression	O
test	O
showed	O
more	O
than	O
80	O
%	O
suppression	O
of	O
dehydroepiandrosterone	O
-	O
sulphate	O
and	O
a	O
variable	O
(	O
40	O
-	O
60	O
%	O
)	O
reduction	O
of	O
testosterone	O
and	O
androstenedione	O
levels	O
.	O

The	O
ratio	O
of	O
P	O
-	O
31	O
NMR	O
-	O
S	O
derived	O
inorganic	O
phosphates	O
[	O
Pi	O
]	O
to	O
phosphocreatine	O
[	O
PCr	O
]	O
was	O
significantly	O
greater	O
at	O
rest	O
in	O
LVH	O
baboons	O
[	O
0	O
.	O
53	O
+	O
/	O
-	O
0	O
.	O
06	O
versus	O
controls	O
=	O
0	O
.	O
41	O
+	O
/	O
-	O
0	O
.	O
17	O
;	O
P	O
less	O
than	O
0	O
.	O
05	O
]	O
.	O

Cutaneous	O
necrosis	O
associated	O
with	O
protein	B-GENE
S	I-GENE
deficiency	O
.	O

Critical	O
study	O

Regional	O
cerebral	O
blood	O
flow	O
was	O
measured	O
using	O
N	O
-	O
isopropyl	O
-	O
123I	O
-	O
iodoamphetamine	O
with	O
single	O
-	O
photon	O
emission	O
computed	O
tomography	O
(	O
CT	O
)	O
in	O
16	O
aged	O
patients	O
with	O
noninsulin	O
-	O
dependent	O
diabetes	O
mellitus	O
(	O
NIDDM	O
,	O
average	O
age	O
72	O
.	O
8	O
years	O
,	O
average	O
fasting	O
plasma	O
glucose	O
7	O
.	O
7	O
mmol	O
/	O
L	O
)	O
,	O
and	O
12	O
nondiabetic	O
subjects	O
(	O
71	O
.	O
6	O
years	O
,	O
5	O
.	O
3	O
mmol	O
/	O
L	O
)	O
.	O

Mean	O
ROI	O
-	O
A	O
/	O
B	O
ratio	O
was	O
49	O
.	O
6	O
+	O
/	O
-	O
1	O
.	O
7	O
%	O
in	O
the	O
diabetic	O
group	O
,	O
significantly	O
lower	O
than	O
the	O
57	O
.	O
9	O
+	O
/	O
-	O
1	O
.	O
6	O
%	O
at	O
the	O
nondiabetic	O
group	O
(	O
p	O
less	O
than	O
0	O
.	O
005	O
)	O
.	O

These	O
data	O
strongly	O
implicate	O
the	O
normal	O
product	O
of	O
the	O
int	B-GENE
-	I-GENE
2	I-GENE
gene	I-GENE
,	O
which	O
is	O
related	O
to	O
the	O
fibroblast	B-GENE
growth	I-GENE
factor	I-GENE
family	I-GENE
,	O
as	O
a	O
contributory	O
factor	O
in	O
virally	O
induced	O
mammary	O
tumors	O
.	O

The	O
PC2	B-GENE
protein	I-GENE
also	O
shows	O
great	O
similarity	O
to	O
the	O
incomplete	O
NH2	O
-	O
terminal	O
sequence	O
of	O
the	O
human	B-GENE
furin	I-GENE
gene	I-GENE
product	I-GENE
,	O
a	O
putative	O
membrane	O
-	O
inserted	O
receptor	O
-	O
like	O
molecule	O
.	O

Whether	O
or	O
not	O
there	O
are	O
sequences	O
conferring	O
cAMP	O
responsiveness	O
which	O
are	O
common	O
both	O
to	O
P	B-GENE
-	I-GENE
450scc	I-GENE
and	O
the	O
other	O
steroidogenic	O
P	B-GENE
-	I-GENE
450	I-GENE
genes	I-GENE
remains	O
to	O
be	O
established	O
.	O

In	O
this	O
study	O
,	O
we	O
used	O
footprinting	O
and	O
gel	O
mobility	O
retardation	O
assays	O
to	O
reveal	O
that	O
bacterially	O
synthesized	O
Zta	B-GENE
fusion	I-GENE
proteins	I-GENE
bound	O
directly	O
to	O
six	O
TGTGCAA	O
-	O
like	O
motifs	O
within	O
DSL	B-GENE
.	O

The	O
zta	B-GENE
transactivator	I-GENE
involved	O
in	O
induction	O
of	O
lytic	O
cycle	O
gene	O
expression	O
in	O
Epstein	O
-	O
Barr	O
virus	O
-	O
infected	O
lymphocytes	O
binds	O
to	O
both	O
AP	B-GENE
-	I-GENE
1	I-GENE
and	O
ZRE	B-GENE
sites	I-GENE
in	O
target	O
promoter	O
and	O
enhancer	O
regions	O
.	O

It	O
is	O
the	O
human	O
homolog	O
of	O
the	O
mouse	B-GENE
Mx	I-GENE
protein	I-GENE
involved	O
in	O
resistance	O
to	O
influenza	O
virus	O
.	O

Fragments	O
containing	O
the	O
21	O
-	O
base	O
-	O
pair	O
repeat	O
region	O
,	O
the	O
enhancer	B-GENE
of	I-GENE
simian	I-GENE
virus	I-GENE
40	I-GENE
or	O
both	O
strongly	O
stimulated	O
beta	B-GENE
-	I-GENE
galactosidase	I-GENE
synthesis	O
,	O
and	O
three	O
fragments	O
from	O
the	O
polyomavirus	B-GENE
enhancer	I-GENE
region	I-GENE
stimulated	O
moderate	O
levels	O
.	O

The	O
sites	O
targeted	O
for	O
mutagenesis	O
,	O
residues	O
60	O
,	O
61	O
,	O
and	O
66	O
,	O
are	O
located	O
within	O
a	O
putative	O
helical	O
loop	O
structure	O
which	O
may	O
be	O
involved	O
in	O
substrate	O
recognition	O
by	O
the	O
enzyme	O
.	O

The	O
possible	O
benefits	O
of	O
LMW	O
heparin	O
(	O
reduced	O
frequency	O
of	O
bleeding	O
,	O
alleviation	O
of	O
hypertriglyceridemia	O
)	O
were	O
not	O
,	O
however	O
,	O
apparent	O
,	O
possibly	O
because	O
of	O
the	O
short	O
observation	O
period	O
and	O
the	O
low	O
incidence	O
of	O
hemorrhagic	O
complications	O
in	O
routine	O
dialyses	O
.	O

The	O
deduced	O
amino	O
acid	O
sequence	O
of	O
destrin	B-GENE
is	O
165	O
residues	O
long	O
and	O
is	O
very	O
similar	O
(	O
71	O
%	O
identical	O
)	O
to	O
that	O
of	O
cofilin	B-GENE
,	O
a	O
widely	O
distributed	O
,	O
pH	O
-	O
sensitive	O
actin	B-GENE
-	O
modulating	O
protein	O
.	O

Summers	O
,	O
Virology	O
89	O
:	O
517	O
-	O
527	O
,	O
1978	O
)	O
.	O

With	O
only	O
purified	O
T	B-GENE
antigen	I-GENE
in	O
the	O
presence	O
of	O
topoisomerase	B-GENE
I	I-GENE
to	O
unwind	O
purified	O
DNA	O
,	O
ori	O
-	O
auxiliary	O
sequences	O
strongly	O
facilitated	O
T	B-GENE
-	I-GENE
antigen	I-GENE
-	O
dependent	O
DNA	O
conformational	O
changes	O
consistent	O
with	O
melting	O
the	O
first	O
50	O
base	O
pairs	O
.	O

A	O
rabbit	O
antiserum	O
was	O
raised	O
against	O
a	O
synthetic	O
peptide	O
corresponding	O
to	O
a	O
hydrophilic	O
portion	O
of	O
the	O
translated	O
murine	O
cDNA	O
sequence	O
.	O

Conservation	O
of	O
function	O
of	O
Drosophila	B-GENE
melanogaster	I-GENE
abl	I-GENE
and	O
murine	B-GENE
v	I-GENE
-	I-GENE
abl	I-GENE
proteins	I-GENE
in	O
transformation	O
of	O
mammalian	O
cells	O
.	O

Specific	O
binding	O
of	O
the	O
protein	O
factors	O
to	O
the	O
sites	O
,	O
possibly	O
to	O
the	O
three	O
Mt	O
sequences	O
,	O
may	O
play	O
an	O
important	O
role	O
in	O
the	O
coordinate	O
regulation	O
of	O
the	O
transcription	O
of	O
nuclear	O
genes	O
encoding	O
subunits	O
responsible	O
for	O
mitochondrial	O
oxidative	O
phosphorylation	O
.	O

This	O
points	O
to	O
a	O
specific	O
interference	O
with	O
HSV	O
-	O
induced	O
DNA	O
amplification	O
.	O

Constructs	O
were	O
made	O
in	O
which	O
an	O
AATAAA	O
and	O
the	O
GT	O
-	O
rich	O
region	O
were	O
separated	O
by	O
various	O
distances	O
ranging	O
from	O
7	O
to	O
43	O
bp	O
.	O

To	O
address	O
this	O
issue	O
,	O
the	O
gene	O
for	O
factor	B-GENE
Y	I-GENE
has	O
been	O
cloned	O
molecularly	O
and	O
its	O
DNA	O
sequence	O
has	O
been	O
determined	O
.	O

We	O
cloned	O
and	O
sequenced	O
the	O
cDNAs	O
against	O
genomic	O
RNA	O
and	O
mRNA	O
for	O
phosphoprotein	B-GENE
(	I-GENE
P	I-GENE
)	I-GENE
of	O
human	O
parainfluenza	O
type	O
2	O
virus	O
(	O
PIV	O
-	O
2	O
)	O
.	O
cDNA	O
clone	O
from	O
genomic	O
RNA	O
was	O
1439	O
nucleotides	O
in	O
length	O
excluding	O
poly	O
(	O
A	O
)	O
and	O
was	O
found	O
to	O
have	O
two	O
small	O
open	O
reading	O
frames	O
encoding	O
proteins	O
of	O
233	O
and	O
249	O
amino	O
acids	O
.	O

We	O
show	O
that	O
cytR	B-GENE
expression	O
is	O
negatively	O
controlled	O
by	O
the	O
CytR	B-GENE
protein	I-GENE
and	O
positively	O
affected	O
by	O
the	O
cAMP	B-GENE
/	I-GENE
CAP	I-GENE
complex	I-GENE
.	O

The	O
cDNA	O
sequence	O
has	O
an	O
813	O
-	O
bp	O
open	O
reading	O
frame	O
(	O
ORF	O
)	O
whose	O
predicted	O
amino	O
acid	O
sequence	O
is	O
97	O
.	O
6	O
%	O
identical	O
to	O
the	O
272	O
carboxy	O
-	O
terminal	O
amino	O
acids	O
of	O
the	O
human	B-GENE
ets	I-GENE
-	I-GENE
1	I-GENE
protein	I-GENE
.	O

To	O
characterize	O
the	O
O7	B-GENE
-	I-GENE
LPS	I-GENE
region	I-GENE
,	O
the	O
recombinant	O
cosmids	O
pJHCV31	O
and	O
pJHCV32	O
were	O
mutagenized	O
by	O
transposon	O
mutagenesis	O
with	O
Tn3HoHo1	B-GENE
,	O
which	O
carries	O
a	O
promoterless	O
lac	B-GENE
operon	I-GENE
and	O
can	O
therefore	O
generate	O
lacZ	B-GENE
transcriptional	O
fusions	O
with	O
target	O
DNA	O
sequences	O
.	O

The	O
sacT	B-GENE
gene	I-GENE
regulating	O
the	O
sacPA	B-GENE
operon	I-GENE
in	I-GENE
Bacillus	I-GENE
subtilis	I-GENE
shares	O
strong	O
homology	O
with	O
transcriptional	O
antiterminators	O
.	O

Various	O
mutant	B-GENE
HN	I-GENE
genes	I-GENE
were	O
constructed	O
to	O
examine	O
the	O
role	O
of	O
residues	O
flanking	O
the	O
signal	O
-	O
anchor	O
domain	O
,	O
including	O
the	O
cytoplasmic	O
tail	O
,	O
on	O
assembly	O
and	O
intracellular	O
transport	O
of	O
the	O
HN	B-GENE
glycoprotein	I-GENE
.	O

Our	O
studies	O
extend	O
these	O
findings	O
and	O
show	O
that	O
the	O
E2	B-GENE
transactivation	I-GENE
gene	I-GENE
is	O
expressed	O
from	O
multiple	O
promoters	O
.	O

Furthermore	O
,	O
analysis	O
of	O
the	O
E2	B-GENE
proteins	I-GENE
present	O
in	O
various	O
cell	O
lines	O
harboring	O
specific	O
BPV	O
-	O
1	O
mutants	O
,	O
including	O
the	O
2558	O
acceptor	O
mutant	O
,	O
proves	O
that	O
alternate	O
modes	O
of	O
E2	B-GENE
expression	O
exist	O
.	O

Disruption	O
of	O
the	O
IRA2	B-GENE
gene	I-GENE
resulted	O
in	O
(	O
i	O
)	O
increased	O
sensitivity	O
to	O
heat	O
shock	O
and	O
nitrogen	O
starvation	O
,	O
(	O
ii	O
)	O
sporulation	O
defects	O
,	O
and	O
(	O
iii	O
)	O
suppression	O
of	O
the	O
lethality	O
of	O
the	O
cdc25	B-GENE
mutant	I-GENE
.	O

This	O
cohort	O
of	O
patients	O
was	O
selected	O
on	O
the	O
basis	O
of	O
clinical	O
stage	O
.	O

The	O
diagnosis	O
of	O
miliary	O
tuberculosis	O
should	O
be	O
systematically	O
considered	O
in	O
ARDS	O
of	O
unknown	O
origin	O
.	O

In	O
order	O
to	O
characterize	O
the	O
functional	O
elements	O
of	O
the	O
promoter	O
that	O
in	O
some	O
way	O
must	O
respond	O
to	O
these	O
regulatory	O
signals	O
,	O
a	O
number	O
of	O
promoter	O
mutations	O
were	O
constructed	O
,	O
including	O
a	O
set	O
of	O
linker	O
-	O
scanning	O
mutations	O
across	O
the	O
entire	O
promoter	O
region	O
.	O

A	O
DNA	O
motif	O
related	O
to	O
the	O
cAMP	O
-	O
responsive	O
element	O
and	O
an	O
exon	B-GENE
-	I-GENE
located	I-GENE
activator	I-GENE
protein	I-GENE
-	I-GENE
2	I-GENE
binding	I-GENE
site	I-GENE
in	O
the	O
human	B-GENE
tissue	I-GENE
-	I-GENE
type	I-GENE
plasminogen	I-GENE
activator	I-GENE
gene	I-GENE
promoter	I-GENE
cooperate	O
in	O
basal	O
expression	O
and	O
convey	O
activation	O
by	O
phorbol	O
ester	O
and	O
cAMP	O
.	O

The	O
26S	B-GENE
rRNA	I-GENE
binding	I-GENE
ribosomal	I-GENE
protein	I-GENE
equivalent	O
to	O
bacterial	B-GENE
protein	I-GENE
L11	I-GENE
is	O
encoded	O
by	O
unspliced	O
duplicated	O
genes	O
in	O
Saccharomyces	O
cerevisiae	O
.	O

Five	O
healthy	O
male	O
subjects	O
inspired	O
air	O
for	O
20	O
min	O
and	O
then	O
5	O
%	O
CO2	O
/	O
95	O
%	O
O2	O
for	O
30	O
min	O
,	O
of	O
which	O
the	O
first	O
10	O
min	O
was	O
used	O
to	O
achieve	O
a	O
steady	O
-	O
state	O
end	O
-	O
tidal	O
CO2	O
measurement	O
.	O

The	O
transcripts	O
were	O
equally	O
active	O
with	O
or	O
without	O
a	O
5	O
'	O
methylated	O
capstructure	O
as	O
expected	O
,	O
since	O
EMCV	O
-	O
RNA	O
is	O
one	O
of	O
the	O
mRNAs	O
capable	O
of	O
internal	O
initiation	O
.	O

The	O
E6	B-GENE
/	O
E7	B-GENE
promoter	O
of	O
all	O
genital	O
human	O
papillomaviruses	O
is	O
responsible	O
for	O
expression	O
of	O
the	O
viral	O
transforming	O
genes	O
.	O

A	O
case	O
of	O
Goodpasture	O
'	O
s	O
syndrome	O
.	O

Seventy	O
-	O
two	O
of	O
73	O
negative	O
controls	O
and	O
all	O
positive	O
blocks	O
as	O
seen	O
on	O
soft	O
tissue	O
radiographs	O
(	O
STRs	O
)	O
were	O
correctly	O
coded	O
(	O
specificity	O
98	O
.	O
6	O
%	O
,	O
sensitivity	O
100	O
%	O
)	O
.	O

No	O
symptomatic	O
abnormality	O
has	O
been	O
noted	O
in	O
the	O
neonatal	O
period	O
except	O
periventricular	O
calcifications	O
.	O

Immunohistochemical	O
analysis	O
of	O
several	O
rat	O
organs	O
also	O
showed	O
staining	O
in	O
epithelial	O
cells	O
.	O

Transcription	O
of	O
the	O
first	O
operon	O
coding	O
for	O
m	O
-	O
xylene	O
-	O
degrading	O
enzymes	O
on	O
the	O
TOL	O
plasmid	O
of	O
Pseudomonas	O
putida	O
is	O
activated	O
by	O
the	O
xylR	B-GENE
gene	I-GENE
product	I-GENE
in	O
the	O
presence	O
of	O
m	O
-	O
xylene	O
.	O

Some	O
of	O
the	O
mutations	O
obtained	O
do	O
not	O
contain	O
a	O
copy	O
of	O
the	O
Ulysses	B-GENE
element	I-GENE
at	O
the	O
mutant	O
locus	O
,	O
suggesting	O
that	O
a	O
different	O
transposable	O
element	O
may	O
be	O
responsible	O
for	O
the	O
mutation	O
.	O

Determination	O
of	O
diquat	O
in	O
biological	O
materials	O
by	O
electron	O
spin	O
resonance	O
spectroscopy	O
.	O

We	O
show	O
also	O
that	O
RA	O
represses	O
the	O
transcriptional	O
activity	O
of	O
a	O
reporter	O
gene	O
containing	O
a	O
TPA	O
responding	O
AP1	B-GENE
binding	I-GENE
site	I-GENE
driving	O
the	O
HSV	B-GENE
tk	I-GENE
promoter	I-GENE
.	O

Moreover	O
,	O
radiolabeled	O
EFI	B-GENE
,	O
NF	B-GENE
-	I-GENE
Y	I-GENE
,	O
or	O
CBF	B-GENE
DNAs	I-GENE
give	O
rise	O
to	O
identical	O
gel	O
retardation	O
patterns	O
in	O
extracts	O
from	O
a	O
variety	O
of	O
different	O
cell	O
types	O
.	O

Risk	O
factors	O
influencing	O
lymph	O
nodes	O
metastasis	O
in	O
lung	O
cancer	O
with	O
stage	O
I	O
,	O
II	O
or	O
IIIA	O

Multifunctional	B-GENE
protein	I-GENE
kinase	I-GENE
(	O
MFPK	B-GENE
)	O
phosphorylates	O
ATP	B-GENE
-	I-GENE
citrate	I-GENE
lyase	I-GENE
on	O
peptide	B-GENE
B	I-GENE
on	O
two	O
sites	O
,	O
BT	O
and	O
BS	O
,	O
on	O
threonine	O
and	O
serine	O
,	O
respectively	O
,	O
inhibitor	B-GENE
2	I-GENE
on	O
a	O
threonyl	O
residue	O
,	O
and	O
glycogen	B-GENE
synthase	I-GENE
at	O
sites	O
2	O
and	O
3	O
.	O

The	O
electrically	O
induced	O
motile	O
responses	O
were	O
not	O
suppressed	O
in	O
the	O
presence	O
of	O
dinitrophenol	O
or	O
cytochalasin	O
B	O
.	O

Unlike	O
p59v	B-GENE
-	O
rel	B-GENE
,	O
which	O
is	O
a	O
nuclear	O
protein	O
in	O
CEF	O
,	O
indirect	O
immunofluorescence	O
showed	O
that	O
p68c	B-GENE
-	O
rel	B-GENE
in	O
JD214c	O
-	O
rel	O
infected	O
CEF	O
is	O
located	O
exclusively	O
in	O
the	O
cytoplasm	O
of	O
these	O
cells	O
,	O
even	O
though	O
the	O
sequence	O
of	O
p68c	B-GENE
-	O
rel	B-GENE
showed	O
that	O
it	O
contains	O
a	O
nuclear	O
localizing	O
sequence	O
identical	O
to	O
the	O
one	O
previously	O
identified	O
in	O
p59v	B-GENE
-	O
rel	B-GENE
.	O

Kinetic	O
experiments	O
revealed	O
that	O
within	O
10	O
min	O
this	O
radiolabeled	O
precursor	O
protein	O
was	O
converted	O
in	O
HL	O
-	O
60	O
cells	O
into	O
an	O
Mr	O
approximately	O
150	O
,	O
000	O
chondroitin	O
sulfate	O
proteoglycan	O
intermediate	O
.	O

Blood	O
flow	O
and	O
velocity	O
(	O
measured	O
using	O
Doppler	O
ultrasound	O
)	O
gradually	O
decreased	O
during	O
diastole	O
and	O
ultimately	O
reversed	O
in	O
direction	O
as	O
cotyledon	O
resistance	O
was	O
increased	O
up	O
to	O
14	O
fold	O
.	O

A	O
total	O
of	O
112	O
patients	O
received	O
anistreplase	O
and	O
119	O
received	O
heparin	O
within	O
a	O
mean	O
period	O
of	O
188	O
+	O
/	O
-	O
62	O
min	O
following	O
the	O
onset	O
of	O
symptoms	O
.	O

The	O
promoter	O
activity	O
was	O
measured	O
by	O
a	O
transient	O
expression	O
of	O
a	O
chloramphenicol	B-GENE
acetyltransferase	I-GENE
(	O
CAT	B-GENE
)	O
gene	O
connected	O
with	O
various	O
5	O
'	O
-	O
deletion	O
mutants	O
of	O
the	O
5	O
'	O
-	O
flanking	O
region	O
.	O

The	O
Saccharomyces	B-GENE
cerevisiae	I-GENE
14DM	I-GENE
gene	I-GENE
,	O
encoding	O
cytochrome	B-GENE
P450	I-GENE
lanosterol	I-GENE
14	I-GENE
alpha	I-GENE
-	I-GENE
demethylase	I-GENE
(	O
14DM	B-GENE
)	O
,	O
was	O
overexpressed	O
in	O
various	O
S	O
.	O
cerevisiae	O
strains	O
under	O
the	O
control	O
of	O
three	O
strong	O
heterologous	O
yeast	O
transcription	O
promoters	O
(	O
pADC1	B-GENE
,	O
pGPD	B-GENE
,	O
pPHO5	B-GENE
)	O
and	O
under	O
the	O
control	O
of	O
its	O
own	O
promoter	O
.	O

Truncations	O
composed	O
of	O
78	O
and	O
64	O
amino	O
acids	O
were	O
translocated	O
across	O
the	O
endoplasmic	O
reticulum	O
membrane	O
,	O
and	O
translocation	O
was	O
found	O
to	O
be	O
strictly	O
co	O
-	O
translational	O
and	O
SRP	B-GENE
-	O
dependent	O
.	O

Pulmonary	O
vascular	O
resistance	O
was	O
not	O
altered	O
,	O
ejection	O
fraction	O
remained	O
unchanged	O
and	O
isovolumic	O
relaxation	O
period	O
was	O
lengthened	O
(	O
119	O
+	O
/	O
-	O
20	O
.	O
1	O
to	O
147	O
.	O
39	O
+	O
/	O
-	O
21	O
.	O
15	O
,	O
P	O
less	O
than	O
0	O
.	O
05	O
)	O
.	O

The	O
ANB1	B-GENE
locus	I-GENE
of	O
Saccharomyces	O
cerevisiae	O
encodes	O
the	O
protein	B-GENE
synthesis	I-GENE
initiation	I-GENE
factor	I-GENE
eIF	I-GENE
-	I-GENE
4D	I-GENE
.	O

Serum	B-GENE
beta	I-GENE
2	I-GENE
-	I-GENE
microglobulin	I-GENE
levels	O
(	O
beta	B-GENE
-	I-GENE
2	I-GENE
-	I-GENE
M	I-GENE
)	O
were	O
studied	O
in	O
150	O
drug	O
addicts	O
,	O
50	O
of	O
them	O
asymptomatic	O
carriers	O
of	O
anti	B-GENE
HIV	I-GENE
-	I-GENE
1	I-GENE
antibodies	I-GENE
,	O
50	O
symptomatic	O
carriers	O
with	O
persistent	O
generalized	O
lymphadenopathy	O
(	O
P	O
.	O
G	O
.	O
L	O
.	O
)	O
and	O
50	O
serum	O
negative	O
patients	O
who	O
had	O
been	O
living	O
in	O
a	O
closed	O
community	O
for	O
at	O
least	O
2	O
years	O
.	O

This	O
emancipation	O
of	O
the	O
ability	O
to	O
copulate	O
from	O
hormonal	O
influence	O
makes	O
female	O
sexual	O
motivation	O
the	O
primary	O
regulator	O
of	O
mating	O
in	O
primates	O
.	O

No	O
therapy	O
exists	O
for	O
halting	O
the	O
progression	O
of	O
the	O
disease	O
with	O
the	O
possible	O
exception	O
of	O
laser	O
photocoagulation	O
treatment	O
used	O
to	O
ablate	O
subretinal	O
neovascular	O
membranes	O
in	O
an	O
attempt	O
to	O
avoid	O
complications	O
of	O
subretinal	O
hemorrhages	O
.	O

R	O
.	O

Specific	O
hyperimmune	B-GENE
globulins	I-GENE
to	O
pathogens	O
such	O
as	O
Haemophilus	O
influenzae	O
and	O
Streptococcus	O
pneumoniae	O
have	O
also	O
been	O
studied	O
.	O

Therapeutic	O
effects	O
of	O
cefpirome	O
(	O
HR	O
810	O
)	O
on	O
experimental	O
mixed	O
infections	O
with	O
Enterococcus	O
faecalis	O
and	O
Escherichia	O
coli	O
in	O
mice	O
.	O

Regulation	O
of	O
yeast	B-GENE
LEU2	I-GENE
.	O

Homozygous	O
individuals	O
usually	O
develop	O
purpura	O
fulminans	O
as	O
newborns	O
;	O
heterozygous	O
protein	B-GENE
C	I-GENE
-	O
deficient	O
individuals	O
are	O
at	O
increased	O
risk	O
for	O
venous	O
thrombosis	O
and	O
pulmonary	O
embolism	O
.	O

Ischemic	O
stroke	O
due	O
to	O
protein	B-GENE
C	I-GENE
deficiency	O
.	O

TREB7	B-GENE
and	O
TREB36	B-GENE
protected	O
all	O
three	O
repeats	O
of	O
the	O
21	O
bp	O
,	O
but	O
TREB5	B-GENE
protected	O
only	O
the	O
second	O
repeat	O
.	O

These	O
results	O
suggest	O
that	O
5	O
KE	O
X	O
3	O
/	O
W	O
may	O
be	O
the	O
optimal	O
regimen	O
to	O
augment	O
the	O
antitumor	O
immunity	O
of	O
RNL	O
.	O

Analysis	O
of	O
various	O
deletion	O
mutants	O
indicates	O
that	O
the	O
sequence	O
requirements	O
for	O
binding	O
by	O
QBP	B-GENE
in	O
vitro	O
are	O
indistinguishable	O
from	O
those	O
necessary	O
for	O
Q	O
activity	O
in	O
vivo	O
,	O
strongly	O
suggesting	O
that	O
QBP	B-GENE
is	O
required	O
for	O
the	O
function	O
of	O
this	O
TATA	O
-	O
independent	O
promoter	O
.	O

Since	O
general	B-GENE
regulatory	I-GENE
factor	I-GENE
I	I-GENE
(	O
GRFI	B-GENE
)	O
/	O
repressor	B-GENE
/	I-GENE
activator	I-GENE
site	I-GENE
binding	I-GENE
protein	I-GENE
1	I-GENE
(	O
RAP1	B-GENE
)	O
/	O
translation	B-GENE
upstream	I-GENE
factor	I-GENE
(	O
TUF	B-GENE
)	O
is	O
believed	O
to	O
be	O
an	O
activator	O
of	O
MAT	B-GENE
alpha	I-GENE
expression	O
,	O
we	O
examined	O
whether	O
PYK1	B-GENE
,	O
which	O
is	O
known	O
to	O
be	O
regulated	O
by	O
GRFI	B-GENE
/	O
RAP1	B-GENE
/	O
TUF	B-GENE
,	O
is	O
also	O
affected	O
by	O
the	O
gal11	B-GENE
mutation	I-GENE
.	O

Yeast	B-GENE
Gal11	I-GENE
protein	I-GENE
mediates	O
the	O
transcriptional	O
activation	O
signal	O
of	O
two	O
different	O
transacting	O
factors	O
,	O
Gal4	B-GENE
and	O
general	B-GENE
regulatory	I-GENE
factor	I-GENE
I	I-GENE
/	O
repressor	B-GENE
/	I-GENE
activator	I-GENE
site	I-GENE
binding	I-GENE
protein	I-GENE
1	I-GENE
/	O
translation	B-GENE
upstream	I-GENE
factor	I-GENE
.	O

Deletion	O
from	O
either	O
the	O
N	O
-	O
or	O
C	O
-	O
terminal	O
ends	O
of	O
repA	B-GENE
(	O
28	O
and	O
69	O
codons	O
,	O
respectively	O
,	O
out	O
of	O
the	O
286	O
-	O
codon	O
open	O
reading	O
frame	O
)	O
affected	O
the	O
initiator	O
but	O
not	O
the	O
inhibitory	O
activity	O
.	O

The	O
two	O
larger	O
peptides	O
,	O
one	O
containing	O
amino	O
acids	O
1	O
-	O
228	O
and	O
the	O
other	O
containing	O
amino	O
acids	O
85	O
-	O
228	O
,	O
formed	O
dimers	O
in	O
solution	O
and	O
bound	O
DNA	O
specifically	O
as	O
a	O
dimer	O
.	O

In	O
vitro	O
transcription	O
extracts	O
from	O
ret1	B-GENE
-	I-GENE
1	I-GENE
cells	O
terminate	O
less	O
efficiently	O
at	O
weak	O
transcription	O
termination	O
signals	O
than	O
those	O
from	O
RET1	B-GENE
cells	O
,	O
using	O
a	O
variety	O
of	O
tRNA	O
templates	O
.	O

Guiding	O
patients	O
in	O
the	O
decision	O
should	O
involve	O
a	O
multidisciplinary	O
team	O
composed	O
of	O
a	O
surgical	O
oncologist	O
,	O
geneticist	O
,	O
pathologist	O
,	O
psychotherapist	O
and	O
plastic	O
surgeon	O
.	O

These	O
factors	O
belong	O
to	O
a	O
set	O
of	O
genetically	O
distinct	O
molecules	O
,	O
including	O
AP	B-GENE
-	I-GENE
4	I-GENE
and	O
MLTF	B-GENE
,	O
that	O
bind	O
to	O
the	O
CACCTGTC	O
motif	O
or	O
related	O
sequences	O
.	O

Among	O
known	O
flea	O
larvae	O
,	O
the	O
genus	O
Anomiopsyllus	O
(	O
Anomiopsyllinae	O
,	O
Anomiopsyllini	O
)	O
is	O
as	O
distinctive	O
in	O
larval	O
form	O
as	O
are	O
the	O
adults	O
.	O

Here	O
,	O
we	O
have	O
used	O
specific	O
antibody	O
to	O
identify	O
and	O
characterize	O
the	O
SSN6	B-GENE
protein	I-GENE
.	O

These	O
latter	O
results	O
showed	O
that	O
the	O
ABFI	B-GENE
protein	I-GENE
,	O
like	O
the	O
RAP1	B-GENE
protein	I-GENE
,	O
bound	O
sequences	O
required	O
for	O
positive	O
as	O
well	O
as	O
negative	O
regulation	O
of	O
gene	O
expression	O
.	O

Clinical	O
nutrition	O
of	O
adult	O
horses	O
.	O

The	O
computer	O
-	O
programmed	O
cytocentrifuge	O
is	O
currently	O
most	O
popular	O
.	O

RNase	B-GENE
protection	O
assays	O
reveal	O
that	O
this	O
gene	O
,	O
unr	B-GENE
,	O
is	O
transcribed	O
in	O
the	O
same	O
direction	O
as	O
N	B-GENE
-	I-GENE
ras	I-GENE
and	O
that	O
its	O
3	O
'	O
end	O
is	O
located	O
just	O
130	O
base	O
pairs	O
away	O
from	O
the	O
point	O
at	O
which	O
N	B-GENE
-	I-GENE
ras	I-GENE
transcription	O
begins	O
.	O

Isolation	O
of	O
a	O
temperature	O
-	O
sensitive	O
mutant	O
with	O
an	O
altered	O
tRNA	B-GENE
nucleotidyltransferase	I-GENE
and	O
cloning	O
of	O
the	O
gene	B-GENE
encoding	I-GENE
tRNA	I-GENE
nucleotidyltransferase	I-GENE
in	I-GENE
the	I-GENE
yeast	I-GENE
Saccharomyces	I-GENE
cerevisiae	I-GENE
.	O

The	O
juxtamembrane	O
region	O
of	O
the	O
insulin	B-GENE
receptor	I-GENE
(	I-GENE
IR	I-GENE
)	I-GENE
beta	I-GENE
-	I-GENE
subunit	I-GENE
contains	O
an	O
unphosphorylated	O
tyrosyl	O
residue	O
(	O
Tyr960	O
)	O
that	O
is	O
essential	O
for	O
insulin	B-GENE
-	O
stimulated	O
tyrosyl	O
phosphorylation	O
of	O
some	O
endogenous	O
substrates	O
and	O
certain	O
biological	O
responses	O
(	O
White	O
,	O
M	O
.	O
F	O
.	O
,	O
Livingston	O
,	O
J	O
.	O
N	O
.	O
,	O
Backer	O
,	O
J	O
.	O
M	O
.	O
,	O
Lauris	O
,	O
V	O
.	O
,	O
Dull	O
,	O
T	O
.	O
J	O
.	O
,	O
Ullrich	O
,	O
A	O
.	O
,	O
and	O
Kahn	O
,	O
C	O
.	O
R	O
.	O

This	O
gene	O
joins	O
the	O
group	O
of	O
genes	O
whose	O
members	O
are	O
rapidly	O
transcribed	O
in	O
response	O
to	O
insulin	B-GENE
and	O
other	O
mitogens	O
.	O

The	O
3	O
'	O
region	O
,	O
GA2	B-GENE
,	O
is	O
necessary	O
for	O
maximal	O
expression	O
.	O

Pups	O
placed	O
into	O
the	O
novel	O
environment	O
with	O
their	O
mothers	O
exhibited	O
an	O
intermediate	O
level	O
of	O
DA	O
turnover	O
.	O

The	O
efficacy	O
and	O
safety	O
of	O
a	O
novel	O
percutaneous	O
anaesthetic	O
preparation	O
based	O
on	O
amethocaine	O
has	O
been	O
investigated	O
in	O
the	O
paediatric	O
clinical	O
environment	O
.	O

Homozygous	O
protein	B-GENE
C	I-GENE
(	O
PC	B-GENE
)	O
deficiency	O
is	O
reported	O
in	O
two	O
siblings	O
(	O
girl	O
and	O
boy	O
)	O
who	O
received	O
their	O
proper	O
diagnoses	O
at	O
the	O
ages	O
of	O
7	O
4	O
/	O
12	O
and	O
1	O
3	O
/	O
12	O
years	O
respectively	O
.	O

The	O
grandfather	O
and	O
the	O
granddaughter	O
both	O
had	O
microtia	O
and	O
meatal	O
atresia	O
,	O
whereas	O
the	O
daughter	O
had	O
a	O
normal	O
outer	O
ear	O
except	O
for	O
a	O
narrow	O
meatus	O
and	O
auricular	O
appendages	O
.	O

Abnormal	O
intrapulmonary	O
shunting	O
(	O
IPS	O
)	O
,	O
which	O
was	O
proved	O
in	O
4	O
cases	O
by	O
whole	O
-	O
body	O
radionuclide	O
scanning	O
with	O
99mTc	O
-	O
MAA	O
,	O
is	O
suggested	O
as	O
the	O
major	O
cause	O
of	O
cyanosis	O
in	O
liver	O
cirrhosis	O
.	O

More	O
generally	O
,	O
Ets1	B-GENE
and	O
Ets2	B-GENE
could	O
regulate	O
transcription	O
of	O
cellular	O
genes	O
.	O

Within	O
this	O
sequence	O
the	O
MSAS	B-GENE
gene	I-GENE
was	O
identified	O
as	O
a	O
5322	O
-	O
bp	O
-	O
long	O
open	O
reading	O
frame	O
coding	O
for	O
a	O
protein	O
of	O
1774	O
amino	O
acids	O
and	O
190	O
,	O
731	O
Da	O
molecular	O
mass	O
.	O

Horseradish	B-GENE
peroxidase	I-GENE
as	O
a	O
permeability	O
marker	O
in	O
injured	O
rat	O
caudal	O
and	O
iliac	O
arteries	O
.	O

Standardized	O
gastric	O
wall	O
specimens	O
from	O
the	O
area	O
of	O
grossly	O
healed	O
ulcers	O
were	O
obtained	O
,	O
processed	O
,	O
and	O
evaluated	O
by	O
light	O
microscopy	O
and	O
by	O
transmission	O
electron	O
microscopy	O
.	O

2	O
.	O

The	O
effects	O
of	O
coenzyme	O
Q10	O
(	O
CoQ	O
)	O
and	O
captopril	O
on	O
functional	O
capacity	O
,	O
hemodynamics	O
and	O
survival	O
were	O
studied	O
in	O
154	O
rats	O
that	O
recovered	O
after	O
experimental	O
myocardial	O
infarction	O
.	O

Evidence	O
that	O
therapeutic	O
alterations	O
of	O
a	O
circadian	O
rhythm	O
for	O
gastric	O
emptying	O
response	O
may	O
be	O
possible	O
.	O

The	O
interrelation	O
of	O
the	O
levels	O
of	O
glucocorticoids	O
and	O
insulin	B-GENE
in	O
the	O
blood	O
of	O
irradiated	O
animals	O

This	O
last	O
includes	O
tissue	O
O2	O
transfer	O
(	O
Ft	O
'	O
)	O
and	O
mitochondrial	O
O2	O
utilization	O
(	O
Fm	O
'	O
)	O
.	O

Foveating	O
saccades	O
,	O
therefore	O
,	O
can	O
be	O
distinguished	O
from	O
other	O
FEMs	O
on	O
the	O
basis	O
of	O
speed	O
.	O

Incidence	O
correlated	O
with	O
the	O
grade	O
of	O
oral	O
hygiene	O
und	O
periodontal	O
disease	O
.	O

Our	O
study	O
shows	O
that	O
the	O
area	O
of	O
Alcoy	O
is	O
a	O
medium	O
MS	O
risk	O
region	O
according	O
to	O
the	O
thesis	O
of	O
Kurzke	O
,	O
although	O
high	O
MS	O
areas	O
may	O
be	O
found	O
,	O
thus	O
confirming	O
that	O
MS	O
distribution	O
in	O
southern	O
Europe	O
is	O
not	O
uniform	O
.	O

On	O
an	O
antithrombin	B-GENE
unit	O
basis	O
,	O
CY	O
216	O
and	O
CY	O
222	O
were	O
equivalent	O
and	O
more	O
potent	O
than	O
UH	O
.	O

Chick	B-GENE
brain	I-GENE
actin	I-GENE
depolymerizing	I-GENE
factor	I-GENE
(	O
ADF	B-GENE
)	O
is	O
a	O
19	O
-	O
kDa	O
protein	O
that	O
severs	O
actin	B-GENE
filaments	I-GENE
and	O
binds	O
actin	B-GENE
monomers	I-GENE
.	O

Initial	O
experience	O
with	O
a	O
serotonin	O
agonist	O
.	O

Comprehensive	O
care	O
of	O
the	O
patient	O
exposed	O
to	O
a	O
human	O
teratogen	O
may	O
also	O
include	O
discussion	O
of	O
prenatal	O
diagnostic	O
procedures	O
and	O
other	O
pregnancy	O
management	O
options	O
.	O

Primer	O
extension	O
analysis	O
and	O
RNA	O
sequencing	O
demonstrates	O
that	O
the	O
transcription	O
start	O
point	O
of	O
rat	B-GENE
ODC	I-GENE
mRNA	I-GENE
is	O
located	O
303	O
nt	O
upstream	O
from	O
the	O
A	O
residue	O
in	O
the	O
start	O
codon	O
.	O

For	O
85Sr	O
,	O
larger	O
-	O
than	O
-	O
expected	O
distribution	O
coefficients	O
were	O
obtained	O
in	O
the	O
desorption	O
experiments	O
,	O
an	O
indication	O
of	O
the	O
irreversible	O
formation	O
of	O
metal	O
-	O
oxyhydroxides	O
during	O
a	O
slow	O
reaction	O
.	O

Gene	O
constructs	O
possessing	O
the	O
complete	B-GENE
tat	I-GENE
,	O
rev	B-GENE
(	O
tat	B-GENE
+	I-GENE
rev	B-GENE
+	I-GENE
)	O
and	O
env	B-GENE
genes	I-GENE
were	O
transiently	O
expressed	O
in	O
COS	O
-	O
1	O
cells	O
as	O
precursor	B-GENE
SU	I-GENE
-	I-GENE
TM	I-GENE
(	O
gp160	B-GENE
)	O
,	O
SU	B-GENE
.	I-GENE
TM	I-GENE
(	O
gp120	B-GENE
x	I-GENE
41	I-GENE
)	O
,	O
and	O
nucleolar	B-GENE
rev	I-GENE
protein	I-GENE
.	O

This	O
growth	O
arrest	O
is	O
partly	O
suppressed	O
on	O
minimal	O
medium	O
or	O
under	O
conditions	O
in	O
which	O
the	O
cells	O
are	O
less	O
dependent	O
on	O
mitochondrial	O
metabolism	O
.	O

Giant	O
pilomatrix	O
carcinoma	O
:	O
report	O
and	O
review	O
of	O
the	O
literature	O
.	O

Further	O
studies	O
of	O
mandibular	O
movement	O
at	O
initial	O
tooth	O
contact	O
.	O

Each	O
parent	O
interacted	O
with	O
their	O
4	O
-	O
or	O
5	O
-	O
year	O
-	O
old	O
son	O
or	O
daughter	O
in	O
each	O
of	O
two	O
conversations	O
-	O
-	O
unstructured	O
(	O
social	O
conversation	O
)	O
and	O
structured	O
(	O
task	O
activity	O
)	O
.	O

Droperidol	O
-	O
induced	O
extrapyramidal	O
symptoms	O
in	O
an	O
adolescent	O
following	O
strabismus	O
surgery	O
.	O

These	O
results	O
indicate	O
that	O
the	O
cis	O
-	O
regulatory	O
elements	O
required	O
for	O
developmental	O
control	O
of	O
the	O
HaG3	B-GENE
-	I-GENE
A	I-GENE
helianthinin	I-GENE
gene	I-GENE
are	O
located	O
in	O
a	O
2	O
.	O
4	O
kb	O
upstream	O
region	O
of	O
this	O
gene	O
.	O

The	O
induction	O
by	O
pseudorabies	O
virus	O
of	O
an	O
IL	B-GENE
-	I-GENE
6	I-GENE
construct	I-GENE
containing	O
the	O
IL	B-GENE
-	I-GENE
6	I-GENE
TATA	I-GENE
box	I-GENE
and	O
the	O
RNA	O
start	O
site	O
(	O
"	O
initiator	O
"	O
or	O
Inr	O
element	O
)	O
but	O
not	O
the	O
MRE	O
region	O
was	O
also	O
repressed	O
by	O
Dex	O
in	O
the	O
presence	O
of	O
wild	B-GENE
-	I-GENE
type	I-GENE
GR	I-GENE
.	O

Some	O
mutations	O
affected	O
Dhfr	B-GENE
in	O
a	O
qualitative	O
manner	O
,	O
such	O
as	O
by	O
changing	O
the	O
startpoint	O
of	O
one	O
of	O
the	O
major	O
Dhfr	B-GENE
transcripts	I-GENE
or	O
changing	O
the	O
relative	O
abundance	O
of	O
the	O
two	O
major	O
Dhfr	B-GENE
transcripts	I-GENE
.	O

The	O
glial	O
cyst	O
wall	O
was	O
lined	O
in	O
part	O
by	O
flattened	O
or	O
cuboidal	O
epithelium	O
.	O

We	O
conclude	O
that	O
class	O
I	O
cytologic	O
smears	O
with	O
moderate	O
to	O
severe	O
inflammation	O
may	O
be	O
associated	O
with	O
findings	O
of	O
condylomata	O
and	O
cervical	O
dysplasia	O
.	O

As	O
in	O
mammals	O
,	O
considerable	O
nucleotide	O
diversity	O
was	O
observed	O
at	O
the	O
junctions	O
of	O
the	O
variable	O
,	O
diversity	O
,	O
and	O
joining	O
elements	O
in	O
chicken	B-GENE
TCR	I-GENE
beta	I-GENE
cDNAs	I-GENE
.	O

The	O
protooncogene	O
c	B-GENE
-	I-GENE
myb	I-GENE
encodes	O
a	O
nuclear	O
transcription	O
factor	O
that	O
binds	O
to	O
DNA	O
in	O
a	O
sequence	O
-	O
specific	O
manner	O
and	O
transactivates	O
transcription	O
of	O
several	O
viral	O
and	O
cellular	O
genes	O
.	O

Modification	O
by	O
this	O
latter	O
compound	O
was	O
so	O
extensive	O
that	O
the	O
amount	O
of	O
membrane	O
-	O
associated	O
N	O
-	O
myristoylated	O
protein	O
was	O
decreased	O
.	O

S6	B-GENE
kinase	I-GENE
activation	O
requires	O
displacement	O
of	O
this	O
inhibitory	O
segment	O
,	O
which	O
is	O
proposed	O
to	O
occur	O
consequent	O
to	O
its	O
multiple	O
phosphorylation	O
.	O

Cerebral	O
flow	O
and	O
resistance	O
showed	O
minor	O
reductions	O
with	O
HD	O
.	O

Utilization	O
of	O
alternative	O
polyadenylation	O
signals	O
was	O
previously	O
shown	O
to	O
generate	O
two	O
sialophorin	B-GENE
mRNAs	I-GENE
of	I-GENE
1	I-GENE
.	I-GENE
9	I-GENE
and	I-GENE
4	I-GENE
.	I-GENE
3	I-GENE
kb	I-GENE
,	O
which	O
differ	O
in	O
the	O
length	O
of	O
their	O
3	O
'	O
untranslated	O
regions	O
.	O

Presidential	O
address	O
1990	O
-	O
-	O
coming	O
in	O
from	O
the	O
cold	O
.	O

The	O
Jenkins	O
Activity	O
Survey	O
and	O
the	O
CPI	O
-	O
revised	O
:	O
further	O
evidence	O
of	O
adaptive	O
and	O
maladaptive	O
type	O
A	O
traits	O
.	O

There	O
was	O
evidence	O
of	O
attenuated	O
regression	O
slopes	O
relating	O
recalled	O
to	O
observed	O
portion	O
sizes	O
for	O
4	O
of	O
the	O
10	O
food	O
groups	O
;	O
adjusted	O
r2	O
values	O
for	O
the	O
recalled	O
portion	O
sizes	O
ranged	O
from	O
0	O
.	O
02	O
to	O
0	O
.	O
94	O
.	O

The	O
result	O
suggests	O
that	O
this	O
non	O
-	O
invasive	O
TTD	O
method	O
is	O
easily	O
available	O
and	O
useful	O
in	O
monitoring	O
the	O
intraoperative	O
cardiac	O
output	O
.	O

The	O
TUP1	B-GENE
gene	I-GENE
was	O
isolated	O
in	O
a	O
screen	O
for	O
genes	O
that	O
regulate	O
mating	O
type	O
(	O
V	O
.	O
L	O
.	O

The	O
SUP44	B-GENE
suppressor	I-GENE
mutation	I-GENE
occurs	O
near	O
a	O
region	O
of	O
the	O
protein	O
that	O
corresponds	O
to	O
the	O
known	O
positions	O
of	O
alterations	O
in	O
E	B-GENE
.	I-GENE
coli	I-GENE
S5	I-GENE
ram	I-GENE
mutations	I-GENE
.	O

Interestingly	O
,	O
disruption	O
of	O
the	O
VPS34	B-GENE
locus	I-GENE
resulted	O
in	O
a	O
temperature	O
-	O
sensitive	O
growth	O
defect	O
,	O
indicating	O
that	O
the	O
VPS34	B-GENE
gene	I-GENE
is	O
essential	O
for	O
vegetative	O
growth	O
only	O
at	O
elevated	O
growth	O
temperatures	O
.	O

We	O
describe	O
a	O
case	O
of	O
a	O
perinephric	O
abscess	O
treated	O
with	O
amphotericin	O
B	O
and	O
nephrectomy	O
.	O

This	O
interaction	O
occurs	O
over	O
a	O
wide	O
range	O
of	O
both	O
parameters	O
;	O
for	O
charge	O
density	O
from	O
at	O
least	O
10	O
to	O
800	O
microC	O
/	O
cm2	O
and	O
,	O
for	O
charge	O
per	O
phase	O
,	O
from	O
at	O
least	O
0	O
.	O
05	O
to	O
5	O
.	O
0	O
microC	O
per	O
phase	O
.	O

Perceptions	O
of	O
illness	O
intrusiveness	O
were	O
significantly	O
higher	O
when	O
both	O
muscle	O
cramp	O
and	O
headache	O
symptoms	O
occurred	O
during	O
one	O
or	O
more	O
assessment	O
intervals	O
as	O
compared	O
to	O
when	O
muscle	O
cramps	O
or	O
headaches	O
,	O
only	O
,	O
occurred	O
.	O

Results	O
have	O
surprisingly	O
revealed	O
the	O
presence	O
of	O
three	O
U14	B-GENE
snRNA	I-GENE
-	I-GENE
homologous	I-GENE
regions	I-GENE
positioned	O
within	O
introns	O
5	O
,	O
6	O
,	O
and	O
8	O
of	O
the	O
mouse	O
cognate	O
hsc70	B-GENE
heat	O
shock	O
gene	O
.	O

65	O
-	O
kilodalton	O
protein	O
phosphorylated	O
by	O
interleukin	B-GENE
2	I-GENE
stimulation	O
bears	O
two	O
putative	O
actin	B-GENE
-	I-GENE
binding	I-GENE
sites	I-GENE
and	O
two	O
calcium	O
-	O
binding	O
sites	O
.	O

The	O
highly	O
restrained	O
girls	O
had	O
a	O
significantly	O
higher	O
EAT	O
score	O
than	O
the	O
low	O
-	O
restrained	O
girls	O
,	O
and	O
shared	O
with	O
their	O
mothers	O
a	O
susceptibility	O
to	O
the	O
disinhibitory	O
effects	O
of	O
negative	O
mood	O
states	O
on	O
their	O
eating	O
behaviour	O
.	O

Sequence	O
and	O
genetic	O
organization	O
of	O
a	O
Zymomonas	O
mobilis	O
gene	O
cluster	O
that	O
encodes	O
several	O
enzymes	O
of	O
glucose	O
metabolism	O
.	O

For	O
this	O
,	O
cDNAs	O
containing	O
the	O
60K	O
,	O
87K	O
,	O
110K	O
and	O
170K	O
protein	O
coding	O
sequences	O
were	O
each	O
provided	O
with	O
an	O
ATG	O
start	O
codon	O
and	O
the	O
cDNA	O
containing	O
the	O
60K	O
coding	O
sequence	O
with	O
a	O
TAA	O
stop	O
codon	O
immediately	O
downstream	O
of	O
the	O
coding	O
sequence	O
.	O

Finally	O
,	O
a	O
complementary	O
footprinting	O
analysis	O
of	O
the	O
upstream	O
region	O
of	O
the	O
constitutively	O
expressed	O
HSC82	B-GENE
gene	I-GENE
reveals	O
the	O
presence	O
of	O
three	O
discrete	O
protein	O
complexes	O
.	O

Pathophysiology	O
of	O
bone	O
loss	O
in	O
castrated	O
animals	O
.	O

Auditory	O
-	O
visual	O
interaction	O
in	O
the	O
generation	O
of	O
saccades	O
in	O
man	O
.	O

First	O
,	O
each	O
lung	O
was	O
cut	O
into	O
slices	O
,	O
from	O
which	O
primary	O
disectors	O
were	O
sampled	O
systematically	O
with	O
a	O
known	O
sampling	O
fraction	O
.	O

The	O
upstream	O
promoter	O
is	O
located	O
within	O
the	O
coding	O
sequence	O
of	O
a	O
divergent	O
gene	O
expressing	O
a	O
protein	O
of	O
Mr	O
39	O
kDa	O
of	O
unknown	O
function	O
.	O

Assuming	O
O2	O
consumption	O
of	O
the	O
isolated	O
skin	O
to	O
be	O
same	O
as	O
in	O
situ	O
,	O
calculations	O
showed	O
that	O
when	O
water	O
PO2	O
was	O
high	O
(	O
150	O
mm	O
Hg	O
)	O
,	O
about	O
40	O
%	O
of	O
total	O
cutaneous	O
O2	O
uptake	O
was	O
consumed	O
by	O
the	O
skin	O
.	O

MCh	O
infusion	O
caused	O
a	O
concentration	O
-	O
dependent	O
increase	O
in	O
airway	O
resistance	O
at	O
constant	O
QBA	O
.	O

Plasma	O
concentrations	O
of	O
atracurium	O
and	O
laudanosine	O
were	O
0	O
.	O
73	O
-	O
3	O
.	O
11	O
micrograms	O
ml	O
-	O
1	O
and	O
0	O
.	O
48	O
-	O
8	O
.	O
65	O
micrograms	O
ml	O
-	O
1	O
,	O
respectively	O
;	O
CSF	O
concentration	O
of	O
laudanosine	O
was	O
70	O
-	O
440	O
ng	O
ml	O
-	O
1	O
.	O

Plasma	O
Al	O
was	O
obtained	O
during	O
each	O
baseline	O
and	O
drug	O
course	O
.	O

The	O
survival	O
in	O
the	O
case	O
of	O
these	O
patients	O
was	O
studied	O
five	O
years	O
later	O
.	O

The	O
occurrence	O
,	O
maintenance	O
and	O
possible	O
involvement	O
of	O
these	O
repeated	O
sequences	O
,	O
capable	O
of	O
forming	O
stable	O
secondary	O
structures	O
,	O
are	O
discussed	O
in	O
relation	O
to	O
their	O
location	O
in	O
the	O
region	O
of	O
control	O
signals	O
.	O

IST	B-GENE
is	O
not	O
the	O
RNA	O
target	O
(	O
TAR	O
)	O
for	O
Tat	B-GENE
trans	O
-	O
activation	O
;	O
however	O
,	O
because	O
it	O
relies	O
entirely	O
on	O
cellular	O
factors	O
for	O
activity	O
,	O
IST	B-GENE
may	O
serve	O
to	O
provide	O
abundant	O
RNA	O
targets	O
for	O
Tat	B-GENE
trans	O
-	O
activation	O
without	O
a	O
requirement	O
for	O
full	O
-	O
length	O
viral	O
mRNA	O
expression	O
.	O

Genotoxic	O
activity	O
of	O
a	O
tobacco	O
-	O
specific	O
nitrosamine	O
.	O

The	O
endodontal	O
treatment	O
need	O
has	O
been	O
forming	O
a	O
clinical	O
order	O
of	O
magnitude	O
.	O

These	O
results	O
may	O
suggest	O
involvement	O
of	O
peripheral	O
enkephalins	O
in	O
pain	O
modulation	O
in	O
patients	O
with	O
episodic	O
cluster	O
headache	O
.	O

Effects	O
of	O
cisapride	O
on	O
upper	O
-	O
gastrointestinal	O
motility	O
and	O
digestive	O
hormones	O

Common	O
foot	O
pathologies	O
are	O
heel	O
pain	O
,	O
metatarsalgia	O
,	O
hammertoes	O
and	O
clawtoes	O
,	O
bunions	O
,	O
hallux	O
rigidus	O
,	O
corns	O
and	O
calluses	O
,	O
nail	O
pathologies	O
,	O
arthritis	O
,	O
and	O
neuropathies	O
.	O

Liver	O
dysfunction	O
in	O
the	O
presence	O
of	O
different	O
adverse	O
reactions	O
presented	O
with	O
a	O
higher	O
activity	O
in	O
the	O
blood	O
serum	O
of	O
indicator	O
liver	O
enzymes	O
and	O
its	O
impaired	O
protein	O
-	O
forming	O
function	O
.	O

Coenzyme	O
Q10	O
:	O
blood	O
levels	O
and	O
metabolic	O
demand	O
.	O

The	O
CT	O
characteristics	O
are	O
discussed	O
and	O
the	O
recent	O
literature	O
is	O
reviewed	O
.	O

Unfortunately	O
,	O
these	O
preservatives	O
may	O
also	O
interfere	O
with	O
microbiological	O
assays	O
used	O
to	O
determine	O
product	O
sterility	O
or	O
bioburden	O
levels	O
.	O

In	O
26	O
patients	O
with	O
angina	O
pectoris	O
,	O
the	O
changes	O
of	O
LVEF	O
,	O
LVESV	O
and	O
PSP	O
/	O
LVESV	O
were	O
more	O
sensitive	O
for	O
the	O
detection	O
of	O
exercise	O
-	O
induced	O
ischemia	O
than	O
the	O
appearance	O
of	O
chest	O
pain	O
and	O
the	O
changes	O
of	O
ECG	O
.	O

In	O
both	O
groups	O
there	O
were	O
5	O
management	O
failure	O
of	O
therapy	O
,	O
so	O
that	O
alternative	O
medication	O
or	O
a	O
cesarean	O
section	O
lead	O
to	O
delivery	O
.	O

Serum	O
Fibrin	B-GENE
Degradation	I-GENE
Products	I-GENE
(	O
FDP	B-GENE
)	O
were	O
determined	O
in	O
50	O
oral	O
cancer	O
patients	O
and	O
50	O
normal	O
individuals	O
prior	O
to	O
any	O
kind	O
of	O
treatment	O
.	O

The	O
uteroglobin	B-GENE
promoter	I-GENE
contains	O
a	O
noncanonical	O
estrogen	O
responsive	O
element	O
.	O

Prostaglandin	O
synthesis	O
inhibitors	O
have	O
been	O
shown	O
to	O
delay	O
healing	O
of	O
bone	O
and	O
this	O
has	O
led	O
to	O
limitations	O
on	O
their	O
use	O
clinically	O
in	O
some	O
situations	O
.	O

The	O
inspiratory	O
oxygen	O
concentration	O
needed	O
(	O
FiO2	O
)	O
and	O
the	O
Horowitz	O
quotient	O
differed	O
in	O
a	O
highly	O
significant	O
manner	O
beginning	O
on	O
the	O
1st	O
day	O
after	O
trauma	O
.	O

The	O
corn	O
and	O
mineral	O
oil	O
emulsions	O
were	O
almost	O
as	O
effective	O
as	O
milk	O
but	O
less	O
effective	O
than	O
sucrose	O
(	O
0	O
.	O
3M	O
)	O
in	O
stimulating	O
ingestion	O
.	O

Significance	O
of	O
thin	O
glomerular	O
basement	O
membranes	O
in	O
hematuric	O
children	O
.	O

Significance	O
of	O
cytokine	O
production	O
and	O
adhesion	O
molecules	O
in	O
malarial	O
immunopathology	O
.	O

The	O
former	O
procedure	O
is	O
economical	O
but	O
complicated	O
,	O
whereas	O
the	O
latter	O
is	O
simple	O
and	O
labour	O
-	O
saving	O
,	O
but	O
a	O
special	O
ultrafiltration	O
tube	O
is	O
required	O
.	O

Simple	O
method	O
for	O
determination	O
of	O
the	O
cephalosporin	O
DQ	O
-	O
2556	O
in	O
biological	O
fluids	O
by	O
high	O
-	O
performance	O
liquid	O
chromatography	O
.	O

Since	O
one	O
group	O
of	O
adolescents	O
more	O
difficult	O
to	O
influence	O
are	O
those	O
whose	O
parents	O
smoke	O
,	O
parental	O
involvement	O
in	O
smoking	O
prevention	O
may	O
be	O
a	O
powerful	O
enhancer	O
.	O

Further	O
research	O
is	O
recommended	O
to	O
identify	O
the	O
coping	O
styles	O
associated	O
with	O
the	O
high	O
EE	O
/	O
low	O
EE	O
research	O
classification	O
.	O

Staining	O
with	O
IF	O
MoAB	O
alone	O
of	O
BAL	O
fluid	O
only	O
seemed	O
to	O
be	O
even	O
more	O
sensitive	O
than	O
silver	O
methenamine	O
staining	O
of	O
BAL	O
,	O
TBB	O
and	O
brushing	O
material	O
.	O

Ultrastructural	O
and	O
morphometric	O
study	O
of	O
the	O
myeloid	O
parenchyma	O
cells	O
of	O
mice	O
prior	O
and	O
after	O
X	O
-	O
ray	O
exposure	O

Using	O
an	O
audiotape	O
cassette	O
and	O
headphones	O
the	O
duration	O
of	O
the	O
hallucinations	O
decreased	O
significantly	O
.	O

The	O
mean	O
change	O
in	O
HbA1	B-GENE
,	O
adjusted	O
for	O
the	O
initial	O
value	O
,	O
was	O
-	O
0	O
.	O
4	O
%	O
in	O
the	O
experimental	O
and	O
+	O
0	O
.	O
5	O
%	O
in	O
the	O
control	O
group	O
(	O
p	O
less	O
than	O
0	O
.	O
05	O
)	O
.	O

Effect	O
of	O
biliary	O
obstruction	O
and	O
cholangitis	O
on	O
serum	B-GENE
SPan	I-GENE
-	I-GENE
1	I-GENE
level	O

Very	O
good	O
accuracy	O
(	O
r	O
greater	O
than	O
0	O
.	O
9	O
)	O
was	O
found	O
when	O
except	O
comparing	O
H	O
*	O
2	O
with	O
the	O
other	O
machine	O
and	O
the	O
reference	O
methods	O
,	O
except	O
for	O
MCHCH	O
and	O
basophil	O
count	O
.	O

The	O
second	O
part	O
of	O
this	O
paper	O
shows	O
some	O
medical	O
applications	O
of	O
these	O
two	O
aspects	O
of	O
NMR	O
,	O
with	O
help	O
of	O
some	O
examples	O
,	O
taken	O
from	O
the	O
literature	O
,	O
according	O
to	O
what	O
is	O
concerned	O
with	O
endocrinology	O
.	O

Interlimb	O
coordination	O
during	O
fictive	O
locomotion	O
in	O
the	O
thalamic	O
cat	O
.	O

Antileukoproteinase	B-GENE
(	O
ALP	B-GENE
)	O
is	O
a	O
low	O
mol	O
wt	O
mucosal	O
secretory	O
protein	O
which	O
,	O
in	O
human	O
tissues	O
,	O
inhibits	O
the	O
activities	O
of	O
the	O
neutral	O
serine	B-GENE
lysosomal	I-GENE
proteinases	I-GENE
elastase	B-GENE
and	O
cathepsin	B-GENE
-	I-GENE
G	I-GENE
.	O

By	O
introducing	O
a	O
series	O
of	O
deletions	O
in	O
the	O
vimentin	B-GENE
promoter	O
,	O
we	O
further	O
restrict	O
these	O
sequences	O
to	O
30	O
base	O
pairs	O
,	O
located	O
between	O
241	O
and	O
210	O
base	O
pairs	O
upstream	O
of	O
the	O
mRNA	O
cap	O
site	O
.	O

In	O
particular	O
,	O
71	O
and	O
69	O
%	O
amino	O
acid	O
sequence	O
similarities	O
were	O
identified	O
with	O
hsp70	B-GENE
of	I-GENE
Escherichia	I-GENE
coli	I-GENE
and	I-GENE
Bacillus	I-GENE
megaterium	I-GENE
,	O
respectively	O
.	O

All	O
89	O
participating	O
household	O
members	O
were	O
anti	B-GENE
-	I-GENE
HIV	I-GENE
seronegative	O
,	O
and	O
78	O
who	O
were	O
tested	O
were	O
serum	B-GENE
p24	I-GENE
antigen	I-GENE
negative	O
.	O

To	O
those	O
of	O
us	O
who	O
are	O
not	O
satisfied	O
with	O
the	O
present	O
outlook	O
there	O
is	O
much	O
to	O
be	O
investigated	O
and	O
much	O
to	O
be	O
contributed	O
.	O

To	O
determine	O
the	O
effects	O
on	O
the	O
pulmonary	O
barrier	O
of	O
several	O
surface	O
active	O
agents	O
,	O
a	O
series	O
of	O
metered	O
dose	O
inhalers	O
(	O
MDIs	O
)	O
was	O
prepared	O
and	O
used	O
to	O
dose	O
aerosolized	O
surfactant	O
to	O
the	O
airways	O
of	O
isolated	O
perfused	O
rat	O
lungs	O
.	O

The	O
beta	O
chain	O
contains	O
five	O
potential	O
N	O
-	O
linked	O
glycosylation	O
sites	O
,	O
and	O
endoglycosidase	B-GENE
digestion	O
suggested	O
that	O
the	O
beta	O
chain	O
contained	O
multiple	O
complex	O
carbohydrate	O
side	O
chains	O
.	O

The	O
therapeutic	O
protocole	O
used	O
at	O
the	O
Gustave	O
Roussy	O
Institute	O
for	O
invasive	O
epithelioma	O
of	O
the	O
uterine	O
cervix	O
rests	O
,	O
for	O
limited	O
forms	O
(	O
T1B	O
-	O
T2	O
proximal	O
)	O
,	O
on	O
combined	O
radiology	O
and	O
surgery	O
.	O

Thyrotropin	B-GENE
-	O
induced	O
expression	O
of	O
a	O
gene	O
for	O
a	O
ribosomal	B-GENE
protein	I-GENE
related	O
to	O
the	O
trk	B-GENE
oncogene	I-GENE
.	O

The	O
introns	O
are	O
1	O
.	O
6	O
-	O
1	O
.	O
9	O
kbp	O
long	O
.	O

After	O
an	O
initial	O
titration	O
period	O
and	O
adjustment	O
of	O
the	O
therapeutic	O
dose	O
,	O
the	O
individual	O
doses	O
were	O
from	O
21	O
to	O
500	O
micrograms	O
/	O
24	O
hrs	O
(	O
mean	O
160	O
micrograms	O
/	O
24	O
hrs	O
)	O
.	O

In	O
the	O
first	O
series	O
of	O
experiments	O
,	O
Sprague	O
-	O
Dawley	O
male	O
rats	O
were	O
implanted	O
unilaterally	O
with	O
guide	O
cannulas	O
aimed	O
at	O
the	O
lateral	O
ventricle	O
.	O

Use	O
of	O
Selenastrum	O
capricornutum	O
and	O
Microfeast	O
as	O
food	O
for	O
Daphnia	O
pulex	O
.	O

The	O
persistence	O
of	O
members	O
of	O
the	O
prostigmatid	O
families	O
Tydeidae	O
,	O
Nanorchestidae	O
and	O
Tarsonemidae	O
in	O
the	O
moisture	O
-	O
deficient	O
90	O
%	O
-	O
concentration	O
treatments	O
supports	O
previous	O
evidence	O
of	O
adaptations	O
to	O
low	O
-	O
water	O
-	O
content	O
habitats	O
.	O

To	O
define	O
the	O
mechanism	O
responsible	O
for	O
the	O
loss	O
of	O
transcription	O
elongation	O
blockage	O
and	O
resulting	O
c	B-GENE
-	I-GENE
myc	I-GENE
deregulation	O
in	O
Burkitt	O
'	O
s	O
lymphoma	O
,	O
we	O
analyzed	O
transcription	O
patterns	O
after	O
transfer	O
of	O
normal	O
and	O
Burkitt	O
'	O
s	O
lymphoma	O
c	B-GENE
-	I-GENE
myc	I-GENE
alleles	O
into	O
murine	O
cells	O
and	O
Xenopus	O
oocyte	O
germinal	O
vesicles	O
.	O

From	O
an	O
RNK	O
-	O
16	O
lambda	O
-	O
gt11	O
library	O
,	O
we	O
have	O
isolated	O
and	O
sequenced	O
a	O
novel	O
cDNA	O
rat	B-GENE
NK	I-GENE
cell	I-GENE
protease	I-GENE
1	I-GENE
(	O
RNKP	B-GENE
-	I-GENE
1	I-GENE
)	O
that	O
has	O
characteristics	O
unique	O
to	O
serine	B-GENE
proteases	I-GENE
.	O

The	O
induction	O
of	O
RNKP	B-GENE
-	I-GENE
1	I-GENE
expression	O
in	O
the	O
Con	B-GENE
A	I-GENE
-	O
cultured	O
spleen	O
cells	O
is	O
accompanied	O
by	O
increases	O
in	O
both	O
NK	O
and	O
lymphokine	O
-	O
activated	O
killer	O
lymphocyte	O
activities	O
.	O

The	O
paper	O
is	O
concerned	O
with	O
the	O
data	O
on	O
change	O
in	O
the	O
blood	O
level	O
of	O
ACTH	B-GENE
,	O
STH	B-GENE
,	O
TSH	B-GENE
,	O
cortisol	O
,	O
T3	O
,	O
insulin	B-GENE
,	O
C	B-GENE
-	I-GENE
peptide	I-GENE
during	O
a	O
25	O
-	O
minute	O
session	O
of	O
respiration	O
using	O
a	O
gaseous	O
hypoxic	O
mixture	O
with	O
10	O
%	O
oxygen	O
(	O
GHM	O
-	O
10	O
)	O
.	O

The	O
abscess	O
was	O
debrided	O
and	O
the	O
septum	O
was	O
patched	O
with	O
a	O
single	O
layer	O
of	O
autologous	O
pericardium	O
.	O

In	O
18	O
%	O
lymphography	O
was	O
clearly	O
positive	O
and	O
CT	O
negative	O
.	O

The	O
present	O
study	O
examined	O
the	O
effect	O
of	O
intensity	O
,	O
rate	O
,	O
and	O
polarity	O
on	O
the	O
spectral	O
content	O
of	O
ABRs	O
of	O
15	O
normal	O
-	O
hearing	O
subjects	O
.	O

Similar	O
memory	O
impairments	O
found	O
in	O
medial	O
septal	O
-	O
vertical	O
diagonal	O
band	O
of	O
Broca	O
and	O
nucleus	O
basalis	O
lesioned	O
rats	O
:	O
are	O
memory	O
defects	O
induced	O
by	O
nucleus	O
basalis	O
lesions	O
related	O
to	O
the	O
degree	O
of	O
non	O
-	O
specific	O
subcortical	O
cell	O
loss	O
?	O
The	O
function	O
of	O
nucleus	O
basalis	O
(	O
NB	O
)	O
and	O
medial	O
septal	O
-	O
vertical	O
diagonal	O
band	O
of	O
Broca	O
(	O
MS	O
-	O
VDBB	O
)	O
in	O
a	O
place	O
navigation	O
task	O
requiring	O
reference	O
memory	O
was	O
investigated	O
.	O

Studies	O
also	O
have	O
alluded	O
to	O
a	O
relationship	O
between	O
the	O
MSMR	O
cyst	O
and	O
certain	O
signs	O
or	O
symptoms	O
of	O
disease	O
.	O

The	O
BAL	O
-	O
to	O
-	O
plasma	O
specific	O
activity	O
of	O
urea	O
was	O
about	O
twice	O
that	O
of	O
Na	O
+	O
,	O
indicating	O
that	O
urea	O
diffused	O
into	O
the	O
ELF	O
more	O
rapidly	O
than	O
Na	O
+	O
during	O
the	O
70	O
s	O
that	O
elapsed	O
between	O
the	O
time	O
the	O
radioactive	O
urea	O
and	O
Na	O
+	O
were	O
injected	O
into	O
the	O
circulation	O
and	O
the	O
time	O
when	O
lavage	O
was	O
complete	O
.	O

The	O
kappa	O
coefficient	O
of	O
agreement	O
between	O
the	O
Patho	O
Dx	O
Kit	O
and	O
the	O
standard	O
method	O
was	O
0	O
.	O
958	O
.	O

Senior	O
systems	O
-	O
-	O
45	O
;	O
Mental	O
health	O
and	O
illness	O
in	O
old	O
age	O
-	O
-	O
3	O
.	O

When	O
normalized	O
for	O
imaging	O
time	O
,	O
all	O
parameters	O
are	O
significantly	O
higher	O
with	O
RASE	O
,	O
with	O
a	O
C	O
/	O
A	O
per	O
unit	O
time	O
that	O
was	O
338	O
%	O
higher	O
.	O

Patients	O
with	O
acute	O
myocardial	O
infarction	O
had	O
higher	O
plasma	O
concentrations	O
of	O
neutrophil	B-GENE
elastase	I-GENE
and	O
the	O
non	O
-	O
peroxide	O
diene	O
conjugated	O
isomer	O
of	O
linoleic	O
acid	O
than	O
normal	O
volunteers	O
or	O
patients	O
with	O
stable	O
ischaemic	O
heart	O
disease	O
.	O

The	O
cis	O
-	O
acting	O
element	O
,	O
identified	O
as	O
CACGTGACCCG	O
,	O
is	O
located	O
34	O
bp	O
upstream	O
from	O
the	O
transcription	O
initiation	O
site	O
,	O
and	O
contains	O
the	O
core	O
sequence	O
of	O
the	O
upstream	O
promoter	O
sequence	O
of	O
Ad2MLP	B-GENE
.	O

The	O
clinical	O
relevance	O
of	O
these	O
findings	O
is	O
strengthened	O
by	O
the	O
observation	O
that	O
similar	O
results	O
were	O
obtained	O
when	O
P	O
.	O
HCl	O
was	O
given	O
by	O
the	O
intravenous	O
route	O
.	O

TMBr	B-GENE
-	I-GENE
1	I-GENE
is	O
identical	O
to	O
striated	B-GENE
muscle	I-GENE
alpha	I-GENE
-	I-GENE
tropomyosin	I-GENE
from	O
amino	O
acids	O
1	O
through	O
258	O
but	O
contains	O
a	O
novel	O
COOH	O
-	O
terminal	O
region	O
from	O
amino	O
acids	O
259	O
through	O
281	O
.	O

The	O
procedure	O
has	O
been	O
applied	O
to	O
three	O
materials	O
:	O
particle	O
board	O
with	O
carpet	O
;	O
gypsum	O
board	O
with	O
wallpaper	O
;	O
and	O
plywood	O
with	O
polyurethane	O
lacquer	O
,	O
for	O
which	O
the	O
steady	O
-	O
state	O
emission	O
factors	O
(	O
mg	O
m	O
-	O
2	O
h	O
-	O
1	O
)	O
of	O
several	O
compounds	O
are	O
given	O
.	O

Intron	O
1	O
is	O
6	O
.	O
5	O
kb	O
long	O
,	O
and	O
the	O
minimal	O
sizes	O
of	O
introns	O
2	O
and	O
3	O
are	O
estimated	O
to	O
be	O
32	O
kb	O
each	O
.	O

After	O
4	O
h	O
,	O
lesions	O
in	O
the	O
secretory	O
part	O
of	O
the	O
stomach	O
were	O
scored	O
and	O
mucosal	O
prostaglandin	O
E2	O
synthesis	O
was	O
determined	O
by	O
the	O
ex	O
vivo	O
prostaglandin	O
generation	O
technique	O
.	O

Comparison	O
of	O
transmembrane	O
and	O
cytoplasmic	O
domains	O
to	O
a	O
third	O
cell	O
-	O
surface	O
proteoglycan	O
,	O
48K5	B-GENE
from	O
human	O
lung	O
fibroblasts	O
(	O
Marynen	O
,	O
P	O
.	O
,	O
Zhang	O
,	O
J	O
.	O
,	O
Cassiman	O
,	O
J	O
.	O
,	O
Vanden	O
Berghe	O
,	O
H	O
.	O
,	O
and	O
David	O
,	O
C	O
.	O

Approximately	O
65	O
%	O
of	O
the	O
total	O
cAMP	B-GENE
-	I-GENE
dependent	I-GENE
phosphotransferase	I-GENE
activity	O
is	O
recovered	O
in	O
particulate	O
fractions	O
of	O
homogenates	O
prepared	O
from	O
asynchronous	O
populations	O
of	O
C	O
.	O
elegans	O
.	O

High	O
levels	O
of	O
C	B-GENE
subunits	I-GENE
are	O
observed	O
in	O
several	O
subsequent	O
larval	O
and	O
adult	O
stages	O
of	O
development	O
.	O

A	O
second	O
,	O
novel	O
C	O
subunit	O
(	O
CeCAT	B-GENE
alpha	I-GENE
'	I-GENE
,	O
374	O
residues	O
)	O
has	O
a	O
unique	O
56	O
-	O
residue	O
carboxyl	O
-	O
terminal	O
region	O
that	O
is	O
generated	O
by	O
the	O
alternative	O
splicing	O
of	O
the	O
C	B-GENE
pre	I-GENE
-	I-GENE
mRNA	I-GENE
.	O

The	O
alternative	O
exon	O
introduces	O
the	O
novel	O
carboxyl	O
terminus	O
and	O
a	O
new	O
translation	O
stop	O
signal	O
,	O
while	O
simultaneously	O
converting	O
the	O
coding	O
sequence	O
for	O
40	O
carboxyl	O
-	O
terminal	O
residues	O
in	O
CeCAT	B-GENE
alpha	I-GENE
into	O
3	O
'	O
-	O
untranslated	O
nucleotides	O
.	O

French	O
,	O
M	O
.	O

Slowly	O
adapting	O
type	O
I	O
mechanoreceptor	O
discharge	O
as	O
a	O
function	O
of	O
dynamic	O
force	O
versus	O
dynamic	O
displacement	O
of	O
glabrous	O
skin	O
of	O
raccoon	O
and	O
squirrel	O
monkey	O
hand	O
.	O

Plasma	O
lecithin	B-GENE
/	I-GENE
cholesterol	I-GENE
acyltransferase	I-GENE
(	O
LCAT	B-GENE
)	O
activity	O
in	O
multiple	O
-	O
organ	O
donors	O
:	O
a	O
predictor	O
of	O
allograft	O
viability	O
in	O
clinical	O
liver	O
transplantation	O
.	O

Axillary	O
nodal	O
status	O
,	O
tumour	O
progesterone	B-GENE
receptor	I-GENE
status	O
,	O
and	O
season	O
of	O
tumour	O
detection	O
significantly	O
influenced	O
survival	O
in	O
both	O
older	O
(	O
greater	O
than	O
50	O
yrs	O
)	O
and	O
younger	O
(	O
less	O
than	O
50	O
yrs	O
)	O
patients	O
.	O

The	O
application	O
of	O
these	O
microelectrodes	O
to	O
the	O
measurement	O
of	O
rapid	O
,	O
transient	O
changes	O
in	O
retinal	O
[	O
K	O
+	O
]	O
o	O
is	O
presented	O
.	O

Expression	O
,	O
cellular	O
localization	O
and	O
in	O
vitro	O
transcription	O
studies	O
establish	O
that	O
cloned	B-GENE
hUBF	I-GENE
encodes	O
a	O
nucleolar	O
factor	O
that	O
binds	O
specifically	O
to	O
the	O
upstream	O
control	O
element	O
and	O
core	O
of	O
the	O
rRNA	O
gene	O
promoter	O
to	O
activate	O
transcription	O
in	O
a	O
binding	O
site	O
-	O
dependent	O
manner	O
.	O

Combining	O
multiple	O
laboratory	O
studies	O
may	O
be	O
of	O
value	O
in	O
predetermining	O
the	O
eventual	O
outcome	O
in	O
near	O
-	O
drowning	O
.	O

There	O
was	O
a	O
gradual	O
increase	O
in	O
the	O
myocyte	O
diameter	O
according	O
to	O
age	O
in	O
the	O
biopsy	O
and	O
autopsy	O
specimens	O
.	O

Despite	O
the	O
absence	O
of	O
exercise	O
-	O
induced	O
asthma	O
(	O
EIA	O
)	O
while	O
breathing	O
WH	O
air	O
,	O
asthmatic	O
patients	O
still	O
had	O
significantly	O
higher	O
mean	O
GH	O
increments	O
than	O
normal	O
subjects	O
(	O
9	O
.	O
2	O
vs	O
2	O
.	O
3	O
ng	O
/	O
ml	O
,	O
P	O
less	O
than	O
0	O
.	O
05	O
)	O
.	O

The	O
afferents	O
'	O
phase	O
of	O
response	O
was	O
unmodified	O
by	O
electrical	O
EVS	O
stimulation	O
.	O

Solving	O
an	O
age	O
old	O
problem	O
.	O

The	O
distribution	O
of	O
their	O
fibrinogen	B-GENE
levels	O
was	O
Gaussian	O
,	O
but	O
more	O
wide	O
-	O
based	O
than	O
the	O
distribution	O
of	O
our	O
normal	O
controls	O
.	O

In	O
a	O
stepwise	O
logistic	O
regression	O
analysis	O
of	O
SPT	O
and	O
RAST	O
data	O
,	O
the	O
occurrence	O
of	O
serum	B-GENE
IgE	I-GENE
antibodies	I-GENE
to	I-GENE
P	I-GENE
.	I-GENE
orbiculare	I-GENE
had	O
the	O
highest	O
explanatory	O
value	O
for	O
current	O
eczema	O
.	O

The	O
examination	O
was	O
focused	O
on	O
assessment	O
of	O
different	O
types	O
of	O
drusen	O
,	O
on	O
evaluation	O
of	O
the	O
development	O
and	O
incidence	O
of	O
risk	O
factors	O
leading	O
to	O
complications	O
and	O
loss	O
of	O
central	O
vision	O
.	O

They	O
were	O
then	O
subjected	O
to	O
whole	O
-	O
body	O
heat	O
stress	O
(	O
water	O
-	O
perfused	O
suits	O
)	O
,	O
and	O
the	O
3	O
minutes	O
of	O
LBNP	O
was	O
repeated	O
.	O

An	O
NF1	B-GENE
-	I-GENE
related	I-GENE
vitellogenin	I-GENE
activator	I-GENE
element	I-GENE
mediates	O
transcription	O
from	O
the	O
estrogen	O
-	O
regulated	O
Xenopus	B-GENE
laevis	I-GENE
vitellogenin	I-GENE
promoter	I-GENE
.	O

At	O
the	O
carboxyl	O
terminus	O
,	O
deletion	O
as	O
far	O
as	O
residue	O
388	O
did	O
not	O
affect	O
in	O
vitro	O
TRF	B-GENE
.	I-GENE
C	I-GENE
assembly	O
,	O
although	O
trans	O
-	O
activating	O
activity	O
was	O
abolished	O
.	O

The	O
effects	O
of	O
mean	O
luminance	O
were	O
also	O
measured	O
and	O
a	O
general	O
expression	O
that	O
would	O
take	O
them	O
into	O
account	O
was	O
derived	O
.	O

Effect	O
of	O
hyperglycemia	O
on	O
pain	O
threshold	O
in	O
alloxan	O
-	O
diabetic	O
rats	O
.	O

We	O
have	O
synthesized	O
[	O
7	O
,	O
7	O
-	O
2H2	O
]	O
-	O
19	O
-	O
OHA	O
with	O
high	O
deuterium	O
content	O
and	O
,	O
together	O
with	O
[	O
7	O
,	O
7	O
-	O
2H2	O
]	O
A	O
and	O
[	O
9	O
,	O
11	O
-	O
2H2	O
]	O
estrone	O
(	O
E1	O
)	O
,	O
have	O
developed	O
a	O
quantitative	O
assay	O
of	O
serum	O
level	O
19	O
-	O
OHA	O
,	O
A	O
,	O
and	O
E1	O
using	O
the	O
gas	O
chromatography	O
/	O
mass	O
spectrometry	O
-	O
mass	O
fragmentography	O
method	O
to	O
monitor	O
individual	O
subjects	O
throughout	O
pregnancy	O
.	O

Sequence	O
analysis	O
of	O
these	O
genes	O
and	O
their	O
surrounding	O
sequences	O
are	O
presented	O
and	O
compared	O
with	O
other	O
known	O
tRNA	O
genes	O
from	O
plant	O
mitochondria	O
.	O

Experiments	O
were	O
performed	O
in	O
which	O
brain	O
-	O
stem	O
auditory	O
-	O
evoked	O
responses	O
(	O
BAERs	O
)	O
were	O
elicited	O
by	O
two	O
types	O
of	O
pseudorandom	O
pulse	O
trains	O
:	O
maximum	O
length	O
sequences	O
(	O
MLS	O
)	O
and	O
Legendre	O
sequences	O
(	O
LGS	O
)	O
.	O

The	O
pseudolymphoma	O
syndrome	O
is	O
a	O
reversible	O
reactive	O
condition	O
consisting	O
of	O
fever	O
,	O
lymphadenopathy	O
and	O
generalized	O
rash	O
.	O

In	O
the	O
local	O
geomagnetic	O
field	O
,	O
the	O
animals	O
preferred	O
the	O
SE	O
-	O
sector	O
.	O

In	O
the	O
artificial	O
lung	O
,	O
like	O
in	O
the	O
natural	O
lung	O
and	O
peripheral	O
tissues	O
,	O
gas	O
exchanges	O
depend	O
on	O
several	O
parameters	O
:	O
blood	O
inlet	O
conditions	O
,	O
blood	O
flow	O
rate	O
,	O
temperature	O
,	O
composition	O
of	O
the	O
gas	O
mixture	O
used	O
for	O
ventilation	O
,	O
blood	O
tissue	O
perfusion	O
,	O
O2	O
consumption	O
,	O
etc	O
.	O

Mean	O
(	O
+	O
/	O
-	O
SE	O
)	O
measurements	O
of	O
clearance	O
(	O
24	O
.	O
5	O
+	O
/	O
-	O
2	O
.	O
06	O
v	O
26	O
.	O
5	O
+	O
/	O
-	O
2	O
.	O
05	O
mL	O
/	O
min	O
/	O
m2	O
)	O
,	O
half	O
-	O
life	O
(	O
5	O
.	O
7	O
+	O
/	O
-	O
0	O
.	O
5	O
v	O
6	O
.	O
4	O
+	O
/	O
-	O
0	O
.	O
5	O
hours	O
)	O
,	O
and	O
volume	O
of	O
distribution	O
(	O
12	O
.	O
4	O
+	O
/	O
-	O
1	O
.	O
1	O
v	O
13	O
.	O
7	O
+	O
/	O
-	O
1	O
.	O
6	O
L	O
/	O
m2	O
)	O
were	O
not	O
significantly	O
different	O
in	O
patients	O
with	O
jaundice	O
when	O
compared	O
with	O
controls	O
.	O

Attitudes	O
were	O
found	O
to	O
be	O
multidimensional	O
,	O
with	O
similar	O
dimensions	O
being	O
identified	O
in	O
both	O
samples	O
.	O

We	O
conclude	O
that	O
DNA	O
ploidy	O
is	O
a	O
major	O
objective	O
prognostic	O
factor	O
and	O
therapeutic	O
determinant	O
for	O
endometrial	O
carcinoma	O
.	O

A	O
semiautomatic	O
digital	O
system	O
(	O
Videoplan	O
2	O
)	O
was	O
used	O
.	O

Environmental	O
factors	O
were	O
more	O
important	O
in	O
the	O
older	O
cohorts	O
(	O
perhaps	O
because	O
of	O
less	O
reliable	O
recall	O
)	O
.	O

Dopamine	O
SERS	O
spectra	O
from	O
these	O
electrodes	O
are	O
similar	O
to	O
those	O
obtained	O
at	O
uncoated	O
electrodes	O
.	O

These	O
findings	O
indicate	O
that	O
hypergastrinemia	O
induced	O
by	O
surgical	O
removal	O
of	O
acid	O
-	O
producing	O
mucosa	O
in	O
the	O
rat	O
has	O
the	O
same	O
effects	O
on	O
oxyntical	O
mucosal	B-GENE
HDC	I-GENE
activity	O
,	O
histamine	O
concentration	O
and	O
ECL	O
cell	O
density	O
as	O
hypergastrinemia	O
induced	O
by	O
continuous	O
gastrin	B-GENE
infusion	O
or	O
by	O
long	O
-	O
term	O
treatment	O
with	O
effective	O
antisecretagogues	O
.	O

The	O
order	O
of	O
the	O
helicase	B-GENE
motif	I-GENE
and	O
the	O
nsP3	B-GENE
homology	I-GENE
region	I-GENE
in	O
the	O
RUB	O
genome	O
is	O
reversed	O
with	O
respect	O
to	O
the	O
alphavirus	O
genome	O
indicating	O
that	O
a	O
genetic	O
rearrangement	O
has	O
occurred	O
during	O
the	O
evolution	O
of	O
these	O
viruses	O
.	O

The	O
results	O
suggest	O
followings	O
-	O
-	O
1	O
)	O
both	O
eosinophils	O
and	O
neutrophils	O
participate	O
in	O
hypersecretion	O
of	O
type	O
Ib	O
in	O
atopic	O
cases	O
,	O
and	O
only	O
eosinophils	O
in	O
non	O
-	O
atopic	O
cases	O
.	O

There	O
were	O
5	O
treatments	O
:	O
control	O
(	O
C	O
)	O
;	O
a	O
wooden	O
surround	O
in	O
one	O
rear	O
corner	O
of	O
the	O
cage	O
(	O
S	O
)	O
;	O
a	O
fiberglass	O
rollaway	O
hollow	O
in	O
one	O
rear	O
corner	O
of	O
the	O
cage	O
(	O
H	O
)	O
;	O
a	O
hollow	O
and	O
a	O
surround	O
(	O
H	O
/	O
S	O
)	O
;	O
a	O
nest	O
box	O
attached	O
to	O
the	O
back	O
of	O
the	O
cage	O
,	O
containing	O
a	O
hollow	O
(	O
N	O
)	O
.	O

While	O
no	O
significant	O
differences	O
in	O
the	O
tensile	O
responses	O
or	O
failure	O
characteristics	O
were	O
noted	O
for	O
irradiated	O
and	O
nonirradiated	O
grafts	O
in	O
the	O
drip	O
,	O
in	O
the	O
bath	O
environment	O
the	O
nonirradiated	O
tissues	O
had	O
greater	O
strength	O
and	O
modulus	O
.	O

The	O
patient	O
was	O
treated	O
with	O
benzathine	O
penicillin	O
,	O
2	O
,	O
400	O
,	O
000	O
U	O
weekly	O
for	O
three	O
weeks	O
.	O

A	O
consensus	O
binding	O
site	O
for	O
the	O
transcription	O
factor	O
SP1	B-GENE
was	O
identified	O
in	O
intron	O
As	O
downstream	O
of	O
the	O
proenkephalin	B-GENE
germ	I-GENE
cell	I-GENE
cap	I-GENE
site	I-GENE
region	I-GENE
.	O

This	O
proposed	O
method	O
is	O
similar	O
in	O
principle	O
to	O
the	O
sets	O
technique	O
but	O
is	O
shown	O
to	O
have	O
much	O
better	O
expected	O
time	O
to	O
alarm	O
properties	O
.	O

Drug	O
and	O
personnel	O
costs	O
were	O
reduced	O
when	O
batch	O
manufacturing	O
with	O
40	O
-	O
mL	O
multidose	O
vials	O
was	O
compared	O
with	O
extemporaneous	O
compounding	O
with	O
unit	O
-	O
dose	O
vials	O
.	O

Changes	O
in	O
prognosis	O
of	O
twin	O
births	O
over	O
20	O
years	O
.	O

Dermal	O
toxicity	O
and	O
carcinogenicity	O
of	O
4	O
-	O
vinyl	O
-	O
1	O
-	O
cyclohexene	O
diepoxide	O
in	O
Fischer	O
rats	O
and	O
B6C3F1	O
mice	O
.	O

Per	O
kg	O
FFM	O
SMR	O
was	O
almost	O
restored	O
to	O
baseline	O
values	O
for	O
the	O
EX	O
group	O
,	O
whereas	O
the	O
non	O
-	O
exercising	O
subjects	O
still	O
showed	O
depressed	O
values	O
(	O
EX	O
3	O
.	O
7	O
per	O
cent	O
and	O
D	O
+	O
DE	O
15	O
.	O
8	O
per	O
cent	O
lower	O
than	O
before	O
treatment	O
;	O
P	O
less	O
than	O
0	O
.	O
05	O
)	O
.	O

MK	O
-	O
927	O
:	O
a	O
topically	O
active	O
ocular	O
hypotensive	O
carbonic	B-GENE
anhydrase	I-GENE
inhibitor	O
.	O

PCR	O
-	O
derived	O
fragments	O
were	O
used	O
as	O
probes	O
for	O
the	O
isolation	O
of	O
the	O
U3	B-GENE
snRNA	I-GENE
genes	I-GENE
from	O
a	O
genomic	O
library	O
of	O
Arabidopsis	O
.	O

The	O
transcriptional	O
unit	O
spans	O
a	O
chromosomal	O
region	O
of	O
about	O
55	O
kilobase	O
pairs	O
(	O
kbp	O
)	O
.	O

100	O
of	O
the	O
patients	O
who	O
would	O
have	O
died	O
survive	O
.	O

The	O
effects	O
of	O
tap	O
(	O
TW	O
)	O
or	O
carbonated	O
(	O
CW	O
)	O
water	O
on	O
arterial	O
pH	O
,	O
partial	O
pressure	O
of	O
carbon	O
dioxide	O
(	O
PCO2	O
)	O
and	O
plasma	O
lactate	O
were	O
determined	O
in	O
heat	O
-	O
stressed	O
broilers	O
.	O

Transient	O
expression	O
of	O
human	B-GENE
and	I-GENE
chicken	I-GENE
progesterone	I-GENE
receptors	I-GENE
does	O
not	O
support	O
alternative	O
translational	O
initiation	O
from	O
a	O
single	O
mRNA	O
as	O
the	O
mechanism	O
generating	O
two	O
receptor	O
isoforms	O
.	O

The	O
Community	O
Adjustment	O
Scale	O
provided	O
outcome	O
data	O
related	O
to	O
the	O
subjects	O
'	O
degree	O
of	O
productivity	O
,	O
ability	O
to	O
maintain	O
close	O
relationships	O
,	O
and	O
presence	O
/	O
absence	O
of	O
symptomatology	O
an	O
average	O
of	O
32	O
years	O
after	O
initial	O
admission	O
.	O

However	O
,	O
at	O
18	O
months	O
of	O
age	O
,	O
significantly	O
higher	O
levels	O
of	O
IgG1	B-GENE
(	O
P	O
less	O
than	O
0	O
.	O
05	O
)	O
and	O
of	O
IgG4	B-GENE
(	O
P	O
less	O
than	O
0	O
.	O
01	O
)	O
were	O
found	O
in	O
infants	O
with	O
an	O
elevated	O
IgE	B-GENE
(	O
greater	O
than	O
or	O
equal	O
to	O
8	O
.	O
0	O
kU	O
/	O
l	O
)	O
than	O
in	O
those	O
with	O
a	O
lower	O
level	O
.	O

The	O
protein	O
sequence	O
contains	O
seven	O
potential	O
N	O
-	O
linked	O
glycosylation	O
sites	O
and	O
a	O
threonine	O
/	O
serine	O
-	O
rich	O
region	O
which	O
is	O
a	O
potential	O
site	O
for	O
attachment	O
of	O
O	O
-	O
linked	O
carbohydrate	O
.	O

Thus	O
adaptation	O
to	O
continuous	O
mild	O
stress	O
has	O
a	O
potent	O
antiarrhythmic	O
effect	O
which	O
occurs	O
due	O
to	O
the	O
increased	O
vagal	O
tone	O
.	O

The	O
eluent	O
from	O
the	O
column	O
was	O
mixed	O
with	O
the	O
chemiluminescent	O
solution	O
containing	O
lucigenin	B-GENE
and	O
Triton	O
X	O
-	O
100	O
and	O
a	O
0	O
.	O
28	O
M	O
KOH	O
solution	O
by	O
pumps	O
and	O
monitored	O
by	O
a	O
chemiluminescence	O
detector	O
.	O

On	O
histologic	O
examination	O
the	O
cuboidal	O
epithelium	O
of	O
the	O
mucous	O
membrane	O
was	O
found	O
to	O
be	O
changed	O
into	O
columnar	O
epithelium	O
,	O
with	O
uneven	O
distribution	O
of	O
enlarged	O
nuclei	O
in	O
the	O
vacuolized	O
cytoplasm	O
.	O

These	O
results	O
suggest	O
an	O
increased	O
risk	O
of	O
developing	O
cancer	O
among	O
polyp	O
patients	O
and	O
the	O
possibility	O
of	O
prophylactic	O
effect	O
of	O
polypectomy	O
against	O
subsequent	O
cancer	O
.	O

The	O
same	O
trend	O
was	O
noted	O
between	O
YG	O
4	O
.	O
5	O
heifers	O
and	O
YG	O
5	O
.	O
5	O
steers	O
,	O
indicating	O
a	O
sex	O
-	O
related	O
deposition	O
of	O
seam	O
fat	O
in	O
fed	O
cattle	O
.	O

The	O
nucleotide	O
sequence	O
consists	O
of	O
48	O
bp	O
of	O
5	O
'	O
-	O
end	O
non	O
-	O
coding	O
region	O
,	O
1695	O
bp	O
of	O
coding	O
region	O
and	O
212	O
bp	O
of	O
3	O
'	O
-	O
end	O
non	O
-	O
coding	O
region	O
including	O
a	O
20	O
bp	O
poly	O
(	O
A	O
)	O
tail	O
.	O

Toxicities	O
included	O
:	O
nausea	O
/	O
vomiting	O
(	O
69	O
%	O
)	O
,	O
headache	O
(	O
25	O
%	O
)	O
,	O
chills	O
(	O
69	O
%	O
)	O
,	O
pain	O
at	O
tumor	O
sites	O
(	O
63	O
%	O
)	O
,	O
hypotension	O
(	O
31	O
%	O
)	O
,	O
and	O
hypertension	O
(	O
38	O
%	O
)	O
.	O

The	O
results	O
also	O
showed	O
that	O
although	O
oyster	O
shell	O
supplementation	O
generally	O
increased	O
alkaline	B-GENE
phosphatase	I-GENE
activity	O
,	O
bone	O
mineralization	O
was	O
relatively	O
uninfluenced	O
as	O
judged	O
by	O
the	O
low	O
coefficients	O
of	O
variation	O
(	O
CV	O
)	O
of	O
3	O
.	O
14	O
-	O
3	O
.	O
51	O
%	O
and	O
3	O
.	O
39	O
-	O
4	O
.	O
82	O
%	O
for	O
calcium	O
and	O
phosphorus	O
content	O
in	O
the	O
femur	O
and	O
tibia	O
respectively	O
.	O

In	O
6	O
of	O
24	O
infants	O
studied	O
(	O
27th	O
-	O
40th	O
weeks	O
of	O
gestation	O
)	O
,	O
acquired	O
and	O
congenital	O
structural	O
anomalies	O
of	O
the	O
airways	O
were	O
detected	O
with	O
an	O
ultrathin	O
flexible	O
fiberscope	O
(	O
Olympus	O
PF18	O
S	O
,	O
1	O
.	O
8	O
mm	O
)	O
.	O

Fatal	O
encephalitis	O
in	O
a	O
patient	O
with	O
chronic	O
graft	O
-	O
versus	O
-	O
host	O
disease	O
.	O

Compared	O
to	O
its	O
counterpart	O
in	O
the	O
GPB	B-GENE
gene	I-GENE
,	O
exon	O
3	O
of	O
the	O
GPE	B-GENE
gene	I-GENE
contains	O
several	O
point	O
mutations	O
,	O
an	O
insertion	O
of	O
24	O
bp	O
,	O
and	O
a	O
stop	O
codon	O
which	O
shortens	O
the	O
reading	O
frame	O
.	O

Molecular	O
cloning	O
of	O
a	O
cDNA	O
encoding	O
rat	B-GENE
NADH	I-GENE
-	I-GENE
cytochrome	I-GENE
b5	I-GENE
reductase	I-GENE
and	O
the	O
corresponding	O
gene	O
.	O

The	O
results	O
corroborate	O
the	O
idea	O
that	O
the	O
structure	O
of	O
relaxation	O
curves	O
contains	O
information	O
on	O
the	O
distance	O
scale	O
and	O
on	O
the	O
architecture	O
of	O
the	O
pore	O
space	O
,	O
even	O
if	O
it	O
is	O
difficult	O
to	O
extract	O
it	O
without	O
ambiguities	O
.	O

Serotonin	B-GENE
5	I-GENE
-	I-GENE
HT2	I-GENE
receptor	I-GENE
binding	O
on	O
blood	O
platelets	O
as	O
a	O
state	O
dependent	O
marker	O
in	O
major	O
affective	O
disorder	O
.	O

Although	O
%	O
BF	O
was	O
correlated	O
with	O
all	O
the	O
BMIs	O
(	O
r	O
=	O
0	O
.	O
60	O
-	O
0	O
.	O
82	O
)	O
,	O
applying	O
objective	O
definitions	O
of	O
obesity	O
based	O
on	O
BMIs	O
or	O
%	O
BF	O
by	O
densitometry	O
often	O
produced	O
conflicting	O
results	O
.	O

The	O
RF	O
values	O
correlated	O
well	O
with	O
the	O
angiographic	O
semiquantitative	O
scale	O
of	O
severity	O
of	O
aortal	O
insufficiency	O
(	O
r	O
=	O
0	O
.	O
805	O
;	O
p	O
less	O
than	O
0	O
.	O
001	O
)	O
,	O
although	O
they	O
enabled	O
the	O
authors	O
only	O
to	O
make	O
a	O
partial	O
differentiation	O
of	O
haemodynamically	O
severe	O
regurgitations	O
and	O
mild	O
or	O
insignificant	O
ones	O
.	O

Promoter	O
elements	O
include	O
an	O
atypical	O
TATA	O
box	O
(	O
GTTA	O
)	O
,	O
one	O
CCAAT	O
box	O
much	O
further	O
from	O
the	O
initiation	O
site	O
,	O
three	O
reverse	O
compliments	O
of	O
CCAAT	O
(	O
ATTGG	O
)	O
,	O
and	O
two	O
pyrimidine	O
-	O
rich	O
nucleotide	O
stretches	O
.	O

The	O
cloned	O
genes	O
were	O
identified	O
in	O
genetic	O
libraries	O
by	O
hybridization	O
screening	O
using	O
four	O
deoxyoligonucleotide	O
probes	O
which	O
corresponded	O
to	O
the	O
partial	O
amino	O
acid	O
sequence	O
of	O
the	O
purified	O
enzyme	O
.	O

The	O
pattern	O
for	O
catalytic	O
zinc	O
sites	O
included	O
two	O
ligands	O
close	O
in	O
sequence	O
,	O
a	O
sequence	O
-	O
distant	O
ligand	O
,	O
and	O
a	O
main	O
-	O
chain	O
hydrogen	O
bond	O
joining	O
two	O
ligands	O
.	O

Results	O
of	O
the	O
long	O
-	O
term	O
observation	O
and	O
treatment	O
of	O
patients	O
with	O
arterial	O
hypertension	O

Eucaryotic	O
transcription	O
factors	O
that	O
stimulate	O
RNA	B-GENE
polymerase	I-GENE
II	I-GENE
by	O
increasing	O
the	O
efficiency	O
of	O
elongation	O
of	O
specifically	O
or	O
randomly	O
initiated	O
RNA	O
chains	O
have	O
been	O
isolated	O
and	O
characterized	O
.	O

Sprague	O
-	O
Dawley	O
newborn	O
rats	O
(	O
n	O
=	O
85	O
)	O
breathed	O
100	O
%	O
oxygen	O
(	O
O2	O
)	O
or	O
room	O
air	O
(	O
RA	O
)	O
during	O
the	O
first	O
8	O
days	O
of	O
life	O
,	O
and	O
then	O
RA	O
.	O

The	O
Lm	O
increased	O
and	O
the	O
alveoli	O
/	O
mm2	O
and	O
elastic	O
recoil	O
pressure	O
decreased	O
.	O

In	O
Experiment	O
II	O
,	O
as	O
performing	O
moderate	O
supine	O
cycling	O
(	O
55	O
%	O
VO2	O
max	O
)	O
for	O
50	O
minutes	O
under	O
several	O
LBNP	O
conditions	O
in	O
5	O
sedentary	O
women	O
,	O
there	O
were	O
correspondingly	O
similar	O
changing	O
manners	O
of	O
the	O
cardiovascular	O
adjustments	O
to	O
each	O
of	O
the	O
phases	O
given	O
in	O
Experiment	O
I	O
.	O

Commercially	O
available	O
formulations	O
of	O
2	O
.	O
5	O
%	O
and	O
5	O
%	O
lambdacyhalothrin	O
can	O
be	O
diluted	O
either	O
with	O
water	O
for	O
ULV	O
cold	O
aerosol	O
space	O
-	O
spraying	O
or	O
with	O
diesel	O
/	O
kerosene	O
for	O
thermal	O
fogging	O
at	O
recommended	O
application	O
rates	O
of	O
0	O
.	O
5	O
-	O
1	O
g	O
ai	O
/	O
ha	O
for	O
mosquito	O
control	O
and	O
2	O
g	O
ai	O
/	O
ha	O
for	O
housefly	O
control	O
.	O

Thus	O
,	O
this	O
reading	O
frame	O
was	O
concluded	O
to	O
encode	O
the	O
precursor	O
of	O
mitochondrial	B-GENE
fumarase	I-GENE
.	O

Sequence	O
analysis	O
indicates	O
that	O
in	O
addition	O
to	O
an	O
ATA	O
and	O
GC	O
box	O
,	O
this	O
region	O
contains	O
domains	O
that	O
have	O
been	O
implicated	O
in	O
the	O
regulation	O
of	O
other	O
muscle	O
-	O
specific	O
genes	O
:	O
a	O
CArG	O
box	O
at	O
-	O
91	O
bp	O
;	O
myocyte	B-GENE
-	I-GENE
specific	I-GENE
enhancer	I-GENE
-	I-GENE
binding	I-GENE
nuclear	I-GENE
factor	I-GENE
1	I-GENE
binding	I-GENE
site	I-GENE
homologies	O
at	O
-	O
58	O
,	O
-	O
535	O
,	O
and	O
-	O
583	O
bp	O
;	O
and	O
a	O
muscle	O
-	O
CAAT	O
consensus	O
sequence	O
at	O
-	O
394	O
bp	O
relative	O
to	O
the	O
cap	O
site	O
.	O

The	O
trk	B-GENE
-	I-GENE
2h	I-GENE
oncogene	I-GENE
,	O
isolated	O
from	O
the	O
human	O
breast	O
carcinoma	O
cell	O
line	O
MDA	O
-	O
MB	O
231	O
by	O
genomic	O
DNA	O
-	O
transfection	O
into	O
NIH3T3	O
cells	O
,	O
consists	O
of	O
the	O
trk	B-GENE
proto	I-GENE
-	I-GENE
oncogene	I-GENE
receptor	I-GENE
kinase	I-GENE
domain	I-GENE
fused	O
to	O
a	O
N	O
-	O
terminal	O
41	O
amino	O
acid	O
activating	O
sequence	O
(	O
Kozma	O
,	O
S	O
.	O
C	O
.	O
,	O
Redmond	O
,	O
S	O
.	O
M	O
.	O
S	O
.	O
,	O
Xiao	O
-	O
Chang	O
,	O
F	O
.	O
,	O
Saurer	O
,	O
S	O
.	O
M	O
.	O
,	O
Groner	O
,	O
B	O
.	O
and	O
Hynes	O
,	O
N	O
.	O
E	O
.	O

Antibodies	O
raised	O
against	O
a	O
bacterially	O
produced	O
beta	B-GENE
gal	I-GENE
-	O
trk	B-GENE
receptor	O
kinase	O
fusion	O
protein	O
recognized	O
a	O
44	O
kd	O
phosphoprotein	O
phosphorylated	O
on	O
serine	O
,	O
threonine	O
and	O
tyrosine	O
in	O
extracts	O
of	O
trk	B-GENE
-	I-GENE
2h	I-GENE
transformed	O
NIH3T3	O
cells	O
.	O

Since	O
very	O
recent	O
scanning	O
-	O
deletion	O
analysis	O
indicates	O
that	O
there	O
is	O
a	O
critical	O
region	O
for	O
activity	O
near	O
Cys	O
-	O
118	O
and	O
that	O
Cys	O
-	O
118	O
is	O
necessary	O
for	O
maximal	O
activity	O
,	O
we	O
conclude	O
that	O
the	O
Cys	O
-	O
118	O
residue	O
is	O
necessary	O
for	O
proper	O
glycosylation	O
and	O
maximal	O
biologic	O
activity	O
of	O
GM	B-GENE
-	I-GENE
CSF	I-GENE
.	O

Molecular	O
and	O
functional	O
characterization	O
of	O
the	O
promoter	O
of	O
ETS2	B-GENE
,	O
the	O
human	O
c	B-GENE
-	I-GENE
ets	I-GENE
-	I-GENE
2	I-GENE
gene	O
.	O

Information	O
about	O
immunologic	O
drug	O
interactions	O
is	O
needed	O
by	O
pharmacists	O
to	O
make	O
rational	O
drug	O
-	O
use	O
decisions	O
.	O

Branch	O
occlusion	O
of	O
Heubner	O
'	O
s	O
artery	O
,	O
or	O
perforators	O
from	O
the	O
proximal	O
anterior	O
or	O
middle	O
cerebral	O
arteries	O
were	O
the	O
posited	O
mechanism	O
of	O
infarction	O
.	O

All	O
ABFI	B-GENE
-	I-GENE
binding	I-GENE
sites	I-GENE
,	O
regardless	O
of	O
origin	O
,	O
provided	O
weak	O
UAS	O
function	O
in	O
vivo	O
when	O
examined	O
in	O
test	O
plasmids	O
.	O

An	O
examination	O
of	O
the	O
properties	O
of	O
sequences	O
surrounding	O
ARS1	O
left	O
open	O
the	O
possibility	O
that	O
ABFI	B-GENE
enhances	O
the	O
initiation	O
of	O
DNA	O
replication	O
at	O
ARS1	O
by	O
transcriptional	O
activation	O
.	O

Likewise	O
,	O
whether	O
or	O
not	O
the	O
hypotensive	O
action	O
of	O
converting	O
enzyme	O
inhibitors	O
is	O
age	O
-	O
related	O
is	O
as	O
yet	O
unknown	O
.	O

Polyclonal	O
antiserum	O
generated	O
to	O
the	O
fusion	O
protein	O
was	O
capable	O
of	O
detecting	O
42	O
-	O
and	O
46	O
-	O
kilodalton	O
polypeptides	O
from	O
virus	O
particles	O
;	O
both	O
polypeptides	O
were	O
also	O
shown	O
to	O
contain	O
HBsAg	B-GENE
determinants	I-GENE
.	O

Role	O
of	O
superoxide	B-GENE
dismutase	I-GENE
in	O
cellular	O
oxidative	O
processes	O
and	O
method	O
of	O
its	O
determination	O
in	O
biological	O
materials	O

At	O
maximum	O
photosensitivity	O
the	O
inhibitory	O
amino	O
acids	O
gamma	O
-	O
aminobutyric	O
acid	O
and	O
taurine	O
were	O
lower	O
,	O
and	O
those	O
of	O
asparagine	O
(	O
metabolite	O
of	O
the	O
excitatory	O
amino	O
acid	O
aspartate	O
)	O
were	O
higher	O
,	O
than	O
when	O
the	O
animals	O
were	O
not	O
photosensitive	O
.	O

The	O
priming	O
activity	O
of	O
DNA	O
incised	O
by	O
either	O
of	O
the	O
Drosophila	O
enzymes	O
can	O
be	O
enhanced	O
,	O
however	O
,	O
by	O
an	O
additional	O
incubation	O
with	O
E	B-GENE
.	I-GENE
coli	I-GENE
endonuclease	I-GENE
IV	I-GENE
,	O
which	O
is	O
known	O
to	O
cleave	O
depurinated	O
DNA	O
on	O
the	O
5	O
'	O
-	O
side	O
of	O
an	O
apurinic	O
site	O
.	O

A	O
.	O

Therefore	O
,	O
in	O
conjunction	O
with	O
a	O
positive	O
pregnancy	O
test	O
and	O
the	O
patient	O
'	O
s	O
clinical	O
history	O
,	O
a	O
severely	O
depressed	O
or	O
absent	O
serum	O
PAPP	B-GENE
-	I-GENE
A	I-GENE
level	O
may	O
aid	O
in	O
the	O
diagnosis	O
of	O
extrauterine	O
pregnancy	O
.	O

The	O
levels	O
of	O
both	O
MAP1	B-GENE
-	I-GENE
specific	I-GENE
and	I-GENE
MAP2	I-GENE
-	I-GENE
specific	I-GENE
mRNAs	I-GENE
decline	O
in	O
the	O
postnatal	O
developing	O
brain	O
;	O
the	O
level	O
of	O
MAP1	B-GENE
-	I-GENE
specific	I-GENE
mRNA	I-GENE
also	O
increases	O
slightly	O
in	O
rat	O
PC12	O
cells	O
upon	O
exposure	O
to	O
nerve	B-GENE
growth	I-GENE
factor	I-GENE
.	O

The	O
cDNAs	O
cross	O
-	O
hybridize	O
with	O
genomic	O
sequences	O
in	O
rat	O
,	O
human	O
,	O
and	O
chicken	O
DNA	O
,	O
but	O
not	O
with	O
DNA	O
from	O
frog	O
,	O
Drosophila	O
,	O
or	O
sea	O
urchin	O
.	O

Colorimetric	O
method	O
of	O
determining	O
glycerin	O
in	O
the	O
blood	O

Deletion	O
analysis	O
was	O
carried	O
out	O
within	O
a	O
part	O
of	O
the	O
5	O
'	O
-	O
flanking	O
region	O
showing	O
homology	O
to	O
the	O
upstream	O
region	O
of	O
the	O
yeast	B-GENE
CYC1	I-GENE
gene	I-GENE
.	O

The	O
N1	O
and	O
P2	O
were	O
comparable	O
in	O
amplitude	O
and	O
both	O
had	O
prolonged	O
refractory	O
periods	O
.	O

Tolerance	O
to	O
fenfluramine	O
anorexia	O
:	O
fact	O
or	O
fiction	O
?	O
Recent	O
findings	O
in	O
this	O
laboratory	O
with	O
regard	O
to	O
tolerance	O
to	O
fenfluramine	O
anorexia	O
are	O
reviewed	O
with	O
respect	O
to	O
generality	O
of	O
the	O
behavioural	O
phenomenon	O
.	O

In	O
30	O
dogs	O
the	O
left	O
limb	O
(	O
tail	O
)	O
of	O
the	O
pancreas	O
was	O
removed	O
but	O
left	O
in	O
the	O
abdominal	O
cavity	O
after	O
cessation	O
of	O
blood	O
flow	O
to	O
produce	O
warm	O
ischemia	O
for	O
30	O
,	O
60	O
,	O
and	O
120	O
min	O
(	O
10	O
dogs	O
at	O
each	O
time	O
point	O
)	O
,	O
and	O
then	O
was	O
flushed	O
with	O
cold	O
Ringers	O
'	O
lactate	O
and	O
transplanted	O
to	O
the	O
iliac	O
vessels	O
.	O

Furthermore	O
,	O
beta	B-GENE
2	I-GENE
-	I-GENE
adrenoceptor	I-GENE
sensitivity	O
appears	O
to	O
be	O
unaltered	O
in	O
BHT	O
.	O

These	O
results	O
suggest	O
that	O
the	O
negative	O
inotropic	O
action	O
of	O
nicorandil	O
is	O
caused	O
by	O
inhibition	O
of	O
Ca	O
influx	O
and	O
intracellular	O
mobilization	O
of	O
Ca	O
.	O

Comparison	O
of	O
elastase	B-GENE
-	I-GENE
1	I-GENE
with	O
amylase	B-GENE
,	O
lipase	B-GENE
,	O
and	O
trypsin	B-GENE
-	O
like	O
immunoreactivity	O
in	O
the	O
diagnosis	O
of	O
acute	O
pancreatitis	O
.	O

A	O
probe	O
evoked	O
potentials	O
procedure	O
was	O
used	O
to	O
assess	O
the	O
relative	O
engagement	O
of	O
both	O
cerebral	O
hemispheres	O
during	O
a	O
language	O
task	O
in	O
the	O
following	O
four	O
groups	O
of	O
dextral	O
adults	O
:	O
left	O
hemisphere	O
(	O
LH	O
)	O
-	O
damaged	O
aphasics	O
recovering	O
from	O
stroke	O
,	O
dysarthrics	O
,	O
right	O
hemisphere	O
(	O
RH	O
)	O
-	O
damaged	O
nonaphasic	O
patients	O
,	O
and	O
normal	O
control	O
subjects	O
.	O

Mucolipidosis	O
type	O
IV	O
:	O
clinical	O
spectrum	O
and	O
natural	O
history	O
.	O

Two	O
of	O
the	O
three	O
groups	O
were	O
administered	O
dauricine	O
,	O
as	O
a	O
new	O
calcium	O
channel	O
blocker	O
,	O
and	O
verapamil	O
,	O
as	O
a	O
generally	O
recognized	O
calcium	O
channel	O
blocker	O
,	O
respectively	O
,	O
from	O
15	O
minutes	O
pre	O
-	O
bypass	O
to	O
the	O
end	O
of	O
the	O
bypass	O
procedure	O
(	O
a	O
period	O
of	O
95	O
minutes	O
)	O
.	O

No	O
reflow	O
occurred	O
in	O
approximately	O
30	O
percent	O
of	O
the	O
muscle	O
microvasculature	O
upon	O
reperfusion	O
.	O

Lysozyme	B-GENE
activity	O
was	O
evidently	O
increased	O
as	O
well	O
in	O
undiluted	O
as	O
in	O
diluted	O
sera	O
in	O
all	O
our	O
tested	O
patients	O
.	O

The	O
first	O
involved	O
measurements	O
of	O
the	O
steady	O
state	O
levels	O
of	O
mRNAs	O
for	O
subunit	O
5	O
of	O
cytochrome	B-GENE
oxidase	I-GENE
and	O
the	O
beta	O
subunit	O
of	O
F1	B-GENE
ATPase	I-GENE
in	O
wild	O
type	O
and	O
in	O
a	O
hem2	B-GENE
mutant	I-GENE
.	O

A	O
5	B-GENE
.	I-GENE
8S	I-GENE
-	I-GENE
like	I-GENE
structure	I-GENE
is	O
present	O
within	O
the	O
5	O
'	O
-	O
terminal	O
region	O
of	O
all	O
three	O
fungal	B-GENE
mitochondrial	I-GENE
LSU	I-GENE
rRNAs	I-GENE
;	O
in	O
contrast	O
,	O
no	O
4	B-GENE
.	I-GENE
5S	I-GENE
-	I-GENE
like	I-GENE
structure	I-GENE
is	O
evident	O
at	O
the	O
3	O
'	O
end	O
of	O
these	O
molecules	O
.	O

The	O
recovery	O
of	O
labelled	O
methoxydextrane	O
is	O
98	O
+	O
/	O
-	O
7	O
%	O
.	O

ASL	O
-	O
8123	O
demonstrated	O
weak	O
competitive	O
beta	B-GENE
-	I-GENE
adrenoreceptor	I-GENE
blocking	O
activity	O
in	O
isolated	O
guinea	O
pig	O
right	O
atria	O
with	O
a	O
pA2	O
of	O
3	O
.	O
73	O
+	O
/	O
-	O
0	O
.	O
07	O
;	O
no	O
agonist	O
-	O
like	O
activity	O
was	O
observed	O
in	O
this	O
tissue	O
at	O
concentrations	O
of	O
ASL	O
-	O
8123	O
from	O
3	O
X	O
10	O
(	O
-	O
5	O
)	O
to	O
1	O
X	O
10	O
(	O
-	O
2	O
)	O
M	O
.	O

We	O
discuss	O
the	O
results	O
in	O
relation	O
to	O
previous	O
systems	O
for	O
parcellating	O
the	O
posterior	O
ectosylvian	O
gyrus	O
of	O
the	O
cat	O
and	O
consider	O
the	O
possibility	O
that	O
divisions	O
of	O
the	O
feline	O
posterior	O
ectosylvian	O
gyrus	O
correspond	O
directly	O
to	O
areas	O
making	O
up	O
the	O
superior	O
temporal	O
gyrus	O
in	O
primates	O
.	O

The	O
4	O
-	O
AP	O
(	O
4	O
-	O
20	O
mM	O
)	O
effect	O
resulted	O
in	O
a	O
decrease	O
of	O
the	O
sensory	O
activity	O
,	O
which	O
was	O
fully	O
restored	O
by	O
TEA	O
or	O
Ba2	O
+	O
.	O

Hybridization	O
of	O
a	O
probe	O
from	O
this	O
region	O
to	O
electrophoretic	O
blots	O
of	O
RNAs	O
from	O
different	O
human	O
tissues	O
showed	O
a	O
predominant	O
2	O
.	O
8	O
-	O
kilobase	O
(	O
kb	O
)	O
message	O
accompanied	O
by	O
weaker	O
bands	O
4	O
.	O
1	O
and	O
2	O
.	O
1	O
kb	O
in	O
size	O
.	O

Prognosis	O
of	O
asymptomatic	O
multiple	O
myeloma	O
.	O

A	O
new	O
method	O
for	O
the	O
quantitative	O
analysis	O
of	O
sleep	O
spindles	O
during	O
continuous	O
overnight	O
EEG	O
recordings	O
.	O

Svensson	O
et	O
al	O
.	O

Endogenous	O
release	O
of	O
neuronal	O
serotonin	O
and	O
5	O
-	O
hydroxyindoleacetic	O
acid	O
in	O
the	O
caudate	O
-	O
putamen	O
of	O
the	O
rat	O
as	O
revealed	O
by	O
intracerebral	O
dialysis	O
coupled	O
to	O
high	O
-	O
performance	O
liquid	O
chromatography	O
with	O
fluorimetric	O
detection	O
.	O

In	O
this	O
report	O
we	O
describe	O
for	O
the	O
first	O
time	O
the	O
complete	O
primary	O
structure	O
of	O
type	B-GENE
X	I-GENE
collagen	I-GENE
,	O
based	O
on	O
cloning	O
and	O
sequencing	O
of	O
cDNA	O
and	O
genomic	O
DNA	O
.	O

Viable	O
flap	O
areas	O
were	O
established	O
following	O
vascular	O
pedicle	O
ligation	O
(	O
both	O
vessels	O
or	O
only	O
artery	O
or	O
vein	O
)	O
,	O
on	O
the	O
third	O
day	O
after	O
flap	O
replantation	O
in	O
both	O
island	O
and	O
free	O
flaps	O
.	O

The	O
size	O
discrepancy	O
is	O
not	O
due	O
to	O
glycosylation	O
or	O
phosphorylation	O
of	O
Ag35	B-GENE
but	O
may	O
result	O
from	O
a	O
proline	O
-	O
rich	O
sequence	O
which	O
occurs	O
in	O
this	O
polypeptide	O
.	O

A	O
9	O
.	O
5	O
-	O
kb	O
KpnI	B-GENE
-	O
SalI	B-GENE
fragment	O
,	O
where	O
all	O
the	O
DNA	O
changes	O
associated	O
with	O
su	B-GENE
(	I-GENE
Hw	I-GENE
)	I-GENE
mutations	I-GENE
were	O
mapped	O
,	O
was	O
able	O
to	O
rescue	O
the	O
su	B-GENE
(	I-GENE
Hw	I-GENE
)	I-GENE
mutant	I-GENE
phenotype	O
after	O
P	O
-	O
element	O
-	O
mediated	O
germ	O
-	O
line	O
transformation	O
.	O

The	O
corticosterone	O
synthesis	O
inhibitor	O
metyrapone	O
(	O
75	O
mg	O
/	O
kg	O
i	O
.	O
p	O
.	O
)	O
was	O
given	O
to	O
attenuate	O
the	O
rise	O
of	O
corticosterone	O
to	O
a	O
level	O
typical	O
of	O
stressed	O
males	O
.	O

The	O
effects	O
of	O
L655	O
,	O
240	O
,	O
a	O
selective	O
thromboxane	O
and	O
prostaglandin	O
endoperoxide	O
antagonist	O
,	O
on	O
ischemia	O
-	O
and	O
reperfusion	O
-	O
induced	O
cardiac	O
arrhythmias	O
.	O

In	O
10	O
pentobarbitalized	O
dogs	O
,	O
plasma	O
viscosity	O
(	O
Ep	O
)	O
was	O
raised	O
fourfold	O
while	O
apparent	O
blood	O
viscosity	O
(	O
Ea	O
)	O
increased	O
about	O
twofold	O
by	O
two	O
steps	O
of	O
exchange	O
transfusion	O
of	O
200	O
ml	O
of	O
plasma	O
with	O
plasma	O
containing	O
high	O
molecular	O
weight	O
dextran	O
(	O
mol	O
wt	O
500	O
,	O
000	O
,	O
20	O
%	O
wt	O
/	O
vol	O
)	O
.	O

The	O
small	B-GENE
IGF	I-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
is	O
abundant	O
in	O
human	O
amniotic	O
fluid	O
.	O

Serum	O
prostatic	B-GENE
acid	I-GENE
phosphatase	I-GENE
levels	O
showed	O
a	O
significantly	O
weaker	O
correlation	O
with	O
cancer	O
volume	O
(	O
r	O
equals	O
0	O
.	O
51	O
)	O
and	O
every	O
other	O
pathological	O
parameter	O
.	O

The	O
investigation	O
was	O
thereafter	O
continued	O
in	O
an	O
open	O
fashion	O
by	O
administering	O
a	O
single	O
10	O
mg	O
dose	O
of	O
the	O
MAO	B-GENE
-	I-GENE
B	I-GENE
inhibitor	O
deprenyl	O
to	O
the	O
same	O
subjects	O
.	O

Their	O
studies	O
have	O
revealed	O
a	O
considerable	O
increase	O
of	O
CSF	B-GENE
AP	I-GENE
activity	O
in	O
purulent	O
meningitides	O
whereas	O
in	O
serous	O
meningitides	O
it	O
grows	O
negligibly	O
.	O

A	O
cDNA	O
encoding	O
a	O
new	O
human	O
lymphocyte	O
cell	O
surface	O
molecule	O
has	O
been	O
isolated	O
and	O
shown	O
to	O
identify	O
a	O
fourth	O
member	O
of	O
a	O
recently	O
discovered	O
family	O
of	O
adhesion	O
proteins	O
.	O

Dopamine	O
caused	O
a	O
prominent	O
potassium	O
efflux	O
measured	O
as	O
86Rb	O
+	O
efflux	O
from	O
control	O
glands	O
,	O
but	O
was	O
without	O
effect	O
in	O
denervated	O
glands	O
.	O

This	O
approach	O
was	O
examined	O
utilizing	O
the	O
fetal	O
protein	O
,	O
HGB	B-GENE
F	I-GENE
.	O

The	O
investigation	O
was	O
apt	O
at	O
studying	O
the	O
relationship	O
between	O
urinary	O
metabolites	O
of	O
serotonin	O
and	O
catecholamine	O
(	O
5	O
-	O
HIAA	O
and	O
VMA	O
)	O
,	O
T	O
-	O
cells	O
(	O
OKT3	B-GENE
+	I-GENE
)	O
,	O
T	O
-	O
helper	O
(	O
OKT4	B-GENE
+	I-GENE
)	O
,	O
T	O
-	O
suppressor	O
(	O
OKT8	B-GENE
+	I-GENE
)	O
and	O
B	O
-	O
cells	O
(	O
EAC	O
-	O
rosette	O
forming	O
cells	O
)	O
in	O
normal	O
(	O
10	O
subjects	O
,	O
1	O
female	O
,	O
9	O
male	O
,	O
age	O
21	O
+	O
/	O
-	O
5	O
years	O
)	O
and	O
stress	O
administered	O
subjects	O
(	O
20	O
subjects	O
,	O
3	O
female	O
,	O
17	O
male	O
,	O
age	O
20	O
+	O
/	O
-	O
4	O
years	O
)	O
.	O

Their	O
hydropathic	O
plots	O
are	O
very	O
similar	O
and	O
both	O
possess	O
three	O
hydrophobic	O
segments	O
that	O
are	O
likely	O
alpha	O
-	O
helical	O
transmembrane	O
segments	O
.	O

Angiotensin	B-GENE
converting	I-GENE
enzyme	I-GENE
inhibitors	O
enhance	O
the	O
antihypertensive	O
efficacy	O
of	O
diuretics	O
and	O
blunt	O
or	O
prevent	O
adverse	O
metabolic	O
effects	O
.	O

In	O
addition	O
to	O
the	O
significant	O
reduction	O
in	O
blood	O
pressure	O
,	O
the	O
angiotensin	B-GENE
converting	I-GENE
enzyme	I-GENE
(	O
ACE	B-GENE
)	O
inhibitor	O
ramipril	O
caused	O
a	O
significant	O
regression	O
of	O
pathologic	O
left	O
ventricular	O
hypertrophy	O
demonstrated	O
by	O
magnetic	O
resonance	O
imaging	O
and	O
echocardiography	O
.	O

The	O
ratio	O
of	O
radioactivity	O
in	O
tumour	O
compared	O
with	O
normal	O
tissue	O
(	O
T	O
:	O
N	O
ratio	O
)	O
was	O
determined	O
after	O
simultaneously	O
injecting	O
microspheres	O
into	O
the	O
portal	O
and	O
arterial	O
circulation	O
of	O
each	O
animal	O
.	O

The	O
mRNA	O
was	O
converted	O
to	O
cDNA	O
and	O
amplified	O
by	O
the	O
polymerase	O
chain	O
reaction	O
technique	O
.	O

Tissue	O
necrosis	O
was	O
evaluated	O
using	O
triphenyltetrazolium	O
staining	O
and	O
was	O
related	O
to	O
two	O
major	O
baseline	O
predictors	O
of	O
infarct	O
size	O
:	O
anatomic	O
risk	O
zone	O
size	O
and	O
coronary	O
collateral	O
flow	O
.	O

To	O
study	O
the	O
retinal	O
surface	O
in	O
the	O
human	O
eye	O
in	O
normal	O
and	O
diseased	O
states	O
we	O
used	O
laser	O
scanning	O
tomography	O
.	O

Previously	O
,	O
we	O
reported	O
the	O
sequence	O
of	O
the	O
gene	B-GENE
encoding	I-GENE
human	I-GENE
K14	I-GENE
(	O
D	O
.	O

Cotransfection	O
of	O
either	O
construct	O
with	O
plasmids	O
encoding	O
PKI	B-GENE
(	I-GENE
1	I-GENE
-	I-GENE
31	I-GENE
)	I-GENE
inhibits	O
cAMP	O
-	O
stimulated	O
but	O
not	O
basal	O
-	O
or	O
phorbol	O
ester	O
-	O
stimulated	O
expression	O
.	O

Sequence	O
analysis	O
of	O
the	O
5	O
'	O
flanking	O
region	O
revealed	O
several	O
GC	O
boxes	O
but	O
no	O
identifiable	O
TATA	O
box	O
.	O

The	O
underlying	O
cirrhosis	O
was	O
alcoholic	O
in	O
11	O
(	O
53	O
.	O
3	O
%	O
)	O
,	O
cryptogenic	O
in	O
5	O
(	O
23	O
.	O
8	O
%	O
)	O
,	O
and	O
hepatitis	O
B	O
chronic	O
infection	O
related	O
in	O
5	O
(	O
23	O
.	O
8	O
%	O
)	O
.	O

Once	O
P	B-GENE
-	I-GENE
450scc	I-GENE
mRNA	I-GENE
is	O
induced	O
as	O
a	O
consequence	O
of	O
the	O
LH	B-GENE
/	O
hCG	B-GENE
surge	O
it	O
is	O
constitutively	O
maintained	O
by	O
luteinized	O
cells	O
in	O
vivo	O
(	O
0	O
-	O
4	O
days	O
)	O
and	O
in	O
vitro	O
(	O
0	O
-	O
9	O
days	O
)	O
in	O
the	O
absence	O
of	O
gonadotropins	B-GENE
,	O
is	O
susceptible	O
to	O
modulation	O
by	O
prolactin	B-GENE
and	O
is	O
no	O
longer	O
regulated	O
by	O
cAMP	O
.	O

Similarly	O
,	O
a	O
human	O
but	O
not	O
a	O
bovine	B-GENE
alpha	I-GENE
transgene	I-GENE
was	O
expressed	O
in	O
placenta	O
in	O
transgenic	O
mice	O
.	O

A	O
rapid	O
staining	O
technique	O
for	O
Leishmania	O
parasites	O
in	O
splenic	O
aspirate	O
smears	O
.	O

NIK	O
-	O
244	O
suppressed	O
coronary	O
ligation	O
-	O
and	O
digitalis	O
-	O
induced	O
arrhythmias	O
,	O
and	O
the	O
minimum	O
effective	O
plasma	O
concentrations	O
for	O
arrhythmias	O
induced	O
by	O
24	O
-	O
h	O
and	O
48	O
-	O
h	O
coronary	O
ligation	O
and	O
digitalis	O
were	O
0	O
.	O
41	O
+	O
/	O
-	O
0	O
.	O
10	O
(	O
by	O
1	O
mg	O
/	O
kg	O
i	O
.	O
v	O
.	O
)	O
,	O
0	O
.	O
70	O
+	O
/	O
-	O
0	O
.	O
13	O
(	O
by	O
1	O
mg	O
/	O
kg	O
i	O
.	O
v	O
.	O
)	O
,	O
and	O
0	O
.	O
21	O
+	O
/	O
-	O
0	O
.	O
08	O
(	O
by	O
0	O
.	O
5	O
mg	O
/	O
kg	O
i	O
.	O
v	O
.	O
)	O
microgram	O
/	O
ml	O
,	O
respectively	O
(	O
mean	O
+	O
/	O
-	O
SD	O
of	O
the	O
mean	O
,	O
n	O
=	O
6	O
)	O
.	O

In	O
TNF	B-GENE
-	O
resistant	O
T24	O
bladder	O
carcinoma	O
cells	O
,	O
TNF	B-GENE
failed	O
to	O
alter	O
EGF	B-GENE
-	I-GENE
R	I-GENE
tyrosine	B-GENE
protein	I-GENE
kinase	I-GENE
activity	O
although	O
both	O
EGF	B-GENE
and	O
phorbol	O
ester	O
were	O
shown	O
to	O
modulate	O
the	O
enzymatic	O
activity	O
of	O
the	O
receptor	O
in	O
these	O
cells	O
.	O

Thus	O
,	O
phosphodiesterase	O
inhibitors	O
that	O
produce	O
an	O
opiate	O
quasi	O
-	O
withdrawal	O
syndrome	O
potentiate	O
interoceptive	O
stimuli	O
and	O
weight	O
loss	O
associated	O
with	O
the	O
withdrawal	O
syndrome	O
precipitated	O
by	O
naltrexone	O
in	O
morphine	O
-	O
dependent	O
rats	O
.	O

The	O
diagnostic	O
value	O
of	O
blood	O
serum	O
and	O
urinary	B-GENE
amylase	I-GENE
,	O
lipase	B-GENE
,	O
and	O
trypsin	B-GENE
in	O
exacerbations	O
of	O
chronic	O
relapsing	O
pancreatitis	O
is	O
discussed	O
.	O

On	O
the	O
basis	O
of	O
the	O
mechanism	O
of	O
action	O
,	O
two	O
groups	O
of	O
inodilators	O
are	O
distinguished	O
,	O
the	O
phosphodiesterase	O
inhibitors	O
and	O
the	O
dopaminergic	O
agents	O
.	O

Structural	O
organization	O
and	O
expression	O
of	O
the	O
mouse	B-GENE
estrogen	I-GENE
receptor	I-GENE
.	O

Intravenous	O
gamma	B-GENE
globulins	I-GENE

Following	O
chondroitinase	B-GENE
AC	I-GENE
and	I-GENE
ABC	I-GENE
digestion	O
,	O
staining	O
reactions	O
suggested	O
that	O
the	O
highest	O
levels	O
of	O
dermatan	O
sulfate	O
were	O
in	O
the	O
diabetes	O
resistant	O
group	O
(	O
p	O
less	O
than	O
0	O
.	O
001	O
compared	O
to	O
diabetic	O
,	O
p	O
less	O
than	O
0	O
.	O
001	O
compared	O
to	O
diabetes	O
prone	O
)	O
and	O
the	O
highest	O
levels	O
of	O
chondroitin	O
sulfates	O
were	O
in	O
the	O
diabetes	O
prone	O
group	O
(	O
p	O
less	O
than	O
0	O
.	O
001	O
)	O
.	O

Myocardial	O
perfusion	O
was	O
evaluated	O
using	O
the	O
enhanced	O
gray	O
level	O
after	O
contrast	O
injection	O
,	O
and	O
the	O
level	O
was	O
compared	O
with	O
the	O
morphology	O
and	O
degree	O
of	O
collateral	O
development	O
.	O

Once	O
NGF	B-GENE
administration	O
is	O
proven	O
effective	O
it	O
will	O
be	O
possible	O
to	O
develop	O
alternative	O
ways	O
of	O
NGF	B-GENE
administration	O
.	O

During	O
the	O
program	O
'	O
s	O
use	O
at	O
the	O
RSNA	O
meeting	O
,	O
the	O
program	O
selected	O
the	O
correct	O
diagnosis	O
in	O
the	O
top	O
five	O
22	O
%	O
of	O
the	O
time	O
.	O

Immunoglobulin	B-GENE
light	I-GENE
chain	I-GENE
(	O
IgL	B-GENE
)	O
diversity	O
is	O
generated	O
in	O
the	O
chicken	O
by	O
recombination	O
between	O
the	O
single	O
functional	O
variable	O
(	O
VL	B-GENE
)	O
and	O
joining	O
(	O
JL	B-GENE
)	O
gene	O
segments	O
and	O
subsequent	O
somatic	O
diversification	O
of	O
the	O
rearranged	O
VL	B-GENE
region	O
.	O

The	O
results	O
were	O
as	O
follows	O
:	O
1	O
)	O
Total	O
integrated	O
EMG	O
activity	O
of	O
FB	O
group	O
was	O
approximately	O
equal	O
in	O
any	O
occluded	O
position	O
,	O
whereas	O
that	O
of	O
CG	O
and	O
GF	O
group	O
varied	O
from	O
position	O
to	O
position	O
.	O

Muscle	O
action	O
potential	O
and	O
masticatory	O
rhythm	O
of	O
anterior	O
temporal	O
and	O
masseter	O
muscles	O
in	O
children	O
and	O
adults	O

The	O
thrombolytic	O
effects	O
of	O
native	O
tissue	B-GENE
-	I-GENE
type	I-GENE
plasminogen	I-GENE
activator	I-GENE
(	O
AK	B-GENE
-	I-GENE
124	I-GENE
)	O
on	O
experimental	O
canine	O
coronary	O
thrombosis	O
.	O

O2	O
and	O
CO2	O
in	O
the	O
tracheostomy	O
tube	O
were	O
continuously	O
monitored	O
by	O
mass	O
spectrometry	O
using	O
a	O
special	O
sample	O
-	O
hold	O
phase	O
-	O
locked	O
sampling	O
technique	O
.	O

Enzyme	O
-	O
linked	O
immunosorbent	O
assay	O
for	O
screening	O
aflatoxin	O
B1	O
in	O
cottonseed	O
products	O
and	O
mixed	O
feed	O
:	O
collaborative	O
study	O
.	O

However	O
,	O
experiments	O
with	O
S1	B-GENE
mapping	O
of	O
in	O
vivo	O
transcripts	O
,	O
gene	O
disruptions	O
in	O
the	O
alpha	O
region	O
,	O
and	O
a	O
single	O
-	O
copy	O
transcriptional	O
fusion	O
vector	O
all	O
suggested	O
that	O
these	O
possible	O
promoters	O
were	O
largely	O
inactive	O
during	O
logarithmic	O
growth	O
,	O
that	O
the	O
major	O
promoter	O
for	O
the	O
alpha	O
operon	O
lay	O
upstream	O
from	O
the	O
region	O
cloned	O
,	O
and	O
that	O
the	O
genes	O
in	O
the	O
IF1	B-GENE
to	O
L17	B-GENE
interval	O
were	O
cotranscribed	O
.	O

Two	O
specific	O
DNA	O
-	O
protein	O
complexes	O
were	O
identified	O
in	O
gel	O
retardation	O
assays	O
using	O
HeLa	O
cell	O
nuclear	O
extracts	O
and	O
an	O
oligonucleotide	O
probe	O
spanning	O
the	O
footprinted	O
region	O
.	O

After	O
transfection	O
,	O
specific	O
TSH	B-GENE
beta	I-GENE
promoter	I-GENE
activity	O
was	O
evident	O
in	O
both	O
TRH	B-GENE
-	O
responsive	O
pituitary	O
-	O
derived	O
GH3	O
and	O
primary	O
pituitary	O
cell	O
cultures	O
.	O

In	O
transformed	O
E	O
.	O
coli	O
,	O
constitutive	B-GENE
CAT	I-GENE
expression	O
is	O
maintained	O
when	O
as	O
little	O
as	O
0	O
.	O
3	O
kilobase	O
of	O
DNA	O
from	O
the	O
3	O
'	O
end	O
of	O
the	O
1	O
.	O
6	O
-	O
kilobase	O
segment	O
is	O
inserted	O
in	O
the	O
correct	O
orientation	O
in	O
front	O
of	O
the	O
CAT	B-GENE
gene	I-GENE
.	O

Lowering	O
of	O
the	O
renal	O
blood	O
flow	O
alters	O
the	O
glomerular	O
and	O
tubular	O
excretion	O
processes	O
.	O

Tonometry	O
of	O
blood	O
samples	O
from	O
patients	O
may	O
also	O
be	O
used	O
in	O
the	O
determination	O
of	O
acid	O
-	O
base	O
quantities	O
and	O
hemoglobin	B-GENE
-	O
oxygen	O
affinity	O
e	O
.	O
g	O
.	O
p50	O
.	O

100	O
and	O
14	O
p	O
.	O

Here	O
,	O
we	O
alter	O
the	O
dimerization	O
specificity	O
of	O
Fos	B-GENE
by	O
precisely	O
replacing	O
its	O
leucine	O
zipper	O
with	O
that	O
from	O
GCN4	B-GENE
.	O

Fourth	O
,	O
sometime	O
between	O
4	O
and	O
24	O
hours	O
of	O
recovery	O
is	O
necessary	O
to	O
reverse	O
the	O
effect	O
of	O
chronic	O
hypoxia	O
on	O
cerebral	O
blood	O
flow	O
.	O

Kindling	O
of	O
the	O
primary	O
visual	O
cortex	O
(	O
VC	O
)	O
was	O
compared	O
with	O
that	O
of	O
the	O
amygdala	O
in	O
cats	O
.	O

Abundant	O
infiltration	O
of	O
lymphocytes	O
and	O
plasma	O
cells	O
was	O
also	O
wide	O
-	O
spread	O
beneath	O
the	O
carcinoma	O
in	O
situ	O
,	O
together	O
with	O
the	O
lymphoid	O
follicles	O
.	O

These	O
case	O
reports	O
provide	O
further	O
evidence	O
that	O
LiCO3	O
can	O
be	O
a	O
useful	O
medication	O
in	O
the	O
treatment	O
of	O
aggressive	O
behavior	O
and	O
affective	O
instability	O
after	O
brain	O
injury	O
,	O
but	O
that	O
it	O
has	O
significant	O
potential	O
for	O
neurotoxicity	O
in	O
this	O
population	O
,	O
particularly	O
when	O
used	O
in	O
conjunction	O
with	O
neuroleptic	O
agents	O
.	O

Among	O
100	O
cases	O
of	O
post	O
-	O
transfusion	O
hepatitis	O
,	O
10	O
are	O
due	O
to	O
the	O
hepatitis	O
B	O
virus	O
(	O
despite	O
systematic	O
search	O
for	O
HBs	B-GENE
Ag	I-GENE
)	O
,	O
89	O
are	O
due	O
to	O
one	O
of	O
the	O
non	O
-	O
A	O
non	O
-	O
B	O
viruses	O
(	O
not	O
detectable	O
by	O
specific	O
serological	O
tests	O
)	O
and	O
1	O
to	O
several	O
viruses	O
,	O
specially	O
CMV	O
.	O

Recessive	O
lethal	O
mutations	O
were	O
isolated	O
based	O
upon	O
failure	O
to	O
complement	O
the	O
recessive	O
lethality	O
of	O
Df	O
(	O
3L	O
)	O
RR2	O
,	O
a	O
deletion	O
of	O
the	O
DRE	O
region	O
that	O
removes	O
16	O
-	O
18	O
polytene	O
chromosome	O
bands	O
.	O

Current	O
status	O
and	O
future	O
perspectives	O

K	O
.	O

A	O
215	O
-	O
base	O
-	O
pair	O
(	O
bp	O
)	O
region	O
of	O
the	O
mouse	B-GENE
MOPC	I-GENE
41	I-GENE
kappa	I-GENE
light	I-GENE
-	I-GENE
chain	I-GENE
immunoglobulin	I-GENE
gene	I-GENE
enhancer	I-GENE
has	O
been	O
analyzed	O
for	O
specific	O
binding	O
of	O
lymphoid	O
and	O
nonlymphoid	O
nuclear	O
factors	O
.	O

Follow	O
-	O
up	O
study	O
showed	O
85	O
%	O
of	O
these	O
patients	O
with	O
effectiveness	O
.	O

The	O
other	O
patients	O
continued	O
the	O
trial	O
with	O
single	O
daily	O
doses	O
of	O
monotherapy	O
.	O

Neonatal	O
Chagas	O
disease	O
:	O
laboratory	O
diagnosis	O
during	O
the	O
first	O
year	O
of	O
life	O

Using	O
mutated	B-GENE
IL2R	I-GENE
alpha	I-GENE
promoter	I-GENE
constructs	I-GENE
in	O
transient	O
transfection	O
and	O
DNA	O
binding	O
assays	O
,	O
we	O
now	O
demonstrate	O
that	O
sequences	O
located	O
immediately	O
upstream	O
and	O
downstream	O
of	O
the	O
kappa	B-GENE
B	I-GENE
enhancer	I-GENE
also	O
contribute	O
to	O
the	O
regulation	O
of	O
IL2R	B-GENE
alpha	I-GENE
gene	I-GENE
expression	O
.	O

Palindromic	O
rheumatism	O

Forty	O
patients	O
,	O
divided	O
according	O
to	O
their	O
initial	O
total	O
gastrointestinal	O
transit	O
times	O
and	O
presenting	O
symptoms	O
,	O
were	O
treated	O
with	O
cimetropium	O
bromide	O
50	O
mg	O
t	O
.	O
d	O
.	O
s	O
.	O
or	O
placebo	O
for	O
1	O
month	O
according	O
to	O
a	O
double	O
-	O
blind	O
,	O
parallel	O
group	O
design	O
.	O

An	O
immunologically	O
related	O
protein	O
was	O
detected	O
in	O
ribosome	O
and	O
membrane	O
fractions	O
of	O
mitochondria	O
from	O
Saccharomyces	O
cerevisiae	O
.	O

Mapping	O
of	O
RNA	O
-	O
temperature	B-GENE
-	I-GENE
sensitive	I-GENE
mutants	I-GENE
of	I-GENE
Sindbis	I-GENE
virus	I-GENE
:	I-GENE
complementation	I-GENE
group	I-GENE
F	I-GENE
mutants	I-GENE
have	O
lesions	O
in	O
nsP4	B-GENE
.	O

The	O
effect	O
of	O
the	O
thromboxane	B-GENE
A2	I-GENE
(	I-GENE
TXA2	I-GENE
)	I-GENE
/	I-GENE
prostaglandin	I-GENE
endoperoxide	I-GENE
receptor	I-GENE
antagonist	O
,	O
SQ	O
29	O
,	O
548	O
on	O
pacing	O
-	O
induced	O
ischemia	O
was	O
determined	O
in	O
anesthetized	O
open	O
-	O
chest	O
dogs	O
.	O

The	O
recovery	O
index	O
(	O
T25	O
-	O
T75	O
)	O
after	O
the	O
infusion	O
stopped	O
was	O
similar	O
in	O
patients	O
who	O
received	O
mivacurium	O
and	O
those	O
who	O
received	O
suxamethonium	O
.	O

The	O
sign	O
of	O
Leser	O
-	O
Trelat	O
:	O
does	O
it	O
exist	O
?	O
The	O
sign	O
of	O
Leser	O
-	O
Trelat	O
is	O
usually	O
regarded	O
as	O
a	O
reliable	O
cutaneous	O
marker	O
of	O
internal	O
malignancy	O
.	O

Three	O
missense	O
mutants	O
in	O
subunit	O
a	O
of	O
the	O
Escherichia	B-GENE
coli	I-GENE
F1F0	I-GENE
-	I-GENE
ATPase	I-GENE
were	O
isolated	O
and	O
characterized	O
after	O
hydroxylamine	O
mutagenesis	O
of	O
a	O
plasmid	O
carrying	O
the	O
uncB	B-GENE
(	I-GENE
subunit	I-GENE
a	I-GENE
)	I-GENE
gene	I-GENE
.	O

Moreover	O
,	O
exons	O
2a	O
and	O
2b	O
share	O
the	O
same	O
5	O
'	O
sequence	O
but	O
differ	O
from	O
each	O
other	O
by	O
the	O
use	O
of	O
two	O
distinct	O
donor	O
splice	O
sites	O
171	O
bp	O
apart	O
in	O
the	O
gene	O
.	O

S1	B-GENE
nuclease	I-GENE
analysis	O
of	O
RNA	O
prepared	O
after	O
transfection	O
of	O
these	O
HIV	O
constructs	O
into	O
HeLa	O
cells	O
infected	O
with	O
wild	O
-	O
type	O
adenovirus	O
indicated	O
that	O
the	O
enhancer	O
,	O
SP1	B-GENE
,	O
TATA	O
,	O
and	O
a	O
portion	O
of	O
the	O
transactivation	O
-	O
responsive	O
element	O
were	O
each	O
required	O
for	O
complete	O
E1A	B-GENE
/	O
E1B	B-GENE
-	O
mediated	O
activation	O
of	O
the	O
HIV	B-GENE
LTR	I-GENE
.	O

In	O
supine	O
position	O
,	O
plasma	O
ANP	B-GENE
levels	O
ranged	O
from	O
12	O
pg	O
/	O
ml	O
to	O
51	O
.	O
5	O
pg	O
/	O
ml	O
,	O
with	O
an	O
average	O
level	O
of	O
35	O
.	O
3	O
+	O
/	O
-	O
11	O
.	O
5	O
pg	O
/	O
ml	O
.	O

The	O
overall	O
prevalence	O
of	O
HBV	O
markers	O
was	O
higher	O
among	O
staff	O
members	O
than	O
in	O
the	O
blood	O
donors	O
of	O
our	O
area	O
.	O

Quantitative	O
predictions	O
are	O
confirmed	O
for	O
the	O
positive	O
responses	O
,	O
but	O
not	O
for	O
the	O
negatives	O
,	O
suggesting	O
that	O
the	O
SSTS	O
model	O
is	O
incorrect	O
.	O

Plasma	O
concentrations	O
of	O
ANF	B-GENE
(	O
pANF	B-GENE
)	O
,	O
aldosterone	O
(	O
PAC	O
)	O
and	O
renin	B-GENE
(	O
PRC	B-GENE
)	O
were	O
measured	O
daily	O
,	O
as	O
were	O
hemodynamic	O
parameters	O
.	O

The	O
adenovirus	B-GENE
E1A	I-GENE
gene	I-GENE
encodes	O
a	O
protein	O
that	O
transcriptionally	O
activates	O
viral	B-GENE
early	I-GENE
genes	I-GENE
.	O

Administration	O
of	O
dexamethasone	O
was	O
associated	O
with	O
progressive	O
rises	O
in	O
plasma	O
17	O
alpha	O
OH	O
progesterone	O
,	O
11	O
beta	O
-	O
desoxycortisol	O
,	O
DHEA	O
sulphate	O
,	O
androstenedione	O
and	O
testosterone	O
,	O
together	O
with	O
increased	O
urinary	O
excretion	O
of	O
androsterone	O
,	O
11	O
beta	O
OH	O
androsterone	O
,	O
etiocholanolone	O
,	O
DHEA	O
,	O
and	O
16	O
alpha	O
OH	O
DHEA	O
.	O

RNA	O
transcripts	O
that	O
hybridize	O
to	O
the	O
introduced	O
foreign	O
gene	O
have	O
been	O
identified	O
.	O

In	O
HeLa	O
cells	O
,	O
it	O
activated	O
transcription	O
from	O
the	O
herpes	B-GENE
simplex	I-GENE
virus	I-GENE
type	I-GENE
1	I-GENE
thymidine	I-GENE
kinase	I-GENE
promoter	I-GENE
linked	O
to	O
the	O
chloramphenicol	B-GENE
acetyltransferase	I-GENE
gene	I-GENE
when	O
located	O
in	O
inverted	O
orientation	O
upstream	O
of	O
the	O
thymidine	B-GENE
kinase	I-GENE
promoter	I-GENE
or	O
downstream	O
of	O
the	O
chloramphenicol	B-GENE
acetyltransferase	I-GENE
gene	I-GENE
coding	I-GENE
sequence	I-GENE
.	O

At	O
the	O
basal	O
unstimulated	O
condition	O
,	O
Ren1d	B-GENE
5	I-GENE
'	I-GENE
flanking	I-GENE
sequence	I-GENE
in	O
the	O
sense	O
orientation	O
inhibited	O
basal	O
CAT	B-GENE
expression	O
from	O
the	O
TK	B-GENE
promoter	I-GENE
of	O
pUTKAT1	O
,	O
whereas	O
the	O
same	O
sequence	O
in	O
the	O
antisense	O
orientation	O
did	O
not	O
.	O

None	O
were	O
restricted	O
from	O
clinical	O
duties	O
,	O
were	O
given	O
varicella	B-GENE
-	I-GENE
zoster	I-GENE
immune	I-GENE
globulin	I-GENE
,	O
or	O
developed	O
disease	O
.	O

In	O
the	O
formalin	O
test	O
,	O
however	O
,	O
naloxone	O
attenuated	O
morphine	O
analgesia	O
at	O
the	O
lower	O
doses	O
(	O
0	O
.	O
1	O
and	O
0	O
.	O
3	O
mg	O
/	O
kg	O
)	O
and	O
potentiated	O
morphine	O
analgesia	O
at	O
the	O
highest	O
dose	O
(	O
10	O
mg	O
/	O
kg	O
)	O
.	O

We	O
have	O
isolated	O
cDNA	O
clones	O
from	O
rat	O
brain	O
and	O
human	O
liver	O
encoding	O
a	O
putative	O
isoform	O
of	O
the	O
Na	B-GENE
,	I-GENE
K	I-GENE
-	I-GENE
ATPase	I-GENE
beta	I-GENE
subunit	I-GENE
.	O

We	O
have	O
determined	O
that	O
several	O
E1	B-GENE
mutants	I-GENE
mapping	O
in	O
both	O
the	O
M	O
and	O
R	O
regions	O
and	O
a	O
single	O
mutant	O
of	O
the	O
upstream	O
regulatory	O
region	O
have	O
a	O
higher	O
transforming	O
activity	O
on	O
mouse	O
C127	O
cells	O
than	O
the	O
wild	O
-	O
type	O
genome	O
does	O
.	O

UbiA	B-GENE
is	O
also	O
unique	O
among	O
known	O
polyubiquitin	B-GENE
genes	I-GENE
in	O
containing	O
four	O
cis	O
-	O
spliced	O
introns	O
within	O
its	O
coding	O
sequence	O
.	O

That	O
of	O
the	O
T2	B-GENE
gene	I-GENE
contains	O
numerous	O
potential	O
sites	O
for	O
binding	O
the	O
mammalian	B-GENE
transcription	I-GENE
factor	I-GENE
SP1	I-GENE
,	O
but	O
no	O
TATA	O
or	O
CCAAT	O
sequences	O
are	O
evident	O
near	O
to	O
its	O
5	O
'	O
end	O
,	O
although	O
these	O
latter	O
features	O
are	O
associated	O
with	O
the	O
human	B-GENE
T1	I-GENE
gene	I-GENE
.	O

Radiation	O
therapy	O
was	O
effective	O
in	O
controlling	O
symptomatic	O
metastasis	O
in	O
all	O
three	O
patients	O
.	O

These	O
results	O
indicate	O
that	O
patients	O
who	O
undergo	O
postoperative	O
irradiation	O
for	O
low	O
grade	O
spinal	O
astrocytomas	O
and	O
localized	O
spinal	O
ependymomas	O
achieve	O
excellent	O
survival	O
.	O

The	O
methylation	O
of	O
nuclear	O
and	O
chloroplast	O
DNAs	O
has	O
been	O
examined	O
in	O
relation	O
to	O
the	O
known	O
differential	O
expression	O
of	O
C4	B-GENE
photosynthesis	I-GENE
genes	I-GENE
in	O
the	O
bundle	O
sheath	O
and	O
mesophyll	O
cells	O
of	O
etiolated	O
,	O
greening	O
,	O
and	O
fully	O
green	O
maize	O
leaves	O
.	O

S1	B-GENE
nuclease	I-GENE
analysis	O
of	O
RNA	O
from	O
chemically	O
induced	O
B95	O
-	O
8	O
cells	O
and	O
from	O
Vero	O
cells	O
cotransfected	O
with	O
NotI	B-GENE
repeat	I-GENE
promoter	I-GENE
-	O
CAT	B-GENE
and	O
Z	B-GENE
showed	O
that	O
Z	B-GENE
transactivation	O
increased	O
the	O
level	O
of	O
correctly	O
initiated	O
,	O
stable	O
RNA	O
transcripts	O
.	O

Analysis	O
of	O
the	O
DNA	O
from	O
15	O
cases	O
of	O
sporadic	O
and	O
familial	O
Wilms	O
'	O
tumor	O
did	O
not	O
reveal	O
any	O
changes	O
,	O
indicating	O
that	O
the	O
translocation	O
breakpoint	O
does	O
not	O
reside	O
in	O
this	O
gene	O
.	O

We	O
also	O
provide	O
evidence	O
that	O
neither	O
the	O
lambda	B-GENE
O	I-GENE
and	O
P	B-GENE
initiators	I-GENE
nor	O
the	O
E	B-GENE
.	I-GENE
coli	I-GENE
DnaJ	I-GENE
and	O
DnaK	B-GENE
heat	O
shock	O
proteins	O
play	O
a	O
direct	O
role	O
in	O
the	O
propagation	O
of	O
lambda	O
replication	O
forks	O
in	O
vitro	O
.	O

Synthetic	O
oligonucleotides	O
representing	O
the	O
19	O
bp	O
repeat	O
unit	O
strongly	O
reduced	O
the	O
activity	O
of	O
the	O
IE1	B-GENE
/	I-GENE
2	I-GENE
enhancer	I-GENE
/	I-GENE
promoter	I-GENE
in	O
cotransfection	O
assays	O
after	O
transient	O
expression	O
.	O

Effects	O
of	O
nitrogen	O
(	O
PN2	O
:	O
5	O
and	O
14	O
MPa	O
)	O
and	O
helium	O
(	O
PHe	O
:	O
13	O
and	O
14	O
MPa	O
)	O
were	O
also	O
tested	O
.	O

The	O
mustard	B-GENE
chloroplast	I-GENE
gene	I-GENE
rps16	I-GENE
is	O
split	O
by	O
an	O
887	O
bp	O
group	O
II	O
(	O
or	O
III	O
)	O
intron	O
.	O

Antibodies	O
raised	O
to	O
the	O
expressed	O
NS3	B-GENE
by	O
immunization	O
of	O
mice	O
detected	O
both	O
NS3	B-GENE
and	O
NS3A	B-GENE
in	O
BTV	O
-	O
10	O
-	O
infected	O
BHK	O
cells	O
but	O
not	O
in	O
purified	O
BTV	O
-	O
10	O
virus	O
particles	O
.	O

Similarly	O
,	O
supraventricular	O
tachycaydia	O
following	O
resuscitative	O
efforts	O
appeared	O
to	O
be	O
associated	O
with	O
a	O
negative	O
outcome	O
.	O

The	O
negative	O
calcium	O
balance	O
with	O
hyperparathyroidemia	O
occurred	O
after	O
continuous	O
oral	O
administration	O
of	O
Cd	O
and	O
developed	O
via	O
increased	O
urinary	O
excretion	O
of	O
calcium	O
.	O

Clone	O
4c	O
(	O
2681	O
bp	O
)	O
had	O
a	O
coding	O
region	O
identical	O
to	O
that	O
of	O
clone	O
22c	O
but	O
it	O
included	O
a	O
putative	O
intron	O
of	O
959	O
bp	O
.	O

The	O
application	O
of	O
ISH	O
and	O
IHC	O
did	O
not	O
change	O
significantly	O
the	O
routine	O
histologic	O
classification	O
of	O
pneumonias	O
into	O
CMV	O
-	O
IP	O
and	O
IIP	O
.	O

Validity	O
of	O
immunohistology	O
and	O
in	O
situ	O
hybridization	O
in	O
the	O
differential	O
diagnosis	O
of	O
cytomegalovirus	O
pneumonia	O
and	O
idiopathic	O
interstitial	O
pneumonia	O
after	O
allogenic	O
bone	O
marrow	O
transplantation	O

The	O
unique	O
nature	O
and	O
arrangement	O
of	O
the	O
ANT1	B-GENE
transcriptional	I-GENE
control	I-GENE
elements	I-GENE
may	O
account	O
for	O
this	O
differential	O
expression	O
.	O

The	O
Bacillus	B-GENE
subtilis	I-GENE
phage	I-GENE
phi	I-GENE
105	I-GENE
repressor	I-GENE
,	O
a	O
lambda	B-GENE
repressor	I-GENE
-	O
like	O
transcriptional	O
regulatory	O
protein	O
,	O
was	O
overproduced	O
in	O
Escherichia	O
coli	O
and	O
purified	O
to	O
near	O
homogeneity	O
in	O
order	O
to	O
examine	O
its	O
in	O
vitro	O
DNA	O
-	O
binding	O
properties	O
.	O

In	O
consequence	O
,	O
the	O
gpI	B-GENE
derived	O
from	O
cells	O
infected	O
with	O
mO74	O
showed	O
antigenic	O
characteristics	O
similar	O
to	O
those	O
of	O
gpI	B-GENE
from	O
VZV	O
-	O
infected	O
cells	O
as	O
determined	O
from	O
the	O
immunoprecipitation	O
pattern	O
,	O
although	O
the	O
molecular	O
weight	O
of	O
each	O
polypeptide	O
was	O
different	O
,	O
and	O
antibody	O
produced	O
in	O
rabbits	O
infected	O
with	O
recombinant	O
virus	O
had	O
a	O
high	O
neutralizing	O
activity	O
,	O
when	O
the	O
reaction	O
was	O
performed	O
with	O
complement	O
.	O

However	O
,	O
bilateral	O
diffuse	O
pulmonary	O
infiltrations	O
developed	O
21	O
days	O
later	O
.	O

Grossly	O
,	O
the	O
incidence	O
of	O
a	O
type	O
IIc	O
carcinoma	O
was	O
46	O
.	O
5	O
%	O
and	O
that	O
of	O
a	O
IIc	O
+	O
III	O
type	O
was	O
20	O
.	O
5	O
%	O
,	O
respectively	O
.	O

VP5	B-GENE
,	O
which	O
encodes	O
the	O
major	B-GENE
capsid	I-GENE
protein	I-GENE
,	O
each	O
fused	O
to	O
the	O
chloramphenicol	B-GENE
acetyltransferase	I-GENE
gene	I-GENE
.	O

Of	O
202	O
initially	O
seronegative	O
caretakers	O
(	O
observed	O
for	O
an	O
average	O
of	O
305	O
days	O
per	O
woman	O
)	O
,	O
19	O
seroconverted	O
,	O
for	O
an	O
annual	O
seroconversion	O
rate	O
of	O
11	O
percent	O
.	O

First	O
,	O
a	O
pet54	B-GENE
:	O
:	O
LEU2	B-GENE
cytoductant	O
bearing	O
the	O
'	O
short	O
'	O
mitochondrial	O
genome	O
that	O
lacks	O
both	O
COX1	B-GENE
introns	I-GENE
aI5	B-GENE
alpha	I-GENE
and	O
aI5	B-GENE
beta	I-GENE
is	O
defective	O
only	O
in	O
COX3	B-GENE
gene	I-GENE
expression	O
and	O
not	O
in	O
COX1	B-GENE
mRNA	I-GENE
splicing	O
or	O
mRNA	O
translation	O
.	O

Insert2	O
contains	O
repetitive	O
non	O
-	O
Ig	B-GENE
-	O
related	O
sequences	O
and	O
a	O
small	B-GENE
Ig	I-GENE
-	I-GENE
related	I-GENE
sequence	I-GENE
.	O

Since	O
considerable	O
variations	O
in	O
length	O
and	O
primary	O
sequence	O
in	O
the	O
CDR3	B-GENE
(	O
complementarity	B-GENE
determining	I-GENE
region	I-GENE
)	O
peptides	O
of	O
all	O
the	O
H	B-GENE
-	I-GENE
chains	I-GENE
are	O
evident	O
,	O
conservation	O
of	O
the	O
D	B-GENE
-	I-GENE
region	I-GENE
structure	O
does	O
not	O
appear	O
to	O
be	O
necessary	O
for	O
effective	O
hapten	O
binding	O
.	O

Tyrosine	B-GENE
kinase	I-GENE
oncogenes	O
abrogate	O
interleukin	B-GENE
-	I-GENE
3	I-GENE
dependence	O
of	O
murine	O
myeloid	O
cells	O
through	O
signaling	O
pathways	O
involving	O
c	B-GENE
-	I-GENE
myc	I-GENE
:	O
conditional	O
regulation	O
of	O
c	B-GENE
-	I-GENE
myc	I-GENE
transcription	O
by	O
temperature	O
-	O
sensitive	O
v	B-GENE
-	I-GENE
abl	I-GENE
.	O

The	O
DNA	O
helix	O
at	O
the	O
tandemly	O
repeated	O
,	O
13mer	O
sequence	O
is	O
thermodynamically	O
unstable	O
,	O
as	O
evidenced	O
by	O
hypersensitivity	O
to	O
single	B-GENE
-	I-GENE
strand	I-GENE
-	I-GENE
specific	I-GENE
nuclease	I-GENE
in	O
a	O
negatively	O
supercoiled	O
plasmid	O
,	O
and	O
demonstrated	O
by	O
stable	O
DNA	O
unwinding	O
seen	O
after	O
two	O
-	O
dimensional	O
gel	O
electrophoresis	O
of	O
topoisomers	O
.	O

There	O
has	O
been	O
similar	O
improvement	O
in	O
treating	O
ampullary	O
and	O
periampullary	O
cancer	O
,	O
gallbladder	O
cancer	O
,	O
or	O
extrahepatic	O
bile	O
duct	O
cancer	O
.	O

Beta	B-GENE
-	I-GENE
endorphin	I-GENE
,	O
ACTH	B-GENE
and	O
cortisol	O
secretion	O
were	O
measured	O
in	O
twelve	O
healthy	O
adult	O
males	O
after	O
nasal	O
spray	O
administration	O
200	O
IU	O
salmon	B-GENE
calcitonin	I-GENE
.	O

The	O
data	O
indicate	O
that	O
calcitonin	B-GENE
induced	O
a	O
beta	B-GENE
-	I-GENE
endorphin	I-GENE
increase	O
independent	O
of	O
enhanced	O
corticotrophin	B-GENE
-	O
cortisol	O
release	O
.	O

Other	O
hemostatic	O
values	O
evaluated	O
were	O
activated	O
partial	O
thromboplastin	B-GENE
times	O
,	O
prothrombin	B-GENE
times	O
,	O
thrombin	B-GENE
times	O
,	O
fibrinogen	B-GENE
,	O
platelet	O
counts	O
,	O
and	O
fibrin	B-GENE
/	O
fibrinogen	B-GENE
degradation	O
products	O
.	O

Rare	O
neurogenic	O
tumor	O
with	O
metastasis	O
to	O
mouth	O
,	O
jaw	O
and	O
face	O
regions	O

We	O
have	O
designated	O
the	O
protein	O
"	B-GENE
cellular	I-GENE
NBP	I-GENE
"	I-GENE
(	O
CNBP	B-GENE
)	O
.	O

Responsiveness	O
to	O
beta	O
-	O
2	O
agonist	O
therapy	O
was	O
retained	O
with	O
both	O
agents	O
(	O
p	O
less	O
than	O
0	O
.	O
05	O
)	O
.	O

Drug	O
use	O
in	O
trauma	O
victims	O
.	O

A	O
critical	O
heart	O
rate	O
and	O
/	O
or	O
appropriate	O
sympathetic	O
state	O
was	O
found	O
to	O
provoke	O
all	O
instances	O
of	O
reentrant	O
or	O
automatic	O
atrial	O
tachycardia	O
and	O
atypical	O
junctional	O
tachycardia	O
.	O

In	O
contrast	O
,	O
the	O
neu	B-GENE
proto	I-GENE
-	I-GENE
oncogene	I-GENE
did	O
not	O
show	O
kinase	O
activity	O
or	O
transforming	O
properties	O
when	O
expressed	O
at	O
similar	O
levels	O
in	O
NIH	O
3T3	O
cells	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
250	O
WORDS	O
)	O

The	O
65	O
-	O
bp	O
sequence	O
contains	O
the	O
octameric	O
cAMP	O
-	O
responsive	O
enhancer	O
(	O
CRE	O
)	O
TGACGTCA	O
(	O
nucleotides	O
-	O
48	O
to	O
-	O
41	O
)	O
.	O

Somatostatin	B-GENE
gene	I-GENE
expression	O
in	O
pancreatic	O
islet	O
cells	O
is	O
directed	O
by	O
cell	O
-	O
specific	O
DNA	O
control	O
elements	O
and	O
DNA	O
-	O
binding	O
proteins	O
.	O

In	O
contrast	O
,	O
the	O
full	O
mu	O
-	O
opioid	O
agonists	O
fentanyl	O
,	O
morphine	O
,	O
I	O
-	O
methadone	O
and	O
levorphanol	O
produced	O
50	O
%	O
fentanyl	O
-	O
appropriate	O
responding	O
at	O
doses	O
only	O
1	O
.	O
3	O
to	O
10	O
.	O
9	O
times	O
smaller	O
than	O
those	O
required	O
to	O
decrease	O
response	O
rates	O
by	O
50	O
%	O
.	O

After	O
overtraining	O
on	O
the	O
original	O
discrimination	O
,	O
the	O
controls	O
showed	O
the	O
normal	O
difficulty	O
in	O
learning	O
the	O
first	O
reversal	O
.	O

Isolation	O
and	O
characterization	O
of	O
a	O
cDNA	O
encoding	O
a	O
putative	O
cytokine	O
which	O
is	O
induced	O
by	O
stimulation	O
via	O
the	O
CD2	B-GENE
structure	I-GENE
on	O
human	O
T	O
lymphocytes	O
.	O

After	O
termination	O
of	O
medication	O
the	O
animals	O
were	O
kindled	O
electrically	O
in	O
the	O
nucleus	O
amygdala	O
.	O

Haploid	O
cells	O
of	O
mating	O
type	O
A	O
of	O
the	O
basidiomycetous	O
yeast	O
Rhodosporidium	O
toruloides	O
secrete	O
a	O
mating	O
pheromone	O
,	O
rhodotorucine	B-GENE
A	I-GENE
,	O
which	O
is	O
an	O
undecapeptide	O
containing	O
S	O
-	O
farnesyl	O
cysteine	O
at	O
its	O
carboxy	O
terminus	O
.	O

Tumour	B-GENE
necrosis	I-GENE
factor	I-GENE
and	O
adult	O
respiratory	O
distress	O
syndrome	O
.	O

Monitoring	O
of	O
rheumatoid	O
arthritis	O
.	O

The	O
decrease	O
in	O
left	O
ventricular	O
(	O
LV	O
)	O
stroke	O
volume	O
during	O
positive	O
end	O
-	O
expiratory	O
pressure	O
(	O
PEEP	O
)	O
has	O
been	O
attributed	O
to	O
reduced	O
LV	O
filling	O
and	O
a	O
decreased	O
contractile	O
state	O
.	O

An	O
experiment	O
on	O
the	O
return	O
-	O
of	O
-	O
fear	O
(	O
ROF	O
)	O
was	O
carried	O
out	O
on	O
40	O
snake	O
-	O
or	O
spider	O
-	O
phobic	O
subjects	O
in	O
order	O
to	O
determine	O
whether	O
an	O
arousing	O
event	O
that	O
occurs	O
shortly	O
before	O
retest	O
influences	O
the	O
magnitude	O
of	O
the	O
ROF	O
.	O

Evolutionary	O
conservation	O
of	O
homeodomain	B-GENE
-	O
binding	O
sites	O
and	O
other	O
sequences	O
upstream	O
and	O
within	O
the	O
major	O
transcription	O
unit	O
of	O
the	O
Drosophila	B-GENE
segmentation	I-GENE
gene	I-GENE
engrailed	I-GENE
.	O

To	O
assess	O
the	O
functional	O
importance	O
of	O
these	O
NBS	O
in	O
the	O
overall	O
drug	O
resistance	O
phenotype	O
conferred	O
by	O
mdr1	B-GENE
,	O
we	O
introduced	O
amino	O
acid	O
substitutions	O
in	O
the	O
core	O
consensus	O
sequence	O
for	O
nucleotide	O
binding	O
,	O
GXGKST	O
.	O

When	O
the	O
first	O
twitch	O
of	O
TOF	O
spontaneously	O
recovered	O
to	O
10	O
%	O
of	O
control	O
value	O
,	O
neostigmine	O
was	O
injected	O
(	O
40	O
micrograms	O
/	O
kg	O
in	O
adults	O
,	O
30	O
micrograms	O
/	O
kg	O
in	O
infants	O
and	O
children	O
)	O
.	O

No	O
significant	O
differences	O
were	O
found	O
in	O
relation	O
to	O
Type	O
A	O
behaviour	O
and	O
beta	B-GENE
-	I-GENE
adrenoceptor	I-GENE
blockade	O
.	O

Selection	O
of	O
the	O
22	O
items	O
of	O
the	O
Clinical	O
Institute	O
Withdrawal	O
Assessment	O
-	O
Benzodiazepines	O
(	O
CIWA	O
-	O
B	O
)	O
was	O
based	O
on	O
statistically	O
significant	O
differences	O
between	O
baseline	O
and	O
critical	O
withdrawal	O
periods	O
in	O
high	O
-	O
dose	O
subjects	O
and	O
between	O
symptoms	O
associated	O
with	O
placebo	O
and	O
diazepam	O
in	O
low	O
-	O
dose	O
subjects	O
,	O
using	O
contingency	O
tables	O
and	O
logistic	O
regression	O
analysis	O
.	O

Northern	O
blot	O
analysis	O
revealed	O
multiple	O
oIGF	B-GENE
-	I-GENE
I	I-GENE
transcripts	I-GENE
in	O
a	O
broad	O
band	O
at	O
800	O
-	O
1	O
,	O
100	O
nucleotides	O
and	O
other	O
transcripts	O
of	O
higher	O
molecular	O
weight	O
in	O
liver	O
.	O

Materials	O
science	O
studies	O
on	O
the	O
soldering	O
of	O
different	O
orthodontic	O
wires	O

The	O
latency	O
time	O
for	O
the	O
lactate	O
concentration	O
to	O
reach	O
the	O
top	O
values	O
was	O
reduced	O
by	O
aerobic	O
training	O
(	O
T2	O
)	O
.	O

In	O
patients	O
resistant	O
to	O
VAD	O
,	O
high	O
-	O
dose	O
therapies	O
with	O
intravenous	O
melphalan	O
,	O
a	O
CBV	O
combination	O
(	O
cyclophosphamide	O
-	O
BCNU	O
-	O
VP	O
-	O
16	O
)	O
or	O
an	O
EDAP	O
regimen	O
(	O
VP	O
-	O
16	O
-	O
platinum	O
)	O
produced	O
responses	O
in	O
about	O
40	O
%	O
of	O
patients	O
.	O

The	O
avian	O
cellular	O
homolog	O
of	O
the	O
oncogene	B-GENE
jun	I-GENE
.	O

High	O
ATP	O
/	O
GTP	O
ratios	O
promoted	O
initiation	O
of	O
RNA	O
primer	O
synthesis	O
at	O
3	O
'	O
-	O
dCTTT	O
sites	O
,	O
whereas	O
low	O
ATP	O
/	O
GTP	O
ratios	O
promoted	O
initiation	O
at	O
3	O
'	O
-	O
dCCC	O
sites	O
.	O

After	O
hepatitis	O
B	O
vaccine	O
immunization	O
,	O
serum	O
antibody	O
response	O
was	O
of	O
primary	O
type	O
in	O
33	O
cases	O
with	O
anti	B-GENE
-	I-GENE
HBs	I-GENE
less	O
than	O
2	O
.	O
1	O
S	O
/	O
N	O
(	O
S	O
/	O
N	O
Ratio	O
Unit	O
)	O
at	O
T0	O
,	O
the	O
anti	B-GENE
-	I-GENE
HBs	I-GENE
positive	O
rate	O
was	O
39	O
.	O
4	O
%	O
,	O
84	O
.	O
8	O
%	O
,	O
96	O
.	O
7	O
%	O
and	O
96	O
.	O
7	O
%	O
in	O
T1	O
,	O
T2	O
,	O
T0	O
and	O
T12	O
respectively	O
.	O

The	O
experimental	O
design	O
incorporated	O
a	O
multiple	O
regression	O
model	O
,	O
sequential	O
treatments	O
and	O
a	O
proportional	O
end	O
point	O
(	O
95	O
%	O
)	O
for	O
protection	O
time	O
.	O

Interspecific	O
complementation	O
tests	O
showed	O
that	O
the	O
P7	B-GENE
proteins	I-GENE
are	O
unable	O
to	O
complement	O
P1	B-GENE
parA	B-GENE
or	O
parB	B-GENE
mutants	I-GENE
,	O
and	O
the	O
P1	B-GENE
proteins	I-GENE
fail	O
to	O
complement	O
the	O
P7	B-GENE
mutations	I-GENE
.	O

GN101	O
,	O
YC819	O
-	O
9	O
,	O
and	O
SB3	O
.	O

Analysis	O
of	O
the	O
inferred	O
1	B-GENE
,	I-GENE
859	I-GENE
-	I-GENE
residue	I-GENE
ama	I-GENE
-	I-GENE
1	I-GENE
product	I-GENE
showed	O
considerable	O
identity	O
with	O
the	O
largest	O
subunit	O
of	O
RNAP	B-GENE
II	I-GENE
from	O
other	O
organisms	O
,	O
including	O
the	O
presence	O
of	O
a	O
zinc	O
finger	O
motif	O
near	O
the	O
amino	O
terminus	O
,	O
and	O
a	O
carboxyl	O
-	O
terminal	O
domain	O
of	O
42	O
tandemly	O
reiterated	O
heptamers	O
with	O
the	O
consensus	O
Tyr	O
Ser	O
Pro	O
Thr	O
Ser	O
Pro	O
Ser	O
.	O

5	O
.	O

None	O
of	O
the	O
measured	O
parameters	O
(	O
heart	O
contents	O
of	O
neutral	O
lipids	O
,	O
total	O
phospholipids	O
,	O
phosphatidylcholine	O
,	O
phosphatidylethanolamine	O
,	O
diphosphatidylglycerol	O
,	O
sphingomyelin	O
and	O
fatty	O
acid	O
composition	O
of	O
each	O
phospholipid	O
class	O
)	O
appeared	O
to	O
be	O
related	O
with	O
the	O
grading	O
of	O
the	O
lesions	O
.	O

Of	O
165	O
women	O
with	O
non	O
-	O
malignant	O
diagnoses	O
26	O
(	O
16	O
%	O
)	O
had	O
CA	B-GENE
125	I-GENE
levels	O
in	O
excess	O
of	O
35	O
U	O
/	O
ml	O
and	O
8	O
(	O
5	O
%	O
)	O
greater	O
than	O
65	O
U	O
/	O
ml	O
.	O

We	O
conclude	O
that	O
at	O
steady	O
state	O
the	O
timing	O
of	O
a	O
light	O
meal	O
is	O
unlikely	O
to	O
alter	O
in	O
any	O
clinically	O
important	O
manner	O
the	O
pharmacokinetics	O
of	O
nifedipine	O
released	O
from	O
'	O
biphasic	O
'	O
tablets	O
.	O

The	O
GALT	O
-	O
primed	O
calves	O
had	O
increased	O
serum	O
IgG	B-GENE
,	O
lavage	O
IgG	B-GENE
and	O
IgA	B-GENE
and	O
increased	O
LNA	B-GENE
titers	O
in	O
both	O
lavage	O
fluids	O
and	O
serum	O
following	O
the	O
SC	O
dose	O
of	O
killed	O
bacteria	O
.	O

Recent	O
investigations	O
have	O
shown	O
that	O
Grenz	O
rays	O
can	O
suppress	O
the	O
allergic	O
contact	O
dermatitis	O
reaction	O
completely	O
and	O
that	O
Langerhans	O
cells	O
,	O
identified	O
by	O
OKT6	B-GENE
antibodies	I-GENE
and	O
electron	O
microscopy	O
,	O
disappear	O
from	O
the	O
epidermis	O
at	O
the	O
same	O
time	O
.	O

The	O
elements	O
responsible	O
for	O
glucocorticoid	O
stimulation	O
of	O
ADH	B-GENE
gene	I-GENE
transcription	O
appear	O
to	O
reside	O
outside	O
of	O
this	O
region	O
.	O

1	O
.	O

The	O
present	O
studies	O
compare	O
the	O
biochemical	O
characteristics	O
,	O
Kanagawa	O
hemolysin	B-GENE
reactions	O
,	O
and	O
plasmid	O
profiles	O
of	O
13	O
patient	O
and	O
221	O
environmental	O
isolates	O
of	O
the	O
organism	O
.	O

High	O
values	O
of	O
both	O
retinol	O
and	O
beta	O
-	O
carotene	O
were	O
found	O
in	O
full	O
fat	O
cheeses	O
and	O
whipping	O
cream	O
:	O
from	O
179	O
.	O
0	O
(	O
cheese	O
,	O
Edam	O
-	O
type	O
)	O
to	O
318	O
.	O
7	O
micrograms	O
/	O
100	O
g	O
(	O
whipping	O
cream	O
)	O
and	O
from	O
86	O
.	O
7	O
(	O
cheese	O
,	O
Edam	O
-	O
type	O
)	O
to	O
186	O
.	O
5	O
micrograms	O
/	O
100	O
g	O
(	O
whipping	O
cream	O
)	O
for	O
all	O
-	O
trans	O
retinol	O
and	O
total	O
beta	O
-	O
carotene	O
,	O
respectively	O
.	O

COGLAB	O
includes	O
measures	O
of	O
preattentional	O
,	O
attentional	O
,	O
conceptual	O
,	O
and	O
psychomotor	O
performance	O
.	O

With	O
respect	O
to	O
effective	O
diffusivity	O
of	O
platelets	O
(	O
De	O
)	O
and	O
the	O
surface	O
reactivity	O
constant	O
(	O
K	O
)	O
,	O
less	O
significant	O
differences	O
were	O
found	O
among	O
artificial	O
materials	O
.	O

The	O
two	O
most	O
recent	O
patients	O
(	O
35	O
and	O
132	O
days	O
)	O
received	O
only	O
oral	O
dipyridamole	O
(	O
75	O
mg	O
X	O
3	O
/	O
day	O
)	O
and	O
aspirin	O
(	O
80	O
mg	O
/	O
day	O
)	O
after	O
the	O
early	O
recovery	O
period	O
(	O
four	O
-	O
six	O
days	O
)	O
,	O
resulting	O
in	O
normal	O
prothrombin	B-GENE
and	O
partial	O
thromboplastin	B-GENE
times	O
.	O

Middle	O
-	O
latency	O
auditory	O
evoked	O
potentials	O
(	O
MAEPs	O
)	O
were	O
recorded	O
in	O
controls	O
and	O
patients	O
with	O
focal	O
lesions	O
in	O
dorsolateral	O
prefrontal	O
cortex	O
.	O

Specifically	O
,	O
they	O
were	O
performed	O
to	O
determine	O
whether	O
detection	O
of	O
envelope	O
phase	O
disparity	O
was	O
consistent	O
with	O
processing	O
within	O
a	O
single	O
channel	O
in	O
which	O
the	O
AM	O
tones	O
were	O
simply	O
added	O
.	O

Gel	O
retardation	O
assays	O
combined	O
with	O
DNase	B-GENE
I	I-GENE
footprinting	O
and	O
diethyl	O
pyrocarbonate	O
interference	O
showed	O
that	O
a	O
nuclear	O
factor	O
from	O
differentiated	O
C2	O
myotubes	O
and	O
BC3H1	O
myocytes	O
recognized	O
a	O
conserved	O
A	O
+	O
T	O
-	O
rich	O
sequence	O
within	O
the	O
peripheral	O
activating	O
region	O
.	O

Such	O
transgenic	O
plants	O
should	O
enable	O
not	O
only	O
the	O
mutational	O
analysis	O
of	O
sequence	O
elements	O
within	O
the	O
replication	O
origin	O
region	O
,	O
but	O
also	O
the	O
construction	O
of	O
a	O
new	O
generation	O
of	O
vectors	O
for	O
gene	O
amplification	O
in	O
plants	O
,	O
based	O
on	O
a	O
minimal	O
virus	O
replicon	O
.	O

Ventral	O
rhinotomy	O
is	O
no	O
more	O
difficult	O
than	O
dorsal	O
rhinotomy	O
,	O
has	O
less	O
patient	O
morbidity	O
and	O
fewer	O
postoperative	O
complications	O
,	O
and	O
is	O
more	O
cosmetically	O
acceptable	O
.	O

Four	O
full	O
-	O
thickness	O
skin	O
incisions	O
were	O
made	O
in	O
the	O
back	O
of	O
10	O
female	O
pigs	O
that	O
treated	O
twice	O
a	O
day	O
for	O
14	O
days	O
with	O
2	O
ml	O
of	O
epidermal	B-GENE
growth	I-GENE
factor	I-GENE
(	O
300	O
ng	O
/	O
ml	O
)	O
or	O
2	O
ml	O
of	O
Ringer	O
'	O
s	O
lactate	O
solution	O
in	O
a	O
single	O
-	O
blind	O
,	O
randomized	O
fashion	O
.	O

During	O
challenge	O
,	O
rebiopsy	O
was	O
done	O
when	O
reticulin	B-GENE
antibodies	I-GENE
turned	O
positive	O
(	O
mean	O
0	O
.	O
6	O
years	O
,	O
range	O
0	O
.	O
2	O
-	O
2	O
.	O
0	O
)	O
or	O
at	O
the	O
end	O
of	O
the	O
two	O
year	O
study	O
.	O

The	O
effect	O
of	O
iron	O
intake	O
on	O
59Fe	O
absorption	O
throughout	O
pregnancy	O
,	O
and	O
on	O
maternal	O
and	O
fetal	O
Fe	O
status	O
towards	O
the	O
end	O
of	O
pregnancy	O
,	O
was	O
investigated	O
in	O
rats	O
.	O

The	O
deduced	O
protein	O
sequence	O
is	O
characterized	O
by	O
a	O
putative	O
16	O
-	O
residue	O
amino	O
-	O
terminal	O
signal	O
peptide	O
that	O
is	O
cleaved	O
,	O
resulting	O
in	O
a	O
239	O
-	O
residue	O
polypeptide	O
.	O

Analysis	O
of	O
the	O
rate	O
constants	O
indicated	O
that	O
the	O
isomerization	O
rate	O
k12	O
was	O
approximately	O
equal	O
to	O
the	O
apparent	O
degradation	O
rate	O
of	O
the	O
delta	O
3	O
ester	O
kdeg	O
,	O
and	O
slower	O
than	O
the	O
hydrolysis	O
rate	O
of	O
the	O
delta	O
2	O
ester	O
k24	O
.	O

A	O
protocol	O
is	O
elaborated	O
for	O
the	O
preparation	O
and	O
characterization	O
of	O
a	O
quality	O
control	O
material	O
(	O
QCM	O
)	O
containing	O
intrinsic	O
concentration	O
of	O
cadmium	O
(	O
Cd	O
)	O
(	O
0	O
.	O
8	O
microgram	O
/	O
L	O
)	O
and	O
lead	O
(	O
Pb	O
)	O
(	O
13	O
.	O
4	O
micrograms	O
/	O
dL	O
)	O
from	O
bovine	O
blood	O
and	O
an	O
elevated	O
QCM	O
containing	O
Cd	O
(	O
5	O
.	O
0	O
micrograms	O
/	O
L	O
)	O
,	O
mercury	O
(	O
Hg	O
)	O
(	O
11	O
.	O
2	O
micrograms	O
/	O
L	O
)	O
,	O
and	O
Pb	O
(	O
34	O
.	O
5	O
micrograms	O
/	O
dL	O
)	O
from	O
bovine	O
blood	O
spiked	O
with	O
aqueous	O
spiking	O
-	O
solutions	O
prepared	O
with	O
salts	O
of	O
Cd	O
,	O
Hg	O
,	O
and	O
Pb	O
.	O

Reagent	O
strips	O
are	O
frequently	O
used	O
in	O
the	O
practice	O
of	O
laboratory	O
medicine	O
as	O
well	O
as	O
outside	O
the	O
professional	O
laboratories	O
.	O

Precipitating	O
antibodies	O
for	O
Thermophilic	O
actinomycetes	O
and	O
M	O
.	O
f	O
.	O
were	O
negative	O
.	O

LON	O
-	O
72	O
(	O
34	O
isolates	O
)	O
,	O
LON	O
-	O
73	O
(	O
1	O
)	O
,	O
LON	O
-	O
71	O
(	O
2	O
)	O
and	O
LON	O
-	O
10	O
(	O
2	O
)	O
were	O
found	O
at	O
altitudes	O
around	O
2000	O
m	O
,	O
3	O
of	O
them	O
in	O
a	O
single	O
village	O
.	O

Animal	O
experimental	O
and	O
clinical	O
applications	O
of	O
plates	O
,	O
screws	O
and	O
spinal	O
segmental	O
replacement	O
implants	O
made	O
of	O
this	O
composite	O
material	O
have	O
shown	O
good	O
results	O
so	O
far	O
.	O

Significance	O
of	O
delta	O
-	O
aminolevulinic	O
acid	O
analysis	O
in	O
clinical	O
tests	O

No	O
changes	O
were	O
evident	O
in	O
the	O
FR	O
-	O
task	O
performance	O
of	O
controls	O
that	O
received	O
daily	O
saline	O
injections	O
.	O

Although	O
the	O
fertility	O
decline	O
in	O
the	O
black	O
population	O
in	O
the	O
Mississippi	O
Delta	O
between	O
the	O
late	O
1870	O
'	O
s	O
and	O
early	O
1930	O
'	O
s	O
closely	O
paralleled	O
that	O
of	O
the	O
national	O
black	O
population	O
,	O
it	O
rose	O
much	O
more	O
dramatically	O
in	O
the	O
1940	O
'	O
s	O
and	O
1950	O
'	O
s	O
to	O
almost	O
1880	O
levels	O
.	O

According	O
to	O
their	O
staining	O
affinity	O
for	O
anti	B-GENE
-	I-GENE
T	I-GENE
antibodies	I-GENE
,	O
the	O
glandular	O
tissue	O
cells	O
were	O
classified	O
as	O
T	B-GENE
-	O
,	O
T	B-GENE
+	O
,	O
T	B-GENE
+	O
+	O
,	O
and	O
T	B-GENE
and	O
the	O
annual	O
changes	O
in	O
the	O
numbers	O
of	O
these	O
cell	O
populations	O
,	O
as	O
well	O
as	O
in	O
the	O
volume	O
occupied	O
by	O
the	O
glandular	O
tissue	O
,	O
were	O
calculated	O
.	O

Ampicillin	O
(	O
AMP	O
)	O
alone	O
or	O
with	O
an	O
aminoglycoside	O
(	O
AMI	O
)	O
was	O
the	O
treatment	O
in	O
9	O
and	O
16	O
cases	O
,	O
respectively	O
.	O

Alkoxymetgyl	O
-	O
3	O
,	O
4	O
-	O
dimethylpyridinium	O
chlorides	O
were	O
synthetized	O
by	O
reacting	O
3	O
,	O
4	O
-	O
dimethylpyridine	O
with	O
chloromethyl	O
alkyl	O
ethers	O
,	O
while	O
1	O
-	O
ethyloxymethyl	O
-	O
3	O
-	O
alkylthiomethylimidazolium	O
chlorides	O
were	O
obtained	O
in	O
reactions	O
of	O
1	O
-	O
ethyloxymethylimidazol	O
with	O
chloromethyl	O
alkyl	O
sulfides	O
.	O

We	O
investigated	O
the	O
incidence	O
of	O
congenital	O
color	O
deficiency	O
among	O
Koreans	O
by	O
the	O
use	O
of	O
H	O
-	O
R	O
-	O
R	O
pseudoisochromatic	O
plates	O
.	O

Eighty	O
patients	O
presenting	O
to	O
HGGM	O
with	O
non	O
-	O
Hodgkin	O
'	O
s	O
lymphomas	O
between	O
1962	O
and	O
1986	O
,	O
were	O
reviewed	O
.	O

The	O
relation	O
between	O
VE	O
/	O
VO2	O
and	O
Q	O
/	O
VO2	O
showed	O
a	O
significant	O
negative	O
correlation	O
(	O
r	O
=	O
-	O
0	O
.	O
93	O
,	O
p	O
less	O
than	O
0	O
.	O
01	O
)	O
.	O

Retrograde	O
filling	O
consists	O
in	O
sealing	O
endodontics	O
system	O
directly	O
at	O
the	O
apical	O
zone	O
after	O
surgical	O
approach	O
.	O

Collaborative	O
study	O
of	O
Japanese	O
Pharmacopoeia	O
Heparin	O
Sodium	O
Reference	O
Standard	O

Serological	O
studies	O
at	O
the	O
early	O
relapse	O
stage	O
of	O
this	O
disease	O
showed	O
increased	O
serum	B-GENE
ANA	I-GENE
,	O
IgA	B-GENE
and	O
IgM	B-GENE
level	O
with	O
normal	O
IgG	B-GENE
and	O
decrease	O
of	O
C3	B-GENE
and	O
C4	B-GENE
.	O

The	O
maximum	O
stress	O
due	O
to	O
the	O
hygroscopic	O
examination	O
of	O
the	O
composite	O
was	O
0	O
.	O
74	O
kg	O
/	O
mm2	O
at	O
equilibrium	O
of	O
the	O
water	O
absorbed	O
of	O
the	O
composite	O
.	O

Ischemic	O
heart	O
disease	O
evaluated	O
by	O
exercise	O
stress	O
thallium	O
-	O
201	O
myocardial	O
scintigraphy	O
:	O
a	O
comparison	O
of	O
SPECT	O
and	O
bull	O
'	O
s	O
eye	O
display	O

Sequence	O
analysis	O
of	O
the	O
47	B-GENE
-	I-GENE
kilodalton	I-GENE
major	I-GENE
integral	I-GENE
membrane	I-GENE
immunogen	I-GENE
of	I-GENE
Treponema	I-GENE
pallidum	I-GENE
.	O

Potential	O
consensus	O
sequences	O
for	O
early	O
and	O
late	O
regulatory	O
elements	O
were	O
identified	O
.	O

Construction	O
of	O
a	O
RIP1	B-GENE
deletion	O
strain	O
and	O
isolation	O
of	O
temperature	O
-	O
sensitive	O
mutants	O
.	O

These	O
data	O
suggest	O
that	O
hypocitraturia	O
in	O
type	O
I	O
renal	O
tubular	O
acidosis	O
may	O
be	O
due	O
to	O
a	O
defect	O
in	O
proximal	O
tubule	O
function	O
.	O

Concomitant	O
chronic	O
lymphocytic	O
leukemia	O
,	O
acute	O
myeloid	O
leukemia	O
,	O
and	O
thrombosis	O
with	O
protein	B-GENE
C	I-GENE
deficiency	O
.	O

Vivid	O
visual	O
hallucinations	O
without	O
other	O
psychopathology	O
have	O
been	O
reported	O
for	O
several	O
hundred	O
years	O
.	O

In	O
the	O
whole	O
group	O
,	O
basal	O
GH	B-GENE
and	O
somatomedin	B-GENE
-	I-GENE
C	I-GENE
levels	O
decreased	O
from	O
a	O
mean	O
(	O
+	O
/	O
-	O
standard	O
error	O
of	O
the	O
mean	O
)	O
of	O
52	O
.	O
3	O
+	O
/	O
-	O
12	O
.	O
7	O
to	O
11	O
.	O
1	O
+	O
/	O
-	O
6	O
.	O
3	O
ng	O
/	O
ml	O
and	O
from	O
7	O
.	O
6	O
+	O
/	O
-	O
0	O
.	O
7	O
to	O
2	O
.	O
5	O
+	O
/	O
-	O
0	O
.	O
5	O
U	O
/	O
ml	O
,	O
respectively	O
.	O

Application	O
of	O
different	O
criteria	O
of	O
cure	O
revealed	O
that	O
19	O
patients	O
(	O
66	O
%	O
)	O
had	O
basal	O
GH	B-GENE
levels	O
below	O
5	O
ng	O
/	O
ml	O
,	O
17	O
patients	O
(	O
59	O
%	O
)	O
had	O
normal	O
somatomedin	B-GENE
-	I-GENE
C	I-GENE
values	O
,	O
16	O
patients	O
(	O
55	O
%	O
)	O
had	O
complete	O
GH	B-GENE
suppression	O
(	O
less	O
than	O
1	O
ng	O
/	O
ml	O
)	O
during	O
OGTT	O
,	O
and	O
13	O
patients	O
(	O
45	O
%	O
)	O
met	O
the	O
above	O
-	O
mentioned	O
criteria	O
with	O
disappearance	O
of	O
the	O
paradoxical	O
GH	B-GENE
response	O
to	O
TRH	B-GENE
/	O
GnRH	B-GENE
test	O
.	O

It	O
suggests	O
a	O
sequence	O
of	O
surgical	O
planning	O
that	O
can	O
prevent	O
them	O
and	O
also	O
offers	O
ways	O
of	O
dealing	O
with	O
the	O
problems	O
should	O
they	O
occur	O
.	O

In	O
Rat	O
-	O
1a	O
cells	O
the	O
expression	O
of	O
human	B-GENE
c	I-GENE
-	I-GENE
jun	I-GENE
mRNA	I-GENE
was	O
associated	O
with	O
the	O
ability	O
to	O
clone	O
in	O
soft	O
agarose	O
and	O
form	O
tumors	O
in	O
nude	O
mice	O
.	O

Furthermore	O
,	O
formation	O
of	O
foci	O
of	O
transformed	O
RECs	O
by	O
the	O
c	B-GENE
-	I-GENE
jun	I-GENE
/	O
ras	B-GENE
combination	O
was	O
augmented	O
3	O
-	O
fold	O
by	O
the	O
tumor	O
promoter	O
phorbol	O
12	O
-	O
tetradecanoate	O
13	O
-	O
acetate	O
.	O

Platelet	B-GENE
activating	I-GENE
factor	I-GENE
was	O
given	O
in	O
six	O
doses	O
at	O
15	O
minute	O
intervals	O
and	O
airway	O
response	O
measured	O
as	O
change	O
in	O
partial	O
expiratory	O
flow	O
at	O
30	O
%	O
of	O
vital	O
capacity	O
(	O
Vp30	O
)	O
.	O

There	O
was	O
no	O
significant	O
correlation	O
between	O
baseline	O
PC40	O
methacholine	O
and	O
the	O
maximal	O
fall	O
in	O
Vp30	O
after	O
either	O
the	O
first	O
(	O
12	O
micrograms	O
)	O
or	O
the	O
second	O
dose	O
(	O
24	O
micrograms	O
)	O
of	O
platelet	B-GENE
activating	I-GENE
factor	I-GENE
.	O

Both	O
BG	O
and	O
IRI	B-GENE
concentrations	O
during	O
the	O
OGTT	O
were	O
the	O
lowest	O
in	O
body	O
builders	O
,	O
medium	O
in	O
controls	O
,	O
and	O
the	O
highest	O
in	O
obese	O
men	O
.	O

Although	O
it	O
is	O
well	O
known	O
that	O
calcium	O
channel	O
blockers	O
can	O
influence	O
contraction	O
of	O
vascular	O
smooth	O
muscle	O
,	O
there	O
is	O
less	O
knowledge	O
on	O
its	O
effect	O
on	O
excitation	O
contraction	O
coupling	O
in	O
the	O
endocrine	O
glands	O
and	O
more	O
specifically	O
on	O
insulin	B-GENE
and	O
glucagon	B-GENE
release	O
.	O

Many	O
studies	O
have	O
pointed	O
out	O
the	O
possibility	O
of	O
"	O
masked	O
"	O
organic	O
factors	O
in	O
erectile	O
impotence	O
,	O
detectable	O
only	O
by	O
means	O
of	O
laboratory	O
investigations	O
:	O
mild	O
hypogonadism	O
,	O
hyperprolactinemia	O
,	O
occlusions	O
selectively	O
located	O
at	O
the	O
site	O
of	O
the	O
sexual	O
arteries	O
,	O
venous	O
incompetence	O
,	O
subclinical	O
neuropathies	O
.	O

The	O
site	O
-	O
specific	O
DNA	O
inversion	O
system	O
Cin	B-GENE
encoded	O
by	O
the	O
bacteriophage	O
P1	O
consists	O
of	O
a	O
recombinase	B-GENE
,	O
two	O
inverted	O
crossing	O
-	O
over	O
sites	O
and	O
a	O
recombinational	O
enhancer	O
.	O

The	O
terminator	O
region	O
supported	O
termination	O
of	O
transcripts	O
initiated	O
by	O
RNA	B-GENE
polymerase	I-GENE
I	I-GENE
in	O
vivo	O
.	O

US	O
-	O
Doppler	O
has	O
recently	O
gained	O
attention	O
as	O
a	O
noninvasive	O
method	O
for	O
the	O
functional	O
evaluation	O
of	O
arteriovenous	O
fistulas	O
(	O
FAV	O
)	O
.	O

Doppler	O
echo	O
in	O
evaluating	O
arteriovenous	O
fistulae	O
for	O
dialysis	O

Following	O
the	O
patients	O
during	O
a	O
course	O
of	O
therapy	O
with	O
a	O
selective	O
vasodilator	O
calcium	O
antagonist	O
,	O
the	O
beta	O
-	O
adrenergic	O
reflex	O
vasodilation	O
became	O
substantially	O
attenuated	O
but	O
was	O
preserved	O
during	O
a	O
placebo	O
course	O
of	O
therapy	O
.	O

Of	O
110	O
previously	O
untreated	O
patients	O
who	O
had	O
entered	O
the	O
study	O
of	O
protocol	O
TCL821	O
,	O
96	O
were	O
evaluable	O
.	O

There	O
were	O
3	O
/	O
32	O
(	O
9	O
.	O
4	O
per	O
cent	O
)	O
adverse	O
reactions	O
(	O
ADRs	O
)	O
,	O
and	O
one	O
case	O
each	O
of	O
nausea	O
,	O
dizziness	O
and	O
increased	O
menstrual	O
flow	O
.	O

More	O
mRNA	O
corresponding	O
to	O
nagB	B-GENE
and	O
nagA	B-GENE
is	O
detected	O
than	O
that	O
corresponding	O
to	O
the	O
distal	O
genes	O
,	O
nagC	B-GENE
and	O
nagD	B-GENE
.	O

Tumor	B-GENE
necrosis	I-GENE
factor	I-GENE
(	O
TNF	B-GENE
)	O
is	O
reported	O
to	O
cause	O
a	O
shock	O
syndrome	O
similar	O
to	O
that	O
produced	O
by	O
endotoxin	O
(	O
LPS	O
)	O
.	O

The	O
p34	B-GENE
.	I-GENE
8	I-GENE
gene	I-GENE
has	O
a	O
strong	O
codon	O
usage	O
bias	O
which	O
is	O
strikingly	O
different	O
from	O
that	O
of	O
the	O
polyhedrin	B-GENE
gene	I-GENE
.	O

Of	O
the	O
single	O
-	O
stranded	O
DNA	O
transformants	O
,	O
65	O
%	O
resulted	O
from	O
replacement	O
of	O
the	O
resident	O
met2	B-GENE
mutation	I-GENE
by	O
the	O
exogenous	O
wild	O
-	O
type	O
allele	O
.	O

The	O
results	O
strongly	O
support	O
the	O
notion	O
that	O
the	O
OBF1	B-GENE
-	I-GENE
binding	I-GENE
sites	I-GENE
and	O
the	O
OBF1	B-GENE
protein	I-GENE
are	O
important	O
for	O
normal	O
ARS	O
function	O
as	O
an	O
origin	O
of	O
replication	O
.	O

On	O
the	O
basis	O
of	O
S1	B-GENE
nuclease	I-GENE
protection	O
analysis	O
of	O
RNA	O
preparations	O
from	O
several	O
mouse	O
tissues	O
,	O
both	O
dhfr	B-GENE
and	O
divergent	O
genes	O
showed	O
similar	O
levels	O
of	O
expression	O
but	O
did	O
show	O
some	O
specificity	O
in	O
start	O
site	O
utilization	O
.	O

Four	O
out	O
of	O
10	O
patients	O
showed	O
clinical	O
improvement	O
according	O
to	O
Ritchie	O
-	O
Index	O
,	O
pain	O
score	O
,	O
ESR	O
and	O
CRP	B-GENE
.	O

62	O
:	O
2491	O
-	O
2499	O
,	O
1987	O
)	O
.	O

Survival	O
rates	O
for	O
the	O
original	O
treatment	O
group	O
were	O
84	O
.	O
5	O
%	O
and	O
57	O
.	O
6	O
%	O
at	O
12	O
and	O
21	O
months	O
,	O
respectively	O
;	O
for	O
the	O
delayed	O
treatment	O
group	O
,	O
78	O
.	O
8	O
%	O
and	O
64	O
.	O
6	O
%	O
at	O
12	O
and	O
21	O
months	O
,	O
respectively	O
,	O
and	O
78	O
.	O
8	O
%	O
and	O
47	O
.	O
5	O
%	O
at	O
12	O
and	O
21	O
months	O
,	O
respectively	O
,	O
for	O
77	O
subjects	O
with	O
AIDS	O
and	O
93	O
.	O
0	O
%	O
and	O
71	O
.	O
8	O
%	O
,	O
respectively	O
,	O
for	O
50	O
subjects	O
with	O
AIDS	O
-	O
related	O
complex	O
in	O
the	O
original	O
treatment	O
group	O
.	O

The	O
products	O
of	O
genes	O
ura10	B-GENE
and	O
ura3	B-GENE
are	O
proposed	O
to	O
participate	O
in	O
the	O
channeling	O
of	O
orotidine	O
monophosphate	O
.	O

After	O
the	O
application	O
of	O
RS	O
86	O
,	O
REM	O
latency	O
was	O
shortened	O
in	O
all	O
groups	O
under	O
investigation	O
.	O

Hybridization	O
analysis	O
showed	O
that	O
the	O
size	O
of	O
the	O
mRNA	O
is	O
about	O
1	O
.	O
4	O
kilobases	O
.	O

Agranulocytosis	O
treatment	O
with	O
rhGM	B-GENE
-	I-GENE
CSF	I-GENE

The	O
R	B-GENE
.	I-GENE
meliloti	I-GENE
nifH	I-GENE
promoter	I-GENE
but	O
not	O
the	O
K	B-GENE
.	I-GENE
pneumoniae	I-GENE
nifH	I-GENE
promoter	I-GENE
showed	O
sigma	B-GENE
54	I-GENE
-	O
dependent	O
methylation	O
protection	O
of	O
guanine	O
residues	O
at	O
-	O
14	O
,	O
-	O
25	O
and	O
-	O
26	O
,	O
the	O
most	O
conserved	O
nucleotides	O
characteristic	O
of	O
sigma	B-GENE
54	I-GENE
-	I-GENE
dependent	I-GENE
promoters	I-GENE
.	O

Major	O
clinical	O
symptoms	O
of	O
the	O
disease	O
were	O
defined	O
in	O
this	O
group	O
of	O
patients	O
.	O

Routine	O
clinical	O
analysis	O
revealed	O
lower	O
hematocrit	O
and	O
hemoglobin	B-GENE
,	O
and	O
elevated	O
BUN	O
and	O
alkaline	B-GENE
phosphatase	I-GENE
in	O
the	O
treated	O
group	O
.	O

To	O
assess	O
the	O
health	O
significance	O
of	O
the	O
early	O
renal	O
changes	O
after	O
chronic	O
exposure	O
to	O
cadmium	O
,	O
23	O
workers	O
removed	O
from	O
exposure	O
because	O
of	O
the	O
discovery	O
of	O
an	O
increased	O
urinary	O
excretion	O
of	O
beta	B-GENE
2	I-GENE
-	I-GENE
microglobulin	I-GENE
or	O
retinol	B-GENE
binding	I-GENE
protein	I-GENE
,	O
or	O
both	O
,	O
have	O
been	O
examined	O
once	O
a	O
year	O
for	O
five	O
years	O
.	O

In	O
order	O
to	O
study	O
the	O
structural	O
and	O
functional	O
organization	O
of	O
the	O
eukaryotic	O
nucleolus	O
,	O
we	O
have	O
started	O
to	O
isolate	O
and	O
characterize	O
nucleolar	O
components	O
of	O
the	O
yeast	O
Saccharomyces	O
cerevisiae	O
.	O

A	O
transcription	O
factor	O
exclusion	O
assay	O
was	O
used	O
to	O
show	O
that	O
the	O
PCF1	B-GENE
mutation	I-GENE
affects	O
two	O
distinct	O
stages	O
in	O
transcription	O
:	O
one	O
prior	O
to	O
and	O
one	O
after	O
stable	O
complex	O
formation	O
;	O
and	O
that	O
these	O
effects	O
are	O
mediated	O
by	O
a	O
component	O
of	O
the	O
stable	O
complex	O
.	O

Psychiatry	O
and	O
the	O
skin	O
.	O

These	O
adverse	O
effects	O
usually	O
abate	O
with	O
time	O
.	O

The	O
cytosolic	O
glutathione	B-GENE
S	I-GENE
-	I-GENE
transferases	I-GENE
(	O
GSTs	B-GENE
,	O
EC	B-GENE
2	I-GENE
.	I-GENE
5	I-GENE
.	I-GENE
1	I-GENE
.	I-GENE
18	I-GENE
)	O
are	O
a	O
superfamily	O
of	O
dimeric	O
isoenzymes	O
which	O
catalyze	O
the	O
conjugation	O
of	O
electrophilic	O
substrates	O
with	O
glutathione	O
.	O

Furthermore	O
,	O
the	O
3	O
'	O
-	O
untranslated	O
regions	O
of	O
pmGT10	B-GENE
display	O
a	O
marked	O
degree	O
of	O
homology	O
to	O
the	O
3	O
'	O
region	O
of	O
the	O
rat	B-GENE
Yb1	I-GENE
gene	I-GENE
,	O
while	O
this	O
region	O
of	O
pmGT2	B-GENE
displays	O
marked	O
homology	O
to	O
the	O
corresponding	O
region	O
of	O
the	O
rat	B-GENE
Yb2	I-GENE
gene	I-GENE
.	O

Model	O
IV	O
:	O
primary	O
abutments	O
with	O
the	O
lateral	O
incisor	O
and	O
the	O
second	O
molar	O
as	O
secondary	O
abutments	O
.	O

The	O
incidence	O
of	O
fetal	O
breathing	O
movements	O
(	O
06	O
.	O
00	O
-	O
10	O
.	O
00	O
h	O
)	O
decreased	O
with	O
increasing	O
gestational	O
age	O
while	O
fetal	O
arterial	O
concentrations	O
of	O
plasma	O
PGE	O
increased	O
significantly	O
over	O
the	O
same	O
period	O
of	O
gestation	O
.	O

During	O
the	O
first	O
3	O
min	O
of	O
recovery	O
,	O
plasma	O
potassium	O
fell	O
rapidly	O
in	O
spite	O
of	O
nearly	O
unchanged	O
blood	O
acidosis	O
and	O
significantly	O
decreasing	O
bicarbonate	O
concentration	O
.	O

The	O
present	O
data	O
also	O
suggest	O
that	O
when	O
compared	O
to	O
the	O
systemic	O
vascular	O
bed	O
,	O
the	O
pulmonary	O
vascular	O
bed	O
is	O
less	O
responsive	O
to	O
bolus	O
administration	O
of	O
ET	B-GENE
-	I-GENE
1	I-GENE
.	O

In	O
comparison	O
with	O
normal	O
pregnant	O
women	O
and	O
normal	O
non	O
-	O
pregnant	O
women	O
,	O
women	O
with	O
PIH	O
showed	O
an	O
increase	O
in	O
heart	O
rate	O
,	O
suggesting	O
an	O
increased	O
peripheral	O
sympathetic	O
tone	O
,	O
and	O
an	O
initial	O
derangement	O
in	O
renal	O
function	O
as	O
shown	O
by	O
the	O
increase	O
in	O
serum	O
uric	O
acid	O
and	O
reduction	O
in	O
sodium	O
excretion	O
and	O
total	O
and	O
fractional	O
calcium	O
excretion	O
at	O
any	O
given	O
level	O
of	O
sodium	O
excretion	O
.	O

We	O
have	O
examined	O
the	O
role	O
of	O
two	O
recombination	O
-	O
and	O
repair	O
-	O
defective	O
mutations	O
,	O
rad1	B-GENE
and	O
rad52	B-GENE
,	O
on	O
direct	O
repeat	O
recombination	O
in	O
transcriptionally	O
active	O
and	O
inactive	O
sequences	O
.	O

The	O
encoded	O
protein	O
has	O
a	O
leader	O
sequence	O
of	O
27	O
amino	O
acids	O
.	O

On	O
the	O
other	O
hand	O
,	O
knowledge	O
of	O
the	O
epidemiology	O
of	O
Parkinson	O
'	O
s	O
disease	O
is	O
necessary	O
in	O
creating	O
etiological	O
hypotheses	O
,	O
since	O
only	O
hypotheses	O
consistent	O
with	O
the	O
epidemiological	O
profile	O
deserve	O
careful	O
testing	O
.	O

The	O
stereoselectivity	O
of	O
drug	O
action	O
.	O

Scotchbond	O
2	O
showed	O
the	O
least	O
dye	O
penetration	O
but	O
not	O
statistically	O
less	O
than	O
the	O
XR	O
bond	O
/	O
Silus	O
Plus	O
combination	O
.	O

A	O
combination	O
of	O
cisplatin	O
and	O
5	O
-	O
fluorouracil	O
,	O
both	O
administered	O
4	O
days	O
continuously	O
as	O
infusion	O
,	O
was	O
assessed	O
in	O
advanced	O
head	O
and	O
neck	O
cancer	O
.	O

Diagnosis	O
of	O
primary	O
sclerosing	O
cholangitis	O
in	O
a	O
blood	O
donor	O
with	O
elevated	O
serum	B-GENE
alanine	I-GENE
aminotransferase	I-GENE
.	O

When	O
statistically	O
analyzed	O
in	O
various	O
subgroupings	O
,	O
the	O
obtained	O
average	O
sedimentation	O
coefficients	O
and	O
polydispersity	O
profiles	O
supported	O
the	O
following	O
conclusions	O
:	O
(	O
a	O
)	O
loss	O
of	O
proteoglycan	O
aggregation	O
and	O
sedimentability	O
is	O
confirmed	O
to	O
be	O
a	O
primary	O
sign	O
of	O
cartilage	O
matrix	O
degradation	O
;	O
(	O
b	O
)	O
higher	O
S	O
values	O
for	O
proteoglycans	O
of	O
the	O
high	O
weight	O
(	O
HW	O
)	O
-	O
bearing	O
areas	O
and	O
lower	O
values	O
for	O
those	O
of	O
the	O
low	O
weight	O
(	O
LW	O
)	O
-	O
bearing	O
areas	O
were	O
a	O
typical	O
finding	O
in	O
normal	O
cartilage	O
samples	O
;	O
(	O
c	O
)	O
inversion	O
of	O
this	O
pattern	O
was	O
indicative	O
of	O
matrix	O
degradation	O
,	O
suggesting	O
that	O
the	O
HW	O
regions	O
are	O
more	O
affected	O
than	O
the	O
LW	O
-	O
bearing	O
areas	O
;	O
(	O
d	O
)	O
the	O
average	O
S	O
value	O
distribution	O
across	O
cartilage	O
thickness	O
tended	O
to	O
resemble	O
the	O
corresponding	O
proteoglycan	O
content	O
versus	O
distance	O
from	O
articular	O
surface	O
;	O
and	O
(	O
e	O
)	O
the	O
deepest	O
cartilage	O
layer	O
had	O
,	O
in	O
most	O
cases	O
,	O
the	O
smallest	O
amount	O
of	O
aggregates	O
while	O
the	O
highest	O
average	O
sedimentability	O
was	O
observed	O
at	O
the	O
middle	O
zone	O
of	O
the	O
normal	O
samples	O
.	O

End	O
points	O
measured	O
were	O
perioperative	O
(	O
30	O
-	O
day	O
)	O
myocardial	O
infarction	O
(	O
MI	O
)	O
rate	O
and	O
death	O
.	O

The	O
predicted	O
molecular	O
weight	O
of	O
the	O
polyprotein	O
encoded	O
by	O
ORF1	O
is	O
33	O
kilodaltons	O
(	O
kDa	O
)	O
.	O

Thus	O
RV	O
O2	O
demand	O
fell	O
when	O
RC	O
O2	O
supply	O
was	O
reduced	O
,	O
although	O
a	O
flow	O
reserve	O
was	O
available	O
.	O

An	O
alternative	O
method	O
of	O
UKM	O
is	O
proposed	O
based	O
on	O
collecting	O
a	O
small	O
fraction	O
of	O
spent	O
dialysate	O
flow	O
for	O
3	O
consecutive	O
dialyses	O
.	O

Primer	O
extension	O
experiments	O
indicated	O
that	O
the	O
transcription	O
initiation	O
site	O
mapped	O
to	O
a	O
position	O
on	O
gene	B-GENE
IV	I-GENE
that	O
was	O
analogous	O
to	O
that	O
reported	O
for	O
the	O
structurally	O
similar	O
P	B-GENE
-	I-GENE
450e	I-GENE
gene	I-GENE
.	O

Significantly	O
,	O
the	O
polymerase	O
chain	O
reaction	O
results	O
demonstrated	O
that	O
gene	B-GENE
IV	I-GENE
transcripts	I-GENE
were	O
associated	O
with	O
hepatic	O
polysome	O
fractions	O
,	O
indicating	O
their	O
active	O
utilization	O
in	O
this	O
tissue	O
.	O

Validation	O
of	O
the	O
survey	O
of	O
work	O
styles	O
:	O
a	O
profile	O
measure	O
of	O
the	O
type	O
A	O
behaviour	O
pattern	O
.	O

Only	O
one	O
ADR	O
was	O
related	O
definitely	O
to	O
ciprofloxacin	O
therapy	O
.	O

HIV	O
infectiousness	O
and	O
the	O
AIDS	O
epidemic	O
.	O

From	O
day	O
30	O
after	O
turnout	O
,	O
the	O
PFB	O
-	O
group	O
had	O
significantly	O
lower	O
serum	B-GENE
pepsinogen	I-GENE
levels	O
,	O
which	O
reflects	O
the	O
low	O
degree	O
of	O
abomasal	O
damage	O
in	O
these	O
animals	O
.	O

The	O
corresponding	O
inhibition	O
of	O
acid	B-GENE
phosphatase	I-GENE
activity	O
in	O
control	O
male	O
and	O
female	O
guinea	O
pigs	O
was	O
15	O
.	O
91	O
%	O
and	O
20	O
.	O
33	O
%	O
respectively	O
.	O

Its	O
clinical	O
and	O
histopathologic	O
characteristics	O
.	O

Normocapnic	O
(	O
PACO2	O
=	O
40	O
mm	O
Hg	O
)	O
ventilatory	O
drive	O
increased	O
significantly	O
(	O
p	O
less	O
than	O
0	O
.	O
05	O
)	O
in	O
six	O
subjects	O
(	O
Type	O
1	O
response	O
)	O
and	O
decreased	O
substantially	O
in	O
the	O
others	O
(	O
Type	O
2	O
response	O
)	O
;	O
with	O
hypercapnia	O
,	O
the	O
changes	O
in	O
drive	O
were	O
attenuated	O
in	O
both	O
groups	O
.	O

Fundus	O
changes	O
in	O
(	O
type	O
II	O
)	O
mesangiocapillary	O
glomerulonephritis	O
simulating	O
drusen	O
:	O
a	O
histopathological	O
report	O
.	O

Chronic	O
dose	O
effects	O
of	O
methyl	O
parathion	O
on	O
nuthatches	O
:	O
cholinesterase	B-GENE
and	O
ptilochronology	O
.	O

Allelic	O
variation	O
in	O
HLA	B-GENE
-	I-GENE
B	I-GENE
and	O
HLA	B-GENE
-	I-GENE
C	I-GENE
sequences	I-GENE
and	O
the	O
evolution	O
of	O
the	O
HLA	B-GENE
-	I-GENE
B	I-GENE
alleles	I-GENE
.	O

A	O
method	O
for	O
determining	O
optimal	O
development	O
conditions	O
by	O
summary	O
oxygen	O
consumption	O

Men	O
were	O
more	O
positive	O
about	O
their	O
physical	O
fitness	O
than	O
women	O
.	O

Handgrip	O
dynamometry	O
was	O
also	O
carried	O
out	O
in	O
249	O
of	O
the	O
patients	O
.	O

In	O
cerebrospinal	O
fluid	O
,	O
an	O
ADA	B-GENE
catalytic	O
concentration	O
above	O
0	O
.	O
15	O
mu	O
kat	O
/	O
L	O
strongly	O
suggests	O
tuberculous	O
meningitis	O
in	O
patients	O
older	O
than	O
7	O
years	O
(	O
sensitivity	O
1	O
.	O
00	O
,	O
specificity	O
0	O
.	O
99	O
and	O
efficiency	O
0	O
.	O
99	O
)	O
.	O

NERVTRACK	O
contains	O
4000	O
anatomical	O
data	O
items	O
arranged	O
in	O
a	O
tree	O
-	O
like	O
manner	O
reflecting	O
structural	O
and	O
functional	O
relationships	O
.	O

Perfusion	O
washout	O
:	O
increasing	O
a	O
microvascular	O
free	O
flap	O
tolerance	O
to	O
ischemia	O
.	O

Similarly	O
,	O
the	O
sequence	O
of	O
the	O
U2	B-GENE
RNA	I-GENE
region	I-GENE
shown	O
to	O
be	O
involved	O
in	O
pre	O
-	O
mRNA	O
branchpoint	O
recognition	O
in	O
yeast	O
,	O
and	O
exactly	O
conserved	O
in	O
metazoan	B-GENE
U2	I-GENE
RNAs	I-GENE
,	O
was	O
totally	O
divergent	O
in	O
trypanosomes	O
.	O

It	O
is	O
striking	O
that	O
the	O
active	O
CHO	O
spacer	O
promoter	O
violated	O
the	O
otherwise	O
universal	O
rule	O
that	O
metazoan	B-GENE
RNA	I-GENE
polymerase	I-GENE
I	I-GENE
promoters	I-GENE
all	O
have	O
a	O
G	O
residue	O
at	O
position	O
-	O
16	O
.	O

Significant	O
intergroup	O
differences	O
are	O
highlighted	O
for	O
both	O
selected	O
dentoskeletal	O
and	O
soft	O
tissue	O
profile	O
variables	O
.	O

The	O
author	O
provides	O
a	O
rationale	O
for	O
an	O
interactional	O
view	O
and	O
presents	O
a	O
case	O
in	O
which	O
post	O
-	O
surgical	O
hiccups	O
were	O
successfully	O
treated	O
,	O
using	O
principles	O
developed	O
by	O
the	O
Mental	O
Research	O
Institute	O
.	O

The	O
relative	O
toxicity	O
of	O
nickel	O
oxide	O
(	O
NiO	O
)	O
,	O
nickel	O
sulfate	O
hexahydrate	O
(	O
NiSO4	O
.	O
6H2O	O
)	O
,	O
and	O
nickel	O
subsulfide	O
(	O
Ni3S2	O
)	O
was	O
studied	O
in	O
F344	O
/	O
N	O
rats	O
and	O
B6C3F1	O
mice	O
after	O
inhalation	O
exposure	O
for	O
6	O
hr	O
/	O
day	O
,	O
5	O
days	O
/	O
week	O
,	O
for	O
13	O
weeks	O
.	O

Light	O
microscopical	O
and	O
routine	O
immunohistochemical	O
studies	O
of	O
a	O
cervical	O
neoplasm	O
in	O
a	O
32	O
year	O
old	O
woman	O
initially	O
suggested	O
a	O
histiocytic	O
lymphoma	O
,	O
but	O
histochemical	O
staining	O
for	O
chloroacetate	B-GENE
esterase	I-GENE
established	O
the	O
correct	O
diagnosis	O
.	O

From	O
the	O
National	O
Institutes	O
of	O
Health	O
.	O

Molecular	O
cloning	O
and	O
characterisation	O
of	O
the	O
two	O
homologous	O
genes	O
coding	O
for	O
nitrate	B-GENE
reductase	I-GENE
in	I-GENE
tobacco	I-GENE
.	O

In	O
the	O
final	O
model	O
,	O
grade	O
(	O
p	O
=	O
0	O
.	O
0002	O
)	O
,	O
peritoneal	O
cytologic	O
results	O
(	O
p	O
=	O
0	O
.	O
0002	O
)	O
,	O
progesterone	B-GENE
receptor	I-GENE
status	O
(	O
p	O
=	O
0	O
.	O
004	O
)	O
,	O
and	O
age	O
as	O
a	O
continuous	O
variable	O
(	O
p	O
=	O
0	O
.	O
008	O
)	O
were	O
most	O
closely	O
associated	O
with	O
disease	O
-	O
free	O
survival	O
.	O

In	O
contrast	O
,	O
despite	O
external	O
radiation	O
therapy	O
,	O
brain	O
metastases	O
proved	O
fatal	O
.	O

COUP	B-GENE
transcription	I-GENE
factor	I-GENE
is	O
a	O
member	O
of	O
the	O
steroid	B-GENE
receptor	I-GENE
superfamily	I-GENE
.	O

Cosmid	O
clones	O
containing	O
both	O
VNTR	O
sequences	O
were	O
identified	O
,	O
and	O
restriction	O
mapping	O
showed	O
them	O
to	O
be	O
less	O
than	O
15	O
kb	O
apart	O
.	O

The	O
oxygen	O
uptake	O
(	O
VO2	O
)	O
,	O
carbon	O
dioxide	O
output	O
(	O
VCO2	O
)	O
,	O
respiratory	O
rate	O
(	O
fR	O
)	O
,	O
minute	O
ventilation	O
(	O
VE	O
)	O
,	O
alveolar	O
ventilation	O
(	O
VA	O
)	O
,	O
alveolar	O
oxygen	O
pressure	O
(	O
PAO2	O
)	O
,	O
and	O
VE	O
/	O
VO2	O
ratio	O
were	O
higher	O
in	O
the	O
cows	O
,	O
while	O
the	O
tidal	O
volume	O
(	O
VT	O
)	O
and	O
physiological	O
dead	O
space	O
(	O
VD	O
)	O
were	O
larger	O
in	O
the	O
horses	O
.	O

Epithelial	O
damage	O
was	O
not	O
observed	O
in	O
any	O
controls	O
but	O
was	O
in	O
all	O
tissues	O
exposed	O
to	O
SO2	O
.	O

The	O
present	O
study	O
investigates	O
whether	O
prostaglandins	O
"	O
cytoprotect	O
"	O
the	O
gastric	O
mucosa	O
against	O
hemorrhage	O
-	O
induced	O
stress	O
ulceration	O
by	O
assessing	O
the	O
influence	O
of	O
16	O
,	O
16	O
-	O
dimethyl	O
prostaglandin	O
E2	O
(	O
16	O
,	O
16	O
-	O
dm	O
PGE2	O
)	O
on	O
gross	O
and	O
microscopic	O
lesion	O
formation	O
,	O
intramucosal	O
tissue	O
pH	O
,	O
H	O
+	O
back	O
-	O
diffusion	O
,	O
and	O
mucosal	O
blood	O
flow	O
in	O
rat	O
gastric	O
mucosa	O
exposed	O
to	O
luminal	O
acid	O
(	O
100	O
mM	O
HCl	O
)	O
during	O
hemorrhagic	O
shock	O
(	O
13	O
ml	O
/	O
kg	O
for	O
20	O
min	O
)	O
.	O

Transcripts	O
characterized	O
include	O
(	O
i	O
)	O
abundant	O
monocistronic	O
L11e	B-GENE
and	O
tricistronic	O
L1e	B-GENE
-	O
L10e	B-GENE
-	O
L12e	B-GENE
transcripts	O
;	O
(	O
ii	O
)	O
less	O
abundant	O
bicistronic	O
NAB	B-GENE
-	O
L11e	B-GENE
and	O
monocistronic	O
NAB	B-GENE
transcripts	I-GENE
and	O
(	O
iii	O
)	O
a	O
very	O
rare	O
ORF	O
monocistronic	O
transcript	O
.	O

Qualitatively	O
,	O
the	O
results	O
are	O
similar	O
for	O
the	O
two	O
species	O
:	O
Both	O
rhesus	O
monkey	O
and	O
man	O
have	O
photopic	O
and	O
scotopic	O
branches	O
,	O
which	O
cross	O
at	O
approximately	O
the	O
same	O
time	O
in	O
the	O
dark	O
and	O
at	O
approximately	O
the	O
same	O
background	O
luminance	O
.	O

At	O
each	O
level	O
of	O
PaO2	O
we	O
obtained	O
simultaneous	O
measures	O
of	O
arterial	O
and	O
venous	O
blood	O
gases	O
,	O
venous	O
lactate	O
concentration	O
,	O
and	O
changes	O
in	O
the	O
relative	O
concentrations	O
of	O
inorganic	O
phosphate	O
,	O
phosphocreatine	O
,	O
and	O
ATP	O
measured	O
with	O
31P	O
magnetic	O
resonance	O
spectroscopy	O
.	O

Endometrial	O
biopsies	O
and	O
plasma	O
oestradiol	O
(	O
E2	O
)	O
and	O
progesterone	O
(	O
P4	O
)	O
levels	O
in	O
23	O
patients	O
were	O
evaluated	O
during	O
26	O
replacement	O
therapy	O
cycles	O
for	O
premature	O
ovarian	O
failure	O
.	O

The	O
mobility	O
of	O
the	O
upper	O
and	O
lower	O
premolars	O
under	O
load	O
was	O
investigated	O
in	O
relation	O
to	O
the	O
interproximal	O
contact	O
and	O
occlusal	O
facets	O
.	O

This	O
suggested	O
that	O
baboon	B-GENE
liver	I-GENE
class	I-GENE
I	I-GENE
ADH	I-GENE
is	O
of	O
the	O
same	O
ancestral	O
lineage	O
as	O
the	O
human	B-GENE
ADH	I-GENE
-	I-GENE
beta	I-GENE
.	O

Each	O
individual	O
shot	O
25	O
bullets	O
in	O
about	O
5	O
minutes	O
,	O
at	O
an	O
intensity	O
level	O
calculated	O
at	O
163	O
dB	O
.	O

Dynamic	O
and	O
static	O
scintigrams	O
,	O
using	O
99mtechnetium	O
methylene	O
diphosphonate	O
,	O
were	O
obtained	O
at	O
zero	O
,	O
six	O
,	O
and	O
12	O
weeks	O
after	O
fracture	O
.	O

On	O
admission	O
to	O
our	O
department	O
in	O
September	O
,	O
1987	O
,	O
the	O
patient	O
was	O
alert	O
and	O
had	O
spastic	O
paraparesis	O
,	O
the	O
impairment	O
of	O
all	O
sensory	O
modalities	O
below	O
the	O
level	O
of	O
Th	O
10	O
and	O
urinary	O
disturbance	O
.	O

Prostaglandins	O
and	O
gallstones	O

The	O
nature	O
of	O
the	O
process	O
formed	O
by	O
the	O
successive	O
occurrences	O
of	O
this	O
arrhythmia	O
was	O
studied	O
in	O
8	O
patients	O
with	O
a	O
history	O
of	O
symptomatic	O
paroxysmal	O
AF	O
.	O

This	O
would	O
have	O
had	O
the	O
effect	O
of	O
positioning	O
the	O
genes	O
currently	O
on	O
the	O
long	O
arm	O
adjacent	O
to	O
the	O
centromeric	O
heterochromatin	O
,	O
perhaps	O
resulting	O
in	O
a	O
"	O
position	O
effect	O
"	O
on	O
transcription	O
of	O
these	O
genes	O
.	O

Initial	O
experience	O
with	O
a	O
microprocessor	O
controlled	O
current	O
based	O
defibrillator	O
.	O

Obesity	O
was	O
strongly	O
associated	O
with	O
the	O
proportions	O
of	O
nonprotein	O
-	O
bound	O
and	O
albumin	B-GENE
-	O
bound	O
estradiol	O
,	O
and	O
inversely	O
associated	O
with	O
sex	B-GENE
hormone	I-GENE
binding	I-GENE
globulin	I-GENE
(	O
SHBG	B-GENE
)	O
levels	O
and	O
the	O
proportion	O
of	O
SHBG	B-GENE
-	O
bound	O
estradiol	O
.	O

Heterogeneous	B-GENE
nuclear	I-GENE
ribonucleoprotein	I-GENE
(	I-GENE
hnRNP	I-GENE
)	I-GENE
core	I-GENE
protein	I-GENE
A1	I-GENE
is	O
a	O
major	O
component	O
of	O
mammalian	B-GENE
hnRNP	I-GENE
40	I-GENE
S	I-GENE
particles	I-GENE
.	O

Brain	B-GENE
cholinesterase	I-GENE
activity	O
of	O
nestling	O
great	O
egrets	O
,	O
snowy	O
egrets	O
and	O
black	O
-	O
crowned	O
night	O
-	O
herons	O
.	O
inhibition	O
of	O
brain	B-GENE
cholinesterase	I-GENE
(	O
ChE	B-GENE
)	O
activity	O
in	O
birds	O
is	O
often	O
used	O
to	O
diagnose	O
exposure	O
or	O
death	O
from	O
organophosphorus	O
or	O
carbamate	O
pesticides	O
.	O

The	O
effect	O
of	O
zinc	O
deficiency	O
on	O
trace	O
metals	O
in	O
the	O
liver	O
,	O
spleen	O
,	O
kidney	O
,	O
pancreas	O
and	O
duodenum	O
was	O
investigated	O
in	O
the	O
control	O
and	O
zinc	O
-	O
deficient	O
rats	O
at	O
17	O
days	O
and	O
20	O
days	O
of	O
pregnancy	O
.	O

Our	O
findings	O
support	O
the	O
view	O
of	O
a	O
multifactorial	O
genesis	O
of	O
the	O
cardiac	O
involvement	O
in	O
uremic	O
patients	O
.	O

Heating	O
cells	O
to	O
43	O
degrees	O
C	O
decreased	O
the	O
amount	O
of	O
newly	O
synthesized	O
rRNA	O
to	O
less	O
than	O
5	O
%	O
of	O
the	O
control	O
level	O
and	O
led	O
to	O
greater	O
than	O
95	O
%	O
inhibition	O
of	O
transcription	O
termination	O
at	O
a	O
region	O
355	O
to	O
362	O
nucleotides	O
downstream	O
of	O
the	O
3	O
'	O
end	O
of	O
28S	B-GENE
rRNA	I-GENE
,	O
with	O
readthrough	O
continuing	O
into	O
the	O
next	O
transcription	O
unit	O
.	O

Deletion	O
analysis	O
showed	O
that	O
the	O
NF	B-GENE
-	I-GENE
4FA	I-GENE
,	O
NF	B-GENE
-	I-GENE
4FB	I-GENE
,	O
and	O
AP	B-GENE
-	I-GENE
1	I-GENE
sequences	O
are	O
each	O
necessary	O
for	O
full	O
enhancer	O
activity	O
.	O

Cord	O
swelling	O
was	O
observed	O
in	O
2	O
patients	O
who	O
developed	O
complete	O
lesions	O
.	O

Reye	O
'	O
s	O
syndrome	O
:	O
reports	O
of	O
7	O
cases	O
in	O
the	O
period	O
1982	O
-	O
1987	O

PULSE	O
is	O
used	O
to	O
set	O
such	O
NMR	O
spectroscopic	O
parameters	O
as	O
the	O
delay	O
and	O
duration	O
of	O
rf	O
transmit	O
and	O
receive	O
gates	O
,	O
rf	O
phase	O
,	O
sampling	O
times	O
,	O
and	O
such	O
imaging	O
parameters	O
as	O
rf	O
pulse	O
shape	O
and	O
gradient	O
waveforms	O
.	O

Definite	O
JPsA	O
(	O
24	O
patients	O
)	O
was	O
defined	O
as	O
arthritis	O
associated	O
,	O
but	O
not	O
necessarily	O
coincident	O
,	O
with	O
a	O
typical	O
psoriatic	O
rash	O
,	O
or	O
arthritis	O
plus	O
at	O
least	O
3	O
of	O
4	O
minor	O
criteria	O
:	O
dactylitis	O
,	O
nail	O
pitting	O
,	O
psoriasis	O
-	O
like	O
rash	O
,	O
or	O
family	O
history	O
of	O
psoriasis	O
.	O

Hence	O
follows	O
Kurti	O
'	O
s	O
demand	O
to	O
mete	O
out	O
appropriate	O
importance	O
to	O
the	O
arguments	O
.	O

The	O
author	O
gives	O
an	O
account	O
of	O
antipsychotic	O
,	O
analgetic	O
,	O
myorelaxing	O
and	O
vasodilatating	O
effects	O
of	O
some	O
calcium	O
antagonists	O
,	O
and	O
their	O
clinical	O
application	O
is	O
discussed	O
.	O

A	O
correlation	O
coefficient	O
was	O
used	O
for	O
assessing	O
the	O
similarity	O
of	O
each	O
map	O
pattern	O
with	O
the	O
normal	O
mean	O
IQRST	O
map	O
.	O

A	O
hospital	O
-	O
based	O
study	O
of	O
the	O
relationship	O
between	O
retained	O
placenta	O
and	O
mastitis	O
in	O
dairy	O
cows	O
.	O

This	O
indicates	O
that	O
lipid	O
peroxidation	O
may	O
be	O
involved	O
in	O
the	O
development	O
of	O
senile	O
cataract	O
and	O
,	O
as	O
a	O
direct	O
consequence	O
of	O
retinal	O
damage	O
,	O
also	O
in	O
the	O
pathogenesis	O
of	O
cataract	O
in	O
diabetes	O
and	O
in	O
severe	O
myopia	O
.	O

The	O
histological	O
grading	O
was	O
certified	O
in	O
68	O
cases	O
:	O
12	O
G1	O
,	O
39	O
G2	O
,	O
17	O
G3	O
;	O
extracapsular	O
spread	O
was	O
found	O
in	O
20	O
/	O
54	O
cases	O
(	O
37	O
%	O
)	O
.	O

Asthma	O
was	O
significantly	O
more	O
often	O
associated	O
with	O
ASA	O
group	O
(	O
91	O
%	O
)	O
vs	O
46	O
%	O
at	O
AT	O
and	O
in	O
only	O
16	O
%	O
at	O
INTR	O
group	O
.	O

A	O
value	O
of	O
1	O
.	O
1	O
l	O
/	O
kg	O
was	O
used	O
for	O
V	O
in	O
calculating	O
all	O
single	O
sample	O
estimates	O
of	O
clearance	O
(	O
CL	O
)	O
,	O
and	O
a	O
value	O
of	O
4	O
.	O
3	O
l	O
/	O
kg	O
was	O
used	O
to	O
calculate	O
single	O
sample	O
estimates	O
of	O
clearance	O
of	O
plasma	O
unbound	O
drug	O
(	O
CLunb	O
)	O
.	O

The	O
solitary	O
kidney	O
:	O
a	O
model	O
of	O
chronic	O
hyperfiltration	O
in	O
humans	O
.	O

Halothane	O
is	O
metabolized	O
by	O
an	O
oxidative	O
pathway	O
to	O
stable	O
,	O
nonvolatile	O
end	O
products	O
,	O
trifluoroacetic	O
acid	O
(	O
TFAA	O
)	O
and	O
bromide	O
(	O
Br	O
-	O
)	O
,	O
and	O
by	O
reductive	O
pathways	O
to	O
Br	O
-	O
and	O
inorganic	O
fluoride	O
(	O
F	O
-	O
)	O
.	O

The	O
values	O
were	O
consistently	O
lower	O
(	O
P	O
less	O
than	O
0	O
.	O
01	O
)	O
during	O
summer	O
(	O
3	O
.	O
79	O
+	O
/	O
-	O
0	O
.	O
13	O
micrograms	O
/	O
100	O
ml	O
)	O
,	O
as	O
compared	O
to	O
winter	O
(	O
5	O
.	O
06	O
+	O
/	O
-	O
0	O
.	O
27	O
)	O
.	O

These	O
results	O
suggest	O
that	O
HAPE	O
-	O
S	O
-	O
S	O
are	O
prone	O
to	O
irregular	O
nocturnal	O
breathing	O
patterns	O
at	O
high	O
altitude	O
,	O
which	O
is	O
associated	O
with	O
the	O
development	O
of	O
AMS	O
,	O
but	O
it	O
was	O
not	O
possible	O
to	O
determine	O
whether	O
these	O
abnormal	O
breathing	O
patterns	O
are	O
a	O
cause	O
or	O
an	O
effect	O
of	O
AMS	O
.	O

It	O
was	O
possible	O
to	O
classify	O
the	O
animals	O
into	O
high	O
and	O
low	O
responders	O
according	O
to	O
the	O
pattern	O
of	O
humoral	O
immune	O
response	O
.	O

Heart	O
rate	O
(	O
HR	O
)	O
,	O
rectal	O
temperature	O
(	O
Tre	O
)	O
,	O
blood	O
pressure	O
,	O
temperature	O
and	O
relative	O
humidity	O
changes	O
inside	O
clothing	O
were	O
measured	O
on	O
18	O
professional	O
firemen	O
(	O
mean	O
age	O
29	O
.	O
4	O
+	O
/	O
-	O
7	O
.	O
4	O
yr	O
,	O
VO2	O
max	O
41	O
.	O
4	O
+	O
8	O
.	O
8	O
ml	O
kg	O
-	O
1	O
min	O
-	O
1	O
)	O
wearing	O
fire	O
fighter	O
'	O
s	O
uniforms	O
(	O
SU	O
)	O
or	O
aluminized	O
,	O
fire	O
resistant	O
,	O
impermeable	O
clothing	O
with	O
self	O
contained	O
breathing	O
apparatus	O
(	O
FE	O
)	O
.	O

The	O
clinical	O
tolerance	O
and	O
pharmacokinetics	O
of	O
FCE	O
22101	O
(	O
sodium	O
(	O
5R	O
,	O
6S	O
)	O
-	O
6	O
-	O
[	O
(	O
1R	O
)	O
-	O
hydroxyethyl	O
]	O
-	O
2	O
-	O
carbamoyloxymethyl	O
-	O
2	O
-	O
penem	O
-	O
3	O
-	O
carboxylate	O
)	O
,	O
a	O
new	O
penem	O
antibiotic	O
,	O
have	O
been	O
studied	O
after	O
giving	O
a	O
single	O
i	O
.	O
v	O
.	O
dose	O
of	O
4	O
mg	O
.	O
kg	O
-	O
1	O
to	O
ten	O
healthy	O
male	O
volunteers	O
.	O

DNA	O
blot	O
hybridization	O
suggests	O
that	O
the	O
rat	O
genome	O
may	O
contain	O
more	O
than	O
one	O
gene	O
encoding	O
PtdIns	B-GENE
transfer	I-GENE
protein	I-GENE
.	O

Another	O
segment	O
of	O
CRL3	B-GENE
(	O
-	O
296	O
to	O
-	O
184	O
)	O
,	O
also	O
displaying	O
enhancer	O
function	O
,	O
contained	O
tandem	O
repeated	O
sequences	O
(	O
DR	O
-	O
A1	O
and	O
DR	O
-	O
A2	O
)	O
.	O

1	O
-	O
(	O
1	O
-	O
Naphthyl	O
)	O
piperazine	O
(	O
1	O
-	O
NP	O
)	O
has	O
been	O
reported	O
to	O
have	O
serotonin	O
antagonist	O
properties	O
at	O
the	O
5	B-GENE
-	I-GENE
HT2	I-GENE
subtype	I-GENE
of	O
receptor	O
,	O
and	O
it	O
has	O
been	O
suggested	O
that	O
it	O
may	O
have	O
agonist	O
actions	O
at	O
the	O
5	B-GENE
-	I-GENE
HT1	I-GENE
site	I-GENE
.	O

1	O
-	O
(	O
m	O
-	O
Chlorophenyl	O
)	O
piperazine	O
(	O
mCPP	O
,	O
0	O
.	O
1	O
-	O
3	O
.	O
0	O
mg	O
/	O
kg	O
)	O
and	O
1	O
-	O
(	O
m	O
-	O
trifluoromethylphenyl	O
)	O
piperazine	O
(	O
TFMPP	O
,	O
0	O
.	O
1	O
-	O
3	O
.	O
0	O
mg	O
/	O
kg	O
)	O
,	O
both	O
thought	O
to	O
act	O
primarily	O
at	O
5	B-GENE
-	I-GENE
HT1	I-GENE
sites	I-GENE
,	O
also	O
decreased	O
responding	O
and	O
this	O
effect	O
was	O
blocked	O
by	O
methysergide	O
and	O
by	O
1	O
-	O
NP	O
,	O
but	O
not	O
by	O
ketanserin	O
.	O

The	O
characteristic	O
feature	O
of	O
liver	O
and	O
spleen	O
MP	O
function	O
in	O
patients	O
with	O
VHA	O
associated	O
with	O
HBsAg	B-GENE
carriership	O
consisted	O
in	O
the	O
lack	O
of	O
the	O
compensatory	O
reaction	O
on	O
the	O
part	O
of	O
spleen	O
MP	O
,	O
which	O
was	O
likely	O
to	O
be	O
connected	O
with	O
overstrain	O
of	O
long	O
standing	O
and	O
depletion	O
of	O
the	O
MP	O
system	O
due	O
to	O
permanent	O
antigenic	O
stimulation	O
of	O
HBsAg	B-GENE
.	O

Changes	O
in	O
xanthine	B-GENE
oxidase	I-GENE
activity	O
in	O
patients	O
with	O
circulatory	O
failure	O

A	O
soap	O
and	O
water	O
(	O
1	O
:	O
1	O
,	O
v	O
/	O
v	O
)	O
solution	O
effectively	O
decontaminated	O
powdered	O
stratum	O
corneum	O
.	O

The	O
cytoprotective	O
and	O
antiulcer	O
activities	O
of	O
the	O
antacid	O
magaldrate	O
(	O
ES	O
Riopan	O
)	O
as	O
well	O
as	O
its	O
effects	O
on	O
gastric	O
mucosal	O
blood	O
flow	O
and	O
mucus	O
secretions	O
,	O
were	O
determined	O
in	O
the	O
rat	O
.	O

The	O
human	O
immunodeficiency	O
virus	O
type	O
1	O
(	O
HIV	O
-	O
1	O
)	O
preferentially	O
infects	O
CD4	B-GENE
+	I-GENE
T	O
lymphocytes	O
and	O
may	O
exist	O
as	O
a	O
latent	O
provirus	O
within	O
these	O
cells	O
for	O
extended	O
periods	O
.	O

Histiocytic	O
panniculitis	O
was	O
observed	O
in	O
biopsy	O
specimens	O
with	O
cytophagocytosis	O
.	O

We	O
have	O
utilized	O
the	O
human	B-GENE
4F2	I-GENE
heavy	I-GENE
chain	I-GENE
(	O
4F2HC	B-GENE
)	O
gene	O
as	O
a	O
model	O
system	O
in	O
studies	O
designed	O
to	O
elucidate	O
the	O
molecular	O
events	O
involved	O
in	O
regulating	O
inducible	O
gene	O
expression	O
during	O
normal	O
human	O
T	O
-	O
cell	O
activation	O
.	O

A	O
cDNA	O
encoding	O
the	O
NF	B-GENE
-	I-GENE
4FB	I-GENE
enhancer	I-GENE
binding	I-GENE
protein	I-GENE
has	O
been	O
cloned	O
by	O
screening	O
a	O
lambda	O
gt11	O
cDNA	O
library	O
with	O
a	O
rabiolabelled	O
oligonucleotide	O
corresponding	O
to	O
the	O
NF	B-GENE
-	I-GENE
4FB	I-GENE
recognition	I-GENE
sequence	I-GENE
.	O

Electrocardiographic	O
right	O
ventricular	O
hypertrophy	O
was	O
seen	O
in	O
4	O
,	O
and	O
biventricular	O
hypertrophy	O
in	O
5	O
patients	O
.	O

Sequencing	O
analysis	O
revealed	O
that	O
the	O
0	O
.	O
54	O
-	O
and	O
0	O
.	O
4	O
-	O
kb	O
fragments	O
are	O
identical	O
except	O
for	O
150	O
nucleotides	O
missing	O
at	O
the	O
5	O
'	O
region	O
of	O
the	O
0	O
.	O
4	O
-	O
kb	O
fragment	O
.	O

The	O
mature	O
protein	O
also	O
contains	O
a	O
cysteine	O
-	O
rich	O
,	O
highly	O
hydrophilic	O
region	O
homologous	O
to	O
the	O
ovomucoid	B-GENE
serine	I-GENE
protease	I-GENE
inhibitors	I-GENE
(	O
residues	O
76	O
-	O
132	O
)	O
.	O

Oligosynaptic	O
EPSP	O
components	O
were	O
consistently	O
modulated	O
only	O
in	O
the	O
superficial	O
peroneal	O
responses	O
in	O
flexor	O
motoneurons	O
,	O
which	O
exhibited	O
enhanced	O
amplitude	O
during	O
the	O
flexion	O
phase	O
.	O

Experiments	O
on	O
23	O
white	O
rats	O
and	O
10	O
guinea	O
pigs	O
have	O
shown	O
that	O
preliminarily	O
indomethacin	O
-	O
induced	O
inhibition	O
of	O
prostaglandins	O
synthesis	O
prevented	O
development	O
of	O
pulmonary	O
oedema	O
,	O
evoked	O
by	O
heterologous	O
serum	O
in	O
rats	O
and	O
by	O
vagotomy	O
in	O
guinea	O
pigs	O
.	O

On	O
the	O
other	O
hand	O
,	O
lack	O
of	O
conservation	O
of	O
the	O
membrane	O
attachment	O
sequence	O
arginine	O
-	O
glycine	O
-	O
aspartic	O
acid	O
argues	O
against	O
its	O
functional	O
importance	O
in	O
CgA	B-GENE
.	O

Third	O
-	O
and	O
later	O
-	O
parity	O
cows	O
were	O
randomly	O
assigned	O
after	O
each	O
parturition	O
to	O
Charolais	O
and	O
Red	O
Poll	O
bulls	O
in	O
multiple	O
-	O
sire	O
pastures	O
.	O

Within	O
each	O
lobe	O
,	O
the	O
PA	O
dispersion	O
was	O
up	O
to	O
10	O
cmH2O	O
at	O
CFV	O
of	O
90	O
l	O
/	O
min	O
;	O
when	O
flow	O
decreased	O
,	O
PA	O
at	O
all	O
sites	O
decreased	O
,	O
as	O
did	O
the	O
intralobar	O
dispersion	O
.	O

The	O
system	O
consisted	O
of	O
the	O
intact	O
canine	O
heart	O
connected	O
to	O
a	O
microcomputer	O
that	O
operated	O
as	O
the	O
modulated	O
parasystolic	O
pacemaker	O
.	O

In	O
order	O
to	O
identify	O
and	O
classify	O
the	O
basic	O
CT	O
appearances	O
of	O
interstitial	O
pneumonia	O
,	O
radiologic	O
-	O
pathologic	O
correlative	O
study	O
was	O
performed	O
using	O
inflated	O
and	O
fixed	O
lungs	O
from	O
autopsy	O
and	O
surgery	O
.	O

The	O
disease	O
ran	O
an	O
atypical	O
course	O
;	O
with	O
early	O
jaundice	O
syndrome	O
,	O
severe	O
enterorrhagia	O
and	O
late	O
appearance	O
of	O
roseola	O
.	O

The	O
transcription	O
factor	O
Sp1	B-GENE
bound	O
to	O
eight	O
sites	O
,	O
as	O
demonstrated	O
by	O
footprinting	O
assays	O
and	O
gel	O
shift	O
analysis	O
with	O
purified	O
Sp1	B-GENE
.	O

The	O
combination	O
PIP	O
64	O
micrograms	O
-	O
PEF	O
4	O
micrograms	O
prevents	O
the	O
frequent	O
secondary	O
regrowth	O
seen	O
after	O
6	O
hours	O
with	O
the	O
antibiotics	O
used	O
alone	O
.	O

With	O
a	O
sample	O
of	O
mothers	O
of	O
healthy	O
infants	O
,	O
all	O
three	O
subscales	O
of	O
the	O
revised	O
instrument	O
,	O
WPL	O
-	O
R	O
,	O
had	O
acceptable	O
levels	O
of	O
internal	O
consistency	O
at	O
7	O
,	O
30	O
,	O
and	O
90	O
days	O
postpartum	O
,	O
and	O
stability	O
across	O
administrations	O
.	O

Since	O
1948	O
,	O
the	O
use	O
of	O
saline	O
-	O
washed	O
red	O
cells	O
(	O
WRBCs	O
)	O
has	O
been	O
advocated	O
to	O
minimize	O
hemolysis	O
after	O
transfusion	O
to	O
patients	O
with	O
PNH	O
.	O

In	O
the	O
group	O
of	O
asthmatics	O
statistically	O
significant	O
correlation	O
was	O
found	O
between	O
PC20	O
PGF2	O
alpha	O
and	O
histamine	O
values	O
(	O
r	O
=	O
0	O
.	O
538	O
,	O
p	O
less	O
than	O
0	O
.	O
05	O
)	O
.	O

Acute	O
experiments	O
on	O
nembutal	O
-	O
anesthetized	O
cats	O
(	O
50	O
mg	O
/	O
kg	O
)	O
were	O
employed	O
to	O
investigate	O
the	O
effect	O
of	O
1	O
T	O
pulsating	O
magnetic	O
field	O
(	O
PMF	O
)	O
on	O
neuromuscular	O
system	O
of	O
the	O
leg	O
.	O

No	O
significant	O
differences	O
were	O
found	O
between	O
the	O
TS	O
and	O
the	O
PTS	O
.	O

The	O
percentages	O
of	O
formed	O
cysts	O
and	O
growth	O
rates	O
were	O
monthly	O
estimated	O
and	O
analyzed	O
rhythmometrically	O
by	O
cosinor	O
for	O
5	O
clonal	O
cultures	O
of	O
Scripsiella	O
trochoidea	O
Stein	O
grown	O
for	O
2	O
years	O
under	O
laboratory	O
conditions	O
,	O
rended	O
as	O
constant	O
as	O
possible	O
from	O
the	O
view	O
point	O
of	O
environmental	O
temperature	O
(	O
24	O
+	O
/	O
-	O
1	O
degree	O
C	O
)	O
,	O
lighting	O
(	O
25	O
microEin	O
m	O
-	O
2	O
s	O
-	O
1	O
)	O
,	O
and	O
artificial	O
seawater	O
.	O

A	O
genomic	O
DNA	O
clone	O
encoding	O
oryzacystatin	B-GENE
(	O
Oc	B-GENE
)	O
,	O
a	O
cysteine	B-GENE
proteinase	I-GENE
inhibitor	O
(	O
cystatin	B-GENE
)	O
of	O
rice	O
,	O
was	O
isolated	O
from	O
a	O
lambda	O
EMBL3	O
phage	O
library	O
constructed	O
with	O
Sau3AI	B-GENE
partial	O
digests	O
of	O
rice	O
chromosomal	O
DNA	O
,	O
by	O
screening	O
with	O
an	O
oc	B-GENE
cDNA	I-GENE
as	O
a	O
probe	O
.	O

The	O
use	O
of	O
an	O
appropriate	O
solution	O
of	O
methylene	O
blue	O
(	O
0	O
.	O
2	O
%	O
in	O
0	O
.	O
9	O
M	O
NaCl	O
for	O
15	O
min	O
)	O
permits	O
the	O
staining	O
of	O
premalignant	O
areas	O
and	O
CIS	O
,	O
and	O
their	O
early	O
diagnosis	O
.	O

Lower	O
limits	O
(	O
to	O
10	O
micrograms	O
/	O
kg	O
)	O
were	O
detectable	O
,	O
but	O
with	O
lower	O
reliability	O
(	O
60	O
%	O
)	O
.	O

Instead	O
,	O
some	O
small	O
negative	O
effects	O
are	O
observed	O
,	O
particularly	O
involving	O
effects	O
of	O
husbands	O
'	O
retirement	O
on	O
the	O
marital	O
satisfaction	O
of	O
employed	O
wives	O
.	O

This	O
in	O
turn	O
will	O
further	O
enhance	O
the	O
role	O
of	O
meta	O
-	O
analysis	O
in	O
helping	O
clinicians	O
and	O
policy	O
makers	O
answer	O
clinical	O
questions	O
.	O

The	O
accuracies	O
of	O
presence	O
or	O
absence	O
of	O
neuroblastoma	O
were	O
compared	O
between	O
131I	O
-	O
MIBG	O
imaging	O
and	O
several	O
tumor	O
markers	O
.	O

The	O
congenital	O
forms	O
(	O
7	O
cases	O
)	O
all	O
occurred	O
in	O
female	O
infants	O
and	O
involved	O
the	O
mucosa	O
overlying	O
either	O
the	O
anterior	O
ridge	O
of	O
the	O
maxilla	O
or	O
the	O
mandible	O
.	O

Immunohistochemical	O
studies	O
revealed	O
positive	O
staining	O
for	O
S100	B-GENE
protein	I-GENE
in	O
all	O
the	O
granular	O
cell	O
tumors	O
of	O
the	O
adult	O
but	O
in	O
none	O
of	O
the	O
congenital	O
granular	O
cell	O
epulides	O
.	O

We	O
also	O
found	O
that	O
the	O
same	O
males	O
,	O
breeding	O
in	O
different	O
years	O
on	O
the	O
same	O
territories	O
,	O
had	O
significantly	O
larger	O
harems	O
in	O
the	O
years	O
they	O
had	O
familiar	O
neighbors	O
.	O

Male	B-GENE
-	I-GENE
enhanced	I-GENE
antigen	I-GENE
gene	I-GENE
is	O
phylogenetically	O
conserved	O
and	O
expressed	O
at	O
late	O
stages	O
of	O
spermatogenesis	O
.	O

In	O
rats	O
bearing	O
Walker	O
-	O
256	O
-	O
carcinosarcoma	O
4	O
-	O
EPI	O
was	O
effective	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
250	O
WORDS	O
)	O

Pacing	O
the	O
Roux	O
limb	O
abolished	O
the	O
ectopic	O
pacemakers	O
,	O
restored	O
the	O
slow	O
emptying	O
of	O
liquids	O
to	O
the	O
more	O
rapid	O
rate	O
found	O
in	O
the	O
Billroth	O
dogs	O
(	O
t1	O
/	O
2	O
:	O
paced	O
Roux	O
,	O
72	O
+	O
/	O
-	O
15	O
minutes	O
;	O
Billroth	O
,	O
43	O
+	O
/	O
-	O
9	O
minutes	O
;	O
p	O
greater	O
than	O
0	O
.	O
05	O
)	O
and	O
did	O
not	O
change	O
emptying	O
of	O
solids	O
.	O

The	O
treatments	O
were	O
60	O
mg	O
t	O
.	O
i	O
.	O
d	O
.	O
and	O
120	O
mg	O
t	O
.	O
i	O
.	O
d	O
.	O
during	O
14	O
days	O
'	O
treatment	O
,	O
with	O
the	O
last	O
dose	O
pulsed	O
with	O
1	O
.	O
85	O
MBq	O
[	O
14C	O
]	O
diltiazem	O
.	O

The	O
subepicardial	O
lymphatic	O
capillaries	O
were	O
ramified	O
and	O
anastomosed	O
with	O
each	O
other	O
to	O
form	O
a	O
relatively	O
dense	O
network	O
which	O
extended	O
over	O
the	O
entire	O
surface	O
of	O
both	O
ventricles	O
.	O

The	O
examination	O
must	O
include	O
T1	O
and	O
T2	O
sequences	O
and	O
scans	O
in	O
three	O
planes	O
.	O

A	O
great	O
deal	O
of	O
information	O
is	O
available	O
on	O
the	O
morphology	O
of	O
the	O
claustrum	O
in	O
various	O
animal	O
species	O
,	O
as	O
well	O
as	O
on	O
its	O
neuronal	O
distribution	O
and	O
relationships	O
with	O
the	O
cerebral	O
cortex	O
and	O
other	O
nuclei	O
.	O

Low	O
-	O
grade	O
glioma	O
.	O

In	O
terms	O
of	O
sequence	O
repetitions	O
,	O
seven	O
tandemly	O
repeated	O
copies	O
of	O
the	O
hexanucleotide	O
ATTGTT	O
and	O
three	O
flanking	O
regions	O
of	O
dyad	O
symmetry	O
were	O
detected	O
,	O
all	O
in	O
ORF	O
T3C	O
.	O

The	O
significance	O
of	O
these	O
palindromic	O
domains	O
in	O
this	O
ORF	O
is	O
unclear	O
but	O
the	O
coincidence	O
of	O
the	O
end	O
of	O
one	O
larger	O
palindrome	O
with	O
the	O
end	O
of	O
the	O
translated	O
protein	O
sequence	O
that	O
has	O
homology	O
with	O
the	O
B	O
chain	O
of	O
insulin	B-GENE
suggests	O
that	O
the	O
palindromes	O
may	O
divide	O
the	O
T2	B-GENE
protein	I-GENE
into	O
several	O
functional	O
units	O
.	O

During	O
sub	O
-	O
maximal	O
exercise	O
,	O
DCR	O
in	O
the	O
UT	O
dogs	O
decreased	O
from	O
a	O
resting	O
value	O
of	O
4	O
.	O
08	O
+	O
/	O
-	O
0	O
.	O
18	O
mm	O
Hg	O
X	O
ml	O
-	O
1	O
X	O
min	O
-	O
1	O
to	O
1	O
.	O
91	O
+	O
/	O
-	O
0	O
.	O
17	O
mm	O
Hg	O
X	O
ml	O
-	O
1	O
X	O
min	O
-	O
1	O
at	O
a	O
workload	O
of	O
6	O
.	O
4	O
kph	O
(	O
speed	O
)	O
/	O
16	O
%	O
(	O
grade	O
)	O
.	O

7	O
.	O

These	O
data	O
suggest	O
that	O
the	O
G	B-GENE
-	I-GENE
protein	I-GENE
gene	I-GENE
family	I-GENE
may	O
be	O
distributed	O
over	O
at	O
least	O
two	O
human	O
chromosomes	O
.	O

The	O
major	O
inserted	O
DNA	O
has	O
no	O
significant	O
homology	O
to	O
published	O
human	O
nucleic	O
acid	O
sequences	O
.	O

We	O
have	O
also	O
found	O
that	O
the	O
in	O
vitro	O
interaction	O
between	O
the	O
SV40	O
octamer	O
motif	O
and	O
the	O
lymphoid	B-GENE
cell	I-GENE
-	I-GENE
specific	I-GENE
protein	I-GENE
oct	I-GENE
-	I-GENE
B2	I-GENE
was	O
negatively	O
modulated	O
by	O
a	O
component	O
present	O
in	O
the	O
nuclear	O
extracts	O
from	O
several	O
lymphoid	O
cell	O
lines	O
.	O

Anoxia	O
was	O
introduced	O
by	O
perfusing	O
the	O
gill	O
with	O
water	O
deprived	O
of	O
oxygen	O
or	O
by	O
halting	O
the	O
water	O
flow	O
to	O
the	O
gill	O
.	O

Growth	O
,	O
4	O
-	O
PA	O
and	O
14C	O
turnover	O
data	O
indicated	O
that	O
WB	O
contributed	O
to	O
B	O
-	O
6	O
intake	O
of	O
these	O
rats	O
.	O

DNA	O
sequence	O
analysis	O
revealed	O
that	O
these	O
clones	O
encode	O
two	O
distinct	O
forms	O
of	O
translocase	B-GENE
.	O

RPA190	B-GENE
encodes	O
a	O
polypeptide	O
chain	O
of	O
186	O
,	O
270	O
daltons	O
in	O
a	O
large	O
uninterrupted	O
reading	O
frame	O
.	O

Both	O
the	O
intact	B-GENE
A1	I-GENE
protein	I-GENE
and	O
its	O
proteolytic	O
fragment	O
,	O
the	O
UP1	B-GENE
protein	I-GENE
,	O
can	O
be	O
cleaved	O
by	O
Staphylococcus	B-GENE
aureus	I-GENE
V	I-GENE
-	I-GENE
8	I-GENE
protease	I-GENE
to	O
produce	O
two	O
polypeptides	O
of	O
92	O
amino	O
acids	O
.	O

Irmiere	O
,	O
and	O
W	O
.	O

These	O
offspring	O
of	O
the	O
alpha	B-GENE
-	I-GENE
MSH	I-GENE
treated	O
mothers	O
were	O
less	O
sensitive	O
to	O
pain	O
and	O
as	O
adults	O
showed	O
a	O
reduced	O
analgesic	O
response	O
to	O
morphine	O
.	O

Simian	O
immunodeficiency	O
virus	O
(	O
SIV	O
)	O
is	O
a	O
lentivirus	O
with	O
morphological	O
and	O
antigenic	O
similarities	O
to	O
human	O
immunodeficiency	O
virus	O
,	O
the	O
causative	O
agent	O
of	O
acquired	O
immunodeficiency	O
syndrome	O
(	O
AIDS	O
)	O
of	O
humans	O
.	O

The	O
lack	O
of	O
change	O
in	O
the	O
ratio	O
of	O
the	O
two	O
spliced	O
products	O
expressed	O
from	O
either	O
the	O
normal	O
or	O
the	O
5	B-GENE
'	I-GENE
-	I-GENE
rearranged	I-GENE
myb	I-GENE
further	O
indicates	O
that	O
the	O
insertion	O
of	O
the	O
unique	O
121	O
amino	O
acids	O
in	O
the	O
larger	O
myb	B-GENE
transcripts	I-GENE
is	O
not	O
a	O
consequence	O
of	O
tumor	O
-	O
specific	O
activation	O
of	O
the	O
mouse	B-GENE
myb	I-GENE
oncogene	I-GENE
.	O

The	O
use	O
of	O
CRF	B-GENE
-	I-GENE
41	I-GENE
in	O
the	O
differential	O
diagnosis	O
of	O
Cushing	O
'	O
s	O
syndrome	O
and	O
obesity	O
.	O

We	O
detected	O
mos	B-GENE
transcripts	I-GENE
by	O
Northern	O
(	O
RNA	O
)	O
analyses	O
in	O
RNA	O
prepared	O
from	O
chicken	O
and	O
quail	O
ovaries	O
and	O
testes	O
.	O

The	O
results	O
suggest	O
that	O
the	O
organization	O
of	O
functional	O
units	O
of	O
the	O
72	O
-	O
bp	O
repeat	O
required	O
for	O
transcriptional	O
enhancement	O
of	O
the	O
early	O
promoter	O
is	O
different	O
from	O
that	O
required	O
for	O
late	O
promoter	O
function	O
.	O

Variations	O
in	O
the	O
5	O
'	O
half	O
of	O
U3	O
were	O
primarily	O
due	O
to	O
insertions	O
and	O
deletions	O
.	O

An	O
analysis	O
of	O
the	O
steady	O
state	O
RNA	O
levels	O
in	O
T	O
-	O
lymphoid	O
cell	O
lines	O
showed	O
that	O
at	O
least	O
three	O
different	O
incomplete	O
proviral	O
transcripts	O
and	O
their	O
spliced	O
products	O
made	O
up	O
the	O
majority	O
of	O
expressed	O
RD	B-GENE
-	I-GENE
114	I-GENE
mRNA	I-GENE
,	O
and	O
further	O
demonstrated	O
that	O
partially	O
deleted	O
proviral	O
loci	O
have	O
the	O
potential	O
to	O
be	O
transcriptionally	O
vigorous	O
in	O
certain	O
feline	O
cell	O
types	O
.	O

Either	O
two	O
or	O
more	O
different	O
sequences	O
can	O
promote	O
cleavage	O
,	O
or	O
a	O
single	O
element	O
exists	O
which	O
is	O
long	O
and	O
diffuse	O
.	O

Low	O
molecular	O
weight	O
heparins	O
have	O
stimulated	O
much	O
interest	O
because	O
of	O
their	O
supposedly	O
more	O
selective	O
action	O
on	O
Xa	B-GENE
factor	I-GENE
.	O

Sodium	O
dodecyl	O
sulphate	O
-	O
induced	O
cleavage	O
by	O
eukaryotic	B-GENE
topoisomerase	I-GENE
I	I-GENE
is	O
known	O
to	O
yield	O
enzyme	O
covalently	O
attached	O
to	O
the	O
3	O
'	O
cut	O
end	O
of	O
the	O
DNA	O
.	O

Amino	O
acid	O
sequence	O
of	O
one	O
human	O
liver	O
clone	O
(	O
HL	O
-	O
14	O
)	O
was	O
identical	O
to	O
the	O
rabbit	B-GENE
skeletal	I-GENE
muscle	I-GENE
phosphatase	I-GENE
2A	I-GENE
cDNA	I-GENE
(	O
with	O
97	O
%	O
nucleotide	O
identity	O
)	O
.	O

Herpes	O
virus	O
infection	O
was	O
characterized	O
by	O
inversion	O
of	O
the	O
T4	O
/	O
T8	O
ratio	O
below	O
1	O
.	O
0	O
(	O
sensitivity	O
90	O
%	O
,	O
specificity	O
88	O
%	O
)	O
,	O
caused	O
by	O
proliferation	O
of	O
the	O
T8	O
subpopulation	O
,	O
which	O
-	O
-	O
compared	O
with	O
the	O
findings	O
in	O
patients	O
with	O
rejection	O
crises	O
-	O
-	O
was	O
significantly	O
raised	O
(	O
P	O
less	O
than	O
0	O
.	O
001	O
)	O
.	O

Quantitative	O
assays	O
in	O
which	O
the	O
activity	O
of	O
the	O
synthetic	B-GENE
alpha	I-GENE
s	I-GENE
-	I-GENE
1	I-GENE
was	O
compared	O
to	O
that	O
of	O
native	O
purified	O
human	B-GENE
erythrocyte	I-GENE
type	I-GENE
-	I-GENE
1	I-GENE
Gs	I-GENE
,	O
indicated	O
that	O
the	O
two	O
products	O
are	O
equipotent	O
within	O
a	O
2	O
-	O
fold	O
margin	O
of	O
error	O
.	O

In	O
these	O
cells	O
,	O
E2	B-GENE
proteins	I-GENE
had	O
little	O
or	O
no	O
stimulatory	O
effect	O
on	O
the	O
transcriptional	O
activity	O
of	O
the	O
HPV	B-GENE
-	I-GENE
11	I-GENE
enhancer	I-GENE
-	O
SV40	B-GENE
promoter	I-GENE
.	O

The	O
mechanism	O
by	O
which	O
E2	B-GENE
-	I-GENE
C	I-GENE
represses	O
E2	B-GENE
-	I-GENE
dependent	I-GENE
enhancer	I-GENE
activity	O
most	O
likely	O
involves	O
competition	O
with	O
E2	B-GENE
for	O
binding	O
to	O
a	O
common	O
transcriptional	O
regulatory	O
site	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
400	O
WORDS	O
)	O

Accurate	O
evaluation	O
of	O
the	O
treatment	O
results	O
in	O
unresectable	O
lung	O
cancer	O
patients	O
must	O
take	O
the	O
strong	O
prognostic	O
factors	O
into	O
account	O
.	O

(	O
anti	B-GENE
-	I-GENE
IIa	I-GENE
)	O
and	O
Holmer	O
et	O
al	O
.	O

Introduction	O
of	O
v	B-GENE
-	I-GENE
fms	I-GENE
into	O
a	O
CSF	B-GENE
-	I-GENE
1	I-GENE
dependent	O
murine	O
macrophage	O
cell	O
line	O
induced	O
factor	O
independence	O
and	O
tumorigenicity	O
by	O
a	O
nonautocrine	O
mechanism	O
.	O

Chronic	O
E	O
-	O
B	O
virus	O
infection	O
terminated	O
in	O
malignant	O
lymphoma	O
:	O
a	O
case	O
report	O

Whereas	O
the	O
muscle	O
isoform	O
consists	O
of	O
997	O
amino	O
acids	O
and	O
terminates	O
with	O
the	O
sequence	O
Ala	O
-	O
Ile	O
-	O
Leu	O
-	O
Glu	O
,	O
the	O
second	O
isoform	O
is	O
1043	O
amino	O
acids	O
in	O
length	O
due	O
to	O
the	O
replacement	O
of	O
these	O
last	O
4	O
amino	O
acids	O
with	O
a	O
50	O
-	O
amino	O
acid	O
sequence	O
that	O
contains	O
a	O
potential	O
transmembrane	O
domain	O
followed	O
by	O
a	O
consensus	O
sequence	O
for	O
an	O
N	O
-	O
linked	O
glycosylation	O
site	O
.	O

Substitution	O
of	O
a	O
threonine	O
residue	O
by	O
an	O
alanine	O
residue	O
at	O
position	O
-	O
2	O
(	O
P2	O
)	O
of	O
this	O
cleavage	O
site	O
abolished	O
cleavage	O
,	O
whereas	O
substitution	O
of	O
a	O
tyrosine	O
residue	O
by	O
a	O
phenylalanine	O
residue	O
at	O
amino	O
acid	O
position	O
-	O
1	O
(	O
P1	O
)	O
of	O
the	O
cleavage	O
site	O
did	O
not	O
influence	O
processing	O
.	O

A	O
highly	O
hydrophobic	O
sequence	O
located	O
near	O
the	O
carboxyl	O
-	O
terminal	O
extremity	O
of	O
the	O
molecule	O
most	O
likely	O
constitutes	O
the	O
anchor	O
to	O
the	O
plasma	O
membrane	O
.	O

The	O
SV40	B-GENE
enhancer	I-GENE
augmented	O
replication	O
1	O
.	O
5	O
-	O
10	O
fold	O
.	O

One	O
of	O
these	O
,	O
the	O
origin	O
core	O
,	O
is	O
required	O
only	O
for	O
DNA	O
replication	O
.	O

Induction	O
of	O
proto	B-GENE
-	I-GENE
oncogene	I-GENE
fos	I-GENE
transcription	O
through	O
the	O
adenylate	B-GENE
cyclase	I-GENE
pathway	O
:	O
characterization	O
of	O
a	O
cAMP	O
-	O
responsive	O
element	O
.	O

A	O
17	O
-	O
mer	O
oligodeoxynucleotide	O
,	O
corresponding	O
to	O
a	O
region	O
of	O
the	O
VtHb	B-GENE
amino	I-GENE
acid	I-GENE
sequence	I-GENE
was	O
used	O
as	O
a	O
hybridization	O
probe	O
to	O
screen	O
a	O
Vitreoscilla	O
genomic	O
library	O
constructed	O
in	O
broad	O
-	O
host	O
-	O
range	O
cosmid	O
vector	O
pVK102	O
.	O

(	O
total	O
soluble	O
solids	O
)	O
and	O
organoleptic	O
characteristics	O
under	O
the	O
influence	O
of	O
different	O
treatments	O
.	O

Causes	O
of	O
death	O
found	O
in	O
an	O
epidemiological	O
study	O
of	O
native	O
chickens	O
in	O
Thai	O
villages	O
.	O

The	O
progression	O
of	O
non	O
-	O
A	O
,	O
non	O
-	O
B	O
hepatitis	O
to	O
chronic	O
diseases	O
,	O
and	O
the	O
transformation	O
to	O
hepatocellular	O
carcinoma	O

Elevated	O
IOP	O
developed	O
in	O
35	O
patients	O
(	O
44	O
eyes	O
)	O
during	O
the	O
study	O
.	O

Use	O
of	O
serum	O
thyroglobulin	B-GENE
determination	O
in	O
the	O
follow	O
-	O
up	O
of	O
differentiated	O
carcinomas	O
of	O
the	O
thyroid	O

Poor	O
response	O
when	O
laboratory	O
recommended	O
range	O
for	O
serum	O
lithium	O
is	O
changed	O
.	O

The	O
aim	O
of	O
this	O
study	O
was	O
to	O
investigate	O
the	O
effects	O
of	O
nebulized	O
ipratropium	O
in	O
patients	O
with	O
acute	O
asthma	O
in	O
order	O
to	O
determine	O
whether	O
it	O
augments	O
the	O
bronchodilator	O
effect	O
of	O
a	O
beta	O
agonist	O
drug	O
.	O

Further	O
analysis	O
of	O
this	O
DNA	O
fragment	O
showed	O
that	O
four	O
genes	O
are	O
present	O
encoding	O
proteins	O
of	O
16	O
,	O
18	O
.	O
5	O
,	O
21	O
and	O
89	O
kDal	O
.	O

Hantaan	O
virus	O
.	O

Changes	O
in	O
dopamine	B-GENE
receptor	I-GENE
sensitivity	O
in	O
humans	O
after	O
heavy	O
alcohol	O
intake	O
.	O

No	O
significant	O
differences	O
between	O
the	O
two	O
treatment	O
groups	O
were	O
found	O
,	O
but	O
rapid	O
responders	O
had	O
a	O
smaller	O
mean	O
initial	O
platelet	B-GENE
-	I-GENE
associated	I-GENE
IgG	I-GENE
index	O
which	O
returned	O
more	O
rapidly	O
and	O
more	O
permanently	O
to	O
normal	O
than	O
that	O
of	O
slow	O
responders	O
.	O

Replacement	B-GENE
variant	I-GENE
histone	I-GENE
genes	I-GENE
contain	O
intervening	O
sequences	O
.	O

Double	O
-	O
blind	O
randomised	O
trial	O
of	O
intravenous	O
tissue	B-GENE
-	I-GENE
type	I-GENE
plasminogen	I-GENE
activator	I-GENE
versus	O
placebo	O
in	O
acute	O
myocardial	O
infarction	O
.	O

The	O
C	O
-	O
terminal	O
domains	O
(	O
CTDs	O
)	O
of	O
the	O
RPase	B-GENE
beta	I-GENE
subunit	I-GENE
and	O
DNA	B-GENE
primase	I-GENE
(	O
dnaG	B-GENE
protein	I-GENE
)	O
were	O
not	O
only	O
strongly	O
homologous	O
to	O
each	O
other	O
but	O
also	O
considerably	O
homologous	O
to	O
the	O
RPase	B-GENE
alpha	I-GENE
,	O
suggesting	O
that	O
an	O
alpha	O
subunit	O
-	O
like	O
enzyme	O
must	O
have	O
been	O
commonly	O
ancestral	O
to	O
core	B-GENE
enzyme	I-GENE
subunits	I-GENE
and	O
primase	B-GENE
.	O

However	O
,	O
vancomycin	O
and	O
fosfomycin	O
,	O
which	O
revealed	O
suboptimal	O
in	O
vitro	O
bactericidal	O
activity	O
,	O
proved	O
as	O
efficacious	O
as	O
penicillin	O
G	O
and	O
imipenem	O
in	O
an	O
experimental	O
mode	O
of	O
murine	O
gas	O
gangrene	O
.	O

Fentanyl	O
,	O
a	O
prototypic	O
mu	B-GENE
-	I-GENE
opiate	I-GENE
receptor	I-GENE
agonist	O
,	O
has	O
been	O
previously	O
shown	O
to	O
produce	O
a	O
syndrome	O
characterized	O
by	O
marked	O
analgesia	O
and	O
locomotor	O
stimulation	O
as	O
well	O
as	O
tachycardia	O
,	O
tachypnoea	O
and	O
behavioural	O
arousal	O
.	O

Bisoprolol	O
was	O
found	O
to	O
be	O
an	O
effective	O
beta	B-GENE
-	I-GENE
adrenoceptor	I-GENE
antagonist	O
,	O
the	O
pA2	O
values	O
determined	O
against	O
isoprenaline	O
in	O
guinea	O
pig	O
atria	O
and	O
tracheal	O
muscle	O
being	O
7	O
.	O
45	O
and	O
6	O
.	O
41	O
,	O
respectively	O
.	O

Output	O
of	O
99mTcO	O
-	O
4	O
by	O
the	O
parotid	O
gland	O
closely	O
mimicked	O
fluctuations	O
in	O
parotid	O
saliva	O
flow	O
rate	O
.	O

The	O
Hagen	O
-	O
Poiseuille	O
equation	O
is	O
used	O
to	O
assess	O
the	O
effects	O
of	O
attached	O
parasites	O
in	O
the	O
foregut	O
of	O
Leishmania	O
-	O
infected	O
sandflies	O
on	O
blood	O
flow	O
.	O

Moreover	O
,	O
in	O
rats	O
allowed	O
to	O
choose	O
in	O
a	O
T	O
-	O
maze	O
between	O
immediate	O
-	O
but	O
-	O
small	O
vs	O
.	O
delayed	O
-	O
but	O
-	O
large	O
reward	O
,	O
BZP	O
significantly	O
decreased	O
the	O
frequency	O
with	O
which	O
the	O
delayed	O
reward	O
was	O
chosen	O
,	O
with	O
5	O
-	O
HT	O
uptake	O
blockers	O
producing	O
opposite	O
effects	O
.	O

An	O
endometrial	O
luteal	O
phase	O
deficiency	O
was	O
detected	O
in	O
15	O
(	O
30	O
%	O
)	O
of	O
aborting	O
patients	O
.	O

Prenatal	O
exposure	O
to	O
the	O
fungicide	O
dinocap	O
causes	O
behavioral	O
torticollis	O
,	O
ballooning	O
and	O
cleft	O
palate	O
in	O
mice	O
,	O
but	O
not	O
rats	O
or	O
hamsters	O
.	O

Reperfusion	O
with	O
normal	O
blood	O
in	O
the	O
beating	O
,	O
working	O
hearts	O
caused	O
extensive	O
structural	O
damage	O
,	O
reduced	O
reflow	O
,	O
and	O
failed	O
to	O
restore	O
contractility	O
in	O
any	O
instance	O
(	O
-	O
27	O
%	O
systolic	O
shortening	O
,	O
p	O
less	O
than	O
0	O
.	O
05	O
)	O
.	O

The	O
sensitivity	O
of	O
the	O
vas	O
deferens	O
to	O
adrenaline	O
was	O
also	O
reduced	O
in	O
scorbutic	O
guinea	O
pigs	O
,	O
thus	O
decreasing	O
their	O
fertility	O
rate	O
.	O

In	O
metabolic	O
acidosis	O
there	O
was	O
a	O
marked	O
stimulation	O
when	O
clamped	O
at	O
-	O
10	O
to	O
-	O
100	O
mV	O
.	O

On	O
Days	O
1	O
and	O
14	O
,	O
most	O
young	O
and	O
elderly	O
subjects	O
exhibited	O
monoexponential	O
decline	O
in	O
bevantolol	O
plasma	O
concentrations	O
after	O
absorption	O
phase	O
.	O

Mature	O
and	O
old	O
B6AF1	O
and	O
B6D2F1	O
mice	O
were	O
given	O
acidified	O
tap	O
water	O
or	O
promethazine	O
HCl	O
(	O
a	O
phenothiazine	O
with	O
H1	B-GENE
receptor	I-GENE
blocking	O
activity	O
)	O
,	O
chlorpheniramine	O
(	O
an	O
H1	B-GENE
blocker	O
)	O
or	O
trifluoperazine	O
(	O
a	O
phenothiazine	O
with	O
no	O
H1	B-GENE
blocking	O
activity	O
)	O
in	O
their	O
drinking	O
water	O
,	O
and	O
the	O
effects	O
of	O
these	O
agents	O
on	O
bone	O
mineral	O
content	O
were	O
assessed	O
by	O
intermittently	O
measuring	O
the	O
24	O
-	O
h	O
whole	O
body	O
retention	O
of	O
Tc	O
99m	O
methylene	O
diphosphonate	O
(	O
Tc	O
99m	O
MDP	O
,	O
an	O
indicator	O
of	O
bone	O
metabolism	O
)	O
and	O
at	O
the	O
end	O
of	O
the	O
studies	O
by	O
determining	O
ash	O
weights	O
of	O
femur	O
,	O
ilium	O
and	O
sacrum	O
.	O

Present	O
results	O
reveal	O
a	O
frequency	O
-	O
dependent	O
inhibition	O
of	O
ganglionic	O
transmission	O
by	O
diltiazem	O
,	O
and	O
suggest	O
that	O
diltiazem	O
may	O
depress	O
excessive	O
sympathetic	O
activity	O
without	O
affecting	O
normal	O
ganglionic	O
transmission	O
.	O

Effects	O
of	O
a	O
new	O
antihypertensive	O
agent	O
,	O
SGB	O
-	O
1534	O
,	O
on	O
rat	O
platelet	O
aggregation	O
.	O

Since	O
the	O
stability	O
of	O
TF1	B-GENE
resides	O
in	O
its	O
primary	O
structure	O
,	O
we	O
cloned	O
a	O
gene	O
coding	O
for	O
TF1	B-GENE
,	O
and	O
the	O
primary	O
structure	O
of	O
the	O
beta	O
subunit	O
was	O
deduced	O
from	O
the	O
nucleotide	O
sequence	O
of	O
the	O
gene	O
to	O
compare	O
the	O
sequence	O
with	O
those	O
of	O
beta	O
'	O
s	O
of	O
three	O
major	O
categories	O
of	O
F1	B-GENE
'	O
s	O
;	O
prokaryotic	O
membranes	O
,	O
chloroplasts	O
,	O
and	O
mitochondria	O
.	O

Body	O
temperature	O
and	O
overall	O
conductance	O
in	O
the	O
cold	O
appear	O
to	O
be	O
more	O
variable	O
in	O
P	O
.	O
s	O
.	O
campbelli	O
than	O
in	O
nominative	O
sp	O
.	O

A	O
drug	O
with	O
ISA	O
"	O
down	O
regulates	O
"	O
beta	B-GENE
receptors	I-GENE
;	O
thus	O
,	O
when	O
the	O
drug	O
is	O
withdrawn	O
there	O
is	O
no	O
post	O
-	O
beta	O
-	O
blocking	O
drug	O
hypersensitivity	O
in	O
contrast	O
to	O
agents	O
without	O
ISA	O
.	O

Six	O
patients	O
with	O
human	O
T	O
-	O
cell	O
lymphotropic	O
virus	O
type	O
I	O
(	O
HTLV	O
-	O
I	O
)	O
-	O
associated	O
myelopathy	O
(	O
HAM	O
)	O
were	O
studied	O
by	O
electrophysiologic	O
methods	O
.	O

Terazosin	O
,	O
a	O
structural	O
analog	O
of	O
prazosin	O
,	O
also	O
inhibits	O
alpha	B-GENE
1	I-GENE
adrenoceptors	I-GENE
and	O
is	O
recommended	O
as	O
once	O
or	O
twice	O
-	O
daily	O
therapy	O
.	O

Testing	O
blood	O
donors	O
for	O
non	O
-	O
A	O
,	O
non	O
-	O
B	O
hepatitis	O
:	O
irrational	O
,	O
perhaps	O
,	O
but	O
inescapable	O
.	O

Most	O
patients	O
with	O
high	O
blood	O
pressure	O
(	O
BP	O
)	O
can	O
be	O
managed	O
by	O
using	O
one	O
of	O
4	O
classes	O
of	O
compounds	O
:	O
a	O
diuretic	O
,	O
beta	O
blocker	O
,	O
converting	O
enzyme	O
inhibitor	O
or	O
calcium	O
antagonist	O
.	O

In	O
a	O
randomised	O
double	O
-	O
blind	O
study	O
,	O
46	O
first	O
episode	O
schizophrenics	O
were	O
given	O
pimozide	O
or	O
flupenthixol	O
for	O
up	O
to	O
5	O
weeks	O
;	O
the	O
mean	O
daily	O
dose	O
at	O
the	O
end	O
was	O
18	O
.	O
8	O
mg	O
pimozide	O
and	O
20	O
mg	O
flupenthixol	O
.	O

Somatostatin	B-GENE
-	O
producing	O
endocrine	O
pancreatic	O
tumor	O
in	O
Recklinghausen	O
'	O
s	O
neurofibromatosis	O
.	O

Direct	O
and	O
inverted	O
repeat	O
elements	O
of	O
10	O
,	O
11	O
,	O
16	O
,	O
19	O
,	O
and	O
22	O
nucleotides	O
(	O
nt	O
)	O
flank	O
the	O
promoter	O
site	O
.	O

We	O
have	O
been	O
able	O
to	O
map	O
specific	O
DNA	O
fragments	O
at	O
the	O
bases	O
of	O
chromatin	O
loops	O
with	O
the	O
help	O
of	O
a	O
novel	O
extraction	O
procedure	O
by	O
using	O
lithium	O
-	O
3	O
'	O
,	O
5	O
'	O
-	O
diiodosalicylate	O
.	O

Seventy	O
-	O
one	O
supplementary	O
doses	O
of	O
vecuronium	O
were	O
used	O
for	O
muscle	O
relaxation	O
during	O
a	O
22	O
-	O
h	O
-	O
long	O
NLA	O
II	O
anaesthesia	O
.	O

Finally	O
,	O
the	O
recovery	O
indexes	O
represented	O
by	O
the	O
times	O
required	O
for	O
T1	O
/	O
T0	O
and	O
T4	O
/	O
T1	O
to	O
rise	O
from	O
25	O
%	O
to	O
75	O
%	O
respectively	O
were	O
studied	O
.	O

Transformed	O
bacterial	O
colonies	O
were	O
screened	O
for	O
recombinant	O
plasmids	O
containing	O
cDNA	O
coding	O
for	O
BiP	B-GENE
by	O
hybrid	O
-	O
selected	O
mRNA	O
translation	O
.	O

DPA	O
attenuated	O
the	O
increase	O
of	O
the	O
intensity	O
of	O
the	O
ischemic	O
and	O
pressure	O
pain	O
components	O
with	O
increasing	O
ischemia	O
duration	O
,	O
but	O
only	O
the	O
effect	O
on	O
the	O
pressure	O
pain	O
component	O
was	O
significant	O
.	O

Topical	O
1	O
percent	O
isoproterenol	O
in	O
the	O
presence	O
of	O
the	O
phosphodiesterase	O
inhibitor	O
theophylline	O
was	O
tested	O
for	O
its	O
ability	O
to	O
stimulate	O
the	O
rate	O
of	O
aqueous	O
humor	O
flow	O
through	O
the	O
anterior	O
chamber	O
of	O
the	O
normal	O
and	O
the	O
partially	O
adrenergically	O
denervated	O
human	O
eye	O
(	O
Horner	O
'	O
s	O
syndrome	O
)	O
.	O

Hyperthyroidism	O
is	O
one	O
of	O
the	O
numerous	O
causes	O
of	O
infertility	O
and	O
recurrent	O
abortion	O
.	O

A	O
strong	O
correlation	O
exists	O
between	O
the	O
numbers	O
of	O
CFU	O
-	O
GM	O
transfused	O
and	O
the	O
rate	O
of	O
granulocytes	O
and	O
platelets	O
recovery	O
.	O

Oestrogen	O
implant	O
overdose	O
.	O

Three	O
sequence	O
elements	O
are	O
shown	O
to	O
be	O
required	O
for	O
accurate	O
and	O
efficient	O
transcription	O
termination	O
by	O
RNA	B-GENE
polymerase	I-GENE
I	I-GENE
(	O
pol	B-GENE
I	I-GENE
)	O
assayed	O
both	O
in	O
a	O
cell	O
-	O
free	O
transcription	O
system	O
and	O
in	O
vivo	O
after	O
transfection	O
of	O
rDNA	O
minigene	O
constructs	O
into	O
3T6	O
cells	O
.	O

A	O
new	O
physiopathological	O
treatment	O
of	O
HBV	O
-	O
related	O
polyarteritis	O
inspired	O
by	O
advances	O
in	O
the	O
treatment	O
of	O
chronic	O
active	O
hepatitis	O
B	O
was	O
tested	O
in	O
7	O
patients	O
.	O

The	O
subunit	B-GENE
-	I-GENE
a	I-GENE
gene	I-GENE
is	O
preceded	O
by	O
a	O
gene	O
coding	O
for	O
a	O
small	O
hydrophobic	O
protein	O
,	O
as	O
has	O
been	O
observed	O
previously	O
in	O
the	O
atp	B-GENE
operons	I-GENE
in	O
E	O
.	O
coli	O
,	O
bacterium	O
PS3	O
and	O
cyanobacteria	O
.	O

Here	O
,	O
we	O
describe	O
the	O
isolation	O
of	O
bovine	B-GENE
and	I-GENE
rat	I-GENE
GHF	I-GENE
-	I-GENE
1	I-GENE
cDNA	I-GENE
clones	O
.	O

To	O
explore	O
the	O
functional	O
properties	O
of	O
the	O
protein	O
encoded	O
by	O
neu	B-GENE
,	O
we	O
created	O
a	O
fusion	O
gene	O
that	O
joins	O
the	O
cytoplasmic	O
domain	O
of	O
neu	B-GENE
to	O
the	O
extracellular	O
portion	O
of	O
an	O
immunoglobulin	B-GENE
heavy	I-GENE
chain	I-GENE
.	O

By	O
sequence	O
comparison	O
,	O
42	O
blocks	O
of	O
homology	O
are	O
defined	O
in	O
the	O
5	O
'	O
-	O
terminal	O
region	O
,	O
of	O
which	O
36	O
appear	O
in	O
the	O
CpG	O
island	O
and	O
contain	O
numerous	O
conserved	O
CpG	O
dinucleotides	O
.	O

Among	O
unusual	O
features	O
,	O
we	O
report	O
numerous	O
large	O
G	O
+	O
C	O
-	O
rich	O
conserved	O
sequences	O
located	O
in	O
the	O
first	O
intron	O
.	O

In	O
the	O
first	O
group	O
,	O
0	O
.	O
02	O
%	O
Prazosin	O
(	O
0	O
.	O
5	O
mg	O
/	O
kg	O
)	O
was	O
administered	O
intravenously	O
for	O
1	O
.	O
5	O
hours	O
before	O
the	O
application	O
of	O
Oxy	O
-	O
Hb	O
or	O
PGF2	O
alpha	O
.	O

A	O
decamer	O
sequence	O
,	O
5	O
'	O
-	O
CGA	O
-	O
CCCCUCC	O
-	O
3	O
'	O
,	O
complementary	O
to	O
a	O
conserved	O
sequence	O
adjacent	O
to	O
the	O
enzymatic	O
cleavage	O
site	O
on	O
the	O
mitochondrial	O
RNA	O
substrate	O
,	O
is	O
present	O
in	O
the	O
RNAase	B-GENE
MRP	I-GENE
RNA	I-GENE
.	O

Effects	O
of	O
aging	O
and	O
beta	O
-	O
adrenergic	O
-	O
blockade	O
on	O
standing	O
-	O
induced	O
QT	O
/	O
QS2	O
changes	O
.	O

A	O
patient	O
with	O
an	O
infected	O
wound	O
or	O
one	O
on	O
a	O
primary	O
area	O
(	O
hands	O
,	O
feet	O
,	O
face	O
,	O
or	O
perineum	O
)	O
may	O
have	O
to	O
be	O
hospitalized	O
to	O
ensure	O
proper	O
care	O
.	O

Pharmacology	O
studies	O
with	O
potassium	O
chloride	O
and	O
acetylcholine	O
suggest	O
that	O
raveron	O
acts	O
as	O
a	O
calcium	O
antagonist	O
by	O
blocking	O
the	O
influx	O
of	O
extracellular	O
calcium	O
.	O

On	O
admission	O
to	O
the	O
ICU	O
,	O
117	O
patients	O
(	O
61	O
percent	O
)	O
had	O
hypomagnesemia	O
(	O
serum	O
Mg	O
less	O
than	O
1	O
.	O
5	O
mEq	O
/	O
dl	O
)	O
,	O
66	O
patients	O
(	O
34	O
percent	O
)	O
had	O
normomagnesemia	O
(	O
1	O
.	O
5	O
to	O
2	O
.	O
0	O
mEq	O
/	O
dl	O
)	O
,	O
and	O
ten	O
patients	O
(	O
5	O
percent	O
)	O
had	O
hypermagnesemia	O
(	O
greater	O
than	O
2	O
.	O
0	O
mEq	O
/	O
dl	O
)	O
.	O

The	O
risk	O
factors	O
studied	O
were	O
male	O
sex	O
,	O
hypertension	O
,	O
diabetes	O
mellitus	O
,	O
hypercholesterolemia	O
,	O
cigarette	O
smoking	O
,	O
sedentary	O
life	O
-	O
style	O
,	O
and	O
family	O
history	O
.	O

Neither	O
verapamil	O
nor	O
nifedipine	O
changed	O
collateral	O
myocardial	O
blood	O
flow	O
from	O
0	O
.	O
10	O
+	O
/	O
-	O
0	O
.	O
02	O
in	O
the	O
subendocardium	O
and	O
0	O
.	O
17	O
+	O
/	O
-	O
0	O
.	O
03	O
ml	O
/	O
min	O
/	O
g	O
in	O
the	O
subepicardium	O
.	O

There	O
were	O
35	O
boys	O
and	O
15	O
girls	O
,	O
with	O
a	O
mean	O
age	O
of	O
five	O
and	O
a	O
half	O
years	O
.	O

Controlled	O
versus	O
uncontrolled	O
reperfusion	O
of	O
ischemic	O
myocardium	O
after	O
experimental	O
coronary	O
artery	O
occlusion	O
was	O
studied	O
to	O
determine	O
the	O
effect	O
on	O
regional	O
ventricular	O
wall	O
motion	O
and	O
associated	O
biochemical	O
alterations	O
.	O

Cardiac	O
disease	O
was	O
not	O
detected	O
with	O
M	O
-	O
mode	O
,	O
2	O
-	O
dimensional	O
real	O
-	O
time	O
or	O
pulsed	O
-	O
wave	O
Doppler	O
echocardiography	O
.	O

Hemodynamic	O
assessment	O
was	O
obtained	O
before	O
and	O
following	O
administration	O
of	O
digoxin	O
10	O
micrograms	O
/	O
kg	O
IV	O
or	O
dopamine	O
,	O
5	O
to	O
12	O
micrograms	O
/	O
kg	O
/	O
min	O
IV	O
.	O

We	O
conclude	O
that	O
at	O
these	O
low	O
levels	O
studied	O
,	O
aluminum	O
accumulates	O
in	O
intestinal	O
tissue	O
,	O
and	O
that	O
this	O
accumulation	O
is	O
enhanced	O
by	O
citrate	O
ligand	O
.	O

Thus	O
,	O
the	O
effects	O
of	O
father	O
absence	O
under	O
routine	O
conditions	O
in	O
relatively	O
healthy	O
samples	O
may	O
exert	O
no	O
significant	O
effects	O
independent	O
of	O
intervening	O
family	O
stressors	O
or	O
maternal	O
psychopathology	O
.	O

Recently	O
,	O
an	O
electrical	O
-	O
mechanical	O
analog	O
model	O
of	O
heat	O
flow	O
within	O
the	O
brain	O
has	O
been	O
developed	O
from	O
which	O
an	O
expression	O
for	O
CBF	O
has	O
been	O
derived	O
:	O
CBF	O
=	O
Cb	O
/	O
(	O
tau	O
rho	O
c	O
)	O
where	O
tau	O
is	O
the	O
thermal	O
decay	O
constant	O
,	O
rho	O
is	O
the	O
density	O
of	O
blood	O
,	O
and	O
c	O
is	O
its	O
specific	O
heat	O
.	O

All	O
of	O
the	O
newly	O
acquired	O
proviruses	O
identified	O
in	O
mosaic	O
founder	O
SWR	O
/	O
J	O
-	O
RF	O
/	O
J	O
mice	O
that	O
could	O
be	O
transmitted	O
through	O
the	O
germ	O
line	O
were	O
also	O
present	O
in	O
somatic	O
tissues	O
,	O
demonstrating	O
that	O
viral	O
integration	O
occurred	O
before	O
the	O
germ	O
line	O
was	O
set	O
aside	O
from	O
the	O
somatic	O
lineages	O
.	O

Molecular	O
cloning	O
of	O
the	O
cDNA	O
for	O
the	O
human	B-GENE
U2	I-GENE
snRNA	I-GENE
-	I-GENE
specific	I-GENE
A	I-GENE
'	I-GENE
protein	I-GENE
.	O

For	O
the	O
present	O
work	O
we	O
used	O
water	O
saturated	O
with	O
a	O
50	O
/	O
50	O
mixture	O
of	O
H2	O
and	O
O2	O
gases	O
,	O
for	O
which	O
the	O
heat	O
defect	O
is	O
calculated	O
to	O
be	O
-	O
2	O
.	O
1	O
%	O
.	O

During	O
flexion	O
whiplash	O
,	O
the	O
torque	O
at	O
the	O
occipital	O
condyle	O
reverses	O
its	O
direction	O
at	O
about	O
25	O
ms	O
after	O
impact	O
.	O

The	O
data	O
indicates	O
the	O
presence	O
of	O
5	B-GENE
-	I-GENE
HT2	I-GENE
serotonergic	I-GENE
receptors	I-GENE
in	O
the	O
bronchial	O
artery	O
of	O
these	O
species	O
.	O

Oxfendazole	O
,	O
which	O
was	O
active	O
for	O
the	O
shortest	O
time	O
(	O
about	O
65	O
days	O
)	O
from	O
the	O
start	O
of	O
grazing	O
(	O
May	O
1	O
)	O
,	O
produced	O
a	O
78	O
.	O
1	O
per	O
cent	O
reduction	O
in	O
Ostertagia	O
species	O
and	O
an	O
84	O
.	O
4	O
per	O
cent	O
reduction	O
in	O
D	O
viviparus	O
.	O

By	O
adapting	O
a	O
method	O
for	O
DNA	O
-	O
footprinting	O
using	O
impure	O
extracts	O
of	O
ner	B-GENE
overproducing	O
cells	O
,	O
we	O
were	O
able	O
to	O
determine	O
that	O
the	O
ner	B-GENE
-	I-GENE
binding	I-GENE
sites	I-GENE
are	O
located	O
between	O
nucleotides	O
1026	O
and	O
1058	O
from	O
the	O
Mu	O
left	O
end	O
.	O

Platelet	O
function	O
and	O
platelet	O
-	O
polymorphonuclear	O
-	O
neutrophil	O
interaction	O
in	O
patients	O
with	O
deficient	O
platelet	B-GENE
lipoxygenase	I-GENE
activity	O
.	O

Spontaneous	O
degradation	O
of	O
atracurium	O
in	O
plasma	O
is	O
the	O
major	O
route	O
of	O
elimination	O
in	O
man	O
and	O
contributes	O
to	O
a	O
short	O
elimination	O
half	O
-	O
life	O
(	O
approximatively	O
20	O
min	O
)	O
.	O

Transformed	O
cell	O
lines	O
expressing	O
solely	O
E1a	B-GENE
or	O
E1a	B-GENE
and	O
E1b	B-GENE
gene	I-GENE
products	I-GENE
derived	O
from	O
these	O
viruses	O
display	O
enhanced	O
anchorage	O
-	O
independent	O
growth	O
at	O
37	O
degrees	O
C	O
versus	O
32	O
degrees	O
C	O
and	O
display	O
a	O
cytoskeletal	O
architecture	O
resembling	O
untransformed	O
fibroblastic	O
CREF	O
cells	O
.	O

Partial	O
N	O
-	O
terminal	O
amino	O
acid	O
sequence	O
analysis	O
showed	O
that	O
the	O
43K	B-GENE
and	I-GENE
42K	I-GENE
T	I-GENE
antigens	I-GENE
contain	O
methionine	O
at	O
residues	O
1	O
and	O
5	O
,	O
as	O
predicted	O
from	O
the	O
DNA	O
sequence	O
,	O
whereas	O
no	O
methionine	O
was	O
released	O
from	O
the	O
39K	B-GENE
T	I-GENE
antigen	I-GENE
during	O
the	O
first	O
six	O
cycles	O
of	O
Edman	O
degradation	O
.	O

Group	O
A	O
was	O
treated	O
with	O
three	O
or	O
four	O
doses	O
of	O
hepatitis	B-GENE
B	I-GENE
immune	I-GENE
globulin	I-GENE
(	O
HBIG	B-GENE
)	O
in	O
one	O
of	O
three	O
different	O
schedules	O
.	O

In	O
the	O
former	O
instance	O
,	O
in	O
addition	O
to	O
serum	O
calcium	O
and	O
phosphorous	O
ion	O
concentrations	O
,	O
tissue	O
pH	O
,	O
blood	O
supply	O
,	O
hormones	O
,	O
i	O
.	O
e	O
.	O
,	O
vitamin	O
D	O
,	O
vitamin	O
A	O
,	O
and	O
various	O
enzymes	O
(	O
e	O
.	O
g	O
.	O
,	O
alkaline	B-GENE
phosphatase	I-GENE
and	O
pyrophosphatase	B-GENE
)	O
may	O
all	O
play	O
significant	O
,	O
ancillary	O
,	O
time	O
-	O
dependent	O
,	O
but	O
as	O
yet	O
undetermined	O
roles	O
.	O

Penicillinase	B-GENE
production	O
in	O
Staphylococcus	O
aureus	O
strains	O
of	O
clinical	O
importance	O
.	O

Thus	O
,	O
quantitative	O
analysis	O
of	O
thallium	O
-	O
201	O
uptake	O
and	O
washout	O
provided	O
objective	O
evidence	O
for	O
improved	O
myocardial	O
perfusion	O
after	O
coronary	O
angioplasty	O
.	O

This	O
study	O
reports	O
the	O
effects	O
of	O
a	O
preparation	O
with	O
50	O
micrograms	O
ethinyl	O
estradiol	O
and	O
2	O
mg	O
cyproterone	O
acetate	O
on	O
gonadotropins	B-GENE
,	O
prolactin	B-GENE
,	O
testosterone	O
,	O
sex	B-GENE
hormone	I-GENE
binding	I-GENE
globulin	I-GENE
(	O
SHBG	B-GENE
)	O
,	O
androstenedione	O
,	O
and	O
calculated	O
free	O
testosterone	O
index	O
before	O
and	O
after	O
six	O
months	O
of	O
treatment	O
.	O

In	O
nine	O
patients	O
with	O
renal	O
failure	O
routine	O
haemodialysis	O
was	O
accompanied	O
by	O
a	O
30	O
per	O
cent	O
reduction	O
in	O
plasma	O
ANP	B-GENE
concentration	O
.	O

To	O
investigate	O
the	O
effects	O
of	O
isotretinoin	O
on	O
HDL	B-GENE
,	O
we	O
measured	O
HDL	B-GENE
-	I-GENE
C	I-GENE
,	O
HDL	B-GENE
phospholipids	O
(	O
HDL	B-GENE
-	I-GENE
PL	I-GENE
)	O
,	O
apoprotein	B-GENE
A1	I-GENE
(	O
apo	B-GENE
A	I-GENE
-	I-GENE
1	I-GENE
)	O
,	O
and	O
HDL	B-GENE
-	I-GENE
C	I-GENE
subfractions	O
(	O
HDL2	B-GENE
-	I-GENE
C	I-GENE
and	O
HDL3	B-GENE
-	I-GENE
C	I-GENE
)	O
in	O
24	O
healthy	O
,	O
male	O
patients	O
receiving	O
a	O
16	O
-	O
week	O
course	O
of	O
isotretinoin	O
(	O
1	O
.	O
0	O
mg	O
/	O
kg	O
/	O
day	O
)	O
for	O
treatment	O
of	O
severe	O
acne	O
vulgaris	O
.	O

The	O
clinical	O
picture	O
and	O
laboratory	O
parameters	O
were	O
consistent	O
with	O
a	O
serum	O
sickness	O
reaction	O
.	O

Preventive	O
effect	O
of	O
ONO	O
-	O
3708	O
on	O
thrombosis	O
and	O
vasospasms	O
in	O
vitro	O
and	O
in	O
vivo	O
.	O

The	O
frequency	O
of	O
PPNG	O
strains	O
increased	O
from	O
1	O
.	O
7	O
%	O
in	O
1981	O
to	O
6	O
.	O
7	O
%	O
in	O
1985	O
.	O

Monospecific	O
antibodies	O
,	O
eluted	O
from	O
the	O
beta	B-GENE
-	I-GENE
galactosidase	I-GENE
fusion	O
protein	O
of	O
either	O
clone	O
reacted	O
with	O
the	O
U1	B-GENE
snRNP	I-GENE
-	O
specific	O
A	B-GENE
antigen	I-GENE
.	O

The	O
pathogenesis	O
of	O
Limited	O
Joint	O
Mobility	O
(	O
LJM	O
)	O
in	O
diabetes	O
is	O
unknown	O
,	O
but	O
the	O
abnormality	O
is	O
said	O
to	O
be	O
associated	O
with	O
an	O
increased	O
incidence	O
of	O
microangiopathy	O
.	O

The	O
experimental	O
end	O
points	O
were	O
the	O
time	O
required	O
for	O
treated	O
tumors	O
to	O
reach	O
3	O
times	O
their	O
treatment	O
size	O
,	O
the	O
survival	O
of	O
stem	O
cells	O
in	O
the	O
duodenal	O
crypts	O
,	O
and	O
the	O
breathing	O
rate	O
measured	O
early	O
(	O
19	O
-	O
23	O
weeks	O
)	O
and	O
late	O
(	O
41	O
-	O
46	O
weeks	O
)	O
after	O
treatment	O
.	O

Schedule	O
2	O
,	O
in	O
which	O
2	O
.	O
4	O
mg	O
/	O
kg	O
c	O
-	O
DDP	O
was	O
administered	O
immediately	O
before	O
X	O
-	O
ray	O
on	O
5	O
consecutive	O
days	O
produced	O
the	O
highest	O
degree	O
of	O
enhancement	O
of	O
radiation	O
effect	O
(	O
expressed	O
as	O
dose	O
-	O
effect	O
factor	O
)	O
;	O
and	O
the	O
next	O
greatest	O
enhancement	O
was	O
produced	O
by	O
12	O
mg	O
/	O
kg	O
c	O
-	O
DDP	O
administered	O
24	O
h	O
before	O
the	O
start	O
of	O
fractionated	O
daily	O
radiotherapy	O
.	O

The	O
cpc	B-GENE
-	I-GENE
1	I-GENE
-	I-GENE
encoded	I-GENE
transcript	I-GENE
contains	O
three	O
open	O
reading	O
frames	O
,	O
two	O
of	O
which	O
are	O
located	O
in	O
the	O
720	O
-	O
nucleotide	O
leader	O
segment	O
preceding	O
the	O
cpc	B-GENE
-	I-GENE
1	I-GENE
coding	I-GENE
region	I-GENE
.	O

The	O
HOI	O
induced	O
a	O
nearly	O
fourfold	O
increase	O
in	O
ANF	B-GENE
in	O
the	O
elderly	O
,	O
whereas	O
that	O
for	O
the	O
young	O
was	O
threefold	O
.	O

To	O
assess	O
the	O
ability	O
of	O
the	O
atria	O
to	O
maintain	O
elevated	O
plasma	O
concentrations	O
of	O
atrial	B-GENE
natriuretic	I-GENE
peptide	I-GENE
(	O
ANP	B-GENE
)	O
,	O
the	O
temporal	O
changes	O
in	O
plasma	B-GENE
ANP	I-GENE
concentrations	O
were	O
studied	O
in	O
seven	O
chloralose	O
-	O
anaesthetized	O
dogs	O
during	O
4	O
h	O
of	O
sustained	O
rapid	O
cardiac	O
pacing	O
.	O

Ig	B-GENE
D	I-GENE
-	O
JH	B-GENE
recombinations	O
may	O
precede	O
TcR	B-GENE
gene	I-GENE
recombination	O
in	O
these	O
early	O
T	O
cell	O
lines	O
,	O
and	O
some	O
but	O
not	O
all	O
express	O
sterile	O
Cmu	B-GENE
transcripts	I-GENE
.	O

The	O
RAD18	B-GENE
gene	I-GENE
open	I-GENE
reading	I-GENE
frame	I-GENE
encodes	O
a	O
protein	O
of	O
487	O
amino	O
acids	O
,	O
with	O
a	O
calculated	O
molecular	O
weight	O
of	O
55	O
,	O
512	O
.	O

Atomic	O
absorption	O
spectrophotometry	O
applied	O
to	O
bacterially	O
expressed	O
E1A	B-GENE
proteins	I-GENE
revealed	O
that	O
the	O
289	O
-	O
amino	O
acid	O
protein	O
binds	O
one	O
zinc	O
ion	O
,	O
whereas	O
the	O
243	O
-	O
amino	O
acid	O
protein	O
binds	O
no	O
zinc	O
.	O

Most	O
patients	O
preferred	O
tablets	O
to	O
injection	O
both	O
on	O
day	O
1	O
(	O
313	O
v	O
200	O
)	O
and	O
at	O
follow	O
up	O
(	O
373	O
v	O
104	O
)	O
.	O

Plots	O
of	O
RV	O
,	O
LV	O
+	O
S	O
and	O
2A	O
weight	O
vs	O
real	O
hematocrit	O
showed	O
sharp	O
upward	O
inflections	O
at	O
real	O
hematocrit	O
65	O
%	O
,	O
suggesting	O
a	O
possible	O
role	O
of	O
increased	O
viscosity	O
in	O
CO	O
cardiomegaly	O
at	O
the	O
higher	O
hematocrit	O
.	O

The	O
absorbable	O
perisplenic	O
mesh	O
is	O
an	O
important	O
improvement	O
,	O
and	O
in	O
some	O
cases	O
it	O
may	O
replace	O
other	O
techniques	O
for	O
arresting	O
splenic	O
bleeding	O
.	O

A	O
rare	O
chronic	O
course	O
of	O
Budd	O
-	O
Chiari	O
syndrome	O
associated	O
with	O
thrombosis	O
of	O
the	O
portal	O
vein	O
was	O
observed	O
in	O
a	O
30	O
-	O
year	O
-	O
old	O
male	O
patient	O
suffering	O
from	O
postmyocarditic	O
cardiosclerosis	O
.	O

After	O
one	O
accommodation	O
night	O
,	O
sleep	O
EEG	O
recordings	O
were	O
performed	O
during	O
three	O
consecutive	O
nights	O
in	O
ten	O
drug	O
-	O
free	O
inpatients	O
presenting	O
generalized	O
anxiety	O
disorder	O
(	O
GAD	O
)	O
with	O
significant	O
depression	O
,	O
compared	O
with	O
a	O
age	O
-	O
and	O
sex	O
-	O
matched	O
group	O
of	O
patients	O
with	O
GAD	O
and	O
a	O
group	O
of	O
primary	O
major	O
depressive	O
disorder	O
(	O
MDD	O
)	O
patients	O
.	O

Oligonucleotide	O
mutagenesis	O
of	O
these	O
binding	O
domains	O
indicated	O
their	O
importance	O
in	O
the	O
transcriptional	O
regulation	O
of	O
the	O
E3	B-GENE
promoter	I-GENE
in	O
yeast	O
cells	O
.	O

The	O
concentration	O
of	O
PGI2	O
on	O
the	O
newly	O
-	O
formed	O
luminal	O
surface	O
remained	O
low	O
.	O

Effects	O
of	O
single	O
and	O
combined	O
maltose	O
tetrapalmitate	O
immunotherapy	O
,	O
cyclophosphamide	O
chemotherapy	O
and	O
radiotherapy	O
on	O
ethyl	O
carbamate	O
accelerated	O
primary	O
lung	O
cancer	O
in	O
A	O
/	O
J	O
mice	O
.	O

D	O
.	O

Phase	O
II	O
study	O
of	O
VP	O
-	O
16	O
(	O
capsule	O
)	O
in	O
solid	O
tumors	O
.	O

When	O
the	O
coding	O
segments	O
,	O
including	O
both	O
framework	O
and	O
complementarity	O
-	O
determining	O
regions	O
,	O
of	O
these	O
genes	O
and	O
the	O
murine	O
probe	O
sequences	O
are	O
compared	O
by	O
metric	O
analysis	O
,	O
it	O
is	O
apparent	O
that	O
the	O
caiman	O
genes	O
are	O
only	O
slightly	O
more	O
related	O
to	O
each	O
other	O
than	O
to	O
the	O
mammalian	O
sequence	O
,	O
consistent	O
with	O
significant	O
preservation	O
of	O
nucleotide	O
sequence	O
over	O
an	O
extended	O
period	O
of	O
phylogenetic	O
time	O
.	O

An	O
unusual	O
feature	O
of	O
these	O
replicative	O
genes	O
is	O
that	O
the	O
smaller	O
mRNA	O
begins	O
within	O
a	O
long	O
open	O
reading	O
frame	O
of	O
the	O
larger	O
mRNA	O
.	O

Different	O
sequence	O
elements	O
of	O
both	O
the	O
retroviral	O
vectors	O
and	O
the	O
c	B-GENE
-	I-GENE
myc	I-GENE
gene	I-GENE
recombined	O
during	O
genesis	O
of	O
highly	O
oncogenic	O
retroviruses	O
CMII	O
,	O
MC29	O
,	O
or	O
MH2	O
.	O

81	O
milk	O
samples	O
collected	O
from	O
35	O
donors	O
3	O
days	O
to	O
7	O
months	O
after	O
delivery	O
were	O
examined	O
for	O
the	O
occurrence	O
of	O
cytomegalovirus	O
(	O
CMV	O
)	O
.	O

Subcloning	O
of	O
DNA	O
fragments	O
from	O
the	O
8	O
.	O
5	O
-	O
kilobase	O
(	O
kb	O
)	O
insert	O
of	O
pAVO4	O
defined	O
a	O
4	O
-	O
kb	O
DNA	O
fragment	O
which	O
contained	O
the	O
functional	B-GENE
FBP	I-GENE
+	I-GENE
gene	I-GENE
and	O
its	O
regulatory	O
region	O
.	O

Three	O
cases	O
of	O
primary	O
signet	O
-	O
ring	O
cell	O
carcinoma	O
of	O
the	O
rectum	O
are	O
described	O
.	O

The	O
data	O
obtained	O
up	O
to	O
now	O
only	O
suggest	O
the	O
future	O
potentiality	O
of	O
Bestatin	O
treatment	O
for	O
these	O
types	O
of	O
malignancy	O
.	O

These	O
data	O
suggest	O
that	O
dopaminergic	O
regulation	O
of	O
adrenal	O
zona	O
glomerulosa	O
corticosteroid	O
and	O
renal	B-GENE
renin	I-GENE
secretion	O
is	O
absent	O
in	O
patients	O
with	O
high	O
spinal	O
cord	O
transections	O
,	O
suggesting	O
that	O
intact	O
neural	O
pathways	O
from	O
the	O
central	O
nervous	O
system	O
are	O
necessary	O
for	O
metoclopramide	O
stimulation	O
of	O
aldosterone	O
and	O
renin	B-GENE
secretion	O
in	O
men	O
.	O

In	O
the	O
absence	O
of	O
enhancer	O
sequences	O
,	O
the	O
adenovirus	B-GENE
E1A	I-GENE
gene	I-GENE
can	O
not	O
stimulate	O
CATase	B-GENE
synthesis	O
.	O

These	O
IgG	B-GENE
antibodies	I-GENE
in	O
the	O
babies	O
diminished	O
rapidly	O
after	O
delivery	O
,	O
and	O
were	O
detectable	O
only	O
in	O
3	O
cases	O
at	O
2	O
,	O
3	O
,	O
and	O
5	O
months	O
of	O
ages	O
out	O
of	O
38	O
babies	O
up	O
to	O
21	O
months	O
.	O

Fine	O
analysis	O
at	O
the	O
nucleotide	O
level	O
of	O
the	O
early	O
events	O
in	O
the	O
digestion	O
with	O
nuclease	B-GENE
S1	I-GENE
shows	O
that	O
the	O
enzyme	O
attacks	O
preferentially	O
the	O
sequence	O
(	O
G	O
-	O
A	O
)	O
12	O
on	O
the	O
message	O
complementary	O
strand	O
.	O

Those	O
dosages	O
that	O
inhibited	O
mean	O
NTE	B-GENE
activity	O
in	O
spinal	O
cord	O
greater	O
than	O
or	O
equal	O
to	O
72	O
%	O
and	O
brain	O
greater	O
than	O
or	O
equal	O
to	O
66	O
%	O
of	O
control	O
values	O
within	O
44	O
hr	O
postexposure	O
produced	O
marked	O
spinal	O
cord	O
pathology	O
14	O
days	O
postexposure	O
in	O
greater	O
than	O
or	O
equal	O
to	O
90	O
%	O
of	O
similarly	O
dosed	O
animals	O
.	O

FK	O
33	O
-	O
824	O
,	O
a	O
methionine	O
-	O
enkephalin	B-GENE
analogue	O
,	O
suppressed	O
plasma	O
ACTH	B-GENE
to	O
85	O
%	O
of	O
basal	O
level	O
,	O
while	O
bromocriptine	O
(	O
CB	O
-	O
154	O
)	O
caused	O
no	O
significant	O
change	O
.	O

A	O
v	B-GENE
-	I-GENE
erbB	I-GENE
-	I-GENE
related	I-GENE
protooncogene	I-GENE
,	O
c	B-GENE
-	I-GENE
erbB	I-GENE
-	I-GENE
2	I-GENE
,	O
is	O
distinct	O
from	O
the	O
c	B-GENE
-	I-GENE
erbB	I-GENE
-	I-GENE
1	I-GENE
/	O
epidermal	B-GENE
growth	I-GENE
factor	I-GENE
-	I-GENE
receptor	I-GENE
gene	O
and	O
is	O
amplified	O
in	O
a	O
human	O
salivary	O
gland	O
adenocarcinoma	O
.	O

The	O
sequence	O
analysis	O
of	O
both	O
products	O
of	O
individual	O
phi	O
80	O
site	O
-	O
specific	O
recombination	O
events	O
in	O
vivo	O
shows	O
that	O
recombination	O
with	O
a	O
secondary	O
attachment	O
(	O
att	O
)	O
site	O
generates	O
several	O
different	O
novel	O
joints	O
at	O
the	O
mismatched	O
position	O
:	O
one	O
recombination	O
event	O
resulted	O
in	O
a	O
single	O
base	O
-	O
pair	O
deletion	O
and	O
two	O
other	O
recombination	O
events	O
resulted	O
in	O
two	O
different	O
single	O
base	O
-	O
pair	O
substitutions	O
.	O

This	O
L	B-GENE
-	I-GENE
myc	I-GENE
sequence	I-GENE
is	O
amplified	O
10	O
-	O
20	O
-	O
fold	O
in	O
four	O
SCLC	O
cell	O
line	O
DNAs	O
and	O
in	O
one	O
SCLC	O
tumour	O
specimen	O
taken	O
directly	O
from	O
a	O
patient	O
.	O

Temperature	O
-	O
shift	O
experiments	O
using	O
synchronously	O
grown	O
cells	O
of	O
a	O
delta	B-GENE
top1	I-GENE
top2	B-GENE
temperature	I-GENE
-	I-GENE
sensitive	I-GENE
(	I-GENE
ts	I-GENE
)	I-GENE
double	I-GENE
mutant	I-GENE
and	O
its	O
isogenic	O
top2	B-GENE
ts	O
strain	O
show	O
that	O
,	O
whereas	O
mitotic	O
blocks	O
can	O
prevent	O
killing	O
of	O
the	O
top2	B-GENE
ts	I-GENE
mutant	I-GENE
at	O
a	O
nonpermissive	O
temperature	O
,	O
the	O
same	O
treatments	O
are	O
ineffective	O
in	O
preventing	O
cell	O
death	O
of	O
the	O
delta	B-GENE
top1	I-GENE
top2	B-GENE
ts	I-GENE
double	I-GENE
mutant	I-GENE
.	O

The	O
homology	O
to	O
v	B-GENE
-	I-GENE
mil	I-GENE
starts	O
within	O
the	O
coding	O
sequence	O
of	O
exon	O
1	O
and	O
ends	O
within	O
the	O
3	O
'	O
untranslated	O
region	O
of	O
exon	O
11	O
,	O
12	O
nucleotides	O
downstream	O
from	O
the	O
nonsense	O
codon	O
terminating	O
the	O
large	O
open	O
reading	O
frame	O
shared	O
between	O
c	B-GENE
-	I-GENE
mil	I-GENE
and	O
v	B-GENE
-	I-GENE
mil	I-GENE
.	O

Examination	O
of	O
the	O
sequence	O
of	O
the	O
Punta	B-GENE
Toro	I-GENE
M	I-GENE
gene	I-GENE
product	I-GENE
reveals	O
the	O
presence	O
of	O
multiple	O
hydrophobic	O
sequences	O
including	O
a	O
19	O
-	O
amino	O
acid	O
,	O
carboxy	O
-	O
proximal	O
,	O
hydrophobic	O
region	O
(	O
G2	O
)	O
.	O

Six	O
(	O
four	O
FAP	O
;	O
two	O
primary	O
amyloidosis	O
)	O
also	O
had	O
diffusely	O
positive	O
myocardial	O
uptakes	O
,	O
but	O
the	O
intensity	O
was	O
less	O
than	O
that	O
of	O
the	O
sternum	O
.	O

The	O
intensity	O
of	O
myocardial	O
uptake	O
of	O
Tc	O
-	O
99m	O
-	O
PYP	O
in	O
patients	O
with	O
echocardiographic	O
left	O
ventricular	O
hypertrophy	O
and	O
/	O
or	O
highly	O
refractile	O
myocardial	O
echoes	O
,	O
so	O
-	O
called	O
granular	O
sparkling	O
appearance	O
(	O
GS	O
)	O
was	O
slightly	O
greater	O
than	O
that	O
in	O
patients	O
with	O
neither	O
myocardial	O
hypertrophy	O
nor	O
GS	O
.	O

Alveolar	O
lymphocytes	O
were	O
surprisingly	O
increased	O
in	O
most	O
patients	O
with	O
AIDS	O
(	O
mean	O
26	O
.	O
1	O
+	O
/	O
-	O
21	O
.	O
9	O
%	O
;	O
range	O
1	O
-	O
76	O
%	O
)	O
and	O
CGL	O
(	O
mean	O
26	O
.	O
6	O
+	O
/	O
-	O
22	O
.	O
6	O
%	O
;	O
range	O
3	O
-	O
76	O
%	O
)	O
with	O
criteria	O
of	O
activation	O
contrasting	O
with	O
the	O
blood	O
lymphopenia	O
.	O

We	O
have	O
determined	O
that	O
these	O
nicks	O
occur	O
in	O
both	O
the	O
wild	O
-	O
type	O
and	O
the	O
mutant	O
sites	O
.	O

The	O
sequence	O
was	O
determined	O
for	O
a	O
4024	O
-	O
base	O
pair	O
(	O
bp	O
)	O
segment	O
that	O
extends	O
from	O
149	O
bp	O
5	O
'	O
to	O
the	O
cap	O
site	O
of	O
alpha	B-GENE
1	I-GENE
to	O
207	O
bp	O
3	O
'	O
to	O
psi	B-GENE
alpha	I-GENE
.	O

When	O
phosphorylation	O
of	O
exogenous	O
peptide	O
substrates	O
was	O
measured	O
as	O
a	O
function	O
of	O
receptor	O
self	O
-	O
phosphorylation	O
,	O
tyrosine	B-GENE
kinase	I-GENE
activity	O
was	O
found	O
to	O
be	O
enhanced	O
two	O
to	O
threefold	O
at	O
1	O
-	O
2	O
mol	O
of	O
phosphate	O
per	O
mol	O
of	O
receptor	O
.	O

The	O
pet56	B-GENE
and	O
his3	B-GENE
genes	I-GENE
are	O
transcribed	O
divergently	O
from	O
initiation	O
sites	O
that	O
are	O
separated	O
by	O
only	O
192	O
bp	O
.	O

It	O
is	O
concluded	O
that	O
in	O
patients	O
with	O
first	O
-	O
attack	O
genital	O
herpes	O
,	O
the	O
type	O
of	O
HSV	O
is	O
the	O
most	O
important	O
determinant	O
of	O
subsequent	O
recurrences	O
and	O
that	O
intravenous	O
acyclovir	O
has	O
little	O
effect	O
on	O
subsequent	O
recurrences	O
.	O

Comparison	O
of	O
sequences	O
of	O
ovine	O
and	O
bovine	O
,	O
rat	O
and	O
guinea	B-GENE
-	I-GENE
pig	I-GENE
alpha	I-GENE
s1	I-GENE
-	I-GENE
casein	I-GENE
mRNAs	I-GENE
has	O
revealed	O
a	O
greater	O
homology	O
in	O
the	O
3	O
'	O
and	O
especially	O
5	O
'	O
non	O
coding	O
regions	O
.	O

Comparison	O
with	O
a	O
recently	O
described	O
c	B-GENE
-	I-GENE
sis	I-GENE
cDNA	I-GENE
clone	I-GENE
(	O
Collins	O
et	O
al	O
.	O
,	O
Nature	O
316	O
,	O
748	O
-	O
750	O
(	O
1985	O
)	O
)	O
revealed	O
that	O
the	O
1	O
.	O
9	O
kbp	O
DNA	O
region	O
contained	O
a	O
large	O
5	B-GENE
'	I-GENE
c	I-GENE
-	I-GENE
sis	I-GENE
exon	I-GENE
of	O
at	O
least	O
1050	O
bp	O
.	O

It	O
was	O
also	O
suggested	O
that	O
the	O
biological	O
activities	O
of	O
5	O
-	O
FU	O
,	O
ADM	O
and	O
MMC	O
in	O
FAMLIP	O
were	O
stable	O
in	O
FULIP	O
,	O
ADRLIP	O
and	O
MMCLIP	O
.	O

Surprisingly	O
,	O
a	O
C	O
to	O
G	O
transversion	O
at	O
the	O
first	O
residue	O
of	O
the	O
CAT	B-GENE
pentanucleotide	I-GENE
,	O
which	O
severely	O
impairs	O
the	O
activity	O
of	O
both	O
promoters	O
,	O
appears	O
to	O
increase	O
affinity	O
of	O
the	O
CAT	B-GENE
binding	I-GENE
protein	I-GENE
.	O

The	O
nucleotide	O
sequence	O
of	O
3874	O
bp	O
of	O
cloned	O
R	O
.	O
sphaeroides	O
chromosomal	O
DNA	O
,	O
including	O
the	O
three	O
structural	O
genes	O
fbcF	B-GENE
,	O
fbcB	B-GENE
and	O
fbcC	B-GENE
has	O
been	O
determined	O
.	O

The	O
N	O
-	O
terminal	O
sequence	O
of	O
one	O
hydrophilic	O
peptide	O
of	O
the	O
FeS	B-GENE
protein	I-GENE
has	O
been	O
also	O
obtained	O
confirming	O
the	O
fbcF	B-GENE
reading	O
frame	O
.	O

The	O
5	O
'	O
and	O
3	O
'	O
untranslated	O
sequences	O
contain	O
characteristic	O
sequences	O
that	O
are	O
involved	O
in	O
the	O
initiation	O
and	O
termination	O
of	O
transcription	O
,	O
including	O
two	O
possible	O
promoters	O
,	O
one	O
of	O
which	O
may	O
contain	O
two	O
overlapping	O
-	O
10	O
sequences	O
.	O

Unlike	O
P135gag	B-GENE
-	O
myb	B-GENE
-	O
ets	B-GENE
and	O
the	O
Mr	O
75	O
,	O
000	O
translation	O
product	O
of	O
c	B-GENE
-	I-GENE
myb	I-GENE
(	O
P75c	B-GENE
-	I-GENE
myb	I-GENE
)	O
,	O
which	O
are	O
nuclear	O
proteins	O
,	O
P54c	B-GENE
-	I-GENE
ets	I-GENE
was	O
found	O
to	O
be	O
predominantly	O
cytoplasmic	O
.	O

The	O
Dox	B-GENE
-	I-GENE
A2	I-GENE
locus	I-GENE
is	O
within	O
3	O
.	O
4	O
to	O
4	O
.	O
4	O
kb	O
of	O
the	O
Df	B-GENE
(	I-GENE
2L	I-GENE
)	I-GENE
OD15	I-GENE
breakpoint	I-GENE
,	O
placing	O
four	O
of	O
the	O
vital	O
loci	O
within	O
a	O
maximum	O
of	O
15	O
.	O
5	O
kb	O
.	O

The	O
C	O
-	O
terminal	O
end	O
of	O
this	O
polypeptide	O
harbors	O
three	O
types	O
of	O
repeated	O
sequences	O
.	O

Further	O
outbreaks	O
of	O
ocular	O
disease	O
in	O
farmed	O
red	O
deer	O
calves	O
caused	O
by	O
HVC	O
-	O
1	O
were	O
investigated	O
.	O

From	O
our	O
ultrastructural	O
and	O
biochemical	O
studies	O
,	O
it	O
is	O
evident	O
that	O
Type	O
II	O
pneumocytes	O
are	O
an	O
early	O
target	O
of	O
radiation	O
and	O
the	O
release	O
of	O
surfactant	O
into	O
the	O
alveolus	O
shortly	O
after	O
exposure	O
persists	O
for	O
days	O
and	O
weeks	O
.	O

Thirty	O
of	O
the	O
clones	O
contained	O
a	O
complete	O
340	O
base	O
-	O
pair	O
dimer	O
unit	O
of	O
the	O
repeat	O
.	O

Two	O
copies	O
of	O
the	O
72	O
-	O
bp	O
repeat	O
provided	O
efficient	O
activation	O
of	O
gene	O
expression	O
.	O

The	O
open	O
reading	O
frames	O
of	O
rbsD	B-GENE
,	O
rbsA	B-GENE
,	O
and	O
rbsC	B-GENE
encode	O
proteins	O
of	O
139	O
,	O
501	O
,	O
and	O
321	O
amino	O
acid	O
residues	O
,	O
respectively	O
.	O

Cattaneo	O
,	O
and	O
J	O
.	O

Human	B-GENE
alpha	I-GENE
-	I-GENE
galactosidase	I-GENE
A	I-GENE
:	O
nucleotide	O
sequence	O
of	O
a	O
cDNA	O
clone	O
encoding	O
the	O
mature	O
enzyme	O
.	O

The	O
amino	O
acid	O
sequence	O
was	O
determined	O
to	O
be	O
residues	O
716	O
-	O
724	O
and	O
hence	O
lysine	O
residue	O
721	O
is	O
located	O
within	O
the	O
ATP	O
-	O
binding	O
site	O
.	O

Osteocalcin	B-GENE
(	O
and	O
urinary	O
hydroxyproline	O
)	O
were	O
not	O
elevated	O
in	O
isolated	O
hyperphosphatasaemia	O
,	O
indicating	O
that	O
mechanisms	O
other	O
than	O
increased	O
bone	O
turnover	O
may	O
account	O
for	O
the	O
markedly	O
elevated	O
serum	B-GENE
alkaline	I-GENE
phosphatase	I-GENE
activity	O
in	O
these	O
subjects	O
.	O

Analysis	O
of	O
glucocorticoid	O
unresponsive	O
cell	O
variants	O
using	O
a	O
mouse	B-GENE
glucocorticoid	I-GENE
receptor	I-GENE
complementary	O
DNA	O
clone	O
.	O

Among	O
the	O
v	B-GENE
-	I-GENE
myc	I-GENE
codons	O
,	O
the	O
first	O
5	O
are	O
derived	O
from	O
the	O
noncoding	O
5	O
'	O
terminus	O
of	O
the	O
second	O
c	B-GENE
-	I-GENE
myc	I-GENE
exon	O
,	O
and	O
412	O
codons	O
correspond	O
to	O
the	O
c	B-GENE
-	I-GENE
myc	I-GENE
coding	O
region	O
.	O

A	O
recombinant	O
vector	O
,	O
p410	O
+	O
,	O
was	O
constructed	O
which	O
carried	O
the	O
BamHI	B-GENE
-	I-GENE
K	I-GENE
fragment	I-GENE
(	O
nucleotides	O
107565	O
to	O
112625	O
of	O
the	O
B95	O
-	O
8	O
strain	O
,	O
encoding	O
the	O
EBV	O
-	O
associated	O
nuclear	O
antigen	O
EBNA	B-GENE
-	I-GENE
1	I-GENE
)	O
,	O
the	O
cis	O
-	O
acting	O
sequence	O
from	O
the	O
BamHI	B-GENE
-	I-GENE
C	I-GENE
fragment	I-GENE
,	O
and	O
a	O
dominant	O
selectable	O
marker	O
gene	O
encoding	O
G	O
-	O
418	O
resistance	O
in	O
animal	O
cells	O
.	O

13	O
men	O
with	O
a	O
history	O
of	O
recurrent	O
genital	O
herpes	O
simplex	O
virus	O
type	O
2	O
(	O
HSV	O
-	O
2	O
)	O
infection	O
were	O
followed	O
daily	O
for	O
4	O
weeks	O
with	O
samples	O
taken	O
from	O
the	O
urethra	O
for	O
virus	O
isolation	O
.	O

Next	O
,	O
with	O
carcinoma	O
presenting	O
a	O
leather	O
bottle	O
(	O
linitis	O
plastica	O
type	O
)	O
of	O
the	O
stomach	O
itself	O
,	O
the	O
II	O
c	O
portion	O
of	O
the	O
stomach	O
consisted	O
of	O
fundic	O
glands	O
(	O
undifferentiated	O
carcinoma	O
)	O
shall	O
become	O
the	O
primary	O
focus	O
supporting	O
Nakamura	O
'	O
s	O
theory	O
.	O

During	O
the	O
biosynthesis	O
of	O
all	O
three	O
mutant	O
polypeptides	O
,	O
the	O
signal	O
peptide	O
is	O
efficiently	O
and	O
accurately	O
cleaved	O
from	O
the	O
nascent	O
protein	O
,	O
even	O
though	O
in	O
mutants	O
X2	O
and	O
X3	O
the	O
cleavage	O
site	O
itself	O
has	O
been	O
altered	O
.	O

The	O
hexanucleotide	O
5	O
'	O
-	O
TGTCCT	O
-	O
3	O
'	O
,	O
thought	O
to	O
be	O
important	O
for	O
GRE	O
activity	O
,	O
not	O
only	O
was	O
found	O
in	O
this	O
sequence	O
and	O
in	O
the	O
5	O
'	O
-	O
flanking	O
region	O
,	O
but	O
also	O
was	O
present	O
twice	O
in	O
the	O
3	O
'	O
end	O
of	O
the	O
gene	O
that	O
did	O
not	O
show	O
specific	O
receptor	O
binding	O
.	O

The	O
smallest	O
of	O
the	O
mini	O
-	O
Mu	O
elements	O
is	O
only	O
7	O
.	O
9	O
kilobase	O
pairs	O
long	O
,	O
allowing	O
the	O
cloning	O
of	O
DNA	O
fragments	O
of	O
up	O
to	O
31	O
.	O
1	O
kilobase	O
pairs	O
,	O
and	O
the	O
largest	O
of	O
them	O
is	O
21	O
.	O
7	O
kilobase	O
pairs	O
,	O
requiring	O
that	O
clones	O
carry	O
insertions	O
of	O
less	O
than	O
17	O
.	O
3	O
kilobase	O
pairs	O
.	O

The	O
52	O
-	O
protein	O
subunit	O
of	O
T4	B-GENE
DNA	I-GENE
topoisomerase	I-GENE
is	O
homologous	O
to	O
the	O
gyrA	B-GENE
-	I-GENE
protein	I-GENE
of	O
gyrase	B-GENE
.	O

The	O
latent	O
periods	O
from	O
the	O
antral	O
exclusion	O
to	O
the	O
occurrence	O
of	O
anastomotic	O
ulcers	O
after	O
a	O
subtotal	O
gastrectomy	O
with	O
Billroth	O
'	O
s	O
type	O
II	O
reconstruction	O
varied	O
from	O
a	O
few	O
days	O
to	O
19	O
years	O
,	O
with	O
an	O
average	O
of	O
2	O
.	O
8	O
years	O
.	O

The	O
nucleosomal	O
arrays	O
detected	O
by	O
MPE	O
X	O
Fe	O
(	O
II	O
)	O
were	O
characterized	O
by	O
a	O
considerable	O
loss	O
of	O
detail	O
and	O
significantly	O
enhanced	O
accessibility	O
,	O
the	O
extent	O
of	O
which	O
probably	O
reflected	O
the	O
relative	O
transcription	O
rate	O
of	O
each	O
gene	O
.	O

The	O
molecular	O
weight	O
of	O
in	O
vivo	O
-	O
labeled	O
proteins	O
was	O
increased	O
relative	O
to	O
that	O
of	O
in	O
vitro	O
-	O
translated	O
proteins	O
,	O
indicating	O
that	O
a	O
posttranslational	O
modification	O
had	O
occurred	O
.	O

Insertion	O
of	O
4	O
bp	O
reduced	O
SV40	B-GENE
early	I-GENE
promoter	I-GENE
-	O
dependent	O
chloramphenicol	B-GENE
acetyltransferase	I-GENE
(	O
CAT	B-GENE
)	O
expression	O
by	O
six	O
-	O
to	O
eightfold	O
.	O

In	O
the	O
DNAs	O
of	O
all	O
Ph1	O
-	O
positive	O
chronic	O
myelocytic	O
leukemia	O
patients	O
studied	O
to	O
date	O
,	O
a	O
breakpoint	O
on	O
chromosome	O
22	O
(	O
the	O
Ph1	O
chromosome	O
)	O
can	O
be	O
demonstrated	O
with	O
a	O
probe	O
from	O
the	O
bcr	B-GENE
(	O
breakpoint	B-GENE
cluster	I-GENE
region	I-GENE
)	O
.	O

Nuclease	O
footprinting	O
revealed	O
that	O
purified	O
glucocorticoid	B-GENE
receptor	I-GENE
bound	O
at	O
multiple	O
discrete	O
sites	O
within	O
and	O
at	O
the	O
borders	O
of	O
the	O
tandemly	O
repeated	O
sequence	O
motif	O
that	O
defines	O
Sa	B-GENE
.	O

The	O
96	O
-	O
bp	O
insert	O
contained	O
a	O
termination	O
signal	O
which	O
caused	O
the	O
premature	O
termination	O
of	O
the	O
protein	O
,	O
leading	O
to	O
the	O
generation	O
of	O
a	O
p53	B-GENE
product	I-GENE
9	O
amino	O
acids	O
shorter	O
than	O
usual	O
.	O

All	O
tumors	O
proved	O
histologically	O
to	O
be	O
neuroendocrine	O
in	O
origin	O
.	O

The	O
coding	O
region	O
of	O
2385	O
nucleotides	O
corresponds	O
to	O
a	O
polypeptide	O
chain	O
of	O
795	O
amino	O
acids	O
,	O
giving	O
a	O
molecular	O
weight	O
of	O
91	O
,	O
555	O
for	O
the	O
hsp108	B-GENE
protein	I-GENE
.	O

Transcriptional	O
control	O
signals	O
of	O
a	O
herpes	B-GENE
simplex	I-GENE
virus	I-GENE
type	I-GENE
1	I-GENE
late	I-GENE
(	I-GENE
gamma	I-GENE
2	I-GENE
)	I-GENE
gene	I-GENE
lie	O
within	O
bases	O
-	O
34	O
to	O
+	O
124	O
relative	O
to	O
the	O
5	O
'	O
terminus	O
of	O
the	O
mRNA	O
.	O

A	O
noncatalytic	O
domain	O
conserved	O
among	O
cytoplasmic	B-GENE
protein	I-GENE
-	I-GENE
tyrosine	I-GENE
kinases	I-GENE
modifies	O
the	O
kinase	O
function	O
and	O
transforming	O
activity	O
of	O
Fujinami	B-GENE
sarcoma	I-GENE
virus	I-GENE
P130gag	I-GENE
-	O
fps	B-GENE
.	O

Gluzman	O
,	O
EMBO	O
J	O
.	O

A	O
single	O
exon	O
encodes	O
the	O
carboxyl	O
-	O
terminal	O
26	O
amino	O
acids	O
of	O
the	O
ssd	B-GENE
chain	I-GENE
and	O
the	O
3	O
'	O
untranslated	O
region	O
of	O
its	O
mRNA	O
,	O
ending	O
with	O
a	O
poly	O
(	O
A	O
)	O
-	O
addition	O
site	O
.	O

The	O
5	O
'	O
-	O
nontranslated	O
sequences	O
and	O
parts	O
of	O
the	O
coding	O
sequences	O
of	O
various	O
yeast	O
genes	O
have	O
been	O
cloned	O
into	O
representative	O
lacZ	B-GENE
fusion	O
vectors	O
.	O

Two	O
activities	O
of	O
the	O
D	B-GENE
protein	I-GENE
of	O
the	O
miniF	O
plasmid	O
have	O
been	O
found	O
.	O

SPECT	O
examination	O
of	O
the	O
TMJ	O
using	O
99m	O
Tc	O
-	O
MDP	O
was	O
performed	O
in	O
43	O
patients	O
with	O
arthrographically	O
proven	O
anterior	O
dislocation	O
of	O
the	O
disc	O
and	O
in	O
30	O
normals	O
.	O

Plasma	B-GENE
renin	I-GENE
activity	O
rose	O
and	O
the	O
plasma	O
aldosterone	O
level	O
fell	O
after	O
taking	O
lisinopril	O
.	O

The	O
second	O
group	O
of	O
homologous	O
elements	O
is	O
present	O
in	O
the	O
upstream	O
region	O
of	O
both	O
genes	O
.	O

Constitutive	O
function	O
of	O
a	O
positively	O
regulated	O
promoter	O
reveals	O
new	O
sequences	O
essential	O
for	O
activity	O
.	O

We	O
inserted	O
genes	O
or	O
gene	O
segments	O
,	O
that	O
code	O
for	O
the	O
bacterial	B-GENE
chloramphenicol	I-GENE
acetyltransferase	I-GENE
,	O
the	O
bacterial	O
gene	O
conferring	O
resistance	O
against	O
hygromycin	O
,	O
and	O
the	O
ORF	O
E7	B-GENE
of	O
the	O
human	O
papillomavirus	O
type	O
18	O
into	O
these	O
vectors	O
.	O

By	O
contrast	O
,	O
their	O
basal	O
adrenal	O
androgen	O
levels	O
were	O
significantly	O
decreased	O
compared	O
to	O
those	O
in	O
normal	O
subjects	O
on	O
both	O
the	O
day	O
on	O
and	O
the	O
day	O
off	O
prednisone	O
(	O
P	O
less	O
than	O
0	O
.	O
05	O
)	O
.	O

Identification	O
of	O
p40x	O
-	O
responsive	O
regulatory	O
sequences	O
within	O
the	O
human	O
T	O
-	O
cell	O
leukemia	O
virus	O
type	O
I	O
long	O
terminal	O
repeat	O
.	O

During	O
pentobarbital	O
anesthesia	O
,	O
the	O
basal	O
VO2	O
was	O
5	O
.	O
26	O
ml	O
/	O
kg	O
/	O
min	O
and	O
was	O
increased	O
by	O
epinephrine	O
in	O
a	O
dose	O
dependent	O
manner	O
at	O
plasma	O
concentrations	O
between	O
3	O
.	O
9	O
ng	O
/	O
ml	O
(	O
VO2	O
=	O
5	O
.	O
68	O
ml	O
/	O
kg	O
/	O
min	O
)	O
and	O
36	O
.	O
5	O
ng	O
/	O
ml	O
(	O
VO2	O
=	O
6	O
.	O
47	O
ml	O
/	O
kg	O
/	O
min	O
)	O
.	O

Oligonucleotide	O
-	O
directed	O
mutagenesis	O
was	O
used	O
to	O
create	O
an	O
NdeI	B-GENE
restriction	I-GENE
site	I-GENE
at	O
the	O
natural	O
ATG	O
of	O
the	O
yeast	O
R	O
.	O

ACTH	B-GENE
release	O
is	O
transiently	O
suppressed	O
in	O
some	O
children	O
after	O
exogenous	O
ACTH	B-GENE
treatment	O
.	O

We	O
previously	O
showed	O
that	O
the	O
upstream	O
promoter	O
element	O
of	O
the	O
yeast	B-GENE
RP39A	I-GENE
gene	I-GENE
consists	O
of	O
these	O
identical	O
sequence	O
motifs	O
.	O

These	O
data	O
suggest	O
that	O
mammalian	O
erythroid	O
alpha	B-GENE
-	I-GENE
spectrin	I-GENE
evolved	O
by	O
duplication	O
and	O
rapid	O
divergence	O
from	O
an	O
ancestral	O
alpha	B-GENE
-	I-GENE
fodrin	I-GENE
-	I-GENE
like	I-GENE
gene	I-GENE
.	O

One	O
group	O
of	O
six	O
cDNA	O
clones	O
was	O
derived	O
from	O
a	O
2	O
.	O
9	O
-	O
kilobase	O
early	O
transcript	O
encoded	O
by	O
the	O
IR2	O
repeat	O
element	O
and	O
showed	O
restriction	O
site	O
polymorphism	O
for	O
the	O
enzyme	B-GENE
SmaI	I-GENE
.	O

Combined	O
immunochemotherapy	O
with	O
cyclophosphamide	O
plus	O
BCG	O
gave	O
a	O
better	O
enhancement	O
of	O
the	O
antitumor	O
effect	O
of	O
the	O
cytostatic	O
than	O
that	O
of	O
the	O
combination	O
of	O
methotrexate	O
plus	O
BCG	O
and	O
cyclophosphamide	O
plus	O
levamisole	O
.	O

Indeed	O
,	O
A	O
-	O
MuLV	O
pseudotyped	O
with	O
some	O
viruses	O
,	O
such	O
as	O
the	O
Moloney	O
MuLV	O
,	O
has	O
been	O
shown	O
to	O
be	O
highly	O
lymphogenic	O
,	O
whereas	O
A	O
-	O
MuLV	O
pseudotyped	O
with	O
other	O
viruses	O
,	O
such	O
as	O
the	O
BALB	O
/	O
c	O
endogenous	O
N	O
-	O
tropic	O
MuLV	O
,	O
has	O
been	O
shown	O
to	O
be	O
devoid	O
of	O
lymphogenic	O
potential	O
(	O
N	O
.	O

The	O
presence	O
of	O
circulating	O
platelet	O
aggregates	O
and	O
elevated	O
levels	O
of	O
fibrinopeptide	B-GENE
A	I-GENE
(	O
a	O
cleavage	O
product	O
of	O
fibrin	B-GENE
)	O
suggests	O
that	O
platelet	O
activation	O
and	O
fibrin	B-GENE
deposition	O
may	O
play	O
a	O
role	O
in	O
the	O
pathogenesis	O
of	O
this	O
disorder	O
.	O

4	O
.	O

In	O
general	O
,	O
the	O
values	O
obtained	O
by	O
the	O
two	O
methods	O
were	O
in	O
agreement	O
for	O
each	O
species	O
of	O
epidermal	B-GENE
growth	I-GENE
factor	I-GENE
and	O
followed	O
the	O
order	O
:	O
wild	O
type	O
greater	O
than	O
Glu24	O
-	O
-	O
-	O
-	O
Gly	O
greater	O
than	O
Asp27	O
-	O
-	O
-	O
-	O
Gly	O
much	O
greater	O
than	O
Pro7	O
-	O
-	O
-	O
-	O
Thr	O
greater	O
than	O
Tyr29	O
-	O
-	O
-	O
-	O
Gly	O
greater	O
than	O
Leu47	O
-	O
-	O
-	O
-	O
His	O
.	O

It	O
is	O
concluded	O
that	O
suppression	O
of	O
elevated	O
prolactin	B-GENE
levels	O
in	O
progressive	O
metastatic	O
breast	O
cancer	O
patients	O
is	O
not	O
effective	O
in	O
restoring	O
tumor	O
sensitivity	O
to	O
chemotherapy	O
.	O

We	O
report	O
a	O
prevalence	O
study	O
of	O
the	O
best	O
visual	O
acuity	O
in	O
the	O
affected	O
eye	O
of	O
100	O
selected	O
patients	O
with	O
herpetic	O
keratitis	O
seen	O
during	O
a	O
two	O
-	O
year	O
period	O
.	O

We	O
also	O
found	O
an	O
eIF	B-GENE
-	I-GENE
4A	I-GENE
intronless	O
retroposon	O
which	O
,	O
when	O
compared	O
to	O
the	O
cDNA	O
,	O
contains	O
a	O
single	O
nucleotide	O
difference	O
.	O

After	O
infection	O
of	O
293	O
cells	O
(	O
which	O
provide	O
complementary	O
E1a	B-GENE
-	O
E1b	B-GENE
functions	O
)	O
,	O
both	O
viruses	O
directed	O
equal	O
amounts	O
of	O
P	B-GENE
/	I-GENE
C	I-GENE
-	I-GENE
specific	I-GENE
mRNA	I-GENE
transcription	O
.	O

This	O
observation	O
cannot	O
be	O
explained	O
by	O
the	O
scanning	O
model	O
for	O
ribosomal	O
initiation	O
and	O
suggests	O
that	O
ribosomes	O
may	O
be	O
binding	O
directly	O
at	O
an	O
internal	O
mRNA	O
site	O
at	O
or	O
near	O
the	O
initiator	O
AUG	O
codon	O
for	O
the	O
C	B-GENE
protein	I-GENE
.	O

In	O
view	O
of	O
these	O
results	O
,	O
simultaneous	O
pancreas	O
-	O
kidney	O
transplantation	O
appears	O
to	O
be	O
the	O
treatment	O
of	O
choice	O
for	O
Type	O
I	O
diabetic	O
patients	O
.	O

This	O
makes	O
these	O
compounds	O
attractive	O
as	O
vehicles	O
for	O
these	O
and	O
other	O
gases	O
in	O
-	O
vivo	O
and	O
in	O
-	O
vitro	O
.	O

DNA	O
sequencing	O
of	O
the	O
DPM1	B-GENE
gene	I-GENE
revealed	O
an	O
open	O
reading	O
frame	O
of	O
801	O
bases	O
.	O

The	O
relationship	O
between	O
primary	O
malignant	O
lymphoma	O
of	O
the	O
thyroid	O
and	O
chronic	O
thyroiditis	O
is	O
discussed	O
.	O

Administration	O
of	O
anticoagulants	O
,	O
i	O
.	O
e	O
.	O
,	O
heparin	O
,	O
prostaglandin	O
E1	O
and	O
ticlopidine	O
seems	O
to	O
be	O
effective	O
in	O
alleviating	O
symptoms	O
and	O
might	O
prevent	O
further	O
deterioration	O
.	O

Mutational	O
analysis	O
of	O
the	O
L1	B-GENE
binding	I-GENE
site	I-GENE
of	O
23S	B-GENE
rRNA	I-GENE
in	I-GENE
Escherichia	I-GENE
coli	I-GENE
.	O

Animals	O
may	O
be	O
immunized	O
by	O
oral	O
vaccination	O
,	O
but	O
natural	O
mechanisms	O
that	O
also	O
can	O
terminate	O
outbreaks	O
are	O
discussed	O
.	O

Prostacyclin	O
formation	O
,	O
reflected	O
by	O
the	O
excretion	O
rate	O
of	O
its	O
stable	O
metabolite	O
6	O
-	O
keto	O
-	O
prostaglandin	O
F1	O
alpha	O
,	O
was	O
measured	O
by	O
means	O
of	O
radioimmunoassay	O
in	O
4	O
-	O
hour	O
urine	O
specimens	O
obtained	O
during	O
a	O
smoking	O
-	O
free	O
period	O
and	O
after	O
participants	O
had	O
inhaled	O
smoke	O
from	O
four	O
high	O
-	O
nicotine	O
cigarettes	O
.	O

However	O
,	O
excretion	O
of	O
6	O
-	O
keto	O
-	O
prostaglandin	O
F1	O
alpha	O
was	O
further	O
reduced	O
in	O
the	O
smokers	O
who	O
used	O
oral	O
contraceptives	O
(	O
133	O
+	O
/	O
-	O
20	O
to	O
86	O
+	O
/	O
-	O
9	O
ng	O
/	O
gm	O
of	O
creatinine	O
,	O
p	O
less	O
than	O
0	O
.	O
05	O
)	O
.	O

The	O
in	O
vitro	O
activity	O
of	O
mecillinam	O
and	O
amoxicillin	O
/	O
clavulanic	O
acid	O
against	O
Escherichia	O
coli	O
strains	O
producing	O
beta	B-GENE
-	I-GENE
lactamases	I-GENE
of	O
the	O
TEM	B-GENE
-	I-GENE
1	I-GENE
,	O
Oxa	B-GENE
-	I-GENE
1	I-GENE
and	O
chromosomal	O
type	O
were	O
studied	O
using	O
the	O
broth	O
and	O
agar	O
dilution	O
technique	O
.	O

GCN4	B-GENE
encodes	O
a	O
transcriptional	O
activator	O
of	O
amino	O
acid	O
biosynthetic	O
genes	O
in	O
Saccharomyces	O
cerevisiae	O
.	O

These	O
results	O
imply	O
that	O
the	O
GCN3	B-GENE
product	I-GENE
can	O
promote	O
either	O
repression	O
or	O
activation	O
of	O
GCN4	B-GENE
expression	O
depending	O
on	O
amino	O
acid	O
availability	O
.	O

The	O
efficacy	O
of	O
these	O
immunosuppressive	O
drugs	O
is	O
clinical	O
proven	O
.	O

The	O
amino	O
acid	O
sequence	O
of	O
the	O
S	O
.	O
aureus	O
peptide	O
carrying	O
the	O
phosphoryl	O
group	O
was	O
found	O
to	O
be	O
Gln	O
-	O
Val	O
-	O
Val	O
-	O
Ser	O
-	O
Thr	O
-	O
Phe	O
-	O
Met	O
-	O
Gly	O
-	O
Asn	O
-	O
Gly	O
-	O
Leu	O
-	O
Ala	O
-	O
Ile	O
-	O
Pro	O
-	O
His	O
-	O
Gly	O
-	O
Thr	O
-	O
Asp	O
-	O
Asp	O
.	O

These	O
mutations	O
alter	O
two	O
regions	O
of	O
GAL4	B-GENE
protein	I-GENE
:	O
the	O
DNA	O
binding	O
domain	O
,	O
and	O
the	O
transcription	O
activation	O
domain	O
.	O

The	O
results	O
indicated	O
that	O
two	O
genes	O
(	O
citA	B-GENE
and	O
citB	B-GENE
)	O
have	O
separate	O
promoters	O
,	O
and	O
the	O
location	O
of	O
the	O
promoter	O
for	O
the	O
citB	B-GENE
gene	I-GENE
in	O
the	O
Tn3411	B-GENE
nucleotide	O
sequence	O
was	O
different	O
from	O
that	O
in	O
pMS185	O
.	O

The	O
rci	B-GENE
gene	I-GENE
was	O
fused	O
with	O
lacZ	B-GENE
and	O
its	O
gene	O
product	O
was	O
identified	O
by	O
Western	O
blot	O
analysis	O
.	O

Structure	O
and	O
regulation	O
of	O
a	O
nuclear	O
gene	O
in	O
Saccharomyces	O
cerevisiae	O
that	O
specifies	O
MRP13	B-GENE
,	O
a	O
protein	O
of	O
the	O
small	O
subunit	O
of	O
the	O
mitochondrial	O
ribosome	O
.	O

After	O
a	O
survey	O
of	O
the	O
anatomical	O
and	O
physiological	O
basis	O
of	O
operative	O
treatment	O
of	O
behaviour	O
disorders	O
by	O
stereotactic	O
lesions	O
in	O
the	O
amygdala	O
and	O
the	O
posterior	O
medial	O
hypothalamus	O
the	O
author	O
describes	O
his	O
own	O
experiences	O
with	O
603	O
operations	O
for	O
control	O
of	O
conservatively	O
untreatable	O
aggressiveness	O
.	O

Although	O
large	O
epidemiologic	O
studies	O
are	O
best	O
able	O
to	O
identify	O
the	O
relative	O
contributions	O
of	O
specific	O
risk	O
factors	O
while	O
controlling	O
for	O
other	O
risk	O
factors	O
,	O
new	O
studies	O
need	O
to	O
focus	O
on	O
important	O
unresolved	O
questions	O
.	O

The	O
amino	O
acid	O
sequences	O
of	O
the	O
yeast	O
and	O
mammalian	O
mitochondrial	O
targeting	O
sequences	O
are	O
similar	O
but	O
less	O
related	O
than	O
the	O
mature	O
polypeptides	O
.	O

During	O
insulin	B-GENE
infusion	O
,	O
a	O
20	O
%	O
dextrose	O
solution	O
was	O
infused	O
by	O
a	O
Biostator	O
in	O
order	O
to	O
maintain	O
the	O
patient	O
'	O
s	O
glycemia	O
at	O
90	O
mg	O
/	O
dl	O
.	O

Amounts	O
of	O
glucose	O
infused	O
during	O
the	O
last	O
20	O
min	O
of	O
each	O
2	O
hour	O
insulin	B-GENE
infusion	O
were	O
(	O
at	O
1	O
and	O
10	O
m	O
/	O
kg	O
/	O
min	O
respectively	O
)	O
:	O
before	O
treatment	O
(	O
K	O
+	O
=	O
2	O
.	O
7	O
mmol	O
/	O
l	O
)	O
:	O
2	O
.	O
4	O
and	O
8	O
.	O
4	O
mg	O
/	O
kg	O
/	O
min	O
;	O
after	O
spironolactone	O
(	O
K	O
+	O
=	O
3	O
.	O
9	O
mmol	O
/	O
l	O
)	O
:	O
3	O
.	O
3	O
and	O
15	O
.	O
4	O
mg	O
/	O
kg	O
/	O
min	O
;	O
after	O
indomethacine	O
(	O
K	O
+	O
=	O
3	O
.	O
7	O
mmol	O
/	O
l	O
)	O
:	O
5	O
and	O
19	O
mg	O
/	O
kg	O
/	O
min	O
after	O
stopping	O
drugs	O
(	O
K	O
+	O
=	O
2	O
.	O
9	O
mmol	O
/	O
l	O
)	O
:	O
2	O
.	O
5	O
and	O
5	O
.	O
3	O
mg	O
/	O
kg	O
/	O
min	O
.	O

Mycobacterium	O
avium	O
-	O
intracellulare	O
complex	O
infections	O
in	O
the	O
acquired	O
immunodeficiency	O
syndrome	O
.	O

Recurrence	O
of	O
oxalate	O
deposition	O
in	O
a	O
renal	O
transplant	O
during	O
ciclosporin	O
A	O
therapy	O
.	O

The	O
bile	O
acid	O
sequestrants	O
(	O
cholestyramine	O
and	O
colestipol	O
)	O
,	O
nicotinic	O
acid	O
,	O
fenofibrate	O
and	O
inhibitors	O
of	O
hydroxymethylglutaryl	B-GENE
coenzyme	I-GENE
A	I-GENE
(	I-GENE
HMG	I-GENE
CoA	I-GENE
)	I-GENE
reductase	I-GENE
(	O
e	O
.	O
g	O
.	O
lovastatin	O
or	O
simvastatin	O
)	O
are	O
the	O
most	O
effective	O
drugs	O
for	O
use	O
in	O
patients	O
with	O
primary	O
hypercholesterolaemia	O
;	O
these	O
agents	O
reduce	O
plasma	O
concentrations	O
of	O
total	O
and	O
LDL	B-GENE
-	I-GENE
cholesterol	I-GENE
by	O
15	O
to	O
45	O
%	O
.	O

Finally	O
,	O
the	O
pathophysiological	O
aspects	O
of	O
urinary	O
acidification	O
are	O
discussed	O
,	O
focusing	O
on	O
renal	O
tubular	O
acidosis	O
models	O
(	O
induced	O
by	O
maleate	O
and	O
amphotericin	O
B	O
treatment	O
)	O
and	O
their	O
cellular	O
mechanisms	O
,	O
as	O
well	O
as	O
the	O
role	O
of	O
adrenal	O
steroids	O
in	O
urinary	O
acidification	O
.	O

Analysis	O
in	O
3	O
groups	O
of	O
patients	O
suffering	O
from	O
simple	O
acute	O
and	O
pernicious	O
malarial	O
flare	O
-	O
ups	O

Statement	O
on	O
the	O
development	O
of	O
guidelines	O
for	O
the	O
prevention	O
of	O
AIDS	O
transmission	O
in	O
the	O
workplace	O
.	O

Modifications	O
of	O
the	O
involuntary	O
postcontraction	O
in	O
diseased	O
people	O
.	O

Cocaine	O
-	O
treated	O
rats	O
acquired	O
a	O
preference	O
for	O
cocaine	O
-	O
associated	O
contextual	O
stimuli	O
(	O
CS	O
)	O
relative	O
to	O
saline	O
-	O
injected	O
control	O
rats	O
.	O

Under	O
these	O
schedules	O
,	O
a	O
reinforced	O
response	O
run	O
consisted	O
of	O
responding	O
between	O
eight	O
and	O
12	O
times	O
on	O
one	O
response	O
key	O
(	O
work	O
key	O
)	O
and	O
then	O
responding	O
once	O
on	O
a	O
second	O
response	O
key	O
(	O
reinforced	O
key	O
)	O
.	O

Intravenous	O
glucose	O
tolerance	O
tests	O
were	O
performed	O
before	O
operation	O
,	O
before	O
starting	O
CyA	O
and	O
after	O
3	O
weeks	O
.	O

The	O
effects	O
of	O
glutaraldehyde	O
on	O
dimensions	O
and	O
ultrastructure	O
of	O
microvascular	O
beds	O
in	O
rat	O
mesentery	O
were	O
studied	O
in	O
two	O
kinds	O
of	O
experiment	O
,	O
administering	O
the	O
fixative	O
by	O
intra	O
-	O
arterial	O
perfusion	O
at	O
a	O
pressure	O
of	O
80	O
mm	O
Hg	O
and	O
by	O
superfusion	O
of	O
the	O
exteriorized	O
mesenteric	O
membrane	O
.	O

This	O
gave	O
rise	O
to	O
RNA	O
molecules	O
with	O
3	O
'	O
-	O
untranslated	O
regions	O
of	O
roughly	O
375	O
,	O
655	O
,	O
and	O
945	O
base	O
pairs	O
.	O

Also	O
,	O
the	O
BALB	B-GENE
/	I-GENE
c	I-GENE
gene	I-GENE
contains	O
a	O
single	O
substitution	O
in	O
a	O
conserved	O
octamer	O
sequence	O
approximately	O
equal	O
to	O
100	O
nucleotides	O
upstream	O
of	O
the	O
coding	O
region	O
,	O
which	O
could	O
affect	O
its	O
expression	O
.	O

Our	O
data	O
suggest	O
that	O
it	O
may	O
be	O
possible	O
to	O
individualize	O
hCG	B-GENE
administration	O
at	O
midcycle	O
by	O
determining	O
the	O
number	O
of	O
follicles	O
greater	O
than	O
1	O
cm	O
by	O
ultrasound	O
on	O
cycle	O
day	O
12	O
or	O
13	O
and	O
giving	O
hCG	B-GENE
when	O
serum	O
E2	O
levels	O
reach	O
1100	O
to	O
1200	O
pmol	O
/	O
l	O
per	O
follicle	O
.	O

Within	O
Stage	O
IA	O
,	O
141	O
patients	O
had	O
well	O
differentiated	O
tumor	O
(	O
G1	O
)	O
,	O
20	O
had	O
moderately	O
well	O
differentiated	O
tumor	O
(	O
G2	O
)	O
,	O
and	O
12	O
patients	O
had	O
poorly	O
differentiated	O
(	O
G3	O
)	O
.	O

Mechanism	O
of	O
the	O
t	O
(	O
14	O
;	O
18	O
)	O
chromosomal	O
translocation	O
:	O
structural	O
analysis	O
of	O
both	O
derivative	O
14	O
and	O
18	O
reciprocal	O
partners	O
.	O

After	O
age	O
30	O
,	O
mean	O
hemoglobin	B-GENE
levels	O
for	O
men	O
gradually	O
declined	O
,	O
while	O
those	O
in	O
women	O
rose	O
,	O
so	O
that	O
the	O
sex	O
difference	O
diminished	O
after	O
60	O
years	O
of	O
age	O
.	O

Ritanserin	O
is	O
a	O
new	O
substance	O
with	O
highly	O
selective	O
blocking	O
activity	O
on	O
S2	B-GENE
receptors	I-GENE
for	O
5	O
-	O
HT	O
in	O
the	O
central	O
nervous	O
system	O
.	O

Ethylene	O
glycol	O
and	O
diethylene	O
glycol	O
were	O
each	O
administered	O
once	O
weekly	O
subcutaneously	O
to	O
groups	O
of	O
100	O
female	O
NMRI	O
mice	O
at	O
3	O
dosages	O
(	O
30	O
;	O
10	O
und	O
3	O
mg	O
single	O
dose	O
per	O
mouse	O
)	O
.	O

Research	O
on	O
ethylene	O
glycol	O
and	O
diethylene	O
glycol	O
for	O
carcinogenic	O
effects	O

The	O
results	O
suggest	O
that	O
the	O
greater	O
estrogenic	O
influence	O
associated	O
with	O
the	O
ethinyl	O
estradiol	O
-	O
containing	O
OC	O
resulted	O
in	O
inhibition	O
of	O
coronary	O
artery	O
atherosclerosis	O
despite	O
a	O
pronounced	O
progestin	O
-	O
induced	O
lowering	O
of	O
plasma	O
HDL	B-GENE
cholesterol	I-GENE
concentration	O
and	O
,	O
further	O
,	O
that	O
hormonal	O
balance	O
may	O
have	O
a	O
marked	O
influence	O
on	O
the	O
relationship	O
between	O
plasma	O
lipids	O
and	O
atherogenesis	O
.	O

During	O
BH	O
the	O
ventilator	O
was	O
disconnected	O
and	O
a	O
bias	O
flow	O
of	O
50	O
%	O
O2	O
at	O
4	O
-	O
5	O
l	O
/	O
min	O
was	O
delivered	O
through	O
the	O
side	O
ports	O
of	O
a	O
small	O
catheter	O
whose	O
tip	O
was	O
positioned	O
1	O
cm	O
cephalad	O
of	O
the	O
carina	O
.	O

Comparison	O
of	O
beta	B-GENE
2	I-GENE
-	I-GENE
microglobulin	I-GENE
removal	O
using	O
the	O
same	O
polysulphone	O
membrane	O
for	O
haemodialysis	O
and	O
haemofiltration	O
shows	O
that	O
beta	B-GENE
2	I-GENE
-	I-GENE
microglobulin	I-GENE
is	O
more	O
effectively	O
removed	O
by	O
convection	O
than	O
by	O
diffusion	O
when	O
both	O
treatment	O
modes	O
are	O
matched	O
for	O
blood	O
flow	O
and	O
urea	O
clearance	O
.	O

40	O
.	O
3	O
+	O
/	O
-	O
10	O
.	O
1	O
mg	O
/	O
l	O
(	O
SD	O
)	O
vs	O
31	O
.	O
2	O
+	O
/	O
-	O
8	O
.	O
0	O
,	O
P	O
less	O
than	O
0	O
.	O
01	O
)	O
.	O
beta	B-GENE
2m	I-GENE
was	O
not	O
significantly	O
higher	O
in	O
patients	O
with	O
bone	O
cysts	O
(	O
37	O
.	O
7	O
+	O
/	O
-	O
11	O
.	O
4	O
mg	O
/	O
l	O
vs	O
37	O
.	O
0	O
+	O
/	O
-	O
10	O
.	O
0	O
)	O
,	O
but	O
median	O
duration	O
of	O
dialysis	O
was	O
significantly	O
(	O
P	O
less	O
than	O
0	O
.	O
01	O
)	O
longer	O
in	O
patients	O
with	O
bone	O
cysts	O
(	O
90	O
vs	O
57	O
months	O
)	O
.	O
beta	B-GENE
2m	I-GENE
was	O
lower	O
in	O
patients	O
maintained	O
on	O
dialysis	O
for	O
less	O
than	O
1	O
year	O
and	O
whose	O
residual	O
urine	O
volume	O
was	O
greater	O
than	O
0	O
.	O
1	O
litre	O
per	O
day	O
.	O

The	O
mean	O
percentage	O
of	O
linoleic	O
acid	O
in	O
the	O
triglycerides	O
of	O
the	O
subcutaneous	O
adipose	O
tissue	O
(	O
PLASAT	O
)	O
of	O
these	O
subjects	O
was	O
substantially	O
higher	O
than	O
that	O
in	O
a	O
similar	O
group	O
examined	O
in	O
1975	O
-	O
1976	O
.	O

In	O
overdoses	O
up	O
to	O
2	O
g	O
fluvoxamine	O
no	O
lasting	O
toxic	O
effects	O
were	O
observed	O
.	O

It	O
is	O
concluded	O
that	O
the	O
plasma	B-GENE
prolactin	I-GENE
response	O
to	O
12	O
.	O
5	O
micrograms	O
i	O
.	O
v	O
.	O

The	O
remaining	O
six	O
patients	O
had	O
slightly	O
decreased	O
(	O
n	O
=	O
3	O
)	O
or	O
normal	O
(	O
n	O
=	O
3	O
)	O
seminal	O
parameters	O
.	O

In	O
addition	O
,	O
a	O
wild	O
-	O
type	O
strain	O
containing	O
a	O
temperature	B-GENE
-	I-GENE
sensitive	I-GENE
threonyl	I-GENE
-	I-GENE
tRNA	I-GENE
synthetase	I-GENE
mutation	I-GENE
showed	O
increased	O
thr	B-GENE
operon	I-GENE
expression	O
at	O
the	O
non	O
-	O
permissive	O
temperature	O
,	O
whereas	O
none	O
of	O
the	O
mutants	O
showed	O
any	O
change	O
.	O

Significant	O
treatment	O
-	O
related	O
problems	O
appeared	O
during	O
the	O
second	O
decade	O
in	O
5	O
patients	O
,	O
including	O
one	O
chest	O
wall	O
sarcoma	O
;	O
all	O
of	O
these	O
patients	O
had	O
received	O
at	O
least	O
60	O
Gy	O
to	O
breast	O
and	O
regional	O
nodal	O
areas	O
.	O

Of	O
7	O
patients	O
treated	O
with	O
cyclophosphamide	O
,	O
hexamethylmelamine	O
,	O
adriamycin	O
and	O
cisplatin	O
(	O
CHAP	O
-	O
5	O
)	O
,	O
6	O
had	O
measurable	O
disease	O
,	O
of	O
whom	O
5	O
yielded	O
a	O
response	O
(	O
2	O
complete	O
responses	O
for	O
19	O
+	O
and	O
40	O
months	O
and	O
3	O
partial	O
responses	O
for	O
4	O
,	O
7	O
and	O
8	O
months	O
)	O
.	O

Isolation	O
and	O
characterization	O
of	O
a	O
vinculin	B-GENE
cDNA	I-GENE
from	I-GENE
chick	I-GENE
-	I-GENE
embryo	I-GENE
fibroblasts	I-GENE
.	O

A	O
complementary	O
study	O
,	O
showing	O
a	O
good	O
agreement	O
between	O
surface	O
and	O
oesophageal	O
EMGd	O
seems	O
to	O
confirm	O
that	O
surface	O
EMGd	O
is	O
a	O
useful	O
and	O
promising	O
tool	O
for	O
clinical	O
investigation	O
.	O

No	O
differences	O
in	O
fixation	O
quality	O
were	O
observed	O
between	O
cochleas	O
fixed	O
by	O
intravascular	O
perfusion	O
and	O
cochleas	O
fixed	O
by	O
intralabyrinthine	O
perfusion	O
.	O

The	O
DNA	O
sequence	O
encodes	O
a	O
protein	O
of	O
1520	O
amino	O
acids	O
with	O
sequence	O
homology	O
to	O
the	O
human	B-GENE
c	I-GENE
-	I-GENE
abl	I-GENE
proto	I-GENE
-	I-GENE
oncogene	I-GENE
product	I-GENE
,	O
beginning	O
at	O
the	O
amino	O
terminus	O
and	O
extending	O
656	O
amino	O
acids	O
through	O
the	O
region	O
essential	O
for	O
tyrosine	B-GENE
kinase	I-GENE
activity	O
.	O

The	O
requirement	O
of	O
different	O
essential	O
fatty	O
acids	O
in	O
patients	O
with	O
total	O
parenteral	O
nutrition	O
after	O
heavy	O
injury	O
is	O
of	O
special	O
interest	O
with	O
respect	O
to	O
the	O
development	O
and	O
prognosis	O
of	O
shock	O
,	O
sepsis	O
or	O
adult	O
respiratory	O
distress	O
syndrome	O
.	O

The	O
Drosophila	B-GENE
melanogaster	I-GENE
Gart	I-GENE
gene	I-GENE
encodes	O
three	O
enzymatic	O
activities	O
in	O
the	O
pathway	O
for	O
purine	O
de	O
novo	O
synthesis	O
.	O

The	O
role	O
of	O
neuroplasticity	O
in	O
the	O
response	O
to	O
drugs	O
.	O

Biol	O
.	O

The	O
heart	O
rate	O
,	O
respiratory	O
rate	O
,	O
arterial	O
O2	O
and	O
systemic	O
vascular	O
resistance	O
were	O
not	O
significantly	O
altered	O
.	O

Human	B-GENE
rIL	I-GENE
-	I-GENE
3	I-GENE
expressed	O
in	O
COS7	O
cells	O
has	O
multipotential	O
CSF	B-GENE
activity	O
in	O
semisolid	O
cultures	O
of	O
bone	O
marrow	O
cells	O
,	O
and	O
selectively	O
induced	O
the	O
proliferation	O
of	O
My	O
-	O
10	O
+	O
marrow	O
or	O
cord	O
blood	O
cells	O
in	O
liquid	O
cultures	O
.	O

In	O
14	O
patients	O
whose	O
PaCO2	O
was	O
greater	O
than	O
or	O
equal	O
to	O
39	O
torr	O
(	O
range	O
39	O
to	O
58	O
torr	O
)	O
and	O
clinical	O
asthma	O
score	O
was	O
6	O
or	O
greater	O
,	O
PaCO2	O
decreased	O
a	O
mean	O
of	O
11	O
.	O
7	O
torr	O
during	O
a	O
mean	O
of	O
8	O
.	O
1	O
hours	O
.	O

A	O
randomized	O
,	O
prospective	O
study	O
was	O
conducted	O
to	O
compare	O
ovarian	O
stimulation	O
with	O
human	B-GENE
menopausal	I-GENE
gonadotropin	I-GENE
(	O
hMG	B-GENE
)	O
and	O
human	B-GENE
follicle	I-GENE
-	I-GENE
stimulating	I-GENE
hormone	I-GENE
(	O
hFSH	B-GENE
)	O
in	O
an	O
in	O
vitro	O
fertilization	O
and	O
embryo	O
transfer	O
(	O
IVF	O
-	O
ET	O
)	O
program	O
.	O

Our	O
findings	O
suggest	O
that	O
the	O
mtr	B-GENE
product	I-GENE
causes	O
both	O
transcription	O
attenuation	O
and	O
inhibition	O
of	O
translation	O
of	O
trpE	B-GENE
mRNA	I-GENE
.	O

Apropos	O
of	O
a	O
case	O

A	O
prostaglandin	O
analogue	O
given	O
in	O
early	O
pregnancy	O
and	O
human	B-GENE
chorionic	I-GENE
gonadotropin	I-GENE
given	O
near	O
the	O
end	O
of	O
the	O
ensuing	O
follicular	O
phase	O
were	O
used	O
for	O
controlling	O
the	O
reproductive	O
cycle	O
,	O
timing	O
oocyte	O
collection	O
,	O
and	O
synchronizing	O
the	O
cycles	O
of	O
oocyte	O
donors	O
and	O
embryo	O
recipients	O
.	O

The	O
nucleolin	B-GENE
gene	I-GENE
extends	O
over	O
9000	O
base	O
-	O
pairs	O
and	O
is	O
split	O
into	O
14	O
exons	O
that	O
encode	O
the	O
706	O
amino	O
acid	O
residues	O
of	O
the	O
protein	O
.	O

Although	O
L	O
-	O
threo	O
-	O
dihydroxyphenylserine	O
(	O
DOPS	O
)	O
,	O
an	O
artificial	O
norepinephrine	O
(	O
NE	O
)	O
precursor	O
,	O
did	O
not	O
change	O
immobility	O
in	O
intact	O
mice	O
,	O
DOPS	O
significantly	O
reduced	O
immobility	O
in	O
mice	O
pretreated	O
with	O
the	O
selective	O
NE	O
neurotoxin	O
DSP4	O
.	O

Substantial	O
amounts	O
of	O
liposomal	O
ampicillin	O
were	O
recovered	O
from	O
isolated	O
Kupffer	O
cells	O
,	O
the	O
target	O
cells	O
of	O
L	O
.	O
monocytogenes	O
after	O
intravenous	O
inoculation	O
.	O

This	O
suggested	O
that	O
delta	O
6	O
and	O
delta	O
5	O
desaturation	O
activities	O
are	O
normal	O
in	O
these	O
conditions	O
with	O
this	O
C18	O
:	O
2w6	O
supply	O
.	O

Here	O
we	O
report	O
the	O
complete	O
6	O
-	O
kilobase	O
cDNA	O
sequence	O
coding	O
for	O
a	O
chain	O
of	O
1775	O
amino	O
acids	O
,	O
as	O
well	O
as	O
the	O
genomic	O
structure	O
.	O

HDL	B-GENE
-	I-GENE
cholesterol	I-GENE
(	O
+	O
6	O
%	O
,	O
P	O
less	O
than	O
.	O
01	O
)	O
and	O
apolipoprotein	B-GENE
A	I-GENE
-	I-GENE
I	I-GENE
(	O
+	O
6	O
%	O
,	O
P	O
less	O
than	O
.	O
01	O
)	O
concentrations	O
increased	O
significantly	O
only	O
in	O
the	O
young	O
.	O

The	O
Euglena	B-GENE
ribosomal	I-GENE
protein	I-GENE
gene	I-GENE
cluster	I-GENE
resembles	O
the	O
S	B-GENE
-	I-GENE
10	I-GENE
ribosomal	I-GENE
protein	I-GENE
operon	I-GENE
of	I-GENE
Escherichia	I-GENE
coli	I-GENE
in	O
gene	O
organization	O
and	O
follows	O
the	O
exact	O
linear	O
order	O
of	O
the	O
analogous	O
genes	O
in	O
the	O
tobacco	O
and	O
liverwort	O
chloroplast	O
genomes	O
.	O

The	O
distribution	O
of	O
the	O
sites	O
of	O
recombinational	O
resolution	O
is	O
inversely	O
correlated	O
with	O
that	O
of	O
the	O
gradient	O
of	O
sequence	O
divergence	O
,	O
with	O
only	O
approximately	O
7	O
%	O
of	O
the	O
X	O
recombinants	O
resolved	O
within	O
the	O
3	O
'	O
third	O
of	O
the	O
X	O
blocks	O
where	O
two	O
diverged	O
Alu	B-GENE
family	O
repeats	O
reside	O
.	O

The	O
nucleotide	O
sequence	O
of	O
the	O
region	O
upstream	O
from	O
M	B-GENE
.	I-GENE
voltae	I-GENE
ORFtrpA	I-GENE
was	O
determined	O
and	O
revealed	O
the	O
presence	O
of	O
an	O
ORF	O
of	O
1227	O
nucleotides	O
(	O
ORFtrpB	B-GENE
)	O
encoding	O
a	O
409	O
amino	O
acid	O
polypeptide	O
of	O
mol	O
.	O
wt	O
.	O

Of	O
49	O
receptors	O
which	O
fired	O
in	O
phase	O
with	O
ventilation	O
,	O
13	O
behaved	O
like	O
mammalian	O
rapidly	O
adapting	O
pulmonary	O
stretch	O
receptors	O
,	O
19	O
like	O
mammalian	O
slowly	O
adapting	O
pulmonary	O
stretch	O
receptors	O
(	O
PSR	O
)	O
,	O
and	O
17	O
like	O
avian	O
intrapulmonary	O
CO2	O
-	O
sensitive	O
chemoreceptors	O
(	O
IPC	O
)	O
.	O

Symptomatic	O
hyperventilators	O
had	O
a	O
larger	O
number	O
of	O
sighs	O
and	O
abnormally	O
wide	O
fluctuations	O
in	O
baseline	O
for	O
inspiratory	O
time	O
,	O
expiratory	O
time	O
,	O
and	O
PETCO2	O
.	O

In	O
the	O
IA	O
task	O
,	O
post	O
-	O
training	O
intraperitoneal	O
injections	O
of	O
picrotoxin	O
and	O
bicuculline	O
induced	O
a	O
dose	O
-	O
dependent	O
enhancement	O
of	O
retention	O
measured	O
24	O
h	O
after	O
the	O
training	O
,	O
while	O
retention	O
was	O
not	O
affected	O
by	O
bicuculline	O
methiodide	O
(	O
a	O
GABA	B-GENE
receptor	I-GENE
antagonist	O
that	O
does	O
not	O
readily	O
cross	O
the	O
blood	O
-	O
brain	O
barrier	O
)	O
.	O

Clinical	O
research	O
of	O
non	O
-	O
A	O
,	O
non	O
-	O
B	O
post	O
-	O
transfusion	O
hepatitis	O

It	O
is	O
suggested	O
that	O
the	O
use	O
of	O
endogenous	O
creatinine	O
clearance	O
to	O
estimate	O
the	O
glomerular	O
filtration	O
rate	O
(	O
GFR	O
)	O
requires	O
caution	O
and	O
the	O
recognition	O
of	O
the	O
limitations	O
of	O
the	O
method	O
,	O
and	O
that	O
simpler	O
techniques	O
(	O
serum	O
creatinine	O
or	O
estimated	O
endogenous	O
creatinine	O
clearance	O
)	O
are	O
preferable	O
in	O
routine	O
practice	O
.	O

The	O
protein	O
mixtures	O
of	O
sesame	O
flour	O
and	O
soybean	O
flour	O
were	O
well	O
accepted	O
.	O

The	O
5	O
'	O
end	O
of	O
the	O
coding	O
region	O
was	O
located	O
precisely	O
by	O
comparing	O
the	O
deduced	O
amino	O
acid	O
sequence	O
to	O
the	O
actual	O
N	O
-	O
terminal	O
amino	O
acid	O
sequence	O
of	O
IHF	B-GENE
.	O

A	O
protein	O
footprint	O
also	O
was	O
identified	O
for	O
a	O
GC	O
box	O
element	O
at	O
nucleotides	O
-	O
59	O
to	O
-	O
45	O
.	O

Insulin	B-GENE
-	I-GENE
like	I-GENE
growth	I-GENE
factor	I-GENE
II	I-GENE
(	O
IGFII	B-GENE
)	O
is	O
a	O
mitogenic	O
polypeptide	O
,	O
the	O
mRNAs	O
of	O
which	O
are	O
present	O
in	O
multiple	O
forms	O
,	O
despite	O
derivation	O
from	O
a	O
single	O
gene	O
.	O

The	O
central	O
visual	O
fields	O
of	O
2165	O
normal	O
and	O
106	O
glaucoma	O
eyes	O
were	O
measured	O
using	O
a	O
threshold	O
related	O
suprathreshold	O
strategy	O
.	O

Effect	O
of	O
chronic	O
undernutrition	O
on	O
susceptibility	O
to	O
cold	O
stress	O
in	O
young	O
adult	O
and	O
aged	O
rats	O
.	O

This	O
effect	O
and	O
the	O
fact	O
that	O
all	O
three	O
doses	O
were	O
toxic	O
to	O
the	O
dams	O
dictated	O
that	O
a	O
second	O
experiment	O
be	O
carried	O
out	O
at	O
lower	O
doses	O
.	O

The	O
CHARGE	O
association	O
is	O
a	O
collection	O
of	O
multisystem	O
congenital	O
anomalies	O
including	O
choanal	O
atresia	O
.	O

Esophageal	O
brush	O
cytological	O
screening	O
was	O
undertaken	O
and	O
blood	O
concentrations	O
of	O
micronutrients	O
(	O
vitamin	O
A	O
,	O
E	O
,	O
B12	O
,	O
folic	O
acid	O
and	O
methionine	O
)	O
determined	O
from	O
adults	O
at	O
risk	O
for	O
esophageal	O
carcinoma	O
(	O
EC	O
)	O
in	O
Transkei	O
and	O
Ciskei	O
,	O
Southern	O
Africa	O
.	O

Aviators	O
from	O
the	O
Light	O
Attack	O
Wing	O
,	O
Pacific	O
were	O
surveyed	O
and	O
the	O
results	O
were	O
categorized	O
by	O
aircraft	O
type	O
.	O

Evaluation	O
of	O
human	O
and	O
bovine	O
modified	O
-	O
hemoglobin	B-GENE
solution	O
as	O
oxygen	O
-	O
carrying	O
fluid	O
for	O
blood	O
volume	O
replacement	O
.	O

Delayed	O
gallbladder	O
visualization	O
and	O
reduction	O
in	O
ejection	O
fraction	O
were	O
sensitive	O
but	O
nonspecific	O
indicators	O
of	O
biliary	O
disease	O
.	O

26	O
micrograms	O
PAF	B-GENE
or	O
placebo	O
was	O
sprayed	O
into	O
each	O
nasal	O
cavity	O
8	O
h	O
and	O
1	O
h	O
before	O
a	O
nasal	O
allergen	O
challenge	O
.	O

Sci	O
.	O

Chem	O
.	O

Sequential	O
MR	O
examinations	O
of	O
the	O
nasal	O
cavity	O
and	O
paranasal	O
sinuses	O
were	O
performed	O
within	O
a	O
6	O
-	O
8	O
h	O
period	O
in	O
five	O
normal	O
volunteers	O
.	O

Comparison	O
was	O
made	O
with	O
other	O
neuroradiological	O
imaging	O
modalities	O
including	O
CT	O
,	O
myelography	O
,	O
CT	O
ventriculography	O
,	O
and	O
CT	O
myelocisternography	O
.	O

The	O
feed	O
given	O
to	O
young	O
broiler	O
chickens	O
was	O
contaminated	O
artificially	O
with	O
Salmonella	O
kedougou	O
,	O
a	O
serotype	O
associated	O
with	O
both	O
subclinical	O
infections	O
in	O
commercially	O
reared	O
chickens	O
and	O
food	O
poisoning	O
in	O
humans	O
.	O

A	O
poor	O
correlation	O
was	O
found	O
between	O
a	O
mildly	O
-	O
atypical	O
(	O
inflammatory	O
)	O
cytological	O
result	O
(	O
class	O
2	O
)	O
and	O
a	O
benign	O
histological	O
diagnosis	O
:	O
48	O
%	O
of	O
class	O
-	O
2	O
smears	O
were	O
diagnosed	O
histologically	O
as	O
dysplasia	O
or	O
worse	O
.	O

Change	O
in	O
plasma	B-GENE
cystyl	I-GENE
aminopeptidase	I-GENE
(	O
oxytocinase	B-GENE
)	O
between	O
30	O
-	O
34	O
weeks	O
'	O
gestation	O
as	O
a	O
predictor	O
of	O
pregnancy	O
-	O
induced	O
hypertension	O
.	O

The	O
test	O
for	O
alpha	B-GENE
-	I-GENE
naphthyl	I-GENE
esterase	I-GENE
and	O
quantitation	O
of	O
macrophages	O
(	O
absolute	O
number	O
)	O
per	O
infiltration	O
area	O
unit	O
adjacent	O
to	O
the	O
abscess	O
suggest	O
a	O
direct	O
correlation	O
between	O
the	O
absolute	O
number	O
of	O
macrophages	O
and	O
the	O
width	O
of	O
the	O
capsule	O
.	O

Determined	O
as	O
migration	O
differentials	O
,	O
chemotactic	O
and	O
chemokinetic	O
responsiveness	O
tended	O
to	O
be	O
higher	O
in	O
the	O
neutropenic	O
group	O
.	O

The	O
deduced	O
96	O
-	O
residue	O
amino	O
acid	O
coding	O
sequence	O
of	O
the	O
murine	O
HMG	B-GENE
-	I-GENE
I	I-GENE
(	I-GENE
Y	I-GENE
)	I-GENE
cDNA	O
is	O
very	O
similar	O
to	O
the	O
reported	O
amino	O
acid	O
sequence	O
of	O
human	O
HMG	B-GENE
-	I-GENE
I	I-GENE
,	O
except	O
that	O
it	O
lacks	O
11	O
internal	O
amino	O
acids	O
reported	O
in	O
the	O
human	O
protein	O
.	O

Interpersonal	O
style	O
differences	O
among	O
drug	O
abusers	O
were	O
explored	O
using	O
Ryan	O
'	O
s	O
(	O
1977	O
)	O
typological	O
system	O
of	O
FIRO	O
-	O
B	O
interpretation	O
.	O

Statement	O
of	O
the	O
American	O
Academy	O
of	O
Implant	O
Dentistry	O
.	O

Sera	O
from	O
euthyroid	O
post	O
-	O
menopausal	O
or	O
pregnant	O
women	O
yielded	O
TSH	B-GENE
levels	O
within	O
the	O
normal	O
range	O
.	O

No	O
UOxase	B-GENE
mRNA	I-GENE
was	O
detected	O
in	O
11	O
nonhepatic	O
tissues	O
of	O
rat	O
,	O
suggesting	O
tissue	O
specificity	O
of	O
expression	O
of	O
this	O
UOxase	B-GENE
gene	I-GENE
.	O

The	O
platelet	O
adhesion	O
rate	O
on	O
these	O
layers	O
were	O
tested	O
concerning	O
the	O
valuation	O
of	O
the	O
haemocompatibility	O
of	O
the	O
basic	O
-	O
polymers	O
polyurethane	O
(	O
PUR	O
)	O
,	O
polyvinylchloride	O
(	O
PVC	O
)	O
,	O
and	O
polystyrene	O
(	O
PS	O
)	O
in	O
two	O
different	O
worked	O
test	O
chambers	O
.	O

In	O
a	O
112	O
-	O
d	O
feedlot	O
trial	O
,	O
105	O
heifers	O
were	O
assigned	O
to	O
light	O
,	O
medium	O
and	O
heavy	O
weight	O
blocks	O
on	O
five	O
treatments	O
:	O
dietary	O
MGA	O
(	O
.	O
5	O
mg	O
.	O
hd	O
-	O
1	O
.	O
d	O
-	O
1	O
)	O
,	O
control	O
(	O
no	O
MGA	O
)	O
or	O
DEPO	O
-	O
MGA	O
on	O
d	O
1	O
at	O
.	O
5	O
,	O
1	O
.	O
0	O
or	O
1	O
.	O
5	O
ml	O
/	O
hd	O
(	O
30	O
,	O
60	O
or	O
90	O
mg	O
MGA	O
/	O
hd	O
,	O
respectively	O
)	O
.	O

Existence	O
and	O
uniqueness	O
of	O
solutions	O
of	O
the	O
appropriate	O
boundary	O
value	O
problems	O
are	O
established	O
,	O
in	O
the	O
case	O
of	O
small	O
permeability	O
coefficients	O
and	O
transport	O
rates	O
,	O
or	O
large	O
diffusion	O
coefficients	O
and	O
small	O
resistance	O
to	O
flow	O
constants	O
.	O

There	O
were	O
gene	O
clusters	O
encoding	O
photosynthesis	O
components	O
such	O
as	O
the	O
psbB	B-GENE
-	O
psbH	B-GENE
-	O
petB	B-GENE
-	O
petD	B-GENE
and	O
the	O
psbE	O
-	O
psbF	O
clusters	O
.	O

The	O
partial	O
sequence	O
of	O
the	O
62	B-GENE
-	I-GENE
kDa	I-GENE
nuclear	I-GENE
pore	I-GENE
glycoprotein	I-GENE
shows	O
little	O
similarity	O
to	O
other	O
characterized	O
proteins	O
and	O
elucidates	O
structural	O
features	O
of	O
a	O
member	O
of	O
the	O
family	O
of	O
nuclear	B-GENE
pore	I-GENE
glycoproteins	I-GENE
.	O

Seventy	O
-	O
two	O
hours	O
after	O
administration	O
of	O
vitamin	O
K1	O
,	O
plasma	O
concentrations	O
of	O
the	O
vitamin	O
were	O
not	O
different	O
from	O
normal	O
.	O

The	O
glomerular	O
filtration	O
rate	O
did	O
not	O
change	O
but	O
lithium	O
clearance	O
fell	O
by	O
30	O
%	O
.	O

The	O
pathogenesis	O
of	O
Dupuytren	O
'	O
s	O
contracture	O

An	O
ELISA	O
procedure	O
was	O
developed	O
for	O
monitoring	O
the	O
specific	O
IgE	B-GENE
response	O
in	O
dogs	O
to	O
Dirofilaria	O
immitis	O
infection	O
.	O

Fifty	O
min	O
after	O
release	O
from	O
stress	O
,	O
increases	O
in	O
plasma	O
corticosterone	O
levels	O
induced	O
by	O
stress	O
recovered	O
in	O
the	O
biting	O
group	O
but	O
remained	O
high	O
in	O
the	O
non	O
-	O
biting	O
group	O
.	O

The	O
only	O
isolate	O
of	O
Aeromonas	O
hydrophila	O
produced	O
cytotoxic	O
enterotoxin	O
and	O
was	O
invasive	O
.	O

The	O
incidence	O
of	O
early	O
neonatal	O
convulsions	O
for	O
inborn	O
babies	O
was	O
3	O
.	O
0	O
/	O
1000	O
live	O
births	O
.	O

Of	O
the	O
43	O
infants	O
with	O
a	O
(	O
probable	O
)	O
loss	O
18	O
were	O
examined	O
again	O
at	O
3	O
months	O
corrected	O
age	O
.	O

Variety	O
of	O
cows	O
and	O
sires	O
according	O
to	O
types	O
of	O
dermatoglyphics	O
(	O
patterns	O
)	O
of	O
the	O
nose	O
-	O
labial	O
mirror	O
of	O
cattle	O

Although	O
not	O
consistently	O
identified	O
in	O
all	O
samples	O
,	O
secondary	O
Academic	O
,	O
Personal	O
Responsibility	O
,	O
and	O
Community	O
/	O
Vocational	O
dimensions	O
were	O
also	O
identified	O
.	O

Recovery	O
was	O
characterized	O
by	O
rapid	O
improvement	O
such	O
that	O
all	O
measured	O
parameters	O
normalized	O
by	O
1	O
week	O
,	O
except	O
for	O
cross	O
-	O
sectional	O
cardiac	O
area	O
which	O
remained	O
dilated	O
up	O
to	O
4	O
weeks	O
(	O
14	O
+	O
/	O
-	O
3	O
cm2	O
,	O
p	O
less	O
than	O
0	O
.	O
05	O
versus	O
control	O
)	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
250	O
WORDS	O
)	O

Not	O
even	O
extensive	O
pancreatic	O
resection	O
could	O
prevent	O
pancreatic	O
remnant	O
infection	O
.	O

It	O
has	O
been	O
calculated	O
that	O
600	O
,	O
000	O
new	O
cases	O
of	O
lung	O
cancer	O
occur	O
worldwide	O
every	O
year	O
,	O
most	O
of	O
them	O
due	O
to	O
smoking	O
.	O

Incorporation	O
of	O
0	O
.	O
1	O
or	O
0	O
.	O
2	O
M	O
sodium	O
dihydrogen	O
phosphate	O
in	O
the	O
sugar	O
solutions	O
resulted	O
in	O
a	O
decrease	O
in	O
the	O
shelf	O
-	O
life	O
of	O
diltiazem	O
.	O

None	O
had	O
a	O
past	O
history	O
of	O
opportunistic	O
infections	O
;	O
neither	O
did	O
any	O
have	O
lymphopenia	O
.	O

Increasing	O
the	O
phosphorus	O
content	O
of	O
the	O
diet	O
improved	O
the	O
reabsorption	O
of	O
calcium	O
and	O
magnesium	O
.	O

Post	O
-	O
transcriptional	O
regulation	O
of	O
ribosomal	B-GENE
protein	I-GENE
gene	I-GENE
expression	O
during	O
development	O
in	O
Dictyostelium	O
discoideum	O
.	O

The	O
increase	O
in	O
amplitudes	O
of	O
the	O
b	O
-	O
wave	O
during	O
the	O
adaptation	O
period	O
was	O
more	O
prominent	O
in	O
lead	O
-	O
exposed	O
subjects	O
than	O
in	O
controls	O
.	O

Possible	O
factors	O
for	O
the	O
development	O
of	O
psychotic	O
symptomatology	O
during	O
group	O
activities	O
and	O
the	O
role	O
of	O
group	O
dynamics	O
acting	O
as	O
stress	O
factors	O
precipitating	O
functional	O
psychoses	O
,	O
especially	O
bipolar	O
manifestations	O
,	O
are	O
discussed	O
.	O

Baseline	O
measurements	O
of	O
forced	O
expiratory	O
volume	O
in	O
1	O
s	O
(	O
FEV1	O
)	O
,	O
specific	O
airway	O
conductance	O
(	O
SGaw	O
)	O
and	O
the	O
provocative	O
dose	O
of	O
carbachol	O
causing	O
a	O
35	O
%	O
reduction	O
in	O
SGaw	O
(	O
PD35	O
)	O
,	O
and	O
a	O
20	O
%	O
reduction	O
in	O
FEV1	O
(	O
PD20	O
)	O
were	O
established	O
on	O
entry	O
while	O
each	O
subject	O
was	O
still	O
smoking	O
.	O

Many	O
children	O
with	O
BGC	O
are	O
delayed	O
in	O
their	O
development	O
,	O
but	O
calcifications	O
are	O
not	O
directly	O
related	O
to	O
specific	O
forms	O
of	O
neurologic	O
dysfunction	O
.	O

R	O
-	O
wave	O
voltage	O
in	O
the	O
right	O
precordial	O
leads	O
in	O
anthracycline	O
cardiomyopathy	O
:	O
a	O
clinical	O
study	O
.	O

The	O
results	O
indicate	O
that	O
the	O
pooling	O
requirements	O
are	O
task	O
dependent	O
.	O

These	O
results	O
indicate	O
that	O
CSFHU	B-GENE
can	O
increase	O
neutrophil	O
counts	O
by	O
increasing	O
the	O
number	O
and	O
maturity	O
of	O
the	O
marrow	O
neutrophil	O
precursors	O
in	O
some	O
types	O
of	O
childhood	O
chronic	O
neutropenia	O
.	O

The	O
purposes	O
of	O
this	O
study	O
were	O
1	O
)	O
to	O
examine	O
the	O
effect	O
of	O
high	O
intensity	O
,	O
low	O
frequency	O
transcutaneous	O
electrical	O
nerve	O
stimulation	O
at	O
auricular	O
acupuncture	O
points	O
on	O
experimental	O
pain	O
threshold	O
measured	O
at	O
the	O
wrist	O
and	O
2	O
)	O
to	O
determine	O
the	O
changes	O
in	O
effect	O
over	O
time	O
.	O

In	O
the	O
infected	O
neonates	O
serum	O
alpha	B-GENE
-	I-GENE
amylase	I-GENE
value	O
,	O
as	O
determined	O
by	O
the	O
blue	O
starch	O
method	O
,	O
was	O
only	O
40	O
%	O
that	O
of	O
healthy	O
controls	O
;	O
the	O
mean	O
value	O
of	O
175	O
.	O
1	O
+	O
/	O
-	O
64	O
.	O
9	O
IU	O
/	O
l	O
for	O
healthy	O
neonates	O
was	O
significantly	O
higher	O
(	O
p	O
less	O
than	O
0	O
.	O
0010	O
)	O
than	O
the	O
value	O
of	O
82	O
.	O
8	O
+	O
/	O
-	O
44	O
.	O
4	O
IU	O
/	O
l	O
for	O
the	O
infected	O
neonates	O
.	O

Records	O
of	O
31	O
children	O
with	O
AIDS	O
or	O
AIDS	O
-	O
related	O
complex	O
admitted	O
to	O
the	O
pediatric	O
intensive	O
care	O
unit	O
for	O
acute	O
respiratory	O
failure	O
throughout	O
a	O
46	O
-	O
month	O
period	O
were	O
reviewed	O
.	O

SPECT	O
is	O
an	O
important	O
aid	O
in	O
the	O
diagnosis	O
of	O
AIDS	O
dementia	O
complex	O
and	O
contributes	O
to	O
the	O
understanding	O
of	O
the	O
pathophysiological	O
mechanisms	O
of	O
this	O
disorder	O
.	O

We	O
were	O
interested	O
in	O
studying	O
the	O
relationship	O
between	O
the	O
circadian	O
rhythm	O
in	O
body	O
temperature	O
and	O
24	O
-	O
h	O
variations	O
in	O
plasma	O
concentrations	O
of	O
iron	O
,	O
zinc	O
,	O
circulating	O
leukocyte	O
counts	O
,	O
and	O
plasma	O
interleukin	B-GENE
1	I-GENE
(	O
IL	B-GENE
-	I-GENE
1	I-GENE
)	O
activity	O
.	O

The	O
murine	B-GENE
MHC	I-GENE
class	I-GENE
I	I-GENE
genes	I-GENE
,	O
H	B-GENE
-	I-GENE
2Dq	I-GENE
and	O
H	B-GENE
-	I-GENE
2Lq	I-GENE
,	O
are	O
strikingly	O
homologous	O
to	O
each	O
other	O
,	O
H	B-GENE
-	I-GENE
2Ld	I-GENE
,	O
and	O
two	O
genes	O
reported	O
to	O
encode	O
tumor	O
-	O
specific	O
antigens	O
.	O

The	O
active	O
derivatives	O
of	O
the	O
present	O
series	O
were	O
also	O
tested	O
for	O
their	O
analgesic	O
activity	O
against	O
aconitine	O
-	O
induced	O
writhing	O
in	O
albino	O
mice	O
and	O
ulcerogenic	O
activity	O
in	O
albino	O
rats	O
.	O

In	O
untreated	O
mice	O
,	O
bactericidal	O
activity	O
of	O
peritoneal	O
macrophages	O
decreased	O
from	O
one	O
day	O
to	O
3	O
days	O
after	O
ip	O
injection	O
of	O
killed	O
L	O
.	O
monocytogenes	O
.	O

Among	O
a	O
population	O
of	O
18	O
,	O
175	O
children	O
below	O
7	O
years	O
of	O
age	O
in	O
medium	O
sized	O
towns	O
and	O
rural	O
areas	O
in	O
south	O
-	O
western	O
Germany	O
552	O
(	O
3	O
.	O
03	O
%	O
)	O
cases	O
of	O
croup	O
were	O
registered	O
during	O
a	O
12	O
months	O
period	O
in	O
1984	O
-	O
85	O
by	O
their	O
physicians	O
.	O

We	O
concluded	O
that	O
Ga	O
-	O
fbg	O
scintigraphy	O
is	O
a	O
very	O
simple	O
method	O
and	O
sufficiently	O
useful	O
for	O
detecting	O
active	O
left	O
ventricular	O
thrombi	O
and	O
for	O
monitoring	O
the	O
effect	O
of	O
anticoagulant	O
therapy	O
.	O

In	O
vitro	O
assessment	O
of	O
the	O
biocompatibility	O
of	O
dental	O
materials	O
-	O
-	O
the	O
millipore	O
filter	O
method	O
.	O

Hypomagnesemia	O
was	O
due	O
to	O
magnesium	O
wasting	O
by	O
the	O
kidney	O
.	O

Dentalplaque	O
was	O
controlled	O
by	O
the	O
oral	O
higienic	O
index	O
of	O
the	O
whole	O
dentition	O
daily	O
,	O
after	O
staining	O
with	O
1	O
per	O
cent	O
alkaline	O
fuxin	O
.	O

GRFI	B-GENE
bound	O
to	O
sequences	O
at	O
the	O
negative	O
regulatory	O
elements	O
(	O
silencers	O
)	O
of	O
the	O
silent	B-GENE
mating	I-GENE
type	I-GENE
loci	I-GENE
HML	B-GENE
E	I-GENE
and	O
HMR	B-GENE
E	I-GENE
and	O
to	O
the	O
upstream	O
activating	O
sequence	O
(	O
UAS	O
)	O
required	O
for	O
transcription	O
of	O
the	O
MAT	B-GENE
alpha	I-GENE
genes	I-GENE
.	O

The	O
effects	O
of	O
these	O
mutations	O
on	O
RNA	B-GENE
polymerase	I-GENE
II	I-GENE
activity	O
were	O
assayed	O
by	O
measuring	O
the	O
ability	O
of	O
mutant	O
genes	O
to	O
confer	O
alpha	B-GENE
-	I-GENE
amanitin	I-GENE
resistance	O
after	O
transfection	O
of	O
susceptible	O
rodent	O
cells	O
.	O

We	O
report	O
the	O
use	O
of	O
a	O
new	O
technetium	O
-	O
99m	O
-	O
albumin	B-GENE
colloid	O
white	O
blood	O
cell	O
(	O
TAC	O
-	O
WBC	O
)	O
scan	O
in	O
the	O
evaluation	O
of	O
appendicitis	O
.	O

In	O
one	O
of	O
these	O
tumors	O
the	O
observed	O
rearrangement	O
was	O
not	O
due	O
to	O
the	O
insertion	O
of	O
an	O
intact	O
MoMuLV	O
provirus	O
.	O

The	O
indications	O
for	O
its	O
use	O
include	O
every	O
primary	O
and	O
secondary	O
rhinoplasty	O
candidate	O
unless	O
tip	O
grafts	O
are	O
going	O
to	O
be	O
under	O
tension	O
or	O
if	O
the	O
deformity	O
is	O
minor	O
.	O

Mutations	O
at	O
the	O
suf12	B-GENE
locus	I-GENE
were	O
isolated	O
in	O
Saccharomyces	O
cerevisiae	O
as	O
extragenic	O
suppressors	O
of	O
+	O
1	O
frameshift	O
mutations	O
in	O
glycine	O
(	O
GGX	O
)	O
and	O
proline	O
(	O
CCX	O
)	O
codons	O
,	O
as	O
well	O
as	O
UGA	O
and	O
UAG	O
nonsense	O
mutations	O
.	O

The	O
behavior	O
of	O
suf12	B-GENE
-	I-GENE
null	I-GENE
/	I-GENE
SUF12	I-GENE
+	I-GENE
heterozygotes	I-GENE
indicates	O
that	O
suf12	B-GENE
is	O
co	O
-	O
dominantly	O
expressed	O
and	O
suggests	O
that	O
suf12	B-GENE
allele	O
-	O
specific	O
suppression	O
may	O
result	O
from	O
functionally	O
distinct	O
mutant	O
proteins	O
rather	O
than	O
variation	O
in	O
residual	O
wild	B-GENE
-	I-GENE
type	I-GENE
SUF12	I-GENE
+	I-GENE
activity	O
.	O

Antituberculosis	O
agents	O
.	O

The	O
putative	O
immunity	O
protein	O
was	O
detected	O
among	O
the	O
[	O
35S	O
]	O
methionine	O
-	O
labelled	O
proteins	O
produced	O
by	O
minicells	O
carrying	O
cni	B-GENE
cloned	O
under	O
lac	B-GENE
promoter	I-GENE
control	O
,	O
and	O
when	O
the	O
gene	O
was	O
subcloned	O
into	O
expression	O
vectors	O
under	O
the	O
control	O
of	O
a	O
bacteriophage	O
T7	O
promoter	O
.	O

Antibodies	O
made	O
against	O
fusion	O
protein	O
produced	O
by	O
the	O
DP1A	B-GENE
clone	O
reacted	O
specifically	O
with	O
DP	B-GENE
-	I-GENE
I	I-GENE
and	I-GENE
-	I-GENE
II	I-GENE
on	O
immunoblots	O
.	O

Finally	O
,	O
over	O
a	O
similar	O
range	O
of	O
QO2	O
,	O
oxygen	O
extraction	O
was	O
greater	O
in	O
patients	O
with	O
ARDS	O
compared	O
to	O
patients	O
with	O
non	O
-	O
ARDS	O
respiratory	O
failure	O
(	O
r	O
=	O
-	O
0	O
.	O
67	O
and	O
slope	O
=	O
-	O
0	O
.	O
62	O
vs	O
r	O
=	O
-	O
0	O
.	O
45	O
and	O
slope	O
=	O
-	O
0	O
.	O
35	O
;	O
p	O
less	O
than	O
0	O
.	O
05	O
)	O
.	O

Stable	O
patients	O
have	O
mucous	O
hypersecretion	O
and	O
little	O
evidence	O
of	O
acute	O
inflammation	O
.	O

Hyperprolactinaemia	O
,	O
moderate	O
hypogonadism	O
,	O
infraclinical	O
neuropathies	O
,	O
arterial	O
stenoses	O
and	O
moderate	O
venous	O
leakages	O
seem	O
to	O
play	O
a	O
partial	O
role	O
of	O
organic	O
starter	O
or	O
cofactor	O
,	O
the	O
sexual	O
consequences	O
of	O
which	O
are	O
amplified	O
by	O
psychological	O
factors	O
,	O
partly	O
secondary	O
to	O
the	O
initial	O
sexual	O
failures	O
.	O

Yang	O
and	O
H	O
.	O

Secretory	O
function	O
of	O
the	O
prostate	O
gland	O
.	O

Chronic	O
endotoxemia	O
appears	O
to	O
be	O
associated	O
with	O
an	O
elevated	O
pulmonary	O
microvascular	O
permeability	O
and	O
a	O
tendency	O
toward	O
a	O
hyperdynamic	O
circulation	O
but	O
with	O
an	O
appreciable	O
degree	O
of	O
refractoriness	O
associated	O
with	O
regional	O
hemodynamics	O
and	O
eicosanoid	O
biosynthesis	O
.	O

In	O
contrast	O
,	O
we	O
observed	O
high	O
concentrations	O
in	O
29	O
of	O
75	O
patients	O
with	O
tumors	O
of	O
the	O
central	O
nervous	O
system	O
,	O
especially	O
in	O
meningioma	O
(	O
6	O
/	O
9	O
)	O
,	O
glioblastoma	O
(	O
9	O
/	O
23	O
)	O
,	O
and	O
neurinoma	O
(	O
5	O
/	O
5	O
)	O
.	O

Diet	O
and	O
atopic	O
eczema	O
.	O

Time	O
delay	O
effects	O
on	O
the	O
tensile	O
bond	O
strength	O
developed	O
by	O
the	O
Silicoater	O
.	O

The	O
future	O
of	O
research	O
with	O
interferon	B-GENE
may	O
be	O
divided	O
into	O
three	O
areas	O
:	O
Efforts	O
must	O
be	O
made	O
to	O
determine	O
how	O
best	O
to	O
translate	O
the	O
in	O
vitro	O
synergy	O
into	O
clinically	O
meaningful	O
terms	O
;	O
in	O
order	O
to	O
exploit	O
the	O
fullest	O
potential	O
of	O
IFN	B-GENE
,	O
research	O
is	O
moving	O
toward	O
using	O
this	O
agent	O
earlier	O
in	O
disease	O
either	O
as	O
an	O
adjuvant	O
after	O
tumor	O
debulking	O
or	O
after	O
initial	O
diagnosis	O
;	O
the	O
medical	O
community	O
must	O
rethink	O
the	O
natural	O
history	O
of	O
some	O
diseases	O
,	O
because	O
the	O
fullest	O
potential	O
of	O
the	O
biologic	O
agents	O
will	O
most	O
likely	O
manifest	O
itself	O
when	O
these	O
agents	O
are	O
used	O
together	O
.	O

Six	O
healthy	O
male	O
subjects	O
received	O
single	O
oral	O
doses	O
of	O
regular	O
release	O
(	O
RR	O
)	O
quinidine	O
sulfate	O
,	O
sustained	O
release	O
(	O
SR	O
)	O
quinidine	O
bisulfate	O
and	O
the	O
same	O
dose	O
of	O
the	O
SR	O
product	O
with	O
food	O
(	O
SR	O
-	O
F	O
)	O
.	O

This	O
report	O
expands	O
on	O
previous	O
work	O
with	O
interferon	B-GENE
alfa	I-GENE
-	I-GENE
2b	I-GENE
(	I-GENE
Intron	I-GENE
A	I-GENE
;	I-GENE
Schering	I-GENE
-	I-GENE
Plough	I-GENE
)	I-GENE
in	O
the	O
treatment	O
of	O
hairy	O
cell	O
leukemia	O
(	O
HCL	O
)	O
.	O

Oxygen	O
delivery	O
and	O
base	O
excess	O
decreased	O
significantly	O
and	O
four	O
pigs	O
died	O
.	O

Clinical	O
chemistry	O
.	O

Revascularization	O
after	O
anterior	O
maxillary	O
and	O
mandibular	O
osteotomy	O

Static	O
orthoses	O
for	O
the	O
management	O
of	O
microstomia	O
.	O

The	O
intrapancreatic	O
spread	O
of	O
the	O
carcinoma	O
correlated	O
with	O
portal	O
invasion	O
of	O
carcinoma	O
,	O
hardness	O
of	O
the	O
body	O
and	O
tail	O
,	O
obstruction	O
of	O
main	O
pancreatic	O
duct	O
and	O
irregular	O
pancreaticogram	O
.	O

Lysosomal	O
enzymes	O
that	O
degrade	O
cartilage	O
are	O
released	O
.	O

Contrary	O
to	O
the	O
observation	O
made	O
with	O
other	O
S	O
.	O
pombe	O
genes	O
transcribed	O
in	O
the	O
budding	O
yeast	O
,	O
the	O
heterologous	O
actin	B-GENE
gene	I-GENE
transcript	I-GENE
is	O
initiated	O
39	O
nucleotides	O
upstream	O
of	O
the	O
initiation	O
start	O
site	O
used	O
in	O
the	O
homologous	O
yeast	O
.	O

A	O
multicentre	O
study	O
involving	O
9	O
Italian	O
institutions	O
was	O
carried	O
out	O
to	O
compare	O
the	O
efficacy	O
and	O
safety	O
of	O
ranitidine	O
150	O
mg	O
b	O
.	O
i	O
.	O
d	O
.	O
and	O
ranitidine	O
300	O
mg	O
nocte	O
in	O
the	O
treatment	O
of	O
reflux	O
oesophagitis	O
.	O

Monotherapy	O
with	O
ceftazidime	O
was	O
clinically	O
and	O
bacteriologically	O
as	O
effective	O
as	O
a	O
combination	O
therapy	O
with	O
cefazolin	O
and	O
tobramycin	O
.	O

The	O
N3	O
wave	O
of	O
the	O
SSEP	O
'	O
s	O
,	O
which	O
has	O
been	O
found	O
to	O
correlate	O
best	O
with	O
neurological	O
recovery	O
,	O
returned	O
to	O
65	O
%	O
+	O
/	O
-	O
48	O
%	O
of	O
the	O
preischemia	O
amplitude	O
in	O
the	O
insulin	B-GENE
-	O
treated	O
animals	O
,	O
compared	O
to	O
40	O
%	O
+	O
/	O
-	O
34	O
%	O
in	O
the	O
fasted	O
group	O
and	O
26	O
%	O
+	O
/	O
-	O
24	O
%	O
in	O
the	O
control	O
animals	O
.	O

Proctoscopy	O
and	O
roentgenographic	O
studies	O
may	O
be	O
an	O
important	O
part	O
of	O
evaluation	O
,	O
especially	O
in	O
patients	O
who	O
present	O
with	O
perianal	O
suppuration	O
,	O
masses	O
,	O
or	O
anal	O
fissures	O
.	O

In	O
the	O
control	O
group	O
the	O
histological	O
picture	O
resembled	O
osteoarthritis	O
.	O

In	O
contrast	O
to	O
this	O
mRNA	O
,	O
90	O
%	O
of	O
alpha	B-GENE
and	I-GENE
beta	I-GENE
actin	I-GENE
mRNAs	I-GENE
were	O
translated	O
in	O
both	O
myoblasts	O
and	O
myotubes	O
.	O

If	O
this	O
is	O
unavailable	O
,	O
then	O
Supramid	O
has	O
a	O
proven	O
record	O
for	O
good	O
tissue	O
compatibility	O
and	O
resistance	O
to	O
infection	O
.	O

The	O
size	O
of	O
the	O
group	O
allocated	O
to	O
the	O
good	O
compliance	O
category	O
by	O
the	O
use	O
of	O
the	O
digoxin	O
marker	O
was	O
equivalent	O
in	O
size	O
to	O
a	O
group	O
of	O
patients	O
who	O
had	O
returned	O
less	O
than	O
15	O
%	O
of	O
their	O
prescribed	O
dose	O
or	O
reported	O
a	O
deviation	O
of	O
less	O
than	O
6	O
%	O
from	O
their	O
prescription	O
.	O

Bullous	O
keratopathy	O
was	O
usually	O
aphakic	O
in	O
origin	O
in	O
1982	O
,	O
but	O
after	O
1983	O
pseudophakic	O
bullous	O
keratopathy	O
(	O
PBK	O
)	O
was	O
the	O
most	O
common	O
cause	O
of	O
bullous	O
keratopathy	O
.	O

The	O
ultrastructural	O
findings	O
,	O
as	O
well	O
as	O
the	O
urinary	O
C	B-GENE
-	I-GENE
peptide	I-GENE
excretion	O
,	O
confirmed	O
that	O
the	O
glycemic	O
effects	O
should	O
not	O
be	O
thought	O
to	O
be	O
due	O
to	O
a	O
direct	O
action	O
of	O
the	O
drugs	O
used	O
on	O
the	O
endocrine	O
pancreas	O
.	O

In	O
vitro	O
antimalarial	O
activity	O
of	O
neem	O
(	O
Azadirachta	O
indica	O
A	O
.	O

"	O
In	O
vitro	O
"	O
study	O
of	O
dentin	O
adhesion	O
to	O
adhesives	O
made	O
from	O
urethane	O
molecules	O
with	O
free	O
groups	O
of	O
isocyanate	O

There	O
is	O
a	O
cysteine	O
clustering	O
region	O
in	O
an	O
N	O
-	O
terminal	O
region	O
of	O
the	O
c	B-GENE
-	I-GENE
raf	I-GENE
(	I-GENE
-	I-GENE
1	I-GENE
)	I-GENE
product	I-GENE
deduced	O
from	O
the	O
nucleotide	O
sequence	O
,	O
and	O
this	O
cysteine	O
clustering	O
region	O
was	O
found	O
to	O
be	O
highly	O
homologous	O
to	O
that	O
present	O
in	O
an	O
N	O
-	O
terminal	O
region	O
of	O
protein	B-GENE
kinase	I-GENE
C	I-GENE
,	O
although	O
,	O
in	O
the	O
latter	O
cysteine	O
clusters	O
are	O
present	O
in	O
duplicate	O
.	O

Hand	O
-	O
held	O
,	O
continuous	O
-	O
wave	O
Doppler	O
probes	O
,	O
coupled	O
with	O
sound	O
spectral	O
analysis	O
,	O
can	O
successfully	O
predict	O
carotid	O
artery	O
stenosis	O
.	O

The	O
German	O
Society	O
of	O
Pediatric	O
Oncology	O
in	O
1981	O
initiated	O
the	O
Cooperative	O
Ewing	O
'	O
s	O
Sarcoma	O
Study	O
(	O
CESS	O
81	O
)	O
using	O
a	O
four	O
-	O
drug	O
combination	O
of	O
chemotherapy	O
prior	O
to	O
definitive	O
local	O
control	O
with	O
surgery	O
and	O
/	O
or	O
radiation	O
.	O

The	O
program	O
has	O
been	O
written	O
in	O
a	O
generic	O
BASIC	O
in	O
order	O
to	O
make	O
the	O
procedure	O
user	O
-	O
friendly	O
.	O

Since	O
high	O
levels	O
of	O
immunoglobulin	B-GENE
G	I-GENE
were	O
demonstrated	O
against	O
the	O
surface	O
of	O
the	O
NVS	O
after	O
immunization	O
,	O
passive	O
transfer	O
experiments	O
were	O
initiated	O
.	O

A	O
study	O
was	O
conducted	O
of	O
a	O
human	O
male	O
who	O
had	O
inhaled	O
a	O
mixture	O
of	O
241Am	O
and	O
Pu	O
.	O

An	O
analytic	O
method	O
for	O
comparative	O
parameter	O
weighting	O
in	O
magnetic	O
resonance	O
(	O
MR	O
)	O
imaging	O
has	O
been	O
developed	O
using	O
the	O
concept	O
of	O
"	O
fractional	O
sensitivity	O
.	O
"	O
This	O
new	O
approach	O
results	O
in	O
easily	O
calculated	O
indexes	O
for	O
T1	O
,	O
T2	O
,	O
and	O
hydrogen	O
weighting	O
.	O

Fifty	O
-	O
four	O
patients	O
were	O
divided	O
into	O
groups	O
according	O
to	O
their	O
clinical	O
presentation	O
;	O
seven	O
asymptomatic	O
volunteers	O
,	O
20	O
patients	O
with	O
duodenal	O
-	O
gastric	O
reflux	O
gastropathy	O
(	O
DRG	O
)	O
,	O
16	O
patients	O
with	O
recurrent	O
ulcers	O
of	O
the	O
duodenal	O
bulb	O
(	O
RUD	O
)	O
,	O
and	O
11	O
patients	O
with	O
Moynihan	O
'	O
s	O
disease	O
.	O

No	O
previous	O
studies	O
have	O
determined	O
the	O
pharmaco	O
-	O
dynamics	O
of	O
intravenous	O
procainamide	O
when	O
administered	O
in	O
a	O
dose	O
of	O
15	O
mg	O
/	O
kg	O
and	O
at	O
a	O
rate	O
of	O
50	O
mg	O
/	O
min	O
,	O
as	O
is	O
common	O
practice	O
during	O
electropharmacologic	O
testing	O
.	O

High	O
concentrations	O
of	O
tumor	O
-	O
associated	O
trypsin	B-GENE
inhibitor	O
in	O
hemodialyzed	O
patients	O
.	O

In	O
the	O
chicken	O
liver	O
,	O
levels	O
of	O
chicken	B-GENE
MT	I-GENE
mRNA	I-GENE
were	O
rapidly	O
induced	O
by	O
metals	O
(	O
Cd2	O
+	O
,	O
Zn2	O
+	O
,	O
Cu2	O
+	O
)	O
,	O
glucocorticoids	O
and	O
lipopolysaccharide	O
.	O

With	O
histology	O
and	O
Evans	O
blue	O
injections	O
,	O
blood	O
-	O
brain	O
barrier	O
alterations	O
were	O
seen	O
as	O
early	O
as	O
4	O
days	O
after	O
a	O
dose	O
of	O
50	O
Gy	O
.	O

Dosimetric	O
estimates	O
for	O
these	O
organs	O
were	O
2	O
.	O
3	O
+	O
/	O
-	O
1	O
.	O
1	O
and	O
2	O
.	O
3	O
+	O
/	O
-	O
1	O
.	O
4	O
rad	O
(	O
.	O
02	O
+	O
/	O
-	O
.	O
01	O
Gy	O
)	O
,	O
respectively	O
,	O
with	O
a	O
whole	O
-	O
body	O
estimate	O
of	O
0	O
.	O
28	O
rad	O
(	O
.	O
003	O
Gy	O
)	O
.	O

A	O
significant	O
association	O
between	O
a	O
family	O
history	O
and	O
a	O
higher	O
urinary	O
pH	O
was	O
observed	O
among	O
the	O
female	O
calcium	O
stone	O
patients	O
.	O

New	O
technologies	O
in	O
diagnosis	O
and	O
classification	O
of	O
malignancy	O
.	O

Thus	O
the	O
present	O
data	O
also	O
suggest	O
that	O
BP	O
and	O
HR	O
measurements	O
are	O
influenced	O
not	O
only	O
by	O
state	O
-	O
dependent	O
factors	O
but	O
also	O
by	O
at	O
least	O
three	O
different	O
factors	O
that	O
are	O
each	O
independent	O
of	O
the	O
state	O
:	O
one	O
leads	O
to	O
BP	O
and	O
HR	O
values	O
that	O
are	O
influenced	O
by	O
the	O
cycle	O
the	O
animal	O
is	O
in	O
and	O
the	O
other	O
two	O
influence	O
,	O
respectively	O
,	O
the	O
ranking	O
of	O
the	O
individual	O
'	O
s	O
BP	O
and	O
HR	O
levels	O
within	O
the	O
population	O
.	O

The	O
correlation	O
between	O
PaCO2	O
and	O
PtcO2	O
in	O
RDS	O
was	O
insufficient	O
to	O
make	O
clinical	O
judgement	O
.	O

Since	O
1967	O
at	O
the	O
times	O
of	O
their	O
biennial	O
ABCC	O
/	O
RERF	O
radiological	O
examinations	O
,	O
all	O
Adult	O
Health	O
Study	O
(	O
AHS	O
)	O
subjects	O
have	O
been	O
interviewed	O
to	O
determine	O
the	O
exposures	O
to	O
medical	O
x	O
-	O
rays	O
they	O
experienced	O
in	O
institutions	O
other	O
than	O
RERF	O
in	O
order	O
to	O
estimate	O
the	O
numbers	O
of	O
examinations	O
and	O
corresponding	O
doses	O
which	O
they	O
received	O
.	O

One	O
millimolar	O
ouabain	O
completely	O
inhibited	O
net	O
HCO3	O
-	O
secretion	O
.	O

There	O
are	O
regions	O
with	O
long	O
runs	O
of	O
up	O
to	O
45	O
%	O
C	O
or	O
35	O
%	O
G	O
residues	O
.	O

The	O
same	O
rhythmic	O
structure	O
enables	O
a	O
prediction	O
to	O
be	O
made	O
concerning	O
when	O
vowels	O
of	O
stressed	O
syllables	O
will	O
be	O
auditorily	O
perceived	O
.	O

Vocal	O
cord	O
abduction	O
rehabilitation	O
by	O
nervous	O
selective	O
anastomosis	O
.	O

UK	O
'	O
s	O
biotechnology	O
lacking	O
specialists	O
.	O

Distant	O
spread	O
was	O
found	O
in	O
46	O
patients	O
(	O
34	O
%	O
)	O
,	O
42	O
of	O
whom	O
had	O
serum	O
Tg	B-GENE
greater	O
than	O
10	O
micrograms	O
/	O
l	O
.	O

The	O
glomerular	O
filtration	O
rate	O
and	O
effective	O
renal	O
plasma	O
flow	O
were	O
determined	O
by	O
a	O
standard	O
clearance	O
method	O
,	O
employing	O
continuous	O
infusion	O
of	O
inulin	O
and	O
para	O
-	O
aminohippuric	O
acid	O
.	O

After	O
the	O
meal	O
containing	O
potato	O
,	O
plasma	O
glucose	O
levels	O
rose	O
sharply	O
,	O
peaked	O
at	O
30	O
-	O
45	O
min	O
and	O
fell	O
below	O
initial	O
levels	O
2	O
to	O
3	O
h	O
later	O
.	O

The	O
relations	O
among	O
various	O
negative	O
emotional	O
and	O
behavioral	O
characteristics	O
(	O
e	O
.	O
g	O
.	O
,	O
aggression	O
,	O
anxiety	O
,	O
undercompliance	O
,	O
depressive	O
mood	O
)	O
and	O
adjustment	O
were	O
examined	O
through	O
use	O
of	O
data	O
from	O
the	O
31	O
-	O
year	O
-	O
old	O
New	O
York	O
Longitudinal	O
Study	O
.	O

To	O
evaluate	O
the	O
effect	O
of	O
altitude	O
on	O
adolescent	O
growth	O
and	O
development	O
,	O
three	O
groups	O
of	O
healthy	O
,	O
well	O
-	O
nourished	O
youth	O
of	O
similar	O
socioeconomic	O
status	O
and	O
ethnic	O
grouping	O
who	O
resided	O
at	O
sea	O
level	O
(	O
n	O
=	O
1262	O
subjects	O
)	O
,	O
mid	O
-	O
altitude	O
(	O
n	O
=	O
1743	O
subjects	O
)	O
,	O
and	O
high	O
altitude	O
(	O
n	O
=	O
1137	O
subjects	O
)	O
were	O
studied	O
.	O

Because	O
the	O
CAP	O
measures	O
variables	O
predictive	O
of	O
abusive	O
behavior	O
,	O
a	O
substantial	O
relationship	O
was	O
expected	O
between	O
the	O
CAP	O
and	O
the	O
MHI	O
Loss	O
of	O
Behavioral	O
/	O
Emotional	O
Control	O
scale	O
.	O

We	O
have	O
improved	O
our	O
system	O
for	O
nuclear	O
contour	O
digitization	O
and	O
determined	O
its	O
theoretical	O
limitations	O
by	O
digitizing	O
standardized	O
objects	O
.	O

Such	O
a	O
change	O
may	O
involve	O
increased	O
mammary	O
utilization	O
of	O
pre	O
-	O
formed	O
long	O
-	O
chain	O
fatty	O
acid	O
and	O
increased	O
metabolism	O
of	O
glucose	O
via	O
glycolysis	O
.	O

The	O
skin	O
site	O
,	O
6	O
-	O
cm	O
-	O
distal	O
and	O
-	O
proximal	O
subcutaneous	O
segments	O
of	O
the	O
catheter	O
,	O
exudates	O
,	O
and	O
blood	O
were	O
cultured	O
.	O

Because	O
of	O
its	O
great	O
reliability	O
,	O
conventional	O
arteriography	O
occupies	O
a	O
place	O
of	O
choice	O
among	O
the	O
medical	O
imaging	O
techniques	O
.	O

Rapid	O
detection	O
of	O
radioisotopically	O
contaminated	O
test	O
serum	O
before	O
radioassay	O
of	O
vitamin	O
B12	O
.	O

The	O
former	O
group	O
did	O
excrete	O
less	O
dry	O
fecal	O
material	O
compared	O
to	O
both	O
other	O
groups	O
.	O

Electronic	O
data	O
processing	O
(	O
EDP	O
)	O
latex	O
immunoassay	O
using	O
anti	B-GENE
-	I-GENE
human	I-GENE
seminal	I-GENE
acid	I-GENE
phosphatase	I-GENE
(	O
anti	B-GENE
-	I-GENE
HSAP	I-GENE
)	O
immune	O
serum	O
was	O
applied	O
for	O
the	O
species	O
and	O
organ	O
identification	O
of	O
human	O
seminal	O
stains	O
.	O

The	O
maximum	O
deflections	O
of	O
phase	O
IV	O
for	O
Ar	O
and	O
N2	O
from	O
extrapolated	O
phase	O
III	O
slopes	O
were	O
smaller	O
in	O
the	O
prone	O
position	O
,	O
suggesting	O
more	O
uniform	O
tracer	O
gas	O
concentrations	O
across	O
the	O
lungs	O
.	O

Recent	O
developments	O
in	O
drugs	O
antagonistic	O
to	O
factors	O
causing	O
peptic	O
ulcer	O
-	O
-	O
clinical	O
efficacy	O
and	O
problems	O
;	O
gastrin	B-GENE
receptor	I-GENE
blockaders	O

Static	O
magnetic	O
fields	O
affect	O
the	O
diffusion	O
of	O
biological	O
particles	O
in	O
solutions	O
through	O
the	O
Lorentz	O
force	O
and	O
Maxwell	O
stress	O
.	O

Psychological	O
disturbance	O
was	O
greater	O
in	O
the	O
high	O
life	O
stress	O
group	O
as	O
indicated	O
by	O
significant	O
elevations	O
on	O
the	O
global	O
severity	O
index	O
of	O
the	O
Symptom	O
Checklist	O
-	O
90	O
and	O
elevations	O
on	O
somatization	O
,	O
obsessive	O
compulsive	O
,	O
interpersonal	O
sensitivity	O
,	O
depression	O
,	O
anxiety	O
and	O
psychoticism	O
subscales	O
.	O

Chronic	O
administration	O
of	O
sodium	O
cyanate	O
decreases	O
O2	O
extraction	O
ratio	O
in	O
dogs	O
.	O

Nucleotide	O
sequencing	O
indicates	O
that	O
this	O
E1	B-GENE
alpha	I-GENE
cDNA	I-GENE
clone	O
is	O
1821	O
base	O
pairs	O
(	O
bp	O
)	O
in	O
length	O
with	O
an	O
open	O
reading	O
frame	O
of	O
1365	O
bp	O
and	O
a	O
3	O
'	O
-	O
untranslated	O
region	O
of	O
356	O
bp	O
.	O

SPA	O
from	O
PAG	O
sites	O
was	O
associated	O
with	O
aversion	O
.	O

In	O
contrast	O
,	O
the	O
MAN	O
showed	O
a	O
unimodal	O
,	O
skewed	O
distribution	O
,	O
with	O
a	O
range	O
from	O
approximately	O
1	O
to	O
14	O
micron	O
and	O
a	O
maximum	O
at	O
3	O
-	O
4	O
micron	O
.	O

Abnormal	O
technetium	O
Tc	O
99m	O
medronate	O
scans	O
in	O
patients	O
with	O
previously	O
undiagnosed	O
polyarthralgias	O
suggested	O
inflammatory	O
arthropathy	O
and	O
influenced	O
management	O
decisions	O
with	O
favorable	O
therapeutic	O
outcomes	O
.	O

Practical	O
interest	O
of	O
such	O
studies	O
is	O
limited	O
since	O
the	O
pharmacokinetic	O
parameters	O
are	O
systematically	O
evaluated	O
in	O
man	O
during	O
phase	O
I	O
trials	O
.	O

The	O
artery	O
cuff	O
was	O
slightly	O
superior	O
to	O
the	O
fat	O
wrap	O
,	O
particularly	O
in	O
having	O
fewer	O
adhesions	O
and	O
a	O
better	O
histological	O
picture	O
.	O

Lithium	O
-	O
carbonate	O
action	O
during	O
radiation	O
therapy	O
has	O
been	O
studied	O
,	O
valuing	O
the	O
positive	O
effect	O
on	O
leukopoiesis	O
and	O
the	O
consequent	O
better	O
clinical	O
conditions	O
of	O
the	O
patients	O
in	O
course	O
of	O
treatment	O
.	O

Of	O
the	O
53	O
units	O
tested	O
during	O
sinusoidal	O
motion	O
at	O
0	O
.	O
05	O
Hz	O
(	O
9	O
.	O
1	O
cm	O
/	O
s	O
)	O
,	O
1	O
(	O
1	O
.	O
9	O
%	O
)	O
was	O
responsive	O
to	O
the	O
otolith	O
input	O
only	O
,	O
13	O
(	O
24	O
.	O
5	O
%	O
)	O
were	O
influenced	O
by	O
the	O
visual	O
input	O
only	O
and	O
23	O
(	O
43	O
.	O
4	O
%	O
)	O
responded	O
to	O
both	O
modalities	O
.	O

Electroglottography	O
is	O
a	O
useful	O
,	O
non	O
-	O
invasive	O
technique	O
that	O
can	O
assist	O
in	O
the	O
assessment	O
of	O
vocal	O
fold	O
dysfunction	O
.	O

Statistical	O
analysis	O
of	O
the	O
degrees	O
of	O
secondary	O
spinal	O
cord	O
compression	O
was	O
performed	O
in	O
group	O
-	O
1	O
dogs	O
by	O
measuring	O
and	O
comparing	O
ratios	O
of	O
the	O
vertical	O
to	O
the	O
horizontal	O
diameters	O
of	O
the	O
transverse	O
spinal	O
cord	O
sections	O
from	O
locations	O
within	O
(	O
T12	O
to	O
L1	O
)	O
and	O
out	O
of	O
(	O
T11	O
,	O
T11	O
-	O
12	O
,	O
L1	O
-	O
2	O
,	O
and	O
L2	O
)	O
the	O
region	O
of	O
surgical	O
intervention	O
.	O

The	O
pharmacological	O
effects	O
of	O
the	O
novel	O
compound	O
WEB	O
1881	O
FU	O
(	O
4	O
-	O
amino	O
-	O
methyl	O
-	O
1	O
-	O
benzyl	O
-	O
pyrrolidine	O
-	O
2	O
-	O
one	O
-	O
fumarate	O
)	O
were	O
investigated	O
.	O

Histopathological	O
examination	O
revealed	O
dose	O
-	O
related	O
proliferation	O
of	O
type	O
II	O
pneumocytes	O
in	O
dams	O
and	O
proliferation	O
of	O
interstitial	O
cells	O
and	O
delayed	O
septal	O
/	O
capillary	O
development	O
in	O
neonates	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
250	O
WORDS	O
)	O

So	O
far	O
no	O
problems	O
with	O
multiply	O
resistant	O
strains	O
have	O
developed	O
.	O

The	O
state	O
of	O
the	O
liver	O
in	O
generalized	O
forms	O
of	O
meningococcal	O
infection	O

The	O
effects	O
produced	O
by	O
oral	O
administration	O
of	O
500	O
mg	O
/	O
kg	O
p	O
-	O
xylene	O
or	O
toluene	O
lasted	O
at	O
least	O
8	O
hr	O
,	O
while	O
the	O
effect	O
of	O
inhaled	O
p	O
-	O
xylene	O
dissipated	O
within	O
75	O
min	O
of	O
removal	O
from	O
the	O
exposure	O
.	O

Thin	O
melanomas	O
can	O
metastasize	O
and	O
be	O
lethal	O
.	O

The	O
TA	O
muscle	O
was	O
fatigued	O
by	O
four	O
forms	O
of	O
repeated	O
isometric	O
contractions	O
:	O
(	O
1	O
)	O
maximal	O
voluntary	O
contractions	O
(	O
MVC	O
)	O
,	O
(	O
2	O
)	O
MVC	O
with	O
circulation	O
occluded	O
,	O
(	O
3	O
)	O
electrically	O
evoked	O
contractions	O
with	O
20	O
Hz	O
supramaximal	O
voltage	O
stimulation	O
and	O
(	O
4	O
)	O
electrically	O
evoked	O
contractions	O
with	O
circulation	O
occluded	O
.	O

The	O
actuarial	O
local	O
control	O
rates	O
at	O
10	O
years	O
for	O
the	O
three	O
treatment	O
groups	O
were	O
as	O
follows	O
:	O
subtotal	O
excision	O
alone	O
,	O
18	O
%	O
;	O
subtotal	O
excision	O
plus	O
postoperative	O
radiation	O
therapy	O
,	O
82	O
%	O
;	O
and	O
total	O
excision	O
alone	O
,	O
77	O
%	O
.	O

The	O
effects	O
of	O
anabolic	O
implants	O
on	O
rate	O
,	O
composition	O
and	O
energetic	O
efficiency	O
of	O
growth	O
were	O
determined	O
in	O
steers	O
fed	O
diets	O
varying	O
in	O
forage	O
and	O
grain	O
content	O
.	O

Prolonged	O
suspension	O
induced	O
a	O
significant	O
change	O
in	O
the	O
geometric	O
configuration	O
of	O
the	O
femur	O
middiaphysis	O
by	O
increasing	O
the	O
minimum	O
diameter	O
(	O
12	O
%	O
)	O
without	O
any	O
significant	O
alterations	O
in	O
cortical	O
area	O
,	O
density	O
,	O
mineral	O
,	O
and	O
collagen	B-GENE
concentrations	O
.	O

Thyroid	O
function	O
tests	O
were	O
performed	O
on	O
300	O
admissions	O
,	O
leaving	O
707	O
untested	O
.	O

Data	O
on	O
the	O
line	O
spread	O
function	O
(	O
LSF	O
)	O
were	O
obtained	O
from	O
the	O
image	O
of	O
a	O
0	O
.	O
2	O
mm	O
wide	O
slit	O
between	O
tungsten	O
blocks	O
that	O
were	O
positioned	O
at	O
the	O
isocentre	O
in	O
front	O
of	O
a	O
polystyrene	O
phantom	O
.	O

Primary	O
infection	O
is	O
usually	O
managed	O
conservatively	O
.	O

Papers	O
of	O
the	O
Society	O
for	O
Clinical	O
Vascular	O
Surgery	O
.	O

Prognosis	O
in	O
Bowen	O
'	O
s	O
disease	O
localized	O
to	O
the	O
ano	O
-	O
genital	O
region	O
.	O

Taken	O
together	O
,	O
the	O
results	O
suggest	O
that	O
chlorphentermine	O
may	O
be	O
capable	O
of	O
producing	O
dual	O
stimulus	O
effects	O
in	O
animals	O
.	O

These	O
findings	O
indicate	O
that	O
autophosphorylation	O
of	O
Thr286	O
(	O
alpha	O
subunit	O
)	O
and	O
Thr287	O
(	O
beta	O
subunit	O
)	O
is	O
responsible	O
for	O
transition	O
of	O
CaM	B-GENE
-	I-GENE
kinase	I-GENE
II	I-GENE
to	O
the	O
Ca2	O
+	O
-	O
independent	O
form	O
.	O

This	O
rapid	O
and	O
extensive	O
penetration	O
of	O
intrathecally	O
administered	O
chemotherapy	O
may	O
offer	O
insight	O
into	O
the	O
myelopathy	O
observed	O
with	O
these	O
treatments	O
.	O

The	O
interaction	O
of	O
radiation	O
and	O
hyperthermia	O
was	O
systematically	O
studied	O
in	O
the	O
Dunning	O
R3327G	O
prostatic	O
adenocarcinoma	O
,	O
the	O
preeminent	O
animal	O
model	O
for	O
human	O
prostatic	O
cancer	O
.	O

Pregnant	O
rats	O
were	O
exposed	O
to	O
one	O
of	O
the	O
following	O
:	O
(	O
1	O
)	O
10	O
%	O
O2	O
in	O
N2	O
or	O
100	O
%	O
O2	O
for	O
2	O
days	O
beginning	O
at	O
day	O
7	O
,	O
11	O
,	O
14	O
,	O
or	O
18	O
of	O
pregnancy	O
;	O
(	O
2	O
)	O
10	O
%	O
O2	O
in	O
N2	O
or	O
100	O
%	O
O2	O
for	O
10	O
h	O
/	O
day	O
beginning	O
at	O
day	O
7	O
;	O
or	O
(	O
3	O
)	O
14	O
-	O
11	O
%	O
O2	O
in	O
N2	O
continuously	O
beginning	O
at	O
day	O
14	O
till	O
day	O
21	O
when	O
they	O
were	O
sacrificed	O
.	O

Seven	O
patients	O
(	O
8	O
.	O
3	O
percent	O
)	O
had	O
latent	O
hypothyroidism	O
only	O
discovered	O
by	O
hormonal	O
determinations	O
.	O

Addition	O
of	O
sucralfate	O
or	O
De	O
-	O
Nol	O
resulted	O
in	O
increments	O
of	O
gastric	O
HCO3	O
secretion	O
,	O
reaching	O
about	O
45	O
%	O
and	O
59	O
%	O
,	O
respectively	O
,	O
of	O
the	O
maximal	O
HCO3	O
response	O
to	O
16	O
,	O
16	O
-	O
dimethyl	O
PGE2	O
(	O
dmPGE2	O
)	O
.	O

Moreover	O
,	O
unlike	O
control	O
rats	O
operated	O
animals	O
did	O
not	O
show	O
aversion	O
to	O
the	O
highest	O
concentrations	O
of	O
saccharin	O
solutions	O
.	O

In	O
Salmo	O
gairdneri	O
,	O
no	O
specialized	O
system	O
of	O
portal	O
vessels	O
appears	O
to	O
exist	O
between	O
the	O
pineal	O
organ	O
and	O
other	O
portions	O
of	O
the	O
brain	O
.	O

Nuclear	B-GENE
factor	I-GENE
III	I-GENE
(	O
NFIII	B-GENE
)	O
is	O
a	O
protein	O
from	O
HeLa	O
cells	O
that	O
stimulates	O
the	O
initiation	O
of	O
adenovirus	O
type	O
2	O
(	O
Ad2	O
)	O
DNA	O
replication	O
by	O
binding	O
to	O
a	O
specific	O
nucleotide	O
sequence	O
in	O
the	O
origin	O
,	O
adjacent	O
to	O
the	O
nuclear	B-GENE
factor	I-GENE
I	I-GENE
recognition	I-GENE
site	I-GENE
.	O

We	O
conclude	O
that	O
cephalothin	O
clearance	O
of	O
S	O
.	O
aureus	O
from	O
a	O
site	O
accessible	O
to	O
phagocytes	O
was	O
delayed	O
when	O
compared	O
to	O
a	O
phagocyte	O
-	O
inaccessible	O
site	O
.	O

The	O
findings	O
are	O
discussed	O
in	O
the	O
context	O
of	O
known	O
properties	O
of	O
cortical	O
-	O
bar	O
detectors	O
.	O

Mean	O
rCBF	O
increased	O
in	O
some	O
patients	O
4	O
-	O
8	O
weeks	O
after	O
surgery	O
on	O
the	O
ipsilateral	O
side	O
.	O

Quantitative	O
computed	O
tomography	O
for	O
measuring	O
vertebral	O
bone	O
mineral	O
content	O
offers	O
high	O
sensitivity	O
and	O
reproducibility	O
.	O

The	O
structure	O
of	O
the	O
enhancer	O
was	O
also	O
probed	O
by	O
inserting	O
a	O
pair	O
of	O
complementary	O
synthetic	O
oligodeoxynucleotides	O
which	O
represented	O
the	O
region	O
between	O
nt	O
positions	O
-	O
235	O
and	O
-	O
215	O
into	O
a	O
truncated	O
template	O
which	O
lacked	O
the	O
enhancer	O
.	O

Kf	O
,	O
c	O
and	O
CT	O
(	O
referenced	O
to	O
the	O
initial	O
lung	O
mass	O
)	O
decreased	O
linearly	O
with	O
reductions	O
in	O
lung	O
mass	O
%	O
delta	O
Kf	O
,	O
c	O
=	O
1	O
.	O
26	O
-	O
0	O
.	O
98	O
%	O
mass	O
removed	O
(	O
r	O
=	O
0	O
.	O
90	O
,	O
P	O
less	O
than	O
0	O
.	O
01	O
)	O
and	O
%	O
delta	O
CT	O
=	O
-	O
3	O
.	O
99	O
-	O
0	O
.	O
98	O
%	O
mass	O
removed	O
(	O
r	O
=	O
0	O
.	O
82	O
,	O
P	O
less	O
than	O
0	O
.	O
01	O
)	O
relationships	O
that	O
were	O
not	O
altered	O
by	O
blocker	O
pretreatment	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
250	O
WORDS	O
)	O

Two	O
scintigraphic	O
methods	O
,	O
resting	O
dipyridamole	O
and	O
exercise	O
thallium	O
-	O
201	O
myocardial	O
perfusion	O
imaging	O
,	O
to	O
detect	O
and	O
localize	O
coronary	O
artery	O
stenosis	O
were	O
compared	O
in	O
32	O
patients	O
suffering	O
from	O
coronary	O
artery	O
disease	O
.	O

From	O
these	O
results	O
,	O
it	O
is	O
concluded	O
that	O
EDLF	O
has	O
clear	O
vasoconstrictor	O
properties	O
which	O
are	O
not	O
due	O
to	O
adrenergic	O
or	O
calcium	O
entry	O
mechanisms	O
and	O
that	O
there	O
are	O
differences	O
in	O
the	O
vasoconstrictor	O
effects	O
of	O
EDLFs	O
with	O
respect	O
to	O
different	O
vascular	O
beds	O
.	O

Research	O
was	O
carried	O
out	O
on	O
the	O
rheumatoid	B-GENE
factors	I-GENE
in	O
the	O
serum	O
of	O
917	O
patients	O
by	O
means	O
of	O
two	O
tests	O
(	O
one	O
using	O
polystyrene	O
and	O
one	O
with	O
erythrocytes	O
)	O
and	O
the	O
results	O
obtained	O
were	O
compared	O
using	O
a	O
method	O
of	O
reference	O
.	O

A	O
low	O
aspirin	B-GENE
esterase	I-GENE
activity	O
may	O
be	O
a	O
contributory	O
factor	O
in	O
precipitating	O
these	O
aspirin	O
sensitive	O
reactions	O
.	O

In	O
both	O
experiments	O
,	O
average	O
daily	O
gain	O
and	O
gain	O
-	O
to	O
-	O
feed	O
ratio	O
were	O
similar	O
for	O
TR	O
and	O
CR	O
.	O

Overall	O
least	O
-	O
squares	O
means	O
for	O
uncooked	O
and	O
cooked	O
longissimus	O
muscle	O
and	O
subcutaneous	O
fat	O
were	O
63	O
.	O
32	O
,	O
80	O
.	O
27	O
and	O
98	O
.	O
90	O
mg	O
of	O
cholesterol	O
/	O
100	O
g	O
of	O
tissue	O
,	O
respectively	O
.	O

The	O
role	O
of	O
supercritical	O
fluid	O
chromatography	O
(	O
SFC	O
)	O
as	O
a	O
viable	O
technique	O
for	O
analyzing	O
agricultural	O
products	O
has	O
been	O
investigated	O
using	O
packed	O
and	O
capillary	O
column	O
methodology	O
.	O

Nitrofurazone	O
significantly	O
reduced	O
the	O
rise	O
in	O
LH	B-GENE
induced	O
by	O
LHRH	B-GENE
.	O

Ovarian	O
tumors	O
in	O
pregnancy	O
.	O

Ultrastructural	O
study	O
of	O
polyarteritis	O

X2	O
test	O
,	O
with	O
Yates	O
correction	O
if	O
need	O
,	O
was	O
used	O
as	O
statistical	O
.	O
method	O
.	O

After	O
a	O
baseline	O
study	O
,	O
WPW	O
syndrome	O
was	O
simulated	O
by	O
stimulation	O
at	O
seven	O
different	O
sites	O
around	O
the	O
base	O
of	O
the	O
ventricles	O
,	O
and	O
RNV	O
'	O
s	O
were	O
obtained	O
.	O

All	O
patients	O
had	O
the	O
CA	B-GENE
125	I-GENE
assay	O
performed	O
within	O
one	O
week	O
before	O
their	O
second	O
-	O
look	O
operation	O
.	O

Allergy	O
and	O
Tourette	O
'	O
s	O
syndrome	O
.	O

The	O
criterion	O
was	O
reached	O
after	O
two	O
sessions	O
and	O
generalization	O
to	O
a	O
variety	O
of	O
pills	O
and	O
capsules	O
occurred	O
.	O

Clinical	O
method	O
for	O
the	O
treatment	O
of	O
Class	O
II	O
occlusal	O
anomalies	O
with	O
open	O
bite	O

Enoxacin	O
appears	O
to	O
be	O
well	O
suited	O
for	O
the	O
treatment	O
of	O
complicated	O
UTI	O
.	O

An	O
industry	O
-	O
wide	O
retrospective	O
cohort	O
mortality	O
study	O
was	O
conducted	O
on	O
6	O
,	O
152	O
chemical	O
workers	O
(	O
2	O
,	O
460	O
exposed	O
and	O
3	O
,	O
692	O
nonexposed	O
)	O
engaged	O
in	O
chloromethyl	O
ether	O
manufacture	O
at	O
7	O
major	O
U	O
.	O
S	O
.	O
companies	O
between	O
1948	O
and	O
1980	O
.	O

The	O
diagnosis	O
of	O
amyloidosis	O
was	O
determined	O
from	O
a	O
labial	O
salivary	O
gland	O
biopsy	O
.	O

Hair	O
and	O
blood	O
samples	O
were	O
taken	O
before	O
vitamin	O
C	O
or	O
placebo	O
supplementation	O
was	O
started	O
and	O
at	O
monthly	O
intervals	O
thereafter	O
for	O
three	O
months	O
.	O

In	O
treated	O
herds	O
,	O
cows	O
more	O
than	O
40	O
d	O
postpartum	O
with	O
a	O
corpus	O
luteum	O
received	O
prostaglandin	O
F2	O
alpha	O
.	O

Emergency	O
treatment	O
of	O
facial	O
and	O
maxillary	O
/	O
mandibular	O
injuries	O

In	O
14	O
cases	O
,	O
isolates	O
were	O
biotyped	O
yielding	O
eight	O
with	O
biotype	O
II	O
,	O
four	O
with	O
biotype	O
III	O
,	O
and	O
one	O
each	O
with	O
biotypes	O
IV	O
and	O
V	O
.	O

A	O
total	O
of	O
117	O
EVS	O
treatments	O
were	O
performed	O
on	O
34	O
patients	O
.	O

Most	O
of	O
the	O
prepeptide	O
portion	O
of	O
the	O
precursor	O
polypeptide	O
is	O
encoded	O
by	O
the	O
next	O
three	O
exons	O
,	O
and	O
the	O
mature	O
form	O
of	O
IL	B-GENE
-	I-GENE
1	I-GENE
alpha	I-GENE
is	O
encoded	O
by	O
the	O
remaining	O
three	O
exons	O
.	O

A	O
stochastic	O
version	O
of	O
Kernell	O
'	O
s	O
(	O
1968	O
,	O
1972	O
)	O
model	O
with	O
cumulative	O
afterhyperpolarization	O
(	O
AHP	O
)	O
was	O
simulated	O
.	O

In	O
a	O
previous	O
interim	O
report	O
we	O
noted	O
more	O
prompt	O
resolution	O
of	O
dermatomal	O
signs	O
and	O
symptoms	O
with	O
acyclovir	O
treatment	O
.	O

The	O
detectability	O
of	O
the	O
defects	O
in	O
RCA	O
or	O
LAD	O
region	O
was	O
80	O
%	O
in	O
single	O
-	O
position	O
scans	O
in	O
stress	O
studies	O
.	O

Pharmacologic	O
properties	O
of	O
serotonergic	O
agents	O
and	O
antidepressant	O
drugs	O
.	O

This	O
brief	O
hypercapnic	O
challenge	O
induced	O
a	O
rapid	O
increase	O
in	O
CBF	O
in	O
the	O
absence	O
of	O
any	O
change	O
in	O
MABP	O
.	O

Osteocalcin	B-GENE
(	O
serum	B-GENE
bone	I-GENE
-	I-GENE
Gla	I-GENE
protein	I-GENE
,	O
sBGP	B-GENE
)	O
,	O
serum	B-GENE
alkaline	I-GENE
phosphatase	I-GENE
(	O
sAP	B-GENE
)	O
and	O
urinary	O
hydroxyproline	O
/	O
creatinine	O
ratio	O
(	O
uOH	O
-	O
Prol	O
/	O
creatinine	O
)	O
have	O
been	O
measured	O
in	O
21	O
patients	O
with	O
primary	O
hyperparathyroidism	O
(	O
PHPT	O
)	O
and	O
in	O
nine	O
patients	O
with	O
hypercalcaemia	O
of	O
malignancy	O
(	O
HM	O
)	O
.	O

Multivariate	O
logistic	O
regression	O
analysis	O
indicated	O
that	O
seropositivity	O
was	O
strongly	O
associated	O
with	O
the	O
prevalence	O
of	O
hepatitis	O
B	O
in	O
an	O
employee	O
'	O
s	O
country	O
of	O
birth	O
and	O
with	O
age	O
.	O

Hexsyn	O
is	O
the	O
Goodyear	O
Tire	O
and	O
Rubber	O
Company	O
tradename	O
for	O
a	O
polyolefin	O
rubber	O
synthesized	O
from	O
1	O
-	O
hexene	O
with	O
3	O
-	O
5	O
%	O
methylhexadiene	O
as	O
the	O
source	O
of	O
residual	O
double	O
bonds	O
for	O
vulcanization	O
.	O

Chimeric	O
phage	O
-	O
plasmid	O
expression	O
vectors	O
were	O
constructed	O
from	O
pUC18	O
/	O
19	O
plasmids	O
by	O
cloning	O
a	O
single	O
-	O
stranded	O
DNA	O
(	O
ssDNA	O
)	O
origin	O
of	O
replication	O
from	O
bacteriophage	O
f1	O
and	O
inserting	O
a	O
bacteriophage	O
T7	O
promoter	O
within	O
the	O
beta	B-GENE
-	I-GENE
galactosidase	I-GENE
gene	I-GENE
.	O

By	O
order	O
of	O
decreasing	O
rate	O
,	O
finger	O
flexors	O
,	O
jaw	O
,	O
crossed	O
adductors	O
,	O
and	O
triceps	O
reflexes	O
were	O
less	O
frequently	O
elicited	O
in	O
both	O
groups	O
.	O

Natl	O
.	O

Five	O
out	O
of	O
eight	O
consecutive	O
cases	O
with	O
initial	O
symptoms	O
of	O
a	O
'	O
midline	O
granuloma	O
'	O
were	O
identified	O
as	O
malignant	O
histiocytosis	O
(	O
histiocytic	O
sarcoma	O
)	O
which	O
within	O
5	O
months	O
to	O
4	O
years	O
led	O
to	O
generalization	O
and	O
death	O
.	O

All	O
patients	O
then	O
received	O
suxamethonium	O
1	O
.	O
5	O
mg	O
kg	O
-	O
1	O
i	O
.	O
v	O
.	O

The	O
highest	O
postoperative	O
CK	B-GENE
-	I-GENE
MB	I-GENE
level	O
was	O
less	O
after	O
BC	O
(	O
BC	O
,	O
31	O
+	O
/	O
-	O
17	O
U	O
/	O
L	O
;	O
CC	O
,	O
56	O
+	O
/	O
-	O
13	O
U	O
/	O
L	O
;	O
p	O
less	O
than	O
0	O
.	O
05	O
)	O
.	O

No	O
relevant	O
changes	O
in	O
heart	O
rate	O
,	O
body	O
weight	O
,	O
and	O
plasma	O
levels	O
of	O
renin	B-GENE
activity	O
and	O
aldosterone	O
concentration	O
were	O
observed	O
.	O

High	O
trough	O
serum	O
TOB	O
concentrations	O
were	O
associated	O
with	O
death	O
and	O
very	O
low	O
levels	O
with	O
recovery	O
.	O

State	O
-	O
approved	O
schools	O
of	O
nursing	O
R	O
.	O
N	O
.	O

In	O
a	O
maxicell	O
system	O
a	O
protein	O
with	O
an	O
approximate	O
molecular	O
weight	O
of	O
36	O
,	O
000	O
was	O
synthesized	O
.	O

The	O
incidence	O
of	O
second	O
malignant	O
neoplasms	O
was	O
lower	O
(	O
1	O
.	O
3	O
%	O
)	O
in	O
the	O
group	O
treated	O
with	O
5	O
-	O
fluorouracil	O
,	O
doxorubicin	O
,	O
and	O
cyclophosphamide	O
than	O
in	O
the	O
historical	O
control	O
group	O
(	O
4	O
.	O
8	O
%	O
)	O
.	O

Ovulation	O
was	O
induced	O
in	O
8	O
(	O
56	O
.	O
7	O
%	O
)	O
patients	O
who	O
conceived	O
.	O

In	O
previous	O
work	O
(	O
E	O
.	O

The	O
small	O
size	O
and	O
placement	O
of	O
the	O
mutagenesis	O
marker	O
(	O
the	O
supF	B-GENE
suppressor	I-GENE
tRNA	I-GENE
gene	I-GENE
from	I-GENE
Escherichia	I-GENE
coli	I-GENE
)	O
within	O
the	O
vector	O
substantially	O
reduced	O
the	O
frequency	O
of	O
spontaneous	O
mutations	O
normally	O
observed	O
after	O
transfection	O
of	O
mammalian	O
cells	O
with	O
plasmid	O
DNA	O
;	O
hence	O
,	O
UV	O
-	O
induced	O
mutations	O
were	O
easily	O
identified	O
above	O
the	O
spontaneous	O
background	O
.	O

W	O
.	O

Tetrad	O
analysis	O
and	O
mitotic	O
recombination	O
experiments	O
localized	O
the	O
PEP4	B-GENE
gene	I-GENE
proximal	O
to	O
GAL4	B-GENE
on	O
chromosome	O
XVI	O
.	O

Based	O
on	O
our	O
observations	O
,	O
we	O
propose	O
a	O
model	O
whereby	O
inactive	O
precursor	O
molecules	O
produced	O
from	O
the	O
PEP4	B-GENE
gene	I-GENE
self	O
-	O
activate	O
within	O
the	O
yeast	O
vacuole	O
and	O
subsequently	O
activate	O
other	O
vacuolar	B-GENE
hydrolases	I-GENE
.	O

In	O
vitro	O
translation	O
of	O
RNA	O
synthesized	O
from	O
the	O
cloned	O
cDNAs	O
predicts	O
that	O
P0	B-GENE
transcripts	I-GENE
are	O
translated	O
into	O
a	O
novel	O
12	O
.	O
5	O
-	O
kilodalton	O
protein	O
corresponding	O
to	O
the	O
first	O
open	O
reading	O
frame	O
.	O

The	O
N	O
-	O
terminal	O
amino	O
acid	O
sequence	O
of	O
Mop	B-GENE
has	O
sequence	O
homology	O
with	O
DNA	O
binding	O
proteins	O
.	O

Several	O
new	O
techniques	O
are	O
available	O
for	O
monitoring	O
control	O
of	O
diabetes	O
.	O

Ciprofloxacin	O
:	O
an	O
overview	O
of	O
adverse	O
experiences	O
.	O

The	O
rho	B-GENE
genes	I-GENE
comprise	O
an	O
evolutionarily	O
conserved	O
family	O
with	O
significant	O
homology	O
to	O
the	O
ras	B-GENE
oncogene	I-GENE
family	I-GENE
.	O

Also	O
,	O
component	O
I	O
significantly	O
correlated	O
with	O
fasting	O
insulin	B-GENE
and	O
VO2	O
max	O
for	O
both	O
sexes	O
and	O
with	O
basal	O
metabolism	O
and	O
HDL	B-GENE
-	I-GENE
cholesterol	I-GENE
for	O
females	O
and	O
males	O
,	O
respectively	O
.	O

The	O
glucose	O
areas	O
following	O
the	O
ingestion	O
of	O
the	O
foods	O
were	O
:	O
Study	O
1	O
:	O
glucose	O
11	O
.	O
7	O
,	O
orange	O
juice	O
7	O
.	O
3	O
,	O
sucrose	O
5	O
.	O
2	O
,	O
glucose	O
+	O
fructose	O
6	O
.	O
3	O
,	O
and	O
fructose	O
0	O
.	O
7	O
mmol	O
X	O
h	O
/	O
l	O
;	O
Study	O
2	O
:	O
glucose	O
14	O
.	O
6	O
,	O
orange	O
juice	O
7	O
.	O
3	O
,	O
apples	O
5	O
.	O
5	O
,	O
and	O
apple	O
juice	O
4	O
.	O
7	O
mmol	O
X	O
h	O
/	O
l	O
;	O
Study	O
3	O
:	O
glucose	O
12	O
.	O
6	O
,	O
ice	O
cream	O
8	O
.	O
1	O
,	O
milk	O
3	O
.	O
7	O
,	O
and	O
lactose	O
4	O
.	O
1	O
mmol	O
X	O
h	O
/	O
l	O
.	O

The	O
serum	B-GENE
insulin	I-GENE
response	O
cannot	O
.	O

SCL	O
prolonged	O
promptly	O
after	O
verapamil	O
,	O
and	O
sinus	O
arrest	O
developed	O
in	O
two	O
of	O
10	O
group	O
2	O
and	O
two	O
of	O
five	O
group	O
3	O
animals	O
.	O

Postglucose	O
serum	B-GENE
insulin	I-GENE
levels	O
showed	O
no	O
significant	O
correlations	O
with	O
systolic	O
or	O
diastolic	O
blood	O
pressure	O
levels	O
in	O
men	O
,	O
but	O
in	O
female	O
diabetic	O
and	O
non	O
-	O
diabetic	O
subjects	O
significant	O
correlations	O
were	O
found	O
in	O
particular	O
with	O
systolic	O
blood	O
pressure	O
level	O
.	O

We	O
used	O
oligonucleotide	O
-	O
directed	O
mutagenesis	O
to	O
alter	O
a	O
site	O
in	O
MucA	B-GENE
homologous	O
to	O
the	O
Ala	O
-	O
Gly	O
cleavage	O
site	O
of	O
LexA	B-GENE
.	O

The	O
latter	O
was	O
determined	O
as	O
follows	O
:	O
Type	O
I	O
-	O
solid	O
tumor	O
tissue	O
without	O
significant	O
peripheral	O
isolated	O
tumor	O
cells	O
;	O
Type	O
II	O
-	O
solid	O
tumor	O
tissue	O
associated	O
with	O
peripheral	O
isolated	O
tumor	O
cells	O
;	O
Type	O
III	O
-	O
isolated	O
tumor	O
cells	O
only	O
.	O

The	O
pharmacology	O
of	O
carnitine	O
.	O

Acute	O
inhalation	O
toxicity	O
of	O
T	O
-	O
2	O
mycotoxin	O
in	O
mice	O
.	O

The	O
present	O
investigation	O
sought	O
to	O
identify	O
the	O
principal	O
dimensions	O
of	O
the	O
Framingham	O
Type	O
A	O
scale	O
(	O
FTAS	O
)	O
and	O
then	O
to	O
examine	O
their	O
physiological	O
and	O
psychological	O
correlates	O
.	O

A	O
preliminary	O
study	O
on	O
pyogenic	O
arthritis	O
.	O

Legionella	O
,	O
microbial	O
ecology	O
,	O
and	O
inconspicuous	O
consumption	O
.	O

Lymphatics	O
in	O
the	O
aorta	O
of	O
rats	O
treated	O
with	O
a	O
soy	O
-	O
bean	O
oil	O
extract	O
(	O
lipofundin	O
)	O
.	O

For	O
signal	O
durations	O
less	O
than	O
10	O
ms	O
,	O
however	O
,	O
the	O
SoNo	O
and	O
S	O
pi	O
No	O
threshold	O
functions	O
converged	O
and	O
the	O
masking	O
-	O
level	O
difference	O
decreased	O
.	O

The	O
spleen	O
rate	O
of	O
about	O
600	O
villagers	O
of	O
RK	O
I	O
examined	O
was	O
54	O
.	O
3	O
%	O
and	O
the	O
parasite	O
rate	O
13	O
.	O
2	O
%	O
before	O
the	O
drug	O
intervention	O
.	O

Multiple	O
dosing	O
four	O
times	O
daily	O
for	O
7	O
days	O
of	O
indoprofen	O
200	O
mg	O
,	O
a	O
non	O
-	O
steroidal	O
anti	O
-	O
inflammatory	O
drug	O
with	O
a	O
short	O
half	O
-	O
life	O
(	O
t1	O
/	O
2	O
)	O
,	O
revealed	O
drug	O
accumulation	O
in	O
eight	O
elderly	O
subjects	O
.	O

In	O
10	O
patients	O
with	O
subacute	O
cardiac	O
tamponade	O
,	O
pulmonary	O
wedge	O
pressure	O
(	O
PWP	O
)	O
,	O
RAP	O
,	O
and	O
IPP	O
were	O
measured	O
along	O
with	O
indexes	O
of	O
systolic	O
function	O
.	O

Encompassing	O
tamponade	O
and	O
pericardiocentesis	O
data	O
,	O
left	O
ventricular	O
stroke	O
work	O
index	O
showed	O
positive	O
correlation	O
with	O
TMFP1	O
(	O
r	O
=	O
.	O
59	O
)	O
and	O
TMFP2	O
(	O
r	O
=	O
.	O
52	O
)	O
but	O
not	O
with	O
TMFP3	O
.	O

Rabbits	O
developed	O
profound	O
hypocalcemia	O
,	O
with	O
levels	O
falling	O
from	O
15	O
.	O
5	O
+	O
/	O
-	O
0	O
.	O
2	O
to	O
7	O
.	O
6	O
+	O
/	O
-	O
0	O
.	O
4	O
mg	O
/	O
dl	O
under	O
the	O
influence	O
of	O
TSST	B-GENE
-	I-GENE
1	I-GENE
.	O

Similarly	O
,	O
actuarial	O
interpretations	O
for	O
the	O
second	O
protocols	O
were	O
not	O
more	O
frequently	O
selected	O
by	O
therapists	O
as	O
more	O
valid	O
,	O
regardless	O
of	O
treatment	O
condition	O
and	O
elevation	O
of	O
the	O
F	O
and	O
F	O
-	O
K	O
indices	O
on	O
the	O
first	O
MMPI	O
profile	O
.	O

The	O
study	O
disclosed	O
generalized	O
atrophy	O
and	O
diffuse	O
symmetric	O
white	O
matter	O
hypodensities	O
.	O

The	O
diagnosis	O
of	O
metachromatic	O
leukodystrophy	O
(	O
MLD	O
)	O
was	O
confirmed	O
by	O
the	O
finding	O
of	O
low	O
arylsulfatase	B-GENE
A	I-GENE
(	O
ASA	B-GENE
)	O
levels	O
in	O
cultured	O
fibroblasts	O
in	O
both	O
sisters	O
.	O

Drugs	O
that	O
are	O
transformed	O
via	O
phase	O
II	O
reactions	O
usually	O
do	O
not	O
require	O
dosage	O
adjustment	O
.	O

A	O
study	O
of	O
human	O
genes	O
coding	O
for	O
U4	B-GENE
small	I-GENE
nuclear	I-GENE
RNA	I-GENE
is	O
presented	O
.	O

Using	O
the	O
balloon	O
-	O
gas	O
procedure	O
with	O
a	O
single	O
gas	O
injection	O
,	O
a	O
bubble	O
was	O
obtained	O
that	O
was	O
large	O
enough	O
to	O
tamponade	O
a	O
giant	O
tear	O
without	O
prior	O
drainage	O
of	O
subretinal	O
fluid	O
or	O
vitrectomy	O
.	O

Development	O
of	O
a	O
provisional	O
information	O
-	O
retrieval	O
descriptor	O
language	O
for	O
"	O
Roentgenology	O
and	O
Medical	O
Radiology	O
"	O
for	O
use	O
in	O
the	O
Medinform	O
system	O

Persistent	O
acantholytic	O
dermatosis	O
with	O
increased	O
light	O
sensitivity	O

Thus	O
,	O
a	O
negative	O
test	O
is	O
compatible	O
with	O
low	O
disease	O
activity	O
and	O
/	O
or	O
efficacy	O
of	O
calcium	O
antagonist	O
treatment	O
.	O

Thus	O
,	O
a	O
negative	O
test	O
is	O
compatible	O
with	O
low	O
disease	O
activity	O
and	O
/	O
or	O
efficacy	O
of	O
calcium	O
antagonist	O
treatment	O
.	O

Dorsal	O
foot	O
TcpO2	O
was	O
measured	O
by	O
using	O
oxygen	O
-	O
sensing	O
electrodes	O
with	O
surface	O
temperatures	O
of	O
42	O
degrees	O
C	O
and	O
45	O
degrees	O
C	O
;	O
in	O
theory	O
,	O
changes	O
in	O
sympathetic	O
activity	O
should	O
affect	O
vasomotor	O
tone	O
and	O
TcpO2	O
in	O
skin	O
beneath	O
an	O
electrode	O
at	O
42	O
degrees	O
C	O
(	O
submaximal	O
vasodilation	O
)	O
,	O
but	O
not	O
at	O
45	O
degrees	O
C	O
(	O
maximal	O
vasodilation	O
)	O
.	O

In	O
subjects	O
(	O
n	O
=	O
5	O
)	O
with	O
quadriplegia	O
and	O
reduced	O
sympathetic	O
tone	O
secondary	O
to	O
cervical	O
cord	O
trauma	O
,	O
TcpO2	O
at	O
42	O
degrees	O
C	O
and	O
vasodilation	O
index	O
were	O
increased	O
(	O
45	O
.	O
0	O
mmHg	O
and	O
0	O
.	O
61	O
)	O
;	O
TcpO2	O
at	O
45	O
degrees	O
C	O
did	O
not	O
change	O
.	O

The	O
other	O
model	O
was	O
a	O
continuous	O
exponential	O
plus	O
constant	O
of	O
the	O
form	O
La	O
-	O
=	O
a	O
+	O
b	O
[	O
exp	O
(	O
cVO2	O
)	O
]	O
.	O

Cell	O
.	O

Timing	O
of	O
symptoms	O
and	O
oocyst	O
excretion	O
in	O
human	O
cryptosporidiosis	O
.	O

After	O
dopamine	O
infusion	O
in	O
women	O
with	O
polycystic	O
ovary	O
syndrome	O
and	O
in	O
matched	O
controls	O
,	O
steady	O
state	O
levels	O
of	O
plasma	O
dopamine	O
,	O
norepinephrine	O
,	O
and	O
the	O
ratio	O
of	O
dopamine	O
/	O
norepinephrine	O
were	O
similar	O
in	O
the	O
two	O
groups	O
.	O

Diagnostic	O
importance	O
of	O
determining	O
the	O
complement	O
constituents	O
in	O
children	O
with	O
autoimmune	O
thyroiditis	O

The	O
4	O
patients	O
with	O
carboxyhemoglobin	B-GENE
levels	O
in	O
excess	O
of	O
10	O
%	O
may	O
represent	O
occult	O
carbon	O
monoxide	O
poisoning	O
in	O
this	O
population	O
.	O

All	O
these	O
processes	O
were	O
fully	O
developed	O
during	O
the	O
last	O
month	O
of	O
pregnancy	O
,	O
offering	O
the	O
same	O
picture	O
as	O
the	O
controls	O
.	O

Hypoglycemic	O
action	O
of	O
"	O
he	O
xiang	O
zhuang	O
qi	O
gong	O
"	O
and	O
its	O
mechanism	O
on	O
diabetes	O
mellitus	O

This	O
region	O
of	O
60	O
amino	O
acids	O
may	O
be	O
involved	O
in	O
coiled	O
-	O
coil	O
interactions	O
similar	O
to	O
those	O
that	O
facilitate	O
the	O
filament	O
formation	O
in	O
the	O
rod	O
region	O
.	O

This	O
approach	O
enables	O
the	O
sources	O
of	O
error	O
in	O
the	O
calculation	O
of	O
nutrient	O
utilization	O
to	O
be	O
readily	O
identified	O
,	O
and	O
their	O
effect	O
on	O
precision	O
to	O
be	O
assessed	O
in	O
different	O
nutritional	O
and	O
metabolic	O
states	O
.	O

The	O
effect	O
of	O
dietary	O
zinc	O
deficiency	O
on	O
the	O
mossy	O
fiber	O
zinc	O
content	O
of	O
the	O
rat	O
hippocampus	O
.	O

Weaned	O
rats	O
were	O
fed	O
a	O
normal	O
diet	O
or	O
a	O
low	O
-	O
protein	O
,	O
low	O
-	O
energy	O
diet	O
,	O
and	O
injected	O
with	O
saline	O
or	O
thyroxine	O
(	O
5	O
micrograms	O
/	O
100	O
g	O
BW	O
)	O
for	O
22	O
days	O
.	O

The	O
effects	O
of	O
several	O
opioid	O
agonists	O
and	O
the	O
opioid	O
antagonist	O
naloxone	O
were	O
examined	O
in	O
rats	O
responding	O
under	O
a	O
fixed	O
-	O
consecutive	O
-	O
number	O
(	O
FCN	O
)	O
schedule	O
.	O

The	O
rate	O
-	O
decreasing	O
effects	O
of	O
morphine	O
and	O
U50488	O
were	O
reversed	O
completely	O
by	O
a	O
0	O
.	O
01	O
and	O
1	O
.	O
0	O
mg	O
/	O
kg	O
dose	O
of	O
naloxone	O
,	O
respectively	O
.	O

An	O
intralobar	O
change	O
in	O
temperature	O
above	O
or	O
below	O
36	O
degrees	O
C	O
decreases	O
only	O
the	O
lobar	O
bronchial	O
blood	O
flow	O
and	O
does	O
not	O
influence	O
blood	O
flow	O
to	O
other	O
nearby	O
tissues	O
including	O
those	O
vascularized	O
by	O
the	O
bronchial	O
circulation	O
.	O

Convulsive	O
status	O
epilepticus	O
after	O
infusion	O
of	O
cisplatin	O

The	O
following	O
markers	O
were	O
looked	O
for	O
in	O
the	O
serum	O
,	O
skin	O
and	O
liver	O
of	O
all	O
patients	O
with	O
chronic	O
hepatitis	O
:	O
HBV	O
(	O
HBs	B-GENE
Ag	I-GENE
and	O
HBe	B-GENE
Ag	I-GENE
,	O
anti	B-GENE
-	I-GENE
HBs	I-GENE
,	O
anti	B-GENE
-	I-GENE
HBe	I-GENE
and	O
anti	B-GENE
-	I-GENE
HBc	I-GENE
in	O
the	O
serum	O
,	O
HBs	B-GENE
and	I-GENE
HBc	I-GENE
Ag	I-GENE
in	O
the	O
liver	O
)	O
;	O
non	B-GENE
-	I-GENE
A	I-GENE
non	I-GENE
-	I-GENE
B	I-GENE
(	O
non	B-GENE
-	I-GENE
A	I-GENE
,	I-GENE
non	I-GENE
-	I-GENE
B	I-GENE
Ag	I-GENE
and	I-GENE
antibody	I-GENE
,	O
anti	B-GENE
non	I-GENE
-	I-GENE
A	I-GENE
non	I-GENE
-	I-GENE
Bc	I-GENE
in	O
the	O
serum	O
,	O
non	B-GENE
-	I-GENE
A	I-GENE
,	I-GENE
non	I-GENE
-	I-GENE
Bc	I-GENE
Ag	I-GENE
in	O
the	O
liver	O
)	O
.	O

Groups	O
of	O
male	O
and	O
female	O
Fischer	O
344	O
rats	O
,	O
B6C3F1	O
mice	O
,	O
and	O
Hartley	O
guinea	O
pigs	O
were	O
exposed	O
once	O
for	O
6	O
hr	O
to	O
mean	O
concentrations	O
of	O
10	O
.	O
5	O
,	O
5	O
.	O
4	O
,	O
2	O
.	O
4	O
,	O
1	O
.	O
0	O
,	O
or	O
0	O
(	O
control	O
)	O
ppm	O
of	O
methyl	O
isocyanate	O
(	O
MIC	O
)	O
vapor	O
.	O

Radionuclide	O
study	O
and	O
endomyocardial	O
biopsy	O
revealed	O
remarkable	O
degeneration	O
of	O
myocardium	O
.	O

Immobilization	O
of	O
the	O
fracture	O
in	O
a	O
collar	O
and	O
cuff	O
sling	O
was	O
as	O
effective	O
as	O
more	O
elaborate	O
methods	O
.	O

Comparison	O
of	O
patients	O
receiving	O
phenytoin	O
and	O
those	O
who	O
were	O
not	O
showed	O
significantly	O
lower	O
serum	O
folate	O
in	O
the	O
sub	O
-	O
group	O
receiving	O
phenytoin	O
,	O
but	O
there	O
was	O
no	O
significant	O
difference	O
between	O
the	O
sub	O
-	O
groups	O
with	O
respect	O
to	O
vitamin	O
B12	O
or	O
behaviour	O
problem	O
rating	O
.	O

Typical	O
and	O
atypical	O
clinical	O
features	O
of	O
this	O
lacrimal	O
sac	O
cyst	O
are	O
emphasized	O
.	O

The	O
role	O
of	O
saliva	O
in	O
sour	O
taste	O
perception	O
was	O
investigated	O
in	O
a	O
series	O
of	O
4	O
experiments	O
.	O

Separate	O
experiments	O
measured	O
AIB	O
and	O
86RbCl	O
uptake	O
in	O
36B	O
-	O
10	O
cells	O
in	O
vitro	O
1	O
and	O
2	O
days	O
following	O
20	O
Gy	O
irradiation	O
to	O
assess	O
whether	O
this	O
radiation	O
dose	O
reduced	O
the	O
capacity	O
of	O
tumor	O
cells	O
to	O
trap	O
AIB	O
or	O
Rb	O
+	O
.	O

For	O
patients	O
with	O
recurrent	O
or	O
metastatic	O
disease	O
,	O
the	O
data	O
suggest	O
that	O
I	O
-	O
131	O
MIBG	O
scintigraphy	O
is	O
the	O
examination	O
of	O
choice	O
.	O

W	O
.	O

Cyclosporine	O
treatment	O
for	O
intractable	O
polymyositis	O
.	O

In	O
addition	O
,	O
on	O
the	O
Cohler	O
'	O
s	O
maternal	O
scale	O
,	O
Korean	O
mothers	O
were	O
found	O
to	O
view	O
their	O
infants	O
as	O
more	O
passive	O
and	O
dependent	O
than	O
American	O
mothers	O
did	O
(	O
P	O
less	O
than	O
0	O
.	O
00	O
)	O
.	O

A	O
preoperative	O
teaching	O
booklet	O
for	O
pediatric	O
patients	O
.	O

Hyperthyroidism	O

We	O
conclude	O
that	O
for	O
mono	O
-	O
intronic	O
precursors	O
in	O
which	O
there	O
is	O
only	O
one	O
choice	O
of	O
splice	O
sites	O
,	O
most	O
of	O
the	O
exon	O
sequences	O
are	O
not	O
mechanistically	O
involved	O
in	O
the	O
splicing	O
process	O
.	O

UVA	O
-	O
induced	O
melanocytic	O
lesions	O
.	O

Ex	O
vivo	O
MAO	B-GENE
inhibition	O
data	O
indicated	O
DPGPEA	O
to	O
be	O
an	O
inhibitor	O
of	O
MAO	B-GENE
-	I-GENE
B	I-GENE
,	O
although	O
the	O
effect	O
was	O
much	O
weaker	O
than	O
seen	O
with	O
tranylcypromine	O
or	O
pargyline	O
.	O

Thus	O
in	O
this	O
region	O
of	O
the	O
vessel	O
pyridinoline	O
represents	O
the	O
major	O
stabilising	O
crosslink	O
of	O
collagen	B-GENE
.	O

A	O
careful	O
,	O
radiolabelled	O
tissue	O
-	O
distribution	O
study	O
is	O
warranted	O
to	O
elucidate	O
the	O
complicated	O
metabolic	O
fate	O
of	O
perhexiline	O
.	O

Systemic	O
lupus	O
erythematosus	O
was	O
diagnosed	O
.	O

In	O
the	O
evening	O
,	O
the	O
amplitude	O
of	O
the	O
responses	O
to	O
both	O
O2	O
and	O
CO2	O
increased	O
but	O
the	O
increase	O
in	O
CO2	O
sensitivity	O
was	O
proportionally	O
more	O
important	O
.	O

The	O
statistical	O
significance	O
of	O
the	O
prognosis	O
factors	O
was	O
studied	O
by	O
uni	O
-	O
and	O
multivariative	O
methods	O
,	O
according	O
to	O
the	O
model	O
of	O
Cox	O
,	O
with	O
the	O
help	O
of	O
an	O
IMB	O
computer	O
.	O

These	O
changes	O
at	O
the	O
site	O
of	O
injection	O
consist	O
of	O
a	O
focal	O
abnormality	O
characterized	O
by	O
a	O
slight	O
increase	O
in	O
signal	O
intensity	O
on	O
T1	O
weighted	O
images	O
and	O
markedly	O
increased	O
signal	O
intensity	O
on	O
T2	O
weighted	O
images	O
.	O

These	O
results	O
suggest	O
that	O
less	O
antidopaminergic	O
activity	O
of	O
RHAL	O
in	O
this	O
neuroleptic	O
test	O
might	O
be	O
explained	O
by	O
the	O
lesser	O
conversion	O
of	O
RHAL	O
to	O
HAL	O
.	O

Organisms	O
were	O
recovered	O
from	O
the	O
conjunctiva	O
for	O
several	O
weeks	O
,	O
and	O
persistent	O
genital	O
and	O
gastrointestinal	O
infection	O
also	O
resulted	O
from	O
the	O
ocular	O
infection	O
in	O
some	O
cats	O
.	O

In	O
vivo	O
epiluminescence	O
microscopy	O
of	O
pigmented	O
skin	O
lesions	O
.	O

These	O
equilibrium	O
solutions	O
are	O
then	O
shown	O
to	O
arise	O
from	O
the	O
vertices	O
of	O
a	O
particular	O
convex	O
polyhedron	O
.	O

Statistically	O
significant	O
effects	O
were	O
noted	O
at	O
doses	O
which	O
did	O
not	O
appear	O
to	O
be	O
maternally	O
toxic	O
.	O

Low	O
MAO	B-GENE
subjects	O
showed	O
a	O
pattern	O
of	O
higher	O
scores	O
in	O
KSP	O
Impulsiveness	O
,	O
EPQ	O
Neuroticism	O
,	O
and	O
KSP	O
Somatic	O
Anxiety	O
and	O
Irritability	O
and	O
lower	O
scores	O
in	O
KSP	O
Socialization	O
,	O
in	O
line	O
with	O
personality	O
profiles	O
found	O
in	O
alcoholics	O
,	O
psychopaths	O
,	O
and	O
suicide	O
attempters	O
who	O
also	O
tend	O
to	O
have	O
low	O
platelet	O
MAO	B-GENE
activity	O
.	O

In	O
group	O
I	O
,	O
Paw	O
,	O
delta	O
V	O
,	O
PaO2	O
,	O
Vinj	O
and	O
VT	O
significantly	O
decreased	O
whereas	O
operating	O
pressure	O
and	O
E	O
significantly	O
increased	O
when	O
the	O
internal	O
diameter	O
of	O
the	O
injector	O
cannula	O
was	O
reduced	O
.	O

In	O
calves	O
receiving	O
milk	O
-	O
substitute	O
diets	O
containing	O
80	O
-	O
260	O
g	O
DM	O
/	O
kg	O
,	O
milk	O
intakes	O
were	O
reduced	O
by	O
up	O
to	O
30	O
%	O
on	O
the	O
1st	O
day	O
that	O
calves	O
were	O
fed	O
once	O
daily	O
instead	O
of	O
twice	O
daily	O
.	O

Today	O
there	O
is	O
no	O
doubt	O
that	O
elevated	O
plasma	O
cholesterol	O
levels	O
should	O
be	O
lowered	O
first	O
by	O
dietary	O
modification	O
even	O
in	O
early	O
childhood	O
,	O
beginning	O
at	O
the	O
age	O
of	O
two	O
years	O
.	O

These	O
results	O
suggest	O
that	O
N	O
-	O
nitroso	O
compounds	O
can	O
be	O
formed	O
in	O
vivo	O
in	O
the	O
infected	O
bladder	O
,	O
which	O
could	O
explain	O
the	O
association	O
between	O
urinary	O
-	O
tract	O
infections	O
and	O
increased	O
risk	O
for	O
bladder	O
cancer	O
.	O

Epithelial	O
nerve	O
fiber	O
defects	O
included	O
absence	O
or	O
distorted	O
architecture	O
of	O
the	O
basal	O
epithelial	O
plexus	O
and	O
intra	O
-	O
epithelial	O
terminals	O
.	O

The	O
histologic	O
grade	O
for	O
the	O
same	O
anatomic	O
site	O
varied	O
among	O
hearts	O
and	O
among	O
different	O
anatomic	O
sites	O
in	O
the	O
same	O
heart	O
.	O

Serum	O
levels	O
of	O
albumin	B-GENE
,	O
globulin	B-GENE
,	O
and	O
coagulation	B-GENE
protein	I-GENE
activity	O
were	O
measured	O
preshock	O
,	O
postshock	O
,	O
and	O
daily	O
for	O
3	O
days	O
;	O
skin	O
lymph	O
levels	O
were	O
measured	O
on	O
Day	O
3	O
.	O

For	O
colostral	O
milk	O
there	O
was	O
a	O
significant	O
correlation	O
of	O
vitamin	O
K1	O
to	O
cholesterol	O
(	O
r	O
=	O
0	O
.	O
62	O
)	O
but	O
not	O
to	O
total	O
lipid	O
or	O
phospholipid	O
suggesting	O
a	O
role	O
for	O
cholesterol	O
in	O
the	O
secretion	O
of	O
vitamin	O
K1	O
into	O
colostral	O
milk	O
.	O

Endurance	O
training	O
resulted	O
in	O
an	O
increase	O
of	O
stiffness	O
associated	O
with	O
a	O
decrease	O
of	O
type	O
II	O
fibers	O
.	O

A	O
rate	O
-	O
decreasing	O
dose	O
of	O
physostigmine	O
,	O
an	O
acetylcholinesterase	B-GENE
inhibitor	O
,	O
was	O
studied	O
in	O
combination	O
with	O
the	O
range	O
of	O
atropine	O
doses	O
.	O

References	O
for	O
occupational	O
fitness	O
of	O
adolescents	O
with	O
diseases	O
of	O
the	O
respiratory	O
tract	O
and	O
lungs	O

Salzburg	O
,	O
9	O
-	O
12	O
September	O
1987	O
.	O

Two	O
new	O
glucosidase	B-GENE
inhibitors	O
(	O
BAY	O
m	O
1099	O
and	O
BAY	O
o	O
1248	O
)	O
were	O
studied	O
in	O
volunteers	O
and	O
type	O
II	O
diabetics	O
under	O
various	O
conditions	O
.	O

The	O
models	O
accurately	O
localized	O
the	O
common	O
boundaries	O
between	O
the	O
PBB	O
and	O
CN	O
.	O

However	O
,	O
conversions	O
of	O
12	O
mm	O
or	O
more	O
from	O
a	O
documented	O
negative	O
result	O
indicated	O
spread	O
of	O
infection	O
.	O

The	O
maximum	O
amplitude	O
of	O
evoked	O
responses	O
in	O
the	O
cervical	O
sympathetic	O
trunk	O
was	O
obtained	O
when	O
the	O
T2	O
white	O
ramus	O
was	O
stimulated	O
and	O
decreased	O
gradually	O
when	O
followed	O
by	O
the	O
stimulation	O
of	O
T1	O
,	O
T3	O
,	O
T4	O
and	O
T5	O
white	O
rami	O
.	O

It	O
is	O
concluded	O
that	O
contact	O
allergy	O
to	O
K	O
-	O
CG	O
is	O
common	O
.	O

The	O
effect	O
of	O
a	O
beta	B-GENE
-	I-GENE
adrenoceptor	I-GENE
antagonist	O
,	O
pindolol	O
,	O
on	O
uterine	O
smooth	O
muscle	O
in	O
term	O
pregnant	O
women	O
was	O
studied	O
in	O
vitro	O
and	O
in	O
vivo	O
(	O
in	O
hypertensive	O
women	O
)	O
.	O

The	O
less	O
-	O
polar	O
mycolic	O
acid	O
-	O
containing	O
Rhodococcus	O
species	O
showed	O
chromatographic	O
patterns	O
that	O
partially	O
overlapped	O
(	O
in	O
elution	O
times	O
)	O
the	O
patterns	O
of	O
Nocardia	O
asteroides	O
,	O
N	O
.	O
otitidiscaviarum	O
,	O
and	O
N	O
.	O
brasiliensis	O
,	O
but	O
the	O
larger	O
number	O
of	O
peaks	O
in	O
the	O
last	O
species	O
made	O
separation	O
between	O
the	O
genera	O
possible	O
.	O

Blood	B-GENE
serum	I-GENE
erythropoietin	I-GENE
level	O
and	O
basic	O
hematological	O
indices	O
during	O
the	O
adaptation	O
of	O
healthy	O
newborn	O
infants	O

49	O
,	O
XXXXY	O
chromosome	O
anomaly	O
:	O
an	O
unusual	O
variant	O
of	O
Klinefelter	O
'	O
s	O
syndrome	O
.	O

Oxygen	O
delivery	O
and	O
consumption	O
and	O
P50	O
in	O
patients	O
with	O
acute	O
myocardial	O
infarction	O
.	O

Infants	O
of	O
this	O
sample	O
had	O
monocular	O
PL	O
visual	O
acuities	O
similar	O
to	O
those	O
established	O
by	O
McDonald	O
et	O
al	O
.	O
in	O
a	O
laboratory	O
setting	O
.	O

These	O
results	O
indicate	O
that	O
the	O
effect	O
of	O
the	O
isomers	O
of	O
pentobarbital	O
and	O
secobarbital	O
on	O
mult	O
FR30	O
FI600	O
responding	O
and	O
on	O
suppressed	O
responding	O
are	O
qualitatively	O
similar	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
250	O
WORDS	O
)	O

The	O
number	O
of	O
crystalline	O
deposits	O
is	O
less	O
in	O
the	O
advanced	O
atrophic	O
areas	O
of	O
the	O
RPE	O
-	O
choriocapillaris	O
complex	O
.	O

All	O
33	O
subjects	O
were	O
given	O
psychometric	O
instruments	O
for	O
measuring	O
various	O
components	O
of	O
anger	O
and	O
anxiety	O
:	O
Spielberger	O
'	O
s	O
State	O
-	O
Trait	O
Personality	O
Inventory	O
,	O
the	O
Anger	O
Expression	O
Scale	O
,	O
and	O
the	O
State	O
Anger	O
Reaction	O
Scale	O
.	O

It	O
was	O
found	O
that	O
the	O
primary	O
visual	O
cortex	O
of	O
the	O
rat	O
is	O
asymmetrical	O
in	O
volume	O
,	O
and	O
that	O
the	O
asymmetry	O
reflects	O
side	O
differences	O
in	O
the	O
number	O
of	O
neurons	O
.	O

The	O
subjects	O
received	O
a	O
single	O
500	O
mg	O
dose	O
of	O
acetaminophen	O
i	O
.	O
v	O
.	O
and	O
concentrations	O
in	O
plasma	O
were	O
measured	O
for	O
360	O
minutes	O
and	O
in	O
urine	O
for	O
24	O
h	O
in	O
order	O
to	O
estimate	O
the	O
production	O
of	O
metabolites	O
.	O

Mean	O
weighted	O
skin	O
temperature	O
(	O
Tsk	O
)	O
was	O
lower	O
(	O
P	O
less	O
than	O
0	O
.	O
01	O
)	O
following	O
acclimation	O
than	O
before	O
,	O
and	O
acclimation	O
resulted	O
in	O
a	O
larger	O
(	O
P	O
less	O
than	O
0	O
.	O
02	O
)	O
Tre	O
-	O
to	O
-	O
Tsk	O
gradient	O
.	O

Indium	O
-	O
111	O
leukocyte	O
imaging	O
in	O
patients	O
with	O
rheumatoid	O
arthritis	O
.	O

The	O
effect	O
of	O
L	O
-	O
methionine	O
supplementation	O
on	O
the	O
utilization	O
of	O
a	O
soy	O
protein	O
isolate	O
(	O
SPI	O
)	O
was	O
evaluated	O
by	O
short	O
-	O
term	O
nitrogen	O
balance	O
studies	O
in	O
young	O
women	O
.	O

Primary	O
invasive	O
Haemophilus	O
influenzae	O
type	O
b	O
disease	O
:	O
a	O
population	O
-	O
based	O
assessment	O
of	O
risk	O
factors	O
.	O

Overall	O
,	O
lesions	O
infiltrating	O
the	O
deep	O
lamina	O
propria	O
do	O
not	O
exhibit	O
a	O
reduced	O
frequency	O
of	O
occurrence	O
compared	O
to	O
lesions	O
infiltrating	O
the	O
skeletal	O
muscle	O
;	O
however	O
,	O
carcinomas	O
affecting	O
other	O
oral	O
sites	O
showed	O
a	O
reduced	O
frequency	O
of	O
deeply	O
infiltrating	O
lesions	O
in	O
comparison	O
to	O
more	O
superficial	O
lesions	O
.	O

Factors	O
that	O
showed	O
significant	O
correlation	O
to	O
elevated	O
CIC	O
'	O
s	O
in	O
the	O
highly	O
elevated	O
portion	O
of	O
our	O
CIC	O
population	O
were	O
poor	O
NIH	O
score	O
,	O
increased	O
patient	O
age	O
,	O
low	O
peak	O
expiratory	O
flow	O
rate	O
,	O
and	O
elevated	O
total	O
serum	B-GENE
IgG	I-GENE
.	O

Induction	O
of	O
both	O
potential	O
transcripts	O
follows	O
heat	O
shock	O
in	O
vivo	O
.	O

New	O
and	O
successful	O
steps	O
have	O
been	O
made	O
in	O
immunodiagnostics	O
,	O
immunotherapy	O
,	O
and	O
immunoprophylaxis	O
of	O
immunologically	O
conditioned	O
infertility	O
.	O

Estimated	O
nucleic	O
acid	O
N	O
absorption	O
is	O
7	O
-	O
8	O
%	O
of	O
N	O
intake	O
.	O

Adhesion	O
,	O
phagocytosis	O
,	O
chemotactic	O
and	O
random	O
migration	O
,	O
nitroblue	O
tetrazolium	O
dye	O
reduction	O
of	O
peritoneal	O
exudate	O
neutrophils	O
and	O
macrophages	O
,	O
fibrinogen	B-GENE
level	O
,	O
gelation	O
of	O
soluble	O
fibrin	B-GENE
and	O
serial	O
dilution	O
protamine	O
sulfate	O
test	O
were	O
investigated	O
in	O
115	O
New	O
Zealand	O
white	O
rabbits	O
with	O
experimentally	O
induced	O
Shwartzman	O
phenomenon	O
in	O
the	O
colon	O
,	O
and	O
in	O
control	O
animals	O
.	O

The	O
FFA	O
levels	O
were	O
not	O
affected	O
(	O
P	O
greater	O
than	O
.	O
1	O
)	O
by	O
meal	O
interval	O
.	O

He	O
visited	O
our	O
hospital	O
and	O
left	O
solitary	O
renal	O
cyst	O
was	O
suspected	O
.	O

However	O
,	O
further	O
analyses	O
of	O
the	O
data	O
indicate	O
that	O
increasing	O
VO2	O
AT	O
(	O
r	O
=	O
-	O
0	O
.	O
63	O
,	O
P	O
less	O
than	O
0	O
.	O
05	O
)	O
rather	O
than	O
VO2max	O
(	O
r	O
=	O
-	O
0	O
.	O
15	O
)	O
could	O
result	O
in	O
improving	O
the	O
10	O
,	O
000	O
m	O
race	O
performance	O
to	O
a	O
larger	O
extent	O
,	O
and	O
that	O
the	O
absolute	O
amount	O
of	O
change	O
(	O
delta	O
)	O
in	O
the	O
10	O
,	O
000	O
m	O
run	O
time	O
is	O
best	O
accounted	O
for	O
by	O
a	O
combination	O
of	O
delta	O
VO2	O
AT	O
and	O
delta	O
5	O
,	O
000	O
m	O
run	O
time	O
.	O

A	O
significant	O
herd	O
X	O
period	O
interaction	O
existed	O
for	O
liver	O
TG	O
and	O
serum	O
dextran	O
precipitable	O
cholesterol	O
concentrations	O
.	O

Liver	O
TG	O
and	O
serum	O
NEFA	O
concentrations	O
were	O
positively	O
correlated	O
.	O

The	O
results	O
show	O
that	O
nerve	O
and	O
roots	O
differ	O
considerably	O
both	O
in	O
the	O
force	O
they	O
sustain	O
before	O
failure	O
and	O
in	O
the	O
other	O
biomechanics	O
they	O
exhibit	O
.	O

When	O
the	O
coronary	O
sinus	O
pressure	O
reached	O
15	O
torr	O
,	O
there	O
was	O
a	O
significant	O
decrease	O
in	O
cardiac	O
index	O
(	O
3	O
.	O
60	O
+	O
/	O
-	O
0	O
.	O
5	O
to	O
2	O
.	O
70	O
+	O
/	O
-	O
0	O
.	O
6	O
L	O
/	O
min	O
/	O
m2	O
,	O
p	O
less	O
than	O
0	O
.	O
001	O
)	O
,	O
coronary	O
blood	O
flow	O
(	O
13	O
.	O
7	O
+	O
/	O
-	O
3	O
.	O
1	O
to	O
7	O
.	O
0	O
+	O
/	O
-	O
2	O
.	O
1	O
ml	O
/	O
min	O
,	O
p	O
less	O
than	O
0	O
.	O
001	O
)	O
,	O
rate	O
of	O
rise	O
of	O
left	O
ventricular	O
pressure	O
(	O
1	O
,	O
567	O
+	O
/	O
-	O
275	O
to	O
1	O
,	O
331	O
+	O
/	O
-	O
314	O
,	O
p	O
less	O
than	O
0	O
.	O
05	O
)	O
,	O
and	O
an	O
increase	O
in	O
coronary	O
arteriovenous	O
difference	O
(	O
62	O
.	O
8	O
%	O
+	O
/	O
-	O
9	O
.	O
3	O
%	O
to	O
70	O
.	O
5	O
%	O
+	O
/	O
-	O
5	O
.	O
4	O
%	O
saturation	O
,	O
p	O
less	O
than	O
0	O
.	O
03	O
)	O
.	O

Calcifications	O
in	O
the	O
thoracic	O
aorta	O
at	O
the	O
level	O
of	O
the	O
11th	O
and	O
the	O
12th	O
thoracic	O
vertebrae	O
in	O
592	O
men	O
and	O
333	O
women	O
were	O
studied	O
using	O
computed	O
tomography	O
.	O

In	O
a	O
series	O
of	O
402	O
consecutive	O
autopsies	O
,	O
parietal	O
pleural	O
plaques	O
(	O
PP	O
)	O
were	O
found	O
in	O
68	O
individuals	O
above	O
40	O
years	O
of	O
age	O
.	O

Approximately	O
60	O
%	O
of	O
cell	O
bodies	O
of	O
primary	O
neurons	O
innervating	O
the	O
intra	O
and	O
perioral	O
structures	O
through	O
the	O
inferior	O
alveolar	O
,	O
lingual	O
,	O
mental	O
,	O
and	O
buccal	O
nerves	O
were	O
in	O
the	O
range	O
between	O
300	O
and	O
600	O
micron	O
2	O
in	O
cross	O
-	O
sectional	O
area	O
:	O
mean	O
+	O
/	O
-	O
SD	O
509	O
+	O
/	O
-	O
243	O
micron	O
2	O
,	O
420	O
+	O
/	O
-	O
181	O
micron	O
2	O
,	O
469	O
+	O
/	O
-	O
200	O
micron	O
2	O
,	O
and	O
444	O
+	O
/	O
-	O
186	O
micron	O
2	O
,	O
respectively	O
.	O

Pharmacological	O
action	O
of	O
eptazocine	O
(	O
l	O
-	O
1	O
,	O
4	O
-	O
dimethyl	O
-	O
10	O
-	O
hydroxy	O
-	O
2	O
,	O
3	O
,	O
4	O
,	O
5	O
,	O
6	O
,	O
7	O
-	O
hexahydro	O
-	O
1	O
,	O
6	O
-	O
methano	O
-	O
1H	O
-	O
4	O
-	O
benz	O
azonine	O
)	O
.	O

On	O
transition	O
from	O
high	O
to	O
low	O
voltage	O
there	O
was	O
a	O
significant	O
fall	O
in	O
arterial	O
pressure	O
(	O
7	O
%	O
)	O
and	O
an	O
increase	O
in	O
flow	O
(	O
19	O
-	O
38	O
%	O
)	O
to	O
areas	O
of	O
the	O
brain	O
corresponding	O
to	O
the	O
arborization	O
of	O
the	O
reticular	O
formation	O
,	O
i	O
.	O
e	O
.	O
excluding	O
the	O
cerebrum	O
and	O
cerebellum	O
.	O

One	O
hundred	O
and	O
four	O
(	O
14	O
per	O
cent	O
)	O
second	O
primary	O
tumours	O
were	O
reported	O
.	O

Failures	O
of	O
colorimetric	O
additivity	O
under	O
these	O
experimental	O
conditions	O
are	O
discussed	O
.	O

There	O
have	O
been	O
five	O
problems	O
(	O
extravasation	O
2	O
,	O
suspected	O
sepsis	O
1	O
,	O
and	O
hematoma	O
2	O
)	O
during	O
a	O
total	O
of	O
2	O
,	O
927	O
days	O
of	O
exposure	O
.	O

It	O
is	O
suggested	O
that	O
these	O
results	O
may	O
raise	O
the	O
interesting	O
possibility	O
of	O
providing	O
a	O
means	O
of	O
identifying	O
greater	O
or	O
lesser	O
susceptibility	O
to	O
the	O
coronary	O
effects	O
of	O
Type	O
A	O
behavior	O
.	O

Two	O
studies	O
assessed	O
two	O
types	O
of	O
reliability	O
of	O
the	O
student	O
Jenkins	O
Activity	O
Survey	O
(	O
JAS	O
;	O
a	O
questionnaire	O
measure	O
of	O
Type	O
A	O
behavior	O
)	O
.	O

When	O
phencyclidine	O
was	O
administered	O
alone	O
,	O
overall	O
response	O
rate	O
decreased	O
and	O
percent	O
errors	O
increased	O
with	O
increasing	O
doses	O
.	O

Possibilities	O
and	O
outlook	O
for	O
wrist	O
joint	O
endoprosthesis	O

Study	O
of	O
the	O
energy	O
metabolism	O
of	O
the	O
sensomotor	O
cortex	O
and	O
hippocampus	O
by	O
the	O
(	O
14C	O
)	O
2	O
-	O
deoxyglucose	O
method	O
during	O
the	O
development	O
of	O
dissociated	O
states	O

Malignant	O
lymphoma	O
is	O
very	O
heterogeneous	O
in	O
terms	O
of	O
its	O
biological	O
behavior	O
.	O

Further	O
investigations	O
are	O
necessary	O
to	O
elucidate	O
the	O
biochemical	O
and	O
physiological	O
properties	O
of	O
DLIS	O
.	O

Among	O
them	O
,	O
26	O
cases	O
were	O
benign	O
and	O
34	O
malignant	O
.	O

Of	O
the	O
cases	O
with	O
PLD	O
,	O
50	O
%	O
had	O
associated	O
renal	O
cysts	O
and	O
10	O
%	O
of	O
the	O
cases	O
with	O
APCD	O
had	O
associated	O
liver	O
cysts	O
.	O

Fast	O
goal	O
-	O
directed	O
voluntary	O
movements	O
of	O
the	O
human	O
upper	O
extremity	O
are	O
known	O
to	O
be	O
associated	O
with	O
three	O
distinct	O
bursts	O
of	O
EMG	O
activity	O
in	O
antagonistic	O
muscles	O
.	O

The	O
combination	O
of	O
F1	O
and	O
F2	O
which	O
was	O
the	O
best	O
predictor	O
of	O
CHD	O
in	O
this	O
population	O
(	O
G1	O
)	O
might	O
be	O
interpreted	O
as	O
reflecting	O
trunk	O
adiposity	O
mainly	O
abdominal	O
.	O

Renal	O
clearance	O
fell	O
from	O
19	O
.	O
0	O
+	O
/	O
-	O
4	O
.	O
9	O
ml	O
/	O
min	O
/	O
1	O
.	O
73	O
m2	O
(	O
group	O
I	O
)	O
to	O
1	O
.	O
0	O
+	O
/	O
-	O
0	O
.	O
4	O
ml	O
/	O
min	O
/	O
1	O
.	O
73	O
m2	O
(	O
group	O
IV	O
)	O
.	O

The	O
relations	O
between	O
type	O
A	O
behavior	O
,	O
clinically	O
relevant	O
behavior	O
,	O
academic	O
achievement	O
,	O
and	O
IQ	O
in	O
children	O
.	O

She	O
also	O
had	O
slight	O
weakness	O
of	O
the	O
upper	O
extremities	O
.	O

Results	O
of	O
electron	O
therapy	O
of	O
tumors	O
in	O
different	O
sites	O

The	O
mechanism	O
of	O
action	O
is	O
explored	O
in	O
some	O
detail	O
,	O
specifically	O
as	O
it	O
relates	O
to	O
reticuloendothelial	O
system	O
(	O
RES	O
)	O
Fc	B-GENE
receptor	I-GENE
blockade	O
and	O
suppression	O
of	O
antiplatelet	O
antibody	O
synthesis	O
.	O

Incidences	O
of	O
nonfatal	O
stroke	O
,	O
myocardial	O
infarction	O
,	O
angina	O
pectoris	O
und	O
left	O
ventricular	O
hypertrophy	O
could	O
also	O
be	O
lowered	O
.	O

High	O
radial	O
r	O
values	O
with	O
small	O
standard	O
deviations	O
were	O
observed	O
in	O
normal	O
LV	O
(	O
0	O
.	O
972	O
+	O
/	O
-	O
0	O
.	O
016	O
)	O
and	O
in	O
non	O
-	O
MI	O
regions	O
(	O
0	O
.	O
964	O
+	O
/	O
-	O
0	O
.	O
018	O
)	O
,	O
indicating	O
temporally	O
homogeneous	O
radial	O
shortening	O
.	O

These	O
results	O
indicate	O
that	O
during	O
pregnancy	O
there	O
are	O
increases	O
in	O
bone	O
formation	O
rates	O
contributing	O
to	O
the	O
increases	O
in	O
skeletal	O
mass	O
.	O

We	O
analyzed	O
data	O
from	O
56	O
patients	O
with	O
Systemic	O
Lupus	O
Erythematosus	O
(	O
SLE	O
)	O
in	O
whom	O
renal	O
biopsies	O
were	O
done	O
systematically	O
.	O

Prevention	O
by	O
a	O
heparin	O
-	O
antithrombin	B-GENE
III	I-GENE
combination	O

MICs	O
of	O
four	O
antifungal	O
agents	O
(	O
5	O
-	O
fluorocytosine	O
,	O
miconazole	O
,	O
ketoconazole	O
,	O
and	O
amphotericin	O
B	O
)	O
for	O
84	O
clinical	O
isolates	O
of	O
various	O
Candida	O
species	O
were	O
then	O
determined	O
with	O
both	O
media	O
in	O
agar	O
dilution	O
and	O
microtiter	O
broth	O
dilution	O
systems	O
.	O

There	O
were	O
18	O
patients	O
with	O
Group	O
II	O
(	O
a	O
)	O
tumors	O
;	O
although	O
tumor	O
biopsy	O
was	O
attempted	O
on	O
eight	O
of	O
these	O
,	O
pathological	O
diagnosis	O
at	O
the	O
time	O
of	O
surgery	O
was	O
made	O
in	O
only	O
one	O
case	O
.	O

Evidence	O
that	O
opiate	O
addiction	O
is	O
in	O
part	O
an	O
immune	O
response	O
.	O

Parasitological	O
post	O
-	O
mortem	O
examination	O
of	O
all	O
seropositive	O
animals	O
showed	O
five	O
and	O
seven	O
false	O
-	O
positive	O
animals	O
when	O
E	B-GENE
/	I-GENE
S	I-GENE
and	I-GENE
CWE	I-GENE
antigens	I-GENE
were	O
used	O
,	O
respectively	O
.	O

Glucocorticoid	O
induced	O
hypertension	O
has	O
been	O
regarded	O
as	O
independent	O
of	O
sodium	O
(	O
Na	O
)	O
,	O
in	O
contrast	O
to	O
mineralocorticoid	O
induced	O
hypertension	O
,	O
which	O
is	O
Na	O
+	O
-	O
dependent	O
.	O

Seventeen	O
of	O
them	O
were	O
on	O
treatment	O
with	O
systemic	O
steroids	O
.	O

Examples	O
of	O
its	O
use	O
in	O
the	O
intensive	O
therapy	O
unit	O
are	O
described	O
.	O

Only	O
seven	O
patients	O
,	O
five	O
of	O
whom	O
have	O
metastatic	O
disease	O
,	O
survive	O
more	O
than	O
10	O
years	O
after	O
first	O
presentation	O
;	O
nine	O
patients	O
,	O
one	O
of	O
whom	O
has	O
secondaries	O
,	O
survive	O
for	O
5	O
years	O
or	O
less	O
.	O

Although	O
differences	O
were	O
not	O
significant	O
,	O
infants	O
in	O
the	O
experimental	O
group	O
had	O
more	O
changes	O
in	O
the	O
intermittent	O
mandatory	O
ventilation	O
(	O
IMV	O
)	O
settings	O
during	O
transport	O
,	O
and	O
more	O
such	O
infants	O
arrived	O
at	O
the	O
receiving	O
hospital	O
with	O
acceptable	O
pH	O
and	O
PCO2	O
values	O
.	O

Repetitive	O
sequences	O
are	O
present	O
in	O
at	O
least	O
three	O
introns	O
of	O
the	O
cytochrome	B-GENE
P	I-GENE
-	I-GENE
450PBc2	I-GENE
gene	I-GENE
,	O
but	O
not	O
in	O
exons	O
or	O
the	O
5	O
'	O
-	O
flanking	O
region	O
.	O

A	O
large	O
increase	O
of	O
serum	O
ketones	O
occurred	O
under	O
all	O
conditions	O
,	O
and	O
the	O
exercise	O
respiratory	O
quotient	O
suggested	O
some	O
increase	O
of	O
fat	O
utilization	O
,	O
WW	O
(	O
0	O
.	O
85	O
)	O
through	O
CW	O
(	O
0	O
.	O
84	O
)	O
to	O
CC	O
(	O
0	O
.	O
83	O
)	O
.	O

This	O
lack	O
of	O
correlation	O
may	O
be	O
due	O
to	O
variations	O
in	O
the	O
metabolic	O
activity	O
of	O
the	O
endometriotic	O
implants	O
present	O
at	O
different	O
stages	O
of	O
the	O
disease	O
.	O

Respiratory	O
adaptation	O
to	O
chronic	O
hypoxia	O
in	O
newborn	O
rats	O
.	O

Compound	O
1	O
is	O
either	O
21	O
-	O
O	O
-	O
angeloyl	O
,	O
22	O
-	O
O	O
-	O
tigloyl	O
R1	O
-	O
barrigenol	O
,	O
or	O
21	O
-	O
O	O
-	O
tigloyl	O
,	O
22	O
-	O
O	O
-	O
angeloyl	O
R1	O
-	O
barrigenol	O
.	O

Human	O
and	O
Chinese	B-GENE
hamster	I-GENE
S14	I-GENE
protein	I-GENE
sequences	I-GENE
deduced	O
from	O
the	O
cDNAs	O
are	O
identical	O
.	O

RPS14	B-GENE
introns	O
3	O
and	O
4	O
both	O
contain	O
Alu	B-GENE
sequences	O
.	O

One	O
of	O
the	O
most	O
relevant	O
aspects	O
in	O
achieving	O
the	O
consistent	O
survival	O
of	O
an	O
animal	O
undergoing	O
the	O
experimental	O
implantation	O
of	O
a	O
total	O
artificial	O
heart	O
is	O
obviously	O
related	O
to	O
the	O
correct	O
anatomic	O
placement	O
of	O
prosthetic	O
ventricles	O
inside	O
the	O
chest	O
.	O

An	O
exaggerated	O
tissue	O
response	O
adjacent	O
to	O
the	O
cyanoacrylate	O
site	O
suggested	O
a	O
potential	O
toxic	O
chemical	O
or	O
thermal	O
reaction	O
,	O
or	O
both	O
,	O
to	O
the	O
tissue	O
adhesive	O
,	O
but	O
there	O
was	O
no	O
evidence	O
of	O
any	O
distant	O
ocular	O
effects	O
.	O

These	O
findings	O
suggest	O
that	O
there	O
may	O
be	O
a	O
relationship	O
between	O
the	O
pathogenesis	O
of	O
MAL	O
,	O
narcolepsy	O
,	O
and	O
OSA	O
.	O

Among	O
82	O
superficial	O
lesions	O
34	O
were	O
classified	O
as	O
showing	O
CR	O
and	O
another	O
23	O
as	O
showing	O
PR	O
,	O
with	O
a	O
response	O
rate	O
of	O
69	O
.	O
5	O
%	O
.	O

While	O
the	O
examiner	O
observed	O
the	O
interior	O
of	O
the	O
eye	O
with	O
indirect	O
ophthalmoscopy	O
,	O
the	O
point	O
source	O
of	O
light	O
from	O
the	O
fiberoptic	O
light	O
pipe	O
was	O
moved	O
along	O
the	O
margins	O
of	O
the	O
episcleral	O
plaque	O
.	O

These	O
fusion	O
proteins	O
also	O
allowed	O
the	O
localization	O
of	O
the	O
transcriptional	O
activation	O
and	O
DNA	O
binding	O
domains	O
of	O
the	O
ToxR	B-GENE
protein	I-GENE
to	O
its	O
cytoplasmically	O
located	O
N	O
-	O
terminal	O
portion	O
.	O

From	O
life	O
-	O
table	O
analyses	O
of	O
these	O
patients	O
,	O
we	O
estimated	O
that	O
the	O
incidence	O
of	O
secondary	O
chondrosarcoma	O
in	O
patients	O
who	O
have	O
Ollier	O
disease	O
is	O
about	O
25	O
per	O
cent	O
at	O
the	O
age	O
of	O
forty	O
years	O
,	O
and	O
that	O
malignant	O
degeneration	O
is	O
almost	O
a	O
certainty	O
in	O
patients	O
who	O
have	O
Maffucci	O
syndrome	O
.	O

The	O
lethal	O
toxicity	O
of	O
inorganic	O
(	O
HgCl2	O
)	O
and	O
organic	O
(	O
CH3HgCl	O
)	O
mercury	O
chloride	O
was	O
compared	O
for	O
Coturnix	O
(	O
Japanese	O
quail	O
,	O
Coturnix	O
japonica	O
)	O
of	O
different	O
ages	O
from	O
hatch	O
through	O
adulthood	O
by	O
single	O
-	O
dose	O
acute	O
oral	O
and	O
intramuscular	O
injections	O
and	O
by	O
a	O
5	O
-	O
d	O
dietary	O
trial	O
.	O

Since	O
the	O
integrated	O
13h00	O
-	O
16h00	O
plasma	O
cortisol	O
estimation	O
is	O
cheaper	O
and	O
simpler	O
than	O
the	O
mean	O
13h00	O
-	O
16h00	O
plasma	O
cortisol	O
estimation	O
,	O
we	O
recommend	O
it	O
as	O
an	O
adjunct	O
in	O
the	O
diagnosis	O
of	O
Cushing	O
'	O
s	O
syndrome	O
.	O

Most	O
of	O
the	O
patients	O
had	O
locally	O
advanced	O
lesions	O
(	O
63	O
T3	O
-	O
4	O
:	O
91	O
.	O
5	O
%	O
)	O
according	O
to	O
the	O
adopted	O
TNM	O
system	O
(	O
Lederman	O
-	O
Gadeberg	O
,	O
Sisson	O
-	O
Jesse	O
)	O
.	O

Chlorambucil	O
and	O
interferon	B-GENE
for	O
low	O
grade	O
non	O
-	O
Hodgkin	O
'	O
s	O
lymphoma	O
.	O

Selenium	O
(	O
.	O
1	O
ppm	O
)	O
and	O
E	O
(	O
50	O
IU	O
/	O
kg	O
)	O
supplementation	O
of	O
the	O
diet	O
of	O
the	O
sow	O
increased	O
plasma	O
tocopherol	O
and	O
Se	O
concentrations	O
,	O
but	O
did	O
not	O
increase	O
plasma	B-GENE
glutathione	I-GENE
peroxidase	I-GENE
(	O
GSH	B-GENE
-	I-GENE
Px	I-GENE
)	O
activity	O
.	O

Framingham	O
Type	O
A	O
behavior	O
was	O
positively	O
associated	O
with	O
diastolic	O
blood	O
pressure	O
(	O
r	O
=	O
0	O
.	O
17	O
,	O
p	O
less	O
than	O
0	O
.	O
05	O
)	O
among	O
the	O
women	O
.	O

The	O
in	O
vitro	O
antibacterial	O
potency	O
is	O
greatest	O
when	O
the	O
1	O
-	O
substituent	O
is	O
2	O
,	O
4	O
-	O
difluorophenyl	O
and	O
the	O
7	O
-	O
substituent	O
is	O
a	O
3	O
-	O
amino	O
-	O
1	O
-	O
pyrrolidinyl	O
group	O
.	O

The	O
M	B-GENE
reading	I-GENE
frame	I-GENE
differed	O
from	O
the	O
reported	O
sequence	O
by	O
a	O
single	O
nucleotide	O
corresponding	O
to	O
a	O
conservative	O
lysine	O
to	O
arginine	O
amino	O
acid	O
substitution	O
near	O
the	O
carboxy	O
-	O
terminus	O
conserved	O
among	O
the	O
M	B-GENE
proteins	I-GENE
of	O
paramyxoviruses	O
.	O

An	O
ion	O
chromatographic	O
method	O
was	O
used	O
to	O
determine	O
Br	O
ion	O
in	O
the	O
urine	O
of	O
Greyhounds	O
.	O

II	O
.	O

Laryngographic	O
changes	O
following	O
endotracheal	O
intubation	O
in	O
adults	O
.	O

Autotransplantation	O
of	O
a	O
vein	O
segment	O
with	O
valve	O
in	O
the	O
treatment	O
of	O
deep	O
vein	O
valvular	O
insufficiency	O
of	O
the	O
lower	O
extremity	O

The	O
relationships	O
among	O
four	O
descriptors	O
of	O
lactate	O
increase	O
:	O
lactate	O
threshold	O
(	O
LT	O
)	O
(	O
the	O
VO2	O
at	O
which	O
blood	O
lactate	O
concentration	O
begins	O
to	O
increase	O
above	O
the	O
resting	O
level	O
during	O
an	O
incremental	O
exercise	O
test	O
)	O
,	O
LT1	O
(	O
the	O
VO2	O
at	O
which	O
blood	O
lactate	O
increases	O
1	O
mM	O
above	O
the	O
resting	O
level	O
)	O
,	O
LT2	O
(	O
the	O
VO2	O
at	O
which	O
blood	O
lactate	O
concentration	O
reaches	O
a	O
fixed	O
value	O
of	O
2	O
mM	O
)	O
,	O
onset	O
of	O
blood	O
lactate	O
accumulation	O
(	O
OBLA	O
;	O
the	O
VO2	O
at	O
which	O
blood	O
lactate	O
reaches	O
a	O
concentration	O
of	O
4	O
mM	O
)	O
,	O
were	O
compared	O
with	O
aerobic	O
capacity	O
(	O
VO2max	O
)	O
and	O
12	O
min	O
running	O
performance	O
in	O
19	O
untrained	O
female	O
students	O
.	O

This	O
is	O
based	O
on	O
partitioning	O
an	O
underlying	O
multivariate	O
normal	O
distribution	O
.	O

The	O
observation	O
of	O
late	O
effects	O
after	O
irradiations	O
or	O
after	O
space	O
flights	O
show	O
the	O
difficulties	O
encountered	O
in	O
assessing	O
radiative	O
risks	O
during	O
long	O
duration	O
space	O
flights	O
.	O

Practical	O
use	O
and	O
interpretation	O
of	O
viral	O
hepatitis	O
B	O
markers	O
and	O
hepatic	O
biopsy	O
in	O
HBs	B-GENE
Ag	I-GENE
carriers	O
and	O
at	O
the	O
chronic	O
hepatitis	O
stage	O

The	O
1	O
,	O
2	O
,	O
3	O
and	O
4	O
year	O
survival	O
rates	O
were	O
94	O
%	O
,	O
84	O
%	O
,	O
76	O
%	O
and	O
63	O
%	O
,	O
respectively	O
.	O

Northern	O
blotting	O
with	O
a	O
unique	O
17	O
-	O
mer	O
oligonucleotide	O
demonstrated	O
the	O
absence	O
of	O
the	O
mutant	O
sequence	O
in	O
the	O
mRNA	O
from	O
which	O
the	O
cDNA	O
library	O
giving	O
rise	O
to	O
the	O
mutant	O
cDNA	O
was	O
constructed	O
.	O

Chemotherapy	O
of	O
metastasizing	O
breast	O
cancer	O

In	O
recent	O
years	O
,	O
successful	O
physiological	O
models	O
have	O
been	O
developed	O
for	O
a	O
variety	O
of	O
volatile	O
and	O
nonvolatile	O
chemicals	O
,	O
and	O
their	O
ability	O
to	O
perform	O
the	O
extrapolations	O
needed	O
in	O
risk	O
assessment	O
has	O
been	O
demonstrated	O
.	O

Linear	O
extrapolation	O
is	O
used	O
below	O
the	O
experimental	O
data	O
range	O
to	O
establish	O
an	O
upper	O
bound	O
on	O
carcinogenic	O
risk	O
at	O
low	O
doses	O
.	O

Hisako	O
Minowa	O
who	O
has	O
worked	O
as	O
a	O
psychiatric	O
counsellor	O
in	O
industry	O
for	O
the	O
past	O
20	O
years	O

Deletion	O
mapping	O
studies	O
revealed	O
that	O
the	O
upstream	O
DNA	O
sequences	O
up	O
to	O
-	O
86	O
were	O
sufficient	O
for	O
the	O
optimal	O
basal	O
level	O
transcription	O
in	O
HeLa	O
cells	O
and	O
also	O
for	O
the	O
EIA	B-GENE
-	O
induced	O
transcription	O
.	O

Incorporation	O
of	O
the	O
polyene	O
antibiotic	O
amphotericin	O
B	O
(	O
AMB	O
)	O
in	O
liposomes	O
results	O
in	O
a	O
marked	O
reduction	O
in	O
drug	O
toxicity	O
with	O
no	O
loss	O
of	O
antifungal	O
potency	O
.	O

Eleven	O
healthy	O
,	O
normotensive	O
males	O
undergoing	O
routine	O
restorative	O
dental	O
care	O
were	O
evaluated	O
during	O
treatment	O
for	O
possible	O
hemodynamic	O
alterations	O
in	O
response	O
to	O
potential	O
sympathetic	O
nervous	O
system	O
stimulation	O
.	O

Serum	B-GENE
IgM	I-GENE
and	O
IgE	B-GENE
concentrations	O
,	O
allergen	B-GENE
-	I-GENE
specific	I-GENE
IgE	I-GENE
scores	O
,	O
and	O
the	O
tumor	O
E2R	B-GENE
status	O
were	O
combined	O
to	O
construct	O
a	O
three	O
-	O
level	O
risk	O
classification	O
that	O
was	O
more	O
prognostic	O
than	O
any	O
of	O
the	O
individual	O
components	O
.	O

Within	O
the	O
Strep	O
.	O
mutans	O
group	O
there	O
was	O
a	O
highly	O
-	O
significant	O
difference	O
between	O
Strep	O
.	O
mutans	O
/	O
Strep	O
.	O
cricetus	O
(	O
p	O
less	O
than	O
0	O
.	O
01	O
)	O
with	O
respect	O
to	O
mean	O
clump	O
size	O
.	O

These	O
results	O
indicate	O
that	O
T	O
.	O
C	O
.	O
,	O
LDL	B-GENE
-	I-GENE
C	I-GENE
.	O
,	O
HDL	B-GENE
-	I-GENE
C	I-GENE
.	O
,	O
HDL2	B-GENE
-	I-GENE
C	I-GENE
.	O
,	O
apo	B-GENE
B	I-GENE
,	O
apo	B-GENE
A	I-GENE
-	I-GENE
I	I-GENE
/	I-GENE
B	I-GENE
ratio	O
and	O
apo	B-GENE
A	I-GENE
-	I-GENE
II	I-GENE
/	I-GENE
B	I-GENE
ratio	O
are	O
predictive	O
risk	O
factors	O
of	O
the	O
coronary	O
heart	O
disease	O
.	O

It	O
is	O
concluded	O
that	O
the	O
unique	O
suppository	O
formulation	O
of	O
CZX	O
-	O
S	O
is	O
useful	O
in	O
the	O
treatment	O
of	O
infections	O
in	O
children	O
with	O
heavy	O
psychophysiologic	O
disorders	O
and	O
in	O
children	O
who	O
cannot	O
take	O
oral	O
drugs	O
because	O
of	O
severe	O
vomiting	O
.	O

Single	O
photon	O
emission	O
computerized	O
tomography	O
(	O
SPECT	O
)	O
,	O
by	O
providing	O
three	O
-	O
dimensional	O
representation	O
of	O
myocardial	O
Tl	O
-	O
201	O
,	O
offers	O
promise	O
for	O
improved	O
localization	O
of	O
CAD	O
.	O

Computer	O
assisted	O
mapping	O
in	O
quantitative	O
analysis	O
of	O
cerebral	O
positron	O
emission	O
tomograms	O
.	O

Documentation	O
of	O
a	O
successful	O
intrauterine	O
fertilization	O
with	O
delivery	O
of	O
a	O
term	O
baby	O
supports	O
the	O
theoretical	O
feasibility	O
of	O
the	O
EP	O
;	O
however	O
,	O
anovulation	O
incurred	O
by	O
our	O
procedure	O
appears	O
to	O
be	O
the	O
major	O
drawback	O
.	O

MRI	O
disclosed	O
one	O
or	O
more	O
of	O
the	O
following	O
abnormalities	O
in	O
24	O
(	O
63	O
%	O
)	O
of	O
38	O
treated	O
kidneys	O
:	O
(	O
1	O
)	O
loss	O
of	O
corticomedullary	O
differentiation	O
,	O
(	O
2	O
)	O
perirenal	O
fluid	O
,	O
(	O
3	O
)	O
subcapsular	O
hematoma	O
,	O
(	O
4	O
)	O
hemorrhage	O
into	O
a	O
renal	O
cyst	O
,	O
and	O
(	O
5	O
)	O
unexplained	O
abnormalities	O
.	O

The	O
results	O
obtained	O
are	O
similar	O
to	O
those	O
described	O
with	O
the	O
previous	O
Cremophor	O
formulation	O
although	O
greater	O
variability	O
in	O
induction	O
and	O
recovery	O
times	O
was	O
noted	O
with	O
the	O
emulsion	O
formulation	O
.	O

The	O
percentage	O
RFR	O
reduction	O
at	O
the	O
end	O
of	O
CPB	O
showed	O
significant	O
correlation	O
with	O
1	O
)	O
CPB	O
duration	O
(	O
r	O
=	O
0	O
.	O
49	O
)	O
,	O
2	O
)	O
oxygen	O
flow	O
rate	O
index	O
(	O
OFRI	O
)	O
,	O
i	O
.	O
e	O
.	O
flow	O
/	O
min	O
in	O
the	O
bubble	O
oxygenator	O
/	O
m2	O
bsa	O
(	O
r	O
=	O
0	O
.	O
38	O
)	O
,	O
and	O
3	O
)	O
blood	O
flow	O
rate	O
index	O
(	O
BFRI	O
)	O
,	O
i	O
.	O
e	O
.	O
average	O
volume	O
of	O
blood	O
pumped	O
through	O
the	O
heart	O
-	O
lung	O
machine	O
/	O
min	O
CPB	O
time	O
/	O
m2	O
bsa	O
(	O
r	O
=	O
0	O
.	O
51	O
)	O
.	O

Diagnosis	O
of	O
unilateral	O
renal	O
artery	O
lesions	O
after	O
captopril	O
administration	O
.	O

A	O
retrospective	O
study	O
of	O
banked	O
sera	O
from	O
19	O
cats	O
with	O
the	O
eosinophilic	O
granuloma	O
complex	O
revealed	O
that	O
68	O
%	O
of	O
affected	O
cats	O
had	O
circulating	O
antibodies	O
to	O
components	O
of	O
normal	O
cat	O
epithelium	O
.	O

In	O
memory	O
of	O
Magdelaine	O
Comtesse	O

These	O
results	O
suggest	O
that	O
indoramin	O
may	O
have	O
Class	O
III	O
antiarrhythmic	O
activity	O
.	O

A	O
high	O
efficacy	O
of	O
the	O
combined	O
use	O
of	O
nontoxic	O
doses	O
of	O
two	O
pharmaceuticals	O
:	O
cystamine	O
(	O
50	O
mg	O
/	O
kg	O
)	O
and	O
mexamine	O
(	O
25	O
mg	O
/	O
kg	O
)	O
under	O
the	O
conditions	O
of	O
short	O
-	O
term	O
exogenous	O
hypoxia	O
(	O
7	O
.	O
5	O
%	O
O2	O
)	O
was	O
found	O
in	O
(	O
CBA	O
X	O
C57Bl	O
)	O
F1	O
mice	O
.	O

The	O
Mean	O
was	O
74	O
,	O
3	O
+	O
/	O
-	O
53	O
,	O
6	O
micrograms	O
J	O
/	O
g	O
Cr	O
,	O
the	O
Median	O
61	O
micrograms	O
J	O
/	O
g	O
Cr	O
.	O

In	O
the	O
region	O
Walgau	O
with	O
mixed	O
industrial	O
-	O
rural	O
population	O
an	O
iodine	O
deficiency	O
I	O
was	O
found	O
in	O
81	O
%	O
and	O
an	O
iodine	O
deficiency	O
II	O
in	O
45	O
%	O
.	O

The	O
structural	O
gene	O
for	O
hydrogenase	B-GENE
encodes	O
a	O
protein	O
product	O
of	O
molecular	O
mass	O
45820	O
Da	O
.	O

Pancreaticoduodenal	O
lymph	O
node	O
enlargement	O
,	O
regardless	O
of	O
cause	O
,	O
has	O
been	O
a	O
source	O
of	O
imaging	O
confusion	O
because	O
of	O
its	O
propensity	O
to	O
mimic	O
pancreatic	O
malignancy	O
yet	O
not	O
cause	O
biliary	O
obstruction	O
.	O

Interference	O
with	O
rheumatoid	B-GENE
factor	I-GENE
was	O
only	O
observed	O
in	O
the	O
ELISA	O
enzygnost	O
if	O
sera	O
were	O
not	O
pretreated	O
with	O
latex	O
adsorbents	O
.	O

All	O
patients	O
had	O
elevated	O
levels	O
of	O
serum	B-GENE
IgE	I-GENE
antibodies	I-GENE
to	O
the	O
crude	O
soybean	O
extract	O
;	O
binding	O
values	O
ranged	O
from	O
2	O
.	O
3	O
to	O
28	O
.	O
1	O
times	O
that	O
of	O
a	O
negative	O
control	O
serum	O
.	O

New	O
techniques	O
for	O
the	O
mass	O
spectrometry	O
of	O
natural	O
products	O
.	O

Dual	O
radionuclide	O
subtraction	O
imaging	O
of	O
the	O
spleen	O
using	O
67Ga	O
citrate	O
and	O
99mTc	O
is	O
useful	O
in	O
further	O
delineating	O
lesions	O
that	O
are	O
identified	O
on	O
either	O
a	O
routine	O
radiogallium	O
survey	O
or	O
on	O
a	O
conventional	O
sulfur	O
colloid	O
liver	O
-	O
spleen	O
image	O
.	O

Nursing	O
education	O
-	O
-	O
the	O
computer	O
obligation	O
.	O

Shear	O
bond	O
strength	O
of	O
a	O
composite	O
resin	O
to	O
an	O
etched	O
glass	O
ionomer	O
.	O

An	O
additional	O
advantage	O
is	O
that	O
the	O
resin	O
can	O
be	O
removed	O
and	O
the	O
immunoperoxidase	B-GENE
technique	O
carried	O
out	O
on	O
thin	O
sections	O
.	O

Such	O
a	O
concept	O
is	O
crucial	O
to	O
our	O
understanding	O
of	O
the	O
pathology	O
of	O
ageing	O
in	O
general	O
.	O

We	O
consider	O
that	O
DIL	O
-	O
CP	O
is	O
a	O
safe	O
and	O
excellent	O
CP	O
in	O
CABG	O
surgery	O
and	O
we	O
are	O
now	O
utilizing	O
this	O
CP	O
in	O
all	O
patients	O
requiring	O
CABG	O
surgery	O
.	O

We	O
have	O
earlier	O
evolved	O
an	O
experimental	O
model	O
by	O
means	O
of	O
which	O
changes	O
identical	O
to	O
the	O
microembolism	O
syndrome	O
can	O
be	O
induced	O
from	O
a	O
reproducible	O
musculo	O
-	O
skeletal	O
trauma	O
in	O
pigs	O
observed	O
under	O
long	O
-	O
term	O
anesthesia	O
under	O
standardized	O
conditions	O
.	O

Although	O
no	O
statistical	O
significance	O
was	O
achieved	O
,	O
it	O
is	O
remarkable	O
that	O
there	O
was	O
a	O
clear	O
trend	O
for	O
the	O
superiority	O
of	O
Galphimia	O
D6	O
while	O
the	O
Galphimia	O
dilution	O
10	O
(	O
-	O
6	O
)	O
was	O
about	O
equally	O
effective	O
compared	O
with	O
placebo	O
.	O

The	O
volume	O
of	O
blood	O
to	O
the	O
flap	O
ranges	O
from	O
1	O
to	O
2	O
ml	O
/	O
min	O
,	O
collateral	O
circulation	O
to	O
the	O
flap	O
exists	O
,	O
but	O
is	O
negligible	O
,	O
and	O
there	O
is	O
little	O
change	O
in	O
the	O
capillary	O
blood	O
flow	O
as	O
the	O
flap	O
ages	O
.	O

With	O
aging	O
,	O
many	O
aspects	O
of	O
immune	O
function	O
change	O
.	O

Oral	O
candidiasis	O

In	O
addition	O
,	O
the	O
gcd1	B-GENE
-	I-GENE
101	I-GENE
mutation	I-GENE
suppressed	O
the	O
low	O
translational	O
efficiency	O
of	O
GCN4	B-GENE
-	O
lacZ	B-GENE
mRNA	O
observed	O
in	O
gcn2	B-GENE
-	I-GENE
and	O
gcn3	B-GENE
-	I-GENE
cells	O
.	O

This	O
suggests	O
that	O
alaproclate	O
acutely	O
increases	O
the	O
responsiveness	O
of	O
postsynaptic	O
muscarinic	B-GENE
and	I-GENE
alpha	I-GENE
1	I-GENE
adrenoceptors	I-GENE
.	O

The	O
distribution	O
of	O
patients	O
was	O
as	O
follows	O
:	O
group	O
1	O
-	O
-	O
complex	O
gamma	O
-	O
therapy	O
(	O
55	O
cases	O
)	O
,	O
group	O
2	O
-	O
-	O
complex	O
gamma	O
-	O
therapy	O
plus	O
iliac	O
lymphadenectomy	O
(	O
50	O
cases	O
)	O
and	O
group	O
3	O
-	O
-	O
complex	O
radiation	O
treatment	O
with	O
megavolt	O
bremsstrahlung	O
beam	O
from	O
the	O
luc	O
type	O
installation	O
and	O
iliac	O
lymphadenectomy	O
(	O
50	O
cases	O
)	O
.	O

The	O
availability	O
of	O
cryoprecipitate	O
and	O
DDAVP	O
offers	O
an	O
alternative	O
and	O
effective	O
treatment	O
for	O
the	O
temporary	O
reversal	O
of	O
uremic	O
bleeding	O
in	O
patients	O
who	O
require	O
urgent	O
invasive	O
procedures	O
.	O

Thrombophlebitis	O
and	O
pulmonary	O
embolism	O
in	O
congenital	O
factor	B-GENE
XII	I-GENE
deficiency	O

Biopsies	O
of	O
the	O
jejunal	O
mucosa	O
have	O
shown	O
abnormal	O
enzyme	O
activity	O
or	O
deficiencies	O
in	O
transport	O
mechanisms	O
.	O

Laboratory	O
pyrolyses	O
have	O
indeed	O
shown	O
that	O
PCBs	O
give	O
significant	O
yields	O
of	O
PCDFs	O
,	O
and	O
chlorobenzenes	O
give	O
both	O
PCDFs	O
and	O
PCDDs	O
.	O

A	O
significant	O
degree	O
of	O
homology	O
was	O
also	O
found	O
among	O
these	O
genes	O
and	O
the	O
Mtase	B-GENE
gene	I-GENE
of	O
related	O
phage	O
SPR	O
,	O
which	O
codes	O
for	O
an	O
enzyme	O
with	O
different	O
modification	O
specificity	O
.	O

In	O
a	O
blind	O
controlled	O
trial	O
,	O
15	O
patients	O
with	O
COCM	O
(	O
NYHA	O
II	O
-	O
III	O
)	O
with	O
sinus	O
rhythm	O
and	O
a	O
left	O
ventricular	O
ejection	O
fraction	O
(	O
LV	O
-	O
EF	O
)	O
of	O
34	O
.	O
5	O
+	O
/	O
-	O
2	O
.	O
6	O
%	O
received	O
consecutively	O
D	O
(	O
0	O
.	O
25	O
-	O
0	O
.	O
5	O
mg	O
/	O
d	O
)	O
,	O
placebo	O
(	O
PLAC	O
)	O
,	O
P	O
(	O
slow	O
releases	O
=	O
SR	O
)	O
(	O
80	O
mg	O
/	O
d	O
SR	O
)	O
and	O
both	O
drugs	O
combined	O
in	O
respective	O
doses	O
.	O

Mild	O
orbital	O
discomfort	O
occurred	O
in	O
some	O
patients	O
.	O

The	O
sample	O
is	O
deproteinized	O
and	O
after	O
centrifugation	O
valproic	O
acid	O
in	O
the	O
supernatant	O
is	O
measured	O
in	O
the	O
free	O
form	O
by	O
direct	O
injection	O
into	O
the	O
gas	O
chromatograph	O
.	O

Changes	O
in	O
muscarinic	B-GENE
acetylcholine	I-GENE
receptors	I-GENE
in	O
guinea	O
-	O
pig	O
lung	O
:	O
effects	O
of	O
aging	O
,	O
inhalation	O
of	O
an	O
allergen	O
,	O
administration	O
of	O
drugs	O
,	O
and	O
vagotomy	O
.	O

In	O
the	O
absence	O
of	O
other	O
stabilizers	O
,	O
increased	O
sucrose	O
can	O
provide	O
increased	O
thermoresistance	O
to	O
the	O
virus	O
in	O
2	O
.	O
5	O
%	O
albumin	B-GENE
.	O

The	O
overall	O
prevalence	O
of	O
psoriasis	O
was	O
4	O
.	O
79	O
%	O
in	O
men	O
and	O
4	O
.	O
85	O
%	O
in	O
women	O
.	O

Greek	O
classicism	O
in	O
living	O
structure	O
?	O
Some	O
deductive	O
pathways	O
in	O
animal	O
morphology	O
.	O

The	O
possible	O
origin	O
and	O
role	O
of	O
CSF	B-GENE
prolactin	I-GENE
are	O
discussed	O
.	O

Three	O
chromosomal	B-GENE
crsA	I-GENE
mutations	I-GENE
,	O
crsA1	B-GENE
,	O
crsA4	B-GENE
,	O
and	O
crsA47	B-GENE
,	O
were	O
transferred	O
by	O
the	O
"	O
gene	O
conversion	O
"	O
process	O
to	O
B	O
.	O
subtilis	O
plasmid	O
pRPD11	O
,	O
which	O
consists	O
of	O
the	O
entire	O
wild	B-GENE
-	I-GENE
type	I-GENE
rpoD	I-GENE
coding	I-GENE
sequence	I-GENE
,	O
encoding	O
the	O
major	B-GENE
sigma	I-GENE
43	I-GENE
factor	I-GENE
of	I-GENE
B	I-GENE
.	I-GENE
subtilis	I-GENE
RNA	I-GENE
polymerase	I-GENE
,	O
and	O
pUB110	O
.	O

Selective	O
effect	O
of	O
pulmonary	O
oedema	O
on	O
prostaglandin	O
E2	O
pharmacokinetics	O
in	O
rat	O
lung	O
.	O

This	O
article	O
will	O
briefly	O
review	O
the	O
published	O
data	O
on	O
the	O
morphology	O
,	O
function	O
,	O
and	O
biochemistry	O
of	O
the	O
normal	O
renal	O
medulla	O
and	O
the	O
pathology	O
associated	O
with	O
RPN	O
,	O
together	O
with	O
the	O
secondary	O
changes	O
which	O
give	O
rise	O
to	O
cortical	O
degeneration	O
or	O
epithelial	O
carcinoma	O
.	O

The	O
data	O
indicate	O
that	O
the	O
five	O
different	O
(	O
and	O
partially	O
overlapping	O
)	O
sry	B-GENE
messenger	I-GENE
RNAs	I-GENE
detectable	O
in	O
early	O
embryos	O
are	O
initiated	O
at	O
three	O
separate	O
sites	O
,	O
each	O
directly	O
upstream	O
from	O
one	O
of	O
the	O
three	O
protein	O
-	O
coding	O
regions	O
,	O
designated	O
(	O
in	O
5	O
'	O
to	O
3	O
'	O
order	O
)	O
beta	O
,	O
alpha	O
and	O
delta	O
.	O

Chronic	O
thyroiditis	O
as	O
a	O
risk	O
factor	O
of	O
B	O
-	O
cell	O
lymphoma	O
in	O
the	O
thyroid	O
gland	O
.	O

Plasma	B-GENE
secretin	I-GENE
levels	O
also	O
augmented	O
after	O
the	O
administration	O
of	O
ethanol	O
solutions	O
,	O
with	O
a	O
delay	O
of	O
about	O
one	O
hour	O
after	O
the	O
onset	O
of	O
acid	O
secretion	O
.	O

Spectrophotometric	O
microanalysis	O
of	O
ethylenediaminotetracetic	O
acid	O
in	O
pharmaceutical	O
preparations	O

A	O
comparison	O
among	O
the	O
5	O
'	O
flanking	O
regions	O
encompassing	O
the	O
presumptive	O
HS	B-GENE
promoter	I-GENE
of	O
the	O
soybean	B-GENE
HS	I-GENE
-	I-GENE
protein	I-GENE
genes	I-GENE
demonstrated	O
this	O
region	O
to	O
be	O
extremely	O
homologous	O
.	O

Using	O
this	O
method	O
,	O
we	O
measured	O
absorption	O
of	O
low	O
doses	O
of	O
vitamin	O
A	O
,	O
which	O
may	O
provide	O
a	O
more	O
physiological	O
approach	O
to	O
assessment	O
of	O
fat	O
malabsorption	O
.	O

Fulminant	O
hepatitis	O
A	O
in	O
chronic	O
HBV	O
carrier	O
.	O

During	O
this	O
time	O
,	O
the	O
patients	O
all	O
had	O
the	O
characteristic	O
plasma	O
thyroid	O
hormone	O
changes	O
associated	O
with	O
amiodarone	O
therapy	O
,	O
i	O
.	O
e	O
.	O
increased	O
T4	O
,	O
free	O
T4	O
,	O
and	O
rT3	O
and	O
decreased	O
T3	O
,	O
while	O
remaining	O
clinically	O
euthyroid	O
.	O

Drug	O
and	O
nutrient	O
interactions	O
.	O

In	O
each	O
compartment	O
O2	O
is	O
removed	O
by	O
the	O
tissues	O
as	O
a	O
chemical	O
reaction	O
takes	O
place	O
between	O
O2	O
and	O
oxyhemoglobin	B-GENE
(	O
HbO2	B-GENE
)	O
.	O

To	O
evaluate	O
the	O
effects	O
of	O
propranolol	O
on	O
myocardial	O
metabolism	O
after	O
coronary	O
reperfusion	O
,	O
serial	O
measurements	O
of	O
myocardial	B-GENE
creatine	I-GENE
kinase	I-GENE
(	O
CK	B-GENE
)	O
and	O
calcium	O
(	O
Ca	O
)	O
contents	O
and	O
CK	B-GENE
and	O
lactic	O
acid	O
(	O
LA	O
)	O
concentrations	O
in	O
coronary	O
sinus	O
blood	O
were	O
carried	O
out	O
in	O
33	O
open	O
-	O
chest	O
dogs	O
.	O

Cortisol	O
excretion	O
,	O
appeared	O
to	O
be	O
markedly	O
affected	O
by	O
the	O
season	O
although	O
other	O
factors	O
such	O
as	O
social	O
and	O
environmental	O
stress	O
cannot	O
be	O
discounted	O
.	O

Two	O
studies	O
on	O
the	O
relationship	O
between	O
taking	O
a	O
commercial	O
coaching	O
course	O
and	O
performance	O
on	O
the	O
Medical	O
College	O
Admission	O
Test	O
(	O
MCAT	O
)	O
are	O
reported	O
.	O

A	O
total	O
of	O
90	O
patients	O
were	O
randomly	O
allocated	O
either	O
to	O
an	O
MY	O
-	O
1	O
treated	O
or	O
an	O
untreated	O
group	O
.	O

Below	O
50	O
%	O
decrease	O
of	O
PaO2	O
,	O
NADH	O
was	O
reduced	O
largely	O
.	O

Angiography	O
was	O
performed	O
following	O
the	O
rCBF	O
study	O
and	O
the	O
degree	O
of	O
vasospasm	O
was	O
measured	O
on	O
the	O
angiograms	O
.	O

The	O
financial	O
impact	O
of	O
childhood	O
asthma	O
has	O
not	O
been	O
assessed	O
since	O
Vance	O
and	O
Taylor	O
reported	O
their	O
data	O
in	O
Annals	O
of	O
Allergy	O
13	O
years	O
ago	O
.	O

Hypersplenism	O

Electrical	O
activity	O
was	O
evaluated	O
by	O
monitoring	O
the	O
general	O
electrocorticogram	O
(	O
ECoG	O
)	O
as	O
well	O
as	O
local	O
DC	O
steady	O
potential	O
(	O
two	O
sites	O
)	O
.	O

The	O
topography	O
and	O
trajectories	O
of	O
the	O
commissural	O
fibers	O
of	O
the	O
superior	O
temporal	O
region	O
(	O
STR	O
)	O
are	O
studied	O
using	O
the	O
autoradiographic	O
technique	O
.	O

The	O
diabetic	O
state	O
was	O
characterized	O
by	O
mild	O
insulin	B-GENE
deficiency	O
,	O
plasma	O
levels	O
being	O
73	O
%	O
of	O
controls	O
,	O
and	O
mild	O
hyperglycemia	O
,	O
with	O
nonfasting	O
plasma	O
glucose	O
levels	O
of	O
1	O
.	O
5	O
times	O
normal	O
.	O

No	O
consistent	O
correlation	O
between	O
blood	O
pressure	O
change	O
and	O
SCR	O
-	O
change	O
was	O
seen	O
.	O

Shoulder	O
forearm	O
support	O
for	O
the	O
subluxed	O
shoulder	O
.	O

Piroxicam	O
produced	O
a	O
lower	O
incidence	O
of	O
gastric	O
ulcers	O
than	O
equivalent	O
doses	O
of	O
indomethacin	O
.	O

These	O
findings	O
suggest	O
that	O
both	O
in	O
the	O
early	O
stages	O
(	O
0T	O
,	O
0N	O
)	O
and	O
in	O
more	O
severe	O
stages	O
of	O
VWF	O
(	O
stages	O
1	O
-	O
2	O
)	O
cold	O
induced	O
hyperreactivity	O
in	O
the	O
digital	O
vessels	O
and	O
Raynaud	O
'	O
s	O
syndrome	O
are	O
vascular	O
disorders	O
of	O
functional	O
origin	O
occurring	O
without	O
any	O
prethrombotic	O
alterations	O
.	O

In	O
MCCP	O
functions	O
of	O
the	O
source	O
emission	O
,	O
surface	O
reflection	O
,	O
photoacceptor	O
sensitivity	O
are	O
approximated	O
by	O
the	O
normal	O
distribution	O
curves	O
.	O

To	O
assess	O
the	O
effects	O
of	O
alveolar	O
hypoxia	O
and	O
angiotensin	B-GENE
II	I-GENE
infusion	O
on	O
distribution	O
of	O
blood	O
flow	O
to	O
the	O
lung	O
we	O
performed	O
perfusion	O
lung	O
scans	O
on	O
anesthetized	O
mechanically	O
ventilated	O
lambs	O
.	O

A	O
flow	O
rate	O
of	O
at	O
least	O
5	O
mL	O
/	O
h	O
is	O
required	O
through	O
the	O
receptor	O
(	O
volume	O
,	O
0	O
.	O
4	O
mL	O
)	O
for	O
accurate	O
results	O
.	O

We	O
have	O
now	O
located	O
the	O
5	O
'	O
ends	O
of	O
the	O
two	O
remaining	O
late	O
mRNAs	O
.	O

The	O
efficacy	O
of	O
quantitative	O
and	O
qualitative	O
chloride	O
titrators	O
in	O
the	O
estimation	O
of	O
human	O
salt	O
intake	O
.	O

Doctor	O
Berglund	O
warns	O
members	O
of	O
union	O
pitfalls	O
.	O

Acute	O
appearance	O
of	O
hemiparesis	O
or	O
hemiplegia	O
with	O
initial	O
marked	O
spasticity	O
was	O
observed	O
in	O
8	O
stroke	O
patients	O
.	O

Recurrent	O
acute	O
rhinosinusitis	O
was	O
common	O
in	O
both	O
groups	O
of	O
patients	O
,	O
but	O
the	O
development	O
of	O
chronic	O
rhinosinusitis	O
was	O
only	O
found	O
in	O
patients	O
with	O
CVID	O
,	O
indicating	O
the	O
more	O
severe	O
nature	O
of	O
this	O
condition	O
compared	O
with	O
selective	O
IgA	B-GENE
deficiency	O
.	O

These	O
data	O
suggest	O
that	O
AP	B-GENE
-	I-GENE
A	I-GENE
may	O
be	O
potentially	O
useful	O
in	O
the	O
management	O
of	O
heart	O
failure	O
.	O

The	O
various	O
muscles	O
of	O
the	O
pelvic	O
floor	O
region	O
could	O
be	O
reflexly	O
activated	O
either	O
individually	O
or	O
as	O
a	O
mass	O
unit	O
depending	O
on	O
the	O
intensity	O
of	O
stimulation	O
.	O

The	O
frequency	O
of	O
lactase	B-GENE
phenotypes	I-GENE
in	O
Aymara	O
children	O
.	O

Activities	O
of	O
hepatic	O
cytochrome	B-GENE
P	I-GENE
-	I-GENE
450	I-GENE
-	O
dependent	O
metabolizing	O
enzymes	O
such	O
as	O
aminopyrine	B-GENE
-	I-GENE
and	I-GENE
TMO	I-GENE
N	I-GENE
-	I-GENE
demethylase	I-GENE
and	O
aniline	B-GENE
hydroxylase	I-GENE
activity	O
were	O
decreased	O
by	O
pretreatment	O
of	O
rats	O
with	O
cimetidine	O
,	O
whereas	O
in	O
the	O
rats	O
pretreated	O
with	O
ranitidine	O
,	O
these	O
enzyme	O
activities	O
were	O
not	O
changed	O
.	O

Doxorubicin	O
,	O
dacarbazine	O
,	O
vincristine	O
,	O
and	O
cyclophosphamide	O
in	O
the	O
treatment	O
of	O
advanced	O
gastrointestinal	O
leiomyosarcoma	O
.	O

The	O
effect	O
of	O
the	O
opiate	O
antagonist	O
naloxone	O
was	O
evaluated	O
in	O
11	O
unselected	O
patients	O
with	O
cerebral	O
ischemia	O
.	O

Electrochemical	O
detection	O
of	O
depressed	O
circulating	O
levels	O
of	O
vitamin	O
K1	O
in	O
osteoporosis	O
.	O

In	O
the	O
present	O
experiments	O
,	O
we	O
investigate	O
the	O
role	O
played	O
by	O
the	O
temporal	O
pattern	O
of	O
neural	O
activity	O
during	O
the	O
ontogeny	O
of	O
frequency	O
tuning	O
in	O
the	O
mouse	O
central	O
auditory	O
system	O
.	O

Ultrastructure	O
of	O
the	O
tumor	O
in	O
1	O
patient	O
in	O
whom	O
transurethral	O
resection	O
was	O
performed	O
2	O
weeks	O
after	O
alum	O
irrigation	O
revealed	O
well	O
preserved	O
nuclear	O
chromatin	O
,	O
thus	O
,	O
suggesting	O
that	O
whatever	O
changes	O
occur	O
after	O
alum	O
irrigation	O
are	O
short	O
-	O
lived	O
.	O

The	O
generally	O
adopted	O
criteria	O
enabling	O
to	O
classify	O
the	O
examined	O
persons	O
into	O
the	O
following	O
3	O
groups	O
have	O
been	O
used	O
:	O
(	O
a	O
)	O
diseased	O
of	O
BEN	O
;	O
(	O
b	O
)	O
suspect	O
to	O
be	O
diseased	O
of	O
BEN	O
,	O
and	O
(	O
c	O
)	O
individuals	O
without	O
signs	O
of	O
a	O
renal	O
disease	O
.	O

The	O
POEMS	O
syndrome	O
(	O
Polyneuropathy	O
,	O
Organomegaly	O
,	O
Endocrinopathy	O
,	O
Monoclonal	O
component	O
,	O
Skin	O
)	O
.	O

During	O
a	O
disease	O
remission	O
there	O
was	O
an	O
increase	O
in	O
GAG	O
secretion	O
with	O
urine	O
,	O
linked	O
with	O
hyperheparinuria	O
(	O
13	O
.	O
1	O
-	O
fold	O
,	O
P	O
less	O
than	O
0	O
.	O
001	O
)	O
.	O

In	O
metastasis	O
-	O
free	O
patients	O
,	O
the	O
best	O
results	O
were	O
obtained	O
with	O
tumor	O
diameters	O
under	O
2	O
cm	O
regardless	O
of	O
their	O
localization	O
in	O
lung	O
tissue	O
and	O
with	O
2	O
-	O
-	O
4	O
.	O
9	O
cm	O
tumors	O
embedded	O
in	O
lung	O
parenchyma	O
.	O

Two	O
siblings	O
with	O
hemolytic	O
anemia	O
caused	O
by	O
triosephosphate	B-GENE
isomerase	I-GENE
deficiency	O
developed	O
a	O
progressive	O
neurological	O
syndrome	O
featuring	O
dystonic	O
movements	O
,	O
tremor	O
,	O
pyramidal	O
tract	O
signs	O
,	O
and	O
evidence	O
of	O
spinal	O
motor	O
neuron	O
involvement	O
.	O

One	O
extract	O
with	O
the	O
lowest	O
PCA	O
content	O
was	O
non	O
-	O
carcinogenic	O
.	O

Aortic	O
diameters	O
in	O
infants	O
and	O
young	O
children	O
:	O
normative	O
angiographic	O
data	O
.	O

The	O
present	O
investigation	O
has	O
revealed	O
that	O
the	O
distribution	O
of	O
the	O
main	O
fatty	O
acids	O
in	O
Leptospira	O
phospholipids	O
is	O
similar	O
to	O
their	O
distribution	O
in	O
Leptospira	O
neutral	O
lipids	O
with	O
the	O
exception	O
of	O
unsaturated	O
fatty	O
acid	O
with	O
14	O
carbon	O
atoms	O
,	O
occurring	O
mainly	O
in	O
phospholipids	O
.	O

Since	O
1970	O
the	O
frequency	O
of	O
potassium	O
-	O
induced	O
ulceration	O
has	O
been	O
low	O
-	O
-	O
3	O
cases	O
per	O
100	O
000	O
patient	O
-	O
years	O
of	O
slow	O
-	O
release	O
tablet	O
use	O
.	O

Hydrocortisone	O
caused	O
lymphopenia	O
and	O
inhibited	O
the	O
blastogenic	O
response	O
of	O
peripheral	O
blood	O
lymphocytes	O
to	O
phytohemagglutinin	B-GENE
and	O
concanavalin	B-GENE
A	I-GENE
mitogens	O
.	O

To	O
test	O
the	O
feasibility	O
of	O
using	O
liposomes	O
to	O
deliver	O
therapeutic	O
agents	O
to	O
the	O
lungs	O
,	O
the	O
effect	O
of	O
liposome	O
-	O
encapsulated	O
superoxide	B-GENE
dismutase	I-GENE
(	O
SOD	B-GENE
)	O
or	O
catalase	B-GENE
on	O
pulmonary	O
oxygen	O
toxicity	O
was	O
studied	O
in	O
rats	O
.	O

Marrow	O
cell	O
necrosis	O
in	O
anorexia	O
nervosa	O
and	O
involuntary	O
starvation	O
.	O

For	O
comparison	O
conventional	O
heparin	O
was	O
used	O
during	O
18	O
dialyses	O
in	O
the	O
same	O
patients	O
.	O

Chenodeoxycholic	O
acid	O
(	O
cheno	O
)	O
and	O
ursodeoxycholic	O
acid	O
(	O
urso	O
)	O
dissolve	O
cholesterol	O
gallstones	O
in	O
man	O
.	O

Sensory	O
evoked	O
field	O
potentials	O
were	O
recorded	O
from	O
the	O
mesencephalic	O
reticular	O
formation	O
(	O
MRF	O
)	O
,	O
central	O
gray	O
(	O
CG	O
)	O
and	O
somatosensory	O
cortex	O
(	O
SCX	O
)	O
,	O
following	O
incremental	O
doses	O
of	O
halothane	O
in	O
freely	O
-	O
moving	O
rats	O
.	O

Ultrastructure	O
of	O
the	O
heart	O
muscle	O
in	O
experimental	O
myocardial	O
infarct	O
following	O
physical	O
training	O

Pharmacological	O
desympathization	O
leads	O
to	O
the	O
development	O
of	O
hyper	O
-	O
reactivity	O
of	O
the	O
true	O
pacemakers	O
to	O
noradrenaline	O
and	O
dopamine	O
and	O
triggers	O
off	O
changes	O
in	O
the	O
regulation	O
of	O
the	O
electric	O
activity	O
of	O
these	O
cells	O
by	O
catecholamines	O
.	O

OODG	O
is	O
a	O
diagnostic	O
method	O
permitting	O
assessment	O
of	O
ocular	O
pulse	O
curves	O
and	O
objective	O
determination	O
of	O
blood	O
pressures	O
in	O
the	O
ophthalmic	O
circulatory	O
system	O
(	O
retinal	O
and	O
ciliary	O
arterial	O
blood	O
pressures	O
)	O
simultaneously	O
for	O
both	O
eyes	O
,	O
without	O
dilatation	O
of	O
the	O
pupils	O
.	O

Viral	O
infections	O
have	O
long	O
been	O
suspected	O
to	O
be	O
causative	O
agents	O
in	O
a	O
number	O
of	O
inner	O
ear	O
dysfunctions	O
.	O

55	O
+	O
/	O
-	O
11	O
%	O
)	O
,	O
all	O
other	O
parameters	O
showed	O
a	O
significant	O
increase	O
:	O
RS	O
index	O
5	O
.	O
4	O
+	O
/	O
-	O
1	O
.	O
4	O
mVolt	O
to	O
6	O
.	O
0	O
+	O
/	O
-	O
1	O
.	O
7	O
mVolt	O
(	O
p	O
less	O
than	O
0	O
.	O
01	O
)	O
;	O
EDD	O
6	O
.	O
3	O
+	O
/	O
-	O
0	O
.	O
7	O
to	O
6	O
.	O
8	O
+	O
/	O
-	O
0	O
.	O
9	O
cm	O
(	O
p	O
less	O
than	O
0	O
.	O
001	O
)	O
;	O
HV	O
1017	O
+	O
/	O
-	O
151	O
ml	O
to	O
1099	O
+	O
/	O
-	O
261	O
ml	O
(	O
p	O
less	O
than	O
0	O
.	O
01	O
)	O
;	O
EDV	O
371	O
+	O
/	O
-	O
131	O
ml	O
to	O
441	O
+	O
/	O
-	O
175	O
ml	O
(	O
p	O
less	O
than	O
0	O
.	O
001	O
)	O
;	O
RBV	O
117	O
+	O
/	O
-	O
57	O
ml	O
to	O
151	O
+	O
/	O
-	O
77	O
ml	O
(	O
p	O
less	O
than	O
0	O
.	O
001	O
)	O
.	O

Retrospective	O
analyses	O
of	O
this	O
death	O
revealed	O
a	O
significant	O
decrease	O
of	O
the	O
left	O
ventricular	O
(	O
LV	O
)	O
end	O
-	O
diastolic	O
volume	O
index	O
(	O
EDVI	O
)	O
of	O
21	O
ml	O
/	O
m2	O
(	O
36	O
%	O
of	O
normal	O
)	O
.	O

In	O
group	O
I	O
adults	O
both	O
of	O
these	O
variables	O
increased	O
.	O

Individual	O
alcohol	O
reaction	O
profiles	O
.	O

Vitiligo	O
in	O
diabetes	O
mellitus	O
.	O

The	O
pharmacokinetics	O
of	O
each	O
tetracycline	O
in	O
serum	O
and	O
dermal	O
,	O
suction	O
blister	O
fluid	O
were	O
determined	O
after	O
oral	O
doses	O
of	O
300	O
mg	O
lymecycline	O
or	O
100	O
mg	O
doxycycline	O
on	O
the	O
3rd	O
day	O
.	O

A	O
high	O
degree	O
of	O
correlation	O
in	O
the	O
sense	O
of	O
the	O
classic	O
conception	O
of	O
brain	O
localization	O
of	O
neuropsychological	O
syndromes	O
was	O
found	O
.	O

35	O
patients	O
with	O
acute	O
arterial	O
occlusions	O
[	O
27	O
]	O
and	O
graft	O
thromboses	O
[	O
8	O
]	O
,	O
responsible	O
for	O
severe	O
and	O
recent	O
ischemia	O
,	O
were	O
treated	O
by	O
fibrinolytic	O
therapy	O
(	O
Urokinase	B-GENE
:	O
1	O
000	O
units	O
/	O
kg	O
/	O
hour	O
,	O
and	O
Lys	O
Plasminogen	B-GENE
)	O
.	O

We	O
conclude	O
that	O
androgenic	O
hormones	O
reduce	O
HDL	B-GENE
-	I-GENE
cholesterol	I-GENE
concentrations	O
and	O
the	O
HDL2	B-GENE
-	I-GENE
cholesterol	I-GENE
subfraction	O
,	O
possibly	O
by	O
enhancing	O
hepatic	B-GENE
triglyceride	I-GENE
lipase	I-GENE
activity	O
.	O

Because	O
of	O
its	O
wide	O
spectrum	O
of	O
activity	O
particularly	O
against	O
ampicillin	O
resistant	O
strains	O
of	O
H	O
.	O
influenzae	O
and	O
because	O
of	O
its	O
good	O
tolerance	O
Cefaclor	O
is	O
very	O
useful	O
in	O
treatment	O
of	O
respiratory	O
tract	O
infections	O
in	O
children	O
.	O

Shape	O
factor	O
correlated	O
well	O
with	O
hemodynamic	O
data	O
for	O
RV	O
/	O
LV	O
systolic	O
pressure	O
ratios	O
(	O
r	O
=	O
0	O
.	O
93	O
,	O
p	O
less	O
than	O
0	O
.	O
001	O
)	O
for	O
normalized	O
interventricular	O
pressure	O
differences	O
(	O
r	O
=	O
-	O
0	O
.	O
95	O
,	O
p	O
less	O
than	O
0	O
.	O
001	O
)	O
.	O

The	O
effective	O
and	O
low	O
toxic	O
dose	O
schedules	O
of	O
KW	O
-	O
2083	O
should	O
be	O
investigated	O
further	O
.	O

Furthermore	O
,	O
the	O
initial	O
plasma	O
retinol	O
level	O
in	O
conjunction	O
with	O
RBP	B-GENE
was	O
found	O
to	O
be	O
even	O
lower	O
in	O
12	O
patients	O
(	O
35	O
.	O
1	O
micrograms	O
dl	O
-	O
1	O
,	O
3	O
.	O
7	O
mg	O
dl	O
-	O
1	O
)	O
who	O
subsequently	O
had	O
cancer	O
recurrence	O
than	O
in	O
those	O
who	O
remained	O
free	O
of	O
apparent	O
cancer	O
(	O
44	O
.	O
5	O
micrograms	O
dl	O
-	O
1	O
,	O
4	O
.	O
6	O
mg	O
dl	O
-	O
1	O
)	O
.	O

The	O
results	O
indicate	O
that	O
:	O
1	O
)	O
the	O
initial	O
response	O
to	O
tethering	O
varies	O
according	O
to	O
previous	O
penning	O
and	O
handling	O
experience	O
,	O
2	O
)	O
although	O
the	O
circadian	O
rhythm	O
of	O
cortisol	O
was	O
either	O
altered	O
or	O
disrupted	O
during	O
estrus	O
,	O
such	O
disruptions	O
were	O
not	O
influenced	O
by	O
type	O
of	O
penning	O
and	O
3	O
)	O
tether	O
stalls	O
may	O
chronically	O
increase	O
cortisol	O
concentrations	O
in	O
gilts	O
.	O

This	O
laser	O
provided	O
sufficient	O
power	O
in	O
an	O
amniotic	O
fluid	O
medium	O
to	O
occlude	O
placental	O
vessels	O
as	O
large	O
as	O
7	O
mm	O
in	O
diameter	O
within	O
6	O
seconds	O
at	O
a	O
power	O
density	O
of	O
2000	O
W	O
/	O
cm2	O
.	O

On	O
d	O
112	O
,	O
progesterone	O
was	O
higher	O
(	O
P	O
less	O
than	O
.	O
05	O
)	O
in	O
hysterectomized	O
heifers	O
than	O
in	O
other	O
treatment	O
groups	O
.	O

Male	O
Japanese	O
quail	O
were	O
chronically	O
exposed	O
to	O
5000	O
ppm	O
manganese	O
(	O
Mn	O
)	O
as	O
particulate	O
manganese	O
oxide	O
(	O
Mn3O4	O
)	O
in	O
their	O
diet	O
from	O
hatching	O
to	O
75	O
days	O
of	O
age	O
.	O

This	O
study	O
indicated	O
that	O
the	O
Japanese	O
quail	O
was	O
less	O
sensitive	O
to	O
particulate	O
Mn3O4	O
exposure	O
than	O
rodents	O
treated	O
comparably	O
.	O

Plasma	O
and	O
bladder	O
platinum	O
concentration	O
were	O
measured	O
following	O
intravesical	O
DDP	O
,	O
and	O
also	O
histopathological	O
examination	O
,	O
urinalysis	O
,	O
complete	O
blood	O
count	O
and	O
blood	O
chemistry	O
were	O
performed	O
in	O
order	O
to	O
know	O
the	O
toxicity	O
of	O
intravesical	O
DDP	O
.	O

Scintigraphic	O
visualisation	O
of	O
Walker	O
carcinoma	O
-	O
256	O
in	O
Sprague	O
-	O
Dawley	O
rats	O
by	O
means	O
of	O
99mTc	O
-	O
labelled	O
monocytes	O
.	O

Rabbit	O
eyes	O
were	O
removed	O
and	O
held	O
in	O
temperature	O
-	O
regulated	O
chambers	O
and	O
irrigated	O
with	O
saline	O
.	O

Before	O
birth	O
,	O
there	O
were	O
a	O
few	O
perivascular	O
adrenergic	O
nerves	O
and	O
correspondingly	O
low	O
ovarian	O
NE	O
levels	O
.	O

Monitoring	O
changes	O
in	O
the	O
heart	O
rate	O
of	O
the	O
premature	O
fetus	O
during	O
tocolysis	O
with	O
the	O
beta	O
-	O
adrenomimetics	O
partusisten	O
and	O
Pre	O
-	O
par	O

Since	O
September	O
1980	O
to	O
June	O
1983	O
we	O
have	O
treated	O
32	O
patients	O
with	O
ovarian	O
cancer	O
.	O

The	O
results	O
suggest	O
that	O
the	O
calcium	O
antagonist	O
,	O
diltiazem	O
,	O
may	O
modify	O
the	O
effects	O
of	O
isoflurane	O
on	O
myocardial	O
function	O
.	O

Supraventricular	O
arrhythmias	O
-	O
-	O
digoxin	O
and	O
quinidine	O
revisited	O
.	O

Visidex	O
I	O
is	O
unsuitable	O
for	O
storage	O
and	O
re	O
-	O
reading	O
.	O

The	O
Cox	O
proportional	O
hazards	O
model	O
was	O
applied	O
to	O
the	O
data	O
in	O
order	O
to	O
determine	O
the	O
prognostic	O
factors	O
for	O
long	O
-	O
term	O
survival	O
.	O

This	O
suggests	O
that	O
mechanisms	O
other	O
than	O
an	O
excessive	O
increase	O
in	O
myocardial	O
oxygen	O
demand	O
may	O
be	O
responsible	O
for	O
the	O
many	O
episodes	O
occurring	O
outside	O
the	O
hospital	O
.	O

These	O
data	O
showed	O
:	O
that	O
progesterone	O
secretion	O
is	O
pulsatile	O
throughout	O
the	O
human	O
luteal	O
phase	O
,	O
with	O
maximum	O
frequency	O
in	O
the	O
mid	O
-	O
luteal	O
phase	O
;	O
that	O
during	O
the	O
mid	O
-	O
luteal	O
phase	O
most	O
subjects	O
had	O
progesterone	O
levels	O
both	O
above	O
and	O
below	O
currently	O
accepted	O
ovulatory	O
thresholds	O
;	O
the	O
use	O
of	O
a	O
single	O
measurement	O
of	O
progesterone	O
in	O
the	O
mid	O
-	O
luteal	O
phase	O
is	O
not	O
always	O
a	O
reliable	O
indicator	O
of	O
ovulation	O
;	O
a	O
threshold	O
greater	O
than	O
20	O
nmol	O
/	O
l	O
may	O
yield	O
an	O
unacceptable	O
number	O
of	O
false	O
negative	O
results	O
.	O

This	O
slope	O
tended	O
to	O
be	O
higher	O
(	O
approximately	O
1	O
.	O
6	O
dB	O
/	O
dB	O
)	O
for	O
L1	O
=	O
L2	O
greater	O
than	O
80	O
dB	O
.	O

Histamine	O
reactivity	O
was	O
significantly	O
reduced	O
after	O
the	O
nifedipine	O
aerosol	O
,	O
the	O
geometric	O
mean	O
provocative	O
concentration	O
causing	O
a	O
35	O
%	O
fall	O
in	O
specific	O
airway	O
conductance	O
,	O
rising	O
from	O
5	O
.	O
0	O
to	O
10	O
.	O
9	O
mg	O
/	O
ml	O
of	O
histamine	O
(	O
p	O
less	O
than	O
0	O
.	O
05	O
)	O
.	O

Pharmacologic	O
doses	O
of	O
vitamin	O
B6	O
administered	O
to	O
lactating	O
women	O
have	O
been	O
reported	O
to	O
suppress	O
plasma	B-GENE
prolactin	I-GENE
.	O

There	O
was	O
a	O
significant	O
but	O
similar	O
elevation	O
of	O
mean	O
O2	O
uptake	O
during	O
40	O
min	O
postexercise	O
by	O
13	O
.	O
6	O
%	O
in	O
both	O
the	O
fasted	O
(	O
p	O
less	O
than	O
0	O
.	O
001	O
)	O
and	O
fed	O
state	O
(	O
p	O
less	O
than	O
0	O
.	O
001	O
)	O
.	O

In	O
controls	O
,	O
most	O
of	O
the	O
output	O
from	O
the	O
conduit	O
occurred	O
during	O
type	O
I	O
activity	O
(	O
73	O
+	O
/	O
-	O
14	O
%	O
)	O
.	O

Greater	O
attenuation	O
of	O
the	O
N1	O
-	O
P2	O
and	O
baseline	O
-	O
P2	O
amplitude	O
of	O
the	O
probe	O
EPs	O
was	O
observed	O
when	O
the	O
probe	O
stimulus	O
was	O
presented	O
to	O
the	O
right	O
ear	O
and	O
the	O
verbal	O
material	O
presented	O
to	O
the	O
left	O
ear	O
than	O
when	O
the	O
opposite	O
stimulation	O
arrangement	O
was	O
used	O
.	O

Twenty	O
-	O
five	O
patients	O
(	O
80	O
,	O
6	O
%	O
)	O
with	O
mixed	O
neoplasms	O
were	O
operated	O
on	O
by	O
total	O
conservative	O
parotidectomy	O
(	O
T	O
.	O
C	O
.	O
P	O
.	O
)	O
,	O
3	O
(	O
9	O
,	O
7	O
%	O
)	O
by	O
S	O
.	O
P	O
.	O
and	O
3	O
(	O
9	O
,	O
7	O
%	O
)	O
by	O
En	O
.	O

The	O
comparisons	O
revealed	O
that	O
female	O
homicide	O
-	O
suicide	O
perpetrators	O
were	O
more	O
likely	O
than	O
female	O
homicide	O
-	O
suicide	O
victims	O
to	O
live	O
in	O
mobile	O
homes	O
,	O
kill	O
their	O
lover	O
or	O
ex	O
-	O
lover	O
,	O
have	O
their	O
crime	O
accidentally	O
discovered	O
,	O
leave	O
a	O
suicide	O
note	O
,	O
kill	O
on	O
a	O
weekend	O
,	O
and	O
be	O
depressed	O
,	O
but	O
are	O
less	O
likely	O
than	O
female	O
homicide	O
-	O
suicide	O
victims	O
to	O
live	O
with	O
a	O
spouse	O
.	O

Germ	O
-	O
free	O
rabbits	O
given	O
mouse	O
CRF	O
-	O
flora	O
showed	O
values	O
quite	O
different	O
from	O
control	O
animals	O
for	O
most	O
parameters	O
,	O
indicating	O
unsuitability	O
of	O
mouse	O
CRF	O
flora	O
to	O
'	O
normalize	O
'	O
rabbits	O
.	O

The	O
weak	O
relationships	O
between	O
F	O
and	O
Zn	O
to	O
Mg	O
clearly	O
have	O
no	O
significant	O
effect	O
on	O
the	O
contents	O
of	O
these	O
elements	O
in	O
bone	O
.	O

L3	O
-	O
L4	O
compressive	O
load	O
was	O
calculated	O
using	O
a	O
model	O
of	O
the	O
anatomy	O
of	O
the	O
trunk	O
musculoskeletal	O
system	O
.	O

Component	O
P100	O
was	O
associated	O
with	O
a	O
frontal	O
negativity	O
of	O
similar	O
latency	O
favoring	O
the	O
hypothesis	O
of	O
a	O
dipolar	O
occipital	O
generator	O
.	O

Although	O
no	O
differences	O
were	O
noted	O
in	O
the	O
decrease	O
in	O
platelet	O
counts	O
between	O
the	O
two	O
groups	O
,	O
fibrinogen	B-GENE
levels	O
and	O
alpha	B-GENE
2	I-GENE
-	I-GENE
antiplasmin	I-GENE
levels	O
declined	O
less	O
drastically	O
in	O
the	O
antithrombin	B-GENE
-	O
treated	O
group	O
.	O

Failure	O
of	O
stapedius	O
reflexometry	O
in	O
the	O
diagnosis	O
of	O
myasthenia	O
gravis	O
.	O

Factors	O
influencing	O
semen	O
characteristics	O
in	O
young	O
boars	O
reared	O
in	O
a	O
subtropical	O
environment	O
were	O
studied	O
.	O

[	O
14C	O
]	O
-	O
beta	O
-	O
phenethylamine	O
,	O
its	O
distribution	O
after	O
administration	O
by	O
various	O
routes	O
to	O
cats	O
,	O
and	O
the	O
effects	O
of	O
monoamine	B-GENE
oxidase	I-GENE
inhibitors	O
.	O

All	O
runners	O
drank	O
a	O
total	O
of	O
1	O
.	O
4	O
L	O
of	O
water	O
during	O
the	O
race	O
.	O

The	O
rates	O
of	O
total	O
energy	O
use	O
(	O
mean	O
+	O
/	O
-	O
SD	O
=	O
39	O
.	O
3	O
+	O
/	O
-	O
1	O
.	O
2	O
vs	O
35	O
.	O
7	O
+	O
/	O
-	O
1	O
.	O
3	O
kJ	O
X	O
min	O
-	O
1	O
;	O
P	O
less	O
than	O
0	O
.	O
05	O
)	O
were	O
significantly	O
higher	O
at	O
-	O
10	O
degrees	O
C	O
than	O
at	O
22	O
degrees	O
C	O
.	O

Clinical	O
aspects	O
and	O
therapy	O

Following	O
seven	O
days	O
'	O
incubation	O
both	O
at	O
20	O
degrees	O
C	O
and	O
28	O
degrees	O
C	O
,	O
Ae	O
.	O
vexans	O
nip	O
.	O
was	O
capable	O
of	O
transmitting	O
the	O
virus	O
.	O

Blood	O
eosinophils	O
in	O
patients	O
with	O
Taenia	O
saginata	O
taeniasis	O
.	O

The	O
recommendation	O
is	O
made	O
that	O
specific	O
sub	O
-	O
groups	O
of	O
attempters	O
need	O
to	O
be	O
identified	O
and	O
may	O
warrant	O
specialized	O
intervention	O
strategies	O
.	O

There	O
was	O
no	O
correlation	O
between	O
secretor	O
status	O
and	O
clinical	O
status	O
,	O
spirometry	O
measurements	O
,	O
salivary	B-GENE
and	I-GENE
serum	I-GENE
lysozyme	I-GENE
levels	O
or	O
rates	O
of	O
respiratory	O
tract	O
colonization	O
with	O
P	O
.	O
aeruginosa	O
and	O
S	O
.	O
aureus	O
.	O

There	O
was	O
no	O
correlation	O
between	O
secretor	O
status	O
and	O
clinical	O
status	O
,	O
spirometry	O
measurements	O
,	O
salivary	O
and	O
serum	B-GENE
lysozyme	I-GENE
levels	O
or	O
rates	O
of	O
respiratory	O
tract	O
colonization	O
with	O
P	O
.	O
aeruginosa	O
and	O
S	O
.	O
aureus	O
.	O

Gains	O
increased	O
3	O
.	O
5	O
%	O
(	O
P	O
less	O
than	O
.	O
10	O
)	O
and	O
feed	O
conversion	O
improved	O
5	O
.	O
9	O
%	O
(	O
P	O
less	O
than	O
.	O
07	O
)	O
in	O
steers	O
fed	O
.	O
28	O
%	O
AS	O
-	O
VFA	O
compared	O
with	O
gain	O
and	O
feed	O
conversion	O
of	O
the	O
control	O
steers	O
.	O

Daily	O
and	O
seasonal	O
rhythmicity	O
in	O
the	O
methylation	O
of	O
pineal	O
indolic	O
compounds	O
in	O
adult	O
male	O
golden	O
hamsters	O
,	O
kept	O
under	O
natural	O
conditions	O
.	O

The	O
transit	O
time	O
was	O
significantly	O
shortened	O
.	O

Among	O
the	O
patients	O
grades	O
1	O
-	O
2	O
-	O
3	O
,	O
81	O
%	O
had	O
a	O
good	O
out	O
come	O
without	O
any	O
neurological	O
abnormality	O
,	O
among	O
the	O
patients	O
graded	O
4	O
-	O
5	O
,	O
only	O
27	O
%	O
had	O
a	O
fair	O
out	O
come	O
.	O

Activity	O
of	O
acid	B-GENE
hydrolases	I-GENE
of	O
peripheral	O
blood	O
leukocytes	O
in	O
focal	O
and	O
segmental	O
pneumonia	O
in	O
children	O

Comparative	O
studies	O
of	O
the	O
antithrombin	B-GENE
III	I-GENE
level	O
and	O
plasminogen	B-GENE
activator	I-GENE
activity	O
in	O
patients	O
with	O
thrombophlebitis	O

Relations	O
between	O
cellular	O
electrical	O
activity	O
and	O
cardiac	O
mechanical	O
activity	O
in	O
man	O
,	O
the	O
dog	O
and	O
the	O
rabbit	O

Treatment	O
of	O
Paget	O
'	O
s	O
disease	O
.	O

Improvement	O
of	O
the	O
CRT	O
display	O
of	O
an	O
averager	O
.	O

Is	O
desensitization	O
'	O
for	O
ragweed	O
hay	O
fever	O
immunologically	O
specific	O
?	O

Renal	O
excretion	O
of	O
sulphadimidine	O
in	O
normal	O
and	O
uraemic	O
subjects	O
.	O

Experiences	O
with	O
the	O
clinical	O
and	O
experimental	O
use	O
of	O
Urat	O
-	O
I	O
lithotriptor	O
.	O

Formation	O
of	O
hyphae	O
and	O
chlamydospores	O
by	O
Cryptococcus	O
laurentii	O
.	O

Evaluation	O
of	O
thyroid	O
function	O
.	O

The	O
effect	O
of	O
a	O
tissue	O
emulsion	O
,	O
vitamin	O
A	O
and	O
nonspecific	O
gamma	B-GENE
-	I-GENE
globulin	I-GENE
on	O
the	O
blood	O
clearance	O
in	O
rabbits	O

HL	B-GENE
-	I-GENE
A	I-GENE
antibodies	I-GENE
in	O
polytransfused	O
patients	O

Demonstration	O
of	O
fine	O
structure	O
of	O
the	O
guinea	O
pig	O
organ	O
of	O
Corti	O
after	O
electron	O
microscopic	O
silver	O
staining	O

Histamine	O
metabolism	O
in	O
hemorrhagic	O
-	O
hypotensive	O
shock	O

Relaxation	O
of	O
catch	O
in	O
a	O
molluscan	O
smooth	O
muscle	O
.	O

Studies	O
on	O
alcoholic	O
liver	O
injury	O
.	O

Hypothalamic	O
control	O
of	O
coronary	O
circulation	O
in	O
the	O
dog	O
.	O

Evidence	O
for	O
two	O
distinctive	O
clinical	O
,	O
epidemiological	O
,	O
and	O
immunological	O
types	O
of	O
infection	O
.	O

Ultraviolet	O
light	O
-	O
induced	O
kinin	B-GENE
formation	O
in	O
human	O
skin	O
.	O

Poliomyelitis	O
from	O
a	O
vaccine	O
.	O

To	O
the	O
problem	O
of	O
the	O
stimulation	O
of	O
the	O
growth	O
of	O
transplantable	O
tumors	O
of	O
animals	O
previously	O
treated	O
with	O
antineoplastic	O
antibiotics	O

Assessment	O
of	O
nutrient	O
media	O
in	O
the	O
diagnosis	O
of	O
diptheria	O

Aluminium	O
resin	O
for	O
the	O
treatment	O
of	O
the	O
hyperkalamia	O
of	O
renal	O
failure	O
.	O

Value	O
of	O
the	O
EMG	O
in	O
the	O
diagnosis	O
of	O
a	O
cardiomyopathy	O
associated	O
with	O
a	O
myotonic	O
myopathy	O
.	O

D	O
.	O

Prevention	O
of	O
maternal	O
Rh	O
sensitization	O
:	O
anti	B-GENE
-	I-GENE
Rh	I-GENE
immune	I-GENE
globulin	I-GENE
.	O

Serotonin	O
levels	O
in	O
infant	O
hypothyroidism	O
.	O

Cerebrospinal	O
fluid	O
transferrin	B-GENE
II	I-GENE
studies	O
in	O
ischemic	O
disorders	O
of	O
the	O
central	O
nervous	O
system	O
.	O

High	O
dosages	O
of	O
D	O
-	O
penicillamine	O
in	O
pulmonary	O
fibroses	O

Inverse	O
relation	O
between	O
serum	O
IgG	B-GENE
concentration	O
and	O
glucose	O
and	O
xylose	O
absorption	O
in	O
Zambian	O
African	O
adults	O
.	O

Disorders	O
of	O
platelet	O
function	O
in	O
chronic	O
myeloid	O
leukemias	O

The	O
effect	O
of	O
anticonvulsants	O
on	O
sodium	B-GENE
-	I-GENE
potassium	I-GENE
-	I-GENE
activated	I-GENE
ATPase	I-GENE
,	O
sodium	O
,	O
and	O
potassim	O
in	O
cortex	O
.	O

Effect	O
of	O
immune	O
lymphocytes	O
and	O
of	O
rabbit	B-GENE
-	I-GENE
anti	I-GENE
-	I-GENE
lymphocyte	I-GENE
globulin	I-GENE
(	O
RAMLG	B-GENE
)	O
on	O
infected	O
macrophages	O
exposed	O
to	O
increased	O
incubation	O
temperature	O
in	O
vitro	O
.	O

Lactation	O
of	O
baboons	O
fed	O
a	O
low	O
protein	O
maintenance	O
diet	O
.	O

A	O
medical	O
-	O
geographical	O
review	O

Age	O
and	O
sex	O
structure	O
of	O
the	O
natural	O
population	O
of	O
Ornithodoros	O
tatarovski	O
Ol	O
.	O

Vitamin	O
D3	O
and	O
calcium	O
absorption	O
in	O
the	O
chick	O
.	O

The	O
incidence	O
of	O
tumours	O
in	O
young	O
chickens	O
.	O

Laboratory	O
aspects	O
with	O
particular	O
reference	O
to	O
chemotherapy	O
and	O
control	O
.	O

Their	O
effect	O
on	O
the	O
guinea	O
pig	O
vas	O
deferens	O
.	O

Androgens	O
and	O
growth	O
.	O

Therapeutic	O
action	O
of	O
a	O
new	O
antibiotic	O
-	O
corticoid	O
association	O
used	O
for	O
instillations	O
in	O
otology	O

Clinico	O
-	O
physiological	O
experiment	O

Enzyme	O
histochemical	O
findings	O
in	O
the	O
ultimobranchial	O
body	O
of	O
the	O
horse	O

Familial	O
glutathione	B-GENE
reductase	I-GENE
deficiency	O
and	O
disorder	O
of	O
glutathione	O
synthesis	O
in	O
the	O
erythrocyte	O

Studies	O
on	O
swine	O
enteroviruses	O
.	O

Serodiagnosis	O
of	O
ectromelia	O
in	O
laboratory	O
mice	O

Ultrasound	O
effect	O
on	O
the	O
cytochrome	B-GENE
oxidase	I-GENE
activity	O

Genesis	O
of	O
foam	O
cells	O
:	O
study	O
in	O
rats	O
after	O
administration	O
of	O
Cloforex	O
.	O

Conditions	O
influencing	O
inhibitors	O
of	O
the	O
colony	B-GENE
-	I-GENE
stimulating	I-GENE
factor	I-GENE
(	O
CSF	B-GENE
)	O
.	O

Absence	O
of	O
action	O
potentials	O
in	O
frog	O
slow	O
muscle	O
fibres	O
paralysed	O
by	O
botulinum	B-GENE
toxin	I-GENE
.	O

An	O
automated	O
method	O
for	O
the	O
quantitative	O
analysis	O
of	O
the	O
polyamines	O
putrescine	O
,	O
spermidine	O
and	O
spermine	O
in	O
cerebrospinal	O
fluid	O
(	O
CSF	O
)	O
was	O
used	O
to	O
analyze	O
CSF	O
samples	O
from	O
37	O
patients	O
with	O
central	O
nervous	O
system	O
(	O
CNS	O
)	O
tumors	O
and	O
from	O
13	O
patients	O
without	O
tumors	O
.	O

Disulfiram	O
and	O
the	O
drug	O
-	O
induced	O
effects	O
on	O
motility	O
.	O

Particles	O
resembling	O
microbodies	O
in	O
normal	O
and	O
neoplastic	O
perianal	O
glands	O
of	O
dogs	O
.	O

Natural	O
and	O
induced	O
malarias	O
in	O
western	O
hemisphere	O
monkeys	O
.	O

Intracranial	O
arachnoid	O
cyst	O
of	O
the	O
middle	O
fossa	O
demonstrated	O
by	O
positive	O
99mTc	O
brainscintigraphy	O
.	O

Effects	O
of	O
estrogen	O
and	O
glucocorticoids	O
on	O
the	O
adrenal	O
development	O
of	O
the	O
fetus	O
.	O

Copper	O
and	O
ceruloplasmin	B-GENE
content	O
in	O
pregnant	O
women	O
and	O
in	O
women	O
with	O
certain	O
gynecological	O
diseases	O

Effect	O
of	O
noise	O
on	O
CO	O
-	O
induced	O
increases	O
of	O
LAP	B-GENE
and	O
GPT	B-GENE
activity	O
in	O
the	O
plasma	O
of	O
rats	O

Kinetics	O
of	O
calcium	O
metabolism	O
.	O

On	O
the	O
transport	O
of	O
mucus	O
and	O
its	O
rheologic	O
simulants	O
in	O
ciliated	O
systems	O
.	O

A	O
hydrodynamic	O
description	O
of	O
the	O
osmotic	O
reflection	O
coefficient	O
with	O
application	O
to	O
the	O
pore	O
theory	O
of	O
transcapillary	O
exchange	O
.	O

Pathology	O
of	O
neuritis	O
caudae	O
equinae	O
in	O
the	O
horse	O

Abnormal	O
characteristics	O
and	O
verticillation	O
in	O
Platynothrus	O
peltifer	O

Selected	O
topics	O
in	O
laboratory	O
animal	O
medicine	O
.	O

On	O
parents	O

From	O
the	O
Icelandic	O
Red	O
Cross	O
activities	O

Effects	O
of	O
alcoholism	O
on	O
the	O
family	O

Treatment	O
and	O
care	O
of	O
adult	O
diabetes	O
mellitus	O
without	O
coma	O

Junctions	O
between	O
cells	O
of	O
the	O
human	O
enamel	O
organ	O
.	O

Electrocardiograms	O
of	O
the	O
month	O
.	O

Composites	O
as	O
restoration	O
materials	O

Hodgkin	O
'	O
s	O
disease	O
.	O

Value	O
of	O
Normotest	O
and	O
antithrombin	B-GENE
3	I-GENE
in	O
the	O
assessment	O
of	O
liver	O
function	O
.	O

Glutathione	B-GENE
peroxidase	I-GENE
in	O
human	O
red	O
cells	O
in	O
health	O
and	O
disease	O
.	O

Histopathologic	O
response	O
of	O
gingival	O
tissues	O
to	O
hemodent	O
and	O
aluminum	O
chloride	O
solutions	O
as	O
tissue	O
displacement	O
materials	O
.	O

Changes	O
following	O
periodontal	O
surgery	O
.	O

Intracellular	O
pH	O
,	O
H	O
ion	O
flux	O
and	O
H	O
ion	O
permeability	O
coefficient	O
in	O
bullfrog	O
toe	O
muscle	O
.	O

Directives	O
concerning	O
medical	O
care	O

Proceedings	O
:	O
Reversible	O
complete	O
heart	O
block	O
following	O
surgery	O
of	O
congenital	O
heart	O
defects	O

Method	O
of	O
synthesis	O
of	O
the	O
rheumatoid	B-GENE
factor	I-GENE
in	O
clinico	O
-	O
immunological	O
studies	O

Variations	O
of	O
the	O
timing	O
of	O
deflections	O
in	O
the	O
His	O
bundle	O
recordings	O
.	O

Extracellular	O
fibril	O
formation	O
by	O
neuroglial	O
cells	O
at	O
the	O
vitreoretinal	O
junction	O
of	O
the	O
human	O
eye	O
.	O

Blood	O
platelets	O
,	O
coagulation	O
factors	O
and	O
morphologic	O
organ	O
changes	O
following	O
scalding	O
shock	O
in	O
rhesus	O
monkeys	O

Cell	O
viability	O
and	O
lysosomal	B-GENE
enzymes	I-GENE

State	O
-	O
approved	O
schools	O
of	O
nursing	O
-	O
-	O
R	O
.	O
N	O
.	O
,	O
1972	O
.	O

Further	O
investigation	O
on	O
the	O
chemotactic	O
influence	O
of	O
thymic	B-GENE
hormone	I-GENE
on	O
lymphocytes	O

1	O
,	O
3	O
-	O
bis	O
(	O
2	O
-	O
chloroethyl	O
)	O
-	O
1	O
-	O
nitrosourea	O
(	O
bcnu	O
)	O
and	O
other	O
nitrosoureas	O
in	O
cancer	O
treatment	O
:	O
a	O
review	O
.	O

Pneumothorax	O
following	O
lung	O
abscess	O
in	O
the	O
renal	O
transplant	O
patient	O
.	O

Taxonomically	O
significant	O
colour	O
changes	O
in	O
Brevibacterium	O
linens	O
probably	O
associated	O
with	O
a	O
carotenoid	O
-	O
like	O
pigment	O
.	O

Temporal	O
relationships	O
and	O
the	O
development	O
phase	O
affected	O
.	O

A	O
short	O
history	O
of	O
dermatology	O
in	O
Lagos	O
,	O
Nigeria	O
.	O

Local	O
graft	O
irradiation	O
as	O
an	O
adjunct	O
to	O
pharmacologic	O
immunosuppression	O
.	O

Letter	O
:	O
Salmonella	O
detection	O

Role	O
of	O
biocenosis	O
in	O
the	O
manifestation	O
of	O
Shigella	O
virulence	O

The	O
effect	O
of	O
antilymphocyte	O
sera	O
on	O
formation	O
of	O
transplantation	O
and	O
anti	O
-	O
infection	O
immunity	O
in	O
mice	O

Cortical	O
afferents	O
to	O
the	O
entorhinal	O
cortex	O
of	O
the	O
Rhesus	O
monkey	O
.	O

Mechanism	O
of	O
immunogenesis	O
in	O
vaccination	O
with	O
streptomycin	O
-	O
dependent	O
mutants	O
of	O
salmonellae	O
and	O
shigellae	O
.	O

Resistance	O
pattern	O
of	O
Mycobacterium	O
tuberculosis	O
(	O
H	O
37	O
Rv	O
)	O
to	O
a	O
new	O
antibiotic	O
,	O
lividomycin	O

Pulmonary	O
arterial	O
pressure	O
and	O
structure	O
in	O
the	O
patas	O
monkey	O
after	O
prolonged	O
administration	O
of	O
aminorex	O
fumarate	O
.	O

Effect	O
of	O
triftazin	O
and	O
aminazin	O
on	O
hippocampal	O
bioelectric	O
activity	O

Sex	O
ratio	O
at	O
birth	O
.	O

Pathological	O
processes	O
in	O
the	O
cervix	O
uteri	O

General	O
formulae	O
for	O
estimating	O
heritability	O
in	O
a	O
population	O
with	O
related	O
parents	O
.	O

Measurement	O
of	O
open	O
-	O
loop	O
responses	O
to	O
electrical	O
stimulation	O
in	O
olfactory	O
bulb	O
of	O
cat	O
.	O

Glucose	O
disappearance	O
rate	O
and	O
changes	O
in	O
plasma	O
nutrients	O
after	O
intravenouly	O
injected	O
glucose	O
in	O
normoglycaemic	O
and	O
hypoglycaemic	O
underweight	O
newborns	O
.	O

Normal	O
values	O
for	O
the	O
peripheral	O
blood	O
and	O
bone	O
marrow	O
of	O
the	O
grey	O
(	O
Armenian	O
)	O
hamster	O

The	O
relationship	O
of	O
human	O
umbilical	O
arterial	O
and	O
venous	O
plasma	O
levels	O
of	O
corticosteroids	O
to	O
gestational	O
age	O
.	O

Antibiotic	O
effect	O
of	O
the	O
mud	O
from	O
heviz	O

Sulfuric	O
acid	O
concentration	O
in	O
the	O
catalyzed	O
breathalyzer	O
ampules	O
.	O

Role	O
of	O
histoclinical	O
studies	O
in	O
the	O
prophylaxis	O
of	O
spontaneous	O
abortions	O

Range	O
behavior	O
of	O
Hereford	O
,	O
Hereford	O
x	O
Holstein	O
and	O
Holstein	O
non	O
-	O
lactating	O
heifers	O
.	O

Chemical	O
constituents	O
of	O
the	O
gentianaceae	O
V	O
:	O
tetraoxygenated	O
xanthones	O
of	O
Swertia	O
chirata	O
Buch	O
.	O
-	O
Ham	O
.	O

Microdetermination	O
of	O
adrenocortical	O
steroids	O
by	O
double	O
isotope	O
method	O
.	O

Compensative	O
justice	O
and	O
moral	O
investment	O
among	O
Japanese	O
,	O
Chinese	O
,	O
and	O
Koreans	O
.	O

Effects	O
of	O
cortisone	O
,	O
starvation	O
,	O
and	O
rickets	O
on	O
oxidative	O
enzyme	O
activities	O
of	O
epiphyseal	O
cartilage	O
from	O
rats	O
.	O

Metal	O
coordination	O
compounds	O
of	O
thiabendazole	O
.	O

Estimation	O
of	O
renin	B-GENE
secretion	O
rate	O
and	O
renal	O
plasma	O
flow	O
from	O
peripheral	O
and	O
renal	B-GENE
vein	I-GENE
renin	I-GENE
levels	O
.	O

Choice	O
of	O
vessel	O
.	O

Suppression	O
of	O
food	O
intake	O
in	O
the	O
rat	O
by	O
tung	O
oil	O
.	O

Studies	O
of	O
lipoprotein	B-GENE
-	I-GENE
X	I-GENE
(	O
LP	B-GENE
-	I-GENE
X	I-GENE
)	O
and	O
bile	O
acids	O
in	O
familial	O
LCAT	B-GENE
deficiency	O
.	O

Pneumothorax	O
complicated	O
by	O
chronic	O
steroid	O
treatment	O
.	O

Manifest	O
anxiety	O
of	O
Vietnam	O
returnees	O
and	O
undergraduates	O
.	O

Familial	O
juvenile	O
nephronophthisis	O

Early	O
heparin	O
therapy	O
in	O
60	O
children	O
with	O
acute	O
meningococcemia	O
.	O

9	O
,	O
11	O
-	O
Seco	O
steroids	O
derived	O
from	O
estradiol	O
3	O
-	O
methyl	O
ether	O
.	O

Psychological	O
examinations	O
in	O
patients	O
with	O
chronic	O
kidney	O
insufficiency	O

Possibilities	O
of	O
needleless	O
administration	O
of	O
various	O
substances	O
to	O
animals	O

Change	O
in	O
the	O
makeup	O
of	O
the	O
blood	O
following	O
a	O
short	O
-	O
term	O
local	O
action	O
of	O
a	O
permanent	O
magnetic	O
field	O
on	O
the	O
human	O
body	O

Observations	O
on	O
the	O
flight	O
activities	O
of	O
Chrysops	O
caecutiens	O
L	O
.	O

Combination	O
of	O
3	O
multiple	O
primary	O
malignant	O
and	O
benign	O
tumors	O
of	O
the	O
breasts	O
and	O
uterus	O

Proceedings	O
:	O
Barrels	O
and	O
somatotopy	O
in	O
S	O
I	O
neocortex	O
of	O
the	O
brush	O
-	O
tailed	O
possum	O
.	O

Antivitamin	O
K	O
agents	O

Canine	O
reproduction	O
:	O
effects	O
of	O
a	O
single	O
injection	O
of	O
medroxyprogesterone	O
acetate	O
on	O
the	O
reproductive	O
organs	O
of	O
the	O
bitch	O
.	O

3	O
.	O

Hypoglycemic	O
and	O
antidiabetic	O
properties	O

Hematopoietic	O
system	O
in	O
streptococcal	O
allergy	O
.	O

Letter	O
:	O
Aryl	B-GENE
hydrocarbon	I-GENE
hydroxylase	I-GENE
and	O
smoking	O
.	O

Evaluation	O
of	O
1	O
,	O
10	O
-	O
phenanthroline	O
as	O
a	O
reagent	O
for	O
sialic	O
acid	O
determinations	O
.	O

Delta	O
-	O
aminolevulinic	O
acid	O
in	O
physiological	O
conditions	O
and	O
some	O
diseases	O
in	O
children	O

Nonteratogenicity	O
in	O
rats	O
of	O
blighted	O
potatoes	O
and	O
compounds	O
contained	O
in	O
them	O
.	O

Isolation	O
of	O
tha	O
avian	O
reticuloendothelial	O
virus	O
(	O
strain	O
T	O
)	O
.	O

Observations	O
on	O
saccules	O
of	O
rats	O
exposed	O
to	O
long	O
-	O
term	O
hypergravity	O
.	O

The	O
levels	O
of	O
galactosyltransferase	B-GENE
activity	O
in	O
sera	O
from	O
normal	O
children	O
and	O
patients	O
with	O
cystic	O
fibrosis	O
.	O

Lack	O
of	O
effect	O
of	O
the	O
appetite	O
stimulant	O
pizotifen	O
(	O
BC	O
105	O
)	O
on	O
the	O
absorption	O
of	O
isonicotinylhydrazine	O
.	O

Relationship	O
between	O
gross	O
lesions	O
and	O
Escherichia	O
coli	O
serotypes	O
in	O
chronic	O
respiratory	O
disease	O
(	O
CRD	O
)	O
of	O
poultry	O
.	O

Immunelectrophoretic	O
pattern	O
of	O
Wassermann	O
reagin	O
and	O
comparison	O
of	O
the	O
appearance	O
time	O
between	O
RPCF	B-GENE
and	O
FTA	B-GENE
antibodies	I-GENE

Motile	O
nocardoid	O
Actinomycetales	O
.	O

Electrocardiographic	O
QRS	O
complexes	O
and	O
vectorcardiographic	O
QRS	O
loop	O

Cardiac	O
preservation	O
.	O

Labial	O
bar	O
.	O

Yusuf	O
Dawood	O
Docrat	O
L	O
.	O
R	O
.	O
C	O
.	O
P	O
.	O

Dr	O
.	O

The	O
metabolism	O
and	O
pharmacology	O
of	O
5	O
-	O
fluorouracil	O
.	O

Spleen	O
weight	O
in	O
rats	O
during	O
tumour	O
growth	O
and	O
in	O
homograft	O
rejection	O
.	O

Isolation	O
of	O
Proteus	O
vulgaris	O
MC	O
-	O
63	O
from	O
carcinoma	O
63	O
and	O
its	O
antitumor	O
effect	O
on	O
Crocker	O
sarcoma	O
180	O
and	O
Ehrlich	O
carcinoma	O
.	O

Human	O
synovial	O
fluid	O
:	O
detection	O
of	O
a	O
new	O
component	O
.	O

Effects	O
of	O
temperature	O
and	O
moulting	O
cycle	O
on	O
melanin	O
synthesis	O
in	O
the	O
newt	O
,	O
Triturus	O
cristatus	O
.	O

LA	O
-	O
3848	O
-	O
MS	O
.	O

Immunochemical	O
studies	O
with	O
filarial	O
antigens	O
.	O

Morphological	O
and	O
functional	O
alterations	O
noted	O
after	O
baboon	O
renal	O
allotransplantation	O
.	O

Heterogeneity	O
of	O
human	B-GENE
serum	I-GENE
albumin	I-GENE
.	O

Analysis	O
of	O
corticosteroids	O
.	O

Plasma	B-GENE
histaminase	I-GENE
in	O
patients	O
of	O
bronchial	O
asthma	O
and	O
the	O
effect	O
of	O
prednisolone	O
administration	O
on	O
it	O
.	O

A	O
comparative	O
study	O
of	O
the	O
cortical	O
end	O
of	O
the	O
auditory	O
analyzer	O
during	O
postnatal	O
ontogenesis	O
in	O
lower	O
monkeys	O
and	O
man	O

Immunogenicity	O
of	O
various	O
mycobacteria	O
and	O
the	O
corresponding	O
levels	O
of	O
cross	O
-	O
protection	O
developed	O
between	O
species	O
.	O

Ten	O
-	O
year	O
experience	O
with	O
one	O
-	O
stage	O
proctocolectomy	O
and	O
anal	O
ileostomy	O
.	O

Factors	O
affecting	O
the	O
inhibition	O
of	O
phagocytosis	O
by	O
chlorpromazine	O
.	O

Photopic	O
spectral	O
sensitivity	O
determined	O
electroretinographically	O
for	O
the	O
pigeon	O
eye	O
.	O

Angiography	O
of	O
aneurysmal	O
bone	O
cyst	O
.	O

Cholinesterase	B-GENE

Sodium	O
restriction	O
in	O
cardiac	O
failure	O
.	O

Clinical	O
and	O
angiographic	O
examinations	O
in	O
occlusion	O
disease	O
of	O
the	O
great	O
intestinal	O
arteries	O

Serum	O
lipid	O
changes	O
during	O
pregnancy	O
due	O
to	O
oral	O
calcium	O
administration	O

Successful	O
treatment	O
of	O
candidiasis	O
with	O
transfer	B-GENE
factor	I-GENE
.	O

Clinicopathologic	O
studies	O
in	O
feminizing	O
tumors	O
of	O
the	O
ovary	O
.	O

On	O
the	O
constituents	O
of	O
Dryopteris	O
polylepis	O

Relation	O
between	O
mixing	O
ratio	O
of	O
raw	O
materials	O
and	O
composition	O
of	O
products	O
in	O
the	O
synthesis	O
of	O
aluminosilicates	O

Influence	O
of	O
diet	O
on	O
urinary	O
VMA	O
excretion	O
.	O

Oscilloscope	O
triggering	O
circuit	O
for	O
recording	O
long	O
transients	O
at	O
fast	O
sweep	O
speeds	O
.	O

Derivatives	O
of	O
boswellic	O
acids	O
.	O

The	O
status	O
of	O
education	O
and	O
training	O
programs	O
in	O
speech	O
pathology	O
and	O
audiology	O
-	O
-	O
1971	O
-	O
72	O
.	O

Coronary	O
arteries	O
-	O
-	O
old	O
and	O
new	O
.	O

Antiviral	O
agents	O
.	O

Separation	O
of	O
ninhydrin	O
-	O
positive	O
compounds	O
in	O
urine	O
by	O
the	O
combined	O
methods	O
of	O
medium	O
-	O
tension	O
intophoresis	O
and	O
partition	O
chromatography	O

Conservative	O
treatment	O
of	O
central	O
nervous	O
system	O
injuries	O

Spasmus	O
nutans	O
:	O
a	O
syndrome	O
of	O
auto	O
-	O
arousal	O
.	O

6	O
.	O

1st	O
data	O
on	O
the	O
immunosuppressive	O
therapy	O
of	O
scleroderma	O

Slowed	O
lysosomal	B-GENE
enzyme	I-GENE
release	O
and	O
its	O
normalization	O
by	O
drugs	O
in	O
adjuvant	O
-	O
induced	O
polyarthritis	O
.	O

Treatment	O
of	O
ovarian	O
neoplasms	O

Experimental	O
pancreatitis	O
in	O
pigs	O
.	O

Bacterial	O
metabolism	O
of	O
4	O
-	O
chlorophenoxyacetate	O
.	O

I	O
.	O

Surgical	O
treatment	O
of	O
pathologic	O
scars	O
of	O
myocardial	O
infarct	O

The	O
interaction	O
of	O
caffeine	O
,	O
theophylline	O
and	O
theobromine	O
with	O
monoamine	B-GENE
oxidase	I-GENE
inhibitors	O
.	O

Effect	O
of	O
phenformin	O
on	O
gluconeogenesis	O
in	O
perfused	O
rat	O
liver	O
.	O

New	O
alkaloids	O
from	O
bark	O
of	O
Erythrophleum	O
ivorense	O
.	O

Radiosensitive	O
nature	O
of	O
paravascular	O
infiltrate	O
-	O
producing	O
potential	O
of	O
parental	O
spleen	O
cells	O
.	O

Sinusoidal	O
oscillations	O
of	O
a	O
gas	O
dilution	O
indicator	O

The	O
value	O
of	O
different	O
sources	O
of	O
nitrogen	O
in	O
diets	O
for	O
the	O
early	O
-	O
weaned	O
calf	O
.	O

1	O
.	O

Abdominal	O
tumors	O
in	O
childhood	O
.	O

Studies	O
on	O
the	O
hereditary	O
nature	O
of	O
sole	O
prints	O
-	O
-	O
with	O
special	O
reference	O
to	O
interdigital	O
and	O
triradii	O

The	O
problem	O
of	O
disablement	O
due	O
to	O
pulmonary	O
tuberculosis	O
,	O
on	O
the	O
basis	O
of	O
an	O
analysis	O
of	O
the	O
history	O
of	O
395	O
cases	O
as	O
observed	O
in	O
Gdansk	O
in	O
the	O
years	O
1946	O
-	O
1965	O

Cleidocranial	O
dysostosis	O

Proposals	O
on	O
authorization	O
;	O
by	O
a	O
group	O
of	O
nurses	O
from	O
psychiatric	O
hospitals	O

Successive	O
abdominal	O
scintillation	O
with	O
131	O
-	O
I	O
-	O
tagged	O
BSP	O
-	O
-	O
description	O
of	O
the	O
thyroid	O
gland	O
,	O
kidney	O
and	O
spleen	O
(	O
comparison	O
with	O
131	O
-	O
I	O
-	O
RB	O
)	O

Pneumonia	O
in	O
children	O

Osteosarcoma	O
caused	O
by	O
3	O
,	O
4	O
-	O
benzopyrene	O

Relapse	O
of	O
leukemia	O
after	O
prolonged	O
remission	O
.	O

Influence	O
of	O
cigarette	O
smoking	O
on	O
some	O
blood	O
coagulation	O
tests	O
.	O

Second	O
report	O
of	O
the	O
Norwegian	O
Cancer	O
Society	O
.	O

SAM	O
-	O
TR	O
-	O
68	O
-	O
54	O
.	O

A	O
brief	O
discussion	O
of	O
color	O
deficiencies	O
.	O

BIM	O
130	O
.	O

Problems	O
in	O
the	O
determination	O
of	O
the	O
antigenic	O
content	O
of	O
influenza	O
vaccines	O
.	O

Aedes	O
aegypti	O
(	O
L	O
.	O
)	O
and	O
Aedes	O
albopictus	O
(	O
Skuse	O
)	O
in	O
Singapore	O
City	O
.	O

Homograft	O
response	O
and	O
hemagglutinin	B-GENE
production	O
by	O
sensitized	O
thymectomized	O
irradiated	O
adult	O
mice	O
.	O

Comparative	O
study	O
on	O
acute	O
oral	O
overload	O
using	O
tolbutamide	O
and	O
tolazamide	O
in	O
normal	O
and	O
diabetic	O
subjects	O
.	O

Mycotoxins	O
in	O
feeds	O
and	O
foods	O
.	O

Spinal	O
cord	O
representation	O
of	O
the	O
micturition	O
reflex	O
.	O

Biological	O
action	O
and	O
kinetics	O
of	O
the	O
elimination	O
of	O
tritium	O
oxide	O
in	O
dogs	O

Auto	O
-	O
and	O
isotopy	O
of	O
the	O
conjunctiva	O

IX	O
.	O

Pitfalls	O
in	O
the	O
use	O
of	O
chromosome	O
aberration	O
analysis	O
for	O
biological	O
radiation	O
dosimetry	O
.	O

Renin	B-GENE
secretion	O
in	O
essential	O
and	O
accelerated	O
hypertension	O
.	O

The	O
need	O
for	O
including	O
forensic	O
medical	O
expertise	O
in	O
the	O
list	O
of	O
urgent	O
criminal	O
investigative	O
actions	O

Histopathology	O
and	O
pathogenesis	O
of	O
exanthematous	O
viroses	O

CNS	O
effects	O
of	O
local	O
anesthetics	O
only	O
partially	O
dependent	O
on	O
biogenic	O
amine	O
mechanisms	O
.	O

Diethylene	O
benzene	O

The	O
effects	O
of	O
taloximine	O
and	O
aminophylline	O
on	O
isolated	O
human	O
smooth	O
muscle	O
.	O

The	O
exploratory	O
behaviour	O
in	O
normal	O
and	O
aggressive	O
mice	O
.	O

Genitography	O
in	O
intersexual	O
states	O
.	O

The	O
role	O
of	O
ascorbic	O
acid	O
in	O
the	O
prevention	O
of	O
bladder	O
tumor	O
formation	O
.	O

The	O
"	O
28	O
percent	O
"	O
Venturi	O
mask	O
in	O
obstructive	O
airway	O
disease	O
.	O

3	O
'	O
-	O
Methyl	O
,	O
8	O
-	O
methyl	O
,	O
and	O
8	O
-	O
phenyl	O
derivatives	O
of	O
5	O
,	O
9	O
-	O
dimethyl	O
-	O
6	O
,	O
7	O
-	O
benzomorphans	O
.	O

Antidromic	O
invasion	O
of	O
impulses	O
and	O
recurrent	O
collateral	O
inhibition	O
in	O
pyramidal	O
tract	O
neurones	O
.	O

Lipid	O
concentration	O
and	O
lipase	B-GENE
activity	O
in	O
the	O
epiphysis	O
of	O
adrenalectomized	O
rats	O
consuming	O
food	O
with	O
different	O
sodium	O
content	O

Behavior	O
of	O
aspartate	B-GENE
aminotransferase	I-GENE
(	O
EC	B-GENE
2	I-GENE
.	I-GENE
6	I-GENE
.	I-GENE
1	I-GENE
.	I-GENE
1	I-GENE
)	O
and	O
alanine	B-GENE
aminotransferase	I-GENE
(	O
EC	B-GENE
2	I-GENE
.	I-GENE
6	I-GENE
.	I-GENE
1	I-GENE
.	I-GENE
2	I-GENE
)	O
in	O
rat	O
serum	O
during	O
the	O
course	O
of	O
acute	O
radiation	O
syndrome	O
following	O
whole	O
body	O
X	O
-	O
irradiation	O

Diminished	O
forearm	O
arteriolar	O
dilator	O
capacity	O
produced	O
by	O
mineralocorticoid	O
-	O
induced	O
salt	O
retention	O
in	O
man	O
.	O

Studies	O
on	O
the	O
pathogenicity	O
of	O
ECHO	O
9	O
(	O
HILL	O
)	O
virus	O
and	O
its	O
mutants	O
for	O
suckling	O
mice	O

Counter	O
-	O
current	O
heat	O
exchange	O
in	O
the	O
respiratory	O
passages	O
:	O
effect	O
on	O
water	O
and	O
heat	O
balance	O
.	O

Calibration	O
and	O
a	O
correction	O
of	O
blood	O
O2	O
content	O
measured	O
by	O
Po2	O
and	O
CO	O
saturation	O
.	O

Mae	O
West	O
and	O
the	O
doctor	O
shortage	O
.	O

Elimination	O
of	O
gamma	O
-	O
irradiation	O
induced	O
oxidation	O
in	O
aqueous	O
drug	O
preparations	O

Teratogenic	O
effects	O
of	O
actinomycin	O
D	O
in	O
rats	O

The	O
plasma	B-GENE
growth	I-GENE
hormone	I-GENE
concentration	O
of	O
the	O
foetal	O
lamb	O
.	O

Bimodal	O
cochlear	O
response	O
curves	O
in	O
rodents	O
.	O

A	O
new	O
hemagglutination	O
test	O
for	O
the	O
on	O
-	O
slide	O
assay	O
of	O
rheumatoid	B-GENE
factor	I-GENE

The	O
biology	O
of	O
Hyostrongylus	O
ruidus	O
.	O

Foreign	O
profiles	O
in	O
air	O
pollution	O
control	O
activities	O
.	O

Effects	O
of	O
chronic	O
metaraminol	O
treatment	O
on	O
the	O
sympathetic	O
activity	O
of	O
intact	O
and	O
adrenal	O
demedullated	O
rats	O
kept	O
in	O
warm	O
or	O
cold	O
environments	O
.	O

The	O
association	O
of	O
clopamide	O
and	O
hydergine	O
(	O
Brinedine	O
)	O
in	O
the	O
treatment	O
of	O
the	O
vasculo	O
-	O
renal	O
syndromes	O
of	O
pregnancy	O

Leukemia	O
in	O
twins	O
:	O
world	O
-	O
wide	O
review	O
of	O
clinical	O
cases	O
.	O

Preliminary	O
report	O
.	O

Gastrointestinal	O
manifestations	O
of	O
systemic	O
sclerosis	O

Total	O
body	O
water	O
,	O
rhodanide	O
space	O
and	O
I	B-GENE
-	I-GENE
131	I-GENE
-	I-GENE
albumin	I-GENE
space	O
under	O
the	O
acute	O
effect	O
of	O
furosemide	O

V	O
.	O

18F	O
and	O
85Sr	O
scintimetry	O
in	O
the	O
study	O
of	O
primary	O
arthropathies	O
.	O

Health	O
:	O
an	O
integrative	O
reticulum	O
.	O

Sensitive	O
fluorometric	O
method	O
of	O
determining	O
SH	O
-	O
and	O
S	O
-	O
S	O
-	O
groups	O
when	O
jointly	O
present	O

Behavioral	O
and	O
electrographic	O
expression	O
of	O
natural	O
sleep	O
and	O
wakefulness	O
in	O
reptiles	O

Sensitivities	O
of	O
thromboplastins	B-GENE
to	O
factor	B-GENE
VII	I-GENE
deficiency	O
.	O

Central	O
venous	O
catheter	O
used	O
for	O
recording	O
intracardiac	O
electrocardiogram	O
.	O

Two	O
Lab	O
8	O
computer	O
programmes	O
for	O
use	O
in	O
the	O
study	O
of	O
the	O
isometric	O
and	O
isotonic	O
contractile	O
characteristics	O
of	O
skeletal	O
muscle	O
.	O

Open	O
head	O
-	O
brain	O
injuries	O

The	O
modification	O
of	O
P32	O
uptake	O
into	O
the	O
Jensen	O
sarcoma	O
in	O
vitro	O
by	O
adding	O
of	O
peroxide	O
to	O
the	O
nutritive	O
medium	O

Students	O
,	O
parents	O
,	O
teachers	O
and	O
hearing	O
disorders	O

Changing	O
and	O
predicting	O
doses	O
of	O
Cs137	O
irradiation	O

Positive	O
shifts	O
of	O
basal	O
skin	O
potentials	O
during	O
human	O
sleep	O
.	O

Evaluating	O
dietary	O
department	O
management	O
.	O

5	O
-	O
(	O
Dimethylaminopropyl	O
)	O
-	O
19	O
,	O
11	O
-	O
dihydro	O
-	O
5H	O
-	O
benzo	O
[	O
2	O
,	O
3	O
]	O
pyrido	O
[	O
6	O
,	O
7	O
-	O
b	O
]	O
azepine	O
.	O

Osteogenesis	O
imperfecta	O

Investigation	O
on	O
the	O
exchange	O
of	O
Ca45	O
in	O
intact	O
and	O
burned	O
rats	O
by	O
the	O
kinetic	O
analysis	O
method	O

Effect	O
of	O
thrombotic	O
and	O
antithrombotic	O
drugs	O
on	O
the	O
surface	O
charge	O
characteristics	O
of	O
canine	O
blood	O
vessels	O
:	O
in	O
vivo	O
and	O
in	O
vitro	O
studies	O
.	O

Measurements	O
of	O
activity	O
with	O
the	O
radioprotective	O
chamber	O
VA	O
-	O
K	O
-	O
254	O
of	O
the	O
osimeter	O
VA	O
-	O
J18	O

3	O
-	O
(	O
N	O
-	O
Alkyl	O
-	O
N	O
-	O
2	O
-	O
chloroethylaminomethyl	O
)	O
-	O
5	O
-	O
or	O
7	O
-	O
halogenobenzo	O
[	O
b	O
]	O
thiophen	O
hydrochlorides	O
.	O

Determination	O
of	O
transaminases	O
with	O
an	O
autoanalyzer	O

Sterols	O
in	O
pollen	O
.	O

Dermoid	O
cyst	O
in	O
a	O
free	O
skin	O
flap	O
as	O
the	O
complication	O
after	O
treatment	O
of	O
recurring	O
hernia	O

Histological	O
observations	O
on	O
the	O
decidua	O
in	O
the	O
second	O
half	O
of	O
pregnancy	O

Endocardial	O
fibro	O
-	O
elastosis	O
,	O
mitral	O
incompetence	O
,	O
and	O
coarctation	O
of	O
abdominal	O
aorta	O
.	O

Studies	O
on	O
the	O
method	O
of	O
size	O
reduction	O
of	O
medicinal	O
compounds	O
.	O

Children	O
with	O
defective	O
vision	O

Identification	O
and	O
estimation	O
of	O
monosaccharides	O
and	O
disaccharides	O
in	O
urine	O
by	O
gas	O
-	O
liquid	O
chromatography	O
.	O

Steroids	O
in	O
germfree	O
and	O
conventional	O
rats	O
.	O

The	O
effects	O
of	O
loading	O
the	O
respiratory	O
pumps	O
on	O
the	O
oxygen	O
consumption	O
of	O
Callionymus	O
lyra	O
.	O

Trials	O
of	O
sevine	O
activity	O
against	O
mosquito	O
larvae	O

The	O
significance	O
of	O
structural	O
integrity	O
of	O
lymphoid	O
tissue	O
for	O
antibody	O
production	O
in	O
culture	O
in	O
vivo	O

Studies	O
carried	O
out	O
with	O
the	O
Glossina	O
morsitans	O
colony	O
of	O
Lisbon	O
.	O

Transformations	O
in	O
the	O
morphine	O
series	O
.	O

Dissociative	O
anesthetics	O
2	O
-	O
(	O
o	O
-	O
chlorophenyl	O
)	O
-	O
2	O
-	O
methyl	O
-	O
amino	O
cyclohexane	O
HCL	O
(	O
CI	O
-	O
581	O
)	O

Estrus	O
and	O
copulative	O
abilities	O
of	O
androgen	O
-	O
sterilized	O
rats	O

Hemodynamics	O
changes	O
in	O
man	O
during	O
flight	O

Caries	O
prevention	O
in	O
the	O
dental	O
office	O
.	O

I	O
.	O

Clinical	O
applications	O
of	O
inhibition	O
of	O
beta	B-GENE
-	I-GENE
adrenergic	I-GENE
receptors	I-GENE
with	O
propranolol	O
.	O

Automatic	O
view	O
box	O
.	O

Measurement	O
of	O
gastric	O
acid	O
secretion	O
by	O
conductivity	O
.	O

Relationship	O
of	O
mast	O
cells	O
to	O
sarcoidosis	O
granuloma	O
of	O
the	O
skin	O

Long	O
-	O
term	O
effects	O
of	O
clofibrate	O
(	O
Atromid	O
-	O
S	O
)	O
on	O
serum	O
lipids	O
in	O
man	O
.	O

Phosphate	B-GENE
glucose	I-GENE
dehydrogenase	I-GENE
deficiency	O
causing	O
hyperbilirubinemia	O
in	O
the	O
newborn	O

Evidence	O
forthe	O
electroosmosis	O
theory	O
of	O
transport	O
in	O
the	O
phloem	O
.	O

Effects	O
of	O
beta	B-GENE
-	I-GENE
adrenergic	I-GENE
receptor	I-GENE
blockade	O
on	O
airway	O
conductance	O
and	O
lung	O
volume	O
in	O
normal	O
and	O
asthmatic	O
subjects	O
.	O

I	O
.	O

Specialist	O
in	O
family	O
practice	O
-	O
-	O
prototype	O
of	O
a	O
doctor	O
.	O

The	O
possibility	O
of	O
selective	O
chemotherapy	O
of	O
progressive	O
recurring	O
ovarian	O
carcinoma	O
with	O
the	O
aid	O
of	O
cytodiagnosis	O
and	O
incorporation	O
of	O
tagged	O
idoxuridine	O

Variation	O
in	O
the	O
temporal	O
-	O
spatial	O
distribution	O
of	O
228Ra	O
and	O
224Ra	O
in	O
the	O
RES	O
and	O
marrow	O
-	O
free	O
skeleton	O
after	O
incorporation	O
of	O
colloidal	O
ThO2	O

Oxidative	O
degradation	O
of	O
adrenaline	O
solutions	O
:	O
study	O
of	O
the	O
intermediate	O
stages	O
and	O
their	O
analytic	O
value	O
for	O
the	O
control	O
of	O
this	O
solute	O

Absorption	O
of	O
electrolytes	O
from	O
the	O
colon	O
in	O
cases	O
of	O
ulcerative	O
colitis	O
and	O
in	O
control	O
subjects	O
.	O

Ion	O
injection	O
.	O

Polyvinyl	O
alcohol	O
as	O
a	O
solution	O
mediator	O

Mining	O
the	O
diagnostic	O
iron	O
ore	O
.	O

The	O
structure	O
of	O
digiprogenin	O
.	O

I	O
.	O

On	O
the	O
character	O
of	O
changes	O
in	O
the	O
enzyme	O
activity	O
in	O
the	O
brain	O
tissue	O
during	O
reflex	O
epilepsy	O

A	O
malignant	O
true	O
teratoma	O
of	O
liver	O
in	O
childhood	O
.	O

Methoxyflurane	O
and	O
renal	O
function	O

Histochemistry	O
and	O
electron	O
microscopy	O
of	O
acute	O
liver	O
lesions	O
induced	O
by	O
Aflatoxin	O
B1	O
in	O
ducklings	O
.	O

Functional	O
disorders	O
of	O
the	O
ureter	O
following	O
gynecologic	O
surgery	O

Study	O
of	O
the	O
alterations	O
of	O
intestinal	O
absorption	O
,	O
by	O
means	O
of	O
I	O
-	O
131	O
-	O
triolein	O
,	O
in	O
the	O
whole	O
body	O
irradiated	O
rat	O

Chemical	O
histologic	O
and	O
immunologic	O
responses	O
in	O
rats	O
to	O
CC1	O
-	O
4	O
by	O
different	O
routes	O
of	O
administration	O
.	O

Clinical	O
trials	O
with	O
1	O
,	O
3	O
-	O
bis	O
(	O
2	O
-	O
chloroethyl	O
)	O
-	O
1	O
-	O
nitrosourea	O
,	O
NSC	O
-	O
409962	O
.	O

Hydroxypropyl	O
methacrylate	O
,	O
a	O
new	O
water	O
-	O
miscible	O
embedding	O
medium	O
for	O
electron	O
microscopy	O
.	O

On	O
the	O
diagnosis	O
of	O
bovine	O
leucosis	O
and	O
its	O
control	O
in	O
southern	O
Lower	O
Saxony	O

Experience	O
with	O
the	O
restoration	O
of	O
agglutination	O
properties	O
of	O
non	O
-	O
agglutinating	O
dysenterial	O
cultures	O
with	O
the	O
use	O
of	O
Rzhaninov	O
'	O
s	O
method	O

Study	O
on	O
micromelias	O
in	O
the	O
mouse	O
fetus	O
caused	O
by	O
x	O
-	O
radiation	O
,	O
hypoxia	O
,	O
trypan	O
blue	O
injection	O
of	O
hypervitaminosis	O
-	O
A	O
upon	O
mother	O
animals	O
during	O
pregnancy	O
.	O

Human	O
antitetanus	O
serum	O
:	O
an	O
unused	O
wealth	O

(	O
3	O
)	O
.	O

Studies	O
on	O
the	O
intracutaneous	O
infection	O
of	O
rabbits	O
by	O
Staphylococcus	O
aureus	O
.	O

On	O
catabolism	O
of	O
aminoketones	O
in	O
climacteric	O
age	O

The	O
effect	O
of	O
feeding	O
patterns	O
on	O
fat	O
deposition	O
in	O
mice	O
.	O

IV	O
.	O

Studies	O
on	O
powdered	O
preparations	O
.	O

A	O
case	O
report	O
with	O
angiographic	O
follow	O
-	O
up	O
study	O
.	O

Interactions	O
between	O
adrenergics	O
,	O
adrenolytics	O
and	O
monoamine	B-GENE
oxidase	I-GENE
inhibitors	O

Further	O
studies	O
on	O
a	O
"	O
new	O
"	O
human	O
isoprecipitin	B-GENE
system	O
(	O
Australia	O
antigen	O
)	O
.	O

Pigmentary	O
rhythms	O
as	O
indicators	O
of	O
neurosecretion	O
.	O

When	O
the	O
cervical	O
Pap	O
smear	O
is	O
positive	O
.	O

I	O
.	O

The	O
3	O
-	O
hour	O
test	O
iodine	O
(	O
I	O
-	O
132	O
)	O
uptake	O
by	O
the	O
thyroid	O
in	O
children	O
with	O
growth	O
deficiency	O

Persistence	O
of	O
toxaphene	O
in	O
treated	O
lakes	O
.	O

Studies	O
on	O
Coxsackie	O
B	O
Type	O
5	O
virus	O
infections	O
.	O

Adrenergic	O
nerve	O
function	O
,	O
noradrenaline	O
level	O
and	O
noradrenaline	O
uptake	O
in	O
cat	O
nictitating	O
membrane	O
after	O
reserpine	O
treatment	O
.	O

Concussion	O
of	O
the	O
spinal	O
cord	O

Study	O
on	O
the	O
evagination	O
of	O
Cysticercus	O
pisiformis	O
.	O

The	O
pathogenicity	O
of	O
Achromobacter	O
puntatum	O
for	O
cold	O
blooded	O
and	O
warm	O
blooded	O
animals	O

Consanguinity	O
and	O
migration	O
in	O
the	O
marriages	O
of	O
the	O
region	O
of	O
Nunoa	O
,	O
Santiago	O
,	O
1850	O
-	O
1960	O

Studies	O
of	O
lipogenesis	O
by	O
labelled	O
precursors	O
in	O
the	O
pregnant	O
rat	O
.	O

Pharmacodynamic	O
studies	O
on	O
the	O
cardiovascular	O
system	O
of	O
spontaneously	O
hypertensive	O
rats	O
.	O

Nuclear	O
spin	O
of	O
249Bk	O
from	O
the	O
hyperfine	O
structure	O
in	O
its	O
emission	O
spectrum	O
.	O

Further	O
observations	O
on	O
resorption	O
in	O
guinea	O
pigs	O
following	O
injections	O
of	O
trypan	O
blue	O
.	O

Derivatives	O
of	O
fluorene	O
.	O

Note	O
on	O
Slot	O
'	O
s	O
method	O
for	O
the	O
specific	O
determination	O
of	O
creatinine	O
.	O

Retention	O
behavior	O
of	O
steroids	O
in	O
gas	O
chromatography	O
with	O
a	O
series	O
of	O
combination	O
columns	O
.	O

Compensatory	O
renal	O
hypertrophy	O
in	O
parabiotic	O
rats	O
.	O

(	O
3	O
)	O
.	O

XXI	O
.	O

In	O
vitro	O
evaluation	O
of	O
the	O
mucolytic	O
action	O
of	O
urea	O
.	O

Electrophoretic	O
characteriaztion	O
of	O
virus	O
-	O
induced	O
interferon	B-GENE
of	O
the	O
blood	O
and	O
urine	O
in	O
rabbits	O

Iron	O
and	O
folate	O
deficiency	O
in	O
pregnancy	O

Symposium	O
on	O
presenile	O
spongy	O
encephalopathies	O
.	O

Twenty	O
-	O
two	O
of	O
the	O
24	O
patients	O
had	O
a	O
rise	O
in	O
the	O
total	O
serum	O
amylase	B-GENE
following	O
ERCP	O
.	O

Elevated	O
maternal	B-GENE
alpha	I-GENE
fetoproteins	I-GENE
and	O
oligoamnios	O
:	O
fetal	O
prognosis	O

Also	O
discussed	O
is	O
the	O
possibility	O
of	O
a	O
combined	O
genetic	O
and	O
environmental	O
etiology	O
.	O

Courses	O
were	O
repeated	O
monthly	O
upon	O
recovery	O
of	O
myelosuppression	O
.	O

Stimulation	O
with	O
MCh	O
produced	O
a	O
Ca	O
-	O
dependent	O
transient	O
elevation	O
of	O
cGMP	O
level	O
from	O
10	O
to	O
80	O
fmol	O
/	O
gland	O
,	O
peaking	O
at	O
1	O
-	O
2	O
min	O
but	O
returning	O
to	O
the	O
basal	O
level	O
by	O
5	O
min	O
.	O

Two	O
hundred	O
forty	O
-	O
three	O
patients	O
have	O
received	O
WR	O
-	O
2721	O
in	O
Phase	O
I	O
-	O
II	O
studies	O
.	O

The	O
PEPCK	B-GENE
promoter	O
fragment	O
was	O
introduced	O
either	O
in	O
the	O
proper	O
orientation	O
for	O
transcription	O
of	O
the	O
TK	B-GENE
gene	I-GENE
or	O
in	O
the	O
opposite	O
orientation	O
.	O

Many	O
mammary	O
tumors	O
induced	O
by	O
mouse	O
mammary	O
tumor	O
virus	O
(	O
MMTV	O
)	O
contain	O
a	O
provirus	O
in	O
the	O
same	O
region	O
of	O
the	O
host	O
-	O
cell	O
genome	O
,	O
leading	O
to	O
expression	O
of	O
a	O
putative	O
cellular	O
oncogene	O
called	O
int	B-GENE
-	I-GENE
1	I-GENE
.	O

In	O
these	O
cases	O
,	O
asbestos	O
or	O
erionite	O
-	O
tissue	O
burden	O
followed	O
by	O
fibrosis	O
was	O
frequently	O
observed	O
.	O

Hepatitis	O
B	O
virus	O
and	O
hepatoma	O
.	O

USA	O
80	O
,	O
3618	O
-	O
3622	O
)	O
The	O
two	O
proteins	O
show	O
36	O
%	O
identities	O
in	O
their	O
amino	O
acid	O
sequence	O
,	O
in	O
an	O
alignment	O
requiring	O
six	O
gaps	O
.	O

The	O
envelope	B-GENE
glycoproteins	I-GENE
of	I-GENE
Rous	I-GENE
sarcoma	I-GENE
virus	I-GENE
(	I-GENE
RSV	I-GENE
)	I-GENE
,	O
gp85	B-GENE
and	O
gp37	B-GENE
,	O
are	O
anchored	O
in	O
the	O
membrane	O
by	O
a	O
27	O
-	O
amino	O
acid	O
,	O
hydrophobic	O
domain	O
that	O
lies	O
adjacent	O
to	O
a	O
22	O
-	O
amino	O
acid	O
,	O
cytoplasmic	O
domain	O
at	O
the	O
carboxy	O
terminus	O
of	O
gp37	B-GENE
.	O

The	O
drug	O
was	O
given	O
in	O
a	O
daily	O
oral	O
dose	O
of	O
0	O
.	O
5	O
g	O
/	O
m2	O
,	O
3	O
.	O
5	O
h	O
prior	O
to	O
each	O
radiation	O
treatment	O
.	O

Histogenetic	O
aspects	O
of	O
mesoblastic	O
nephroma	O
.	O

Effect	O
of	O
acute	O
and	O
chronic	O
psychogenic	O
stress	O
on	O
corticoadrenal	O
and	O
pituitary	B-GENE
-	I-GENE
thyroid	I-GENE
hormones	I-GENE
in	O
male	O
rats	O
.	O

An	O
intact	O
5	O
.	O
7	O
-	O
kb	O
provirus	O
of	O
the	O
avian	O
erythroblastosis	O
virus	O
E26	O
has	O
been	O
molecularly	O
cloned	O
for	O
comparisons	O
with	O
avian	O
myeloblastosis	O
virus	O
(	O
AMV	O
)	O
and	O
other	O
avian	O
tumor	O
viruses	O
.	O

It	O
is	O
concluded	O
that	O
haloperidol	O
selectively	O
reduced	O
the	O
animal	O
'	O
s	O
capacity	O
to	O
'	O
programme	O
non	O
-	O
stimulus	O
directed	O
motor	O
behaviour	O
'	O
.	O

Neither	O
side	O
effect	O
nor	O
abnormal	O
laboratory	O
findings	O
due	O
to	O
this	O
drug	O
were	O
observed	O
.	O

The	O
results	O
presented	O
in	O
this	O
report	O
suggest	O
that	O
the	O
SV40	O
G	O
-	O
C	O
-	O
rich	O
sequences	O
can	O
function	O
as	O
independent	O
RNA	B-GENE
polymerase	I-GENE
II	I-GENE
transcriptional	O
-	O
control	O
elements	O
.	O

Construction	O
of	O
human	O
cell	O
lines	O
which	O
contain	O
and	O
express	O
the	O
adenovirus	O
DNA	O
binding	O
protein	O
gene	O
by	O
cotransformation	O
with	O
the	O
HSV	B-GENE
-	I-GENE
1	I-GENE
tk	I-GENE
gene	I-GENE
.	O

Diagnosis	O
and	O
treatment	O
of	O
insulin	B-GENE
-	O
secreting	O
tumours	O
.	O

Theories	O
proffered	O
to	O
account	O
for	O
the	O
modality	O
shift	O
effect	O
are	O
critically	O
evaluated	O
.	O

The	O
effects	O
of	O
cardioselective	O
beta	O
-	O
1	O
adrenergic	O
agonist	O
,	O
1	O
-	O
(	O
4	O
-	O
hydroxyphenoxy	O
)	O
-	O
isopropylamino	O
-	O
2	O
-	O
propanol	O
)	O
,	O
i	O
.	O
e	O
.	O
,	O
prenalterol	O
,	O
were	O
examined	O
on	O
direct	O
and	O
continuous	O
measurements	O
of	O
left	O
ventricular	O
(	O
LV	O
)	O
pressure	O
,	O
diameter	O
,	O
dP	O
/	O
dt	O
,	O
velocity	O
of	O
shortening	O
,	O
arterial	O
pressure	O
,	O
iliac	O
blood	O
flow	O
and	O
heart	O
rate	O
in	O
10	O
conscious	O
dogs	O
.	O

Endorphins	B-GENE
at	O
the	O
approach	O
of	O
death	O
.	O

Trial	O
treatment	O
of	O
schizophrenia	O
with	O
des	B-GENE
-	I-GENE
Tyr	I-GENE
-	I-GENE
gamma	I-GENE
-	I-GENE
endorphin	I-GENE

Cardiac	O
taurine	O
levels	O
and	O
sarcolemmal	O
calcium	O
binding	O
activity	O
in	O
furazolidone	O
-	O
induced	O
cardiomyopathy	O
.	O

Separation	O
of	O
malaria	O
-	O
infected	O
erythrocytes	O
from	O
whole	O
blood	O
:	O
use	O
of	O
a	O
selective	O
high	O
-	O
gradient	O
magnetic	O
separation	O
technique	O
.	O

The	O
roll	O
-	O
over	O
test	O
to	O
predict	O
toxemia	O
in	O
pregnancy	O
.	O

Can	O
thyroglobulin	B-GENE
assay	O
really	O
supplant	O
radioiodine	O
scans	O
in	O
patients	O
with	O
differentiated	O
thyroid	O
cancer	O
?	O

3	O
Significant	O
reductions	O
in	O
lying	O
mean	O
arterial	O
blood	O
pressure	O
were	O
observed	O
with	O
daily	O
doses	O
of	O
200	O
mg	O
(	O
-	O
9	O
%	O
)	O
,	O
400	O
mg	O
(	O
-	O
10	O
%	O
)	O
and	O
800	O
mg	O
(	O
-	O
14	O
%	O
)	O
,	O
and	O
were	O
associated	O
with	O
significant	O
decreases	O
in	O
heart	O
rate	O
and	O
plasma	B-GENE
renin	I-GENE
activity	O
.	O

Isolation	O
of	O
Aeromonas	O
from	O
faeces	O
.	O

(	O
iii	O
)	O
The	O
mRNA	O
is	O
not	O
efficiently	O
polyadenylated	O
at	O
sequences	O
in	O
the	O
3	O
'	O
end	O
of	O
the	O
DHFR	B-GENE
cDNA	I-GENE
but	O
rather	O
uses	O
polyadenylation	O
signals	O
downstream	O
from	O
the	O
DHFR	B-GENE
cDNA	I-GENE
.	O

At	O
both	O
water	O
temperatures	O
,	O
VO2	O
increased	O
linearly	O
with	O
increasing	O
swimming	O
velocity	O
.	O

Brief	O
report	O
.	O

Hybrid	O
-	O
selection	O
experiments	O
against	O
total	O
PB	O
-	O
inducible	O
RNA	O
were	O
performed	O
with	O
plasmid	O
DNA	O
derived	O
from	O
clones	O
enriched	O
in	O
PB	O
-	O
inducible	O
information	O
.	O

Risk	O
of	O
HTLV	O
infection	O
in	O
patients	O
on	O
haemodialysis	O
.	O

In	O
vitro	O
metabolism	O
of	O
progesterone	O
by	O
the	O
human	O
undescended	O
testis	O
.	O

Two	O
patients	O
withdrew	O
from	O
therapy	O
,	O
one	O
for	O
personal	O
reasons	O
and	O
one	O
because	O
a	O
paraspinal	O
mass	O
developed	O
.	O

All	O
patients	O
received	O
VCR	O
1	O
.	O
0	O
mg	O
/	O
m2	O
weekly	O
for	O
6	O
weeks	O
with	O
dose	O
modification	O
for	O
neurotoxicity	O
.	O

Glutamic	O
acid	O
in	O
a	O
dose	O
of	O
1	O
/	O
100	O
of	O
the	O
LD50	O
was	O
injected	O
in	O
the	O
form	O
of	O
sodium	O
salt	O
into	O
male	O
and	O
female	O
Wistar	O
rats	O
for	O
7	O
days	O
after	O
8	O
-	O
and	O
12	O
-	O
day	O
injections	O
of	O
dexazone	O
.	O

Serum	O
ascorbic	O
acid	O
had	O
an	O
inverse	O
and	O
the	O
strongest	O
association	O
with	O
systolic	O
blood	O
pressure	O
among	O
the	O
risk	O
factors	O
including	O
blood	O
pressure	O
,	O
total	O
cholesterol	O
,	O
triglyceride	O
,	O
gamma	B-GENE
-	I-GENE
GTP	I-GENE
and	O
obesity	O
.	O

Effect	O
of	O
bromazepam	O
on	O
growth	B-GENE
hormone	I-GENE
and	O
prolactin	B-GENE
secretion	O
in	O
normal	O
subjects	O
.	O

In	O
several	O
cases	O
of	O
definite	O
SjS	O
,	O
labial	O
salivary	O
gland	O
examinations	O
after	O
more	O
than	O
a	O
one	O
year	O
interval	O
were	O
performed	O
on	O
two	O
occasions	O
,	O
and	O
the	O
clinical	O
and	O
histopathological	O
changes	O
were	O
investigated	O
.	O

All	O
radiologists	O
using	O
the	O
machine	O
found	O
that	O
the	O
reporting	O
terminal	O
was	O
simple	O
to	O
operate	O
,	O
but	O
found	O
that	O
reporting	O
abnormalities	O
caused	O
an	O
increased	O
effort	O
and	O
took	O
a	O
longer	O
time	O
.	O

Thalamotomy	O
aiming	O
at	O
the	O
CM	O
-	O
Pf	O
complex	O
and	O
using	O
stereotactic	O
gamma	O
irradiation	O
has	O
been	O
performed	O
in	O
a	O
series	O
of	O
52	O
patients	O
with	O
severe	O
pain	O
due	O
to	O
malignancy	O
.	O

2	O
Silastic	O
capsules	O
,	O
each	O
containing	O
22	O
-	O
23	O
mg	O
of	O
ethinyl	O
estradiol	O
,	O
were	O
inserted	O
subcutaneously	O
in	O
5	O
men	O
with	O
benign	O
prostatic	O
hypertrophy	O
.	O

When	O
used	O
subcutaneously	O
or	O
intravenously	O
in	O
maximum	O
tolerated	O
doses	O
the	O
antibiotic	O
inhibited	O
the	O
development	O
of	O
lymphadenosis	O
NK	O
/	O
Li	O
by	O
90	O
and	O
70	O
per	O
cent	O
respectively	O
.	O

Effect	O
of	O
2	O
-	O
(	O
p	O
-	O
chlorophenyl	O
)	O
cyclopropylamine	O
on	O
5	O
-	O
hydroxyindole	O
concentration	O
and	O
monoamine	B-GENE
oxidase	I-GENE
activity	O
in	O
rat	O
brain	O
.	O

Then	O
,	O
pure	O
pancreatic	O
juice	O
was	O
infused	O
into	O
the	O
duodenum	O
.	O

An	O
experiment	O
was	O
carried	O
on	O
133	O
grown	O
up	O
fowls	O
and	O
broilers	O
from	O
4	O
industrial	O
farms	O
,	O
vaccinated	O
with	O
spray	O
lento	O
and	O
mesogenic	O
vaccines	O
for	O
straining	O
the	O
immunity	O
against	O
pseodopest	O
through	O
RIHA	O
and	O
provoking	O
pseudoplague	O
with	O
a	O
pathogenic	O
virus	O
.	O

(	O
2	O
)	O
The	O
inappropriateness	O
of	O
adaptive	O
segmentation	O
for	O
the	O
isolation	O
of	O
spikes	O
and	O
sharp	O
waves	O
,	O
which	O
had	O
been	O
anticipated	O
in	O
view	O
of	O
the	O
short	O
duration	O
of	O
such	O
transients	O
in	O
relation	O
to	O
the	O
length	O
of	O
the	O
window	O
(	O
1	O
.	O
2	O
sec	O
)	O
used	O
for	O
the	O
autocorrelation	O
functions	O
employed	O
in	O
the	O
segmentation	O
algorithm	O
,	O
was	O
confirmed	O
.	O

The	O
ability	O
of	O
chronic	O
UM	O
-	O
272	O
(	O
dimethylpropranolol	O
)	O
treatment	O
to	O
prevent	O
the	O
induction	O
of	O
reentrant	O
ventricular	O
tachyarrhythmias	O
was	O
assessed	O
in	O
the	O
conscious	O
dog	O
subjected	O
to	O
serial	O
programmed	O
electrical	O
stimulation	O
on	O
days	O
3	O
-	O
-	O
5	O
after	O
myocardial	O
infarction	O
.	O

The	O
effect	O
of	O
echothiophate	O
on	O
the	O
biphasic	O
response	O
of	O
rabbit	O
ocular	O
pressure	O
to	O
dipivefrin	O
.	O

In	O
most	O
cases	O
of	O
acute	O
transmural	O
infarction	O
,	O
the	O
reciprocal	O
ST	O
segment	O
depressions	O
observed	O
in	O
contralateral	O
leads	O
are	O
less	O
marked	O
than	O
the	O
primary	O
ST	O
segment	O
elevations	O
.	O

Bacillus	O
cereus	O
cross	O
-	O
infection	O
in	O
a	O
maternity	O
-	O
unit	O
.	O

In	O
the	O
latter	O
category	O
particular	O
emphasis	O
is	O
being	O
placed	O
on	O
new	O
anthracycline	O
analogues	O
of	O
doxorubicin	O
and	O
analogues	O
of	O
cisplatinum	O
diammine	O
dichloride	O
.	O

Late	O
mRNA	O
selected	O
by	O
a	O
cDNA	O
homologous	O
to	O
the	O
HindIII	B-GENE
-	I-GENE
P	I-GENE
/	O
EcoRI	B-GENE
-	I-GENE
B	I-GENE
region	O
of	O
the	O
AcNPV	O
map	O
directed	O
the	O
synthesis	O
of	O
31K	O
and	O
30K	O
proteins	O
which	O
comigrated	O
with	O
the	O
31K	O
and	O
30K	O
proteins	O
translated	O
from	O
RNA	O
selected	O
by	O
the	O
HindIII	B-GENE
-	I-GENE
A	I-GENE
/	O
EcoRI	B-GENE
-	I-GENE
C	I-GENE
/	O
SstI	B-GENE
-	I-GENE
G	I-GENE
cDNA	O
.	O

Intraoperatively	O
the	O
complement	B-GENE
factor	I-GENE
C3c	I-GENE
decreased	O
by	O
20	O
%	O
,	O
while	O
alpha	B-GENE
1	I-GENE
-	I-GENE
antitrypsin	I-GENE
showed	O
postoperatively	O
an	O
increase	O
by	O
30	O
%	O
.	O

A	O
polypeptide	O
chain	O
of	O
34	O
residues	O
of	O
the	O
deduced	O
yeast	O
amino	O
acid	O
sequence	O
closely	O
resembles	O
a	O
peptide	O
sequence	O
at	O
the	O
ADP	O
binding	O
site	O
of	O
bovine	B-GENE
muscle	I-GENE
pyruvate	I-GENE
kinase	I-GENE
.	O

The	O
P165	O
component	O
,	O
however	O
,	O
could	O
be	O
differentiated	O
from	O
the	O
two	O
later	O
components	O
since	O
it	O
increased	O
in	O
amplitude	O
with	O
increased	O
task	O
demands	O
while	O
the	O
N2	O
and	O
P3	O
amplitudes	O
remained	O
constant	O
.	O

Differential	O
drawing	O
size	O
associated	O
with	O
unilateral	O
brain	O
damage	O
.	O

The	O
intracoronary	O
administration	O
of	O
both	O
drugs	O
markedly	O
reduced	O
the	O
incidence	O
of	O
VF	O
induced	O
by	O
the	O
release	O
of	O
a	O
40	O
-	O
min	O
coronary	O
artery	O
occlusion	O
.	O

These	O
fusions	O
are	O
contained	O
on	O
plasmids	O
which	O
have	O
both	O
yeast	O
and	O
E	O
.	O
coli	O
replication	O
origins	O
and	O
selectable	O
markers	O
and	O
,	O
therefore	O
,	O
can	O
be	O
used	O
to	O
transform	O
either	O
yeast	O
or	O
E	O
.	O
coli	O
cells	O
.	O

Therefore	O
,	O
it	O
was	O
concluded	O
that	O
thrombotic	O
tendency	O
certainly	O
existed	O
in	O
patients	O
with	O
MS	O
compared	O
to	O
those	O
with	O
non	O
RHD	O
and	O
that	O
it	O
was	O
one	O
of	O
the	O
causes	O
of	O
the	O
significantly	O
high	O
incidence	O
of	O
thromboembolism	O
in	O
comparison	O
with	O
non	O
RHD	O
.	O

Subdural	O
electrodes	O
may	O
yield	O
larger	O
VEP	O
amplitudes	O
than	O
skull	O
or	O
scalp	O
electrodes	O
.	O

Products	O
of	O
immune	O
cells	O
such	O
as	O
transfer	B-GENE
factor	I-GENE
and	O
lymphokines	O
form	O
the	O
third	O
and	O
possibly	O
most	O
important	O
group	O
of	O
immune	O
-	O
stimulating	O
agents	O
.	O

Use	O
of	O
the	O
immunofluorescence	O
method	O
for	O
identification	O
of	O
enteroviruses	O
in	O
cell	O
cultures	O

This	O
fraction	O
is	O
resistant	O
to	O
digestions	O
by	O
DNase	B-GENE
I	I-GENE
and	O
RNase	B-GENE
T1	I-GENE
and	O
disappears	O
completely	O
upon	O
alkali	O
hydrolysis	O
.	O

The	O
construction	O
of	O
a	O
small	O
library	O
of	O
mouse	O
repetitive	O
DNA	O
has	O
been	O
previously	O
reported	O
(	O
Pietras	O
et	O
al	O
.	O
,	O
Nucleic	O
Acids	O
Res	O
.	O

No	O
direct	O
repeats	O
flank	O
the	O
pseudogene	O
in	O
the	O
U2	B-GENE
/	I-GENE
4	I-GENE
locus	I-GENE
.	O

The	O
direct	O
effects	O
of	O
transmitter	O
release	O
were	O
(	O
a	O
)	O
an	O
early	O
fall	O
in	O
MAP	O
followed	O
by	O
a	O
late	O
pressor	O
effect	O
;	O
and	O
(	O
b	O
)	O
an	O
early	O
bradycardia	O
followed	O
by	O
a	O
late	O
tachycardia	O
.	O

The	O
number	O
of	O
elements	O
and	O
their	O
sizes	O
relative	O
to	O
the	O
configuration	O
were	O
varied	O
in	O
a	O
series	O
of	O
five	O
experiments	O
.	O

In	O
addition	O
,	O
the	O
overall	O
chance	O
that	O
a	O
patient	O
would	O
undergo	O
ET	O
was	O
greater	O
in	O
a	O
cycle	O
in	O
which	O
more	O
than	O
one	O
follicle	O
20	O
mm	O
or	O
larger	O
was	O
developing	O
than	O
in	O
a	O
cycle	O
in	O
which	O
a	O
single	O
large	O
follicle	O
was	O
developing	O
.	O

Five	O
of	O
the	O
patients	O
with	O
increased	O
L	O
-	O
L	O
size	O
had	O
a	O
normal	O
A	O
-	O
P	O
diameter	O
.	O

Immunochemotherapy	O
with	O
schizophyllan	O
(	O
SPG	O
)	O
combined	O
with	O
chemotherapeutic	O
agents	O
was	O
evaluated	O
in	O
two	O
syngeneic	O
tumor	O
-	O
C3H	O
/	O
He	O
mouse	O
systems	O
.	O

However	O
,	O
when	O
combined	O
with	O
mitomycin	O
C	O
given	O
with	O
1	O
to	O
5	O
-	O
days	O
interval	O
,	O
the	O
concurrent	O
administration	O
of	O
SPG	O
prolonged	O
significantly	O
the	O
life	O
-	O
span	O
of	O
the	O
tumor	O
-	O
bearing	O
mice	O
.	O

Data	O
are	O
presented	O
hinting	O
that	O
the	O
15	O
beta	O
-	O
hydroxy	O
-	O
,	O
metabolite	O
of	O
CPA	O
may	O
actually	O
be	O
the	O
biologically	O
active	O
agent	O
.	O

In	O
contrast	O
,	O
in	O
LL	O
patients	O
during	O
ENL	O
the	O
ConA	B-GENE
-	O
induced	O
suppressor	O
response	O
was	O
markedly	O
reduced	O
.	O

Functional	O
characterization	O
of	O
a	O
fraction	O
identified	O
by	O
its	O
activity	O
in	O
a	O
second	O
template	O
rescue	O
assay	O
.	O

It	O
has	O
been	O
established	O
that	O
preoperative	O
irradiation	O
in	O
the	O
form	O
of	O
the	O
fractionation	O
of	O
a	O
single	O
focal	O
dose	O
of	O
6	O
Gy	O
every	O
other	O
day	O
,	O
the	O
summary	O
dose	O
of	O
24	O
Gy	O
within	O
8	O
-	O
10	O
days	O
followed	O
by	O
surgery	O
1	O
-	O
3	O
days	O
after	O
irradiation	O
does	O
not	O
either	O
complicate	O
its	O
performance	O
or	O
the	O
course	O
of	O
the	O
postoperative	O
period	O
,	O
and	O
by	O
the	O
short	O
-	O
and	O
long	O
-	O
term	O
results	O
it	O
is	O
no	O
worse	O
than	O
the	O
routine	O
dose	O
fractionation	O
.	O

Fibrin	B-GENE
gels	O
and	O
their	O
possible	O
implication	O
for	O
surface	O
hemorheology	O
in	O
health	O
and	O
disease	O
.	O

Hepatitis	O
-	O
B	O
vaccination	O
in	O
the	O
elderly	O
.	O

Radiogallium	O
imaging	O
is	O
thus	O
of	O
limited	O
use	O
in	O
evaluation	O
of	O
suspected	O
giant	O
cell	O
tumors	O
of	O
bone	O
.	O

Ventricular	O
volume	O
stiffness	O
vs	O
.	O
the	O
mean	O
wall	O
stress	O
relationship	O
of	O
LVH	O
shifted	O
upward	O
,	O
whereas	O
the	O
normalized	O
wall	O
muscle	O
stiffness	O
vs	O
.	O
the	O
mean	O
wall	O
stress	O
relationship	O
of	O
LVH	O
showed	O
a	O
smaller	O
slope	O
.	O

Synthesis	O
of	O
(	O
+	O
)	O
-	O
lysergic	O
acid	O
diethylamide	O
tartrate	O

Weight	O
loss	O
reduces	O
arterial	O
pressure	O
by	O
a	O
decrease	O
in	O
intravascular	O
volume	O
and	O
cardiac	O
output	O
associated	O
with	O
a	O
fall	O
in	O
sympathetic	O
activity	O
.	O

The	O
effect	O
of	O
treatment	O
may	O
thus	O
be	O
divided	O
into	O
two	O
main	O
phases	O
-	O
-	O
an	O
initial	O
phase	O
with	O
a	O
reduction	O
in	O
LV	O
mass	O
and	O
a	O
reduction	O
in	O
cardiac	O
output	O
and	O
no	O
change	O
in	O
total	O
peripheral	O
resistance	O
-	O
-	O
and	O
a	O
second	O
phase	O
with	O
a	O
constant	O
LV	O
mass	O
but	O
an	O
increase	O
in	O
cardiac	O
output	O
to	O
the	O
pretreatment	O
level	O
again	O
and	O
a	O
concomitant	O
decrease	O
in	O
total	O
peripheral	O
resistance	O
.	O

This	O
study	O
was	O
undertaken	O
to	O
assess	O
the	O
effects	O
of	O
hypothermia	O
and	O
chemical	O
cardioplegia	O
on	O
the	O
functional	O
recovery	O
of	O
hypertrophied	O
non	O
-	O
failing	O
rat	O
hearts	O
subjected	O
to	O
an	O
extended	O
period	O
of	O
global	O
ischaemia	O
.	O

Oxygen	O
profiles	O
calculated	O
for	O
the	O
Krogh	O
model	O
with	O
excentric	O
diffusion	O
were	O
similar	O
to	O
those	O
derived	O
for	O
the	O
two	O
models	O
of	O
concentric	O
diffusion	O
.	O

Cultivation	O
technics	O
for	O
Codonopsis	O
pilosula	O

Radioimmunoassay	O
of	O
serum	O
creatine	B-GENE
kinase	I-GENE
B	I-GENE
isoenzyme	I-GENE
in	O
the	O
diagnosis	O
of	O
acute	O
myocardial	O
infarction	O
.	O

Selective	O
macrophage	O
inhibition	O
abolishes	O
warfarin	O
-	O
induced	O
reduction	O
of	O
metastasis	O
.	O

Restriction	O
enzyme	O
and	O
heteroduplex	O
analyses	O
confirmed	O
that	O
sequences	O
unique	O
to	O
FeSV	O
(	O
src	B-GENE
sequences	I-GENE
)	O
are	O
located	O
at	O
the	O
center	O
of	O
the	O
FeSV	O
genome	O
and	O
are	O
approximately	O
1	O
.	O
5	O
kilobase	O
pairs	O
in	O
length	O
.	O

Catecholamines	O
and	O
aversive	O
learning	O
:	O
a	O
review	O
.	O

A	O
haemolytic	O
enterotoxigenic	O
strain	O
of	O
E	O
.	O
coli	O
(	O
O149	O
:	O
K88	O
:	O
H10	O
)	O
was	O
regularly	O
recovered	O
from	O
piglets	O
with	O
PWD	O
while	O
rotavirus	O
was	O
demonstrated	O
on	O
a	O
number	O
of	O
occasions	O
.	O

The	O
antibody	O
titer	O
of	O
202	O
chickens	O
to	O
SA	O
-	O
11	O
rotavirus	O
was	O
determined	O
by	O
enzyme	O
-	O
linked	O
immunosorbent	O
blocking	O
assay	O
.	O

Poly	O
(	O
dT	O
)	O
and	O
denatured	O
calf	O
thymus	O
DNA	O
were	O
more	O
effective	O
than	O
were	O
other	O
polynucleotides	O
tested	O
in	O
promoting	O
accumulation	O
of	O
19	O
HDP	B-GENE
*	I-GENE
;	O
(	O
dT	O
)	O
8	O
was	O
as	O
effective	O
as	O
were	O
longer	O
molecules	O
of	O
(	O
dT	O
)	O
n	O
,	O
but	O
(	O
dT	O
)	O
4	O
and	O
(	O
dT	O
)	O
6	O
were	O
much	O
less	O
effective	O
,	O
indicating	O
that	O
the	O
binding	O
site	O
involved	O
in	O
19	O
HDP	B-GENE
*	I-GENE
accumulation	O
covered	O
between	O
6	O
and	O
8	O
residues	O
of	O
(	O
dT	O
)	O
n	O
.	O

A	O
double	O
-	O
blind	O
trial	O
of	O
half	O
-	O
strength	O
Polybactrin	O
Soluble	O
GU	O
bladder	O
irrigation	O
in	O
cystoscopy	O
.	O

Thus	O
it	O
appears	O
that	O
insertion	O
of	O
a	O
transposable	O
element	O
near	O
the	O
5	O
'	O
terminus	O
of	O
the	O
structural	O
gene	O
can	O
produce	O
constitutive	O
expression	O
of	O
a	O
normally	O
glucose	O
-	O
repressed	O
enzyme	O
.	O

Five	O
experiments	O
examined	O
the	O
influence	O
of	O
opiate	O
antagonists	O
on	O
both	O
the	O
short	O
-	O
term	O
analgesic	O
reaction	O
resulting	O
30	O
min	O
after	O
exposure	O
to	O
inescapable	O
shock	O
and	O
the	O
long	O
-	O
term	O
analgesic	O
reaction	O
resulting	O
after	O
reexposure	O
to	O
shock	O
24	O
hr	O
after	O
inescapable	O
shock	O
exposure	O
.	O

Experiment	O
3	O
showed	O
that	O
the	O
long	O
-	O
term	O
analgesic	O
reaction	O
could	O
also	O
be	O
reduced	O
by	O
administration	O
of	O
naltrexone	O
prior	O
to	O
reexposure	O
to	O
shock	O
.	O

A	O
22K	O
polypeptide	O
was	O
detected	O
as	O
a	O
translation	O
product	O
of	O
late	O
RNA	O
that	O
hybridized	O
to	O
this	O
DNA	O
fragment	O
.	O

Replicating	O
simian	O
virus	O
40	O
(	O
SV40	O
)	O
chromosomes	O
were	O
found	O
to	O
be	O
similar	O
to	O
other	O
eukaryotic	O
chromosomes	O
in	O
that	O
the	O
rate	O
and	O
extent	O
of	O
micrococcal	B-GENE
nuclease	I-GENE
(	O
MNase	B-GENE
)	O
digestion	O
were	O
greater	O
with	O
replicating	O
than	O
with	O
nonreplicating	O
mature	O
SV40	O
chromatin	O
.	O

A	O
hypothesis	O
.	O

Physiology	O
and	O
Physiopathology	O

The	O
genome	O
of	O
avian	O
erythroblastosis	O
virus	O
contains	O
two	O
independently	O
expressed	O
genetic	O
loci	O
(	O
v	B-GENE
-	I-GENE
erbA	I-GENE
and	O
v	B-GENE
-	I-GENE
erbB	I-GENE
)	O
whose	O
activities	O
are	O
probably	O
responsible	O
for	O
oncogenesis	O
by	O
the	O
virus	O
.	O

Because	O
RNase	B-GENE
III	I-GENE
host	I-GENE
mutants	I-GENE
are	O
defective	O
in	O
sib	B-GENE
regulation	O
,	O
processing	O
of	O
the	O
PL	B-GENE
mRNA	I-GENE
at	O
sib	B-GENE
by	O
this	O
endoribonuclease	O
may	O
cause	O
int	B-GENE
mRNA	I-GENE
decay	O
and	O
decrease	O
int	B-GENE
synthesis	O
.	O

At	O
least	O
one	O
clone	O
,	O
lambda	O
HHG	O
41	O
,	O
contains	O
,	O
in	O
addition	O
to	O
the	O
histone	B-GENE
genes	I-GENE
,	O
a	O
region	O
that	O
hybridizes	O
with	O
a	O
cytoplasmic	O
RNA	O
approximately	O
330	O
nucleotides	O
in	O
length	O
.	O

Both	O
neural	O
and	O
hormonal	O
pathways	O
and	O
both	O
opiate	O
and	O
nonopiate	O
substances	O
play	O
roles	O
in	O
the	O
complex	O
modulation	O
of	O
pain	O
transmission	O
.	O

Restoration	O
of	O
impaired	O
immune	O
functions	O
in	O
aging	O
animals	O
.	O

Postoperative	O
serum	O
ACTH	B-GENE
levels	O
were	O
normal	O
.	O

In	O
fact	O
,	O
families	O
of	O
polypeptides	O
were	O
produced	O
by	O
initiation	O
of	O
translation	O
at	O
AUG	O
codons	O
within	O
sequences	O
coding	O
for	O
VP1	B-GENE
and	O
T	B-GENE
,	O
presumably	O
as	O
a	O
result	O
of	O
transcription	O
initiation	O
events	O
that	O
generated	O
5	O
'	O
ends	O
immediately	O
upstream	O
from	O
these	O
AUGs	O
.	O

In	O
addition	O
,	O
TRP1	B-GENE
RI	O
Circle	O
DNA	O
is	O
organized	O
into	O
nucleosomes	O
whose	O
size	O
and	O
spacing	O
are	O
indistinguishable	O
from	O
that	O
of	O
bulk	O
yeast	O
chromatin	O
.	O

The	O
frequency	O
of	O
previous	O
transfusion	O
in	O
chronic	O
hepatitis	O
,	O
cirrhosis	O
and	O
hepatocellular	O
carcinoma	O
of	O
type	O
NANB	O
was	O
42	O
.	O
8	O
,	O
37	O
.	O
1	O
and	O
15	O
.	O
1	O
%	O
,	O
respectively	O
,	O
whereas	O
the	O
incidence	O
of	O
early	O
posttransfusion	O
hepatitis	O
was	O
8	O
.	O
5	O
,	O
8	O
.	O
6	O
and	O
7	O
.	O
5	O
%	O
,	O
respectively	O
.	O
in	O
chronic	O
liver	O
diseases	O
with	O
a	O
history	O
of	O
jaundice	O
and	O
/	O
or	O
hepatitis	O
,	O
previous	O
transfusions	O
are	O
more	O
frequently	O
associated	O
with	O
type	O
NANB	O
than	O
with	O
type	O
B	O
disease	O
.	O

Of	O
115	O
hepatitis	O
B	O
patients	O
seen	O
at	O
12	O
months	O
,	O
6	O
%	O
had	O
chronic	O
hepatitis	O
Bs	O
antigenaemia	O
,	O
60	O
%	O
had	O
developed	O
anti	B-GENE
-	I-GENE
HBs	I-GENE
antibodies	I-GENE
,	O
and	O
7	O
.	O
3	O
%	O
still	O
had	O
abnormal	O
liver	O
function	O
.	O

Survey	O
on	O
antibody	O
against	O
egg	O
drop	O
syndrome	O
-	O
1976	O
virus	O
among	O
chicken	O
flocks	O
in	O
Japan	O
.	O

In	O
49	O
patients	O
in	O
whom	O
gated	O
equilibrium	O
ventriculography	O
and	O
cardiac	O
catheterization	O
were	O
performed	O
within	O
a	O
6	O
day	O
interval	O
,	O
total	O
and	O
fractional	O
portions	O
of	O
global	O
and	O
regional	O
right	O
ventricular	O
ejection	O
fraction	O
(	O
RVEF	O
)	O
were	O
correlated	O
with	O
pulmonary	O
arterial	O
systolic	O
pressure	O
.	O

74	O
,	O
193	O
-	O
197	O
)	O
.	O

The	O
combination	O
of	O
MISO	O
and	O
WR	O
-	O
2721	O
gave	O
an	O
intermediate	O
response	O
compared	O
with	O
either	O
drug	O
used	O
alone	O
,	O
resulting	O
in	O
some	O
sensitization	O
with	O
single	O
doses	O
and	O
an	O
overall	O
protection	O
with	O
repeated	O
small	O
doses	O
.	O

Two	O
mutations	O
that	O
affect	O
larval	B-GENE
cuticle	I-GENE
protein	I-GENE
gene	I-GENE
expression	O
in	O
the	O
2	O
/	O
3	O
variant	O
Drosophila	O
melanogaster	O
strain	O
were	O
investigated	O
.	O

A	O
cDNA	O
cloning	O
vector	O
that	O
permits	O
expression	O
of	O
cDNA	O
inserts	O
in	O
mammalian	O
cells	O
.	O

Hybridization	O
of	O
plasmid	O
-	O
transformed	O
Escherichia	O
coli	O
RR1	O
colonies	O
with	O
32P	O
-	O
labeled	O
viral	O
genome	O
RNAs	O
demonstrated	O
the	O
presence	O
of	O
DNA	O
clones	O
representative	O
of	O
each	O
of	O
the	O
10	O
reovirus	O
RNAs	O
and	O
10	O
of	O
the	O
11	O
constituent	O
segments	O
of	O
the	O
rotavirus	O
genome	O
.	O

Another	O
sequence	O
,	O
GGGXGGAG	O
,	O
which	O
is	O
repeated	O
several	O
times	O
in	O
many	O
polyomaviruses	O
and	O
adenoviruses	O
,	O
and	O
which	O
is	O
thought	O
to	O
play	O
a	O
role	O
in	O
DNA	O
replication	O
and	O
/	O
or	O
transcription	O
,	O
is	O
not	O
found	O
in	O
the	O
JCV	O
sequence	O
presented	O
.	O

Lung	O
density	O
increased	O
in	O
quartz	O
-	O
exposed	O
,	O
but	O
not	O
in	O
volcanic	O
-	O
ash	O
-	O
exposed	O
animals	O
.	O

The	O
hepatitis	B-GENE
A	I-GENE
virus	I-GENE
antibody	I-GENE
(	O
anti	B-GENE
-	I-GENE
HAV	I-GENE
)	O
in	O
chronic	O
diffuse	O
liver	O
diseases	O

The	O
junctions	O
between	O
viral	O
and	O
cellular	O
sequences	O
were	O
determined	O
by	O
DNA	O
sequence	O
analysis	O
to	O
be	O
517	O
nucleotides	O
into	O
the	O
p30	B-GENE
sequence	I-GENE
and	O
1	O
,	O
920	O
nucleotides	O
into	O
the	O
polymerase	O
sequence	O
.	O

Naloxone	O
(	O
2	O
mg	O
/	O
kg	O
bolus	O
+	O
2	O
mg	O
X	O
kg	O
-	O
1	O
X	O
h	O
-	O
1	O
)	O
was	O
given	O
with	O
one	O
of	O
the	O
two	O
doses	O
of	O
the	O
lipopolysaccharide	O
.	O

I	O
.	O

Viral	O
RNA	O
,	O
molecularly	O
cloned	O
proviral	O
DNA	O
,	O
and	O
virus	O
-	O
specific	O
protein	O
of	O
avian	O
retrovirus	O
MH2	O
were	O
analyzed	O
.	O

Intracellular	O
recordings	O
were	O
performed	O
on	O
the	O
optic	O
tectum	O
of	O
the	O
carp	O
in	O
vitro	O
.	O

Molecular	O
structure	O
and	O
evolutionary	O
origin	O
of	O
human	B-GENE
cardiac	I-GENE
muscle	I-GENE
actin	I-GENE
gene	I-GENE
.	O

The	O
mutants	O
were	O
obtained	O
by	O
substitution	O
into	O
a	O
molecular	O
clone	O
of	O
M	O
-	O
MuLV	O
DNA	O
by	O
DNA	O
from	O
two	O
acutely	O
transforming	O
viruses	O
,	O
Ableson	O
MuLV	O
(	O
Ab	O
-	O
MuLV	O
)	O
and	O
Moloney	O
murine	O
sarcoma	O
virus	O
(	O
M	O
-	O
MSV	O
)	O
.	O

Plasmids	O
for	O
the	O
cloning	O
and	O
expression	O
of	O
full	O
-	O
length	O
double	O
-	O
stranded	O
cDNAs	O
under	O
control	O
of	O
the	O
SV40	B-GENE
early	I-GENE
or	O
late	B-GENE
gene	I-GENE
promoter	O
.	O

Supplementing	O
a	O
soybean	O
protein	O
and	O
sucrose	O
-	O
based	O
diet	O
with	O
levels	O
of	O
2	O
.	O
2	O
,	O
11	O
,	O
and	O
55	O
ppm	O
of	O
the	O
antibiotic	O
,	O
from	O
the	O
two	O
sources	O
each	O
with	O
two	O
different	O
purities	O
,	O
improved	O
weight	O
gain	O
of	O
chicks	O
an	O
average	O
of	O
23	O
%	O
and	O
improved	O
feed	O
efficiency	O
an	O
average	O
of	O
13	O
%	O
at	O
the	O
higher	O
levels	O
(	O
all	O
P	O
less	O
than	O
.	O
01	O
)	O
.	O

Overall	O
prevalences	O
of	O
antibody	O
were	O
70	O
per	O
cent	O
in	O
cattle	O
,	O
67	O
per	O
cent	O
in	O
sheep	O
and	O
76	O
per	O
cent	O
in	O
goats	O
as	O
assessed	O
by	O
an	O
immunodiffusion	O
test	O
.	O

Expression	O
of	O
herpes	O
simplex	O
virus	O
beta	O
and	O
gamma	O
genes	O
integrated	O
in	O
mammalian	O
cells	O
and	O
their	O
induction	O
by	O
an	O
alpha	O
gene	O
product	O
.	O

The	O
splice	O
acceptor	O
site	O
is	O
ca	O
.	O

This	O
is	O
consistent	O
with	O
a	O
model	O
proposing	O
that	O
SSV	O
was	O
generated	O
by	O
recombination	O
between	O
proviral	O
DNA	O
of	O
a	O
simian	O
sarcoma	O
associated	O
virus	O
and	O
proto	B-GENE
-	I-GENE
sis	I-GENE
and	O
that	O
introns	O
were	O
spliced	O
out	O
subsequently	O
from	O
a	O
fused	O
viral	B-GENE
-	I-GENE
sis	I-GENE
messenger	I-GENE
RNA	I-GENE
.	O

We	O
conclude	O
that	O
,	O
with	O
autonomic	O
nervous	O
system	O
activity	O
intact	O
,	O
carotid	O
chemoreceptor	O
reflex	O
activation	O
can	O
elicit	O
an	O
absolute	O
reflexly	O
mediated	O
reduction	O
in	O
coronary	O
blood	O
flow	O
in	O
the	O
normal	O
,	O
conscious	O
dog	O
,	O
despite	O
an	O
increase	O
in	O
arterial	O
pressure	O
.	O

Female	O
subjects	O
,	O
including	O
both	O
normal	O
subjects	O
and	O
idiopathic	O
calcium	O
stone	O
-	O
formers	O
,	O
have	O
higher	O
urinary	O
cyclic	O
AMP	O
levels	O
than	O
their	O
male	O
counterparts	O
,	O
and	O
this	O
difference	O
is	O
significant	O
when	O
urinary	O
cyclic	O
AMP	O
is	O
expressed	O
in	O
the	O
units	O
mumol	O
/	O
g	O
of	O
creatinine	O
.	O

We	O
conclude	O
that	O
the	O
'	O
morning	O
dip	O
'	O
observed	O
in	O
asthmatic	O
patients	O
cannot	O
simply	O
be	O
explained	O
by	O
changes	O
in	O
cell	O
receptor	O
number	O
or	O
affinity	O
,	O
as	O
our	O
results	O
suggest	O
that	O
both	O
groups	O
have	O
intact	O
beta	B-GENE
-	I-GENE
adrenoceptor	I-GENE
function	O
.	O

The	O
effect	O
of	O
desipramine	O
probably	O
represents	O
inhibition	O
of	O
neuronal	O
uptake	O
and	O
that	O
of	O
amitriptyline	O
and	O
mianserin	O
blockade	O
of	O
neuronal	O
uptake	O
and	O
prejunctional	O
alpha	B-GENE
2	I-GENE
-	I-GENE
adrenoreceptors	I-GENE
.	O

We	O
conclude	O
that	O
the	O
gp54	B-GENE
structural	I-GENE
gene	I-GENE
is	O
required	O
for	O
initiation	O
or	O
amplification	O
of	O
the	O
splenic	O
erythroblast	O
hyperplasia	O
which	O
characterizes	O
the	O
preleukemic	O
phase	O
of	O
Rauscher	O
disease	O
.	O

Surgical	O
treatment	O
of	O
pulmonary	O
metastases	O
.	O

A	O
promoter	O
sequence	O
(	O
Goldberg	O
-	O
Hogness	O
or	O
TATA	O
box	O
)	O
is	O
situated	O
28	O
base	O
pairs	O
upstream	O
from	O
the	O
point	O
of	O
initiation	O
of	O
transcription	O
which	O
was	O
found	O
by	O
S1	B-GENE
nuclease	I-GENE
mapping	O
and	O
by	O
oligonucleotide	O
-	O
primed	O
reverse	O
transcription	O
of	O
rat	B-GENE
PTH	I-GENE
mRNA	I-GENE
.	O

Each	O
of	O
these	O
spliced	O
mRNAs	O
has	O
an	O
untranslated	O
leader	O
sequence	O
of	O
249	O
bases	O
and	O
a	O
single	O
intron	O
of	O
approximately	O
540	O
bases	O
which	O
are	O
contained	O
entirely	O
within	O
TRs	O
/	O
IRs	O
sequences	O
.	O

The	O
expression	O
of	O
chloramphenicol	B-GENE
acetyltransferase	I-GENE
was	O
detected	O
within	O
1	O
h	O
after	O
infection	O
of	O
cells	O
with	O
recombinant	O
virus	O
,	O
reflecting	O
the	O
early	O
nature	O
of	O
the	O
promoters	O
used	O
.	O

NPT	B-GENE
II	I-GENE
synthesis	O
,	O
measured	O
by	O
agar	O
plate	O
assays	O
of	O
kanamycin	O
resistance	O
and	O
by	O
immunoprecipitation	O
of	O
the	O
NPT	B-GENE
II	I-GENE
protein	I-GENE
,	O
was	O
repressed	O
in	O
the	O
presence	O
of	O
cysteine	O
and	O
derepressed	O
in	O
its	O
absence	O
.	O

A	O
computed	O
tomographic	O
scan	O
obtained	O
after	O
EOE	O
-	O
13	O
infusion	O
accurately	O
showed	O
the	O
perfusion	O
pattern	O
of	O
the	O
implanted	O
catheter	O
.	O

The	O
12	B-GENE
,	I-GENE
000	I-GENE
MW	I-GENE
(	I-GENE
12K	I-GENE
)	I-GENE
IE	I-GENE
polypeptide	I-GENE
encoded	O
by	O
IEmRNA	B-GENE
-	I-GENE
5	I-GENE
is	O
translated	O
from	O
an	O
88	O
codon	O
open	O
reading	O
frame	O
,	O
leaving	O
a	O
1200	O
base	O
3	O
'	O
non	O
-	O
translated	O
region	O
.	O

The	O
greatest	O
difference	O
between	O
the	O
Ad7	B-GENE
and	I-GENE
Ad5	I-GENE
DBPs	I-GENE
is	O
the	O
absence	O
,	O
in	O
the	O
Ad7	O
protein	O
,	O
of	O
12	O
amino	O
acids	O
located	O
between	O
the	O
two	O
functional	O
domains	O
in	O
the	O
Ad5	O
protein	O
(	O
amino	O
acids	O
151	O
-	O
162	O
)	O
.	O

No	O
significant	O
correlation	O
was	O
found	O
between	O
LVM	O
or	O
wall	O
thickness	O
and	O
body	O
surface	O
area	O
,	O
age	O
,	O
blood	O
pressure	O
,	O
heart	O
rate	O
,	O
cardiac	O
output	O
,	O
total	O
peripheral	O
resistance	O
and	O
left	O
ventricular	O
systolic	O
wall	O
stress	O
,	O
whereas	O
CD25	O
was	O
correlated	O
with	O
urinary	O
catecholamines	O
only	O
in	O
hypertensive	O
patients	O
(	O
r	O
=	O
0	O
.	O
606	O
,	O
p	O
less	O
than	O
0	O
.	O
001	O
)	O
.	O

Furthermore	O
,	O
no	O
Shine	O
-	O
Dalgarno	O
sequences	O
are	O
present	O
upstream	O
of	O
the	O
presumed	O
translational	O
start	O
codons	O
.	O

The	O
gene	B-GENE
cat	I-GENE
-	I-GENE
86	I-GENE
,	O
specifying	O
chloramphenicol	B-GENE
-	I-GENE
inducible	I-GENE
chloramphenicol	I-GENE
acetyltransferase	I-GENE
,	O
is	O
located	O
on	O
the	O
1	O
.	O
1	O
-	O
kilobase	O
cloned	O
DNA	O
.	O

The	O
myeloproliferative	O
sarcoma	O
virus	O
(	O
MPSV	O
)	O
was	O
derived	O
by	O
passage	O
of	O
Moloney	O
sarcoma	O
virus	O
(	O
Mo	O
-	O
MuSV	O
)	O
in	O
adult	O
mice	O
.	O

The	O
same	O
-	O
sized	O
EBNA	B-GENE
protein	I-GENE
(	I-GENE
approximately	I-GENE
78	I-GENE
,	I-GENE
000	I-GENE
)	I-GENE
was	O
made	O
after	O
transfection	O
with	O
BamHI	B-GENE
-	I-GENE
K	I-GENE
(	I-GENE
5	I-GENE
.	I-GENE
2	I-GENE
kilobase	I-GENE
pairs	I-GENE
[	I-GENE
kbp	I-GENE
]	I-GENE
)	I-GENE
or	O
the	O
I1f	O
subfragment	O
(	O
2	O
.	O
9	O
kbp	O
)	O
.	O

They	O
generated	O
ca	O
.	O

Here	O
we	O
have	O
determined	O
the	O
nucleotide	O
sequence	O
of	O
3	O
.	O
5	O
kb	O
from	O
the	O
3	O
'	O
end	O
of	O
delta	B-GENE
gag	I-GENE
to	O
the	O
3	O
'	O
end	O
of	O
molecularly	O
cloned	O
proviral	O
MH2	O
DNA	O
,	O
in	O
order	O
to	O
elucidate	O
the	O
genetic	O
structure	O
of	O
the	O
virus	O
and	O
to	O
compare	O
it	O
with	O
other	O
mht	B-GENE
-	O
and	O
myc	B-GENE
-	O
containing	O
oncogenic	O
viruses	O
as	O
well	O
as	O
with	O
the	O
chicken	B-GENE
proto	I-GENE
-	I-GENE
myc	I-GENE
gene	I-GENE
.	O

USA	O
80	O
,	O
802	O
-	O
806	O
]	O
was	O
used	O
to	O
isolate	O
a	O
genomic	O
clone	O
lambda	O
PGK	B-GENE
-	I-GENE
1	I-GENE
containing	O
a	O
portion	O
of	O
an	O
autosomal	O
locus	O
for	O
phosphoglycerate	B-GENE
kinase	I-GENE
(	O
PGK	B-GENE
)	O
.	O

A	O
.	O

188	O
patients	O
received	O
cimetidine	O
400	O
mg	O
q	O
.	O
i	O
.	O
d	O
.	O
intravenously	O
and	O
1	O
,	O
000	O
mg	O
daily	O
orally	O
in	O
divided	O
doses	O
.	O

An	O
immunologic	O
test	O
using	O
stomach	O
and	O
tumor	O
antigens	O
for	O
screening	O
of	O
those	O
at	O
high	O
risk	O
for	O
stomach	O
cancer	O
is	O
suggested	O
.	O

Thirty	O
isolates	O
of	O
Haemophilus	O
influenzae	O
type	O
b	O
were	O
obtained	O
during	O
an	O
outbreak	O
of	O
invasive	O
H	O
.	O
influenzae	O
type	O
b	O
disease	O
and	O
were	O
classified	O
by	O
the	O
electrophoretic	O
profile	O
of	O
their	O
lipopolysaccharide	O
(	O
LPS	O
)	O
.	O

Tiaprofenic	O
acid	O
overdose	O
.	O

Frog	O
type	O
I	O
(	O
Ft	O
I	O
)	O
and	O
frog	O
type	O
II	O
(	O
Ft	O
II	O
)	O
slowly	O
adapting	O
(	O
SA	O
)	O
units	O
produced	O
spikes	O
only	O
at	O
the	O
indentation	O
phase	O
,	O
and	O
the	O
threshold	O
response	O
phase	O
(	O
TRP	O
)	O
,	O
i	O
.	O
e	O
.	O
.	O
the	O
phase	O
of	O
the	O
first	O
spike	O
was	O
for	O
ca	O
.	O

Frog	O
type	O
I	O
(	O
Ft	O
I	O
)	O
and	O
frog	O
type	O
II	O
(	O
Ft	O
II	O
)	O
slowly	O
adapting	O
(	O
SA	O
)	O
units	O
produced	O
spikes	O
only	O
at	O
the	O
indentation	O
phase	O
,	O
and	O
the	O
threshold	O
response	O
phase	O
(	O
TRP	O
)	O
,	O
i	O
.	O
e	O
.	O
.	O
the	O
phase	O
of	O
the	O
first	O
spike	O
was	O
for	O
ca	O
.	O

DMCM	O
also	O
permits	O
extension	O
of	O
the	O
possibilities	O
of	O
obtaining	O
and	O
transplanting	O
donor	O
organs	O
.	O

Grimelius	O
stain	O
was	O
positive	O
,	O
Masson	O
Fontana	O
stain	O
negative	O
.	O

Blood	O
glucose	O
and	O
plasma	O
insulin	B-GENE
were	O
measured	O
at	O
zero	O
time	O
and	O
then	O
at	O
15	O
,	O
30	O
,	O
60	O
,	O
90	O
and	O
120	O
min	O
after	O
ingestion	O
of	O
25	O
g	O
glucose	O
,	O
fructose	O
or	O
lactose	O
,	O
or	O
30	O
g	O
honey	O
,	O
50	O
g	O
white	O
bread	O
,	O
125	O
g	O
white	O
rice	O
or	O
potatoes	O
,	O
150	O
g	O
apples	O
or	O
260	O
g	O
carrots	O
.	O

Clinical	O
use	O
of	O
absorbable	O
polyglycolic	O
acid	O
suture	O
in	O
Blalock	O
-	O
Taussig	O
'	O
s	O
operation	O

Among	O
these	O
are	O
:	O
(	O
1	O
)	O
Is	O
there	O
sufficient	O
understanding	O
of	O
family	O
pathophysiology	O
,	O
of	O
the	O
sensitivity	O
and	O
specificity	O
of	O
diagnostic	O
techniques	O
and	O
of	O
the	O
safety	O
and	O
efficacy	O
of	O
therapeutic	O
modalities	O
to	O
make	O
true	O
family	O
health	O
care	O
possible	O
?	O
(	O
2	O
)	O
If	O
this	O
type	O
of	O
care	O
is	O
possible	O
,	O
how	O
are	O
the	O
needs	O
of	O
the	O
family	O
and	O
its	O
individual	O
members	O
met	O
,	O
or	O
value	O
judgements	O
made	O
about	O
their	O
relative	O
importance	O
?	O
and	O
(	O
3	O
)	O
What	O
are	O
the	O
consequences	O
for	O
the	O
health	O
care	O
delivery	O
system	O
of	O
this	O
type	O
of	O
care	O
?	O
An	O
extensive	O
literature	O
review	O
is	O
used	O
in	O
an	O
attempt	O
to	O
answer	O
these	O
queries	O
,	O
from	O
which	O
questions	O
for	O
further	O
study	O
are	O
posed	O
.	O

In	O
patients	O
in	O
group	O
A	O
(	O
"	O
normal	O
"	O
CI	O
)	O
,	O
the	O
CI	O
,	O
heart	O
rate	O
and	O
the	O
mean	O
circumferential	O
fiber	O
shortening	O
velocity	O
(	O
mVCF	O
)	O
were	O
normal	O
,	O
but	O
the	O
TPR	O
was	O
increased	O
significantly	O
.	O

Immunologically	O
reactive	O
insulin	B-GENE
levels	O
were	O
determined	O
in	O
freely	O
-	O
moving	O
normal	O
rats	O
offered	O
three	O
different	O
test	O
-	O
meals	O
.	O

These	O
results	O
indicate	O
that	O
both	O
naturally	O
acquired	O
and	O
passive	O
(	O
modified	O
immune	B-GENE
serum	I-GENE
globulin	I-GENE
)	O
antibodies	O
to	O
type	B-GENE
III	I-GENE
group	I-GENE
B	I-GENE
Streptococcus	I-GENE
antigen	I-GENE
are	O
partially	O
protective	O
against	O
intra	O
-	O
amniotic	O
infection	O
.	O

In	O
the	O
posthospital	O
phase	O
of	O
AMI	O
,	O
as	O
well	O
as	O
in	O
CCHD	O
,	O
the	O
occurrence	O
of	O
high	O
-	O
grade	O
VPBs	O
usually	O
indicates	O
more	O
advanced	O
degrees	O
of	O
both	O
coronary	O
and	O
left	O
ventricular	O
disease	O
as	O
well	O
as	O
the	O
possibility	O
of	O
cardiac	O
and	O
/	O
or	O
sudden	O
death	O
.	O

The	O
genes	O
at	O
each	O
locus	O
are	O
divergently	O
transcribed	O
and	O
the	O
coding	O
sequences	O
are	O
separated	O
by	O
646	O
base	O
-	O
pairs	O
at	O
one	O
locus	O
and	O
676	O
base	O
-	O
pairs	O
at	O
the	O
other	O
.	O

The	O
enzymic	O
hydrolysis	O
of	O
urea	O
produces	O
ammonia	O
which	O
causes	O
a	O
vivid	O
yellow	O
to	O
purple	O
colour	O
change	O
in	O
the	O
pH	O
indicator	O
.	O

The	O
clinical	O
efficacy	O
rates	O
evaluated	O
in	O
151	O
cases	O
(	O
KS	O
-	O
R1	O
group	O
in	O
77	O
cases	O
,	O
oral	O
group	O
in	O
74	O
cases	O
)	O
on	O
standard	O
criteria	O
of	O
committee	O
members	O
were	O
88	O
.	O
3	O
%	O
for	O
the	O
KS	O
-	O
R1	O
group	O
and	O
86	O
.	O
5	O
%	O
for	O
the	O
oral	O
group	O
,	O
respectively	O
.	O

Side	O
effect	O
including	O
subjective	O
and	O
objective	O
symptoms	O
were	O
strictly	O
evaluated	O
in	O
163	O
cases	O
(	O
KS	O
-	O
R1	O
group	O
in	O
83	O
cases	O
,	O
oral	O
group	O
in	O
80	O
cases	O
)	O
,	O
but	O
the	O
incidence	O
rate	O
which	O
was	O
22	O
.	O
9	O
%	O
for	O
the	O
KS	O
-	O
R1	O
group	O
and	O
23	O
.	O
8	O
%	O
for	O
the	O
oral	O
group	O
showed	O
no	O
significant	O
difference	O
.	O

Plasma	O
renin	B-GENE
activity	O
did	O
not	O
change	O
in	O
response	O
to	O
head	O
-	O
up	O
tilt	O
or	O
isoprenaline	O
infusion	O
in	O
the	O
patients	O
.	O

Martin	O
Luther	O
and	O
his	O
physicians	O
.	O

Enhancement	O
of	O
the	O
immune	O
response	O
by	O
aspecific	O
action	O
of	O
vaccine	O
additives	O
in	O
the	O
aerogenic	O
immunization	O
of	O
swine	O
against	O
swine	O
plague	O

Induced	O
gamma	O
-	O
ray	O
spectroscopy	O

Analysis	O
of	O
proteins	O
synthesized	O
by	O
plasmids	O
containing	O
deleted	O
forms	O
of	O
the	O
trfA	B-GENE
region	I-GENE
indicates	O
that	O
the	O
A2	B-GENE
protein	I-GENE
is	O
the	O
essential	O
trfA	B-GENE
-	I-GENE
encoded	I-GENE
replication	I-GENE
protein	I-GENE
of	O
plasmid	O
RK2	O
.	O

Effects	O
of	O
negative	O
pleural	O
pressure	O
on	O
left	O
ventricular	O
hemodynamics	O
.	O

Resting	O
plasma	O
norepinephrine	O
(	O
NE	O
)	O
and	O
epinephrine	O
(	O
E	O
)	O
levels	O
were	O
lower	O
during	O
active	O
therapy	O
than	O
2	O
wk	O
after	O
withdrawal	O
(	O
guanfacine	O
and	O
control	O
:	O
plasma	O
NE	O
,	O
0	O
.	O
27	O
+	O
/	O
-	O
0	O
.	O
03	O
/	O
0	O
.	O
64	O
+	O
/	O
-	O
0	O
.	O
13	O
ng	O
/	O
ml	O
;	O
plasma	O
E	O
,	O
0	O
.	O
09	O
+	O
/	O
-	O
0	O
.	O
02	O
/	O
0	O
.	O
17	O
+	O
/	O
-	O
0	O
.	O
05	O
ng	O
/	O
ml	O
)	O
.	O

Renal	O
response	O
to	O
captopril	O
in	O
severe	O
heart	O
failure	O
:	O
role	O
of	O
furosemide	O
in	O
natriuresis	O
and	O
reversal	O
of	O
hyponatremia	O
.	O

Lauciello	O
describes	O
a	O
technique	O
for	O
the	O
placement	O
of	O
functionally	O
generated	O
amalgam	O
stops	O
as	O
restorations	O
within	O
mandibular	O
acrylic	O
teeth	O
.	O

Eleven	O
biopsy	O
specimens	O
(	O
five	O
papules	O
and	O
six	O
dusky	O
or	O
crusted	O
lesions	O
)	O
from	O
four	O
patients	O
with	O
pityriasis	O
lichenoides	O
et	O
varioliformis	O
acuta	O
(	O
PLEVA	O
)	O
were	O
studied	O
by	O
direct	O
immunofluorescence	O
and	O
immunoperoxidase	B-GENE
technics	O
.	O

These	O
data	O
suggest	O
that	O
a	O
major	O
part	O
of	O
the	O
reduction	O
in	O
food	O
intake	O
in	O
hyperphagic	O
rats	O
eating	O
a	O
quinine	O
-	O
adulterated	O
diet	O
is	O
due	O
to	O
postingestional	O
events	O
.	O

The	O
aspirate	O
from	O
a	O
parathyroid	O
cyst	O
was	O
watery	O
clear	O
and	O
contained	O
high	O
amount	O
of	O
parathyroid	B-GENE
hormone	I-GENE
.	O

EGV	O
had	O
no	O
detectable	O
effect	O
on	O
PP	B-GENE
secretion	O
under	O
basal	O
or	O
stimulated	O
conditions	O
.	O

The	O
numerous	O
tests	O
demonstrate	O
that	O
the	O
HDL	O
-	O
2M	O
can	O
be	O
extensively	O
and	O
successfully	O
used	O
for	O
therapy	O
of	O
insulin	B-GENE
-	O
dependent	O
diabetes	O
mellitus	O
in	O
clinical	O
practice	O
.	O

Lung	O
prostacyclin	O
production	O
may	O
be	O
related	O
to	O
flow	O
.	O

For	O
the	O
first	O
30	O
min	O
following	O
insulin	B-GENE
administration	O
,	O
the	O
rate	O
of	O
change	O
in	O
glucose	O
levels	O
was	O
significantly	O
less	O
among	O
the	O
patients	O
with	O
major	O
depressive	O
disorder	O
than	O
among	O
either	O
the	O
patients	O
with	O
dysthymic	O
disorder	O
or	O
the	O
normal	O
control	O
subjects	O
.	O

Management	O
of	O
hypertension	O
in	O
the	O
elderly	O
.	O

Transplantation	O
of	O
kidneys	O
of	O
juvenile	O
donors	O
in	O
adult	O
recipients	O
.	O

Ten	O
patients	O
with	O
advanced	O
,	O
diffuse	O
Hodgkin	O
'	O
s	O
and	O
non	O
-	O
Hodgkin	O
'	O
s	O
lymphomas	O
responding	O
poorly	O
to	O
the	O
most	O
widely	O
employed	O
primary	O
chemotherapy	O
regimens	O
were	O
treated	O
with	O
a	O
high	O
-	O
dose	O
chemotherapy	O
(	O
HDC	O
)	O
followed	O
by	O
rescue	O
with	O
non	O
-	O
frozen	O
autologous	O
bone	O
marrow	O
infusion	O
(	O
ABMT	O
)	O
.	O

Effect	O
of	O
proteolytic	O
enzymes	O
and	O
polypeptides	O
on	O
the	O
antacid	O
activity	O
of	O
almagate	O
and	O
other	O
antacids	O
.	O

Results	O
of	O
a	O
controlled	O
study	O

Hydrallazine	O
also	O
caused	O
a	O
slight	O
increase	O
in	O
plasma	B-GENE
renin	I-GENE
activity	O
and	O
urinary	O
excretion	O
of	O
noradrenaline	O
.	O

Urease	B-GENE
activity	O
of	O
97	O
%	O
of	O
these	O
organisms	O
became	O
evident	O
within	O
30	O
min	O
.	O

After	O
description	O
of	O
his	O
short	O
life	O
and	O
an	O
explanation	O
of	O
the	O
light	O
conductor	O
Bozzini	O
'	O
s	O
merit	O
is	O
emphasized	O
,	O
by	O
his	O
invention	O
as	O
first	O
physician	O
to	O
have	O
made	O
accessible	O
to	O
medicine	O
endoscopic	O
diagnostic	O
possibilities	O
.	O

The	O
effect	O
of	O
lithium	O
on	O
the	O
osmoregulation	O
of	O
arginine	B-GENE
vasopressin	I-GENE
secretion	O
.	O

Antithrombin	B-GENE
III	I-GENE
(	O
AT	B-GENE
III	I-GENE
)	O
is	O
a	O
plasma	O
protein	O
which	O
acts	O
as	O
the	O
principal	O
inhibitor	O
of	O
thrombin	B-GENE
and	O
is	O
a	O
major	O
modulator	O
of	O
intravascular	O
coagulation	O
.	O

Eighteen	O
patients	O
were	O
untreated	O
,	O
and	O
8	O
had	O
been	O
given	O
previous	O
treatment	O
with	O
depot	O
testosterone	O
100	O
mg	O
intramuscularly	O
every	O
2	O
-	O
3	O
weeks	O
for	O
an	O
average	O
duration	O
of	O
4	O
.	O
7	O
years	O
.	O

195mPt	O
-	O
labeled	O
cisplatin	O
was	O
administered	O
iv	O
and	O
ip	O
to	O
control	O
mice	O
and	O
to	O
mice	O
bearing	O
Sarcoma	O
180	O
.	O

New	O
beta	O
-	O
blocking	O
drugs	O
have	O
been	O
introduced	O
which	O
may	O
prove	O
beneficial	O
in	O
certain	O
clinical	O
situations	O
since	O
they	O
exert	O
more	O
selective	O
blockade	O
of	O
the	O
cardiac	B-GENE
receptors	I-GENE
(	O
beta1	B-GENE
)	O
as	O
opposed	O
to	O
smooth	B-GENE
muscle	I-GENE
receptors	I-GENE
(	O
beta2	B-GENE
)	O
.	O

In	O
the	O
37	O
patients	O
without	O
lung	O
disease	O
respiratory	O
muscle	O
weakness	O
was	O
accompanied	O
by	O
significant	O
decreases	O
in	O
vital	O
capacity	O
,	O
total	O
lung	O
capacity	O
,	O
and	O
maximum	O
voluntary	O
ventilation	O
;	O
by	O
significant	O
increases	O
in	O
residual	O
volume	O
and	O
arterial	O
carbon	O
dioxide	O
tension	O
(	O
PaCO2	O
)	O
;	O
and	O
greater	O
likelihood	O
of	O
dependence	O
on	O
ventilators	O
,	O
atelectasis	O
,	O
and	O
pneumonia	O
.	O

Commun	O
.	O

Total	O
cumulative	O
doses	O
of	O
doxorubicin	O
ranged	O
from	O
145	O
to	O
625	O
mg	O
.	O
/	O
m	O
.	O
2	O
.	O

Movement	O
programming	O
depends	O
on	O
understanding	O
of	O
behavioral	O
requirements	O
.	O

Following	O
20	O
min	O
of	O
steady	O
state	O
anaesthesia	O
during	O
which	O
measurements	O
of	O
IOP	O
,	O
arterial	O
pressure	O
,	O
heart	O
rate	O
,	O
FIO2	O
,	O
FE	O
'	O
CO2	O
and	O
CVP	O
were	O
recorded	O
,	O
one	O
group	O
of	O
patients	O
received	O
atracurium	O
0	O
.	O
45	O
mg	O
kg	O
-	O
1	O
and	O
the	O
other	O
pancuronium	O
0	O
.	O
1	O
mg	O
kg	O
-	O
1	O
.	O

Gonadotropin	B-GENE
levels	O
in	O
mothers	O
who	O
have	O
had	O
two	O
sets	O
of	O
DZ	O
twins	O
.	O

Freezing	O
of	O
plasma	O
to	O
obtain	O
better	O
yield	O
of	O
factor	B-GENE
VIII	I-GENE
:	O
C	O
.	O

These	O
children	O
were	O
grouped	O
into	O
four	O
diagnostic	O
categories	O
:	O
1	O
)	O
idiopathic	O
GH	B-GENE
deficiency	O
(	O
n	O
=	O
10	O
)	O
;	O
2	O
)	O
organic	O
hypopituitarism	O
(	O
n	O
=	O
7	O
)	O
;	O
3	O
)	O
intrauterine	O
growth	O
retardation	O
(	O
n	O
=	O
5	O
)	O
;	O
and	O
4	O
)	O
constitutional	O
delay	O
of	O
growth	O
and	O
/	O
or	O
familial	O
short	O
stature	O
(	O
n	O
=	O
18	O
)	O
,	O
by	O
standard	O
clinical	O
criteria	O
and	O
physiological	O
and	O
pharmacological	O
tests	O
of	O
GH	B-GENE
reserve	O
.	O

Each	O
patient	O
had	O
measurable	O
LH	B-GENE
and	O
FSH	B-GENE
levels	O
,	O
with	O
pulsed	O
nocturnal	O
secretion	O
,	O
and	O
pubertal	O
LH	B-GENE
and	O
FSH	B-GENE
responses	O
to	O
LRH	B-GENE
.	O

These	O
changes	O
were	O
the	O
result	O
of	O
a	O
decrease	O
in	O
afterload	O
:	O
mean	O
aortic	O
pressure	O
fell	O
from	O
85	O
+	O
/	O
-	O
11	O
.	O
8	O
to	O
68	O
+	O
/	O
-	O
19	O
.	O
6	O
mmHg	O
(	O
p	O
less	O
than	O
0	O
.	O
01	O
)	O
and	O
systemic	O
arterial	O
resistance	O
fell	O
from	O
2	O
886	O
+	O
/	O
-	O
745	O
to	O
2	O
010	O
+	O
/	O
-	O
610	O
dynes	O
/	O
cm	O
-	O
5	O
/	O
sec	O
/	O
m	O
-	O
2	O
(	O
p	O
less	O
than	O
0	O
.	O
01	O
)	O
.	O

Cimetidine	O
800	O
mg	O
given	O
at	O
night	O
is	O
as	O
effective	O
as	O
400	O
mg	O
twice	O
daily	O
;	O
the	O
single	O
dose	O
regimen	O
may	O
improve	O
patient	O
compliance	O
,	O
thus	O
facilitating	O
treatment	O
.	O

Ceftazidime	O
shows	O
promise	O
as	O
single	O
-	O
agent	O
therapy	O
for	O
serious	O
gram	O
-	O
negative	O
bacillary	O
infections	O
.	O

Regional	O
CBF	O
was	O
determined	O
by	O
clearance	O
of	O
xenon	O
133	O
in	O
67	O
patients	O
undergoing	O
coronary	O
bypass	O
grafting	O
procedures	O
.	O

Our	O
results	O
indicate	O
that	O
serum	B-GENE
BGP	I-GENE
is	O
a	O
valuable	O
measurement	O
of	O
bone	O
metabolism	O
.	O

The	O
management	O
of	O
the	O
"	O
chronic	O
"	O
patient	O
.	O

Study	O
of	O
bacterial	O
motility	O
and	O
rate	O
of	O
movement	O
using	O
a	O
closed	O
circuit	O
television	O

Finding	O
of	O
Rhodnius	O
prolixus	O
Stal	O
,	O
1859	O
,	O
in	O
babassu	O
palm	O
trees	O

Each	O
causative	O
organism	O
has	O
a	O
species	O
-	O
specific	O
preference	O
and	O
requirement	O
for	O
temperature	O
,	O
salinity	O
,	O
pH	O
,	O
the	O
basic	O
nutrients	O
,	O
and	O
growth	O
factors	O
,	O
and	O
the	O
toxin	O
formation	O
is	O
affected	O
by	O
these	O
environmental	O
factors	O
.	O

Deformities	O
of	O
the	O
tip	O
of	O
the	O
olecranon	O
and	O
of	O
the	O
coronoid	O
process	O
are	O
also	O
described	O
(	O
De	O
Palma	O
1956	O
,	O
Jordan	O
1958	O
,	O
Ahlberg	O
1965	O
,	O
Weseloh	O
1973	O
)	O
.	O

There	O
was	O
significant	O
correlation	O
of	O
LVM	O
/	O
M2	O
and	O
PWVn	O
for	O
pre	O
-	O
AVR	O
and	O
post	O
AVR	O
studies	O
.	O

Statokinesimetric	O
recording	O
in	O
Huntington	O
choreas	O

The	O
development	O
and	O
histostructural	O
organization	O
of	O
intrahepatic	O
biliary	O
ducts	O
were	O
studied	O
on	O
a	O
human	O
embryofetal	O
material	O
6	O
to	O
32	O
weeks	O
old	O
.	O

It	O
has	O
been	O
shown	O
in	O
an	O
animal	O
experiment	O
that	O
alterations	O
of	O
the	O
renal	O
vasculature	O
and	O
parenchyma	O
after	O
hemostasis	O
performed	O
by	O
Infrared	O
-	O
Contact	O
-	O
Coagulation	O
are	O
best	O
shown	O
by	O
intravital	O
magnification	O
angiography	O
(	O
magnification	O
factor	O
2	O
.	O
22	O
)	O
.	O

Cardiovascular	O
and	O
adrenal	O
medullo	O
-	O
sympathetic	O
reactions	O
to	O
acute	O
tobacco	O
poisoning	O

Intravenous	O
injections	O
of	O
SG	O
-	O
75	O
(	O
0	O
.	O
03	O
-	O
1	O
mg	O
/	O
kg	O
)	O
decreased	O
systemic	O
blood	O
pressure	O
(	O
SBP	O
)	O
and	O
increased	O
peripheral	O
(	O
coronary	O
,	O
renal	O
,	O
mesenteric	O
and	O
femoral	O
)	O
blood	O
flow	O
(	O
PBF	O
)	O
dose	O
-	O
dependently	O
.	O

In	O
doses	O
of	O
0	O
.	O
03	O
-	O
0	O
.	O
3	O
mg	O
/	O
kg	O
i	O
.	O
v	O
.	O
,	O
SG	O
-	O
75	O
did	O
not	O
significantly	O
affect	O
pulse	O
pressure	O
,	O
heart	O
rate	O
,	O
aortic	O
blood	O
flow	O
,	O
left	O
ventricular	O
pressure	O
(	O
LVP	O
)	O
and	O
LVdP	O
/	O
dt	O
max	O
.	O

Resting	O
VE	O
in	O
the	O
luteal	O
phase	O
was	O
7	O
.	O
8	O
%	O
greater	O
than	O
that	O
in	O
the	O
follicular	O
phase	O
.	O

Exposure	O
of	O
endothelium	O
to	O
pulsatile	O
shear	O
stresses	O
that	O
followed	O
a	O
tape	O
recording	O
of	O
physiological	O
flow	O
waveforms	O
(	O
electromagnetic	O
flowmeter	O
)	O
did	O
not	O
cause	O
gross	O
injury	O
or	O
denudation	O
even	O
when	O
peak	O
shear	O
exceeded	O
1500	O
dyne	O
/	O
cm2	O
.	O

Modern	O
cancer	O
therapy	O
has	O
included	O
surgery	O
,	O
radiotherapy	O
,	O
chemotherapy	O
,	O
and	O
most	O
recently	O
,	O
immunotherapy	O
and	O
hyperthermia	O
.	O

There	O
was	O
a	O
close	O
correlation	O
between	O
plasma	O
clearance	O
of	O
NT	O
by	O
10	O
-	O
hydroxylation	O
and	O
the	O
D	O
metabolic	O
ratio	O
(	O
D	O
/	O
4	O
-	O
OH	O
-	O
D	O
in	O
urine	O
)	O
in	O
the	O
Ghanaians	O
(	O
rs	O
=	O
-	O
0	O
.	O
95	O
;	O
P	O
less	O
than	O
0	O
.	O
01	O
)	O
and	O
Swedes	O
(	O
rs	O
=	O
-	O
0	O
.	O
84	O
;	O
P	O
less	O
than	O
0	O
.	O
01	O
)	O
.	O

The	O
response	O
properties	O
of	O
cat	O
horizontal	O
canal	O
afferents	O
(	O
N	O
=	O
81	O
)	O
were	O
characterized	O
by	O
three	O
parameters	O
:	O
their	O
long	O
time	O
constants	O
(	O
tau	O
)	O
,	O
low	O
frequency	O
gain	O
constants	O
(	O
G1	O
)	O
,	O
and	O
middle	O
frequency	O
gain	O
constants	O
(	O
Gm	O
)	O
.	O

Despite	O
supraphysiologic	O
E2	O
concentrations	O
,	O
however	O
,	O
cervical	O
mucus	O
scores	O
were	O
significantly	O
reduced	O
in	O
the	O
CC	O
-	O
treated	O
group	O
(	O
P	O
less	O
than	O
0	O
.	O
01	O
)	O
.	O

Stimulation	O
of	O
the	O
caudate	O
nucleus	O
'	O
dophamine	O
-	O
reactive	O
system	O
in	O
dogs	O
by	O
means	O
of	O
administration	O
of	O
dophamine	O
(	O
60	O
micrograms	O
)	O
and	O
phenamine	O
led	O
to	O
deterioration	O
of	O
conditioned	O
and	O
unconditioned	O
components	O
of	O
feeding	O
behaviour	O
.	O

Value	O
of	O
urine	O
glucose	O
tests	O
in	O
the	O
management	O
of	O
type	O
II	O
diabetes	O
mellitus	O
.	O

This	O
experiment	O
was	O
conducted	O
to	O
determine	O
if	O
the	O
sex	O
or	O
actual	O
egg	O
production	O
was	O
the	O
important	O
factor	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
250	O
WORDS	O
)	O

A	O
pharmacokinetic	O
study	O
of	O
apalcillin	O
was	O
performed	O
in	O
12	O
patients	O
in	O
an	O
intensive	O
-	O
care	O
unit	O
.	O

Thrombocyte	O
function	O
was	O
impaired	O
in	O
all	O
patients	O
,	O
characterized	O
by	O
a	O
diminished	O
platelet	O
shape	O
change	O
.	O

The	O
findings	O
demonstrate	O
that	O
AMPH	O
administration	O
induces	O
a	O
significant	O
increase	O
in	O
the	O
height	O
of	O
a	O
major	O
electroactive	O
peak	O
in	O
the	O
caudate	O
nucleus	O
of	O
pigtail	O
monkeys	O
,	O
and	O
further	O
that	O
such	O
amphetamine	O
-	O
induced	O
increases	O
can	O
be	O
manipulated	O
by	O
altering	O
the	O
affective	O
and	O
/	O
or	O
emotional	O
state	O
of	O
the	O
animal	O
.	O

In	O
two	O
experiments	O
,	O
neonatal	O
female	O
BALB	O
/	O
cCrgl	O
or	O
BALB	O
/	O
cfC3HCrgl	O
mice	O
were	O
given	O
subcutaneous	O
injections	O
of	O
5	O
micrograms	O
17	O
beta	O
-	O
estradiol	O
or	O
sesame	O
oil	O
for	O
the	O
first	O
3	O
days	O
of	O
life	O
and	O
were	O
ovariectomized	O
at	O
60	O
days	O
of	O
age	O
,	O
at	O
which	O
time	O
vaginal	O
concretions	O
(	O
Experiments	O
I	O
and	O
II	O
)	O
or	O
silica	O
(	O
Experiment	O
II	O
)	O
were	O
implanted	O
intravaginally	O
.	O

For	O
228	O
of	O
425	O
deaths	O
(	O
54	O
%	O
)	O
occurring	O
among	O
26	O
100	O
people	O
of	O
known	O
age	O
in	O
the	O
Malumfashi	O
area	O
of	O
northern	O
Nigeria	O
,	O
data	O
were	O
collected	O
on	O
symptoms	O
present	O
prior	O
to	O
death	O
.	O

Salivary	O
estradiol	O
17	O
beta	O
(	O
E2	O
-	O
17	O
beta	O
)	O
and	O
progesterone	O
(	O
P	O
)	O
were	O
determined	O
by	O
using	O
radioimmunoassay	O
techniques	O
in	O
30	O
pregnant	O
females	O
in	O
the	O
first	O
,	O
second	O
and	O
third	O
trimesters	O
as	O
well	O
as	O
in	O
10	O
non	O
-	O
pregnant	O
controls	O
during	O
the	O
luteal	O
phase	O
of	O
the	O
menstrual	O
cycle	O
.	O

Other	O
than	O
d	O
7	O
,	O
there	O
was	O
no	O
significant	O
effect	O
on	O
the	O
number	O
of	O
implants	O
.	O

Variable	O
FHR	O
decelerations	O
or	O
bradycardias	O
were	O
encountered	O
on	O
95	O
nonstress	O
tests	O
(	O
18	O
.	O
8	O
%	O
)	O
in	O
80	O
(	O
33	O
.	O
5	O
%	O
)	O
postdate	O
patients	O
.	O

The	O
response	O
chain	O
in	O
each	O
component	O
was	O
maintained	O
by	O
food	O
presentation	O
under	O
a	O
fixed	O
-	O
ratio	O
schedule	O
.	O

The	O
results	O
imply	O
that	O
kindling	O
does	O
not	O
produce	O
its	O
facilitating	O
effect	O
on	O
acquisition	O
of	O
HPC	O
SS	O
by	O
removing	O
a	O
disruptive	O
effect	O
of	O
the	O
stimulation	O
.	O

The	O
persistent	O
fetal	O
dispersion	O
of	O
nodal	O
and	O
Hiss	O
bundle	O
fragments	O
within	O
the	O
ventricular	O
septum	O
is	O
proposed	O
as	O
a	O
possible	O
explanation	O
.	O

According	O
to	O
the	O
biochemical	O
tests	O
,	O
high	O
activity	O
(	O
over	O
200	O
U	O
/	O
l	O
)	O
of	O
alkaline	B-GENE
phosphatase	I-GENE
was	O
recorded	O
exclusively	O
in	O
patients	O
with	O
the	O
lymphogranulomatosis	O
-	O
induced	O
liver	O
damage	O
.	O

Changes	O
of	O
plasma	O
cortisol	O
level	O
in	O
late	O
asthmatic	O
responses	O

Significant	O
alterations	O
in	O
the	O
vasectomized	O
rats	O
from	O
sham	O
rats	O
included	O
:	O
testicular	O
and	O
epididymal	O
hypertrophy	O
,	O
formation	O
of	O
pathologic	O
vas	O
deferens	O
granulomas	O
,	O
decreased	O
total	O
serum	O
protein	O
,	O
lowered	O
alpha	B-GENE
-	I-GENE
globulin	I-GENE
levels	O
as	O
shown	O
by	O
serum	O
electrophoresis	O
,	O
and	O
increased	O
sperm	O
agglutinin	B-GENE
antibody	O
titers	O
.	O

SFP	O
was	O
significantly	O
elevated	O
in	O
Hn	O
(	O
s	O
)	O
.	O

The	O
average	O
birth	O
mass	O
of	O
these	O
newborns	O
was	O
3491	O
.	O
9	O
+	O
/	O
-	O
2	O
SD	O
780	O
.	O
5	O
g	O
and	O
that	O
in	O
the	O
control	O
group	O
3	O
,	O
767	O
.	O
5	O
+	O
/	O
-	O
2	O
SD	O
824	O
.	O
2	O
g	O
(	O
P	O
less	O
than	O
0	O
.	O
05	O
)	O
.	O

This	O
machine	O
drift	O
,	O
which	O
was	O
not	O
associated	O
with	O
a	O
rise	O
in	O
water	O
phantom	O
temperature	O
and	O
did	O
not	O
consistently	O
correlate	O
with	O
estimated	O
x	O
-	O
ray	O
tube	O
heat	O
,	O
could	O
result	O
in	O
a	O
significant	O
overestimation	O
of	O
regional	O
cerebral	O
blood	O
flow	O
(	O
rCBF	O
)	O
for	O
a	O
xenon	O
/	O
CT	O
rCBF	O
protocol	O
involving	O
5	O
-	O
7	O
sequential	O
scans	O
obtained	O
at	O
1	O
-	O
min	O
interscan	O
intervals	O
.	O

Other	O
uncertainties	O
in	O
the	O
dosimetry	O
at	O
Y	O
-	O
12	O
and	O
Vinca	O
are	O
unaltered	O
.	O

E2	O
treatments	O
elevated	O
hen	O
plasma	O
TG	O
7	O
.	O
2X	O
,	O
PL	O
5	O
.	O
1X	O
,	O
and	O
C	O
7	O
.	O
2X	O
;	O
and	O
pullet	O
plasma	O
TG	O
6	O
.	O
8X	O
,	O
PL	O
3	O
.	O
7X	O
,	O
and	O
C	O
2	O
.	O
5X	O
.	O

By	O
contrast	O
,	O
kidneys	O
from	O
rats	O
with	O
chronic	O
metabolic	O
acidosis	O
produced	O
significantly	O
more	O
NH3	O
than	O
both	O
these	O
groups	O
(	O
2	O
.	O
73	O
+	O
/	O
-	O
0	O
.	O
29	O
mumol	O
X	O
min	O
-	O
1	O
X	O
g	O
-	O
1	O
)	O
.	O

Serodiagnosis	O
of	O
trypanosomiasis	O
in	O
dromedary	O
camels	O
using	O
a	O
card	O
agglutination	O
test	O
set	O
(	O
Testryp	O
CATT	O
)	O
.	O

Adenyl	B-GENE
cyclase	I-GENE
activity	O
of	O
gastric	O
mucosa	O
in	O
patients	O
with	O
duodenal	O
ulcer	O
before	O
and	O
after	O
treatment	O

Proteinuria	O
-	O
-	O
selected	O
physiopathological	O
and	O
clinical	O
problems	O

However	O
,	O
subcutaneously	O
administered	O
pneumococci	O
gave	O
a	O
lower	O
mortality	O
than	O
pneumococci	O
given	O
intravenously	O
or	O
intraperitoneally	O
.	O

Reaction	O
of	O
human	O
organism	O
to	O
exercise	O
.	O

HA	O
resulted	O
in	O
decreased	O
(	O
p	O
less	O
than	O
0	O
.	O
05	O
)	O
Tre	O
(	O
0	O
.	O
4	O
degrees	O
C	O
)	O
and	O
HR	O
(	O
17	O
b	O
X	O
min	O
-	O
1	O
)	O
,	O
and	O
increased	O
(	O
p	O
less	O
than	O
0	O
.	O
05	O
)	O
Msw	O
(	O
16	O
g	O
X	O
m	O
-	O
2	O
X	O
h	O
-	O
1	O
)	O
during	O
the	O
saline	O
experiments	O
.	O

The	O
results	O
obtained	O
were	O
as	O
follows	O
:	O
The	O
mitral	O
valve	O
orifice	O
area	O
(	O
MVA	O
)	O
was	O
significantly	O
smaller	O
in	O
patients	O
with	O
type	O
III	O
of	O
the	O
LVIT	O
flow	O
velocity	O
pattern	O
than	O
in	O
patients	O
with	O
type	O
I	O
(	O
p	O
less	O
than	O
0	O
.	O
001	O
)	O
.	O

Scientific	O
cooperation	O
of	O
CMEA	O
member	O
countries	O
has	O
been	O
carried	O
out	O
since	O
1974	O
under	O
the	O
sponsorship	O
of	O
the	O
Cancer	O
Research	O
Institute	O
,	O
Slovak	O
Academy	O
of	O
Sciences	O
(	O
Czechoslovakia	O
)	O
within	O
the	O
framework	O
of	O
CMEA	O
.	O

This	O
compares	O
favorably	O
to	O
results	O
of	O
similarly	O
sized	O
melanomas	O
treated	O
by	O
enucleation	O
.	O

A	O
new	O
variant	O
of	O
the	O
EMG	O
-	O
BFB	O
method	O
(	O
multichannel	O
)	O
is	O
offered	O
which	O
has	O
made	O
it	O
possible	O
to	O
use	O
the	O
method	O
not	O
only	O
for	O
training	O
weakened	O
muscles	O
and	O
reducing	O
spasticity	O
in	O
their	O
antagonists	O
but	O
also	O
for	O
improving	O
motor	O
coordination	O
.	O

Lymphocytes	O
from	O
all	O
3	O
species	O
yielded	O
maximum	O
responses	O
with	O
a	O
48	O
-	O
hour	O
prelabel	O
and	O
12	O
-	O
to	O
-	O
16	O
hour	O
postlabel	O
incubation	O
period	O
at	O
41	O
C	O
and	O
1	O
:	O
20	O
blood	O
dilution	O
.	O

However	O
,	O
there	O
was	O
a	O
difference	O
in	O
the	O
quality	O
of	O
immunity	O
:	O
fever	O
and	O
body	O
weight	O
loss	O
were	O
seen	O
in	O
hamsters	O
vaccinated	O
with	O
the	O
killed	O
-	O
toxoplasma	O
vaccine	O
after	O
they	O
were	O
challenge	O
exposed	O
with	O
T	O
-	O
1	O
strain	O
,	O
whereas	O
these	O
changes	O
were	O
rarely	O
seen	O
in	O
hamsters	O
given	O
the	O
live	O
-	O
toxoplasma	O
vaccine	O
and	O
then	O
challenge	O
exposed	O
with	O
RH	O
strain	O
.	O

Alternating	O
proline	O
/	O
alanine	O
sequence	O
of	O
beta	B-GENE
B1	I-GENE
subunit	I-GENE
originates	O
from	O
a	O
repetitive	O
DNA	O
sequence	O
.	O

The	O
segmental	O
and	O
regional	O
projections	O
of	O
the	O
sciatic	O
,	O
tibial	O
and	O
common	O
peroneal	O
nerves	O
to	O
the	O
substantia	O
gelatinosa	O
of	O
the	O
spinal	O
cord	O
in	O
rats	O
-	O
-	O
an	O
experimental	O
study	O
by	O
means	O
of	O
an	O
acid	B-GENE
phosphatase	I-GENE
(	O
ACP	B-GENE
)	O
method	O
.	O

Removal	O
of	O
lipid	O
fractions	O
of	O
plant	O
extractions	O
with	O
hexane	O
is	O
recommended	O
to	O
avoid	O
damage	O
to	O
the	O
HPLC	O
column	O
.	O

In	O
the	O
Arithmetic	O
subtest	O
one	O
of	O
the	O
items	O
would	O
not	O
meet	O
the	O
difficulty	O
grading	O
shown	O
while	O
the	O
last	O
two	O
items	O
offer	O
very	O
little	O
possibility	O
of	O
success	O
for	O
all	O
subjects	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
250	O
WORDS	O
)	O

The	O
toxicological	O
evaluation	O
of	O
chlorofluorocarbon	O
22	O
(	O
CFC	O
22	O
)	O
.	O

All	O
patients	O
were	O
evaluable	O
for	O
toxicity	O
and	O
9	O
for	O
response	O
.	O

Methods	O
of	O
clinical	O
and	O
experimental	O
algesimetry	O
are	O
described	O
that	O
have	O
been	O
used	O
to	O
evaluate	O
effects	O
of	O
peripherally	O
and	O
centrally	O
acting	O
analgesics	O
.	O

We	O
propose	O
that	O
the	O
ambiguous	O
discrimination	O
required	O
a	O
greater	O
time	O
for	O
simulus	O
evaluation	O
and	O
that	O
this	O
was	O
reflected	O
in	O
the	O
delayed	O
P3	O
latencies	O
.	O

Ammonia	O
concentration	O
dropped	O
significantly	O
in	O
all	O
treatments	O
,	O
a	O
finding	O
which	O
suggests	O
a	O
protective	O
effect	O
on	O
protein	O
nitrogen	O
degradation	O
to	O
non	O
-	O
protein	O
nitrogen	O
(	O
NH3	O
)	O
.	O

In	O
this	O
respect	O
C	B-GENE
reactive	I-GENE
protein	I-GENE
concentrations	O
are	O
superior	O
to	O
white	O
cell	O
count	O
,	O
erythrocyte	O
sedimentation	O
rate	O
,	O
and	O
temperature	O
and	O
the	O
concentrations	O
of	O
antiproteases	O
.	O

Human	B-GENE
thyroid	I-GENE
stimulator	I-GENE
(	O
HTS	B-GENE
)	O
in	O
thyroid	O
diseases	O

We	O
conclude	O
that	O
administration	O
of	O
the	O
calcium	O
antagonist	O
Verapamil	O
is	O
of	O
no	O
additional	O
value	O
in	O
tocolytic	O
treatment	O
with	O
beta	O
-	O
mimetics	O
.	O

Effects	O
of	O
ketamine	O
on	O
the	O
circulatory	O
functions	O
and	O
body	O
tissue	O
oxygenation	O
in	O
dogs	O
under	O
normal	O
and	O
hypovolemic	O
conditions	O
.	O

Besides	O
,	O
it	O
was	O
considered	O
that	O
the	O
NPF	O
was	O
a	O
useful	O
tool	O
for	O
activation	O
of	O
velopharyngeal	O
activity	O
by	O
way	O
of	O
visual	O
feed	O
-	O
back	O
control	O
.	O

To	O
evaluate	O
the	O
comparative	O
safety	O
of	O
U	O
-	O
P	O
and	O
D	O
&	O
E	O
,	O
we	O
analyzed	O
2	O
,	O
805	O
U	O
-	O
P	O
and	O
9	O
,	O
572	O
D	O
&	O
E	O
abortions	O
at	O
13	O
to	O
24	O
menstrual	O
weeks	O
'	O
gestation	O
.	O

Three	O
radiologists	O
without	O
knowledge	O
of	O
patients	O
'	O
data	O
and	O
treatment	O
analyzed	O
30	O
angiograms	O
with	O
and	O
30	O
examinations	O
without	O
PGF	O
.	O

In	O
a	O
man	O
with	O
myelomonocytic	O
leukemia	O
,	O
the	O
association	O
of	O
increased	O
prostatic	B-GENE
acid	I-GENE
phosphatase	I-GENE
activity	O
in	O
serum	O
and	O
the	O
presence	O
of	O
typical	O
bone	O
lesions	O
on	O
roentgenography	O
suggested	O
the	O
existence	O
of	O
disseminated	O
prostatic	O
carcinoma	O
.	O

An	O
experimental	O
long	O
-	O
term	O
study	O
.	O

No	O
anisotropism	O
was	O
recorded	O
in	O
a	O
tetrahydrofuran	O
solution	O
.	O

The	O
calculated	O
values	O
of	O
lambda	O
tb	O
at	O
37	O
degrees	O
C	O
and	O
50	O
per	O
cent	O
haematocrit	O
were	O
0	O
.	O
650	O
for	O
the	O
pulp	O
,	O
0	O
.	O
674	O
for	O
the	O
tongue	O
,	O
0	O
.	O
828	O
for	O
the	O
submandibular	O
gland	O
and	O
0	O
.	O
881	O
for	O
the	O
gingiva	O
of	O
the	O
dog	O
.	O
lambda	O
cp	O
increased	O
and	O
lambda	O
tp	O
decreased	O
as	O
the	O
temperature	O
was	O
reduced	O
from	O
37	O
to	O
4	O
degrees	O
C	O
.	O

As	O
pleural	O
thickening	O
is	O
seen	O
commonly	O
in	O
asbestosis	O
and	O
may	O
influence	O
lung	O
volumes	O
and	O
the	O
ratio	O
of	O
transfer	B-GENE
factor	I-GENE
to	O
effective	O
alveolar	O
volume	O
,	O
the	O
results	O
of	O
these	O
measurements	O
were	O
compared	O
only	O
in	O
the	O
cases	O
showing	O
absent	O
or	O
minimal	O
pleural	O
thickening	O
.	O

The	O
invasive	O
pattern	O
of	O
squamous	O
cell	O
carcinoma	O
in	O
the	O
mandibular	O
gingiva	O

Azygos	O
vein	O
abutting	O
the	O
posterior	O
wall	O
of	O
the	O
right	O
main	O
and	O
upper	O
lobe	O
bronchi	O
:	O
a	O
normal	O
CT	O
variant	O
.	O

However	O
,	O
the	O
history	O
of	O
acute	O
severe	O
complications	O
from	O
otitis	O
media	O
revealed	O
a	O
higher	O
frequency	O
in	O
those	O
individuals	O
with	O
alpha	B-GENE
1	I-GENE
-	I-GENE
antitrypsin	I-GENE
deficiency	O
as	O
compared	O
to	O
normals	O
.	O

All	O
other	O
changes	O
at	O
the	O
3	O
-	O
,	O
5	O
-	O
,	O
and	O
6	O
-	O
positions	O
,	O
as	O
well	O
as	O
the	O
replacement	O
of	O
the	O
phenyl	O
group	O
at	O
position	O
2	O
,	O
caused	O
a	O
marked	O
decrease	O
of	O
activity	O
.	O

Limb	O
allografts	O
in	O
rats	O
immunosuppressed	O
with	O
cyclosporin	O
A	O
.	O

The	O
method	O
involved	O
deproteinizing	O
samples	O
with	O
two	O
volumes	O
of	O
acetonitrile	O
followed	O
by	O
injection	O
of	O
5	O
microliters	O
of	O
deproteinized	O
supernatant	O
onto	O
a	O
C18	O
reversed	O
-	O
phase	O
column	O
.	O

Refractory	O
periods	O
of	O
the	O
AV	O
junction	O
were	O
altered	O
in	O
a	O
comparable	O
fashion	O
to	O
conduction	O
through	O
the	O
AV	O
node	O
.	O

This	O
paper	O
brings	O
together	O
data	O
,	O
obtained	O
from	O
a	O
variety	O
of	O
sources	O
,	O
on	O
the	O
extent	O
of	O
prescription	O
and	O
use	O
of	O
psychotropic	O
drugs	O
in	O
the	O
late	O
1960s	O
and	O
early	O
1970s	O
.	O

Sixteen	O
patients	O
were	O
studied	O
within	O
24	O
hours	O
of	O
resuscitation	O
and	O
all	O
showed	O
depressed	O
right	O
ventricular	O
ejection	O
(	O
RVEF	O
)	O
and	O
/	O
or	O
an	O
increased	O
end	O
-	O
diastolic	O
volume	O
(	O
RVEDVI	O
)	O
.	O

During	O
a	O
single	O
LAD	O
occlusion	O
lasting	O
35	O
minutes	O
(	O
series	O
I	O
,	O
n	O
=	O
10	O
)	O
9	O
microns	O
TMs	O
were	O
infused	O
immediately	O
and	O
30	O
minutes	O
after	O
ligation	O
,	O
15	O
microns	O
TMs	O
being	O
infused	O
after	O
15	O
-	O
20	O
minutes	O
.	O

The	O
population	O
of	O
between	O
75	O
,	O
000	O
and	O
100	O
,	O
000	O
was	O
largely	O
unstable	O
,	O
and	O
cost	O
per	O
capita	O
was	O
$	O
0	O
.	O
95	O
to	O
$	O
1	O
.	O
21	O
.	O

HL	O
02	O
type	O
oculomotor	O
stimulator	O
.	O

Four	O
patients	O
(	O
group	O
1	O
)	O
had	O
type	O
I	O
basement	O
membrane	O
nephropathy	O
,	O
characterized	O
by	O
marked	O
thickening	O
and	O
lamellation	O
of	O
the	O
basement	O
membrane	O
in	O
a	O
pattern	O
resembling	O
that	O
of	O
Alport	O
'	O
s	O
syndrome	O
.	O

Brain	O
pH	O
following	O
3	O
h	O
of	O
cerebral	O
focal	O
ischemia	O
changed	O
from	O
a	O
normal	O
value	O
of	O
7	O
.	O
0	O
to	O
6	O
.	O
5	O
and	O
6	O
.	O
2	O
in	O
animals	O
studied	O
under	O
barbiturate	O
and	O
halothane	O
anesthesia	O
,	O
respectively	O
.	O

Our	O
results	O
demonstrate	O
the	O
importance	O
of	O
phosphate	O
and	O
calcium	O
in	O
influencing	O
the	O
secretion	O
of	O
PTH	B-GENE
and	O
CT	B-GENE
in	O
uremia	O
.	O

Thin	O
-	O
layer	O
chromatographic	O
methods	O
were	O
up	O
-	O
dated	O
for	O
pharmacokinetic	O
studies	O
of	O
imipramine	O
in	O
plasma	O
and	O
urine	O
.	O

Increasing	O
the	O
cut	O
-	O
off	O
point	O
to	O
3	O
positive	O
responses	O
decreased	O
the	O
sensitivity	O
to	O
81	O
%	O
and	O
increased	O
the	O
specificity	O
to	O
94	O
%	O
.	O

After	O
clofelin	O
administration	O
the	O
autoregulation	O
borders	O
shifted	O
to	O
the	O
right	O
i	O
.	O
e	O
.	O
towards	O
higher	O
AP	O
levels	O
.	O

This	O
phenomenon	O
may	O
be	O
regarded	O
as	O
a	O
variant	O
of	O
selective	O
individual	O
cell	O
death	O
,	O
currently	O
referred	O
to	O
as	O
apoptosis	O
,	O
which	O
has	O
not	O
been	O
previously	O
reported	O
in	O
a	O
case	O
of	O
embryonal	O
rhabdomyosarcoma	O
.	O

A	O
combined	O
series	O
of	O
patients	O
experienced	O
a	O
TOL	O
after	O
two	O
or	O
more	O
previous	O
cesarean	O
deliveries	O
;	O
the	O
rate	O
of	O
vaginal	O
delivery	O
was	O
66	O
%	O
,	O
and	O
there	O
was	O
virtually	O
no	O
morbidity	O
.	O

Nursing	O
home	O
discharges	O
in	O
clinical	O
practice	O
.	O

The	O
carcinogen	O
bioassay	O
therefore	O
is	O
a	O
very	O
important	O
component	O
of	O
the	O
battery	O
of	O
toxicological	O
tests	O
used	O
in	O
hazard	O
evaluation	O
.	O

Harmful	O
effects	O
in	O
animals	O
and	O
man	O
may	O
result	O
from	O
both	O
deficient	O
or	O
excessive	O
amounts	O
of	O
intake	O
.	O

Angionephroscintigraphy	O
in	O
the	O
diagnosis	O
of	O
diseases	O
of	O
the	O
kidney	O

The	O
analysis	O
of	O
the	O
structure	O
of	O
the	O
sleep	O
period	O
as	O
a	O
whole	O
reveals	O
that	O
with	O
increasing	O
of	O
the	O
age	O
the	O
delta	O
-	O
wave	O
stage	O
(	O
DS	O
)	O
of	O
the	O
QS	O
(	O
determined	O
by	O
defined	O
polygraphic	O
parameters	O
)	O
increases	O
,	O
while	O
the	O
paradoxical	O
phase	O
of	O
sleep	O
(	O
PS	O
)	O
decreases	O
,	O
this	O
change	O
being	O
more	O
pronounced	O
during	O
the	O
first	O
six	O
months	O
than	O
during	O
the	O
second	O
ones	O
of	O
the	O
first	O
year	O
of	O
the	O
life	O
.	O

[	O
82Br	O
]	O
MISO	O
was	O
prepared	O
by	O
irradiating	O
samples	O
of	O
Br	O
-	O
MISO	O
in	O
a	O
SLOWPOKE	O
reactor	O
for	O
2	O
h	O
at	O
a	O
thermal	O
neutron	O
flux	O
of	O
10	O
(	O
12	O
)	O
n	O
cm	O
-	O
2	O
s	O
-	O
1	O
.	O

Morphofunctional	O
status	O
of	O
the	O
formed	O
elements	O
of	O
the	O
blood	O
in	O
rats	O
subjected	O
to	O
different	O
variants	O
of	O
combined	O
and	O
isolated	O
exposure	O
to	O
BR	O
-	O
1	O
benzene	O

The	O
liver	O
in	O
the	O
severely	O
ill	O

In	O
a	O
randomized	O
study	O
on	O
150	O
patients	O
(	O
ASA	O
1	O
)	O
undergoing	O
induction	O
of	O
anaesthesia	O
,	O
the	O
effects	O
of	O
Fentanyl	O
(	O
0	O
.	O
1	O
mg	O
)	O
,	O
the	O
combination	O
of	O
Fentanyl	O
(	O
0	O
.	O
1	O
mg	O
)	O
and	O
Droperidol	O
(	O
5	O
mg	O
)	O
(	O
Innovar	O
,	O
Thalamonal	O
)	O
and	O
Atropine	O
(	O
0	O
.	O
01	O
mg	O
/	O
kg	O
b	O
.	O
w	O
.	O
)	O
alone	O
on	O
cardiocirculatory	O
parameters	O
were	O
studied	O
.	O

These	O
results	O
confirming	O
the	O
high	O
validity	O
of	O
NOM	O
inhibiting	O
test	O
in	O
the	O
diagnosis	O
of	O
tumoural	O
hyperprolactinemic	O
states	O
,	O
reveal	O
contradictory	O
responses	O
to	O
CD	O
/	O
LD	O
,	O
LD	O
and	O
DOM	O
,	O
with	O
sustain	O
the	O
existence	O
of	O
2	O
sub	O
-	O
group	O
of	O
Prolactinomas	O
:	O
with	O
or	O
without	O
a	O
maintained	O
DA	O
central	O
tonus	O
supporting	O
the	O
possibility	O
of	O
different	O
etiopathogenetical	O
factors	O
in	O
inducing	O
a	O
tumoural	O
hyperprolactinemic	O
states	O
.	O

Low	O
NA	O
and	O
A	O
may	O
participate	O
in	O
lowering	O
the	O
plasma	B-GENE
renin	I-GENE
activity	O
which	O
in	O
PA	O
in	O
suppressed	O
,	O
sometimes	O
disproportionately	O
to	O
the	O
actual	O
body	O
sodium	O
content	O
.	O

Amikacin	O
concentrations	O
in	O
serum	O
and	O
blister	O
fluid	O
in	O
healthy	O
volunteers	O
and	O
in	O
patients	O
with	O
renal	O
impairment	O
.	O

The	O
subgroup	O
innervating	O
the	O
medial	O
rectus	O
lies	O
exclusively	O
along	O
the	O
medial	O
face	O
of	O
the	O
oculomotor	O
nucleus	O
,	O
with	O
no	O
aberrant	O
neurons	O
in	O
the	O
medial	O
longitudinal	O
fasciculus	O
,	O
as	O
have	O
been	O
found	O
in	O
other	O
mammals	O
.	O

Hepatitis	O
B	O
vaccination	O
strategy	O
for	O
health	O
-	O
care	O
workers	O
in	O
a	O
country	O
of	O
intermediate	O
hepatitis	O
B	O
endemicity	O
.	O

An	O
intravenous	O
drip	O
infusion	O
of	O
AMK	O
in	O
adequate	O
dosage	O
would	O
be	O
beneficial	O
to	O
use	O
against	O
some	O
infectious	O
diseases	O
of	O
otorhinolaryngologic	O
field	O
.	O

Out	O
of	O
these	O
families	O
74	O
,	O
3	O
%	O
planned	O
next	O
pregnancy	O
(	O
table	O
IX	O
)	O
,	O
57	O
,	O
6	O
%	O
wanted	O
to	O
have	O
prenatal	O
diagnosis	O
(	O
table	O
VI	O
)	O
.	O

The	O
authors	O
have	O
tested	O
the	O
interference	O
of	O
the	O
hemoglobin	B-GENE
by	O
two	O
routine	O
methods	O
(	O
Berthelot	O
classic	O
and	O
Berthelot	O
modified	O
)	O
for	O
the	O
determination	O
of	O
plasmatic	O
urea	O
.	O

Parkinsonian	O
patients	O
had	O
a	O
significantly	O
lower	O
prevalence	O
of	O
alcohol	O
use	O
.	O

These	O
cells	O
averaged	O
17	O
microns	O
in	O
diameter	O
and	O
reproduced	O
by	O
fission	O
,	O
forming	O
clusters	O
of	O
two	O
or	O
four	O
daughter	O
cells	O
.	O

Female	O
but	O
not	O
male	O
mortalities	O
were	O
significantly	O
higher	O
for	O
cake	O
-	O
fed	O
rats	O
than	O
for	O
those	O
fed	O
diet	O
41B	O
.	O

Urinary	B-GENE
N	I-GENE
-	I-GENE
acetylglucosaminidase	I-GENE
activity	O
per	O
mg	O
creatinine	O
did	O
not	O
differ	O
significantly	O
between	O
groups	O
.	O

The	O
associations	O
between	O
sex	B-GENE
-	I-GENE
hormone	I-GENE
-	I-GENE
binding	I-GENE
globulin	I-GENE
capacity	O
(	O
SHBG	B-GENE
)	O
,	O
age	O
,	O
body	O
mass	O
index	O
(	O
BMI	O
)	O
,	O
and	O
physical	O
fitness	O
have	O
been	O
studied	O
in	O
34	O
men	O
and	O
36	O
women	O
.	O

Dipetalonema	O
(	O
Alafilaria	O
)	O
hydrochoerus	O
subgen	O
.	O
et	O
sp	O
.	O
n	O
.	O

After	O
1	O
.	O
5	O
years	O
of	O
such	O
photoperiodic	O
control	O
,	O
all	O
ewes	O
were	O
blinded	O
by	O
bilateral	O
orbital	O
enucleation	O
.	O

The	O
concentrations	O
of	O
C4	B-GENE
and	O
C1	B-GENE
-	I-GENE
INH	I-GENE
increased	O
with	O
advancing	O
stage	O
of	O
disease	O
and	O
were	O
above	O
normal	O
mean	O
values	O
in	O
all	O
stages	O
.	O

Less	O
antibacterial	O
activity	O
was	O
shown	O
toward	O
the	O
Gram	O
-	O
negative	O
bacilli	O
,	O
i	O
.	O
e	O
.	O
,	O
Pseudomonas	O
,	O
Klebsiella	O
-	O
Enterobacter	O
,	O
Shigella	O
,	O
Escherichia	O
coli	O
,	O
Serratia	O
marcescens	O
and	O
Proteus	O
.	O

The	O
mucosal	O
defence	O
capacity	O
against	O
proteolytic	O
leukocyte	O
enzymes	O
.	O

The	O
apparatus	O
consists	O
of	O
an	O
Am	O
-	O
241	O
exciting	O
source	O
(	O
300	O
mCi	O
)	O
and	O
pure	O
Ge	O
detector	O
(	O
50	O
mm2	O
X	O
5	O
mm	O
)	O
for	O
measuring	O
K	O
alpha	O
fluorescent	O
x	O
-	O
rays	O
(	O
28	O
.	O
3	O
and	O
28	O
.	O
6	O
KeV	O
)	O
emitted	O
from	O
exited	O
iodine	O
.	O

Ultrastructural	O
studies	O
of	O
retinopathy	O
of	O
premature	O
infants	O

The	O
range	O
of	O
serum	O
concentrations	O
,	O
mean	O
values	O
,	O
median	O
values	O
,	O
and	O
standard	O
deviations	O
for	O
each	O
analyte	O
are	O
reported	O
for	O
males	O
and	O
females	O
and	O
for	O
three	O
age	O
groups	O
(	O
25	O
-	O
44	O
,	O
45	O
-	O
59	O
,	O
60	O
-	O
70	O
)	O
.	O

The	O
effects	O
of	O
antithrombotic	O
drugs	O
in	O
patients	O
with	O
left	O
ventricular	O
thrombi	O
:	O
assessment	O
with	O
indium	O
-	O
111	O
platelet	O
imaging	O
and	O
two	O
-	O
dimensional	O
echocardiography	O
.	O

A	O
stable	O
interface	O
depends	O
on	O
overall	O
stress	O
and	O
microstress	O
distribution	O
on	O
the	O
bone	O
,	O
particularly	O
trabecular	O
bone	O
.	O

Plasma	O
NE	O
was	O
also	O
low	O
in	O
the	O
anephric	O
group	O
(	O
289	O
mg	O
/	O
liter	O
+	O
/	O
-	O
126	O
(	O
1	O
SD	O
)	O
vs	O
612	O
+	O
/	O
-	O
189	O
,	O
P	O
=	O
0	O
.	O
033	O
,	O
resting	O
)	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
250	O
WORDS	O
)	O

10	O
long	O
-	O
term	O
hemodialysis	O
patients	O
had	O
immediate	O
and	O
redistribution	O
thallium	O
-	O
201	O
myocardial	O
imaging	O
performed	O
after	O
a	O
course	O
of	O
hemodialysis	O
.	O

The	O
Prolactin	B-GENE
levels	O
were	O
within	O
the	O
physiological	O
norms	O
;	O
the	O
responses	O
to	O
TRH	B-GENE
were	O
normal	O
,	O
and	O
elevated	O
only	O
in	O
a	O
few	O
cases	O
.	O

Despite	O
total	O
tumor	O
resection	O
,	O
multiple	O
intraperitoneal	O
tumor	O
nodules	O
of	O
varying	O
sizes	O
were	O
found	O
and	O
resected	O
six	O
months	O
and	O
one	O
year	O
later	O
.	O

Private	O
hospital	O
accreditation	O
.	O

Antithrombin	B-GENE
III	I-GENE
in	O
hip	O
surgery	O

In	O
14	O
of	O
21	O
infant	O
hearts	O
(	O
66	O
%	O
)	O
with	O
aortic	O
arch	O
interruption	O
between	O
the	O
left	O
common	O
carotid	O
and	O
left	O
subclavian	O
arteries	O
(	O
type	O
B	O
of	O
Celoria	O
and	O
Patton	O
)	O
,	O
the	O
right	O
subclavian	O
artery	O
(	O
SA	O
)	O
arose	O
anomalously	O
.	O

We	O
suggest	O
that	O
sensitivity	O
to	O
photoperiod	O
in	O
pallid	O
bats	O
,	O
as	O
in	O
several	O
other	O
mammals	O
,	O
is	O
mediated	O
by	O
the	O
pineal	O
gland	O
.	O

Absorption	O
was	O
rapid	O
,	O
with	O
a	O
mean	O
time	O
to	O
peak	O
of	O
39	O
min	O
.	O

Additionally	O
,	O
observations	O
that	O
patients	O
with	O
mitral	O
versus	O
aortic	O
regurgitation	O
respond	O
differently	O
to	O
valve	O
replacement	O
suggest	O
that	O
differences	O
exist	O
preoperatively	O
between	O
these	O
two	O
types	O
of	O
volume	O
overload	O
.	O

A	O
case	O
of	O
manifest	O
latent	O
nystagmus	O
of	O
late	O
onset	O
in	O
a	O
13	O
-	O
year	O
-	O
old	O
girl	O
is	O
reported	O
.	O

Within	O
the	O
compartment	O
or	O
dimension	O
of	O
severity	O
of	O
depression	O
a	O
subscale	O
of	O
the	O
Hamilton	O
Depression	O
Scale	O
(	O
or	O
the	O
Melancholia	O
Scale	O
)	O
was	O
shown	O
to	O
have	O
reached	O
an	O
instrumental	O
perfection	O
,	O
e	O
.	O
g	O
.	O
as	O
an	O
outcome	O
measure	O
of	O
antidepressant	O
treatment	O
.	O

Significant	O
immunoglobulinuria	O
developed	O
prior	O
to	O
the	O
development	O
of	O
azotemia	O
,	O
significantly	O
decreased	O
creatinine	O
clearance	O
,	O
significant	O
proteinuria	O
(	O
greater	O
than	O
or	O
equal	O
to	O
3	O
+	O
dipstick	O
or	O
greater	O
than	O
or	O
equal	O
to	O
5	O
gm	O
per	O
24	O
-	O
hour	O
urine	O
collection	O
)	O
,	O
or	O
oliguria	O
.	O

A	O
total	O
number	O
of	O
1628	O
cases	O
were	O
collected	O
from	O
135	O
medical	O
institutions	O
.	O

Epileptiform	O
activity	O
recorded	O
from	O
superficial	O
laminae	O
bordering	O
layer	O
4	O
,	O
and	O
into	O
which	O
layer	O
4	O
'	O
s	O
primary	O
projections	O
terminate	O
,	O
is	O
suppressed	O
preferentially	O
by	O
phenytoin	O
.	O

Is	O
nisoldipine	O
capable	O
of	O
reducing	O
left	O
ventricular	O
preload	O
?	O
In	O
ten	O
anesthetized	O
pigs	O
,	O
nisoldipine	O
(	O
2	O
-	O
4	O
micrograms	O
X	O
kg	O
-	O
1	O
X	O
min	O
-	O
1	O
)	O
,	O
a	O
calcium	O
channel	O
blocker	O
structurally	O
related	O
to	O
nifedipine	O
,	O
reduced	O
left	O
ventricular	O
systolic	O
pressure	O
(	O
40	O
%	O
)	O
and	O
systemic	O
vascular	O
resistance	O
(	O
35	O
%	O
)	O
,	O
whereas	O
maxLVdP	O
/	O
dt	O
decreased	O
by	O
20	O
%	O
and	O
cardiac	O
output	O
was	O
unchanged	O
.	O

Monkeys	O
were	O
evaluated	O
before	O
and	O
after	O
unilateral	O
and	O
serial	O
bilateral	O
removal	O
of	O
superior	O
temporal	O
cortex	O
.	O

Plasma	B-GENE
lactoferrin	I-GENE
and	O
the	O
blood	O
count	O
of	O
polynuclear	O
neutrophils	O

The	O
importance	O
of	O
selective	O
renal	O
vein	O
phlebography	O
in	O
the	O
evaluation	O
of	O
unexplained	O
hematuria	O
and	O
filing	O
defects	O
in	O
the	O
excretory	O
urogram	O
is	O
illustrated	O
.	O

The	O
statistical	O
analysis	O
consist	O
of	O
the	O
F	O
test	O
followed	O
by	O
Snedecor	O
'	O
s	O
contrast	O
test	O
.	O

The	O
pyramidal	O
tract	O
and	O
Mesencephalic	O
Reticular	O
Formation	O
(	O
MRF	O
)	O
were	O
stimulated	O
before	O
and	O
after	O
the	O
transection	O
.	O

No	O
patient	O
with	O
bradyarrhythmia	O
-	O
related	O
SCD	O
had	O
manifest	O
atrioventricular	O
block	O
or	O
bundle	O
branch	O
block	O
.	O

The	O
measurement	O
of	O
the	O
areas	O
of	O
fibrin	B-GENE
,	O
of	O
tissue	O
and	O
fibrinolysis	O
,	O
at	O
the	O
above	O
mentioned	O
times	O
,	O
has	O
been	O
effected	O
at	O
standard	O
magnification	O
(	O
15	O
X	O
)	O
by	O
an	O
image	O
analyser	O
(	O
Videoplan	O
)	O
scale	O
1	O
:	O
8	O
.	O

Diclofenac	O
sodium	O
-	O
chlormezanone	O
poisoning	O
.	O

Postprandial	O
plasma	B-GENE
enteroglucagon	I-GENE
concentration	O
after	O
90	O
minutes	O
in	O
untreated	O
patients	O
correlated	O
positively	O
to	O
the	O
faecal	O
fat	O
excretion	O
(	O
r	O
=	O
0	O
.	O
58	O
,	O
p	O
less	O
than	O
0	O
.	O
02	O
)	O
.	O

Blood	O
pressure	O
in	O
children	O
.	O

In	O
this	O
study	O
the	O
splenectomized	O
captive	O
born	O
cynomolgus	O
appeared	O
to	O
be	O
capable	O
of	O
supplementing	O
rhesus	O
as	O
an	O
antimalarial	O
drug	O
testing	O
model	O
.	O

The	O
results	O
showed	O
that	O
the	O
sensitivity	O
of	O
the	O
3	O
given	O
guinea	O
pig	O
strains	O
was	O
comparable	O
.	O

Adult	O
Amblyomma	O
lepidum	O
ticks	O
fed	O
as	O
nymphs	O
on	O
this	O
goat	O
transmitted	O
heartwater	O
to	O
a	O
Friesian	O
(	O
Bos	O
taurus	O
)	O
calf	O
.	O

Morphine	O
injected	O
into	O
the	O
lateral	O
ventricle	O
of	O
the	O
rat	O
produced	O
unilateral	O
analgesia	O
in	O
the	O
formalin	O
test	O
,	O
which	O
involves	O
continuous	O
,	O
moderate	O
pain	O
.	O

The	O
maps	O
of	O
Case	O
2	O
showed	O
that	O
a	O
maximum	O
first	O
appeared	O
on	O
the	O
upper	O
right	O
back	O
and	O
then	O
moved	O
down	O
the	O
right	O
side	O
of	O
the	O
posterior	O
thorax	O
.	O

Urinary	O
urate	O
excretion	O
,	O
urate	O
clearance	O
,	O
and	O
fractional	O
excretion	O
of	O
urate	O
all	O
increased	O
significantly	O
during	O
water	O
immersion	O
,	O
and	O
decreased	O
in	O
the	O
hour	O
following	O
water	O
immersion	O
.	O

Mutations	O
in	O
seven	O
other	O
lts	B-GENE
genes	I-GENE
do	O
not	O
result	O
in	O
the	O
mak	B-GENE
-	I-GENE
phenotype	I-GENE
.	O

Twenty	O
-	O
eight	O
were	O
excluded	O
as	O
gallstones	O
were	O
not	O
proved	O
:	O
of	O
the	O
remainder	O
,	O
21	O
patients	O
received	O
glucagon	B-GENE
and	O
22	O
placebo	O
.	O

4	O
Five	O
patients	O
died	O
within	O
one	O
month	O
of	O
captopril	O
and	O
five	O
between	O
four	O
and	O
seven	O
months	O
,	O
three	O
of	O
whom	O
had	O
improved	O
to	O
class	O
IIM	O
and	O
one	O
to	O
IIS	O
before	O
death	O
.	O

Regions	O
of	O
the	O
translated	O
open	O
reading	O
frames	O
of	O
cobA	B-GENE
and	O
the	O
third	O
intron	O
of	O
the	O
cob	B-GENE
gene	I-GENE
in	I-GENE
yeast	I-GENE
show	O
high	O
amino	O
acid	O
homology	O
.	O

Multiresistant	O
strains	O
isolated	O
from	O
humans	O
in	O
enteral	O
toxico	O
-	O
infections	O
kill	O
orally	O
infected	O
mice	O
more	O
frequently	O
than	O
strains	O
isolated	O
in	O
hospital	O
infections	O
.	O

Single	O
tooth	O
replacement	O
with	O
the	O
aid	O
of	O
the	O
ITI	O
(	O
International	O
Team	O
fur	O
Implantologie	O
)	O
type	O
F	O
hollow	O
-	O
cylinder	O
implant	O

The	O
13	O
,	O
14	O
-	O
dihydro	O
-	O
15	O
-	O
keto	O
-	O
metabolites	O
of	O
PGE2	O
and	O
PGF2	O
alpha	O
had	O
no	O
statistically	O
significant	O
antiarrhythmic	O
effect	O
.	O

Nucleotide	O
sequence	O
of	O
DNA	O
controlling	O
expression	O
of	O
genes	O
for	O
maltosaccharide	O
utilization	O
in	O
Streptococcus	O
pneumoniae	O
.	O

Colorimetric	O
determination	O
of	O
urinary	O
iron	O
,	O
chelated	O
with	O
deferoxamine	O
B	O
,	O
using	O
a	O
single	O
reagent	O

Measurements	O
of	O
perfusion	O
also	O
showed	O
significantly	O
higher	O
values	O
under	O
active	O
therapy	O
.	O

HLA	B-GENE
-	I-GENE
A	I-GENE
and	I-GENE
B	I-GENE
phenotypes	O
of	O
105	O
patients	O
suffering	O
from	O
malignant	O
melanomas	O
were	O
determined	O
,	O
with	O
special	O
regard	O
for	O
metastatic	O
form	O
or	O
relapse	O
.	O

Trypanosoma	O
cruzi	O
.	O

The	O
subjects	O
of	O
the	O
study	O
were	O
10	O
normal	O
subjects	O
and	O
64	O
patients	O
with	O
gastroduodenal	O
disease	O
.	O

This	O
study	O
represents	O
the	O
first	O
published	O
long	O
-	O
term	O
follow	O
-	O
up	O
regarding	O
this	O
mode	O
of	O
treatment	O
in	O
patients	O
with	O
alveolar	O
hypoventilation	O
.	O

A	O
convenient	O
measure	O
of	O
this	O
impairment	O
may	O
be	O
obtained	O
using	O
the	O
ratio	O
of	O
urine	O
volume	O
(	O
V	O
)	O
divided	O
by	O
lithium	O
clearance	O
(	O
CLi	O
)	O
.	O

Nitrogen	O
balance	O
was	O
compared	O
,	O
and	O
metabolic	O
complications	O
were	O
monitored	O
by	O
evaluating	O
BUN	O
,	O
serum	O
creatinine	O
,	O
creatinine	O
clearance	O
,	O
serum	O
CO2	O
,	O
SGOT	B-GENE
,	O
SGPT	B-GENE
,	O
serum	B-GENE
LDH	I-GENE
,	O
and	O
serum	B-GENE
alkaline	I-GENE
phosphatase	I-GENE
.	O

Production	O
of	O
C	B-GENE
mu	I-GENE
RNAs	I-GENE
,	O
unlike	O
mu	B-GENE
mRNAs	I-GENE
,	O
does	O
not	O
require	O
recombination	O
with	O
the	O
joining	B-GENE
region	I-GENE
(	O
JH	B-GENE
)	O
locus	O
.	O

The	O
1	O
.	O
9	O
-	O
kb	O
C	B-GENE
mu	I-GENE
RNA	O
contains	O
the	O
3	O
'	O
sequence	O
characteristic	O
of	O
secreted	O
mu	B-GENE
chain	I-GENE
,	O
whereas	O
the	O
longer	O
species	O
bear	O
that	O
of	O
membrane	O
-	O
bound	O
mu	B-GENE
chin	O
.	O

Transcripts	O
of	O
the	O
immunoglobulin	B-GENE
C	I-GENE
mu	I-GENE
gene	I-GENE
vary	O
in	O
structure	O
and	O
splicing	O
during	O
lymphoid	O
development	O
.	O

Non	O
-	O
complement	O
-	O
dependent	O
sperm	O
-	O
immobilizing	O
activity	O
was	O
also	O
detected	O
in	O
the	O
cervical	O
mucus	O
of	O
several	O
patients	O
.	O

Although	O
the	O
mechanism	O
of	O
action	O
of	O
ICRF	O
-	O
159	O
and	O
187	O
has	O
not	O
been	O
clearly	O
defined	O
,	O
it	O
is	O
evident	O
from	O
both	O
preclinical	O
and	O
early	O
clinical	O
studies	O
that	O
these	O
compounds	O
are	O
of	O
interest	O
.	O

All	O
62	O
isolates	O
were	O
resistant	O
to	O
lincomycin	O
,	O
colistin	O
,	O
nystatin	O
,	O
amphotericin	O
B	O
,	O
trimethoprim	O
lactate	O
,	O
polymyxin	O
B	O
,	O
and	O
anisomycin	O
.	O

The	O
evaluation	O
of	O
amniotic	O
fluid	O
delta	O
OD450	O
is	O
considered	O
to	O
be	O
the	O
cornerstone	O
of	O
clinical	O
management	O
.	O

Host	O
lipids	O
in	O
tuberculous	O
infection	O
.	O

The	O
sympathetic	O
neuroeffector	O
influence	O
on	O
the	O
myocardium	O
with	O
ATCI	O
depends	O
to	O
a	O
large	O
measure	O
on	O
the	O
intensity	O
of	O
the	O
neurotransmitter	O
biosynthesis	O
and	O
function	O
of	O
cardiomyocyte	O
adrenoreceptors	O
.	O

Lens	B-GENE
aldose	I-GENE
reductase	I-GENE
in	O
diabetic	O
and	O
galactosemic	O
cataracts	O
.	O

Fenfluramine	O
(	O
in	O
doses	O
ranging	O
from	O
0	O
.	O
0625	O
-	O
4	O
.	O
0	O
mg	O
/	O
kg	O
/	O
infusion	O
)	O
did	O
not	O
maintain	O
self	O
-	O
administration	O
behavior	O
at	O
or	O
above	O
the	O
minimum	O
requirement	O
(	O
FR	O
30	O
)	O
.	O

In	O
the	O
course	O
of	O
Hepatitis	B-GENE
A	I-GENE
HBs	I-GENE
-	I-GENE
and	I-GENE
HBe	I-GENE
-	I-GENE
antigen	I-GENE
as	O
well	O
as	O
HBc	B-GENE
(	I-GENE
IgM	I-GENE
and	I-GENE
IgG	I-GENE
)	I-GENE
-	I-GENE
,	I-GENE
HBs	I-GENE
-	I-GENE
and	I-GENE
HBe	I-GENE
-	I-GENE
antibodies	I-GENE
can	O
be	O
detected	O
.	O

The	O
effect	O
of	O
the	O
fatty	B-GENE
acid	I-GENE
cyclo	I-GENE
-	I-GENE
oxygenase	I-GENE
inhibitor	O
indomethacin	O
on	O
cerebral	O
blood	O
flow	O
(	O
CBF	O
)	O
and	O
the	O
metabolic	O
rate	O
for	O
oxygen	O
(	O
CMRO2	O
)	O
was	O
studied	O
in	O
paralyzed	O
and	O
artificially	O
ventilated	O
rats	O
.	O

The	O
rat	O
incisor	O
is	O
an	O
excellent	O
model	O
system	O
in	O
which	O
to	O
study	O
amelgenesis	O
.	O

The	O
already	O
elevated	O
prolactin	B-GENE
levels	O
in	O
nursing	O
women	O
were	O
not	O
influenced	O
by	O
chronic	O
oestradiol	O
administration	O
.	O

Morphine	O
-	O
dependent	O
and	O
control	O
rats	O
in	O
an	O
oral	O
free	O
-	O
choice	O
protocol	O
were	O
treated	O
with	O
gamma	O
-	O
vinyl	O
GABA	O
(	O
GVG	O
)	O
,	O
60	O
,	O
120	O
and	O
240	O
mg	O
/	O
kg	O
IP	O
,	O
for	O
3	O
days	O
over	O
three	O
successive	O
periods	O
.	O

Significance	O
of	O
the	O
pulmonary	O
gas	O
exchange	O
reaction	O
to	O
physical	O
loading	O
in	O
evaluating	O
the	O
effectiveness	O
of	O
mitral	O
commissurotomy	O

Thyreoliberin	B-GENE
VUFB	O
in	O
thyroid	O
gammagraphy	O

Advances	O
in	O
hemophilia	O
treatment	O
:	O
a	O
hepatitis	O
-	O
safe	O
factor	B-GENE
VIII	I-GENE
concentrate	O

This	O
study	O
was	O
designed	O
to	O
assess	O
and	O
compare	O
the	O
ability	O
of	O
three	O
different	O
forms	O
of	O
DSG	O
to	O
block	O
EIB	O
.	O

Comparison	O
of	O
three	O
different	O
preparations	O
of	O
disodium	O
cromoglycate	O
in	O
the	O
prevention	O
of	O
exercise	O
-	O
induced	O
bronchospasm	O
:	O
a	O
double	O
-	O
blind	O
study	O
.	O

LCBF	O
in	O
normal	O
and	O
hypoxic	O
puppies	O
was	O
correlated	O
with	O
local	O
cerebral	O
glucose	O
utilization	O
(	O
LCGU	O
)	O
obtained	O
under	O
the	O
same	O
experimental	O
conditions	O
(	O
Duffy	O
et	O
al	O
,	O
1982	O
)	O
.	O

Phagocytosis	O
of	O
tubercle	O
bacilli	O
by	O
macrophages	O
.	O

Detection	O
of	O
hemophilia	O
A	O
carriers	O
.	O

The	O
stability	O
of	O
isoniazid	O
solutions	O
increases	O
markedly	O
with	O
increasing	O
NTA	O
or	O
EDTA	O
concentration	O
up	O
to	O
1	O
mmol	O
/	O
l	O
.	O

Bile	O
bilirubin	O
did	O
not	O
rise	O
within	O
12	O
h	O
after	O
haem	O
infusion	O
a	O
finding	O
which	O
warrants	O
further	O
investigation	O
.	O

Autoimmune	O
manipulation	O
aids	O
juvenile	O
diabetes	O
management	O
.	O

Other	O
properties	O
of	O
Hg	O
-	O
and	O
Cd	O
-	O
spores	O
were	O
similar	O
to	O
those	O
of	O
control	O
spores	O
.	O

The	O
decrease	O
in	O
HDL	B-GENE
-	I-GENE
cholesterol	I-GENE
with	O
increasing	O
VLDL	B-GENE
-	I-GENE
triglycerides	I-GENE
was	O
relatively	O
much	O
larger	O
than	O
the	O
concomitant	O
decrease	O
in	O
apo	B-GENE
A	I-GENE
-	I-GENE
I	I-GENE
.	O

Apo	B-GENE
A	I-GENE
-	I-GENE
I	I-GENE
level	O
was	O
unrelated	O
to	O
age	O
,	O
but	O
increased	O
with	O
ethanol	O
consumption	O
and	O
decreased	O
with	O
adiposity	O
.	O

The	O
osmotic	O
diuretic	O
mannitol	O
was	O
administered	O
to	O
21	O
patients	O
.	O

Of	O
270	O
patients	O
with	O
well	O
-	O
defined	O
drug	O
reactions	O
,	O
190	O
(	O
70	O
per	O
cent	O
)	O
gave	O
a	O
positive	O
response	O
to	O
the	O
mast	O
cell	O
test	O
.	O

Selenium	O
,	O
as	O
a	O
constituent	O
of	O
glutathione	B-GENE
peroxidase	I-GENE
,	O
plays	O
a	O
role	O
in	O
the	O
antioxidant	O
defense	O
systems	O
of	O
the	O
body	O
,	O
but	O
other	O
metabolic	O
roles	O
for	O
selenium	O
may	O
yet	O
be	O
discovered	O
.	O

Diagnostic	O
value	O
of	O
serum	B-GENE
myoglobin	I-GENE
in	O
cases	O
of	O
neuromuscular	O
disease	O

At	O
43	O
%	O
blood	O
pressure	O
reduction	O
,	O
PCO2	O
fell	O
by	O
0	O
.	O
53	O
kPa	O
,	O
a	O
decrease	O
which	O
could	O
not	O
explain	O
the	O
observed	O
CBF	O
fall	O
of	O
27	O
%	O
.	O

During	O
the	O
last	O
6	O
months	O
of	O
the	O
study	O
a	O
striking	O
change	O
in	O
epidemiology	O
concerning	O
hepatitis	O
A	O
was	O
seen	O
,	O
apparently	O
caused	O
by	O
a	O
steep	O
increase	O
in	O
the	O
incidence	O
of	O
this	O
type	O
of	O
hepatitis	O
among	O
drug	O
addicts	O
.	O

Asthmatic	O
patients	O
showed	O
greater	O
responses	O
of	O
both	O
parameters	O
to	O
adrenaline	O
than	O
controls	O
indicating	O
that	O
long	O
-	O
term	O
corticosteroid	O
treatment	O
enhances	O
the	O
acute	O
responses	O
of	O
plasminogen	B-GENE
activator	I-GENE
and	O
clotting	B-GENE
factor	I-GENE
VIII	I-GENE
to	O
adrenaline	O
infusion	O
.	O

Sulphur	O
amino	O
acids	O
(	O
g	O
/	O
16	O
g	O
N	O
)	O
were	O
higher	O
in	O
the	O
isolates	O
than	O
in	O
the	O
flours	O
.	O

Time	O
shifts	O
increase	O
growth	B-GENE
hormone	I-GENE
release	O
.	O

It	O
then	O
merged	O
with	O
right	O
ventricular	O
wavefronts	O
ending	O
along	O
the	O
right	O
ventricular	O
anterior	O
atrioventricular	O
groove	O
and	O
outflow	O
tract	O
.	O

Many	O
of	O
these	O
landfill	O
operations	O
were	O
undertaken	O
in	O
the	O
early	O
1950s	O
and	O
1960s	O
,	O
when	O
knowledge	O
regarding	O
the	O
safe	O
and	O
prolonged	O
containment	O
of	O
the	O
waste	O
buried	O
was	O
nonexistent	O
or	O
minimal	O
at	O
best	O
.	O

Vesicles	O
could	O
be	O
induced	O
only	O
with	O
multiple	O
exposures	O
to	O
UVA	O
.	O

The	O
level	O
of	O
contamination	O
in	O
the	O
wound	O
can	O
be	O
determined	O
with	O
the	O
rapid	O
biopsy	O
fixation	O
technique	O
.	O

Self	O
-	O
heating	O
after	O
deep	O
hypothermia	O
(	O
20	O
degrees	O
C	O
)	O
causes	O
a	O
considerable	O
increase	O
in	O
the	O
brain	O
tissues	O
glutaminase	B-GENE
activity	O
at	O
all	O
studied	O
incubation	O
temperatures	O
(	O
37	O
,	O
30	O
,	O
20	O
and	O
10	O
degrees	O
C	O
)	O
as	O
compared	O
to	O
control	O
rats	O
and	O
rats	O
under	O
hypothermia	O
.	O

According	O
to	O
Sugiura	O
'	O
s	O
classification	O
,	O
they	O
consisted	O
of	O
Type	O
Ia	O
in	O
63	O
%	O
,	O
Type	O
Ib	O
in	O
11	O
%	O
,	O
Type	O
II	O
in	O
11	O
%	O
,	O
and	O
Type	O
III	O
in	O
16	O
%	O
.	O

This	O
study	O
was	O
undertaken	O
to	O
define	O
the	O
mechanism	O
for	O
the	O
respiratory	O
inhibition	O
observed	O
during	O
high	O
-	O
frequency	O
oscillatory	O
ventilation	O
(	O
HFOV	O
)	O
.	O

Determination	O
of	O
20	O
alpha	O
-	O
hydroxy	O
-	O
9	O
beta	O
,	O
10	O
alpha	O
-	O
pregna	O
-	O
4	O
,	O
6	O
-	O
dien	O
-	O
3	O
-	O
one	O
in	O
plasma	O
by	O
selected	O
ion	O
monitoring	O
.	O

A	O
case	O
of	O
a	O
dense	O
epidermoid	O
cyst	O
of	O
the	O
suprasellar	O
cistern	O
is	O
presented	O
.	O

Copper	O
treatments	O
were	O
assigned	O
to	O
simulate	O
the	O
different	O
levels	O
of	O
copper	O
intake	O
that	O
might	O
result	O
from	O
differences	O
in	O
daily	O
feed	O
intake	O
similar	O
to	O
the	O
practice	O
followed	O
with	O
commercial	O
industry	O
.	O

Because	O
of	O
a	O
rapid	O
development	O
of	O
the	O
connective	O
tissue	O
scars	O
,	O
however	O
,	O
at	O
the	O
place	O
of	O
the	O
destroyed	O
glandular	O
parenchyma	O
areas	O
,	O
there	O
is	O
no	O
normalization	O
of	O
the	O
organ	O
'	O
s	O
structure	O
and	O
function	O
by	O
the	O
42d	O
day	O
.	O

Histological	O
signs	O
of	O
the	O
flare	O
-	O
up	O
reaction	O
were	O
already	O
present	O
at	O
6	O
hr	O
after	O
i	O
.	O
v	O
.	O
challenge	O
and	O
lasted	O
for	O
at	O
least	O
4	O
days	O
.	O

Significant	O
GMBF	O
reductions	O
occurred	O
in	O
early	O
shock	O
in	O
both	O
treatment	O
groups	O
.	O

Of	O
254	O
children	O
with	O
neuroblastoma	O
treated	O
at	O
St	O
.	O

Penicillin	O
-	O
G	O
degradation	O
products	O
inhibit	O
in	O
vitro	O
granulopoiesis	O
.	O

Plasma	O
fibrinogen	B-GENE
was	O
measured	O
by	O
the	O
turbidimetric	O
method	O
in	O
timol	O
turbidimetric	O
units	O
.	O

Five	O
patients	O
with	O
type	O
III	O
musculoskeletal	O
infection	O
from	O
nongonococcal	O
Neisseria	O
species	O
were	O
examined	O
during	O
a	O
13	O
-	O
month	O
period	O
.	O

Distal	O
tubular	O
acidification	O
and	O
the	O
threshold	O
for	O
proximal	O
tubular	O
bicarbonate	O
reabsorption	O
were	O
normal	O
,	O
as	O
was	O
urine	O
concentrating	O
capacity	O
.	O

The	O
Tullio	O
phenomenon	O
,	O
fistula	O
test	O
,	O
and	O
Hennebert	O
'	O
s	O
sign	O
:	O
clinical	O
significance	O
.	O

These	O
results	O
indicate	O
that	O
significant	O
pulmonary	O
metabolism	O
of	O
5	O
-	O
HT	O
followed	O
by	O
efflux	O
of	O
5	O
-	O
HIAA	O
into	O
venous	O
output	O
occurs	O
during	O
single	O
-	O
pass	O
circulation	O
.	O

Disturbances	O
of	O
placental	O
maturation	O
,	O
2	O
.	O

On	O
the	O
basis	O
of	O
histopathological	O
findings	O
,	O
the	O
origin	O
of	O
amyloid	O
appeared	O
to	O
be	O
closely	O
related	O
to	O
the	O
fibroblasts	O
.	O

Serum	O
lactate	B-GENE
dehydrogenase	I-GENE
and	O
haptoglobin	B-GENE
levels	O
were	O
normal	O
,	O
and	O
total	O
bilirubin	O
was	O
only	O
slightly	O
elevated	O
.	O

Low	O
-	O
dose	O
D	O
(	O
0	O
.	O
4	O
-	O
0	O
.	O
8	O
mg	O
)	O
and	O
DB	O
(	O
1	O
.	O
0	O
-	O
5	O
.	O
0	O
mg	O
)	O
did	O
not	O
significantly	O
alter	O
any	O
parameter	O
from	O
control	O
.	O

Leads	O
from	O
the	O
MMWR	O
.	O

The	O
presence	O
of	O
visna	O
-	O
maedi	O
in	O
Italy	O
is	O
reported	O
for	O
the	O
first	O
time	O
.	O

High	O
levels	O
of	O
IC	O
coincided	O
with	O
relative	O
hypocomplementemia	O
.	O

Acute	O
type	O
A	O
hepatitis	O
in	O
three	O
patients	O
with	O
chronic	O
HBV	O
infection	O
.	O

Pathogenetic	O
relationships	O
between	O
renal	O
tubular	O
acidosis	O
and	O
sodium	O
metabolism	O
alterations	O
in	O
liver	O
cirrhosis	O
.	O

5	O
microU	O
/	O
l	O
thyrotropin	B-GENE
:	O
75	O
%	O
(	O
1974	O
)	O
,	O
45	O
%	O
(	O
1977	O
)	O
and	O
20	O
%	O
(	O
1980	O
)	O
.	O

Echosismography	O
enables	O
to	O
improve	O
the	O
diagnosis	O
when	O
compared	O
with	O
classical	O
sonography	O
in	O
about	O
20	O
%	O
of	O
cases	O
.	O

Relationships	O
with	O
the	O
acquired	O
immune	O
deficiency	O
syndrome	O
.	O

The	O
prevalence	O
of	O
CPAF	O
was	O
similar	O
in	O
type	O
1	O
and	O
type	O
2	O
diabetes	O
,	O
was	O
greater	O
in	O
women	O
than	O
in	O
men	O
,	O
and	O
was	O
significantly	O
greater	O
after	O
repeated	O
administrations	O
than	O
after	O
one	O
single	O
administration	O
of	O
chlorpropamide	O
.	O

A	O
reassessment	O
of	O
the	O
prevalence	O
data	O
was	O
carried	O
out	O
in	O
the	O
southern	O
province	O
of	O
Uusimaa	O
and	O
in	O
the	O
western	O
province	O
of	O
Vaasa	O
,	O
the	O
prevalence	O
day	O
being	O
January	O
1	O
,	O
1979	O
.	O

The	O
results	O
confirm	O
and	O
extend	O
previous	O
work	O
by	O
other	O
researchers	O
.	O

In	O
patients	O
with	O
complete	O
or	O
partial	O
remission	O
of	O
the	O
tumor	O
,	O
the	O
neopterine	O
excretion	O
dropped	O
to	O
normal	O
values	O
.	O

In	O
visible	O
tumours	O
the	O
best	O
results	O
were	O
obtained	O
with	O
FB	O
(	O
85	O
%	O
)	O
while	O
TBN	O
was	O
positive	O
in	O
65	O
%	O
.	O

Total	O
PGE	O
levels	O
in	O
synovial	O
fluid	O
remained	O
significantly	O
depressed	O
in	O
the	O
patient	O
group	O
for	O
24	O
hours	O
after	O
the	O
400	O
-	O
mg	O
test	O
dose	O
of	O
tolmetin	O
on	O
day	O
8	O
.	O

Normal	O
rates	O
of	O
weight	O
gain	O
were	O
seen	O
once	O
absorbed	O
energy	O
intakes	O
reached	O
100	O
-	O
110	O
%	O
of	O
requirements	O
.	O

Its	O
vasodilatory	O
,	O
anti	O
-	O
vasopressor	O
,	O
and	O
platelet	O
stabilizing	O
effects	O
could	O
be	O
expected	O
to	O
counteract	O
the	O
placental	O
ischemia	O
,	O
hypertension	O
and	O
excessive	O
coagulation	O
that	O
are	O
seen	O
in	O
pre	O
-	O
eclampsia	O
.	O

Behcet	O
'	O
s	O
syndrome	O

Survival	O
of	O
111	O
Indium	O
-	O
labelled	O
autologous	O
platelets	O
was	O
studied	O
in	O
2	O
patients	O
after	O
correction	O
of	O
platelet	O
count	O
and	O
was	O
still	O
found	O
shortened	O
.	O

The	O
effect	O
of	O
emotional	O
-	O
painful	O
stress	O
(	O
EPS	O
)	O
on	O
myocardial	O
extensibility	O
and	O
contractility	O
was	O
studied	O
on	O
an	O
isolated	O
rat	O
atrium	O
.	O

When	O
O2	O
therapy	O
was	O
controlled	O
for	O
,	O
the	O
association	O
between	O
RBT	O
and	O
RLF	O
did	O
not	O
achieve	O
statistical	O
significance	O
(	O
P	O
=	O
.	O
07	O
)	O
.	O

This	O
two	O
-	O
helix	O
motif	O
is	O
thought	O
to	O
be	O
involved	O
in	O
specific	O
DNA	O
sequence	O
recognition	O
by	O
CAP	B-GENE
.	O

Statistics	O
for	O
nurse	O
managers	O
-	O
-	O
3	O
.	O

The	O
infection	O
rate	O
was	O
five	O
times	O
greater	O
in	O
patients	O
with	O
Hickman	O
catheters	O
than	O
in	O
those	O
with	O
Broviac	O
catheters	O
(	O
p	O
=	O
0	O
.	O
01	O
)	O
.	O

Setting	O
takes	O
place	O
through	O
complex	O
formation	O
of	O
(	O
NH4Mg	O
PO4	O
.	O
6H2O	O
)	O
n	O
,	O
excess	O
reactants	O
,	O
and	O
water	O
.	O

Serum	B-GENE
IgE	I-GENE
levels	O
in	O
Tauranga	O
children	O
.	O

Use	O
of	O
prostaglandin	O
F2	O
alpha	O
(	O
PGF2	O
alpha	O
)	O
in	O
cattle	O
breeding	O
.	O

Thus	O
it	O
appears	O
that	O
the	O
management	O
of	O
blood	O
,	O
including	O
washing	O
is	O
of	O
great	O
importance	O
.	O

Range	O
,	O
variations	O
and	O
neoplastic	O
potential	O
.	O

The	O
scores	O
are	O
dependent	O
in	O
part	O
on	O
the	O
reliability	O
of	O
faculty	O
evaluations	O
.	O

Study	O
on	O
distribution	O
of	O
metal	O
in	O
the	O
teeth	O
treated	O
by	O
iontophoresis	O
with	O
transparent	O
specimens	O

Whereas	O
creatine	B-GENE
kinase	I-GENE
activity	O
declined	O
exponentially	O
from	O
a	O
single	O
peak	O
,	O
myoglobin	B-GENE
appeared	O
in	O
multiple	O
episodes	O
inadequately	O
represented	O
by	O
a	O
single	O
peak	O
value	O
and	O
having	O
no	O
clear	O
clinical	O
correlation	O
.	O

Utero	O
-	O
placental	O
blood	O
flow	O
and	O
the	O
effect	O
of	O
beta	B-GENE
2	I-GENE
-	I-GENE
adrenoceptor	I-GENE
stimulating	O
drugs	O
.	O

Development	O
of	O
basophilic	O
leukemia	O
with	O
trisomy	O
8	O
and	O
atypical	O
erythroblastosis	O
in	O
a	O
patient	O
with	O
a	O
history	O
of	O
aplastic	O
anemia	O
22	O
years	O
earlier	O

The	O
arginyl	O
peptide	O
bonds	O
that	O
are	O
cleaved	O
in	O
the	O
conversion	O
of	O
human	B-GENE
factor	I-GENE
IX	I-GENE
to	O
factor	B-GENE
IXa	I-GENE
by	O
factor	B-GENE
XIa	I-GENE
were	O
identified	O
as	O
Arg145	O
-	O
Ala146	O
and	O
Arg180	O
-	O
Val181	O
.	O

Alveolar	O
growth	O
,	O
contemporary	O
with	O
dental	O
eruption	O
,	O
is	O
sufficient	O
to	O
compensate	O
possible	O
hypotrophy	O
of	O
maxillary	O
bone	O
bases	O
.	O

Renal	O
and	O
extrarenal	O
arterial	O
fibromuscular	O
hyperplasia	O
with	O
hypertension	O
.	O

Both	O
examinations	O
are	O
sensitive	O
indicators	O
of	O
CNS	O
abnormalities	O
associated	O
with	O
bacterial	O
meningeal	O
infections	O
and	O
are	O
important	O
determinants	O
of	O
the	O
therapy	O
and	O
ultimate	O
prognosis	O
of	O
such	O
complications	O
.	O

Similar	O
clinical	O
evaluation	O
of	O
an	O
obligate	O
carrier	O
revealed	O
no	O
ocular	O
abnormalities	O
.	O

A	O
case	O
of	O
anterior	O
cleavage	O
syndrome	O
in	O
a	O
27	O
-	O
year	O
-	O
old	O
female	O
patient	O
is	O
described	O
.	O

The	O
daily	O
administration	O
of	O
betamethasone	O
for	O
three	O
weeks	O
markedly	O
reduced	O
the	O
absorption	O
of	O
calcium	O
and	O
phosphate	O
as	O
well	O
as	O
the	O
growth	O
rate	O
.	O

Endorphins	B-GENE
and	O
legal	O
issues	O
.	O

At	O
necropsy	O
28	O
days	O
post	O
-	O
inoculation	O
,	O
F344	O
rats	O
had	O
no	O
gross	O
lung	O
lesions	O
,	O
even	O
those	O
given	O
the	O
maximum	O
dose	O
of	O
1	O
.	O
4	O
X	O
10	O
(	O
9	O
)	O
colony	O
-	O
forming	O
units	O
of	O
M	O
.	O
pulmonis	O
.	O

Aneurysmectomy	O
and	O
the	O
performance	O
of	O
CABG	O
were	O
not	O
significantly	O
associated	O
with	O
postoperative	O
ECG	O
changes	O
,	O
but	O
more	O
bypass	O
grafts	O
per	O
patient	O
grafted	O
appeared	O
in	O
the	O
group	O
with	O
postoperative	O
ECG	O
changes	O
,	O
suggesting	O
that	O
coronary	O
artery	O
disease	O
may	O
be	O
more	O
severe	O
in	O
that	O
group	O
.	O

REV	O
I	O
:	O
All	O
vessels	O
up	O
to	O
50	O
%	O
stenosed	O
have	O
a	O
patent	O
graft	O
.	O

Complete	O
sequences	O
were	O
obtained	O
for	O
the	O
three	O
large	O
thrombic	O
peptides	O
,	O
and	O
these	O
were	O
aligned	O
by	O
using	O
peptides	O
from	O
the	O
V8	B-GENE
protease	I-GENE
digest	O
.	O

The	O
extraction	O
measurements	O
were	O
used	O
to	O
test	O
for	O
extracerebral	O
contamination	O
of	O
venous	O
outflow	O
.	O

Contractile	O
responses	O
to	O
norepinephrine	O
,	O
serotonin	O
and	O
potassium	O
(	O
K	O
+	O
)	O
and	O
relaxant	O
responses	O
to	O
isoproterenol	O
and	O
papaverine	O
were	O
studied	O
in	O
vitro	O
with	O
spirally	O
cut	O
thoracic	O
aortic	O
strips	O
from	O
aortic	O
coarcted	O
hypertensive	O
rats	O
(	O
AHR	O
)	O
2	O
,	O
6	O
,	O
14	O
and	O
28	O
days	O
postoperatively	O
and	O
compared	O
to	O
time	O
-	O
matched	O
,	O
sham	O
-	O
operated	O
normotensive	O
controls	O
.	O

On	O
line	O
calculation	O
of	O
steroid	O
concentrations	O
by	O
radioimmunoassay	O

Detection	O
of	O
congenital	O
hypothyroidism	O
in	O
26	O
,	O
282	O
newborn	O
infants	O

In	O
rubella	O
patients	O
with	O
serologic	O
confirmation	O
by	O
HI	O
,	O
the	O
IF	O
test	O
detected	O
significant	O
rises	O
in	O
219	O
(	O
99	O
.	O
1	O
%	O
)	O
of	O
221	O
patients	O
and	O
the	O
PHA	B-GENE
test	O
detected	O
antibody	O
conversion	O
in	O
68	O
(	O
93	O
%	O
)	O
of	O
73	O
patients	O
.	O

The	O
effect	O
of	O
sodium	O
saccharin	O
in	O
the	O
diet	O
on	O
caecal	O
microflora	O
.	O

The	O
residue	O
functions	O
,	O
R	O
(	O
t	O
)	O
,	O
for	O
C	O
-	O
11	O
CPZ	O
and	O
In	O
-	O
113m	O
transferrin	B-GENE
were	O
plotted	O
against	O
time	O
for	O
selected	O
areas	O
of	O
interest	O
,	O
and	O
the	O
CPZ	O
area	O
-	O
weighted	O
extraction	O
,	O
E	O
(	O
t	O
)	O
,	O
was	O
computed	O
for	O
the	O
same	O
areas	O
every	O
250	O
msec	O
using	O
the	O
formula	O
:	O
E	O
(	O
t	O
)	O
=	O
[	O
RT	O
(	O
t	O
)	O
-	O
RR	O
(	O
t	O
)	O
]	O
/	O
[	O
1	O
-	O
RR	O
(	O
t	O
)	O
]	O
,	O
where	O
RT	O
and	O
RR	O
are	O
the	O
normalized	O
residue	O
functions	O
for	O
CPZ	O
and	O
transferrin	B-GENE
,	O
respectively	O
.	O

Synchronous	O
extracts	O
showed	O
no	O
significant	O
migration	O
inhibition	O
in	O
allogeneic	O
assays	O
.	O

Ten	O
days	O
of	O
cefadroxil	O
therapy	O
was	O
used	O
to	O
treat	O
44	O
children	O
with	O
urinary	O
tract	O
infection	O
and	O
CRP	B-GENE
values	O
greater	O
than	O
or	O
equal	O
to	O
28	O
microgram	O
/	O
ml	O
(	O
CRP	B-GENE
-	O
positive	O
group	O
)	O
.	O

Both	O
resting	O
blood	O
flow	O
(	O
RBF	O
)	O
and	O
maximal	O
blood	O
flow	O
(	O
NBF	O
)	O
were	O
studied	O
by	O
Xenon	O
133	O
clearance	O
.	O

Plasma	B-GENE
renin	I-GENE
concentration	O
is	O
significantly	O
higher	O
in	O
the	O
subcapsular	O
venous	O
outflow	O
,	O
which	O
drains	O
the	O
superficial	O
cortex	O
,	O
than	O
in	O
the	O
deep	O
venous	O
outflow	O
,	O
which	O
drains	O
the	O
inner	O
half	O
of	O
the	O
cortex	O
and	O
medulla	O
of	O
the	O
cat	O
kidney	O
.	O

After	O
acclimation	O
,	O
resting	O
supine	O
and	O
sitting	O
DPB	O
decreased	O
(	O
P	O
less	O
than	O
0	O
.	O
05	O
)	O
by	O
6	O
and	O
9	O
mmHg	O
,	O
respectively	O
.	O

In	O
the	O
diabetics	O
,	O
Ca2	O
+	O
infusions	O
induced	O
a	O
rise	O
of	O
plasma	O
Ca2	O
+	O
up	O
to	O
3	O
.	O
2	O
+	O
/	O
-	O
0	O
.	O
1	O
mmol	O
/	O
1	O
and	O
a	O
fall	O
of	O
circulating	O
glucagon	B-GENE
(	O
-	O
26	O
.	O
4	O
+	O
/	O
-	O
5	O
.	O
7	O
%	O
;	O
p	O
less	O
than	O
0	O
.	O
001	O
)	O
and	O
glucose	O
(	O
-	O
23	O
.	O
3	O
+	O
/	O
-	O
3	O
.	O
6	O
%	O
;	O
p	O
less	O
than	O
0	O
.	O
05	O
)	O
.	O

Fifty	O
-	O
eight	O
RMI	O
'	O
s	O
occurred	O
in	O
the	O
placebo	O
group	O
as	O
compared	O
to	O
only	O
twenty	O
in	O
the	O
AC	O
group	O
(	O
p	O
less	O
than	O
0	O
.	O
01	O
)	O
.	O

All	O
patients	O
in	O
the	O
control	O
group	O
showed	O
a	O
significant	O
improvement	O
in	O
their	O
PEFR	O
while	O
only	O
3	O
patients	O
in	O
the	O
treated	O
group	O
showed	O
an	O
improvement	O
.	O

Facts	O
on	O
the	O
Economic	O
Recovery	O
Tax	O
Act	O
of	O
1981	O
for	O
speech	O
-	O
language	O
pathologists	O
and	O
audiologists	O
.	O

From	O
Pap	O
to	O
ApUp	O
.	O

The	O
relationship	O
between	O
the	O
rare	O
complications	O
mentioned	O
above	O
and	O
the	O
pathophysiology	O
of	O
Bartter	O
'	O
s	O
syndrome	O
is	O
still	O
obscure	O
.	O

Using	O
an	O
opsonophagocytic	O
bacterial	O
assay	O
and	O
a	O
suckling	O
rat	O
model	O
of	O
GBS	O
sepsis	O
,	O
we	O
analyzed	O
a	O
modified	O
human	B-GENE
immunoglobulin	I-GENE
for	O
opsonic	O
and	O
protective	O
antibody	O
.	O

Glomerular	O
lesions	O
in	O
renal	O
allografts	O
.	O

Commonly	O
observed	O
systemic	O
toxic	O
effects	O
(	O
bone	O
marrow	O
,	O
gastrointestinal	O
tract	O
,	O
and	O
heart	O
)	O
were	O
not	O
seen	O
in	O
this	O
study	O
.	O

2	O
.	O

When	O
vascular	O
pressure	O
(	O
Pvas	O
)	O
was	O
raised	O
abruptly	O
from	O
-	O
5	O
to	O
+	O
25	O
cmH2O	O
by	O
air	O
inflation	O
for	O
60	O
min	O
,	O
Px	O
(	O
f	O
)	O
became	O
abruptly	O
less	O
negative	O
,	O
then	O
remained	O
stable	O
.	O

(	O
1980	O
)	O
:	O
Science	O
210	O
,	O
77	O
-	O
72	O
)	O
that	O
stimulating	O
the	O
crossed	O
olivocochlear	O
bundle	O
(	O
COCB	O
)	O
can	O
change	O
the	O
magnitude	O
of	O
the	O
distortion	O
product	O
(	O
f2	O
-	O
f1	O
)	O
in	O
the	O
ear	O
-	O
canal	O
sound	O
pressure	O
.	O

Rats	O
underwent	O
either	O
a	O
90	O
-	O
95	O
%	O
JIB	O
or	O
a	O
sham	O
operation	O
.	O

When	O
the	O
l	O
-	O
methadone	O
-	O
sensitive	O
,	O
opioid	B-GENE
receptor	I-GENE
is	O
blocked	O
by	O
naloxone	O
or	O
tolerance	O
has	O
developed	O
,	O
than	O
l	O
-	O
methadone	O
can	O
produce	O
behavioral	O
effects	O
by	O
a	O
nonopioid	O
mechanism	O
.	O

Microwave	O
hyperthermia	O
-	O
induced	O
blood	O
-	O
brain	O
barrier	O
alterations	O
.	O

Large	O
and	O
small	O
medullary	O
lesions	O
inhibited	O
the	O
occurrence	O
of	O
target	O
fibres	O
in	O
the	O
tenotomized	O
muscles	O
,	O
the	O
smallest	O
one	O
being	O
neurolysis	O
of	O
the	O
dorsal	O
roots	O
.	O

In	O
10	O
control	O
sheep	O
mean	O
plasma	O
TXB2	O
concentration	O
increased	O
from	O
0	O
.	O
39	O
ng	O
/	O
ml	O
prebypass	O
to	O
about	O
1	O
.	O
1	O
ng	O
/	O
ml	O
at	O
8	O
and	O
16	O
min	O
of	O
bypass	O
.	O

The	O
respiratory	O
rate	O
was	O
13	O
+	O
/	O
-	O
1	O
breaths	O
/	O
min	O
with	O
52	O
+	O
/	O
-	O
4	O
%	O
of	O
the	O
respiratory	O
cycle	O
spent	O
in	O
inspiration	O
;	O
end	O
-	O
tidal	O
CO2	O
pressure	O
increased	O
by	O
3	O
.	O
3	O
+	O
/	O
-	O
1	O
.	O
0	O
Torr	O
during	O
runs	O
at	O
SIP	O
.	O

There	O
was	O
no	O
further	O
increase	O
in	O
oxygen	O
consumption	O
when	O
these	O
subjects	O
breathed	O
with	O
inspiratory	O
pressures	O
above	O
SIP	O
.	O

We	O
compared	O
the	O
volume	O
of	O
the	O
pulmonary	O
extravascular	O
,	O
extracellular	O
water	O
space	O
using	O
sodium	O
and	O
sucrose	O
indicators	O
in	O
8	O
normal	O
and	O
11	O
edematous	O
rabbit	O
lungs	O
by	O
steady	O
-	O
state	O
techniques	O
.	O

Investigated	O
the	O
reliability	O
,	O
validity	O
and	O
dimensionality	O
of	O
scores	O
obtained	O
by	O
acute	O
psychiatric	O
inpatients	O
(	O
N	O
=	O
120	O
)	O
on	O
the	O
Michigan	O
Alcoholism	O
Screening	O
Test	O
adapted	O
to	O
assess	O
lifetime	O
and	O
current	O
symptomatology	O
.	O

A	O
simple	O
method	O
for	O
measuring	O
urinary	O
iron	O
following	O
the	O
administration	O
of	O
desferrioxamine	O
(	O
DF	O
)	O
is	O
described	O
.	O

During	O
conventional	O
hemofiltration	O
using	O
substitution	O
fluid	O
with	O
a	O
Na	O
+	O
concentration	O
of	O
140	O
mEq	O
/	O
L	O
,	O
a	O
decrease	O
in	O
extracellular	O
fluid	O
volume	O
was	O
noted	O
whereas	O
the	O
intracellular	O
fluid	O
volume	O
was	O
unaltered	O
.	O

Transvenous	O
serial	O
xeroradiography	O
.	O

Recommendations	O
to	O
deal	O
with	O
these	O
and	O
related	O
issues	O
are	O
presented	O
.	O

Use	O
of	O
subcutaneous	O
deferoxamine	O
in	O
a	O
child	O
with	O
hemochromatosis	O
associated	O
with	O
congenital	O
dyserythropoietic	O
anemia	O
,	O
type	O
I	O
.	O

Although	O
noninhibitory	O
fluid	O
had	O
higher	O
mean	O
concentrations	O
of	O
phosphorus	O
and	O
zinc	O
,	O
these	O
differences	O
did	O
not	O
hold	O
after	O
meconium	O
-	O
stained	O
samples	O
were	O
excluded	O
.	O

Selenium	O
status	O
of	O
thoroughbreds	O
in	O
the	O
United	O
Kingdom	O
.	O

During	O
an	O
8	O
-	O
wk	O
follow	O
-	O
up	O
,	O
parasites	O
reappeared	O
in	O
10	O
patients	O
,	O
5	O
after	O
each	O
drug	O
,	O
between	O
1	O
and	O
7	O
wk	O
after	O
treatment	O
.	O

Preparation	O
of	O
a	O
stable	O
phospholipid	O
reagent	O
for	O
coagulation	O
assays	O
.	O

Before	O
turnout	O
,	O
a	O
morantel	O
sustained	O
release	O
bolus	O
(	O
MSRB	O
)	O
was	O
administered	O
to	O
each	O
animal	O
in	O
the	O
"	O
treated	O
"	O
category	O
.	O

In	O
a	O
longitudinal	O
study	O
,	O
14	O
low	O
-	O
risk	O
fetuses	O
were	O
studied	O
at	O
2	O
-	O
week	O
intervals	O
from	O
32	O
weeks	O
of	O
gestation	O
onward	O
.	O

Further	O
,	O
intracerebroventricular	O
injections	O
of	O
KA	O
resulted	O
in	O
the	O
substantial	O
loss	O
of	O
pyramidal	O
cells	O
in	O
the	O
whole	O
CA3	O
field	O
of	O
the	O
hippocampus	O
.	O

Seventeen	O
of	O
the	O
35	O
patients	O
were	O
randomly	O
chosen	O
to	O
receive	O
a	O
training	O
program	O
(	O
lasting	O
approximately	O
1	O
month	O
)	O
designed	O
to	O
establish	O
a	O
systematic	O
strategy	O
of	O
organizing	O
complex	O
visual	O
material	O
.	O

The	O
duration	O
and	O
the	O
amplitude	O
of	O
the	O
negative	O
potential	O
were	O
greatest	O
for	O
completely	O
regenerating	O
ears	O
with	O
overgrowth	O
,	O
smaller	O
for	O
partially	O
regenerating	O
ears	O
,	O
and	O
smallest	O
for	O
the	O
nonregenerating	O
ears	O
.	O

Samples	O
obtained	O
from	O
normal	O
volunteers	O
and	O
from	O
the	O
great	O
majority	O
of	O
the	O
patients	O
,	O
excluding	O
those	O
with	O
asthma	O
,	O
had	O
no	O
effect	O
on	O
ciliary	O
beating	O
.	O

These	O
results	O
suggested	O
the	O
possibility	O
that	O
the	O
fetus	O
played	O
some	O
role	O
in	O
the	O
production	O
of	O
E3	O
-	O
16	O
-	O
G	O
in	O
early	O
pregnancy	O
.	O

In	O
this	O
way	O
it	O
is	O
possible	O
to	O
simulate	O
the	O
growth	O
function	O
of	O
the	O
embryofetal	O
curve	O
of	O
the	O
length	O
'	O
increase	O
of	O
man	O
and	O
the	O
curve	O
of	O
the	O
mass	O
'	O
increase	O
of	O
rat	O
.	O

The	O
highest	O
doses	O
were	O
found	O
for	O
drivers	O
who	O
transported	O
large	O
numbers	O
of	O
99Mo	O
generators	O
.	O

The	O
steepness	O
of	O
the	O
standard	O
O2	O
dissociation	O
curve	O
becomes	O
greater	O
during	O
the	O
training	O
period	O
(	O
increase	O
in	O
Hill	O
'	O
s	O
n	O
from	O
2	O
.	O
68	O
+	O
/	O
-	O
0	O
.	O
10	O
to	O
2	O
.	O
96	O
+	O
/	O
-	O
0	O
.	O
15	O
)	O
.	O

Conjugated	O
and	O
unconjugated	O
phenylacetic	O
acid	O
and	O
m	O
-	O
and	O
p	O
-	O
hydroxyphenylacetic	O
acid	O
have	O
been	O
determined	O
in	O
the	O
plasma	O
of	O
normal	O
,	O
healthy	O
subjects	O
after	O
fasting	O
,	O
consumption	O
of	O
a	O
meal	O
and	O
ingestion	O
of	O
deuterium	O
labelled	O
amine	O
precursors	O
,	O
by	O
high	O
-	O
resolution	O
gas	O
chromatography	O
-	O
-	O
high	O
resolution	O
mass	O
spectrometry	O
with	O
selected	O
ion	O
monitoring	O
of	O
their	O
trifluoroethyl	O
-	O
pentafluoropropionyl	O
derivatives	O
.	O

In	O
concept	O
II	O
62	O
patients	O
were	O
treated	O
with	O
selective	O
vagotomy	O
and	O
pyloroplasty	O
.	O

They	O
consisted	O
of	O
behavioural	O
disorders	O
,	O
tetraparesis	O
,	O
incontinence	O
and	O
oculomotor	O
paralysis	O
.	O

CSF	O
adenosine	B-GENE
deaminase	I-GENE
activity	O
(	O
ADA	O
)	O
was	O
measured	O
at	O
the	O
same	O
time	O
.	O

Histamine	O
reactivity	O
had	O
returned	O
to	O
normal	O
in	O
half	O
the	O
workers	O
who	O
had	O
left	O
their	O
original	O
factories	O
,	O
but	O
in	O
only	O
one	O
worker	O
who	O
had	O
moved	O
within	O
her	O
original	O
factory	O
.	O

It	O
was	O
also	O
found	O
that	O
there	O
is	O
no	O
significant	O
difference	O
between	O
the	O
prevalence	O
of	O
nasal	O
carriage	O
of	O
S	O
.	O
aureus	O
amongst	O
the	O
hospital	O
staff	O
and	O
the	O
patients	O
.	O

Ficat	O
and	O
Bizou	O
'	O
s	O
condylar	O
depth	O
index	O
and	O
the	O
condylar	O
-	O
joint	O
surface	O
angle	O
of	O
Brattstrom	O
are	O
recommended	O
as	O
especially	O
suitable	O
methods	O
of	O
measurement	O
.	O

There	O
were	O
no	O
significant	O
differences	O
in	O
EF	O
between	O
the	O
two	O
studies	O
,	O
both	O
at	O
rest	O
(	O
56	O
.	O
0	O
+	O
/	O
-	O
13	O
.	O
8	O
%	O
vs	O
58	O
.	O
2	O
+	O
/	O
-	O
11	O
.	O
7	O
%	O
,	O
p	O
=	O
NS	O
)	O
and	O
with	O
exercise	O
(	O
51	O
.	O
1	O
+	O
/	O
-	O
17	O
.	O
6	O
%	O
vs	O
54	O
.	O
3	O
+	O
/	O
-	O
17	O
.	O
6	O
%	O
,	O
p	O
=	O
NS	O
)	O
and	O
a	O
highly	O
significant	O
correlation	O
was	O
shown	O
between	O
the	O
two	O
groups	O
of	O
values	O
(	O
rest	O
r	O
=	O
0	O
.	O
90	O
,	O
exercise	O
r	O
=	O
0	O
.	O
93	O
,	O
p	O
less	O
than	O
0	O
.	O
001	O
)	O
.	O

After	O
MOPP	O
therapy	O
,	O
complete	O
remission	O
of	O
Hodgkin	O
'	O
s	O
disease	O
was	O
accompanied	O
by	O
normalization	O
of	O
the	O
glucocerebrosidase	B-GENE
level	O
and	O
disappearance	O
of	O
Gaucher	O
'	O
s	O
cells	O
.	O

Specifically	O
,	O
by	O
the	O
type	O
of	O
adjuvant	O
therapy	O
,	O
the	O
median	O
disease	O
-	O
free	O
interval	O
and	O
survival	O
from	O
stage	O
IVA	O
for	O
23	O
patients	O
receiving	O
Corynebacterium	O
parvum	O
were	O
6	O
.	O
9	O
and	O
19	O
months	O
;	O
for	O
39	O
patients	O
receiving	O
BCG	O
,	O
eight	O
months	O
and	O
26	O
months	O
;	O
for	O
24	O
patients	O
receiving	O
BCG	O
+	O
DTIC	O
,	O
eight	O
and	O
17	O
.	O
4	O
months	O
;	O
and	O
for	O
all	O
51	O
DTIC	O
treated	O
patients	O
6	O
.	O
3	O
and	O
17	O
.	O
8	O
months	O
,	O
respectively	O
.	O

The	O
COP	O
-	O
PAWP	O
gradient	O
was	O
markedly	O
decreased	O
in	O
both	O
shock	O
and	O
non	O
-	O
shock	O
patients	O
with	O
pulmonary	O
edema	O
.	O

Re	O
:	O
A	O
modified	O
method	O
for	O
the	O
in	O
vivo	O
labeling	O
of	O
red	O
blood	O
cells	O
with	O
Tc	O
-	O
99m	O
.	O

A	O
limited	O
study	O
in	O
a	O
glassware	O
factory	O
(	O
As2O3	O
exposure	O
)	O
involving	O
the	O
measurement	O
of	O
total	O
airborne	O
arsenic	O
,	O
the	O
determination	O
of	O
urinary	O
arsenic	O
,	O
and	O
the	O
evaluation	O
of	O
hand	O
and	O
mouth	O
contamination	O
by	O
arsenic	O
before	O
and	O
after	O
the	O
workshift	O
suggests	O
that	O
the	O
high	O
urinary	O
arsenic	O
levels	O
(	O
300	O
microgram	O
/	O
g	O
creatinine	O
)	O
are	O
likely	O
to	O
be	O
more	O
related	O
to	O
an	O
increased	O
oral	O
intake	O
from	O
contaminated	O
hands	O
than	O
to	O
an	O
increased	O
absorption	O
from	O
the	O
lungs	O
.	O

The	O
pia	O
mater	O
at	O
the	O
site	O
of	O
the	O
entry	O
of	O
blood	O
vessels	O
into	O
the	O
central	O
nervous	O
system	O
.	O

Experimental	O
reproduction	O
of	O
malignant	O
catarrhal	O
fever	O
in	O
Bali	O
cattle	O

1	O
A	O
colonic	O
delivery	O
system	O
is	O
described	O
to	O
deliver	O
orally	O
ingested	O
drugs	O
to	O
the	O
colon	O
and	O
release	O
them	O
at	O
that	O
site	O
by	O
coating	O
with	O
an	O
acrylic	O
based	O
resin	O
(	O
Eudragit	O
S	O
)	O
.	O

Administration	O
of	O
the	O
dopamine	O
agonist	O
bromocriptine	O
(	O
2	O
.	O
5	O
mg	O
three	O
times	O
a	O
day	O
for	O
4	O
days	O
)	O
suppressed	O
(	O
P	O
less	O
than	O
0	O
.	O
01	O
)	O
mean	O
24	O
-	O
h	O
plasma	O
18	O
-	O
OHB	O
levels	O
from	O
21	O
.	O
9	O
+	O
/	O
-	O
2	O
.	O
0	O
to	O
14	O
.	O
8	O
+	O
/	O
-	O
1	O
.	O
4	O
ng	O
/	O
dl	O
.	O

Restarting	O
time	O
was	O
not	O
affected	O
by	O
magnesium	O
cardioplegia	O
.	O

The	O
most	O
common	O
types	O
of	O
malformations	O
were	O
eye	O
defects	O
and	O
open	O
coeloms	O
.	O

Repair	O
of	O
a	O
cosmetic	O
defect	O
of	O
the	O
lower	O
leg	O
with	O
a	O
myocutaneous	O
free	O
flap	O
.	O

According	O
to	O
the	O
literature	O
,	O
second	O
malignant	O
epithelial	O
tumours	O
are	O
,	O
in	O
contrast	O
to	O
mesenchymal	O
tumours	O
such	O
as	O
osteosarcoma	O
,	O
very	O
rare	O
in	O
retinoblastoma	O
survivors	O
.	O

In	O
Malmo	O
,	O
Sweden	O
,	O
17	O
,	O
181	O
school	O
children	O
born	O
in	O
the	O
years	O
1961	O
-	O
1965	O
were	O
screened	O
for	O
scoliosis	O
once	O
a	O
year	O
between	O
the	O
ages	O
of	O
7	O
and	O
16	O
years	O
,	O
during	O
1971	O
-	O
1980	O
.	O

Intra	O
-	O
articular	O
dislocation	O
of	O
the	O
patella	O
.	O

This	O
study	O
demonstrates	O
secretion	O
of	O
bicarbonate	O
by	O
the	O
human	O
stomach	O
in	O
vivo	O
at	O
a	O
rate	O
equivalent	O
to	O
10	O
-	O
-	O
20	O
%	O
of	O
basal	O
acid	O
secretion	O
.	O

Histological	O
evaluation	O
revealed	O
a	O
more	O
than	O
twofold	O
increase	O
in	O
the	O
number	O
of	O
interepithelial	O
mononuclear	O
cells	O
(	O
p	O
less	O
than	O
0	O
.	O
005	O
)	O
,	O
while	O
the	O
number	O
of	O
epithelial	O
cells	O
/	O
100	O
microns	O
of	O
villous	O
mucosa	O
and	O
the	O
mean	O
height	O
of	O
the	O
epithelial	O
cells	O
were	O
comparable	O
in	O
both	O
groups	O
.	O

Cramps	O
in	O
extrapyramidal	O
disorders	O
.	O

A	O
suspected	O
new	O
storage	O
disease	O
in	O
cattle	O
.	O

For	O
various	O
dog	O
vessels	O
in	O
vivo	O
,	O
Q	O
/	O
Dk	O
ranged	O
from	O
0	O
.	O
15	O
to	O
47	O
X	O
10	O
(	O
5	O
)	O
Torr	O
/	O
cm2	O
.	O

The	O
tetraphasic	O
action	O
of	O
lidocaine	O
on	O
CNS	O
electrical	O
activity	O
and	O
behavior	O
in	O
cats	O
.	O

Asymptomatic	O
bacteriospermia	O
and	O
fertility	O

Triumph	O
of	O
Leninist	O
national	O
policy	O

The	O
favourable	O
effect	O
of	O
thymic	O
shielding	O
was	O
also	O
reflected	O
in	O
a	O
significant	O
increase	O
of	O
LD50	O
/	O
30	O
,	O
and	O
the	O
dose	O
reduction	O
factor	O
was	O
equal	O
to	O
2	O
.	O

The	O
application	O
of	O
ultrafiltration	O
to	O
sample	O
preparation	O
in	O
the	O
detection	O
and	O
quantification	O
of	O
ethylene	O
glycol	O
in	O
plasma	O
by	O
gas	O
chromatography	O
is	O
described	O
.	O

Mastocytosis	O
.	O

A	O
new	O
Onchocerca	O
species	O
,	O
a	O
parasite	O
of	O
domestic	O
cattle	O
,	O
in	O
Senegal	O

It	O
was	O
suggested	O
that	O
the	O
absence	O
of	O
pronounced	O
differences	O
between	O
conditions	O
may	O
have	O
been	O
due	O
to	O
the	O
complexity	O
of	O
the	O
task	O
or	O
the	O
type	O
of	O
prompts	O
employed	O
.	O

A	O
limiting	O
factor	O
were	O
disturbances	O
in	O
the	O
system	O
of	O
energy	O
transport	O
(	O
creatine	O
phosphate	O
,	O
creatine	B-GENE
phosphokinase	I-GENE
)	O
and	O
of	O
the	O
calcium	O
pump	O
(	O
Ca	B-GENE
+	I-GENE
+	I-GENE
-	I-GENE
ATPase	I-GENE
of	O
the	O
sarcoplasmic	O
reticulum	O
,	O
SPR	O
)	O
,	O
which	O
evidently	O
led	O
to	O
a	O
decrease	O
of	O
the	O
inotropic	O
properties	O
of	O
the	O
myocardium	O
at	O
70	O
%	O
restriction	O
of	O
coronary	O
blood	O
flow	O
.	O

Serum	B-GENE
creatine	I-GENE
kinase	I-GENE
(	O
SCK	B-GENE
)	O
was	O
measured	O
in	O
ten	O
subjects	O
in	O
the	O
laboratory	O
before	O
and	O
after	O
the	O
performance	O
of	O
bicycle	O
ergometry	O
and	O
a	O
lifting	O
task	O
.	O

Organisms	O
were	O
not	O
observed	O
in	O
the	O
5	O
bobcats	O
trapped	O
in	O
2	O
other	O
counties	O
.	O

The	O
cause	O
of	O
death	O
is	O
often	O
quite	O
apparent	O
from	O
the	O
pathological	O
and	O
toxicological	O
findings	O
;	O
however	O
,	O
the	O
manner	O
of	O
death	O
often	O
gives	O
the	O
examining	O
official	O
some	O
difficulty	O
.	O

The	O
average	O
annual	O
cost	O
per	O
head	O
of	O
population	O
was	O
US	O
+	O
0	O
X	O
46	O
.	O

It	O
is	O
postulated	O
that	O
altered	O
blood	O
flow	O
,	O
mediated	O
through	O
the	O
well	O
-	O
known	O
prostaglandin	B-GENE
synthetase	I-GENE
inhibitory	O
effects	O
of	O
ibuprofen	O
,	O
resulted	O
in	O
tubular	O
necrosis	O
.	O

Either	O
20	O
mg	O
mitomycin	O
/	O
20	O
ml	O
distilled	O
water	O
or	O
40	O
mg	O
/	O
40	O
ml	O
distilled	O
water	O
was	O
locally	O
instilled	O
into	O
the	O
bladder	O
with	O
a	O
catheter	O
after	O
emptying	O
it	O
and	O
was	O
left	O
for	O
about	O
25	O
-	O
l20	O
min	O
.	O

Both	O
groups	O
rejected	O
pops	O
with	O
added	O
SOA	O
,	O
decreasing	O
mouthing	O
times	O
as	O
SOA	O
concentration	O
increased	O
.	O

The	O
mean	O
extracted	O
concentration	O
of	O
flucloxacillin	O
obtained	O
at	O
operation	O
was	O
12	O
.	O
9	O
micrograms	O
/	O
ml	O
(	O
SD	O
5	O
.	O
25	O
)	O
in	O
synovial	O
fluid	O
;	O
2	O
.	O
9	O
micrograms	O
/	O
g	O
(	O
SD	O
3	O
.	O
59	O
)	O
in	O
synovium	O
;	O
2	O
.	O
0	O
micrograms	O
/	O
g	O
(	O
SD	O
1	O
.	O
48	O
)	O
in	O
cancellous	O
bone	O
and	O
1	O
.	O
3	O
micrograms	O
/	O
g	O
(	O
SD	O
1	O
.	O
25	O
)	O
in	O
cortical	O
bone	O
.	O

A	O
preliminary	O
study	O
of	O
vincristine	O
,	O
methotrexate	O
,	O
and	O
prednisolone	O
(	O
VM	O
*	O
P	O
)	O
combination	O
chemotherapy	O
for	O
advanced	O
adult	O
non	O
-	O
Hodgkin	O
'	O
s	O
lymphoma	O

Lacrimal	O
secretion	O
in	O
hyperthyroidism	O

Re	O
-	O
examination	O
of	O
the	O
ED01	O
study	O
.	O

Based	O
on	O
213	O
determinations	O
,	O
the	O
control	O
mean	O
serum	B-GENE
CPK	I-GENE
activity	O
was	O
262	O
+	O
/	O
-	O
113	O
I	O
.	O
U	O
.	O
/	O
liter	O
.	O

A	O
further	O
study	O
on	O
plasminogen	B-GENE
activator	I-GENE
release	O
by	O
vasoactive	O
agents	O
in	O
the	O
isolated	O
perfused	O
dog	O
leg	O
.	O

CDDP	O
is	O
active	O
as	O
a	O
single	O
agent	O
in	O
non	O
-	O
Hodgkin	O
'	O
s	O
lymphoma	O
.	O

Treatment	O
of	O
meat	O
muscle	O
800	O
V	O
for	O
45	O
s	O
reduced	O
weeping	O
but	O
increased	O
slightly	O
the	O
rate	O
of	O
autoxidation	O
of	O
lipids	O
.	O

A	O
method	O
for	O
determining	O
cumulative	O
behavioral	O
toxicity	O
after	O
chronic	O
oral	O
administration	O
of	O
l	O
-	O
alpha	O
-	O
acetylmethadol	O
to	O
female	O
rats	O
.	O

After	O
successful	O
subtotal	O
parathyroidectomy	O
,	O
evident	O
by	O
the	O
decrease	O
of	O
serum	O
iPTH	B-GENE
levels	O
,	O
both	O
the	O
CL	O
of	O
group	O
2	O
PMNs	O
and	O
the	O
ability	O
of	O
group	O
2	O
sera	O
to	O
induce	O
augmented	O
CL	O
in	O
normal	O
PMNs	O
decreased	O
(	O
p	O
<	O
0	O
.	O
025	O
)	O
.	O

TCZ	O
provides	O
quick	O
,	O
inexpensive	O
,	O
noninvasive	O
indication	O
of	O
tissue	O
necrosis	O
,	O
moderate	O
-	O
to	O
-	O
severe	O
intracranial	O
hemorrhage	O
,	O
and	O
delayed	O
brain	O
maturation	O
.	O

The	O
number	O
of	O
muricidal	O
rats	O
increased	O
with	O
increase	O
in	O
the	O
duration	O
of	O
Cd	O
administration	O
in	O
association	O
with	O
greater	O
accumulation	O
of	O
Cd	O
in	O
the	O
olfactory	O
bulb	O
than	O
in	O
any	O
other	O
region	O
of	O
the	O
brain	O
.	O

This	O
test	O
should	O
provide	O
another	O
practical	O
means	O
to	O
study	O
leprosy	O
.	O

The	O
preferences	O
were	O
for	O
intact	O
vis	O
-	O
a	O
-	O
vis	O
castrated	O
males	O
,	O
though	O
injections	O
of	O
TP	O
restored	O
the	O
castrates	O
'	O
attractiveness	O
to	O
the	O
females	O
.	O

Each	O
trial	O
consisted	O
of	O
light	O
and	O
buzzer	O
for	O
five	O
seconds	O
as	O
conditioned	O
stimuli	O
and	O
electric	O
shock	O
for	O
five	O
seconds	O
as	O
an	O
unconditioned	O
stimulus	O
.	O

Family	O
visits	O
and	O
involvement	O
in	O
treatment	O
of	O
patients	O
at	O
a	O
state	O
hospital	O
.	O

A	O
transparent	O
overlay	O
for	O
assessing	O
amplitude	O
of	O
ECG	O
wave	O
forms	O
.	O

Adverse	O
reaction	O
of	O
the	O
apparently	O
healthy	O
partner	O
in	O
response	O
to	O
improvement	O
in	O
the	O
overtly	O
dysfunctional	O
partner	O
.	O

Brain	O
scan	O
with	O
99mTc	O
-	O
labelled	O
macroaggregated	B-GENE
albumin	I-GENE
(	O
MAA	B-GENE
brain	O
scan	O
)	O
and	O
computed	O
tomography	O
studies	O
(	O
CT	O
)	O
were	O
performed	O
on	O
78	O
patients	O
with	O
intracranial	O
diseases	O
.	O

Inhibition	O
of	O
Fusarium	O
moniliforme	O
var	O
.	O
subglutinans	O
,	O
the	O
causal	O
agent	O
of	O
pine	O
pitch	O
canker	O
,	O
by	O
the	O
soil	O
bacterium	O
Arthrobacter	O
sp	O
.	O

The	O
five	O
-	O
drug	O
combination	O
of	O
fluorouracil	O
imidazole	O
carboxamide	O
dimethyl	O
triazeno	O
,	O
vincristine	O
,	O
bis	O
-	O
chloroethyl	O
nitrosourea	O
,	O
and	O
prednisone	O
(	O
FIVB	O
+	O
P	O
)	O
was	O
given	O
to	O
120	O
women	O
with	O
metastatic	O
breast	O
cancer	O
.	O

A	O
method	O
is	O
described	O
for	O
the	O
simultaneous	O
determination	O
of	O
1	O
,	O
alpha	O
-	O
acetylmethadol	O
(	O
LAAM	O
)	O
and	O
five	O
active	O
metabolites	O
-	O
-	O
noracetylmethadol	O
,	O
dinoracetylmethadol	O
,	O
methadol	O
,	O
normethadol	O
,	O
and	O
dinormethadol	O
-	O
-	O
in	O
biofluids	O
by	O
high	O
-	O
performance	O
liquid	O
chromatography	O
using	O
a	O
normal	O
-	O
phase	O
column	O
and	O
a	O
UV	O
detector	O
at	O
218	O
nm	O
.	O

Clinical	O
and	O
anatomical	O
considerations	O

Theory	O
and	O
applications	O
of	O
pulse	O
dosing	O
:	O
a	O
summary	O
of	O
the	O
symposium	O
.	O

These	O
results	O
show	O
that	O
the	O
neonate	O
differs	O
from	O
the	O
adult	O
in	O
respect	O
of	O
both	O
the	O
nature	O
of	O
effects	O
of	O
the	O
drug	O
and	O
sensitivity	O
to	O
it	O
.	O

To	O
evaluate	O
the	O
gas	O
chromatographic	O
electron	O
capture	O
detection	O
method	O
described	O
earlier	O
,	O
23	O
plasma	O
samples	O
have	O
been	O
analysed	O
by	O
both	O
techniques	O
.	O

The	O
hemodynamics	O
of	O
isoproterenol	O
-	O
induced	O
cardiac	O
failure	O
in	O
the	O
rat	O
.	O

Several	O
authors	O
have	O
recently	O
reported	O
interference	O
in	O
theophylline	O
analysis	O
by	O
paraxanthine	O
(	O
1	O
,	O
7	O
-	O
dimethylxanthine	O
)	O
,	O
an	O
important	O
metabolite	O
of	O
caffeine	O
.	O

Multi	O
drug	O
regimens	O
like	O
C	O
-	O
MOPP	O
,	O
CHOP	O
and	O
BACOP	O
led	O
to	O
high	O
remission	O
rates	O
and	O
in	O
some	O
cases	O
probably	O
also	O
to	O
a	O
cure	O
of	O
the	O
disease	O
.	O

Morphological	O
features	O
of	O
Jat	O
dentition	O
.	O

Clinical	O
accuracy	O
of	O
updated	O
version	O
of	O
the	O
Phadebas	O
RAST	O
test	O
.	O

Five	O
control	O
subjects	O
with	O
COPD	O
,	O
who	O
performed	O
the	O
same	O
sequence	O
of	O
tests	O
without	O
breathing	O
30	O
%	O
O2	O
,	O
showed	O
no	O
change	O
in	O
flow	O
rates	O
or	O
density	O
dependence	O
.	O

Following	O
extended	O
recovery	O
hippocampal	O
EEG	O
was	O
normal	O
despite	O
extensive	O
cellular	O
loss	O
in	O
areas	O
CA3	O
and	O
CA4	O
.	O

Cross	O
reactivity	O
in	O
theophylline	O
RIA	O
kit	O
decreased	O
.	O

Strontium	O
-	O
90	O
was	O
inject	O
i	O
.	O
v	O
.	O
into	O
pregnant	O
rats	O
on	O
day	O
18	O
post	O
conception	O
(	O
p	O
.	O
c	O
.	O
)	O
.	O

Recording	O
of	O
the	O
digital	O
sphygmic	O
activity	O
in	O
the	O
lower	O
extremities	O
with	O
the	O
photoplethysmographic	O
and	O
strain	O
-	O
gauge	O
methods	O
.	O

Eight	O
hr	O
of	O
acidosis	O
caused	O
a	O
significant	O
(	O
P	O
less	O
than	O
0	O
.	O
01	O
)	O
decrease	O
in	O
P50	O
in	O
vitro	O
which	O
fell	O
from	O
29	O
.	O
0	O
to	O
24	O
.	O
4	O
torr	O
.	O

Catheter	O
transit	O
slows	O
the	O
response	O
to	O
a	O
step	O
increase	O
in	O
concentration	O
by	O
about	O
0	O
.	O
13	O
s	O
(	O
from	O
10	O
per	O
cent	O
-	O
90	O
per	O
cent	O
)	O
and	O
prolongs	O
the	O
transit	O
time	O
through	O
the	O
catheter	O
for	O
a	O
volatile	O
anesthetic	O
by	O
about	O
0	O
.	O
04	O
s	O
more	O
than	O
N2	O
.	O

These	O
women	O
should	O
not	O
be	O
given	O
the	O
current	O
estrogen	O
PPI	O
,	O
which	O
was	O
designed	O
to	O
warn	O
women	O
of	O
the	O
risks	O
of	O
long	O
-	O
term	O
estrogen	O
use	O
;	O
a	O
PPI	O
should	O
be	O
written	O
specifically	O
for	O
patients	O
receiving	O
short	O
courses	O
.	O

The	O
oral	O
temperature	O
rose	O
and	O
the	O
serum	B-GENE
creatine	I-GENE
kinase	I-GENE
levels	O
fell	O
only	O
in	O
those	O
patients	O
who	O
were	O
actively	O
warmed	O
.	O

Determination	O
of	O
aortic	O
distensibility	O
and	O
its	O
variations	O
in	O
arterial	O
hypertension	O
.	O

We	O
studied	O
the	O
role	O
of	O
prostaglandins	O
in	O
acid	O
-	O
induced	O
esophagitis	O
and	O
the	O
associated	O
LES	O
hypotension	O
by	O
simultaneous	O
treatment	O
of	O
some	O
animals	O
with	O
indomethacin	O
(	O
150	O
micrograms	O
/	O
kg	O
intravenous	O
)	O
,	O
a	O
specific	O
inhibitor	O
of	O
prostaglandin	O
synthesis	O
,	O
either	O
during	O
production	O
of	O
esophagitis	O
or	O
during	O
recovery	O
.	O

Since	O
only	O
58	O
%	O
of	O
our	O
sample	O
could	O
be	O
adequately	O
classified	O
with	O
one	O
diagnosis	O
,	O
we	O
expect	O
that	O
the	O
ASDC	O
nosology	O
will	O
need	O
to	O
evolve	O
further	O
.	O

A	O
surgical	O
technique	O
for	O
correcting	O
this	O
problem	O
is	O
described	O
.	O

Effects	O
of	O
prostaglandin	O
inhibitors	O
on	O
the	O
onset	O
of	O
proteinuria	O
and	O
stroke	O
in	O
stroke	O
-	O
prone	O
spontaneously	O
hypertensive	O
rats	O
.	O

In	O
this	O
study	O
,	O
the	O
general	O
clinical	O
criteria	O
for	O
inhalation	O
injury	O
-	O
-	O
presence	O
of	O
facial	O
or	O
oropharyngeal	O
burns	O
,	O
carboxyhemoglobin	B-GENE
levels	O
,	O
carbonaceous	O
sputum	O
,	O
or	O
closed	O
space	O
injury	O
-	O
-	O
did	O
not	O
differentiate	O
patients	O
with	O
airway	O
injury	O
only	O
from	O
those	O
with	O
parenchymal	O
injury	O
.	O

Methisergide	O
(	O
0	O
.	O
5	O
mg	O
/	O
kg	O
,	O
i	O
.	O
p	O
.	O
)	O
,	O
a	O
blocker	O
of	O
serotonin	B-GENE
receptors	I-GENE
,	O
prevented	O
the	O
development	O
of	O
the	O
antinociceptive	O
effect	O
of	O
serotonin	O
.	O

The	O
plasma	O
half	O
-	O
life	O
of	O
slow	O
disposition	O
phase	O
t1	O
/	O
2	O
beta	O
,	O
increases	O
from	O
0	O
.	O
26	O
hour	O
in	O
rabbits	O
with	O
normal	O
renal	O
function	O
to	O
5	O
.	O
41	O
hours	O
in	O
rabbits	O
with	O
severe	O
renal	O
impairment	O
.	O

Effects	O
of	O
early	O
monocular	O
deprivation	O
on	O
development	O
of	O
cortico	O
-	O
geniculate	O
projections	O
in	O
the	O
cat	O
.	O

Corticosteroid	O
therapy	O
is	O
known	O
to	O
be	O
hazardous	O
in	O
patients	O
with	O
occult	O
infection	O
but	O
the	O
mechanism	O
by	O
which	O
the	O
host	O
parasite	O
relationship	O
is	O
altered	O
by	O
steroids	O
is	O
not	O
known	O
.	O
We	O
have	O
used	O
an	O
intestinal	O
protozoal	O
parasite	O
,	O
Giardia	O
muris	O
,	O
to	O
examine	O
the	O
effects	O
of	O
corticosteroids	O
on	O
the	O
number	O
of	O
parasites	O
in	O
the	O
intestine	O
in	O
the	O
course	O
of	O
a	O
primary	O
infection	O
.	O

Static	O
lung	O
function	O
in	O
puppies	O
after	O
pneumonectomy	O
.	O

Bilateral	O
Charnley	O
arthroplasty	O
as	O
a	O
single	O
procedure	O
.	O

The	O
relationship	O
between	O
estrogenic	O
properties	O
of	O
Tamoxifen	O
and	O
breast	O
cancer	O
management	O
is	O
discussed	O
.	O

A	O
fluoroimmunoassay	O
for	O
the	O
determination	O
of	O
serum	O
of	O
plasma	O
levels	O
of	O
propranolol	O
was	O
developed	O
using	O
antibodies	O
to	O
propranolol	O
coupled	O
to	O
magnetizable	O
solid	O
-	O
phase	O
particles	O
and	O
fluorescein	O
-	O
labeled	O
propranolol	O
as	O
tracer	O
.	O

The	O
syncytial	O
microvillous	O
projections	O
seemed	O
to	O
be	O
more	O
numerous	O
and	O
longer	O
in	O
CNF	O
,	O
otherwise	O
the	O
structure	O
of	O
the	O
trophoblastic	O
layer	O
of	O
the	O
villi	O
and	O
the	O
lining	O
of	O
the	O
subtrophoblastic	O
vessels	O
were	O
identical	O
in	O
CNF	O
and	O
controls	O
.	O

When	O
pollen	O
allergen	O
from	O
three	O
grass	O
species	O
were	O
used	O
,	O
The	O
RAST	O
-	O
test	O
results	O
did	O
not	O
differ	O
from	O
duplicate	O
values	O
either	O
.	O

DMI	O
and	O
2	O
-	O
OH	O
-	O
DMI	O
concentrations	O
were	O
determined	O
in	O
a	O
similar	O
group	O
of	O
61	O
DMI	O
-	O
treated	O
patients	O
.	O

It	O
has	O
been	O
shown	O
in	O
experiments	O
in	O
vitro	O
that	O
the	O
hepatotrophic	O
organic	O
anions	O
,	O
the	O
radiographic	O
contrast	O
agent	O
(	O
RCA	O
)	O
bilignost	O
used	O
in	O
cholecystography	O
and	O
Bengal	O
pink	O
,	O
have	O
an	O
affinity	O
,	O
unlike	O
the	O
urographic	O
RCA	O
triombrin	O
and	O
renotrophic	O
dye	O
indigo	O
-	O
carmine	O
,	O
for	O
the	O
plasmatic	O
membranes	O
(	O
PM	O
)	O
of	O
liver	O
cells	O
.	O

33	O
out	O
of	O
90	O
neurons	O
of	O
the	O
cat	O
medial	O
geniculate	O
body	O
revealed	O
the	O
selectivity	O
of	O
their	O
afterdischarges	O
to	O
movement	O
of	O
sound	O
when	O
velocity	O
of	O
the	O
movement	O
changed	O
from	O
30	O
to	O
180	O
deg	O
/	O
s	O
.	O

In	O
controls	O
,	O
only	O
modest	O
differences	O
were	O
observed	O
.	O

Assay	O
of	O
serum	B-GENE
immunoreactive	I-GENE
trypsin	I-GENE
in	O
dried	O
blood	O
spots	O
and	O
the	O
early	O
detection	O
of	O
cystic	O
fibrosis	O
.	O

Similar	O
waves	O
were	O
seen	O
on	O
cross	O
-	O
correlating	O
a	O
motor	O
unit	O
with	O
an	O
electronic	O
oscillator	O
,	O
confirming	O
that	O
their	O
occurrence	O
does	O
not	O
necessarily	O
demonstrate	O
the	O
existence	O
of	O
active	O
neural	O
interactions	O
.	O

Leukocyte	O
enzyme	O
activity	O
and	O
blood	O
lymphocyte	O
blast	O
transformation	O
in	O
chronic	O
bronchitis	O

In	O
literature	O
,	O
the	O
HBE	O
has	O
been	O
displayed	O
by	O
application	O
of	O
the	O
averaging	O
method	O
.	O

Forty	O
-	O
five	O
cases	O
were	O
surgically	O
by	O
direct	O
approach	O
to	O
the	O
tumour	O
,	O
while	O
two	O
cases	O
were	O
treated	O
only	O
with	O
a	O
shunt	O
.	O

In	O
Group	O
V	O
,	O
the	O
salvaged	O
tissue	O
was	O
primarily	O
subepicardial	O
with	O
virtually	O
no	O
lateral	O
zone	O
of	O
salvaged	O
tissue	O
(	O
ratio	O
of	O
salvaged	O
subepicardium	O
to	O
salvaged	O
subendocardium	O
14	O
.	O
8	O
+	O
/	O
-	O
1	O
.	O
9	O
to	O
1	O
)	O
.	O

Progressive	O
100	O
-	O
mmHg	O
stepwise	O
decreases	O
in	O
superfusate	O
oxygen	O
partial	O
pressure	O
(	O
PO2	O
)	O
from	O
control	O
(	O
95	O
%	O
O2	O
aeration	O
,	O
PO2	O
,	O
620	O
-	O
650	O
mmHg	O
)	O
were	O
produced	O
,	O
and	O
subsequent	O
changes	O
in	O
isometric	O
active	O
and	O
resting	O
tension	O
were	O
measured	O
.	O

The	O
known	O
B1	O
-	O
deficiency	O
reaches	O
excessive	O
high	O
values	O
with	O
light	O
exercise	O
.	O

Based	O
on	O
AUC	O
infinity	O
analyses	O
,	O
the	O
pharmacokinetics	O
of	O
buflomedil	O
were	O
found	O
to	O
be	O
linear	O
within	O
the	O
dose	O
ranges	O
studied	O
(	O
50	O
to	O
200	O
mg	O
for	O
i	O
.	O
v	O
.	O
injection	O
and	O
150	O
to	O
450	O
mg	O
for	O
oral	O
administration	O
)	O
.	O

Gastrin	B-GENE
secretion	O
during	O
food	O
stimulation	O
in	O
digestive	O
system	O
diseases	O

Fibrinogen	B-GENE
determination	O
using	O
the	O
KZM	O
-	O
1	O
meter	O

Delayed	O
or	O
paradoxically	O
emptying	O
regions	O
of	O
the	O
left	O
ventricle	O
were	O
detected	O
by	O
a	O
relatively	O
new	O
nuclear	O
technique	O
-	O
-	O
phase	O
imaging	O
.	O

Responses	O
to	O
brainstem	O
of	O
nuclei	O
medialis	O
dorsalis	O
,	O
lateralis	O
posterior	O
were	O
of	O
considerably	O
longer	O
latency	O
.	O

Nineteen	O
patients	O
with	O
non	O
-	O
visualized	O
gallbladder	O
with	O
OCG	O
subsequently	O
had	O
Tc	O
-	O
99m	O
-	O
PyG	O
cholescintigraphy	O
performed	O
.	O

One	O
was	O
allowed	O
fresh	O
drinking	O
water	O
ad	O
libitum	O
whilst	O
the	O
other	O
received	O
Aludrox	O
in	O
their	O
drinking	O
water	O
.	O

Anamnestic	O
data	O
were	O
obtained	O
from	O
case	O
history	O
,	O
smoking	O
habits	O
were	O
not	O
known	O
in	O
collective	O
A	O
and	O
C	O
.	O

The	O
determination	O
of	O
physical	O
performance	O
capacity	O
was	O
based	O
on	O
W170	O
,	O
W85	O
%	O
and	O
on	O
predicted	O
VO2	O
max	O
measured	O
with	O
continuously	O
increasing	O
work	O
load	O
on	O
a	O
bicycle	O
ergometer	O
.	O

Determination	O
of	O
lead	O
in	O
blood	O
.	O

Effect	O
of	O
indomethacin	O
and	O
prostaglandin	O
F2	O
alpha	O
on	O
parturition	O
in	O
swine	O
.	O

LD50	O
values	O
of	O
terms	O
of	O
KP	O
were	O
84	O
mg	O
/	O
kg	O
in	O
male	O
rats	O
and	O
122	O
mg	O
/	O
kg	O
in	O
female	O
rats	O
when	O
KP	O
-	O
CMC	O
was	O
administered	O
intrarectally	O
,	O
and	O
117	O
mg	O
/	O
kg	O
in	O
male	O
and	O
92	O
mg	O
/	O
kg	O
in	O
female	O
when	O
KP	O
-	O
T10	O
was	O
administered	O
intrarectally	O
.	O
,	O
while	O
peroral	O
administration	O
of	O
KP	O
-	O
CMC	O
showed	O
LD50	O
values	O
of	O
68	O
mg	O
/	O
kg	O
in	O
males	O
and	O
78	O
mg	O
/	O
kg	O
in	O
females	O
in	O
terms	O
of	O
KP	O
.	O

Autotransfusion	O
was	O
performed	O
as	O
follows	O
:	O
Heparin	O
-	O
ACD	O
-	O
B	O
-	O
Heparin	O
-	O
DPD	O
-	O
Heparin	O
-	O
ACD	O
-	O
B	O
etc	O
.	O

Generally	O
the	O
differences	O
between	O
short	O
gut	O
and	O
sham	O
operation	O
animals	O
disappeared	O
when	O
the	O
data	O
were	O
normalised	O
for	O
mucosal	O
weight	O
.	O

A	O
simplified	O
thin	O
-	O
layer	O
chromatographic	O
determination	O
of	O
hippuric	O
acid	O
and	O
methylhippuric	O
acids	O
.	O

The	O
architecture	O
of	O
microvasculature	O
in	O
these	O
two	O
regions	O
was	O
also	O
examined	O
by	O
scanning	O
electron	O
microscopy	O
,	O
using	O
the	O
resin	O
casting	O
method	O
.	O

MSMS	O
Council	O
hears	O
new	O
public	O
health	O
director	O
.	O

Chordoma	O
of	O
the	O
spinal	O
cord	O
in	O
a	O
F344	O
rat	O
.	O

Micro	O
high	O
-	O
performance	O
liquid	O
chromatographic	O
system	O
with	O
micro	O
precolumn	O
and	O
dual	O
electrochemical	O
detector	O
for	O
direct	O
injection	O
analysis	O
of	O
catecholamines	O
in	O
body	O
fluids	O
.	O

A	O
narrow	O
zone	O
of	O
myelin	O
-	O
axonal	O
dissociation	O
was	O
also	O
observed	O
.	O

The	O
IgA	B-GENE
deficiency	O
is	O
combined	O
with	O
the	O
IgE	B-GENE
one	O
.	O

In	O
PB	O
mice	O
,	O
there	O
was	O
only	O
a	O
small	O
deficit	O
in	O
the	O
number	O
of	O
the	O
hippocampal	O
pyramidal	O
neurons	O
compared	O
to	O
controls	O
(	O
15	O
%	O
,	O
p	O
less	O
than	O
0	O
.	O
01	O
)	O
,	O
and	O
no	O
deficit	O
in	O
the	O
granule	O
cells	O
.	O

Nutritional	O
cataracts	O
in	O
timber	O
wolves	O
.	O

The	O
quantitative	O
determination	O
of	O
HBSAG	B-GENE
-	O
-	O
a	O
valuable	O
aid	O
in	O
evaluating	O
the	O
infectiousness	O
of	O
hepatitis	O
B	O
virus	O
carriers	O

2	O
.	O
numerous	O
narrow	O
shunt	O
vessels	O
departing	O
continuously	O
from	O
the	O
primary	O
arteries	O
to	O
feed	O
a	O
secondary	O
arterial	O
system	O
which	O
parallels	O
the	O
primary	O
one	O
.	O

Urological	O
complications	O
are	O
frequent	O
during	O
and	O
after	O
the	O
treatment	O
of	O
gynecological	O
malignancy	O
.	O

Arachnoid	O
cyst	O
.	O

Hypotension	O
was	O
produced	O
by	O
head	O
up	O
tilt	O
.	O

Therefore	O
the	O
procedure	O
of	O
Lich	O
-	O
Gregoir	O
is	O
not	O
to	O
be	O
recommended	O
in	O
adults	O
.	O

Mucoepidermoid	O
and	O
acinous	O
cell	O
carcinomas	O
of	O
salivary	O
tissues	O
.	O

Twenty	O
patients	O
aged	O
45	O
or	O
older	O
with	O
the	O
diagnosis	O
of	O
endogenous	O
depression	O
were	O
evaluated	O
in	O
terms	O
of	O
safety	O
and	O
efficacy	O
in	O
their	O
response	O
to	O
multiple	O
monitored	O
electroconvulsive	O
therapy	O
(	O
MMECT	O
)	O
versus	O
single	O
electroconvulsive	O
therapy	O
(	O
SECT	O
)	O
.	O

Longitudinal	O
force	O
-	O
length	O
relationships	O
of	O
guinea	O
pig	O
ureter	O
were	O
studied	O
in	O
vitro	O
in	O
animals	O
3	O
weeks	O
,	O
3	O
months	O
,	O
and	O
3	O
years	O
of	O
age	O
.	O

Tests	O
of	O
the	O
method	O
indicate	O
(	O
1	O
)	O
the	O
Mossbauer	O
source	O
can	O
be	O
placed	O
on	O
the	O
basilar	O
membrane	O
without	O
altering	O
the	O
signal	O
-	O
transmission	O
properties	O
of	O
the	O
cochlea	O
,	O
and	O
(	O
2	O
)	O
the	O
source	O
adheres	O
to	O
the	O
basilar	O
membrane	O
.	O

Angiographic	O
work	O
-	O
up	O
in	O
a	O
patient	O
with	O
late	O
vaginal	O
metastasis	O
from	O
a	O
renal	O
carcinoma	O
.	O

The	O
authors	O
conclude	O
that	O
nonspecificity	O
of	O
low	O
platelet	B-GENE
MAO	I-GENE
as	O
a	O
possible	O
correlate	O
of	O
bipolar	O
affective	O
disorder	O
,	O
as	O
well	O
as	O
schizophrenia	O
,	O
increases	O
the	O
burden	O
of	O
proof	O
necessary	O
before	O
findings	O
of	O
low	O
platelet	B-GENE
MAO	I-GENE
can	O
be	O
accepted	O
as	O
primary	O
.	O

Ecthyma	O
,	O
a	O
known	O
disease	O
,	O
of	O
which	O
little	O
is	O
known	O

Estrogen	O
replacement	O
,	O
either	O
as	O
17	O
beta	O
-	O
estradiol	O
or	O
beta	O
-	O
estradiol	O
-	O
3	O
-	O
benzoate	O
via	O
subcutaneous	O
Silastic	O
capsules	O
,	O
was	O
associated	O
with	O
elevated	O
rates	O
of	O
heat	O
production	O
and	O
dry	O
heat	O
loss	O
relative	O
to	O
untreated	O
ovariectomized	O
controls	O
.	O

The	O
following	O
aspects	O
were	O
assessed	O
:	O
(	O
1	O
)	O
The	O
effect	O
on	O
the	O
cardiovascular	O
system	O
in	O
terms	O
of	O
brachial	O
arterial	O
pressure	O
,	O
pulse	O
rate	O
,	O
and	O
oxygen	O
consumption	O
(	O
VO2	O
)	O
during	O
exercise	O
in	O
5	O
health	O
volunteers	O
;	O
(	O
2	O
)	O
emg	O
activity	O
of	O
the	O
tibialis	O
anterior	O
and	O
gastrocnemius	O
muscles	O
during	O
exercise	O
in	O
the	O
same	O
5	O
volunteers	O
;	O
and	O
(	O
3	O
)	O
postexercise	O
ankle	O
pressure	O
changes	O
in	O
10	O
subjects	O
with	O
angiographically	O
proven	O
occlusive	O
arterial	O
diseases	O
of	O
the	O
lower	O
extremities	O
.	O

It	O
was	O
argued	O
that	O
this	O
arose	O
from	O
the	O
possibility	O
that	O
the	O
nature	O
of	O
blue	O
collar	O
jobs	O
was	O
physical	O
,	O
and	O
that	O
loss	O
of	O
myocardial	O
tissue	O
might	O
be	O
expected	O
to	O
more	O
markedly	O
interfere	O
with	O
their	O
work	O
efficiency	O
(	O
on	O
returning	O
to	O
work	O
)	O
than	O
it	O
would	O
the	O
efficiency	O
of	O
the	O
more	O
sedentary	O
jobs	O
of	O
white	O
collar	O
workers	O
.	O

Importance	O
of	O
determining	O
the	O
blood	O
sulfhydryl	O
groups	O
in	O
fractures	O
of	O
the	O
long	O
tubular	O
bones	O
complicated	O
by	O
infection	O

The	O
results	O
revealed	O
increased	O
blood	O
lead	O
level	O
associated	O
with	O
decreased	O
blood	B-GENE
haemoglobin	I-GENE
and	O
increased	O
urinary	O
excretion	O
of	O
delta	O
amino	O
levulinic	O
acid	O
.	O

Following	O
iv	O
injection	O
of	O
0	O
.	O
5	O
g	O
galactose	O
per	O
kg	O
body	O
weight	O
,	O
together	O
with	O
2	O
mu	O
Ci	O
generally	O
14C	O
-	O
labelled	O
galactose	O
,	O
14CO2	O
is	O
collected	O
in	O
regular	O
intervals	O
during	O
one	O
hour	O
.	O

Specific	O
clotting	O
factor	O
assays	O
showed	O
an	O
isolated	O
deficiency	O
of	O
factor	B-GENE
X	I-GENE
ranging	O
from	O
7	O
to	O
12	O
per	O
cent	O
on	O
three	O
determinations	O
.	O

Blood	O
variables	O
measured	O
at	O
eight	O
intervals	O
before	O
,	O
during	O
,	O
and	O
after	O
operation	O
were	O
as	O
follows	O
:	O
seven	O
plasma	O
proteins	O
,	O
free	O
hemoglobin	B-GENE
,	O
formed	O
elements	O
,	O
and	O
clotting	O
functions	O
.	O

The	O
ability	O
of	O
sodium	O
phenobarbital	O
(	O
60	O
mg	O
/	O
kg	O
)	O
and	O
sodium	O
barbital	O
(	O
80	O
mg	O
/	O
kg	O
)	O
to	O
produce	O
a	O
taste	O
aversion	O
in	O
23	O
hr	O
fluid	O
deprived	O
rats	O
was	O
examined	O
using	O
a	O
discrimination	O
or	O
two	O
bottle	O
taste	O
aversion	O
task	O
(	O
0	O
.	O
125	O
%	O
sodium	O
saccharin	O
solution	O
or	O
water	O
)	O
.	O

It	O
appears	O
that	O
the	O
pulmonary	O
gas	O
exchange	O
parenchyma	O
of	O
these	O
smallest	O
mammals	O
is	O
well	O
suited	O
to	O
supply	O
the	O
organism	O
with	O
the	O
comparatively	O
high	O
levels	O
of	O
O2	O
required	O
by	O
the	O
high	O
metabolic	O
rates	O
,	O
exhibiting	O
a	O
structural	O
adaptation	O
of	O
the	O
lung	O
to	O
higher	O
VO2	O
.	O

Underestimations	O
by	O
as	O
much	O
as	O
35	O
%	O
may	O
occur	O
due	O
to	O
the	O
problems	O
in	O
the	O
existing	O
methodologies	O
.	O

Chemotherapy	O
was	O
administered	O
without	O
altering	O
the	O
course	O
of	O
the	O
disorder	O
.	O

Drug	O
inhibition	O
of	O
whole	O
blood	O
aspirin	B-GENE
esterase	I-GENE
.	O

However	O
,	O
at	O
lower	O
temperature	O
the	O
positive	O
staircase	O
was	O
not	O
clear	O
and	O
rather	O
negative	O
staircase	O
appeared	O
(	O
1	O
-	O
-	O
3	O
Hz	O
)	O
.	O

Visual	O
averaged	O
evoked	O
responses	O
and	O
platelet	B-GENE
monoamine	I-GENE
oxidase	I-GENE
in	O
patients	O
suffering	O
from	O
alcoholism	O
.	O

At	O
the	O
end	O
of	O
the	O
experiment	O
the	O
urinary	O
porphyrin	O
excretion	O
and	O
the	O
porphyrin	O
content	O
in	O
lijver	O
and	O
skin	O
were	O
diminished	O
in	O
HCB	O
-	O
CQ	O
-	O
treated	O
animals	O
by	O
about	O
50	O
%	O
compared	O
to	O
the	O
HCB	O
controls	O
.	O

Although	O
stone	O
-	O
formers	O
were	O
not	O
found	O
to	O
display	O
any	O
features	O
of	O
magnesium	O
metabolism	O
that	O
were	O
different	O
from	O
those	O
in	O
the	O
control	O
group	O
,	O
their	O
lower	O
urinary	O
excretion	O
of	O
magnesium	O
in	O
relation	O
to	O
calcium	O
may	O
be	O
a	O
factor	O
in	O
their	O
increased	O
stone	O
-	O
forming	O
propensity	O
.	O

A	O
16	O
-	O
year	O
follow	O
-	O
up	O
study	O
of	O
69	O
paraplegics	O
with	O
complete	O
lesions	O
from	O
T1	O
-	O
L3	O
is	O
presented	O
.	O

Hippocampal	O
stimulation	O
overlapping	O
conditioned	O
stimulus	O
preexposure	O
produced	O
attenuation	O
of	O
latent	O
inhibition	O
,	O
as	O
did	O
stimulation	O
presented	O
during	O
conditioning	O
after	O
preexposure	O
.	O

The	O
centromedial	O
amygdala	O
and	O
gastric	O
pathology	O
in	O
rats	O
.	O

Cataract	O
extraction	O
in	O
primary	O
glaucoma	O

Number	O
and	O
size	O
of	O
the	O
myelin	O
structures	O
in	O
the	O
pneumocytes	O
typ	O
II	O
increased	O
simultaneously	O
.	O

In	O
the	O
intact	O
animal	O
,	O
postextrasystolic	O
potentiation	O
depended	O
on	O
the	O
basic	O
pacing	O
interval	O
,	O
t0	O
,	O
and	O
the	O
timing	O
of	O
the	O
extrasystole	O
,	O
t1	O
:	O
when	O
t0	O
was	O
held	O
constant	O
and	O
t1	O
was	O
increased	O
,	O
potentiation	O
decreased	O
;	O
when	O
t1	O
was	O
held	O
constant	O
and	O
t0	O
was	O
increased	O
,	O
potentiation	O
increased	O
.	O

In	O
spite	O
of	O
this	O
and	O
other	O
complications	O
of	O
corticosteroids	O
,	O
she	O
made	O
a	O
full	O
recovery	O
from	O
the	O
fungal	O
infection	O
following	O
treatment	O
with	O
amphotericin	O
B	O
and	O
surgical	O
excision	O
of	O
the	O
lung	O
abscess	O
.	O

Implications	O
of	O
this	O
observation	O
for	O
pediatrics	O
are	O
discussed	O
.	O

For	O
the	O
study	O
of	O
the	O
transition	O
of	O
long	O
to	O
short	O
waves	O
(	O
deep	O
-	O
water	O
waves	O
)	O
a	O
closed	O
-	O
form	O
solution	O
is	O
advantageous	O
;	O
this	O
can	O
,	O
however	O
,	O
only	O
be	O
obtained	O
at	O
the	O
cost	O
of	O
further	O
simplification	O
.	O

Treatment	O
of	O
suppurative	O
peritonitis	O

We	O
report	O
a	O
case	O
of	O
pheochromocytoma	O
manifesting	O
during	O
the	O
third	O
trimester	O
of	O
pregnancy	O
.	O

Fasting	O
plasma	O
and	O
lipoprotein	O
lipid	O
concentrations	O
,	O
adipose	B-GENE
tissue	I-GENE
lipoprotein	I-GENE
lipase	I-GENE
activity	O
,	O
anthropometric	O
data	O
,	O
alcohol	O
consumption	O
,	O
smoking	O
habits	O
,	O
weekly	O
mileage	O
run	O
and	O
performance	O
on	O
a	O
bicycle	O
ergometer	O
were	O
recorded	O
before	O
and	O
after	O
the	O
training	O
period	O
.	O

The	O
C18	O
:	O
1	O
:	O
C10	O
value	O
is	O
a	O
convenient	O
measure	O
of	O
these	O
changes	O
and	O
can	O
be	O
determined	O
more	O
rapidly	O
than	O
determining	O
all	O
the	O
lower	O
fatty	O
acids	O
.	O

A	O
progressive	O
growth	O
of	O
blood	O
erythrocyte	O
membrane	O
injury	O
has	O
been	O
demonstrated	O
after	O
rats	O
were	O
exposed	O
to	O
gamma	O
-	O
irradiaton	O
at	O
a	O
dose	O
of	O
100	O
to	O
500	O
Gy	O
.	O

Within	O
the	O
3	O
'	O
terminal	O
50	O
nucleotides	O
,	O
the	O
mouse	B-GENE
mt	I-GENE
12S	I-GENE
rRNA	I-GENE
contains	O
a	O
potential	O
10	O
bp	O
hairpin	O
structure	O
and	O
a	O
sequence	O
of	O
15	O
consecutive	O
nucleotides	O
common	O
to	O
the	O
RNA	O
of	O
the	O
small	O
ribosomal	O
subunit	O
in	O
all	O
systems	O
,	O
but	O
does	O
not	O
contain	O
the	O
mRNA	O
binding	O
site	O
(	O
ACCUCC	O
)	O
found	O
in	O
E	O
.	O
coli	O
and	O
corn	O
chloroplast	O
rRNAs	O
.	O

Thirty	O
cadaver	O
brains	O
were	O
examined	O
under	O
X	O
6	O
to	O
16	O
magnification	O
in	O
order	O
to	O
define	O
the	O
microsurgical	O
anatomy	O
of	O
the	O
pineal	O
region	O
,	O
particularly	O
the	O
relationship	O
of	O
the	O
pineal	O
body	O
,	O
posterior	O
cerebral	O
artery	O
,	O
superior	O
cerebellar	O
artery	O
,	O
vein	O
of	O
Galen	O
,	O
basal	O
vein	O
of	O
Rosenthal	O
,	O
internal	O
cerebral	O
vein	O
,	O
straight	O
sinus	O
,	O
bridging	O
vein	O
,	O
the	O
size	O
of	O
the	O
tentorial	O
notch	O
,	O
and	O
the	O
third	O
and	O
the	O
fourth	O
cranial	O
nerves	O
.	O

Serum	O
antibody	O
titre	O
was	O
not	O
significantly	O
associated	O
with	O
the	O
recurrence	O
rate	O
or	O
the	O
duration	O
of	O
infection	O
.	O

We	O
propose	O
that	O
refeeding	O
may	O
be	O
an	O
important	O
mechanism	O
for	O
activation	O
of	O
certain	O
viral	O
infections	O
previously	O
suppressed	O
by	O
famine	O
.	O

One	O
hundred	O
twenty	O
units	O
of	O
deglycerolized	O
red	O
blood	O
cells	O
,	O
some	O
with	O
glycerol	O
added	O
so	O
as	O
to	O
exceed	O
an	O
acceptable	O
1	O
%	O
glycerol	O
content	O
,	O
had	O
measurements	O
made	O
of	O
the	O
post	O
-	O
wash	O
supernatant	O
fluid	O
by	O
refractive	O
index	O
and	O
osmometry	O
.	O

The	O
symptoms	O
and	O
objective	O
findings	O
were	O
caused	O
by	O
a	O
malignant	O
lymphoma	O
,	O
and	O
the	O
diagnosis	O
was	O
established	O
from	O
a	O
drill	O
biopsy	O
.	O

Our	O
study	O
differs	O
from	O
previous	O
studies	O
in	O
that	O
it	O
is	O
limited	O
to	O
one	O
diagnostic	O
entity	O
,	O
yet	O
at	O
the	O
same	O
time	O
evaluates	O
a	O
broad	O
range	O
of	O
social	O
and	O
work	O
-	O
related	O
factors	O
in	O
disability	O
.	O

It	O
is	O
suggested	O
that	O
a	O
raised	O
hydroxykynurenine	O
/	O
hydroxyanthranilic	O
acid	O
ratio	O
does	O
not	O
necessarily	O
indicate	O
vitamin	O
B6	O
deficiency	O
but	O
may	O
represent	O
a	O
nonspecific	O
response	O
of	O
tryptophan	O
metabolism	O
to	O
stress	O
.	O

All	O
control	O
persons	O
had	O
a	O
normal	O
reaction	O
to	O
DNFB	O
.	O

In	O
a	O
control	O
group	O
both	O
common	O
carotid	O
arteries	O
(	O
CCA	O
)	O
were	O
ligated	O
.	O

At	O
pH	O
6	O
.	O
9	O
,	O
the	O
same	O
lidocaine	O
concentrations	O
significantly	O
reduced	O
resting	O
potential	O
(	O
3	O
-	O
10	O
%	O
)	O
,	O
action	O
potential	O
amplitude	O
(	O
3	O
-	O
8	O
%	O
)	O
and	O
Vmax	O
(	O
14	O
-	O
22	O
%	O
)	O
.	O

Simultaneous	O
right	O
and	O
left	O
adrenal	O
and	O
peripheral	O
blood	O
samples	O
were	O
collected	O
for	O
determination	O
of	O
oestrone	O
(	O
E1	O
)	O
and	O
oestradiol	O
(	O
E2	O
)	O
.	O

Arm	O
function	O
tests	O
.	O

All	O
lambs	O
with	O
B	O
breeding	O
had	O
significantly	O
higher	O
Hb	B-GENE
levels	O
at	O
the	O
end	O
of	O
the	O
experiment	O
than	O
did	O
NB	O
lambs	O
.	O
b	O
and	O
S	O
x	O
B	O
lambs	O
had	O
higher	O
(	O
P	O
<	O
.	O
05	O
)	O
Hb	B-GENE
levels	O
than	O
the	O
D	O
x	O
B	O
lambs	O
,	O
and	O
B	O
lambs	O
had	O
the	O
highest	O
(	O
P	O
<	O
.	O
05	O
)	O
mean	O
corpuscular	O
hemoglobin	B-GENE
concentrations	O
.	O

The	O
same	O
response	O
occurs	O
whether	O
acrylamide	O
is	O
given	O
immediately	O
after	O
nerve	O
ligation	O
or	O
1	O
week	O
later	O
.	O

The	O
operation	O
recommended	O
is	O
excision	O
of	O
3	O
mm	O
of	O
central	O
slip	O
followed	O
by	O
end	O
-	O
to	O
-	O
end	O
repair	O
of	O
the	O
tendon	O
.	O

In	O
the	O
unclipped	O
group	O
arterial	O
pressure	O
decreased	O
50	O
mmHg	O
to	O
normal	O
by	O
24	O
h	O
and	O
was	O
associated	O
with	O
increased	O
diuresis	O
and	O
a	O
small	O
decrease	O
in	O
blood	O
volume	O
(	O
9	O
.	O
8	O
%	O
)	O
.	O

Marked	O
sedative	O
activity	O
was	O
observed	O
with	O
9	O
-	O
methoxy	O
-	O
5	O
-	O
phenylpyrrolo	O
[	O
2	O
,	O
1	O
-	O
d	O
]	O
[	O
1	O
,	O
5	O
]	O
benzothiazepin	O
-	O
6	O
,	O
6	O
-	O
dioxide	O
(	O
NF19	O
)	O
and	O
9	O
-	O
chloro	O
-	O
5	O
-	O
p	O
-	O
nitrophenylpyrrolo	O
[	O
2	O
,	O
1	O
-	O
d	O
]	O
[	O
1	O
,	O
5	O
]	O
benzothiazepin	O
-	O
6	O
,	O
6	O
-	O
dioxide	O
(	O
NF20	O
)	O
.	O

In	O
patients	O
,	O
the	O
effect	O
of	O
CCK	B-GENE
-	O
PZ	B-GENE
on	O
the	O
movement	O
of	O
the	O
terminal	O
part	O
of	O
the	O
bile	O
duct	O
was	O
measured	O
with	O
a	O
pressure	O
sensor	O
using	O
a	O
duodenofiberscope	O
.	O

As	O
high	O
-	O
speed	O
,	O
volumetric	O
imaging	O
,	O
computed	O
tomographic	O
scan	O
machines	O
such	O
as	O
the	O
Dynamic	O
Spatial	O
Reconstructor	O
become	O
available	O
with	O
higher	O
density	O
resolution	O
,	O
perhaps	O
a	O
single	O
injection	O
of	O
contrast	O
agent	O
into	O
the	O
right	O
atrium	O
or	O
even	O
a	O
peripheral	O
vein	O
may	O
be	O
adequate	O
to	O
obtain	O
all	O
these	O
measurements	O
.	O

The	O
ESEG	O
'	O
s	O
are	O
a	O
direct	O
result	O
of	O
the	O
NEXT	O
study	O
.	O

The	O
potentially	O
SLE	O
-	O
inducing	O
drugs	O
are	O
reviewed	O
.	O

A	O
third	O
series	O
of	O
mice	O
were	O
given	O
a	O
single	O
injection	O
of	O
5	O
-	O
OH	O
-	O
DA	O
,	O
sacrificed	O
,	O
and	O
prepared	O
for	O
ultrastructural	O
study	O
.	O

Fourteen	O
different	O
species	O
(	O
eight	O
Platyhelmintha	O
,	O
one	O
Nematoda	O
and	O
five	O
Crustacea	O
)	O
have	O
been	O
inventorized	O
.	O

No	O
symptoms	O
other	O
than	O
hot	O
flush	O
showed	O
such	O
significant	O
correlation	O
with	O
plasma	O
epinephrine	O
or	O
norepinephrine	O
levels	O
.	O

The	O
mean	O
values	O
of	O
the	O
concentrations	O
of	O
the	O
components	O
due	O
to	O
tobacco	O
smoke	O
are	O
:	O
CO	O
=	O
1	O
.	O
1	O
ppm	O
,	O
NO	O
=	O
32	O
ppb	O
,	O
NO2	O
=	O
24	O
ppb	O
,	O
nicotine	O
=	O
0	O
.	O
9	O
micrograms	O
/	O
m3	O
,	O
particulate	O
matter	O
=	O
133	O
micrograms	O
/	O
m3	O
.	O

The	O
average	O
backscatter	O
coefficient	O
was	O
six	O
time	O
larger	O
in	O
regions	O
of	O
infarct	O
studied	O
8	O
-	O
-	O
10	O
weeks	O
after	O
occlusion	O
than	O
that	O
in	O
regions	O
of	O
infarct	O
studied	O
5	O
-	O
-	O
6	O
weeks	O
after	O
occlusion	O
.	O

At	O
4	O
wk	O
however	O
,	O
tumor	O
relapse	O
was	O
noted	O
in	O
6	O
of	O
7	O
group	O
4	O
responders	O
,	O
10	O
of	O
12	O
in	O
group	O
5	O
,	O
13	O
of	O
16	O
in	O
group	O
7	O
,	O
but	O
only	O
4	O
of	O
19	O
group	O
8	O
responders	O
(	O
p	O
less	O
than	O
.	O
001	O
group	O
8	O
versus	O
4	O
,	O
5	O
,	O
7	O
)	O
.	O

Early	O
infection	O
was	O
detected	O
in	O
one	O
of	O
50	O
control	O
women	O
who	O
gave	O
birth	O
to	O
a	O
healthy	O
infant	O
.	O

Pentachlorophenol	O
accelerates	O
the	O
onset	O
of	O
HCB	O
porphyria	O
,	O
in	O
other	O
words	O
it	O
increases	O
the	O
total	O
urinary	O
porphyrin	O
excretion	O
and	O
causes	O
an	O
earlier	O
disturbance	O
of	O
the	O
porphyrin	O
pattern	O
.	O

Family	O
planning	O
continues	O
to	O
play	O
a	O
minor	O
role	O
,	O
and	O
only	O
25	O
.	O
3	O
per	O
cent	O
of	O
all	O
patients	O
reviewed	O
took	O
to	O
oral	O
contraceptives	O
for	O
shorter	O
or	O
longer	O
periods	O
of	O
time	O
.	O
-	O
The	O
percentages	O
of	O
primiparae	O
and	O
secundiparae	O
in	O
all	O
births	O
as	O
well	O
as	O
the	O
high	O
percentage	O
of	O
multigravidity	O
are	O
parameters	O
by	O
which	O
the	O
approach	O
to	O
reproduction	O
differs	O
substantively	O
from	O
behaviour	O
patterns	O
in	O
Europe	O
.	O

The	O
term	O
osteomesopycnosis	O
is	O
proposed	O
for	O
a	O
sclerosing	O
bone	O
disease	O
with	O
dominant	O
inheritance	O
that	O
has	O
been	O
discovered	O
in	O
five	O
members	O
of	O
four	O
different	O
families	O
.	O

The	O
87K	O
protein	O
,	O
together	O
with	O
proteins	O
of	O
105	O
,	O
000	O
and	O
75	O
,	O
000	O
daltons	O
,	O
are	O
translated	O
from	O
leftward	O
transcribed	O
(	O
1	O
-	O
strand	O
)	O
messenger	O
RNAs	O
that	O
are	O
complementary	O
to	O
the	O
viral	O
genome	O
between	O
positions	O
11	O
.	O
2	O
and	O
31	O
.	O
5	O
.	O

The	O
identification	O
of	O
viable	O
myocardium	O
with	O
both	O
99mTc	O
-	O
tetrofosmin	O
and	O
201Tl	O
can	O
be	O
greatly	O
enhanced	O
to	O
a	O
similar	O
degree	O
if	O
the	O
severity	O
of	O
reduction	O
in	O
activity	O
within	O
nonreversible	O
defects	O
is	O
considered	O
.	O

The	O
temporal	O
component	O
lacked	O
a	O
mandibular	O
fossa	O
as	O
well	O
as	O
articular	O
eminence	O
.	O

EUK	O
-	O
8	O
is	O
a	O
novel	O
,	O
synthetic	O
,	O
low	O
-	O
molecular	O
-	O
weight	O
salen	O
-	O
manganese	O
complex	O
that	O
exhibits	O
both	O
superoxide	B-GENE
dismutase	I-GENE
and	O
catalase	B-GENE
activities	O
in	O
vitro	O
.	O

The	O
protein	B-GENE
ELT	I-GENE
-	I-GENE
1	I-GENE
,	O
encoded	O
by	O
a	O
single	O
-	O
copy	O
gene	O
homologous	O
to	O
the	O
GATA	B-GENE
family	I-GENE
of	I-GENE
vertebrate	I-GENE
transcription	I-GENE
factors	I-GENE
,	O
is	O
potentially	O
capable	O
of	O
interacting	O
with	O
this	O
element	O
.	O

However	O
,	O
in	O
contrast	O
with	O
previous	O
in	O
vitro	O
cell	O
-	O
free	O
integration	O
studies	O
,	O
alteration	O
of	O
the	O
highly	O
conserved	O
CA	O
dinucleotide	O
resulted	O
in	O
a	O
mutant	O
which	O
still	O
retained	O
40	O
%	O
of	O
wild	O
-	O
type	O
integration	O
activity	O
.	O

These	O
results	O
demonstrate	O
that	O
although	O
PI2	O
and	O
PI3	O
viruses	O
belong	O
to	O
the	O
same	O
parainfluenza	O
virus	O
genus	O
,	O
these	O
viruses	O
show	O
marked	O
differences	O
with	O
respect	O
to	O
functional	O
requirements	O
for	O
the	O
cytoplasmic	O
tail	O
of	O
the	O
F	B-GENE
glycoprotein	I-GENE
.	O

By	O
site	O
-	O
specific	O
mutagenesis	O
,	O
we	O
also	O
show	O
that	O
individual	O
ICP27	B-GENE
C	I-GENE
-	I-GENE
terminal	I-GENE
amino	I-GENE
acid	I-GENE
residues	I-GENE
that	O
are	O
positionally	O
conserved	O
in	O
ICP27	B-GENE
homologs	I-GENE
in	O
other	O
herpesviruses	O
(	O
D	O
-	O
357	O
,	O
E	O
-	O
358	O
,	O
H	O
-	O
479	O
,	O
C	O
-	O
400	O
,	O
C	O
-	O
483	O
,	O
and	O
C	O
-	O
488	O
)	O
are	O
critical	O
for	O
trans	O
-	O
regulatory	O
activity	O
.	O

Magnetic	O
resonance	O
imaging	O
(	O
MRI	O
)	O
has	O
enabled	O
us	O
to	O
see	O
the	O
spinal	O
intramedullary	O
pathology	O
as	O
differences	O
in	O
signal	O
intensity	O
.	O

Patients	O
with	O
psychotropic	O
drugs	O
showed	O
significantly	O
higher	O
PRL	B-GENE
levels	O
.	O

The	O
Laser	O
Scanning	O
Ophthalmoscope	O
enables	O
a	O
fundus	O
-	O
based	O
examination	O
and	O
therefore	O
allows	O
exact	O
comparison	O
between	O
morphologic	O
appearance	O
and	O
corresponding	O
function	O
.	O

Malaria	O
,	O
anaemia	O
,	O
and	O
HIV	O
-	O
1	O
transmission	O
in	O
central	O
Africa	O
.	O

In	O
addition	O
,	O
two	O
-	O
dimensional	O
nuclear	O
magnetic	O
resonance	O
studies	O
with	O
F17A	O
,	O
K13Q	O
,	O
F15Y	O
and	O
F27Y	O
revealed	O
that	O
the	O
mutants	O
have	O
the	O
same	O
overall	O
structure	O
as	O
the	O
wild	B-GENE
-	I-GENE
type	I-GENE
CspB	I-GENE
protein	I-GENE
.	O

Considerably	O
high	O
levels	O
of	O
IgE	B-GENE
antibodies	I-GENE
was	O
also	O
established	O
while	O
other	O
pollens	O
did	O
not	O
show	O
such	O
correspondence	O
.	O

This	O
is	O
particularly	O
intriguing	O
because	O
SKUT	O
-	O
1B	O
-	O
20	O
cells	O
lack	O
the	O
transcription	O
factor	O
Pit	B-GENE
-	I-GENE
1	I-GENE
.	O

Some	O
strains	O
of	O
A	O
.	O
parasiticus	O
produced	O
all	O
four	O
aflatoxins	O
B1	O
B2	O
G1	O
G2	O
,	O
while	O
the	O
other	O
ones	O
produced	O
AF	O
B1	O
+	O
G1	O
only	O
,	O
with	O
concentrations	O
of	O
aflatoxins	O
from	O
0	O
.	O
1	O
to	O
450	O
mg	O
/	O
kg	O
.	O

We	O
have	O
isolated	O
a	O
new	O
,	O
larger	O
rat	B-GENE
B	I-GENE
-	I-GENE
myc	I-GENE
genomic	I-GENE
clone	I-GENE
.	O

In	O
addition	O
to	O
the	O
nine	O
and	O
51	O
terminal	O
amino	O
acid	O
forms	O
already	O
known	O
,	O
we	O
identified	O
a	O
third	O
with	O
43	O
terminal	O
amino	O
acids	O
predicted	O
to	O
encode	O
a	O
novel	O
RET	B-GENE
protein	I-GENE
isoform	I-GENE
.	O

Both	O
classes	O
of	O
MHBst	B-GENE
proteins	I-GENE
were	O
found	O
to	O
form	O
dimers	O
;	O
an	O
which	O
is	O
involved	O
in	O
mediating	O
the	O
dimerization	O
.	O

She	O
had	O
been	O
receiving	O
MTX	O
7	O
.	O
5	O
mg	O
/	O
week	O
for	O
2	O
.	O
5	O
months	O
because	O
of	O
her	O
vasculitis	O
symptoms	O
.	O

Analysis	O
of	O
the	O
sequence	O
identified	O
four	O
open	O
reading	O
frames	O
(	O
ORFs	O
)	O
which	O
are	O
designated	O
UL1	B-GENE
,	O
UL2	B-GENE
,	O
UL3	B-GENE
,	O
and	O
UL3	B-GENE
.	I-GENE
5	I-GENE
based	O
on	O
their	O
homology	O
with	O
proteins	O
of	O
herpes	O
simplex	O
virus	O
-	O
1	O
(	O
HSV	O
-	O
1	O
)	O
,	O
pseudorabies	O
virus	O
(	O
PRV	O
)	O
,	O
equine	O
herpesvirus	O
-	O
1	O
,	O
and	O
varicella	O
-	O
zoster	O
virus	O
.	O

These	O
HPV16	O
E6	B-GENE
/	O
E7	B-GENE
cDNAs	O
were	O
cloned	O
under	O
the	O
SV40	B-GENE
enhancer	I-GENE
/	I-GENE
promoter	I-GENE
and	O
the	O
MMTV	B-GENE
LTR	I-GENE
to	O
examine	O
the	O
activities	O
of	O
ras	B-GENE
-	O
collaborative	O
transformation	O
and	O
induction	O
of	O
cellular	O
DNA	O
synthesis	O
,	O
both	O
of	O
which	O
depend	O
on	O
the	O
E7	B-GENE
gene	I-GENE
product	O
.	O

Correlation	O
coefficients	O
between	O
the	O
reference	O
methods	O
and	O
NIT	O
were	O
>	O
or	O
=	O
0	O
.	O
95	O
for	O
water	O
,	O
fat	O
,	O
crude	O
protein	O
and	O
connective	O
-	O
tissue	O
-	O
protein	O
frei	O
meat	O
protein	O
,	O
and	O
>	O
or	O
=	O
0	O
.	O
86	O
for	O
connective	O
-	O
tissue	O
-	O
protein	O
.	O

The	O
translation	O
products	O
of	O
both	O
clones	O
are	O
highly	O
homologous	O
to	O
APS1	B-GENE
(	O
66	O
and	O
86	O
%	O
identity	O
,	O
respectively	O
)	O
over	O
their	O
entire	O
lengths	O
,	O
including	O
amino	O
terminal	O
sequences	O
resembling	O
transit	O
peptides	O
for	O
plastid	O
localization	O
.	O

The	O
serum	O
levels	O
of	O
IgE	B-GENE
,	O
and	O
asIgE	B-GENE
and	O
IgG	B-GENE
-	I-GENE
4	I-GENE
against	O
14	O
common	O
food	O
allergens	O
were	O
determined	O
.	O

Two	O
experiments	O
investigating	O
the	O
effects	O
of	O
short	O
-	O
term	O
spaceflight	O
on	O
cancellous	O
bone	O
turnover	O
were	O
carried	O
out	O
:	O
Physiological	O
Systems	O
Experiment	O
-	O
1	O
(	O
PSE	O
-	O
1	O
)	O
(	O
a	O
4	O
-	O
d	O
orbital	O
spaceflight	O
)	O
and	O
PSE	O
-	O
2	O
(	O
a	O
10	O
-	O
d	O
flight	O
)	O
.	O

Functional	O
analysis	O
of	O
aryl	B-GENE
hydrocarbon	I-GENE
receptor	I-GENE
nuclear	I-GENE
translocator	I-GENE
interactions	O
with	O
aryl	B-GENE
hydrocarbon	I-GENE
receptor	I-GENE
in	O
the	O
yeast	O
two	O
-	O
hybrid	O
system	O
.	O

Histopathologic	O
observations	O
showed	O
that	O
both	O
somatostatin	B-GENE
and	O
triamcinolone	O
acetonide	O
reduced	O
the	O
inflammatory	O
signs	O
in	O
the	O
joint	O
structures	O
,	O
although	O
triamcinolone	O
acetonide	O
appeared	O
to	O
be	O
more	O
effective	O
.	O

An	O
approach	O
to	O
a	O
biomathematical	O
model	O
of	O
lymphocytopoiesis	O
.	O

The	O
influenza	O
virus	O
NS1	B-GENE
protein	O
is	O
a	O
unique	O
posttranscriptional	O
regulator	O
that	O
has	O
two	O
activities	O
:	O
inhibition	O
of	O
the	O
nuclear	O
export	O
of	O
poly	O
A	O
-	O
containing	O
mRNAs	O
and	O
inhibition	O
of	O
pre	O
-	O
mRNA	O
splicing	O
.	O

These	O
are	O
two	O
regions	O
of	O
known	O
conserved	O
synteny	O
,	O
providing	O
further	O
evidence	O
that	O
the	O
human	B-GENE
STEP	I-GENE
is	O
a	O
true	O
homolog	O
of	O
the	O
murine	B-GENE
STEP	I-GENE
gene	I-GENE
.	O

Molecular	O
cloning	O
of	O
the	O
human	O
homolog	O
of	O
a	O
striatum	B-GENE
-	I-GENE
enriched	I-GENE
phosphatase	I-GENE
(	B-GENE
STEP	I-GENE
)	I-GENE
gene	I-GENE
and	O
chromosomal	O
mapping	O
of	O
the	O
human	O
and	O
murine	O
loci	O
.	O

Carbonic	B-GENE
anhydrase	I-GENE
V	I-GENE
(	O
CA	B-GENE
V	I-GENE
)	O
is	O
expressed	O
in	O
mitochondrial	O
matrix	O
in	O
liver	O
and	O
several	O
other	O
tissues	O
.	O

Vitamin	O
D3	O
plus	O
nicotine	O
treatment	O
produced	O
parallel	O
increases	O
in	O
cardiac	O
mass	O
and	O
elastic	O
modulus	O
,	O
with	O
a	O
significant	O
correlation	O
between	O
the	O
two	O
.	O

The	O
latter	O
domain	O
appears	O
to	O
be	O
involved	O
in	O
targeting	O
Num1p	B-GENE
to	O
the	O
mother	O
cell	O
cortex	O
.	O

This	O
finding	O
is	O
consistent	O
with	O
the	O
notion	O
that	O
the	O
dsRNA	O
binding	O
domains	O
may	O
be	O
composed	O
of	O
two	O
separate	O
functional	O
subdomains	O
.	O

Preferential	O
heterodimeric	O
parallel	O
coiled	O
-	O
coil	O
formation	O
by	O
synthetic	B-GENE
Max	I-GENE
and	O
c	B-GENE
-	I-GENE
Myc	I-GENE
leucine	I-GENE
zippers	I-GENE
:	O
a	O
description	O
of	O
putative	O
electrostatic	O
interactions	O
responsible	O
for	O
the	O
specificity	O
of	O
heterodimerization	O
.	O

Comparison	O
to	O
other	O
coxI	B-GENE
genes	I-GENE
revealed	O
a	O
966	O
-	O
bp	O
group	O
I	O
intron	O
,	O
which	O
,	O
based	O
on	O
homology	O
with	O
the	O
related	O
yeast	B-GENE
coxI	I-GENE
intron	I-GENE
aI4	I-GENE
,	O
potentially	O
encodes	O
a	O
279	O
-	O
amino	O
-	O
acid	O
site	O
-	O
specific	O
DNA	B-GENE
endonuclease	I-GENE
.	O

We	O
studied	O
the	O
GR	B-GENE
in	O
DMS	O
-	O
79	O
cells	O
derived	O
from	O
a	O
human	O
ACTH	B-GENE
-	O
secreting	O
small	O
cell	O
lung	O
cancer	O
.	O

This	O
study	O
analyzed	O
whether	O
the	O
localization	O
of	O
an	O
accessory	O
pathway	O
could	O
be	O
predicted	O
by	O
using	O
the	O
polarity	O
of	O
the	O
QRS	O
complex	O
during	O
sinus	O
rhythm	O
on	O
the	O
surface	O
ECG	O
,	O
instead	O
of	O
the	O
delta	O
wave	O
polarity	O
as	O
used	O
in	O
many	O
reports	O
.	O

The	O
promoter	O
mutation	O
is	O
complemented	O
in	O
trans	O
by	O
E1A	B-GENE
products	O
of	O
the	O
heterologous	O
helper	O
adenovirus	O
type	O
5	O
(	O
Ad5	O
)	O
.	O

Thus	O
,	O
as	O
expected	O
,	O
trans	O
-	O
splicing	O
depends	O
on	O
the	O
integrity	O
of	O
U2	B-GENE
,	O
U4	B-GENE
,	O
and	O
U6	B-GENE
snRNAs	I-GENE
.	O

Treatment	O
of	O
PCC4	O
.	O
aza1R	O
cells	O
with	O
an	O
RAR	B-GENE
-	O
selective	O
agonist	O
also	O
repressed	O
the	O
expression	O
of	O
EC	B-GENE
-	I-GENE
1	I-GENE
mRNA	I-GENE
while	O
treatment	O
with	O
an	O
RXR	B-GENE
-	O
selective	O
agonist	O
reduced	O
EC	B-GENE
-	I-GENE
1	I-GENE
expression	O
slightly	O
.	O

Shift	O
-	O
down	O
experiments	O
indicated	O
that	O
the	O
10	O
(	O
4	O
)	O
-	O
to	O
10	O
(	O
5	O
)	O
-	O
fold	O
reduction	O
in	O
virus	O
yield	O
at	O
the	O
nonpermissive	O
temperature	O
was	O
due	O
to	O
the	O
disfunction	O
of	O
alpha	B-GENE
TIF	I-GENE
late	O
in	O
infection	O
,	O
presumably	O
in	O
virion	O
maturation	O
.	O

These	O
results	O
demonstrate	O
that	O
tip	B-GENE
acts	O
at	O
an	O
early	O
stage	O
of	O
the	O
T	O
-	O
cell	O
signal	O
transduction	O
cascade	O
by	O
associating	O
with	O
Lck	B-GENE
and	O
downregulating	O
Lck	O
-	O
mediated	O
activation	O
.	O

Human	B-GENE
immunodeficiency	I-GENE
virus	I-GENE
type	I-GENE
1	I-GENE
Vpr	I-GENE
is	O
a	O
virion	O
-	O
associated	O
,	O
regulatory	O
protein	O
that	O
is	O
required	O
for	O
efficient	O
viral	O
replication	O
in	O
monocytes	O
/	O
macrophages	O
.	O

Here	O
we	O
examine	O
the	O
potential	O
for	O
VP16	B-GENE
protein	O
-	O
protein	O
interactions	O
specific	O
to	O
virus	O
-	O
infected	O
cells	O
and	O
show	O
that	O
VP16	B-GENE
copurifies	O
in	O
a	O
highly	O
enriched	O
fraction	O
with	O
a	O
single	O
major	O
polypeptide	O
which	O
we	O
identify	O
as	O
the	O
virus	O
-	O
encoded	O
structural	O
protein	O
VP22	B-GENE
.	O

Thus	O
,	O
transcriptional	O
regulation	O
,	O
splicing	O
,	O
kinase	O
interaction	O
sites	O
,	O
and	O
tyrosine	O
phosphorylation	O
of	O
the	O
LMP2A	B-GENE
homologs	I-GENE
have	O
been	O
conserved	O
despite	O
significant	O
sequences	O
heterogeneity	O
in	O
the	O
preterminal	O
repeat	O
regions	O
of	O
these	O
human	O
and	O
nonhuman	O
primate	O
EBVs	O
.	O

Results	O
of	O
the	O
ECAT	O
Angina	O
Pectoris	O
Study	O
Group	O
.	O

Therefore	O
,	O
a	O
prospective	O
Phase	O
II	O
trial	O
was	O
conducted	O
to	O
determine	O
the	O
safety	O
and	O
efficacy	O
of	O
cryosurgery	O
following	O
radiation	O
therapy	O
in	O
men	O
with	O
local	O
recurrence	O
.	O

These	O
motifs	O
include	O
a	O
Chi	O
motif	O
and	O
a	O
Chi	O
-	O
like	O
element	O
previously	O
found	O
in	O
the	O
recombination	O
hotspot	O
region	O
of	O
the	O
Bcl	B-GENE
-	I-GENE
2	I-GENE
proto	I-GENE
-	I-GENE
oncogene	I-GENE
and	O
close	O
to	O
chromosomal	O
breakpoints	O
in	O
T	O
-	O
ALL	O
lines	O
.	O

Common	O
history	O
and	O
prospects	O
in	O
surgical	O
gynecology	O
of	O
the	O
Charite	O
and	O
the	O
Vienna	O
University	O
Clinic	O

In	O
contrast	O
with	O
the	O
previously	O
reported	O
HMGR1	B-GENE
mRNA	I-GENE
(	O
HMGR1S	B-GENE
mRNA	I-GENE
)	O
,	O
which	O
is	O
detected	O
at	O
high	O
levels	O
in	O
all	O
tissues	O
of	O
the	O
plant	O
,	O
HMGR1L	B-GENE
mRNA	I-GENE
is	O
present	O
at	O
relatively	O
low	O
levels	O
and	O
its	O
expression	O
is	O
restricted	O
mostly	O
to	O
seedlings	O
,	O
roots	O
and	O
inflorescences	O
.	O

However	O
,	O
the	O
requirement	O
of	O
rev3	B-GENE
for	O
the	O
production	O
of	O
G	O
.	O
C	O
-	O
-	O
>	O
T	O
.	O
A	O
transversions	O
by	O
the	O
rad18	B-GENE
mutator	I-GENE
,	O
which	O
induces	O
only	O
these	O
substitutions	O
,	O
was	O
similar	O
to	O
that	O
for	O
rad6	B-GENE
-	O
mediated	O
G	O
.	O
C	O
-	O
-	O
>	O
T	O
.	O
A	O
transversion	O
.	O

The	O
second	O
mutation	O
present	O
in	O
the	O
original	O
mutant	O
proved	O
to	O
be	O
an	O
allele	O
of	O
a	O
known	O
gene	O
,	O
PBS2	B-GENE
,	O
which	O
encodes	O
a	O
putative	O
protein	O
kinase	O
that	O
functions	O
in	O
the	O
high	O
osmolarity	O
stress	O
pathway	O
.	O

In	O
adult	O
tissues	O
,	O
it	O
was	O
less	O
restricted	O
,	O
indicating	O
that	O
RAFTK	B-GENE
expression	O
is	O
developmentally	O
up	O
-	O
regulated	O
.	O

As	O
hGM	B-GENE
-	I-GENE
CSF	I-GENE
receptor	I-GENE
(	O
hGMR	B-GENE
)	O
does	O
not	O
contain	O
a	O
consensus	O
sequence	O
for	O
binding	O
of	O
PI	B-GENE
3	I-GENE
-	I-GENE
kinase	I-GENE
,	O
hGMR	B-GENE
must	O
use	O
a	O
distinct	O
mechanism	O
for	O
its	O
association	O
with	O
and	O
activation	O
of	O
PI	B-GENE
3	I-GENE
-	I-GENE
kinase	I-GENE
.	O

J	O
.	O

The	O
identity	O
between	O
hnRNPs	B-GENE
H	I-GENE
and	O
H	B-GENE
'	I-GENE
is	O
96	O
%	O
,	O
between	O
H	B-GENE
and	O
F	B-GENE
78	O
%	O
,	O
and	O
between	O
H	B-GENE
'	I-GENE
and	O
F	B-GENE
75	O
%	O
,	O
respectively	O
.	O

In	O
the	O
present	O
study	O
,	O
we	O
transiently	O
expressed	O
in	O
primary	O
cultures	O
of	O
rat	O
hepatocytes	O
plasmids	O
consisting	O
of	O
CYP3A1	B-GENE
5	I-GENE
'	I-GENE
-	I-GENE
flanking	I-GENE
sequences	I-GENE
fused	O
to	O
a	O
chloramphenicol	B-GENE
acetyltransferase	I-GENE
reporter	I-GENE
plasmid	O
.	O

We	O
show	O
that	O
stimulation	O
of	O
resting	O
splenic	O
B	O
cells	O
with	O
CD40L	B-GENE
-	O
expressing	O
Sf9	O
cells	O
induces	O
germ	O
-	O
line	O
gamma	O
1	O
and	O
epsilon	O
transcripts	O
independently	O
of	O
cytokines	O
.	O

At	O
the	O
time	O
of	O
the	O
13	O
latest	O
BPVs	O
,	O
age	O
ranged	O
from	O
three	O
days	O
to	O
13	O
.	O
1	O
years	O
(	O
mean	O
5	O
.	O
7	O
+	O
/	O
-	O
SD	O
4	O
.	O
8	O
years	O
)	O
.	O

A	O
tobacco	O
homologue	O
(	O
trolC	B-GENE
)	O
of	O
the	O
rolC	B-GENE
gene	I-GENE
of	I-GENE
the	I-GENE
Agrobacterium	I-GENE
rhizogenes	I-GENE
Ri	I-GENE
-	I-GENE
plasmid	I-GENE
was	O
cloned	O
and	O
sequenced	O
from	O
Nicotiana	O
tabacum	O
L	O
.	O
cv	O
.	O

High	O
ADR1	B-GENE
gene	I-GENE
dosage	O
increased	O
the	O
transcription	O
of	O
genes	O
encoding	O
peroxisomal	O
proteins	O
as	O
compared	O
to	O
one	O
copy	O
of	O
the	O
ADR1	B-GENE
gene	I-GENE
.	O

Of	O
the	O
three	O
known	O
C	B-GENE
/	I-GENE
EBP	I-GENE
family	I-GENE
inhibitors	O
,	O
Ig	B-GENE
/	I-GENE
EBP	I-GENE
,	O
LIP	B-GENE
and	O
CHOP	B-GENE
-	I-GENE
10	I-GENE
,	O
only	O
Ig	B-GENE
/	I-GENE
EBP	I-GENE
is	O
ubiquitously	O
expressed	O
.	O

The	O
effects	O
of	O
a	O
1	O
-	O
or	O
24	O
-	O
hour	O
pretreatment	O
regimen	O
with	O
monophosphoryl	O
lipid	O
A	O
(	O
MLA	O
,	O
35	O
micrograms	O
/	O
kg	O
i	O
.	O
v	O
.	O
)	O
on	O
myocardial	O
stunning	O
produced	O
by	O
repetitive	O
coronary	O
occlusions	O
were	O
studied	O
in	O
barbital	O
-	O
anesthetized	O
dogs	O
.	O

A	O
platelet	B-GENE
-	I-GENE
derived	I-GENE
growth	I-GENE
factor	I-GENE
receptor	I-GENE
(	O
PDGF	B-GENE
-	I-GENE
R	I-GENE
)	O
phosphopeptide	O
containing	O
Tyr	O
-	O
857	O
does	O
not	O
bind	O
appreciably	O
to	O
the	O
Src	B-GENE
SH2	I-GENE
domain	I-GENE
,	O
suggesting	O
it	O
is	O
not	O
the	O
PDGF	B-GENE
-	I-GENE
R	I-GENE
binding	O
site	O
for	O
Src	B-GENE
as	O
previously	O
reported	O
.	O

We	O
have	O
also	O
tested	O
Src	B-GENE
SH2	B-GENE
mutants	O
for	O
their	O
binding	O
properties	O
and	O
have	O
interpreted	O
our	O
results	O
in	O
light	O
of	O
the	O
recent	O
crystal	O
structure	O
solution	O
for	O
the	O
Src	B-GENE
SH2	B-GENE
domain	O
.	O

These	O
observations	O
link	O
actin	B-GENE
plaque	O
assembly	O
to	O
increased	O
cell	O
substrate	O
adhesion	O
.	O

The	O
early	O
lethality	O
of	O
the	O
left	O
-	O
sided	O
resectio	O
was	O
0	O
%	O
and	O
the	O
postoperative	O
survival	O
-	O
-	O
5	O
-	O
10	O
months	O
.	O

There	O
are	O
two	O
immunogenic	O
sites	O
on	O
the	O
type	O
A	O
influenza	O
A	O
/	O
Japan	O
/	O
57	O
(	O
H2N2	O
)	O
hemagglutinin	B-GENE
(	O
HA	B-GENE
)	O
that	O
can	O
be	O
recognized	O
by	O
class	B-GENE
I	I-GENE
major	I-GENE
histocompatibility	I-GENE
complex	I-GENE
(	O
MHC	B-GENE
)	O
,	O
H	B-GENE
-	I-GENE
2Kd	I-GENE
-	O
restricted	O
cytolytic	O
T	O
lymphocytes	O
(	O
CTLs	O
)	O
.	O

This	O
enhancer	O
activates	O
both	O
the	O
K19	B-GENE
and	O
TK	B-GENE
basal	I-GENE
promoters	I-GENE
in	O
HeLa	O
cells	O
.	O

Interestingly	O
,	O
one	O
IRF	B-GENE
binding	I-GENE
site	I-GENE
was	O
found	O
within	O
the	O
IRF	B-GENE
-	I-GENE
2	I-GENE
promoter	I-GENE
,	O
and	O
expression	O
of	O
the	O
IRF	B-GENE
-	I-GENE
2	I-GENE
gene	I-GENE
was	O
affected	O
by	O
both	O
transient	O
and	O
stable	O
IRF	B-GENE
-	I-GENE
1	I-GENE
expression	O
.	O

Therefore	O
,	O
we	O
studied	O
ninety	O
coagulopathic	O
patients	O
with	O
the	O
aim	O
of	O
determining	O
the	O
prevalence	O
of	O
hepatitis	B-GENE
C	I-GENE
virus	I-GENE
(	I-GENE
HCV	I-GENE
)	I-GENE
antibodies	I-GENE
using	O
the	O
ELISA	O
and	O
RIBA	O
methods	O
.	O

The	O
highest	O
decrease	O
in	O
mutagenic	O
activity	O
was	O
observed	O
when	O
enzymatic	O
bleaching	O
was	O
used	O
together	O
with	O
chlorine	O
.	O

There	O
was	O
also	O
a	O
highly	O
significant	O
correlation	O
between	O
total	O
selenium	O
intake	O
and	O
liver	O
selenium	O
concentration	O
(	O
r	O
=	O
0	O
.	O
99	O
,	O
p	O
<	O
0	O
.	O
01	O
)	O
after	O
1	O
mo	O
of	O
treatment	O
,	O
but	O
this	O
time	O
liver	O
selenium	O
did	O
not	O
change	O
with	O
time	O
,	O
and	O
the	O
correlation	O
remained	O
highly	O
significant	O
throughout	O
the	O
investigation	O
.	O

Antibodies	O
affinity	O
-	O
purified	O
using	O
the	O
bacterially	O
expressed	O
recombinant	O
protein	O
recognized	O
the	O
56K	B-GENE
autoantigen	I-GENE
in	O
a	O
HeLa	O
cell	O
extract	O
.	O
cDNA	O
sequencing	O
revealed	O
that	O
the	O
56K	B-GENE
cDNA	I-GENE
shares	O
a	O
high	O
degree	O
of	O
homology	O
in	O
both	O
nucleotide	O
(	O
87	O
%	O
)	O
and	O
amino	O
acid	O
sequence	O
(	O
92	O
.	O
5	O
%	O
)	O
with	O
bovine	B-GENE
annexin	I-GENE
XI	I-GENE
,	O
indicating	O
that	O
the	O
56K	B-GENE
cDNA	I-GENE
encodes	O
the	O
human	B-GENE
homologue	I-GENE
of	I-GENE
annexin	I-GENE
XI	I-GENE
,	O
a	O
member	O
of	O
the	O
Ca	B-GENE
(	I-GENE
2	I-GENE
+	I-GENE
)	I-GENE
-	I-GENE
dependent	I-GENE
phospholipid	I-GENE
binding	I-GENE
protein	I-GENE
family	I-GENE
.	O

The	O
avidin	B-GENE
-	I-GENE
biotin	I-GENE
complex	I-GENE
peroxidase	I-GENE
(	O
ABC	B-GENE
-	I-GENE
P	I-GENE
)	O
method	O
was	O
used	O
to	O
detect	O
Mycobacterium	O
bovis	O
,	O
and	O
the	O
results	O
were	O
compared	O
with	O
those	O
obtained	O
by	O
the	O
Ziehl	O
-	O
Neelsen	O
(	O
ZN	O
)	O
technique	O
.	O

Its	O
role	O
in	O
these	O
processes	O
suggests	O
that	O
the	O
function	O
of	O
c	B-GENE
-	I-GENE
Myb	I-GENE
may	O
be	O
important	O
early	O
in	O
the	O
establishment	O
of	O
the	O
hematopoietic	O
lineage	O
.	O

The	O
transforming	O
gene	O
of	O
the	O
avian	B-GENE
sarcoma	I-GENE
virus	I-GENE
CT10	I-GENE
encodes	O
a	O
fusion	O
protein	O
(	O
p47gag	B-GENE
-	O
crk	B-GENE
or	O
v	B-GENE
-	I-GENE
Crk	I-GENE
)	O
containing	O
viral	B-GENE
Gag	I-GENE
sequences	I-GENE
fused	O
to	O
cellular	O
sequences	O
consisting	O
primarily	O
of	O
Src	B-GENE
homology	I-GENE
regions	I-GENE
2	I-GENE
and	I-GENE
3	I-GENE
(	O
SH2	B-GENE
and	O
SH3	B-GENE
sequences	I-GENE
)	O
.	O

This	O
specific	O
methylation	O
pattern	O
caused	O
inactivation	O
of	O
the	O
HSV	B-GENE
tk	I-GENE
gene	I-GENE
,	O
while	O
methylation	O
of	O
the	O
cytosine	O
residues	O
within	O
the	O
nucleotide	O
sequence	O
from	O
+	O
811	O
to	O
+	O
1309	O
had	O
no	O
effect	O
on	O
HSV	B-GENE
tk	I-GENE
gene	I-GENE
activity	O
.	O

CONCLUSION	O
:	O
This	O
study	O
documents	O
that	O
regression	O
of	O
choroidal	O
neovascularization	O
that	O
occurred	O
with	O
alpha	B-GENE
interferon	I-GENE
treatment	O
was	O
minimal	O
.	O

Long	O
-	O
range	O
mapping	O
of	O
the	O
11q23	O
region	O
involved	O
in	O
chromosome	O
aberrations	O
in	O
human	O
tumors	O
by	O
pulsed	O
-	O
field	O
gel	O
electrophoresis	O
with	O
a	O
yeast	O
artificial	O
chromosome	O
.	O

GTRE	O
,	O
TRE	O
,	O
and	O
CRE	O
oligonucleotides	O
all	O
compete	O
more	O
efficiently	O
for	O
protein	O
binding	O
to	O
their	O
labeled	O
congeners	O
than	O
for	O
protein	O
binding	O
to	O
either	O
of	O
the	O
other	O
labeled	O
oligonucleotides	O
,	O
suggesting	O
that	O
the	O
GTRE	O
,	O
TRE	O
,	O
and	O
CRE	O
oligonucleotides	O
,	O
suggesting	O
that	O
the	O
GTRE	O
,	O
TRE	O
,	O
and	O
CRE	O
oligonucleotides	O
each	O
bind	O
unique	O
as	O
well	O
as	O
common	O
proteins	O
,	O
likely	O
to	O
be	O
members	O
of	O
the	O
Jun	B-GENE
/	O
Fos	B-GENE
and	O
cAMP	B-GENE
-	I-GENE
responsive	I-GENE
element	I-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
/	O
activating	B-GENE
transcription	I-GENE
factors	I-GENE
(	O
CREB	B-GENE
/	O
ATF	B-GENE
)	O
families	O
of	O
transcription	O
factors	O
,	O
in	O
chromaffin	O
cells	O
.	O

One	O
patient	O
only	O
had	O
any	O
test	O
abnormalities	O
.	O

One	O
antibody	O
,	O
mAb1C2	B-GENE
,	O
and	O
a	O
synthetic	O
peptide	O
comprising	O
its	O
epitope	O
selectively	O
inhibited	O
in	O
vitro	O
transcription	O
from	O
TATA	O
-	O
containing	O
,	O
but	O
not	O
from	O
TATA	O
-	O
less	O
promoters	O
,	O
irrespective	O
of	O
whether	O
they	O
were	O
transcribed	O
by	O
Pol	B-GENE
II	I-GENE
or	O
Pol	B-GENE
III	I-GENE
.	O

The	O
lymph	O
nodes	O
from	O
two	O
of	O
the	O
patients	O
with	O
rheumatoid	O
arthritis	O
contained	O
numerous	O
sarcoid	O
like	O
granulomata	O
,	O
further	O
indicating	O
a	O
possible	O
association	O
between	O
sarcoidosis	O
and	O
rheumatoid	O
arthritis	O
.	O

HCV	O
infection	O
acquired	O
during	O
or	O
after	O
BMT	O
caused	O
only	O
mild	O
acute	O
hepatitis	O
C	O
,	O
which	O
progressed	O
to	O
chronic	O
hepatitis	O
C	O
in	O
one	O
patient	O
surviving	O
10	O
years	O
after	O
BMT	O
.	O

Hepatitis	O
C	O
virus	O
infection	O
is	O
a	O
risk	O
factor	O
for	O
liver	O
failure	O
from	O
veno	O
-	O
occlusive	O
disease	O
after	O
bone	O
marrow	O
transplantation	O
.	O

High	O
plasma	O
concentrations	O
of	O
soluble	O
E	B-GENE
-	I-GENE
selectin	I-GENE
were	O
closely	O
associated	O
with	O
multiple	O
-	O
organ	O
dysfunction	O
and	O
death	O
.	O

These	O
human	O
IFN	B-GENE
-	I-GENE
beta	I-GENE
-	O
transformed	O
cell	O
populations	O
have	O
acquired	O
a	O
low	O
,	O
constitutive	O
production	O
of	O
human	B-GENE
IFN	I-GENE
,	O
while	O
replicating	O
at	O
a	O
rate	O
similar	O
to	O
that	O
of	O
untransformed	O
cells	O
and	O
of	O
cells	O
transformed	O
with	O
the	O
control	O
vector	O
carrying	O
a	O
human	B-GENE
IFN	I-GENE
-	I-GENE
beta	I-GENE
sequence	I-GENE
encoding	O
an	O
inactive	O
,	O
mutated	O
protein	O
.	O

Improvement	O
of	O
the	O
polypyrimidine	O
tract	O
also	O
increased	O
the	O
splicing	O
efficiency	O
,	O
but	O
to	O
a	O
degree	O
slightly	O
less	O
than	O
that	O
obtained	O
with	O
the	O
branchpoint	O
mutation	O
.	O

Activation	O
of	O
the	O
SH2	B-GENE
-	I-GENE
containing	I-GENE
protein	I-GENE
tyrosine	I-GENE
phosphatase	I-GENE
,	O
SH	B-GENE
-	I-GENE
PTP2	I-GENE
,	O
by	O
phosphotyrosine	O
-	O
containing	O
peptides	O
derived	O
from	O
insulin	B-GENE
receptor	I-GENE
substrate	I-GENE
-	I-GENE
1	I-GENE
.	O

In	O
contrast	O
,	O
injection	O
of	O
a	O
plasmid	O
encoding	O
simian	B-GENE
virus	I-GENE
40	I-GENE
small	I-GENE
t	I-GENE
antigen	I-GENE
,	O
which	O
interacts	O
with	O
PP2A	B-GENE
to	O
inhibit	O
its	O
activity	O
towards	O
several	O
phosphoprotein	O
substrates	O
,	O
had	O
no	O
effect	O
on	O
the	O
phosphorylation	O
state	O
of	O
CREB	B-GENE
in	O
stimulated	O
or	O
unstimulated	O
NIH	O
3T3	O
cells	O
.	O

Several	O
Src	B-GENE
SH3	I-GENE
-	I-GENE
binding	I-GENE
proteins	I-GENE
were	O
phosphorylated	O
in	O
Src	B-GENE
-	O
transformed	O
cells	O
.	O

We	O
also	O
examined	O
the	O
effect	O
of	O
proteolytic	O
processing	O
in	O
the	O
MVE	O
nonstructural	O
polyprotein	O
segment	O
mediated	O
by	O
the	O
viral	B-GENE
proteinase	I-GENE
NS3	I-GENE
on	O
antigen	O
processing	O
and	O
presentation	O
of	O
the	O
MVE	O
H	O
-	O
2Kk	O
-	O
restricted	O
T	O
cell	O
determinant	O
.	O

A	O
full	B-GENE
-	I-GENE
length	I-GENE
PRL	I-GENE
receptor	I-GENE
(	O
PRLR	B-GENE
)	O
complementary	O
DNA	O
from	O
pigeons	O
was	O
obtained	O
by	O
screening	O
pigeon	O
crop	O
sac	O
libraries	O
and	O
by	O
reverse	O
transcription	O
coupled	O
with	O
polymerase	O
chain	O
reaction	O
.	O

After	O
7	O
days	O
,	O
a	O
spontaneous	O
regression	O
of	O
the	O
morphologic	O
alterations	O
caused	O
by	O
caerulein	O
-	O
induced	O
acute	O
pancreatitis	O
occurs	O
;	O
however	O
,	O
recovery	O
of	O
the	O
secretory	O
function	O
of	O
the	O
pancreas	O
was	O
only	O
reached	O
after	O
this	O
period	O
of	O
time	O
when	O
L	O
-	O
364	O
,	O
718	O
was	O
administered	O
therapeutically	O
(	O
0	O
.	O
1	O
mg	O
/	O
kg	O
/	O
day	O
)	O
.	O

We	O
observed	O
that	O
dephosphorylation	O
severely	O
inhibits	O
the	O
DNA	O
-	O
binding	O
ability	O
of	O
C	B-GENE
/	I-GENE
EBP	I-GENE
-	I-GENE
delta	I-GENE
and	O
its	O
transactivating	O
potential	O
increases	O
in	O
the	O
presence	O
of	O
cellular	O
phosphatase	O
inhibitors	O
,	O
such	O
as	O
okadaic	O
acid	O
and	O
sodium	O
orthovanadate	O
.	O

Two	O
promoters	O
were	O
identified	O
by	O
S1	B-GENE
nuclease	I-GENE
mapping	O
:	O
P1	O
,	O
which	O
lies	O
about	O
72	O
bp	O
upstream	O
from	O
the	O
structural	O
gene	O
;	O
and	O
P2	O
,	O
which	O
lies	O
about	O
35	O
bp	O
upstream	O
.	O

On	O
the	O
other	O
hand	O
,	O
cells	O
containing	O
a	O
PTP1C	B-GENE
in	O
which	O
the	O
catalytic	O
site	O
had	O
been	O
inactivated	O
through	O
mutagenesis	O
,	O
stably	O
phosphorylated	O
the	O
phosphatase	O
.	O

We	O
recently	O
found	O
that	O
the	O
p72syk	B-GENE
protein	I-GENE
tyrosine	I-GENE
kinase	I-GENE
is	O
physically	O
associated	O
with	O
the	O
TCR	B-GENE
/	O
CD3	B-GENE
complex	O
and	O
is	O
rapidly	O
tyrosine	O
phosphorylated	O
and	O
activated	O
by	O
receptor	O
triggering	O
also	O
in	O
T	O
cells	O
lacking	O
p56lck	B-GENE
.	O

The	O
transforming	O
protein	O
of	O
Rous	O
sarcoma	O
virus	O
,	O
pp60v	B-GENE
-	I-GENE
src	I-GENE
,	O
and	O
its	O
normal	O
cellular	O
homolog	O
,	O
pp60c	B-GENE
-	I-GENE
src	I-GENE
,	O
differ	O
not	O
only	O
in	O
oncogenic	O
potential	O
but	O
also	O
in	O
their	O
subcellular	O
localization	O
and	O
cytoskeletal	O
binding	O
ability	O
.	O
pp60v	B-GENE
-	I-GENE
src	I-GENE
has	O
been	O
shown	O
to	O
stably	O
associate	O
with	O
a	O
detergent	O
-	O
insoluble	O
cytoskeletal	O
matrix	O
,	O
whereas	O
pp60c	B-GENE
-	I-GENE
src	I-GENE
does	O
not	O
.	O

Organization	O
of	O
the	O
bovine	O
gene	O
encoding	O
the	O
endothelial	B-GENE
nitric	I-GENE
oxide	I-GENE
synthase	I-GENE
.	O

We	O
determined	O
whether	O
regional	O
myocardial	O
work	O
efficiency	O
(	O
segment	O
work	O
/	O
regional	O
O2	O
consumption	O
)	O
would	O
be	O
elevated	O
by	O
surgically	O
-	O
augmented	O
inflow	O
.	O

In	O
female	O
Sl	B-GENE
(	I-GENE
pan	I-GENE
)	I-GENE
/	I-GENE
Sl	I-GENE
(	I-GENE
pan	I-GENE
)	I-GENE
mice	O
,	O
ovarian	O
follicle	O
development	O
is	O
arrested	O
at	O
the	O
one	O
layered	O
cuboidal	O
stage	O
as	O
a	O
result	O
of	O
reduced	O
KL	B-GENE
expression	O
in	O
follicle	O
cells	O
,	O
indicating	O
a	O
role	O
for	O
c	B-GENE
-	I-GENE
kit	I-GENE
in	O
oocyte	O
growth	O
.	O

Anti	B-GENE
-	I-GENE
NPROSP	I-GENE
-	I-GENE
C	I-GENE
also	O
exclusively	O
detected	O
time	O
-	O
dependent	O
appearances	O
of	O
5	B-GENE
-	I-GENE
10	I-GENE
-	I-GENE
kDa	I-GENE
proSP	I-GENE
-	I-GENE
C	I-GENE
forms	O
in	O
lamellar	O
bodies	O
and	O
homogenates	O
.	O

In	O
the	O
B6	O
-	O
derived	O
Db	B-GENE
mutant	I-GENE
B6	I-GENE
.	I-GENE
CH	I-GENE
-	I-GENE
2bm13	I-GENE
(	I-GENE
bm13	I-GENE
)	I-GENE
strain	O
,	O
part	O
of	O
the	O
class	B-GENE
I	I-GENE
Db	I-GENE
antigen	I-GENE
-	I-GENE
presenting	I-GENE
groove	I-GENE
is	O
shaped	O
by	O
a	O
class	B-GENE
I	I-GENE
Kb	I-GENE
-	I-GENE
encoded	I-GENE
sequence	I-GENE
.	O

Our	O
findings	O
confirm	O
the	O
high	O
frequency	O
of	O
proximal	O
nerve	O
lesions	O
in	O
early	O
GBS	O
and	O
CIDP	O
,	O
not	O
all	O
of	O
which	O
are	O
associated	O
with	O
distal	O
motor	O
conduction	O
abnormalities	O
,	O
and	O
suggest	O
that	O
assessment	O
of	O
multiple	O
F	O
wave	O
parameters	O
,	O
in	O
particular	O
chronodispersion	O
,	O
mean	O
latency	O
and	O
mean	O
amplitude	O
(	O
in	O
addition	O
to	O
absence	O
and	O
minimum	O
latency	O
)	O
,	O
increases	O
the	O
yield	O
of	O
F	O
wave	O
studies	O
.	O

Effects	O
of	O
alterations	O
of	O
primer	O
-	O
binding	O
site	O
sequences	O
on	O
human	O
immunodeficiency	O
virus	O
type	O
1	O
replication	O
.	O

Presentation	O
of	O
a	O
horse	B-GENE
cytochrome	I-GENE
c	I-GENE
peptide	I-GENE
by	O
multiple	O
H	B-GENE
-	I-GENE
2b	I-GENE
class	I-GENE
I	I-GENE
major	I-GENE
histocompatibility	I-GENE
complex	I-GENE
(	O
MHC	B-GENE
)	O
molecules	O
to	O
C57BL	O
/	O
6	O
-	O
and	O
bm1	O
-	O
derived	O
cytotoxic	O
T	O
lymphocytes	O
:	O
presence	O
of	O
a	O
single	O
MHC	B-GENE
anchor	I-GENE
residue	I-GENE
may	O
confer	O
efficient	O
peptide	O
-	O
specific	O
CTL	O
recognition	O
.	O

Diagnosis	O
of	O
prostatic	O
carcinoma	O
:	O
the	O
yield	O
of	O
serum	B-GENE
prostate	I-GENE
specific	I-GENE
antigen	I-GENE
,	O
digital	O
rectal	O
examination	O
and	O
transrectal	O
ultrasonography	O
.	O

Increased	O
granulocyte	B-GENE
-	I-GENE
colony	I-GENE
stimulating	I-GENE
factor	I-GENE
(	O
G	B-GENE
-	I-GENE
CSF	I-GENE
)	O
levels	O
in	O
neonates	O
with	O
perinatal	O
complications	O
.	O

The	O
results	O
revealed	O
a	O
hierarchy	O
of	O
ligand	O
affinities	O
that	O
mirrored	O
their	O
adhesive	O
activity	O
(	O
rsVCAM	B-GENE
-	I-GENE
1	I-GENE
>	O
fibronectin	B-GENE
variants	I-GENE
containing	O
CS1	B-GENE
>	O
>	O
other	O
fibronectin	B-GENE
variants	I-GENE
)	O
.	O

When	O
expressed	O
in	O
and	O
purified	O
from	O
Escherichia	O
coli	O
,	O
both	O
full	B-GENE
-	I-GENE
length	I-GENE
Fpr3	I-GENE
and	O
its	O
isolated	O
COOH	O
-	O
terminal	O
domain	O
exhibit	O
readily	O
detectable	O
PPIase	B-GENE
activity	O
.	O

However	O
,	O
expression	O
of	O
sigma	B-GENE
3	I-GENE
from	O
S4	B-GENE
(	O
3	B-GENE
'	I-GENE
UTR	I-GENE
/	I-GENE
S1	I-GENE
)	O
,	O
which	O
included	O
the	O
PKR	B-GENE
activator	I-GENE
sequence	I-GENE
from	O
S1	B-GENE
within	O
the	O
3	B-GENE
'	I-GENE
-	I-GENE
UTR	I-GENE
of	I-GENE
S4	I-GENE
,	O
was	O
comparable	O
to	O
that	O
from	O
wild	B-GENE
-	I-GENE
type	I-GENE
S4	I-GENE
.	O

Microvessels	O
were	O
counted	O
in	O
a	O
x200	O
field	O
(	O
0	O
.	O
754	O
mm2	O
)	O
in	O
the	O
area	O
of	O
maximal	O
angiogenesis	O
.	O

Recent	O
studies	O
have	O
demonstrated	O
that	O
the	O
activated	O
GH	B-GENE
receptor	I-GENE
can	O
stimulate	O
Stat1	B-GENE
,	O
a	O
cytoplasmic	O
transcription	O
factor	O
that	O
becomes	O
tyrosine	O
phosphorylated	O
and	O
translocates	O
to	O
the	O
nucleus	O
,	O
where	O
it	O
can	O
interact	O
with	O
specific	O
DNA	O
sequences	O
to	O
modulate	O
gene	O
expression	O
.	O

In	O
viral	O
infections	O
,	O
G	B-GENE
-	I-GENE
CSF	I-GENE
was	O
correlated	O
with	O
mononuclear	O
cells	O
(	O
rs	O
=	O
0	O
.	O
41	O
,	O
P	O
<	O
0	O
.	O
05	O
)	O
,	O
white	O
blood	O
cell	O
counts	O
(	O
rs	O
=	O
0	O
.	O
56	O
,	O
P	O
<	O
0	O
.	O
01	O
)	O
,	O
neutrophils	O
(	O
rs	O
=	O
0	O
.	O
41	O
,	O
P	O
<	O
0	O
.	O
05	O
)	O
and	O
CRP	B-GENE
(	O
rs	O
=	O
0	O
.	O
47	O
,	O
P	O
<	O
0	O
.	O
05	O
)	O
.	O

Minor	O
initiation	O
sites	O
were	O
found	O
at	O
positions	O
-	O
128	O
,	O
-	O
111	O
,	O
-	O
91	O
,	O
and	O
-	O
74	O
.	O

Phosphoamino	O
acid	O
analysis	O
of	O
radiolabeled	O
ASGPR	B-GENE
subunits	I-GENE
identified	O
Ser	O
(	O
P	O
)	O
as	O
the	O
predominant	O
(	O
approximately	O
95	O
%	O
)	O
and	O
Thr	O
(	O
P	O
)	O
as	O
a	O
minor	O
(	O
approximately	O
5	O
%	O
)	O
phosphoamino	O
acid	O
in	O
each	O
polypeptide	O
and	O
confirmed	O
the	O
presence	O
of	O
Tyr	O
(	O
P	O
)	O
(	O
approximately	O
1	O
%	O
)	O
in	O
RHL1	B-GENE
.	O

To	O
further	O
define	O
the	O
structural	O
requirements	O
for	O
ZAP	B-GENE
-	I-GENE
70	I-GENE
interaction	O
with	O
the	O
TCR	B-GENE
,	O
we	O
developed	O
a	O
binding	O
assay	O
using	O
immobilized	O
glutathione	B-GENE
S	I-GENE
-	I-GENE
transferase	I-GENE
fusion	I-GENE
proteins	I-GENE
containing	O
the	O
NH2	O
-	O
and	O
/	O
or	O
COOH	B-GENE
-	I-GENE
terminal	I-GENE
SH2	I-GENE
domains	I-GENE
of	O
ZAP	B-GENE
-	I-GENE
70	I-GENE
,	O
and	O
soluble	O
synthetic	O
peptides	O
with	O
the	O
sequence	O
of	O
the	O
cytoplasmic	O
region	O
of	O
the	O
TCR	B-GENE
zeta	I-GENE
chain	I-GENE
(	O
TCR	B-GENE
zeta	I-GENE
cyt	I-GENE
)	O
or	O
individual	O
TCR	B-GENE
zeta	I-GENE
and	O
CD3	B-GENE
epsilon	I-GENE
TAM	I-GENE
motifs	I-GENE
.	O

All	O
four	O
doubly	O
tyrosine	O
phosphorylated	O
TAM	O
peptides	O
cross	O
-	O
compete	O
with	O
each	O
other	O
for	O
binding	O
to	O
the	O
tandem	O
SH2	B-GENE
domains	I-GENE
of	O
ZAP	B-GENE
-	I-GENE
70	I-GENE
.	O

The	O
three	O
-	O
dimensional	O
structure	O
of	O
RT	B-GENE
shows	O
that	O
it	O
is	O
a	O
strikingly	O
asymmetric	O
heterodimer	O
consisting	O
of	O
two	O
differently	O
folded	O
subunits	O
(	O
molecular	O
weights	O
66	O
kDa	O
and	O
51	O
kDa	O
)	O
with	O
identical	O
amino	O
-	O
terminal	O
amino	O
acid	O
sequences	O
(	O
residues	O
1	O
-	O
428	O
)	O
.	O

Pharmacological	O
and	O
pharmacokinetic	O
characteristics	O
of	O
the	O
non	O
-	O
ionic	O
monomeric	O
X	O
-	O
ray	O
contrast	O
agent	O
iopromide	O
(	O
Ultravist	O
,	O
CAS	O
73334	O
-	O
07	O
-	O
3	O
)	O
were	O
evaluated	O
in	O
preclinical	O
studies	O
.	O

All	O
subsequent	O
patients	O
were	O
treated	O
at	O
the	O
maximal	O
tolerated	O
dose	O
of	O
EDXR	O
(	O
35	O
mg	O
/	O
m2	O
/	O
day	O
)	O
.	O

Addition	O
of	O
soluble	O
recombinant	B-GENE
human	I-GENE
SLF	I-GENE
to	O
SI4	O
-	O
h220	O
cultures	O
enhanced	O
reduction	O
of	O
cell	O
-	O
surface	O
c	B-GENE
-	I-GENE
kit	I-GENE
expression	O
and	O
its	O
protein	O
degradation	O
.	O

Membrane	O
-	O
bound	O
Steel	B-GENE
factor	I-GENE
induces	O
more	O
persistent	O
tyrosine	B-GENE
kinase	I-GENE
activation	O
and	O
longer	O
life	O
span	O
of	O
c	B-GENE
-	I-GENE
kit	I-GENE
gene	O
-	O
encoded	O
protein	O
than	O
its	O
soluble	O
form	O
.	O

Analysis	O
of	O
the	O
sequences	O
with	O
the	O
BLAST	O
and	O
GRAIL	O
programs	O
provided	O
additional	O
independent	O
evidence	O
that	O
15	O
of	O
these	O
17	O
clones	O
contain	O
coding	O
sequences	O
and	O
that	O
nine	O
other	O
clones	O
are	O
likely	O
to	O
contain	O
sequences	O
coding	O
for	O
portions	O
of	O
new	O
genes	O
.	O

Patients	O
with	O
more	O
than	O
250	O
PVC	O
/	O
24	O
hours	O
were	O
selected	O
for	O
distribution	O
of	O
PVC	O
and	O
CI	O
evaluation	O
.	O

Horvath	O
,	O
I	O
.	O

Cell	O
lines	O
derived	O
from	O
the	O
tumors	O
were	O
examined	O
by	O
fluorescent	O
in	O
situ	O
hybridization	O
for	O
the	O
status	O
of	O
the	O
transferred	O
human	O
chromosome	O
and	O
by	O
PCR	O
for	O
marker	O
loss	O
.	O

However	O
,	O
multiple	O
alanine	O
substitutions	O
or	O
proline	O
(	O
helix	O
-	O
destabilizing	O
)	O
substitutions	O
disrupted	O
both	O
oligomerization	O
and	O
transport	O
of	O
GP64	B-GENE
EFP	I-GENE
.	O

The	O
FinO	B-GENE
protein	I-GENE
of	O
IncF	O
plasmids	O
binds	O
FinP	B-GENE
antisense	I-GENE
RNA	I-GENE
and	O
its	O
target	O
,	O
traJ	B-GENE
mRNA	I-GENE
,	O
and	O
promotes	O
duplex	O
formation	O
.	O

We	O
linked	O
a	O
4	O
.	O
1	O
-	O
kilobase	O
pair	O
HindIII	B-GENE
DNA	I-GENE
fragment	I-GENE
from	O
the	O
region	O
upstream	O
of	O
the	O
human	B-GENE
AP	I-GENE
endonuclease	I-GENE
gene	I-GENE
(	O
APE	B-GENE
)	O
to	O
the	O
chloramphenicol	B-GENE
acetyltransferase	I-GENE
(	O
CAT	B-GENE
)	O
gene	O
.	O

The	O
overexpressed	O
His6	B-GENE
-	I-GENE
tagged	I-GENE
GrsA	I-GENE
derivatives	I-GENE
were	O
affinity	O
-	O
purified	O
,	O
and	O
the	O
catalytic	O
properties	O
of	O
the	O
deletion	O
mutants	O
were	O
examined	O
by	O
biochemical	O
studies	O
including	O
ATP	O
-	O
dependent	O
amino	O
acid	O
activation	O
,	O
carboxyl	O
thioester	O
formation	O
,	O
and	O
the	O
ability	O
to	O
racemize	O
the	O
covalently	O
bound	O
phenylalanine	O
from	O
L	O
-	O
to	O
the	O
D	O
-	O
isomer	O
.	O

CD7	B-GENE
+	O
/	O
CD3	B-GENE
-	O
T	O
-	O
cell	O
precursors	O
exhibit	O
V	B-GENE
delta	I-GENE
2D	I-GENE
delta	I-GENE
3	I-GENE
rearrangements	I-GENE
.	O

HVH2	B-GENE
mRNA	I-GENE
showed	O
an	O
expression	O
pattern	O
distinct	O
from	O
CL100	B-GENE
(	O
human	B-GENE
homologue	I-GENE
of	I-GENE
mouse	I-GENE
MKP1	I-GENE
)	O
and	O
PAC1	B-GENE
,	O
two	O
previously	O
identified	O
MAP	B-GENE
kinase	I-GENE
phosphatases	I-GENE
.	O

These	O
data	O
suggest	O
that	O
these	O
sequences	O
located	O
immediately	O
3	O
'	O
to	O
the	O
breakpoint	O
of	O
the	O
HPFH	B-GENE
-	I-GENE
3	I-GENE
deletion	I-GENE
,	O
exhibit	O
both	O
the	O
structure	O
and	O
the	O
function	O
of	O
an	O
enhancer	O
,	O
and	O
can	O
modify	O
the	O
developmental	O
specificity	O
of	O
the	O
fetal	B-GENE
gamma	I-GENE
-	I-GENE
globin	I-GENE
genes	I-GENE
,	O
resulting	O
in	O
their	O
continued	O
expression	O
during	O
adult	O
life	O
.	O

Our	O
results	O
indicate	O
that	O
interaction	O
between	O
Jak2	B-GENE
and	O
PRLR	B-GENE
requires	O
a	O
proline	O
-	O
rich	O
sequence	O
in	O
the	O
membrane	O
proximal	O
region	O
of	O
the	O
receptor	O
,	O
which	O
is	O
conserved	O
among	O
the	O
different	O
members	O
of	O
the	O
cytokine	B-GENE
receptor	I-GENE
superfamily	I-GENE
.	O

Transcription	O
of	O
the	O
vascular	B-GENE
cell	I-GENE
adhesion	I-GENE
molecule	I-GENE
1	I-GENE
(	O
VCAM	B-GENE
-	I-GENE
1	I-GENE
)	O
gene	O
in	O
endothelial	O
cells	O
is	O
induced	O
by	O
lipopolysaccharide	O
and	O
the	O
inflammatory	O
cytokines	B-GENE
interleukin	I-GENE
-	I-GENE
1	I-GENE
beta	I-GENE
and	O
tumor	B-GENE
necrosis	I-GENE
factor	I-GENE
alpha	I-GENE
(	O
TNF	B-GENE
-	I-GENE
alpha	I-GENE
)	O
.	O

Experiments	O
with	O
recombinant	O
proteins	O
showed	O
that	O
p50	B-GENE
/	O
p65	B-GENE
and	O
high	B-GENE
-	I-GENE
mobility	I-GENE
-	I-GENE
group	I-GENE
I	I-GENE
(	I-GENE
Y	I-GENE
)	I-GENE
protein	I-GENE
cooperatively	O
facilitated	O
the	O
binding	O
of	O
IRF	B-GENE
-	I-GENE
1	I-GENE
to	O
the	O
VCAM1	B-GENE
IRF	B-GENE
binding	I-GENE
site	I-GENE
and	O
that	O
IRF	B-GENE
-	I-GENE
1	I-GENE
physically	O
interacted	O
with	O
p50	B-GENE
and	O
with	O
high	B-GENE
-	I-GENE
mobility	I-GENE
-	I-GENE
group	I-GENE
I	I-GENE
(	I-GENE
Y	I-GENE
)	I-GENE
protein	I-GENE
.	O

Based	O
on	O
these	O
results	O
the	O
minimal	O
control	O
element	O
(	O
AX	O
470	O
)	O
specifying	O
the	O
anterior	O
boundary	O
of	O
Hox	B-GENE
expression	O
was	O
designated	O
as	O
Hoxa	B-GENE
-	I-GENE
7	I-GENE
enhancer	I-GENE
.	O

In	O
this	O
report	O
we	O
describe	O
the	O
isolation	O
of	O
a	O
Fab	B-GENE
fragment	I-GENE
(	O
Fab	B-GENE
A8	I-GENE
)	O
showing	O
a	O
high	O
relative	O
affinity	O
for	O
the	O
receptor	O
(	O
0	O
.	O
5	O
nM	O
)	O
.	O

MBP	B-GENE
-	O
Rep68	B-GENE
delta	I-GENE
-	O
mediated	O
DNA	O
-	O
RNA	O
helicase	O
activity	O
required	O
ATP	O
hydrolysis	O
and	O
the	O
presence	O
of	O
Mg2	O
+	O
ions	O
and	O
was	O
inhibited	O
by	O
high	O
ionic	O
strength	O
.	O

To	O
identify	O
critical	O
regions	O
mediating	O
growth	O
signal	O
transduction	O
by	O
hG	B-GENE
-	I-GENE
CSFR	I-GENE
,	O
deletions	O
or	O
site	O
-	O
directed	O
amino	O
acid	O
substitutions	O
were	O
introduced	O
into	O
the	O
cytoplasmic	O
domain	O
of	O
hG	B-GENE
-	I-GENE
CSFR	I-GENE
,	O
and	O
the	O
mutant	O
cDNAs	O
were	O
transfected	O
into	O
the	O
murine	B-GENE
interleukin	I-GENE
-	I-GENE
3	I-GENE
(	O
IL	B-GENE
-	I-GENE
3	I-GENE
)	O
-	O
dependent	O
Ba	O
/	O
F3	O
and	O
FDCP	O
cell	O
lines	O
.	O

When	O
combined	O
with	O
independent	O
activating	O
mutations	O
in	O
the	O
c	B-GENE
-	I-GENE
abl	I-GENE
kinase	I-GENE
domain	I-GENE
or	O
NH2	O
-	O
terminus	O
,	O
the	O
G128R	B-GENE
mutation	O
blocked	O
transformation	O
by	O
the	O
double	O
mutant	O
,	O
suggesting	O
that	O
the	O
G128R	B-GENE
mutant	I-GENE
was	O
unable	O
to	O
transform	O
cells	O
for	O
trivial	O
reasons	O
.	O

Both	O
mutations	O
completely	O
abolished	O
binding	O
of	O
the	O
Abl	B-GENE
SH3	B-GENE
domain	O
to	O
proline	O
-	O
rich	O
target	O
proteins	O
in	O
a	O
filter	O
-	O
binding	O
assay	O
.	O

Changes	O
induced	O
in	O
the	O
gills	O
of	O
milkfish	O
(	O
Chanos	O
chanos	O
Forsskal	O
)	O
fingerlings	O
after	O
acute	O
exposure	O
to	O
nifurpirinol	O
(	O
Furanace	O
;	O
P	O
-	O
7138	O
)	O
.	O

Retreatment	O
of	O
these	O
2	O
dogs	O
resulted	O
in	O
a	O
similar	O
,	O
but	O
blunted	O
,	O
response	O
to	O
human	B-GENE
immunoglobulin	I-GENE
.	O

The	O
levels	O
of	O
NSE	B-GENE
and	O
MBP	B-GENE
in	O
the	O
IJVB	O
were	O
compared	O
to	O
those	O
in	O
the	O
PVB	O
.	O

Morphologic	O
variables	O
included	O
cancer	O
volume	O
,	O
histologic	O
grade	O
,	O
capsular	O
penetration	O
,	O
seminal	O
vesicle	O
invasion	O
,	O
and	O
lymph	O
node	O
metastasis	O
.	O

Sequence	O
analysis	O
of	O
these	O
regions	O
showed	O
a	O
CAAT	O
box	O
upstream	O
of	O
exon	O
1a	O
and	O
high	O
G	O
-	O
C	O
content	O
regions	O
within	O
both	O
P1	O
and	O
P2	O
.	O

The	O
fusion	O
proteins	O
were	O
tested	O
by	O
ELISA	O
for	O
reactivity	O
with	O
a	O
panel	O
of	O
human	B-GENE
anti	I-GENE
-	I-GENE
La	I-GENE
sera	I-GENE
in	O
order	O
to	O
define	O
the	O
nature	O
of	O
the	O
epitopes	O
.	O

GCD10	B-GENE
was	O
first	O
identified	O
genetically	O
as	O
a	O
translational	O
repressor	O
of	O
GCN4	B-GENE
.	O

GCD10	B-GENE
binds	O
RNA	O
in	O
vitro	O
and	O
we	O
present	O
strong	O
biochemical	O
evidence	O
that	O
it	O
is	O
identical	O
to	O
the	O
RNA	O
-	O
binding	O
subunit	O
of	O
yeast	B-GENE
initiation	I-GENE
factor	I-GENE
-	I-GENE
3	I-GENE
(	O
eIF	B-GENE
-	I-GENE
3	I-GENE
)	O
.	O
eIF	B-GENE
-	I-GENE
3	I-GENE
is	O
a	O
multisubunit	O
complex	O
that	O
stimulates	O
translation	O
initiation	O
in	O
vitro	O
at	O
several	O
different	O
steps	O
.	O

Sources	O
of	O
noise	O
in	O
these	O
signals	O
were	O
evaluated	O
in	O
preparations	O
stained	O
with	O
the	O
potentiometric	O
probe	O
RH	O
-	O
414	O
.	O

1993	O
.	O

A	O
transformation	O
-	O
competent	O
mutant	O
,	O
like	O
the	O
wild	B-GENE
-	I-GENE
type	I-GENE
E5	I-GENE
protein	I-GENE
,	O
bound	O
the	O
receptor	O
and	O
induced	O
receptor	O
tyrosine	O
phosphorylation	O
and	O
down	O
-	O
regulation	O
.	O

We	O
conclude	O
that	O
cAMP	O
,	O
acting	O
through	O
PKA	B-GENE
,	O
is	O
an	O
essential	O
regulator	O
of	O
basal	O
CFTR	B-GENE
gene	I-GENE
expression	O
and	O
may	O
mediate	O
an	O
induction	O
of	O
CFTR	B-GENE
in	O
responsive	O
cell	O
types	O
.	O

Both	O
PPC	O
-	O
1	O
and	O
ALVA	O
-	O
31	O
cells	O
display	O
tumorigenesis	O
and	O
invasiveness	O
in	O
nude	O
mice	O
,	O
whereas	O
LNCap	O
cells	O
exhibit	O
a	O
less	O
malignant	O
phenotype	O
,	O
suggesting	O
a	O
correlation	O
between	O
CD44	B-GENE
variant	I-GENE
(	O
CD44v	B-GENE
)	O
expression	O
and	O
aggressive	O
prostate	O
tumor	O
behavior	O
.	O

Two	O
such	O
genes	O
,	O
designated	O
hsiggll150	B-GENE
and	O
hsiggll295	B-GENE
,	O
were	O
cloned	O
and	O
sequenced	O
from	O
genomic	O
DNA	O
.	O

A	O
retrospective	O
epidemiological	O
study	O
is	O
reported	O
concerning	O
burn	O
injuries	O
in	O
775	O
children	O
hospitalized	O
at	O
the	O
unit	O
of	O
burn	O
care	O
of	O
Casablanca	O
between	O
1985	O
and	O
1993	O
.	O

Our	O
results	O
suggest	O
that	O
protein	O
binding	O
to	O
the	O
E2F	B-GENE
-	I-GENE
like	I-GENE
sequences	I-GENE
may	O
act	O
to	O
reduce	O
expression	O
.	O

The	O
RAD6	B-GENE
/	O
UBC2	B-GENE
gene	O
from	O
Saccharomyces	O
cerevisiae	O
encodes	O
a	O
ubiquitin	B-GENE
-	I-GENE
conjugating	I-GENE
enzyme	I-GENE
involved	O
in	O
DNA	O
repair	O
,	O
induced	O
mutagenesis	O
,	O
and	O
sporulation	O
.	O

Echocardiography	O
revealed	O
right	O
ventricular	O
diastolic	O
collapse	O
(	O
RVDC	O
)	O
without	O
physical	O
signs	O
of	O
cardiac	O
tamponade	O
.	O

In	O
on	O
-	O
going	O
screening	O
programmes	O
,	O
the	O
Haemoccult	O
test	O
consists	O
of	O
six	O
slides	O
and	O
a	O
test	O
is	O
considered	O
positive	O
if	O
at	O
least	O
one	O
slide	O
is	O
coloured	O
.	O

We	O
showed	O
previously	O
that	O
a	O
fusion	O
protein	O
(	O
GAL4	B-GENE
-	O
p40	B-GENE
)	O
containing	O
the	O
DNA	O
-	O
binding	O
domain	O
of	O
GAL4	B-GENE
and	O
sequences	O
of	O
chicken	B-GENE
l	I-GENE
kappa	I-GENE
B	I-GENE
-	I-GENE
alpha	I-GENE
(	O
p40	B-GENE
)	O
inhibits	O
growth	O
in	O
the	O
yeast	O
Saccharomyces	O
cerevisiae	O
.	O

We	O
have	O
demonstrated	O
previously	O
that	O
two	O
binding	O
sites	O
in	O
the	O
-	B-GENE
184	I-GENE
HNF	I-GENE
-	I-GENE
3	I-GENE
beta	I-GENE
promoter	I-GENE
are	O
recognized	O
by	O
widely	O
distributed	O
factors	O
and	O
that	O
there	O
is	O
also	O
a	O
critical	O
autoregulatory	O
site	O
,	O
we	O
identified	O
a	O
binding	O
site	O
for	O
a	O
cell	O
-	O
specific	O
factor	O
,	O
LF	B-GENE
-	I-GENE
H3	I-GENE
beta	I-GENE
,	O
that	O
may	O
function	O
in	O
restricting	O
HNF	B-GENE
-	I-GENE
3	I-GENE
beta	I-GENE
gene	I-GENE
expression	O
to	O
hepatocytes	O
.	O

In	O
4	O
spinalized	O
cats	O
,	O
the	O
effects	O
of	O
afferent	O
inputs	O
from	O
hindlimb	O
cutaneous	O
nerves	O
(	O
sural	O
cutaneous	O
nerve	O
:	O
Sur	O
)	O
on	O
mono	O
-	O
and	O
poly	O
-	O
synaptic	O
reflex	O
recorded	O
from	O
tail	O
muscle	O
motoneurons	O
were	O
studied	O
before	O
and	O
after	O
spinal	O
lesioning	O
at	O
S2	O
-	O
3	O
level	O
.	O

The	O
flow	O
rate	O
of	O
phosphate	O
buffered	O
saline	O
through	O
dermis	O
was	O
measured	O
as	O
a	O
function	O
of	O
applied	O
pressure	O
.	O

However	O
,	O
parallax	O
measurements	O
showed	O
that	O
at	O
150K	O
,	O
collapse	O
of	O
Epon	O
sections	O
does	O
not	O
take	O
place	O
.	O

Although	O
within	O
normal	O
limits	O
,	O
latency	O
was	O
high	O
.	O

The	O
outcome	O
of	O
the	O
optimization	O
of	O
the	O
seven	O
-	O
field	O
plan	O
prompted	O
an	O
investigation	O
into	O
the	O
best	O
results	O
that	O
could	O
be	O
achieved	O
by	O
an	O
"	O
ideal	O
"	O
conformal	O
radiotherapy	O
technique	O
.	O

Specific	O
requirements	O
for	O
branched	O
-	O
chain	O
amino	O
acids	O
,	O
glutamine	O
,	O
and	O
arginine	O
are	O
evaluated	O
.	O

The	O
pea	B-GENE
rps10	I-GENE
intron	I-GENE
is	O
homologous	O
to	O
introns	O
in	O
rrn26	B-GENE
and	O
cox3	B-GENE
in	O
the	O
Marchantia	O
mitochondrial	O
genome	O
,	O
while	O
the	O
Marchantia	B-GENE
rps10	I-GENE
gene	I-GENE
lacks	O
an	O
intron	O
.	O

Serum	O
magnesium	O
in	O
79	O
patients	O
of	O
gynecologic	O
neoplasms	O
treated	O
with	O
cisplatin	O
and	O
their	O
controls	O
was	O
measured	O
.	O

Alanine	B-GENE
aminotransferase	I-GENE
(	O
ALT	B-GENE
)	O
levels	O
had	O
been	O
elevated	O
for	O
six	O
months	O
in	O
all	O
patients	O
and	O
hepatitis	O
B	O
viral	O
infection	O
was	O
replicative	O
.	O

In	O
this	O
study	O
we	O
have	O
investigated	O
the	O
role	O
of	O
C	B-GENE
/	I-GENE
EBP	I-GENE
beta	I-GENE
in	O
initiating	O
the	O
adipogenic	O
program	O
by	O
overexpressing	O
C	B-GENE
/	I-GENE
EBP	I-GENE
beta	I-GENE
in	O
multipotential	O
NIH	O
-	O
3T3	O
fibroblasts	O
.	O

XYL1	B-GENE
was	O
isolated	O
as	O
a	O
highly	O
expressed	O
fusion	O
clone	O
from	O
a	O
'	B-GENE
lacZ	I-GENE
translational	O
fusion	O
library	O
.	O

Various	O
transcripts	O
are	O
generated	O
from	O
the	O
VCSA1	B-GENE
gene	I-GENE
by	O
alternative	O
splicing	O
and	O
poly	O
(	O
A	O
)	O
processing	O
in	O
the	O
rat	O
submandibular	O
gland	O
.	O

However	O
,	O
division	O
of	O
the	O
chest	O
wall	O
muscles	O
,	O
usually	O
with	O
diathermy	O
,	O
contributes	O
to	O
prolonged	O
pain	O
and	O
morbidity	O
.	O

Closure	O
of	O
an	O
open	O
high	O
below	O
-	O
knee	O
guillotine	O
amputation	O
wound	O
using	O
a	O
skin	O
-	O
stretching	O
device	O
.	O

Our	O
study	O
was	O
addressed	O
to	O
the	O
synthesis	O
of	O
some	O
derivatives	O
of	O
this	O
sequence	O
in	O
order	O
to	O
obtain	O
both	O
peptide	O
substrates	O
suitable	O
for	O
the	O
detection	O
of	O
the	O
Src	B-GENE
-	O
like	O
tyrosine	B-GENE
kinase	I-GENE
activity	O
and	O
active	O
site	O
-	O
directed	O
inhibitors	O
specific	O
for	O
this	O
class	O
of	O
enzymes	O
.	O

Citrate	B-GENE
synthase	I-GENE
activity	O
was	O
increased	O
in	O
the	O
medial	O
head	O
(	O
81	O
%	O
,	O
P	O
<	O
0	O
.	O
001	O
)	O
and	O
the	O
red	O
long	O
head	O
(	O
88	O
%	O
,	O
P	O
<	O
0	O
.	O
001	O
)	O
of	O
the	O
triceps	O
brachii	O
muscle	O
in	O
R	O
rats	O
but	O
not	O
in	O
the	O
white	O
long	O
head	O
(	O
25	O
%	O
,	O
P	O
=	O
0	O
.	O
06	O
)	O
.	O

The	O
expression	O
of	O
the	O
putative	O
operon	O
bglPH	B-GENE
of	O
Bacillus	O
subtilis	O
was	O
studied	O
by	O
using	O
bglP	B-GENE
'	I-GENE
-	O
lacZ	B-GENE
transcriptional	O
fusions	O
.	O

Although	O
eight	O
contiguous	O
genes	O
necessary	O
for	O
urease	B-GENE
activity	O
have	O
been	O
cloned	O
and	O
sequenced	O
,	O
the	O
transcriptional	O
organization	O
and	O
regulation	O
of	O
specific	O
genes	O
within	O
the	O
Proteus	B-GENE
gene	I-GENE
cluster	I-GENE
has	O
not	O
been	O
investigated	O
in	O
detail	O
.	O

The	O
hypBFCDE	B-GENE
operon	I-GENE
from	O
Rhizobium	O
leguminosarum	O
biovar	O
viciae	O
is	O
expressed	O
from	O
an	O
Fnr	B-GENE
-	I-GENE
type	I-GENE
promoter	I-GENE
that	O
escapes	O
mutagenesis	O
of	O
the	O
fnrN	B-GENE
gene	I-GENE
.	O

We	O
demonstrate	O
that	O
a	O
VT	O
+	O
peptide	O
was	O
specifically	O
phosphorylated	O
by	O
protein	B-GENE
kinase	I-GENE
C	I-GENE
(	O
PKC	B-GENE
)	O
in	O
vitro	O
,	O
but	O
not	O
by	O
protein	B-GENE
kinase	I-GENE
A	I-GENE
(	O
PKA	B-GENE
)	O
.	O

R	O
.	O

15	O
,	O
2500	O
-	O
2508	O
;	O
O	O
'	O
Neill	O
,	O
T	O
.	O

Control	O
experiments	O
showed	O
that	O
each	O
fusion	O
protein	O
had	O
a	O
high	O
affinity	O
binding	O
site	O
for	O
estradiol	O
-	O
17	O
beta	O
and	O
could	O
transactivate	O
an	O
ERE	O
-	O
LacZ	B-GENE
reporter	O
gene	O
in	O
yeast	O
similar	O
to	O
the	O
wild	B-GENE
type	I-GENE
ER	I-GENE
.	O

Although	O
Micrococcus	B-GENE
luteus	I-GENE
UV	I-GENE
endonuclease	I-GENE
has	O
been	O
reported	O
to	O
be	O
an	O
18	O
-	O
kDa	O
enzyme	O
with	O
possible	O
homology	O
to	O
the	O
16	B-GENE
-	I-GENE
kDa	I-GENE
endonuclease	I-GENE
V	I-GENE
from	I-GENE
bacteriophage	I-GENE
T4	I-GENE
(	O
Gordon	O
,	O
L	O
.	O

Several	O
different	O
oncogenes	O
and	O
growth	O
factors	O
promote	O
G1	O
phase	O
progression	O
.	O

Cyclin	B-GENE
D1	I-GENE
promoter	I-GENE
activity	O
was	O
stimulated	O
by	O
overexpression	O
of	O
mitogen	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
kinase	I-GENE
(	O
p41MAPK	B-GENE
)	O
or	O
c	B-GENE
-	I-GENE
Ets	I-GENE
-	I-GENE
2	I-GENE
through	O
the	O
proximal	O
22	O
base	O
pairs	O
.	O

Indeed	O
,	O
ERM	B-GENE
and	O
c	B-GENE
-	I-GENE
Jun	I-GENE
synergistically	O
activated	O
the	O
EBS	O
-	O
CRE	O
without	O
making	O
an	O
apparent	O
ternary	O
complex	O
.	O

In	O
addition	O
,	O
the	O
R206S	B-GENE
HSF	I-GENE
substitution	O
exhibits	O
constitutive	O
transcriptional	O
activation	O
from	O
a	O
consensus	O
HSE	O
(	O
HSE2	O
)	O
.	O

After	O
recovery	O
,	O
a	O
hypertonic	O
saline	O
challenge	O
was	O
performed	O
.	O

The	O
range	O
of	O
eosinophils	O
was	O
22	O
-	O
56	O
%	O
of	O
the	O
number	O
of	O
peripheral	O
white	O
blood	O
cells	O
(	O
mean	O
nadir	O
33	O
%	O
)	O
.	O

Comparisons	O
of	O
rrnB	B-GENE
P1	B-GENE
-	O
lacZ	B-GENE
expression	O
at	O
different	O
ppGpp	O
levels	O
is	O
interpreted	O
for	O
the	O
rpoD	B-GENE
(	I-GENE
P504L	I-GENE
)	I-GENE
mutant	I-GENE
as	O
resulting	O
from	O
a	O
hypersensitivity	O
to	O
ppGpp	O
.	O

These	O
intron	O
chimeras	O
show	O
that	O
peripheral	O
sequences	O
and	O
the	O
elements	O
that	O
define	O
the	O
splice	O
sites	O
are	O
adequate	O
for	O
self	O
-	O
splicing	O
activity	O
but	O
that	O
the	O
central	O
portions	O
containing	O
the	O
catalytic	O
cores	O
of	O
ai4	B-GENE
and	O
bi4	B-GENE
are	O
deficient	O
;	O
these	O
cores	O
are	O
the	O
likely	O
targets	O
of	O
the	O
splicing	O
proteins	O
.	O

Here	O
we	O
demonstrate	O
genetically	O
that	O
plus	O
-	O
strand	O
DNA	O
synthesis	O
of	O
the	O
yeast	B-GENE
Ty1	I-GENE
element	I-GENE
is	O
initiated	O
at	O
two	O
sites	O
located	O
at	O
the	O
5	O
'	O
boundary	O
of	O
the	O
3	O
'	O
long	O
terminal	O
repeat	O
(	O
PPT1	B-GENE
)	O
and	O
near	O
the	O
middle	O
of	O
the	O
pol	B-GENE
gene	I-GENE
in	O
the	O
integrase	B-GENE
coding	I-GENE
sequence	I-GENE
(	O
PPT2	B-GENE
)	O
.	O

Characterization	O
of	O
the	O
3	O
'	O
ends	O
of	O
the	O
plus	O
-	O
strand	O
DNA	O
fragments	O
reveals	O
(	O
1	O
)	O
that	O
the	O
upstream	O
fragment	O
is	O
elongated	O
beyond	O
PPT2	B-GENE
creating	O
a	O
plus	O
-	O
strand	O
overlap	O
and	O
(	O
2	O
)	O
that	O
the	O
majority	O
of	O
plus	O
-	O
strand	O
strong	O
-	O
stop	O
DNA	O
fragments	O
bear	O
a	O
copy	O
of	O
the	O
minus	O
-	O
strand	O
primer	O
binding	O
site	O
in	O
agreement	O
with	O
the	O
accepted	O
model	O
of	O
retroviral	O
genomic	O
RNA	O
reverse	O
transcription	O
.	O

The	O
patients	O
undergoing	O
VTLB	O
had	O
significantly	O
shorter	O
operative	O
times	O
(	O
VTLB	O
,	O
100	O
.	O
2	O
+	O
/	O
-	O
27	O
.	O
2	O
min	O
.	O
vs	O
OLB	O
,	O
119	O
.	O
8	O
+	O
/	O
-	O
42	O
.	O
6	O
min	O
;	O
p	O
<	O
0	O
.	O
01	O
)	O
and	O
less	O
blood	O
loss	O
(	O
VTLB	O
,	O
4	O
.	O
7	O
+	O
/	O
-	O
14	O
.	O
6	O
ml	O
vs	O
OLB	O
,	O
65	O
.	O
7	O
+	O
/	O
-	O
77	O
.	O
0	O
ml	O
;	O
p	O
<	O
0	O
.	O
001	O
)	O
.	O

By	O
150	O
minutes	O
after	O
Cr2O3	O
inhalation	O
,	O
FEV1	O
.	O
0	O
had	O
decreased	O
by	O
32	O
%	O
.	O

This	O
combined	O
intravenous	O
anaesthetic	O
regimen	O
gave	O
good	O
anaesthesia	O
and	O
analgesia	O
to	O
pigs	O
for	O
up	O
to	O
2	O
h	O
as	O
monitored	O
by	O
clinical	O
signs	O
.	O

Twenty	O
food	O
products	O
were	O
contaminated	O
with	O
V	O
.	O
cholerae	O
O1	O
,	O
Ogawa	O
,	O
toxigenic	O
and	O
not	O
toxigenic	O
strains	O
:	O
yoghurt	O
,	O
cream	O
cheese	O
,	O
apricot	O
marmelade	O
,	O
hip	O
rose	O
marmelade	O
,	O
mayonnaise	O
,	O
italian	O
pasta	O
for	O
"	O
empanadas	O
"	O
,	O
"	O
dulce	O
de	O
leche	O
"	O
,	O
meat	O
sausage	O
,	O
meat	O
and	O
spinach	O
ravioli	O
,	O
margarine	O
,	O
milk	O
dessert	O
(	O
made	O
with	O
cocoa	O
,	O
milk	O
confiture	O
,	O
starch	O
and	O
additives	O
)	O
,	O
lettuce	O
,	O
tuna	O
fish	O
,	O
ricotta	O
and	O
sterilized	O
milk	O
.	O

It	O
is	O
impossible	O
to	O
define	O
only	O
one	O
clinical	O
outline	O
because	O
both	O
symptomatic	O
and	O
asymptomatic	O
infected	O
NB	O
may	O
be	O
found	O
with	O
gestational	O
age	O
at	O
term	O
and	O
pre	O
-	O
term	O
and	O
when	O
born	O
with	O
a	O
weight	O
above	O
or	O
below	O
2000	O
g	O
.	O

The	O
expression	O
of	O
the	O
pilin	B-GENE
gene	I-GENE
,	O
tcpA	B-GENE
,	O
is	O
dependent	O
upon	O
ToxR	B-GENE
and	O
upon	O
ToxT	B-GENE
.	O

Ras	B-GENE
p21Val	I-GENE
inhibits	O
myogenesis	O
without	O
altering	O
the	O
DNA	O
binding	O
or	O
transcriptional	O
activities	O
of	O
the	O
myogenic	B-GENE
basic	I-GENE
helix	I-GENE
-	I-GENE
loop	I-GENE
-	I-GENE
helix	I-GENE
factors	I-GENE
.	O

In	O
cells	O
limited	O
for	O
His	O
,	O
increased	O
expression	O
of	O
arg	B-GENE
-	I-GENE
2	I-GENE
and	O
cpc	B-GENE
-	I-GENE
1	I-GENE
,	O
and	O
decreased	O
expression	O
of	O
cox	B-GENE
-	I-GENE
5	I-GENE
,	O
also	O
had	O
translational	O
and	O
transcriptional	O
components	O
.	O

The	O
peptide	O
sequences	O
reveal	O
that	O
the	O
factor	O
consists	O
of	O
GABP	B-GENE
alpha	I-GENE
and	O
GABP	B-GENE
beta	I-GENE
1	I-GENE
with	O
Ets	B-GENE
and	O
Notch	B-GENE
motifs	I-GENE
,	O
respectively	O
.	O

Immunofluorescence	O
microscopy	O
and	O
cell	O
fractionation	O
analyses	O
showed	O
that	O
the	O
110	O
-	O
kDa	O
protein	O
was	O
exclusively	O
nuclear	O
,	O
whereas	O
the	O
150	O
-	O
kDa	O
protein	O
was	O
present	O
in	O
both	O
the	O
cytoplasm	O
and	O
nucleus	O
of	O
human	O
cells	O
.	O

Expression	O
and	O
regulation	O
by	O
interferon	B-GENE
of	O
a	O
double	B-GENE
-	I-GENE
stranded	I-GENE
-	I-GENE
RNA	I-GENE
-	I-GENE
specific	I-GENE
adenosine	I-GENE
deaminase	I-GENE
from	O
human	O
cells	O
:	O
evidence	O
for	O
two	O
forms	O
of	O
the	O
deaminase	O
.	O

T	O
-	O
cell	O
hybridomas	O
,	O
thymocytes	O
,	O
and	O
T	O
cells	O
can	O
be	O
induced	O
to	O
undergo	O
apoptotic	O
cell	O
death	O
by	O
activation	O
through	O
the	O
T	B-GENE
-	I-GENE
cell	I-GENE
receptor	I-GENE
.	O

Deletions	O
were	O
examined	O
in	O
the	O
LYS2	B-GENE
gene	I-GENE
,	O
using	O
a	O
set	O
of	O
31	O
-	O
to	O
156	O
-	O
bp	O
inserts	O
that	O
included	O
inserts	O
with	O
no	O
apparent	O
potential	O
for	O
secondary	O
structure	O
as	O
well	O
as	O
two	O
quasipalindromes	O
.	O

Overexpression	O
of	O
SCS1	B-GENE
could	O
not	O
complement	O
an	O
HSP60	B-GENE
-	I-GENE
null	I-GENE
allele	I-GENE
,	O
indicating	O
that	O
suppression	O
was	O
not	O
due	O
to	O
the	O
bypassing	O
of	O
Hsp60	B-GENE
activity	O
.	O

The	O
DNA	O
binding	O
domain	O
of	O
NirA	B-GENE
was	O
expressed	O
as	O
a	O
fusion	O
protein	O
with	O
the	O
glutathione	B-GENE
S	I-GENE
-	I-GENE
transferase	I-GENE
of	O
Schistosoma	O
japonicum	O
.	O

The	O
kinase	O
is	O
essential	O
in	O
vivo	O
for	O
normal	O
phosphorylation	O
of	O
the	O
CTD	O
and	O
for	O
normal	O
growth	O
and	O
differentiation	O
.	O

Finally	O
,	O
we	O
demonstrate	O
that	O
C	B-GENE
/	I-GENE
EBP	I-GENE
alpha	I-GENE
can	O
also	O
active	O
the	O
GM	B-GENE
-	I-GENE
CSF	I-GENE
receptor	I-GENE
alpha	I-GENE
promoter	O
in	O
nonmyeloid	O
cells	O
.	O

Endocytosis	O
and	O
vacuolar	O
degradation	O
of	O
the	O
plasma	O
membrane	O
-	O
localized	O
Pdr5	B-GENE
ATP	I-GENE
-	I-GENE
binding	I-GENE
cassette	I-GENE
multidrug	I-GENE
transporter	I-GENE
in	O
Saccharomyces	O
cerevisiae	O
.	O

Disruption	O
of	O
the	O
HOG1	B-GENE
and	O
PBS2	B-GENE
genes	I-GENE
leads	O
to	O
a	O
dramatic	O
decrease	O
of	O
the	O
HSP12	B-GENE
inducibility	O
in	O
osmostressed	O
cells	O
,	O
whereas	O
overproduction	O
of	O
Hog1	B-GENE
produces	O
a	O
fivefold	O
increase	O
in	O
wild	O
-	O
type	O
induced	O
levels	O
upon	O
a	O
shift	O
to	O
a	O
high	O
salt	O
concentration	O
.	O

Deletion	O
or	O
inactivation	O
of	O
CRY1	B-GENE
leads	O
to	O
5	O
-	O
to	O
10	O
-	O
fold	O
-	O
increased	O
levels	O
of	O
CRY2	B-GENE
mRNA	I-GENE
.	O

(	O
1986	O
)	O
method	O
of	O
separation	O
of	O
Cryptosporidium	O
spp	O
.	O
oocysts	O
from	O
feces	O
by	O
using	O
a	O
percoll	O
discontinuous	O
density	O
gradient	O
appeared	O
a	O
method	O
of	O
choice	O
for	O
obtaining	O
large	O
numbers	O
of	O
oocysts	O
of	O
C	O
.	O
parvum	O
free	O
of	O
fecal	O
contamination	O
.	O

METHODS	O
:	O
We	O
obtained	O
maximal	O
inspiratory	O
and	O
expiratory	O
flow	O
-	O
volume	O
curves	O
in	O
41	O
unselected	O
patients	O
with	O
essential	O
tremor	O
(	O
14	O
males	O
,	O
27	O
females	O
,	O
age	O
61	O
.	O
7	O
+	O
/	O
-	O
2	O
.	O
14	O
years	O
)	O
.	O

Our	O
findings	O
also	O
provide	O
the	O
basis	O
for	O
the	O
development	O
of	O
assays	O
to	O
screen	O
for	O
the	O
ligands	O
to	O
testis	B-GENE
receptor	I-GENE
2	I-GENE
and	O
hERR1	B-GENE
.	O

Four	O
p53	B-GENE
DNA	I-GENE
-	I-GENE
binding	I-GENE
domain	I-GENE
peptides	I-GENE
bind	O
natural	O
p53	B-GENE
-	I-GENE
response	I-GENE
elements	I-GENE
and	O
bend	O
the	O
DNA	O
.	O

The	O
Stat5b	B-GENE
mRNA	I-GENE
has	O
a	O
size	O
of	O
5	O
.	O
6	O
kb	O
and	O
encodes	O
a	O
protein	O
of	O
786	O
amino	O
acids	O
.	O

The	O
hydropathy	O
plot	O
revealed	O
a	O
rather	O
hydrophilic	O
N	O
-	O
terminal	O
region	O
and	O
the	O
absence	O
of	O
a	O
hydrophobic	O
signal	O
peptide	O
.	O

This	O
report	O
focused	O
on	O
the	O
relationship	O
between	O
Type	O
A	O
behavior	O
and	O
eight	O
basic	O
emotion	O
dimensions	O
.	O

All	O
carcasses	O
resulted	O
in	O
contamination	O
with	O
aerobic	O
mesophilic	O
bacteria	O
in	O
the	O
range	O
from	O
6	O
x	O
10	O
(	O
3	O
)	O
to	O
1	O
.	O
2	O
x	O
10	O
(	O
6	O
)	O
CFU	O
/	O
ml	O
liquid	O
washed	O
,	O
and	O
94	O
%	O
them	O
with	O
sporulate	O
bacteria	O
,	O
the	O
threshold	O
being	O
under	O
100	O
CFU	O
/	O
ml	O
(	O
Figure	O
1	O
)	O
.	O

As	O
for	O
31	O
stage	O
I	O
-	O
II	O
lung	O
cancer	O
patients	O
,	O
CR	O
has	O
been	O
observed	O
in	O
82	O
.	O
8	O
%	O
of	O
them	O
and	O
PR	O
in	O
13	O
.	O
8	O
%	O
;	O
the	O
response	O
was	O
always	O
assessed	O
with	O
chest	O
radiography	O
,	O
CT	O
,	O
FBS	O
,	O
cytology	O
and	O
/	O
or	O
histology	O
.	O

Pediatric	O
medical	O
emergencies	O
in	O
a	O
regional	O
hospital	O
:	O
appropriate	O
locale	O
?	O

Protein	O
electrophoresis	O
showed	O
decreased	O
albumin	B-GENE
levels	O
in	O
both	O
groups	O
,	O
with	O
lower	O
values	O
in	O
G2	O
.	O

METHODS	O
:	O
All	O
these	O
30	O
non	O
-	O
responders	O
received	O
an	O
extra	O
dose	O
of	O
the	O
same	O
vaccine	O
2	O
months	O
after	O
primary	O
immunization	O
and	O
a	O
booster	O
dose	O
with	O
a	O
yeast	O
-	O
derived	O
vaccine	O
6	O
years	O
later	O
.	O

An	O
abnormally	O
high	O
percentage	O
of	O
hypertensive	O
patients	O
(	O
approximately	O
30	O
%	O
)	O
undergoing	O
cardiac	O
catheterization	O
because	O
of	O
anginal	O
pain	O
and	O
/	O
or	O
exercise	O
-	O
induced	O
ST	O
-	O
segment	O
depressions	O
has	O
angiographically	O
normal	O
coronary	O
arteries	O
.	O

Mibefradil	O
(	O
Ro	O
40	O
-	O
5967	O
)	O
is	O
a	O
novel	O
calcium	O
antagonist	O
from	O
a	O
new	O
chemical	O
class	O
and	O
is	O
the	O
first	O
that	O
selectively	O
blocks	O
the	O
T	O
-	O
type	O
calcium	O
channel	O
.	O

However	O
,	O
2	O
minimum	O
alveolar	O
concentration	O
anesthesia	O
did	O
significantly	O
decrease	O
the	O
calculated	O
VE	O
at	O
a	O
PCO2	O
of	O
60	O
mmHg	O
(	O
from	O
7	O
.	O
4	O
+	O
/	O
-	O
1	O
.	O
2	O
to	O
4	O
.	O
0	O
+	O
/	O
-	O
0	O
.	O
6	O
l	O
.	O
min	O
-	O
1	O
)	O
,	O
indicating	O
a	O
rightward	O
shift	O
in	O
the	O
response	O
relationship	O
.	O

cDNA	O
encoding	O
a	O
functional	O
feline	B-GENE
liver	I-GENE
/	I-GENE
bone	I-GENE
/	I-GENE
kidney	I-GENE
-	I-GENE
type	I-GENE
alkaline	I-GENE
phosphatase	I-GENE
.	O

Protein	B-GENE
kinase	I-GENE
C	I-GENE
(	O
PKC	B-GENE
)	O
,	O
a	O
widely	O
-	O
distributed	O
enzyme	O
implicated	O
in	O
the	O
regulation	O
of	O
many	O
physiological	O
processes	O
,	O
consists	O
of	O
a	O
family	O
of	O
at	O
least	O
twelve	O
isoenzymes	O
which	O
differ	O
in	O
tissue	O
distribution	O
,	O
subcellular	O
localization	O
,	O
regulatory	O
properties	O
,	O
etc	O
.	O

This	O
work	O
,	O
therefore	O
,	O
also	O
emphasizes	O
the	O
importance	O
of	O
careful	O
choice	O
of	O
oligonucleotide	O
and	O
cDNA	O
probes	O
to	O
study	O
PKC	B-GENE
zeta	I-GENE
mRNA	I-GENE
.	O

This	O
action	O
is	O
dependent	O
on	O
helix	B-GENE
-	I-GENE
loop	I-GENE
-	I-GENE
helix	I-GENE
factors	I-GENE
bound	O
to	O
the	O
E1	B-GENE
element	O
.	O

The	O
debate	O
over	O
electives	O
-	O
-	O
1899	O
.	O

Polypeptide	O
growth	O
factors	O
and	O
cytokines	O
mediate	O
their	O
biochemical	O
functions	O
through	O
their	O
responsive	O
receptors	O
.	O

However	O
,	O
a	O
strongly	O
increased	O
frequency	O
of	O
CpG	O
dinucleotides	O
was	O
found	O
.	O

During	O
the	O
dose	O
-	O
finding	O
,	O
two	O
patients	O
were	O
temporarily	O
withdrawn	O
from	O
medication	O
and	O
one	O
patient	O
was	O
excluded	O
because	O
of	O
elevated	O
levels	O
of	O
liver	O
enzymes	O
.	O

In	O
comparison	O
of	O
cDNA	O
and	O
genomic	O
sequences	O
four	O
RNA	O
editing	O
events	O
were	O
found	O
in	O
both	O
atp9	B-GENE
genes	I-GENE
.	O

MZF	B-GENE
-	I-GENE
1	I-GENE
represses	O
CAT	B-GENE
reporter	I-GENE
gene	I-GENE
expression	O
via	O
GAL4	B-GENE
binding	I-GENE
sites	I-GENE
in	O
the	O
nonhematopoietic	O
cell	O
lines	O
NIH	O
3T3	O
and	O
293	O
.	O

As	O
with	O
the	O
heterologous	O
DNA	O
binding	O
domain	O
,	O
MZF	B-GENE
-	I-GENE
1	I-GENE
represses	O
reporter	O
gene	O
expression	O
in	O
nonhematopoietic	O
cell	O
lines	O
and	O
activates	O
expression	O
in	O
hematopoietic	O
cell	O
lines	O
.	O

Analyses	O
of	O
hGMR	B-GENE
beta	I-GENE
subunit	I-GENE
mutants	I-GENE
revealed	O
two	O
cytoplasmic	O
regions	O
involved	O
in	O
activation	O
of	O
the	O
c	B-GENE
-	I-GENE
myc	I-GENE
promoter	I-GENE
,	O
one	O
is	O
essential	O
and	O
the	O
other	O
is	O
dispensable	O
but	O
enhances	O
the	O
activity	O
.	O

Similarly	O
,	O
we	O
observed	O
synthetic	O
phenotypes	O
between	O
mutations	O
in	O
MIF2	B-GENE
and	O
trans	O
-	O
acting	O
mutations	O
in	O
three	O
known	O
yeast	O
centromere	O
protein	O
genes	O
-	O
CEP1	B-GENE
/	O
CBF1	B-GENE
/	O
CPF1	B-GENE
,	O
NDC10	B-GENE
/	O
CBF2	B-GENE
,	O
and	O
CEP3	B-GENE
/	O
CBF3B	B-GENE
.	O

Taken	O
together	O
,	O
these	O
data	O
suggest	O
that	O
the	O
Mif2	B-GENE
protein	I-GENE
interacts	O
with	O
Cep1p	B-GENE
at	O
the	O
centromere	O
and	O
that	O
the	O
yeast	O
centromere	O
indeed	O
exists	O
as	O
a	O
higher	O
order	O
protein	O
-	O
DNA	O
complex	O
.	O

To	O
accomplish	O
this	O
,	O
actin	B-GENE
cables	O
and	O
patches	O
are	O
redistributed	O
during	O
the	O
cell	O
cycle	O
to	O
direct	O
secretory	O
components	O
to	O
appropriate	O
sites	O
for	O
cell	O
growth	O
.	O

The	O
effects	O
of	O
Codonopsis	O
pilosula	O
oral	O
liquor	O
(	O
CPOL	O
)	O
on	O
tissue	B-GENE
-	I-GENE
type	I-GENE
plasminogen	I-GENE
activator	I-GENE
(	O
t	B-GENE
-	I-GENE
PA	I-GENE
)	O
and	O
plasminogen	B-GENE
activator	I-GENE
inhibitor	I-GENE
(	O
PAI	B-GENE
)	O
in	O
the	O
plasma	O
of	O
25	O
patients	O
of	O
coronary	O
heart	O
disease	O
with	O
blood	O
stasis	O
were	O
studied	O
.	O

Estimated	O
daily	O
intakes	O
(	O
EDIs	O
)	O
per	O
person	O
were	O
0	O
.	O
56	O
microgram	O
for	O
total	O
HCH	O
,	O
0	O
.	O
20	O
microgram	O
for	O
gamma	O
-	O
HCH	O
,	O
0	O
.	O
09	O
microgram	O
for	O
dieldrin	O
,	O
1	O
.	O
42	O
micrograms	O
for	O
total	O
DDT	O
,	O
and	O
0	O
.	O
15	O
microgram	O
for	O
HCB	O
.	O

In	O
two	O
further	O
cases	O
(	O
one	O
type	O
I	O
and	O
one	O
type	O
III	O
SMA	O
)	O
,	O
de	O
novo	O
deletions	O
of	O
only	O
one	O
copy	O
of	O
Ag1	B-GENE
-	I-GENE
CA	I-GENE
and	O
C212	B-GENE
were	O
found	O
.	O

With	O
each	O
of	O
the	O
three	O
pairs	O
of	O
isolates	O
(	O
case	O
and	O
suspicious	O
case	O
)	O
,	O
identical	O
IS6110	O
banding	O
patterns	O
were	O
found	O
suggesting	O
identical	O
MTB	O
strains	O
.	O

HRES	O
has	O
been	O
found	O
to	O
be	O
clinically	O
useful	O
in	O
assessing	O
histologic	O
damage	O
following	O
pneumatic	O
dilatation	O
and	O
in	O
localizing	O
the	O
LES	O
during	O
the	O
administration	O
of	O
intrasphincter	O
botulinum	B-GENE
toxin	I-GENE
injection	O
in	O
the	O
treatment	O
of	O
achalasia	O
.	O

These	O
early	O
structural	O
processes	O
are	O
assumed	O
to	O
be	O
subserved	O
by	O
the	O
anterior	O
parts	O
of	O
the	O
left	O
hemisphere	O
,	O
as	O
event	O
-	O
related	O
brain	O
potentials	O
show	O
this	O
area	O
to	O
be	O
maximally	O
activated	O
when	O
phrase	O
structure	O
violations	O
are	O
processed	O
and	O
as	O
circumscribed	O
lesions	O
in	O
this	O
area	O
lead	O
to	O
an	O
impairment	O
of	O
the	O
on	O
-	O
line	O
structural	O
assignment	O
.	O

In	O
men	O
with	O
BMI	O
<	O
30	O
,	O
the	O
OR	O
was	O
1	O
.	O
83	O
for	O
postprandial	O
TG	O
(	O
P	O
=	O
.	O
041	O
)	O
and	O
2	O
.	O
77	O
for	O
postprandial	O
RP	O
(	O
P	O
=	O
.	O
032	O
)	O
in	O
models	O
that	O
included	O
fasting	O
TG	O
,	O
LDL	B-GENE
-	I-GENE
C	I-GENE
,	O
and	O
hypertension	O
.	O

A	O
pyrazolo	O
-	O
quinoline	O
compound	O
,	O
6	O
-	O
methoxy	O
-	O
4	O
-	O
[	O
2	O
-	O
[	O
(	O
2	O
-	O
hydroxyethoxyl	O
)	O
-	O
ethyl	O
]	O
amino	O
]	O
-	O
3	O
-	O
methyl	O
-	O
1M	O
-	O
pyrazo	O
lo	O
[	O
3	O
,	O
4	O
-	O
b	O
]	O
quinoline	O
(	O
SCH	O
51344	O
)	O
,	O
was	O
identified	O
based	O
on	O
its	O
ability	O
to	O
derepress	O
human	O
smooth	O
muscle	O
alpha	B-GENE
-	I-GENE
actin	I-GENE
promoter	I-GENE
activity	O
in	O
ras	B-GENE
-	O
transformed	O
cells	O
.	O

On	O
the	O
basis	O
of	O
these	O
relations	O
,	O
a	O
risk	O
factor	O
-	O
selection	O
scale	O
(	O
RFSS	O
)	O
(	O
range	O
,	O
0	O
to	O
10	O
)	O
was	O
developed	O
by	O
computing	O
appropriate	O
weights	O
for	O
each	O
risk	O
factor	O
.	O

The	O
Caenorhabditis	B-GENE
elegans	I-GENE
death	I-GENE
susceptibility	I-GENE
gene	I-GENE
,	O
ced	B-GENE
-	I-GENE
3	I-GENE
,	O
has	O
a	O
number	O
of	O
homologs	O
in	O
vertebrate	O
species	O
,	O
including	O
interleukin	B-GENE
-	I-GENE
1	I-GENE
beta	I-GENE
(	I-GENE
IL	I-GENE
-	I-GENE
1	I-GENE
beta	I-GENE
)	I-GENE
-	I-GENE
converting	I-GENE
enzyme	I-GENE
(	O
ICE	B-GENE
)	O
,	O
Ich	B-GENE
-	I-GENE
1long	I-GENE
,	O
and	O
CPP32	B-GENE
.	O

Repression	O
of	O
glucocorticoid	B-GENE
receptor	I-GENE
-	O
mediated	O
transcriptional	O
activation	O
by	O
unliganded	O
thyroid	B-GENE
hormone	I-GENE
receptor	I-GENE
(	O
TR	B-GENE
)	O
is	O
TR	B-GENE
isoform	O
-	O
specific	O
.	O

The	O
results	O
indicate	O
considerable	O
flexibility	O
in	O
the	O
spacing	O
between	O
DH	B-GENE
regulatory	O
sites	O
.	O

Obstruction	O
of	O
the	O
ERF	B-GENE
repressor	I-GENE
function	O
by	O
the	O
transactivating	O
members	O
of	O
the	O
ets	B-GENE
family	I-GENE
of	O
genes	O
(	O
i	O
.	O
e	O
.	O
gag	B-GENE
-	O
myb	B-GENE
-	O
ets	B-GENE
)	O
may	O
be	O
essential	O
for	O
the	O
control	O
of	O
genes	O
involved	O
in	O
cell	O
proliferation	O
and	O
may	O
also	O
underlie	O
their	O
tumorigenic	O
effects	O
.	O

We	O
show	O
that	O
c	B-GENE
-	I-GENE
Fos	I-GENE
(	O
the	O
c	B-GENE
-	I-GENE
fos	I-GENE
protooncogene	I-GENE
product	I-GENE
)	O
,	O
which	O
is	O
an	O
intrinsically	O
unstable	O
nuclear	O
protein	O
,	O
is	O
metabolically	O
highly	O
stabilized	O
,	O
and	O
greatly	O
enhances	O
the	O
transforming	O
efficiency	O
of	O
NIH	O
3T3	O
cells	O
,	O
by	O
Mos	B-GENE
.	O

Cloning	O
,	O
sequencing	O
and	O
expression	O
of	O
the	O
3	B-GENE
-	I-GENE
phosphoglycerate	I-GENE
kinase	I-GENE
gene	I-GENE
of	O
Pyrococcus	O
woesei	O
in	O
Escherichia	O
coli	O
and	O
characterization	O
of	O
the	O
protein	O
.	O

We	O
sought	O
to	O
determine	O
whether	O
such	O
differences	O
in	O
polyadenylation	O
affect	O
the	O
steady	O
-	O
state	O
levels	O
of	O
DHFR	B-GENE
and	O
mRNAs	O
expressed	O
from	O
either	O
allele	O
and	O
,	O
in	O
a	O
more	O
general	O
sense	O
,	O
to	O
ask	O
whether	O
differences	O
in	O
3	O
'	O
end	O
RNA	O
processing	O
in	O
a	O
gene	O
containing	O
multiple	O
poly	O
(	O
A	O
)	O
sites	O
affects	O
the	O
final	O
level	O
of	O
gene	O
expression	O
.	O

The	O
finding	O
that	O
the	O
chimeric	B-GENE
TdT	I-GENE
:	O
:	O
Pol	B-GENE
beta	I-GENE
protein	I-GENE
possessed	O
significant	O
template	O
-	O
dependent	O
polymerase	O
activity	O
suggests	O
that	O
aa	O
1	O
-	O
60	O
of	O
Pol	B-GENE
beta	I-GENE
are	O
involved	O
in	O
template	O
utilization	O
during	O
the	O
polymerization	O
reaction	O
,	O
as	O
suggested	O
by	O
the	O
previous	O
finding	O
that	O
the	O
8	O
-	O
kDa	O
N	O
-	O
terminal	O
domain	O
of	O
Pol	B-GENE
beta	I-GENE
possesses	O
ssDNA	O
-	O
binding	O
activity	O
[	O
Kumar	O
et	O
al	O
.	O
,	O
J	O
.	O

The	O
average	O
values	O
were	O
199	O
and	O
424	O
revertants	O
/	O
g	O
for	O
the	O
hamburgers	O
and	O
hot	O
dogs	O
,	O
respectively	O
.	O

Cholangiography	O
was	O
performed	O
in	O
all	O
cases	O
and	O
classified	O
by	O
a	O
scoring	O
system	O
specifically	O
developed	O
for	O
pediatric	O
patients	O
.	O

In	O
Trial	O
1	O
,	O
eight	O
sows	O
were	O
allowed	O
to	O
farrow	O
naturally	O
(	O
d	O
114	O
,	O
NF	O
sows	O
)	O
and	O
eight	O
sows	O
were	O
induced	O
to	O
farrow	O
(	O
IF	O
sows	O
)	O
prematurely	O
by	O
injection	O
of	O
prostaglandin	O
F2	O
alpha	O
on	O
d	O
112	O
of	O
gestation	O
.	O

End	O
-	O
tidal	O
PO2	O
and	O
the	O
ratio	O
of	O
minute	O
ventilation	O
to	O
oxygen	O
consumption	O
(	O
VE	O
/	O
VO2	O
)	O
were	O
lower	O
while	O
PETCO2	O
was	O
higher	O
for	O
Hyp	O
(	O
P	O
<	O
or	O
=	O
0	O
.	O
01	O
)	O
.	O

These	O
results	O
suggested	O
that	O
NfxB	B-GENE
negatively	O
autoregulates	O
the	O
expression	O
of	O
nfxB	B-GENE
itself	O
.	O

A511	O
is	O
a	O
broad	O
-	O
host	O
-	O
range	O
,	O
virulent	O
myovirus	O
for	O
Listeria	O
monocytogenes	O
.	O

The	O
mechanism	O
of	O
peroxisome	O
proliferation	O
is	O
poorly	O
understood	O
.	O

If	O
NCR	O
-	O
sensitive	O
gene	O
expression	O
occurs	O
exclusively	O
by	O
this	O
pathway	O
,	O
as	O
has	O
been	O
thought	O
to	O
be	O
the	O
case	O
,	O
then	O
the	O
NCR	O
sensitivity	O
of	O
a	O
gene	O
'	O
s	O
expression	O
should	O
be	O
abolished	O
by	O
a	O
ure2	B-GENE
delta	I-GENE
mutation	I-GENE
.	O

The	O
single	O
-	O
stranded	O
DNA	O
Pur	B-GENE
alpha	I-GENE
recognition	I-GENE
element	I-GENE
disrupts	O
these	O
complexes	O
.	O

Association	O
of	O
human	B-GENE
Pur	I-GENE
alpha	I-GENE
with	O
the	O
retinoblastoma	B-GENE
protein	I-GENE
,	O
Rb	B-GENE
,	O
regulates	O
binding	O
to	O
the	O
single	O
-	O
stranded	O
DNA	O
Pur	B-GENE
alpha	I-GENE
recognition	I-GENE
element	I-GENE
.	O

The	O
insulin	B-GENE
-	O
induced	O
DNA	O
-	O
binding	O
complex	O
was	O
identified	O
as	O
the	O
p50	B-GENE
/	O
p65	B-GENE
heterodimer	O
.	O

Using	O
varying	O
conditions	O
,	O
three	O
distinct	O
complexes	O
were	O
shown	O
to	O
interact	O
specifically	O
with	O
the	O
NIP	B-GENE
region	I-GENE
,	O
although	O
only	O
one	O
correlates	O
with	O
repressor	O
activity	O
.	O

Exchange	O
of	O
the	O
LPL	B-GENE
and	O
HL	B-GENE
lids	O
resulted	O
in	O
a	O
reversal	O
of	O
the	O
phospholipase	B-GENE
/	O
neutral	O
lipase	B-GENE
ratio	O
,	O
establishing	O
the	O
important	O
role	O
of	O
this	O
region	O
in	O
mediating	O
substrate	O
specificity	O
.	O

The	O
interferon	B-GENE
-	O
inducible	O
protein	B-GENE
kinase	I-GENE
PKR	I-GENE
modulates	O
the	O
transcriptional	O
activation	O
of	O
immunoglobulin	B-GENE
kappa	I-GENE
gene	I-GENE
.	O

Truncated	O
forms	O
of	O
a	O
novel	O
yeast	O
protein	O
suppress	O
the	O
lethality	O
of	O
a	O
G	B-GENE
protein	I-GENE
alpha	I-GENE
subunit	I-GENE
deficiency	O
by	O
interacting	O
with	O
the	O
beta	O
subunit	O
.	O

Another	O
common	O
mutation	O
involved	O
amino	O
acids	O
that	O
are	O
thought	O
to	O
make	O
specific	O
contacts	O
with	O
DNA	O
.	O

Levels	O
of	O
TSG	B-GENE
-	I-GENE
14	I-GENE
protein	I-GENE
(	O
also	O
termed	O
PTX	B-GENE
-	I-GENE
3	I-GENE
)	O
become	O
elevated	O
in	O
the	O
serum	O
of	O
mice	O
and	O
humans	O
after	O
injection	O
with	O
bacterial	O
lipopolysaccharide	O
,	O
but	O
in	O
contrast	O
to	O
conventional	O
acute	O
phase	O
proteins	O
,	O
the	O
bulk	O
of	O
TSG	B-GENE
-	I-GENE
14	I-GENE
synthesis	O
in	O
the	O
intact	O
organism	O
occurs	O
outside	O
the	O
liver	O
.	O

The	O
mouse	B-GENE
beta	I-GENE
2	I-GENE
-	I-GENE
syntrophin	I-GENE
gene	I-GENE
(	O
>	O
33	O
kilobases	O
)	O
contains	O
seven	O
exons	O
,	O
all	O
of	O
which	O
have	O
homologues	O
at	O
the	O
corresponding	O
position	O
in	O
the	O
alpha	B-GENE
1	I-GENE
-	I-GENE
syntrophin	I-GENE
gene	I-GENE
.	O

Altogether	O
our	O
data	O
indicate	O
that	O
PEDF	B-GENE
belongs	O
to	O
the	O
subgroup	O
of	O
noninhibitory	O
serpins	B-GENE
and	O
that	O
its	O
N	O
-	O
terminal	O
region	O
confers	O
a	O
neurite	O
-	O
promoting	O
activity	O
to	O
the	O
protein	O
.	O

We	O
report	O
here	O
the	O
cloning	O
of	O
the	O
murine	O
p44	B-GENE
MAP	B-GENE
kinase	I-GENE
(	O
extracellular	B-GENE
signal	I-GENE
-	I-GENE
regulated	I-GENE
kinase	I-GENE
1	I-GENE
)	O
gene	O
,	O
the	O
determination	O
of	O
its	O
intron	O
/	O
exon	O
boundaries	O
,	O
and	O
the	O
characterization	O
of	O
its	O
promoter	O
.	O

It	O
contains	O
three	O
putative	O
TATA	O
boxes	O
far	O
upstream	O
of	O
the	O
main	O
start	O
sites	O
region	O
,	O
one	O
AP	B-GENE
-	I-GENE
1	I-GENE
box	I-GENE
,	O
one	O
AP	B-GENE
-	I-GENE
2	I-GENE
box	I-GENE
,	O
one	O
Malt	B-GENE
box	I-GENE
,	O
one	O
GAGA	O
box	O
,	O
one	O
half	O
serum	O
-	O
responsive	O
element	O
,	O
and	O
putative	O
binding	O
sites	O
for	O
Sp1	B-GENE
(	O
five	O
)	O
,	O
GC	B-GENE
-	I-GENE
rich	I-GENE
binding	I-GENE
factor	I-GENE
(	O
five	O
)	O
,	O
CTF	B-GENE
-	I-GENE
NF1	I-GENE
(	O
one	O
)	O
,	O
Myb	B-GENE
(	O
one	O
)	O
,	O
p53	B-GENE
(	O
two	O
)	O
,	O
Ets	B-GENE
-	I-GENE
1	I-GENE
(	O
one	O
)	O
,	O
NF	B-GENE
-	I-GENE
IL6	I-GENE
(	O
two	O
)	O
,	O
MyoD	B-GENE
(	O
two	O
)	O
,	O
Zeste	B-GENE
(	O
one	O
)	O
,	O
and	O
hepatocyte	B-GENE
nuclear	I-GENE
factor	I-GENE
-	I-GENE
5	I-GENE
(	O
one	O
)	O
.	O

We	O
conclude	O
that	O
this	O
new	O
measurement	O
technique	O
provides	O
an	O
easy	O
and	O
accurate	O
P0	O
.	O
1	O
measurement	O
using	O
standard	O
respiratory	O
equipment	O
when	O
tested	O
in	O
a	O
lung	O
model	O
.	O

Effects	O
of	O
verapamil	O
and	O
propranolol	O
on	O
early	O
afterdepolarizations	O
and	O
ventricular	O
arrhythmias	O
induced	O
by	O
epinephrine	O
in	O
congenital	O
long	O
QT	O
syndrome	O
.	O

Deletion	O
of	O
the	O
NF	B-GENE
-	I-GENE
IL6	I-GENE
beta	I-GENE
leucine	I-GENE
zipper	I-GENE
domain	I-GENE
also	O
greatly	O
diminished	O
the	O
interaction	O
between	O
these	O
two	O
proteins	O
.	O

After	O
cells	O
were	O
stably	O
transfected	O
with	O
CIITA	B-GENE
,	O
endogenous	O
MHC	B-GENE
class	I-GENE
II	I-GENE
genes	I-GENE
were	O
constitutively	O
expressed	O
,	O
and	O
MHC	B-GENE
class	I-GENE
II	I-GENE
promoters	I-GENE
,	O
delivered	O
by	O
transfection	O
,	O
were	O
actively	O
transcribed	O
in	O
CIITA	B-GENE
-	O
expressing	O
cells	O
.	O

Two	O
domains	O
of	O
EBNA2	B-GENE
defined	O
by	O
deletion	O
of	O
amino	O
acids	O
247	O
-	O
337	O
and	O
437	O
-	O
476	O
were	O
found	O
to	O
be	O
important	O
for	O
the	O
activation	O
of	O
both	O
promoters	O
,	O
while	O
two	O
different	O
domains	O
corresponding	O
to	O
residues	O
4	O
-	O
18	O
and	O
118	O
-	O
198	O
were	O
required	O
solely	O
for	O
the	O
LMP1	B-GENE
promoter	I-GENE
.	O

The	O
peak	O
velocities	O
of	O
the	O
atrial	O
systolic	O
waves	O
of	O
the	O
transmitral	O
and	O
pulmonary	O
venous	O
flow	O
velocities	O
(	O
A	O
and	O
PVA	O
,	O
respectively	O
)	O
and	O
first	O
systolic	O
wave	O
(	O
PVS1	O
)	O
of	O
pulmonary	O
venous	O
flow	O
,	O
durations	O
of	O
both	O
atrial	O
systolic	O
waves	O
,	O
and	O
amplitude	O
of	O
interatrial	O
septal	O
motion	O
during	O
atrial	O
systole	O
increased	O
significantly	O
ten	O
days	O
after	O
cardioversion	O
compared	O
with	O
those	O
measured	O
within	O
a	O
day	O
of	O
cardioversion	O
in	O
all	O
patients	O
except	O
the	O
5	O
patients	O
with	O
dilated	O
cardiomyopathy	O
.	O

These	O
results	O
suggest	O
that	O
low	O
concentrations	O
of	O
IL	B-GENE
-	I-GENE
1	I-GENE
beta	I-GENE
may	O
be	O
useful	O
for	O
nonsurgical	O
treatment	O
of	O
human	O
vitreous	O
hemorrhage	O
.	O

We	O
conclude	O
that	O
pancreatic	O
polypeptide	O
and	O
motilin	B-GENE
responses	O
to	O
a	O
meal	O
are	O
different	O
in	O
encopretic	O
children	O
than	O
in	O
children	O
in	O
the	O
control	O
group	O
.	O

Here	O
we	O
report	O
the	O
cloning	O
,	O
expression	O
,	O
and	O
biochemical	O
characterization	O
of	O
the	O
32	O
-	O
kDa	O
subunit	O
of	O
human	O
(	O
h	O
)	O
TFIID	B-GENE
,	O
termed	O
hTAFII32	B-GENE
.	O

Hemolytic	O
jaundice	O
due	O
to	O
G6PD	B-GENE
deficiency	O
causing	O
kernicterus	O
in	O
a	O
female	O
newborn	O
.	O

Two	O
transcripts	O
of	O
1	O
.	O
6	O
kb	O
and	O
5	O
.	O
8	O
kb	O
are	O
5	O
'	O
coterminal	O
and	O
may	O
both	O
encode	O
the	O
novel	O
glycoprotein	B-GENE
gene	I-GENE
EUS4	I-GENE
.	O

However	O
,	O
the	O
few	O
studies	O
that	O
address	O
antimicrobial	O
prophylaxis	O
in	O
bone	O
marrow	O
transplantation	O
have	O
not	O
always	O
shown	O
a	O
survival	O
benefit	O
.	O

The	O
fracture	O
groups	O
were	O
significantly	O
older	O
and	O
had	O
more	O
years	O
since	O
menopause	O
than	O
the	O
control	O
groups	O
.	O

In	O
addition	O
,	O
we	O
found	O
differences	O
in	O
the	O
binding	O
of	O
nuclear	O
factors	O
from	O
shoots	O
versus	O
from	O
roots	O
,	O
in	O
agreement	O
with	O
the	O
different	O
activities	O
of	O
the	O
promoter	O
in	O
these	O
two	O
organs	O
.	O

The	O
prevalence	O
and	O
incidence	O
of	O
human	O
immunodeficiency	O
virus	O
types	O
1	O
and	O
2	O
(	O
HIV	O
-	O
1	O
,	O
HIV	O
-	O
2	O
)	O
,	O
human	O
T	O
-	O
lymphotropic	O
virus	O
types	O
I	O
and	O
II	O
(	O
HTLV	O
-	O
I	O
/	O
II	O
)	O
,	O
and	O
syphilitic	O
infections	O
and	O
the	O
association	O
between	O
these	O
infections	O
were	O
determined	O
in	O
a	O
cohort	O
of	O
police	O
officers	O
in	O
Guinea	O
-	O
Bissau	O
.	O

We	O
now	O
show	O
that	O
the	O
BAT1	B-GENE
translation	I-GENE
product	I-GENE
is	O
the	O
homolog	O
of	O
the	O
rat	B-GENE
p47	I-GENE
nuclear	I-GENE
protein	I-GENE
,	O
the	O
WM6	B-GENE
Drosophila	I-GENE
gene	I-GENE
product	I-GENE
,	O
and	O
probably	O
also	O
Ce08102	B-GENE
of	O
Caenorhabditis	O
elegans	O
,	O
all	O
members	O
of	O
the	O
DEAD	B-GENE
protein	I-GENE
family	I-GENE
of	O
ATP	B-GENE
-	I-GENE
dependent	I-GENE
RNA	I-GENE
helicases	I-GENE
.	O

By	O
using	O
lacZ	B-GENE
fusions	I-GENE
,	O
it	O
was	O
possible	O
to	O
localize	O
the	O
DNA	O
sequences	O
required	O
to	O
mediate	O
nitrate	O
repression	O
to	O
the	O
pfl	B-GENE
promoter	I-GENE
-	I-GENE
regulatory	I-GENE
region	I-GENE
.	O

In	O
this	O
report	O
,	O
we	O
describe	O
the	O
characterization	O
of	O
two	O
early	O
class	B-GENE
II	I-GENE
flagellar	I-GENE
genes	I-GENE
contained	O
in	O
the	O
orfX	O
-	O
fliP	B-GENE
locus	O
.	O

Vestibular	O
adaptation	O
exercises	O
and	O
recovery	O
:	O
acute	O
stage	O
after	O
acoustic	O
neuroma	O
resection	O
.	O

There	O
were	O
no	O
significant	O
changes	O
in	O
either	O
the	O
fatty	O
acid	O
composition	O
of	O
biliary	O
lecithin	O
or	O
in	O
the	O
bile	O
acid	O
composition	O
of	O
bile	O
.	O

Although	O
further	O
studies	O
are	O
required	O
to	O
determine	O
the	O
precise	O
role	O
of	O
PEBP2	B-GENE
in	O
the	O
GM	B-GENE
-	I-GENE
CSF	I-GENE
promoter	I-GENE
activity	O
,	O
the	O
present	O
findings	O
suggested	O
the	O
importance	O
of	O
the	O
relative	O
ratio	O
of	O
different	O
PEBP2	B-GENE
isoforms	I-GENE
in	O
regulating	O
the	O
levels	O
of	O
the	O
promoter	O
activity	O
.	O

Benefits	O
of	O
obtaining	O
board	O
certification	O
in	O
pharmacotherapy	O
.	O

Basal	O
plasma	O
renin	B-GENE
activity	O
(	O
PRA	O
)	O
was	O
slightly	O
raised	O
prior	O
to	O
training	O
(	O
P	O
<	O
0	O
.	O
07	O
)	O
compared	O
to	O
the	O
controls	O
and	O
post	O
-	O
training	O
.	O

The	O
structural	O
gene	O
encoding	O
the	O
novel	O
lantibiotic	O
epilancin	B-GENE
K7	I-GENE
from	O
Staphylococcus	O
epidermidis	O
K7	O
was	O
cloned	O
and	O
its	O
nucleotide	O
sequence	O
was	O
determined	O
.	O

The	O
spectrum	O
of	O
phenotypes	O
caused	O
by	O
these	O
mutations	O
was	O
strikingly	O
different	O
than	O
mutations	O
in	O
the	O
adaptor	O
for	O
the	O
VP16	B-GENE
activation	I-GENE
domain	I-GENE
.	O

The	O
5	O
'	O
flanking	O
region	O
is	O
highly	O
GC	O
rich	O
,	O
with	O
multiple	O
CpG	O
doublets	O
,	O
and	O
contains	O
multiple	O
binding	O
sites	O
for	O
Sp1	B-GENE
.	O

To	O
discern	O
whether	O
these	O
disorders	O
of	O
GnRH	B-GENE
deficiency	O
are	O
associated	O
with	O
altered	O
melatonin	O
secretion	O
profiles	O
,	O
we	O
compared	O
untreated	O
young	O
males	O
IGD	O
(	O
n	O
=	O
7	O
)	O
and	O
DP	O
(	O
n	O
=	O
7	O
)	O
to	O
normal	O
pubertal	O
male	O
controls	O
(	O
n	O
=	O
6	O
)	O
.	O

Increased	O
blood	O
pressure	O
during	O
CyA	O
treatment	O
was	O
independent	O
of	O
circulating	O
ET	B-GENE
-	I-GENE
1	I-GENE
levels	O
.	O

Analysis	O
of	O
several	O
Tat	B-GENE
mutants	I-GENE
indicated	O
that	O
both	O
the	O
cysteine	O
-	O
rich	O
and	O
the	O
core	O
domains	O
of	O
this	O
transactivator	O
are	O
necessary	O
and	O
sufficient	O
to	O
activate	O
transcription	O
when	O
TBP	B-GENE
is	O
overexpressed	O
.	O

In	O
addition	O
,	O
depletion	O
of	O
Oct	B-GENE
-	I-GENE
1	I-GENE
from	O
the	O
nuclear	O
extract	O
by	O
using	O
Oct	B-GENE
-	I-GENE
1	I-GENE
-	O
specific	O
antiserum	O
or	O
a	O
sequence	O
-	O
specific	O
DNA	O
affinity	O
resin	O
decreased	O
in	O
vitro	O
transcription	O
from	O
the	O
wild	O
-	O
type	O
MMTV	O
promoter	O
to	O
a	O
level	O
identical	O
to	O
that	O
obtained	O
from	O
a	O
promoter	O
in	O
which	O
all	O
three	O
octamer	O
-	O
related	O
sequences	O
were	O
mutated	O
.	O

Transactivation	O
of	O
the	O
HIV	B-GENE
-	I-GENE
1	I-GENE
LTR	I-GENE
by	O
T3R	B-GENE
alpha	I-GENE
and	O
several	O
receptor	O
mutants	O
revealed	O
that	O
the	O
50	O
-	O
amino	O
-	O
acid	O
N	O
-	O
terminal	O
A	O
/	O
B	O
region	O
of	O
T3R	B-GENE
alpha	I-GENE
,	O
known	O
to	O
interact	O
with	O
the	O
basal	B-GENE
transcription	I-GENE
factor	I-GENE
TFIIB	I-GENE
,	O
is	O
critical	O
for	O
activation	O
of	O
both	O
Tat	B-GENE
-	O
dependent	O
and	O
Tat	B-GENE
-	O
independent	O
responsive	O
sequences	O
of	O
the	O
LTR	O
.	O

M	O
.	O
M	O
.	O
C	O
.	O
was	O
used	O
for	O
2	O
.	O
5	O
minutes	O
in	O
44	O
cases	O
(	O
20	O
HR	O
patients	O
,	O
24	O
LR	O
patients	O
)	O
,	O
and	O
for	O
5	O
minutes	O
in	O
66	O
cases	O
(	O
46	O
HR	O
patients	O
,	O
20	O
LR	O
patients	O
)	O
.	O

Finally	O
,	O
we	O
show	O
that	O
complexes	O
similar	O
to	O
the	O
C25	B-GENE
,	O
C30	B-GENE
and	O
C35	B-GENE
complexes	I-GENE
are	O
formed	O
by	O
rat	O
cortex	O
nuclear	O
extracts	O
and	O
the	O
SAA	O
element	O
in	O
EMSA	O
experiments	O
,	O
suggesting	O
the	O
relevance	O
of	O
our	O
in	O
vitro	O
observations	O
to	O
the	O
in	O
vivo	O
functioning	O
of	O
the	O
rat	B-GENE
APP	I-GENE
promoter	I-GENE
.	O

Oncological	O
,	O
clinical	O
and	O
psychological	O
aspects	O
are	O
evaluated	O
according	O
to	O
experience	O
accumulated	O
in	O
recent	O
years	O
,	O
with	O
immediate	O
and	O
delayed	O
reconstruction	O
,	O
carried	O
out	O
in	O
the	O
most	O
diverse	O
specialized	O
centers	O
.	O

The	O
analysis	O
of	O
the	O
prevalence	O
values	O
shows	O
clearly	O
that	O
the	O
global	O
MS	O
-	O
frequency	O
is	O
closer	O
related	O
to	O
the	O
geomagnetic	O
than	O
to	O
the	O
geographic	O
latitude	O
.	O

Diltiazem	O
caused	O
significant	O
decrease	O
in	O
the	O
ventricular	O
response	O
without	O
conversion	O
to	O
sinus	O
rhythm	O
.	O

Subhuman	O
primates	O
appear	O
to	O
be	O
more	O
sensitive	O
to	O
reproductive	O
and	O
other	O
adverse	O
effects	O
of	O
PCBs	O
than	O
humans	O
.	O

When	O
excluding	O
children	O
with	O
ocular	O
and	O
cerebral	O
pathology	O
,	O
32	O
matched	O
pairs	O
of	O
premature	O
and	O
control	O
children	O
remained	O
.	O

The	O
cryptococcal	B-GENE
antigen	I-GENE
test	O
was	O
positive	O
at	O
1	O
:	O
125	O
by	O
latex	O
agglutination	O
.	O

Functional	O
analysis	O
of	O
DNase	B-GENE
-	I-GENE
I	I-GENE
hypersensitive	O
sites	O
at	O
the	O
mouse	B-GENE
porphobilinogen	I-GENE
deaminase	I-GENE
gene	I-GENE
locus	I-GENE
.	O

These	O
transcripts	O
have	O
a	O
unique	O
5	O
'	O
untranslated	O
region	O
and	O
NH2	O
-	O
terminal	O
sequence	O
and	O
encode	O
a	O
predicted	O
protein	O
of	O
121	O
kD	O
.	O

Both	O
mu	B-GENE
and	I-GENE
gamma	I-GENE
2b	I-GENE
heavy	I-GENE
chain	I-GENE
genes	I-GENE
cause	O
this	O
feedback	O
inhibition	O
of	O
heavy	O
chain	O
gene	O
rearrangement	O
.	O

Purified	O
CarP	B-GENE
binds	O
in	O
vitro	O
to	O
the	O
carAB	B-GENE
control	I-GENE
region	I-GENE
and	O
protects	O
against	O
DNase	B-GENE
I	I-GENE
two	O
approximately	O
25	O
bp	O
long	O
stretches	O
,	O
one	O
of	O
which	O
is	O
located	O
just	O
downstream	O
of	O
the	O
GATC	O
sequence	O
.	O

They	O
include	O
genes	O
encoding	O
three	O
subunits	O
of	O
the	O
cytochrome	B-GENE
oxidase	I-GENE
(	O
cox1	B-GENE
to	I-GENE
3	I-GENE
)	O
,	O
apocytochrome	B-GENE
b	I-GENE
(	O
cob	B-GENE
)	O
,	O
seven	O
subunits	O
of	O
the	O
NADH	B-GENE
dehydrogenase	I-GENE
complex	I-GENE
(	O
nad1	B-GENE
to	I-GENE
6	I-GENE
,	O
nad4L	B-GENE
)	O
,	O
two	O
ATPase	B-GENE
subunits	O
(	O
atp6	B-GENE
and	O
atp9	B-GENE
)	O
,	O
three	O
ribosomal	O
RNAs	O
(	O
rrn5	B-GENE
,	O
srn	B-GENE
and	O
lrn	B-GENE
)	O
,	O
23	O
tRNAs	O
and	O
four	O
ribosomal	O
proteins	O
(	O
rps3	B-GENE
,	O
rps11	B-GENE
,	O
rps12	B-GENE
and	O
rpl16	B-GENE
)	O
.	O

From	O
day	O
10	O
,	O
a	O
significant	O
increase	O
in	O
platelet	O
count	O
was	O
observed	O
in	O
eight	O
of	O
the	O
ten	O
patients	O
treated	O
with	O
heparin	O
(	O
p	O
<	O
0	O
.	O
05	O
)	O
,	O
with	O
return	O
to	O
the	O
initial	O
value	O
after	O
heparin	O
cessation	O
in	O
six	O
of	O
the	O
responders	O
.	O

These	O
"	O
nucleocapsid	O
-	O
like	O
"	O
structures	O
were	O
readily	O
purified	O
by	O
density	O
gradient	O
centrifugation	O
.	O

Resources	O
for	O
helping	O
patients	O
to	O
quit	O
smoking	O
.	O

The	O
PEBP2	B-GENE
alpha	I-GENE
proteins	I-GENE
contain	O
a	O
128	O
-	O
amino	O
-	O
acid	O
(	O
aa	O
)	O
region	O
highly	O
homologous	O
to	O
the	O
Drosophila	B-GENE
melanogaster	I-GENE
segmentation	I-GENE
gene	I-GENE
runt	I-GENE
.	O

In	O
human	O
proliferative	O
cells	O
,	O
the	O
NADP	O
-	O
dependent	O
ME	B-GENE
activity	O
is	O
poorly	O
expressed	O
and	O
barely	O
inducible	O
by	O
thyroid	O
hormones	O
.	O

Based	O
on	O
previous	O
mapping	O
of	O
the	O
G	B-GENE
beta	I-GENE
gamma	I-GENE
binding	I-GENE
region	I-GENE
of	O
beta	B-GENE
ARK	I-GENE
,	O
and	O
conserved	O
residues	O
within	O
the	O
PH	B-GENE
domain	I-GENE
,	O
we	O
have	O
constructed	O
a	O
series	O
of	O
mutants	O
in	O
the	O
carboxyl	O
terminus	O
of	O
beta	B-GENE
ARK	I-GENE
in	O
order	O
to	O
determine	O
important	O
residues	O
involved	O
in	O
G	B-GENE
beta	I-GENE
gamma	I-GENE
and	O
PIP2	O
binding	O
.	O

To	O
dissect	O
these	O
mechanisms	O
,	O
wild	O
-	O
type	O
and	O
mutant	B-GENE
Raf	I-GENE
-	I-GENE
1	I-GENE
proteins	I-GENE
were	O
studied	O
in	O
an	O
in	O
vitro	O
system	O
with	O
purified	O
plasma	O
membranes	O
from	O
v	B-GENE
-	I-GENE
Ras	I-GENE
-	O
and	O
v	B-GENE
-	I-GENE
Src	I-GENE
-	O
transformed	O
cells	O
(	O
transformed	O
membranes	O
)	O
.	O

In	O
CV	O
-	O
1	O
cells	O
,	O
cotransfection	O
of	O
the	O
retinoid	B-GENE
and	I-GENE
estrogen	I-GENE
receptors	I-GENE
led	O
to	O
mutual	O
inhibition	O
of	O
the	O
other	O
'	O
s	O
activity	O
,	O
while	O
an	O
RA	O
-	O
dependent	O
inhibition	O
of	O
ER	B-GENE
activity	O
was	O
observed	O
in	O
breast	O
cancer	O
cells	O
.	O

D	O
.	O

It	O
was	O
proposed	O
that	O
the	O
synthetase	O
-	O
related	O
sequences	O
of	O
GCN2	B-GENE
stimulate	O
the	O
activity	O
of	O
the	O
kinase	O
by	O
interacting	O
directly	O
with	O
uncharged	O
tRNA	O
that	O
accumulates	O
during	O
amino	O
acid	O
limitation	O
.	O

However	O
,	O
unlike	O
Bcl	B-GENE
-	I-GENE
2	I-GENE
and	O
the	O
E1B	B-GENE
19K	I-GENE
proteins	I-GENE
,	O
which	O
completely	O
block	O
apoptosis	O
but	O
not	O
p53	B-GENE
-	O
dependent	O
growth	O
arrest	O
,	O
H	B-GENE
-	I-GENE
ras	I-GENE
expression	O
permitted	O
DNA	O
synthesis	O
and	O
cell	O
proliferation	O
in	O
the	O
presence	O
of	O
high	O
levels	O
of	O
wild	B-GENE
-	I-GENE
type	I-GENE
p53	I-GENE
.	O

To	O
compare	O
the	O
PAX3	B-GENE
and	O
putative	O
PAX3	B-GENE
-	O
FKHR	B-GENE
transactivation	O
domains	O
,	O
we	O
fused	O
C	O
-	O
terminal	O
test	O
fragments	O
to	O
the	O
heterologous	O
GAL4	B-GENE
DNA	I-GENE
-	I-GENE
binding	I-GENE
domain	I-GENE
and	O
tested	O
activation	O
of	O
a	O
reporter	O
gene	O
co	O
-	O
transfected	O
into	O
four	O
cell	O
types	O
.	O

All	O
subjects	O
were	O
submitted	O
to	O
ECG	O
and	O
arterial	O
blood	O
pressure	O
determination	O
and	O
were	O
assayed	O
for	O
TSH	B-GENE
,	O
thyroid	O
hormone	O
,	O
PRL	B-GENE
,	O
glucose	O
,	O
creatinine	O
,	O
nitrogen	O
,	O
glutamine	B-GENE
transaminase	I-GENE
,	O
cholesterol	O
and	O
triglycerides	O
plasma	O
levels	O
before	O
therapy	O
(	O
T0	O
)	O
,	O
after	O
30	O
treatment	O
days	O
(	O
T30	O
)	O
and	O
after	O
a	O
15	O
days	O
washout	O
(	O
T45	O
)	O
.	O

Acute	O
decrease	O
in	O
body	O
temperature	O
(	O
TB	O
)	O
lowered	O
PaCO2	O
(	O
32	O
.	O
5	O
to	O
14	O
.	O
5	O
mmHg	O
)	O
and	O
[	O
HCO3	O
-	O
]	O
a	O
(	O
24	O
.	O
20	O
mEq	O
/	O
L	O
to	O
17	O
.	O
56	O
mEq	O
/	O
L	O
)	O
,	O
increased	O
pHa	O
(	O
7	O
.	O
481	O
to	O
7	O
.	O
608	O
)	O
and	O
diminished	O
the	O
[	O
OH	O
-	O
]	O
/	O
[	O
H	O
+	O
]	O
ratio	O
,	O
but	O
had	O
no	O
significant	O
effect	O
on	O
[	O
SID	O
]	O
or	O
[	O
Atot	O
]	O
,	O
although	O
both	O
total	O
phosphorus	O
[	O
PT	O
]	O
and	O
inorganic	O
phosphate	O
[	O
Pi	O
]	O
increased	O
.	O

Hepatitis	O
B	O
vaccine	O
:	O
still	O
has	O
its	O
problems	O
.	O

Basal	O
promoter	O
activity	O
is	O
enhanced	O
by	O
a	O
functional	O
M1	O
domain	O
in	O
LHR	B-GENE
-	O
expressing	O
mouse	O
Leydig	O
tumor	O
cells	O
(	O
MLTC	O
)	O
but	O
not	O
in	O
non	O
-	O
expressing	O
CHO	O
cells	O
.	O

For	O
Al	O
,	O
the	O
exposure	O
to	O
1	O
.	O
36	O
mg	O
/	O
m3	O
during	O
the	O
shift	O
corresponded	O
to	O
a	O
urinary	O
concentration	O
at	O
the	O
end	O
of	O
the	O
shift	O
of	O
200	O
microgram	O
/	O
g	O
creatinine	O
.	O

Tumor	B-GENE
necrosis	I-GENE
factor	I-GENE
-	I-GENE
alpha	I-GENE
(	O
TNF	B-GENE
alpha	I-GENE
)	O
,	O
a	O
proinflammatory	O
cytokine	O
,	O
inhibits	O
cAMP	O
-	O
stimulated	O
testosterone	O
production	O
in	O
mouse	O
Leydig	O
cells	O
.	O

The	O
Drosophila	B-GENE
insulin	I-GENE
receptor	I-GENE
homolog	I-GENE
:	O
a	O
gene	O
essential	O
for	O
embryonic	O
development	O
encodes	O
two	O
receptor	O
isoforms	O
with	O
different	O
signaling	O
potential	O
.	O

We	O
show	O
here	O
that	O
RA	O
and	O
E1A	B-GENE
induce	O
phosphorylation	O
of	O
the	O
E1A	B-GENE
-	I-GENE
associated	I-GENE
300	I-GENE
kDa	I-GENE
protein	I-GENE
(	O
p300	B-GENE
)	O
during	O
the	O
differentiation	O
of	O
F9	O
cells	O
.	O

The	O
double	O
-	O
stranded	O
RNA	O
binding	O
domain	O
(	O
dsRBD	O
)	O
is	O
an	O
approximately	O
65	O
amino	O
acid	O
motif	O
that	O
is	O
found	O
in	O
a	O
variety	O
of	O
proteins	O
that	O
interact	O
with	O
double	O
-	O
stranded	O
(	O
ds	O
)	O
RNA	O
,	O
such	O
as	O
Escherichia	O
coli	O
RNase	B-GENE
III	I-GENE
and	O
the	O
dsRNA	B-GENE
-	I-GENE
dependent	I-GENE
kinase	I-GENE
,	O
PKR	B-GENE
.	O

SCA	B-GENE
was	O
resistant	O
to	O
inhibitors	O
of	O
serine	O
,	O
aspartyl	O
,	O
and	O
metalloproteases	B-GENE
,	O
but	O
it	O
was	O
sensitive	O
to	O
N	O
-	O
ethylmaleimide	O
.	O

Mutational	O
analysis	O
of	O
potential	O
activating	O
phosphorylation	O
sites	O
found	O
in	O
NIMA	B-GENE
,	O
NIM	B-GENE
-	I-GENE
1	I-GENE
,	O
and	O
related	O
protein	O
kinases	O
was	O
performed	O
on	O
NIMA	B-GENE
.	O

However	O
,	O
a	O
similar	O
mutation	O
of	O
a	O
leucine	O
residue	O
to	O
arginine	O
at	O
position	O
422	O
showed	O
no	O
alteration	O
of	O
heterodimerization	O
,	O
DNA	O
binding	O
,	O
or	O
transcriptional	O
activation	O
.	O

Expression	O
of	O
the	O
CYP11A1	B-GENE
gene	I-GENE
is	O
increased	O
by	O
hormones	O
,	O
such	O
as	O
adrenocorticotropin	B-GENE
and	O
luteinizing	B-GENE
hormone	I-GENE
,	O
as	O
well	O
as	O
by	O
a	O
number	O
of	O
growth	O
factors	O
,	O
suggesting	O
that	O
its	O
promoter	O
may	O
contain	O
regulatory	O
elements	O
that	O
respond	O
to	O
multiple	O
signal	O
transduction	O
pathways	O
.	O

NH2	O
-	O
and	O
COOH	O
-	O
terminal	O
deletion	O
analysis	O
revealed	O
that	O
both	O
the	O
PH	B-GENE
and	O
putative	O
guanine	B-GENE
nucleotide	I-GENE
exchange	I-GENE
factor	I-GENE
domains	I-GENE
are	O
required	O
,	O
but	O
the	O
zinc	O
butterfly	O
is	O
dispensable	O
,	O
for	O
transformation	O
.	O

The	O
objective	O
of	O
our	O
study	O
was	O
to	O
evaluate	O
the	O
age	O
,	O
sex	O
,	O
clinical	O
conditions	O
,	O
family	O
history	O
,	O
site	O
,	O
catheter	O
association	O
,	O
means	O
of	O
radiologic	O
evaluation	O
,	O
development	O
of	O
pulmonary	O
involvement	O
,	O
prevalence	O
of	O
antithrombin	B-GENE
III	I-GENE
,	O
protein	B-GENE
C	I-GENE
and	O
protein	B-GENE
S	I-GENE
deficiencies	O
,	O
and	O
lupus	O
anticoagulants	O
in	O
children	O
who	O
suffered	O
a	O
thrombotic	O
event	O
.	O

Harel	O
,	O
E	O
.	O
M	O
.	O

Radiotherapy	O
and	O
early	O
orchiectomy	O
in	O
stage	O
D1	O
prostatic	O
carcinoma	O

Structural	O
organization	O
and	O
developmental	O
expression	O
pattern	O
of	O
the	O
mouse	B-GENE
WD	I-GENE
-	I-GENE
repeat	I-GENE
gene	I-GENE
DMR	I-GENE
-	I-GENE
N9	I-GENE
immediately	O
upstream	O
of	O
the	O
myotonic	B-GENE
dystrophy	I-GENE
locus	I-GENE
.	O

The	O
ARX2	O
procedure	O
models	O
the	O
recorded	O
signal	O
as	O
the	O
sum	O
of	O
three	O
signals	O
:	O
(	O
a	O
)	O
the	O
background	O
EEG	O
activity	O
,	O
modelled	O
as	O
an	O
autoregressive	O
process	O
driven	O
by	O
a	O
white	O
noise	O
;	O
(	O
b	O
)	O
a	O
filtered	O
version	O
of	O
a	O
reference	O
signal	O
carrying	O
the	O
average	O
information	O
contained	O
in	O
each	O
sweep	O
;	O
(	O
c	O
)	O
a	O
signal	O
due	O
to	O
the	O
ocular	O
artefact	O
propagation	O
.	O

The	O
expression	O
of	O
the	O
gene	O
encoding	O
the	O
enzyme	O
(	O
CYP19	B-GENE
)	O
is	O
regulated	O
,	O
in	O
part	O
,	O
by	O
tissue	O
-	O
specific	O
promoters	O
through	O
the	O
use	O
of	O
alternative	O
-	O
splicing	O
mechanisms	O
.	O

CIITA	B-GENE
mRNA	I-GENE
is	O
normally	O
inducible	O
by	O
IFN	B-GENE
-	I-GENE
gamma	I-GENE
in	O
class	O
II	O
non	O
-	O
inducible	O
,	O
RB	O
-	O
defective	O
lines	O
,	O
and	O
in	O
one	O
line	O
,	O
re	O
-	O
expression	O
of	O
RB	B-GENE
has	O
no	O
effect	O
on	O
CIITA	B-GENE
mRNA	I-GENE
induction	O
levels	O
.	O

Consistent	O
with	O
the	O
protein	O
expression	O
data	O
,	O
V	B-GENE
beta	I-GENE
8	I-GENE
.	I-GENE
3	I-GENE
gene	I-GENE
transcripts	I-GENE
were	O
found	O
only	O
in	O
the	O
transgenic	O
lines	O
with	O
the	O
wild	O
-	O
type	O
promoter	O
.	O

One	O
month	O
after	O
the	O
DTaP	O
booster	O
vaccination	O
,	O
both	O
groups	O
had	O
6	O
-	O
to	O
40	O
-	O
fold	O
increases	O
in	O
serum	O
antibody	O
concentrations	O
to	O
all	O
antigens	O
tested	O
;	O
the	O
concentrations	O
against	O
the	O
three	O
pertussis	B-GENE
antigens	I-GENE
were	O
higher	O
in	O
the	O
DTaP	O
-	O
primed	O
children	O
(	O
p	O
<	O
0	O
.	O
05	O
)	O
.	O

Interestingly	O
,	O
this	O
amino	O
-	O
terminal	O
determinant	O
appears	O
not	O
to	O
reside	O
in	O
the	O
HSV	O
-	O
alpha	B-GENE
TIF	I-GENE
,	O
which	O
displays	O
no	O
independent	O
amino	O
-	O
terminal	O
activity	O
.	O

We	O
also	O
show	O
that	O
in	O
fusions	O
with	O
the	O
DNA	O
binding	O
domain	O
of	O
GAL4	B-GENE
,	O
full	O
activity	O
requires	O
the	O
entire	O
BHV	B-GENE
-	I-GENE
alpha	I-GENE
TIF	I-GENE
,	O
although	O
both	O
amino	O
and	O
carboxyl	O
termini	O
display	O
some	O
activity	O
on	O
their	O
own	O
.	O

To	O
investigate	O
the	O
potential	O
role	O
of	O
SP1	B-GENE
,	O
we	O
examined	O
nuclear	O
extracts	O
from	O
HCMV	O
-	O
infected	O
cells	O
.	O

Here	O
we	O
show	O
that	O
messenger	O
RNAs	O
encoding	O
trans	O
-	O
sialidases	O
containing	O
the	O
repeats	O
are	O
not	O
present	O
in	O
epimastigotes	O
but	O
are	O
abundant	O
in	O
trypomastigotes	O
.	O

From	O
May	O
1985	O
to	O
May	O
1989	O
,	O
126	O
necropsies	O
were	O
performed	O
at	O
the	O
Sao	O
Paulo	O
City	O
Morgue	O
on	O
cadavers	O
of	O
individuals	O
AIDS	O
victims	O
whose	O
unnatural	O
deaths	O
had	O
prompted	O
police	O
investigations	O
.	O

A	O
model	O
with	O
age	O
and	O
weight	O
described	O
the	O
best	O
fit	O
for	O
TBBMD	O
,	O
whereas	O
age	O
,	O
weight	O
,	O
and	O
height	O
described	O
the	O
best	O
fit	O
for	O
total	O
body	O
TBBMC	O
.	O

As	O
retinoic	O
acid	O
and	O
thyroid	O
hormone	O
are	O
frequently	O
involved	O
in	O
developmental	O
regulatory	O
processes	O
,	O
it	O
is	O
possible	O
that	O
this	O
element	O
may	O
be	O
important	O
in	O
the	O
process	O
of	O
islet	O
cell	O
differentiation	O
.	O

The	O
C	O
-	O
terminal	O
peptide	O
sequences	O
of	O
the	O
human	B-GENE
lymphocyte	I-GENE
-	I-GENE
specific	I-GENE
high	I-GENE
mobility	I-GENE
group	I-GENE
(	I-GENE
HMG	I-GENE
)	I-GENE
-	I-GENE
box	I-GENE
transcription	I-GENE
factor	I-GENE
TCF	I-GENE
-	I-GENE
1	I-GENE
are	O
determined	O
by	O
alternative	O
splice	O
mechanisms	O
affecting	O
the	O
exons	O
VIII	O
to	O
X	O
.	O

Thromboxane	O
B2	O
increased	O
(	O
97	O
+	O
/	O
-	O
105	O
versus	O
40	O
+	O
/	O
-	O
26	O
pg	O
/	O
ml	O
)	O
and	O
was	O
significantly	O
higher	O
during	O
heparin	O
free	O
hemodialysis	O
than	O
during	O
hemodialysis	O
with	O
heparin	O
(	O
p	O
=	O
0	O
.	O
01	O
,	O
Wilcoxon	O
matched	O
pairs	O
signed	O
rank	O
test	O
)	O
.	O

To	O
explore	O
the	O
mechanism	O
of	O
RSK	B-GENE
activation	O
,	O
a	O
cloned	O
human	O
RSK	B-GENE
cDNA	O
(	O
RSK3	B-GENE
)	O
was	O
used	O
to	O
generate	O
and	O
characterize	O
several	O
site	O
-	O
directed	O
RSK	B-GENE
mutants	I-GENE
;	O
K91A	O
(	O
N	O
-	O
Lys	O
,	O
NH2	O
-	O
terminal	O
ATP	O
-	O
binding	O
mutant	O
)	O
,	O
K444A	O
(	O
C	O
-	O
Lys	O
,	O
COOH	O
-	O
terminal	O
ATP	O
-	O
binding	O
mutant	O
)	O
,	O
N	O
/	O
C	O
-	O
Lys	O
(	O
double	O
ATP	O
-	O
binding	O
mutant	O
)	O
T570A	O
(	O
C	O
-	O
Thr	O
,	O
mutant	O
of	O
the	O
putative	O
MAPK	B-GENE
phosphorylation	O
site	O
in	O
subdomain	O
VIII	O
of	O
the	O
C	O
-	O
domain	O
)	O
,	O
S218A	O
(	O
N	O
-	O
Ser	O
,	O
mutant	O
of	O
the	O
corresponding	O
NH2	O
-	O
terminal	O
residue	O
)	O
.	O

In	O
contrast	O
,	O
both	O
C	O
-	O
Lys	O
and	O
C	O
-	O
Thr	O
retained	O
high	O
levels	O
of	O
kinase	O
activity	O
and	O
were	O
capable	O
of	O
responding	O
to	O
stimulation	O
.	O

Conversely	O
,	O
treatment	O
of	O
human	B-GENE
protein	I-GENE
-	I-GENE
tyrosine	I-GENE
phosphatase	I-GENE
alpha	I-GENE
-	O
overexpressing	O
cells	O
with	O
phenylarsine	O
oxide	O
led	O
to	O
a	O
loss	O
of	O
the	O
constitutive	O
NF	B-GENE
-	I-GENE
kappa	I-GENE
B	I-GENE
activity	O
.	O

A	O
TATA	O
-	O
less	O
promoter	O
containing	O
binding	O
sites	O
for	O
ubiquitous	O
transcription	O
factors	O
mediates	O
cell	O
type	O
-	O
specific	O
regulation	O
of	O
the	O
gene	O
for	O
transcription	B-GENE
enhancer	I-GENE
factor	I-GENE
-	I-GENE
1	I-GENE
(	O
TEF	B-GENE
-	I-GENE
1	I-GENE
)	O
.	O

Since	O
electrical	O
stimulation	O
of	O
neurones	O
may	O
activate	O
not	O
only	O
cell	O
bodies	O
but	O
also	O
neuronal	O
fibres	O
,	O
this	O
study	O
aimed	O
to	O
test	O
a	O
selectively	O
cholinergic	O
neurochemical	O
stimulation	O
of	O
the	O
rat	O
substantia	O
innominata	O
(	O
SI	O
)	O
by	O
the	O
local	O
microinjection	O
of	O
carbachol	O
;	O
the	O
effects	O
of	O
this	O
acetylcholine	O
agonist	O
were	O
compared	O
with	O
glutamate	O
.	O

We	O
purified	O
both	O
proteins	O
from	O
human	O
platelet	O
membranes	O
using	O
DEAE	O
-	O
Sepharose	O
chromatography	O
followed	O
by	O
mAb	B-GENE
F11	I-GENE
affinity	O
chromatography	O
.	O

The	O
homeobox	B-GENE
gene	I-GENE
ATK1	I-GENE
of	O
Arabidopsis	O
thaliana	O
is	O
expressed	O
in	O
the	O
shoot	O
apex	O
of	O
the	O
seedling	O
and	O
in	O
flowers	O
and	O
inflorescence	O
stems	O
of	O
mature	O
plants	O
.	O

The	O
most	O
likely	O
explanation	O
for	O
this	O
is	O
that	O
gold	O
principally	O
accumulates	O
in	O
the	O
Kupffer	O
cells	O
and	O
renal	O
cortex	O
and	O
these	O
cells	O
do	O
not	O
express	O
Type	B-GENE
I	I-GENE
deiodinase	I-GENE
.	O

These	O
results	O
suggest	O
that	O
different	O
models	O
of	O
intestinal	O
ischemia	O
have	O
different	O
cytokine	O
profiles	O
and	O
that	O
the	O
early	O
TNF	B-GENE
response	O
associated	O
with	O
SMA	O
occlusion	O
model	O
is	O
primarily	O
due	O
to	O
the	O
laparotomy	O
.	O

Our	O
evidence	O
derives	O
from	O
three	O
principal	O
observations	O
:	O
1	O
)	O
a	O
transfection	O
construct	O
containing	O
only	O
122	O
nucleotides	O
(	O
nt	O
)	O
of	O
promoter	O
1	O
and	O
328	O
nt	O
of	O
the	O
5	O
'	O
-	O
UTR	O
retained	O
full	O
PGE2	O
-	O
stimulated	O
reporter	O
expression	O
;	O
2	O
)	O
maximal	O
PGE2	O
-	O
driven	O
reporter	O
expression	O
required	O
the	O
presence	O
of	O
nt	O
196	O
to	O
328	O
of	O
exon	O
1	O
when	O
tested	O
within	O
the	O
context	O
of	O
IGF	B-GENE
-	I-GENE
I	I-GENE
promoter	I-GENE
1	I-GENE
;	O
3	O
)	O
cotransfection	O
of	O
IGF	B-GENE
-	I-GENE
I	I-GENE
promoter	I-GENE
-	O
luciferase	B-GENE
-	O
reporter	O
constructs	O
with	O
a	O
plasmid	O
encoding	O
the	O
alpha	O
-	O
isoform	O
of	O
the	O
catalytic	O
subunit	O
of	O
murine	B-GENE
cAMP	I-GENE
-	I-GENE
dependent	I-GENE
protein	I-GENE
kinase	I-GENE
(	O
PKA	B-GENE
)	O
produced	O
results	O
comparable	O
to	O
those	O
seen	O
with	O
PGE2	O
treatment	O
,	O
whereas	O
cotransfection	O
with	O
a	O
plasmid	O
encoding	O
a	O
mutant	O
regulatory	O
subunit	O
of	O
PKA	B-GENE
that	O
cannot	O
bind	O
cAMP	O
blocked	O
PGE2	O
-	O
induced	O
reporter	O
expression	O
.	O

The	O
changes	O
after	O
treatment	O
were	O
observed	O
chiefly	O
by	O
electromyography	O
while	O
sensory	O
and	O
motor	O
improvement	O
were	O
also	O
recorded	O
as	O
auxiliary	O
indicators	O
.	O

Band	O
-	O
shift	O
assays	O
and	O
DNase	B-GENE
I	I-GENE
footprinting	O
experiments	O
using	O
purified	O
42	O
kDa	O
repressor	O
isoform	O
confirmed	O
that	O
CIRs	B-GENE
5	I-GENE
and	I-GENE
6	I-GENE
were	O
indeed	O
the	O
targets	O
for	O
binding	O
of	O
this	O
protein	O
.	O

Retransformation	O
of	O
uvsH77	B-GENE
mutants	I-GENE
with	O
the	O
rescued	O
cosmids	O
from	O
the	O
MMS	O
-	O
resistant	O
transformants	O
resulted	O
in	O
restoration	O
of	O
both	O
UV	O
and	O
MMS	O
resistance	O
to	O
wild	O
-	O
type	O
levels	O
.	O

Furthermore	O
,	O
this	O
element	O
confers	O
p53	B-GENE
induction	O
to	O
the	O
otherwise	O
nonresponsive	O
adenovirus	O
major	O
late	O
promoter	O
.	O

In	O
flies	O
,	O
the	O
dShc	B-GENE
protein	I-GENE
physically	O
associates	O
with	O
the	O
activated	O
Drosophila	B-GENE
epidermal	I-GENE
growth	I-GENE
factor	I-GENE
receptor	I-GENE
homolog	I-GENE
(	O
DER	B-GENE
)	O
and	O
is	O
inducibly	O
phosphorylated	O
on	O
tyrosine	O
by	O
DER	B-GENE
.	O

A	O
potential	O
binding	O
site	O
for	O
the	O
dShc	B-GENE
PTB	O
domain	O
is	O
located	O
at	O
Tyr	O
-	O
1228	O
of	O
DER	B-GENE
.	O

A	O
Drosophila	B-GENE
shc	I-GENE
gene	I-GENE
product	I-GENE
is	O
implicated	O
in	O
signaling	O
by	O
the	O
DER	B-GENE
receptor	I-GENE
tyrosine	I-GENE
kinase	I-GENE
.	O

This	O
inhibition	O
can	O
be	O
overcome	O
by	O
mutating	O
either	O
the	O
exon	O
'	O
s	O
5	O
'	O
or	O
3	O
'	O
splice	O
site	O
to	O
make	O
it	O
correspond	O
more	O
closely	O
to	O
the	O
relevant	O
consensus	O
sequence	O
.	O

Biochemical	O
analysis	O
shows	O
that	O
Ssm1p	B-GENE
is	O
a	O
structural	O
protein	O
that	O
forms	O
part	O
of	O
the	O
largest	O
60S	B-GENE
ribosomal	I-GENE
subunit	I-GENE
,	O
which	O
does	O
not	O
exist	O
in	O
a	O
pool	O
of	O
free	O
proteins	O
.	O

In	O
wild	O
-	O
type	O
cells	O
,	O
SSM1b	B-GENE
transcripts	I-GENE
accumulate	O
to	O
twice	O
the	O
level	O
of	O
SSM1a	B-GENE
transcripts	I-GENE
,	O
suggesting	O
that	O
SSM1b	B-GENE
is	O
responsible	O
for	O
the	O
majority	O
of	O
the	O
Ssm1p	B-GENE
pool	O
.	O

Northern	O
blot	O
analysis	O
revealed	O
the	O
expression	O
of	O
LIMK	B-GENE
-	I-GENE
1	I-GENE
mRNA	I-GENE
predominantly	O
in	O
the	O
brain	O
and	O
the	O
expression	O
of	O
LIMK	B-GENE
-	I-GENE
2	I-GENE
mRNA	I-GENE
in	O
various	O
tissues	O
in	O
the	O
rat	O
.	O

On	O
the	O
basis	O
of	O
this	O
anatomic	O
concept	O
,	O
the	O
brachioplasty	O
procedure	O
was	O
modified	O
to	O
provide	O
secure	O
anchoring	O
of	O
the	O
arm	O
flap	O
to	O
the	O
axillary	O
fascia	O
along	O
with	O
strong	O
superficial	O
fascial	O
system	O
repair	O
of	O
incisions	O
,	O
reducing	O
the	O
risk	O
of	O
widening	O
or	O
migration	O
of	O
scars	O
and	O
unnatural	O
contours	O
.	O

Furthermore	O
,	O
microinjection	O
of	O
dominant	O
negative	O
forms	O
of	O
Rac	B-GENE
and	O
Cdc42	B-GENE
or	O
of	O
the	O
Rho	B-GENE
inhibitor	O
C3	B-GENE
transferase	I-GENE
blocked	O
serum	O
-	O
induced	O
DNA	O
synthesis	O
.	O

INF	B-GENE
-	I-GENE
alpha	I-GENE
therapy	O
has	O
been	O
a	O
major	O
development	O
in	O
the	O
treatment	O
of	O
CML	O
.	O

A	O
series	O
of	O
amino	O
terminal	O
deletion	O
mutants	O
(	O
d10	O
,	O
d20	O
,	O
d27	O
,	O
d31	O
,	O
d40	O
,	O
d44	O
,	O
and	O
d73	O
)	O
were	O
compared	O
for	O
processing	O
,	O
cell	O
surface	O
expression	O
,	O
and	O
maintenance	O
of	O
their	O
biological	O
attributes	O
by	O
recombinant	O
expression	O
of	O
mutant	O
genes	O
using	O
a	O
plasmid	O
vector	O
(	O
pcDL	O
-	O
SR	O
alpha	O
-	O
296	O
)	O
in	O
CV	O
-	O
1	O
and	O
HeLa	O
cells	O
.	O

Intrathecal	O
acetyl	B-GENE
cholinesterase	I-GENE
inhibitors	O
produce	O
analgesia	O
that	O
is	O
synergistic	O
with	O
morphine	O
and	O
clonidine	O
in	O
rats	O
.	O

After	O
determining	O
isoflurane	O
MAC	O
in	O
triplicate	O
,	O
birds	O
were	O
given	O
a	O
mu	O
-	O
opioid	O
agonist	O
(	O
morphine	O
,	O
n	O
=	O
9	O
)	O
or	O
a	O
kappa	O
-	O
opioid	O
agonist	O
(	O
U50488H	O
,	O
n	O
=	O
9	O
)	O
.	O

Max	B-GENE
was	O
constantly	O
transcribed	O
at	O
a	O
relatively	O
low	O
level	O
during	O
cell	O
cycle	O
progression	O
.	O

The	O
yeast	O
enzyme	O
was	O
6	O
-	O
fold	O
slower	O
than	O
the	O
mammalian	O
enzymes	O
,	O
which	O
made	O
it	O
amenable	O
to	O
pre	O
-	O
steady	O
-	O
state	O
stopped	O
-	O
flow	O
spectroscopic	O
kinetic	O
analysis	O
at	O
30	O
degrees	O
C	O
and	O
pH	O
6	O
.	O
0	O
.	O

Key	O
areas	O
of	O
the	O
selection	O
process	O
including	O
medical	O
and	O
surgical	O
alternatives	O
to	O
transplantation	O
,	O
the	O
composition	O
of	O
the	O
transplant	O
work	O
-	O
up	O
,	O
specific	O
inclusion	O
criteria	O
as	O
well	O
as	O
specific	O
psychosocial	O
factors	O
and	O
specific	O
disease	O
etiologies	O
and	O
co	O
-	O
morbidities	O
that	O
might	O
represent	O
contraindications	O
were	O
extensively	O
reviewed	O
.	O

In	O
both	O
shoots	O
and	O
roots	O
,	O
GT	B-GENE
-	I-GENE
2	I-GENE
protein	I-GENE
is	O
undetectable	O
in	O
meristematic	O
tissue	O
but	O
becomes	O
expressed	O
at	O
later	O
stages	O
of	O
cellular	O
development	O
,	O
consistent	O
with	O
a	O
role	O
in	O
contributing	O
to	O
the	O
pattern	O
of	O
phytochrome	B-GENE
A	I-GENE
gene	I-GENE
expression	O
.	O

Comparative	O
DNA	O
sequence	O
analysis	O
showed	O
the	O
Genethon	O
microsatellite	B-GENE
D19S596	I-GENE
lies	O
2	O
.	O
2	O
kb	O
downstream	O
of	O
the	O
coding	O
region	O
of	O
FUT1	B-GENE
,	O
indicating	O
that	O
the	O
cluster	O
comprising	O
the	O
closely	O
linked	O
FUT1	B-GENE
and	O
FUT2	B-GENE
genes	I-GENE
is	O
located	O
4	O
cM	O
distal	O
to	O
D19S412	B-GENE
(	O
lod	O
score	O
13	O
.	O
7	O
)	O
and	O
9	O
cM	O
proximal	O
to	O
D19S571	B-GENE
(	O
lod	O
score	O
11	O
.	O
7	O
)	O
.	O

We	O
conclude	O
that	O
transcription	O
activation	O
by	O
LEF	B-GENE
-	I-GENE
1	I-GENE
in	O
vitro	O
is	O
a	O
chromatin	O
-	O
dependent	O
process	O
that	O
requires	O
a	O
functional	O
trans	O
-	O
activation	O
domain	O
in	O
addition	O
to	O
the	O
HMG	B-GENE
domain	I-GENE
.	O

TH	B-GENE
-	O
SH3	B-GENE
binding	O
in	O
vitro	O
is	O
abolished	O
by	O
specific	O
,	O
single	O
amino	O
acid	O
substitutions	O
within	O
the	O
Btk	B-GENE
TH	B-GENE
domain	I-GENE
or	O
the	O
Fyn	B-GENE
SH3	B-GENE
domain	I-GENE
.	O

These	O
results	O
indicate	O
that	O
K	B-GENE
-	I-GENE
glypican	I-GENE
is	O
a	O
novel	O
GPI	B-GENE
-	I-GENE
anchored	I-GENE
HSPG	I-GENE
involved	O
in	O
embryonic	O
development	O
.	O

Protein	B-GENE
S	I-GENE
levels	O
were	O
virtually	O
undetectable	O
at	O
the	O
time	O
of	O
admission	O
and	O
failed	O
to	O
respond	O
to	O
infusions	O
of	O
fresh	O
frozen	O
plasma	O
,	O
despite	O
correction	O
of	O
other	O
procoagulant	O
and	O
anticoagulant	O
factors	O
.	O

The	O
test	O
was	O
not	O
performed	O
in	O
3923	O
patients	O
because	O
of	O
contraindications	O
.	O

The	O
ubiquitous	O
transcription	O
factor	O
Oct	B-GENE
-	I-GENE
1	I-GENE
forms	O
complexes	O
with	O
an	O
octamer	O
motif	O
present	O
within	O
FPIV	O
by	O
gel	O
shift	O
analysis	O
with	O
liver	O
and	O
kidney	O
extracts	O
,	O
making	O
Oct	B-GENE
-	I-GENE
1	I-GENE
an	O
intriguing	O
candidate	O
for	O
partnership	O
in	O
androgen	O
regulation	O
.	O

We	O
used	O
deletion	O
analysis	O
and	O
transfection	O
assays	O
with	O
reporter	O
gene	O
constructs	O
to	O
examine	O
the	O
transcription	O
control	O
elements	O
in	O
the	O
5	O
'	O
flanking	O
region	O
of	O
the	O
human	B-GENE
EpoR	I-GENE
gene	I-GENE
.	O

Incubation	O
of	O
the	O
purified	O
fusion	O
proteins	O
with	O
[	O
gamma	O
-	O
32P	O
]	O
ATP	O
in	O
an	O
in	O
vitro	O
assay	O
showed	O
that	O
both	O
proteins	O
were	O
capable	O
of	O
autophosphorylation	O
.	O

The	O
character	O
of	O
specific	O
immune	O
response	O
in	O
101	O
immunized	O
children	O
and	O
in	O
12	O
adults	O
belonging	O
to	O
a	O
high	O
risk	O
group	O
with	O
respect	O
to	O
VHB	O
.	O

After	O
nadolol	O
,	O
heart	O
rate	O
decreased	O
(	O
-	O
22	O
+	O
/	O
-	O
8	O
%	O
)	O
,	O
and	O
so	O
did	O
PBV	O
and	O
PBF	O
(	O
8	O
.	O
8	O
+	O
/	O
-	O
3	O
.	O
4	O
vs	O
.	O

Adrenergic	O
system	O
activation	O
,	O
indicated	O
by	O
metanephrine	O
/	O
epinephrine	O
ratio	O
,	O
increased	O
with	O
time	O
in	O
losing	O
males	O
,	O
except	O
that	O
after	O
one	O
month	O
of	O
cohabitation	O
,	O
turnover	O
returned	O
to	O
levels	O
that	O
equaled	O
those	O
of	O
control	O
animals	O
.	O

Transabdominal	O
repair	O
of	O
type	O
IV	O
thoraco	O
-	O
abdominal	O
aortic	O
aneurysms	O
.	O

A	O
.	O

Primer	O
extension	O
and	O
cDNA	O
cloning	O
were	O
used	O
to	O
isolate	O
the	O
complete	O
5	O
'	O
end	O
of	O
the	O
Nramp1	B-GENE
mRNA	I-GENE
.	O

Primer	O
extension	O
and	O
S1	B-GENE
nuclease	I-GENE
mapping	O
experiments	O
were	O
used	O
to	O
locate	O
the	O
transcription	O
initiation	O
site	O
of	O
Nramp1	B-GENE
and	O
revealed	O
the	O
presence	O
of	O
one	O
major	O
and	O
several	O
minor	O
initiation	O
sites	O
.	O

Sequence	O
analysis	O
of	O
the	O
5	O
'	O
-	O
flanking	O
region	O
of	O
the	O
CD69	B-GENE
gene	I-GENE
revealed	O
the	O
presence	O
of	O
a	O
potential	O
TATA	O
element	O
30	O
base	O
pairs	O
upstream	O
of	O
the	O
major	O
transcription	O
initiation	O
site	O
and	O
several	O
putative	O
binding	O
sequences	O
for	O
inducible	O
transcription	O
factors	O
(	O
NF	B-GENE
-	I-GENE
kappa	I-GENE
B	I-GENE
,	O
Egr	B-GENE
-	I-GENE
1	I-GENE
,	O
AP	B-GENE
-	I-GENE
1	I-GENE
)	O
,	O
which	O
might	O
mediate	O
the	O
inducible	O
expression	O
of	O
this	O
gene	O
.	O

The	O
plasmin	B-GENE
-	I-GENE
derived	I-GENE
D	I-GENE
(	I-GENE
approximately	I-GENE
105	I-GENE
-	I-GENE
kDa	I-GENE
)	I-GENE
product	I-GENE
,	O
however	O
,	O
could	O
be	O
cross	O
-	O
linked	O
into	O
DD	O
dimers	O
.	O

All	O
clinical	O
isolates	O
were	O
concomitantly	O
tested	O
by	O
disk	O
diffusion	O
and	O
agar	O
dilution	O
procedures	O
as	O
outlined	O
by	O
the	O
National	O
Committee	O
for	O
Clinical	O
Laboratory	O
Standards	O
.	O

IgE	B-GENE
levels	O
showed	O
higher	O
values	O
compared	O
to	O
normal	O
individuals	O
and	O
IgE	B-GENE
levels	O
were	O
higher	O
in	O
children	O
groups	O
than	O
in	O
adults	O
regardless	O
of	O
the	O
intensity	O
of	O
infection	O
.	O

Tissue	O
-	O
specific	O
expression	O
of	O
the	O
tmy	B-GENE
-	I-GENE
1	I-GENE
gene	I-GENE
was	O
determined	O
by	O
microinjection	O
of	O
a	O
promoter	B-GENE
/	I-GENE
lacZ	I-GENE
fusion	I-GENE
gene	I-GENE
and	O
with	O
immunohistochemistry	O
by	O
using	O
affinity	O
-	O
purified	O
tissue	B-GENE
-	I-GENE
specific	I-GENE
anti	I-GENE
-	I-GENE
tropomyosins	I-GENE
.	O

The	O
nucleotide	O
sequence	O
of	O
the	O
chloroplast	O
(	O
cp	O
)	O
DNA	O
from	O
maize	O
(	O
Zea	O
mays	O
)	O
has	O
been	O
completed	O
.	O

Investigation	O
of	O
the	O
control	O
of	O
coronavirus	O
subgenomic	O
mRNA	O
transcription	O
by	O
using	O
T7	O
-	O
generated	O
negative	O
-	O
sense	O
RNA	O
transcripts	O
.	O

Initiation	O
of	O
translation	O
of	O
the	O
human	O
hepatitis	O
C	O
virus	O
(	O
HCV	O
)	O
RNA	O
genome	O
occurs	O
by	O
internal	O
ribosome	O
entry	O
into	O
the	O
5	O
'	O
noncoding	O
region	O
(	O
5	O
'	O
NCR	O
)	O
in	O
a	O
cap	O
-	O
independent	O
manner	O
.	O

Mean	O
longitudinal	O
extension	O
of	O
the	O
epidural	O
lesion	O
was	O
2	O
.	O
6	O
vertebral	O
segments	O
.	O

The	O
association	O
of	O
p255	B-GENE
with	O
splicing	O
complexes	O
is	O
suggested	O
by	O
the	O
finding	O
that	O
mAb	B-GENE
CC3	I-GENE
can	O
inhibit	O
in	O
vitro	O
splicing	O
and	O
immunoprecipitate	O
pre	O
-	O
messenger	O
RNA	O
and	O
splicing	O
products	O
.	O

L	O
-	O
735	O
,	O
524	O
free	O
base	O
or	O
sulfate	O
salt	O
was	O
administered	O
orally	O
as	O
suspension	O
,	O
solution	O
or	O
in	O
solid	O
dosage	O
forms	O
to	O
fasted	O
or	O
fed	O
Beagle	O
dogs	O
.	O

Doppler	O
ultrasound	O
studies	O
of	O
long	O
-	O
term	O
follow	O
-	O
up	O
of	O
children	O
with	O
hemolytic	O
-	O
uremic	O
syndrome	O

Thus	O
,	O
endemic	O
cumlations	O
of	O
hepatitis	O
A	O
diseases	O
are	O
possible	O
.	O

(	O
1991	O
)	O
.	O

The	O
properties	O
of	O
the	O
phi	O
29	O
SSB	B-GENE
-	I-GENE
ssDNA	I-GENE
complex	O
are	O
described	O
.	O

This	O
shows	O
that	O
the	O
characteristically	O
diffuse	O
banding	O
pattern	O
of	O
plant	O
nuclear	O
proteins	O
interacting	O
with	O
the	O
G	O
-	O
box	O
is	O
also	O
observed	O
in	O
a	O
binding	O
assay	O
using	O
only	O
one	O
recombinant	B-GENE
GBF	I-GENE
.	O

We	O
studied	O
120	O
male	O
and	O
42	O
female	O
patients	O
with	O
early	O
CAD	O
who	O
were	O
unrelated	O
to	O
each	O
other	O
but	O
were	O
from	O
families	O
in	O
which	O
at	O
least	O
one	O
other	O
sibling	O
had	O
early	O
CAD	O
.	O

The	O
physical	O
linkage	O
of	O
the	O
FHR2	B-GENE
and	O
the	O
factor	B-GENE
H	I-GENE
genes	I-GENE
provides	O
additional	O
evidence	O
for	O
a	O
close	O
relatedness	O
of	O
complement	B-GENE
factor	I-GENE
H	I-GENE
and	O
the	O
factor	B-GENE
H	I-GENE
-	I-GENE
related	I-GENE
proteins	I-GENE
.	O

Genomic	O
structure	O
and	O
chromosomal	O
location	O
of	O
the	O
mouse	B-GENE
pre	I-GENE
-	I-GENE
T	I-GENE
-	I-GENE
cell	I-GENE
receptor	I-GENE
alpha	I-GENE
gene	I-GENE
.	O

The	O
third	O
domain	O
had	O
the	O
motif	O
of	O
a	O
cAMP	O
response	O
element	O
(	O
CRE	O
)	O
.	O

The	O
tyrosine	O
-	O
phosphorylated	O
state	O
of	O
CAK	B-GENE
beta	I-GENE
was	O
not	O
reduced	O
on	O
trypsinization	O
,	O
nor	O
enhanced	O
in	O
response	O
to	O
plating	O
3Y1	O
cells	O
onto	O
fibronectin	B-GENE
.	O

Our	O
results	O
suggest	O
that	O
while	O
many	O
muscle	O
gene	O
E	O
-	O
boxes	O
are	O
capable	O
of	O
binding	O
the	O
previously	O
characterized	O
spectrum	O
of	O
MDF	B-GENE
/	I-GENE
bH	I-GENE
-	I-GENE
L	I-GENE
-	I-GENE
H	I-GENE
heterodimers	I-GENE
in	O
vitro	O
,	O
MCK	B-GENE
-	I-GENE
L	I-GENE
type	O
E	O
-	O
boxes	O
probably	O
bind	O
qualitatively	O
different	O
factors	O
in	O
vivo	O
.	O

A	O
single	O
-	O
case	O
experimental	O
ABAB	O
multiple	O
baseline	O
design	O
was	O
employed	O
to	O
test	O
for	O
treatment	O
effectiveness	O
.	O

These	O
clones	O
were	O
found	O
to	O
share	O
a	O
common	O
domain	O
encoded	O
by	O
p	O
(	O
CA	O
)	O
n	O
repeats	O
;	O
a	O
simple	O
sequence	O
length	O
polymorphism	O
(	O
SSLP	O
)	O
.	O

In	O
one	O
glioblastoma	O
cell	O
line	O
,	O
a	O
Shc	B-GENE
-	O
associated	O
p190	B-GENE
was	O
identified	O
as	O
the	O
activated	O
PDGFR	B-GENE
.	O

The	O
serum	O
concentration	O
of	O
iP	O
before	O
dialysis	O
(	O
HD	O
)	O
was	O
on	O
average	O
3	O
.	O
06	O
(	O
+	O
/	O
-	O
0	O
.	O
81	O
)	O
mmol	O
/	O
l	O
and	O
D	O
was	O
on	O
average	O
55	O
.	O
6	O
(	O
+	O
/	O
-	O
10	O
.	O
0	O
)	O
mmol	O
.	O

A	O
significant	O
correlation	O
between	O
a	O
number	O
of	O
functional	O
parameters	O
of	O
gastric	O
secretion	O
,	O
incretion	O
and	O
histological	O
changes	O
of	O
gastric	O
mucosa	O
was	O
found	O
in	O
patients	O
with	O
chronic	O
gastritis	O
.	O

The	O
TAF	O
factor	O
appears	O
to	O
be	O
particularly	O
significant	O
in	O
OCD	O
.	O

RNase	B-GENE
protection	O
analyses	O
indicate	O
that	O
either	O
61	B-GENE
-	I-GENE
kDa	I-GENE
CaM	I-GENE
PDE	I-GENE
mRNA	I-GENE
or	O
structurally	O
related	O
transcripts	O
encoding	O
different	O
CaM	B-GENE
PDE	I-GENE
isoforms	I-GENE
are	O
expressed	O
in	O
a	O
tissue	O
-	O
specific	O
manner	O
.	O

Little	O
or	O
no	O
protection	O
was	O
detected	O
using	O
adrenal	O
cortex	O
,	O
adrenal	O
medulla	O
,	O
liver	O
,	O
kidney	O
cortex	O
,	O
spleen	O
,	O
or	O
T	O
-	O
lymphocyte	O
total	O
RNA	O
.	O

The	O
PDGFR	B-GENE
mutants	I-GENE
that	O
failed	O
to	O
associate	O
with	O
PLC	B-GENE
gamma	I-GENE
were	O
not	O
able	O
to	O
mediate	O
the	O
PDGF	B-GENE
-	O
dependent	O
production	O
of	O
inositol	O
phosphates	O
.	O

We	O
found	O
a	O
direct	O
correlation	O
between	O
the	O
levels	O
of	O
transcription	O
of	O
the	O
acc	B-GENE
genes	I-GENE
and	O
the	O
rate	O
of	O
cellular	O
growth	O
.	O

The	O
hybridizing	O
clone	O
of	O
V	O
.	O
vulnificus	O
chromosomal	O
DNA	O
complemented	O
a	O
V	B-GENE
.	I-GENE
cholerae	I-GENE
fur	I-GENE
mutant	I-GENE
.	O

We	O
generated	O
transformed	O
B	O
lymphoblast	O
cell	O
lines	O
from	O
controls	O
,	O
from	O
four	O
patients	O
with	O
p47	B-GENE
-	O
phox	B-GENE
-	O
deficient	O
chronic	O
granulomatous	O
disease	O
,	O
and	O
from	O
three	O
parents	O
.	O

RNase	B-GENE
protection	O
and	O
primer	O
extension	O
assays	O
confirmed	O
that	O
the	O
5	O
'	O
non	O
-	O
coding	O
exon	O
is	O
included	O
in	O
the	O
DDT1	O
aFGF	B-GENE
mRNA	I-GENE
and	O
that	O
a	O
major	O
transcription	O
start	O
site	O
is	O
approximately	O
136	O
bp	O
upstream	O
of	O
the	O
5	O
'	O
non	O
-	O
coding	O
splice	O
junction	O
of	O
this	O
exon	O
.	O

These	O
results	O
suggest	O
that	O
FK	O
506	O
is	O
a	O
useful	O
immunosuppressive	O
agent	O
in	O
kidney	O
transplantation	O
.	O

The	O
roles	O
of	O
phorbol	O
esters	O
and	O
cyclic	O
AMP	O
in	O
mediating	O
the	O
GnRH	B-GENE
response	O
were	O
also	O
investigated	O
.	O

RT	O
-	O
PCR	O
using	O
1	O
.	O
D	O
-	O
specific	O
primers	O
showed	O
that	O
kidney	O
,	O
brain	O
and	O
prostate	O
do	O
not	O
express	O
1	O
.	O
D	O
mRNA	O
even	O
though	O
kidney	O
and	O
brain	O
are	O
the	O
most	O
abundant	O
source	O
for	O
aFGF	B-GENE
protein	I-GENE
.	O

Molecular	O
cloning	O
and	O
characterization	O
of	O
two	O
genes	B-GENE
encoding	I-GENE
gp138	I-GENE
,	O
a	O
cell	O
surface	O
glycoprotein	O
involved	O
in	O
the	O
sexual	O
cell	O
fusion	O
of	O
Dictyostelium	O
discoideum	O
.	O

Two	O
-	O
dimensional	O
phosphotryptic	O
analyses	O
indicate	O
that	O
phosphorylation	O
on	O
Ser	O
-	O
12	O
and	O
Ser	O
-	O
48	O
in	O
unstimulated	O
cells	O
is	O
associated	O
with	O
the	O
ability	O
of	O
overexpressed	O
pp60c	B-GENE
-	I-GENE
src	I-GENE
to	O
potentiate	O
beta	O
-	O
adrenergic	O
signalling	O
.	O

Piroximone	O
is	O
a	O
new	O
phosphodiesterase	B-GENE
III	I-GENE
inhibitor	O
that	O
combines	O
inotropic	O
and	O
vasodilator	O
properties	O
.	O

Cytogenetic	O
studies	O
were	O
performed	O
in	O
lymphocytes	O
from	O
hospital	O
workers	O
exposed	O
to	O
low	O
doses	O
of	O
radiation	O
(	O
1	O
.	O
6	O
-	O
42	O
.	O
71	O
mSv	O
)	O
.	O

To	O
study	O
the	O
origin	O
of	O
different	O
fMLF	B-GENE
-	I-GENE
R	I-GENE
transcripts	I-GENE
,	O
the	O
genetic	O
linkage	O
of	O
chemotactic	O
receptor	O
genes	O
,	O
and	O
the	O
regulation	O
of	O
fMLF	B-GENE
-	I-GENE
R	I-GENE
gene	I-GENE
expression	O
,	O
we	O
determined	O
the	O
copy	O
number	O
,	O
chromosomal	O
location	O
,	O
structural	O
organization	O
,	O
and	O
5	O
'	O
-	O
flanking	O
sequence	O
of	O
the	O
human	B-GENE
fMLF	I-GENE
-	I-GENE
R	I-GENE
gene	I-GENE
.	O

The	O
first	O
exon	O
encodes	O
66	O
bp	O
of	O
the	O
5	O
'	O
-	O
untranslated	O
sequence	O
,	O
while	O
exon	O
2	O
encodes	O
the	O
coding	O
and	O
3	O
'	O
-	O
untranslated	O
sequences	O
.	O

The	O
genomic	O
structure	O
of	O
four	O
members	O
of	O
the	O
SRC	B-GENE
-	I-GENE
family	I-GENE
revealed	O
nearly	O
identical	O
exon	O
/	O
intron	O
boundaries	O
within	O
the	O
catalytic	O
domain	O
of	O
this	O
family	O
.	O

Since	O
we	O
have	O
observed	O
effects	O
of	O
growth	O
factors	O
and	O
cAMP	O
as	O
well	O
as	O
estradiol	O
(	O
E2	O
)	O
on	O
regulation	O
of	O
expression	O
of	O
some	O
genes	O
stimulated	O
by	O
the	O
estrogen	B-GENE
receptor	I-GENE
(	O
ER	B-GENE
)	O
,	O
we	O
have	O
undertaken	O
studies	O
to	O
examine	O
directly	O
whether	O
activators	O
of	O
protein	O
kinases	O
can	O
modulate	O
transcriptional	O
activity	O
of	O
the	O
ER	B-GENE
.	O

Using	O
the	O
polymerase	O
chain	O
reaction	O
,	O
Whipple	O
-	O
specific	O
DNA	O
fragments	O
of	O
284	O
base	O
pairs	O
from	O
the	O
genome	O
of	O
the	O
Whipple	O
bacterium	O
(	O
Tropheryma	O
whippelii	O
)	O
were	O
demonstrated	O
.	O

RNA	B-GENE
polymerase	I-GENE
bound	O
to	O
the	O
+	O
10A	O
promoter	O
partially	O
protects	O
a	O
20	O
base	O
-	O
pair	O
sequence	O
from	O
DNase	B-GENE
I	I-GENE
digestion	O
upstream	O
of	O
the	O
start	O
site	O
.	O

Salivary	O
sodium	O
,	O
calcium	O
,	O
and	O
magnesium	O
concentrations	O
were	O
significantly	O
higher	O
in	O
the	O
SLE	O
patients	O
with	O
systemic	O
lupus	O
erythematosus	O
,	O
whereas	O
potassium	O
and	O
total	O
protein	O
concentrations	O
and	O
amylase	B-GENE
activity	O
did	O
not	O
differ	O
significantly	O
from	O
the	O
controls	O
.	O

Chem	O
.	O

Recombinant	O
plasmid	O
pFV100	O
was	O
subsequently	O
isolated	O
by	O
its	O
ability	O
to	O
complement	O
B	O
-	O
band	O
expression	O
in	O
ge6	B-GENE
.	O

The	O
immunosuppressant	O
FK506	O
inhibits	O
amino	O
acid	O
import	O
in	O
Saccharomyces	O
cerevisiae	O
.	O

Protein	O
phosphorylation	O
appears	O
to	O
play	O
a	O
critical	O
role	O
in	O
uPA	B-GENE
gene	I-GENE
expression	O
in	O
these	O
cells	O
;	O
protein	B-GENE
kinase	I-GENE
C	I-GENE
-	O
activating	O
phorbol	O
esters	O
cooperate	O
with	O
pp60v	B-GENE
-	I-GENE
src	I-GENE
to	O
synergistically	O
increase	O
uPA	B-GENE
mRNA	I-GENE
,	O
whereas	O
cyclic	B-GENE
AMP	I-GENE
(	I-GENE
cAMP	I-GENE
)	I-GENE
-	I-GENE
dependent	I-GENE
protein	I-GENE
kinase	I-GENE
-	O
activating	O
agents	O
(	O
e	O
.	O
g	O
.	O
,	O
8	O
-	O
bromo	O
cAMP	O
)	O
repress	O
uPA	B-GENE
mRNA	I-GENE
levels	O
.	O

This	O
300	O
bp	O
5	O
'	O
-	O
upstream	O
sequence	O
of	O
K3	B-GENE
keratin	I-GENE
gene	I-GENE
,	O
which	O
can	O
function	O
in	O
vitro	O
as	O
a	O
keratinocyte	O
-	O
specific	O
promoter	O
,	O
contains	O
two	O
clusters	O
of	O
partially	O
overlapping	O
motifs	O
,	O
one	O
with	O
an	O
NFkB	B-GENE
consensus	O
sequence	O
and	O
another	O
with	O
a	O
GC	O
box	O
.	O

BACKGROUND	O
:	O
Delineation	O
of	O
the	O
morphologic	O
aspects	O
of	O
age	O
-	O
related	O
macular	O
degeneration	O
(	O
ARMD	O
)	O
is	O
helpful	O
in	O
correlation	O
with	O
the	O
clinical	O
features	O
and	O
may	O
contribute	O
to	O
understanding	O
the	O
pathogenesis	O
.	O

An	O
abundant	O
1	O
.	O
1	O
-	O
kb	O
virion	O
-	O
sense	O
polyadenylated	O
RNA	O
and	O
four	O
complementary	O
-	O
sense	O
polyadenylated	O
RNAs	O
of	O
1	O
.	O
7	O
,	O
1	O
.	O
5	O
,	O
1	O
.	O
3	O
,	O
and	O
0	O
.	O
7	O
kb	O
have	O
been	O
identified	O
by	O
northern	O
blot	O
hybridization	O
,	O
confirming	O
the	O
bidirectional	O
transcription	O
strategy	O
implied	O
by	O
the	O
arrangement	O
of	O
ORFs	O
.	O

Risk	O
factors	O
associated	O
with	O
a	O
high	O
seroprevalence	O
of	O
hepatitis	O
C	O
virus	O
infection	O
in	O
Egyptian	O
blood	O
donors	O
.	O

Here	O
the	O
cloning	O
and	O
molecular	O
analysis	O
of	O
the	O
Zm	B-GENE
-	I-GENE
ERabp1	I-GENE
,	O
Zm	B-GENE
-	I-GENE
ERabp4	I-GENE
,	O
and	O
Zm	B-GENE
-	I-GENE
ERabp5	I-GENE
genes	I-GENE
is	O
presented	O
.	O

This	O
agent	O
,	O
isolated	O
from	O
the	O
fungus	O
Streptomyces	O
tsukubaensis	O
,	O
has	O
a	O
mechanism	O
of	O
action	O
similar	O
to	O
that	O
of	O
cyclosporine	O
.	O

DNase	B-GENE
I	I-GENE
footprinting	O
of	O
the	O
proximal	O
promoter	O
revealed	O
four	O
regions	O
of	O
protection	O
.	O

Finally	O
,	O
the	O
stability	O
of	O
the	O
nucleotide	O
binding	O
function	O
of	O
the	O
two	O
proteins	O
is	O
similar	O
as	O
assessed	O
by	O
sensitivity	O
to	O
urea	O
.	O

In	O
addition	O
,	O
an	O
mck1	B-GENE
mds1	B-GENE
mrk1	B-GENE
triple	O
disruptant	O
was	O
viable	O
.	O

However	O
,	O
there	O
were	O
some	O
properties	O
of	O
Rak	B-GENE
that	O
are	O
distinct	O
from	O
Src	B-GENE
-	I-GENE
like	I-GENE
kinases	I-GENE
:	O
(	O
a	O
)	O
expression	O
of	O
Rak	B-GENE
was	O
predominantly	O
in	O
epithelial	O
-	O
derived	O
cell	O
lines	O
and	O
tissues	O
,	O
especially	O
normal	O
liver	O
and	O
kidney	O
,	O
and	O
cell	O
lines	O
of	O
breast	O
and	O
colon	O
origin	O
;	O
(	O
b	O
)	O
Rak	B-GENE
does	O
not	O
harbor	O
the	O
NH2	O
-	O
terminal	O
glycine	O
essential	O
for	O
myristylation	O
and	O
membrane	O
localization	O
;	O
and	O
(	O
c	O
)	O
Rak	B-GENE
possesses	O
a	O
putative	O
bipartite	O
nuclear	O
localization	O
signal	O
in	O
the	O
SH2	B-GENE
domain	I-GENE
,	O
and	O
subcellular	O
fractionation	O
studies	O
revealed	O
that	O
p54rak	B-GENE
resides	O
predominantly	O
in	O
the	O
nucleus	O
.	O

A	O
small	O
amount	O
of	O
HSP81	B-GENE
-	I-GENE
1	I-GENE
mRNA	I-GENE
was	O
detected	O
only	O
in	O
roots	O
.	O

Cell	O
adhesion	O
and	O
migration	O
assays	O
demonstrate	O
that	O
alpha	B-GENE
6	I-GENE
beta	I-GENE
1	I-GENE
is	O
the	O
major	O
laminin	B-GENE
receptor	I-GENE
in	O
undifferentiated	O
F9	O
cells	O
as	O
well	O
as	O
F9	O
-	O
derived	O
PE	O
cells	O
.	O

No	O
local	O
destruction	O
by	O
tumor	O
or	O
infection	O
could	O
be	O
demonstrated	O
apart	O
from	O
HIV	O
infection	O
.	O

Among	O
the	O
mixed	O
race	O
persons	O
one	O
Chukcha	O
-	O
Eskimo	O
had	O
AS	O
,	O
one	O
Eskimo	O
-	O
Russian	O
had	O
psoriatic	O
arthritis	O
(	O
PsA	O
)	O
.	O

Our	O
data	O
complement	O
other	O
studies	O
of	O
circumpolar	O
populations	O
and	O
reinforce	O
the	O
reported	O
high	O
prevalences	O
of	O
SPA	O
and	O
HLA	B-GENE
-	I-GENE
B27	I-GENE
among	O
those	O
populations	O
.	O

Clinical	O
studies	O
SY5555	O
was	O
administered	O
to	O
45	O
patients	O
with	O
various	O
infectious	O
diseases	O
(	O
2	O
with	O
acute	O
pharyngitis	O
,	O
8	O
with	O
acute	O
tonsillitis	O
,	O
4	O
with	O
lacunar	O
tonsillitis	O
,	O
3	O
each	O
with	O
acute	O
bronchitis	O
,	O
pneumonia	O
and	O
pertussis	O
,	O
7	O
with	O
scarlet	O
fever	O
,	O
3	O
with	O
impetigo	O
contagiosa	O
,	O
6	O
with	O
acute	O
urinary	O
tract	O
infections	O
,	O
2	O
with	O
balanoposthitis	O
and	O
1	O
each	O
with	O
cervical	O
lymphadenitis	O
,	O
S	O
.	O
S	O
.	O
S	O
.	O
S	O
.	O
,	O
vulvitis	O
and	O
acute	O
colitis	O
)	O
at	O
daily	O
doses	O
between	O
3	O
.	O
4	O
-	O
10	O
mg	O
/	O
kg	O
,	O
t	O
.	O
i	O
.	O
d	O
.	O
,	O
for	O
3	O
-	O
14	O
days	O
.	O

Although	O
most	O
SH2	B-GENE
-	O
pTyr	B-GENE
interactions	O
occur	O
between	O
two	O
different	O
types	O
of	O
molecules	O
,	O
some	O
appear	O
to	O
involve	O
only	O
a	O
single	O
molecular	O
type	O
.	O

RESULTS	O
:	O
Closure	O
time	O
of	O
fistulas	O
in	O
patients	O
receiving	O
TPN	O
+	O
somatostatin	B-GENE
was	O
significantly	O
shorter	O
(	O
13	O
.	O
86	O
+	O
/	O
-	O
1	O
.	O
84	O
versus	O
20	O
.	O
4	O
+	O
/	O
-	O
2	O
.	O
89	O
days	O
)	O
than	O
in	O
those	O
receiving	O
TPN	O
alone	O
.	O

Scratching	O
during	O
sleep	O
in	O
children	O
with	O
atopic	O
dermatitis	O
is	O
associated	O
with	O
increased	O
VO2	O
.	O

Within	O
-	O
subject	O
BP	O
differences	O
between	O
fish	O
oil	O
and	O
corn	O
oil	O
treatment	O
were	O
similar	O
for	O
Dinamap	O
(	O
3	O
.	O
2	O
+	O
/	O
-	O
1	O
.	O
8	O
/	O
2	O
.	O
5	O
+	O
/	O
-	O
1	O
.	O
0	O
mm	O
Hg	O
)	O
and	O
for	O
24	O
-	O
h	O
ABP	O
(	O
2	O
.	O
5	O
+	O
/	O
-	O
1	O
.	O
0	O
/	O
2	O
.	O
3	O
+	O
/	O
-	O
0	O
.	O
8	O
mm	O
Hg	O
)	O
,	O
but	O
were	O
more	O
significant	O
with	O
the	O
latter	O
.	O

Escherichia	O
coli	O
JRG582	O
is	O
an	O
ampD	B-GENE
ampE	B-GENE
deletion	O
derivative	O
of	O
strain	O
HfrH	O
and	O
accordingly	O
it	O
is	O
derepressed	O
for	O
expression	O
of	O
the	O
cloned	O
inducible	O
beta	B-GENE
-	I-GENE
lactamase	I-GENE
gene	I-GENE
of	O
Citrobacter	O
freundii	O
,	O
carried	O
on	O
plasmid	O
pNU305	O
.	O

Such	O
a	O
mechanism	O
may	O
allow	O
acceleration	O
of	O
degenerative	O
joint	O
conditions	O
,	O
and	O
may	O
account	O
for	O
the	O
increased	O
prevalence	O
of	O
such	O
conditions	O
seen	O
with	O
HMS	O
subjects	O
.	O

Solitary	O
thyroid	O
nodule	O
.	O

Male	O
contraception	O
:	O
ideas	O
for	O
the	O
future	O
.	O

While	O
daily	O
food	O
intake	O
was	O
almost	O
constant	O
regardless	O
of	O
the	O
dietary	O
protein	O
level	O
,	O
water	O
intake	O
and	O
urine	O
volume	O
increased	O
with	O
increasing	O
the	O
dietary	O
protein	O
.	O

We	O
propose	O
that	O
Mad	B-GENE
and	O
Medea	B-GENE
encode	O
rate	O
-	O
limiting	O
components	O
integral	O
to	O
dpp	B-GENE
pathways	O
throughout	O
development	O
.	O

Transcriptional	O
regulation	O
of	O
the	O
vacuolar	B-GENE
H	I-GENE
(	I-GENE
+	I-GENE
)	I-GENE
-	I-GENE
ATPase	I-GENE
B2	I-GENE
subunit	I-GENE
gene	I-GENE
in	O
differentiating	O
THP	O
-	O
1	O
cells	O
.	O

However	O
,	O
the	O
inability	O
to	O
export	O
RNA	O
from	O
the	O
nucleus	O
to	O
the	O
cytoplasm	O
was	O
not	O
limited	O
to	O
a	O
particular	O
phase	O
of	O
the	O
cell	O
division	O
cycle	O
.	O

An	O
E	O
box	O
element	O
is	O
required	O
for	O
the	O
expression	O
of	O
the	O
ad4bp	B-GENE
gene	I-GENE
,	O
a	O
mammalian	B-GENE
homologue	I-GENE
of	I-GENE
ftz	I-GENE
-	I-GENE
f1	I-GENE
gene	I-GENE
,	O
which	O
is	O
essential	O
for	O
adrenal	O
and	O
gonadal	O
development	O
.	O

Inhibition	O
assays	O
performed	O
with	O
over	O
30	O
different	O
natural	O
and	O
synthetic	O
sialylated	O
and	O
/	O
or	O
sulfated	O
compounds	O
are	O
utilized	O
to	O
define	O
in	O
greater	O
detail	O
specific	O
structural	O
features	O
involved	O
in	O
oligosaccharide	O
-	O
protein	O
binding	O
.	O

The	O
amino	O
acid	O
sequence	O
of	O
the	O
protein	O
in	O
the	O
region	O
of	O
the	O
specificity	O
pocket	O
is	O
similar	O
to	O
that	O
of	O
S	B-GENE
.	I-GENE
griseus	I-GENE
proteases	I-GENE
A	I-GENE
,	I-GENE
B	I-GENE
,	I-GENE
and	I-GENE
C	I-GENE
.	O

This	O
experimental	O
design	O
was	O
used	O
to	O
determine	O
the	O
effect	O
of	O
displacement	O
of	O
the	O
alpha	B-GENE
4	I-GENE
-	I-GENE
2	I-GENE
binding	I-GENE
site	I-GENE
on	O
the	O
repression	O
of	O
alpha	B-GENE
4	I-GENE
gene	I-GENE
transcription	O
by	O
ICP4	B-GENE
.	O

Immediate	O
-	O
early	O
transcription	O
from	O
the	O
channel	O
catfish	O
virus	O
genome	O
:	O
characterization	O
of	O
two	O
immediate	B-GENE
-	I-GENE
early	I-GENE
transcripts	I-GENE
.	O

The	O
GRE	O
at	O
nucleotide	O
7640	O
is	O
a	O
composite	O
GRE	O
(	O
cGRE	O
)	O
containing	O
an	O
overlapping	O
activator	B-GENE
protein	I-GENE
-	I-GENE
1	I-GENE
(	O
AP	B-GENE
-	I-GENE
1	I-GENE
)	O
motif	O
for	O
the	O
c	B-GENE
-	I-GENE
jun	I-GENE
homodimer	I-GENE
and	O
c	B-GENE
-	I-GENE
jun	I-GENE
/	O
c	B-GENE
-	I-GENE
fos	I-GENE
heterodimer	O
.	O

In	O
contrast	O
to	O
some	O
results	O
previously	O
published	O
for	O
a	O
very	O
close	O
sequence	O
variant	O
(	O
see	O
ref	O
.	O

Transcriptional	O
activation	O
by	O
thyroid	O
hormone	O
(	O
T3	O
)	O
requires	O
interactions	O
between	O
the	O
T3	B-GENE
receptor	I-GENE
(	O
TR	B-GENE
)	O
and	O
T3	O
response	O
elements	O
(	O
TREs	O
)	O
composed	O
of	O
two	O
copies	O
of	O
sequences	O
related	O
to	O
AGGTCA	O
.	O

A	O
multivariate	O
analysis	O
of	O
risk	O
factors	O
for	O
relapse	O
examined	O
age	O
,	O
WBC	O
at	O
diagnosis	O
,	O
blast	O
count	O
at	O
diagnosis	O
,	O
percentage	O
of	O
marrow	O
blasts	O
,	O
FAB	B-GENE
subtype	O
,	O
the	O
number	O
of	O
remission	O
induction	O
courses	O
to	O
achieve	O
a	O
remission	O
,	O
maintenance	O
therapy	O
,	O
consolidation	O
therapy	O
,	O
marrow	O
cell	O
dose	O
,	O
donor	O
-	O
recipient	O
sex	O
,	O
GVHD	O
prophylaxis	O
regimen	O
and	O
isolation	O
and	O
decontamination	O
in	O
laminar	O
airflow	O
rooms	O
.	O

Carnitine	B-GENE
palmitoyltransferase	I-GENE
(	I-GENE
CPT	I-GENE
)	I-GENE
II	I-GENE
deficiency	O
is	O
the	O
most	O
common	O
inherited	O
disorder	O
of	O
lipid	O
metabolism	O
affecting	O
skeletal	O
muscle	O
.	O

We	O
show	O
that	O
these	O
three	O
gain	O
-	O
of	O
-	O
function	O
mutants	O
differ	O
considerably	O
in	O
their	O
ability	O
to	O
bypass	O
the	O
sex	O
determination	O
signal	O
,	O
with	O
SxlM4	B-GENE
being	O
the	O
strongest	O
and	O
SxlM1	B-GENE
the	O
weakest	O
.	O

We	O
show	O
that	O
these	O
three	O
gain	O
-	O
of	O
-	O
function	O
mutants	O
differ	O
considerably	O
in	O
their	O
ability	O
to	O
bypass	O
the	O
sex	O
determination	O
signal	O
,	O
with	O
SxlM4	B-GENE
being	O
the	O
strongest	O
and	O
SxlM1	B-GENE
the	O
weakest	O
.	O

Blood	O
pressure	O
also	O
was	O
increased	O
by	O
lidocaine	O
(	O
6	O
mg	O
kg	O
-	O
1	O
)	O
.	O

Anesthesiologists	O
often	O
use	O
more	O
than	O
one	O
drug	O
in	O
a	O
patient	O
to	O
achieve	O
a	O
target	O
response	O
,	O
such	O
as	O
a	O
desired	O
blood	O
pressure	O
.	O

We	O
suggest	O
that	O
this	O
gene	O
cluster	O
codes	O
for	O
(	O
parts	O
of	O
)	O
a	O
multisubunit	B-GENE
cytochrome	I-GENE
c	I-GENE
haem	I-GENE
lyase	I-GENE
.	O

In	O
this	O
paper	O
,	O
a	O
comparison	O
between	O
the	O
number	O
and	O
shape	O
of	O
corneal	O
endothelial	O
cells	O
has	O
been	O
performed	O
in	O
25	O
patients	O
before	O
and	O
6	O
months	O
after	O
PRK	O
.	O

Standard	O
reference	O
sources	O
indicate	O
that	O
an	O
able	O
-	O
bodied	O
11	O
-	O
year	O
-	O
old	O
child	O
of	O
comparable	O
height	O
requires	O
1	O
,	O
493	O
kcal	O
/	O
d	O
for	O
support	O
of	O
basal	O
metabolic	O
functions	O
.	O

In	O
contrast	O
to	O
the	O
myoD	B-GENE
promoter	I-GENE
,	O
the	O
myoD	B-GENE
enhancer	I-GENE
shows	O
striking	O
conservation	O
between	O
humans	O
and	O
mice	O
both	O
in	O
its	O
sequence	O
and	O
its	O
distal	O
position	O
.	O

However	O
,	O
a	O
clear	O
difference	O
exists	O
between	O
myoblasts	O
and	O
10T1	O
/	O
2	O
cells	O
(	O
and	O
other	O
non	O
-	O
muscle	O
cell	O
types	O
)	O
in	O
the	O
chromatin	O
structure	O
of	O
the	O
chromosomal	O
myoD	B-GENE
core	I-GENE
enhancer	I-GENE
,	O
suggesting	O
that	O
the	O
myoD	B-GENE
enhancer	I-GENE
is	O
repressed	O
by	O
epigenetic	O
mechanisms	O
in	O
10T1	O
/	O
2	O
cells	O
.	O

Using	O
Ki	B-GENE
-	I-GENE
ras	I-GENE
-	O
transformed	O
3T3	O
cells	O
as	O
a	O
model	O
system	O
,	O
we	O
show	O
that	O
both	O
RA	O
and	O
the	O
'	O
dissociating	O
'	O
retinoids	O
inhibit	O
anchorage	O
-	O
independent	O
cell	O
proliferation	O
,	O
suggesting	O
that	O
retinoid	O
-	O
induced	O
growth	O
inhibition	O
may	O
be	O
related	O
to	O
AP1	B-GENE
transrepression	O
.	O

The	O
Oct	B-GENE
and	O
HMG2	B-GENE
proteins	I-GENE
also	O
interact	O
in	O
vivo	O
.	O

Atopic	O
dermatitis	O
is	O
an	O
"	O
itch	O
which	O
rashes	O
and	O
not	O
a	O
rash	O
which	O
itches	O
"	O
and	O
therefore	O
,	O
any	O
patient	O
treatment	O
program	O
should	O
address	O
the	O
multiplicity	O
of	O
potential	O
trigger	O
factors	O
that	O
provoke	O
this	O
itching	O
.	O

Primer	O
extension	O
experiments	O
showed	O
that	O
there	O
are	O
two	O
transcription	O
initiation	O
sites	O
16	O
bp	O
apart	O
in	O
the	O
mouse	B-GENE
type	I-GENE
2	I-GENE
receptor	I-GENE
gene	I-GENE
.	O

The	O
beta	O
subunit	O
of	O
the	O
Fc	B-GENE
epsilon	I-GENE
R1	I-GENE
is	O
a	O
33	O
-	O
kDa	O
tyrosine	O
phosphoprotein	O
,	O
but	O
the	O
p33	B-GENE
Grb2	B-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
described	O
in	O
the	O
present	O
report	O
is	O
not	O
the	O
Fc	B-GENE
epsilon	I-GENE
R1	I-GENE
beta	I-GENE
chain	I-GENE
and	O
its	O
identity	O
is	O
unknown	O
.	O

To	O
study	O
the	O
mechanisms	O
as	O
well	O
as	O
magnitude	O
of	O
the	O
transmembrane	O
transfer	O
of	O
bacterial	O
products	O
from	O
the	O
dialysate	O
,	O
we	O
developed	O
a	O
computerized	O
in	O
vitro	O
dialysis	O
model	O
which	O
provides	O
continuous	O
pressure	O
recording	O
from	O
the	O
arterial	O
,	O
venous	O
,	O
dialysate	O
inflow	O
and	O
outflow	O
ports	O
.	O

After	O
24	O
hour	O
incubation	O
,	O
total	O
cell	O
-	O
associated	O
IL	B-GENE
-	I-GENE
1Ra	I-GENE
and	O
IL	B-GENE
-	I-GENE
1	I-GENE
beta	I-GENE
were	O
measured	O
by	O
specific	O
radioimmunoassay	O
.	O

1972	O
.	O

In	O
contrast	O
,	O
recent	O
evidence	O
suggests	O
that	O
children	O
with	O
sickle	B-GENE
-	I-GENE
hemoglobin	I-GENE
C	I-GENE
disease	O
do	O
not	O
develop	O
functional	O
asplenia	O
before	O
3	O
to	O
4	O
years	O
of	O
age	O
and	O
thus	O
may	O
not	O
benefit	O
from	O
penicillin	O
prophylaxis	O
.	O

Deletion	O
analysis	O
indicates	O
that	O
TBP	B-GENE
and	O
hTAFII18	B-GENE
bind	O
to	O
distinct	O
domains	O
of	O
hTAFII28	B-GENE
.	O
hTAFII18	B-GENE
also	O
interacts	O
with	O
TBP	B-GENE
,	O
but	O
it	O
interacts	O
more	O
strongly	O
with	O
hTAFII28	B-GENE
and	O
hTAFII30	B-GENE
.	O

Vascular	O
endothelial	O
cells	O
undergo	O
profound	O
changes	O
upon	O
cellular	O
activation	O
including	O
expression	O
of	O
a	O
spectrum	O
of	O
cell	O
activation	O
-	O
associated	O
genes	O
.	O

Because	O
ATF	B-GENE
-	I-GENE
1	I-GENE
and	O
CREM	B-GENE
are	O
known	O
to	O
bind	O
to	O
cAMP	O
response	O
elements	O
(	O
CRE	O
)	O
,	O
this	O
functional	O
sequence	O
was	O
named	O
the	O
kappa	B-GENE
E3	I-GENE
'	I-GENE
-	O
CRE	O
.	O

The	O
amino	O
acid	O
sequences	O
of	O
the	O
known	O
largest	O
subunits	O
of	O
DdRPs	B-GENE
from	O
different	O
species	O
contain	O
highly	O
conserved	O
regions	O
.	O

The	O
TTG	B-GENE
-	I-GENE
2	I-GENE
gene	I-GENE
has	O
been	O
identified	O
at	O
the	O
site	O
of	O
chromosomal	O
translocations	O
in	O
acute	O
T	O
-	O
cell	O
leukemia	O
'	O
s	O
(	O
T	O
-	O
ALL	O
)	O
.	O

In	O
vitro	O
studies	O
with	O
blood	O
cells	O
incubated	O
with	O
acetate	O
or	O
bicarbonate	O
ions	O
in	O
concentrations	O
,	O
which	O
are	O
observed	O
in	O
vivo	O
during	O
hemodialysis	O
,	O
suggest	O
that	O
probably	O
these	O
ions	O
do	O
not	O
directly	O
affect	O
superoxide	O
anions	O
generation	O
,	O
erythrocyte	O
SOD	B-GENE
-	I-GENE
1	I-GENE
and	O
catalase	B-GENE
activities	O
and	O
erythrocyte	O
membrane	O
lipid	O
peroxidation	O
.	O

Short	O
therapy	O
with	O
omeprazole	O
20	O
mg	O
/	O
b	O
.	O
i	O
.	O
d	O
.	O
,	O
clarithromycin	O
500	O
mg	O
/	O
b	O
.	O
i	O
.	O
d	O
.	O
,	O
and	O
CBS	O
120	O
mg	O
/	O
q	O
.	O
i	O
.	O
d	O
.	O
is	O
a	O
safe	O
,	O
well	O
tolerated	O
combination	O
that	O
achieves	O
a	O
80	O
.	O
6	O
%	O
eradication	O
rate	O
of	O
H	O
.	O
pylori	O
and	O
duodenal	O
ulcer	O
healing	O
rates	O
as	O
good	O
as	O
those	O
achieved	O
by	O
omeprazole	O
20	O
mg	O
/	O
d	O
when	O
given	O
for	O
4	O
wk	O
.	O

The	O
concentration	O
of	O
mite	O
allergen	O
was	O
very	O
low	O
(	O
mean	O
0	O
.	O
18	O
micrograms	O
Der	O
p	O
milligrams	O
sieved	O
house	O
dust	O
)	O
,	O
whereas	O
that	O
of	O
cat	O
allergen	O
was	O
high	O
in	O
homes	O
with	O
a	O
cat	O
(	O
80	O
.	O
8	O
micrograms	O
Fel	O
d	O
milligrams	O
)	O
but	O
also	O
in	O
homes	O
with	O
no	O
cat	O
(	O
3	O
.	O
2	O
micrograms	O
Fel	O
d	O
milligrams	O
)	O
.	O

CONCLUSIONS	O
:	O
A	O
comparison	O
of	O
the	O
LysU	B-GENE
crystal	O
structure	O
with	O
the	O
structures	O
of	O
seryl	B-GENE
-	I-GENE
and	I-GENE
aspartyl	I-GENE
-	I-GENE
tRNA	I-GENE
synthetases	I-GENE
enables	O
a	O
conserved	O
core	O
to	O
be	O
identified	O
.	O

Whole	O
bowel	O
irrigation	O
is	O
a	O
recently	O
described	O
technique	O
to	O
enhance	O
the	O
passage	O
of	O
drugs	O
already	O
beyond	O
the	O
pylorus	O
.	O

The	O
MPS1	B-GENE
open	I-GENE
reading	I-GENE
frame	I-GENE
has	O
been	O
fused	O
to	O
those	O
that	O
encode	O
the	O
LexA	B-GENE
protein	I-GENE
or	O
the	O
GST	B-GENE
protein	I-GENE
and	O
both	O
of	O
these	O
constructs	O
function	O
in	O
yeast	O
.	O

Hematopoietic	B-GENE
growth	I-GENE
factors	I-GENE
have	O
already	O
had	O
an	O
enormous	O
impact	O
on	O
transfusion	O
practice	O
by	O
eliminating	O
or	O
reducing	O
the	O
need	O
for	O
red	O
blood	O
cell	O
transfusions	O
in	O
a	O
variety	O
of	O
anemic	O
states	O
characterized	O
by	O
an	O
absolute	O
or	O
relative	O
decrease	O
in	O
erythropoietin	B-GENE
.	O

However	O
,	O
the	O
mouse	O
has	O
previously	O
been	O
shown	O
to	O
possess	O
only	O
three	O
forms	O
of	O
ADH	B-GENE
.	O

During	O
IC	O
breaths	O
and	O
following	O
EC	O
and	O
VC	O
breaths	O
at	O
rest	O
,	O
end	O
-	O
tidal	O
CO2	O
pressure	O
(	O
PET	O
,	O
CO2	O
)	O
fell	O
by	O
7	O
.	O
5	O
,	O
8	O
.	O
5	O
and	O
9	O
.	O
5	O
mmHg	O
,	O
respectively	O
.	O

Phylogenetic	O
analyses	O
of	O
19	O
amino	O
acid	O
sequences	O
of	O
6	O
related	O
protein	O
types	O
indicate	O
that	O
actin	B-GENE
-	O
associated	O
proteins	O
related	O
to	O
gelsolin	B-GENE
are	O
monophyletic	O
to	O
a	O
common	O
ancestor	O
and	O
include	O
flightless	B-GENE
proteins	I-GENE
.	O

No	O
homologs	O
of	O
other	O
members	O
of	O
the	O
Surfeit	B-GENE
gene	I-GENE
cluster	I-GENE
were	O
detected	O
in	O
close	O
proximity	O
to	O
the	O
D	O
.	O
melanogaster	O
Surf	B-GENE
-	I-GENE
3	I-GENE
/	O
rpL7a	B-GENE
gene	O
.	O

Moreover	O
,	O
we	O
found	O
that	O
cyclin	B-GENE
E	I-GENE
,	O
in	O
contrast	O
to	O
cyclin	B-GENE
D1	I-GENE
,	O
was	O
required	O
for	O
the	O
G1	O
/	O
S	O
transition	O
even	O
in	O
cells	O
lacking	O
retinoblastoma	B-GENE
protein	I-GENE
function	O
.	O

The	O
predicted	O
amino	O
acid	O
sequence	O
of	O
the	O
SGC1	B-GENE
gene	I-GENE
product	I-GENE
includes	O
a	O
region	O
with	O
substantial	O
similarity	O
to	O
the	O
basic	O
-	O
helix	O
-	O
loop	O
-	O
helix	O
domain	O
of	O
the	O
Myc	B-GENE
family	I-GENE
of	O
DNA	O
-	O
binding	O
proteins	O
.	O

By	O
creating	O
Pax	B-GENE
-	I-GENE
6	I-GENE
-	O
BSAP	B-GENE
fusion	O
proteins	O
,	O
we	O
were	O
able	O
to	O
identify	O
a	O
short	O
amino	O
acid	O
stretch	O
in	O
the	O
N	O
-	O
terminal	O
part	O
of	O
the	O
paired	B-GENE
domain	O
which	O
is	O
responsible	O
for	O
these	O
differences	O
in	O
DNA	O
-	O
binding	O
specificity	O
.	O

To	O
establish	O
a	O
possible	O
association	O
between	O
familial	O
dysfibrinogenemia	O
and	O
thrombophilia	O
,	O
data	O
on	O
cases	O
with	O
both	O
affections	O
were	O
collected	O
in	O
a	O
study	O
within	O
the	O
framework	O
of	O
the	O
SSC	O
Subcommittee	O
on	O
Fibrinogen	B-GENE
of	O
the	O
International	O
Society	O
on	O
Thrombosis	O
and	O
Haemostasis	O
.	O

Conjugated	O
estrogens	O
shorten	O
bleeding	O
time	O
in	O
uraemia	O
:	O
a	O
possible	O
role	O
of	O
serotonin	O
?	O

These	O
six	O
districts	O
have	O
an	O
area	O
of	O
34	O
,	O
000	O
km2	O
and	O
hold	O
a	O
population	O
of	O
30	O
million	O
.	O

According	O
to	O
symptoms	O
,	O
signs	O
,	O
imaging	O
features	O
,	O
operation	O
findings	O
,	O
the	O
original	O
places	O
and	O
the	O
expansive	O
directions	O
of	O
the	O
tumor	O
,	O
they	O
were	O
divided	O
into	O
four	O
clinical	O
types	O
:	O
sellar	O
,	O
clival	O
,	O
occipito	O
-	O
temporal	O
and	O
extent	O
.	O

The	O
cases	O
included	O
35	O
de	O
novo	O
diffuse	O
aggressive	O
lymphomas	O
(	O
DAL	O
;	O
19	O
large	O
-	O
cell	O
,	O
4	O
mixed	O
-	O
cell	O
,	O
and	O
12	O
large	O
-	O
cell	O
immunoblastic	O
)	O
,	O
52	O
transformed	O
aggressive	O
lymphomas	O
derived	O
from	O
follicular	O
lymphomas	O
(	O
TFL	O
)	O
,	O
42	O
indolent	O
follicular	O
lymphomas	O
(	O
FL	O
)	O
,	O
14	O
mantle	O
cell	O
lymphomas	O
(	O
MCL	O
)	O
,	O
and	O
27	O
small	O
noncleaved	O
cell	O
lymphomas	O
(	O
SNCL	O
)	O
.	O

Icterus	O
and	O
beta	O
-	O
thalassemia	O
in	O
Congolese	O
children	O
in	O
Brazzaville	O

Female	O
patients	O
with	O
breast	O
cancer	O
diagnosed	O
between	O
1982	O
and	O
1991	O
at	O
Roswell	O
Park	O
Cancer	O
Institute	O
(	O
RPCI	O
)	O
in	O
Buffalo	O
,	O
New	O
York	O
,	O
who	O
provided	O
information	O
on	O
their	O
cigarette	O
smoking	O
history	O
at	O
the	O
time	O
of	O
their	O
diagnosis	O
were	O
included	O
.	O

Upon	O
analysis	O
of	O
the	O
tissue	O
distribution	O
of	O
AAMP	B-GENE
,	O
it	O
was	O
found	O
to	O
be	O
expressed	O
strongly	O
in	O
endothelial	O
cells	O
,	O
cytotrophoblasts	O
,	O
and	O
poorly	O
differentiated	O
colon	O
adenocarcinoma	O
cells	O
found	O
in	O
lymphatics	O
.	O

Data	O
from	O
the	O
V	O
-	O
HeFT	O
II	O
show	O
that	O
at	O
2	O
-	O
year	O
follow	O
-	O
up	O
,	O
a	O
progressive	O
rise	O
of	O
plasma	O
norepinephrine	O
was	O
observed	O
in	O
both	O
treatment	O
arms	O
,	O
suggesting	O
that	O
disease	O
progresses	O
despite	O
treatment	O
with	O
either	O
an	O
angiotensin	B-GENE
-	I-GENE
converting	I-GENE
enzyme	I-GENE
inhibitor	O
,	O
enalapril	O
,	O
or	O
vasodilator	O
therapy	O
with	O
hydralazine	O
/	O
isosorbide	O
dinitrate	O
.	O

Analysis	O
of	O
Bcl	B-GENE
-	I-GENE
2	I-GENE
/	O
Bcl	B-GENE
-	I-GENE
2	I-GENE
homodimerization	O
using	O
both	O
in	O
vitro	O
binding	O
assays	O
as	O
well	O
as	O
a	O
yeast	O
two	O
-	O
hybrid	O
method	O
provided	O
evidence	O
in	O
support	O
of	O
a	O
head	O
-	O
to	O
-	O
tail	O
model	O
for	O
Bcl	B-GENE
-	I-GENE
2	I-GENE
/	O
Bcl	B-GENE
-	I-GENE
2	I-GENE
homodimerization	O
and	O
revealed	O
that	O
sequences	O
within	O
the	O
NH2	O
-	O
terminal	O
A	O
domain	O
interact	O
with	O
a	O
structure	O
that	O
requires	O
the	O
presence	O
of	O
both	O
the	O
carboxyl	O
B	O
and	O
C	O
domains	O
in	O
combination	O
.	O

The	O
protein	O
is	O
composed	O
of	O
a	O
central	O
alpha	O
-	O
helical	O
portion	O
with	O
globular	O
domains	O
at	O
both	O
NH2	O
and	O
COOH	O
termini	O
,	O
and	O
the	O
epitope	O
to	O
the	O
monoclonal	O
antibody	O
resides	O
in	O
the	O
central	O
alpha	O
-	O
helical	O
stalk	O
.	O

Radioligand	O
binding	O
was	O
indistinguishable	O
for	O
both	O
transiently	O
expressed	O
constructs	O
.	O

Diagnosis	O
of	O
FHCS	O
has	O
been	O
weighed	O
upon	O
laparoscopic	O
findings	O
.	O

Human	B-GENE
papillomavirus	I-GENE
type	I-GENE
31b	I-GENE
late	I-GENE
gene	I-GENE
expression	O
is	O
regulated	O
through	O
protein	B-GENE
kinase	I-GENE
C	I-GENE
-	O
mediated	O
changes	O
in	O
RNA	O
processing	O
.	O

Interestingly	O
,	O
virions	O
also	O
contained	O
smaller	O
proteins	O
that	O
reacted	O
with	O
antibodies	O
specific	O
for	O
the	O
accessory	O
proteins	O
as	O
well	O
as	O
SN	B-GENE
and	O
CAT	B-GENE
fusion	I-GENE
partners	O
.	O

Studies	O
using	O
an	O
inhibitor	O
or	O
a	O
mutant	B-GENE
Lb	I-GENE
proteinase	I-GENE
indicated	O
that	O
stimulation	O
of	O
IRES	O
-	O
driven	O
translation	O
is	O
mediated	O
via	O
proteolysis	O
of	O
some	O
cellular	O
component	O
(	O
s	O
)	O
.	O

Restriction	O
mapping	O
analysis	O
localized	O
this	O
cDNA	O
to	O
the	O
HHV	B-GENE
-	I-GENE
6A	I-GENE
(	I-GENE
U1102	I-GENE
)	I-GENE
genomic	I-GENE
BamHI	I-GENE
G	I-GENE
fragment	I-GENE
,	O
at	O
the	O
right	O
end	O
of	O
the	O
unique	O
long	O
segment	O
of	O
the	O
genome	O
and	O
to	O
the	O
SalI	B-GENE
L	I-GENE
and	O
SalI	B-GENE
O	I-GENE
fragments	I-GENE
within	O
the	O
left	O
and	O
right	O
terminal	O
direct	O
repeat	O
regions	O
,	O
respectively	O
.	O

For	O
replication	O
reporter	O
constructs	O
where	O
E1	B-GENE
and	O
E2	B-GENE
are	O
supplied	O
in	O
trans	O
by	O
the	O
respective	O
expression	O
vectors	O
,	O
distance	O
between	O
the	O
half	O
sites	O
seems	O
to	O
play	O
a	O
major	O
role	O
,	O
yet	O
the	O
phasing	O
relationships	O
are	O
measurable	O
.	O

As	O
it	O
had	O
been	O
previously	O
reported	O
that	O
the	O
18	O
-	O
bp	O
palindrome	O
contains	O
sufficient	O
nucleotide	O
sequence	O
information	O
for	O
E1	B-GENE
binding	O
,	O
we	O
speculate	O
that	O
a	O
minimal	O
E1	B-GENE
recognition	O
motif	O
is	O
presented	O
in	O
each	O
half	O
site	O
.	O

METHODS	O
:	O
Out	O
of	O
171	O
patients	O
receiving	O
anticoagulation	O
between	O
July	O
1992	O
and	O
December	O
1993	O
,	O
83	O
patients	O
with	O
hemispheric	O
embolisms	O
received	O
heparin	O
within	O
72	O
hours	O
from	O
onset	O
(	O
activated	O
partial	O
thromboplastin	B-GENE
time	O
[	O
aPTT	O
]	O
1	O
.	O
5	O
times	O
control	O
value	O
)	O
.	O

In	O
the	O
commercially	O
available	O
intravenous	O
formulation	O
of	O
Cyclosporin	O
A	O
(	O
Sandimmun	O
)	O
,	O
polyoxyethylated	O
castor	O
oil	O
(	O
Cremophor	O
EL	O
)	O
is	O
used	O
as	O
a	O
solubilizing	O
agent	O
.	O

Sequence	O
comparisons	O
of	O
prokaryotic	B-GENE
RCR	I-GENE
initiators	I-GENE
has	O
revealed	O
a	O
set	O
of	O
three	O
common	O
motifs	O
,	O
two	O
of	O
which	O
,	O
a	O
putative	O
metal	O
coordination	O
site	O
and	O
a	O
downstream	O
active	O
-	O
site	O
tyrosine	O
motif	O
,	O
could	O
be	O
tentatively	O
identified	O
in	O
parvoviral	B-GENE
replicator	I-GENE
proteins	I-GENE
.	O

The	O
mean	O
marginal	O
discrepancy	O
of	O
provisional	O
restorations	O
was	O
compared	O
for	O
restorations	O
fabricated	O
from	O
stone	O
,	O
low	O
-	O
viscosity	O
poly	O
(	O
vinyl	O
siloxane	O
)	O
,	O
and	O
medium	O
-	O
viscosity	O
poly	O
(	O
vinyl	O
siloxane	O
)	O
.	O

The	O
characterized	O
Aplysia	B-GENE
Afurin2	I-GENE
is	O
a	O
candidate	O
PC	B-GENE
that	O
may	O
play	O
an	O
important	O
role	O
in	O
the	O
processing	O
of	O
egg	B-GENE
-	I-GENE
laying	I-GENE
hormone	I-GENE
(	O
ELH	B-GENE
)	O
-	O
related	O
precursors	O
in	O
the	O
secretory	O
cells	O
of	O
the	O
atrial	O
gland	O
.	O

Rats	O
treated	O
with	O
8	O
-	O
OH	O
-	O
DPAT	O
were	O
not	O
impaired	O
in	O
their	O
ability	O
to	O
learn	O
a	O
visual	O
discrimination	O
in	O
a	O
water	O
maze	O
.	O

The	O
term	O
endovascular	O
papillary	O
haemangioma	O
is	O
suggested	O
.	O

In	O
addition	O
,	O
two	O
internal	O
promoters	O
,	O
PmiaA	B-GENE
and	O
P1hfq	B-GENE
were	O
identified	O
and	O
mapped	O
to	O
201	O
and	O
837	O
nucleotides	O
upstream	O
from	O
the	O
respective	O
translation	O
start	O
sites	O
.	O

These	O
results	O
indicate	O
that	O
mutL	B-GENE
,	O
miaA	B-GENE
,	O
and	O
hfq	B-GENE
expression	O
could	O
be	O
regulated	O
by	O
multiple	O
mechanisms	O
,	O
including	O
degree	O
of	O
cotranscription	O
from	O
upstream	O
genes	O
,	O
modulation	O
of	O
internal	O
promoter	O
strength	O
,	O
and	O
by	O
RNase	B-GENE
E	I-GENE
activity	O
.	O

Coronary	O
T1	O
and	O
T2	O
weighted	O
images	O
were	O
obtained	O
.	O

The	O
2	O
kb	O
of	O
5	O
'	O
-	O
flanking	O
region	O
and	O
the	O
1	O
.	O
1	O
kb	O
of	O
the	O
entire	O
sGTH	B-GENE
alpha	I-GENE
subunit	I-GENE
coding	O
region	O
were	O
sequenced	O
from	O
the	O
genomic	O
clone	O
,	O
sGTH	B-GENE
alpha	I-GENE
-	I-GENE
G1	I-GENE
.	O

Functional	O
analysis	O
of	O
the	O
sGTH	B-GENE
alpha	I-GENE
subunit	I-GENE
promoter	I-GENE
by	O
the	O
transient	O
transfection	O
of	O
several	O
sGTH	B-GENE
alpha	I-GENE
/	O
CAT	B-GENE
chimeric	O
plasmids	O
into	O
rainbow	O
trout	O
pituitary	O
cells	O
suggests	O
that	O
its	O
pituitary	O
-	O
specific	O
expression	O
is	O
GSE	B-GENE
-	O
dependent	O
.	O

Indium	O
-	O
111	O
OncoScint	O
CR	O
/	O
OV	O
and	O
F	O
-	O
18	O
FDG	O
in	O
colorectal	O
and	O
ovarian	O
carcinoma	O
recurrences	O
.	O

His	O
carnitine	B-GENE
palmitoyltransferase	I-GENE
(	I-GENE
CPT	I-GENE
)	I-GENE
I	I-GENE
and	I-GENE
II	I-GENE
activities	O
were	O
0	O
.	O
06	O
and	O
0	O
.	O
12	O
nmol	O
/	O
min	O
/	O
mg	O
protein	O
,	O
as	O
compared	O
with	O
a	O
mean	O
value	O
of	O
0	O
.	O
22	O
+	O
/	O
-	O
0	O
.	O
14	O
and	O
0	O
.	O
27	O
+	O
/	O
-	O
0	O
.	O
07	O
nmol	O
/	O
min	O
/	O
mg	O
protein	O
,	O
respectively	O
,	O
in	O
control	O
subjects	O
.	O

The	O
Myc	B-GENE
LZ	I-GENE
was	O
found	O
to	O
prevent	O
homodimeric	O
interactions	O
,	O
thus	O
explaining	O
Myc	B-GENE
inability	O
to	O
homodimerize	O
efficiently	O
.	O

Thus	O
,	O
VF	O
resistant	O
to	O
defibrillation	O
is	O
not	O
necessarily	O
associated	O
with	O
both	O
toxic	O
plasma	O
drug	O
level	O
and	O
remarkably	O
decreased	O
conduction	O
.	O

The	O
smallest	O
active	B-GENE
FecR	I-GENE
derivative	I-GENE
contained	O
59	O
amino	O
acid	O
residues	O
as	O
compared	O
to	O
the	O
317	O
residues	O
of	O
wild	B-GENE
-	I-GENE
type	I-GENE
FecR	I-GENE
.	O

The	O
gene	O
pairs	O
psbB	B-GENE
-	O
psbT	B-GENE
and	O
psbH	B-GENE
-	O
psbN	B-GENE
are	O
cotranscribed	O
from	O
opposite	O
strands	O
.	O

The	O
predicted	O
amino	O
acid	O
sequence	O
contains	O
regions	O
identical	O
to	O
the	O
sequences	O
of	O
peptides	O
derived	O
from	O
bovine	B-GENE
liver	I-GENE
eIF	I-GENE
-	I-GENE
2B	I-GENE
alpha	I-GENE
subunit	I-GENE
.	O

Expression	O
of	O
this	O
cDNA	O
in	O
vitro	O
yields	O
a	O
peptide	O
which	O
comigrates	O
with	O
natural	B-GENE
eIF	I-GENE
-	I-GENE
2B	I-GENE
alpha	I-GENE
in	O
SDS	O
/	O
polyacrylamide	O
gels	O
.	O

When	O
RNA	O
encoding	O
the	O
tail	O
domain	O
of	O
desmoglein	B-GENE
was	O
coinjected	O
with	O
plakoglobin	B-GENE
RNA	I-GENE
,	O
both	O
the	O
dorsalizing	O
effect	O
and	O
nuclear	O
accumulation	O
of	O
plakoglobin	B-GENE
were	O
suppressed	O
.	O

Six	O
of	O
them	O
,	O
NUC1	B-GENE
,	O
PRP21	B-GENE
(	O
also	O
called	O
SPP91	B-GENE
)	O
,	O
CDC6	B-GENE
,	O
CRY2	B-GENE
,	O
the	O
gene	O
encoding	O
the	O
ribosomal	B-GENE
protein	I-GENE
S24	I-GENE
and	O
the	O
gene	O
coding	O
for	O
a	O
hypothetical	O
protein	O
of	O
599	O
amino	O
acids	O
,	O
have	O
been	O
sequenced	O
previously	O
.	O

Intrastriatal	O
grafts	O
of	O
nigral	O
and	O
adrenal	O
tissues	O
have	O
been	O
found	O
to	O
be	O
effective	O
in	O
alleviating	O
many	O
of	O
the	O
simple	O
motor	O
and	O
sensorimotor	O
deficits	O
associated	O
with	O
lesions	O
of	O
the	O
nigrostriatal	O
dopamine	O
system	O
.	O

OBJECTIVE	O
:	O
To	O
determine	O
the	O
impact	O
of	O
the	O
introduction	O
of	O
clarithromycin	O
and	O
azithromycin	O
on	O
the	O
treatment	O
and	O
survival	O
of	O
patients	O
with	O
AIDS	O
and	O
disseminated	O
Mycobacterium	O
avium	O
complex	O
(	O
DMAC	O
)	O
.	O

Thereafter	O
,	O
the	O
aggregation	O
rose	O
to	O
the	O
initial	O
100	O
%	O
value	O
4	O
h	O
after	O
drug	O
application	O
and	O
remained	O
at	O
this	O
level	O
during	O
the	O
observation	O
period	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
250	O
WORDS	O
)	O

Growth	O
curves	O
indicated	O
that	O
proliferation	O
of	O
clone	O
CA9	O
in	O
the	O
presence	O
of	O
10	O
%	O
serum	O
was	O
reduced	O
by	O
60	O
%	O
compared	O
with	O
clone	O
ME10	O
.	O

The	O
protein	O
coding	O
region	O
,	O
1	O
,	O
696	O
bps	O
long	O
,	O
is	O
divided	O
by	O
an	O
intron	O
into	O
two	O
exons	O
.	O

The	O
UAS	O
of	O
the	O
AAC2	B-GENE
gene	I-GENE
contains	O
at	O
least	O
two	O
distinct	O
motifs	O
for	O
DNA	O
-	O
binding	O
transcriptional	O
activators	O
,	O
including	O
one	O
which	O
is	O
identical	O
with	O
the	O
core	O
HAP2	B-GENE
/	I-GENE
3	I-GENE
/	I-GENE
4	I-GENE
binding	I-GENE
motif	I-GENE
,	O
and	O
a	O
second	O
one	O
with	O
the	O
ABF1	B-GENE
consensus	I-GENE
binding	I-GENE
sequence	I-GENE
.	O

The	O
emerging	O
complexity	O
of	O
the	O
5	O
'	O
regulatory	O
region	O
of	O
the	O
GH	B-GENE
receptor	I-GENE
gene	I-GENE
was	O
emphasised	O
by	O
the	O
observation	O
that	O
probes	O
derived	O
from	O
exon	O
1B	O
and	O
the	O
distal	O
3	O
'	O
intron	O
boundary	O
do	O
not	O
hybridise	O
with	O
previously	O
cloned	O
genomic	O
sequences	O
that	O
span	O
the	O
liver	O
-	O
specific	O
P1	O
promoter	O
and	O
exon	O
2	O
.	O

A	O
polymorphic	O
dinucleotide	O
(	O
GT	O
/	O
CA	O
)	O
n	O
repeat	O
contained	O
in	O
the	O
NHE5	O
cosmid	O
was	O
identified	O
and	O
developed	O
into	O
a	O
microsatellite	O
PCR	O
marker	O
.	O

The	O
proteins	O
are	O
more	O
than	O
90	O
%	O
identical	O
to	O
each	O
other	O
within	O
the	O
protein	O
kinase	O
domain	O
but	O
only	O
51	O
-	O
59	O
%	O
identical	O
to	O
other	O
casein	B-GENE
kinase	I-GENE
I	I-GENE
isoforms	I-GENE
within	O
this	O
region	O
.	O

We	O
used	O
two	O
approaches	O
to	O
ascertain	O
whether	O
CDP	B-GENE
/	O
cut	B-GENE
serves	O
as	O
a	O
repressor	O
of	O
gp91	B-GENE
-	O
phox	B-GENE
gene	O
expression	O
.	O

Despite	O
the	O
activation	O
of	O
these	O
intracellular	O
signaling	O
molecules	O
,	O
PDGF	B-GENE
beta	I-GENE
receptor	I-GENE
activation	O
elicited	O
no	O
detectable	O
effect	O
on	O
cell	O
proliferation	O
or	O
differentiation	O
.	O

UAS1	O
is	O
the	O
binding	O
site	O
for	O
the	O
transcriptional	O
regulator	O
Adr1p	B-GENE
.	O

In	O
the	O
context	O
of	O
the	O
ADH2	B-GENE
upstream	I-GENE
regulatory	I-GENE
region	I-GENE
,	O
including	O
UAS1	O
,	O
working	O
in	O
concert	O
with	O
the	O
ADH2	B-GENE
basal	I-GENE
promoter	I-GENE
elements	I-GENE
,	O
UAS2	O
-	O
dependent	O
gene	O
activation	O
was	O
dependent	O
on	O
orientation	O
,	O
copy	O
number	O
,	O
and	O
helix	O
phase	O
.	O

Induction	O
in	O
AP	B-GENE
-	I-GENE
1	I-GENE
DNA	O
binding	O
correlates	O
with	O
a	O
concomitant	O
GH	B-GENE
trans	O
-	O
activation	O
of	O
c	B-GENE
-	I-GENE
jun	I-GENE
and	O
c	B-GENE
-	I-GENE
fos	I-GENE
genes	I-GENE
described	O
previously	O
.	O

Inactivation	O
of	O
MAP	B-GENE
kinases	I-GENE
occurs	O
via	O
a	O
specific	O
phosphatase	O
,	O
MKP	B-GENE
-	I-GENE
1	I-GENE
.	O

Short	O
-	O
course	O
amphotericin	O
B	O
therapy	O
for	O
candidemia	O
in	O
pediatric	O
patients	O
.	O

Furthermore	O
,	O
45Ca	O
-	O
binding	O
assays	O
revealed	O
that	O
CCaMK	B-GENE
directly	O
binds	O
Ca2	O
+	O
.	O

The	O
protein	O
expressed	O
from	O
the	O
cloned	O
cDNA	O
is	O
secreted	O
into	O
the	O
culture	O
medium	O
and	O
yields	O
of	O
up	O
to	O
40	O
mg	O
per	O
litre	O
have	O
been	O
obtained	O
.	O

Plasmids	O
pAMS12	O
,	O
pAMS13	O
and	O
pAMS14	O
were	O
transformed	O
into	O
a	O
laboratory	O
strain	O
of	O
Saccharomyces	O
cerevisiae	O
,	O
whereas	O
pAMS15	O
was	O
stably	O
introduced	O
into	O
two	O
commercial	O
wine	O
yeast	O
strains	O
.	O

The	O
maximum	O
induction	O
of	O
ACC	B-GENE
-	I-GENE
oxidase	I-GENE
transcripts	I-GENE
occurred	O
at	O
about	O
6	O
h	O
after	O
excision	O
,	O
while	O
the	O
maximum	O
enzyme	O
activity	O
was	O
observed	O
at	O
24	O
h	O
.	O

Within	O
their	O
polypeptide	O
chain	O
,	O
they	O
all	O
contain	O
those	O
conserved	O
features	O
that	O
define	O
a	O
plant	O
CDPK	B-GENE
;	O
kinase	O
catalytic	O
sequences	O
are	O
linked	O
to	O
a	O
calmodulin	B-GENE
-	I-GENE
like	I-GENE
regulatory	I-GENE
domain	I-GENE
through	O
a	O
junction	O
region	O
.	O

Repair	O
of	O
this	O
insertion	O
by	O
homologous	O
recombination	O
restores	O
the	O
activity	O
of	O
the	O
hprt	B-GENE
locus	I-GENE
,	O
thus	O
confirming	O
the	O
site	O
of	O
mutation	O
.	O

The	O
timing	O
of	O
fla	B-GENE
gene	I-GENE
expression	O
in	O
the	O
cell	O
cycle	O
is	O
determined	O
by	O
specialized	O
forms	O
of	O
RNA	B-GENE
polymerase	I-GENE
and	O
the	O
appearance	O
and	O
/	O
or	O
activation	O
of	O
regulatory	O
proteins	O
.	O

Primer	O
extension	O
experiments	O
revealed	O
a	O
strong	O
transcription	O
initiation	O
site	O
102	O
bp	O
upstream	O
of	O
the	O
translational	O
start	O
site	O
.	O

Polypeptides	O
of	O
the	O
same	O
apparent	O
sizes	O
are	O
detected	O
in	O
spores	O
of	O
a	O
cotE	B-GENE
null	O
mutant	O
,	O
on	O
which	O
basis	O
we	O
infer	O
that	O
the	O
products	O
of	O
the	O
cotJ	B-GENE
operon	I-GENE
are	O
required	O
for	O
the	O
normal	O
formation	O
of	O
the	O
inner	O
layers	O
of	O
the	O
coat	O
or	O
are	O
themselves	O
structural	O
components	O
of	O
the	O
coat	O
.	O

Based	O
on	O
the	O
estimated	O
values	O
of	O
divergence	O
of	O
apobec1	B-GENE
sequences	I-GENE
in	O
terms	O
of	O
the	O
numbers	O
of	O
synonymous	O
and	O
non	O
-	O
synonymous	O
suhstitutions	O
per	O
site	O
,	O
we	O
found	O
that	O
apobec1	B-GENE
is	O
a	O
fairly	O
rapidly	O
evolving	O
protein	O
.	O

EEA1	B-GENE
is	O
a	O
conserved	O
alpha	O
-	O
helical	O
peripheral	O
membrane	O
protein	O
flanked	O
by	O
cysteine	O
"	O
fingers	O
"	O
and	O
contains	O
a	O
calmodulin	B-GENE
-	I-GENE
binding	I-GENE
IQ	I-GENE
motif	I-GENE
.	O

Nucleotide	O
sequences	O
of	O
the	O
clones	O
revealed	O
that	O
one	O
clone	O
,	O
cap3	B-GENE
,	O
contained	O
an	O
open	O
reading	O
frame	O
(	O
ORF	O
)	O
that	O
would	O
code	O
for	O
a	O
26	O
-	O
amino	O
acid	O
,	O
cysteine	O
-	O
rich	O
peptide	O
with	O
significant	O
homology	O
to	O
Neurospora	B-GENE
crassa	I-GENE
copper	I-GENE
metallothionein	I-GENE
.	O

Sensing	O
with	O
chemically	O
and	O
biologically	O
modified	O
carbon	O
electrodes	O
.	O

Elevation	O
of	O
the	O
tissues	O
of	O
the	O
face	O
is	O
essentially	O
vertical	O
and	O
acts	O
on	O
the	O
forehead	O
,	O
temporal	O
region	O
,	O
gaze	O
and	O
cheekbones	O
.	O

This	O
region	O
binds	O
two	O
ubiquitous	O
nuclear	O
factors	O
,	O
USF	B-GENE
/	O
MLTF	B-GENE
and	O
the	O
CAAT	B-GENE
-	I-GENE
binding	I-GENE
transcription	I-GENE
factor	I-GENE
/	O
nuclear	B-GENE
factor	I-GENE
1	I-GENE
(	O
CTF	B-GENE
/	O
NF1	B-GENE
)	O
.	O

The	O
potential	O
impact	O
of	O
using	O
a	O
rapid	O
diagnostic	O
test	O
(	O
Strep	O
A	O
OIA	O
)	O
on	O
detection	O
and	O
treatment	O
of	O
group	O
A	O
beta	O
-	O
hemolytic	O
streptococcal	O
(	O
GABHS	O
)	O
pharyngitis	O
in	O
a	O
large	O
-	O
volume	O
pediatric	O
and	O
adolescent	O
clinic	O
was	O
examined	O
.	O

The	O
bHLH	B-GENE
proteins	I-GENE
function	O
as	O
potent	O
transcriptional	O
activators	O
of	O
tissue	O
-	O
specific	O
genes	O
by	O
forming	O
heterodimers	O
between	O
ubiquitous	O
and	O
cell	O
-	O
restricted	O
family	O
members	O
.	O

YAC	O
and	O
cosmid	O
contigs	O
spanning	O
the	O
BRCA1	B-GENE
region	I-GENE
were	O
used	O
to	O
select	O
cDNA	O
clones	O
from	O
pools	O
of	O
cDNAs	O
derived	O
from	O
human	O
placenta	O
,	O
HeLa	O
cells	O
,	O
activated	O
T	O
cells	O
,	O
and	O
fetal	O
head	O
.	O

This	O
study	O
assesses	O
the	O
feasibility	O
and	O
toxicity	O
of	O
adoptive	O
immunotherapy	O
with	O
tumor	O
infiltrating	O
lymphocytes	O
and	O
recombinant	B-GENE
interleukin	I-GENE
-	I-GENE
2	I-GENE
in	O
29	O
patients	O
who	O
underwent	O
resection	O
for	O
stage	O
III	O
non	O
-	O
small	O
-	O
cell	O
lung	O
cancer	O
.	O

The	O
present	O
study	O
describes	O
the	O
cell	O
volume	O
dynamics	O
in	O
intact	O
rat	O
hearts	O
,	O
during	O
ischemia	O
and	O
after	O
reperfusion	O
.	O

In	O
contrast	O
,	O
COUP	B-GENE
-	I-GENE
TF	I-GENE
alone	O
had	O
no	O
effect	O
on	O
repCRS2	O
-	O
dependent	O
reporter	O
gene	O
activity	O
.	O

DNA	O
sequencing	O
and	O
Southern	O
blot	O
analyses	O
established	O
that	O
the	O
cDNA	O
clones	O
are	O
derived	O
from	O
two	O
different	O
genes	O
.	O

Mutation	O
of	O
the	O
Sp1	B-GENE
element	I-GENE
,	O
which	O
abolishes	O
Sp1	B-GENE
binding	O
,	O
results	O
in	O
a	O
6	O
-	O
10	O
-	O
fold	O
reduction	O
in	O
reporter	O
activity	O
.	O

The	O
c	B-GENE
-	I-GENE
myc	I-GENE
gene	I-GENE
is	O
overexpressed	O
in	O
a	O
variety	O
of	O
tumor	O
types	O
and	O
appears	O
to	O
play	O
an	O
important	O
role	O
in	O
the	O
abnormal	O
growth	O
of	O
a	O
number	O
of	O
cell	O
types	O
.	O

Schooling	O
is	O
found	O
to	O
be	O
related	O
to	O
good	O
health	O
even	O
after	O
controlling	O
for	O
differences	O
in	O
observable	O
health	O
inputs	O
.	O

With	O
this	O
bisected	O
diastolic	O
driving	O
,	O
the	O
abnormal	O
echo	O
disappeared	O
completely	O
.	O

It	O
acts	O
on	O
Cdks	B-GENE
in	O
the	O
G1	O
and	O
S	O
phases	O
of	O
the	O
cell	O
cycle	O
,	O
and	O
also	O
binds	O
to	O
proliferating	B-GENE
cell	I-GENE
nuclear	I-GENE
antigen	I-GENE
(	O
PCNA	B-GENE
)	O
,	O
blocking	O
DNA	O
replication	O
in	O
vitro	O
.	O

Two	O
major	O
and	O
one	O
minor	O
transcription	O
initiation	O
sites	O
were	O
assigned	O
to	O
positions	O
+	O
1	O
and	O
+	O
24	O
and	O
position	O
+	O
14	O
,	O
respectively	O
,	O
by	O
a	O
combination	O
of	O
ribonuclease	O
protection	O
,	O
primer	O
extension	O
,	O
and	O
5	O
'	O
RACE	O
analyses	O
.	O

Further	O
,	O
the	O
ORFs	O
of	O
components	O
3	O
and	O
5	O
potentially	O
encoded	O
proteins	O
of	O
about	O
20	O
kDa	O
,	O
the	O
size	O
of	O
the	O
BBTV	B-GENE
coat	I-GENE
protein	I-GENE
.	O

CodY	B-GENE
does	O
not	O
have	O
any	O
homologues	O
in	O
the	O
data	O
-	O
bases	O
.	O

OBJECTIVE	O
:	O
To	O
investigate	O
the	O
incidence	O
and	O
presentation	O
of	O
acute	O
pernicious	O
or	O
fulminating	O
beriberi	O
in	O
a	O
general	O
district	O
hospital	O
.	O

Unlike	O
most	O
other	O
small	B-GENE
G	I-GENE
proteins	I-GENE
which	O
are	O
expressed	O
ubiquitously	O
,	O
TTF	B-GENE
was	O
transcribed	O
only	O
in	O
hemopoietic	O
cells	O
as	O
a	O
2	O
.	O
2	O
kb	O
transcript	O
.	O

An	O
explanation	O
explored	O
for	O
this	O
lack	O
of	O
gene	O
expression	O
was	O
that	O
increased	O
levels	O
of	O
RAR	B-GENE
alpha	I-GENE
or	O
PML	B-GENE
might	O
suppress	O
APL	O
cell	O
growth	O
.	O

Cytosolic	O
extracts	O
from	O
a	O
variety	O
of	O
mammalian	O
cell	O
lines	O
(	O
monkey	O
Cos7	O
,	O
several	O
mouse	O
fibrosarcomas	O
and	O
human	O
HeLa	O
S3	O
)	O
demonstrated	O
similar	O
TGF	B-GENE
-	I-GENE
beta	I-GENE
1	I-GENE
dependent	O
RNA	O
-	O
protein	O
band	O
shifts	O
as	O
cell	O
extract	O
from	O
BALB	O
/	O
c	O
3T3	O
mouse	O
fibroblasts	O
.	O

The	O
provisional	O
reports	O
are	O
based	O
mainly	O
upon	O
macroscopic	O
findings	O
,	O
whereas	O
the	O
final	O
reports	O
include	O
the	O
information	O
provided	O
by	O
supplementary	O
investigations	O
such	O
as	O
microscopy	O
,	O
histochemistry	O
,	O
more	O
rarely	O
electron	O
microscopy	O
,	O
immunohistochemistry	O
and	O
/	O
or	O
microbiology	O
.	O

Circulating	O
thrombomodulin	B-GENE
:	O
current	O
knowledge	O
and	O
future	O
prospects	O

CPT	O
-	O
11	O
was	O
administered	O
as	O
a	O
30	O
-	O
minute	O
i	O
.	O
v	O
.	O
infusion	O
at	O
a	O
dose	O
of	O
350	O
mg	O
/	O
m2	O
diluted	O
in	O
250	O
ml	O
normal	O
saline	O
every	O
3	O
weeks	O
.	O

A	O
73	O
bp	O
fragment	O
(	O
X1	O
region	O
)	O
of	O
the	O
PRB	B-GENE
-	I-GENE
1b	I-GENE
promoter	I-GENE
,	O
located	O
between	O
positions	O
-	O
213	O
and	O
-	O
141	O
,	O
was	O
sufficient	O
to	O
confer	O
ethylene	O
responsiveness	O
to	O
the	O
reporter	O
gene	O
.	O

To	O
assess	O
the	O
function	O
(	O
s	O
)	O
of	O
E74	B-GENE
during	O
metamorphosis	O
,	O
we	O
have	O
isolated	O
and	O
characterized	O
recessive	O
loss	O
-	O
of	O
-	O
function	O
mutations	O
specific	O
to	O
each	O
transcription	O
unit	O
.	O

Although	O
the	O
extracellular	O
domain	O
of	O
the	O
TSH	B-GENE
-	I-GENE
R	I-GENE
is	O
sufficient	O
for	O
high	O
affinity	O
binding	O
of	O
TSH	B-GENE
,	O
we	O
conclude	O
that	O
the	O
hyt	O
mutation	O
in	O
the	O
fourth	O
transmembrane	O
domain	O
eliminates	O
TSH	B-GENE
binding	O
.	O

Lipiodol	O
was	O
covalently	O
conjugated	O
with	O
EDTB	O
.	O

Moreover	O
,	O
Western	O
blots	O
demonstrated	O
at	O
least	O
six	O
types	O
of	O
Ypt	B-GENE
in	O
both	O
Cr	O
and	O
Vc	O
,	O
suggesting	O
that	O
these	O
Ypt	B-GENE
are	O
used	O
for	O
household	O
functions	O
responsible	O
for	O
vesicle	O
transport	O
rather	O
than	O
for	O
cellular	O
differentiation	O
.	O

The	O
absence	O
of	O
other	O
regions	O
of	O
hybridization	O
suggests	O
that	O
there	O
are	O
no	O
closely	O
related	O
sequences	O
(	O
e	O
.	O
g	O
.	O
,	O
reverse	O
transcribed	O
pseudogenes	O
)	O
scattered	O
throughout	O
the	O
genome	O
and	O
that	O
if	O
there	O
are	O
closely	O
related	O
genes	O
,	O
they	O
must	O
be	O
clustered	O
near	O
GSTT2	B-GENE
.	O

However	O
,	O
the	O
lens	O
dose	O
(	O
3	O
.	O
6	O
Gy	O
/	O
25	O
fractions	O
)	O
was	O
higher	O
compared	O
to	O
the	O
other	O
techniques	O
.	O

Antibodies	O
to	O
the	O
human	B-GENE
PTS1R	I-GENE
recognize	O
this	O
protein	O
in	O
human	O
,	O
monkey	O
,	O
rat	O
,	O
and	O
hamster	O
cells	O
.	O

There	O
is	O
a	O
national	O
effort	O
to	O
begin	O
to	O
ask	O
all	O
female	O
patients	O
about	O
family	O
violence	O
.	O

GnRH	B-GENE
treatment	O
was	O
found	O
to	O
increase	O
the	O
phosphorylation	O
of	O
tyrosine	O
residues	O
of	O
MAPK	B-GENE
and	O
to	O
increase	O
MAPK	B-GENE
activity	O
,	O
as	O
determined	O
by	O
an	O
immune	O
complex	O
kinase	O
assay	O
.	O

Molecular	O
cloning	O
of	O
an	O
amphibian	B-GENE
insulin	I-GENE
receptor	I-GENE
substrate	I-GENE
1	I-GENE
-	I-GENE
like	I-GENE
cDNA	I-GENE
and	O
involvement	O
of	O
phosphatidylinositol	B-GENE
3	I-GENE
-	I-GENE
kinase	I-GENE
in	O
insulin	B-GENE
-	O
induced	O
Xenopus	O
oocyte	O
maturation	O
.	O

We	O
report	O
here	O
that	O
in	O
cultured	O
Jurkat	O
T	O
cells	O
,	O
Cbl	B-GENE
is	O
coprecipitated	O
with	O
antibody	O
against	O
the	O
adapter	B-GENE
protein	I-GENE
Grb2	I-GENE
.	O

The	O
effect	O
of	O
these	O
cell	O
cycle	O
regulators	O
is	O
not	O
specific	O
to	O
the	O
rap1s	B-GENE
or	O
hmr	B-GENE
delta	I-GENE
A	I-GENE
mutation	I-GENE
,	O
since	O
swi6	B-GENE
,	O
swi4	B-GENE
,	O
and	O
clb5	B-GENE
mutations	I-GENE
also	O
suppress	O
mutations	O
in	O
SIR1	B-GENE
,	O
another	O
gene	O
implicated	O
in	O
the	O
establishment	O
of	O
silencing	O
.	O

ICP4	B-GENE
has	O
been	O
shown	O
to	O
form	O
tripartite	O
complexes	O
cooperatively	O
with	O
the	O
TATA	B-GENE
box	I-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
and	O
TFIIB	B-GENE
on	O
DNA	O
containing	O
an	O
ICP4	B-GENE
binding	I-GENE
site	I-GENE
and	O
a	O
TATA	O
box	O
(	O
C	O
.	O

Characterization	O
of	O
fus1	B-GENE
of	O
Schizosaccharomyces	O
pombe	O
:	O
a	O
developmentally	O
controlled	O
function	O
needed	O
for	O
conjugation	O
.	O

SRY	B-GENE
-	I-GENE
related	I-GENE
cDNA	I-GENE
encoding	O
a	O
protein	O
with	O
a	O
high	B-GENE
-	I-GENE
mobility	I-GENE
-	I-GENE
group	I-GENE
(	O
HMG	B-GENE
)	O
box	O
and	O
a	O
leucine	O
zipper	O
motif	O
,	O
which	O
was	O
designated	O
SOX	B-GENE
-	I-GENE
LZ	I-GENE
,	O
was	O
isolated	O
from	O
a	O
rainbow	O
trout	O
testis	O
cDNA	O
library	O
.	O

Scalp	O
flaps	O
can	O
be	O
expanded	O
just	O
to	O
the	O
point	O
of	O
becoming	O
noticeable	O
over	O
4	O
to	O
6	O
weeks	O
followed	O
by	O
scalp	O
flap	O
transposition	O
and	O
easy	O
closure	O
of	O
the	O
donor	O
site	O
.	O

In	O
the	O
Center	O
for	O
Human	O
Genetics	O
in	O
Leuven	O
,	O
predictive	O
DNA	O
-	O
testing	O
for	O
Huntington	O
'	O
s	O
disease	O
is	O
available	O
as	O
a	O
clinical	O
service	O
since	O
November	O
1987	O
,	O
initially	O
by	O
DNA	O
-	O
linkage	O
and	O
since	O
mid	O
1993	O
by	O
direct	O
mutation	O
analysis	O
.	O

Risks	O
of	O
chronicity	O
following	O
acute	O
hepatitis	O
B	O
virus	O
infection	O
:	O
a	O
review	O
.	O

Examination	O
of	O
neurohumoral	O
factors	O
revealed	O
a	O
hyperactive	O
sympathetic	O
nervous	O
system	O
and	O
an	O
increase	O
in	O
plasma	O
renin	B-GENE
activity	O
.	O

We	O
compared	O
the	O
inhibitory	O
effect	O
of	O
naturally	O
occurring	O
mutant	B-GENE
hTR	I-GENE
beta	I-GENE
1	I-GENE
,	O
artificially	O
created	O
hTR	B-GENE
alpha	I-GENE
1	I-GENE
mutants	I-GENE
,	O
c	B-GENE
-	I-GENE
erbA	I-GENE
alpha	I-GENE
2	I-GENE
and	O
the	O
human	B-GENE
peroxisome	I-GENE
proliferator	I-GENE
-	I-GENE
activated	I-GENE
receptor	I-GENE
(	O
hPPAR	B-GENE
)	O
on	O
three	O
prototypic	O
T3	O
-	O
response	O
elements	O
(	O
TREs	O
)	O
,	O
TRE	O
-	O
PAL	O
,	O
DR	O
+	O
4	O
and	O
TRE	O
-	O
LAP	O
.	O

The	O
amino	O
-	O
terminal	O
DNA	O
-	O
binding	O
domain	O
of	O
Pip	B-GENE
exhibits	O
a	O
high	O
degree	O
of	O
homology	O
to	O
the	O
DNA	O
-	O
binding	O
domains	O
of	O
members	O
of	O
the	O
interferon	B-GENE
regulatory	I-GENE
factor	I-GENE
(	O
IRF	B-GENE
)	O
family	O
,	O
which	O
includes	O
IRF	B-GENE
-	I-GENE
1	I-GENE
,	O
IRF	B-GENE
-	I-GENE
2	I-GENE
,	O
ICSBP	B-GENE
,	O
and	O
ISGF3	B-GENE
gamma	I-GENE
.	O

An	O
outbreak	O
of	O
hepatitis	O
A	O
among	O
homosexual	O
men	O
in	O
Amsterdam	O
,	O
1991	O
-	O
1993	O
.	O

The	O
RAP74	B-GENE
subunit	I-GENE
of	O
TFIIF	B-GENE
alone	O
contained	O
the	O
stimulatory	O
activity	O
and	O
the	O
minimal	O
region	O
sufficient	O
for	O
stimulation	O
corresponds	O
to	O
COOH	O
-	O
terminal	O
residues	O
358	O
-	O
517	O
.	O

We	O
have	O
generated	O
various	O
base	O
substitutions	O
and	O
internal	O
deletions	O
in	O
and	O
around	O
DRE	O
(	O
nucleotide	O
positions	O
-	O
93	O
to	O
-	O
100	O
with	O
respect	O
to	O
the	O
transcription	O
initiation	O
site	O
)	O
of	O
the	O
PCNA	B-GENE
gene	I-GENE
in	O
vitro	O
and	O
subsequently	O
examined	O
their	O
effects	O
on	O
the	O
binding	O
to	O
DREF	B-GENE
(	O
DRE	B-GENE
-	I-GENE
binding	I-GENE
factor	I-GENE
)	O
and	O
PCNA	B-GENE
gene	I-GENE
promote	O
activity	O
in	O
cultured	O
Drosophila	O
Kc	O
cells	O
as	O
well	O
as	O
in	O
living	O
flies	O
.	O

The	O
hsp70	B-GENE
gene	I-GENE
family	I-GENE
of	O
Neurospora	O
crassa	O
:	O
cloning	O
,	O
sequence	O
analysis	O
,	O
expression	O
,	O
and	O
genetic	O
mapping	O
of	O
the	O
major	O
stress	O
-	O
inducible	O
member	O
.	O

The	O
deduced	O
amino	O
acid	O
sequences	O
of	O
each	O
of	O
the	O
W3A1	B-GENE
ETF	I-GENE
subunits	I-GENE
exhibit	O
only	O
approximately	O
30	O
%	O
identity	O
with	O
the	O
corresponding	O
subunits	O
of	O
the	O
ETF	B-GENE
from	O
human	O
,	O
rat	O
,	O
and	O
Paracoccus	O
denitrificans	O
,	O
which	O
as	O
a	O
group	O
are	O
greater	O
than	O
50	O
%	O
identical	O
.	O

This	O
last	O
region	O
contains	O
two	O
sites	O
that	O
bind	O
Ets	B-GENE
-	I-GENE
related	I-GENE
proteins	I-GENE
present	O
in	O
liver	O
nuclear	O
extracts	O
as	O
well	O
as	O
recombinant	B-GENE
purified	I-GENE
Ets	I-GENE
-	I-GENE
1	I-GENE
protein	I-GENE
.	O

Other	O
assays	O
also	O
distinguished	O
the	O
processive	O
replication	O
of	O
pNeo	O
.	O
Myc	O
-	O
2	O
.	O
4	O
from	O
the	O
dispersive	O
labeling	O
of	O
control	O
plasmids	O
.	O

Therefore	O
,	O
it	O
is	O
hoped	O
that	O
by	O
defining	O
the	O
transcriptional	O
control	O
of	O
the	O
L7	B-GENE
gene	I-GENE
insights	O
into	O
the	O
mechanisms	O
that	O
control	O
functional	O
fate	O
and	O
organization	O
in	O
the	O
nervous	O
system	O
can	O
be	O
gained	O
.	O

In	O
contrast	O
,	O
a	O
Maf	B-GENE
-	I-GENE
related	I-GENE
protein	I-GENE
,	O
Nrl	B-GENE
,	O
completely	O
mimicked	O
c	B-GENE
-	I-GENE
Maf	I-GENE
actions	O
.	O

The	O
27	O
-	O
base	O
element	O
interacts	O
with	O
a	O
PDGF	B-GENE
-	O
activated	O
serine	O
/	O
threonine	O
phosphoprotein	O
that	O
is	O
detected	O
only	O
within	O
the	O
nucleus	O
of	O
PDGF	O
-	O
treated	O
3T3	O
cells	O
.	O

By	O
contrast	O
,	O
deletion	O
of	O
this	O
Ras	B-GENE
-	I-GENE
binding	I-GENE
site	I-GENE
did	O
not	O
diminish	O
activation	O
of	O
Raf	B-GENE
-	I-GENE
1	I-GENE
kinase	I-GENE
by	O
Src	B-GENE
,	O
implying	O
that	O
Src	B-GENE
and	O
Ras	B-GENE
can	O
activate	O
Raf	B-GENE
-	I-GENE
1	I-GENE
through	O
independent	O
mechanisms	O
.	O

In	O
studies	O
of	O
many	O
different	O
phenotypically	O
distinct	O
cells	O
,	O
the	O
CRE	O
of	O
the	O
somatostatin	B-GENE
gene	I-GENE
promoter	I-GENE
is	O
a	O
prototype	O
of	O
a	O
highly	O
cAMP	O
-	O
responsive	O
element	O
regulated	O
by	O
CREB	B-GENE
.	O

The	O
first	O
gene	O
,	O
NSR1	B-GENE
,	O
a	O
previously	O
identified	O
gene	O
,	O
encodes	O
a	O
protein	O
involved	O
in	O
ribosomal	O
RNA	O
maturation	O
and	O
possibly	O
in	O
transport	O
of	O
proteins	O
into	O
the	O
nucleus	O
.	O

Characterization	O
of	O
the	O
promoter	O
for	O
the	O
human	B-GENE
85	I-GENE
kDa	I-GENE
cytosolic	I-GENE
phospholipase	I-GENE
A2	I-GENE
gene	I-GENE
.	O

This	O
paper	O
describes	O
the	O
advantages	O
and	O
limitations	O
of	O
the	O
main	O
study	O
approaches	O
used	O
.	O

Comparative	O
study	O
of	O
the	O
differential	O
white	O
blood	O
cell	O
count	O
using	O
three	O
automated	O
analyzers	O
:	O
Coulter	O
STKS	O
,	O
Sysmex	O
NE	O
8000	O
and	O
Technicon	O
H	O
-	O
1	O
.	O

Characterization	O
of	O
FIII	B-GENE
/	O
YY1	B-GENE
,	O
a	O
Xenopus	B-GENE
laevis	I-GENE
conserved	I-GENE
zinc	I-GENE
-	I-GENE
finger	I-GENE
protein	I-GENE
binding	O
to	O
the	O
first	O
exon	O
of	O
L1	B-GENE
and	O
L14	B-GENE
ribosomal	I-GENE
protein	I-GENE
genes	I-GENE
.	O

Further	O
studies	O
established	O
that	O
the	O
Ep	B-GENE
-	O
induced	O
increase	O
in	O
beta	B-GENE
-	I-GENE
globin	I-GENE
mRNA	I-GENE
could	O
be	O
inhibited	O
by	O
the	O
tyrosine	B-GENE
kinase	I-GENE
inhibitor	O
genistein	O
and	O
the	O
protein	B-GENE
kinase	I-GENE
C	I-GENE
inhibitor	O
Compound	O
3	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
250	O
WORDS	O
)	O

This	O
structure	O
of	O
cucumisin	B-GENE
suggests	O
that	O
it	O
is	O
probably	O
synthesized	O
as	O
an	O
inactive	O
precursor	O
.	O

Molecular	O
dissection	O
of	O
the	O
multimeric	O
CD3	B-GENE
-	O
TCR	B-GENE
complex	O
revealed	O
that	O
at	O
least	O
two	O
associated	O
polypeptides	O
,	O
CD3	B-GENE
zeta	I-GENE
and	O
CD3	B-GENE
epsilon	I-GENE
,	O
autonomously	O
couple	O
antigenic	O
recognition	O
event	O
to	O
early	O
and	O
late	O
events	O
of	O
the	O
intracytoplasmic	O
activation	O
cascade	O
.	O

This	O
study	O
investigated	O
the	O
degree	O
to	O
which	O
racial	O
identity	O
influences	O
Mexican	O
-	O
Americans	O
'	O
performance	O
on	O
the	O
L	O
,	O
K	O
,	O
and	O
MF	O
scales	O
of	O
the	O
MMPI	O
-	O
2	O
.	O

Both	O
can	O
be	O
elevated	O
on	O
a	O
single	O
vascular	O
pedicle	O
based	O
on	O
the	O
superficial	O
temporal	O
artery	O
,	O
the	O
double	O
-	O
layered	O
temporal	O
fascia	O
flap	O
.	O

To	O
do	O
this	O
,	O
segments	O
of	O
DNA	O
from	O
the	O
5	O
'	O
flank	O
of	O
the	O
initiation	O
sites	O
for	O
germline	O
epsilon	O
RNA	O
were	O
ligated	O
to	O
a	O
luciferase	B-GENE
reporter	I-GENE
gene	I-GENE
and	O
transfected	O
into	O
two	O
mouse	O
B	O
cell	O
lines	O
,	O
one	O
of	O
which	O
can	O
be	O
induced	O
to	O
switch	O
to	O
IgE	B-GENE
.	O

The	O
negative	O
predictive	O
value	O
is	O
92	O
%	O
,	O
vs	O
80	O
%	O
for	O
the	O
NCEP	O
I	O
.	O

Oncogenic	O
capacity	O
of	O
the	O
E2F1	B-GENE
gene	I-GENE
.	O

In	O
some	O
of	O
the	O
cases	O
of	O
solitary	O
lesion	O
,	O
serum	B-GENE
TSH	I-GENE
levels	O
,	O
serum	B-GENE
thyroglobulin	I-GENE
values	O
,	O
and	O
131I	O
protein	O
bounded	O
iodine	O
(	O
131I	O
-	O
PBI	O
)	O
were	O
measured	O
,	O
but	O
there	O
were	O
no	O
significant	O
differences	O
between	O
successful	O
and	O
unsuccessful	O
therapy	O
.	O

Endo16	B-GENE
transcripts	I-GENE
are	O
confined	O
to	O
the	O
definitive	O
vegetal	O
plate	O
in	O
blastula	O
stage	O
embryos	O
;	O
at	O
gastrula	O
stage	O
this	O
gene	O
is	O
expressed	O
throughout	O
the	O
archenteron	O
,	O
but	O
later	O
only	O
in	O
the	O
midgut	O
.	O

A	O
unique	O
leucine	O
-	O
proline	O
repeat	O
element	O
found	O
N	O
-	O
terminal	O
to	O
the	O
DNA	O
-	O
binding	O
domain	O
of	O
EmBP	B-GENE
-	I-GENE
1	I-GENE
does	O
not	O
appear	O
to	O
play	O
a	O
role	O
in	O
DNA	O
-	O
binding	O
or	O
dimerization	O
.	O

Another	O
full	O
ORF	O
was	O
found	O
on	O
the	O
opposite	O
strand	O
downstream	O
from	O
the	O
nspC	B-GENE
gene	I-GENE
.	O

Two	O
related	O
cDNAs	O
were	O
isolated	O
that	O
encode	O
proteins	O
that	O
recognize	O
the	O
XMyoDa	B-GENE
TATA	I-GENE
motif	I-GENE
.	O

Deletion	O
of	O
both	O
prfA	B-GENE
and	O
ponA	B-GENE
resulted	O
in	O
extremely	O
slow	O
growth	O
and	O
a	O
reduction	O
in	O
sporulation	O
efficiency	O
.	O

In	O
broken	O
L	O
-	O
cell	O
membranes	O
expressing	O
wild	O
type	O
or	O
mutant	B-GENE
M6P	I-GENE
/	I-GENE
IGF	I-GENE
II	I-GENE
receptors	I-GENE
,	O
30	O
nM	O
IGF	B-GENE
II	I-GENE
also	O
failed	O
to	O
affect	O
the	O
pertussis	B-GENE
toxin	I-GENE
substrate	O
activity	O
.	O

Chem	O
.	O

For	O
the	O
first	O
time	O
we	O
describe	O
deletion	O
and	O
point	O
mutations	O
within	O
the	O
plasma	B-GENE
membrane	I-GENE
family	I-GENE
of	I-GENE
guanylyl	I-GENE
cyclase	I-GENE
receptors	I-GENE
that	O
result	O
in	O
the	O
formation	O
of	O
effective	O
dominant	O
negative	O
proteins	O
.	O

Increase	O
in	O
blood	O
NEFA	O
was	O
further	O
augmented	O
by	O
fat	O
plus	O
AA	O
supplementation	O
,	O
but	O
no	O
changes	O
in	O
concentrations	O
of	O
Lys	O
or	O
Met	O
in	O
blood	O
were	O
found	O
.	O

Virol	O
.	O

Comparison	O
of	O
the	O
deduced	O
amino	B-GENE
acid	I-GENE
sequence	I-GENE
of	I-GENE
gamma	I-GENE
-	I-GENE
kafirin	I-GENE
with	O
the	O
published	O
sequences	B-GENE
of	I-GENE
gamma	I-GENE
-	I-GENE
prolamins	I-GENE
of	I-GENE
maize	I-GENE
,	I-GENE
and	I-GENE
Coix	I-GENE
revealed	O
highly	O
conserved	O
domains	O
.	O

These	O
results	O
suggest	O
that	O
HAC1	B-GENE
may	O
also	O
be	O
one	O
of	O
the	O
meiotic	O
genes	O
.	O

We	O
characterized	O
three	O
Arabidopsis	O
thaliana	O
cDNA	O
clones	O
that	O
could	O
rescue	O
the	O
sterile	O
phenotype	O
of	O
the	O
Schizosaccharomyces	B-GENE
pombe	I-GENE
pde1	I-GENE
mutant	I-GENE
,	O
which	O
is	O
defective	O
in	O
cAMP	B-GENE
phosphodiesterase	I-GENE
.	O

Furthermore	O
,	O
the	O
identification	O
of	O
a	O
Dr1	B-GENE
-	I-GENE
like	I-GENE
protein	I-GENE
in	O
A	O
.	O
thaliana	O
strongly	O
argues	O
for	O
the	O
ubiquity	O
of	O
this	O
protein	O
among	O
eukaryotic	O
genera	O
and	O
for	O
a	O
conserved	O
mechanism	O
to	O
regulate	O
transcription	O
initiation	O
that	O
involves	O
Dr1	B-GENE
.	O

Similarly	O
approximately	O
300	O
bp	O
of	O
sequence	O
downstream	O
of	O
the	O
translation	O
terminator	O
TGA	O
of	O
the	O
beta	B-GENE
-	I-GENE
tubulin	I-GENE
2	I-GENE
(	O
BTU2	B-GENE
)	O
gene	O
could	O
substitute	O
for	O
the	O
3	O
'	O
region	O
of	O
the	O
H4	B-GENE
-	I-GENE
I	I-GENE
gene	I-GENE
.	O

These	O
data	O
demonstrate	O
that	O
the	O
STR	B-GENE
family	I-GENE
of	O
genes	O
is	O
represented	O
in	O
a	O
nematode	O
whose	O
ancestor	O
appeared	O
well	O
before	O
the	O
branching	O
that	O
gave	O
rise	O
to	O
the	O
Arthropoda	O
and	O
Chordata	O
.	O

The	O
pre	O
-	O
and	O
postoperative	O
haemoglobin	B-GENE
concentrations	O
in	O
the	O
autologous	O
group	O
were	O
lower	O
by	O
15	O
and	O
10	O
g	O
/	O
L	O
,	O
respectively	O
,	O
after	O
primary	O
THR	O
and	O
by	O
10	O
g	O
/	O
L	O
in	O
both	O
instances	O
after	O
revision	O
THR	O
.	O

The	O
introduction	O
of	O
an	O
acidic	O
residue	O
at	O
the	O
second	O
site	O
was	O
essential	O
for	O
suppression	O
of	O
the	O
Asn	O
-	O
285	O
mutation	O
because	O
Lys	O
-	O
220	O
and	O
Gln	O
-	O
220	O
second	O
-	O
site	O
mutants	O
of	O
the	O
Asn	O
-	O
285	O
mutant	O
showed	O
very	O
low	O
tetracycline	O
resistance	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
250	O
WORDS	O
)	O

Tumor	B-GENE
necrosis	I-GENE
factor	I-GENE
alpha	I-GENE
,	O
the	O
cytokine	O
that	O
participates	O
in	O
the	O
autocrine	O
growth	O
control	O
of	O
hairy	O
cell	O
leukemia	O
has	O
strong	O
bone	O
resorptive	O
properties	O
.	O

(	O
iv	O
)	O
Although	O
UCRBP	B-GENE
has	O
been	O
previously	O
shown	O
to	O
act	O
as	O
a	O
transcriptional	O
repressor	O
,	O
we	O
show	O
here	O
that	O
UCRBP	B-GENE
can	O
also	O
act	O
as	O
a	O
positive	O
transactivator	O
of	O
a	O
reporter	O
driven	O
by	O
UCR	O
elements	O
when	O
used	O
in	O
co	O
-	O
transfection	O
assays	O
.	O

The	O
sequence	O
of	O
monkey	B-GENE
opsin	I-GENE
closely	O
resembles	O
the	O
human	O
sequence	O
at	O
the	O
nucleotide	O
and	O
the	O
amino	O
acid	O
levels	O
,	O
with	O
the	O
latter	O
having	O
only	O
7	O
differences	O
out	O
of	O
348	O
residues	O
.	O

One	O
complex	O
appears	O
to	O
be	O
ubiquitous	O
but	O
enriched	O
in	O
lymphoid	O
cells	O
and	O
represents	O
the	O
binding	O
of	O
a	O
potentially	O
novel	O
factor	O
with	O
an	O
apparent	O
molecular	O
mass	O
of	O
approximately	O
50	O
kDa	O
.	O

Chem	O
.	O

Conversely	O
,	O
activation	O
of	O
Oct	B-GENE
-	I-GENE
3	I-GENE
/	I-GENE
4	I-GENE
promoter	I-GENE
by	O
RAR	B-GENE
:	O
RXR	B-GENE
heterodimers	I-GENE
was	O
completely	O
abolished	O
by	O
EAR	B-GENE
-	I-GENE
3	I-GENE
/	O
COUP	B-GENE
-	I-GENE
TFI	I-GENE
and	O
by	O
ARP	B-GENE
-	I-GENE
1	I-GENE
/	O
COUP	B-GENE
-	I-GENE
TFII	I-GENE
.	O

These	O
results	O
demonstrate	O
that	O
EKLF	B-GENE
provides	O
a	O
crucial	O
transactivation	O
function	O
for	O
globin	B-GENE
expression	O
and	O
further	O
reinforce	O
the	O
idea	O
that	O
EKLF	B-GENE
is	O
an	O
important	O
regulator	O
of	O
CACCC	O
element	O
-	O
directed	O
transcription	O
in	O
erythroid	O
cells	O
.	O

Using	O
a	O
battery	O
of	O
I	B-GENE
kappa	I-GENE
B	I-GENE
alpha	I-GENE
mutants	I-GENE
,	O
we	O
show	O
that	O
(	O
i	O
)	O
a	O
dimer	O
binds	O
a	O
single	O
I	B-GENE
kappa	I-GENE
B	I-GENE
alpha	I-GENE
molecule	I-GENE
,	O
(	O
ii	O
)	O
the	O
acidic	O
C	O
-	O
terminal	O
region	O
of	O
I	B-GENE
kappa	I-GENE
B	I-GENE
alpha	I-GENE
is	O
not	O
required	O
for	O
protein	O
-	O
protein	O
binding	O
and	O
does	O
not	O
mask	O
the	O
nuclear	O
localization	O
signal	O
of	O
the	O
dimer	O
,	O
(	O
iii	O
)	O
the	O
same	O
C	O
-	O
terminal	O
region	O
is	O
required	O
for	O
inhibition	O
of	O
DNA	O
binding	O
,	O
and	O
(	O
iv	O
)	O
this	O
inhibition	O
may	O
be	O
accomplished	O
by	O
direct	O
interaction	O
between	O
the	O
PEST	O
-	O
like	O
region	O
and	O
the	O
DNA	O
-	O
binding	O
region	O
of	O
one	O
of	O
the	O
subunits	O
of	O
the	O
dimer	O
.	O

The	O
negative	O
regulatory	O
activity	O
of	O
the	O
N	O
-	O
terminal	O
domain	O
was	O
antagonized	O
by	O
a	O
C	O
-	O
terminal	O
segment	O
of	O
Pho81p	B-GENE
supplied	O
in	O
trans	O
.	O

At	O
different	O
times	O
of	O
the	O
surgical	O
procedures	O
(	O
thorax	O
opening	O
and	O
closure	O
,	O
period	O
of	O
cardiopulmonary	O
bypass	O
)	O
67	O
to	O
100	O
%	O
of	O
the	O
patients	O
in	O
group	O
1	O
had	O
vancomycin	O
concentrations	O
in	O
the	O
studied	O
tissues	O
above	O
the	O
MIC	O
90	O
for	O
Staphylococcus	O
aureus	O
(	O
1	O
microgram	O
/	O
g	O
)	O
and	O
Staphylococcus	O
epidermidis	O
(	O
2	O
micrograms	O
/	O
g	O
)	O
.	O

On	O
-	O
line	O
angioscopic	O
images	O
of	O
tissue	O
flaps	O
floating	O
in	O
the	O
lumen	O
,	O
recent	O
or	O
structured	O
thrombi	O
,	O
artery	O
wall	O
dissections	O
,	O
plaque	O
ruptures	O
,	O
deep	O
fissurations	O
and	O
sub	O
-	O
intimal	O
haemorrhages	O
demonstrate	O
,	O
in	O
live	O
colour	O
,	O
the	O
pathophysiological	O
mechanisms	O
of	O
coronary	O
artery	O
stenosis	O
.	O

The	O
enhanced	O
cysteine	O
formation	O
in	O
a	O
pCSK4F	O
plant	O
responding	O
to	O
sulfite	O
was	O
also	O
observed	O
in	O
leaf	O
discs	O
.	O

Each	O
type	O
was	O
divided	O
into	O
two	O
subgroups	O
on	O
the	O
basis	O
of	O
whether	O
the	O
body	O
and	O
tail	O
of	O
the	O
pancreas	O
showed	O
intense	O
fatty	O
replacement	O
(	O
type	O
a	O
=	O
negative	O
for	O
intense	O
fatty	O
replacement	O
,	O
type	O
b	O
=	O
positive	O
for	O
intense	O
fatty	O
replacement	O
)	O
.	O

A	O
new	O
hypothesis	O
on	O
mechanisms	O
for	O
inhibiting	O
catalytic	O
subunits	O
by	O
gamma	O
-	O
subunits	O
and	O
activation	O
of	O
a	O
holoenzyme	O
by	O
transducin	B-GENE

Binding	O
of	O
SSP	B-GENE
to	O
the	O
stage	B-GENE
selector	I-GENE
element	I-GENE
(	O
SSE	B-GENE
)	O
in	O
the	O
proximal	O
gamma	B-GENE
-	I-GENE
globin	I-GENE
promoter	I-GENE
is	O
integral	O
to	O
the	O
competitive	O
silencing	O
of	O
a	O
linked	O
beta	B-GENE
-	I-GENE
promoter	I-GENE
in	O
embryonic	O
/	O
fetal	O
stage	O
erythroleukemia	O
(	O
K562	O
)	O
cells	O
.	O

This	O
failure	O
to	O
execute	O
regulated	O
G1	O
/	O
S	O
arrest	O
is	O
correlated	O
with	O
enhanced	O
thermosensitivity	O
of	O
colony	O
-	O
forming	O
ability	O
.	O

Mutations	O
that	O
alter	O
photoreceptor	O
cell	O
structure	O
and	O
development	O
were	O
isolated	O
that	O
fail	O
to	O
complement	O
these	O
deletions	O
.	O

It	O
is	O
possible	O
that	O
the	O
telomeres	O
of	O
the	O
two	O
nuclei	O
have	O
different	O
functions	O
.	O

The	O
marker	O
orders	O
from	O
the	O
genetic	O
and	O
RH	O
maps	O
were	O
consistent	O
.	O

Integrated	O
mapping	O
analysis	O
of	O
the	O
Werner	O
syndrome	O
region	O
of	O
chromosome	O
8	O
.	O

The	O
region	O
between	O
DXS52	B-GENE
and	O
Factor	B-GENE
VIII	I-GENE
gene	I-GENE
in	O
the	O
human	O
Xq28	O
chromosomal	O
band	O
contains	O
a	O
G	O
+	O
C	O
-	O
rich	O
isochore	O
to	O
which	O
many	O
genes	O
have	O
been	O
mapped	O
.	O

Haplotype	O
mapping	O
and	O
sequence	O
analysis	O
of	O
the	O
mouse	O
Nramp	B-GENE
gene	I-GENE
predict	O
susceptibility	O
to	O
infection	O
with	O
intracellular	O
parasites	O
.	O

This	O
utilization	O
of	O
an	O
intronic	O
polyadenylation	O
site	O
without	O
alternative	O
exon	O
usage	O
is	O
comparable	O
to	O
the	O
mechanism	O
whereby	O
both	O
secreted	O
and	O
membrane	O
-	O
bound	O
forms	O
of	O
the	O
immunoglobulin	B-GENE
mu	I-GENE
heavy	I-GENE
chain	I-GENE
are	O
made	O
from	O
a	O
single	O
genetic	O
locus	O
.	O

To	O
further	O
our	O
knowledge	O
about	O
the	O
systemic	O
humoral	O
immune	O
system	O
response	O
to	O
weak	O
hapten	O
-	O
syngeneic	O
or	O
allogeneic	O
protein	O
conjugates	O
(	O
corrosion	O
and	O
wear	O
products	O
of	O
metallic	O
orthopedic	O
devices	O
)	O
,	O
a	O
sensitive	O
enzyme	O
-	O
linked	O
immunosorbent	O
assay	O
(	O
ELISA	O
)	O
method	O
for	O
testing	O
for	O
antibody	O
(	O
humoral	O
immunity	O
)	O
to	O
metals	O
was	O
developed	O
.	O

In	O
contrast	O
,	O
peak	O
filling	O
rate	O
(	O
PFR	O
)	O
,	O
normalized	O
to	O
end	O
diastolic	O
volume	O
(	O
EDV	O
)	O
,	O
or	O
stroke	O
volume	O
(	O
SV	O
)	O
,	O
or	O
expressed	O
as	O
the	O
ratio	O
of	O
PFR	O
-	O
to	O
-	O
PER	O
was	O
reduced	O
(	O
p	O
<	O
0	O
.	O
01	O
)	O
,	O
time	O
to	O
PFR	O
(	O
TPFR	O
)	O
was	O
prolonged	O
(	O
p	O
<	O
0	O
.	O
01	O
)	O
,	O
and	O
echocardiographic	O
left	O
ventricular	O
mass	O
index	O
was	O
higher	O
(	O
p	O
<	O
0	O
.	O
001	O
)	O
in	O
patients	O
with	O
acromegaly	O
compared	O
to	O
normals	O
.	O

A	O
genetic	O
complementation	O
system	O
was	O
developed	O
in	O
which	O
tobacco	B-GENE
etch	I-GENE
virus	I-GENE
(	I-GENE
TEV	I-GENE
)	I-GENE
polymerase	I-GENE
(	O
NIb	B-GENE
)	O
-	O
expressing	O
transgenic	O
plants	O
or	O
protoplasts	O
were	O
inoculated	O
with	O
NIb	B-GENE
-	O
defective	O
TEV	B-GENE
mutants	I-GENE
.	O

Nucleotide	O
sequence	O
and	O
transcriptional	O
analysis	O
of	O
the	O
DNA	B-GENE
polymerase	I-GENE
gene	I-GENE
of	I-GENE
Bombyx	I-GENE
mori	I-GENE
nuclear	I-GENE
polyhedrosis	I-GENE
virus	I-GENE
.	O

Comparison	O
of	O
the	O
genomes	O
of	O
PMTV	O
,	O
BNYVV	O
,	O
and	O
SBWMV	O
shows	O
that	O
furoviruses	O
exhibit	O
considerable	O
heterogeneity	O
in	O
genome	O
organization	O
.	O

The	O
drug	O
sensitivity	O
was	O
100	O
%	O
for	O
vancomycin	O
(	O
VCM	O
)	O
,	O
30	O
%	O
for	O
imipenam	O
(	O
IMP	O
)	O
,	O
31	O
%	O
for	O
minomycin	O
(	O
MINO	O
)	O
,	O
31	O
%	O
for	O
amikacin	O
(	O
AMK	O
)	O
,	O
and	O
7	O
%	O
for	O
fosfomycin	O
(	O
FOM	O
)	O
.	O

Deglycosylation	O
with	O
endoglycosidase	B-GENE
H	I-GENE
showed	O
that	O
the	O
mutant	O
receptors	O
had	O
mainly	O
high	O
-	O
mannose	O
oligosaccharide	O
chains	O
.	O

Dietary	O
supplement	O
with	O
fish	O
oil	O
and	O
related	O
n	O
-	O
3	O
EFAs	O
has	O
been	O
used	O
to	O
study	O
their	O
antihypertensive	O
property	O
in	O
animals	O
and	O
humans	O
with	O
borderline	O
and	O
essential	O
hypertension	O
.	O

The	O
HSD3B1	B-GENE
and	O
HSD3B2	B-GENE
genes	I-GENE
encoding	O
the	O
types	B-GENE
I	I-GENE
and	I-GENE
II	I-GENE
3	I-GENE
beta	I-GENE
-	I-GENE
HSD	I-GENE
isoenzymes	I-GENE
,	O
respectively	O
,	O
have	O
been	O
previously	O
assigned	O
by	O
in	O
situ	O
hybridization	O
to	O
the	O
chromosome	O
1p13	O
.	O
1	O
region	O
.	O

Therefore	O
the	O
prevalences	O
of	O
total	O
diabetes	O
and	O
GDM	O
were	O
1	O
.	O
19	O
%	O
and	O
0	O
.	O
56	O
%	O
,	O
respectively	O
.	O

Insulin	B-GENE
-	O
stimulated	O
glucose	O
transport	O
in	O
adipocytes	O
is	O
mediated	O
by	O
the	O
insulin	B-GENE
receptor	I-GENE
.	O

After	O
selection	O
and	O
conversion	O
to	O
adipocytes	O
,	O
the	O
level	O
of	O
EGFR	B-GENE
expression	O
was	O
retained	O
in	O
infectant	O
adipocytes	O
(	O
150	O
,	O
000	O
and	O
250	O
,	O
000	O
/	O
cell	O
,	O
respectively	O
)	O
,	O
but	O
not	O
in	O
the	O
parental	O
3T3	O
-	O
L1	O
adipocytes	O
(	O
<	O
5000	O
/	O
cell	O
)	O
.	O

Intron	O
-	O
exon	O
structure	O
of	O
the	O
porcine	B-GENE
I	I-GENE
kappa	I-GENE
B	I-GENE
alpha	I-GENE
-	I-GENE
encoding	I-GENE
gene	I-GENE
.	O

Fraction	O
2	O
contains	O
1	O
,	O
25	O
(	O
OH	O
)	O
2	O
-	O
vitamin	O
D3	O
,	O
vitamin	O
D3	O
,	O
25	O
(	O
OH	O
)	O
-	O
vitamin	O
D3	O
and	O
1	O
,	O
24	O
,	O
25	O
(	O
OH	O
)	O
3	O
-	O
vitamin	O
D3	O
.	O

The	O
kallistatin	B-GENE
gene	I-GENE
was	O
localized	O
by	O
in	O
situ	O
hybridization	O
to	O
human	O
chromosome	O
14q31	O
-	O
q32	O
.	O
1	O
,	O
close	O
to	O
the	O
serpin	B-GENE
genes	I-GENE
encoding	O
alpha	B-GENE
1	I-GENE
-	I-GENE
antichymotrypsin	I-GENE
,	O
protein	B-GENE
C	I-GENE
inhibitor	I-GENE
,	O
alpha	B-GENE
1	I-GENE
-	I-GENE
antitrypsin	I-GENE
,	O
and	O
corticosteroid	B-GENE
-	I-GENE
binding	I-GENE
globulin	I-GENE
.	O

The	O
locus	O
encoding	O
the	O
XD	B-GENE
gene	I-GENE
(	O
designated	O
Xd	B-GENE
)	O
was	O
mapped	O
to	O
the	O
distal	O
part	O
of	O
mouse	O
chromosome	O
17	O
by	O
haplotype	O
analysis	O
of	O
114	O
interspecific	O
backcross	O
mice	O
.	O

Some	O
studies	O
of	O
exercise	O
have	O
associated	O
beta	B-GENE
-	I-GENE
endorphin	I-GENE
release	O
with	O
increased	O
exertion	O
levels	O
,	O
but	O
other	O
evidence	O
suggests	O
that	O
acidosis	O
may	O
stimulate	O
the	O
release	O
of	O
beta	B-GENE
-	I-GENE
endorphin	I-GENE
.	O

An	O
interatrial	O
communication	O
mitigates	O
the	O
impairment	O
of	O
LV	O
function	O
after	O
an	O
acute	O
and	O
sustained	O
drop	O
of	O
intrathoracic	O
pressure	O
.	O

The	O
characteristics	O
of	O
the	O
VirD1	B-GENE
/	O
VirD2	B-GENE
-	O
mediated	O
cleavage	O
reaction	O
strongly	O
resemble	O
those	O
observed	O
with	O
relaxosomes	O
of	O
IncP	O
plasmids	O
involved	O
in	O
initiation	O
of	O
transfer	O
DNA	O
replication	O
during	O
bacterial	O
conjugation	O
.	O

Isoelectric	O
focusing	O
of	O
tryptic	O
peptides	O
generated	O
from	O
MHC	B-GENE
-	I-GENE
B	I-GENE
phosphorylated	O
with	O
cdc2	B-GENE
kinase	I-GENE
revealed	O
one	O
major	O
phosphopeptide	O
that	O
was	O
purified	O
by	O
reverse	O
-	O
phase	O
high	O
performance	O
liquid	O
chromatography	O
and	O
sequenced	O
.	O

The	O
deduced	O
protein	O
sequence	O
was	O
88	O
%	O
homologous	O
to	O
that	O
of	O
hNUC	B-GENE
I	I-GENE
,	O
isolated	O
from	O
human	O
osteosarcoma	O
cells	O
.	O

A	O
comparison	O
of	O
the	O
Flavobacterium	O
glycosylasparaginase	B-GENE
with	O
a	O
mammalian	O
glycosylasparaginase	B-GENE
revealed	O
30	O
%	O
structural	O
identity	O
and	O
60	O
%	O
overall	O
similarity	O
between	O
the	O
prokaryotic	O
and	O
eukaryotic	O
forms	O
of	O
the	O
enzyme	O
.	O

Dissociation	O
and	O
complexation	O
of	O
the	O
fluoroquinolone	O
antimicrobials	O
-	O
-	O
an	O
update	O
.	O

Superoxide	B-GENE
dismutase	I-GENE
(	O
SOD	B-GENE
)	O
activity	O
decreased	O
significantly	O
in	O
sperm	O
subjected	O
to	O
direct	O
electric	O
current	O
in	O
comparison	O
to	O
the	O
control	O
or	O
the	O
sample	O
incubated	O
with	O
electrolyzed	O
medium	O
.	O

These	O
studies	O
indicate	O
that	O
in	O
vitro	O
and	O
in	O
vivo	O
electrical	O
stimulation	O
generate	O
reactive	O
oxygen	O
species	O
and	O
affect	O
SOD	B-GENE
activity	O
,	O
which	O
in	O
part	O
are	O
responsible	O
for	O
decreased	O
sperm	O
motion	O
and	O
viability	O
.	O

Sex	O
selection	O
via	O
albumin	B-GENE
columns	O
:	O
20	O
years	O
of	O
results	O
.	O

They	O
also	O
reported	O
that	O
E	B-GENE
mu	I-GENE
pim	I-GENE
-	I-GENE
1	I-GENE
transgenic	O
mice	O
show	O
greatly	O
accelerated	O
lymphoma	O
development	O
when	O
infected	O
with	O
wild	O
-	O
type	O
M	O
-	O
MuLV	O
at	O
birth	O
.	O

Comparison	O
of	O
human	B-GENE
and	I-GENE
murine	I-GENE
blk	I-GENE
sequences	I-GENE
indicated	O
that	O
they	O
share	O
86	O
%	O
amino	O
acid	O
identity	O
,	O
the	O
most	O
conserved	O
region	O
being	O
the	O
catalytic	O
domain	O
(	O
93	O
%	O
identity	O
)	O
.	O

The	O
effect	O
of	O
ethanol	O
on	O
human	O
sensorimotor	O
reactivity	O
was	O
assessed	O
by	O
examining	O
the	O
acoustic	O
startle	O
response	O
.	O

Digitalis	O
glycosides	O
or	O
beta	B-GENE
-	I-GENE
receptor	I-GENE
antagonists	O
are	O
not	O
helpful	O
in	O
the	O
therapy	O
of	O
this	O
form	O
of	O
atrial	O
fibrillation	O
whereas	O
class	O
I	O
antiarrhythmic	O
drugs	O
have	O
been	O
shown	O
to	O
be	O
more	O
effective	O
.	O

Atrial	O
fibrillation	O
and	O
the	O
autonomic	O
nervous	O
system	O

VIII	O
in	O
doses	O
2	O
-	O
3	O
times	O
higher	O
than	O
usually	O
used	O
in	O
haemophiliacs	O
without	O
inhibitor	O
were	O
successful	O
.	O

A	O
reduction	O
of	O
the	O
aspartate	B-GENE
aminotransferase	I-GENE
activity	O
was	O
observed	O
from	O
800	O
mg	O
/	O
kg	O
b	O
.	O
w	O
.	O
/	O
d	O
onwards	O
.	O

Thus	O
,	O
these	O
studies	O
indicate	O
that	O
the	O
104	O
-	O
kDa	O
isoform	O
is	O
required	O
for	O
normal	O
proliferation	O
of	O
female	O
germline	O
cells	O
and	O
perhaps	O
for	O
oocyte	O
differentiation	O
.	O

Physical	O
analysis	O
maps	O
SAL6	B-GENE
to	O
chromosome	O
XVI	O
between	O
TPK2	B-GENE
and	O
spt14	B-GENE
.	O

The	O
newly	O
devised	O
DCT	O
method	O
yields	O
reliable	O
data	O
in	O
measuring	O
TBF	O
.	O

Removal	O
of	O
PDMP	O
from	O
the	O
cell	O
medium	O
resulted	O
in	O
reversal	O
of	O
the	O
cell	O
cycle	O
changes	O
,	O
with	O
cells	O
re	O
-	O
entering	O
the	O
S	O
phase	O
.	O

Rho	B-GENE
GDP	I-GENE
/	I-GENE
GTP	I-GENE
exchange	I-GENE
inhibitor	I-GENE
,	O
Rho	B-GENE
GDI	I-GENE
,	O
comigrated	O
with	O
Rac2	B-GENE
and	O
RhoA	B-GENE
,	O
but	O
not	O
Rac1	B-GENE
.	O

Schnell	O
,	O
J	O
.	O

Encapsidation	O
of	O
poliovirus	O
replicons	O
encoding	O
the	O
complete	O
human	B-GENE
immunodeficiency	I-GENE
virus	I-GENE
type	I-GENE
1	I-GENE
gag	I-GENE
gene	I-GENE
by	O
using	O
a	O
complementation	O
system	O
which	O
provides	O
the	O
P1	B-GENE
capsid	I-GENE
protein	I-GENE
in	O
trans	O
.	O

The	O
requirement	O
of	O
PilE	B-GENE
in	O
pilus	O
biogenesis	O
was	O
confirmed	O
by	O
demonstrating	O
that	O
chromosomal	B-GENE
pilE	I-GENE
insertion	I-GENE
mutants	I-GENE
were	O
pilus	O
-	O
and	O
twitching	O
-	O
motility	O
deficient	O
.	O

The	O
pilE	B-GENE
gene	I-GENE
product	I-GENE
of	I-GENE
Pseudomonas	I-GENE
aeruginosa	I-GENE
,	O
required	O
for	O
pilus	O
biogenesis	O
,	O
shares	O
amino	O
acid	O
sequence	O
identity	O
with	O
the	O
N	O
-	O
termini	O
of	O
type	B-GENE
4	I-GENE
prepilin	I-GENE
proteins	I-GENE
.	O

Because	O
of	O
the	O
functional	O
conservation	O
of	O
cell	O
cycle	O
control	O
elements	O
,	O
the	O
expression	O
of	O
a	O
vertebrate	B-GENE
wee1	I-GENE
or	O
mik1	B-GENE
homolog	I-GENE
would	O
be	O
expected	O
to	O
rescue	O
such	O
lethal	O
mutations	O
in	O
yeast	O
.	O

The	O
expression	O
of	O
this	O
clone	O
in	O
a	O
wee1	B-GENE
/	O
mik1	B-GENE
-	O
deficient	O
mutant	O
causes	O
an	O
elongated	O
cell	O
phenotype	O
under	O
non	O
-	O
permissive	O
growth	O
conditions	O
.	O

These	O
data	O
indicate	O
that	O
phosphorylation	O
of	O
M	B-GENE
protein	I-GENE
at	O
the	O
major	O
in	O
vivo	O
sites	O
is	O
not	O
essential	O
for	O
virus	O
assembly	O
.	O

Near	O
a	O
third	O
(	O
31	O
.	O
6	O
%	O
)	O
of	O
Insulin	B-GENE
Dependent	O
and	O
a	O
third	O
(	O
33	O
.	O
41	O
%	O
)	O
for	O
Non	O
Insulin	B-GENE
Dependent	O
were	O
of	O
D	O
,	O
F	O
,	O
H	O
White	O
'	O
s	O
Class	O
.	O

The	O
activity	O
of	O
6	O
-	O
fluoroquinolones	O
and	O
their	O
nonfluorinated	O
derivatives	O
is	O
compared	O
in	O
general	O
.	O

As	O
the	O
half	O
-	O
life	O
of	O
the	O
compound	O
did	O
never	O
exceed	O
8	O
-	O
9	O
h	O
,	O
the	O
data	O
do	O
not	O
support	O
any	O
change	O
of	O
pidotimod	O
administration	O
schedule	O
(	O
every	O
24	O
-	O
12	O
h	O
)	O
.	O

The	O
MAP	B-GENE
kinase	I-GENE
cascade	O
is	O
highly	O
conserved	O
in	O
all	O
eukaryotes	O
and	O
involved	O
in	O
numerous	O
cellular	O
responses	O
.	O

A	O
comparative	O
study	O
by	O
holographic	O
interferometry	O
of	O
ten	O
porcine	O
bioprosthetic	O
valves	O
(	O
seven	O
Carpentier	O
-	O
Edwards	O
SAV	O
,	O
two	O
BioImplant	O
and	O
one	O
Valcor	O
)	O
with	O
five	O
human	O
aortic	O
valves	O
before	O
and	O
after	O
glutaraldehyde	O
treatment	O
is	O
presented	O
.	O

No	O
serious	O
side	O
effects	O
were	O
observed	O
.	O

This	O
region	O
constitutes	O
the	O
DNA	O
-	O
binding	O
domain	O
with	O
basic	O
-	O
helix	O
-	O
loop	O
-	O
helix	O
and	O
leucine	O
-	O
zipper	O
motifs	O
,	O
features	O
common	O
to	O
the	O
myc	B-GENE
-	I-GENE
related	I-GENE
transcription	I-GENE
factor	I-GENE
family	I-GENE
.	O

The	O
mean	O
jitter	O
and	O
the	O
fiber	O
density	O
did	O
not	O
change	O
significantly	O
from	O
day	O
0	O
(	O
30	O
.	O
1	O
+	O
/	O
-	O
3	O
.	O
6	O
microseconds	O
;	O
1	O
.	O
4	O
+	O
/	O
-	O
0	O
.	O
07	O
)	O
to	O
day	O
30	O
(	O
34	O
.	O
5	O
+	O
/	O
-	O
2	O
.	O
7	O
microseconds	O
;	O
1	O
.	O
6	O
+	O
/	O
-	O
0	O
.	O
13	O
)	O
.	O

Lack	O
of	O
cyclin	B-GENE
D	I-GENE
-	O
Cdk	B-GENE
complexes	O
in	O
Rb	B-GENE
-	O
negative	O
cells	O
correlates	O
with	O
high	O
levels	O
of	O
p16INK4	B-GENE
/	O
MTS1	B-GENE
tumour	O
suppressor	O
gene	O
product	O
.	O

Recombinant	B-GENE
human	I-GENE
serum	I-GENE
albumin	I-GENE
(	O
rHSA	B-GENE
)	O
produced	O
by	O
cultured	O
fermentation	O
has	O
been	O
prepared	O
in	O
the	O
form	O
of	O
microcapsules	O
nominally	O
3	O
-	O
5	O
microns	O
in	O
diameter	O
and	O
radiolabelled	O
with	O
technetium	O
-	O
99m	O
following	O
reduction	O
with	O
stannous	O
chloride	O
.	O

We	O
have	O
measured	O
the	O
release	O
of	O
interleukin	B-GENE
-	I-GENE
1	I-GENE
beta	I-GENE
(	O
IL	B-GENE
-	I-GENE
1	I-GENE
)	O
and	O
tumour	B-GENE
necrosis	I-GENE
factor	I-GENE
-	I-GENE
alpha	I-GENE
(	O
TNF	B-GENE
)	O
by	O
unstimulated	O
monocytes	O
and	O
monocytes	O
stimulated	O
with	O
lipopolysaccharide	O
(	O
LPS	O
)	O
isolated	O
from	O
the	O
peripheral	O
blood	O
of	O
two	O
patients	O
with	O
acute	O
poststreptococcal	O
glomerulonephritis	O
(	O
AGN	O
)	O
and	O
16	O
healthy	O
controls	O
.	O

Such	O
an	O
intervention	O
may	O
be	O
of	O
considerable	O
use	O
for	O
the	O
treatment	O
of	O
angiogenesis	O
-	O
dependent	O
diseases	O
involving	O
FGF	B-GENE
-	I-GENE
2	I-GENE
.	O

UV	O
cross	O
-	O
linking	O
experiments	O
show	O
that	O
TEP	B-GENE
has	O
an	O
apparent	O
molecular	O
mass	O
of	O
approximately	O
65	O
kDa	O
.	O

Alternatively	O
,	O
loss	O
-	O
of	O
-	O
function	O
alleles	O
of	O
genes	O
that	O
inhibit	O
cAPK	B-GENE
lead	O
to	O
the	O
inability	O
to	O
undergo	O
sexual	O
differentiation	O
.	O

One	O
member	O
of	O
this	O
family	O
,	O
RFX1	B-GENE
,	O
is	O
a	O
transcription	O
factor	O
for	O
a	O
variety	O
of	O
viral	O
and	O
cellular	O
genes	O
.	O

This	O
mutant	O
was	O
identified	O
by	O
screening	O
with	O
a	O
TGF	B-GENE
-	I-GENE
beta	I-GENE
-	O
inducible	O
vector	O
a	O
series	O
of	O
mink	O
lung	O
epithelial	O
cell	O
clones	O
that	O
have	O
normal	O
TGF	B-GENE
-	I-GENE
beta	I-GENE
binding	O
activity	O
but	O
have	O
lost	O
antiproliferative	O
and	O
transcriptional	O
responses	O
to	O
TGF	B-GENE
-	I-GENE
beta	I-GENE
.	O

Cloning	O
by	O
complementation	O
and	O
subsequent	O
physical	O
and	O
genetic	O
analysis	O
revealed	O
that	O
it	O
maps	O
to	O
RAF1	B-GENE
.	O

In	O
the	O
presence	O
of	O
inositol	O
and	O
choline	O
(	O
repressing	O
)	O
,	O
the	O
product	O
of	O
the	O
OPI1	B-GENE
gene	I-GENE
represses	O
transcription	O
dictated	O
by	O
the	O
UASINO	O
element	O
.	O

By	O
treating	O
monkey	O
COS	O
cells	O
with	O
oligonucleotides	O
linked	O
to	O
psoralen	O
,	O
we	O
have	O
generated	O
targeted	O
mutations	O
in	O
a	O
simian	O
virus	O
40	O
(	O
SV40	O
)	O
vector	O
contained	O
within	O
the	O
cells	O
via	O
intracellular	O
triple	O
helix	O
formation	O
.	O

The	O
interleukin	B-GENE
2	I-GENE
receptor	I-GENE
alpha	I-GENE
-	I-GENE
chain	I-GENE
(	O
IL	B-GENE
-	I-GENE
2R	I-GENE
alpha	I-GENE
)	O
gene	O
is	O
rapidly	O
and	O
potently	O
induced	O
in	O
T	O
cells	O
in	O
response	O
to	O
mitogenic	O
stimuli	O
.	O

The	O
Wilms	B-GENE
'	I-GENE
tumour	I-GENE
suppressor	I-GENE
protein	I-GENE
(	O
WT1	B-GENE
)	O
is	O
a	O
putative	O
transcriptional	O
regulatory	O
protein	O
with	O
four	O
zinc	O
fingers	O
,	O
the	O
last	O
three	O
of	O
which	O
have	O
extensive	O
sequence	O
homology	O
to	O
the	O
early	B-GENE
growth	I-GENE
response	I-GENE
-	I-GENE
1	I-GENE
(	O
EGR	B-GENE
-	I-GENE
1	I-GENE
)	O
protein	O
.	O

OBJECTIVES	O
:	O
1	O
)	O
to	O
determine	O
serum	B-GENE
ACE	I-GENE
activity	O
in	O
patients	O
with	O
COPD	O
treated	O
with	O
and	O
without	O
continuous	O
ambulatory	O
oxygen	O
therapy	O
(	O
CAOT	O
)	O
;	O
2	O
)	O
to	O
verify	O
whether	O
there	O
is	O
a	O
correlation	O
between	O
ACE	B-GENE
and	O
any	O
hematological	O
,	O
spirometric	O
or	O
gasometric	O
parameter	O
.	O

In	O
order	O
to	O
infer	O
shape	O
from	O
contour	O
,	O
the	O
human	O
visual	O
system	O
must	O
selectively	O
integrate	O
fragments	O
projecting	O
from	O
a	O
common	O
object	O
while	O
keeping	O
fragments	O
from	O
different	O
objects	O
separate	O
.	O

Among	O
9	O
group	O
I	O
patients	O
with	O
a	O
positive	O
result	O
on	O
head	O
-	O
up	O
tilt	O
-	O
table	O
testing	O
and	O
no	O
evidence	O
of	O
structural	O
heart	O
disease	O
(	O
mean	O
follow	O
-	O
up	O
4	O
.	O
3	O
years	O
)	O
,	O
7	O
are	O
without	O
further	O
episodes	O
of	O
syncope	O
;	O
3	O
have	O
discontinued	O
medication	O
and	O
5	O
have	O
resumed	O
at	O
least	O
limited	O
exercise	O
.	O

Constructs	O
designed	O
and	O
expressed	O
were	O
E2L1	B-GENE
(	I-GENE
1	I-GENE
-	I-GENE
98	I-GENE
)	I-GENE
,	O
E2L1	B-GENE
.	I-GENE
H1	I-GENE
(	I-GENE
1	I-GENE
-	I-GENE
128	I-GENE
)	I-GENE
,	O
E2L2	B-GENE
(	I-GENE
120	I-GENE
-	I-GENE
233	I-GENE
)	I-GENE
,	O
E2H1	B-GENE
.	I-GENE
L2	I-GENE
(	I-GENE
98	I-GENE
-	I-GENE
233	I-GENE
)	I-GENE
,	O
and	O
E2L1	B-GENE
.	I-GENE
H1	I-GENE
.	I-GENE
L2	I-GENE
(	I-GENE
1	I-GENE
-	I-GENE
233	I-GENE
)	I-GENE
,	O
where	O
numbers	O
in	O
parentheses	O
give	O
the	O
amino	O
acid	O
sequence	O
for	O
the	O
portions	O
of	O
the	O
E2	B-GENE
component	O
incorporated	O
into	O
a	O
construct	O
.	O

Thus	O
,	O
we	O
have	O
produced	O
lipoyl	O
domain	O
constructs	O
that	O
can	O
be	O
employed	O
in	O
sorting	O
the	O
specific	O
roles	O
of	O
E2L1	B-GENE
and	O
E2L2	B-GENE
in	O
facilitating	O
catalytic	O
and	O
regulatory	O
processes	O
.	O

METHODS	O
:	O
Ten	O
influenza	O
A	O
(	O
H3N2	O
)	O
viruses	O
isolated	O
during	O
the	O
outbreaks	O
were	O
examined	O
for	O
resistance	O
to	O
amantadine	O
and	O
rimantadine	O
by	O
means	O
of	O
an	O
enzyme	O
immunoassay	O
and	O
by	O
sequencing	O
of	O
the	O
viral	O
nucleic	O
acid	O
that	O
encodes	O
the	O
transmembrane	O
domain	O
of	O
the	O
M2	B-GENE
protein	I-GENE
.	O

The	O
first	O
contains	O
ATF	B-GENE
/	O
CRE	O
and	O
TBP	B-GENE
/	O
TATA	O
sequence	O
motifs	O
within	O
an	O
87	O
-	O
bp	O
region	O
.	O

Gene	O
expression	O
occurs	O
in	O
a	O
circadian	O
rhythm	O
and	O
induced	O
by	O
light	O
in	O
leaves	O
of	O
dark	O
-	O
adapted	O
plants	O
.	O

Our	O
results	O
suggested	O
that	O
the	O
hexamer	O
and	O
the	O
octamer	O
motifs	O
may	O
play	O
important	O
role	O
(	O
s	O
)	O
in	O
regulation	O
of	O
replication	O
-	O
dependent	O
but	O
not	O
of	O
replication	O
-	O
independent	O
expression	O
of	O
the	O
wheat	B-GENE
histone	I-GENE
H3	I-GENE
gene	I-GENE
.	O

The	O
tissue	O
-	O
specific	O
expression	O
of	O
DP	B-GENE
family	I-GENE
members	I-GENE
suggests	O
that	O
the	O
combination	O
of	O
DP	B-GENE
/	O
E2F	B-GENE
heterodimers	O
that	O
constitute	O
DRTF1	B-GENE
/	O
E2F	B-GENE
is	O
influenced	O
by	O
the	O
phenotype	O
of	O
the	O
cell	O
.	O

In	O
a	O
second	O
experiment	O
involving	O
an	O
18	O
-	O
h	O
lung	O
clearance	O
assay	O
,	O
we	O
used	O
the	O
mAb	B-GENE
3	I-GENE
.	I-GENE
2	I-GENE
.	I-GENE
3	I-GENE
to	O
deplete	O
rats	O
of	O
LGL	O
/	O
NK	O
cells	O
with	O
the	O
following	O
rationale	O
:	O
if	O
LGL	O
/	O
NK	O
cells	O
are	O
necessary	O
to	O
mediate	O
an	O
event	O
,	O
then	O
in	O
their	O
absence	O
,	O
that	O
event	O
should	O
not	O
occur	O
.	O

Treatment	O
of	O
recurrent	O
FSGS	O
has	O
included	O
high	O
-	O
dose	O
steroids	O
,	O
high	O
-	O
dose	O
cyclosporine	O
(	O
CSA	O
)	O
,	O
plasmapheresis	O
,	O
and	O
ACE	B-GENE
inhibitors	O
with	O
mixed	O
results	O
.	O

Our	O
results	O
concluded	O
that	O
1	O
)	O
the	O
two	O
inhibin	B-GENE
/	O
activin	B-GENE
beta	O
B	O
-	O
subunit	O
mRNAs	O
were	O
transcribed	O
from	O
different	O
initiation	O
sites	O
;	O
2	O
)	O
both	O
promoters	O
may	O
be	O
controlled	O
by	O
up	O
-	O
stream	O
negative	O
regulatory	O
elements	O
;	O
and	O
3	O
)	O
neither	O
of	O
these	O
promoters	O
is	O
responsive	O
to	O
cAMP	O
and	O
/	O
or	O
phorbol	O
esters	O
under	O
the	O
conditions	O
employed	O
.	O

Promoter	O
region	O
of	O
the	O
transcriptional	O
unit	O
for	O
human	B-GENE
alpha	I-GENE
1	I-GENE
-	I-GENE
chimaerin	I-GENE
,	O
a	O
neuron	B-GENE
-	I-GENE
specific	I-GENE
GTPase	I-GENE
-	I-GENE
activating	I-GENE
protein	I-GENE
for	O
p21rac	B-GENE
.	O
alpha	B-GENE
1	I-GENE
-	I-GENE
chimaerin	I-GENE
is	O
a	O
neuron	B-GENE
-	I-GENE
specific	I-GENE
GTPase	I-GENE
-	I-GENE
activating	I-GENE
protein	I-GENE
for	O
p21rac	B-GENE
,	O
a	O
protein	O
involved	O
in	O
morphological	O
events	O
.	O

Upstream	O
from	O
the	O
transcription	O
start	O
point	O
(	O
tsp	O
)	O
,	O
a	O
nucleotide	O
sequence	O
highly	O
homologous	O
to	O
the	O
consensus	B-GENE
sequence	I-GENE
motif	I-GENE
for	I-GENE
the	I-GENE
sigma	I-GENE
35	I-GENE
-	I-GENE
recognized	I-GENE
promoters	I-GENE
was	O
found	O
.	O

In	O
this	O
paper	O
,	O
an	O
analysis	O
of	O
the	O
dynamics	O
in	O
the	O
closing	O
phase	O
of	O
the	O
occluder	O
of	O
a	O
mechanical	O
monoleaflet	O
heart	O
valve	O
prosthesis	O
is	O
presented	O
.	O

During	O
ISO	O
+	O
AT	O
infusion	O
,	O
abdominal	O
fat	O
blood	O
flow	O
was	O
still	O
significantly	O
increased	O
as	O
compared	O
with	O
control	O
values	O
in	O
lean	O
and	O
obese	O
subjects	O
.	O

When	O
expressed	O
per	O
kilogram	O
body	O
weight	O
,	O
mean	O
GIT	O
increased	O
in	O
the	O
dF	O
group	O
from	O
0	O
.	O
14	O
%	O
to	O
0	O
.	O
16	O
%	O
above	O
RMR	O
,	O
with	O
a	O
significant	O
decrease	O
from	O
0	O
.	O
15	O
%	O
to	O
0	O
.	O
13	O
%	O
in	O
the	O
P	O
group	O
.	O

In	O
nucleus	O
ventralis	O
anterior	O
thalami	O
-	O
nucleus	O
ventralis	O
lateralis	O
thalami	O
neurons	O
with	O
an	O
inhibitory	O
input	O
from	O
nucleus	O
entopeduncularis	O
,	O
a	O
shortening	O
of	O
inhibition	O
from	O
17	O
.	O
5	O
+	O
/	O
-	O
3	O
.	O
6	O
to	O
9	O
.	O
1	O
+	O
/	O
-	O
1	O
.	O
8	O
ms	O
(	O
P	O
<	O
0	O
.	O
05	O
)	O
under	O
the	O
haloperidol	O
influence	O
was	O
evident	O
.	O

However	O
,	O
inclusion	O
of	O
the	O
neighboring	O
CGGAAR	O
motifs	O
from	O
the	O
ICP4	B-GENE
promoter	I-GENE
,	O
which	O
bind	O
factors	O
GABP	B-GENE
alpha	I-GENE
and	I-GENE
beta	I-GENE
,	O
results	O
in	O
a	O
strong	O
synergistic	O
activation	O
.	O

This	O
finding	O
represents	O
both	O
a	O
potentially	O
important	O
mechanism	O
by	O
which	O
HPV	O
gene	O
expression	O
can	O
be	O
regulated	O
and	O
an	O
interesting	O
model	O
for	O
the	O
study	O
of	O
transcriptional	O
cooperativity	O
.	O

Using	O
this	O
method	O
,	O
VLPs	O
were	O
obtained	O
in	O
quantities	O
sufficient	O
for	O
further	O
characterization	O
.	O

Analysis	O
of	O
the	O
sequence	O
upstream	O
of	O
this	O
initiation	O
codon	O
reveals	O
the	O
presence	O
of	O
a	O
promotor	O
sequence	O
.	O

SUP46	B-GENE
is	O
implicated	O
in	O
translation	O
fidelity	O
and	O
encodes	O
the	O
ribosomal	B-GENE
protein	I-GENE
S13	I-GENE
.	O

To	O
explore	O
the	O
functional	O
relationship	O
between	O
c	B-GENE
-	I-GENE
fos	I-GENE
and	O
Rb	B-GENE
,	O
a	O
eukaryotic	O
expression	O
plasmid	O
was	O
constructed	O
containing	O
the	O
c	B-GENE
-	I-GENE
fos	I-GENE
gene	I-GENE
under	O
control	O
of	O
the	O
SV40	B-GENE
promoter	I-GENE
complex	O
.	O

The	O
high	O
degree	O
of	O
sequence	O
identity	O
(	O
96	O
%	O
)	O
between	O
hydrolase	B-GENE
B	I-GENE
and	I-GENE
C	I-GENE
,	O
particularly	O
in	O
the	O
3	O
'	O
untranslated	O
region	O
,	O
suggests	O
that	O
the	O
genes	O
encoding	O
these	O
two	O
carboxylesterases	B-GENE
evolved	O
by	O
duplication	O
and	O
divergence	O
of	O
a	O
common	O
ancestral	O
gene	O
.	O

The	O
regions	O
of	O
the	O
tooth	O
fracture	O
are	O
determined	O
.	O

Secondary	O
pancreatic	O
involvement	O
of	O
mycosis	O
fungoides	O
detected	O
by	O
a	O
clinically	O
palpable	O
mass	O
.	O

The	O
NR2	O
hybrid	O
is	O
a	O
powerful	O
tool	O
for	O
the	O
mapping	O
of	O
new	O
probes	O
of	O
this	O
region	O
,	O
as	O
well	O
as	O
for	O
obtaining	O
new	O
informative	O
probes	O
specific	O
for	O
the	O
deletion	O
by	O
subtractive	O
cloning	O
of	O
the	O
region	O
.	O

TDEYA	O
at	O
doses	O
of	O
200	O
to	O
500	O
mg	O
/	O
kg	O
significantly	O
suppressed	O
xanthine	B-GENE
oxidase	I-GENE
(	O
XO	B-GENE
)	O
activity	O
in	O
the	O
stomach	O
tissue	O
following	O
its	O
oral	O
administration	O
.	O

Like	O
humans	O
,	O
the	O
PITSLRE	B-GENE
PK	I-GENE
genes	I-GENE
in	I-GENE
chickens	I-GENE
must	O
be	O
closely	O
linked	O
,	O
based	O
on	O
fluorescent	O
in	O
situ	O
hybridization	O
(	O
FISH	O
)	O
localization	O
of	O
these	O
genes	O
to	O
a	O
single	O
chicken	O
microchromosome	O
.	O

Here	O
,	O
we	O
report	O
the	O
characterization	O
of	O
an	O
alternatively	O
processed	O
form	O
of	O
AFAP	B-GENE
-	I-GENE
110	I-GENE
that	O
encodes	O
an	O
additional	O
258	O
base	O
pair	O
(	O
bp	O
)	O
of	O
open	O
reading	O
frame	O
.	O

Expression	O
of	O
class	B-GENE
IV	I-GENE
ADH	I-GENE
mRNA	I-GENE
was	O
detected	O
in	O
human	O
stomach	O
but	O
not	O
liver	O
.	O

In	O
ICE	B-GENE
gamma	I-GENE
,	O
most	O
of	O
the	O
propeptide	O
(	O
amino	O
acids	O
20	O
-	O
112	O
)	O
is	O
deleted	O
,	O
which	O
suggests	O
that	O
it	O
may	O
function	O
as	O
a	O
catalyst	O
for	O
ICE	B-GENE
autoprocessing	O
in	O
vivo	O
.	O

Endocytosis	O
and	O
lysosomal	O
targeting	O
of	O
epidermal	B-GENE
growth	I-GENE
factor	I-GENE
receptors	I-GENE
are	O
mediated	O
by	O
distinct	O
sequences	O
independent	O
of	O
the	O
tyrosine	B-GENE
kinase	I-GENE
domain	I-GENE
.	O

It	O
is	O
now	O
recognized	O
that	O
essentially	O
all	O
eukaryotic	O
and	O
prokaryotic	O
genes	O
whose	O
5	O
'	O
-	O
flanking	O
regions	O
are	O
known	O
and	O
that	O
encode	O
barbiturate	O
-	O
inducible	O
proteins	O
contain	O
the	O
Barbie	O
box	O
element	O
.	O

Mutation	O
of	O
the	O
P450BM	B-GENE
-	I-GENE
3	I-GENE
Barbie	I-GENE
box	I-GENE
significantly	O
increased	O
the	O
expression	O
of	O
both	O
P450BM	B-GENE
-	I-GENE
3	I-GENE
and	O
Bm3P1	B-GENE
(	O
another	O
small	O
gene	O
located	O
upstream	O
of	O
the	O
P450BM	B-GENE
-	I-GENE
3	I-GENE
gene	I-GENE
that	O
encodes	O
a	O
second	O
putative	O
regulatory	O
protein	O
)	O
in	O
response	O
to	O
pentobarbital	O
induction	O
but	O
left	O
the	O
basal	O
levels	O
unaffected	O
.	O

A	O
potential	O
outcome	O
of	O
these	O
biochemical	O
effects	O
may	O
include	O
the	O
limited	O
responsiveness	O
of	O
infected	O
T	O
cells	O
to	O
antigenic	O
stimulation	O
observed	O
during	O
HIV	O
-	O
1	O
infection	O
.	O

The	O
full	O
protocol	O
was	O
completed	O
by	O
33	O
patients	O
(	O
45	O
%	O
of	O
original	O
cohort	O
)	O
.	O

In	O
addition	O
,	O
we	O
found	O
that	O
cell	O
-	O
specific	O
suppression	O
of	O
RA	O
-	O
stimulated	O
zif268	B-GENE
gene	I-GENE
expression	O
can	O
be	O
attributed	O
to	O
a	O
29	O
base	O
pair	O
nucleotide	O
sequence	O
,	O
located	O
downstream	O
of	O
the	O
RA	O
-	O
responsive	O
region	O
in	O
the	O
zif268	B-GENE
gene	I-GENE
.	O

We	O
show	O
that	O
CBF	B-GENE
-	I-GENE
A	I-GENE
and	O
CBF	B-GENE
-	I-GENE
C	I-GENE
interact	O
with	O
each	O
other	O
to	O
form	O
a	O
CBF	B-GENE
-	I-GENE
A	I-GENE
-	O
CBF	B-GENE
-	I-GENE
C	I-GENE
complex	O
and	O
that	O
CBF	B-GENE
-	I-GENE
B	I-GENE
does	O
not	O
interact	O
with	O
CBF	B-GENE
-	I-GENE
A	I-GENE
or	O
CBF	B-GENE
-	I-GENE
C	I-GENE
individually	O
but	O
that	O
it	O
associates	O
with	O
the	O
CBF	B-GENE
-	I-GENE
A	I-GENE
-	O
CBF	B-GENE
-	I-GENE
C	I-GENE
complex	O
.	O

In	O
the	O
first	O
,	O
homologous	O
sequences	O
were	O
deleted	O
from	O
a	O
mouse	O
enhancer	O
,	O
resulting	O
in	O
a	O
tissue	O
-	O
specific	O
loss	O
of	O
activity	O
when	O
assayed	O
in	O
transgenic	O
mice	O
.	O

OKT3	B-GENE
prophylaxis	O
improves	O
long	O
-	O
term	O
renal	O
graft	O
survival	O
in	O
high	O
-	O
risk	O
patients	O
as	O
compared	O
to	O
cyclosporine	O
:	O
combined	O
results	O
from	O
the	O
prospective	O
,	O
randomized	O
Belgian	O
and	O
US	O
studies	O
.	O

The	O
major	O
PKC	B-GENE
beta	I-GENE
transcription	O
initiation	O
site	O
was	O
identified	O
by	O
primer	O
extension	O
and	O
S1	B-GENE
nuclease	I-GENE
protection	O
.	O

In	O
the	O
course	O
of	O
a	O
study	O
of	O
low	O
dose	O
X	O
-	O
rays	O
effects	O
,	O
we	O
found	O
that	O
male	O
ICR	O
white	O
Swiss	O
mice	O
showed	O
remarkable	O
suppression	O
of	O
mounting	O
behavior	O
after	O
whole	O
body	O
irradiation	O
by	O
5	O
to	O
15	O
cGy	O
X	O
-	O
rays	O
.	O

A	O
quantitative	O
analysis	O
of	O
the	O
diffraction	O
intensity	O
as	O
function	O
of	O
the	O
accumulated	O
electron	O
dose	O
suggests	O
the	O
possibility	O
of	O
recording	O
up	O
to	O
250	O
diffraction	O
patterns	O
with	O
3	O
.	O
5	O
A	O
resolution	O
from	O
a	O
single	O
crotoxin	O
complex	O
crystal	O
128	O
A	O
thick	O
.	O

Supplementary	O
Phase	O
Contraste	O
RSE	O
(	O
"	O
Rapid	O
Sequential	O
Excitation	O
"	O
)	O
sequences	O
were	O
carried	O
out	O
in	O
29	O
patients	O
.	O

In	O
yeast	O
,	O
the	O
products	O
of	O
the	O
UPF1	B-GENE
and	O
UPF3	B-GENE
genes	I-GENE
are	O
required	O
for	O
this	O
decay	O
pathway	O
,	O
and	O
in	O
this	O
report	O
we	O
focus	O
on	O
the	O
identification	O
and	O
characterization	O
of	O
additional	O
factors	O
required	O
for	O
rapid	O
decay	O
of	O
nonsense	O
-	O
containing	O
mRNAs	O
.	O

Mutations	O
in	O
UPF1	B-GENE
lead	O
to	O
the	O
selective	O
stabilization	O
of	O
mRNAs	O
containing	O
early	O
nonsense	O
mutations	O
without	O
affecting	O
the	O
decay	O
rates	O
of	O
most	O
other	O
mRNAs	O
.	O

A	O
DNA	O
fragment	O
encoding	O
the	O
DNA	O
-	O
binding	O
domain	O
(	O
amino	O
acids	O
1	O
-	O
60	O
)	O
of	O
the	O
Escherichia	B-GENE
coli	I-GENE
fru	I-GENE
transcriptional	I-GENE
regulator	I-GENE
was	O
cloned	O
into	O
the	O
pGEX	O
-	O
KT	O
vector	O
and	O
expressed	O
in	O
frame	O
with	O
the	O
fused	O
gene	O
encoding	O
glutathione	B-GENE
S	I-GENE
-	I-GENE
transferase	I-GENE
.	O

0	O
.	O
61	O
+	O
/	O
-	O
0	O
.	O
04	O
)	O
.	O

Several	O
nuclear	O
factors	O
that	O
interact	O
with	O
sequences	O
in	O
the	O
5	O
'	O
flanking	O
region	O
of	O
the	O
mouse	B-GENE
tyrosinase	I-GENE
gene	I-GENE
were	O
identified	O
using	O
band	O
shift	O
and	O
methylation	O
interference	O
assays	O
.	O

With	O
a	O
population	O
of	O
853	O
million	O
there	O
should	O
be	O
51	O
,	O
204	O
patients	O
with	O
hemophilia	O
A	O
in	O
India	O
assuming	O
a	O
prevalence	O
of	O
6	O
/	O
100	O
,	O
000	O
population	O
.	O

When	O
combined	O
with	O
serum	O
ferritin	B-GENE
and	O
hemoglobin	B-GENE
determinations	O
,	O
the	O
serum	O
transferrin	B-GENE
receptor	I-GENE
assay	O
is	O
a	O
valuable	O
addition	O
in	O
epidemiologic	O
surveys	O
because	O
it	O
provides	O
a	O
quantitative	O
measure	O
of	O
functional	O
iron	O
deficiency	O
and	O
it	O
distinguishes	O
true	O
IDA	O
from	O
the	O
anemia	O
of	O
chronic	O
disease	O
.	O

Since	O
1990	O
the	O
University	O
Hospital	O
of	O
Tromso	O
has	O
provided	O
local	O
hospitals	O
in	O
northern	O
Norway	O
with	O
a	O
remote	O
frozen	O
section	O
service	O
and	O
with	O
access	O
to	O
video	O
conferences	O
for	O
the	O
review	O
of	O
microscopic	O
findings	O
and	O
for	O
the	O
discussion	O
of	O
major	O
diagnostic	O
issues	O
.	O

Current	O
status	O
of	O
telepathology	O
.	O

PMEK1	B-GENE
displays	O
96	O
and	O
80	O
%	O
identity	O
respectively	O
with	O
the	O
tobacco	B-GENE
NTF3	I-GENE
and	O
Arabidopsis	B-GENE
ATMPK1	I-GENE
kinases	I-GENE
,	O
and	O
only	O
50	O
%	O
to	O
the	O
more	O
distantly	O
related	O
plant	O
MAP	O
kinase	O
MsERK1	B-GENE
from	O
alfalfa	O
.	O

Translation	O
of	O
the	O
coding	O
segment	O
,	O
which	O
was	O
designated	O
MsPRP2	B-GENE
,	O
suggested	O
it	O
encodes	O
a	O
chimeric	O
40	O
,	O
569	O
Da	O
cell	O
wall	O
protein	O
with	O
an	O
amino	O
-	O
terminal	O
signal	O
sequence	O
,	O
a	O
repetitive	O
proline	O
-	O
rich	O
sequence	O
,	O
and	O
a	O
cysteine	O
-	O
rich	O
carboxyl	O
-	O
terminal	O
sequence	O
homologous	O
to	O
nonspecific	O
lipid	O
transfer	O
proteins	O
.	O

The	O
presence	O
of	O
type	O
I	O
hypersensitivity	O
in	O
a	O
subgroup	O
of	O
aspergillomas	O
suggests	O
an	O
immunoallergic	O
component	O
to	O
this	O
disease	O
which	O
could	O
contribute	O
to	O
a	O
chronic	O
inflammatory	O
response	O
to	O
Aspergillus	O
in	O
some	O
aspergillomas	O
.	O

This	O
concept	O
is	O
supported	O
by	O
the	O
identification	O
of	O
RH	B-GENE
-	I-GENE
like	I-GENE
genes	I-GENE
in	O
non	O
human	O
primates	O
.	O

With	O
steady	O
illumination	O
,	O
outer	O
retinal	O
(	O
photoreceptor	O
)	O
QO2	O
decreased	O
to	O
1	O
.	O
4	O
+	O
/	O
-	O
0	O
.	O
9	O
ml	O
O2	O
/	O
(	O
100	O
g	O
.	O
min	O
)	O
,	O
but	O
inner	O
retinal	O
QO2	O
remained	O
unchanged	O
at	O
3	O
.	O
7	O
+	O
/	O
-	O
1	O
.	O
5	O
ml	O
O2	O
/	O
(	O
100	O
g	O
.	O
min	O
)	O
(	O
5	O
cats	O
)	O
.	O

We	O
have	O
screened	O
the	O
mouse	O
cDNA	O
library	O
of	O
an	O
MIN6	O
cell	O
line	O
,	O
derived	O
from	O
pancreatic	O
beta	O
cells	O
,	O
for	O
its	O
novel	O
isoform	O
and	O
have	O
identified	O
a	O
cDNA	O
encoding	O
a	O
593	O
-	O
amino	O
acid	O
protein	O
having	O
63	O
,	O
53	O
,	O
and	O
30	O
%	O
identity	O
with	O
munc	B-GENE
-	I-GENE
18	I-GENE
/	I-GENE
n	I-GENE
-	I-GENE
Sec1	I-GENE
/	I-GENE
rbSec1	I-GENE
,	O
Caenorhabditis	B-GENE
elegans	I-GENE
unc18	I-GENE
,	O
and	O
Saccharomyces	B-GENE
cerevisiae	I-GENE
Sec1p	I-GENE
,	O
respectively	O
.	O

The	O
catenins	B-GENE
bind	O
to	O
APC	B-GENE
and	O
E	B-GENE
-	I-GENE
cadherin	I-GENE
in	O
a	O
similar	O
fashion	O
,	O
but	O
APC	B-GENE
and	O
E	B-GENE
-	I-GENE
cadherin	I-GENE
do	O
not	O
associate	O
with	O
each	O
other	O
either	O
in	O
the	O
presence	O
or	O
absence	O
of	O
catenins	B-GENE
.	O

However	O
,	O
addition	O
of	O
core	B-GENE
DNA	I-GENE
polymerase	I-GENE
III	I-GENE
to	O
preinitiation	O
complex	O
,	O
fully	O
reconstituting	O
holoenzyme	O
resulted	O
in	O
replacement	O
of	O
gamma	O
by	O
alpha	O
at	O
the	O
primer	O
terminus	O
.	O

Computerized	O
detection	O
of	O
abnormal	O
asymmetry	O
in	O
digital	O
chest	O
radiographs	O
.	O

These	O
results	O
suggest	O
that	O
gluconeogenic	O
genes	O
are	O
derepressed	O
upon	O
binding	O
of	O
Cat8p	B-GENE
,	O
whose	O
synthesis	O
depends	O
on	O
the	O
release	O
of	O
Cat4p	B-GENE
(	O
Mig1p	B-GENE
)	O
from	O
the	O
CAT8	B-GENE
promoter	I-GENE
.	O

We	O
show	O
here	O
that	O
the	O
binding	O
of	O
C1F	B-GENE
in	O
vitro	O
is	O
sensitive	O
to	O
the	O
concentration	O
of	O
calcium	O
ions	O
.	O

Survival	O
after	O
development	O
of	O
symptomatic	O
infection	O
(	O
P	O
-	O
2	O
)	O
did	O
not	O
differ	O
by	O
transmission	O
mode	O
.	O

These	O
data	O
suggest	O
that	O
the	O
function	O
of	O
the	O
DS2	B-GENE
may	O
be	O
the	O
protection	O
of	O
the	O
nuclear	O
DNA	O
from	O
desiccation	O
.	O

Glomerular	O
hemodynamics	O
during	O
abortion	O
induced	O
by	O
RU	O
486	O
and	O
sepsis	O
in	O
rats	O
.	O

The	O
aim	O
of	O
this	O
retrospective	O
study	O
was	O
to	O
demonstrate	O
that	O
in	O
certain	O
cases	O
of	O
expulsive	O
choroidal	O
hemorrhage	O
(	O
ECH	O
)	O
anatomical	O
success	O
and	O
useful	O
vision	O
can	O
be	O
obtained	O
with	O
repeated	O
vitreoretinal	O
surgery	O
.	O

The	O
function	O
of	O
the	O
C	O
-	O
terminal	O
tail	O
in	O
telomere	O
maintenance	O
is	O
not	O
mediated	O
through	O
the	O
RAP1	B-GENE
interacting	I-GENE
factor	I-GENE
RIF1	B-GENE
:	O
rap1	B-GENE
alleles	I-GENE
defective	O
in	O
both	O
the	O
C	O
-	O
terminal	O
tail	O
and	O
RIF1	B-GENE
interaction	I-GENE
domains	I-GENE
have	O
additive	O
effects	O
on	O
telomere	O
length	O
.	O

The	O
contribution	O
of	O
skin	O
flow	O
to	O
the	O
changes	O
in	O
760	O
-	O
800	O
nm	O
absorption	O
was	O
investigated	O
by	O
simultaneous	O
measurement	O
of	O
skin	O
flow	O
by	O
laser	O
flow	O
Doppler	O
and	O
NIR	O
recordings	O
during	O
hot	O
water	O
immersion	O
.	O

Proteins	O
immunoprecipitated	O
from	O
lysates	O
of	O
control	O
-	O
and	O
VEGF	B-GENE
-	O
stimulated	O
BAEC	O
with	O
antisera	O
to	O
phospholipase	B-GENE
C	I-GENE
-	I-GENE
gamma	I-GENE
(	O
PLC	B-GENE
-	I-GENE
gamma	I-GENE
)	O
were	O
fractionated	O
by	O
SDS	O
-	O
polyacrylamide	O
gel	O
electrophoresis	O
and	O
transferred	O
to	O
Immobilon	O
-	O
P	O
.	O

Alternatively	O
processed	O
isoforms	O
of	O
cellular	B-GENE
nucleic	I-GENE
acid	I-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
interact	O
with	O
a	O
suppressor	O
region	O
of	O
the	O
human	B-GENE
beta	I-GENE
-	I-GENE
myosin	I-GENE
heavy	I-GENE
chain	I-GENE
gene	I-GENE
.	O

Involvement	O
of	O
early	B-GENE
growth	I-GENE
response	I-GENE
factor	I-GENE
Egr	I-GENE
-	I-GENE
1	I-GENE
in	O
apolipoprotein	B-GENE
AI	I-GENE
gene	I-GENE
transcription	O
.	O

The	O
wild	O
-	O
type	O
and	O
altered	O
forms	O
of	O
the	O
F	B-GENE
protein	I-GENE
were	O
expressed	O
in	O
BHK	O
-	O
21	O
and	O
HeLa	O
T4	O
cells	O
by	O
use	O
of	O
the	O
recombinant	B-GENE
vaccinia	I-GENE
virus	I-GENE
-	I-GENE
encoding	I-GENE
T7	I-GENE
polymerase	I-GENE
system	O
.	O

Erythrocyte	B-GENE
delta	I-GENE
-	I-GENE
aminolevulinic	I-GENE
acid	I-GENE
dehydratase	I-GENE
(	O
ALAD	B-GENE
)	O
activity	O
,	O
erythrocyte	O
zinc	O
protoporphyrin	O
(	O
ZPP	O
)	O
/	O
heme	O
ratio	O
,	O
and	O
urinary	O
coproporphyrin	O
(	O
UC	O
)	O
concentration	O
have	O
been	O
employed	O
as	O
biological	O
indicators	O
of	O
moderate	O
-	O
to	O
high	O
-	O
level	O
lead	O
exposure	O
,	O
corresponding	O
to	O
blood	O
levels	O
in	O
excess	O
of	O
50	O
micrograms	O
/	O
dl	O
,	O
in	O
human	O
subjects	O
.	O

The	O
relative	O
risk	O
of	O
graft	O
loss	O
after	O
conversion	O
to	O
azathioprine	O
compared	O
with	O
graft	O
loss	O
after	O
conversion	O
to	O
azathioprine	O
compared	O
with	O
cyclosporin	O
maintenance	O
was	O
0	O
.	O
71	O
(	O
0	O
.	O
37	O
-	O
1	O
.	O
38	O
)	O
and	O
the	O
relative	O
risk	O
of	O
patient	O
death	O
was	O
0	O
.	O
57	O
(	O
0	O
.	O
23	O
-	O
1	O
.	O
41	O
)	O
.	O

The	O
"	O
tobacco	O
issue	O
"	O
.	O

The	O
effect	O
of	O
the	O
Ca	O
entry	O
blocker	O
nitrendipine	O
,	O
the	O
antioxidant	O
superoxide	B-GENE
dismutase	I-GENE
(	O
SOD	B-GENE
)	O
,	O
and	O
a	O
combination	O
of	O
nitrendipine	O
and	O
superoxide	B-GENE
dismutase	I-GENE
on	O
postischemic	O
renal	O
function	O
was	O
studied	O
in	O
four	O
groups	O
(	O
n	O
=	O
24	O
)	O
of	O
rats	O
.	O

PURPOSE	O
:	O
The	O
aim	O
of	O
this	O
study	O
was	O
to	O
evaluate	O
the	O
bony	O
anchorage	O
of	O
a	O
new	O
implant	O
(	O
orderly	O
wired	O
surface	O
effect	O
with	O
alloy	O
Ti	O
Al	O
Va	O
and	O
ordered	O
pores	O
of	O
488	O
mu	O
)	O
.	O

To	O
determine	O
whether	O
food	O
and	O
/	O
or	O
water	O
in	O
the	O
gastrointestinal	O
tract	O
affects	O
restitution	O
of	O
blood	O
volume	O
and	O
plasma	O
protein	O
after	O
hemorrhage	O
,	O
fed	O
and	O
24	O
-	O
h	O
-	O
fasted	O
awake	O
rats	O
received	O
a	O
20	O
ml	O
.	O
kg	O
-	O
1	O
x	O
3	O
min	O
-	O
1	O
hemorrhage	O
,	O
and	O
restitution	O
of	O
blood	O
volume	O
was	O
measured	O
by	O
Evans	O
blue	O
dye	O
and	O
dilution	O
of	O
hematocrit	O
.	O

Cooperative	O
dimerization	O
of	O
paired	B-GENE
class	O
homeo	O
domains	O
on	O
DNA	O
.	O

We	O
took	O
advantage	O
of	O
the	O
high	O
degree	O
of	O
aa	O
sequence	O
homology	O
between	O
DAHPSs	B-GENE
from	O
several	O
species	O
to	O
isolate	O
ARO3	B-GENE
homologues	I-GENE
from	O
the	O
pathogenic	O
yeast	O
Candida	O
albicans	O
.	O

In	O
this	O
study	O
,	O
we	O
demonstrate	O
that	O
BOX	O
DNA	O
enhances	O
transcription	O
from	O
the	O
thymidine	B-GENE
kinase	I-GENE
(	O
TK	B-GENE
)	O
promoter	O
in	O
various	O
EC	O
cells	O
.	O

Deletion	O
analyses	O
of	O
the	O
construct	O
revealed	O
that	O
the	O
transcription	O
of	O
BOXF1	B-GENE
gene	I-GENE
is	O
regulated	O
by	O
BOX	O
DNA	O
,	O
preferentially	O
in	O
undifferentiated	O
EC	O
cells	O
versus	O
differentiated	O
cells	O
.	O

The	O
presence	O
of	O
an	O
unusual	O
transcript	O
possessing	O
IVS2C	B-GENE
beta	I-GENE
1	I-GENE
at	O
the	O
5	O
'	O
terminus	O
suggests	O
that	O
cleavage	O
of	O
its	O
splice	O
acceptor	O
is	O
inefficient	O
or	O
negatively	O
regulated	O
.	O

During	O
chronic	O
treatment	O
,	O
when	O
plasma	O
concentrations	O
fluctuated	O
between	O
23	O
.	O
5	O
ng	O
.	O
ml	O
-	O
1	O
at	O
8	O
h	O
and	O
14	O
ng	O
.	O
ml	O
-	O
1	O
at	O
24	O
h	O
post	O
-	O
dosing	O
,	O
ST	O
segment	O
depression	O
at	O
an	O
individually	O
comparable	O
workload	O
was	O
significantly	O
decreased	O
by	O
28	O
%	O
compared	O
with	O
placebo	O
(	O
P	O
<	O
0	O
.	O
005	O
)	O
at	O
both	O
points	O
in	O
time	O
.	O

Results	O
from	O
in	O
vitro	O
transcription	O
-	O
translation	O
analysis	O
and	O
maxicell	O
experiments	O
suggested	O
that	O
the	O
447	O
-	O
bp	O
ORF	O
was	O
the	O
one	O
being	O
actively	O
expressed	O
.	O

Preliminary	O
experiments	O
demonstrated	O
that	O
it	O
was	O
possible	O
to	O
produce	O
fasD	B-GENE
mutants	I-GENE
,	O
whose	O
products	O
remain	O
functional	O
for	O
fimbrial	O
export	O
and	O
assembly	O
.	O

Evoked	O
electromyographic	O
response	O
to	O
indirect	O
supramaximal	O
stimulation	O
at	O
1	O
Hz	O
was	O
monitored	O
in	O
ten	O
adult	O
goats	O
under	O
thiopentone	O
-	O
halothane	O
anaesthesia	O
.	O

313	O
,	O
98	O
-	O
102	O
)	O
.	O

Group	O
6	O
was	O
given	O
physostigmine	O
,	O
0	O
.	O
1	O
mg	O
/	O
kg	O
i	O
.	O
v	O
.	O
,	O
known	O
to	O
inhibit	O
cholinesterase	B-GENE
degradation	O
,	O
5	O
min	O
before	O
bupivacaine	O
administration	O
,	O
and	O
Group	O
7	O
received	O
a	O
combination	O
of	O
physostigmine	O
pretreatment	O
and	O
electrical	O
vagal	O
stimulation	O
.	O

To	O
examine	O
the	O
possibility	O
that	O
LNNB	O
performance	O
of	O
the	O
schizophrenic	O
groups	O
may	O
have	O
been	O
related	O
to	O
neuroleptic	O
medication	O
,	O
analyses	O
were	O
completed	O
on	O
the	O
relationship	O
between	O
medication	O
levels	O
and	O
LNNB	O
scores	O
.	O

ISIS	O
5	O
possibilities	O
.	O

The	O
use	O
of	O
specific	O
antibodies	O
allowed	O
the	O
identification	O
of	O
at	O
least	O
RAR	B-GENE
beta	I-GENE
in	O
some	O
of	O
the	O
DNA	O
-	O
protein	O
complexes	O
,	O
although	O
the	O
four	O
sequences	O
bind	O
single	O
RARs	B-GENE
transfected	O
in	O
COS	O
cells	O
much	O
less	O
efficiently	O
,	O
or	O
not	O
at	O
all	O
,	O
when	O
compared	O
to	O
a	O
canonical	O
RAR	B-GENE
responsive	I-GENE
element	I-GENE
.	O

The	O
present	O
treatment	O
strategy	O
in	O
progressive	O
disorders	O
is	O
mainly	O
based	O
on	O
the	O
complementary	O
effect	O
of	O
intensive	O
radiochemotherapy	O
,	O
autologous	O
stem	O
-	O
cell	O
transplantation	O
and	O
the	O
rational	O
use	O
of	O
cytokines	O
,	O
mostly	O
colony	B-GENE
-	I-GENE
stimulating	I-GENE
factors	I-GENE
.	O

Our	O
study	O
cohorts	O
consisted	O
of	O
15	O
patients	O
who	O
received	O
SC	O
rIL	B-GENE
-	I-GENE
2	I-GENE
at	O
doses	O
of	O
4	O
.	O
8	O
-	O
14	O
.	O
4	O
million	O
IU	O
/	O
m2	O
/	O
day	O
on	O
5	O
days	O
per	O
week	O
for	O
a	O
total	O
of	O
8	O
weeks	O
,	O
20	O
patients	O
who	O
received	O
rIFN	B-GENE
-	I-GENE
alpha	I-GENE
2b	I-GENE
at	O
3	O
.	O
0	O
-	O
6	O
.	O
0	O
million	O
U	O
/	O
m2	O
/	O
day	O
thrice	O
weekly	O
for	O
a	O
total	O
of	O
6	O
weeks	O
,	O
and	O
72	O
patients	O
who	O
were	O
given	O
SC	O
rIFN	B-GENE
-	I-GENE
alpha	I-GENE
2b	I-GENE
at	O
6	O
.	O
0	O
million	O
U	O
/	O
m2	O
/	O
day	O
thrice	O
weekly	O
plus	O
SC	O
rIL	B-GENE
-	I-GENE
2	I-GENE
at	O
14	O
.	O
4	O
-	O
18	O
.	O
0	O
million	O
IU	O
/	O
m2	O
/	O
day	O
on	O
days	O
1	O
and	O
2	O
,	O
followed	O
by	O
4	O
.	O
8	O
million	O
IU	O
/	O
m2	O
/	O
day	O
,	O
5	O
days	O
per	O
week	O
for	O
6	O
consecutive	O
weeks	O
.	O

At	O
the	O
MTD	O
(	O
8	O
mg	O
/	O
m2	O
/	O
day	O
)	O
,	O
the	O
dose	O
-	O
limiting	O
toxicity	O
of	O
this	O
agent	O
is	O
myelosuppression	O
.	O

Mitogen	O
-	O
induced	O
lymphocyte	O
proliferation	O
was	O
diminished	O
.	O

A	O
decanucleotide	O
promoter	O
sequence	O
homologous	O
to	O
those	O
found	O
in	O
humans	O
and	O
mice	O
was	O
located	O
in	O
the	O
5	O
'	O
untranslated	O
region	O
of	O
one	O
horse	O
gene	O
.	O

Some	O
of	O
these	O
targets	O
were	O
reported	O
to	O
code	O
for	O
molecules	O
involved	O
in	O
cell	O
-	O
cell	O
interactions	O
,	O
whereas	O
no	O
relationship	O
has	O
yet	O
been	O
demonstrated	O
between	O
Hox	B-GENE
genes	I-GENE
and	O
other	O
transcription	O
factors	O
involved	O
in	O
determining	O
and	O
/	O
or	O
maintaining	O
tissue	O
specificity	O
.	O

HER2	B-GENE
overexpressing	O
cells	O
showed	O
a	O
single	O
prominent	O
DNase	B-GENE
I	I-GENE
hypersensitive	O
site	O
near	O
a	O
conserved	O
and	O
hitherto	O
unrecognized	O
ets	B-GENE
response	O
element	O
(	O
GAGGAA	O
)	O
,	O
located	O
38	O
bases	O
down	O
-	O
stream	O
from	O
the	O
CAAT	O
box	O
and	O
directly	O
5	O
'	O
of	O
the	O
TATA	O
box	O
in	O
the	O
human	B-GENE
HER2	I-GENE
promoter	I-GENE
.	O

Gel	O
-	O
shift	O
assays	O
with	O
nuclear	O
extracts	O
and	O
oligonucleotide	O
sequences	O
spanning	O
the	O
0	O
.	O
125	O
-	O
kb	O
promoter	O
region	O
detected	O
an	O
ETS	B-GENE
-	O
immunoreactive	O
complex	O
,	O
present	O
most	O
abundantly	O
in	O
cells	O
overexpressing	O
HER2	B-GENE
,	O
whose	O
high	O
-	O
affinity	O
binding	O
depended	O
on	O
the	O
GAGGAA	O
response	O
element	O
.	O

Comparison	O
of	O
cDNA	O
sequences	O
revealed	O
that	O
the	O
two	O
mRNA	O
species	O
arise	O
as	O
a	O
result	O
of	O
alternate	O
use	O
of	O
poly	O
(	O
A	O
)	O
-	O
addition	O
sites	O
.	O

The	O
gene	O
for	O
the	O
RNA	B-GENE
-	I-GENE
dependent	I-GENE
eIF	I-GENE
-	I-GENE
2	I-GENE
alpha	I-GENE
protein	I-GENE
kinase	I-GENE
(	O
PKR	B-GENE
)	O
was	O
isolated	O
from	O
mouse	O
genomic	O
DNA	O
and	O
characterized	O
.	O

High	O
-	O
frequency	O
electrical	O
stimulation	O
in	O
the	O
hippocampus	O
leads	O
to	O
an	O
increase	O
in	O
synaptic	O
efficacy	O
that	O
lasts	O
for	O
many	O
hours	O
.	O

Similar	O
to	O
the	O
mouse	O
gene	O
,	O
the	O
5	O
'	O
flanking	O
region	O
of	O
human	B-GENE
CD79	I-GENE
alpha	I-GENE
lacks	O
a	O
TATA	O
box	O
;	O
however	O
,	O
unlike	O
mouse	B-GENE
CD79	I-GENE
alpha	I-GENE
,	O
a	O
classical	O
octamer	O
motif	O
could	O
not	O
be	O
identified	O
in	O
the	O
human	O
gene	O
.	O

Detailed	O
molecular	O
organization	O
of	O
the	O
coding	O
and	O
upstream	O
regulatory	O
regions	O
of	O
the	O
murine	O
homeodomain	B-GENE
-	I-GENE
containing	I-GENE
gene	I-GENE
,	O
Msx	B-GENE
-	I-GENE
1	I-GENE
,	O
is	O
reported	O
.	O

We	O
report	O
here	O
the	O
cloning	O
of	O
the	O
human	B-GENE
goosecoid	I-GENE
gene	I-GENE
(	O
GSC	B-GENE
)	O
from	O
a	O
genomic	O
library	O
and	O
the	O
sequence	O
of	O
its	O
encoded	O
protein	O
.	O

This	O
virus	O
is	O
not	O
merely	O
a	O
South	O
African	O
strain	O
of	O
passion	O
fruit	O
woodiness	O
virus	O
(	O
PWV	O
)	O
:	O
the	O
deduced	O
CP	B-GENE
sequence	I-GENE
is	O
only	O
distantly	O
related	O
to	O
CPs	B-GENE
of	O
other	O
sequenced	O
strains	O
of	O
PWV	O
,	O
although	O
it	O
is	O
part	O
of	O
a	O
distinct	O
subgroup	O
of	O
potyviruses	O
related	O
to	O
PWV	O
.	O

The	O
ratio	O
of	O
the	O
activity	O
of	O
arogenate	B-GENE
dehydrogenase	I-GENE
to	O
that	O
of	O
prephenate	B-GENE
dehydrogenase	I-GENE
(	O
approximately	O
3	O
:	O
1	O
)	O
remained	O
constant	O
throughout	O
purification	O
,	O
and	O
the	O
two	O
activities	O
were	O
therefore	O
inseparable	O
.	O

A	O
leucine	O
zipper	O
domain	O
of	O
the	O
suppressor	B-GENE
of	I-GENE
Hairy	I-GENE
-	I-GENE
wing	I-GENE
protein	I-GENE
mediates	O
its	O
repressive	O
effect	O
on	O
enhancer	O
function	O
.	O

It	O
is	O
concluded	O
that	O
CT	O
should	O
be	O
routinely	O
employed	O
in	O
patients	O
with	O
N1	O
-	O
N3	O
neck	O
disease	O
to	O
determine	O
the	O
proper	O
electron	O
-	O
energy	O
prescription	O
.	O

The	O
predicted	O
DNA	O
-	O
binding	O
,	O
zinc	B-GENE
finger	I-GENE
domain	I-GENE
protein	I-GENE
sequence	O
was	O
strictly	O
conserved	O
.	O

60	O
patients	O
were	O
entered	O
into	O
a	O
randomised	O
study	O
comparing	O
vindesine	O
(	O
3	O
mg	O
/	O
m2	O
/	O
week	O
)	O
plus	O
interferon	B-GENE
-	I-GENE
alpha	I-GENE
2b	I-GENE
(	O
6	O
U	O
/	O
m2	O
3	O
times	O
per	O
week	O
)	O
to	O
vindesine	O
alone	O
or	O
to	O
interferon	B-GENE
alone	O
for	O
the	O
treatment	O
of	O
metastatic	O
malignant	O
melanoma	O
.	O

BACKGROUND	O
:	O
We	O
conducted	O
a	O
phase	O
I	O
study	O
with	O
MDL	O
73	O
,	O
147EF	O
,	O
a	O
new	O
5	B-GENE
hydroxytryptamine	I-GENE
3	I-GENE
(	I-GENE
5	I-GENE
-	I-GENE
HT3	I-GENE
)	I-GENE
receptor	I-GENE
antagonist	O
,	O
in	O
25	O
patients	O
requiring	O
emetogenic	O
chemotherapy	O
.	O

In	O
the	O
presence	O
of	O
the	O
in	O
vivo	O
reducing	O
system	O
(	O
thioredoxin	B-GENE
,	O
thioredoxin	B-GENE
reductase	I-GENE
,	O
and	O
NADPH	O
)	O
,	O
however	O
,	O
each	O
of	O
these	O
mutants	O
catalyzed	O
the	O
formation	O
of	O
only	O
0	O
.	O
6	O
-	O
0	O
.	O
8	O
dCTPs	O
per	O
mole	O
of	O
enzyme	O
.	O

These	O
genetic	O
alterations	O
do	O
not	O
affect	O
synthesis	O
of	O
the	O
major	O
c	B-GENE
-	I-GENE
myc	I-GENE
protein	I-GENE
,	O
p64	B-GENE
,	O
which	O
is	O
initiated	O
from	O
the	O
first	O
AUG	O
codon	O
in	O
exon	O
2	O
.	O

In	O
addition	O
,	O
both	O
the	O
exon	O
1	O
-	O
and	O
exon	O
2	O
-	O
initiated	O
forms	O
of	O
the	O
c	B-GENE
-	I-GENE
Myc	I-GENE
protein	I-GENE
stimulated	O
transcription	O
of	O
a	O
Myc	B-GENE
/	O
Max	B-GENE
-	O
responsive	O
reporter	O
construct	O
to	O
a	O
similar	O
level	O
.	O

Biological	O
activities	O
of	O
hematopoietic	B-GENE
growth	I-GENE
factors	I-GENE
that	O
lead	O
to	O
future	O
clinical	O
application	O
.	O

Expression	O
is	O
exclusively	O
limited	O
to	O
the	O
CNS	O
at	O
this	O
and	O
later	O
stages	O
.	O

Disruption	O
of	O
any	O
one	O
of	O
the	O
four	O
genes	O
encoding	O
the	O
newly	O
identified	O
SRP	B-GENE
proteins	I-GENE
results	O
in	O
slow	O
cell	O
growth	O
and	O
inefficient	O
protein	O
translocation	O
across	O
the	O
ER	O
membrane	O
.	O

Genetic	O
alterations	O
in	O
elements	O
of	O
normal	O
signal	O
transduction	O
mechanisms	O
are	O
known	O
to	O
be	O
oncogenic	O
events	O
often	O
resulting	O
in	O
aberrant	O
activation	O
of	O
programs	O
of	O
gene	O
transcription	O
.	O

The	O
expression	O
pattern	O
of	O
GL2	B-GENE
,	O
as	O
demonstrated	O
by	O
in	O
situ	O
hybridization	O
,	O
indicated	O
that	O
the	O
gene	O
is	O
expressed	O
in	O
trichome	O
progenitor	O
cells	O
and	O
at	O
stages	O
associated	O
with	O
trichome	O
development	O
.	O

NOT4	B-GENE
interacts	O
with	O
NOT1	B-GENE
and	O
NOT3	B-GENE
in	O
the	O
two	O
-	O
hybrid	O
assay	O
,	O
and	O
overexpression	O
of	O
NOT3	B-GENE
or	O
NOT4	B-GENE
suppresses	O
not1	B-GENE
and	O
not2	B-GENE
mutations	O
.	O

Binding	O
site	O
selection	O
using	O
in	O
vitro	O
-	O
synthesized	O
proteins	O
reveals	O
that	O
the	O
ROR	B-GENE
alpha	I-GENE
1	I-GENE
and	O
ROR	B-GENE
alpha	I-GENE
2	I-GENE
isoforms	I-GENE
bind	O
DNA	O
as	O
monomers	O
to	O
hormone	O
response	O
elements	O
composed	O
of	O
a	O
6	O
-	O
bp	O
AT	O
-	O
rich	O
sequence	O
preceding	O
a	O
half	O
-	O
site	O
core	O
motif	O
PuGGTCA	O
(	O
RORE	B-GENE
)	O
.	O

The	O
p73pct1	B-GENE
/	O
p85cdc10	B-GENE
complex	O
binds	O
both	O
in	O
vitro	O
and	O
in	O
vivo	O
to	O
MCB	B-GENE
but	O
not	O
SCB	B-GENE
or	O
E2F	B-GENE
sites	I-GENE
.	O

We	O
show	O
that	O
the	O
en	B-GENE
stripes	O
expand	O
anteriorly	O
in	O
slp	B-GENE
mutant	O
embryos	O
and	O
that	O
slp	B-GENE
activity	O
is	O
an	O
absolute	O
requirement	O
for	O
maintenance	O
of	O
wg	B-GENE
expression	O
at	O
the	O
same	O
time	O
that	O
wg	B-GENE
transcription	O
is	O
dependent	O
on	O
hh	B-GENE
.	O

The	O
DNA	O
sequence	O
adjacent	O
to	O
the	O
lacZ	B-GENE
gene	I-GENE
has	O
been	O
determined	O
for	O
91	O
vegetative	O
fusion	O
genes	O
whose	O
products	O
have	O
been	O
localized	O
and	O
for	O
43	O
meiotically	O
induced	O
fusions	O
.	O

CMV	O
hyperimmunoglobulin	B-GENE
treatment	O
(	O
Cytotect	O
,	O
Biotest	O
)	O
was	O
started	O
(	O
2	O
ml	O
/	O
kg	O
bw	O
on	O
day	O
1	O
and	O
3	O
,	O
and	O
1	O
ml	O
/	O
kg	O
on	O
days	O
5	O
,	O
7	O
and	O
9	O
)	O
,	O
which	O
led	O
to	O
the	O
eradication	O
of	O
the	O
residual	O
infiltrate	O
and	O
CMV	O
-	O
DNA	O
in	O
the	O
myocardium	O
.	O

In	O
eight	O
groups	O
of	O
subjects	O
operating	O
various	O
hand	O
-	O
held	O
vibrating	O
tools	O
and	O
aged	O
from	O
30	O
to	O
59	O
years	O
,	O
the	O
prevalence	O
rates	O
of	O
vibration	O
-	O
induced	O
white	O
finger	O
(	O
VWF	O
)	O
and	O
numbness	O
,	O
pain	O
,	O
or	O
stiffness	O
in	O
the	O
upper	O
and	O
lower	O
extremities	O
were	O
investigated	O
.	O

DNA	O
sequence	O
analysis	O
showed	O
that	O
the	O
gene	O
was	O
525	O
bp	O
long	O
and	O
encoded	O
a	O
175	O
-	O
amino	O
-	O
acid	O
protein	O
with	O
a	O
molecular	O
weight	O
of	O
19	O
,	O
094	O
containing	O
a	O
21	O
-	O
residue	O
typical	O
lipoprotein	O
signal	O
peptide	O
and	O
consensus	O
prolipoprotein	O
processing	O
site	O
.	O

DNA	O
sequence	O
and	O
functions	O
of	O
the	O
actVI	B-GENE
region	I-GENE
of	O
the	O
actinorhodin	B-GENE
biosynthetic	I-GENE
gene	I-GENE
cluster	I-GENE
of	I-GENE
Streptomyces	I-GENE
coelicolor	I-GENE
A3	I-GENE
(	I-GENE
2	I-GENE
)	I-GENE
.	O

(	O
1992	O
)	O
Genomics	O
12	O
,	O
58	O
-	O
62	O
)	O
.	O

A	O
comparison	O
of	O
the	O
predicted	O
polypeptide	O
sequence	O
of	O
the	O
Drosophila	O
protein	O
with	O
the	O
equivalent	O
subunits	O
from	O
mouse	O
and	O
yeast	O
suggests	O
that	O
they	O
are	O
closely	O
related	O
and	O
defines	O
three	O
conserved	O
regions	O
which	O
are	O
likely	O
to	O
be	O
important	O
for	O
enzyme	O
activity	O
.	O

Cytoplasmic	B-GENE
dynein	I-GENE
is	O
a	O
multisubunit	O
,	O
microtubule	O
-	O
dependent	O
mechanochemical	O
enzyme	O
that	O
has	O
been	O
proposed	O
to	O
function	O
in	O
a	O
variety	O
of	O
intracellular	O
movements	O
,	O
including	O
minus	O
-	O
end	O
-	O
directed	O
transport	O
of	O
organelles	O
.	O

Identification	O
of	O
the	O
plakoglobin	B-GENE
-	O
binding	O
domain	O
in	O
desmoglein	B-GENE
and	O
its	O
role	O
in	O
plaque	O
assembly	O
and	O
intermediate	O
filament	O
anchorage	O
.	O

PATIENTS	O
AND	O
METHODS	O
:	O
One	O
hundred	O
eighty	O
-	O
four	O
chemotherapy	O
-	O
naive	O
patients	O
receiving	O
high	O
-	O
dose	O
cisplatin	O
(	O
81	O
to	O
120	O
mg	O
/	O
m2	O
)	O
were	O
randomized	O
to	O
receive	O
one	O
of	O
four	O
granisetron	O
doses	O
(	O
5	O
,	O
10	O
,	O
20	O
,	O
or	O
40	O
micrograms	O
/	O
kg	O
)	O
administered	O
before	O
chemotherapy	O
.	O

Nine	O
new	O
naphthalene	O
related	O
compounds	O
(	O
I	O
,	O
IV	O
,	O
V	O
,	O
VII	O
-	O
XII	O
)	O
together	O
with	O
four	O
known	O
compounds	O
(	O
II	O
,	O
III	O
,	O
VI	O
,	O
XIII	O
)	O
were	O
isolated	O
from	O
the	O
root	O
bark	O
of	O
Oroxylum	O
indicum	O
Vent	O
.	O

As	O
shown	O
previously	O
,	O
EBNA2	B-GENE
transactivates	O
the	O
promoters	O
of	O
the	O
viral	B-GENE
latent	I-GENE
membrane	I-GENE
proteins	I-GENE
.	O

We	O
previously	O
showed	O
that	O
v	B-GENE
-	I-GENE
Rel	I-GENE
,	O
the	O
oncoprotein	O
of	O
the	O
avian	O
retrovirus	O
Rev	O
-	O
T	O
,	O
can	O
increase	O
expression	O
from	O
promoters	O
containing	O
binding	O
sites	O
for	O
the	O
cellular	O
transcription	O
factor	O
Sp1	B-GENE
in	O
chicken	O
embryo	O
fibroblasts	O
(	O
S	O
.	O

Previous	O
studies	O
have	O
demonstrated	O
that	O
the	O
TATA	O
element	O
is	O
critical	O
for	O
basal	O
and	O
Tat	B-GENE
-	O
induced	O
HIV	O
-	O
1	O
gene	O
expression	O
.	O

A	O
comparison	O
of	O
the	O
nucleotide	O
sequence	O
of	O
the	O
p54	B-GENE
gene	I-GENE
carried	O
by	O
two	O
virulent	O
ASFV	O
strains	O
(	O
E70	O
and	O
E75	O
)	O
with	O
that	O
obtained	O
from	O
virus	O
Ba71V	O
showed	O
100	O
%	O
similarity	O
.	O

The	O
p55	B-GENE
mRNA	I-GENE
is	O
undetectable	O
in	O
non	O
-	O
EBV	O
-	O
infected	O
B	O
-	O
and	O
T	O
-	O
cell	O
lines	O
or	O
in	O
a	O
myelomonocytic	O
cell	O
line	O
(	O
U937	O
)	O
.	O

A	O
simple	O
registration	O
as	O
an	O
incentive	O
for	O
improvement	O

RESULTS	O
:	O
The	O
diagnostic	O
quality	O
of	O
FDG	O
images	O
was	O
at	O
least	O
as	O
good	O
as	O
that	O
of	O
their	O
Tl	O
-	O
201	O
counterparts	O
,	O
with	O
less	O
liver	O
background	O
in	O
all	O
but	O
one	O
FDG	O
study	O
.	O

The	O
coordinated	O
expression	O
of	O
CD4	B-GENE
and	O
CD8	B-GENE
during	O
T	O
-	O
cell	O
development	O
is	O
tightly	O
coupled	O
with	O
the	O
maturation	O
state	O
of	O
the	O
T	O
cell	O
.	O

The	O
dying	O
tTG	B-GENE
-	O
transfected	O
cells	O
exhibit	O
both	O
cytoplasmic	O
and	O
nuclear	O
changes	O
characteristic	O
of	O
cells	O
undergoing	O
apoptosis	O
.	O

Using	O
an	O
RNase	B-GENE
H	I-GENE
-	O
mediated	O
mapping	O
technique	O
,	O
we	O
show	O
that	O
the	O
64	O
-	O
kDa	O
subunit	O
of	O
CstF	B-GENE
can	O
be	O
photo	O
cross	O
-	O
linked	O
to	O
pre	O
-	O
mRNAs	O
at	O
U	O
-	O
rich	O
regions	O
located	O
downstream	O
of	O
the	O
cleavage	O
site	O
of	O
the	O
simian	O
virus	O
40	O
late	O
and	O
adenovirus	B-GENE
L3	I-GENE
pre	I-GENE
-	I-GENE
mRNAs	I-GENE
.	O

The	O
protein	O
encoded	O
is	O
114	O
kDa	O
and	O
contains	O
eight	O
zinc	O
finger	O
motifs	O
,	O
seven	O
of	O
which	O
are	O
present	O
in	O
two	O
clusters	O
at	O
opposite	O
ends	O
of	O
the	O
molecule	O
.	O

Tissue	O
-	O
specific	O
expression	O
of	O
the	O
diazepam	B-GENE
-	I-GENE
binding	I-GENE
inhibitor	I-GENE
in	O
Drosophila	O
melanogaster	O
:	O
cloning	O
,	O
structure	O
,	O
and	O
localization	O
of	O
the	O
gene	O
.	O

Using	O
a	O
v	B-GENE
-	I-GENE
erbA	I-GENE
probe	O
,	O
we	O
obtained	O
a	O
cDNA	O
which	O
encodes	O
a	O
novel	O
445	O
-	O
amino	O
-	O
acid	O
protein	O
,	O
RLD	B-GENE
-	I-GENE
1	I-GENE
,	O
that	O
contains	O
the	O
characteristic	O
domains	O
of	O
nuclear	O
receptors	O
.	O

Only	O
two	O
of	O
the	O
isoforms	O
possess	O
the	O
N	O
-	O
terminal	O
zinc	O
finger	O
domain	O
that	O
is	O
necessary	O
and	O
sufficient	O
for	O
TdT	B-GENE
promoter	I-GENE
binding	O
.	O

This	O
study	O
provides	O
direct	O
evidence	O
that	O
USF	B-GENE
,	O
a	O
member	O
of	O
the	O
basic	B-GENE
helix	I-GENE
-	I-GENE
loop	I-GENE
-	I-GENE
helix	I-GENE
leucine	I-GENE
zipper	I-GENE
family	I-GENE
,	O
binds	O
to	O
MLE1	B-GENE
,	O
HF	B-GENE
-	I-GENE
1a	I-GENE
,	O
and	O
PRE	B-GENE
B	I-GENE
sites	I-GENE
and	O
suggests	O
that	O
it	O
is	O
a	O
component	O
of	O
protein	O
complexes	O
that	O
may	O
coordinately	O
control	O
the	O
expression	O
of	O
MLC	B-GENE
-	I-GENE
2v	I-GENE
and	O
alpha	B-GENE
-	I-GENE
myosin	I-GENE
heavy	I-GENE
-	I-GENE
chain	I-GENE
genes	I-GENE
.	O

Activation	O
of	O
c	B-GENE
-	I-GENE
fos	I-GENE
gene	I-GENE
expression	O
by	O
a	O
kinase	O
-	O
deficient	O
epidermal	B-GENE
growth	I-GENE
factor	I-GENE
receptor	I-GENE
.	O

Because	O
endogenous	O
HSF	B-GENE
DNA	O
-	O
binding	O
activity	O
is	O
low	O
and	O
anti	B-GENE
-	I-GENE
hHSF1	I-GENE
antibody	I-GENE
does	O
not	O
recognize	O
Xenopus	B-GENE
HSF	I-GENE
,	O
we	O
employed	O
this	O
system	O
for	O
mapping	O
regions	O
in	O
hHSF1	B-GENE
that	O
are	O
required	O
for	O
the	O
maintenance	O
of	O
the	O
monomeric	O
state	O
.	O

Enhancers	O
containing	O
disrupted	O
Ets	B-GENE
-	I-GENE
1	I-GENE
binding	I-GENE
sites	I-GENE
were	O
tested	O
in	O
transient	O
expression	O
assays	O
in	O
the	O
murine	O
T	O
-	O
cell	O
line	O
EL4	O
.	O
E1	O
;	O
alterations	O
in	O
the	O
LVb	O
element	O
affected	O
constitutive	O
enhancer	O
activity	O
,	O
while	O
mutation	O
of	O
either	O
the	O
LVb	O
or	O
LVc	O
element	O
disrupted	O
phorbol	O
ester	O
-	O
induced	O
enhancer	O
activity	O
.	O

The	O
predominant	O
binding	O
activity	O
was	O
not	O
Ets	B-GENE
-	I-GENE
1	I-GENE
but	O
rather	O
two	O
independent	O
DNA	O
-	O
protein	O
complexes	O
that	O
comigrated	O
in	O
mobility	O
shift	O
assays	O
.	O

Treatment	O
with	O
amphotericin	O
B	O
and	O
flucytosine	O
led	O
to	O
improvement	O
of	O
the	O
symptoms	O
but	O
did	O
not	O
eradicate	O
the	O
micro	O
-	O
organisms	O
from	O
the	O
cerebrospinal	O
fluid	O
(	O
CSF	O
)	O
.	O

The	O
unexpected	O
presence	O
of	O
the	O
tRNA	B-GENE
(	I-GENE
trp	I-GENE
)	I-GENE
(	I-GENE
CCA	I-GENE
)	I-GENE
-	I-GENE
gene	I-GENE
transcript	I-GENE
in	I-GENE
mitochondria	I-GENE
is	O
also	O
reported	O
.	O

The	O
parameters	O
of	O
nonspecific	O
humoral	O
immunity	O
-	O
-	O
serum	B-GENE
immunoglobulins	I-GENE
and	O
immune	O
complexes	O
-	O
-	O
were	O
evaluated	O
in	O
irradiated	O
group	O
of	O
patients	O
with	O
uterine	O
cervix	O
carcinoma	O
(	O
Stages	O
IIB	O
and	O
IIIB	O
)	O
,	O
during	O
one	O
year	O
follow	O
up	O
.	O

Mutation	O
of	O
KRKR	O
to	O
NGER	O
retains	O
MO15	B-GENE
in	O
the	O
cytoplasmic	O
compartment	O
,	O
whilst	O
the	O
wild	O
-	O
type	O
protein	O
is	O
detected	O
exclusively	O
in	O
the	O
nucleus	O
.	O

To	O
confirm	O
the	O
binding	O
of	O
protein	O
to	O
these	O
sites	O
in	O
cells	O
,	O
we	O
carried	O
out	O
an	O
in	O
vivo	O
genomic	O
footprinting	O
analysis	O
of	O
this	O
portion	O
of	O
the	O
TGF	B-GENE
alpha	I-GENE
promoter	I-GENE
in	O
normal	O
and	O
transformed	O
rat	O
liver	O
epithelial	O
cell	O
lines	O
that	O
express	O
the	O
endogenous	O
gene	O
at	O
varying	O
levels	O
.	O

Strikingly	O
,	O
this	O
subdomain	O
is	O
also	O
present	O
in	O
the	O
otherwise	O
unrelated	O
N	O
-	O
terminal	O
activating	O
region	O
of	O
p58c	B-GENE
-	I-GENE
ets	I-GENE
-	I-GENE
2	I-GENE
and	O
was	O
thus	O
named	O
BEC	B-GENE
for	O
Ets	B-GENE
-	I-GENE
1	I-GENE
-	I-GENE
beta	I-GENE
/	O
Ets	B-GENE
-	I-GENE
2	I-GENE
-	I-GENE
Conserved	I-GENE
sequence	I-GENE
.	O

This	O
work	O
unravels	O
a	O
new	O
model	O
for	O
the	O
ets	B-GENE
-	I-GENE
1	I-GENE
/	O
ets	B-GENE
-	I-GENE
2	I-GENE
gene	I-GENE
'	O
s	O
evolution	O
,	O
based	O
for	O
the	O
first	O
time	O
on	O
both	O
structural	O
and	O
functional	O
evidences	O
.	O

The	O
v	B-GENE
-	I-GENE
ets	I-GENE
oncogene	I-GENE
of	O
the	O
avian	O
retrovirus	O
E26	O
differs	O
from	O
its	O
cellular	O
progenitor	O
p68c	B-GENE
-	I-GENE
ets	I-GENE
-	I-GENE
1	I-GENE
by	O
two	O
amino	O
acid	O
substitutions	O
(	O
alanine	O
285	O
and	O
isoleucine	O
445	O
in	O
c	B-GENE
-	I-GENE
ets	I-GENE
-	I-GENE
1	I-GENE
both	O
substituted	O
by	O
valine	O
in	O
v	B-GENE
-	I-GENE
ets	I-GENE
,	O
mutations	O
A	O
and	O
B	O
respectively	O
)	O
and	O
its	O
carboxy	O
-	O
terminal	O
end	O
(	O
mutation	O
C	O
)	O
.	O

Consequently	O
functional	O
mRNAs	O
can	O
be	O
produced	O
by	O
endogenous	B-GENE
RNA	I-GENE
polymerase	I-GENE
I	O
.	O

The	O
individual	O
subunits	O
of	O
Ku	B-GENE
have	O
been	O
difficult	O
to	O
isolate	O
from	O
human	O
cells	O
without	O
denaturation	O
and	O
attempts	O
to	O
produce	O
functional	B-GENE
recombinant	I-GENE
Ku	I-GENE
have	O
been	O
largely	O
unsuccessful	O
.	O

Using	O
this	O
method	O
,	O
we	O
were	O
able	O
to	O
select	O
strong	O
enhancer	O
-	O
type	O
activation	O
domains	O
from	O
the	O
immediate	B-GENE
early	I-GENE
regions	I-GENE
of	O
two	O
herpesviruses	O
,	O
namely	O
pseudorabies	O
virus	O
and	O
bovine	O
herpesvirus	O
1	O
.	O

A	O
genetic	O
system	O
was	O
devised	O
to	O
select	O
for	O
pi	B-GENE
protein	I-GENE
mutants	I-GENE
which	O
discriminate	O
between	O
IR	O
and	O
DR	O
(	O
York	O
et	O
al	O
.	O
,	O
Gene	O
(	O
Amst	O
.	O
)	O
116	O
,	O
7	O
-	O
12	O
,	O
1992	O
;	O
York	O
and	O
Filutowicz	O
,	O
J	O
.	O

Univariate	O
statistical	O
analysis	O
based	O
on	O
Kaplan	O
-	O
Meier	O
-	O
estimates	O
and	O
Log	O
-	O
Rank	O
-	O
Test	O
showed	O
the	O
following	O
prognostically	O
beneficial	O
factors	O
:	O
Limited	O
disease	O
stage	O
(	O
p	O
=	O
0	O
.	O
009	O
)	O
,	O
NSE	B-GENE
serum	O
level	O
less	O
than	O
25	O
micrograms	O
/	O
l	O
(	O
p	O
=	O
0	O
.	O
016	O
)	O
,	O
serum	O
alkaline	B-GENE
phosphatase	I-GENE
less	O
than	O
200	O
U	O
/	O
l	O
(	O
p	O
=	O
0	O
.	O
035	O
)	O
,	O
normal	O
serum	O
albumin	B-GENE
(	O
p	O
=	O
0	O
.	O
003	O
)	O
and	O
activity	O
index	O
of	O
minimum	O
of	O
70	O
(	O
p	O
<	O
0	O
.	O
001	O
)	O
.	O

HBx	B-GENE
strongly	O
elevates	O
levels	O
of	O
GTP	O
-	O
bound	O
Ras	B-GENE
,	O
activated	O
and	O
phosphorylated	O
Raf	B-GENE
,	O
and	O
tyrosine	O
-	O
phosphorylated	O
and	O
activated	O
MAP	B-GENE
kinase	I-GENE
.	O

Role	O
of	O
c	B-GENE
-	I-GENE
myc	I-GENE
in	O
simian	B-GENE
virus	I-GENE
40	I-GENE
large	I-GENE
tumor	I-GENE
antigen	I-GENE
-	O
induced	O
DNA	O
synthesis	O
in	O
quiescent	O
3T3	O
-	O
L1	O
mouse	O
fibroblasts	O
.	O

Laser	O
therapy	O
of	O
penile	O
carcinoma	O

A	O
15	O
.	O
1	O
kb	O
fragment	O
of	O
the	O
yeast	O
genome	O
was	O
allocated	O
to	O
the	O
centromeric	O
region	O
of	O
chromosome	O
XIV	O
by	O
genetic	O
mapping	O
.	O

A	O
third	O
one	O
is	O
homologous	O
in	O
half	O
of	O
its	O
length	O
to	O
the	O
prokaryotic	B-GENE
hydantoinase	I-GENE
HyuA	B-GENE
and	O
in	O
the	O
other	O
half	O
to	O
hydatoinase	B-GENE
HyuB	B-GENE
.	O

It	O
was	O
shown	O
that	O
estradiol	O
concentrations	O
obtained	O
after	O
estradiol	O
valerate	O
and	O
micronized	O
estradiol	O
ingestion	O
were	O
dependent	O
on	O
the	O
patient	O
'	O
s	O
age	O
as	O
well	O
as	O
on	O
the	O
constitutional	O
type	O
.	O

Constipation	O
is	O
not	O
a	O
risk	O
factor	O
for	O
hemorrhoids	O
:	O
a	O
case	O
-	O
control	O
study	O
of	O
potential	O
etiological	O
agents	O
.	O

Of	O
419	O
persons	O
surveyed	O
,	O
207	O
(	O
49	O
.	O
4	O
%	O
)	O
were	O
antigen	O
-	O
positive	O
with	O
the	O
Og4C3	B-GENE
assay	O
.	O

Vibrio	O
cholerae	O
O139	O
in	O
Calcutta	O
.	O

Sequence	O
analysis	O
of	O
the	O
zebrafish	B-GENE
egr1	I-GENE
coding	I-GENE
region	I-GENE
revealed	O
a	O
high	O
level	O
of	O
homology	O
to	O
the	O
mouse	O
,	O
rat	O
,	O
and	O
human	B-GENE
Egr1	I-GENE
genes	I-GENE
with	O
the	O
notable	O
exception	O
of	O
a	O
polymorphic	O
,	O
triplet	O
nucleotide	O
repeat	O
sequence	O
in	O
the	O
region	O
coding	O
for	O
the	O
amino	O
terminus	O
of	O
the	O
Egr1	B-GENE
protein	I-GENE
.	O

The	O
fibrinogen	B-GENE
,	O
serum	O
proteins	O
,	O
sodium	O
heparin	O
and	O
membrane	O
contributed	O
to	O
Cm	O
by	O
20	O
%	O
,	O
14	O
%	O
,	O
2	O
%	O
and	O
64	O
%	O
,	O
respectively	O
.	O

In	O
these	O
vectors	O
the	O
chimeric	B-GENE
long	I-GENE
terminal	I-GENE
repeat	I-GENE
(	O
chLTR	B-GENE
)	O
drives	O
the	O
expression	O
of	O
the	O
chloramphenicol	B-GENE
acetyl	I-GENE
transferase	I-GENE
(	O
CAT	B-GENE
)	O
reporter	O
gene	O
that	O
is	O
followed	O
by	O
an	O
internal	O
SV40	B-GENE
virus	I-GENE
early	I-GENE
region	I-GENE
promoter	I-GENE
linked	O
to	O
the	O
neomycin	B-GENE
phosphotransferase	I-GENE
II	I-GENE
(	O
NEO	B-GENE
)	O
gene	O
.	O

Optima	O
)	O
genomic	O
library	O
by	O
hybridizing	O
with	O
elicitor	O
-	O
induced	O
stilbene	B-GENE
synthase	I-GENE
cDNA	I-GENE
as	O
a	O
probe	O
.	O

A	O
total	O
of	O
125	O
acute	O
leukemia	O
adult	O
patients	O
were	O
autografted	O
with	O
bone	O
marrow	O
(	O
BM	O
)	O
purged	O
by	O
mafosfamide	O
(	O
ASTA	O
Z	O
)	O
during	O
the	O
period	O
of	O
January	O
1983	O
to	O
January	O
1993	O
.	O

The	O
pretransplant	O
regimen	O
consisted	O
of	O
cyclophosphamide	O
(	O
120	O
mg	O
/	O
kg	O
)	O
and	O
total	O
body	O
irradiation	O
.	O

The	O
site	O
-	O
directed	O
mutation	O
of	O
the	O
kappa	B-GENE
B	I-GENE
motif	I-GENE
in	O
IL	B-GENE
-	I-GENE
6	I-GENE
/	O
CAT	B-GENE
plasmid	O
resulted	O
in	O
the	O
complete	O
abrogation	O
of	O
IL	B-GENE
-	I-GENE
6	I-GENE
promoter	I-GENE
activity	O
in	O
these	O
cells	O
.	O

Curiously	O
,	O
testololactone	O
was	O
earlier	O
and	O
more	O
widely	O
used	O
than	O
aminoglutethimide	O
in	O
treating	O
advanced	O
breast	O
carcinoma	O
.	O

Use	O
of	O
the	O
vena	O
cava	O
to	O
extend	O
the	O
right	O
renal	O
vein	O
for	O
cadaver	O
transplantation	O
is	O
controversial	O
.	O

Enhanced	O
hepatic	O
portal	O
blood	O
flow	O
induced	O
by	O
prostaglandin	O
E1	O
following	O
liver	O
transplantation	O
in	O
pigs	O
.	O

One	O
gene	O
appears	O
ubiquitously	O
expressed	O
while	O
the	O
other	O
is	O
prominently	O
expressed	O
in	O
muscle	O
.	O

For	O
HeLa	O
,	O
293	O
,	O
U937	O
,	O
and	O
A549	O
cells	O
,	O
participation	O
of	O
E2F	B-GENE
-	I-GENE
1	I-GENE
,	O
DP	B-GENE
-	I-GENE
1	I-GENE
,	O
cyclin	B-GENE
A	I-GENE
,	O
and	O
RB	B-GENE
was	O
involved	O
in	O
formation	O
of	O
some	O
complexes	O
only	O
,	O
assuming	O
participation	O
of	O
factors	O
different	O
from	O
E2F	B-GENE
-	I-GENE
1	I-GENE
or	O
DP	B-GENE
-	I-GENE
1	I-GENE
in	O
others	O
.	O

E1A	B-GENE
autoactivation	O
mediated	O
by	O
these	O
sites	O
was	O
about	O
twofold	O
compared	O
with	O
a	O
ninefold	O
activation	O
described	O
for	O
the	O
complete	O
E1A	B-GENE
promoter	I-GENE
.	O

Cestode	O
invasion	O
in	O
irradiated	O
host	O
organism	O
increases	O
the	O
negative	O
effect	O
of	O
ionizing	O
radiation	O
on	O
the	O
hamster	O
immune	O
system	O
.	O

During	O
heat	O
exposure	O
,	O
chicks	O
that	O
had	O
been	O
subjected	O
to	O
early	O
60	O
%	O
restriction	O
with	O
non	O
-	O
metyrapone	O
-	O
treated	O
food	O
had	O
lower	O
H	O
/	O
L	O
ratios	O
and	O
improved	O
resistance	O
to	O
marble	O
spleen	O
disease	O
infection	O
.	O

Analyses	O
of	O
additional	O
tumors	O
induced	O
in	O
mice	O
from	O
two	O
reciprocal	O
crosses	O
,	O
A	O
/	O
J	O
x	O
C3H	O
/	O
HeJ	O
F1	O
(	O
hereafter	O
called	O
AC3F1	O
)	O
and	O
C3H	O
/	O
HeJ	O
x	O
A	O
/	O
J	O
F1	O
(	O
hereafter	O
called	O
C3AF1	O
)	O
,	O
provided	O
evidence	O
for	O
the	O
inactivation	O
of	O
one	O
allele	O
of	O
the	O
putative	O
chromosome	O
4	O
tumor	O
suppressor	O
gene	O
by	O
parental	O
imprinting	O
.	O

ERV1	B-GENE
is	O
involved	O
in	O
the	O
cell	O
-	O
division	O
cycle	O
and	O
the	O
maintenance	O
of	O
mitochondrial	O
genomes	O
in	O
Saccharomyces	O
cerevisiae	O
.	O

Lesion	O
diameters	O
of	O
greater	O
than	O
20	O
mm	O
and	O
the	O
large	O
sessile	O
-	O
type	O
configurations	O
were	O
factors	O
that	O
were	O
associated	O
with	O
incomplete	O
removal	O
.	O

Routinely	O
collected	O
,	O
processed	O
and	O
stored	O
breast	O
cancer	O
tissue	O
blocks	O
recovered	O
from	O
the	O
archives	O
of	O
the	O
Pathology	O
laboratory	O
in	O
Dar	O
es	O
Salaam	O
after	O
storage	O
of	O
up	O
to	O
3	O
years	O
were	O
analysed	O
by	O
a	O
flow	O
cytometry	O
for	O
DNA	O
ploidy	O
and	O
S	O
-	O
phase	O
fraction	O
.	O

Cbf3	B-GENE
contains	O
three	O
proteins	O
,	O
Cbf3a	B-GENE
,	O
Cbf3b	B-GENE
and	O
Cbf3c	B-GENE
.	O

Such	O
an	O
interaction	O
could	O
be	O
detected	O
using	O
a	O
GST	B-GENE
-	O
POU	B-GENE
fusion	O
protein	O
bound	O
to	O
glutathione	O
-	O
agarose	O
beads	O
.	O

These	O
mutations	O
are	O
localized	O
in	O
the	O
same	O
region	O
where	O
the	O
HSV	B-GENE
transactivator	I-GENE
VP16	I-GENE
binds	O
,	O
but	O
did	O
not	O
coincide	O
with	O
the	O
VP16	B-GENE
contacts	O
.	O

Notably	O
,	O
these	O
residues	O
are	O
located	O
in	O
different	O
domains	O
.	O

However	O
,	O
rapamycin	O
inhibited	O
proliferation	O
of	O
Ba	O
/	O
F3	O
-	O
EpoRgp55	O
but	O
not	O
of	O
MEL	O
cells	O
despite	O
inhibition	O
of	O
p70	B-GENE
S6	I-GENE
kinase	I-GENE
activity	O
in	O
both	O
cells	O
.	O

Intraventricular	O
injection	O
of	O
(	O
2S	O
,	O
1	O
'	O
R	O
,	O
2	O
'	O
R	O
,	O
3	O
'	O
R	O
)	O
-	O
2	O
-	O
(	O
2	O
,	O
3	O
-	O
dicarboxycyclopropyl	O
)	O
glycine	O
(	O
DCG	O
-	O
IV	O
)	O
,	O
a	O
potent	O
agonist	O
for	O
metabotropic	O
glutamate	B-GENE
receptors	I-GENE
,	O
to	O
rats	O
retarded	O
dose	O
-	O
dependently	O
the	O
recovery	O
from	O
halothane	O
anesthesia	O
at	O
a	O
dose	O
range	O
from	O
30	O
to	O
300	O
pmol	O
/	O
rat	O
.	O

The	O
hepatocyte	B-GENE
nuclear	I-GENE
factor	I-GENE
-	I-GENE
3	I-GENE
(	O
HNF	B-GENE
-	I-GENE
3	I-GENE
)	O
/	O
forkhead	B-GENE
(	O
fkh	B-GENE
)	O
proteins	O
consist	O
of	O
an	O
extensive	O
family	O
of	O
tissue	O
-	O
specific	O
and	O
developmental	O
gene	O
regulators	O
which	O
share	O
homology	O
within	O
the	O
winged	O
helix	O
DNA	O
binding	O
motif	O
.	O

Interestingly	O
,	O
dTFIIA	B-GENE
-	I-GENE
L	I-GENE
/	I-GENE
S	I-GENE
is	O
also	O
able	O
to	O
significantly	O
enhance	O
transcriptional	O
activation	O
by	O
upstream	O
transcription	O
factors	O
including	O
Sp1	B-GENE
,	O
VP16	B-GENE
,	O
and	O
NTF	B-GENE
-	I-GENE
1	I-GENE
.	O

In	O
particular	O
,	O
changes	O
in	O
intracellular	O
Ca2	O
+	O
have	O
the	O
potential	O
to	O
either	O
inhibit	O
or	O
augment	O
the	O
ability	O
of	O
cAMP	O
to	O
stimulate	O
transcription	O
,	O
depending	O
on	O
the	O
presence	O
of	O
specific	O
forms	O
of	O
Ca2	B-GENE
+	I-GENE
/	I-GENE
calmodulin	I-GENE
-	I-GENE
dependent	I-GENE
protein	I-GENE
kinases	I-GENE
.	O

Antibodies	O
directed	O
against	O
the	O
SNM1	B-GENE
protein	I-GENE
immunoprecipitated	O
RNase	B-GENE
MRP	I-GENE
RNA	I-GENE
from	O
whole	O
-	O
cell	O
extracts	O
without	O
precipitating	O
the	O
structurally	O
and	O
functionally	O
related	O
RNase	B-GENE
P	I-GENE
RNA	I-GENE
.	O

Our	O
results	O
show	O
that	O
the	O
ORF	O
of	O
hAMPK	B-GENE
encodes	O
552	O
amino	O
acids	O
(	O
aa	O
)	O
(	O
62	O
.	O
250	O
kDa	O
)	O
and	O
is	O
highly	O
conserved	O
with	O
rAMPK	B-GENE
with	O
identities	O
of	O
97	O
.	O
3	O
and	O
90	O
%	O
at	O
the	O
aa	O
and	O
nt	O
levels	O
,	O
respectively	O
.	O

In	O
human	O
brain	O
,	O
contactin	B-GENE
was	O
first	O
identified	O
by	O
amino	O
terminal	O
and	O
peptide	O
sequencing	O
of	O
the	O
lentil	B-GENE
-	I-GENE
lectin	I-GENE
-	I-GENE
binding	I-GENE
glycoprotein	I-GENE
Gp135	I-GENE
.	O

The	O
centromeric	O
YAC	O
contig	O
,	O
which	O
consists	O
of	O
23	O
overlapping	O
YACs	O
and	O
orders	O
19	O
sequence	O
-	O
tagged	O
sites	O
(	O
STSs	O
)	O
,	O
covers	O
a	O
minimum	O
of	O
2	O
.	O
2	O
Mb	O
and	O
spans	O
the	O
Ewing	O
sarcoma	O
breakpoint	O
.	O
c	B-GENE
-	I-GENE
ets	I-GENE
1	I-GENE
and	O
Fli	B-GENE
-	I-GENE
1	I-GENE
,	O
two	O
members	O
of	O
the	O
ets	B-GENE
family	I-GENE
,	O
have	O
been	O
linked	O
within	O
400	O
kb	O
of	O
intervening	O
DNA	O
within	O
this	O
contig	O
,	O
which	O
also	O
comprises	O
a	O
polymorphic	O
microsatellite	O
,	O
D11S912	B-GENE
(	O
CA	O
)	O
n	O
,	O
which	O
we	O
have	O
localized	O
within	O
the	O
Fli	B-GENE
-	I-GENE
1	I-GENE
gene	I-GENE
.	O

A	O
cDNA	O
for	O
a	O
newly	O
discovered	O
pseudogene	O
,	O
closely	O
related	O
to	O
the	O
mouse	B-GENE
mast	I-GENE
cell	I-GENE
chymases	I-GENE
was	O
isolated	O
by	O
polymerase	O
chain	O
reaction	O
amplification	O
from	O
a	O
mouse	O
connective	O
tissue	O
-	O
like	O
mast	O
cell	O
line	O
.	O

IFI16	B-GENE
consists	O
of	O
ten	O
exons	O
and	O
nine	O
intervening	O
introns	O
spanning	O
at	O
least	O
28	O
kilobases	O
(	O
kb	O
)	O
of	O
DNA	O
.	O

Courses	O
were	O
repeated	O
every	O
four	O
weeks	O
.	O

Peter	O
Elfer	O
explores	O
the	O
implications	O
of	O
the	O
ruling	O
.	O

Other	O
adverse	O
events	O
with	O
incidences	O
significantly	O
higher	O
than	O
with	O
placebo	O
were	O
dizziness	O
,	O
constipation	O
,	O
sweating	O
,	O
nervousness	O
,	O
and	O
abnormal	O
ejaculation	O
.	O

Homology	O
was	O
also	O
detected	O
between	O
the	O
putative	O
transit	O
peptide	O
sequence	O
of	O
cysteine	B-GENE
synthase	I-GENE
C	I-GENE
and	O
other	O
mitochondrion	O
-	O
targeting	O
leader	O
sequences	O
.	O

Furthermore	O
,	O
our	O
data	O
also	O
show	O
that	O
,	O
in	O
addition	O
to	O
TEF	B-GENE
-	I-GENE
1	I-GENE
,	O
another	O
HF	B-GENE
-	I-GENE
1a	I-GENE
-	I-GENE
related	I-GENE
factor	I-GENE
may	O
be	O
recognized	O
by	O
the	O
alpha	B-GENE
-	I-GENE
MHC	I-GENE
gene	I-GENE
EM	O
element	O
.	O

Rat	B-GENE
kidney	I-GENE
carboxylesterase	I-GENE
.	O

Recombinant	B-GENE
I	I-GENE
-	I-GENE
kappa	I-GENE
B	I-GENE
alpha	I-GENE
inhibited	O
kappa	B-GENE
B	I-GENE
motif	I-GENE
binding	O
by	O
nuclear	B-GENE
factor	I-GENE
-	I-GENE
kappa	I-GENE
B1	I-GENE
,	O
RelA	B-GENE
,	O
and	O
c	B-GENE
-	I-GENE
Rel	I-GENE
as	O
indicated	O
by	O
studies	O
using	O
UV	O
radiation	O
-	O
induced	O
covalent	O
cross	O
-	O
linking	O
to	O
a	O
bromodeoxyuridine	O
-	O
substituted	O
kappa	B-GENE
B	I-GENE
oligonucleotide	I-GENE
.	O

The	O
physical	O
and	O
chemical	O
stability	O
of	O
a	O
combination	O
of	O
drugs	O
commonly	O
administered	O
into	O
the	O
epidural	O
or	O
intrathecal	O
space	O
for	O
the	O
treatment	O
of	O
chronic	O
pain	O
was	O
investigated	O
.	O

Therefore	O
,	O
mechanisms	O
that	O
control	O
activation	O
of	O
the	O
MAP	B-GENE
kinase	I-GENE
cascade	O
temporally	O
and	O
spatially	O
may	O
be	O
important	O
for	O
specification	O
of	O
cellular	O
responses	O
.	O

A	O
candidate	O
gene	O
for	O
Bcg	B-GENE
,	O
designated	O
natural	B-GENE
resistance	I-GENE
-	I-GENE
associated	I-GENE
macrophage	I-GENE
protein	I-GENE
(	O
Nramp	B-GENE
)	O
,	O
has	O
been	O
isolated	O
and	O
shown	O
to	O
encode	O
a	O
novel	O
macrophage	O
-	O
specific	O
membrane	O
protein	O
,	O
which	O
is	O
altered	O
in	O
susceptible	O
animals	O
.	O

This	O
motif	O
is	O
similar	O
to	O
but	O
distinct	O
from	O
the	O
LIM	B-GENE
domain	I-GENE
and	O
the	O
RING	B-GENE
finger	I-GENE
family	I-GENE
,	O
and	O
is	O
reminiscent	O
of	O
known	O
metal	O
-	O
binding	O
regions	O
.	O

The	O
P131	O
ORF	O
is	O
followed	O
in	O
-	O
frame	O
by	O
a	O
second	O
ORF	O
which	O
is	O
probably	O
expressed	O
by	O
partial	O
readthrough	O
of	O
the	O
UGA	O
termination	O
codon	O
of	O
the	O
P131	O
ORF	O
to	O
produce	O
a	O
polypeptide	O
of	O
M	O
(	O
r	O
)	O
191044	O
(	O
P191	O
)	O
.	O

One	O
hundred	O
fifty	O
patients	O
were	O
reviewed	O
at	O
1	O
year	O
after	O
arthroplasty	O
.	O

Elementary	O
visual	O
hallucinations	O
in	O
migraine	O
and	O
epilepsy	O
.	O

The	O
influence	O
of	O
patient	O
-	O
related	O
factors	O
on	O
inter	O
-	O
observer	O
variability	O
in	O
the	O
evaluation	O
of	O
neurological	O
signs	O
was	O
investigated	O
.	O

The	O
defined	O
length	O
of	O
the	O
mRNA	O
,	O
1	O
,	O
838	O
nucleotides	O
,	O
was	O
in	O
agreement	O
with	O
that	O
of	O
a	O
1	O
.	O
9	O
-	O
kb	O
RNA	O
expressed	O
throughout	O
the	O
replication	O
cycle	O
,	O
starting	O
at	O
the	O
early	O
stages	O
of	O
infection	O
.	O

Infect	O
.	O

Transient	O
transfections	O
of	O
a	O
construct	O
expressing	O
the	O
RNA	O
transcript	O
defined	O
by	O
clone	O
B1	O
.	O
1	O
into	O
D17	O
cells	O
led	O
to	O
the	O
expression	O
of	O
an	O
Env	B-GENE
/	O
Mlvi	B-GENE
-	I-GENE
4	I-GENE
fusion	O
protein	O
with	O
an	O
apparent	O
molecular	O
mass	O
of	O
33	O
kDa	O
.	O

Roizman	O
,	O
J	O
.	O

Articles	O
addressing	O
valvular	O
heart	O
disease	O
or	O
heart	O
failure	O
secondary	O
to	O
acute	O
myocardial	O
infarction	O
or	O
Chagas	O
'	O
disease	O
were	O
excluded	O
.	O

All	O
nuclear	O
receptors	O
have	O
several	O
well	O
-	O
characterized	O
structural	O
domains	O
,	O
including	O
a	O
conserved	O
DNA	O
-	O
binding	O
domain	O
,	O
and	O
a	O
ligand	O
binding	O
domain	O
at	O
the	O
carboxyl	O
terminus	O
of	O
the	O
receptor	O
.	O

The	O
sample	O
includes	O
all	O
the	O
HIV	O
-	O
infected	O
-	O
patients	O
continuously	O
referred	O
to	O
the	O
Outpatient	O
Service	O
of	O
the	O
Infectious	O
Diseases	O
dept	O
.	O
of	O
Bologna	O
'	O
s	O
"	O
Ospedale	O
Maggiore	O
"	O
General	O
Hospital	O
during	O
some	O
five	O
days	O
(	O
19	O
-	O
23rd	O
,	O
July	O
1993	O
)	O
.	O

Using	O
in	O
organello	O
footprint	O
analysis	O
,	O
we	O
demonstrate	O
that	O
within	O
human	O
placental	O
mitochondria	O
there	O
is	O
a	O
high	O
level	O
of	O
protein	O
-	O
DNA	O
binding	O
at	O
regularly	O
phased	O
intervals	O
throughout	O
a	O
500	O
-	O
bp	O
region	O
encompassing	O
the	O
D	O
-	O
loop	O
DNA	O
origins	O
and	O
two	O
promoter	O
regions	O
.	O

The	O
Nur77	B-GENE
protein	I-GENE
can	O
act	O
as	O
a	O
potent	O
transcription	O
activator	O
and	O
may	O
function	O
to	O
regulate	O
the	O
expression	O
of	O
downstream	O
genes	O
in	O
response	O
to	O
extracellular	O
stimuli	O
.	O

One	O
class	O
of	O
plasmids	O
contained	O
tRNA	B-GENE
(	I-GENE
His	I-GENE
)	I-GENE
genes	I-GENE
and	O
conferred	O
efficient	O
suppression	O
only	O
when	O
cells	O
were	O
starved	O
for	O
histidine	O
;	O
these	O
plasmids	O
suppressed	O
a	O
gcn2	B-GENE
deletion	O
much	O
less	O
efficiently	O
than	O
they	O
suppressed	O
gcn2	B-GENE
-	I-GENE
507	I-GENE
.	O

Thus	O
,	O
the	O
presence	O
of	O
the	O
Cln2	B-GENE
PEST	I-GENE
domain	I-GENE
was	O
sufficient	O
to	O
destabilize	O
a	O
heterologous	O
protein	O
.	O

Electrophoretic	O
mobility	O
shift	O
assays	O
with	O
each	O
of	O
these	O
sequences	O
demonstrated	O
complexes	O
with	O
mobilities	O
identical	O
to	O
those	O
of	O
the	O
NF	B-GENE
-	I-GENE
kappa	I-GENE
B	I-GENE
site	I-GENE
from	O
the	O
kappa	B-GENE
light	I-GENE
-	I-GENE
chain	I-GENE
gene	I-GENE
.	O

Although	O
a	O
carboxyl	O
-	O
terminal	O
HSF	B-GENE
transcriptional	O
activation	O
domain	O
is	O
critical	O
for	O
the	O
activation	O
of	O
CUP1	B-GENE
transcription	O
in	O
response	O
to	O
both	O
heat	O
shock	O
stress	O
and	O
glucose	O
starvation	O
,	O
this	O
region	O
is	O
dispensable	O
for	O
transient	O
heat	O
shock	O
activation	O
of	O
at	O
least	O
two	O
genes	O
encoding	O
members	O
of	O
the	O
S	O
.	O
cerevisiae	O
hsp70	B-GENE
family	I-GENE
.	O

We	O
have	O
recently	O
detected	O
high	O
levels	O
of	O
CKB	B-GENE
mRNA	I-GENE
in	O
HeLa	O
cells	O
and	O
,	O
in	O
this	O
study	O
,	O
have	O
tested	O
whether	O
this	O
may	O
be	O
due	O
to	O
the	O
extremely	O
low	O
amounts	O
of	O
p53	B-GENE
protein	I-GENE
present	O
in	O
HeLa	O
cells	O
.	O

Distal	O
lower	O
motor	O
neuron	O
syndrome	O
with	O
high	O
-	O
titer	O
serum	B-GENE
IgM	I-GENE
anti	I-GENE
-	I-GENE
GM1	I-GENE
antibodies	I-GENE
:	O
improvement	O
following	O
immunotherapy	O
with	O
monthly	O
plasma	O
exchange	O
and	O
intravenous	O
cyclophosphamide	O
.	O

Regulators	O
responsible	O
for	O
the	O
pervasive	O
,	O
nonsex	O
-	O
specific	O
alternative	O
pre	O
-	O
mRNA	O
splicing	O
characteristic	O
of	O
metazoans	O
are	O
almost	O
entirely	O
unknown	O
or	O
uncertain	O
.	O

A	O
normal	O
systemic	O
response	O
was	O
obtained	O
after	O
IF	O
,	O
indicating	O
that	O
rhG	B-GENE
-	I-GENE
CSF	I-GENE
retains	O
activity	O
in	O
the	O
solid	O
state	O
.	O

PAI	B-GENE
-	I-GENE
1	I-GENE
levels	O
increased	O
significantly	O
in	O
patients	O
who	O
received	O
iohexol	O
but	O
not	O
in	O
those	O
who	O
received	O
ioxaglate	O
.	O

Determination	O
of	O
potassium	O
iodide	O
in	O
Polish	O
edible	O
salt	O

The	O
recovery	O
value	O
of	O
systolic	O
pressure	O
was	O
higher	O
than	O
diastolic	O
pressure	O
and	O
pulse	O
pressure	O
increased	O
.	O

The	O
importance	O
of	O
hepatitis	O
C	O
virus	O
(	O
HCV	O
)	O
infection	O
as	O
a	O
cause	O
of	O
chronic	O
liver	O
disease	O
has	O
become	O
clear	O
with	O
the	O
introduction	O
of	O
serologic	O
detection	O
methods	O
.	O

Human	O
adenovirus	O
type	O
41	O
contains	O
two	O
fibers	O
.	O

Outflow	O
obstruction	O
of	O
pancreatic	O
juice	O
,	O
i	O
.	O
e	O
.	O
,	O
"	O
relative	O
stenosis	O
of	O
the	O
minor	O
papilla	O
,	O
"	O
was	O
considered	O
to	O
be	O
present	O
in	O
the	O
patients	O
with	O
type	O
II	O
papilla	O
,	O
and	O
,	O
therefore	O
,	O
the	O
patients	O
with	O
type	O
II	O
papilla	O
might	O
suffer	O
from	O
acute	O
pancreatitis	O
resulting	O
from	O
poor	O
drainage	O
of	O
pancreatic	O
juice	O
and	O
excessive	O
pressure	O
in	O
the	O
dorsal	O
duct	O
.	O

Sequencing	O
of	O
the	O
TP53	B-GENE
transcripts	I-GENE
from	O
exons	O
2	O
to	O
10	O
,	O
however	O
,	O
did	O
not	O
reveal	O
mutations	O
of	O
the	O
remaining	O
allele	O
in	O
any	O
of	O
these	O
tumors	O
.	O

An	O
unusual	O
complication	O
in	O
an	O
unsuitable	O
patient	O
.	O

In	O
the	O
ISO	O
group	O
,	O
at	O
pre	O
-	O
DEX	O
,	O
CBF	O
increased	O
from	O
86	O
+	O
/	O
-	O
8	O
to	O
166	O
+	O
/	O
-	O
19	O
mL	O
.	O
min	O
-	O
1	O
.	O
100	O
g	O
-	O
1	O
in	O
response	O
to	O
hypercapnia	O
(	O
PCO2	O
approximately	O
90	O
mmHg	O
)	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
250	O
WORDS	O
)	O

All	O
other	O
ejaculate	O
parameters	O
(	O
density	O
,	O
motility	O
,	O
swelling	O
test	O
,	O
penetration	O
test	O
)	O
remained	O
unchanged	O
,	O
and	O
there	O
was	O
only	O
one	O
post	O
-	O
therapeutic	O
pregnancy	O
.	O

KRN2391	O
and	O
cromakalim	O
produced	O
a	O
dose	O
-	O
dependent	O
increase	O
in	O
aortic	O
and	O
coronary	O
blood	O
flow	O
.	O

In	O
H4IIE	O
rat	O
hepatoma	O
cells	O
,	O
glucocorticoids	O
,	O
retinoic	O
acid	O
and	O
cyclic	O
AMP	O
(	O
cAMP	O
)	O
increase	O
PEPCK	B-GENE
gene	I-GENE
transcription	O
whereas	O
insulin	B-GENE
and	O
phorbol	O
esters	O
have	O
the	O
opposite	O
effect	O
.	O

Acta	O
572	O
,	O
113	O
-	O
120	O
]	O
.	O

Basal	O
plasma	O
AVP	B-GENE
levels	O
and	O
AVP	B-GENE
release	O
after	O
postural	O
change	O
were	O
assessed	O
,	O
and	O
plasma	O
NPY	B-GENE
levels	O
were	O
measured	O
in	O
the	O
same	O
samples	O
.	O

A	O
stretch	O
of	O
16	O
nucleotides	O
just	O
upstream	O
of	O
the	O
IL	B-GENE
-	I-GENE
4RE	I-GENE
contributed	O
to	O
IL	B-GENE
-	I-GENE
4	I-GENE
inducibility	O
and	O
formed	O
nucleoprotein	O
complexes	O
with	O
constitutive	O
factors	O
.	O

Our	O
previous	O
study	O
suggested	O
that	O
pertussis	B-GENE
toxin	I-GENE
(	O
IAP	B-GENE
)	O
-	O
sensitive	O
GTP	B-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
(	I-GENE
s	I-GENE
)	I-GENE
(	O
G	B-GENE
-	I-GENE
protein	I-GENE
)	O
is	O
involved	O
in	O
the	O
process	O
of	O
differentiation	O
by	O
hormones	O
/	O
IBMX	O
,	O
accompanied	O
by	O
c	B-GENE
-	I-GENE
fos	I-GENE
induction	O
.	O

ATX	B-GENE
,	O
like	O
PC	B-GENE
-	I-GENE
1	I-GENE
,	O
was	O
found	O
to	O
hydrolyze	O
the	O
type	B-GENE
I	I-GENE
phosphodiesterase	I-GENE
substrate	O
p	O
-	O
nitrophenyl	O
thymidine	O
-	O
5	O
'	O
-	O
monophosphate	O
.	O

The	O
effect	O
of	O
site	O
-	O
specific	O
mutations	O
in	O
the	O
mouse	B-GENE
platelet	I-GENE
-	I-GENE
derived	I-GENE
growth	I-GENE
factor	I-GENE
(	I-GENE
PDGF	I-GENE
)	I-GENE
beta	I-GENE
-	I-GENE
receptor	I-GENE
on	O
activation	O
of	O
the	O
Na	B-GENE
+	I-GENE
/	I-GENE
H	I-GENE
+	I-GENE
exchanger	I-GENE
was	O
examined	O
in	O
normal	O
murine	O
mammary	O
gland	O
epithelial	O
(	O
NMuMG	O
)	O
and	O
Chinese	O
hamster	O
ovary	O
(	O
CHO	O
)	O
cells	O
.	O

Sequence	O
analysis	O
revealed	O
:	O
1	O
)	O
a	O
kinase	O
catalytic	O
domain	O
most	O
characteristic	O
of	O
serine	B-GENE
/	I-GENE
threonine	I-GENE
kinases	I-GENE
but	O
hybrid	O
between	O
members	O
of	O
the	O
family	O
of	O
microtubule	B-GENE
-	I-GENE
associated	I-GENE
protein	I-GENE
kinase	I-GENE
kinase	I-GENE
kinases	I-GENE
and	O
the	O
fibroblast	B-GENE
growth	I-GENE
factor	I-GENE
receptor	I-GENE
family	I-GENE
;	O
2	O
)	O
two	O
putative	O
alpha	O
-	O
helical	O
leucine	O
zipper	O
motifs	O
separated	O
by	O
a	O
25	O
-	O
amino	O
acid	O
charged	O
intermediate	O
segment	O
but	O
lacking	O
an	O
NH2	O
-	O
terminal	O
basic	O
domain	O
;	O
and	O
3	O
)	O
COOH	O
-	O
terminal	O
and	O
NH2	O
-	O
terminal	O
proline	O
-	O
rich	O
domains	O
suggestive	O
of	O
src	B-GENE
homology	I-GENE
3	I-GENE
(	O
SH3	B-GENE
)	O
domain	O
binding	O
regions	O
.	O

Type	O
2	O
genomes	O
containing	O
this	O
sequence	O
presumably	O
more	O
closely	O
reflect	O
the	O
structure	O
of	O
the	O
infectious	O
,	O
replication	O
-	O
competent	O
retrovirus	O
ancestors	O
of	O
the	O
HERV	O
-	O
K	O
family	O
than	O
do	O
type	O
1	O
genomes	O
that	O
lack	O
the	O
sequence	O
.	O

However	O
,	O
when	O
domain	O
I	O
and	O
domain	O
II	O
were	O
linked	O
on	O
the	O
same	O
plasmid	O
,	O
high	O
levels	O
of	O
replication	O
were	O
observed	O
.	O

Point	O
mutations	O
that	O
suppressed	O
the	O
in	O
vitro	O
binding	O
of	O
NF	B-GENE
-	I-GENE
Y	I-GENE
to	O
the	O
internal	O
palindromic	O
arm	O
reduced	O
the	O
activity	O
of	O
the	O
resident	O
P4	O
promoter	O
,	O
while	O
those	O
preventing	O
complex	O
formation	O
with	O
USF	B-GENE
did	O
not	O
,	O
as	O
determined	O
by	O
transient	O
expression	O
assays	O
using	O
the	O
luciferase	B-GENE
reporter	O
gene	O
.	O

Surprisingly	O
,	O
nuclear	O
forms	O
of	O
IE110	B-GENE
were	O
found	O
to	O
move	O
a	O
cytoplasmic	O
form	O
of	O
IE175	B-GENE
into	O
nuclear	O
punctate	O
structures	O
,	O
and	O
a	O
cytoplasmic	O
form	O
of	O
IE110	B-GENE
was	O
able	O
to	O
retain	O
nuclear	O
forms	O
of	O
IE175	B-GENE
in	O
cytoplasmic	O
punctate	O
structures	O
.	O

Transcription	O
of	O
the	O
gene	O
for	O
ivanolysin	B-GENE
O	I-GENE
and	O
expression	O
of	O
other	O
genes	O
of	O
the	O
virulence	B-GENE
gene	I-GENE
cluster	I-GENE
in	I-GENE
L	I-GENE
.	I-GENE
ivanovii	I-GENE
were	O
dependent	O
on	O
PrfA	B-GENE
.	O

Moreover	O
,	O
by	O
complementation	O
of	O
the	O
WA	B-GENE
fyuA	I-GENE
mutant	I-GENE
by	O
the	O
cloned	O
fyuA	B-GENE
gene	I-GENE
,	O
yersiniabactin	O
uptake	O
and	O
mouse	O
virulence	O
were	O
restored	O
.	O

The	O
ICBF	O
in	O
the	O
ischaemic	O
cortex	O
revealed	O
a	O
graded	O
reduction	O
from	O
the	O
ischaemic	O
centre	O
to	O
the	O
surrounding	O
tissues	O
.	O

The	O
treatment	O
of	O
hydronephrosis	O
in	O
children	O

The	O
inflation	O
hub	O
of	O
the	O
probe	O
is	O
recreated	O
by	O
modifying	O
a	O
standard	O
USCI	O
Tuohy	O
-	O
Borst	O
Y	O
adaptor	O
and	O
attaching	O
this	O
to	O
the	O
transected	O
probe	O
hypotube	O
.	O

The	O
other	O
element	O
bound	O
RBP	B-GENE
-	I-GENE
J	I-GENE
kappa	I-GENE
with	O
low	O
affinity	O
.	O

The	O
basal	O
promoter	O
strength	O
of	O
constructs	O
that	O
contained	O
deletions	O
in	O
the	O
U5	B-GENE
region	I-GENE
of	O
the	O
LTR	O
was	O
analyzed	O
by	O
chloramphenicol	B-GENE
acetyltransferase	I-GENE
(	O
CAT	B-GENE
)	O
assays	O
following	O
transfection	O
of	O
HeLa	O
cells	O
or	O
Jurkat	O
T	O
-	O
cells	O
in	O
the	O
presence	O
or	O
absence	O
of	O
viral	O
transactivator	O
tax	B-GENE
protein	O
.	O

In	O
reviewing	O
a	O
number	O
of	O
the	O
most	O
intensely	O
studied	O
environmentally	O
inducible	O
promoters	O
it	O
becomes	O
clear	O
that	O
the	O
presence	O
of	O
two	O
cis	O
-	O
acting	O
elements	O
are	O
critical	O
for	O
promoter	O
activity	O
,	O
one	O
of	O
which	O
is	O
the	O
G	O
-	O
box	O
(	O
CCACGTGG	O
)	O
.	O

Recently	O
,	O
a	O
protein	O
designated	O
GF14	B-GENE
has	O
been	O
isolated	O
that	O
is	O
associated	O
with	O
the	O
GBF	B-GENE
protein	I-GENE
complex	I-GENE
.	O

New	O
diagnostic	O
strategies	O
for	O
lupus	O
anticoagulants	O
and	O
antiphospholipid	O
antibodies	O
.	O

Propafenone	O
is	O
well	O
tolerated	O
in	O
the	O
majority	O
of	O
young	O
patients	O
.	O

Mutational	O
analysis	O
of	O
yeast	B-GENE
CEG1	I-GENE
demonstrated	O
that	O
four	O
of	O
the	O
five	O
conserved	O
motifs	O
are	O
essential	O
for	O
capping	B-GENE
enzyme	I-GENE
function	O
in	O
vivo	O
.	O

2	O
patients	O
(	O
11	O
%	O
)	O
had	O
significant	O
morbidity	O
502	O
and	O
529	O
days	O
respectively	O
after	O
transplantation	O
.	O

Alternative	O
splicing	O
of	O
the	O
cytoplasmic	O
tail	O
appears	O
to	O
generate	O
multiple	O
PECAM	B-GENE
-	I-GENE
1	I-GENE
isoforms	I-GENE
that	O
may	O
regulate	O
phosphorylation	O
,	O
cytoskeletal	O
association	O
,	O
and	O
affinity	O
modulation	O
of	O
the	O
mature	O
protein	O
.	O

Transfer	O
also	O
correlated	O
inversely	O
with	O
gastric	O
juice	O
pH	O
(	O
r	O
=	O
-	O
0	O
.	O
619	O
,	O
P	O
<	O
0	O
.	O
02	O
)	O
.	O

This	O
technique	O
has	O
a	O
sensitivity	O
and	O
a	O
specificity	O
of	O
almost	O
100	O
%	O
,	O
and	O
is	O
currently	O
the	O
best	O
way	O
to	O
diagnose	O
nodal	O
involvement	O
,	O
apart	O
from	O
laparotomy	O
.	O

The	O
data	O
show	O
conclusively	O
that	O
phosphorylation	O
of	O
His	O
-	O
304	O
is	O
not	O
essential	O
for	O
any	O
of	O
the	O
known	O
functions	O
of	O
A	B-GENE
.	I-GENE
vinelandii	I-GENE
NifL	I-GENE
.	O

If	O
this	O
is	O
present	O
,	O
such	O
patients	O
should	O
be	O
closely	O
monitored	O
,	O
and	O
any	O
atypical	O
lesions	O
biopsied	O
.	O

Cumulated	O
maximum	O
lod	O
scores	O
between	O
FRDA	B-GENE
and	O
D9S5	B-GENE
and	O
between	O
FRDA	B-GENE
and	O
D9S15	B-GENE
are	O
above	O
36	O
and	O
61	O
,	O
respectively	O
,	O
at	O
a	O
recombination	O
fraction	O
of	O
0	O
,	O
indicating	O
that	O
recombination	O
events	O
needed	O
to	O
orient	O
the	O
search	O
of	O
the	O
gene	O
are	O
very	O
difficult	O
to	O
identify	O
and	O
ascertain	O
.	O

A	O
receptor	B-GENE
-	I-GENE
like	I-GENE
protein	I-GENE
kinase	I-GENE
,	O
OsPK10	B-GENE
,	O
has	O
been	O
cloned	O
from	O
rice	O
(	O
Oryza	O
sativa	O
)	O
.	O

A	O
sequence	O
representing	O
about	O
50	O
%	O
of	O
the	O
expected	O
complete	O
sequence	O
was	O
obtained	O
by	O
translation	O
of	O
the	O
two	O
open	O
reading	O
frames	O
present	O
on	O
a	O
1	O
.	O
6	O
kb	O
DNA	O
genomic	O
fragment	O
.	O

Goodpasture	O
'	O
s	O
-	O
like	O
syndrome	O
and	O
effect	O
of	O
extracorporeal	O
membrane	O
oxygenator	O
support	O
.	O

A	O
cDNA	O
clone	O
pCZ1	O
,	O
with	O
a	O
1	O
.	O
1	O
kb	O
insert	O
,	O
was	O
isolated	O
from	O
a	O
NaCl	O
-	O
adapted	O
tobacco	O
cell	O
cDNA	O
library	O
that	O
encodes	O
an	O
apparently	O
full	O
-	O
length	O
29	O
kDa	O
protein	O
(	O
251	O
amino	O
acids	O
)	O
with	O
a	O
calculated	O
pI	O
of	O
5	O
.	O
7	O
.	O

METHODS	O
-	O
-	O
16	O
volunteered	O
for	O
spirometry	O
with	O
methacholine	O
provocation	O
test	O
including	O
a	O
test	O
for	O
small	O
airways	O
function	O
by	O
volume	O
of	O
trapped	O
gas	O
(	O
VTG	O
)	O
.	O

Relationship	O
of	O
CDK	B-GENE
-	I-GENE
activating	I-GENE
kinase	I-GENE
and	O
RNA	B-GENE
polymerase	I-GENE
II	I-GENE
CTD	O
kinase	O
TFIIH	B-GENE
/	O
TFIIK	B-GENE
.	O

These	O
same	O
regions	O
showed	O
remarkable	O
homology	O
to	O
two	O
invertebrate	O
proteins	O
,	O
CNC	B-GENE
and	O
skin	B-GENE
-	I-GENE
1	I-GENE
,	O
postulated	O
to	O
regulate	O
embryonic	O
development	O
in	O
Drosophila	O
melanogaster	O
and	O
Caenorhabditis	O
elegans	O
,	O
respectively	O
.	O

DNA	O
sequence	O
analysis	O
has	O
confirmed	O
that	O
this	O
mutation	O
affects	O
the	O
C	O
-	O
terminal	O
region	O
of	O
the	O
alpha	O
subunit	O
,	O
changing	O
a	O
leucine	O
residue	O
at	O
position	O
290	O
to	O
a	O
histidine	O
(	O
rpoAL290H	B-GENE
)	O
.	O

CONCLUSIONS	O
:	O
These	O
findings	O
indicate	O
a	O
physical	O
barrier	O
of	O
oesophageal	O
surfactant	O
which	O
could	O
offer	O
some	O
degree	O
of	O
protection	O
against	O
gastro	O
-	O
oesophageal	O
reflux	O
but	O
one	O
which	O
is	O
particularly	O
prone	O
to	O
attack	O
by	O
bile	O
.	O

Differential	O
screening	O
of	O
mitochondrial	O
cDNA	O
libraries	O
from	O
male	O
-	O
fertile	O
and	O
cytoplasmic	O
male	O
-	O
sterile	O
sugar	O
-	O
beet	O
reveals	O
genome	O
rearrangements	O
at	O
atp6	B-GENE
and	O
atpA	B-GENE
loci	I-GENE
.	O

The	O
effects	O
of	O
social	O
isolation	O
on	O
morphine	O
-	O
induced	O
locomotor	O
activity	O
were	O
compared	O
in	O
:	O
(	O
i	O
)	O
animals	O
with	O
an	O
intact	O
hypothalamo	O
-	O
pituitary	O
-	O
adrenal	O
(	O
HPA	O
)	O
axis	O
;	O
(	O
ii	O
)	O
animals	O
in	O
which	O
stress	O
-	O
induced	O
corticosterone	O
secretion	O
was	O
blocked	O
by	O
adrenalectomy	O
.	O

Using	O
this	O
reporter	O
gene	O
system	O
,	O
we	O
previously	O
showed	O
that	O
EPO	B-GENE
-	O
induced	O
activation	O
of	O
the	O
c	B-GENE
-	I-GENE
fos	I-GENE
promoter	I-GENE
can	O
be	O
detected	O
rapidly	O
and	O
sensitively	O
as	O
an	O
elevation	O
of	O
cellular	B-GENE
luciferase	I-GENE
activity	O
.	O

I	O
hypothesize	O
that	O
white	B-GENE
gene	I-GENE
expression	O
from	O
P	B-GENE
[	I-GENE
en	I-GENE
]	I-GENE
is	O
repressed	O
by	O
the	O
formation	O
of	O
a	O
protein	O
complex	O
which	O
is	O
initiated	O
at	O
the	O
engrailed	B-GENE
PS	I-GENE
sites	I-GENE
and	O
also	O
requires	O
interactions	O
with	O
flanking	O
genomic	O
DNA	O
.	O

SPP41	B-GENE
was	O
cloned	O
and	O
sequenced	O
and	O
found	O
to	O
be	O
essential	O
.	O
spp43	B-GENE
is	O
allelic	O
to	O
the	O
previously	O
identified	O
suppressor	B-GENE
srn1	I-GENE
,	O
which	O
encodes	O
a	O
negative	O
regulator	O
of	O
gene	O
expression	O
.	O

Standard	O
curve	O
correlation	O
coefficients	O
of	O
0	O
.	O
995	O
or	O
greater	O
were	O
obtained	O
during	O
validation	O
experiments	O
and	O
analysis	O
of	O
study	O
samples	O
.	O

To	O
see	O
if	O
a	O
pulse	O
oximeter	O
can	O
monitor	O
the	O
fetus	O
during	O
labour	O
we	O
recruited	O
100	O
Caucasian	O
women	O
in	O
normal	O
uncomplicated	O
labour	O
.	O

There	O
was	O
no	O
difference	O
in	O
plasma	O
concentrations	O
of	O
PGI2	O
(	O
figure	O
4	O
)	O
and	O
TxA2	O
in	O
patients	O
with	O
normal	O
blood	O
pressure	O
,	O
mild	O
preeclampsia	O
and	O
hypotension	O
,	O
whereas	O
in	O
severe	O
preeclampsia	O
,	O
the	O
plasma	O
concentration	O
of	O
PGI2	O
was	O
significantly	O
lower	O
(	O
p	O
<	O
0	O
.	O
001	O
)	O
and	O
of	O
TxA2	O
significantly	O
higher	O
(	O
p	O
<	O
0	O
.	O
001	O
)	O
.	O

A	O
causal	O
analysis	O
of	O
secondary	O
variables	O
showed	O
that	O
the	O
formation	O
of	O
FB	O
memories	O
was	O
primarily	O
associated	O
with	O
the	O
level	O
of	O
importance	O
attached	O
to	O
the	O
event	O
and	O
level	O
of	O
affective	O
response	O
to	O
the	O
news	O
.	O

The	O
IPL1	B-GENE
gene	I-GENE
is	O
required	O
for	O
high	O
-	O
fidelity	O
chromosome	O
segregation	O
in	O
the	O
budding	O
yeast	O
Saccharomyces	O
cerevisiae	O
.	O

2	O
.	O

The	O
complete	O
gene	O
organization	O
was	O
obtained	O
by	O
combining	O
the	O
results	O
of	O
the	O
sequence	O
of	O
these	O
clones	O
and	O
those	O
of	O
the	O
characterization	O
of	O
polymerase	O
chain	O
reaction	O
-	O
amplified	O
genomic	O
segments	O
.	O

INO2	B-GENE
,	O
a	O
regulatory	O
gene	O
in	O
yeast	O
phospholipid	O
biosynthesis	O
,	O
affects	O
nuclear	O
segregation	O
and	O
bud	O
pattern	O
formation	O
.	O

The	O
pentafluorobenzyl	O
derivative	O
of	O
clonidine	O
yields	O
an	O
intense	O
ion	O
fragment	O
at	O
m	O
/	O
z	O
354	O
,	O
and	O
the	O
lower	O
limit	O
of	O
detection	O
is	O
0	O
.	O
025	O
ng	O
/	O
ml	O
for	O
a	O
1	O
-	O
ml	O
plasma	O
sample	O
.	O

Mammalian	B-GENE
ABPs	I-GENE
and	O
SHBGs	B-GENE
bind	O
sex	O
steroids	O
with	O
high	O
affinity	O
,	O
but	O
some	O
binding	O
properties	O
differ	O
among	O
species	O
.	O

Src	B-GENE
homology	I-GENE
(	O
SH	B-GENE
)	O
domain	O
dependent	O
protein	O
-	O
protein	O
interactions	O
are	O
important	O
to	O
tyrosine	B-GENE
kinase	I-GENE
receptor	I-GENE
signal	O
transduction	O
.	O

Sample	O
treatment	O
was	O
optimized	O
in	O
order	O
to	O
achieve	O
a	O
complete	O
extraction	O
of	O
labetalol	O
diastereoisomers	O
and	O
to	O
avoid	O
racemization	O
during	O
extraction	O
.	O

Under	O
resting	O
conditions	O
,	O
activity	O
levels	O
of	O
cardiac	O
vagal	O
and	O
sympathetic	O
outflows	O
are	O
not	O
related	O
across	O
young	O
,	O
healthy	O
human	O
subjects	O
and	O
peripheral	O
interaction	O
is	O
not	O
manifest	O
between	O
the	O
autonomic	O
divisions	O
.	O

Both	O
proprioceptive	O
and	O
electroreceptive	O
units	O
showed	O
a	O
progression	O
of	O
receptive	O
fields	O
from	O
anterior	O
to	O
posterior	O
body	O
in	O
the	O
rostral	O
to	O
caudal	O
direction	O
along	O
the	O
length	O
of	O
DGR	O
.	O

In	O
control	O
patients	O
,	O
baseline	O
images	O
presented	O
Type	O
I	O
in	O
25	O
,	O
Type	O
II	O
in	O
7	O
,	O
and	O
the	O
Type	O
III	O
&	O
IV	O
in	O
0	O
,	O
and	O
the	O
Type	O
after	O
loading	O
was	O
the	O
same	O
as	O
the	O
Type	O
at	O
baseline	O
.	O

A	O
more	O
complete	O
analysis	O
of	O
dose	O
response	O
,	O
time	O
and	O
mode	O
of	O
Ga	O
administration	O
(	O
preinjury	O
or	O
postinjury	O
)	O
,	O
and	O
availability	O
of	O
Ga	O
across	O
the	O
blood	O
-	O
brain	O
barrier	O
is	O
needed	O
to	O
further	O
evaluate	O
the	O
efficacy	O
of	O
this	O
compound	O
.	O

The	O
presence	O
of	O
regulatory	O
sequences	O
for	O
the	O
binding	O
of	O
transcription	O
factors	O
such	O
as	O
NF	B-GENE
-	I-GENE
kappa	I-GENE
B	I-GENE
and	O
AP	B-GENE
-	I-GENE
2	I-GENE
,	O
whose	O
activation	O
is	O
associated	O
with	O
the	O
immediate	O
response	O
of	O
the	O
cell	O
to	O
an	O
injury	O
,	O
may	O
be	O
an	O
indication	O
of	O
the	O
important	O
role	O
which	O
HO	B-GENE
-	I-GENE
1	I-GENE
may	O
play	O
in	O
defense	O
mechanisms	O
against	O
tissue	O
injury	O
.	O

Granisetron	O
,	O
but	O
not	O
saline	O
,	O
abolished	O
vomiting	O
and	O
nausea	O
when	O
given	O
as	O
intervention	O
after	O
this	O
combined	O
emetic	O
regimen	O
.	O

The	O
femoroarterial	O
coronary	O
sinus	O
difference	O
in	O
lactate	O
turned	O
negative	O
,	O
and	O
pH	O
,	O
PCO2	O
and	O
potassium	O
differences	O
increased	O
in	O
group	O
2	O
during	O
pacing	O
.	O

This	O
was	O
obtained	O
with	O
the	O
thermal	O
neutron	O
fluency	O
2	O
.	O
0	O
x	O
10	O
(	O
10	O
)	O
n	O
/	O
cm2	O
.	O

Endotoxemia	O
induced	O
by	O
gram	O
-	O
negative	O
bacteria	O
leads	O
to	O
endotoxic	O
shock	O
pathogenetically	O
stemming	O
from	O
the	O
integral	O
component	O
of	O
the	O
bacterial	O
wall	O
-	O
-	O
lipid	O
A	O
.	O

The	O
study	O
made	O
to	O
define	O
the	O
ability	O
of	O
lipid	B-GENE
A	I-GENE
monoclonal	I-GENE
antibodies	I-GENE
to	O
correct	O
hemodynamic	O
disturbances	O
due	O
to	O
endotoxemia	O
in	O
dog	O
experiments	O
showed	O
the	O
efficacy	O
of	O
the	O
antibodies	O
administration	O
.	O

A	O
randomised	O
,	O
controlled	O
trial	O
was	O
undertaken	O
in	O
40	O
patients	O
with	O
active	O
Crohn	O
'	O
s	O
disease	O
to	O
evaluate	O
clinical	O
and	O
nutritional	O
outcomes	O
after	O
an	O
amino	O
acid	O
based	O
diet	O
containing	O
3	O
%	O
fat	O
was	O
given	O
by	O
a	O
feeding	O
tube	O
compared	O
with	O
a	O
peptide	O
based	O
diet	O
containing	O
33	O
%	O
fat	O
.	O

The	O
sequenced	O
genomic	O
region	O
thus	O
accounts	O
for	O
essentially	O
all	O
of	O
the	O
longest	O
known	O
transcript	O
(	O
4	O
.	O
5	O
kb	O
)	O
,	O
although	O
the	O
precise	O
ends	O
of	O
this	O
transcript	O
have	O
not	O
been	O
defined	O
.	O

The	O
pexB	B-GENE
upstream	I-GENE
region	I-GENE
contained	O
245	O
nucleotides	O
within	O
which	O
sequences	O
approximating	O
the	O
consensus	O
for	O
cyclic	B-GENE
AMP	I-GENE
receptor	I-GENE
protein	I-GENE
and	O
integration	B-GENE
host	I-GENE
factor	I-GENE
binding	O
sites	O
were	O
discernible	O
.	O

The	O
fepA	B-GENE
-	O
entD	B-GENE
and	O
fes	B-GENE
-	O
entF	B-GENE
operons	O
in	O
the	O
enterobactin	O
synthesis	O
and	O
transport	O
system	O
are	O
divergently	O
transcribed	O
from	O
overlapping	O
promoters	O
,	O
and	O
both	O
are	O
inhibited	O
by	O
the	O
Fur	B-GENE
repressor	I-GENE
protein	I-GENE
under	O
iron	O
-	O
replete	O
conditions	O
.	O

Sequence	O
analysis	O
of	O
a	O
6	O
.	O
3	O
-	O
kbp	O
genomic	O
EcoRI	B-GENE
-	O
fragment	O
of	O
Alcaligenes	O
eutrophus	O
,	O
which	O
was	O
recently	O
identified	O
by	O
using	O
a	O
dihydrolipoamide	B-GENE
dehydrogenase	I-GENE
-	O
specific	O
DNA	O
probe	O
(	O
A	O
.	O

Using	O
a	O
previously	O
published	O
two	O
-	O
frequency	O
(	O
AC	O
excitation	O
)	O
three	O
-	O
electrode	O
method	O
,	O
the	O
admittance	O
locus	O
plot	O
(	O
ALP	O
)	O
in	O
the	O
low	O
-	O
frequency	O
region	O
(	O
<	O
1000	O
Hz	O
)	O
has	O
been	O
shown	O
to	O
be	O
very	O
well	O
approximated	O
by	O
a	O
straight	O
line	O
and	O
can	O
be	O
described	O
with	O
frequency	O
-	O
independent	O
parameters	O
;	O
phase	O
angle	O
alpha	O
pi	O
/	O
2	O
,	O
conductance	O
at	O
extrapolated	O
zero	O
frequency	O
G0	O
=	O
1	O
/	O
R0	O
,	O
and	O
ion	O
relaxation	O
time	O
tau	O
.	O

Intraoperative	O
measurement	O
of	O
activated	O
partial	O
thromboplastin	B-GENE
time	O
and	O
prothrombin	B-GENE
time	O
with	O
a	O
new	O
compact	O
monitor	O
.	O

In	O
addition	O
,	O
we	O
sought	O
to	O
test	O
the	O
hypothesis	O
that	O
,	O
when	O
equal	O
volumes	O
are	O
administered	O
intrathecally	O
,	O
significant	O
differences	O
exist	O
in	O
the	O
potential	O
to	O
three	O
commonly	O
used	O
anesthetic	O
solutions	O
to	O
induce	O
sensory	O
impairment	O
.	O

In	O
an	O
in	O
vitro	O
study	O
,	O
10	O
/	O
0	O
nylon	O
was	O
found	O
to	O
require	O
a	O
significantly	O
lower	O
laser	O
energy	O
density	O
to	O
produce	O
suture	O
lysis	O
following	O
a	O
single	O
shot	O
than	O
either	O
10	O
/	O
0	O
Dacron	O
or	O
10	O
/	O
0	O
prolene	O
.	O

The	O
proteins	O
encoded	O
downstream	O
of	O
rpoN	B-GENE
are	O
known	O
to	O
negatively	O
regulate	O
sigma	B-GENE
54	I-GENE
activity	O
.	O

We	O
report	O
here	O
that	O
microinjection	O
of	O
an	O
anti	B-GENE
-	I-GENE
CBP	I-GENE
antiserum	I-GENE
into	O
fibroblasts	O
can	O
inhibit	O
transcription	O
from	O
a	O
cAMP	O
responsive	O
promoter	O
.	O

These	O
results	O
demonstrate	O
that	O
a	O
class	O
of	O
proline	O
-	O
rich	O
activator	O
proteins	O
and	O
RNA	B-GENE
polymerase	I-GENE
II	I-GENE
possess	O
a	O
common	O
structural	O
and	O
functional	O
component	O
which	O
can	O
interact	O
with	O
the	O
same	O
target	O
in	O
the	O
general	O
transcription	O
machinery	O
.	O

Cloning	O
of	O
higher	B-GENE
plant	I-GENE
omega	I-GENE
-	I-GENE
3	I-GENE
fatty	I-GENE
acid	I-GENE
desaturases	I-GENE
.	O

65	O
,	O
3829	O
-	O
3838	O
,	O
1991	O
)	O
,	O
a	O
truncated	O
form	O
of	O
the	O
IE	B-GENE
polypeptide	I-GENE
lacking	O
IE	B-GENE
amino	I-GENE
acid	I-GENE
residues	I-GENE
1	I-GENE
-	I-GENE
322	I-GENE
(	O
and	O
,	O
therefore	O
lacks	O
the	O
deduced	O
transcriptional	O
activation	O
domain	O
)	O
,	O
fails	O
to	O
transactivate	O
the	O
EHV	B-GENE
-	I-GENE
1	I-GENE
tk	I-GENE
promoter	I-GENE
,	O
but	O
retains	O
the	O
ability	O
to	O
down	O
-	O
regulate	O
the	O
EHV	B-GENE
-	I-GENE
1	I-GENE
IE	I-GENE
promoter	I-GENE
.	O

CONCLUSION	O
:	O
Human	O
preterm	O
birth	O
is	O
associated	O
with	O
significantly	O
lower	O
progesterone	O
/	O
17	O
beta	O
-	O
estradiol	O
ratios	O
than	O
those	O
of	O
women	O
with	O
preterm	O
labor	O
delivered	O
at	O
term	O
.	O

In	O
conclusion	O
,	O
the	O
disposition	O
of	O
venlafaxine	O
and	O
O	O
-	O
desmethylvenlafaxine	O
is	O
markedly	O
altered	O
in	O
renal	O
disease	O
;	O
therefore	O
dosage	O
adjustment	O
is	O
warranted	O
for	O
patients	O
with	O
creatinine	O
clearance	O
values	O
below	O
30	O
ml	O
/	O
min	O
.	O

The	O
availability	O
of	O
sequence	O
from	O
multiple	O
species	O
has	O
permitted	O
us	O
to	O
determine	O
that	O
the	O
UBE	O
site	O
has	O
close	O
similarity	O
to	O
motifs	O
that	O
bind	O
members	O
of	O
the	O
NF	B-GENE
-	I-GENE
1	I-GENE
family	I-GENE
of	I-GENE
transcription	I-GENE
factors	I-GENE
.	O

The	O
incidence	O
of	O
HSV	O
-	O
2	O
positive	O
subjects	O
(	O
HSV	B-GENE
-	I-GENE
2	I-GENE
/	I-GENE
HSV	I-GENE
-	I-GENE
1	I-GENE
antibody	I-GENE
ratio	O
>	O
or	O
=	O
1	O
)	O
was	O
low	O
in	O
the	O
Jewish	O
Israeli	O
population	O
,	O
compared	O
to	O
other	O
demographic	O
areas	O
.	O

The	O
mechanism	O
whereby	O
zeta	B-GENE
PKC	I-GENE
regulates	O
NF	B-GENE
-	I-GENE
kappa	I-GENE
B	I-GENE
most	O
probably	O
involves	O
the	O
activation	O
of	O
a	O
putative	O
I	B-GENE
kappa	I-GENE
B	I-GENE
kinase	I-GENE
of	O
molecular	O
mass	O
approximately	O
50	O
kDa	O
,	O
which	O
phosphorylates	O
and	O
inactivates	O
I	B-GENE
kappa	I-GENE
B	I-GENE
.	O

Stable	O
expression	O
of	O
truncated	B-GENE
inositol	I-GENE
1	I-GENE
,	I-GENE
4	I-GENE
,	I-GENE
5	I-GENE
-	I-GENE
trisphosphate	I-GENE
receptor	I-GENE
subunits	I-GENE
in	O
3T3	O
fibroblasts	O
.	O

We	O
report	O
the	O
identification	O
and	O
characterization	O
of	O
myr	B-GENE
4	I-GENE
(	O
myosin	B-GENE
from	I-GENE
rat	I-GENE
)	O
,	O
the	O
first	O
mammalian	B-GENE
myosin	I-GENE
I	I-GENE
that	O
is	O
not	O
closely	O
related	O
to	O
brush	O
border	O
myosin	B-GENE
I	I-GENE
.	O

M	O
.	O
,	O
and	O
D	O
.	O

In	O
addition	O
,	O
computer	O
analysis	O
suggests	O
that	O
sequences	O
similar	O
to	O
the	O
A	O
stem	O
element	O
are	O
present	O
within	O
the	O
three	O
AAV	B-GENE
promoter	I-GENE
regions	O
.	O

At	O
least	O
some	O
of	O
the	O
difference	O
in	O
stability	O
of	O
the	O
two	O
kinds	O
of	O
complexes	O
was	O
due	O
to	O
the	O
fact	O
that	O
the	O
dissociation	O
rate	O
of	O
the	O
A	O
stem	O
substrate	O
from	O
the	O
protein	O
-	O
DNA	O
complexes	O
was	O
approximately	O
fourfold	O
faster	O
than	O
that	O
of	O
the	O
complete	O
TR	B-GENE
.	O

Processing	O
of	O
the	O
NS3	B-GENE
'	I-GENE
-	O
5B	B-GENE
polyprotein	O
was	O
complex	O
and	O
occurred	O
rapidly	O
.	O

However	O
,	O
each	O
promoter	O
activated	O
by	O
IEP86	B-GENE
was	O
synergistically	O
affected	O
by	O
the	O
addition	O
of	O
IEP72	B-GENE
.	O

32Pi	O
labeling	O
or	O
isoelectric	O
focusing	O
analysis	O
of	O
eIF	B-GENE
-	I-GENE
2	I-GENE
alpha	I-GENE
from	O
conditional	O
casein	B-GENE
kinase	I-GENE
II	I-GENE
mutants	I-GENE
indicated	O
that	O
phosphorylation	O
of	O
eIF	B-GENE
-	I-GENE
2	I-GENE
alpha	I-GENE
is	O
abolished	O
or	O
dephosphorylated	O
forms	O
of	O
eIF	B-GENE
-	I-GENE
2	I-GENE
alpha	I-GENE
are	O
detected	O
when	O
these	O
strains	O
are	O
grown	O
at	O
the	O
restrictive	O
growth	O
conditions	O
.	O

The	O
R2	O
region	O
within	O
the	O
class	O
I	O
enhancer	O
acts	O
as	O
a	O
negative	O
element	O
in	O
Ad12	O
-	O
transformed	O
cells	O
and	O
exhibits	O
a	O
stronger	O
binding	O
activity	O
than	O
is	O
observed	O
in	O
nontumorigenic	O
Ad5	O
-	O
transformed	O
cells	O
,	O
which	O
are	O
not	O
reduced	O
in	O
class	O
I	O
expression	O
.	O

PURPOSE	O
:	O
To	O
evaluate	O
the	O
kinetics	O
of	O
erythropoietin	B-GENE
(	O
EPO	B-GENE
)	O
production	O
and	O
address	O
the	O
pathogenesis	O
of	O
anemia	O
of	O
prematurity	O
,	O
we	O
measured	O
EPO	B-GENE
levels	O
in	O
infants	O
during	O
the	O
first	O
year	O
of	O
life	O
.	O

The	O
nerve	B-GENE
growth	I-GENE
factor	I-GENE
beta	I-GENE
gene	I-GENE
(	O
NGFB	B-GENE
)	O
belongs	O
to	O
a	O
conserved	O
syntenic	O
group	O
on	O
human	O
chromosome	O
1	O
and	O
mouse	O
Chromosome	O
3	O
.	O

Furthermore	O
,	O
an	O
upstream	O
element	O
,	O
collagen	B-GENE
element	I-GENE
I	I-GENE
(	I-GENE
-	I-GENE
370	I-GENE
/	I-GENE
-	I-GENE
344	I-GENE
)	I-GENE
,	O
which	O
shares	O
homology	O
with	O
the	O
LAP	B-GENE
binding	O
cis	O
-	O
element	O
of	O
the	O
albumin	B-GENE
promoter	I-GENE
(	O
9	O
of	O
13	O
bp	O
)	O
is	O
described	O
.	O

Number	O
and	O
size	O
of	O
silver	O
-	O
stained	O
nucleoli	O
(	O
Ag	O
-	O
NOR	O
clusters	O
)	O
in	O
canine	O
seminomas	O
:	O
correlation	O
with	O
histological	O
features	O
and	O
tumour	O
behaviour	O
.	O

We	O
speculate	O
that	O
mast	O
cell	O
degranulation	O
may	O
be	O
involved	O
in	O
the	O
pathogenesis	O
of	O
necrobiosis	O
by	O
altering	O
fibroblast	O
enzyme	O
activity	O
and	O
/	O
or	O
producing	O
prolonged	O
inflammatory	O
reactions	O
.	O

Molecular	O
cloning	O
of	O
a	O
cysteine	B-GENE
synthase	I-GENE
cDNA	I-GENE
from	O
Citrullus	O
vulgaris	O
(	O
watermelon	O
)	O
by	O
genetic	O
complementation	O
in	O
an	O
Escherichia	O
coli	O
Cys	O
-	O
auxotroph	O
.	O

In	O
earlier	O
studies	O
we	O
identified	O
several	O
regulatory	O
elements	O
that	O
control	O
transcriptional	O
activation	O
and	O
aerobic	O
repression	O
of	O
one	O
of	O
these	O
genes	O
,	O
COX5b	B-GENE
.	O

Although	O
elevated	O
serum	O
levels	O
of	O
antibodies	O
to	O
the	O
nicotinic	B-GENE
acetylcholine	I-GENE
receptor	I-GENE
(	O
nAChR	B-GENE
)	O
have	O
been	O
reported	O
in	O
neuroleptic	O
treated	O
patients	O
with	O
tardive	O
dyskinesia	O
,	O
such	O
antibodies	O
have	O
not	O
been	O
determined	O
in	O
comparable	O
nondyskinetic	O
patients	O
.	O

The	O
tumor	O
suppressor	O
and	O
transcriptional	O
factor	O
p53	B-GENE
is	O
a	O
phosphorylated	O
protein	O
.	O

This	O
DNA	O
containing	O
promoter	O
activity	O
has	O
been	O
sequenced	O
in	O
its	O
entirety	O
and	O
found	O
to	O
contain	O
multiple	O
putative	O
regulatory	O
sites	O
.	O

However	O
,	O
Southern	O
blot	O
and	O
karyotype	O
analyses	O
did	O
not	O
reveal	O
any	O
significant	O
changes	O
in	O
copy	O
number	O
or	O
gross	O
rearrangements	O
of	O
the	O
p53	B-GENE
gene	I-GENE
in	O
any	O
of	O
the	O
p53	B-GENE
-	I-GENE
cell	O
lines	O
.	O

HupI	B-GENE
showed	O
strong	O
identity	O
to	O
rubredoxin	B-GENE
and	O
rubredoxin	B-GENE
-	I-GENE
like	I-GENE
proteins	I-GENE
from	O
many	O
other	O
bacteria	O
.	O

The	O
PCr	O
resynthesis	O
rate	O
(	O
P	O
<	O
0	O
.	O
01	O
)	O
and	O
the	O
effective	O
maximal	O
rate	O
of	O
mitochondrial	O
ATP	O
synthesis	O
(	O
P	O
<	O
0	O
.	O
05	O
)	O
also	O
improved	O
.	O

An	O
examination	O
was	O
performed	O
in	O
15	O
patients	O
who	O
had	O
developed	O
pronounced	O
osteomalacia	O
following	O
gastric	O
resection	O
.	O

However	O
,	O
regional	O
MVO2	O
increased	O
to	O
about	O
the	O
same	O
extent	O
in	O
the	O
CFX	O
(	O
from	O
6	O
.	O
0	O
+	O
/	O
-	O
0	O
.	O
7	O
to	O
12	O
.	O
4	O
+	O
/	O
-	O
0	O
.	O
9	O
ml	O
O2	O
.	O
min	O
-	O
1	O
times	O
100	O
g	O
-	O
1	O
)	O
and	O
the	O
LAD	O
region	O
(	O
from	O
7	O
.	O
0	O
+	O
/	O
-	O
0	O
.	O
6	O
to	O
14	O
.	O
5	O
+	O
/	O
-	O
1	O
.	O
3	O
ml	O
O2	O
.	O
min	O
-	O
1	O
times	O
100	O
g	O
-	O
1	O
)	O
.	O

IGF	B-GENE
I	I-GENE
and	O
insulin	B-GENE
receptors	I-GENE
are	O
homologous	O
proteins	O
that	O
function	O
in	O
distinct	O
physiological	O
pathways	O
.	O

Immunodepression	O
was	O
combined	O
with	O
the	O
increase	O
of	O
glucocorticoid	O
activity	O
of	O
adrenal	O
cortex	O
,	O
while	O
no	O
significant	O
changes	O
in	O
thyroid	O
hormones	O
were	O
registered	O
.	O

Aberrant	O
protein	O
phosphorylation	O
at	O
tyrosine	O
is	O
responsible	O
for	O
the	O
growth	O
-	O
inhibitory	O
action	O
of	O
pp60v	B-GENE
-	I-GENE
src	I-GENE
expressed	O
in	O
the	O
yeast	O
Saccharomyces	O
cerevisiae	O
.	O

Acute	O
pancreatitis	O
:	O
a	O
multisystem	O
disease	O
.	O

Alginate	O
biosynthesis	O
is	O
controlled	O
by	O
a	O
complex	O
regulatory	O
mechanism	O
.	O

The	O
sequence	O
upstream	O
of	O
the	O
rhlA	B-GENE
promoter	I-GENE
contains	O
two	O
inverted	O
repeats	O
which	O
define	O
putative	O
binding	O
sites	O
for	O
the	O
RhlR	B-GENE
regulator	I-GENE
.	O

We	O
have	O
examined	O
by	O
in	O
vitro	O
footprinting	O
a	O
region	O
located	O
downstream	O
of	O
the	O
human	O
immunodeficiency	O
virus	O
,	O
type	O
1	O
(	O
HIV	O
-	O
1	O
)	O
promoter	O
found	O
to	O
be	O
hypersensitive	O
to	O
DNase	B-GENE
I	I-GENE
digestion	O
in	O
vivo	O
.	O

The	O
relative	O
abundance	O
of	O
each	O
alternatively	O
spliced	O
mRNA	O
was	O
determined	O
by	O
reverse	O
transcription	O
-	O
polymerase	O
chain	O
reaction	O
in	O
various	O
human	O
tissues	O
and	O
cell	O
lines	O
.	O

The	O
retention	O
index	O
of	O
201Tl	O
SPECT	O
is	O
a	O
useful	O
indicator	O
of	O
metastatic	O
potential	O
,	O
thereby	O
facilitating	O
the	O
prediction	O
of	O
prognosis	O
,	O
and	O
provides	O
insight	O
into	O
the	O
relationship	O
between	O
201Tl	O
uptake	O
and	O
malignancy	O
.	O

The	O
central	O
globular	O
domain	O
is	O
highly	O
similar	O
to	O
those	O
regions	O
from	O
other	O
H1	B-GENE
molecules	I-GENE
,	O
and	O
the	O
carboxyl	O
-	O
terminal	O
domain	O
contains	O
a	O
repeating	O
hexapeptide	O
motif	O
,	O
variants	O
of	O
which	O
are	O
conserved	O
among	O
H1	B-GENE
molecules	I-GENE
.	O

The	O
location	O
and	O
approximate	O
length	O
of	O
the	O
intron	O
are	O
conserved	O
in	O
both	O
the	O
tomato	O
and	O
Arabidopsis	O
genes	O
,	O
with	O
the	O
intron	O
separating	O
the	O
'	O
nose	O
'	O
region	O
(	O
encoded	O
by	O
exon	O
1	O
)	O
from	O
the	O
central	O
globular	O
domain	O
(	O
exon	O
2	O
)	O
.	O

The	O
topology	O
and	O
chain	O
folding	O
of	O
the	O
beta	O
subunits	O
in	O
the	O
artifactual	O
beta	O
60	O
capsid	O
are	O
similar	O
to	O
the	O
native	B-GENE
alpha	I-GENE
3	I-GENE
beta	I-GENE
60	I-GENE
enzyme	I-GENE
.	O

A	O
constitutive	O
mutant	O
form	O
with	O
a	O
single	O
substitution	O
(	O
V88A	O
)	O
in	O
the	O
amino	O
-	O
terminal	O
(	O
response	O
regulator	O
)	O
region	O
was	O
used	O
.	O

Comparisons	O
of	O
the	O
four	O
operon	O
control	O
regions	O
studied	O
indicate	O
that	O
the	O
NarL	B-GENE
heptamers	I-GENE
are	O
arranged	O
with	O
diverse	O
orientations	O
and	O
spacing	O
.	O

Direct	O
binding	O
and	O
competition	O
assays	O
using	O
30	O
-	O
mer	O
oligonucleotide	O
probes	O
representing	O
the	O
individual	O
CBF1	B-GENE
binding	I-GENE
sites	I-GENE
indicated	O
that	O
CBF1	B-GENE
bound	O
less	O
efficiently	O
to	O
the	O
CD23	B-GENE
promoter	I-GENE
and	O
the	O
EBV	B-GENE
LMP	I-GENE
-	I-GENE
1	I-GENE
promoter	I-GENE
sites	I-GENE
than	O
to	O
the	O
Cp	B-GENE
site	I-GENE
.	O

We	O
have	O
found	O
a	O
satisfactory	O
reproducibility	O
in	O
vitro	O
(	O
T1	O
:	O
1	O
.	O
9	O
%	O
;	O
T2	O
:	O
6	O
.	O
2	O
%	O
)	O
,	O
while	O
the	O
reproducibility	O
was	O
less	O
satisfactory	O
in	O
vivo	O
(	O
T1	O
:	O
16	O
.	O
4	O
%	O
;	O
T2	O
:	O
13	O
.	O
4	O
%	O
)	O
.	O

CONCLUSION	O
:	O
Sonographic	O
angiography	O
has	O
a	O
possible	O
role	O
in	O
the	O
detection	O
of	O
small	O
nodules	O
in	O
patients	O
with	O
CRF	O
.	O

Each	O
expressed	O
domain	O
,	O
as	O
well	O
as	O
FKBP	B-GENE
-	I-GENE
33	I-GENE
itself	O
,	O
possesses	O
peptidyl	B-GENE
-	I-GENE
prolyl	I-GENE
cis	I-GENE
-	I-GENE
trans	I-GENE
isomerase	I-GENE
activity	O
,	O
though	O
with	O
much	O
lower	O
specific	O
activities	O
than	O
FKBP	B-GENE
-	I-GENE
12	I-GENE
.	O

The	O
first	O
85	O
nt	O
upstream	O
of	O
the	O
transcription	O
initiation	O
site	O
of	O
the	O
mouse	B-GENE
desmin	I-GENE
gene	I-GENE
,	O
which	O
contain	O
an	O
E	O
box	O
(	O
E1	O
)	O
,	O
the	O
binding	O
site	O
of	O
the	O
helix	B-GENE
-	I-GENE
loop	I-GENE
-	I-GENE
helix	I-GENE
myogenic	I-GENE
regulators	I-GENE
,	O
are	O
sufficient	O
to	O
confer	O
low	O
level	O
muscle	O
-	O
specific	O
expression	O
.	O

The	O
acfD	B-GENE
gene	I-GENE
encompasses	O
254	O
nt	O
that	O
are	O
predicted	O
to	O
encode	O
an	O
88	O
-	O
amino	O
-	O
acid	O
(	O
aa	O
)	O
protein	O
.	O

We	O
find	O
that	O
beta	B-GENE
II	I-GENE
PKC	I-GENE
phosphorylates	O
nuclear	B-GENE
envelope	I-GENE
lamin	I-GENE
B	I-GENE
at	O
10	O
-	O
20	O
times	O
the	O
rate	O
of	O
alpha	B-GENE
PKC	I-GENE
,	O
whereas	O
both	O
kinases	O
phosphorylate	O
soluble	B-GENE
lamin	I-GENE
B	I-GENE
at	O
similar	O
rates	O
.	O

Regulation	O
of	O
parathyroid	B-GENE
hormone	I-GENE
-	I-GENE
related	I-GENE
protein	I-GENE
(	O
PTHrP	B-GENE
)	O
gene	O
expression	O
.	O

We	O
conclude	O
that	O
c	B-GENE
-	I-GENE
Abl	I-GENE
activates	O
c	B-GENE
-	I-GENE
myc	I-GENE
transcription	O
indirectly	O
with	O
no	O
requirement	O
for	O
DNA	O
binding	O
by	O
c	B-GENE
-	I-GENE
Abl	I-GENE
.	O

Long	O
-	O
latency	O
:	O
locked	O
units	O
responded	O
to	O
shocks	O
with	O
little	O
jitter	O
and	O
long	O
latency	O
(	O
4	O
-	O
11	O
ms	O
)	O
.	O

The	O
highly	O
conserved	O
ninth	O
heptad	O
,	O
which	O
is	O
involved	O
in	O
heterodimerization	O
,	O
appears	O
to	O
participate	O
in	O
the	O
receptor	O
-	O
inhibitor	O
interaction	O
,	O
suggesting	O
that	O
the	O
inhibitor	O
is	O
a	O
related	O
member	O
of	O
the	O
receptor	O
gene	O
family	O
.	O

Here	O
we	O
show	O
that	O
for	O
expression	O
of	O
snRNA	O
genes	O
in	O
maize	O
,	O
a	O
monocotyledonous	O
plant	O
,	O
the	O
USE	O
and	O
TATA	O
elements	O
are	O
essential	O
,	O
but	O
not	O
sufficient	O
,	O
for	O
transcription	O
.	O

Extensive	O
DNA	O
rearrangement	O
occurs	O
during	O
the	O
development	O
of	O
the	O
somatic	O
macronucleus	O
from	O
the	O
germ	O
line	O
micronucleus	O
in	O
ciliated	O
protozoans	O
.	O

An	O
in	O
vitro	O
binding	O
site	O
selection	O
procedure	O
was	O
used	O
to	O
determine	O
DNA	O
sequences	O
preferentially	O
bound	O
by	O
wild	B-GENE
-	I-GENE
type	I-GENE
HLF	I-GENE
and	O
chimeric	O
E2A	B-GENE
-	O
HLF	B-GENE
proteins	O
isolated	O
from	O
various	O
t	O
(	O
17	O
;	O
19	O
)	O
-	O
bearing	O
leukemias	O
.	O

The	O
Oct	B-GENE
-	I-GENE
2	I-GENE
glutamine	O
-	O
rich	O
and	O
proline	O
-	O
rich	O
activation	O
domains	O
can	O
synergize	O
with	O
each	O
other	O
or	O
duplicates	O
of	O
themselves	O
to	O
activate	O
transcription	O
.	O

Taken	O
together	O
,	O
our	O
data	O
suggest	O
that	O
Dbf8p	B-GENE
plays	O
an	O
essential	O
role	O
in	O
chromosome	O
segregation	O
.	O

Ariga	O
,	O
Biochem	O
.	O

The	O
diagnostic	O
significance	O
of	O
creatine	B-GENE
phosphokinase	I-GENE
antibodies	O
in	O
the	O
cardiac	O
muscle	O
in	O
non	O
-	O
coronarogenic	O
myocardial	O
diseases	O

According	O
to	O
the	O
results	O
of	O
assays	O
obtained	O
with	O
the	O
use	O
of	O
assay	O
systems	O
ORTHO	O
ELISA	O
and	O
ABBOTT	O
HCV	O
EIA	O
(	O
USA	O
)	O
,	O
the	O
detection	O
rate	O
of	O
anti	B-GENE
-	I-GENE
HCV	I-GENE
-	I-GENE
C100	I-GENE
-	I-GENE
3	I-GENE
among	O
primary	O
blood	O
donors	O
in	O
Moscow	O
was	O
1	O
.	O
37	O
%	O
and	O
was	O
not	O
different	O
from	O
that	O
among	O
HBsAg	B-GENE
carriers	O
(	O
1	O
.	O
8	O
%	O
)	O
and	O
among	O
donors	O
with	O
anti	B-GENE
-	I-GENE
HCV	I-GENE
-	I-GENE
C100	I-GENE
-	I-GENE
3	I-GENE
in	O
the	O
blood	O
(	O
1	O
.	O
6	O
%	O
)	O
(	O
p	O
<	O
0	O
.	O
01	O
)	O
.	O

We	O
examined	O
the	O
hypothesis	O
that	O
the	O
coronary	O
vasomotor	O
responses	O
to	O
etomidate	O
(	O
ETO	O
)	O
,	O
propofol	O
(	O
PRO	O
)	O
,	O
and	O
sodium	O
thiopental	O
(	O
STP	O
)	O
are	O
mediated	O
through	O
contrasting	O
effects	O
on	O
the	O
resting	O
nitric	O
oxide	O
(	O
NO	O
)	O
-	O
dependent	O
vasodilator	O
tone	O
that	O
opposes	O
adrenergic	O
vasoconstrictor	O
activity	O
in	O
the	O
intact	O
dog	O
.	O

These	O
alternative	O
splice	O
variants	O
were	O
detected	O
in	O
RNA	O
isolated	O
from	O
several	O
sources	O
,	O
including	O
primary	O
leptomeningeal	O
tissue	O
and	O
an	O
established	O
line	O
of	O
leptomeningeal	O
cells	O
(	O
LMC	O
)	O
.	O

Roux	O
-	O
en	O
-	O
Y	O
gastroenterostomy	O
severely	O
disturbs	O
emptying	O
of	O
the	O
gallbladder	O
.	O

Surface	O
-	O
coil	O
experiments	O
on	O
phantoms	O
and	O
on	O
human	O
calf	O
muscles	O
in	O
vivo	O
are	O
presented	O
.	O

Large	O
interpatient	O
variation	O
in	O
peak	O
PCZ	O
plasma	O
levels	O
(	O
91	O
-	O
3215	O
ng	O
/	O
ml	O
)	O
was	O
seen	O
,	O
with	O
the	O
plasma	O
half	O
-	O
life	O
(	O
t1	O
/	O
2	O
alpha	O
)	O
being	O
approximately	O
57	O
min	O
in	O
patients	O
given	O
135	O
-	O
180	O
mg	O
/	O
m2	O
PCZ	O
.	O

The	O
maximal	O
effect	O
was	O
seen	O
at	O
100	O
ng	O
/	O
ml	O
EGF	B-GENE
,	O
with	O
a	O
time	O
lag	O
of	O
about	O
5	O
h	O
.	O

KAR1	B-GENE
encodes	O
an	O
essential	O
component	O
of	O
the	O
yeast	O
spindle	O
pole	O
body	O
(	O
SPB	O
)	O
that	O
is	O
required	O
for	O
karyogamy	O
and	O
SPB	O
duplication	O
.	O

CDC31	B-GENE
is	O
required	O
for	O
SPB	O
duplication	O
and	O
encodes	O
a	O
calmodulin	B-GENE
-	I-GENE
like	I-GENE
protein	I-GENE
that	O
is	O
most	O
closely	O
related	O
to	O
caltractin	B-GENE
/	O
centrin	B-GENE
,	O
a	O
protein	O
associated	O
with	O
the	O
Chlamydomonas	O
basal	O
body	O
.	O

During	O
transcript	O
elongation	O
,	O
the	O
sizes	O
of	O
the	O
DNA	O
footprint	O
and	O
the	O
single	O
-	O
stranded	O
transcription	O
bubble	O
vary	O
markedly	O
among	O
transcription	O
complexes	O
halted	O
at	O
different	O
template	O
positions	O
.	O

All	O
our	O
patients	O
had	O
polyps	O
,	O
23	O
(	O
54	O
%	O
)	O
had	O
asthma	O
,	O
12	O
(	O
27	O
%	O
)	O
had	O
aspirin	O
sensitivity	O
,	O
20	O
(	O
65	O
%	O
)	O
had	O
eosinophilia	O
,	O
and	O
9	O
(	O
69	O
%	O
)	O
had	O
increased	O
total	O
IgE	B-GENE
levels	O
.	O

A	O
new	O
generation	O
of	O
information	O
retrieval	O
tools	O
for	O
biologists	O
:	O
the	O
example	O
of	O
the	O
ExPASy	O
WWW	O
server	O
.	O

The	O
partial	O
ORF	O
was	O
found	O
to	O
be	O
identical	O
to	O
the	O
C	O
terminus	O
of	O
HrpJ2	B-GENE
.	O

The	O
partial	O
ORF	O
was	O
found	O
to	O
be	O
identical	O
to	O
the	O
C	O
terminus	O
of	O
HrpJ2	B-GENE
.	O

Rapid	O
detection	O
of	O
this	O
mutation	O
is	O
achieved	O
by	O
restriction	O
digestion	O
of	O
PCR	O
-	O
amplified	O
genomic	O
DNA	O
;	O
a	O
mismatch	O
primer	O
combined	O
with	O
the	O
point	O
mutation	O
creates	O
a	O
Tru9I	B-GENE
restriction	I-GENE
site	I-GENE
.	O

Wild	B-GENE
type	I-GENE
and	I-GENE
mutant	I-GENE
Epo	I-GENE
cDNAs	I-GENE
were	O
transiently	O
expressed	O
at	O
high	O
levels	O
in	O
COS1	O
and	O
COS7	O
cells	O
.	O

OBJECTIVE	O
-	O
-	O
To	O
assess	O
the	O
risk	O
of	O
hepatitis	O
A	O
in	O
international	O
travelers	O
and	O
to	O
recommend	O
preventive	O
measures	O
.	O

The	O
bactericidal	O
effect	O
of	O
disinfectants	O
against	O
biofilm	O
cells	O
was	O
found	O
to	O
be	O
considerably	O
enhanced	O
by	O
increasing	O
the	O
concentrations	O
of	O
the	O
disinfectants	O
.	O

Expression	O
of	O
ME31B	B-GENE
cDNA	I-GENE
in	O
S	O
.	O
pombe	O
suppresses	O
the	O
ste13	B-GENE
mutation	O
.	O

Use	O
of	O
Medi	O
-	O
Jector	O
EZ	O
dermojet	O
for	O
anesthesia	O
in	O
minor	O
surgery	O

The	O
immune	O
response	O
of	O
past	O
-	O
infection	O
of	O
cytomegalovirus	O
in	O
the	O
patients	O
of	O
RTID	O
is	O
rather	O
remarkable	O
.	O

Acupuncture	O
effect	O
on	O
deep	O
receptors	O
was	O
not	O
limited	O
to	O
one	O
point	O
but	O
within	O
a	O
certain	O
area	O
,	O
namely	O
distant	O
effect	O
existed	O
.	O

Reduced	O
NK	O
activity	O
correlates	O
with	O
active	O
disease	O
in	O
HIV	O
-	O
patients	O
with	O
multidrug	O
-	O
resistant	O
pulmonary	O
tuberculosis	O
.	O

Smoking	O
history	O
and	O
awake	O
oxygen	O
saturation	O
(	O
SaO2	O
)	O
was	O
recorded	O
in	O
all	O
of	O
them	O
.	O

(	O
LH	B-GENE
P	O
<	O
0	O
.	O
05	O
,	O
LH	B-GENE
/	O
FSH	B-GENE
P	O
<	O
0	O
.	O
01	O
)	O
.	O

The	O
relative	O
R	O
-	O
and	O
L	O
-	O
brain	O
weights	O
were	O
found	O
to	O
be	O
inversely	O
related	O
to	O
the	O
relative	O
R	O
-	O
L	O
brain	O
weight	O
only	O
in	O
the	O
RH	O
female	O
cats	O
with	O
R	O
-	O
L	O
brain	O
weight	O
smaller	O
than	O
zero	O
(	O
testosterone	O
in	O
males	O
,	O
estrogen	O
in	O
females	O
)	O
.	O

This	O
mode	O
of	O
ternary	O
complex	O
formation	O
is	O
in	O
contrast	O
to	O
the	O
one	O
seen	O
in	O
the	O
promoter	O
of	O
the	O
c	B-GENE
-	I-GENE
fos	I-GENE
protooncogene	I-GENE
,	O
where	O
formation	O
of	O
the	O
ternary	O
complex	O
is	O
dependent	O
on	O
the	O
prior	O
assembly	O
of	O
the	O
serum	B-GENE
response	I-GENE
factor	I-GENE
-	I-GENE
DNA	I-GENE
binary	I-GENE
complex	I-GENE
.	O

Vaccinia	O
virus	O
-	O
expressed	O
,	O
purified	O
full	B-GENE
-	I-GENE
length	I-GENE
HPV	I-GENE
-	I-GENE
16	I-GENE
and	I-GENE
BPV	I-GENE
-	I-GENE
1	I-GENE
E2	I-GENE
proteins	I-GENE
bound	O
a	O
consensus	O
E2	B-GENE
site	I-GENE
with	O
high	O
specific	O
affinities	O
(	O
Kd	O
=	O
approximately	O
10	O
(	O
-	O
9	O
)	O
M	O
)	O
and	O
stimulated	O
in	O
vitro	O
transcription	O
up	O
to	O
six	O
-	O
to	O
eightfold	O
.	O

This	O
alternatively	O
spliced	O
transcript	O
contained	O
an	O
open	O
reading	O
frame	O
extending	O
from	O
the	O
upstream	O
J	O
alpha	O
11	O
-	O
2	O
region	O
to	O
82	O
nucleotides	O
downstream	O
of	O
the	O
beginning	O
of	O
the	O
TCR	B-GENE
C	I-GENE
alpha	I-GENE
region	I-GENE
,	O
and	O
potentially	O
encoded	O
a	O
36	O
amino	O
acid	O
polypeptide	O
.	O

In	O
HeLa	O
x	O
fibroblast	O
cell	O
hybrids	O
its	O
expression	O
correlates	O
with	O
tumorigenicity	O
.	O

Demographic	O
characteristics	O
and	O
risk	O
factor	O
data	O
for	O
76	O
,	O
672	O
clients	O
were	O
studied	O
to	O
characterize	O
the	O
distribution	O
of	O
infection	O
with	O
human	O
immunodeficiency	O
virus	O
(	O
HIV	O
)	O
and	O
the	O
use	O
of	O
counseling	O
and	O
testing	O
facilities	O
in	O
Houston	O
,	O
Tex	O
.	O

Results	O
indicate	O
that	O
KNM	O
-	O
LU	O
335	O
differs	O
from	O
both	O
human	O
and	O
chimpanzee	O
M1s	O
in	O
relative	O
distances	O
(	O
measured	O
in	O
three	O
dimensions	O
)	O
between	O
crown	O
fissure	O
termini	O
.	O

We	O
describe	O
49	O
cases	O
with	O
papillary	O
tumor	O
<	O
1	O
cm	O
.	O

Comparison	O
with	O
the	O
bovine	O
gene	O
showed	O
that	O
the	O
5	O
'	O
-	O
flanking	O
region	O
of	O
the	O
hATP1	B-GENE
gene	I-GENE
has	O
an	O
unconserved	O
guanine	O
-	O
cytosine	O
(	O
GC	O
)	O
rich	O
region	O
,	O
including	O
several	O
binding	O
motifs	O
of	O
transcriptional	O
factors	O
,	O
such	O
as	O
Sp1	B-GENE
,	O
AP	B-GENE
-	I-GENE
2	I-GENE
,	O
and	O
GCF	B-GENE
.	O

Structure	O
,	O
promoter	O
analysis	O
and	O
chromosomal	O
assignment	O
of	O
the	O
human	B-GENE
APEX	I-GENE
gene	I-GENE
.	O

The	O
polyubiquitin	B-GENE
gene	I-GENE
was	O
transcribed	O
throughout	O
the	O
Volvox	O
life	O
cycle	O
with	O
peaks	O
in	O
the	O
1	O
.	O
6	O
-	O
kb	O
mRNA	O
levels	O
during	O
pre	O
-	O
cleavage	O
,	O
cleavage	O
,	O
and	O
post	O
-	O
inversion	O
.	O

Thus	O
,	O
in	O
stress	O
-	O
induced	O
arrhythmic	O
disease	O
as	O
well	O
as	O
in	O
ischemic	O
heart	O
disease	O
,	O
the	O
main	O
pathogenetic	O
links	O
are	O
outside	O
the	O
heart	O
,	O
but	O
they	O
differ	O
from	O
those	O
observed	O
in	O
ischemia	O
.	O

Here	O
,	O
we	O
present	O
genetic	O
evidence	O
in	O
Saccharomyces	O
cerevisiae	O
for	O
a	O
functional	O
interaction	O
between	O
the	O
DEAH	B-GENE
protein	I-GENE
Prp16	B-GENE
,	O
and	O
the	O
U6	B-GENE
and	O
U2	B-GENE
spliceosomal	I-GENE
snRNAs	I-GENE
.	O

The	O
consensus	O
gene	O
order	O
deduced	O
by	O
combining	O
data	O
from	O
both	O
crosses	O
is	O
D2Mit1	B-GENE
-	O
(	O
Dbh	B-GENE
,	O
Notch1	B-GENE
)	O
-	O
(	O
Col5a1	B-GENE
,	O
Rxra	B-GENE
)	O
-	O
Spna2	B-GENE
-	O
Ab	B-GENE
l	I-GENE
-	O
(	O
Ak1	B-GENE
,	O
Fpgs	B-GENE
)	O
-	O
(	O
Grp78	B-GENE
,	O
Pbx3	B-GENE
)	O
-	O
(	O
Epb7	B-GENE
.	I-GENE
2	I-GENE
,	I-GENE
Hc	I-GENE
,	I-GENE
Gsn	I-GENE
)	O
-	O
Acra	B-GENE
.	O

The	O
high	O
level	O
of	O
transformation	O
-	O
associated	O
deletions	O
in	O
the	O
human	O
YACs	O
was	O
reduced	O
over	O
10	O
-	O
fold	O
when	O
the	O
host	O
was	O
a	O
recombination	O
-	O
deficient	O
strain	O
deleted	O
for	O
the	O
RAD52	B-GENE
gene	I-GENE
.	O

In	O
addition	O
,	O
the	O
megabase	O
region	O
surrounding	O
the	O
dagA	B-GENE
locus	I-GENE
was	O
mapped	O
.	O

These	O
mutants	O
had	O
deletions	O
of	O
the	O
extreme	O
amino	O
-	O
terminal	O
residues	O
as	O
far	O
as	O
amino	O
acid	O
residue	O
30	O
.	O

SECONDARY	O
OUTCOME	O
MEASURE	O
-	O
-	O
Double	O
-	O
blind	O
caffeine	O
-	O
withdrawal	O
evaluation	O
.	O

Elimination	O
of	O
natural	O
antibodies	O
in	O
discordant	O
xenografts	O

An	O
8	O
-	O
bp	O
sequence	O
(	O
ATTTCAAA	O
)	O
within	O
the	O
protected	O
region	O
shares	O
significant	O
homology	O
with	O
promoter	O
sequences	O
required	O
for	O
ethylene	O
responsiveness	O
from	O
the	O
tomato	O
fruit	O
-	O
ripening	O
E4	B-GENE
gene	I-GENE
.	O

We	O
present	O
evidence	O
that	O
DNA	B-GENE
polymerase	I-GENE
delta	I-GENE
of	I-GENE
Saccharomyces	I-GENE
cerevisiae	I-GENE
,	O
an	O
enzyme	O
that	O
is	O
essential	O
for	O
viability	O
and	O
chromosomal	O
replication	O
,	O
is	O
also	O
required	O
for	O
base	O
excision	O
repair	O
of	O
exogenous	O
DNA	O
methylation	O
damage	O
.	O

We	O
have	O
identified	O
two	O
Marek	O
'	O
s	O
Disease	O
Virus	O
(	O
MDV	O
)	O
genes	O
within	O
the	O
EcoRI	B-GENE
-	I-GENE
B	I-GENE
fragment	I-GENE
of	O
MDV	O
-	O
GA	O
genomic	O
DNA	O
.	O

Cowpox	O
virus	O
contains	O
two	O
copies	O
of	O
an	O
early	B-GENE
gene	I-GENE
encoding	O
a	O
soluble	O
secreted	O
form	O
of	O
the	O
type	B-GENE
II	I-GENE
TNF	I-GENE
receptor	I-GENE
.	O

Mutagenesis	O
of	O
each	O
NRF	B-GENE
-	I-GENE
1	I-GENE
motif	I-GENE
in	O
the	O
ALAS	B-GENE
promoter	I-GENE
gave	O
substantially	O
lowered	O
levels	O
of	O
chloramphenicol	B-GENE
acetyltransferase	I-GENE
expression	O
,	O
whereas	O
mutagenesis	O
of	O
both	O
NRF	B-GENE
-	I-GENE
1	I-GENE
motifs	I-GENE
resulted	O
in	O
the	O
almost	O
complete	O
loss	O
of	O
expression	O
.	O

DNase	B-GENE
I	I-GENE
footprinting	O
analysis	O
indicated	O
that	O
DREF	B-GENE
binds	O
to	O
the	O
24	O
-	O
bp	O
DRE	O
region	O
of	O
the	O
DNA	B-GENE
polymerase	I-GENE
alpha	I-GENE
gene	I-GENE
in	O
which	O
8	O
-	O
bp	O
palindromic	O
sequences	O
are	O
centered	O
.	O

Novel	O
8	O
-	O
base	O
pair	O
sequence	O
(	O
Drosophila	O
DNA	O
replication	O
-	O
related	O
element	O
)	O
and	O
specific	O
binding	O
factor	O
involved	O
in	O
the	O
expression	O
of	O
Drosophila	O
genes	O
for	O
DNA	B-GENE
polymerase	I-GENE
alpha	I-GENE
and	O
proliferating	B-GENE
cell	I-GENE
nuclear	I-GENE
antigen	I-GENE
.	O

Most	O
,	O
however	O
,	O
would	O
tell	O
the	O
spouse	O
the	O
full	O
truth	O
about	O
both	O
diagnosis	O
and	O
prognosis	O
.	O

Metabolism	O
of	O
calcium	O
and	O
vitamin	O
D3	O
in	O
patients	O
with	O
acute	O
tubulointerstitial	O
nephritis	O
:	O
a	O
study	O
of	O
41	O
patients	O
with	O
nephropathia	O
epidemica	O
.	O

Furthermore	O
,	O
this	O
study	O
demonstrates	O
that	O
reduced	O
inotropy	O
with	O
timolol	O
helped	O
uniform	O
local	O
contraction	O
as	O
estimated	O
by	O
the	O
increased	O
LONG	O
/	O
CIRC	O
ratio	O
,	O
a	O
transition	O
that	O
could	O
improve	O
contraction	O
efficacy	O
.	O

Effects	O
of	O
moderate	O
hypercapnia	O
on	O
hypothermia	O
induced	O
by	O
cold	O
He	O
-	O
O2	O
in	O
rats	O
.	O

We	O
recommend	O
that	O
ovarian	O
stimulation	O
is	O
done	O
only	O
if	O
there	O
is	O
a	O
valid	O
indication	O
after	O
proper	O
assessment	O
of	O
the	O
ovaries	O
,	O
and	O
that	O
women	O
who	O
have	O
had	O
ovarian	O
stimulation	O
are	O
followed	O
for	O
longer	O
than	O
at	O
present	O
.	O

A23187	O
did	O
not	O
induce	O
any	O
modifications	O
of	O
the	O
endolymphatic	O
potential	O
,	O
the	O
ampullar	O
direct	O
current	O
or	O
the	O
frequency	O
of	O
the	O
evoked	O
afferent	O
spikes	O
.	O

Activation	O
of	O
the	O
aboral	O
ectoderm	B-GENE
-	I-GENE
specific	I-GENE
Spec2a	I-GENE
gene	I-GENE
in	O
blastula	O
-	O
stage	O
sea	O
urchin	O
embryos	O
requires	O
an	O
upstream	O
regulatory	O
region	O
that	O
is	O
part	O
of	O
a	O
repetitive	O
sequence	O
element	O
(	O
RSR	O
)	O
associated	O
with	O
all	O
Spec1	B-GENE
/	O
Spec2	B-GENE
genes	O
.	O

A	O
transcript	O
of	O
about	O
2	O
kb	O
is	O
expected	O
for	O
each	O
PPO	B-GENE
.	O

Mutations	O
in	O
a	O
region	O
located	O
15	O
to	O
30	O
bp	O
downstream	O
from	O
the	O
major	O
transcription	O
start	O
site	O
that	O
shows	O
good	O
homology	O
to	O
a	O
sequence	O
in	O
the	O
first	O
exon	O
of	O
c	B-GENE
-	I-GENE
fos	I-GENE
implicated	O
as	O
a	O
negative	O
regulatory	O
element	O
resulted	O
in	O
a	O
significant	O
increase	O
in	O
basal	O
gene	O
expression	O
but	O
did	O
not	O
affect	O
regulation	O
.	O

Salazopyrine	O
desensitization	O

During	O
exercise	O
,	O
the	O
Pes	O
-	O
Ves	O
relation	O
was	O
shifted	O
toward	O
the	O
left	O
and	O
the	O
slope	O
[	O
end	O
-	O
systolic	O
elastance	O
(	O
Ees	O
)	O
]	O
increased	O
from	O
7	O
.	O
7	O
+	O
/	O
-	O
2	O
.	O
8	O
to	O
12	O
.	O
7	O
+	O
/	O
-	O
4	O
.	O
2	O
(	O
SD	O
)	O
mmHg	O
/	O
ml	O
(	O
P	O
<	O
0	O
.	O
05	O
)	O
.	O

We	O
show	O
that	O
HRI	B-GENE
and	O
dsRNA	B-GENE
-	I-GENE
PK	I-GENE
phosphorylate	O
yeast	B-GENE
eIF	I-GENE
-	I-GENE
2	I-GENE
alpha	I-GENE
in	O
vitro	O
and	O
in	O
vivo	O
and	O
functionally	O
substitute	O
for	O
GCN2	B-GENE
protein	I-GENE
to	O
stimulate	O
GCN4	B-GENE
translation	O
in	O
yeast	O
.	O

Double	O
-	O
staining	O
confirmed	O
that	O
there	O
were	O
separate	O
populations	O
of	O
CD68	B-GENE
-	O
positive	O
macrophages	O
and	O
XIIIa	B-GENE
-	O
positive	O
dendrocytes	O
.	O

Interestingly	O
,	O
in	O
the	O
adult	O
,	O
transgene	O
expression	O
patterns	O
within	O
the	O
cerebellum	O
in	O
two	O
lines	O
appeared	O
to	O
mark	O
distinct	O
anterior	O
-	O
posterior	O
compartments	O
.	O

The	O
concentrations	O
of	O
plasma	O
ACTH	B-GENE
and	O
cortisol	O
increased	O
by	O
40	O
%	O
and	O
60	O
%	O
after	O
MPTP	O
treatment	O
,	O
respectively	O
.	O

Instead	O
,	O
the	O
results	O
support	O
the	O
idea	O
that	O
Pc	B-GENE
group	I-GENE
products	I-GENE
provide	O
stable	O
memory	O
or	O
imprinting	O
of	O
boundaries	O
which	O
are	O
initially	O
specified	O
by	O
gap	O
and	O
pair	O
-	O
rule	O
regulators	O
.	O

To	O
investigate	O
the	O
regulation	O
of	O
expression	O
of	O
the	O
human	B-GENE
mdr1	I-GENE
gene	I-GENE
,	O
the	O
response	O
of	O
the	O
mdr1	B-GENE
promoter	I-GENE
to	O
signals	O
involved	O
in	O
cell	O
proliferation	O
was	O
examined	O
.	O

Tobacco	O
mosaic	O
virus	O
-	O
infected	O
tobacco	O
(	O
Nicotiana	O
tabacum	O
var	O
.	O

Through	O
a	O
stretch	O
of	O
56	O
amino	O
acids	O
,	O
constituting	O
the	O
MADS	B-GENE
domain	I-GENE
,	O
the	O
two	O
proteins	O
are	O
identical	O
except	O
for	O
two	O
conservative	O
amino	O
acid	O
substitutions	O
.	O

Isolation	O
and	O
characterization	O
of	O
SRF	B-GENE
accessory	I-GENE
proteins	I-GENE
.	O

These	O
data	O
suggest	O
that	O
:	O
(	O
a	O
)	O
proSRIF	B-GENE
cleavage	O
is	O
initiated	O
in	O
the	O
TGN	O
,	O
and	O
(	O
b	O
)	O
this	O
reaction	O
requires	O
an	O
acidic	O
pH	O
which	O
is	O
facilitated	O
by	O
a	O
Golgi	B-GENE
-	I-GENE
associated	I-GENE
vacuolar	I-GENE
-	I-GENE
type	I-GENE
ATPase	I-GENE
.	O

Clinical	O
aspects	O
of	O
early	O
increase	O
in	O
serum	O
gamma	B-GENE
-	I-GENE
glutamyl	I-GENE
transferase	I-GENE
in	O
cerebral	O
infarction	O
.	O

In	O
the	O
3	O
'	O
flanking	O
region	O
of	O
the	O
27	B-GENE
kDa	I-GENE
zein	I-GENE
gene	I-GENE
,	O
several	O
AATAAA	O
-	O
like	O
sequences	O
and	O
a	O
sequence	O
resembling	O
the	O
mammalian	O
GT	O
-	O
rich	O
sequence	O
are	O
present	O
around	O
the	O
polyadenylation	O
sites	O
.	O

The	O
indoor	O
radon	O
concentration	O
in	O
the	O
summer	O
(	O
1990	O
)	O
period	O
ranged	O
between	O
8	O
and	O
81	O
Bq	O
m	O
-	O
3	O
,	O
while	O
in	O
the	O
winter	O
(	O
1989	O
-	O
1990	O
)	O
it	O
ranged	O
between	O
20	O
and	O
143	O
Bq	O
m	O
-	O
3	O
for	O
the	O
first	O
year	O
of	O
measurements	O
or	O
between	O
8	O
and	O
92	O
Bq	O
m	O
-	O
3	O
in	O
the	O
summer	O
(	O
1991	O
)	O
period	O
and	O
between	O
12	O
and	O
119	O
Bq	O
m	O
-	O
3	O
in	O
the	O
winter	O
(	O
1990	O
-	O
1991	O
)	O
for	O
the	O
second	O
year	O
of	O
measurements	O
.	O

DtxR	B-GENE
is	O
an	O
iron	O
-	O
dependent	O
sequence	O
-	O
specific	O
DNA	O
-	O
binding	O
protein	O
that	O
binds	O
to	O
the	O
tox	B-GENE
operator	I-GENE
,	O
an	O
inverted	O
-	O
repeat	O
nucleotide	O
sequence	O
located	O
upstream	O
from	O
the	O
diphtheria	B-GENE
toxin	I-GENE
gene	I-GENE
.	O

Vasopressin	B-GENE
(	O
AVP	B-GENE
)	O
,	O
the	O
antidiuretic	O
hormone	O
,	O
is	O
a	O
cyclic	O
nonapeptide	O
that	O
acts	O
through	O
binding	O
to	O
G	B-GENE
protein	I-GENE
-	I-GENE
coupled	I-GENE
specific	I-GENE
membrane	I-GENE
receptors	I-GENE
pharmacologically	O
divided	O
into	O
three	O
subtypes	O
(	O
V1a	B-GENE
,	O
V1b	B-GENE
,	O
and	O
V2	B-GENE
)	O
linked	O
to	O
distinct	O
second	O
messengers	O
.	O

These	O
results	O
confirmed	O
that	O
cleavage	O
of	O
the	O
leader	O
peptide	O
is	O
the	O
last	O
step	O
in	O
nisin	B-GENE
maturation	O
and	O
is	O
necessary	O
to	O
generate	O
a	O
biologically	O
active	O
peptide	O
.	O

When	O
the	O
promoter	O
region	O
was	O
linked	O
with	O
a	O
heterologous	O
reporter	O
gene	O
,	O
we	O
found	O
that	O
the	O
promoter	O
region	O
is	O
inducible	O
by	O
both	O
interferons	B-GENE
(	O
interferon	B-GENE
-	I-GENE
alpha	I-GENE
and	I-GENE
-	I-GENE
gamma	I-GENE
)	O
and	O
interferon	B-GENE
regulatory	I-GENE
factor	I-GENE
1	I-GENE
.	O

Anti	B-GENE
-	I-GENE
B	I-GENE
.	I-GENE
burgdorferi	I-GENE
,	O
anti	B-GENE
-	I-GENE
B	I-GENE
.	I-GENE
turicatae	I-GENE
and	O
anti	B-GENE
-	I-GENE
B	I-GENE
.	I-GENE
parkeri	I-GENE
antibodies	I-GENE
,	O
tested	O
by	O
the	O
indirect	O
immunofluorescent	O
assay	O
(	O
IFA	O
)	O
,	O
were	O
detected	O
in	O
10	O
.	O
8	O
,	O
16	O
.	O
1	O
and	O
8	O
.	O
2	O
%	O
of	O
the	O
serum	O
samples	O
tested	O
,	O
and	O
confirmed	O
by	O
IFA	O
-	O
ABS	O
in	O
1	O
.	O
3	O
,	O
1	O
.	O
3	O
and	O
1	O
.	O
0	O
%	O
,	O
respectively	O
.	O

The	O
approach	O
derives	O
from	O
a	O
recently	O
described	O
strategy	O
for	O
making	O
recombinants	O
from	O
five	O
overlapping	O
EBV	O
cosmid	O
-	O
cloned	O
DNAs	O
(	O
B	O
.	O

Evaluation	O
of	O
desmopressin	O
for	O
dental	O
extractions	O
in	O
patients	O
with	O
hemostatic	O
disorders	O
.	O

Comparative	O
analysis	O
with	O
an	O
antiandrogen	O
niftolid	O
and	O
synthetic	B-GENE
GnRH	I-GENE
was	O
carried	O
out	O
in	O
22	O
normal	O
subjects	O
,	O
14	O
patients	O
with	O
primary	O
and	O
20	O
ones	O
with	O
secondary	O
hypogonadism	O
,	O
and	O
in	O
5	O
patients	O
with	O
clinical	O
signs	O
of	O
gonadal	O
insufficiency	O
and	O
obscure	O
diagnosis	O
in	O
order	O
to	O
elucidate	O
the	O
pituitary	B-GENE
gonadotropin	I-GENE
reserves	O
.	O

The	O
cis	O
-	O
acting	O
regulatory	O
properties	O
of	O
an	O
872	O
bp	O
promoter	O
fragment	O
of	O
a	O
B	O
.	O
napus	O
oleosin	B-GENE
gene	I-GENE
were	O
examined	O
by	O
analysis	O
of	O
beta	B-GENE
-	I-GENE
glucuronidase	I-GENE
(	O
GUS	B-GENE
)	O
expression	O
in	O
transgenic	O
tobacco	O
plants	O
containing	O
an	O
oleosin	B-GENE
promoter	I-GENE
-	O
GUS	B-GENE
transcriptional	O
fusion	O
.	O

This	O
indicates	O
that	O
the	O
mechanism	O
by	O
which	O
CX	O
blocks	O
rapid	O
degradation	O
of	O
tubulin	B-GENE
mRNA	I-GENE
in	O
vivo	O
is	O
not	O
simply	O
by	O
preventing	O
its	O
translation	O
and	O
suggests	O
the	O
involvement	O
of	O
an	O
altered	O
trans	O
-	O
factor	O
.	O

Increasing	O
the	O
extracellular	O
calcium	O
concentration	O
enhanced	O
detrusor	O
contractility	O
in	O
a	O
dose	O
-	O
dependent	O
manner	O
in	O
both	O
control	O
and	O
obstructed	O
bladders	O
.	O

Structural	O
organization	O
of	O
the	O
gene	O
encoding	O
the	O
human	B-GENE
lipocalin	I-GENE
tear	I-GENE
prealbumin	I-GENE
and	O
synthesis	O
of	O
the	O
recombinant	O
protein	O
in	O
Escherichia	O
coli	O
.	O

The	O
sequence	O
has	O
a	O
1092	O
-	O
bp	O
open	O
reading	O
frame	O
encoding	O
a	O
protein	O
of	O
364	O
amino	O
acids	O
.	O

The	O
gene	O
organization	O
of	O
CRSV	B-GENE
RNA	I-GENE
-	I-GENE
1	I-GENE
is	O
similar	O
to	O
those	O
of	O
red	O
clover	O
necrotic	O
mosaic	O
(	O
RCNMV	O
)	O
and	O
sweet	O
clover	O
necrotic	O
mosaic	O
(	O
SCNMV	O
)	O
dianthoviruses	O
with	O
the	O
exception	O
that	O
CRSV	B-GENE
RNA	I-GENE
-	I-GENE
1	I-GENE
contains	O
the	O
additional	O
3	O
'	O
-	O
terminal	O
ORF	O
.	O

We	O
have	O
previously	O
shown	O
that	O
LBP	B-GENE
-	I-GENE
1	I-GENE
represses	O
HIV	O
-	O
1	O
transcription	O
by	O
inhibiting	O
the	O
binding	O
of	O
TFIID	B-GENE
to	O
the	O
TATA	O
box	O
.	O

These	O
results	O
illustrate	O
an	O
important	O
role	O
for	O
La	B-GENE
in	O
RNA	O
production	O
by	O
demonstrating	O
its	O
ability	O
to	O
clear	O
the	O
termination	O
sites	O
of	O
class	O
III	O
templates	O
,	O
thereby	O
promoting	O
efficient	O
use	O
of	O
transcription	O
complexes	O
by	O
pol	B-GENE
III	I-GENE
.	O

The	O
films	O
were	O
analyzed	O
using	O
a	O
scanning	O
helium	O
-	O
neon	O
laser	O
densitometer	O
with	O
a	O
small	O
aperture	O
of	O
5	O
-	O
10	O
microns	O
.	O

The	O
GafChromic	O
method	O
has	O
proven	O
to	O
be	O
an	O
accurate	O
and	O
rapid	O
method	O
of	O
analysis	O
and	O
could	O
be	O
easily	O
incorporated	O
into	O
a	O
quality	O
assurance	O
program	O
.	O

Viral	O
genomic	O
RNA	O
for	O
these	O
reactions	O
was	O
obtained	O
directly	O
from	O
fecal	O
specimens	O
of	O
infected	O
infant	O
rats	O
.	O

GATA	B-GENE
-	I-GENE
1	I-GENE
mRNA	I-GENE
was	O
present	O
in	O
equivalent	O
levels	O
in	O
both	O
erythroid	O
cell	O
lines	O
,	O
but	O
at	O
a	O
low	O
level	O
in	O
FDC	O
-	O
P1	O
cells	O
.	O

Tumor	B-GENE
necrosis	I-GENE
factor	I-GENE
-	I-GENE
alpha	I-GENE
(	O
TNF	B-GENE
alpha	I-GENE
)	O
is	O
one	O
of	O
several	O
autocrine	O
/	O
paracrine	O
factors	O
known	O
to	O
exert	O
potent	O
inhibitory	O
effects	O
on	O
bone	O
.	O

We	O
have	O
investigated	O
the	O
role	O
of	O
cellular	B-GENE
p21ras	I-GENE
protein	I-GENE
in	O
insulin	B-GENE
and	O
insulin	B-GENE
-	I-GENE
like	I-GENE
growth	I-GENE
factor	I-GENE
-	I-GENE
I	I-GENE
(	O
IGF	B-GENE
-	I-GENE
I	I-GENE
)	O
signaling	O
pathways	O
.	O

The	O
lack	O
of	O
the	O
C2	B-GENE
domain	O
of	O
the	O
Ca	B-GENE
(	I-GENE
2	I-GENE
+	I-GENE
)	I-GENE
-	I-GENE
dependent	I-GENE
PKCs	I-GENE
and	O
the	O
presence	O
of	O
a	O
unique	O
NH2	O
-	O
terminal	O
sequence	O
with	O
a	O
potential	O
signal	O
peptide	O
and	O
a	O
transmembrane	O
domain	O
suggest	O
that	O
PKC	B-GENE
mu	I-GENE
is	O
a	O
novel	O
member	O
of	O
the	O
subgroup	O
of	O
atypical	O
PKCs	B-GENE
.	O

Moreover	O
,	O
we	O
observed	O
that	O
the	O
function	O
of	O
T3R	B-GENE
-	O
RXR	B-GENE
heterodimers	O
on	O
response	O
elements	O
composed	O
of	O
two	O
half	O
-	O
sites	O
in	O
a	O
directly	O
repeated	O
orientation	O
spaced	O
by	O
4	O
nucleotides	O
is	O
determined	O
in	O
major	O
parts	O
by	O
the	O
5	O
'	O
-	O
flanking	O
sequence	O
of	O
the	O
upstream	O
half	O
-	O
site	O
.	O

However	O
,	O
three	O
Hm1	B-GENE
mutants	I-GENE
that	O
were	O
moderately	O
deficient	O
in	O
stimulating	O
PI	O
turnover	O
displayed	O
normal	O
sequestration	O
,	O
suggesting	O
distinct	O
mechanisms	O
.	O

Furthermore	O
,	O
in	O
vitro	O
decay	O
reaction	O
mixtures	O
supplemented	O
with	O
the	O
20	O
-	O
nt	O
sense	O
RNA	O
transcript	O
resulted	O
in	O
stabilization	O
of	O
R2	B-GENE
message	I-GENE
.	O

Deletion	O
analyses	O
of	O
the	O
pCD41	B-GENE
ORF	I-GENE
-	I-GENE
A	I-GENE
and	O
the	O
use	O
of	O
promoter	O
constructs	O
further	O
mapped	O
an	O
internal	O
functional	O
promoter	O
within	O
the	O
pCD41	B-GENE
sequence	I-GENE
that	O
can	O
direct	O
the	O
synthesis	O
of	O
the	O
trans	O
-	O
activating	O
protein	O
.	O

The	O
inferred	O
amino	O
acid	O
sequence	O
of	O
the	O
cyanobacterial	B-GENE
HemB	I-GENE
protein	I-GENE
indicates	O
a	O
significant	O
difference	O
in	O
the	O
metal	O
cofactor	O
requirement	O
from	O
the	O
higher	O
-	O
plant	O
enzymes	O
,	O
which	O
was	O
confirmed	O
by	O
overexpression	O
and	O
biochemical	O
analysis	O
.	O

METHODS	O
AND	O
RESULTS	O
:	O
In	O
25	O
open	O
-	O
chest	O
,	O
anesthetized	O
dogs	O
,	O
progressive	O
circumflex	O
artery	O
stenosis	O
led	O
to	O
a	O
concordant	O
decrease	O
of	O
circumflex	O
artery	O
resting	O
and	O
hyperemic	O
flow	O
,	O
coronary	O
flow	O
reserve	O
,	O
and	O
inverse	O
angiographic	O
mean	O
transit	O
time	O
Tmicro	O
-	O
1	O
(	O
P	O
<	O
.	O
01	O
)	O
.	O

However	O
,	O
a	O
correlation	O
was	O
observed	O
between	O
SF	O
levels	O
of	O
IL	B-GENE
-	I-GENE
8	I-GENE
with	O
those	O
of	O
lactate	O
,	O
LDH	B-GENE
,	O
beta	B-GENE
2	I-GENE
-	I-GENE
microglobulin	I-GENE
and	O
glucose	O
.	O

Sodium	O
-	O
taurocholate	O
-	O
induced	O
acute	O
necrotizing	O
pancreatitis	O
does	O
not	O
affect	O
jejunal	O
oxygenation	O
in	O
pigs	O
.	O

Although	O
inactive	O
in	O
cells	O
under	O
normal	O
conditions	O
,	O
the	O
CHOP	B-GENE
gene	I-GENE
is	O
markedly	O
induced	O
by	O
a	O
variety	O
of	O
cellular	O
stresses	O
,	O
including	O
nutrient	O
deprivation	O
and	O
metabolic	O
perturbations	O
.	O

The	O
ipiO	B-GENE
genes	I-GENE
code	O
for	O
two	O
almost	O
identical	O
152	O
-	O
aa	O
proteins	O
which	O
do	O
not	O
have	O
any	O
homology	O
with	O
sequences	O
present	O
in	O
data	O
libraries	O
.	O

Sterol	O
analysis	O
of	O
the	O
disrupted	O
mutant	O
demonstrated	O
the	O
accumulation	O
of	O
ignosterol	O
,	O
indicating	O
a	O
loss	O
of	O
Erg24p	B-GENE
activity	O
.	O

In	O
these	O
experiments	O
we	O
begin	O
to	O
study	O
the	O
potential	O
functions	O
of	O
the	O
alpha	B-GENE
7	I-GENE
cytoplasmic	I-GENE
domain	I-GENE
by	O
analyzing	O
homologies	O
between	O
the	O
rat	O
and	O
human	O
sequences	O
,	O
by	O
immunologic	O
studies	O
using	O
an	O
anti	O
-	O
cytoplasmic	O
domain	O
antiserum	O
,	O
and	O
by	O
identifying	O
two	O
alternate	O
forms	O
.	O

The	O
alpha	O
7A	O
form	O
RNA	O
contains	O
an	O
additional	O
113	O
nucleotides	O
compared	O
to	O
the	O
B	O
form	O
,	O
and	O
a	O
common	O
coding	O
region	O
in	O
the	O
A	O
and	O
B	O
form	O
RNAs	O
is	O
used	O
in	O
alternate	O
reading	O
frames	O
.	O

In	O
order	O
to	O
evaluate	O
the	O
function	O
of	O
the	O
hypothalamic	O
-	O
pituitary	O
-	O
thyroid	O
(	O
HPT	O
)	O
-	O
axis	O
in	O
unipolar	O
depression	O
,	O
the	O
authors	O
measured	O
basal	O
0800h	O
plasma	O
levels	O
of	O
free	O
thyroxine	O
(	O
FT4	O
)	O
,	O
free	O
triiodothyronine	O
(	O
FT3	O
)	O
,	O
and	O
thyroid	B-GENE
stimulating	I-GENE
hormone	I-GENE
(	O
TSH	B-GENE
)	O
by	O
means	O
of	O
the	O
new	O
,	O
ultrasensitive	O
assays	O
(	O
TSH	O
-	O
IRMA	O
)	O
in	O
69	O
healthy	O
controls	O
,	O
62	O
minor	O
,	O
101	O
simple	O
major	O
,	O
and	O
57	O
melancholic	O
depressed	O
subjects	O
.	O

CRS	B-GENE
function	O
in	O
a	O
5	O
'	O
LTR	O
-	O
linked	O
gene	O
expression	O
assay	O
correlates	O
with	O
the	O
ability	O
of	O
both	O
p60CRS	B-GENE
and	O
p40CRS	B-GENE
to	O
interact	O
with	O
5	O
'	O
LTR	O
RNA	O
in	O
vitro	O
.	O

Serial	O
levels	O
of	O
troponin	B-GENE
T	I-GENE
and	O
the	O
activity	O
of	O
CK	B-GENE
-	I-GENE
MB	I-GENE
were	O
measured	O
6	O
,	O
12	O
,	O
24	O
and	O
48	O
h	O
after	O
aortic	O
unclamping	O
.	O

Regionalization	O
of	O
drug	O
delivery	O
is	O
a	O
potential	O
method	O
to	O
avoid	O
this	O
problem	O
.	O

The	O
epidemic	O
occurred	O
in	O
a	O
group	O
of	O
26	O
community	O
members	O
(	O
23	O
men	O
and	O
3	O
women	O
,	O
mean	O
age	O
,	O
28	O
.	O
9	O
-	O
-	O
3	O
years	O
)	O
living	O
and	O
working	O
together	O
,	O
who	O
underwent	O
acute	O
and	O
convalescent	O
serologic	O
tests	O
for	O
Mycoplasma	O
pneumoniae	O
,	O
Legionella	O
pneumophila	O
,	O
cytomegalovirus	O
,	O
adenovirus	O
,	O
Coxiella	O
burnetii	O
,	O
and	O
Chlamydia	O
pneumoniae	O
.	O

MEK	B-GENE
itself	O
is	O
activated	O
via	O
serine	O
phosphorylation	O
by	O
upstream	B-GENE
activator	I-GENE
kinases	I-GENE
,	O
including	O
c	B-GENE
-	I-GENE
raf	I-GENE
,	O
mos	B-GENE
and	O
MEK	B-GENE
kinase	I-GENE
.	O

Members	O
of	O
SVA	B-GENE
are	O
also	O
present	O
in	O
the	O
complement	B-GENE
C2	I-GENE
gene	I-GENE
located	O
about	O
20	O
kilobases	O
upstream	O
of	O
RP1	B-GENE
in	O
the	O
HLA	B-GENE
and	O
in	O
the	O
cytochrome	B-GENE
CYP1A1	I-GENE
gene	I-GENE
.	O

European	O
Community	O
Huntington	O
'	O
s	O
Disease	O
Collaborative	O
Study	O
Group	O
.	O

The	O
c	B-GENE
-	I-GENE
myc	I-GENE
and	O
skeletal	B-GENE
alpha	I-GENE
-	I-GENE
actin	I-GENE
gene	I-GENE
promoters	I-GENE
contain	O
YY1	B-GENE
binding	I-GENE
sites	I-GENE
thought	O
to	O
act	O
either	O
as	O
positive	O
or	O
negative	O
cis	O
-	O
acting	O
elements	O
.	O

MSSP	B-GENE
-	I-GENE
1	I-GENE
produced	O
in	O
E	O
.	O
coli	O
as	O
a	O
fusion	O
protein	O
with	O
GST	B-GENE
specifically	O
interacted	O
with	O
single	O
-	O
stranded	O
TCTTAT	O
(	O
plus	O
myc	B-GENE
(	O
H	O
-	O
P	O
)	O
21	O
)	O
and	O
ACT	O
-	O
ATT	O
(	O
in	O
minus	O
myc	B-GENE
(	O
H	O
-	O
P	O
)	O
21	O
)	O
,	O
the	O
consensus	O
of	O
which	O
can	O
be	O
referred	O
to	O
as	O
A	O
/	O
TCTA	O
/	O
TA	O
/	O
TT	O
.	O

Within	O
12	O
hours	O
after	O
MR	O
tomography	O
the	O
patients	O
were	O
surgically	O
explored	O
,	O
biopsied	O
and	O
if	O
necessary	O
orchiectomised	O
.	O

Varieties	O
of	O
envious	O
experience	O
.	O

The	O
results	O
show	O
that	O
both	O
the	O
amino	O
and	O
carboxy	O
termini	O
of	O
the	O
NS1	B-GENE
protein	I-GENE
molecule	I-GENE
and	O
the	O
cysteines	O
at	O
residues	O
337	O
and	O
340	O
are	O
essential	O
for	O
tubule	O
formation	O
.	O

The	O
3	O
'	O
UTR	O
has	O
several	O
stable	O
hairpins	O
that	O
are	O
flanked	O
by	O
single	O
-	O
stranded	O
(	O
A	O
/	O
U	O
)	O
UGC	O
sequences	O
.	O

Moreover	O
,	O
the	O
major	O
site	O
of	O
transcriptional	O
initiation	O
,	O
which	O
was	O
localized	O
by	O
primer	O
extension	O
250	O
bp	O
upstream	O
of	O
the	O
5	O
'	O
end	O
of	O
the	O
Ets	B-GENE
-	I-GENE
1	I-GENE
cDNA	I-GENE
clone	I-GENE
,	O
was	O
shown	O
to	O
be	O
identical	O
in	O
normal	O
cells	O
and	O
tumors	O
carrying	O
a	O
provirus	O
in	O
the	O
Tpl	B-GENE
-	I-GENE
1	I-GENE
locus	I-GENE
.	O

Specifically	O
,	O
by	O
oligonucleotide	O
-	O
directed	O
site	O
-	O
specific	O
mutagenesis	O
,	O
we	O
demonstrate	O
that	O
of	O
10	O
cysteine	O
residues	O
in	O
the	O
ORF4	O
polypeptide	O
,	O
only	O
C	O
-	O
421	O
and	O
C	O
-	O
426	O
are	O
essential	O
for	O
transactivator	O
function	O
and	O
suggest	O
that	O
these	O
cysteine	O
residues	O
may	O
participate	O
in	O
critical	O
protein	O
-	O
protein	O
interactions	O
rather	O
than	O
protein	O
-	O
nucleic	O
acid	O
interactions	O
to	O
mediate	O
ORF4	O
inducibility	O
.	O

To	O
search	O
for	O
genes	O
that	O
interact	O
with	O
the	O
SLK1	B-GENE
-	O
SLT2	B-GENE
pathway	O
,	O
a	O
synthetic	O
lethal	O
suppression	O
screen	O
was	O
carried	O
out	O
.	O

Genetic	O
and	O
phenotypic	O
analysis	O
indicates	O
that	O
NHP6A	B-GENE
and	O
NHP6B	B-GENE
function	O
downstream	O
of	O
SLT2	B-GENE
.	O

In	O
this	O
report	O
,	O
we	O
present	O
two	O
lines	O
of	O
evidence	O
that	O
all	O
ribosomes	O
which	O
synthesize	O
GCN4	B-GENE
have	O
previously	O
translated	O
uORF1	O
,	O
resumed	O
scanning	O
,	O
and	O
reinitiated	O
at	O
the	O
GCN4	B-GENE
start	O
site	O
.	O

Identical	O
components	O
of	O
yeast	O
transcription	B-GENE
factor	I-GENE
IIIB	I-GENE
are	O
required	O
and	O
sufficient	O
for	O
transcription	O
of	O
TATA	O
box	O
-	O
containing	O
and	O
TATA	O
-	O
less	O
genes	O
.	O

Concordantly	O
,	O
it	O
was	O
shown	O
that	O
the	O
dnHLH	B-GENE
protein	I-GENE
Id1	B-GENE
inhibits	O
differentiation	O
of	O
muscle	O
and	O
myeloid	O
cells	O
in	O
vitro	O
.	O

RNP1	B-GENE
,	O
a	O
new	O
ribonucleoprotein	O
gene	O
of	O
the	O
yeast	O
Saccharomyces	O
cerevisiae	O
.	O

Crohn	O
'	O
s	O
disease	O
in	O
prolonged	O
remission	O
:	O
should	O
one	O
augment	O
protein	O
-	O
calorie	O
intake	O
as	O
compared	O
to	O
healthy	O
subjects	O
?	O
]	O
The	O
aim	O
of	O
our	O
two	O
year	O
prospective	O
study	O
was	O
to	O
evaluate	O
whether	O
adult	O
Crohn	O
'	O
s	O
disease	O
patients	O
in	O
prolonged	O
remission	O
(	O
CDAI	O
<	O
150	O
)	O
,	O
in	O
order	O
to	O
maintain	O
their	O
body	O
weight	O
as	O
close	O
as	O
possible	O
to	O
the	O
ideal	O
one	O
,	O
need	O
a	O
protein	O
-	O
calorie	O
intake	O
higher	O
than	O
the	O
predicted	O
one	O
and	O
that	O
of	O
healthy	O
controls	O
.	O

To	O
achieve	O
complete	O
dissection	O
of	O
the	O
anterior	O
vitreous	O
,	O
we	O
remove	O
even	O
a	O
clear	O
lens	O
during	O
the	O
first	O
surgical	O
intervention	O
in	O
selected	O
cases	O
.	O

Restoration	O
of	O
opponens	O
function	O
with	O
transplantation	O
of	O
free	O
composites	O
dorsal	O
pedal	O
skin	O
flap	O
containing	O
m	O
.	O
extensor	O
hallucis	O
brevis	O

Neither	O
ethanol	O
regimen	O
impaired	O
spontaneous	O
alternation	O
,	O
but	O
the	O
4	O
g	O
ethanol	O
.	O
kg	O
-	O
1	O
x	O
day	O
-	O
1	O
regimen	O
increased	O
the	O
percent	O
completed	O
trials	O
.	O

The	O
mean	O
(	O
+	O
/	O
-	O
sd	O
)	O
intra	O
-	O
vesicular	O
pressure	O
(	O
IVP	O
)	O
and	O
maximal	O
urethral	O
closure	O
pressures	O
(	O
MUCP	O
)	O
were	O
10	O
.	O
3	O
(	O
+	O
/	O
-	O
1	O
.	O
7	O
)	O
and	O
129	O
.	O
8	O
(	O
+	O
/	O
-	O
19	O
.	O
6	O
)	O
cmH2O	O
,	O
respectively	O
,	O
and	O
the	O
ratio	O
between	O
MUCP	O
and	O
IVP	O
was	O
13	O
.	O
2	O
(	O
+	O
/	O
-	O
2	O
.	O
5	O
)	O
.	O

Several	O
highly	O
conserved	O
regions	O
were	O
identified	O
at	O
the	O
near	O
N	O
terminus	O
,	O
middle	O
and	O
C	O
terminus	O
.	O

Thioredoxin	B-GENE
(	O
TR	B-GENE
)	O
is	O
a	O
small	O
ubiquitous	O
dithiol	B-GENE
-	I-GENE
reductase	I-GENE
enzyme	I-GENE
first	O
identified	O
in	O
bacteria	O
and	O
plants	O
.	O

The	O
mutation	O
within	O
the	O
asgB480	B-GENE
allele	I-GENE
was	O
identified	O
as	O
an	O
A	O
-	O
to	O
-	O
G	O
transition	O
that	O
results	O
in	O
a	O
threonine	O
-	O
to	O
-	O
alanine	O
substitution	O
in	O
the	O
predicted	O
protein	O
product	O
.	O

The	O
cysteine	O
-	O
rich	O
region	O
of	O
raf	B-GENE
-	I-GENE
1	I-GENE
kinase	I-GENE
contains	O
zinc	O
,	O
translocates	O
to	O
liposomes	O
,	O
and	O
is	O
adjacent	O
to	O
a	O
segment	O
that	O
binds	O
GTP	B-GENE
-	I-GENE
ras	I-GENE
.	O

Kinetic	O
coupling	O
and	O
requirement	O
for	O
ATP	O
hydrolysis	O
.	O

ATP	O
by	O
itself	O
also	O
reduced	O
polypeptide	O
binding	O
to	O
Ssb1	B-GENE
/	I-GENE
2p	I-GENE
to	O
a	O
level	O
that	O
was	O
intermediate	O
between	O
that	O
observed	O
for	O
the	O
Ssa	B-GENE
Hsp70	B-GENE
proteins	I-GENE
tested	O
and	O
BiP	B-GENE
and	O
DnaK	B-GENE
.	O

Digestion	O
of	O
NF	B-GENE
-	I-GENE
IL6	I-GENE
with	O
endoprotease	B-GENE
Asp	I-GENE
-	I-GENE
N	I-GENE
produced	O
a	O
domain	O
smaller	O
than	O
the	O
TCD	B-GENE
(	O
NF	B-GENE
-	I-GENE
IL6	I-GENE
bZIP	I-GENE
domains	I-GENE
(	O
NFBD	B-GENE
)	O
(	O
272	O
-	O
345	O
)	O
)	O
,	O
a	O
domain	O
identified	O
either	O
in	O
the	O
absence	O
or	O
the	O
presence	O
of	O
DNA	O
.	O

Signaling	O
by	O
tyrosine	B-GENE
kinases	I-GENE
involves	O
direct	O
associations	O
between	O
proteins	O
with	O
Src	B-GENE
homology	I-GENE
2	I-GENE
(	O
SH2	B-GENE
)	O
domains	O
and	O
sites	O
of	O
tyrosine	O
phosphorylation	O
.	O

Rather	O
,	O
complete	O
skipping	O
of	O
exon	O
V	O
and	O
subsequent	O
joining	O
of	O
exon	O
IV	O
to	O
exon	O
VI	O
caused	O
a	O
shift	O
in	O
the	O
open	O
reading	O
frame	O
,	O
which	O
remodeled	O
GPHe	B-GENE
(	I-GENE
P2	I-GENE
)	I-GENE
with	O
an	O
elongated	O
new	O
hydrophobic	O
sequence	O
for	O
membrane	O
anchoring	O
.	O

The	O
responses	O
of	O
the	O
"	O
stress	O
hormones	O
"	O
cortisol	O
,	O
11	O
-	O
deoxycortisol	O
,	O
ACTH	B-GENE
,	O
vasopressin	B-GENE
(	O
AVP	B-GENE
)	O
,	O
and	O
corticotropin	B-GENE
releasing	I-GENE
factor	I-GENE
(	O
CRF	B-GENE
)	O
were	O
studied	O
in	O
6	O
normal	O
males	O
in	O
response	O
to	O
acute	O
cortisol	O
deficiency	O
induced	O
by	O
the	O
11	B-GENE
-	I-GENE
beta	I-GENE
-	I-GENE
hydroxylase	I-GENE
inhibitor	O
,	O
metyrapone	O
.	O

Thus	O
our	O
observations	O
establish	O
a	O
functional	O
link	O
between	O
the	O
PKC	B-GENE
and	O
retinoid	O
pathways	O
,	O
which	O
are	O
generally	O
considered	O
to	O
have	O
antagonistic	O
activities	O
on	O
differentiation	O
processes	O
.	O

The	O
colony	B-GENE
-	I-GENE
stimulating	I-GENE
factors	I-GENE
(	O
CSFs	B-GENE
)	O
principally	O
involved	O
in	O
the	O
production	O
of	O
neutrophils	O
and	O
monocytes	O
are	O
granulocyte	B-GENE
CSF	I-GENE
,	O
granulocyte	B-GENE
-	I-GENE
macrophage	I-GENE
CSF	I-GENE
,	O
macrophage	B-GENE
CSF	I-GENE
,	O
and	O
interleukin	B-GENE
3	I-GENE
(	O
sometimes	O
called	O
multi	B-GENE
-	I-GENE
CSF	I-GENE
)	O
.	O

The	O
degree	O
of	O
lung	O
destruction	O
,	O
reflected	O
by	O
interstitial	O
hemorrhage	O
was	O
assessed	O
by	O
measuring	O
hemoglobin	B-GENE
content	O
in	O
the	O
fluid	O
of	O
the	O
lavaged	O
lungs	O
.	O

Expression	O
plasmids	O
harboring	O
full	O
-	O
length	O
or	O
kinase	O
domain	O
of	O
PKC	B-GENE
alpha	I-GENE
and	O
PKC	B-GENE
delta	I-GENE
(	O
PKC	B-GENE
alpha	I-GENE
K	I-GENE
and	O
PKC	B-GENE
delta	I-GENE
K	I-GENE
)	O
were	O
constructed	O
.	O

These	O
results	O
indicate	O
that	O
both	O
PKC	B-GENE
alpha	I-GENE
(	O
calcium	O
dependent	O
)	O
and	O
PKC	B-GENE
delta	I-GENE
(	O
calcium	O
independent	O
)	O
may	O
mediate	O
the	O
transcription	O
of	O
TPA	O
-	O
inducible	O
genes	O
through	O
both	O
AP	B-GENE
-	I-GENE
1	I-GENE
and	O
non	O
-	O
AP	B-GENE
-	I-GENE
1	I-GENE
sequences	O
.	O

With	O
a	O
cutoff	O
level	O
for	O
TSST	B-GENE
-	I-GENE
1	I-GENE
of	O
less	O
than	O
100	O
pg	O
/	O
ml	O
,	O
28	O
samples	O
obtained	O
from	O
12	O
patients	O
were	O
positive	O
for	O
TSST	B-GENE
-	I-GENE
1	I-GENE
.	O

Panlobular	O
emphysema	O

Since	O
the	O
ETS	B-GENE
domain	I-GENE
,	O
which	O
is	O
localized	O
in	O
the	O
carboxy	O
terminal	O
region	O
of	O
the	O
encoded	O
protein	O
,	O
is	O
95	O
%	O
and	O
96	O
%	O
identical	O
to	O
that	O
of	O
PEA3	B-GENE
and	O
ER81	B-GENE
,	O
respectively	O
,	O
we	O
named	O
this	O
new	O
member	O
'	B-GENE
Ets	I-GENE
Related	I-GENE
Molecule	I-GENE
PEA3	I-GENE
-	I-GENE
like	I-GENE
'	I-GENE
(	O
ERM	B-GENE
)	O
.	O

Gel	O
shift	O
analysis	O
indicates	O
that	O
the	O
full	B-GENE
-	I-GENE
length	I-GENE
ERM	I-GENE
protein	I-GENE
is	O
able	O
to	O
bind	O
specifically	O
to	O
an	O
oligonucleotide	O
containing	O
the	O
consensus	O
nucleotide	O
core	O
sequence	O
GGAA	O
recognized	O
by	O
the	O
Ets	B-GENE
proteins	O
.	O

Effects	O
of	O
estradiol	O
on	O
worm	O
burden	O
and	O
peripheral	O
leukocytes	O
in	O
Parastrongylus	O
malaysiensis	O
-	O
infected	O
rats	O
.	O

Dotarizine	O
produced	O
arterial	O
dilation	O
in	O
both	O
systemic	O
and	O
pulmonary	O
circulation	O
:	O
the	O
total	O
peripheral	O
resistance	O
dropped	O
,	O
and	O
femoral	O
artery	O
flow	O
rose	O
;	O
aortic	O
and	O
pulmonary	O
artery	O
mean	O
and	O
diastolic	O
pressures	O
declined	O
,	O
and	O
systolic	O
pressures	O
remained	O
almost	O
stable	O
.	O

These	O
issues	O
include	O
the	O
use	O
of	O
LMWHs	O
in	O
patients	O
with	O
arterial	O
thrombosis	O
or	O
myocardial	O
infarction	O
(	O
e	O
.	O
g	O
.	O
in	O
conjunction	O
with	O
thrombolytic	O
treatment	O
)	O
,	O
and	O
in	O
patients	O
with	O
pulmonary	O
embolism	O
.	O

The	O
usefulness	O
of	O
the	O
lambda	O
PG15	O
and	O
the	O
lambda	O
AD5	O
cloning	O
vectors	O
was	O
demonstrated	O
by	O
constructing	O
large	O
Neurospora	O
crassa	O
cDNA	O
libraries	O
.	O

Endoscopic	O
transthoracic	O
sympathectomy	O
as	O
adjuvant	O
treatment	O
for	O
critical	O
upper	O
-	O
limb	O
ischaemia	O
.	O

Sequence	O
comparisons	O
have	O
shown	O
that	O
Aps1p	B-GENE
is	O
more	O
similar	O
to	O
the	O
sigma	O
subunit	O
of	O
the	O
Golgi	O
-	O
localized	O
mammalian	O
AP	B-GENE
-	I-GENE
1	I-GENE
complex	I-GENE
than	O
Aps2p	B-GENE
,	O
which	O
is	O
more	O
related	O
to	O
the	O
plasma	O
membrane	O
AP	B-GENE
-	I-GENE
2	I-GENE
sigma	I-GENE
subunit	O
.	O

The	O
Saccharomyces	B-GENE
cerevisiae	I-GENE
APS1	I-GENE
gene	I-GENE
encodes	O
a	O
homolog	O
of	O
the	O
small	O
subunit	O
of	O
the	O
mammalian	B-GENE
clathrin	I-GENE
AP	B-GENE
-	I-GENE
1	I-GENE
complex	I-GENE
:	O
evidence	O
for	O
functional	O
interaction	O
with	O
clathrin	B-GENE
at	O
the	O
Golgi	O
complex	O
.	O

These	O
results	O
are	O
the	O
first	O
to	O
demonstrate	O
the	O
structural	O
organization	O
of	O
a	O
vertebrate	O
gene	O
encoding	O
an	O
integral	O
membrane	O
protein	O
of	O
the	O
nuclear	O
envelope	O
that	O
may	O
be	O
a	O
member	O
of	O
a	O
family	O
of	O
polypeptides	O
conserved	O
in	O
evolution	O
.	O

Biochemical	O
characterization	O
of	O
valosin	B-GENE
-	I-GENE
containing	I-GENE
protein	I-GENE
,	O
a	O
protein	B-GENE
tyrosine	I-GENE
kinase	I-GENE
substrate	O
in	O
hematopoietic	O
cells	O
.	O

The	O
presence	O
of	O
the	O
foreign	O
gene	O
was	O
confirmed	O
by	O
Southern	O
analysis	O
.	O

All	O
patients	O
with	O
deterioriation	O
in	O
mental	O
status	O
showed	O
a	O
marked	O
increase	O
in	O
liver	O
enzymes	O
(	O
aspartate	B-GENE
and	I-GENE
alanine	I-GENE
aminotransaminases	I-GENE
)	O
and	O
severe	O
coagulopathy	O
.	O

Functional	O
postnatal	O
development	O
of	O
the	O
rat	O
primary	O
visual	O
cortex	O
and	O
the	O
role	O
of	O
visual	O
experience	O
:	O
dark	O
rearing	O
and	O
monocular	O
deprivation	O
.	O

Eleven	O
patients	O
tested	O
positive	O
for	O
the	O
hepatitis	B-GENE
B	I-GENE
surface	I-GENE
antigen	I-GENE
(	O
HBsAg	B-GENE
)	O
.	O

The	O
xylose	B-GENE
isomerase	I-GENE
-	I-GENE
encoding	I-GENE
gene	I-GENE
(	O
xylA	B-GENE
)	O
of	O
Clostridium	O
thermosaccharolyticum	O
:	O
cloning	O
,	O
sequencing	O
and	O
phylogeny	O
of	O
XylA	B-GENE
enzymes	I-GENE
.	O

Two	O
phosphopeptides	O
,	O
identified	O
as	O
RS	O
-	O
[	O
32P	O
]	O
SGASGLLTSEHHSR	O
and	O
S	O
-	O
[	O
32P	O
]	O
SGASGLLTSEHHSR	O
,	O
were	O
obtained	O
after	O
stoichiometric	O
phosphorylation	O
and	O
trypsinization	O
of	O
the	O
peptide	O
.	O

Altogether	O
,	O
these	O
data	O
suggest	O
that	O
Ypt51p	B-GENE
,	O
Ypt52p	B-GENE
,	O
and	O
Ypt53p	B-GENE
are	O
required	O
for	O
transport	O
in	O
the	O
endocytic	O
pathway	O
and	O
for	O
correct	O
sorting	O
of	O
vacuolar	B-GENE
hydrolases	I-GENE
suggesting	O
a	O
possible	O
intersection	O
of	O
the	O
endocytic	O
with	O
the	O
vacuolar	O
sorting	O
pathway	O
.	O

All	O
of	O
the	O
basal	O
TPN	O
solutions	O
were	O
isonitrogenous	O
and	O
identical	O
in	O
nutrient	O
composition	O
,	O
except	O
for	O
the	O
difference	O
in	O
energy	O
level	O
,	O
which	O
was	O
adjusted	O
with	O
glucose	O
.	O

Surprisingly	O
,	O
TFIIIC	B-GENE
alpha	I-GENE
has	O
no	O
homology	O
to	O
any	O
of	O
the	O
yeast	B-GENE
TFIIIC	I-GENE
subunits	I-GENE
already	O
cloned	O
,	O
suggesting	O
a	O
significant	O
degree	O
of	O
evolutionary	O
divergence	O
for	O
RNA	B-GENE
polymerase	I-GENE
III	I-GENE
factors	I-GENE
.	O

Transactivation	O
domain	O
is	O
located	O
downstream	O
of	O
the	O
128	B-GENE
-	I-GENE
amino	I-GENE
-	I-GENE
acid	I-GENE
runt	I-GENE
homology	I-GENE
region	I-GENE
,	O
referred	O
to	O
as	O
the	O
Runt	B-GENE
domain	I-GENE
.	O

We	O
estimate	O
that	O
the	O
protease	O
activity	O
is	O
at	O
least	O
35	O
-	O
fold	O
greater	O
in	O
mature	O
B	O
cells	O
than	O
in	O
pre	O
-	O
B	O
cells	O
.	O

The	O
ligand	O
for	O
RXR	B-GENE
,	O
9	O
-	O
cis	O
retinoic	O
acid	O
,	O
has	O
the	O
opposite	O
effect	O
of	O
destabilizing	O
the	O
heterodimeric	O
-	O
DNA	O
complex	O
.	O

Cerebral125	B-GENE
albumin	I-GENE
was	O
increased	O
to	O
similar	O
proportions	O
in	O
those	O
groups	O
submitted	O
to	O
hyperosmolality	O
.	O

Retrogradely	O
labelled	O
neurons	O
significantly	O
prevailed	O
in	O
the	O
ipsilateral	O
substantia	O
nigra	O
pars	O
compacta	O
.	O

Therefore	O
,	O
the	O
amino	O
-	O
terminal	O
sequence	O
of	O
the	O
purified	O
carA	B-GENE
product	I-GENE
is	O
identical	O
to	O
that	O
derived	O
from	O
the	O
nucleotide	O
sequence	O
in	O
both	O
organisms	O
,	O
P	O
.	O
stutzeri	O
having	O
four	O
additional	O
amino	O
acids	O
.	O

Aneurysmal	O
bone	O
cyst	O
of	O
the	O
jaws	O
:	O
analysis	O
of	O
11	O
cases	O
.	O

Location	O
and	O
orientation	O
of	O
an	O
activating	O
region	O
in	O
the	O
Escherichia	O
coli	O
transcription	O
factor	O
,	O
FNR	B-GENE
.	O

Moxidectin	O
(	O
at	O
3	O
times	O
the	O
therapeutic	O
dose	O
)	O
did	O
not	O
have	O
deleterious	O
effects	O
on	O
cow	O
reproductive	O
performance	O
as	O
examined	O
(	O
eg	O
,	O
at	O
folliculogenesis	O
,	O
ovulation	O
,	O
and	O
the	O
early	O
embryonic	O
phase	O
of	O
development	O
)	O
.	O

Northern	O
-	O
blot	O
analysis	O
of	O
mRNA	O
from	O
Avicel	O
-	O
grown	O
N	O
.	O
patriciarum	O
showed	O
that	O
xynB	B-GENE
hybridized	O
to	O
a	O
3	O
.	O
4	O
kb	O
mRNA	O
species	O
.	O

The	O
variable	O
regions	O
of	O
vertebrate	O
striated	O
TnT	B-GENE
isoforms	I-GENE
reflect	O
the	O
subsequent	O
addition	O
and	O
modification	O
of	O
genomic	O
sequences	O
to	O
give	O
rise	O
to	O
members	O
of	O
the	O
TnT	B-GENE
multigene	I-GENE
family	I-GENE
.	O

Simple	O
reaction	O
time	O
(	O
RT	O
)	O
to	O
a	O
peripheral	O
visual	O
target	O
(	O
S2	O
)	O
is	O
shortened	O
when	O
a	O
non	O
-	O
informative	O
cue	O
(	O
S1	O
)	O
is	O
flashed	O
at	O
the	O
S2	O
location	O
100	O
-	O
150	O
ms	O
before	O
target	O
onset	O
(	O
early	O
facilitation	O
)	O
.	O

These	O
viruses	O
depend	O
on	O
the	O
host	O
cell	O
machinery	O
for	O
their	O
existence	O
,	O
and	O
interference	O
with	O
these	O
processes	O
typically	O
interferes	O
with	O
other	O
important	O
host	O
physiology	O
.	O

Treatment	O
was	O
well	O
-	O
tolerated	O
.	O

A	O
concentration	O
of	O
12	O
.	O
5	O
ppm	O
SO2	O
induced	O
a	O
decrease	O
from	O
baseline	O
values	O
of	O
approximately	O
80	O
%	O
in	O
mean	O
MCA	O
and	O
of	O
roughly	O
70	O
%	O
in	O
mean	O
CBF	O
.	O

We	O
have	O
used	O
these	O
modified	O
assay	O
conditions	O
to	O
extend	O
studies	O
on	O
the	O
transposition	O
pathway	O
.	O

Renal	O
cell	O
carcinoma	O
in	O
children	O
:	O
a	O
single	O
institution	O
'	O
s	O
experience	O
.	O

The	O
data	O
suggest	O
that	O
ICP10	B-GENE
constitutively	O
increases	O
ras	B-GENE
activity	O
,	O
and	O
its	O
TM	O
segment	O
plays	O
a	O
critical	O
role	O
in	O
transformation	O
-	O
related	O
signaling	O
pathways	O
.	O

Five	O
concensus	O
poly	O
A	O
addition	O
sites	O
are	O
located	O
in	O
the	O
350	O
base	O
pairs	O
immediately	O
following	O
the	O
protein	B-GENE
IX	I-GENE
coding	O
region	O
.	O

Factors	O
associated	O
with	O
intrafamilial	O
transmission	O
of	O
hepatitis	O
B	O
virus	O
infection	O
in	O
Korea	O
.	O

Northern	O
analysis	O
,	O
to	O
search	O
for	O
a	O
pcbAB	B-GENE
transcript	I-GENE
,	O
showed	O
no	O
distinct	O
transcript	O
and	O
indicated	O
severely	O
degraded	O
mRNA	O
.	O

The	O
high	O
degree	O
of	O
conservation	O
between	O
NQO2	B-GENE
and	O
NQO1	B-GENE
gene	I-GENE
organization	O
and	O
sequence	O
confirmed	O
that	O
NQO2	B-GENE
gene	I-GENE
encodes	O
for	O
a	O
second	O
member	O
of	O
the	O
NQO	B-GENE
gene	I-GENE
family	I-GENE
in	O
human	O
.	O

The	O
efficacy	O
of	O
a	O
Propionibacterium	O
acnes	O
product	O
for	O
treatment	O
of	O
coliform	O
mastitis	O
was	O
evaluated	O
following	O
intramammary	O
infusion	O
of	O
Escherichia	O
coli	O
.	O

The	O
human	B-GENE
eps15	I-GENE
gene	I-GENE
,	O
encoding	O
a	O
tyrosine	B-GENE
kinase	I-GENE
substrate	O
,	O
is	O
conserved	O
in	O
evolution	O
and	O
maps	O
to	O
1p31	O
-	O
p32	O
.	O

The	O
gene	O
encoding	O
the	O
105	B-GENE
-	I-GENE
kDa	I-GENE
protein	I-GENE
(	I-GENE
p105	I-GENE
)	I-GENE
precursor	I-GENE
of	O
the	O
p50	B-GENE
subunit	I-GENE
of	O
transcription	O
factor	O
NF	B-GENE
-	I-GENE
kappa	I-GENE
B	I-GENE
also	O
encodes	O
a	O
p70	B-GENE
I	I-GENE
kappa	I-GENE
B	I-GENE
protein	I-GENE
,	O
I	B-GENE
kappa	I-GENE
B	I-GENE
gamma	I-GENE
,	O
which	O
is	O
identical	O
to	O
the	O
C	O
-	O
terminal	O
607	O
amino	O
acids	O
of	O
p105	B-GENE
.	O

Alternative	O
splicing	O
of	O
RNA	O
transcripts	O
encoded	O
by	O
the	O
murine	O
p105	B-GENE
NF	B-GENE
-	I-GENE
kappa	I-GENE
B	I-GENE
gene	O
generates	O
I	B-GENE
kappa	I-GENE
B	I-GENE
gamma	I-GENE
isoforms	I-GENE
with	O
different	O
inhibitory	O
activities	O
.	O

The	O
experiment	O
included	O
6	O
male	O
and	O
4	O
female	O
healthy	O
subjects	O
who	O
,	O
during	O
a	O
24	O
-	O
hour	O
stay	O
in	O
the	O
respiration	O
chambers	O
,	O
performed	O
,	O
in	O
the	O
morning	O
and	O
afternoon	O
,	O
15	O
min	O
cycling	O
with	O
the	O
total	O
work	O
of	O
6	O
,	O
750	O
kg	O
m	O
.	O

These	O
rearrangements	O
result	O
in	O
the	O
formation	O
of	O
chimeric	O
genes	O
showing	O
the	O
tyrosine	B-GENE
kinase	I-GENE
domain	I-GENE
of	O
ret	B-GENE
fused	O
with	O
the	O
5	O
'	O
end	O
sequences	O
of	O
different	O
genes	O
.	O

Frequent	O
loss	O
of	O
heterozygosity	O
(	O
LOH	O
)	O
of	O
>	O
30	O
%	O
of	O
the	O
informative	O
cases	O
was	O
observed	O
on	O
chromosomes	O
3p	O
(	O
41	O
.	O
1	O
%	O
)	O
,	O
5q	O
(	O
52	O
.	O
6	O
%	O
)	O
,	O
6p	O
(	O
30	O
.	O
4	O
%	O
)	O
,	O
8p	O
(	O
33	O
.	O
3	O
%	O
)	O
,	O
9p	O
(	O
35	O
.	O
7	O
%	O
)	O
,	O
9q	O
(	O
30	O
.	O
8	O
%	O
)	O
,	O
11p	O
(	O
32	O
.	O
4	O
%	O
)	O
,	O
13q	O
(	O
52	O
.	O
7	O
%	O
)	O
,	O
17p	O
(	O
55	O
.	O
2	O
%	O
)	O
,	O
17q	O
(	O
33	O
.	O
3	O
%	O
)	O
,	O
18q	O
(	O
45	O
.	O
7	O
%	O
)	O
,	O
and	O
19q	O
(	O
30	O
.	O
4	O
%	O
)	O
.	O

A	O
single	O
amino	O
acid	O
change	O
in	O
the	O
CPY	B-GENE
vacuolar	I-GENE
sorting	I-GENE
signal	I-GENE
prevents	O
this	O
interaction	O
.	O

Glutamyl	B-GENE
-	I-GENE
tRNA	I-GENE
synthetase	I-GENE
and	O
prolyl	B-GENE
-	I-GENE
tRNA	I-GENE
synthetase	I-GENE
belong	O
to	O
different	O
classes	O
of	O
aminoacyl	B-GENE
-	I-GENE
tRNA	I-GENE
synthetases	I-GENE
that	O
are	O
thought	O
to	O
have	O
evolved	O
along	O
independent	O
evolutionary	O
pathways	O
.	O

Using	O
the	O
sequence	O
data	O
obtained	O
from	O
the	O
human	O
TCRAC	B-GENE
/	O
TCRDC	B-GENE
region	O
,	O
we	O
have	O
extended	O
a	O
polymerase	O
chain	O
reaction	O
-	O
based	O
assay	O
to	O
test	O
for	O
the	O
expression	O
of	O
the	O
individual	O
TCRAJ	B-GENE
gene	I-GENE
segments	I-GENE
.	O

This	O
analysis	O
revealed	O
an	O
intact	O
gene	O
(	O
arg4	B-GENE
)	O
showing	O
a	O
high	O
degree	O
of	O
homology	O
with	O
the	O
Saccharomyces	B-GENE
cerevisiae	I-GENE
CPA2	I-GENE
gene	I-GENE
encoding	O
the	O
large	O
subunit	O
of	O
carbamoyl	B-GENE
-	I-GENE
phosphate	I-GENE
synthetase	I-GENE
(	O
CPS	B-GENE
-	I-GENE
A	I-GENE
)	O
.	O

The	O
baroreflex	O
latency	O
(	O
from	O
the	O
ECG	O
R	O
-	O
wave	O
to	O
the	O
integrated	O
MSNA	O
burst	O
peak	O
)	O
was	O
constant	O
at	O
approximately	O
1	O
.	O
20	O
s	O
during	O
sleep	O
,	O
suggesting	O
that	O
pulse	O
-	O
synchronicity	O
was	O
maintained	O
.	O

DESIGN	O
-	O
-	O
A	O
randomised	O
study	O
was	O
conducted	O
in	O
all	O
women	O
aged	O
50	O
-	O
70	O
years	O
who	O
were	O
eligible	O
for	O
breast	O
cancer	O
screening	O
and	O
living	O
in	O
the	O
city	O
of	O
Utrecht	O
.	O

Identification	O
of	O
an	O
immediate	B-GENE
-	I-GENE
early	I-GENE
gene	I-GENE
in	O
the	O
Marek	O
'	O
s	O
disease	O
virus	O
long	O
internal	O
repeat	O
region	O
which	O
encodes	O
a	O
unique	O
14	O
-	O
kilodalton	O
polypeptide	O
.	O

We	O
have	O
used	O
a	O
full	O
-	O
length	O
cDNA	O
clone	O
of	O
a	O
mouse	O
hepatitis	O
virus	O
strain	O
A59	O
defective	O
interfering	O
(	O
DI	O
)	O
RNA	O
,	O
pMIDI	B-GENE
-	I-GENE
C	I-GENE
,	O
and	O
cassette	O
mutagenesis	O
to	O
study	O
the	O
mechanism	O
of	O
coronavirus	O
subgenomic	O
mRNA	O
synthesis	O
.	O

To	O
study	O
the	O
structure	O
-	O
function	O
of	O
the	O
gene	B-GENE
5	I-GENE
product	I-GENE
,	O
wild	O
-	O
type	O
and	O
mutant	O
forms	O
of	O
NS53	B-GENE
were	O
produced	O
by	O
using	O
a	O
recombinant	O
baculovirus	O
expression	O
system	O
and	O
a	O
recombinant	O
vaccinia	O
virus	O
/	O
T7	O
(	O
vTF7	O
-	O
3	O
)	O
expression	O
system	O
.	O

Gel	O
electrophoresis	O
and	O
Western	O
immunoblot	O
analyses	O
of	O
intracellular	O
fractions	O
derived	O
from	O
infected	O
cells	O
revealed	O
that	O
large	O
amounts	O
of	O
NS53	B-GENE
were	O
present	O
in	O
the	O
cytosol	O
and	O
in	O
association	O
with	O
the	O
cytoskeletal	O
matrix	O
.	O

The	O
transcription	B-GENE
factor	I-GENE
AP	I-GENE
-	I-GENE
2	I-GENE
is	O
encoded	O
by	O
a	O
gene	O
located	O
on	O
chromosome	O
6	O
near	O
the	O
HLA	B-GENE
locus	I-GENE
.	O

The	O
mature	O
AP	B-GENE
-	I-GENE
2	I-GENE
mRNA	I-GENE
is	O
spliced	O
from	O
7	O
exons	O
distributed	O
over	O
a	O
region	O
of	O
18	O
kb	O
genomic	O
DNA	O
.	O

San	O
Martin	O
'	O
s	O
psychological	O
traits	O
coupled	O
to	O
his	O
work	O
with	O
masonic	O
lodges	O
that	O
allowed	O
him	O
to	O
display	O
his	O
abilities	O
as	O
strategist	O
and	O
political	O
ruler	O
.	O

The	O
participants	O
were	O
homosexual	O
men	O
in	O
hepatitis	O
B	O
vaccine	O
trials	O
in	O
Amsterdam	O
(	O
n	O
=	O
74	O
)	O
,	O
New	O
York	O
City	O
(	O
n	O
=	O
120	O
)	O
,	O
and	O
San	O
Francisco	O
(	O
n	O
=	O
168	O
)	O
.	O

Comparison	O
with	O
the	O
crystal	O
structure	O
of	O
Desulfovibrio	O
gigas	O
,	O
Dg	O
,	O
Fd	B-GENE
(	O
Kissinger	O
et	O
al	O
.	O
,	O
1991	O
)	O
reveals	O
a	O
very	O
similar	O
folding	O
topology	O
,	O
although	O
several	O
secondary	O
structural	O
elements	O
are	O
extended	O
in	O
Pf	O
relative	O
to	O
Dg	O
Fd	B-GENE
.	O

CONCLUSIONS	O
:	O
Serum	B-GENE
prolactin	I-GENE
concentrations	O
show	O
age	O
related	O
variations	O
in	O
presumably	O
fertile	O
men	O
.	O

Eight	O
highly	O
trained	O
male	O
kayakers	O
were	O
studied	O
to	O
determine	O
the	O
relationship	O
between	O
critical	O
power	O
(	O
CP	O
)	O
and	O
the	O
onset	O
of	O
blood	O
lactate	O
accumulation	O
(	O
OBLA	O
)	O
.	O

As	O
in	O
S	O
.	O
cerevisiae	O
,	O
the	O
sequence	O
of	O
rhp51	B-GENE
+	I-GENE
showed	O
two	O
MluI	B-GENE
cell	I-GENE
-	I-GENE
cycle	I-GENE
boxes	I-GENE
and	O
a	O
putative	O
DNA	O
damage	O
-	O
responsive	O
element	O
in	O
its	O
upstream	O
region	O
.	O

A	O
partial	O
cDNA	O
sequence	O
indicated	O
that	O
the	O
T	B-GENE
lymphocyte	I-GENE
early	I-GENE
-	I-GENE
activation	I-GENE
gene	I-GENE
(	O
Tea	B-GENE
)	O
encodes	O
a	O
protein	O
related	O
to	O
the	O
dual	O
-	O
function	O
ecotropic	B-GENE
retrovirus	I-GENE
receptor	I-GENE
/	O
cationic	B-GENE
amino	I-GENE
acid	I-GENE
transporter	I-GENE
(	O
ecoR	B-GENE
/	O
CAT1	B-GENE
)	O
,	O
and	O
RNA	O
blots	O
suggested	O
highest	O
Tea	B-GENE
expression	O
in	O
T	O
lymphocytes	O
and	O
liver	O
(	O
MacLeod	O
,	O
C	O
.	O
L	O
.	O
,	O
Finley	O
,	O
K	O
.	O
,	O
Kakuda	O
,	O
D	O
.	O

Furthermore	O
,	O
unlike	O
the	O
case	O
for	O
HIS3	B-GENE
where	O
only	O
a	O
limited	O
subset	O
of	O
TATA	O
-	O
like	O
sequences	O
can	O
activate	O
transcription	O
in	O
conjunction	O
with	O
GCN4p	B-GENE
,	O
many	O
divergent	O
TATA	O
-	O
like	O
sequences	O
allowed	O
GCN4p	B-GENE
activation	O
of	O
TRP3	B-GENE
.	O

Bacterially	O
expressed	O
protein	O
,	O
as	O
well	O
as	O
the	O
in	O
vitro	O
reticulocyte	O
lysate	O
translation	O
product	O
,	O
comigrated	O
with	O
the	O
purified	O
37	O
-	O
kDa	O
protein	O
on	O
sodium	O
dodecyl	O
sulfate	O
-	O
polyacrylamide	O
gels	O
.	O

In	O
addition	O
,	O
this	O
kinase	O
is	O
well	O
conserved	O
evolutionarily	O
,	O
ubiquitously	O
expressed	O
,	O
and	O
its	O
genes	O
map	O
to	O
a	O
position	O
on	O
human	O
chromosome	O
1	O
frequently	O
deleted	O
in	O
the	O
late	O
stages	O
of	O
tumorigenesis	O
.	O

Deletion	O
analysis	O
of	O
the	O
ICL1	B-GENE
promoter	I-GENE
led	O
to	O
the	O
identification	O
of	O
an	O
upstream	O
activating	O
sequence	O
element	O
,	O
UASICL1	O
(	O
5	O
'	O
CATTCATCCG	O
3	O
'	O
)	O
,	O
necessary	O
and	O
sufficient	O
for	O
conferring	O
carbon	O
source	O
-	O
dependent	O
regulation	O
on	O
a	O
heterologous	O
reporter	O
gene	O
.	O

In	O
Mv1Lu	O
lung	O
epithelial	O
cells	O
,	O
ActR	B-GENE
-	I-GENE
IB	I-GENE
and	O
T	B-GENE
beta	I-GENE
R	I-GENE
-	I-GENE
I	I-GENE
signal	O
a	O
common	O
set	O
of	O
growth	O
-	O
inhibitory	O
and	O
transcriptional	O
responses	O
in	O
association	O
with	O
their	O
corresponding	O
ligands	O
and	O
type	B-GENE
II	I-GENE
receptors	I-GENE
.	O

H	O
-	O
7	O
,	O
which	O
specifically	O
,	O
although	O
weakly	O
,	O
inhibited	O
PKC	B-GENE
activation	O
,	O
had	O
no	O
effect	O
on	O
tyrosine	O
phosphorylation	O
and	O
PtdIns	O
(	O
3	O
,	O
4	O
)	O
P2	O
production	O
.	O

The	O
effects	O
of	O
systemic	O
glucose	O
concentration	O
on	O
brain	O
metabolism	O
following	O
repeated	O
brain	O
ischemia	O
.	O

A	O
-	O
69	O
-	O
year	O
-	O
old	O
patient	O
with	O
postoperative	O
small	O
-	O
bowel	O
obstruction	O
underwent	O
laparotomy	O
three	O
times	O
.	O

On	O
physical	O
examination	O
a	O
mild	O
symmetrical	O
polyarthritis	O
of	O
small	O
and	O
large	O
joints	O
was	O
seen	O
.	O

We	O
conclude	O
that	O
the	O
SIMV	O
is	O
useful	O
in	O
weaning	O
neonates	O
from	O
the	O
ventilator	O
.	O

VP	O
-	O
16	O
,	O
ifosfamide	O
and	O
cisplatin	O
(	O
VIP	O
)	O
for	O
extensive	O
small	O
cell	O
lung	O
cancer	O
.	O

A	O
total	O
of	O
7	O
(	O
4	O
males	O
and	O
3	O
females	O
)	O
patients	O
were	O
included	O
in	O
this	O
retrospective	O
study	O
to	O
determine	O
the	O
sensitivity	O
of	O
radioimmunoscintigraphy	O
with	O
I	O
-	O
131	O
labeled	O
anti	B-GENE
CEA	I-GENE
/	O
CA	B-GENE
19	I-GENE
-	I-GENE
9	I-GENE
monoclonal	O
antibodies	O
.	O

A	O
genomic	O
clone	O
for	O
the	O
cyc07	B-GENE
gene	I-GENE
,	O
which	O
is	O
expressed	O
specifically	O
at	O
the	O
S	O
phase	O
during	O
the	O
cell	O
cycle	O
in	O
synchronous	O
cultures	O
of	O
periwinkle	O
(	O
Catharanthus	O
roseus	O
)	O
cells	O
,	O
was	O
isolated	O
.	O

CONCLUSIONS	O
:	O
Translocation	O
of	O
bacteria	O
or	O
endotoxin	O
from	O
the	O
gastrointestinal	O
tract	O
into	O
the	O
bloodstream	O
has	O
been	O
noted	O
in	O
animal	O
experiments	O
;	O
however	O
,	O
translocation	O
was	O
not	O
detected	O
in	O
our	O
patients	O
with	O
hemorrhagic	O
shock	O
.	O

Southern	O
blotting	O
analysis	O
implied	O
the	O
occurrence	O
of	O
multiple	O
COXVb	B-GENE
genes	I-GENE
in	O
the	O
rat	O
genome	O
.	O

Acylation	O
with	O
the	O
palmitate	O
analog	O
was	O
prevented	O
when	O
Gly	O
-	O
2	O
was	O
mutated	O
to	O
alanine	O
,	O
implying	O
that	O
N	O
-	O
myristylation	O
is	O
required	O
for	O
palmitylation	O
,	O
and	O
when	O
either	O
Cys	O
-	O
3	O
or	O
Cys	O
-	O
6	O
was	O
mutated	O
to	O
serine	O
.	O

Subunit	O
composition	O
and	O
domain	O
structure	O
of	O
the	O
Spo0A	B-GENE
sporulation	I-GENE
transcription	I-GENE
factor	I-GENE
of	I-GENE
Bacillus	I-GENE
subtilis	I-GENE
.	O

Electrophoretic	O
mobility	O
shift	O
analysis	O
indicates	O
that	O
NF	B-GENE
-	I-GENE
IL	I-GENE
-	I-GENE
6	I-GENE
,	O
as	O
well	O
as	O
other	O
related	O
members	O
of	O
this	O
family	O
,	O
bind	O
specifically	O
to	O
the	O
NF	B-GENE
-	I-GENE
IL	I-GENE
-	I-GENE
6	I-GENE
site	O
in	O
the	O
IL	B-GENE
-	I-GENE
8	I-GENE
promoter	I-GENE
.	O

BYV	O
,	O
citrus	O
tristeza	O
virus	O
(	O
CTV	O
)	O
,	O
beet	O
yellow	O
stunt	O
virus	O
(	O
BYSV	O
)	O
and	O
carnation	O
necrotic	O
fleck	O
virus	O
templates	O
produced	O
1	O
kb	O
amplification	O
products	O
,	O
which	O
were	O
shown	O
by	O
sequencing	O
to	O
represent	O
fragments	O
of	O
the	O
respective	O
HSP70	B-GENE
genes	I-GENE
.	O

The	O
p53	B-GENE
tumor	I-GENE
suppressor	I-GENE
gene	I-GENE
product	I-GENE
,	O
a	O
sequence	O
-	O
specific	O
DNA	O
-	O
binding	O
protein	O
,	O
has	O
been	O
shown	O
to	O
act	O
as	O
a	O
transcriptional	O
activator	O
and	O
repressor	O
both	O
in	O
vitro	O
and	O
in	O
vivo	O
.	O

Mutational	O
analysis	O
of	O
chromosomal	O
segment	O
64AB	O
,	O
a	O
region	O
containing	O
the	O
glutamic	B-GENE
acid	I-GENE
decarboxylase	I-GENE
gene	I-GENE
.	O

Rearrangements	O
of	O
the	O
NFKB2	B-GENE
gene	I-GENE
are	O
associated	O
with	O
lymphoid	O
malignancies	O
,	O
but	O
the	O
functional	O
significance	O
of	O
these	O
alterations	O
is	O
not	O
known	O
.	O

Cloning	O
and	O
sequencing	O
of	O
the	O
corresponding	O
cDNAs	O
indicates	O
that	O
,	O
via	O
alternative	O
splicing	O
,	O
the	O
rearranged	O
gene	O
codes	O
for	O
two	O
proteins	O
of	O
84	O
and	O
85	O
kD	O
(	O
p84	B-GENE
/	I-GENE
85	I-GENE
)	O
which	O
retain	O
the	O
DNA	O
-	O
binding	O
rel	B-GENE
domain	I-GENE
and	O
the	O
first	O
five	O
ankyrin	B-GENE
repeats	O
,	O
but	O
have	O
lost	O
their	O
carboxy	O
-	O
terminus	O
including	O
the	O
seventh	O
ankyrin	B-GENE
repeat	O
.	O

Transient	O
co	O
-	O
transfection	O
assays	O
involving	O
NFKB2	B-GENE
expression	O
vectors	O
and	O
kappa	B-GENE
B	I-GENE
-	O
driven	O
reporter	O
plasmids	O
indicate	O
that	O
NFKB2	B-GENE
p85	B-GENE
has	O
lost	O
the	O
transcriptional	O
repressor	O
functions	O
typical	O
of	O
normal	O
NFKB2	B-GENE
p52	B-GENE
.	O

Also	O
,	O
HR21ap	B-GENE
as	O
well	O
as	O
HR21Xap	B-GENE
are	O
specific	O
in	O
their	O
inhibition	O
of	O
Sp1	B-GENE
binding	O
.	O

Intravenous	O
antibiotic	O
therapy	O
in	O
cystic	O
fibrosis	O
:	O
in	O
hospital	O
or	O
at	O
home	O
?	O

Open	O
reading	O
frames	O
in	O
a	O
4556	O
nucleotide	O
sequence	O
within	O
MDV	B-GENE
-	I-GENE
1	I-GENE
BamHI	I-GENE
-	I-GENE
D	I-GENE
DNA	I-GENE
fragment	I-GENE
:	O
evidence	O
for	O
splicing	O
of	O
mRNA	O
from	O
a	O
new	O
viral	O
glycoprotein	O
gene	O
.	O

The	O
ns2	B-GENE
gene	I-GENE
comprises	O
an	O
open	O
reading	O
frame	O
(	O
ORF	O
)	O
encoding	O
a	O
putative	O
nonstructural	O
(	O
ns	O
)	O
protein	O
of	O
279	O
amino	O
acids	O
with	O
a	O
predicted	O
molecular	O
mass	O
of	O
32	O
-	O
kDa	O
.	O

The	O
hydrophobicity	O
profile	O
of	O
the	O
methyltransferase	O
reveals	O
the	O
presence	O
of	O
at	O
least	O
five	O
potential	O
transmembrane	O
domains	O
.	O

Measurement	O
of	O
SaO2	O
at	O
moderate	O
altitude	O
can	O
be	O
helpful	O
in	O
the	O
care	O
of	O
both	O
healthy	O
and	O
ill	O
newborns	O
or	O
infants	O
.	O

To	O
determine	O
whether	O
the	O
excess	O
prevalence	O
of	O
human	O
immunodeficiency	O
virus	O
type	O
1	O
(	O
HIV	O
-	O
1	O
)	O
infection	O
in	O
US	O
black	O
and	O
Hispanic	O
homosexual	O
men	O
relative	O
to	O
white	O
men	O
can	O
be	O
explained	O
by	O
differences	O
in	O
sociodemographic	O
factors	O
,	O
history	O
of	O
sexually	O
transmitted	O
diseases	O
,	O
or	O
sexual	O
and	O
drug	O
-	O
use	O
behaviors	O
,	O
the	O
authors	O
conducted	O
a	O
cross	O
-	O
sectional	O
analysis	O
of	O
baseline	O
HIV	O
-	O
1	O
seroprevalence	O
and	O
HIV	O
-	O
1	O
risk	O
factors	O
among	O
4	O
,	O
475	O
non	O
-	O
Hispanic	O
white	O
,	O
234	O
Hispanic	O
white	O
,	O
and	O
194	O
black	O
homosexual	O
men	O
from	O
four	O
centers	O
in	O
the	O
United	O
States	O
(	O
Baltimore	O
/	O
Washington	O
,	O
DC	O
,	O
Pittsburgh	O
,	O
Chicago	O
,	O
and	O
Los	O
Angeles	O
)	O
.	O

The	O
patients	O
in	O
one	O
group	O
had	O
intrauterine	O
catheters	O
inserted	O
and	O
oxytocin	B-GENE
was	O
titrated	O
to	O
achieve	O
the	O
75th	O
percentile	O
of	O
uterine	O
activity	O
observed	O
in	O
spontaneous	O
normal	O
labour	O
according	O
to	O
parity	O
.	O

Continued	O
development	O
of	O
the	O
rat	O
conditioning	O
paradigm	O
is	O
especially	O
warranted	O
because	O
of	O
the	O
ability	O
to	O
record	O
sympathetic	O
nerve	O
activity	O
in	O
intact	O
,	O
awake	O
subjects	O
and	O
the	O
large	O
number	O
of	O
readily	O
available	O
genetic	O
strains	O
,	O
which	O
model	O
human	O
pathological	O
states	O
.	O

The	O
ultrastructure	O
of	O
retinal	O
vessels	O
was	O
examined	O
in	O
three	O
eyes	O
from	O
diabetic	O
patients	O
and	O
two	O
eyes	O
from	O
control	O
subjects	O
.	O

The	O
regulatory	O
region	O
also	O
has	O
a	O
sequence	O
similar	O
to	O
the	O
binding	O
site	O
for	O
a	O
liver	O
-	O
specific	O
transcription	O
factor	O
,	O
hepatocyte	B-GENE
nuclear	I-GENE
factor	I-GENE
1	I-GENE
(	O
HNF	B-GENE
-	I-GENE
1	I-GENE
)	O
,	O
at	O
positions	O
-	O
120	O
to	O
-	O
132	O
.	O

Thus	O
,	O
we	O
have	O
identified	O
a	O
GRE	O
sufficient	O
to	O
account	O
for	O
full	O
glucocorticoid	O
inducibility	O
and	O
an	O
HNF	B-GENE
-	I-GENE
1	I-GENE
site	I-GENE
close	O
to	O
the	O
promoter	O
that	O
are	O
major	O
determinants	O
of	O
transcriptional	O
control	O
of	O
the	O
Xenopus	B-GENE
fibrinogen	I-GENE
B	I-GENE
beta	I-GENE
subunit	I-GENE
gene	I-GENE
in	O
cells	O
from	O
normal	O
liver	O
tissue	O
.	O

Acad	O
.	O

The	O
PRB	B-GENE
-	I-GENE
1b	I-GENE
gene	I-GENE
encodes	O
for	O
a	O
basic	O
-	O
type	O
component	O
of	O
the	O
pathogenesis	O
-	O
related	O
PR	B-GENE
-	I-GENE
1	I-GENE
protein	I-GENE
family	I-GENE
.	O

Replacement	O
of	O
the	O
CRE	O
with	O
a	O
second	O
copy	O
of	O
the	O
AP	B-GENE
-	I-GENE
1	I-GENE
site	I-GENE
results	O
in	O
a	O
level	O
of	O
transcriptional	O
activity	O
comparable	O
with	O
that	O
of	O
the	O
wild	O
-	O
type	O
sequence	O
,	O
but	O
replacement	O
of	O
the	O
AP	B-GENE
-	I-GENE
1	I-GENE
site	I-GENE
with	O
a	O
CRE	O
abolishes	O
activity	O
.	O

The	O
T	B-GENE
-	I-GENE
cyt	I-GENE
promoter	I-GENE
,	O
although	O
of	O
bacterial	O
origin	O
is	O
active	O
in	O
planta	O
and	O
the	O
30	B-GENE
bp	I-GENE
cyt	I-GENE
-	I-GENE
1	I-GENE
element	I-GENE
is	O
located	O
within	O
a	O
region	O
that	O
is	O
essential	O
for	O
T	B-GENE
-	I-GENE
cyt	I-GENE
promotor	I-GENE
activity	O
in	O
leaf	O
,	O
stem	O
and	O
root	O
cells	O
of	O
tobacco	O
plants	O
.	O

Reviewing	O
manuscripts	O
:	O
developing	O
an	O
efficient	O
system	O
.	O

We	O
suggest	O
that	O
CT	O
scan	O
be	O
preferable	O
in	O
diagnosis	O
of	O
tumors	O
in	O
that	O
area	O
.	O

Effect	O
of	O
aging	O
on	O
respiratory	O
skeletal	O
muscles	O
.	O

Two	O
BASIC	O
computer	O
programs	O
using	O
logit	O
transformation	O
for	O
the	O
analysis	O
of	O
S	O
-	O
shaped	O
curves	O
are	O
presented	O
.	O

The	O
yeast	B-GENE
SSS1	I-GENE
gene	I-GENE
is	O
essential	O
for	O
secretory	O
protein	O
translocation	O
and	O
encodes	O
a	O
conserved	O
protein	O
of	O
the	O
endoplasmic	O
reticulum	O
.	O

The	O
lengths	O
of	O
the	O
complete	O
polypeptide	O
chain	O
of	O
the	O
recombinant	O
enzyme	O
and	O
its	O
transit	O
peptide	O
are	O
388	O
and	O
53	O
residues	O
,	O
respectively	O
.	O

The	O
absence	O
of	O
H4PteGlun	O
bound	O
to	O
the	O
T	B-GENE
protein	I-GENE
in	O
our	O
experimental	O
conditions	O
demonstrates	O
that	O
H4PteGlun	O
is	O
not	O
covalently	O
linked	O
to	O
the	O
T	B-GENE
protein	I-GENE
.	O

TATA	O
and	O
CCAAT	O
boxes	O
are	O
located	O
34	O
-	O
bp	O
and	O
68	O
-	O
bp	O
,	O
respectively	O
,	O
upstream	O
of	O
the	O
transcription	O
start	O
site	O
,	O
the	O
5	O
'	O
-	O
untranslated	O
leader	O
is	O
78	O
nucleotides	O
long	O
,	O
and	O
the	O
intronless	O
gene	O
has	O
at	O
least	O
two	O
different	O
polyadenylation	O
sites	O
.	O

GGS1	B-GENE
is	O
the	O
same	O
gene	O
as	O
TPS1	B-GENE
which	O
was	O
identified	O
as	O
encoding	O
a	O
subunit	O
of	O
the	O
trehalose	B-GENE
-	I-GENE
6	I-GENE
-	I-GENE
phosphate	I-GENE
synthase	I-GENE
/	I-GENE
phosphatase	I-GENE
complex	I-GENE
and	O
it	O
is	O
allelic	O
to	O
the	O
fdp1	B-GENE
,	O
byp1	B-GENE
,	O
glc6	B-GENE
and	O
cif1	O
mutations	O
.	O

We	O
also	O
compared	O
the	O
sequence	O
with	O
the	O
partly	O
homologous	O
products	O
of	O
the	O
S	O
.	O
cerevisiae	O
genes	O
TPS2	B-GENE
and	O
TSL1	B-GENE
which	O
code	O
for	O
the	O
larger	O
subunits	O
of	O
the	O
trehalose	B-GENE
synthase	I-GENE
complex	I-GENE
and	O
with	O
a	O
TSL1	B-GENE
homologue	I-GENE
,	O
TPS3	B-GENE
,	O
of	O
unknown	O
function	O
.	O

Stroop	O
interference	O
:	O
aging	O
effects	O
assessed	O
with	O
the	O
Stroop	O
Color	O
-	O
Word	O
Test	O
.	O

CONCLUSION	O
:	O
The	O
study	O
demonstrates	O
that	O
transvaginal	O
ultrasonography	O
has	O
an	O
efficiency	O
of	O
88	O
%	O
in	O
differentiating	O
endometriomas	O
from	O
other	O
ovarian	O
masses	O
with	O
a	O
specificity	O
of	O
90	O
%	O
.	O

Genomic	O
Southern	O
blot	O
analysis	O
of	O
rat	B-GENE
EFIA	I-GENE
(	O
gene	O
encoding	O
enhancer	B-GENE
factor	I-GENE
I	I-GENE
subunit	I-GENE
A	I-GENE
)	O
reveals	O
a	O
complex	O
band	O
pattern	O
when	O
cDNA	O
subfragment	O
probes	O
are	O
used	O
.	O

The	O
effect	O
of	O
ibopamine	O
and	O
furosemide	O
in	O
130	O
patients	O
with	O
NYHA	O
Class	O
I	O
and	O
II	O
heart	O
failure	O
were	O
studied	O
in	O
a	O
parallel	O
,	O
double	O
-	O
blind	O
,	O
randomized	O
placebo	O
-	O
controlled	O
multi	O
-	O
centre	O
trial	O
.	O

The	O
nit	B-GENE
-	I-GENE
3	I-GENE
gene	I-GENE
of	I-GENE
the	I-GENE
filamentous	I-GENE
fungus	I-GENE
Neurospora	I-GENE
crassa	I-GENE
encodes	O
nitrate	B-GENE
reductase	I-GENE
,	O
the	O
enzyme	O
which	O
catalyzes	O
the	O
first	O
step	O
in	O
nitrate	O
assimilation	O
.	O

Unfolding	O
can	O
be	O
described	O
by	O
a	O
two	O
-	O
state	O
process	O
since	O
a	O
ratio	O
of	O
delta	O
Hcalorimetric	O
to	O
delta	O
Hvan	O
'	O
t	O
Hoff	O
equals	O
0	O
.	O
96	O
.	O

This	O
motif	O
has	O
been	O
shown	O
to	O
mediate	O
protein	O
interactions	O
in	O
the	O
case	O
of	O
ankyrin	B-GENE
as	O
well	O
as	O
several	O
other	O
repeat	O
-	O
bearing	O
proteins	O
.	O

[	B-GENE
Ala85	I-GENE
]	I-GENE
Dk	I-GENE
(	I-GENE
69	I-GENE
-	I-GENE
85	I-GENE
)	I-GENE
retains	O
full	O
biological	O
activity	O
.	O

The	O
major	O
myosin	B-GENE
-	I-GENE
binding	I-GENE
domain	I-GENE
of	O
skeletal	B-GENE
muscle	I-GENE
MyBP	I-GENE
-	I-GENE
C	I-GENE
(	O
C	B-GENE
protein	I-GENE
)	O
resides	O
in	O
the	O
COOH	O
-	O
terminal	O
,	O
immunoglobulin	B-GENE
C2	B-GENE
motif	I-GENE
.	O

Our	O
results	O
indicate	O
that	O
periseizure	O
lipid	O
accumulation	O
is	O
related	O
to	O
cortical	O
oxygenation	O
.	O

We	O
conclude	O
that	O
the	O
QLMI	O
questionnaire	O
has	O
good	O
potential	O
as	O
an	O
instrument	O
for	O
assessing	O
QL	O
in	O
post	O
-	O
AMI	O
patients	O
and	O
that	O
it	O
can	O
be	O
successfully	O
self	O
-	O
administered	O
.	O

Most	O
smokers	O
would	O
prefer	O
to	O
quit	O
smoking	O
on	O
their	O
own	O
.	O

The	O
inhibitory	O
response	O
to	O
taps	O
is	O
essentially	O
a	O
protective	O
reflex	O
which	O
probably	O
serves	O
to	O
reduce	O
the	O
activity	O
of	O
the	O
jaw	O
-	O
closing	O
muscles	O
when	O
one	O
bites	O
unexpectedly	O
on	O
hard	O
objects	O
.	O

The	O
action	O
of	O
nef	B-GENE
was	O
specific	O
to	O
the	O
LTR	O
,	O
as	O
expression	O
of	O
nef	B-GENE
had	O
no	O
effect	O
on	O
the	O
activity	O
of	O
the	O
simian	O
virus	O
40	O
,	O
c	B-GENE
-	I-GENE
fms	I-GENE
,	O
urokinase	B-GENE
plasminogen	I-GENE
activator	I-GENE
,	O
or	O
type	B-GENE
5	I-GENE
acid	I-GENE
phosphatase	I-GENE
promoter	I-GENE
.	O
trans	O
-	O
activating	O
activity	O
was	O
also	O
manifested	O
by	O
a	O
frameshift	O
mutant	O
expressing	O
only	O
the	O
first	O
35	O
amino	O
acids	O
of	O
the	O
protein	O
.	O

The	O
product	O
of	O
the	O
vpr	B-GENE
open	I-GENE
reading	I-GENE
frame	I-GENE
of	I-GENE
human	I-GENE
immunodeficiency	I-GENE
virus	I-GENE
type	I-GENE
1	I-GENE
(	I-GENE
HIV	I-GENE
-	I-GENE
1	I-GENE
)	I-GENE
is	O
a	O
15	O
-	O
kDa	O
,	O
arginine	O
-	O
rich	O
protein	O
that	O
is	O
present	O
in	O
virions	O
in	O
molar	O
quantities	O
equivalent	O
to	O
that	O
of	O
Gag	B-GENE
.	O

The	O
recombinant	B-GENE
vaccinia	I-GENE
virus	I-GENE
-	I-GENE
expressed	I-GENE
mutant	I-GENE
P1	I-GENE
polyproteins	I-GENE
were	O
analyzed	O
for	O
proteolytic	O
processing	O
defects	O
in	O
cells	O
coinfected	O
with	O
a	O
recombinant	O
vaccinia	O
virus	O
(	O
VVP3	O
)	O
that	O
expresses	O
the	O
poliovirus	B-GENE
3CD	I-GENE
protease	I-GENE
and	O
for	O
processing	O
and	O
assembly	O
defects	O
by	O
using	O
a	O
trans	O
complementation	O
system	O
in	O
which	O
P1	B-GENE
-	O
expressing	O
recombinant	O
vaccinia	O
viruses	O
provide	O
capsid	B-GENE
precursor	I-GENE
to	O
a	O
defective	O
poliovirus	O
genome	O
that	O
does	O
not	O
express	O
functional	O
capsid	B-GENE
proteins	I-GENE
(	O
D	O
.	O

In	O
contrast	O
,	O
capsid	B-GENE
proteins	I-GENE
derived	O
from	O
the	O
P1	B-GENE
precursor	I-GENE
with	O
a	O
valine	O
substitution	O
at	O
the	O
amino	O
terminus	O
of	O
VP1	B-GENE
(	O
VP1	B-GENE
-	I-GENE
G001V	I-GENE
)	O
assembled	O
empty	O
capsid	O
particles	O
but	O
were	O
deficient	O
in	O
assembling	O
RNA	O
-	O
containing	O
virions	O
.	O

RESULTS	O
:	O
In	O
an	O
18	O
moth	O
period	O
and	O
out	O
of	O
a	O
total	O
of	O
284	O
positive	O
blood	O
cultures	O
(	O
154	O
significant	O
isolations	O
)	O
14	O
episodes	O
of	O
bacteremia	O
by	O
M	O
.	O
tuberculosis	O
were	O
studied	O
in	O
12	O
prison	O
patients	O
coinfected	O
by	O
the	O
human	O
immunodeficiency	O
virus	O
with	O
associated	O
severe	O
immunosuppression	O
(	O
mean	O
of	O
CD4	B-GENE
=	O
0	O
.	O
068	O
x	O
10	O
(	O
9	O
)	O
/	O
l	O
)	O
.	O

Acid	O
instilled	O
on	O
the	O
larynx	O
of	O
maturing	O
rabbits	O
resulted	O
in	O
significant	O
obstructive	O
,	O
central	O
,	O
and	O
mixed	O
apnea	O
.	O

By	O
using	O
total	O
-	O
protein	O
extracts	O
from	O
mycelia	O
grown	O
under	O
penicillin	O
producing	O
conditions	O
we	O
have	O
detected	O
a	O
DNA	O
-	O
binding	O
activity	O
that	O
specifically	O
shifts	O
a	O
promoter	O
fragment	O
located	O
between	O
-	O
654	O
and	O
-	O
455	O
(	O
relative	O
to	O
IPNS	B-GENE
tsp	I-GENE
)	O
.	O

Similar	O
synergistic	O
activation	O
was	O
observed	O
in	O
the	O
IL	B-GENE
-	I-GENE
8	I-GENE
promoter	I-GENE
,	O
which	O
also	O
contains	O
both	O
NF	B-GENE
-	I-GENE
IL6	I-GENE
and	O
NF	B-GENE
-	I-GENE
kappa	I-GENE
B	I-GENE
binding	I-GENE
sites	I-GENE
.	O

Notice	O
of	O
retraction	O
.	O

No	O
homology	O
was	O
found	O
between	O
the	O
36K	O
protein	O
and	O
known	O
structures	O
of	O
proteins	O
.	O

We	O
report	O
an	O
odd	O
case	O
of	O
marked	O
enlargement	O
of	O
suprapineal	O
recess	O
in	O
a	O
patient	O
with	O
triventricular	O
hydrocephalus	O
.	O

At	O
a	O
PaCO2	O
of	O
40	O
mmHg	O
,	O
baseline	O
brain	O
pHi	O
measured	O
7	O
.	O
03	O
+	O
/	O
-	O
0	O
.	O
04	O
,	O
while	O
regional	O
cortical	O
blood	O
flow	O
was	O
47	O
.	O
0	O
+	O
/	O
-	O
4	O
.	O
3	O
ml	O
.	O
100	O
g	O
-	O
1	O
.	O
min	O
-	O
1	O
.	O

CPAP	O
reduced	O
isotime	O
(	O
defined	O
as	O
the	O
last	O
common	O
minute	O
of	O
exercise	O
)	O
VO2	O
and	O
dyspnea	O
in	O
those	O
patients	O
with	O
more	O
severe	O
lung	O
disease	O
,	O
but	O
these	O
values	O
tended	O
to	O
increase	O
slightly	O
in	O
the	O
patients	O
with	O
only	O
mild	O
lung	O
disease	O
.	O

Effects	O
of	O
diltiazem	O
on	O
netilmicin	O
-	O
induced	O
nephrotoxicity	O
in	O
rabbits	O
.	O

Four	O
forms	O
of	O
salmonellosis	O
were	O
recognised	O
in	O
feedlots	O
and	O
during	O
transport	O
by	O
sea	O
:	O
septicaemic	O
,	O
and	O
acute	O
,	O
subacute	O
and	O
chronic	O
enteric	O
.	O

About	O
20	O
%	O
of	O
single	O
-	O
stranded	O
DNA	O
binding	O
was	O
observed	O
in	O
the	O
presence	O
of	O
MgdTDP	O
,	O
but	O
none	O
was	O
detectable	O
in	O
the	O
absence	O
of	O
nucleotides	O
.	O

Both	O
4	O
,	O
8	O
-	O
DiMeIQx	O
and	O
A	O
alpha	O
C	O
were	O
found	O
at	O
<	O
1	O
p	O
.	O
p	O
.	O
b	O
.	O

Three	O
cysteine	O
and	O
four	O
tryptophan	O
residues	O
,	O
previously	O
identified	O
as	O
conserved	O
amongst	O
nitrous	B-GENE
-	I-GENE
oxide	I-GENE
reductases	I-GENE
,	O
are	O
found	O
in	O
the	O
Paracoccus	O
enzyme	O
.	O

Recombinant	B-GENE
Leishmania	I-GENE
surface	I-GENE
glycoprotein	I-GENE
GP63	I-GENE
is	O
secreted	O
in	O
the	O
baculovirus	O
expression	O
system	O
as	O
a	O
latent	O
metalloproteinase	B-GENE
.	O

Delineating	O
the	O
molecular	O
basis	O
for	O
agonist	O
-	O
induced	O
destabilization	O
of	O
mRNA	O
of	O
G	B-GENE
-	I-GENE
protein	I-GENE
-	I-GENE
linked	I-GENE
receptors	I-GENE
that	O
contributes	O
to	O
receptor	O
down	O
-	O
regulation	O
is	O
fundamental	O
to	O
our	O
understanding	O
of	O
long	O
-	O
term	O
regulation	O
of	O
receptors	O
by	O
agonist	O
.	O

These	O
cells	O
produce	O
a	O
low	O
level	O
of	O
IL	B-GENE
-	I-GENE
5	I-GENE
when	O
stimulated	O
with	O
PMA	O
alone	O
;	O
however	O
,	O
N6	O
,	O
O2	O
-	O
dibutyryl	O
cAMP	O
(	O
Bt2cAMP	O
)	O
,	O
in	O
combination	O
with	O
PMA	O
,	O
augmented	O
by	O
more	O
than	O
tenfold	O
the	O
IL	B-GENE
-	I-GENE
5	I-GENE
production	O
at	O
the	O
mRNA	O
and	O
the	O
protein	O
levels	O
.	O

Hu	B-GENE
-	I-GENE
Met	I-GENE
-	I-GENE
1	I-GENE
mRNA	I-GENE
expression	O
in	O
a	O
small	O
number	O
of	O
human	O
T	O
cell	O
tumor	O
lines	O
did	O
not	O
correlate	O
with	O
any	O
particular	O
phenotype	O
or	O
stage	O
of	O
development	O
.	O

Partial	O
engorgement	O
was	O
higher	O
in	O
the	O
treatments	O
.	O

In	O
addition	O
to	O
the	O
protein	B-GENE
-	I-GENE
tyrosine	I-GENE
kinase	I-GENE
domain	I-GENE
,	O
p56lck	B-GENE
possesses	O
Src	B-GENE
homology	I-GENE
2	I-GENE
and	I-GENE
3	I-GENE
(	O
SH2	B-GENE
and	O
SH3	B-GENE
)	O
domains	O
as	O
well	O
as	O
a	O
unique	O
N	O
-	O
terminal	O
region	O
.	O

Strains	O
bearing	O
the	O
drs2	B-GENE
mutation	I-GENE
process	O
the	O
20S	B-GENE
precursor	I-GENE
of	O
the	O
mature	B-GENE
18S	I-GENE
rRNA	I-GENE
slowly	O
and	O
are	O
deficient	O
in	O
40S	B-GENE
ribosomal	I-GENE
subunits	I-GENE
.	O

Hepatitis	O
B	O
and	O
liver	O
transplantation	O
.	O

These	O
combined	O
observations	O
define	O
a	O
promoter	O
and	O
an	O
enhancer	O
for	O
the	O
chicken	B-GENE
L	I-GENE
-	I-GENE
CAM	I-GENE
gene	I-GENE
.	O

Clipping	O
resulted	O
in	O
a	O
serious	O
mislocalization	O
of	O
the	O
position	O
of	O
the	O
peak	O
of	O
the	O
epicortical	O
potential	O
field	O
.	O

The	O
duration	O
of	O
diabetes	O
mellitus	O
in	O
these	O
patients	O
was	O
from	O
5	O
months	O
to	O
6	O
years	O
,	O
and	O
in	O
all	O
patients	O
this	O
was	O
the	O
first	O
myocardial	O
infarction	O
.	O

The	O
247	O
-	O
kDa	O
complex	O
appears	O
to	O
contain	O
two	O
distinct	O
protein	O
-	O
DNA	O
complexes	O
of	O
approximately	O
232	O
and	O
256	O
kDa	O
and	O
represents	O
two	O
proteins	O
covalently	O
cross	O
-	O
linked	O
to	O
a	O
single	O
DRE	O
oligonucleotide	O
,	O
while	O
the	O
97	O
,	O
105	O
,	O
and	O
115	O
-	O
kDa	O
complexes	O
represent	O
single	O
protein	O
-	O
DRE	O
cross	O
-	O
links	O
.	O

The	O
promoter	O
and	O
upstream	O
region	O
of	O
the	O
Brassica	B-GENE
napus	I-GENE
2S	I-GENE
storage	I-GENE
protein	I-GENE
napA	I-GENE
gene	I-GENE
were	O
studied	O
to	O
identify	O
cis	O
-	O
acting	O
sequences	O
involved	O
in	O
developmental	O
seed	O
-	O
specific	O
expression	O
.	O

However	O
,	O
limited	O
comparisons	O
reveal	O
domains	O
in	O
the	O
NH2	O
and	O
COOH	O
termini	O
that	O
have	O
a	O
high	O
degree	O
of	O
similarity	O
suggesting	O
functional	O
conservation	O
.	O

Rinit	O
reflects	O
the	O
Newtonian	O
resistances	O
and	O
Rdiff	O
represents	O
the	O
viscoelastic	O
/	O
inhomogeneous	O
pressure	O
dissipations	O
in	O
the	O
system	O
.	O

We	O
have	O
explored	O
the	O
mechanism	O
of	O
action	O
of	O
the	O
fibronectin	B-GENE
splicing	I-GENE
enhancer	I-GENE
and	O
found	O
that	O
the	O
SE	O
element	O
is	O
required	O
for	O
efficient	O
assembly	O
of	O
early	O
splicing	O
complexes	O
,	O
allowing	O
a	O
more	O
efficient	O
interaction	O
of	O
the	O
U2	B-GENE
snRNP	I-GENE
with	O
branch	O
site	O
sequences	O
.	O

Inspection	O
of	O
enhancer	O
mutants	O
suggests	O
that	O
trans	O
-	O
activation	O
by	O
hLEF	B-GENE
/	O
GAL4	B-GENE
is	O
especially	O
dependent	O
on	O
TCF	B-GENE
-	I-GENE
2	I-GENE
,	O
a	O
distinct	O
T	O
-	O
cell	O
-	O
enriched	O
protein	O
that	O
binds	O
to	O
sequences	O
flanking	O
the	O
hLEF	B-GENE
-	I-GENE
binding	I-GENE
site	I-GENE
in	O
the	O
enhancer	O
.	O

We	O
conclude	O
that	O
sequences	O
outside	O
of	O
the	O
hLEF	B-GENE
HMG	I-GENE
box	I-GENE
mediate	O
cell	O
-	O
and	O
context	O
-	O
specific	O
activation	O
of	O
the	O
TCR	B-GENE
alpha	I-GENE
enhancer	I-GENE
and	O
may	O
facilitate	O
interactions	O
between	O
hLEF	B-GENE
and	O
other	O
T	O
-	O
cell	O
-	O
specific	O
factors	O
recruited	O
to	O
the	O
enhancer	O
.	O

A	O
cAMP	O
response	O
element	O
(	O
CRE	O
)	O
consensus	O
signal	O
was	O
identified	O
in	O
the	O
5	O
'	O
-	O
noncoding	O
region	O
.	O
cAMP	O
regulates	O
the	O
expression	O
of	O
Kv1	B-GENE
.	I-GENE
5	I-GENE
gene	I-GENE
in	O
a	O
cell	O
-	O
specific	O
manner	O
.	O

A	O
number	O
of	O
serological	O
tests	O
measuring	O
the	O
presence	O
of	O
Helicobacter	O
pylori	O
-	O
specific	O
serum	O
immunoglobulin	B-GENE
G	I-GENE
(	O
IgG	B-GENE
)	O
are	O
now	O
commercially	O
available	O
.	O

Using	O
a	O
series	O
of	O
mutant	B-GENE
T	I-GENE
antigens	I-GENE
expressed	O
by	O
recombinant	O
baculoviruses	O
in	O
Sf9	O
cells	O
,	O
we	O
find	O
that	O
the	O
origin	O
unwinding	O
activities	O
of	O
both	O
TS677	O
-	O
-	O
>	O
A	O
and	O
TS677	O
,	O
679	O
-	O
-	O
>	O
A	O
are	O
inhibited	O
by	O
the	O
T	B-GENE
-	I-GENE
antigen	I-GENE
kinase	I-GENE
,	O
as	O
is	O
wild	B-GENE
-	I-GENE
type	I-GENE
T	I-GENE
antigen	I-GENE
.	O

The	O
degree	O
of	O
hypoperfusion	O
was	O
slightly	O
related	O
to	O
decrease	O
in	O
FEV1	O
.	O
0	O
%	O
,	O
V25	O
and	O
PaO2	O
and	O
increase	O
in	O
circulating	O
blood	O
volume	O
and	O
peripheral	O
red	O
blood	O
cell	O
counts	O
.	O

In	O
the	O
present	O
study	O
,	O
lesions	O
of	O
the	O
OPT	O
complex	O
(	O
the	O
thalamic	O
source	O
of	O
afferents	O
to	O
IHA	O
and	O
HD	O
)	O
were	O
found	O
to	O
have	O
no	O
effect	O
on	O
color	O
-	O
reversal	O
learning	O
performance	O
.	O

The	O
fourth	O
dose	O
produced	O
favorable	O
results	O
(	O
66	O
.	O
7	O
%	O
)	O
in	O
individuals	O
with	O
HB	B-GENE
antibodies	I-GENE
between	O
10	O
and	O
100	O
IU	O
/	O
ml	O
and	O
unfavorable	O
ones	O
(	O
3	O
.	O
8	O
%	O
)	O
where	O
the	O
HB	B-GENE
antibodies	I-GENE
were	O
below	O
10	O
IU	O
/	O
ml	O
.	O

CONCLUSIONS	O
:	O
In	O
our	O
patients	O
and	O
within	O
the	O
range	O
of	O
treatment	O
variables	O
studied	O
,	O
age	O
,	O
Karnofsky	O
index	O
,	O
and	O
graft	O
-	O
versus	O
-	O
host	O
disease	O
are	O
the	O
most	O
important	O
factors	O
related	O
with	O
early	O
mortality	O
.	O

Nucleotide	O
sequence	O
analysis	O
of	O
the	O
HA	B-GENE
gene	I-GENE
in	O
these	O
two	O
mutants	O
confirmed	O
the	O
HA	B-GENE
-	I-GENE
phenotype	O
.	O

This	O
intron	O
occupies	O
a	O
conserved	O
position	O
corresponding	O
to	O
that	O
of	O
intron	O
1	O
in	O
the	O
transit	O
peptide	O
region	O
of	O
chloroplast	B-GENE
GAPDH	I-GENE
genes	I-GENE
(	O
GapA	B-GENE
and	O
GapB	B-GENE
)	O
of	O
higher	O
plants	O
.	O

The	O
drug	O
-	O
resistant	O
cell	O
lines	O
P388	O
/	O
ADR	O
/	O
3	O
and	O
P388	O
/	O
ADR	O
/	O
7	O
express	O
a	O
shortened	O
topo	B-GENE
II	I-GENE
alpha	I-GENE
mRNA	I-GENE
transcript	I-GENE
in	O
addition	O
to	O
the	O
native	O
transcript	O
present	O
in	O
the	O
drug	O
-	O
sensitive	O
P388	O
/	O
4	O
cell	O
line	O
.	O

Using	O
a	O
3	O
'	O
-	O
rapid	O
amplification	O
of	O
cDNA	O
ends	O
strategy	O
,	O
we	O
have	O
cloned	O
cDNAs	O
representing	O
the	O
3	O
'	O
-	O
termini	O
of	O
both	O
the	O
native	O
and	O
mutant	O
transcripts	O
from	O
both	O
P388	O
/	O
ADR	O
/	O
3	O
and	O
P388	O
/	O
ADR	O
/	O
7	O
cells	O
.	O

The	O
phi	B-GENE
AP3	I-GENE
factor	I-GENE
is	O
a	O
nuclear	O
phosphoprotein	O
;	O
the	O
extent	O
of	O
its	O
phosphorylation	O
is	O
regulated	O
during	O
the	O
cell	O
cycle	O
.	O

Similarly	O
,	O
the	O
N	O
-	O
terminal	O
cytoplasmic	O
domain	O
of	O
the	O
latent	B-GENE
membrane	I-GENE
protein	I-GENE
2A	I-GENE
(	O
LMP2A	B-GENE
)	O
of	O
the	O
Epstein	O
-	O
Barr	O
virus	O
(	O
EBV	O
)	O
contains	O
a	O
single	O
copy	O
of	O
the	O
Tyr	O
-	O
X	O
-	O
X	O
-	O
Leu	O
/	O
Ile	O
-	O
containing	O
motif	O
which	O
could	O
play	O
a	O
critical	O
role	O
in	O
B	O
cell	O
transformation	O
.	O

The	O
functional	O
homology	O
of	O
Cwg2	B-GENE
with	O
Cdc43	B-GENE
,	O
which	O
has	O
been	O
implicated	O
in	O
the	O
control	O
of	O
cell	O
polarity	O
,	O
suggests	O
a	O
link	O
between	O
two	O
morphogenetic	O
events	O
such	O
as	O
establishment	O
of	O
cell	O
polarity	O
and	O
cell	O
wall	O
biosynthesis	O
.	O

Molecular	O
cloning	O
of	O
a	O
P	B-GENE
-	I-GENE
type	I-GENE
ATPase	I-GENE
gene	I-GENE
from	O
the	O
cyanobacterium	O
Synechocystis	O
sp	O
.	O

The	O
cloning	O
of	O
PTR2	B-GENE
represents	O
the	O
first	O
example	O
of	O
the	O
molecular	O
genetic	O
characterization	O
of	O
a	O
eucaryotic	O
peptide	O
transport	O
gene	O
.	O

To	O
examine	O
the	O
biochemical	O
basis	O
of	O
the	O
end	O
joining	O
,	O
nuclear	O
extracts	O
were	O
prepared	O
from	O
a	O
wide	O
variety	O
of	O
mammalian	O
cell	O
lines	O
and	O
tested	O
for	O
their	O
ability	O
to	O
join	O
test	O
plasmid	O
substrates	O
.	O

These	O
data	O
indicate	O
that	O
the	O
largest	O
subunit	O
of	O
RNA	B-GENE
polymerase	I-GENE
II	I-GENE
and	O
TFIIB	B-GENE
are	O
important	O
determinants	O
of	O
transcription	O
start	O
site	O
selection	O
in	O
S	O
.	O
cerevisiae	O
and	O
suggest	O
that	O
this	O
function	O
might	O
be	O
conferred	O
by	O
interaction	O
between	O
these	O
two	O
proteins	O
.	O

Recombinant	O
expression	O
of	O
a	O
chimeric	O
EGFR	B-GENE
/	O
ErbB	B-GENE
-	I-GENE
3	I-GENE
receptor	I-GENE
in	O
NIH	O
3T3	O
fibroblasts	O
allowed	O
us	O
to	O
investigate	O
cytoplasmic	O
events	O
associated	O
with	O
ErbB	B-GENE
-	I-GENE
3	I-GENE
signal	O
transduction	O
upon	O
ligand	O
activation	O
.	O

Analysis	O
of	O
strains	O
harboring	O
an	O
mds1	B-GENE
null	I-GENE
mutation	I-GENE
demonstrates	O
that	O
MDS1	B-GENE
is	O
not	O
essential	O
during	O
normal	O
vegetative	O
growth	O
but	O
appears	O
to	O
be	O
required	O
for	O
meiosis	O
.	O

Val	O
-	O
-	O
>	O
Ala	O
mutations	O
selectively	O
alter	O
helix	O
-	O
helix	O
packing	O
in	O
the	O
transmembrane	O
segment	O
of	O
phage	B-GENE
M13	I-GENE
coat	I-GENE
protein	I-GENE
.	O

Strategic	O
change	O
in	O
the	O
NHS	O
.	O

A	O
much	O
less	O
expensive	O
solution	O
than	O
UW	O
,	O
containing	O
only	O
K	O
(	O
+	O
)	O
-	O
lactobionate	O
,	O
KH2PO4	O
,	O
MgSO4	O
and	O
raffinose	O
,	O
can	O
be	O
used	O
successfully	O
for	O
preservation	O
of	O
rat	O
hepatocytes	O
for	O
24	O
hr	O
for	O
drug	O
transport	O
studies	O
.	O

Human	B-GENE
bcl3	I-GENE
protein	I-GENE
specifically	O
displaces	O
(	B-GENE
p50	I-GENE
)	I-GENE
2	I-GENE
-	I-GENE
DNA	I-GENE
complexes	I-GENE
.	O

In	O
vitro	O
translation	O
experiments	O
show	O
that	O
human	O
cDNA	O
derived	O
RNA	O
translates	O
into	O
a	O
protein	O
with	O
a	O
mobility	O
of	O
44	O
-	O
46	O
kD	O
on	O
SDS	O
polyacrylamide	O
gels	O
.	O

After	O
peripheral	O
administration	O
of	O
both	O
CRF	B-GENE
and	O
TRH	B-GENE
,	O
ACTH	B-GENE
levels	O
were	O
significantly	O
higher	O
on	O
the	O
tumor	O
side	O
in	O
all	O
patients	O
.	O

A	O
sequence	O
homology	O
analysis	O
between	O
human	B-GENE
nm23	I-GENE
-	I-GENE
H1	I-GENE
and	O
the	O
homolog	O
gene	O
of	O
the	O
rat	O
(	O
NDP	B-GENE
-	I-GENE
K	I-GENE
beta	I-GENE
)	O
shows	O
that	O
exon	O
-	O
intron	O
boundaries	O
are	O
well	O
conserved	O
between	O
these	O
two	O
species	O
.	O

A	O
favourable	O
response	O
was	O
achieved	O
with	O
a	O
combination	O
of	O
amphotericin	O
B	O
and	O
cotrimoxazole	O
.	O

Response	O
durations	O
were	O
short	O
.	O

RESULTS	O
:	O
At	O
the	O
beginning	O
of	O
the	O
QA	O
/	O
QI	O
process	O
,	O
monitoring	O
of	O
blood	O
administration	O
practices	O
revealed	O
that	O
a	O
variance	O
from	O
institutional	O
blood	O
administration	O
policy	O
occurred	O
during	O
50	O
percent	O
of	O
blood	O
and	O
component	O
transfusions	O
.	O

Drug	O
effect	O
,	O
measured	O
as	O
postural	O
sway	O
,	O
was	O
also	O
similar	O
in	O
the	O
patients	O
with	O
cirrhosis	O
and	O
control	O
subjects	O
;	O
therefore	O
the	O
ratio	O
of	O
effect	O
area	O
under	O
the	O
curve	O
to	O
concentration	O
area	O
under	O
the	O
curve	O
,	O
a	O
measure	O
of	O
sensitivity	O
,	O
did	O
not	O
differ	O
significantly	O
between	O
the	O
patients	O
with	O
cirrhosis	O
and	O
the	O
control	O
subjects	O
.	O

We	O
present	O
evidence	O
that	O
YY1	B-GENE
,	O
a	O
ubiquitously	O
expressed	O
DNA	O
-	O
binding	O
protein	O
,	O
regulates	O
the	O
activity	O
of	O
the	O
c	B-GENE
-	I-GENE
fos	I-GENE
promoter	I-GENE
primarily	O
through	O
an	O
effect	O
on	O
DNA	O
structure	O
.	O

In	O
a	O
retrospective	O
analysis	O
of	O
first	O
-	O
time	O
total	O
colonoscopies	O
in	O
685	O
patients	O
,	O
we	O
investigated	O
the	O
relationship	O
between	O
hyperplastic	O
and	O
adenomatous	O
polyps	O
.	O

The	O
rate	O
of	O
decrement	O
in	O
DPOAE	O
amplitude	O
over	O
a	O
prescribed	O
time	O
period	O
was	O
utilized	O
as	O
a	O
measure	O
of	O
susceptibility	O
to	O
the	O
acoustic	O
trauma	O
.	O

Effect	O
of	O
single	O
base	O
substitutions	O
at	O
glycine	O
-	O
870	O
codon	O
of	O
gramicidin	B-GENE
S	I-GENE
synthetase	I-GENE
2	I-GENE
gene	I-GENE
on	O
proline	O
activation	O
.	O

The	O
predicted	O
Pay4p	B-GENE
sequence	I-GENE
contains	O
two	O
putative	O
ATP	O
-	O
binding	O
domains	O
and	O
shows	O
structural	O
relationships	O
to	O
other	O
potential	O
ATP	B-GENE
-	I-GENE
binding	I-GENE
proteins	I-GENE
involved	O
in	O
biological	O
processes	O
as	O
diverse	O
as	O
peroxisome	O
biogenesis	O
,	O
vesicle	O
-	O
mediated	O
protein	O
transport	O
,	O
cell	O
cycle	O
control	O
,	O
and	O
transcriptional	O
regulation	O
.	O

The	O
results	O
show	O
that	O
the	O
structure	O
of	O
the	O
decorin	B-GENE
gene	I-GENE
promoter	I-GENE
is	O
different	O
from	O
that	O
of	O
any	O
other	O
proteoglycan	O
promoter	O
characterized	O
so	O
far	O
and	O
indicate	O
that	O
the	O
pur	O
/	O
pyr	O
segment	O
plays	O
a	O
role	O
in	O
the	O
regulation	O
of	O
gene	O
transcription	O
.	O

The	O
kinase	O
inhibitor	O
staurosporine	O
(	O
1	O
microM	O
)	O
blocks	O
LPA	O
-	O
induced	O
,	O
but	O
not	O
epidermal	O
growth	O
factor	O
-	O
induced	O
,	O
activation	O
of	O
p21ras	B-GENE
and	O
MAP	B-GENE
kinase	I-GENE
,	O
consistent	O
with	O
an	O
intermediate	O
protein	O
kinase	O
linking	O
the	O
LPA	B-GENE
receptor	I-GENE
to	O
p21ras	B-GENE
activation	O
.	O

267	O
,	O
4870	O
-	O
4877	O
)	O
)	O
indicates	O
an	O
overall	O
identity	O
of	O
58	O
and	O
56	O
%	O
,	O
respectively	O
,	O
with	O
a	O
91	O
and	O
92	O
%	O
identity	O
in	O
the	O
highly	O
conserved	O
transmembrane	O
and	O
cytoplasmic	O
domains	O
.	O

S	O
.	O
,	O
K	O
.	O

The	O
survival	O
rate	O
at	O
forty	O
months	O
in	O
15	O
patients	O
with	O
N2	O
disease	O
who	O
underwent	O
R2b	O
operation	O
was	O
51	O
%	O
.	O

Mothers	O
with	O
severe	O
anatomical	O
abnormalities	O
,	O
who	O
are	O
HIV	O
positive	O
,	O
have	O
active	O
TB	O
or	O
whose	O
children	O
have	O
inherited	O
mono	O
-	O
or	O
disaccharide	O
intolerances	O
should	O
not	O
breastfeed	O
.	O

G	O
.	O

The	O
psaD	B-GENE
,	O
psaF	B-GENE
,	O
psaH	B-GENE
,	O
and	O
psaL	B-GENE
products	I-GENE
have	O
two	O
isoforms	O
each	O
that	O
are	O
distinguished	O
by	O
different	O
mobilities	O
in	O
polyacrylamide	O
gel	O
electrophoresis	O
,	O
and	O
the	O
psaE	B-GENE
product	I-GENE
has	O
four	O
isoforms	O
.	O

When	O
Hy	O
-	O
Vac	O
SPF	O
type	O
V	O
embryos	O
were	O
exposed	O
to	O
either	O
0	O
.	O
20	O
ml	O
50	O
%	O
ethanol	O
in	O
CRS	O
or	O
to	O
0	O
.	O
20	O
ml	O
CRS	O
(	O
controls	O
)	O
,	O
ethanol	O
-	O
treated	O
embryos	O
showed	O
a	O
VSD	O
incidence	O
of	O
34	O
.	O
1	O
%	O
compared	O
with	O
a	O
3	O
.	O
6	O
%	O
incidence	O
in	O
the	O
controls	O
(	O
P	O
=	O
0	O
.	O
0017	O
)	O
.	O

Peripheral	O
vitreochorioretinal	O
dystrophies	O
in	O
myopia	O
patients	O

The	O
secondary	O
,	O
but	O
not	O
the	O
primary	O
,	O
antibody	O
responses	O
of	O
male	O
C57Bl	O
/	O
6	O
mice	O
were	O
higher	O
among	O
mice	O
housed	O
alone	O
compared	O
to	O
mice	O
housed	O
in	O
groups	O
;	O
differences	O
were	O
observed	O
for	O
both	O
IgM	B-GENE
and	O
IgG	B-GENE
anti	I-GENE
-	I-GENE
KLH	I-GENE
antibodies	I-GENE
.	O

However	O
,	O
a	O
surprisingly	O
high	O
degree	O
of	O
conservation	O
of	O
intron	O
sequences	O
was	O
observed	O
between	O
both	O
species	O
.	O

Interleukin	B-GENE
-	I-GENE
6	I-GENE
may	O
possibly	O
potentiate	O
metastasis	O
of	O
cardiac	O
myxoma	O
.	O

Other	O
parameters	O
of	O
iron	O
metabolism	O
,	O
including	O
ferritin	B-GENE
,	O
were	O
not	O
found	O
to	O
contribute	O
to	O
the	O
risk	O
.	O

Responses	O
to	O
the	O
Plowright	O
Rinderpest	O
vaccine	O
by	O
43	O
calves	O
and	O
70	O
adult	O
cattle	O
in	O
Uganda	O
in	O
1990	O
,	O
through	O
the	O
production	O
of	O
IgG	B-GENE
antibodies	I-GENE
,	O
were	O
monitored	O
for	O
4	O
weeks	O
using	O
the	O
ELISA	O
assay	O
.	O

Tumours	O
of	O
the	O
cavum	O
oris	O
and	O
oropharynx	O
of	O
T1	O
-	O
stage	O
are	O
possible	O
only	O
in	O
1	O
of	O
3	O
cases	O
.	O

Thomas	O
'	O
Hospital	O
solution	O
(	O
with	O
95	O
%	O
O2	O
:	O
5	O
%	O
CO2	O
)	O
can	O
meet	O
the	O
metabolic	O
demand	O
of	O
the	O
ischaemic	O
myocardium	O
and	O
thus	O
increase	O
the	O
safe	O
duration	O
of	O
cardiac	O
arrest	O
.	O

Plasma	O
,	O
LDL	B-GENE
and	O
liver	O
cholesterol	O
concentrations	O
were	O
higher	O
in	O
the	O
hyperlipidemic	O
control	O
than	O
the	O
nonhyperlipidemic	O
control	O
and	O
lower	O
in	O
the	O
groups	O
fed	O
diets	O
containing	O
pectin	B-GENE
or	O
prune	O
fiber	O
than	O
in	O
the	O
hyperlipidemic	O
control	O
group	O
.	O

Routine	O
psychometric	O
screening	O
of	O
IHD	O
patients	O
may	O
provide	O
a	O
cost	O
-	O
effective	O
means	O
of	O
alerting	O
cardiologists	O
and	O
internists	O
to	O
the	O
relatively	O
high	O
levels	O
of	O
distress	O
among	O
their	O
patients	O
.	O

Employing	O
this	O
sequence	O
information	O
from	O
c11	O
/	O
1	O
,	O
the	O
c11	O
/	O
1	O
-	O
specific	O
cDNA	O
was	O
generated	O
from	O
poly	O
(	O
A	O
)	O
+	O
RNA	O
of	O
bovine	O
PMNLs	O
by	O
reverse	O
transcription	O
and	O
a	O
combination	O
of	O
polymerase	O
chain	O
reaction	O
(	O
PCR	O
)	O
methods	O
.	O

The	O
deduced	O
amino	O
acid	O
sequence	O
of	O
the	O
mouse	B-GENE
HO	I-GENE
-	I-GENE
1	I-GENE
gene	I-GENE
is	O
identical	O
to	O
that	O
of	O
p32	B-GENE
,	O
initially	O
identified	O
as	O
a	O
stress	O
-	O
induced	O
protein	O
in	O
mouse	O
BALBc	O
/	O
3T3	O
cells	O
.	O

Using	O
a	O
polymerase	O
chain	O
reaction	O
-	O
based	O
approach	O
,	O
we	O
cloned	O
a	O
150	O
-	O
base	O
pair	O
fragment	O
of	O
a	O
new	O
sialymotif	O
from	O
human	O
placenta	O
mRNA	O
,	O
which	O
was	O
then	O
used	O
as	O
a	O
probe	O
to	O
clone	O
the	O
complete	O
coding	O
sequence	O
of	O
the	O
corresponding	O
gene	O
from	O
a	O
cDNA	O
library	O
.	O

The	O
structural	O
analysis	O
also	O
demonstrated	O
that	O
the	O
heterogeneity	O
of	O
the	O
HDC	B-GENE
mRNA	I-GENE
is	O
caused	O
by	O
an	O
insertion	O
of	O
the	O
seventh	O
intron	O
sequence	O
and	O
alternative	O
use	O
of	O
the	O
splicing	O
acceptor	O
site	O
at	O
the	O
12th	O
exon	O
.	O

A	O
complementary	O
DNA	O
was	O
isolated	O
from	O
Caenorhabditis	O
elegans	O
that	O
encoded	O
a	O
polypeptide	O
of	O
1438	O
amino	O
acid	O
residues	O
,	O
CeGAP	B-GENE
,	O
which	O
contains	O
a	O
domain	O
with	O
sequence	O
similarity	O
to	O
the	O
COOH	B-GENE
-	I-GENE
terminal	I-GENE
segment	I-GENE
(	I-GENE
GTPase	I-GENE
-	I-GENE
activating	I-GENE
protein	I-GENE
region	I-GENE
)	I-GENE
of	O
Bcr	B-GENE
and	O
other	O
known	O
GTPase	B-GENE
-	I-GENE
activating	I-GENE
proteins	I-GENE
of	O
the	O
Rho	B-GENE
subfamily	I-GENE
.	O

Additional	O
exonuclease	B-GENE
III	I-GENE
protection	O
was	O
observed	O
beyond	O
the	O
core	O
region	O
on	O
both	O
the	O
5	O
'	O
and	O
3	O
'	O
sides	O
,	O
suggesting	O
that	O
E1	B-GENE
interacted	O
with	O
more	O
distal	O
sequences	O
as	O
well	O
.	O

Repression	O
is	O
alleviated	O
when	O
the	O
two	O
(	O
for	O
E2	B-GENE
)	O
or	O
three	O
(	O
for	O
E2	B-GENE
-	I-GENE
C	I-GENE
)	O
promoter	O
-	O
proximal	O
copies	O
of	O
E2	B-GENE
-	O
RS	O
are	O
mutated	O
.	O

A	O
mutant	O
in	O
the	O
AAV	O
terminal	O
resolution	O
site	O
(	O
trs	O
)	O
was	O
defective	O
for	O
DNA	O
replication	O
in	O
the	O
in	O
vitro	O
assay	O
.	O

The	O
results	O
indicate	O
that	O
rep	B-GENE
strongly	O
enhances	O
the	O
function	O
of	O
negative	O
regulatory	O
elements	O
of	O
the	O
LTR	O
.	O

The	O
Oct	B-GENE
-	I-GENE
3	I-GENE
/	I-GENE
4	I-GENE
gene	I-GENE
product	I-GENE
,	O
which	O
belongs	O
to	O
the	O
POU	B-GENE
family	I-GENE
of	I-GENE
transcription	I-GENE
factors	I-GENE
,	O
is	O
a	O
good	O
candidate	O
for	O
regulating	O
initial	O
differentiation	O
decisions	O
.	O

Using	O
site	O
-	O
directed	O
mutagenesis	O
,	O
we	O
show	O
that	O
the	O
RAREoct	B-GENE
contributes	O
to	O
the	O
transcriptional	O
activation	O
of	O
Oct	B-GENE
-	I-GENE
3	I-GENE
/	I-GENE
4	I-GENE
promoter	I-GENE
in	O
P19	O
cells	O
and	O
,	O
most	O
interestingly	O
,	O
mediates	O
the	O
RA	O
-	O
induced	O
repression	O
in	O
RA	O
-	O
differentiated	O
EC	O
cells	O
.	O

176	O
:	O
787	O
-	O
792	O
,	O
1992	O
;	O
M	O
.	O

Furthermore	O
,	O
the	O
negative	O
transcriptional	O
effect	O
of	O
COUP	B-GENE
-	I-GENE
TFs	I-GENE
is	O
dominant	O
over	O
the	O
activating	O
effect	O
of	O
the	O
Oct4	B-GENE
embryonic	I-GENE
stem	I-GENE
cell	I-GENE
-	I-GENE
specific	I-GENE
enhancer	I-GENE
.	O

Analysis	O
of	O
mig	B-GENE
/	O
CAT	B-GENE
chimeric	O
constructs	O
transiently	O
transfected	O
into	O
the	O
RAW	O
264	O
.	O
7	O
mouse	O
monocytic	O
cell	O
line	O
revealed	O
a	O
unique	O
IFN	B-GENE
-	I-GENE
gamma	I-GENE
-	I-GENE
responsive	I-GENE
element	I-GENE
(	O
gamma	B-GENE
RE	I-GENE
-	I-GENE
1	I-GENE
)	O
.	O

When	O
expressed	O
alone	O
in	O
test	O
cells	O
,	O
Atr	B-GENE
-	I-GENE
I	I-GENE
is	O
unable	O
to	O
bind	O
TGF	B-GENE
-	I-GENE
beta	I-GENE
,	O
activin	B-GENE
,	O
or	O
bone	B-GENE
morphogenetic	I-GENE
protein	I-GENE
2	I-GENE
.	O

Therefore	O
,	O
Mxi1	B-GENE
and	O
Mad	B-GENE
might	O
antagonize	O
Myc	B-GENE
function	O
and	O
are	O
candidate	O
tumor	O
suppressor	O
genes	O
.	O

To	O
our	O
knowledge	O
,	O
type	O
IV	O
renal	O
tubular	O
acidosis	O
has	O
not	O
been	O
reported	O
previously	O
in	O
association	O
with	O
Alport	O
'	O
s	O
syndrome	O
in	O
an	O
adult	O
patient	O
.	O

A	O
cDNA	O
clone	O
was	O
isolated	O
from	O
a	O
chicken	O
embryo	O
cDNA	O
library	O
employing	O
a	O
PCR	O
-	O
generated	O
radiolabeled	O
probe	O
specific	O
for	O
the	O
U3	B-GENE
region	I-GENE
of	O
the	O
Rous	B-GENE
sarcoma	I-GENE
virus	I-GENE
LTR	I-GENE
.	O

Two	O
basic	O
patterns	O
of	O
locomotor	O
behavior	O
and	O
corresponding	O
torso	O
morphology	O
exist	O
among	O
extant	O
anthropoids	O
.	O

Animal	O
age	O
and	O
sex	O
had	O
no	O
significant	O
effects	O
on	O
CSF	O
composition	O
,	O
but	O
serum	O
IgG	B-GENE
concentration	O
increased	O
with	O
age	O
.	O

Fast	O
continuous	O
expansion	O
.	O

A	O
randomized	O
,	O
multicenter	O
study	O
comparing	O
the	O
efficacy	O
and	O
tolerability	O
of	O
tropisetron	O
,	O
a	O
new	O
5	B-GENE
-	I-GENE
HT3	I-GENE
receptor	I-GENE
antagonist	O
,	O
with	O
a	O
metoclopramide	O
-	O
containing	O
antiemetic	O
cocktail	O
in	O
the	O
prevention	O
of	O
cisplatin	O
-	O
induced	O
emesis	O
.	O

Each	O
repeat	O
consists	O
of	O
12	O
nt	O
,	O
coding	O
for	O
the	O
reiterated	O
sequence	O
,	O
K	O
/	O
NPAG	O
.	O

BACKGROUND	O
:	O
To	O
determine	O
the	O
predictors	O
of	O
desipramine	O
-	O
refractory	O
depression	O
,	O
the	O
authors	O
examined	O
the	O
outcome	O
in	O
patients	O
with	O
major	O
depression	O
who	O
were	O
admitted	O
to	O
a	O
general	O
hospital	O
and	O
treated	O
with	O
desipramine	O
adjusted	O
to	O
an	O
adequate	O
blood	O
level	O
.	O

Analysis	O
of	O
the	O
intact	O
hGH	B-GENE
gene	I-GENE
or	O
hGH	B-GENE
5	I-GENE
'	I-GENE
-	I-GENE
flanking	I-GENE
DNA	I-GENE
(	I-GENE
5	I-GENE
'	I-GENE
-	I-GENE
FR	I-GENE
)	I-GENE
coupled	O
to	O
the	O
hGh	B-GENE
cDNA	I-GENE
or	O
chloramphenicol	B-GENE
acetyltransferase	I-GENE
or	O
luciferase	B-GENE
genes	I-GENE
,	O
indicated	O
that	O
cAMP	O
primarily	O
stimulated	O
hGH	B-GENE
promoter	I-GENE
activity	O
.	O

The	O
predicted	O
amino	O
acid	O
sequence	O
of	O
the	O
SAP	B-GENE
-	I-GENE
1	I-GENE
cDNA	I-GENE
showed	O
that	O
mature	B-GENE
SAP	I-GENE
-	I-GENE
1	I-GENE
consisted	O
of	O
1093	O
amino	O
acids	O
and	O
a	O
transmembrane	B-GENE
-	I-GENE
type	I-GENE
PTP	I-GENE
,	O
which	O
possessed	O
a	O
single	O
PTP	B-GENE
-	I-GENE
conserved	I-GENE
domain	I-GENE
in	O
the	O
cytoplasmic	O
region	O
.	O

Several	O
features	O
of	O
10	O
.	O
24	O
.	O
6	O
cells	O
suggest	O
that	O
the	O
mutation	O
disrupts	O
normal	O
intracellular	O
formation	O
of	O
peptide	B-GENE
/	I-GENE
DR	I-GENE
complexes	I-GENE
.	O

This	O
distribution	O
parallels	O
that	O
of	O
the	O
neurotransmitters	O
glutamate	O
and	O
aspartate	O
;	O
however	O
,	O
neither	O
of	O
these	O
excitatory	O
amino	O
acids	O
is	O
a	O
substrate	O
for	O
transport	O
.	O

The	O
Harleco	O
apparatus	O
is	O
a	O
simple	O
,	O
useful	O
,	O
cost	O
-	O
effective	O
adjunct	O
to	O
the	O
diagnosis	O
and	O
treatment	O
of	O
this	O
life	O
-	O
threatening	O
condition	O
.	O

Co	O
-	O
transfection	O
of	O
expression	O
vectors	O
for	O
CCAAT	B-GENE
/	I-GENE
enhancer	I-GENE
binding	I-GENE
protein	I-GENE
(	I-GENE
C	I-GENE
/	I-GENE
EBP	I-GENE
)	I-GENE
alpha	I-GENE
and	O
C	B-GENE
/	I-GENE
EBP	I-GENE
beta	I-GENE
trans	O
-	O
activated	O
the	O
rat	B-GENE
uncoupling	I-GENE
protein	I-GENE
gene	I-GENE
promoter	I-GENE
due	O
to	O
sequences	O
in	O
the	O
5	O
'	O
proximal	O
region	O
.	O

It	O
was	O
not	O
possible	O
to	O
study	O
the	O
basis	O
for	O
tissue	O
-	O
specific	O
expression	O
of	O
this	O
gene	O
,	O
because	O
the	O
beta	B-GENE
3	I-GENE
gene	I-GENE
promoter	I-GENE
had	O
not	O
been	O
isolated	O
previously	O
.	O

Isolation	O
and	O
characterization	O
of	O
a	O
TATA	O
-	O
less	O
promoter	O
for	O
the	O
human	B-GENE
beta	I-GENE
3	I-GENE
integrin	I-GENE
gene	I-GENE
.	O

Subretinal	O
fluid	O
was	O
punctured	O
on	O
the	O
poorer	O
eye	O
in	O
19	O
eyes	O
(	O
52	O
.	O
7	O
%	O
)	O
and	O
on	O
the	O
better	O
eye	O
in	O
7	O
eyes	O
(	O
19	O
.	O
4	O
%	O
)	O
.	O

These	O
data	O
indicate	O
that	O
activation	O
of	O
these	O
enzymes	O
is	O
not	O
sufficient	O
for	O
the	O
acute	O
stimulation	O
of	O
glucose	O
transport	O
.	O

The	O
inserted	O
region	O
,	O
which	O
represents	O
an	O
intron	O
in	O
brain	O
and	O
muscle	O
,	O
is	O
expressed	O
in	O
the	O
tumor	O
cell	O
lines	O
either	O
as	O
a	O
"	O
readthrough	O
"	O
form	O
or	O
with	O
78	O
residues	O
deleted	O
from	O
its	O
5	O
'	O
end	O
.	O

Concordance	O
of	O
IBDQ	O
scores	O
was	O
tested	O
in	O
280	O
stable	O
subjects	O
.	O

Regression	O
line	O
slopes	O
of	O
IBDQ	O
scores	O
were	O
significantly	O
different	O
in	O
patients	O
who	O
deteriorated	O
from	O
those	O
who	O
remained	O
stable	O
(	O
[	O
b	O
]	O
<	O
0	O
.	O
15	O
;	O
P	O
<	O
0	O
.	O
0001	O
)	O
.	O

Inhibition	O
of	O
erythromycin	O
synthesis	O
by	O
disruption	O
of	O
malonyl	B-GENE
-	I-GENE
coenzyme	I-GENE
A	I-GENE
decarboxylase	I-GENE
gene	I-GENE
eryM	B-GENE
in	O
Saccharopolyspora	O
erythraea	O
.	O

This	O
region	O
is	O
required	O
for	O
activation	O
of	O
DNA	O
binding	O
of	O
MyoD	B-GENE
and	O
E12	B-GENE
homodimers	I-GENE
and	O
E12	B-GENE
/	O
MyoD	B-GENE
heterodimers	O
.	O

Site	O
-	O
directed	O
mutagenesis	O
of	O
the	O
traI	B-GENE
structural	I-GENE
gene	I-GENE
and	O
application	O
of	O
purified	O
mutant	O
TraI	B-GENE
proteins	I-GENE
for	O
in	O
vitro	O
assays	O
served	O
to	O
evaluate	O
the	O
functional	O
importance	O
of	O
conserved	O
amino	O
acid	O
residues	O
.	O

Concerted	O
action	O
of	O
three	O
distinct	O
domains	O
in	O
the	O
DNA	O
cleaving	O
-	O
joining	O
reaction	O
catalyzed	O
by	O
relaxase	B-GENE
(	O
TraI	B-GENE
)	O
of	O
conjugative	O
plasmid	O
RP4	O
.	O

The	O
COOH	O
-	O
terminal	O
46	O
codons	O
of	O
slyD	B-GENE
encode	O
a	O
remarkable	O
histidine	O
-	O
rich	O
peptide	O
sequence	O
which	O
is	O
at	O
least	O
partly	O
dispensable	O
for	O
slyD	B-GENE
function	O
in	O
E	B-GENE
-	O
mediated	O
lysis	O
.	O

We	O
studied	O
GSH	O
-	O
Px	O
enzyme	O
activity	O
in	O
serum	O
after	O
acute	O
myocardial	O
infarction	O
(	O
AMI	O
)	O
and	O
unstable	O
angina	O
pectoris	O
(	O
UAP	O
)	O
.	O

The	O
HGF	B-GENE
-	O
induced	O
cell	O
motility	O
was	O
mimicked	O
by	O
12	O
-	O
0	O
-	O
tetradecanoyl	O
-	O
phorbol	O
-	O
13	O
-	O
acetate	O
,	O
a	O
protein	B-GENE
kinase	I-GENE
C	I-GENE
-	O
activating	O
phorbol	O
ester	O
,	O
but	O
not	O
by	O
Ca2	O
+	O
ionophore	O
.	O

In	O
addition	O
,	O
lexical	O
priming	O
was	O
examined	O
by	O
presenting	O
an	O
identity	O
prime	O
earlier	O
in	O
the	O
text	O
.	O

METHODS	O
:	O
Forty	O
-	O
nine	O
cases	O
with	O
intrahepatic	O
multiple	O
nodules	O
of	O
HCC	O
,	O
by	O
gross	O
examination	O
,	O
among	O
184	O
consecutive	O
resected	O
HCCs	O
were	O
examined	O
clinicopathologically	O
.	O

In	O
the	O
present	O
report	O
,	O
66	O
hemochromatosis	O
families	O
yielding	O
151	O
hemochromatosis	O
chromosomes	O
and	O
182	O
normal	O
chromosomes	O
were	O
RFLP	O
-	O
typed	O
with	O
a	O
battery	O
of	O
probes	O
,	O
including	O
two	O
newly	O
derived	O
polymorphic	O
markers	O
from	O
the	O
6	O
.	O
7	O
and	O
HLA	B-GENE
-	I-GENE
F	I-GENE
loci	I-GENE
located	O
150	O
and	O
250	O
kb	O
telomeric	O
to	O
HLA	B-GENE
-	I-GENE
A	I-GENE
,	O
respectively	O
.	O

Pneumothorax	O
during	O
laparoscopic	O
dissection	O
of	O
the	O
diaphragmatic	O
hiatus	O
.	O

Different	O
cortical	O
malformations	O
were	O
produced	O
in	O
rats	O
by	O
a	O
single	O
dose	O
of	O
X	O
-	O
rays	O
(	O
200	O
cGy	O
)	O
given	O
on	O
different	O
days	O
during	O
gestation	O
.	O

T2	O
cancers	O
should	O
not	O
be	O
excluded	O
from	O
the	O
benefit	O
of	O
preoperative	O
irradiation	O
.	O

IFN	B-GENE
alpha	I-GENE
and	O
IFN	B-GENE
gamma	I-GENE
inducibility	O
is	O
mediated	O
by	O
a	O
single	O
element	O
:	O
a	O
high	O
affinity	O
,	O
nearly	O
palindromic	O
version	O
of	O
the	O
IFN	B-GENE
gamma	I-GENE
activation	I-GENE
site	I-GENE
(	O
GAS	B-GENE
)	O
.	O

Twenty	O
-	O
three	O
sequence	O
-	O
tagged	O
sites	O
(	O
STSs	O
)	O
were	O
mapped	O
within	O
the	O
contig	O
,	O
a	O
density	O
of	O
approximately	O
1	O
per	O
200	O
kb	O
.	O

In	O
this	O
paper	O
,	O
we	O
demonstrate	O
that	O
binding	O
of	O
the	O
GA	B-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
(	O
GABP	B-GENE
)	O
to	O
ets	B-GENE
sequence	I-GENE
motifs	I-GENE
within	O
each	O
repeated	O
unit	O
is	O
required	O
for	O
transcriptional	O
activation	O
of	O
the	O
COXIV	B-GENE
promoter	I-GENE
.	O

To	O
gain	O
further	O
insight	O
into	O
the	O
pathogenesis	O
of	O
the	O
adult	O
respiratory	O
distress	O
syndrome	O
(	O
ARDS	O
)	O
,	O
the	O
authors	O
studied	O
possible	O
relationships	O
among	O
the	O
activation	O
status	O
of	O
circulating	O
polymorphonuclear	O
neutrophils	O
(	O
PMN	O
)	O
,	O
cytokine	O
levels	O
,	O
and	O
the	O
severity	O
of	O
lung	O
injury	O
in	O
31	O
patients	O
:	O
15	O
with	O
ARDS	O
,	O
9	O
with	O
severe	O
pneumonia	O
uncomplicated	O
by	O
ARDS	O
,	O
and	O
7	O
mechanically	O
ventilated	O
patients	O
with	O
neither	O
ARDS	O
nor	O
pneumonia	O
.	O

Amiodarone	O
,	O
seldom	O
used	O
as	O
first	O
-	O
line	O
treatment	O
,	O
appears	O
to	O
be	O
the	O
most	O
effective	O
drug	O
.	O

These	O
results	O
demonstrate	O
that	O
dopamine	B-GENE
receptor	I-GENE
stimulation	O
by	O
different	O
dopamine	O
agonists	O
produces	O
a	O
different	O
pattern	O
of	O
effects	O
on	O
the	O
characteristics	O
of	O
the	O
reaction	O
time	O
response	O
.	O

Two	O
experiments	O
were	O
conducted	O
to	O
study	O
the	O
vacuous	O
jaw	O
movements	O
induced	O
in	O
rats	O
by	O
acute	O
administration	O
of	O
the	O
monoamine	O
-	O
depleting	O
agent	O
reserpine	O
.	O

Depletion	O
of	O
dopamine	O
in	O
the	O
nucleus	O
accumbens	O
led	O
to	O
a	O
dramatic	O
shift	O
in	O
behavior	O
in	O
which	O
there	O
was	O
a	O
significant	O
decrease	O
in	O
lever	O
pressing	O
but	O
a	O
significant	O
increase	O
in	O
consumption	O
of	O
lab	O
chow	O
.	O

We	O
have	O
investigated	O
the	O
influence	O
of	O
NaFe3	O
+	O
EDTA	O
,	O
and	O
of	O
increasing	O
dietary	O
levels	O
of	O
Na2EDTA	O
,	O
on	O
Zn	O
,	O
Cu	O
and	O
Ca	O
metabolism	O
in	O
rats	O
fed	O
on	O
Zn	O
-	O
sufficient	O
and	O
Zn	O
-	O
deficient	O
soya	O
-	O
bean	O
-	O
isolate	O
-	O
based	O
diets	O
.	O

Recovery	O
of	O
carbimazole	O
-	O
induced	O
agranulocytosis	O
following	O
recombinant	B-GENE
granulocyte	I-GENE
-	I-GENE
macrophage	I-GENE
colony	I-GENE
stimulating	I-GENE
factor	I-GENE
(	O
rhGM	B-GENE
-	I-GENE
CSF	I-GENE
)	O
administration	O
.	O

Thus	O
,	O
the	O
system	O
can	O
be	O
used	O
to	O
detect	O
and	O
study	O
dynamic	O
perfusion	O
changes	O
from	O
the	O
brain	O
surface	O
with	O
minimal	O
tissue	O
damage	O
.	O

The	O
neglect	O
of	O
Richards	O
'	O
s	O
theory	O
demonstrates	O
the	O
range	O
of	O
factors	O
,	O
other	O
than	O
the	O
strictly	O
scientific	O
,	O
which	O
can	O
be	O
important	O
in	O
determining	O
the	O
influence	O
or	O
otherwise	O
of	O
a	O
psychological	O
theory	O
.	O

The	O
positive	O
-	O
acting	O
global	O
sulfur	O
regulatory	O
protein	O
,	O
CYS3	B-GENE
,	O
of	O
Neurospora	O
crassa	O
turns	O
on	O
the	O
expression	O
of	O
a	O
family	O
of	O
unlinked	O
structural	O
genes	O
that	O
encode	O
enzymes	O
of	O
sulfur	O
catabolism	O
.	O

Analysis	O
of	O
the	O
upstream	O
untranslated	O
region	O
of	O
CHL15	B-GENE
revealed	O
the	O
presence	O
of	O
the	O
hexamer	O
element	O
,	O
ACGCGT	O
(	O
an	O
MluI	B-GENE
restriction	I-GENE
site	I-GENE
)	O
controlling	O
both	O
the	O
periodic	O
expression	O
and	O
coordinate	O
regulation	O
of	O
the	O
DNA	O
synthesis	O
genes	O
in	O
budding	O
yeast	O
.	O

The	O
C	O
-	O
terminal	O
region	O
of	O
the	O
150	O
-	O
kDa	O
protein	O
contains	O
an	O
NTP	O
-	O
binding	O
helicase	B-GENE
motif	I-GENE
and	O
the	O
readthrough	O
region	O
,	O
an	O
RNA	B-GENE
polymerase	I-GENE
motif	I-GENE
,	O
indicating	O
that	O
these	O
two	O
overlapping	O
proteins	O
may	O
form	O
an	O
RNA	O
replication	O
complex	O
similar	O
to	O
those	O
of	O
tobamo	O
-	O
and	O
tobraviruses	O
.	O

On	O
T2	O
weighted	O
images	O
,	O
low	O
intensity	O
areas	O
in	O
the	O
thalamus	O
,	O
the	O
striatum	O
,	O
the	O
anterior	O
limb	O
of	O
the	O
internal	O
capsule	O
,	O
the	O
tegmentum	O
of	O
midbrain	O
,	O
high	O
intensity	O
areas	O
in	O
middle	O
cerebellar	O
peduncle	O
,	O
the	O
posterior	O
limb	O
of	O
the	O
internal	O
capsule	O
,	O
the	O
lateral	O
part	O
of	O
the	O
cerebral	O
peduncle	O
,	O
and	O
the	O
cerebral	O
white	O
matter	O
were	O
noted	O
.	O

Using	O
the	O
rap1t	B-GENE
alleles	I-GENE
to	O
generate	O
wild	O
-	O
type	O
cells	O
differing	O
only	O
in	O
telomere	O
tract	O
lengths	O
,	O
we	O
also	O
show	O
that	O
telomere	O
position	O
effects	O
are	O
highly	O
sensitive	O
to	O
changes	O
in	O
the	O
size	O
(	O
or	O
structure	O
)	O
of	O
the	O
telomeric	O
tract	O
.	O

Pronounced	O
microangiopathy	O
characterized	O
by	O
avascular	O
fields	O
,	O
enlarged	O
and	O
tortuous	O
capillaries	O
and	O
increased	O
transcapillary	O
diffusion	O
of	O
sodium	O
fluorescein	O
,	O
was	O
clearly	O
demonstrable	O
in	O
the	O
area	O
of	O
the	O
nodules	O
.	O

Epigenetic	O
switching	O
of	O
transcriptional	O
states	O
:	O
cis	O
-	O
and	O
trans	O
-	O
acting	O
factors	O
affecting	O
establishment	O
of	O
silencing	O
at	O
the	O
HMR	B-GENE
locus	I-GENE
in	O
Saccharomyces	O
cerevisiae	O
.	O

The	O
two	O
methods	O
identify	O
the	O
same	O
patients	O
only	O
if	O
micturitional	O
pressures	O
are	O
normal	O
(	O
40	O
to	O
60	O
cmH2O	O
)	O
to	O
high	O
(	O
over	O
60	O
cmH2O	O
)	O
and	O
the	O
Sussett	O
formula	O
is	O
used	O
with	O
a	O
higher	O
(	O
95th	O
centile	O
)	O
cutoff	O
.	O

There	O
was	O
no	O
clear	O
correlation	O
between	O
the	O
MFA	O
and	O
the	O
severity	O
of	O
the	O
UTS	O
phenotype	O
.	O

Chicken	O
sterol	B-GENE
carrier	I-GENE
protein	I-GENE
2	I-GENE
/	O
sterol	B-GENE
carrier	I-GENE
protein	I-GENE
x	I-GENE
:	O
cDNA	O
cloning	O
reveals	O
evolutionary	O
conservation	O
of	O
structure	O
and	O
regulated	O
expression	O
.	O

The	O
plasmatic	B-GENE
albumin	I-GENE
concentration	O
(	O
3	O
.	O
5	O
-	O
4	O
.	O
5	O
g	O
/	O
dl	O
)	O
represents	O
about	O
60	O
%	O
of	O
the	O
total	O
plasma	O
protein	O
.	O

A	O
single	O
five	O
minute	O
period	O
of	O
rapid	O
atrial	O
pacing	O
fails	O
to	O
limit	O
infarct	O
size	O
in	O
the	O
in	O
situ	O
rabbit	O
heart	O
.	O

Neither	O
RD19	B-GENE
nor	O
RD21	B-GENE
mRNA	I-GENE
synthesis	O
was	O
responsive	O
to	O
cold	O
or	O
to	O
heat	O
stress	O
.	O

Previous	O
studies	O
indicated	O
that	O
the	O
20S	B-GENE
proteasome	I-GENE
is	O
a	O
catalytic	O
core	O
of	O
the	O
26S	B-GENE
proteolytic	I-GENE
complex	I-GENE
that	O
possesses	O
a	O
latent	O
multicatalytic	O
proteinase	O
activity	O
and	O
catalyzes	O
an	O
ATP	O
-	O
dependent	O
,	O
selective	O
breakdown	O
of	O
proteins	O
ligated	O
to	O
ubiquitin	B-GENE
.	O

The	O
O2	O
deficit	O
was	O
not	O
related	O
to	O
blood	O
lactate	O
during	O
submaximal	O
exercise	O
,	O
muscle	O
enzyme	O
activity	O
(	O
citrate	B-GENE
synthase	I-GENE
,	O
3	B-GENE
-	I-GENE
hydroxyacyl	I-GENE
-	I-GENE
CoA	I-GENE
-	I-GENE
dehydrogenase	I-GENE
,	O
lactate	B-GENE
dehydrogenase	I-GENE
)	O
,	O
number	O
of	O
muscle	O
capillaries	O
,	O
%	O
ST	O
fibres	O
or	O
muscle	O
buffer	O
capacity	O
.	O

The	O
sequence	O
of	O
the	O
putative	O
RBP1	B-GENE
protein	I-GENE
contains	O
two	O
copies	O
of	O
an	O
RNA	O
recognition	O
motif	O
,	O
two	O
glutamine	O
stretches	O
,	O
an	O
asparagine	O
-	O
rich	O
region	O
,	O
a	O
methionine	O
-	O
rich	O
region	O
,	O
and	O
two	O
long	O
potential	O
alpha	O
-	O
helixes	O
.	O

One	O
defective	O
RNA	O
with	O
a	O
large	O
deletion	O
in	O
the	O
p70	B-GENE
coding	I-GENE
region	I-GENE
was	O
able	O
to	O
replicate	O
efficiently	O
,	O
both	O
when	O
inoculated	O
with	O
the	O
helper	O
genome	O
and	O
when	O
inoculated	O
with	O
a	O
second	O
complementing	O
defective	O
RNA	O
that	O
supplied	O
a	O
wild	B-GENE
-	I-GENE
type	I-GENE
p70	I-GENE
.	O

Complete	O
nucleotide	O
sequence	O
of	O
the	O
bacteriophage	B-GENE
K1F	I-GENE
tail	I-GENE
gene	I-GENE
encoding	O
endo	B-GENE
-	I-GENE
N	I-GENE
-	I-GENE
acylneuraminidase	I-GENE
(	O
endo	B-GENE
-	I-GENE
N	I-GENE
)	O
and	O
comparison	O
to	O
an	O
endo	B-GENE
-	I-GENE
N	I-GENE
homolog	I-GENE
in	O
bacteriophage	O
PK1E	O
.	O

Binding	O
of	O
U2	B-GENE
small	I-GENE
nuclear	I-GENE
ribonucleoprotein	I-GENE
was	O
partially	O
inhibited	O
.	O

Morphometrical	O
quantification	O
of	O
brain	O
edema	O
related	O
to	O
experimental	O
multiple	O
micro	O
-	O
infarcts	O
in	O
mice	O
:	O
assessment	O
of	O
neurotropin	B-GENE
effect	O
.	O

One	O
member	O
of	O
this	O
multigene	O
family	O
,	O
GATA	B-GENE
-	I-GENE
3	I-GENE
,	O
is	O
most	O
abundantly	O
expressed	O
in	O
T	O
lymphocytes	O
,	O
a	O
cellular	O
target	O
for	O
human	O
immunodeficiency	O
virus	O
type	O
1	O
(	O
HIV	O
-	O
1	O
)	O
infection	O
and	O
replication	O
.	O

Indeed	O
,	O
significant	O
level	O
of	O
CAT	B-GENE
activity	O
was	O
observed	O
in	O
human	O
lung	O
adenocarcinoma	O
(	O
A549	O
-	O
1	O
)	O
cells	O
which	O
had	O
been	O
incubated	O
with	O
a	O
complex	O
of	O
T7	B-GENE
RNA	I-GENE
polymerase	I-GENE
,	O
pT7	B-GENE
-	I-GENE
EMC	I-GENE
-	I-GENE
CAT	I-GENE
DNA	I-GENE
and	O
DC	O
-	O
chol	O
cationic	O
liposomes	O
.	O

Pneumoscrotum	O
is	O
a	O
rare	O
condition	O
that	O
receives	O
little	O
discussion	O
in	O
standard	O
texts	O
of	O
urology	O
.	O

The	O
first	O
gene	O
codes	O
for	O
a	O
protein	O
containing	O
11	O
cystein	O
residues	O
in	O
an	O
arrangement	O
typical	O
for	O
Fe	B-GENE
/	I-GENE
S	I-GENE
proteins	I-GENE
.	O

Triton	O
-	O
disrupted	O
cells	O
retained	O
capacity	O
for	O
activation	O
of	O
the	O
pathway	O
by	O
both	O
peptide	O
growth	O
factors	O
and	O
by	O
addition	O
of	O
GTP	O
-	O
loaded	O
p21	B-GENE
rasVal12	B-GENE
.	O

To	O
begin	O
to	O
examine	O
the	O
mechanism	O
controlling	O
expression	O
of	O
this	O
gene	O
during	O
the	O
cell	O
-	O
cycle	O
,	O
a	O
mouse	B-GENE
B	I-GENE
-	I-GENE
myb	I-GENE
5	I-GENE
'	I-GENE
flanking	I-GENE
sequence	I-GENE
was	O
isolated	O
from	O
a	O
cosmid	O
library	O
and	O
shown	O
to	O
promote	O
efficiently	O
the	O
transcription	O
of	O
a	O
luciferase	B-GENE
reporter	I-GENE
gene	I-GENE
when	O
transfected	O
into	O
NIH3T3	O
fibroblasts	O
.	O

The	O
influence	O
of	O
a	O
high	O
ionic	O
strength	O
on	O
the	O
resolution	O
was	O
clearly	O
shown	O
.	O

The	O
number	O
of	O
bacteria	O
in	O
the	O
lung	O
,	O
peripheral	O
white	O
blood	O
cell	O
and	O
BAL	O
fluid	O
cell	O
also	O
decreased	O
by	O
the	O
administration	O
of	O
FN	B-GENE
.	O

In	O
mice	O
,	O
three	O
major	O
families	O
of	O
L1	O
elements	O
,	O
termed	O
"	O
A	O
,	O
"	O
"	O
F	O
,	O
"	O
and	O
"	O
V	O
,	O
"	O
have	O
been	O
defined	O
on	O
the	O
basis	O
of	O
the	O
sequence	O
found	O
at	O
the	O
5	O
'	O
terminus	O
.	O

TFEC	B-GENE
,	O
a	O
basic	B-GENE
helix	I-GENE
-	I-GENE
loop	I-GENE
-	I-GENE
helix	I-GENE
protein	I-GENE
,	O
forms	O
heterodimers	O
with	O
TFE3	B-GENE
and	O
inhibits	O
TFE3	B-GENE
-	O
dependent	O
transcription	O
activation	O
.	O

Similar	O
results	O
were	O
seen	O
on	O
Western	O
blots	O
of	O
Autographa	O
californica	O
MNPV	O
(	O
AcMNPV	O
)	O
-	O
infected	O
Spodoptera	O
frugiperda	O
cells	O
.	O

In	O
infected	O
mammalian	O
cells	O
,	O
the	O
ARV	B-GENE
G	I-GENE
and	O
GNS	B-GENE
genes	I-GENE
are	O
transcribed	O
primarily	O
as	O
a	O
polycistronic	O
mRNA	O
which	O
appears	O
to	O
extend	O
from	O
the	O
consensus	O
sequence	O
(	O
AACAG	O
)	O
at	O
the	O
start	O
of	O
the	O
G	B-GENE
gene	I-GENE
to	O
the	O
next	O
recognized	O
polyadenylation	O
signal	O
(	O
CATG	O
[	O
A	O
]	O
7	O
)	O
located	O
697	O
nucleotides	O
downstream	O
of	O
the	O
GNS	B-GENE
protein	I-GENE
termination	O
codon	O
.	O

Molecular	O
cloning	O
and	O
expression	O
of	O
RPE65	B-GENE
,	O
a	O
novel	O
retinal	O
pigment	O
epithelium	O
-	O
specific	O
microsomal	O
protein	O
that	O
is	O
post	O
-	O
transcriptionally	O
regulated	O
in	O
vitro	O
.	O

The	O
mean	O
power	O
(	O
in	O
mu	O
W	O
)	O
required	O
to	O
produce	O
the	O
observed	O
flow	O
rate	O
was	O
estimated	O
at	O
each	O
outflow	O
pressure	O
as	O
the	O
product	O
of	O
the	O
flow	O
rate	O
and	O
the	O
pressure	O
across	O
the	O
lymphatic	O
vessel	O
.	O

Although	O
antisperm	O
antibodies	O
are	O
associated	O
with	O
infertility	O
,	O
many	O
hospital	O
laboratories	O
do	O
not	O
test	O
for	O
these	O
antibodies	O
.	O

PPD	B-GENE
-	O
specific	O
IgG	B-GENE
subclass	O
responses	O
were	O
evident	O
to	O
all	O
four	O
IgG	B-GENE
subclasses	O
.	O

Anterior	O
body	O
pattern	O
in	O
Drosophila	O
is	O
specified	O
by	O
the	O
graded	O
distribution	O
of	O
the	O
bicoid	B-GENE
protein	I-GENE
(	O
bcd	B-GENE
)	O
,	O
which	O
activates	O
subordinate	O
genes	O
in	O
distinct	O
anterior	O
domains	O
.	O

GAP	B-GENE
-	I-GENE
N	I-GENE
bound	O
constitutively	O
to	O
p190	B-GENE
in	O
both	O
serum	O
-	O
deprived	O
and	O
growth	O
factor	O
-	O
stimulated	O
cells	O
.	O

The	O
peptide	O
sequence	O
contains	O
a	O
region	O
of	O
80	O
amino	O
acids	O
that	O
shows	O
similarity	O
to	O
bcl	B-GENE
-	I-GENE
2	I-GENE
and	O
to	O
the	O
recently	O
described	O
bcl	B-GENE
-	I-GENE
2	I-GENE
-	I-GENE
related	I-GENE
gene	I-GENE
,	O
MCL1	B-GENE
.	O

The	O
phosphorylation	O
efficiency	O
is	O
improved	O
by	O
increasing	O
the	O
number	O
of	O
N	O
-	O
terminal	O
arginine	O
residues	O
and	O
by	O
moving	O
the	O
arginyl	O
cluster	O
one	O
residue	O
further	O
away	O
from	O
the	O
serine	O
,	O
the	O
nonapeptide	O
(	O
Arg	O
)	O
4	O
-	O
Ala	O
-	O
Ala	O
-	O
Ser	O
-	O
Val	O
-	O
Ala	O
being	O
the	O
best	O
substrate	O
among	O
all	O
the	O
short	O
peptides	O
tested	O
(	O
Km	O
=	O
15	O
microM	O
)	O
.	O

The	O
Saccharomyces	B-GENE
cerevisiae	I-GENE
GAL1	I-GENE
and	O
GAL10	B-GENE
genes	I-GENE
are	O
controlled	O
in	O
response	O
to	O
the	O
availability	O
of	O
galactose	O
and	O
glucose	O
by	O
multiple	O
activating	O
and	O
repressing	O
proteins	O
bound	O
at	O
adjacent	O
or	O
overlapping	O
sites	O
in	O
UASG	O
.	O

Surprisingly	O
,	O
the	O
results	O
of	O
several	O
experiments	O
suggest	O
that	O
the	O
TSF	B-GENE
genes	I-GENE
encode	O
global	O
regulatory	O
factors	O
.	O
tsf1	B-GENE
to	O
tsf6	B-GENE
mutations	O
derepressed	O
expression	O
from	O
yeast	O
CYC	B-GENE
-	O
GAL	B-GENE
hybrid	O
promoters	O
(	O
fused	O
to	O
lacZ	B-GENE
)	O
that	O
harbor	O
a	O
variety	O
of	O
operator	O
sequences	O
,	O
and	O
caused	O
pleiotropic	O
defects	O
in	O
cell	O
growth	O
,	O
mating	O
,	O
and	O
sporulation	O
.	O

Sex	O
of	O
calf	O
(	O
variate	O
2	O
)	O
was	O
associated	O
most	O
closely	O
with	O
width	O
of	O
muzzle	O
and	O
head	O
.	O

Sequence	O
comparison	O
indicates	O
that	O
exons	O
5	O
'	O
/	O
L	O
and	O
L	O
/	O
N	O
in	O
PSG12	B-GENE
and	O
PSG12	B-GENE
psi	I-GENE
are	O
99	O
%	O
identical	O
,	O
except	O
that	O
the	O
L	O
/	O
N	O
exon	O
in	O
the	O
PSG12	B-GENE
psi	I-GENE
gene	I-GENE
contains	O
a	O
stop	O
codon	O
.	O

The	O
mechanisms	O
that	O
govern	O
the	O
activation	O
or	O
suppression	O
of	O
the	O
CD8	B-GENE
gene	I-GENE
are	O
likely	O
to	O
be	O
central	O
to	O
the	O
T	O
cell	O
development	O
program	O
.	O

We	O
suggest	O
that	O
the	O
ER	O
lumenal	O
variable	O
domain	O
of	O
gp19K	B-GENE
has	O
a	O
specific	O
tertiary	O
structure	O
that	O
is	O
important	O
for	O
binding	O
to	O
the	O
polymorphic	O
alpha	O
1	O
and	O
alpha	O
2	O
domains	O
of	O
class	B-GENE
I	I-GENE
heavy	I-GENE
(	I-GENE
alpha	I-GENE
)	I-GENE
chains	I-GENE
.	O

We	O
recently	O
found	O
that	O
17	O
beta	O
-	O
estradiol	O
(	O
E2	O
)	O
not	O
only	O
suppresses	O
bone	O
resorption	O
but	O
also	O
stimulates	O
bone	O
formation	O
in	O
the	O
cancellous	O
bone	O
of	O
female	O
rats	O
.	O

Recombinant	B-GENE
human	I-GENE
erythropoietin	I-GENE
(	O
epoetin	B-GENE
)	O
is	O
approved	O
to	O
be	O
administered	O
by	O
the	O
intravenous	O
(	O
i	O
.	O
v	O
.	O
)	O
or	O
subcutaneous	O
(	O
SC	O
)	O
route	O
.	O

Single	O
-	O
photon	O
emission	O
computed	O
tomography	O
(	O
SPECT	O
)	O
with	O
99mTc	O
-	O
hexamethylpropyleneamine	O
oxime	O
(	O
HMPAO	O
)	O
was	O
used	O
to	O
investigate	O
changes	O
in	O
cerebral	O
blood	O
flow	O
in	O
seven	O
patients	O
with	O
cortical	O
visual	O
impairment	O
.	O

The	O
rCBF	O
ratio	O
was	O
mainly	O
reduced	O
in	O
frontal	O
lobes	O
(	O
65	O
%	O
)	O
.	O

METHODS	O
:	O
Twenty	O
-	O
two	O
patients	O
were	O
grouped	O
according	O
to	O
their	O
etiology	O
based	O
on	O
the	O
study	O
of	O
antiadrenal	O
antibodies	O
at	O
diagnosis	O
of	O
the	O
disease	O
:	O
7	O
were	O
positive	O
(	O
autoimmune	O
etiology	O
or	O
EAA	O
)	O
,	O
11	O
were	O
negative	O
(	O
tuberculous	O
etiology	O
or	O
EAT	O
)	O
and	O
in	O
four	O
serologic	O
study	O
was	O
not	O
available	O
(	O
undetermined	O
etiology	O
or	O
EAI	O
)	O
.	O

The	O
UV	O
induction	O
of	O
c	B-GENE
-	I-GENE
jun	I-GENE
is	O
mediated	O
by	O
two	O
UV	O
response	O
elements	O
consisting	O
of	O
AP	B-GENE
-	I-GENE
1	I-GENE
-	I-GENE
like	I-GENE
sequences	I-GENE
within	O
its	O
5	O
'	O
control	O
region	O
.	O

Protein	B-GENE
tyrosine	I-GENE
phosphatases	I-GENE
(	O
PTPs	B-GENE
)	O
,	O
together	O
with	O
protein	B-GENE
tyrosine	I-GENE
kinases	I-GENE
(	O
PTKs	B-GENE
)	O
,	O
are	O
involved	O
in	O
the	O
regulation	O
of	O
cell	O
activation	O
,	O
growth	O
,	O
and	O
differentiation	O
.	O

ST	O
elevation	O
occurs	O
in	O
5	O
patients	O
(	O
55	O
.	O
5	O
%	O
)	O
of	O
subgroup	O
A	O
and	O
in	O
no	O
patient	O
of	O
the	O
subgroup	O
B	O
.	O

Furthermore	O
,	O
a	O
p21X	B-GENE
protein	I-GENE
lacking	O
the	O
N	O
-	O
terminus	O
of	O
Rex1	B-GENE
was	O
expressed	O
at	O
high	O
levels	O
;	O
our	O
data	O
indicate	O
that	O
p21X	B-GENE
is	O
translated	O
from	O
the	O
1	O
.	O
6	O
-	O
kb	O
mRNA	O
which	O
is	O
derived	O
primarily	O
from	O
deleted	O
proviruses	O
.	O

HTLV	O
-	O
1	O
gene	O
expression	O
by	O
defective	O
proviruses	O
in	O
an	O
infected	O
T	O
-	O
cell	O
line	O
.	O

Thus	O
,	O
it	O
was	O
confirmed	O
that	O
the	O
sodium	O
lauryl	O
sulfate	O
method	O
of	O
estimating	O
hemoglobin	B-GENE
concentration	O
is	O
an	O
appropriate	O
alternative	O
to	O
the	O
cyanmethemoglobin	B-GENE
method	O
and	O
avoids	O
the	O
generation	O
of	O
toxic	O
wastes	O
.	O

A	O
comparison	O
of	O
the	O
predicted	O
amino	O
acid	O
sequences	O
of	O
the	O
two	O
human	B-GENE
PKC	I-GENE
-	I-GENE
delta	I-GENE
clones	O
with	O
the	O
rat	O
and	O
mouse	O
homologues	O
indicated	O
a	O
greater	O
degree	O
of	O
sequence	O
divergence	O
(	O
89	O
-	O
90	O
%	O
homology	O
)	O
compared	O
to	O
the	O
high	O
degree	O
of	O
sequence	O
conservation	O
observed	O
with	O
other	O
human	B-GENE
PKC	I-GENE
family	I-GENE
members	I-GENE
and	O
their	O
mammalian	O
counterparts	O
.	O

XII	O
.	O

When	O
comparing	O
the	O
barley	B-GENE
PSI	I-GENE
-	I-GENE
K	I-GENE
and	O
PSI	B-GENE
-	I-GENE
G	I-GENE
with	O
the	O
reported	O
PSI	B-GENE
-	I-GENE
K	I-GENE
sequence	I-GENE
from	I-GENE
Synechococcus	I-GENE
vulcanus	I-GENE
,	O
the	O
degree	O
of	O
similarity	O
is	O
equal	O
,	O
suggesting	O
that	O
an	O
ancestral	O
gene	O
has	O
been	O
duplicated	O
in	O
a	O
chloroplast	O
progenitor	O
but	O
not	O
in	O
a	O
cyanobacterial	O
.	O

Under	O
these	O
conditions	O
,	O
transfections	O
with	O
cDNAs	O
of	O
the	O
NF	B-GENE
-	I-GENE
kappa	I-GENE
B	I-GENE
p50	B-GENE
and	O
serum	B-GENE
response	I-GENE
factor	I-GENE
(	O
SRF	B-GENE
)	O
produced	O
a	O
factor	O
(	O
s	O
)	O
that	O
mediated	O
Tax	B-GENE
binding	O
to	O
the	O
NF	B-GENE
-	I-GENE
kappa	I-GENE
B	I-GENE
site	I-GENE
and	O
the	O
CArG	O
box	O
respectively	O
.	O

We	O
show	O
here	O
that	O
v	B-GENE
-	I-GENE
Rel	I-GENE
specifically	O
increased	O
expression	O
from	O
a	O
reporter	O
plasmid	O
containing	O
multiple	O
Sp1	B-GENE
binding	I-GENE
sites	I-GENE
approximately	O
sixfold	O
in	O
chicken	O
embryo	O
fibroblasts	O
(	O
CEFs	O
)	O
,	O
even	O
though	O
v	B-GENE
-	I-GENE
Rel	I-GENE
did	O
not	O
bind	O
directly	O
to	O
these	O
sites	O
.	O
v	B-GENE
-	I-GENE
Rel	I-GENE
also	O
increased	O
expression	O
from	O
a	O
reporter	O
plasmid	O
containing	O
a	O
human	B-GENE
immunodeficiency	I-GENE
virus	I-GENE
type	I-GENE
1	I-GENE
(	I-GENE
HIV	I-GENE
-	I-GENE
1	I-GENE
)	I-GENE
long	I-GENE
terminal	I-GENE
repeat	I-GENE
(	O
LTR	O
)	O
in	O
which	O
the	O
kappa	B-GENE
B	I-GENE
binding	I-GENE
sites	I-GENE
were	O
mutated	O
but	O
which	O
still	O
contained	O
intact	O
Sp1	B-GENE
binding	I-GENE
sites	I-GENE
.	O

The	O
simultaneous	O
recording	O
of	O
electrical	O
activity	O
from	O
the	O
surface	O
electrocardiogram	O
,	O
right	O
ventricular	O
apex	O
,	O
His	O
bundle	O
,	O
high	O
right	O
atrium	O
,	O
coronary	O
sinus	O
,	O
with	O
or	O
without	O
a	O
roving	O
mapping	O
catheter	O
,	O
enables	O
us	O
to	O
precisely	O
map	O
the	O
electrical	O
activation	O
sequence	O
in	O
the	O
heart	O
.	O

CONCLUSION	O
:	O
This	O
retrospective	O
analysis	O
does	O
not	O
confirm	O
the	O
efficacy	O
of	O
one	O
course	O
of	O
simultaneous	O
Mitomycin	O
-	O
C	O
and	O
5	O
-	O
fluorouracil	O
,	O
at	O
least	O
in	O
association	O
with	O
full	O
-	O
dose	O
radiotherapy	O
incorporating	O
Iridium	O
-	O
192	O
boost	O
.	O

Despite	O
the	O
existence	O
of	O
30	O
cysteine	O
residues	O
,	O
carboxymethylation	O
prevented	O
the	O
formation	O
of	O
most	O
if	O
not	O
all	O
disulfide	O
bonds	O
that	O
otherwise	O
occurred	O
when	O
the	O
cells	O
were	O
sonicated	O
.	O

Cerebro	O
-	O
oculo	O
-	O
facioskeletal	O
syndrome	O
(	O
Pena	O
-	O
Shokeir	O
syndrome	O
II	O
)	O

Most	O
importantly	O
,	O
the	O
addition	O
of	O
purified	O
17S	B-GENE
U2	I-GENE
snRNPs	I-GENE
,	O
but	O
not	O
of	O
12S	B-GENE
U2	I-GENE
snRNPs	I-GENE
,	O
to	O
HeLa	O
splicing	O
extracts	O
in	O
which	O
the	O
endogeneous	B-GENE
U2	I-GENE
snRNPs	I-GENE
have	O
been	O
functionally	O
neutralized	O
with	O
anti	B-GENE
-	I-GENE
PRP9	I-GENE
antibodies	I-GENE
fully	O
restores	O
the	O
mRNA	O
-	O
splicing	O
activity	O
of	O
the	O
extracts	O
.	O

Differences	O
in	O
profiles	O
of	O
viscosity	O
variables	O
between	O
subgroups	O
of	O
EAD	O
in	O
RA	O
patients	O
were	O
observed	O
.	O

These	O
contain	O
a	O
single	O
1977	O
-	O
bp	O
exon	O
that	O
encodes	O
900	O
bp	O
of	O
the	O
5	O
'	O
and	O
3	O
'	O
untranslated	O
sequences	O
in	O
addition	O
to	O
a	O
1077	O
-	O
bp	O
open	O
reading	O
frame	O
identical	O
to	O
that	O
found	O
in	O
vascular	B-GENE
smooth	I-GENE
muscle	I-GENE
cell	I-GENE
AT1a	I-GENE
receptor	I-GENE
cDNAs	I-GENE
.	O

Deletion	O
of	O
a	O
53	O
-	O
bp	O
early	O
promoter	O
region	O
containing	O
the	O
transcription	O
start	O
site	O
and	O
a	O
putative	O
TATA	O
box	O
completely	O
abolishes	O
the	O
ability	O
of	O
upstream	O
elements	O
to	O
drive	O
transcription	O
of	O
the	O
luciferase	B-GENE
cDNA	I-GENE
.	O

One	O
chimpanzee	O
reliably	O
selected	O
the	O
larger	O
numeral	O
4	O
during	O
testing	O
with	O
a	O
nonadjacent	O
pair	O
(	O
2	O
-	O
4	O
)	O
,	O
and	O
2	O
chimps	O
showed	O
no	O
preference	O
.	O

Dissipation	O
of	O
claudication	O
pain	O
after	O
walking	O
:	O
implications	O
for	O
endurance	O
training	O
.	O

Alternative	O
transcript	O
of	O
the	O
nonselective	O
-	O
type	O
endothelin	B-GENE
receptor	I-GENE
from	O
rat	O
brain	O
.	O

The	O
Drosophila	O
clathrin	B-GENE
heavy	I-GENE
chain	I-GENE
gene	O
:	O
clathrin	B-GENE
function	O
is	O
essential	O
in	O
a	O
multicellular	O
organism	O
.	O

The	O
binding	O
specificity	O
of	O
this	O
protein	O
was	O
compared	O
to	O
that	O
of	O
human	B-GENE
E2F	I-GENE
using	O
a	O
number	O
of	O
mutant	B-GENE
E2F	I-GENE
sites	I-GENE
as	O
competitors	O
.	O

To	O
analyze	O
the	O
VH	O
regions	O
of	O
polyreactive	O
antibodies	O
,	O
with	O
particular	O
attention	O
at	O
their	O
somatically	O
mutated	O
status	O
,	O
we	O
generated	O
five	O
IgG	B-GENE
(	O
three	O
IgG1	B-GENE
and	O
two	O
IgG3	B-GENE
)	O
mAb	O
(	O
using	O
B	O
cells	O
from	O
a	O
healthy	O
subject	O
,	O
a	O
patient	O
with	O
insulin	B-GENE
-	O
dependent	O
diabetes	O
mellitus	O
and	O
a	O
patient	O
with	O
SLE	O
)	O
,	O
which	O
bound	O
with	O
various	O
efficiencies	O
a	O
number	O
of	O
different	O
self	O
and	O
foreign	O
Ag	O
.	O

It	O
is	O
possible	O
that	O
the	O
patch	O
determines	O
the	O
proper	O
conformation	O
of	O
the	O
site	O
and	O
thereby	O
contributes	O
to	O
recognition	O
indirectly	O
.	O

The	O
7	O
-	O
kb	O
mRNA	O
differs	O
by	O
alternative	O
splicing	O
such	O
that	O
it	O
encodes	O
a	O
protein	O
with	O
a	O
distinct	O
amino	O
terminus	O
.	O

Kinetics	O
of	O
the	O
inhibition	O
indicated	O
that	O
this	O
polymerase	O
domain	O
can	O
inhibit	O
viral	O
replication	O
only	O
during	O
the	O
preinitiation	O
stage	O
.	O

3	O
.	O

McCann	O
III	O
,	O
F	O
.	O

In	O
order	O
to	O
investigate	O
to	O
what	O
extent	O
this	O
interaction	O
might	O
contribute	O
to	O
tumor	O
induction	O
by	O
the	O
virus	O
,	O
we	O
have	O
introduced	O
two	O
different	O
point	O
mutations	O
within	O
the	O
putative	O
pRb	B-GENE
-	I-GENE
binding	I-GENE
sequence	I-GENE
of	O
large	B-GENE
T	I-GENE
antigen	I-GENE
,	O
and	O
as	O
a	O
preliminary	O
to	O
in	O
vivo	O
experiments	O
we	O
have	O
studied	O
their	O
effects	O
in	O
vitro	O
on	O
some	O
biological	O
activities	O
relevant	O
to	O
tumor	O
induction	O
.	O

We	O
conclude	O
that	O
the	O
conservation	O
of	O
nucleotides	O
154	O
to	O
156	O
is	O
likely	O
to	O
be	O
a	O
consequence	O
of	O
their	O
role	O
as	O
a	O
sequence	O
-	O
specific	O
recognition	O
element	O
for	O
the	O
SRP54	B-GENE
protein	I-GENE
.	O

A	O
region	O
of	O
the	O
deduced	O
protein	O
shares	O
extensive	O
homology	O
with	O
a	O
catalytic	O
region	O
of	O
Raf	B-GENE
kinases	I-GENE
,	O
a	O
feature	O
shared	O
only	O
with	O
TFIIE	B-GENE
among	O
transcription	O
factors	O
.	O

The	O
low	O
molecular	O
mass	O
polypeptide	O
complex	O
is	O
assumed	O
to	O
be	O
involved	O
in	O
antigen	O
presentation	O
,	O
generating	O
peptides	O
from	O
cytosolic	O
protein	O
antigens	O
,	O
which	O
are	O
subsequently	O
presented	O
to	O
cytotoxic	O
T	O
-	O
lymphocytes	O
on	O
the	O
cell	O
surface	O
.	O

Secondary	O
cleavage	O
of	O
RT	B-GENE
at	O
Trp	O
-	O
595	O
-	O
Tyr	O
-	O
596	O
of	O
Pol	B-GENE
yields	O
a	O
truncated	O
form	O
lacking	O
the	O
C	B-GENE
-	I-GENE
terminal	I-GENE
RNase	I-GENE
H	I-GENE
domain	I-GENE
.	O

The	O
C	O
-	O
terminal	O
approximately	O
50	O
amino	O
acids	O
of	O
Bel	B-GENE
-	I-GENE
1	I-GENE
are	O
shown	O
to	O
be	O
essential	O
for	O
Bel	B-GENE
-	I-GENE
1	I-GENE
activity	O
but	O
can	O
be	O
effectively	O
substituted	O
by	O
the	O
C	O
-	O
terminal	O
activation	O
domain	O
of	O
VP16	B-GENE
.	O

Since	O
the	O
-	O
172	O
/	O
-	O
148	O
element	O
also	O
conferred	O
estrogen	O
and	O
thyroid	O
hormone	O
responsiveness	O
,	O
it	O
can	O
be	O
considered	O
a	O
composite	O
hormone	O
response	O
element	O
.	O

Optimal	O
activation	O
of	O
T	O
cells	O
requires	O
at	O
least	O
two	O
signals	O
.	O

Together	O
with	O
a	O
considerably	O
shortened	O
and	O
interrupted	O
aromatic	O
aa	O
stretch	O
in	O
this	O
region	O
,	O
these	O
differences	O
are	O
discussed	O
in	O
terms	O
of	O
the	O
peculiar	O
affinity	O
of	O
cyanobacterial	B-GENE
cytochrome	I-GENE
oxidases	I-GENE
for	O
acidic	O
c	B-GENE
-	I-GENE
type	I-GENE
cytochromes	I-GENE
.	O

All	O
four	O
of	O
the	O
genes	O
have	O
a	O
similar	O
structure	O
,	O
with	O
the	O
receptor	O
protein	O
encoded	O
in	O
a	O
single	O
exon	O
.	O

Identity	O
of	O
GABP	B-GENE
with	O
NRF	B-GENE
-	I-GENE
2	I-GENE
,	O
a	O
multisubunit	O
activator	O
of	O
cytochrome	B-GENE
oxidase	I-GENE
expression	O
,	O
reveals	O
a	O
cellular	O
role	O
for	O
an	O
ETS	B-GENE
domain	I-GENE
activator	O
of	O
viral	O
promoters	O
.	O

The	O
intracellular	O
basic	B-GENE
region	I-GENE
/	I-GENE
helix	I-GENE
-	I-GENE
loop	I-GENE
-	I-GENE
helix	I-GENE
(	I-GENE
bHLH	I-GENE
)	I-GENE
dioxin	I-GENE
receptor	I-GENE
mediates	O
signal	O
transduction	O
by	O
dioxin	O
(	O
2	O
,	O
3	O
,	O
7	O
,	O
8	O
-	O
tetrachlorodibenzo	O
-	O
p	O
-	O
dioxin	O
)	O
and	O
functions	O
as	O
a	O
ligand	O
-	O
activated	O
DNA	O
binding	O
protein	O
directly	O
interacting	O
with	O
target	O
genes	O
by	O
binding	O
to	O
dioxin	O
response	O
elements	O
.	O

The	O
alpha	B-GENE
2A	I-GENE
-	I-GENE
adrenergic	I-GENE
receptor	I-GENE
(	O
alpha	B-GENE
2AAR	I-GENE
)	O
is	O
coupled	O
to	O
a	O
variety	O
of	O
effectors	O
via	O
pertussis	B-GENE
toxin	I-GENE
-	O
sensitive	O
GTP	B-GENE
-	I-GENE
binding	I-GENE
proteins	I-GENE
.	O

A	O
sequence	O
comparison	O
reveals	O
two	O
CCAAT	B-GENE
/	I-GENE
enhancer	I-GENE
binding	I-GENE
protein	I-GENE
(	O
C	B-GENE
/	I-GENE
EBP	I-GENE
)	O
consensus	O
sequences	O
,	O
basic	O
DNA	O
binding	O
region	O
and	O
leucine	O
zippers	O
1	O
and	O
2	O
(	O
bZIP1	O
and	O
bZIP2	O
)	O
,	O
within	O
this	O
region	O
.	O

One	O
of	O
these	O
genes	O
,	O
REC114	B-GENE
,	O
is	O
described	O
here	O
,	O
and	O
the	O
data	O
confirm	O
that	O
REC114	B-GENE
is	O
a	O
meiosis	O
-	O
specific	O
recombination	O
gene	O
with	O
no	O
detectable	O
function	O
in	O
mitosis	O
.	O

The	O
transactivation	O
function	O
of	O
EBNA2	B-GENE
was	O
also	O
observed	O
in	O
the	O
HeLa	O
epithelial	O
cell	O
line	O
,	O
which	O
suggests	O
that	O
EBV	O
and	O
HIV	O
-	O
1	O
infection	O
of	O
non	O
-	O
B	O
cells	O
may	O
result	O
in	O
HIV	B-GENE
-	I-GENE
1	I-GENE
promoter	I-GENE
activation	O
.	O

Mutation	O
of	O
the	O
C	B-GENE
/	I-GENE
EBP	I-GENE
binding	I-GENE
sites	I-GENE
in	O
the	O
Rous	B-GENE
sarcoma	I-GENE
virus	I-GENE
long	I-GENE
terminal	I-GENE
repeat	I-GENE
and	O
gag	B-GENE
enhancers	I-GENE
.	O

Nuclear	B-GENE
protein	I-GENE
phosphatase	I-GENE
2A	I-GENE
dephosphorylates	O
protein	B-GENE
kinase	I-GENE
A	I-GENE
-	O
phosphorylated	O
CREB	B-GENE
and	O
regulates	O
CREB	B-GENE
transcriptional	O
stimulation	O
.	O

We	O
show	O
that	O
IL	B-GENE
-	I-GENE
6	I-GENE
activates	O
JRE	B-GENE
-	I-GENE
IL6	I-GENE
through	O
an	O
H7	O
-	O
sensitive	O
pathway	O
that	O
does	O
not	O
involve	O
protein	B-GENE
kinase	I-GENE
C	I-GENE
,	O
cyclic	B-GENE
AMP	I-GENE
-	I-GENE
dependent	I-GENE
kinase	I-GENE
,	O
Ca	B-GENE
(	I-GENE
2	I-GENE
+	I-GENE
)	I-GENE
-	I-GENE
or	I-GENE
calmodulin	I-GENE
-	I-GENE
dependent	I-GENE
kinases	I-GENE
,	O
Ras	B-GENE
,	O
Raf	B-GENE
-	I-GENE
1	I-GENE
,	O
or	O
NF	B-GENE
-	I-GENE
IL6	I-GENE
(	O
C	B-GENE
/	I-GENE
EBP	I-GENE
beta	I-GENE
)	O
.	O

Mutation	O
of	O
the	O
presumptive	O
phosphorylated	O
tyrosine	O
and	O
threonine	O
residues	O
of	O
Mpk1p	B-GENE
individually	O
to	O
phenylalanine	O
and	O
alanine	O
,	O
respectively	O
,	O
severely	O
impaired	O
Mpk1p	B-GENE
function	O
.	O

Growth	O
factor	O
stimulation	O
rapidly	O
induces	O
a	O
reversible	O
change	O
in	O
the	O
electrophoretic	O
mobility	O
of	O
the	O
ternary	O
complex	O
,	O
accompanied	O
by	O
increased	O
phosphorylation	O
of	O
the	O
Elk	B-GENE
-	I-GENE
1	I-GENE
C	I-GENE
-	I-GENE
terminal	I-GENE
region	I-GENE
and	O
by	O
the	O
activation	O
of	O
a	O
42	B-GENE
kd	I-GENE
cellular	I-GENE
Elk	I-GENE
-	I-GENE
1	I-GENE
kinase	I-GENE
.	O

In	O
contrast	O
to	O
the	O
situation	O
in	O
mammalian	O
cells	O
,	O
prolonged	O
exposure	O
of	O
the	O
agonist	O
(	O
24	O
h	O
)	O
does	O
not	O
result	O
in	O
down	O
regulation	O
of	O
the	O
remaining	O
70	O
%	O
of	O
the	O
receptors	O
.	O

This	O
stimulatory	O
effect	O
could	O
also	O
be	O
elicited	O
by	O
c	B-GENE
-	I-GENE
Jun	I-GENE
,	O
which	O
interacts	O
with	O
topo	B-GENE
II	I-GENE
,	O
but	O
not	O
by	O
c	B-GENE
-	I-GENE
Fos	I-GENE
,	O
which	O
does	O
not	O
bind	O
topo	B-GENE
II	I-GENE
in	O
our	O
in	O
vitro	O
assay	O
.	O

The	O
regulation	O
of	O
Myf	B-GENE
-	I-GENE
5	I-GENE
and	O
MyoD	B-GENE
function	O
by	O
a	O
cAMP	O
-	O
dependent	O
pathway	O
may	O
partly	O
explain	O
how	O
external	O
signals	O
generated	O
by	O
serum	O
and	O
certain	O
peptide	O
growth	O
factors	O
can	O
be	O
transduced	O
to	O
the	O
nucleus	O
and	O
inhibit	O
dominant	O
-	O
acting	O
factors	O
that	O
are	O
responsible	O
for	O
myoblast	O
differentiation	O
.	O

16	O
,	O
99	O
-	O
104	O
)	O
.	O

We	O
have	O
previously	O
reported	O
that	O
high	O
level	O
human	B-GENE
desmin	I-GENE
expression	O
depends	O
on	O
a	O
280	O
-	O
base	O
pair	O
muscle	O
-	O
specific	O
enhancer	O
which	O
can	O
function	O
not	O
only	O
in	O
myotubes	O
,	O
but	O
can	O
also	O
activate	O
gene	O
expression	O
in	O
myoblasts	O
.	O

After	O
surgery	O
,	O
patients	O
self	O
administered	O
one	O
of	O
three	O
possible	O
postsurgical	O
medications	O
,	O
which	O
included	O
placebo	O
,	O
codeine	O
60	O
mg	O
,	O
and	O
ibuprofen	O
400	O
mg	O
,	O
when	O
their	O
pain	O
reached	O
a	O
moderate	O
or	O
severe	O
intensity	O
.	O

Replacement	O
of	O
the	O
wild	O
-	O
type	O
5	O
'	O
-	O
regulatory	O
region	O
with	O
either	O
of	O
the	O
mutants	O
'	O
cis	O
-	O
acting	O
regulatory	O
element	O
resulted	O
in	O
the	O
anaerobic	O
expression	O
of	O
active	B-GENE
Mn	I-GENE
-	I-GENE
superoxide	I-GENE
dismutase	I-GENE
.	O

The	O
orf61	B-GENE
gene	I-GENE
product	I-GENE
,	O
when	O
expressed	O
from	O
an	O
exogenous	O
promoter	O
,	O
inhibited	O
int	B-GENE
-	O
mediated	O
integration	O
at	O
the	O
chromosomal	B-GENE
attB	I-GENE
site	I-GENE
.	O

Expression	O
in	O
established	O
LCLs	O
,	O
occurring	O
irrespective	O
of	O
virus	O
producer	O
status	O
,	O
was	O
not	O
a	O
consequence	O
of	O
continued	O
in	O
vitro	O
passage	O
;	O
thus	O
,	O
appropriately	O
spliced	O
BamHI	B-GENE
-	I-GENE
A	I-GENE
transcripts	I-GENE
could	O
be	O
amplified	O
from	O
normal	O
B	O
cells	O
within	O
1	O
day	O
of	O
their	O
experimental	O
infection	O
in	O
vitro	O
,	O
along	O
with	O
BamHI	B-GENE
-	I-GENE
C	I-GENE
/	I-GENE
W	I-GENE
promoter	O
-	O
initiated	O
but	O
not	O
BamHI	B-GENE
-	I-GENE
F	I-GENE
promoter	I-GENE
-	I-GENE
initiated	I-GENE
mRNAs	I-GENE
.	O

Analysis	O
by	O
cell	O
surface	O
immunofluorescence	O
showed	O
that	O
the	O
UL28	B-GENE
gene	I-GENE
is	O
not	O
required	O
for	O
expression	O
of	O
viral	O
glycoproteins	O
on	O
the	O
surface	O
of	O
infected	O
cells	O
.	O

Furthermore	O
,	O
a	O
mutant	O
receptor	O
(	O
Y977F	O
/	O
Y989F	O
[	O
PLC	B-GENE
gamma	I-GENE
-	O
binding	O
sites	O
]	O
)	O
could	O
fully	O
activate	O
Ras	B-GENE
,	O
and	O
the	O
direct	O
activation	O
of	O
protein	B-GENE
kinase	I-GENE
C	I-GENE
and	O
calcium	O
mobilization	O
had	O
almost	O
no	O
effect	O
on	O
the	O
GDP	O
/	O
GTP	O
state	O
of	O
Ras	B-GENE
in	O
this	O
cell	O
line	O
.	O

Estrogen	O
treatment	O
in	O
high	O
doses	O
is	O
effective	O
in	O
reducing	O
adult	O
stature	O
in	O
constitutionally	O
tall	O
girls	O
.	O

Uracil	B-GENE
DNA	I-GENE
glycosylase	I-GENE
catalyzes	O
the	O
initial	O
step	O
in	O
the	O
repair	O
pathway	O
that	O
removes	O
potentially	O
mutagenic	O
uracil	O
from	O
duplex	O
DNA	O
.	O

Current	O
clinical	O
trials	O
should	O
answer	O
the	O
question	O
of	O
which	O
of	O
the	O
therapeutic	O
options	O
impairs	O
quality	O
of	O
life	O
less	O
.	O

In	O
this	O
report	O
,	O
we	O
focus	O
on	O
the	O
genetics	O
of	O
the	O
region	O
of	O
the	O
17	B-GENE
hep	I-GENE
syn	I-GENE
gB	I-GENE
gene	I-GENE
that	O
conferred	O
both	O
the	O
syncytial	O
and	O
pathogenic	O
phenotypes	O
to	O
17	B-GENE
syn	I-GENE
+	I-GENE
.	O

Recipients	O
with	O
acute	O
leukaemia	O
in	O
first	O
remission	O
or	O
chronic	O
myeloid	O
leukaemia	O
in	O
first	O
chronic	O
phase	O
were	O
analysed	O
as	O
good	O
risk	O
,	O
and	O
those	O
beyond	O
these	O
stages	O
,	O
as	O
poor	O
risk	O
patients	O
.	O

Elledge	O
,	O
P	O
.	O

Drugs	O
suppressed	O
>	O
or	O
=	O
75	O
%	O
of	O
the	O
total	O
premature	O
ventricular	O
contractions	O
in	O
all	O
patients	O
who	O
had	O
both	O
use	O
-	O
dependent	O
QRS	O
prolongation	O
and	O
reverse	O
use	O
-	O
dependent	O
QT	O
prolongation	O
,	O
in	O
79	O
%	O
of	O
patients	O
with	O
use	O
-	O
dependent	O
QRS	O
prolongation	O
alone	O
,	O
in	O
70	O
%	O
with	O
reverse	O
use	O
-	O
dependent	O
QT	O
prolongation	O
alone	O
,	O
and	O
in	O
11	O
%	O
with	O
neither	O
use	O
-	O
dependent	O
QRS	O
prolongation	O
nor	O
reverse	O
use	O
-	O
dependent	O
QT	O
prolongation	O
.	O

Losses	O
during	O
the	O
complete	O
procedure	O
are	O
corrected	O
for	O
using	O
radioactive	O
estrogen	O
conjugates	O
during	O
the	O
first	O
steps	O
and	O
later	O
by	O
adding	O
deuterated	O
internal	O
standards	O
of	O
all	O
compounds	O
measured	O
(	O
matairesinol	O
,	O
enterodiol	O
,	O
enterolactone	O
,	O
daidzein	O
,	O
O	O
-	O
desmethylangolensin	O
,	O
equol	O
,	O
and	O
genistein	O
)	O
.	O

The	O
Sp1	B-GENE
region	I-GENE
,	O
however	O
,	O
is	O
converted	O
to	O
a	O
functionally	O
strong	O
TRE	O
by	O
the	O
viral	B-GENE
tat	I-GENE
factor	I-GENE
.	O

Three	O
group	O
1	O
patients	O
developed	O
CMV	O
disease	O
;	O
1	O
group	O
2	O
patient	O
developed	O
CMV	O
hepatitis	O
.	O

The	O
ability	O
of	O
spt2	B-GENE
mutations	I-GENE
to	O
suppress	O
the	O
transcriptional	O
interference	O
caused	O
by	O
the	O
delta	B-GENE
promoter	I-GENE
insertion	I-GENE
his	I-GENE
-	I-GENE
4	I-GENE
-	I-GENE
912	I-GENE
delta	I-GENE
correlates	O
with	O
an	O
increase	O
in	O
wild	B-GENE
-	I-GENE
type	I-GENE
HIS4	I-GENE
mRNA	I-GENE
levels	O
.	O

Nuclear	O
localization	O
and	O
protein	O
sequence	O
similarities	O
suggested	O
that	O
the	O
SPT2	B-GENE
/	O
SIN1	B-GENE
protein	O
may	O
be	O
related	O
to	O
the	O
nonhistone	B-GENE
chromosomal	I-GENE
protein	I-GENE
HMG1	I-GENE
.	O

The	O
conserved	O
ninth	O
C	O
-	O
terminal	O
heptad	O
in	O
thyroid	O
hormone	O
and	O
retinoic	B-GENE
acid	I-GENE
receptors	I-GENE
mediates	O
diverse	O
responses	O
by	O
affecting	O
heterodimer	O
but	O
not	O
homodimer	O
formation	O
.	O

Genetic	O
interactions	O
between	O
BCK2	B-GENE
and	O
other	O
pathway	O
components	O
suggested	O
that	O
BCK2	B-GENE
functions	O
on	O
a	O
common	O
pathway	O
branch	O
with	O
PPZ1	B-GENE
and	O
PPZ2	B-GENE
.	O

Steroidogenic	B-GENE
factor	I-GENE
1	I-GENE
,	O
an	O
orphan	B-GENE
nuclear	I-GENE
receptor	I-GENE
,	O
regulates	O
the	O
expression	O
of	O
the	O
rat	B-GENE
aromatase	I-GENE
gene	I-GENE
in	O
gonadal	O
tissues	O
.	O

To	O
study	O
the	O
functional	O
differences	O
between	O
cutaneous	O
HPV5	O
and	O
HPV8	O
E7s	B-GENE
and	O
genital	B-GENE
HPV16	I-GENE
E7	I-GENE
,	O
we	O
cloned	O
each	O
of	O
the	O
E7	B-GENE
open	O
reading	O
frames	O
and	O
tested	O
their	O
immortalizing	O
and	O
transforming	O
activities	O
,	O
the	O
binding	O
ability	O
of	O
their	O
products	O
with	O
retinoblastoma	B-GENE
protein	I-GENE
(	O
RB	B-GENE
)	O
and	O
their	O
complementation	O
activity	O
of	O
a	O
RB	B-GENE
-	I-GENE
nonbinding	I-GENE
adenovirus	I-GENE
E1A	I-GENE
mutant	I-GENE
.	O

The	O
rhaB	B-GENE
transcription	I-GENE
start	I-GENE
site	I-GENE
was	O
mapped	O
to	O
-	O
24	O
relative	O
to	O
the	O
start	O
of	O
translation	O
.	O

Several	O
lines	O
of	O
evidence	O
demonstrate	O
that	O
this	O
growth	O
inhibition	O
requires	O
active	O
PKA	B-GENE
subunits	I-GENE
and	O
cAMP	O
:	O
(	O
i	O
)	O
this	O
phenotype	O
is	O
dependent	O
on	O
cAMP	O
since	O
it	O
is	O
not	O
seen	O
in	O
a	O
strain	O
lacking	O
adenylyl	B-GENE
cyclase	I-GENE
activity	O
,	O
but	O
the	O
growth	O
rate	O
of	O
these	O
transformants	O
is	O
slower	O
when	O
exogenous	O
cAMP	O
is	O
added	O
;	O
(	O
ii	O
)	O
normal	O
growth	O
occurs	O
when	O
wild	O
-	O
type	O
RI	B-GENE
cDNA	O
is	O
replaced	O
by	O
a	O
mutant	B-GENE
RI	I-GENE
cDNA	I-GENE
encoding	O
a	O
RI	B-GENE
protein	I-GENE
with	O
reduced	O
cAMP	O
binding	O
;	O
and	O
(	O
iii	O
)	O
the	O
growth	O
-	O
inhibited	O
phenotype	O
of	O
the	O
transformed	O
BL21	O
(	O
DE3	O
)	O
cells	O
requires	O
soluble	O
,	O
active	O
C	B-GENE
alpha	I-GENE
protein	I-GENE
.	O

Liu	O
,	O
B	O
.	O

BCR	B-GENE
-	O
ABL	B-GENE
and	O
v	B-GENE
-	I-GENE
abl	I-GENE
oncogenes	I-GENE
induce	O
distinct	O
patterns	O
of	O
thymic	O
lymphoma	O
involving	O
different	O
lymphocyte	O
subsets	O
.	O

These	O
experiments	O
confirm	O
that	O
the	O
6	O
-	O
S	O
liganded	O
form	O
of	O
the	O
receptor	O
identified	O
in	O
nuclear	O
extracts	O
of	O
cells	O
treated	O
with	O
2	O
,	O
3	O
,	O
7	O
,	O
8	O
-	O
tetrachlorodibenzo	O
-	O
p	O
-	O
dioxin	O
(	O
TCDD	O
)	O
contains	O
the	O
Ah	B-GENE
receptor	I-GENE
protein	I-GENE
and	O
ARNT	B-GENE
but	O
not	O
the	O
90	B-GENE
-	I-GENE
kDa	I-GENE
heat	I-GENE
shock	I-GENE
protein	I-GENE
.	O

LDL	B-GENE
cholesterol	I-GENE
decreased	O
from	O
4	O
.	O
74	O
+	O
/	O
-	O
0	O
.	O
87	O
to	O
3	O
.	O
78	O
+	O
/	O
-	O
0	O
.	O
78	O
mmol	O
/	O
l	O
after	O
8	O
weeks	O
on	O
simvastatin	O
(	O
P	O
<	O
0	O
.	O
001	O
)	O
,	O
and	O
apo	B-GENE
B	I-GENE
fell	O
from	O
142	O
+	O
/	O
-	O
31	O
to	O
112	O
+	O
/	O
-	O
22	O
mg	O
/	O
dl	O
(	O
P	O
<	O
0	O
.	O
001	O
)	O
.	O

LDL	B-GENE
cholesterol	I-GENE
decreased	O
from	O
4	O
.	O
74	O
+	O
/	O
-	O
0	O
.	O
87	O
to	O
3	O
.	O
78	O
+	O
/	O
-	O
0	O
.	O
78	O
mmol	O
/	O
l	O
after	O
8	O
weeks	O
on	O
simvastatin	O
(	O
P	O
<	O
0	O
.	O
001	O
)	O
,	O
and	O
apo	B-GENE
B	I-GENE
fell	O
from	O
142	O
+	O
/	O
-	O
31	O
to	O
112	O
+	O
/	O
-	O
22	O
mg	O
/	O
dl	O
(	O
P	O
<	O
0	O
.	O
001	O
)	O
.	O

This	O
negative	O
element	O
may	O
,	O
at	O
least	O
in	O
part	O
,	O
be	O
responsible	O
for	O
the	O
cell	O
type	O
-	O
specific	O
expression	O
of	O
the	O
DGK	B-GENE
gene	I-GENE
.	O

Regulated	O
activity	O
of	O
the	O
distal	O
promoter	O
-	O
like	O
element	O
of	O
the	O
human	B-GENE
corticotropin	I-GENE
-	I-GENE
releasing	I-GENE
hormone	I-GENE
gene	I-GENE
and	O
secondary	O
structural	O
features	O
of	O
its	O
corresponding	O
transcripts	O
.	O

A	O
new	O
bioencapsulation	O
technology	O
for	O
microbial	O
inoculants	O
.	O

We	O
linked	O
hypersensitivity	O
site	O
2	O
(	O
HS2	O
)	O
from	O
the	O
locus	O
control	O
region	O
(	O
LCR	O
)	O
to	O
a	O
A	B-GENE
gamma	I-GENE
-	I-GENE
globin	I-GENE
gene	O
(	O
A	B-GENE
gamma	I-GENE
*	I-GENE
)	O
mutationally	O
marked	O
to	O
allow	O
its	O
transcript	O
to	O
be	O
distinguished	O
from	O
endogenous	O
gamma	B-GENE
-	I-GENE
globin	I-GENE
mRNA	O
.	O

INTERVENTIONS	O
-	O
-	O
Patients	O
allocated	O
to	O
treatment	O
with	O
levodopa	B-GENE
/	I-GENE
dopa	I-GENE
decarboxylase	I-GENE
inhibitor	O
alone	O
(	O
arm	O
1	O
)	O
,	O
levodopa	B-GENE
/	I-GENE
decarboxylase	I-GENE
inhibitor	O
/	O
selegiline	O
in	O
combination	O
(	O
arm	O
2	O
)	O
,	O
or	O
bromocriptine	O
(	O
arm	O
3	O
)	O
.	O

It	O
contains	O
three	O
putative	O
binding	O
sites	O
for	O
transcription	B-GENE
factor	I-GENE
Sp1	I-GENE
as	O
well	O
as	O
several	O
short	O
sequences	O
that	O
are	O
similar	O
to	O
known	O
cis	O
-	O
acting	O
enhancers	O
or	O
binding	O
sites	O
for	O
transcription	O
factors	O
.	O

French	O
bean	O
contains	O
a	O
small	O
family	O
of	O
genes	B-GENE
encoding	I-GENE
PAL	I-GENE
and	O
two	O
of	O
these	O
genes	O
,	O
PAL2	B-GENE
and	O
PAL3	B-GENE
,	O
have	O
been	O
shown	O
to	O
be	O
differentially	O
expressed	O
at	O
the	O
mRNA	O
level	O
in	O
bean	O
tissues	O
.	O

Plasma	O
thromboxane	O
B2	O
levels	O
in	O
the	O
older	O
group	O
were	O
about	O
double	O
those	O
in	O
younger	O
piglets	O
.	O

By	O
stepwise	O
linear	O
multiple	O
regression	O
analysis	O
,	O
ionized	O
magnesium	O
was	O
significantly	O
related	O
to	O
cyclosporin	O
trough	O
level	O
and	O
total	O
cholesterol	O
but	O
not	O
to	O
serum	O
creatinine	O
,	O
time	O
after	O
transplant	O
or	O
the	O
dose	O
of	O
cyclosporin	O
.	O

The	O
human	B-GENE
insulin	I-GENE
-	I-GENE
like	I-GENE
growth	I-GENE
factor	I-GENE
II	I-GENE
(	O
IGF	B-GENE
-	I-GENE
II	I-GENE
)	O
gene	O
contains	O
four	O
promoters	O
(	O
P1	O
,	O
P2	O
,	O
P3	O
and	O
P4	O
)	O
.	O

Moreover	O
,	O
in	O
transient	O
transfection	O
assays	O
,	O
PU	B-GENE
.	I-GENE
1	I-GENE
alone	O
activated	O
reporter	O
constructs	O
containing	O
the	O
JB	O
cis	O
-	O
element	O
,	O
and	O
the	O
activation	O
was	O
shown	O
to	O
be	O
dependent	O
on	O
a	O
glutamine	O
-	O
rich	O
sequence	O
in	O
the	O
amino	O
-	O
terminal	O
portion	O
of	O
PU	B-GENE
.	I-GENE
1	I-GENE
.	O

Army	O
veterans	O
given	O
yellow	O
fever	O
vaccine	O
contaminated	O
with	O
hepatitis	O
B	O
virus	O
in	O
1942	O
and	O
controls	O
and	O
(	O
b	O
)	O
a	O
case	O
-	O
control	O
study	O
comparing	O
veterans	O
with	O
hepatocellular	O
carcinoma	O
in	O
Veterans	O
Affairs	O
hospitals	O
with	O
matched	O
controls	O
with	O
respect	O
to	O
receipt	O
of	O
contaminated	O
vaccine	O
in	O
1942	O
.	O

They	O
were	O
found	O
to	O
be	O
seropositive	O
for	O
antibodies	O
to	O
hepatitis	O
C	O
virus	O
by	O
second	O
-	O
generation	O
testing	O
(	O
RIBA	O
2	O
,	O
Ortho	O
Diagnostic	O
Systems	O
Inc	O
,	O
Westwood	O
,	O
MA	O
)	O
.	O

When	O
introduced	O
into	O
recJ	B-GENE
+	I-GENE
strains	O
,	O
srjA	B-GENE
mutations	O
conferred	O
hyperrecombinational	O
and	O
hyper	B-GENE
-	I-GENE
UVr	I-GENE
phenotypes	O
.	O

Distinguishing	O
roles	O
of	O
the	O
membrane	O
-	O
cytoskeleton	O
and	O
cadherin	B-GENE
mediated	O
cell	O
-	O
cell	O
adhesion	O
in	O
generating	O
different	O
Na	B-GENE
+	I-GENE
,	I-GENE
K	I-GENE
(	I-GENE
+	I-GENE
)	I-GENE
-	I-GENE
ATPase	I-GENE
distributions	O
in	O
polarized	O
epithelia	O
.	O

Neonatal	O
lupus	O
erythematosus	O
is	O
most	O
often	O
associated	O
with	O
autoantibodies	O
against	O
Ro	B-GENE
and	O
La	B-GENE
antigens	O
.	O

Genetic	O
abnormalities	O
that	O
could	O
lead	O
to	O
mutagenesis	O
include	O
chromosomal	O
abnormalities	O
and	O
single	O
-	O
gene	O
mutations	O
.	O

Hops	O
,	O
and	O
L	O
.	O

Continued	O
absorption	O
of	O
amino	O
acids	O
by	O
the	O
NBB	O
carrier	O
(	O
for	O
neutral	O
amino	O
acids	O
)	O
,	O
the	O
Y	O
+	O
system	O
(	O
for	O
dibasic	O
amino	O
acids	O
)	O
,	O
and	O
the	O
PHE	O
carrier	O
were	O
operative	O
even	O
during	O
the	O
actively	O
purging	O
stage	O
of	O
watery	O
diarrhoea	O
due	O
to	O
cholera	O
.	O

1	O
)	O
CFDN	O
,	O
AMPC	O
and	O
MNZ	O
showed	O
a	O
potent	O
antimicrobial	O
activity	O
against	O
H	O
.	O
pylori	O
,	O
and	O
especially	O
,	O
AMPC	O
showed	O
a	O
marked	O
bactericidal	O
activity	O
in	O
a	O
short	O
time	O
.	O

Creutzfeldt	O
-	O
Jakob	O
disease	O
and	O
lyophilised	O
dura	O
mater	O
grafts	O
:	O
report	O
of	O
two	O
cases	O
.	O

A	O
high	O
mean	O
intensity	O
of	O
CLTPA	O
(	O
standardized	O
multivariate	O
regression	O
coefficient	O
beta	O
-	O
0	O
.	O
059	O
,	O
p	O
=	O
0	O
.	O
020	O
)	O
and	O
a	O
high	O
maximal	O
oxygen	O
uptake	O
(	O
beta	O
-	O
0	O
.	O
163	O
,	O
p	O
<	O
0	O
.	O
001	O
)	O
were	O
associated	O
with	O
reduced	O
plasma	B-GENE
fibrinogen	I-GENE
when	O
adjusting	O
for	O
the	O
strongest	O
covariates	O
.	O

What	O
young	O
people	O
think	O
and	O
do	O
when	O
the	O
option	O
for	O
cystic	O
fibrosis	O
carrier	O
testing	O
is	O
available	O
.	O

A	O
patient	O
matches	O
a	O
PIC	O
patient	O
if	O
both	O
have	O
the	O
same	O
mechanism	O
of	O
injury	O
,	O
the	O
same	O
coding	O
of	O
Revised	O
Trauma	O
Score	O
variables	O
(	O
Glascow	O
Coma	O
Scale	O
score	O
,	O
systolic	O
blood	O
pressure	O
,	O
respiratory	O
rate	O
)	O
,	O
the	O
same	O
coded	O
age	O
per	O
A	O
Severity	O
Characterization	O
of	O
Trauma	O
)	O
(	O
ASCOT	O
)	O
,	O
and	O
if	O
they	O
differ	O
by	O
no	O
more	O
than	O
0	O
.	O
5	O
for	O
A	O
,	O
B	O
,	O
and	O
C	O
(	O
the	O
ASCOT	O
components	O
for	O
serious	O
injuries	O
)	O
.	O

Skin	O
and	O
bowel	O
TPO2	O
varied	O
with	O
DO2	O
and	O
each	O
other	O
(	O
P	O
<	O
0	O
.	O
05	O
)	O
.	O

We	O
have	O
isolated	O
a	O
cosmid	O
containing	O
DNA	O
that	O
corresponds	O
to	O
the	O
site	O
of	O
transposon	O
insertion	O
in	O
257DH4	O
and	O
have	O
localized	O
Tn5	B-GENE
on	O
an	O
8	B-GENE
.	I-GENE
0	I-GENE
kb	I-GENE
EcoRI	I-GENE
fragment	I-GENE
.	O

The	O
scr	B-GENE
regulon	I-GENE
of	O
pUR400	O
and	O
the	O
chromosomally	B-GENE
encoded	I-GENE
scr	I-GENE
regulon	I-GENE
of	I-GENE
Klebsiella	I-GENE
pneumoniae	I-GENE
KAY2026	I-GENE
are	O
both	O
negatively	O
controlled	O
by	O
a	O
specific	O
repressor	O
(	O
ScrR	B-GENE
)	O
.	O

Although	O
the	O
molecular	O
mechanisms	O
involved	O
in	O
this	O
regulation	O
are	O
currently	O
being	O
elucidated	O
,	O
very	O
little	O
is	O
known	O
about	O
the	O
trans	O
-	O
acting	O
factors	O
that	O
allow	O
expression	O
of	O
the	O
nitrate	B-GENE
and	I-GENE
nitrite	I-GENE
reductase	I-GENE
genes	I-GENE
which	O
code	O
for	O
the	O
first	O
enzymes	O
in	O
the	O
pathway	O
.	O

The	O
Ntl1	B-GENE
gene	I-GENE
is	O
present	O
as	O
a	O
unique	O
copy	O
in	O
the	O
diploid	O
N	O
.	O
plumbaginifolia	O
species	O
.	O

Transient	O
transfection	O
experiments	O
revealed	O
that	O
Pax	B-GENE
-	I-GENE
8	I-GENE
isoforms	I-GENE
a	I-GENE
and	I-GENE
b	I-GENE
,	O
but	O
not	O
c	O
and	O
d	O
,	O
strongly	O
stimulate	O
transcription	O
from	O
a	O
promoter	O
containing	O
six	O
copies	O
of	O
a	O
paired	B-GENE
-	I-GENE
domain	I-GENE
recognition	I-GENE
sequence	I-GENE
.	O

The	O
amino	O
-	O
terminal	O
third	O
of	O
the	O
protein	O
contains	O
a	O
high	B-GENE
-	I-GENE
mobility	I-GENE
-	I-GENE
group	I-GENE
motif	I-GENE
characteristic	O
of	O
DNA	O
-	O
binding	O
proteins	O
.	O

We	O
have	O
examined	O
the	O
ability	O
of	O
various	O
NF	B-GENE
-	I-GENE
kappa	I-GENE
B	I-GENE
subunits	I-GENE
to	O
bind	O
to	O
,	O
and	O
activate	O
transcription	O
from	O
,	O
the	O
IL	B-GENE
-	I-GENE
8	I-GENE
promoter	I-GENE
.	O

When	O
multiple	O
copies	O
of	O
the	O
IL	B-GENE
-	I-GENE
1	I-GENE
beta	I-GENE
NF	B-GENE
-	I-GENE
kappa	I-GENE
B	I-GENE
site	I-GENE
were	O
linked	O
to	O
an	O
enhancerless	O
simian	B-GENE
virus	I-GENE
40	I-GENE
promoter	I-GENE
,	O
this	O
element	O
was	O
able	O
to	O
mediate	O
phorbol	O
ester	O
-	O
or	O
lipopolysaccharide	O
-	O
inducible	O
gene	O
expression	O
.	O

We	O
found	O
that	O
the	O
3	O
'	O
-	O
end	O
-	O
adjacent	O
sequence	O
CA	O
(	O
N	O
)	O
3	O
-	O
10AGTNNAA	O
,	O
conserved	O
in	O
plant	O
Pol	B-GENE
II	I-GENE
-	O
specific	O
U	B-GENE
snRNA	I-GENE
genes	I-GENE
,	O
is	O
essential	O
for	O
the	O
3	O
'	O
-	O
end	O
formation	O
of	O
U2	B-GENE
transcripts	I-GENE
and	O
,	O
similar	O
to	O
the	O
vertebrate	O
3	O
'	O
box	O
,	O
is	O
highly	O
tolerant	O
to	O
mutation	O
.	O

These	O
results	O
indicate	O
that	O
Rb	B-GENE
protein	I-GENE
is	O
interacting	O
with	O
some	O
component	O
(	O
s	O
)	O
of	O
the	O
cell	O
cycle	O
-	O
regulatory	O
machinery	O
during	O
G2	O
phase	O
.	O

MDBP	B-GENE
from	O
HeLa	O
and	O
Raji	O
cells	O
formed	O
DNA	O
-	O
protein	O
complexes	O
with	O
X	O
-	O
box	O
oligonucleotides	O
that	O
coelectrophoresed	O
with	O
those	O
containing	O
standard	O
MDBP	B-GENE
sites	I-GENE
.	O

Transgenic	O
mice	O
harboring	O
the	O
rat	O
TnI	B-GENE
-	O
CAT	B-GENE
fusion	O
gene	O
expressed	O
the	O
reporter	O
specifically	O
in	O
the	O
skeletal	O
muscle	O
.	O

The	O
ADP	B-GENE
-	I-GENE
ribosylation	I-GENE
factor	I-GENE
(	O
ARF	B-GENE
)	O
family	O
is	O
one	O
of	O
four	O
subfamilies	O
of	O
the	O
RAS	B-GENE
superfamily	I-GENE
of	O
low	B-GENE
molecular	I-GENE
weight	I-GENE
GTP	I-GENE
-	I-GENE
binding	I-GENE
proteins	I-GENE
(	O
G	B-GENE
proteins	I-GENE
)	O
.	O

The	O
E1	B-GENE
gene	I-GENE
is	O
located	O
within	O
the	O
first	O
intron	O
of	O
the	O
gene	O
for	O
RCC1	B-GENE
,	O
a	O
protein	O
that	O
regulates	O
onset	O
of	O
mitosis	O
.	O

Genomic	O
Southern	O
blot	O
analysis	O
and	O
chromosome	O
mapping	O
showed	O
that	O
GPRK6	B-GENE
hybridizes	O
to	O
two	O
closely	O
related	O
genes	O
located	O
on	O
chromosomes	O
5	O
and	O
13	O
and	O
are	O
,	O
therefore	O
,	O
distinct	O
from	O
the	O
GPRK	B-GENE
located	O
near	O
the	O
Huntington	B-GENE
disease	I-GENE
locus	I-GENE
on	O
chromosome	O
4	O
.	O

Metabolic	O
labeling	O
studies	O
in	O
S	O
.	O
cerevisiae	O
and	O
co	O
-	O
expression	O
of	O
nmt72p	B-GENE
with	O
several	O
protein	O
substrates	O
of	O
Nmt1p	B-GENE
in	O
Escherichia	O
coli	O
indicate	O
that	O
the	O
Leu99	O
-	O
-	O
>	O
Pro	O
substitution	O
causes	O
a	O
reduction	O
in	O
the	O
acylation	O
of	O
some	O
but	O
not	O
all	O
protein	O
substrates	O
.	O

These	O
CTD	B-GENE
kinases	I-GENE
,	O
designated	O
CTDK1	B-GENE
and	O
CTDK2	B-GENE
,	O
are	O
fractionated	O
by	O
chromatography	O
on	O
Mono	O
Q	O
.	O

Previously	O
,	O
we	O
identified	O
a	O
51	O
-	O
bp	O
promoter	O
fragment	O
,	O
oligo31	O
/	O
32	O
,	O
which	O
conferred	O
heat	O
shock	O
inducibility	O
on	O
the	O
heterologous	O
CYC1	B-GENE
-	O
lacZ	B-GENE
reporter	O
gene	O
in	O
S	O
.	O
cerevisiae	O
(	O
N	O
.	O

To	O
identify	O
factors	O
that	O
may	O
modify	O
the	O
heterosexual	O
transmission	O
of	O
human	O
T	O
cell	O
leukemia	O
/	O
lymphoma	O
virus	O
type	O
I	O
(	O
HTLV	O
-	O
I	O
)	O
,	O
534	O
married	O
couples	O
enrolled	O
in	O
the	O
Miyazaki	O
Cohort	O
Study	O
between	O
November	O
1984	O
and	O
April	O
1989	O
were	O
studied	O
:	O
95	O
husband	O
HTLV	O
-	O
I	O
-	O
seropositive	O
(	O
H	O
+	O
)	O
/	O
wife	O
seropositive	O
(	O
W	O
+	O
)	O
,	O
33	O
H	O
+	O
/	O
W	O
-	O
,	O
64	O
H	O
-	O
/	O
W	O
+	O
,	O
and	O
342	O
H	O
-	O
/	O
W	O
-	O
.	O

To	O
characterize	O
the	O
expression	O
of	O
this	O
DNA	B-GENE
repair	I-GENE
enzyme	I-GENE
,	O
we	O
have	O
isolated	O
the	O
corresponding	O
genomic	O
clone	O
.	O

L	O
.	O
,	O
Stange	O
,	O
G	O
.	O
,	O
Markovich	O
,	O
D	O
.	O
,	O
Biber	O
,	O
J	O
.	O
,	O
Testar	O
,	O
X	O
.	O
,	O
Zorzano	O
,	O
A	O
.	O
,	O
Palacin	O
,	O
M	O
.	O
,	O
and	O
Murer	O
,	O
H	O
.	O

The	O
nucleotide	O
sequence	O
of	O
the	O
gene	O
predicts	O
a	O
polypeptide	O
of	O
215	O
amino	O
acids	O
(	O
25	O
.	O
2	O
kDa	O
)	O
with	O
two	O
putative	O
membrane	O
-	O
spanning	O
domains	O
.	O

SAECG	O
,	O
echocardiography	O
and	O
thallium	O
-	O
201	O
imaging	O
were	O
performed	O
before	O
and	O
1	O
month	O
after	O
attempted	O
angioplasty	O
.	O

They	O
were	O
called	O
PACE4	B-GENE
and	O
PC4	B-GENE
.	O

Both	O
fusion	O
proteins	O
form	O
stable	O
specific	O
complexes	O
with	O
a	O
short	O
DNA	O
duplex	O
harboring	O
the	O
CTGT	O
(	O
at	O
)	O
4ACAG	O
consensus	O
sequence	O
of	O
the	O
LexA	B-GENE
repressor	I-GENE
.	O

Ten	O
selenocysteine	O
residues	O
(	O
deduced	O
)	O
are	O
present	O
.	O

CONCLUSIONS	O
:	O
Free	O
protein	B-GENE
S	I-GENE
deficiency	O
is	O
common	O
among	O
hospitalized	O
patients	O
,	O
even	O
in	O
the	O
absence	O
of	O
a	O
recognized	O
predisposing	O
condition	O
.	O

During	O
the	O
past	O
decade	O
,	O
different	O
types	O
of	O
endogenous	O
retroviral	O
sequences	O
have	O
been	O
defined	O
in	O
the	O
human	O
genome	O
usually	O
by	O
low	O
stringency	O
hybridization	O
employing	O
DNA	O
probes	O
of	O
evolutionary	O
conserved	O
animal	O
retrovirus	O
genes	O
.	O

As	O
the	O
components	O
of	O
these	O
complexes	O
,	O
at	O
least	O
five	O
TRBPs	B-GENE
(	O
p30	B-GENE
,	O
p37	B-GENE
,	O
p46	B-GENE
,	O
p50	B-GENE
,	O
and	O
p56	B-GENE
)	O
showing	O
specific	O
binding	O
to	O
the	O
TAR	O
RNA	O
were	O
detected	O
in	O
the	O
uv	O
cross	O
-	O
linking	O
assay	O
.	O

The	O
obvious	O
functional	O
necessity	O
for	O
editing	O
in	O
kinetoplastid	O
mitochondria	O
is	O
the	O
formation	O
of	O
translatable	O
mRNAs	O
.	O

An	O
extensive	O
inverted	O
repeat	O
is	O
present	O
3	O
'	O
of	O
rpeA	B-GENE
;	O
inverted	O
repeats	O
are	O
found	O
downstream	O
of	O
all	O
PE	B-GENE
operons	I-GENE
sequenced	O
to	O
date	O
,	O
although	O
the	O
sequence	O
is	O
not	O
conserved	O
.	O

Large	O
differences	O
between	O
the	O
groups	O
were	O
not	O
observed	O
in	O
HA	B-GENE
-	I-GENE
synthesizing	I-GENE
enzyme	I-GENE
activity	O
,	O
but	O
degradative	O
enzyme	O
activity	O
was	O
much	O
higher	O
in	O
aspirin	O
-	O
induced	O
asthma	O
-	O
related	O
polyps	O
than	O
in	O
other	O
types	O
of	O
nasal	O
polyps	O
tested	O
.	O

In	O
the	O
multivariate	O
analysis	O
,	O
six	O
variables	O
were	O
independently	O
correlated	O
with	O
survival	O
:	O
blood	O
urea	O
nitrogen	O
level	O
,	O
serum	B-GENE
aspartate	I-GENE
aminotransferase	I-GENE
level	O
,	O
community	O
-	O
acquired	O
vs	O
.	O
hospital	O
-	O
acquired	O
peritonitis	O
,	O
age	O
,	O
Child	O
-	O
Pugh	O
score	O
and	O
ileus	O
.	O

Localization	O
of	O
the	O
intronless	O
gene	O
coding	O
for	O
calmodulin	B-GENE
-	I-GENE
like	I-GENE
protein	I-GENE
CLP	B-GENE
to	O
human	O
chromosome	O
10p13	O
-	O
ter	O
.	O

In	O
wandering	O
stage	O
larvae	O
,	O
the	O
OBP	B-GENE
transcript	I-GENE
appeared	O
to	O
be	O
at	O
least	O
250	O
-	O
fold	O
less	O
abundant	O
than	O
ribosomal	O
RNA	O
.	O

One	O
such	O
mutant	O
also	O
affects	O
the	O
overlapping	O
-	O
10	O
hexamer	O
of	O
PR	O
and	O
results	O
in	O
reduced	O
occupancy	O
by	O
both	O
MerR	B-GENE
and	O
RNA	B-GENE
polymerase	I-GENE
,	O
likely	O
as	O
a	O
result	O
of	O
inefficient	O
transcriptional	O
initiation	O
of	O
merR	B-GENE
mRNA	I-GENE
.	O

This	O
promoter	O
could	O
direct	O
the	O
constitutive	O
expression	O
of	O
the	O
reporter	O
beta	B-GENE
-	I-GENE
galactosidase	I-GENE
at	O
high	O
frequency	O
in	O
transfected	O
colonies	O
of	O
transformed	O
cells	O
that	O
express	O
L	B-GENE
-	I-GENE
plastin	I-GENE
constitutively	O
;	O
by	O
contrast	O
,	O
this	O
promoter	O
was	O
virtually	O
inactive	O
in	O
transfected	O
colonies	O
of	O
normal	O
fibroblasts	O
and	O
it	O
exhibited	O
a	O
low	O
frequency	O
of	O
constitutive	O
activation	O
in	O
transfected	O
colonies	O
of	O
in	O
vitro	O
SV40	O
-	O
transformed	O
fibroblasts	O
which	O
did	O
not	O
exhibit	O
L	B-GENE
-	I-GENE
plastin	I-GENE
expression	O
.	O

The	O
half	O
-	O
life	O
of	O
the	O
serum	O
-	O
induced	O
CBP	B-GENE
/	O
tk	B-GENE
binding	O
activity	O
was	O
estimated	O
to	O
be	O
less	O
than	O
1	O
h	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
400	O
WORDS	O
)	O

The	O
gene	O
includes	O
three	O
exons	O
and	O
two	O
introns	O
within	O
1	O
.	O
6	O
kilobases	O
of	O
DNA	O
,	O
and	O
the	O
entire	O
open	O
reading	O
frame	O
for	O
glycoprotein	B-GENE
IX	I-GENE
is	O
included	O
within	O
the	O
third	O
exon	O
.	O

Rhizobium	O
meliloti	O
large	O
plasmid	O
pRmeGR4b	O
carries	O
the	O
nodulation	O
competitiveness	O
locus	O
nfe	B-GENE
responsible	O
for	O
the	O
nodulation	O
efficiency	O
and	O
competitive	O
ability	O
of	O
strain	O
GR4	O
on	O
alfalfa	O
roots	O
.	O

Further	O
,	O
the	O
ability	O
of	O
recombinant	O
beta	O
and	O
/	O
or	O
gamma	O
chains	O
to	O
function	O
in	O
defined	O
biochemical	O
assays	O
of	O
beta	O
gamma	O
activity	O
was	O
assessed	O
for	O
membrane	O
extracts	O
and	O
supernatant	O
fractions	O
from	O
infected	O
Sf9	O
cells	O
.	O

This	O
report	O
describes	O
the	O
identification	O
of	O
a	O
gene	O
of	O
related	O
function	O
,	O
SMD1	B-GENE
,	O
located	O
immediately	O
3	O
'	O
to	O
PRP38	B-GENE
.	O

These	O
data	O
establish	O
Smd1p	B-GENE
as	O
a	O
required	O
component	O
of	O
the	O
cellular	O
splicing	O
apparatus	O
and	O
a	O
factor	O
in	O
snRNA	O
maturation	O
and	O
stability	O
.	O

This	O
study	O
compared	O
the	O
gross	O
and	O
fine	O
motor	O
performance	O
of	O
14	O
traumatically	O
brain	O
-	O
injured	O
children	O
(	O
five	O
to	O
15	O
years	O
old	O
,	O
with	O
loss	O
of	O
consciousness	O
for	O
at	O
least	O
24	O
hours	O
)	O
to	O
14	O
normal	O
children	O
group	O
matched	O
for	O
age	O
and	O
sex	O
.	O

We	O
compared	O
the	O
parameters	O
pleural	B-GENE
adenosine	I-GENE
deaminase	I-GENE
(	O
PADA	B-GENE
,	O
determined	O
in	O
405	O
patients	O
)	O
,	O
the	O
PADA	B-GENE
/	O
serum	B-GENE
ADA	I-GENE
ratio	O
(	O
P	B-GENE
/	O
SADA	B-GENE
;	O
276	O
cases	O
)	O
,	O
pleural	B-GENE
lysozyme	I-GENE
(	O
PLYS	B-GENE
,	O
276	O
cases	O
)	O
,	O
the	O
PLYS	B-GENE
/	O
serum	B-GENE
LYS	I-GENE
ratio	O
(	O
P	B-GENE
/	O
SLYS	B-GENE
;	O
276	O
cases	O
)	O
,	O
and	O
pleural	B-GENE
interferon	I-GENE
gamma	I-GENE
(	O
IFN	B-GENE
,	O
145	O
cases	O
)	O
regarding	O
their	O
ability	O
to	O
differentiate	O
tuberculous	O
pleural	O
effusions	O
from	O
others	O
.	O

These	O
exons	O
were	O
identified	O
by	O
cloning	O
and	O
sequencing	O
cDNAs	O
obtained	O
by	O
polymerase	O
chain	O
reaction	O
amplification	O
of	O
a	O
fibroblast	O
cDNA	O
library	O
.	O

Deletion	O
of	O
the	O
apeA	B-GENE
gene	I-GENE
,	O
either	O
with	O
or	O
without	O
deletion	O
of	O
other	O
proteinases	O
(	O
protease	B-GENE
IV	I-GENE
and	O
aminopeptidase	B-GENE
N	I-GENE
)	O
,	O
did	O
not	O
have	O
any	O
effect	O
on	O
cell	O
growth	O
in	O
the	O
various	O
media	O
tested	O
.	O

In	O
Experiment	O
2	O
scopolamine	O
hydrobromide	O
,	O
0	O
.	O
5	O
and	O
1	O
.	O
0	O
mg	O
/	O
kg	O
i	O
.	O
p	O
.	O
,	O
was	O
administered	O
1	O
h	O
before	O
each	O
electrical	O
stimulation	O
until	O
each	O
rat	O
showed	O
the	O
stage	O
-	O
3	O
seizure	O
.	O

PNT	O
,	O
ADD	O
and	O
BSS	O
in	O
the	O
initial	O
stage	O
of	O
kindling	O
,	O
kindling	O
rate	O
for	O
the	O
stage	O
-	O
3	O
and	O
-	O
5	O
seizures	O
,	O
seizure	O
parameters	O
at	O
the	O
first	O
stage	O
-	O
3	O
and	O
-	O
5	O
were	O
recorded	O
and	O
compared	O
to	O
the	O
values	O
of	O
saline	O
-	O
treated	O
,	O
control	O
group	O
.	O

CONCLUSIONS	O
.	O

There	O
was	O
a	O
positive	O
correlation	O
between	O
pyridinium	O
cross	O
-	O
link	O
excretion	O
and	O
thyroid	O
hormone	O
concentrations	O
.	O

Mutations	O
truncating	O
as	O
many	O
as	O
143	O
C	O
-	O
terminal	O
residues	O
from	O
the	O
transcriptional	O
activator	O
encoded	O
by	O
the	O
areA	B-GENE
gene	I-GENE
,	O
mediating	O
nitrogen	O
metabolite	O
repression	O
in	O
Aspergillus	O
nidulans	O
,	O
do	O
not	O
significantly	O
reduce	O
the	O
ability	O
of	O
the	O
areA	B-GENE
product	I-GENE
to	O
activate	O
expression	O
of	O
most	O
genes	O
under	O
areA	B-GENE
control	O
.	O

A	O
region	O
in	O
the	O
C	O
-	O
terminus	O
of	O
adenovirus	B-GENE
2	I-GENE
/	I-GENE
5	I-GENE
E1a	I-GENE
protein	I-GENE
is	O
required	O
for	O
association	O
with	O
a	O
cellular	O
phosphoprotein	O
and	O
important	O
for	O
the	O
negative	O
modulation	O
of	O
T24	O
-	O
ras	B-GENE
mediated	O
transformation	O
,	O
tumorigenesis	O
and	O
metastasis	O
.	O

These	O
studies	O
demonstrate	O
that	O
both	O
G	B-GENE
alpha	I-GENE
i	I-GENE
genes	I-GENE
are	O
dynamically	O
regulated	O
in	O
LLC	O
-	O
PK1	O
cells	O
by	O
both	O
growth	O
,	O
differentiation	O
,	O
and	O
hormone	O
signals	O
.	O

Constructs	O
containing	O
the	O
full	B-GENE
-	I-GENE
length	I-GENE
PfCPK	I-GENE
cDNA	I-GENE
have	O
been	O
expressed	O
in	O
Escherichia	O
coli	O
at	O
a	O
high	O
level	O
to	O
generate	O
a	O
60	O
-	O
kDa	O
recombinant	O
protein	O
.	O

In	O
mitogen	O
-	O
stimulated	O
splenocytes	O
,	O
Gfi	B-GENE
-	I-GENE
1	I-GENE
expression	O
begins	O
to	O
rise	O
at	O
12	O
h	O
after	O
stimulation	O
and	O
reaches	O
very	O
high	O
levels	O
after	O
50	O
h	O
,	O
suggesting	O
that	O
it	O
may	O
be	O
functionally	O
involved	O
in	O
events	O
occurring	O
after	O
the	O
interaction	O
of	O
IL	B-GENE
-	I-GENE
2	I-GENE
with	O
its	O
receptor	O
,	O
perhaps	O
during	O
the	O
transition	O
from	O
the	O
G1	O
to	O
the	O
S	O
phase	O
of	O
the	O
cell	O
cycle	O
.	O

We	O
have	O
isolated	O
and	O
characterized	O
the	O
GCD6	B-GENE
and	O
GCD7	B-GENE
genes	I-GENE
and	O
shown	O
that	O
their	O
products	O
are	O
required	O
to	O
repress	O
GCN4	B-GENE
translation	O
under	O
nonstarvation	O
conditions	O
.	O

The	O
plateau	O
MO2	O
value	O
was	O
that	O
predicted	O
by	O
allometric	O
relation	O
.	O

While	O
the	O
latter	O
corresponded	O
to	O
a	O
protein	O
of	O
824	O
amino	O
acids	O
,	O
an	O
upstream	O
open	O
reading	O
frame	O
(	O
uORF	O
)	O
within	O
the	O
5	O
'	O
leader	O
could	O
potentially	O
encode	O
a	O
54	O
amino	O
acid	O
peptide	O
.	O

The	O
SCH9	B-GENE
protein	I-GENE
kinase	I-GENE
mRNA	I-GENE
contains	O
a	O
long	O
5	O
'	O
leader	O
with	O
a	O
small	O
open	O
reading	O
frame	O
.	O

In	O
contrast	O
to	O
T	O
cells	O
,	O
in	O
fibroblasts	O
PILOT	B-GENE
gene	I-GENE
expression	O
requires	O
only	O
one	O
signal	O
(	O
PMA	O
)	O
and	O
is	O
not	O
affected	O
by	O
CyA	O
.	O

Histochemical	O
localization	O
of	O
GUS	B-GENE
revealed	O
promoter	O
function	O
in	O
leaf	O
epidermis	O
,	O
mesophyll	O
and	O
vascular	O
bundles	O
,	O
in	O
the	O
cortex	O
and	O
vascular	O
cylinder	O
of	O
the	O
root	O
.	O

In	O
order	O
to	O
investigate	O
how	O
these	O
expression	O
patterns	O
are	O
established	O
,	O
we	O
fused	O
promoter	O
regions	O
of	O
an	O
acidic	O
and	O
a	O
basic	O
glucanase	B-GENE
gene	I-GENE
to	O
the	O
beta	B-GENE
-	I-GENE
glucuronidase	I-GENE
(	O
GUS	B-GENE
)	O
reporter	O
gene	O
and	O
examined	O
expression	O
of	O
these	O
constructs	O
in	O
transgenic	O
tobacco	O
plants	O
.	O

Sudomoina	O
,	O
A	O
.	O

Zinc	O
fingers	O
(	O
Zf	O
)	O
are	O
a	O
common	O
structural	O
motif	O
found	O
in	O
many	O
nucleic	O
acid	O
-	O
binding	O
proteins	O
.	O

The	O
deduced	O
bovine	O
EFIA	B-GENE
#	I-GENE
1	I-GENE
amino	O
acid	O
(	O
aa	O
)	O
sequence	O
is	O
98	O
%	O
identical	O
to	O
rat	O
EFIA	B-GENE
and	O
100	O
%	O
identical	O
to	O
human	O
EFIA	B-GENE
/	O
DbpB	B-GENE
/	O
YB	B-GENE
-	I-GENE
1	I-GENE
family	O
member	O
DNA	B-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
B	I-GENE
(	O
DbpB	B-GENE
)	O
.	O

Effect	O
of	O
tracheal	O
insufflation	O
of	O
deferoxamine	O
on	O
acute	O
ozone	O
toxicity	O
in	O
rats	O
.	O

Localization	O
of	O
the	O
insertion	O
locus	O
in	O
the	O
yeast	O
genome	O
and	O
complementation	O
studies	O
with	O
the	O
temperature	O
-	O
sensitive	O
mutant	O
indicate	O
that	O
the	O
two	O
mutations	O
are	O
allelic	O
.	O

Replacement	O
of	O
the	O
spacer	O
sequence	O
between	O
the	O
two	O
ARMs	O
with	O
a	O
shorter	O
stretch	O
of	O
sequence	O
also	O
reduced	O
RNA	O
binding	O
in	O
vitro	O
.	O

Second	O
,	O
the	O
transcription	B-GENE
factor	I-GENE
Gal	I-GENE
-	I-GENE
ER	I-GENE
was	O
rendered	O
more	O
potent	O
and	O
less	O
susceptible	O
to	O
cell	O
type	O
-	O
specific	O
variation	O
by	O
fusing	O
the	O
strong	O
activating	O
domain	O
of	O
the	O
herpesvirus	B-GENE
protein	I-GENE
VP16	I-GENE
onto	O
its	O
C	O
terminus	O
.	O

The	O
exogenous	O
fos	B-GENE
gene	I-GENE
was	O
rapidly	O
induced	O
to	O
maximal	O
levels	O
within	O
1	O
-	O
2	O
hr	O
of	O
estrogen	O
addition	O
.	O

Elimination	O
of	O
Haemophilus	O
influenzae	O
type	O
b	O
meningitis	O
after	O
introduction	O
of	O
vaccination	O

Endosonography	O
accurately	O
assessed	O
tumor	O
extension	O
in	O
two	O
T2	O
tumors	O
,	O
14	O
T3	O
tumors	O
,	O
and	O
seven	O
T4	O
tumors	O
.	O

Analysis	O
of	O
cell	O
cycle	O
regulation	O
in	O
the	O
budding	O
yeast	O
Saccharomyces	O
cerevisiae	O
has	O
shown	O
that	O
a	O
central	O
regulatory	O
protein	O
kinase	O
,	O
Cdc28	B-GENE
,	O
undergoes	O
changes	O
in	O
activity	O
through	O
the	O
cell	O
cycle	O
by	O
associating	O
with	O
distinct	O
groups	O
of	O
cyclins	B-GENE
that	O
accumulate	O
at	O
different	O
times	O
.	O

Overlapping	O
clones	O
representing	O
full	O
-	O
length	O
cDNAs	O
for	O
MMI	B-GENE
alpha	I-GENE
were	O
obtained	O
from	O
mouse	O
brain	O
.	O

The	O
method	O
involves	O
preliminary	O
isolation	O
of	O
oxiracetam	O
and	O
internal	O
standard	O
from	O
plasma	O
by	O
solid	O
-	O
phase	O
extraction	O
prior	O
to	O
the	O
formation	O
of	O
their	O
n	O
-	O
propyl	O
carbamate	O
derivatives	O
.	O

Pathways	O
linking	O
the	O
olfactory	O
bulbs	O
with	O
the	O
medial	O
preoptic	O
anterior	O
hypothalamus	O
are	O
important	O
for	O
intermale	O
aggression	O
in	O
mice	O
.	O

In	O
contrast	O
,	O
rats	O
receiving	O
U74500A	O
(	O
2	O
mg	O
/	O
kg	O
i	O
.	O
v	O
.	O
infusion	O
commencing	O
30	O
min	O
prior	O
to	O
revascularisation	O
)	O
exhibited	O
enhanced	O
GMBF	O
throughout	O
reperfusion	O
[	O
PI	O
10	O
min	O
:	O
3	O
.	O
26	O
(	O
2	O
.	O
56	O
-	O
3	O
.	O
63	O
)	O
;	O
120	O
min	O
:	O
2	O
.	O
03	O
(	O
1	O
.	O
73	O
-	O
2	O
.	O
25	O
)	O
;	O
240	O
min	O
:	O
2	O
.	O
13	O
(	O
1	O
.	O
75	O
-	O
2	O
.	O
44	O
)	O
,	O
p	O
<	O
0	O
.	O
01	O
vs	O
.	O
controls	O
and	O
normals	O
]	O
with	O
complete	O
muscle	O
salvage	O
[	O
GMV	O
100	O
%	O
in	O
all	O
reperfused	O
muscles	O
,	O
p	O
<	O
0	O
.	O
01	O
vs	O
.	O
controls	O
,	O
not	O
significant	O
(	O
NS	O
)	O
vs	O
.	O
normals	O
and	O
6	O
h	O
ischaemia	O
]	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
250	O
WORDS	O
)	O

Sequencing	O
of	O
a	O
1	O
.	O
3	O
-	O
kilobase	O
fragment	O
of	O
the	O
5	O
'	O
-	O
flanking	O
region	O
of	O
the	O
TSG6	B-GENE
gene	I-GENE
identified	O
TATA	O
-	O
like	O
and	O
CAAT	O
sequences	O
near	O
the	O
transcription	O
start	O
site	O
.	O

The	O
region	O
that	O
imparts	O
inducibility	O
by	O
IL	B-GENE
-	I-GENE
1	I-GENE
or	O
TNF	B-GENE
(	O
positions	O
-	O
165	O
to	O
-	O
58	O
)	O
contains	O
potential	O
binding	O
sites	O
for	O
IRF	B-GENE
-	I-GENE
1	I-GENE
and	I-GENE
-	I-GENE
2	I-GENE
,	O
AP	B-GENE
-	I-GENE
1	I-GENE
,	O
and	O
NF	B-GENE
-	I-GENE
IL	I-GENE
-	I-GENE
6	I-GENE
.	O

Ig	B-GENE
-	I-GENE
alpha	I-GENE
and	O
Ig	B-GENE
-	I-GENE
beta	I-GENE
contain	O
extended	O
cytoplasmic	O
structure	O
(	O
61	O
and	O
48	O
amino	O
acids	O
,	O
respectively	O
)	O
and	O
associate	O
with	O
cytoplasmic	O
effectors	O
indicating	O
that	O
they	O
are	O
directly	O
involved	O
in	O
signal	O
transduction	O
.	O

We	O
studied	O
the	O
functional	O
interaction	O
between	O
human	O
embryonic	O
zeta	B-GENE
2	I-GENE
globin	I-GENE
promoter	O
and	O
the	O
alpha	B-GENE
globin	I-GENE
regulatory	I-GENE
element	I-GENE
(	O
HS	B-GENE
-	I-GENE
40	I-GENE
)	O
located	O
40	O
kb	O
upstream	O
of	O
the	O
zeta	B-GENE
2	I-GENE
globin	I-GENE
gene	I-GENE
.	O

It	O
was	O
shown	O
by	O
transient	O
expression	O
assay	O
that	O
HS	B-GENE
-	I-GENE
40	I-GENE
behaved	O
as	O
an	O
authentic	O
enhancer	O
for	O
high	O
-	O
level	O
zeta	B-GENE
2	I-GENE
globin	I-GENE
promoter	I-GENE
activity	O
in	O
K562	O
cells	O
,	O
an	O
erythroid	O
cell	O
line	O
of	O
embryonic	O
and	O
/	O
or	O
fetal	O
origin	O
.	O

Initial	O
results	O
indicate	O
that	O
this	O
23S	B-GENE
pre	I-GENE
-	I-GENE
rRNA	I-GENE
is	O
the	O
same	O
as	O
the	O
species	O
detected	O
on	O
depletion	O
of	O
the	O
small	B-GENE
nucleolar	I-GENE
RNA	I-GENE
-	I-GENE
associated	I-GENE
proteins	I-GENE
NOP1	B-GENE
and	O
GAR1	B-GENE
and	O
in	O
an	O
snr10	B-GENE
mutant	I-GENE
strain	O
.	O

Breitbart	O
,	O
L	O
.	O

This	O
study	O
evaluates	O
the	O
feasibility	O
of	O
indirect	O
mesenteric	O
lymphangiography	O
as	O
a	O
colonoscopic	O
technique	O
in	O
a	O
canine	O
model	O
.	O

Internal	O
amino	O
acid	O
sequence	O
has	O
now	O
been	O
obtained	O
from	O
this	O
protein	O
which	O
shares	O
50	O
-	O
100	O
%	O
sequence	O
identity	O
with	O
sequences	O
encoded	O
by	O
mammalian	B-GENE
G	I-GENE
alpha	I-GENE
11	I-GENE
and	O
G	B-GENE
alpha	I-GENE
q	I-GENE
cDNAs	I-GENE
.	O

Estradiol	O
is	O
known	O
to	O
induce	O
expression	O
of	O
certain	O
proto	O
-	O
oncogenes	O
,	O
and	O
this	O
led	O
us	O
to	O
examine	O
potential	O
regulatory	O
regions	O
of	O
the	O
cellular	B-GENE
c	I-GENE
-	I-GENE
fos	I-GENE
oncogene	I-GENE
.	O

Air	O
lead	O
was	O
not	O
a	O
significant	O
explanatory	O
variable	O
.	O

We	O
now	O
show	O
that	O
regulation	O
of	O
flaN	B-GENE
transcription	O
in	O
vivo	O
depends	O
on	O
a	O
sigma	B-GENE
54	I-GENE
promoter	I-GENE
and	O
two	O
ftr	O
elements	O
located	O
downstream	O
of	O
the	O
transcription	O
start	O
site	O
at	O
+	O
86	O
(	O
ftr2	O
)	O
and	O
+	O
120	O
(	O
ftr3	O
)	O
.	O

Fibular	O
dimelia	O
with	O
deficiency	O
of	O
the	O
tibia	O
.	O

This	O
prospective	O
study	O
compared	O
the	O
measured	O
energy	O
expenditures	O
of	O
30	O
patients	O
using	O
indirect	O
calorimetry	O
with	O
their	O
predicted	O
basal	O
energy	O
expenditure	O
according	O
to	O
the	O
Harris	O
-	O
Benedict	O
equation	O
,	O
or	O
their	O
calculated	O
energy	O
expenditure	O
derived	O
from	O
basal	O
energy	O
expenditure	O
times	O
,	O
an	O
activity	O
factor	O
,	O
and	O
a	O
stress	O
factor	O
.	O

However	O
,	O
after	O
repeated	O
infections	O
,	O
hypobiotic	O
larvae	O
were	O
numerous	O
.	O

This	O
was	O
performed	O
in	O
a	O
double	O
blinded	O
,	O
randomized	O
,	O
placebo	O
-	O
controlled	O
study	O
.	O

Group	O
I	O
consisted	O
of	O
six	O
noncholestatic	O
patients	O
;	O
group	O
II	O
consisted	O
of	O
nine	O
mildly	O
cholestatic	O
patients	O
with	O
mild	O
hepatic	O
impairment	O
(	O
conjugated	O
bilirubin	O
,	O
47	O
mumol	O
liter	O
-	O
1	O
;	O
alkaline	B-GENE
phosphatase	I-GENE
,	O
280	O
IU	O
liter	O
-	O
1	O
;	O
gamma	B-GENE
-	I-GENE
glutamyltranspeptidase	I-GENE
,	O
190	O
IU	O
liter	O
-	O
1	O
)	O
;	O
group	O
III	O
consisted	O
of	O
six	O
benign	O
intrahepatic	O
cholestatic	O
patients	O
with	O
high	O
isolated	O
conjugated	O
hyperbilirubinemia	O
(	O
98	O
.	O
1	O
mumol	O
liter	O
-	O
1	O
)	O
.	O

There	O
was	O
either	O
no	O
change	O
or	O
an	O
improvement	O
in	O
renographic	O
findings	O
(	O
t1	O
/	O
2	O
time	O
and	O
/	O
or	O
split	O
function	O
)	O
in	O
40	O
patients	O
(	O
93	O
%	O
)	O
.	O

We	O
discuss	O
the	O
need	O
to	O
use	O
animals	O
older	O
than	O
3	O
months	O
for	O
the	O
study	O
of	O
'	O
adult	O
'	O
regeneration	O
phenomena	O
since	O
3	O
-	O
month	O
-	O
old	O
rats	O
may	O
be	O
somewhat	O
immature	O
.	O

Nuclear	B-GENE
beta	I-GENE
II	I-GENE
PKC	I-GENE
,	O
like	O
p34cdc2	B-GENE
kinase	I-GENE
,	O
may	O
function	O
to	O
regulate	O
nuclear	O
lamina	O
structural	O
stability	O
during	O
cell	O
cycle	O
.	O

In	O
situ	O
copper	O
-	O
phenanthroline	O
footprinting	O
of	O
individual	O
gel	O
shift	O
assembly	O
intermediates	O
shows	O
that	O
on	O
the	O
302	O
-	O
nucleotide	O
G4oric	O
,	O
the	O
first	O
two	O
SSB	B-GENE
tetramers	I-GENE
assemble	O
at	O
random	O
,	O
but	O
the	O
addition	O
of	O
more	O
SSB	B-GENE
tetramers	I-GENE
results	O
in	O
formation	O
of	O
a	O
unique	O
structure	O
.	O

Effects	O
of	O
intramammary	O
endotoxin	O
infusion	O
on	O
milking	O
-	O
induced	O
oxytocin	B-GENE
release	O
.	O

A	O
rat	O
cDNA	O
that	O
encodes	O
eIF	B-GENE
-	I-GENE
5	I-GENE
has	O
been	O
isolated	O
and	O
expressed	O
in	O
Escherichia	O
coli	O
to	O
yield	O
a	O
catalytically	O
active	O
eIF	B-GENE
-	I-GENE
5	I-GENE
protein	I-GENE
.	O

In	O
F42A	O
-	O
stimulated	O
internalization	O
assays	O
on	O
forskolin	O
-	O
induced	O
YT	O
-	O
1	O
cells	O
,	O
the	O
IL	B-GENE
-	I-GENE
2R	I-GENE
alpha	I-GENE
chain	I-GENE
is	O
consistently	O
endocytosed	O
together	O
with	O
the	O
IL	B-GENE
-	I-GENE
2R	I-GENE
beta	I-GENE
subunit	I-GENE
indicating	O
that	O
IL	B-GENE
-	I-GENE
2R	I-GENE
alpha	I-GENE
is	O
stably	O
associated	O
with	O
the	O
F42A	B-GENE
-	I-GENE
IL	I-GENE
-	I-GENE
2R	I-GENE
beta	I-GENE
complex	I-GENE
even	O
though	O
the	O
alpha	O
-	O
subunit	O
contributes	O
little	O
if	O
any	O
affinity	O
to	O
the	O
F42A	O
binding	O
reaction	O
.	O

The	O
microcirculatory	O
dynamics	O
of	O
prostaglandin	O
E1	O
and	O
/	O
or	O
nicardipine	O
and	O
their	O
different	O
reactions	O
in	O
the	O
hyper	O
-	O
and	O
hypodynamic	O
state	O
of	O
septic	O
shock	O
in	O
a	O
rat	O
model	O

The	O
short	O
-	O
term	O
synthesis	O
and	O
infant	O
-	O
regulated	O
removal	O
of	O
milk	O
in	O
lactating	O
women	O
.	O

Based	O
on	O
these	O
results	O
,	O
a	O
new	O
model	O
for	O
the	O
regulation	O
of	O
nif	B-GENE
/	O
fix	B-GENE
gene	O
expression	O
in	O
A	O
.	O
caulinodans	O
is	O
proposed	O
.	O

Nitric	O
oxide	O
inhalation	O
selectively	O
reduces	O
pulmonary	O
hypertension	O
in	O
porcine	O
endotoxin	O
shock	O
and	O
improves	O
arterial	O
oxygenation	O
and	O
pH	O
with	O
a	O
marked	O
attenuation	O
of	O
sympathetic	O
activation	O
.	O

B	O
cell	O
-	O
specific	O
mb	B-GENE
-	I-GENE
1	I-GENE
and	O
B29	B-GENE
genes	I-GENE
encode	O
the	O
alpha	O
/	O
beta	O
components	O
of	O
the	O
BCR	B-GENE
-	I-GENE
associated	I-GENE
complex	I-GENE
in	O
mature	O
sIgM	B-GENE
+	I-GENE
B	O
cells	O
.	O

Bipolarity	O
in	O
Jungian	O
type	O
theory	O
and	O
the	O
Myers	O
-	O
Briggs	O
Type	O
Indicator	O
.	O

A	O
variety	O
of	O
nuclear	O
ribonucleoproteins	O
are	O
believed	O
to	O
associate	O
directly	O
with	O
nascent	O
RNA	B-GENE
polymerase	I-GENE
II	I-GENE
transcripts	I-GENE
and	O
remain	O
associated	O
during	O
subsequent	O
nuclear	O
RNA	O
processing	O
reactions	O
,	O
including	O
pre	O
-	O
mRNA	O
polyadenylation	O
and	O
splicing	O
as	O
well	O
as	O
nucleocytoplasmic	O
mRNA	O
transport	O
.	O

Mutations	O
at	O
three	O
sites	O
have	O
larger	O
effects	O
in	O
muscle	O
than	O
nonmuscle	O
cells	O
;	O
an	O
A	O
/	O
T	O
-	O
rich	O
site	O
mutation	O
has	O
a	O
pronounced	O
effect	O
in	O
both	O
striated	O
muscle	O
types	O
,	O
mutations	O
at	O
the	O
MEF1	B-GENE
(	I-GENE
Right	I-GENE
E	I-GENE
-	I-GENE
box	I-GENE
)	I-GENE
site	I-GENE
are	O
relatively	O
specific	O
to	O
expression	O
in	O
skeletal	O
muscle	O
,	O
and	O
mutations	O
at	O
the	O
CArG	O
site	O
are	O
relatively	O
specific	O
to	O
expression	O
in	O
cardiac	O
muscle	O
.	O

Transient	O
transfection	O
analysis	O
with	O
these	O
mutations	O
revealed	O
that	O
only	O
a	O
10	O
-	O
bp	O
region	O
,	O
containing	O
precisely	O
the	O
Ets	B-GENE
and	O
proximal	O
LyF	B-GENE
-	I-GENE
1	I-GENE
binding	I-GENE
sites	I-GENE
,	O
was	O
needed	O
for	O
D	O
'	O
activity	O
.	O

However	O
,	O
despite	O
its	O
relationship	O
to	O
the	O
TR	B-GENE
,	O
Rev	B-GENE
-	O
Erb	B-GENE
bound	O
poorly	O
to	O
TR	B-GENE
binding	I-GENE
sites	I-GENE
.	O

We	O
report	O
here	O
that	O
a	O
25	O
-	O
bp	O
promoter	O
element	O
previously	O
shown	O
to	O
be	O
important	O
for	O
the	O
G1	O
-	O
S	O
activation	O
of	O
the	O
human	B-GENE
thymidine	I-GENE
kinase	I-GENE
(	O
htk	B-GENE
)	O
promoter	O
in	O
growth	O
-	O
stimulated	O
cells	O
is	O
a	O
cellular	O
target	O
of	O
cyclin	B-GENE
A	I-GENE
and	O
the	O
p33cdk2	B-GENE
complexes	I-GENE
.	O

These	O
protective	O
influences	O
were	O
observed	O
throughout	O
the	O
range	O
of	O
filling	O
pressures	O
measured	O
,	O
from	O
0	O
to	O
30	O
mmHg	O
.	O

DNase	B-GENE
I	I-GENE
footprinting	O
with	O
rat	O
liver	O
nuclear	O
extracts	O
identified	O
7	O
major	O
protein	O
-	O
binding	O
domains	O
termed	O
P1	O
through	O
P7	O
in	O
a	O
796	O
base	O
pair	O
DNA	O
fragment	O
(	O
base	O
pairs	O
-	O
763	O
to	O
+	O
33	O
)	O
.	O

Neither	O
clone	O
encoded	O
the	O
cognate	O
endonuclease	O
.	O

The	O
nifJ	B-GENE
and	O
nifH	B-GENE
promoters	I-GENE
of	I-GENE
Klebsiella	I-GENE
pneumoniae	I-GENE
are	O
divergently	O
transcribed	O
sigma	B-GENE
54	I-GENE
-	I-GENE
dependent	I-GENE
promoters	I-GENE
that	O
are	O
positively	O
activated	O
by	O
the	O
NifA	B-GENE
protein	I-GENE
.	O

Both	O
inhaled	O
and	O
superfused	O
isoflurane	O
dilated	O
the	O
baseline	O
vein	O
diameter	O
before	O
stimulation	O
.	O

Prevalence	O
of	O
rheumatoid	O
arthritis	O
and	O
rheumatoid	B-GENE
factor	I-GENE
in	O
women	O
:	O
evidence	O
for	O
a	O
secular	O
decline	O
.	O

Although	O
olfactory	O
associative	O
conditioning	O
in	O
newborn	O
rats	O
produces	O
marked	O
structural	O
and	O
functional	O
changes	O
in	O
the	O
olfactory	O
bulb	O
,	O
recent	O
evidence	O
suggests	O
that	O
extrabulbar	O
circuits	O
must	O
be	O
involved	O
in	O
storing	O
these	O
early	O
memories	O
.	O

The	O
fission	B-GENE
yeast	I-GENE
dsk1	I-GENE
+	I-GENE
gene	I-GENE
,	O
a	O
multicopy	O
suppressor	O
for	O
cold	O
-	O
sensitive	O
dis1	B-GENE
mutants	I-GENE
,	O
encodes	O
a	O
novel	O
61	O
-	O
kd	O
protein	O
kinase	O
.	O

Closure	O
of	O
the	O
patent	O
ductus	O
arteriosus	O
with	O
a	O
Ligaclip	O
through	O
a	O
minithoracotomy	O
.	O

Sequence	O
comparison	O
between	O
the	O
translated	O
ORF	O
and	O
a	O
protein	O
database	O
reveal	O
between	O
26	O
.	O
5	O
and	O
23	O
.	O
4	O
%	O
aa	O
sequence	O
homology	O
to	O
bacterial	B-GENE
transmembrane	I-GENE
(	I-GENE
TM	I-GENE
)	I-GENE
proteins	I-GENE
including	O
those	O
mediating	O
chloramphenicol	O
(	O
Cm	O
)	O
and	O
tetracycline	O
(	O
Tc	O
)	O
resistance	O
and	O
an	O
arabinose	O
-	O
proton	O
symport	O
protein	O
.	O

The	O
strategies	O
by	O
which	O
hepatitis	O
B	O
and	O
hepatitis	O
D	O
can	O
be	O
diminished	O
and	O
eventually	O
eliminated	O
are	O
:	O
immunization	O
,	O
measures	O
to	O
prevent	O
exposure	O
to	O
infective	O
blood	O
or	O
blood	O
derivatives	O
and	O
education	O
(	O
in	O
particular	O
awareness	O
that	O
hepatitis	O
B	O
is	O
a	O
sexually	O
transmitted	O
disease	O
)	O
.	O

The	O
technical	O
construction	O
of	O
the	O
mouth	O
protectors	O
is	O
illustrated	O
,	O
as	O
is	O
the	O
need	O
for	O
instrumentation	O
and	O
its	O
costs	O
and	O
the	O
materials	O
required	O
to	O
manufacture	O
these	O
mouth	O
protectors	O
.	O

Three	O
patients	O
had	O
well	O
-	O
,	O
6	O
patients	O
had	O
moderately	O
-	O
,	O
and	O
5	O
patients	O
had	O
poorly	O
-	O
differentiated	O
adenocarcinoma	O
of	O
the	O
prostate	O
.	O

Spontaneous	O
burst	O
firing	O
in	O
cat	O
primary	O
auditory	O
cortex	O
:	O
age	O
and	O
depth	O
dependence	O
and	O
its	O
effect	O
on	O
neural	O
interaction	O
measures	O
.	O

By	O
applying	O
the	O
potentiometric	O
method	O
,	O
in	O
aqueous	O
medium	O
of	O
ionic	O
strength	O
mu	O
=	O
0	O
.	O
2	O
,	O
the	O
stability	O
constants	O
,	O
log	O
beta	O
1	O
=	O
4	O
.	O
42	O
and	O
log	O
beta	O
2	O
=	O
8	O
.	O
57	O
were	O
obtained	O
.	O

Cryopreservation	O
straws	O
filled	O
with	O
media	O
plus	O
additive	O
are	O
emersed	O
below	O
the	O
surface	O
of	O
an	O
unprocessed	O
donor	O
ejaculate	O
.	O

The	O
bcl	B-GENE
-	I-GENE
2	I-GENE
gene	I-GENE
can	O
potentially	O
encode	O
26	O
-	O
and	O
22	O
-	O
kDa	O
proteins	O
that	O
differ	O
only	O
in	O
their	O
carboxyl	O
tails	O
because	O
of	O
an	O
alternative	O
splicing	O
mechanism	O
.	O

The	O
active	O
open	O
reading	O
frame	O
in	O
the	O
clone	O
maps	O
at	O
27	O
min	O
on	O
the	O
E	O
.	O
coli	O
chromosome	O
and	O
is	O
identical	O
in	O
sequence	O
to	O
a	O
wild	O
type	O
counterpart	O
.	O

Subsequent	O
cloning	O
and	O
nucleotide	O
sequence	O
analysis	O
of	O
the	O
S	B-GENE
.	I-GENE
pombe	I-GENE
adenylate	I-GENE
kinase	I-GENE
gene	I-GENE
,	O
adk1	B-GENE
,	O
revealed	O
a	O
coding	O
region	O
of	O
660	O
nucleotides	O
.	O

As	O
a	O
result	O
of	O
alternative	O
splicing	O
,	O
the	O
BGP	B-GENE
gene	I-GENE
is	O
transcribed	O
into	O
at	O
least	O
seven	O
distinct	O
mRNA	O
species	O
.	O

However	O
,	O
essential	O
contrast	O
differences	O
existing	O
between	O
the	O
FSE	O
sequences	O
and	O
their	O
routine	O
asymmetric	O
dual	O
SE	O
counterpart	O
can	O
be	O
identified	O
.	O

The	O
level	O
of	O
the	O
SUP4A53T61	B-GENE
transcript	I-GENE
was	O
threefold	O
higher	O
in	O
the	O
tap1	B-GENE
-	I-GENE
1	I-GENE
mutant	I-GENE
than	O
in	O
the	O
wild	O
type	O
.	O

This	O
sequence	O
similarity	O
raises	O
the	O
possibility	O
that	O
GCN1	B-GENE
interacts	O
with	O
ribosomes	O
or	O
tRNA	O
molecules	O
and	O
functions	O
in	O
conjunction	O
with	O
GCN2	B-GENE
in	O
monitoring	O
uncharged	O
tRNA	O
levels	O
during	O
the	O
process	O
of	O
translation	O
elongation	O
.	O

NF	B-GENE
-	I-GENE
HB	I-GENE
(	O
BSAP	B-GENE
)	O
is	O
a	O
repressor	O
of	O
the	O
murine	B-GENE
immunoglobulin	I-GENE
heavy	I-GENE
-	I-GENE
chain	I-GENE
3	I-GENE
'	I-GENE
alpha	I-GENE
enhancer	I-GENE
at	O
early	O
stages	O
of	O
B	O
-	O
cell	O
differentiation	O
.	O

In	O
conclusion	O
,	O
changes	O
in	O
carotid	O
sinus	O
stimulation	O
alters	O
blood	O
flow	O
to	O
the	O
hindlimb	O
through	O
changes	O
in	O
both	O
Pcrit	O
and	O
Ra	O
.	O

Multizone	O
PRK	O
has	O
been	O
suggested	O
to	O
increase	O
the	O
predictability	O
of	O
higher	O
myopic	O
corrections	O
.	O

In	O
17	O
patients	O
with	O
deletions	O
,	O
the	O
parental	O
origin	O
of	O
deletion	O
was	O
determined	O
.	O

The	O
COL7A1	B-GENE
gene	I-GENE
,	O
which	O
encodes	O
type	B-GENE
VII	I-GENE
collagen	I-GENE
,	O
has	O
been	O
implicated	O
as	O
a	O
candidate	O
gene	O
for	O
dominantly	O
and	O
recessively	O
inherited	O
forms	O
of	O
dystrophic	O
epidermolysis	O
bullosa	O
.	O

However	O
,	O
study	O
of	O
the	O
productive	O
gamma	O
gene	O
showed	O
that	O
the	O
skipped	O
variable	O
exon	O
was	O
bounded	O
by	O
normal	O
splicing	O
signals	O
and	O
that	O
the	O
adjacent	O
intron	O
organization	O
was	O
not	O
altered	O
.	O

We	O
conclude	O
that	O
grade	O
III	O
BGCT	O
can	O
be	O
treated	O
by	O
modified	O
intralesional	O
excision	O
provided	O
the	O
articular	O
surfaces	O
and	O
part	O
of	O
the	O
metaphysis	O
are	O
intact	O
.	O

Second	O
,	O
nitrate	O
induction	O
of	O
aeg	B-GENE
-	I-GENE
46	I-GENE
.	I-GENE
5	I-GENE
operon	I-GENE
expression	O
is	O
substantially	O
enhanced	O
in	O
narL	B-GENE
null	O
strains	O
(	O
M	O
.	O
H	O
.	O

This	O
new	O
knowledge	O
has	O
contributed	O
to	O
the	O
development	O
of	O
a	O
successful	O
immunoprophylactic	O
strategy	O
for	O
eliminating	O
Hib	O
disease	O
.	O

The	O
HMG	B-GENE
CoA	I-GENE
reductase	I-GENE
inhibitors	O
are	O
the	O
most	O
effective	O
cholesterol	O
-	O
lowering	O
agents	O
currently	O
available	O
.	O

The	O
etiology	O
,	O
pathology	O
,	O
brain	O
CT	O
scan	O
features	O
,	O
clinical	O
manifestations	O
and	O
treatment	O
of	O
these	O
accidents	O
were	O
discussed	O
.	O

Drosophila	O
230	O
-	O
kD	O
TFIID	B-GENE
subunit	O
,	O
a	O
functional	O
homolog	O
of	O
the	O
human	O
cell	O
cycle	O
gene	O
product	O
,	O
negatively	O
regulates	O
DNA	O
binding	O
of	O
the	O
TATA	B-GENE
box	I-GENE
-	I-GENE
binding	I-GENE
subunit	I-GENE
of	I-GENE
TFIID	I-GENE
.	O

One	O
enigmatic	O
aspect	O
of	O
GATA	B-GENE
factor	I-GENE
expression	O
is	O
that	O
several	O
GATA	B-GENE
proteins	I-GENE
,	O
which	O
ostensibly	O
share	O
the	O
same	O
DNA	O
-	O
binding	O
site	O
specificity	O
,	O
are	O
coexpressed	O
in	O
erythroid	O
cells	O
.	O

Pit	B-GENE
-	I-GENE
1	I-GENE
is	O
a	O
tissue	O
-	O
specific	O
POU	B-GENE
domain	I-GENE
factor	I-GENE
obligatory	O
for	O
the	O
appearance	O
of	O
three	O
cell	O
phenotypes	O
in	O
the	O
anterior	O
pituitary	O
gland	O
.	O

Maximum	O
number	O
of	O
strains	O
(	O
39	O
.	O
1	O
%	O
)	O
were	O
resistant	O
in	O
S	O
.	O
bareilly	O
serotype	O
,	O
followed	O
by	O
S	O
.	O
typhimurium	O
(	O
21	O
.	O
7	O
%	O
)	O
and	O
least	O
in	O
S	O
.	O
typhi	O
(	O
17	O
.	O
4	O
%	O
)	O
.	O

Characterization	O
and	O
hormonal	O
regulation	O
of	O
the	O
promoter	O
of	O
the	O
rat	B-GENE
prostaglandin	I-GENE
endoperoxide	I-GENE
synthase	I-GENE
2	I-GENE
gene	I-GENE
in	O
granulosa	O
cells	O
.	O

The	O
retention	O
of	O
75SeHCAT	O
was	O
low	O
.	O

Members	O
of	O
the	O
C	B-GENE
/	I-GENE
EBP	I-GENE
family	I-GENE
of	O
basic	B-GENE
-	I-GENE
leucine	I-GENE
zipper	I-GENE
(	I-GENE
bZip	I-GENE
)	I-GENE
transcription	I-GENE
factors	I-GENE
form	O
heterodimers	O
and	O
bind	O
to	O
the	O
CAAT	O
box	O
and	O
other	O
sequence	O
-	O
related	O
enhancer	O
motifs	O
.	O

In	O
mammalian	O
cells	O
,	O
phosphorylation	O
of	O
eIF	B-GENE
-	I-GENE
2	I-GENE
alpha	I-GENE
inhibits	O
the	O
activity	O
of	O
eIF	B-GENE
-	I-GENE
2B	I-GENE
,	O
the	O
GDP	B-GENE
-	I-GENE
GTP	I-GENE
exchange	I-GENE
factor	I-GENE
for	O
eIF	B-GENE
-	I-GENE
2	I-GENE
.	O

In	O
conclusion	O
,	O
these	O
observations	O
demonstrated	O
that	O
stratification	O
of	O
acute	O
MI	O
patients	O
by	O
plasma	O
ANF	B-GENE
level	O
is	O
a	O
useful	O
non	O
-	O
invasive	O
method	O
for	O
predicting	O
prognosis	O
and	O
for	O
identifying	O
individuals	O
at	O
high	O
risk	O
of	O
cardiac	O
death	O
.	O

Analysis	O
of	O
the	O
binding	O
of	O
Lrp	B-GENE
to	O
a	O
set	O
of	O
circularly	O
permuted	O
DNA	O
fragments	O
from	O
this	O
region	O
indicates	O
that	O
Lrp	B-GENE
induces	O
DNA	O
bending	O
.	O

Seven	O
out	O
of	O
34	O
patients	O
died	O
,	O
giving	O
a	O
mortality	O
rate	O
of	O
21	O
%	O
.	O

A	O
36	O
-	O
kDa	O
protein	O
that	O
was	O
localized	O
to	O
the	O
membrane	O
fraction	O
was	O
detected	O
in	O
minicells	O
containing	O
plasmids	O
with	O
the	O
ftsN	B-GENE
gene	I-GENE
,	O
confirming	O
that	O
FtsN	B-GENE
was	O
a	O
membrane	O
protein	O
.	O

SSG1	B-GENE
,	O
a	O
gene	O
encoding	O
a	O
sporulation	B-GENE
-	I-GENE
specific	I-GENE
1	I-GENE
,	I-GENE
3	I-GENE
-	I-GENE
beta	I-GENE
-	I-GENE
glucanase	I-GENE
in	O
Saccharomyces	O
cerevisiae	O
.	O

Expression	O
of	O
this	O
protein	O
in	O
E	O
.	O
coli	O
demonstrated	O
that	O
tyrosine	O
was	O
incorporated	O
during	O
suppression	O
and	O
that	O
yeast	B-GENE
cytoplasmic	I-GENE
TyrRS	I-GENE
activity	O
was	O
produced	O
.	O

The	O
first	O
involved	O
complementation	O
of	O
a	O
nonphotosynthetic	O
mutant	O
of	O
Chlamydomonas	O
,	O
CC	O
-	O
2341	O
(	O
ac	O
-	O
u	O
-	O
g	O
-	O
2	O
.	O
3	O
)	O
,	O
which	O
has	O
a	O
frameshift	O
mutation	O
in	O
the	O
psaB	B-GENE
gene	I-GENE
,	O
and	O
selection	O
of	O
photosynthetic	O
transformants	O
on	O
minimal	O
medium	O
.	O

Against	O
200	O
strains	O
of	O
methicillin	O
-	O
resistant	O
Staphylococcus	O
aureus	O
(	O
MRSA	O
)	O
isolated	O
from	O
1990	O
to	O
1991	O
,	O
minimum	O
inhibitory	O
concentrations	O
(	O
MICs	O
)	O
of	O
a	O
total	O
of	O
15	O
antibacterial	O
agents	O
including	O
arbekacin	O
(	O
ABK	O
)	O
were	O
determined	O
.	O

It	O
is	O
reported	O
that	O
,	O
at	O
present	O
,	O
most	O
of	O
the	O
MRSAs	O
spreading	O
in	O
Japan	O
are	O
acceleratedly	O
acquiring	O
resistance	O
to	O
many	O
drugs	O
,	O
and	O
especially	O
,	O
they	O
are	O
developing	O
high	O
resistance	O
against	O
beta	O
-	O
lactams	O
.	O

Beg2	B-GENE
and	O
Beg1	B-GENE
are	O
regulated	O
differently	O
which	O
may	O
indicate	O
variation	O
in	O
storage	O
or	O
utilization	O
properties	O
among	O
the	O
barley	B-GENE
globulins	I-GENE
.	O

Here	O
,	O
we	O
have	O
more	O
closely	O
investigated	O
transactivation	O
of	O
the	O
human	B-GENE
HSP70	I-GENE
promoter	I-GENE
by	O
Myb	B-GENE
proteins	I-GENE
.	O

We	O
have	O
found	O
out	O
that	O
one	O
-	O
year	O
-	O
old	O
carps	O
are	O
extremely	O
sensitive	O
to	O
ichthiomycin	O
in	O
concentrations	O
between	O
25	O
-	O
125	O
micrograms	O
/	O
dm3	O
.	O

RESULTS	O
:	O
Statistically	O
significant	O
differences	O
were	O
obtained	O
between	O
group	O
I	O
and	O
II	O
concerning	O
the	O
number	O
of	O
patients	O
in	O
whom	O
induced	O
atrial	O
fibrillation	O
with	O
conduction	O
by	O
the	O
accessory	O
pathway	O
and	O
RR	O
<	O
or	O
=	O
250	O
msec	O
was	O
found	O
(	O
0	O
vs	O
6	O
,	O
p	O
=	O
0	O
.	O
0045	O
)	O
.	O

We	O
studied	O
the	O
effect	O
of	O
skinfold	O
thickness	O
on	O
the	O
correlation	O
between	O
serum	O
total	O
bilirubin	O
level	O
and	O
transcutaneous	O
bilirubin	O
(	O
TcB	O
)	O
readings	O
.	O

The	O
GTPase	B-GENE
activity	O
of	O
CDC42Ce	B-GENE
is	O
moderately	O
stimulated	O
by	O
human	B-GENE
n	I-GENE
-	I-GENE
chimaerin	I-GENE
,	O
a	O
GTPase	B-GENE
-	I-GENE
activating	I-GENE
protein	I-GENE
for	O
the	O
related	O
p21	B-GENE
rac1	B-GENE
.	O

Tl	O
-	O
201	O
uptake	O
ratio	O
of	O
the	O
right	O
ventricle	O
,	O
which	O
represents	O
the	O
ratio	O
of	O
total	O
counts	O
of	O
the	O
right	O
ventricle	O
to	O
counts	O
of	O
the	O
administered	O
dose	O
of	O
Tl	O
-	O
201	O
,	O
was	O
higher	O
in	O
COPD	O
,	O
especially	O
in	O
pulmonary	O
emphysema	O
and	O
B	O
type	O
COPD	O
by	O
Burrows	O
classification	O
than	O
in	O
controls	O
.	O

A	O
second	O
hydrophobic	O
domain	O
,	O
bordered	O
by	O
two	O
hydrophilic	O
regions	O
strongly	O
suggests	O
a	O
transmembrane	O
region	O
.	O

This	O
gene	O
spans	O
23	O
kb	O
and	O
is	O
composed	O
of	O
five	O
exons	O
and	O
four	O
introns	O
.	O

The	O
remaining	O
RAD	B-GENE
+	I-GENE
cells	O
progressed	O
to	O
form	O
microcolonies	O
(	O
<	O
30	O
cells	O
)	O
containing	O
aberrantly	O
shaped	O
inviable	O
cells	O
.	O

The	O
11	O
;	O
22	O
chromosomal	O
translocation	O
specifically	O
linked	O
to	O
Ewing	O
sarcoma	O
and	O
primitive	O
neuroectodermal	O
tumor	O
results	O
in	O
a	O
chimeric	O
molecule	O
fusing	O
the	O
amino	O
-	O
terminal	O
-	O
encoding	O
portion	O
of	O
the	O
EWS	B-GENE
gene	I-GENE
to	O
the	O
carboxyl	O
-	O
terminal	O
DNA	O
-	O
binding	O
domain	O
encoded	O
by	O
the	O
FLI1	B-GENE
gene	I-GENE
.	O

These	O
findings	O
suggest	O
that	O
a	O
range	O
of	O
microenvironmental	O
conditions	O
exist	O
within	O
purified	O
water	O
systems	O
,	O
leading	O
to	O
variable	O
populations	O
of	O
bacteria	O
.	O

X	O
-	O
linked	O
liver	O
glycogenosis	O
:	O
localization	O
and	O
isolation	O
of	O
a	O
candidate	O
gene	O
.	O

This	O
conclusion	O
is	O
based	O
on	O
the	O
observations	O
of	O
the	O
immunologic	O
changes	O
that	O
characterize	O
the	O
acute	O
stages	O
of	O
illness	O
as	O
well	O
as	O
on	O
the	O
demonstrated	O
association	O
with	O
toxin	O
-	O
producing	O
bacteria	O
in	O
the	O
pharynx	O
and	O
gastrointestinal	O
tract	O
.	O

Measurement	O
of	O
anti	B-GENE
-	I-GENE
HCV	I-GENE
IgM	I-GENE
antibodies	I-GENE
with	O
an	O
experimental	O
kit	O

Embryo	O
coculture	O
system	O
may	O
contribute	O
to	O
understand	O
the	O
mechanisms	O
underlying	O
the	O
decrease	O
of	O
fertility	O
with	O
aging	O
.	O

These	O
cell	O
lines	O
displayed	O
methylation	O
of	O
the	O
CpG	O
island	O
surrounding	O
the	O
first	O
exon	O
of	O
p16INK4A	B-GENE
and	O
expressed	O
abundant	O
levels	O
of	O
a	O
nontranslated	O
mRNA	O
containing	O
an	O
alternative	O
first	O
exon	O
(	O
E1	O
beta	O
)	O
,	O
as	O
did	O
all	O
other	O
cell	O
lines	O
in	O
which	O
the	O
p16INK4A	B-GENE
locus	I-GENE
was	O
not	O
deleted	O
.	O

An	O
immunoperoxidase	B-GENE
reaction	O
,	O
PAP	B-GENE
method	O
,	O
with	O
the	O
antiserum	O
of	O
Factor	B-GENE
VIII	I-GENE
as	O
the	O
primary	O
antibody	O
,	O
was	O
carried	O
out	O
in	O
the	O
endometrial	O
biopsies	O
to	O
detect	O
the	O
Factor	B-GENE
VIII	I-GENE
activity	O
in	O
the	O
endometrial	O
endothelium	O
before	O
and	O
after	O
insertion	O
of	O
LNG	O
-	O
IUD	O
-	O
20	O
.	O

Egd1p	B-GENE
is	O
homologous	O
to	O
human	B-GENE
BTF3b	I-GENE
,	O
recently	O
identified	O
as	O
the	O
beta	O
subunit	O
of	O
the	O
heterodimeric	B-GENE
nascent	I-GENE
-	I-GENE
polypeptide	I-GENE
-	I-GENE
associated	I-GENE
complex	I-GENE
(	O
NAC	B-GENE
)	O
involved	O
in	O
ensuring	O
signal	O
-	O
sequence	O
-	O
specific	O
protein	O
sorting	O
and	O
translocation	O
[	O
Wiedmann	O
et	O
al	O
.	O
,	O
Nature	O
370	O
(	O
1994	O
)	O
434	O
-	O
440	O
]	O
.	O

Purified	O
PLB	B-GENE
showed	O
optimal	O
lyase	B-GENE
activity	O
at	O
pH	O
10	O
.	O
0	O
.	O

The	O
5	O
'	O
flanking	O
regions	O
of	O
both	O
pelA	B-GENE
and	O
pelB	B-GENE
were	O
translationally	O
fused	O
to	O
the	O
beta	B-GENE
-	I-GENE
glucuronidase	I-GENE
gene	I-GENE
and	O
introduced	O
into	O
F	O
.	O
solani	O
f	O
.	O
sp	O
.	O
pisi	O
,	O
and	O
beta	B-GENE
-	I-GENE
glucuronidase	I-GENE
activities	O
of	O
the	O
transformants	O
were	O
measured	O
.	O

When	O
nifA	B-GENE
mRNA	I-GENE
5	O
'	O
start	O
points	O
were	O
mapped	O
by	O
primer	O
extension	O
,	O
both	O
a	O
minor	O
upstream	O
transcript	O
(	O
s	O
)	O
starting	O
45	O
bp	O
distal	O
to	O
the	O
anaerobox	O
and	O
a	O
major	O
downstream	O
transcript	O
starting	O
10	O
bp	O
distal	O
to	O
the	O
sigma	B-GENE
54	I-GENE
box	O
were	O
observed	O
.	O

We	O
failed	O
to	O
find	O
these	O
data	O
to	O
be	O
useful	O
in	O
predicting	O
the	O
time	O
of	O
onset	O
of	O
initial	O
seizures	O
after	O
acute	O
ischemic	O
stroke	O
and	O
recurrence	O
.	O

The	O
human	B-GENE
papillomavirus	I-GENE
type	I-GENE
16	I-GENE
E7	I-GENE
protein	I-GENE
complements	O
adenovirus	B-GENE
type	I-GENE
5	I-GENE
E1A	I-GENE
amino	O
-	O
terminus	O
-	O
dependent	O
transactivation	O
of	O
adenovirus	B-GENE
type	I-GENE
5	I-GENE
early	I-GENE
genes	I-GENE
and	O
increases	O
ATF	B-GENE
and	O
Oct	B-GENE
-	I-GENE
1	I-GENE
DNA	O
binding	O
activity	O
.	O

A	O
chaotropic	O
detergent	O
,	O
0	O
.	O
1	O
%	O
Nonidet	O
P	O
-	O
40	O
,	O
also	O
abolished	O
the	O
interaction	O
,	O
further	O
supporting	O
the	O
hydrophobic	O
nature	O
of	O
the	O
interaction	O
.	O

Degradation	O
of	O
the	O
soybean	B-GENE
ribulose	I-GENE
-	I-GENE
1	I-GENE
,	I-GENE
5	I-GENE
-	I-GENE
bisphosphate	I-GENE
carboxylase	I-GENE
small	I-GENE
-	I-GENE
subunit	I-GENE
mRNA	I-GENE
,	O
SRS4	B-GENE
,	O
initiates	O
with	O
endonucleolytic	O
cleavage	O
.	O

Cloning	O
and	O
sequencing	O
revealed	O
that	O
dMax	B-GENE
contains	O
a	O
deletion	O
spanning	O
the	O
basic	O
region	O
and	O
helix	O
1	O
and	O
the	O
loop	O
of	O
the	O
helix	O
-	O
loop	O
-	O
helix	O
region	O
,	O
presumably	O
as	O
a	O
result	O
of	O
alternative	O
splicing	O
of	O
max	B-GENE
RNA	I-GENE
.	O

The	O
domain	O
structure	O
of	O
bovine	B-GENE
LTBP	I-GENE
-	I-GENE
2	I-GENE
is	O
very	O
similar	O
to	O
that	O
of	O
the	O
human	B-GENE
LTBP	I-GENE
-	I-GENE
2	I-GENE
,	O
containing	O
20	O
examples	O
of	O
6	O
-	O
cysteine	O
epidermal	B-GENE
growth	I-GENE
factor	I-GENE
-	I-GENE
like	I-GENE
repeats	I-GENE
,	O
16	O
of	O
which	O
have	O
the	O
consensus	O
sequence	O
for	O
calcium	O
binding	O
,	O
together	O
with	O
4	O
examples	O
of	O
8	O
-	O
cysteine	O
motifs	O
characteristic	O
of	O
fibrillins	B-GENE
and	O
LTBP	B-GENE
-	I-GENE
1	I-GENE
.	O

Similarly	O
,	O
expression	O
of	O
a	O
transiently	O
transfected	O
wild	B-GENE
-	I-GENE
type	I-GENE
prothymosin	I-GENE
alpha	I-GENE
gene	I-GENE
as	O
the	O
reporter	O
was	O
not	O
affected	O
by	O
a	O
repertoire	O
of	O
myc	B-GENE
-	I-GENE
derived	I-GENE
genes	I-GENE
,	O
including	O
myc	B-GENE
itself	O
and	O
dominant	O
or	O
recessive	O
negative	O
myc	B-GENE
mutants	I-GENE
.	O

Differential	O
regulation	O
of	O
the	O
alpha	B-GENE
/	I-GENE
beta	I-GENE
interferon	I-GENE
-	O
stimulated	O
Jak	B-GENE
/	O
Stat	B-GENE
pathway	O
by	O
the	O
SH2	B-GENE
domain	O
-	O
containing	O
tyrosine	B-GENE
phosphatase	I-GENE
SHPTP1	I-GENE
.	O

We	O
now	O
report	O
the	O
isolation	O
and	O
expression	O
of	O
cDNAs	O
encoding	O
PTF	B-GENE
gamma	I-GENE
and	O
PTF	B-GENE
delta	I-GENE
,	O
as	O
well	O
as	O
functional	O
studies	O
with	O
cognate	O
antibodies	O
that	O
recognize	O
the	O
native	O
PTF	B-GENE
complex	I-GENE
in	O
HeLa	O
extracts	O
.	O

Results	O
from	O
the	O
mechanism	O
study	O
have	O
revealed	O
that	O
YY1	B-GENE
is	O
able	O
to	O
inhibit	O
transactivation	O
mediated	O
by	O
either	O
AP1	B-GENE
or	O
the	O
Sp1	B-GENE
-	I-GENE
related	I-GENE
protein	I-GENE
,	O
and	O
YY1	B-GENE
suppressive	O
activity	O
is	O
DNA	O
binding	O
dependent	O
.	O

The	O
skp1	B-GENE
+	I-GENE
gene	I-GENE
is	O
not	O
essential	O
.	O

The	O
TEA1	B-GENE
(	O
Ty	B-GENE
enhancer	I-GENE
activator	I-GENE
)	O
gene	O
sequence	O
predicts	O
a	O
protein	O
of	O
86	O
.	O
9	O
kDa	O
whose	O
N	O
terminus	O
contains	O
a	O
zinc	O
cluster	O
and	O
dimerization	O
motif	O
typical	O
of	O
the	O
Gal4	B-GENE
-	I-GENE
type	I-GENE
family	I-GENE
of	O
DNA	O
-	O
binding	O
proteins	O
.	O

Videonystagmoscopy	O
has	O
been	O
used	O
to	O
subjectively	O
observe	O
the	O
responses	O
of	O
the	O
vestibular	O
system	O
in	O
a	O
population	O
of	O
patients	O
with	O
vestibular	O
deficits	O
.	O

The	O
MCA	O
and	O
UA	O
PI	O
values	O
showed	O
the	O
greatest	O
deviation	O
for	O
any	O
single	O
-	O
vessel	O
parameter	O
.	O

Stems	O
contain	O
distinctly	O
less	O
P	B-GENE
protein	I-GENE
mRNA	I-GENE
and	O
the	O
relative	O
level	O
in	O
roots	O
is	O
very	O
low	O
but	O
still	O
clearly	O
detectable	O
.	O

The	O
B	B-GENE
.	I-GENE
germanica	I-GENE
cyclophilin	I-GENE
amino	I-GENE
acid	I-GENE
sequence	I-GENE
shares	O
83	O
%	O
identity	O
with	O
the	O
cytosolic	B-GENE
cyclophilin	I-GENE
isoform	I-GENE
from	I-GENE
Drosophila	I-GENE
melanogaster	I-GENE
(	O
Cyp	B-GENE
-	I-GENE
1	I-GENE
)	O
.	O

The	O
minimal	O
region	O
of	O
overlap	O
of	O
Langer	O
-	O
Giedion	O
syndrome	O
deletions	O
,	O
previously	O
identified	O
by	O
analysis	O
of	O
15	O
patients	O
,	O
was	O
placed	O
on	O
the	O
map	O
by	O
analysis	O
of	O
2	O
patients	O
whose	O
deletions	O
define	O
the	O
endpoints	O
.	O

Comparison	O
of	O
promoters	O
repressed	O
by	O
c	B-GENE
-	I-GENE
myc	I-GENE
reveals	O
a	O
weak	O
consensus	O
sequence	O
of	O
the	O
initiator	O
(	O
Inr	O
)	O
element	O
:	O
TCA	O
(	O
+	O
1	O
)	O
YYYNY	O
.	O

The	O
human	B-GENE
gp39	I-GENE
promoter	I-GENE
.	O

Transfection	O
analyses	O
indicate	O
that	O
mutation	O
of	O
any	O
one	O
of	O
these	O
TGACCT	O
motifs	O
or	O
truncation	O
of	O
the	O
entire	O
HD	B-GENE
PPRE	O
into	O
a	O
separate	O
DR1	O
and	O
DR2	O
element	O
significantly	O
reduced	O
the	O
transcriptional	O
response	O
of	O
HD	B-GENE
PPRE	O
to	O
peroxisome	O
proliferators	O
.	O

The	O
site	O
of	O
autophosphorylation	O
is	O
Tyr397	O
which	O
corresponds	O
to	O
the	O
consensus	O
autophosphorylation	O
site	O
of	O
other	O
Src	B-GENE
family	I-GENE
tyrosine	B-GENE
kinases	I-GENE
.	O

This	O
protein	O
-	O
protein	O
interaction	O
does	O
not	O
require	O
the	O
simultaneous	O
binding	O
of	O
Oct	B-GENE
proteins	I-GENE
to	O
DNA	O
,	O
and	O
high	O
resolution	O
footprinting	O
of	O
the	O
Oct	B-GENE
-	I-GENE
DNA	I-GENE
interaction	O
reveals	O
that	O
binding	O
of	O
BOB	B-GENE
.	I-GENE
1	I-GENE
/	O
OBF	B-GENE
.	I-GENE
1	I-GENE
to	O
Oct1	B-GENE
or	O
Oct2	B-GENE
does	O
not	O
alter	O
the	O
interaction	O
with	O
DNA	O
.	O

Together	O
,	O
our	O
data	O
suggest	O
that	O
the	O
TR2	B-GENE
orphan	I-GENE
receptor	I-GENE
may	O
be	O
a	O
master	O
regulator	O
in	O
modulating	O
the	O
activation	O
of	O
two	O
key	O
HREs	O
,	O
RARE	O
beta	O
and	O
CRBPIIp	O
,	O
involved	O
in	O
the	O
retinoic	O
acid	O
signal	O
transduction	O
pathway	O
.	O

Using	O
a	O
series	O
of	O
mutant	O
proteins	O
,	O
we	O
have	O
characterized	O
domains	O
responsible	O
for	O
activation	O
or	O
repression	O
.	O

It	O
is	O
considered	O
that	O
the	O
recurrent	O
annular	O
erythema	O
is	O
a	O
specific	O
skin	O
manifestation	O
of	O
SjS	O
with	O
anti	B-GENE
SS	I-GENE
-	I-GENE
A	I-GENE
/	O
SS	B-GENE
-	I-GENE
B	I-GENE
antibodies	I-GENE
.	O

Competition	O
needs	O
to	O
be	O
better	O
studied	O
,	O
since	O
in	O
Central	O
America	O
and	O
Caribean	O
islands	O
this	O
kind	O
of	O
study	O
has	O
favored	O
the	O
biological	O
control	O
of	O
planorbid	O
species	O
.	O

In	O
this	O
paper	O
we	O
describe	O
properties	O
of	O
the	O
cdc10	B-GENE
-	O
C4	O
mutant	O
of	O
the	O
fission	O
yeast	O
Schizosaccharomyces	O
pombe	O
.	O

TIEG	B-GENE
expression	O
in	O
hFOB	O
cells	O
was	O
highly	O
induced	O
by	O
TGF	B-GENE
-	I-GENE
beta	I-GENE
and	O
bone	B-GENE
morphogenetic	I-GENE
protein	I-GENE
-	I-GENE
2	I-GENE
(	O
BMP	B-GENE
-	I-GENE
2	I-GENE
)	O
,	O
with	O
a	O
moderate	O
induction	O
by	O
epidermal	B-GENE
growth	I-GENE
factor	I-GENE
(	O
EGF	B-GENE
)	O
,	O
but	O
no	O
induction	O
by	O
other	O
growth	O
factors	O
/	O
cytokines	O
was	O
observed	O
.	O

The	O
predicted	O
protein	O
products	O
of	O
ORFs	B-GENE
N2417	I-GENE
and	O
N2403	B-GENE
present	O
similarities	O
with	O
domains	O
from	O
proteins	O
of	O
other	O
organisms	O
:	O
the	O
Candida	O
maltosa	O
cycloheximide	B-GENE
-	I-GENE
resistance	I-GENE
protein	I-GENE
,	O
the	O
human	O
interleukin	B-GENE
enhancer	I-GENE
-	I-GENE
binding	I-GENE
factor	I-GENE
(	O
ILF	B-GENE
-	I-GENE
2	I-GENE
)	O
.	O

In	O
particular	O
,	O
the	O
highly	O
expressed	O
ADH1	B-GENE
gene	I-GENE
is	O
represented	O
in	O
this	O
database	O
by	O
no	O
less	O
than	O
20	O
EST	O
sequences	O
.	O

Five	O
families	O
of	O
Ashkenazi	O
Jewish	O
descent	O
carried	O
the	O
185delAG	O
mutation	O
and	O
shared	O
the	O
same	O
haplotype	O
at	O
eight	O
polymorphic	O
markers	O
spanning	O
approximately	O
850	O
kb	O
at	O
BRCA1	B-GENE
.	O

The	O
subjects	O
from	O
the	O
two	O
regions	O
with	O
a	O
higher	O
pollution	O
level	O
had	O
lower	O
FVC	O
and	O
FEV1	O
values	O
than	O
those	O
from	O
the	O
Viskovo	O
region	O
.	O

PTP	B-GENE
-	I-GENE
S3	I-GENE
differs	O
from	O
PTP	B-GENE
-	I-GENE
S4	I-GENE
in	O
having	O
a	O
deletion	O
of	O
19	O
amino	O
acids	O
corresponding	O
to	O
exon	O
E1	O
.	O

When	O
differentiated	O
G0	O
-	O
arrested	O
leaf	O
cells	O
were	O
induced	O
to	O
resume	O
cell	O
division	O
by	O
treatment	O
with	O
plant	O
hormones	O
,	O
cycMs4	B-GENE
transcription	O
was	O
induced	O
before	O
the	O
onset	O
of	O
DNA	O
synthesis	O
.	O

A	O
survey	O
is	O
given	O
of	O
the	O
pharmacological	O
backgrounds	O
that	O
are	O
relevant	O
for	O
the	O
drug	O
treatment	O
of	O
essential	O
hypertension	O
in	O
the	O
elderly	O
.	O

Protein	O
kinases	O
play	O
pivotal	O
roles	O
in	O
the	O
control	O
of	O
many	O
cellular	O
processes	O
.	O

Interestingly	O
,	O
internal	O
and	O
5	O
'	O
deletions	O
revealed	O
tha	O
the	O
distal	O
promoter	O
was	O
not	O
required	O
for	O
full	O
transcriptional	O
activity	O
and	O
that	O
the	O
first	O
631	O
base	O
pairs	O
of	O
WNT	B-GENE
-	I-GENE
5A	I-GENE
harbored	O
the	O
strongest	O
promoter	O
activity	O
.	O

The	O
protein	O
kinase	O
domains	O
of	O
LIMK1	B-GENE
and	O
LIMK2	B-GENE
are	O
unique	O
in	O
that	O
they	O
contain	O
an	O
unusual	O
sequence	O
motif	O
Asp	O
-	O
Leu	O
-	O
Asn	O
-	O
Ser	O
-	O
His	O
-	O
Asn	O
in	O
subdomain	O
VIB	O
and	O
a	O
highly	O
basic	O
insert	O
between	O
subdomains	O
VII	O
and	O
VIII	O
.	O

A	O
human	O
recombinant	O
cDNA	O
clone	O
that	O
encoded	O
253	O
amino	O
acids	O
residues	O
of	O
a	O
zinc	B-GENE
-	I-GENE
finger	I-GENE
protein	I-GENE
(	O
THZif	B-GENE
-	I-GENE
1	I-GENE
)	O
was	O
cloned	O
by	O
screening	O
a	O
cDNA	O
library	O
prepared	O
from	O
human	O
promyelocytic	O
leukemia	O
HL60	O
cells	O
with	O
synthetic	O
oligodeoxynucleotide	O
probes	O
that	O
corresponded	O
to	O
the	O
amino	O
acid	O
sequences	O
of	O
tryptic	O
peptides	O
derived	O
from	O
the	O
DNA	O
-	O
binding	O
protein	O
specific	O
for	O
the	O
nuclease	B-GENE
-	I-GENE
hypersensitive	I-GENE
element	I-GENE
(	O
NHE	B-GENE
)	O
of	O
the	O
human	B-GENE
c	I-GENE
-	I-GENE
myc	I-GENE
gene	I-GENE
.	O

Erythrocyte	O
AA	O
in	O
FO	O
+	O
EPO	B-GENE
-	O
supplemented	O
infants	O
remained	O
low	O
and	O
below	O
breast	O
-	O
and	O
placebo	O
formula	O
-	O
fed	O
levels	O
.	O

Taking	O
into	O
consideration	O
weight	O
and	O
seasonal	O
changes	O
in	O
bone	O
mass	O
,	O
total	O
(	O
TBBMC	O
)	O
and	O
regional	O
body	O
bone	O
mineral	O
content	O
were	O
measured	O
in	O
38	O
women	O
treated	O
with	O
GnRH	B-GENE
agonists	O
for	O
6	O
months	O
for	O
endometriosis	O
or	O
leiomyomata	O
.	O

The	O
encoded	O
polypeptide	O
is	O
similar	O
in	O
sequence	O
to	O
the	O
ABA	B-GENE
-	I-GENE
1	I-GENE
allergen	I-GENE
of	I-GENE
Ascaris	I-GENE
,	O
the	O
gp15	B-GENE
/	I-GENE
400	I-GENE
'	I-GENE
ladder	I-GENE
'	I-GENE
protein	I-GENE
of	I-GENE
Brugia	I-GENE
malayi	I-GENE
,	I-GENE
Brugia	I-GENE
pahangi	I-GENE
and	I-GENE
Wuchereria	I-GENE
bancrofti	I-GENE
,	O
and	O
a	O
15	B-GENE
-	I-GENE
kDa	I-GENE
antigen	I-GENE
of	I-GENE
Dirofilaria	I-GENE
immitis	I-GENE
.	O

Spontaneous	O
recovery	O
occurs	O
within	O
30	O
min	O
to	O
2	O
hrs	O
.	O

DAF	B-GENE
is	O
a	O
70	O
kD	O
glycoprotein	O
containing	O
complement	O
regulatory	O
short	O
consensus	O
repeats	O
(	O
SCRs	O
)	O
;	O
its	O
gene	O
is	O
located	O
in	O
the	O
regulation	B-GENE
of	I-GENE
complement	I-GENE
activation	I-GENE
(	O
RCA	B-GENE
)	O
gene	O
cluster	O
on	O
chromosome	O
1	O
and	O
is	O
about	O
40	O
kb	O
in	O
size	O
.	O

There	O
is	O
no	O
TATA	O
box	O
around	O
the	O
transcriptional	O
start	O
points	O
(	O
tsp	O
)	O
,	O
as	O
determined	O
by	O
primer	O
extension	O
analysis	O
.	O

According	O
to	O
the	O
investigation	O
,	O
the	O
recent	O
burst	O
of	O
pseudoterranovosis	O
in	O
this	O
area	O
can	O
be	O
attributed	O
to	O
the	O
increased	O
presence	O
of	O
sea	O
lions	O
,	O
which	O
proliferate	O
in	O
the	O
Arctic	O
region	O
,	O
then	O
migrate	O
to	O
the	O
northern	O
Japan	O
Sea	O
and	O
eat	O
the	O
intermediate	O
host	O
fish	O
.	O

In	O
summary	O
,	O
the	O
efficacies	O
of	O
adjuvant	O
carboplatin	O
and	O
of	O
abdominal	O
radiotherapy	O
seem	O
to	O
be	O
identical	O
.	O

To	O
identify	O
some	O
of	O
the	O
genes	O
expressed	O
in	O
LPS	O
-	O
activated	O
coelomocytes	O
,	O
we	O
sequenced	O
randomly	O
chosen	O
clones	O
from	O
a	O
directionally	O
constructed	O
cDNA	O
library	O
to	O
produce	O
a	O
set	O
of	O
expressed	O
sequence	O
tags	O
(	O
ESTs	O
)	O
.	O

Characterization	O
of	O
an	O
EcR	B-GENE
/	O
USP	B-GENE
heterodimer	O
target	O
site	O
that	O
mediates	O
ecdysone	O
responsiveness	O
of	O
the	O
Drosophila	B-GENE
Lsp	I-GENE
-	I-GENE
2	I-GENE
gene	I-GENE
.	O

Thus	O
,	O
SPECT	O
was	O
not	O
as	O
sensitive	O
as	O
PET	O
in	O
this	O
activation	O
task	O
.	O

Transcriptional	O
activation	O
of	O
the	O
chicken	B-GENE
lysozyme	I-GENE
gene	I-GENE
by	O
NF	B-GENE
-	I-GENE
kappa	I-GENE
Bp65	I-GENE
(	O
RelA	B-GENE
)	O
and	O
c	B-GENE
-	I-GENE
Rel	I-GENE
,	O
but	O
not	O
by	O
NF	B-GENE
-	I-GENE
kappa	I-GENE
Bp50	I-GENE
.	O

The	O
results	O
indicate	O
that	O
the	O
bradycardic	O
agents	O
alinidine	O
and	O
zatebradine	O
do	O
not	O
exert	O
antiarrhythmic	O
efficacy	O
against	O
SVT	O
induced	O
during	O
subacute	O
myocardial	O
infarction	O
in	O
conscious	O
dogs	O
.	O

In	O
vivo	O
,	O
selective	O
activation	O
of	O
SAPKs	B-GENE
stimulates	O
formation	O
of	O
the	O
ternary	O
complex	O
containing	O
Elk	B-GENE
-	I-GENE
1	I-GENE
,	O
serum	B-GENE
response	I-GENE
factor	I-GENE
and	O
the	O
serum	O
response	O
element	O
,	O
and	O
enhances	O
Elk	B-GENE
-	I-GENE
1	I-GENE
-	O
dependent	O
transcription	O
.	O

An	O
epidemic	O
of	O
hepatitis	O
B	O
virus	O
infection	O
among	O
intravenous	O
drug	O
users	O
in	O
Iceland	O
.	O

Three	O
of	O
these	O
subunits	O
are	O
also	O
homologous	O
to	O
the	O
dimeric	O
POR	B-GENE
from	O
a	O
mesophilic	O
archaeon	O
,	O
Halobacterium	O
halobium	O
(	O
21	O
%	O
identity	O
)	O
.	O

The	O
transposon	O
-	O
inactivated	O
gene	O
,	O
designated	O
pilP	B-GENE
,	O
is	O
525	O
bp	O
long	O
,	O
potentially	O
encoding	O
a	O
19	O
.	O
1	O
-	O
kDa	O
protein	O
precursor	O
that	O
contains	O
a	O
typical	O
membrane	O
lipoprotein	O
leader	O
sequence	O
.	O

Cheung	O
and	O
S	O
.	O

Upstream	O
of	O
the	O
dra	B-GENE
gene	I-GENE
an	O
open	O
reading	O
frame	O
of	O
313	O
amino	O
acids	O
was	O
identified	O
.	O

Sucrose	O
-	O
specific	O
regulation	O
of	O
scrB	B-GENE
was	O
also	O
lost	O
upon	O
deletion	O
of	O
4	O
bp	O
of	O
a	O
palindromic	O
sequence	O
(	O
OB	O
)	O
covering	O
positions	O
+	O
6	O
to	O
+	O
21	O
downstream	O
of	O
the	O
scrB	B-GENE
transcriptional	O
start	O
site	O
.	O

In	O
E	O
.	O
coli	O
,	O
CheW	B-GENE
mediates	O
the	O
physical	O
coupling	O
of	O
the	O
receptors	O
to	O
the	O
kinase	O
CheA	B-GENE
.	O

The	O
promoter	O
of	O
the	O
first	O
gene	O
,	O
epiF	B-GENE
,	O
responded	O
to	O
the	O
activator	B-GENE
protein	I-GENE
EpiQ	I-GENE
and	O
contained	O
a	O
palindromic	O
sequence	O
similar	O
to	O
the	O
EpiQ	B-GENE
binding	I-GENE
site	I-GENE
of	O
the	O
epiA	B-GENE
promoter	I-GENE
,	O
which	O
is	O
also	O
activated	O
by	O
EpiQ	B-GENE
.	O

CXC	O
chemokines	O
bind	O
to	O
unique	O
sets	O
of	O
selectivity	O
determinants	O
that	O
can	O
function	O
independently	O
and	O
are	O
broadly	O
distributed	O
on	O
multiple	O
domains	O
of	O
human	O
interleukin	B-GENE
-	I-GENE
8	I-GENE
receptor	I-GENE
B	I-GENE
.	O

Oligodeoxynucleotides	O
antisense	O
to	O
the	O
predicted	O
translation	O
initiation	O
regions	O
of	O
ICP4	B-GENE
and	O
pp38	B-GENE
mRNAs	I-GENE
inhibited	O
proliferation	O
of	O
MSB1	O
cells	O
but	O
not	O
MDCC	O
-	O
CU91	O
(	O
CU91	O
)	O
reticuloendotheliosis	O
virus	O
-	O
transformed	O
cells	O
.	O

Retroviral	O
replication	O
requires	O
that	O
a	O
portion	O
of	O
the	O
primary	O
transcripts	O
generated	O
from	O
proviral	O
DNA	O
be	O
spliced	O
to	O
serve	O
as	O
mRNA	O
for	O
the	O
envelope	B-GENE
protein	I-GENE
and	O
in	O
Rous	O
sarcoma	O
virus	O
as	O
src	B-GENE
mRNA	I-GENE
.	O

In	O
this	O
case	O
the	O
degree	O
of	O
promoter	O
methylation	O
,	O
which	O
could	O
extend	O
beyond	O
the	O
T	O
-	O
DNA	O
borders	O
,	O
was	O
not	O
correlated	O
with	O
the	O
reduction	O
in	O
steady	O
-	O
state	O
poly	O
(	O
A	O
)	O
+	O
mRNA	O
levels	O
,	O
the	O
silenced	O
state	O
was	O
transmitted	O
through	O
meiosis	O
and	O
reactivation	O
lasted	O
several	O
generations	O
.	O

Thus	O
,	O
the	O
consensus	O
sequences	O
for	O
phosphatase	O
regulation	O
are	O
5	O
'	O
-	O
GCACGTGGG	O
-	O
3	O
'	O
and	O
5	O
'	O
-	O
GCACGTTTT	O
-	O
3	O
'	O
which	O
differ	O
from	O
the	O
binding	O
sequences	O
for	O
the	O
Cpflp	B-GENE
protein	O
required	O
for	O
transcription	O
of	O
the	O
genes	O
in	O
methionine	O
biosynthesis	O
and	O
for	O
centromere	O
function	O
.	O

Here	O
we	O
report	O
that	O
the	O
proline	O
-	O
rich	O
region	O
of	O
CAP	B-GENE
is	O
recognized	O
by	O
the	O
SH3	B-GENE
domains	I-GENE
of	O
several	O
proteins	O
,	O
including	O
the	O
yeast	B-GENE
actin	I-GENE
-	I-GENE
associated	I-GENE
protein	I-GENE
Abp1p	I-GENE
.	O

We	O
have	O
identified	O
and	O
characterized	O
a	O
vitamin	O
D	O
response	O
element	O
(	O
VDRE	O
)	O
in	O
the	O
promoter	O
of	O
c	B-GENE
-	I-GENE
fos	I-GENE
.	O

In	O
addition	O
to	O
protein	O
binding	O
at	O
sequences	O
known	O
to	O
be	O
involved	O
in	O
the	O
regulation	O
of	O
transcription	O
,	O
genomic	O
footprinting	O
of	O
the	O
entire	O
promoter	O
region	O
also	O
showed	O
that	O
a	O
protein	O
factor	O
is	O
constitutively	O
bound	O
to	O
the	O
first	O
intron	O
of	O
the	O
rep3	B-GENE
gene	I-GENE
.	O

Differentiation	O
was	O
not	O
observed	O
after	O
cellular	O
expression	O
of	O
GTPase	B-GENE
-	O
deficient	O
forms	O
of	O
alpha	B-GENE
i2	I-GENE
or	O
alpha	B-GENE
0	I-GENE
,	O
indicating	O
selectivity	O
for	O
the	O
Gq	B-GENE
family	I-GENE
of	O
G	B-GENE
proteins	I-GENE
.	O

Consistent	O
with	O
a	O
possible	O
role	O
in	O
transcription	O
,	O
Paf1p	B-GENE
is	O
localized	O
to	O
the	O
nucleus	O
.	O

By	O
comparing	O
the	O
abundances	O
of	O
many	O
yeast	O
transcripts	O
in	O
isogenic	O
wild	O
-	O
type	O
and	O
paf1	B-GENE
mutant	I-GENE
strains	O
,	O
we	O
have	O
identified	O
genes	O
whose	O
expression	O
is	O
affected	O
by	O
PAF1	B-GENE
.	O

Paf1p	B-GENE
may	O
therefore	O
be	O
required	O
for	O
both	O
positive	O
and	O
negative	O
regulation	O
of	O
subsets	O
of	O
yeast	O
genes	O
.	O

Using	O
a	O
high	O
-	O
copy	O
suppression	O
strategy	O
,	O
we	O
have	O
identified	O
a	O
yeast	O
gene	O
(	O
UBS1	B-GENE
)	O
whose	O
elevated	O
expression	O
suppresses	O
the	O
conditional	O
cell	O
cycle	O
defects	O
associated	O
with	O
cdc34	B-GENE
mutations	O
.	O

Molecular	O
characterization	O
of	O
malignant	O
melanoma	O
of	O
soft	O
parts	O
or	O
soft	O
tissue	O
clear	O
cell	O
sarcoma	O
which	O
shares	O
t	O
(	O
12	O
;	O
22	O
)	O
chromosome	O
translocation	O
revealed	O
fusion	O
of	O
EWS	B-GENE
with	O
a	O
transcriptional	O
factor	O
gene	B-GENE
ATF	I-GENE
-	I-GENE
1	I-GENE
.	O

Clones	O
that	O
expressed	O
DBD	O
exhibited	O
a	O
dominant	O
negative	O
phenotype	O
and	O
did	O
not	O
elicit	O
antiviral	O
activity	O
against	O
vesicular	O
stomatitis	O
virus	O
(	O
VSV	O
)	O
infection	O
upon	O
IFN	B-GENE
treatment	O
.	O

Abp1	B-GENE
preferentially	O
binds	O
to	O
multiple	O
sites	O
in	O
ARS	B-GENE
3002	I-GENE
and	O
to	O
the	O
DNA	O
polymer	O
poly	O
[	O
d	O
(	O
A	O
.	O
T	O
)	O
]	O
.	O

Identification	O
,	O
purification	O
,	O
and	O
molecular	O
cloning	O
of	O
autonomously	B-GENE
replicating	I-GENE
sequence	I-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
1	I-GENE
from	I-GENE
fission	I-GENE
yeast	I-GENE
Schizosaccharomyces	I-GENE
pombe	I-GENE
.	O

A	O
short	O
open	O
reading	O
frame	O
(	O
ORF2	O
)	O
,	O
of	O
unknown	O
function	O
,	O
is	O
present	O
in	O
all	O
FIV	O
isolates	O
.	O

The	O
patient	O
was	O
homozygous	O
for	O
the	O
underlying	O
mutation	O
,	O
which	O
was	O
found	O
to	O
be	O
a	O
G	O
-	O
-	O
>	O
T	O
transversion	O
within	O
the	O
acceptor	O
splice	O
site	O
between	O
intron	O
e	O
and	O
exon	O
6	O
,	O
abolishing	O
normal	O
RNA	O
splicing	O
.	O

These	O
regions	O
overlap	O
with	O
the	O
HIT	B-GENE
protein	I-GENE
similarity	I-GENE
regions	I-GENE
.	O

We	O
tested	O
10	O
rats	O
with	O
electrophysiologically	O
guided	O
,	O
ibotenic	O
acid	O
lesions	O
of	O
the	O
PBN	O
(	O
PBNx	O
)	O
to	O
determine	O
whether	O
they	O
could	O
acquire	O
a	O
LiCl	O
-	O
induced	O
CTA	O
to	O
l	O
-	O
alanine	O
(	O
0	O
.	O
3	O
M	O
)	O
or	O
demonstrate	O
a	O
sodium	O
appetite	O
following	O
furosemide	O
treatment	O
and	O
overnight	O
access	O
to	O
sodium	O
deficient	O
chow	O
.	O

Liposomal	O
Amphotericin	O
-	O
B	O
failed	O
in	O
6	O
/	O
7	O
patients	O
with	O
culture	O
-	O
proven	O
mycosis	O
who	O
died	O
from	O
infection	O
with	O
Aspergillus	O
(	O
n	O
=	O
2	O
)	O
and	O
Candida	O
(	O
n	O
=	O
4	O
)	O
,	O
respectively	O
.	O

Mg2	O
+	O
and	O
Mn2	O
+	O
compete	O
for	O
binding	O
sites	O
,	O
with	O
the	O
former	O
having	O
lower	O
affinity	O
.	O

Magnetic	O
storm	O
indicators	O
could	O
be	O
used	O
in	O
medicine	O
,	O
in	O
geophysics	O
and	O
for	O
special	O
purposes	O
.	O

Transgenic	O
tobacco	O
plants	O
(	O
ppa	B-GENE
-	I-GENE
1	I-GENE
)	O
constitutively	O
expressing	O
Escherichia	B-GENE
coli	I-GENE
pyrophosphatase	I-GENE
behind	O
the	O
35S	B-GENE
CaMV	I-GENE
promoter	I-GENE
accumulate	O
high	O
levels	O
of	O
soluble	O
sugars	O
in	O
their	O
leaves	O
[	O
27	O
]	O
.	O

Hb	B-GENE
levels	O
remained	O
adequate	O
(	O
Hb	B-GENE
=	O
10	O
.	O
68	O
+	O
/	O
-	O
0	O
.	O
77	O
g	O
/	O
dl	O
)	O
after	O
14	O
.	O
6	O
+	O
/	O
-	O
7	O
.	O
64	O
months	O
.	O

CBT	O
is	O
discussed	O
in	O
comparison	O
with	O
the	O
Wisconsin	O
Card	O
Sorting	O
Test	O
as	O
a	O
potential	O
cognitive	O
activation	O
task	O
for	O
functional	O
neuroimaging	O
of	O
the	O
frontal	O
lobes	O
.	O

These	O
data	O
indicate	O
that	O
although	O
218leu	O
retains	O
normal	O
transactivation	O
activity	O
on	O
a	O
p53	B-GENE
promoter	I-GENE
in	O
yeast	O
at	O
physiological	O
temperatures	O
,	O
it	O
is	O
not	O
capable	O
of	O
normal	O
p53	B-GENE
function	O
in	O
the	O
presence	O
of	O
a	O
248trp	B-GENE
allele	I-GENE
in	O
SNU	O
-	O
C5	O
cells	O
.	O

Neither	O
class	O
II	O
nor	O
IV	O
infections	O
precluded	O
transplantation	O
.	O

Although	O
a	O
great	O
deal	O
is	O
understood	O
about	O
how	O
bHLH	B-GENE
factors	I-GENE
activate	O
gene	O
transcription	O
via	O
E	O
-	O
box	O
DNA	O
consensus	O
sequences	O
,	O
studies	O
of	O
bHLH	B-GENE
factor	I-GENE
function	O
in	O
higher	O
eukaryotes	O
often	O
have	O
been	O
hindered	O
by	O
the	O
presence	O
of	O
multiple	O
family	O
members	O
.	O

Mobility	O
and	O
supershift	O
assays	O
demonstrated	O
that	O
upstream	B-GENE
stimulatory	I-GENE
factor	I-GENE
(	O
USF	B-GENE
)	O
and	O
Sp1	B-GENE
bind	O
to	O
the	O
former	O
elements	O
and	O
competition	O
experiments	O
confirmed	O
that	O
CREB	B-GENE
/	O
ATF	B-GENE
and	O
AP	B-GENE
-	I-GENE
1	I-GENE
bind	O
to	O
the	O
CRE	O
/	O
TRE	O
element	O
.	O

In	O
these	O
cases	O
,	O
greatly	O
increased	O
human	B-GENE
chorionic	I-GENE
gonadotropin	I-GENE
(	O
hCG	B-GENE
)	O
levels	O
and	O
suppressed	O
TSH	B-GENE
levels	O
suggest	O
that	O
hCG	B-GENE
has	O
thyrotropic	O
activity	O
.	O

High	O
fibrinogen	B-GENE
levels	O
could	O
thus	O
be	O
a	O
risk	O
for	O
perioperative	O
thrombosis	O
.	O

Strontium	O
chloride	O
Sr	O
89	O
is	O
costly	O
,	O
but	O
preliminary	O
analysis	O
indicates	O
that	O
it	O
may	O
reduce	O
management	O
expenditures	O
overall	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
250	O
WORDS	O
)	O

We	O
propose	O
that	O
epigenetic	O
features	O
of	O
tissue	O
-	O
specific	O
control	O
and	O
of	O
the	O
control	O
of	O
allelic	O
expression	O
are	O
intricately	O
linked	O
.	O

This	O
study	O
determined	O
the	O
arthritogenic	O
potential	O
of	O
silicone	O
gel	O
by	O
either	O
mixing	O
it	O
with	O
bovine	B-GENE
collagen	I-GENE
II	I-GENE
(	O
BII	B-GENE
)	O
or	O
by	O
injecting	O
silicone	O
gel	O
alone	O
in	O
DA	O
rats	O
.	O

This	O
5	O
'	O
splice	O
site	O
sequence	O
was	O
required	O
for	O
enhanced	O
polyadenylation	O
and	O
was	O
recognized	O
by	O
both	O
U1	B-GENE
small	I-GENE
nuclear	I-GENE
ribonucleoproteins	I-GENE
(	O
snRNPs	O
)	O
and	O
alternative	B-GENE
splicing	I-GENE
factor	I-GENE
/	O
splicing	B-GENE
factor	I-GENE
2	I-GENE
(	O
ASF	B-GENE
/	O
SF2	B-GENE
)	O
.	O

This	O
analysis	O
revealed	O
that	O
SAP	B-GENE
145	I-GENE
,	O
together	O
with	O
four	O
other	O
SF3a	B-GENE
/	O
SF3b	B-GENE
subunits	O
,	O
UV	O
cross	O
-	O
links	O
to	O
pre	O
-	O
mRNA	O
in	O
a	O
20	O
-	O
nucleotide	O
region	O
upstream	O
of	O
the	O
BPS	O
.	O

Although	O
the	O
consumption	O
of	O
myoglobin	B-GENE
-	O
bound	O
O2	O
(	O
MbO2	O
)	O
stores	O
in	O
seal	O
muscles	O
has	O
been	O
demonstrated	O
in	O
seal	O
muscles	O
during	O
laboratory	O
simulations	O
of	O
diving	O
,	O
this	O
may	O
not	O
be	O
a	O
feature	O
of	O
normal	O
field	O
diving	O
in	O
which	O
measurements	O
of	O
heart	O
rate	O
and	O
lactate	O
production	O
show	O
marked	O
differences	O
from	O
the	O
profound	O
diving	O
response	O
induced	O
by	O
forced	O
immersion	O
.	O

The	O
human	B-GENE
purH	I-GENE
cDNA	I-GENE
is	O
1776	O
base	O
pairs	O
in	O
length	O
encoding	O
for	O
a	O
591	O
-	O
amino	O
acid	O
polypeptic	O
(	O
Mr	O
=	O
64	O
,	O
425	O
)	O
.	O

The	O
Saccharomyces	O
cerevisiae	O
spindle	O
pole	O
body	O
duplication	O
gene	B-GENE
MPS1	I-GENE
is	O
part	O
of	O
a	O
mitotic	O
checkpoint	O
.	O

In	O
our	O
opinion	O
,	O
the	O
SM	O
-	O
CMA	O
system	O
is	O
,	O
despite	O
some	O
shortcomings	O
in	O
its	O
user	O
-	O
interface	O
,	O
a	O
useful	O
and	O
versatile	O
instrument	O
for	O
examination	O
of	O
human	O
semen	O
samples	O
,	O
with	O
desirable	O
features	O
.	O

Oligonucleotides	O
,	O
designed	O
on	O
the	O
basis	O
of	O
conserved	O
flanking	O
amino	O
acid	O
sequence	O
segments	O
within	O
the	O
catalytic	O
domain	O
of	O
eukaryotic	B-GENE
protein	I-GENE
kinase	I-GENE
C	I-GENE
(	O
PKC	B-GENE
)	O
proteins	O
,	O
were	O
used	O
as	O
primers	O
for	O
polymerase	O
chain	O
reactions	O
to	O
amplify	O
a	O
427	O
-	O
bp	O
chromosomal	O
DNA	O
fragment	O
from	O
the	O
filamentous	O
fungus	O
Trichoderma	O
reesei	O
.	O

Disruption	O
of	O
RB	B-GENE
/	O
E2F	B-GENE
-	I-GENE
1	I-GENE
interaction	O
by	O
single	O
point	O
mutations	O
in	O
E2F	B-GENE
-	I-GENE
1	I-GENE
enhances	O
S	O
-	O
phase	O
entry	O
and	O
apoptosis	O
.	O

Apparent	O
loss	O
of	O
differentiation	O
markers	O
characterizes	O
advanced	O
malignant	O
neoplasms	O
.	O

The	O
method	O
has	O
been	O
satisfactorily	O
applied	O
to	O
the	O
determination	O
of	O
paracetamol	O
in	O
pharmaceutical	O
formulations	O
and	O
biological	O
fluids	O
.	O

These	O
primers	O
yielded	O
a	O
PCR	O
product	O
of	O
a	O
characteristic	O
length	O
within	O
most	O
Xanthomonas	O
species	O
and	O
pathovars	O
tested	O
.	O

Rad6	B-GENE
mutants	I-GENE
display	O
a	O
remarkably	O
pleiotropic	O
phenotype	O
,	O
implicating	O
the	O
protein	O
in	O
DNA	O
damage	O
-	O
induced	O
mutagenesis	O
,	O
postreplication	O
repair	O
,	O
repression	O
of	O
retrotransposition	O
,	O
and	O
sporulation	O
.	O

RNase	B-GENE
protection	O
assays	O
revealed	O
a	O
correlation	O
between	O
the	O
levels	O
of	O
dorsal	O
and	O
ventral	O
skin	O
expression	O
with	O
pigmentation	O
/	O
phaeomelanin	O
phenotypes	O
.	O

Molecular	O
cloning	O
,	O
expression	O
pattern	O
,	O
and	O
chromosomal	O
localization	O
of	O
human	O
CDKN2D	B-GENE
/	O
INK4d	B-GENE
,	O
an	O
inhibitor	O
of	O
cyclin	B-GENE
D	I-GENE
-	I-GENE
dependent	I-GENE
kinases	I-GENE
.	O

Overproduction	O
of	O
HrcA	B-GENE
protein	I-GENE
from	O
a	O
second	O
copy	O
of	O
hrcA	B-GENE
derived	O
from	O
a	O
plasmid	O
(	O
phrcA	B-GENE
+	O
)	O
in	O
B	O
.	O
subtilis	O
wild	O
-	O
type	O
and	O
delta	O
hrcA	B-GENE
strains	O
prevented	O
heat	O
shock	O
induction	O
of	O
the	O
dnaK	B-GENE
and	O
groE	B-GENE
operons	I-GENE
at	O
the	O
level	O
of	O
transcription	O
almost	O
completely	O
and	O
strongly	O
reduced	O
the	O
amounts	O
of	O
mRNA	O
at	O
a	O
low	O
temperature	O
as	O
well	O
.	O

We	O
report	O
the	O
molecular	O
cloning	O
and	O
functional	O
characterization	O
of	O
USF2	B-GENE
isoforms	I-GENE
,	O
corresponding	O
to	O
a	O
44	O
-	O
kDa	O
subunit	O
,	O
USF2a	B-GENE
,	O
and	O
a	O
new	O
38	O
-	O
kDa	O
subunit	O
,	O
USF2b	B-GENE
,	O
generated	O
by	O
differential	O
splicing	O
.	O

The	O
preferential	O
heterodimerization	O
of	O
USF	B-GENE
subunits	I-GENE
was	O
reproduced	O
ex	O
vivo	O
,	O
while	O
the	O
in	O
vitro	O
association	O
of	O
cotranslated	O
subunits	O
,	O
or	O
recombinant	B-GENE
USF	I-GENE
proteins	I-GENE
,	O
appeared	O
to	O
be	O
random	O
.	O

Activated	O
PKR	B-GENE
may	O
exist	O
as	O
a	O
dimer	O
and	O
phosphorylates	O
the	O
eukaryotic	B-GENE
translation	I-GENE
initiation	I-GENE
factor	I-GENE
2	I-GENE
alpha	I-GENE
subunit	I-GENE
(	O
cIF	B-GENE
-	I-GENE
2	I-GENE
alpha	I-GENE
)	O
to	O
inhibit	O
polypeptide	O
chain	O
initiation	O
.	O

GRP78	B-GENE
,	O
a	O
molecular	O
chaperone	O
expressed	O
in	O
the	O
endoplasmic	O
reticulum	O
,	O
is	O
a	O
"	O
glucose	O
-	O
regulated	O
protein	O
"	O
induced	O
by	O
stress	O
responses	O
that	O
deplete	O
glucose	O
or	O
intracisternal	O
calcium	O
or	O
otherwise	O
disrupt	O
glycoprotein	O
trafficking	O
.	O

The	O
IL	B-GENE
-	I-GENE
8	I-GENE
receptor	I-GENE
is	O
a	O
seven	O
-	O
transmembrane	O
spanning	O
receptor	O
coupled	O
to	O
specific	O
heterotrimeric	B-GENE
G	I-GENE
proteins	I-GENE
including	O
Gi	B-GENE
and	O
G16	B-GENE
.	O

In	O
a	O
second	O
series	O
of	O
experiments	O
,	O
the	O
efficacy	O
of	O
PDC	O
/	O
HDC	O
Ac	O
was	O
evaluated	O
in	O
both	O
single	O
and	O
multiple	O
dose	O
regiments	O
.	O

To	O
elucidate	O
the	O
functional	O
significance	O
of	O
Fyn	B-GENE
in	O
the	O
expression	O
of	O
viral	O
promoters	O
,	O
we	O
transfected	O
a	O
Fyn	B-GENE
-	O
expression	O
vector	O
together	O
with	O
a	O
reporter	O
plasmid	O
containing	O
the	O
chloramphenicol	B-GENE
acetyltransferase	I-GENE
gene	I-GENE
driven	O
by	O
HIV	B-GENE
LTR	I-GENE
into	O
a	O
human	O
T	O
cell	O
line	O
,	O
Jurkat	O
.	O

We	O
conducted	O
a	O
prospective	O
,	O
randomized	O
controlled	O
trial	O
of	O
metoprolol	O
,	O
a	O
selective	O
beta	O
-	O
blocker	O
for	O
prevention	O
of	O
gastrointestinal	O
bleeding	O
from	O
portal	O
hypertension	O
in	O
29	O
non	O
-	O
selected	O
patients	O
with	O
liver	O
disease	O
and	O
previous	O
gastrointestinal	O
bleeding	O
.	O

A	O
genetic	O
and	O
molecular	O
analysis	O
of	O
non	O
-	O
inducible	O
qutA	B-GENE
mutants	I-GENE
showed	O
that	O
all	O
23	O
mutations	O
analysed	O
map	O
within	O
the	O
N	O
-	O
terminal	O
half	O
of	O
the	O
encoded	O
QUTA	B-GENE
protein	I-GENE
.	O

These	O
studies	O
indicate	O
that	O
the	O
acidimetric	O
test	O
was	O
less	O
sensitive	O
than	O
the	O
chromogenic	O
cephalosporin	O
substrates	O
and	O
that	O
nitrocefin	O
and	O
S1	O
could	O
be	O
used	O
to	O
screen	O
for	O
beta	B-GENE
-	I-GENE
lactamase	I-GENE
production	O
in	O
these	O
tested	O
species	O
.	O

Suppressors	O
of	O
defective	O
silencing	O
in	O
yeast	O
:	O
effects	O
on	O
transcriptional	O
repression	O
at	O
the	O
HMR	B-GENE
locus	I-GENE
,	O
cell	O
growth	O
and	O
telomere	O
structure	O
.	O

Although	O
ANP	B-GENE
induced	O
systemic	O
capillary	O
filtration	O
,	O
in	O
the	O
calf	O
,	O
filtration	O
was	O
reduced	O
with	O
ANP	B-GENE
.	O

Recent	O
literature	O
has	O
suggested	O
that	O
beta	B-GENE
-	I-GENE
2	I-GENE
transferrin	I-GENE
can	O
also	O
be	O
used	O
as	O
a	O
clinical	O
marker	O
for	O
perilymph	O
.	O

With	O
current	O
methodology	O
beta	B-GENE
-	I-GENE
2	I-GENE
transferrin	I-GENE
does	O
not	O
appear	O
to	O
be	O
a	O
reliable	O
clinical	O
marker	O
for	O
perilymph	O
in	O
the	O
operative	O
setting	O
.	O

The	O
hIGF	B-GENE
-	I-GENE
I	I-GENE
gene	I-GENE
has	O
two	O
promoters	O
,	O
P1	O
and	O
P2	O
.	O

Gel	O
mobility	O
shift	O
assays	O
indicated	O
that	O
at	O
least	O
four	O
nuclear	O
proteins	O
with	O
distinct	O
biochemical	O
and	O
binding	O
properties	O
possess	O
the	O
ability	O
to	O
bind	O
the	O
3	O
beta	O
I	O
-	O
A	O
element	O
to	O
produce	O
four	O
DNA	O
-	O
protein	O
complexes	O
(	O
R1	O
to	O
R4	O
)	O
.	O

Sixty	O
-	O
five	O
patients	O
(	O
aged	O
between	O
3	O
years	O
5	O
months	O
and	O
60	O
years	O
)	O
suffering	O
from	O
medically	O
resistant	O
temporal	O
lobe	O
epilepsy	O
(	O
TLE	O
)	O
were	O
operated	O
on	O
over	O
a	O
period	O
of	O
33	O
months	O
in	O
Bethel	O
Epilepsy	O
Center	O
.	O

Significant	O
correlations	O
existed	O
between	O
FEV1	O
and	O
the	O
corresponding	O
values	O
of	O
Raw	O
,	O
MEF50	O
and	O
MEF25	O
,	O
although	O
there	O
were	O
considerable	O
individual	O
differences	O
between	O
test	O
results	O
.	O

Hybrid	O
female	O
mice	O
(	O
C57BL	O
x	O
CBA	O
)	O
were	O
paired	O
with	O
breeder	O
males	O
(	O
CD	O
-	O
1	O
)	O
and	O
LNG	O
pellets	O
were	O
implanted	O
on	O
day	O
0	O
,	O
the	O
day	O
on	O
which	O
copulation	O
plugs	O
were	O
found	O
,	O
or	O
on	O
day	O
2	O
or	O
day	O
3	O
in	O
the	O
postcoital	O
period	O
.	O

This	O
gene	O
encodes	O
a	O
putative	O
transcription	O
factor	O
with	O
regions	O
of	O
homology	O
to	O
several	O
other	O
proteins	O
including	O
the	O
zinc	O
fingers	O
and	O
other	O
domains	O
of	O
the	O
Drosophila	B-GENE
trithorax	I-GENE
gene	I-GENE
product	I-GENE
,	O
and	O
the	O
"	O
AT	O
-	O
hook	O
"	O
DNA	O
-	O
binding	O
motif	O
of	O
high	B-GENE
mobility	I-GENE
group	I-GENE
proteins	I-GENE
.	O

Using	O
reference	O
probes	O
as	O
internal	O
standards	O
,	O
we	O
show	O
that	O
the	O
ost	B-GENE
transcription	I-GENE
unit	I-GENE
is	O
located	O
within	O
the	O
cytogenetic	O
band	O
interval	O
89A1	O
,	O
2	O
on	O
the	O
right	O
arm	O
of	O
the	O
third	O
chromosome	O
,	O
and	O
that	O
it	O
exerts	O
diagnostic	O
segmentation	O
gene	O
expression	O
patterns	O
in	O
the	O
embryo	O
.	O

The	O
purified	O
recombinant	O
enzyme	O
catalyzed	O
specific	O
phosphoryl	O
transfer	O
from	O
ATP	O
to	O
UMP	O
and	O
CMP	O
.	O

Studies	O
on	O
the	O
life	O
cycle	O
of	O
Haplorchis	O
pumilio	O
(	O
Looss	O
,	O
1896	O
)	O
Looss	O
,	O
1899	O
with	O
morphological	O
redescription	O
of	O
larval	O
and	O
adult	O
stages	O
.	O

Regressing	O
microaneurysms	O
in	O
5	O
cases	O
of	O
hepatitis	O
B	O
virus	O
related	O
polyarteritis	O
nodosa	O
.	O

During	O
the	O
following	O
pregnancy	O
ultrasonographic	O
studies	O
of	O
the	O
male	O
fetus	O
in	O
the	O
16th	O
week	O
of	O
gestation	O
revealed	O
severe	O
micrognathia	O
,	O
short	O
and	O
wide	O
thumbs	O
,	O
and	O
big	O
toes	O
,	O
and	O
bowed	O
tibiae	O
.	O

Despite	O
an	O
overall	O
survival	O
rate	O
of	O
43	O
%	O
,	O
survival	O
to	O
discharge	O
varied	O
greatly	O
(	O
0	O
to	O
100	O
%	O
)	O
among	O
the	O
24	O
diagnostic	O
groups	O
:	O
tumor	O
lysis	O
syndrome	O
and	O
systemic	O
lupus	O
erythematosus	O
(	O
3	O
/	O
3	O
patients	O
each	O
,	O
100	O
%	O
)	O
,	O
hemolytic	O
uremic	O
syndrome	O
(	O
8	O
/	O
9	O
patients	O
,	O
89	O
%	O
)	O
.	O

One	O
hundred	O
units	O
/	O
kg	O
of	O
recombinant	B-GENE
human	I-GENE
erythropoietin	I-GENE
(	O
rhEPO	B-GENE
)	O
was	O
given	O
subcutaneously	O
3	O
times	O
a	O
week	O
for	O
3	O
weeks	O
.	O

A	O
3	O
-	O
week	O
regimen	O
of	O
erythropoietin	B-GENE
may	O
help	O
prevent	O
the	O
donor	O
'	O
s	O
need	O
to	O
receive	O
allogeneic	O
blood	O
transfusion	O
,	O
when	O
the	O
initial	O
Hb	B-GENE
levels	O
were	O
below	O
130	O
milligrams	O
.	O

The	O
mean	O
body	O
mass	O
index	O
(	O
BMI	O
)	O
was	O
31	O
.	O
8	O
+	O
/	O
-	O
6	O
.	O
3	O
kg	O
/	O
m2	O
and	O
28	O
.	O
5	O
+	O
/	O
-	O
6	O
.	O
3	O
kg	O
/	O
m2	O
in	O
women	O
and	O
men	O
,	O
respectively	O
.	O

These	O
findings	O
demonstrate	O
that	O
haemodialysis	O
patients	O
with	O
chronic	O
hepatitis	O
C	O
respond	O
well	O
to	O
interferon	B-GENE
treatment	O
and	O
that	O
a	O
long	O
-	O
term	O
response	O
is	O
achieved	O
in	O
a	O
high	O
proportion	O
of	O
patients	O
.	O

Synthetic	O
enantiomers	O
of	O
drugs	O

Polysome	O
analysis	O
further	O
indicated	O
that	O
these	O
germ	B-GENE
cell	I-GENE
-	I-GENE
specific	I-GENE
Sp1	I-GENE
mRNAs	I-GENE
are	O
translated	O
,	O
albeit	O
with	O
a	O
lower	O
efficiency	O
than	O
the	O
somatic	O
transcript	O
.	O

In	O
nondiabetics	O
the	O
response	O
of	O
tcPO2	O
but	O
not	O
of	O
LDF	O
was	O
influenced	O
by	O
the	O
values	O
at	O
rest	O
.	O

This	O
study	O
proposes	O
an	O
estimator	O
for	O
such	O
global	O
synchronizing	O
effects	O
upon	O
unit	O
-	O
pair	O
correlations	O
based	O
on	O
local	O
field	O
potentials	O
(	O
LFPs	O
)	O
.	O

The	O
assembly	O
of	O
sequence	O
ready	O
,	O
high	O
-	O
resolution	O
physical	O
maps	O
and	O
construction	O
of	O
minimally	O
overlapping	O
contigs	O
for	O
the	O
human	O
as	O
well	O
as	O
model	O
genomes	O
requires	O
accurate	O
determination	O
of	O
the	O
extent	O
of	O
overlap	O
between	O
adjacent	O
clones	O
as	O
well	O
as	O
their	O
relative	O
orientation	O
.	O

The	O
DNA	O
sequences	O
upstream	O
of	O
these	O
termini	O
exhibit	O
homology	O
to	O
plant	O
mitochondrial	O
-	O
processing	O
sites	O
,	O
therefore	O
the	O
proximal	O
5	O
'	O
ends	O
are	O
most	O
probably	O
generated	O
by	O
RNA	O
processing	O
.	O

Curing	O
shrinkage	O
and	O
volumetric	O
changes	O
of	O
resin	O
-	O
modified	O
glass	O
ionomer	O
restorative	O
materials	O
.	O

Here	O
we	O
present	O
genetic	O
evidence	O
suggesting	O
that	O
PP2A	B-GENE
functions	O
downstream	O
of	O
Ras1	B-GENE
in	O
the	O
Sevenless	B-GENE
receptor	B-GENE
tyrosine	I-GENE
kinase	I-GENE
(	O
RTK	B-GENE
)	O
signal	O
transduction	O
pathway	O
that	O
specifies	O
R7	O
photoreceptor	O
cell	O
fate	O
in	O
the	O
developing	O
Drosophila	O
eye	O
.	O

QBMDs	O
for	O
a	O
5	O
%	O
change	O
in	O
response	O
(	O
QBMD05	O
)	O
were	O
6	O
-	O
fold	O
lower	O
,	O
on	O
average	O
,	O
than	O
the	O
corresponding	O
NOAEL	O
.	O

The	O
gene	O
encodes	O
an	O
ATP	B-GENE
-	I-GENE
binding	I-GENE
cassette	I-GENE
,	O
ABC	B-GENE
transporter	I-GENE
.	O

The	O
T	O
-	O
box	O
motif	O
is	O
present	O
in	O
a	O
family	O
of	O
genes	O
whose	O
structural	O
features	O
and	O
expression	O
patterns	O
support	O
their	O
involvement	O
in	O
developmental	O
gene	O
regulation	O
.	O

Molecular	O
analysis	O
of	O
a	O
novel	O
schizosaccharomyces	O
pombe	O
gene	O
containing	O
two	O
RNP	O
consensus	O
-	O
sequence	O
RNA	O
-	O
binding	O
domains	O
.	O

Do	O
overall	O
treatment	O
time	O
,	O
field	O
size	O
,	O
and	O
treatment	O
energy	O
influence	O
local	O
control	O
of	O
T1	O
-	O
T2	O
squamous	O
cell	O
carcinomas	O
of	O
the	O
glottic	O
larynx	O
?	O
PURPOSE	O
:	O
To	O
evaluate	O
treatment	O
and	O
patient	O
related	O
prognostic	O
factors	O
that	O
may	O
influence	O
local	O
control	O
in	O
the	O
treatment	O
of	O
T1	O
-	O
T2	O
squamous	O
cell	O
carcinoma	O
of	O
the	O
glottic	O
larynx	O
.	O

In	O
contrast	O
to	O
the	O
signaling	O
triggered	O
by	O
surface	O
Ig	B-GENE
engagement	O
in	O
B	O
lymphocytes	O
,	O
CD38	B-GENE
ligation	O
did	O
not	O
appear	O
to	O
induce	O
tyrosine	O
phosphorylation	O
of	O
the	O
src	B-GENE
-	I-GENE
like	I-GENE
protein	I-GENE
tyrosine	I-GENE
kinases	I-GENE
lyn	B-GENE
,	O
fyn	B-GENE
,	O
and	O
btk	B-GENE
,	O
or	O
of	O
vav	B-GENE
-	I-GENE
and	I-GENE
ras	I-GENE
-	I-GENE
GTPase	I-GENE
-	I-GENE
activating	I-GENE
protein	I-GENE
,	O
nor	O
did	O
it	O
induce	O
detectable	O
changes	O
in	O
cytosolic	O
CA2	O
+	O
concentrations	O
.	O

Mutations	O
in	O
the	O
alpha	B-GENE
-	I-GENE
amanitin	I-GENE
conserved	O
domain	O
of	O
the	O
largest	O
subunit	O
of	O
yeast	B-GENE
RNA	I-GENE
polymerase	I-GENE
III	I-GENE
affect	O
pausing	O
,	O
RNA	O
cleavage	O
and	O
transcriptional	O
transitions	O
.	O

The	O
evidence	O
presented	O
here	O
suggests	O
that	O
the	O
p40	B-GENE
complex	I-GENE
is	O
a	O
ribonucleoprotein	O
complex	O
containing	O
L1Hs	B-GENE
RNA	I-GENE
(	I-GENE
s	I-GENE
)	I-GENE
and	O
that	O
protein	O
-	O
protein	O
interactions	O
in	O
which	O
alpha	O
-	O
helix	O
structures	O
participate	O
,	O
for	O
example	O
coiled	O
-	O
coils	O
,	O
may	O
occur	O
in	O
the	O
complex	O
.	O

Our	O
data	O
suggest	O
that	O
trans	O
-	O
activation	O
from	O
the	O
prothymosin	B-GENE
intron	I-GENE
enhancer	I-GENE
is	O
a	O
faithful	O
reflection	O
of	O
the	O
transforming	O
properties	O
of	O
the	O
Myc	B-GENE
protein	I-GENE
.	O

The	O
5	O
'	O
external	O
transcribed	O
spacer	O
(	O
ETS	O
)	O
region	O
of	O
the	O
pre	O
-	O
rRNA	O
in	O
Saccharomyces	O
cerevisiae	O
contains	O
a	O
sequence	O
with	O
10	O
bp	O
of	O
perfect	O
complementarity	O
to	O
the	O
U3	B-GENE
snoRNA	I-GENE
.	O

These	O
animals	O
were	O
viable	O
and	O
fertile	O
.	O

These	O
data	O
suggest	O
that	O
RPF	B-GENE
-	I-GENE
1	I-GENE
is	O
likely	O
to	O
be	O
involved	O
in	O
early	O
steps	O
in	O
the	O
differentiation	O
of	O
amacrine	O
and	O
ganglion	O
cells	O
.	O

Carboxy	O
-	O
terminal	O
Spc110p	B-GENE
truncations	O
lacking	O
the	O
calmodulin	B-GENE
binding	O
site	O
can	O
support	O
growth	O
and	O
are	O
also	O
phosphorylated	O
in	O
a	O
cell	O
cycle	O
-	O
specific	O
manner	O
.	O

Both	O
EWS	B-GENE
-	O
FLI	B-GENE
-	I-GENE
1	I-GENE
and	O
FLI	B-GENE
-	I-GENE
1	I-GENE
proteins	I-GENE
function	O
as	O
transcription	O
factors	O
that	O
bind	O
specifically	O
to	O
ets	B-GENE
sequences	O
(	O
the	O
ets	B-GENE
boxes	O
)	O
present	O
in	O
promoter	O
elements	O
.	O

In	O
electromobility	O
shift	O
assays	O
,	O
EWS	B-GENE
-	O
FLI	B-GENE
-	I-GENE
1	I-GENE
binding	O
to	O
the	O
SRE	O
is	O
detectable	O
in	O
the	O
absence	O
of	O
SRF	B-GENE
whereas	O
the	O
binding	O
of	O
FLI	B-GENE
-	I-GENE
1	I-GENE
is	O
not	O
,	O
suggesting	O
that	O
the	O
interaction	O
with	O
DNA	O
is	O
the	O
step	O
which	O
limits	O
ternary	O
complex	O
formation	O
by	O
FLI	B-GENE
-	I-GENE
1	I-GENE
.	O

Additional	O
studies	O
with	O
new	O
and	O
reprocessed	O
regenerated	O
cellulose	O
dialyzers	O
comparing	O
450	O
and	O
220	O
mL	O
/	O
min	O
blood	O
flow	O
rates	O
at	O
10	O
minutes	O
showed	O
no	O
change	O
in	O
BTG	O
.	O

DNA	O
methylation	O
,	O
especially	O
of	O
either	O
one	O
or	O
both	O
of	O
the	O
deoxyadenosines	O
at	O
the	O
two	O
GATC	O
motifs	O
(	O
one	O
in	O
the	O
first	O
exon	O
and	O
the	O
other	O
in	O
the	O
first	O
intron	O
of	O
the	O
rice	O
CatA	B-GENE
gene	I-GENE
)	O
,	O
appeared	O
to	O
be	O
responsible	O
for	O
the	O
CatA	B-GENE
promoter	I-GENE
activity	O
identified	O
in	O
the	O
transient	O
assay	O
.	O

The	O
viral	B-GENE
LTR	I-GENE
was	O
used	O
as	O
the	O
promoter	O
.	O

Overlapping	O
cDNA	O
clones	O
were	O
isolated	O
and	O
sequenced	O
.	O

Epitope	O
mapping	O
revealed	O
that	O
these	O
three	O
clones	O
appear	O
to	O
recognize	O
an	O
identical	O
epitope	O
domain	O
present	O
on	O
the	O
C	O
-	O
terminal	O
RNP	O
motif	O
of	O
the	O
U1A	B-GENE
protein	I-GENE
.	O

Variables	O
evaluated	O
were	O
number	O
of	O
weekly	O
anginal	O
events	O
,	O
data	O
from	O
ergometric	O
exercise	O
testing	O
with	O
simultaneous	O
electrocardiographic	O
registration	O
,	O
semiquantitative	O
evaluation	O
of	O
Tc	O
-	O
99m	O
2	O
-	O
methoxy	O
isobutyl	O
isonitrile	O
(	O
MIBI	O
)	O
scans	O
and	O
rheologic	O
variables	O
.	O

As	O
the	O
length	O
of	O
the	O
fatty	O
acid	O
decreased	O
,	O
the	O
binding	O
affinity	O
was	O
reduced	O
;	O
myristic	O
acid	O
(	O
14	O
:	O
0	O
)	O
bound	O
with	O
a	O
K	O
(	O
d	O
)	O
of	O
1409	O
+	O
/	O
-	O
423	O
nM	O
,	O
but	O
medium	O
-	O
chain	O
(	O
decanoic	O
acid	O
,	O
10	O
:	O
0	O
)	O
and	O
short	O
-	O
chain	O
(	O
octanoic	O
acid	O
,	O
8	O
:	O
0	O
)	O
lipids	O
were	O
not	O
bound	O
at	O
all	O
.	O

The	O
membrane	O
-	O
distal	O
cytoplasmic	O
region	O
of	O
human	B-GENE
granulocyte	I-GENE
colony	I-GENE
-	I-GENE
stimulating	I-GENE
factor	I-GENE
receptor	I-GENE
is	O
required	O
for	O
STAT3	B-GENE
but	O
not	O
STAT1	B-GENE
homodimer	I-GENE
formation	O
.	O

However	O
,	O
whether	O
or	O
not	O
nonsense	O
codon	O
recognition	O
within	O
TPI	B-GENE
transcripts	I-GENE
takes	O
place	O
prior	O
to	O
or	O
after	O
splicing	O
remained	O
unresolved	O
.	O

Although	O
some	O
residues	O
are	O
found	O
reactive	O
toward	O
dimethylsulphate	O
and	O
kethoxal	O
in	O
regions	O
predicted	O
to	O
be	O
unpaired	O
by	O
the	O
phylogenetic	O
secondary	O
structure	O
model	O
of	O
4	B-GENE
.	I-GENE
5S	I-GENE
RNA	I-GENE
,	O
generally	O
the	O
reactivity	O
is	O
low	O
,	O
and	O
some	O
residues	O
in	O
internal	O
loops	O
are	O
not	O
reactive	O
at	O
all	O
.	O

Ongoing	O
and	O
future	O
investigations	O
may	O
better	O
define	O
the	O
optimal	O
approach	O
for	O
local	O
control	O
,	O
the	O
optimal	O
duration	O
of	O
maintenance	O
chemotherapy	O
,	O
and	O
the	O
possible	O
role	O
of	O
biologic	O
response	O
modifiers	O
and	O
growth	O
factors	O
in	O
further	O
improving	O
the	O
outcome	O
for	O
patients	O
with	O
this	O
disease	O
.	O

SUMMARY	O
OF	O
REVIEW	O
:	O
We	O
discuss	O
the	O
criteria	O
that	O
make	O
such	O
studies	O
comparable	O
,	O
drawing	O
on	O
the	O
experiences	O
of	O
recent	O
studies	O
performed	O
around	O
the	O
world	O
.	O

Forty	O
-	O
five	O
patients	O
with	O
pleural	O
lesions	O
identified	O
on	O
CT	O
scans	O
were	O
subsequently	O
examined	O
by	O
MR	O
imaging	O
at	O
0	O
.	O
5	O
T	O
.	O

RESULTS	O
:	O
Basal	O
plasma	B-GENE
IGF	I-GENE
-	I-GENE
I	I-GENE
levels	O
as	O
well	O
as	O
body	O
mass	O
index	O
(	O
BMI	O
)	O
were	O
lower	O
in	O
amenorrheic	O
patients	O
than	O
in	O
healthy	O
controls	O
.	O

The	O
alpha	O
T3	O
-	O
1	O
cell	O
line	O
,	O
a	O
GnRH	B-GENE
-	O
responsive	O
gonadotroph	O
cell	O
line	O
developed	O
by	O
targeted	O
oncogenesis	O
in	O
transgenic	O
mice	O
,	O
was	O
used	O
to	O
study	O
regulation	O
of	O
the	O
glycoprotein	B-GENE
hormone	I-GENE
alpha	I-GENE
-	I-GENE
subunit	I-GENE
by	O
activin	B-GENE
.	O

Cotransfection	O
with	O
the	O
ie1	B-GENE
gene	I-GENE
resulted	O
in	O
a	O
dramatic	O
increase	O
in	O
the	O
amount	O
of	O
the	O
two	O
enzymes	O
expressed	O
in	O
the	O
transfected	O
cells	O
.	O

As	O
expected	O
,	O
glycosylation	O
of	O
Env	B-GENE
produced	O
from	O
mutants	O
was	O
affected	O
but	O
,	O
irrespective	O
of	O
the	O
glycosylation	O
phenotype	O
,	O
(	O
i	O
)	O
similar	O
quantities	O
of	O
Env	B-GENE
were	O
synthesized	O
,	O
(	O
ii	O
)	O
the	O
immunoreactivity	O
of	O
V3	B-GENE
was	O
similar	O
,	O
(	O
iii	O
)	O
gp160	B-GENE
was	O
efficiently	O
cleaved	O
into	O
gp120	B-GENE
and	O
gp41	B-GENE
,	O
(	O
vi	O
)	O
Env	B-GENE
was	O
exposed	O
at	O
the	O
cell	O
membrane	O
,	O
(	O
v	O
)	O
secreted	O
gp120	B-GENE
bound	O
CD4	B-GENE
,	O
and	O
(	O
vi	O
)	O
membrane	O
gp41	B-GENE
was	O
able	O
to	O
induce	O
membrane	O
fusion	O
with	O
CD4	B-GENE
+	I-GENE
cells	O
.	O

Effects	O
of	O
posteroventral	O
pallidotomy	O
on	O
Parkinson	O
'	O
s	O
disease	O
.	O

On	O
the	O
trail	O
of	O
Dr	O
.	O

However	O
,	O
only	O
complete	B-GENE
DnaJ	I-GENE
can	O
cooperate	O
with	O
DnaK	B-GENE
and	O
a	O
third	O
protein	O
,	O
GrpE	B-GENE
,	O
in	O
refolding	O
denatured	B-GENE
firefly	I-GENE
luciferase	I-GENE
.	O

The	O
two	O
different	O
phosphoforms	O
of	O
STAT5	B-GENE
have	O
identical	O
in	O
vitro	O
DNA	O
binding	O
specificity	O
and	O
reactivity	O
with	O
tyrosine	O
phosphopeptides	O
,	O
but	O
differ	O
in	O
their	O
cellular	O
localization	O
.	O

We	O
have	O
isolated	O
a	O
novel	O
protein	O
from	O
Drosophila	O
nuclear	O
extracts	O
which	O
binds	O
specifically	O
to	O
a	O
site	O
in	O
this	O
second	O
region	O
.	O

Control	O
of	O
transcription	O
of	O
the	O
erbB	B-GENE
-	I-GENE
2	I-GENE
gene	I-GENE
is	O
an	O
important	O
determinant	O
of	O
receptor	O
expression	O
.	O

DNase	B-GENE
I	I-GENE
footprinting	O
and	O
electrophoretic	O
mobility	O
shift	O
assays	O
indicate	O
that	O
PBP	B-GENE
binds	O
to	O
the	O
half	O
-	O
site	O
of	O
each	O
palindrome	O
with	O
the	O
core	O
recognition	O
sequence	O
TGGGAG	O
.	O

These	O
results	O
demonstrate	O
that	O
sequences	O
in	O
the	O
SH2	B-GENE
/	O
SH3	B-GENE
/	O
SH2	B-GENE
region	O
of	O
p120	B-GENE
GAP	B-GENE
are	O
required	O
for	O
full	O
catalytic	O
activity	O
toward	O
Ras	B-GENE
.	O

Further	O
analysis	O
of	O
this	O
domain	O
by	O
in	O
vitro	O
mutagenesis	O
pointed	O
to	O
a	O
core	O
of	O
hydrophobic	O
and	O
acidic	O
residues	O
as	O
critical	O
for	O
the	O
activity	O
.	O

Analysis	O
of	O
RAR	B-GENE
alpha	I-GENE
mutants	I-GENE
in	O
transfection	O
studies	O
reveals	O
that	O
the	O
DNA	O
binding	O
domain	O
is	O
sufficient	O
for	O
inhibition	O
of	O
BZLF1	B-GENE
activity	O
.	O

We	O
measured	O
serum	B-GENE
hepatocyte	I-GENE
growth	I-GENE
factor	I-GENE
(	O
HGF	B-GENE
)	O
in	O
patients	O
with	O
acute	O
myocardial	O
infarction	O
,	O
angina	O
pectoris	O
,	O
and	O
other	O
heart	O
diseases	O
.	O

The	O
neural	O
mechanism	O
of	O
parkinsonian	O
motor	O
symptoms	O
,	O
i	O
.	O
e	O
.	O
,	O
rigidity	O
,	O
tremor	O
and	O
akinesia	O
,	O
which	O
are	O
the	O
result	O
of	O
nigrostriatal	O
dopamine	O
deficiency	O
,	O
is	O
interpreted	O
from	O
long	O
-	O
term	O
observations	O
on	O
the	O
effect	O
of	O
surgical	O
and	O
pharmacological	O
treatment	O
of	O
the	O
disease	O
in	O
relation	O
to	O
the	O
neuropathological	O
findings	O
within	O
the	O
substantia	O
nigra	O
zona	O
compacta	O
(	O
SNc	O
)	O
.	O

Protein	O
splicing	O
:	O
evidence	O
for	O
an	O
N	O
-	O
O	O
acyl	O
rearrangement	O
as	O
the	O
initial	O
step	O
in	O
the	O
splicing	O
process	O
.	O

In	O
agreement	O
with	O
these	O
data	O
,	O
western	O
blot	O
experiments	O
using	O
an	O
antibody	O
directed	O
against	O
the	O
carboxy	O
-	O
terminal	O
portion	O
of	O
the	O
mouse	O
c	B-GENE
-	I-GENE
kit	I-GENE
protein	I-GENE
showed	O
that	O
a	O
polypeptide	O
,	O
of	O
the	O
size	O
predicted	O
by	O
the	O
open	O
reading	O
frame	O
of	O
the	O
spermatid	B-GENE
-	I-GENE
specific	I-GENE
c	I-GENE
-	I-GENE
kit	I-GENE
cDNA	I-GENE
,	O
accumulates	O
in	O
the	O
latest	O
stages	O
of	O
spermatogenesis	O
and	O
in	O
epididymal	O
spermatozoa	O
.	O

It	O
is	O
shown	O
that	O
the	O
(	O
G	O
+	O
C	O
)	O
-	O
rich	O
element	O
of	O
the	O
aldolase	B-GENE
C	I-GENE
promoter	I-GENE
directs	O
transcription	O
in	O
neuronal	O
as	O
well	O
as	O
in	O
nonneuronal	O
cells	O
.	O

Treatment	O
of	O
keratinocytes	O
expressing	O
a	O
normal	O
epidermal	B-GENE
growth	I-GENE
factor	I-GENE
receptor	I-GENE
(	O
EGFR	B-GENE
)	O
with	O
TGFalpha	B-GENE
or	O
epidermal	B-GENE
growth	I-GENE
factor	I-GENE
for	O
5	O
min	O
induced	O
PKCdelta	B-GENE
tyrosine	O
phosphorylation	O
.	O

Only	O
one	O
of	O
these	O
bands	O
was	O
supershifted	O
by	O
antibody	O
to	O
p50	B-GENE
,	O
whereas	O
antibodies	O
to	O
p65	B-GENE
or	O
other	O
NF	B-GENE
-	I-GENE
kappaB	I-GENE
proteins	I-GENE
had	O
no	O
effect	O
.	O

We	O
isolated	O
a	O
complementary	O
DNA	O
(	O
cDNA	O
)	O
clone	O
from	O
an	O
RL95	O
-	O
2	O
expression	O
library	O
that	O
encodes	O
the	O
C1	B-GENE
site	I-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
.	O

Biol	O
.	O

In	O
addition	O
,	O
anti	B-GENE
-	I-GENE
phosphotyrosine	I-GENE
antibodies	I-GENE
immunoprecipitated	O
80K	B-GENE
-	I-GENE
H	I-GENE
from	O
cell	O
lysates	O
of	O
FGF	B-GENE
-	O
stimulated	O
but	O
not	O
from	O
control	O
fibroblasts	O
.	O

The	O
novel	O
protein	O
kinases	O
,	O
c	B-GENE
-	I-GENE
Jun	I-GENE
NH2	I-GENE
-	I-GENE
terminal	I-GENE
kinases	I-GENE
(	O
JNKs	B-GENE
)	O
/	O
stress	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
kinases	I-GENE
,	O
are	O
also	O
activated	O
by	O
TNF	B-GENE
-	I-GENE
alpha	I-GENE
,	O
IL	B-GENE
-	I-GENE
1	I-GENE
,	O
and	O
CD28	B-GENE
costimulation	O
.	O

Thus	O
,	O
hGRbeta	B-GENE
potentially	O
functions	O
as	O
a	O
dominant	O
negative	O
inhibitor	O
of	O
hGRalpha	B-GENE
activity	O
.	O

Gas6	B-GENE
contains	O
an	O
NH2	O
-	O
terminal	O
Gla	O
domain	O
followed	O
by	O
four	O
epidermal	B-GENE
growth	I-GENE
factor	I-GENE
-	I-GENE
like	I-GENE
repeats	I-GENE
and	O
tandem	O
globular	O
(	O
G	O
)	O
domains	O
.	O

Both	O
P5CDh	B-GENE
cDNA	I-GENE
clones	O
detect	O
a	O
single	O
3	O
.	O
2	O
-	O
kb	O
transcript	O
on	O
Northern	O
blots	O
of	O
multiple	O
human	O
tissues	O
,	O
indicating	O
the	O
long	O
cDNA	O
containing	O
the	O
3	O
'	O
-	O
untranslated	O
intron	O
represents	O
the	O
predominant	O
transcript	O
.	O

Polymerization	O
of	O
neurofilament	B-GENE
L	I-GENE
protein	I-GENE
in	O
vitro	O
was	O
inhibited	O
by	O
phosphorylation	O
of	O
neurofilament	B-GENE
L	I-GENE
protein	I-GENE
by	O
PKN	B-GENE
.	O

We	O
and	O
others	O
have	O
demonstrated	O
that	O
the	O
c	B-GENE
-	I-GENE
cbl	I-GENE
proto	I-GENE
-	I-GENE
oncogene	I-GENE
product	I-GENE
is	O
one	O
of	O
the	O
earliest	O
targets	O
of	O
tyrosine	O
phosphorylation	O
upon	O
T	B-GENE
cell	I-GENE
receptor	I-GENE
stimulation	O
.	O

A	O
substantial	O
fraction	O
of	O
Cbl	B-GENE
was	O
constitutively	O
associated	O
with	O
Grb2	B-GENE
and	O
this	O
interaction	O
was	O
mediated	O
by	O
Grb2	B-GENE
SH3	B-GENE
domains	O
.	O

An	O
AP	B-GENE
-	I-GENE
1	I-GENE
binding	I-GENE
sequence	I-GENE
is	O
essential	O
for	O
regulation	O
of	O
the	O
human	B-GENE
alpha2	I-GENE
(	I-GENE
I	I-GENE
)	I-GENE
collagen	I-GENE
(	O
COL1A2	B-GENE
)	O
promoter	O
activity	O
by	O
transforming	B-GENE
growth	I-GENE
factor	I-GENE
-	I-GENE
beta	I-GENE
.	O

Only	O
two	O
patients	O
(	O
0	O
.	O
3	O
%	O
)	O
had	O
a	O
CA	B-GENE
125	I-GENE
response	O
at	O
the	O
time	O
of	O
clinical	O
progression	O
.	O

The	O
men	O
self	O
-	O
selected	O
a	O
prescribed	O
diet	O
at	O
home	O
emphasizing	O
saturated	O
fat	O
as	O
the	O
visible	O
fat	O
for	O
1	O
week	O
.	O

These	O
results	O
illuminate	O
a	O
hitherto	O
unanticipated	O
function	O
of	O
U6	B-GENE
RNA	I-GENE
:	O
the	O
modulation	O
of	O
a	O
phosphorylation	O
-	O
dephosphorylation	O
cycle	O
of	O
C1	B-GENE
hnRNP	I-GENE
protein	I-GENE
that	O
influences	O
the	O
binding	O
affinity	O
of	O
this	O
protein	O
for	O
pre	O
-	O
mRNA	O
.	O

Inclusion	O
of	O
the	O
extended	O
N	O
terminus	O
into	O
the	O
originally	O
reported	O
protein	O
resulted	O
in	O
a	O
striking	O
similarity	O
to	O
the	O
lymphoid	B-GENE
factor	I-GENE
Lef	I-GENE
-	I-GENE
1	I-GENE
.	O

Truncated	O
mammalian	B-GENE
Notch1	I-GENE
activates	O
CBF1	B-GENE
/	O
RBPJk	B-GENE
-	O
repressed	O
genes	O
by	O
a	O
mechanism	O
resembling	O
that	O
of	O
Epstein	B-GENE
-	I-GENE
Barr	I-GENE
virus	I-GENE
EBNA2	I-GENE
.	O

Electrophoretic	O
mobility	O
shift	O
assays	O
(	O
EMSAs	O
)	O
using	O
purified	O
glucocorticoid	B-GENE
receptor	I-GENE
DNA	I-GENE
binding	I-GENE
domain	I-GENE
(	O
DBD	O
)	O
demonstrated	O
that	O
both	O
GRE	B-GENE
-	I-GENE
2	I-GENE
and	I-GENE
-	I-GENE
3	I-GENE
motifs	I-GENE
interact	O
with	O
DBD	O
and	O
oligonucleotide	O
competition	O
experiments	O
established	O
that	O
these	O
have	O
different	O
affinities	O
for	O
DBD	O
.	O

The	O
large	O
subfamily	O
of	O
receptor	B-GENE
tyrosine	I-GENE
kinases	I-GENE
(	O
RTKs	B-GENE
)	O
for	O
which	O
EPH	B-GENE
is	O
the	O
prototype	O
have	O
likely	O
roles	O
in	O
intercellular	O
communication	O
during	O
normal	O
mammalian	O
development	O
,	O
but	O
the	O
biochemical	O
signalling	O
pathways	O
utilised	O
by	O
this	O
family	O
are	O
poorly	O
characterised	O
.	O

The	O
17	O
-	O
kDa	O
protein	O
is	O
required	O
for	O
the	O
systemic	O
infection	O
of	O
plants	O
.	O

We	O
present	O
here	O
a	O
detailed	O
genomic	O
sequencing	O
analysis	O
of	O
the	O
cytosine	O
methylation	O
patterns	O
of	O
the	O
transposase	B-GENE
binding	O
sites	O
within	O
both	O
Ac	B-GENE
ends	O
in	O
the	O
wx	B-GENE
-	I-GENE
m9	I-GENE
:	O
:	O
Ac	B-GENE
allele	I-GENE
,	O
where	O
Ac	B-GENE
is	O
inserted	O
into	O
the	O
tenth	O
exon	O
of	O
the	O
Waxy	B-GENE
gene	I-GENE
.	O

Krox	B-GENE
-	I-GENE
20	I-GENE
,	O
a	O
zinc	B-GENE
finger	I-GENE
gene	I-GENE
,	O
has	O
a	O
highly	O
conserved	O
pattern	O
of	O
expression	O
in	O
r3	O
and	O
r5	O
and	O
is	O
functionally	O
required	O
for	O
their	O
maintenance	O
in	O
mouse	O
embryos	O
.	O

Pituitary	O
adenylate	B-GENE
cyclase	I-GENE
-	I-GENE
activating	I-GENE
polypeptide	I-GENE
regulates	O
prolactin	B-GENE
promoter	I-GENE
activity	O
via	O
a	O
protein	B-GENE
kinase	I-GENE
A	I-GENE
-	O
mediated	O
pathway	O
that	O
is	O
independent	O
of	O
the	O
transcriptional	O
pathway	O
employed	O
by	O
thyrotropin	B-GENE
-	I-GENE
releasing	I-GENE
hormone	I-GENE
.	O

Clones	O
33F	O
and	O
34B	O
encoded	O
identical	O
aromatase	B-GENE
proteins	I-GENE
of	O
503	O
amino	O
acids	O
,	O
but	O
differed	O
in	O
size	O
due	O
to	O
alternative	O
polyadenylation	O
signal	O
usage	O
for	O
the	O
corresponding	O
mRNAs	O
.	O

In	O
sorted	O
bone	O
marrow	O
cells	O
expression	O
of	O
both	O
VpreB	B-GENE
genes	I-GENE
was	O
detected	O
in	O
pro	O
-	O
B	O
/	O
pre	O
-	O
BI	O
and	O
large	O
pre	O
-	O
BII	O
cells	O
,	O
while	O
the	O
RNA	O
steady	O
state	O
levels	O
were	O
at	O
least	O
100	O
-	O
fold	O
lower	O
in	O
small	O
pre	O
-	O
BII	O
and	O
immature	O
/	O
mature	O
B	O
cells	O
.	O

We	O
have	O
cloned	O
and	O
sequenced	O
a	O
3574	O
-	O
bp	O
Bacillus	O
subtilis	O
(	O
Bs	O
)	O
DNA	O
fragment	O
located	O
between	O
the	O
nrdA	B-GENE
and	O
citB	B-GENE
genes	I-GENE
at	O
about	O
169	O
degrees	O
on	O
the	O
chromosome	O
.	O

Aeromonas	O
salmonicida	O
possesses	O
two	O
genes	O
encoding	O
homologs	O
of	O
the	O
major	B-GENE
outer	I-GENE
membrane	I-GENE
protein	I-GENE
,	O
OmpA	B-GENE
.	O

Expression	O
of	O
Msp	B-GENE
was	O
toxic	O
to	O
E	O
.	O
coli	O
when	O
the	O
entire	O
msp	B-GENE
gene	I-GENE
was	O
present	O
.	O

In	O
agreement	O
with	O
previous	O
in	O
vitro	O
data	O
,	O
we	O
have	O
shown	O
that	O
UmuD	B-GENE
and	O
UmuD	B-GENE
'	I-GENE
are	O
able	O
to	O
form	O
both	O
homodimers	O
(	O
UmuD	B-GENE
-	O
UmuD	B-GENE
and	O
UmuD	B-GENE
'	I-GENE
-	O
UmuD	B-GENE
'	I-GENE
)	O
and	O
a	O
heterodimer	O
(	O
UmuD	B-GENE
-	O
UmuD	B-GENE
'	I-GENE
)	O
.	O

Lyn	B-GENE
kinase	I-GENE
immunoprecipitated	O
from	O
lysates	O
of	O
irradiated	O
BCP	O
as	O
well	O
as	O
a	O
full	O
-	O
length	O
glutathione	B-GENE
S	I-GENE
-	I-GENE
transferase	I-GENE
(	O
GST	B-GENE
)	O
-	O
Lyn	B-GENE
fusion	O
protein	O
-	O
phosphorylated	O
recombinant	B-GENE
human	I-GENE
p34cdc2	I-GENE
on	O
tyrosine	O
15	O
.	O

Binding	O
specificity	O
and	O
modulation	O
of	O
the	O
ApoA	B-GENE
-	I-GENE
I	I-GENE
promoter	I-GENE
activity	O
by	O
homo	O
-	O
and	O
heterodimers	O
of	O
nuclear	O
receptors	O
.	O

There	O
is	O
growing	O
evidence	O
that	O
mammalian	B-GENE
AMP	I-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
kinase	I-GENE
(	O
AMPK	B-GENE
)	O
plays	O
a	O
role	O
in	O
protecting	O
cells	O
from	O
stresses	O
that	O
cause	O
ATP	O
depletion	O
by	O
switching	O
off	O
ATP	O
-	O
consuming	O
biosynthetic	O
pathways	O
.	O

Sterol	O
-	O
mediated	O
suppression	O
of	O
cleavage	O
of	O
SREBP	B-GENE
-	I-GENE
1	I-GENE
was	O
found	O
to	O
be	O
dependent	O
on	O
the	O
extreme	O
COOH	O
-	O
terminal	O
region	O
(	O
residue	O
1034	O
to	O
the	O
COOH	O
terminus	O
)	O
,	O
which	O
exists	O
in	O
two	O
forms	O
as	O
a	O
result	O
of	O
alternative	O
splicing	O
.	O

Am	O
.	O

EMSA	O
competition	O
experiments	O
showed	O
that	O
mutations	O
within	O
the	O
direct	O
repeats	O
failed	O
to	O
compete	O
for	O
binding	O
of	O
the	O
nuclear	O
proteins	O
to	O
labeled	O
wild	O
type	O
oligonucleotide	O
.	O

Transcription	O
from	O
the	O
promoter	O
containing	O
the	O
mutated	O
direct	O
repeats	O
was	O
increased	O
greatly	O
,	O
consistent	O
with	O
the	O
conclusion	O
that	O
these	O
motifs	O
functions	O
in	O
vivo	O
to	O
repress	O
GPT	B-GENE
gene	I-GENE
expression	O
.	O

However	O
,	O
a	O
>	O
10	O
-	O
fold	O
increase	O
in	O
ERK3	B-GENE
activity	O
in	O
each	O
PKC	B-GENE
beta	I-GENE
transfectant	O
was	O
shown	O
by	O
immunoprecipitation	O
with	O
anti	B-GENE
-	I-GENE
ERK3	I-GENE
monoclonal	I-GENE
antibody	I-GENE
followed	O
by	O
either	O
immune	O
complex	O
kinase	O
assay	O
or	O
by	O
in	O
gel	O
kinase	O
assay	O
.	O

Sequence	O
analysis	O
of	O
this	O
100	O
-	O
bp	O
Col2a1	B-GENE
enhancer	I-GENE
revealed	O
several	O
sequence	O
motifs	O
similar	O
to	O
motifs	O
present	O
within	O
the	O
regulatory	O
region	O
of	O
the	O
link	B-GENE
protein	I-GENE
gene	I-GENE
,	O
another	O
cartilage	O
gene	O
.	O

Retinoid	O
-	O
dependent	O
activation	O
of	O
the	O
tissue	B-GENE
transglutaminase	I-GENE
promoter	I-GENE
depends	O
on	O
both	O
a	O
proximal	O
regulatory	O
region	O
containing	O
sequences	O
highly	O
conserved	O
between	O
the	O
human	O
and	O
the	O
mouse	B-GENE
tissue	I-GENE
transglutaminase	I-GENE
promoters	I-GENE
and	O
a	O
distal	O
region	O
that	O
includes	O
a	O
30	O
-	O
base	O
pair	O
retinoid	O
response	O
element	O
(	O
mTGRRE1	O
)	O
.	O
mTGRRE1	O
contains	O
three	O
hexanucleotide	O
half	O
-	O
sites	O
(	O
two	O
canonical	O
and	O
one	O
non	O
-	O
canonical	O
)	O
in	O
a	O
DR7	B-GENE
/	O
DR5	B-GENE
motif	O
that	O
bind	O
both	O
RAR	B-GENE
*	O
RXR	B-GENE
heterodimers	O
and	O
RXR	B-GENE
homodimers	I-GENE
.	O

Significantly	O
,	O
pPKR	B-GENE
is	O
capable	O
of	O
specifically	O
phosphorylating	O
Ser51	O
in	O
a	O
synthetic	B-GENE
eIF	I-GENE
-	I-GENE
2alpha	I-GENE
peptide	I-GENE
,	O
a	O
key	O
characteristic	O
of	O
the	O
eIF	B-GENE
-	I-GENE
2alpha	I-GENE
kinase	I-GENE
family	I-GENE
.	O

Vertebrate	B-GENE
synapsins	I-GENE
constitute	O
a	O
family	O
of	O
synaptic	O
proteins	O
that	O
participate	O
in	O
the	O
regulation	O
of	O
neurotransmitter	O
release	O
.	O

Electrophoretic	O
mobility	O
shift	O
assays	O
using	O
crude	O
extracts	O
from	O
FREJ4	O
cells	O
revealed	O
the	O
binding	O
of	O
a	O
member	O
(	O
s	O
)	O
of	O
the	O
Ets	B-GENE
family	I-GENE
of	I-GENE
transcription	I-GENE
factors	I-GENE
to	O
the	O
P4	B-GENE
EBS	I-GENE
,	O
as	O
well	O
as	O
the	O
interaction	O
of	O
two	O
members	O
of	O
the	O
Sp1	B-GENE
family	I-GENE
,	O
Sp1	B-GENE
and	O
Sp3	B-GENE
,	O
with	O
the	O
adjacent	O
GC	O
box	O
.	O

ZEBRA	B-GENE
and	O
cellular	O
AP	B-GENE
-	I-GENE
1	I-GENE
bZip	I-GENE
activators	I-GENE
,	O
such	O
as	O
c	B-GENE
-	I-GENE
Fos	I-GENE
,	O
have	O
homologous	O
DNA	O
-	O
binding	O
domains	O
,	O
and	O
their	O
DNA	O
-	O
binding	O
specificities	O
overlap	O
.	O

This	O
result	O
suggested	O
that	O
mutant	O
I299	O
has	O
diminished	O
cap	O
-	O
binding	O
activity	O
.	O

UV	O
cross	O
-	O
linking	O
experiments	O
demonstrated	O
that	O
HSV	O
infection	O
caused	O
enhanced	O
binding	O
of	O
protein	O
factors	O
,	O
including	O
the	O
64	B-GENE
-	I-GENE
kDa	I-GENE
component	I-GENE
of	I-GENE
cleavage	I-GENE
stimulation	I-GENE
factor	I-GENE
(	O
CstF	B-GENE
)	O
,	O
to	O
poly	O
(	O
A	O
)	O
site	O
RNAs	O
from	O
virus	O
genes	O
of	O
all	O
temporal	O
classes	O
and	O
that	O
this	O
enhanced	O
binding	O
required	O
expression	O
of	O
IE63	B-GENE
.	O

CM	B-GENE
-	I-GENE
ACO3	I-GENE
is	O
expressed	O
in	O
flowers	O
and	O
is	O
not	O
induced	O
by	O
any	O
of	O
the	O
stimuli	O
tested	O
.	O

We	O
show	O
here	O
that	O
these	O
Jun	B-GENE
/	O
eb1	B-GENE
chimeras	O
are	O
potent	O
transactivators	O
of	O
AP1	B-GENE
sites	I-GENE
and	O
that	O
they	O
can	O
cooperate	O
with	O
c	B-GENE
-	I-GENE
Ha	I-GENE
-	I-GENE
Ras	I-GENE
to	O
induce	O
foci	O
.	O

In	O
synchronized	O
HeLa	O
cells	O
,	O
expression	O
of	O
luciferase	B-GENE
activity	O
was	O
induced	O
at	O
the	O
beginning	O
of	O
DNA	O
synthesis	O
and	O
was	O
dependent	O
on	O
the	O
presence	O
of	O
an	O
E2F	B-GENE
-	I-GENE
binding	I-GENE
site	I-GENE
in	O
the	O
H2A	B-GENE
.	I-GENE
1	I-GENE
promoter	I-GENE
.	O

Utilizing	O
transient	O
transfection	O
studies	O
in	O
HepG2	O
cells	O
,	O
we	O
have	O
shown	O
that	O
deletion	O
of	O
the	O
factor	B-GENE
VIII	I-GENE
promoter	I-GENE
sequences	I-GENE
distal	O
to	O
nucleotide	O
-	O
44	O
results	O
in	O
a	O
significant	O
but	O
small	O
increase	O
in	O
promoter	O
activity	O
.	O

We	O
constructed	O
a	O
yeast	O
reporter	O
strain	O
containing	O
the	O
lacZ	B-GENE
gene	I-GENE
under	O
the	O
control	O
of	O
the	O
CYC1	B-GENE
promoter	I-GENE
associated	O
with	O
three	O
copies	O
of	O
TRE	B-GENE
-	I-GENE
1	I-GENE
.	O

If	O
hnRNP	B-GENE
K	I-GENE
is	O
a	O
transcription	O
factor	O
,	O
then	O
interactions	O
with	O
the	O
RNA	B-GENE
polymerase	I-GENE
II	I-GENE
transcription	O
apparatus	O
are	O
predicted	O
.	O

A	O
developmentally	O
regulated	O
4	O
.	O
6	O
kb	O
mRNA	O
is	O
recognized	O
on	O
Northern	O
blots	O
of	O
oocyte	O
RNA	O
using	O
the	O
X	O
.	O
laevis	O
cDNA	O
.	O

Sequence	O
conservation	O
is	O
greatest	O
for	O
residues	O
located	O
near	O
the	O
active	O
centers	O
of	O
the	O
exo	B-GENE
and	O
pol	B-GENE
domains	I-GENE
of	O
the	O
E	B-GENE
.	I-GENE
coli	I-GENE
DNA	I-GENE
polymerase	I-GENE
I	I-GENE
structure	O
.	O

Despite	O
the	O
favourable	O
natural	O
history	O
of	O
acute	O
BI	O
,	O
mild	O
,	O
moderate	O
,	O
and	O
severe	O
posttraumatic	O
changes	O
were	O
shown	O
to	O
appear	O
as	O
cicatricial	O
-	O
adhesive	O
and	O
atrophic	O
processes	O
,	O
intracerebral	O
cysts	O
,	O
porencephaly	O
,	O
which	O
result	O
in	O
posttraumatic	O
epilepsy	O
,	O
hydrocephalus	O
,	O
etc	O
.	O

Several	O
cytokines	O
exhibit	O
a	O
high	O
degree	O
of	O
temporal	O
regulation	O
as	O
well	O
as	O
somnogenic	O
potency	O
(	O
e	O
.	O
g	O
.	O
,	O
interleukin	B-GENE
-	I-GENE
1	I-GENE
[	O
IL	B-GENE
-	I-GENE
1	I-GENE
]	O
,	O
tumor	B-GENE
necrosis	I-GENE
factor	I-GENE
-	I-GENE
alpha	I-GENE
[	O
TNF	B-GENE
-	I-GENE
alpha	I-GENE
]	O
)	O
.	O

As	O
pH	O
and	O
Hb	B-GENE
can	O
also	O
affect	O
mixed	O
venous	O
CO2	O
content	O
,	O
the	O
effect	O
on	O
Q	O
was	O
also	O
assessed	O
.	O

No	O
difference	O
in	O
elastin	B-GENE
peptide	I-GENE
concentration	O
was	O
observed	O
between	O
emphysematous	O
patients	O
and	O
control	O
subjects	O
(	O
mean	O
+	O
/	O
-	O
SD	O
=	O
2	O
.	O
39	O
+	O
/	O
-	O
1	O
.	O
18	O
micrograms	O
/	O
ml	O
in	O
patients	O
versus	O
2	O
.	O
55	O
+	O
/	O
-	O
1	O
.	O
34	O
micrograms	O
/	O
ml	O
in	O
policemen	O
and	O
2	O
.	O
59	O
+	O
/	O
-	O
1	O
.	O
20	O
micrograms	O
/	O
ml	O
in	O
coal	O
miners	O
)	O
.	O

Identification	O
of	O
this	O
region	O
as	O
the	O
E	B-GENE
.	I-GENE
coli	I-GENE
tmk	I-GENE
gene	I-GENE
was	O
confirmed	O
by	O
functional	O
complementation	O
of	O
a	O
yeast	B-GENE
dTMP	I-GENE
kinase	I-GENE
temperature	O
-	O
sensitive	O
mutant	O
and	O
by	O
in	O
vitro	O
enzyme	O
assay	O
of	O
the	O
thymidylate	B-GENE
kinase	I-GENE
activity	O
in	O
cell	O
extracts	O
of	O
E	O
.	O
coli	O
by	O
use	O
of	O
tmk	B-GENE
-	O
overproducing	O
plasmids	O
.	O

The	O
structural	O
gene	O
for	O
copper	B-GENE
-	I-GENE
and	I-GENE
topa	I-GENE
quinone	I-GENE
-	I-GENE
containing	I-GENE
monoamine	I-GENE
oxidase	I-GENE
(	O
maoA	B-GENE
)	O
and	O
an	O
unknown	O
amine	B-GENE
oxidase	I-GENE
gene	I-GENE
have	O
been	O
located	O
at	O
30	O
.	O
9	O
min	O
on	O
the	O
Escherichia	O
coli	O
chromosome	O
.	O

This	O
interaction	O
is	O
mediated	O
by	O
the	O
SH2	B-GENE
domain	I-GENE
of	O
Crk	B-GENE
and	O
can	O
be	O
inhibited	O
with	O
a	O
phosphopeptide	O
containing	O
the	O
Crk	B-GENE
-	O
SH2	B-GENE
binding	O
motif	O
.	O

The	O
cDNA	O
corresponding	O
to	O
the	O
FPS1	B-GENE
gene	I-GENE
was	O
isolated	O
by	O
functional	O
complementation	O
of	O
a	O
mutant	O
yeast	O
strain	O
defective	O
in	O
FPS	B-GENE
activity	O
(	O
Delourme	O
,	O
D	O
.	O
,	O
Lacroute	O
,	O
F	O
.	O
,	O
and	O
Karst	O
,	O
F	O
.	O

The	O
isolated	O
plasmin	B-GENE
fragments	O
of	O
VEGF	B-GENE
were	O
compared	O
with	O
respect	O
to	O
heparin	O
binding	O
,	O
interaction	O
with	O
soluble	O
VEGF	B-GENE
receptors	I-GENE
,	O
and	O
ability	O
to	O
promote	O
endothelial	O
cell	O
mitogenesis	O
.	O

The	O
members	O
of	O
the	O
Myb	B-GENE
family	I-GENE
of	I-GENE
transcription	I-GENE
factors	I-GENE
are	O
defined	O
by	O
homology	O
in	O
the	O
DNA	O
-	O
binding	O
domain	O
;	O
all	O
bind	O
the	O
Myb	B-GENE
-	I-GENE
binding	I-GENE
site	I-GENE
(	O
MBS	B-GENE
)	O
sequence	O
(	O
YG	O
(	O
A	O
/	O
G	O
)	O
C	O
(	O
A	O
/	O
C	O
/	O
G	O
)	O
GTT	O
(	O
G	O
/	O
A	O
)	O
)	O
.	O

In	O
contrast	O
,	O
when	O
the	O
isoform	O
containing	O
the	O
C	O
epsilon4	O
domain	O
joined	O
directly	O
to	O
the	O
M2	O
exon	O
(	O
IgE	B-GENE
grande	I-GENE
)	O
is	O
expressed	O
in	O
the	O
J558L	O
cell	O
line	O
,	O
it	O
is	O
degraded	O
intracellularly	O
,	O
suggesting	O
a	O
cell	O
line	O
-	O
dependent	O
regulation	O
of	O
secretion	O
.	O

Human	B-GENE
cytomegalovirus	I-GENE
immediate	I-GENE
-	I-GENE
early	I-GENE
protein	I-GENE
IE2	I-GENE
tethers	O
a	O
transcriptional	O
repression	O
domain	O
to	O
p53	B-GENE
.	O

The	O
specificity	O
of	O
action	O
of	O
C	B-GENE
/	I-GENE
EBP	I-GENE
family	I-GENE
members	I-GENE
may	O
be	O
derived	O
from	O
the	O
characteristics	O
of	O
each	O
factor	O
,	O
including	O
the	O
expression	O
profiles	O
,	O
the	O
DNA	O
binding	O
affinities	O
,	O
the	O
cofactors	O
,	O
and	O
so	O
on	O
,	O
in	O
addition	O
to	O
the	O
DNA	O
binding	O
specificities	O
.	O

The	O
antibodies	O
inhibited	O
specifically	O
the	O
transcription	O
of	O
DNA	B-GENE
polymerase	I-GENE
alpha	I-GENE
promoter	O
in	O
vitro	O
.	O

Immunocytochemical	O
analysis	O
demonstrated	O
the	O
presence	O
of	O
DREF	B-GENE
polypeptide	I-GENE
in	O
nuclei	O
after	O
the	O
eighth	O
nuclear	O
division	O
cycle	O
,	O
suggesting	O
that	O
nuclear	O
accumulation	O
of	O
DREF	B-GENE
is	O
important	O
for	O
the	O
coordinate	O
zygotic	O
expression	O
of	O
DNA	O
replication	O
-	O
related	O
genes	O
carrying	O
DRE	O
sequences	O
.	O

A	O
DNA	O
fragment	O
carrying	O
1	O
,	O
100	O
nucleotides	O
derived	O
from	O
the	O
5	O
'	O
-	O
flanking	O
region	O
of	O
the	O
UGT1A1	B-GENE
gene	I-GENE
was	O
enough	O
for	O
MC	O
induction	O
.	O

This	O
result	O
supports	O
the	O
argument	O
that	O
the	O
beta	O
'	O
subunit	O
plays	O
an	O
essential	O
role	O
in	O
determining	O
the	O
progress	O
of	O
transcription	O
elongation	O
.	O

Two	O
XPG	B-GENE
regions	I-GENE
with	O
putative	O
NLS	O
[	O
amino	O
acid	O
(	O
AA	O
)	O
coordinates	O
:	O
NLS	O
-	O
B	O
(	O
AA	O
1057	O
-	O
1074	O
)	O
and	O
NLS	O
-	O
C	O
(	O
AA	O
1171	O
-	O
1185	O
)	O
]	O
were	O
each	O
shown	O
to	O
independently	O
localize	O
the	O
beta	B-GENE
-	I-GENE
gal	I-GENE
extensively	O
(	O
>	O
80	O
%	O
)	O
to	O
the	O
nucleus	O
of	O
HeLa	O
cells	O
.	O

The	O
lacS	B-GENE
gene	I-GENE
was	O
cloned	O
in	O
an	O
E	O
.	O
coli	O
-	O
Streptococcus	O
shuttle	O
vector	O
and	O
was	O
expressed	O
both	O
in	O
a	O
lacS	B-GENE
deletion	O
derivative	O
of	O
S	O
.	O
thermophilus	O
and	O
in	O
a	O
pNZ63	O
-	O
cured	O
strain	O
,	O
L	O
.	O
lactis	O
NZ6091	O
.	O

The	O
genome	O
of	O
all	O
retroviruses	O
consists	O
of	O
two	O
identical	O
RNAs	O
noncovalently	O
linked	O
near	O
their	O
5	O
'	O
end	O
.	O

The	O
extraction	O
recovery	O
of	O
Amphotericin	O
B	O
from	O
the	O
cerebrospinal	O
fluid	O
is	O
higher	O
than	O
90	O
%	O
over	O
the	O
entire	O
linear	O
range	O
.	O

HuEpo	B-GENE
-	I-GENE
R	I-GENE
Ab	I-GENE
inhibited	O
Epo	B-GENE
-	O
induced	O
parental	O
UT	O
-	O
7	O
cell	O
growth	O
,	O
but	O
not	O
that	O
of	O
cells	O
of	O
clone	O
12	O
,	O
suggesting	O
that	O
the	O
muEpo	B-GENE
-	I-GENE
R	I-GENE
is	O
able	O
to	O
induce	O
human	O
UT	O
-	O
7	O
cell	O
proliferation	O
.	O

The	O
frequency	O
of	O
integrations	O
that	O
led	O
to	O
transcription	O
of	O
the	O
lacZ	B-GENE
gene	I-GENE
was	O
estimated	O
to	O
be	O
0	O
.	O
5	O
%	O
of	O
all	O
integrations	O
,	O
of	O
which	O
14	O
%	O
were	O
downregulated	O
on	O
differentiation	O
of	O
32D	O
cells	O
towards	O
neutrophils	O
.	O

Interaction	O
of	O
the	O
Fur	B-GENE
repressor	I-GENE
with	O
a	O
150	O
-	O
bp	O
fragment	O
encompassing	O
the	O
pvdS	B-GENE
promoter	I-GENE
was	O
demonstrated	O
in	O
vivo	O
by	O
the	O
Fur	B-GENE
titration	O
assay	O
and	O
confirmed	O
in	O
vitro	O
by	O
gel	O
retardation	O
experiments	O
with	O
a	O
partially	O
purified	O
Fur	B-GENE
preparation	O
.	O

This	O
protein	O
encoded	O
by	O
this	O
cDNA	O
,	O
which	O
we	O
have	O
termed	O
p150TSP	B-GENE
(	O
for	O
TPR	O
-	O
containing	O
,	O
SH2	B-GENE
-	I-GENE
binding	I-GENE
phosphoprotein	I-GENE
)	O
,	O
is	O
located	O
predominantly	O
in	O
the	O
nucleus	O
and	O
is	O
highly	O
conserved	O
in	O
evolution	O
.	O

Both	O
mutant	O
receptors	O
were	O
expressed	O
on	O
the	O
cell	O
surface	O
and	O
bound	O
insulin	B-GENE
normally	O
,	O
but	O
showed	O
markedly	O
impaired	O
autophosphorylation	O
in	O
response	O
to	O
insulin	B-GENE
.	O

EMBO	O
J	O
.	O

Taken	O
together	O
,	O
our	O
results	O
indicate	O
that	O
thrombin	B-GENE
-	O
stimulated	O
vascular	O
smooth	O
muscle	O
proliferation	O
is	O
delayed	O
and	O
requires	O
the	O
de	O
novo	O
expression	O
of	O
one	O
or	O
more	O
autocrine	O
mitogens	O
.	O

Transcription	O
from	O
adenovirus	B-GENE
E2	I-GENE
-	I-GENE
early	I-GENE
promoter	I-GENE
is	O
controlled	O
by	O
a	O
unique	O
array	O
of	O
four	O
cis	O
-	O
acting	O
elements	O
which	O
include	O
an	O
atypical	O
TBP	B-GENE
site	I-GENE
,	O
two	O
E2F	B-GENE
sites	I-GENE
present	O
in	O
an	O
inverted	O
orientation	O
relative	O
to	O
each	O
other	O
,	O
and	O
an	O
ATF	B-GENE
site	I-GENE
.	O

Furthermore	O
,	O
we	O
showed	O
that	O
the	O
IL	B-GENE
-	I-GENE
6	I-GENE
/	O
interferon	B-GENE
gamma	I-GENE
(	O
IFN	B-GENE
gamma	I-GENE
)	O
response	O
element	O
in	O
the	O
IRF	B-GENE
-	I-GENE
1	I-GENE
promoter	I-GENE
(	O
IR	B-GENE
/	O
IRF	B-GENE
-	I-GENE
1	I-GENE
)	O
,	O
which	O
contains	O
a	O
Stat	B-GENE
-	I-GENE
binding	I-GENE
site	I-GENE
and	O
an	O
adjacent	O
CRE	O
-	O
like	O
site	O
,	O
also	O
makes	O
IL	B-GENE
-	I-GENE
6	I-GENE
-	O
induced	O
binding	O
complexes	O
similar	O
to	O
JRE	O
-	O
IL6	B-GENE
-	O
BCs	O
.	O

A	O
second	O
peptide	O
(	O
amino	O
acids	O
58	O
-	O
77	O
)	O
also	O
antagonized	O
p21	B-GENE
-	O
activity	O
,	O
but	O
this	O
peptide	O
did	O
not	O
affect	O
the	O
ability	O
of	O
p21	B-GENE
to	O
interact	O
with	O
cyclin	B-GENE
E	I-GENE
/	O
Cdk2	B-GENE
.	O

A	O
p21	B-GENE
peptide	I-GENE
spanning	O
amino	O
acids	O
139	O
-	O
164	O
was	O
found	O
to	O
bind	O
PCNA	B-GENE
in	O
a	O
filter	O
binding	O
assay	O
and	O
this	O
peptide	O
suppressed	O
recombinant	O
p21	B-GENE
-	O
PCNA	B-GENE
interaction	O
.	O

Results	O
were	O
supported	O
by	O
the	O
agar	O
diffusion	O
method	O
for	O
Y	O
.	O
enterocolitica	O
,	O
whereas	O
inhibition	O
activity	O
was	O
not	O
found	O
for	O
A	O
.	O
hydrophila	O
.	O

OND	O
8	O
mg	O
tid	O
days	O
2	O
-	O
3	O
,	O
and	O
8	O
mg	O
tid	O
prn	O
days	O
4	O
-	O
5	O
and	O
prednisolone	O
75	O
-	O
100	O
mg	O
qds	O
days	O
2	O
-	O
5	O
and	O
2	O
)	O
MCP	O
30	O
mg	O
/	O
metylprednisolone	O
80	O
mg	O
i	O
.	O
v	O
.	O
before	O
CT	O
and	O
MCP	O
20	O
mg	O
p	O
.	O
r	O
.	O
after	O
4	O
and	O
8	O
h	O
respectively	O
.	O

The	O
dynamic	O
properties	O
of	O
this	O
protein	O
fragment	O
were	O
measured	O
and	O
analyzed	O
using	O
both	O
isotropic	O
and	O
anisotropic	O
models	O
of	O
molecular	O
motion	O
.	O

Adduction	O
of	O
the	O
human	B-GENE
N	I-GENE
-	I-GENE
ras	I-GENE
codon	I-GENE
61	I-GENE
sequence	I-GENE
with	O
(	O
-	O
)	O
-	O
(	O
7S	O
,	O
8R	O
,	O
9R	O
,	O
10S	O
)	O
-	O
7	O
,	O
8	O
-	O
dihydroxy	O
-	O
9	O
,	O
10	O
-	O
epoxy	O
-	O
7	O
,	O
8	O
,	O
9	O
,	O
10	O
-	O
tetrahydrobenzo	O
[	O
a	O
]	O
pyrene	O
:	O
structural	O
refinement	O
of	O
the	O
intercalated	O
SRSR	O
(	O
61	O
,	O
2	O
)	O
(	O
-	O
)	O
-	O
(	O
7S	O
,	O
8R	O
,	O
9S	O
,	O
10R	O
)	O
-	O
N6	O
-	O
[	O
10	O
-	O
(	O
7	O
,	O
8	O
,	O
9	O
,	O
10	O
-	O
tetrahydrobenzo	O
[	O
a	O
]	O
pyrenyl	O
)	O
]	O
-	O
2	O
'	O
-	O
deoxyadenosyl	O
adduct	O
from	O
1H	O
NMR	O
.	O

This	O
fragment	O
can	O
bind	O
several	O
trans	O
-	O
acting	O
factors	O
in	O
vitro	O
,	O
including	O
GATA	B-GENE
-	I-GENE
1	I-GENE
and	O
members	O
of	O
the	O
Ets	B-GENE
family	I-GENE
.	O

These	O
different	O
observations	O
exclude	O
a	O
heterozygosity	O
of	O
the	O
A	O
-	O
-	O
>	O
G	O
mutation	O
at	O
codon	O
beta	O
77	O
,	O
as	O
well	O
as	O
a	O
deletion	O
comparable	O
to	O
that	O
of	O
Hbs	B-GENE
Lepore	I-GENE
or	I-GENE
Kenya	I-GENE
,	O
or	O
a	O
beta	B-GENE
-	I-GENE
globin	I-GENE
gene	I-GENE
duplication	O
,	O
and	O
point	O
to	O
a	O
nontraditional	O
inheritance	O
of	O
Hb	B-GENE
Costa	I-GENE
Rica	I-GENE
.	O

This	O
is	O
the	O
first	O
description	O
,	O
to	O
our	O
knowledge	O
,	O
of	O
regulatory	O
elements	O
that	O
control	O
expression	O
of	O
a	O
gene	O
encoding	O
a	O
B7	B-GENE
costimulatory	I-GENE
molecule	I-GENE
.	O

DNA	B-GENE
-	I-GENE
STAT	I-GENE
complexes	I-GENE
were	O
detected	O
in	O
all	O
Bcr	B-GENE
/	O
Abl	B-GENE
-	O
transformed	O
cell	O
lines	O
and	O
they	O
were	O
supershifted	O
by	O
antibodies	O
against	O
STAT1	B-GENE
and	O
STAT5	B-GENE
.	O

When	O
overexpressed	O
in	O
an	O
appropriate	O
cell	O
line	O
,	O
TAN	B-GENE
-	I-GENE
1C	I-GENE
prevented	O
kappa	B-GENE
B	I-GENE
-	O
dependent	O
transactivation	O
in	O
transient	O
reporter	O
gene	O
assays	O
in	O
a	O
fashion	O
similar	O
to	O
the	O
structurally	O
related	O
protein	O
,	O
Bcl	B-GENE
-	I-GENE
3	I-GENE
.	O

T	O
cell	O
leukemia	O
-	O
associated	O
human	O
Notch	B-GENE
/	O
translocation	O
-	O
associated	O
Notch	B-GENE
homologue	O
has	O
I	B-GENE
kappa	I-GENE
B	I-GENE
-	O
like	O
activity	O
and	O
physically	O
interacts	O
with	O
nuclear	B-GENE
factor	I-GENE
-	I-GENE
kappa	I-GENE
B	I-GENE
proteins	O
in	O
T	O
cells	O
.	O

Polyprotein	O
processing	O
in	O
Southampton	O
virus	O
:	O
identification	O
of	O
3C	B-GENE
-	I-GENE
like	I-GENE
protease	I-GENE
cleavage	O
sites	O
by	O
in	O
vitro	O
mutagenesis	O
.	O

The	O
humanized	B-GENE
LL2	I-GENE
(	O
hLL2	B-GENE
)	O
,	O
lacking	O
light	B-GENE
chain	I-GENE
variable	I-GENE
region	I-GENE
glycosylation	O
,	O
exhibited	O
immunoreactivities	O
that	O
were	O
comparable	O
to	O
that	O
of	O
chimeric	B-GENE
LL2	I-GENE
(	O
cLL2	B-GENE
)	O
,	O
which	O
was	O
shown	O
previously	O
to	O
have	O
antigen	O
-	O
binding	O
properties	O
similar	O
to	O
its	O
murine	O
counterpart	O
,	O
suggesting	O
that	O
the	O
VK	O
-	O
appended	O
oligosaccharides	O
found	O
in	O
mLL2	B-GENE
are	O
not	O
necessary	O
for	O
antigen	O
binding	O
.	O

An	O
apparent	O
N	O
-	O
terminal	O
transit	O
peptide	O
in	O
the	O
coding	O
region	O
and	O
a	O
3	O
'	O
poly	O
(	O
A	O
)	O
tail	O
exist	O
in	O
the	O
cDNA	O
clone	O
indicated	O
that	O
this	O
chloroplast	O
protein	O
as	O
nuclear	O
encoded	O
.	O

Thus	O
,	O
a	O
critical	O
question	O
is	O
how	O
HOX	B-GENE
proteins	I-GENE
select	O
the	O
correct	O
sets	O
of	O
target	O
genes	O
in	O
vivo	O
.	O

RAS2val19	B-GENE
,	O
a	O
dominant	O
activated	O
form	O
of	O
Saccharomyces	B-GENE
cerevisiae	I-GENE
Ras2	I-GENE
,	O
stimulates	O
both	O
filamentous	O
growth	O
and	O
expression	O
of	O
a	O
transcriptional	O
reporter	O
FG	B-GENE
(	O
TyA	B-GENE
)	O
:	O
:	O
lacZ	B-GENE
but	O
does	O
not	O
induce	O
the	O
mating	B-GENE
pathway	I-GENE
reporter	I-GENE
FUS1	I-GENE
:	O
:	O
lacZ	B-GENE
.	O

Moreover	O
,	O
the	O
Rho	B-GENE
family	I-GENE
protein	I-GENE
Cdc42	B-GENE
,	O
a	O
conserved	O
morphogenetic	B-GENE
G	I-GENE
protein	I-GENE
,	O
is	O
also	O
a	O
potent	O
regulator	O
of	O
filamentous	O
growth	O
and	O
FG	B-GENE
(	O
TyA	B-GENE
)	O
:	O
:	O
lacZ	B-GENE
expression	O
in	O
S	O
.	O
cerevisiae	O
.	O

Each	O
immunoprecipitate	O
contained	O
a	O
complex	O
of	O
N1	B-GENE
(	I-GENE
deltaEC	I-GENE
)	I-GENE
and	O
CBF1	B-GENE
.	O

This	O
region	O
includes	O
verA	B-GENE
,	O
a	O
structural	O
gene	O
previously	O
shown	O
to	O
be	O
required	O
for	O
ST	O
biosynthesis	O
,	O
and	O
24	O
additional	O
closely	O
spaced	O
transcripts	O
ranging	O
in	O
size	O
from	O
0	O
.	O
6	O
to	O
7	O
.	O
2	O
kb	O
that	O
are	O
coordinately	O
induced	O
only	O
under	O
ST	O
-	O
producing	O
conditions	O
.	O

Subcellular	O
localizations	O
of	O
the	O
wild	B-GENE
-	I-GENE
type	I-GENE
CBFbeta	I-GENE
and	O
the	O
CBFbeta	B-GENE
-	O
SMMHC	B-GENE
fusion	O
protein	O
were	O
determined	O
by	O
immunofluorescence	O
of	O
NIH	O
3T3	O
cells	O
that	O
overexpress	O
wild	O
-	O
type	O
or	O
fusion	O
protein	O
.	O

Menstrual	O
-	O
cycle	O
phase	O
did	O
not	O
significantly	O
affect	O
personality	O
variables	O
in	O
either	O
group	O
.	O

We	O
report	O
the	O
isolation	O
of	O
human	O
cDNAs	O
homologous	O
to	O
the	O
Drosophila	B-GENE
dishevelled	I-GENE
(	O
dsh	B-GENE
)	O
segment	O
-	O
polarity	O
gene	O
.	O

Ca2	O
+	O
decreased	O
Zn2	O
+	O
binding	O
in	O
S100	B-GENE
beta	I-GENE
but	O
it	O
did	O
not	O
influence	O
binding	O
to	O
MRP14	B-GENE
,	O
suggesting	O
that	O
the	O
Zn2	O
+	O
binding	O
site	O
was	O
distinct	O
from	O
and	O
independent	O
of	O
the	O
two	O
Ca2	O
+	O
binding	O
domains	O
.	O

Two	O
overlapping	O
clones	O
contained	O
the	O
complete	O
Adh	B-GENE
-	I-GENE
2	I-GENE
gene	I-GENE
composed	O
of	O
nine	O
exons	O
in	O
a	O
12	O
-	O
kb	O
region	O
,	O
with	O
the	O
placement	O
of	O
introns	O
matching	O
that	O
observed	O
in	O
other	O
mammalian	B-GENE
ADH	I-GENE
genes	I-GENE
.	O

Ligation	O
of	O
CD40	B-GENE
rescues	O
Ramos	O
-	O
Burkitt	O
lymphoma	O
B	O
cells	O
from	O
calcium	O
ionophore	O
-	O
and	O
antigen	O
receptor	O
-	O
triggered	O
apoptosis	O
by	O
inhibiting	O
activation	O
of	O
the	O
cysteine	B-GENE
protease	I-GENE
CPP32	B-GENE
/	O
Yama	B-GENE
and	O
cleavage	O
of	O
its	O
substrate	O
PARP	B-GENE
.	O

Large	B-GENE
T	I-GENE
antigen	I-GENE
was	O
coimmunoprecipitated	O
by	O
antibodies	O
to	O
epitope	O
-	O
tagged	O
TBP	B-GENE
,	O
endogenous	O
TBP	B-GENE
,	O
hTAF	B-GENE
(	I-GENE
II	I-GENE
)	I-GENE
100	I-GENE
,	O
hTAF	B-GENE
(	I-GENE
II	I-GENE
)	I-GENE
130	I-GENE
,	O
and	O
hTAF	B-GENE
(	I-GENE
II	I-GENE
)	I-GENE
250	I-GENE
,	O
under	O
conditions	O
where	O
holo	B-GENE
-	I-GENE
TFIID	I-GENE
would	O
be	O
precipitated	O
.	O

Northern	O
blot	O
hybridization	O
demonstrated	O
that	O
HEP	B-GENE
-	O
COP	B-GENE
was	O
expressed	O
in	O
a	O
wide	O
range	O
of	O
human	O
adult	O
and	O
fetal	O
tissues	O
.	O

A	O
direct	O
role	O
for	O
sterol	B-GENE
regulatory	I-GENE
element	I-GENE
binding	I-GENE
protein	I-GENE
in	O
activation	O
of	O
3	B-GENE
-	I-GENE
hydroxy	I-GENE
-	I-GENE
3	I-GENE
-	I-GENE
methylglutaryl	I-GENE
coenzyme	I-GENE
A	I-GENE
reductase	I-GENE
gene	I-GENE
.	O

E3	B-GENE
/	I-GENE
19K	I-GENE
resides	O
in	O
the	O
endoplasmic	O
reticulum	O
where	O
it	O
binds	O
to	O
MHC	B-GENE
class	I-GENE
I	I-GENE
molecules	I-GENE
,	O
thereby	O
preventing	O
their	O
transport	O
to	O
the	O
cell	O
surface	O
.	O

When	O
the	O
PHT	O
and	O
CSA	O
groups	O
were	O
compared	O
,	O
Hyp	O
levels	O
were	O
significantly	O
higher	O
in	O
the	O
PHT	O
-	O
GO	O
+	O
group	O
than	O
in	O
the	O
CSA	O
-	O
GO	O
+	O
group	O
.	O

Among	O
the	O
LE6	B-GENE
deletions	O
,	O
only	O
one	O
had	O
a	O
reduced	O
transformation	O
efficiency	O
,	O
while	O
seven	O
transformed	O
cells	O
at	O
least	O
as	O
efficiently	O
as	O
wild	B-GENE
-	I-GENE
type	I-GENE
LE6	I-GENE
.	O

ORF	B-GENE
E8	I-GENE
colinear	O
with	O
ORF	B-GENE
E6	I-GENE
,	O
which	O
could	O
generate	O
a	O
50	O
-	O
amino	O
-	O
acid	O
protein	O
with	O
a	O
hydrophobic	O
segment	O
,	O
did	O
not	O
transform	O
cells	O
when	O
cloned	O
into	O
the	O
pZipNeo	O
vector	O
.	O

Clb2	B-GENE
/	O
Cdc28	B-GENE
kinase	O
is	O
not	O
required	O
for	O
the	O
repression	O
of	O
MCB	B-GENE
-	I-GENE
binding	I-GENE
factor	I-GENE
transcriptional	O
activity	O
in	O
G2	O
and	O
M	O
phase	O
.	O

The	O
carboxy	O
terminus	O
of	O
Mbp1	B-GENE
is	O
sufficient	O
for	O
interaction	O
with	O
Swi6	B-GENE
,	O
and	O
the	O
carboxy	O
terminus	O
of	O
Swi6	B-GENE
is	O
required	O
for	O
interaction	O
with	O
Mbp1	B-GENE
.	O

Multiple	O
single	O
-	O
stranded	O
cis	O
elements	O
are	O
associated	O
with	O
activated	O
chromatin	O
of	O
the	O
human	B-GENE
c	I-GENE
-	I-GENE
myc	I-GENE
gene	I-GENE
in	O
vivo	O
.	O

A	O
new	O
UASH	O
consensus	O
sequence	O
derived	O
from	O
this	O
mutational	O
analysis	O
closely	O
matches	O
a	O
consensus	O
Abf1	B-GENE
binding	I-GENE
site	I-GENE
.	O

We	O
have	O
isolated	O
and	O
analyzed	O
human	B-GENE
CTCF	I-GENE
cDNA	I-GENE
clones	O
and	O
show	O
here	O
that	O
the	O
ubiquitously	O
expressed	O
11	B-GENE
-	I-GENE
zinc	I-GENE
-	I-GENE
finger	I-GENE
factor	I-GENE
CTCF	I-GENE
is	O
an	O
exceptionally	O
highly	O
conserved	O
protein	O
displaying	O
93	O
%	O
identity	O
between	O
avian	O
and	O
human	O
amino	O
acid	O
sequences	O
.	O

Mutational	O
analysis	O
of	O
the	O
P2	B-GENE
-	I-GENE
proximal	I-GENE
CTCF	I-GENE
binding	I-GENE
site	I-GENE
and	O
transient	O
-	O
cotransfection	O
experiments	O
demonstrate	O
that	O
CTCF	B-GENE
is	O
a	O
transcriptional	O
repressor	O
of	O
the	O
human	B-GENE
c	I-GENE
-	I-GENE
myc	I-GENE
gene	I-GENE
.	O

A	O
chromosome	B-GENE
transmission	I-GENE
fidelity	I-GENE
(	O
ctf	B-GENE
)	O
mutant	O
,	O
s138	O
,	O
of	O
Saccharomyces	O
cerevisiae	O
was	O
identified	O
by	O
its	O
centromere	O
(	O
CEN	O
)	O
transcriptional	O
readthrough	O
phenotype	O
,	O
suggesting	O
perturbed	O
kinetochore	O
integrity	O
in	O
vivo	O
.	O

The	O
growth	O
defect	O
of	O
a	O
reg1	B-GENE
reg2	B-GENE
double	I-GENE
mutant	I-GENE
is	O
alleviated	O
by	O
a	O
loss	O
-	O
of	O
-	O
function	O
mutation	O
in	O
the	O
SNF1	B-GENE
-	I-GENE
encoded	I-GENE
protein	I-GENE
kinase	I-GENE
.	O

Expression	O
of	O
the	O
phenylalanine	B-GENE
hydroxylase	I-GENE
gene	I-GENE
in	O
livers	O
and	O
kidneys	O
of	O
rodents	O
is	O
activated	O
at	O
birth	O
and	O
is	O
induced	O
by	O
glucocorticoids	O
and	O
cyclic	O
AMP	O
in	O
the	O
liver	O
.	O

We	O
report	O
here	O
the	O
identification	O
of	O
a	O
cDNA	O
that	O
encodes	O
a	O
new	O
member	O
of	O
the	O
GTPase	B-GENE
-	I-GENE
activating	I-GENE
protein	I-GENE
(	O
GAP	B-GENE
)	O
family	O
of	O
GTPase	B-GENE
regulators	O
.	O

In	O
this	O
study	O
,	O
we	O
further	O
investigated	O
the	O
regulation	O
of	O
the	O
synthesis	O
of	O
the	O
c	B-GENE
-	I-GENE
mos	I-GENE
oncogene	I-GENE
product	I-GENE
,	O
which	O
is	O
necessary	O
for	O
the	O
activation	O
of	O
Cdc2	B-GENE
.	O

The	O
heterogeneity	O
of	O
bovine	B-GENE
IgG2	I-GENE
-	I-GENE
-	I-GENE
VIII	I-GENE
.	O

The	O
ability	O
of	O
BCL	B-GENE
-	I-GENE
6	I-GENE
to	O
function	O
as	O
a	O
transcriptional	O
repressor	O
may	O
contribute	O
to	O
its	O
ability	O
to	O
transform	O
B	O
lymphocytes	O
in	O
diffuse	O
large	O
cell	O
lymphoma	O
.	O

Positioning	O
this	O
uORF	O
,	O
together	O
with	O
its	O
accompanying	O
Kozak	O
sequences	O
,	O
between	O
a	O
heterologous	O
promoter	O
from	O
SV40	O
and	O
a	O
CAT	B-GENE
reporter	I-GENE
gene	I-GENE
resulted	O
in	O
marked	O
inhibition	O
of	O
CAT	B-GENE
protein	I-GENE
production	O
without	O
a	O
decrease	O
in	O
CAT	B-GENE
mRNA	I-GENE
.	O

A	O
secondary	O
spread	O
of	O
an	O
imported	O
methicillin	O
-	O
resistant	O
Staphylococcus	O
aureus	O
strain	O
(	O
MRSA	O
)	O
to	O
two	O
other	O
patients	O
occurred	O
within	O
a	O
Danish	O
surgical	O
ward	O
in	O
spite	O
of	O
isolation	O
of	O
a	O
multitraumatized	O
index	O
-	O
patient	O
immediately	O
after	O
arrival	O
from	O
a	O
hospital	O
in	O
the	O
Mediterranean	O
area	O
.	O

Mesial	O
temporal	O
sclerosis	O
was	O
characterized	O
by	O
severe	O
neuronal	O
loss	O
accompanied	O
by	O
gliosis	O
occurring	O
in	O
the	O
CA1	O
/	O
prosubiculum	O
(	O
27	O
patients	O
,	O
100	O
%	O
)	O
,	O
focally	O
in	O
the	O
dentate	O
gyrus	O
(	O
12	O
patients	O
,	O
44	O
%	O
)	O
,	O
and	O
in	O
the	O
CA4	O
region	O
(	O
11	O
patients	O
,	O
41	O
%	O
)	O
.	O

Mesial	O
temporal	O
sclerosis	O
.	O

More	O
specific	O
adverse	O
events	O
,	O
also	O
frequently	O
considered	O
as	O
dose	O
-	O
limiting	O
toxicities	O
,	O
include	O
hypotension	O
with	O
IL	B-GENE
-	I-GENE
1	I-GENE
,	O
severe	O
headache	O
or	O
skin	O
rash	O
with	O
IL	B-GENE
-	I-GENE
3	I-GENE
,	O
and	O
nasal	O
congestion	O
and	O
gastroduodenal	O
lesions	O
with	O
IL	B-GENE
-	I-GENE
4	I-GENE
.	O

Therefore	O
,	O
magnetic	O
resonance	O
imaging	O
was	O
used	O
to	O
determine	O
liver	O
volume	O
in	O
pediatric	O
and	O
adolescent	O
patients	O
,	O
in	O
whom	O
systemic	O
clearance	O
of	O
three	O
model	O
substrates	O
[	O
lorazepam	O
(	O
0	O
.	O
03	O
mg	O
/	O
kg	O
)	O
,	O
antipyrine	O
(	O
10	O
mg	O
/	O
kg	O
)	O
,	O
and	O
indocyanine	O
green	O
(	O
ICG	O
;	O
0	O
.	O
5	O
mg	O
/	O
kg	O
)	O
]	O
was	O
also	O
determined	O
.	O

A	O
mutational	O
analysis	O
has	O
resolved	O
a	O
region	O
of	O
seven	O
amino	O
acids	O
(	O
amino	O
acids	O
26	O
-	O
32	O
)	O
in	O
the	O
N	O
-	O
terminus	O
of	O
Bob1	B-GENE
that	O
are	O
important	O
for	O
contacting	O
the	O
DNA	B-GENE
binding	I-GENE
POU	I-GENE
domain	I-GENE
of	O
Oct	B-GENE
-	I-GENE
1	I-GENE
or	O
Oct	B-GENE
-	I-GENE
2	I-GENE
.	O

155	O
aa	O
,	O
shares	O
78	O
%	O
identity	O
with	O
the	O
analogous	O
region	O
of	O
Xenopus	O
laevis	O
FGF3	B-GENE
and	O
72	O
%	O
identity	O
with	O
the	O
product	O
of	O
the	O
more	O
distantly	O
related	O
human	O
gene	O
.	O

The	O
transcription	O
start	O
point	O
of	O
the	O
proximal	O
promoter	O
aligns	O
to	O
that	O
of	O
mouse	O
promoter	O
P3	O
and	O
lies	O
within	O
a	O
conserved	O
region	O
of	O
sequence	O
.	O

A	O
novel	O
gene	O
designated	O
cmr	B-GENE
,	O
which	O
mapped	O
to	O
18	O
.	O
8	O
min	O
of	O
the	O
Escherichia	O
coli	O
K	O
-	O
12	O
genome	O
,	O
was	O
shown	O
to	O
mediate	O
resistance	O
to	O
chloramphenicol	O
when	O
it	O
was	O
expressed	O
from	O
a	O
multicopy	O
vector	O
.	O

In	O
addition	O
,	O
5	O
'	O
deletions	O
removing	O
all	O
but	O
34	O
bp	O
upstream	O
of	O
the	O
transcription	O
start	O
point	O
retained	O
greater	O
than	O
90	O
%	O
promoter	O
activity	O
,	O
suggesting	O
that	O
the	O
-	O
35	O
hexamer	O
was	O
not	O
essential	O
for	O
promoter	O
activity	O
.	O

The	O
DNA	O
sequence	O
immediately	O
upstream	O
from	O
the	O
-	O
10	O
hexamer	O
contained	O
the	O
TGn	O
motif	O
described	O
as	O
an	O
extended	O
-	O
10	O
region	O
in	O
prokaryotic	O
promoters	O
.	O

An	O
apparent	O
ufo	B-GENE
mRNA	I-GENE
overexpression	O
was	O
not	O
found	O
in	O
any	O
of	O
the	O
positive	O
leukemia	O
cell	O
lines	O
,	O
but	O
was	O
identified	O
in	O
the	O
drug	O
-	O
resistant	O
subclones	O
of	O
the	O
cervix	O
carcinoma	O
cell	O
line	O
HeLa	O
.	O

We	O
conclude	O
from	O
these	O
studies	O
that	O
CKII	B-GENE
may	O
act	O
as	O
a	O
positive	O
regulator	O
of	O
myogenesis	O
by	O
preventing	O
E	B-GENE
protein	I-GENE
homodimers	I-GENE
from	O
binding	O
to	O
muscle	O
gene	O
regulatory	O
elements	O
.	O

The	O
role	O
of	O
negative	O
regulators	O
such	O
as	O
NCE3	B-GENE
,	O
as	O
well	O
as	O
the	O
previously	O
described	O
SIN5	B-GENE
gene	I-GENE
,	O
in	O
determining	O
the	O
promoter	O
specificity	O
of	O
homologous	O
activators	O
is	O
discussed	O
.	O

Transcriptional	O
regulators	O
utilizing	O
the	O
POU	B-GENE
domain	I-GENE
DNA	I-GENE
-	I-GENE
binding	I-GENE
motif	I-GENE
have	O
been	O
shown	O
to	O
form	O
multi	O
-	O
protein	O
complexes	O
dependent	O
on	O
the	O
POU	B-GENE
domain	I-GENE
itself	O
and	O
its	O
flexible	O
recognition	O
of	O
various	O
octamer	O
sequence	O
elements	O
.	O

We	O
found	O
strand	O
selective	O
repair	O
in	O
DNA	O
fragments	O
within	O
two	O
active	O
genes	O
,	O
DHFR	B-GENE
and	O
an	O
unknown	O
gene	O
adjacent	O
to	O
DHFR	B-GENE
.	O

MATERIALS	O
AND	O
METHODS	O
:	O
Coronal	O
3D	O
GRE	O
imaging	O
was	O
used	O
to	O
study	O
the	O
volar	O
,	O
middle	O
,	O
and	O
dorsal	O
portions	O
of	O
the	O
SLL	O
in	O
14	O
patients	O
with	O
an	O
arthroscopically	O
normal	O
SLL	O
and	O
in	O
five	O
cadaveric	O
wrists	O
that	O
had	O
a	O
normal	O
SLL	O
proved	O
with	O
dissection	O
.	O

In	O
an	O
effort	O
to	O
contribute	O
to	O
the	O
transcript	O
map	O
of	O
human	O
chromosome	O
21	O
and	O
the	O
understanding	O
of	O
the	O
pathophysiology	O
of	O
trisomy	O
21	O
,	O
we	O
have	O
used	O
exon	O
trapping	O
to	O
identify	O
fragments	O
of	O
chromosome	O
21	O
genes	O
.	O

Reproducing	O
populations	O
of	O
this	O
aphid	O
were	O
first	O
detected	O
in	O
Puerto	O
Rico	O
in	O
April	O
1992	O
.	O

The	O
model	O
captures	O
the	O
essence	O
of	O
predator	O
-	O
prey	O
dynamics	O
to	O
provide	O
reasonable	O
predictions	O
of	O
population	O
patterns	O
.	O

At	O
cuticular	O
positions	O
exhibiting	O
the	O
Brd	B-GENE
bristle	I-GENE
loss	I-GENE
phenotype	I-GENE
,	O
we	O
have	O
found	O
that	O
the	O
progeny	O
of	O
the	O
multiplied	O
SOPs	O
develop	O
aberrantly	O
,	O
in	O
that	O
neurons	O
and	O
thecogen	O
(	O
sheath	O
)	O
cells	O
appear	O
but	O
not	O
trichogen	O
(	O
shaft	O
)	O
and	O
tormogen	O
(	O
socket	O
)	O
cells	O
.	O

Transcriptional	O
blockade	O
was	O
reversed	O
by	O
co	O
-	O
transfections	O
of	O
a	O
wild	B-GENE
-	I-GENE
type	I-GENE
SRF	I-GENE
expression	O
vector	O
,	O
but	O
was	O
not	O
rescued	O
by	O
the	O
expression	O
of	O
other	O
myogenic	O
factors	O
,	O
such	O
as	O
MyoD	B-GENE
and	O
Mef	B-GENE
-	I-GENE
2C	I-GENE
.	O

The	O
mMIWC1	B-GENE
promoter	I-GENE
was	O
identified	O
and	O
contained	O
TATA	O
,	O
CAAT	O
,	O
GATA	O
,	O
and	O
AP	B-GENE
-	I-GENE
2	I-GENE
elements	I-GENE
;	O
primer	O
extension	O
revealed	O
mMIWC	B-GENE
transcription	O
initiation	O
at	O
621	O
bp	O
upstream	O
from	O
the	O
mMIWC1	B-GENE
translational	O
initiation	O
site	O
.	O

Human	B-GENE
MN	I-GENE
/	I-GENE
CA9	I-GENE
gene	I-GENE
,	O
a	O
novel	O
member	O
of	O
the	O
carbonic	B-GENE
anhydrase	I-GENE
family	I-GENE
:	O
structure	O
and	O
exon	O
to	O
protein	O
domain	O
relationships	O
.	O

The	O
exon	O
-	O
intron	O
distribution	O
of	O
Cdebp	B-GENE
appears	O
strikingly	O
similar	O
to	O
that	O
of	O
the	O
App	B-GENE
gene	I-GENE
in	O
the	O
regions	O
encoding	O
the	O
conserved	O
domains	O
,	O
with	O
a	O
divergent	O
structure	O
in	O
the	O
other	O
parts	O
.	O

DNA	O
sequence	O
analysis	O
reveals	O
that	O
the	O
gene	O
encodes	O
a	O
protein	O
highly	O
homologous	O
to	O
rat	B-GENE
CRP1	I-GENE
.	O

The	O
gene	O
was	O
expressed	O
as	O
an	O
approximately	O
1	O
.	O
5	O
-	O
kb	O
mRNA	O
in	O
most	O
nonlymphoid	O
human	O
cells	O
/	O
tissues	O
including	O
prostate	O
,	O
lung	O
,	O
liver	O
,	O
and	O
colon	O
.	O

Both	O
of	O
these	O
domains	O
have	O
striking	O
sequence	O
homology	O
with	O
human	O
SIM	B-GENE
and	O
Drosophila	O
SIM	B-GENE
proteins	O
.	O

We	O
have	O
obtained	O
the	O
human	B-GENE
EP4	I-GENE
receptor	I-GENE
gene	I-GENE
sequence	I-GENE
and	O
determined	O
its	O
structure	O
relative	O
to	O
EP4R	B-GENE
cDNA	I-GENE
synthesized	O
from	O
peripheral	O
blood	O
lymphocytes	O
.	O

Some	O
users	O
will	O
willingly	O
comply	O
with	O
management	O
measures	O
,	O
other	O
users	O
will	O
comply	O
in	O
response	O
to	O
education	O
,	O
but	O
there	O
will	O
be	O
another	O
group	O
who	O
will	O
only	O
respond	O
to	O
enforcement	O
activities	O
.	O

Three	O
separate	O
activation	O
subdomains	O
,	O
and	O
one	O
negative	O
-	O
acting	O
region	O
,	O
which	O
function	O
in	O
yeast	O
were	O
located	O
in	O
the	O
carboxyl	O
-	O
terminal	O
region	O
of	O
NIT4	B-GENE
.	O

The	O
front	O
(	O
F	O
)	O
interaction	O
occurs	O
ahead	O
of	O
the	O
growing	O
end	O
of	O
RNA	O
.	O

Collectively	O
,	O
these	O
data	O
indicate	O
that	O
HIP	B-GENE
is	O
a	O
membrane	O
-	O
associated	O
HP	B-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
expressed	O
on	O
the	O
surface	O
of	O
normal	O
human	O
uterine	O
epithelia	O
and	O
uterine	O
epithelial	O
cell	O
lines	O
.	O

The	O
corresponding	O
gene	O
was	O
identified	O
in	O
the	O
GenBankTM	O
data	O
base	O
by	O
sequence	O
alignment	O
and	O
termed	O
RPS30A	B-GENE
.	O

The	O
location	O
of	O
multiple	O
GRK2	B-GENE
and	O
GRK5	B-GENE
phosphoacceptor	I-GENE
sites	I-GENE
at	O
the	O
extreme	O
carboxyl	O
terminus	O
of	O
the	O
beta2AR	B-GENE
is	O
highly	O
reminiscent	O
of	O
GRK1	B-GENE
-	O
mediated	O
phosphorylation	O
of	O
rhodopsin	B-GENE
.	O

This	O
regulation	O
could	O
not	O
be	O
appreciably	O
modified	O
by	O
enhanced	O
expression	O
of	O
STAT	B-GENE
proteins	I-GENE
.	O

Receptors	O
for	O
interleukin	B-GENE
(	I-GENE
IL	I-GENE
)	I-GENE
-	I-GENE
10	I-GENE
and	O
IL	B-GENE
-	I-GENE
6	I-GENE
-	I-GENE
type	I-GENE
cytokines	I-GENE
use	O
similar	O
signaling	O
mechanisms	O
for	O
inducing	O
transcription	O
through	O
IL	B-GENE
-	I-GENE
6	I-GENE
response	O
elements	O
.	O

Specifically	O
,	O
the	O
deduced	O
FR	B-GENE
-	I-GENE
19	I-GENE
amino	I-GENE
acid	I-GENE
sequence	I-GENE
has	O
approximately89	O
,	O
77	O
,	O
and	O
68	O
%	O
overall	O
identity	O
to	O
chicken	B-GENE
TEF	I-GENE
-	I-GENE
1A	I-GENE
,	O
mouse	B-GENE
TEF	I-GENE
-	I-GENE
1	I-GENE
,	O
and	O
mouse	B-GENE
embryonic	I-GENE
TEA	I-GENE
domain	I-GENE
-	I-GENE
containing	I-GENE
factor	I-GENE
,	O
respectively	O
.	O

The	O
receptor	B-GENE
for	I-GENE
hyaluronan	I-GENE
mediated	I-GENE
motility	I-GENE
(	B-GENE
RHAMM	I-GENE
)	I-GENE
gene	I-GENE
expression	O
is	O
markedly	O
elevated	O
in	O
fibrosarcomas	O
exposed	O
to	O
transforming	B-GENE
growth	I-GENE
factor	I-GENE
-	I-GENE
beta1	I-GENE
(	O
TGF	B-GENE
-	I-GENE
beta1	I-GENE
)	O
.	O

Oncogenic	B-GENE
Raf	I-GENE
-	I-GENE
1	I-GENE
activates	O
p70	B-GENE
S6	I-GENE
kinase	I-GENE
via	O
a	O
mitogen	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
kinase	I-GENE
-	O
independent	O
pathway	O
.	O

Hydropathy	O
analysis	O
of	O
KCC1	B-GENE
indicates	O
structural	O
homology	O
to	O
NKCC	B-GENE
,	O
including	O
12	O
transmembrane	O
domains	O
,	O
a	O
large	O
extracellular	O
loop	O
with	O
potential	O
N	O
-	O
linked	O
glycosylation	O
sites	O
,	O
and	O
cytoplasmic	O
N	O
-	O
and	O
C	O
-	O
terminal	O
regions	O
.	O

This	O
protein	O
with	O
a	O
hydrophobic	O
amino	O
terminus	O
appears	O
to	O
be	O
a	O
secreted	O
protein	O
.	O

Notably	O
,	O
SRF	B-GENE
has	O
been	O
found	O
to	O
be	O
a	O
key	O
regulator	O
of	O
members	O
of	O
a	O
class	O
of	O
cellular	O
response	O
genes	O
termed	O
immediate	B-GENE
-	I-GENE
early	I-GENE
genes	I-GENE
(	O
IEGs	B-GENE
)	O
,	O
many	O
of	O
which	O
are	O
believed	O
to	O
be	O
involved	O
in	O
regulating	O
cell	O
growth	O
and	O
differentiation	O
.	O

The	O
final	O
sigma54	B-GENE
-	I-GENE
dependent	I-GENE
DmpR	I-GENE
activator	I-GENE
regulates	O
transcription	O
of	O
the	O
dmp	B-GENE
operon	I-GENE
that	O
encodes	O
the	O
enzymes	O
for	O
catabolism	O
of	O
(	O
methyl	O
)	O
phenols	O
.	O

In	O
this	O
study	O
,	O
we	O
have	O
cloned	O
the	O
human	B-GENE
DSG3	I-GENE
gene	I-GENE
and	O
examined	O
the	O
transcriptional	O
regulation	O
of	O
its	O
expression	O
.	O

Clinical	O
evaluation	O
of	O
the	O
Allergan	O
Humphrey	O
500	O
autorefractor	O
and	O
the	O
Nidek	O
AR	O
-	O
1000	O
autorefractor	O
.	O

None	O
of	O
the	O
five	O
proprotein	O
processing	O
proteases	O
tested	O
were	O
capable	O
of	O
cleaving	O
human	B-GENE
pro	I-GENE
-	I-GENE
LPH	I-GENE
,	O
strongly	O
suggesting	O
that	O
they	O
are	O
not	O
involved	O
in	O
the	O
maturation	O
of	O
this	O
enzyme	O
.	O

These	O
changes	O
may	O
be	O
the	O
result	O
of	O
,	O
on	O
the	O
one	O
hand	O
,	O
an	O
increased	O
sensitivity	O
of	O
the	O
neuromuscular	O
transmission	O
and	O
/	O
or	O
decreased	O
muscle	O
contractility	O
and	O
,	O
on	O
the	O
other	O
hand	O
,	O
the	O
result	O
of	O
a	O
reduced	O
plasma	O
clearance	O
during	O
hypothermia	O
.	O

By	O
using	O
interleukin	B-GENE
-	I-GENE
3	I-GENE
-	O
dependent	O
cells	O
that	O
ectopically	O
express	O
the	O
three	O
ErbB	B-GENE
proteins	I-GENE
or	O
their	O
combinations	O
,	O
we	O
found	O
that	O
ErbB	B-GENE
-	I-GENE
3	I-GENE
is	O
devoid	O
of	O
any	O
biological	O
activity	O
but	O
both	O
ErbB	B-GENE
-	I-GENE
1	I-GENE
and	O
ErbB	B-GENE
-	I-GENE
2	I-GENE
can	O
reconstitute	O
its	O
extremely	O
potent	O
mitogenic	O
activity	O
.	O

ZIOS	O
was	O
significantly	O
more	O
sensitive	O
than	O
all	O
subsequent	O
methods	O
,	O
and	O
Ptc	O
,	O
O2	O
was	O
significantly	O
more	O
sensitive	O
than	O
FEV1	O
.	O

These	O
findings	O
suggest	O
that	O
direct	O
cDNA	O
mapping	O
using	O
fluorescence	O
in	O
situ	O
hybridization	O
provides	O
an	O
accurate	O
and	O
rapid	O
approach	O
to	O
the	O
definition	O
of	O
a	O
transcribed	O
map	O
of	O
the	O
human	O
genome	O
.	O

YAC	O
and	O
cosmid	O
contigs	O
spanning	O
the	O
Batten	B-GENE
disease	I-GENE
(	O
CLN3	B-GENE
)	O
region	O
at	O
16p12	O
.	O
1	O
-	O
p11	O
.	O
2	O
.	O

Isolation	O
of	O
a	O
near	O
full	O
-	O
length	O
cDNA	O
from	O
a	O
human	O
fetal	O
brain	O
cDNA	O
library	O
revealed	O
a	O
protein	B-GENE
serine	I-GENE
-	I-GENE
threonine	I-GENE
phosphatase	I-GENE
with	O
a	O
tetratricopeptide	O
motif	O
,	O
almost	O
identical	O
to	O
human	B-GENE
PPP5C	I-GENE
(	O
PP5	B-GENE
)	O
and	O
highly	O
homologous	O
to	O
rat	B-GENE
PPT	I-GENE
.	O

Ly	B-GENE
-	I-GENE
49	I-GENE
is	O
a	O
family	B-GENE
type	I-GENE
II	I-GENE
transmembrane	I-GENE
proteins	I-GENE
encoded	O
by	O
a	O
gene	O
cluster	O
on	O
murine	O
chromosome	O
6	O
.	O

The	O
Dox	B-GENE
-	I-GENE
A2	I-GENE
ORF	I-GENE
driven	O
by	O
the	O
TDH3	B-GENE
promoter	I-GENE
complemented	O
the	O
phenotype	O
of	O
a	O
strain	O
deleted	O
for	O
sun2	B-GENE
.	O

The	O
introduction	O
of	O
hARF4	B-GENE
to	O
the	O
cells	O
maintained	O
the	O
balance	O
between	O
cytosolic	O
and	O
membrane	O
-	O
associated	O
Sec7p	B-GENE
pools	O
.	O

Vacuolar	O
membrane	O
vesicles	O
from	O
hum1	B-GENE
mutants	I-GENE
lack	O
all	O
Ca2	O
+	O
/	O
H	O
+	O
antiport	O
activity	O
,	O
demonstrating	O
that	O
Hum1p	B-GENE
catalyzes	O
the	O
exchange	O
of	O
Ca2	O
+	O
for	O
H	O
+	O
across	O
the	O
yeast	O
vacuolar	O
membrane	O
.	O

Detailed	O
mutagenesis	O
of	O
the	O
element	O
'	O
s	O
rare	O
-	O
codon	O
/	O
AU	O
-	O
rich	O
sequence	O
boundary	O
revealed	O
that	O
the	O
destabilizing	O
activity	O
of	O
the	O
MATalpha1	B-GENE
IE	I-GENE
is	O
observed	O
when	O
the	O
terminal	O
codon	O
of	O
the	O
element	O
'	O
s	O
rare	O
-	O
codon	O
interval	O
is	O
translated	O
.	O

FTF	B-GENE
is	O
also	O
abundantly	O
expressed	O
in	O
the	O
pancreas	O
and	O
may	O
exert	O
differentiation	O
functions	O
in	O
endodermal	O
sublineages	O
,	O
similar	O
to	O
SF	B-GENE
-	I-GENE
1	I-GENE
in	O
steroidogenic	O
tissues	O
.	O

The	O
incidence	O
of	O
cardiac	O
death	O
(	O
one	O
per	O
group	O
)	O
,	O
Q	O
wave	O
MI	O
(	O
propofol	O
,	O
n	O
=	O
7	O
;	O
midazolam	O
,	O
n	O
=	O
3	O
;	O
P	O
=	O
0	O
.	O
27	O
)	O
,	O
or	O
non	O
Q	O
wave	O
MI	O
(	O
propofol	O
,	O
n	O
=	O
16	O
;	O
midazolam	O
,	O
n	O
=	O
18	O
;	O
P	O
=	O
0	O
.	O
81	O
)	O
did	O
not	O
differ	O
between	O
treatment	O
groups	O
.	O

Cluster	O
formation	O
of	O
E	B-GENE
-	I-GENE
cadherin	I-GENE
on	O
the	O
cell	O
surface	O
is	O
believed	O
to	O
be	O
of	O
major	O
importance	O
for	O
cell	O
-	O
cell	O
adhesion	O
.	O

DNA	B-GENE
polymerase	I-GENE
E	I-GENE
,	O
DNA	B-GENE
ligase	I-GENE
III	I-GENE
and	O
a	O
DNA	O
structure	O
-	O
specific	O
endonuclease	O
co	O
-	O
purify	O
with	O
the	O
five	O
polypeptide	O
complex	O
.	O

By	O
using	O
reporter	O
gene	O
constructs	O
,	O
it	O
is	O
shown	O
that	O
upstream	O
sequences	O
of	O
the	O
P1	O
promoter	O
contain	O
several	O
regions	O
that	O
modulate	O
the	O
expression	O
either	O
positively	O
or	O
negatively	O
.	O

The	O
factor	O
structure	O
of	O
"	O
schizotypal	O
'	O
traits	O
:	O
a	O
large	O
replication	O
study	O
.	O

Interestingly	O
,	O
however	O
,	O
it	O
is	O
homologous	O
to	O
several	O
expressed	O
sequence	O
tags	O
(	O
EST	O
)	O
of	O
unknown	O
function	O
from	O
Caenorhabditis	O
elegans	O
,	O
Oryza	O
sativa	O
and	O
Homo	O
sapiens	O
.	O

RESULTS	O
:	O
The	O
bilinear	O
model	O
provided	O
a	O
significantly	O
better	O
fit	O
to	O
the	O
acuity	O
outcome	O
data	O
.	O

Outcome	O
of	O
severe	O
congenital	O
hypothyroidism	O
.	O

Nonreturn	O
rates	O
can	O
be	O
used	O
to	O
derive	O
more	O
elementary	O
biological	O
measures	O
for	O
reproductive	O
efficiency	O
,	O
such	O
as	O
conception	O
rate	O
and	O
calving	O
rate	O
,	O
which	O
separately	O
might	O
be	O
more	O
reliable	O
than	O
nonreturn	O
rate	O
itself	O
to	O
evaluate	O
the	O
fertility	O
of	O
a	O
bull	O
or	O
the	O
performance	O
of	O
an	O
AI	O
technician	O
.	O

However	O
,	O
if	O
EMPD	O
involves	O
the	O
glans	O
penis	O
or	O
perianal	O
area	O
,	O
a	O
search	O
for	O
internal	O
malignancy	O
is	O
still	O
warranted	O
.	O

The	O
mean	O
values	O
of	O
protease	O
activity	O
were	O
significantly	O
higher	O
in	O
the	O
test	O
groups	O
than	O
in	O
the	O
control	O
group	O
at	O
baseline	O
.	O

Each	O
half	O
molecule	O
contains	O
four	O
disulfide	O
linkages	O
and	O
four	O
cis	O
peptides	O
.	O

Only	O
fully	O
processed	O
Pra	B-GENE
(	O
N0	O
and	O
Nb	O
)	O
and	O
ICP35	B-GENE
(	O
ICP35	B-GENE
e	I-GENE
,	I-GENE
f	I-GENE
)	O
are	O
present	O
in	O
B	O
capsids	O
,	O
which	O
are	O
believed	O
to	O
be	O
precursors	O
of	O
mature	O
virions	O
.	O

However	O
,	O
one	O
3	O
'	O
splice	O
site	O
,	O
located	O
at	O
nucleotide	O
(	O
nt	O
)	O
3225	O
,	O
is	O
used	O
for	O
the	O
processing	O
of	O
most	O
BPV	O
-	O
1	O
pre	O
-	O
mRNAs	O
in	O
BPV	O
-	O
1	O
-	O
transformed	O
C127	O
cells	O
and	O
at	O
early	O
to	O
intermediate	O
times	O
in	O
productively	O
infected	O
warts	O
.	O

Here	O
,	O
the	O
cloning	O
and	O
characterization	O
of	O
S	B-GENE
-	I-GENE
RNase	I-GENE
genes	I-GENE
from	O
two	O
species	O
of	O
Rosaceae	O
,	O
apple	O
(	O
Malus	O
x	O
domestica	O
)	O
and	O
Japanese	O
pear	O
(	O
Pyrus	O
serotina	O
)	O
is	O
described	O
and	O
these	O
sequences	O
are	O
compared	O
with	O
those	O
of	O
other	O
T2	B-GENE
-	I-GENE
type	I-GENE
RNases	I-GENE
.	O

A	O
phylogenetic	O
tree	O
of	O
members	O
of	O
the	O
T2	B-GENE
/	I-GENE
S	I-GENE
-	I-GENE
RNase	I-GENE
superfamily	I-GENE
in	O
plants	O
was	O
obtained	O
.	O

In	O
a	O
Hoosier	O
Oncology	O
Group	O
randomized	O
study	O
involving	O
extensive	O
-	O
disease	O
SCLC	O
patients	O
,	O
VIP	O
was	O
superior	O
to	O
etoposide	O
/	O
cisplatin	O
with	O
regard	O
to	O
median	O
time	O
to	O
progression	O
(	O
6	O
.	O
6	O
v	O
5	O
.	O
8	O
months	O
)	O
,	O
median	O
survival	O
times	O
(	O
9	O
.	O
1	O
v	O
7	O
.	O
3	O
months	O
)	O
,	O
and	O
2	O
-	O
and	O
3	O
-	O
year	O
survival	O
rates	O
(	O
13	O
%	O
v	O
5	O
%	O
and	O
5	O
%	O
v	O
0	O
%	O
,	O
respectively	O
)	O
.	O

It	O
was	O
shown	O
that	O
administration	O
of	O
immunomodulator	O
neurotropin	B-GENE
(	O
NSP	B-GENE
)	O
results	O
in	O
more	O
steady	O
consolidation	O
and	O
retention	O
of	O
feeding	O
and	O
avoidance	O
behavior	O
,	O
and	O
some	O
neurophysiological	O
mechanisms	O
of	O
that	O
phenomena	O
were	O
revealed	O
.	O

Sestamibi	O
scintigraphy	O
,	O
performed	O
in	O
70	O
patients	O
,	O
was	O
less	O
sensitive	O
than	O
ultrasonography	O
(	O
80	O
%	O
)	O
.	O

Atopic	O
allergy	O
and	O
other	O
hypersensitivities	O
.	O

After	O
6	O
h	O
of	O
reperfusion	O
,	O
PO2	O
/	O
FlO2	O
ratio	O
was	O
significantly	O
better	O
after	O
Combined	O
Therapy	O
(	O
372	O
+	O
/	O
-	O
52	O
mm	O
Hg	O
)	O
than	O
in	O
the	O
Recipient	O
Instilled	O
(	O
117	O
+	O
/	O
-	O
47	O
mm	O
Hg	O
)	O
and	O
Control	O
groups	O
(	O
87	O
+	O
/	O
-	O
26	O
mm	O
Hg	O
)	O
,	O
with	O
intermediate	O
values	O
in	O
Donor	O
Aerosol	O
dogs	O
(	O
232	O
+	O
/	O
-	O
64	O
mm	O
Hg	O
)	O
.	O

The	O
euglobulin	B-GENE
clot	O
lysis	O
time	O
was	O
slightly	O
longer	O
in	O
the	O
smokers	O
than	O
in	O
the	O
non	O
-	O
smokers	O
in	O
all	O
three	O
experimental	O
situations	O
,	O
but	O
the	O
differences	O
were	O
not	O
significant	O
.	O

HS	O
inducibility	O
required	O
the	O
HSE	O
which	O
was	O
bound	O
by	O
HS	B-GENE
transcription	I-GENE
factor	I-GENE
-	I-GENE
1	I-GENE
(	O
HSF	B-GENE
-	I-GENE
1	I-GENE
)	O
present	O
in	O
extracts	O
prepared	O
from	O
cells	O
exposed	O
to	O
HS	O
.	O

Although	O
the	O
DSK2	B-GENE
-	I-GENE
1	I-GENE
mutation	I-GENE
alters	O
a	O
conserved	O
residue	O
in	O
the	O
Dsk2p	B-GENE
ubiquitin	B-GENE
-	I-GENE
like	I-GENE
domain	I-GENE
,	O
we	O
detect	O
no	O
differences	O
in	O
Dsk2p	B-GENE
or	O
Cdc31p	B-GENE
stability	O
.	O

Consistent	O
with	O
this	O
interpretation	O
,	O
recombinant	B-GENE
CREB	I-GENE
and	O
activating	B-GENE
transcription	I-GENE
factor	I-GENE
proteins	I-GENE
bound	O
the	O
junB	B-GENE
CRE	O
-	O
like	O
site	O
,	O
but	O
did	O
not	O
interact	O
with	O
a	O
mutant	O
CRE	O
-	O
like	O
site	O
.	O

Collectively	O
,	O
these	O
results	O
suggest	O
that	O
components	O
of	O
the	O
protein	B-GENE
kinase	I-GENE
A	I-GENE
signaling	O
pathway	O
are	O
recruited	O
by	O
mIg	B-GENE
to	O
induce	O
junB	B-GENE
transcription	O
.	O

Immunofluorescence	O
microscopy	O
revealed	O
extensive	O
deposition	O
of	O
such	O
extracellular	O
matrices	O
as	O
type	B-GENE
IV	I-GENE
collagen	I-GENE
and	O
laminin	B-GENE
in	O
the	O
vascular	O
wall	O
.	O

OBJECTIVE	O
:	O
To	O
compare	O
pregnancy	O
complications	O
in	O
women	O
having	O
genetic	O
amniocentesis	O
at	O
11	O
-	O
14	O
weeks	O
versus	O
those	O
undergoing	O
amniocentesis	O
at	O
16	O
-	O
19	O
weeks	O
'	O
gestation	O
.	O

Three	O
ORFs	O
(	O
9765orfR002	O
,	O
9765orfR011	O
and	O
9765orfR013	O
)	O
were	O
found	O
to	O
be	O
homologous	O
with	O
Schizosaccharomyces	O
pombe	O
polyadenylate	B-GENE
binding	I-GENE
protein	I-GENE
,	O
Escherichia	O
coli	O
hypothetical	O
38	O
.	O
1	O
-	O
kDa	O
protein	O
in	O
the	O
BCR	B-GENE
5	O
'	O
region	O
,	O
and	O
transcription	O
regulatory	O
protein	O
Swi3	B-GENE
,	O
respectively	O
.	O

Two	O
new	O
flavone	O
glucosides	O
,	O
nevadensin	O
5	O
-	O
O	O
-	O
beta	O
-	O
D	O
-	O
glucoside	O
and	O
nevadensin	O
5	O
-	O
O	O
-	O
beta	O
-	O
D	O
-	O
glucosyl	O
(	O
1	O
-	O
-	O
>	O
6	O
)	O
beta	O
-	O
D	O
-	O
glucoside	O
,	O
have	O
been	O
isolated	O
from	O
the	O
aerial	O
parts	O
of	O
Lysionotus	O
pauciflorus	O
.	O

Recently	O
,	O
our	O
laboratory	O
developed	O
a	O
screen	O
that	O
identified	O
five	O
multicopy	O
suppressors	O
that	O
can	O
rescue	O
lethal	O
strains	O
of	O
clathrin	B-GENE
heavy	O
chain	O
-	O
deficient	O
yeast	O
(	O
Chc	B-GENE
-	O
scd1	B-GENE
-	I-GENE
i	I-GENE
)	O
to	O
viability	O
.	O

Reproductive	O
period	O
affects	O
water	O
intake	O
in	O
heat	O
-	O
stressed	O
dehydrated	O
goats	O
.	O

The	O
logistic	O
regression	O
analysis	O
of	O
the	O
manual	O
method	O
(	O
percentage	O
normal	O
morphology	O
)	O
and	O
IVOS	O
indicated	O
that	O
both	O
were	O
predictors	O
of	O
fertilization	O
.	O

METHODS	O
:	O
Rats	O
received	O
continuous	O
intragastric	O
infusion	O
of	O
elemental	O
diet	O
or	O
with	O
supplementation	O
of	O
oatbase	O
,	O
Lactobacillus	O
reuteri	O
R2LC	O
,	O
and	O
Lactobacillus	O
plantarum	O
DSM	O
9843	O
,	O
with	O
and	O
without	O
fermentation	O
,	O
from	O
the	O
beginning	O
of	O
the	O
study	O
.	O

However	O
,	O
D8	B-GENE
binding	O
was	O
observed	O
by	O
nuclease	O
protection	O
with	O
lactotroph	B-GENE
-	I-GENE
as	I-GENE
well	I-GENE
as	I-GENE
somatotroph	I-GENE
-	I-GENE
like	I-GENE
cell	I-GENE
nuclear	I-GENE
protein	I-GENE
.	O

The	O
ability	O
of	O
A20	B-GENE
to	O
block	O
NF	B-GENE
-	I-GENE
kappaB	I-GENE
activation	O
was	O
mapped	O
to	O
its	O
C	O
-	O
terminal	O
zinc	O
finger	O
domain	O
.	O

By	O
using	O
a	O
DNA	O
sequence	O
selected	O
for	O
its	O
ability	O
to	O
bind	O
recombinant	B-GENE
BCL	I-GENE
-	I-GENE
6	I-GENE
in	O
vitro	O
,	O
we	O
show	O
here	O
that	O
BCL	B-GENE
-	I-GENE
6	I-GENE
is	O
present	O
in	O
DNA	O
-	O
binding	O
complexes	O
in	O
nuclear	O
extracts	O
from	O
various	O
B	O
-	O
cell	O
lines	O
.	O

The	O
predictive	O
value	O
of	O
a	O
positive	O
flag	O
was	O
77	O
.	O
7	O
%	O
.	O

Because	O
chromosome	O
X	O
is	O
frequently	O
involved	O
in	O
structural	O
alterations	O
in	O
neoplastic	O
Syrian	O
hamster	O
cells	O
transformed	O
by	O
chemical	O
carcinogens	O
and	O
oncogenic	O
viruses	O
,	O
the	O
localization	O
of	O
the	O
cph	B-GENE
locus	I-GENE
on	O
this	O
chromosome	O
supports	O
the	O
notion	O
that	O
the	O
cph	B-GENE
oncogene	I-GENE
plays	O
a	O
role	O
in	O
the	O
malignant	O
conversion	O
of	O
chemically	O
transformed	O
hamster	O
fibroblasts	O
.	O

Gap1	B-GENE
(	I-GENE
IP4BP	I-GENE
)	I-GENE
,	O
one	O
of	O
a	O
member	O
of	O
Ras	B-GENE
GTPase	I-GENE
-	I-GENE
activating	I-GENE
proteins	I-GENE
,	O
has	O
been	O
identified	O
as	O
a	O
specific	O
inositol	B-GENE
1	I-GENE
,	I-GENE
3	I-GENE
,	I-GENE
4	I-GENE
,	I-GENE
5	I-GENE
-	I-GENE
tetrakisphosphate	I-GENE
(	I-GENE
IP4	I-GENE
)	I-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
(	O
Cullen	O
,	O
P	O
.	O

We	O
previously	O
described	O
the	O
purification	O
of	O
an	O
83	B-GENE
-	I-GENE
kDa	I-GENE
phosphatidic	I-GENE
acid	I-GENE
phosphatase	I-GENE
(	O
PAP	B-GENE
)	O
from	O
the	O
porcine	O
thymus	O
membranes	O
(	O
Kanoh	O
,	O
H	O
.	O
,	O
Imai	O
,	O
S	O
.	O
-	O
i	O
.	O
,	O
Yamada	O
,	O
K	O
.	O
and	O
Sakane	O
,	O
F	O
.	O
(	O
1992	O
)	O
J	O
.	O

A	O
cDNA	O
encoding	O
the	O
amino	O
-	O
terminal	O
17	O
%	O
of	O
apoB	B-GENE
(	O
apoB17	B-GENE
)	O
was	O
fused	O
to	O
a	O
cDNA	O
coding	O
for	O
the	O
last	O
37	O
amino	O
acids	O
of	O
decay	B-GENE
-	I-GENE
accelerating	I-GENE
factor	I-GENE
(	O
DAF	B-GENE
)	O
,	O
which	O
contains	O
the	O
signal	O
for	O
glycosylphosphatidylinositol	O
anchor	O
attachment	O
.	O

Next	O
,	O
we	O
stably	O
overexpressed	O
wild	B-GENE
-	I-GENE
type	I-GENE
Shc	I-GENE
or	O
Y317F	B-GENE
mutant	I-GENE
Shc	I-GENE
into	O
HIRc	O
cells	O
.	O

The	O
small	B-GENE
GTPase	I-GENE
Rho	B-GENE
is	O
implicated	O
in	O
physiological	O
functions	O
associated	O
with	O
actin	B-GENE
-	O
myosin	B-GENE
filaments	O
such	O
as	O
cytokinesis	O
,	O
cell	O
motility	O
,	O
and	O
smooth	O
muscle	O
contraction	O
.	O

Conversely	O
,	O
activation	O
of	O
this	O
signaling	O
pathway	O
by	O
expression	O
of	O
a	O
constitutively	O
active	O
MKK1	B-GENE
mutant	I-GENE
dramatically	O
increased	O
cyclin	B-GENE
D1	I-GENE
promoter	O
activity	O
and	O
cyclin	B-GENE
D1	I-GENE
protein	I-GENE
expression	O
,	O
in	O
a	O
growth	O
factor	O
-	O
independent	O
manner	O
.	O

Furthermore	O
,	O
upstream	O
insertion	O
of	O
the	O
GSTP1	B-GENE
silencer	I-GENE
element	I-GENE
failed	O
to	O
inhibit	O
activity	O
of	O
a	O
heterologous	O
promoter	O
in	O
MCF7	O
cells	O
.	O

In	O
order	O
to	O
delineate	O
structural	O
motifs	O
regulating	O
substrate	O
affinity	O
and	O
recognition	O
for	O
the	O
human	B-GENE
dopamine	I-GENE
transporter	I-GENE
(	O
DAT	B-GENE
)	O
,	O
we	O
assessed	O
[	O
3H	O
]	O
dopamine	O
uptake	O
kinetics	O
and	O
[	O
3H	O
]	O
CFT	O
binding	O
characteristics	O
of	O
COS	O
-	O
7	O
cells	O
transiently	O
expressing	O
mutant	B-GENE
DATs	I-GENE
in	O
which	O
the	O
COOH	O
terminus	O
was	O
truncated	O
or	O
substituted	O
.	O

An	O
expression	O
library	O
was	O
constructed	O
by	O
inserting	O
5	O
'	O
portion	O
-	O
enriched	O
cDNAs	O
from	O
phytohemagglutinin	B-GENE
-	O
stimulated	O
peripheral	O
blood	O
mononuclear	O
cells	O
into	O
upstream	O
of	O
signal	B-GENE
sequence	I-GENE
-	I-GENE
deleted	I-GENE
CD4	I-GENE
cDNA	I-GENE
in	O
an	O
Epstein	O
-	O
Barr	O
virus	O
shuttle	O
vector	O
.	O

Radiolabeled	O
recombinant	B-GENE
TARC	I-GENE
specifically	O
bound	O
to	O
T	O
cell	O
lines	O
and	O
peripheral	O
T	O
cells	O
but	O
not	O
to	O
monocytes	O
or	O
granulocytes	O
.	O

Therefore	O
,	O
we	O
have	O
identified	O
a	O
cis	O
-	O
acting	O
element	O
,	O
the	O
E1	O
E	O
-	O
box	O
,	O
located	O
in	O
the	O
GAP	B-GENE
-	I-GENE
43	I-GENE
promoter	O
region	O
that	O
modulates	O
either	O
positively	O
or	O
negatively	O
the	O
expression	O
of	O
the	O
GAP	B-GENE
-	I-GENE
43	I-GENE
gene	I-GENE
depending	O
on	O
which	O
E	B-GENE
-	I-GENE
box	I-GENE
-	I-GENE
binding	I-GENE
proteins	I-GENE
occupy	O
this	O
site	O
.	O

Collectively	O
,	O
our	O
findings	O
demonstrate	O
that	O
SF	B-GENE
-	I-GENE
1	I-GENE
plays	O
a	O
key	O
role	O
in	O
controlling	O
the	O
basal	O
and	O
cAMP	O
-	O
stimulated	O
expression	O
of	O
the	O
StAR	B-GENE
gene	I-GENE
.	O

Using	O
one	O
of	O
the	O
six	O
fragments	O
(	O
CPK3	B-GENE
-	I-GENE
8	I-GENE
)	O
,	O
we	O
isolated	O
a	O
2022	B-GENE
bp	I-GENE
cDNA	I-GENE
(	I-GENE
VrCDPK	I-GENE
-	I-GENE
1	I-GENE
)	I-GENE
from	O
a	O
Vigna	O
radiata	O
lambda	O
gt11	O
library	O
.	O

However	O
,	O
in	O
TF	O
-	O
1	O
cells	O
grown	O
on	O
GM	B-GENE
-	I-GENE
CSF	I-GENE
before	O
starvation	O
,	O
CREB	B-GENE
phosphorylation	O
was	O
observed	O
10	O
minutes	O
after	O
PIXY321	B-GENE
stimulation	O
.	O

Workplace	O
violence	O
-	O
-	O
nurses	O
at	O
risk	O
.	O

RESULTS	O
:	O
The	O
LV	O
maximum	O
brightness	O
and	O
area	O
under	O
the	O
curve	O
showed	O
significant	O
negative	O
correlations	O
(	O
p	O
=	O
<	O
0	O
.	O
004	O
)	O
with	O
the	O
FIO2	O
,	O
while	O
the	O
minimum	O
brightness	O
showed	O
a	O
significant	O
positive	O
correlation	O
(	O
p	O
=	O
<	O
0	O
.	O
002	O
)	O
.	O

The	O
results	O
also	O
imply	O
that	O
the	O
absence	O
of	O
perforin	B-GENE
expression	O
in	O
non	O
-	O
cytotoxic	O
cells	O
may	O
be	O
due	O
to	O
the	O
suppression	O
of	O
the	O
induction	O
of	O
the	O
killer	O
-	O
cell	O
-	O
specific	O
trans	O
-	O
acting	O
factor	O
NF	B-GENE
-	I-GENE
P2	I-GENE
.	O

We	O
identify	O
considerable	O
spatio	O
-	O
temporal	O
similarities	O
between	O
reported	O
expression	O
patterns	O
of	O
Ypr10	B-GENE
genes	I-GENE
and	O
ribonuclease	O
genes	O
,	O
which	O
,	O
together	O
with	O
the	O
significant	O
sequence	O
similarity	O
to	O
the	O
ginseng	B-GENE
ribonuclease	I-GENE
,	O
support	O
the	O
hypothesis	O
of	O
a	O
ribonuclease	O
function	O
for	O
PR	B-GENE
-	I-GENE
10	I-GENE
proteins	I-GENE
and	O
allow	O
the	O
prediction	O
of	O
possible	O
biological	O
roles	O
.	O

The	O
expression	O
of	O
ERV3	B-GENE
env	I-GENE
mRNA	I-GENE
was	O
found	O
to	O
be	O
differentiation	O
-	O
associated	O
,	O
with	O
high	O
expression	O
detected	O
in	O
the	O
late	O
stages	O
of	O
monocytic	O
development	O
.	O

Initial	O
estimates	O
indicate	O
that	O
27	O
,	O
193	O
people	O
are	O
either	O
in	O
receipt	O
of	O
or	O
in	O
need	O
of	O
mental	O
handicap	O
services	O
.	O

It	O
is	O
exclusively	O
observed	O
in	O
smooth	O
muscle	O
cells	O
by	O
Northern	O
blotting	O
and	O
immunohistochemical	O
analysis	O
and	O
therefore	O
designated	O
"	B-GENE
smoothelin	I-GENE
.	I-GENE
"	I-GENE
A	O
human	O
smooth	O
muscle	O
cDNA	O
library	O
was	O
screened	O
with	O
the	O
monoclonal	B-GENE
antibody	I-GENE
R4A	I-GENE
,	O
and	O
a	O
full	O
-	O
size	O
cDNA	O
of	O
the	O
protein	O
was	O
selected	O
.	O

Concurrent	O
with	O
ligand	O
-	O
dependent	O
uptake	O
,	O
we	O
now	O
show	O
that	O
the	O
receptor	O
undergoes	O
ligand	O
-	O
induced	O
ubiquitination	O
,	O
suggesting	O
that	O
receptor	O
ubiquitination	O
may	O
function	O
in	O
the	O
ligand	O
-	O
dependent	O
endocytosis	O
of	O
the	O
a	B-GENE
-	I-GENE
factor	I-GENE
receptor	I-GENE
as	O
well	O
as	O
in	O
its	O
constitutive	O
endocytosis	O
.	O

Epstein	B-GENE
-	I-GENE
Barr	I-GENE
virus	I-GENE
nuclear	I-GENE
protein	I-GENE
2	I-GENE
(	O
EBNA2	B-GENE
)	O
binds	O
to	O
a	O
component	O
of	O
the	O
human	O
SNF	B-GENE
-	O
SWI	B-GENE
complex	O
,	O
hSNF5	B-GENE
/	O
Ini1	B-GENE
.	O

Our	O
studies	O
also	O
excluded	O
the	O
possibility	O
that	O
the	O
phosphorylation	O
of	O
Ser	O
-	O
2	O
,	O
Ser	O
-	O
123	O
,	O
or	O
Ser	O
-	O
210	O
,	O
had	O
roles	O
in	O
the	O
trans	O
-	O
suppression	O
activity	O
of	O
the	O
large	B-GENE
HDAg	I-GENE
,	O
in	O
the	O
assembly	O
of	O
empty	O
virus	B-GENE
-	I-GENE
like	I-GENE
HDAg	I-GENE
particle	I-GENE
,	O
and	O
in	O
the	O
nuclear	O
transport	O
of	O
HDAgs	B-GENE
.	O

Homologous	O
recombination	O
between	O
the	O
Autographa	O
californica	O
nuclear	O
polyhedrosis	O
virus	O
(	O
AcNPV	O
)	O
genome	O
and	O
a	O
0	O
.	O
6	O
-	O
kbp	O
-	O
long	O
DNA	O
fragment	O
derived	O
from	O
the	O
putative	O
DNA	B-GENE
helicase	I-GENE
gene	I-GENE
of	I-GENE
Bombyx	I-GENE
mori	I-GENE
nuclear	I-GENE
polyhedrosis	I-GENE
virus	I-GENE
generates	O
eh2	O
-	O
AcNPV	O
,	O
an	O
expanded	O
-	O
host	O
-	O
range	O
AcNPV	O
mutant	O
(	O
S	O
.	O

The	O
data	O
further	O
indicate	O
that	O
the	O
IL	B-GENE
-	I-GENE
7R	I-GENE
alpha	I-GENE
chains	I-GENE
are	O
directly	O
involved	O
in	O
the	O
activation	O
of	O
JAKs	B-GENE
and	O
STATs	B-GENE
and	O
have	O
a	O
major	O
role	O
in	O
proliferative	O
signaling	O
in	O
precursor	O
B	O
cells	O
.	O

Furthermore	O
,	O
the	O
potency	O
of	O
Dacarbacine	O
in	O
the	O
treatment	O
of	O
carcinoid	O
tumors	O
seems	O
to	O
be	O
underestimated	O
up	O
to	O
now	O
.	O

5	O
)	O
We	O
'	O
ve	O
noticed	O
that	O
the	O
mean	O
value	O
of	O
the	O
cost	O
for	O
episode	O
of	O
pnx	O
s	O
.	O
in	O
class	O
A	O
was	O
more	O
than	O
15	O
%	O
compared	O
to	O
class	O
B	O
and	O
the	O
cost	O
for	O
patient	O
in	O
class	O
A	O
was	O
nearly	O
double	O
than	O
in	O
class	O
B	O
.	O

Cbl	B-GENE
constitutively	O
interacts	O
with	O
the	O
SH3	B-GENE
domains	I-GENE
of	O
Grb2	B-GENE
,	O
with	O
a	O
preference	O
for	O
the	O
amino	O
-	O
terminal	O
domain	O
,	O
and	O
is	O
in	O
this	O
way	O
recruited	O
to	O
Shc	B-GENE
upon	O
BCR	B-GENE
stimulation	O
.	O

Activation	O
mediated	O
by	O
Cat8p	B-GENE
was	O
no	O
longer	O
detectable	O
in	O
a	O
cat1	B-GENE
mutant	I-GENE
.	O

Treatment	O
is	O
instituted	O
with	O
prednisone	O
and	O
cyclophosphamide	O
.	O

Laboratory	O
evaluation	O
was	O
normal	O
,	O
and	O
neuroimaging	O
failed	O
to	O
confirm	O
obstruction	O
of	O
venous	O
or	O
lymphatic	O
drainage	O
.	O

Microcomputer	O
management	O
of	O
chronic	O
hepatitis	O
B	O
virus	O
asymptomatic	O
patients	O

While	O
fusion	O
to	O
the	O
N	O
-	O
terminus	O
required	O
a	O
linker	O
to	O
become	O
surface	O
accessible	O
,	O
both	O
fusion	O
to	O
the	O
N	O
-	O
terminus	O
and	O
to	O
the	O
C	O
-	O
terminus	O
was	O
compatible	O
with	O
particle	O
assembly	O
and	O
preserved	O
the	O
native	O
antigenicity	O
and	O
immunogenicity	O
of	O
HBcAg	B-GENE
.	O

The	O
standard	O
dosage	O
of	O
anti	B-GENE
-	I-GENE
D	I-GENE
currently	O
given	O
at	O
all	O
gestational	O
ages	O
is	O
1	O
ampoule	O
containing	O
125	O
micrograms	O
of	O
anti	B-GENE
-	I-GENE
D	I-GENE
.	O

We	O
report	O
here	O
the	O
molecular	O
cloning	O
of	O
a	O
putative	O
adhesive	O
molecule	O
from	O
P	O
.	O
falciparum	O
that	O
shares	O
both	O
sequence	O
and	O
structural	O
similarities	O
with	O
a	O
sporozoite	O
surface	O
molecule	O
from	O
Plasmodium	O
termed	O
the	O
thrombospondin	B-GENE
-	I-GENE
related	I-GENE
anonymous	I-GENE
protein	I-GENE
(	O
TRAP	B-GENE
)	O
and	O
,	O
to	O
a	O
lesser	O
extent	O
,	O
with	O
the	O
circumsporozoite	B-GENE
(	I-GENE
CS	I-GENE
)	I-GENE
protein	I-GENE
.	O

There	O
are	O
no	O
introns	O
within	O
the	O
gene	O
,	O
which	O
contains	O
a	O
9360	O
-	O
bp	O
open	O
reading	O
frame	O
and	O
encodes	O
a	O
377	O
-	O
kDa	O
protein	O
.	O

METHODS	O
:	O
DSF	O
was	O
instilled	O
in	O
one	O
eye	O
chosen	O
at	O
random	O
and	O
CF	O
in	O
the	O
fellow	O
eye	O
of	O
13	O
normal	O
subjects	O
and	O
in	O
13	O
patients	O
with	O
KCS	O
.	O

CONCLUSION	O
:	O
The	O
results	O
demonstrate	O
that	O
at	O
the	O
site	O
of	O
lumbar	O
disc	O
herniation	O
,	O
inflammatory	O
cytokines	O
such	O
as	O
interleukin	B-GENE
-	I-GENE
1	I-GENE
alpha	I-GENE
are	O
produced	O
,	O
which	O
increases	O
prostaglandin	O
E2	O
production	O
.	O

The	O
predominant	O
sensitizing	O
allergens	O
in	O
Swedish	O
asthmatic	O
children	O
are	O
furred	O
pet	O
animals	O
.	O

Our	O
results	O
demonstrate	O
that	O
distinct	O
cytoplasmic	O
domains	O
of	O
these	O
cytokine	O
receptors	O
elicit	O
convergent	O
signaling	O
pathways	O
and	O
provide	O
evidence	O
that	O
beta	B-GENE
c	I-GENE
and	O
IL	B-GENE
-	I-GENE
2R	I-GENE
beta	I-GENE
function	O
as	O
a	O
complete	O
signal	O
transducer	O
.	O

In	O
addition	O
,	O
they	O
display	O
common	O
features	O
that	O
make	O
them	O
strikingly	O
related	O
to	O
snoRNA	B-GENE
U14	I-GENE
.	O

U24	B-GENE
has	O
two	O
separate	O
12	O
nt	O
long	O
complementarities	O
to	O
a	O
highly	O
conserved	O
tract	O
of	O
28S	B-GENE
rRNA	I-GENE
.	O

This	O
complex	O
interacts	O
at	O
the	O
GTPase	B-GENE
domain	I-GENE
in	O
the	O
large	O
subunit	O
rRNA	O
,	O
overlapping	O
the	O
binding	O
site	O
of	O
the	O
protein	B-GENE
L11	I-GENE
-	I-GENE
like	I-GENE
eukaryotic	I-GENE
counterpart	I-GENE
(	O
Saccharomyces	B-GENE
cerevisiae	I-GENE
protein	I-GENE
L15	I-GENE
and	O
mammalian	B-GENE
protein	I-GENE
L12	I-GENE
)	O
.	O

Chromatin	O
repression	O
of	O
these	O
replacement	O
genes	O
would	O
be	O
avoided	O
,	O
consistent	O
with	O
the	O
high	O
,	O
constitutive	O
expression	O
of	O
replacement	O
H3	B-GENE
histone	I-GENE
genes	I-GENE
in	O
plants	O
.	O

This	O
transition	O
is	O
regulated	O
positively	O
by	O
G1	B-GENE
-	I-GENE
specific	I-GENE
cyclin	I-GENE
-	I-GENE
dependent	I-GENE
kinases	I-GENE
(	O
cdks	B-GENE
)	O
and	O
negatively	O
by	O
the	O
product	O
of	O
the	O
retinoblastoma	B-GENE
tumour	I-GENE
suppressor	I-GENE
gene	I-GENE
,	O
pRb	B-GENE
.	O

To	O
derive	O
quantitative	O
concentration	O
changes	O
from	O
measurements	O
of	O
light	O
attenuation	O
,	O
the	O
optical	O
path	O
length	O
must	O
be	O
known	O
.	O

STUDY	O
DESIGN	O
.	O

Following	O
the	O
injection	O
of	O
PGF2	O
alpha	O
,	O
heifers	O
were	O
observed	O
visually	O
for	O
signs	O
of	O
estrus	O
at	O
0730	O
and	O
1630	O
(	O
45	O
min	O
each	O
)	O
.	O

Differential	O
activation	O
of	O
the	O
extracellular	B-GENE
signal	I-GENE
-	I-GENE
regulated	I-GENE
kinase	I-GENE
,	O
Jun	B-GENE
kinase	I-GENE
and	O
Janus	B-GENE
kinase	I-GENE
-	O
Stat	B-GENE
pathways	O
by	O
oncostatin	B-GENE
M	I-GENE
and	O
basic	B-GENE
fibroblast	I-GENE
growth	I-GENE
factor	I-GENE
in	O
AIDS	O
-	O
derived	O
Kaposi	O
'	O
s	O
sarcoma	O
cells	O
.	O

There	O
is	O
general	O
agreement	O
that	O
the	O
hepatitis	O
C	O
virus	O
is	O
efficiently	O
transmitted	O
parenterally	O
,	O
while	O
data	O
on	O
viral	O
transmission	O
from	O
mothers	O
to	O
babies	O
or	O
by	O
sexual	O
or	O
non	O
-	O
sexual	O
household	O
contact	O
are	O
conflicting	O
.	O

Ten	O
weeks	O
after	O
reconstruction	O
,	O
the	O
regenerating	O
nerves	O
already	O
resembled	O
normal	O
nerves	O
.	O

The	O
distribution	O
and	O
organization	O
of	O
projections	O
from	O
the	O
spinal	O
cervical	O
enlargement	O
to	O
subnucleus	O
reticularis	O
dorsalis	O
(	O
SRD	O
)	O
and	O
the	O
neighbouring	O
Cuneate	O
nucleus	O
(	O
Cu	O
)	O
area	O
was	O
studied	O
in	O
the	O
rat	O
by	O
using	O
microinjections	O
of	O
Phaseolus	B-GENE
vulgaris	I-GENE
leucoagglutinin	I-GENE
(	O
PHA	B-GENE
-	I-GENE
L	I-GENE
)	O
into	O
different	O
laminae	O
around	O
the	O
C7	O
level	O
.	O

The	O
levels	O
of	O
fibrinogen	B-GENE
as	O
well	O
as	O
antithrombin	B-GENE
III	I-GENE
(	O
ATIII	B-GENE
)	O
and	O
heparin	B-GENE
cofactor	I-GENE
II	I-GENE
(	O
HCII	B-GENE
)	O
activities	O
were	O
steadily	O
increased	O
in	O
loop	O
-	O
bearing	O
animals	O
.	O

Amplification	O
and	O
overexpression	O
of	O
the	O
c	B-GENE
-	I-GENE
erbB	I-GENE
-	I-GENE
2	I-GENE
gene	I-GENE
in	O
21MT	O
-	O
2	O
and	O
21MT	O
-	O
1	O
human	O
breast	O
carcinoma	O
cells	O
results	O
in	O
progressively	O
elevated	O
levels	O
of	O
constitutively	O
tyrosine	B-GENE
-	I-GENE
phosphorylated	I-GENE
p185erbB	I-GENE
-	I-GENE
2	I-GENE
and	O
is	O
associated	O
with	O
progressive	O
insulin	B-GENE
-	I-GENE
like	I-GENE
growth	I-GENE
factor	I-GENE
(	O
IGF	B-GENE
)	O
and	O
combined	O
IGF	B-GENE
/	O
epidermal	B-GENE
growth	I-GENE
factor	I-GENE
(	O
EGF	B-GENE
)	O
independence	O
in	O
culture	O
.	O

Facioscapulohumeral	O
muscular	O
dystrophy	O
(	O
FSHD	O
)	O
is	O
an	O
autosomal	O
dominant	O
,	O
neuromuscular	O
disorder	O
characterized	O
by	O
progressive	O
weakness	O
of	O
muscles	O
in	O
the	O
face	O
,	O
shoulder	O
and	O
upper	O
arm	O
.	O

The	O
mature	O
chromosome	O
4	O
FRG1	B-GENE
transcript	I-GENE
is	O
1042	O
bp	O
in	O
length	O
and	O
contains	O
nine	O
exons	O
which	O
encode	O
a	O
putative	O
protein	O
of	O
258	O
amino	O
acid	O
residues	O
.	O

Patients	O
who	O
have	O
undergone	O
thyroidectomy	O
for	O
thyroid	O
carcinoma	O
are	O
frequently	O
subjected	O
to	O
periods	O
of	O
induced	O
severe	O
hypothyroidism	O
in	O
preparation	O
for	O
131I	O
whole	O
body	O
scanning	O
and	O
measurement	O
of	O
serum	O
TG	B-GENE
.	O

Full	O
thyroid	O
function	O
testing	O
was	O
performed	O
on	O
600	O
randomly	O
selected	O
samples	O
with	O
normal	O
TSH	B-GENE
values	O
and	O
also	O
on	O
subjects	O
with	O
abnormal	O
TSH	B-GENE
levels	O
.	O

In	O
a	O
third	O
experiment	O
,	O
crossover	O
AM	O
between	O
dissimilar	O
textures	O
was	O
investigated	O
,	O
and	O
it	O
was	O
found	O
that	O
the	O
more	O
salient	O
textures	O
carried	O
the	O
AM	O
.	O

The	O
relative	O
tumor	O
FDG	O
-	O
uptake	O
(	O
Q	O
-	O
MRGlu	O
)	O
(	O
tumor	O
/	O
contralateral	O
cortex	O
)	O
of	O
all	O
meningiomas	O
was	O
calculated	O
with	O
0	O
.	O
73	O
+	O
/	O
-	O
0	O
.	O
37	O
(	O
0	O
.	O
24	O
-	O
1	O
.	O
79	O
)	O
.	O

Zatebradine	O
weakly	O
depressed	O
the	O
ectopic	O
ventricular	O
rate	O
but	O
not	O
the	O
arrhythmic	O
ratio	O
of	O
the	O
ventricular	O
arrhythmias	O
induced	O
by	O
two	O
-	O
stage	O
coronary	O
ligation	O
24	O
h	O
after	O
the	O
ligation	O
in	O
conscious	O
dogs	O
.	O

Catha	O
edulis	O
,	O
a	O
plant	O
that	O
has	O
amphetamine	O
effects	O
.	O

The	O
predicted	O
protein	O
,	O
Seb1p	B-GENE
,	O
consists	O
of	O
82	O
amino	O
acids	O
and	O
contains	O
one	O
potential	O
membrane	O
-	O
spanning	O
region	O
at	O
the	O
C	O
-	O
terminus	O
but	O
no	O
N	O
-	O
terminal	O
signal	O
sequence	O
.	O

The	O
SEB1	B-GENE
homologue	O
thus	O
isolated	O
,	O
SEB2	B-GENE
,	O
encodes	O
a	O
protein	O
53	O
%	O
identical	O
to	O
Seb1p	B-GENE
.	O

Nonetheless	O
,	O
that	O
ventricular	O
afferents	O
,	O
in	O
certain	O
special	O
settings	O
,	O
are	O
able	O
to	O
induce	O
e	O
.	O
g	O
.	O
generalised	O
vasodilation	O
and	O
hypotension	O
cannot	O
be	O
excluded	O
.	O

Large	O
ones	O
were	O
similar	O
in	O
size	O
to	O
the	O
main	O
lobe	O
and	O
small	O
ones	O
were	O
approximately	O
1	O
/	O
4	O
of	O
the	O
length	O
of	O
the	O
main	O
lobe	O
.	O

Fragments	O
and	O
analogs	O
of	O
the	O
hormone	O
ACTH	B-GENE
were	O
previously	O
shown	O
to	O
have	O
beneficial	O
effect	O
on	O
the	O
outcome	O
of	O
head	O
injury	O
,	O
while	O
elevated	O
levels	O
of	O
corticosterone	O
(	O
CS	O
)	O
exacerbate	O
it	O
.	O

Fifty	O
-	O
one	O
patients	O
with	O
primary	O
refractory	O
or	O
relapsed	O
malignant	O
lymphoma	O
(	O
47	O
non	O
-	O
Hodgkin	O
'	O
s	O
lymphoma	O
and	O
four	O
Hodgkin	O
'	O
s	O
disease	O
)	O
were	O
treated	O
with	O
a	O
new	O
chemotherapeutic	O
regimen	O
(	O
cisplatinum	O
,	O
methyl	O
GAG	O
,	O
bleomocyin	O
,	O
methyl	O
prednisolon	O
)	O
.	O

With	O
the	O
increasing	O
use	O
of	O
ACE	B-GENE
inhibitors	O
,	O
the	O
incidence	O
of	O
rare	O
adverse	O
effects	O
such	O
as	O
potentially	O
lethal	O
pancreatitis	O
is	O
likely	O
to	O
increase	O
.	O

In	O
3	O
treatments	O
the	O
diet	O
was	O
supplemented	O
with	O
0	O
,	O
100	O
and	O
150	O
mg	O
probiotic	O
/	O
kg	O
food	O
.	O

Low	O
-	O
dose	O
aspirin	O
and	O
recurrent	O
miscarriage	O
.	O

Protein	O
films	O
are	O
distinctly	O
different	O
in	O
mechanical	O
profiles	O
from	O
those	O
films	O
made	O
of	O
other	O
materials	O
.	O

Furthermore	O
,	O
cpxA	B-GENE
*	I-GENE
mutations	O
suppress	O
the	O
toxicity	O
conferred	O
by	O
the	O
LamB	B-GENE
-	O
LacZ	B-GENE
hybrid	O
protein	O
,	O
which	O
exerts	O
its	O
effects	O
in	O
the	O
cytoplasm	O
,	O
sequestered	O
from	O
DegP	B-GENE
.	O

The	O
PI3K	B-GENE
_	I-GENE
68D	I-GENE
cDNA	I-GENE
encodes	O
a	O
protein	O
of	O
210	O
kDa	O
,	O
which	O
lacks	O
sequences	O
implicated	O
in	O
linking	O
p110	B-GENE
PI	B-GENE
3	I-GENE
-	I-GENE
kinases	I-GENE
to	O
p85	B-GENE
adaptor	I-GENE
proteins	I-GENE
,	O
but	O
contains	O
an	O
amino	O
-	O
terminal	O
proline	O
-	O
rich	O
sequence	O
,	O
which	O
could	O
bind	O
to	O
SH3	B-GENE
domains	I-GENE
,	O
and	O
a	O
carboxy	O
-	O
terminal	O
C2	B-GENE
domain	O
.	O

AIMS	O
/	O
METHODS	O
:	O
Reticuloendothelial	O
system	O
function	O
,	O
as	O
assessed	O
by	O
clearance	O
of	O
radiolabelled	O
bacteria	O
,	O
was	O
evaluated	O
in	O
acute	O
liver	O
injury	O
induced	O
by	O
D	O
-	O
galactosamine	O
in	O
rats	O
,	O
and	O
compared	O
with	O
that	O
after	O
70	O
%	O
liver	O
resection	O
model	O
.	O

Our	O
laboratory	O
and	O
others	O
have	O
shown	O
alternative	O
splicing	O
of	O
up	O
to	O
ten	O
exons	O
at	O
a	O
discrete	O
extracellular	O
site	O
to	O
be	O
primarily	O
responsible	O
for	O
the	O
generation	O
of	O
CD44	B-GENE
variant	I-GENE
(	O
CD44v	B-GENE
)	O
isoforms	O
.	O

Study	O
groups	O
were	O
control	O
,	O
and	O
those	O
treated	O
with	O
the	O
alpha1	B-GENE
-	I-GENE
adrenoceptor	I-GENE
-	I-GENE
subtype	I-GENE
blockers	O
WB4101	O
(	O
0	O
.	O
5	O
mg	O
/	O
kg	O
i	O
.	O
v	O
.	O
)	O
or	O
chloroethylclonidine	O
(	O
1	O
.	O
9	O
mg	O
/	O
kg	O
i	O
.	O
v	O
.	O
)	O
.	O

This	O
caused	O
severe	O
cortical	O
damage	O
and	O
neuronal	O
loss	O
in	O
hippocampus	O
subfields	O
CA1	O
,	O
CA3	O
,	O
and	O
hilus	O
.	O

The	O
occurrence	O
of	O
multiple	O
malignancy	O
was	O
studied	O
in	O
674	O
patients	O
with	O
hematologic	O
malignancies	O
who	O
were	O
admitted	O
to	O
this	O
department	O
during	O
the	O
past	O
10	O
years	O
.	O

The	O
upTRE	O
binds	O
more	O
T3R	B-GENE
homodimers	I-GENE
and	O
less	O
T3R	B-GENE
-	O
RXR	B-GENE
heterodimers	O
than	O
the	O
dnTRE	O
,	O
and	O
T3	O
more	O
readily	O
facilitates	O
heterodimer	O
binding	O
to	O
the	O
dn	O
-	O
than	O
to	O
the	O
upTRE	O
.	O

Transcriptional	O
control	O
of	O
a	O
nuclear	O
gene	O
encoding	O
a	O
mitochondrial	O
fatty	O
acid	O
oxidation	O
enzyme	O
in	O
transgenic	O
mice	O
:	O
role	O
for	O
nuclear	O
receptors	O
in	O
cardiac	O
and	O
brown	O
adipose	O
expression	O
.	O

Hoeben	O
,	O
F	O
.	O
J	O
.	O

Moreover	O
,	O
glucan	B-GENE
synthase	I-GENE
activity	O
,	O
which	O
is	O
activated	O
by	O
Rho1p	B-GENE
,	O
was	O
significantly	O
reduced	O
in	O
the	O
deltabem4	B-GENE
mutant	I-GENE
.	O

In	O
gel	O
retardation	O
assays	O
,	O
an	O
RCS	O
cell	O
-	O
specific	O
protein	O
and	O
another	O
closely	O
related	O
protein	O
expressed	O
only	O
in	O
RCS	O
cells	O
and	O
primary	O
chondrocytes	O
bound	O
to	O
a	O
10	O
-	O
bp	O
sequence	O
within	O
the	O
18	O
-	O
mer	O
.	O

Two	O
classes	O
of	O
Xanthomonas	O
pathogens	O
evading	O
Bs2	O
host	O
resistance	O
and	O
displaying	O
reduced	O
fitness	O
were	O
found	O
to	O
be	O
specifically	O
mutated	O
in	O
avrBs2	B-GENE
.	O

Thus	O
,	O
the	O
characterization	O
of	O
the	O
promoter	O
region	O
should	O
help	O
to	O
define	O
regulatory	O
elements	O
that	O
control	O
neuron	O
-	O
specific	O
and	O
developmental	O
expression	O
of	O
the	O
MAP1B	B-GENE
gene	I-GENE
.	O

Mutants	O
lacking	O
the	O
3	O
'	O
stem	O
-	O
loop	O
exhibited	O
a	O
75	O
%	O
reduction	O
in	O
the	O
level	O
of	O
psaB	B-GENE
mRNA	O
.	O

The	O
deduced	O
amino	O
acid	O
sequence	O
was	O
highly	O
conserved	O
across	O
the	O
wide	O
range	O
of	O
eukaryotes	O
(	O
vertebrates	O
,	O
invertebrates	O
,	O
fungi	O
,	O
plants	O
and	O
protozoa	O
)	O
in	O
which	O
this	O
gene	O
has	O
now	O
been	O
identified	O
.	O

Semidominant	O
mutations	O
in	O
the	O
yeast	B-GENE
Rad51	I-GENE
protein	I-GENE
and	O
their	O
relationships	O
with	O
the	O
Srs2	B-GENE
helicase	I-GENE
.	O

Alterations	O
of	O
the	O
5q23	O
-	O
q31	O
interval	O
are	O
frequently	O
observed	O
in	O
myelodysplasia	O
and	O
myeloid	O
leukemia	O
.	O

Previous	O
studies	O
have	O
suggested	O
that	O
the	O
616	O
amino	O
acid	O
,	O
70	B-GENE
-	I-GENE
kDa	I-GENE
subunit	I-GENE
of	I-GENE
RPA	I-GENE
(	O
RPA	B-GENE
70	I-GENE
)	O
is	O
composed	O
of	O
multiple	O
structural	O
/	O
functional	O
domains	O
.	O

Neurons	O
were	O
held	O
at	O
-	O
67	O
mV	O
to	O
equate	O
voltage	O
-	O
dependent	O
effects	O
.	O

This	O
site	O
acts	O
as	O
a	O
negative	O
element	O
when	O
transferred	O
to	O
the	O
thymidine	B-GENE
kinase	I-GENE
promoter	I-GENE
,	O
but	O
does	O
not	O
confer	O
inducibility	O
.	O

The	O
extent	O
of	O
the	O
fbpA	B-GENE
operator	I-GENE
sequence	I-GENE
(	I-GENE
42	I-GENE
bp	I-GENE
)	I-GENE
,	O
as	O
defined	O
by	O
our	O
footprinting	O
analysis	O
,	O
would	O
suggest	O
the	O
binding	O
of	O
two	O
Fur	B-GENE
repressor	I-GENE
dimers	I-GENE
.	O

The	O
structural	O
similarity	O
between	O
Vav	B-GENE
and	O
other	O
guanine	B-GENE
nucleotide	I-GENE
exchange	I-GENE
factors	I-GENE
for	O
small	B-GENE
GTP	I-GENE
-	I-GENE
binding	I-GENE
proteins	I-GENE
,	O
together	O
with	O
the	O
recent	O
identification	O
of	O
biochemical	O
routes	O
specific	O
for	O
members	O
of	O
the	O
Ras	B-GENE
and	O
Rho	B-GENE
family	I-GENE
of	O
GTPases	B-GENE
,	O
prompted	O
us	O
to	O
explore	O
whether	O
MAPK	B-GENE
or	O
JNK	B-GENE
are	O
downstream	O
components	O
of	O
the	O
Vav	B-GENE
signaling	O
pathways	O
.	O

CONCLUSION	O
:	O
Twice	O
daily	O
treatment	O
with	O
inhaled	O
fluticasone	O
propionate	O
50	O
micrograms	O
or	O
100	O
micrograms	O
was	O
significantly	O
more	O
effective	O
than	O
theophylline	O
in	O
the	O
treatment	O
of	O
mild	O
-	O
to	O
-	O
moderate	O
asthma	O
.	O

Our	O
results	O
support	O
a	O
model	O
where	O
both	O
E2F	B-GENE
-	O
and	O
CDE	O
-	O
mediated	O
repression	O
,	O
acting	O
at	O
different	O
stages	O
in	O
the	O
cell	O
cycle	O
,	O
are	O
dependent	O
on	O
promoter	O
-	O
specific	O
CHR	O
elements	O
.	O

The	O
cDNA	O
clone	O
was	O
used	O
as	O
a	O
homologous	O
probe	O
to	O
isolate	O
a	O
truncated	O
genomic	O
clone	O
encoding	O
H2A1	B-GENE
.	O

Comparison	O
of	O
the	O
deduced	O
amino	O
acid	O
sequences	O
with	O
protein	O
sequences	O
of	O
T	O
.	O
pyriformis	O
H2As	B-GENE
showed	O
only	O
two	O
and	O
three	O
differences	O
respectively	O
,	O
in	O
a	O
total	O
of	O
137	O
amino	O
acids	O
for	O
H2A1	B-GENE
,	O
and	O
132	O
amino	O
acids	O
for	O
H2A2	B-GENE
,	O
indicating	O
the	O
two	O
genes	O
arose	O
before	O
the	O
divergence	O
of	O
these	O
two	O
species	O
.	O

Cognitive	O
visual	O
dysfunction	O
in	O
a	O
child	O
with	O
cerebral	O
damage	O
.	O

Interaction	O
was	O
apparently	O
determined	O
by	O
the	O
N	O
-	O
terminal	O
splice	O
region	O
of	O
RPDE	B-GENE
-	I-GENE
6	I-GENE
,	O
as	O
the	O
PDE4A	B-GENE
splice	O
variant	O
RPDE	B-GENE
-	I-GENE
39	I-GENE
,	O
which	O
differs	O
from	O
RPDE	B-GENE
-	I-GENE
6	I-GENE
at	O
the	O
extreme	O
N	O
-	O
terminus	O
,	O
failed	O
to	O
associate	O
with	O
v	B-GENE
-	I-GENE
Src	I-GENE
-	O
SH3	B-GENE
;	O
met26RD1	B-GENE
(	O
where	O
RD1	B-GENE
is	O
rat	B-GENE
'	I-GENE
dunc	I-GENE
-	I-GENE
like	I-GENE
'	I-GENE
PDE	I-GENE
)	O
,	O
which	O
has	O
the	O
N	O
-	O
terminal	O
splice	O
region	O
deleted	O
,	O
failed	O
to	O
associate	O
with	O
v	B-GENE
-	I-GENE
Src	I-GENE
-	O
SH3	B-GENE
,	O
and	O
the	O
association	O
of	O
RPDE	B-GENE
-	I-GENE
6	I-GENE
and	O
v	B-GENE
-	I-GENE
Src	I-GENE
-	O
SH3	B-GENE
was	O
blocked	O
by	O
a	O
fusion	O
protein	O
formed	O
from	O
the	O
N	O
-	O
terminal	O
splice	O
region	O
.	O

Potentially	O
load	O
-	O
insensitive	O
measures	O
of	O
ventricular	O
performance	O
were	O
therefore	O
evaluated	O
in	O
10	O
open	O
-	O
and	O
closed	O
-	O
chested	O
,	O
anesthetized	O
rabbits	O
.	O

Large	O
strain	O
differences	O
were	O
found	O
for	O
all	O
variables	O
recorded	O
,	O
i	O
.	O
e	O
.	O
,	O
the	O
proportion	O
of	O
attacking	O
males	O
,	O
the	O
time	O
spent	O
in	O
the	O
brightly	O
lit	O
box	O
,	O
and	O
the	O
number	O
of	O
transitions	O
between	O
the	O
lit	O
and	O
the	O
dark	O
boxes	O
.	O

It	O
is	O
the	O
oxidation	O
peak	O
of	O
this	O
product	O
,	O
arising	O
in	O
acidic	O
media	O
at	O
0	O
.	O
42	O
V	O
,	O
which	O
was	O
analysed	O
using	O
DPV	O
,	O
again	O
following	O
the	O
accumulation	O
of	O
clenbuterol	O
at	O
the	O
Nafion	O
-	O
modified	O
CPE	O
.	O

Phenylephrine	O
is	O
a	O
pure	O
alpha	B-GENE
-	I-GENE
1	I-GENE
adrenoreceptor	I-GENE
agonist	O
known	O
to	O
produce	O
marked	O
systemic	O
vasoconstriction	O
and	O
associated	O
hypertension	O
with	O
occasional	O
profound	O
reflex	O
bradycardia	O
.	O

The	O
expression	O
of	O
the	O
first	O
two	O
genes	O
located	O
in	O
this	O
unit	O
(	O
c	B-GENE
-	I-GENE
gvpD	I-GENE
and	O
c	B-GENE
-	I-GENE
gvpE	I-GENE
)	O
was	O
also	O
monitored	O
by	O
Western	O
blot	O
(	O
immunoblot	O
)	O
analyses	O
using	O
antisera	O
raised	O
against	O
these	O
proteins	O
synthesized	O
in	O
Escherichia	O
coli	O
.	O

One	O
unit	O
encodes	O
traA	B-GENE
,	O
traF	B-GENE
,	O
and	O
traB	B-GENE
,	O
while	O
the	O
second	O
encodes	O
traC	B-GENE
,	O
traD	B-GENE
,	O
and	O
traG	B-GENE
.	O

A	O
.	O

In	O
an	O
effort	O
to	O
isolate	O
genes	O
with	O
down	O
-	O
regulated	O
expression	O
at	O
the	O
mRNA	O
level	O
during	O
oncogenic	O
transformation	O
of	O
human	O
mammary	O
epithelial	O
cells	O
(	O
MECs	O
)	O
,	O
we	O
performed	O
subtractive	O
hybridization	O
between	O
normal	O
MEC	O
strain	O
76N	O
and	O
its	O
radiation	O
-	O
transformed	O
tumorigenic	O
derivative	O
76R	O
-	O
30	O
.	O

CASE	O
REPORT	O
:	O
Referred	O
because	O
of	O
a	O
right	O
corneal	O
perforation	O
with	O
cellular	O
reaction	O
in	O
anterior	O
chamber	O
,	O
a	O
patient	O
was	O
sutured	O
and	O
treated	O
with	O
a	O
single	O
intravitreal	O
injection	O
of	O
0	O
.	O
2	O
ml	O
(	O
1	O
mg	O
)	O
Amikacin	O
and	O
0	O
.	O
2	O
ml	O
(	O
1	O
mg	O
)	O
Vancomycin	O
.	O

The	O
P	B-GENE
-	I-GENE
wr	I-GENE
and	O
P	B-GENE
-	I-GENE
rr	I-GENE
cDNA	I-GENE
sequences	I-GENE
are	O
very	O
similar	O
in	O
their	O
5	O
'	O
regions	O
.	O

Because	O
the	O
hcf109	B-GENE
locus	I-GENE
was	O
mapped	O
at	O
a	O
distance	O
<	O
0	O
.	O
1	O
centimorgans	O
from	O
the	O
phytochrome	B-GENE
C	I-GENE
gene	I-GENE
,	O
its	O
molecular	O
characterization	O
by	O
positional	O
cloning	O
is	O
possible	O
.	O

The	O
human	B-GENE
MSH	I-GENE
-	I-GENE
2	I-GENE
gene	I-GENE
product	I-GENE
is	O
a	O
member	O
of	O
a	O
highly	O
conserved	O
family	O
of	O
proteins	O
which	O
are	O
involved	O
in	O
post	O
-	O
replication	O
mismatch	O
repair	O
.	O
hMSH	B-GENE
-	I-GENE
2	I-GENE
is	O
homologous	O
to	O
Escherichia	O
coli	O
(	O
E	O
.	O
coli	O
)	O
MutS	B-GENE
and	O
Sacchromyces	B-GENE
cerevisiae	I-GENE
MSH	I-GENE
-	I-GENE
1	I-GENE
and	O
MSH	B-GENE
-	I-GENE
2	I-GENE
proteins	I-GENE
,	O
which	O
recognise	O
heteroduplex	O
DNA	O
at	O
the	O
sites	O
of	O
all	O
single	O
base	O
mismatches	O
and	O
deletions	O
or	O
insertions	O
up	O
to	O
4	O
base	O
pairs	O
.	O
hMSH	B-GENE
-	I-GENE
2	I-GENE
is	O
one	O
of	O
the	O
hereditary	B-GENE
non	I-GENE
-	I-GENE
polyposis	I-GENE
colorectal	I-GENE
cancer	I-GENE
(	I-GENE
HNPCC	I-GENE
)	I-GENE
tumor	I-GENE
suppressor	I-GENE
genes	I-GENE
,	O
and	O
maps	O
to	O
human	O
chromosome	O
2p16	O
.	O

We	O
have	O
recently	O
shown	O
that	O
the	O
tissue	O
-	O
specific	O
expression	O
of	O
the	O
RAR	B-GENE
beta	I-GENE
2	I-GENE
gene	I-GENE
in	I-GENE
mouse	I-GENE
embryos	I-GENE
is	O
regulated	O
at	O
the	O
translational	O
level	O
by	O
short	O
upstream	O
open	O
reading	O
frames	O
(	O
uORFs	O
)	O
In	O
the	O
5	O
'	O
-	O
untranslated	O
region	O
(	O
Zimmer	O
,	O
A	O
.	O
,	O
A	O
.	O
M	O
.	O

We	O
have	O
previously	O
isolated	O
a	O
cDNA	O
for	O
a	O
transcription	O
factor	O
referred	O
to	O
as	O
Zfhep	B-GENE
(	O
zinc	B-GENE
finger	I-GENE
homeodomain	I-GENE
enhancer	I-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
)	O
containing	O
two	O
separate	O
zinc	O
finger	O
domains	O
,	O
ZD1	B-GENE
and	O
ZD2	B-GENE
,	O
each	O
of	O
which	O
binds	O
DNA	O
,	O
and	O
a	O
homeodomain	O
.	O

Increased	O
PTHRP	B-GENE
production	O
by	O
a	O
tyrosine	B-GENE
kinase	I-GENE
oncogene	I-GENE
,	O
Tpr	B-GENE
-	I-GENE
Met	I-GENE
:	O
role	O
of	O
the	O
Ras	B-GENE
signaling	O
pathway	O
.	O

Subsequent	O
to	O
their	O
secretion	O
,	O
the	O
IGF	B-GENE
-	I-GENE
II	I-GENE
in	O
xz97	O
and	O
G11	O
cells	O
accumulated	O
in	O
the	O
conditioned	O
medium	O
mostly	O
as	O
two	O
partially	O
processed	O
species	O
with	O
appMr	O
,	O
of	O
17K	O
and	O
14K	O
,	O
respectively	O
.	O

Paradoxically	O
,	O
coexpression	O
of	O
the	O
transcriptionally	O
inactive	O
,	O
amino	O
-	O
terminally	O
deleted	O
IDX	B-GENE
-	I-GENE
1	I-GENE
mutant	I-GENE
proteins	I-GENE
,	O
either	O
with	O
the	O
wild	B-GENE
-	I-GENE
type	I-GENE
IDX	I-GENE
-	I-GENE
1	I-GENE
or	O
with	O
themselves	O
,	O
results	O
in	O
a	O
marked	O
enhancement	O
of	O
transactivation	O
of	O
the	O
transcriptional	O
TAAT	B-GENE
-	I-GENE
1	I-GENE
element	I-GENE
reporter	I-GENE
.	O

All	O
patients	O
had	O
abnormal	O
von	B-GENE
Willebrand	I-GENE
factor	I-GENE
(	O
vWF	B-GENE
)	O
fragmentation	O
as	O
reflected	O
by	O
decreased	O
high	O
molecular	O
weight	O
and	O
increased	O
low	O
molecular	O
weight	O
vWF	B-GENE
multimers	I-GENE
in	O
the	O
circulation	O
.	O

In	O
an	O
attempt	O
to	O
investigate	O
whether	O
the	O
intergenic	O
region	O
between	O
the	O
oleosin	B-GENE
and	O
a	O
second	O
open	O
reading	O
frame	O
(	O
ORFII	O
)	O
in	O
Brassica	O
napus	O
(	O
L	O
.	O
)	O
is	O
a	O
divergent	O
promoter	O
,	O
and	O
also	O
to	O
characterize	O
the	O
ORFII	B-GENE
,	O
cDNA	B-GENE
clones	I-GENE
homologous	I-GENE
to	I-GENE
ORFII	I-GENE
were	O
isolated	O
from	O
a	O
leaf	O
cDNA	O
library	O
.	O

The	O
ORFII	B-GENE
gene	I-GENE
product	I-GENE
is	O
targeted	O
to	O
the	O
chloroplast	O
,	O
which	O
is	O
consistent	O
with	O
previous	O
data	O
indicating	O
the	O
presence	O
of	O
PMSR	B-GENE
activity	O
in	O
the	O
chloroplast	O
.	O

Characterization	O
of	O
LRP	B-GENE
,	O
a	O
leucine	B-GENE
-	I-GENE
rich	I-GENE
repeat	I-GENE
(	I-GENE
LRR	I-GENE
)	I-GENE
protein	I-GENE
from	I-GENE
tomato	I-GENE
plants	I-GENE
that	O
is	O
processed	O
during	O
pathogenesis	O
.	O

To	O
test	O
whether	O
Sp1	B-GENE
and	O
zif268	B-GENE
/	O
egr	B-GENE
-	I-GENE
1	I-GENE
interact	O
with	O
this	O
motif	O
,	O
gel	O
retardation	O
assays	O
were	O
performed	O
.	O

OBJECTIVES	O
:	O
The	O
aim	O
of	O
the	O
study	O
was	O
to	O
analyze	O
the	O
clinical	O
characteristics	O
,	O
treatment	O
and	O
outcome	O
of	O
310	O
patients	O
with	O
hydatidiform	O
mole	O
.	O

Stably	O
transfected	O
human	O
kidney	O
293	O
cells	O
expressing	O
the	O
wild	B-GENE
type	I-GENE
rat	I-GENE
LH	I-GENE
/	I-GENE
CG	I-GENE
receptor	I-GENE
(	O
rLHR	B-GENE
)	O
or	O
receptors	O
with	O
C	O
-	O
terminal	O
tails	O
truncated	O
at	O
residues	O
653	O
,	O
631	O
,	O
or	O
628	O
(	O
designated	O
rLHR	B-GENE
-	I-GENE
t653	I-GENE
,	O
rLHR	B-GENE
-	I-GENE
t631	I-GENE
,	O
and	O
rLHR	B-GENE
-	I-GENE
t628	I-GENE
)	O
were	O
used	O
to	O
probe	O
the	O
importance	O
of	O
this	O
region	O
on	O
the	O
regulation	O
of	O
hormonal	O
responsiveness	O
.	O

Are	O
low	O
P300	O
amplitudes	O
a	O
marker	O
for	O
schizophrenia	O
.	O

Sleep	O
was	O
determined	O
again	O
for	O
an	O
additional	O
3	O
days	O
and	O
6	O
hours	O
.	O

The	O
patients	O
are	O
two	O
healthy	O
adult	O
males	O
.	O

Indoor	O
concentrations	O
were	O
only	O
weakly	O
correlated	O
with	O
outdoor	O
concentrations	O
,	O
however	O
,	O
and	O
personal	O
exposures	O
were	O
even	O
more	O
poorly	O
correlated	O
with	O
outdoor	O
concentrations	O
.	O

A	O
neuropsychological	O
test	O
battery	O
was	O
used	O
that	O
contained	O
the	O
Wisconsin	O
card	O
sorting	O
test	O
,	O
Street	O
completion	O
test	O
,	O
Stroop	O
test	O
,	O
a	O
dichotic	O
memory	O
listening	O
test	O
,	O
and	O
a	O
facial	O
recognition	O
test	O
.	O

We	O
present	O
this	O
case	O
because	O
of	O
the	O
rarity	O
of	O
left	O
ventricular	O
involvement	O
associated	O
with	O
ARVD	O
.	O

In	O
a	O
randomized	O
single	O
-	O
blind	O
3	O
x	O
3	O
Latin	O
-	O
square	O
study	O
with	O
corrections	O
for	O
any	O
carryover	O
effects	O
,	O
27	O
males	O
and	O
30	O
females	O
consumed	O
supplements	O
containing	O
glucose	O
or	O
resistant	O
starch	O
(	O
RS	O
)	O
from	O
raw	O
high	O
-	O
amylose	O
cornstarch	O
(	O
RS2	O
)	O
or	O
from	O
retrograded	O
high	O
-	O
amylose	O
cornstarch	O
(	O
RS3	O
)	O
.	O

The	O
5	O
'	O
flanking	O
region	O
of	O
the	O
mouse	B-GENE
Met	I-GENE
-	I-GENE
ase	I-GENE
-	I-GENE
1	I-GENE
gene	I-GENE
also	O
shares	O
considerable	O
regions	O
of	O
identity	O
with	O
the	O
5	O
'	O
flanking	O
region	O
of	O
the	O
rat	B-GENE
Met	I-GENE
-	I-GENE
ase	I-GENE
-	I-GENE
1	I-GENE
gene	I-GENE
.	O

The	O
[	O
18F	O
]	O
FMISO	O
TMRR	O
is	O
a	O
simple	O
and	O
clinically	O
useful	O
index	O
for	O
detecting	O
tumour	O
hypoxia	O
in	O
NPC	O
.	O

Improved	O
methods	O
have	O
been	O
developed	O
for	O
maintaining	O
and	O
breeding	O
the	O
neotropical	O
short	O
-	O
tailed	O
fruit	O
bat	O
,	O
Carollia	O
perspicillata	O
,	O
in	O
an	O
easily	O
-	O
reproduced	O
,	O
laboratory	O
setting	O
.	O

In	O
addition	O
,	O
the	O
time	O
to	O
engraftment	O
was	O
significantly	O
shorter	O
in	O
the	O
amifostine	O
arm	O
in	O
both	O
cohorts	O
.	O

We	O
conclude	O
that	O
CPET	O
is	O
a	O
useful	O
investigation	O
in	O
the	O
management	O
of	O
patients	O
with	O
cardiopulmonary	O
disease	O
and	O
complements	O
the	O
various	O
other	O
investigations	O
offered	O
by	O
a	O
pulmonary	O
function	O
laboratory	O
.	O

Using	O
fluorescence	O
in	O
situ	O
hybridization	O
,	O
we	O
mapped	O
the	O
chromosome	O
-	O
17	O
breakpoint	O
in	O
a	O
patient	O
with	O
acampomelic	O
CMPD	O
and	O
sex	O
reversal	O
,	O
who	O
carries	O
a	O
de	O
novo	O
constitutional	O
t	O
(	O
12	O
;	O
17	O
)	O
translocation	O
,	O
between	O
two	O
known	O
cosmid	O
markers	O
in	O
the	O
17q24	O
-	O
q25	O
region	O
.	O

This	O
is	O
concluded	O
from	O
the	O
isolation	O
of	O
cDNAs	O
from	O
spinach	O
(	O
Spinacia	O
oleracea	O
)	O
and	O
barley	O
(	O
Hordeum	O
vulgare	O
cv	O
.	O

The	O
data	O
presented	O
in	O
this	O
work	O
indicate	O
that	O
thi1	B-GENE
may	O
also	O
be	O
involved	O
in	O
DNA	O
damage	O
tolerance	O
in	O
plant	O
cells	O
.	O

In	O
the	O
rat	B-GENE
rnu	I-GENE
allele	I-GENE
described	O
here	O
,	O
a	O
nonsense	O
mutation	O
in	O
exon	O
8	O
of	O
the	O
whn	B-GENE
gene	I-GENE
was	O
identified	O
.	O

Control	O
intact	O
rats	O
were	O
age	O
-	O
matched	O
to	O
the	O
different	O
treated	O
groups	O
.	O

DESIGN	O
:	O
A	O
cross	O
-	O
sectional	O
study	O
.	O

We	O
have	O
identified	O
a	O
strong	O
Tas	B-GENE
-	I-GENE
responsive	I-GENE
element	I-GENE
,	O
designated	O
TRE	B-GENE
(	O
GP	B-GENE
)	O
,	O
near	O
the	O
3	O
'	O
end	O
of	O
the	O
gag	B-GENE
gene	I-GENE
and	O
preceding	O
the	O
pol	B-GENE
gene	I-GENE
of	O
SFV	O
-	O
1	O
.	O

Although	O
the	O
binding	O
of	O
IE2	B-GENE
86	I-GENE
to	O
nonphosphorylated	O
full	B-GENE
-	I-GENE
length	I-GENE
CREB	I-GENE
or	O
deltaCREB	B-GENE
is	O
minimal	O
,	O
IE2	B-GENE
86	I-GENE
does	O
form	O
complexes	O
with	O
p300	B-GENE
and	O
the	O
CREB	B-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
(	O
CBP	B-GENE
)	O
,	O
which	O
in	O
turn	O
bind	O
to	O
CREB	B-GENE
and	O
can	O
serve	O
as	O
adaptor	O
proteins	O
for	O
CREB	B-GENE
function	O
.	O

A	O
transgenic	O
complementation	O
assay	O
was	O
used	O
to	O
test	O
whether	O
NIa	B-GENE
supplied	O
in	O
trans	O
could	O
rescue	O
amplification	O
-	O
defective	O
viral	O
genomes	O
encoding	O
altered	O
NIa	B-GENE
proteins	I-GENE
.	O

On	O
the	O
basis	O
of	O
its	O
bZIP	O
structural	O
homology	O
,	O
meq	B-GENE
is	O
perhaps	O
the	O
only	O
member	O
of	O
the	O
jun	B-GENE
-	O
fos	B-GENE
gene	O
family	O
completely	O
viral	O
in	O
origin	O
.	O

The	O
rCBF	O
and	O
vasomotion	O
were	O
recorded	O
by	O
laser	O
-	O
doppler	O
fluxmetry	O
.	O

Although	O
basal	O
vessels	O
may	O
constrict	O
distal	O
parenchymal	O
vessels	O
tend	O
to	O
dilate	O
after	O
SAH	O
.	O

The	O
triple	O
combination	O
of	O
nizatidine	O
,	O
clarithromycin	O
,	O
and	O
bismuth	O
subcitrate	O
resulted	O
in	O
an	O
ulcer	O
healing	O
rate	O
of	O
98	O
%	O
and	O
an	O
H	O
.	O
pylori	O
eradication	O
rate	O
of	O
90	O
%	O
.	O

Several	O
lines	O
of	O
evidence	O
presented	O
here	O
suggest	O
that	O
PKC	B-GENE
-	I-GENE
zeta	I-GENE
plays	O
a	O
role	O
in	O
alpha	B-GENE
2	I-GENE
integrin	I-GENE
gene	I-GENE
expression	O
.	O

Plasma	O
thrombomodulin	B-GENE
:	O
a	O
marker	O
for	O
microvascular	O
complications	O
in	O
diabetes	O
mellitus	O
.	O

Update	O
:	O
diphtheria	O
epidemic	O
in	O
the	O
newly	O
independent	O
states	O
of	O
the	O
former	O
USSR	O
,	O
January	O
1995	O
-	O
March	O
1996	O
.	O

The	O
characterization	O
of	O
the	O
promoter	O
region	O
indicated	O
that	O
three	O
distinct	O
regulatory	O
elements	O
corresponding	O
to	O
an	O
AP	B-GENE
-	I-GENE
1	I-GENE
binding	I-GENE
site	I-GENE
(	O
or	O
TRE	O
)	O
,	O
a	O
PRDII	B-GENE
/	O
kappaB	B-GENE
domain	O
,	O
and	O
a	O
CAAT	O
box	O
are	O
involved	O
in	O
the	O
activation	O
by	O
pp60	B-GENE
(	B-GENE
v	I-GENE
-	I-GENE
)	I-GENE
src	I-GENE
.	O

Serine	O
528	O
is	O
phosphorylated	O
in	O
vivo	O
in	O
several	O
cell	O
lines	O
,	O
and	O
substitution	O
of	O
serine	O
528	O
to	O
alanine	O
(	O
S528A	O
)	O
resulted	O
in	O
an	O
increased	O
ability	O
of	O
Myb	B-GENE
to	O
transactivate	O
a	O
synthetic	O
promoter	O
containing	O
five	O
copies	O
of	O
the	O
mim	B-GENE
-	I-GENE
1A	I-GENE
Myb	B-GENE
-	O
responsive	O
element	O
and	O
a	O
minimal	O
herpes	B-GENE
tk	I-GENE
promoter	I-GENE
.	O

The	O
DNA	O
binding	O
and	O
multimerization	O
activities	O
of	O
c	B-GENE
-	I-GENE
Myb	I-GENE
appear	O
to	O
be	O
unaffected	O
by	O
the	O
S528A	O
substitution	O
,	O
suggesting	O
that	O
phosphorylation	O
of	O
serine	O
528	O
may	O
mediate	O
its	O
effect	O
on	O
the	O
transcription	O
transactivating	O
activity	O
of	O
c	B-GENE
-	I-GENE
Myb	I-GENE
by	O
regulating	O
interactions	O
with	O
other	O
proteins	O
.	O

The	O
amount	O
of	O
these	O
factors	O
was	O
reduced	O
in	O
GEO	O
cells	O
in	O
which	O
the	O
u	B-GENE
-	I-GENE
PAR	I-GENE
gene	I-GENE
is	O
only	O
weakly	O
transcriptionally	O
activated	O
.	O

PIP2	O
,	O
when	O
incorporated	O
into	O
phosphatidylcholine	O
carrier	O
vesicles	O
,	O
binds	O
tightly	O
to	O
the	O
guanine	O
nucleotide	O
-	O
depleted	O
form	O
of	O
Cdc42Hs	B-GENE
and	O
weakly	O
to	O
the	O
GDP	O
-	O
bound	O
form	O
of	O
the	O
GTP	B-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
but	O
does	O
not	O
bind	O
to	O
GTP	O
-	O
bound	O
Cdc42Hs	B-GENE
,	O
similar	O
to	O
what	O
was	O
observed	O
for	O
the	O
Dbl	B-GENE
oncoprotein	I-GENE
.	O

Purified	O
spleen	O
GAP	B-GENE
accelerated	O
hydrolysis	O
of	O
GTP	O
bound	O
to	O
recombinant	B-GENE
ARF1	I-GENE
,	O
ARF3	B-GENE
,	O
ARF5	B-GENE
,	O
and	O
ARF6	B-GENE
;	O
no	O
effect	O
of	O
NH2	O
-	O
terminal	O
myristoylation	O
was	O
observed	O
.	O

Biol	O
.	O

A	O
novel	O
phosphotyrosine	O
-	O
binding	O
domain	O
in	O
the	O
N	O
-	O
terminal	O
transforming	O
region	O
of	O
Cbl	B-GENE
interacts	O
directly	O
and	O
selectively	O
with	O
ZAP	B-GENE
-	I-GENE
70	I-GENE
in	O
T	O
cells	O
.	O

Cys	O
-	O
757	O
within	O
the	O
(	O
Fe4S4	O
)	O
-	O
siroheme	O
-	O
binding	O
domain	O
was	O
essential	O
for	O
native	O
enzyme	O
activity	O
.	O

Its	O
transcription	O
has	O
been	O
shown	O
to	O
be	O
induced	O
40	O
-	O
50	O
-	O
fold	O
in	O
response	O
to	O
oxygen	O
or	O
heme	O
deficiency	O
,	O
in	O
part	O
through	O
relief	O
of	O
repression	O
exerted	O
by	O
Rox1p	B-GENE
and	O
in	O
part	O
by	O
activation	O
mediated	O
by	O
an	O
upstream	O
activation	O
sequence	O
(	O
UAS	O
)	O
.	O

Altogether	O
,	O
our	O
results	O
indicate	O
that	O
the	O
transcriptional	O
activity	O
of	O
Cut	B-GENE
proteins	I-GENE
is	O
modulated	O
by	O
PKC	B-GENE
.	O

Lck	B-GENE
has	O
been	O
postulated	O
to	O
dimerize	O
through	O
the	O
SH2	B-GENE
and	O
SH3	B-GENE
domains	I-GENE
.	O

Furthermore	O
,	O
freezing	O
in	O
the	O
presence	O
of	O
bovine	B-GENE
lactalbumin	I-GENE
resulted	O
in	O
a	O
good	O
maintenance	O
of	O
the	O
cellular	O
viability	O
and	O
of	O
the	O
CCCD	O
heterogeneity	O
in	O
respect	O
to	O
fresh	O
cells	O
.	O

Myelomatous	O
pleural	O
effusion	O
as	O
presentation	O
form	O
of	O
multiple	O
myeloma	O

The	O
presence	O
of	O
unidentified	O
macroscopic	O
or	O
microscopic	O
clusters	O
of	O
neoplastic	O
cells	O
,	O
lying	O
around	O
,	O
more	O
or	O
less	O
close	O
to	O
,	O
the	O
line	O
of	O
insertion	O
of	O
lesion	O
,	O
could	O
render	O
any	O
attempt	O
to	O
gain	O
a	O
"	O
radical	O
"	O
excision	O
useless	O
.	O

The	O
partial	O
categories	O
of	O
the	O
SIP	O
that	O
were	O
more	O
affected	O
were	O
work	O
,	O
recreation	O
and	O
pastimes	O
,	O
home	O
management	O
,	O
and	O
sleep	O
and	O
rest	O
.	O

Northern	O
blot	O
analysis	O
,	O
using	O
the	O
Ltp4	B-GENE
-	O
specific	O
probe	O
,	O
indicated	O
that	O
Xanthomonas	O
campestris	O
pv	O
.	O
translucens	O
induced	O
an	O
increase	O
over	O
basal	O
levels	O
of	O
Ltp4	B-GENE
mRNA	I-GENE
,	O
while	O
Pseudomonas	O
syringae	O
pv	O
.	O
japonica	O
caused	O
a	O
decrease	O
.	O

Furthermore	O
,	O
the	O
use	O
of	O
zero	O
-	O
loss	O
filtering	O
in	O
combination	O
with	O
exit	O
wavefront	O
reconstruction	O
is	O
considerably	O
more	O
effective	O
at	O
removing	O
the	O
effects	O
of	O
multiple	O
elastic	O
and	O
inelastic	O
scattering	O
and	O
microscope	O
objective	O
lens	O
aberrations	O
than	O
either	O
technique	O
by	O
itself	O
.	O

Transcripts	O
for	O
both	O
ODV	B-GENE
-	I-GENE
E18	I-GENE
and	O
ODV	B-GENE
-	I-GENE
EC27	I-GENE
initiate	O
from	O
conserved	O
TAAG	O
motifs	O
,	O
and	O
transcripts	O
are	O
detected	O
from	O
16	O
through	O
72	O
hr	O
p	O
.	O
i	O
.	O

In	O
order	O
to	O
determine	O
which	O
sequences	O
in	O
the	O
GATA	B-GENE
-	I-GENE
1	I-GENE
promoter	I-GENE
are	O
crucial	O
for	O
activation	O
by	O
the	O
ME26	B-GENE
viral	I-GENE
protein	I-GENE
,	O
we	O
made	O
deletions	O
of	O
the	O
promoter	O
,	O
cloned	O
them	O
into	O
a	O
luciferase	B-GENE
expression	O
vector	O
and	O
tested	O
their	O
activity	O
in	O
mouse	O
fibroblasts	O
,	O
which	O
do	O
not	O
express	O
GATA	B-GENE
-	I-GENE
1	I-GENE
.	O

A	O
3	O
-	O
yr	O
retrospective	O
review	O
is	O
effective	O
and	O
detects	O
94	O
%	O
of	O
the	O
undercalls	O
.	O

Isolation	O
and	O
identification	O
of	O
genes	O
activating	O
UAS2	B-GENE
-	I-GENE
dependent	I-GENE
ADH2	I-GENE
expression	O
in	O
Saccharomyces	O
cerevisiae	O
.	O

METHODS	O
AND	O
RESULTS	O
:	O
A	O
64	O
-	O
year	O
-	O
old	O
woman	O
with	O
confirmed	O
AV	O
nodal	O
reentrant	O
tachycardia	O
underwent	O
a	O
successful	O
"	O
slow	O
pathway	O
"	O
AV	O
modification	O
with	O
a	O
single	O
radiofrequency	O
application	O
.	O

Patients	O
with	O
low	O
probability	O
of	O
having	O
aluminum	O
overload	O
(	O
serum	O
iron	O
levels	O
<	O
40	O
micrograms	O
/	O
L	O
and	O
DAI	O
<	O
150	O
micrograms	O
/	O
L	O
)	O
had	O
significantly	O
higher	O
values	O
of	O
serum	O
iron	O
,	O
iron	O
transferrin	B-GENE
saturation	O
,	O
and	O
serum	B-GENE
ferritin	I-GENE
levels	O
compared	O
with	O
those	O
patients	O
with	O
a	O
high	O
probability	O
of	O
having	O
aluminum	O
overload	O
(	O
serum	O
aluminum	O
levels	O
>	O
40	O
micrograms	O
/	O
L	O
and	O
DAI	O
>	O
150	O
micrograms	O
/	O
L	O
)	O
.	O

Although	O
the	O
RAD23	B-GENE
equivalents	O
are	O
well	O
conserved	O
during	O
evolution	O
,	O
the	O
mammalian	O
genes	O
did	O
not	O
express	O
the	O
UV	O
-	O
inducible	O
phenotype	O
of	O
their	O
yeast	O
counterpart	O
.	O

Ha	B-GENE
-	I-GENE
RasV12	I-GENE
and	O
activated	O
proteins	O
in	O
both	O
the	O
extra	B-GENE
-	I-GENE
cellular	I-GENE
regulated	I-GENE
kinase	I-GENE
(	O
ERK	B-GENE
)	O
and	O
the	O
stress	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
kinase	I-GENE
(	O
SAPK	B-GENE
)	O
or	O
Jun	B-GENE
N	I-GENE
-	I-GENE
terminal	I-GENE
kinase	I-GENE
(	O
JNK	B-GENE
)	O
cascades	O
independently	O
stimulated	O
PEA3	B-GENE
-	O
mediated	O
gene	O
expression	O
.	O

Sequence	O
analysis	O
of	O
reverse	O
transcribed	O
,	O
amplified	O
cDNA	O
generated	O
from	O
total	O
RNA	O
isolated	O
from	O
transfected	O
cells	O
demonstrated	O
the	O
presence	O
of	O
abnormally	O
spliced	O
products	O
containing	O
13	O
and	O
78	O
additional	O
bases	O
as	O
well	O
as	O
the	O
accumulation	O
of	O
unspliced	O
mRNA	O
.	O

A	O
1	O
.	O
5	O
-	O
kb	O
HindIII	B-GENE
genomic	O
fragment	O
carrying	O
the	O
vspA	B-GENE
gene	O
from	O
M	O
.	O
bovis	O
PG45	O
was	O
cloned	O
and	O
sequenced	O
.	O

Carbon	O
catabolite	O
repression	O
of	O
the	O
gnt	B-GENE
operon	I-GENE
of	I-GENE
Bacillus	I-GENE
subtilis	I-GENE
is	O
mediated	O
by	O
the	O
catabolite	O
control	O
protein	O
CcpA	B-GENE
and	O
by	O
HPr	B-GENE
,	O
a	O
phosphocarrier	O
protein	O
of	O
the	O
phosphotransferase	O
system	O
.	O

Melatonin	O
and	O
seasonality	O
:	O
filling	O
the	O
gap	O
.	O

A	O
subsequent	O
screen	O
for	O
the	O
loss	O
of	O
the	O
positively	O
selectable	O
target	O
locus	O
marker	O
detects	O
the	O
desired	O
replacement	O
at	O
modest	O
frequency	O
(	O
>	O
2	O
%	O
)	O
.	O

Here	O
we	O
demonstrate	O
that	O
another	O
cellular	O
protein	O
linked	O
to	O
BCR	B-GENE
/	O
ABL	B-GENE
through	O
the	O
CRKL	B-GENE
-	O
SH2	B-GENE
domain	O
is	O
p130	B-GENE
(	O
CAS	B-GENE
)	O
.	O
p130	B-GENE
(	O
CAS	B-GENE
)	O
was	O
found	O
to	O
be	O
tyrosine	O
phosphorylated	O
and	O
associated	O
with	O
CRKL	B-GENE
in	O
BCR	B-GENE
/	O
ABL	B-GENE
expressing	O
cell	O
lines	O
and	O
in	O
samples	O
obtained	O
from	O
CML	O
and	O
ALL	O
patients	O
,	O
but	O
not	O
in	O
samples	O
from	O
controls	O
.	O

The	O
effects	O
of	O
procedural	O
variations	O
on	O
lateralized	O
Stroop	O
effects	O
.	O

In	O
a	O
third	O
experiment	O
,	O
a	O
Chessmaster	O
gradually	O
increases	O
the	O
number	O
of	O
boards	O
he	O
can	O
reproduce	O
with	O
higher	O
than	O
70	O
%	O
average	O
accuracy	O
to	O
nine	O
,	O
replacing	O
as	O
many	O
as	O
160	O
pieces	O
correctly	O
.	O

PCNA	B-GENE
mRNA	I-GENE
has	O
a	O
3	O
'	O
UTR	O
antisense	O
to	O
yellow	O
crescent	O
RNA	O
and	O
is	O
localized	O
in	O
ascidian	O
eggs	O
and	O
embryos	O
.	O

A	O
1	O
.	O
8	O
-	O
kb	O
cDNA	O
clone	O
(	O
designed	O
hKID	B-GENE
,	O
gene	B-GENE
symbol	I-GENE
AQP2L	I-GENE
)	O
with	O
homology	O
to	O
the	O
aquaporins	B-GENE
was	O
isolated	O
from	O
a	O
human	O
kidney	O
cDNA	O
library	O
.	O

PCR	O
/	O
Southern	O
blot	O
analysis	O
of	O
human	O
kidney	O
cDNA	O
using	O
primers	O
flanking	O
the	O
hKID	B-GENE
coding	I-GENE
sequence	I-GENE
revealed	O
expression	O
of	O
a	O
full	O
-	O
length	O
mRNA	O
and	O
short	O
transcripts	O
with	O
partial	O
exon	O
1	O
and	O
partial	O
exon	O
4	O
deletions	O
.	O

The	O
high	O
sequence	O
homology	O
,	O
similar	O
genomic	O
structure	O
,	O
and	O
identical	O
chromosomal	O
loci	O
of	O
hKID	B-GENE
,	O
MIP	B-GENE
,	O
and	O
AQP	B-GENE
-	I-GENE
2	I-GENE
suggest	O
a	O
MIP	B-GENE
family	I-GENE
gene	I-GENE
cluster	I-GENE
at	O
chromosome	O
locus	O
12q13	O
.	O

The	O
third	O
ORF	O
generates	O
a	O
transcript	O
of	O
1	O
.	O
6	O
kb	O
and	O
encodes	O
a	O
protein	O
of	O
382	O
residues	O
including	O
a	O
perfect	O
match	O
to	O
the	O
consensus	O
sequence	O
of	O
a	O
C2H2	O
zinc	O
finger	O
domain	O
;	O
it	O
shares	O
a	O
strong	O
homology	O
with	O
yeast	B-GENE
Mig1p	I-GENE
and	O
Cre	B-GENE
-	I-GENE
A	I-GENE
from	I-GENE
Aspergillus	I-GENE
,	I-GENE
Emericella	I-GENE
and	I-GENE
E	I-GENE
.	I-GENE
coli	I-GENE
.	O

Adding	O
phytase	B-GENE
and	O
nP	O
improved	O
the	O
orderliness	O
of	O
development	O
,	O
mineralization	O
and	O
arrangement	O
of	O
cartilage	O
and	O
bone	O
cells	O
,	O
and	O
alleviated	O
the	O
effects	O
of	O
P	O
deficiency	O
on	O
the	O
histological	O
and	O
gross	O
structure	O
of	O
the	O
tibias	O
.	O

The	O
importance	O
of	O
temporal	O
factors	O
on	O
the	O
presence	O
and	O
severity	O
of	O
ethanol	O
withdrawal	O
signs	O
in	O
the	O
rat	O
was	O
quantified	O
using	O
rating	O
scale	O
,	O
tremor	O
,	O
and	O
acoustic	O
startle	O
paradigms	O
.	O

Data	O
supported	O
the	O
brevity	O
of	O
the	O
WISC	O
-	O
III	O
short	O
form	O
and	O
the	O
criterion	O
-	O
related	O
validity	O
of	O
both	O
the	O
K	O
-	O
FAST	O
and	O
and	O
Kaufman	O
Short	O
Neuropsychological	O
Assessment	O
Procedure	O
(	O
K	O
-	O
SNAP	O
)	O
.	O

Thus	O
,	O
the	O
multidomained	O
ROK	B-GENE
alpha	I-GENE
appears	O
to	O
be	O
involved	O
in	O
reorganization	O
of	O
the	O
cytoskeleton	O
,	O
with	O
the	O
N	O
and	O
C	O
termini	O
acting	O
as	O
positive	O
and	O
negative	O
regulators	O
,	O
respectively	O
,	O
of	O
the	O
kinase	O
domain	O
whose	O
activity	O
is	O
crucial	O
for	O
formation	O
of	O
stress	O
fibers	O
and	O
focal	O
adhesion	O
complexes	O
.	O

These	O
findings	O
and	O
the	O
differential	O
tissue	O
distribution	O
of	O
p54	B-GENE
suggest	O
that	O
this	O
novel	O
SR	B-GENE
protein	I-GENE
may	O
participate	O
in	O
regulation	O
of	O
alternative	O
splicing	O
in	O
a	O
tissue	O
-	O
and	O
substrate	O
-	O
dependent	O
manner	O
.	O

The	O
elevation	O
of	O
cyclic	O
AMP	O
(	O
cAMP	O
)	O
levels	O
in	O
the	O
cell	O
downregulates	O
the	O
activity	O
of	O
the	O
Raf	B-GENE
-	I-GENE
1	I-GENE
kinase	I-GENE
.	O

An	O
interaction	O
screen	O
with	O
the	O
repression	O
domain	O
of	O
the	O
orphan	B-GENE
receptor	I-GENE
RevErb	I-GENE
identified	O
N	B-GENE
-	I-GENE
CoR	I-GENE
,	O
the	O
corepressor	O
for	O
thyroid	B-GENE
hormone	I-GENE
receptor	I-GENE
(	O
TR	B-GENE
)	O
and	O
retinoic	B-GENE
acid	I-GENE
receptor	I-GENE
(	O
RAR	B-GENE
)	O
.	O

These	O
results	O
indicate	O
that	O
inhibition	O
of	O
Jun	B-GENE
kinase	I-GENE
activation	O
was	O
sufficient	O
to	O
inhibit	O
Ras	B-GENE
transformation	O
even	O
in	O
the	O
presence	O
of	O
activated	O
Erk	B-GENE
-	I-GENE
2	I-GENE
.	O

Our	O
analysis	O
suggests	O
that	O
Upf1p	B-GENE
is	O
a	O
multifunctional	O
protein	O
with	O
separable	O
activities	O
that	O
can	O
affect	O
mRNA	O
turnover	O
and	O
nonsense	O
suppression	O
.	O

Identification	O
of	O
Ste4	B-GENE
as	O
a	O
potential	O
regulator	O
of	O
Byr2	B-GENE
in	O
the	O
sexual	O
response	O
pathway	O
of	O
Schizosaccharomyces	O
pombe	O
.	O

Two	O
closely	O
related	O
variants	O
of	O
Stat5	B-GENE
,	O
Stat5a	B-GENE
and	O
Stat5b	B-GENE
,	O
are	O
encoded	O
by	O
distinct	O
genes	O
.	O

Mutations	O
in	O
three	O
loci	O
(	O
SIC1	B-GENE
,	O
SWI5	B-GENE
,	O
and	O
RIC3	B-GENE
)	O
were	O
identified	O
.	O

The	O
serine	B-GENE
/	I-GENE
threonine	I-GENE
kinase	I-GENE
Raf	B-GENE
-	I-GENE
1	I-GENE
functions	O
downstream	O
of	O
Rats	B-GENE
in	O
a	O
signal	O
transduction	O
cascade	O
which	O
transmits	O
mitogenic	O
stimuli	O
from	O
the	O
plasma	O
membrane	O
to	O
the	O
nucleus	O
.	O

In	O
transient	O
cotransfections	O
E1A	B-GENE
could	O
induce	O
the	O
activity	O
of	O
the	O
p53	B-GENE
promoter	I-GENE
to	O
a	O
high	O
level	O
;	O
12S	B-GENE
E1A	I-GENE
was	O
threefold	O
as	O
efficient	O
as	O
13S	B-GENE
E1A	I-GENE
in	O
this	O
activity	O
,	O
and	O
YY1	B-GENE
bound	O
to	O
the	O
composite	O
element	O
was	O
shown	O
to	O
mediate	O
55	O
%	O
of	O
this	O
induction	O
.	O

The	O
retinoid	B-GENE
Z	I-GENE
receptor	I-GENE
beta	I-GENE
(	O
RZR	B-GENE
beta	I-GENE
)	O
,	O
an	O
orphan	O
receptor	O
,	O
is	O
a	O
member	O
of	O
the	O
retinoic	B-GENE
acid	I-GENE
receptor	I-GENE
(	O
RAR	B-GENE
)	O
/	O
thyroid	B-GENE
hormone	I-GENE
receptor	I-GENE
(	O
TR	B-GENE
)	O
subfamily	O
of	O
nuclear	O
receptors	O
.	O

DNA	B-GENE
-	I-GENE
dependent	I-GENE
protein	I-GENE
kinase	I-GENE
(	O
DNA	B-GENE
-	I-GENE
PK	I-GENE
)	O
consists	O
of	O
a	O
heterodimeric	O
protein	O
(	O
Ku	B-GENE
)	O
and	O
a	O
large	O
catalytic	O
subunit	O
(	O
DNA	B-GENE
-	I-GENE
PKcs	I-GENE
)	O
.	O

Sequencing	O
of	O
the	O
16p	O
11	O
.	O
1	O
/	O
Xq28	O
duplication	O
breakpoints	O
has	O
revealed	O
the	O
presence	O
of	O
repetitive	O
immunoglobulin	B-GENE
-	I-GENE
like	I-GENE
CAGGG	I-GENE
pentamer	I-GENE
sequences	I-GENE
at	O
or	O
near	O
the	O
paralogy	O
boundaries	O
.	O

However	O
,	O
in	O
a	O
multivariate	O
analysis	O
considering	O
age	O
,	O
gender	O
,	O
and	O
a	O
previous	O
history	O
of	O
cardiovascular	O
diseases	O
,	O
female	O
gender	O
was	O
not	O
independently	O
associated	O
with	O
death	O
.	O

Moreover	O
,	O
following	O
a	O
single	O
intravenous	O
injection	O
of	O
the	O
bicistronic	O
vector	O
complexed	O
to	O
cationic	O
liposomes	O
into	O
recipient	O
mice	O
,	O
delivery	O
of	O
MDR1	B-GENE
and	O
GC	B-GENE
cDNAs	I-GENE
was	O
achieved	O
in	O
all	O
the	O
organs	O
we	O
tested	O
.	O

The	O
limits	O
of	O
agreement	O
between	O
DBS	O
and	O
TOF	O
responses	O
were	O
so	O
wide	O
that	O
they	O
cannot	O
be	O
used	O
interchangeably	O
.	O

The	O
harpin	B-GENE
-	O
encoding	O
hrpZ	B-GENE
gene	I-GENE
is	O
located	O
in	O
an	O
operon	O
that	O
also	O
encodes	O
Hrp	B-GENE
secretion	I-GENE
pathway	I-GENE
components	I-GENE
and	O
is	O
part	O
of	O
the	O
functional	O
cluster	O
of	O
hrp	B-GENE
genes	I-GENE
carried	O
on	O
cosmid	O
pHIR11	O
that	O
enables	O
saprophytic	O
bacteria	O
like	O
Escherichia	O
coli	O
and	O
Pseudomonas	O
fluorescens	O
to	O
elicit	O
the	O
HR	O
in	O
tobacco	O
leaves	O
.	O

Despite	O
the	O
presence	O
of	O
one	O
additional	O
ribonucleotide	B-GENE
reductase	I-GENE
,	O
the	O
nrdAB	B-GENE
-	I-GENE
encoded	I-GENE
enzyme	I-GENE
is	O
essential	O
to	O
the	O
aerobic	O
growth	O
of	O
the	O
cell	O
because	O
nrdAB	B-GENE
-	I-GENE
defective	I-GENE
mutants	I-GENE
of	O
both	O
species	O
are	O
not	O
viable	O
in	O
the	O
presence	O
of	O
oxygen	O
.	O

Altogether	O
,	O
the	O
results	O
demonstrate	O
that	O
the	O
two	O
isoforms	O
elicit	O
similar	O
responses	O
in	O
vivo	O
despite	O
differences	O
in	O
their	O
regulation	O
.	O

Motivational	O
factors	O
focusing	O
on	O
attitudes	O
,	O
perceived	O
susceptibility	O
to	O
pregnancy	O
,	O
and	O
normative	O
factors	O
were	O
also	O
relevant	O
.	O

High	O
-	O
resolution	O
structure	O
of	O
the	O
diphtheria	B-GENE
toxin	I-GENE
repressor	I-GENE
complexed	O
with	O
cobalt	O
and	O
manganese	O
reveals	O
an	O
SH3	B-GENE
-	I-GENE
like	I-GENE
third	O
domain	O
and	O
suggests	O
a	O
possible	O
role	O
of	O
phosphate	O
as	O
co	O
-	O
corepressor	O
.	O

Titration	O
of	O
the	O
human	O
and	O
porcine	O
proteins	O
with	O
2	O
-	O
nitro	O
-	O
5	O
-	O
thiosulfabenzoate	O
indicates	O
that	O
membrane	B-GENE
dipeptidase	I-GENE
additionally	O
possesses	O
two	O
intrachain	O
disulfide	O
bonds	O
.	O

FEV1	O
did	O
not	O
fall	O
significantly	O
in	O
patients	O
without	O
acute	O
or	O
chronic	O
GVHD	O
and	O
recovered	O
earlier	O
than	O
in	O
patients	O
without	O
posttransplant	O
pulmonary	O
infection	O
.	O

Administration	O
of	O
adrenaline	O
resulted	O
in	O
a	O
large	O
overestimation	O
of	O
the	O
SaO2	O
in	O
6	O
of	O
the	O
7	O
measurements	O
.	O

Therapy	O
with	O
dietary	O
modification	O
and	O
triglyceride	O
lowering	O
drugs	O
resulted	O
in	O
resolution	O
of	O
symptoms	O
and	O
parotid	O
swelling	O
in	O
one	O
patient	O
.	O

Chernoff	O
,	O
submitted	O
for	O
publication	O
)	O
.	O

We	O
have	O
cloned	O
a	O
novel	O
protein	O
kinase	O
,	O
termed	O
hematopoietic	B-GENE
progenitor	I-GENE
kinase	I-GENE
1	I-GENE
(	O
HPK1	B-GENE
)	O
,	O
that	O
is	O
expressed	O
predominantly	O
in	O
hematopoietic	O
cells	O
,	O
including	O
early	O
progenitor	O
cells	O
.	O

Human	O
ESP1	B-GENE
/	O
CRP2	B-GENE
protein	O
has	O
two	O
LIM	B-GENE
domains	O
,	O
and	O
each	O
shares	O
35	O
.	O
1	O
%	O
and	O
77	O
or	O
79	O
%	O
identical	O
residues	O
with	O
human	B-GENE
cysteine	I-GENE
-	I-GENE
rich	I-GENE
protein	I-GENE
(	O
CRP	B-GENE
)	O
and	O
rat	B-GENE
CRIP	I-GENE
,	O
respectively	O
.	O

The	O
fragments	O
are	O
separated	O
and	O
directly	O
sized	O
by	O
agarose	O
gel	O
electrophoresis	O
.	O

Linkage	O
studies	O
have	O
shown	O
locus	O
heterogeneity	O
with	O
one	O
TSC	B-GENE
gene	I-GENE
mapped	O
to	O
chromosome	O
9q34	O
and	O
a	O
second	O
to	O
16p13	O
.	O
3	O
.	O

The	O
cytogenetic	O
expression	O
of	O
the	O
folate	O
sensitive	O
fragile	O
site	O
,	O
FRAXE	B-GENE
,	O
is	O
due	O
to	O
the	O
expansion	O
of	O
a	O
GCC	O
repeat	O
in	O
proximal	O
Xq28	O
of	O
the	O
human	O
X	O
chromosome	O
and	O
is	O
associated	O
with	O
a	O
mild	O
form	O
of	O
mental	O
handicap	O
.	O

DNA	O
sequence	O
analysis	O
of	O
a	O
3213	O
bp	O
BamHI	B-GENE
-	O
ClaI	B-GENE
fragment	O
revealed	O
that	O
three	O
open	O
reading	O
frames	O
(	O
ORFs	O
)	O
were	O
encoded	O
in	O
the	O
same	O
orientation	O
.	O

The	O
initial	O
inpatient	O
experience	O
for	O
individuals	O
with	O
HIV	O
-	O
related	O
TB	O
may	O
be	O
pivotal	O
to	O
the	O
acceptance	O
of	O
and	O
participation	O
in	O
ongoing	O
TB	O
care	O
.	O

This	O
element	O
,	O
termed	O
CREsp	O
-	O
a	O
(	O
TGACCTCA	O
)	O
,	O
differs	O
by	O
one	O
nucleotide	O
from	O
a	O
palindromic	O
CRE	O
(	O
CREpal	O
,	O
TGACGTCA	O
)	O
,	O
which	O
is	O
known	O
to	O
bind	O
CREB	B-GENE
as	O
a	O
homodimer	O
.	O

Analysis	O
of	O
human	O
genomic	O
DNA	O
reveals	O
an	O
intronless	O
sequence	O
with	O
strong	O
homology	O
to	O
human	B-GENE
G	I-GENE
alpha	I-GENE
q	I-GENE
cDNA	I-GENE
.	O

The	O
complete	O
exon	O
-	O
intron	O
structure	O
of	O
the	O
156	B-GENE
-	I-GENE
kb	I-GENE
human	I-GENE
gene	I-GENE
NFKB1	I-GENE
,	O
which	O
encodes	O
the	O
p105	B-GENE
and	O
p50	B-GENE
proteins	I-GENE
of	O
transcription	O
factors	O
NF	B-GENE
-	I-GENE
kappa	I-GENE
B	I-GENE
and	O
I	B-GENE
kappa	I-GENE
B	I-GENE
-	I-GENE
gamma	I-GENE
:	O
implications	O
for	O
NF	B-GENE
-	I-GENE
kappa	I-GENE
B	I-GENE
-	O
mediated	O
signal	O
transduction	O
.	O

An	O
inverted	O
Alu	B-GENE
repeat	O
element	O
,	O
flanked	O
by	O
nonamer	O
direct	O
repeats	O
,	O
was	O
identified	O
within	O
the	O
region	O
-	O
913	O
/	O
-	O
620	O
,	O
relative	O
to	O
the	O
cap	O
site	O
.	O

Comparison	O
of	O
the	O
amino	O
acid	O
sequences	O
of	O
the	O
RPO1	B-GENE
polypeptides	I-GENE
of	I-GENE
IIV6	I-GENE
,	I-GENE
LCDV	I-GENE
,	I-GENE
and	I-GENE
MCV	I-GENE
-	I-GENE
1	I-GENE
with	O
the	O
corresponding	O
prokaryotic	O
,	O
eukaryotic	O
,	O
and	O
viral	O
proteins	O
revealed	O
differences	O
in	O
amino	O
acid	O
similarity	O
and	O
phylogenetic	O
relationships	O
.	O

The	O
RPO1	B-GENE
of	O
LCDV	O
shows	O
the	O
highest	O
similarity	O
to	O
the	O
RPO1	B-GENE
of	O
IIV6	O
and	O
significant	O
lower	O
similarity	O
to	O
the	O
eukaryotic	B-GENE
polymerases	I-GENE
II	I-GENE
and	I-GENE
III	I-GENE
as	O
well	O
as	O
to	O
the	O
archaebacteral	O
subunit	O
.	O

The	O
use	O
of	O
primary	O
GE	O
cells	O
thus	O
provides	O
a	O
convenient	O
in	O
vitro	O
system	O
for	O
further	O
study	O
of	O
the	O
endocrine	O
,	O
paracrine	O
,	O
and	O
autocrine	O
factors	O
regulating	O
endometrial	O
gene	O
expression	O
during	O
pregnancy	O
.	O

We	O
performed	O
dipole	O
estimation	O
of	O
spikes	O
and	O
SEP	O
components	O
in	O
identical	O
patients	O
.	O

Proximal	O
CBD	O
was	O
inversely	O
correlated	O
with	O
bone	B-GENE
alkaline	I-GENE
phosphatase	I-GENE
(	O
r	O
=	O
-	O
0	O
.	O
71	O
,	O
p	O
<	O
0	O
.	O
01	O
)	O
and	O
intact	O
PTH	B-GENE
(	O
r	O
=	O
-	O
0	O
.	O
59	O
,	O
p	O
<	O
0	O
.	O
05	O
)	O
.	O

In	O
addition	O
,	O
a	O
comparison	O
of	O
the	O
hCHLR	B-GENE
gene	I-GENE
sequences	I-GENE
with	O
available	O
databases	O
indicates	O
that	O
a	O
large	O
portion	O
of	O
these	O
genes	O
,	O
including	O
exons	O
encoding	O
two	O
functional	O
domains	O
of	O
the	O
carboxyl	O
-	O
terminal	O
region	O
of	O
these	O
proteins	O
,	O
has	O
been	O
duplicated	O
as	O
part	O
of	O
a	O
larger	O
human	O
telomeric	O
repeat	O
sequence	O
found	O
on	O
many	O
human	O
chromosomes	O
.	O

We	O
show	O
here	O
that	O
the	O
LIM	B-GENE
domain	I-GENE
homeobox	B-GENE
protein	I-GENE
isl	B-GENE
-	I-GENE
1	I-GENE
activates	O
the	O
rat	B-GENE
amylin	I-GENE
promoter	I-GENE
in	O
both	O
fibroblast	O
and	O
islet	O
cell	O
lines	O
.	O

Although	O
isl	B-GENE
-	I-GENE
1	I-GENE
binds	O
to	O
both	O
the	O
insulin	B-GENE
and	O
amylin	B-GENE
gene	I-GENE
promoter	I-GENE
elements	I-GENE
in	O
vitro	O
,	O
these	O
sequences	O
display	O
marked	O
differences	O
in	O
their	O
relative	O
transcriptional	O
properties	O
when	O
ligated	O
adjacent	O
to	O
a	O
heterologous	O
promoter	O
and	O
transfected	O
into	O
InR1	O
-	O
G9	O
islet	O
cells	O
.	O

It	O
is	O
likely	O
that	O
other	O
pathways	O
involve	O
alternate	O
signal	O
transduction	O
events	O
(	O
e	O
.	O
g	O
.	O
,	O
calcium	O
mobilization	O
)	O
and	O
promoter	O
response	O
elements	O
(	O
e	O
.	O
g	O
.	O
,	O
SRE	O
)	O
.	O

The	O
CD4	B-GENE
count	O
at	O
which	O
remission	O
occurs	O
may	O
reflect	O
severe	O
immunodeficiency	O
such	O
that	O
risk	O
for	O
AIDS	O
-	O
related	O
infection	O
is	O
high	O
.	O

Although	O
diagnostic	O
laparoscopy	O
is	O
still	O
considered	O
the	O
standard	O
reference	O
in	O
the	O
diagnosis	O
of	O
ectopic	O
pregnancy	O
(	O
EP	O
)	O
,	O
use	O
of	O
high	O
-	O
resolution	O
endovaginal	O
sonography	O
,	O
in	O
conjunction	O
with	O
qualitative	O
serum	O
assays	O
of	O
the	O
beta	O
subunit	O
of	O
human	B-GENE
chorionic	I-GENE
gonadotropin	I-GENE
(	O
beta	B-GENE
-	I-GENE
hCG	I-GENE
)	O
,	O
allows	O
detection	O
of	O
earlier	O
and	O
smaller	O
EPs	O
.	O

Bifunctionality	O
of	O
the	O
AcMNPV	B-GENE
homologous	I-GENE
region	I-GENE
sequence	I-GENE
(	O
hr1	B-GENE
)	O
:	O
enhancer	O
and	O
ori	O
functions	O
have	O
different	O
sequence	O
requirements	O
.	O

Neither	O
CES1	B-GENE
nor	O
CES4	B-GENE
is	O
essential	O
for	O
cell	O
growth	O
,	O
and	O
a	O
double	O
deletion	O
mutant	O
is	O
viable	O
.	O

Their	O
use	O
established	O
that	O
the	O
BrAAP	O
activity	O
catalyzed	O
both	O
a	O
postproline	O
and	O
a	O
postglutamate	O
cleavage	O
and	O
therefore	O
has	O
a	O
broader	O
specificity	O
than	O
previously	O
recognized	O
.	O

To	O
explore	O
the	O
functional	O
significance	O
of	O
these	O
subdomains	O
in	O
PRL	B-GENE
binding	O
and	O
signal	O
transduction	O
,	O
deletion	O
mutants	O
of	O
S1	O
or	O
/	O
and	O
S2	O
subdomains	O
were	O
constructed	O
.	O

A	O
stable	O
heterologous	O
cell	O
line	O
containing	O
the	O
mouse	B-GENE
TRH	I-GENE
receptor	I-GENE
was	O
constructed	O
by	O
transfection	O
of	O
nonexcitable	O
293	O
cells	O
,	O
which	O
lack	O
L	O
channel	O
activity	O
.	O

To	O
understand	O
further	O
the	O
expression	O
and	O
regulation	O
of	O
the	O
V1aR	B-GENE
,	O
we	O
now	O
describe	O
the	O
genomic	O
characteristics	O
,	O
tissue	O
expression	O
,	O
chromosomal	O
localization	O
,	O
and	O
regional	O
mapping	O
of	O
the	O
human	B-GENE
V1aR	I-GENE
gene	I-GENE
,	O
AVPR1A	B-GENE
.	O

The	O
final	O
predicted	O
structure	O
has	O
an	O
overall	O
backbone	O
deviation	O
of	O
0	O
.	O
7	O
A	O
from	O
that	O
of	O
ras	B-GENE
-	O
p21	B-GENE
.	O

Genomic	O
organization	O
of	O
the	O
human	B-GENE
beta	I-GENE
-	I-GENE
catenin	I-GENE
gene	I-GENE
(	O
CTNNB1	B-GENE
)	O
.	O

Furthermore	O
,	O
although	O
the	O
regional	O
distribution	O
of	O
lean	O
tissue	O
mass	O
in	O
the	O
trunk	O
and	O
legs	O
remained	O
fairly	O
constant	O
at	O
different	O
pubertal	O
stages	O
,	O
the	O
regional	O
distribution	O
of	O
fat	O
was	O
altered	O
significantly	O
,	O
becoming	O
more	O
central	O
and	O
less	O
peripheral	O
.	O

Thus	O
,	O
the	O
predicted	O
CD30v	B-GENE
protein	I-GENE
retains	O
most	O
of	O
the	O
cytoplasmic	O
region	O
,	O
but	O
lacks	O
the	O
extracellular	O
and	O
transmembrane	O
domains	O
.	O

Constitutive	O
phosphorylation	O
of	O
the	O
CD30v	B-GENE
protein	I-GENE
was	O
demonstrated	O
by	O
in	O
vitro	O
labeling	O
with	O
[	O
32P	O
]	O
.	O

17	O
.	O
5	O
%	O
of	O
cycles	O
)	O
.	O

We	O
report	O
here	O
the	O
discovery	O
of	O
a	O
new	O
actin	B-GENE
-	I-GENE
related	I-GENE
gene	I-GENE
in	O
this	O
organism	O
,	O
which	O
we	O
have	O
named	O
ACT4	B-GENE
.	O

Two	O
of	O
the	O
ORFs	O
are	O
completely	O
internal	O
to	O
longer	O
ones	O
and	O
a	O
third	O
is	O
partially	O
embedded	O
in	O
G2850	B-GENE
.	O

MVR	O
typing	O
of	O
rare	O
-	O
length	O
alleles	O
indicates	O
that	O
they	O
are	O
comprised	O
of	O
disorganized	O
sequences	O
,	O
although	O
they	O
usually	O
bear	O
a	O
resemblance	O
to	O
one	O
of	O
the	O
common	O
alleles	O
at	O
the	O
5	O
'	O
-	O
most	O
end	O
.	O

Plasmid	O
pAL618	O
contains	O
the	O
genetic	O
determinants	O
for	O
H2	O
uptake	O
(	O
hup	B-GENE
)	O
from	O
Rhizobium	O
leguminosarum	O
bv	O
.	O
viciae	O
,	O
including	O
a	O
cluster	O
of	O
17	O
genes	O
named	O
hupSLCDEFGHIJK	B-GENE
-	I-GENE
hypABFCDE	I-GENE
.	O

An	O
open	O
-	O
label	O
,	O
placebo	O
-	O
controlled	O
,	O
randomized	O
,	O
two	O
-	O
way	O
crossover	O
study	O
was	O
performed	O
in	O
12	O
healthy	O
volunteers	O
(	O
between	O
20	O
and	O
44	O
years	O
of	O
age	O
)	O
to	O
assess	O
the	O
effect	O
of	O
orlistat	O
,	O
a	O
gastrointestinal	B-GENE
lipase	I-GENE
inhibitor	O
that	O
reduces	O
dietary	O
fat	O
absorption	O
and	O
is	O
being	O
developed	O
for	O
weight	O
control	O
in	O
obesity	O
,	O
on	O
the	O
absorption	O
of	O
vitamins	O
A	O
and	O
E	O
.	O

Tilmicosin	O
is	O
a	O
novel	O
macrolide	O
antibiotic	O
developed	O
for	O
exclusive	O
use	O
in	O
veterinary	O
medicine	O
.	O

Effect	O
of	O
nitrous	O
oxide	O
(	O
N2O	O
)	O
on	O
the	O
somatosympathetic	O
A	O
-	O
and	O
C	O
-	O
reflexes	O
was	O
investigated	O
using	O
artificially	O
ventilated	O
rats	O
anesthetized	O
with	O
alpha	O
-	O
chloralose	O
and	O
urethane	O
.	O

Restriction	O
enzyme	O
mapping	O
and	O
Southern	O
analysis	O
indicated	O
further	O
that	O
the	O
human	B-GENE
MZF	I-GENE
-	I-GENE
1	I-GENE
gene	I-GENE
is	O
a	O
single	O
-	O
copy	O
gene	O
.	O

In	O
the	O
absence	O
of	O
Swi4	B-GENE
and	O
Swi6	B-GENE
cell	O
viability	O
is	O
lost	O
,	O
but	O
can	O
be	O
regained	O
by	O
ectopic	O
expression	O
of	O
the	O
G1	B-GENE
cyclin	I-GENE
encoding	I-GENE
genes	I-GENE
,	O
CLN1	B-GENE
or	O
CLN2	B-GENE
.	O

The	O
detection	O
ratio	O
peaked	O
at	O
ages	O
30	O
to	O
34	O
and	O
decreased	O
heavily	O
during	O
the	O
next	O
15	O
years	O
of	O
age	O
.	O

How	O
many	O
embryos	O
to	O
transfer	O
in	O
patients	O
undergoing	O
IVF	O
?	O

The	O
nonconsensus	O
TATA	O
box	O
in	O
promoter	O
B	O
plays	O
a	O
more	O
important	O
role	O
in	O
promoter	O
activity	O
than	O
the	O
TATA	O
box	O
in	O
promoter	O
A	O
.	O

These	O
properties	O
indicate	O
that	O
Gle1	B-GENE
is	O
an	O
RNA	O
-	O
export	O
factor	O
and	O
that	O
Rev	B-GENE
may	O
mediate	O
viral	O
RNA	O
export	O
by	O
mimicking	O
the	O
function	O
of	O
Gle1	B-GENE
.	O

Demispan	O
is	O
a	O
reliable	O
and	O
reproducible	O
measure	O
of	O
stature	O
in	O
the	O
elderly	O
.	O

Two	O
techniques	O
based	O
on	O
assay	O
coefficients	O
of	O
variation	O
were	O
employed	O
to	O
characterize	O
a	O
normal	O
circadian	O
pattern	O
of	O
cortisol	O
.	O

A	O
system	O
is	O
described	O
in	O
which	O
the	O
volume	O
flow	O
rate	O
of	O
blood	O
in	O
a	O
vessel	O
is	O
determined	O
using	O
transverse	O
colour	O
Doppler	O
ultrasound	O
imaging	O
.	O

The	O
enzyme	O
activities	O
studied	O
are	O
important	O
elements	O
in	O
the	O
pathophysiology	O
of	O
dental	O
caries	O
and	O
may	O
even	O
be	O
addressed	O
as	O
virulence	O
factors	O
.	O

In	O
lean	O
mice	O
,	O
the	O
fat	O
/	O
water	O
intensity	O
ratio	O
was	O
about	O
1	O
:	O
4	O
,	O
about	O
half	O
that	O
in	O
normal	O
mice	O
.	O

Pharmacokinetic	O
parameters	O
were	O
similar	O
to	O
values	O
given	O
in	O
the	O
literature	O
for	O
intravenous	O
(	O
IV	O
)	O
or	O
intraarterial	O
(	O
IA	O
)	O
bolus	O
MMC	O
injections	O
(	O
Tmax	O
=	O
7	O
.	O
0	O
min	O
following	O
the	O
beginning	O
of	O
MMC	O
infusion	O
,	O
Vss	O
=	O
0	O
.	O
57	O
1	O
/	O
kg	O
,	O
C1	O
=	O
8	O
.	O
9	O
ml	O
/	O
min	O
.	O
kg	O
,	O
T1	O
/	O
2	O
alpha	O
=	O
8	O
.	O
3	O
min	O
,	O
T1	O
/	O
2	O
beta	O
=	O
58	O
.	O
6	O
min	O
)	O
.	O

In	O
this	O
study	O
,	O
we	O
identified	O
four	O
distinct	O
E2F	B-GENE
complexes	I-GENE
present	O
in	O
aged	O
and	O
senescent	O
normal	O
,	O
human	O
diploid	O
fibroblasts	O
.	O

This	O
paper	O
gives	O
an	O
overview	O
of	O
the	O
global	O
pattern	O
of	O
casualties	O
in	O
earthquakes	O
which	O
occurred	O
during	O
the	O
30	O
-	O
month	O
period	O
from	O
1	O
September	O
1993	O
to	O
29	O
February	O
1996	O
.	O

If	O
we	O
apply	O
the	O
finding	O
of	O
non	O
-	O
visualization	O
of	O
the	O
GB	O
at	O
4	O
h	O
post	O
injection	O
as	O
the	O
criterion	O
for	O
the	O
diagnosis	O
of	O
AC	O
,	O
the	O
diagnostic	O
accuracy	O
was	O
only	O
40	O
.	O
7	O
%	O
(	O
11	O
/	O
27	O
)	O
.	O

Alternative	O
processing	O
of	O
the	O
tryptophanyl	B-GENE
-	I-GENE
tRNA	I-GENE
synthetase	I-GENE
mRNA	I-GENE
from	O
interferon	B-GENE
-	O
treated	O
human	O
cells	O
.	O

Evidence	O
for	O
the	O
promoting	O
role	O
of	O
the	O
intra	B-GENE
-	I-GENE
uterine	I-GENE
kinin	I-GENE
release	O
in	O
the	O
development	O
of	O
late	O
hypertonic	O
saline	O
-	O
induced	O
abortion	O
.	O

This	O
GAP	B-GENE
activity	O
was	O
observed	O
in	O
3T3	O
-	O
L1	O
adipocyte	O
lysates	O
,	O
and	O
was	O
able	O
to	O
accelerate	O
the	O
hydrolysis	O
of	O
the	O
[	O
alpha	O
-	O
32P	O
]	O
GTP	O
bound	O
to	O
GST	B-GENE
-	O
Rab4	B-GENE
into	O
[	O
alpha	O
-	O
32P	O
]	O
GDP	O
.	O

CONCLUSION	O
:	O
During	O
chronic	O
treatment	O
,	O
the	O
haemodynamic	O
response	O
to	O
oral	O
cilazapril	O
was	O
attenuated	O
,	O
indicating	O
that	O
continued	O
clinical	O
improvement	O
in	O
patients	O
with	O
CHF	O
on	O
CLZ	O
is	O
independent	O
of	O
to	O
its	O
acute	O
haemodynamic	O
effects	O
.	O

We	O
conclude	O
that	O
,	O
in	O
AIDS	O
patients	O
with	O
cryptococcosis	O
,	O
tolerance	O
to	O
ILd	O
-	O
AmB	O
was	O
acceptable	O
when	O
the	O
daily	O
dosage	O
did	O
not	O
exceed	O
1	O
mg	O
/	O
kg	O
,	O
but	O
the	O
higher	O
1	O
.	O
5	O
mg	O
/	O
kg	O
daily	O
dosage	O
was	O
associated	O
with	O
an	O
unacceptable	O
rate	O
of	O
nephrotoxicity	O
.	O

Moreover	O
,	O
the	O
second	O
RCC1	B-GENE
-	I-GENE
like	I-GENE
motif	I-GENE
located	O
at	O
the	O
amino	O
-	O
terminus	O
of	O
p619	B-GENE
stimulates	O
guanine	O
nucleotide	O
exchange	O
on	O
ARF1	B-GENE
and	O
on	O
members	O
of	O
the	O
related	O
Rab	B-GENE
proteins	I-GENE
,	O
but	O
not	O
on	O
other	O
small	B-GENE
GTP	I-GENE
binding	I-GENE
proteins	I-GENE
such	O
as	O
Ran	B-GENE
or	O
R	B-GENE
-	I-GENE
Ras2	I-GENE
/	O
TC21	B-GENE
.	O

The	O
reconstituted	O
RNA	B-GENE
polymerases	I-GENE
containing	O
the	O
mutant	O
alpha	O
subunits	O
were	O
examined	O
for	O
their	O
response	O
to	O
transcription	O
activation	O
by	O
cAMP	B-GENE
-	I-GENE
CRP	I-GENE
and	O
the	O
rrnBP1	B-GENE
UP	I-GENE
element	I-GENE
.	O

Transcription	O
factor	O
recognition	O
surface	O
on	O
the	O
RNA	B-GENE
polymerase	I-GENE
alpha	I-GENE
subunit	I-GENE
is	O
involved	O
in	O
contact	O
with	O
the	O
DNA	O
enhancer	O
element	O
.	O

Consistent	O
with	O
this	O
similarity	O
,	O
the	O
cdc28	B-GENE
-	O
P8	O
mutant	O
accumulates	O
unspliced	O
precursors	O
at	O
the	O
restrictive	O
temperature	O
.	O

A	O
decrease	O
of	O
erythrocyte	O
Mn	O
with	O
age	O
,	O
expressed	O
in	O
nmol	O
/	O
L	O
,	O
was	O
noted	O
(	O
p	O
<	O
0	O
.	O
02	O
)	O
.	O

Cloning	O
and	O
sequence	O
analyses	O
revealed	O
a	O
second	O
cDNA	O
with	O
a	O
95	O
-	O
nt	O
deletion	O
in	O
the	O
region	O
coding	O
for	O
the	O
putative	O
second	O
intracellular	O
loop	O
and	O
the	O
fourth	O
transmembrane	O
domain	O
of	O
the	O
5	B-GENE
-	I-GENE
HT2C	I-GENE
-	I-GENE
R	I-GENE
.	O

Expression	O
of	O
thymidine	B-GENE
kinase	I-GENE
gene	I-GENE
in	O
normal	O
human	O
diploid	O
cells	O
is	O
both	O
cell	O
cycle	O
-	O
and	O
age	O
-	O
dependent	O
and	O
appears	O
to	O
be	O
transcriptionally	O
regulated	O
.	O

The	O
minimum	O
inhibitory	O
concentrations	O
(	O
MICs	O
)	O
of	O
ketoconazole	O
,	O
miconazole	O
,	O
itraconazole	O
,	O
fluconazole	O
,	O
and	O
amphotericin	O
B	O
were	O
significantly	O
influenced	O
by	O
the	O
inoculum	O
size	O
,	O
regardless	O
of	O
the	O
techniques	O
used	O
.	O

These	O
bacteria	O
produce	O
and	O
export	O
proteins	O
capable	O
of	O
specific	O
interactions	O
with	O
key	O
mammalian	O
cell	O
regulatory	O
molecules	O
in	O
order	O
to	O
derail	O
the	O
normal	O
functions	O
of	O
the	O
cells	O
.	O

Thus	O
,	O
although	O
p28	B-GENE
may	O
play	O
only	O
a	O
limited	O
role	O
during	O
the	O
early	O
embryonic	O
cleavages	O
,	O
it	O
may	O
function	O
later	O
in	O
development	O
to	O
establish	O
a	O
somatic	O
type	O
of	O
cell	O
cycle	O
.	O

The	O
main	O
aim	O
of	O
the	O
contribution	O
,	O
which	O
opens	O
an	O
arena	O
for	O
discussion	O
on	O
the	O
Rivista	O
dell	O
'	O
Infermiere	O
is	O
to	O
critically	O
appraise	O
published	O
research	O
works	O
focusing	O
both	O
on	O
strengths	O
and	O
novelty	O
and	O
weaknesses	O
in	O
the	O
hypothesis	O
formulation	O
,	O
methods	O
and	O
instruments	O
used	O
,	O
discussion	O
of	O
results	O
.	O

Moreover	O
,	O
it	O
also	O
discusses	O
the	O
effects	O
of	O
antihypertensive	O
drugs	O
currently	O
regarded	O
as	O
first	O
-	O
choice	O
agents	O
,	O
i	O
.	O
e	O
.	O
calcium	O
antagonists	O
and	O
the	O
angiotensin	B-GENE
converting	I-GENE
enzyme	I-GENE
inhibitors	O
,	O
on	O
intrarenal	O
hemodynamics	O
.	O

It	O
is	O
suggested	O
that	O
the	O
observed	O
clinical	O
phenomena	O
in	O
response	O
to	O
morphine	O
can	O
be	O
explained	O
by	O
differences	O
in	O
expression	O
and	O
sensitivity	O
of	O
some	O
opioid	B-GENE
receptor	I-GENE
subtypes	O
in	O
migraine	O
.	O

Previous	O
studies	O
demonstrated	O
that	O
the	O
flavin	B-GENE
-	I-GENE
containing	I-GENE
monooxygenases	I-GENE
(	O
FMO	B-GENE
)	O
are	O
expressed	O
in	O
a	O
tissue	O
-	O
specific	O
manner	O
.	O

Thus	O
,	O
despite	O
the	O
potential	O
for	O
common	O
regulatory	O
mechanisms	O
,	O
the	O
available	O
evidence	O
indicates	O
that	O
the	O
Mtx	B-GENE
minimal	I-GENE
promoter	I-GENE
does	O
not	O
significantly	O
affect	O
Thbs3	B-GENE
gene	I-GENE
expression	O
.	O

MSSP	B-GENE
proteins	I-GENE
have	O
been	O
identified	O
by	O
their	O
binding	O
to	O
an	O
upstream	O
element	O
of	O
c	B-GENE
-	I-GENE
myc	I-GENE
.	O

Gene	B-GENE
1	I-GENE
has	O
been	O
completely	O
sequenced	O
.	O

B	B-GENE
cell	I-GENE
antigen	I-GENE
receptor	I-GENE
(	O
BCR	B-GENE
)	O
-	O
induced	O
apoptosis	O
in	O
the	O
WEHI	O
-	O
231	O
B	O
lymphoma	O
cell	O
line	O
can	O
be	O
prevented	O
by	O
engaging	O
CD40	B-GENE
.	O

Both	O
alleles	O
are	O
functionally	O
expressed	O
and	O
are	O
distributed	O
within	O
CD4	B-GENE
+	O
/	O
CD8	B-GENE
+	O
T	O
cell	O
subsets	O
.	O

The	O
deduced	O
amino	O
acid	O
sequence	O
of	O
LvUSF2	B-GENE
is	O
nearly	O
identical	O
to	O
LvUSF1	B-GENE
except	O
at	O
the	O
amino	O
end	O
,	O
where	O
they	O
are	O
sharply	O
divergent	O
.	O

ECM	O
disruption	O
in	O
Lytechinus	O
embryos	O
caused	O
a	O
relative	O
drop	O
in	O
USF	B-GENE
RNA	I-GENE
accumulation	O
levels	O
to	O
approximately	O
60	O
%	O
of	O
control	O
embryos	O
,	O
while	O
LpS1	B-GENE
RNA	I-GENE
accumulation	O
levels	O
dropped	O
to	O
less	O
than	O
5	O
%	O
.	O

Five	O
of	O
these	O
eight	O
patients	O
in	O
group	O
II	O
also	O
received	O
8	O
-	O
in	O
-	O
1	O
chemotherapy	O
.	O

Sixty	O
days	O
after	O
the	O
intervention	O
,	O
twitch	O
and	O
tetanic	O
tensions	O
remained	O
dependent	O
upon	O
the	O
extracellular	O
Ca2	O
+	O
concentration	O
(	O
[	O
Ca	O
]	O
o	O
)	O
both	O
in	O
groups	O
A	O
and	O
B	O
.	O

Recently	O
,	O
a	O
distantly	O
related	O
UmuC	B-GENE
-	I-GENE
homolog	I-GENE
,	O
DinB	B-GENE
,	O
has	O
also	O
been	O
identified	O
in	O
E	O
.	O
coli	O
.	O

To	O
study	O
the	O
regulation	O
of	O
mdr2	B-GENE
expression	O
,	O
the	O
promoter	O
of	O
the	O
mdr2	B-GENE
gene	I-GENE
has	O
been	O
isolated	O
from	O
a	O
murine	O
vinblastine	O
-	O
resistant	O
cell	O
line	O
,	O
J7	O
.	O
V2	O
-	O
1	O
,	O
and	O
characterized	O
.	O

The	O
amplification	O
was	O
achieved	O
using	O
two	O
primers	O
which	O
correspond	O
to	O
TRH	B-GENE
progenitor	I-GENE
sequence	I-GENE
(	O
Lys	O
/	O
Arg	O
-	O
Arg	O
-	O
Gln	O
-	O
His	O
-	O
Pro	O
-	O
Gly	O
-	O
Lys	O
/	O
Arg	O
-	O
Arg	O
)	O
.	O

The	O
intranodal	O
mesothelial	O
cells	O
occupied	O
the	O
sinusoids	O
of	O
the	O
lymph	O
nodes	O
and	O
were	O
initially	O
suspected	O
of	O
being	O
metastatic	O
from	O
the	O
ovarian	O
tumor	O
in	O
each	O
case	O
.	O

The	O
gene	B-GENE
ccpA	I-GENE
encoding	O
the	O
catabolite	B-GENE
control	I-GENE
protein	I-GENE
CcpA	I-GENE
of	O
Staphylococcus	O
xylosus	O
has	O
been	O
cloned	O
and	O
characterized	O
.	O

An	O
InlC	B-GENE
deletion	I-GENE
mutant	I-GENE
shows	O
reduced	O
virulence	O
when	O
tested	O
in	O
an	O
intravenous	O
mouse	O
model	O
,	O
but	O
intracellular	O
replication	O
of	O
the	O
mutant	O
in	O
Caco	O
-	O
2	O
and	O
J774	O
cells	O
appears	O
to	O
be	O
comparable	O
with	O
that	O
of	O
the	O
wild	O
-	O
type	O
strain	O
.	O

Thus	O
,	O
the	O
N	B-GENE
-	O
Nus	B-GENE
complex	O
may	O
be	O
affected	O
through	O
contacts	O
with	O
the	O
CTD	O
of	O
the	O
alpha	O
subunit	O
of	O
RNA	B-GENE
polymerase	I-GENE
,	O
as	O
is	O
a	O
group	O
of	O
regulatory	O
proteins	O
that	O
influences	O
initiation	O
of	O
transcription	O
.	O

Administration	O
of	O
RIFA	O
at	O
200	O
mg	O
/	O
kg	O
/	O
day	O
in	O
combination	O
with	O
ATO	O
at	O
100	O
mg	O
/	O
kg	O
/	O
day	O
resulted	O
in	O
a	O
marked	O
prolongation	O
of	O
survival	O
compared	O
with	O
that	O
for	O
mice	O
that	O
received	O
ATO	O
or	O
RIFA	O
alone	O
.	O

Two	O
of	O
seven	O
initiation	O
sites	O
were	O
flanked	O
by	O
a	O
sequence	O
homologous	O
to	O
the	O
consensus	O
promoter	O
motif	O
that	O
includes	O
the	O
CRTA	O
motif	O
(	O
where	O
R	O
is	O
A	O
or	O
G	O
)	O
of	O
the	O
rice	O
mitochondrion	O
.	O

Selection	O
using	O
SC	O
EPD	O
was	O
more	O
effective	O
than	O
phenotypic	O
selection	O
in	O
reducing	O
age	O
at	O
puberty	O
in	O
daughters	O
.	O

Sodium	O
polystyrene	O
sulfonate	O
treatment	O
for	O
lithium	O
toxicity	O
:	O
effects	O
on	O
serum	O
potassium	O
concentrations	O
.	O

The	O
mammalian	B-GENE
homeodomain	I-GENE
proteins	I-GENE
encoded	O
by	O
Hox	B-GENE
genes	I-GENE
play	O
an	O
important	O
role	O
in	O
embryonic	O
development	O
by	O
providing	O
positional	O
queues	O
which	O
define	O
developmental	O
identities	O
along	O
the	O
anteroposterior	O
axis	O
of	O
developing	O
organisms	O
.	O

Interferon	B-GENE
stimulated	I-GENE
gene	I-GENE
factor	I-GENE
3	I-GENE
(	O
ISGF3	B-GENE
)	O
is	O
a	O
trimeric	O
transcription	O
factor	O
activated	O
on	O
treatment	O
of	O
cells	O
with	O
interferon	B-GENE
-	I-GENE
alpha	I-GENE
and	I-GENE
beta	I-GENE
(	O
type	B-GENE
I	I-GENE
IFNs	I-GENE
)	O
.	O

The	O
TYAC	O
/	O
P1	O
resource	O
,	O
derivative	O
STSs	O
,	O
and	O
polymorphisms	O
constitute	O
an	O
enabling	O
resource	O
to	O
further	O
studies	O
of	O
telomere	O
structure	O
and	O
function	O
and	O
a	O
means	O
for	O
physical	O
and	O
genetic	O
map	O
integration	O
and	O
closure	O
.	O

Confirmatory	O
statistics	O
included	O
item	O
2	O
of	O
the	O
Clinical	O
Global	O
Impression	O
(	O
CGI	O
)	O
,	O
the	O
total	O
score	O
of	O
the	O
Sandoz	O
Clinical	O
Assessment	O
Geriatric	O
(	O
SCAG	O
)	O
scale	O
,	O
the	O
subscale	O
'	O
need	O
for	O
help	O
'	O
of	O
the	O
nurse	O
'	O
s	O
rating	O
of	O
geriatric	O
patients	O
(	O
Beurteilungsskala	O
fur	O
geriatrische	O
Patienten	O
;	O
BGP	O
)	O
and	O
the	O
total	O
score	O
of	O
the	O
Short	O
Cognitive	O
Performance	O
Test	O
(	O
Syndrom	O
-	O
Kurztest	O
;	O
SKT	O
)	O
.	O

Three	O
mutants	O
were	O
isolated	O
from	O
the	O
widely	O
used	O
strain	O
,	O
PAO1	O
.	O

As	O
extensively	O
examined	O
with	O
the	O
myogenin	B-GENE
promoter	I-GENE
,	O
presence	O
of	O
one	O
or	O
multiple	O
copies	O
of	O
Me	B-GENE
in	O
the	O
vectors	O
elevated	O
the	O
expression	O
activity	O
in	O
myotubes	O
by	O
4	O
.	O
5	O
-	O
to	O
19	O
-	O
fold	O
over	O
those	O
without	O
Me	B-GENE
,	O
but	O
not	O
significantly	O
in	O
myoblasts	O
.	O

We	O
conclude	O
that	O
common	O
upstream	O
signals	O
cause	O
activation	O
of	O
Ras	B-GENE
and	O
TC21	B-GENE
,	O
but	O
activated	O
TC21	B-GENE
controls	O
cell	O
growth	O
via	O
distinct	O
Raf	B-GENE
-	O
independent	O
downstream	O
signaling	O
pathways	O
.	O

Fission	B-GENE
yeast	I-GENE
mal2	I-GENE
+	I-GENE
is	O
required	O
for	O
chromosome	O
segregation	O
.	O

Selection	O
was	O
based	O
on	O
expression	O
of	O
an	O
integrated	O
DNA	O
fragment	O
containing	O
the	O
con	B-GENE
-	I-GENE
10	I-GENE
promoter	I-GENE
-	I-GENE
regulatory	I-GENE
region	I-GENE
followed	O
by	O
the	O
initial	O
segment	O
of	O
the	O
con	B-GENE
-	I-GENE
10	I-GENE
open	I-GENE
reading	I-GENE
frame	I-GENE
fused	O
in	O
frame	O
with	O
the	O
bacterial	B-GENE
hygromycin	I-GENE
B	I-GENE
phosphotransferase	I-GENE
structural	I-GENE
gene	I-GENE
(	O
con10	B-GENE
'	I-GENE
-	I-GENE
'	I-GENE
hph	I-GENE
)	O
.	O

Mutations	O
at	O
two	O
neighboring	O
sites	O
,	O
serine	O
242	O
and	O
threonine	O
255	O
,	O
exacerbated	O
the	O
effect	O
.	O

IRF	B-GENE
-	I-GENE
1	I-GENE
acts	O
as	O
a	O
transcriptional	O
activator	O
,	O
while	O
IRF	B-GENE
-	I-GENE
2	I-GENE
acts	O
as	O
a	O
repressor	O
.	O

In	O
contrast	O
,	O
cotransfection	O
of	O
TFIIB	B-GENE
and	O
IRF	B-GENE
-	I-GENE
1	I-GENE
into	O
NIH	O
3T3	O
cells	O
resulted	O
in	O
a	O
dose	O
-	O
dependent	O
repression	O
of	O
promoter	O
activation	O
which	O
occurred	O
in	O
a	O
TATA	O
-	O
dependent	O
manner	O
.	O

The	O
requirement	O
of	O
Tyr	O
-	O
19	O
dephosphorylation	O
for	O
spindle	O
assembly	O
is	O
also	O
observed	O
under	O
conditions	O
in	O
which	O
spindle	O
formation	O
is	O
independent	O
of	O
mitosis	O
,	O
suggesting	O
that	O
the	O
involvement	O
of	O
Cdc28	B-GENE
/	O
Clb	B-GENE
kinase	O
in	O
SPB	O
separation	O
is	O
direct	O
.	O

Expression	O
of	O
the	O
proapoptotic	B-GENE
protein	I-GENE
Bax	I-GENE
under	O
the	O
control	O
of	O
a	O
GAL10	B-GENE
promoter	I-GENE
in	O
Saccharomyces	O
cerevisiae	O
resulted	O
in	O
galactose	O
-	O
inducible	O
cell	O
death	O
.	O

This	O
technique	O
was	O
employed	O
in	O
12	O
patients	O
with	O
a	O
unicameral	O
bone	O
cyst	O
.	O

The	O
amino	O
-	O
terminal	O
region	O
of	O
E1A	B-GENE
binds	O
several	O
high	O
molecular	O
weight	O
proteins	O
and	O
inhibits	O
the	O
transcriptional	O
coactivator	O
function	O
of	O
p300	B-GENE
and	O
the	O
homologous	O
cAMP	B-GENE
response	I-GENE
element	I-GENE
(	I-GENE
CRE	I-GENE
)	I-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
.	O

Transient	O
transfection	O
assays	O
using	O
reporter	O
gene	O
constructs	O
containing	O
various	O
lengths	O
of	O
the	O
5	B-GENE
'	I-GENE
mdr1b	I-GENE
sequences	I-GENE
revealed	O
that	O
the	O
sequence	O
located	O
between	O
-	O
247	O
to	O
-	O
126	O
bp	O
was	O
important	O
for	O
the	O
expression	O
of	O
the	O
reporter	O
gene	O
in	O
many	O
different	O
cell	O
lines	O
.	O

We	O
show	O
that	O
the	O
5	O
'	O
UTR	O
characteristic	O
of	O
testis	B-GENE
-	I-GENE
specific	I-GENE
c	I-GENE
-	I-GENE
mos	I-GENE
mRNA	I-GENE
strongly	O
represses	O
translation	O
relative	O
to	O
the	O
translation	O
of	O
transcripts	O
that	O
contain	O
a	O
5	O
'	O
UTR	O
derived	O
from	O
beta	B-GENE
-	I-GENE
globin	I-GENE
mRNA	I-GENE
,	O
and	O
this	O
is	O
mainly	O
due	O
to	O
the	O
four	O
uORFs	O
.	O

To	O
address	O
the	O
biological	O
effect	O
of	O
specific	O
isoform	O
expression	O
,	O
NIH3T3	O
cells	O
were	O
transfected	O
with	O
a	O
eukaryotic	O
expression	O
vector	O
containing	O
cDNA	O
for	O
FGF8a	B-GENE
,	O
FGF8b	B-GENE
,	O
or	O
FGF8e	B-GENE
.	O

These	O
findings	O
suggest	O
that	O
the	O
F	O
-	O
wave	O
may	O
be	O
elicited	O
in	O
motoneuron	O
of	O
different	O
depolarization	O
threshold	O
but	O
primarily	O
in	O
larger	O
and	O
faster	O
nerve	O
fibers	O
,	O
with	O
a	O
lower	O
threshold	O
of	O
depolarization	O
.	O

In	O
addition	O
,	O
carp	B-GENE
JAK1	I-GENE
shows	O
higher	O
sequence	O
homology	O
to	O
mammalian	B-GENE
JAK1	I-GENE
in	O
both	O
the	O
kinase	O
-	O
like	O
(	O
JH2	B-GENE
)	O
and	O
kinase	O
(	O
JH1	B-GENE
)	O
domains	O
(	O
approximately	O
70	O
%	O
identity	O
)	O
.	O

When	O
this	O
DNA	O
fragment	O
was	O
placed	O
upstream	O
of	O
the	O
chloramphenicol	B-GENE
acetyltransferase	I-GENE
(	O
CAT	B-GENE
)	O
reporter	O
gene	O
and	O
transfected	O
into	O
a	O
carp	O
CF	O
cell	O
line	O
,	O
it	O
could	O
drive	O
the	O
synthesis	O
of	O
CAT	B-GENE
enzyme	I-GENE
16	O
times	O
more	O
efficiently	O
than	O
the	O
promoterless	O
pCAT	B-GENE
-	I-GENE
Basic	I-GENE
.	O

Molecular	O
cloning	O
of	O
Elk	B-GENE
-	I-GENE
3	I-GENE
,	O
a	O
new	O
member	O
of	O
the	O
Ets	B-GENE
family	I-GENE
expressed	O
during	O
mouse	O
embryogenesis	O
and	O
analysis	O
of	O
its	O
transcriptional	O
repression	O
activity	O
.	O

We	O
report	O
an	O
example	O
of	O
an	O
MDV	O
-	O
transformed	O
T	O
-	O
lymphoblastoid	O
cell	O
line	O
(	O
T9	O
)	O
expressing	O
high	O
levels	O
of	O
a	O
truncated	B-GENE
C	I-GENE
-	I-GENE
MYB	I-GENE
protein	I-GENE
as	O
a	O
result	O
of	O
RAV	O
integration	O
within	O
one	O
c	B-GENE
-	I-GENE
myb	I-GENE
allele	I-GENE
.	O

Frozen	O
/	O
thawed	O
extensor	O
digitorum	O
longus	O
muscle	O
tendon	O
units	O
had	O
significantly	O
lower	O
values	O
for	O
load	O
to	O
failure	O
(	O
p	O
<	O
0	O
.	O
01	O
)	O
,	O
energy	O
absorbed	O
to	O
failure	O
(	O
p	O
<	O
0	O
.	O
01	O
)	O
,	O
and	O
strain	O
at	O
failure	O
(	O
p	O
<	O
0	O
.	O
01	O
)	O
,	O
and	O
they	O
tended	O
to	O
fail	O
at	O
a	O
different	O
anatomic	O
location	O
(	O
p	O
<	O
0	O
.	O
01	O
)	O
(	O
broadly	O
at	O
the	O
fascia	O
-	O
muscle	O
interface	O
as	O
compared	O
with	O
horizontally	O
at	O
the	O
musculotendinous	O
junction	O
)	O
than	O
fresh	O
units	O
.	O

Northern	O
analysis	O
of	O
the	O
3	B-GENE
.	I-GENE
1	I-GENE
-	I-GENE
kb	I-GENE
PWP2H	I-GENE
cDNA	I-GENE
revealed	O
that	O
a	O
3	O
.	O
3	O
-	O
kb	O
major	O
transcript	O
is	O
ubiquitously	O
expressed	O
in	O
human	O
adult	O
tissues	O
.	O

Forty	O
-	O
eight	O
10	O
-	O
12	O
-	O
week	O
-	O
old	O
male	O
Sprague	O
-	O
Dawley	O
rats	O
were	O
randomized	O
to	O
receive	O
,	O
daily	O
for	O
28	O
days	O
:	O
(	O
1	O
)	O
CsA	O
vehicle	O
p	O
.	O
o	O
.	O
plus	O
FB	O
vehicle	O
sc	O
;	O
(	O
2	O
)	O
CsA	O
(	O
15	O
mg	O
/	O
kg	O
)	O
p	O
.	O
o	O
.	O
plus	O
FB	O
vehicle	O
sc	O
,	O
(	O
3	O
)	O
CsA	O
vehicle	O
p	O
.	O
o	O
.	O
plus	O
FB	O
(	O
1	O
.	O
5	O
mg	O
/	O
kg	O
)	O
sc	O
;	O
and	O
(	O
4	O
)	O
CsA	O
(	O
15	O
mg	O
/	O
kg	O
)	O
p	O
.	O
o	O
.	O
plus	O
FB	O
(	O
1	O
.	O
5	O
mg	O
/	O
kg	O
)	O
sc	O
.	O

CsA	O
alone	O
resulted	O
in	O
elevated	O
bone	O
turnover	O
.	O

Individuals	O
attending	O
the	O
GUM	O
Department	O
in	O
the	O
Royal	O
Infirmary	O
of	O
Edinburgh	O
between	O
1990	O
and	O
1994	O
with	O
the	O
diagnosis	O
of	O
HIV	O
infection	O
,	O
genital	O
warts	O
,	O
genital	O
herpes	O
,	O
non	O
-	O
specific	O
genital	O
infection	O
(	O
NSGI	O
)	O
,	O
gonorrhoea	O
and	O
syphilis	O
were	O
included	O
in	O
the	O
study	O
.	O

Northern	O
blotting	O
showed	O
that	O
MDMX	B-GENE
,	O
like	O
MDM2	B-GENE
,	O
is	O
expressed	O
in	O
all	O
tissues	O
tested	O
,	O
and	O
that	O
several	O
mRNAs	O
for	O
MDMX	B-GENE
can	O
be	O
detected	O
.	O

The	O
nucleotide	O
sequence	O
of	O
22	O
,	O
846	O
bp	O
of	O
the	O
left	O
arm	O
of	O
chromosome	O
IV	O
is	O
described	O
.	O

Natural	O
FL	B-GENE
protein	I-GENE
has	O
been	O
purified	O
from	O
a	O
stromal	O
cell	O
line	O
and	O
shown	O
to	O
be	O
a	O
65	O
kD	O
nondisulfide	O
-	O
linked	O
homodimeric	O
glycoprotein	O
comprised	O
of	O
30	O
kD	O
subunits	O
,	O
each	O
containing	O
12	O
kD	O
of	O
N	O
-	O
and	O
O	O
-	O
linked	O
sugars	O
.	O

The	O
objective	O
of	O
this	O
study	O
was	O
to	O
examine	O
the	O
influence	O
of	O
HHCA	O
and	O
other	O
serological	O
factors	O
upon	O
the	O
development	O
of	O
VGS	O
.	O

Spliced	O
exons	O
of	O
adenovirus	O
late	O
RNAs	O
colocalize	O
with	O
snRNP	O
in	O
a	O
specific	O
nuclear	O
domain	O
.	O

Using	O
Spurr	O
'	O
s	O
resin	O
as	O
a	O
mounting	O
medium	O
,	O
we	O
could	O
observe	O
thick	O
specimens	O
with	O
oil	O
immersion	O
objective	O
lens	O
without	O
the	O
use	O
of	O
coverslips	O
,	O
then	O
avoid	O
air	O
bubbles	O
near	O
the	O
specimen	O
.	O

The	O
present	O
study	O
investigated	O
dose	O
dependence	O
and	O
time	O
course	O
effects	O
of	O
the	O
benzodiazepine	O
(	O
BDZ	O
)	O
partial	O
inverse	O
agonist	O
,	O
RO19	O
-	O
4603	O
(	O
0	O
.	O
005	O
-	O
0	O
.	O
30	O
mg	O
/	O
kg	O
)	O
alone	O
,	O
and	O
in	O
combination	O
with	O
the	O
BDZ	B-GENE
receptor	I-GENE
antagonists	O
flumazenil	O
,	O
ZK	O
93426	O
,	O
and	O
CGS	O
8216	O
(	O
20	O
mg	O
/	O
kg	O
)	O
in	O
selectively	O
bred	O
alcohol	O
-	O
preferring	O
(	O
P	O
)	O
rats	O
provided	O
a	O
two	O
-	O
bottle	O
choice	O
test	O
between	O
ethanol	O
(	O
EtOH	O
)	O
(	O
10	O
%	O
v	O
/	O
v	O
)	O
,	O
and	O
a	O
palatable	O
saccharin	O
(	O
0	O
.	O
0125	O
%	O
g	O
/	O
v	O
)	O
solution	O
.	O

Beyond	O
the	O
Tower	O
of	O
Babel	O
:	O
a	O
nomenclature	O
for	O
suicidology	O
.	O

Infection	O
with	O
Neisseria	O
meningitidis	O
group	O
B	O
has	O
been	O
difficult	O
to	O
detect	O
,	O
partly	O
because	O
this	O
bacterial	O
group	O
'	O
s	O
polysaccharide	O
is	O
a	O
weak	O
immunogen	O
.	O

Rss1p	B-GENE
encodes	O
a	O
novel	O
essential	O
protein	O
of	O
538	O
amino	O
acids	O
,	O
which	O
contains	O
an	O
extended	O
predicted	O
coiled	O
-	O
coil	O
domain	O
and	O
is	O
located	O
both	O
at	O
nuclear	O
pore	O
complexes	O
(	O
NPCs	O
)	O
and	O
in	O
the	O
cytoplasm	O
.	O

To	O
map	O
this	O
regulatory	O
serine	O
phosphorylation	O
site	O
we	O
developed	O
a	O
baculovirus	O
-	O
mediated	O
expression	O
system	O
for	O
wild	B-GENE
-	I-GENE
type	I-GENE
annexin	I-GENE
II	I-GENE
and	O
for	O
a	O
series	O
of	O
annexin	B-GENE
II	I-GENE
mutants	I-GENE
which	O
contained	O
substitutions	O
in	O
one	O
or	O
more	O
serine	O
residues	O
present	O
in	O
the	O
N	O
-	O
terminal	O
domain	O
.	O

The	O
PAI	B-GENE
-	I-GENE
2	I-GENE
gene	I-GENE
is	O
one	O
of	O
the	O
most	O
TNF	B-GENE
-	I-GENE
responsive	I-GENE
genes	I-GENE
known	O
and	O
is	O
also	O
highly	O
induced	O
by	O
the	O
phorbol	O
ester	O
phorbol	O
12	O
-	O
myristate	O
13	O
-	O
acetate	O
(	O
PMA	O
)	O
and	O
the	O
phosphatase	O
inhibitor	O
,	O
okadaic	O
acid	O
,	O
in	O
both	O
HT	O
-	O
1080	O
fibrosarcoma	O
and	O
U	O
-	O
937	O
histiocytic	O
cells	O
.	O

220	O
,	O
263	O
-	O
273	O
)	O
.	O

T	O
.	O
,	O
Patel	O
,	O
S	O
.	O

Growth	O
factors	O
induce	O
the	O
expression	O
of	O
the	O
immediate	B-GENE
early	I-GENE
gene	I-GENE
products	I-GENE
MAP	B-GENE
kinase	I-GENE
phosphatase	I-GENE
-	I-GENE
1	I-GENE
(	O
MKP	B-GENE
-	I-GENE
1	I-GENE
)	O
,	O
c	B-GENE
-	I-GENE
Fos	I-GENE
and	O
c	B-GENE
-	I-GENE
Jun	I-GENE
.	O

The	O
up	O
-	O
regulation	O
of	O
E	B-GENE
-	I-GENE
selectin	I-GENE
,	O
one	O
of	O
the	O
adhesion	O
molecules	O
on	O
the	O
endothelium	O
,	O
is	O
an	O
important	O
event	O
in	O
the	O
mediation	O
of	O
the	O
inflammatory	O
response	O
.	O

The	O
NIT2	B-GENE
protein	I-GENE
is	O
localised	O
in	O
nuclei	O
and	O
could	O
not	O
be	O
detected	O
in	O
the	O
cytoplasmic	O
fraction	O
of	O
cells	O
subjected	O
to	O
nitrogen	O
derepression	O
or	O
nitrogen	O
repression	O
,	O
indicating	O
that	O
the	O
nuclear	O
import	O
of	O
NIT2	B-GENE
is	O
not	O
regulated	O
.	O

In	O
spite	O
of	O
much	O
effort	O
,	O
no	O
one	O
has	O
succeeded	O
in	O
isolating	O
and	O
characterizing	O
the	O
enzyme	O
(	O
s	O
)	O
responsible	O
for	O
synthesis	O
of	O
cellulose	O
,	O
the	O
major	O
cell	O
wall	O
polymer	O
of	O
plants	O
.	O

Vascular	O
responses	O
to	O
reactive	O
hyperemia	O
(	O
with	O
flow	O
increase	O
leading	O
to	O
endothelium	O
-	O
dependent	O
dilation	O
)	O
and	O
to	O
sublingual	O
glyceryl	O
trinitrate	O
(	O
GTN	O
;	O
endothelium	O
-	O
independent	O
dilation	O
)	O
were	O
recorded	O
.	O

During	O
this	O
period	O
,	O
administration	O
of	O
additional	O
exogenous	B-GENE
PRL	I-GENE
did	O
not	O
stimulate	O
further	O
activation	O
(	O
binding	O
)	O
of	O
the	O
Stat	B-GENE
factors	I-GENE
.	O

Intraperitoneal	O
administration	O
of	O
L	O
-	O
5	O
-	O
hydroxytryptophan	O
(	O
L	O
-	O
5	O
-	O
HTP	O
)	O
at	O
doses	O
of	O
25	O
to	O
100	O
mg	O
/	O
kg	O
dramatically	O
increase	O
defecation	O
in	O
mice	O
.	O

In	O
the	O
VA	O
-	O
SMV	O
mode	O
,	O
the	O
connection	O
was	O
made	O
with	O
valved	O
conduits	O
from	O
the	O
LV	O
apex	O
(	O
inflow	O
)	O
to	O
the	O
ascending	O
aorta	O
(	O
outflow	O
)	O
(	O
n	O
=	O
11	O
)	O
or	O
to	O
the	O
DAo	O
(	O
n	O
=	O
12	O
)	O
.	O

Factor	O
V	O
Leiden	O
is	O
a	O
genetic	O
disorder	O
associated	O
with	O
an	O
increased	O
risk	O
of	O
venous	O
thrombosis	O
.	O

This	O
is	O
the	O
first	O
determination	O
of	O
the	O
complete	O
secondary	O
structure	O
of	O
an	O
RNA	O
spliced	O
in	O
a	O
spliceosome	O
.	O

The	O
majority	O
of	O
the	O
cases	O
with	O
0	O
-	O
I	O
or	O
0	O
-	O
III	O
components	O
were	O
sm	O
.	O
cancer	O
.	O

These	O
patients	O
appear	O
to	O
have	O
slightly	O
better	O
pulmonary	O
function	O
and	O
nutritional	O
status	O
;	O
yet	O
,	O
they	O
seem	O
to	O
have	O
a	O
higher	O
degree	O
of	O
health	O
care	O
utilization	O
.	O

This	O
observation	O
calls	O
for	O
careful	O
monitoring	O
of	O
calcium	O
and	O
alkaline	B-GENE
phosphatase	I-GENE
values	O
and	O
possible	O
adjustments	O
of	O
vitamin	O
D	O
intake	O
when	O
fortifiers	O
are	O
used	O
for	O
extended	O
periods	O
.	O

We	O
have	O
found	O
that	O
PEA2	B-GENE
is	O
also	O
required	O
for	O
the	O
bipolar	O
budding	O
pattern	O
and	O
that	O
it	O
encodes	O
a	O
novel	O
protein	O
with	O
a	O
predicted	O
coiled	O
-	O
coil	O
domain	O
.	O

Signaling	O
from	O
the	O
small	B-GENE
GTP	I-GENE
-	I-GENE
binding	I-GENE
proteins	I-GENE
Rac1	I-GENE
and	O
Cdc42	B-GENE
to	O
the	O
c	B-GENE
-	I-GENE
Jun	I-GENE
N	I-GENE
-	I-GENE
terminal	I-GENE
kinase	I-GENE
/	O
stress	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
kinase	I-GENE
pathway	O
.	O

Percent	O
identities	O
of	O
the	O
mouse	B-GENE
PP2	I-GENE
to	O
mouse	B-GENE
Y1	I-GENE
,	O
mouse	O
Y4	B-GENE
/	O
PP1	B-GENE
and	O
human	B-GENE
Y2	I-GENE
receptors	I-GENE
are	O
53	O
,	O
42	O
,	O
and	O
31	O
,	O
respectively	O
.	O

Correlating	O
with	O
the	O
previous	O
observation	O
that	O
CBF	B-GENE
binding	O
to	O
the	O
78C1	O
site	O
is	O
enhanced	O
by	O
EGTA	O
and	O
EDTA	O
,	O
these	O
divalent	O
cation	O
chelators	O
specifically	O
stimulate	O
78C1	O
-	O
directed	O
transcription	O
.	O

The	O
human	O
gene	O
fragment	O
ligated	O
to	O
the	O
minimal	O
rat	O
liver	O
glucokinase	B-GENE
promoter	O
was	O
shown	O
to	O
work	O
as	O
an	O
enhancer	O
in	O
the	O
hepatocyte	O
transfection	O
system	O
.	O

To	O
test	O
the	O
role	O
of	O
ML	O
in	O
human	O
reproductive	O
axis	O
,	O
128	O
healthy	O
children	O
,	O
68	O
boys	O
and	O
60	O
girls	O
,	O
were	O
studied	O
.	O

However	O
,	O
the	O
truncated	O
deer	B-GENE
receptor	I-GENE
lacks	O
the	O
most	O
C	O
-	O
terminal	O
tyrosine	O
residue	O
in	O
the	O
intracellular	O
domain	O
which	O
is	O
believed	O
to	O
be	O
essential	O
for	O
activation	O
of	O
the	O
beta	B-GENE
-	I-GENE
casein	I-GENE
promoter	I-GENE
.	O

This	O
report	O
provides	O
further	O
evidence	O
for	O
the	O
riMLF	O
in	O
the	O
control	O
of	O
downgaze	O
,	O
and	O
a	O
synkinesis	O
is	O
postulated	O
for	O
the	O
development	O
of	O
the	O
convergence	O
retraction	O
nystagmus	O
.	O

Ninety	O
-	O
four	O
percent	O
of	O
the	O
EPs	O
were	O
tubal	O
,	O
and	O
90	O
%	O
of	O
the	O
tubes	O
exhibited	O
some	O
pathologic	O
changes	O
,	O
including	O
chronic	O
salpingitis	O
(	O
49	O
.	O
5	O
%	O
)	O
and	O
follicular	O
salpingitis	O
(	O
10	O
%	O
)	O
,	O
among	O
others	O
.	O

The	O
assessment	O
using	O
7	O
H	O
9	O
liquid	O
medium	O
by	O
the	O
former	O
author	O
demonstrated	O
the	O
potent	O
activities	O
of	O
both	O
CS	O
-	O
940	O
*	O
and	O
sparfloxacin	O
(	O
SPFX	O
)	O
,	O
followed	O
by	O
AM	O
-	O
1155	O
*	O
,	O
ciprofloxacin	O
(	O
CPFX	O
)	O
,	O
levofloxacin	O
(	O
LVFX	O
)	O
,	O
OPC	O
-	O
17116	O
*	O
,	O
NM	O
-	O
394	O
*	O
in	O
sequence	O
.	O

The	O
STE20	B-GENE
gene	I-GENE
,	O
encoding	O
a	O
protein	O
kinase	O
required	O
for	O
pheromone	O
signal	O
transduction	O
,	O
has	O
recently	O
been	O
identified	O
in	O
a	O
genetic	O
screen	O
for	O
high	O
-	O
gene	O
-	O
dosage	O
suppressors	O
of	O
a	O
partly	O
defective	O
G	B-GENE
beta	I-GENE
mutation	O
.	O

This	O
enzyme	O
is	O
designated	O
(	B-GENE
1	I-GENE
-	I-GENE
-	I-GENE
>	I-GENE
4	I-GENE
)	I-GENE
-	I-GENE
beta	I-GENE
-	I-GENE
xylan	I-GENE
endohydrolase	I-GENE
isoenzyme	I-GENE
X	I-GENE
-	I-GENE
I	I-GENE
.	O

Magnetic	O
resonance	O
imaging	O
in	O
coccidioidal	O
arthritis	O
.	O

Moloney	O
murine	O
leukemia	O
virus	O
(	O
MMLV	O
)	O
-	O
derived	O
pUCMoTiN	O
-	O
based	O
retroviral	O
vectors	O
were	O
engineered	O
to	O
allow	O
constitutive	O
and	O
Tat	B-GENE
(	O
trans	B-GENE
-	I-GENE
activator	I-GENE
of	I-GENE
transcription	I-GENE
)	O
-	O
inducible	O
expression	O
of	O
five	O
hammerhead	O
ribozymes	O
targeted	O
against	O
highly	O
conserved	O
sequences	O
within	O
the	O
group	B-GENE
antigen	I-GENE
(	O
Gag	B-GENE
)	O
,	O
protease	B-GENE
(	O
Pro	B-GENE
)	O
,	O
reverse	B-GENE
transcriptase	I-GENE
(	O
RT	B-GENE
)	O
,	O
tat	B-GENE
,	O
and	O
envelope	B-GENE
(	O
Env	B-GENE
)	O
coding	O
regions	O
of	O
human	O
immunodeficiency	O
virus	O
type	O
-	O
1	O
(	O
HIV	O
-	O
1	O
)	O
RNA	O
.	O

REM	O
sleep	O
deprivation	O
was	O
performed	O
using	O
the	O
platform	O
technique	O
.	O

The	O
same	O
ligands	O
also	O
exhibit	O
a	O
similar	O
inhibitory	O
effect	O
on	O
PDGF	B-GENE
-	I-GENE
BB	I-GENE
-	O
dependent	O
[	O
3H	O
]	O
thymidine	O
incorporation	O
in	O
PAE	O
cells	O
expressing	O
the	O
PDGF	B-GENE
beta	I-GENE
-	I-GENE
receptors	I-GENE
.	O

We	O
analyzed	O
serial	O
biopsy	O
specimens	O
from	O
eight	O
patients	O
with	O
FL	O
for	O
secondary	O
alterations	O
of	O
the	O
rearranged	B-GENE
bcl	I-GENE
-	I-GENE
2	I-GENE
gene	I-GENE
in	O
the	O
breakpoint	O
and	O
open	O
reading	O
frame	O
(	O
ORF	O
)	O
regions	O
.	O

In	O
all	O
eight	O
cases	O
,	O
neither	O
FL	O
nor	O
DLL	O
cells	O
showed	O
alterations	O
of	O
bcl	B-GENE
-	I-GENE
2	I-GENE
gene	I-GENE
sequences	I-GENE
in	O
the	O
breakpoint	O
region	O
,	O
suggesting	O
high	O
conservation	O
of	O
the	O
bcl	B-GENE
-	I-GENE
2	I-GENE
gene	I-GENE
during	O
both	O
t	O
(	O
14	O
;	O
18	O
)	O
translocation	O
and	O
morphologic	O
transformation	O
of	O
the	O
FL	O
cells	O
.	O

BACKGROUND	O
:	O
The	O
Bazett	O
-	O
corrected	O
QT	O
(	O
QTc	O
)	O
interval	O
during	O
exercise	O
has	O
been	O
used	O
as	O
a	O
marker	O
for	O
ischemic	O
disease	O
,	O
arrhythmogenic	O
substrate	O
and	O
the	O
long	O
QT	O
syndrome	O
.	O

An	O
essential	O
role	O
of	O
c	B-GENE
-	I-GENE
Jun	I-GENE
and	O
c	B-GENE
-	I-GENE
Fos	I-GENE
in	O
basal	O
and	O
PMA	O
-	O
stimulated	O
transcription	O
of	O
the	O
PAI	B-GENE
-	I-GENE
1	I-GENE
gene	I-GENE
is	O
demonstrated	O
by	O
our	O
finding	O
that	O
antisense	O
c	B-GENE
-	I-GENE
jun	I-GENE
and	O
c	B-GENE
-	I-GENE
fos	I-GENE
oligodeoxynucleotides	O
both	O
strongly	O
reduced	O
basal	O
and	O
PMA	O
-	O
stimulated	O
PAI	B-GENE
-	I-GENE
1	I-GENE
synthesis	O
.	O

To	O
analyze	O
the	O
mechanism	O
of	O
fos	B-GENE
/	O
jun	B-GENE
activation	O
by	O
TCDD	O
we	O
have	O
used	O
electrophoretic	O
mobility	O
shift	O
and	O
transient	O
expression	O
assays	O
of	O
reporter	O
gene	O
constructs	O
containing	O
response	O
elements	O
for	O
12	O
-	O
O	O
-	O
tetradecanoyl	O
-	O
phorbol	O
-	O
13	O
-	O
acetate	O
(	O
TRE	O
)	O
,	O
serum	O
(	O
SRE	O
)	O
,	O
cAMP	O
(	O
CRE	O
)	O
,	O
and	O
aromatic	O
hydrocarbons	O
(	O
AhRE	O
)	O
from	O
the	O
fos	B-GENE
and	O
jun	B-GENE
genes	I-GENE
fused	O
to	O
the	O
firefly	B-GENE
luciferase	I-GENE
gene	I-GENE
under	O
the	O
control	O
of	O
the	O
SV40	B-GENE
minimal	I-GENE
promoter	I-GENE
.	O

The	O
optimal	O
sequence	O
for	O
interaction	O
with	O
mu	B-GENE
2	I-GENE
and	O
with	O
AP	B-GENE
-	I-GENE
2	I-GENE
has	O
tyrosine	O
as	O
an	O
anchor	O
and	O
prefers	O
arginine	O
at	O
position	O
Y	O
+	O
2	O
and	O
leucine	O
at	O
position	O
Y	O
+	O
3	O
.	O

STK	B-GENE
/	O
RON	B-GENE
-	O
expressing	O
Ba	O
/	O
F3	O
pro	O
-	O
B	O
cells	O
(	O
BaF	O
/	O
STK	B-GENE
)	O
exhibited	O
MSP	B-GENE
-	O
dependent	O
growth	O
,	O
whereas	O
STK	B-GENE
/	O
RON	B-GENE
-	O
expressing	O
mouse	O
erythroleukaemia	O
cells	O
(	O
MEL	O
/	O
STK	B-GENE
)	O
displayed	O
MSP	B-GENE
-	O
induced	O
apoptosis	O
.	O

In	O
vitro	O
DNase	B-GENE
I	I-GENE
footprinting	O
showed	O
that	O
OxyR	B-GENE
-	I-GENE
C199S	I-GENE
protected	O
Pmom	B-GENE
from	O
-	O
104	O
to	O
-	O
46	O
on	O
the	O
top	O
strand	O
and	O
produced	O
a	O
protection	O
pattern	O
characteristic	O
of	O
reduced	B-GENE
wild	I-GENE
-	I-GENE
type	I-GENE
OxyR	I-GENE
.	O

Kss1	B-GENE
binds	O
specifically	O
to	O
a	O
GST	B-GENE
-	O
Dig1	B-GENE
fusion	O
in	O
the	O
absence	O
of	O
any	O
other	O
yeast	O
protein	O
.	O

In	O
contrast	O
,	O
dig1	B-GENE
dig2	B-GENE
cells	O
constitutively	O
invade	O
agar	O
medium	O
,	O
whereas	O
a	O
dig1	B-GENE
dig2	B-GENE
ste12	B-GENE
triple	O
mutant	O
does	O
not	O
,	O
indicating	O
that	O
Dig1	B-GENE
and	O
Dig2	B-GENE
share	O
a	O
role	O
in	O
negatively	O
regulating	O
the	O
invasive	O
growth	O
pathway	O
.	O

Comparison	O
of	O
the	O
sequences	O
of	O
the	O
xFxFG	O
repeat	O
regions	O
of	O
p62	B-GENE
and	O
Nsplp	B-GENE
indicated	O
that	O
NTF2	B-GENE
was	O
probably	O
interacting	O
with	O
the	O
phenylalanine	O
-	O
containing	O
core	O
of	O
these	O
repeats	O
and	O
not	O
the	O
intervening	O
hydrophilic	O
linkers	O
.	O

This	O
is	O
the	O
first	O
report	O
of	O
the	O
successful	O
resection	O
of	O
a	O
MFH	O
originating	O
in	O
the	O
renal	O
capsular	O
tissue	O
and	O
extending	O
into	O
the	O
inferior	O
vena	O
cava	O
.	O

Transient	O
expression	O
of	O
VSF	B-GENE
-	I-GENE
1	I-GENE
in	O
protoplasts	O
stimulated	O
vs	B-GENE
-	I-GENE
1	I-GENE
dependent	O
activation	O
of	O
the	O
-	B-GENE
76	I-GENE
/	I-GENE
grp1	I-GENE
.	I-GENE
8	I-GENE
minimal	I-GENE
promoter	I-GENE
.	O

Keeping	O
in	O
mind	O
the	O
limited	O
range	O
of	O
age	O
and	O
dosages	O
,	O
advantages	O
and	O
disadvantages	O
of	O
the	O
drug	O
are	O
discussed	O
,	O
comparing	O
the	O
experimental	O
results	O
with	O
those	O
derived	O
from	O
the	O
literature	O
.	O

Blood	O
sampling	O
procedures	O
were	O
videotaped	O
.	O

Analysis	O
of	O
one	O
cDNA	O
revealed	O
an	O
unusual	O
splicing	O
event	O
involving	O
EZH1	B-GENE
and	O
a	O
tandemly	O
linked	O
gene	O
GPR2	B-GENE
and	O
suggests	O
a	O
potential	O
mechanism	O
for	O
modifying	O
the	O
EZH1	B-GENE
protein	I-GENE
in	O
the	O
conserved	O
C	O
-	O
terminal	O
domain	O
.	O

A	O
given	O
standard	O
input	O
function	O
and	O
a	O
given	O
value	O
of	O
distribution	O
volume	O
(	O
Vd	O
)	O
used	O
for	O
the	O
rCBF	O
measurement	O
of	O
this	O
method	O
were	O
calculated	O
from	O
the	O
dynamic	O
study	O
by	O
six	O
normal	O
volunteers	O
.	O

They	O
lack	O
a	O
predicted	O
single	O
stranded	O
(	O
ss	O
)	O
DNA	O
binding	O
motif	O
that	O
is	O
unique	O
the	O
large	O
terminase	B-GENE
proteins	I-GENE
in	O
T4	B-GENE
gp17	I-GENE
,	O
and	O
that	O
has	O
been	O
implicated	O
in	O
recognizing	O
ssDNA	O
regions	O
in	O
replicating	O
and	O
recombining	O
T4DNA	O
destined	O
to	O
be	O
packaged	O
.	O

It	O
can	O
be	O
concluded	O
that	O
in	O
normotensive	O
subjects	O
,	O
uric	O
acid	O
and	O
xanthine	B-GENE
oxidase	I-GENE
have	O
significant	O
association	O
with	O
blood	O
pressure	O
and	O
thus	O
are	O
one	O
of	O
the	O
many	O
factors	O
which	O
are	O
involved	O
in	O
the	O
cause	O
or	O
effect	O
of	O
hypertension	O
.	O

Immunoblotting	O
of	O
expressed	O
recombinant	O
proteins	O
with	O
the	O
monoclonal	B-GENE
08L	I-GENE
antibody	I-GENE
localized	O
the	O
08L	B-GENE
epitope	O
to	O
the	O
carboxyl	O
end	O
of	O
the	O
protein	O
.	O

We	O
infer	O
that	O
the	O
dominant	O
negative	O
inhibition	O
results	O
from	O
both	O
direct	O
proteolysis	O
of	O
the	O
beta	B-GENE
-	I-GENE
galactosidase	I-GENE
tetramer	I-GENE
by	O
the	O
fusion	O
subunit	O
and	O
detour	O
of	O
the	O
tetramer	O
to	O
the	O
lysosome	O
.	O

The	O
current	O
study	O
defines	O
the	O
vinculin	B-GENE
-	O
and	O
FAK	B-GENE
-	I-GENE
interaction	I-GENE
domains	I-GENE
on	O
paxillin	B-GENE
and	O
identifies	O
the	O
principal	O
paxillin	B-GENE
focal	O
adhesion	O
targeting	O
motif	O
.	O

These	O
data	O
demonstrate	O
the	O
presence	O
of	O
a	O
single	O
binding	O
site	O
for	O
vinculin	B-GENE
,	O
and	O
at	O
least	O
two	O
binding	O
sites	O
for	O
FAK	B-GENE
that	O
are	O
separated	O
by	O
an	O
intervening	O
stretch	O
of	O
100	O
amino	O
acids	O
.	O

These	O
data	O
demonstrate	O
that	O
paxillin	B-GENE
localizes	O
to	O
focal	O
adhesions	O
independent	O
of	O
interactions	O
with	O
vinculin	B-GENE
and	O
/	O
or	O
FAK	B-GENE
,	O
and	O
represents	O
the	O
first	O
definitive	O
demonstration	O
of	O
LIM	B-GENE
domains	I-GENE
functioning	O
as	O
a	O
primary	O
determinant	O
of	O
protein	O
subcellular	O
localization	O
to	O
focal	O
adhesions	O
.	O

A	O
single	O
protease	O
-	O
resistant	O
structure	O
formed	O
by	O
the	O
entirety	O
of	O
both	O
PDZ	B-GENE
repeats	I-GENE
1	I-GENE
and	I-GENE
2	I-GENE
(	O
PDZ1	B-GENE
-	I-GENE
2	I-GENE
)	O
contains	O
the	O
protein	B-GENE
4	I-GENE
.	I-GENE
1	I-GENE
-	I-GENE
binding	I-GENE
site	I-GENE
.	O

Several	O
agents	O
have	O
been	O
tried	O
for	O
treatment	O
,	O
often	O
limited	O
by	O
toxic	O
side	O
effects	O
.	O

Jerseys	O
had	O
higher	O
hepatic	O
Cu	O
concentrations	O
than	O
did	O
Holsteins	O
on	O
d	O
60	O
(	O
346	O
vs	O
.	O

These	O
results	O
are	O
consistent	O
with	O
the	O
well	O
established	O
polarity	O
of	O
RXR	B-GENE
heterodimer	O
binding	O
to	O
bipartite	O
hormone	O
response	O
elements	O
,	O
with	O
the	O
VDR	B-GENE
recognizing	O
the	O
3	O
'	O
-	O
half	O
-	O
element	O
.	O

PPAR	B-GENE
gamma	I-GENE
mRNA	I-GENE
levels	O
were	O
reduced	O
by	O
95	O
%	O
with	O
3	O
nM	O
TNF	B-GENE
alpha	I-GENE
treatment	O
for	O
24	O
h	O
.	O

Exons	O
III	O
to	O
VIII	O
,	O
which	O
cover	O
the	O
coding	O
region	O
and	O
the	O
3	O
'	O
untranslated	O
region	O
,	O
are	O
almost	O
identical	O
in	O
all	O
types	O
of	O
PST	B-GENE
or	O
AST	B-GENE
cDNAs	I-GENE
.	O

Growth	O
factor	O
allows	O
effective	O
dose	O
-	O
intensive	O
regimen	O
in	O
advanced	O
breast	O
cancer	O
patients	O
.	O

Recombinant	B-GENE
erythropoietin	I-GENE
(	O
r	B-GENE
-	I-GENE
HuEPO	I-GENE
)	O
in	O
the	O
treatment	O
of	O
anemia	O
in	O
multiple	O
myeloma	O

In	O
1993	O
and	O
1994	O
and	O
infection	O
with	O
body	O
lice	O
was	O
registered	O
41	O
times	O
in	O
31	O
patients	O
at	O
the	O
clinic	O
for	O
homeless	O
of	O
the	O
Community	O
Health	O
Service	O
of	O
Utrecht	O
.	O

Ki	B-GENE
-	I-GENE
ras	I-GENE
and	O
p53	B-GENE
mutations	I-GENE
in	O
pancreatic	O
ductal	O
adenocarcinoma	O
.	O

Epidemiological	O
data	O
are	O
quite	O
controversial	O
but	O
sudden	O
death	O
occurring	O
during	O
sporting	O
activity	O
is	O
probably	O
not	O
a	O
rare	O
occurrence	O
.	O

However	O
,	O
the	O
ratio	O
M	O
/	O
Pc	O
provides	O
a	O
useful	O
index	O
that	O
seems	O
to	O
be	O
independent	O
of	O
the	O
metabolic	O
demand	O
.	O

Rat	B-GENE
liver	I-GENE
catalase	I-GENE
is	O
sorted	O
to	O
peroxisomes	O
by	O
its	O
C	O
-	O
terminal	O
tripeptide	O
Ala	O
-	O
Asn	O
-	O
Leu	O
,	O
not	O
by	O
the	O
internal	O
Ser	O
-	O
Lys	O
-	O
Leu	O
motif	O
.	O

These	O
data	O
provide	O
strong	O
evidence	O
that	O
E2F	B-GENE
or	O
an	O
E2F	B-GENE
-	I-GENE
related	I-GENE
transcription	I-GENE
factor	I-GENE
is	O
involved	O
in	O
the	O
regulation	O
of	O
nonmuscle	B-GENE
myosin	I-GENE
expression	O
.	O

When	O
the	O
E1A	B-GENE
N	I-GENE
-	I-GENE
terminus	I-GENE
is	O
used	O
as	O
a	O
competitor	O
in	O
squelshing	O
experiments	O
it	O
abolishes	O
CBP	B-GENE
-	O
induced	O
activation	O
of	O
E2F1	B-GENE
/	O
DP1	B-GENE
,	O
whereas	O
an	O
E1A	B-GENE
mutant	I-GENE
lacking	O
CBP	B-GENE
binding	O
ability	O
fails	O
to	O
do	O
so	O
.	O

Small	O
Maf	B-GENE
proteins	I-GENE
interact	O
with	O
the	O
human	O
transcription	O
factor	O
TCF11	B-GENE
/	O
Nrf1	B-GENE
/	O
LCR	B-GENE
-	I-GENE
F1	I-GENE
.	O

On	O
the	O
third	O
occasion	O
water	O
(	O
W	O
)	O
was	O
ingested	O
throughout	O
the	O
run	O
.	O

The	O
effect	O
of	O
maternal	O
ingestion	O
of	O
the	O
reduced	O
energy	O
sweetener	O
erythritol	O
was	O
investigated	O
in	O
KBL	O
:	O
JW	O
strain	O
pregnant	O
rabbits	O
.	O

The	O
nm23	B-GENE
-	I-GENE
H1	I-GENE
/	O
nm23	B-GENE
-	I-GENE
H2	I-GENE
gene	O
transcriptional	O
activity	O
ratio	O
varied	O
depending	O
on	O
the	O
cell	O
line	O
.	O

CONCLUSION	O
:	O
Intravenous	O
diazepam	O
administration	O
before	O
EGD	O
produces	O
a	O
significant	O
fall	O
in	O
SpO2	O
during	O
the	O
procedure	O
,	O
and	O
so	O
should	O
be	O
avoided	O
;	O
continuous	O
monitoring	O
of	O
SpO2	O
should	O
be	O
done	O
during	O
EGD	O
.	O

The	O
nucleotide	O
sequence	O
alignment	O
between	O
mouse	O
and	O
human	B-GENE
CA	I-GENE
IV	I-GENE
shows	O
69	O
%	O
identity	O
in	O
the	O
coding	O
region	O
and	O
all	O
of	O
the	O
exon	O
-	O
intron	O
boundaries	O
are	O
conserved	O
,	O
as	O
are	O
the	O
sizes	O
of	O
the	O
introns	O
.	O

Discordance	O
on	O
the	O
cost	O
dimension	O
correlated	O
negatively	O
with	O
G	B-GENE
Hb	I-GENE
,	O
suggesting	O
better	O
glycemic	O
control	O
with	O
greater	O
disagreement	O
.	O

DATA	O
SOURCES	O
:	O
Epidemiologic	O
studies	O
,	O
research	O
studies	O
,	O
review	O
articles	O
,	O
and	O
government	O
reports	O
pertaining	O
to	O
epidemiology	O
of	O
lung	O
cancer	O
.	O

Histological	O
changes	O
,	O
including	O
cortical	O
cell	O
involution	O
and	O
hemorrhage	O
occurring	O
during	O
the	O
neonatal	O
period	O
,	O
would	O
seem	O
to	O
have	O
crucial	O
relevance	O
to	O
the	O
remodeling	O
of	O
the	O
adrenal	O
vasculature	O
.	O

Furthermore	O
,	O
co	O
-	O
expression	O
of	O
both	O
p46	B-GENE
and	O
p54	B-GENE
subunits	I-GENE
markedly	O
altered	O
the	O
subcellular	O
distribution	O
of	O
p46	B-GENE
;	O
co	O
-	O
expressed	O
p46	B-GENE
was	O
transported	O
into	O
the	O
nucleus	O
as	O
efficiently	O
as	O
p54	B-GENE
.	O

The	O
results	O
suggest	O
that	O
,	O
although	O
both	O
the	O
N	O
-	O
and	O
C	O
-	O
terminal	O
regions	O
of	O
talin	B-GENE
bind	O
actin	B-GENE
,	O
the	O
properties	O
of	O
these	O
two	O
regions	O
of	O
the	O
protein	O
are	O
distinct	O
.	O

Merr	O
.	O
)	O
embryo	O
library	O
.	O

The	O
accumulation	O
of	O
both	O
LHA4	B-GENE
and	O
LHA2	B-GENE
mRNAs	I-GENE
is	O
induced	O
by	O
the	O
addition	O
of	O
exogenous	O
sugars	O
and	O
this	O
induction	O
appears	O
to	O
be	O
dependent	O
on	O
sugar	O
uptake	O
and	O
metabolism	O
,	O
because	O
mannitol	O
and	O
3	O
-	O
O	O
-	O
methylglucose	O
do	O
not	O
stimulate	O
mRNA	O
accumulation	O
.	O

Using	O
the	O
yeast	O
one	O
-	O
hybrid	O
screen	O
with	O
integrated	O
NRE	O
and	O
flanking	O
DNA	O
as	O
bait	O
,	O
the	O
predominant	O
clone	O
obtained	O
was	O
bovine	B-GENE
Nrl	I-GENE
.	O

As	O
the	O
rate	O
of	O
protein	O
synthesis	O
decreases	O
during	O
late	O
embryogenesis	O
,	O
levels	O
of	O
SEC	B-GENE
-	I-GENE
1	I-GENE
and	O
its	O
cognate	O
mRNA	O
decline	O
precipitously	O
.	O

These	O
findings	O
suggest	O
that	O
fodrin	B-GENE
proteolysis	O
in	O
vivo	O
may	O
reflect	O
the	O
activity	O
of	O
multiple	O
ICE	B-GENE
/	O
Ced	B-GENE
-	I-GENE
3	I-GENE
proteases	O
whose	O
partial	O
sensitivity	O
to	O
DEVD	O
-	O
CHO	O
reflects	O
a	O
limited	O
contribution	O
from	O
CPP32	B-GENE
,	O
or	O
an	O
ICE	B-GENE
/	O
Ced	B-GENE
-	I-GENE
3	I-GENE
protease	O
less	O
sensitive	O
than	O
CPP32	B-GENE
to	O
DEVD	O
-	O
CHO	O
inhibition	O
.	O

In	O
3Y1	O
and	O
3Y1	O
v	B-GENE
-	I-GENE
crk	I-GENE
-	O
transformed	O
fibroblasts	O
,	O
almost	O
all	O
of	O
the	O
total	O
PTP1B	B-GENE
and	O
about	O
40	O
%	O
of	O
total	O
p130	B-GENE
(	O
Cas	B-GENE
)	O
co	O
-	O
sediment	O
with	O
membranes	O
composed	O
primarily	O
of	O
endoplasmic	O
reticulum	O
.	O

Replacing	O
residues	O
405	O
-	O
419	O
on	O
delta419	O
with	O
the	O
conserved	O
AF	O
-	O
2	O
domain	O
from	O
the	O
vitamin	B-GENE
D3	I-GENE
receptor	I-GENE
or	O
the	O
estrogen	B-GENE
receptor	I-GENE
results	O
in	O
a	O
receptor	O
with	O
wild	O
-	O
type	O
or	O
low	O
transcriptional	O
activity	O
,	O
respectively	O
.	O

Recurrent	O
G	O
-	O
to	O
-	O
A	O
substitution	O
in	O
a	O
single	O
codon	O
of	O
SREBP	B-GENE
cleavage	I-GENE
-	I-GENE
activating	I-GENE
protein	I-GENE
causes	O
sterol	O
resistance	O
in	O
three	O
mutant	O
Chinese	O
hamster	O
ovary	O
cell	O
lines	O
.	O

The	O
Escherichia	B-GENE
coli	I-GENE
tet	I-GENE
-	I-GENE
repressor	I-GENE
(	O
TetR	B-GENE
)	O
operator	O
system	O
was	O
used	O
to	O
develop	O
a	O
variation	O
of	O
the	O
yeast	O
two	O
-	O
hybrid	O
assay	O
in	O
which	O
disruptions	O
of	O
protein	O
-	O
protein	O
interactions	O
can	O
be	O
identified	O
by	O
a	O
positive	O
selection	O
.	O

Recent	O
studies	O
have	O
suggested	O
that	O
SHP	B-GENE
-	I-GENE
1	I-GENE
regulates	O
the	O
function	O
of	O
Jak	B-GENE
family	O
tyrosine	B-GENE
kinases	I-GENE
,	O
as	O
shown	O
by	O
its	O
constitutive	O
association	O
with	O
the	O
Tyk2	B-GENE
kinase	I-GENE
and	O
the	O
hyperphosphorylation	O
of	O
Jak	B-GENE
kinases	I-GENE
in	O
the	O
motheaten	O
cells	O
that	O
lack	O
functional	O
SHP	B-GENE
-	I-GENE
1	I-GENE
.	O

Administration	O
of	O
a	O
second	O
dose	O
of	O
vaccine	O
during	O
the	O
outbreak	O
was	O
not	O
protective	O
.	O

But	O
,	O
as	O
Theriault	O
explains	O
,	O
improvements	O
in	O
assessing	O
exposure	O
have	O
not	O
yet	O
translated	O
into	O
clear	O
and	O
consistent	O
findings	O
.	O

Biol	O
.	O

Structural	O
basis	O
for	O
activation	O
of	O
human	B-GENE
lymphocyte	I-GENE
kinase	I-GENE
Lck	B-GENE
upon	O
tyrosine	O
phosphorylation	O
.	O

Evolutive	O
morphology	O
of	O
the	O
olfactory	O
bulb	O
in	O
man	O
and	O
certain	O
non	O
-	O
human	O
mammals	O

From	O
these	O
results	O
,	O
we	O
concluded	O
that	O
this	O
ORF	O
is	O
the	O
FRDS	B-GENE
gene	I-GENE
.	O

FK506	O
is	O
10	O
-	O
to	O
100	O
-	O
fold	O
more	O
potent	O
than	O
cyclosporin	O
A	O
in	O
preventing	O
organ	O
rejection	O
and	O
in	O
toxicity	O
.	O

These	O
results	O
suggest	O
that	O
Rho1p	B-GENE
regulates	O
cytoskeletal	O
reorganization	O
at	O
least	O
through	O
Bni1p	B-GENE
and	O
Pkc1p	B-GENE
.	O

Waves	O
N1	O
,	O
P3	O
and	O
CNV	O
were	O
recorded	O
during	O
a	O
CNV	O
paradigm	O
in	O
a	O
simple	O
reaction	O
time	O
task	O
with	O
a	O
constant	O
interstimulus	O
interval	O
(	O
ISI	O
)	O
of	O
1	O
sec	O
.	O

Therefore	O
,	O
both	O
the	O
Chilean	O
and	O
the	O
Japanese	O
samples	O
collected	O
in	O
high	O
-	O
risk	O
areas	O
showed	O
higher	O
mutagenic	O
rates	O
than	O
the	O
Japanese	O
ones	O
in	O
a	O
low	O
-	O
risk	O
area	O
,	O
with	O
a	O
statistical	O
significance	O
(	O
p	O
<	O
0	O
.	O
001	O
)	O
,	O
chi	O
-	O
square	O
test	O
)	O
.	O

Regulation	O
of	O
ASN1	B-GENE
and	O
ASN2	B-GENE
expression	O
was	O
studied	O
using	O
lacZ	B-GENE
fusions	I-GENE
and	O
both	O
genes	O
were	O
found	O
to	O
be	O
several	O
times	O
less	O
expressed	O
in	O
the	O
absence	O
of	O
the	O
transcription	O
activator	O
Gcn4p	B-GENE
.	O

Several	O
particular	O
features	O
of	O
this	O
polypeptide	O
fragment	O
from	O
the	O
hamster	B-GENE
lysyl	I-GENE
-	I-GENE
tRNA	I-GENE
synthetase	I-GENE
suggest	O
that	O
it	O
is	O
implicated	O
in	O
the	O
assembly	O
of	O
that	O
enzyme	O
within	O
the	O
multisynthetase	O
complex	O
.	O

He	O
is	O
well	O
,	O
five	O
years	O
after	O
relapse	O
.	O

Comparison	O
of	O
the	O
proportion	O
of	O
nonsynonymous	O
(	O
pN	O
)	O
and	O
synonymous	O
(	O
pS	O
)	O
substitutions	O
occurring	O
per	O
site	O
within	O
tamarin	B-GENE
variable	I-GENE
region	I-GENE
genes	I-GENE
demonstrated	O
a	O
reduction	O
in	O
pN	O
in	O
the	O
framework	O
regions	O
compared	O
with	O
pN	O
in	O
the	O
presumed	O
MHC	B-GENE
contact	I-GENE
regions	I-GENE
(	O
CDR1	B-GENE
and	O
CDR2	B-GENE
)	O
.	O

The	O
effects	O
of	O
oral	O
vanadyl	O
sulfate	O
(	O
VOSO4	O
)	O
(	O
0	O
.	O
5	O
mg	O
/	O
kg	O
/	O
day	O
)	O
on	O
anthropometry	O
,	O
body	O
composition	O
,	O
and	O
performance	O
were	O
investigated	O
in	O
a	O
12	O
-	O
week	O
,	O
double	O
-	O
blind	O
,	O
placebo	O
-	O
controlled	O
trial	O
involving	O
weight	O
-	O
training	O
volunteers	O
.	O

Later	O
in	O
development	O
,	O
Tbx6	B-GENE
expression	O
is	O
restricted	O
to	O
presomitic	O
,	O
paraxial	O
mesoderm	O
and	O
to	O
the	O
tail	O
bud	O
,	O
which	O
replaces	O
the	O
streak	O
as	O
the	O
source	O
of	O
mesoderm	O
.	O

Disruption	O
of	O
re	O
-	O
replication	O
control	O
by	O
overexpression	O
of	O
human	B-GENE
ORC1	I-GENE
in	O
fission	O
yeast	O
.	O

Our	O
results	O
demonstrate	O
that	O
the	O
promoter	O
and	O
enhancer	O
regions	O
identified	O
here	O
are	O
essential	O
for	O
maintaining	O
the	O
efficient	O
promoter	O
activity	O
of	O
the	O
human	B-GENE
activin	I-GENE
betaA	I-GENE
subunit	I-GENE
gene	I-GENE
.	O

Recombinant	O
,	O
bacterially	O
expressed	O
PIP5KIalpha	B-GENE
possessed	O
PIP5K	B-GENE
activity	O
and	O
was	O
immunoreactive	O
with	O
erythroid	B-GENE
PIP5KI	I-GENE
antibodies	I-GENE
.	O

Human	B-GENE
acid	I-GENE
ceramidase	I-GENE
(	O
(	B-GENE
AC	I-GENE
)	I-GENE
N	I-GENE
-	I-GENE
acylsphingosine	I-GENE
amidohydrolase	I-GENE
,	O
EC	B-GENE
3	I-GENE
.	I-GENE
5	I-GENE
.	O

The	O
0	O
.	O
22	O
-	O
kb	O
NheI	B-GENE
/	O
BglII	B-GENE
promoter	O
exhibited	O
PMA	O
inducibility	O
in	O
myeloid	O
cells	O
and	O
contained	O
a	O
PMA	O
-	O
responsive	O
element	O
recognized	O
by	O
Sp1	B-GENE
and	O
EGR	B-GENE
-	I-GENE
1	I-GENE
transcription	I-GENE
factors	I-GENE
.	O

Northern	O
(	O
RNA	O
)	O
blot	O
analyses	O
indicated	O
that	O
the	O
cdh	B-GENE
genes	I-GENE
encoding	O
the	O
five	O
subunits	O
and	O
an	O
open	O
reading	O
frame	O
(	O
ORF1	O
)	O
with	O
unknown	O
function	O
are	O
cotranscribed	O
during	O
growth	O
on	O
acetate	O
.	O

Two	O
classes	O
of	O
mutations	O
were	O
obtained	O
:	O
(	O
i	O
)	O
those	O
that	O
altered	O
the	O
coding	O
region	O
of	O
HOL1	B-GENE
,	O
conferring	O
the	O
ability	O
to	O
take	O
up	O
histidinol	O
;	O
and	O
(	O
ii	O
)	O
cis	O
-	O
acting	O
mutations	O
(	O
selected	O
in	O
a	O
mutant	O
HOL1	B-GENE
-	I-GENE
1	I-GENE
background	O
)	O
that	O
increased	O
expression	O
of	O
the	O
Hol1	B-GENE
protein	I-GENE
.	O

Damage	O
to	O
the	O
BBB	O
was	O
judged	O
by	O
extravasation	O
of	O
Evans	O
Blue	O
(	O
EB	O
)	O
dye	O
,	O
which	O
was	O
administered	O
either	O
2	O
,	O
3	O
,	O
24	O
or	O
48	O
h	O
after	O
onset	O
of	O
MCAo	O
.	O

Lipid	O
hydroperoxide	O
levels	O
in	O
plasma	O
and	O
LDL	B-GENE
remained	O
unchanged	O
throughout	O
the	O
study	O
.	O

We	O
report	O
a	O
case	O
of	O
vasculitis	O
(	O
cutaneous	O
and	O
neurologic	O
)	O
which	O
led	O
to	O
the	O
discovery	O
of	O
a	O
selective	O
immunodeficit	O
towards	O
EBV	O
,	O
similar	O
to	O
Purtilo	O
'	O
s	O
syndrome	O
.	O

To	O
elucidate	O
whether	O
potential	O
endocrine	O
changes	O
resulted	O
from	O
acute	O
hypoxaemia	O
alone	O
,	O
the	O
underlying	O
disease	O
,	O
or	O
unspecific	O
influences	O
connected	O
with	O
the	O
ICU	O
setting	O
,	O
all	O
measurements	O
were	O
compared	O
to	O
those	O
of	O
a	O
completely	O
healthy	O
reference	O
group	O
(	O
REF	O
)	O
with	O
comparable	O
acute	O
experimental	O
hypoxaemia	O
.	O

There	O
were	O
no	O
significant	O
differences	O
in	O
graft	O
survival	O
between	O
groups	O
with	O
early	O
graft	O
function	O
(	O
EGF	O
)	O
and	O
DGF	O
,	O
either	O
in	O
first	O
transplantations	O
or	O
retransplantations	O
.	O

These	O
results	O
suggested	O
that	O
the	O
GG	O
motifs	O
contributed	O
to	O
the	O
cell	O
-	O
specific	O
transcription	O
of	O
the	O
human	B-GENE
insulin	I-GENE
gene	I-GENE
in	O
association	O
with	O
the	O
binding	O
of	O
the	O
sequence	O
-	O
specific	O
nuclear	O
factor	O
.	O

Abnormal	O
urinary	O
coproporphyrin	O
levels	O
in	O
patients	O
infected	O
by	O
hepatitis	O
C	O
virus	O
with	O
or	O
without	O
human	O
immunodeficiency	O
virus	O
.	O

The	O
determination	O
of	O
immunoglobulin	B-GENE
E	I-GENE
(	O
IgE	B-GENE
)	O
antibodies	O
by	O
one	O
of	O
several	O
laboratory	O
tests	O
,	O
by	O
skin	O
-	O
prick	O
tests	O
or	O
by	O
appropriate	O
challenge	O
procedures	O
is	O
useful	O
either	O
to	O
identify	O
atopic	O
individuals	O
or	O
as	O
outcome	O
predictors	O
in	O
wheezy	O
children	O
.	O

Thrombosis	O
of	O
the	O
renal	O
vein	O
may	O
be	O
dramatic	O
and	O
include	O
renal	O
failure	O
.	O

Filter	O
and	O
cytocentrifuge	O
preparations	O
of	O
the	O
urine	O
were	O
studied	O
and	O
all	O
cases	O
displayed	O
numerous	O
scattered	O
aggregates	O
or	O
single	O
tumor	O
cells	O
in	O
an	O
inflammatory	O
background	O
.	O

The	O
promoter	O
segment	O
was	O
inactive	O
when	O
introduced	O
into	O
the	O
rat	O
glioma	O
cell	O
line	O
C6B4	O
,	O
the	O
rat	O
submandibular	O
cell	O
line	O
RSMT	O
-	O
A5	O
,	O
and	O
the	O
rat	O
pancreatic	O
beta	O
cell	O
line	O
RIN	O
-	O
5AH	O
,	O
all	O
of	O
which	O
do	O
not	O
express	O
the	O
endogenous	O
alpha2c	B-GENE
-	I-GENE
AR	I-GENE
gene	I-GENE
.	O

The	O
sequencing	O
of	O
the	O
conditional	O
lethal	O
mutation	O
ts	O
-	O
A13	O
,	O
localized	O
in	O
the	O
nrdE	B-GENE
cistron	I-GENE
,	O
and	O
the	O
lethality	O
of	O
insertional	O
mutations	O
targeted	O
in	O
the	O
internal	O
region	O
of	O
nrdE	B-GENE
and	O
nrdF	B-GENE
,	O
demonstrated	O
the	O
essential	O
role	O
of	O
this	O
locus	O
.	O

The	O
microdensitometric	O
scores	O
and	O
their	O
side	O
-	O
to	O
-	O
side	O
differences	O
in	O
patients	O
correlated	O
negatively	O
with	O
the	O
serum	O
25	O
-	O
OHD	O
concentration	O
and	O
positively	O
with	O
the	O
degree	O
of	O
paralysis	O
.	O

These	O
data	O
do	O
not	O
support	O
the	O
use	O
of	O
LDD	O
to	O
reduce	O
risk	O
of	O
progression	O
to	O
MSOF	O
in	O
sepsis	O
.	O

This	O
correlated	O
with	O
reduced	O
levels	O
of	O
secreted	O
hepatitis	B-GENE
B	I-GENE
e	I-GENE
antigen	I-GENE
and	O
increased	O
intracellular	O
levels	O
of	O
core	B-GENE
and	O
Pol	B-GENE
proteins	I-GENE
and	O
replicative	O
HBV	O
DNA	O
intermediates	O
.	O

In	O
contrast	O
,	O
extracts	O
of	O
the	O
mutant	O
virions	O
catalyze	O
the	O
wild	O
-	O
type	O
level	O
of	O
transcription	O
from	O
an	O
exogenous	O
template	O
containing	O
an	O
early	O
promoter	O
.	O

The	O
SCMV	B-GENE
SNE	I-GENE
sites	I-GENE
contain	O
potential	O
overlapping	O
core	O
recognition	O
binding	O
motifs	O
for	O
SRF	B-GENE
,	O
Rel	B-GENE
/	O
NFkappaB	B-GENE
,	O
ETS	B-GENE
,	O
and	O
YY1	B-GENE
class	I-GENE
transcription	I-GENE
factors	I-GENE
but	O
fail	O
to	O
respond	O
to	O
either	O
serum	O
or	O
tumor	B-GENE
necrosis	I-GENE
factor	I-GENE
alpha	I-GENE
.	O

Upon	O
serum	O
withdrawal	O
at	O
the	O
permissive	O
temperature	O
,	O
p53	B-GENE
-	O
mediated	O
apoptosis	O
was	O
induced	O
in	O
50	O
to	O
60	O
%	O
of	O
the	O
cells	O
.	O

To	O
circumvent	O
this	O
problem	O
,	O
a	O
simple	O
two	O
-	O
step	O
strategy	O
was	O
devised	O
by	O
which	O
essential	O
cis	O
-	O
acting	O
sites	O
like	O
the	O
a	O
sequence	O
can	O
be	O
readily	O
deleted	O
from	O
their	O
natural	O
loci	O
in	O
large	O
viral	O
DNA	O
genomes	O
.	O

On	O
the	O
basis	O
of	O
serological	O
studies	O
,	O
the	O
highly	O
conserved	O
A	O
domain	O
of	O
HspA	B-GENE
was	O
found	O
to	O
be	O
the	O
immunodominant	O
domain	O
.	O

In	O
Group	O
IV	O
dogs	O
that	O
received	O
alpha	B-GENE
-	I-GENE
MSH	I-GENE
only	O
during	O
reperfusion	O
,	O
BAEPs	O
were	O
increased	O
approximately	O
10	O
to	O
14	O
%	O
more	O
than	O
in	O
Group	O
II	O
during	O
the	O
late	O
reperfusion	O
period	O
.	O

The	O
Fas	B-GENE
receptor	I-GENE
mediates	O
a	O
signalling	O
cascade	O
resulting	O
in	O
programmed	O
cell	O
death	O
(	O
apoptosis	O
)	O
within	O
hours	O
of	O
receptor	O
cross	O
-	O
linking	O
.	O

Fas	B-GENE
has	O
been	O
shown	O
to	O
require	O
ICE	B-GENE
(	O
interleukin	B-GENE
-	I-GENE
1	I-GENE
beta	I-GENE
-	I-GENE
converting	I-GENE
enzyme	I-GENE
)	O
family	O
proteases	O
to	O
induce	O
apoptosis	O
from	O
studies	O
utilizing	O
the	O
cowpox	O
ICE	B-GENE
inhibitor	I-GENE
protein	I-GENE
CrmA	B-GENE
,	O
the	O
synthetic	O
tetrapeptide	O
ICE	B-GENE
inhibitor	O
YVAD	B-GENE
-	I-GENE
CMK	I-GENE
,	O
and	O
the	O
tripeptide	O
pan	O
-	O
ICE	B-GENE
inhibitor	O
Z	B-GENE
-	I-GENE
VAD	I-GENE
-	I-GENE
FMK	I-GENE
.	O

The	O
imprinted	O
expression	O
of	O
the	O
endogenous	O
gene	O
can	O
be	O
recapitulated	O
in	O
mice	O
by	O
using	O
a	O
14	O
-	O
kb	O
transgene	O
encompassing	O
4	O
kb	O
of	O
5	O
'	O
-	O
flanking	O
sequence	O
,	O
8	O
kb	O
of	O
3	O
'	O
-	O
flanking	O
sequence	O
,	O
which	O
includes	O
the	O
two	O
endoderm	O
-	O
specific	O
enhancers	O
,	O
and	O
an	O
internally	O
deleted	O
structural	O
gene	O
.	O

In	O
this	O
report	O
,	O
we	O
demonstrate	O
that	O
hGCN5	B-GENE
is	O
also	O
an	O
HAT	B-GENE
and	O
has	O
the	O
same	O
substrate	O
specificity	O
as	O
yGCN5	B-GENE
.	O

Complementary	O
DNAs	O
encompassing	O
the	O
coat	B-GENE
protein	I-GENE
coding	O
and	O
adjacent	O
regions	O
of	O
Agropyron	O
mosaic	O
virus	O
(	O
AgMV	O
)	O
and	O
Hordeum	O
mosaic	O
virus	O
(	O
HoMV	O
)	O
were	O
cloned	O
and	O
sequenced	O
.	O

In	O
some	O
cases	O
,	O
factor	O
-	O
induced	O
Rac	B-GENE
activation	O
results	O
in	O
Rho	B-GENE
activation	O
,	O
and	O
factor	O
-	O
induced	O
Cdc42	B-GENE
activation	O
leads	O
to	O
Rac	B-GENE
activation	O
,	O
as	O
determined	O
by	O
specific	O
morphological	O
changes	O
.	O

Several	O
cDNAs	O
corresponding	O
to	O
the	O
human	B-GENE
PWP2	I-GENE
gene	I-GENE
were	O
identified	O
and	O
partially	O
sequenced	O
.	O

Isolation	O
and	O
genomic	O
structure	O
of	O
a	O
human	O
homolog	O
of	O
the	O
yeast	B-GENE
periodic	I-GENE
tryptophan	I-GENE
protein	I-GENE
2	I-GENE
(	O
PWP2	B-GENE
)	O
gene	O
mapping	O
to	O
21q22	O
.	O
3	O
.	O

Patterns	O
defined	O
by	O
combinations	O
of	O
normal	O
and	O
abnormal	O
laboratory	O
results	O
had	O
decreased	O
the	O
likelihood	O
of	O
PEM	O
from	O
an	O
all	O
-	O
2	O
to	O
all	O
-	O
0	O
pattern	O
.	O

To	O
examine	O
whether	O
thiamine	O
(	O
vitamin	O
B1	O
)	O
deficiency	O
is	O
associated	O
with	O
recurrent	O
aphthous	O
stomatitis	O
,	O
we	O
studied	O
vitamin	O
B1	O
levels	O
in	O
70	O
patients	O
with	O
recurrent	O
aphthous	O
stomatitis	O
and	O
in	O
50	O
members	O
of	O
a	O
control	O
group	O
.	O

Liver	O
injuries	O

By	O
screening	O
a	O
cDNA	O
library	O
with	O
a	O
probe	O
derived	O
from	O
sequences	O
downstream	O
of	O
the	O
p53p2	B-GENE
start	O
site	O
,	O
we	O
have	O
cloned	O
and	O
characterized	O
a	O
cDNA	O
that	O
represents	O
a	O
mRNA	O
that	O
appears	O
to	O
have	O
been	O
initiated	O
from	O
the	O
p53p2	B-GENE
promoter	I-GENE
.	O

However	O
,	O
we	O
did	O
not	O
observe	O
a	O
correlation	O
between	O
serum	O
and	O
seminal	B-GENE
plasma	I-GENE
PSA	I-GENE
levels	O
.	O

The	O
implications	O
for	O
estimates	O
of	O
cortical	O
magnification	O
and	O
possible	O
differences	O
in	O
the	O
specializations	O
of	O
foveal	O
and	O
peripheral	O
vision	O
are	O
discussed	O
.	O

G	B-GENE
-	I-GENE
CSF	I-GENE
activates	O
multiple	O
signaling	O
molecules	O
,	O
including	O
the	O
JAK1	B-GENE
and	O
JAK2	B-GENE
kinases	I-GENE
and	O
the	O
STAT	B-GENE
transcription	O
factors	O
.	O

Mutants	O
lacking	O
any	O
tyrosine	O
residues	O
in	O
the	O
cytoplasmic	O
domain	O
maintain	O
their	O
ability	O
to	O
activate	O
STAT5	B-GENE
and	O
STAT1	B-GENE
but	O
cannot	O
activate	O
STAT3	B-GENE
,	O
implying	O
that	O
STAT5	B-GENE
and	O
STAT1	B-GENE
activation	O
does	O
not	O
require	O
receptor	O
tyrosine	O
phosphorylation	O
.	O

In	O
addition	O
,	O
double	O
mutants	O
with	O
either	O
dim1	B-GENE
-	I-GENE
delta	I-GENE
or	O
dim2	B-GENE
-	I-GENE
1	I-GENE
and	O
the	O
endocytosis	O
mutants	B-GENE
end4	I-GENE
-	I-GENE
1	I-GENE
or	O
act1	B-GENE
-	I-GENE
1	I-GENE
displayed	O
synthetic	O
growth	O
defects	O
,	O
indicating	O
that	O
the	O
DIM	B-GENE
gene	I-GENE
products	I-GENE
function	O
in	O
a	O
common	O
or	O
parallel	O
endocytic	O
pathway	O
.	O

Such	O
multisensory	O
interactions	O
can	O
be	O
significant	O
for	O
behavior	O
.	O

The	O
P13	O
and	O
N22	O
of	O
ppSEPs	O
had	O
phase	O
reversal	O
relationship	O
with	O
the	O
P2	O
and	O
N2	O
recorded	O
from	O
the	O
PES	O
,	O
respectively	O
.	O

The	O
cDNA	O
of	O
cpm7	B-GENE
encodes	O
a	O
closely	O
related	O
protein	O
of	O
36	O
.	O
8	O
kDa	O
.	O

Finally	O
,	O
the	O
C	O
-	O
terminal	O
region	O
of	O
ENBP1	B-GENE
shows	O
strong	O
homology	O
to	O
a	O
protein	O
from	O
rat	O
that	O
is	O
specifically	O
expressed	O
in	O
testis	O
tissue	O
.	O

The	O
conservation	O
of	O
both	O
the	O
G	O
-	O
box	O
and	O
H	O
-	O
box	O
in	O
different	O
CHS	B-GENE
promoters	I-GENE
emphasizes	O
their	O
importance	O
as	O
regulatory	O
motifs	O
.	O

Mortality	O
on	O
the	O
last	O
ranch	O
was	O
particularly	O
severe	O
among	O
certain	O
segregated	O
groups	O
of	O
turkeys	O
that	O
included	O
toms	O
,	O
heavier	O
birds	O
,	O
and	O
birds	O
undergoing	O
a	O
stressful	O
event	O
such	O
as	O
artificial	O
insemination	O
.	O

Further	O
,	O
the	O
PIP2	O
content	O
of	O
the	O
85	O
-	O
90	O
kDa	O
protein	O
appeared	O
to	O
decrease	O
with	O
CSF	B-GENE
-	I-GENE
1	I-GENE
treatment	O
.	O

Further	O
,	O
the	O
PIP2	O
content	O
of	O
the	O
85	O
-	O
90	O
kDa	O
protein	O
appeared	O
to	O
decrease	O
with	O
CSF	B-GENE
-	I-GENE
1	I-GENE
treatment	O
.	O

Just	O
before	O
inserting	O
on	O
the	O
anterior	O
margin	O
and	O
apex	O
of	O
the	O
iliac	O
crest	O
it	O
widens	O
,	O
assuming	O
the	O
aspect	O
of	O
a	O
small	O
cone	O
.	O

Reperfusion	O
caused	O
a	O
transient	O
reduction	O
in	O
lactate	O
production	O
and	O
a	O
significant	O
increase	O
in	O
LDH	B-GENE
release	O
.	O

To	O
evaluate	O
the	O
hepatic	O
regenerative	O
response	O
in	O
patients	O
with	O
alcoholic	O
liver	O
disease	O
,	O
sera	O
from	O
263	O
patients	O
with	O
severe	O
alcoholic	O
hepatitis	O
and	O
/	O
or	O
cirrhosis	O
were	O
analyzed	O
for	O
hepatocyte	B-GENE
growth	I-GENE
factor	I-GENE
(	O
HGF	B-GENE
)	O
and	O
alpha	B-GENE
-	I-GENE
fetoprotein	I-GENE
(	O
AFP	B-GENE
)	O
.	O

Children	O
born	O
from	O
chronic	O
alcoholic	O
mothers	O
have	O
shown	O
behavioral	O
teratogenic	O
effects	O
more	O
frequently	O
than	O
morphological	O
malformations	O
.	O

INTERVENTION	O
(	O
S	O
)	O
:	O
Twenty	O
-	O
six	O
hemostasis	O
parameters	O
evaluated	O
repeatedly	O
in	O
patients	O
undergoing	O
IVF	O
-	O
ET	O
.	O

Here	O
we	O
report	O
that	O
expression	O
of	O
the	O
I	B-GENE
-	I-GENE
POU	I-GENE
/	O
tI	B-GENE
-	I-GENE
POU	I-GENE
message	O
is	O
maximal	O
late	O
in	O
the	O
embryonic	O
phase	O
of	O
Drosophila	O
development	O
,	O
and	O
I	B-GENE
-	I-GENE
POU	I-GENE
is	O
the	O
preferred	O
splice	O
variant	O
.	O

The	O
patient	O
'	O
s	O
role	O
,	O
organized	O
by	O
the	O
prerequisites	O
of	O
expressive	O
freedom	O
,	O
is	O
counter	O
posed	O
with	O
the	O
psychoanalyst	O
'	O
s	O
,	O
which	O
is	O
structured	O
to	O
empower	O
listening	O
and	O
understanding	O
.	O

The	O
most	O
common	O
risk	O
factor	O
reported	O
for	O
both	O
recent	O
and	O
all	O
other	O
hepatitis	O
C	O
cases	O
was	O
a	O
history	O
of	O
injecting	O
drug	O
use	O
,	O
although	O
the	O
proportion	O
of	O
cases	O
with	O
that	O
history	O
was	O
different	O
in	O
NT	O
from	O
ACT	O
and	O
Queensland	O
.	O

Silencing	O
can	O
be	O
restored	O
by	O
creation	O
of	O
a	O
telomere	O
at	O
13	O
kb	O
from	O
the	O
reporter	O
construct	O
,	O
or	O
by	O
insertion	O
of	O
340	O
bp	O
of	O
yeast	O
telomeric	O
repeat	O
sequence	O
at	O
this	O
site	O
without	O
chromosomal	O
truncation	O
.	O

In	O
contrast	O
with	O
previous	O
two	O
-	O
pool	O
models	O
,	O
provisions	O
were	O
made	O
for	O
folate	O
turnover	O
by	O
urinary	O
folate	O
excretion	O
(	O
as	O
measured	O
here	O
)	O
and	O
by	O
fecal	O
excretion	O
and	O
catabolic	O
processes	O
.	O

When	O
voltage	O
-	O
operated	O
Ca2	O
+	O
channels	O
(	O
VOC	O
)	O
were	O
blocked	O
by	O
nifedipine	O
,	O
midazolam	O
,	O
in	O
concentrations	O
more	O
than	O
1	O
microM	O
,	O
attenuated	O
both	O
phasic	O
and	O
tonic	O
responses	O
.	O

Although	O
p48	B-GENE
gene	I-GENE
induction	O
is	O
dependent	O
on	O
STAT1	B-GENE
and	O
JAK1	B-GENE
,	O
activated	O
STAT1	B-GENE
does	O
not	O
bind	O
to	O
GATE	B-GENE
.	O

The	O
syndrome	O
of	O
resistance	O
to	O
thyroid	O
hormone	O
is	O
characterized	O
by	O
elevated	O
serum	O
free	O
thyroid	O
hormones	O
,	O
failure	O
to	O
suppress	O
pituitary	B-GENE
thyrotropin	I-GENE
secretion	O
,	O
and	O
variable	O
peripheral	O
refractoriness	O
to	O
hormone	O
action	O
.	O

Finally	O
,	O
nonphotosynthetic	O
mutants	O
,	O
including	O
the	O
tscA	B-GENE
-	I-GENE
lacking	I-GENE
photosystem	I-GENE
I	I-GENE
mutant	I-GENE
,	O
H13	O
,	O
did	O
not	O
show	O
evidence	O
of	O
light	O
-	O
stimulated	O
RNA	O
processing	O
.	O

The	O
progression	O
of	O
acute	O
bronchitis	O
is	O
associated	O
with	O
elevated	O
blood	O
concentrations	O
of	O
acute	O
-	O
phase	O
proteins	O
,	O
KKS	B-GENE
activation	O
in	O
the	O
blood	O
and	O
high	O
serotonin	O
and	O
lactic	O
acid	O
content	O
in	O
the	O
humor	O
condensated	O
from	O
the	O
exhaled	O
air	O
.	O

Because	O
of	O
the	O
potential	O
implications	O
of	O
these	O
findings	O
in	O
human	O
physiology	O
,	O
we	O
cloned	O
the	O
hPACAP	B-GENE
-	I-GENE
R	I-GENE
gene	I-GENE
.	O

Differential	O
signaling	O
and	O
immediate	B-GENE
-	I-GENE
early	I-GENE
gene	I-GENE
activation	O
by	O
four	O
splice	O
variants	O
of	O
the	O
human	B-GENE
pituitary	I-GENE
adenylate	I-GENE
cyclase	I-GENE
-	I-GENE
activating	I-GENE
polypeptide	I-GENE
receptor	I-GENE
(	O
hPACAP	B-GENE
-	I-GENE
R	I-GENE
)	O
.	O

We	O
discuss	O
these	O
results	O
with	O
respect	O
to	O
the	O
transcriptional	O
induction	O
of	O
the	O
HNF	B-GENE
-	I-GENE
3	I-GENE
alpha	I-GENE
gene	I-GENE
in	O
respiratory	O
epithelium	O
during	O
embryogenesis	O
.	O

BACKGROUND	O
:	O
Mitosis	O
is	O
regulated	O
by	O
MPF	B-GENE
(	O
maturation	B-GENE
promoting	I-GENE
factor	I-GENE
)	O
,	O
the	O
active	O
form	O
of	O
Cdc2	B-GENE
/	I-GENE
28	I-GENE
-	O
cyclin	B-GENE
B	I-GENE
complexes	O
.	O

Ectopic	O
expression	O
of	O
Apo	B-GENE
-	I-GENE
3	I-GENE
in	O
HEK293	O
or	O
HeLa	O
cells	O
induced	O
marked	O
apoptosis	O
.	O

An	O
N	O
-	O
terminal	O
arm	O
from	O
each	O
subunit	O
wraps	O
around	O
the	O
dinucleotide	O
-	O
binding	O
domain	O
of	O
an	O
adjacent	O
subunit	O
,	O
covering	O
the	O
adenine	O
ring	O
of	O
NADP	O
.	O

Similarity	O
is	O
most	O
striking	O
in	O
the	O
zinc	O
knuckle	O
region	O
,	O
a	O
region	O
characteristic	O
of	O
gag	B-GENE
genes	I-GENE
of	O
most	O
replication	O
-	O
competent	O
retroelements	O
.	O

D	O
.	O
melanogaster	O
HeT	B-GENE
-	I-GENE
A	I-GENE
coding	O
sequences	O
have	O
a	O
polymorphic	O
region	O
with	O
insertions	O
/	O
deletions	O
of	O
1	O
-	O
31	O
codons	O
and	O
many	O
nucleotide	O
changes	O
.	O

Eukaryotic	B-GENE
initiation	I-GENE
factor	I-GENE
3	I-GENE
(	O
eIF3	B-GENE
)	O
is	O
a	O
large	O
multisubunit	O
complex	O
that	O
stabilizes	O
the	O
ternary	O
complex	O
,	O
eIF2	B-GENE
x	O
GTP	O
x	O
tRNA	B-GENE
(	I-GENE
Met	I-GENE
)	I-GENE
i	I-GENE
and	O
promotes	O
mRNA	O
binding	O
to	O
the	O
40	B-GENE
S	I-GENE
ribosomal	I-GENE
subunit	I-GENE
.	O
eIF3	B-GENE
also	O
functions	O
as	O
a	O
ribosome	O
subunit	O
anti	O
-	O
association	O
factor	O
.	O

Our	O
data	O
,	O
combined	O
with	O
those	O
of	O
Hershey	O
and	O
co	O
-	O
workers	O
,	O
suggest	O
that	O
mammalian	B-GENE
eIF3	I-GENE
is	O
composed	O
of	O
at	O
least	O
10	O
subunits	O
:	O
p170	B-GENE
,	O
p116	B-GENE
(	O
hPrt1	B-GENE
)	O
,	O
p110	B-GENE
,	O
p66	B-GENE
,	O
p48	B-GENE
,	O
p47	B-GENE
,	O
p44	B-GENE
,	O
p40	B-GENE
,	O
p36	B-GENE
,	O
and	O
p35	B-GENE
.	O

Identification	O
of	O
a	O
cis	O
-	O
acting	O
element	O
in	O
the	O
class	B-GENE
I	I-GENE
major	I-GENE
histocompatibility	I-GENE
complex	I-GENE
gene	I-GENE
promoter	I-GENE
responsive	O
to	O
activation	O
by	O
retroviral	O
sequences	O
.	O

The	O
results	O
demonstrate	O
that	O
(	O
i	O
)	O
no	O
intact	O
capsids	O
were	O
assembled	O
when	O
the	O
full	O
-	O
length	O
or	O
a	O
truncated	O
(	O
missing	O
the	O
C	O
-	O
terminal	O
65	O
amino	O
acids	O
)	O
UL80	B-GENE
.	I-GENE
5	I-GENE
protein	I-GENE
was	O
tested	O
;	O
(	O
ii	O
)	O
when	O
the	O
C	O
-	O
terminal	O
65	O
amino	O
acids	O
of	O
the	O
UL80	B-GENE
.	I-GENE
5	I-GENE
protein	I-GENE
were	O
replaced	O
with	O
the	O
C	O
-	O
terminal	O
25	O
amino	O
acids	O
of	O
the	O
UL26	B-GENE
.	I-GENE
5	I-GENE
protein	I-GENE
,	O
intact	O
capsids	O
were	O
made	O
and	O
direct	O
interaction	O
of	O
the	O
UL80	B-GENE
.	I-GENE
5	I-GENE
protein	I-GENE
with	O
VP5	B-GENE
was	O
detected	O
;	O
(	O
iii	O
)	O
assembly	O
of	O
intact	O
capsids	O
was	O
demonstrated	O
when	O
the	O
sequence	O
of	O
the	O
last	O
12	O
amino	O
acids	O
of	O
the	O
UL80	B-GENE
.	I-GENE
5	I-GENE
protein	I-GENE
was	O
changed	O
from	O
RRIFVA	O
ALNKLE	O
to	O
RRIFVAAMMKLE	O
;	O
(	O
iv	O
)	O
self	O
-	O
interaction	O
of	O
the	O
scaffold	O
proteins	O
is	O
mediated	O
by	O
sequences	O
N	O
terminal	O
to	O
the	O
maturation	O
cleavage	O
site	O
;	O
and	O
(	O
v	O
)	O
the	O
UL26	B-GENE
.	I-GENE
5	I-GENE
and	O
UL80	B-GENE
.	I-GENE
5	I-GENE
proteins	I-GENE
will	O
not	O
coassemble	O
into	O
scaffold	O
structures	O
.	O

Fourth	O
,	O
the	O
3	O
'	O
-	O
region	O
splice	O
junctions	O
of	O
the	O
MSRs	B-GENE
during	O
latent	O
and	O
productive	O
infection	O
were	O
determined	O
by	O
sequencing	O
RNA	O
-	O
PCR	O
products	O
generated	O
with	O
primers	O
that	O
flank	O
the	O
3	O
'	O
splice	O
region	O
.	O

(	O
ii	O
)	O
ICP27	B-GENE
binds	O
preferentially	O
to	O
less	O
modified	O
forms	O
of	O
ICP4	B-GENE
,	O
a	O
protein	O
that	O
is	O
extensively	O
modified	O
posttranslationally	O
.	O

Lack	O
of	O
sufficient	O
data	O
on	O
vibration	O
measurements	O
and	O
employment	O
durations	O
add	O
to	O
the	O
uncertainty	O
,	O
as	O
do	O
variations	O
in	O
tool	O
conditions	O
(	O
grinder	O
wheels	O
,	O
etc	O
)	O
and	O
inherent	O
difficulties	O
in	O
measurement	O
.	O

C	B-GENE
/	I-GENE
EBP	I-GENE
beta	I-GENE
V	I-GENE
>	O
A	O
selectively	O
binds	O
only	O
the	O
subset	O
of	O
C	B-GENE
/	I-GENE
EBP	I-GENE
sites	I-GENE
that	O
are	O
also	O
DBP	B-GENE
sites	I-GENE
,	O
both	O
as	O
oligonucleotides	O
and	O
within	O
the	O
natural	O
contexts	O
of	O
the	O
albumin	B-GENE
and	O
cholesterol	B-GENE
hydroxylase	I-GENE
promoters	I-GENE
.	O

Specific	O
IgG	B-GENE
,	O
specific	O
IgE	B-GENE
and	O
total	O
IgE	B-GENE
immunoglobulins	I-GENE
against	O
Toxocara	B-GENE
canis	I-GENE
excretory	I-GENE
/	I-GENE
secretory	I-GENE
antigens	I-GENE
(	O
TES	B-GENE
)	O
were	O
detected	O
by	O
using	O
ELISA	O
technique	O
.	O

SUMMARY	O
BACKGROUND	O
DATA	O
:	O
Melanoma	O
care	O
has	O
not	O
changed	O
significantly	O
in	O
the	O
last	O
20	O
years	O
,	O
and	O
the	O
controversy	O
of	O
elective	O
lymph	O
node	O
dissections	O
in	O
this	O
disease	O
continues	O
to	O
be	O
discussed	O
.	O

The	O
differences	O
among	O
subgenera	O
of	O
the	O
genus	O
Dermacentor	O
are	O
more	O
significant	O
.	O

Mutating	O
the	O
E	O
-	O
box	O
in	O
the	O
context	O
of	O
the	O
3	O
'	O
-	O
flanking	O
region	O
confirmed	O
that	O
it	O
contributes	O
to	O
the	O
enhancement	O
of	O
transcriptional	O
activity	O
of	O
the	O
alpha1	B-GENE
(	I-GENE
I	I-GENE
)	I-GENE
collagen	I-GENE
gene	I-GENE
promoter	I-GENE
.	O

Expression	O
of	O
neuronal	O
traits	O
in	O
pancreatic	O
beta	O
cells	O
.	O

We	O
propose	O
that	O
Mnt	B-GENE
:	O
Max	B-GENE
:	O
Sin3	B-GENE
complexes	O
normally	O
function	O
to	O
restrict	O
Myc	B-GENE
:	O
Max	B-GENE
activities	O
associated	O
with	O
cell	O
proliferation	O
.	O

Phenotypic	O
changes	O
induced	O
by	O
wild	B-GENE
type	I-GENE
and	I-GENE
variant	I-GENE
c	I-GENE
-	I-GENE
src	I-GENE
genes	I-GENE
carrying	O
C	O
-	O
terminal	O
sequence	O
alterations	O
.	O

The	O
resurgence	O
of	O
drug	O
-	O
resistant	O
malaria	O
makes	O
urgent	O
the	O
evaluation	O
of	O
new	O
antimalarial	O
agents	O
.	O

In	O
the	O
p51	B-GENE
subunit	I-GENE
,	O
the	O
Cys181	O
side	O
-	O
chain	O
is	O
oriented	O
in	O
a	O
similar	O
direction	O
to	O
the	O
Tyr181	O
side	O
-	O
chain	O
in	O
the	O
wild	O
-	O
type	O
complex	O
.	O

The	O
relatively	O
high	O
level	O
transcription	O
from	O
this	O
gene	O
shows	O
that	O
the	O
polymorphic	O
chromosome	O
ends	O
of	O
P	O
.	O
falciparum	O
,	O
which	O
have	O
been	O
proposed	O
to	O
be	O
transcriptionally	O
silent	O
,	O
can	O
be	O
active	O
expression	O
sites	O
for	O
var	B-GENE
genes	I-GENE
.	O

NUP145	B-GENE
was	O
previously	O
identified	O
by	O
using	O
a	O
genetic	O
synthetic	O
lethal	O
screen	O
(	O
E	O
.	O

Prevalence	O
of	O
sleep	O
-	O
disordered	O
breathing	O
(	O
SDB	O
)	O
is	O
reported	O
to	O
increase	O
in	O
menopausal	O
women	O
.	O

In	O
all	O
cases	O
the	O
antigenemia	O
was	O
transient	O
and	O
cleared	O
by	O
28th	O
day	O
post	O
-	O
vaccination	O
.	O

A	O
total	O
of	O
1459	O
men	O
aged	O
48	O
to	O
84	O
years	O
,	O
who	O
were	O
diagnosed	O
for	O
the	O
first	O
time	O
by	O
physicians	O
as	O
having	O
BPH	O
in	O
1994	O
and	O
who	O
had	O
not	O
received	O
treatment	O
,	O
participated	O
in	O
the	O
study	O
.	O

In	O
vitro	O
translation	O
of	O
the	O
mTRF1	B-GENE
cDNA	I-GENE
resulted	O
in	O
a	O
56	O
kDa	O
protein	O
that	O
binds	O
to	O
TTAGGG	O
repeat	O
arrays	O
.	O
mTRF1	B-GENE
displayed	O
the	O
same	O
sequence	O
specificity	O
as	O
hTRF1	B-GENE
,	O
preferring	O
arrays	O
of	O
TTAGGG	O
repeats	O
as	O
a	O
binding	O
substrate	O
over	O
TTAGGC	O
and	O
TTGGGG	O
repeats	O
.	O

The	O
ubiquitously	O
expressed	O
E12	B-GENE
bHLH	I-GENE
protein	I-GENE
dimerizes	O
with	O
numerous	O
cell	O
-	O
specific	O
bHLH	B-GENE
factors	I-GENE
.	O

The	O
E	O
-	O
box	O
sequence	O
in	O
the	O
SE2	B-GENE
fragment	I-GENE
of	O
the	O
transferrin	B-GENE
promoter	I-GENE
was	O
CATCTG	O
and	O
was	O
similar	O
in	O
gel	O
shifts	O
to	O
the	O
consensus	O
E	O
-	O
box	O
elements	O
(	O
CANNTG	O
)	O
previously	O
characterized	O
.	O

A	O
5	O
.	O
3	O
-	O
kb	O
DNA	O
fragment	O
,	O
which	O
included	O
the	O
entire	O
structural	O
porin	B-GENE
gene	I-GENE
(	O
named	O
porCa	B-GENE
)	O
and	O
its	O
flanking	O
regions	O
,	O
was	O
identified	O
.	O

The	O
human	B-GENE
p100	I-GENE
protein	I-GENE
was	O
recently	O
identified	O
as	O
a	O
coactivator	O
of	O
the	O
Epstein	B-GENE
-	I-GENE
Barr	I-GENE
virus	I-GENE
nuclear	I-GENE
antigen	I-GENE
2	I-GENE
.	O

However	O
,	O
five	O
new	O
mutation	O
sites	O
(	O
S61	B-GENE
,	O
SL1	B-GENE
,	O
S29	B-GENE
,	O
SL11	B-GENE
,	O
SL196	B-GENE
and	O
SL126	B-GENE
)	O
are	O
unique	O
to	O
the	O
nrdB	B-GENE
intron	O
and	O
disrupt	O
self	O
-	O
splicing	O
.	O

This	O
report	O
presents	O
the	O
isolation	O
and	O
characterization	O
of	O
the	O
5	O
'	O
-	O
flanking	O
region	O
(	O
1	O
.	O
2	O
kb	O
)	O
and	O
exon	O
1	O
of	O
the	O
human	B-GENE
RII	I-GENE
alpha	I-GENE
gene	I-GENE
.	O

A	O
cohort	O
of	O
Swedish	O
children	O
was	O
monitored	O
from	O
6	O
months	O
to	O
11	O
years	O
of	O
age	O
.	O

The	O
aim	O
of	O
this	O
study	O
was	O
to	O
assess	O
the	O
reproducibility	O
of	O
a	O
number	O
of	O
simplified	O
clearance	O
methods	O
using	O
chromium	O
-	O
51	O
ethylenediamine	O
tetraacetic	O
acid	O
(	O
51Cr	O
-	O
EDTA	O
)	O
and	O
to	O
compare	O
these	O
with	O
the	O
multiple	O
blood	O
sample	O
technique	O
.	O

The	O
primary	O
structure	O
of	O
a	O
2671	O
bp	O
DNA	O
fragment	O
between	O
the	O
pla	B-GENE
gene	I-GENE
(	O
encoding	O
plasminogen	B-GENE
activator	I-GENE
)	O
and	O
the	O
origin	O
of	O
replication	O
of	O
the	O
wild	O
-	O
type	O
Yersinia	O
pestis	O
plasmid	O
pYP358	O
was	O
determined	O
.	O

MAIN	O
OUTCOME	O
MEASURES	O
:	O
Associations	O
of	O
factor	O
analysis	O
-	O
derived	O
syndromes	O
with	O
risk	O
factors	O
for	O
chemical	O
interactions	O
that	O
inhibit	O
butyrylcholinesterase	B-GENE
and	O
neuropathy	O
target	O
esterase	B-GENE
.	O

CONCLUSION	O
:	O
Some	O
Gulf	O
War	O
veterans	O
may	O
have	O
delayed	O
,	O
chronic	O
neurotoxic	O
syndromes	O
from	O
wartime	O
exposure	O
to	O
combinations	O
of	O
chemicals	O
that	O
inhibit	O
butyrylcholinesterase	B-GENE
and	O
neuropathy	B-GENE
target	I-GENE
esterase	I-GENE
.	O

No	O
correlation	O
between	O
the	O
age	O
of	O
the	O
horses	O
and	O
the	O
antibody	O
level	O
could	O
be	O
found	O
.	O

The	O
GHR	B-GENE
mRNA	I-GENE
:	O
GHBP	B-GENE
mRNA	I-GENE
ratio	O
was	O
1	O
.	O
1	O
+	O
/	O
-	O
0	O
.	O
12	O
and	O
remained	O
unchanged	O
during	O
differentiation	O
.	O

The	O
results	O
demonstrate	O
(	O
i	O
)	O
that	O
the	O
selenocysteine	O
-	O
specific	O
UGA	O
codon	O
is	O
readily	O
suppressed	O
under	O
conditions	O
where	O
the	O
homologous	B-GENE
SelB	I-GENE
protein	I-GENE
is	O
absent	O
and	O
(	O
ii	O
)	O
that	O
apart	O
from	O
the	O
specificity	O
of	O
the	O
SelB	B-GENE
-	I-GENE
mRNA	I-GENE
interaction	O
,	O
a	O
structural	O
compatibility	O
of	O
the	O
quaternary	O
complex	O
with	O
the	O
ribosome	O
is	O
required	O
.	O

One	O
linker	O
-	O
peptide	O
insertion	O
in	O
the	O
RsaA	B-GENE
C	I-GENE
terminus	I-GENE
(	I-GENE
amino	I-GENE
acid	I-GENE
784	I-GENE
)	I-GENE
had	O
no	O
effect	O
on	O
S	O
-	O
layer	O
biogenesis	O
,	O
while	O
another	O
(	O
amino	O
acid	O
907	O
)	O
disrupted	O
secretion	O
of	O
the	O
protein	O
,	O
suggesting	O
that	O
RsaA	B-GENE
possesses	O
a	O
secretion	O
signal	O
lying	O
C	O
terminal	O
to	O
amino	O
acid	O
784	O
,	O
near	O
or	O
including	O
amino	O
acid	O
907	O
.	O

To	O
characterize	O
the	O
gene	O
products	O
,	O
the	O
cvaA	B-GENE
gene	I-GENE
was	O
subcloned	O
and	O
expressed	O
under	O
the	O
control	O
of	O
T7	B-GENE
RNA	I-GENE
polymerase	I-GENE
promoter	I-GENE
.	O

PrpB	B-GENE
showed	O
homology	O
to	O
carboxyphosphonoenolpyruvate	B-GENE
phosphonomutase	I-GENE
of	I-GENE
Streptomyces	I-GENE
hygroscopicus	I-GENE
and	O
to	O
its	O
homolog	O
in	O
the	O
carnation	O
Dianthus	O
caryophyllus	O
;	O
PrpC	B-GENE
was	O
homologous	O
to	O
both	O
archaeal	B-GENE
and	I-GENE
bacterial	I-GENE
citrate	I-GENE
synthases	I-GENE
;	O
PrpD	B-GENE
showed	O
homology	O
to	O
yeast	O
and	O
Bacillus	O
subtilis	O
proteins	O
of	O
unknown	O
function	O
;	O
PrpE	B-GENE
showed	O
homology	O
to	O
acetyl	B-GENE
coenzyme	I-GENE
A	I-GENE
synthetases	I-GENE
.	O

MAIN	O
OUTCOME	O
MEASURES	O
:	O
Systemic	O
and	O
pulmonary	O
hemodynamics	O
,	O
arterial	O
blood	O
gas	O
determination	O
,	O
bronchoalveolar	O
lavage	O
protein	O
and	O
neutrophil	O
content	O
,	O
neutrophil	O
oxidant	O
burst	O
,	O
lung	B-GENE
myeloperoxidase	I-GENE
content	O
,	O
and	O
scanning	O
electron	O
micrographic	O
studies	O
.	O

We	O
have	O
isolated	O
a	O
cDNA	O
encoding	O
human	B-GENE
MEKK3	I-GENE
.	O

To	O
investigate	O
the	O
mechanisms	O
involved	O
in	O
the	O
transcriptional	O
control	O
of	O
retinoid	B-GENE
X	I-GENE
receptor	I-GENE
(	O
RXR	B-GENE
)	O
gene	O
expression	O
,	O
the	O
5	O
'	O
-	O
flanking	O
region	O
of	O
the	O
human	B-GENE
RXRgamma2	I-GENE
isoform	I-GENE
was	O
characterized	O
.	O

JNK	B-GENE
and	O
p38	B-GENE
are	O
constitutively	O
present	O
in	O
the	O
nucleus	O
,	O
and	O
DNA	O
-	O
bound	O
c	B-GENE
-	I-GENE
JUN	I-GENE
and	O
ATF	B-GENE
-	I-GENE
2	I-GENE
are	O
stably	O
contacted	O
by	O
JNK	B-GENE
and	O
p38	B-GENE
,	O
respectively	O
.	O

The	O
effects	O
of	O
dominant	O
interfering	O
forms	O
of	O
the	O
JNK	B-GENE
/	O
p38	B-GENE
signaling	O
pathway	O
demonstrate	O
that	O
activation	O
of	O
these	O
kinases	O
is	O
critical	O
for	O
cytokine	O
-	O
induced	O
E	B-GENE
-	I-GENE
selectin	I-GENE
gene	I-GENE
expression	O
.	O

Sp1	B-GENE
binds	O
the	O
CTC	O
repeat	O
with	O
an	O
affinity	O
,	O
KD	O
=	O
0	O
.	O
37	O
nM	O
,	O
at	O
least	O
as	O
high	O
as	O
the	O
consensus	O
GC	O
box	O
.	O

Identification	O
of	O
the	O
region	O
in	O
actin	B-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
that	O
binds	O
to	O
the	O
cytoplasmic	O
domain	O
of	O
glycoprotein	B-GENE
IBalpha	I-GENE
.	O

Mutant	O
enzyme	O
forms	O
were	O
prepared	O
to	O
eliminate	O
the	O
initial	O
autoprocessing	O
site	O
and	O
thus	O
form	O
an	O
active	O
single	O
-	O
chain	O
protein	O
for	O
structure	O
-	O
function	O
studies	O
.	O

The	O
primer	O
is	O
generated	O
by	O
a	O
cleavage	O
that	O
occurs	O
between	O
bases	O
11	O
and	O
12	O
of	O
the	O
Tf1	B-GENE
mRNA	I-GENE
.	O

Similarly	O
,	O
we	O
examined	O
whether	O
the	O
ELK1	B-GENE
,	O
SAP1a	B-GENE
,	O
FLI1	B-GENE
,	O
EWS	B-GENE
-	O
FLI1	B-GENE
,	O
ETS1	B-GENE
,	O
ETS2	B-GENE
,	O
PEA3	B-GENE
and	O
PU	B-GENE
.	I-GENE
1	I-GENE
proteins	I-GENE
can	O
form	O
ternary	O
complexes	O
with	O
SRF	B-GENE
on	O
the	O
Egr1	B-GENE
SREI	B-GENE
and	I-GENE
II	I-GENE
.	O

This	O
R	O
-	O
domain	O
may	O
modulate	O
the	O
interaction	O
with	O
SRF	B-GENE
,	O
providing	O
a	O
mechanism	O
that	O
would	O
be	O
unique	O
to	O
FLI1	B-GENE
and	O
EWS	B-GENE
-	O
FLI1	B-GENE
,	O
thus	O
implicating	O
a	O
novel	O
function	O
for	O
these	O
ETS	B-GENE
transcription	I-GENE
factors	I-GENE
in	O
the	O
regulation	O
of	O
the	O
Egr1	B-GENE
gene	I-GENE
.	O

The	O
murine	O
chromosomal	O
locations	O
of	O
the	O
five	O
NMDA	B-GENE
receptor	I-GENE
channel	I-GENE
subunits	I-GENE
,	O
the	O
epsilon	B-GENE
1	I-GENE
(	O
Grin2a	B-GENE
)	O
,	O
epsilon	B-GENE
2	I-GENE
(	O
Grin2b	B-GENE
)	O
,	O
epsilon	B-GENE
3	I-GENE
(	O
Grin2c	B-GENE
)	O
,	O
epsilon	B-GENE
4	I-GENE
(	O
Grin2d	B-GENE
)	O
and	O
zeta	B-GENE
1	I-GENE
(	O
Grinl	B-GENE
)	O
subunits	O
,	O
were	O
determined	O
using	O
an	O
interspecific	O
backcross	O
mapping	O
panel	O
derived	O
from	O
crosses	O
of	O
[	O
(	O
C57BL	O
/	O
6JxM	O
.	O
spretus	O
)	O
F1xC57BL	O
/	O
6J	O
]	O
mice	O
.	O

CDNA	O
cloning	O
of	O
chick	B-GENE
brain	I-GENE
alpha	I-GENE
-	I-GENE
amino	I-GENE
-	I-GENE
3	I-GENE
-	I-GENE
hydroxy	I-GENE
-	I-GENE
5	I-GENE
-	I-GENE
methyl	I-GENE
-	I-GENE
4	I-GENE
-	I-GENE
isoxazolepropionic	I-GENE
acid	I-GENE
receptors	I-GENE
reveals	O
conservation	O
of	O
structure	O
,	O
function	O
and	O
post	O
-	O
transcriptional	O
processes	O
with	O
mammalian	O
receptors	O
.	O

Remarkably	O
,	O
both	O
TTD	O
-	O
A	O
and	O
XP	O
-	O
D	O
defects	O
are	O
associated	O
with	O
subunits	O
of	O
TFIIH	B-GENE
,	O
a	O
basal	O
transcription	O
factor	O
with	O
a	O
second	O
function	O
in	O
DNA	O
repair	O
.	O

Adjustment	O
for	O
age	O
,	O
total	O
cholesterol	O
,	O
HDL	B-GENE
cholesterol	I-GENE
,	O
triglycerides	O
,	O
current	O
smoking	O
,	O
and	O
systolic	O
pressure	O
slightly	O
reduced	O
the	O
association	O
between	O
fibrinogen	B-GENE
and	O
atherosclerosis	O
.	O

Cholesterol	B-GENE
side	I-GENE
-	I-GENE
chain	I-GENE
cleavage	I-GENE
cytochrome	I-GENE
P450	I-GENE
(	O
CYP11A	B-GENE
;	O
P450scc	B-GENE
)	O
gene	O
expression	O
is	O
regulated	O
by	O
gonadotropins	B-GENE
via	O
cAMP	O
in	O
the	O
ovary	O
and	O
by	O
ACTH	B-GENE
via	O
cAMP	O
in	O
adrenal	O
cortical	O
cells	O
.	O

One	O
possible	O
solution	O
is	O
a	O
thin	O
radial	O
forearm	O
free	O
flap	O
.	O

Structural	O
analysis	O
and	O
characterization	O
of	O
tissue	O
and	O
hormonal	O
responsive	O
expression	O
of	O
the	O
avian	B-GENE
bone	I-GENE
sialoprotein	I-GENE
(	O
BSP	B-GENE
)	O
gene	O
.	O

The	O
Y	O
-	O
type	O
structural	O
motif	O
is	O
also	O
conserved	O
among	O
a	O
number	O
of	O
divergent	O
BiP	B-GENE
mRNAs	I-GENE
.	O

A	O
false	O
positive	O
marker	O
screen	O
was	O
associated	O
with	O
the	O
occurrence	O
of	O
hand	O
-	O
foot	O
syndrome	O
even	O
when	O
the	O
effect	O
of	O
regimen	O
was	O
accounted	O
for	O
by	O
stratification	O
(	O
p	O
=	O
.	O
01	O
)	O
.	O

The	O
detection	O
of	O
ORF	B-GENE
-	I-GENE
1	I-GENE
sequences	O
in	O
human	O
tumors	O
,	O
while	O
not	O
proof	O
per	O
se	O
,	O
is	O
a	O
prerequisite	O
for	O
establishing	O
its	O
role	O
in	O
tumor	O
development	O
.	O

Phylogenetic	O
analysis	O
gave	O
evidence	O
for	O
a	O
close	O
evolutionary	O
relationship	O
between	O
PhHV	O
-	O
1	O
and	O
members	O
of	O
the	O
Varicellovirus	O
genus	O
of	O
the	O
alpha	O
-	O
Herpesvirinae	O
and	O
canid	O
herpesvirus	O
in	O
particular	O
.	O

In	O
this	O
method	O
,	O
PLP	O
in	O
plasma	O
can	O
be	O
determined	O
with	O
high	O
sensitivity	O
using	O
derivatization	O
with	O
sodium	O
bisulfite	O
in	O
the	O
mobile	O
phase	O
.	O

Both	O
HEF1	B-GENE
and	O
Cas	B-GENE
were	O
found	O
to	O
complex	O
with	O
the	O
related	B-GENE
adhesion	I-GENE
focal	I-GENE
tyrosine	I-GENE
kinase	I-GENE
(	O
RAFTK	B-GENE
)	O
,	O
and	O
when	O
tyrosine	O
phosphorylated	O
,	O
with	O
the	O
adapter	O
molecule	O
CrkL	B-GENE
.	O

SIM1	B-GENE
and	O
SIM2	B-GENE
do	O
not	O
form	O
homodimers	O
,	O
and	O
they	O
do	O
not	O
interact	O
with	O
AHR	B-GENE
.	O

Complexes	O
of	O
qTBP42	B-GENE
with	O
each	O
complementary	O
strand	O
of	O
telomeric	O
DNA	O
and	O
with	O
quadruplex	O
forms	O
of	O
the	O
guanine	O
-	O
rich	O
strand	O
had	O
3	O
.	O
7	O
-	O
14	O
.	O
6	O
nM	O
dissociation	O
constants	O
,	O
Kd	O
,	O
whereas	O
complexes	O
with	O
double	O
-	O
stranded	O
telomeric	O
DNA	O
had	O
up	O
to	O
100	O
-	O
fold	O
higher	O
Kd	O
values	O
.	O

Moreover	O
,	O
the	O
effect	O
exerted	O
by	O
TIS1	B-GENE
appeared	O
to	O
be	O
selective	O
for	O
the	O
MCK	B-GENE
promoter	I-GENE
.	O

What	O
'	O
s	O
new	O
in	O
gynecologic	O
and	O
obstetrical	O
surgery	O
.	O

The	O
dnaK	B-GENE
operon	I-GENE
of	I-GENE
Bacillus	I-GENE
subtilis	I-GENE
is	O
heptacistronic	O
.	O

Moreover	O
,	O
expression	O
of	O
CBF1	B-GENE
in	O
yeast	O
was	O
found	O
to	O
activate	O
transcription	O
of	O
reporter	O
genes	O
containing	O
the	O
C	O
-	O
repeat	O
/	O
DRE	O
as	O
an	O
upstream	O
activator	O
sequence	O
but	O
not	O
mutant	O
versions	O
of	O
the	O
DNA	O
element	O
.	O

Forty	O
-	O
one	O
ASA	O
physical	O
status	O
I	O
or	O
II	O
adult	O
patients	O
undergoing	O
a	O
variety	O
of	O
1	O
-	O
1	O
.	O
5	O
h	O
surgical	O
procedures	O
were	O
randomly	O
allocated	O
to	O
receive	O
CCA	O
with	O
desflurane	O
or	O
isoflurane	O
with	O
ventilation	O
being	O
either	O
spontaneous	O
or	O
controlled	O
.	O

OBJECTIVE	O
:	O
Our	O
goal	O
was	O
to	O
determine	O
whether	O
chlamydia	O
-	O
infected	O
women	O
have	O
a	O
higher	O
rate	O
of	O
febrile	O
complications	O
after	O
postpartum	O
tubal	O
ligation	O
.	O

In	O
the	O
electrophoresis	O
mobility	O
shift	O
assay	O
using	O
nuclear	O
extracts	O
of	O
the	O
myogenic	O
cells	O
,	O
MyoD	B-GENE
and	O
myogenin	B-GENE
bound	O
to	O
the	O
right	O
E	O
-	O
box	O
in	O
the	O
enhancer	O
region	O
of	O
the	O
MCK	B-GENE
gene	I-GENE
even	O
in	O
the	O
presence	O
of	O
BMP	B-GENE
-	I-GENE
2	I-GENE
.	O

A	O
heterologous	O
promoter	O
construct	O
containing	O
three	O
repeats	O
of	O
a	O
consensus	O
Sp1	B-GENE
site	I-GENE
,	O
cloned	O
upstream	O
of	O
a	O
single	O
copy	O
of	O
the	O
ZII	B-GENE
(	O
CREB	B-GENE
/	I-GENE
AP1	I-GENE
)	O
element	O
from	O
the	O
BZLF1	B-GENE
promoter	I-GENE
linked	O
to	O
the	O
beta	B-GENE
-	I-GENE
globin	I-GENE
TATA	O
box	O
,	O
exhibited	O
phorbol	O
ester	O
inducibility	O
.	O

Subsequent	O
experiments	O
showed	O
that	O
motoric	O
tasks	O
rather	O
than	O
cognitive	O
aspects	O
of	O
the	O
COWA	O
task	O
were	O
critical	O
in	O
potentiating	O
finger	O
-	O
tapping	O
performance	O
.	O

cDNA	O
cloning	O
,	O
expression	O
analysis	O
,	O
and	O
chromosomal	O
localization	O
of	O
a	O
gene	O
with	O
high	O
homology	O
to	O
wheat	B-GENE
eIF	I-GENE
-	I-GENE
(	I-GENE
iso	I-GENE
)	I-GENE
4F	I-GENE
and	O
mammalian	B-GENE
eIF	I-GENE
-	I-GENE
4G	I-GENE
.	O

Therefore	O
,	O
it	O
is	O
important	O
to	O
control	O
hypertension	O
and	O
keep	O
appropriate	O
renal	O
blood	O
flow	O
during	O
living	O
renal	O
transplantation	O
surgery	O
.	O

The	O
initial	O
patients	O
treated	O
with	O
AZQ	O
and	O
mitroxantrone	O
experienced	O
prolonged	O
bone	O
marrow	O
suppression	O
and	O
,	O
therefore	O
,	O
subsequent	O
cohorts	O
were	O
treated	O
with	O
G	B-GENE
-	I-GENE
CSF	I-GENE
,	O
5	O
micrograms	O
/	O
kg	O
,	O
beginning	O
the	O
day	O
after	O
completion	O
of	O
the	O
third	O
cycle	O
of	O
chemotherapy	O
.	O

Human	B-GENE
granulocyte	I-GENE
-	I-GENE
macrophage	I-GENE
colony	I-GENE
-	I-GENE
stimulating	I-GENE
factor	I-GENE
(	O
hGM	B-GENE
-	I-GENE
CSF	I-GENE
)	O
activates	O
a	O
set	O
of	O
genes	O
such	O
as	O
c	B-GENE
-	I-GENE
fos	I-GENE
,	O
jun	B-GENE
,	O
myc	B-GENE
,	O
and	O
early	B-GENE
growth	I-GENE
response	I-GENE
gene	I-GENE
1	I-GENE
(	O
egr	B-GENE
-	I-GENE
1	I-GENE
)	O
.	O

In	O
order	O
to	O
provide	O
adequate	O
local	O
control	O
without	O
compromising	O
cosmetic	O
outcome	O
,	O
the	O
amount	O
of	O
breast	O
tissue	O
that	O
must	O
be	O
excised	O
in	O
BCT	O
needs	O
to	O
be	O
individualized	O
.	O

Surprisingly	O
,	O
however	O
,	O
TCR	B-GENE
-	O
mediated	O
tyrosine	O
phosphorylation	O
of	O
phospholipase	B-GENE
C	I-GENE
gamma	I-GENE
1	I-GENE
remains	O
intact	O
in	O
the	O
Jurkat	O
cells	O
expressing	O
the	O
A2	B-GENE
/	O
HCP	B-GENE
chimera	O
.	O

The	O
14	B-GENE
.	I-GENE
1	I-GENE
(	I-GENE
IGLL1	I-GENE
)	I-GENE
gene	I-GENE
is	O
expressed	O
in	O
a	O
lineage	O
-	O
and	O
stage	O
-	O
restricted	O
manner	O
.	O

The	O
interferon	B-GENE
(	O
IFN	B-GENE
)	O
-	O
induced	O
double	B-GENE
-	I-GENE
stranded	I-GENE
RNA	I-GENE
(	I-GENE
dsRNA	I-GENE
)	I-GENE
-	I-GENE
activated	I-GENE
Ser	I-GENE
/	I-GENE
Thr	I-GENE
protein	I-GENE
kinase	I-GENE
(	O
PKR	B-GENE
)	O
plays	O
a	O
role	O
in	O
the	O
antiviral	O
and	O
antiproliferative	O
effects	O
of	O
IFN	B-GENE
.	O

Together	O
,	O
the	O
data	O
suggest	O
that	O
cAMP	O
-	O
dependent	O
control	O
of	O
the	O
amounts	O
of	O
the	O
activator	O
SF	B-GENE
-	I-GENE
1	I-GENE
vs	O
.	O
the	O
repressor	O
COUP	B-GENE
-	I-GENE
TF	I-GENE
could	O
influence	O
CRS2	O
-	O
dependent	O
transcription	O
.	O

Object	O
relations	O
,	O
affect	O
management	O
,	O
and	O
psychic	O
structure	O
formation	O
.	O

When	O
expressed	O
in	O
COS	O
-	O
7	O
cells	O
,	O
MKP	B-GENE
-	I-GENE
4	I-GENE
blocks	O
activation	O
of	O
MAP	B-GENE
kinases	I-GENE
with	O
the	O
selectivity	O
ERK	B-GENE
>	O
p38	B-GENE
=	O
JNK	B-GENE
/	O
SAPK	B-GENE
.	O

Most	O
kinases	O
are	O
not	O
significantly	O
inhibited	O
by	O
roscovitine	O
.	O
cdc2	B-GENE
/	O
cyclin	B-GENE
B	I-GENE
,	O
cdk2	B-GENE
/	O
cyclin	B-GENE
A	I-GENE
,	O
cdk2	B-GENE
/	O
cyclin	B-GENE
E	I-GENE
and	O
cdk5	B-GENE
/	O
p35	B-GENE
only	O
are	O
substantially	O
inhibited	O
(	O
IC50	O
values	O
of	O
0	O
.	O
65	O
,	O
0	O
.	O
7	O
,	O
0	O
.	O
7	O
and	O
0	O
.	O
2	O
microM	O
,	O
respectively	O
)	O
.	O
cdk4	B-GENE
/	O
cyclin	B-GENE
D1	I-GENE
and	O
cdk6	B-GENE
/	O
cyclin	B-GENE
D2	I-GENE
are	O
very	O
poorly	O
inhibited	O
by	O
roscovitine	O
(	O
IC50	O
>	O
100	O
microM	O
)	O
.	O

Interaction	O
of	O
Ets	B-GENE
-	I-GENE
1	I-GENE
and	O
the	O
POU	B-GENE
-	I-GENE
homeodomain	I-GENE
protein	I-GENE
GHF	B-GENE
-	I-GENE
1	I-GENE
/	O
Pit	B-GENE
-	I-GENE
1	I-GENE
reconstitutes	O
pituitary	O
-	O
specific	O
gene	O
expression	O
.	O

Although	O
Pho85	B-GENE
is	O
not	O
essential	O
for	O
viability	O
,	O
Pcl1	B-GENE
,	I-GENE
2	I-GENE
-	O
Pho85	B-GENE
kinase	O
complexes	O
become	O
essential	O
for	O
Start	O
in	O
the	O
absence	O
of	O
Cln1	B-GENE
,	I-GENE
2	I-GENE
-	O
Cdc28	B-GENE
kinases	O
.	O

Using	O
the	O
yeast	O
two	O
-	O
hybrid	O
system	O
to	O
screen	O
for	O
proteins	O
which	O
interact	O
with	O
Tax1	B-GENE
,	O
we	O
isolated	O
the	O
B	O
subunit	O
of	O
the	O
CCAAT	O
binding	O
protein	O
NF	B-GENE
-	I-GENE
Y	I-GENE
from	O
a	O
HeLa	O
cDNA	O
library	O
.	O

Enhancer	O
activity	O
requires	O
both	O
the	O
AP	B-GENE
-	I-GENE
1	I-GENE
site	I-GENE
and	O
these	O
adjacent	O
sequences	O
.	O

Studies	O
using	O
HLA	B-GENE
-	I-GENE
DR	I-GENE
-	O
B7	B-GENE
-	I-GENE
1	I-GENE
-	O
LFA	B-GENE
-	I-GENE
3	I-GENE
triple	O
transfectants	O
showed	O
that	O
the	O
LFA	B-GENE
-	I-GENE
3	I-GENE
-	O
induced	O
NF	B-GENE
-	I-GENE
AT	I-GENE
DNA	O
binding	O
activity	O
was	O
negatively	O
regulated	O
by	O
B7	B-GENE
-	I-GENE
1	I-GENE
costimulation	O
.	O

Constitutive	O
activation	O
of	O
Rac1	B-GENE
and	O
RhoA	B-GENE
causes	O
tumorigenic	O
transformation	O
of	O
NIH	O
3T3	O
cells	O
,	O
and	O
their	O
functions	O
may	O
be	O
required	O
for	O
full	O
Ras	B-GENE
transformation	O
.	O

Furthermore	O
,	O
Rac1	B-GENE
activation	O
of	O
JNK	B-GENE
or	O
SRF	B-GENE
,	O
or	O
induction	O
of	O
lamellipodia	O
,	O
was	O
neither	O
necessary	O
nor	O
sufficient	O
for	O
Rac1	B-GENE
transforming	O
activity	O
.	O

Overexpression	O
of	O
the	O
bZip	O
interaction	O
domain	O
of	O
CBP	B-GENE
specifically	O
abolishes	O
the	O
positive	O
cross	O
talk	O
between	O
TR	B-GENE
and	O
p45	B-GENE
/	O
NF	B-GENE
-	I-GENE
E2	I-GENE
.	O

This	O
inhibitory	O
domain	O
has	O
been	O
deleted	O
in	O
all	O
naturally	O
occurring	O
AHC	B-GENE
deletion	I-GENE
mutants	I-GENE
described	O
to	O
date	O
.	O

Identification	O
of	O
a	O
promoter	O
-	O
specific	O
transactivation	O
domain	O
in	O
the	O
herpes	B-GENE
simplex	I-GENE
virus	I-GENE
regulatory	I-GENE
protein	I-GENE
ICP4	I-GENE
.	O

DNA	O
sequencing	O
of	O
a	O
17	O
-	O
kb	O
segment	O
encompassing	O
a	O
gammaherpesvirus	O
divergent	O
locus	O
(	O
DL	O
-	O
B	O
)	O
between	O
ORF11	O
and	O
ORF17	O
revealed	O
the	O
presence	O
of	O
nine	O
viral	O
ORFs	O
with	O
predicted	O
gene	O
products	O
related	O
to	O
cellular	O
proteins	O
.	O

Studies	O
in	O
mammalian	O
cells	O
have	O
correlated	O
induction	O
of	O
inhibitory	O
tyrosine	O
15	O
(	O
Y15	O
)	O
phosphorylation	O
on	O
p34cdc2	B-GENE
with	O
the	O
response	O
to	O
DNA	O
damage	O
.	O

We	O
report	O
herein	O
the	O
case	O
of	O
a	O
30	O
-	O
year	O
-	O
old	O
man	O
in	O
whom	O
ectopic	O
mediastinal	O
parathyroid	O
adenoma	O
was	O
detected	O
by	O
99mTc	O
-	O
methoxyisobutylisonitrile	O
scintigraphy	O
(	O
99mTc	O
-	O
MIBI	O
)	O
.	O

Cardiac	B-GENE
endothelin	I-GENE
release	O
and	O
infarct	O
size	O
,	O
myocardial	O
blood	O
flow	O
,	O
and	O
ventricular	O
function	O
in	O
canine	O
infarction	O
and	O
reperfusion	O
.	O

The	O
workup	O
included	O
skin	O
tests	O
(	O
up	O
to	O
1	O
microgram	O
/	O
ml	O
,	O
Pharmacia	O
)	O
,	O
measurement	O
of	O
specific	O
serum	O
IgE	B-GENE
with	O
RAST	O
-	O
CAP	O
(	O
Pharmacia	O
)	O
,	O
and	O
CAST	O
with	O
three	O
concentrations	O
of	O
bee	O
(	O
Apis	O
mellifera	O
)	O
and	O
wasp	O
(	O
Vespula	O
spec	O
.	O
)	O
venom	O
(	O
Aquagen	O
ALK	O
)	O
.	O

The	O
proliferation	B-GENE
potential	I-GENE
protein	I-GENE
-	I-GENE
related	I-GENE
(	O
P2P	B-GENE
-	I-GENE
R	I-GENE
)	O
gene	O
with	O
domains	O
encoding	O
heterogeneous	O
nuclear	O
ribonucleoprotein	O
association	O
and	O
Rb1	B-GENE
binding	O
shows	O
repressed	O
expression	O
during	O
terminal	O
differentiation	O
.	O

Recent	O
application	O
of	O
recombinant	O
canarypox	O
ALVAC	O
/	O
HIV	O
-	O
1	O
vectors	O
as	O
vaccine	O
immunogens	O
in	O
HIV	O
-	O
1	O
,	O
-	O
noninfected	O
volunteers	O
has	O
produced	O
CTL	O
responses	O
in	O
a	O
significant	O
number	O
of	O
vaccinees	O
.	O

The	O
relevance	O
of	O
these	O
elements	O
in	O
conferring	O
anaerobic	O
induction	O
of	O
gpc4	B-GENE
gene	I-GENE
expression	O
is	O
discussed	O
.	O

Exons	O
A1a	O
and	O
A1b	O
are	O
separated	O
from	O
each	O
other	O
by	O
a	O
124	O
-	O
nucleotide	O
intron	O
.	O

A	O
MEK	B-GENE
-	O
specific	O
inhibitor	O
(	O
PD098059	O
)	O
(	O
Dudley	O
,	O
D	O
.	O

These	O
data	O
support	O
the	O
idea	O
that	O
the	O
repression	O
activity	O
of	O
NRSF	B-GENE
/	O
REST	B-GENE
depends	O
upon	O
the	O
species	O
of	O
promoter	O
to	O
which	O
it	O
is	O
linked	O
and	O
upon	O
the	O
proteins	O
that	O
bind	O
to	O
those	O
promoters	O
.	O

Enhanced	O
period	O
-	O
peak	O
analysis	O
of	O
electro	O
-	O
encephalograms	O
using	O
a	O
fast	O
sinc	O
function	O
.	O

In	O
summary	O
,	O
p56	B-GENE
(	O
lck	B-GENE
)	O
activity	O
stimulates	O
G1	O
/	O
S	O
transition	O
in	O
immature	O
thymoblasts	O
and	O
maintains	O
cell	O
viability	O
via	O
transduction	O
of	O
constitutive	O
activation	O
signals	O
downstream	O
to	O
components	O
of	O
the	O
Ras	B-GENE
/	O
Raf	B-GENE
/	O
MAPK	B-GENE
pathway	O
.	O

These	O
findings	O
suggest	O
that	O
intraarterial	O
neoadjuvant	O
chemotherapy	O
should	O
be	O
effective	O
on	O
advanced	O
cervical	O
cancer	O
.	O

The	O
FBF	O
questionnaire	O
did	O
not	O
highlight	O
a	O
characteristic	O
basic	O
symptoms	O
profile	O
of	O
schizoaffective	O
disorder	O
,	O
when	O
compared	O
with	O
bipolar	O
affective	O
disorder	O
and	O
schizophrenia	O
.	O

The	O
alternative	O
sigma	B-GENE
factor	I-GENE
sigmaB	I-GENE
in	I-GENE
Staphylococcus	I-GENE
aureus	I-GENE
:	O
regulation	O
of	O
the	O
sigB	B-GENE
operon	I-GENE
in	O
response	O
to	O
growth	O
phase	O
and	O
heat	O
shock	O

Cognate	O
promoter	O
elements	O
implicated	O
in	O
glucocorticoid	O
-	O
and	O
cAMP	O
-	O
mediated	O
regulation	O
as	O
well	O
as	O
in	O
liver	O
-	O
,	O
myeloid	O
-	O
,	O
and	O
lymphocyte	O
-	O
specific	O
expression	O
are	O
located	O
within	O
the	O
5	O
'	O
flanking	O
sequence	O
.	O

We	O
have	O
studied	O
the	O
biokinetics	O
of	O
BLM	O
labeled	O
with	O
indium	O
-	O
111	O
(	O
In	O
-	O
111	O
)	O
.	O

CD3	B-GENE
cross	O
-	O
linking	O
induced	O
tyrosine	O
phosphorylation	O
of	O
Sam68	B-GENE
in	O
uninfected	O
T	O
cells	O
.	O

Acetoin	O
-	O
dependent	O
expression	O
of	O
the	O
acoABCD	B-GENE
operon	I-GENE
could	O
be	O
restored	O
in	O
the	O
E	B-GENE
.	I-GENE
coli	I-GENE
acoK	I-GENE
mutants	I-GENE
by	O
supplying	O
a	O
plasmid	O
carrying	O
an	O
intact	O
acoK	B-GENE
,	O
suggesting	O
a	O
transactivating	O
function	O
of	O
the	O
gene	O
product	O
.	O

Mutations	O
in	O
the	O
alpha	B-GENE
and	I-GENE
sigma	I-GENE
-	I-GENE
70	I-GENE
subunits	I-GENE
of	I-GENE
RNA	I-GENE
polymerase	I-GENE
affect	O
expression	O
of	O
the	O
mer	B-GENE
operon	I-GENE
.	O

Taken	O
together	O
,	O
we	O
provide	O
evidence	O
for	O
the	O
existence	O
of	O
an	O
activator	O
,	O
NFE	B-GENE
,	O
which	O
in	O
combination	O
with	O
the	O
p50	B-GENE
and	O
c	B-GENE
-	I-GENE
Rel	I-GENE
proteins	I-GENE
,	O
are	O
part	O
of	O
the	O
transcription	O
factor	O
machinery	O
that	O
regulates	O
3	O
'	O
enhancer	O
activity	O
,	O
and	O
thus	O
the	O
control	O
of	O
the	O
IgH	B-GENE
locus	I-GENE
in	O
late	O
B	O
lymphocyte	O
development	O
.	O

The	O
neuroprotective	O
efficacy	O
of	O
the	O
selective	O
N	O
-	O
type	O
voltage	O
-	O
sensitive	O
calcium	O
channel	O
blocker	O
,	O
SNX	O
-	O
111	O
,	O
was	O
evaluated	O
in	O
spontaneously	O
hypertensive	O
rats	O
subjected	O
to	O
60	O
min	O
of	O
focal	O
cerebral	O
ischemia	O
by	O
permanent	O
ligation	O
of	O
the	O
right	O
common	O
carotid	O
artery	O
and	O
temporary	O
occlusion	O
of	O
the	O
right	O
middle	O
cerebral	O
artery	O
.	O

The	O
genes	O
encoding	O
the	O
transcription	B-GENE
factor	I-GENE
yTAFII60	I-GENE
,	O
the	O
G4p1	B-GENE
protein	I-GENE
and	O
a	O
putative	O
glucose	O
transporter	O
are	O
contained	O
in	O
a	O
12	O
.	O
3	O
kb	O
DNA	O
fragment	O
on	O
the	O
left	O
arm	O
of	O
Saccharomyces	O
cerevisiae	O
chromosome	O
VII	O
.	O

The	O
protector	O
doubled	O
the	O
estimated	O
fall	O
distance	O
for	O
fracture	O
of	O
the	O
trochanter	O
.	O

Marinol	O
/	O
marijuana	O
usage	O
was	O
associated	O
with	O
depressed	O
CD4	B-GENE
+	I-GENE
counts	O
and	O
elevated	O
amylase	B-GENE
levels	O
within	O
the	O
DDI	O
subgroup	O
.	O

METHODS	O
:	O
Fifty	O
-	O
eight	O
patients	O
who	O
underwent	O
a	O
curative	O
hepatic	O
resection	O
for	O
HCC	O
and	O
whose	O
preoperative	O
AFP	B-GENE
levels	O
were	O
>	O
100	O
ng	O
/	O
ml	O
,	O
were	O
selected	O
for	O
this	O
study	O
.	O

Calmodulin	B-GENE
-	I-GENE
binding	I-GENE
peptide	I-GENE
(	O
CBP	B-GENE
)	O
,	O
a	O
peptide	O
of	O
26	O
amino	O
acids	O
derived	O
from	O
muscle	B-GENE
myosin	I-GENE
light	I-GENE
chain	I-GENE
kinase	I-GENE
(	O
MLCK	B-GENE
)	O
,	O
binds	O
to	O
calmodulin	B-GENE
with	O
nanomolar	O
affinity	O
.	O

Here	O
we	O
show	O
that	O
the	O
type	O
of	O
tyrosine	B-GENE
kinase	I-GENE
receptor	I-GENE
stimulated	O
also	O
participates	O
in	O
the	O
nature	O
of	O
the	O
cAMP	O
effect	O
.	O

To	O
gain	O
insight	O
into	O
the	O
possible	O
involvement	O
of	O
p21	B-GENE
in	O
liver	O
cell	O
growth	O
,	O
the	O
expression	O
and	O
regulation	O
of	O
the	O
p21	B-GENE
gene	I-GENE
was	O
evaluated	O
in	O
rodent	O
models	O
of	O
liver	O
regeneration	O
and	O
specimens	O
of	O
human	O
liver	O
diseases	O
.	O

Northern	O
blot	O
analysis	O
of	O
LeMT	B-GENE
(	I-GENE
A	I-GENE
)	I-GENE
and	O
LeMT	B-GENE
(	I-GENE
B	I-GENE
)	I-GENE
showed	O
that	O
transcripts	O
of	O
both	O
MT	B-GENE
-	I-GENE
like	I-GENE
genes	I-GENE
were	O
more	O
abundant	O
in	O
leaves	O
than	O
roots	O
in	O
tomato	O
plants	O
grown	O
without	O
addition	O
of	O
extra	O
metal	O
ions	O
,	O
a	O
characteristic	O
of	O
type	B-GENE
II	I-GENE
MTs	I-GENE
.	O

The	O
HBP	B-GENE
gene	I-GENE
is	O
composed	O
of	O
eight	O
exons	O
covering	O
19	O
.	O
5	O
kb	O
on	O
the	O
short	O
arm	O
of	O
chromosome	O
4	O
.	O

In	O
some	O
instances	O
,	O
this	O
is	O
partly	O
mediated	O
by	O
the	O
expression	O
of	O
virally	O
encoded	O
proteases	O
which	O
lead	O
to	O
the	O
cleavage	O
of	O
initiation	B-GENE
factor	I-GENE
eIF4G	I-GENE
.	O

The	O
best	O
endometrial	O
ablation	O
was	O
seen	O
when	O
SnET2	O
was	O
given	O
by	O
intrauterine	O
administration	O
with	O
light	O
treatment	O
at	O
150	O
J	O
/	O
cm	O
24	O
hours	O
later	O
.	O

Unlike	O
class	O
II	O
-	O
and	O
III	O
-	O
specific	O
TBP	B-GENE
-	O
TAF	B-GENE
complexes	O
,	O
the	O
corresponding	O
murine	O
and	O
human	O
class	O
I	O
-	O
specific	O
transcription	O
initiation	O
factor	O
TIF	B-GENE
-	I-GENE
IB	I-GENE
/	O
SL1	B-GENE
exhibits	O
a	O
pronounced	O
selectivity	O
for	O
its	O
homologous	O
promoter	O
.	O

We	O
now	O
describe	O
the	O
identification	O
of	O
DEK	B-GENE
as	O
this	O
43	B-GENE
-	I-GENE
kDa	I-GENE
pets	I-GENE
factor	I-GENE
.	O

These	O
elements	O
comprise	O
a	O
binding	O
site	O
for	O
Krox	B-GENE
proteins	I-GENE
,	O
one	O
for	O
nuclear	B-GENE
factor	I-GENE
1	I-GENE
,	O
an	O
octamer	O
motif	O
that	O
binds	O
POU	B-GENE
-	I-GENE
homeodomain	I-GENE
proteins	I-GENE
,	O
and	O
a	O
novel	O
TN	B-GENE
control	I-GENE
element	I-GENE
.	O

Tissue	O
samples	O
were	O
obtained	O
either	O
from	O
rats	O
that	O
had	O
been	O
exposed	O
to	O
opiate	O
withdrawal	O
following	O
a	O
seven	O
day	O
morphine	O
infusion	O
or	O
sham	O
treated	O
control	O
subjects	O
.	O

Therefore	O
,	O
the	O
impaired	O
floor	O
plate	O
development	O
in	O
oep	B-GENE
mutants	I-GENE
is	O
not	O
caused	O
by	O
the	O
absence	O
of	O
the	O
floor	B-GENE
plate	I-GENE
inducer	I-GENE
shh	I-GENE
.	O

RESULTS	O
:	O
The	O
medians	O
of	O
average	O
daily	O
CD34	B-GENE
+	I-GENE
cell	O
yields	O
for	O
patients	O
who	O
received	O
paclitaxel	O
plus	O
CY	O
,	O
CE	O
,	O
and	O
CEP	O
with	O
G	B-GENE
-	I-GENE
CSF	I-GENE
were	O
12	O
.	O
9	O
,	O
11	O
.	O
03	O
,	O
and	O
5	O
.	O
37	O
x	O
10	O
(	O
6	O
)	O
/	O
kg	O
,	O
respectively	O
,	O
compared	O
with	O
2	O
.	O
02	O
x	O
10	O
(	O
6	O
)	O
/	O
kg	O
in	O
the	O
reference	O
group	O
that	O
received	O
CY	O
with	O
G	B-GENE
-	I-GENE
CSF	I-GENE
(	O
P	O
=	O
<	O
.	O
0001	O
,	O
.	O
002	O
,	O
and	O
.	O
09	O
,	O
respectively	O
)	O
.	O

Increased	O
p53	B-GENE
activity	O
induced	O
by	O
OP	O
is	O
not	O
due	O
to	O
elevated	O
p53	B-GENE
mRNA	I-GENE
nor	O
to	O
protein	O
levels	O
.	O

CONCLUSION	O
:	O
Chronic	O
administration	O
of	O
misoprostol	O
may	O
have	O
caused	O
a	O
negative	O
natriuretic	O
effect	O
in	O
cirrhotic	O
patients	O
with	O
ascites	O
.	O

The	O
intensity	O
of	O
the	O
SSTEs	O
is	O
an	O
order	O
of	O
magnitude	O
larger	O
than	O
that	O
of	O
the	O
MSEs	O
and	O
determines	O
the	O
signal	O
contrast	O
if	O
both	O
effects	O
are	O
selected	O
simultaneously	O
.	O

In	O
eukaryotic	O
cells	O
,	O
premature	O
termination	O
of	O
translation	O
at	O
nonsense	O
codons	O
has	O
been	O
implicated	O
as	O
the	O
cause	O
of	O
a	O
variety	O
of	O
posttranscriptional	O
events	O
,	O
including	O
rapid	O
mRNA	O
decay	O
in	O
the	O
cytoplasm	O
or	O
the	O
nucleus	O
,	O
altered	O
splice	O
site	O
selection	O
,	O
and	O
exon	O
skipping	O
.	O

The	O
region	O
of	O
plasmid	O
pCM2	O
encoding	O
the	O
pathogenicity	B-GENE
locus	I-GENE
pat	I-GENE
-	I-GENE
1	I-GENE
was	O
mapped	O
by	O
deletion	O
analysis	O
and	O
complementation	O
studies	O
to	O
a	O
1	O
.	O
5	O
-	O
kb	O
Bg	B-GENE
/	I-GENE
II	I-GENE
/	O
SmaI	B-GENE
DNA	O
fragment	O
.	O

Transient	O
cotransfection	O
of	O
tat	B-GENE
cDNA	I-GENE
in	O
sense	O
orientation	O
(	O
tat	B-GENE
/	I-GENE
S	I-GENE
)	O
,	O
together	O
with	O
a	O
plasmid	O
containing	O
the	O
c	B-GENE
-	I-GENE
fos	I-GENE
promoter	I-GENE
(	O
FC3	B-GENE
,	O
from	O
-	O
711	O
to	O
+	O
42	O
)	O
in	O
front	O
of	O
the	O
bacterial	B-GENE
chloramphenicol	I-GENE
acetyltransferase	I-GENE
(	O
CAT	B-GENE
)	O
gene	O
significantly	O
enhanced	O
CAT	B-GENE
activity	O
in	O
Jurkat	O
cells	O
activated	O
by	O
the	O
addition	O
of	O
15	O
%	O
fetal	O
calf	O
serum	O
(	O
FCS	O
)	O
or	O
5	O
micrograms	O
/	O
mL	O
phytohemagglutinin	B-GENE
plus	O
10	O
(	O
-	O
7	O
)	O
mol	O
/	O
L	O
phorbol	O
myristate	O
acetate	O
(	O
PMA	O
)	O
and	O
U937	O
cells	O
activated	O
by	O
15	O
%	O
FCS	O
or	O
10	O
(	O
-	O
7	O
)	O
mol	O
/	O
L	O
PMA	O
.	O

Snail	O
mortality	O
did	O
not	O
differ	O
among	O
the	O
various	O
treatment	O
conditions	O
.	O

Exploratory	O
-	O
motor	O
task	O
to	O
evaluate	O
right	O
frontal	O
lobe	O
damage	O
.	O

To	O
avoid	O
complications	O
,	O
accurate	O
quantitative	O
analysis	O
of	O
NO	O
and	O
NO2	O
is	O
necessary	O
during	O
this	O
therapy	O
.	O

Our	O
results	O
demonstrate	O
that	O
cis	O
elements	O
positioned	O
between	O
the	O
alpha	B-GENE
3	I-GENE
and	O
beta	B-GENE
4	I-GENE
coding	O
regions	O
are	O
important	O
for	O
establishing	O
part	O
of	O
the	O
restricted	O
CNS	O
patterns	O
of	O
beta	B-GENE
4	I-GENE
,	O
alpha	B-GENE
3	I-GENE
,	O
and	O
alpha	B-GENE
5	I-GENE
gene	I-GENE
transcription	O
.	O

RNase	B-GENE
protection	O
experiments	O
confirmed	O
the	O
presence	O
of	O
the	O
GHR1	B-GENE
-	I-GENE
279	I-GENE
variant	I-GENE
in	O
IM	O
-	O
9	O
cells	O
and	O
human	O
liver	O
.	O

Functional	O
tests	O
using	O
a	O
reporter	O
gene	O
,	O
containing	O
Stat5	B-GENE
-	I-GENE
binding	I-GENE
elements	I-GENE
,	O
confirmed	O
that	O
while	O
the	O
variant	O
form	O
was	O
inactive	O
by	O
itself	O
,	O
it	O
could	O
inhibit	O
the	O
function	O
of	O
the	O
full	O
-	O
length	O
receptor	O
.	O

Conversely	O
,	O
activated	O
glucocorticoid	B-GENE
receptors	I-GENE
suppressed	O
the	O
transactivation	O
function	O
of	O
p53	B-GENE
,	O
while	O
transrepression	O
by	O
p53	B-GENE
was	O
largely	O
unaffected	O
.	O

This	O
promoter	O
segment	O
could	O
drive	O
expression	O
of	O
a	O
luciferase	B-GENE
reporter	I-GENE
gene	I-GENE
,	O
could	O
confer	O
correct	O
transcriptional	O
initiation	O
to	O
the	O
reporter	O
and	O
could	O
confer	O
the	O
EGF	B-GENE
-	O
responsiveness	O
previously	O
observed	O
in	O
the	O
native	O
gene	O
.	O

This	O
is	O
the	O
first	O
report	O
that	O
an	O
in	O
vitro	O
-	O
synthesized	O
alphavirus	O
RNA	O
lacking	O
a	O
poly	O
(	O
A	O
)	O
tail	O
can	O
initiate	O
infection	O
and	O
produce	O
3	O
'	O
polyadenylated	O
viral	O
genome	O
in	O
vivo	O
.	O

The	O
human	O
coreceptor	O
was	O
as	O
active	O
as	O
the	O
simian	O
for	O
SIV	O
entry	O
.	O

RESULTS	O
:	O
Among	O
women	O
,	O
the	O
age	O
-	O
related	O
decline	O
in	O
BMD	O
at	O
all	O
non	O
-	O
spine	O
skeletal	O
sites	O
was	O
significantly	O
different	O
from	O
zero	O
,	O
with	O
the	O
largest	O
decline	O
seen	O
at	O
the	O
femoral	O
neck	O
(	O
-	O
.	O
0038	O
g	O
/	O
cm2	O
/	O
y	O
,	O
p	O
<	O
.	O
001	O
)	O
and	O
the	O
smallest	O
at	O
the	O
trochanter	O
of	O
the	O
hip	O
(	O
-	O
.	O
0023	O
g	O
/	O
cm2	O
/	O
y	O
,	O
p	O
=	O
.	O
03	O
)	O
.	O

Sixty	O
-	O
nine	O
(	O
44	O
%	O
)	O
patients	O
were	O
administered	O
250	O
MBq	O
(	O
7	O
mCi	O
)	O
99Tcm	O
-	O
tetrofosmin	O
at	O
rest	O
followed	O
4	O
h	O
later	O
by	O
750	O
MBq	O
(	O
21	O
mCi	O
)	O
during	O
stress	O
(	O
the	O
1	O
day	O
protocol	O
)	O
,	O
whereas	O
88	O
(	O
56	O
%	O
)	O
patients	O
had	O
rest	O
and	O
stress	O
imaging	O
studies	O
on	O
two	O
separate	O
days	O
,	O
receiving	O
a	O
500	O
MBq	O
(	O
14	O
mCi	O
)	O
dose	O
of	O
99Tcm	O
-	O
tetrofosmin	O
on	O
each	O
occasion	O
(	O
the	O
2	O
day	O
protocol	O
)	O
.	O

Myocardial	O
SPET	O
imaging	O
with	O
99Tcm	O
-	O
tetrofosmin	O
in	O
clinical	O
practice	O
:	O
comparison	O
of	O
a	O
1	O
day	O
and	O
a	O
2	O
day	O
imaging	O
protocol	O
.	O

99Tcm	O
-	O
DMP	O
-	O
HSA	O
showed	O
an	O
almost	O
identical	O
behaviour	O
to	O
in	O
vitro	O
labelled	O
red	O
blood	O
cells	O
(	O
RBCs	O
)	O
,	O
which	O
are	O
generally	O
considered	O
the	O
reference	O
standard	O
for	O
blood	O
pool	O
agents	O
.	O

Relief	O
from	O
autoinhibition	O
and	O
a	O
subsequent	O
10	O
-	O
60	O
-	O
fold	O
increase	O
in	O
V	O
(	O
max	O
)	O
have	O
been	O
observed	O
upon	O
N	B-GENE
-	I-GENE
SH2	I-GENE
domain	I-GENE
engagement	O
by	O
a	O
specific	O
phosphotyrosyl	O
ligand	O
or	O
upon	O
deletion	O
of	O
the	O
SH2	B-GENE
domains	I-GENE
to	O
yield	O
the	O
catalytic	O
PTPase	B-GENE
domain	I-GENE
.	O

We	O
have	O
thus	O
identified	O
the	O
first	O
mammalian	B-GENE
homolog	I-GENE
of	I-GENE
yeast	I-GENE
UPF1	I-GENE
,	O
a	O
protein	O
that	O
regulates	O
levels	O
of	O
nonsense	O
mRNA	O
,	O
and	O
we	O
tentatively	O
name	O
this	O
protein	O
human	B-GENE
HUPF1	I-GENE
(	O
for	O
human	B-GENE
homolog	I-GENE
of	I-GENE
UPF1	I-GENE
)	O
.	O

A	O
miracle	O
cure	O
and	O
its	O
solution	O

The	O
addition	O
of	O
zidovudine	O
did	O
not	O
influence	O
this	O
transfer	O
.	O

DNA	O
strand	O
exchange	O
catalyzed	O
by	O
Rad51	B-GENE
protein	I-GENE
is	O
also	O
greatly	O
stimulated	O
by	O
RPA	B-GENE
.	O

Ume6p	B-GENE
,	O
which	O
also	O
controls	O
the	O
expression	O
of	O
early	O
meiotic	O
genes	O
,	O
represses	O
CAR1	B-GENE
expression	O
through	O
a	O
sequence	O
called	O
URS	O
,	O
as	O
a	O
function	O
of	O
nitrogen	O
availability	O
.	O

The	O
second	O
class	O
of	O
cDNA	O
hybridized	O
to	O
a	O
13	O
kb	O
transcript	O
,	O
which	O
was	O
approximately	O
twice	O
as	O
large	O
as	O
the	O
mammalian	B-GENE
lactase	I-GENE
mRNA	I-GENE
.	O

In	O
cell	O
lines	O
transformed	O
by	O
BCR	B-GENE
/	O
ABL	B-GENE
,	O
CRKL	B-GENE
was	O
tyrosine	O
phosphorylated	O
,	O
while	O
CRK	B-GENE
was	O
not	O
.	O

In	O
untransformed	O
cells	O
,	O
three	O
major	O
proteins	O
coprecipitated	O
with	O
CRKL	B-GENE
,	O
identified	O
as	O
C3G	B-GENE
,	O
SOS	B-GENE
and	O
c	B-GENE
-	I-GENE
ABL	I-GENE
.	O

RESULTS	O
:	O
Nodular	O
opacities	O
,	O
mainly	O
centrilobular	O
in	O
distribution	O
,	O
were	O
the	O
most	O
common	O
finding	O
,	O
seen	O
in	O
21	O
(	O
72	O
%	O
)	O
and	O
15	O
(	O
65	O
%	O
)	O
of	O
patients	O
with	O
MTB	O
and	O
NTMB	O
,	O
respectively	O
.	O

Circulating	O
oxytocin	B-GENE
in	O
male	O
guinea	O
pigs	O
affected	O
by	O
the	O
female	O
cohabitation	O
and	O
reproductive	O
condition	O
.	O

Antisense	O
transcription	O
of	O
a	O
murine	B-GENE
FGFR	I-GENE
-	I-GENE
3	I-GENE
psuedogene	I-GENE
during	O
fetal	O
developement	O
.	O

A	O
previous	O
report	O
described	O
that	O
a	O
548	O
-	O
bp	O
BglII	B-GENE
-	O
SmaI	B-GENE
fragment	O
has	O
an	O
SSO	O
activity	O
(	O
ori2	O
;	O
Kataoka	O
et	O
al	O
.	O
,	O
Mol	O
.	O

The	O
human	B-GENE
CD38	I-GENE
gene	I-GENE
consists	O
of	O
8	O
exons	O
that	O
extend	O
more	O
than	O
77	O
kb	O
on	O
the	O
human	O
genome	O
.	O

Type	O
IV	O
splice	O
pattern	O
,	O
containing	O
exon	O
U3	O
and	O
S	O
was	O
found	O
both	O
in	O
kidney	O
and	O
ovary	O
.	O

GH	B-GENE
deficiency	O
may	O
be	O
absolute	O
,	O
but	O
often	O
is	O
not	O
and	O
the	O
diagnosis	O
may	O
be	O
complicated	O
by	O
a	O
constellation	O
of	O
physical	O
and	O
hormonal	O
findings	O
that	O
are	O
along	O
a	O
spectrum	O
from	O
low	O
normal	O
GH	B-GENE
sufficiency	O
to	O
absent	O
GH	B-GENE
secretion	O
.	O

Positive	O
CRP	B-GENE
test	O
were	O
seen	O
.	O

During	O
the	O
febrile	O
period	O
,	O
pleocytosis	O
was	O
associated	O
with	O
high	O
levels	O
of	O
IgG	B-GENE
,	O
IL	B-GENE
-	I-GENE
6	I-GENE
,	O
TNF	B-GENE
-	I-GENE
alpha	I-GENE
,	O
and	O
PGE2	O
in	O
the	O
cerebrospinal	O
fluid	O
.	O

Recognition	O
mechanisms	O
of	O
the	O
minus	O
-	O
strand	O
origin	O
of	O
phage	O
f1	O
by	O
Escherichia	B-GENE
coli	I-GENE
RNA	I-GENE
polymerase	I-GENE
.	O

The	O
minimum	O
and	O
essential	O
subunits	O
for	O
RNA	O
synthesis	O
have	O
not	O
yet	O
been	O
identified	O
.	O

Syndecan	B-GENE
-	I-GENE
4	I-GENE
is	O
a	O
focal	O
adhesion	O
component	O
,	O
and	O
this	O
interaction	O
may	O
both	O
localize	O
PKC	B-GENE
and	O
amplify	O
its	O
activity	O
at	O
sites	O
of	O
forming	O
adhesions	O
.	O

The	O
3ASubE	O
cells	O
expressing	O
CXCR2	B-GENE
with	O
mutation	O
of	O
Ser	O
-	O
346	O
,	O
-	O
347	O
,	O
and	O
-	O
348	O
to	O
alanine	O
,	O
or	O
with	O
mutation	O
of	O
only	O
one	O
serine	O
in	O
this	O
domain	O
,	O
continue	O
to	O
be	O
phosphorylated	O
in	O
response	O
to	O
ligand	O
and	O
are	O
60	O
-	O
70	O
%	O
desensitized	O
following	O
the	O
initial	O
ligand	O
challenge	O
.	O

Members	O
of	O
the	O
MAPK	B-GENE
family	I-GENE
include	O
the	O
extracellular	B-GENE
response	I-GENE
kinases	I-GENE
(	O
ERKs	B-GENE
or	O
p42	B-GENE
/	I-GENE
44	I-GENE
(	O
MAPK	B-GENE
)	O
)	O
,	O
the	O
c	B-GENE
-	I-GENE
Jun	I-GENE
amino	I-GENE
-	I-GENE
terminal	I-GENE
kinases	I-GENE
(	O
JNKs	B-GENE
)	O
,	O
and	O
the	O
p38	B-GENE
/	O
Hog	B-GENE
1	I-GENE
protein	O
kinases	O
.	O

MOP5	B-GENE
contained	O
the	O
characteristic	O
PAS	B-GENE
domain	O
and	O
a	O
variable	O
C	O
terminus	O
;	O
it	O
is	O
possible	O
that	O
the	O
cDNA	O
contains	O
a	O
bHLH	O
domain	O
,	O
but	O
the	O
entire	O
open	O
reading	O
frame	O
has	O
yet	O
to	O
be	O
completed	O
.	O

Some	O
8	O
.	O
8	O
kb	O
of	O
the	O
Lactobacillus	O
sake	O
plasmid	O
pCIM1	O
was	O
sequenced	O
,	O
revealing	O
eight	O
tightly	O
clustered	O
open	O
reading	O
frames	O
(	O
ORFs	O
)	O
downstream	O
from	O
lasA	B-GENE
,	O
which	O
encodes	O
pre	B-GENE
-	I-GENE
lactocin	I-GENE
S	I-GENE
.	O

Purified	B-GENE
Pra	I-GENE
was	O
also	O
shown	O
to	O
physically	O
interact	O
with	O
pyruvate	B-GENE
kinase	I-GENE
(	O
Pk	B-GENE
)	O
;	O
Pk	B-GENE
and	O
Pra	B-GENE
can	O
form	O
a	O
complex	O
,	O
but	O
when	O
the	O
12	B-GENE
-	I-GENE
kDa	I-GENE
Ndk	I-GENE
,	O
Pk	B-GENE
,	O
and	O
Pra	B-GENE
are	O
all	O
present	O
,	O
Pk	B-GENE
has	O
a	O
higher	O
affinity	O
than	O
Pra	B-GENE
for	O
forming	O
a	O
complex	O
with	O
the	O
12	B-GENE
-	I-GENE
kDa	I-GENE
Ndk	I-GENE
.	O

Molecular	O
characterization	O
of	O
a	O
large	O
Borrelia	O
burgdorferi	O
motility	O
operon	O
which	O
is	O
initiated	O
by	O
a	O
consensus	O
sigma70	B-GENE
promoter	I-GENE
.	O

M	B-GENE
.	I-GENE
leprae	I-GENE
OxyR	I-GENE
was	O
overproduced	O
and	O
purified	O
,	O
and	O
its	O
binding	O
to	O
the	O
oxyR	B-GENE
-	O
ahpC	B-GENE
intergenic	O
region	O
of	O
M	O
.	O
leprae	O
was	O
demonstrated	O
.	O

The	O
binding	O
site	O
for	O
OxyR	B-GENE
overlapped	O
P1oxyR	B-GENE
,	O
reminiscent	O
of	O
the	O
autoregulatory	O
loops	O
controlling	O
expression	O
of	O
oxyR	B-GENE
in	O
enteric	O
bacteria	O
and	O
characteristic	O
of	O
the	O
LysR	B-GENE
superfamily	I-GENE
in	O
general	O
.	O

Thirty	O
-	O
five	O
patients	O
were	O
included	O
.	O

Grade	O
3	O
-	O
4	O
mucositis	O
was	O
present	O
in	O
13	O
%	O
of	O
the	O
cycles	O
.	O

Therefore	O
more	O
active	O
and	O
tolerable	O
salvage	O
regimens	O
are	O
needed	O
.	O

None	O
of	O
these	O
organic	O
manifestations	O
was	O
discovered	O
by	O
scintigraphic	O
means	O
.	O

While	O
TGF	B-GENE
-	I-GENE
beta1	I-GENE
does	O
not	O
alter	O
the	O
mitogen	O
-	O
induced	O
expression	O
and	O
abundance	O
of	O
G1	O
phase	O
cyclin	B-GENE
D1	I-GENE
and	O
cdks	B-GENE
4	I-GENE
and	I-GENE
2	I-GENE
in	O
MCs	O
,	O
it	O
inhibits	O
cyclin	B-GENE
E	I-GENE
-	O
cdk	B-GENE
2	I-GENE
activity	O
,	O
thus	O
preventing	O
mitogen	O
-	O
elicited	O
phosphorylation	O
and	O
inactivation	O
of	O
pRb	B-GENE
in	O
G1	O
phase	O
and	O
transition	O
to	O
S	O
phase	O
.	O

However	O
,	O
the	O
range	O
of	O
values	O
observed	O
is	O
suggestive	O
of	O
the	O
need	O
to	O
investigate	O
districts	O
with	O
contrasting	O
values	O
of	O
SYPLR	O
with	O
respect	O
to	O
the	O
inter	O
-	O
relationships	O
between	O
sociodemographic	O
characteristics	O
,	O
duration	O
of	O
symptoms	O
,	O
clinical	O
presentation	O
and	O
treatment	O
efficacy	O
.	O

The	O
prominent	O
lesions	O
were	O
confined	O
to	O
the	O
cerebral	O
surface	O
layer	O
and	O
leptomeningeal	O
tissue	O
including	O
the	O
arachnoid	O
vessels	O
,	O
which	O
were	O
all	O
bathed	O
in	O
the	O
cerebrospinal	O
fluid	O
,	O
suggesting	O
that	O
some	O
necrotizing	O
toxins	O
had	O
been	O
secreted	O
into	O
the	O
fluid	O
by	O
the	O
B	O
.	O
cereus	O
.	O

This	O
fragment	O
contained	O
the	O
C	O
-	O
terminal	O
47	O
nucleotides	O
of	O
leuB	B-GENE
,	O
encoding	O
3	B-GENE
-	I-GENE
isopropylmalate	I-GENE
dehydrogenase	I-GENE
;	O
asd	B-GENE
,	O
encoding	O
aspartate	B-GENE
-	I-GENE
beta	I-GENE
-	I-GENE
semialdehyde	I-GENE
dehydrogenase	I-GENE
(	O
Asd	B-GENE
)	O
;	O
and	O
orfA	O
,	O
whose	O
product	O
showed	O
similarity	O
to	O
the	O
Asd	B-GENE
proteins	I-GENE
from	I-GENE
Vibrio	I-GENE
spp	I-GENE
.	O

Hovenitin	O
I	O
and	O
(	O
+	O
)	O
-	O
ampelopsin	O
,	O
both	O
of	O
which	O
were	O
principal	O
ingredients	O
of	O
the	O
active	O
fractions	O
from	O
this	O
natural	O
medicine	O
,	O
were	O
found	O
to	O
show	O
an	O
inhibitory	O
activity	O
on	O
the	O
ethanol	O
-	O
induced	O
muscle	O
relaxation	O
in	O
rats	O
.	O

Purified	B-GENE
P7	I-GENE
could	O
be	O
assembled	O
onto	O
particles	O
lacking	O
P7	B-GENE
and	O
particles	O
lacking	O
both	O
P2	B-GENE
(	O
RNA	B-GENE
polymerase	I-GENE
)	O
and	O
P7	B-GENE
.	O

However	O
,	O
the	O
same	O
U1A	B-GENE
peptide	I-GENE
,	O
when	O
conjugated	O
to	O
BSA	B-GENE
,	O
inhibits	O
vertebrate	B-GENE
PAP	I-GENE
.	O

Plasma	O
levels	O
of	O
protein	B-GENE
C	I-GENE
,	O
protein	B-GENE
S	I-GENE
,	O
and	O
antithrombin	B-GENE
III	I-GENE
in	O
patients	O
with	O
subarachnoid	O
haemorrhage	O
.	O

Idiopathic	O
bilateral	O
recurrent	O
branch	O
retinal	O
arterial	O
occlusion	O
(	O
IBRBRAO	O
)	O
is	O
a	O
rare	O
syndrome	O
characterized	O
by	O
migraine	O
headaches	O
,	O
tinnitus	O
,	O
vertigo	O
,	O
hearing	O
loss	O
,	O
and	O
recurrent	O
branch	O
retinal	O
artery	O
occlusion	O
of	O
unknown	O
etiology	O
.	O

Epithelial	O
and	O
corneal	O
thickness	O
measurements	O
by	O
in	O
vivo	O
confocal	O
microscopy	O
through	O
focusing	O
(	O
CMTF	O
)	O
.	O

Sequences	O
downstream	O
of	O
the	O
two	O
human	B-GENE
CA	I-GENE
genes	I-GENE
,	O
possibly	O
containing	O
homologous	O
enhancer	O
elements	O
,	O
have	O
not	O
yet	O
been	O
reported	O
.	O

Recombinant	O
plasmids	O
containing	O
the	O
entire	O
322	O
nt	O
5	O
'	O
UTR	O
of	O
exon	O
1	O
and	O
a	O
1630	O
nt	O
segment	O
of	O
5	O
'	O
flanking	O
sequence	O
stimulated	O
luciferase	B-GENE
activity	O
nearly	O
70	O
times	O
higher	O
than	O
a	O
promoterless	O
control	O
plasmid	O
.	O

Analysis	O
for	O
DNA	O
-	O
protein	O
interactions	O
by	O
in	O
vitro	O
DNase	B-GENE
-	I-GENE
I	I-GENE
footprinting	O
identified	O
a	O
broad	O
region	O
of	O
protection	O
extending	O
from	O
nt	O
-	O
12	O
to	O
+	O
38	O
.	O

It	O
is	O
also	O
homologous	O
to	O
other	O
sugar	O
carriers	O
from	O
human	O
,	O
mouse	O
and	O
Escherichia	O
coli	O
.	O

Until	O
now	O
,	O
each	O
of	O
these	O
loci	O
was	O
considered	O
to	O
contain	O
three	O
genes	O
(	O
for	O
regulator	B-GENE
,	O
permease	B-GENE
and	O
alpha	B-GENE
-	I-GENE
glucosidase	I-GENE
)	O
,	O
but	O
a	O
fourth	O
gene	O
,	O
presumably	O
an	O
extra	O
alpha	B-GENE
-	I-GENE
glucosidase	I-GENE
gene	I-GENE
,	O
was	O
found	O
at	O
MAL1	B-GENE
adjacent	O
to	O
the	O
usual	O
cluster	O
of	O
three	O
genes	O
.	O

Autorosette	O
-	O
forming	O
cells	O
are	O
characterized	O
by	O
a	O
high	O
activity	O
of	O
alkaline	B-GENE
and	I-GENE
acid	I-GENE
phosphatases	I-GENE
and	O
low	O
NBT	O
-	O
test	O
values	O
.	O

Analysis	O
of	O
homologous	O
DNA	O
sequences	O
within	O
the	O
first	O
intron	O
of	O
the	O
mouse	B-GENE
and	I-GENE
human	I-GENE
mts1	I-GENE
genes	I-GENE
:	O
kB	B-GENE
-	I-GENE
like	I-GENE
site	I-GENE
and	O
microsatellite	O
DNA	O

The	O
integration	O
at	O
the	O
VIP	B-GENE
CyRE	B-GENE
of	O
the	O
Jak	B-GENE
-	O
Stat	B-GENE
and	O
AP	B-GENE
-	I-GENE
1	I-GENE
signaling	O
pathways	O
with	O
other	O
pre	O
-	O
existing	O
proteins	O
provides	O
a	O
cellular	O
mechanism	O
for	O
cell	O
-	O
and	O
cytokine	O
-	O
specific	O
signaling	O
.	O

These	O
studies	O
point	O
to	O
the	O
involvement	O
of	O
the	O
MAP	B-GENE
kinase	I-GENE
pathway	O
in	O
the	O
activation	O
of	O
monocytic	O
cells	O
during	O
transmigration	O
to	O
inflammatory	O
sites	O
.	O

Our	O
results	O
show	O
that	O
the	O
temperature	B-GENE
-	I-GENE
sensitive	I-GENE
rad54	I-GENE
-	I-GENE
3	I-GENE
allele	I-GENE
blocks	O
mitotic	O
recombination	O
between	O
tandemly	O
repeated	O
DYZ3	B-GENE
satellite	I-GENE
sequences	I-GENE
and	O
significantly	O
stabilizes	O
a	O
human	B-GENE
DYZ5	I-GENE
satellite	O
-	O
containing	O
YAC	O
clone	O
.	O

A	O
P22	O
R17	O
derivative	O
with	O
an	O
OcRNA	O
site	O
(	O
P22	O
R17	O
[	O
A	O
(	O
-	O
10	O
)	O
U	O
]	O
)	O
develops	O
lytically	O
following	O
infection	O
of	O
these	O
strains	O
.	O

Circularized	O
Ac	B-GENE
/	O
Ds	B-GENE
transposons	O
:	O
formation	O
,	O
structure	O
and	O
fate	O
.	O

In	O
this	O
study	O
,	O
we	O
have	O
examined	O
the	O
regulation	O
of	O
B	B-GENE
-	I-GENE
Myb	I-GENE
activity	O
by	O
cyclin	B-GENE
-	O
Cdks	B-GENE
.	O

Candidate	O
tumor	O
suppressor	O
genes	O
,	O
Mts1	B-GENE
(	O
p16INK4a	B-GENE
)	O
and	O
Mts2	B-GENE
(	O
p15INK4b	B-GENE
)	O
,	O
have	O
been	O
mapped	O
to	O
this	O
region	O
,	O
but	O
by	O
Southern	O
blot	O
analysis	O
,	O
no	O
homozygous	O
deletions	O
were	O
detected	O
in	O
either	O
gene	O
.	O

Excision	O
repair	O
at	O
the	O
level	O
of	O
the	O
nucleotide	O
in	O
the	O
Saccharomyces	B-GENE
cerevisiae	I-GENE
MFA2	I-GENE
gene	I-GENE
:	O
mapping	O
of	O
where	O
enhanced	O
repair	O
in	O
the	O
transcribed	O
strand	O
begins	O
or	O
ends	O
and	O
identification	O
of	O
only	O
a	O
partial	O
rad16	B-GENE
requisite	O
for	O
repairing	O
upstream	O
control	O
sequences	O
.	O

This	O
locus	O
maps	O
approximately	O
160	O
kbp	O
from	O
the	O
genes	O
encoding	O
cytadherence	O
-	O
associated	O
proteins	O
HMW1	B-GENE
and	O
HMW3	B-GENE
,	O
and	O
yet	O
insertions	O
therein	O
result	O
in	O
loss	O
of	O
these	O
proteins	O
and	O
a	O
hemadsorption	O
-	O
negative	O
(	O
HA	O
-	O
)	O
phenotype	O
,	O
prompting	O
the	O
designation	O
cytadherence	B-GENE
-	I-GENE
regulatory	I-GENE
locus	I-GENE
(	O
crl	B-GENE
)	O
.	O

Coliphage	B-GENE
186	I-GENE
B	I-GENE
is	O
a	O
72	O
-	O
amino	O
acid	O
protein	O
belonging	O
to	O
the	O
Ogr	B-GENE
family	O
of	O
analogous	O
transcription	O
factors	O
present	O
in	O
P2	O
-	O
like	O
phage	O
,	O
which	O
contain	O
a	O
Cys	O
-	O
X2	O
-	O
Cys	O
-	O
X22	O
-	O
Cys	O
-	O
X4	O
-	O
Cys	O
presumptive	O
zinc	O
-	O
finger	O
motif	O
.	O

The	O
UV	O
absorption	O
spectrum	O
revealed	O
a	O
shoulder	O
at	O
250	O
nm	O
,	O
characteristic	O
of	O
CysS	O
-	O
Cd	O
(	O
II	O
)	O
ligand	O
-	O
to	O
-	O
metal	O
charge	O
-	O
transfer	O
transitions	O
,	O
and	O
the	O
difference	O
absorption	O
coefficient	O
after	O
acidification	O
(	O
delta	O
epsilon	O
248	O
,	O
24	O
mM	O
-	O
1	O
cm	O
-	O
1	O
)	O
indicated	O
the	O
presence	O
of	O
a	O
Cd	O
(	O
Cys	O
-	O
S	O
)	O
4	O
center	O
.	O

Diacylglycerol	B-GENE
kinase	I-GENE
(	O
DGK	B-GENE
)	O
attenuates	O
levels	O
of	O
second	O
messenger	O
diacylglycerol	O
in	O
cells	O
and	O
produces	O
another	O
(	O
putative	O
)	O
messenger	O
,	O
phosphatidic	O
acid	O
.	O

Recently	O
,	O
we	O
have	O
reported	O
the	O
cloning	O
of	O
the	O
germ	O
cell	O
-	O
specific	O
,	O
nuclear	O
orphan	O
receptor	O
germ	B-GENE
cell	I-GENE
nuclear	I-GENE
factor	I-GENE
(	O
GCNF	B-GENE
)	O
/	O
RTR	B-GENE
.	O

Based	O
on	O
the	O
sequence	O
of	O
the	O
conRTRE	B-GENE
,	O
we	O
located	O
a	O
putative	O
RTRE	B-GENE
,	O
referred	O
to	O
as	O
P2	B-GENE
-	I-GENE
RE	I-GENE
,	O
in	O
the	O
5	O
'	O
promoter	O
-	O
flanking	O
region	O
of	O
the	O
mouse	B-GENE
protamine	I-GENE
2	I-GENE
gene	I-GENE
,	O
which	O
is	O
induced	O
during	O
the	O
same	O
stage	O
of	O
spermatogenesis	O
as	O
RTR	B-GENE
.	O

Active	O
complexes	O
eluted	O
at	O
a	O
higher	O
molecular	O
weight	O
than	O
inactive	O
complexes	O
,	O
were	O
relatively	O
deficient	O
in	O
both	O
p21	B-GENE
and	O
p27	B-GENE
,	O
and	O
contained	O
Cdk2	B-GENE
with	O
increased	O
threonine	O
160	O
phosphorylation	O
,	O
consistent	O
with	O
a	O
mechanism	O
of	O
activation	O
of	O
cyclin	B-GENE
E	I-GENE
-	O
Cdk2	B-GENE
involving	O
both	O
reduced	O
CDK	B-GENE
inhibitor	O
association	O
and	O
CDK	B-GENE
-	I-GENE
activating	I-GENE
kinase	I-GENE
-	O
mediated	O
phosphorylation	O
of	O
Cdk2	B-GENE
.	O

Thirty	O
Class	O
I	O
and	O
Class	O
II	O
recessions	O
in	O
30	O
patients	O
were	O
treated	O
with	O
a	O
modified	O
subepithelial	O
connective	O
tissue	O
graft	O
procedure	O
.	O

The	O
derivatives	O
of	O
the	O
latter	O
two	O
cell	O
lines	O
showed	O
increased	O
expression	O
of	O
the	O
p27Kip1	B-GENE
protein	I-GENE
and	O
inhibition	O
of	O
cell	O
growth	O
.	O

The	O
perioperative	O
mortality	O
of	O
all	O
patients	O
was	O
1	O
.	O
9	O
%	O
,	O
the	O
mortality	O
of	O
patients	O
older	O
than	O
70	O
years	O
was	O
4	O
.	O
3	O
%	O
.	O

Chronic	O
renal	O
failure	O
patients	O
essentially	O
die	O
from	O
cardiovascular	O
causes	O
,	O
and	O
the	O
frequency	O
of	O
malignant	O
disease	O
responsible	O
for	O
death	O
is	O
estimated	O
to	O
be	O
10	O
%	O
.	O

The	O
new	O
FIGO	O
definition	O
of	O
cervical	O
cancer	O
stage	O
IA	O
:	O
a	O
critique	O
.	O

The	O
effect	O
of	O
Vpu	B-GENE
on	O
class	O
I	O
biogenesis	O
was	O
analyzed	O
in	O
more	O
detail	O
using	O
a	O
Vpu	B-GENE
-	O
expressing	O
recombinant	O
vaccinia	O
virus	O
(	O
VV	O
)	O
.	O

Inductively	O
coupled	O
plasma	O
atomic	O
emission	O
spectroscopy	O
was	O
employed	O
to	O
obtain	O
the	O
tissue	O
silicon	O
measurements	O
.	O

An	O
egg	O
protein	O
,	O
lysozyme	B-GENE
,	O
is	O
a	O
still	O
unlabeled	O
additive	O
currently	O
used	O
in	O
cheese	O
preparation	O
.	O

Similarly	O
,	O
the	O
DNA	O
-	O
binding	O
activity	O
of	O
activator	B-GENE
protein	I-GENE
1	I-GENE
(	O
AP	B-GENE
-	I-GENE
1	I-GENE
)	O
is	O
modified	O
by	O
a	O
DNA	B-GENE
repair	I-GENE
enzyme	I-GENE
,	O
redox	B-GENE
factor	I-GENE
1	I-GENE
(	O
Ref	B-GENE
-	I-GENE
1	I-GENE
)	O
,	O
which	O
is	O
identical	O
to	O
a	O
DNA	B-GENE
repair	I-GENE
enzyme	I-GENE
,	O
AP	B-GENE
endonuclease	I-GENE
.	O

Having	O
an	O
LRR	B-GENE
domain	I-GENE
and	O
an	O
SH3	B-GENE
-	I-GENE
binding	I-GENE
domain	I-GENE
,	O
Acan125	B-GENE
and	O
the	O
C	O
.	O
elegans	O
homologue	O
define	O
a	O
novel	O
family	O
of	O
bifunctional	O
binding	O
proteins	O
.	O

However	O
,	O
its	O
participation	O
in	O
gagging	O
induced	O
by	O
oropharyngeal	O
irritation	O
is	O
unclear	O
.	O

The	O
capacity	O
to	O
repair	O
8	O
-	O
OxoG	O
has	O
been	O
measured	O
in	O
cell	O
-	O
free	O
extracts	O
of	O
wild	O
-	O
type	O
and	O
ogg1	B-GENE
strains	O
using	O
a	O
34mer	O
DNA	O
fragment	O
containing	O
a	O
single	O
8	O
-	O
OxoG	O
residue	O
paired	O
with	O
a	O
cytosine	O
(	O
8	O
-	O
OxoG	O
/	O
C	O
)	O
as	O
a	O
substrate	O
.	O

Results	O
from	O
our	O
and	O
other	O
laboratories	O
have	O
suggested	O
that	O
UCN	O
-	O
01	O
induces	O
preferential	O
G1	O
-	O
phase	O
accumulation	O
in	O
several	O
human	O
tumor	O
cell	O
lines	O
tested	O
.	O

Northern	O
and	O
RT	O
-	O
PCR	O
analysis	O
of	O
Ube3a	B-GENE
expression	O
in	O
mouse	O
tissues	O
from	O
animals	O
with	O
segmental	O
,	O
paternal	O
uniparental	O
disomy	O
failed	O
to	O
detect	O
substantially	O
reduced	O
or	O
absent	O
expression	O
compared	O
to	O
control	O
animals	O
,	O
failing	O
to	O
provide	O
any	O
evidence	O
for	O
maternal	O
-	O
specific	O
expression	O
from	O
this	O
locus	O
.	O

Two	O
predominant	O
effects	O
were	O
noted	O
:	O
(	O
i	O
)	O
the	O
Xaa	O
residue	O
in	O
the	O
dual	O
phosphorylation	O
motif	O
Thr	O
-	O
Xaa	O
-	O
Tyr	O
as	O
well	O
as	O
the	O
length	O
of	O
L12	O
influence	O
p38	B-GENE
substrate	O
specificity	O
,	O
and	O
(	O
ii	O
)	O
the	O
length	O
of	O
L12	O
plays	O
a	O
major	O
role	O
in	O
controlling	O
autophosphorylation	O
.	O

A	O
novel	O
,	O
testis	B-GENE
-	I-GENE
specific	I-GENE
mRNA	I-GENE
transcript	I-GENE
encoding	O
an	O
NH2	B-GENE
-	I-GENE
terminal	I-GENE
truncated	I-GENE
nitric	I-GENE
-	I-GENE
oxide	I-GENE
synthase	I-GENE
.	O
mRNA	O
diversity	O
represents	O
a	O
major	O
theme	O
of	O
neuronal	B-GENE
nitric	I-GENE
-	I-GENE
oxide	I-GENE
synthase	I-GENE
(	O
nNOS	B-GENE
)	O
gene	O
expression	O
in	O
somatic	O
cells	O
/	O
tissues	O
.	O

Unlike	O
the	O
MAR	O
-	O
binding	O
domain	O
,	O
the	O
homeodomain	B-GENE
when	O
isolated	O
binds	O
poorly	O
and	O
with	O
low	O
specificity	O
to	O
DNA	O
.	O

Cyclin	B-GENE
D1	I-GENE
could	O
not	O
be	O
displaced	O
from	O
cdk4	B-GENE
in	O
the	O
resistant	O
184A1L5R	O
cell	O
lysates	O
.	O

The	O
importance	O
of	O
posttranslational	O
regulation	O
of	O
p15INK4B	B-GENE
by	O
TGF	B-GENE
-	I-GENE
beta	I-GENE
is	O
underlined	O
by	O
the	O
observation	O
that	O
in	O
TGF	B-GENE
-	I-GENE
beta	I-GENE
-	O
resistant	O
184A1L5R	O
,	O
although	O
the	O
p15	B-GENE
transcript	I-GENE
increased	O
,	O
p15INK4B	B-GENE
protein	I-GENE
was	O
not	O
stabilized	O
and	O
did	O
not	O
accumulate	O
,	O
and	O
cyclin	B-GENE
D1	I-GENE
-	O
cdk	B-GENE
association	O
and	O
kinase	O
activation	O
were	O
not	O
inhibited	O
.	O

To	O
identify	O
cis	O
-	O
acting	O
elements	O
that	O
target	O
c	B-GENE
-	I-GENE
myc	I-GENE
mRNA	I-GENE
for	O
downregulation	O
during	O
myogenesis	O
,	O
we	O
stably	O
transfected	O
C2C12	O
cells	O
with	O
mutant	B-GENE
myc	I-GENE
genes	I-GENE
or	O
chimeric	O
genes	O
in	O
which	O
various	O
myc	B-GENE
sequences	I-GENE
were	O
fused	O
to	O
the	O
human	B-GENE
beta	I-GENE
-	I-GENE
globin	I-GENE
gene	I-GENE
or	O
to	O
the	O
bacterial	B-GENE
chloramphenicol	I-GENE
acetyltransferase	I-GENE
(	O
CAT	B-GENE
)	O
gene	O
.	O

Furthermore	O
,	O
experiments	O
with	O
32D	O
temperature	O
-	O
sensitive	O
p53	B-GENE
cells	O
indicate	O
that	O
aberrant	O
tal	B-GENE
-	I-GENE
1	I-GENE
expression	O
at	O
the	O
permissive	O
temperature	O
does	O
not	O
exert	O
a	O
proliferative	O
effect	O
but	O
causes	O
p53	B-GENE
-	O
mediated	O
apoptosis	O
,	O
i	O
.	O
e	O
.	O
,	O
the	O
tal	B-GENE
-	I-GENE
1	I-GENE
proliferative	O
effect	O
depends	O
on	O
the	O
integrity	O
of	O
the	O
cell	O
cycle	O
checkpoints	O
of	O
the	O
host	O
cell	O
,	O
as	O
observed	O
for	O
c	B-GENE
-	I-GENE
myc	I-GENE
and	O
other	O
oncogenes	O
.	O
tal	B-GENE
-	I-GENE
1	I-GENE
mutant	I-GENE
experiments	O
indicate	O
that	O
ectopic	O
tal	B-GENE
-	I-GENE
1	I-GENE
effects	O
are	O
mediated	O
by	O
both	O
the	O
DNA	O
-	O
binding	O
and	O
the	O
heterodimerization	O
domains	O
,	O
while	O
the	O
N	B-GENE
-	I-GENE
terminally	I-GENE
truncated	I-GENE
tal	I-GENE
-	I-GENE
1	I-GENE
variant	I-GENE
(	O
M3	B-GENE
)	O
expressed	O
in	O
T	O
-	O
ALL	O
malignant	O
cells	O
mimics	O
the	O
effects	O
of	O
the	O
wild	O
-	O
type	O
protein	O
.	O

DNA	O
-	O
binding	O
activity	O
was	O
not	O
increased	O
by	O
the	O
addition	O
of	O
forskolin	O
to	O
thecal	O
or	O
luteal	O
cells	O
.	O

However	O
,	O
in	O
some	O
of	O
them	O
either	O
pattern	O
may	O
predominate	O
or	O
be	O
exclusively	O
present	O
.	O

Upon	O
induction	O
of	O
SOS	O
,	O
viability	O
increased	O
2	O
-	O
6	O
-	O
fold	O
.	O

In	O
particular	O
,	O
Western	O
,	O
supershift	O
,	O
and	O
promoter	O
deletion	O
analyses	O
suggested	O
a	O
role	O
for	O
CCAAT	B-GENE
/	I-GENE
enhancer	I-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
-	I-GENE
beta	I-GENE
(	O
C	B-GENE
/	I-GENE
EBP	I-GENE
-	I-GENE
beta	I-GENE
)	O
binding	O
site	O
between	O
-	O
2010	O
and	O
-	O
1954	O
in	O
regulating	O
transcription	O
of	O
collagenase	B-GENE
-	I-GENE
1	I-GENE
in	O
monocytic	O
cells	O
.	O

11	O
-	O
Aminoundecanoyl	O
-	O
SK	O
-	O
NH2	O
and	O
11	O
-	O
aminoundecanoyl	O
-	O
SH	O
-	O
NH2	O
establish	O
that	O
a	O
simple	O
alkyl	O
backbone	O
can	O
maintain	O
an	O
appropriate	O
distance	O
between	O
three	O
elements	O
critical	O
for	O
recognition	O
by	O
the	O
fungal	O
enzyme	O
'	O
s	O
peptide	O
-	O
binding	O
site	O
:	O
a	O
simple	O
omega	O
-	O
terminal	O
amino	O
group	O
,	O
a	O
beta	O
-	O
hydroxyl	O
,	O
and	O
an	O
epsilon	O
-	O
amino	O
group	O
or	O
an	O
imidazole	O
.	O

Cdc2	B-GENE
co	O
-	O
precipitates	O
with	O
Pch1	B-GENE
in	O
S	O
.	O
pombe	O
cell	O
lysates	O
,	O
although	O
Cdc2	B-GENE
may	O
not	O
be	O
the	O
major	O
catalytic	O
partner	O
of	O
a	O
Pch1	B-GENE
kinase	I-GENE
in	O
vivo	O
.	O

Little	O
is	O
known	O
about	O
the	O
mechanism	O
,	O
but	O
the	O
availability	O
of	O
rapid	O
facile	O
assays	O
for	O
monitoring	O
immunoglobulin	B-GENE
hypermutation	O
would	O
greatly	O
aid	O
the	O
development	O
of	O
culture	O
systems	O
for	O
hypermutating	O
B	O
cells	O
as	O
well	O
as	O
the	O
screening	O
for	O
individuals	O
deficient	O
in	O
the	O
process	O
.	O

Expression	O
of	O
the	O
human	B-GENE
heat	I-GENE
shock	I-GENE
protein	I-GENE
70	I-GENE
gene	I-GENE
(	O
hsp70	B-GENE
)	O
is	O
induced	O
by	O
various	O
kinds	O
of	O
stress	O
and	O
by	O
oncogenes	O
.	O

Of	O
these	O
proteins	O
,	O
five	O
have	O
previously	O
been	O
shown	O
to	O
be	O
phosphorylated	O
during	O
mitosis	O
(	O
epithelial	B-GENE
-	I-GENE
microtubule	I-GENE
associated	I-GENE
protein	I-GENE
-	I-GENE
115	I-GENE
,	O
Oct91	B-GENE
,	O
Elongation	B-GENE
factor	I-GENE
1gamma	I-GENE
,	O
BRG1	B-GENE
and	O
Ribosomal	B-GENE
protein	I-GENE
L18A	I-GENE
)	O
,	O
five	O
are	O
related	O
to	O
proteins	O
postulated	O
to	O
have	O
roles	O
in	O
mitosis	O
(	O
epithelial	B-GENE
-	I-GENE
microtubule	I-GENE
associated	I-GENE
protein	I-GENE
-	I-GENE
115	I-GENE
,	O
Schizosaccharomyces	B-GENE
pombe	I-GENE
Cdc5	I-GENE
,	O
innercentrosome	B-GENE
protein	I-GENE
,	O
BRG1	B-GENE
and	O
the	O
RNA	B-GENE
helicase	I-GENE
WM6	I-GENE
)	O
,	O
and	O
nine	O
are	O
related	O
to	O
transcription	O
factors	O
(	O
BRG1	B-GENE
,	O
negative	B-GENE
co	I-GENE
-	I-GENE
factor	I-GENE
2alpha	I-GENE
,	O
Oct91	B-GENE
,	O
S	O
.	O
pombe	O
Cdc5	B-GENE
,	O
HoxD1	B-GENE
,	O
Sox3	B-GENE
,	O
Vent2	B-GENE
,	O
and	O
two	O
isoforms	O
of	O
Xbr1b	B-GENE
)	O
.	O

Thus	O
,	O
depending	O
on	O
their	O
location	O
,	O
psoralen	O
cross	O
-	O
links	O
affected	O
different	O
steps	O
in	O
the	O
initiation	O
process	O
.	O

Activation	O
of	O
alpha	B-GENE
4	I-GENE
beta	I-GENE
1	I-GENE
with	O
TS2	B-GENE
/	I-GENE
16	I-GENE
inhibited	O
the	O
cytoplasmic	O
protrusions	O
and	O
cell	O
migration	O
but	O
did	O
not	O
affect	O
the	O
pattern	O
of	O
phosphorylation	O
.	O

Performance	O
on	O
two	O
verbal	O
measures	O
-	O
the	O
National	O
Adult	O
Reading	O
Test	O
-	O
Revised	O
(	O
NART	O
-	O
R	O
)	O
and	O
the	O
Vocabulary	O
subtest	O
from	O
the	O
Wechsler	O
Adult	O
Intelligence	O
Scale	O
-	O
Revised	O
(	O
WAIS	O
-	O
R	O
)	O
-	O
showed	O
strong	O
correlations	O
with	O
level	O
of	O
education	O
.	O

L	O
-	O
canavanine	O
,	O
a	O
selective	O
inhibitor	O
of	O
the	O
inducible	O
nitric	B-GENE
oxide	I-GENE
synthase	I-GENE
,	O
increases	O
the	O
mean	O
systemic	O
filling	O
pressure	O
,	O
thereby	O
improving	O
venous	O
return	O
,	O
under	O
these	O
conditions	O
.	O

RESULTS	O
:	O
Of	O
the	O
29	O
patients	O
who	O
received	O
concurrent	O
chemotherapy	O
and	O
G	B-GENE
-	I-GENE
CSF	I-GENE
,	O
ten	O
(	O
34	O
%	O
;	O
95	O
%	O
confidence	O
interval	O
[	O
CI	O
]	O
,	O
17	O
.	O
9	O
to	O
54	O
.	O
3	O
%	O
)	O
were	O
believed	O
to	O
have	O
clinically	O
significant	O
bleomycin	O
toxicity	O
.	O

The	O
exonic	O
sequence	O
encodes	O
a	O
protein	O
of	O
495	O
amino	O
acids	O
that	O
is	O
nearly	O
identical	O
to	O
the	O
previously	O
reported	O
protein	O
sequence	O
of	O
human	B-GENE
GPT	I-GENE
-	I-GENE
1	I-GENE
.	O

Here	O
we	O
characterize	O
an	O
S	B-GENE
.	I-GENE
cerevisiae	I-GENE
Swi3	I-GENE
homolog	I-GENE
(	O
Swh3	B-GENE
)	O
and	O
present	O
evidence	O
that	O
it	O
associates	O
in	O
a	O
complex	O
with	O
a	O
Snf2	B-GENE
homolog	I-GENE
,	O
Sthl	B-GENE
.	O

Shc	B-GENE
stimulates	O
Ras	B-GENE
/	O
mitogen	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
kinase	I-GENE
(	O
MAPK	B-GENE
)	O
through	O
forming	O
a	O
complex	O
with	O
Grb2	B-GENE
at	O
the	O
phosphorylated	O
tyrosine	O
(	O
Y	O
)	O
residue	O
317	O
.	O

In	O
contrast	O
,	O
Y239	B-GENE
/	I-GENE
240F	I-GENE
Shc	I-GENE
,	O
but	O
not	O
Y317F	B-GENE
Shc	I-GENE
,	O
reduced	O
the	O
EGF	B-GENE
-	O
induced	O
c	B-GENE
-	I-GENE
myc	I-GENE
message	O
.	O

The	O
Ras	B-GENE
guanine	I-GENE
nucleotide	I-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
functions	O
as	O
a	O
molecular	O
switch	O
in	O
signalling	O
downstream	O
of	O
protein	B-GENE
-	I-GENE
tyrosine	I-GENE
kinases	I-GENE
.	O

We	O
show	O
that	O
Rlm1	B-GENE
and	O
Smp1	B-GENE
have	O
MEF2	B-GENE
-	O
related	O
DNA	O
-	O
binding	O
specificities	O
:	O
Rlm1	B-GENE
binds	O
with	O
the	O
same	O
specificity	O
as	O
MEF2	B-GENE
,	O
CTA	B-GENE
(	I-GENE
T	I-GENE
/	I-GENE
A	I-GENE
)	I-GENE
4TAG	I-GENE
,	O
while	O
SMP1	B-GENE
binds	O
a	O
more	O
extended	O
consensus	O
sequence	O
,	O
ACTACTA	O
(	O
T	O
/	O
A	O
)	O
4TAG	O
.	O

Domains	O
I	O
and	O
II	O
of	O
B	B-GENE
"	I-GENE
are	O
buried	O
upon	O
assembly	O
of	O
the	O
TFIIIB	B-GENE
-	I-GENE
DNA	I-GENE
complex	I-GENE
,	O
as	O
determined	O
by	O
protein	O
footprinting	O
.	O

Domain	O
switch	O
experiments	O
reveal	O
that	O
C	B-GENE
/	I-GENE
EBP	I-GENE
beta	I-GENE
proteins	I-GENE
containing	O
either	O
the	O
leucine	O
zipper	O
or	O
the	O
activation	O
domain	O
of	O
C	B-GENE
/	I-GENE
EBP	I-GENE
alpha	I-GENE
are	O
unable	O
to	O
stimulate	O
the	O
2D5	B-GENE
promoter	I-GENE
yet	O
are	O
fully	O
capable	O
of	O
transactivating	O
an	O
artificial	O
promoter	O
bearing	O
a	O
high	O
-	O
affinity	O
C	B-GENE
/	I-GENE
EBP	I-GENE
site	I-GENE
.	O

PRH75	B-GENE
,	O
a	O
new	O
nucleus	O
-	O
localized	O
member	O
of	O
the	O
DEAD	B-GENE
-	I-GENE
box	I-GENE
protein	I-GENE
family	I-GENE
from	O
higher	O
plants	O
.	O

These	O
activities	O
are	O
all	O
required	O
for	O
stimulation	O
of	O
cell	O
growth	O
by	O
middle	B-GENE
-	I-GENE
T	I-GENE
and	O
activate	O
members	O
of	O
the	O
MAP	B-GENE
kinase	I-GENE
family	I-GENE
.	O

A	O
role	O
for	O
the	O
small	B-GENE
GTPase	I-GENE
Rac	I-GENE
in	O
polyomavirus	B-GENE
middle	I-GENE
-	I-GENE
T	I-GENE
antigen	I-GENE
-	O
mediated	O
activation	O
of	O
the	O
serum	O
response	O
element	O
and	O
in	O
cell	O
transformation	O
.	O

Time	O
-	O
activity	O
curves	O
from	O
the	O
gastric	O
region	O
of	O
interest	O
were	O
used	O
,	O
after	O
subjection	O
to	O
appropriate	O
corrective	O
procedures	O
,	O
to	O
calculate	O
the	O
mean	O
gastric	O
transit	O
time	O
(	O
MTT	O
90	O
)	O
and	O
the	O
fraction	O
of	O
the	O
test	O
meal	O
retained	O
in	O
the	O
stomach	O
after	O
90	O
min	O
(	O
F90	O
)	O
.	O

This	O
study	O
provides	O
a	O
direct	O
demonstration	O
of	O
a	O
role	O
for	O
G	B-GENE
betagamma	I-GENE
in	O
mediating	O
the	O
agonist	O
-	O
stimulated	O
translocation	O
of	O
GRK2	B-GENE
and	O
GRK3	B-GENE
in	O
an	O
intact	O
cellular	O
system	O
and	O
demonstrates	O
isoform	O
specificity	O
in	O
the	O
interaction	O
of	O
these	O
components	O
.	O

Our	O
results	O
indicate	O
that	O
RA	O
-	O
mediated	O
repression	O
of	O
the	O
hMGP	B-GENE
gene	I-GENE
is	O
due	O
to	O
binding	O
of	O
liganded	O
RAR	B-GENE
/	O
RXR	B-GENE
to	O
a	O
novel	O
negative	O
RA	O
response	O
element	O
.	O

Point	O
mutations	O
of	O
the	O
five	O
tyrosine	O
residues	O
in	O
the	O
cytoplasmic	O
domain	O
of	O
the	O
receptor	O
were	O
subsequently	O
used	O
to	O
confirm	O
our	O
conclusions	O
.	O

We	O
describe	O
a	O
novel	O
method	O
using	O
Saccharomyces	O
cerevisiae	O
for	O
detecting	O
protein	O
-	O
truncating	O
mutations	O
in	O
any	O
gene	O
of	O
interest	O
.	O

Hepatocellular	O
injury	O
during	O
preservation	O
of	O
human	O
livers	O
with	O
UW	O
and	O
HTK	O
solution	O
.	O

The	O
electromyographically	O
recorded	O
responses	O
consisted	O
of	O
an	O
early	O
R1	O
response	O
in	O
the	O
orbicularis	O
oculi	O
muscle	O
ipsilateral	O
to	O
the	O
side	O
of	O
stimulation	O
,	O
a	O
bilateral	O
late	O
response	O
(	O
ipsilateral	O
R2	O
and	O
contralateral	O
Rc	O
)	O
and	O
a	O
third	O
,	O
R3	O
response	O
,	O
in	O
the	O
ipsilateral	O
orbicularis	O
oculi	O
muscle	O
.	O

The	O
prognosis	O
of	O
seven	O
patients	O
who	O
received	O
ABSCT	O
was	O
significantly	O
better	O
than	O
that	O
of	O
13	O
patients	O
who	O
received	O
conventional	O
therapy	O
alone	O
.	O

(	O
1994	O
,	O
Hum	O
.	O

The	O
pigment	O
intensity	O
of	O
both	O
melanized	O
colonies	O
and	O
appressoria	O
of	O
CAL	O
transformants	O
was	O
weaker	O
than	O
that	O
of	O
the	O
wild	O
type	O
.	O

Malonate	O
decarboxylation	O
in	O
Malonomonas	O
rubra	O
involves	O
the	O
formation	O
of	O
malonyl	B-GENE
-	I-GENE
S	I-GENE
-	I-GENE
[	I-GENE
acyl	I-GENE
-	I-GENE
carrier	I-GENE
protein	I-GENE
]	I-GENE
from	O
acetyl	B-GENE
-	I-GENE
S	I-GENE
-	I-GENE
[	I-GENE
acyl	I-GENE
-	I-GENE
carrier	I-GENE
protein	I-GENE
]	I-GENE
and	O
malonate	O
,	O
carboxyltransfer	O
to	O
a	O
biotin	B-GENE
protein	I-GENE
and	O
its	O
decarboxylation	O
that	O
is	O
coupled	O
to	O
delta	O
mu	O
Na	O
+	O
generation	O
.	O

The	O
Jem	B-GENE
peptide	O
sequence	O
shows	O
a	O
'	O
leucine	O
-	O
zipper	O
'	O
dimerisation	O
motif	O
with	O
limited	O
homology	O
to	O
Fos	B-GENE
/	O
Jun	B-GENE
and	O
ATF	B-GENE
/	O
CREB	B-GENE
proteins	O
and	O
several	O
putative	O
phosphorylation	O
sites	O
.	O

Here	O
we	O
report	O
the	O
cloning	O
of	O
the	O
protein	O
that	O
binds	O
to	O
enhancer	O
site	O
III	O
.	O

Further	O
support	O
for	O
a	O
direct	O
interaction	O
of	O
Tub4p	B-GENE
,	O
Spc98p	B-GENE
and	O
Spc97p	B-GENE
comes	O
from	O
the	O
toxicity	O
of	O
strong	O
SPC97	B-GENE
overexpression	O
which	O
is	O
suppressed	O
by	O
co	O
-	O
overexpression	O
of	O
TUB4	B-GENE
or	O
SPC98	B-GENE
.	O

Sequences	O
needed	O
for	O
iron	O
-	O
regulated	O
expression	O
of	O
sid1	B-GENE
were	O
localized	O
to	O
a	O
306	O
bp	O
region	O
mapping	O
2	O
.	O
3	O
and	O
2	O
.	O
6	O
kb	O
upstream	O
of	O
the	O
ATG	O
.	O

Comparison	O
of	O
the	O
p50	B-GENE
sequence	I-GENE
to	O
other	O
cloned	O
proteins	O
revealed	O
89	O
%	O
homology	O
with	O
a	O
glycosaminoglycan	O
-	O
binding	O
protein	O
and	O
54	O
%	O
homology	O
with	O
Drosophila	B-GENE
cell	I-GENE
cycle	I-GENE
control	I-GENE
protein	I-GENE
(	I-GENE
cdc	I-GENE
)	I-GENE
37	O
.	O

Additional	O
information	O
including	O
echocardiographic	O
sequences	O
,	O
perioperative	O
video	O
sequences	O
,	O
x	O
-	O
ray	O
analysis	O
,	O
angiograms	O
,	O
etc	O
.	O
is	O
represented	O
in	O
the	O
program	O
.	O

We	O
report	O
here	O
that	O
constitutively	O
active	O
Mek1	B-GENE
could	O
activate	O
p96h2bk	B-GENE
in	O
the	O
absence	O
of	O
oncogenic	B-GENE
Ras	I-GENE
.	O

In	O
Schizosaccharomyces	O
pombe	O
,	O
the	O
activity	O
of	O
the	O
M	O
-	O
phase	O
-	O
inducing	O
Cdc2	B-GENE
/	O
Cdc13	B-GENE
cyclin	O
-	O
dependent	O
kinase	O
is	O
inhibited	O
by	O
Wee1	B-GENE
and	O
Mik1	B-GENE
tyrosine	B-GENE
kinases	I-GENE
,	O
and	O
activated	O
by	O
Cdc25	B-GENE
and	O
Pyp3	B-GENE
tyrosine	B-GENE
phosphatases	I-GENE
.	O

The	O
sequencing	O
of	O
Stellate	B-GENE
copies	O
located	O
along	O
the	O
discontinuous	O
cluster	O
revealed	O
a	O
complex	O
pattern	O
of	O
diversification	O
.	O

The	O
results	O
indicate	O
that	O
DNA	O
methylation	O
,	O
chromatin	O
structure	O
,	O
and	O
transactivation	O
at	O
an	O
Sp1	B-GENE
site	I-GENE
contribute	O
to	O
the	O
highly	O
restricted	O
expression	O
of	O
this	O
myelomonocytic	O
lineage	O
specific	O
gene	O
.	O

In	O
gel	O
mobility	O
shift	O
assays	O
,	O
factors	O
present	O
in	O
nuclear	O
extracts	O
derived	O
from	O
differentiated	O
osteoblast	O
bound	O
to	O
oligonucleotide	O
probes	O
containing	O
the	O
E	O
-	O
box	O
1	O
and	O
E	O
-	O
box	O
2	O
elements	O
.	O

Laboratory	O
exam	O
:	O
IDR	O
of	O
the	O
tuberculin	B-GENE
was	O
high	O
positive	O
,	O
chest	O
radiography	O
shows	O
hilar	O
bilateral	O
calcifications	O
,	O
ORL	O
exam	O
shows	O
a	O
tumor	O
at	O
the	O
foot	O
of	O
the	O
epiglottis	O
and	O
anatomopathological	O
exam	O
shows	O
low	O
differentiated	O
epidermoid	O
carcinoma	O
.	O

Finally	O
,	O
we	O
show	O
that	O
PhLP	B-GENE
complexes	O
,	O
at	O
least	O
partially	O
,	O
with	O
Gbetagamma	B-GENE
in	O
vivo	O
.	O

CTF1alpha	B-GENE
,	O
expressed	O
in	O
Escherichia	O
coli	O
,	O
showed	O
specific	O
binding	O
to	O
the	O
palindrome	O
2	O
DNA	O
fragment	O
but	O
not	O
to	O
palindrome	O
1	O
or	O
mutant	O
palindrome	O
2	O
DNA	O
fragments	O
,	O
suggesting	O
specific	O
binding	O
of	O
CTF1alpha	B-GENE
to	O
palindrome	O
2	O
.	O

Cyclin	B-GENE
G2	I-GENE
is	O
highly	O
expressed	O
in	O
the	O
immune	O
system	O
where	O
immunologic	O
tolerance	O
subjects	O
self	O
-	O
reactive	O
lymphocytes	O
to	O
negative	O
selection	O
and	O
clonal	O
deletion	O
via	O
apoptosis	O
.	O

A	O
sterol	O
-	O
regulated	O
protease	O
initiates	O
release	O
of	O
the	O
NH2	O
-	O
terminal	O
segments	O
of	O
sterol	B-GENE
regulatory	I-GENE
element	I-GENE
-	I-GENE
binding	I-GENE
proteins	I-GENE
(	O
SREBPs	B-GENE
)	O
from	O
cell	O
membranes	O
,	O
thereby	O
allowing	O
them	O
to	O
enter	O
the	O
nucleus	O
and	O
to	O
stimulate	O
transcription	O
of	O
genes	O
involved	O
in	O
the	O
uptake	O
and	O
synthesis	O
of	O
cholesterol	O
and	O
fatty	O
acids	O
.	O

Thus	O
,	O
the	O
P	O
.	O
aeruginosa	O
orfX	O
and	O
vfr	B-GENE
promoters	I-GENE
are	O
arranged	O
in	O
a	O
back	O
-	O
to	O
-	O
back	O
orientation	O
rather	O
than	O
the	O
face	O
-	O
to	O
-	O
face	O
orientation	O
of	O
the	O
dorf	O
and	O
crp	B-GENE
promoters	I-GENE
.	O

Sequence	O
analysis	O
of	O
cloned	O
PCR	O
products	O
confirmed	O
the	O
presence	O
of	O
two	O
different	O
nifV	B-GENE
-	I-GENE
like	I-GENE
DNA	I-GENE
fragments	I-GENE
,	O
which	O
were	O
subsequently	O
used	O
as	O
nifV	B-GENE
-	O
and	O
leuA	B-GENE
-	I-GENE
specific	I-GENE
probes	I-GENE
,	O
respectively	O
,	O
to	O
clone	O
XbaI	B-GENE
fragments	I-GENE
of	O
2	O
.	O
1	O
kbp	O
(	O
pOST4	O
)	O
and	O
2	O
.	O
6	O
kbp	O
(	O
pOST2	O
)	O
.	O

In	O
contrast	O
,	O
the	O
Anabaena	O
strain	O
7120	O
leuA	B-GENE
gene	O
did	O
not	O
complement	O
the	O
nifV	B-GENE
mutation	I-GENE
of	O
R229I	O
efficiently	O
.	O

(	O
3	O
)	O
This	O
effect	O
occurs	O
without	O
removing	O
TRs	B-GENE
from	O
the	O
TRE	O
.	O

In	O
a	O
model	O
of	O
the	O
ternary	O
complex	O
,	O
the	O
segment	O
of	O
NFAT	B-GENE
nearest	O
AP	B-GENE
-	I-GENE
1	I-GENE
is	O
the	O
Rel	B-GENE
insert	O
region	O
(	O
RIR	O
)	O
,	O
a	O
feature	O
that	O
is	O
notable	O
for	O
its	O
hypervariability	O
in	O
size	O
and	O
in	O
sequence	O
amongst	O
members	O
of	O
the	O
Rel	B-GENE
transcription	I-GENE
factor	I-GENE
family	I-GENE
.	O

We	O
thus	O
conclude	O
that	O
the	O
NFAT	B-GENE
RIR	I-GENE
plays	O
an	O
essential	O
dual	O
role	O
in	O
DNA	O
recognition	O
and	O
cooperative	O
binding	O
to	O
AP	B-GENE
-	I-GENE
1	I-GENE
family	I-GENE
transcription	I-GENE
factors	I-GENE
.	O

Thus	O
,	O
the	O
association	O
of	O
PS1	B-GENE
fragments	I-GENE
may	O
be	O
maintained	O
during	O
cycles	O
of	O
phosphorylation	O
/	O
dephosphorylation	O
of	O
the	O
PS1	B-GENE
CTF	I-GENE
.	O

This	O
protein	O
can	O
bind	O
to	O
a	O
region	O
of	O
the	O
promoter	O
of	O
an	O
Arabidopsis	B-GENE
light	I-GENE
-	I-GENE
harvesting	I-GENE
chlorophyll	I-GENE
a	I-GENE
/	I-GENE
b	I-GENE
protein	I-GENE
gene	I-GENE
,	O
Lhcb1	B-GENE
*	I-GENE
3	I-GENE
,	O
which	O
is	O
necessary	O
for	O
its	O
regulation	O
by	O
phytochrome	B-GENE
.	O

A	O
patient	O
of	O
Group	O
B	O
had	O
severe	O
athetoid	O
CP	O
with	O
spasticity	O
,	O
being	O
unable	O
to	O
right	O
his	O
trunk	O
and	O
neck	O
.	O

Dystonic	O
movement	O
of	O
the	O
left	O
upper	O
limb	O
in	O
a	O
case	O
of	O
the	O
right	O
pontine	O
hemorrhage	O

It	O
has	O
repeatedly	O
been	O
shown	O
that	O
HCMV	O
IE1	B-GENE
/	O
IE2	B-GENE
can	O
independently	O
transactivate	O
HIV	B-GENE
-	I-GENE
1	I-GENE
LTR	I-GENE
.	O

TAR	B-GENE
and	O
Sp1	B-GENE
-	O
independent	O
transactivation	O
of	O
HIV	B-GENE
long	I-GENE
terminal	I-GENE
repeat	I-GENE
by	O
the	O
Tat	B-GENE
protein	I-GENE
in	O
the	O
presence	O
of	O
human	O
cytomegalovirus	O
IE1	B-GENE
/	O
IE2	B-GENE
.	O

Respiratory	O
chain	O
enzyme	O
activity	O
was	O
normal	O
.	O

Cellular	B-GENE
Csk	I-GENE
was	O
associated	O
with	O
several	O
phosphoproteins	O
,	O
some	O
of	O
which	O
were	O
interacting	O
with	O
the	O
Csk	B-GENE
SH2	B-GENE
domain	I-GENE
.	O

Thus	O
,	O
our	O
studies	O
suggest	O
that	O
pV	O
-	O
mediated	O
activation	O
of	O
HIV	B-GENE
-	I-GENE
1	I-GENE
LTR	I-GENE
activity	O
is	O
controlled	O
by	O
the	O
nuclear	O
translocation	O
of	O
the	O
NF	B-GENE
-	I-GENE
kappaB	I-GENE
transcription	I-GENE
factor	I-GENE
,	O
which	O
is	O
mediated	O
by	O
IkappaBalpha	B-GENE
serine	O
phosphorylation	O
and	O
degradation	O
,	O
but	O
also	O
by	O
a	O
still	O
undefined	O
NF	B-GENE
-	I-GENE
kappaB	I-GENE
-	O
independent	O
pathway	O
.	O

FN	B-GENE
-	O
stimulated	O
c	B-GENE
-	I-GENE
Src	I-GENE
PTK	B-GENE
activity	O
was	O
enhanced	O
by	O
wild	O
type	O
FAK	B-GENE
expression	O
,	O
whereas	O
FN	B-GENE
-	O
stimulated	O
activation	O
of	O
ERK2	B-GENE
was	O
blocked	O
by	O
expression	O
of	O
the	O
c	B-GENE
-	I-GENE
Src	I-GENE
binding	I-GENE
site	I-GENE
Phe	I-GENE
-	I-GENE
397	I-GENE
mutant	I-GENE
of	O
FAK	B-GENE
.	O

A	O
promising	O
new	O
cement	O
,	O
4	O
-	O
META	O
/	O
MMA	O
-	O
TBB	O
opaque	O
resin	O
,	O
has	O
shown	O
remarkable	O
adhesive	O
properties	O
as	O
a	O
bone	O
cement	O
in	O
vivo	O
.	O

Each	O
sample	O
was	O
analysed	O
as	O
soon	O
as	O
possible	O
,	O
and	O
repeated	O
15	O
,	O
30	O
,	O
60	O
and	O
120	O
min	O
after	O
sampling	O
.	O

Like	O
the	O
elicitors	O
of	O
the	O
hypersensitive	O
reaction	O
(	O
HR	O
)	O
produced	O
by	O
E	O
.	O
chrysanthemi	O
(	O
HarpinEch	O
)	O
and	O
E	O
.	O
amylovora	O
(	O
HarpinEa	O
)	O
,	O
the	O
deduced	O
36	O
-	O
kDa	O
protein	O
does	O
not	O
possess	O
a	O
typical	O
signal	O
sequence	O
,	O
but	O
it	O
contains	O
a	O
putative	O
membrane	O
-	O
spanning	O
domain	O
.	O

Molecular	O
characterization	O
and	O
expression	O
of	O
the	O
Erwinia	B-GENE
carotovora	I-GENE
hrpNEcc	I-GENE
gene	I-GENE
,	O
which	O
encodes	O
an	O
elicitor	O
of	O
the	O
hypersensitive	O
reaction	O
.	O

The	O
mRNA	O
from	O
this	O
gene	O
,	O
termed	O
HES1	B-GENE
,	O
is	O
ubiquitously	O
expressed	O
,	O
but	O
strongly	O
so	O
in	O
heart	O
and	O
skeletal	O
muscle	O
.	O

Anesthesia	O
was	O
maintained	O
with	O
isoflurane	O
(	O
ISO	O
)	O
/	O
N2O	O
/	O
O2	O
inhalation	O
.	O

They	O
observed	O
depressed	O
protein	B-GENE
C	I-GENE
activity	O
that	O
significantly	O
(	O
p	O
<	O
0	O
.	O
005	O
)	O
increased	O
and	O
became	O
normal	O
immediately	O
after	O
hemodialysis	O
while	O
factor	B-GENE
X	I-GENE
and	O
factor	B-GENE
VII	I-GENE
increased	O
(	O
p	O
<	O
0	O
.	O
01	O
;	O
p	O
<	O
0	O
.	O
05	O
)	O
despite	O
heparinization	O
together	O
with	O
amount	O
of	O
serum	B-GENE
lipoprotein	I-GENE
(	I-GENE
a	I-GENE
)	I-GENE
.	O

We	O
present	O
a	O
case	O
of	O
type	O
II	O
hyperbetalipoproteinemia	O
in	O
a	O
patient	O
whose	O
diagnosis	O
had	O
been	O
previously	O
unrecognized	O
,	O
and	O
who	O
had	O
previously	O
been	O
misdiagnosed	O
with	O
rheumatoid	O
arthritis	O
and	O
later	O
gout	O
.	O

These	O
data	O
provide	O
evidence	O
that	O
the	O
2	B-GENE
.	I-GENE
0	I-GENE
-	I-GENE
kb	I-GENE
LAT	I-GENE
is	O
an	O
intron	O
of	O
the	O
mLAT	B-GENE
pre	I-GENE
-	I-GENE
mRNA	I-GENE
with	O
a	O
unique	O
branch	O
point	O
.	O

The	O
altered	O
amino	O
acid	O
residues	O
of	O
the	O
seven	O
mutant	B-GENE
9ORF1	I-GENE
polypeptides	I-GENE
clustered	O
within	O
three	O
separate	O
regions	O
referred	O
to	O
as	O
region	O
I	O
(	O
residues	O
34	O
to	O
41	O
)	O
,	O
region	O
II	O
(	O
residues	O
89	O
to	O
91	O
)	O
,	O
and	O
C	O
-	O
terminal	O
region	O
III	O
(	O
residues	O
122	O
to	O
125	O
)	O
.	O

Rep	B-GENE
-	O
Rep	B-GENE
protein	O
interaction	O
was	O
confirmed	O
in	O
vitro	O
through	O
coimmunoprecipitation	O
experiments	O
with	O
a	O
bacterially	O
expressed	O
maltose	B-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
-	O
Rep78	B-GENE
fusion	O
protein	O
in	O
combination	O
with	O
[	O
35S	O
]	O
methionine	O
-	O
labeled	O
Rep78	B-GENE
synthesized	O
in	O
a	O
coupled	O
in	O
vitro	O
transcription	O
-	O
translation	O
system	O
.	O

Fourteen	O
patients	O
with	O
New	O
York	O
Heart	O
Association	O
class	O
II	O
congestive	O
heart	O
failure	O
were	O
enrolled	O
in	O
a	O
double	O
-	O
blind	O
,	O
cross	O
-	O
over	O
study	O
.	O

The	O
main	O
advantages	O
of	O
Multi	O
-	O
MUP	O
analysis	O
are	O
:	O
(	O
1	O
)	O
quick	O
acquisition	O
of	O
many	O
MUPs	O
;	O
(	O
2	O
)	O
simultaneous	O
collection	O
of	O
several	O
MUPs	O
at	O
one	O
recording	O
site	O
;	O
(	O
3	O
)	O
possibility	O
to	O
analyze	O
not	O
only	O
low	O
threshold	O
MUPs	O
;	O
(	O
4	O
)	O
less	O
bias	O
in	O
the	O
selection	O
of	O
MUPs	O
and	O
(	O
5	O
)	O
the	O
reproducibility	O
of	O
the	O
results	O
that	O
allow	O
the	O
same	O
reference	O
values	O
to	O
be	O
used	O
in	O
different	O
laboratories	O
.	O

In	O
several	O
studies	O
the	O
RDFS	O
has	O
shown	O
evidence	O
of	O
reliability	O
and	O
validity	O
.	O

These	O
results	O
suggest	O
that	O
dietary	O
safflower	O
phospholipids	O
may	O
be	O
a	O
valuable	O
ingredient	O
to	O
layers	O
for	O
reducing	O
liver	O
triglycerides	O
and	O
serum	O
cholesterol	O
without	O
any	O
adverse	O
effects	O
.	O

Using	O
various	O
techniques	O
,	O
we	O
have	O
undertaken	O
a	O
systematic	O
analysis	O
of	O
the	O
natural	O
TATA	O
-	O
less	O
human	B-GENE
DNA	I-GENE
polymerase	I-GENE
beta	I-GENE
(	O
beta	B-GENE
-	I-GENE
pol	I-GENE
)	O
gene	O
promoter	O
.	O

Saturable	O
spermidine	O
transport	O
in	O
stk2	B-GENE
:	O
:	O
lacZ	B-GENE
mutants	I-GENE
had	O
an	O
approximately	O
fivefold	O
-	O
lower	O
affinity	O
and	O
twofold	O
-	O
lower	O
Vmax	O
than	O
in	O
the	O
parental	O
strain	O
.	O

Inhibition	O
of	O
the	O
Raf	B-GENE
-	I-GENE
1	I-GENE
kinase	I-GENE
by	O
cyclic	O
AMP	O
agonists	O
causes	O
apoptosis	O
of	O
v	B-GENE
-	I-GENE
abl	I-GENE
-	O
transformed	O
cells	O
.	O

Previous	O
studies	O
have	O
indicated	O
that	O
a	O
hamster	O
cell	O
line	O
(	O
ts13	O
)	O
with	O
a	O
point	O
mutation	O
in	O
the	O
TAF	B-GENE
(	I-GENE
II	I-GENE
)	I-GENE
250	I-GENE
/	O
CCG1	B-GENE
(	O
TAF	B-GENE
(	I-GENE
II	I-GENE
)	I-GENE
250	I-GENE
)	O
gene	O
shows	O
temperature	O
-	O
sensitive	O
expression	O
of	O
a	O
subset	O
of	O
genes	O
and	O
arrests	O
in	O
late	O
G1	O
at	O
39	O
.	O
5	O
degrees	O
C	O
.	O

We	O
show	O
here	O
that	O
the	O
protein	O
kinase	O
MEKK1	B-GENE
can	O
induce	O
reporter	O
gene	O
expression	O
from	O
the	O
atrial	B-GENE
natriuretic	I-GENE
factor	I-GENE
(	O
ANF	B-GENE
)	O
promoter	O
,	O
a	O
genetic	O
marker	O
that	O
is	O
activated	O
during	O
in	O
vivo	O
hypertrophy	O
.	O

Overexpression	O
of	O
EFG1	B-GENE
in	O
C	O
.	O
albicans	O
leads	O
to	O
enhanced	O
filamentous	O
growth	O
in	O
the	O
form	O
of	O
extended	O
pseudohyphae	O
in	O
liquid	O
and	O
on	O
solid	O
media	O
.	O

To	O
determine	O
if	O
signing	O
,	O
when	O
established	O
,	O
would	O
compete	O
with	O
SIB	O
when	O
both	O
were	O
reinforced	O
,	O
extinction	O
was	O
then	O
withdrawn	O
.	O

The	O
husband	O
in	O
one	O
of	O
the	O
married	O
couples	O
was	O
treated	O
for	O
hepatitis	O
of	O
unidentified	O
etiology	O
in	O
an	O
Infectology	O
Department	O
four	O
years	O
ago	O
.	O

Both	O
quantitative	O
and	O
qualitative	O
analysis	O
of	O
individual	O
cytoarchitectonic	O
peculiarities	O
of	O
Meynart	O
'	O
s	O
nucleus	O
as	O
well	O
as	O
of	O
external	O
part	O
of	O
dorsomedial	O
nucleus	O
of	O
thalamus	O
was	O
performed	O
in	O
mentally	O
normal	O
individuals	O
.	O

Positional	O
cloning	O
has	O
already	O
produced	O
the	O
sequences	O
of	O
more	O
than	O
70	O
human	O
genes	O
associated	O
with	O
specific	O
diseases	O
.	O

The	O
30	O
-	O
day	O
mortality	O
in	O
the	O
CPB	O
group	O
and	O
the	O
non	O
-	O
CPB	O
group	O
were	O
20	O
%	O
and	O
4	O
.	O
6	O
%	O
,	O
respectively	O
which	O
was	O
not	O
statistically	O
significant	O
(	O
p	O
=	O
0	O
.	O
06	O
)	O
.	O

As	O
opposed	O
to	O
in	O
vitro	O
co	O
-	O
precipitation	O
studies	O
,	O
the	O
yeast	O
two	O
-	O
hybrid	O
screen	O
reveals	O
in	O
vivo	O
protein	O
-	O
protein	O
interactions	O
.	O

This	O
association	O
appears	O
to	O
be	O
mediated	O
by	O
Src	B-GENE
-	O
SH2	B-GENE
domain	O
,	O
because	O
PECAM	B-GENE
-	I-GENE
1	I-GENE
can	O
be	O
precipitated	O
by	O
a	O
GST	B-GENE
-	O
Src	B-GENE
-	O
SH2	B-GENE
affinity	O
matrix	O
.	O

MKK3	B-GENE
autophosphorylation	O
and	O
activation	O
of	O
p38	B-GENE
was	O
also	O
observed	O
following	O
coexpression	O
of	O
MKK3	B-GENE
with	O
MEKK3	B-GENE
,	O
but	O
not	O
with	O
MEKK2	B-GENE
.	O

An	O
alternatively	O
spliced	O
MAdCAM	B-GENE
-	I-GENE
1	I-GENE
variant	O
was	O
identified	O
that	O
lacks	O
exon	O
4	O
encoding	O
the	O
mucin	B-GENE
domain	O
,	O
and	O
may	O
mediate	O
leukocyte	O
adhesion	O
to	O
LPAM	B-GENE
-	I-GENE
1	I-GENE
without	O
adhesion	O
to	O
the	O
alternate	O
receptor	O
,	O
L	B-GENE
-	I-GENE
selectin	I-GENE
.	O

In	O
summary	O
,	O
the	O
data	O
establish	O
that	O
the	O
previously	O
reported	O
human	B-GENE
MAdCAM	I-GENE
-	I-GENE
1	I-GENE
cDNA	I-GENE
does	O
indeed	O
encode	O
the	O
human	O
homologue	O
of	O
mouse	B-GENE
MAdCAM	I-GENE
-	I-GENE
1	I-GENE
,	O
despite	O
gross	O
dissimilarities	O
in	O
the	O
MAdCAM	B-GENE
-	I-GENE
1	I-GENE
C	O
-	O
terminal	O
structures	O
.	O

We	O
have	O
used	O
a	O
site	O
-	O
directed	O
mutagenesis	O
approach	O
to	O
examine	O
how	O
the	O
Xaa	O
and	O
hydroxy	O
(	O
Ser	O
/	O
Thr	O
)	O
amino	O
acid	O
residues	O
in	O
sequons	O
influence	O
core	O
-	O
glycosylation	O
efficiency	O
.	O

MATERIAL	O
AND	O
METHODS	O
:	O
The	O
authors	O
analyzed	O
41	O
persons	O
formerly	O
submitted	O
to	O
surgery	O
(	O
after	O
8	O
years	O
and	O
4	O
months	O
,	O
as	O
a	O
mean	O
)	O
,	O
31	O
to	O
highly	O
selective	O
vagotomy	O
,	O
and	O
10	O
to	O
truncal	O
or	O
selective	O
vagotomy	O
plus	O
gastroduodenal	O
drainage	O
.	O

This	O
region	O
does	O
not	O
contain	O
an	O
identifiable	O
TATA	O
element	O
,	O
indicating	O
that	O
transcription	O
of	O
the	O
glutaminase	B-GENE
gene	I-GENE
is	O
driven	O
by	O
a	O
TATA	O
-	O
less	O
promoter	O
.	O

Serum	B-GENE
alkaline	I-GENE
phosphatase	I-GENE
activity	O
,	O
bone	O
mass	O
measurements	O
,	O
dual	O
energy	O
x	O
-	O
ray	O
absortiometric	O
analysis	O
of	O
mineral	O
density	O
,	O
and	O
mechanical	O
testing	O
values	O
in	O
vertebrae	O
and	O
femora	O
of	O
the	O
-	O
D	O
Sal	O
animals	O
did	O
not	O
significantly	O
differ	O
from	O
those	O
in	O
+	O
D	O
Sal	O
animals	O
.	O

The	O
monkey	B-GENE
LHR	I-GENE
cDNA	I-GENE
displayed	O
83	O
-	O
94	O
%	O
overall	O
sequence	O
homology	O
with	O
the	O
other	O
mammalian	B-GENE
LHR	I-GENE
cDNAs	I-GENE
.	O

In	O
conclusion	O
,	O
marmoset	B-GENE
monkey	I-GENE
LHR	I-GENE
seems	O
to	O
lack	O
the	O
sequence	O
corresponding	O
to	O
exon	O
10	O
of	O
the	O
LHR	B-GENE
gene	I-GENE
in	O
other	O
mammalian	O
species	O
.	O

In	O
unc	B-GENE
-	I-GENE
4	I-GENE
mutants	I-GENE
,	O
VA	O
motor	O
neurons	O
assume	O
the	O
pattern	O
of	O
synaptic	O
input	O
normally	O
reserved	O
for	O
their	O
lineal	O
sister	O
cells	O
,	O
the	O
VB	O
motor	O
neurons	O
;	O
the	O
loss	O
of	O
normal	O
input	O
to	O
the	O
VAs	O
produces	O
a	O
distinctive	O
backward	O
movement	O
defect	O
.	O

Intracavitary	O
irradiation	O
was	O
carried	O
out	O
with	O
a	O
microSelectron	O
HDR	O
afterloading	O
device	O
and	O
usually	O
22	O
.	O
5	O
Gy	O
was	O
given	O
in	O
three	O
fractions	O
repeated	O
weekly	O
.	O

No	O
patient	O
in	O
group	O
2	O
developed	O
HAT	O
(	O
P	O
=	O
0	O
.	O
006	O
versus	O
group	O
1	O
)	O
.	O

Sequence	O
comparison	O
of	O
the	O
0	O
.	O
38	O
kb	O
promoter	O
sequence	O
with	O
the	O
promoters	O
of	O
the	O
Sm	B-GENE
-	I-GENE
E	I-GENE
gene	O
and	O
U1	B-GENE
snRNA	I-GENE
genes	I-GENE
revealed	O
several	O
homologous	O
motifs	O
,	O
suggesting	O
that	O
genes	O
encoding	O
the	O
snRNP	O
components	O
may	O
be	O
coordinately	O
regulated	O
.	O

METHODS	O
:	O
The	O
responses	O
of	O
a	O
31	O
-	O
year	O
-	O
old	O
woman	O
with	O
complex	O
regional	O
pain	O
syndrome	O
type	O
I	O
(	O
reflex	O
sympathetic	O
dystrophy	O
)	O
to	O
a	O
thermal	O
grill	O
were	O
evaluated	O
before	O
and	O
after	O
stellate	O
ganglion	O
block	O
.	O

More	O
recently	O
,	O
however	O
,	O
a	O
number	O
of	O
developments	O
such	O
as	O
the	O
successful	O
use	O
of	O
the	O
inhaled	O
steroid	O
budesonide	O
and	O
oral	O
dexamethasone	O
have	O
reinforced	O
the	O
argument	O
for	O
using	O
steroids	O
.	O

In	O
AcMNPV	O
-	O
infected	O
Sf9	O
cells	O
,	O
late	O
transcription	O
initiation	O
is	O
detected	O
from	O
only	O
two	O
upstream	O
TAAG	O
sites	O
and	O
not	O
from	O
three	O
downstream	O
TAAG	O
sites	O
.	O

Mutation	O
of	O
nucleotides	O
adjacent	O
to	O
the	O
AP	B-GENE
-	I-GENE
1	I-GENE
cis	I-GENE
-	I-GENE
response	I-GENE
elements	I-GENE
had	O
no	O
effect	O
on	O
trans	O
-	O
activation	O
.	O

The	O
close	O
proximity	O
of	O
the	O
two	O
neuropeptide	B-GENE
Y	I-GENE
receptor	I-GENE
genes	I-GENE
suggests	O
that	O
they	O
have	O
evolved	O
from	O
a	O
gene	O
duplication	O
event	O
with	O
the	O
small	O
intron	O
interrupting	O
the	O
coding	O
sequence	O
of	O
the	O
y1	B-GENE
gene	I-GENE
being	O
converted	O
into	O
a	O
functional	O
sequence	O
within	O
the	O
y5	B-GENE
gene	I-GENE
,	O
while	O
the	O
reverse	O
complementary	O
sequence	O
was	O
utilized	O
as	O
an	O
alternatively	O
spliced	O
5	O
'	O
exon	O
for	O
the	O
y1	B-GENE
gene	I-GENE
.	O

The	O
mammalian	B-GENE
phosphoinositide	I-GENE
3	I-GENE
-	I-GENE
kinases	I-GENE
(	O
PI3Ks	B-GENE
)	O
p110alpha	B-GENE
,	I-GENE
beta	I-GENE
,	I-GENE
and	I-GENE
delta	I-GENE
form	O
heterodimers	O
with	O
Src	B-GENE
homology	I-GENE
2	I-GENE
(	O
SH2	B-GENE
)	O
domain	O
-	O
containing	O
adaptors	O
such	O
as	O
p85alpha	B-GENE
or	O
p55	B-GENE
(	O
PIK	B-GENE
)	O
.	O

In	O
the	O
studies	O
reported	O
here	O
,	O
the	O
5	O
'	O
-	O
flanking	O
region	O
of	O
the	O
human	B-GENE
gp130	I-GENE
gene	I-GENE
was	O
isolated	O
and	O
the	O
transcription	O
initiation	O
sites	O
were	O
mapped	O
.	O

Localization	O
of	O
the	O
cytokine	O
response	O
element	O
by	O
5	O
'	O
-	O
deletion	O
analysis	O
and	O
site	O
-	O
directed	O
mutagenesis	O
revealed	O
a	O
cis	O
-	O
acting	O
binding	O
site	O
for	O
activated	O
STAT	B-GENE
complexes	O
.	O

Insulin	B-GENE
regulation	O
of	O
mitogen	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
kinase	I-GENE
kinase	I-GENE
(	O
MEK	B-GENE
)	O
,	O
mitogen	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
kinase	I-GENE
and	O
casein	B-GENE
kinase	I-GENE
in	O
the	O
cell	O
nucleus	O
:	O
a	O
possible	O
role	O
in	O
the	O
regulation	O
of	O
gene	O
expression	O
.	O

Sequencing	O
of	O
the	O
three	O
pag	B-GENE
-	I-GENE
3	I-GENE
alleles	I-GENE
showed	O
that	O
two	O
apparent	O
null	O
alleles	O
encode	O
a	O
nonsense	O
mutation	O
before	O
the	O
zinc	O
fingers	O
and	O
a	O
missense	O
mutation	O
in	O
the	O
fourth	O
zinc	O
finger	O
that	O
changes	O
a	O
coordinating	O
histidine	O
to	O
a	O
tyrosine	O
.	O

Here	O
,	O
a	O
case	O
of	O
Sjogren	O
'	O
s	O
syndrome	O
is	O
presented	O
that	O
was	O
initially	O
diagnosed	O
because	O
of	O
dental	O
complaints	O
,	O
and	O
long	O
-	O
term	O
treatment	O
of	O
Sjogren	O
'	O
s	O
patients	O
is	O
discussed	O
.	O

Cloning	O
and	O
characterization	O
of	O
a	O
cDNA	O
encoding	O
a	O
bacteriophage	B-GENE
-	I-GENE
type	I-GENE
RNA	I-GENE
polymerase	I-GENE
from	O
the	O
higher	O
plant	O
Chenopodium	O
album	O
.	O

Similarly	O
,	O
overexpression	O
of	O
increasing	O
concentration	O
of	O
COUP	B-GENE
-	I-GENE
TFI	I-GENE
,	O
but	O
not	O
COUP	B-GENE
-	I-GENE
TFI	I-GENE
delta35	I-GENE
,	O
can	O
squelch	O
the	O
silencing	O
activity	O
of	O
the	O
unliganded	O
TRbeta	B-GENE
.	O

In	O
ciliates	O
,	O
both	O
mechanisms	O
are	O
readily	O
observed	O
.	O

Based	O
on	O
the	O
occurrence	O
of	O
several	O
transcription	O
signals	O
in	O
the	O
Thermus	B-GENE
pyr	I-GENE
promoter	I-GENE
region	I-GENE
and	O
strong	O
amino	O
acid	O
sequence	O
identities	O
(	O
about	O
60	O
%	O
)	O
between	O
Thermus	B-GENE
PyrR	I-GENE
and	O
the	O
PyrR	B-GENE
attenuation	I-GENE
proteins	I-GENE
of	O
two	O
Bacillus	O
sp	O
.	O
,	O
we	O
propose	O
a	O
regulatory	O
mechanism	O
involving	O
transcriptional	O
attenuation	O
to	O
control	O
pyr	B-GENE
gene	I-GENE
expression	O
in	O
Thermus	O
.	O

Diver	O
respiratory	O
responses	O
to	O
a	O
tunable	O
closed	O
-	O
circuit	O
breathing	O
apparatus	O
.	O

Measurement	O
of	O
the	O
time	O
constant	O
of	O
VO2	O
and	O
oxygen	O
pulse	O
during	O
constant	O
work	O
rate	O
exercise	O
are	O
useful	O
for	O
the	O
objective	O
evaluation	O
of	O
the	O
training	O
effect	O
of	O
patients	O
with	O
COPD	O
.	O

Characterization	O
of	O
CR1	B-GENE
repeat	O
random	O
PCR	O
markers	O
for	O
mapping	O
the	O
chicken	O
genome	O
.	O

A	O
reversed	O
-	O
phase	O
high	O
-	O
performance	O
liquid	O
chromatographic	O
(	O
HPLC	O
)	O
method	O
for	O
the	O
determination	O
of	O
cocaine	O
metabolites	O
produced	O
in	O
vitro	O
by	O
serum	B-GENE
and	I-GENE
liver	I-GENE
esterases	I-GENE
is	O
described	O
.	O

Mutational	O
studies	O
provide	O
evidence	O
to	O
this	O
end	O
and	O
indicate	O
that	O
the	O
side	O
chains	O
of	O
subdomain	O
4	O
.	O
2	O
make	O
specific	O
contacts	O
with	O
the	O
nucleotides	O
at	O
-	O
35	O
.	O

It	O
is	O
concluded	O
that	O
fludarabine	O
is	O
a	O
highly	O
useful	O
agent	O
in	O
CLL	O
.	O

Three	O
different	O
techniques	O
of	O
EA	O
analysis	O
were	O
used	O
in	O
the	O
study	O
:	O
1	O
)	O
fast	O
Fourier	O
transformation	O
(	O
FFT	O
)	O
of	O
EA	O
in	O
a	O
broad	O
band	O
,	O
2	O
)	O
developed	O
by	O
us	O
alternative	O
method	O
of	O
non	O
-	O
harmonic	O
expansion	O
of	O
the	O
EEG	O
curves	O
taking	O
into	O
account	O
their	O
shape	O
,	O
3	O
)	O
factor	O
analysis	O
of	O
the	O
EA	O
spectral	O
densities	O
.	O

Concomitantly	O
,	O
p34CDC2	B-GENE
histone	B-GENE
H1	I-GENE
kinase	O
activity	O
increases	O
in	O
the	O
former	O
,	O
but	O
not	O
in	O
the	O
latter	O
cell	O
lines	O
,	O
hence	O
suggesting	O
a	O
role	O
for	O
this	O
protein	O
in	O
radiation	O
-	O
induced	O
cell	O
death	O
.	O

Thus	O
,	O
the	O
B	O
-	O
S	O
mutant	O
does	O
not	O
mimic	O
efficiently	O
the	O
chloroplastic	B-GENE
GAPDHs	I-GENE
,	O
and	O
long	O
-	O
range	O
and	O
/	O
or	O
second	O
-	O
layer	O
effects	O
,	O
not	O
easily	O
predictable	O
from	O
visual	O
inspection	O
of	O
three	O
-	O
dimensional	O
structures	O
,	O
need	O
to	O
be	O
taken	O
into	O
account	O
for	O
designing	O
a	O
true	O
"	O
chloroplastic	O
-	O
like	O
"	O
mutant	O
of	O
cytosolic	B-GENE
GAPDH	I-GENE
.	O

Computer	O
software	O
assisted	O
ordering	O
(	O
CSAO	O
)	O
was	O
developed	O
to	O
integrate	O
PN	O
Ca	O
:	O
P	O
solubility	O
with	O
clinical	O
data	O
to	O
improve	O
parenteral	O
Ca	O
and	O
P	O
administration	O
.	O

A	O
similar	O
chimera	O
was	O
assembled	O
from	O
the	O
two	O
halves	O
of	O
the	O
molecule	O
expressed	O
separately	O
in	O
different	O
bacteria	O
and	O
refolded	O
together	O
.	O

The	O
conditions	O
for	O
obtaining	O
titanium	O
dioxide	O
from	O
the	O
substrates	O
titanium	O
tetrachloride	O
and	O
oxygen	O
and	O
applying	O
this	O
to	O
a	O
surgical	O
stainless	O
steel	O
of	O
the	O
type	O
316L	O
by	O
the	O
plasma	O
assisted	O
chemical	O
vapour	O
deposition	O
method	O
have	O
been	O
determined	O
.	O

All	O
six	O
genes	O
were	O
cloned	O
and	O
characterised	O
.	O

We	O
analysed	O
two	O
regions	O
involved	O
in	O
preS2	B-GENE
/	O
S	B-GENE
gene	I-GENE
transcription	O
of	O
the	O
HBV	O
adw	O
subtype	O
:	O
the	O
diverged	O
TATA	O
box	O
and	O
a	O
putative	O
initiator	O
element	O
.	O

Indeed	O
the	O
predicted	O
folding	O
of	O
the	O
5	O
'	O
and	O
3	O
'	O
-	O
untranslated	O
regions	O
revealed	O
patterns	O
of	O
stem	O
and	O
loop	O
structures	O
conserved	O
for	O
all	O
tick	O
-	O
borne	O
flaviviruses	O
suggesting	O
a	O
purifying	O
selection	O
for	O
preservation	O
of	O
essential	O
RNA	O
secondary	O
structures	O
which	O
could	O
be	O
involved	O
in	O
translational	O
control	O
and	O
replication	O
.	O

EGF	B-GENE
acts	O
primarily	O
by	O
means	O
of	O
transactivation	O
domain	O
AF	O
-	O
1	O
,	O
whereas	O
cAMP	O
acts	O
via	O
transactivation	O
domain	O
AF	O
-	O
2	O
of	O
the	O
ER	B-GENE
.	O

To	O
determine	O
which	O
region	O
of	O
SulA	B-GENE
is	O
essential	O
for	O
the	O
inhibition	O
of	O
cell	O
division	O
,	O
we	O
constructed	O
a	O
series	O
of	O
N	O
-	O
terminal	O
and	O
C	O
-	O
terminal	O
deletions	O
of	O
SulA	B-GENE
and	O
a	O
series	O
of	O
alanine	O
substitution	O
mutants	O
.	O

We	O
have	O
inactivated	O
Krox	B-GENE
-	I-GENE
20	I-GENE
by	O
homologous	O
recombination	O
in	O
ES	O
cells	O
and	O
demonstrated	O
that	O
the	O
mutation	O
leads	O
to	O
the	O
deletion	O
of	O
r3	O
and	O
r5	O
.	O

Recently	O
we	O
have	O
performed	O
a	O
detailed	O
analysis	O
of	O
specific	O
neuronal	O
populations	O
affected	O
by	O
the	O
mutation	O
which	O
shed	O
new	O
light	O
on	O
the	O
role	O
of	O
Krox	B-GENE
-	I-GENE
20	I-GENE
in	O
the	O
segmentation	O
and	O
on	O
the	O
physiological	O
consequences	O
of	O
its	O
inactivation	O
.	O

Consistent	O
with	O
its	O
role	O
in	O
p53	B-GENE
ubiquitination	O
,	O
mE6	B-GENE
-	I-GENE
AP	I-GENE
was	O
found	O
both	O
in	O
the	O
nucleus	O
and	O
cytosol	O
,	O
while	O
Nedd	B-GENE
-	I-GENE
4	I-GENE
was	O
found	O
only	O
in	O
the	O
cytosol	O
.	O

SPP	B-GENE
also	O
induced	O
transient	O
tyrosine	O
phosphorylation	O
of	O
focal	B-GENE
adhesion	I-GENE
kinase	I-GENE
(	O
p125	B-GENE
(	O
FAK	B-GENE
)	O
)	O
,	O
a	O
cytosolic	B-GENE
tyrosine	I-GENE
kinase	I-GENE
that	O
localizes	O
in	O
focal	O
adhesions	O
,	O
and	O
of	O
the	O
cytoskeleton	B-GENE
-	I-GENE
associated	I-GENE
protein	I-GENE
paxillin	I-GENE
.	O

Evaluation	O
of	O
myocardial	O
perfusion	O
by	O
99mTc	O
-	O
tetrofosmin	O
SPECT	O
before	O
and	O
after	O
emergent	O
percutaneous	O
transluminal	O
coronary	O
angioplasty	O
for	O
acute	O
myocardial	O
infarction	O

A	O
neonatal	O
alloimmune	O
thrombocytopenia	O
with	O
an	O
HPA	B-GENE
-	I-GENE
3a	I-GENE
(	O
Baka	O
)	O
incompatibility	O
was	O
confirmed	O
.	O

Most	O
eukaryotic	O
mRNAs	O
are	O
translated	O
by	O
a	O
"	O
scanning	O
ribosome	O
"	O
mechanism	O
.	O

Comparison	O
of	O
Tc	O
-	O
99m	O
sestamibi	O
perfusion	O
imaging	O
and	O
echocardiography	O
using	O
an	O
arbutamine	O
infusion	O
for	O
the	O
detection	O
of	O
coronary	O
artery	O
disease	O
.	O

Five	O
of	O
these	O
have	O
ocular	O
or	O
oculocutaneous	O
albinism	O
.	O

Comprising	O
a	O
126	O
-	O
nucleotide	O
5	O
'	O
untranscribed	O
genomic	O
sequence	O
and	O
a	O
466	O
-	O
nucleotide	O
5	O
'	O
noncoding	O
cDNA	O
sequence	O
,	O
the	O
592	O
-	O
nucleotide	O
5	O
'	O
CpG	O
island	O
lacked	O
TATA	O
and	O
CAAT	O
boxes	O
but	O
displayed	O
a	O
high	O
G	O
+	O
C	O
content	O
,	O
was	O
enriched	O
for	O
CpG	O
dinucleotides	O
,	O
and	O
contained	O
a	O
potential	O
Sp1	B-GENE
-	I-GENE
binding	I-GENE
site	I-GENE
,	O
i	O
.	O
e	O
.	O
,	O
features	O
compatible	O
with	O
a	O
housekeeping	O
gene	O
.	O

SSeCKS	B-GENE
(	O
pronounced	O
essex	O
)	O
encodes	O
a	O
major	O
protein	B-GENE
kinase	I-GENE
C	I-GENE
substrate	O
,	O
the	O
expression	O
of	O
which	O
is	O
down	O
-	O
regulated	O
in	O
src	B-GENE
-	O
and	O
ras	B-GENE
-	O
transformed	O
rodent	O
fibroblasts	O
but	O
not	O
in	O
raf	O
-	O
transformed	O
rodent	O
fibroblasts	O
(	O
X	O
.	O

The	O
1	O
.	O
1	O
-	O
and	O
1	O
.	O
3	O
-	O
kb	O
mRNA	O
species	O
were	O
found	O
only	O
in	O
the	O
heart	O
,	O
and	O
the	O
2	O
.	O
6	O
-	O
kb	O
species	O
was	O
found	O
in	O
the	O
heart	O
,	O
kidney	O
and	O
brain	O
,	O
but	O
not	O
in	O
skeletal	O
muscle	O
or	O
liver	O
.	O

Taurine	O
deficiency	O
significantly	O
depressed	O
the	O
amplitude	O
of	O
OP1	O
and	O
OP4	O
.	O

We	O
have	O
found	O
that	O
mcs4	B-GENE
-	O
cells	O
are	O
defective	O
at	O
activation	O
of	O
Spc1	B-GENE
in	O
response	O
to	O
various	O
forms	O
of	O
stress	O
.	O

The	O
extended	O
rat	B-GENE
SP	I-GENE
-	I-GENE
A	I-GENE
isoforms	I-GENE
were	O
enriched	O
in	O
the	O
more	O
fully	O
glycosylated	O
and	O
multimeric	O
SP	B-GENE
-	I-GENE
A	I-GENE
species	O
separated	O
on	O
SDS	O
-	O
PAGE	O
gels	O
.	O

Alternative	O
splicing	O
of	O
CDC25B	B-GENE
may	O
therefore	O
contribute	O
to	O
the	O
control	O
of	O
cell	O
proliferation	O
.	O

This	O
investigation	O
was	O
undertaken	O
to	O
determine	O
whether	O
consuming	O
several	O
small	O
feedings	O
of	O
preexercise	O
carbohydrate	O
(	O
CHO	O
)	O
,	O
rather	O
than	O
a	O
single	O
bolus	O
,	O
would	O
affect	O
blood	O
glucose	O
and	O
insulin	B-GENE
responses	O
during	O
rest	O
and	O
exercise	O
.	O

The	O
findings	O
suggest	O
that	O
ERP	O
effects	O
of	O
distinct	O
memory	O
processes	O
are	O
differentially	O
influenced	O
by	O
the	O
encoding	O
instructions	O
.	O

This	O
coat	B-GENE
protein	I-GENE
consists	O
of	O
Sar1p	B-GENE
,	O
the	O
Sec23p	B-GENE
protein	I-GENE
complex	I-GENE
containing	O
Sec23p	B-GENE
and	O
Sec24p	B-GENE
,	O
and	O
the	O
Sec13p	B-GENE
protein	I-GENE
complex	I-GENE
containing	O
Sec13p	B-GENE
and	O
a	O
novel	O
150	B-GENE
-	I-GENE
kDa	I-GENE
protein	I-GENE
,	I-GENE
p150	I-GENE
.	O

The	O
second	O
primary	O
mutant	O
contained	O
a	O
proline	O
-	O
to	O
-	O
leucine	O
change	O
at	O
position	O
243	O
(	O
P243L	O
)	O
.	O

Induction	O
of	O
correctly	O
spliced	O
germline	O
transcripts	O
is	O
necessary	O
to	O
target	O
a	O
switch	O
region	O
for	O
recombination	O
and	O
switching	O
.	O

Thus	O
,	O
the	O
PCE	B-GENE
binds	O
a	O
Pbx	B-GENE
dimer	I-GENE
partner	I-GENE
that	O
behaves	O
unlike	O
Class	B-GENE
I	I-GENE
Hox	I-GENE
proteins	I-GENE
.	O

Furthermore	O
,	O
the	O
NH2	O
-	O
terminal	O
portion	O
of	O
the	O
homologue	O
was	O
not	O
translocated	O
into	O
the	O
outer	O
membrane	O
without	O
its	O
COOH	O
-	O
terminal	O
part	O
.	O

Molecular	O
cloning	O
and	O
characterization	O
of	O
a	O
cDNA	O
,	O
CHEMR1	B-GENE
,	O
encoding	O
a	O
chemokine	O
receptor	O
with	O
a	O
homology	O
to	O
the	O
human	B-GENE
C	I-GENE
-	I-GENE
C	I-GENE
chemokine	I-GENE
receptor	I-GENE
,	O
CCR	B-GENE
-	I-GENE
4	I-GENE
.	O

Organization	O
of	O
the	O
human	B-GENE
LU	I-GENE
gene	I-GENE
and	O
molecular	O
basis	O
of	O
the	O
Lu	B-GENE
(	I-GENE
a	I-GENE
)	I-GENE
/	O
Lu	B-GENE
(	I-GENE
b	I-GENE
)	I-GENE
blood	O
group	O
polymorphism	O
.	O

Whereas	O
the	O
mutant	O
enzymes	O
terminate	O
normally	O
at	O
the	O
late	O
terminator	O
in	O
T7	O
DNA	O
(	O
T	O
(	O
phi	O
)	O
)	O
and	O
rrnB	B-GENE
T2	O
,	O
they	O
fail	O
to	O
terminate	O
at	O
one	O
of	O
the	O
termination	O
sites	O
of	O
rrnB	B-GENE
T1	O
,	O
and	O
also	O
fail	O
to	O
recognize	O
the	O
PTH	B-GENE
and	O
CJ	O
signals	O
.	O

Cytological	O
data	O
suggest	O
that	O
the	O
transgenes	O
associate	O
with	O
a	O
nucleolus	O
.	O

Light	B-GENE
regulatory	I-GENE
unit	I-GENE
1	I-GENE
(	O
LRU1	B-GENE
)	O
is	O
necessary	O
for	O
and	O
sufficient	O
to	O
mediate	O
light	O
-	O
dependent	O
activation	O
of	O
the	O
chalcone	B-GENE
synthase	I-GENE
(	I-GENE
CHS	I-GENE
)	I-GENE
minimal	I-GENE
promoter	I-GENE
in	O
Petroselinum	O
crispum	O
.	O

The	O
active	O
state	O
is	O
terminated	O
by	O
hydrolysis	O
of	O
bound	O
GTP	O
,	O
producing	O
inactive	O
ARF	B-GENE
-	I-GENE
GDP	I-GENE
.	O

We	O
suggest	O
that	O
apart	O
from	O
the	O
World	O
Summit	O
for	O
Children	O
'	O
s	O
under	O
-	O
five	O
mortality	O
target	O
for	O
the	O
year	O
2000	O
,	O
intraregional	O
targets	O
to	O
reduce	O
geographical	O
inequalities	O
in	O
under	O
-	O
five	O
mortality	O
should	O
be	O
specified	O
.	O

The	O
immunophilin	B-GENE
,	O
which	O
can	O
be	O
of	O
the	O
FK506	O
-	O
or	O
cyclosporin	O
A	O
-	O
binding	O
class	O
,	O
binds	O
to	O
hsp90	B-GENE
via	O
its	O
tetratricopeptide	O
repeat	O
(	O
TPR	O
)	O
domain	O
,	O
and	O
different	O
receptor	O
heterocomplexes	O
exist	O
depending	O
upon	O
which	O
immunophilin	B-GENE
occupies	O
the	O
TPR	O
-	O
binding	O
region	O
of	O
hsp90	B-GENE
.	O

Sequencing	O
of	O
the	O
facB	B-GENE
gene	I-GENE
revealed	O
that	O
it	O
encodes	O
a	O
protein	O
that	O
contains	O
an	O
N	O
-	O
terminal	O
GAL4	B-GENE
-	O
like	O
Zn	O
(	O
II	O
)	O
2Cys6	O
(	O
or	O
C6	O
zinc	O
)	O
binuclear	O
cluster	O
for	O
DNA	O
binding	O
,	O
leucine	O
zipper	O
-	O
like	O
heptad	O
repeat	O
motifs	O
and	O
central	O
and	O
C	O
-	O
terminal	O
acidic	O
alpha	O
-	O
helical	O
regions	O
,	O
consistent	O
with	O
a	O
function	O
as	O
a	O
DNA	O
-	O
binding	O
transcriptional	O
activator	O
.	O

Overexpression	O
of	O
Sed5p	B-GENE
allowed	O
growth	O
in	O
the	O
absence	O
of	O
Vti1p	B-GENE
.	O

The	O
coding	O
region	O
of	O
mkh1	B-GENE
is	O
contained	O
within	O
a	O
single	O
exon	O
encoding	O
a	O
1	O
,	O
116	O
-	O
amino	O
-	O
acid	O
protein	O
.	O

Strikingly	O
,	O
stoichiometric	O
association	O
of	O
p107	B-GENE
or	O
p130	B-GENE
with	O
either	O
cyclin	B-GENE
E	I-GENE
-	O
cdk2	B-GENE
or	O
cyclin	B-GENE
A	I-GENE
-	O
cdk2	B-GENE
negated	O
the	O
activities	O
of	O
these	O
kinases	O
.	O

Furthermore	O
,	O
p150	B-GENE
suppresses	O
actin	B-GENE
gelation	O
,	O
which	O
is	O
induced	O
by	O
smooth	B-GENE
muscle	I-GENE
alpha	I-GENE
-	I-GENE
actinin	I-GENE
.	O

Denaturation	O
of	O
the	O
simian	O
virus	O
40	O
origin	O
of	O
replication	O
mediated	O
by	O
human	B-GENE
replication	I-GENE
protein	I-GENE
A	I-GENE
.	O

This	O
effect	O
was	O
abolished	O
once	O
the	O
EM	O
motif	O
in	O
the	O
promoter	O
-	O
reporter	O
construct	O
was	O
mutated	O
,	O
thus	O
suggesting	O
that	O
the	O
synergistic	O
transactivation	O
function	O
of	O
the	O
TEF	B-GENE
-	I-GENE
1	I-GENE
-	O
Max	B-GENE
heterotypic	O
complex	O
is	O
mediated	O
through	O
binding	O
of	O
the	O
complex	O
to	O
the	O
EM	O
motif	O
.	O

Interdigitated	O
residues	O
within	O
a	O
small	O
region	O
of	O
VP16	B-GENE
interact	O
with	O
Oct	B-GENE
-	I-GENE
1	I-GENE
,	O
HCF	B-GENE
,	O
and	O
DNA	O
.	O

With	O
a	O
view	O
to	O
identifying	O
other	O
important	O
U14	B-GENE
interactions	O
,	O
a	O
stem	O
-	O
loop	O
domain	O
required	O
for	O
activity	O
of	O
Saccharomyces	B-GENE
cerevisiae	I-GENE
U14	I-GENE
RNAs	I-GENE
(	O
the	O
Y	O
domain	O
)	O
was	O
first	O
subjected	O
to	O
detailed	O
mutational	O
analysis	O
.	O

Based	O
on	O
these	O
results	O
and	O
because	O
Cdc68	B-GENE
has	O
been	O
implicated	O
as	O
a	O
regulator	O
of	O
chromatin	O
structure	O
,	O
we	O
postulate	O
that	O
polymerase	B-GENE
alpha	I-GENE
may	O
interact	O
with	O
these	O
proteins	O
to	O
gain	O
access	O
to	O
its	O
template	O
or	O
to	O
origins	O
of	O
replication	O
in	O
vivo	O
.	O

Even	O
when	O
the	O
inoculum	O
size	O
was	O
reduced	O
sixfold	O
(	O
i	O
.	O
e	O
.	O
,	O
6	O
x	O
10	O
(	O
6	O
)	O
CFU	O
/	O
mouse	O
)	O
,	O
50	O
%	O
of	O
the	O
RB6	B-GENE
-	I-GENE
8C5	I-GENE
-	O
treated	O
animals	O
died	O
within	O
6	O
days	O
.	O

In	O
12	O
cases	O
(	O
3	O
.	O
1	O
%	O
)	O
,	O
a	O
change	O
in	O
stage	O
resulted	O
.	O

Promoter	O
recognition	O
algorithms	O
identified	O
divergent	O
promoter	O
elements	O
within	O
the	O
CpG	O
island	O
,	O
which	O
lies	O
between	O
the	O
ATM	B-GENE
and	O
E14	B-GENE
/	O
NPAT	B-GENE
genes	O
,	O
and	O
provide	O
evidence	O
for	O
a	O
putative	O
second	O
ATM	B-GENE
promoter	I-GENE
located	O
within	O
intron	O
3	O
,	O
immediately	O
upstream	O
of	O
the	O
first	O
coding	O
exon	O
.	O

Recombinant	B-GENE
soluble	I-GENE
pMCP	I-GENE
that	O
lacked	O
transmembrane	O
and	O
cytoplasmic	O
domains	O
had	O
factor	B-GENE
I	I-GENE
cofactor	I-GENE
activity	O
in	O
C3b	B-GENE
cleavage	O
,	O
indicating	O
that	O
it	O
is	O
functionally	O
,	O
as	O
well	O
as	O
structurally	O
homologous	O
to	O
MCP	B-GENE
.	O

Clinical	O
and	O
haematological	O
signs	O
are	O
not	O
specific	O
in	O
this	O
setting	O
,	O
and	O
the	O
diagnosis	O
relies	O
on	O
histological	O
features	O
,	O
mainly	O
bone	O
marrow	O
examination	O
.	O

Spatial	O
zones	O
for	O
muscle	O
coactivation	O
and	O
the	O
control	O
of	O
postural	O
stability	O
.	O

Liquid	O
chromatographic	O
separation	O
was	O
achieved	O
on	O
a	O
Zorbax	O
RX	O
C8	O
analytical	O
column	O
using	O
gradient	O
elution	O
.	O

The	O
linear	O
plasmid	O
pDHL1	O
from	O
Debaryomyces	O
hansenii	O
encodes	O
a	O
protein	O
highly	O
homologous	O
to	O
the	O
pGKL1	B-GENE
-	I-GENE
plasmid	I-GENE
DNA	I-GENE
polymerase	I-GENE
.	O

The	O
p20	B-GENE
-	I-GENE
CGGBP	I-GENE
gene	I-GENE
is	O
conserved	O
among	O
mammals	O
but	O
shows	O
no	O
homology	O
to	O
non	O
-	O
vertebrate	O
species	O
.	O

The	O
data	O
suggest	O
that	O
like	O
in	O
yeast	O
,	O
in	O
plants	O
a	O
certain	O
subfamily	O
of	O
UBC	B-GENE
is	O
specifically	O
involved	O
in	O
the	O
proteolytic	O
degradation	O
of	O
abnormal	O
proteins	O
as	O
result	O
of	O
stress	O
.	O

The	O
pWP	B-GENE
-	I-GENE
19	I-GENE
also	O
encodes	O
the	O
AAV	O
inverted	O
terminal	O
repeats	O
for	O
integration	O
and	O
replication	O
and	O
the	O
herpes	O
virus	O
thymidine	B-GENE
kinase	I-GENE
promoter	O
-	O
driven	O
gene	O
for	O
neomycin	O
resistance	O
(	O
neoR	B-GENE
)	O
.	O

We	O
have	O
developed	O
a	O
rAAV	O
-	O
mediated	O
gene	O
transfer	O
system	O
for	O
the	O
rat	B-GENE
preproinsulin	I-GENE
II	I-GENE
gene	I-GENE
.	O

A	O
striking	O
feature	O
of	O
the	O
recombinant	B-GENE
H19	I-GENE
allele	I-GENE
is	O
the	O
occurrence	O
of	O
a	O
parental	O
imprint	O
set	O
on	O
the	O
neo	B-GENE
replacement	I-GENE
cassette	I-GENE
.	O

This	O
indicates	O
that	O
recruitment	O
of	O
large	B-GENE
T	I-GENE
antigen	I-GENE
to	O
the	O
rRNA	O
promoter	O
by	O
SL1	B-GENE
constitutes	O
a	O
crucial	O
step	O
in	O
the	O
activation	O
process	O
.	O

In	O
1990	O
,	O
an	O
International	O
Commission	O
for	O
the	O
Certification	O
of	O
Eradication	O
of	O
Poliomyelitis	O
Eradication	O
(	O
ICCPE	O
)	O
was	O
established	O
by	O
the	O
Pan	O
American	O
Health	O
Organization	O
to	O
eventually	O
determine	O
if	O
transmission	O
was	O
interrupted	O
.	O

Functional	O
and	O
regulatory	O
analysis	O
of	O
the	O
two	O
copies	O
of	O
the	O
fixNOQP	B-GENE
operon	I-GENE
of	O
Rhizobium	O
leguminosarum	O
strain	O
VF39	O
.	O

This	O
study	O
describes	O
a	O
new	O
MADS	B-GENE
box	I-GENE
gene	I-GENE
,	O
nmhC5	B-GENE
,	O
which	O
along	O
with	O
nmh7	B-GENE
(	O
J	O
.	O

Lung	O
and	O
multi	O
-	O
system	O
damage	O
were	O
early	O
indicators	O
of	O
poor	O
outcome	O
in	O
severe	O
non	O
-	O
fatal	O
disease	O
.	O

The	O
results	O
suggest	O
that	O
the	O
bulbospinal	O
micturition	O
reflex	O
evoked	O
by	O
bladder	O
filling	O
and	O
L	O
-	O
dopa	O
involves	O
a	O
descending	O
pathway	O
where	O
transmission	O
is	O
partly	O
mediated	O
by	O
spinal	B-GENE
alpha	I-GENE
1	I-GENE
-	I-GENE
adrenoceptors	I-GENE
.	O

Disturbance	O
of	O
regeneration	O
in	O
the	O
above	O
pathological	O
condition	O
results	O
from	O
the	O
damage	O
to	O
tunica	O
propria	O
and	O
loss	O
of	O
its	O
function	O
for	O
the	O
support	O
of	O
structural	O
homeostasis	O
.	O

Sternocleidomastoid	O
,	O
neck	O
or	O
facial	O
muscles	O
wasting	O
were	O
also	O
found	O
in	O
three	O
cases	O
.	O

Identification	O
of	O
five	O
new	O
genes	O
,	O
closely	O
related	O
to	O
the	O
interleukin	B-GENE
-	I-GENE
1beta	I-GENE
converting	I-GENE
enzyme	I-GENE
gene	I-GENE
,	O
that	O
do	O
not	O
encode	O
functional	O
proteases	O
.	O

The	O
C	O
-	O
terminal	O
mature	O
region	O
is	O
highly	O
conserved	O
in	O
other	O
serine	B-GENE
carboxypeptidases	I-GENE
.	O

Here	O
we	O
demonstrate	O
that	O
AML1a	B-GENE
,	O
which	O
solely	O
has	O
no	O
effects	O
as	O
a	O
transcriptional	O
regulator	O
,	O
dominantly	O
suppresses	O
transcriptional	O
activation	O
by	O
AML1b	B-GENE
,	O
and	O
that	O
AML1a	B-GENE
exhibits	O
the	O
higher	O
affinity	O
for	O
DNA	O
-	O
binding	O
than	O
AML1b	B-GENE
.	O

However	O
,	O
using	O
ATL	O
-	O
16T	O
nuclear	O
extract	O
,	O
we	O
demonstrated	O
that	O
GATA	B-GENE
-	I-GENE
4	I-GENE
is	O
the	O
only	O
GATA	B-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
that	O
forms	O
specific	O
DNA	O
-	O
protein	O
complex	O
with	O
the	O
-	O
70	O
GATA	O
site	O
.	O

The	O
impact	O
of	O
social	O
support	O
on	O
the	O
relationships	O
of	O
gay	O
male	O
couples	O
is	O
examined	O
.	O

The	O
ubiquitously	O
expressed	O
hypoxia	B-GENE
-	I-GENE
inducible	I-GENE
factor	I-GENE
-	I-GENE
1	I-GENE
(	O
HIF	B-GENE
-	I-GENE
1	I-GENE
)	O
is	O
involved	O
in	O
expression	O
of	O
a	O
large	O
number	O
of	O
oxygen	O
-	O
regulated	O
genes	O
.	O

Stromelysin	B-GENE
-	I-GENE
1	I-GENE
,	O
matrix	B-GENE
metalloproteinase	I-GENE
-	I-GENE
3	I-GENE
(	O
MMP	B-GENE
-	I-GENE
3	I-GENE
)	O
,	O
is	O
an	O
important	O
endopeptidase	O
selectively	O
expressed	O
by	O
somatic	O
cells	O
in	O
organ	O
tissues	O
.	O

Tendon	O
also	O
shows	O
a	O
degree	O
of	O
extensibility	O
.	O

Surveillance	O
for	O
preeclampsia	O
was	O
conducted	O
by	O
personnel	O
unaware	O
of	O
treatment	O
-	O
group	O
assignments	O
,	O
using	O
standardized	O
measurements	O
of	O
blood	O
pressure	O
and	O
urinary	O
protein	O
excretion	O
at	O
uniformly	O
scheduled	O
prenatal	O
visits	O
,	O
protocols	O
for	O
monitoring	O
these	O
measurements	O
during	O
the	O
hospitalization	O
for	O
delivery	O
,	O
and	O
reviews	O
of	O
medical	O
records	O
of	O
unscheduled	O
outpatient	O
visits	O
and	O
all	O
hospitalizations	O
.	O

DNase	B-GENE
I	I-GENE
footprint	O
analysis	O
identified	O
a	O
protected	O
region	O
from	O
-	O
37	O
to	O
-	O
53	O
.	O

We	O
isolated	O
several	O
overlapping	O
A	O
-	O
phage	O
and	O
cosmid	O
clones	O
that	O
cover	O
more	O
than	O
100	O
kb	O
of	O
human	O
DNA	O
and	O
contained	O
the	O
entire	O
VDR	B-GENE
gene	I-GENE
.	O

Here	O
,	O
we	O
correlate	O
Dox	O
effects	O
on	O
cell	O
cycle	O
with	O
changes	O
of	O
E2F	B-GENE
/	O
DP	B-GENE
complexes	O
and	O
activity	O
in	O
differentiating	O
C2C12	O
myocytes	O
.	O

The	O
products	O
of	O
the	O
Saccharomyces	B-GENE
cerevisiae	I-GENE
CIN1	I-GENE
,	O
CIN2	B-GENE
and	O
CIN4	B-GENE
genes	I-GENE
participate	O
in	O
a	O
nonessential	O
pathway	O
required	O
for	O
normal	O
microtubule	O
function	O
.	O

Vitrectomy	O
was	O
still	O
a	O
significant	O
risk	O
factor	O
when	O
macular	O
holes	O
were	O
excluded	O
.	O

Invited	O
editorial	O
on	O
"	O
Acute	O
and	O
chronic	O
effects	O
of	O
exercise	O
on	O
leptin	B-GENE
levels	O
in	O
humans	O
"	O
.	O

Both	O
promoters	O
lack	O
a	O
TATA	O
box	O
,	O
and	O
Pint	B-GENE
belongs	O
to	O
the	O
MED	B-GENE
-	I-GENE
1	I-GENE
class	O
of	O
promoters	O
,	O
which	O
initiate	O
transcription	O
at	O
multiple	O
sites	O
.	O

Serum	B-GENE
response	I-GENE
factor	I-GENE
(	O
SRF	B-GENE
)	O
,	O
a	O
member	O
of	O
an	O
ancient	O
family	O
of	O
DNA	O
-	O
binding	O
proteins	O
,	O
is	O
generally	O
assumed	O
to	O
be	O
a	O
ubiquitous	O
transcription	O
factor	O
involved	O
in	O
regulating	O
growth	O
factor	O
-	O
responsive	O
genes	O
.	O

We	O
have	O
initiated	O
studies	O
to	O
identify	O
candidate	O
signal	O
transducers	O
that	O
associate	O
with	O
the	O
cytosolic	O
domain	O
(	O
cd	O
)	O
of	O
the	O
IL	B-GENE
-	I-GENE
1R	I-GENE
.	O

In	O
this	O
study	O
,	O
we	O
sought	O
to	O
identify	O
mechanisms	O
that	O
could	O
account	O
for	O
the	O
antimitogenic	O
effects	O
of	O
IL	B-GENE
-	I-GENE
4	I-GENE
.	O

Pseudomonas	O
aeruginosa	O
strains	O
infecting	O
patients	O
with	O
cystic	O
fibrosis	O
(	O
CF	O
)	O
acquire	O
a	O
mucoid	O
phenotype	O
due	O
to	O
overproduction	O
of	O
alginate	O
.	O

Activity	O
of	O
palgD	B-GENE
in	O
the	O
cysB	B-GENE
mutant	I-GENE
,	O
in	O
CHA	O
and	O
in	O
the	O
non	O
-	O
mucoid	O
strain	O
PAO	O
was	O
assessed	O
by	O
the	O
use	O
of	O
a	O
transcriptional	O
algD	B-GENE
-	O
xylE	B-GENE
fusion	O
.	O

The	O
Man9	B-GENE
-	I-GENE
mannosidase	I-GENE
specificity	O
of	O
the	O
cDNA	O
construct	O
was	O
verified	O
by	O
the	O
observation	O
that	O
all	O
peptide	O
sequences	O
derived	O
from	O
a	O
previously	O
purified	O
,	O
catalytically	O
active	O
49	O
-	O
kDa	O
fragment	O
were	O
found	O
within	O
the	O
coding	O
region	O
.	O

A	O
soluble	O
62	O
-	O
kDa	O
protein	O
was	O
produced	O
without	O
the	O
proteolytic	O
processing	O
by	O
inserting	O
the	O
coding	O
sequence	O
of	O
amino	O
acids	O
112	O
to	O
660	O
of	O
ORF	O
-	O
2	O
in	O
a	O
baculovirus	O
expression	O
vector	O
and	O
using	O
the	O
corresponding	O
virus	O
to	O
infect	O
Sf9	O
cells	O
.	O

The	O
CPK	B-GENE
-	I-GENE
MB	I-GENE
isoenzyme	O
showed	O
no	O
percentage	O
increase	O
of	O
total	O
CPK	B-GENE
higher	O
than	O
5	O
%	O
,	O
measured	O
at	O
6	O
,	O
12	O
,	O
and	O
24	O
h	O
after	O
the	O
shock	O
,	O
independent	O
of	O
the	O
number	O
of	O
attempts	O
of	O
cardioversion	O
.	O

Serum	O
and	O
peritoneal	O
dialysis	O
fluid	O
(	O
PDF	O
)	O
were	O
collected	O
for	O
assay	O
throughout	O
the	O
course	O
of	O
the	O
study	O
and	O
for	O
5	O
days	O
thereafter	O
.	O

Results	O
support	O
the	O
hypothesis	O
that	O
endogenous	B-GENE
corticotropin	I-GENE
-	I-GENE
releasing	I-GENE
factor	I-GENE
,	O
perhaps	O
acting	O
at	O
a	O
peripheral	O
binding	O
site	O
,	O
suppresses	O
the	O
active	O
behavioral	O
response	O
characteristic	O
of	O
pups	O
during	O
the	O
early	O
phase	O
of	O
isolation	O
in	O
novel	O
surroundings	O
.	O

Liver	O
regional	O
blood	O
volume	O
(	O
LRBV	O
)	O
is	O
altered	O
by	O
several	O
disease	O
states	O
and	O
various	O
drugs	O
.	O

The	O
gray	O
matter	O
NAA	O
/	O
mI	O
ratio	O
clearly	O
separated	O
the	O
two	O
groups	O
.	O

As	O
with	O
the	O
murine	B-GENE
and	I-GENE
human	I-GENE
mb	I-GENE
-	I-GENE
1	I-GENE
genes	I-GENE
,	O
the	O
5	O
'	O
region	O
of	O
the	O
bovine	B-GENE
mb	I-GENE
-	I-GENE
1	I-GENE
gene	I-GENE
lacked	O
a	O
TATA	O
box	O
.	O

Chloramphenicol	B-GENE
acetyltransferase	I-GENE
assays	O
examining	O
the	O
ability	O
of	O
IE86	B-GENE
to	O
repress	O
activity	O
from	O
the	O
HCMV	O
major	O
IE	B-GENE
promoter	I-GENE
or	O
activate	O
the	O
HCMV	B-GENE
early	I-GENE
promoter	I-GENE
for	O
the	O
2	O
.	O
2	O
-	O
kb	O
class	O
of	O
RNAs	O
demonstrated	O
the	O
functional	O
integrity	O
of	O
the	O
IE86	B-GENE
protein	I-GENE
.	O

ORF	O
M1	O
has	O
striking	O
homology	O
to	O
poxvirus	O
serpins	B-GENE
,	O
while	O
ORF	O
M11	O
encodes	O
a	O
potential	O
homolog	O
of	O
Bcl	B-GENE
-	I-GENE
2	I-GENE
-	I-GENE
like	I-GENE
molecules	I-GENE
encoded	O
by	O
other	O
gammaherpesviruses	O
(	O
gene	B-GENE
16	I-GENE
of	O
HVS	O
and	O
KSHV	O
and	O
the	O
BHRF1	B-GENE
gene	I-GENE
of	O
EBV	O
)	O
.	O

Transcription	O
factor	O
binding	O
sites	O
downstream	O
of	O
the	O
human	O
immunodeficiency	O
virus	O
type	O
1	O
transcription	O
start	O
site	O
are	O
important	O
for	O
virus	O
infectivity	O
.	O

Crystal	O
structure	O
of	O
an	O
oligomer	O
of	O
proteolytic	O
zymogens	O
:	O
detailed	O
conformational	O
analysis	O
of	O
the	O
bovine	O
ternary	O
complex	O
and	O
implications	O
for	O
their	O
activation	O
.	O

Through	O
transient	O
transfection	O
of	O
NIH3T3	O
fibroblast	O
cells	O
and	O
gel	O
mobility	O
shift	O
assays	O
,	O
the	O
functional	O
binding	O
site	O
was	O
localized	O
to	O
a	O
short	O
region	O
(	O
-	O
318	O
to	O
-	O
303	O
bp	O
from	O
the	O
transcription	O
start	O
site	O
)	O
which	O
has	O
a	O
CTCCC	O
sequence	O
.	O

We	O
suppose	O
that	O
this	O
injection	O
speed	O
(	O
0	O
.	O
1	O
-	O
0	O
.	O
2	O
ml	O
.	O
s	O
-	O
1	O
)	O
is	O
suitable	O
for	O
spinal	O
anesthesia	O
.	O

The	O
current	O
study	O
demonstrates	O
that	O
T3	O
-	O
activated	O
transcription	O
of	O
the	O
NADPH	B-GENE
:	I-GENE
cytochrome	I-GENE
P450	I-GENE
oxidoreductase	I-GENE
(	O
P450R	B-GENE
)	O
gene	O
is	O
dependent	O
on	O
the	O
thyroid	O
hormonal	O
status	O
of	O
the	O
animal	O
,	O
with	O
both	O
transcriptional	O
and	O
post	O
-	O
transcriptional	O
pathways	O
being	O
important	O
in	O
regulating	O
the	O
cellular	O
P450R	B-GENE
mRNA	O
level	O
.	O

The	O
behavior	O
of	O
different	O
types	O
of	O
polytetrafluoroethylene	O
(	O
PTFE	O
)	O
prostheses	O
in	O
the	O
reparative	O
scarring	O
process	O
of	O
abdominal	O
wall	O
defects	O
.	O

The	O
control	O
group	O
revealed	O
significantly	O
higher	O
levels	O
of	O
coagulation	B-GENE
factors	I-GENE
II	I-GENE
,	I-GENE
V	I-GENE
and	I-GENE
VIII	I-GENE
,	O
compared	O
to	O
the	O
index	O
group	O
.	O

Stereotactic	O
radiofrequency	O
lesioning	O
of	O
the	O
hamartoma	O
resulted	O
in	O
seizure	O
remission	O
without	O
complications	O
20	O
months	O
after	O
surgery	O
.	O

If	O
E	O
.	O
coli	O
is	O
present	O
in	O
any	O
source	O
water	O
sample	O
,	O
the	O
borehole	O
and	O
any	O
directly	O
connected	O
borehole	O
should	O
be	O
embargoed	O
.	O

The	O
following	O
technique	O
describes	O
a	O
modification	O
to	O
a	O
bar	O
superstructure	O
that	O
provided	O
the	O
advantages	O
of	O
convenience	O
,	O
security	O
,	O
and	O
consistent	O
positioning	O
even	O
though	O
one	O
implant	O
was	O
lost	O
and	O
the	O
angulation	O
of	O
implants	O
limited	O
accuracy	O
.	O

In	O
summary	O
,	O
DDC	O
express	O
receptors	O
for	O
a	O
broad	O
panel	O
of	O
cytokines	O
,	O
even	O
receptors	O
for	O
cytokines	O
whose	O
effects	O
on	O
DC	O
are	O
still	O
unknown	O
(	O
i	O
.	O
e	O
.	O

Its	O
potential	O
as	O
a	O
diagnostic	O
tool	O
for	O
epidemiological	O
surveillance	O
was	O
assessed	O
in	O
comparison	O
with	O
three	O
other	O
diagnostic	O
tests	O
:	O
stool	O
examination	O
,	O
ELISA	O
with	O
soluble	B-GENE
egg	I-GENE
antigen	I-GENE
(	O
SEA	B-GENE
)	O
and	O
the	O
circumoval	O
precipitin	B-GENE
test	O
(	O
COPT	O
)	O
.	O

These	O
analyses	O
demonstrate	O
that	O
the	O
dUTPase	B-GENE
isoforms	O
are	O
encoded	O
by	O
the	O
same	O
gene	O
with	O
isoform	O
-	O
specific	O
transcripts	O
arising	O
through	O
the	O
use	O
of	O
alternative	O
5	O
'	O
exons	O
.	O

The	O
selective	O
5	B-GENE
-	I-GENE
HT3	I-GENE
receptor	I-GENE
antagonists	O
ramosetron	O
(	O
YM060	O
)	O
,	O
YM114	O
(	O
KAE	O
-	O
393	O
)	O
,	O
granisetron	O
and	O
ondansetron	O
,	O
and	O
the	O
substituted	O
benzamides	O
(	O
5	B-GENE
-	I-GENE
HT4	I-GENE
receptor	I-GENE
agonist	O
/	O
5	B-GENE
-	I-GENE
HT3	I-GENE
receptor	I-GENE
antagonists	O
)	O
cisapride	O
mosapride	O
and	O
SC	O
-	O
53116	O
dose	O
-	O
dependently	O
enhanced	O
gastric	O
emptying	O
in	O
normal	O
rats	O
.	O

Re	O
-	O
evaluation	O
of	O
the	O
biopsy	O
specimen	O
from	O
the	O
right	O
hip	O
taken	O
at	O
the	O
time	O
of	O
the	O
initial	O
operation	O
showed	O
areas	O
of	O
chondrosarcoma	O
arising	O
in	O
the	O
background	O
of	O
synovial	O
chondromatosis	O
.	O

All	O
corneal	O
buttons	O
were	O
processed	O
for	O
histopathologic	O
and	O
electron	O
microscopic	O
studies	O
.	O

3600	O
-	O
fold	O
to	O
apparent	O
homogeneity	O
with	O
a	O
41	O
%	O
yield	O
by	O
affinity	O
chromatography	O
utilizing	O
DNA	O
-	O
cellulose	O
;	O
the	O
purity	O
of	O
the	O
final	O
preparation	O
was	O
assessed	O
by	O
SDS	O
/	O
PAGE	O
,	O
lack	O
of	O
contamination	O
by	O
other	O
nucleases	O
and	O
production	O
of	O
a	O
monospecific	O
antibody	O
against	O
the	O
enzyme	O
.	O

Human	B-GENE
thymine	I-GENE
-	I-GENE
DNA	I-GENE
glycosylase	I-GENE
maps	O
at	O
chromosome	O
12q22	O
-	O
q24	O
.	O
1	O
:	O
a	O
region	O
of	O
high	O
loss	O
of	O
heterozygosity	O
in	O
gastric	O
cancer	O
.	O

FOG	B-GENE
is	O
coexpressed	O
with	O
GATA	B-GENE
-	I-GENE
1	I-GENE
during	O
embryonic	O
development	O
and	O
in	O
erythroid	O
and	O
megakaryocytic	O
cells	O
.	O

We	O
further	O
found	O
that	O
KmMig1p	B-GENE
is	O
fully	O
functional	O
when	O
expressed	O
in	O
S	O
.	O
cerevisiae	O
.	O

Autoimmune	O
neutropenia	O
(	O
AIN	O
)	O
is	O
a	O
frequent	O
cause	O
of	O
chronic	O
neutropenia	O
especially	O
in	O
youngest	O
children	O
.	O

With	O
regard	O
to	O
the	O
characteristic	O
expression	O
pattern	O
of	O
DJ	B-GENE
protein	I-GENE
and	O
its	O
conspicuous	O
repeat	O
units	O
possible	O
functional	O
roles	O
are	O
discussed	O
.	O

Future	O
analysis	O
of	O
long	O
-	O
term	O
outcome	O
measures	O
of	O
performance	O
with	O
the	O
implant	O
will	O
confirm	O
or	O
dispute	O
the	O
benefit	O
of	O
ear	O
selection	O
using	O
the	O
Prom	O
-	O
EABR	O
.	O

This	O
protein	O
,	O
designated	O
p532	B-GENE
based	O
on	O
its	O
predicted	O
molecular	O
weight	O
(	O
EMBO	O
J	O
15	O
:	O
5738	O
,	O
1996	O
)	O
,	O
contains	O
multiple	O
structural	O
domains	O
including	O
two	O
regions	O
of	O
seven	O
internal	O
repeats	O
highly	O
related	O
to	O
the	O
cell	O
cycle	O
regulator	O
RCC1	B-GENE
,	O
a	O
guanine	B-GENE
nucleotide	I-GENE
exchange	I-GENE
factor	I-GENE
for	O
the	O
small	B-GENE
GTP	I-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
Ran	B-GENE
,	O
seven	O
beta	O
-	O
repeat	O
domains	O
characteristic	O
of	O
the	O
beta	O
subunit	O
of	O
heterotrimeric	B-GENE
G	I-GENE
proteins	I-GENE
,	O
three	O
putative	O
SH3	B-GENE
binding	I-GENE
sites	I-GENE
,	O
a	O
putative	O
leucine	O
-	O
zipper	O
and	O
a	O
carboxy	B-GENE
-	I-GENE
terminal	I-GENE
HECT	I-GENE
domain	I-GENE
characteristic	O
of	O
E3	B-GENE
ubiquitin	I-GENE
-	I-GENE
protein	I-GENE
ligases	I-GENE
.	O

Thus	O
,	O
the	O
L45	O
sequence	O
between	O
kinase	O
subdomains	O
IV	O
and	O
V	O
specifies	O
TGF	B-GENE
-	I-GENE
beta	I-GENE
responsiveness	O
of	O
the	O
type	B-GENE
I	I-GENE
receptor	I-GENE
.	O

The	O
two	O
mouse	O
lines	O
carrying	O
the	O
unfragmented	O
Hnf3g	B-GENE
-	O
lacZ	B-GENE
YAC	O
showed	O
tissue	O
-	O
specific	O
,	O
copy	O
number	O
-	O
dependent	O
and	O
position	O
-	O
independent	O
expression	O
,	O
proving	O
that	O
170	O
kb	O
of	O
the	O
Hnf3g	B-GENE
locus	O
contain	O
all	O
elements	O
important	O
in	O
the	O
regulation	O
of	O
Hnf3g	B-GENE
.	O

Second	O
,	O
plasmid	O
-	O
derived	O
transgenes	O
and	O
gene	O
targeting	O
of	O
the	O
endogenous	B-GENE
Hnf3g	I-GENE
gene	I-GENE
locus	I-GENE
were	O
used	O
to	O
demonstrate	O
that	O
the	O
3	O
'	O
-	O
flanking	O
region	O
of	O
the	O
gene	O
is	O
necessary	O
and	O
sufficient	O
to	O
direct	O
reporter	O
gene	O
expression	O
in	O
liver	O
,	O
pancreas	O
,	O
stomach	O
and	O
small	O
intestine	O
.	O

Here	O
we	O
have	O
tested	O
the	O
hypothesis	O
that	O
the	O
short	O
transcripts	O
,	O
or	O
proteins	O
translated	O
from	O
the	O
short	O
transcripts	O
,	O
are	O
also	O
required	O
for	O
respiration	O
.	O

Upstream	O
activating	O
sequences	O
(	O
UASs	O
)	O
derived	O
from	O
known	O
Ste12p	B-GENE
-	O
dependent	O
genes	O
have	O
previously	O
been	O
characterized	O
to	O
require	O
either	O
multiple	O
PREs	O
or	O
a	O
single	O
PRE	O
coupled	O
to	O
a	O
binding	O
site	O
for	O
a	O
second	O
protein	O
.	O

Prominent	O
protein	O
kinase	O
cascades	O
are	O
those	O
that	O
activate	O
mitogen	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
(	I-GENE
MAP	I-GENE
)	I-GENE
kinases	I-GENE
.	O

JNK	B-GENE
is	O
additionally	O
regulated	O
by	O
the	O
Ras	B-GENE
-	O
related	O
G	B-GENE
proteins	I-GENE
Rac	B-GENE
and	O
Cdc42	B-GENE
.	O

In	O
this	O
study	O
,	O
we	O
tested	O
this	O
notion	O
by	O
using	O
ligation	O
-	O
mediated	O
PCR	O
to	O
assess	O
the	O
formation	O
of	O
recombination	B-GENE
-	I-GENE
activating	I-GENE
gene	I-GENE
(	O
RAG	B-GENE
)	O
-	O
dependent	O
double	O
-	O
strand	O
breaks	O
(	O
DSBs	O
)	O
at	O
RSSs	O
3	O
'	O
of	O
Ddelta3	B-GENE
and	O
5	O
'	O
of	O
Jdelta1	B-GENE
.	O

Recent	O
studies	O
have	O
demonstrated	O
that	O
Cbl	B-GENE
,	O
the	O
120	O
-	O
kDa	O
protein	O
product	O
of	O
the	O
c	B-GENE
-	I-GENE
cbl	I-GENE
proto	I-GENE
-	I-GENE
oncogene	I-GENE
,	O
serves	O
as	O
a	O
substrate	O
of	O
a	O
number	O
of	O
receptor	B-GENE
-	I-GENE
coupled	I-GENE
tyrosine	I-GENE
kinases	I-GENE
and	O
forms	O
complexes	O
with	O
SH3	B-GENE
and	O
SH2	B-GENE
domain	O
-	O
containing	O
proteins	O
,	O
pointing	O
to	O
its	O
role	O
in	O
signal	O
transduction	O
.	O

Although	O
neither	O
constitutively	O
activated	O
MEK	B-GENE
(	O
MEK	B-GENE
-	I-GENE
2E	I-GENE
)	O
nor	O
v	B-GENE
-	I-GENE
Src	I-GENE
was	O
sufficient	O
individually	O
to	O
differentiate	O
the	O
H19	O
-	O
7	O
cells	O
,	O
coexpression	O
of	O
constitutively	O
activated	O
MEK	B-GENE
and	O
v	B-GENE
-	I-GENE
Src	I-GENE
induced	O
neurite	O
outgrowth	O
.	O

This	O
mechanism	O
is	O
in	O
contrast	O
to	O
other	O
cases	O
of	O
splicing	O
regulation	O
by	O
PTB	B-GENE
,	O
in	O
which	O
the	O
protein	O
represses	O
the	O
splice	O
site	O
to	O
which	O
it	O
binds	O
.	O

While	O
important	O
for	O
ligand	O
-	O
dependent	O
transactivation	O
,	O
this	O
interaction	O
surface	O
is	O
not	O
directly	O
involved	O
in	O
transrepression	O
of	O
AP	B-GENE
-	I-GENE
1	I-GENE
activity	O
.	O

Gal4	B-GENE
-	O
Eed	B-GENE
fusion	O
protein	O
represses	O
transcription	O
of	O
a	O
reporter	O
gene	O
driven	O
by	O
a	O
promoter	O
that	O
contains	O
Gal4	B-GENE
-	I-GENE
binding	I-GENE
DNA	I-GENE
elements	I-GENE
.	O

In	O
situ	O
hybridization	O
analysis	O
in	O
adult	O
rat	O
tissue	O
reveals	O
good	O
correlation	O
with	O
this	O
pattern	O
and	O
indicates	O
that	O
drm	B-GENE
mRNA	I-GENE
is	O
most	O
highly	O
expressed	O
in	O
nondividing	O
and	O
terminally	O
differentiated	O
cells	O
,	O
such	O
as	O
neurons	O
,	O
type	O
1	O
lung	O
cells	O
,	O
and	O
goblet	O
cells	O
.	O

A	O
2	O
years	O
and	O
9	O
months	O
old	O
female	O
patient	O
,	O
with	O
the	O
diagnosis	O
of	O
Weaver	O
syndrome	O
is	O
reported	O
.	O

Confirming	O
measures	O
made	O
by	O
nurses	O
and	O
additionally	O
,	O
ABPM	O
for	O
women	O
,	O
seem	O
to	O
lessen	O
this	O
effect	O
.	O

In	O
a	O
series	O
of	O
patients	O
with	O
neuroinfection	O
,	O
Lyme	O
disease	O
,	O
Guillain	O
Barre	O
syndrome	O
,	O
demyelinization	O
,	O
partial	O
or	O
generalized	O
,	O
epilepsy	O
,	O
we	O
have	O
investigated	O
antiphospholipid	O
antibodies	O
of	O
IgG	B-GENE
and	O
IgM	B-GENE
subtypes	O
,	O
together	O
with	O
anticoagulant	O
factors	O
,	O
member	O
of	O
thrombocytes	O
,	O
sedimentation	O
rate	O
of	O
erythrocytes	O
.	O

Second	O
,	O
the	O
membrane	O
expression	O
of	O
alpha	O
and	O
beta	O
subunits	O
was	O
mimicked	O
by	O
cholesterol	O
and	O
17	O
-	O
ketocholesterol	O
,	O
both	O
of	O
which	O
inhibit	O
HMG	B-GENE
-	I-GENE
CoA	I-GENE
reductase	I-GENE
.	O

Our	O
results	O
suggest	O
that	O
Lrp	B-GENE
binds	O
a	O
central	O
palindromic	O
site	O
,	O
interacting	O
predominantly	O
with	O
the	O
major	O
groove	O
of	O
its	O
DNA	O
target	O
,	O
and	O
that	O
additional	O
dimers	O
bind	O
to	O
flanking	O
sites	O
to	O
form	O
a	O
nucleoprotein	O
activation	O
complex	O
.	O

Sustained	O
activation	O
of	O
p21	B-GENE
expression	O
is	O
proposed	O
to	O
be	O
a	O
distinguishing	O
feature	O
of	O
the	O
activity	O
of	O
NGF	B-GENE
that	O
contributes	O
to	O
PC12	O
growth	O
arrest	O
during	O
differentiation	O

The	O
remaining	O
80	O
patients	O
underwent	O
recordings	O
of	O
ECG	O
,	O
beat	O
-	O
to	O
-	O
beat	O
arterial	O
oxygen	O
saturation	O
(	O
SaO2	O
)	O
,	O
and	O
respiration	O
during	O
both	O
spontaneous	O
and	O
controlled	O
breathing	O
.	O

The	O
mean	O
total	O
white	O
cell	O
count	O
increased	O
from	O
a	O
baseline	O
of	O
11	O
.	O
3	O
x	O
10	O
(	O
9	O
)	O
/	O
L	O
(	O
SD	O
2	O
.	O
3	O
)	O
to	O
16	O
.	O
2	O
x	O
10	O
(	O
9	O
)	O
/	O
L	O
(	O
SD	O
4	O
.	O
6	O
)	O
on	O
day	O
1	O
,	O
normalising	O
thereafter	O
.	O

In	O
all	O
experimental	O
eyes	O
,	O
there	O
was	O
a	O
marked	O
reduction	O
,	O
but	O
never	O
a	O
complete	O
absence	O
of	O
adrenergic	O
nerves	O
in	O
the	O
iris	O
.	O

These	O
lesions	O
may	O
be	O
treated	O
by	O
propranolol	O
or	O
phentolamine	O
.	O

Furthermore	O
,	O
ICER	B-GENE
negatively	O
autoregulates	O
the	O
alternative	O
promoter	O
,	O
thus	O
generating	O
a	O
feedback	O
loop	O
.	O

This	O
night	O
-	O
day	O
oscillation	O
is	O
driven	O
by	O
the	O
endogenous	O
clock	O
(	O
located	O
in	O
the	O
suprachiasmatic	O
nucleus	O
,	O
SCN	O
)	O
.	O

The	O
Ogg1	B-GENE
protein	I-GENE
efficiently	O
cleaves	O
a	O
DNA	O
duplex	O
where	O
a	O
preformed	O
AP	B-GENE
site	I-GENE
is	O
placed	O
opposite	O
a	O
cytosine	O
(	O
AP	O
/	O
C	O
)	O
.	O

A	O
consensus	O
sequence	O
indicates	O
a	O
highly	O
conserved	O
lysine	O
residue	O
,	O
K120	O
of	O
endonuclease	B-GENE
III	I-GENE
or	O
K241	O
of	O
Ogg1	B-GENE
,	O
respectively	O
.	O

Overall	O
,	O
these	O
findings	O
demonstrate	O
that	O
mutations	O
E768D	O
and	O
V804L	O
are	O
gain	O
-	O
of	O
-	O
function	O
mutations	O
that	O
confer	O
to	O
the	O
long	B-GENE
RET	I-GENE
isoform	I-GENE
the	O
capacity	O
to	O
exert	O
a	O
biological	O
effect	O
,	O
although	O
these	O
mutations	O
are	O
more	O
weakly	O
activating	O
than	O
the	O
MEN2A	B-GENE
and	O
MEN2B	B-GENE
mutations	O
.	O

Volunteers	O
were	O
irradiated	O
on	O
their	O
backs	O
with	O
suberythemal	O
UV	O
daily	O
for	O
5	O
d	O
after	O
application	O
of	O
the	O
sunscreens	O
and	O
their	O
base	O
lotion	O
to	O
different	O
sites	O
.	O

E2F	B-GENE
is	O
a	O
heterodimeric	O
complex	O
consisting	O
of	O
E2F	B-GENE
family	I-GENE
members	I-GENE
(	I-GENE
1	I-GENE
-	I-GENE
5	I-GENE
)	I-GENE
and	O
DP	B-GENE
proteins	I-GENE
(	I-GENE
1	I-GENE
-	I-GENE
3	I-GENE
)	I-GENE
.	O

EBER1	B-GENE
mRNA	I-GENE
,	O
a	O
consistent	O
marker	O
of	O
viral	O
latency	O
,	O
was	O
positive	O
in	O
all	O
PEL	O
cases	O
,	O
although	O
at	O
lower	O
levels	O
than	O
in	O
the	O
non	O
-	O
PEL	O
controls	O
due	O
to	O
EBER1	B-GENE
expression	O
by	O
only	O
a	O
variable	O
subset	O
of	O
lymphoma	O
cells	O
.	O

METHODS	O
:	O
Four	O
hundred	O
fifty	O
patients	O
with	O
the	O
diagnosis	O
of	O
squamous	O
cell	O
carcinoma	O
of	O
the	O
oral	O
cavity	O
received	O
their	O
primary	O
treatment	O
at	O
Roswell	O
Park	O
Cancer	O
Center	O
(	O
RPCI	O
)	O
from	O
1971	O
to	O
1991	O
.	O

Therefore	O
,	O
use	O
of	O
presaturation	O
is	O
recommended	O
for	O
myocardial	O
motion	O
studies	O
using	O
cine	O
PC	O
velocity	O
data	O
.	O

In	O
addition	O
,	O
the	O
DNA	O
-	O
binding	O
experiments	O
show	O
that	O
either	O
one	O
of	O
the	O
two	O
MADS	B-GENE
domains	I-GENE
of	O
a	O
dimer	O
can	O
be	O
sufficient	O
to	O
confer	O
a	O
particular	O
DNA	O
-	O
binding	O
specificity	O
to	O
the	O
complex	O
and	O
that	O
sequences	O
outside	O
the	O
amino	O
-	O
terminal	O
basic	O
region	O
of	O
the	O
MADS	B-GENE
domain	O
can	O
,	O
in	O
some	O
cases	O
,	O
contribute	O
to	O
the	O
DNA	O
-	O
binding	O
specificity	O
of	O
the	O
proteins	O
.	O

PURPOSE	O
/	O
OBJECTIVES	O
:	O
To	O
examine	O
the	O
question	O
of	O
whether	O
an	O
early	O
first	O
full	O
-	O
term	O
pregnancy	O
(	O
FFTP	O
)	O
protects	O
against	O
breast	O
cancer	O
and	O
whether	O
interruption	O
of	O
the	O
pregnancy	O
with	O
an	O
induced	O
abortion	O
increases	O
breast	O
cancer	O
risk	O
.	O

Two	O
related	O
studies	O
conducted	O
over	O
a	O
five	O
week	O
period	O
measured	O
and	O
typed	O
HLA	B-GENE
-	I-GENE
DQA1	I-GENE
from	O
accumulated	O
DNA	O
on	O
autopsy	O
room	O
and	O
Forensic	O
DNA	O
Laboratory	O
structures	O
.	O

Thirty	O
-	O
two	O
rats	O
were	O
divided	O
into	O
four	O
groups	O
.	O

Mutagenesis	O
of	O
the	O
pecT	B-GENE
regulatory	O
region	O
revealed	O
the	O
presence	O
of	O
two	O
sites	O
in	O
which	O
insertions	O
reproduced	O
the	O
pec	B-GENE
-	I-GENE
1	I-GENE
phenotype	O
.	O

BRCA1	B-GENE
,	O
a	O
familial	O
breast	O
and	O
ovarian	O
cancer	O
susceptibility	O
gene	O
encodes	O
nuclear	O
phosphoproteins	O
that	O
function	O
as	O
tumor	O
suppressors	O
in	O
human	O
breast	O
cancer	O
cells	O
.	O

The	O
alternative	O
splice	O
sites	O
for	O
the	O
smallest	O
adducin	B-GENE
isoform	O
,	O
beta	B-GENE
-	I-GENE
3	I-GENE
,	O
are	O
alternative	O
donor	O
and	O
acceptor	O
sites	O
within	O
exons	O
7	O
and	O
12	O
.	O

Two	O
new	O
temperature	O
-	O
sensitive	O
alleles	O
of	O
SEC3	B-GENE
,	O
1	O
of	O
10	O
late	O
-	O
acting	O
SEC	B-GENE
genes	I-GENE
required	O
for	O
targeting	O
or	O
fusion	O
of	O
post	O
-	O
Golgi	O
secretory	O
vesicles	O
to	O
the	O
plasma	O
membrane	O
in	O
Saccharomyces	O
cerevisiae	O
,	O
were	O
isolated	O
in	O
a	O
screen	O
for	O
temperature	O
-	O
sensitive	O
secretory	O
mutants	O
that	O
are	O
synthetically	O
lethal	O
with	O
sec4	B-GENE
-	I-GENE
8	I-GENE
.	O

Cell	O
49	O
,	O
753	O
-	O
761	O
]	O
.	O

Twenty	O
-	O
one	O
ELISA	O
-	O
positive	O
sera	O
were	O
tested	O
and	O
confirmed	O
positive	O
by	O
plaque	O
reduction	O
neutralization	O
testing	O
.	O

Patients	O
received	O
either	O
diltiazem	O
CD	O
180	O
mg	O
or	O
placebo	O
once	O
/	O
day	O
in	O
combination	O
with	O
existing	O
antianginal	O
therapy	O
.	O

Reactive	O
lymphoid	O
hyperplasia	O
was	O
found	O
in	O
15	O
cases	O
,	O
2	O
cases	O
had	O
angiofollicular	O
lymphoid	O
hyperplasia	O
or	O
Castleman	O
'	O
s	O
disease	O
,	O
atypical	O
lymphoid	O
hyperplasia	O
suggestive	O
of	O
malignant	O
lymphoma	O
was	O
observed	O
in	O
3	O
cases	O
,	O
and	O
malignant	O
lymphoma	O
was	O
diagnosed	O
in	O
the	O
remaining	O
4	O
cases	O
.	O

Tyrosine	O
1356	O
forms	O
a	O
multisubstrate	O
binding	O
site	O
for	O
the	O
Grb2	B-GENE
and	O
Shc	B-GENE
adaptor	I-GENE
proteins	I-GENE
,	O
the	O
p85	B-GENE
subunit	I-GENE
of	O
phosphatidylinositol	B-GENE
3	I-GENE
'	I-GENE
-	I-GENE
kinase	I-GENE
,	O
phospholipase	B-GENE
Cgamma	I-GENE
,	O
and	O
a	O
phosphatase	O
,	O
SHP2	B-GENE
.	O

Then	O
we	O
correlated	O
HRCT	O
findings	O
with	O
the	O
clinical	O
features	O
,	O
pulmonary	O
functions	O
and	O
methacholine	O
PC20	O
(	O
PC20M	O
)	O
and	O
studied	O
their	O
clinical	O
significance	O
.	O

Gtx	B-GENE
mRNA	I-GENE
accumulates	O
in	O
parallel	O
with	O
the	O
RNAs	O
encoding	O
the	O
major	O
structural	O
proteins	O
of	O
myelin	O
,	O
myelin	B-GENE
basic	I-GENE
protein	I-GENE
(	O
MBP	B-GENE
)	O
,	O
and	O
proteolipid	B-GENE
protein	I-GENE
(	O
PLP	B-GENE
)	O
during	O
postnatal	O
brain	O
development	O
;	O
Gtx	B-GENE
mRNA	I-GENE
decreases	O
in	O
parallel	O
with	O
MBP	B-GENE
and	O
PLP	B-GENE
mRNAs	I-GENE
in	O
the	O
brains	O
of	O
myelin	O
-	O
deficient	O
rats	O
,	O
which	O
have	O
a	O
point	O
mutation	O
in	O
the	O
PLP	B-GENE
gene	I-GENE
.	O

Contacts	O
between	O
Bacillus	O
subtilis	O
catabolite	O
regulatory	O
protein	O
CcpA	B-GENE
and	O
amyO	B-GENE
target	O
site	O
.	O

They	O
also	O
interact	O
with	O
GTPase	B-GENE
activating	I-GENE
proteins	I-GENE
encoded	O
by	O
IRA1	B-GENE
and	O
IRA2	B-GENE
.	O

For	O
E2	O
,	O
each	O
cat	O
was	O
given	O
either	O
5	O
(	O
group	O
[	O
G	O
]	O
1	O
)	O
or	O
10	O
(	O
G2	O
)	O
mg	O
of	O
itraconazole	O
/	O
kg	O
(	O
capsules	O
)	O
twice	O
daily	O
for	O
6	O
weeks	O
.	O

RESULTS	O
:	O
For	O
E1	O
,	O
itraconazole	O
plasma	O
drug	O
concentration	O
extrapolated	O
to	O
time	O
zero	O
(	O
IV	O
dose	O
)	O
was	O
5	O
.	O
2	O
+	O
/	O
-	O
1	O
.	O
4	O
micrograms	O
/	O
ml	O
,	O
and	O
mean	O
residence	O
time	O
(	O
MRT	O
)	O
was	O
37	O
+	O
/	O
-	O
16	O
hours	O
.	O

The	O
human	O
U4	B-GENE
/	O
U6	B-GENE
snRNP	O
contains	O
60	O
and	O
90kD	O
proteins	O
that	O
are	O
structurally	O
homologous	O
to	O
the	O
yeast	O
splicing	O
factors	O
Prp4p	B-GENE
and	O
Prp3p	B-GENE
.	O

G	B-GENE
-	I-GENE
CSF	I-GENE
was	O
started	O
on	O
day	O
3	O
of	O
each	O
cycle	O
(	O
5	O
microg	O
/	O
kg	O
/	O
day	O
)	O
and	O
was	O
stopped	O
the	O
day	O
before	O
the	O
last	O
apheresis	O
or	O
when	O
absolute	O
neutrophil	O
count	O
was	O
above	O
0	O
.	O
5	O
x	O
10	O
(	O
9	O
)	O
/	O
l	O
.	O

Supershift	O
assays	O
,	O
using	O
Jun	B-GENE
and	I-GENE
Fos	I-GENE
family	I-GENE
member	I-GENE
-	I-GENE
specific	I-GENE
antibodies	I-GENE
,	O
showed	O
that	O
protein	O
complexes	O
formed	O
by	O
AtT	O
-	O
20	O
cell	O
nuclear	O
extracts	O
bound	O
to	O
the	O
c	B-GENE
-	I-GENE
jun	I-GENE
AP	B-GENE
-	I-GENE
1	I-GENE
site	I-GENE
were	O
comprised	O
of	O
Jun	B-GENE
family	O
members	O
,	O
JunD	B-GENE
,	O
JunB	B-GENE
,	O
and	O
cJun	B-GENE
.	O

The	O
majority	O
of	O
PI	B-GENE
kinase	I-GENE
activity	O
appeared	O
to	O
be	O
cbl	B-GENE
-	O
associated	O
after	O
PRL	B-GENE
stimulation	O
.	O

Mutation	O
of	O
Enh4	B-GENE
,	O
an	O
essential	O
GT	B-GENE
-	I-GENE
IIC	I-GENE
-	I-GENE
like	I-GENE
enhanson	I-GENE
in	O
the	O
context	O
of	O
the	O
intact	O
enhancer	O
,	O
abolishes	O
silencer	O
activity	O
,	O
and	O
multimerized	O
GT	B-GENE
-	I-GENE
IIC	I-GENE
enhansons	I-GENE
mimic	O
the	O
intact	O
CSEn	B-GENE
enhancer	I-GENE
/	I-GENE
silencer	I-GENE
activities	O
in	O
BeWo	O
and	O
GC	O
cells	O
,	O
respectively	O
.	O

Using	O
lectin	B-GENE
-	O
affinity	O
chromatography	O
,	O
discordance	O
between	O
the	O
pattern	O
of	O
O	O
-	O
glycosylation	O
of	O
SSBP	B-GENE
and	O
DSBP	B-GENE
was	O
demonstrated	O
.	O

Deletion	O
mapping	O
experiments	O
determined	O
that	O
the	O
sequences	O
required	O
for	O
full	O
activity	O
in	O
MSC	O
-	O
1	O
cells	O
were	O
included	O
within	O
619	O
bp	O
of	O
the	O
start	O
site	O
and	O
identified	O
several	O
regions	O
that	O
demonstrated	O
increased	O
luciferase	B-GENE
activity	O
:	O
the	O
-	O
583	O
bp	O
to	O
-	O
564	O
bp	O
,	O
-	O
503	O
bp	O
to	O
-	O
484	O
bp	O
,	O
and	O
-	O
114	O
bp	O
to	O
-	O
65	O
regions	O
.	O

Furthermore	O
,	O
the	O
PH	B-GENE
and	O
PTB	O
domains	O
are	O
highly	O
homologous	O
(	O
at	O
least	O
40	O
%	O
identical	O
)	O
to	O
those	O
found	O
in	O
insulin	B-GENE
receptor	I-GENE
substrates	I-GENE
1	I-GENE
,	I-GENE
2	I-GENE
,	I-GENE
and	I-GENE
3	I-GENE
(	O
IRS	B-GENE
-	I-GENE
1	I-GENE
,	O
IRS	B-GENE
-	I-GENE
2	I-GENE
,	O
and	O
IRS	B-GENE
-	I-GENE
3	I-GENE
)	O
.	O

The	O
mouse	O
extracellular	B-GENE
signal	I-GENE
-	I-GENE
regulated	I-GENE
kinase	I-GENE
2	I-GENE
gene	I-GENE
.	O

As	O
demonstrated	O
by	O
gel	O
mobility	O
shift	O
analysis	O
and	O
supershift	O
experiments	O
,	O
FIRE1	B-GENE
,	O
located	O
between	O
-	O
516	O
and	O
-	O
498	O
,	O
is	O
responsible	O
for	O
binding	O
NF	B-GENE
-	I-GENE
Y	I-GENE
.	O

MR	O
imaging	O
of	O
traumatic	O
head	O
injuries	O
using	O
FLAIR	O
technique	O

Gag	B-GENE
protein	O
sequence	O
motifs	O
of	O
the	O
NC	B-GENE
domain	I-GENE
of	O
primate	O
foamy	O
viruses	O
assumed	O
to	O
be	O
involved	O
in	O
genome	O
encapsidation	O
are	O
not	O
conserved	O
in	O
FeFV	O
.	O

Induction	O
of	O
B	O
cell	O
apoptosis	O
by	O
co	O
-	O
cross	O
-	O
linking	O
CD23	B-GENE
and	O
sIg	B-GENE
involves	O
aberrant	O
regulation	O
of	O
c	B-GENE
-	I-GENE
myc	I-GENE
and	O
is	O
inhibited	O
by	O
bcl	B-GENE
-	I-GENE
2	I-GENE
.	O

Here	O
,	O
we	O
report	O
theoretical	O
models	O
for	O
the	O
Gla	O
and	O
EGF	B-GENE
-	I-GENE
1	I-GENE
modules	I-GENE
of	O
human	B-GENE
PS	I-GENE
constructed	O
using	O
prothrombin	B-GENE
and	O
factor	B-GENE
X	I-GENE
experimental	O
structures	O
.	O

The	O
Cut9	B-GENE
subunit	I-GENE
is	O
likely	O
to	O
be	O
a	O
target	O
for	O
regulating	O
APC	B-GENE
/	I-GENE
cyclosome	I-GENE
function	O
through	O
protein	O
-	O
protein	O
interactions	O
and	O
phosphorylation	O
.	O

The	O
dose	O
was	O
50	O
Gy	O
/	O
20	O
fractions	O
/	O
5	O
weeks	O
.	O

All	O
the	O
women	O
received	O
13	O
.	O
5	O
mg	O
plain	O
bupivacaine	O
via	O
subarachnoid	O
injection	O
at	O
the	O
L2	O
-	O
3	O
interspace	O
.	O

Far	O
from	O
this	O
being	O
the	O
case	O
,	O
however	O
,	O
the	O
measurement	O
of	O
apo	B-GENE
B	I-GENE
has	O
met	O
every	O
reasonable	O
standard	O
of	O
laboratory	O
precision	O
and	O
reliability	O
to	O
allow	O
its	O
widespread	O
introduction	O
in	O
clinical	O
laboratories	O
.	O

Two	O
soybean	O
cDNA	O
clones	O
,	O
SPK	B-GENE
-	I-GENE
3	I-GENE
and	O
SPK	B-GENE
-	I-GENE
4	I-GENE
,	O
encoding	O
putative	O
protein	O
kinases	O
were	O
isolated	O
and	O
characterized	O
.	O

Genes	O
belonging	O
to	O
the	O
ras	B-GENE
superfamily	I-GENE
encode	O
low	B-GENE
-	I-GENE
molecular	I-GENE
-	I-GENE
weight	I-GENE
GTP	I-GENE
/	I-GENE
GDP	I-GENE
-	I-GENE
binding	I-GENE
proteins	I-GENE
that	O
are	O
highly	O
conserved	O
in	O
wide	O
variety	O
of	O
organisms	O
.	O

Ent	B-GENE
-	I-GENE
kaurene	I-GENE
synthase	I-GENE
from	I-GENE
the	I-GENE
fungus	I-GENE
Phaeosphaeria	I-GENE
sp	O
.	O

In	O
this	O
report	O
,	O
we	O
identify	O
and	O
characterize	O
two	O
overlapping	O
ELL	B-GENE
functional	I-GENE
domains	I-GENE
that	O
govern	O
its	O
interaction	O
with	O
RNA	B-GENE
polymerase	I-GENE
II	I-GENE
and	O
the	O
ternary	O
elongation	O
complex	O
.	O

Eight	O
induced	O
cDNA	O
sequences	O
were	O
identified	O
and	O
designated	O
message	B-GENE
up	I-GENE
-	I-GENE
regulated	I-GENE
during	I-GENE
death	I-GENE
(	B-GENE
mud	I-GENE
)	I-GENE
-	I-GENE
1	I-GENE
-	I-GENE
8	I-GENE
.	O

The	O
position	O
,	O
transcription	O
orientation	O
,	O
and	O
imprinted	O
status	O
of	O
the	O
genes	O
immediately	O
flanking	O
Igf2r	B-GENE
have	O
been	O
assessed	O
.	O

Here	O
,	O
we	O
describe	O
directional	O
chromosome	O
walking	O
studies	O
starting	O
from	O
D8S260	B-GENE
as	O
well	O
as	O
D8S285	B-GENE
.	O

We	O
describe	O
a	O
novel	O
zinc	B-GENE
finger	I-GENE
protein	I-GENE
,	O
dsRBP	B-GENE
-	I-GENE
ZFa	I-GENE
,	O
isolated	O
by	O
screening	O
an	O
expression	O
library	O
with	O
dsRNA	O
.	O

Our	O
results	O
indicate	O
that	O
the	O
retroplasmid	O
reverse	B-GENE
transcriptase	I-GENE
is	O
uniquely	O
adapted	O
to	O
initiate	O
cDNA	O
synthesis	O
by	O
recognizing	O
a	O
3	O
'	O
CCA	O
sequence	O
.	O

Nasal	O
absorption	O
was	O
rapid	O
,	O
nasal	O
bioavailability	O
was	O
43	O
%	O
,	O
and	O
the	O
iv	O
and	O
nasal	O
elimination	O
profiles	O
were	O
similar	O
.	O

Together	O
,	O
these	O
results	O
suggest	O
that	O
EGF	B-GENE
/	O
Ras	B-GENE
/	O
Raf	B-GENE
induces	O
transcription	O
via	O
combined	O
activation	O
of	O
ATF3	B-GENE
/	O
c	B-GENE
-	I-GENE
Jun	I-GENE
and	O
a	O
52	O
-	O
kDa	O
nuclear	O
factor	O
,	O
whereas	O
JunD	B-GENE
acts	O
as	O
a	O
repressor	O
of	O
this	O
response	O
.	O

Together	O
,	O
these	O
data	O
support	O
a	O
model	O
in	O
which	O
Tax	B-GENE
anchors	O
CBP	B-GENE
to	O
the	O
HTLV	B-GENE
-	I-GENE
1	I-GENE
promoter	I-GENE
,	O
with	O
strong	O
transcriptional	O
activation	O
resulting	O
from	O
the	O
CBP	B-GENE
-	O
associated	O
activities	O
of	O
nucleosome	O
remodeling	O
and	O
recruitment	O
of	O
the	O
general	O
transcription	O
machinery	O
.	O

DNase	B-GENE
I	I-GENE
and	O
1	O
,	O
10	O
-	O
phenanthroline	O
-	O
copper	O
footprinting	O
of	O
MURA	B-GENE
-	O
Mu1	B-GENE
TIR	O
complexes	O
indicate	O
that	O
MURA	B-GENE
binds	O
to	O
a	O
conserved	O
approximately	O
32	O
-	O
bp	O
region	O
in	O
the	O
TIR	O
of	O
Mu1	B-GENE
.	O

Various	O
assays	O
demonstrate	O
promoter	O
activity	O
in	O
this	O
sequence	O
that	O
reproduces	O
the	O
normal	O
control	O
of	O
E2F2	B-GENE
expression	O
during	O
a	O
growth	O
stimulation	O
.	O

In	O
the	O
adult	O
mouse	O
,	O
ERR	B-GENE
alpha	I-GENE
is	O
most	O
highly	O
expressed	O
in	O
kidney	O
,	O
heart	O
,	O
and	O
brown	O
adipocytes	O
,	O
tissues	O
which	O
preferentially	O
metabolize	O
fatty	O
acids	O
.	O

The	O
MCAD	B-GENE
nuclear	I-GENE
receptor	I-GENE
response	I-GENE
element	I-GENE
1	I-GENE
(	O
NRRE	B-GENE
-	I-GENE
1	I-GENE
)	O
interacts	O
in	O
vitro	O
with	O
ERR	B-GENE
alpha	I-GENE
expressed	O
in	O
COS	O
-	O
7	O
cells	O
.	O

Mapping	O
features	O
of	O
HIV	B-GENE
-	I-GENE
1	I-GENE
integrase	I-GENE
near	O
selected	O
sites	O
on	O
viral	O
and	O
target	O
DNA	O
molecules	O
in	O
an	O
active	O
enzyme	O
-	O
DNA	O
complex	O
by	O
photo	O
-	O
cross	O
-	O
linking	O
.	O

The	O
complete	O
response	O
(	O
CR	O
)	O
rate	O
was	O
34	O
%	O
in	O
the	O
CODE	O
with	O
rhG	B-GENE
-	I-GENE
CSF	I-GENE
group	O
and	O
23	O
%	O
in	O
the	O
CODE	O
alone	O
group	O
;	O
the	O
median	O
survival	O
was	O
59	O
and	O
32	O
weeks	O
,	O
respectively	O
,	O
in	O
these	O
groups	O
(	O
P	O
=	O
0	O
.	O
004	O
)	O
.	O

Heterogeneous	B-GENE
nuclear	I-GENE
ribonucleoprotein	I-GENE
A1	I-GENE
binds	O
to	O
the	O
transcription	O
-	O
regulatory	O
region	O
of	O
mouse	O
hepatitis	O
virus	O
RNA	O
.	O

In	O
the	O
first	O
part	O
of	O
our	O
study	O
,	O
the	O
highest	O
mutagenicity	O
was	O
revealed	O
by	O
TA98	O
strain	O
without	O
enzymatic	O
activation	O
,	O
suggesting	O
a	O
direct	O
-	O
acting	O
mutagenicity	O
prevalence	O
in	O
diesel	O
particulate	O
.	O

The	O
addition	O
of	O
culture	O
to	O
the	O
CC	O
and	O
CC	O
:	O
SW	O
by	O
-	O
products	O
resulted	O
in	O
pH	O
values	O
lower	O
(	O
P	O
<	O
0	O
.	O
05	O
)	O
than	O
those	O
without	O
culture	O
on	O
Day	O
21	O
,	O
and	O
the	O
15	O
%	O
carbohydrate	O
treatment	O
significantly	O
reduced	O
pH	O
beyond	O
the	O
5	O
%	O
carbohydrate	O
.	O

Myocardial	O
interstitial	O
edema	O
is	O
more	O
likely	O
a	O
potential	O
mechanism	O
of	O
diastolic	O
dysfunction	O
after	O
DC	O
shocks	O
.	O

Two	O
experiments	O
(	O
N	O
=	O
20	O
each	O
)	O
were	O
carried	O
out	O
to	O
explore	O
the	O
nature	O
of	O
ERP	O
negativities	O
in	O
a	O
visuospatial	O
memory	O
task	O
and	O
in	O
an	O
auditory	O
spatial	O
memory	O
task	O
,	O
respectively	O
.	O

Biol	O
.	O

The	O
pattern	O
and	O
timing	O
of	O
CARP	B-GENE
mRNA	I-GENE
expression	O
,	O
including	O
transient	O
expression	O
in	O
the	O
tongue	O
at	O
14	O
.	O
5	O
days	O
p	O
.	O
c	O
.	O
,	O
coincides	O
with	O
that	O
of	O
Nkx2	B-GENE
.	I-GENE
5	I-GENE
/	O
Csx	B-GENE
(	O
a	O
putative	O
homolog	O
of	O
tinman	B-GENE
,	O
the	O
Drosophila	O
melanogaster	O
gene	O
responsible	O
for	O
cardiac	O
development	O
)	O
.	O

Overexpression	O
of	O
CARP	B-GENE
in	O
cardiomyocytes	O
suppresses	O
cardiac	B-GENE
troponin	I-GENE
C	I-GENE
and	O
atrial	B-GENE
natriuretic	I-GENE
factor	I-GENE
transcription	O
.	O

Substrate	O
specificity	O
of	O
the	O
RNase	B-GENE
activity	O
of	O
yeast	B-GENE
RNA	I-GENE
polymerase	I-GENE
III	I-GENE
.	O

Electrophoretic	O
mobility	O
shift	O
assays	O
and	O
competition	O
experiments	O
showed	O
that	O
site	O
A	O
is	O
recognized	O
by	O
an	O
NF1	B-GENE
protein	I-GENE
.	O

Examination	O
of	O
the	O
MMP	B-GENE
-	I-GENE
2	I-GENE
RE1	I-GENE
sequence	I-GENE
revealed	O
an	O
incomplete	O
Y	O
-	O
box	O
sequence	O
(	O
CTGCTGGGCAAG	O
)	O
,	O
which	O
specifically	O
interacted	O
with	O
recombinant	B-GENE
YB	I-GENE
-	I-GENE
1	I-GENE
on	O
DMS	O
protection	O
footprinting	O
analysis	O
.	O

Hence	O
,	O
scs32	B-GENE
only	O
partially	O
suppressed	O
the	O
ts	O
phenotype	O
and	O
was	O
unable	O
to	O
suppress	O
the	O
Ino	O
-	O
phenotype	O
of	O
rpo26	B-GENE
-	I-GENE
31	I-GENE
.	O

In	O
contrast	O
,	O
both	O
Sp1	B-GENE
and	O
ETS	B-GENE
proteins	I-GENE
are	O
required	O
to	O
bring	O
about	O
full	O
promoter	O
activity	O
in	O
the	O
Surf	B-GENE
-	I-GENE
1	I-GENE
direction	O
.	O

We	O
have	O
subcloned	O
into	O
pBR322	O
deoxyribonucleic	O
acid	O
(	O
DNA	O
)	O
sequences	O
mapping	O
either	O
in	O
the	O
coding	O
region	O
,	O
the	O
5	O
'	O
spacer	O
,	O
or	O
the	O
3	O
'	O
spacer	O
of	O
the	O
H2B	B-GENE
histone	I-GENE
gene	I-GENE
.	O

The	O
combination	O
of	O
hydralazine	O
hydrochloride	O
and	O
isosorbide	O
dinitrate	O
also	O
improves	O
survival	O
,	O
but	O
direct	O
comparison	O
of	O
both	O
regimens	O
provided	O
evidence	O
for	O
a	O
less	O
favourable	O
effect	O
than	O
that	O
of	O
the	O
ACE	B-GENE
inhibitors	O
.	O

To	O
address	O
mechanisms	O
that	O
define	O
interactions	O
of	O
Site	B-GENE
II	I-GENE
regulatory	I-GENE
factors	I-GENE
with	O
this	O
cell	O
cycle	O
control	O
element	O
,	O
we	O
have	O
investigated	O
these	O
determinants	O
of	O
transcriptional	O
regulation	O
at	O
the	O
G1	O
/	O
S	O
phase	O
transition	O
in	O
FDC	O
-	O
P1	O
hematopoietic	O
progenitor	O
cells	O
.	O

The	O
goal	O
of	O
this	O
study	O
was	O
to	O
identify	O
neuronal	O
cell	O
cultures	O
that	O
express	O
RC3	B-GENE
/	O
neurogranin	B-GENE
,	O
to	O
check	O
whether	O
they	O
are	O
sensitive	O
to	O
T3	O
,	O
and	O
to	O
examine	O
the	O
mechanism	O
of	O
regulation	O
.	O

Their	O
circadian	O
responses	O
to	O
both	O
photic	O
and	O
non	O
-	O
photic	O
cues	O
were	O
then	O
tested	O
.	O

Human	B-GENE
Duo	I-GENE
contains	O
a	O
guanine	B-GENE
nucleotide	I-GENE
exchange	I-GENE
factor	I-GENE
(	O
GEF	B-GENE
)	O
domain	O
that	O
is	O
likely	O
to	O
be	O
rac1	B-GENE
-	O
specific	O
,	O
a	O
pleckstrin	B-GENE
homology	I-GENE
(	O
PH	B-GENE
)	O
domain	O
and	O
spectrin	B-GENE
-	I-GENE
like	I-GENE
repeat	I-GENE
units	I-GENE
.	O

ArgR	B-GENE
was	O
shown	O
to	O
be	O
a	O
dimer	O
of	O
two	O
equal	O
subunits	O
,	O
each	O
with	O
a	O
molecular	O
mass	O
of	O
37	O
,	O
000	O
Da	O
.	O

Plasma	B-GENE
leptin	I-GENE
concentrations	O
were	O
higher	O
in	O
women	O
than	O
men	O
,	O
even	O
after	O
the	O
adjustment	O
for	O
differences	O
in	O
fat	O
mass	O
(	O
28	O
+	O
/	O
-	O
3	O
ng	O
/	O
ml	O
for	O
women	O
vs	O
.	O

Consistent	O
with	O
effects	O
on	O
STAT	B-GENE
activation	O
,	O
altered	O
SHP	B-GENE
-	I-GENE
1	I-GENE
expression	O
also	O
affected	O
EGF	B-GENE
-	O
induced	O
activation	O
of	O
the	O
mitogen	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
kinase	I-GENE
pathway	O
;	O
expression	O
of	O
SHP	B-GENE
-	I-GENE
1	I-GENE
-	I-GENE
(	I-GENE
Cys	I-GENE
-	I-GENE
-	I-GENE
>	I-GENE
Ser	I-GENE
)	I-GENE
inhibited	O
activity	O
of	O
MEK	B-GENE
by	O
approximately	O
25	O
%	O
,	O
whereas	O
expression	O
of	O
SHP	B-GENE
-	I-GENE
1	I-GENE
resulted	O
in	O
a	O
approximately	O
25	O
%	O
increase	O
.	O

This	O
interaction	O
involved	O
the	O
SH3	B-GENE
region	I-GENE
of	O
p50	B-GENE
(	O
csk	B-GENE
)	O
and	O
a	O
proline	O
-	O
rich	O
region	O
(	O
PPPLPERTPESFVLADM	O
)	O
outside	O
the	O
catalytic	O
region	O
of	O
PTP	B-GENE
-	O
PEST	O
.	O

Following	O
2	O
.	O
5	O
Gy	O
,	O
HbO2	B-GENE
changes	O
were	O
minimal	O
.	O

Among	O
38	O
patients	O
with	O
inducible	O
reentrant	O
VTs	O
who	O
underwent	O
electrophysiologic	O
study	O
(	O
EPS	O
)	O
,	O
10	O
VTs	O
of	O
six	O
patients	O
were	O
selected	O
.	O

The	O
cycle	O
length	O
of	O
induced	O
VT	O
(	O
n	O
=	O
10	O
VTs	O
)	O
was	O
380	O
+	O
/	O
-	O
41	O
msec	O
.	O

Transient	O
hyperammonaemia	O
in	O
an	O
adult	O
German	O
shepherd	O
dog	O
.	O

We	O
established	O
that	O
the	O
2	O
.	O
6	O
kb	O
mRNA	O
V	O
-	O
1	O
and	O
the	O
2	O
.	O
3	O
kb	O
GGT	B-GENE
mRNA	O
V	O
-	O
2	O
derive	O
,	O
by	O
alternate	O
splicing	O
,	O
from	O
a	O
primary	O
transcript	O
initiated	O
on	O
a	O
distal	O
promoter	O
on	O
the	O
rat	B-GENE
GGT	I-GENE
gene	I-GENE
.	O

A	O
specific	O
distal	O
promoter	O
controls	O
gamma	B-GENE
-	I-GENE
glutamyl	I-GENE
transpeptidase	I-GENE
gene	I-GENE
expression	O
in	O
undifferentiated	O
rat	O
transformed	O
liver	O
cells	O
.	O

These	O
repressor	O
sites	O
are	O
pyrimidine	O
rich	O
and	O
bind	O
avidly	O
to	O
the	O
polypyrimidine	B-GENE
tract	I-GENE
binding	I-GENE
protein	I-GENE
(	O
PTB	B-GENE
)	O
in	O
HeLa	O
nuclear	O
extracts	O
as	O
determined	O
by	O
UV	O
crosslinking	O
/	O
competition	O
assays	O
.	O

For	O
higher	O
expression	O
of	O
lipA	B-GENE
in	O
S	O
.	O
lividans	O
,	O
the	O
gene	O
was	O
cloned	O
next	O
to	O
the	O
strong	O
aphII	B-GENE
promoter	I-GENE
.	O

Within	O
a	O
135	O
-	O
bp	O
core	O
homology	O
region	O
,	O
the	O
human	B-GENE
HS12	I-GENE
enhancers	I-GENE
are	O
approximately	O
90	O
%	O
identical	O
to	O
the	O
murine	O
homolog	O
and	O
include	O
several	O
motifs	O
previously	O
demonstrated	O
to	O
be	O
important	O
for	O
function	O
of	O
the	O
murine	O
enhancer	O
;	O
additional	O
segments	O
of	O
high	O
sequence	O
conservation	O
suggest	O
the	O
possibility	O
of	O
previously	O
unrecognized	O
functional	O
motifs	O
.	O

The	O
two	O
cysteine	O
residues	O
located	O
in	O
this	O
additional	O
region	O
may	O
be	O
involved	O
in	O
the	O
formation	O
of	O
a	O
disulfide	O
bridge	O
associated	O
with	O
the	O
activation	O
process	O
of	O
the	O
catalytic	O
activity	O
.	O

The	O
por	B-GENE
gene	I-GENE
has	O
been	O
expressed	O
,	O
for	O
the	O
first	O
time	O
,	O
in	O
anaerobically	O
grown	O
Escherichia	O
coli	O
behind	O
the	O
isopropyl	O
-	O
beta	O
-	O
D	O
-	O
thiogalactopyranoside	O
-	O
inducible	O
tac	B-GENE
promoter	I-GENE
,	O
resulting	O
in	O
the	O
production	O
of	O
POR	B-GENE
in	O
its	O
active	O
form	O
.	O

When	O
the	O
downstream	O
operator	O
was	O
altered	O
,	O
there	O
was	O
a	O
fourfold	O
reduction	O
in	O
reporter	O
enzyme	O
levels	O
.	O

The	O
ORF3	O
mutant	O
produced	O
reduced	O
levels	O
of	O
tabtoxin	B-GENE
,	O
indicating	O
that	O
ORF3	O
may	O
have	O
a	O
role	O
in	O
T	B-GENE
beta	I-GENE
L	I-GENE
biosynthesis	O
.	O

Refined	O
Cox	O
models	O
using	O
a	O
CD4	B-GENE
count	O
of	O
150	O
/	O
microL	O
rather	O
than	O
200	O
/	O
microL	O
to	O
distinguish	O
I0	O
and	O
I1	O
yielded	O
a	O
simplified	O
model	O
with	O
better	O
fit	O
to	O
the	O
observed	O
data	O
.	O

However	O
,	O
the	O
published	O
reports	O
consist	O
of	O
a	O
small	O
number	O
of	O
patients	O
and	O
limited	O
data	O
.	O

These	O
transcripts	O
contain	O
the	O
5	O
'	O
ends	O
of	O
mature	O
UbCRBP	B-GENE
mRNAs	I-GENE
;	O
extend	O
through	O
UbCRBP	B-GENE
,	O
across	O
the	O
intergenic	O
region	O
,	O
and	O
a	O
significant	O
distance	O
3	O
'	O
into	O
the	O
enolase	B-GENE
gene	I-GENE
.	O

The	O
distribution	O
of	O
cryptosporidia	O
in	O
the	O
intestine	O
and	O
number	O
of	O
cryptosporidia	O
per	O
ileal	O
villus	O
on	O
different	O
DPI	O
were	O
also	O
estimated	O
for	O
detailed	O
characterization	O
of	O
the	O
infection	O
in	O
kids	O
as	O
a	O
model	O
for	O
experimental	O
cryptosporidiosis	O
.	O

As	O
a	O
result	O
,	O
the	O
subendocardial	O
/	O
subepicardial	O
blood	O
flow	O
ratio	O
(	O
ENDO	O
/	O
EPI	O
)	O
increased	O
from	O
0	O
.	O
44	O
+	O
/	O
-	O
0	O
.	O
09	O
during	O
control	O
stenosis	O
to	O
0	O
.	O
85	O
+	O
/	O
-	O
0	O
.	O
13	O
after	O
ITF	O
1129	O
(	O
10	O
micrograms	O
/	O
kg	O
/	O
min	O
i	O
.	O
v	O
.	O
)	O
and	O
to	O
0	O
.	O
81	O
+	O
/	O
-	O
0	O
.	O
12	O
after	O
NTG	O
.	O

Proteasomes	O
are	O
the	O
multisubunit	O
protease	O
involved	O
in	O
the	O
generation	O
of	O
peptides	O
presented	O
by	O
MHC	B-GENE
class	I-GENE
I	I-GENE
molecules	I-GENE
.	O

Takahashi	O
,	O
H	O
.	O

For	O
sputum	B-GENE
interleukin	I-GENE
-	I-GENE
8	I-GENE
there	O
was	O
an	O
estimated	O
true	O
treatment	O
median	O
difference	O
of	O
142	O
pg	O
/	O
ml	O
(	O
95	O
%	O
confidence	O
interval	O
(	O
CI	O
)	O
8	O
to	O
2866	O
pg	O
/	O
ml	O
)	O
in	O
favour	O
of	O
placebo	O
;	O
while	O
for	O
maximal	O
expiratory	O
flow	O
at	O
25	O
%	O
(	O
MEF25	O
%	O
)	O
remaining	O
forced	O
vital	O
capacity	O
predicted	O
for	O
sex	O
and	O
height	O
there	O
was	O
a	O
15	O
percentage	O
points	O
(	O
pp	O
)	O
(	O
95	O
%	O
CI	O
4	O
to	O
26	O
pp	O
)	O
mean	O
treatment	O
difference	O
in	O
favour	O
of	O
placebo	O
.	O

However	O
,	O
although	O
deletion	O
of	O
Fp1	B-GENE
in	O
the	O
hCRBP1	B-GENE
gene	I-GENE
yielded	O
increased	O
CAT	B-GENE
activity	O
,	O
pointing	O
toward	O
a	O
negative	O
regulatory	O
function	O
exerted	O
by	O
this	O
element	O
,	O
its	O
insertion	O
upstream	O
of	O
the	O
p12	B-GENE
basal	I-GENE
promoter	I-GENE
results	O
in	O
an	O
impressive	O
positive	O
stimulation	O
of	O
CAT	B-GENE
gene	I-GENE
expression	O
.	O

Gaucher	O
'	O
s	O
disease	O
is	O
a	O
rare	O
metabolic	O
disorder	O
characterized	O
by	O
the	O
lack	O
of	O
beta	B-GENE
-	I-GENE
glucocerebrosidase	I-GENE
enzyme	I-GENE
.	O

The	O
9	O
;	O
22	O
chromosomal	O
translocation	O
characteristic	O
of	O
CML	O
results	O
in	O
a	O
fused	O
bcr	B-GENE
/	O
abl	B-GENE
gene	O
and	O
an	O
abnormal	O
fusion	O
protein	O
,	O
p210bcr	B-GENE
/	O
abl	B-GENE
.	O

By	O
analyzing	O
the	O
RanGAP	B-GENE
activity	O
of	O
a	O
series	O
of	O
recombinantly	O
expressed	O
rna1p	B-GENE
mutant	I-GENE
derivatives	O
,	O
we	O
show	O
that	O
the	O
highly	O
acidic	O
sequence	O
in	O
the	O
C	O
-	O
terminal	O
domain	O
of	O
both	O
yeast	O
proteins	O
is	O
indispensable	O
for	O
activating	O
Ran	B-GENE
-	O
mediated	O
GTP	O
hydrolysis	O
.	O

In	O
the	O
absence	O
of	O
MHC	B-GENE
class	I-GENE
II	I-GENE
,	O
purified	B-GENE
soluble	I-GENE
D10	I-GENE
TCR	I-GENE
bound	O
to	O
Staphylococcus	B-GENE
aureus	I-GENE
enterotoxin	I-GENE
C2	I-GENE
with	O
an	O
association	O
rate	O
of	O
1	O
.	O
69	O
+	O
/	O
-	O
0	O
.	O
12	O
x	O
10	O
(	O
4	O
)	O
M	O
(	O
-	O
1	O
)	O
sec	O
(	O
-	O
1	O
)	O
and	O
a	O
dissociation	O
rate	O
of	O
1	O
.	O
9	O
+	O
/	O
-	O
0	O
.	O
47	O
x	O
10	O
(	O
-	O
2	O
)	O
sec	O
(	O
-	O
1	O
)	O
,	O
giving	O
a	O
dissociation	O
constant	O
of	O
1	O
.	O
1	O
microM	O
.	O

Evidence	O
for	O
such	O
peak	O
shifts	O
has	O
been	O
found	O
in	O
the	O
responses	O
of	O
auditory	O
nerve	O
fibers	O
,	O
cochlear	O
microphonics	O
,	O
and	O
the	O
responses	O
of	O
outer	O
hair	O
cells	O
and	O
supporting	O
cells	O
in	O
the	O
cochlea	O
,	O
as	O
well	O
as	O
in	O
basilar	O
membrane	O
vibration	O
measurements	O
,	O
and	O
indirectly	O
,	O
in	O
psychophysical	O
data	O
.	O

Mnt	B-GENE
:	O
Max	B-GENE
complexes	O
also	O
efficiently	O
suppress	O
Myc	B-GENE
-	O
dependent	O
activation	O
from	O
the	O
same	O
promoter	O
.	O

Assays	O
of	O
total	O
cholesterol	O
as	O
well	O
as	O
the	O
HDL	B-GENE
,	O
HDL2	B-GENE
,	O
LDL	B-GENE
,	O
triglycerides	O
,	O
endothelin	B-GENE
-	I-GENE
1	I-GENE
,	O
lipoprotein	B-GENE
(	I-GENE
a	I-GENE
)	I-GENE
,	O
estradiol	O
and	O
FSH	B-GENE
were	O
also	O
obtained	O
at	O
baseline	O
before	O
receiving	O
ERT	O
and	O
after	O
3	O
months	O
of	O
ERT	O
.	O

Six	O
tandem	O
repeats	O
of	O
the	O
P	B-GENE
element	I-GENE
linked	O
to	O
the	O
SV40	B-GENE
promoter	I-GENE
responded	O
to	O
phorbol	O
12	O
-	O
myristate	O
13	O
-	O
acetate	O
,	O
while	O
that	O
of	O
other	O
elements	O
did	O
not	O
.	O

The	O
distributed	O
current	O
density	O
J	O
is	O
calculated	O
within	O
the	O
volume	O
defined	O
by	O
the	O
motor	O
unit	O
.	O

The	O
cleavage	O
dipeptides	O
of	O
C1YVV	B-GENE
NIa	I-GENE
protease	I-GENE
are	O
Q	O
(	O
E	O
)	O
/	O
S	O
(	O
A	O
,	O
G	O
)	O
.	O

However	O
,	O
we	O
were	O
unable	O
to	O
identify	O
a	O
p4	B-GENE
molecule	O
.	O

(	O
iv	O
)	O
The	O
accumulation	O
of	O
cyclin	B-GENE
D3	I-GENE
protein	I-GENE
in	O
Vero	O
cells	O
infected	O
with	O
an	O
alpha0	B-GENE
deletion	I-GENE
mutant	I-GENE
was	O
reduced	O
relative	O
to	O
that	O
of	O
cells	O
infected	O
with	O
wild	O
-	O
type	O
virus	O
or	O
a	O
recombinant	O
virus	O
in	O
which	O
the	O
deleted	O
alpha0	B-GENE
sequences	I-GENE
were	O
restored	O
.	O

We	O
report	O
the	O
preliminary	O
biochemical	O
characterization	O
of	O
the	O
T	B-GENE
antigens	I-GENE
encoded	O
by	O
three	O
SV40	O
mutants	O
,	O
5030	O
,	O
5031	O
,	O
and	O
5061	O
,	O
each	O
of	O
which	O
have	O
altered	O
residues	O
within	O
or	O
near	O
the	O
ATP	O
binding	O
pocket	O
.	O

These	O
effects	O
were	O
abrogated	O
by	O
co	O
-	O
expression	O
of	O
kinase	B-GENE
-	I-GENE
deficient	I-GENE
PKC	I-GENE
zeta	I-GENE
and	O
inhibition	O
of	O
phosphatidylinositol	B-GENE
3	I-GENE
-	I-GENE
kinase	I-GENE
p85alpha	B-GENE
-	O
p110	B-GENE
by	O
wortmannin	O
,	O
LY294002	O
and	O
a	O
dominant	O
-	O
negative	O
mutant	O
of	O
p85alpha	B-GENE
.	O

Protein	B-GENE
phosphatase	I-GENE
2A	I-GENE
is	O
a	O
critical	O
regulator	O
of	O
protein	B-GENE
kinase	I-GENE
C	I-GENE
zeta	I-GENE
signaling	O
targeted	O
by	O
SV40	B-GENE
small	I-GENE
t	I-GENE
to	O
promote	O
cell	O
growth	O
and	O
NF	B-GENE
-	I-GENE
kappaB	I-GENE
activation	O
.	O

Interestingly	O
,	O
the	O
RXRalphaF318A	B-GENE
constitutive	O
activity	O
generated	O
within	O
heterodimers	O
in	O
the	O
presence	O
of	O
BMS614	O
requires	O
the	O
integrity	O
of	O
both	O
RXR	B-GENE
and	O
RAR	B-GENE
AF	O
-	O
2	O
domains	O
.	O

These	O
introns	O
contain	O
only	O
single	O
snoRNA	B-GENE
genes	I-GENE
and	O
their	O
processing	O
involves	O
exonucleolytic	O
release	O
of	O
the	O
snoRNA	O
from	O
debranched	O
intron	O
lariats	O
.	O

Recent	O
studies	O
have	O
shown	O
that	O
the	O
Src	B-GENE
homology	I-GENE
-	I-GENE
2	I-GENE
(	O
SH2	B-GENE
)	O
domain	O
-	O
containing	O
protein	B-GENE
-	I-GENE
tyrosine	I-GENE
phosphatase	I-GENE
,	O
SHP	B-GENE
-	I-GENE
2	I-GENE
,	O
associates	O
with	O
the	O
cytoplasmic	O
domain	O
of	O
PECAM	B-GENE
-	I-GENE
1	I-GENE
as	O
it	O
becomes	O
tyrosine	O
-	O
phosphorylated	O
during	O
platelet	O
aggregation	O
:	O
a	O
process	O
that	O
can	O
be	O
mimicked	O
in	O
part	O
by	O
small	O
synthetic	O
phosphopeptides	O
corresponding	O
to	O
the	O
cytoplasmic	O
domain	O
of	O
PECAM	B-GENE
-	I-GENE
1	I-GENE
encompassing	O
tyrosine	O
residues	O
Tyr	O
-	O
663	O
or	O
Tyr	O
-	O
686	O
.	O

Underlying	O
the	O
clustering	O
of	O
these	O
risk	O
variables	O
were	O
three	O
factors	O
.	O

Supplementation	O
was	O
stopped	O
when	O
pl	B-GENE
-	I-GENE
ALB	I-GENE
reached	O
2	O
.	O
0	O
g	O
/	O
dL	O
.	O

Detection	O
of	O
airborne	O
Mycobacterium	O
tuberculosis	O
by	O
air	O
filtration	O
and	O
polymerase	O
chain	O
reaction	O
.	O

These	O
findings	O
show	O
that	O
EBP50	B-GENE
is	O
a	O
physiologically	O
relevant	O
ezrin	B-GENE
binding	I-GENE
protein	I-GENE
.	O

This	O
family	O
of	O
proteins	O
binds	O
GC	O
-	O
rich	O
motifs	O
widely	O
distributed	O
in	O
gene	O
promoters	O
,	O
resulting	O
in	O
distinct	O
activation	O
or	O
repression	O
of	O
transcriptional	O
activities	O
.	O

Deletion	O
of	O
the	O
POR2	B-GENE
gene	I-GENE
alone	O
had	O
no	O
detectable	O
phenotype	O
,	O
while	O
yeasts	O
with	O
deletions	O
of	O
both	O
the	O
POR1	B-GENE
and	O
POR2	B-GENE
genes	I-GENE
were	O
viable	O
and	O
able	O
to	O
grow	O
on	O
glycerol	O
at	O
30	O
degrees	O
C	O
,	O
albeit	O
more	O
slowly	O
than	O
delta	B-GENE
por1	I-GENE
single	I-GENE
mutants	I-GENE
.	O

Furthermore	O
,	O
our	O
novel	O
observation	O
that	O
expression	O
of	O
a	O
highly	O
activated	O
FGFR3	B-GENE
kinase	I-GENE
domain	I-GENE
is	O
able	O
to	O
morphologically	O
transform	O
fibroblasts	O
suggests	O
that	O
dysregulation	O
of	O
FGFR3	B-GENE
has	O
the	O
potential	O
to	O
play	O
a	O
role	O
in	O
human	O
neoplasia	O
.	O

Involvement	O
of	O
AP	B-GENE
-	I-GENE
2	I-GENE
in	O
regulation	O
of	O
the	O
R	B-GENE
-	I-GENE
FABP	I-GENE
gene	I-GENE
in	O
the	O
developing	O
chick	O
retina	O
.	O

However	O
,	O
Cbf5p	B-GENE
was	O
found	O
to	O
be	O
nucleolar	O
and	O
is	O
highly	O
homologous	O
to	O
the	O
rat	B-GENE
nucleolar	I-GENE
protein	I-GENE
NAP57	I-GENE
,	O
which	O
coimmunoprecipitates	O
with	O
Nopp140	B-GENE
and	O
which	O
is	O
postulated	O
to	O
be	O
involved	O
in	O
nucleolar	O
-	O
cytoplasmic	O
shuttling	O
(	O
U	O
.	O

This	O
newly	O
described	O
organism	O
was	O
difficult	O
to	O
identify	O
due	O
to	O
discrepancies	O
between	O
the	O
Vitek	O
and	O
API	O
20E	O
identification	O
systems	O
.	O

Ig	B-GENE
heavy	I-GENE
chain	I-GENE
class	O
switching	O
is	O
directed	O
by	O
cytokines	O
inducing	O
transcription	O
from	O
unrearranged	O
CH	B-GENE
genes	I-GENE
.	O

The	O
available	O
data	O
suggest	O
that	O
the	O
NF	B-GENE
kappa	I-GENE
B2	I-GENE
nucleoprotein	I-GENE
complex	I-GENE
may	O
cooperate	O
with	O
DNA	O
-	O
bound	O
STAT6	B-GENE
to	O
achieve	O
IL	B-GENE
-	I-GENE
4	I-GENE
-	O
dependent	O
activation	O
of	O
the	O
human	B-GENE
IgE	I-GENE
germline	I-GENE
gene	I-GENE
.	O

EXERCISE	O
IN	O
THE	O
TERRESTRIAL	O
CHRISTMAS	O
ISLAND	O
RED	O
CRAB	O
GECARCOIDEA	O
NATALIS	O
-	O
ENERGETICS	O
OF	O
LOCOMOTION	O

THE	O
SCALING	O
OF	O
SONG	O
FREQUENCY	O
IN	O
CICADAS	O

In	O
this	O
study	O
we	O
have	O
introduced	O
mutations	O
into	O
the	O
corresponding	O
elements	O
of	O
two	O
cox3	B-GENE
promoters	I-GENE
and	O
show	O
that	O
while	O
the	O
core	O
element	O
is	O
essential	O
for	O
cox3	B-GENE
promoter	I-GENE
activity	O
,	O
upstream	O
element	O
mutations	O
have	O
little	O
or	O
no	O
effect	O
.	O

We	O
found	O
that	O
multiple	O
tumor	O
suppressor	O
genes	O
(	O
e	O
.	O
g	O
.	O
,	O
p53	B-GENE
,	O
DCC	B-GENE
,	O
APC	B-GENE
,	O
MCC	B-GENE
,	O
BRCA1	B-GENE
,	O
and	O
WAF1	B-GENE
/	O
CIP1	B-GENE
)	O
were	O
inactivated	O
at	O
different	O
frequencies	O
via	O
various	O
mechanisms	O
[	O
e	O
.	O
g	O
.	O
,	O
loss	O
of	O
heterozygosity	O
(	O
LOH	O
)	O
,	O
loss	O
of	O
expression	O
(	O
LOE	O
)	O
,	O
mutation	O
,	O
and	O
inactivation	O
by	O
cellular	O
binding	O
protein	O
]	O
.	O

The	O
histidine	O
-	O
tagged	O
gene	O
,	O
rpoCHIS	B-GENE
,	O
was	O
used	O
to	O
replace	O
the	O
wild	O
-	O
type	O
allele	O
in	O
the	O
chromosome	O
of	O
S	O
.	O
coelicolor	O
and	O
S	O
.	O
lividans	O
.	O

Because	O
the	O
deletion	O
included	O
the	O
TK	B-GENE
gene	I-GENE
,	O
selection	O
with	O
gancyclovir	O
against	O
cells	O
not	O
having	O
undergone	O
recombination	O
was	O
possible	O
.	O

Lack	O
of	O
controlled	O
prospective	O
studies	O
of	O
sleep	O
electroencephalograms	O
(	O
EEG	O
)	O
,	O
and	O
the	O
use	O
of	O
medication	O
,	O
in	O
children	O
with	O
developmental	O
dysphasia	O
,	O
may	O
deny	O
appropriate	O
treatment	O
strategies	O
to	O
children	O
with	O
severe	O
developmental	O
speech	O
and	O
language	O
disorders	O
.	O

Widening	O
of	O
the	O
abdominal	O
aortic	O
wall	O
on	O
an	O
ultrasound	O
examination	O
was	O
the	O
key	O
to	O
the	O
incidental	O
diagnosis	O
of	O
a	O
clinically	O
unsuspected	O
type	O
B	O
dissection	O
.	O

Fermentation	O
process	O
after	O
supplementation	O
of	O
nitrate	O
,	O
nitrite	O
,	O
lactic	O
acid	O
bacteria	O
and	O
formic	O
acid	O

Substrates	O
include	O
the	O
p21	B-GENE
(	O
ras	B-GENE
)	O
proteins	O
,	O
nuclear	B-GENE
lamins	I-GENE
,	O
and	O
a	O
series	O
of	O
retinal	O
proteins	O
.	O

Ovaries	O
of	O
10	O
animals	O
per	O
group	O
from	O
16	O
studies	O
in	O
CD	O
-	O
1	O
mice	O
and	O
1	O
study	O
each	O
in	O
C3H	O
and	O
C57BL	O
/	O
6	O
mice	O
were	O
sectioned	O
serially	O
at	O
6	O
microm	O
.	O

The	O
Trx	B-GENE
-	O
CT	B-GENE
fusion	O
protein	O
was	O
produced	O
less	O
efficiently	O
(	O
20	O
%	O
of	O
total	O
soluble	O
cellular	O
protein	O
)	O
.	O

A	O
data	O
base	O
homology	O
search	O
revealed	O
that	O
the	O
predicted	O
ER1	B-GENE
amino	O
acid	O
sequence	O
contains	O
three	O
regions	O
of	O
similarity	O
to	O
the	O
rat	O
and	O
human	O
proteins	O
encoded	O
by	O
the	O
metastasis	O
-	O
associated	O
gene	O
,	O
mta1	B-GENE
,	O
and	O
two	O
regions	O
of	O
similarity	O
to	O
the	O
Caenorhabditis	O
elegans	O
sequence	O
that	O
is	O
similar	O
to	O
mta1	B-GENE
.	O

The	O
sequenced	O
cDNA	O
predicts	O
a	O
704	O
-	O
amino	O
acid	O
protein	O
80	O
%	O
identical	O
to	O
human	B-GENE
progelatinase	I-GENE
B	I-GENE
.	O

The	O
inhibition	O
by	O
cytosolic	O
Ca2	O
+	O
was	O
caused	O
by	O
a	O
decrease	O
in	O
cooperativity	O
and	O
by	O
a	O
shift	O
in	O
EC50	O
toward	O
higher	O
InsP3	O
concentrations	O
.	O

RESULTS	O
:	O
The	O
standardised	O
mortality	O
ratio	O
(	O
SMR	O
)	O
for	O
all	O
malignant	O
neoplasms	O
was	O
94	O
(	O
95	O
%	O
CI	O
74	O
to	O
118	O
)	O
.	O

Sequence	O
analysis	O
of	O
this	O
region	O
revealed	O
three	O
eight	O
-	O
bp	O
repetitive	O
elements	O
,	O
the	O
deletion	O
of	O
which	O
restored	O
wild	O
-	O
type	O
levels	O
of	O
luciferase	B-GENE
activity	O
to	O
the	O
-	O
916	O
-	O
bp	O
reporter	O
plasmid	O
.	O

Using	O
5	O
'	O
RACE	O
and	O
reverse	O
transcription	O
-	O
PCR	O
(	O
RT	O
-	O
PCR	O
)	O
methodologies	O
,	O
we	O
cloned	O
these	O
sequences	O
from	O
brain	O
and	O
placenta	O
and	O
found	O
this	O
material	O
to	O
be	O
composed	O
of	O
alternatively	O
spliced	O
exons	O
using	O
a	O
previously	O
reported	O
noncoding	O
exon	O
(	O
1A	O
)	O
and	O
a	O
novel	O
97	O
-	O
bp	O
noncoding	O
exon	O
(	O
1B	O
)	O
.	O

This	O
is	O
the	O
first	O
study	O
in	O
which	O
mutation	O
screening	O
has	O
been	O
performed	O
for	O
both	O
the	O
EXT1	B-GENE
and	O
EXT2	B-GENE
genes	I-GENE
prior	O
to	O
any	O
linkage	O
analysis	O
.	O

Positron	O
emission	O
tomography	O
radioligands	O
for	O
dopamine	B-GENE
transporters	I-GENE
and	O
studies	O
in	O
human	O
and	O
nonhuman	O
primates	O
.	O

Expression	O
from	O
this	O
element	O
is	O
regulated	O
by	O
a	O
heteromeric	O
protein	O
complex	O
containing	O
ubiquitous	O
(	O
i	O
.	O
e	O
.	O
the	O
E2A	B-GENE
-	O
and	O
HEB	B-GENE
-	I-GENE
encoded	I-GENE
proteins	I-GENE
)	O
and	O
islet	O
-	O
enriched	O
members	O
of	O
the	O
bHLH	B-GENE
family	I-GENE
.	O

Thus	O
,	O
the	O
CCAAT	O
box	O
also	O
has	O
tissue	O
-	O
specific	O
characteristics	O
that	O
assist	O
in	O
targeting	O
expression	O
of	O
the	O
alpha	B-GENE
-	I-GENE
subunit	I-GENE
gene	I-GENE
to	O
trophoblasts	O
.	O

U4	B-GENE
/	O
U6	B-GENE
snRNP	O
is	O
one	O
of	O
four	O
essential	O
small	O
nuclear	O
ribonucleoprotein	O
(	O
snRNP	O
)	O
particles	O
(	O
U1	B-GENE
,	O
U2	B-GENE
,	O
U5	B-GENE
and	O
U4	B-GENE
/	O
U6	B-GENE
)	O
present	O
in	O
the	O
spliceosome	O
.	O

Hprp3p	B-GENE
is	O
a	O
77	O
kDa	O
protein	O
,	O
which	O
is	O
homologous	O
to	O
the	O
Saccharomyces	B-GENE
cerevisiae	I-GENE
splicing	I-GENE
factor	I-GENE
Prp3p	I-GENE
.	O

The	O
growth	O
-	O
promoting	O
properties	O
of	O
the	O
retroviral	B-GENE
v	I-GENE
-	I-GENE
erbA	I-GENE
oncogene	I-GENE
,	O
a	O
highly	O
mutated	O
version	O
of	O
the	O
chicken	B-GENE
thyroid	I-GENE
hormone	I-GENE
receptor	I-GENE
(	I-GENE
TR	I-GENE
)	I-GENE
alpha	I-GENE
,	O
have	O
so	O
far	O
exclusively	O
been	O
linked	O
to	O
dominant	O
repression	O
of	O
the	O
antimitogenic	O
roles	O
of	O
TR	B-GENE
and	O
retinoic	B-GENE
acid	I-GENE
receptors	I-GENE
.	O

We	O
cloned	O
a	O
complete	O
cDNA	O
(	O
2	O
.	O
9	O
kb	O
)	O
for	O
HET	B-GENE
from	O
an	O
MCF	O
-	O
7	O
cDNA	O
library	O
.	O

The	O
most	O
common	O
grade	O
3	O
toxicity	O
was	O
neutropenia	O
,	O
thrombocytopenia	O
,	O
and	O
parasthesias	O
(	O
observed	O
in	O
<	O
10	O
%	O
of	O
cycles	O
)	O
.	O

Serum	O
concentrations	O
of	O
E2	O
and	O
TBOH	O
were	O
measured	O
on	O
d	O
0	O
,	O
1	O
,	O
3	O
,	O
5	O
,	O
7	O
,	O
13	O
,	O
21	O
,	O
28	O
,	O
42	O
,	O
56	O
,	O
84	O
,	O
112	O
,	O
and	O
140	O
in	O
finishing	O
heifers	O
administered	O
the	O
following	O
treatments	O
:	O
1	O
)	O
control	O
;	O
2	O
)	O
MGA	O
,	O
.	O
5	O
mg	O
per	O
heifer	O
daily	O
;	O
3	O
)	O
Revalor	O
-	O
H	O
(	O
140	O
mg	O
TBA	O
+	O
14	O
mg	O
E2	O
)	O
;	O
4	O
)	O
Revalor	O
-	O
H	O
+	O
MGA	O
;	O
5	O
)	O
Finaplix	O
-	O
H	O
(	O
200	O
mg	O
TBA	O
)	O
;	O
and	O
6	O
)	O
Finaplix	O
-	O
H	O
+	O
MGA	O
.	O

Serum	O
E2	O
concentrations	O
increased	O
numerically	O
two	O
-	O
to	O
threefold	O
from	O
d	O
56	O
to	O
140	O
in	O
controls	O
fed	O
MGA	O
,	O
compared	O
with	O
controls	O
not	O
fed	O
MGA	O
.	O

Interferon	B-GENE
Regulatory	I-GENE
Factor	I-GENE
(	I-GENE
IRF	I-GENE
)	I-GENE
-	I-GENE
1	I-GENE
has	O
been	O
characterized	O
as	O
an	O
important	O
growth	O
regulatory	O
and	O
immunomodulatory	O
transcription	O
factor	O
.	O

The	O
genomic	O
structure	O
of	O
brk	B-GENE
consists	O
of	O
8	O
exons	O
,	O
whose	O
boundaries	O
are	O
distinct	O
from	O
other	O
non	O
-	O
receptor	O
PTK	B-GENE
family	I-GENE
members	O
,	O
again	O
indicating	O
a	O
structural	O
and	O
functional	O
divergence	O
.	O

We	O
have	O
previously	O
reported	O
that	O
expression	O
of	O
a	O
tumour	O
derived	O
brk	B-GENE
cDNA	I-GENE
in	O
mouse	O
embryonic	O
fibroblasts	O
and	O
human	O
mammary	O
epithelial	O
cells	O
supports	O
anchorage	O
independent	O
growth	O
,	O
and	O
in	O
the	O
latter	O
potentiates	O
the	O
mitogenic	O
response	O
to	O
epidermal	B-GENE
growth	I-GENE
factor	I-GENE
.	O

Anti	B-GENE
-	I-GENE
hepatitis	I-GENE
A	I-GENE
virus	O
(	O
HAV	O
)	O
titer	O
after	O
vaccination	O
was	O
measured	O
in	O
83	O
HIV	O
-	O
positive	O
and	O
39	O
HIV	O
-	O
negative	O
men	O
.	O

One	O
skull	O
does	O
not	O
a	O
species	O
make	O
.	O

Surprisingly	O
,	O
calf	B-GENE
thymus	I-GENE
CstF	I-GENE
contained	O
an	O
additional	O
,	O
novel	O
form	O
of	O
the	O
64	O
-	O
kDa	O
subunit	O
with	O
a	O
molecular	O
mass	O
of	O
70	O
kDa	O
.	O

Our	O
results	O
favor	O
the	O
possibility	O
that	O
the	O
Drosophila	B-GENE
EGF	I-GENE
receptor	I-GENE
DER	B-GENE
/	O
Egfr	B-GENE
expressed	O
by	O
the	O
EMA	O
cells	O
functions	O
as	O
a	O
receptor	O
for	O
Vein	B-GENE
.	O

PATIENTS	O
AND	O
METHODS	O
:	O
In	O
807	O
consecutive	O
patients	O
from	O
the	O
Chilean	O
National	O
Registry	O
of	O
Acute	O
Myocardial	O
Infarction	O
we	O
analyzed	O
the	O
resolution	O
of	O
chest	O
pain	O
and	O
ST	O
segment	O
elevation	O
over	O
50	O
%	O
within	O
the	O
first	O
90	O
min	O
,	O
abrupt	O
CK	B-GENE
rise	O
within	O
8	O
h	O
and	O
T	O
wave	O
inversion	O
in	O
infarct	O
related	O
EKG	O
leads	O
within	O
the	O
first	O
24	O
h	O
after	O
thrombolysis	O
.	O

Because	O
of	O
the	O
operon	O
structure	O
of	O
this	O
organism	O
,	O
traditional	O
methods	O
such	O
as	O
insertional	O
mutagenesis	O
run	O
the	O
risk	O
of	O
introducing	O
polar	O
effects	O
on	O
downstream	O
genes	O
or	O
creating	O
secondary	O
mutations	O
elsewhere	O
in	O
the	O
genome	O
.	O

It	O
has	O
been	O
proposed	O
that	O
the	O
parCBA	B-GENE
operon	I-GENE
encodes	O
a	O
plasmid	O
partitioning	O
system	O
(	O
M	O
.	O

Furthermore	O
,	O
the	O
insertion	O
of	O
the	O
ColE1	B-GENE
cer	I-GENE
site	I-GENE
into	O
the	O
RK2	O
plasmid	O
deleted	O
for	O
the	O
par	O
region	O
failed	O
to	O
stabilize	O
the	O
plasmid	O
in	O
the	O
MC1061K	O
strain	O
,	O
indicating	O
that	O
the	O
multimer	O
resolution	O
activity	O
encoded	O
by	O
parCBA	B-GENE
is	O
not	O
by	O
itself	O
responsible	O
for	O
the	O
stabilization	O
activity	O
observed	O
for	O
this	O
operon	O
.	O

To	O
examine	O
the	O
basis	O
for	O
the	O
apparent	O
differences	O
in	O
postsegregational	O
killing	O
between	O
the	O
two	O
E	O
.	O
coli	O
strains	O
,	O
transformation	O
assays	O
were	O
carried	O
out	O
to	O
determine	O
the	O
relative	O
sensitivities	O
of	O
the	O
strains	O
to	O
the	O
ParE	B-GENE
toxin	I-GENE
protein	I-GENE
.	O

Splice	O
-	O
junction	O
elements	O
and	O
intronic	O
sequences	O
regulate	O
alternative	O
splicing	O
of	O
the	O
Drosophila	O
myosin	B-GENE
heavy	I-GENE
chain	I-GENE
gene	I-GENE
transcript	O
.	O

Nucleotide	O
sequence	O
analysis	O
of	O
R	O
has	O
revealed	O
similarities	O
to	O
the	O
R1	O
plasmid	O
found	O
in	O
some	O
South	O
American	O
maize	O
races	O
with	O
RU	O
cytoplasm	O
,	O
to	O
the	O
M1	O
plasmid	O
found	O
in	O
one	O
source	O
of	O
Zea	O
luxurians	O
teosinte	O
,	O
to	O
the	O
atp9	B-GENE
mitochondrial	I-GENE
gene	I-GENE
and	O
its	O
3	O
'	O
flanking	O
sequence	O
,	O
and	O
also	O
to	O
a	O
region	O
3	O
'	O
to	O
the	O
orf221	B-GENE
gene	I-GENE
.	O

We	O
have	O
measured	O
the	O
kinetics	O
of	O
the	O
recovery	O
of	O
mRNA	O
synthesis	O
in	O
the	O
inducible	O
GAL10	B-GENE
and	O
RNR3	B-GENE
genes	I-GENE
after	O
exposure	O
of	O
yeast	O
cells	O
to	O
ultraviolet	O
(	O
UV	O
)	O
radiation	O
.	O

Cloning	O
of	O
a	O
human	B-GENE
phosphoinositide	I-GENE
3	I-GENE
-	I-GENE
kinase	I-GENE
with	O
a	O
C2	B-GENE
domain	O
that	O
displays	O
reduced	O
sensitivity	O
to	O
the	O
inhibitor	O
wortmannin	O
.	O

Ea	O
value	O
was	O
calculated	O
as	O
the	O
ratio	O
of	O
the	O
steady	O
-	O
state	O
end	O
-	O
systolic	O
aortic	O
pressure	O
(	O
ESAP	O
)	O
to	O
stroke	O
volume	O
(	O
thermodilution	O
)	O
.	O

Functional	O
analysis	O
of	O
promoter	O
activity	O
of	O
the	O
5	O
'	O
-	O
flanking	O
region	O
of	O
cyclin	B-GENE
D2	I-GENE
suggested	O
that	O
the	O
region	O
-	O
1	O
,	O
100	O
to	O
-	O
805	O
including	O
C	B-GENE
/	I-GENE
EBP	I-GENE
,	O
PEA3	B-GENE
,	O
AP2	B-GENE
,	O
NF	B-GENE
-	I-GENE
Y	I-GENE
,	O
c	B-GENE
-	I-GENE
Myc	I-GENE
,	O
and	O
Sp1	B-GENE
may	O
have	O
a	O
major	O
positive	O
regulatory	O
activity	O
for	O
expression	O
of	O
cyclin	B-GENE
D2	I-GENE
.	O

Effect	O
of	O
alcohol	O
on	O
minimal	O
effective	O
nCPAP	O
pressure	O

In	O
contrast	O
,	O
resensitization	O
of	O
a	O
sequestration	O
-	O
impaired	O
beta2AR	B-GENE
mutant	O
(	O
Y326A	O
)	O
was	O
reestablished	O
following	O
the	O
overexpression	O
of	O
either	O
GRK2	B-GENE
or	O
beta	B-GENE
-	I-GENE
arrestin	I-GENE
1	I-GENE
.	O

The	O
medium	O
chains	O
of	O
these	O
complexes	O
,	O
mu1	B-GENE
and	O
mu2	B-GENE
,	O
have	O
been	O
implicated	O
in	O
two	O
types	O
of	O
interaction	O
:	O
assembly	O
with	O
the	O
beta1	B-GENE
and	I-GENE
beta2	I-GENE
chains	I-GENE
of	O
the	O
corresponding	O
complexes	O
and	O
recognition	O
of	O
tyrosine	O
-	O
based	O
sorting	O
signals	O
.	O

Osmotic	O
shock	O
stimulates	O
GLUT4	B-GENE
translocation	O
in	O
3T3L1	O
adipocytes	O
by	O
a	O
novel	O
tyrosine	B-GENE
kinase	I-GENE
pathway	O
.	O

We	O
also	O
identified	O
Sp1	B-GENE
,	O
Sp3	B-GENE
,	O
and	O
NGFI	B-GENE
-	I-GENE
A	I-GENE
/	O
Egr	B-GENE
-	I-GENE
1	I-GENE
as	O
the	O
primary	O
nuclear	O
transcription	O
factors	O
binding	O
to	O
TRE1	B-GENE
which	O
mediate	O
Tax	B-GENE
responsiveness	O
.	O

Interestingly	O
,	O
segment	O
nesting	O
differentially	O
increases	O
the	O
copy	O
number	O
of	O
genes	O
encoded	O
by	O
segment	O
W	O
,	O
suggesting	O
that	O
the	O
unusual	O
genomic	O
organization	O
of	O
PDVs	O
may	O
be	O
directly	O
linked	O
to	O
the	O
unique	O
functions	O
of	O
this	O
virus	O
in	O
its	O
obligate	O
mutualistic	O
association	O
with	O
parasitic	O
wasps	O
.	O

Processivity	O
of	O
DNA	O
synthesis	O
by	O
the	O
mutant	O
holoenzyme	O
containing	O
pcna	B-GENE
-	I-GENE
79	I-GENE
was	O
unaffected	O
on	O
poly	O
(	O
dA	O
)	O
x	O
oligo	O
(	O
dT	O
)	O
but	O
was	O
dramatically	O
reduced	O
on	O
a	O
natural	O
template	O
with	O
secondary	O
structure	O
.	O

Alanine	O
substitution	O
mutations	O
in	O
the	O
Zta	B-GENE
activation	I-GENE
domain	I-GENE
which	O
eliminate	O
the	O
ability	O
of	O
Zta	B-GENE
to	O
stimulate	O
the	O
D	B-GENE
-	I-GENE
A	I-GENE
complex	I-GENE
were	O
examined	O
.	O

The	O
Scm	B-GENE
and	O
ph	B-GENE
proteins	O
share	O
a	O
homology	O
domain	O
with	O
38	O
%	O
identity	O
over	O
a	O
length	O
of	O
65	O
amino	O
acids	O
,	O
termed	O
the	O
SPM	O
domain	O
,	O
that	O
is	O
located	O
at	O
their	O
respective	O
C	O
termini	O
.	O

It	O
has	O
been	O
previously	O
shown	O
that	O
genes	O
transcribed	O
by	O
RNA	B-GENE
polymerase	I-GENE
II	I-GENE
(	O
RNAP	B-GENE
II	I-GENE
)	O
are	O
subject	O
to	O
position	O
effect	O
variegation	O
when	O
located	O
near	O
yeast	O
telomeres	O
.	O

Likewise	O
,	O
rad6	B-GENE
-	I-GENE
delta	I-GENE
reduces	O
silencing	O
of	O
the	O
telomere	B-GENE
-	I-GENE
located	I-GENE
RNAP	I-GENE
II	I-GENE
-	I-GENE
transcribed	I-GENE
genes	I-GENE
URA3	I-GENE
and	O
ADE2	B-GENE
.	O

The	O
amplitude	O
of	O
detrusor	O
contractions	O
at	O
6	O
,	O
12	O
,	O
and	O
24	O
hours	O
showed	O
no	O
significant	O
difference	O
from	O
that	O
in	O
the	O
controls	O
.	O

In	O
the	O
predicted	O
transmembrane	O
domain	O
,	O
Casr	B-GENE
-	I-GENE
rs2	I-GENE
and	O
Casr	B-GENE
-	I-GENE
rs3	I-GENE
are	O
95	O
%	O
identical	O
to	O
Casr	B-GENE
-	I-GENE
rs1	I-GENE
.	O

PET	O
activation	O
studies	O
are	O
performed	O
widely	O
to	O
study	O
human	O
brain	O
function	O
.	O

F	B-GENE
-	I-GENE
box	I-GENE
proteins	I-GENE
are	O
receptors	O
that	O
recruit	O
phosphorylated	O
substrates	O
to	O
the	O
SCF	B-GENE
ubiquitin	B-GENE
-	O
ligase	B-GENE
complex	O
.	O

In	O
the	O
context	O
of	O
liver	O
allograft	O
shortage	O
,	O
our	O
results	O
suggest	O
that	O
an	O
ELT	O
should	O
not	O
be	O
performed	O
in	O
patients	O
with	O
cardiac	O
failure	O
,	O
more	O
than	O
two	O
OSF	O
,	O
or	O
an	O
APACHE	O
II	O
score	O
higher	O
than	O
30	O
.	O

The	O
SH3	B-GENE
domains	I-GENE
of	O
Grb2	B-GENE
bound	O
in	O
vitro	O
to	O
specific	O
proline	O
-	O
rich	O
motifs	O
in	O
the	O
HPK1	B-GENE
tail	O
and	O
functioned	O
synergistically	O
to	O
direct	O
the	O
stable	O
binding	O
of	O
Grb2	B-GENE
to	O
HPK1	B-GENE
in	O
transfected	O
Cos1	O
cells	O
.	O

By	O
far	O
-	O
Western	O
analysis	O
and	O
coimmunoprecipitation	O
studies	O
,	O
we	O
demonstrate	O
that	O
ZNF74	B-GENE
interacts	O
,	O
via	O
its	O
zinc	O
finger	O
domain	O
,	O
with	O
the	O
hyperphosphorylated	O
largest	O
subunit	O
of	O
RNA	B-GENE
polymerase	I-GENE
II	I-GENE
(	O
pol	B-GENE
IIo	I-GENE
)	O
but	O
not	O
with	O
the	O
hypophosphorylated	O
form	O
.	O

Thus	O
,	O
ZNF74	B-GENE
sublocalization	O
in	O
nuclear	O
domains	O
enriched	O
in	O
pre	O
-	O
mRNA	O
maturating	O
factors	O
,	O
its	O
RNA	O
binding	O
activity	O
,	O
and	O
its	O
direct	O
phosphodependent	O
interaction	O
with	O
the	O
pol	B-GENE
IIo	I-GENE
,	O
a	O
form	O
of	O
the	O
RNA	B-GENE
polymerase	I-GENE
functionally	O
associated	O
with	O
pre	O
-	O
mRNA	O
processing	O
,	O
suggest	O
a	O
role	O
for	O
this	O
member	O
of	O
the	O
KRAB	B-GENE
multifinger	I-GENE
protein	I-GENE
family	I-GENE
in	O
RNA	O
processing	O
.	O

Ki	B-GENE
-	I-GENE
ras4BVal	I-GENE
-	I-GENE
12	I-GENE
transfectant	O
cells	O
expressed	O
2	O
-	O
fold	O
elevated	O
protein	O
levels	O
of	O
the	O
lysosomal	B-GENE
cysteine	I-GENE
protease	I-GENE
cathepsin	B-GENE
B	I-GENE
but	O
did	O
not	O
up	O
-	O
regulate	O
cathepsin	B-GENE
B	I-GENE
mRNA	I-GENE
expression	O
.	O

The	O
cellular	O
rate	O
of	O
anticoagulant	B-GENE
heparan	I-GENE
sulfate	I-GENE
proteoglycan	I-GENE
(	O
HSPGact	B-GENE
)	O
generation	O
is	O
determined	O
by	O
the	O
level	O
of	O
a	O
kinetically	O
limiting	O
microsomal	O
activity	O
,	O
HSact	O
conversion	O
activity	O
,	O
which	O
is	O
predominantly	O
composed	O
of	O
the	O
long	O
sought	O
heparan	B-GENE
sulfate	I-GENE
D	I-GENE
-	I-GENE
glucosaminyl	I-GENE
3	I-GENE
-	I-GENE
O	I-GENE
-	I-GENE
sulfotransferase	I-GENE
(	O
3	B-GENE
-	I-GENE
OST	I-GENE
)	O
(	O
Shworak	O
,	O
N	O
.	O

Interestingly	O
,	O
EGF	B-GENE
,	O
but	O
not	O
insulin	B-GENE
,	O
stimulated	O
tyrosine	O
phosphorylation	O
of	O
c	B-GENE
-	I-GENE
cbl	I-GENE
and	O
its	O
association	O
with	O
Crk	B-GENE
-	I-GENE
II	I-GENE
.	O

An	O
end	O
to	O
the	O
lottery	O
.	O

We	O
previously	O
showed	O
that	O
the	O
N	O
-	O
terminal	O
portion	O
common	O
to	O
various	O
chimeric	B-GENE
MLL	I-GENE
products	I-GENE
,	O
as	O
well	O
as	O
to	O
MLL	B-GENE
-	I-GENE
LTG9	I-GENE
and	O
MLL	B-GENE
-	I-GENE
LTG19	I-GENE
,	O
localizes	O
in	O
the	O
nuclei	O
,	O
and	O
therefore	O
suggested	O
that	O
it	O
might	O
play	O
an	O
important	O
role	O
in	O
leukemogenesis	O
.	O

Our	O
results	O
suggest	O
that	O
the	O
pattern	O
of	O
blood	O
supply	O
is	O
relevant	O
to	O
the	O
structural	O
organisation	O
of	O
mature	O
lamellar	O
bone	O
around	O
the	O
implant	O
.	O

Induction	O
of	O
AtP5CS1	B-GENE
mRNA	I-GENE
accumulation	O
in	O
salt	O
-	O
treated	O
seedlings	O
involves	O
an	O
immediate	O
early	O
transcriptional	O
response	O
regulated	O
by	O
ABA	O
signalling	O
that	O
is	O
not	O
inhibited	O
by	O
cycloheximide	O
,	O
but	O
abolished	O
by	O
the	O
deficiency	O
of	O
ABA	O
biosynthesis	O
in	O
the	O
aba1	B-GENE
Arabidopsis	I-GENE
mutant	I-GENE
.	O

It	O
thus	O
appears	O
that	O
MAPK	B-GENE
functions	O
in	O
meiotic	O
maturation	O
by	O
preventing	O
unfertilized	O
eggs	O
from	O
proceeding	O
into	O
parthenogenetic	O
development	O
.	O

A	O
positive	O
correlation	O
between	O
serum	B-GENE
myoglobin	I-GENE
and	O
CA	B-GENE
III	I-GENE
concentrations	O
(	O
rs	O
=	O
0	O
.	O
933	O
,	O
P	O
<	O
0	O
.	O
001	O
)	O
was	O
observed	O
in	O
hemodialyzed	O
patients	O
with	O
chronic	O
renal	O
failure	O
.	O

Furthermore	O
,	O
the	O
over	O
-	O
replication	O
phenotype	O
produced	O
by	O
this	O
mutant	B-GENE
p65cdc18	I-GENE
is	O
resistant	O
to	O
increased	O
mitotic	O
cyclin	B-GENE
/	O
CDK	B-GENE
activity	O
,	O
a	O
known	O
inhibitor	O
of	O
over	O
-	O
replication	O
.	O

Rip1p	B-GENE
is	O
inessential	O
,	O
associated	O
with	O
nuclear	O
pore	O
complexes	O
,	O
and	O
structurally	O
related	O
to	O
the	O
FG	B-GENE
-	I-GENE
nucleoporin	I-GENE
family	I-GENE
of	O
pore	O
proteins	O
.	O

The	O
CNXA	O
domain	O
is	O
similar	O
at	O
the	O
amino	O
acid	O
level	O
to	O
the	O
Escherichia	B-GENE
coli	I-GENE
moaA	I-GENE
gene	I-GENE
product	I-GENE
,	O
while	O
CNXC	O
is	O
similar	O
to	O
the	O
E	B-GENE
.	I-GENE
coli	I-GENE
moaC	I-GENE
product	I-GENE
,	O
with	O
both	O
E	O
.	O
coli	O
products	O
encoded	O
by	O
different	O
cistrons	O
.	O

Deletions	O
in	O
each	O
of	O
these	O
regions	O
abolish	O
membrane	O
localization	O
of	O
Tiam1	B-GENE
and	O
membrane	O
ruffling	O
,	O
suggesting	O
that	O
they	O
function	O
cooperatively	O
.	O

However	O
,	O
besides	O
the	O
kinase	O
catalytic	O
domain	O
and	O
double	O
leucine	O
/	O
isoleucine	O
zippers	O
,	O
there	O
was	O
no	O
significant	O
homology	O
with	O
known	O
proteins	O
.	O

RNA	B-GENE
polymerase	I-GENE
II	I-GENE
inhibition	O
increased	O
the	O
binding	O
of	O
ARE	O
(	O
AUBP	O
activity	O
)	O
and	O
poly	O
(	O
U	O
)	O
-	O
Sepharose	O
by	O
cytoplasmic	B-GENE
hnRNP	I-GENE
A1	I-GENE
,	O
while	O
nuclear	B-GENE
hnRNP	I-GENE
A1	I-GENE
binding	O
was	O
unaffected	O
.	O

Modulation	O
of	O
AUUUA	O
response	O
element	O
binding	O
by	O
heterogeneous	B-GENE
nuclear	I-GENE
ribonucleoprotein	I-GENE
A1	I-GENE
in	O
human	O
T	O
lymphocytes	O
.	O

Histological	O
slides	O
of	O
one	O
biopsy	O
of	O
each	O
patient	O
(	O
formalin	O
-	O
fixed	O
and	O
paraffin	O
-	O
embedded	O
)	O
were	O
stained	O
with	O
a	O
Modified	O
Giemsa	O
(	O
MG	O
)	O
,	O
the	O
Warthin	O
-	O
Starry	O
(	O
WS	O
)	O
,	O
and	O
an	O
immunohistochemical	O
method	O
(	O
IMM	O
)	O
using	O
purified	O
polyclonal	O
H	O
.	O
pylori	O
antiserum	O
(	O
DAKO	O
B471	O
)	O
.	O

Their	O
biosynthesis	O
proceeds	O
via	O
linear	O
precursors	O
that	O
become	O
branched	O
by	O
beta1	B-GENE
,	I-GENE
6	I-GENE
-	I-GENE
GlcNAc	I-GENE
transferases	I-GENE
(	O
IGnT6	O
,	O
GlcNAc	O
to	O
Gal	O
)	O
.	O

These	O
findings	O
indicate	O
that	O
the	O
t	O
(	O
4	O
;	O
14	O
)	O
(	O
p16	O
.	O
3	O
;	O
q32	O
)	O
represents	O
a	O
novel	O
,	O
recurrent	O
chromosomal	O
translocation	O
in	O
MM	O
,	O
and	O
suggest	O
that	O
the	O
FGFR3	B-GENE
gene	I-GENE
may	O
be	O
the	O
target	O
of	O
this	O
abnormality	O
and	O
thus	O
contribute	O
to	O
tumorigenesis	O
in	O
MM	O
.	O

In	O
addition	O
,	O
mutation	O
of	O
the	O
Sp1	B-GENE
site	I-GENE
also	O
significantly	O
reduced	O
promoter	O
activity	O
.	O

Amino	O
acid	O
residues	O
of	O
beta	O
1	O
'	O
,	O
alpha	O
A	O
'	O
,	O
alpha	O
B	O
'	O
,	O
and	O
the	O
loop	O
containing	O
His539	O
of	O
the	O
RNase	B-GENE
H	I-GENE
domain	I-GENE
interact	O
with	O
the	O
primer	O
strand	O
of	O
the	O
dsDNA	O
.	O

Moreover	O
,	O
in	O
one	O
patient	O
with	O
a	O
sarcoma	O
who	O
underwent	O
a	O
leg	O
-	O
sparing	O
procedure	O
,	O
no	O
sciatic	O
nerve	O
enlargement	O
was	O
seen	O
postoperatively	O
.	O

The	O
full	O
length	O
cDNA	O
sequence	O
of	O
a	O
Type	B-GENE
I	I-GENE
transforming	I-GENE
growth	I-GENE
factor	I-GENE
-	I-GENE
beta	I-GENE
(	I-GENE
TGF	I-GENE
-	I-GENE
beta	I-GENE
)	I-GENE
receptor	I-GENE
has	O
been	O
isolated	O
from	O
the	O
filarial	O
parasitic	O
nematode	O
Brugia	O
pahangi	O
.	O

This	O
sequence	O
possessed	O
homology	O
with	O
a	O
methylation	O
-	O
sensitive	O
promoter	O
element	O
,	O
Enh2	O
,	O
present	O
in	O
the	O
LTR	O
of	O
mouse	O
intractisternal	O
A	O
-	O
particles	O
.	O

Codon	O
optimization	O
for	O
high	O
-	O
level	O
expression	O
of	O
human	B-GENE
erythropoietin	I-GENE
(	O
EPO	B-GENE
)	O
in	O
mammalian	O
cells	O
.	O

Parodoxical	O
rise	O
in	O
urinary	B-GENE
albumin	I-GENE
levels	O
after	O
treatment	O
of	O
essential	O
hypertension	O
.	O

20	O
%	O
of	O
total	O
HSL	B-GENE
transcripts	I-GENE
in	O
human	O
subcutaneous	O
adipocytes	O
.	O

Taken	O
together	O
,	O
our	O
data	O
suggest	O
that	O
Rat7p	B-GENE
/	O
Nup159p	B-GENE
is	O
anchored	O
within	O
the	O
NPC	O
through	O
its	O
coiled	O
-	O
coil	O
region	O
and	O
adjacent	O
sequences	O
.	O

In	O
a	O
group	O
of	O
13	O
patients	O
with	O
obliterative	O
arteriopathies	O
of	O
the	O
lower	O
limbs	O
the	O
plasma	O
levels	O
of	O
thrombomodulin	B-GENE
(	O
TM	B-GENE
)	O
,	O
betathromboglobulin	B-GENE
(	O
beta	B-GENE
-	I-GENE
TG	I-GENE
)	O
,	O
D	O
-	O
dimer	O
(	O
DD	O
)	O
and	O
plasminogen	B-GENE
activator	I-GENE
-	I-GENE
inhibitor	I-GENE
(	O
pAI	B-GENE
-	I-GENE
1	I-GENE
)	O
were	O
measured	O
,	O
and	O
compared	O
to	O
the	O
values	O
obtained	O
from	O
10	O
healthy	O
volunteers	O
.	O

These	O
residues	O
,	O
Ile244	O
at	O
the	O
extracellular	O
end	O
of	O
transmembrane	O
helix	O
3	O
,	O
and	O
Tyr318	O
at	O
the	O
COOH	O
-	O
terminal	O
portion	O
of	O
extracellular	O
loop	O
2	O
,	O
are	O
replaced	O
by	O
Leu	O
and	O
Ile	O
in	O
the	O
PTH	B-GENE
-	I-GENE
1	I-GENE
receptor	I-GENE
,	O
respectively	O
.	O

We	O
have	O
now	O
shown	O
that	O
in	O
vivo	O
phosphorylation	O
of	O
14	B-GENE
-	I-GENE
3	I-GENE
-	I-GENE
3	I-GENE
zeta	I-GENE
at	O
the	O
CKIalpha	B-GENE
site	I-GENE
(	I-GENE
Thr	I-GENE
-	I-GENE
233	I-GENE
)	I-GENE
negatively	O
regulates	O
its	O
binding	O
to	O
c	B-GENE
-	I-GENE
Raf	I-GENE
,	O
and	O
may	O
be	O
important	O
in	O
Raf	B-GENE
-	O
mediated	O
signal	O
transduction	O
.	O

Mouse	B-GENE
mast	I-GENE
cell	I-GENE
protease	I-GENE
9	I-GENE
,	O
a	O
novel	O
member	O
of	O
the	O
chromosome	O
14	O
family	O
of	O
serine	B-GENE
proteases	I-GENE
that	O
is	O
selectively	O
expressed	O
in	O
uterine	O
mast	O
cells	O
.	O

A	O
DNase	B-GENE
I	I-GENE
-	I-GENE
hypersensitive	I-GENE
site	I-GENE
has	O
also	O
been	O
mapped	O
in	O
the	O
258	O
-	O
base	O
pair	O
enhancer	O
region	O
.	O

Together	O
,	O
our	O
results	O
show	O
that	O
tinman	B-GENE
is	O
controlled	O
by	O
an	O
array	O
of	O
discrete	O
enhancer	O
elements	O
that	O
are	O
activated	O
successively	O
by	O
differential	O
genetic	O
inputs	O
,	O
as	O
well	O
as	O
by	O
closely	O
linked	O
activator	O
and	O
repressor	O
binding	O
sites	O
within	O
an	O
early	O
-	O
acting	O
enhancer	O
,	O
which	O
restrict	O
twist	B-GENE
activity	O
to	O
specific	O
areas	O
within	O
the	O
twist	B-GENE
expression	I-GENE
domain	I-GENE
.	O

The	O
Fis	B-GENE
protein	I-GENE
regulates	O
site	O
-	O
specific	O
DNA	O
inversion	O
catalyzed	O
by	O
a	O
family	O
of	O
DNA	B-GENE
invertases	I-GENE
when	O
bound	O
to	O
a	O
cis	O
-	O
acting	O
recombinational	O
enhancer	O
.	O

The	O
cell	O
cycle	O
-	O
regulated	O
transcription	O
factor	O
E2F	B-GENE
is	O
also	O
known	O
to	O
bend	O
DNA	O
upon	O
binding	O
.	O

Our	O
study	O
reveals	O
that	O
the	O
modular	O
structure	O
of	O
the	O
FSH	B-GENE
receptor	I-GENE
gene	O
generates	O
motifs	O
that	O
allows	O
coupling	O
to	O
different	O
effectors	O
.	O

Transcriptional	O
regulation	O
of	O
SUP35	B-GENE
and	O
SUP45	B-GENE
in	I-GENE
Saccharomyces	I-GENE
cerevisiae	I-GENE
.	O

These	O
studies	O
serve	O
as	O
the	O
basis	O
for	O
the	O
further	O
characterization	O
of	O
the	O
regulatory	O
mechanism	O
of	O
aromatase	B-GENE
expression	O
in	O
human	O
breast	O
cancer	O
and	O
ASCs	O
.	O

Xenopus	B-GENE
Ran	I-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
1	I-GENE
:	O
molecular	O
interactions	O
and	O
effects	O
on	O
nuclear	O
assembly	O
in	O
Xenopus	O
egg	O
extracts	O
.	O

She	O
improved	O
with	O
a	O
combination	O
of	O
benzodiazepines	O
and	O
the	O
acetylcholinesterase	B-GENE
inhibitor	O
physostigmine	O
.	O

METHODS	O
:	O
Total	O
muscle	O
paralysis	O
was	O
induced	O
under	O
general	O
anesthesia	O
in	O
a	O
group	O
of	O
obese	O
persons	O
(	O
n	O
=	O
9	O
;	O
body	O
mass	O
index	O
,	O
32	O
+	O
/	O
-	O
3	O
kg	O
[	O
-	O
2	O
]	O
)	O
and	O
in	O
a	O
group	O
of	O
nonobese	O
persons	O
(	O
n	O
=	O
9	O
;	O
body	O
mas	O
index	O
,	O
21	O
+	O
/	O
-	O
2	O
kg	O
[	O
-	O
2	O
]	O
)	O
.	O

PKA	B-GENE
phosphorylated	O
WT1	B-GENE
at	O
Ser	O
-	O
365	O
and	O
Ser	O
-	O
393	O
in	O
vitro	O
,	O
as	O
well	O
as	O
at	O
additional	O
sites	O
,	O
and	O
this	O
phosphorylation	O
abolished	O
the	O
DNA	O
-	O
binding	O
activity	O
of	O
WT1	B-GENE
in	O
vitro	O
.	O

Our	O
findings	O
provide	O
the	O
first	O
evidence	O
that	O
the	O
function	O
of	O
WT1	B-GENE
can	O
be	O
modulated	O
by	O
its	O
phosphorylation	O
in	O
vivo	O
.	O

A	O
second	O
aim	O
was	O
to	O
determine	O
whether	O
the	O
decrease	O
in	O
muscle	O
-	O
tendon	O
unit	O
rest	O
length	O
produced	O
by	O
prolonged	O
immobilisation	O
in	O
a	O
shortened	O
position	O
is	O
mediated	O
primarily	O
by	O
adaptations	O
of	O
the	O
muscle	O
or	O
tendon	O
.	O

The	O
presence	O
of	O
an	O
additional	O
sequence	O
of	O
nucleotides	O
145	O
-	O
165	O
from	O
the	O
3	O
'	O
end	O
of	O
RNA3	B-GENE
enhanced	O
template	O
recognition	O
by	O
RdRp	B-GENE
in	O
vitro	O
and	O
accumulation	O
of	O
RNA3	B-GENE
in	O
vivo	O
to	O
wild	O
-	O
type	O
levels	O
.	O

We	O
argue	O
that	O
the	O
primary	O
role	O
of	O
hh	B-GENE
in	O
controlling	O
polarity	O
is	O
to	O
cause	O
anterior	O
compartment	O
cells	O
to	O
reverse	O
their	O
interpretation	O
of	O
an	O
underlying	O
symmetric	O
polarization	O
.	O

The	O
results	O
of	O
this	O
study	O
suggest	O
that	O
NF	B-GENE
-	I-GENE
kappaB	I-GENE
activity	O
may	O
be	O
regulated	O
by	O
its	O
interaction	O
with	O
the	O
cell	O
cycle	O
regulatory	O
protein	O
,	O
E2F	B-GENE
-	I-GENE
1	I-GENE
.	O

The	O
lysozyme	B-GENE
FEF	B-GENE
site	O
is	O
immediately	O
5	O
'	O
to	O
a	O
PU	B-GENE
.	O

Osteocalcin	B-GENE
(	O
OC	B-GENE
)	O
is	O
a	O
matrix	B-GENE
calcium	I-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
expressed	O
in	O
osteoblasts	O
and	O
odontoblasts	O
undergoing	O
mineralization	O
.	O

In	O
this	O
study	O
,	O
we	O
examine	O
the	O
effects	O
of	O
Msx2	B-GENE
expression	O
on	O
OC	B-GENE
promoter	I-GENE
activation	O
(	O
luciferase	B-GENE
reporter	I-GENE
)	O
by	O
FGF2	B-GENE
/	O
FSK	B-GENE
and	O
calcitriol	O
in	O
MC3T3	O
-	O
E1	O
osteoblasts	O
.	O

Thus	O
,	O
unlike	O
other	O
proteins	O
reported	O
to	O
inhibit	O
SRF	B-GENE
activity	O
,	O
the	O
repressor	O
activity	O
associated	O
with	O
the	O
GC	O
-	O
rich	O
element	O
does	O
not	O
appear	O
to	O
function	O
through	O
direct	O
inhibition	O
of	O
SRF	B-GENE
binding	O
.	O

However	O
,	O
one	O
CAK	B-GENE
-	O
phosphorylated	O
phosphopeptide	O
comigrates	O
with	O
a	O
Cdc2	B-GENE
-	O
phosphorylated	O
phosphopeptide	O
previously	O
shown	O
to	O
be	O
mitosis	O
-	O
specific	O
,	O
suggesting	O
that	O
,	O
in	O
vitro	O
,	O
CAK	B-GENE
is	O
able	O
to	O
phosphorylate	O
at	O
least	O
one	O
site	O
that	O
is	O
also	O
phosphorylated	O
in	O
vivo	O
.	O

The	O
pen	O
can	O
heal	O
.	O

The	O
mHIF	B-GENE
-	I-GENE
1	I-GENE
alpha	I-GENE
structural	I-GENE
gene	I-GENE
is	O
composed	O
of	O
15	O
exons	O
.	O

However	O
,	O
when	O
a	O
second	O
,	O
upstream	B-GENE
IRE	I-GENE
-	I-GENE
like	I-GENE
sequence	I-GENE
was	O
evaluated	O
by	O
EMSA	O
,	O
a	O
DNA	O
binding	O
pattern	O
distinct	O
from	O
that	O
seen	O
following	O
exposure	O
to	O
IFN	B-GENE
-	I-GENE
gamma	I-GENE
alone	O
was	O
observed	O
after	O
prolonged	O
stimulation	O
with	O
both	O
IFN	B-GENE
-	I-GENE
alpha	I-GENE
and	O
IFN	B-GENE
-	I-GENE
gamma	I-GENE
.	O

In	O
Arabidopsis	O
,	O
the	O
induction	O
of	O
a	O
dehydration	O
-	O
responsive	O
gene	O
,	O
rd22	B-GENE
,	O
is	O
mediated	O
by	O
abscisic	O
acid	O
(	O
ABA	O
)	O
and	O
requires	O
protein	O
biosynthesis	O
for	O
ABA	O
-	O
dependent	O
gene	O
expression	O
.	O

A	O
cDNA	O
encoding	O
a	O
MYC	B-GENE
-	I-GENE
related	I-GENE
DNA	I-GENE
binding	I-GENE
protein	I-GENE
was	O
isolated	O
by	O
DNA	O
-	O
ligand	O
binding	O
screening	O
,	O
using	O
the	O
67	O
-	O
bp	O
region	O
as	O
a	O
probe	O
,	O
and	O
designated	O
rd22BP1	B-GENE
.	O

Human	B-GENE
PDK1	I-GENE
is	O
homologous	O
to	O
the	O
Drosophila	B-GENE
protein	I-GENE
kinase	I-GENE
DSTPK61	I-GENE
,	O
which	O
has	O
been	O
implicated	O
in	O
the	O
regulation	O
of	O
sex	O
differentiation	O
,	O
oogenesis	O
and	O
spermatogenesis	O
.	O

Thus	O
,	O
the	O
synergistic	O
effects	O
of	O
HNF	B-GENE
-	I-GENE
1beta	I-GENE
and	O
the	O
GR	B-GENE
on	O
dexamethasone	O
-	O
stimulated	O
promoter	O
activity	O
require	O
that	O
they	O
are	O
bound	O
to	O
the	O
HNF	B-GENE
-	I-GENE
1	I-GENE
site	I-GENE
and	O
the	O
GRE	O
,	O
respectively	O
,	O
and	O
may	O
involve	O
protein	O
-	O
protein	O
interactions	O
between	O
the	O
transcription	O
factors	O
,	O
or	O
between	O
them	O
and	O
the	O
basal	O
transcription	O
machinery	O
or	O
a	O
steroid	B-GENE
receptor	I-GENE
coactivator	I-GENE
.	O

Mutational	O
analysis	O
shows	O
that	O
both	O
an	O
AP	B-GENE
-	I-GENE
1	I-GENE
like	I-GENE
sequence	I-GENE
(	O
-	O
294	O
/	O
-	O
285	O
,	O
TGAATCATCA	O
)	O
and	O
an	O
A	O
/	O
T	O
-	O
rich	O
myocyte	B-GENE
enhancer	I-GENE
factor	I-GENE
(	I-GENE
MEF	I-GENE
)	I-GENE
-	I-GENE
2	I-GENE
like	I-GENE
sequence	I-GENE
(	O
-	O
310	O
/	O
-	O
298	O
,	O
TTAAAAATAAAAA	O
)	O
in	O
the	O
33	O
-	O
bp	O
region	O
are	O
necessary	O
for	O
the	O
OP	B-GENE
-	I-GENE
1	I-GENE
effect	O
.	O

Unlike	O
most	O
other	O
members	O
of	O
the	O
Bcl	B-GENE
-	I-GENE
2	I-GENE
family	I-GENE
,	O
BAD	B-GENE
(	O
Bcl	B-GENE
-	I-GENE
xL	I-GENE
/	I-GENE
Bcl	I-GENE
-	I-GENE
2	I-GENE
associated	I-GENE
death	I-GENE
promoter	I-GENE
)	O
,	O
a	O
death	B-GENE
enhancer	I-GENE
,	O
has	O
no	O
C	O
-	O
terminal	O
transmembrane	O
domain	O
for	O
targeting	O
to	O
the	O
outer	O
mitochondrial	O
membrane	O
and	O
nuclear	O
envelope	O
.	O

An	O
open	O
reading	O
frame	O
of	O
2862	O
bp	O
encoding	O
a	O
954	O
amino	O
acid	O
protein	O
was	O
identified	O
.	O

One	O
of	O
these	O
,	O
an	O
AACA	O
motif	O
,	O
has	O
been	O
shown	O
to	O
be	O
a	O
negative	O
regulator	O
in	O
non	O
-	O
seed	O
tissues	O
and	O
has	O
a	O
similarity	O
to	O
the	O
barley	O
gibberellin	O
responsive	O
element	O
recognized	O
by	O
MYB	B-GENE
-	I-GENE
like	I-GENE
DNA	I-GENE
binding	I-GENE
proteins	I-GENE
.	O

Strain	O
CFN037	O
is	O
an	O
R	O
.	O
etli	O
mutant	O
induced	O
by	O
a	O
single	O
Tn5mob	B-GENE
insertion	O
in	O
the	O
promoter	O
region	O
of	O
the	O
thiCOGE	B-GENE
gene	I-GENE
cluster	I-GENE
.	O

Expression	O
of	O
thiamin	O
biosynthetic	O
genes	O
(	O
thiCOGE	B-GENE
)	O
and	O
production	O
of	O
symbiotic	B-GENE
terminal	I-GENE
oxidase	I-GENE
cbb3	I-GENE
in	O
Rhizobium	O
etli	O
.	O

We	O
have	O
cloned	O
and	O
sequenced	O
a	O
region	O
encoding	O
a	O
lipase	B-GENE
operon	I-GENE
and	O
a	O
putative	O
,	O
previously	O
uncharacterized	O
metalloprotease	B-GENE
of	I-GENE
Vibrio	I-GENE
cholerae	I-GENE
O1	I-GENE
.	O

Furthermore	O
,	O
the	O
amount	O
of	O
tRNA	B-GENE
(	I-GENE
3Lys	I-GENE
)	I-GENE
that	O
was	O
placed	O
onto	O
viral	O
RNA	O
in	O
mutated	O
viruses	O
was	O
significantly	O
less	O
than	O
that	O
placed	O
in	O
the	O
wild	O
-	O
type	O
virus	O
.	O

This	O
protein	O
is	O
present	O
in	O
both	O
HeLa	O
nuclear	O
extracts	O
and	O
S100	B-GENE
extracts	O
but	O
absent	O
from	O
SR	B-GENE
protein	I-GENE
preparations	O
,	O
suggesting	O
that	O
it	O
is	O
not	O
a	O
classical	O
SR	B-GENE
protein	I-GENE
.	O

Acad	O
.	O

Chimeras	O
containing	O
IE1	B-GENE
peptides	I-GENE
dramatically	O
activated	O
transcription	O
of	O
the	O
basal	O
promoter	O
only	O
when	O
lac	B-GENE
operator	I-GENE
sequences	I-GENE
were	O
present	O
.	O

The	O
results	O
of	O
replicase	B-GENE
assays	O
performed	O
with	O
mutant	B-GENE
VP2	I-GENE
containing	O
a	O
deletion	O
in	O
its	O
RNA	O
-	O
binding	O
domain	O
suggests	O
that	O
the	O
essential	O
role	O
for	O
VP2	B-GENE
in	O
replication	O
is	O
linked	O
to	O
the	O
protein	O
'	O
s	O
ability	O
to	O
bind	O
the	O
mRNA	O
template	O
for	O
minus	O
-	O
strand	O
synthesis	O
.	O

We	O
previously	O
described	O
two	O
alanine	O
cluster	O
mutations	O
,	O
R77	O
to	O
A	O
(	O
R77A	O
)	O
-	O
K79A	O
and	O
E192A	O
-	O
E194A	O
,	O
which	O
selectively	O
inactivated	O
the	O
triphosphatase	O
component	O
.	O

Transfection	O
of	O
HepG2	O
and	O
SK	O
-	O
N	O
-	O
MC	O
cells	O
with	O
constructs	O
deleted	O
of	O
additional	O
5	O
'	O
-	O
flanking	O
fragments	O
permitted	O
the	O
definition	O
of	O
a	O
minimal	O
200	O
bp	O
promoter	O
fragment	O
containing	O
the	O
pseudo	O
-	O
TATA	O
box	O
and	O
two	O
putative	O
SP1	B-GENE
-	I-GENE
binding	I-GENE
sites	I-GENE
.	O

Both	O
inserts	O
are	O
larger	O
than	O
their	O
homologues	O
in	O
eIF	B-GENE
-	I-GENE
2alpha	I-GENE
kinases	I-GENE
.	O

Three	O
monopolar	O
electrodes	O
were	O
inserted	O
into	O
the	O
left	O
and	O
right	O
lateral	O
vestibulospinal	O
tract	O
(	O
LVST	O
)	O
and	O
medial	O
vestibulospinal	O
tract	O
(	O
MVST	O
)	O
of	O
the	O
C1	O
segment	O
,	O
to	O
determine	O
the	O
pathway	O
of	O
axons	O
.	O

Epitopes	O
of	O
adhesion	O
-	O
perturbing	O
monoclonal	O
antibodies	O
map	O
within	O
a	O
predicted	O
alpha	O
-	O
helical	O
domain	O
of	O
the	O
integrin	B-GENE
beta	I-GENE
1	I-GENE
subunit	I-GENE
.	O

Polyhomeotic	B-GENE
and	I-GENE
Posterior	I-GENE
Sex	I-GENE
Combs	I-GENE
may	O
participate	O
in	O
a	O
more	O
general	O
transcriptional	O
mechanism	O
that	O
causes	O
modulated	O
gene	O
repression	O
,	O
whereas	O
the	O
inclusion	O
of	O
Polycomb	B-GENE
protein	I-GENE
in	O
the	O
complex	O
at	O
PREs	B-GENE
leads	O
to	O
stable	O
silencing	O
.	O

Furthermore	O
,	O
both	O
rhHR23	B-GENE
proteins	I-GENE
function	O
in	O
a	O
defined	O
NER	O
system	O
reconstituted	O
with	O
purified	O
proteins	O
,	O
indicating	O
direct	O
involvement	O
of	O
hHR23	B-GENE
proteins	I-GENE
in	O
the	O
DNA	O
repair	O
reaction	O
via	O
interaction	O
with	O
XPC	B-GENE
.	O

The	O
yeast	O
silent	B-GENE
information	I-GENE
regulator	I-GENE
Sir4p	I-GENE
anchors	O
and	O
partitions	O
plasmids	O
.	O

Polysome	O
analyses	O
in	O
a	O
temperature	O
-	O
sensitive	O
fal1	B-GENE
-	I-GENE
1	I-GENE
mutant	I-GENE
and	O
a	O
Fal1p	B-GENE
-	O
depleted	O
strain	O
reveal	O
a	O
decrease	O
in	O
the	O
number	O
of	O
40S	B-GENE
ribosomal	I-GENE
subunits	I-GENE
.	O

Sequence	O
analysis	O
identified	O
some	O
of	O
these	O
cDNA	O
clones	O
as	O
Dlc	B-GENE
-	I-GENE
1	I-GENE
,	O
a	O
sequence	O
encoding	O
a	O
small	O
,	O
9	B-GENE
-	I-GENE
kDa	I-GENE
human	I-GENE
homolog	I-GENE
of	I-GENE
the	I-GENE
outer	I-GENE
-	I-GENE
arm	I-GENE
dynein	I-GENE
light	I-GENE
-	I-GENE
chain	I-GENE
protein	O
.	O

Importantly	O
,	O
in	O
HeLa	O
and	O
293	O
cells	O
,	O
endogenous	O
and	O
transfected	O
I	B-GENE
kappaB	I-GENE
alpha	I-GENE
coimmunoprecipitated	O
with	O
Myc	B-GENE
-	O
tagged	O
or	O
endogenous	O
Dlc	B-GENE
-	I-GENE
1	I-GENE
.	O

Identification	O
of	O
dynein	B-GENE
heavy	I-GENE
chain	I-GENE
genes	I-GENE
expressed	O
in	O
human	O
and	O
mouse	O
testis	O
:	O
chromosomal	O
localization	O
of	O
an	O
axonemal	B-GENE
dynein	I-GENE
gene	I-GENE
.	O

The	O
proposed	O
mechanism	O
of	O
effect	O
states	O
that	O
mono	O
(	O
2	O
-	O
ethylhexyl	O
)	O
phthalate	O
(	O
MEHP	O
)	O
,	O
the	O
primary	O
hydrolysis	O
product	O
of	O
DEHP	O
,	O
mimics	O
the	O
inducing	O
prostaglandins	O
(	O
PG	O
)	O
PGD	O
(	O
2	O
)	O
,	O
9alpha	O
,	O
11betaPGF2	O
,	O
and	O
PGF2alpha	O
,	O
and	O
thromboxanes	O
in	O
the	O
lungs	O
,	O
thereby	O
increasing	O
the	O
risk	O
of	O
inducing	O
inflammation	O
in	O
the	O
airways	O
,	O
which	O
is	O
a	O
characteristic	O
of	O
asthma	O
.	O

We	O
found	O
14	O
protein	O
binding	O
sites	O
that	O
were	O
occupied	O
in	O
vivo	O
.	O

Constitutive	O
protection	O
of	O
E2F	B-GENE
recognition	I-GENE
sequences	I-GENE
in	O
the	O
human	B-GENE
thymidine	I-GENE
kinase	I-GENE
promoter	I-GENE
during	O
cell	O
cycle	O
progression	O
.	O

Comparison	O
of	O
genomic	O
sequence	O
shows	O
that	O
the	O
ph	B-GENE
locus	I-GENE
has	O
been	O
duplicated	O
,	O
and	O
that	O
it	O
contains	O
proximal	O
and	O
distal	O
transcription	O
units	O
.	O

Radiation	O
decreased	O
the	O
levels	O
of	O
T4	O
and	O
T3	O
6	O
h	O
and	O
72	O
h	O
in	O
group	O
C	O
,	O
in	O
group	O
A	O
at	O
72	O
h	O
,	O
in	O
group	O
B	O
at	O
24	O
h	O
postexposure	O
.	O

We	O
have	O
reviewed	O
the	O
experience	O
of	O
a	O
major	O
MMT	O
general	O
practice	O
with	O
hepatitis	O
C	O
virus	O
(	O
HCV	O
)	O
infection	O
from	O
1991	O
to	O
1995	O
.	O

The	O
author	O
analyzes	O
extensive	O
own	O
data	O
based	O
on	O
study	O
into	O
particular	O
features	O
of	O
cardiovascular	O
disorders	O
in	O
chronic	O
renal	O
impairement	O
with	O
making	O
use	O
of	O
modern	O
diagnostic	O
tools	O
.	O

In	O
this	O
paper	O
,	O
characterization	O
is	O
given	O
of	O
clinical	O
and	O
biochemical	O
features	O
of	O
VH	O
B	O
course	O
against	O
the	O
background	O
of	O
narcomania	O
.	O

447	O
microns	O
for	O
A	O
.	O
microcephalum	O
and	O
350	O
microns	O
for	O
A	O
.	O
wedli	O
)	O
,	O
and	O
fewer	O
testes	O
per	O
proglottis	O
(	O
44	O
-	O
73	O
vs	O
.	O

The	O
ZnF20	B-GENE
cDNA	I-GENE
hybridized	O
to	O
multiple	O
transcripts	O
in	O
a	O
thyroid	O
cancer	O
cell	O
line	O
(	O
8	O
.	O
0	O
,	O
4	O
.	O
5	O
and	O
2	O
kb	O
)	O
that	O
increased	O
after	O
cycloheximide	O
treatment	O
and	O
decayed	O
<	O
2	O
h	O
after	O
addition	O
of	O
actinomycin	O
D	O
.	O

Glutathione	B-GENE
S	I-GENE
-	I-GENE
transferase	I-GENE
(	O
GST	B-GENE
)	O
-	O
E2F	B-GENE
and	O
GST	B-GENE
-	O
DP	B-GENE
fusion	O
proteins	O
were	O
found	O
to	O
cooperate	O
in	O
binding	O
to	O
the	O
three	O
E2F	B-GENE
sites	I-GENE
in	O
the	O
DNA	B-GENE
polymerase	I-GENE
alpha	I-GENE
gene	I-GENE
promoter	I-GENE
in	O
vitro	O
.	O

Two	O
sterol	O
regulatory	O
element	O
-	O
like	O
sequences	O
mediate	O
up	O
-	O
regulation	O
of	O
caveolin	B-GENE
gene	I-GENE
transcription	O
in	O
response	O
to	O
low	B-GENE
density	I-GENE
lipoprotein	I-GENE
free	O
cholesterol	O
.	O

Furthermore	O
,	O
DNA	O
-	O
bound	O
LAZ3	B-GENE
/	O
BCL6	B-GENE
recruits	O
SMRT	B-GENE
in	O
vivo	O
,	O
and	O
both	O
overexpressed	O
proteins	O
completely	O
colocalize	O
in	O
nuclear	O
dots	O
.	O

CONCLUSIONS	O
:	O
We	O
obtained	O
normal	O
EPO	B-GENE
levels	O
for	O
mothers	O
and	O
newborns	O
for	O
our	O
area	O
,	O
similarly	O
to	O
the	O
previously	O
described	O
ones	O
.	O

Ischaemia	O
was	O
induced	O
by	O
a	O
low	O
flow	O
rate	O
of	O
0	O
.	O
8	O
mL	O
min	O
-	O
1	O
for	O
30	O
min	O
,	O
and	O
was	O
followed	O
by	O
a	O
40	O
-	O
minute	O
reperfusion	O
.	O

BACKGROUND	O
:	O
Checkpoint	O
pathways	O
prevent	O
cell	O
-	O
cycle	O
progression	O
in	O
the	O
event	O
of	O
DNA	O
lesions	O
.	O

Direct	O
proof	O
that	O
the	O
heightened	O
renal	O
cellular	O
apoptosis	O
in	O
PKD	O
is	O
not	O
occurring	O
through	O
p53	B-GENE
was	O
obtained	O
by	O
successive	O
matings	O
between	O
SBM	O
and	O
p53	B-GENE
(	O
-	O
/	O
-	O
)	O
mice	O
.	O

Accumulated	O
evidence	O
indicates	O
that	O
,	O
upon	O
stimulation	O
with	O
interferon	B-GENE
-	I-GENE
gamma	I-GENE
(	O
IFN	B-GENE
-	I-GENE
gamma	I-GENE
)	O
,	O
three	O
beta	O
-	O
type	O
subunits	O
,	O
designated	O
LMP2	B-GENE
,	O
LMP7	B-GENE
,	O
and	O
PSMB10	B-GENE
,	O
are	O
incorporated	O
into	O
the	O
20S	B-GENE
proteasome	I-GENE
by	O
displacing	O
the	O
housekeeping	O
beta	O
-	O
type	O
subunits	O
designated	O
PSMB6	B-GENE
,	O
PSMB5	B-GENE
,	O
and	O
PSMB7	B-GENE
,	O
respectively	O
.	O

The	O
major	O
RNase	B-GENE
E	I-GENE
cleavage	O
product	O
(	O
denoted	O
pSok	B-GENE
-	I-GENE
6	I-GENE
)	O
is	O
rapidly	O
degraded	O
by	O
polynucleotide	B-GENE
phosphorylase	I-GENE
(	O
PNPase	B-GENE
)	O
.	O

This	O
difference	O
may	O
result	O
from	O
the	O
lower	O
match	O
to	O
the	O
ARG	O
box	O
consensus	O
of	O
the	O
O	B-GENE
(	I-GENE
rocD	I-GENE
)	I-GENE
site	I-GENE
.	O

Ask	O
AONE	O
'	O
s	O
experts	O
.	O
.	O
.	O
about	O
productivity	O
indicators	O
.	O

All	O
pigs	O
had	O
significant	O
regional	O
LV	O
dysfunction	O
and	O
reduced	O
LV	O
ejection	O
fraction	O
(	O
41	O
+	O
/	O
-	O
11	O
%	O
)	O
.	O

The	O
progress	O
of	O
morphological	O
research	O
on	O
the	O
parabrachial	O
nucleus	O

The	O
amplitudes	O
of	O
DPOAE	O
also	O
recovered	O
to	O
a	O
greater	O
extent	O
and	O
outer	O
hair	O
cell	O
losses	O
were	O
less	O
severe	O
in	O
the	O
R	O
-	O
PIA	O
-	O
treated	O
ears	O
.	O

The	O
data	O
provide	O
evidence	O
both	O
for	O
a	O
signal	O
transduction	O
pathway	O
independent	O
of	O
JNK	B-GENE
,	O
ERK	B-GENE
,	O
and	O
p38	B-GENE
MAP	B-GENE
kinase	I-GENE
to	O
be	O
involved	O
in	O
the	O
induction	O
of	O
rhoB	B-GENE
by	O
genotoxic	O
stress	O
,	O
and	O
furthermore	O
,	O
indicate	O
autoregulation	O
of	O
rhoB	B-GENE
.	O

In	O
an	O
effort	O
to	O
separate	O
domains	O
of	O
FadR	B-GENE
required	O
for	O
DNA	O
binding	O
,	O
dimerization	O
,	O
and	O
ligand	O
binding	O
,	O
chimeric	O
protein	O
fusions	O
between	O
the	O
DNA	O
binding	O
domain	O
of	O
LexA	B-GENE
and	O
different	O
regions	O
of	O
FadR	B-GENE
were	O
constructed	O
.	O

Inhibition	O
appears	O
to	O
result	O
from	O
titration	O
of	O
general	O
transcription	O
factors	O
because	O
MDM2	B-GENE
overexpression	O
inhibits	O
c	B-GENE
-	I-GENE
fos	I-GENE
as	O
well	O
as	O
other	O
promoters	O
in	O
vivo	O
and	O
basal	O
transcription	O
in	O
vitro	O
.	O

4	O
)	O
PU	B-GENE
and	O
PD	B-GENE
lacked	O
the	O
canonical	O
TATA	O
or	O
CAAT	O
motifs	O
,	O
and	O
are	O
AT	O
-	O
rich	O
.	O

The	O
mobility	O
shift	O
of	O
both	O
of	O
these	O
proteins	O
is	O
abolished	O
by	O
treatment	O
with	O
inhibitors	O
of	O
PKC	B-GENE
or	O
mitogen	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
kinase	I-GENE
/	O
extracellular	B-GENE
signal	I-GENE
-	I-GENE
related	I-GENE
kinase	I-GENE
kinase	I-GENE
.	O

During	O
the	O
aftermath	O
of	O
excitation	O
of	O
the	O
skin	O
sympathetic	O
nerve	O
by	O
mental	O
arithmetics	O
,	O
3	O
/	O
12	O
A	O
delta	O
units	O
were	O
turned	O
to	O
the	O
active	O
state	O
with	O
decreased	O
mechanical	O
threshold	O
.	O

In	O
a	O
similar	O
fashion	O
to	O
adipose	O
stromal	O
cells	O
,	O
serum	O
potentiated	O
the	O
response	O
to	O
dexamethasone	O
but	O
had	O
no	O
effect	O
on	O
phorbol	O
ester	O
-	O
stimulated	O
activity	O
.	O

Thus	O
,	O
Hex	B-GENE
expression	O
marks	O
the	O
earliest	O
unequivocal	O
molecular	O
anteroposterior	O
asymmetry	O
in	O
the	O
mouse	O
embryo	O
and	O
indicates	O
that	O
the	O
anteroposterior	O
axis	O
of	O
the	O
embryo	O
develops	O
from	O
conversion	O
of	O
a	O
proximodistal	O
asymmetry	O
established	O
in	O
the	O
primitive	O
endoderm	O
lineage	O
.	O

CONCLUSIONS	O
:	O
While	O
INR	O
correction	O
may	O
be	O
achieved	O
by	O
all	O
the	O
above	O
methods	O
,	O
that	O
relating	O
log	O
reference	O
INR	O
to	O
log	O
local	O
prothrombin	B-GENE
time	O
by	O
linear	O
regression	O
analysis	O
is	O
the	O
simplest	O
to	O
perform	O
.	O

RESULTS	O
:	O
The	O
overall	O
FNF	O
for	O
1992	O
was	O
12	O
.	O
3	O
%	O
and	O
was	O
19	O
.	O
1	O
%	O
,	O
22	O
.	O
2	O
%	O
,	O
3	O
.	O
8	O
%	O
and	O
6	O
.	O
1	O
%	O
per	O
successive	O
quarters	O
in	O
1992	O
.	O

Western	O
blot	O
analysis	O
of	O
various	O
bovine	O
tissues	O
with	O
human	O
NMT	B-GENE
peptide	I-GENE
antibody	I-GENE
indicated	O
a	O
common	O
prominent	O
immunoreactive	O
band	O
with	O
an	O
apparent	O
molecular	O
mass	O
of	O
48	O
.	O
5	O
-	O
50	O
kDa	O
in	O
all	O
tissues	O
.	O

Transcription	O
start	O
sites	O
of	O
the	O
plastid	O
ACCase	B-GENE
genes	I-GENE
were	O
estimated	O
from	O
the	O
longest	O
cDNA	O
clones	O
obtained	O
by	O
5	O
'	O
-	O
RACE	O
(	O
rapid	O
amplification	O
of	O
cDNA	O
ends	O
)	O
.	O

AIDS	O
-	O
related	O
disseminated	O
histoplasmosis	O
in	O
San	O
Francisco	O
,	O
California	O
.	O

Thus	O
,	O
Fis	B-GENE
acts	O
as	O
an	O
accessory	O
transcriptional	O
activator	O
at	O
the	O
mar	B-GENE
promoter	I-GENE
.	O

TNF	B-GENE
-	I-GENE
alpha	I-GENE
exposure	O
markedly	O
increased	O
activity	O
of	O
several	O
RNA	O
-	O
binding	O
proteins	O
,	O
especially	O
a	O
novel	O
Mr	O
50	O
,	O
000	O
-	O
55	O
,	O
000	O
RNA	O
-	O
binding	O
protein	O
.	O

We	O
speculate	O
that	O
the	O
human	O
papillomavirus	O
late	O
mRNAs	O
,	O
produced	O
from	O
several	O
hundred	O
copies	O
of	O
the	O
virus	O
genome	O
present	O
in	O
infected	O
cells	O
,	O
compete	O
with	O
the	O
c	B-GENE
-	I-GENE
fos	I-GENE
mRNAs	I-GENE
for	O
destabilizing	O
cellular	O
factors	O
and	O
that	O
this	O
may	O
lead	O
to	O
elevated	O
Fos	B-GENE
protein	I-GENE
levels	O
in	O
human	O
papillomavirus	O
infected	O
cells	O
.	O

Two	O
closely	O
related	O
IgH	B-GENE
constant	O
region	O
genes	O
,	O
CHA	B-GENE
and	O
CHB	B-GENE
,	O
have	O
been	O
sequenced	O
completely	O
.	O

The	O
aim	O
of	O
this	O
study	O
was	O
to	O
find	O
out	O
whether	O
it	O
was	O
possible	O
to	O
detect	O
normal	O
lymph	O
nodes	O
by	O
high	O
-	O
resolution	O
mediastinal	O
US	O
.	O

To	O
study	O
the	O
role	O
of	O
heavy	O
chain	O
motifs	O
in	O
substrate	O
recognition	O
,	O
secreted	O
variants	O
of	O
recombinant	B-GENE
bovine	I-GENE
proenteropeptidase	I-GENE
were	O
constructed	O
by	O
replacing	O
the	O
transmembrane	O
domain	O
with	O
a	O
signal	O
peptide	O
.	O

CKbeta4GT	B-GENE
-	I-GENE
II	I-GENE
is	O
predicted	O
to	O
encode	O
a	O
type	B-GENE
II	I-GENE
transmembrane	I-GENE
glycoprotein	I-GENE
of	O
43	O
kDa	O
with	O
five	O
potential	O
N	O
-	O
linked	O
glycosylation	O
sites	O
.	O

PATIENTS	O
AND	O
METHODS	O
:	O
Semen	O
analyses	O
were	O
performed	O
on	O
58	O
patients	O
with	O
stages	O
I	O
-	O
III	O
HD	O
before	O
,	O
during	O
,	O
and	O
after	O
chemotherapy	O
and	O
after	O
the	O
sperm	O
count	O
recovered	O
from	O
the	O
effects	O
of	O
abdominal	O
radiotherapy	O
that	O
was	O
given	O
after	O
chemotherapy	O
.	O

Thus	O
,	O
the	O
absence	O
of	O
residual	O
infarct	O
-	O
zone	O
viability	O
discriminates	O
patients	O
who	O
develop	O
progressive	O
left	O
ventricular	O
dilation	O
after	O
reperfused	O
AMI	O
from	O
those	O
who	O
maintain	O
normal	O
left	O
ventricular	O
geometry	O
.	O

With	O
a	O
BMI	O
cutoff	O
of	O
27	O
,	O
mean	O
cardiac	O
NE	O
spillover	O
was	O
46	O
%	O
lower	O
in	O
the	O
obese	O
subjects	O
when	O
compared	O
with	O
the	O
lean	O
subjects	O
(	O
P	O
=	O
.	O
017	O
)	O
.	O

The	O
gene	O
(	O
ApxII	B-GENE
)	O
encoding	O
both	O
chloroplastic	B-GENE
ascorbate	I-GENE
peroxidase	I-GENE
isoenzymes	I-GENE
was	O
isolated	O
and	O
the	O
organization	O
of	O
the	O
gene	O
was	O
determined	O
.	O

This	O
emphasizes	O
the	O
conclusion	O
that	O
CDF	B-GENE
-	I-GENE
1	I-GENE
is	O
not	O
an	O
E2F	B-GENE
family	I-GENE
member	I-GENE
and	O
points	O
to	O
profound	O
differences	O
in	O
the	O
cell	O
cycle	O
regulation	O
of	O
CDF	B-GENE
-	I-GENE
1	I-GENE
and	O
E2F	B-GENE
.	O

The	O
proofreading	O
domain	O
of	O
Escherichia	B-GENE
coli	I-GENE
DNA	I-GENE
polymerase	I-GENE
I	I-GENE
and	O
other	O
DNA	B-GENE
and	I-GENE
/	I-GENE
or	I-GENE
RNA	I-GENE
exonuclease	I-GENE
domains	I-GENE
.	O

Responsibility	O
matters	O
-	O
-	O
this	O
is	O
a	O
scientific	O
council	O

Sequences	O
required	O
for	O
interaction	O
of	O
mu2	B-GENE
and	O
CTLA	B-GENE
-	I-GENE
4	I-GENE
were	O
localized	O
to	O
residues	O
,	O
161TTGVY	O
in	O
CTLA	B-GENE
-	I-GENE
4	I-GENE
;	O
this	O
sequence	O
is	O
N	O
-	O
terminal	O
to	O
,	O
but	O
overlaps	O
with	O
,	O
a	O
previously	O
identified	O
SH2	B-GENE
binding	I-GENE
motif	I-GENE
,	O
165YVKM	O
,	O
involved	O
in	O
CTLA	B-GENE
-	I-GENE
4	I-GENE
signaling	O
.	O

Here	O
,	O
we	O
report	O
that	O
a	O
transfected	O
Chinese	O
hamster	O
ovary	O
(	O
CHO	O
)	O
cell	O
line	O
expressing	O
a	O
murine	B-GENE
CD4	I-GENE
fragment	I-GENE
containing	O
the	O
first	O
two	O
N	O
-	O
terminal	O
domains	O
secretes	O
both	O
monomeric	O
molecules	O
and	O
disulfide	O
-	O
linked	O
multimers	O
.	O

Coexpression	O
of	O
mouse	O
PKR	B-GENE
(	I-GENE
1	I-GENE
-	I-GENE
515	I-GENE
)	I-GENE
WT	I-GENE
as	O
a	O
Gal4	B-GENE
DNA	O
-	O
binding	O
domain	O
fusion	O
with	O
either	O
the	O
catalytic	O
-	O
deficient	O
human	O
PKR	B-GENE
(	I-GENE
1	I-GENE
-	I-GENE
551	I-GENE
)	I-GENE
K296R	O
mutant	O
,	O
the	O
RNA	O
-	O
binding	O
-	O
deficient	O
human	O
PKR	B-GENE
(	I-GENE
1	I-GENE
-	I-GENE
551	I-GENE
)	I-GENE
K64E	I-GENE
/	I-GENE
K296R	I-GENE
double	O
mutant	O
,	O
or	O
wild	O
-	O
type	O
mouse	O
PKR	B-GENE
(	I-GENE
1	I-GENE
-	I-GENE
515	I-GENE
)	I-GENE
WT	I-GENE
as	O
full	O
-	O
length	O
PKR	B-GENE
-	O
Gal4	B-GENE
activation	O
domain	O
fusions	O
resulted	O
in	O
activation	O
of	O
the	O
HIS3	B-GENE
and	O
lacZ	B-GENE
reporters	O
.	O

Using	O
GST	B-GENE
-	O
PKR	B-GENE
fusion	O
chromatography	O
,	O
direct	O
physical	O
interaction	O
between	O
the	O
mouse	O
and	O
human	B-GENE
PKR	I-GENE
homologs	I-GENE
was	O
established	O
.	O

An	O
even	O
greater	O
inflammatory	O
response	O
was	O
observed	O
after	O
intratracheal	O
instillation	O
of	O
ufCB	O
,	O
but	O
not	O
after	O
CB	O
instillation	O
.	O

Interestingly	O
,	O
the	O
avirulent	O
strain	O
H37Ra	O
showed	O
weak	O
hybridization	O
with	O
these	O
two	O
probes	O
,	O
suggesting	O
that	O
these	O
genes	O
might	O
have	O
been	O
deleted	O
in	O
the	O
avirulent	O
strain	O
or	O
are	O
present	O
in	O
limited	O
copy	O
numbers	O
as	O
opposed	O
to	O
those	O
in	O
the	O
virulent	O
strain	O
H37Rv	O
.	O

These	O
defects	O
no	O
doubt	O
impair	O
the	O
folding	O
and	O
configuration	O
necessary	O
for	O
normal	O
processing	O
of	O
the	O
AVP	B-GENE
gene	I-GENE
precursor	I-GENE
.	O

Similarities	O
between	O
the	O
hIGFBP	B-GENE
-	I-GENE
1	I-GENE
and	O
phosphoenolpyruvate	B-GENE
kinase	I-GENE
(	O
PEPCK	B-GENE
)	O
promoters	O
,	O
including	O
regions	O
conferring	O
insulin	B-GENE
,	O
glucocorticoid	O
,	O
and	O
cyclic	O
adenosine	O
-	O
monophosphate	O
responses	O
,	O
are	O
consistent	O
with	O
our	O
previous	O
hypothesis	O
that	O
IGFBP	B-GENE
-	I-GENE
1	I-GENE
is	O
involved	O
in	O
regulation	O
of	O
glucose	O
metabolism	O
.	O

This	O
binary	O
repeat	O
contains	O
repetitive	O
DNA	O
elements	O
that	O
include	O
LINES	O
,	O
SINES	O
,	O
medium	O
reiteration	O
frequency	O
repeats	O
,	O
and	O
a	O
transposon	O
-	O
like	O
element	O
.	O

At	O
60	O
days	O
the	O
amount	O
of	O
gangliosides	O
was	O
on	O
average	O
lower	O
in	O
females	O
than	O
in	O
males	O
,	O
even	O
if	O
with	O
some	O
exception	O
.	O

Large	O
genomic	O
constructs	O
integrate	O
at	O
the	O
endogenous	O
locus	O
by	O
homologous	O
recombination	O
,	O
but	O
cDNA	O
-	O
derived	O
sequences	O
lacking	O
long	O
stretches	O
of	O
contiguous	O
genomic	O
DNA	O
(	O
due	O
to	O
intron	O
excision	O
)	O
typically	O
integrate	O
into	O
chromosomal	O
DNA	O
by	O
nonhomologous	O
recombination	O
.	O

During	O
the	O
conditioning	O
procedure	O
,	O
the	O
C	O
-	O
fiber	O
reflex	O
was	O
facilitated	O
(	O
wind	O
-	O
up	O
)	O
in	O
a	O
stimulus	O
-	O
dependent	O
fashion	O
in	O
intact	O
,	O
anesthetized	O
animals	O
during	O
the	O
application	O
of	O
the	O
first	O
seven	O
conditioning	O
stimuli	O
;	O
thereafter	O
,	O
the	O
magnitude	O
of	O
the	O
responses	O
reached	O
a	O
plateau	O
and	O
then	O
decreased	O
.	O

As	O
a	O
sequence	O
-	O
specific	O
DNA	O
binding	O
transcription	O
factor	O
,	O
p53	B-GENE
specifically	O
binds	O
to	O
a	O
20	O
-	O
bp	O
consensus	O
motif	O
5	O
'	O
-	O
PuPuPuC	O
(	O
A	O
/	O
T	O
)	O
(	O
T	O
/	O
A	O
)	O
GPyPyPyPuPuPuC	O
(	O
A	O
/	O
T	O
)	O
(	O
T	O
/	O
A	O
)	O
GPyPyPy	O
-	O
3	O
'	O
.	O

Upon	O
UV	O
damage	O
,	O
Crb2	B-GENE
is	O
transiently	O
modified	O
,	O
probably	O
phosphorylated	O
,	O
with	O
a	O
similar	O
timing	O
of	O
phosphorylation	O
in	O
Chk1	B-GENE
kinase	I-GENE
,	O
which	O
is	O
reported	O
to	O
restrain	O
Cdc2	B-GENE
activation	O
.	O

Moreover	O
,	O
moderate	O
overexpression	O
of	O
Chk1	B-GENE
suppresses	O
the	O
phenotypes	O
of	O
cut5	B-GENE
and	O
crb2	B-GENE
mutants	I-GENE
.	O

Tcn1p	B-GENE
/	O
Crz1p	B-GENE
,	O
a	O
calcineurin	O
-	O
dependent	O
transcription	O
factor	O
that	O
differentially	O
regulates	O
gene	O
expression	O
in	O
Saccharomyces	O
cerevisiae	O
.	O

Structure	O
and	O
localization	O
of	O
the	O
human	O
gene	O
encoding	O
SR	B-GENE
-	I-GENE
BI	I-GENE
/	O
CLA	B-GENE
-	I-GENE
1	I-GENE
.	O

We	O
introduced	O
the	O
gel	O
technique	O
as	O
a	O
routine	O
assay	O
for	O
antibody	O
detection	O
and	O
identification	O
in	O
1993	O
.	O

Stability	O
of	O
pyrimethamine	O
in	O
a	O
liquid	O
dosage	O
formulation	O
stored	O
for	O
three	O
months	O
.	O

Multiple	O
regression	O
analyses	O
revealed	O
that	O
WAIS	O
-	O
R	O
factor	O
scores	O
Verbal	O
Comprehension	O
and	O
Freedom	O
from	O
Distractibility	O
accounted	O
for	O
up	O
to	O
42	O
%	O
of	O
the	O
variance	O
in	O
WMS	O
-	O
R	O
and	O
CVLT	O
indices	O
.	O

Bilateral	O
basal	O
arteries	O
were	O
measured	O
by	O
the	O
transtemporal	O
approach	O
with	O
a	O
2	O
MHz	O
pulsed	O
Doppler	O
instrument	O
(	O
TC	O
-	O
2	O
64B	O
EME	O
)	O
.	O

At	O
the	O
genomic	O
level	O
,	O
the	O
sequences	O
of	O
two	O
members	O
of	O
this	O
family	O
are	O
known	O
in	O
the	O
rat	O
Rattus	O
norvegicus	O
:	O
the	O
VCSA1	B-GENE
gene	I-GENE
,	O
encoding	O
the	O
prohormone	B-GENE
-	I-GENE
like	I-GENE
polypeptide	I-GENE
SMR1	I-GENE
,	O
and	O
the	O
VCSB1	B-GENE
gene	I-GENE
,	O
encoding	O
a	O
salivary	O
Pro	O
-	O
rich	O
polypeptide	O
.	O

The	O
Saccharomyces	B-GENE
cerevisiae	I-GENE
RAD30	I-GENE
gene	I-GENE
,	O
a	O
homologue	B-GENE
of	I-GENE
Escherichia	I-GENE
coli	I-GENE
dinB	I-GENE
and	O
umuC	B-GENE
,	O
is	O
DNA	O
damage	O
inducible	O
and	O
functions	O
in	O
a	O
novel	O
error	O
-	O
free	O
postreplication	O
repair	O
mechanism	O
.	O

However	O
,	O
in	O
a	O
new	O
experiment	O
in	O
which	O
the	O
deletion	O
task	O
was	O
presented	O
as	O
a	O
puppet	O
game	O
,	O
and	O
with	O
pretraining	O
and	O
selection	O
on	O
vowel	O
deletion	O
,	O
a	O
significantly	O
higher	O
level	O
of	O
success	O
was	O
achieved	O
by	O
the	O
children	O
working	O
with	O
the	O
CVCC	O
material	O
.	O

Diet	O
therapy	O
with	O
soy	O
proteins	O
for	O
chronic	O
stomach	O
ulcers	O

In	O
ICU	O
patients	O
,	O
the	O
LIS	O
related	O
to	O
the	O
postoperative	O
rise	O
in	O
IL	B-GENE
-	I-GENE
6	I-GENE
level	O
only	O
,	O
even	O
though	O
the	O
rise	O
in	O
plasma	O
concentrations	O
of	O
cytokines	O
interrelated	O
.	O

Resistance	O
training	O
shifts	O
the	O
power	O
curve	O
in	O
a	O
positive	O
direction	O
when	O
the	O
measurements	O
are	O
determined	O
with	O
absolute	O
loads	O
,	O
but	O
the	O
increased	O
power	O
may	O
not	O
be	O
transferred	O
to	O
an	O
absolute	O
performance	O
task	O
like	O
the	O
SSP	O
.	O

Gel	O
-	O
shift	O
assays	O
identified	O
two	O
Sp1	B-GENE
binding	I-GENE
sites	I-GENE
within	O
this	O
element	O
.	O

Gel	O
mobility	O
shift	O
and	O
super	O
-	O
shift	O
assays	O
using	O
liver	O
nuclear	O
extracts	O
from	O
either	O
rat	O
liver	O
or	O
DDT1MF	O
-	O
2	O
cells	O
demonstrated	O
that	O
the	O
CRE	O
in	O
the	O
alpha	B-GENE
1B	I-GENE
-	I-GENE
AR	I-GENE
gene	I-GENE
bound	O
CRE	B-GENE
binding	I-GENE
protein	I-GENE
.	O

These	O
results	O
suggest	O
that	O
,	O
in	O
this	O
experimental	O
model	O
,	O
ACE	B-GENE
inhibitors	O
limit	O
the	O
arrhythmias	O
following	O
ischemia	O
-	O
reperfusion	O
and	O
free	O
radical	O
scavenging	O
action	O
of	O
these	O
drugs	O
does	O
not	O
have	O
a	O
major	O
contributory	O
role	O
in	O
their	O
protective	O
effect	O
.	O

The	O
murine	O
Htf9	B-GENE
-	I-GENE
a	I-GENE
/	O
RanBP1	B-GENE
and	O
Htf9	B-GENE
-	I-GENE
c	I-GENE
genes	I-GENE
are	O
divergently	O
transcribed	O
from	O
a	O
shared	O
TATA	O
-	O
less	O
promoter	O
.	O

In	O
accordance	O
with	O
clinical	O
improvement	O
we	O
found	O
a	O
decrease	O
of	O
laboratory	O
indicators	O
of	O
inflammation	O
(	O
C	B-GENE
-	I-GENE
reactive	I-GENE
protein	I-GENE
,	O
alpha	B-GENE
2	I-GENE
-	I-GENE
globuline	I-GENE
,	O
prostaglandin	O
E2	O
)	O
.	O

We	O
have	O
previously	O
reported	O
that	O
depletion	O
of	O
protein	B-GENE
kinase	I-GENE
C	I-GENE
by	O
long	O
-	O
term	O
treatment	O
of	O
B16	O
mouse	O
melanoma	O
cells	O
with	O
phorbol	O
dibutyrate	O
(	O
PDBu	O
)	O
prevented	O
cell	O
density	O
-	O
dependent	O
melanogenesis	O
.	O

Replacement	O
of	O
residues	O
in	O
positions	O
+	O
3	O
(	O
His128Asn	O
)	O
and	O
+	O
2	O
(	O
Gln155Lys	O
)	O
of	O
the	O
reading	O
helices	O
of	O
fingers	O
2	O
and	O
3	O
,	O
respectively	O
,	O
prevented	O
binding	O
.	O

Two	O
disulphide	O
bridges	O
,	O
which	O
are	O
conserved	O
in	O
all	O
spermadhesin	O
molecules	O
and	O
many	O
CUB	O
domains	O
,	O
crosslink	O
loop	O
LA	O
and	O
strand	O
beta	O
4	O
and	O
loops	O
LE	O
and	O
LG	O
,	O
respectively	O
,	O
at	O
opposite	O
edges	O
of	O
the	O
same	O
face	O
of	O
the	O
domain	O
.	O

Mg	B-GENE
-	I-GENE
chelatase	I-GENE
of	O
tobacco	O
:	O
identification	O
of	O
a	O
Chl	B-GENE
D	I-GENE
cDNA	I-GENE
sequence	I-GENE
encoding	O
a	O
third	O
subunit	O
,	O
analysis	O
of	O
the	O
interaction	O
of	O
the	O
three	O
subunits	O
with	O
the	O
yeast	O
two	O
-	O
hybrid	O
system	O
,	O
and	O
reconstitution	O
of	O
the	O
enzyme	O
activity	O
by	O
co	O
-	O
expression	O
of	O
recombinant	B-GENE
CHL	I-GENE
D	I-GENE
,	O
CHL	B-GENE
H	I-GENE
and	O
CHL	B-GENE
I	I-GENE
.	O

One	O
R	O
-	O
EST	O
and	O
one	O
Pto	B-GENE
-	I-GENE
like	I-GENE
sequence	I-GENE
each	O
mapped	O
to	O
two	O
locations	O
.	O

The	O
multidomain	O
structure	O
includes	O
a	O
cysteine	O
-	O
rich	O
motif	O
resembling	O
those	O
of	O
protein	B-GENE
kinase	I-GENE
C	I-GENE
and	O
n	B-GENE
-	I-GENE
chimaerin	I-GENE
and	O
a	O
putative	O
pleckstrin	B-GENE
homology	I-GENE
domain	I-GENE
.	O

271	O
:	O
31290	O
-	O
31295	O
,	O
1996	O
)	O
.	O

Nevertheless	O
,	O
antibodies	O
directed	O
against	O
an	O
epitope	O
-	O
tagged	O
version	O
of	O
Prp42p	B-GENE
specifically	O
precipitate	O
U1	B-GENE
snRNA	I-GENE
from	O
yeast	O
extracts	O
.	O

These	O
results	O
indicate	O
that	O
in	O
addition	O
to	O
Grb2	B-GENE
-	O
mediated	O
activation	O
of	O
Ras	B-GENE
,	O
PLC	B-GENE
-	I-GENE
gamma1	I-GENE
-	O
mediated	O
DAG	O
production	O
is	O
required	O
for	O
EGF	B-GENE
-	O
and	O
PDGF	B-GENE
-	O
induced	O
S	O
-	O
phase	O
entry	O
and	O
gene	O
expression	O
,	O
possibly	O
through	O
activation	O
of	O
PKC	B-GENE
.	O

In	O
this	O
study	O
,	O
we	O
investigated	O
STAT	B-GENE
activation	O
in	O
a	O
panel	O
of	O
rodent	O
fibroblast	O
cell	O
lines	O
stably	O
transformed	O
by	O
diverse	O
viral	O
oncoproteins	O
.	O

In	O
serum	O
-	O
stimulated	O
cells	O
,	O
the	O
binding	O
of	O
NF	B-GENE
-	I-GENE
Y	I-GENE
/	O
CBF	B-GENE
to	O
TKC1	B-GENE
increased	O
gradually	O
,	O
reaching	O
a	O
plateau	O
at	O
the	O
S	O
phase	O
.	O

CONCLUSION	O
:	O
In	O
our	O
animal	O
model	O
,	O
blood	O
-	O
brain	O
barrier	O
disruption	O
was	O
a	O
reproducible	O
,	O
integral	O
finding	O
of	O
single	O
-	O
fraction	O
,	O
high	O
-	O
dose	O
irradiation	O
injury	O
.	O

To	O
facilitate	O
the	O
investigation	O
of	O
parameters	O
that	O
govern	O
selective	O
export	O
in	O
adenovirus	O
-	O
infected	O
cells	O
,	O
we	O
constructed	O
a	O
marked	O
human	O
beta	B-GENE
-	I-GENE
actin	I-GENE
minigene	I-GENE
under	O
the	O
control	O
of	O
the	O
glucocorticoid	B-GENE
-	I-GENE
inducible	I-GENE
enhancer	I-GENE
-	I-GENE
promoter	I-GENE
of	O
mouse	O
mammary	O
tumor	O
virus	O
and	O
introduced	O
it	O
into	O
the	O
left	O
end	O
of	O
the	O
adenovirus	O
type	O
5	O
(	O
Ad5	O
)	O
genome	O
.	O

Cell	O
factor	O
-	O
mediated	O
regulatory	O
interactions	O
are	O
involved	O
in	O
regulating	O
the	O
restricted	O
expression	O
of	O
the	O
HCMV	B-GENE
major	I-GENE
immediate	I-GENE
-	I-GENE
early	I-GENE
(	I-GENE
IE	I-GENE
)	I-GENE
gene	I-GENE
(	O
J	O
.	O

MpB	B-GENE
GroEL	I-GENE
has	O
extensive	O
sequence	O
similarity	O
(	O
92	O
%	O
)	O
with	O
Escherichia	B-GENE
coli	I-GENE
GroEL	I-GENE
and	O
other	O
members	O
of	O
the	O
chaperonin	B-GENE
-	I-GENE
60	I-GENE
family	I-GENE
.	O

The	O
critical	O
mutations	O
were	O
likely	O
to	O
have	O
been	O
multiple	O
and	O
dispersed	O
,	O
including	O
elongation	O
of	O
the	O
TM	O
and	O
Nef	B-GENE
coding	I-GENE
sequences	I-GENE
;	O
changes	O
in	O
RNA	O
splice	O
donor	O
and	O
acceptor	O
sites	O
,	O
TATA	O
box	O
sites	O
,	O
and	O
Sp1	B-GENE
sites	I-GENE
;	O
multiple	O
changes	O
in	O
the	O
V2	B-GENE
region	O
of	O
SU	B-GENE
,	O
including	O
a	O
consensus	O
neutralization	O
epitope	O
;	O
and	O
five	O
new	O
N	O
-	O
linked	O
glycosylation	O
sites	O
in	O
SU	B-GENE
.	O

C	O
.	O

These	O
are	O
the	O
long	O
terminal	O
repeat	O
(	O
LTR	O
)	O
promoter	O
,	O
which	O
regulates	O
expression	O
of	O
the	O
viral	O
structural	O
proteins	O
,	O
and	O
a	O
second	O
internal	O
promoter	O
,	O
located	O
towards	O
the	O
3	O
'	O
end	O
of	O
the	O
env	B-GENE
gene	I-GENE
,	O
that	O
directs	O
expression	O
of	O
the	O
viral	O
auxiliary	O
proteins	O
.	O

The	O
5	O
'	O
end	O
of	O
the	O
genomic	O
RNA	O
of	O
rubella	O
virus	O
(	O
RUB	O
)	O
contains	O
a	O
14	O
-	O
nucleotide	O
(	O
nt	O
)	O
single	O
-	O
stranded	O
leader	O
(	O
ss	O
-	O
leader	O
)	O
followed	O
by	O
a	O
stem	O
-	O
and	O
-	O
loop	O
structure	O
[	O
5	O
'	O
(	O
+	O
)	O
SL	O
]	O
(	O
nt	O
15	O
to	O
65	O
)	O
,	O
the	O
complement	O
of	O
which	O
at	O
the	O
3	O
'	O
end	O
of	O
the	O
minus	O
-	O
strand	O
RNA	O
[	O
3	O
'	O
(	O
-	O
)	O
SL	O
]	O
has	O
been	O
proposed	O
to	O
function	O
as	O
a	O
promoter	O
for	O
synthesis	O
of	O
genomic	O
plus	O
strands	O
.	O

To	O
investigate	O
the	O
requirements	O
for	O
CBF2	B-GENE
binding	O
,	O
we	O
synthesized	O
a	O
series	O
of	O
oligonucleotides	O
carrying	O
double	O
transversion	O
mutations	O
spanning	O
both	O
the	O
conserved	O
core	O
sequence	O
and	O
outside	O
flanking	O
sequences	O
.	O

In	O
addition	O
,	O
the	O
affinities	O
of	O
CBF2	B-GENE
for	O
binding	O
to	O
the	O
LMP	B-GENE
-	I-GENE
1	I-GENE
,	O
LMP	B-GENE
-	I-GENE
2	I-GENE
,	O
and	O
CD23	B-GENE
promoters	I-GENE
were	O
also	O
measured	O
.	O

CONCLUSIONS	O
:	O
The	O
myocardial	O
uptake	O
of	O
99mTc	O
sestamibi	O
in	O
normal	O
subjects	O
and	O
patients	O
with	O
coronary	O
artery	O
disease	O
is	O
comparable	O
after	O
exercise	O
,	O
dipyridamole	O
,	O
and	O
adenosine	O
stress	O
.	O

The	O
SR	B-GENE
protein	I-GENE
family	I-GENE
is	O
involved	O
in	O
constitutive	O
and	O
regulated	O
pre	O
-	O
mRNA	O
splicing	O
and	O
has	O
been	O
found	O
to	O
be	O
evolutionarily	O
conserved	O
in	O
metazoan	O
organisms	O
.	O

To	O
investigate	O
the	O
activity	O
of	O
TCF11	B-GENE
through	O
this	O
selected	O
site	O
,	O
both	O
alone	O
and	O
in	O
the	O
presence	O
of	O
MafG	B-GENE
,	O
we	O
have	O
used	O
a	O
transient	O
transfection	O
assay	O
.	O

These	O
and	O
other	O
comparisons	O
suggest	O
that	O
,	O
during	O
evolution	O
,	O
both	O
the	O
RNA	B-GENE
-	I-GENE
polymerase	I-GENE
specificity	O
of	O
telomerase	B-GENE
RNA	I-GENE
-	I-GENE
gene	I-GENE
promoters	I-GENE
and	O
,	O
more	O
recently	O
,	O
the	O
position	O
of	O
the	O
template	O
sequence	O
in	O
the	O
telomerase	B-GENE
RNA	I-GENE
changed	O
.	O

Deadenylation	O
and	O
decay	O
of	O
beta	B-GENE
-	I-GENE
globin	I-GENE
mRNA	I-GENE
in	O
K562	O
cells	O
is	O
extraordinarily	O
slow	O
compared	O
with	O
NIH	O
3T3	O
cells	O
,	O
suggesting	O
that	O
the	O
increased	O
stability	O
gained	O
by	O
beta	B-GENE
-	I-GENE
globin	I-GENE
mRNA	I-GENE
in	O
K562	O
cells	O
is	O
mainly	O
controlled	O
at	O
the	O
deadenylation	O
step	O
.	O

Holliday	B-GENE
junction	I-GENE
resolvase	I-GENE
in	O
Schizosaccharomyces	O
pombe	O
has	O
identical	O
endonuclease	O
activity	O
to	O
the	O
CCE1	B-GENE
homologue	O
YDC2	B-GENE
.	O

Ca2	B-GENE
+	I-GENE
/	I-GENE
calmodulin	I-GENE
-	I-GENE
dependent	I-GENE
protein	I-GENE
kinase	I-GENE
II	I-GENE
(	O
CaMK	B-GENE
II	I-GENE
)	O
is	O
a	O
multifunctional	O
serine	B-GENE
/	I-GENE
threonine	I-GENE
protein	I-GENE
kinase	I-GENE
that	O
regulates	O
ion	O
channels	O
,	O
metabolic	O
enzymes	O
,	O
cytoskeletal	O
proteins	O
,	O
and	O
possibly	O
transcription	O
factors	O
.	O

A	O
cAMP	O
-	O
responsive	O
element	O
-	O
like	O
(	O
CRE	O
-	O
like	O
,	O
TGACGTGA	O
)	O
promoter	O
sequence	O
and	O
a	O
protein	B-GENE
kinase	I-GENE
A	I-GENE
signaling	O
pathway	O
are	O
involved	O
in	O
this	O
induction	O
,	O
and	O
activation	O
of	O
both	O
CRE	B-GENE
binding	I-GENE
protein	I-GENE
(	O
CREB	B-GENE
)	O
and	O
activating	B-GENE
transcription	I-GENE
factor	I-GENE
-	I-GENE
2	I-GENE
(	O
ATF	B-GENE
-	I-GENE
2	I-GENE
)	O
is	O
required	O
in	O
the	O
above	O
process	O
.	O

IVOX	O
was	O
named	O
as	O
an	O
acronym	O
for	O
intravascular	O
oxygenator	O
.	O

Histopathologically	O
,	O
a	O
cystic	O
lymphangioma	O
was	O
diagnosed	O
because	O
of	O
the	O
morphological	O
features	O
and	O
the	O
immunohistochemical	O
stainings	O
of	O
CD34	B-GENE
and	O
Factor	B-GENE
VIII	I-GENE
related	I-GENE
antigen	I-GENE
which	O
were	O
observed	O
positive	O
reactions	O
in	O
endothelial	O
cells	O
of	O
the	O
cysts	O
.	O

Protease	O
activities	O
in	O
cultures	O
of	O
the	O
streptococcal	O
strains	O
were	O
associated	O
with	O
species	O
of	O
different	O
molecular	O
masses	O
ranging	O
from	O
130	O
to	O
200	O
kDa	O
,	O
suggesting	O
posttranslational	O
processing	O
possibly	O
as	O
a	O
result	O
of	O
autoproteolysis	O
at	O
post	O
-	O
proline	O
peptide	O
bonds	O
in	O
the	O
N	O
-	O
terminal	O
parts	O
of	O
the	O
molecules	O
.	O

The	O
mechanism	O
underlying	O
such	O
analgesia	O
has	O
been	O
suggested	O
to	O
involve	O
the	O
interaction	O
between	O
the	O
two	O
separate	O
but	O
interconnected	O
motivational	O
systems	O
"	O
defense	O
"	O
and	O
"	O
pain	O
.	O
"	O
To	O
determine	O
the	O
developmental	O
course	O
of	O
defense	O
and	O
nociception	O
,	O
these	O
processes	O
were	O
analyzed	O
during	O
early	O
ontogeny	O
in	O
rats	O
.	O

Three	O
large	O
field	O
placement	O
errors	O
(	O
two	O
patients	O
with	O
11	O
.	O
5	O
and	O
16	O
.	O
0	O
mm	O
distances	O
of	O
the	O
planned	O
versus	O
simulated	O
isocenter	O
,	O
respectively	O
and	O
one	O
patient	O
with	O
a	O
7	O
degree	O
rotational	O
error	O
)	O
were	O
detected	O
and	O
,	O
as	O
with	O
the	O
smaller	O
errors	O
,	O
were	O
immediately	O
corrected	O
.	O

In	O
addition	O
,	O
a	O
catalytically	O
inactive	O
version	O
of	O
the	O
Src	B-GENE
family	I-GENE
member	O
,	O
Lck	B-GENE
(	O
lymphoid	B-GENE
cell	I-GENE
kinase	I-GENE
)	O
,	O
was	O
expressed	O
,	O
purified	O
,	O
and	O
evaluated	O
as	O
a	O
Csk	B-GENE
substrate	O
.	O

A	O
.	O
,	O
Swift	O
,	O
A	O
.	O

Neuronal	O
mechanisms	O
underlying	O
stimulus	O
-	O
response	O
(	O
S	O
-	O
R	O
)	O
associations	O
in	O
S	O
-	O
R	O
compatibility	O
tasks	O
were	O
identified	O
in	O
2	O
experiments	O
with	O
monkeys	O
.	O

The	O
c	B-GENE
-	I-GENE
myc	I-GENE
/	O
TGF	B-GENE
-	I-GENE
alpha	I-GENE
HCCs	O
were	O
also	O
characterized	O
by	O
a	O
particularly	O
strong	O
expression	O
of	O
TGF	B-GENE
-	I-GENE
alpha	I-GENE
and	O
very	O
low	O
apoptotic	O
index	O
in	O
contrast	O
to	O
high	O
levels	O
of	O
apoptosis	O
in	O
peritumorous	O
tissues	O
and	O
c	B-GENE
-	I-GENE
myc	I-GENE
HCCs	O
.	O

Taken	O
together	O
,	O
our	O
data	O
suggest	O
that	O
the	O
antagonistic	O
effects	O
of	O
CRP	B-GENE
and	O
KdgR	B-GENE
on	O
the	O
expression	O
of	O
the	O
pectinolysis	B-GENE
genes	I-GENE
occur	O
by	O
different	O
mechanisms	O
,	O
including	O
direct	O
competition	O
between	O
the	O
two	O
regulators	O
or	O
between	O
the	O
repressor	O
and	O
RNA	B-GENE
polymerase	I-GENE
for	O
the	O
occupation	O
of	O
a	O
common	O
DNA	O
region	O
on	O
the	O
target	O
genes	O
.	O

The	O
well	O
-	O
known	O
Rel	B-GENE
/	O
NF	B-GENE
-	I-GENE
kappaB	I-GENE
family	O
of	O
vertebrate	O
transcription	O
factors	O
comprises	O
a	O
number	O
of	O
structurally	O
related	O
,	O
interacting	O
proteins	O
that	O
bind	O
DNA	O
as	O
dimers	O
and	O
whose	O
activity	O
is	O
regulated	O
by	O
subcellular	O
location	O
.	O

The	O
cglIM	B-GENE
gene	I-GENE
is	O
organized	O
in	O
an	O
unusual	O
operon	O
which	O
contains	O
,	O
in	O
addition	O
,	O
two	O
genes	O
encoding	O
stress	O
-	O
sensitive	O
restriction	O
enzymes	O
.	O

The	O
purpose	O
of	O
this	O
investigation	O
was	O
to	O
describe	O
a	O
new	O
formulation	O
of	O
silver	O
sulfadiazine	O
in	O
a	O
water	O
soluble	O
gel	O
,	O
poloxamer	O
188	O
.	O

The	O
study	O
goals	O
were	O
to	O
isolate	O
a	O
full	O
-	O
length	O
clone	O
encoding	O
CO	B-GENE
-	I-GENE
Ag	I-GENE
from	O
a	O
bovine	O
corneal	O
cDNA	O
library	O
and	O
to	O
express	O
this	O
clone	O
in	O
Escherichia	O
coli	O
(	O
E	O
.	O
coli	O
)	O
.	O

The	O
gene	O
contains	O
six	O
exons	O
separated	O
by	O
1	O
.	O
1	O
-	O
5	O
.	O
8	O
kb	O
introns	O
and	O
has	O
been	O
localized	O
to	O
the	O
murine	O
chromosome	O
2	O
by	O
linkage	O
analysis	O
.	O

In	O
Xenopus	O
embryos	O
,	O
the	O
engineered	B-GENE
PDGF	I-GENE
receptor	I-GENE
protein	I-GENE
induced	O
the	O
formation	O
of	O
mesoderm	O
from	O
animal	O
-	O
pole	O
explants	O
in	O
an	O
FK1012	O
-	O
dependent	O
manner	O
.	O

A	O
cytosolic	O
variant	O
of	O
the	O
protein	O
underwent	O
efficient	O
transphosphorylation	O
,	O
yet	O
failed	O
to	O
activate	O
appreciably	O
either	O
p70	B-GENE
(	O
S6k	B-GENE
)	O
or	O
MAP	B-GENE
kinase	I-GENE
following	O
treatment	O
with	O
FK1012	O
.	O

Small	O
-	O
molecule	O
control	O
of	O
insulin	B-GENE
and	O
PDGF	B-GENE
receptor	I-GENE
signaling	O
and	O
the	O
role	O
of	O
membrane	O
attachment	O
.	O

Conversely	O
,	O
the	O
inactive	O
dAK	B-GENE
subunit	I-GENE
is	O
progressively	O
activated	O
by	O
1	O
)	O
association	O
with	O
a	O
dGK	B-GENE
or	O
dCK	B-GENE
subunit	I-GENE
and	O
2	O
)	O
the	O
conformationally	O
driven	O
heterotropic	O
affect	O
of	O
dGuo	B-GENE
or	O
dCyd	B-GENE
bound	O
to	O
the	O
opposing	O
subunit	O
.	O

CONCLUSIONS	O
:	O
A	O
50	O
-	O
mg	O
daily	O
dose	O
of	O
bicalutamide	O
is	O
sufficient	O
when	O
given	O
in	O
combination	O
with	O
an	O
agent	O
,	O
such	O
as	O
a	O
LHRH	B-GENE
-	O
A	O
,	O
that	O
lowers	O
serum	O
testosterone	O
,	O
but	O
higher	O
doses	O
of	O
bicalutamide	O
may	O
be	O
needed	O
when	O
the	O
drug	O
is	O
given	O
as	O
monotherapy	O
.	O

A	O
genomic	O
clone	O
was	O
isolated	O
that	O
contained	O
12	O
.	O
5	O
kb	O
of	O
the	O
5	O
'	O
-	O
flanking	O
region	O
and	O
the	O
first	O
exon	O
of	O
the	O
p69	B-GENE
/	I-GENE
71	I-GENE
2	I-GENE
-	I-GENE
5A	I-GENE
synthetase	I-GENE
gene	I-GENE
.	O

Although	O
the	O
gene	O
is	O
substantially	O
smaller	O
than	O
the	O
human	O
genes	O
for	O
other	O
mitochondrial	O
enzymes	O
,	O
its	O
intron	O
/	O
exon	O
organization	O
is	O
very	O
similar	O
,	O
especially	O
to	O
that	O
of	O
P450scc	B-GENE
.	O

RESULTS	O
:	O
Looking	O
at	O
the	O
question	O
of	O
its	O
benefits	O
,	O
we	O
were	O
unable	O
to	O
find	O
any	O
methodologically	O
sound	O
studies	O
that	O
have	O
shown	O
efficacy	O
for	O
EMDR	O
in	O
eating	O
disorders	O
,	O
or	O
,	O
indeed	O
,	O
any	O
psychiatric	O
disorder	O
.	O

Transient	O
overexpression	O
of	O
mutant	B-GENE
EphB1	I-GENE
receptors	I-GENE
(	O
Y594F	O
)	O
blocked	O
Nck	B-GENE
recruitment	O
to	O
EphB1	B-GENE
,	O
attenuated	O
downstream	O
JNK	B-GENE
activation	O
,	O
and	O
blocked	O
cell	O
attachment	O
responses	O
.	O

S	O
.	O
,	O
and	O
Walter	O
,	O
P	O
.	O

Here	O
we	O
demonstrate	O
that	O
Hh	B-GENE
and	O
Patched	B-GENE
(	O
Ptc	B-GENE
)	O
act	O
through	O
those	O
Ci	B-GENE
binding	O
sites	O
to	O
modulate	O
the	O
level	O
of	O
Ci	B-GENE
-	O
dependent	O
transcriptional	O
activation	O
in	O
S2	O
cells	O
.	O

Furthermore	O
the	O
median	O
increase	O
in	O
cyclosporine	O
DR	O
/	O
C	O
(	O
SS	O
trough	O
)	O
was	O
18	O
l	O
h	O
-	O
1	O
(	O
-	O
3	O
.	O
1	O
to	O
42	O
.	O
1	O
l	O
h	O
-	O
1	O
,	O
interquartile	O
range	O
)	O
.	O

Patients	O
and	O
their	O
relatives	O
must	O
be	O
informed	O
about	O
the	O
available	O
effective	O
treatment	O
possibilities	O
and	O
about	O
the	O
right	O
moment	O
for	O
their	O
application	O
in	O
an	O
individual	O
patient	O
.	O

Several	O
PTPases	B-GENE
were	O
expressed	O
abundantly	O
in	O
the	O
5	O
-	O
FU	O
-	O
treated	O
bone	O
marrow	O
stem	O
cells	O
.	O

Expression	O
of	O
PTPRO	B-GENE
was	O
also	O
observed	O
in	O
human	B-GENE
CD34	I-GENE
+	I-GENE
bone	O
marrow	O
cells	O
and	O
5	O
-	O
FU	O
-	O
treated	O
murine	O
primitive	O
stem	O
cells	O
.	O

The	O
organization	O
of	O
SPP1	B-GENE
genes	I-GENE
involved	O
in	O
the	O
replication	O
,	O
DNA	O
packaging	O
and	O
phage	O
assembly	O
proteins	O
resembles	O
the	O
organization	O
of	O
genes	O
of	O
equivalent	O
regions	O
of	O
different	O
E	O
.	O
coli	O
double	O
-	O
stranded	O
DNA	O
phages	O
.	O

Our	O
results	O
showed	O
that	O
compared	O
to	O
the	O
primary	O
photon	O
fluence	O
,	O
the	O
extra	O
-	O
focal	O
photon	O
fluence	O
from	O
the	O
primary	O
collimator	O
and	O
the	O
flattening	O
filter	O
was	O
11	O
%	O
-	O
16	O
%	O
at	O
the	O
isocenter	O
,	O
among	O
which	O
70	O
%	O
was	O
contributed	O
by	O
the	O
flattening	O
filter	O
.	O

The	O
functional	O
mature	O
domain	O
of	O
pediocin	B-GENE
AcH	I-GENE
(	I-GENE
Lys	I-GENE
+	I-GENE
1	I-GENE
to	I-GENE
Cys	I-GENE
+	I-GENE
44	I-GENE
)	I-GENE
is	O
targeted	O
into	O
the	O
E	O
.	O
coli	O
sec	O
machinery	O
and	O
secreted	O
to	O
the	O
periplasm	O
in	O
active	O
form	O
when	O
fused	O
in	O
frame	O
to	O
the	O
COOH	O
terminus	O
of	O
the	O
secretory	B-GENE
protein	I-GENE
maltose	I-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
(	O
MBP	B-GENE
)	O
.	O

Isomers	O
were	O
differentiated	O
based	O
on	O
the	O
MS	O
-	O
MS	O
data	O
of	O
the	O
trofluoroacetyl	O
-	O
biphenylol	O
derivatives	O
.	O

Clinical	O
value	O
of	O
the	O
estimation	O
of	O
growth	O
kinetics	O
of	O
primary	O
ovarian	O
cancer	O
recurrences	O
by	O
CA125	B-GENE
doubling	O
time	O

This	O
review	O
seeks	O
to	O
summarize	O
the	O
disease	O
,	O
to	O
propose	O
pathways	O
of	O
carcinogenesis	O
and	O
to	O
suggest	O
ways	O
in	O
which	O
the	O
"	O
traditional	O
"	O
risk	O
factors	O
may	O
be	O
interpreted	O
on	O
the	O
basis	O
of	O
evolving	O
knowledge	O
.	O

The	O
patient	O
underwent	O
two	O
intracytoplasmic	O
sperm	O
injection	O
cycles	O
with	O
thawed	O
epididymal	O
spermatozoa	O
,	O
in	O
which	O
,	O
due	O
to	O
a	O
pharmacist	O
'	O
s	O
mistake	O
,	O
ovarian	O
stimulation	O
was	O
carried	O
out	O
by	O
a	O
combination	O
of	O
long	O
-	O
acting	O
gonadotrophin	B-GENE
-	I-GENE
releasing	I-GENE
hormone	I-GENE
agonist	O
(	O
leuprolide	O
depot	O
)	O
and	O
gonadotrophins	B-GENE
.	O

Perhaps	O
in	O
addition	O
to	O
,	O
or	O
as	O
part	O
of	O
,	O
its	O
essential	O
function	O
in	O
late	O
mitosis	O
,	O
MOB1	B-GENE
is	O
required	O
for	O
a	O
cell	O
cycle	O
reset	O
function	O
necessary	O
for	O
the	O
initiation	O
of	O
the	O
spindle	O
pole	O
body	O
duplication	O
.	O

In	O
contrast	O
,	O
overproduction	O
of	O
Der3p	B-GENE
is	O
lethal	O
in	O
a	O
sec61	B-GENE
-	I-GENE
2	I-GENE
strain	O
at	O
the	O
permissive	O
temperature	O
of	O
25	O
degrees	O
C	O
.	O

Normal	O
baseline	O
(	O
day	O
-	O
8	O
)	O
PC	O
levels	O
(	O
86	O
and	O
89	O
%	O
)	O
were	O
markedly	O
reduced	O
in	O
both	O
patients	O
at	O
the	O
time	O
of	O
VOD	O
manifestation	O
on	O
day	O
20	O
and	O
40	O
,	O
respectively	O
(	O
26	O
and	O
31	O
%	O
)	O
.	O

To	O
examine	O
the	O
role	O
of	O
this	O
CE2	O
element	O
in	O
regulating	O
Hoxa1	B-GENE
expression	O
in	O
vivo	O
,	O
transgenic	O
mice	O
were	O
generated	O
which	O
express	O
a	O
Hoxa1	B-GENE
beta	B-GENE
-	I-GENE
galactosidase	I-GENE
reporter	O
gene	O
that	O
contains	O
a	O
mutation	O
in	O
the	O
CE2	O
element	O
.	O

An	O
evolutionary	O
conserved	O
element	O
is	O
essential	O
for	O
somite	O
and	O
adjacent	O
mesenchymal	O
expression	O
of	O
the	O
Hoxa1	B-GENE
gene	I-GENE
.	O

RESULTS	O
:	O
The	O
bovine	O
cDNA	O
insert	O
sequence	O
was	O
273	O
nucleotides	O
in	O
length	O
for	O
the	O
entire	O
mRNA	O
coding	O
region	O
,	O
212	O
nucleotides	O
in	O
the	O
5	O
'	O
untranslated	O
region	O
,	O
83	O
nucleotides	O
in	O
the	O
3	O
'	O
untranslated	O
region	O
and	O
a	O
poly	O
(	O
A	O
)	O
tail	O
.	O

Altogether	O
46	O
phase	O
III	O
activities	O
were	O
recorded	O
.	O

We	O
have	O
previously	O
identified	O
a	O
liver	O
-	O
enriched	O
transcription	O
factor	O
,	O
HNF	B-GENE
-	I-GENE
6	I-GENE
,	O
which	O
is	O
required	O
for	O
HNF	B-GENE
-	I-GENE
3	I-GENE
beta	I-GENE
promoter	I-GENE
activity	O
and	O
also	O
recognizes	O
the	O
regulatory	O
region	O
of	O
numerous	O
hepatocyte	O
-	O
specific	O
genes	O
.	O

A	O
cDNA	O
clone	O
was	O
identified	O
encoding	O
a	O
second	O
GHS	B-GENE
-	I-GENE
R	I-GENE
-	I-GENE
related	I-GENE
gene	I-GENE
(	O
GPR39	B-GENE
)	O
.	O

(	O
1997	O
)	O
Science	O
275	O
,	O
1927	O
-	O
1930	O
)	O
.	O

P	O
.	O
,	O
Peyron	O
,	O
J	O
.	O

A	O
hybridoma	O
clone	O
(	O
7H1	O
)	O
resulting	O
from	O
the	O
fusion	O
between	O
CEMLAI	O
/	O
NP	O
and	O
human	O
embryonic	O
fibroblasts	O
MRC5	O
cells	O
produced	O
very	O
large	O
amounts	O
of	O
P47	B-GENE
that	O
was	O
purified	O
using	O
Jacalin	B-GENE
lectin	I-GENE
(	O
specific	O
for	O
O	O
-	O
glycans	O
)	O
and	O
microsequenced	O
.	O

This	O
information	O
,	O
together	O
with	O
estimation	O
of	O
the	O
size	O
of	O
the	O
deglycosylated	O
A	O
subunit	O
relative	O
to	O
a	O
series	O
of	O
C	B-GENE
-	I-GENE
terminal	I-GENE
truncated	I-GENE
TSHR	I-GENE
ectodomain	I-GENE
variants	I-GENE
,	O
places	O
cleavage	O
Site	O
1	O
in	O
the	O
vicinity	O
of	O
,	O
or	O
closely	O
upstream	O
to	O
,	O
residue	O
317	O
.	O

In	O
vitro	O
DNase	B-GENE
I	I-GENE
footprinting	O
of	O
the	O
200	O
-	O
bp	O
proximal	O
region	O
of	O
the	O
promoter	O
with	O
a	O
murine	O
Hepa	O
1	O
-	O
6	O
cell	O
nuclear	O
extract	O
revealed	O
a	O
clear	O
footprint	O
of	O
a	O
region	O
corresponding	O
to	O
-	O
80	O
to	O
-	O
28	O
bp	O
of	O
the	O
murine	B-GENE
fVII	I-GENE
gene	I-GENE
,	O
suggesting	O
that	O
liver	O
factors	O
interact	O
with	O
this	O
region	O
of	O
the	O
DNA	O
.	O

Both	O
increasing	O
basal	O
FSH	B-GENE
and	O
age	O
were	O
associated	O
significantly	O
with	O
increased	O
total	O
gonadotrophin	B-GENE
dose	O
,	O
and	O
reduced	O
number	O
of	O
oocytes	O
collected	O
and	O
pregnancy	O
rate	O
.	O

A	O
comparative	O
study	O
was	O
undertaken	O
between	O
an	O
enzymatic	O
immunohistochemical	O
technique	O
(	O
EIT	O
)	O
developed	O
for	O
the	O
diagnosis	O
of	O
human	O
trichinellosis	O
and	O
the	O
indirect	O
immunofluorescence	O
test	O
(	O
IIF	O
)	O
,	O
analysing	O
sera	O
from	O
outbreaks	O
of	O
human	O
trichinellosis	O
in	O
Argentina	O
.	O

Our	O
results	O
establish	O
GKLF	B-GENE
as	O
a	O
sequence	O
-	O
specific	O
transcription	O
factor	O
likely	O
involved	O
in	O
regulation	O
of	O
expression	O
of	O
endogenous	O
genes	O
.	O

CES4	B-GENE
on	O
a	O
multicopy	O
plasmid	O
was	O
unable	O
to	O
suppress	O
tif1	B-GENE
-	I-GENE
A79V	I-GENE
.	O

Here	O
we	O
report	O
that	O
in	O
cultured	O
cells	O
from	O
Drosophila	O
melanogaster	O
human	B-GENE
Sp1	I-GENE
efficiently	O
activates	O
transcription	O
from	O
synthetic	O
promoters	O
containing	O
TATA	O
boxes	O
,	O
but	O
not	O
from	O
promoters	O
that	O
contain	O
an	O
initiator	O
instead	O
of	O
a	O
TATA	O
box	O
.	O

No	O
apparent	O
clinical	O
signs	O
indicative	O
of	O
systemic	O
toxicity	O
were	O
observed	O
in	O
the	O
F0	O
and	O
F1	O
animals	O
of	O
either	O
sex	O
.	O

In	O
an	O
effort	O
to	O
identify	O
the	O
USH1C	B-GENE
disease	I-GENE
gene	I-GENE
we	O
have	O
isolated	O
the	O
region	O
between	O
these	O
markers	O
in	O
yeast	O
artificial	O
chromosomes	O
(	O
YACs	O
)	O
using	O
a	O
combination	O
of	O
STS	O
content	O
mapping	O
and	O
Alu	B-GENE
-	O
PCR	O
hybridization	O
.	O

PowerBLAST	O
analysis	O
identified	O
six	O
clusters	O
of	O
expressed	O
sequence	O
tags	O
(	O
ESTs	O
)	O
,	O
two	O
known	O
genes	O
(	O
BIR	B-GENE
,	O
SUR1	B-GENE
)	O
mapped	O
previously	O
to	O
this	O
region	O
,	O
and	O
a	O
previously	O
characterized	O
but	O
unmapped	O
gene	B-GENE
NEFA	I-GENE
(	O
DNA	B-GENE
binding	I-GENE
/	I-GENE
EF	I-GENE
hand	I-GENE
/	I-GENE
acidic	I-GENE
amino	I-GENE
-	I-GENE
acid	I-GENE
-	I-GENE
rich	I-GENE
)	O
.	O

A	O
fusion	O
protein	O
composed	O
of	O
beta	B-GENE
-	I-GENE
galactosidase	I-GENE
and	O
full	B-GENE
-	I-GENE
length	I-GENE
Ahr	I-GENE
translocates	O
from	O
the	O
cytoplasm	O
to	O
the	O
nucleus	O
in	O
a	O
ligand	O
-	O
dependent	O
manner	O
.	O

Reconstitution	O
of	O
Raf	B-GENE
-	I-GENE
1	I-GENE
activity	O
was	O
observed	O
only	O
with	O
kinase	O
active	O
Jak1	B-GENE
in	O
both	O
cell	O
lines	O
.	O

In	O
addition	O
,	O
negatively	O
regulatory	O
region	O
may	O
exist	O
from	O
-	O
1782	O
to	O
-	O
1295	O
bp	O
.	O

The	O
hypothesis	O
of	O
Geisler	O
(	O
Brain	O
Res	O
.	O

The	O
second	O
transcript	O
,	O
rhis4l	B-GENE
,	O
is	O
bicistronic	O
.	O

Consistent	O
with	O
this	O
interpretation	O
,	O
a	O
mutant	O
form	O
of	O
XRN1	B-GENE
,	O
which	O
encodes	O
a	O
5	O
'	O
-	O
3	O
'	O
exonuclease	O
,	O
was	O
identified	O
as	O
an	O
extragenic	O
suppressor	O
that	O
increases	O
the	O
half	O
-	O
life	O
of	O
rhis4	B-GENE
mRNA	I-GENE
,	O
leading	O
to	O
a	O
10	O
-	O
fold	O
increase	O
in	O
steady	O
-	O
state	O
mRNA	O
levels	O
compared	O
to	O
the	O
wild	B-GENE
-	I-GENE
type	I-GENE
HIS4	I-GENE
mRNA	I-GENE
level	O
.	O

Sip1	B-GENE
was	O
initially	O
identified	O
by	O
virtue	O
of	O
its	O
interaction	O
with	O
SC35	B-GENE
,	O
a	O
splicing	O
factor	O
of	O
the	O
SR	B-GENE
family	I-GENE
.	O

Such	O
mutations	O
are	O
thought	O
to	O
exert	O
their	O
dominant	O
phenotype	O
by	O
sequestration	O
of	O
the	O
guanine	B-GENE
nucleotide	I-GENE
exchange	I-GENE
factor	I-GENE
(	O
GNEF	B-GENE
)	O
.	O

Several	O
studies	O
have	O
characterized	O
the	O
upstream	O
regulatory	O
region	O
of	O
c	B-GENE
-	I-GENE
fos	I-GENE
,	O
and	O
identified	O
cis	O
-	O
acting	O
elements	O
termed	O
the	O
cyclic	O
AMP	O
(	O
cAMP	O
)	O
response	O
elements	O
(	O
CREs	O
)	O
that	O
are	O
critical	O
for	O
c	B-GENE
-	I-GENE
fos	I-GENE
transcription	O
in	O
response	O
to	O
a	O
variety	O
of	O
extracellular	O
stimuli	O
.	O

We	O
have	O
cloned	O
a	O
kinase	O
,	O
Nlk	B-GENE
,	O
that	O
is	O
a	O
murine	B-GENE
homolog	I-GENE
of	I-GENE
the	I-GENE
Drosophila	I-GENE
nemo	I-GENE
(	O
nmo	B-GENE
)	O
gene	O
.	O

Our	O
findings	O
suggest	O
that	O
striatal	O
FDG	O
and	O
particularly	O
RACLO	O
are	O
sensitive	O
and	O
effective	O
measures	O
of	O
striatal	O
function	O
and	O
may	O
help	O
characterizing	O
patients	O
with	O
multiple	O
system	O
atrophy	O
.	O

Childhood	O
misbehavior	O
and	O
the	O
risk	O
of	O
injecting	O
drug	O
use	O
.	O

Genetic	O
analysis	O
has	O
subsequently	O
identified	O
subpathways	O
of	O
the	O
DNA	O
structure	O
checkpoints	O
,	O
including	O
the	O
reversible	O
arrest	O
of	O
DNA	O
synthesis	O
.	O

Thus	O
,	O
Esigma54	B-GENE
promoters	I-GENE
are	O
responsive	O
to	O
CRP	B-GENE
,	O
a	O
protein	O
unrelated	O
to	O
sigma54	B-GENE
activators	I-GENE
,	O
and	O
the	O
repression	O
exerted	O
is	O
the	O
direct	O
result	O
of	O
an	O
interaction	O
between	O
Esigma54	B-GENE
and	O
the	O
CRP	B-GENE
-	I-GENE
cAMP	I-GENE
complex	I-GENE
.	O

GlcNAc	O
-	O
and	O
GlcNAc2	O
-	O
PP	O
-	O
Dolichol	O
biosynthesis	O
could	O
be	O
shown	O
with	O
isolated	O
S	O
.	O
cerevisiae	O
membranes	O
from	O
cells	O
harboring	O
the	O
recombinant	O
plasmid	O
and	O
grown	O
on	O
glucose	O
thus	O
suppressing	O
transcription	O
of	O
the	O
endogenous	O
gene	O
.	O

Antibodies	O
raised	O
against	O
GST	B-GENE
mSH2	I-GENE
-	I-GENE
B	I-GENE
identified	O
a	O
cellular	O
protein	O
of	O
92	O
kDa	O
that	O
was	O
not	O
found	O
to	O
be	O
phosphorylated	O
on	O
Tyr	O
.	O

Interleukin	B-GENE
-	I-GENE
6	I-GENE
(	O
IL	B-GENE
-	I-GENE
6	I-GENE
)	O
is	O
a	O
pleiotropic	O
cytokine	O
,	O
which	O
is	O
involved	O
in	O
inflammatory	O
and	O
immune	O
responses	O
,	O
acute	O
phase	O
reactions	O
,	O
and	O
hematopoiesis	O
.	O

Upon	O
analysis	O
of	O
various	O
deletion	O
and	O
point	O
-	O
mutated	O
variants	O
of	O
the	O
human	B-GENE
IL	I-GENE
-	I-GENE
6	I-GENE
gene	I-GENE
promoter	I-GENE
coupled	O
to	O
a	O
reporter	O
gene	O
,	O
we	O
screened	O
for	O
possible	O
cooperating	O
transcription	O
factors	O
.	O

This	O
region	O
,	O
however	O
,	O
contains	O
a	O
CCAATC	O
box	O
in	O
the	O
reverse	O
complement	O
and	O
several	O
GC	O
boxes	O
that	O
are	O
recognition	O
sites	O
for	O
SP1	B-GENE
.	O

Our	O
purpose	O
was	O
to	O
determine	O
if	O
intact	O
perianal	O
(	O
S4	O
-	O
5	O
)	O
pin	O
sensation	O
(	O
PPS	O
)	O
and	O
bulbocavernosus	O
(	O
S2	O
-	O
4	O
)	O
reflex	O
(	O
BCR	O
)	O
shortly	O
after	O
spinal	O
cord	O
injury	O
(	O
SCI	O
)	O
are	O
predictive	O
of	O
bladder	O
function	O
recovery	O
.	O

The	O
correct	O
termination	O
of	O
retroviral	O
transcripts	O
at	O
the	O
3	O
'	O
LTR	O
R	O
/	O
U5	O
junction	O
is	O
primarily	O
dependent	O
on	O
the	O
canonical	O
AAUAAA	O
polyadenylation	O
signal	O
,	O
so	O
we	O
have	O
analyzed	O
the	O
effect	O
of	O
mutating	O
the	O
polyadenylation	O
signal	O
sequences	O
on	O
the	O
properties	O
of	O
a	O
selectable	O
murine	O
retroviral	O
vector	O
.	O

ALT	B-GENE
levels	O
in	O
responders	O
were	O
lowered	O
by	O
46	O
%	O
and	O
AST	B-GENE
levels	O
were	O
lowered	O
by	O
35	O
%	O
after	O
12	O
weeks	O
of	O
vitamin	O
E	O
treatment	O
.	O

51	O
.	O
9	O
%	O
(	O
P	O
=	O
0	O
.	O
0006	O
)	O
in	O
the	O
MMF	O
versus	O
the	O
AZA	O
groups	O
,	O
respectively	O
.	O

Our	O
study	O
was	O
designed	O
to	O
investigate	O
the	O
effect	O
of	O
MMF	O
on	O
in	O
vivo	O
bone	O
mineral	O
metabolism	O
.	O

Pao2	O
increased	O
from	O
15	O
.	O
5	O
+	O
/	O
-	O
5	O
.	O
6	O
kPa	O
(	O
116	O
+	O
/	O
-	O
42	O
mm	O
Hg	O
)	O
to	O
17	O
.	O
3	O
+	O
/	O
-	O
6	O
.	O
3	O
kPa	O
(	O
130	O
+	O
/	O
-	O
47	O
mm	O
Hg	O
)	O
(	O
P	O
<	O
0	O
.	O
05	O
)	O
.	O

Typical	O
configurations	O
of	O
psychosocial	O
stress	O
factors	O
of	O
psychiatrically	O
conspicuous	O
children	O
and	O
adolescents	O

Nine	O
cats	O
received	O
PMEA	O
at	O
a	O
dosage	O
of	O
10	O
mg	O
/	O
kg	O
body	O
weight	O
,	O
nine	O
cats	O
received	O
FPMPA	O
at	O
a	O
dosage	O
of	O
25	O
mg	O
/	O
kg	O
body	O
weight	O
.	O

Resistance	O
to	O
thyroid	O
hormone	O
:	O
implications	O
for	O
neurodevelopmental	O
research	O
on	O
the	O
effects	O
of	O
thyroid	O
hormone	O
disruptors	O
.	O

We	O
present	O
the	O
preliminary	O
results	O
obtained	O
on	O
36	O
patients	O
which	O
were	O
followed	O
for	O
a	O
mean	O
period	O
of	O
12	O
months	O
.	O

Moreover	O
,	O
xTAK1KN	B-GENE
could	O
block	O
the	O
expression	O
of	O
ventral	O
mesoderm	O
marker	O
genes	O
induced	O
by	O
Smad1	B-GENE
or	I-GENE
5	I-GENE
.	O

The	O
assay	O
exhibits	O
a	O
dynamic	O
range	O
of	O
0	O
.	O
1	O
-	O
100	O
micrograms	O
l	O
-	O
1	O
using	O
a	O
monoclonal	O
antibody	O
or	O
alternatively	O
10	O
micrograms	O
l	O
-	O
1	O
to	O
10	O
mg	O
l	O
-	O
1	O
using	O
commercially	O
available	O
antiserum	O
.	O

A	O
canonical	O
TATA	O
box	O
was	O
not	O
detected	O
.	O

Expression	O
and	O
characterization	O
of	O
recombinant	B-GENE
single	I-GENE
-	I-GENE
chain	I-GENE
Fv	I-GENE
and	O
Fv	B-GENE
fragments	I-GENE
derived	O
from	O
a	O
set	O
of	O
catalytic	O
antibodies	O
.	O

A	O
putative	O
inhibitor	O
(	O
s	O
)	O
appears	O
to	O
co	O
-	O
elute	O
in	O
the	O
inactive	O
fraction	O
that	O
blocked	O
the	O
L	B-GENE
(	I-GENE
alpha	I-GENE
)	I-GENE
activity	O
.	O

Platelet	O
aggregation	O
in	O
response	O
to	O
10	O
micrograms	O
collagen	B-GENE
/	O
ml	O
was	O
decreased	O
in	O
parallel	O
after	O
treatment	O
with	O
ASA	O
.	O

Using	O
himA	B-GENE
mutants	I-GENE
,	O
we	O
confirmed	O
that	O
IHF	B-GENE
plays	O
a	O
role	O
in	O
the	O
molybdate	O
-	O
dependent	O
regulation	O
of	O
dmsA	B-GENE
-	O
lacZ	B-GENE
expression	O
in	O
vivo	O
.	O

Cross	O
-	O
talking	O
among	O
Drosophila	O
nuclear	O
receptors	O
at	O
the	O
promiscuous	O
response	O
element	O
of	O
the	O
ng	B-GENE
-	I-GENE
1	I-GENE
and	O
ng	B-GENE
-	I-GENE
2	I-GENE
intermolt	I-GENE
genes	I-GENE
.	O

The	O
ipsilateral	O
breast	O
tumor	O
relapse	O
rate	O
was	O
similar	O
between	O
the	O
PALP	O
and	O
MGDET	O
groups	O
.	O

Sibling	O
aggregation	O
of	O
low	B-GENE
-	I-GENE
and	I-GENE
high	I-GENE
-	I-GENE
density	I-GENE
lipoprotein	I-GENE
cholesterol	I-GENE
and	O
apolipoproteins	B-GENE
B	I-GENE
and	I-GENE
A	I-GENE
-	I-GENE
I	I-GENE
levels	O
in	O
black	O
and	O
white	O
children	O
:	O
the	O
Bogalusa	O
Heart	O
Study	O
.	O

The	O
CAPLC1	B-GENE
protein	I-GENE
also	O
exhibited	O
several	O
unique	O
features	O
,	O
including	O
a	O
novel	O
stretch	O
of	O
18	O
-	O
19	O
amino	O
acid	O
residues	O
within	O
the	O
X	O
domain	O
and	O
an	O
unusually	O
long	O
N	O
-	O
terminus	O
which	O
did	O
not	O
contain	O
a	O
recognizable	O
EF	O
-	O
hand	O
Ca	O
(	O
2	O
+	O
)	O
-	O
binding	O
domain	O
.	O

This	O
hypothesis	O
is	O
consistent	O
with	O
the	O
occurrence	O
of	O
PEA3	B-GENE
binding	I-GENE
sites	I-GENE
in	O
the	O
PEA3	B-GENE
promoter	I-GENE
and	O
with	O
the	O
ability	O
of	O
PEA3	B-GENE
to	O
transactivate	O
this	O
promoter	O
.	O

Pet	B-GENE
-	I-GENE
1	I-GENE
can	O
bind	O
specifically	O
to	O
a	O
PEA3	B-GENE
ETS	B-GENE
DNA	O
-	O
binding	O
motif	O
and	O
can	O
modulate	O
transcription	O
of	O
synthetic	O
promoter	O
constructs	O
in	O
a	O
sequence	O
-	O
specific	O
manner	O
.	O

The	O
protein	O
expressed	O
by	O
F2771	B-GENE
cDNA	I-GENE
in	O
transfected	O
COS	O
cells	O
is	O
localized	O
in	O
the	O
cytoplasm	O
.	O

Northern	O
analysis	O
indicated	O
differential	O
expression	O
by	O
tissue	O
with	O
highest	O
expression	O
in	O
the	O
heart	O
.	O

As	O
well	O
,	O
further	O
deletion	O
of	O
the	O
promoter	O
region	O
to	O
nucleotide	O
-	O
110	O
,	O
which	O
contains	O
only	O
one	O
SF	B-GENE
-	I-GENE
1	I-GENE
binding	I-GENE
site	I-GENE
,	O
still	O
retained	O
the	O
ability	O
to	O
respond	O
to	O
exogenous	O
SF	B-GENE
-	I-GENE
1	I-GENE
.	O

The	O
observation	O
that	O
beta	B-GENE
2m	I-GENE
with	O
covalently	O
attached	O
peptide	O
can	O
effectively	O
create	O
CTL	O
target	O
structures	O
in	O
vitro	O
offers	O
new	O
possibilities	O
for	O
the	O
in	O
vivo	O
induction	O
of	O
epitope	O
-	O
specific	O
CTL	O
responses	O
by	O
either	O
DNA	O
immunization	O
or	O
injection	O
of	O
the	O
purified	O
epitope	O
-	O
linked	O
beta	B-GENE
2m	I-GENE
.	O

The	O
mRNAs	O
of	O
these	O
genes	O
contain	O
respectively	O
one	O
(	O
YAP1	B-GENE
uORF	I-GENE
)	O
and	O
two	O
(	O
YAP2	B-GENE
uORF1	I-GENE
and	O
uORF2	O
)	O
upstream	O
open	O
reading	O
frames	O
.	O
uORF	O
-	O
mediated	O
modulation	O
of	O
post	O
-	O
termination	O
events	O
on	O
the	O
5	O
'	O
-	O
untranslated	O
region	O
(	O
5	O
'	O
-	O
UTR	O
)	O
directs	O
differential	O
control	O
not	O
only	O
of	O
translation	O
but	O
also	O
of	O
mRNA	O
decay	O
.	O

To	O
further	O
investigate	O
the	O
nature	O
of	O
the	O
site	O
specificity	O
a	O
set	O
of	O
deletion	O
mutants	O
of	O
the	O
160	O
bp	O
sequence	O
were	O
analysed	O
.	O

In	O
the	O
tissues	O
tested	O
,	O
except	O
brain	O
,	O
the	O
message	O
for	O
CLIP	B-GENE
-	I-GENE
170	I-GENE
was	O
more	O
abundant	O
than	O
that	O
for	O
Restin	B-GENE
.	O

BACKGROUND	O
:	O
Chemicals	O
vary	O
considerably	O
in	O
their	O
intrinsic	O
ability	O
to	O
cause	O
allergic	O
contact	O
dermatitis	O
.	O

Also	O
,	O
the	O
deduced	O
amino	O
acids	O
of	O
the	O
antigenic	B-GENE
regions	I-GENE
A	I-GENE
,	I-GENE
B	I-GENE
and	I-GENE
C	I-GENE
of	I-GENE
VP7	I-GENE
were	O
nearly	O
conserved	O
within	O
the	O
phylogenetic	O
lineages	O
.	O

The	O
cloned	O
alcR	B-GENE
gene	I-GENE
provided	O
in	O
trans	O
restored	O
these	O
siderophore	O
system	O
activities	O
to	O
the	O
mutants	O
.	O

The	O
cloned	O
alcR	B-GENE
gene	I-GENE
provided	O
in	O
trans	O
restored	O
these	O
siderophore	O
system	O
activities	O
to	O
the	O
mutants	O
.	O

Copyright	O
1998	O
Academic	O
Press	O
.	O

It	O
may	O
also	O
be	O
suggested	O
that	O
particular	O
care	O
should	O
be	O
taken	O
when	O
such	O
a	O
trans	O
-	O
dominant	O
Rev	B-GENE
mutant	I-GENE
is	O
considered	O
to	O
be	O
used	O
as	O
a	O
genetic	O
therapy	O
against	O
HIV	O
-	O
I	O
infection	O
,	O
in	O
individuals	O
infected	O
with	O
both	O
HIV	O
-	O
I	O
and	O
HTLV	O
-	O
1	O
.	O

PATIENTS	O
AND	O
METHODS	O
:	O
Between	O
January	O
1992	O
and	O
June	O
1994	O
at	O
St	O
.	O

The	O
frequency	O
of	O
SPs	O
for	O
both	O
the	O
moderate	O
and	O
severe	O
groups	O
was	O
significantly	O
higher	O
than	O
that	O
in	O
patients	O
with	O
a	O
normal	O
MMFCV	O
(	O
p	O
<	O
.	O
01	O
)	O
;	O
of	O
154	O
arms	O
with	O
a	O
normal	O
MMFCV	O
,	O
only	O
9	O
(	O
6	O
%	O
)	O
had	O
an	O
SP	O
.	O

We	O
analyzed	O
the	O
P	O
-	O
SAECG	O
in	O
the	O
time	O
and	O
frequency	O
domain	O
in	O
23	O
patients	O
with	O
Paf	O
and	O
19	O
controls	O
.	O

Competitive	O
reverse	O
transcription	O
-	O
polymerase	O
chain	O
reaction	O
and	O
HPLC	O
analysis	O
showed	O
that	O
RUSH	B-GENE
-	I-GENE
1alpha	I-GENE
is	O
the	O
progesterone	O
-	O
dependent	O
splice	O
variant	O
.	O

TOR2	B-GENE
is	O
part	O
of	O
two	O
related	O
signaling	O
pathways	O
coordinating	O
cell	O
growth	O
in	O
Saccharomyces	O
cerevisiae	O
.	O

Transcervical	O
amnioinfusion	O
.	O

SETTING	O
:	O
A	O
division	O
of	O
a	O
large	O
tea	O
plantation	O
in	O
Kandy	O
.	O

Simple	O
models	O
of	O
bimolecular	O
interaction	O
did	O
not	O
fully	O
account	O
for	O
the	O
kinetic	O
profiles	O
obtained	O
with	O
the	O
parental	O
antibodies	O
and	O
the	O
hybrids	O
,	O
and	O
this	O
complexity	O
suggested	O
the	O
existence	O
of	O
a	O
conformational	O
heterogeneity	O
in	O
these	O
molecules	O
.	O

In	O
order	O
to	O
decipher	O
the	O
pathway	O
that	O
leads	O
to	O
Hox	B-GENE
gene	I-GENE
induction	O
,	O
we	O
have	O
investigated	O
whether	O
a	O
Hox	B-GENE
gene	I-GENE
regulator	O
,	O
the	O
leucine	O
zipper	O
transcription	O
factor	O
MafB	B-GENE
/	O
Kr	B-GENE
,	O
is	O
itself	O
transcriptionally	O
regulated	O
by	O
the	O
environmental	O
signals	O
.	O

Reporter	O
constructs	O
function	O
in	O
a	O
parallel	O
manner	O
,	O
demonstrating	O
the	O
key	O
role	O
of	O
the	O
AhR	B-GENE
in	O
constitutive	O
as	O
well	O
as	O
TCDD	O
-	O
induced	O
expression	O
of	O
Cyp1B1	B-GENE
in	O
mouse	O
embryo	O
fibroblasts	O
.	O

Transfection	O
studies	O
also	O
showed	O
that	O
3	O
'	O
-	O
deletion	O
of	O
sequences	O
downstream	O
of	O
the	O
transcriptional	O
start	O
site	O
(	O
+	O
1	O
/	O
+	O
47	O
)	O
markedly	O
reduced	O
OSM	B-GENE
-	O
fold	O
induction	O
.	O

Oncostatin	B-GENE
M	I-GENE
stimulates	O
c	B-GENE
-	I-GENE
Fos	I-GENE
to	O
bind	O
a	O
transcriptionally	O
responsive	O
AP	B-GENE
-	I-GENE
1	I-GENE
element	I-GENE
within	O
the	O
tissue	B-GENE
inhibitor	I-GENE
of	I-GENE
metalloproteinase	I-GENE
-	I-GENE
1	I-GENE
promoter	I-GENE
.	O

We	O
have	O
isolated	O
a	O
new	O
human	B-GENE
RING	I-GENE
-	I-GENE
finger	I-GENE
gene	I-GENE
(	O
RNF4	B-GENE
)	O
that	O
encodes	O
a	O
190	O
-	O
amino	O
-	O
acid	O
protein	O
.	O

To	O
elucidate	O
the	O
regulatory	O
mechanism	O
of	O
human	B-GENE
AM	I-GENE
gene	I-GENE
expression	O
,	O
functional	O
elements	O
of	O
5	O
'	O
-	O
flanking	O
region	O
of	O
AM	B-GENE
gene	I-GENE
were	O
studied	O
in	O
human	O
aortic	O
endothelial	O
cells	O
(	O
HAEC	O
)	O
.	O

Soluble	O
FasR	B-GENE
ligand	O
-	O
binding	O
domain	O
:	O
high	O
-	O
yield	O
production	O
of	O
active	O
fusion	O
and	O
non	O
-	O
fusion	O
recombinant	O
proteins	O
using	O
the	O
baculovirus	O
/	O
insect	O
cell	O
system	O
.	O

The	O
inhibition	O
of	O
focus	O
formation	O
observed	O
in	O
the	O
presence	O
of	O
C3G	B-GENE
was	O
not	O
due	O
to	O
toxic	O
effects	O
on	O
cell	O
viability	O
,	O
since	O
transfected	O
C3G	B-GENE
cells	O
exhibited	O
the	O
same	O
survival	O
and	O
growth	O
rates	O
as	O
untransfected	O
NIH3T3	O
cells	O
or	O
cells	O
transfected	O
with	O
plasmid	O
vector	O
alone	O
.	O

C	O
.	O
D2	O
-	O
Chr	O
4	O
congenic	O
strains	O
harboring	O
DBA	O
/	O
2	O
alleles	O
associated	O
with	O
the	O
Pctr1	B-GENE
locus	I-GENE
contained	O
DBA	O
/	O
2	O
"	O
resistant	O
"	O
alleles	O
of	O
the	O
CDK4	B-GENE
/	O
CDK6	B-GENE
inhibitors	O
p16	B-GENE
and	O
p15	B-GENE
.	O

When	O
tested	O
with	O
wild	O
-	O
type	O
(	O
DBA	O
/	O
2	O
)	O
p16	B-GENE
,	O
both	O
A134C	O
and	O
G232A	O
BALB	O
/	O
c	O
-	O
specific	O
variants	O
of	O
p16	B-GENE
were	O
inefficient	O
in	O
their	O
ability	O
to	O
inhibit	O
the	O
activity	O
of	O
cyclin	B-GENE
D2	I-GENE
/	O
CDK4	B-GENE
in	O
kinase	O
assays	O
with	O
retinoblastoma	B-GENE
protein	I-GENE
,	O
suggesting	O
this	O
defective	O
,	O
inherited	O
allele	O
plays	O
an	O
important	O
role	O
in	O
the	O
genetic	O
susceptibility	O
of	O
BALB	O
/	O
c	O
mice	O
for	O
plasmacytoma	O
induction	O
and	O
that	O
p16	B-GENE
(	O
INK4a	B-GENE
)	O
is	O
a	O
strong	O
candidate	O
for	O
the	O
Pctr1	B-GENE
locus	I-GENE
.	O

Despite	O
this	O
there	O
was	O
no	O
difference	O
in	O
the	O
intubating	O
conditions	O
at	O
one	O
minute	O
with	O
25	O
excellent	O
/	O
5	O
good	O
in	O
the	O
suxamethonium	O
group	O
and	O
27	O
excellent	O
/	O
3	O
good	O
in	O
the	O
rocuronium	O
group	O
.	O

Cloning	O
and	O
expression	O
of	O
two	O
genes	O
encoding	O
auxin	B-GENE
-	I-GENE
binding	I-GENE
proteins	I-GENE
from	O
tobacco	O
.	O

Furthermore	O
,	O
direct	O
association	O
with	O
D3	O
phosphatidylinositides	O
seems	O
to	O
be	O
essential	O
for	O
activation	O
of	O
PKB	B-GENE
/	O
Akt	B-GENE
.	O

The	O
FMN	O
moiety	O
but	O
not	O
the	O
[	O
3Fe	O
-	O
4S	O
]	O
cluster	O
of	O
the	O
subunit	O
appears	O
to	O
participate	O
in	O
this	O
reaction	O
.	O

Alison	O
Bell	O
Memorial	O
Award	O
.	O

METHODS	O
:	O
A	O
population	O
survey	O
was	O
undertaken	O
in	O
10	O
,	O
148	O
individuals	O
to	O
measure	O
the	O
prevalence	O
and	O
identify	O
the	O
causes	O
of	O
blindness	O
in	O
Lebanon	O
.	O

The	O
mean	O
duration	O
of	O
pain	O
relief	O
was	O
4	O
-	O
6	O
weeks	O
.	O

The	O
ESEM	O
differs	O
from	O
conventional	O
SEM	O
in	O
that	O
no	O
sample	O
preparation	O
is	O
needed	O
,	O
eliminating	O
artifactual	O
changes	O
.	O

The	O
3	O
'	O
fragment	O
was	O
shown	O
to	O
accumulate	O
as	O
full	O
-	O
length	O
mRNA	O
disappeared	O
in	O
actinomycin	O
D	O
-	O
treated	O
cells	O
,	O
indicating	O
a	O
precursor	O
-	O
product	O
relationship	O
.	O

The	O
TATA	B-GENE
box	I-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
(	O
TBP	B-GENE
)	O
plays	O
an	O
essential	O
role	O
in	O
transcription	O
by	O
all	O
three	O
eukaryotic	O
nuclear	B-GENE
RNA	I-GENE
polymerases	I-GENE
,	O
polymerases	B-GENE
(	I-GENE
Pol	I-GENE
)	I-GENE
I	I-GENE
,	I-GENE
II	I-GENE
,	I-GENE
and	I-GENE
III	I-GENE
.	O

A	O
triple	B-GENE
-	I-GENE
mutant	I-GENE
TBP	I-GENE
(	O
R231E	O
+	O
R235E	O
+	O
R239S	O
)	O
had	O
greatly	O
reduced	O
activity	O
for	O
yeast	B-GENE
U6	I-GENE
snRNA	I-GENE
gene	I-GENE
transcription	O
while	O
remaining	O
active	O
for	O
Pol	B-GENE
II	I-GENE
basal	O
transcription	O
.	O

E2F	B-GENE
activity	O
is	O
regulated	O
in	O
part	O
by	O
the	O
retinoblastoma	B-GENE
family	I-GENE
of	I-GENE
tumor	I-GENE
suppressor	I-GENE
proteins	I-GENE
.	O

This	O
resulted	O
in	O
a	O
complete	O
inhibition	O
of	O
Site	O
-	O
1	O
cleavage	O
that	O
was	O
restored	O
by	O
concomitant	O
overexpression	O
of	O
full	O
-	O
length	O
SCAP	B-GENE
.	O

To	O
determine	O
the	O
true	O
molecular	O
identity	O
of	O
SFD	B-GENE
,	O
both	O
the	O
50	O
-	O
and	O
57	O
-	O
kDa	O
polypeptides	O
were	O
directly	O
sequenced	O
.	O

Molecular	O
characterization	O
of	O
the	O
50	O
-	O
and	O
57	O
-	O
kDa	O
subunits	O
of	O
the	O
bovine	B-GENE
vacuolar	I-GENE
proton	I-GENE
pump	I-GENE
.	O

In	O
C	O
.	O
albicans	O
,	O
HST6	B-GENE
is	O
expressed	O
constitutively	O
at	O
high	O
levels	O
in	O
the	O
different	O
cell	O
types	O
analysed	O
(	O
yeast	O
,	O
hyphae	O
,	O
white	O
and	O
opaque	O
)	O
,	O
demonstrating	O
that	O
HST6	B-GENE
transcription	O
is	O
not	O
repressed	O
in	O
this	O
diploid	O
yeast	O
,	O
unlike	O
in	O
diploid	O
S	O
.	O
cerevisiae	O
,	O
and	O
suggesting	O
a	O
basic	O
biological	O
function	O
for	O
the	O
Hst6p	B-GENE
transporter	O
in	O
C	O
.	O
albicans	O
.	O

Furthermore	O
,	O
binding	O
of	O
recombinant	B-GENE
Myb	I-GENE
and	O
Ets	B-GENE
-	I-GENE
2	I-GENE
protein	I-GENE
to	O
these	O
fragments	O
could	O
be	O
competed	O
with	O
an	O
excess	O
of	O
double	O
stranded	O
oligodeoxynucleotides	O
containing	O
canonical	O
,	O
but	O
not	O
mutated	O
,	O
Myb	B-GENE
-	O
or	O
Ets	B-GENE
-	I-GENE
binding	I-GENE
sites	I-GENE
.	O

This	O
structure	O
interconnects	O
specific	O
triplets	O
of	O
the	O
basal	O
bodies	O
with	O
the	O
microtubular	O
bundles	O
that	O
emerge	O
from	O
the	O
basal	O
apparatus	O
.	O

To	O
understand	O
the	O
regulatory	O
mechanism	O
controlling	O
its	O
expression	O
at	O
low	O
temperature	O
,	O
the	O
promoter	O
region	O
has	O
been	O
characterized	O
.	O

In	O
the	O
current	O
study	O
,	O
the	O
roles	O
of	O
two	O
putative	O
cis	O
-	O
acting	O
elements	O
within	O
the	O
-	O
73	O
to	O
+	O
44	O
region	O
in	O
basal	O
exon	O
2	O
promoter	O
activity	O
were	O
evaluated	O
using	O
mutagenesis	O
and	O
nuclear	O
protein	O
-	O
DNA	O
binding	O
assays	O
.	O

We	O
have	O
examined	O
reporter	O
gene	O
(	O
beta	B-GENE
-	I-GENE
gal	I-GENE
)	O
expression	O
directed	O
by	O
human	B-GENE
heat	I-GENE
shock	I-GENE
transcription	I-GENE
factors	I-GENE
1	I-GENE
and	I-GENE
2	I-GENE
(	O
HSF1	B-GENE
and	O
HSF2	B-GENE
)	O
in	O
HeLa	O
cells	O
and	O
in	O
yeast	O
(	O
Saccharomyces	O
cerevisiae	O
)	O
.	O

Localized	O
fluorescence	O
was	O
detectable	O
only	O
in	O
cells	O
containing	O
a	O
visible	O
midcell	O
constriction	O
,	O
suggesting	O
that	O
FtsK	B-GENE
targeting	O
normally	O
occurs	O
only	O
at	O
a	O
late	O
stage	O
of	O
septation	O
.	O

No	O
TATA	O
box	O
was	O
found	O
in	O
the	O
putative	O
promoter	O
region	O
,	O
but	O
multiple	O
GC	O
boxes	O
were	O
found	O
around	O
the	O
cap	O
sites	O
,	O
supporting	O
the	O
previously	O
inferred	O
housekeeping	O
nature	O
of	O
CYP51	B-GENE
gene	I-GENE
and	O
the	O
existence	O
of	O
the	O
multiple	O
transcription	O
initiation	O
sites	O
.	O

Structural	O
and	O
evolutionary	O
studies	O
on	O
sterol	B-GENE
14	I-GENE
-	I-GENE
demethylase	I-GENE
P450	I-GENE
(	O
CYP51	B-GENE
)	O
,	O
the	O
most	O
conserved	O
P450	B-GENE
monooxygenase	I-GENE
:	O
I	O
.	O

Its	O
expression	O
pattern	O
is	O
representative	O
of	O
many	O
B	O
cell	O
-	O
specific	O
proteins	O
,	O
which	O
are	O
essential	O
for	O
B	O
cell	O
development	O
and	O
activation	O
but	O
are	O
down	O
-	O
regulated	O
after	O
B	O
cells	O
become	O
terminally	O
differentiated	O
plasma	O
cells	O
.	O

The	O
intercistronic	O
gene	O
junctions	O
of	O
vesicular	O
stomatitis	O
virus	O
(	O
VSV	O
)	O
contain	O
conserved	O
sequence	O
elements	O
that	O
are	O
important	O
for	O
polyadenylation	O
and	O
transcription	O
termination	O
of	O
upstream	O
transcript	O
as	O
well	O
as	O
reinitiation	O
of	O
transcription	O
of	O
downstream	O
transcript	O
.	O

Infectious	O
mutant	O
virus	O
progeny	O
was	O
obtained	O
only	O
on	O
complementing	O
gK	B-GENE
-	O
expressing	O
cells	O
,	O
suggesting	O
that	O
gK	B-GENE
has	O
an	O
important	O
function	O
in	O
the	O
replication	O
cycle	O
.	O

Cleavage	O
and	O
DNA	O
joining	O
reactions	O
,	O
carried	O
out	O
by	O
human	B-GENE
immunodeficiency	I-GENE
virus	I-GENE
type	I-GENE
1	I-GENE
(	I-GENE
HIV	I-GENE
-	I-GENE
1	I-GENE
)	I-GENE
integrase	I-GENE
,	O
are	O
necessary	O
to	O
effect	O
the	O
covalent	O
insertion	O
of	O
HIV	O
-	O
1	O
DNA	O
into	O
the	O
host	O
genome	O
.	O

The	O
DSF	O
regimen	O
appears	O
to	O
have	O
significant	O
activity	O
in	O
patients	O
who	O
have	O
metastatic	O
pancreatic	O
islet	O
-	O
cell	O
carcinoma	O
,	O
and	O
patient	O
tolerance	O
of	O
the	O
regimen	O
is	O
excellent	O
,	O
thus	O
warranting	O
further	O
investigation	O
.	O

Activation	O
of	O
the	O
mitogen	B-GENE
activated	I-GENE
protein	I-GENE
(	I-GENE
MAP	I-GENE
)	I-GENE
kinase	I-GENE
is	O
a	O
primary	O
consequence	O
of	O
Ras	B-GENE
activation	O
and	O
plays	O
a	O
key	O
role	O
in	O
mediating	O
Ras	B-GENE
signal	O
transduction	O
.	O

Histone	B-GENE
acetylation	O
levels	O
in	O
cells	O
result	O
from	O
a	O
dynamic	O
equilibrium	O
between	O
competing	O
histone	B-GENE
acetylases	I-GENE
and	I-GENE
deacetylases	I-GENE
.	O

CyIIa	B-GENE
transcription	O
follows	O
,	O
and	O
is	O
therefore	O
downstream	O
of	O
,	O
the	O
initial	O
specification	O
of	O
these	O
embryonic	O
domains	O
.	O

Cis	O
-	O
regulation	O
downstream	O
of	O
cell	O
type	O
specification	O
:	O
a	O
single	O
compact	O
element	O
controls	O
the	O
complex	O
expression	O
of	O
the	O
CyIIa	B-GENE
gene	I-GENE
in	O
sea	O
urchin	O
embryos	O
.	O

We	O
also	O
present	O
evidence	O
that	O
human	B-GENE
HYAL1	I-GENE
is	O
identical	O
to	O
an	O
uncharacterized	O
gene	O
positionally	O
cloned	O
by	O
others	O
from	O
chromosome	O
3p21	O
.	O
3	O
that	O
is	O
homozygously	O
deleted	O
in	O
several	O
small	O
-	O
cell	O
lung	O
carcinoma	O
cell	O
lines	O
.	O

In	O
patients	O
with	O
myalgia	O
,	O
Raynaud	O
'	O
s	O
syndrome	O
,	O
skin	O
vasculitis	O
and	O
vascular	O
diseases	O
WFAg	B-GENE
concentrations	O
were	O
higher	O
than	O
in	O
patients	O
without	O
them	O
.	O

Although	O
the	O
expression	O
of	O
the	O
4E	B-GENE
-	I-GENE
BP1	I-GENE
gene	I-GENE
alone	O
has	O
not	O
yet	O
been	O
accomplished	O
,	O
the	O
gene	O
was	O
expressed	O
in	O
Escherichia	O
coli	O
[	O
BL21	O
(	O
DE3	O
)	O
]	O
as	O
a	O
fusion	O
gene	O
with	O
the	O
glutathione	B-GENE
-	I-GENE
S	I-GENE
-	I-GENE
transferase	I-GENE
(	O
GST	B-GENE
)	O
gene	O
using	O
a	O
prokaryotic	O
gene	O
fusion	O
vector	O
(	O
pGEX	O
-	O
4T	O
-	O
2	O
)	O
,	O
which	O
contains	O
a	O
gene	O
sequence	O
coding	O
the	O
cleavage	O
site	O
for	O
a	O
specific	O
protease	O
,	O
alpha	B-GENE
-	I-GENE
thrombin	I-GENE
.	O

Randomised	O
comparison	O
of	O
addition	O
of	O
autologous	O
bone	O
-	O
marrow	O
transplantation	O
to	O
intensive	O
chemotherapy	O
for	O
acute	O
myeloid	O
leukaemia	O
in	O
first	O
remission	O
:	O
results	O
of	O
MRC	O
AML	O
10	O
trial	O
.	O

Therapeutic	O
use	O
of	O
cannabis	O
.	O

Analysis	O
of	O
intragenic	O
revertants	O
shows	O
that	O
this	O
function	O
depends	O
on	O
the	O
amino	O
acid	O
preceding	O
the	O
first	O
cysteine	O
residue	O
of	O
the	O
DNA	O
-	O
binding	O
domain	O
of	O
Hap1p	B-GENE
.	O

Peripheral	O
visual	O
stimuli	O
and	O
monoaural	O
auditory	O
stimuli	O
were	O
used	O
as	O
targets	O
.	O

A	O
review	O
of	O
studies	O
published	O
between	O
1983	O
and	O
1995	O
shows	O
that	O
there	O
are	O
some	O
common	O
factors	O
as	O
regards	O
the	O
psychological	O
distress	O
and	O
social	O
and	O
functional	O
limitations	O
this	O
group	O
of	O
patients	O
has	O
to	O
deal	O
with	O
.	O

PKC	B-GENE
-	I-GENE
gamma	I-GENE
,	O
which	O
is	O
not	O
present	O
in	O
keratinocytes	O
,	O
also	O
induces	O
involucrin	B-GENE
gene	I-GENE
expression	O
in	O
a	O
TPA	O
-	O
independent	O
manner	O
,	O
when	O
introduced	O
into	O
SVHK	O
cells	O
.	O

Identification	O
and	O
characterization	O
of	O
specific	O
DNA	O
-	O
binding	O
complexes	O
containing	O
members	O
of	O
the	O
Myc	B-GENE
/	O
Max	B-GENE
/	O
Mad	B-GENE
network	O
of	O
transcriptional	O
regulators	O
.	O

We	O
further	O
show	O
that	O
proteolytic	O
targeting	O
by	O
calpain	B-GENE
II	I-GENE
and	O
the	O
proteasome	O
involves	O
different	O
structural	O
elements	O
of	O
YY1	B-GENE
.	O

Primers	O
for	O
subsequent	O
rounds	O
of	O
RACE	O
were	O
designed	O
from	O
the	O
5	O
'	O
-	O
ends	O
of	O
amplified	O
RACE	O
products	O
.	O

Human	O
ZFM1	B-GENE
protein	I-GENE
is	O
a	O
transcriptional	O
repressor	O
that	O
interacts	O
with	O
the	O
transcription	B-GENE
activation	I-GENE
domain	I-GENE
of	I-GENE
stage	I-GENE
-	I-GENE
specific	I-GENE
activator	I-GENE
protein	I-GENE
.	O

Surprisingly	O
,	O
the	O
CSF1R	B-GENE
/	O
IRDelta960	B-GENE
was	O
as	O
effective	O
as	O
the	O
CSF1R	B-GENE
/	O
IR	B-GENE
in	O
mediating	O
CSF	B-GENE
-	I-GENE
1	I-GENE
protection	O
of	O
cells	O
from	O
staurosporine	O
-	O
induced	O
apoptosis	O
.	O

CONCLUSIONS	O
:	O
The	O
special	O
clinical	O
presentation	O
of	O
our	O
case	O
of	O
possible	O
Gardner	O
'	O
s	O
syndrome	O
is	O
discussed	O
.	O

These	O
results	O
would	O
suggest	O
that	O
a	O
high	O
UV	O
sensitivity	O
is	O
associated	O
with	O
high	O
phaeomelanin	O
and	O
low	O
eumelanin	O
levels	O
,	O
and	O
point	O
to	O
the	O
eumelanin	O
/	O
phaeomelanin	O
ratio	O
as	O
a	O
novel	O
chemical	O
parameter	O
that	O
could	O
be	O
used	O
for	O
predicting	O
individuals	O
at	O
high	O
risk	O
for	O
skin	O
cancer	O
and	O
melanoma	O
.	O

In	O
ferrets	O
naturally	O
infected	O
with	O
H	O
.	O
mustelae	O
,	O
a	O
single	O
dose	O
(	O
50	O
mg	O
/	O
kg	O
,	O
per	O
os	O
)	O
of	O
fluorofamide	O
completely	O
inhibited	O
bacterial	B-GENE
urease	I-GENE
.	O

The	O
cAMP	O
-	O
dependent	O
mitogenic	O
pathway	O
is	O
unique	O
as	O
it	O
is	O
independent	O
of	O
mitogen	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
kinase	I-GENE
activation	O
and	O
differs	O
from	O
growth	O
factor	O
-	O
dependent	O
pathways	O
at	O
the	O
level	O
of	O
the	O
expression	O
of	O
several	O
protooncogenes	O
/	O
transcription	O
factors	O
.	O

CONCLUSIONS	O
:	O
Use	O
of	O
the	O
first	O
method	O
was	O
associated	O
with	O
a	O
reduction	O
in	O
the	O
time	O
patients	O
remained	O
in	O
the	O
ICU	O
before	O
transfer	O
to	O
another	O
unit	O
and	O
savings	O
in	O
nursing	O
time	O
,	O
but	O
the	O
two	O
methods	O
did	O
not	O
differ	O
according	O
to	O
clinical	O
outcomes	O
.	O

We	O
have	O
elucidated	O
the	O
exon	O
-	O
intron	O
organization	O
of	O
the	O
entire	O
human	O
CD58	B-GENE
gene	I-GENE
,	O
including	O
approximately	O
2	O
.	O
5	O
kilobases	O
(	O
kb	O
)	O
of	O
5	O
'	O
-	O
flanking	O
DNA	O
.	O

The	O
risk	O
factors	O
for	O
hematuria	O
in	O
patients	O
with	O
renal	O
hypouricemia	O
are	O
the	O
elevation	O
of	O
urinary	O
urate	O
concentration	O
and	O
the	O
subtypes	O
of	O
Post	O
and	O
Secretion	O
.	O

Two	O
hundred	O
sixty	O
-	O
four	O
patients	O
scheduled	O
for	O
DCBM	O
were	O
randomized	O
to	O
receive	O
intravenously	O
geG	O
0	O
.	O
25	O
mg	O
(	O
geG	O
-	O
25	O
)	O
,	O
or	O
geG	O
0	O
.	O
5	O
mg	O
(	O
geG	O
-	O
50	O
)	O
,	O
or	O
HBB	O
20	O
mg	O
as	O
hypotonic	O
agent	O
.	O

If	O
the	O
haemoglobin	B-GENE
concentration	O
(	O
Hb	B-GENE
)	O
was	O
less	O
than	O
12	O
g	O
dL	O
-	O
1	O
they	O
were	O
given	O
a	O
four	O
week	O
course	O
of	O
ferrous	O
sulphate	O
.	O

Based	O
on	O
restriction	O
enzyme	O
analysis	O
,	O
Southern	O
blots	O
,	O
polymerase	O
chain	O
reaction	O
analysis	O
and	O
DNA	O
sequencing	O
,	O
it	O
was	O
confirmed	O
that	O
the	O
three	O
overlapping	O
clones	O
isolated	O
cover	O
the	O
entire	O
cHO	B-GENE
-	I-GENE
1	I-GENE
gene	I-GENE
,	O
as	O
well	O
as	O
approximately	O
10	O
kb	O
of	O
the	O
flanking	O
regions	O
on	O
both	O
ends	O
.	O

Position	O
-	O
independent	O
expression	O
of	O
a	O
human	O
nerve	B-GENE
growth	I-GENE
factor	I-GENE
-	O
luciferase	B-GENE
reporter	O
gene	O
cloned	O
on	O
a	O
yeast	O
artificial	O
chromosome	O
vector	O
.	O

Calcitriol	O
therapy	O
was	O
associated	O
with	O
a	O
decrease	O
in	O
serum	O
iPTH	B-GENE
levels	O
(	O
701	O
+	O
/	O
-	O
103	O
.	O
9	O
vs	O
.	O

Alterations	O
in	O
DNase	B-GENE
I	I-GENE
reactivity	O
of	O
the	O
GC	O
-	O
response	O
element	O
region	O
suggest	O
that	O
GC	B-GENE
receptor	I-GENE
-	I-GENE
GC	I-GENE
complexes	I-GENE
may	O
associate	O
,	O
in	O
a	O
transient	O
manner	O
,	O
with	O
the	O
promoter	O
in	O
the	O
actively	O
transcribing	O
control	O
state	O
.	O

Most	O
pituitary	O
hormone	O
-	O
coding	O
gene	O
promoters	O
are	O
activated	O
by	O
Ptx1	B-GENE
.	O

One	O
of	O
these	O
small	B-GENE
inteins	I-GENE
might	O
be	O
inactive	O
or	O
a	O
"	B-GENE
pseudo	I-GENE
intein	I-GENE
.	I-GENE
"	I-GENE
The	O
results	O
suggest	O
a	O
modular	O
architecture	O
for	O
inteins	B-GENE
,	O
clarify	O
their	O
origin	O
and	O
relationship	O
to	O
other	O
protein	O
families	O
,	O
and	O
extend	O
recent	O
experimental	O
findings	O
on	O
the	O
functional	O
roles	O
of	O
intein	B-GENE
N	I-GENE
,	I-GENE
C	I-GENE
,	I-GENE
and	I-GENE
EN	I-GENE
motifs	I-GENE
.	O

Purification	O
of	O
MvaT	B-GENE
enriched	O
for	O
two	O
polypeptides	O
of	O
approximate	O
molecular	O
mass	O
15	O
kDa	O
and	O
16	O
kDa	O
,	O
designated	O
P15	B-GENE
and	O
P16	B-GENE
.	O

These	O
results	O
indicate	O
that	O
TGF	B-GENE
-	I-GENE
betaf	I-GENE
potentiates	O
the	O
c	B-GENE
-	I-GENE
fos	I-GENE
SRE	O
activated	O
by	O
PKC	B-GENE
through	O
the	O
SRF	B-GENE
binding	I-GENE
site	I-GENE
.	O

BACKGROUND	O
:	O
Defensins	B-GENE
,	O
also	O
known	O
as	O
human	B-GENE
neutrophil	I-GENE
peptides	I-GENE
,	O
are	O
antimicrobial	O
peptides	O
present	O
in	O
the	O
azurophil	O
granules	O
of	O
neutrophils	O
.	O

The	O
spontaneous	O
mutation	O
blocking	O
pca	B-GENE
gene	I-GENE
expression	O
was	O
located	O
in	O
the	O
promoter	O
for	O
the	O
pca	B-GENE
operon	I-GENE
.	O

From	O
250	O
g	O
of	O
cells	O
,	O
we	O
isolated	O
1	O
mg	O
of	O
PDH	B-GENE
complex	I-GENE
with	O
a	O
specific	O
activity	O
of	O
12	O
.	O
6	O
U	O
/	O
mg	O
of	O
protein	O
.	O

The	O
PDH	B-GENE
complex	I-GENE
-	I-GENE
encoding	I-GENE
genes	I-GENE
were	O
identified	O
by	O
hybridization	O
experiments	O
and	O
sequence	O
analysis	O
in	O
two	O
separate	O
gene	O
regions	O
in	O
the	O
genome	O
of	O
Z	O
.	O
mobilis	O
.	O

We	O
have	O
identified	O
two	O
functional	O
elements	O
,	O
both	O
located	O
downstream	O
from	O
the	O
TATA	O
motif	O
,	O
that	O
control	O
Id4	B-GENE
promoter	I-GENE
activity	O
.	O

Azithromycin	O
is	O
a	O
new	O
generation	O
macrolide	O
antibiotic	O
with	O
unusual	O
and	O
favorable	O
pharmacokinetics	O
,	O
and	O
seems	O
to	O
be	O
a	O
very	O
promising	O
agent	O
for	O
innovative	O
anti	O
-	O
H	O
.	O
pylori	O
regimens	O
.	O

The	O
study	O
enrolled	O
994	O
people	O
co	O
-	O
infected	O
with	O
CMV	O
and	O
HIV	O
,	O
with	O
at	O
least	O
one	O
CD4	B-GENE
count	O
recorded	O
<	O
100	O
x	O
10	O
(	O
6	O
)	O
cells	O
/	O
l	O
.	O

National	O
certification	O
:	O
a	O
vital	O
component	O
of	O
quality	O
assurance	O
.	O

Two	O
rare	O
novel	O
mutations	O
,	O
D811N	O
in	O
exon	O
20	O
and	O
R835C	O
in	O
exon	O
21	O
,	O
were	O
identified	O
in	O
the	O
first	O
nucleotide	O
-	O
binding	O
fold	O
(	O
NBF	O
)	O
,	O
a	O
functionally	O
important	O
region	O
of	O
SUR1	B-GENE
,	O
in	O
one	O
patient	O
each	O
,	O
both	O
heterozygotes	O
.	O

Chimaeric	O
VP16	B-GENE
-	O
E2	B-GENE
molecules	O
suggest	O
that	O
the	O
epithelial	O
specific	O
transcriptional	O
activation	O
of	O
the	O
BPV	B-GENE
-	I-GENE
4	I-GENE
LCR	I-GENE
promoter	I-GENE
is	O
mediated	O
by	O
the	O
E2	B-GENE
transactivation	I-GENE
domain	I-GENE
.	O

These	O
changes	O
correlate	O
directly	O
with	O
an	O
increase	O
in	O
the	O
acetylation	O
levels	O
of	O
all	O
four	O
core	B-GENE
histones	I-GENE
in	O
vivo	O
.	O

Drosophila	B-GENE
orthodenticle	I-GENE
(	O
otd	B-GENE
)	O
and	O
murine	B-GENE
Otx	I-GENE
genes	I-GENE
exemplify	O
this	O
,	O
both	O
in	O
terms	O
of	O
expression	O
patterns	O
and	O
mutant	O
phenotypes	O
.	O

APETALA3	B-GENE
transcripts	I-GENE
are	O
first	O
detected	O
in	O
a	O
meristematic	O
region	O
that	O
will	O
give	O
rise	O
to	O
the	O
petal	O
and	O
stamen	O
primordia	O
,	O
and	O
expression	O
is	O
maintained	O
in	O
this	O
region	O
during	O
subsequent	O
development	O
of	O
these	O
organs	O
.	O

We	O
also	O
recovered	O
mutations	O
in	O
the	O
60A	B-GENE
gene	I-GENE
which	O
encodes	O
another	O
TGF	B-GENE
-	I-GENE
beta	I-GENE
-	I-GENE
related	I-GENE
factor	I-GENE
in	O
Drosophila	O
.	O

Cell	O
lines	O
are	O
checked	O
to	O
find	O
out	O
whether	O
they	O
develop	O
tumors	O
in	O
nude	O
mice	O
followed	O
by	O
an	O
analysis	O
of	O
the	O
karyotype	O
.	O

Cervicovaginal	O
foetal	B-GENE
fibronectin	I-GENE
in	O
the	O
prediction	O
of	O
preterm	O
labour	O
in	O
a	O
low	O
-	O
risk	O
population	O
.	O

In	O
addition	O
,	O
IgM	B-GENE
can	O
be	O
absent	O
in	O
children	O
with	O
congenital	O
toxoplasmosis	O
or	O
subjects	O
with	O
secondary	O
reactivation	O
.	O

Both	O
variants	O
display	O
the	O
seven	O
-	O
transmembrane	O
topology	O
that	O
is	O
typical	O
for	O
G	B-GENE
protein	I-GENE
-	I-GENE
coupled	I-GENE
receptors	I-GENE
.	O

A	O
constitutive	O
allele	O
of	O
GPA2	B-GENE
could	O
stimulate	O
growth	O
of	O
a	O
strain	O
lacking	O
both	O
RAS	B-GENE
genes	I-GENE
.	O

The	O
COOH	O
-	O
terminus	O
of	O
this	O
new	O
isoform	O
,	O
which	O
we	O
designate	O
beta	B-GENE
4	I-GENE
,	O
lacks	O
a	O
22	O
amino	O
acid	O
lysine	O
-	O
rich	O
sequence	O
common	O
to	O
both	O
the	O
human	B-GENE
red	I-GENE
cell	I-GENE
alpha	I-GENE
-	I-GENE
and	I-GENE
beta	I-GENE
-	I-GENE
adducin	I-GENE
subunits	I-GENE
and	O
homologous	O
to	O
a	O
highly	O
conserved	O
region	O
in	O
MARCKS	B-GENE
,	O
a	O
filamentous	O
actin	B-GENE
-	O
cross	O
linking	O
protein	O
regulated	O
by	O
protein	B-GENE
kinase	I-GENE
C	I-GENE
and	O
calcium	O
/	O
calmodulin	B-GENE
.	O
beta	B-GENE
4	I-GENE
-	I-GENE
adducin	I-GENE
preserves	O
a	O
previously	O
identified	O
calmodulin	B-GENE
binding	I-GENE
domain	I-GENE
.	O

PCR	O
analysis	O
indicates	O
that	O
this	O
new	O
beta	B-GENE
-	I-GENE
adducin	I-GENE
isoform	I-GENE
is	O
expressed	O
in	O
fetal	O
brain	O
and	O
liver	O
,	O
bone	O
marrow	O
,	O
and	O
NT	O
-	O
2	O
(	O
neuroepithelial	O
)	O
cells	O
,	O
but	O
is	O
not	O
detected	O
in	O
several	O
other	O
tissues	O
.	O

The	O
gene	B-GENE
lac	I-GENE
-	I-GENE
1	I-GENE
,	O
encoding	O
the	O
enzyme	O
laccase	B-GENE
,	O
is	O
the	O
best	O
characterized	O
of	O
a	O
number	O
of	O
genes	O
in	O
the	O
chestnut	O
blight	O
fungus	O
,	O
Cryphonectria	O
parasitica	O
,	O
that	O
are	O
repressed	O
by	O
hypoviruses	O
,	O
a	O
group	O
of	O
virulence	O
-	O
attenuating	O
mycoviruses	O
.	O
lac	B-GENE
-	I-GENE
1	I-GENE
has	O
also	O
been	O
shown	O
to	O
be	O
transcriptionally	O
activated	O
by	O
low	O
concentrations	O
of	O
the	O
translational	O
inhibitor	O
cycloheximide	O
(	O
CHX	O
)	O
and	O
by	O
the	O
immunosuppressant	O
cyclosporin	O
A	O
.	O

Both	O
TRE	O
-	O
like	O
elements	O
were	O
capable	O
of	O
binding	O
AP1	B-GENE
.	O

The	O
hp55	B-GENE
gamma	I-GENE
protein	I-GENE
interacts	O
strongly	O
with	O
the	O
activated	O
IGFIR	B-GENE
but	O
not	O
with	O
the	O
kinase	O
-	O
negative	O
mutant	O
receptor	O
.	O
hp55	B-GENE
gamma	I-GENE
also	O
interacts	O
with	O
the	O
insulin	B-GENE
receptor	I-GENE
(	O
IR	B-GENE
)	O
in	O
the	O
yeast	O
two	O
-	O
hybrid	O
system	O
.	O

The	O
plant	O
protein	O
maintains	O
all	O
the	O
functional	O
domains	O
found	O
in	O
the	O
other	O
proteins	O
,	O
including	O
nuclear	O
localization	O
signal	O
,	O
DNA	O
-	O
binding	O
domain	O
and	O
helicase	B-GENE
motifs	I-GENE
,	O
suggesting	O
that	O
it	O
might	O
also	O
act	O
as	O
part	O
of	O
the	O
RNA	O
transcription	O
apparatus	O
,	O
as	O
well	O
as	O
nucleotide	O
excision	O
repair	O
in	O
plant	O
cells	O
.	O

This	O
paper	O
describes	O
the	O
genomic	O
organization	O
of	O
mouse	O
gC1qBP	B-GENE
and	O
the	O
characterization	O
of	O
its	O
5	O
'	O
flanking	O
region	O
.	O

LysR	B-GENE
proteins	I-GENE
have	O
been	O
shown	O
to	O
regulate	O
urease	B-GENE
in	I-GENE
Klebsiella	I-GENE
aerogenes	I-GENE
(	O
NAC	B-GENE
)	O
,	O
and	O
catalase	B-GENE
in	I-GENE
Escherichia	I-GENE
coli	I-GENE
(	O
OxyR	B-GENE
)	O
,	O
which	O
offers	O
the	O
intracellular	O
bacterium	O
protection	O
from	O
phagolysosome	O
damage	O
.	O

Also	O
,	O
the	O
anti	O
-	O
inflammatory	O
activities	O
of	O
an	O
aqueous	O
extract	O
of	O
Buddleia	O
cordata	O
and	O
its	O
principal	O
glycoside	O
linarin	O
were	O
evaluated	O
.	O

Regulation	O
of	O
the	O
Raf	B-GENE
kinase	I-GENE
in	O
T	O
cells	O
differs	O
from	O
findings	O
with	O
a	O
variety	O
of	O
cell	O
lines	O
that	O
the	O
catalytic	B-GENE
domain	I-GENE
of	I-GENE
Raf	I-GENE
(	O
Raf	B-GENE
(	O
delta26	O
-	O
303	O
)	O
)	O
shows	O
no	O
activity	O
.	O

Full	B-GENE
-	I-GENE
length	I-GENE
FLAP	I-GENE
clones	O
were	O
isolated	O
from	O
a	O
mouse	O
skeletal	O
muscle	O
cDNA	O
library	O
.	O

We	O
have	O
visualized	O
DNA	O
-	O
protein	O
complexes	O
by	O
electron	O
microscopy	O
and	O
a	O
high	O
-	O
affinity	O
binding	O
site	O
of	O
WDV	B-GENE
Rep	I-GENE
protein	I-GENE
within	O
the	O
core	O
element	O
has	O
been	O
mapped	O
to	O
approximately	O
144	O
+	O
/	O
-	O
18	O
bp	O
upstream	O
from	O
the	O
initiation	O
site	O
,	O
between	O
the	O
start	O
site	O
for	O
complementary	O
-	O
sense	O
transcription	O
and	O
the	O
TATA	O
box	O
.	O

Rex	B-GENE
-	I-GENE
1	I-GENE
,	O
a	O
gene	O
encoding	O
a	O
transcription	O
factor	O
expressed	O
in	O
the	O
early	O
embryo	O
,	O
is	O
regulated	O
via	O
Oct	B-GENE
-	I-GENE
3	I-GENE
/	I-GENE
4	I-GENE
and	O
Oct	B-GENE
-	I-GENE
6	I-GENE
binding	O
to	O
an	O
octamer	O
site	O
and	O
a	O
novel	O
protein	O
,	O
Rox	B-GENE
-	I-GENE
1	I-GENE
,	O
binding	O
to	O
an	O
adjacent	O
site	O
.	O

However	O
,	O
inhibition	O
of	O
both	O
the	O
ERK	B-GENE
/	O
RSK	B-GENE
and	O
the	O
p38	B-GENE
/	O
MAPKAP	B-GENE
kinase	I-GENE
2	I-GENE
pathways	O
completely	O
abolished	O
NGF	B-GENE
-	O
induced	O
CREB	B-GENE
Ser	O
-	O
133	O
phosphorylation	O
.	O

Cells	O
respond	O
to	O
the	O
accumulation	O
of	O
unfolded	O
proteins	O
in	O
the	O
endoplasmic	O
reticulum	O
(	O
ER	O
)	O
by	O
increasing	O
the	O
transcription	O
of	O
the	O
genes	O
encoding	O
ER	B-GENE
-	I-GENE
resident	I-GENE
chaperone	I-GENE
proteins	I-GENE
.	O

The	O
mei4	B-GENE
+	I-GENE
gene	I-GENE
of	O
the	O
fission	O
yeast	O
Schizosaccharomyces	O
pombe	O
was	O
cloned	O
by	O
functional	O
complementation	O
.	O

In	O
some	O
cases	O
,	O
the	O
aberrant	O
methylation	O
of	O
CpGs	O
within	O
5	O
'	O
regulatory	O
regions	O
has	O
led	O
to	O
suppression	O
of	O
gene	O
activity	O
.	O

The	O
genomic	O
fragments	O
were	O
fused	O
upstream	O
of	O
the	O
luciferase	B-GENE
reporter	I-GENE
gene	I-GENE
.	O

Cotransfection	O
analyses	O
of	O
the	O
T	B-GENE
/	I-GENE
EBP	I-GENE
promoter	I-GENE
-	I-GENE
reporter	I-GENE
constructs	I-GENE
with	O
a	O
T	B-GENE
/	I-GENE
EBP	I-GENE
expression	O
vector	O
into	O
human	O
HepG2	O
cells	O
,	O
which	O
do	O
not	O
express	O
T	B-GENE
/	I-GENE
EBP	I-GENE
,	O
suggested	O
that	O
autoregulation	O
may	O
be	O
involved	O
in	O
controlling	O
both	O
rat	O
and	O
human	B-GENE
T	I-GENE
/	I-GENE
EBP	I-GENE
gene	I-GENE
expression	O
.	O

Deletion	O
of	O
the	O
last	O
two	O
Ser	O
residues	O
,	O
including	O
one	O
PKC	B-GENE
consensus	O
site	O
in	O
the	O
receptor	O
tail	O
,	O
prevented	O
only	O
phorbol	O
12	O
-	O
myristate	O
13	O
-	O
acetate	O
-	O
induced	O
desensitization	O
by	O
30	O
%	O
.	O

Flap	O
survival	O
depends	O
on	O
the	O
development	O
of	O
a	O
small	O
number	O
of	O
vascular	O
connections	O
between	O
vessels	O
arising	O
from	O
the	O
pedicle	O
and	O
preexisting	O
dermal	O
vessels	O
.	O

Jean	O
Klig	O
reviews	O
recent	O
literature	O
about	O
lower	O
respiratory	O
tract	O
infection	O
in	O
children	O
.	O

Potential	O
indicators	O
were	O
assessed	O
for	O
the	O
two	O
classifications	O
of	O
protein	O
-	O
energy	O
malnutrition	O
in	O
the	O
guidelines	O
for	O
integrated	O
management	O
of	O
childhood	O
illness	O
:	O
severe	O
malnutrition	O
,	O
which	O
requires	O
immediate	O
referral	O
to	O
hospital	O
,	O
and	O
very	O
low	O
weight	O
,	O
which	O
calls	O
for	O
feeding	O
assessment	O
,	O
nutritional	O
counselling	O
and	O
follow	O
-	O
up	O
.	O

Despite	O
its	O
requirement	O
for	O
enhancer	O
-	O
dependent	O
splicing	O
activity	O
in	O
vitro	O
,	O
the	O
dU2AF38	B-GENE
RS	I-GENE
domain	I-GENE
was	O
also	O
inessential	O
in	O
vivo	O
.	O

In	O
vitro	O
binding	O
studies	O
using	O
GST	B-GENE
fusion	O
proteins	O
and	O
yeast	O
extracts	O
defined	O
distinct	O
binding	O
sites	O
on	O
yAP180A	B-GENE
for	O
Pan1p	B-GENE
and	O
clathrin	B-GENE
.	O
yAP180	B-GENE
proteins	I-GENE
and	O
Pan1p	B-GENE
,	O
like	O
actin	B-GENE
,	O
localize	O
to	O
peripheral	O
patches	O
along	O
the	O
plasma	O
membrane	O
.	O

In	O
vitro	O
affinity	O
analyses	O
demonstrated	O
that	O
recombinant	O
130	O
-	O
kD	O
protein	O
directly	O
interacts	O
with	O
ZO	B-GENE
-	I-GENE
1	I-GENE
and	O
the	O
cytoplasmic	O
domain	O
of	O
occludin	B-GENE
,	O
but	O
not	O
with	O
ZO	B-GENE
-	I-GENE
2	I-GENE
.	O

Cytochrome	B-GENE
b	I-GENE
in	O
human	B-GENE
complex	I-GENE
II	I-GENE
(	O
succinate	B-GENE
-	I-GENE
ubiquinone	I-GENE
oxidoreductase	I-GENE
)	O
:	O
cDNA	O
cloning	O
of	O
the	O
components	O
in	O
liver	O
mitochondria	O
and	O
chromosome	O
assignment	O
of	O
the	O
genes	O
for	O
the	O
large	O
(	O
SDHC	B-GENE
)	O
and	O
small	O
(	O
SDHD	B-GENE
)	O
subunits	O
to	O
1q21	O
and	O
11q23	O
.	O

A	O
possible	O
decrease	O
in	O
theophylline	O
'	O
s	O
volume	O
of	O
distribution	O
at	O
4	O
days	O
,	O
but	O
not	O
immediately	O
,	O
after	O
administration	O
of	O
chloroquine	O
was	O
suggested	O
,	O
although	O
this	O
just	O
failed	O
to	O
achieve	O
statistical	O
significance	O
(	O
p	O
=	O
0	O
.	O
055	O
)	O
.	O

The	O
addition	O
of	O
a	O
Paf	B-GENE
-	O
containing	O
extract	O
does	O
not	O
lead	O
to	O
significant	O
protein	O
binding	O
to	O
these	O
two	O
hly	B-GENE
target	I-GENE
sequences	I-GENE
in	O
the	O
absence	O
of	O
PrfA	B-GENE
but	O
converts	O
the	O
complex	O
(	O
CIII	O
)	O
consisting	O
of	O
PrfA	B-GENE
and	O
the	O
109	B-GENE
bp	I-GENE
hly	I-GENE
DNA	I-GENE
fragment	I-GENE
to	O
a	O
slower	O
migrating	O
PrfA	B-GENE
-	O
Paf	B-GENE
-	O
DNA	O
complex	O
(	O
CI	O
)	O
.	O

ROCK	B-GENE
-	I-GENE
I	I-GENE
,	O
Kinectin	B-GENE
,	O
and	O
mDia2	B-GENE
can	O
bind	O
the	O
wild	O
type	O
forms	O
of	O
both	O
RhoA	B-GENE
and	O
Cdc42	B-GENE
in	O
a	O
GTP	O
-	O
dependent	O
manner	O
in	O
vitro	O
.	O

Among	O
three	O
isoforms	O
,	O
the	O
beta	O
isoform	O
has	O
the	O
greatest	O
Vmax	O
value	O
for	O
the	O
PtdIns	B-GENE
(	I-GENE
4	I-GENE
)	I-GENE
P	I-GENE
kinase	I-GENE
activity	O
and	O
the	O
gamma	O
isoform	O
is	O
most	O
markedly	O
stimulated	O
by	O
phosphatidic	O
acid	O
.	O

The	O
beta	O
subunit	O
of	O
the	O
heterotrimeric	B-GENE
G	I-GENE
proteins	I-GENE
that	O
transduce	O
signals	O
across	O
the	O
plasma	O
membrane	O
is	O
made	O
up	O
of	O
an	O
amino	O
-	O
terminal	O
alpha	O
-	O
helical	O
segment	O
followed	O
by	O
seven	O
repeating	O
units	O
called	O
WD	O
(	O
Trp	O
-	O
Asp	O
)	O
repeats	O
that	O
occur	O
in	O
about	O
140	O
different	O
proteins	O
.	O

Two	O
differentially	O
expressed	O
LNX	B-GENE
messages	I-GENE
encode	O
overlapping	O
proteins	O
with	O
predicted	O
molecular	O
masses	O
of	O
80	B-GENE
kDa	I-GENE
(	I-GENE
LNX	I-GENE
)	I-GENE
and	O
70	B-GENE
kDa	I-GENE
(	I-GENE
LNX	I-GENE
-	I-GENE
b	I-GENE
)	I-GENE
.	O

In	O
contrast	O
,	O
the	O
contractile	O
action	O
of	O
arachidonic	O
acid	O
,	O
via	O
a	O
presumed	O
cyclooxygenase	B-GENE
product	O
that	O
mediated	O
the	O
contractions	O
caused	O
by	O
both	O
TF	B-GENE
and	O
EGF	B-GENE
,	O
was	O
not	O
blocked	O
by	O
any	O
of	O
the	O
signal	O
pathway	O
probe	O
inhibitors	O
.	O

On	O
a	O
separate	O
occasion	O
the	O
T1	O
weighted	O
and	O
T2	O
weighted	O
sagittal	O
and	O
T2	O
weighted	O
axial	O
sequences	O
were	O
reported	O
blind	O
in	O
relation	O
to	O
the	O
initial	O
assessment	O
.	O

The	O
iron	O
dependence	O
of	O
transcription	O
and	O
expression	O
of	O
cvaA	B-GENE
,	O
which	O
encodes	O
a	O
transporter	O
accessory	O
protein	O
,	O
and	O
cvi	B-GENE
,	O
encoding	O
the	O
colicin	B-GENE
V	I-GENE
immunity	I-GENE
protein	I-GENE
,	O
was	O
assessed	O
under	O
conditions	O
of	O
iron	O
excess	O
or	O
depletion	O
.	O

Furthermore	O
,	O
the	O
deletion	O
of	O
bcp	B-GENE
from	O
the	O
chromosome	O
had	O
no	O
effect	O
on	O
gcv	B-GENE
-	O
lacZ	B-GENE
expression	O
.	O

Of	O
these	O
sites	O
,	O
PEA3	B-GENE
and	O
STAT	B-GENE
contributed	O
specifically	O
to	O
induction	O
by	O
v	B-GENE
-	I-GENE
src	I-GENE
,	O
whereas	O
the	O
remaining	O
elements	O
were	O
also	O
involved	O
in	O
induction	O
by	O
the	O
phorbol	O
ester	O
phorbol	O
myristate	O
acetate	O
(	O
PMA	O
)	O
.	O

BRCA1	B-GENE
protein	I-GENE
contains	O
an	O
amino	O
-	O
terminal	O
zinc	O
finger	O
motif	O
and	O
a	O
carboxy	O
-	O
terminal	O
acidic	O
region	O
.	O

The	O
mitochondrial	B-GENE
regulatory	I-GENE
region	I-GENE
(	O
mrr	B-GENE
)	O
located	O
between	O
the	O
tRNAPhe	B-GENE
and	O
tRNAPro	B-GENE
genes	I-GENE
of	O
mitochondrial	O
DNA	O
(	O
mtDNA	O
)	O
is	O
essential	O
for	O
regulation	O
of	O
replication	O
and	O
transcription	O
of	O
the	O
mitochondrial	O
genome	O
.	O

In	O
this	O
report	O
,	O
we	O
investigate	O
the	O
mechanism	O
underlying	O
Ras	B-GENE
activation	O
upon	O
stimulation	O
of	O
these	O
two	O
types	O
of	O
receptors	O
in	O
hematopoietic	O
cells	O
.	O

Thus	O
,	O
Sir	B-GENE
proteins	I-GENE
from	O
K	O
.	O
lactis	O
have	O
roles	O
in	O
both	O
silencing	O
and	O
telomere	O
length	O
maintenance	O
,	O
reflecting	O
conserved	O
functional	O
themes	O
.	O

These	O
mutants	O
were	O
tested	O
for	O
ability	O
to	O
bind	O
each	O
of	O
the	O
Site	B-GENE
II	I-GENE
cognate	I-GENE
proteins	I-GENE
,	O
and	O
subsequently	O
evaluated	O
for	O
ability	O
to	O
confer	O
H4	B-GENE
transcriptional	O
activity	O
using	O
chimeric	O
H4	B-GENE
promoter	O
/	O
CAT	B-GENE
fusion	O
constructs	O
in	O
different	O
cell	O
types	O
.	O

Increased	O
plasma	O
IgE	B-GENE
was	O
also	O
confirmed	O
in	O
the	O
NC	O
mice	O
,	O
and	O
treatment	O
with	O
FK506	O
ointment	O
reduced	O
the	O
plasma	O
IgE	B-GENE
level	O
.	O

Furthermore	O
,	O
in	O
the	O
ischemia	O
/	O
angiotension	B-GENE
II	I-GENE
-	O
induced	O
AHF	O
model	O
,	O
NIC	O
decreased	O
left	O
ventricular	O
end	O
-	O
diastolic	O
pressure	O
(	O
LVEDP	O
)	O
.	O

Group	O
A	O
(	O
68	O
.	O
7	O
+	O
/	O
-	O
2	O
.	O
7	O
years	O
)	O
consisted	O
of	O
patients	O
with	O
0	O
or	O
1	O
risk	O
factors	O
;	O
B	O
(	O
68	O
.	O
3	O
+	O
/	O
-	O
4	O
.	O
2	O
years	O
)	O
those	O
with	O
2	O
risk	O
factors	O
;	O
and	O
C	O
(	O
69	O
.	O
2	O
+	O
/	O
-	O
3	O
.	O
6	O
years	O
)	O
those	O
with	O
3	O
or	O
more	O
risk	O
factors	O
.	O

We	O
further	O
demonstrate	O
that	O
RU486	O
-	O
PR	B-GENE
-	I-GENE
B	I-GENE
interacts	O
physically	O
with	O
NCoR	B-GENE
in	O
vitro	O
.	O

PRL	B-GENE
receptor	I-GENE
also	O
activates	O
SHP	B-GENE
-	I-GENE
2	I-GENE
,	O
a	O
cytosolic	B-GENE
tyrosine	I-GENE
phosphatase	I-GENE
.	O

The	O
dominant	O
negative	O
mutant	O
of	O
SHP	B-GENE
-	I-GENE
2	I-GENE
was	O
found	O
to	O
inhibit	O
the	O
induction	O
of	O
tyrosine	O
phosphorylation	O
and	O
DNA	O
-	O
binding	O
activity	O
of	O
m	B-GENE
-	I-GENE
Stat5a	I-GENE
,	O
m	B-GENE
-	I-GENE
Stat5b	I-GENE
,	O
and	O
the	O
carboxyl	O
-	O
terminal	O
deletion	O
variant	O
m	B-GENE
-	I-GENE
Stat5adelta749	I-GENE
,	O
as	O
well	O
as	O
the	O
transactivation	O
potential	O
of	O
m	B-GENE
-	I-GENE
Stat5a	I-GENE
and	O
m	B-GENE
-	I-GENE
Stat5b	I-GENE
.	O

CONCLUSIONS	O
:	O
These	O
routinely	O
collected	O
data	O
provided	O
quantitative	O
estimates	O
of	O
changes	O
in	O
CBZ	O
Cl	O
/	O
F	O
due	O
to	O
comedication	O
and	O
an	O
age	O
-	O
related	O
decrease	O
in	O
Cl	O
/	O
F	O
The	O
derived	O
regression	O
equations	O
reasonably	O
predicted	O
concentrations	O
in	O
a	O
separate	O
validation	O
set	O
.	O

Sites	O
1	O
and	O
4	O
in	O
lumican	B-GENE
and	O
keratocan	B-GENE
are	O
in	O
a	O
homologous	O
location	O
.	O

ATP	O
-	O
dependent	O
assembly	O
of	O
a	O
ternary	O
complex	O
consisting	O
of	O
a	O
DNA	O
mismatch	O
and	O
the	O
yeast	O
MSH2	B-GENE
-	O
MSH6	B-GENE
and	O
MLH1	B-GENE
-	O
PMS1	B-GENE
protein	O
complexes	O
.	O

Mutation	O
of	O
the	O
central	O
Tyr497	O
to	O
Phe	O
blocks	O
the	O
tyrosine	O
phosphorylation	O
of	O
the	O
insulin	B-GENE
receptor	I-GENE
substrate	I-GENE
1	I-GENE
(	O
IRS1	B-GENE
)	O
and	O
diminishes	O
proliferation	O
in	O
response	O
to	O
IL	B-GENE
-	I-GENE
4	I-GENE
.	O

Instead	O
,	O
it	O
contained	O
two	O
tandem	O
kappaB	B-GENE
elements	I-GENE
and	O
a	O
variant	O
activating	B-GENE
transcription	I-GENE
factor	I-GENE
/	I-GENE
cAMP	I-GENE
response	I-GENE
element	I-GENE
site	O
,	O
which	O
closely	O
resembled	O
sites	O
in	O
the	O
E	B-GENE
-	I-GENE
selectin	I-GENE
gene	I-GENE
that	O
are	O
required	O
for	O
TNF	B-GENE
-	I-GENE
alpha	I-GENE
-	O
or	O
LPS	O
-	O
inducible	O
expression	O
.	O

Interestingly	O
,	O
the	O
activated	O
PDGF	B-GENE
beta	I-GENE
-	I-GENE
receptor	I-GENE
was	O
found	O
not	O
to	O
bind	O
Crk	B-GENE
proteins	I-GENE
.	O

Furthermore	O
,	O
interactions	O
were	O
identified	O
between	O
endogenous	B-GENE
E	I-GENE
-	I-GENE
cadherin	I-GENE
and	O
the	O
chimera	O
containing	O
the	O
E	B-GENE
-	I-GENE
cadherin	I-GENE
extracellular	I-GENE
domain	I-GENE
and	O
the	O
desmoglein	B-GENE
1	I-GENE
intracellular	I-GENE
domain	I-GENE
providing	O
in	O
vivo	O
evidence	O
for	O
previously	O
predicted	O
lateral	O
interactions	O
of	O
E	B-GENE
-	I-GENE
cadherin	I-GENE
extracellular	I-GENE
domains	I-GENE
.	O

The	O
ether	O
phospholipid	O
1	O
-	O
O	O
-	O
octadecyl	O
-	O
2	O
-	O
O	O
-	O
methyl	O
-	O
rac	O
-	O
glycero	O
-	O
3	O
-	O
phosphocholine	O
(	O
ET	O
-	O
18	O
-	O
OCH3	O
;	O
edelfosine	O
)	O
is	O
a	O
potent	O
inducer	O
of	O
apoptosis	O
in	O
human	O
tumor	O
cells	O
.	O

In	O
addition	O
to	O
a	O
previously	O
characterized	O
promoter	O
(	O
P1	O
)	O
,	O
we	O
now	O
show	O
the	O
existence	O
of	O
a	O
second	O
promoter	O
for	O
the	O
human	B-GENE
IL	I-GENE
-	I-GENE
5Ralpha	I-GENE
gene	I-GENE
.	O

Serum	O
levels	O
of	O
testosterone	O
also	O
showed	O
no	O
significant	O
changes	O
by	O
exposure	O
to	O
p	O
,	O
p	O
'	O
-	O
DDE	O
under	O
the	O
conditions	O
of	O
this	O
study	O
.	O

Overall	O
agreement	O
between	O
rest	O
/	O
postnitroglycerin	O
technetium	O
-	O
99m	O
tetrofosmin	O
SPET	O
studies	O
and	O
rest	O
/	O
redistribution	O
or	O
rest	O
/	O
reinjection	O
thallium	O
-	O
201	O
SPET	O
studies	O
,	O
regarding	O
the	O
presence	O
of	O
myocardial	O
viability	O
,	O
was	O
87	O
%	O
and	O
90	O
%	O
,	O
respectively	O
.	O

Their	O
use	O
resulted	O
in	O
a	O
sensitivity	O
of	O
73	O
%	O
and	O
a	O
specificity	O
of	O
74	O
%	O
with	O
regard	O
to	O
predictability	O
of	O
ALT	B-GENE
levels	O
increasing	O
during	O
the	O
trial	O
.	O

One	O
hundred	O
replicate	O
data	O
sets	O
of	O
100	O
subjects	O
each	O
were	O
simulated	O
for	O
each	O
missing	O
data	O
scenario	O
.	O

Spatial	O
accuracy	O
of	O
primary	O
and	O
secondary	O
memory	O
-	O
guided	O
saccades	O
in	O
schizophrenic	O
patients	O
.	O

Successful	O
treatment	O
with	O
nasal	O
continuous	O
positive	O
airway	O
pressure	O
(	O
8	O
.	O
3	O
+	O
/	O
-	O
1	O
.	O
5	O
cmH2O	O
)	O
for	O
3	O
days	O
caused	O
a	O
significant	O
decrease	O
in	O
mean	O
blood	O
pressure	O
in	O
OSAS	O
.	O

When	O
data	O
were	O
expressed	O
in	O
a	O
cumulative	O
manner	O
,	O
the	O
response	O
to	O
intravenous	O
adenosine	O
3	O
mg	O
,	O
6	O
mg	O
,	O
9	O
mg	O
and	O
12	O
mg	O
in	O
the	O
24	O
episodes	O
of	O
PSVT	O
were	O
5	O
episodes	O
(	O
21	O
%	O
)	O
,	O
16	O
episodes	O
(	O
67	O
%	O
)	O
,	O
20	O
episodes	O
(	O
83	O
%	O
)	O
and	O
20	O
episodes	O
(	O
83	O
%	O
)	O
respectively	O
.	O

RNAs	O
are	O
not	O
only	O
essential	O
components	O
of	O
both	O
ribosomal	O
subunits	O
but	O
also	O
transiently	O
interacting	O
factors	O
during	O
particle	O
formation	O
.	O

To	O
study	O
retinoid	O
signalling	O
in	O
zebrafish	O
embryos	O
,	O
we	O
developed	O
a	O
novel	O
method	O
to	O
detect	O
endogenous	O
retinoids	O
in	O
situ	O
in	O
embryos	O
,	O
using	O
a	O
fusion	O
protein	O
of	O
the	O
ligand	O
inducible	O
transactivation	O
domain	O
of	O
a	O
retinoic	B-GENE
acid	I-GENE
receptor	I-GENE
and	O
a	O
heterologous	O
DNA	O
binding	O
domain	O
.	O

Fluorescence	O
in	O
situ	O
hybridization	O
of	O
metaphase	O
spreads	O
of	O
chromosome	O
8	O
,	O
containing	O
hybrid	O
cell	O
line	O
706	O
-	O
B6	O
clone	O
17	O
(	O
CL	O
-	O
17	O
)	O
with	O
cosmid	O
c101F1	O
,	O
placed	O
the	O
9804	B-GENE
gene	I-GENE
close	O
to	O
the	O
telomere	O
at	O
8q24	O
.	O
3	O
.	O

Cell	O
survival	O
by	O
Epo	B-GENE
did	O
not	O
require	O
activation	O
of	O
other	O
known	O
signaling	O
pathways	O
including	O
PI	B-GENE
-	I-GENE
3	I-GENE
kinase	I-GENE
,	O
PLC	B-GENE
-	I-GENE
gamma	I-GENE
,	O
Ras	B-GENE
or	O
Stats	B-GENE
.	O

The	O
N	O
-	O
syndecan	O
-	O
dependent	O
neurite	O
outgrowth	O
is	O
inhibited	O
by	O
the	O
tyrosine	B-GENE
kinase	I-GENE
inhibitors	O
herbimycin	O
A	O
and	O
PP1	B-GENE
.	O

An	O
in	O
vivo	O
ZAP	B-GENE
-	I-GENE
70	I-GENE
substrate	O
,	O
SLP	B-GENE
-	I-GENE
76	I-GENE
,	O
implicated	O
in	O
Erk	B-GENE
activation	O
,	O
also	O
became	O
rapidly	O
tyrosine	O
-	O
phosphorylated	O
in	O
Jurkat	O
cells	O
,	O
but	O
not	O
in	O
P116	O
cells	O
,	O
upon	O
treatment	O
with	O
H2O2	O
.	O

The	O
pharmacokinetic	O
patterns	O
of	O
estradiol	O
(	O
CAS	O
50	O
-	O
28	O
-	O
2	O
)	O
and	O
of	O
estrone	O
(	O
CAS	O
53	O
-	O
16	O
-	O
7	O
)	O
were	O
investigated	O
in	O
18	O
women	O
in	O
natural	O
or	O
surgical	O
menopause	O
during	O
the	O
application	O
of	O
a	O
new	O
estradiol	O
transdermal	O
patch	O
with	O
active	O
matrix	O
and	O
without	O
absorption	O
enhancers	O
designed	O
for	O
epicutaneous	O
applications	O
of	O
7	O
days	O
(	O
hereinafter	O
called	O
"	O
patch	O
7D	O
"	O
)	O
.	O

Conversely	O
,	O
the	O
central	O
regions	O
are	O
highly	O
variable	O
.	O

Among	O
the	O
H	B-GENE
/	I-GENE
ACA	I-GENE
snoRNAs	I-GENE
associated	O
with	O
Gar1p	B-GENE
,	O
one	O
can	O
distinguish	O
a	O
large	O
group	O
of	O
snoRNAs	O
that	O
are	O
not	O
essential	O
in	O
yeast	O
and	O
serve	O
as	O
guides	O
for	O
pseudouridine	O
synthesis	O
onto	O
the	O
pre	O
-	O
rRNA	O
molecule	O
.	O

Further	O
studies	O
demonstrated	O
that	O
the	O
PPARalpha	B-GENE
ligand	O
8	O
(	O
S	O
)	O
-	O
hydroxyeicosatetraenoic	O
acid	O
strongly	O
promotes	O
the	O
interaction	O
of	O
PPARalpha	B-GENE
with	O
the	O
co	O
-	O
activator	O
RIP	B-GENE
-	I-GENE
140	I-GENE
but	O
decreases	O
the	O
interaction	O
of	O
PPARalpha	B-GENE
with	O
the	O
co	O
-	O
repressor	O
SMRT	B-GENE
.	O

We	O
previously	O
demonstrated	O
that	O
acute	O
expression	O
of	O
the	O
bovine	O
papillomavirus	O
type	O
1	O
(	O
BPV1	O
)	O
E2	B-GENE
protein	I-GENE
in	O
HeLa	O
and	O
HT	O
-	O
3	O
cervical	O
carcinoma	O
cell	O
lines	O
greatly	O
reduced	O
cellular	O
proliferation	O
by	O
imposing	O
a	O
specific	O
G1	O
/	O
S	O
phase	O
growth	O
arrest	O
.	O

Four	O
possible	O
isoforms	O
(	O
hGli2	B-GENE
alpha	I-GENE
,	I-GENE
beta	I-GENE
,	I-GENE
gamma	I-GENE
,	I-GENE
and	I-GENE
delta	I-GENE
)	O
are	O
formed	O
by	O
combinations	O
of	O
two	O
independent	O
alternative	O
splicings	O
,	O
and	O
all	O
the	O
isoforms	O
could	O
bind	O
to	O
a	O
DNA	O
motif	O
,	O
TRE2S	O
,	O
in	O
the	O
LTR	O
.	O

Specialized	O
actin	B-GENE
tails	O
that	O
propel	O
IEV	O
particles	O
to	O
the	O
periphery	O
and	O
virus	O
-	O
tipped	O
microvilli	O
(	O
both	O
common	O
in	O
wild	O
-	O
type	O
-	O
infected	O
cells	O
)	O
were	O
absent	O
in	O
cells	O
infected	O
with	O
vA33delta	O
.	O

Their	O
mean	O
IOP	O
was	O
15	O
.	O
3	O
(	O
SD	O
3	O
.	O
7	O
)	O
mmHg	O
prior	O
to	O
induction	O
of	O
anesthesia	O
,	O
13	O
.	O
5	O
(	O
SD	O
3	O
.	O
5	O
)	O
mmHg	O
after	O
loss	O
of	O
eyelash	O
reflex	O
following	O
injection	O
of	O
methohexitone	O
,	O
16	O
.	O
1	O
(	O
SD	O
2	O
.	O
4	O
)	O
mmHg	O
after	O
cessation	O
of	O
muscle	O
fasciculations	O
induced	O
by	O
suxamethonium	O
,	O
19	O
.	O
2	O
(	O
SD	O
5	O
.	O
6	O
)	O
mmHg	O
after	O
cessation	O
of	O
convulsion	O
and	O
15	O
.	O
5	O
(	O
SD	O
4	O
.	O
4	O
)	O
mmHg	O
following	O
resumption	O
of	O
regular	O
spontaneous	O
respiration	O
.	O

A	O
cDNA	O
,	O
cak1At	B-GENE
,	O
was	O
isolated	O
that	O
suppressed	O
the	O
CAK	B-GENE
mutation	I-GENE
in	O
budding	O
yeast	O
,	O
and	O
it	O
also	O
complemented	O
a	O
fission	B-GENE
yeast	I-GENE
CAK	I-GENE
mutant	I-GENE
.	O
cak1At	B-GENE
encodes	O
a	O
protein	O
related	O
to	O
animal	B-GENE
CAKs	I-GENE
.	O

Post	O
-	O
translational	O
modifications	O
such	O
as	O
glycosylation	O
and	O
phosphorylation	O
could	O
be	O
excluded	O
as	O
potential	O
explanations	O
for	O
the	O
protein	O
heterogeneity	O
.	O

In	O
addition	O
to	O
restoring	O
checkpoint	O
control	O
,	O
overexpression	O
of	O
sum1	B-GENE
+	I-GENE
inhibits	O
the	O
normal	O
cell	O
cycle	O
response	O
to	O
osmotic	O
stress	O
.	O

Ime1	B-GENE
plays	O
a	O
pivotal	O
role	O
in	O
the	O
initiation	O
of	O
meiosis	O
in	O
a	O
/	O
alpha	O
diploid	O
cells	O
of	O
Saccharomyces	O
cerevisiae	O
.	O

Rhesus	O
macaques	O
and	O
BALB	O
/	O
c	O
mice	O
inoculated	O
with	O
the	O
Mengo	O
virus	O
SIV	O
recombinants	O
failed	O
to	O
develop	O
CTL	O
responses	O
against	O
the	O
SIV	O
gene	O
products	O
,	O
while	O
one	O
of	O
the	O
HIV	B-GENE
-	I-GENE
Nef	I-GENE
recombinants	I-GENE
induced	O
a	O
weak	O
CTL	O
response	O
in	O
mice	O
directed	O
to	O
an	O
HIV1	B-GENE
Nef	I-GENE
peptide	I-GENE
spanning	O
positions	O
182	O
-	O
198	O
.	O

Deltamethrin	O
was	O
most	O
effective	O
on	O
the	O
thatched	O
surface	O
and	O
produced	O
100	O
%	O
mortality	O
of	O
An	O
.	O
culicifacies	O
adults	O
up	O
to	O
12	O
weeks	O
,	O
even	O
when	O
exposed	O
at	O
the	O
lowest	O
dose	O
/	O
12	O
.	O
5	O
mg	O
/	O
m2	O
.	O

Trichloroethylene	O
,	O
in	O
turn	O
,	O
increased	O
the	O
AUC	O
5	O
.	O
0	O
(	O
1	O
.	O
9	O
-	O
13	O
.	O
4	O
)	O
,	O
25	O
.	O
8	O
(	O
8	O
.	O
2	O
-	O
80	O
.	O
8	O
)	O
and	O
2	O
.	O
9	O
(	O
1	O
.	O
6	O
-	O
5	O
.	O
4	O
)	O
,	O
respectively	O
,	O
whereas	O
the	O
corresponding	O
values	O
for	O
n	O
-	O
hexane	O
were	O
1	O
.	O
9	O
(	O
0	O
.	O
7	O
-	O
5	O
.	O
1	O
)	O
,	O
1	O
.	O
5	O
(	O
0	O
.	O
5	O
-	O
4	O
.	O
6	O
)	O
,	O
and	O
3	O
.	O
2	O
(	O
1	O
.	O
8	O
-	O
5	O
.	O
9	O
)	O
.	O

Solution	O
structure	O
of	O
the	O
IRF	B-GENE
-	I-GENE
2	I-GENE
DNA	I-GENE
-	I-GENE
binding	I-GENE
domain	I-GENE
:	O
a	O
novel	O
subgroup	O
of	O
the	O
winged	B-GENE
helix	I-GENE
-	I-GENE
turn	I-GENE
-	I-GENE
helix	I-GENE
family	I-GENE
.	O

In	O
contrast	O
,	O
receptor	B-GENE
/	I-GENE
G	I-GENE
protein	I-GENE
coupling	O
appeared	O
unaffected	O
by	O
expression	O
of	O
loop	O
3i	O
domains	O
derived	O
from	O
two	O
receptors	O
coupled	O
to	O
G	B-GENE
(	I-GENE
i	I-GENE
/	I-GENE
o	I-GENE
)	I-GENE
proteins	I-GENE
(	O
M2Ach	B-GENE
-	I-GENE
muscarinic	I-GENE
and	I-GENE
alpha2A	I-GENE
-	I-GENE
adrenergic	I-GENE
receptors	I-GENE
)	O
.	O

These	O
data	O
indicate	O
that	O
the	O
third	O
intracellular	O
loop	O
of	O
the	O
rat	B-GENE
GnRH	I-GENE
-	I-GENE
R	I-GENE
is	O
involved	O
in	O
receptor	B-GENE
G	I-GENE
(	I-GENE
q	I-GENE
/	I-GENE
11	I-GENE
)	I-GENE
protein	I-GENE
coupling	O
and	O
/	O
or	O
selectivity	O
,	O
and	O
in	O
the	O
GGH	O
(	O
3	O
)	O
1	O
'	O
cell	O
line	O
,	O
this	O
loop	O
is	O
also	O
involved	O
in	O
signal	O
transduction	O
mediated	O
through	O
the	O
Gs	B-GENE
protein	O
pathway	O
.	O

Decreased	O
levels	O
of	O
alpha2	B-GENE
-	I-GENE
antiplasmin	I-GENE
were	O
also	O
observed	O
in	O
the	O
mediastinum	O
(	O
0	O
.	O
50	O
versus	O
0	O
.	O
61	O
U	O
/	O
mL	O
;	O
p	O
<	O
0	O
.	O
05	O
)	O
.	O

A	O
catalytic	O
domain	O
of	O
eukaryotic	B-GENE
DNA	I-GENE
topoisomerase	I-GENE
I	I-GENE
.	O

A	O
cluster	O
of	O
basic	O
amino	O
acids	O
,	O
KKKR	O
,	O
generated	O
by	O
joining	O
of	O
the	O
sequences	O
encoded	O
by	O
the	O
constitutive	O
exon	O
13	O
and	O
the	O
alternative	O
exon	O
16	O
,	O
is	O
necessary	O
for	O
the	O
nuclear	O
targeting	O
of	O
4	B-GENE
.	I-GENE
1H	I-GENE
,	O
as	O
demonstrated	O
by	O
site	O
-	O
directed	O
mutagenesis	O
analysis	O
.	O

All	O
three	O
genes	O
have	O
been	O
mapped	O
precisely	O
to	O
a	O
small	O
region	O
on	O
human	O
chromosome	O
16p12	O
.	O
1	O
-	O
p11	O
.	O
2	O
(	O
homologous	O
to	O
mouse	O
chromosome	O
7	O
)	O
,	O
using	O
somatic	O
cell	O
hybrids	O
and	O
cosmid	O
clones	O
.	O

In	O
fus3	B-GENE
mutants	I-GENE
,	O
the	O
levels	O
of	O
Ty1	B-GENE
RNA	I-GENE
,	O
protein	O
synthesis	O
,	O
and	O
proteolytic	O
processing	O
were	O
not	O
altered	O
relative	O
to	O
those	O
in	O
FUS3	B-GENE
strains	O
but	O
steady	O
-	O
state	O
levels	O
of	O
TyA	B-GENE
,	O
integrase	B-GENE
,	O
and	O
reverse	B-GENE
transcriptase	I-GENE
proteins	O
and	O
Ty1	B-GENE
cDNA	I-GENE
were	O
all	O
increased	O
.	O

Posttranslational	O
regulation	O
of	O
Ty1	B-GENE
retrotransposition	O
by	O
mitogen	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
kinase	I-GENE
Fus3	I-GENE
.	O

Their	O
function	O
is	O
not	O
only	O
to	O
recruit	O
Pho2	B-GENE
to	O
the	O
promoter	O
but	O
to	O
allow	O
cooperative	O
binding	O
of	O
Pho4	B-GENE
together	O
with	O
Pho2	B-GENE
.	O

Substitution	O
of	O
the	O
Ser	O
-	O
Thr	O
sites	O
with	O
the	O
phosphomimetic	O
Asp	O
generated	O
a	O
constitutively	O
active	O
form	O
of	O
IRF	B-GENE
-	I-GENE
3	I-GENE
that	O
functioned	O
as	O
a	O
very	O
strong	O
activator	O
of	O
promoters	O
containing	O
PRDI	B-GENE
-	O
PRDIII	B-GENE
or	O
ISRE	B-GENE
regulatory	I-GENE
elements	I-GENE
.	O

New	O
-	O
onset	O
angina	O
preceding	O
acute	O
myocardial	O
infarction	O
is	O
associated	O
with	O
improved	O
contractile	O
recovery	O
after	O
thrombolysis	O
.	O

In	O
this	O
study	O
,	O
the	O
effect	O
of	O
acute	O
administration	O
of	O
various	O
doses	O
of	O
malathion	O
via	O
oral	O
and	O
dermal	O
routes	O
to	O
mice	O
and	O
rats	O
on	O
serum	O
levels	O
of	O
histamine	O
was	O
evaluated	O
.	O

Fetal	O
growth	O
retardation	O
as	O
a	O
cause	O
of	O
impaired	O
ovarian	O
development	O
.	O

Similarly	O
,	O
PCDFs	O
/	O
PCDDs	O
ratio	O
in	O
ESP	O
ash	O
was	O
lower	O
than	O
that	O
in	O
boiler	O
ash	O
.	O

In	O
addition	O
to	O
DNA	O
-	O
protein	O
interactions	O
,	O
protein	O
-	O
protein	O
interactions	O
with	O
partner	O
proteins	O
often	O
play	O
major	O
roles	O
in	O
targeting	O
ETS	B-GENE
-	I-GENE
domain	I-GENE
proteins	I-GENE
to	O
specific	O
promoters	O
.	O

The	O
complete	O
exon	O
-	O
intron	O
organization	O
of	O
the	O
murine	O
gene	O
encoding	O
M	B-GENE
-	I-GENE
protein	I-GENE
,	O
a	O
structural	O
protein	O
of	O
sarcomeric	O
myofibrils	O
,	O
was	O
determined	O
.	O

PURPOSE	O
:	O
To	O
introduce	O
an	O
image	O
analysis	O
of	O
the	O
cornea	O
in	O
photorefractive	O
keratectomy	O
(	O
PRK	O
)	O
for	O
preoperative	O
and	O
early	O
postoperative	O
determination	O
of	O
changes	O
in	O
the	O
condition	O
of	O
the	O
cornea	O
.	O

Mean	O
+	O
/	O
-	O
SD	O
serum	B-GENE
VEGF	I-GENE
concentrations	O
were	O
significantly	O
higher	O
(	O
P	O
<	O
0	O
.	O
001	O
)	O
in	O
women	O
with	O
PCO	O
and	O
PCOS	O
(	O
3	O
.	O
4	O
+	O
/	O
-	O
0	O
.	O
7	O
and	O
3	O
.	O
2	O
+	O
/	O
-	O
0	O
.	O
66	O
ng	O
/	O
ml	O
respectively	O
)	O
compared	O
with	O
women	O
with	O
normal	O
ovaries	O
(	O
2	O
.	O
3	O
+	O
/	O
-	O
0	O
.	O
5	O
ng	O
/	O
ml	O
)	O
.	O

Strikingly	O
,	O
these	O
cells	O
contain	O
a	O
missense	O
mutation	O
of	O
the	O
p53	B-GENE
gene	I-GENE
at	O
codon	O
242	O
(	O
p53	B-GENE
(	O
242	O
)	O
)	O
,	O
which	O
substitutes	O
alanine	O
for	O
glycine	O
.	O

The	O
new	O
algorithm	O
,	O
called	O
RBI	O
-	O
MAP	O
,	O
is	O
based	O
on	O
the	O
rescaled	O
block	O
iterative	O
EM	O
(	O
RBI	O
-	O
EM	O
)	O
algorithm	O
.	O

A	O
third	O
ORF	O
,	O
ORF5	O
,	O
shows	O
homology	O
with	O
gene	B-GENE
agrB	I-GENE
from	O
Staphylococcus	O
aureus	O
,	O
which	O
is	O
involved	O
in	O
the	O
mechanism	O
of	O
regulation	O
of	O
the	O
virulence	O
phenotype	O
in	O
this	O
species	O
.	O

An	O
association	O
between	O
hSIE	B-GENE
and	O
Stat	B-GENE
-	I-GENE
3	I-GENE
after	O
MHC	B-GENE
-	I-GENE
I	I-GENE
ligation	O
was	O
directly	O
demonstrated	O
by	O
precipitating	O
Stat	B-GENE
-	I-GENE
3	I-GENE
from	O
nuclear	O
extracts	O
with	O
biotinylated	O
hSIE	B-GENE
probe	O
and	O
avidin	B-GENE
-	O
coupled	O
agarose	O
.	O

Transcriptional	O
repression	O
mediated	O
by	O
LysR	B-GENE
-	I-GENE
type	I-GENE
regulator	I-GENE
CatR	I-GENE
bound	O
at	O
multiple	O
binding	O
sites	O
.	O

Two	O
of	O
these	O
resulted	O
in	O
increased	O
levels	O
of	O
the	O
alpha	O
subunit	O
,	O
and	O
one	O
caused	O
a	O
substitution	O
of	O
glycine	O
for	O
the	O
aspartic	O
acid	O
residue	O
at	O
position	O
171	O
,	O
in	O
the	O
N	O
-	O
terminal	O
domain	O
.	O

These	O
two	O
mRNA	O
species	O
are	O
produced	O
by	O
differential	O
polyadenylation	O
site	O
usage	O
.	O

Finally	O
,	O
a	O
role	O
for	O
NF	B-GENE
-	I-GENE
kappaB	I-GENE
in	O
preventing	O
apoptosis	O
induced	O
by	O
ER	O
calcium	O
release	O
was	O
demonstrated	O
by	O
data	O
showing	O
that	O
sAPPalpha	B-GENE
prevents	O
thapsigargin	O
-	O
induced	O
apoptosis	O
,	O
an	O
effect	O
blocked	O
by	O
kappaB	B-GENE
decoy	O
DNA	O
.	O

Many	O
cytokine	O
receptors	O
employ	O
Janus	B-GENE
protein	I-GENE
tyrosine	I-GENE
kinases	I-GENE
(	O
Jaks	B-GENE
)	O
and	O
signal	B-GENE
transducers	I-GENE
and	I-GENE
activators	I-GENE
of	I-GENE
transcription	I-GENE
(	O
Stats	B-GENE
)	O
for	O
nuclear	O
signaling	O
.	O

A	O
site	O
-	O
directed	O
R618K	O
mutation	O
in	O
the	O
Stat5	B-GENE
SH2	B-GENE
domain	I-GENE
abolished	O
the	O
phosphorylation	O
by	O
Jak2	B-GENE
,	O
while	O
deletion	O
of	O
the	O
C	O
terminus	O
led	O
to	O
Stat5	B-GENE
hyperphosphorylation	O
.	O

Specifically	O
,	O
recombination	O
at	O
HMR	B-GENE
was	O
used	O
to	O
produce	O
rings	O
that	O
lacked	O
the	O
E	O
and	O
I	O
silencers	O
.	O

In	O
angiodysplasia	O
,	O
ectatic	O
vessels	O
in	O
the	O
mucosa	O
appeared	O
to	O
contain	O
less	O
collagen	B-GENE
type	I-GENE
IV	I-GENE
than	O
similarly	O
sized	O
vessels	O
in	O
the	O
submucosa	O
,	O
and	O
perforating	O
vessels	O
appeared	O
in	O
many	O
cases	O
to	O
lose	O
staining	O
at	O
the	O
level	O
of	O
the	O
muscularis	O
mucosae	O
.	O

We	O
studied	O
the	O
human	O
vestibulo	O
-	O
ocular	O
reflex	O
(	O
VOR	O
)	O
in	O
response	O
to	O
head	O
'	O
impulses	O
'	O
:	O
brief	O
,	O
unpredictable	O
,	O
passive	O
,	O
high	O
-	O
acceleration	O
(	O
up	O
to	O
4000	O
degrees	O
/	O
s2	O
)	O
,	O
low	O
-	O
amplitude	O
(	O
20	O
-	O
30	O
degrees	O
)	O
head	O
rotations	O
.	O

To	O
clarify	O
whether	O
seizure	O
-	O
offset	O
patterns	O
are	O
reliable	O
in	O
predicting	O
seizure	O
outcome	O
,	O
we	O
studied	O
SEEG	O
/	O
ECoG	O
in	O
a	O
similar	O
group	O
of	O
patients	O
with	O
temporal	O
lobe	O
epilepsy	O
(	O
TLE	O
)	O
.	O

In	O
this	O
study	O
,	O
to	O
characterize	O
the	O
gene	O
for	O
protein	B-GENE
Z	I-GENE
,	O
its	O
organization	O
and	O
structure	O
were	O
determined	O
by	O
a	O
combination	O
of	O
PCR	O
amplification	O
of	O
leukocyte	O
DNA	O
and	O
isolation	O
of	O
phage	O
clones	O
from	O
a	O
human	O
genomic	O
library	O
.	O

These	O
modifications	O
may	O
improve	O
the	O
interlaboratory	O
reproducibility	O
of	O
CD34	B-GENE
determinations	O
due	O
to	O
the	O
reduction	O
in	O
sample	O
handling	O
and	O
calculation	O
of	O
results	O
.	O

The	O
present	O
results	O
demonstrate	O
that	O
rats	O
with	O
relatively	O
small	O
remnants	O
of	O
one	O
olfactory	O
bulb	O
can	O
perform	O
a	O
variety	O
of	O
odor	O
detection	O
and	O
discrimination	O
tasks	O
as	O
well	O
or	O
nearly	O
as	O
well	O
as	O
controls	O
.	O

These	O
patients	O
failed	O
to	O
respond	O
to	O
intravenous	O
cyclophosphamide	O
and	O
steroids	O
and	O
were	O
then	O
changed	O
to	O
receive	O
oral	O
cyclosporine	O
A	O
,	O
at	O
a	O
dose	O
of	O
5	O
mg	O
/	O
kg	O
/	O
day	O
.	O

The	O
predicted	O
amino	O
acid	O
sequence	O
is	O
78	O
.	O
0	O
%	O
identical	O
to	O
the	O
cytoplasmic	B-GENE
dynein	I-GENE
heavy	I-GENE
chain	I-GENE
of	I-GENE
Neurospora	I-GENE
crassa	I-GENE
,	O
70	O
.	O
2	O
%	O
identical	O
to	O
that	O
of	O
Aspergillus	O
nidulans	O
and	O
24	O
.	O
8	O
%	O
identical	O
to	O
that	O
of	O
Saccharomyces	O
cerevisiae	O
.	O

The	O
DNA	O
binding	O
activities	O
of	O
the	O
three	O
repressor	O
preparations	O
were	O
studied	O
using	O
fragments	O
containing	O
CIRs	O
(	O
CIR3	O
-	O
CIR6	O
)	O
from	O
the	O
essential	O
early	O
region	O
as	O
templates	O
for	O
DNase	B-GENE
I	I-GENE
footprinting	O
.	O

Molecular	O
modelling	O
suggested	O
that	O
the	O
tetramerization	O
domain	O
was	O
a	O
four	O
-	O
helix	O
bundle	O
,	O
stabilized	O
by	O
interactions	O
of	O
seven	O
conserved	O
aromatic	O
amino	O
acids	O
.	O

In	O
the	O
present	O
study	O
,	O
we	O
sought	O
to	O
investigate	O
whether	O
constitutive	O
NF	B-GENE
-	I-GENE
kappaB	I-GENE
activity	O
in	O
chronically	O
HIV	O
-	O
1	O
-	O
infected	O
promonocytic	O
U937	O
(	O
U9	O
-	O
IIIB	O
)	O
and	O
myeloblastic	O
PLB	O
-	O
985	O
(	O
PLB	O
-	O
IIIB	O
)	O
cells	O
affects	O
apoptotic	O
signaling	O
.	O

To	O
explore	O
the	O
function	O
of	O
human	O
SINA	B-GENE
-	I-GENE
homologous	I-GENE
(	I-GENE
Siah	I-GENE
)	I-GENE
proteins	I-GENE
,	O
expression	O
plasmids	O
encoding	O
Siah	B-GENE
-	I-GENE
1A	I-GENE
were	O
transiently	O
transfected	O
into	O
293	O
epithelial	O
cells	O
and	O
GM701	O
fibroblast	O
cells	O
,	O
resulting	O
in	O
growth	O
arrest	O
without	O
induction	O
of	O
apoptosis	O
.	O

We	O
have	O
shown	O
previously	O
that	O
GH3	O
cells	O
transfected	O
with	O
the	O
rat	B-GENE
GnRH	I-GENE
receptor	I-GENE
cDNA	I-GENE
(	O
GGH3	O
-	O
1	O
'	O
cells	O
)	O
support	O
the	O
expression	O
of	O
a	O
cotransfected	O
fusion	O
gene	O
composed	O
of	O
797	O
base	O
pairs	O
of	O
rat	B-GENE
LHbeta	I-GENE
gene	I-GENE
5	I-GENE
'	I-GENE
-	I-GENE
flanking	I-GENE
sequence	I-GENE
and	O
the	O
first	O
5	O
base	O
pairs	O
of	O
the	O
5	O
'	O
-	O
untranslated	O
region	O
fused	O
to	O
a	O
luciferase	B-GENE
reporter	I-GENE
(	I-GENE
-	I-GENE
797	I-GENE
/	I-GENE
+	I-GENE
5LHbetaLUC	I-GENE
)	I-GENE
and	O
respond	O
to	O
a	O
GnRH	B-GENE
agonist	O
with	O
a	O
10	O
-	O
fold	O
stimulation	O
of	O
activity	O
.	O

The	O
5	O
'	O
-	O
flanking	O
region	O
,	O
from	O
nucleotide	O
-	O
837	O
to	O
-	O
336	O
,	O
contains	O
TATA	O
and	O
inverted	O
CAAT	O
boxes	O
as	O
well	O
as	O
GATA	B-GENE
-	I-GENE
1	I-GENE
/	O
SP1	B-GENE
erythroid	O
-	O
specific	O
cis	O
-	O
acting	O
regulatory	O
elements	O
.	O

We	O
established	O
the	O
radiosensitive	O
cell	O
line	O
SX9	O
from	O
mammary	O
carcinoma	O
cell	O
line	O
FM3A	O
.	O

Results	O
showed	O
that	O
the	O
mean	O
bond	O
strength	O
of	O
H	O
.	O
T	O
.	O
V	O
.	O
specimens	O
ranged	O
from	O
9	O
.	O
6	O
to	O
13	O
.	O
12	O
kg	O
/	O
cm2	O
,	O
while	O
the	O
mean	O
bond	O
strength	O
of	O
R	O
.	O
T	O
.	O
V	O
.	O
specimens	O
ranged	O
from	O
0	O
.	O
36	O
to	O
1	O
.	O
75	O
kg	O
/	O
cm2	O
.	O

OBJECTIVES	O
:	O
To	O
measure	O
coagulation	B-GENE
factor	I-GENE
VIII	I-GENE
:	I-GENE
coagulant	I-GENE
(	O
F	B-GENE
.	I-GENE
VIII	I-GENE
:	I-GENE
C	I-GENE
)	O
and	O
C1	B-GENE
-	I-GENE
esterase	I-GENE
inhibitor	I-GENE
(	O
C1	B-GENE
-	I-GENE
INH	I-GENE
)	O
,	O
hemostasis	O
-	O
associated	O
acute	O
-	O
phase	O
reactant	O
proteins	O
and	O
coagulation	B-GENE
factors	I-GENE
VII	I-GENE
(	O
F	B-GENE
.	I-GENE
VII	I-GENE
)	O
,	O
IX	O
(	O
F	B-GENE
.	I-GENE
IX	I-GENE
)	O
,	O
and	O
X	O
(	O
F	B-GENE
.	I-GENE
X	I-GENE
)	O
,	O
hemostasis	O
proteins	O
not	O
associated	O
with	O
an	O
acute	O
-	O
phase	O
response	O
,	O
in	O
a	O
select	O
population	O
of	O
horses	O
with	O
colic	O
and	O
hemostasis	O
abnormalities	O
,	O
and	O
presumed	O
to	O
have	O
acute	O
-	O
phase	O
changes	O
.	O

RESULTS	O
:	O
Horses	O
with	O
colic	O
had	O
significantly	O
higher	O
fibrinogen	B-GENE
concentration	O
,	O
greater	O
alpha	B-GENE
2AP	I-GENE
and	O
protein	B-GENE
C	I-GENE
activities	O
,	O
and	O
longer	O
PT	O
and	O
APTT	O
than	O
did	O
healthy	O
horses	O
.	O

The	O
data	O
suggest	O
that	O
plasminogen	B-GENE
,	O
alpha	B-GENE
2AP	I-GENE
,	O
and	O
C1	B-GENE
-	I-GENE
INH	I-GENE
,	O
should	O
be	O
considered	O
equine	O
acute	O
-	O
phase	O
proteins	O
.	O

None	O
of	O
the	O
patients	O
was	O
obese	O
.	O

Marked	O
elevation	O
of	O
creatine	B-GENE
kinase	I-GENE
was	O
observed	O
while	O
serum	O
albumin	B-GENE
,	O
immunoglobulin	B-GENE
,	O
and	O
complement	O
were	O
decreased	O
.	O

DESIGN	O
AND	O
METHODS	O
:	O
Case	O
study	O
.	O

METHODS	O
:	O
A	O
total	O
of	O
15	O
pigs	O
were	O
randomised	O
to	O
ligation	O
of	O
left	O
marginal	O
arteries	O
(	O
infarction	O
group	O
,	O
n	O
=	O
5	O
)	O
,	O
to	O
TMLR	O
of	O
the	O
left	O
lateral	O
wall	O
using	O
a	O
holmium	O
:	O
yttrium	O
-	O
aluminium	O
garnet	O
(	O
Ho	O
:	O
YAG	O
)	O
laser	O
(	O
laser	O
group	O
,	O
n	O
=	O
5	O
)	O
,	O
and	O
to	O
both	O
(	O
laser	O
-	O
infarction	O
group	O
,	O
n	O
=	O
5	O
)	O
.	O

RACK1	B-GENE
,	O
a	O
receptor	O
for	O
activated	B-GENE
C	I-GENE
kinase	I-GENE
and	O
a	O
homolog	O
of	O
the	O
beta	O
subunit	O
of	O
G	B-GENE
proteins	I-GENE
,	O
inhibits	O
activity	O
of	O
src	B-GENE
tyrosine	I-GENE
kinases	I-GENE
and	O
growth	O
of	O
NIH	O
3T3	O
cells	O
.	O

Peptide	O
sequences	O
of	O
the	O
zinc	B-GENE
finger	I-GENE
protein	I-GENE
Ttk	I-GENE
and	O
the	O
transcription	B-GENE
factor	I-GENE
Adf	I-GENE
-	I-GENE
1	I-GENE
were	O
obtained	O
.	O

The	O
same	O
IL	B-GENE
-	I-GENE
4	I-GENE
-	O
inducible	O
reporter	O
gene	O
is	O
also	O
synergistically	O
activated	O
by	O
the	O
endogenous	B-GENE
Stat6	I-GENE
and	O
NF	B-GENE
-	I-GENE
kappaB	I-GENE
proteins	I-GENE
in	O
IL	B-GENE
-	I-GENE
4	I-GENE
-	O
stimulated	O
I	O
.	O
29mu	O
B	O
lymphoma	O
cells	O
.	O

HEF1	B-GENE
,	O
p130	B-GENE
(	O
Cas	B-GENE
)	O
,	O
and	O
Efs	B-GENE
/	O
Sin	B-GENE
constitute	O
a	O
family	O
of	O
multidomain	O
docking	O
proteins	O
that	O
have	O
been	O
implicated	O
in	O
coordinating	O
the	O
regulation	O
of	O
cell	O
adhesion	O
.	O

In	O
support	O
of	O
a	O
role	O
at	O
the	O
spindle	O
,	O
two	O
-	O
hybrid	O
library	O
screening	O
with	O
HEF1	B-GENE
identifies	O
the	O
human	O
homolog	O
of	O
the	O
G2	B-GENE
/	I-GENE
M	I-GENE
spindle	I-GENE
-	I-GENE
regulatory	I-GENE
protein	I-GENE
Dim1p	I-GENE
as	O
a	O
specific	O
interactor	O
with	O
a	O
region	O
of	O
HEF1	B-GENE
encompassed	O
in	O
p55	B-GENE
(	O
HEF1	B-GENE
)	O
.	O

Our	O
data	O
showed	O
that	O
activation	O
of	O
the	O
raf	B-GENE
-	O
ERK	B-GENE
pathway	O
led	O
to	O
activation	O
of	O
TF	B-GENE
expression	O
in	O
breast	O
carcinoma	O
cells	O
and	O
suggested	O
that	O
constitutive	O
activation	O
of	O
this	O
pathway	O
leads	O
to	O
high	O
TF	B-GENE
expression	O
in	O
MDA	O
-	O
MB	O
-	O
231	O
cells	O
.	O

However	O
,	O
a	O
zinc	O
-	O
depleted	O
enzyme	O
was	O
obtained	O
after	O
prolonged	O
dialysis	O
against	O
the	O
specific	O
chelating	O
agent	O
1	O
,	O
10	O
-	O
phenanthroline	O
.	O

The	O
lines	O
also	O
differed	O
in	O
postsynaptic	O
,	O
but	O
not	O
presynaptic	O
,	O
5	B-GENE
-	I-GENE
HT1A	I-GENE
receptors	I-GENE
.	O

Convulsive	O
seizure	O
during	O
a	O
treatment	O
with	O
interferon	B-GENE
alpha	I-GENE
for	O
chronic	O
viral	O
hepatitis	O
C	O

Genetic	O
studies	O
in	O
Drosophila	O
have	O
led	O
to	O
the	O
identification	O
of	O
several	O
components	O
of	O
the	O
Notch	B-GENE
pathway	O
.	O

The	O
bZP2	B-GENE
cDNA	I-GENE
(	I-GENE
115	I-GENE
-	I-GENE
1914	I-GENE
nt	I-GENE
,	I-GENE
1	I-GENE
.	I-GENE
8	I-GENE
kb	I-GENE
)	I-GENE
,	O
excluding	O
sequences	O
coding	O
for	O
N	O
-	O
terminal	O
signal	O
sequence	O
and	O
C	O
-	O
terminal	O
transmembranelike	O
domain	O
,	O
was	O
PCR	O
amplified	O
and	O
Sac1	B-GENE
-	O
Sal1	B-GENE
restricted	O
fragment	O
cloned	O
in	O
frame	O
downstream	O
of	O
the	O
T5	O
promoter	O
under	O
the	O
lac	B-GENE
operator	I-GENE
control	O
in	O
a	O
pQE	O
-	O
30	O
vector	O
.	O

Control	O
subjects	O
'	O
evoked	O
potentials	O
(	O
EPs	O
)	O
were	O
characterized	O
by	O
an	O
initial	O
positivity	O
in	O
the	O
90	O
-	O
140	O
ms	O
range	O
(	O
P1	O
)	O
at	O
the	O
temporo	O
-	O
occipital	O
site	O
.	O

Class	B-GENE
I	I-GENE
alpha1	I-GENE
,	I-GENE
2	I-GENE
-	I-GENE
mannosidases	I-GENE
play	O
an	O
essential	O
role	O
in	O
the	O
elaboration	O
of	O
complex	O
and	O
hybrid	O
N	O
-	O
glycans	O
in	O
mammalian	O
cells	O
.	O

Structural	O
features	O
of	O
the	O
minimal	O
DNA	O
binding	O
domain	O
(	O
M98	O
-	O
F219	O
)	O
of	O
human	B-GENE
nucleotide	I-GENE
excision	I-GENE
repair	I-GENE
protein	I-GENE
XPA	I-GENE
.	O

Amongst	O
other	O
qualities	O
,	O
the	O
book	O
'	O
s	O
importance	O
lies	O
in	O
the	O
fact	O
that	O
it	O
associates	O
an	O
elaborate	O
theoretical	O
construction	O
with	O
the	O
empirical	O
data	O
,	O
working	O
within	O
the	O
possibilities	O
provided	O
by	O
late	O
19th	O
-	O
century	O
moral	O
statistics	O
.	O

The	O
results	O
point	O
to	O
the	O
effectiveness	O
of	O
the	O
educational	O
intervention	O
.	O

The	O
mechanistic	O
implications	O
of	O
aromatic	O
non	O
-	O
responsiveness	O
of	O
autonomously	O
expressed	O
A	O
-	O
domain	O
,	O
despite	O
its	O
demonstrated	O
ability	O
to	O
bind	O
phenol	O
,	O
are	O
discussed	O
.	O

RESULTS	O
:	O
Acetabular	O
index	O
returned	O
to	O
normal	O
gradually	O
as	O
the	O
time	O
went	O
by	O
and	O
significantly	O
within	O
one	O
year	O
after	O
the	O
reduction	O
of	O
developmental	O
dislocation	O
of	O
the	O
hip	O
.	O

Recently	O
,	O
extremely	O
high	O
levels	O
of	O
endothelin	B-GENE
-	I-GENE
1	I-GENE
(	O
ET	B-GENE
-	I-GENE
1	I-GENE
)	O
were	O
detected	O
in	O
the	O
pericardial	O
fluid	O
of	O
patients	O
undergoing	O
cardiac	O
surgery	O
.	O

Consequently	O
,	O
it	O
is	O
not	O
known	O
how	O
knee	O
loading	O
changes	O
following	O
ACL	O
transection	O
,	O
and	O
how	O
it	O
contributes	O
to	O
cartilage	O
degeneration	O
.	O

We	O
show	O
that	O
the	O
surfaces	O
of	O
tracheal	O
cartilage	O
matrix	O
are	O
collagen	B-GENE
-	O
rich	O
and	O
surround	O
a	O
proteoglycan	O
-	O
rich	O
core	O
.	O

Comparative	O
mapping	O
of	O
the	O
Brassica	B-GENE
S	I-GENE
locus	I-GENE
region	I-GENE
and	O
its	O
homeolog	O
in	O
Arabidopsis	O
.	O

Roles	O
of	O
the	O
Candida	B-GENE
albicans	I-GENE
mitogen	I-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
kinase	I-GENE
homolog	I-GENE
,	O
Cek1p	B-GENE
,	O
in	O
hyphal	O
development	O
and	O
systemic	O
candidiasis	O
.	O

Neither	O
the	O
reaction	O
of	O
monosaccharides	O
nor	O
the	O
disaccharides	O
with	O
beta	O
-	O
alanine	O
resulted	O
in	O
the	O
formation	O
of	O
maltol	O
.	O

In	O
most	O
subjects	O
,	O
markers	O
of	O
bone	O
formation	O
and	O
resorption	O
were	O
normal	O
.	O

Analysis	O
of	O
a	O
Mac1p	B-GENE
mutant	I-GENE
,	O
refractile	O
for	O
copper	O
-	O
dependent	O
repression	O
of	O
the	O
Cu	B-GENE
(	I-GENE
I	I-GENE
)	I-GENE
transport	I-GENE
genes	I-GENE
,	O
showed	O
an	O
aberrant	O
pattern	O
of	O
CUP1	B-GENE
expression	O
and	O
copper	O
sensitivity	O
.	O

The	O
DNA	O
sequencing	O
of	O
the	O
recombinant	O
clones	O
revealed	O
the	O
expression	O
of	O
RXR	B-GENE
alpha	I-GENE
and	O
RXR	B-GENE
beta	I-GENE
.	O

A	O
stratified	O
random	O
sample	O
of	O
20	O
active	O
employees	O
from	O
a	O
cohort	O
of	O
phenoxy	O
herbicide	O
workers	O
was	O
selected	O
in	O
1995	O
for	O
determining	O
PCDD	O
and	O
PCDF	O
congeners	O
in	O
blood	O
lipids	O
to	O
assess	O
the	O
extent	O
of	O
past	O
PCDD	O
and	O
PCDF	O
exposure	O
in	O
this	O
cohort	O
and	O
whether	O
that	O
exposure	O
might	O
explain	O
site	O
-	O
specific	O
cancer	O
findings	O
in	O
the	O
total	O
cohort	O
.	O

The	O
clinical	O
and	O
laboratory	O
features	O
of	O
72	O
children	O
with	O
Henoch	O
-	O
Schonlein	O
purpura	O
(	O
HSP	O
)	O
were	O
examined	O
to	O
determine	O
if	O
there	O
were	O
associations	O
between	O
the	O
laboratory	O
indices	O
-	O
-	O
including	O
white	O
blood	O
cell	O
(	O
WBC	O
)	O
counts	O
,	O
serum	B-GENE
C	I-GENE
-	I-GENE
reactive	I-GENE
protein	I-GENE
(	O
CRP	B-GENE
)	O
levels	O
,	O
platelet	O
(	O
PLT	O
)	O
counts	O
-	O
-	O
and	O
the	O
clinical	O
manifestations	O
of	O
acute	O
HSP	O
.	O

We	O
provide	O
community	O
metabolic	O
data	O
that	O
indicate	O
that	O
large	O
changes	O
in	O
CO2	O
concentration	O
can	O
occur	O
in	O
coral	O
reef	O
waters	O
via	O
biogeochemical	O
processes	O
not	O
directly	O
associated	O
with	O
photosynthesis	O
,	O
respiration	O
,	O
calcification	O
,	O
and	O
CaCO3	O
dissolution	O
.	O

In	O
contrast	O
to	O
other	O
known	O
retroviruses	O
,	O
the	O
FV	B-GENE
pol	I-GENE
genes	I-GENE
are	O
expressed	O
via	O
spliced	O
transcripts	O
.	O

Substitution	O
of	O
bulky	O
hydrophobic	O
residues	O
with	O
charged	O
residues	O
within	O
PEP1	B-GENE
affects	O
the	O
fusion	O
activity	O
of	O
the	O
S	B-GENE
protein	I-GENE
without	O
affecting	O
processing	O
and	O
surface	O
expression	O
.	O

Tributyltin	O
and	O
its	O
breakdown	O
products	O
,	O
mono	O
-	O
and	O
di	O
-	O
butyltin	O
,	O
were	O
determined	O
in	O
water	O
birds	O
collected	O
from	O
Lake	O
Huron	O
(	O
the	O
Great	O
Lakes	O
)	O
,	O
marine	O
coastal	O
United	O
States	O
,	O
and	O
the	O
west	O
coast	O
of	O
British	O
Columbia	O
,	O
Canada	O
.	O

The	O
5	O
'	O
flanking	O
region	O
of	O
the	O
CD1	B-GENE
gene	I-GENE
contained	O
the	O
binding	O
motifs	O
for	O
two	O
cytokine	O
-	O
inducible	O
transcription	O
factors	O
,	O
NF	B-GENE
-	I-GENE
IL2	I-GENE
-	I-GENE
A	I-GENE
and	O
NF	B-GENE
-	I-GENE
IL6	I-GENE
.	O

Fregnac	O
,	O
M	O
.	O

GLRaV	O
-	O
2	O
is	O
the	O
only	O
closterovirus	O
,	O
so	O
far	O
,	O
that	O
matches	O
the	O
genome	O
organization	O
of	O
the	O
type	O
member	O
of	O
the	O
group	O
,	O
BYV	O
,	O
and	O
thus	O
can	O
be	O
unambiguously	O
classified	O
as	O
a	O
definitive	O
member	O
of	O
the	O
genus	O
Closterovirus	O
.	O

Demographic	O
and	O
clinical	O
data	O
were	O
compared	O
with	O
a	O
control	O
group	O
of	O
339	O
healthy	O
age	O
-	O
matched	O
women	O
and	O
with	O
a	O
sample	O
of	O
224	O
women	O
with	O
wrist	O
fracture	O
.	O

Identical	O
results	O
were	O
obtained	O
when	O
transfections	O
and	O
mobility	O
shift	O
assays	O
were	O
performed	O
in	O
primary	O
rat	O
hepatocytes	O
in	O
which	O
the	O
endogenous	O
ALS	B-GENE
gene	I-GENE
is	O
expressed	O
.	O

This	O
E	O
box	O
sequence	O
(	O
CACGTG	O
)	O
is	O
identical	O
to	O
the	O
binding	O
element	O
for	O
USF	B-GENE
(	O
upstream	B-GENE
stimulatory	I-GENE
factor	I-GENE
)	O
,	O
a	O
member	O
of	O
the	O
helix	B-GENE
-	I-GENE
loop	I-GENE
-	I-GENE
helix	I-GENE
family	I-GENE
of	I-GENE
transcription	I-GENE
factors	I-GENE
.	O

Interferon	B-GENE
beta	I-GENE
therapy	O
was	O
discontinued	O
for	O
4	O
weeks	O
.	O

We	O
specially	O
devised	O
3	O
types	O
of	O
turbo	O
pumps	O
,	O
a	O
centrifugal	O
pump	O
(	O
CFP	O
)	O
,	O
a	O
mixed	O
flow	O
pump	O
(	O
MFP	O
)	O
,	O
and	O
an	O
axial	O
flow	O
pump	O
(	O
AFP	O
)	O
,	O
and	O
analyzed	O
their	O
in	O
vitro	O
performance	O
.	O

Examination	O
of	O
the	O
mitochondrial	B-GENE
bc1	I-GENE
complex	I-GENE
crystal	I-GENE
structure	I-GENE
[	O
Zhang	O
,	O
Z	O
.	O
,	O
Huang	O
,	O
L	O
.	O
,	O
Shulmeister	O
,	O
V	O
.	O

Two	O
protease	O
-	O
resistant	O
fragments	O
spanning	O
the	O
N	O
-	O
and	O
C	O
-	O
terminal	O
halves	O
of	O
the	O
nuclease	O
were	O
identified	O
using	O
different	O
proteases	O
which	O
cleave	O
the	O
protein	O
in	O
the	O
same	O
region	O
.	O

The	O
side	O
-	O
to	O
-	O
side	O
difference	O
was	O
statistically	O
significant	O
at	O
EXT	O
30	O
degrees	O
/	O
s	O
and	O
60	O
degrees	O
/	O
s	O
(	O
p	O
<	O
0	O
.	O
05	O
)	O
.	O

CONCLUSION	O
:	O
In	O
women	O
who	O
want	O
or	O
require	O
conservative	O
management	O
of	O
grade	O
4	O
prolapse	O
and	O
are	O
unable	O
to	O
retain	O
a	O
single	O
pessary	O
,	O
the	O
placement	O
of	O
two	O
pessaries	O
often	O
will	O
be	O
successful	O
.	O

Rev	B-GENE
-	O
erbAalpha	B-GENE
/	I-GENE
beta	I-GENE
)	O
,	O
Mxi	B-GENE
-	I-GENE
1	I-GENE
and	O
Mad	B-GENE
bHLH	O
-	O
zip	O
proteins	O
and	O
the	O
oncoproteins	O
PLZF	B-GENE
and	O
LAZ3	B-GENE
/	O
BCL6	B-GENE
is	O
mediated	O
by	O
the	O
corepressors	O
N	B-GENE
-	I-GENE
CoR	I-GENE
and	O
SMRT	B-GENE
.	O

The	O
ParaSight	O
-	O
F	O
test	O
alone	O
was	O
used	O
to	O
monitor	O
serum	O
antigen	O
levels	O
after	O
treatment	O
in	O
24	O
patients	O
.	O

The	O
purified	O
recombinant	O
protein	O
was	O
assayed	O
for	O
its	O
enzyme	O
activity	O
by	O
monitoring	O
transfer	O
of	O
[	O
3H	O
]	O
methyl	O
groups	O
from	O
the	O
substrate	O
DNA	O
to	O
the	O
MGMT	B-GENE
protein	I-GENE
;	O
the	O
activity	O
was	O
found	O
to	O
be	O
stable	O
at	O
90	O
degrees	O
C	O
for	O
at	O
least	O
30	O
min	O
.	O

A	O
deproteinization	O
procedure	O
was	O
coupled	O
with	O
a	O
reversed	O
-	O
phase	O
HPLC	O
separation	O
using	O
a	O
250x4	O
.	O
6	O
mm	O
I	O
.	O
D	O
.	O

Elimination	O
of	O
the	O
inducible	O
response	O
requires	O
simultaneous	O
mutation	O
of	O
both	O
sequences	O
,	O
however	O
,	O
in	O
the	O
presence	O
of	O
an	O
intact	O
EpRE	O
the	O
upstream	O
AP	B-GENE
-	I-GENE
1	I-GENE
site	I-GENE
is	O
irrelevant	O
to	O
induction	O
.	O

Three	O
high	B-GENE
mobility	I-GENE
group	I-GENE
-	I-GENE
like	I-GENE
sequences	I-GENE
within	O
a	O
48	O
-	O
base	O
pair	O
enhancer	O
of	O
the	O
Col2a1	B-GENE
gene	I-GENE
are	O
required	O
for	O
cartilage	O
-	O
specific	O
expression	O
in	O
vivo	O
.	O

The	O
sequence	O
contains	O
an	O
open	O
reading	O
frame	O
of	O
1744	O
nt	O
in	O
the	O
virus	O
-	O
sense	O
strand	O
,	O
a	O
3	O
'	O
untranslated	O
region	O
of	O
1360	O
nt	O
and	O
a	O
3	O
'	O
poly	O
(	O
A	O
)	O
tail	O
.	O

A	O
phylogenetic	O
analysis	O
of	O
the	O
reverse	B-GENE
transcriptase	I-GENE
domain	I-GENE
confirms	O
our	O
differential	O
genetic	O
assessment	O
that	O
Cyclops	B-GENE
from	O
pea	O
is	O
a	O
novel	O
element	O
with	O
no	O
specific	O
relationship	O
to	O
the	O
previously	O
described	O
Gypsy	B-GENE
-	I-GENE
like	I-GENE
elements	I-GENE
from	O
plants	O
.	O

At	O
physiological	O
doses	O
,	O
either	O
insulin	B-GENE
-	I-GENE
like	I-GENE
growth	I-GENE
factor	I-GENE
I	I-GENE
(	O
IGF	B-GENE
-	I-GENE
I	I-GENE
)	O
or	O
insulin	B-GENE
turned	O
out	O
to	O
be	O
as	O
potent	O
as	O
dibutyryl	O
cAMP	O
(	O
dbcAMP	O
)	O
in	O
increasing	O
UCP1	B-GENE
gene	I-GENE
transcription	O
rate	O
(	O
1	O
h	O
)	O
and	O
also	O
UCP1	B-GENE
mRNA	I-GENE
accumulation	O
(	O
3	O
h	O
)	O
,	O
their	O
maximal	O
effect	O
(	O
15	O
-	O
fold	O
increase	O
)	O
reached	O
upon	O
treatment	O
for	O
24	O
h	O
.	O

In	O
addition	O
,	O
insulin	B-GENE
induced	O
AP	B-GENE
-	I-GENE
1	I-GENE
DNA	O
binding	O
activity	O
,	O
this	O
effect	O
being	O
totally	O
prevented	O
in	O
the	O
presence	O
of	O
MEK	B-GENE
-	I-GENE
1	I-GENE
inhibitor	O
.	O

Essentially	O
,	O
2	O
'	O
-	O
O	O
-	O
methyl	O
oligoribonucleotides	O
(	O
2	O
'	O
OMeRNA	O
)	O
were	O
delivered	O
to	O
the	O
nuclei	O
of	O
primary	O
mdx	O
myoblasts	O
in	O
culture	O
.	O

Regulation	O
of	O
the	O
human	O
p21	B-GENE
/	O
WAF1	B-GENE
/	O
Cip1	B-GENE
promoter	O
in	O
hepatic	O
cells	O
by	O
functional	O
interactions	O
between	O
Sp1	B-GENE
and	O
Smad	B-GENE
family	I-GENE
members	I-GENE
.	O

RESULTS	O
:	O
We	O
isolated	O
a	O
C	O
.	O
elegans	O
cDNA	O
that	O
encoded	O
a	O
protein	O
which	O
was	O
similar	O
to	O
,	O
but	O
not	O
exactly	O
homologous	O
with	O
mammalian	O
p120	B-GENE
Ras	B-GENE
-	O
GAP	B-GENE
.	O

The	O
weak	O
base	O
ketoconazole	O
showed	O
complete	O
dissolution	O
from	O
a	O
tablet	O
formulation	O
in	O
Simulated	O
Gastric	O
Fluid	O
without	O
pepsin	B-GENE
(	O
SGFsp	O
)	O
within	O
30	O
minutes	O
,	O
70	O
%	O
dissolution	O
in	O
2	O
hours	O
under	O
fed	O
state	O
simulated	O
upper	O
jejunal	O
conditions	O
but	O
only	O
6	O
%	O
dissolution	O
in	O
2	O
hours	O
under	O
fasted	O
state	O
conditions	O
.	O

In	O
mammals	O
,	O
the	O
Rb	B-GENE
protein	I-GENE
interacts	O
specifically	O
with	O
D	B-GENE
-	I-GENE
type	I-GENE
cyclins	I-GENE
and	O
regulates	O
cell	O
proliferation	O
by	O
binding	O
and	O
inhibiting	O
E2F	B-GENE
transcription	I-GENE
factors	I-GENE
.	O

In	O
addition	O
to	O
the	O
signals	O
obtained	O
by	O
ligation	O
of	O
the	O
TCR	B-GENE
,	O
T	O
cells	O
need	O
additional	O
,	O
co	O
-	O
stimulatory	O
signals	O
to	O
be	O
activated	O
.	O

Moreover	O
,	O
the	O
observation	O
of	O
enhanced	O
luteal	B-GENE
HSP	I-GENE
-	I-GENE
27	I-GENE
phosphorylation	O
in	O
vivo	O
,	O
in	O
late	O
pregnancy	O
,	O
when	O
PKC	B-GENE
-	I-GENE
delta	I-GENE
is	O
abundant	O
and	O
active	O
,	O
suggests	O
that	O
select	O
PKC	B-GENE
family	I-GENE
members	I-GENE
contribute	O
to	O
sHSP	B-GENE
phosphorylation	O
events	O
in	O
vivo	O
.	O

We	O
characterized	O
the	O
structure	O
of	O
this	O
leader	O
mRNA	O
by	O
using	O
the	O
program	O
Mfold	O
and	O
a	O
combination	O
of	O
nested	O
and	O
internal	O
deletions	O
transcriptionally	O
fused	O
to	O
a	O
promoterless	O
lac	B-GENE
operon	I-GENE
.	O

The	O
importance	O
of	O
these	O
sites	O
for	O
transcriptional	O
activation	O
was	O
studied	O
by	O
site	O
-	O
directed	O
mutagenesis	O
followed	O
by	O
promoter	O
function	O
analysis	O
of	O
the	O
mutants	O
with	O
a	O
chloramphenicol	B-GENE
acetyltransferase	I-GENE
reporter	I-GENE
system	O
.	O

Routine	O
blood	O
examination	O
showed	O
leukocytosis	O
,	O
thrombocytopenia	O
,	O
positive	O
CRP	B-GENE
,	O
and	O
elevated	O
myocardial	O
enzymes	O
.	O

Previous	O
studies	O
have	O
suggested	O
that	O
moderate	O
cooling	O
increases	O
the	O
responsiveness	O
of	O
vascular	B-GENE
alpha2	I-GENE
-	I-GENE
adrenoceptors	I-GENE
.	O

Two	O
members	O
of	O
the	O
Cbl	B-GENE
family	I-GENE
have	O
since	O
been	O
defined	O
in	O
mammals	O
(	O
c	B-GENE
-	I-GENE
Cbl	I-GENE
and	O
Cbl	B-GENE
-	I-GENE
b	I-GENE
)	O
,	O
one	O
in	O
C	O
.	O
elegans	O
(	O
Sli	B-GENE
-	I-GENE
1	I-GENE
)	O
and	O
one	O
in	O
Drosophila	O
(	O
D	B-GENE
-	I-GENE
Cbl	I-GENE
)	O
.	O

Anti	B-GENE
-	I-GENE
PTB	I-GENE
antibodies	I-GENE
did	O
not	O
inhibit	O
the	O
binding	O
of	O
PTB	B-GENE
to	O
RNA	O
because	O
they	O
were	O
able	O
to	O
supershift	O
RNA	B-GENE
-	I-GENE
PTB	I-GENE
complexes	I-GENE
.	O

The	O
use	O
of	O
antibodies	O
to	O
the	O
polypyrimidine	B-GENE
tract	I-GENE
binding	I-GENE
protein	I-GENE
(	O
PTB	B-GENE
)	O
to	O
analyze	O
the	O
protein	O
components	O
that	O
assemble	O
on	O
alternatively	O
spliced	O
pre	O
-	O
mRNAs	O
that	O
use	O
distant	O
branch	O
points	O
.	O

The	O
therapeutic	O
use	O
of	O
botulinum	B-GENE
toxin	I-GENE
(	O
Botox	B-GENE
)	O
is	O
increasing	O
in	O
popularity	O
.	O

The	O
viral	B-GENE
oncoprotein	I-GENE
E1A	I-GENE
inhibits	O
NFAT	B-GENE
-	O
dependent	O
transactivation	O
in	O
a	O
p300	B-GENE
-	O
dependent	O
manner	O
.	O

We	O
have	O
applied	O
the	O
mRNA	O
differential	O
display	O
method	O
to	O
compare	O
and	O
analyze	O
mRNAs	O
prepared	O
from	O
five	O
normal	O
nasopharyngeal	O
epithelial	O
cell	O
cultures	O
and	O
five	O
nasopharyngeal	O
carcinoma	O
cell	O
lines	O
.	O

Similar	O
experiments	O
with	O
TR	B-GENE
support	O
the	O
high	O
affinity	O
of	O
RIP140	B-GENE
to	O
the	O
RXR	B-GENE
subunit	I-GENE
and	O
also	O
suggest	O
that	O
either	O
partner	O
in	O
the	O
TR	B-GENE
/	O
RXR	B-GENE
heterodimer	O
can	O
independently	O
respond	O
to	O
ligand	O
.	O

SETTING	O
:	O
University	O
hospital	O
-	O
based	O
,	O
tertiary	O
care	O
infertility	O
center	O
.	O

RESULT	O
(	O
S	O
)	O
:	O
In	O
patients	O
with	O
elevated	O
FSH	B-GENE
levels	O
on	O
cycle	O
day	O
3	O
,	O
a	O
low	O
oocyte	O
yield	O
was	O
achieved	O
(	O
7	O
versus	O
11	O
)	O
and	O
a	O
high	O
number	O
of	O
ampules	O
of	O
hMG	B-GENE
was	O
necessary	O
(	O
56	O
versus	O
33	O
)	O
.	O

RESULTS	O
:	O
Of	O
the	O
patients	O
with	O
IS	O
,	O
67	O
%	O
had	O
significantly	O
greater	O
values	O
of	O
directional	O
preponderance	O
on	O
the	O
OVAR	O
test	O
(	O
a	O
measure	O
of	O
otolith	O
system	O
imbalance	O
)	O
compared	O
with	O
control	O
subjects	O
.	O

In	O
the	O
ePTFE	O
specimens	O
,	O
tissue	O
coverage	O
had	O
increased	O
.	O

As	O
predicted	O
by	O
the	O
Wing	O
and	O
Kristofferson	O
model	O
,	O
the	O
durations	O
of	O
successive	O
ISIs	O
tended	O
to	O
be	O
negatively	O
correlated	O
.	O

We	O
found	O
the	O
following	O
:	O
Specific	O
mutations	O
affected	O
the	O
precise	O
carbohydrate	O
structure	O
and	O
folding	O
of	O
the	O
HA	B-GENE
trimer	I-GENE
.	O

The	O
results	O
show	O
that	O
ROS	O
production	O
by	O
viable	O
spermatozoa	O
is	O
highly	O
correlated	O
with	O
the	O
concentration	O
of	O
PMN	B-GENE
elastase	I-GENE
and	O
the	O
number	O
of	O
both	O
peroxidase	B-GENE
-	O
positive	O
and	O
round	O
cells	O
.	O

Yeast	B-GENE
U1	I-GENE
snRNP	I-GENE
is	O
considerably	O
more	O
complex	O
than	O
its	O
metazoan	O
counterpart	O
,	O
which	O
suggests	O
possible	O
differences	O
between	O
yeast	O
and	O
metazoa	O
in	O
early	O
splicing	O
events	O
.	O

Yeast	B-GENE
U1	I-GENE
snRNP	I-GENE
therefore	O
contains	O
16	O
different	O
proteins	O
,	O
including	O
seven	O
snRNP	B-GENE
core	I-GENE
proteins	I-GENE
,	O
three	O
homologues	O
of	O
the	O
metazoan	B-GENE
U1	I-GENE
snRNP	I-GENE
-	I-GENE
specific	I-GENE
proteins	I-GENE
,	O
and	O
six	O
yeast	B-GENE
-	I-GENE
specific	I-GENE
U1	I-GENE
snRNP	I-GENE
proteins	I-GENE
.	O

After	O
the	O
first	O
cycle	O
,	O
18	O
cases	O
were	O
treated	O
at	O
dose	O
level	O
1	O
,	O
after	O
a	O
second	O
cycle	O
,	O
13	O
cases	O
were	O
treated	O
at	O
dose	O
level	O
2	O
.	O

The	O
opioid	O
antagonist	O
naltrexone	O
(	O
0	O
.	O
01	O
-	O
1	O
.	O
0	O
mg	O
/	O
kg	O
)	O
antagonized	O
the	O
discriminative	O
stimulus	O
effects	O
of	O
heroin	O
,	O
but	O
naltrexone	O
at	O
doses	O
up	O
to	O
10	O
mg	O
/	O
kg	O
had	O
no	O
effect	O
on	O
the	O
discriminative	O
stimulus	O
effects	O
of	O
cocaine	O
.	O

In	O
this	O
study	O
we	O
examined	O
hepatic	O
stellate	O
cell	O
regulation	O
of	O
M6P	B-GENE
/	O
IGFIIR	B-GENE
expression	O
and	O
found	O
that	O
M6P	B-GENE
/	O
IGFIIR	B-GENE
mRNA	O
transcript	O
levels	O
increased	O
in	O
stellate	O
cells	O
from	O
rats	O
exposed	O
to	O
carbon	O
tetrachloride	O
(	O
CCl4	O
)	O
,	O
a	O
potent	O
fibrogenic	O
stimulant	O
.	O

One	O
cDNA	O
clone	O
designated	O
NCoA	O
-	O
62	O
,	O
encoded	O
a	O
62	O
,	O
000	O
-	O
Da	O
protein	O
that	O
is	O
highly	O
related	O
to	O
BX42	B-GENE
,	O
a	O
Drosophila	O
melanogaster	O
nuclear	O
protein	O
involved	O
in	O
ecdysone	O
-	O
stimulated	O
gene	O
expression	O
.	O

These	O
widely	O
expressed	O
proteins	O
share	O
a	O
C	O
-	O
terminal	O
region	O
that	O
bears	O
significant	O
sequence	O
homology	O
to	O
a	O
group	O
of	O
GDP	B-GENE
/	I-GENE
GTP	I-GENE
exchange	I-GENE
proteins	I-GENE
for	O
the	O
Rab3	B-GENE
family	I-GENE
of	O
small	B-GENE
GTP	I-GENE
binding	I-GENE
proteins	I-GENE
.	O

Whereas	O
p82	B-GENE
expression	O
had	O
no	O
effect	O
on	O
ERK2	B-GENE
activation	O
by	O
p126	B-GENE
,	O
p70	B-GENE
completely	O
abrogated	O
this	O
activity	O
.	O

The	O
pre	O
-	O
mRNA	O
splicing	O
factor	O
U2AF	B-GENE
(	O
U2	B-GENE
small	I-GENE
nuclear	I-GENE
ribonucleoprotein	I-GENE
particle	I-GENE
[	I-GENE
snRNP	I-GENE
]	I-GENE
auxiliary	I-GENE
factor	I-GENE
)	O
plays	O
a	O
critical	O
role	O
in	O
3	O
'	O
splice	O
site	O
selection	O
.	O

The	O
brackets	O
were	O
bonded	O
to	O
100	O
freshly	O
extracted	O
bovine	O
incisors	O
,	O
and	O
,	O
after	O
storage	O
in	O
tap	O
water	O
at	O
room	O
temperature	O
for	O
24	O
hours	O
,	O
they	O
were	O
subsequently	O
tested	O
in	O
a	O
shear	O
mode	O
using	O
a	O
universal	O
testing	O
machine	O
.	O

Exercise	O
training	O
has	O
become	O
increasingly	O
important	O
in	O
the	O
treatment	O
of	O
heart	O
failure	O
patients	O
.	O

The	O
growth	O
of	O
Aer	O
.	O
hydrophila	O
in	O
filter	O
-	O
sterilized	O
lettuce	O
extract	O
was	O
completely	O
inhibited	O
by	O
0	O
.	O
1	O
%	O
(	O
v	O
/	O
v	O
)	O
BMC	O
whereas	O
that	O
of	O
Ps	O
.	O
fluorescens	O
was	O
not	O
significantly	O
affected	O
by	O
1	O
%	O
(	O
v	O
/	O
v	O
)	O
BMC	O
.	O

Despite	O
continuous	O
compliance	O
,	O
unexplained	O
resurgence	O
of	O
serum	O
ferritin	B-GENE
levels	O
occurred	O
in	O
4	O
/	O
7	O
patients	O
of	O
the	O
'	O
veteran	O
'	O
group	O
after	O
4	O
-	O
5	O
years	O
on	O
L1	O
.	O

Hematocrit	O
and	O
PaO2	O
did	O
not	O
change	O
.	O

Regulation	O
of	O
myosin	B-GENE
phosphatase	I-GENE
activity	O
involves	O
changes	O
in	O
subunit	O
interactions	O
,	O
although	O
molecular	O
mechanisms	O
are	O
not	O
defined	O
.	O

Commutative	O
saccadic	O
generator	O
is	O
sufficient	O
to	O
control	O
a	O
3	O
-	O
D	O
ocular	O
plant	O
with	O
pulleys	O
.	O

The	O
virus	O
-	O
associated	O
VAI	B-GENE
RNA	O
of	O
adenovirus	O
is	O
a	O
small	O
highly	O
structured	O
RNA	O
that	O
is	O
required	O
for	O
the	O
efficient	O
translation	O
of	O
cellular	O
and	O
viral	O
mRNAs	O
at	O
late	O
times	O
after	O
infection	O
.	O

Structure	O
of	O
the	O
gene	O
encoding	O
the	O
human	O
cyclin	B-GENE
-	I-GENE
dependent	I-GENE
kinase	I-GENE
inhibitor	O
p18	B-GENE
and	O
mutational	O
analysis	O
in	O
breast	O
cancer	O
.	O

The	O
YccA	B-GENE
protein	I-GENE
was	O
found	O
to	O
be	O
degraded	O
in	O
an	O
FtsH	B-GENE
-	O
dependent	O
manner	O
in	O
vivo	O
and	O
in	O
vitro	O
,	O
whereas	O
the	O
YccA11	B-GENE
mutant	I-GENE
protein	I-GENE
,	O
lacking	O
eight	O
amino	O
acid	O
residues	O
within	O
the	O
amino	O
-	O
terminal	O
cytoplasmic	O
domain	O
,	O
was	O
refractory	O
to	O
the	O
degradation	O
.	O

The	O
major	O
type	O
involves	O
activator	O
proteins	O
that	O
bind	O
to	O
DNA	O
adjacent	O
to	O
where	O
the	O
RNA	B-GENE
polymerase	I-GENE
(	O
RNAP	B-GENE
)	O
holoenzyme	O
binds	O
,	O
usually	O
assisting	O
in	O
recruitment	O
of	O
the	O
RNAP	B-GENE
to	O
the	O
promoter	O
.	O

A	O
conserved	O
role	O
for	O
L1	B-GENE
as	O
a	O
transmembrane	O
link	O
between	O
neuronal	O
adhesion	O
and	O
membrane	O
cytoskeleton	O
assembly	O
.	O

Atmospheric	O
benzene	O
,	O
urinary	O
muconic	O
acid	O
(	O
tt	O
-	O
MA	O
)	O
and	O
leukocyte	B-GENE
alkaline	I-GENE
phosphatase	I-GENE
activity	O
(	O
LAPA	O
)	O
were	O
evaluated	O
among	O
66	O
car	O
mechanics	O
,	O
34	O
road	O
tanker	O
drivers	O
,	O
and	O
28	O
nonexposed	O
workers	O
.	O

It	O
contains	O
a	O
5	O
'	O
-	O
noncoding	O
region	O
(	O
NCR	O
)	O
of	O
73	O
nucleotides	O
,	O
five	O
open	O
reading	O
frames	O
(	O
ORFs	O
1	O
to	O
5	O
)	O
which	O
encode	O
proteins	O
with	O
M	O
(	O
r	O
)	O
160	B-GENE
kDa	I-GENE
RNA	I-GENE
-	I-GENE
dependent	I-GENE
RNA	I-GENE
polymerase	I-GENE
(	I-GENE
ORF1	I-GENE
)	I-GENE
,	O
26	B-GENE
kDa	I-GENE
movement	I-GENE
protein	I-GENE
1	I-GENE
(	I-GENE
ORF2	I-GENE
)	I-GENE
,	O
13	B-GENE
kDa	I-GENE
movement	I-GENE
protein	I-GENE
2	I-GENE
(	I-GENE
ORF3	I-GENE
)	I-GENE
,	O
10	B-GENE
kDa	I-GENE
movement	I-GENE
protein	I-GENE
3	I-GENE
(	I-GENE
ORF4	I-GENE
)	I-GENE
,	O
24	B-GENE
kDa	I-GENE
coat	I-GENE
protein	I-GENE
(	I-GENE
OFR5	I-GENE
)	I-GENE
,	O
and	O
a	O
3	O
'	O
NCR	O
of	O
76	O
nucleotides	O
.	O

After	O
profound	O
normovolemic	O
hemodilution	O
(	O
Hct	O
9	O
%	O
)	O
superiority	O
of	O
LV	O
MC	O
and	O
LV	O
diastolic	O
properties	O
was	O
found	O
,	O
when	O
myocardial	O
oxygenation	O
was	O
supported	O
by	O
i	O
.	O
v	O
.	O
perflubron	O
emulsion	O
,	O
a	O
temporary	O
O2	O
carrier	O
.	O

These	O
genes	O
may	O
represent	O
interesting	O
targets	O
for	O
new	O
therapeutic	O
strategies	O
.	O

It	O
could	O
also	O
inhibit	O
C1q	B-GENE
-	O
dependent	O
haemolysis	O
of	O
both	O
IgG	B-GENE
-	O
and	O
IgM	B-GENE
-	O
sensitized	O
erythrocytes	O
.	O

3	O
)	O
and	O
one	O
distal	O
(	O
-	O
11	O
.	O
8	O
/	O
-	O
10	O
.	O
9	O
)	O
,	O
presented	O
an	O
enhancer	O
activity	O
in	O
pituitary	O
cells	O
when	O
placed	O
upstream	O
of	O
the	O
SV40	B-GENE
promoter	I-GENE
.	O

3	O
-	O
-	O
It	O
is	O
necessary	O
to	O
think	O
about	O
cosmetic	O
consequences	O
of	O
the	O
chinese	O
flap	O
and	O
consider	O
other	O
possibilities	O
of	O
the	O
flap	O
choice	O
.	O

CONCLUSION	O
:	O
TNF	B-GENE
alpha	I-GENE
,	O
TGF	B-GENE
beta	I-GENE
,	O
PDGF	B-GENE
and	O
IL	B-GENE
-	I-GENE
1beta	I-GENE
increased	O
LDLr	B-GENE
gene	I-GENE
expression	O
by	O
increasing	O
sterol	O
-	O
independent	O
and	O
mitogenesis	O
-	O
independent	O
gene	O
transcription	O
.	O

However	O
,	O
it	O
is	O
only	O
one	O
-	O
half	O
and	O
one	O
-	O
third	O
the	O
size	O
of	O
the	O
proteolipids	O
from	O
M	O
.	O
thermoautotrophicum	O
and	O
M	O
.	O
jannaschii	O
,	O
respectively	O
.	O
ahaK	B-GENE
is	O
expressed	O
in	O
Escherichia	O
coli	O
,	O
and	O
it	O
is	O
incorporated	O
into	O
the	O
cytoplasmic	O
membrane	O
despite	O
the	O
different	O
chemical	O
natures	O
of	O
lipids	O
from	O
archaea	O
and	O
bacteria	O
.	O

In	O
this	O
report	O
we	O
studied	O
the	O
role	O
of	O
protein	B-GENE
-	I-GENE
tyrosine	I-GENE
phosphatase	I-GENE
SHP	B-GENE
-	I-GENE
2	I-GENE
in	O
ErbB	B-GENE
-	O
mediated	O
activation	O
of	O
mitogen	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
kinase	I-GENE
(	O
MAPK	B-GENE
)	O
by	O
overexpressing	O
SHP	B-GENE
-	I-GENE
2	I-GENE
mutants	I-GENE
in	O
COS	O
-	O
7	O
cells	O
.	O

Osteoadherin	B-GENE
is	O
a	O
recently	O
described	O
bone	O
proteoglycan	O
containing	O
keratan	O
sulfate	O
.	O

Intron	O
8	O
harbored	O
a	O
strong	O
erythroid	O
-	O
specific	O
enhancer	O
activity	O
which	O
was	O
orientation	O
-	O
dependent	O
.	O

The	O
intron	O
8	O
enhancer	O
region	O
was	O
not	O
activated	O
by	O
GATA	B-GENE
-	I-GENE
1	I-GENE
together	O
with	O
Sp1	B-GENE
in	O
transactivation	O
experiments	O
in	O
COS	O
-	O
1	O
cells	O
indicating	O
the	O
involvement	O
of	O
a	O
related	O
Sp1	B-GENE
protein	I-GENE
or	O
of	O
another	O
unidentified	O
erythroid	O
factor	O
.	O

The	O
cleavage	O
of	O
Fak	B-GENE
by	O
caspases	B-GENE
may	O
thus	O
play	O
an	O
important	O
role	O
in	O
the	O
execution	O
of	O
the	O
suicide	O
program	O
by	O
disabling	O
the	O
anti	O
-	O
apoptotic	O
function	O
of	O
Fak	B-GENE
.	O

Moreover	O
,	O
the	O
mass	O
estimated	O
with	O
the	O
QCM	O
response	O
through	O
the	O
Sauerbrey	O
equation	O
and	O
the	O
mass	O
which	O
can	O
be	O
measured	O
thanks	O
to	O
other	O
analytical	O
techniques	O
,	O
in	O
our	O
case	O
an	O
enzymatic	O
assay	O
,	O
are	O
different	O
:	O
the	O
deposited	O
mass	O
is	O
generally	O
overestimated	O
by	O
the	O
QCM	O
.	O

Transcription	O
initiation	O
occurred	O
predominantly	O
at	O
the	O
putative	O
sigmaA	B-GENE
-	I-GENE
dependent	I-GENE
promoter	I-GENE
in	O
exponentially	O
growing	O
cells	O
and	O
was	O
induced	O
under	O
stress	O
conditions	O
.	O

The	O
genes	O
encoding	O
(	B-GENE
2Fe	I-GENE
-	I-GENE
2S	I-GENE
)	I-GENE
plant	I-GENE
-	I-GENE
like	I-GENE
ferredoxins	I-GENE
were	O
studied	O
in	O
the	O
widely	O
used	O
cyanobacterium	O
Synechocystis	O
PCC6803	O
.	O

RNA	O
of	O
GBV	O
-	O
C	O
was	O
detected	O
in	O
14	O
(	O
18	O
%	O
)	O
patients	O
before	O
BMT	O
.	O

A	O
major	O
pool	O
of	O
Dsg	B-GENE
-	O
plakoglobin	B-GENE
complexes	O
sedimented	O
at	O
8S	O
and	O
exhibited	O
a	O
1	O
:	O
1	O
stoichiometry	O
.	O

Our	O
results	O
indicate	O
that	O
the	O
binding	O
of	O
CBF	B-GENE
/	O
NF	B-GENE
-	I-GENE
Y	I-GENE
to	O
the	O
inverted	O
CCAAT	O
box	O
is	O
responsible	O
for	O
transcriptional	O
activation	O
of	O
the	O
nTPH	B-GENE
gene	I-GENE
.	O

In	O
macrophages	O
,	O
LPS	O
-	O
inducible	O
HIV	O
-	O
1	O
gene	O
expression	O
is	O
mediated	O
in	O
part	O
by	O
binding	O
of	O
NF	B-GENE
-	I-GENE
kappa	I-GENE
B	I-GENE
to	O
identical	O
tandem	O
binding	O
sites	O
located	O
within	O
the	O
long	O
terminal	O
repeat	O
(	O
LTR	O
)	O
.	O

The	O
influence	O
of	O
p53	B-GENE
on	O
cytokine	O
-	O
triggered	O
Janus	B-GENE
kinase	I-GENE
-	O
STAT	B-GENE
signaling	O
was	O
investigated	O
in	O
human	O
hepatoma	O
Hep3B	O
cell	O
lines	O
engineered	O
to	O
constitutively	O
express	O
the	O
temperature	O
-	O
sensitive	O
Val135	B-GENE
mutant	I-GENE
of	I-GENE
p53	I-GENE
.	O

It	O
can	O
also	O
be	O
used	O
to	O
examine	O
various	O
laryngeal	O
parameters	O
obtained	O
from	O
videotaped	O
endoscopic	O
and	O
stroboscopic	O
examinations	O
.	O

CONCLUSIONS	O
:	O
Two	O
consecutive	O
sets	O
of	O
transrectal	O
ultrasound	O
guided	O
sextant	O
biopsies	O
of	O
the	O
prostate	O
performed	O
in	O
a	O
single	O
office	O
visit	O
represent	O
a	O
cost	O
-	O
effective	O
biopsy	O
strategy	O
for	O
men	O
presenting	O
with	O
an	O
abnormal	O
digital	O
rectal	O
examination	O
and	O
/	O
or	O
elevated	O
serum	B-GENE
PSA	I-GENE
.	O

Examination	O
of	O
nuclear	O
magnetic	O
resonance	O
(	O
NMR	O
)	O
spectra	O
of	O
a	O
series	O
of	O
N	B-GENE
-	I-GENE
terminally	I-GENE
truncated	I-GENE
MIP	I-GENE
-	I-GENE
1	I-GENE
beta	I-GENE
variants	I-GENE
reveals	O
that	O
these	O
proteins	O
possess	O
a	O
range	O
of	O
ability	O
to	O
dimerize	O
.	O

Interestingly	O
,	O
PKA	B-GENE
activity	O
is	O
dispensable	O
in	O
a	O
strain	O
lacking	O
Msn2p	B-GENE
and	O
Msn4p	B-GENE
activity	O
.	O

They	O
also	O
indicate	O
that	O
direct	O
interactions	O
between	O
C	B-GENE
/	I-GENE
EBPs	I-GENE
and	O
specific	O
Ets	B-GENE
family	O
members	O
,	O
together	O
with	O
GATA	B-GENE
-	I-GENE
1	I-GENE
,	O
are	O
important	O
for	O
eosinophil	O
lineage	O
determination	O
.	O

Recently	O
,	O
a	O
human	B-GENE
transcription	I-GENE
elongation	I-GENE
factor	I-GENE
P	I-GENE
-	I-GENE
TEFb	I-GENE
,	O
consisting	O
of	O
CDK9	B-GENE
kinase	I-GENE
,	O
cyclin	B-GENE
T	I-GENE
and	O
other	O
associated	O
factors	O
,	O
has	O
been	O
shown	O
to	O
interact	O
with	O
Tat	B-GENE
to	O
restore	O
Tat	B-GENE
activation	O
in	O
HeLa	O
nuclear	O
extract	O
depleted	O
of	O
P	B-GENE
-	I-GENE
TEFb	I-GENE
.	O

We	O
have	O
used	O
the	O
hydrophobic	O
repeats	O
of	O
the	O
HSF1	B-GENE
trimerization	I-GENE
domain	I-GENE
in	O
the	O
yeast	O
two	O
-	O
hybrid	O
protein	O
interaction	O
assay	O
to	O
identify	O
heat	B-GENE
shock	I-GENE
factor	I-GENE
binding	I-GENE
protein	I-GENE
1	I-GENE
(	O
HSBP1	B-GENE
)	O
,	O
a	O
novel	O
,	O
conserved	O
,	O
76	O
-	O
amino	O
-	O
acid	O
protein	O
that	O
contains	O
two	O
extended	O
arrays	O
of	O
hydrophobic	O
repeats	O
that	O
interact	O
with	O
the	O
HSF1	B-GENE
heptad	I-GENE
repeats	I-GENE
.	O

Genomic	O
and	O
cDNA	O
clones	O
homologous	O
to	O
the	O
yeast	O
GCN2	B-GENE
eIF	B-GENE
-	I-GENE
2alpha	I-GENE
kinase	O
(	O
yGCN2	O
)	O
were	O
isolated	O
from	O
Drosophila	O
melanogaster	O
.	O

The	O
general	O
recombination	O
at	O
a	O
polarizing	O
voltage	O
of	O
300	O
V	O
is	O
less	O
than	O
2	O
%	O
for	O
dose	O
-	O
rates	O
up	O
to	O
about	O
100	O
mGy	O
min	O
-	O
1	O
.	O

The	O
low	O
number	O
of	O
false	O
positives	O
indicates	O
that	O
our	O
scheme	O
would	O
not	O
confuse	O
the	O
radiologist	O
by	O
suggesting	O
normal	O
regions	O
as	O
suspicious	O
.	O

Strengthening	O
the	O
biological	O
weapons	O
convention	O
and	O
implications	O
on	O
the	O
pharmaceutical	O
and	O
biotechnology	O
industry	O
.	O

VirD2	B-GENE
is	O
one	O
of	O
the	O
key	O
Agrobacterium	O
tumefaciens	O
proteins	O
involved	O
in	O
T	O
-	O
DNA	O
processing	O
and	O
transfer	O
.	O

Taken	O
together	O
,	O
these	O
data	O
indicate	O
that	O
the	O
VirD2	B-GENE
omega	I-GENE
domain	I-GENE
is	O
important	O
for	O
efficient	O
T	O
-	O
DNA	O
integration	O
.	O

The	O
DHEAS	O
levels	O
in	O
all	O
stages	O
of	O
decreased	O
BMD	O
were	O
significantly	O
lower	O
than	O
those	O
in	O
the	O
group	O
with	O
normal	O
BMD	O
.	O

Orientation	O
of	O
the	O
nuclear	O
spin	O
system	O
by	O
optical	O
pumping	O
causes	O
an	O
Overhauser	O
shift	O
of	O
the	O
excitonic	O
energy	O
levels	O
proportional	O
to	O
the	O
degree	O
of	O
nuclear	O
orientation	O
.	O

Cystatin	B-GENE
A	I-GENE
,	O
a	O
cysteine	B-GENE
proteinase	I-GENE
inhibitor	O
,	O
is	O
one	O
of	O
the	O
precursor	O
proteins	O
of	O
cornified	B-GENE
cell	I-GENE
envelope	I-GENE
of	O
keratinocytes	O
and	O
is	O
expressed	O
during	O
the	O
late	O
stage	O
of	O
keratinocyte	O
differentiation	O
.	O

A	O
role	O
for	O
RalGDS	B-GENE
and	O
a	O
novel	O
Ras	B-GENE
effector	O
in	O
the	O
Ras	B-GENE
-	O
mediated	O
inhibition	O
of	O
skeletal	O
myogenesis	O
.	O

GTPase	B-GENE
activating	O
specificity	O
of	O
RGS12	B-GENE
and	O
binding	O
specificity	O
of	O
an	O
alternatively	O
spliced	O
PDZ	B-GENE
(	O
PSD	B-GENE
-	I-GENE
95	I-GENE
/	O
Dlg	B-GENE
/	O
ZO	B-GENE
-	I-GENE
1	I-GENE
)	O
domain	O
.	O

However	O
,	O
mutations	O
in	O
the	O
HNF	B-GENE
-	I-GENE
4	I-GENE
binding	I-GENE
site	I-GENE
on	O
element	B-GENE
CIIB	I-GENE
and	O
inhibition	O
of	O
HNF	B-GENE
-	I-GENE
4	I-GENE
synthesis	O
in	O
HepG2	O
cells	O
by	O
antisense	O
HNF	B-GENE
-	I-GENE
4	I-GENE
constructs	I-GENE
decreased	O
the	O
apoCII	B-GENE
promoter	I-GENE
activity	O
to	O
25	O
-	O
40	O
%	O
of	O
the	O
control	O
,	O
indicating	O
that	O
HNF	B-GENE
-	I-GENE
4	I-GENE
is	O
a	O
positive	O
regulator	O
of	O
the	O
apoCII	B-GENE
gene	I-GENE
.	O

272	O
,	O
19107	O
-	O
19110	O
)	O
.	O

In	O
addition	O
,	O
we	O
find	O
that	O
E2F	B-GENE
-	I-GENE
1	I-GENE
can	O
cause	O
apoptosis	O
in	O
p53	B-GENE
-	I-GENE
/	I-GENE
-	I-GENE
tumour	O
cells	O
and	O
further	O
p300	B-GENE
,	O
which	O
also	O
functions	O
as	O
a	O
co	O
-	O
activator	O
for	O
the	O
E2F	B-GENE
/	O
DP	B-GENE
heterodimer	O
,	O
enhances	O
the	O
apoptotic	O
activity	O
of	O
E2F	B-GENE
-	I-GENE
1	I-GENE
.	O

Blocked	O
shift	O
/	O
supershift	O
analysis	O
indicates	O
that	O
Fos	B-GENE
family	I-GENE
member	O
proteins	O
especially	O
Fra	B-GENE
-	I-GENE
1	I-GENE
and	O
Fra	B-GENE
-	I-GENE
2	I-GENE
are	O
related	O
to	O
progression	O
and	O
no	O
changes	O
found	O
in	O
the	O
Jun	B-GENE
family	I-GENE
member	O
proteins	O
although	O
they	O
are	O
present	O
in	O
the	O
AP	B-GENE
-	I-GENE
1	I-GENE
/	I-GENE
DNA	I-GENE
binding	I-GENE
complex	I-GENE
.	O

Initially	O
,	O
we	O
observed	O
that	O
unmutated	O
p53	B-GENE
is	O
strongly	O
expressed	O
in	O
premalignant	O
mammary	O
glands	O
and	O
in	O
mammary	O
tumors	O
derived	O
from	O
the	O
MMTV	O
-	O
c	B-GENE
-	I-GENE
myc	I-GENE
strain	O
.	O

These	O
data	O
show	O
that	O
heterologous	O
virus	O
RNAs	O
(	O
BSMV	O
)	O
can	O
serve	O
as	O
primer	O
donors	O
for	O
MStV	O
mRNA	O
capped	O
RNA	O
-	O
primed	O
transcription	O
in	O
doubly	O
infected	O
plants	O
.	O

Human	O
isoforms	O
,	O
designated	O
1	O
to	O
4	O
,	O
differ	O
from	O
each	O
other	O
by	O
the	O
start	O
codon	O
used	O
.	O

Comparison	O
of	O
cDNA	O
and	O
genomic	O
sequences	O
shows	O
that	O
the	O
ZNF189	B-GENE
gene	I-GENE
spans	O
approximately	O
11	O
kb	O
and	O
is	O
organized	O
into	O
at	O
least	O
four	O
exons	O
,	O
the	O
large	O
3	O
'	O
-	O
end	O
exon	O
coding	O
for	O
the	O
complete	O
zinc	O
finger	O
domain	O
and	O
the	O
3	O
'	O
untranslated	O
region	O
.	O

The	O
gp330	B-GENE
/	O
Megalin	B-GENE
/	O
LRP	B-GENE
-	I-GENE
2	I-GENE
protein	O
belongs	O
to	O
the	O
low	B-GENE
-	I-GENE
density	I-GENE
lipoprotein	I-GENE
receptor	I-GENE
gene	I-GENE
family	I-GENE
and	O
is	O
believed	O
to	O
function	O
as	O
an	O
endocytic	O
receptor	O
for	O
the	O
uptake	O
of	O
lipoproteins	O
and	O
many	O
other	O
ligands	O
.	O

In	O
the	O
DNA	O
recognition	O
helix	O
of	O
finger	O
II	O
,	O
the	O
conserved	O
Arg	O
at	O
position	O
62	O
(	O
N	O
-	O
terminal	O
side	O
of	O
the	O
first	O
zinc	O
-	O
coordinating	O
histidine	O
)	O
was	O
changed	O
to	O
a	O
Leu	O
or	O
Gln	O
.	O

Dosage	O
in	O
both	O
cases	O
was	O
0	O
.	O
2	O
g	O
/	O
m2	O
.	O

Five	O
additional	O
copies	O
of	O
Lian	B-GENE
elements	I-GENE
were	O
isolated	O
,	O
mapped	O
by	O
restriction	O
digestion	O
,	O
and	O
partially	O
sequenced	O
.	O

Evolutionary	O
relationships	O
among	O
putative	O
RNA	B-GENE
-	I-GENE
dependent	I-GENE
RNA	I-GENE
polymerases	I-GENE
encoded	O
by	O
a	O
mitochondrial	O
virus	O
-	O
like	O
RNA	O
in	O
the	O
Dutch	O
elm	O
disease	O
fungus	O
,	O
Ophiostoma	O
novo	O
-	O
ulmi	O
,	O
by	O
other	O
viruses	O
and	O
virus	O
-	O
like	O
RNAs	O
and	O
by	O
the	O
Arabidopsis	O
mitochondrial	O
genome	O
.	O

Role	O
of	O
the	O
transcription	O
start	O
site	O
core	O
region	O
and	O
transcription	B-GENE
factor	I-GENE
YY1	I-GENE
in	O
Rous	B-GENE
sarcoma	I-GENE
virus	I-GENE
long	I-GENE
terminal	I-GENE
repeat	I-GENE
promoter	I-GENE
activity	O
.	O

Addition	O
of	O
Rap	O
or	O
KN62	O
after	O
exposure	O
of	O
cells	O
to	O
progesterone	O
agonist	O
Org	O
2058	O
had	O
no	O
effect	O
on	O
induction	O
of	O
CAT	B-GENE
activity	O
.	O

The	O
Dax	B-GENE
-	I-GENE
1	I-GENE
gene	I-GENE
encodes	O
a	O
protein	O
that	O
is	O
structurally	O
related	O
to	O
members	O
of	O
the	O
orphan	B-GENE
nuclear	I-GENE
receptor	I-GENE
superfamily	I-GENE
.	O

He	O
was	O
administered	O
recombinant	B-GENE
IFN	I-GENE
alpha	I-GENE
-	I-GENE
2b	I-GENE
under	O
the	O
diagnosis	O
of	O
chronic	O
hepatitis	O
C	O
.	O

Regulation	O
at	O
37	O
degrees	O
C	O
,	O
therefore	O
,	O
involves	O
the	O
action	O
of	O
three	O
protein	O
kinase	O
cascades	O
that	O
repress	O
HSF1	B-GENE
through	O
phosphorylation	O
of	O
serine	O
residues	O
303	O
,	O
307	O
,	O
and	O
363	O
and	O
may	O
promote	O
growth	O
by	O
suppressing	O
the	O
heat	O
shock	O
response	O
.	O

Clinical	O
implication	O
of	O
protein	O
levels	O
of	O
IL	B-GENE
-	I-GENE
5	I-GENE
in	O
induced	O
sputum	O
in	O
asthmatic	O
patients	O
.	O

In	O
these	O
cells	O
,	O
ras	B-GENE
-	O
induced	O
transition	O
is	O
accompanied	O
by	O
a	O
strong	O
induction	O
of	O
AP	B-GENE
-	I-GENE
1	I-GENE
-	O
binding	O
activity	O
along	O
with	O
increased	O
expression	O
of	O
CD44	B-GENE
mRNA	I-GENE
and	O
protein	O
.	O

This	O
distribution	O
implies	O
that	O
the	O
polycistronic	O
precursor	O
is	O
imported	O
into	O
the	O
nucleolus	O
for	O
processing	O
to	O
the	O
mature	O
snoRNAs	O
,	O
and	O
that	O
the	O
import	O
or	O
processing	O
pathway	O
involves	O
coiled	O
bodies	O
.	O

Suppressive	O
therapy	O
for	O
thyroid	O
nodules	O
.	O

Fourteen	O
healthy	O
male	O
volunteers	O
completed	O
the	O
study	O
.	O

In	O
the	O
absence	O
of	O
Mg2	O
+	O
,	O
a	O
hydrophobic	O
exonuclease	O
site	O
dominates	O
over	O
the	O
polymerase	O
site	O
for	O
possession	O
of	O
the	O
primer	O
terminus	O
.	O

As	O
the	O
high	O
-	O
affinity	O
Mg2	O
+	O
binding	O
sites	O
are	O
filled	O
,	O
the	O
primer	O
terminus	O
migrates	O
from	O
the	O
exonuclease	O
site	O
to	O
a	O
highly	O
based	O
stacked	O
polymerase	O
active	O
site	O
.	O

One	O
missense	O
allele	O
(	O
P236S	O
)	O
with	O
complete	O
loss	O
of	O
function	O
at	O
30	O
degreesC	O
and	O
four	O
missense	O
alleles	O
(	O
L173F	O
,	O
E225K	O
,	O
S269L	O
and	O
E274K	O
)	O
that	O
conferred	O
a	O
temperature	O
sensitive	O
phenotype	O
were	O
identified	O
.	O

Structural	O
analysis	O
of	O
the	O
5	O
'	O
-	O
regulatory	O
region	O
reveals	O
that	O
the	O
c	B-GENE
-	I-GENE
met	I-GENE
promoter	I-GENE
lacks	O
TATA	O
or	O
CAAT	O
elements	O
but	O
has	O
an	O
extremely	O
high	O
G	O
-	O
C	O
content	O
and	O
multiple	O
Sp1	B-GENE
binding	I-GENE
sites	I-GENE
.	O

The	O
report	O
highlights	O
the	O
possible	O
contribution	O
of	O
stress	O
factors	O
in	O
the	O
context	O
of	O
therapy	O
resistant	O
periodontal	O
disease	O
,	O
and	O
the	O
results	O
seem	O
to	O
be	O
understandable	O
within	O
the	O
context	O
of	O
a	O
stress	O
system	O
disorder	O
perspective	O
.	O

Acute	O
pancreatitis	O
is	O
a	O
rather	O
common	O
abdominal	O
disorder	O
.	O

Each	O
binding	O
site	O
,	O
however	O
,	O
was	O
different	O
in	O
its	O
preference	O
for	O
binding	O
partners	O
.	O

We	O
isolated	O
the	O
human	B-GENE
FGF	I-GENE
-	I-GENE
BP	I-GENE
promoter	I-GENE
and	O
determined	O
by	O
deletion	O
analysis	O
that	O
TPA	O
regulatory	O
elements	O
were	O
all	O
contained	O
in	O
the	O
first	O
118	O
base	O
pairs	O
upstream	O
of	O
the	O
transcription	O
start	O
site	O
.	O

Electrophoretic	O
mobility	O
shift	O
assays	O
demonstrated	O
specific	O
nuclear	O
protein	O
binding	O
to	O
-	O
85	O
/	O
-	O
64	O
,	O
and	O
single	O
point	O
mutations	O
suggested	O
important	O
binding	O
nucleotides	O
between	O
-	O
79	O
/	O
-	O
68	O
with	O
five	O
critical	O
bases	O
between	O
-	O
74	O
/	O
-	O
70	O
(	O
5	O
'	O
-	O
CTCCT	O
-	O
3	O
'	O
)	O
.	O

"	O
Complex	O
partial	O
"	O
seizures	O
.	O

B	B-GENE
cell	I-GENE
antigen	I-GENE
receptor	I-GENE
(	O
BCR	B-GENE
)	O
-	O
mediated	O
formation	O
of	O
a	O
SHP	B-GENE
-	I-GENE
2	I-GENE
-	O
pp120	B-GENE
complex	O
and	O
its	O
inhibition	O
by	O
Fc	B-GENE
gamma	I-GENE
RIIB1	I-GENE
-	O
BCR	B-GENE
coligation	O
.	O

Chem	O
.	O
,	O
270	O
:	O
7117	O
-	O
7124	O
,	O
1995	O
;	O
and	O
MT	O
Hartsough	O
et	O
al	O
.	O
,	O
J	O
.	O

Here	O
we	O
investigate	O
the	O
role	O
of	O
c	B-GENE
-	I-GENE
Cbl	I-GENE
in	O
development	O
and	O
homeostasis	O
in	O
mice	O
by	O
targeted	O
disruption	O
of	O
the	O
c	B-GENE
-	I-GENE
Cbl	I-GENE
locus	I-GENE
.	O
c	B-GENE
-	I-GENE
Cbl	I-GENE
-	O
deficient	O
mice	O
were	O
viable	O
,	O
fertile	O
,	O
and	O
outwardly	O
normal	O
in	O
appearance	O
.	O

One	O
is	O
to	O
act	O
within	O
the	O
visceral	O
endoderm	O
to	O
promote	O
proper	O
streak	O
morphogenesis	O
.	O

We	O
propose	O
that	O
noi	B-GENE
/	O
pax2	B-GENE
.	I-GENE
1	I-GENE
participates	O
in	O
sequential	O
signaling	O
processes	O
as	O
a	O
key	O
integrator	O
of	O
midbrain	O
-	O
hindbrain	O
boundary	O
development	O
.	O

METHODS	O
:	O
Fibrotic	O
changes	O
involving	O
bone	O
marrow	O
were	O
evaluated	O
histologically	O
semiquantitatively	O
using	O
reticulin	B-GENE
fiber	O
impregnation	O
(	O
method	O
of	O
Gomori	O
)	O
.	O

We	O
then	O
studied	O
four	O
unrelated	O
Japanese	O
families	O
with	O
GSD	O
-	O
Ib	O
,	O
and	O
found	O
three	O
novel	O
mutations	O
:	O
a	O
four	O
-	O
base	O
deletion	O
/	O
two	O
-	O
base	O
insertion	O
,	O
a	O
point	O
mutation	O
within	O
a	O
consensus	O
splicing	O
donor	O
site	O
,	O
and	O
a	O
missense	O
mutation	O
(	O
W118R	O
)	O
.	O

Removal	O
of	O
the	O
carboxyl	O
region	O
severely	O
reduced	O
transcriptional	O
activation	O
.	O

A	O
"	O
Level	O
A	O
"	O
in	O
vitro	O
/	O
in	O
vivo	O
correlation	O
was	O
established	O
for	O
a	O
sustained	O
release	O
theophylline	O
(	O
CAS	O
58	O
-	O
55	O
-	O
9	O
)	O
preparation	O
(	O
Bronchoretard	O
)	O
under	O
investigation	O
.	O

METHOD	O
:	O
50	O
consecutive	O
children	O
aged	O
from	O
6	O
months	O
to	O
17	O
years	O
were	O
included	O
into	O
the	O
study	O
which	O
comprised	O
questionnaires	O
of	O
patient	O
and	O
family	O
histories	O
,	O
serological	O
screening	O
tests	O
for	O
common	O
inhalational	O
allergens	O
(	O
CAP	O
SX1	O
)	O
,	O
and	O
determination	O
of	O
total	O
serum	B-GENE
immunoglobulin	I-GENE
E	I-GENE
(	O
IgE	B-GENE
)	O
and	O
of	O
latex	O
-	O
specific	O
serum	B-GENE
IgE	I-GENE
by	O
solid	O
-	O
phase	O
immunoassays	O
.	O

The	O
PDE4A	B-GENE
-	I-GENE
subfamily	I-GENE
-	I-GENE
specific	I-GENE
linker	I-GENE
region	I-GENE
LR1	O
,	O
which	O
joins	O
UCR1	O
and	O
UCR2	O
,	O
is	O
encoded	O
by	O
two	O
exons	O
,	O
whereas	O
LR2	O
,	O
which	O
joins	O
UCR2	O
to	O
the	O
catalytic	O
unit	O
,	O
is	O
encoded	O
by	O
a	O
single	O
exon	O
.	O

Pol32Delta	B-GENE
strains	O
are	O
weak	O
antimutators	O
and	O
are	O
defective	O
for	O
damage	O
-	O
induced	O
mutagenesis	O
.	O

At	O
the	O
same	O
time	O
,	O
the	O
results	O
indicate	O
that	O
p53	B-GENE
plays	O
a	O
defensive	O
role	O
against	O
HBV	O
by	O
transcriptionally	O
repressing	O
the	O
HBV	B-GENE
core	I-GENE
promoter	I-GENE
through	O
liver	B-GENE
-	I-GENE
specific	I-GENE
enhancer	I-GENE
II	I-GENE
and	O
HBx	B-GENE
is	O
required	O
to	O
counteract	O
this	O
inhibitory	O
function	O
of	O
p53	B-GENE
.	O

To	O
gain	O
insight	O
into	O
the	O
expression	O
of	O
the	O
AtCP1	B-GENE
gene	I-GENE
,	O
northern	O
blot	O
analysis	O
was	O
carried	O
out	O
.	O

The	O
aim	O
of	O
the	O
study	O
was	O
to	O
correlate	O
the	O
responsiveness	O
to	O
bronchoprovocation	O
with	O
methacholine	O
in	O
subjects	O
a	O
with	O
allergic	O
rhinitis	O
during	O
and	O
out	O
of	O
the	O
pollen	O
season	O
with	O
total	O
serum	O
IgE	B-GENE
and	O
blood	O
eosinophils	O
.	O

These	O
results	O
provide	O
the	O
first	O
demonstration	O
that	O
an	O
SR	B-GENE
protein	I-GENE
can	O
influence	O
splicing	O
of	O
specific	O
pre	O
-	O
mRNAs	O
in	O
vivo	O
.	O

In	O
particular	O
,	O
the	O
potential	O
for	O
prostate	O
cancer	O
chemoprevention	O
using	O
nonsteroidal	O
anti	O
-	O
inflammatory	O
drugs	O
(	O
cyclo	B-GENE
-	I-GENE
oxygenase	I-GENE
inhibitors	O
;	O
NSAIDs	O
)	O
has	O
received	O
little	O
attention	O
.	O

This	O
study	O
reports	O
the	O
isolation	O
of	O
a	O
P	O
.	O
hybrida	O
gene	O
,	O
jaf13	B-GENE
,	O
encoding	O
a	O
basic	B-GENE
helix	I-GENE
-	I-GENE
loop	I-GENE
-	I-GENE
helix	I-GENE
protein	I-GENE
that	O
,	O
on	O
the	O
basis	O
of	O
sequence	O
homology	O
and	O
intron	O
/	O
exon	O
structure	O
,	O
represents	O
the	O
P	O
.	O
hybrida	O
orthologue	O
of	O
the	O
Z	B-GENE
.	I-GENE
mays	I-GENE
r	I-GENE
genes	I-GENE
.	O

During	O
the	O
past	O
4	O
years	O
,	O
a	O
purposeful	O
search	O
was	O
made	O
for	O
electrocardiograms	O
with	O
documented	O
reversible	O
QRS	O
changes	O
associated	O
with	O
all	O
acute	O
injury	O
pattern	O
.	O

Mutating	O
a	O
potential	O
cleavage	O
site	O
located	O
N	O
-	O
terminal	O
to	O
the	O
protease	O
domain	O
,	O
Gln2526	O
-	O
Asp2527	O
,	O
diminished	O
processing	O
.	O

METHODS	O
:	O
Millipore	O
ultrafiltration	O
membranes	O
of	O
three	O
different	O
pore	O
sizes	O
were	O
used	O
as	O
model	O
lenticule	O
materials	O
.	O
The	O
nominal	O
membrane	O
pore	O
sizes	O
were	O
0	O
.	O
1	O
microm	O
,	O
0	O
.	O
45	O
microm	O
,	O
and	O
3	O
microm	O
;	O
the	O
surface	O
roughness	O
increased	O
in	O
the	O
same	O
order	O
The	O
membranes	O
were	O
coated	O
with	O
a	O
thin	O
layer	O
of	O
collagen	B-GENE
I	I-GENE
and	O
implanted	O
in	O
a	O
circular	O
pocket	O
of	O
the	O
anterior	O
cornea	O
of	O
adult	O
cats	O
,	O
and	O
were	O
clinically	O
evaluated	O
for	O
the	O
extent	O
of	O
epithelialization	O
and	O
the	O
persistence	O
of	O
epithelial	O
attachment	O
.	O

The	O
role	O
of	O
calcitonin	B-GENE
,	O
and	O
other	O
agonists	O
which	O
activate	O
the	O
cAMP	O
pathway	O
,	O
in	O
regulating	O
transcription	O
of	O
the	O
human	B-GENE
parathyroid	I-GENE
hormone	I-GENE
-	I-GENE
related	I-GENE
protein	I-GENE
(	O
PTHrP	B-GENE
)	O
gene	O
was	O
investigated	O
in	O
a	O
human	O
lung	O
cancer	O
cell	O
line	O
(	O
BEN	O
)	O
.	O

The	O
combination	O
of	O
Pitx2	B-GENE
and	O
another	O
homeodomain	B-GENE
protein	I-GENE
,	O
Pit	B-GENE
-	I-GENE
1	I-GENE
,	O
yielded	O
a	O
synergistic	O
55	O
-	O
fold	O
activation	O
of	O
the	O
prolactin	B-GENE
promoter	I-GENE
in	O
transfection	O
assays	O
.	O

The	O
biochemical	O
and	O
molecular	O
spectrum	O
of	O
ornithine	B-GENE
transcarbamylase	I-GENE
deficiency	O
.	O

To	O
further	O
understand	O
the	O
role	O
of	O
cis	O
-	O
acting	O
elements	O
in	O
these	O
regulatory	O
mechanisms	O
,	O
we	O
have	O
characterized	O
a	O
transcriptional	O
promoter	O
that	O
drives	O
germline	O
expression	O
of	O
TCR	B-GENE
beta	I-GENE
gene	I-GENE
segments	I-GENE
in	O
vivo	O
.	O

Our	O
results	O
suggest	O
that	O
the	O
crucial	O
role	O
of	O
the	O
mutations	O
activating	O
v	B-GENE
-	I-GENE
erbA	I-GENE
as	O
an	O
oncogene	O
is	O
to	O
'	O
freeze	O
'	O
c	B-GENE
-	I-GENE
ErbA	I-GENE
/	O
TRalpha	B-GENE
in	O
its	O
non	O
-	O
liganded	O
,	O
repressive	O
conformation	O
and	O
to	O
facilitate	O
its	O
overexpression	O
.	O

In	O
this	O
study	O
,	O
we	O
describe	O
a	O
mammalian	O
cell	O
-	O
free	O
transcription	O
system	O
reconstituted	O
with	O
only	O
recombinant	O
proteins	O
and	O
epitope	O
-	O
tagged	O
multiprotein	O
complexes	O
.	O

This	O
repressor	O
is	O
however	O
unlikely	O
to	O
mediate	O
spi	B-GENE
2	I-GENE
.	I-GENE
3	I-GENE
3	I-GENE
'	I-GENE
UTR	I-GENE
silencer	I-GENE
action	O
since	O
it	O
was	O
not	O
detected	O
in	O
rat	O
hepatocytes	O
.	O

A	O
prerequisite	O
for	O
the	O
synthesis	O
of	O
sialylated	O
glycoconjugates	O
is	O
the	O
activated	O
sugar	O
-	O
nucleotide	O
cytidine	O
5	O
'	O
-	O
monophosphate	O
N	O
-	O
acetylneuraminic	O
acid	O
(	O
CMP	O
-	O
Neu5Ac	O
)	O
,	O
which	O
provides	O
a	O
substrate	O
for	O
Golgi	B-GENE
sialyltransferases	I-GENE
.	O

Thus	O
,	O
the	O
bovine	B-GENE
PEDF	I-GENE
cDNA	I-GENE
isolated	O
here	O
codes	O
for	O
a	O
functional	O
soluble	O
secreted	B-GENE
PEDF	I-GENE
glycoprotein	I-GENE
.	O

We	O
found	O
sequences	O
related	O
to	O
this	O
insertion	O
in	O
wild	O
-	O
type	O
strains	O
of	O
N	O
.	O
crassa	O
and	O
other	O
Neurospora	O
species	O
.	O

When	O
cysteine	O
is	O
scanned	O
through	O
the	O
helices	O
,	O
characteristic	O
repeating	O
patterns	O
of	O
solvent	O
exposure	O
and	O
burial	O
are	O
observed	O
.	O

Human	B-GENE
ULK1	I-GENE
,	O
a	O
novel	O
serine	B-GENE
/	I-GENE
threonine	I-GENE
kinase	I-GENE
related	O
to	O
UNC	B-GENE
-	I-GENE
51	I-GENE
kinase	I-GENE
of	O
Caenorhabditis	O
elegans	O
:	O
cDNA	O
cloning	O
,	O
expression	O
,	O
and	O
chromosomal	O
assignment	O
.	O

Specifically	O
,	O
I	O
use	O
molecular	O
markers	O
that	O
identify	O
particular	O
neuroectodermal	O
domains	O
,	O
all	O
neuroblasts	O
or	O
individual	O
neuroblasts	O
,	O
to	O
show	O
that	O
in	O
DER	B-GENE
mutant	I-GENE
embryos	O
(	O
1	O
)	O
intermediate	O
column	O
neuroblasts	O
do	O
not	O
form	O
,	O
(	O
2	O
)	O
medial	O
column	O
neuroblasts	O
often	O
acquire	O
identities	O
inappropriate	O
for	O
their	O
position	O
,	O
while	O
(	O
3	O
)	O
lateral	O
neuroblasts	O
develop	O
normally	O
.	O

Cochlear	O
microphonic	O
potentials	O
in	O
patients	O
with	O
vestibular	O
schwannomas	O
.	O

These	O
results	O
with	O
clozapine	O
illustrate	O
that	O
LI	O
is	O
sensitive	O
to	O
antipsychotics	O
which	O
differ	O
in	O
their	O
mode	O
of	O
action	O
and	O
furthermore	O
emphasize	O
the	O
value	O
of	O
LI	O
as	O
a	O
test	O
model	O
for	O
detecting	O
the	O
antipsychotic	O
potential	O
of	O
novel	O
drugs	O
.	O

The	O
complement	B-GENE
C3a	I-GENE
anaphylatoxin	I-GENE
receptor	I-GENE
(	O
C3aR	B-GENE
)	O
is	O
a	O
seven	B-GENE
-	I-GENE
transmembrane	I-GENE
G	I-GENE
-	I-GENE
protein	I-GENE
coupled	I-GENE
chemoattractant	I-GENE
receptor	I-GENE
that	O
on	O
binding	O
the	O
C3a	B-GENE
peptide	I-GENE
ligand	I-GENE
mediates	O
numerous	O
cellular	O
responses	O
,	O
including	O
histamine	O
release	O
from	O
mast	O
cells	O
.	O
smooth	O
muscle	O
contraction	O
,	O
and	O
the	O
directed	O
migration	O
of	O
eosinophils	O
.	O

CONCLUSIONS	O
:	O
Significant	O
elevations	O
of	O
IL	B-GENE
-	I-GENE
1alpha	I-GENE
and	O
IL	B-GENE
-	I-GENE
1beta	I-GENE
occur	O
in	O
patients	O
with	O
bacterial	O
cystitis	O
and	O
microscopic	O
hematuria	O
.	O

Band	O
-	O
shift	O
assays	O
were	O
performed	O
using	O
the	O
LPS	B-GENE
-	I-GENE
and	I-GENE
IL	I-GENE
-	I-GENE
1	I-GENE
-	I-GENE
responsive	I-GENE
element	I-GENE
(	O
LILRE	B-GENE
)	O
oligonucleotide	O
,	O
a	O
gamma	B-GENE
interferon	I-GENE
activation	I-GENE
site	I-GENE
-	I-GENE
like	I-GENE
site	I-GENE
that	O
is	O
present	O
in	O
the	O
human	B-GENE
IL	I-GENE
-	I-GENE
1beta	I-GENE
promoter	I-GENE
.	O

The	O
C	O
-	O
terminal	O
region	O
contains	O
the	O
PTP	B-GENE
-	I-GENE
like	I-GENE
domain	I-GENE
,	O
whereas	O
the	O
N	O
-	O
terminal	O
region	O
shows	O
no	O
homology	O
to	O
any	O
known	O
mammalian	O
protein	O
.	O

In	O
addition	O
,	O
and	O
in	O
support	O
of	O
a	O
mediating	O
role	O
of	O
STATs	B-GENE
in	O
the	O
activation	O
of	O
the	O
p21	B-GENE
promoter	I-GENE
,	O
overexpression	O
of	O
Stat3	B-GENE
potentiated	O
the	O
cytokine	O
effect	O
on	O
the	O
p21	B-GENE
promoter	I-GENE
;	O
whereas	O
a	O
dominant	B-GENE
negative	I-GENE
Stat3	I-GENE
,	O
or	O
a	O
mutation	O
of	O
the	O
STAT	B-GENE
response	I-GENE
element	I-GENE
on	O
the	O
promoter	O
,	O
significantly	O
reduced	O
the	O
cytokine	O
effect	O
.	O

The	O
heterogeneous	O
nuclear	B-GENE
ribonucleoprotein	I-GENE
C	I-GENE
protein	I-GENE
tetramer	I-GENE
binds	O
U1	B-GENE
,	O
U2	B-GENE
,	O
and	O
U6	B-GENE
snRNAs	I-GENE
through	O
its	O
high	O
affinity	O
RNA	O
binding	O
domain	O
(	O
the	O
bZIP	O
-	O
like	O
motif	O
)	O
.	O

On	O
the	O
comparison	O
of	O
correlated	O
proportions	O
for	O
clustered	O
data	O
.	O

A	O
safe	O
and	O
simple	O
system	O
for	O
the	O
detection	O
of	O
sudden	O
infant	O
death	O
syndrome	O
(	O
SIDS	O
)	O
is	O
proposed	O
.	O

The	O
resulting	O
mutants	O
were	O
coexpressed	O
with	O
gE	B-GENE
in	O
the	O
vaccinia	O
virus	O
-	O
based	O
vTF7	O
-	O
3	O
system	O
,	O
and	O
the	O
formation	O
and	O
endoplasmic	O
reticulum	O
(	O
ER	O
)	O
-	O
to	O
-	O
Golgi	O
transport	O
of	O
the	O
hetero	O
-	O
oligomeric	O
complex	O
were	O
monitored	O
.	O

Homozygous	O
mutant	O
mice	O
,	O
designated	O
Cux	B-GENE
/	O
CDPDeltaCR1	B-GENE
,	O
display	O
a	O
phenotype	O
characterized	O
by	O
curly	O
vibrissae	O
and	O
wavy	O
hair	O
.	O

The	O
mutant	O
protein	O
is	O
present	O
at	O
levels	O
slightly	O
greater	O
than	O
wild	O
-	O
type	O
,	O
but	O
exhibits	O
the	O
same	O
tissue	O
distribution	O
as	O
wild	O
-	O
type	O
protein	O
,	O
and	O
has	O
approximately	O
normal	O
affinity	O
for	O
known	O
target	O
sequences	O
(	O
though	O
no	O
DNA	O
targets	O
identified	O
to	O
date	O
require	O
the	O
first	O
cut	O
repeat	O
for	O
binding	O
)	O
.	O

METHODS	O
:	O
We	O
retrospectively	O
reviewed	O
242	O
adult	O
cadaveric	O
renal	O
transplant	O
recipients	O
treated	O
between	O
11	O
/	O
91	O
and	O
5	O
/	O
97	O
.	O

The	O
spectrum	O
of	O
age	O
-	O
associated	O
brain	O
abnormalities	O
:	O
their	O
measurement	O
and	O
histopathological	O
correlates	O
.	O

Our	O
laboratory	O
has	O
recently	O
identified	O
two	O
phosducin	B-GENE
-	I-GENE
like	I-GENE
orphan	I-GENE
proteins	I-GENE
(	O
PhLOP1	B-GENE
and	O
PhLOP2	B-GENE
)	O
that	O
lack	O
the	O
ability	O
to	O
interact	O
with	O
Gbetagamma	B-GENE
.	O

Reverse	B-GENE
transcriptase	I-GENE
-	O
polymerase	O
chain	O
reaction	O
(	O
RT	B-GENE
-	O
PCR	O
)	O
was	O
performed	O
using	O
eyestalk	O
complementary	O
DNA	O
of	O
the	O
sand	O
shrimp	O
Metapenaeus	O
ensis	O
.	O

In	O
contrast	O
,	O
transcription	O
initiating	O
from	O
opuE	B-GENE
P	I-GENE
-	I-GENE
1	I-GENE
(	O
sigma	B-GENE
A	I-GENE
)	O
rose	O
in	O
proportion	O
to	O
the	O
external	O
osmolarity	O
and	O
was	O
maintained	O
at	O
high	O
levels	O
.	O

Randomly	O
selected	O
300	O
children	O
aged	O
3	O
months	O
-	O
3	O
yr	O
were	O
analysed	O
over	O
a	O
period	O
of	O
one	O
year	O
for	O
estimating	O
prevalence	O
of	O
nutritional	O
anaemia	O
.	O

In	O
insects	O
,	O
arylalkylamine	B-GENE
N	I-GENE
-	I-GENE
acetyltransferases	I-GENE
(	O
AANATs	B-GENE
)	O
have	O
been	O
implicated	O
in	O
several	O
physiological	O
processes	O
,	O
including	O
sclerotization	O
,	O
inactivation	O
of	O
certain	O
neurotransmitters	O
,	O
and	O
,	O
similar	O
to	O
the	O
function	O
in	O
vertebrates	O
,	O
catalysis	O
of	O
the	O
rate	O
-	O
limiting	O
step	O
in	O
melatonin	O
biosynthesis	O
.	O

These	O
results	O
establish	O
that	O
hydroquinones	O
lead	O
to	O
mutagenicity	O
and	O
carcinogenicity	O
.	O

IA	O
-	O
CT	O
with	O
cisplatin	O
50	O
mg	O
and	O
doxorubicin	O
30	O
mg	O
was	O
administered	O
by	O
one	O
shot	O
method	O
in	O
bilateral	O
internal	O
iliac	O
arteries	O
.	O

Arnt3	B-GENE
mRNA	I-GENE
was	O
expressed	O
in	O
brain	O
,	O
skeletal	O
muscle	O
,	O
13	O
.	O
5	O
-	O
day	O
embryos	O
,	O
and	O
P19	O
cells	O
treated	O
with	O
retinoic	O
acid	O
.	O

The	O
genomic	O
structure	O
and	O
chromosomal	O
location	O
of	O
the	O
human	B-GENE
TR2	I-GENE
orphan	I-GENE
receptor	I-GENE
,	O
a	O
member	O
of	O
the	O
steroid	B-GENE
receptor	I-GENE
superfamily	I-GENE
.	O

Correlation	O
of	O
skin	O
disorders	O
with	O
CD4	B-GENE
lymphocyte	O
counts	O
in	O
patients	O
with	O
HIV	O
/	O
AIDS	O
.	O

E2F	B-GENE
-	I-GENE
6	I-GENE
shares	O
significant	O
homology	O
with	O
E2Fs	B-GENE
1	I-GENE
-	I-GENE
5	I-GENE
,	O
especially	O
within	O
the	O
DNA	O
binding	O
,	O
heterodimerization	O
and	O
marked	O
box	O
domains	O
.	O

The	O
IE13	O
.	O
1	O
cell	O
line	O
was	O
able	O
to	O
complement	O
a	O
recombinant	O
virus	O
in	O
which	O
both	O
copies	O
of	O
the	O
IE	B-GENE
gene	I-GENE
were	O
replaced	O
by	O
insertion	O
of	O
the	O
Escherichia	B-GENE
coli	I-GENE
lacZ	I-GENE
gene	I-GENE
.	O

DNase	B-GENE
I	I-GENE
footprinting	O
and	O
electrophoretic	O
mobility	O
shift	O
analyses	O
revealed	O
two	O
hepatocyte	B-GENE
nuclear	I-GENE
factor	I-GENE
-	I-GENE
1	I-GENE
(	O
HNF1	B-GENE
)	O
,	O
three	O
CCAAT	B-GENE
/	I-GENE
enhancer	I-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
(	O
C	B-GENE
/	I-GENE
EBP	I-GENE
)	O
,	O
and	O
one	O
consensus	O
palindromic	O
thyroid	O
hormone	O
response	O
elements	O
within	O
the	O
first	O
215	O
base	O
pairs	O
(	O
bp	O
)	O
of	O
the	O
promoter	O
sequence	O
of	O
rat	B-GENE
Std	I-GENE
.	O

Thus	O
,	O
these	O
studies	O
on	O
rat	B-GENE
Std	I-GENE
promoter	I-GENE
function	O
indicate	O
that	O
(	O
i	O
)	O
HNF1	B-GENE
and	O
C	B-GENE
/	I-GENE
EBP	I-GENE
are	O
responsible	O
for	O
liver	O
specificity	O
of	O
the	O
rat	B-GENE
Std	I-GENE
gene	I-GENE
;	O
(	O
ii	O
)	O
androgenic	O
repression	O
of	O
the	O
gene	O
requires	O
the	O
presence	O
of	O
all	O
of	O
the	O
OCT	B-GENE
-	I-GENE
1	I-GENE
and	O
C	B-GENE
/	I-GENE
EBP	I-GENE
elements	I-GENE
between	O
positions	O
-	O
231	O
and	O
-	O
292	O
;	O
and	O
(	O
iii	O
)	O
AR	B-GENE
may	O
exert	O
its	O
negative	O
regulatory	O
effect	O
indirectly	O
through	O
transcriptional	O
interference	O
of	O
OCT	B-GENE
-	I-GENE
1	I-GENE
and	O
C	B-GENE
/	I-GENE
EBP	I-GENE
rather	O
than	O
through	O
a	O
direct	O
DNA	B-GENE
-	I-GENE
AR	I-GENE
interaction	O
.	O

Purified	O
Hsk1	B-GENE
phosphorylates	O
the	O
Cdc19	B-GENE
(	O
Mcm2	B-GENE
)	O
subunit	O
of	O
the	O
six	B-GENE
-	I-GENE
member	I-GENE
minichromosome	I-GENE
maintenance	I-GENE
protein	I-GENE
complex	I-GENE
purified	O
from	O
fission	O
yeast	O
.	O

The	O
yeast	B-GENE
MMS2	I-GENE
gene	I-GENE
was	O
cloned	O
by	O
its	O
ability	O
to	O
complement	O
the	O
methyl	O
methanesulfonate	O
sensitivity	O
of	O
the	O
mms2	B-GENE
-	I-GENE
1	I-GENE
mutant	I-GENE
and	O
was	O
later	O
shown	O
to	O
be	O
involved	O
in	O
DNA	O
post	O
-	O
replication	O
repair	O
.	O

Expression	O
of	O
the	O
human	B-GENE
papillomavirus	I-GENE
type	I-GENE
11	I-GENE
E5A	I-GENE
protein	I-GENE
from	O
the	O
E1E4	B-GENE
,	I-GENE
E5	I-GENE
transcript	I-GENE
.	O

Anesthesia	O
with	O
M	O
/	O
K	O
was	O
reversed	O
after	O
41	O
.	O
6	O
min	O
of	O
immobilization	O
with	O
atipamezole	O
.	O

There	O
was	O
no	O
evident	O
inciting	O
agent	O
of	O
the	O
disease	O
.	O

MK	O
-	O
801	O
administration	O
resulted	O
in	O
a	O
biphasic	O
response	O
in	O
seizure	O
latency	O
.	O

In	O
contrast	O
,	O
the	O
distribution	O
of	O
endocytic	O
markers	O
is	O
not	O
affected	O
.	O

Toxicity	O
during	O
the	O
therapeutic	O
period	O
was	O
not	O
significant	O
in	O
the	O
study	O
group	O
compared	O
with	O
the	O
historical	O
control	O
,	O
treated	O
with	O
the	O
same	O
regimen	O
without	O
G	B-GENE
-	I-GENE
CSF	I-GENE
.	O

Both	O
methods	O
were	O
employed	O
for	O
various	O
focal	O
-	O
film	O
distances	O
,	O
image	O
intensifier	O
tube	O
modes	O
and	O
laser	O
printer	O
formats	O
.	O

The	O
effect	O
of	O
Rho	B-GENE
on	O
AP	B-GENE
-	I-GENE
1	I-GENE
is	O
independent	O
of	O
the	O
mitogen	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
kinase	I-GENE
pathway	O
,	O
as	O
a	O
dominant	B-GENE
-	I-GENE
negative	I-GENE
MEK	I-GENE
and	O
a	O
MEK	B-GENE
inhibitor	O
(	O
PD98059	O
)	O
did	O
not	O
affect	O
Rho	B-GENE
-	O
induced	O
AP	B-GENE
-	I-GENE
1	I-GENE
activity	O
.	O

Site	O
-	O
directed	O
mutagenesis	O
of	O
residues	O
in	O
this	O
domain	O
(	O
R82A	O
,	O
K85A	O
,	O
K88A	O
,	O
and	O
V89A	O
)	O
resulted	O
in	O
proteins	O
which	O
failed	O
to	O
transactivate	O
from	O
the	O
HTLV	B-GENE
-	I-GENE
1	I-GENE
LTR	I-GENE
in	O
vivo	O
.	O

Mutations	O
within	O
the	O
C	O
terminus	O
of	O
c	B-GENE
-	I-GENE
fos	I-GENE
at	O
serine	O
residues	O
that	O
are	O
phosphorylation	O
targets	O
for	O
growth	O
factors	O
and	O
MAP	B-GENE
kinase	I-GENE
completely	O
abrogate	O
transactivation	O
and	O
block	O
potentiation	O
by	O
MAP	B-GENE
kinase	I-GENE
.	O

In	O
the	O
former	O
cells	O
,	O
ets	B-GENE
-	I-GENE
2	I-GENE
was	O
a	O
CSF	B-GENE
-	I-GENE
1	I-GENE
immediate	O
-	O
early	O
response	O
gene	O
,	O
and	O
phosphorylated	O
ets	B-GENE
-	I-GENE
2	I-GENE
was	O
detected	O
after	O
2	O
to	O
4	O
h	O
,	O
coincident	O
with	O
expression	O
of	O
ets	B-GENE
-	I-GENE
2	I-GENE
protein	I-GENE
.	O

Persistent	O
activation	O
of	O
mitogen	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
kinases	I-GENE
p42	I-GENE
and	O
p44	B-GENE
and	O
ets	B-GENE
-	I-GENE
2	I-GENE
phosphorylation	O
in	O
response	O
to	O
colony	B-GENE
-	I-GENE
stimulating	I-GENE
factor	I-GENE
1	I-GENE
/	O
c	B-GENE
-	I-GENE
fms	I-GENE
signaling	O
.	O

Identification	O
of	O
a	O
proline	O
-	O
rich	O
sequence	O
in	O
the	O
CD2	B-GENE
cytoplasmic	I-GENE
domain	I-GENE
critical	O
for	O
regulation	O
of	O
integrin	B-GENE
-	O
mediated	O
adhesion	O
and	O
activation	O
of	O
phosphoinositide	B-GENE
3	I-GENE
-	I-GENE
kinase	I-GENE
.	O

Vam7p	B-GENE
,	O
a	O
SNAP	B-GENE
-	I-GENE
25	I-GENE
-	I-GENE
like	I-GENE
molecule	I-GENE
,	O
and	O
Vam3p	B-GENE
,	O
a	O
syntaxin	B-GENE
homolog	I-GENE
,	O
function	O
together	O
in	O
yeast	O
vacuolar	O
protein	O
trafficking	O
.	O

We	O
have	O
tested	O
this	O
possibility	O
by	O
constructing	O
a	O
consecutive	O
series	O
of	O
cysteine	O
substitutions	O
in	O
the	O
Neu	B-GENE
juxtamembrane	I-GENE
domain	I-GENE
in	O
order	O
to	O
force	O
dimerization	O
along	O
a	O
series	O
of	O
interreceptor	O
faces	O
.	O

It	O
has	O
been	O
demonstrated	O
previously	O
that	O
Pax	B-GENE
-	I-GENE
6	I-GENE
,	O
a	O
paired	B-GENE
domain	I-GENE
(	O
PD	B-GENE
)	O
/	O
homeodomain	B-GENE
(	O
HD	B-GENE
)	O
transcription	O
factor	O
critical	O
for	O
eye	O
development	O
,	O
contributes	O
to	O
the	O
activation	O
of	O
the	O
alphaB	B-GENE
-	I-GENE
,	I-GENE
alphaA	I-GENE
-	I-GENE
,	I-GENE
delta1	I-GENE
-	I-GENE
,	I-GENE
and	I-GENE
zeta	I-GENE
-	I-GENE
crystallin	I-GENE
genes	O
in	O
the	O
lens	O
.	O

Tctex	B-GENE
-	I-GENE
1	I-GENE
binding	O
required	O
the	O
first	O
19	O
amino	O
acids	O
of	O
Fyn	B-GENE
and	O
integrity	O
of	O
two	O
lysine	O
residues	O
within	O
this	O
sequence	O
that	O
were	O
previously	O
shown	O
to	O
be	O
important	O
for	O
Fyn	B-GENE
interactions	O
with	O
the	O
immunoreceptor	O
tyrosine	O
-	O
based	O
activation	O
motifs	O
(	O
ITAMs	O
)	O
of	O
lymphocyte	B-GENE
Ag	I-GENE
receptors	I-GENE
.	O

The	O
prothrombin	B-GENE
gene	I-GENE
G20210A	I-GENE
mutation	I-GENE
is	O
not	O
found	O
among	O
Japanese	O
patients	O
with	O
deep	O
vein	O
thrombosis	O
and	O
healthy	O
individuals	O
.	O

In	O
the	O
studies	O
described	O
in	O
this	O
report	O
,	O
we	O
have	O
investigated	O
the	O
signaling	O
pathway	O
(	O
s	O
)	O
that	O
are	O
responsible	O
for	O
CREB	B-GENE
activation	O
in	O
normal	O
T	O
cells	O
.	O

Respondents	O
who	O
lived	O
with	O
a	O
spouse	O
/	O
partner	O
only	O
were	O
less	O
likely	O
to	O
have	O
an	O
unfavorable	O
BMI	O
status	O
than	O
people	O
in	O
the	O
other	O
two	O
groups	O
.	O

Isolation	O
of	O
a	O
novel	O
TP53	B-GENE
target	I-GENE
gene	I-GENE
from	O
a	O
colon	O
cancer	O
cell	O
line	O
carrying	O
a	O
highly	O
regulated	O
wild	B-GENE
-	I-GENE
type	I-GENE
TP53	I-GENE
expression	O
system	O
.	O

Overexpression	O
of	O
MDR1	B-GENE
has	O
been	O
demonstrated	O
in	O
many	O
cancers	O
,	O
both	O
in	O
patient	O
tumors	O
and	O
in	O
cell	O
lines	O
selected	O
with	O
a	O
variety	O
of	O
chemotherapeutic	O
agents	O
.	O

Cytogenetic	O
and	O
molecular	O
characterization	O
of	O
random	O
chromosomal	O
rearrangements	O
activating	O
the	O
drug	O
resistance	O
gene	O
,	O
MDR1	B-GENE
/	O
P	B-GENE
-	I-GENE
glycoprotein	I-GENE
,	O
in	O
drug	O
-	O
selected	O
cell	O
lines	O
and	O
patients	O
with	O
drug	O
refractory	O
ALL	O
.	O

BACKGROUND	O
:	O
It	O
is	O
generally	O
accepted	O
that	O
smoking	O
increases	O
blood	O
pressure	O
and	O
inhibits	O
muscle	O
sympathetic	O
nerve	O
activity	O
(	O
SNA	O
)	O
.	O

When	O
the	O
blood	O
pressure	O
increase	O
in	O
response	O
to	O
smoking	O
was	O
blunted	O
by	O
nitroprusside	O
infusion	O
,	O
there	O
was	O
a	O
striking	O
increase	O
in	O
muscle	O
SNA	O
.	O

After	O
that	O
report	O
,	O
carboxypeptidase	B-GENE
D	I-GENE
(	O
CPD	B-GENE
)	O
was	O
subsequently	O
purified	O
from	O
bovine	O
pituitary	O
and	O
characterized	O
as	O
a	O
novel	O
carboxypeptidase	B-GENE
E	I-GENE
(	O
CPE	B-GENE
)	O
-	O
like	O
enzyme	O
,	O
with	O
many	O
characteristics	O
in	O
common	O
with	O
duck	O
gp180	B-GENE
(	O
Song	O
,	O
L	O
.	O
,	O
Fricker	O
,	O
L	O
.	O
D	O
.	O
,	O
1995	O
.	O

RA	O
-	O
treatment	O
of	O
these	O
transfectants	O
induced	O
morphologic	O
and	O
immunophenotypic	O
maturation	O
,	O
changes	O
in	O
RA	O
-	O
regulated	O
genes	O
,	O
and	O
a	O
G1	O
cell	O
cycle	O
arrest	O
in	O
a	O
manner	O
similar	O
to	O
parental	O
NT2	O
/	O
D1	O
cells	O
.	O

The	O
histopathology	O
and	O
neovascularization	O
did	O
not	O
appreciably	O
differ	O
between	O
xenograft	O
tumors	O
derived	O
from	O
FGF4	B-GENE
over	O
-	O
expressing	O
versus	O
control	O
transfectants	O
.	O

For	O
smaller	O
vessels	O
up	O
to	O
a	O
diameter	O
of	O
0	O
.	O
5	O
mm	O
,	O
treatments	O
at	O
16	O
and	O
18	O
J	O
/	O
cm2	O
showed	O
good	O
results	O
in	O
60	O
and	O
82	O
%	O
respectively	O
;	O
for	O
vessels	O
up	O
to	O
1	O
mm	O
in	O
27	O
and	O
33	O
%	O
.	O

RXR	B-GENE
-	I-GENE
gamma	I-GENE
expression	O
produced	O
significant	O
reduction	O
in	O
levels	O
of	O
RA	O
-	O
responsive	O
genes	O
including	O
the	O
cyclin	B-GENE
-	I-GENE
dependent	I-GENE
kinase	I-GENE
inhibitors	O
p21Cip1	B-GENE
/	O
WAF1	B-GENE
and	O
p27Kip1	B-GENE
,	O
resulting	O
in	O
increased	O
cdc2	B-GENE
and	O
cdk2	B-GENE
kinase	I-GENE
activity	O
and	O
RB	B-GENE
phosphorylation	O
.	O

Generally	O
ILC	O
and	O
ILVF	O
values	O
decreased	O
with	O
increasing	O
exposure	O
time	O
with	O
rate	O
constants	O
ranging	O
from	O
0	O
.	O
03	O
to	O
0	O
.	O
33	O
day	O
-	O
1	O
(	O
wet	O
and	O
lipid	O
weight	O
)	O
for	O
ILC	O
and	O
0	O
.	O
03	O
to	O
0	O
.	O
31	O
day	O
-	O
1	O
for	O
ILVF	O
.	O

These	O
sequence	O
analyses	O
suggest	O
that	O
xIRS	B-GENE
-	I-GENE
u	I-GENE
is	O
a	O
novel	O
member	O
of	O
the	O
IRS	B-GENE
family	I-GENE
rather	O
than	O
a	O
Xenopus	O
homolog	O
of	O
an	O
existing	O
member	O
.	O

The	O
present	O
study	O
sought	O
to	O
develop	O
an	O
equation	O
to	O
estimate	O
VO2peak	O
in	O
peripheral	O
arterial	O
occlusive	O
disease	O
(	O
PAOD	O
)	O
patients	O
with	O
intermittent	O
claudication	O
and	O
to	O
determine	O
independent	O
predictors	O
of	O
VO2peak	O
in	O
this	O
population	O
.	O

The	O
Abbreviated	O
Injury	O
Scale	O
(	O
AIS	O
)	O
,	O
Injury	O
Severity	O
Scale	O
and	O
TRISS	O
methodology	O
comprise	O
a	O
mathematically	O
sound	O
system	O
for	O
the	O
analysis	O
of	O
injuries	O
and	O
injured	O
patients	O
.	O

This	O
hypothesis	O
was	O
tested	O
by	O
introducing	O
mutations	O
at	O
each	O
of	O
the	O
three	O
histidine	O
pairs	O
,	O
the	O
H382	O
-	O
X2	O
-	O
H385	O
pair	O
,	O
the	O
H411	O
-	O
X2	O
-	O
H414	O
pair	O
and	O
the	O
H430	O
-	O
X5	O
-	O
H436	O
pair	O
,	O
which	O
constitute	O
the	O
histidine	O
-	O
rich	O
region	O
near	O
the	O
C	O
terminus	O
of	O
gp17	B-GENE
.	O

Using	O
backcross	O
analysis	O
,	O
both	O
exons	O
1	O
and	O
4	O
mapped	O
to	O
a	O
proximal	O
region	O
of	O
murine	O
Chromosome	O
4	O
indistinguishable	O
from	O
the	O
vacillans	B-GENE
gene	I-GENE
.	O

Seventy	O
-	O
five	O
percent	O
of	O
children	O
who	O
received	O
a	O
second	O
transplant	O
for	O
HCV	O
hepatitis	O
had	O
early	O
histologic	O
recurrence	O
that	O
led	O
to	O
liver	O
failure	O
and	O
death	O
.	O

However	O
,	O
both	O
TPN	O
groups	O
showed	O
a	O
marked	O
increase	O
in	O
activities	O
of	O
liver	O
lysosomal	B-GENE
enzymes	I-GENE
.	O

Regulation	O
of	O
embryonic	O
growth	O
and	O
lysosomal	O
targeting	O
by	O
the	O
imprinted	O
Igf2	B-GENE
/	O
Mpr	B-GENE
gene	O
.	O

Furthermore	O
,	O
early	O
-	O
and	O
late	O
-	O
firing	O
origins	O
differ	O
not	O
in	O
the	O
timing	O
of	O
their	O
recruitment	O
of	O
an	O
Mcm	B-GENE
protein	I-GENE
,	O
but	O
in	O
the	O
timing	O
of	O
RPA	B-GENE
'	I-GENE
s	I-GENE
recruitment	O
.	O

Thus	O
,	O
in	O
the	O
presence	O
of	O
active	B-GENE
S	I-GENE
-	I-GENE
CDKs	I-GENE
and	O
Dbf4	B-GENE
/	O
Cdc7	B-GENE
,	O
Mcms	B-GENE
may	O
open	O
origins	O
and	O
thereby	O
facilitate	O
the	O
loading	O
of	O
RPA	B-GENE
.	O

Tyrosine	O
phosphorylated	O
STATs	B-GENE
dimerize	O
and	O
translocate	O
into	O
the	O
nucleus	O
to	O
activate	O
specific	O
genes	O
.	O

Nonsynonymous	O
substitution	O
in	O
abalone	O
sperm	O
fertilization	O
genes	O
exceeds	O
substitution	O
in	O
introns	O
and	O
mitochondrial	O
DNA	O
.	O

Gel	O
retardation	O
assays	O
detected	O
ZiaR	B-GENE
-	O
dependent	O
complexes	O
forming	O
with	O
the	O
zia	B-GENE
operator	I-GENE
-	I-GENE
promoter	I-GENE
and	O
ZiaR	B-GENE
-	O
DNA	O
binding	O
was	O
enhanced	O
by	O
treatment	O
with	O
a	O
metal	O
-	O
chelator	O
in	O
vitro	O
.	O

CONCLUSION	O
:	O
Although	O
quantitative	O
and	O
qualitative	O
criteria	O
for	O
diagnosing	O
fatty	O
liver	O
on	O
helical	O
CT	O
can	O
be	O
determined	O
,	O
they	O
are	O
protocol	O
-	O
specific	O
.	O

The	O
PC	O
-	O
based	O
RTPS	O
is	O
designed	O
to	O
run	O
in	O
the	O
Microsoft	O
Windows	O
3	O
.	O
11	O
environment	O
(	O
and	O
later	O
versions	O
)	O
,	O
for	O
computers	O
equipped	O
with	O
486	O
or	O
Pentium	O
processors	O
.	O

Alternatively	O
,	O
the	O
similarity	O
in	O
apparent	O
regulatory	O
action	O
of	O
the	O
genes	O
may	O
indicate	O
allelic	O
differences	O
wherein	O
the	O
IS1112C	B-GENE
Rf3	B-GENE
allele	I-GENE
may	O
differ	O
from	O
alleles	O
of	O
maintainer	O
lines	O
by	O
the	O
capability	O
to	O
regulate	O
both	O
orf107	B-GENE
and	O
urf209	B-GENE
processing	O
activities	O
.	O

JCAHO	O
revised	O
interpretation	O

A	O
human	O
SPT3	B-GENE
-	O
TAFII31	B-GENE
-	O
GCN5	B-GENE
-	O
L	B-GENE
acetylase	I-GENE
complex	O
distinct	O
from	O
transcription	B-GENE
factor	I-GENE
IID	I-GENE
.	O

Oleate	O
induced	O
steady	O
-	O
state	O
levels	O
of	O
M	B-GENE
-	I-GENE
CPT	I-GENE
I	I-GENE
mRNA	I-GENE
4	O
.	O
5	O
-	O
fold	O
.	O

Mapping	O
of	O
the	O
DNA	O
binding	O
domain	O
of	O
the	O
copper	O
-	O
responsive	O
transcription	O
factor	O
Mac1	B-GENE
from	I-GENE
Saccharomyces	I-GENE
cerevisiae	I-GENE
.	O

A	O
further	O
mechanism	O
increasing	O
specific	O
activation	O
was	O
cooperation	O
of	O
receptors	O
at	O
multiple	O
and	O
weak	O
HREs	O
,	O
which	O
was	O
accentuated	O
in	O
the	O
presence	O
of	O
both	O
the	O
AR	B-GENE
N	O
terminus	O
and	O
ligand	O
binding	O
domain	O
.	O

Previously	O
,	O
we	O
characterized	O
a	O
DNA	O
-	O
binding	O
protein	O
,	O
HS2NF5	B-GENE
,	O
that	O
bound	O
tightly	O
to	O
a	O
conserved	O
region	O
within	O
hypersensitive	O
site	O
2	O
(	O
HS2	O
)	O
of	O
the	O
human	B-GENE
beta	I-GENE
-	I-GENE
globin	I-GENE
locus	I-GENE
control	I-GENE
region	I-GENE
(	O
LCR	O
)	O
(	O
Lam	O
,	O
L	O
.	O

The	O
CBF1	B-GENE
site	I-GENE
within	O
HS2	O
resides	O
near	O
sites	O
for	O
hematopoietic	O
regulators	O
such	O
as	O
GATA	B-GENE
-	I-GENE
1	I-GENE
,	O
NF	B-GENE
-	I-GENE
E2	I-GENE
,	O
and	O
TAL1	B-GENE
.	O

The	O
rat	B-GENE
branched	I-GENE
-	I-GENE
chain	I-GENE
-	I-GENE
2	I-GENE
-	I-GENE
oxo	I-GENE
-	I-GENE
acid	I-GENE
dehydrogenase	I-GENE
(	I-GENE
BCOD	I-GENE
)	I-GENE
kinase	I-GENE
mRNA	I-GENE
is	O
transcribed	O
from	O
a	O
TATA	O
-	O
less	O
promoter	O
that	O
has	O
GC	O
-	O
rich	O
sequences	O
and	O
two	O
putative	O
Sp1	B-GENE
binding	I-GENE
sites	I-GENE
near	O
the	O
transcription	O
start	O
site	O
.	O

Co	O
-	O
transfection	O
of	O
the	O
Sp1	B-GENE
expression	O
plasmid	O
and	O
the	O
-	O
58	O
promoter	O
construct	O
into	O
Drosophila	O
Schneider	O
cells	O
revealed	O
that	O
Sp1	B-GENE
contributed	O
to	O
the	O
kinase	O
basal	O
promoter	O
activity	O
by	O
binding	O
to	O
the	O
non	O
-	O
consensus	O
site	O
in	O
the	O
-	O
58	O
region	O
.	O

Until	O
such	O
investigations	O
are	O
performed	O
,	O
we	O
conclude	O
that	O
the	O
role	O
for	O
adjuvant	O
treatment	O
is	O
questionable	O
and	O
that	O
TME	O
surgery	O
is	O
preferred	O
as	O
the	O
treatment	O
option	O
for	O
Stage	O
T1	O
-	O
T3	O
rectal	O
cancers	O
.	O

Likewise	O
,	O
at	O
150	O
degrees	O
C	O
with	O
2	O
%	O
APS	O
the	O
surface	O
density	O
of	O
NH2	O
groups	O
reached	O
a	O
maximum	O
at	O
24	O
hr	O
and	O
remained	O
relatively	O
constant	O
up	O
to	O
96	O
hr	O
.	O

Taken	O
together	O
,	O
these	O
results	O
suggest	O
that	O
the	O
cooperation	O
of	O
transcription	B-GENE
factors	I-GENE
NF	I-GENE
-	I-GENE
kappaB	I-GENE
and	O
AP	B-GENE
-	I-GENE
1	I-GENE
is	O
essential	O
for	O
transactivation	O
of	O
IL	B-GENE
-	I-GENE
8	I-GENE
gene	I-GENE
by	O
HTLV	B-GENE
-	I-GENE
I	I-GENE
Tax	I-GENE
.	O

This	O
study	O
examines	O
the	O
cooperative	O
effects	O
of	O
a	O
human	O
estrogen	B-GENE
receptor	I-GENE
-	I-GENE
alpha	I-GENE
(	O
ERalpha	B-GENE
)	O
isoform	O
on	O
estrogen	O
(	O
E2	O
)	O
-	O
mediated	O
gene	O
activation	O
in	O
U2	O
-	O
OS	O
osteosarcoma	O
cells	O
.	O

Transfection	O
of	O
increasing	O
amounts	O
of	O
delta5ERalpha	B-GENE
expression	O
vector	O
into	O
[	O
ERalpha	B-GENE
+	O
]	O
OS	O
cells	O
resulted	O
in	O
potentiation	O
of	O
E2	O
-	O
stimulated	O
ERELuc	B-GENE
activity	O
in	O
a	O
synergistic	O
,	O
dose	O
-	O
dependent	O
manner	O
.	O

Studies	O
using	O
the	O
yeast	O
two	O
-	O
hybrid	O
system	O
also	O
did	O
not	O
provide	O
evidence	O
for	O
the	O
formation	O
of	O
a	O
VDR	B-GENE
-	O
TR	B-GENE
protein	O
-	O
protein	O
interaction	O
.	O

We	O
did	O
not	O
observe	O
any	O
changes	O
in	O
Bcl	B-GENE
-	I-GENE
2	I-GENE
or	O
Bcl	B-GENE
-	I-GENE
2	I-GENE
-	I-GENE
related	I-GENE
proteins	I-GENE
(	O
Bcl	B-GENE
-	I-GENE
x	I-GENE
,	O
Bax	B-GENE
,	O
and	O
Bad	B-GENE
)	O
in	O
control	O
or	O
KCREB	B-GENE
-	O
transfected	O
cells	O
before	O
or	O
after	O
treatment	O
with	O
Tg	O
.	O

Tyrosine	O
112	O
of	O
latent	B-GENE
membrane	I-GENE
protein	I-GENE
2A	I-GENE
is	O
essential	O
for	O
protein	B-GENE
tyrosine	I-GENE
kinase	I-GENE
loading	O
and	O
regulation	O
of	O
Epstein	O
-	O
Barr	O
virus	O
latency	O
.	O

To	O
improve	O
test	O
efficiency	O
,	O
we	O
modified	O
our	O
previously	O
introduced	O
contrast	O
/	O
color	O
card	O
test	O
by	O
including	O
a	O
patterned	O
test	O
stimulus	O
and	O
reducing	O
the	O
number	O
of	O
stimuli	O
in	O
both	O
experimental	O
phases	O
.	O

The	O
defect	O
in	O
these	O
proteins	O
was	O
also	O
uniformly	O
suppressed	O
by	O
either	O
Mn2	O
+	O
,	O
or	O
the	O
Mu	B-GENE
B	I-GENE
protein	I-GENE
in	O
the	O
presence	O
of	O
ATP	O
and	O
target	O
DNA	O
.	O

Using	O
homology	O
cloning	O
techniques	O
,	O
we	O
identified	O
a	O
mouse	O
homologue	O
of	O
E	B-GENE
(	I-GENE
Pc	I-GENE
)	I-GENE
,	O
termed	O
Epc1	B-GENE
,	O
a	O
yeast	O
protein	O
that	O
we	O
name	O
EPL1	B-GENE
,	O
and	O
as	O
well	O
as	O
additional	O
ESTs	O
from	O
Caenorhabditis	O
elegans	O
,	O
mice	O
and	O
humans	O
.	O

Second	O
,	O
the	O
wild	B-GENE
-	I-GENE
type	I-GENE
m8	I-GENE
3	I-GENE
'	I-GENE
UTR	I-GENE
strongly	O
reduces	O
accumulation	O
of	O
heterologous	O
transcripts	O
in	O
vivo	O
,	O
an	O
activity	O
that	O
requires	O
its	O
K	O
box	O
sequences	O
.	O

In	O
particular	O
,	O
unc	B-GENE
-	I-GENE
86	I-GENE
encodes	O
a	O
POU	B-GENE
-	I-GENE
type	I-GENE
homeodomain	I-GENE
protein	I-GENE
needed	O
for	O
the	O
production	O
of	O
the	O
touch	O
cells	O
,	O
while	O
mec	B-GENE
-	I-GENE
3	I-GENE
encodes	O
a	O
LIM	B-GENE
-	I-GENE
type	I-GENE
homeodomain	I-GENE
protein	I-GENE
needed	O
for	O
the	O
differentiation	O
of	O
the	O
touch	O
cells	O
.	O

During	O
the	O
2h	O
resuscitation	O
period	O
,	O
extracellular	O
aspartate	O
and	O
glutamate	O
concentrations	O
in	O
the	O
cerebral	O
striatum	O
were	O
higher	O
during	O
hypoxaemic	O
resuscitation	O
(	O
p	O
=	O
0	O
.	O
044	O
and	O
p	O
=	O
0	O
.	O
055	O
,	O
respectively	O
)	O
than	O
during	O
resuscitation	O
with	O
21	O
%	O
O2	O
or	O
100	O
%	O
O2	O
,	O
suggesting	O
an	O
unfavourable	O
accumulation	O
of	O
potent	O
excitotoxins	O
during	O
hypoxaemic	O
resuscitation	O
.	O

Furthermore	O
,	O
phosphatidylinositol	O
(	O
3	O
,	O
4	O
,	O
5	O
)	O
trisphosphate	O
specifically	O
stimulates	O
the	O
activity	O
of	O
ILK	B-GENE
in	O
vitro	O
,	O
and	O
in	O
addition	O
,	O
membrane	O
targetted	O
constitutively	O
active	O
Pi	B-GENE
(	I-GENE
3	I-GENE
)	I-GENE
K	I-GENE
activates	O
ILK	B-GENE
in	O
vivo	O
.	O

Transfection	O
and	O
in	O
vitro	O
binding	O
studies	O
identified	O
within	O
HEFT1	B-GENE
a	I-GENE
promoter	I-GENE
whose	O
basal	O
activity	O
required	O
a	O
GC	O
box	O
activated	O
by	O
Sp1	B-GENE
or	O
Sp3	B-GENE
.	O

Plasma	O
was	O
tested	O
before	O
and	O
after	O
(	O
14	O
+	O
/	O
-	O
7	O
.	O
5	O
[	O
SD	O
]	O
days	O
)	O
surgery	O
for	O
IgG	B-GENE
antibodies	I-GENE
to	O
the	O
complex	O
of	O
heparin	B-GENE
/	I-GENE
platelet	I-GENE
factor	I-GENE
4	I-GENE
,	O
using	O
a	O
standardized	O
,	O
validated	O
enzyme	O
-	O
linked	O
immunosorbent	O
assay	O
(	O
ELISA	O
)	O
.	O

The	O
FAS	B-GENE
promoter	I-GENE
was	O
up	O
-	O
regulated	O
by	O
insulin	B-GENE
through	O
the	O
proximal	O
insulin	B-GENE
response	I-GENE
sequence	I-GENE
containing	O
an	O
E	O
-	O
box	O
motif	O
at	O
the	O
-	O
65	O
-	O
base	O
pair	O
position	O
.	O

The	O
effect	O
of	O
independent	O
predictors	O
on	O
survival	O
was	O
examined	O
in	O
a	O
Cox	O
regression	O
model	O
with	O
adjustment	O
for	O
existing	O
illnesses	O
.	O

Effects	O
of	O
rhG	B-GENE
-	I-GENE
CSF	I-GENE
on	O
neutrophil	O
functions	O
and	O
survival	O
in	O
sepsis	O
induced	O
diabetic	O
rats	O
.	O

OBJECTIVE	O
:	O
The	O
purpose	O
of	O
this	O
article	O
is	O
to	O
review	O
balance	O
instruments	O
developed	O
within	O
the	O
past	O
10	O
years	O
that	O
can	O
be	O
used	O
in	O
the	O
clinic	O
or	O
home	O
environment	O
.	O

CASE	O
REPORT	O
:	O
We	O
observed	O
a	O
congenital	O
skin	O
defect	O
located	O
exclusively	O
on	O
the	O
trunk	O
.	O

Anastrozole	O
is	O
the	O
first	O
aromatase	B-GENE
inhibitor	O
to	O
show	O
a	O
significant	O
survival	O
advantage	O
over	O
megestrol	O
acetate	O
in	O
post	O
-	O
menopausal	O
women	O
with	O
advanced	O
breast	O
cancer	O
.	O

W	O
.	O

Moritta	O
)	O
and	O
contains	O
Bis	O
-	O
GMA	O
.	O

Mutation	O
of	O
either	O
the	O
AP	B-GENE
-	I-GENE
1	I-GENE
or	O
the	O
ets	B-GENE
component	O
of	O
this	O
site	O
also	O
prevented	O
promoter	O
activity	O
in	O
SMCs	O
.	O

ANIMALS	O
:	O
Fifty	O
dogs	O
with	O
naturally	O
developing	O
DM	O
.	O

Surprisingly	O
,	O
double	O
mutants	O
of	O
the	O
shy2	B-GENE
-	I-GENE
1D	I-GENE
mutant	I-GENE
with	O
the	O
phytochrome	B-GENE
-	O
deficient	O
mutants	O
hy2	B-GENE
,	O
hy3	B-GENE
(	O
phyB	B-GENE
-	I-GENE
1	I-GENE
)	O
and	O
fre1	B-GENE
-	I-GENE
1	I-GENE
(	O
phyA	B-GENE
-	I-GENE
201	I-GENE
)	O
showed	O
reduced	O
photomorphogenic	O
response	O
in	O
darkness	O
with	O
a	O
longer	O
hypocotyl	O
,	O
a	O
longer	O
inflorescence	O
stem	O
,	O
and	O
a	O
lower	O
level	O
expression	O
of	O
the	O
CAB	B-GENE
gene	I-GENE
than	O
the	O
shy2	B-GENE
-	I-GENE
1D	I-GENE
single	I-GENE
mutant	I-GENE
.	O

Laser	O
ablation	O
has	O
been	O
employed	O
as	O
a	O
therapeutic	O
measure	O
for	O
chronic	O
pulmonary	O
emphysema	O
.	O

The	O
SH2	O
-	O
containing	O
adapter	O
protein	O
GRB10	B-GENE
interacts	O
with	O
BCR	B-GENE
-	O
ABL	B-GENE
.	O

Saccharomyces	O
cerevisiae	O
contains	O
four	O
known	O
acyl	B-GENE
-	I-GENE
CoA	I-GENE
synthetases	I-GENE
(	O
fatty	B-GENE
acid	I-GENE
activation	I-GENE
proteins	I-GENE
,	O
Faaps	B-GENE
)	O
.	O

We	O
recently	O
reported	O
a	O
placenta	O
-	O
specific	O
enhancer	O
in	O
the	O
human	B-GENE
leukemia	I-GENE
inhibitory	I-GENE
factor	I-GENE
receptor	I-GENE
(	O
LIFR	B-GENE
)	O
gene	O
and	O
now	O
show	O
detailed	O
characterization	O
of	O
the	O
226	O
-	O
base	O
pair	O
enhancer	O
(	O
-	O
4625	O
/	O
-	O
4400	O
nucleotides	O
)	O
.	O

Copyright	O
1998	O
Elsevier	O
Science	O
B	O
.	O
V	O
.	O

It	O
may	O
be	O
time	O
to	O
reevaluate	O
the	O
dichotomy	O
between	O
AD	O
and	O
VaD	O
.	O

Clone	O
39	O
was	O
a	O
homolog	O
of	O
CONSTANS	B-GENE
,	O
which	O
is	O
a	O
gene	O
involved	O
in	O
controlling	O
the	O
flowering	O
time	O
in	O
Arabidopsis	O
.	O

The	O
effects	O
of	O
high	O
intensity	O
light	O
emissions	O
,	O
produced	O
by	O
a	O
novel	O
pulsed	O
power	O
energization	O
technique	O
(	O
PPET	O
)	O
,	O
on	O
the	O
survival	O
of	O
bacterial	O
populations	O
of	O
verocytotoxigenic	O
Escherichia	O
coli	O
(	O
serotype	O
0157	O
:	O
H7	O
)	O
and	O
Listeria	O
monocytogenes	O
(	O
serotype	O
4b	O
)	O
were	O
investigated	O
.	O

Multiple	O
chemical	O
sensitivity	O
(	O
MCS	O
)	O
is	O
a	O
syndrome	O
in	O
which	O
multiple	O
symptoms	O
reportedly	O
occur	O
with	O
low	O
-	O
level	O
chemical	O
exposure	O
.	O

POU	B-GENE
-	I-GENE
domain	I-GENE
proteins	I-GENE
,	O
such	O
as	O
the	O
pituitary	B-GENE
-	I-GENE
specific	I-GENE
factor	I-GENE
Pit	I-GENE
-	I-GENE
1	I-GENE
,	O
are	O
members	O
of	O
the	O
homeodomain	B-GENE
family	I-GENE
of	O
proteins	O
which	O
are	O
important	O
in	O
development	O
and	O
homeostasis	O
,	O
acting	O
constitutively	O
or	O
in	O
response	O
to	O
signal	O
-	O
transduction	O
pathways	O
to	O
either	O
repress	O
or	O
activate	O
the	O
expression	O
of	O
specific	O
genes	O
.	O

Wild	O
-	O
type	O
and	O
mutant	O
MyoD	B-GENE
were	O
introduced	O
into	O
cells	O
using	O
an	O
E1	B-GENE
,	O
E3	B-GENE
-	O
deleted	O
adenoviral	O
vector	O
.	O

These	O
results	O
suggest	O
that	O
Thr115	O
may	O
play	O
an	O
important	O
role	O
in	O
the	O
regulation	O
of	O
MyoD	B-GENE
function	O
under	O
conditions	O
of	O
high	O
mitogenesis	O
.	O

This	O
and	O
previous	O
results	O
suggest	O
that	O
the	O
CRE	O
and	O
Sp1	B-GENE
site	I-GENE
may	O
synergistically	O
activate	O
TH	B-GENE
transcription	O
in	O
a	O
promoter	O
context	O
-	O
dependent	O
manner	O
.	O

Endoscopic	O
examinations	O
,	O
peripheral	O
white	O
blood	O
cell	O
(	O
WBC	O
)	O
counts	O
,	O
and	O
assays	O
of	O
myeloperoxidase	B-GENE
activity	O
(	O
MPO	B-GENE
)	O
in	O
homogenates	O
of	O
colon	O
mucosa	O
were	O
performed	O
after	O
one	O
week	O
(	O
4	O
%	O
DSS	O
model	O
)	O
and	O
eight	O
weeks	O
(	O
1	O
%	O
DSS	O
model	O
)	O
.	O

T7	O
transcription	O
could	O
be	O
manipulated	O
to	O
achieve	O
different	O
levels	O
of	O
constitutive	O
expression	O
,	O
through	O
the	O
use	O
of	O
promoter	O
mutations	O
.	O

The	O
primers	O
were	O
degenerate	O
sets	O
of	O
oligonucleotides	O
derived	O
from	O
known	O
amino	O
acid	O
sequences	O
of	O
the	O
PBAN	B-GENE
precursor	I-GENE
.	O

Plants	O
transformed	O
with	O
the	O
35S	B-GENE
-	O
1	B-GENE
-	I-GENE
sst	I-GENE
construct	O
accumulated	O
the	O
oligofructans	O
1	O
-	O
kestose	O
(	O
GF2	O
)	O
,	O
1	O
,	O
1	O
-	O
nystose	O
(	O
GF3	O
)	O
and	O
1	O
,	O
1	O
,	O
1	O
-	O
fructosylnystose	O
(	O
GF4	O
)	O
.	O

Based	O
on	O
the	O
comparison	O
of	O
the	O
predicted	O
amino	O
acid	O
sequences	O
of	O
1	B-GENE
-	I-GENE
sst	I-GENE
and	O
1	B-GENE
-	I-GENE
fft	I-GENE
with	O
those	O
of	O
other	O
plant	O
fructosyl	B-GENE
transferase	I-GENE
genes	I-GENE
,	O
we	O
postulate	O
that	O
both	O
plant	O
fructan	B-GENE
genes	I-GENE
have	O
evolved	O
from	O
plant	O
invertase	B-GENE
genes	O
.	O

However	O
,	O
ICK1	B-GENE
was	O
induced	O
by	O
ABA	O
,	O
and	O
along	O
with	O
ICK1	B-GENE
induction	O
there	O
was	O
a	O
decrease	O
in	O
Cdc2	B-GENE
-	I-GENE
like	I-GENE
histone	B-GENE
H1	I-GENE
kinase	I-GENE
activity	O
.	O

Here	O
,	O
we	O
report	O
that	O
swa5	B-GENE
-	I-GENE
1	I-GENE
is	O
a	O
new	O
temperature	O
-	O
sensitive	O
allele	O
of	O
the	O
clathrin	B-GENE
heavy	I-GENE
chain	I-GENE
gene	I-GENE
(	O
chc1	B-GENE
-	I-GENE
5	I-GENE
)	O
,	O
which	O
carries	O
a	O
frameshift	O
mutation	O
near	O
the	O
3	O
'	O
end	O
of	O
the	O
CHC1	B-GENE
open	O
reading	O
frame	O
.	O

We	O
have	O
determined	O
the	O
molecular	O
lesions	O
of	O
nine	O
Scm	B-GENE
mutant	I-GENE
alleles	I-GENE
,	O
which	O
identify	O
functional	O
requirements	O
for	O
specific	O
domains	O
.	O

Intriguingly	O
,	O
three	O
hypomorphic	O
Scm	B-GENE
mutations	O
,	O
which	O
map	O
within	O
an	O
mbt	B-GENE
repeat	I-GENE
,	O
interact	O
with	O
PcG	B-GENE
mutations	I-GENE
more	O
strongly	O
than	O
do	O
Scm	B-GENE
null	O
alleles	O
.	O

Northern	O
analysis	O
revealed	O
no	O
detectable	O
expression	O
of	O
the	O
transcript	O
in	O
diapause	O
-	O
or	O
nondiapause	O
-	O
programmed	O
wandering	O
larvae	O
,	O
and	O
only	O
trace	O
expression	O
in	O
nondiapausing	O
pupae	O
.	O

Besides	O
the	O
characterization	O
and	O
discussion	O
of	O
the	O
experimental	O
setup	O
used	O
,	O
the	O
rate	O
constants	O
obtained	O
are	O
discussed	O
and	O
compared	O
with	O
estimated	O
values	O
.	O

The	O
presence	O
of	O
PDZ	B-GENE
and	O
SAM	O
domains	O
in	O
the	O
KS5	B-GENE
protein	I-GENE
suggests	O
that	O
it	O
may	O
act	O
as	O
a	O
molecular	O
adaptor	O
,	O
promoting	O
and	O
relaying	O
information	O
in	O
a	O
signal	O
transduction	O
pathway	O
.	O

BACKGROUND	O
:	O
Fluoroquinolones	O
(	O
FQ	O
)	O
are	O
contraindicated	O
in	O
children	O
because	O
of	O
the	O
risk	O
of	O
cartilage	O
damage	O
.	O

In	O
analyses	O
with	O
control	O
for	O
multiple	O
variables	O
,	O
relative	O
risk	O
for	O
microalbuminuria	O
(	O
urinary	O
albumin	B-GENE
excretion	O
,	O
20	O
-	O
199	O
microg	O
/	O
min	O
)	O
in	O
men	O
and	O
women	O
was	O
2	O
.	O
51	O
and	O
1	O
.	O
62	O
,	O
respectively	O
,	O
with	O
18	O
mm	O
Hg	O
higher	O
(	O
1	O
SD	O
)	O
systolic	O
blood	O
pressure	O
;	O
2	O
.	O
25	O
and	O
2	O
.	O
10	O
,	O
respectively	O
,	O
with	O
1	O
.	O
0	O
-	O
mmol	O
/	O
L	O
(	O
40	O
mg	O
/	O
dL	O
)	O
higher	O
plasma	O
cholesterol	O
level	O
;	O
1	O
.	O
99	O
and	O
1	O
.	O
91	O
,	O
respectively	O
,	O
for	O
smokers	O
vs	O
nonsmokers	O
;	O
and	O
1	O
.	O
83	O
and	O
1	O
.	O
33	O
,	O
respectively	O
,	O
with	O
4	O
kg	O
/	O
m2	O
higher	O
body	O
mass	O
index	O
.	O

However	O
,	O
while	O
IL	B-GENE
-	I-GENE
1beta	I-GENE
and	O
TNF	B-GENE
-	I-GENE
alpha	I-GENE
both	O
induced	O
nuclear	O
binding	O
of	O
the	O
Rel	B-GENE
proteins	I-GENE
p50	B-GENE
and	O
p65	B-GENE
to	O
an	O
NF	B-GENE
-	I-GENE
kappaB	I-GENE
consensus	I-GENE
oligonucleotide	I-GENE
in	O
gel	O
shift	O
assays	O
and	O
caused	O
transient	O
degradation	O
of	O
inhibitor	B-GENE
of	I-GENE
NF	I-GENE
-	I-GENE
kappaB	I-GENE
-	I-GENE
alpha	I-GENE
(	O
IkappaB	B-GENE
-	I-GENE
alpha	I-GENE
)	O
in	O
the	O
cytoplasm	O
of	O
myofibroblasts	O
,	O
only	O
IL	B-GENE
-	I-GENE
1beta	I-GENE
upregulated	O
PDGF	B-GENE
-	I-GENE
Ralpha	I-GENE
.	O

Cotransfections	O
with	O
ATF	B-GENE
-	I-GENE
2	I-GENE
and	O
HNF	B-GENE
-	I-GENE
4	I-GENE
expression	O
plasmids	O
resulted	O
in	O
additive	O
transactivation	O
of	O
the	O
apoCIII	B-GENE
promoter	I-GENE
.	O

Phosphocreatine	O
hydrolysis	O
during	O
submaximal	O
exercise	O
:	O
the	O
effect	O
of	O
FIO2	O
.	O

Pseudocontact	O
shifts	O
arise	O
from	O
the	O
isotropic	O
reorientational	O
average	O
of	O
the	O
dipolar	O
coupling	O
between	O
unpaired	O
electron	O
and	O
nuclei	O
,	O
in	O
the	O
presence	O
of	O
magnetic	O
susceptibility	O
anisotropy	O
.	O

GETS	B-GENE
-	I-GENE
1	I-GENE
is	O
expressed	O
in	O
many	O
tissues	O
,	O
but	O
is	O
enriched	O
in	O
retina	O
and	O
brain	O
.	O

The	O
interaction	O
of	O
U1	B-GENE
-	I-GENE
70K	I-GENE
with	O
the	O
SRZ	B-GENE
proteins	I-GENE
is	O
confirmed	O
further	O
in	O
vitro	O
using	O
a	O
blot	O
overlay	O
assay	O
.	O

The	O
major	O
phenotypes	O
resulting	O
from	O
Fab1p	B-GENE
kinase	I-GENE
inactivation	O
include	O
temperature	O
-	O
sensitive	O
growth	O
,	O
vacuolar	O
acidification	O
defects	O
,	O
and	O
dramatic	O
increases	O
in	O
vacuolar	O
size	O
.	O

Interestingly	O
,	O
an	O
antibody	O
against	O
N	B-GENE
-	I-GENE
SMase	I-GENE
can	O
abrogate	O
Ox	B-GENE
-	I-GENE
LDL	I-GENE
-	O
and	O
TNF	B-GENE
-	I-GENE
alpha	I-GENE
-	O
induced	O
apoptosis	O
and	O
therefore	O
may	O
be	O
useful	O
for	O
in	O
vivo	O
studies	O
of	O
apoptosis	O
in	O
experimental	O
animals	O
.	O

We	O
found	O
that	O
virulent	O
Ngo	O
strains	O
induce	O
phosphorylation	O
and	O
activation	O
of	O
JNK	B-GENE
but	O
not	O
of	O
p38	B-GENE
kinase	O
.	O

Focused	O
beams	O
of	O
classical	O
light	O
ablate	O
elements	O
of	O
the	O
cell	O
division	O
machinery	O
and	O
switch	O
the	O
beating	O
of	O
hearts	O
on	O
a	O
cellular	O
basis	O
.	O

The	O
human	O
T	O
cell	O
lymphotropic	O
retrovirus	O
type	O
I	O
(	O
HTLV	O
-	O
I	O
)	O
trans	O
-	O
activator	O
,	O
Tax	B-GENE
,	O
interacts	O
specifically	O
with	O
the	O
basic	B-GENE
-	I-GENE
domain	I-GENE
/	I-GENE
leucine	I-GENE
-	I-GENE
zipper	I-GENE
(	I-GENE
bZip	I-GENE
)	I-GENE
protein	I-GENE
,	O
cAMP	B-GENE
response	I-GENE
element	I-GENE
binding	I-GENE
protein	I-GENE
(	O
CREB	B-GENE
)	O
,	O
bound	O
to	O
the	O
viral	B-GENE
Tax	I-GENE
-	I-GENE
responsive	I-GENE
element	I-GENE
consisting	O
of	O
three	O
imperfect	O
21	O
-	O
base	O
pair	O
repeats	O
,	O
each	O
with	O
a	O
cAMP	O
response	O
element	O
core	O
flanked	O
by	O
G	O
/	O
C	O
-	O
rich	O
sequences	O
.	O

This	O
sequence	O
is	O
very	O
similar	O
to	O
the	O
insulin	B-GENE
response	I-GENE
sequence	I-GENE
found	O
in	O
the	O
regulatory	O
region	O
of	O
other	O
genes	O
negatively	O
regulated	O
by	O
insulin	B-GENE
such	O
as	O
those	O
encoding	O
phosphoenolpyruvate	B-GENE
carboxykinase	I-GENE
,	O
tyrosine	B-GENE
aminotransferase	I-GENE
,	O
and	O
insulin	B-GENE
-	I-GENE
like	I-GENE
growth	I-GENE
factor	I-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
1	I-GENE
.	O

The	O
murine	B-GENE
facilitative	I-GENE
glucose	I-GENE
transporter	I-GENE
isoform	I-GENE
3	I-GENE
(	O
Glut	B-GENE
3	I-GENE
)	O
is	O
developmentally	O
regulated	O
and	O
is	O
predominantly	O
expressed	O
in	O
neurons	O
and	O
trophoblasts	O
.	O

However	O
,	O
changing	O
the	O
half	O
-	O
site	O
to	O
the	O
consensus	O
sequence	O
AGGTCA	O
(	O
IRper	O
-	O
1	O
)	O
increased	O
binding	O
of	O
AaEcR	B-GENE
.	I-GENE
AaUSP	I-GENE
10	O
-	O
fold	O
over	O
IRhsp	O
-	O
1	O
and	O
,	O
at	O
the	O
same	O
time	O
,	O
reduced	O
the	O
stringency	O
of	O
the	O
spacer	O
length	O
requirement	O
,	O
with	O
IRper	O
-	O
0	O
to	O
IRper	O
-	O
5	O
showing	O
detectable	O
binding	O
.	O

The	O
levels	O
of	O
transactivation	O
are	O
correlated	O
with	O
the	O
respective	O
binding	O
affinities	O
of	O
the	O
response	O
elements	O
(	O
IRper	O
-	O
1	O
>	O
DR	O
-	O
4	O
>	O
IRhsp	O
-	O
1	O
)	O
.	O

The	O
high	O
density	O
of	O
tegumental	O
spines	O
on	O
posterior	O
half	O
of	O
the	O
body	O
and	O
the	O
distribution	O
of	O
type	O
II	O
papillae	O
on	O
dorsal	O
surface	O
are	O
considered	O
to	O
be	O
characteristic	O
of	O
C	O
.	O
armatus	O
.	O

Inactivation	O
of	O
p53	B-GENE
but	O
not	O
p73	B-GENE
by	O
adenovirus	B-GENE
type	I-GENE
5	I-GENE
E1B	I-GENE
55	I-GENE
-	I-GENE
kilodalton	I-GENE
and	I-GENE
E4	I-GENE
34	I-GENE
-	I-GENE
kilodalton	I-GENE
oncoproteins	I-GENE
.	O

The	O
Epstein	B-GENE
-	I-GENE
Barr	I-GENE
virus	I-GENE
transactivator	I-GENE
Zta	I-GENE
triggers	O
lytic	O
gene	O
expression	O
and	O
is	O
essential	O
for	O
replication	O
of	O
the	O
lytic	O
origin	O
,	O
oriLyt	O
.	O

Cotransfection	O
of	O
the	O
helicase	B-GENE
-	O
primase	B-GENE
proteins	O
,	O
one	O
of	O
which	O
was	O
fused	O
to	O
a	O
heterologous	O
activation	O
domain	O
,	O
led	O
to	O
Zta	B-GENE
-	O
dependent	O
superactivation	O
of	O
CAT	B-GENE
expression	O
.	O

A	O
single	O
rectal	O
dose	O
of	O
25	O
mg	O
/	O
kg	O
will	O
obtain	O
this	O
lower	O
concentration	O
within	O
1	O
h	O
of	O
administration	O
and	O
maintain	O
it	O
for	O
up	O
to	O
6	O
h	O
.	O

Although	O
YopH	B-GENE
is	O
a	O
highly	O
active	O
PTP	B-GENE
,	O
it	O
preferentially	O
targets	O
a	O
subset	O
of	O
tyrosine	O
-	O
phosphorylated	O
proteins	O
in	O
host	O
cells	O
,	O
including	O
p130Cas	B-GENE
.	O

Phylogenetic	O
position	O
of	O
the	O
Phacotaceae	O
within	O
the	O
Chlamydophyceaeas	O
revealed	O
by	O
analysis	O
of	O
18S	B-GENE
rDNA	I-GENE
and	O
rbcL	B-GENE
sequences	I-GENE
.	O

The	O
activation	O
and	O
injury	O
of	O
endothelial	O
cells	O
induced	O
by	O
TNF	B-GENE
and	O
other	O
proinflammatory	O
cytokines	O
may	O
underlie	O
the	O
local	O
effects	O
of	O
these	O
mediators	O
in	O
vivo	O
.	O

A	O
technique	O
for	O
thermal	O
imaging	O
of	O
the	O
animal	O
and	O
human	O
brain	O
cortex	O
using	O
an	O
infrared	O
optical	O
system	O
is	O
described	O
.	O

Here	O
we	O
demonstrate	O
that	O
THOV	B-GENE
NP	I-GENE
contains	O
a	O
motif	O
(	O
KRxxxxxxxxxKTKK	O
)	O
at	O
amino	O
acid	O
positions	O
179	O
-	O
193	O
that	O
represents	O
a	O
classical	O
bipartite	O
nuclear	O
localization	O
signal	O
(	O
NLS	O
)	O
.	O

As	O
PP2A	B-GENE
exerts	O
a	O
range	O
of	O
cellular	O
functions	O
including	O
cell	O
cycle	O
regulation	O
and	O
cell	O
fate	O
determination	O
,	O
we	O
were	O
surprised	O
to	O
find	O
that	O
these	O
embryos	O
develop	O
normally	O
until	O
postimplantation	O
,	O
around	O
embryonic	O
day	O
5	O
.	O
5	O
/	O
6	O
.	O
0	O
.	O

The	O
most	O
frequent	O
risk	O
factor	O
for	O
ischaemic	O
was	O
hypertension	O
.	O

The	O
results	O
indicate	O
that	O
anthraquinone	O
sennoside	O
B	O
and	O
rhein	O
are	O
weakly	O
genotoxic	O
.	O

16	O
subjects	O
were	O
repatch	O
tested	O
to	O
ethylmercury	O
chloride	O
(	O
EtHgCl	O
)	O
and	O
to	O
solutions	O
containing	O
EtHgCl	O
mixed	O
with	O
L	O
-	O
cysteine	O
and	O
glutathione	O
,	O
respectively	O
.	O

The	O
carboxyl	O
-	O
terminal	O
portion	O
of	O
UKLF	B-GENE
contains	O
three	O
zinc	O
fingers	O
of	O
the	O
Cys2	O
-	O
His2	O
type	O
and	O
binds	O
in	O
vitro	O
to	O
the	O
CACCC	O
motif	O
of	O
the	O
beta	B-GENE
-	I-GENE
globin	I-GENE
promoter	I-GENE
and	O
to	O
the	O
Sp1	B-GENE
recognition	I-GENE
sequence	I-GENE
.	O

We	O
have	O
recently	O
identified	O
a	O
mouse	O
enzyme	O
termed	O
gamma	B-GENE
-	I-GENE
glutamyl	I-GENE
leukotrienase	I-GENE
(	O
GGL	B-GENE
)	O
that	O
converts	O
leukotriene	O
C4	O
(	O
LTC4	O
)	O
to	O
leukotriene	O
D4	O
(	O
LTD4	O
)	O
.	O

UGA	O
codon	O
position	O
affects	O
the	O
efficiency	O
of	O
selenocysteine	O
incorporation	O
into	O
glutathione	B-GENE
peroxidase	I-GENE
-	I-GENE
1	I-GENE
.	O

Forskolin	O
significantly	O
enhanced	O
heregulin	B-GENE
-	O
stimulated	O
expression	O
of	O
cyclin	B-GENE
D	I-GENE
and	O
phosphorylation	O
of	O
the	O
retinoblastoma	B-GENE
gene	I-GENE
product	I-GENE
.	O

The	O
ARF	B-GENE
promoter	I-GENE
was	O
also	O
found	O
to	O
be	O
highly	O
responsive	O
to	O
E2F1	B-GENE
expression	O
,	O
in	O
keeping	O
with	O
previous	O
results	O
at	O
the	O
RNA	O
level	O
.	O

Observers	O
with	O
brain	O
injury	O
and	O
control	O
participants	O
performed	O
a	O
vigilance	O
task	O
during	O
which	O
they	O
received	O
periodic	O
whiffs	O
of	O
unscented	O
air	O
or	O
air	O
scented	O
with	O
peppermint	O
.	O

A	O
simple	O
analytical	O
method	O
for	O
l	O
-	O
menthol	O
by	O
high	O
-	O
performance	O
liquid	O
chromatography	O
with	O
a	O
polarized	O
photometric	O
detector	O
was	O
established	O
.	O

After	O
measuring	O
baseline	O
Vmca	O
at	O
a	O
partial	O
pressure	O
of	O
carbon	O
dioxide	O
in	O
arterial	O
blood	O
(	O
PaCO2	O
)	O
of	O
37	O
.	O
7	O
+	O
/	O
-	O
4	O
.	O
5	O
mmHg	O
(	O
mean	O
+	O
/	O
-	O
SD	O
)	O
,	O
measurements	O
were	O
repeated	O
at	O
a	O
PaCO	O
of	O
44	O
.	O
2	O
+	O
/	O
-	O
3	O
.	O
8	O
mmHg	O
,	O
and	O
the	O
carbon	O
dioxide	O
reactivity	O
(	O
absolute	O
value	O
:	O
cm	O
x	O
s	O
(	O
-	O
1	O
)	O
x	O
mmHg	O
(	O
-	O
1	O
)	O
;	O
relative	O
value	O
:	O
percentage	O
of	O
baseline	O
Vmca	O
/	O
mmHg	O
)	O
was	O
calculated	O
.	O

Multivariate	O
Cox	O
survival	O
analysis	O
identified	O
baseline	O
EF	O
<	O
or	O
=	O
30	O
%	O
,	O
presence	O
of	O
significant	O
mitral	O
regurgitation	O
(	O
>	O
2	O
+	O
)	O
before	O
ablation	O
,	O
and	O
failure	O
to	O
exhibit	O
improved	O
cardiac	O
performance	O
by	O
1	O
month	O
after	O
ablation	O
as	O
the	O
only	O
independent	O
predictors	O
of	O
death	O
.	O

We	O
have	O
developed	O
a	O
new	O
method	O
for	O
estimation	O
of	O
regional	O
CBF	O
(	O
rCBF	O
)	O
and	O
cerebrovascular	O
reserve	O
capacity	O
on	O
a	O
pixel	O
-	O
by	O
-	O
pixel	O
basis	O
by	O
means	O
of	O
dynamic	O
magnetic	O
resonance	O
imaging	O
(	O
MRI	O
)	O
.	O

Cost	O
-	O
effectiveness	O
analysis	O
provides	O
a	O
rational	O
means	O
of	O
allocating	O
limited	O
health	O
care	O
resources	O
by	O
allowing	O
the	O
comparison	O
of	O
the	O
costs	O
of	O
lipid	O
-	O
lowering	O
therapy	O
,	O
in	O
particular	O
,	O
therapy	O
with	O
beta	B-GENE
-	I-GENE
hydroxy	I-GENE
-	I-GENE
beta	I-GENE
-	I-GENE
methylglutaryl	I-GENE
-	I-GENE
CoA	I-GENE
(	I-GENE
coenzyme	I-GENE
A	I-GENE
)	I-GENE
reductase	I-GENE
inhibitors	O
(	O
statins	O
)	O
,	O
with	O
the	O
costs	O
of	O
atherosclerosis	O
that	O
could	O
be	O
prevented	O
by	O
lowering	O
cholesterol	O
.	O

Although	O
E2FBP1	B-GENE
lacks	O
the	O
transactivation	O
domain	O
,	O
it	O
stimulates	O
E2F	B-GENE
site	O
-	O
dependent	O
transcription	O
in	O
cooperation	O
with	O
E2F	B-GENE
-	I-GENE
1	I-GENE
.	O

Analysis	O
of	O
Msy2	B-GENE
mRNA	I-GENE
expression	O
in	O
prepubertal	O
and	O
adult	O
mouse	O
testes	O
,	O
and	O
in	O
isolated	O
populations	O
of	O
germ	O
cells	O
,	O
reveals	O
maximal	O
expression	O
in	O
postmeiotic	O
round	O
spermatids	O
,	O
a	O
cell	O
type	O
with	O
abundant	O
amounts	O
of	O
stored	O
messenger	O
ribonucleoproteins	O
.	O

1	O
in	O
Ho	O
Chi	O
Minh	O
City	O
was	O
studied	O
by	O
culture	O
and	O
latex	O
agglutination	O
of	O
blood	O
,	O
cerebrospinal	O
fluid	O
,	O
urine	O
and	O
pleural	O
fluid	O
.	O

Glycogen	O
synthesis	O
and	O
catabolism	O
,	O
gluconeogenesis	O
,	O
glycolysis	O
,	O
motility	O
,	O
cell	O
surface	O
properties	O
and	O
adherence	O
are	O
modulated	O
by	O
csrA	B-GENE
in	I-GENE
Escherichia	I-GENE
coli	I-GENE
,	O
while	O
the	O
production	O
of	O
several	O
secreted	O
virulence	O
factors	O
,	O
the	O
plant	O
hypersensitive	O
response	O
elicitor	O
HrpN	B-GENE
(	O
Ecc	B-GENE
)	O
and	O
,	O
potentially	O
,	O
other	O
secondary	O
metabolites	O
are	O
regulated	O
by	O
rsmA	B-GENE
in	I-GENE
Erwinia	I-GENE
carotovora	I-GENE
.	O

Deletion	O
analysis	O
revealed	O
that	O
the	O
essential	O
domain	O
of	O
this	O
promoter	O
,	O
termed	O
the	O
ORF5	B-GENE
/	I-GENE
deltaX	I-GENE
transcript	I-GENE
promoter	I-GENE
,	O
mapped	O
to	O
nucleotides	O
1525	O
-	O
1625	O
.	O

Some	O
of	O
the	O
peptide	B-GENE
:	I-GENE
MBP	I-GENE
fusions	I-GENE
were	O
also	O
analyzed	O
using	O
surface	O
plasmon	O
resonance	O
.	O

Cardiac	B-GENE
myosin	I-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
C	I-GENE
(	O
MyBP	B-GENE
-	I-GENE
C	I-GENE
)	O
:	O
identification	O
of	O
protein	B-GENE
kinase	I-GENE
A	I-GENE
and	O
protein	B-GENE
kinase	I-GENE
C	I-GENE
phosphorylation	O
sites	O
.	O

Analysis	O
of	O
chromosomal	O
DNA	O
sequence	O
immediately	O
downstream	O
of	O
the	O
transposon	O
insertion	O
identified	O
two	O
open	O
reading	O
frames	O
,	O
designated	O
csrR	B-GENE
and	O
csrS	B-GENE
,	O
which	O
exhibited	O
sequence	O
similarity	O
to	O
bacterial	O
two	O
-	O
component	O
regulatory	O
systems	O
.	O

We	O
previously	O
delineated	O
a	O
region	O
in	O
the	O
fatty	B-GENE
-	I-GENE
acid	I-GENE
synthase	I-GENE
promoter	I-GENE
,	O
which	O
was	O
responsible	O
for	O
obesity	O
-	O
related	O
overexpression	O
of	O
the	O
fatty	B-GENE
-	I-GENE
acid	I-GENE
synthase	I-GENE
(	O
FAS	B-GENE
)	O
gene	O
,	O
by	O
negatively	O
regulating	O
the	O
activity	O
of	O
the	O
downstream	O
promoter	O
in	O
lean	O
but	O
not	O
obese	O
rat	O
fat	O
cells	O
.	O

Finally	O
,	O
using	O
in	O
vitro	O
binding	O
studies	O
,	O
we	O
showed	O
that	O
SREBP2	B-GENE
was	O
able	O
to	O
displace	O
ADD1	B-GENE
/	O
SREBP1	B-GENE
binding	O
from	O
the	O
sterol	O
regulatory	O
element	O
(	O
SRE	O
)	O
site	O
.	O

Thus	O
,	O
IRF	B-GENE
-	I-GENE
7	I-GENE
exhibits	O
functional	O
similarity	O
to	O
IRF	B-GENE
-	I-GENE
3	I-GENE
;	O
however	O
,	O
the	O
preferential	O
expression	O
of	O
IRF	B-GENE
-	I-GENE
7	I-GENE
in	O
lymphoid	O
cells	O
(	O
the	O
cell	O
type	O
that	O
expresses	O
IFNA	B-GENE
)	O
suggests	O
that	O
IRF	B-GENE
-	I-GENE
7	I-GENE
may	O
play	O
a	O
critical	O
role	O
in	O
regulating	O
the	O
IFNA	B-GENE
gene	I-GENE
expression	O
.	O

J	O
.	O

PURPOSE	O
:	O
The	O
role	O
interleukin	B-GENE
-	I-GENE
6	I-GENE
(	O
IL	B-GENE
-	I-GENE
6	I-GENE
)	O
in	O
the	O
treatment	O
of	O
congenital	O
thrombocytopenias	O
is	O
unknown	O
.	O

CKII	B-GENE
as	O
a	O
CD44	B-GENE
-	I-GENE
associated	I-GENE
serine	I-GENE
kinase	I-GENE
therefore	O
may	O
serve	O
as	O
an	O
important	O
molecule	O
in	O
a	O
signaling	O
cascade	O
that	O
produces	O
a	O
variety	O
of	O
cellular	O
responses	O
in	O
MDA231	O
breast	O
cancer	O
cells	O
.	O

Galphaq	B-GENE
,	O
Galpha12	B-GENE
,	O
and	O
Galpha13	B-GENE
,	O
but	O
not	O
Galphai	B-GENE
,	O
activate	O
SRF	B-GENE
through	O
RhoA	B-GENE
.	O

Additionally	O
in	O
seven	O
subjects	O
adrenaline	O
(	O
A	O
)	O
and	O
noradrenaline	O
(	O
NA	O
)	O
concentrations	O
were	O
determined	O
.	O

Northern	O
blot	O
analyses	O
show	O
that	O
the	O
hBub1	B-GENE
mRNA	I-GENE
level	O
is	O
abundantly	O
expressed	O
in	O
tissues	O
or	O
cells	O
with	O
a	O
high	O
mitotic	O
index	O
.	O

We	O
mapped	O
two	O
overlapping	O
expressed	O
sequence	O
tag	O
clones	O
within	O
a	O
genomic	O
contig	O
on	O
human	O
chromosome	O
5	O
,	O
band	O
q31	O
.	O

Htra2	B-GENE
-	I-GENE
beta3	I-GENE
is	O
developmentally	O
regulated	O
and	O
expressed	O
predominantly	O
in	O
brain	O
,	O
liver	O
testis	O
,	O
and	O
weakly	O
in	O
kidney	O
.	O

Gng3lg	B-GENE
transcripts	I-GENE
are	O
expressed	O
in	O
a	O
variety	O
of	O
tissues	O
including	O
both	O
brain	O
and	O
testes	O
.	O

Using	O
an	O
interspecific	O
backcross	O
panel	O
,	O
we	O
localized	O
both	O
Gng3	B-GENE
and	O
Gng3lg	B-GENE
to	O
the	O
same	O
locus	O
on	O
chromosome	O
19	O
.	O

We	O
also	O
raised	O
a	O
polyclonal	O
antibody	O
against	O
the	O
glutathione	B-GENE
S	I-GENE
-	I-GENE
transferase	I-GENE
fusion	I-GENE
protein	I-GENE
containing	O
the	O
NH2	O
-	O
terminal	O
86	O
amino	O
acids	O
of	O
human	B-GENE
NRAMP2	I-GENE
.	O

Inhibition	O
of	O
the	O
apolipoprotein	B-GENE
B	I-GENE
mRNA	I-GENE
editing	O
enzyme	O
-	O
complex	O
by	O
hnRNP	B-GENE
C1	I-GENE
protein	I-GENE
and	O
40S	B-GENE
hnRNP	I-GENE
complexes	I-GENE
.	O

SRC	B-GENE
-	I-GENE
1	I-GENE
can	O
relieve	O
the	O
NF	B-GENE
-	I-GENE
kappaB	I-GENE
-	O
mediated	O
repression	O
of	O
GR	B-GENE
activity	O
.	O

However	O
the	O
sequence	O
surrounding	O
the	O
transcription	O
start	O
site	O
CTCA	O
(	O
+	O
1	O
)	O
TTCC	O
was	O
similar	O
to	O
the	O
consensus	O
CTCA	O
(	O
+	O
1	O
)	O
NTCT	O
(	O
N	O
is	O
any	O
nucleoside	O
)	O
for	O
an	O
initiator	O
element	O
found	O
in	O
terminal	B-GENE
deoxynucleotidyltransferase	I-GENE
and	O
a	O
number	O
of	O
other	O
highly	O
regulated	O
genes	O
.	O

Expression	O
of	O
a	O
dominant	O
-	O
negative	O
mutant	O
of	O
JNK1	B-GENE
also	O
suppressed	O
glucose	O
deprivation	O
-	O
induced	O
JNK1	B-GENE
activation	O
as	O
well	O
as	O
HSP70	B-GENE
gene	I-GENE
expression	O
.	O

The	O
interaction	O
of	O
AF	O
-	O
1	O
with	O
proteins	O
that	O
regulate	O
distinct	O
steps	O
of	O
transcription	O
may	O
provide	O
a	O
mechanism	O
for	O
synergistic	O
activation	O
of	O
gene	O
expression	O
by	O
AF	O
-	O
1	O
.	O

The	O
role	O
of	O
protein	B-GENE
kinase	I-GENE
C	I-GENE
signaling	O
in	O
activated	O
DRA	B-GENE
transcription	O
.	O

Ligand	O
binding	O
to	O
the	O
receptor	O
complex	O
leads	O
to	O
tyrosine	O
phosphorylation	O
and	O
activation	O
of	O
Janus	B-GENE
kinases	I-GENE
(	O
Jak	B-GENE
)	O
,	O
phosphorylation	O
of	O
the	O
signal	B-GENE
transducing	I-GENE
subunit	I-GENE
gp130	I-GENE
,	O
followed	O
by	O
recruitment	O
and	O
phosphorylation	O
of	O
the	O
signal	B-GENE
transducer	I-GENE
and	I-GENE
activator	I-GENE
of	I-GENE
transcription	I-GENE
factors	I-GENE
STAT3	B-GENE
and	O
STAT1	B-GENE
and	O
the	O
src	B-GENE
homology	I-GENE
domain	I-GENE
(	O
SH2	B-GENE
)	O
-	O
containing	O
protein	B-GENE
tyrosine	I-GENE
phosphatase	I-GENE
(	O
SHP2	B-GENE
)	O
.	O

Interestingly	O
,	O
an	O
increase	O
of	O
distance	O
per	O
se	O
did	O
not	O
have	O
a	O
deleterious	O
effect	O
on	O
translation	O
efficiency	O
.	O

We	O
also	O
mapped	O
a	O
3	O
'	O
-	O
polyadenylation	O
site	O
504bp	O
downstream	O
of	O
the	O
TGA	O
stop	O
codon	O
,	O
consistent	O
with	O
the	O
2	O
.	O
5kb	O
transcript	O
size	O
.	O

RBP56	B-GENE
protein	I-GENE
turned	O
out	O
to	O
be	O
hTAFII68	B-GENE
which	O
was	O
isolated	O
as	O
a	O
TATA	B-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
associated	I-GENE
factor	I-GENE
(	O
TAF	B-GENE
)	O
from	O
a	O
sub	O
-	O
population	O
of	O
TFIID	B-GENE
complexes	I-GENE
(	O
Bertolotti	O
A	O
.	O
,	O
Lutz	O
,	O
Y	O
.	O
,	O
Heard	O
,	O
D	O
.	O
J	O
.	O
,	O
Chambon	O
,	O
P	O
.	O
,	O
Tora	O
,	O
L	O
.	O
,	O
1996	O
.	O
hTAFII68	B-GENE
,	O
a	O
novel	O
RNA	O
/	O
ssDNA	O
-	O
binding	O
protein	O
with	O
homology	O
to	O
the	O
proto	O
-	O
oncoproteins	O
TLS	B-GENE
/	O
FUS	B-GENE
and	O
EWS	B-GENE
is	O
associated	O
with	O
both	O
TFIID	B-GENE
and	O
RNA	B-GENE
polymerase	I-GENE
II	I-GENE
.	O

An	O
electrophoretic	O
mobility	O
shift	O
assay	O
was	O
performed	O
to	O
characterize	O
the	O
binding	O
property	O
of	O
TR2	B-GENE
and	O
its	O
truncated	O
isoform	O
.	O

Gel	O
-	O
mobility	O
shift	O
analysis	O
was	O
also	O
performed	O
for	O
the	O
CCAAT	O
motif	O
at	O
-	O
67	O
.	O

RESULTS	O
:	O
We	O
identified	O
a	O
full	O
-	O
length	O
cDNA	O
with	O
an	O
open	O
reading	O
frame	O
of	O
2883	O
bp	O
corresponding	O
to	O
a	O
predicted	O
protein	O
of	O
961	O
amino	O
acids	O
that	O
shares	O
greater	O
than	O
95	O
%	O
homology	O
with	O
the	O
rat	B-GENE
gamma	I-GENE
-	I-GENE
aminobutyric	I-GENE
acid	I-GENE
B	I-GENE
(	I-GENE
GABAB	I-GENE
)	I-GENE
receptor	I-GENE
.	O

On	O
Day	O
8	O
,	O
the	O
CIDR	O
-	O
B	O
was	O
removed	O
and	O
500	O
micrograms	O
cloprostenol	O
injected	O
,	O
IM	O
.	O

Another	O
tentative	O
hotspot	O
mutation	O
in	O
the	O
third	O
patient	O
,	O
a	O
frame	O
shift	O
caused	O
by	O
a	O
G	O
nucleotide	O
insertion	O
in	O
a	O
monotonous	O
repeat	O
of	O
six	O
Gs	O
in	O
HPRT	B-GENE
exon	I-GENE
3	I-GENE
,	O
has	O
been	O
reported	O
previously	O
in	O
three	O
other	O
LN	O
patients	O
.	O

SRF	B-GENE
-	O
deficient	O
embryos	O
(	O
Srf	B-GENE
-	O
/	O
-	O
)	O
have	O
a	O
severe	O
gastrulation	O
defect	O
and	O
do	O
not	O
develop	O
to	O
term	O
.	O

These	O
characteristic	O
structural	O
features	O
were	O
used	O
to	O
create	O
the	O
abbreviation	O
AZF1	B-GENE
(	O
Asparagine	B-GENE
-	I-GENE
rich	I-GENE
Zinc	I-GENE
Finger	I-GENE
protein	I-GENE
)	O
.	O

Over	O
-	O
expression	O
of	O
Azf1p	B-GENE
in	O
the	O
yeast	O
cell	O
does	O
not	O
influence	O
the	O
expression	O
level	O
of	O
the	O
mitochondrial	B-GENE
transcription	I-GENE
factor	I-GENE
Mtf1p	I-GENE
,	O
indicating	O
that	O
the	O
influence	O
of	O
Azf1p	B-GENE
on	O
the	O
suppression	O
of	O
the	O
special	O
mitochondrial	B-GENE
RNA	I-GENE
polymerase	I-GENE
mutant	I-GENE
is	O
an	O
indirect	O
one	O
.	O

We	O
have	O
generated	O
a	O
computer	O
model	O
of	O
the	O
C	O
-	O
terminal	O
domain	O
of	O
the	O
434	O
repressor	O
based	O
on	O
the	O
crystal	O
structure	O
of	O
the	O
homologous	B-GENE
UmuD	I-GENE
'	I-GENE
protein	I-GENE
.	O

Large	O
-	O
scale	O
sequencing	O
of	O
two	O
regions	O
in	O
human	O
chromosome	O
7q22	O
:	O
analysis	O
of	O
650	O
kb	O
of	O
genomic	O
sequence	O
around	O
the	O
EPO	B-GENE
and	O
CUTL1	B-GENE
loci	I-GENE
reveals	O
17	O
genes	O
.	O

Because	O
Trp53	B-GENE
(	O
the	O
mouse	B-GENE
homolog	I-GENE
of	I-GENE
human	I-GENE
TP53	I-GENE
)	O
is	O
located	O
with	O
Tk1	B-GENE
on	O
chromosome	O
11	O
and	O
is	O
critical	O
in	O
regulating	O
cellular	O
responses	O
following	O
exposure	O
to	O
DNA	O
damaging	O
agents	O
,	O
we	O
wanted	O
to	O
determine	O
if	O
these	O
mouse	O
lymphoma	O
cells	O
harbor	O
mutations	O
in	O
Trp53	B-GENE
.	O

One	O
of	O
these	O
fragments	O
shows	O
the	O
highest	O
amino	O
acid	O
sequence	O
homology	O
to	O
the	O
insect	O
ecdysone	O
inducible	O
gene	B-GENE
E75	I-GENE
.	O

The	O
full	O
-	O
length	O
N	B-GENE
gene	I-GENE
,	O
encoded	O
by	O
open	O
reading	O
frame	O
7	O
,	O
was	O
cloned	O
from	O
the	O
Canadian	O
PRRS	O
virus	O
,	O
PA	O
-	O
8	O
.	O

Based	O
on	O
sequence	O
homology	O
,	O
the	O
genes	O
were	O
identified	O
as	O
TEF	B-GENE
,	O
encoding	O
translation	B-GENE
elongation	I-GENE
factor	I-GENE
-	I-GENE
1	I-GENE
alpha	I-GENE
and	O
RPS7	B-GENE
,	O
encoding	O
ribosomal	O
protein	O
S7	B-GENE
.	O

We	O
have	O
previously	O
shown	O
that	O
ARNO	B-GENE
localizes	O
to	O
the	O
plasma	O
membrane	O
in	O
vivo	O
and	O
efficiently	O
catalyzes	O
ARF6	B-GENE
nucleotide	O
exchange	O
in	O
vitro	O
.	O

Renal	O
pathology	O
and	O
long	O
-	O
term	O
outcome	O
in	O
childhood	O
SLE	O
.	O

Transcription	O
factors	O
of	O
the	O
Stat	B-GENE
family	I-GENE
are	O
controlled	O
by	O
protein	O
kinases	O
.	O

We	O
propose	O
that	O
two	O
pathways	O
regulate	O
Stat5	B-GENE
serine	O
phosphorylation	O
,	O
one	O
that	O
is	O
prolactin	B-GENE
-	O
activated	O
and	O
PD98059	O
-	O
resistant	O
and	O
one	O
that	O
is	O
constitutively	O
active	O
and	O
PD98059	O
-	O
sensitive	O
and	O
preferentially	O
targets	O
Stat5a	B-GENE
.	O

An	O
approximately	O
37	O
-	O
kDa	O
cytoplasmic	O
protein	O
is	O
rapidly	O
tyrosine	O
-	O
phosphorylated	O
in	O
the	O
response	O
of	O
mouse	O
BAC1	O
.	O
2F5	O
macrophages	O
to	O
colony	B-GENE
stimulating	I-GENE
factor	I-GENE
-	I-GENE
1	I-GENE
(	O
CSF	B-GENE
-	I-GENE
1	I-GENE
)	O
.	O
pp37	B-GENE
was	O
purified	O
from	O
the	O
cytosolic	O
fraction	O
by	O
anti	B-GENE
-	I-GENE
Tyr	I-GENE
(	I-GENE
P	I-GENE
)	I-GENE
affinity	O
chromatography	O
,	O
size	O
exclusion	O
chromatography	O
,	O
and	O
C4	O
reverse	O
phase	O
high	O
pressure	O
liquid	O
chromatography	O
.	O

Dose	O
of	O
20	O
ig	O
were	O
administered	O
within	O
a	O
scheme	O
from	O
0	O
.	O
1	O
to	O
6	O
months	O
in	O
order	O
to	O
study	O
its	O
immunogenicity	O
,	O
which	O
was	O
evaluated	O
at	O
2	O
,	O
7	O
,	O
and	O
12	O
months	O
after	O
the	O
first	O
dose	O
.	O

This	O
association	O
was	O
independently	O
significant	O
for	O
patients	O
treated	O
primarily	O
(	O
not	O
for	O
recurrence	O
)	O
.	O

CONCLUSION	O
:	O
Local	O
control	O
was	O
highest	O
with	O
Preop	O
in	O
patients	O
presenting	O
primarily	O
with	O
gross	O
disease	O
,	O
and	O
with	O
Postop	O
in	O
patients	O
presenting	O
primarily	O
following	O
gross	O
total	O
excision	O
.	O

Its	O
interaction	O
with	O
RFX5	B-GENE
and	O
RFXAP	B-GENE
is	O
essential	O
for	O
binding	O
of	O
the	O
RFX	B-GENE
complex	I-GENE
to	O
MHC	B-GENE
-	I-GENE
II	I-GENE
promoters	I-GENE
.	O

We	O
have	O
previously	O
mapped	O
the	O
defect	O
in	O
RIIIS	O
/	O
J	O
to	O
distal	O
mouse	O
Chr	O
11	O
,	O
distinct	O
from	O
the	O
Vwf	B-GENE
locus	I-GENE
on	O
Chr	O
6	O
.	O

These	O
data	O
may	O
also	O
aid	O
in	O
the	O
localization	O
of	O
other	O
disease	O
loci	O
mapped	O
to	O
this	O
region	O
,	O
including	O
the	O
gene	O
for	O
tricho	O
-	O
dento	O
-	O
osseous	O
syndrome	O
and	O
a	O
murine	O
locus	O
for	O
susceptibility	O
to	O
ozone	O
-	O
induced	O
acute	O
lung	O
injury	O
.	O

Copyright	O
1998	O
Academic	O
Press	O
.	O

An	O
open	O
reading	O
frame	O
encoding	O
a	O
protein	O
which	O
shows	O
significant	O
similarity	O
to	O
invertases	B-GENE
and	O
resolvases	B-GENE
was	O
located	O
immediately	O
upstream	O
of	O
the	O
Pac25I	B-GENE
R	B-GENE
-	I-GENE
M	I-GENE
operon	I-GENE
.	O

Identification	O
of	O
a	O
new	O
gene	O
in	O
the	O
streptococcal	O
plasmid	O
pLS1	O
:	O
the	O
rnaI	B-GENE
gene	I-GENE
.	O

Rather	O
,	O
usp	B-GENE
is	O
required	O
in	O
late	O
third	O
instar	O
larvae	O
for	O
appropriate	O
developmental	O
and	O
transcriptional	O
responses	O
to	O
the	O
ecdysone	O
pulse	O
that	O
triggers	O
puparium	O
formation	O
.	O

An	O
intact	O
neurovascular	O
supply	O
is	O
essential	O
for	O
the	O
viability	O
of	O
a	O
muscle	O
flap	O
.	O

BACKGROUND	O
:	O
Studies	O
in	O
lean	O
men	O
show	O
poor	O
regulation	O
of	O
energy	O
(	O
EB	O
)	O
and	O
fat	O
balance	O
(	O
FB	O
)	O
during	O
manipulation	O
of	O
dietary	O
ratios	O
of	O
fat	O
to	O
carbohydrate	O
.	O

Fatal	O
apneusis	O
was	O
observed	O
under	O
following	O
conditions	O
:	O
(	O
1	O
)	O
Persistent	O
apnea	O
was	O
produced	O
after	O
a	O
single	O
KA	O
microinjection	O
in	O
one	O
side	O
of	O
the	O
VRG	O
-	O
Apa	O
(	O
5	O
animals	O
)	O
.	O

A	O
comparative	O
analysis	O
of	O
the	O
reported	O
MOCT	O
-	O
associated	O
malignant	O
melanomas	O
emphasizes	O
the	O
singularity	O
of	O
our	O
case	O
in	O
the	O
amelanotic	O
character	O
of	O
the	O
melanoma	O
,	O
its	O
lymphotropism	O
and	O
the	O
coexistence	O
of	O
invasive	O
squamous	O
cell	O
carcinoma	O
.	O

These	O
results	O
indicate	O
that	O
HIV	O
-	O
1	O
Gag	B-GENE
sequences	I-GENE
can	O
influence	O
the	O
viral	B-GENE
PR	I-GENE
-	O
mediated	O
processing	O
of	O
the	O
MuLV	O
TM	B-GENE
Env	I-GENE
protein	I-GENE
p15	B-GENE
(	I-GENE
E	I-GENE
)	I-GENE
.	O

These	O
results	O
demonstrate	O
a	O
specific	O
association	O
of	O
SIV	O
and	O
HIV	B-GENE
-	I-GENE
2	I-GENE
nef	I-GENE
,	O
but	O
not	O
HIV	B-GENE
-	I-GENE
1	I-GENE
nef	I-GENE
,	O
with	O
TCRzeta	B-GENE
.	O

Competition	O
EMSA	O
established	O
that	O
constitutively	O
expressed	O
nuclear	O
proteins	O
bound	O
the	O
KCS	B-GENE
element	I-GENE
selectively	O
;	O
KCS	B-GENE
protein	I-GENE
binding	O
activity	O
correlated	O
with	O
promoter	O
activity	O
in	O
the	O
transient	O
transfection	O
reporter	O
assay	O
.	O

Mechanism	O
of	O
interferon	B-GENE
action	O
:	O
identification	O
of	O
essential	O
positions	O
within	O
the	O
novel	O
15	B-GENE
-	I-GENE
base	I-GENE
-	I-GENE
pair	I-GENE
KCS	I-GENE
element	I-GENE
required	O
for	O
transcriptional	O
activation	O
of	O
the	O
RNA	B-GENE
-	I-GENE
dependent	I-GENE
protein	I-GENE
kinase	I-GENE
pkr	I-GENE
gene	I-GENE
.	O

Expression	O
of	O
a	O
novel	O
murine	B-GENE
phospholipase	I-GENE
D	I-GENE
homolog	I-GENE
coincides	O
with	O
late	O
neuronal	O
development	O
in	O
the	O
forebrain	O
.	O

We	O
detected	O
no	O
effect	O
of	O
deleting	O
YCL024W	B-GENE
,	O
either	O
alone	O
or	O
in	O
combination	O
with	O
deletion	O
of	O
GIN4	B-GENE
.	O

Paralemmin	B-GENE
is	O
also	O
phosphorylated	O
,	O
and	O
its	O
mRNA	O
is	O
differentially	O
spliced	O
in	O
a	O
tissue	O
-	O
specific	O
and	O
developmentally	O
regulated	O
manner	O
.	O

The	O
deduced	O
amino	O
acid	O
sequence	O
of	O
CBP90	B-GENE
had	O
no	O
significant	O
similarity	O
to	O
any	O
other	O
protein	O
,	O
but	O
it	O
had	O
a	O
proline	O
-	O
rich	O
domain	O
at	O
the	O
C	O
-	O
terminal	O
region	O
.	O

The	O
effect	O
of	O
low	O
-	O
profile	O
serine	O
substitutions	O
in	O
the	O
V3	B-GENE
loop	O
of	O
HIV	O
-	O
1	O
gp120	B-GENE
IIIB	I-GENE
/	O
LAI	B-GENE
on	O
the	O
immunogenicity	O
of	O
the	O
envelope	B-GENE
protein	O
.	O

Transcription	O
start	O
site	O
mapping	O
identified	O
the	O
presence	O
of	O
an	O
aphidicolin	O
-	O
sensitive	O
late	O
transcript	O
arising	O
from	O
a	O
TAAG	O
motif	O
located	O
at	O
-	O
352	O
nucleotides	O
and	O
an	O
aphidicolin	O
-	O
insensitive	O
early	O
transcript	O
originating	O
from	O
a	O
TTGT	O
motif	O
located	O
35	O
nucleotides	O
downstream	O
to	O
a	O
TATA	O
box	O
at	O
-	O
312	O
nucleotides	O
,	O
with	O
respect	O
to	O
the	O
+	O
1	O
ATG	O
of	O
lef2	B-GENE
.	O

The	O
human	B-GENE
2	I-GENE
'	I-GENE
,	I-GENE
5	I-GENE
'	I-GENE
-	I-GENE
oligoadenylate	I-GENE
(	I-GENE
2	I-GENE
-	I-GENE
5A	I-GENE
)	I-GENE
synthetases	I-GENE
are	O
members	O
of	O
a	O
family	O
interferon	B-GENE
(	O
IFN	B-GENE
)	O
-	O
inducible	O
anti	B-GENE
-	I-GENE
viral	I-GENE
proteins	I-GENE
.	O

Our	O
findings	O
demonstrate	O
a	O
dose	O
-	O
dependent	O
blockade	O
of	O
the	O
mechanical	O
sensitivity	O
caused	O
by	O
a	O
mild	O
thermal	O
injury	O
by	O
both	O
GBP	O
and	O
IBG	O
.	O

These	O
striations	O
were	O
caused	O
by	O
contact	O
between	O
the	O
sharp	O
edge	O
of	O
the	O
upper	O
canine	O
and	O
the	O
P3	O
during	O
honing	O
(	O
canine	O
/	O
premolar	O
complex	O
)	O
.	O

Low	O
PbrO2	O
readings	O
,	O
however	O
,	O
could	O
be	O
caused	O
by	O
local	O
microhemorrhages	O
,	O
undetectable	O
on	O
CT	O
or	O
MRI	O
.	O

The	O
consequences	O
of	O
intensive	O
swine	O
production	O
on	O
the	O
environment	O
and	O
possible	O
solutions	O
by	O
means	O
of	O
nutrition	O
are	O
outlined	O
.	O

This	O
study	O
demonstrates	O
that	O
alteration	O
of	O
CDKN2	B-GENE
is	O
one	O
of	O
the	O
most	O
frequent	O
genetic	O
abnormalities	O
in	O
prostate	O
cancer	O
and	O
may	O
contribute	O
to	O
prostate	O
carcinogenesis	O
.	O

The	O
pharmacokinetic	O
parameters	O
which	O
helped	O
predict	O
these	O
toxicities	O
included	O
area	O
under	O
the	O
curve	O
and	O
peak	O
plasma	O
level	O
.	O

A	O
Chinese	O
(	O
HK	O
)	O
SF	O
-	O
36	O
survey	O
form	O
was	O
developed	O
by	O
an	O
iterative	O
translation	O
process	O
.	O

However	O
,	O
the	O
use	O
of	O
cyclosporin	O
A	O
is	O
associated	O
with	O
an	O
increased	O
prevalence	O
of	O
hypertension	O
in	O
kidney	O
transplant	O
recipients	O
.	O

PURPOSE	O
:	O
To	O
determine	O
the	O
effects	O
of	O
hypercholesterolemia	O
and	O
atherosclerosis	O
-	O
induced	O
chronic	O
cavernosal	O
arterial	O
insufficiency	O
on	O
cavernosal	O
smooth	O
muscle	O
tone	O
,	O
nitric	B-GENE
oxide	I-GENE
synthase	I-GENE
(	O
NOS	B-GENE
)	O
activity	O
and	O
cavernosal	O
tissue	O
synthesis	O
of	O
constrictor	O
eicosanoids	O
.	O

Characterization	O
of	O
the	O
regulatory	O
regions	O
of	O
the	O
human	B-GENE
aromatase	I-GENE
(	O
P450arom	B-GENE
)	O
gene	O
involved	O
in	O
placenta	O
-	O
specific	O
expression	O
.	O

Recombinant	B-GENE
FVIIa	I-GENE
was	O
stable	O
in	O
the	O
infusion	O
pump	O
for	O
several	O
days	O
at	O
room	O
temperature	O
and	O
for	O
24	O
h	O
at	O
body	O
temperature	O
.	O

(	O
1992	O
)	O
Biochemistry	O
31	O
,	O
3351	O
-	O
3358	O
]	O
.	O

Levels	O
of	O
serum	O
IgE	B-GENE
were	O
measured	O
monthly	O
,	O
and	O
nasal	O
IgE	B-GENE
was	O
measured	O
at	O
the	O
height	O
and	O
end	O
of	O
the	O
season	O
.	O

A	O
mutation	O
in	O
the	O
5	O
'	O
C2U4	O
repeat	O
causes	O
underaccumulation	O
of	O
snR13F	B-GENE
,	O
whereas	O
mutations	O
in	O
the	O
3	O
'	O
C2U4	O
repeat	O
cause	O
the	O
accumulation	O
of	O
two	O
novel	O
RNAs	O
that	O
migrate	O
in	O
the	O
500	O
-	O
nt	O
range	O
.	O

By	O
directly	O
interacting	O
with	O
both	O
Arfs	B-GENE
and	O
tyrosine	B-GENE
kinases	I-GENE
involved	O
in	O
regulating	O
cell	O
growth	O
and	O
cytoskeletal	O
organization	O
,	O
ASAP1	B-GENE
could	O
coordinate	O
membrane	O
remodeling	O
events	O
with	O
these	O
processes	O
.	O

These	O
sorting	B-GENE
nexins	I-GENE
also	O
associated	O
with	O
the	O
long	O
isoform	O
of	O
the	O
leptin	B-GENE
receptor	I-GENE
but	O
not	O
with	O
the	O
short	O
and	O
medium	O
isoforms	O
.	O

Cyclophilins	B-GENE
are	O
cis	B-GENE
-	I-GENE
trans	I-GENE
-	I-GENE
peptidyl	I-GENE
-	I-GENE
prolyl	I-GENE
isomerases	I-GENE
that	O
bind	O
to	O
and	O
are	O
inhibited	O
by	O
the	O
immunosuppressant	O
cyclosporin	O
A	O
(	O
CsA	O
)	O
.	O

In	O
vitro	O
protein	O
retention	O
experiments	O
in	O
which	O
Hsp90	B-GENE
heterocomplexes	I-GENE
were	O
precipitated	O
resulted	O
in	O
coprecipitation	O
of	O
Cns1	B-GENE
.	O

The	O
Ras	B-GENE
-	I-GENE
related	I-GENE
GTPases	I-GENE
are	O
small	O
,	O
20	O
-	O
to	O
25	O
-	O
kDa	O
proteins	O
which	O
cycle	O
between	O
an	O
inactive	O
GDP	O
-	O
bound	O
form	O
and	O
an	O
active	O
GTP	O
-	O
bound	O
state	O
.	O

To	O
modulate	O
transcription	O
,	O
regulatory	O
factors	O
communicate	O
with	O
basal	O
transcription	O
factors	O
and	O
/	O
or	O
RNA	B-GENE
polymerases	I-GENE
in	O
a	O
variety	O
of	O
ways	O
.	O

Endogenous	O
RMP	B-GENE
was	O
immunologically	O
detected	O
interacting	O
with	O
assembled	O
RPB5	B-GENE
in	O
RNA	B-GENE
polymerase	I-GENE
in	O
mammalian	O
cells	O
.	O

In	O
this	O
study	O
,	O
rabbits	O
were	O
used	O
to	O
evaluate	O
the	O
sutured	O
wound	O
reaction	O
with	O
Dexon	O
or	O
nylon	O
in	O
the	O
conjunctival	O
flap	O
1	O
,	O
4	O
,	O
7	O
,	O
14	O
and	O
28	O
days	O
after	O
trabeculectomy	O
surgery	O
with	O
or	O
without	O
the	O
use	O
of	O
mitomycin	O
-	O
C	O
.	O

The	O
mapping	O
was	O
completed	O
with	O
Southern	O
blotting	O
and	O
restriction	O
analysis	O
.	O

The	O
zona	O
pellucida	O
(	O
ZP	O
)	O
,	O
the	O
extracellular	O
glycocalyx	O
that	O
surrounds	O
the	O
oocyte	O
,	O
is	O
well	O
known	O
to	O
mediate	O
homologous	O
gamete	O
interaction	O
.	O

Therapeutic	O
use	O
of	O
continuous	O
subcutaneous	O
infusion	O
of	O
recombinant	B-GENE
human	I-GENE
erythropoietin	I-GENE
in	O
malnourished	O
predialysis	O
anemic	O
patients	O
with	O
diabetic	O
nephropathy	O
.	O

Although	O
pathological	O
thyroid	O
function	O
is	O
related	O
to	O
changes	O
in	O
energy	O
expenditure	O
and	O
body	O
composition	O
,	O
its	O
possible	O
influence	O
on	O
leptin	B-GENE
levels	O
remains	O
to	O
be	O
determined	O
.	O

These	O
cognitive	O
deficits	O
were	O
prevented	O
in	O
animals	O
treated	O
with	O
MK	O
-	O
801	O
during	O
SE	O
.	O

Here	O
we	O
demonstrate	O
that	O
the	O
mechanism	O
of	O
activation	O
of	O
HIF	B-GENE
-	I-GENE
1alpha	I-GENE
is	O
a	O
multi	O
-	O
step	O
process	O
which	O
includes	O
hypoxia	O
-	O
dependent	O
nuclear	O
import	O
and	O
activation	O
(	O
derepression	O
)	O
of	O
the	O
transactivation	O
domain	O
,	O
resulting	O
in	O
recruitment	O
of	O
the	O
CREB	B-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
(	O
CBP	B-GENE
)	O
/	O
p300	B-GENE
coactivator	I-GENE
.	O

Thus	O
,	O
hypoxia	O
-	O
inducible	O
nuclear	O
import	O
and	O
transactivation	O
by	O
recruitment	O
of	O
CBP	B-GENE
can	O
be	O
functionally	O
separated	O
from	O
one	O
another	O
and	O
play	O
critical	O
roles	O
in	O
signal	O
transduction	O
by	O
HIF	B-GENE
-	I-GENE
1alpha	I-GENE
.	O

The	O
rat	B-GENE
aldolase	I-GENE
C	I-GENE
gene	I-GENE
encodes	O
a	O
glycolytic	O
enzyme	O
strongly	O
expressed	O
in	O
adult	O
brain	O
.	O

A	O
synergistic	O
effect	O
on	O
HCK	B-GENE
promoter	I-GENE
activity	O
was	O
observed	O
at	O
high	O
concentrations	O
of	O
Sp1	B-GENE
.	O

Quinone	O
-	O
binding	O
domain	O
and	O
amino	O
acid	O
residues	O
involved	O
in	O
quinone	O
binding	O
.	O

Western	O
analyses	O
with	O
antisera	O
raised	O
against	O
Lu	B-GENE
-	I-GENE
ECAM	I-GENE
-	I-GENE
1	I-GENE
peptides	I-GENE
show	O
that	O
the	O
N	O
-	O
terminal	O
region	O
of	O
the	O
predicted	O
open	O
reading	O
frame	O
is	O
present	O
only	O
in	O
the	O
larger	O
size	O
proteins	O
(	O
i	O
.	O
e	O
.	O

Mammalian	O
sperm	O
motility	O
is	O
regulated	O
by	O
a	O
cascade	O
of	O
cAMP	O
-	O
dependent	O
protein	O
phosphorylation	O
events	O
mediated	O
by	O
protein	B-GENE
kinase	I-GENE
A	I-GENE
.	O

In	O
this	O
paper	O
,	O
we	O
show	O
that	O
,	O
like	O
BAP2	B-GENE
,	O
the	O
expression	O
of	O
the	O
BAP3	B-GENE
gene	I-GENE
in	O
S	O
.	O
cerevisiae	O
is	O
induced	O
by	O
the	O
addition	O
of	O
branched	O
-	O
chain	O
amino	O
acids	O
to	O
the	O
medium	O
.	O

Effect	O
of	O
enteral	O
nutritional	O
products	O
differing	O
in	O
carbohydrate	O
and	O
fat	O
on	O
indices	O
of	O
carbohydrate	O
and	O
lipid	O
metabolism	O
in	O
patients	O
with	O
NIDDM	O
.	O

Low	O
-	O
grade	O
gastric	O
MALT	O
lymphoma	O
and	O
helicobacter	O
heilmannii	O
(	O
Gastrospirillum	O
hominis	O

These	O
studies	O
support	O
the	O
view	O
that	O
HMG	B-GENE
I	I-GENE
(	I-GENE
Y	I-GENE
)	I-GENE
is	O
an	O
important	O
cofactor	O
for	O
HLA	B-GENE
-	I-GENE
DRA	I-GENE
gene	I-GENE
activation	O
by	O
Oct	B-GENE
-	I-GENE
2A	I-GENE
and	O
provide	O
insights	O
into	O
its	O
mechanism	O
of	O
action	O
.	O

In	O
contrast	O
to	O
hemodynamic	O
and	O
histopathological	O
predictors	O
of	O
survival	O
,	O
vWF	B-GENE
:	O
Ag	O
does	O
not	O
require	O
invasive	O
techniques	O
to	O
be	O
determined	O
.	O

CONCLUSION	O
:	O
We	O
were	O
unable	O
to	O
identify	O
features	O
of	O
disease	O
likely	O
to	O
be	O
associated	O
with	O
a	O
clinically	O
useful	O
response	O
to	O
inhaled	O
NO	O
therapy	O
using	O
the	O
parameters	O
studied	O
.	O

We	O
find	O
that	O
BCL	B-GENE
-	I-GENE
6	I-GENE
POZ	O
domain	O
mutations	O
that	O
disrupt	O
the	O
interaction	O
with	O
N	B-GENE
-	I-GENE
CoR	I-GENE
and	O
SMRT	B-GENE
no	O
longer	O
repress	O
transcription	O
.	O

Partial	O
characterization	O
of	O
the	O
active	O
site	O
human	B-GENE
platelet	I-GENE
cAMP	I-GENE
phosphodiesterase	I-GENE
,	O
PDE3A	B-GENE
,	O
by	O
site	O
-	O
directed	O
mutagenesis	O
.	O

This	O
core	O
sequence	O
,	O
along	O
with	O
additional	O
nonspecific	O
downstream	O
nucleotides	O
,	O
is	O
sufficient	O
for	O
partial	O
suppression	O
of	O
spliceosome	O
assembly	O
and	O
splicing	O
of	O
BPV	O
-	O
1	O
pre	O
-	O
mRNAs	O
.	O

Over	O
-	O
expression	O
of	O
the	O
cofactor	O
p300	B-GENE
,	O
which	O
functions	O
as	O
a	O
coactivator	O
of	O
myoD	B-GENE
-	O
mediated	O
transcription	O
,	O
alleviated	O
repression	O
by	O
COUP	B-GENE
-	I-GENE
TF	I-GENE
II	I-GENE
.	O

Familial	O
autoimmune	O
hepatitis	O
and	O
C4	B-GENE
deficiency	O

Since	O
glutathione	B-GENE
peroxidase	I-GENE
(	O
GPX	B-GENE
)	O
and	O
superoxide	B-GENE
dismutase	I-GENE
(	O
SOD	B-GENE
)	O
play	O
a	O
significant	O
role	O
in	O
erythrocyte	O
antioxidative	O
defence	O
,	O
it	O
is	O
very	O
important	O
to	O
determine	O
their	O
activity	O
in	O
occupationally	O
exposed	O
workers	O
.	O

Retroviral	B-GENE
nucleocapsid	I-GENE
proteins	I-GENE
(	O
NCPs	B-GENE
)	O
are	O
CCHC	B-GENE
-	I-GENE
type	I-GENE
zinc	I-GENE
finger	I-GENE
proteins	I-GENE
that	O
mediate	O
virion	O
RNA	O
binding	O
activities	O
associated	O
with	O
retrovirus	O
assembly	O
and	O
genomic	O
RNA	O
encapsidation	O
.	O

The	O
Schizosaccharomyces	B-GENE
pombe	I-GENE
rad1	I-GENE
+	I-GENE
cell	I-GENE
cycle	I-GENE
checkpoint	I-GENE
control	I-GENE
gene	I-GENE
is	O
required	O
for	O
S	O
-	O
phase	O
and	O
G2	O
/	O
M	O
arrest	O
in	O
response	O
to	O
both	O
DNA	O
damage	O
and	O
incomplete	O
DNA	O
replication	O
.	O

It	O
is	O
now	O
well	O
established	O
that	O
progression	O
through	O
the	O
eukaryotic	O
cell	O
cycle	O
is	O
controlled	O
by	O
oscillations	O
in	O
the	O
activity	O
of	O
cyclin	B-GENE
-	I-GENE
dependent	I-GENE
kinases	I-GENE
(	O
CDKs	B-GENE
)	O
.	O

Positive	O
genetic	O
selections	O
for	O
inhibition	O
of	O
cyclin	B-GENE
/	O
CDK	B-GENE
function	O
were	O
characterized	O
using	O
the	O
E	B-GENE
.	I-GENE
coli	I-GENE
neo	I-GENE
and	O
yeast	B-GENE
LEU2	I-GENE
genes	I-GENE
.	O

The	O
hematopoietic	B-GENE
colony	I-GENE
-	I-GENE
stimulating	I-GENE
factors	I-GENE
(	O
CSF	B-GENE
)	O
have	O
been	O
introduced	O
into	O
clinical	O
practice	O
as	O
additional	O
supportive	O
measures	O
that	O
can	O
reduce	O
the	O
incidence	O
of	O
infectious	O
complications	O
in	O
patients	O
with	O
cancer	O
and	O
neutropenia	O
.	O

All	O
injections	O
of	O
CSF	B-GENE
were	O
given	O
after	O
the	O
initiation	O
of	O
neutropenia	O
and	O
continued	O
until	O
the	O
occurrence	O
of	O
an	O
absolute	O
neutrophil	O
recovery	O
.	O
rHu	B-GENE
GM	I-GENE
-	I-GENE
CSF	I-GENE
and	O
rHu	B-GENE
G	I-GENE
-	I-GENE
CSF	I-GENE
,	O
administered	O
once	O
daily	O
at	O
the	O
250	O
microg	O
m	O
(	O
-	O
2	O
)	O
day	O
(	O
-	O
1	O
)	O
and	O
5	O
microg	O
kg	O
(	O
-	O
1	O
)	O
day	O
(	O
-	O
1	O
)	O
level	O
,	O
were	O
effective	O
in	O
increasing	O
the	O
absolute	O
neutrophil	O
count	O
and	O
neutrophil	O
function	O
,	O
as	O
measured	O
by	O
an	O
automated	O
chemiluminescence	O
system	O
.	O

We	O
evaluated	O
regional	O
right	O
ventricular	O
wall	O
motion	O
during	O
systole	O
in	O
patients	O
with	O
surgically	O
repaired	O
tetralogy	O
of	O
Fallot	O
(	O
TOF	O
)	O
using	O
color	O
kinesis	O
imaging	O
.	O

Interestingly	O
,	O
we	O
find	O
that	O
the	O
interaction	O
between	O
Tat	B-GENE
and	O
hCycT1	B-GENE
requires	O
zinc	O
as	O
well	O
as	O
essential	O
cysteine	O
residues	O
in	O
both	O
proteins	O
.	O

During	O
early	O
neurogenesis	O
,	O
Vnd	B-GENE
protein	I-GENE
is	O
restricted	O
to	O
ventral	O
column	O
neuroectoderm	O
and	O
neuroblasts	O
;	O
later	O
it	O
is	O
detected	O
in	O
a	O
complex	O
pattern	O
of	O
neurons	O
.	O

The	O
repression	O
domain	O
,	O
and	O
indeed	O
the	O
entire	O
Cdc68	B-GENE
protein	I-GENE
,	O
is	O
highly	O
conserved	O
,	O
as	O
shown	O
by	O
the	O
sequence	O
of	O
the	O
Cdc68	B-GENE
functional	I-GENE
homolog	I-GENE
from	O
the	O
yeast	O
Kluyveromyces	O
lactis	O
and	O
by	O
database	O
searches	O
.	O

The	O
exodomain	O
alone	O
has	O
the	O
high	O
affinity	O
hormone	O
binding	O
site	O
but	O
is	O
not	O
capable	O
of	O
generating	O
hormonal	O
signal	O
.	O

Pyrrolidine	O
dithiocarbamate	O
,	O
a	O
potent	O
transcriptional	O
inhibitor	O
of	O
the	O
viral	B-GENE
LTR	I-GENE
,	O
abrogated	O
the	O
cytokine	O
responses	O
in	O
both	O
U1	O
and	O
ACH	O
-	O
2	O
cells	O
,	O
suggesting	O
a	O
common	O
TNF	B-GENE
-	I-GENE
alpha	I-GENE
-	O
mediated	O
transcriptional	O
mechanism	O
in	O
these	O
cell	O
types	O
despite	O
their	O
different	O
modes	O
of	O
provirus	O
latency	O
.	O

Furthermore	O
,	O
synergistic	O
activation	O
of	O
ERK2	B-GENE
occurred	O
in	O
the	O
absence	O
of	O
changes	O
in	O
intracellular	O
Ca2	O
+	O
,	O
and	O
was	O
not	O
blocked	O
by	O
inhibition	O
of	O
protein	B-GENE
kinase	I-GENE
C	I-GENE
activity	O
and	O
represents	O
a	O
separate	O
pathway	O
by	O
which	O
CD19	B-GENE
regulates	O
B	O
cell	O
function	O
.	O

The	O
retrovesical	O
hydatid	O
cyst	O
is	O
a	O
very	O
rare	O
site	O
.	O

Biochemical	O
analysis	O
reveals	O
that	O
KS1	B-GENE
is	O
a	O
nuclear	O
protein	O
containing	O
two	O
transcriptional	O
repressor	O
domains	O
,	O
R1	O
and	O
R2	O
.	O

However	O
,	O
the	O
BCH	O
group	O
showed	O
inferior	O
gross	O
motor	O
performance	O
on	O
the	O
Bruininks	O
-	O
Oseretsky	O
Test	O
of	O
Motor	O
Proficiency	O
(	O
Bruininks	O
1978	O
)	O
.	O

We	O
report	O
here	O
that	O
,	O
for	O
a	O
constant	O
amount	O
of	O
transfected	O
DNA	O
,	O
the	O
level	O
of	O
chloramphenicol	B-GENE
acetyltransferase	I-GENE
(	O
CAT	B-GENE
)	O
mRNA	O
is	O
increased	O
in	O
Vpr	B-GENE
-	O
expressing	O
cells	O
using	O
either	O
HIV	O
-	O
1	O
or	O
a	O
murine	O
leukemia	B-GENE
virus	I-GENE
(	I-GENE
MLV	I-GENE
)	I-GENE
SL3	I-GENE
-	I-GENE
3	I-GENE
LTR	I-GENE
-	O
CAT	B-GENE
reporter	O
construct	O
.	O

We	O
identified	O
telSMN	B-GENE
mutations	O
in	O
11	O
of	O
these	O
unrelated	O
SMA	O
-	O
like	O
individuals	O
who	O
carry	O
a	O
single	O
copy	O
of	O
telSMN	B-GENE
:	O
these	O
include	O
two	O
frameshift	O
mutations	O
(	O
800ins11	O
and	O
542delGT	O
)	O
and	O
three	O
missense	O
mutations	O
(	O
A2G	O
,	O
S262I	O
,	O
and	O
T274I	O
)	O
.	O

The	O
decrease	O
of	O
TNF	B-GENE
receptors	I-GENE
by	O
IL	B-GENE
-	I-GENE
4	I-GENE
was	O
accompanied	O
by	O
down	O
-	O
regulation	O
of	O
TNF	B-GENE
-	O
induced	O
activities	O
,	O
including	O
cytotoxicity	O
,	O
caspase	B-GENE
-	I-GENE
3	I-GENE
activation	O
,	O
NF	B-GENE
-	I-GENE
kappaB	I-GENE
and	O
AP	B-GENE
-	I-GENE
1	I-GENE
activation	O
,	O
and	O
c	B-GENE
-	I-GENE
Jun	I-GENE
N	I-GENE
-	I-GENE
terminal	I-GENE
kinase	I-GENE
induction	O
.	O

Type	B-GENE
2	I-GENE
deiodinase	I-GENE
(	O
D2	B-GENE
)	O
catalyzes	O
the	O
5	O
'	O
-	O
deiodination	O
of	O
thyroxine	O
to	O
form	O
3	O
,	O
5	O
,	O
3	O
'	O
-	O
triiodothyronine	O
.	O

We	O
have	O
identified	O
two	O
overlapping	O
expressed	O
sequence	O
tag	O
clones	O
,	O
which	O
contain	O
the	O
missing	O
4	O
.	O
4	O
-	O
kb	O
3	O
'	O
-	O
UTR	O
of	O
the	O
human	B-GENE
D2	I-GENE
(	O
hD2	B-GENE
)	O
cDNA	O
.	O

Biol	O
.	O

Here	O
we	O
have	O
investigated	O
the	O
structural	O
requirements	O
and	O
consequences	O
of	O
regulatory	O
phosphorylation	O
for	O
the	O
interaction	O
between	O
c	B-GENE
-	I-GENE
Jun	I-GENE
and	O
JNK	B-GENE
in	O
vivo	O
.	O

Immunolocalization	O
of	O
Sop1p	B-GENE
revealed	O
a	O
cytoplasmic	O
distribution	O
and	O
cell	O
fractionation	O
studies	O
showed	O
that	O
a	O
significant	O
fraction	O
of	O
Sop1p	B-GENE
was	O
recovered	O
in	O
a	O
sedimentable	O
fraction	O
of	O
the	O
cytosolic	O
material	O
.	O

Resultant	O
activation	O
of	O
c	B-GENE
-	I-GENE
Jun	I-GENE
N	I-GENE
-	I-GENE
terminal	I-GENE
kinase	I-GENE
/	O
stress	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
kinase	I-GENE
(	O
JNK	B-GENE
/	O
SAPK	B-GENE
)	O
.	O

Here	O
we	O
report	O
the	O
full	O
-	O
length	O
coding	O
cDNA	O
sequence	O
of	O
the	O
mouse	B-GENE
homologue	I-GENE
of	I-GENE
MPP3	I-GENE
.	O

The	O
method	O
also	O
eliminates	O
tagging	O
of	O
venous	O
spins	O
and	O
concern	O
about	O
asymmetric	O
magnetization	O
transfer	O
effects	O
.	O

Consistent	O
with	O
this	O
,	O
purified	O
Dlk	B-GENE
phosphorylated	O
core	O
histones	B-GENE
H3	I-GENE
,	O
H2A	B-GENE
and	O
H4	B-GENE
as	O
exogenous	O
substrates	O
and	O
endogenous	O
histone	B-GENE
H3	I-GENE
in	O
kinase	O
assays	O
with	O
nuclear	O
extracts	O
.	O

Neither	O
Ha	B-GENE
-	I-GENE
Ras	I-GENE
(	O
G12V	O
,	O
T35S	O
)	O
(	O
Ha	B-GENE
-	I-GENE
RasV12S35	I-GENE
)	O
,	O
which	O
activates	O
the	O
Rafl	B-GENE
signaling	O
pathway	O
,	O
nor	O
Ha	B-GENE
-	I-GENE
Ras	I-GENE
(	I-GENE
G12V	I-GENE
,	I-GENE
E37G	I-GENE
)	I-GENE
(	O
Ha	B-GENE
-	I-GENE
RasV12G37	I-GENE
)	O
,	O
which	O
stimulates	O
the	O
RalGDS	B-GENE
pathway	O
,	O
did	O
not	O
have	O
significant	O
effects	O
on	O
factor	O
-	O
withdrawal	O
apoptosis	O
of	O
myeloid	O
cells	O
.	O

We	O
have	O
isolated	O
a	O
novel	O
human	B-GENE
cyclin	I-GENE
,	O
cyclin	B-GENE
E2	I-GENE
,	O
that	O
contains	O
significant	O
homology	O
to	O
cyclin	B-GENE
E	I-GENE
.	O

Initial	O
experience	O
with	O
the	O
new	O
technology	O
indicates	O
that	O
SieScape	O
is	O
an	O
alternative	O
to	O
other	O
methods	O
such	O
as	O
CT	O
and	O
MRI	O
.	O

The	O
dopamine	B-GENE
D4	I-GENE
receptor	I-GENE
as	O
well	O
as	O
many	O
other	O
catecholaminergic	B-GENE
receptors	I-GENE
contain	O
several	O
putative	O
SH3	B-GENE
binding	I-GENE
domains	I-GENE
.	O

Schizosaccharomyces	O
pombe	O
cells	O
respond	O
to	O
nutrient	O
deprivation	O
by	O
altering	O
G2	O
/	O
M	O
cell	O
size	O
control	O
.	O

A	O
-	O
tracts	O
functioned	O
best	O
when	O
positioned	O
close	O
to	O
the	O
-	O
35	O
hexamer	O
rather	O
than	O
one	O
helical	O
turn	O
farther	O
upstream	O
,	O
similar	O
to	O
the	O
positioning	O
optimal	O
for	O
UP	O
element	O
function	O
.	O

Pyk2	B-GENE
phosphorylation	O
increased	O
upon	O
adherence	O
of	O
FLG	O
29	O
.	O
1	O
cells	O
to	O
fibronectin	B-GENE
and	O
to	O
ST2	O
stromal	O
cells	O
.	O

Raf	B-GENE
is	O
a	O
key	O
serine	B-GENE
-	I-GENE
threonine	I-GENE
protein	I-GENE
kinase	I-GENE
which	O
participates	O
in	O
the	O
transmission	O
of	O
growth	O
,	O
anti	O
-	O
apoptotic	O
and	O
differentiation	O
messages	O
.	O

The	O
US	O
National	O
Institute	O
on	O
Alcohol	O
Abuse	O
and	O
Alcoholism	O
(	O
NIAAA	O
)	O
recognizes	O
two	O
forms	O
of	O
problematic	O
drinking	O
:	O
'	O
willful	O
alcohol	O
abuse	O
'	O
,	O
a	O
behavioural	O
problem	O
,	O
and	O
'	O
alcohol	O
dependence	O
'	O
,	O
a	O
true	O
medical	O
disorder	O
,	O
which	O
includes	O
a	O
genetic	O
component	O
,	O
that	O
can	O
be	O
scientifically	O
understood	O
and	O
medically	O
treated	O
.	O

Collagen	B-GENE
was	O
extracted	O
from	O
the	O
skin	O
,	O
and	O
the	O
lack	O
of	O
type	B-GENE
III	I-GENE
collagen	I-GENE
was	O
determined	O
by	O
means	O
of	O
sodium	O
dodecyl	O
sulfate	O
-	O
polyacrylamide	O
gel	O
electrophoresis	O
(	O
SDS	O
-	O
PAGE	O
)	O
.	O

RESULTS	O
:	O
During	O
the	O
7	O
-	O
year	O
period	O
,	O
10	O
,	O
331	O
symptomatic	O
duodenal	O
ulcer	O
diseases	O
were	O
diagnosed	O
.	O

In	O
turn	O
,	O
assembly	O
of	O
this	O
complex	O
mediates	O
the	O
enzymatic	O
activation	O
of	O
the	O
p21	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
kinase	I-GENE
1	I-GENE
and	O
facilitates	O
actin	B-GENE
polymerization	O
.	O

Jembrana	O
disease	O
virus	O
(	O
JDV	O
)	O
is	O
a	O
newly	O
identified	O
bovine	O
lentivirus	O
that	O
is	O
closely	O
related	O
to	O
the	O
bovine	O
immunodeficiency	O
virus	O
(	O
BIV	O
)	O
.	O

Approximately	O
50	O
%	O
of	O
the	O
residues	O
are	O
conserved	O
among	O
all	O
three	O
sequences	O
,	O
yet	O
all	O
three	O
viruses	O
have	O
retained	O
response	O
elements	O
for	O
glucocorticoids	O
,	O
two	O
positionally	O
conserved	O
CCAAT	O
boxes	O
,	O
and	O
positionally	O
conserved	O
TATA	O
boxes	O
.	O

Nhp2p	B-GENE
is	O
a	O
highly	O
basic	O
protein	O
that	O
belongs	O
to	O
a	O
family	O
of	O
putative	O
RNA	O
-	O
binding	O
proteins	O
.	O

This	O
survey	O
included	O
3000	O
randomly	O
selected	O
Norwegians	O
above	O
18	O
years	O
of	O
age	O
who	O
received	O
the	O
European	O
Organization	O
for	O
Research	O
and	O
Treatment	O
of	O
Cancer	O
Core	O
Quality	O
of	O
Life	O
Questionnaire	O
(	O
EORTC	O
QLQ	O
-	O
C30	O
(	O
+	O
3	O
)	O
by	O
mail	O
.	O

During	O
presentation	O
of	O
happy	O
facial	O
expressions	O
,	O
we	O
detected	O
a	O
signal	O
increase	O
predominantly	O
in	O
the	O
left	O
anterior	O
cingulate	O
gyrus	O
,	O
bilateral	O
posterior	O
cingulate	O
gyri	O
,	O
medial	O
frontal	O
cortex	O
and	O
right	O
supramarginal	O
gyrus	O
,	O
brain	O
regions	O
previously	O
implicated	O
in	O
visuospatial	O
and	O
emotion	O
processing	O
tasks	O
.	O

Down	O
-	O
regulation	O
of	O
IRS	B-GENE
-	I-GENE
1	I-GENE
is	O
linked	O
to	O
its	O
serine	O
phosphorylation	O
dependent	O
on	O
PI	B-GENE
3	I-GENE
-	I-GENE
kinase	I-GENE
activity	O
and	O
appears	O
required	O
for	O
differentiation	O
to	O
occur	O
,	O
as	O
IRS	B-GENE
-	I-GENE
1	I-GENE
is	O
not	O
modified	O
and	O
continues	O
to	O
accumulate	O
in	O
a	O
nondifferentiating	O
myoblast	O
cell	O
line	O
.	O

This	O
study	O
utilizes	O
the	O
mammalian	O
two	O
-	O
hybrid	O
system	O
to	O
examine	O
the	O
role	O
of	O
ligand	O
in	O
the	O
dimerization	O
of	O
human	B-GENE
progesterone	I-GENE
receptor	I-GENE
(	O
hPR	B-GENE
)	O
.	O

One	O
of	O
its	O
unique	O
features	O
appears	O
to	O
be	O
the	O
unusually	O
short	O
5	O
'	O
-	O
untranslated	O
regions	O
(	O
UTR	O
)	O
(	O
1	O
-	O
6	O
nucleotides	O
(	O
nts	O
)	O
)	O
and	O
the	O
apparent	O
absence	O
of	O
5	O
'	O
-	O
cap	O
structures	O
from	O
its	O
mRNAs	O
.	O

The	O
gene	B-GENE
encoding	I-GENE
human	I-GENE
tissue	I-GENE
-	I-GENE
type	I-GENE
plasminogen	I-GENE
activator	I-GENE
(	O
t	B-GENE
-	I-GENE
PA	I-GENE
)	O
is	O
regulated	O
in	O
a	O
cell	O
-	O
type	O
-	O
specific	O
manner	O
.	O

Both	O
the	O
presence	O
of	O
arginine	O
and	O
anaerobiosis	O
are	O
needed	O
to	O
trigger	O
induction	O
of	O
the	O
pathway	O
.	O

Competition	O
with	O
a	O
putative	O
MADS	B-GENE
box	I-GENE
consensus	O
binding	O
site	O
from	O
the	O
promoter	O
of	O
the	O
coordinately	O
regulated	O
opaque	B-GENE
-	I-GENE
phase	I-GENE
-	I-GENE
specific	I-GENE
gene	I-GENE
PEP1	I-GENE
(	O
SAP1	B-GENE
)	O
and	O
the	O
human	B-GENE
MADS	I-GENE
box	I-GENE
consensus	I-GENE
binding	I-GENE
site	I-GENE
for	O
serum	B-GENE
response	I-GENE
factor	I-GENE
demonstrated	O
that	O
one	O
of	O
the	O
three	O
complexes	O
formed	O
was	O
specific	O
to	O
the	O
OP4	B-GENE
sequence	I-GENE
.	O

The	O
human	B-GENE
SHBG	I-GENE
proximal	I-GENE
promoter	I-GENE
was	O
analyzed	O
by	O
DNase	B-GENE
I	I-GENE
footprinting	O
,	O
and	O
the	O
functional	O
significance	O
of	O
6	O
footprinted	O
regions	O
(	O
FP1	O
-	O
FP6	O
)	O
within	O
the	O
proximal	O
promoter	O
was	O
studied	O
in	O
human	O
HepG2	O
hepatoblastoma	O
cells	O
.	O

In	O
vitro	O
translation	O
and	O
in	O
vivo	O
polysome	O
profile	O
analysis	O
indicated	O
that	O
transcripts	B-GENE
C	I-GENE
and	I-GENE
E	I-GENE
were	O
translated	O
with	O
similar	O
translational	O
efficiencies	O
that	O
are	O
substantially	O
greater	O
than	O
that	O
of	O
transcript	B-GENE
D	I-GENE
,	O
suggesting	O
that	O
5	O
'	O
-	O
untranslated	O
regions	O
play	O
a	O
role	O
in	O
translational	O
control	O
.	O

We	O
have	O
introduced	O
a	O
mutation	O
(	O
Ser36	O
-	O
-	O
>	O
Asn	O
)	O
into	O
this	O
domain	O
of	O
p190	B-GENE
that	O
decreased	O
its	O
ability	O
to	O
bind	O
guanine	O
nucleotide	O
when	O
expressed	O
as	O
a	O
hemagglutinin	B-GENE
(	O
HA	B-GENE
)	O
-	O
tagged	O
protein	O
in	O
COS	O
cells	O
.	O

Wild	O
type	O
HA	B-GENE
-	O
p190	B-GENE
induced	O
a	O
phenotype	O
of	O
rounded	O
cells	O
with	O
long	O
,	O
beaded	O
extensions	O
similar	O
to	O
that	O
seen	O
when	O
Rho	B-GENE
function	O
is	O
disrupted	O
by	O
ADP	O
-	O
ribosylation	O
.	O

We	O
emphasize	O
that	O
ANCA	B-GENE
-	O
associated	O
vasculitis	O
is	O
another	O
important	O
complication	O
of	O
RA	O
.	O

The	O
downstream	O
,	O
TATA	O
-	O
less	O
promoter	O
has	O
high	O
G	O
+	O
C	O
content	O
,	O
and	O
exon	O
1b	O
predominates	O
among	O
abundantly	O
expressed	O
mRNA	O
species	O
.	O

Although	O
we	O
predicted	O
that	O
overexpression	O
of	O
the	O
COOH	O
-	O
terminal	O
domains	O
,	O
which	O
were	O
thought	O
to	O
be	O
involved	O
in	O
the	O
regulation	O
of	O
SREBP	B-GENE
processing	O
,	O
would	O
result	O
in	O
disruption	O
of	O
the	O
SREBP	B-GENE
-	O
dependent	O
transcriptional	O
regulation	O
of	O
several	O
genes	O
,	O
the	O
mRNA	O
levels	O
for	O
3	B-GENE
-	I-GENE
hydroxy	I-GENE
-	I-GENE
3	I-GENE
-	I-GENE
methylglutaryl	I-GENE
coenzyme	I-GENE
A	I-GENE
(	I-GENE
HMG	I-GENE
CoA	I-GENE
)	I-GENE
synthase	I-GENE
in	O
these	O
two	O
cell	O
lines	O
were	O
regulated	O
in	O
a	O
sterol	O
-	O
dependent	O
manner	O
.	O

Dry	O
matter	O
intake	O
,	O
apparent	O
nutrient	O
digestibilities	O
,	O
serum	O
chemistry	O
profiles	O
,	O
sphingolipid	O
concentrations	O
,	O
and	O
persistency	O
of	O
FB1	O
in	O
tissues	O
were	O
evaluated	O
.	O

However	O
,	O
no	O
studies	O
have	O
been	O
conducted	O
to	O
further	O
investigate	O
this	O
potentially	O
hazardous	O
effect	O
of	O
lidocaine	O
.	O

E	O
.	O
,	O
Scott	O
,	O
J	O
.	O

Yap1p	B-GENE
is	O
constitutively	O
nuclear	O
in	O
a	O
crm1	B-GENE
mutant	I-GENE
,	O
and	O
Crm1p	B-GENE
binds	O
to	O
a	O
nuclear	O
export	O
sequence	O
(	O
NES	O
)	O
-	O
like	O
sequence	O
in	O
Yap1p	B-GENE
in	O
the	O
presence	O
of	O
RanGTP	B-GENE
.	O

Mean	O
intake	O
of	O
vitamin	O
A	O
amounted	O
to	O
1	O
.	O
1	O
and	O
0	O
.	O
9	O
mg	O
RE	O
/	O
day	O
for	O
men	O
and	O
women	O
,	O
respectively	O
;	O
the	O
contributions	O
of	O
meat	O
,	O
fats	O
and	O
oils	O
,	O
vegetables	O
and	O
dairy	O
products	O
to	O
total	O
intake	O
were	O
35	O
%	O
,	O
24	O
%	O
,	O
16	O
%	O
,	O
and	O
16	O
%	O
,	O
respectively	O
.	O

Furthermore	O
,	O
RING1	B-GENE
overexpression	O
results	O
in	O
enhanced	O
expression	O
of	O
the	O
proto	O
-	O
oncogenes	O
c	B-GENE
-	I-GENE
jun	I-GENE
and	O
c	B-GENE
-	I-GENE
fos	I-GENE
.	O

The	O
yeast	B-GENE
RER2	I-GENE
gene	I-GENE
,	O
identified	O
by	O
endoplasmic	O
reticulum	O
protein	O
localization	O
mutations	O
,	O
encodes	O
cis	B-GENE
-	I-GENE
prenyltransferase	I-GENE
,	O
a	O
key	O
enzyme	O
in	O
dolichol	O
synthesis	O
.	O

The	O
yeast	O
retrotransposon	B-GENE
Ty5	I-GENE
preferentially	O
integrates	O
into	O
regions	O
of	O
silent	O
chromatin	O
.	O

The	O
loss	O
of	O
SKO1	B-GENE
completely	O
restored	O
ENA1	B-GENE
expression	O
in	O
a	O
hog1	B-GENE
mutant	I-GENE
and	O
partially	O
suppressed	O
the	O
osmotic	O
stress	O
sensitivity	O
,	O
qualifying	O
Sko1p	B-GENE
as	O
a	O
downstream	O
effector	O
of	O
the	O
HOG	B-GENE
pathway	O
.	O

Elevated	O
expression	O
of	O
a	O
previously	O
uncharacterized	O
gene	O
,	O
SPP381	B-GENE
,	O
efficiently	O
suppresses	O
the	O
growth	O
and	O
splicing	O
defects	O
of	O
a	O
temperature	O
-	O
sensitive	O
(	O
Ts	O
)	O
mutant	B-GENE
prp38	I-GENE
-	I-GENE
1	I-GENE
.	O

The	O
slower	O
-	O
electrophoretic	O
-	O
mobility	O
form	O
of	O
p68	B-GENE
was	O
absent	O
in	O
human	O
cells	O
in	O
G1	O
/	O
S	O
and	O
appeared	O
as	O
the	O
cells	O
entered	O
G2	O
/	O
M	O
.	O

We	O
have	O
identified	O
amino	O
acid	O
sequences	O
in	O
mammalian	O
and	O
Xenopus	O
NeuroD1	B-GENE
/	O
BETA2	B-GENE
that	O
are	O
necessary	O
for	O
insulin	B-GENE
gene	I-GENE
expression	O
and	O
ectopic	O
neurogenesis	O
.	O

Recent	O
studies	O
have	O
suggested	O
that	O
Y319	O
also	O
positively	O
regulate	O
ZAP	B-GENE
-	I-GENE
70	I-GENE
function	O
.	O

Genetic	O
and	O
molecular	O
data	O
indicate	O
that	O
wild	B-GENE
-	I-GENE
type	I-GENE
Pan	I-GENE
and	O
CiD	B-GENE
compete	O
for	O
binding	O
to	O
Arm	B-GENE
,	O
leading	O
to	O
a	O
compromised	O
transduction	O
of	O
the	O
Wg	B-GENE
signal	O
in	O
heterozygous	O
ciD	B-GENE
/	I-GENE
+	I-GENE
animals	O
and	O
to	O
a	O
dramatic	O
enhancement	O
of	O
the	O
gain	O
-	O
of	O
-	O
function	O
activity	O
of	O
CiD	B-GENE
in	O
homozygous	O
mutants	O
.	O

Another	O
ORF	O
,	O
dda	B-GENE
.	I-GENE
2	I-GENE
located	O
between	O
modA	B-GENE
and	O
dda	B-GENE
,	O
shares	O
sequence	O
similarity	O
with	O
sigma70	B-GENE
,	O
and	O
we	O
call	O
it	O
srd	B-GENE
.	O

The	O
location	O
of	O
the	O
IBS	O
within	O
the	O
catB	B-GENE
structural	I-GENE
gene	I-GENE
,	O
the	O
cooperativity	O
observed	O
in	O
footprinting	O
studies	O
and	O
phasing	O
studies	O
suggest	O
that	O
the	O
IBS	O
participates	O
in	O
the	O
interaction	O
of	O
CatR	B-GENE
with	O
the	O
upstream	O
binding	O
sites	O
by	O
looping	O
out	O
the	O
intervening	O
DNA	O
.	O

In	O
vitro	O
transcription	O
assays	O
demonstrate	O
that	O
the	O
TCA	O
-	O
cycle	O
intermediate	O
,	O
fumarate	O
,	O
directly	O
and	O
specifically	O
inhibits	O
the	O
formation	O
of	O
the	O
clcA	B-GENE
transcript	I-GENE
.	O

BIAcore	O
analysis	O
gave	O
a	O
Kaff	O
of	O
4	O
.	O
4	O
x	O
10	O
(	O
10	O
)	O
M	O
-	O
1	O
for	O
the	O
binding	O
of	O
N	B-GENE
-	I-GENE
A3	I-GENE
to	O
T84	B-GENE
.	I-GENE
1	I-GENE
and	O
2	O
.	O
2	O
x	O
10	O
(	O
10	O
)	O
M	O
-	O
1	O
for	O
the	O
binding	O
of	O
N	B-GENE
-	I-GENE
A3	I-GENE
to	O
T84	B-GENE
.	I-GENE
66	I-GENE
.	O

Expression	O
of	O
p130	B-GENE
(	O
Cas	B-GENE
)	O
(	O
Cas	B-GENE
)	O
,	O
a	O
major	O
binding	O
protein	O
for	O
the	O
Crk	B-GENE
SH2	B-GENE
-	I-GENE
domain	I-GENE
,	O
also	O
induced	O
JNK	B-GENE
activation	O
,	O
which	O
was	O
blocked	O
by	O
the	O
SH2	B-GENE
-	I-GENE
mutant	I-GENE
of	O
Crk	B-GENE
.	O

Positive	O
correlations	O
were	O
seen	O
between	O
the	O
measurements	O
for	O
protein	O
intake	O
(	O
r	O
=	O
.	O
58	O
,	O
P	O
=	O
.	O
0026	O
)	O
energy	O
intake	O
(	O
r	O
=	O
.	O
78	O
,	O
P	O
<	O
.	O
00001	O
)	O
,	O
with	O
mean	O
differences	O
of	O
.	O
066	O
g	O
/	O
kg	O
/	O
d	O
(	O
SD	O
.	O
38	O
)	O
2	O
.	O
04	O
kcal	O
/	O
kg	O
/	O
day	O
(	O
SD	O
6	O
.	O
67	O
)	O
,	O
respectively	O
.	O

The	O
Og4C3	B-GENE
enzyme	O
-	O
linked	O
immunosorbent	O
assay	O
(	O
ELISA	O
)	O
to	O
detect	O
circulating	O
Wuchereria	B-GENE
bancrofti	I-GENE
antigen	I-GENE
uses	O
50	O
microL	O
of	O
serum	O
.	O

We	O
now	O
show	O
that	O
gp200	B-GENE
-	O
MR6	B-GENE
ligation	O
can	O
also	O
mimic	O
IL	B-GENE
-	I-GENE
4	I-GENE
and	O
have	O
an	O
anti	O
-	O
proliferative	O
pro	O
-	O
maturational	O
influence	O
within	O
the	O
immune	O
system	O
,	O
causing	O
up	O
-	O
regulation	O
of	O
co	O
-	O
stimulatory	O
molecules	O
on	O
B	O
lymphocytes	O
.	O

The	O
Mig1	B-GENE
repressor	I-GENE
is	O
a	O
zinc	B-GENE
finger	I-GENE
protein	I-GENE
that	O
mediates	O
glucose	O
repression	O
in	O
yeast	O
.	O

Recurrent	O
arterial	O
thrombotic	O
disease	O
on	O
young	O
onset	O
and	O
protein	B-GENE
S	I-GENE
deficiency	O
.	O

We	O
showed	O
that	O
Stat3	B-GENE
and	O
Stat3beta	B-GENE
were	O
affinity	O
purified	O
using	O
phosphopeptides	O
containing	O
Y704	O
and	O
Y744	O
but	O
not	O
by	O
nonphosphorylated	O
peptide	O
analogues	O
or	O
by	O
phosphopeptides	O
containing	O
Y729	O
and	O
Y764	O
.	O

Taken	O
together	O
,	O
our	O
results	O
indicate	O
that	O
the	O
FCR1	B-GENE
gene	I-GENE
behaves	O
as	O
a	O
negative	O
regulator	O
of	O
drug	O
resistance	O
in	O
C	O
.	O
albicans	O
and	O
constitute	O
the	O
first	O
evidence	O
that	O
FCZ	O
resistance	O
can	O
result	O
from	O
the	O
inactivation	O
of	O
a	O
regulatory	O
factor	O
such	O
as	O
Fcr1p	B-GENE
.	O

These	O
findings	O
suggest	O
that	O
late	O
MYO	O
/	O
M	O
is	O
more	O
useful	O
than	O
washout	O
rate	O
to	O
assess	O
the	O
effect	O
of	O
treatment	O
on	O
heart	O
failure	O
due	O
to	O
DCM	O
.	O

This	O
study	O
was	O
undertaken	O
to	O
evaluate	O
how	O
couplers	O
and	O
their	O
placement	O
affect	O
the	O
ALGO2	O
click	O
spectral	O
properties	O
.	O

CONCLUSIONS	O
:	O
Pretreatment	O
with	O
OCs	O
prior	O
to	O
pituitary	O
suppression	O
in	O
the	O
early	O
follicular	O
phase	O
decreases	O
ovarian	O
cyst	O
formation	O
,	O
without	O
an	O
apparent	O
effect	O
on	O
subsequent	O
follicular	O
recruitment	O
or	O
pregnancy	O
rates	O
.	O

With	O
regard	O
to	O
the	O
optimal	O
threshold	O
values	O
,	O
sensitivity	O
and	O
specificity	O
were	O
100	O
%	O
/	O
97	O
%	O
and	O
95	O
%	O
/	O
95	O
%	O
with	O
FDG	O
PET	O
,	O
compared	O
to	O
86	O
%	O
/	O
92	O
%	O
and	O
77	O
%	O
/	O
82	O
%	O
with	O
IS	O
,	O
respectively	O
.	O

Dorsal	O
root	O
ganglia	O
neuron	O
-	O
specific	O
promoter	O
activity	O
of	O
the	O
rabbit	B-GENE
beta	I-GENE
-	I-GENE
galactoside	I-GENE
alpha1	I-GENE
,	I-GENE
2	I-GENE
-	I-GENE
fucosyltransferase	I-GENE
gene	I-GENE
.	O

This	O
suggests	O
roles	O
for	O
both	O
the	O
CE1	O
and	O
CE2	O
elements	O
in	O
regulating	O
Hoxb1	B-GENE
gene	I-GENE
expression	O
during	O
development	O
.	O

CAL	O
gain	O
amounted	O
to	O
4	O
.	O
2	O
+	O
/	O
-	O
1	O
.	O
3	O
mm	O
,	O
60	O
%	O
of	O
the	O
defects	O
showing	O
CAL	O
gain	O
>	O
or	O
=	O
4	O
mm	O
.	O

Lead	O
fixation	O
in	O
dogs	O
achieved	O
with	O
RF	O
energy	O
.	O

Further	O
,	O
we	O
show	O
that	O
this	O
EIA	B-GENE
-	O
inducible	O
CBF	O
/	O
cdc2	B-GENE
is	O
related	O
to	O
the	O
CBF	B-GENE
which	O
was	O
shown	O
to	O
activate	O
the	O
heat	B-GENE
shock	I-GENE
protein	I-GENE
70	I-GENE
promoter	I-GENE
.	O

The	O
percutaneous	O
absorption	O
of	O
clindamycin	O
was	O
studied	O
in	O
healthy	O
male	O
volunteers	O
,	O
comparing	O
two	O
investigative	O
clindamycin	O
(	O
%	O
w	O
/	O
v	O
)	O
/	O
tretinoin	O
(	O
0	O
.	O
025	O
%	O
w	O
/	O
v	O
)	O
gels	O
,	O
containing	O
clindamycin	O
phosphate	O
ester	O
and	O
clindamycin	O
HCl	O
,	O
respectively	O
,	O
relative	O
to	O
a	O
clindamycin	O
phosphate	O
lotion	O
(	O
1	O
%	O
clindamycin	O
;	O
Dalacin	O
T	O
)	O
.	O

The	O
BAL	O
concentrations	O
of	O
the	O
nine	O
cytokines	O
evaluated	O
for	O
the	O
more	O
and	O
less	O
affected	O
lungs	O
were	O
compared	O
:	O
interleukin	B-GENE
-	I-GENE
6	I-GENE
(	O
IL	B-GENE
-	I-GENE
6	I-GENE
)	O
,	O
IL	B-GENE
-	I-GENE
8	I-GENE
,	O
IL	B-GENE
-	I-GENE
12	I-GENE
,	O
tumor	B-GENE
necrosis	I-GENE
factor	I-GENE
-	I-GENE
alpha	I-GENE
(	O
TNF	B-GENE
-	I-GENE
alpha	I-GENE
)	O
,	O
and	O
interferon	B-GENE
gamma	I-GENE
(	O
IFN	B-GENE
-	I-GENE
gamma	I-GENE
)	O
showed	O
significant	O
differences	O
(	O
p	O
ranged	O
between	O
0	O
.	O

Phosphorylation	O
analyses	O
indicated	O
that	O
inhibition	O
of	O
ERK	B-GENE
-	I-GENE
1	I-GENE
/	I-GENE
2	I-GENE
decreased	O
okadaic	O
acid	O
-	O
elevated	O
phosphorylation	O
of	O
JunD	B-GENE
and	O
FosB	B-GENE
.	O

Two	O
-	O
way	O
analysis	O
of	O
variance	O
was	O
used	O
to	O
determine	O
whether	O
composite	O
knowledge	O
score	O
differed	O
among	O
patient	O
groups	O
.	O

The	O
human	O
pathogenic	O
bacterium	O
group	O
A	O
Streptococcus	O
produces	O
an	O
extracellular	O
cysteine	B-GENE
protease	I-GENE
[	O
streptococcal	B-GENE
pyrogenic	I-GENE
exotoxin	I-GENE
B	I-GENE
(	O
SpeB	B-GENE
)	O
]	O
that	O
is	O
a	O
critical	O
virulence	O
factor	O
for	O
invasive	O
disease	O
episodes	O
.	O

The	O
orbitofrontal	O
,	O
cingulate	O
,	O
and	O
anteromedial	O
part	O
of	O
the	O
dorsal	O
premotor	O
areas	O
were	O
preferentially	O
activated	O
by	O
the	O
self	O
-	O
initiated	O
hand	O
movement	O
task	O
(	O
SELF	O
)	O
.	O

The	O
peroxisome	O
biogenesis	O
disorders	O
(	O
PBDs	O
)	O
are	O
a	O
set	O
of	O
lethal	O
genetic	O
diseases	O
characterized	O
by	O
peroxisomal	O
metabolic	O
deficiencies	O
,	O
multisystem	O
abnormalities	O
,	O
mental	O
retardation	O
,	O
and	O
premature	O
death	O
.	O

The	O
active	O
site	O
includes	O
the	O
acidic	O
triad	O
Asp53	O
(	O
the	O
site	O
of	O
phosphorylation	O
)	O
,	O
Asp10	O
and	O
Glu9	O
.	O

In	O
PAV	O
-	O
3	O
,	O
the	O
E1A	B-GENE
region	I-GENE
is	O
located	O
between	O
1	O
.	O
5	O
and	O
3	O
.	O
8	O
map	O
units	O
.	O

Six	O
putative	O
MDV	O
genome	O
products	O
,	O
including	O
one	O
Rep	B-GENE
and	O
five	O
non	O
-	O
Rep	B-GENE
proteins	O
,	O
show	O
high	O
(	O
70	O
.	O
4	O
-	O
90	O
.	O
9	O
%	O
)	O
amino	O
acid	O
identity	O
to	O
the	O
corresponding	O
six	O
FBNYV	B-GENE
proteins	I-GENE
,	O
whereas	O
two	O
other	O
Rep	B-GENE
proteins	I-GENE
encoded	O
by	O
MDV	B-GENE
-	I-GENE
C2	I-GENE
and	O
C3	B-GENE
are	O
82	O
.	O
3	O
%	O
and	O
73	O
.	O
0	O
%	O
identical	O
to	O
those	O
encoded	O
by	O
SCSV	B-GENE
-	I-GENE
C2	I-GENE
and	O
C6	B-GENE
,	O
respectively	O
.	O

MPO	B-GENE
was	O
labeled	O
with	O
1	O
mCi	O
125I	O
by	O
a	O
technique	O
of	O
self	O
-	O
labeling	O
in	O
the	O
presence	O
of	O
10	O
(	O
-	O
4	O
)	O
M	O
hydrogen	O
peroxide	O
.	O

It	O
is	O
related	O
to	O
a	O
variety	O
of	O
mammalian	O
Golgi	O
-	O
associated	O
proteins	O
and	O
to	O
the	O
yeast	O
Uso1p	B-GENE
,	O
an	O
essential	O
protein	O
involved	O
in	O
docking	O
of	O
endoplasmic	O
reticulum	O
-	O
derived	O
vesicles	O
to	O
the	O
cis	O
-	O
Golgi	O
.	O

The	O
data	O
indicate	O
that	O
Bmp2	B-GENE
is	O
directly	O
regulated	O
by	O
retinoic	O
acid	O
-	O
bound	O
receptors	O
and	O
Sp1	B-GENE
.	O

Both	O
proteins	O
were	O
shown	O
to	O
be	O
constitutively	O
associated	O
with	O
tubulin	B-GENE
.	O

HEED	B-GENE
was	O
found	O
to	O
bind	O
to	O
MA	B-GENE
protein	I-GENE
in	O
vitro	O
,	O
as	O
efficiently	O
as	O
in	O
vivo	O
in	O
yeast	O
cells	O
.	O

Fas	B-GENE
-	O
resistant	O
DT	O
-	O
40	O
lymphoma	O
B	O
-	O
cells	O
rendered	O
BTK	B-GENE
-	O
deficient	O
through	O
targeted	O
disruption	O
of	O
the	O
btk	B-GENE
gene	I-GENE
by	O
homologous	O
recombination	O
knockout	O
underwent	O
apoptosis	O
after	O
Fas	B-GENE
ligation	O
,	O
but	O
wild	O
-	O
type	O
DT	O
-	O
40	O
cells	O
or	O
BTK	B-GENE
-	O
deficient	O
DT	O
-	O
40	O
cells	O
reconstituted	O
with	O
wild	B-GENE
-	I-GENE
type	I-GENE
human	I-GENE
btk	I-GENE
gene	I-GENE
did	O
not	O
.	O

Varicella	B-GENE
-	I-GENE
zoster	I-GENE
virus	I-GENE
(	I-GENE
VZV	I-GENE
)	I-GENE
glycoprotein	I-GENE
gI	I-GENE
is	O
a	O
type	B-GENE
1	I-GENE
transmembrane	I-GENE
glycoprotein	I-GENE
which	O
is	O
one	O
component	O
of	O
the	O
heterodimeric	O
gE	B-GENE
:	O
gI	B-GENE
Fc	I-GENE
receptor	I-GENE
complex	O
.	O

To	O
this	O
end	O
,	O
we	O
analyzed	O
the	O
phosphorylation	O
status	O
of	O
a	O
universal	O
tyrosine	B-GENE
kinase	I-GENE
substrate	O
,	O
the	O
transforming	O
Shc	B-GENE
adapter	I-GENE
protein	I-GENE
,	O
in	O
fibroblasts	O
expressing	O
the	O
viral	O
oncogene	O
.	O

These	O
genes	O
were	O
expressed	O
in	O
a	O
Saccharomyces	O
cerevisiae	O
mutant	O
in	O
which	O
the	O
endogenous	B-GENE
ferrochelatase	I-GENE
gene	I-GENE
(	O
HEM15	B-GENE
)	O
had	O
been	O
deleted	O
,	O
and	O
the	O
phenotypes	O
of	O
the	O
transformants	O
were	O
characterized	O
.	O

In	O
this	O
study	O
,	O
evidence	O
is	O
presented	O
that	O
temporally	O
and	O
spatially	O
specific	O
mef2	B-GENE
expression	O
is	O
controlled	O
by	O
a	O
complex	O
array	O
of	O
cis	O
-	O
acting	O
regulatory	O
modules	O
that	O
are	O
responsive	O
to	O
different	O
genetic	O
signals	O
.	O

Furthermore	O
,	O
using	O
transgenic	O
mouse	O
technology	O
we	O
localized	O
independent	O
cis	O
-	O
regulatory	O
elements	O
controlling	O
the	O
tissue	O
-	O
specific	O
expression	O
of	O
Pax6	B-GENE
.	O

In	O
the	O
second	O
experiment	O
,	O
a	O
stable	O
nickel	O
isotope	O
,	O
61Ni	O
,	O
was	O
given	O
in	O
drinking	O
water	O
to	O
20	O
nickel	O
-	O
sensitized	O
women	O
and	O
20	O
age	O
-	O
matched	O
controls	O
,	O
both	O
groups	O
having	O
vesicular	O
hand	O
eczema	O
of	O
the	O
pompholyx	O
type	O
.	O

Folded	O
tissue	O
and	O
crimped	O
collagen	B-GENE
fibers	O
in	O
the	O
tunica	O
albuginea	O
permit	O
its	O
expansion	O
during	O
erection	O
.	O

Number	O
of	O
patients	O
infected	O
with	O
nontuberculous	O
mycobacteria	O
(	O
NTM	O
)	O
is	O
increasing	O
world	O
-	O
wide	O
in	O
recent	O
years	O
.	O

Comparison	O
of	O
the	O
sequences	O
of	O
attP	B-GENE
,	O
attB	B-GENE
and	O
bacteria	O
-	O
prophage	O
junctions	O
attL	B-GENE
and	O
attR	B-GENE
showed	O
a	O
26	O
bp	O
common	O
core	O
sequence	O
,	O
where	O
recombination	O
takes	O
place	O
,	O
near	O
the	O
5	O
'	O
end	O
of	O
the	O
integrase	B-GENE
gene	I-GENE
.	O

Interferon	B-GENE
-	I-GENE
alpha	I-GENE
treatment	O
of	O
posttransplant	O
lymphoproliferative	O
disorder	O
in	O
recipients	O
of	O
solid	O
organ	O
transplants	O
.	O

Immunological	O
testing	O
was	O
performed	O
on	O
all	O
brewery	O
workers	O
and	O
some	O
control	O
volunteers	O
using	O
skin	O
prick	O
testing	O
with	O
hops	O
,	O
barley	O
,	O
and	O
yeast	O
antigens	O
as	O
well	O
as	O
other	O
nonoccupational	O
allergens	O
,	O
and	O
by	O
determining	O
total	O
serum	B-GENE
IgE	I-GENE
levels	O
.	O

OBJECTIVE	O
:	O
To	O
evaluate	O
the	O
accuracy	O
of	O
working	O
casts	O
for	O
crown	O
and	O
bridge	O
restorations	O
made	O
from	O
twin	O
mix	O
putty	O
/	O
wash	O
silicone	O
elastomeric	O
impression	O
materials	O
using	O
different	O
types	O
of	O
stock	O
tray	O
.	O

OBJECTIVES	O
:	O
To	O
assess	O
the	O
ability	O
of	O
pretreatment	O
and	O
post	O
-	O
treatment	O
prostate	B-GENE
-	I-GENE
specific	I-GENE
antigen	I-GENE
(	O
PSA	B-GENE
)	O
measurements	O
,	O
clinical	O
tumor	O
stage	O
,	O
tumor	O
grade	O
,	O
Gleason	O
sum	O
,	O
race	O
,	O
age	O
,	O
and	O
radiation	O
dose	O
to	O
predict	O
the	O
recurrence	O
of	O
prostate	O
cancer	O
following	O
external	O
beam	O
radiation	O
therapy	O
(	O
XRT	O
)	O
since	O
the	O
introduction	O
of	O
PSA	B-GENE
as	O
a	O
tumor	O
marker	O
at	O
one	O
tertiary	O
care	O
center	O
.	O

To	O
evaluate	O
whether	O
the	O
human	O
gene	O
is	O
also	O
a	O
target	O
of	O
thyroid	O
hormone	O
we	O
have	O
searched	O
for	O
T3	O
-	O
responsive	O
elements	O
in	O
NRGN	B-GENE
cloned	O
genomic	O
fragments	O
spanning	O
the	O
whole	O
gene	O
.	O

The	O
transcriptional	O
activity	O
of	O
PPARgamma	B-GENE
is	O
positively	O
modulated	O
by	O
ligand	O
binding	O
and	O
negatively	O
regulated	O
by	O
phosphorylation	O
mediated	O
by	O
the	O
MEK	B-GENE
/	O
ERK	B-GENE
signaling	O
pathway	O
.	O

BACKGROUND	O
:	O
Diazepam	O
,	O
one	O
of	O
the	O
benzodiazepine	O
group	O
of	O
tranquilizers	O
,	O
is	O
used	O
as	O
an	O
adjunctive	O
drug	O
for	O
sedation	O
and	O
for	O
relief	O
of	O
anxiety	O
in	O
the	O
treatment	O
of	O
epilepsy	O
.	O

Bioplastique	O
granuloma	O
presents	O
with	O
irregularly	O
shaped	O
cystic	O
spaces	O
of	O
varying	O
size	O
containing	O
jagged	O
,	O
translucent	O
,	O
nonbirefringent	O
foreign	O
bodies	O
whereas	O
Artecoll	O
granuloma	O
shows	O
numerous	O
round	O
vacuoles	O
nearly	O
identical	O
in	O
size	O
and	O
shape	O
enclosing	O
round	O
and	O
sharply	O
circumscribed	O
,	O
translucent	O
,	O
nonbirefringent	O
foreign	O
bodies	O
.	O

This	O
Tbx6	B-GENE
-	I-GENE
subfamily	I-GENE
gene	I-GENE
is	O
likely	O
to	O
participate	O
in	O
paraxial	O
mesoderm	O
formation	O
and	O
somitogenesis	O
in	O
human	O
embryo	O
.	O

Structure	O
-	O
function	O
analysis	O
of	O
the	O
Z	O
-	O
DNA	O
-	O
binding	O
domain	O
Zalpha	O
of	O
dsRNA	B-GENE
adenosine	I-GENE
deaminase	I-GENE
type	I-GENE
I	I-GENE
reveals	O
similarity	O
to	O
the	O
(	B-GENE
alpha	I-GENE
+	I-GENE
beta	I-GENE
)	I-GENE
family	I-GENE
of	O
helix	B-GENE
-	I-GENE
turn	I-GENE
-	I-GENE
helix	I-GENE
proteins	I-GENE
.	O

In	O
addition	O
,	O
the	O
regulation	O
of	O
Glvr	B-GENE
-	I-GENE
1	I-GENE
gene	I-GENE
expression	O
also	O
has	O
potential	O
applications	O
to	O
gene	O
therapy	O
,	O
since	O
retroviral	O
vectors	O
carrying	O
gibbon	B-GENE
ape	I-GENE
leukemia	I-GENE
virus	I-GENE
envelope	I-GENE
proteins	I-GENE
are	O
used	O
for	O
gene	O
delivery	O
into	O
different	O
cell	O
types	O
.	O

Carbohydrates	O
and	O
glycoconjugates	O
biophysical	O
methods	O
.	O

Molecular	O
cloning	O
of	O
mouse	B-GENE
glycolate	I-GENE
oxidase	I-GENE
.	O

In	O
such	O
a	O
manner	O
,	O
activated	O
PKR	B-GENE
inhibits	O
cell	O
growth	O
and	O
induces	O
apoptosis	O
,	O
whereas	O
disruption	O
of	O
normal	O
PKR	B-GENE
signaling	O
results	O
in	O
unregulated	O
cell	O
growth	O
.	O

We	O
isolated	O
a	O
ribosomal	B-GENE
protein	I-GENE
L18	I-GENE
by	O
interaction	O
with	O
PKR	B-GENE
.	O

Processing	O
of	O
the	O
polycistronic	O
precursor	O
requires	O
nucleases	O
also	O
involved	O
in	O
rRNA	O
processing	O
,	O
i	O
.	O
e	O
.	O
,	O
Rnt1p	B-GENE
and	O
Rat1p	B-GENE
.	O

Furthermore	O
,	O
rhoA	B-GENE
-	O
mediated	O
SRE	O
activation	O
was	O
blocked	O
by	O
dominant	O
negative	O
mutants	O
of	O
PKC	B-GENE
-	I-GENE
alpha	I-GENE
or	O
PKC	B-GENE
-	I-GENE
epsilon	I-GENE
.	O

Nip7p	B-GENE
-	O
depleted	O
cells	O
exhibited	O
the	O
same	O
defects	O
as	O
Nop8p	B-GENE
-	O
depleted	O
cells	O
,	O
except	O
that	O
they	O
accumulated	O
27S	B-GENE
precursors	I-GENE
.	O

We	O
show	O
that	O
the	O
Sm	B-GENE
-	I-GENE
binding	I-GENE
site	I-GENE
and	O
stem	O
-	O
loop	O
III	O
structures	O
are	O
necessary	O
for	O
correct	O
3	O
'	O
-	O
end	O
formation	O
.	O

Five	O
different	O
subtypes	O
of	O
spondyloarthropathy	O
(	O
SpA	O
)	O
are	O
now	O
recognized	O
.	O

Further	O
experiments	O
will	O
be	O
required	O
to	O
highlight	O
the	O
in	O
vivo	O
role	O
of	O
ELE1	B-GENE
in	O
nuclear	O
receptor	O
functioning	O
.	O

Overexpression	O
of	O
PTTG	B-GENE
in	O
transfected	O
NIH	O
3T3	O
cells	O
also	O
stimulated	O
expression	O
and	O
secretion	O
of	O
basic	B-GENE
fibroblast	I-GENE
growth	I-GENE
factor	I-GENE
,	O
a	O
human	B-GENE
pituitary	I-GENE
tumor	I-GENE
growth	I-GENE
-	I-GENE
regulating	I-GENE
factor	I-GENE
.	O

The	O
perifascicular	O
connective	O
tissue	O
sheath	O
is	O
important	O
in	O
organising	O
the	O
contraction	O
of	O
the	O
myocardium	O
by	O
preventing	O
lateral	O
spread	O
of	O
conduction	O
and	O
by	O
permitting	O
transmission	O
of	O
the	O
impulse	O
only	O
at	O
the	O
termination	O
of	O
the	O
purkinje	O
fibre	O
.	O

E1	B-GENE
,	O
a	O
DNA	B-GENE
helicase	I-GENE
,	O
collaborates	O
with	O
the	O
HPV	B-GENE
E2	I-GENE
protein	I-GENE
in	O
ori	O
-	O
dependent	O
replication	O
.	O

Here	O
we	O
describe	O
a	O
mutant	O
alpha	O
subunit	O
designed	O
to	O
inhibit	O
receptor	O
-	O
mediated	O
hormonal	O
activation	O
of	O
Gs	B-GENE
,	O
the	O
stimulatory	O
regulator	O
of	O
adenylyl	B-GENE
cyclase	I-GENE
.	O

A	O
gapped	O
search	O
with	O
the	O
C	O
-	O
terminal	O
region	O
of	O
CDED	B-GENE
/	O
LIOR	B-GENE
revealed	O
a	O
36	O
-	O
41	O
%	O
similarity	O
to	O
several	O
proteins	O
related	O
to	O
signal	O
transduction	O
and	O
cell	O
replication	O
,	O
such	O
as	O
ORC1	B-GENE
and	O
KSR	B-GENE
.	O

Northern	O
blot	O
analysis	O
demonstrated	O
the	O
ubiquitous	O
expression	O
of	O
2	O
.	O
9	O
kb	O
and	O
3	O
.	O

Additionally	O
,	O
a	O
variety	O
of	O
regulatory	O
schemes	O
contribute	O
temporal	O
and	O
/	O
or	O
spatial	O
restriction	O
to	O
TGF	B-GENE
-	I-GENE
beta	I-GENE
responses	O
.	O

A	O
comparison	O
of	O
the	O
clinical	O
profile	O
of	O
cavernous	O
malformations	O
with	O
and	O
without	O
associated	O
venous	O
malformations	O
.	O

Magnetically	O
induced	O
optical	O
self	O
-	O
pulsing	O
in	O
a	O
nonlinear	O
resonator	O
.	O

Wave	O
cybernetics	O
:	O
A	O
simple	O
model	O
of	O
wave	O
-	O
controlled	O
nonlinear	O
and	O
nonlocal	O
cooperative	O
phenomena	O
.	O

Autoionization	O
rates	O
and	O
energy	O
levels	O
of	O
triplet	O
nf	O
,	O
v	O
=	O
1	O
Rydberg	O
states	O
of	O
H2	O
.	O

Unitary	O
-	O
group	O
approach	O
to	O
spin	O
-	O
dependent	O
operators	O
.	O

Nonlocal	O
approach	O
to	O
scattering	O
in	O
a	O
one	O
-	O
dimensional	O
problem	O
.	O

Soft	O
-	O
x	O
-	O
ray	O
lasing	O
at	O
32	O
.	O
6	O
nm	O
in	O
Ne	O
-	O
like	O
Ti	O
ions	O
driven	O
by	O
40	O
J	O
of	O
energy	O
from	O
two	O
650	O
-	O
ps	O
laser	O
pulses	O
.	O

Next	O
,	O
to	O
identify	O
regions	O
of	O
the	O
promoter	O
involved	O
,	O
we	O
examined	O
a	O
series	O
of	O
tenascin	B-GENE
-	I-GENE
C	I-GENE
promoter	I-GENE
constructs	I-GENE
with	O
5	O
'	O
deletions	O
and	O
showed	O
that	O
denatured	O
collagen	B-GENE
-	I-GENE
dependent	I-GENE
promoter	I-GENE
activity	O
was	O
retained	O
by	O
a	O
122	O
-	O
base	O
pair	O
element	O
,	O
located	O
-	O
43	O
to	O
-	O
165	O
bp	O
upstream	O
of	O
the	O
RNA	O
start	O
site	O
.	O

Nuclear	B-GENE
factor	I-GENE
kappa	I-GENE
B	I-GENE
(	O
NF	B-GENE
-	I-GENE
kappaB	I-GENE
)	O
is	O
an	O
important	O
transcription	O
factor	O
for	O
the	O
genes	O
of	O
many	O
pro	O
-	O
inflammatory	O
proteins	O
and	O
is	O
strongly	O
activated	O
by	O
the	O
cytokines	O
interleukin	B-GENE
-	I-GENE
1	I-GENE
and	O
tumor	B-GENE
necrosis	I-GENE
factor	I-GENE
(	I-GENE
TNF	I-GENE
)	I-GENE
alpha	I-GENE
under	O
various	O
pathological	O
conditions	O
.	O

Unilateral	O
naris	O
occlusion	O
and	O
the	O
rat	O
accessory	O
olfactory	O
bulb	O
.	O

The	O
promoter	O
of	O
the	O
rat	O
pgp2	B-GENE
/	O
mdr1b	B-GENE
gene	O
has	O
a	O
GC	O
-	O
rich	O
region	O
(	O
pgp2GC	B-GENE
)	O
that	O
is	O
highly	O
conserved	O
in	O
mdr	B-GENE
genes	I-GENE
and	O
contains	O
an	O
consensus	O
Sp1	B-GENE
site	I-GENE
.	O

Sp1	B-GENE
'	O
s	O
role	O
in	O
transactivation	O
of	O
the	O
pgp2	B-GENE
/	O
mdr1b	B-GENE
promoter	O
was	O
tested	O
in	O
Drosophila	O
Schneider	O
cells	O
.	O

Measurements	O
included	O
bone	O
mineral	O
density	O
of	O
the	O
lumbar	O
spine	O
and	O
proximal	O
femur	O
(	O
by	O
dual	O
-	O
energy	O
X	O
-	O
ray	O
absorptiometry	O
)	O
and	O
biochemical	O
markers	O
of	O
bone	O
remodeling	O
(	O
serum	O
bone	O
-	O
specific	O
alkaline	B-GENE
phosphatase	I-GENE
by	O
immunoassay	O
and	O
urine	O
deoxypyridinoline	O
by	O
high	O
-	O
pressure	O
liquid	O
chromatography	O
)	O
.	O

Human	B-GENE
MGP	I-GENE
is	O
a	O
10	B-GENE
-	I-GENE
kD	I-GENE
skeletal	I-GENE
extracellular	I-GENE
matrix	I-GENE
(	I-GENE
ECM	I-GENE
)	I-GENE
protein	I-GENE
that	O
consists	O
of	O
an	O
84	O
-	O
aa	O
mature	O
protein	O
and	O
a	O
19	O
-	O
aa	O
transmembrane	O
signal	O
peptide	O
.	O

Dual	O
roles	O
of	O
p82	B-GENE
,	O
the	O
clam	O
CPEB	B-GENE
homolog	I-GENE
,	O
in	O
cytoplasmic	O
polyadenylation	O
and	O
translational	O
masking	O
.	O

The	O
pattern	O
of	O
RNase	B-GENE
E	I-GENE
digestion	O
of	O
finP305	B-GENE
RNA	I-GENE
differed	O
from	O
FinP	B-GENE
,	O
and	O
GST	B-GENE
-	O
FinO	B-GENE
did	O
not	O
protect	O
finP305	B-GENE
RNA	I-GENE
from	O
cleavage	O
in	O
vitro	O
.	O

Transcription	O
readthrough	O
into	O
the	O
inverted	O
repeats	O
has	O
little	O
effect	O
on	O
this	O
event	O
.	O

In	O
the	O
second	O
case	O
,	O
an	O
epidermal	O
cyst	O
was	O
diagnosed	O
.	O

MotA	B-GENE
also	O
binds	O
a	O
DNA	O
sequence	O
(	O
a	O
MotA	B-GENE
box	I-GENE
)	O
,	O
centered	O
at	O
position	O
-	O
30	O
.	O

We	O
suggest	O
that	O
MotA	B-GENE
and	O
AsiA	B-GENE
may	O
function	O
like	O
certain	O
eukaryotic	B-GENE
TAFs	I-GENE
(	O
TATA	B-GENE
binding	I-GENE
protein	I-GENE
(	I-GENE
TBP	I-GENE
)	I-GENE
associated	I-GENE
factors	I-GENE
)	O
whose	O
binding	O
to	O
TBP	B-GENE
results	O
in	O
transcription	O
from	O
new	O
core	O
promoter	O
sequences	O
.	O

The	O
S229A	O
variant	O
can	O
better	O
flip	O
modified	O
bases	O
but	O
does	O
not	O
tightly	O
lock	O
the	O
flipped	O
base	O
into	O
the	O
adenine	O
-	O
binding	O
pocket	O
,	O
suggesting	O
that	O
Ser229	O
could	O
form	O
a	O
contact	O
to	O
the	O
flipped	O
adenine	O
.	O

The	O
high	O
conservation	O
of	O
the	O
3	O
'	O
terminus	O
suggests	O
that	O
this	O
region	O
directs	O
the	O
assembly	O
of	O
proteins	O
required	O
for	O
the	O
initiation	O
of	O
RNA	O
replication	O
.	O

All	O
stimulations	O
were	O
down	O
-	O
regulated	O
with	O
GnRH	B-GENE
-	I-GENE
a	I-GENE
commenced	O
on	O
day	O
21	O
in	O
a	O
long	O
protocol	O
before	O
gonadotropin	B-GENE
stimulation	O
.	O

The	O
sequence	O
up	O
to	O
-	O
267	O
bp	O
relative	O
to	O
the	O
transcription	O
start	O
site	O
was	O
sufficient	O
to	O
enhance	O
reporter	O
gene	O
expression	O
depending	O
on	O
the	O
mesodermal	O
differentiation	O
of	O
P19	O
cells	O
.	O

No	O
significant	O
differences	O
between	O
the	O
substituted	O
and	O
wild	O
type	O
peptides	O
were	O
observed	O
,	O
suggesting	O
that	O
this	O
substitution	O
in	O
the	O
intact	O
protein	O
may	O
cause	O
disruption	O
of	O
global	O
rather	O
than	O
local	O
structures	O
.	O

C3	B-GENE
toxin	I-GENE
completely	O
inhibited	O
RhoA	B-GENE
function	O
,	O
partially	O
inhibited	O
SRE	O
:	O
Luc	B-GENE
activity	O
,	O
but	O
had	O
no	O
effect	O
on	O
LPA	O
-	O
stimulated	O
c	B-GENE
-	I-GENE
Fos	I-GENE
expression	O
.	O

However	O
,	O
C3	B-GENE
toxin	I-GENE
alone	O
or	O
in	O
combination	O
with	O
growth	O
factors	O
did	O
not	O
stimulate	O
AP	B-GENE
-	I-GENE
1	I-GENE
:	O
Luc	B-GENE
activity	O
and	O
actually	O
antagonized	O
the	O
synergistic	O
activation	O
of	O
AP	B-GENE
-	I-GENE
1	I-GENE
:	O
Luc	B-GENE
observed	O
in	O
response	O
to	O
co	O
-	O
stimulation	O
with	O
growth	O
factors	O
and	O
Ro	O
-	O
31	O
-	O
8220	O
.	O

The	O
aim	O
of	O
the	O
present	O
study	O
was	O
to	O
examine	O
the	O
antimicrobial	O
susceptibility	O
to	O
10	O
currently	O
used	O
antimicrobial	O
agents	O
of	O
50	O
strains	O
of	O
P	O
.	O
acnes	O
isolated	O
from	O
acne	O
lesions	O
and	O
identified	O
using	O
a	O
Rap	O
ID	O
ANA	O
II	O
panel	O
.	O

The	O
role	O
of	O
intraoperative	O
echocardiography	O
in	O
surgery	O
of	O
the	O
heart	O
and	O
large	O
vessels	O

Taken	O
together	O
,	O
our	O
results	O
demonstrate	O
that	O
CAP1	B-GENE
is	O
involved	O
in	O
multidrug	O
resistance	O
and	O
oxidative	O
stress	O
response	O
in	O
C	O
.	O
albicans	O
.	O

Trinipatch	O
is	O
a	O
small	O
,	O
transparent	O
,	O
matricial	O
,	O
monolayer	O
patch	O
with	O
an	O
absorption	O
promoter	O
,	O
marketed	O
in	O
two	O
dose	O
-	O
strengths	O
(	O
5	O
mg	O
/	O
24	O
h	O
and	O
10	O
mg	O
/	O
24	O
h	O
)	O
by	O
Laboratoires	O
Synthelabo	O
.	O

The	O
RMRI	O
was	O
tested	O
for	O
interrater	O
reliability	O
using	O
three	O
simulated	O
and	O
10	O
actual	O
patients	O
.	O

The	O
starting	O
point	O
is	O
the	O
consideration	O
that	O
the	O
conceptions	O
underlying	O
the	O
ICIDH	O
are	O
not	O
suitable	O
to	O
serve	O
as	O
a	O
mainstay	O
of	O
a	O
model	O
for	O
diagnostics	O
in	O
rehabilitation	O
because	O
they	O
do	O
not	O
reflect	O
essential	O
characteristics	O
of	O
the	O
diagnostic	O
process	O
which	O
is	O
the	O
basis	O
for	O
intervention	O
.	O

OBJECTIVE	O
:	O
This	O
meta	O
-	O
analysis	O
of	O
67	O
controlled	O
trials	O
was	O
performed	O
to	O
quantify	O
the	O
cholesterol	O
-	O
lowering	O
effect	O
of	O
major	O
dietary	O
fibers	O
.	O

When	O
the	O
high	O
affinity	O
hnRNP	B-GENE
A1	I-GENE
binding	I-GENE
site	I-GENE
was	O
inserted	O
into	O
the	O
beta	B-GENE
-	I-GENE
globin	I-GENE
reporter	I-GENE
,	O
Rev	B-GENE
was	O
able	O
to	O
increase	O
the	O
cytoplasmic	O
levels	O
of	O
unspliced	O
mRNAs	O
to	O
14	O
%	O
.	O

To	O
date	O
,	O
two	O
such	O
proteins	O
,	O
PLZF	B-GENE
and	O
LAZ	B-GENE
-	I-GENE
3	I-GENE
/	O
BCL	B-GENE
-	I-GENE
6	I-GENE
,	O
have	O
been	O
implicated	O
in	O
oncogenesis	O
.	O

Overexpression	O
of	O
POG1	B-GENE
inhibits	O
alpha	B-GENE
-	I-GENE
factor	I-GENE
-	O
induced	O
G1	O
arrest	O
and	O
transcriptional	O
repression	O
of	O
the	O
CLN1	B-GENE
and	O
CLN2	B-GENE
genes	I-GENE
.	O

We	O
now	O
show	O
that	O
RNU2	B-GENE
fragility	O
can	O
be	O
induced	O
by	O
transfection	O
with	O
an	O
expression	O
vector	O
encoding	O
Ad12	B-GENE
E1B	I-GENE
55	O
kDa	O
alone	O
but	O
not	O
by	O
an	O
E1	B-GENE
vector	O
encoding	O
all	O
E1	B-GENE
products	I-GENE
(	O
3	O
E1A	B-GENE
proteins	I-GENE
,	O
as	O
well	O
as	O
the	O
E1B	B-GENE
19	O
kDa	O
and	O
55	O
kDa	O
proteins	O
)	O
.	O

Competitionsupershift	O
EMSA	O
assays	O
revealed	O
that	O
multiple	O
proteins	O
were	O
involved	O
in	O
bandshift	O
complex	O
formation	O
with	O
KCS	B-GENE
,	O
one	O
of	O
which	O
was	O
identified	O
as	O
factor	O
Sp1	O
.	O

Similarity	O
of	O
DNA	O
binding	O
and	O
transcriptional	O
regulation	O
by	O
Caenorhabditis	B-GENE
elegans	I-GENE
MAB	I-GENE
-	I-GENE
3	I-GENE
and	O
Drosophila	B-GENE
melanogaster	I-GENE
DSX	I-GENE
suggests	O
conservation	O
of	O
sex	O
determining	O
mechanisms	O
.	O

Neither	O
the	O
p42	B-GENE
/	I-GENE
44	I-GENE
nor	O
the	O
JNK	B-GENE
pathway	O
was	O
involved	O
in	O
the	O
action	O
of	O
IL	B-GENE
-	I-GENE
1beta	I-GENE
.	O

In	O
protocol	O
2	O
,	O
eight	O
different	O
subjects	O
performed	O
Con	O
and	O
Ecc	O
arm	O
curls	O
to	O
fatigue	O
,	O
followed	O
by	O
postexercise	O
muscle	O
ischemia	O
,	O
by	O
using	O
the	O
same	O
resistance	O
as	O
in	O
protocol	O
1	O
.	O

Airflow	O
was	O
measured	O
with	O
a	O
custom	O
-	O
designed	O
turbine	O
and	O
a	O
45	O
-	O
ft	O
.	O
-	O
long	O
cable	O
to	O
reach	O
the	O
volume	O
-	O
measuring	O
module	O
.	O

Both	O
mutations	O
confer	O
amino	O
acid	O
substitutions	O
in	O
the	O
viral	B-GENE
coat	I-GENE
protein	I-GENE
but	O
differ	O
in	O
their	O
relative	O
abilities	O
to	O
utilize	O
the	O
foreign	O
scaffolding	B-GENE
protein	I-GENE
.	O

Complete	O
recovery	O
of	O
liver	O
function	O
after	O
this	O
surgery	O
tended	O
to	O
be	O
slow	O
.	O

Although	O
both	O
transcripts	O
share	O
the	O
first	O
nine	O
exons	O
,	O
exon	O
10	O
of	O
ZIS	B-GENE
-	I-GENE
2	I-GENE
is	O
lacking	O
in	O
ZIS	B-GENE
-	I-GENE
1	I-GENE
,	O
and	O
instead	O
,	O
exon	O
11	O
(	O
10th	O
exon	O
)	O
of	O
ZIS	B-GENE
-	I-GENE
1	I-GENE
is	O
larger	O
in	O
size	O
,	O
leading	O
to	O
the	O
longer	O
3	O
'	O
-	O
UTR	O
.	O

IFN	B-GENE
-	I-GENE
gamma	I-GENE
was	O
elevated	O
during	O
active	O
TB	O
when	O
compared	O
with	O
healthy	O
controls	O
,	O
declining	O
during	O
and	O
after	O
treatment	O
.	O

The	O
missing	O
5	O
'	O
sequences	O
were	O
obtained	O
by	O
5	O
'	O
-	O
rapid	O
amplification	O
of	O
cDNA	O
ends	O
and	O
by	O
analysis	O
of	O
an	O
NHE5	B-GENE
genomic	I-GENE
clone	I-GENE
,	O
and	O
the	O
missing	O
3	O
'	O
sequences	O
were	O
obtained	O
by	O
3	O
'	O
-	O
rapid	O
amplification	O
of	O
cDNA	O
ends	O
.	O

If	O
no	O
alloantibodies	O
are	O
detected	O
,	O
further	O
analysis	O
to	O
define	O
a	O
role	O
of	O
drug	O
-	O
related	O
or	O
autoantibodies	O
is	O
required	O
.	O

This	O
dependence	O
,	O
however	O
,	O
can	O
be	O
overcome	O
to	O
a	O
large	O
extent	O
by	O
dividing	O
min	O
LVdP	O
/	O
dt	O
by	O
mean	O
aortic	O
pressure	O
.	O

Genoa	O
,	O
Italy	O
,	O
24	O
-	O
28	O
August	O
1997	O
.	O

Electronic	O
structure	O
of	O
delta	O
-	O
plutonium	O
and	O
of	O
single	O
Al	O
,	O
Ga	O
,	O
and	O
Sc	O
impurities	O
in	O
delta	O
-	O
plutonium	O
.	O

Bound	O
-	O
exciton	O
transfer	O
and	O
photoluminescence	O
undulation	O
spectra	O
for	O
acceptors	O
in	O
ZnTe	O
.	O

Unified	O
theory	O
of	O
segregated	O
-	O
stack	O
organic	O
charge	O
-	O
transfer	O
solids	O
:	O
Magnetic	O
properties	O
.	O

II	O
.	O

Envelope	O
-	O
function	O
matching	O
conditions	O
for	O
GaAs	O
/	O
(	O
Al	O
,	O
Ga	O
)	O
As	O
heterojunctions	O
.	O

Neutron	O
scattering	O
measurements	O
of	O
critical	O
exponents	O
in	O
CsMnBr3	O
:	O
A	O
Z2	O
&	O
gt	O
;	O
=	O
1	O
antiferromagnet	O
.	O

Thus	O
,	O
in	O
normal	O
intestinal	O
epithelial	O
goblet	O
cells	O
,	O
TbetaRI	B-GENE
and	O
TbetaRII	B-GENE
can	O
respond	O
to	O
autocrine	O
but	O
not	O
exogenous	O
TGF	B-GENE
-	I-GENE
beta	I-GENE
without	O
the	O
participation	O
of	O
TbetaRIII	B-GENE
.	O

The	O
history	O
of	O
exposure	O
and	O
carboxyhemoglobin	B-GENE
levels	O
should	O
alert	O
the	O
physician	O
to	O
this	O
diagnosis	O
.	O

The	O
odds	O
ratio	O
for	O
CHD	O
was	O
1	O
.	O
21	O
(	O
95	O
%	O
confidence	O
interval	O
,	O
0	O
.	O
84	O
-	O
1	O
.	O
75	O
)	O
given	O
a	O
positive	O
serostatus	O
of	O
specific	O
IgG	B-GENE
antibodies	O
after	O
adjustment	O
for	O
covariates	O
.	O

Another	O
group	O
of	O
HIPP	O
-	O
and	O
HCX	O
-	O
lesioned	O
animals	O
trained	O
on	O
the	O
tasks	O
after	O
the	O
lesion	O
showed	O
reduced	O
impairments	O
of	O
the	O
type	O
described	O
above	O
,	O
suggesting	O
that	O
extrahippocampal	O
structures	O
trained	O
after	O
the	O
lesion	O
can	O
assume	O
the	O
role	O
of	O
the	O
hippocampus	O
to	O
some	O
degree	O
.	O

The	O
case	O
for	O
neutrinos	O
from	O
SN	O
1987A	O
.	O

Scaling	O
of	O
fluctuations	O
in	O
one	O
-	O
dimensional	O
interface	O
and	O
hopping	O
models	O
.	O

Model	O
of	O
spatiotemporal	O
dynamics	O
of	O
stick	O
-	O
slip	O
motion	O
.	O

NMR	O
of	O
diffusing	O
atoms	O
in	O
a	O
periodic	O
porous	O
medium	O
in	O
the	O
presence	O
of	O
a	O
nonuniform	O
magnetic	O
field	O
.	O

Microstructure	O
and	O
conductivity	O
of	O
hierarchical	O
laminate	O
composites	O
.	O

Anisotropic	O
heat	O
transport	O
in	O
the	O
octylcyanobiphenyl	O
(	O
8CB	O
)	O
liquid	O
crystal	O
.	O

Direct	O
approach	O
to	O
the	O
study	O
of	O
soliton	O
perturbations	O
.	O

Mutations	O
affecting	O
only	O
CD4	B-GENE
regulation	O
mapped	O
to	O
residues	O
previously	O
shown	O
to	O
mediate	O
the	O
binding	O
of	O
Nef	B-GENE
to	O
this	O
receptor	O
,	O
such	O
as	O
W57	O
and	O
L58	O
,	O
as	O
well	O
as	O
to	O
an	O
AP	B-GENE
-	I-GENE
recruiting	I-GENE
dileucine	I-GENE
motif	I-GENE
and	O
to	O
an	O
acidic	O
dipeptide	O
in	O
the	O
C	O
-	O
terminal	O
region	O
of	O
the	O
protein	O
.	O

The	O
lytic	O
cycle	O
of	O
KSHV	O
,	O
probably	O
under	O
the	O
initial	O
control	O
of	O
the	O
KSHV	B-GENE
/	I-GENE
Rta	I-GENE
gene	I-GENE
,	O
may	O
directly	O
contribute	O
to	O
tumor	O
pathogenesis	O
.	O

We	O
conclude	O
that	O
(	O
i	O
)	O
we	O
have	O
identified	O
several	O
candidate	O
latency	O
genes	O
of	O
murine	O
gammaHV68	O
,	O
(	O
ii	O
)	O
expression	O
of	O
genes	O
during	O
latency	O
may	O
be	O
different	O
in	O
different	O
organs	O
,	O
consistent	O
with	O
multiple	O
latency	O
programs	O
and	O
/	O
or	O
multiple	O
cellular	O
sites	O
of	O
latency	O
,	O
and	O
(	O
iii	O
)	O
regions	O
of	O
the	O
viral	O
genome	O
(	O
v	B-GENE
-	I-GENE
bcl	I-GENE
-	I-GENE
2	I-GENE
gene	I-GENE
,	O
v	B-GENE
-	I-GENE
GCR	I-GENE
gene	I-GENE
,	O
and	O
gene	B-GENE
73	I-GENE
)	O
are	O
transcribed	O
during	O
latency	O
with	O
both	O
gammaHV68	O
and	O
primate	O
gammaherpesviruses	O
.	O

These	O
data	O
indicate	O
a	O
functional	O
role	O
for	O
U1	B-GENE
in	O
NRS	B-GENE
-	O
mediated	O
splicing	O
inhibition	O
.	O

This	O
suggests	O
that	O
the	O
DcuS	B-GENE
-	O
DcuR	B-GENE
system	O
responds	O
to	O
external	O
substrates	O
.	O

Crossover	O
in	O
the	O
specific	O
heat	O
of	O
dilute	O
magnets	O
induced	O
by	O
critical	O
spin	O
-	O
wave	O
dynamics	O
.	O

Erratum	O
:	O
Absence	O
of	O
precursor	O
effects	O
above	O
the	O
martensitic	O
transformation	O
in	O
a	O
virgin	O
crystal	O
of	O
Li	O
metal	O

Interplane	O
coupling	O
in	O
the	O
superconductor	O
Y2Ba4Cu7O15	O
as	O
revealed	O
by	O
NQR	O
spin	O
-	O
echo	O
double	O
resonance	O
.	O

Electronic	O
structure	O
of	O
a	O
buried	O
NiSi2	O
or	O
CoSi2	O
layer	O
in	O
bulk	O
Si	O
.	O

Raman	O
investigation	O
of	O
YBa2	O
-	O
xLaxCu3O7	O
ceramics	O
.	O

Effects	O
of	O
point	O
defects	O
on	O
lattice	O
parameters	O
of	O
semiconductors	O
.	O

Chaotic	O
electron	O
dynamics	O
around	O
a	O
single	O
elliptically	O
shaped	O
antidot	O
.	O

However	O
,	O
deletions	O
of	O
the	O
C	O
terminal	O
11	O
or	O
14	O
amino	O
acids	O
had	O
more	O
substantial	O
effects	O
.	O

Sixty	O
months	O
after	O
the	O
initial	O
vaccination	O
,	O
all	O
vaccinees	O
who	O
received	O
annual	O
follow	O
-	O
up	O
still	O
had	O
protective	O
levels	O
of	O
anti	B-GENE
-	I-GENE
HAV	I-GENE
.	O

However	O
,	O
after	O
PRK	O
at	O
5	O
weeks	O
of	O
age	O
,	O
partial	O
retreatment	O
may	O
be	O
necessary	O
due	O
to	O
regression	O
of	O
the	O
PRK	O
effect	O
.	O

Its	O
early	O
lesions	O
were	O
characterized	O
by	O
angiomatosis	O
,	O
vasculopathy	O
,	O
and	O
proliferation	O
of	O
synoviocytes	O
and	O
fibroblasts	O
.	O

Molecular	O
cloning	O
of	O
human	O
cDNA	O
encoding	O
a	O
novel	O
beta1	B-GENE
,	I-GENE
6	I-GENE
-	I-GENE
N	I-GENE
-	I-GENE
acetylglucosaminyltransferase	I-GENE
forming	O
core	O
2	O
and	O
core	O
4	O
.	O

Interspecific	O
mouse	O
back	O
-	O
cross	O
analysis	O
identified	O
the	O
loci	O
for	O
mouse	B-GENE
3Ost	I-GENE
genes	I-GENE
and	O
syntenic	O
assignments	O
of	O
corresponding	O
human	O
isologs	O
were	O
confirmed	O
by	O
the	O
identification	O
of	O
mapped	O
sequence	O
-	O
tagged	O
site	O
markers	O
.	O

The	O
Scales	O
of	O
Cognitive	O
Impairment	O
Rated	O
From	O
Institutional	O
Records	O
(	O
SCIRFIR	O
)	O
,	O
a	O
battery	O
based	O
on	O
commonly	O
used	O
dementia	O
rating	O
instruments	O
,	O
was	O
tested	O
on	O
the	O
records	O
of	O
26	O
chronically	O
institutionalized	O
,	O
elderly	O
schizophrenia	O
patients	O
,	O
for	O
the	O
purpose	O
of	O
retrospectively	O
evaluating	O
the	O
long	O
-	O
term	O
course	O
of	O
cognitive	O
change	O
in	O
schizophrenia	O
and	O
relating	O
it	O
to	O
available	O
autopsy	O
materials	O
.	O

Most	O
recently	O
,	O
the	O
use	O
of	O
the	O
product	O
of	O
brain	O
weight	O
and	O
clearance	O
has	O
been	O
proposed	O
.	O

Recombination	O
and	O
transcription	O
of	O
the	O
endogenous	B-GENE
Ig	I-GENE
heavy	I-GENE
chain	I-GENE
locus	I-GENE
is	O
effected	O
by	O
the	O
Ig	B-GENE
heavy	I-GENE
chain	I-GENE
intronic	I-GENE
enhancer	I-GENE
core	I-GENE
region	I-GENE
in	O
the	O
absence	O
of	O
the	O
matrix	O
attachment	O
regions	O
.	O

Two	O
of	O
these	O
motifs	O
are	O
part	O
of	O
a	O
highly	O
conserved	O
and	O
inducible	O
dyad	O
symmetry	O
element	O
shown	O
previously	O
to	O
control	O
a	O
remote	O
IL	B-GENE
-	I-GENE
2	I-GENE
enhancer	I-GENE
and	O
the	O
CD18	B-GENE
promoter	I-GENE
.	O

In	O
concert	O
with	O
the	O
coactivator	O
CREB	B-GENE
binding	I-GENE
protein	I-GENE
/	O
p300	B-GENE
,	O
which	O
interacts	O
with	O
GABPalpha	B-GENE
,	O
the	O
binding	O
of	O
GABPalpha	B-GENE
and	I-GENE
-	I-GENE
beta	I-GENE
to	O
the	O
dyad	O
symmetry	O
element	O
controls	O
the	O
induction	O
of	O
IL	B-GENE
-	I-GENE
16	I-GENE
promoter	I-GENE
in	O
T	O
cells	O
.	O

TPO	B-GENE
by	O
itself	O
did	O
not	O
activate	O
ERK1	B-GENE
,	O
ERK2	B-GENE
and	O
protein	B-GENE
kinase	I-GENE
C	I-GENE
(	O
PKC	B-GENE
)	O
,	O
whereas	O
TPO	B-GENE
directly	O
enhanced	O
the	O
PKC	B-GENE
-	O
dependent	O
activation	O
of	O
ERKs	B-GENE
induced	O
by	O
other	O
agonists	O
including	O
thrombin	B-GENE
and	O
phorbol	O
esters	O
,	O
without	O
affecting	O
the	O
PKC	B-GENE
activation	O
by	O
those	O
agonists	O
.	O

BACKGROUND	O
:	O
In	O
the	O
ubiquitin	B-GENE
-	O
dependent	O
proteolysis	O
pathway	O
,	O
a	O
ubiquitin	B-GENE
ligase	I-GENE
(	O
E3	B-GENE
)	O
is	O
responsible	O
for	O
substrate	O
selectivity	O
and	O
timing	O
of	O
degradation	O
.	O

CONCLUSIONS	O
:	O
Fission	B-GENE
yeast	I-GENE
SCF	I-GENE
is	O
composed	O
of	O
Pop1	B-GENE
and	O
Pop2	B-GENE
,	O
two	O
structurally	O
related	O
but	O
functionally	O
independent	O
F	B-GENE
-	I-GENE
box	I-GENE
/	I-GENE
WD	I-GENE
-	I-GENE
repeat	I-GENE
proteins	I-GENE
.	O

19F	O
NMR	O
studies	O
in	O
ABF4	O
-	O
type	O
layered	O
antiferromagnets	O
.	O

Optical	O
-	O
absorption	O
spectra	O
,	O
crystal	O
-	O
field	O
energy	O
levels	O
,	O
and	O
transition	O
line	O
strengths	O
of	O
holmium	O
in	O
trigonal	O
Na3	O

Observation	O
of	O
dipolar	O
interactions	O
between	O
Pb0	O
defects	O
at	O
the	O
(	O
111	O
)	O
Si	O
/	O
SiO2	O
interface	O
.	O

Quantum	O
-	O
statistical	O
theory	O
of	O
high	O
-	O
field	O
transport	O
phenomena	O
.	O

NH3	O
and	O
NO	O
interaction	O
with	O
Si	O
(	O
100	O
)	O
-	O
(	O
2	O
x	O
1	O
)	O
surfaces	O
.	O

Far	O
-	O
infrared	O
hopping	O
conductivity	O
in	O
the	O
CuO	O
chains	O
of	O
a	O
single	O
-	O
domain	O
YBa2Cu3O7	O
-	O
delta	O
crystal	O
.	O

Surface	O
spin	O
waves	O
in	O
a	O
Heisenberg	O
ferrimagnet	O
with	O
a	O
single	O
-	O
ion	O
anisotropy	O
(	O
uniaxial	O
and	O
nonuniaxial	O
)	O
.	O

Multilayer	O
-	O
relaxation	O
geometry	O
and	O
electronic	O
structure	O
of	O
a	O
W	O
(	O
111	O
)	O
surface	O
.	O

Temperature	O
dependence	O
of	O
the	O
sublattice	O
spontaneous	O
magnetization	O
of	O
YBa2Cu3O6	O
.	O

GW	O
Gamma	O
approximation	O
for	O
electron	O
self	O
-	O
energies	O
in	O
semiconductors	O
and	O
insulators	O
.	O

Precision	O
measurement	O
of	O
the	O
pion	O
mass	O
difference	O
m	O
pi	O
-	O
-	O
m	O
pi	O
0	O
.	O

Testing	O
gravity	O
to	O
second	O
post	O
-	O
Newtonian	O
order	O
:	O
A	O
field	O
-	O
theory	O
approach	O
.	O

Genetic	O
experiments	O
using	O
mutants	O
defective	O
in	O
apontic	B-GENE
and	O
bruno	B-GENE
reveal	O
a	O
functional	O
interaction	O
between	O
these	O
genes	O
.	O

In	O
the	O
current	O
model	O
,	O
Wingless	B-GENE
/	O
Wnt	B-GENE
signal	O
stabilizes	O
Armadillo	B-GENE
/	O
beta	B-GENE
-	I-GENE
catenin	I-GENE
,	O
which	O
then	O
accumulates	O
in	O
nuclei	O
and	O
binds	O
TCF	B-GENE
/	O
LEF	B-GENE
family	O
proteins	O
,	O
forming	O
bipartite	O
transcription	O
factors	O
which	O
activate	O
transcription	O
of	O
Wingless	B-GENE
/	O
Wnt	B-GENE
responsive	O
genes	O
.	O

In	O
support	O
of	O
clinical	O
antianginal	O
studies	O
,	O
the	O
vasodilator	O
nicorandil	O
(	O
NIC	O
)	O
was	O
combined	O
with	O
the	O
beta	B-GENE
-	I-GENE
adrenergic	I-GENE
receptor	I-GENE
antagonists	O
propranolol	O
(	O
PRO	O
)	O
and	O
atenolol	O
(	O
ATN	O
)	O
and	O
with	O
the	O
calcium	O
channel	O
blocker	O
diltiazem	O
(	O
DTZ	O
)	O
to	O
determine	O
their	O
cardiovascular	O
and	O
pharmacokinetic	O
interactions	O
.	O

Elimination	O
of	O
ETH1	B-GENE
in	O
apn1	B-GENE
strains	O
also	O
increased	O
spontaneous	O
mutation	O
rates	O
9	O
-	O
or	O
31	O
-	O
fold	O
compared	O
to	O
the	O
wild	O
type	O
as	O
determined	O
by	O
reversion	O
to	O
adenine	O
or	O
lysine	O
prototrophy	O
,	O
respectively	O
.	O

Elimination	O
of	O
ETH1	B-GENE
in	O
apn1	B-GENE
strains	O
also	O
increased	O
spontaneous	O
mutation	O
rates	O
9	O
-	O
or	O
31	O
-	O
fold	O
compared	O
to	O
the	O
wild	O
type	O
as	O
determined	O
by	O
reversion	O
to	O
adenine	O
or	O
lysine	O
prototrophy	O
,	O
respectively	O
.	O

Mammalian	O
Ras	B-GENE
GTPase	B-GENE
-	I-GENE
activating	I-GENE
protein	I-GENE
(	O
GAP	B-GENE
)	O
,	O
p120	B-GENE
Ras	B-GENE
-	O
GAP	B-GENE
,	O
has	O
been	O
implicated	O
as	O
both	O
a	O
downregulator	O
and	O
effector	O
of	O
Ras	B-GENE
proteins	I-GENE
,	O
but	O
its	O
precise	O
role	O
in	O
Ras	B-GENE
-	O
mediated	O
signal	O
transduction	O
pathways	O
is	O
unclear	O
.	O

Three	O
mog	B-GENE
-	I-GENE
1	I-GENE
alleles	I-GENE
possess	O
premature	O
stop	O
codons	O
and	O
are	O
likely	O
to	O
be	O
null	O
alleles	O
,	O
and	O
one	O
is	O
a	O
missense	O
mutation	O
and	O
is	O
likely	O
to	O
retain	O
residual	O
activity	O
.	O
mog	B-GENE
-	I-GENE
1	I-GENE
mRNA	I-GENE
is	O
expressed	O
in	O
both	O
germ	O
line	O
and	O
somatic	O
tissues	O
and	O
appears	O
to	O
be	O
ubiquitous	O
.	O

However	O
,	O
unlike	O
the	O
SIN3	B-GENE
gene	I-GENE
of	O
Saccharomyces	O
cerevisiae	O
,	O
pst1	B-GENE
(	I-GENE
+	I-GENE
)	I-GENE
is	O
essential	O
for	O
cell	O
viability	O
.	O

The	O
Nmd3	B-GENE
protein	I-GENE
sequence	I-GENE
does	O
not	O
contain	O
readily	O
recognizable	O
motifs	O
of	O
known	O
function	O
.	O

The	O
distribution	O
of	O
the	O
various	O
repeats	O
suggests	O
its	O
organization	O
is	O
similar	O
to	O
the	O
beta	O
-	O
heterochromatic	O
regions	O
near	O
the	O
base	O
of	O
the	O
major	O
chromosome	O
arms	O
.	O

Calcitonin	B-GENE
simultaneously	O
regulates	O
both	O
periosteal	O
hyperostosis	O
and	O
trabecular	O
osteopenia	O
in	O
the	O
spinal	O
hyperostotic	O
mouse	O
(	O
twy	B-GENE
/	O
twy	B-GENE
)	O
in	O
vivo	O
.	O

In	O
addition	O
,	O
we	O
also	O
show	O
that	O
cdk7	B-GENE
may	O
phosphorylate	O
the	O
carboxy	O
-	O
terminal	O
domain	O
(	O
CTD	O
)	O
of	O
RNA	B-GENE
pol	I-GENE
II	I-GENE
in	O
the	O
absence	O
of	O
promoter	O
opening	O
.	O

The	O
therapy	O
with	O
a	O
H2	B-GENE
-	I-GENE
receptor	I-GENE
antagonist	O
is	O
less	O
effective	O
than	O
the	O
triple	O
therapies	O
with	O
omeprazole	O
or	O
lansoprazole	O
.	O

In	O
humans	O
,	O
three	O
tissue	B-GENE
-	I-GENE
specific	I-GENE
plastin	I-GENE
isoforms	I-GENE
have	O
been	O
identified	O
.	O

No	O
TATA	O
or	O
Inr	O
sequence	O
was	O
found	O
.	O

The	O
inhibition	O
by	O
the	O
RIalpha	B-GENE
subunit	I-GENE
is	O
reversed	O
by	O
addition	O
of	O
nanomolar	O
concentrations	O
of	O
cAMP	O
(	O
Ka	O
=	O
40	O
nM	O
)	O
,	O
thus	O
demonstrating	O
that	O
PrKX	B-GENE
is	O
a	O
novel	O
,	O
type	B-GENE
I	I-GENE
cAMP	I-GENE
-	I-GENE
dependent	I-GENE
protein	I-GENE
kinase	I-GENE
that	O
is	O
activated	O
at	O
lower	O
cAMP	O
concentrations	O
than	O
the	O
holoenzyme	O
with	O
the	O
Calpha	B-GENE
subunit	I-GENE
of	O
cAMP	B-GENE
-	I-GENE
dependent	I-GENE
protein	I-GENE
kinase	I-GENE
.	O

In	O
addition	O
,	O
in	O
vitro	O
mutagenesis	O
of	O
both	O
Engrailed	B-GENE
and	O
Pbx1	B-GENE
sites	I-GENE
indicated	O
that	O
other	O
unidentified	O
sites	O
are	O
responsible	O
for	O
the	O
transcriptional	O
enhancement	O
observed	O
with	O
the	O
intronic	O
fragment	O
.	O

Several	O
secondary	O
structure	O
elements	O
were	O
identified	O
.	O

Here	O
,	O
we	O
evidence	O
that	O
the	O
developmental	O
functions	O
of	O
the	O
family	O
of	O
transcription	O
factors	O
characterized	O
by	O
the	O
POU	B-GENE
DNA	I-GENE
binding	I-GENE
motif	I-GENE
exerts	O
roles	O
in	O
mammalian	O
development	O
.	O

High	O
-	O
affinity	O
site	O
-	O
specific	O
DNA	O
binding	O
by	O
POU	B-GENE
domain	I-GENE
transcription	I-GENE
factors	I-GENE
requires	O
both	O
the	O
POU	B-GENE
-	I-GENE
specific	I-GENE
and	O
the	O
POU	B-GENE
-	I-GENE
homeodomain	I-GENE
.	O

In	O
the	O
Oct	B-GENE
-	I-GENE
1	I-GENE
crystal	O
,	O
the	O
POU	B-GENE
-	I-GENE
specific	I-GENE
domain	I-GENE
recognizes	O
a	O
GCAT	O
half	O
-	O
site	O
,	O
while	O
the	O
corresponding	O
sequence	O
recognized	O
by	O
the	O
Pit	B-GENE
-	I-GENE
1	I-GENE
POU	B-GENE
-	O
specific	O
domain	O
,	O
GTAT	O
,	O
is	O
on	O
the	O
opposing	O
strand	O
.	O

Most	O
other	O
end	O
points	O
were	O
highly	O
significant	O
,	O
and	O
death	O
,	O
which	O
was	O
monitored	O
across	O
the	O
U	O
.	O
S	O
.	O
program	O
,	O
was	O
different	O
with	O
p	O
<	O
0	O
.	O
0001	O
.	O

The	O
other	O
is	O
located	O
at	O
-	O
1335	O
,	O
outside	O
this	O
highly	O
conserved	O
region	O
.	O

Those	O
radiological	O
aspects	O
were	O
distributed	O
in	O
two	O
categories	O
:	O
1	O
)	O
type	O
I	O
-	O
presenting	O
variable	O
sinusoidal	O
filling	O
.	O

Results	O
demonstrated	O
that	O
the	O
presence	O
of	O
myofibroblasts	O
varied	O
considerably	O
from	O
case	O
to	O
case	O
and	O
was	O
always	O
related	O
to	O
smooth	O
muscle	O
cell	O
dispersion	O
,	O
which	O
occurred	O
around	O
medium	O
-	O
sized	O
damaged	O
portal	O
vein	O
branches	O
.	O

Radiative	O
corrections	O
to	O
beta	O
decay	O
and	O
the	O
possibility	O
of	O
a	O
fourth	O
generation	O
.	O

Depth	O
-	O
controlled	O
grazing	O
-	O
incidence	O
diffraction	O
of	O
synchrotron	O
x	O
radiation	O
.	O

Oscillatory	O
exchange	O
of	O
atoms	O
between	O
traps	O
containing	O
Bose	O
condensates	O
.	O

Structure	O
determination	O
of	O
an	O
adsorbate	O
-	O
induced	O
multilayer	O
reconstruction	O
:	O
(	O
1	O
x	O
2	O
)	O
-	O
H	O
/	O
Ni	O
(	O
110	O
)	O
.	O

Magnetic	O
trapping	O
of	O
spin	O
-	O
polarized	O
atomic	O
hydrogen	O
.	O

Northern	O
blot	O
and	O
in	O
situ	O
hybridization	O
analyses	O
revealed	O
GPR34	B-GENE
mRNA	I-GENE
transcripts	I-GENE
in	O
several	O
human	O
and	O
rat	O
brain	O
regions	O
.	O

The	O
microphthalmia	B-GENE
-	I-GENE
TFE	I-GENE
(	O
MiT	B-GENE
)	O
subfamily	O
of	O
basic	B-GENE
helix	I-GENE
-	I-GENE
loop	I-GENE
-	I-GENE
helix	I-GENE
leucine	I-GENE
zipper	I-GENE
(	I-GENE
bHLH	I-GENE
-	I-GENE
ZIP	I-GENE
)	I-GENE
transcription	I-GENE
factors	I-GENE
,	O
including	O
TFE3	B-GENE
,	O
TFEB	B-GENE
,	O
TFEC	B-GENE
,	O
and	O
Mitf	B-GENE
,	O
has	O
been	O
implicated	O
in	O
the	O
regulation	O
of	O
tissue	O
-	O
specific	O
gene	O
expression	O
in	O
several	O
cell	O
lineages	O
.	O

Fifty	O
-	O
seven	O
patients	O
aged	O
<	O
55	O
years	O
with	O
acute	O
lymphoblastic	O
leukemia	O
(	O
ALL	O
)	O
in	O
second	O
or	O
third	O
bone	O
marrow	O
(	O
BM	O
)	O
relapse	O
or	O
refractory	O
to	O
first	O
-	O
line	O
therapy	O
were	O
enrolled	O
in	O
an	O
Italian	O
cooperative	O
study	O
.	O

The	O
dorsal	O
nerves	O
of	O
the	O
penis	O
were	O
anesthetized	O
bilaterally	O
with	O
lidocaine	O
.	O

Early	O
-	O
onset	O
scleral	O
necrosis	O
after	O
iodine	O
I	O
125	O
plaque	O
radiotherapy	O
for	O
ciliochoroidal	O
melanoma	O
.	O

Successful	O
interaction	O
of	O
ARF	B-GENE
and	O
PKC	B-GENE
-	I-GENE
alpha	I-GENE
with	O
PLD1	B-GENE
was	O
not	O
achieved	O
,	O
but	O
a	O
C	O
-	O
terminal	O
fragment	O
of	O
human	B-GENE
PLD1	I-GENE
(	O
denoted	O
"	O
D4	O
"	O
)	O
interacted	O
with	O
the	O
active	O
mutant	O
of	O
RhoA	B-GENE
,	O
RhoAVal	B-GENE
-	I-GENE
14	I-GENE
.	O

Vacuum	O
Rabi	O
splitting	O
as	O
a	O
feature	O
of	O
linear	O
-	O
dispersion	O
theory	O
:	O
Analysis	O
and	O
experimental	O
observations	O
.	O

High	O
-	O
pressure	O
effects	O
on	O
ultrafast	O
-	O
relaxation	O
kinetics	O
of	O
excitons	O
in	O
polydiacetylene	O
4BCMU	O
.	O

Drag	O
reduction	O
in	O
turbulent	O
flows	O
by	O
polymers	O
.	O

Large	O
scale	O
electronic	O
structure	O
calculations	O
.	O

Current	O
world	O
literature	O
.	O

These	O
results	O
show	O
that	O
Ski	B-GENE
is	O
a	O
component	O
of	O
the	O
HDAC	B-GENE
complex	I-GENE
and	O
that	O
Ski	B-GENE
is	O
required	O
for	O
the	O
transcriptional	O
repression	O
mediated	O
by	O
this	O
complex	O
.	O

Recombinant	O
unr	B-GENE
acts	O
synergistically	O
with	O
recombinant	O
PTB	B-GENE
to	O
stimulate	O
translation	O
dependent	O
on	O
the	O
rhinovirus	O
IRES	O
.	O

Analysis	O
of	O
the	O
consensus	O
binding	O
sequence	O
and	O
the	O
DNA	O
-	O
binding	O
domain	O
of	O
ZF5	B-GENE
.	O

Mapping	O
of	O
the	O
human	B-GENE
Voltage	I-GENE
-	I-GENE
Dependent	I-GENE
Anion	I-GENE
Channel	I-GENE
isoforms	I-GENE
1	I-GENE
and	I-GENE
2	I-GENE
reconsidered	O
.	O

Identification	O
of	O
RNase	B-GENE
T	I-GENE
as	O
a	O
high	O
-	O
copy	O
suppressor	O
of	O
the	O
UV	O
sensitivity	O
associated	O
with	O
single	B-GENE
-	I-GENE
strand	I-GENE
DNA	I-GENE
exonuclease	I-GENE
deficiency	O
in	O
Escherichia	O
coli	O
.	O

Inhibition	O
of	O
phosphatidylinositol	B-GENE
-	I-GENE
3	I-GENE
kinase	I-GENE
did	O
not	O
have	O
a	O
significant	O
effect	O
on	O
p53	B-GENE
conformation	O
but	O
did	O
have	O
a	O
weak	O
but	O
significant	O
effect	O
on	O
Tpo	B-GENE
-	O
enhanced	O
viability	O
.	O

No	O
difference	O
in	O
percentage	O
of	O
males	O
in	O
semen	O
production	O
was	O
noted	O
between	O
strains	O
,	O
CP	O
levels	O
,	O
or	O
feeding	O
regimens	O
.	O

Further	O
analysis	O
of	O
AP	B-GENE
-	I-GENE
1	I-GENE
DNA	O
binding	O
activities	O
in	O
7	O
-	O
to	O
14	O
-	O
day	O
culture	O
activated	O
HSCs	O
led	O
to	O
the	O
discovery	O
of	O
high	B-GENE
mobility	I-GENE
AP	I-GENE
-	I-GENE
1	I-GENE
complexes	I-GENE
(	O
HMAP	B-GENE
-	I-GENE
1	I-GENE
)	O
.	O

Mutations	O
of	O
the	O
AP	B-GENE
-	I-GENE
1	I-GENE
site	I-GENE
of	O
the	O
TIMP	B-GENE
-	I-GENE
1	I-GENE
promoter	I-GENE
that	O
prevented	O
formation	O
of	O
HMAP	B-GENE
-	I-GENE
1	I-GENE
caused	O
a	O
70	O
%	O
loss	O
of	O
activity	O
in	O
transfected	O
activated	O
HSCs	O
.	O

STUDY	O
DESIGN	O
:	O
Salivary	B-GENE
immunoglobulin	I-GENE
A	I-GENE
levels	O
of	O
each	O
of	O
20	O
subjects	O
were	O
determined	O
on	O
3	O
occasions	O
:	O
first	O
,	O
while	O
the	O
subject	O
was	O
still	O
smoking	O
;	O
second	O
,	O
7	O
days	O
after	O
cessation	O
of	O
smoking	O
;	O
third	O
,	O
on	O
the	O
14th	O
day	O
after	O
cessation	O
.	O

Role	O
of	O
g2	O
in	O
relating	O
the	O
Schwinger	O
and	O
Gerasimov	O
-	O
Drell	O
-	O
Hearn	O
sum	O
rules	O
.	O

Spectroscopy	O
of	O
negative	O
ions	O
utilizing	O
multiphoton	O
detachment	O
in	O
a	O
Raman	O
coupling	O
regime	O
.	O

Band	O
structure	O
effects	O
of	O
transport	O
properties	O
in	O
icosahedral	O
quasicrystals	O
.	O

Acoustic	O
transmission	O
spectra	O
in	O
the	O
Penrose	O
lattice	O
.	O

Two	O
-	O
Channel	O
Kondo	O
Lattice	O
:	O
An	O
Incoherent	O
Metal	O
.	O

Basal	O
midexpiratory	O
lower	O
esophageal	O
sphincter	O
pressure	O
was	O
similar	O
in	O
the	O
study	O
group	O
(	O
mean	O
[	O
SD	O
]	O
20	O
.	O
1	O
[	O
9	O
.	O
1	O
]	O
mmHg	O
)	O
and	O
controls	O
(	O
17	O
.	O
6	O
[	O
6	O
.	O
0	O
]	O
mmHg	O
)	O
;	O
the	O
pressure	O
did	O
not	O
change	O
following	O
EVS	O
or	O
EVL	O
.	O

On	O
the	O
other	O
hand	O
,	O
subjects	O
with	O
air	O
trapping	O
(	O
residual	O
volume	O
(	O
RV	O
)	O
/	O
total	O
lung	O
capacity	O
(	O
TLC	O
)	O
>	O
37	O
%	O
)	O
disclosed	O
not	O
only	O
a	O
higher	O
n	O
(	O
mit	O
)	O
(	O
0	O
.	O
63	O
+	O
/	O
-	O
0	O
.	O
17	O
versus	O
0	O
.	O
43	O
+	O
/	O
-	O
0	O
.	O
07	O
mt	O
x	O
microm	O
(	O
-	O
2	O
)	O
,	O
p	O
<	O
0	O
.	O
05	O
)	O
but	O
shorter	O
sarcomeres	O
(	O
L	O
(	O
sar	O
)	O
)	O
than	O
subjects	O
without	O
this	O
functional	O
abnormality	O
(	O
2	O
.	O
08	O
+	O
/	O
-	O
0	O
.	O
16	O
to	O
2	O
.	O
27	O
+	O
/	O
-	O
0	O
.	O
15	O
microm	O
,	O
p	O
<	O
0	O
.	O
05	O
)	O
.	O

Cyclin	B-GENE
D1	I-GENE
-	I-GENE
associated	I-GENE
kinase	I-GENE
activity	O
and	O
protein	O
levels	O
were	O
increased	O
in	O
mammary	O
tumors	O
from	O
murine	O
mammary	O
tumor	O
virus	O
-	O
pp60	B-GENE
(	O
c	B-GENE
-	I-GENE
src527F	I-GENE
)	O
transgenic	O
mice	O
.	O

The	O
SH2	B-GENE
domain	I-GENE
-	I-GENE
containing	I-GENE
inositol	I-GENE
5	I-GENE
'	I-GENE
-	I-GENE
phosphatase	I-GENE
(	O
SHIP	B-GENE
)	O
recruits	O
the	O
p85	B-GENE
subunit	I-GENE
of	O
phosphoinositide	B-GENE
3	I-GENE
-	I-GENE
kinase	I-GENE
during	O
FcgammaRIIb1	B-GENE
-	O
mediated	O
inhibition	O
of	O
B	B-GENE
cell	I-GENE
receptor	I-GENE
signaling	O
.	O

An	O
increase	O
in	O
bone	O
mineral	O
density	O
at	O
the	O
spine	O
,	O
total	O
hip	O
,	O
and	O
total	O
body	O
has	O
been	O
reported	O
with	O
raloxifene	O
but	O
seems	O
to	O
be	O
less	O
than	O
that	O
seen	O
with	O
estrogen	O
or	O
alendronate	O
therapy	O
.	O

However	O
,	O
in	O
those	O
studies	O
due	O
to	O
the	O
presence	O
of	O
thiol	O
agents	O
in	O
the	O
PKC	B-GENE
preparations	O
,	O
the	O
sensitive	O
reaction	O
of	O
BPO	O
with	O
redox	O
-	O
active	O
cysteine	O
residues	O
in	O
PKC	B-GENE
was	O
not	O
observed	O
.	O

Interestingly	O
,	O
Csx	B-GENE
/	O
Nkx2	B-GENE
.	O

We	O
also	O
identified	O
an	O
alternative	O
spliced	O
form	O
of	O
Lyp	B-GENE
RNA	I-GENE
,	O
Lyp2	B-GENE
.	O

The	O
costs	O
were	O
DM	O
11	O
,	O
562	O
for	O
a	O
PE	O
,	O
DM	O
12	O
,	O
477	O
for	O
a	O
VR	O
and	O
DM	O
7	O
,	O
532	O
for	O
a	O
MR	O
.	O

We	O
now	O
provide	O
evidence	O
for	O
physical	O
and	O
functional	O
interaction	O
between	O
Doa4	B-GENE
and	O
the	O
proteasome	O
.	O

Nipponbare	O
as	O
well	O
as	O
O	O
.	O
australiensis	O
.	O

In	O
addition	O
,	O
mapping	O
of	O
the	O
promoter	O
region	O
and	O
the	O
identification	O
of	O
putative	O
promoter	O
regulatory	O
sequences	O
should	O
give	O
insight	O
into	O
the	O
transcriptional	O
regulation	O
of	O
UCP2	B-GENE
expression	O
-	O
-	O
in	O
particular	O
by	O
anyone	O
of	O
the	O
above	O
mentioned	O
factors	O
-	O
-	O
in	O
vitro	O
and	O
in	O
vivo	O
.	O

The	O
rate	O
of	O
resectability	O
is	O
low	O
and	O
5	O
-	O
year	O
survival	O
is	O
very	O
poor	O
.	O

In	O
order	O
to	O
better	O
characterize	O
the	O
distribution	O
of	O
ML	O
and	O
MAP	O
estimates	O
under	O
these	O
conditions	O
,	O
we	O
derive	O
a	O
point	O
approximation	O
to	O
density	O
values	O
of	O
the	O
conditional	O
distribution	O
of	O
such	O
estimates	O
.	O

RT	O
-	O
PCR	O
was	O
performed	O
using	O
previously	O
reported	O
degenerate	O
oligonucleotide	O
primers	O
to	O
the	O
ligand	O
binding	O
domain	O
(	O
LBD	O
)	O
of	O
known	O
beta	B-GENE
integrin	I-GENE
subunits	I-GENE
and	O
Bge	B-GENE
cDNA	I-GENE
.	O

The	O
lowest	O
culture	O
failure	O
rate	O
of	O
0	O
.	O
2	O
per	O
cent	O
was	O
found	O
after	O
EAF	O
compared	O
with	O
0	O
.	O
9	O
per	O
cent	O
among	O
CVS	O
.	O

Ectopic	O
expression	O
of	O
d	B-GENE
-	I-GENE
axin	I-GENE
inhibited	O
Wingless	B-GENE
signaling	O
.	O

The	O
corresponding	O
differences	O
in	O
FVIIa	B-GENE
and	O
PAI	B-GENE
-	I-GENE
1	I-GENE
were	O
not	O
statistically	O
significant	O
.	O

On	O
the	O
other	O
side	O
,	O
when	O
the	O
aortic	O
ring	O
was	O
perfused	O
with	O
L	O
-	O
NNA	O
(	O
NO	O
-	O
synthesis	O
inhibitor	O
)	O
or	O
methylene	O
blue	O
(	O
soluble	O
cGMPase	B-GENE
inhibitor	O
)	O
,	O
the	O
changes	O
could	O
be	O
attenuated	O
.	O

Nevertheless	O
,	O
inactivation	O
of	O
the	O
cyclin	B-GENE
E	I-GENE
-	O
Cdk2	B-GENE
complex	O
in	O
response	O
to	O
mitogen	O
starvation	O
occurs	O
normally	O
in	O
MEFs	O
that	O
have	O
a	O
homozygous	O
deletion	O
of	O
the	O
p27	B-GENE
gene	I-GENE
.	O

Identification	O
and	O
characterization	O
of	O
IS2404	B-GENE
and	O
IS2606	B-GENE
:	O
two	O
distinct	O
repeated	O
sequences	O
for	O
detection	O
of	O
Mycobacterium	O
ulcerans	O
by	O
PCR	O
.	O

Taken	O
together	O
,	O
these	O
results	O
are	O
consistent	O
with	O
the	O
possibility	O
that	O
p202	B-GENE
protein	I-GENE
contributes	O
to	O
the	O
cell	O
growth	O
retardation	O
activity	O
of	O
the	O
IFNs	B-GENE
,	O
at	O
least	O
in	O
part	O
,	O
by	O
modulating	O
p21	B-GENE
protein	I-GENE
levels	O
.	O

Similar	O
results	O
were	O
also	O
obtained	O
with	O
a	O
HepG2	O
hepatoblastoma	O
cell	O
line	O
carrying	O
wt	B-GENE
p53	I-GENE
.	O

Partial	O
sequencing	O
of	O
the	O
region	O
downstream	O
of	O
ORF	B-GENE
-	I-GENE
Pto	I-GENE
revealed	O
homology	O
to	O
the	O
ru	B-GENE
/	I-GENE
AB	I-GENE
genes	I-GENE
,	O
involved	O
in	O
UV	O
resistance	O
,	O
from	O
plasmid	O
pPSR1	O
.	O

The	O
MSY2	B-GENE
associated	O
kinase	O
is	O
not	O
casein	B-GENE
kinase	I-GENE
2	I-GENE
,	O
the	O
kinase	O
believed	O
to	O
phosphorylate	O
mRNP3	B-GENE
+	I-GENE
4	I-GENE
in	O
oocytes	O
,	O
but	O
a	O
yet	O
unidentified	O
kinase	O
.	O

This	O
suggests	O
that	O
helicase	B-GENE
-	I-GENE
like	I-GENE
genes	I-GENE
may	O
be	O
involved	O
in	O
the	O
biosynthesis	O
of	O
nucleic	O
acids	O
and	O
proteins	O
,	O
and	O
that	O
the	O
genes	O
can	O
be	O
transcriptionally	O
activated	O
by	O
heat	O
shock	O
to	O
compensate	O
for	O
the	O
repressed	O
synthesis	O
of	O
mRNA	O
and	O
protein	O
.	O

These	O
data	O
provide	O
the	O
molecular	O
tools	O
for	O
the	O
final	O
identification	O
of	O
the	O
MKS	B-GENE
and	O
the	O
MUL	B-GENE
genes	I-GENE
.	O

The	O
origins	O
of	O
reflected	O
light	O
changes	O
associated	O
with	O
neuronal	O
activity	O
(	O
optical	O
signals	O
)	O
were	O
investigated	O
in	O
rat	O
somatosensory	O
cortex	O
with	O
optical	O
imaging	O
,	O
microspectrophotometry	O
,	O
and	O
laser	O
-	O
Doppler	O
flowmetry	O
,	O
and	O
dynamic	O
changes	O
in	O
local	O
hemoglobin	B-GENE
concentration	O
and	O
oxygenation	O
were	O
focused	O
on	O
.	O

Human	B-GENE
neuronal	I-GENE
Elav	I-GENE
-	I-GENE
like	I-GENE
proteins	I-GENE
contain	O
three	O
RNP	O
-	O
type	O
RNA	O
recognition	O
motifs	O
(	O
RRMs	O
)	O
.	O

Comparison	O
of	O
frequencies	O
of	O
atrial	O
fibrillation	O
after	O
coronary	O
artery	O
bypass	O
grafting	O
with	O
and	O
without	O
the	O
use	O
of	O
cardiopulmonary	O
bypass	O
.	O

The	O
results	O
of	O
supershift	O
analysis	O
using	O
specific	O
antibodies	O
against	O
transcription	O
factors	O
suggested	O
that	O
both	O
binding	O
complexes	O
contained	O
the	O
NF	B-GENE
-	I-GENE
kappaB	I-GENE
components	O
p50	B-GENE
and	O
p65	B-GENE
,	O
and	O
did	O
not	O
contain	O
other	O
NF	B-GENE
-	I-GENE
kappaB	I-GENE
proteins	I-GENE
(	O
p52	B-GENE
,	O
c	B-GENE
-	I-GENE
Rel	I-GENE
,	O
Rel	B-GENE
B	I-GENE
)	O
,	O
AP	B-GENE
-	I-GENE
1	I-GENE
proteins	I-GENE
(	O
c	B-GENE
-	I-GENE
Fos	I-GENE
,	O
C	B-GENE
-	I-GENE
Jun	I-GENE
)	O
,	O
CREB	B-GENE
or	O
C	B-GENE
/	I-GENE
EBPbeta	I-GENE
(	O
NF	B-GENE
-	I-GENE
IL6	I-GENE
)	O
.	O

A	O
set	O
of	O
peptides	O
corresponding	O
to	O
the	O
individual	O
elements	O
of	O
secondary	O
structure	O
derived	O
from	O
the	O
N	O
-	O
terminal	O
domain	O
of	O
the	O
ribosomal	B-GENE
protein	I-GENE
L9	I-GENE
have	O
been	O
synthesized	O
.	O

The	O
results	O
showed	O
that	O
IFN	B-GENE
-	I-GENE
gamma	I-GENE
stimulated	O
the	O
rapid	O
accumulation	O
of	O
interferon	B-GENE
regulated	I-GENE
factor	I-GENE
(	I-GENE
IRF	I-GENE
)	I-GENE
-	I-GENE
1	I-GENE
mRNA	I-GENE
,	O
followed	O
by	O
a	O
delayed	O
and	O
dose	O
-	O
dependent	O
inhibition	O
of	O
alpha1	B-GENE
(	I-GENE
I	I-GENE
)	I-GENE
procollagen	I-GENE
mRNA	I-GENE
expression	O
in	O
skin	O
fibroblasts	O
from	O
several	O
different	O
donors	O
.	O

Functional	O
domains	O
of	O
c	B-GENE
-	I-GENE
myc	I-GENE
promoter	I-GENE
binding	I-GENE
protein	I-GENE
1	I-GENE
involved	O
in	O
transcriptional	O
repression	O
and	O
cell	O
growth	O
regulation	O
.	O

Therefore	O
,	O
we	O
have	O
named	O
this	O
gene	O
UBP43	B-GENE
.	O

These	O
results	O
continue	O
to	O
support	O
the	O
hypothesis	O
that	O
HS2	O
,	O
HS3	O
,	O
and	O
HS4	O
act	O
as	O
a	O
single	O
,	O
integral	O
unit	O
to	O
regulate	O
human	B-GENE
globin	I-GENE
gene	I-GENE
transcription	O
as	O
a	O
holocomplex	O
,	O
but	O
they	O
can	O
also	O
be	O
interpreted	O
to	O
say	O
that	O
formation	O
of	O
a	O
DNase	B-GENE
I	I-GENE
hypersensitive	O
holocomplex	O
alone	O
is	O
not	O
sufficient	O
for	O
mediating	O
high	O
-	O
level	O
globin	B-GENE
gene	I-GENE
transcription	O
.	O

Because	O
there	O
is	O
great	O
need	O
for	O
iron	O
in	O
the	O
EPO	B-GENE
-	O
stimulated	O
erythroid	O
progenitors	O
,	O
it	O
is	O
essential	O
that	O
serum	B-GENE
ferritin	I-GENE
and	O
transferrin	B-GENE
saturation	O
levels	O
should	O
be	O
maintained	O
over	O
300	O
microg	O
/	O
liter	O
and	O
30	O
%	O
,	O
respectively	O
.	O

These	O
results	O
indicate	O
that	O
the	O
p33	B-GENE
subunit	I-GENE
of	O
eIF3	B-GENE
plays	O
an	O
important	O
role	O
in	O
the	O
initiation	O
phase	O
of	O
protein	O
synthesis	O
and	O
that	O
its	O
RNA	O
-	O
binding	O
domain	O
is	O
required	O
for	O
optimal	O
activity	O
.	O

KEY	O
WORDS	O
:	O
Melaleuca	O
;	O
Lake	O
Okeechobee	O
;	O
Littoral	O
zone	O
;	O
Water	O
level	O
;	O
Regulation	O
schedule	O

The	O
systolic	O
peak	O
of	O
pulmonary	O
vein	O
was	O
higher	O
than	O
the	O
diastolic	O
peak	O
in	O
45	O
out	O
of	O
56	O
cases	O
.	O

Specimens	O
were	O
assayed	O
for	O
alpha	B-GENE
-	I-GENE
fetoprotein	I-GENE
,	O
unconjugated	O
estriol	O
,	O
free	O
alpha	B-GENE
hCG	I-GENE
,	O
and	O
total	O
hCG	B-GENE
.	O

The	O
following	O
data	O
were	O
recorded	O
at	O
arrival	O
in	O
the	O
intensive	O
care	O
unit	O
6	O
,	O
12	O
,	O
24	O
,	O
and	O
48	O
hours	O
after	O
termination	O
of	O
CPB	O
:	O
heart	O
rate	O
,	O
blood	O
pressure	O
,	O
left	O
atrial	O
pressure	O
,	O
central	O
-	O
peripheral	O
temperature	O
difference	O
,	O
arterial	O
-	O
central	O
venous	O
oxygen	O
saturation	O
difference	O
,	O
urine	O
output	O
,	O
serum	O
creatinine	O
,	O
lactate	O
and	O
neutrophil	B-GENE
elastase	I-GENE
levels	O
,	O
the	O
Doppler	O
echocardiographic	O
factors	O
shortening	O
fraction	O
and	O
preejection	O
period	O
/	O
left	O
-	O
ventricular	O
ejection	O
time	O
,	O
and	O
cumulative	O
doses	O
of	O
catecholamines	O
(	O
epinephrine	O
)	O
,	O
enoximone	O
,	O
and	O
furosemide	O
.	O

MDS1	B-GENE
/	O
EVI1	B-GENE
,	O
located	O
on	O
chromosome	O
3	O
band	O
q26	O
,	O
encodes	O
a	O
zinc	B-GENE
-	I-GENE
finger	I-GENE
DNA	I-GENE
-	I-GENE
binding	I-GENE
transcription	I-GENE
activator	I-GENE
not	O
detected	O
in	O
normal	O
hematopoietic	O
cells	O
but	O
expressed	O
in	O
several	O
normal	O
tissues	O
.	O

The	O
JTc	O
delta	O
among	O
the	O
three	O
groups	O
did	O
not	O
differ	O
as	O
well	O
:	O
JTc	O
delta	O
of	O
the	O
VT	O
group	O
was	O
70	O
ms	O
+	O
/	O
-	O
30	O
ms	O
,	O
the	O
JTc	O
delta	O
of	O
the	O
PVC	O
group	O
was	O
60	O
msec	O
+	O
/	O
-	O
25	O
msec	O
,	O
and	O
the	O
JTc	O
delta	O
of	O
the	O
control	O
group	O
was	O
70	O
ms	O
+	O
/	O
-	O
30	O
ms	O
.	O

In	O
contrast	O
,	O
deletion	O
of	O
the	O
upstream	O
portion	O
of	O
the	O
delta	O
promoter	O
led	O
to	O
a	O
10	O
fold	O
decrease	O
in	O
expression	O
.	O

Site	O
-	O
directed	O
mutagenesis	O
of	O
binding	O
sites	O
for	O
the	O
repressor	B-GENE
proteins	I-GENE
BP1	I-GENE
and	O
BP2	B-GENE
in	O
the	O
upstream	O
portion	O
of	O
the	O
beta	B-GENE
globin	I-GENE
gene	I-GENE
flanking	I-GENE
region	I-GENE
led	O
to	O
a	O
4	O
-	O
6	O
fold	O
increase	O
in	O
promoter	O
activity	O
.	O

However	O
,	O
with	O
the	O
alpha1	O
antagonist	O
prazosin	O
(	O
5	O
x	O
10	O
(	O
-	O
8	O
)	O
-	O
5	O
x	O
10	O
(	O
-	O
7	O
)	O
M	O
)	O
,	O
no	O
relaxation	O
occurred	O
.	O

Differential	O
expression	O
of	O
AP	B-GENE
-	I-GENE
2alpha	I-GENE
and	O
AP	B-GENE
-	I-GENE
2beta	I-GENE
in	O
the	O
developing	O
chick	O
retina	O
:	O
repression	O
of	O
R	B-GENE
-	I-GENE
FABP	I-GENE
promoter	I-GENE
activity	O
by	O
AP	B-GENE
-	I-GENE
2	I-GENE
.	O

The	O
mean	O
value	O
of	O
the	O
CD79b	B-GENE
to	O
the	O
CD79b	B-GENE
internally	O
deleted	O
ratio	O
was	O
0	O
.	O
64	O
+	O
/	O
-	O
0	O
.	O
20	O
SD	O
in	O
normal	O
donors	O
and	O
0	O
.	O
44	O
+	O
/	O
-	O
0	O
.	O
27	O
SD	O
in	O
B	O
-	O
CLL	O
(	O
P	O
=	O
.	O
01	O
)	O
.	O

As	O
normal	O
B	O
cells	O
also	O
present	O
this	O
variant	O
,	O
the	O
mechanism	O
of	O
CD79b	B-GENE
posttranscriptional	O
regulation	O
might	O
reflect	O
the	O
activation	O
stage	O
of	O
the	O
normal	O
B	O
cell	O
from	O
which	O
B	O
-	O
CLL	O
derives	O
.	O

High	O
-	O
level	O
gains	O
(	O
HLGs	O
)	O
indicative	O
of	O
gene	O
amplifications	O
were	O
identified	O
at	O
11q13	O
in	O
two	O
cases	O
,	O
and	O
in	O
one	O
case	O
each	O
at	O
2q33	O
-	O
34	O
,	O
3q25	O
-	O
29	O
,	O
5p15	O
.	O
1	O
-	O
15	O
.	O
2	O
,	O
7q21	O
-	O
22	O
,	O
11p11	O
.	O
2	O
,	O
12p11	O
.	O
2	O
-	O
12	O
,	O
and	O
13q34	O
.	O

With	O
respect	O
to	O
the	O
distribution	O
of	O
active	O
MREs	O
over	O
the	O
promoter	O
region	O
,	O
the	O
hMT	B-GENE
-	I-GENE
IIA	I-GENE
gene	I-GENE
is	O
largely	O
different	O
from	O
the	O
mouse	O
metallothionein	B-GENE
-	I-GENE
I	I-GENE
gene	I-GENE
,	O
suggesting	O
that	O
MRE	O
arrangement	O
is	O
not	O
an	O
important	O
factor	O
for	O
metal	O
regulation	O
.	O

The	O
cDNA	O
was	O
expressed	O
in	O
Saccharomyces	O
cerevisiae	O
under	O
the	O
control	O
of	O
the	O
yeast	B-GENE
triose	I-GENE
phosphate	I-GENE
isomerase	I-GENE
promoter	I-GENE
.	O

Interestingly	O
,	O
the	O
RNA	O
sequences	O
selected	O
by	O
the	O
mutated	O
zinc	B-GENE
knuckle	I-GENE
9G8	I-GENE
variant	I-GENE
are	O
efficiently	O
recognized	O
by	O
SRp20	B-GENE
,	O
in	O
agreement	O
with	O
the	O
fact	O
that	O
the	O
RBD	O
of	O
9G8	B-GENE
and	O
SRp20	B-GENE
are	O
similar	O
.	O

Topoisomerase	B-GENE
II	I-GENE
is	O
a	O
major	O
target	O
of	O
the	O
protein	B-GENE
kinase	I-GENE
casein	I-GENE
kinase	I-GENE
2	I-GENE
(	O
PK	B-GENE
CK2	I-GENE
)	O
in	O
vivo	O
.	O

Recent	O
work	O
in	O
this	O
laboratory	O
has	O
shown	O
that	O
the	O
gene	O
coding	O
for	O
acetate	B-GENE
kinase	I-GENE
(	O
ackA	B-GENE
)	O
in	O
Sinorhizobium	O
meliloti	O
is	O
up	O
-	O
regulated	O
in	O
response	O
to	O
phosphate	O
limitation	O
.	O

All	O
numbers	O
refer	O
to	O
nucleotide	O
positions	O
on	O
the	O
wild	O
-	O
type	O
HIV	O
-	O
1	O
transcript	O
.	O

Here	O
,	O
we	O
report	O
the	O
complete	O
structure	O
of	O
the	O
human	B-GENE
topoisomerase	I-GENE
IIalpha	I-GENE
gene	I-GENE
,	O
which	O
consists	O
of	O
35	O
exons	O
spanning	O
27	O
.	O
5	O
kb	O
.	O

Previous	O
studies	O
characterized	O
a	O
cytokine	O
-	O
inducible	O
,	O
functional	O
nuclear	B-GENE
factor	I-GENE
(	I-GENE
NF	I-GENE
)	I-GENE
-	I-GENE
kappaB	I-GENE
consensus	I-GENE
element	I-GENE
in	O
the	O
immediate	O
5	O
'	O
regulatory	O
region	O
of	O
the	O
MGSA	B-GENE
/	O
GRO	B-GENE
-	I-GENE
alpha	I-GENE
gene	O
at	O
-	O
78	O
bp	O
.	O

An	O
exon	O
that	O
prevents	O
transport	O
of	O
a	O
mature	O
mRNA	O
.	O

Four	O
CsA	O
-	O
treated	O
patients	O
developed	O
persistently	O
elevated	O
UAER	O
>	O
30	O
mg	O
/	O
24	O
h	O
(	O
n	O
=	O
3	O
with	O
microalbuminuria	O
)	O
,	O
whereas	O
all	O
the	O
17	O
placebo	O
-	O
treated	O
patients	O
had	O
normal	O
UAER	O
(	O
<	O
30	O
mg	O
/	O
24	O
h	O
)	O
after	O
7	O
years	O
of	O
follow	O
-	O
up	O
.	O

Mutational	O
analysis	O
of	O
the	O
-	O
84	O
/	O
-	O
55	O
DNA	O
showed	O
that	O
JEG	O
-	O
3	O
nuclear	O
proteins	O
bound	O
to	O
a	O
site	O
containing	O
,	O
but	O
not	O
identical	O
to	O
,	O
the	O
SF	B-GENE
-	I-GENE
1	I-GENE
sequence	I-GENE
.	O

In	O
contrast	O
,	O
no	O
change	O
was	O
detected	O
in	O
the	O
phenotype	O
of	O
'	O
unstressed	O
'	O
clones	O
,	O
with	O
respect	O
to	O
any	O
of	O
the	O
following	O
parameters	O
:	O
proliferation	O
rate	O
in	O
monolayer	O
,	O
serum	O
-	O
dependence	O
for	O
proliferation	O
or	O
survival	O
,	O
tumorigenicity	O
,	O
cellular	O
morphology	O
,	O
or	O
tissue	O
-	O
specific	O
differentiation	O
markers	O
.	O

A	O
high	O
reactor	O
pH	O
(	O
+	O
/	O
-	O
8	O
)	O
,	O
a	O
short	O
solid	O
retention	O
time	O
(	O
<	O
150	O
days	O
)	O
,	O
and	O
the	O
presence	O
of	O
a	O
substantial	O
SRB	O
population	O
in	O
the	O
inoculum	O
may	O
considerably	O
reduce	O
the	O
time	O
required	O
for	O
acetate	O
-	O
utilising	O
SRB	O
to	O
outcompete	O
MB	O
.	O

In	O
throttling	O
valves	O
,	O
the	O
aim	O
is	O
to	O
correlate	O
the	O
effect	O
of	O
shear	O
to	O
a	O
parameter	O
related	O
to	O
the	O
inner	O
geometry	O
of	O
the	O
valve	O
and	O
to	O
operating	O
conditions	O
.	O

A	O
mutation	O
linked	O
to	O
the	O
SOC1	B-GENE
gene	I-GENE
,	O
previously	O
defined	O
by	O
recessive	O
mutations	O
that	O
suppress	O
cbp1	B-GENE
ts	I-GENE
alleles	I-GENE
and	O
stabilize	O
many	O
mitochondrial	O
mRNAs	O
,	O
was	O
also	O
isolated	O
.	O

A	O
deletion	O
mutation	O
analysis	O
of	O
the	O
recombinant	O
protein	O
has	O
shown	O
that	O
the	O
N	O
-	O
terminal	O
region	O
and	O
the	O
two	O
leucine	O
zippers	O
are	O
necessary	O
for	O
the	O
binding	O
.	O

A	O
database	O
search	O
has	O
revealed	O
as	O
the	O
most	O
significative	O
homology	O
a	O
match	O
with	O
the	O
human	B-GENE
mitochondrial	I-GENE
transcription	I-GENE
termination	I-GENE
factor	I-GENE
(	O
mTERF	B-GENE
)	O
,	O
a	O
protein	O
that	O
also	O
binds	O
DNA	O
as	O
a	O
monomer	O
and	O
contains	O
three	O
leucine	O
zippers	O
forming	O
intramolecular	O
interactions	O
.	O

In	O
all	O
trials	O
,	O
antigen	O
challenge	O
followed	O
1	O
h	O
after	O
the	O
last	O
treatment	O
.	O

31	O
,	O
1997	O
,	O
40	O
patients	O
had	O
died	O
(	O
35	O
in	O
the	O
ERA	O
-	O
II	O
group	O
and	O
5	O
in	O
the	O
ERA	O
-	O
III	O
group	O
)	O
,	O
for	O
a	O
crude	O
mortality	O
rate	O
of	O
8	O
.	O
0	O
%	O
.	O

We	O
found	O
that	O
total	O
PSA	B-GENE
can	O
be	O
detected	O
in	O
all	O
cyst	O
fluids	O
and	O
in	O
about	O
75	O
%	O
of	O
female	O
sera	O
.	O

Type	O
I	O
cysts	O
(	O
with	O
a	O
high	O
K	O
+	O
/	O
Na	O
+	O
ratio	O
)	O
tend	O
to	O
have	O
higher	O
total	O
PSA	B-GENE
than	O
Type	O
II	O
cysts	O
.	O

Despite	O
this	O
DNA	O
binding	O
activity	O
,	O
AP	B-GENE
-	I-GENE
1	I-GENE
reporter	I-GENE
activity	O
was	O
suppressed	O
in	O
these	O
cells	O
.	O

A	O
single	O
N	O
-	O
glycosylation	O
site	O
present	O
in	O
chicken	B-GENE
gp42	I-GENE
is	O
conserved	O
among	O
all	O
five	O
of	O
these	O
proteins	O
:	O
carbohydrate	O
analysis	O
of	O
gp42	B-GENE
revealed	O
the	O
presence	O
of	O
a	O
complex	O
type	O
glycan	O
chain	O
at	O
this	O
site	O
.	O

Here	O
we	O
describe	O
the	O
optimization	O
and	O
characterization	O
of	O
a	O
140	O
-	O
residue	O
fragment	O
,	O
containing	O
the	O
Runt	B-GENE
domain	I-GENE
of	O
AML1	B-GENE
,	O
which	O
is	O
suitable	O
for	O
structural	O
studies	O
.	O

Judge	O
OKs	O
docs	O
'	O
bid	O
for	O
Chicago	O
hospital	O
.	O

HANYS	O
criticizes	O
laparoscopic	O
gall	O
bladder	O
guidelines	O
.	O

Groups	O
dicker	O
for	O
price	O
breaks	O
as	O
anesthetic	O
gas	O
goes	O
multi	O
-	O
source	O
.	O

Troubled	O
CareNetwork	O
gets	O
pact	O
from	O
largest	O
teacher	O
union	O
in	O
Wis	O
.	O

Ultrasonography	O
provides	O
excellent	O
intraoperative	O
evaluation	O
of	O
spinal	O
cord	O
injury	O
.	O

UPMC	O
is	O
not	O
the	O
only	O
organization	O
pursuing	O
controlled	O
NHBC	O
organ	O
procurement	O
,	O
however	O
.	O

Because	O
of	O
concerns	O
regarding	O
blood	O
transfusion	O
-	O
related	O
communicable	O
disease	O
(	O
eg	O
,	O
acquired	O
immune	O
deficiency	O
syndrome	O
and	O
non	O
-	O
A	O
,	O
non	O
-	O
B	O
hepatitis	O
)	O
,	O
there	O
has	O
been	O
increasing	O
research	O
effort	O
into	O
postoperative	O
hemorrhage	O
related	O
to	O
cardiopulmonary	O
bypass	O
with	O
extracorporeal	O
circulation	O
.	O

They	O
contrast	O
trends	O
in	O
fertility	O
,	O
life	O
expectancy	O
ratios	O
,	O
and	O
gender	O
differences	O
in	O
these	O
countries	O
with	O
the	O
Hispanic	O
population	O
of	O
the	O
United	O
States	O
.	O

Holger	O
v	O
.	O

Hospital	O
hit	O
for	O
hiring	O
AHERF	O
physicians	O
.	O

Overexpression	O
of	O
either	O
DAP	B-GENE
-	I-GENE
1	I-GENE
or	O
sentrin	B-GENE
causes	O
apoptosis	O
of	O
TNF	B-GENE
-	O
sensitive	O
L929	O
fibroblast	O
cell	O
line	O
,	O
as	O
well	O
as	O
TNF	B-GENE
-	O
resistant	O
osteosarcoma	O
cell	O
line	O
,	O
U2OS	O
.	O

This	O
is	O
in	O
contrast	O
to	O
PPARgamma2	B-GENE
,	O
which	O
was	O
previously	O
shown	O
to	O
be	O
phosphorylated	O
at	O
a	O
single	O
site	O
in	O
a	O
motif	O
that	O
is	O
not	O
homologous	O
to	O
the	O
sites	O
now	O
described	O
in	O
PPARalpha	B-GENE
.	O

These	O
results	O
suggest	O
KCC3	B-GENE
is	O
a	O
new	O
member	O
of	O
the	O
KCC	B-GENE
family	I-GENE
that	O
is	O
under	O
distinct	O
regulation	O
from	O
KCC1	B-GENE
.	O

We	O
have	O
screened	O
the	O
elastin	B-GENE
gene	I-GENE
for	O
mutations	O
responsible	O
for	O
supravalvular	O
aortic	O
stenosis	O
(	O
SVAS	O
)	O
in	O
two	O
large	O
,	O
independently	O
collected	O
families	O
with	O
isolated	O
(	O
nonsyndromic	O
)	O
SVAS	O
.	O

Spatiotemporal	O
expression	O
of	O
the	O
PAX3	B-GENE
gene	I-GENE
is	O
tightly	O
regulated	O
during	O
development	O
.	O

A	O
list	O
of	O
12	O
names	O
for	O
the	O
disease	O
and	O
37	O
diagnostic	O
criteria	O
were	O
proposed	O
to	O
a	O
Consensus	O
Panel	O
of	O
12	O
Italian	O
experts	O
who	O
ranked	O
them	O
in	O
order	O
so	O
as	O
to	O
identify	O
a	O
core	O
set	O
of	O
criteria	O
.	O

Methanesulfonyl	O
fluoride	O
(	O
MSF	O
)	O
:	O
a	O
double	O
-	O
blind	O
,	O
placebo	O
-	O
controlled	O
study	O
of	O
safety	O
and	O
efficacy	O
in	O
the	O
treatment	O
of	O
senile	O
dementia	O
of	O
the	O
Alzheimer	O
type	O
.	O

METHODS	O
:	O
Between	O
August	O
1991	O
and	O
June	O
1994	O
,	O
198	O
men	O
with	O
clinical	O
T2	O
or	O
T3	O
classified	O
(	O
TNM	O
)	O
prostate	O
carcinoma	O
(	O
bone	O
scan	O
negative	O
)	O
who	O
were	O
at	O
high	O
risk	O
of	O
lymph	O
node	O
involvement	O
underwent	O
a	O
111In	O
-	O
capromab	O
pendetide	O
scan	O
prior	O
to	O
staging	O
lymphadenectomy	O
.	O

Voluntary	O
wheel	O
running	O
did	O
not	O
significantly	O
increase	O
estimated	O
alanine	O
or	O
pyruvate	O
Gneo	O
or	O
absolute	O
glycerol	O
Ra	O
.	O

Immediately	O
after	O
surgery	O
,	O
dialysate	O
PGE2	O
and	O
adenosine	O
concentrations	O
were	O
3	O
.	O
7	O
+	O
/	O
-	O
0	O
.	O
7	O
and	O
296	O
+	O
/	O
-	O
127	O
nM	O
,	O
respectively	O
.	O

Because	O
of	O
the	O
probable	O
causal	O
relationship	O
between	O
constitutive	O
p210	B-GENE
(	O
bcr	B-GENE
/	O
abl	B-GENE
)	O
protein	B-GENE
tyrosine	I-GENE
kinase	I-GENE
activity	O
and	O
manifestations	O
of	O
chronic	O
-	O
phase	O
chronic	O
myelogenous	O
leukemia	O
(	O
CML	O
;	O
myeloid	O
expansion	O
)	O
,	O
a	O
key	O
goal	O
is	O
to	O
identify	O
relevant	O
p210	B-GENE
substrates	O
in	O
primary	O
chronic	O
-	O
phase	O
CML	O
hematopoietic	O
progenitor	O
cells	O
.	O

In	O
vitro	O
precipitation	O
with	O
a	O
glutathione	B-GENE
-	I-GENE
S	I-GENE
-	I-GENE
transferase	I-GENE
-	I-GENE
fusion	I-GENE
protein	I-GENE
containing	O
the	O
C	O
-	O
terminal	O
transactivation	O
domain	O
of	O
STAT5a	B-GENE
showed	O
GH	B-GENE
-	O
regulated	O
association	O
of	O
ERK1	B-GENE
/	I-GENE
2	I-GENE
with	O
the	O
fusion	O
protein	O
,	O
while	O
this	O
was	O
not	O
seen	O
when	O
serine	O
780	O
in	O
STAT5a	B-GENE
was	O
changed	O
to	O
alanine	O
.	O

One	O
such	O
element	O
,	O
1P	O
,	O
was	O
employed	O
to	O
clone	O
from	O
a	O
rat	O
pituitary	O
cDNA	O
expression	O
library	O
a	O
novel	O
417	B-GENE
-	I-GENE
amino	I-GENE
acid	I-GENE
WD	I-GENE
protein	I-GENE
,	O
designated	O
PREB	B-GENE
(	I-GENE
PRL	I-GENE
regulatory	I-GENE
element	I-GENE
binding	I-GENE
)	I-GENE
protein	I-GENE
.	O

Characterization	O
of	O
the	O
transcription	B-GENE
factor	I-GENE
MTF	I-GENE
-	I-GENE
1	I-GENE
from	O
the	O
Japanese	O
pufferfish	O
(	O
Fugu	O
rubripes	O
)	O
reveals	O
evolutionary	O
conservation	O
of	O
heavy	O
metal	O
stress	O
response	O
.	O

The	O
peroxisome	B-GENE
proliferator	I-GENE
-	I-GENE
activated	I-GENE
receptors	I-GENE
(	O
PPARs	B-GENE
)	O
are	O
members	O
of	O
the	O
nuclear	B-GENE
hormone	I-GENE
receptor	I-GENE
superfamily	I-GENE
.	O

However	O
,	O
F	B-GENE
-	I-GENE
SRC	I-GENE
-	I-GENE
1	I-GENE
mutant	I-GENE
lacking	O
CBP	B-GENE
-	I-GENE
interacting	I-GENE
domain	I-GENE
still	O
preserved	O
enhancing	O
activity	O
.	O

The	O
catalytic	O
site	O
has	O
an	O
S1	O
pocket	O
lined	O
with	O
conserved	O
hydrophobic	O
residues	O
to	O
accommodate	O
the	O
pyroglutamyl	O
residue	O
.	O

The	O
complete	O
circular	O
TTV	O
genome	O
contained	O
a	O
novel	O
sequence	O
of	O
113	O
nt	O
(	O
nt	O
3740	O
to	O
3852	O
[	O
=	O
0	O
]	O
)	O
in	O
between	O
the	O
known	O
3	O
'	O
-	O
and	O
5	O
'	O
-	O
end	O
arms	O
,	O
forming	O
a	O
117	O
-	O
nt	O
GC	O
-	O
rich	O
stretch	O
(	O
GC	O
content	O
,	O
90	O
.	O
6	O
%	O
at	O
nt	O
3736	O
to	O
3852	O
)	O
.	O

The	O
Asian	O
mouse	O
Mus	O
castaneus	O
is	O
resistant	O
to	O
infection	O
by	O
the	O
polytropic	O
mink	O
cell	O
focus	O
-	O
inducing	O
(	O
MCF	O
)	O
subgroup	O
of	O
murine	O
leukemia	O
viruses	O
(	O
MuLVs	O
)	O
.	O

To	O
determine	O
the	O
function	O
of	O
VZV	B-GENE
gK	I-GENE
in	O
virus	O
growth	O
,	O
a	O
series	O
of	O
gK	B-GENE
deletion	I-GENE
mutants	I-GENE
were	O
constructed	O
with	O
VZV	O
cosmid	O
DNA	O
derived	O
from	O
the	O
Oka	O
strain	O
.	O

CCAAT	B-GENE
displacement	I-GENE
protein	I-GENE
binds	O
to	O
and	O
negatively	O
regulates	O
human	O
papillomavirus	O
type	O
6	O
E6	B-GENE
,	O
E7	B-GENE
,	O
and	O
E1	B-GENE
promoters	O
.	O

Three	O
different	O
site	O
-	O
directed	O
mutations	O
of	O
the	O
cyclic	O
AMP	O
response	O
element	O
each	O
reduced	O
the	O
nerve	B-GENE
growth	I-GENE
factor	I-GENE
effect	O
by	O
>	O
90	O
%	O
.	O

Using	O
an	O
RNase	B-GENE
H	I-GENE
protection	O
assay	O
and	O
specific	O
blocking	O
oligonucleotides	O
,	O
we	O
find	O
that	O
recognition	O
of	O
the	O
5	O
'	O
splice	O
-	O
site	O
(	O
5	O
'	O
ss	O
)	O
and	O
branchpoint	O
sequence	O
(	O
BPS	O
)	O
elements	O
by	O
U11	B-GENE
and	O
U12	B-GENE
snRNPs	I-GENE
,	O
respectively	O
,	O
displays	O
strong	O
cooperativity	O
,	O
requiring	O
both	O
sites	O
in	O
the	O
pre	O
-	O
mRNA	O
substrate	O
for	O
efficient	O
complex	O
formation	O
.	O

Many	O
eukaryotic	O
cell	O
surface	O
proteins	O
are	O
anchored	O
in	O
the	O
lipid	O
bilayer	O
through	O
glycosylphosphatidylinositol	O
(	O
GPI	O
)	O
.	O

An	O
endogenous	O
mammalian	O
regulator	O
of	O
this	O
process	O
,	O
named	O
Usurpin	B-GENE
,	O
has	O
been	O
identified	O
(	O
aliases	O
for	O
Usurpin	B-GENE
include	O
CASH	B-GENE
,	O
Casper	B-GENE
,	O
CLARP	B-GENE
,	O
FLAME	B-GENE
-	I-GENE
1	I-GENE
,	O
FLIP	B-GENE
,	O
I	B-GENE
-	I-GENE
FLICE	I-GENE
and	O
MRIT	B-GENE
)	O
.	O

Plasma	O
glucose	O
,	O
immunoreactive	B-GENE
insulin	I-GENE
(	O
IRI	B-GENE
)	O
,	O
C	B-GENE
-	I-GENE
peptide	I-GENE
,	O
glucagon	B-GENE
,	O
and	O
GLP	B-GENE
-	I-GENE
1	I-GENE
levels	O
at	O
each	O
time	O
point	O
during	O
OGTT	O
were	O
measured	O
.	O

Technetium	O
-	O
99m	O
methylene	O
diphosphonate	O
scintimammography	O
for	O
evaluation	O
of	O
palpable	O
breast	O
masses	O
.	O

Nuclear	O
receptors	O
(	O
NRs	O
)	O
can	O
function	O
as	O
ligandinducible	O
transregulators	O
in	O
both	O
mammalian	O
and	O
yeast	O
cells	O
,	O
indicating	O
that	O
important	O
features	O
of	O
transcriptional	O
control	O
have	O
been	O
conserved	O
throughout	O
evolution	O
.	O

When	O
tethered	O
to	O
a	O
heterologous	O
DNA	O
-	O
binding	O
domain	O
,	O
PSU1	B-GENE
can	O
activate	O
transcription	O
on	O
its	O
own	O
.	O

OBJECTIVE	O
:	O
To	O
follow	O
-	O
up	O
prospectively	O
patients	O
with	O
arthritis	O
after	O
infection	O
with	O
beta	O
-	O
haemolytic	O
streptococci	O
of	O
Lancefield	O
group	O
A	O
(	O
beta	O
HSA	O
)	O
,	O
with	O
emphasis	O
on	O
clinical	O
characteristics	O
and	O
serological	O
features	O
.	O

We	O
found	O
that	O
the	O
expression	O
of	O
the	O
protein	O
was	O
maximum	O
in	O
mitosis	O
and	O
minimum	O
in	O
G1	O
,	O
which	O
correlated	O
with	O
the	O
expression	O
of	O
its	O
messenger	O
RNA	O
.	O

These	O
findings	O
demonstrate	O
that	O
signature	O
-	O
tagged	O
mutagenesis	O
is	O
a	O
viable	O
approach	O
to	O
identify	O
bacterial	O
genes	O
associated	O
with	O
the	O
ability	O
to	O
infect	O
the	O
urinary	O
tract	O
.	O

Pathol	O
.	O

The	O
eukaryotic	O
cell	O
cycle	O
is	O
governed	O
in	O
part	O
by	O
the	O
periodic	O
transcription	O
of	O
cyclin	B-GENE
genes	I-GENE
,	O
whose	O
protein	O
products	O
associate	O
with	O
and	O
positively	O
regulate	O
the	O
cyclin	B-GENE
-	I-GENE
dependent	I-GENE
kinases	I-GENE
.	O

The	O
GAC1	B-GENE
gene	I-GENE
encodes	O
the	O
regulatory	O
subunit	O
for	O
a	O
type	B-GENE
1	I-GENE
serine	I-GENE
/	I-GENE
threonine	I-GENE
phosphoprotein	I-GENE
phosphatase	I-GENE
,	O
Glc7	B-GENE
.	O

The	O
results	O
demonstrate	O
that	O
the	O
Glc7	B-GENE
phosphatase	I-GENE
and	O
its	O
Gac1	B-GENE
regulatory	O
subunit	O
play	O
positive	O
roles	O
in	O
HSF	B-GENE
activation	O
of	O
CUP1	B-GENE
transcription	O
.	O

MEF	B-GENE
and	O
AML1B	B-GENE
synergistically	O
transactivated	O
an	O
interleukin	B-GENE
3	I-GENE
promoter	I-GENE
reporter	I-GENE
gene	I-GENE
construct	I-GENE
,	O
yet	O
the	O
activating	O
activity	O
of	O
MEF	B-GENE
was	O
abolished	O
when	O
MEF	B-GENE
was	O
coexpressed	O
with	O
AML1	B-GENE
/	O
ETO	B-GENE
.	O

Mechanistically	O
,	O
the	O
presence	O
of	O
the	O
GRR	O
appears	O
to	O
stop	O
further	O
degradation	O
of	O
p50	B-GENE
and	O
to	O
stabilize	O
the	O
molecule	O
.	O

This	O
phosphorylation	O
can	O
be	O
catalyzed	O
by	O
a	O
break	O
-	O
ended	O
double	O
-	O
stranded	O
DNA	O
-	O
activated	O
protein	O
kinase	O
activity	O
from	O
the	O
sea	O
urchin	O
nucleus	O
in	O
vitro	O
.	O

Concomitantly	O
,	O
the	O
total	O
cellular	O
level	O
of	O
p21	B-GENE
increased	O
severalfold	O
via	O
a	O
posttranscriptional	O
mechanism	O
.	O

Moreover	O
,	O
when	O
added	O
to	O
the	O
osteoclast	O
cultures	O
,	O
mrIhh	B-GENE
-	I-GENE
N	I-GENE
markedly	O
stimulated	O
the	O
formation	O
of	O
resorption	O
pits	O
on	O
dentine	O
slices	O
.	O

Overall	O
,	O
our	O
results	O
suggest	O
that	O
resistant	O
genotypes	O
exist	O
among	O
the	O
WAD	O
goat	O
population	O
.	O

The	O
molecular	O
mechanism	O
by	O
which	O
Gle2p	B-GENE
and	O
the	O
Gle2p	B-GENE
-	O
Nup116p	B-GENE
interaction	O
function	O
in	O
mRNA	O
export	O
is	O
unknown	O
.	O

The	O
Fyn	B-GENE
NH2	I-GENE
terminus	I-GENE
was	O
necessary	O
but	O
not	O
sufficient	O
for	O
interaction	O
with	O
zeta	O
and	O
both	O
Fyn	B-GENE
kinase	I-GENE
and	O
SH2	B-GENE
domains	I-GENE
were	O
required	O
,	O
directing	O
phosphorylation	O
of	O
zeta	B-GENE
ITAM	I-GENE
tyrosines	O
and	O
binding	O
to	O
zeta	B-GENE
ITAM	I-GENE
phosphotyrosines	O
.	O

In	O
budding	O
yeast	O
,	O
the	O
protein	O
Skp1p	B-GENE
,	O
the	O
cullin	B-GENE
-	I-GENE
family	I-GENE
member	I-GENE
Cdc53p	B-GENE
,	O
and	O
the	O
F	O
-	O
box	O
/	O
WD	O
-	O
repeat	O
protein	O
Cdc4p	B-GENE
form	O
the	O
SCFCdc4p	B-GENE
ubiquitin	B-GENE
ligase	I-GENE
complex	O
,	O
which	O
targets	O
the	O
cyclin	B-GENE
-	I-GENE
dependent	I-GENE
kinase	I-GENE
(	O
Cdk	B-GENE
)	O
inhibitor	O
Sic1p	B-GENE
for	O
proteolysis	O
[	O
3	O
]	O
[	O
4	O
]	O
[	O
5	O
]	O
[	O
6	O
]	O
[	O
7	O
]	O
[	O
8	O
]	O
.	O

We	O
show	O
here	O
that	O
,	O
despite	O
their	O
structural	O
and	O
functional	O
similarities	O
,	O
the	O
pop1	B-GENE
and	O
pop2	B-GENE
genes	I-GENE
fail	O
to	O
complement	O
each	O
other	O
'	O
s	O
deletion	O
phenotypes	O
,	O
indicating	O
that	O
they	O
perform	O
non	O
-	O
redundant	O
,	O
but	O
potentially	O
interdependent	O
,	O
functions	O
in	O
proteolysis	O
.	O

Antithrombin	B-GENE
III	I-GENE
prevents	O
60	O
min	O
warm	O
intestinal	O
ischemia	O
reperfusion	O
injury	O
in	O
rats	O
.	O

In	O
retrospect	O
,	O
the	O
diagnoses	O
were	O
reconsidered	O
applying	O
strict	O
criteria	O
.	O

These	O
observations	O
of	O
elevated	O
serum	B-GENE
lipase	I-GENE
and	O
serum	O
CA	B-GENE
19	I-GENE
-	I-GENE
9	I-GENE
in	O
Sjogren	O
'	O
s	O
syndrome	O
without	O
evidence	O
of	O
malignancy	O
may	O
reflect	O
pancreatic	O
involvement	O
in	O
this	O
disorder	O
.	O

Acute	O
pancreatitis	O
as	O
a	O
complication	O
of	O
polyarteritis	O
nodosa	O
.	O

Significantly	O
greater	O
improvement	O
(	O
p	O
<	O
0	O
.	O
05	O
)	O
in	O
the	O
sertraline	O
group	O
first	O
became	O
apparent	O
by	O
the	O
end	O
of	O
week	O
3	O
on	O
the	O
Y	O
-	O
BOCS	O
and	O
the	O
CGI	O
Improvement	O
scale	O
,	O
and	O
by	O
the	O
end	O
of	O
weeks	O
6	O
and	O
8	O
,	O
respectively	O
,	O
on	O
the	O
NIMH	O
and	O
CGI	O
Severity	O
scale	O
.	O

Stress	B-GENE
-	I-GENE
inducible	I-GENE
protein	I-GENE
kinases	I-GENE
capable	O
of	O
activating	O
c	B-GENE
-	I-GENE
jun	I-GENE
expression	O
include	O
stress	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
kinase	I-GENE
/	O
c	B-GENE
-	I-GENE
Jun	I-GENE
N	I-GENE
-	I-GENE
terminal	I-GENE
protein	I-GENE
kinase	I-GENE
(	O
SAPK	B-GENE
/	O
JNK	B-GENE
)	O
and	O
p38	B-GENE
members	O
of	O
the	O
mitogen	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
kinase	I-GENE
(	O
MAPK	B-GENE
)	O
superfamily	O
of	O
signaling	O
molecules	O
.	O

Transforming	B-GENE
growth	I-GENE
factor	I-GENE
(	I-GENE
TGF	I-GENE
)	I-GENE
-	I-GENE
beta1	I-GENE
induces	O
extracellular	O
matrix	O
deposition	O
and	O
proliferation	O
of	O
mesenchymal	O
cells	O
.	O

Chronotherapeutics	O
in	O
cardiovascular	O
disease	O
.	O

Group	O
psychometric	O
functions	O
for	O
listeners	O
with	O
hearing	O
loss	O
do	O
not	O
show	O
a	O
decrease	O
in	O
performance	O
at	O
the	O
largest	O
values	O
of	O
delta	O
f	O
included	O
in	O
this	O
study	O
.	O

Uroflowmetry	O
can	O
detect	O
dysuria	O
,	O
which	O
may	O
be	O
poorly	O
perceived	O
or	O
even	O
unknown	O
to	O
the	O
subjects	O
themselves	O
.	O

Marked	O
racial	O
variation	O
in	O
birthweight	O
percentiles	O
by	O
gestational	O
age	O
was	O
evident	O
.	O

Significant	O
correlations	O
between	O
mental	O
status	O
as	O
measured	O
by	O
the	O
Mini	O
-	O
Mental	O
State	O
Examination	O
and	O
NA	O
/	O
mI	O
,	O
mI	O
/	O
Cr	O
and	O
NA	O
were	O
found	O
.	O

Glucagon	B-GENE
also	O
induced	O
LUC	B-GENE
activity	O
very	O
strongly	O
when	O
the	O
CRE1	O
and	O
CRE2	O
sites	O
were	O
combined	O
;	O
induction	O
of	O
the	O
(	O
CRE1	O
)	O
3	O
(	O
CRE2	O
)	O
2SV40	O
-	O
LUC	B-GENE
constructs	O
was	O
positively	O
modulated	O
by	O
the	O
pO2	O
.	O

In	O
this	O
study	O
,	O
we	O
report	O
the	O
isolation	O
and	O
characterization	O
of	O
the	O
entire	O
rat	B-GENE
GSTA3	I-GENE
(	O
rGST	B-GENE
Yc1	I-GENE
)	O
subunit	O
gene	O
.	O

Calcinosis	O
cutis	O
following	O
intravenous	O
infusion	O
of	O
calcium	O
gluconate	O
.	O

Finally	O
,	O
we	O
determined	O
the	O
genomic	O
organization	O
of	O
the	O
human	B-GENE
TrxR2	I-GENE
gene	I-GENE
,	O
which	O
consists	O
of	O
18	O
exons	O
spanning	O
about	O
67	O
kb	O
,	O
and	O
its	O
chromosomal	O
localization	O
at	O
position	O
22q11	O
.	O
2	O
.	O

The	O
aims	O
of	O
this	O
study	O
were	O
to	O
determine	O
and	O
rank	O
the	O
frequency	O
of	O
self	O
reported	O
visual	O
disability	O
in	O
daily	O
tasks	O
performed	O
by	O
glaucoma	O
patients	O
;	O
to	O
examine	O
the	O
interrelation	O
between	O
disabilities	O
using	O
factor	O
analysis	O
;	O
to	O
study	O
the	O
relation	O
between	O
perceived	O
visual	O
difficulty	O
and	O
a	O
measure	O
of	O
the	O
severity	O
of	O
visual	O
field	O
loss	O
;	O
to	O
develop	O
a	O
glaucoma	O
specific	O
subgroup	O
of	O
questions	O
;	O
and	O
examine	O
the	O
validity	O
and	O
reliability	O
of	O
this	O
subgroup	O
of	O
questions	O
.	O

Furthermore	O
,	O
the	O
validity	O
of	O
this	O
new	O
subset	O
of	O
questions	O
was	O
shown	O
to	O
be	O
significant	O
(	O
r	O
=	O
0	O
.	O
037	O
,	O
p	O
<	O
0	O
.	O
05	O
)	O
for	O
the	O
correlation	O
between	O
a	O
measure	O
of	O
the	O
severity	O
of	O
binocular	O
visual	O
field	O
loss	O
and	O
the	O
mean	O
score	O
of	O
the	O
variables	O
used	O
in	O
the	O
glaucoma	O
specific	O
subgroup	O
of	O
questions	O
.	O

Sequence	O
comparison	O
of	O
cytochromes	B-GENE
bd	I-GENE
and	O
their	O
homologs	O
from	O
various	O
organisms	O
demonstrates	O
that	O
the	O
proteins	O
can	O
be	O
classified	O
into	O
two	O
subfamilies	O
,	O
a	O
proteobacterial	O
type	O
including	O
E	B-GENE
.	I-GENE
coli	I-GENE
bd	I-GENE
and	O
a	O
more	O
widely	O
distributed	O
type	O
including	O
the	O
B	O
.	O
stearothermophilus	O
enzyme	O
,	O
suggesting	O
that	O
the	O
latter	O
type	O
is	O
evolutionarily	O
older	O
.	O

In	O
11	O
eyes	O
that	O
had	O
been	O
selected	O
at	O
random	O
10	O
micrograms	O
of	O
recombinant	B-GENE
tissue	I-GENE
plasminogen	I-GENE
activator	I-GENE
were	O
injected	O
midvitreally	O
24	O
hrs	O
later	O
.	O

RESULTS	O
AND	O
CONCLUSIONS	O
:	O
Brandt	O
'	O
s	O
double	O
cuff	O
-	O
tubes	O
(	O
G2	O
)	O
succeed	O
in	O
avoiding	O
uncontrolled	O
increase	O
of	O
cuff	O
-	O
pressure	O
during	O
anaesthesia	O
with	O
N2O	O
.	O

Accordingly	O
,	O
we	O
designated	O
this	O
gene	B-GENE
CTL1	I-GENE
(	O
capping	B-GENE
enzyme	I-GENE
RNAtriphosphatase	I-GENE
-	I-GENE
like	I-GENE
1	I-GENE
)	O
.	O

Their	O
afterglows	O
are	O
brighter	O
than	O
supernovae	O
and	O
therefore	O
are	O
called	O
hypernovae	O
.	O

Constrictive	O
pericarditis	O
and	O
pleuropulmonary	O
disease	O
linked	O
to	O
ergot	O
dopamine	O
agonist	O
therapy	O
(	O
cabergoline	O
)	O
for	O
Parkinson	O
'	O
s	O
disease	O
.	O

An	O
undilated	O
type	O
of	O
APBD	O
is	O
frequently	O
associated	O
with	O
AMT	O
and	O
we	O
believe	O
,	O
therefore	O
,	O
that	O
clinicians	O
should	O
be	O
aware	O
of	O
a	O
possible	O
coexistence	O
of	O
APBD	O
and	O
AMT	O
.	O

In	O
addition	O
,	O
we	O
also	O
constructed	O
and	O
expressed	O
chimeric	O
fusion	O
protein	O
that	O
contains	O
HIV	B-GENE
-	I-GENE
2	I-GENE
gag	I-GENE
with	O
V3	B-GENE
domains	O
of	O
HIV	O
-	O
1IIIB	O
,	O
HIV	O
-	O
1MN	O
,	O
HIV	O
-	O
1SF2	O
and	O
HIV	O
-	O
1RF	O
.	O

Our	O
results	O
indicate	O
that	O
V3	B-GENE
peptides	O
from	O
all	O
major	O
clades	O
of	O
HIV	O
-	O
1	O
carried	O
by	O
HIV	B-GENE
-	I-GENE
2	I-GENE
gag	I-GENE
can	O
be	O
used	O
as	O
a	O
potential	O
HIV	O
/	O
AIDS	O
vaccine	O
.	O

Efficacy	O
was	O
determined	O
by	O
responses	O
to	O
question	O
3	O
(	O
ability	O
to	O
achieve	O
an	O
erection	O
)	O
and	O
question	O
4	O
(	O
ability	O
to	O
maintain	O
an	O
erection	O
)	O
of	O
the	O
15	O
-	O
item	O
International	O
Index	O
of	O
Erectile	O
Function	O
(	O
IIEF	O
)	O
.	O

Evidence	O
for	O
the	O
involvement	O
of	O
the	O
Glc7	B-GENE
-	O
Reg1	B-GENE
phosphatase	O
and	O
the	O
Snf1	B-GENE
-	O
Snf4	B-GENE
kinase	O
in	O
the	O
regulation	O
of	O
INO1	B-GENE
transcription	O
in	O
Saccharomyces	O
cerevisiae	O
.	O

In	O
XO	O
males	O
,	O
two	O
her	B-GENE
-	I-GENE
1	I-GENE
mRNAs	I-GENE
,	O
her	B-GENE
-	I-GENE
1a	I-GENE
and	O
her	B-GENE
-	I-GENE
1b	I-GENE
,	O
are	O
transcribed	O
from	O
two	O
separate	O
promoters	O
:	O
P1	O
,	O
located	O
in	O
the	O
5	O
'	O
-	O
flanking	O
region	O
,	O
and	O
P2	O
,	O
located	O
in	O
the	O
large	O
second	O
intron	O
.	O

Induction	O
of	O
Fas	B-GENE
ligand	I-GENE
expression	O
by	O
HIV	O
involves	O
the	O
interaction	O
of	O
Nef	B-GENE
with	O
the	O
T	B-GENE
cell	I-GENE
receptor	I-GENE
zeta	I-GENE
chain	I-GENE
.	O

Receptor	B-GENE
protein	I-GENE
tyrosine	I-GENE
phosphatases	I-GENE
(	O
RPTPs	B-GENE
)	O
comprise	O
a	O
family	O
of	O
proteins	O
that	O
feature	O
intracellular	O
phosphatase	O
domains	O
and	O
an	O
ectodomain	O
with	O
putative	O
ligand	O
-	O
binding	O
motifs	O
.	O

These	O
well	O
-	O
characterized	O
brain	O
regions	O
may	O
provide	O
a	O
basis	O
for	O
future	O
studies	O
of	O
RPTP	B-GENE
-	I-GENE
kappa	I-GENE
function	O
.	O

Commonly	O
used	O
stressors	O
are	O
mental	O
arithmetics	O
,	O
speech	O
tasks	O
,	O
the	O
Stroop	O
test	O
,	O
videogame	O
playing	O
,	O
films	O
or	O
videotapes	O
and	O
interviews	O
.	O

The	O
control	O
group	O
included	O
8	O
afterbirth	O
samples	O
from	O
physiological	O
full	O
-	O
term	O
pregnancies	O
.	O

However	O
,	O
we	O
identified	O
a	O
gene	O
between	O
the	O
MDV2	B-GENE
UL54	I-GENE
and	O
UL55	B-GENE
genes	I-GENE
with	O
homology	O
to	O
the	O
first	B-GENE
ORF	I-GENE
(	I-GENE
ORF	I-GENE
-	I-GENE
1	I-GENE
)	I-GENE
of	I-GENE
equine	I-GENE
herpesvirus	I-GENE
type	I-GENE
1	I-GENE
and	O
corresponding	O
gene	O
identified	O
in	O
pseudorabies	O
virus	O
.	O

In	O
contrast	O
,	O
the	O
loss	O
of	O
MAD2	B-GENE
staining	O
in	O
meiosis	O
was	O
not	O
correlated	O
with	O
initial	O
microtubule	O
attachment	O
but	O
was	O
correlated	O
with	O
a	O
measure	O
of	O
tension	O
:	O
the	O
distance	O
between	O
homologous	O
or	O
sister	O
kinetochores	O
(	O
in	O
meiosis	O
I	O
and	O
II	O
,	O
respectively	O
)	O
.	O

In	O
epithelial	O
cells	O
,	O
the	O
PH	B-GENE
domain	I-GENE
of	O
Akt	B-GENE
/	O
PKB	B-GENE
localised	O
to	O
sites	O
of	O
cell	O
-	O
cell	O
and	O
cell	O
-	O
matrix	O
contact	O
,	O
distinct	O
from	O
focal	O
contacts	O
,	O
even	O
in	O
the	O
absence	O
of	O
serum	O
.	O

The	O
5	O
'	O
untranslated	O
and	O
coding	O
regions	O
are	O
contained	O
within	O
12	O
exons	O
,	O
with	O
the	O
translation	O
start	O
site	O
located	O
within	O
the	O
first	O
exon	O
.	O

The	O
motility	O
of	O
sperm	O
,	O
except	O
for	O
those	O
adjacent	O
to	O
both	O
electrodes	O
,	O
did	O
not	O
change	O
after	O
stimulation	O
for	O
60s	O
,	O
despite	O
a	O
high	O
electrical	O
energy	O
.	O

Induction	O
of	O
the	O
CINC	B-GENE
promoter	I-GENE
by	O
IL	B-GENE
-	I-GENE
17	I-GENE
in	O
IEC	O
-	O
6	O
cells	O
was	O
TNF	B-GENE
receptor	I-GENE
-	I-GENE
associated	I-GENE
factor	I-GENE
-	I-GENE
6	I-GENE
(	O
TRAF6	B-GENE
)	O
,	O
but	O
not	O
TRAF2	B-GENE
,	O
dependent	O
.	O

SCFFWD1	B-GENE
may	O
be	O
critical	O
for	O
tumor	O
development	O
and	O
suppression	O
through	O
regulation	O
of	O
beta	B-GENE
-	I-GENE
catenin	I-GENE
protein	I-GENE
stability	O
.	O

A	O
Bub2p	B-GENE
-	O
dependent	O
spindle	O
checkpoint	O
pathway	O
regulates	O
the	O
Dbf2p	B-GENE
kinase	I-GENE
in	I-GENE
budding	I-GENE
yeast	I-GENE
.	O

We	O
analyzed	O
the	O
modular	O
organization	O
of	O
DNA	B-GENE
polymerase	I-GENE
beta	I-GENE
and	O
found	O
that	O
residues	O
making	O
contact	O
with	O
DNA	O
phosphates	O
were	O
localized	O
to	O
five	O
modules	O
.	O

RESULTS	O
:	O
Cholinergic	O
nerves	O
are	O
mainly	O
involved	O
in	O
the	O
regulation	O
of	O
enteric	O
nerve	O
responses	O
to	O
EFS	O
in	O
the	O
normal	O
IAS	O
.	O

We	O
show	O
that	O
other	O
cdc33	B-GENE
mutants	I-GENE
also	O
arrest	O
in	O
G1	O
.	O

A	O
cdc33	B-GENE
-	I-GENE
1	I-GENE
strain	O
expressing	O
either	O
stable	O
Cln3p	B-GENE
(	O
Cln3	B-GENE
-	I-GENE
1p	I-GENE
)	O
or	O
a	O
hybrid	O
UBI4	B-GENE
5	I-GENE
'	I-GENE
-	I-GENE
CLN3	I-GENE
mRNA	O
,	O
whose	O
translation	O
displays	O
decreased	O
dependence	O
on	O
eIF4E	B-GENE
,	O
arrested	O
randomly	O
in	O
the	O
cell	O
cycle	O
.	O

Regulatory	O
motifs	O
for	O
gene	O
expression	O
such	O
as	O
nuclear	B-GENE
-	I-GENE
factor	I-GENE
-	I-GENE
kappaB	I-GENE
-	I-GENE
binding	I-GENE
-	I-GENE
site	I-GENE
-	I-GENE
like	I-GENE
sequence	I-GENE
(	O
kappaB	B-GENE
site	I-GENE
)	O
and	O
nuclear	B-GENE
-	I-GENE
factor	I-GENE
-	I-GENE
interleukin	I-GENE
-	I-GENE
6	I-GENE
-	I-GENE
binding	I-GENE
-	I-GENE
site	I-GENE
-	I-GENE
like	I-GENE
sequence	I-GENE
(	O
NF	B-GENE
-	I-GENE
IL	I-GENE
-	I-GENE
6	I-GENE
site	I-GENE
)	O
were	O
found	O
in	O
the	O
5	O
'	O
-	O
upstream	O
regulatory	O
region	O
.	O

Total	O
serum	O
calcium	O
was	O
7	O
.	O
8	O
+	O
/	O
-	O
0	O
.	O
8	O
mg	O
/	O
dl	O
,	O
whereas	O
ionized	O
calcium	O
was	O
5	O
.	O
7	O
+	O
/	O
-	O
0	O
.	O
7	O
mg	O
/	O
dl	O
,	O
phosphorus	O
3	O
.	O
2	O
+	O
/	O
-	O
1	O
.	O
2	O
mg	O
/	O
dl	O
,	O
and	O
alkaline	B-GENE
phosphatase	I-GENE
149	O
+	O
/	O
-	O
48	O
.	O
6	O
U	O
/	O
liter	O
.	O

Cranio	O
-	O
caudal	O
differences	O
in	O
granulation	O
tissue	O
formation	O
:	O
an	O
experimental	O
study	O
in	O
the	O
rat	O
.	O

Site	O
-	O
directed	O
mutagenesis	O
showed	O
that	O
two	O
adjacent	O
SP1	B-GENE
sites	I-GENE
proximal	O
to	O
exon	O
1	O
were	O
equally	O
important	O
in	O
sustaining	O
basal	O
promoter	O
activity	O
.	O

Breast	O
-	O
fed	O
newborn	O
infants	O
synthesize	O
n	O
-	O
6	O
long	O
-	O
chain	O
polyunsaturated	O
fatty	O
acids	O
already	O
during	O
the	O
first	O
week	O
of	O
life	O
,	O
but	O
the	O
contribution	O
of	O
endogenous	O
synthesis	O
to	O
the	O
total	O
plasma	O
long	O
-	O
chain	O
polyunsaturated	O
pool	O
is	O
small	O
.	O

Ischemia	O
and	O
reperfusion	O
markedly	O
increased	O
the	O
release	O
of	O
6	O
-	O
keto	O
-	O
PGF1	O
alpha	O
and	O
TXB2	O
.	O

Prostate	B-GENE
-	I-GENE
specific	I-GENE
antigen	I-GENE
(	O
PSA	B-GENE
)	O
promoter	O
-	O
driven	O
androgen	O
-	O
inducible	O
expression	O
of	O
sodium	B-GENE
iodide	I-GENE
symporter	I-GENE
in	O
prostate	O
cancer	O
cell	O
lines	O
.	O

It	O
is	O
clear	O
that	O
subclinical	O
and	O
silent	O
CD	O
exist	O
in	O
a	O
large	O
subgroup	O
of	O
the	O
celiac	O
population	O
.	O

Ras2p	B-GENE
activates	O
invasive	O
growth	O
using	O
either	O
of	O
two	O
downstream	O
signaling	O
pathways	O
,	O
the	O
filamentation	O
MAPK	B-GENE
(	O
Cdc42p	B-GENE
/	O
Ste20p	B-GENE
/	O
MAPK	B-GENE
)	O
cascade	O
or	O
the	O
cAMP	B-GENE
-	I-GENE
dependent	I-GENE
protein	I-GENE
kinase	I-GENE
(	O
Cyr1p	B-GENE
/	O
cAMP	O
/	O
PKA	B-GENE
)	O
pathway	O
.	O

Consistent	O
with	O
this	O
prediction	O
,	O
transfections	O
into	O
the	O
hematopoietic	O
cell	O
line	O
Jurkat	O
showed	O
a	O
9	O
.	O
0	O
-	O
and	O
2	O
.	O
5	O
-	O
fold	O
activation	O
of	O
the	O
mim	B-GENE
-	I-GENE
1	I-GENE
promoter	I-GENE
by	O
the	O
p32	B-GENE
and	O
p30	B-GENE
isoforms	I-GENE
,	O
respectively	O
.	O

Despite	O
the	O
reported	O
detrimental	O
effects	O
on	O
CNS	O
development	O
,	O
a	O
number	O
of	O
animal	O
studies	O
have	O
shown	O
that	O
pretreatment	O
with	O
corticosteroids	O
nevertheless	O
protect	O
the	O
brain	O
from	O
hypoxia	O
-	O
ischemic	O
injury	O
;	O
however	O
,	O
clinically	O
such	O
treatment	O
is	O
no	O
longer	O
favored	O
.	O

In	O
one	O
mechanism	O
,	O
a	O
specialized	O
ubiquitin	B-GENE
-	O
dependent	O
proteolytic	O
system	O
(	O
called	O
the	O
APC	O
-	O
dependent	O
proteolysis	O
machinery	O
)	O
degrades	O
the	O
mitotic	O
(	O
Clb	B-GENE
)	O
cyclin	B-GENE
subunit	I-GENE
.	O

Predictors	O
of	O
success	O
in	O
pharmacy	O
school	O
:	O
PCAT	O
vs	O
.	O
other	O
admission	O
criteria	O
.	O

Canadian	O
survey	O
reveals	O
widespread	O
dissatisfaction	O
among	O
physicians	O
.	O

In	O
a	O
series	O
of	O
16	O
full	O
-	O
scale	O
fire	O
tests	O
,	O
investigators	O
at	O
the	O
IIT	O
Research	O
Institute	O
have	O
concluded	O
that	O
automatic	O
door	O
control	O
in	O
the	O
room	O
of	O
fire	O
origin	O
can	O
significantly	O
reduce	O
the	O
spread	O
of	O
toxic	O
smoke	O
and	O
gases	O
.	O

Reporting	O
of	O
adverse	O
events	O
occurring	O
during	O
clinical	O
trials	O
of	O
investigational	O
drugs	O
is	O
a	O
complex	O
and	O
controversial	O
issue	O
.	O

Medicare	O
SNF	O
benefits	O
revised	O
-	O
-	O
again	O
.	O

In	O
this	O
paper	O
,	O
the	O
current	O
status	O
of	O
the	O
understanding	O
of	O
the	O
interaction	O
mechanisms	O
of	O
ultrasound	O
with	O
biological	O
media	O
and	O
the	O
factors	O
that	O
govern	O
different	O
biological	O
effects	O
are	O
surveyed	O
.	O

Members	O
of	O
the	O
mitogen	B-GENE
activated	I-GENE
protein	I-GENE
(	I-GENE
MAP	I-GENE
)	I-GENE
kinase	I-GENE
family	I-GENE
,	O
extracellular	B-GENE
signal	I-GENE
-	I-GENE
regulated	I-GENE
kinase	I-GENE
,	O
stress	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
kinase	I-GENE
-	I-GENE
1	I-GENE
/	O
c	B-GENE
-	I-GENE
Jun	I-GENE
NH2	I-GENE
-	I-GENE
terminal	I-GENE
kinase	I-GENE
,	O
and	O
p38	B-GENE
,	O
are	O
central	O
elements	O
that	O
transduce	O
the	O
signal	O
generated	O
by	O
growth	O
factors	O
,	O
cytokines	O
,	O
and	O
stressing	O
agents	O
.	O

In	O
the	O
present	O
study	O
,	O
we	O
have	O
investigated	O
the	O
functional	O
role	O
of	O
the	O
other	O
MAP	B-GENE
kinases	I-GENE
in	O
PDGF	B-GENE
-	O
mediated	O
cellular	O
responses	O
.	O

Analyses	O
of	O
tyrosine	O
residue	O
-	O
mutated	O
PDGF	B-GENE
receptors	I-GENE
show	O
that	O
Src	B-GENE
homology	I-GENE
2	I-GENE
domain	I-GENE
-	I-GENE
containing	I-GENE
proteins	I-GENE
including	O
Src	B-GENE
family	I-GENE
kinases	I-GENE
,	O
phosphatidylinositol	B-GENE
3	I-GENE
-	I-GENE
kinase	I-GENE
,	O
the	O
GTPase	B-GENE
-	I-GENE
activating	I-GENE
protein	I-GENE
of	O
Ras	B-GENE
,	O
the	O
Src	B-GENE
homology	I-GENE
2	I-GENE
domain	I-GENE
-	I-GENE
containing	I-GENE
phosphatase	I-GENE
SHP	B-GENE
-	I-GENE
2	I-GENE
,	O
phospholipase	B-GENE
C	I-GENE
-	I-GENE
gamma	I-GENE
,	O
and	O
Crk	B-GENE
do	O
not	O
play	O
a	O
major	O
role	O
in	O
mediating	O
the	O
PDGF	B-GENE
-	O
induced	O
activation	O
of	O
p38	B-GENE
.	O

Here	O
we	O
show	O
that	O
calpeptin	B-GENE
inhibits	O
tyrosine	B-GENE
phosphatases	I-GENE
,	O
enhancing	O
tyrosine	O
phosphorylation	O
particularly	O
of	O
paxillin	B-GENE
.	O

Three	O
-	O
dimensional	O
structural	O
studies	O
using	O
electron	O
cryomicroscopy	O
showed	O
that	O
the	O
binding	O
of	O
one	O
Fab	B-GENE
(	O
8H2	O
/	O
G5	O
)	O
does	O
not	O
affect	O
the	O
conformation	O
of	O
the	O
capsid	O
,	O
and	O
the	O
efficiency	O
of	O
mRNA	O
production	O
is	O
similar	O
to	O
that	O
of	O
the	O
native	O
subviral	O
particle	O
.	O

Further	O
,	O
mutational	O
analysis	O
of	O
NS5A	B-GENE
assigned	O
the	O
SH3	B-GENE
-	I-GENE
binding	I-GENE
region	I-GENE
to	O
a	O
proline	O
-	O
rich	O
motif	O
that	O
is	O
highly	O
conserved	O
among	O
HCV	O
genotypes	O
.	O

Taken	O
together	O
,	O
these	O
findings	O
show	O
that	O
16K	B-GENE
hPRL	I-GENE
inhibits	O
the	O
VEGF	B-GENE
-	O
induced	O
Ras	B-GENE
activation	O
;	O
this	O
antagonism	O
represents	O
a	O
novel	O
and	O
potentially	O
important	O
mechanism	O
for	O
the	O
control	O
of	O
angiogenesis	O
.	O

Analysis	O
of	O
SRE	O
oligonucleotide	O
gel	O
mobility	O
shift	O
assays	O
with	O
nuclear	O
extracts	O
from	O
Sertoli	O
cells	O
demonstrated	O
the	O
presence	O
of	O
both	O
the	O
SRF	B-GENE
and	O
the	O
ubiquitously	O
expressed	O
bHLH	O
protein	O
E12	B-GENE
/	O
E47	B-GENE
.	O

Baseline	O
electrocorticography	O
over	O
the	O
surface	O
of	O
the	O
temporal	O
lobe	O
and	O
depth	O
electrode	O
recordings	O
in	O
the	O
amygdala	O
and	O
hippocampus	O
were	O
obtained	O
,	O
followed	O
by	O
10	O
min	O
of	O
recording	O
before	O
and	O
after	O
the	O
i	O
.	O
v	O
.	O
administration	O
of	O
both	O
alfentanil	O
50	O
microg	O
/	O
kg	O
and	O
fentanyl	O
10	O
microg	O
/	O
kg	O
.	O

We	O
suggest	O
that	O
FlgN	B-GENE
and	O
FliT	B-GENE
are	O
substrate	O
-	O
specific	O
flagellar	O
chaperones	O
that	O
prevent	O
oligomerization	O
of	O
the	O
HAPs	B-GENE
by	O
binding	O
to	O
their	O
helical	O
domains	O
before	O
export	O
.	O

Post	O
and	O
core	O
fabrication	O
for	O
divergent	O
canals	O
with	O
a	O
cast	O
post	O
and	O
core	O
and	O
a	O
prefabricated	O
dowel	O
.	O

Rep63A	B-GENE
(	I-GENE
513	I-GENE
amino	I-GENE
acids	I-GENE
[	I-GENE
aa	I-GENE
]	I-GENE
)	I-GENE
,	O
encoded	O
by	O
the	O
largest	O
ORF	O
,	O
displayed	O
strong	O
similarity	O
(	O
40	O
%	O
identity	O
)	O
to	O
the	O
replication	O
proteins	O
from	O
plasmids	O
pAMbeta1	O
,	O
pIP501	O
,	O
and	O
pSM19035	O
,	O
indicating	O
that	O
the	O
pAW63	O
replicon	O
belongs	O
to	O
the	O
pAMbeta1	O
family	O
of	O
gram	O
-	O
positive	O
theta	O
-	O
replicating	O
plasmids	O
.	O

Here	O
we	O
report	O
the	O
cloning	O
and	O
characterization	O
of	O
Xenopus	B-GENE
Pax	I-GENE
-	I-GENE
5	I-GENE
and	O
Pax	B-GENE
-	I-GENE
8	I-GENE
,	O
two	O
orthologues	O
of	O
the	O
Pax	B-GENE
-	I-GENE
2	I-GENE
/	I-GENE
5	I-GENE
/	I-GENE
8	I-GENE
gene	I-GENE
family	I-GENE
.	O

Km	O
values	O
for	O
ammonium	O
,	O
2	O
-	O
oxoglutarate	O
,	O
NADH	O
,	O
glutamate	O
and	O
NAD	O
+	O
were	O
6	O
.	O
5	O
,	O
3	O
.	O
5	O
,	O
0	O
.	O
06	O
,	O
37	O
.	O
1	O
and	O
0	O
.	O
046	O
mM	O
,	O
respectively	O
.	O

Interferon	B-GENE
-	I-GENE
alpha	I-GENE
may	O
exacerbate	O
cryoblobulinemia	O
-	O
related	O
ischemic	O
manifestations	O
:	O
an	O
adverse	O
effect	O
potentially	O
related	O
to	O
its	O
anti	O
-	O
angiogenic	O
activity	O
.	O

Interferon	B-GENE
-	I-GENE
alpha	I-GENE
may	O
exacerbate	O
cryoblobulinemia	O
-	O
related	O
ischemic	O
manifestations	O
:	O
an	O
adverse	O
effect	O
potentially	O
related	O
to	O
its	O
anti	O
-	O
angiogenic	O
activity	O
.	O

In	O
addition	O
,	O
we	O
demonstrate	O
that	O
the	O
production	O
of	O
active	B-GENE
recombinant	I-GENE
telomerase	I-GENE
requires	O
a	O
factor	O
in	O
rabbit	O
reticulocyte	O
lysate	O
that	O
promotes	O
ribonucleoprotein	O
assembly	O
.	O

Homozygous	O
mutation	O
in	O
two	O
children	O
led	O
to	O
amputation	O
of	O
legs	O
due	O
to	O
purpura	O
fulminans	O
.	O

According	O
to	O
pilot	O
experiments	O
which	O
considered	O
various	O
durations	O
of	O
global	O
no	O
-	O
flow	O
ischemia	O
ranging	O
from	O
10	O
to	O
20	O
minutes	O
,	O
two	O
durations	O
were	O
chosen	O
for	O
the	O
present	O
study	O
:	O
20	O
minutes	O
(	O
group	O
20	O
)	O
in	O
which	O
ventricular	O
fibrillation	O
(	O
VF	O
)	O
was	O
the	O
predominant	O
form	O
of	O
arrhythmias	O
,	O
and	O
18	O
minutes	O
(	O
group	O
18	O
)	O
in	O
which	O
the	O
prevalence	O
of	O
VF	O
was	O
markedly	O
lower	O
despite	O
the	O
small	O
difference	O
in	O
the	O
duration	O
of	O
ischemia	O
.	O

An	O
end	O
-	O
to	O
-	O
end	O
pancreaticojejunostomy	O
using	O
a	O
mechanical	O
purse	O
-	O
string	O
device	O
.	O

Blood	O
samples	O
were	O
obtained	O
daily	O
during	O
this	O
supplementation	O
period	O
and	O
5	O
d	O
thereafter	O
(	O
d	O
11	O
to	O
15	O
)	O
.	O

These	O
results	O
suggest	O
that	O
mitochondrial	O
presequences	O
interact	O
with	O
the	O
mt	B-GENE
-	I-GENE
hsp70	I-GENE
during	O
or	O
after	O
mitochondrial	O
protein	O
import	O
.	O

The	O
3	O
'	O
terminus	O
of	O
the	O
genome	O
can	O
be	O
folded	O
into	O
a	O
tRNA	O
-	O
like	O
secondary	O
structure	O
that	O
has	O
a	O
valine	O
anticodon	O
;	O
the	O
tRNA	O
-	O
like	O
structure	O
lacks	O
a	O
pseudoknot	O
in	O
the	O
aminoacyl	O
stem	O
,	O
a	O
feature	O
common	O
to	O
both	O
genera	O
of	O
tetraviruses	O
.	O

Only	O
one	O
gene	O
,	O
fibronectin	B-GENE
(	O
FN	B-GENE
)	O
,	O
was	O
highly	O
overexpressed	O
(	O
>	O
60	O
-	O
fold	O
)	O
in	O
LNCaP	O
-	O
r	O
cells	O
,	O
consistent	O
with	O
previously	O
reported	O
overexpression	O
of	O
FN	B-GENE
in	O
prostate	O
cancer	O
.	O

We	O
also	O
observed	O
that	O
cell	O
surface	O
CD4	B-GENE
(	O
-	O
)	O
CD8	B-GENE
(	O
-	O
)	O
CD3	B-GENE
(	O
-	O
)	O
cells	O
with	O
rearranged	B-GENE
TCR	I-GENE
genes	I-GENE
developed	O
from	O
Id3	B-GENE
-	O
transduced	O
but	O
not	O
from	O
control	O
-	O
transduced	O
pre	O
-	O
T	O
cells	O
in	O
an	O
FTOC	O
.	O

As	O
determined	O
in	O
a	O
modified	O
yeast	O
two	O
-	O
hybrid	O
system	O
,	O
mIRS3	B-GENE
bound	O
strongly	O
to	O
the	O
p85	B-GENE
subunit	I-GENE
of	O
phosphatidylinositol	B-GENE
3	I-GENE
-	I-GENE
kinase	I-GENE
.	O

Insulin	B-GENE
stimulation	O
promoted	O
the	O
association	O
of	O
mIRS3	B-GENE
with	O
p85	B-GENE
,	O
SHP2	B-GENE
,	O
Nck	B-GENE
,	O
and	O
Shc	B-GENE
.	O

The	O
mRNA	O
expression	O
of	O
RFX1	B-GENE
,	O
RFX2	B-GENE
,	O
and	O
RFX3	B-GENE
was	O
detected	O
ubiquitously	O
,	O
but	O
in	O
transient	O
-	O
transfection	O
assays	O
,	O
multimerized	B-GENE
RFX	I-GENE
binding	I-GENE
sites	I-GENE
in	O
front	O
of	O
a	O
basal	O
promoter	O
efficiently	O
functioned	O
in	O
a	O
tissue	O
-	O
and	O
lineage	O
-	O
specific	O
manner	O
.	O

In	O
the	O
case	O
of	O
the	O
unspliceable	O
intron	O
,	O
repression	O
of	O
luciferase	B-GENE
expression	O
likely	O
involved	O
two	O
AUF1	B-GENE
-	I-GENE
binding	I-GENE
sequences	I-GENE
,	O
since	O
luciferase	B-GENE
expression	O
was	O
increased	O
by	O
deletion	O
of	O
these	O
sites	O
.	O

Thus	O
,	O
VDR	B-GENE
acts	O
selectively	O
on	O
the	O
two	O
components	O
required	O
for	O
activation	O
of	O
this	O
promoter	O
/	O
enhancer	O
:	O
it	O
competes	O
with	O
NFAT1	B-GENE
for	O
binding	O
to	O
the	O
composite	O
site	O
,	O
positioning	O
itself	O
adjacent	O
to	O
Jun	B-GENE
-	O
Fos	B-GENE
on	O
the	O
DNA	O
.	O

Two	O
evolutionarily	O
conserved	O
kinases	O
,	O
the	O
cyclin	B-GENE
B	I-GENE
(	O
Clb	B-GENE
)	O
/	O
cyclin	B-GENE
-	I-GENE
dependent	I-GENE
kinase	I-GENE
(	O
Cdk	B-GENE
/	O
Cdc28p	B-GENE
)	O
and	O
Cdc7p	B-GENE
along	O
with	O
its	O
interacting	O
factor	O
Dbf4p	B-GENE
,	O
are	O
required	O
late	O
in	O
G1	O
to	O
initiate	O
DNA	O
replication	O
.	O

The	O
RanQ69L	B-GENE
preincubation	O
leads	O
to	O
accumulation	O
of	O
CRM1	B-GENE
at	O
the	O
cytoplasmic	O
periphery	O
of	O
the	O
nuclear	O
pore	O
complex	O
(	O
NPC	O
)	O
in	O
association	O
with	O
the	O
p62	B-GENE
complex	I-GENE
and	O
Can	B-GENE
/	O
Nup214	B-GENE
.	O

All	O
of	O
the	O
elements	O
exhibited	O
a	O
uniform	O
structure	O
.	O

In	O
contrast	O
,	O
the	O
deduced	O
amino	O
acid	O
sequence	O
of	O
a	O
second	O
family	O
(	O
ART5	B-GENE
)	O
of	O
transferases	O
,	O
cloned	O
from	O
murine	O
lymphoma	O
cells	O
and	O
expressed	O
in	O
high	O
abundance	O
in	O
testis	O
,	O
displays	O
a	O
hydrophobic	O
amino	O
terminus	O
,	O
consistent	O
with	O
a	O
signal	O
sequence	O
,	O
but	O
lacks	O
a	O
hydrophobic	O
signal	O
sequence	O
at	O
its	O
carboxyl	O
terminus	O
,	O
suggesting	O
that	O
the	O
protein	O
is	O
destined	O
for	O
export	O
.	O

RESULTS	O
:	O
Each	O
year	O
,	O
on	O
average	O
39	O
%	O
of	O
cases	O
seen	O
in	O
Sardinia	O
are	O
notified	O
;	O
646	O
(	O
40	O
%	O
)	O
of	O
the	O
1591	O
patients	O
notified	O
during	O
the	O
study	O
period	O
were	O
never	O
seen	O
by	O
regional	O
medical	O
centres	O
.	O

This	O
dimer	O
interface	O
is	O
likely	O
important	O
for	O
increasing	O
the	O
DNA	O
-	O
binding	O
specificity	O
and	O
affinity	O
of	O
the	O
trimeric	O
form	O
of	O
HSF	B-GENE
,	O
as	O
well	O
as	O
for	O
increasing	O
cooperativity	O
between	O
adjacent	O
trimers	O
.	O

Additionally	O
,	O
deletion	O
analysis	O
of	O
the	O
UCP2	B-GENE
promoter	O
-	O
PLAP	B-GENE
constructs	O
indicated	O
that	O
the	O
minimal	O
region	O
exhibiting	O
the	O
promoter	O
activity	O
was	O
located	O
between	O
nt	O
-	O
33	O
and	O
+	O
100	O
,	O
and	O
that	O
a	O
strong	O
enhancer	O
was	O
present	O
within	O
601	O
bp	O
of	O
the	O
5	O
'	O
-	O
promoter	O
region	O
.	O

The	O
hTERT	B-GENE
gene	I-GENE
encompasses	O
more	O
than	O
37kb	O
and	O
consists	O
of	O
16	O
exons	O
.	O

Both	O
betaAPP	B-GENE
mRNA	I-GENE
and	O
Abeta	B-GENE
levels	O
are	O
increased	O
in	O
trisomy	O
21	O
.	O

In	O
reperfusion	O
B	O
,	O
only	O
the	O
diabetic	O
group	O
demonstrated	O
a	O
significant	O
increase	O
in	O
IL	B-GENE
-	I-GENE
8	I-GENE
concentrations	O
at	O
1	O
and	O
15	O
min	O
compared	O
to	O
nondiabetics	O
.	O

This	O
repression	O
was	O
reversed	O
agonists	O
of	O
either	O
receptor	O
demonstrating	O
a	O
functional	O
interaction	O
between	O
NCoR	B-GENE
and	O
PPARalpha	B-GENE
.	O
RXRalpha	B-GENE
heterodimeric	O
complexes	O
in	O
mammalian	O
cells	O
.	O

Spc42p	B-GENE
also	O
was	O
identified	O
as	O
a	O
component	O
of	O
a	O
cytoplasmic	O
SPB	O
subcomplex	O
containing	O
Spc94p	B-GENE
/	O
Nud1p	B-GENE
,	O
Cnm67p	B-GENE
,	O
and	O
Spc42p	B-GENE
.	O

The	O
average	O
coefficients	O
of	O
correlation	O
were	O
0	O
.	O
9998	O
and	O
0	O
.	O
9993	O
for	O
the	O
QMF	O
and	O
the	O
QIT	O
system	O
,	O
respectively	O
.	O

The	O
5	O
-	O
year	O
OS	O
for	O
stage	O
IIIB	O
was	O
30	O
.	O
9	O
%	O
,	O
compared	O
to	O
7	O
.	O
8	O
%	O
for	O
stage	O
IV	O
.	O

Furthermore	O
,	O
heparin	B-GENE
lyase	I-GENE
treatment	O
of	O
extracts	O
of	O
cells	O
expressing	O
recombinant	B-GENE
YD	I-GENE
-	I-GENE
repeat	I-GENE
protein	I-GENE
releases	O
this	O
protein	O
from	O
high	O
molecular	O
mass	O
aggregates	O
.	O

CDK4	B-GENE
kinase	I-GENE
activities	O
were	O
unaffected	O
,	O
as	O
were	O
the	O
levels	O
of	O
the	O
CDK	B-GENE
inhibitor	O
p21Cip1	B-GENE
present	O
in	O
cyclin	B-GENE
E	I-GENE
immunocomplexes	I-GENE
.	O

The	O
recombinant	O
purified	O
protein	O
expressed	O
in	O
the	O
baculovirus	O
system	O
had	O
an	O
approximate	O
molecular	O
size	O
20	O
kDa	O
with	O
amino	O
-	O
terminal	O
sequence	O
of	O
AVQGP	O
.	O

Induction	O
of	O
the	O
urokinase	B-GENE
promoter	I-GENE
by	O
HGF	B-GENE
/	O
SF	B-GENE
via	O
the	O
Met	B-GENE
receptor	I-GENE
was	O
blocked	O
by	O
co	O
-	O
expression	O
of	O
a	O
dominant	O
-	O
negative	O
Grb2	B-GENE
and	O
Sos1	B-GENE
expression	O
construct	O
.	O

Serine	O
phosphorylation	O
of	O
STAT3	B-GENE
was	O
only	O
apparent	O
after	O
somatostatin	B-GENE
treatment	O
and	O
was	O
abolished	O
by	O
pertussis	B-GENE
toxin	I-GENE
or	O
PD	O
98059	O
,	O
together	O
with	O
the	O
associated	O
increases	O
in	O
proliferation	O
.	O

Nevertheless	O
,	O
we	O
demonstrate	O
that	O
the	O
entire	O
three	O
-	O
component	O
yeast	O
capping	O
apparatus	O
,	O
consisting	O
of	O
RNA	B-GENE
5	I-GENE
'	I-GENE
-	I-GENE
triphosphatase	I-GENE
(	O
Cet1p	B-GENE
)	O
,	O
RNA	B-GENE
guanylyltransferase	I-GENE
(	O
Ceg1p	B-GENE
)	O
,	O
and	O
Abd1p	B-GENE
could	O
be	O
replaced	O
in	O
vivo	O
by	O
the	O
two	O
-	O
component	O
mammalian	O
apparatus	O
consisting	O
of	O
a	O
bifunctional	O
triphosphatase	B-GENE
-	I-GENE
guanylyltransferase	I-GENE
Mce1p	I-GENE
and	O
the	O
methyltransferase	B-GENE
Hcm1	I-GENE
(	I-GENE
121	I-GENE
-	I-GENE
476	I-GENE
)	I-GENE
p	I-GENE
.	O

The	O
IC50	O
values	O
for	O
rat	O
and	O
dog	O
urinary	O
bladder	O
were	O
3	O
.	O
9	O
x	O
10	O
(	O
-	O
6	O
)	O
M	O
and	O
3	O
.	O
8	O
x	O
10	O
(	O
-	O
6	O
)	O
M	O
,	O
respectively	O
.	O

Although	O
it	O
has	O
two	O
potential	O
binding	O
sites	O
,	O
the	O
purified	O
MerR	B-GENE
homodimer	I-GENE
binds	O
only	O
one	O
Hg	O
(	O
II	O
)	O
ion	O
,	O
employing	O
Cys82	O
from	O
one	O
monomer	O
and	O
Cys117	O
and	O
Cys126	O
from	O
the	O
other	O
.	O

The	O
influence	O
of	O
Epstein	O
-	O
Barr	O
virus	O
seropositivity	O
on	O
the	O
efficacy	O
of	O
intravenous	O
immune	B-GENE
globulin	I-GENE
in	O
children	O
with	O
immune	O
thrombocytopenic	O
purpura	O
.	O

The	O
results	O
of	O
the	O
lab	O
and	O
field	O
tests	O
yielded	O
high	O
levels	O
of	O
infestation	O
in	O
larvae	O
with	O
values	O
ranging	O
from	O
90	O
to	O
100	O
%	O
and	O
from	O
85	O
to	O
95	O
%	O
,	O
respectively	O
.	O

Amisulpride	O
400	O
mg	O
had	O
several	O
adverse	O
effects	O
on	O
psychomotor	O
and	O
,	O
although	O
less	O
severe	O
,	O
on	O
cognitive	O
performance	O
on	O
the	O
fifth	O
day	O
only	O
.	O

MutY	B-GENE
is	O
an	O
adenine	B-GENE
-	I-GENE
DNA	I-GENE
glycosylase	I-GENE
with	O
specificity	O
for	O
mismatches	O
involving	O
8	O
-	O
oxoguanine	O
(	O
oG	O
.	O
A	O
)	O
or	O
guanine	O
(	O
G	O
.	O
A	O
)	O
.	O

The	O
kinetics	O
of	O
kinase	O
activity	O
within	O
these	O
complexes	O
compared	O
to	O
CheA	B-GENE
alone	O
indicate	O
approximately	O
a	O
50	O
%	O
decrease	O
in	O
the	O
KM	O
for	O
ATP	O
and	O
a	O
100	O
-	O
fold	O
increase	O
in	O
the	O
Vmax	O
.	O

Latexin	B-GENE
,	O
a	O
carboxypeptidase	B-GENE
A	I-GENE
inhibitor	O
,	O
is	O
expressed	O
in	O
a	O
cell	O
type	O
-	O
specific	O
manner	O
in	O
both	O
central	O
and	O
peripheral	O
nervous	O
systems	O
in	O
the	O
rat	O
.	O

Regression	O
analyses	O
identified	O
7	O
risk	O
and	O
7	O
protective	O
factors	O
with	O
minimal	O
overlap	O
.	O

During	O
1985	O
,	O
1990	O
,	O
and	O
1995	O
,	O
respectively	O
,	O
11	O
.	O
7	O
,	O
11	O
.	O
3	O
,	O
and	O
11	O
.	O
4	O
infants	O
per	O
100	O
,	O
000	O
live	O
births	O
had	O
a	O
diagnosis	O
of	O
HSV	O
(	O
P	O
=	O
.	O
98	O
)	O
.	O

Subsets	O
of	O
patients	O
were	O
performed	O
according	O
to	O
the	O
severity	O
of	O
trauma	O
(	O
ISS	O
<	O
9	O
;	O
9	O
-	O
17	O
;	O
18	O
-	O
31	O
;	O
>	O
32	O
)	O
,	O
based	O
on	O
the	O
different	O
injury	O
pattern	O
,	O
and	O
survivors	O
versus	O
nonsurvivors	O
as	O
well	O
.	O

The	O
median	O
age	O
was	O
33	O
years	O
(	O
range	O
17	O
-	O
56	O
years	O
)	O
.	O

Developmental	O
follow	O
-	O
up	O
at	O
age	O
2	O
years	O
was	O
performed	O
.	O

In	O
the	O
whole	O
group	O
of	O
infected	O
children	O
,	O
an	O
age	O
-	O
specific	O
z	O
score	O
<	O
-	O
2	O
for	O
weight	O
and	O
for	O
FFM	O
was	O
significantly	O
associated	O
with	O
an	O
increased	O
risk	O
of	O
death	O
[	O
relative	O
risk	O
(	O
95	O
%	O
CI	O
)	O
=	O
11	O
.	O
4	O
(	O
3	O
.	O
1	O
,	O
41	O
.	O
0	O
)	O
and	O
5	O
.	O
1	O
(	O
1	O
.	O
5	O
,	O
18	O
.	O
2	O
)	O
,	O
respectively	O
]	O
;	O
when	O
only	O
children	O
with	O
more	O
severe	O
disease	O
were	O
considered	O
,	O
only	O
z	O
score	O
for	O
weight	O
was	O
significantly	O
associated	O
with	O
an	O
increased	O
risk	O
[	O
4	O
.	O
6	O
(	O
1	O
.	O
4	O
,	O
14	O
.	O
9	O
)	O
]	O
.	O

In	O
addition	O
,	O
these	O
cells	O
contained	O
one	O
,	O
two	O
,	O
or	O
multiple	O
nuclei	O
indicative	O
of	O
a	O
G2	O
/	O
M	O
delay	O
in	O
nuclear	O
division	O
and	O
also	O
a	O
defect	O
in	O
cytokinesis	O
and	O
/	O
or	O
cell	O
separation	O
.	O

DAF16	B-GENE
is	O
known	O
to	O
be	O
a	O
component	O
of	O
a	O
signaling	O
pathway	O
that	O
has	O
been	O
partially	O
dissected	O
genetically	O
and	O
includes	O
homologues	O
of	O
the	O
insulin	B-GENE
/	O
IGF	B-GENE
-	I-GENE
1	I-GENE
receptor	I-GENE
,	O
PtdIns	B-GENE
3	I-GENE
-	I-GENE
kinase	I-GENE
and	O
PKB	B-GENE
.	O

However	O
,	O
neu	B-GENE
differentiation	O
factor	O
-	O
induced	O
heterodimers	O
of	O
ErbB2	B-GENE
and	O
ErbB4	B-GENE
activated	O
Stat5	B-GENE
.	O

Although	O
linker	O
regions	O
in	O
transcription	O
factors	O
are	O
known	O
to	O
modulate	O
DNA	O
binding	O
specificity	O
,	O
our	O
studies	O
suggest	O
that	O
the	O
human	B-GENE
HSF1	I-GENE
linker	O
plays	O
no	O
role	O
in	O
determining	O
HSF1	B-GENE
binding	O
preferences	O
in	O
vivo	O
but	O
is	O
a	O
critical	O
determinant	O
in	O
regulating	O
the	O
HSF1	B-GENE
monomer	I-GENE
-	I-GENE
trimer	I-GENE
equilibrium	O
.	O

Modulation	O
of	O
human	B-GENE
heat	I-GENE
shock	I-GENE
factor	I-GENE
trimerization	O
by	O
the	O
linker	O
domain	O
.	O

Both	O
functional	O
analyses	O
in	O
undifferentiated	O
and	O
differentiated	O
F9	O
cells	O
and	O
characterization	O
of	O
DNA	O
-	O
protein	O
complexes	O
in	O
vitro	O
have	O
identified	O
the	O
sequence	O
motifs	O
GTGACT	O
(	O
C	O
)	O
,	O
ATTGT	O
,	O
and	O
GATA	O
as	O
the	O
key	O
transcription	O
factor	O
binding	O
sites	O
.	O

These	O
results	O
suggest	O
that	O
the	O
phenotype	O
of	O
XLP	O
may	O
result	O
from	O
perturbed	O
signaling	O
not	O
only	O
through	O
SLAM	B-GENE
,	O
but	O
also	O
other	O
cell	O
surface	O
molecules	O
that	O
utilize	O
SAP	B-GENE
as	O
a	O
signaling	O
adaptor	O
protein	O
.	O

We	O
also	O
localized	O
the	O
Fra	B-GENE
-	I-GENE
2	I-GENE
phosphorylation	I-GENE
sites	I-GENE
by	O
MAPK	B-GENE
to	O
three	O
threonine	O
and	O
three	O
serine	O
residues	O
in	O
the	O
COOH	O
-	O
terminal	O
region	O
by	O
means	O
of	O
site	O
-	O
directed	O
mutagenesis	O
and	O
showed	O
that	O
the	O
threonine	O
residues	O
were	O
more	O
susceptible	O
to	O
MAPK	B-GENE
.	O

Nevertheless	O
,	O
they	O
are	O
functionally	O
distinct	O
in	O
that	O
FcalphaRI	B-GENE
binds	O
human	B-GENE
IgA	I-GENE
(	O
hIgA	B-GENE
)	O
but	O
not	O
bovine	B-GENE
IgG2	I-GENE
(	O
bIgG2	B-GENE
)	O
,	O
whereas	O
bFcgamma2R	B-GENE
binds	O
bIgG2	B-GENE
but	O
not	O
hIgA	B-GENE
.	O

Vac1p	B-GENE
was	O
found	O
to	O
bind	O
the	O
Sec1p	B-GENE
homologue	I-GENE
Vps45p	B-GENE
.	O

To	O
identify	O
these	O
sites	O
,	O
Cdk2	B-GENE
-	O
phosphorylated	O
MARCKS	B-GENE
was	O
digested	O
with	O
lysyl	B-GENE
endoprotease	I-GENE
and	O
analysed	O
by	O
electrospray	O
MS	O
.	O

The	O
yeast	B-GENE
LPD1	I-GENE
gene	I-GENE
encoding	O
lipoamide	B-GENE
dehydrogenase	I-GENE
is	O
subject	O
to	O
the	O
general	O
control	O
of	O
amino	O
acid	O
biosynthesis	O
mediated	O
by	O
the	O
GCN4	B-GENE
transcription	I-GENE
factor	I-GENE
.	O

However	O
,	O
the	O
serum	B-GENE
TNF	I-GENE
-	I-GENE
a	I-GENE
concentration	O
decreased	O
significantly	O
in	O
patients	O
receiving	O
pentoxifylline	O
(	O
basal	O
623	O
+	O
/	O
-	O
366	O
pg	O
/	O
ml	O
;	O
6th	O
month	O
562	O
+	O
/	O
-	O
358	O
pg	O
/	O
ml	O
,	O
p	O
<	O
0	O
.	O
01	O
)	O
,	O
but	O
not	O
in	O
the	O
control	O
group	O
.	O

In	O
addition	O
,	O
we	O
show	O
that	O
the	O
expression	O
of	O
individual	O
members	O
of	O
one	O
subfamily	O
of	O
KRAB	B-GENE
zinc	I-GENE
finger	I-GENE
genes	I-GENE
is	O
restricted	O
to	O
specific	O
hematopoietic	O
cell	O
lineages	O
.	O

Employing	O
fluorescence	O
spectroscopy	O
and	O
circular	O
dichroism	O
,	O
we	O
showed	O
that	O
the	O
binding	O
of	O
Ca2	O
+	O
to	O
ALG	B-GENE
-	I-GENE
2	I-GENE
induced	O
significant	O
conformational	O
changes	O
in	O
both	O
the	O
N	O
-	O
terminal	O
and	O
C	O
-	O
terminal	O
domains	O
of	O
the	O
protein	O
.	O

They	O
also	O
occur	O
in	O
similar	O
locations	O
in	O
the	O
promoters	O
of	O
several	O
other	O
ribosomal	B-GENE
protein	I-GENE
genes	I-GENE
.	O

RESULTS	O
:	O
Transpulmonary	O
passage	O
of	O
contrast	O
occurred	O
in	O
sufficient	O
amounts	O
to	O
enhance	O
the	O
intensity	O
of	O
the	O
Doppler	O
signal	O
significantly	O
,	O
but	O
the	O
duration	O
of	O
this	O
effect	O
was	O
short	O
.	O

In	O
this	O
paper	O
,	O
such	O
lesions	O
in	O
two	O
cases	O
were	O
evaluated	O
by	O
ultrasonography	O
.	O

These	O
regions	O
contain	O
inverted	O
E	O
-	O
box	O
palindromic	O
or	O
direct	O
repeat	O
motifs	O
and	O
bind	O
SREBP	B-GENE
-	I-GENE
1	I-GENE
with	O
different	O
affinities	O
.	O

To	O
address	O
these	O
questions	O
,	O
a	O
recombinant	O
FRAP	B-GENE
/	O
mTOR	B-GENE
protein	O
and	O
a	O
FRAP	B-GENE
/	O
mTOR	B-GENE
immunoprecipitate	O
were	O
utilized	O
in	O
in	O
vitro	O
kinase	O
assays	O
to	O
phosphorylate	O
4E	B-GENE
-	I-GENE
BP1	I-GENE
.	O

The	O
coexpression	O
of	O
full	O
-	O
length	O
expression	O
constructs	O
for	O
both	O
DBP	B-GENE
and	O
hepatic	B-GENE
leukemia	I-GENE
factor	I-GENE
resulted	O
in	O
a	O
dramatic	O
increase	O
in	O
activation	O
mediated	O
by	O
the	O
GAL4	B-GENE
-	O
DBP	B-GENE
fusion	O
proteins	O
,	O
suggesting	O
the	O
involvement	O
of	O
a	O
regulated	O
coactivator	O
in	O
this	O
process	O
.	O

Cp	B-GENE
is	O
normally	O
the	O
main	O
promoter	O
for	O
EBNA	B-GENE
mRNA	I-GENE
initiation	O
,	O
so	O
it	O
appears	O
that	O
EBNA3C	B-GENE
contributes	O
to	O
a	O
negative	O
autoregulatory	O
control	O
loop	O
.	O

These	O
indications	O
of	O
deregulated	O
signalling	O
in	O
the	O
absence	O
of	O
tyrosine	O
118	O
were	O
substantiated	O
by	O
sustained	O
activation	O
of	O
STAT3	B-GENE
.	O

With	O
exon	O
trapping	O
,	O
we	O
could	O
isolate	O
five	O
potential	O
exons	O
from	O
the	O
YAC	O
946E12	O
that	O
spans	O
the	O
region	O
,	O
four	O
of	O
which	O
could	O
be	O
placed	O
in	O
the	O
contig	O
in	O
the	O
vicinity	O
of	O
the	O
breakpoints	O
.	O

Campomelic	O
dysplasia	O
translocation	O
breakpoints	O
are	O
scattered	O
over	O
1	O
Mb	O
proximal	O
to	O
SOX9	B-GENE
:	O
evidence	O
for	O
an	O
extended	O
control	O
region	O
.	O

The	O
most	O
common	O
characteristics	O
of	O
VRE	O
patients	O
were	O
recent	O
prior	O
vancomycin	O
use	O
,	O
recent	O
prior	O
susceptible	O
enterococcal	O
infection	O
,	O
coinfection	O
with	O
other	O
microbial	O
pathogens	O
,	O
and	O
concurrent	O
fungal	O
infection	O
.	O

A	O
coiled	O
-	O
coil	O
domain	O
,	O
conserved	O
within	O
each	O
encoded	O
protein	O
,	O
serves	O
as	O
a	O
potential	O
interaction	O
motif	O
for	O
FLI	B-GENE
LRR	I-GENE
.	O

Binding	O
affinities	O
of	O
these	O
recombinant	O
phages	O
as	O
determined	O
by	O
the	O
retention	O
of	O
these	O
phages	O
by	O
a	O
His	O
-	O
tag	O
immobilized	O
gp17	B-GENE
column	O
,	O
and	O
by	O
co	O
-	O
immunoprecipitation	O
with	O
purified	O
terminase	B-GENE
supported	O
the	O
specific	O
nature	O
of	O
the	O
portal	B-GENE
protein	I-GENE
and	O
terminase	B-GENE
interaction	I-GENE
sites	I-GENE
.	O

Although	O
the	O
terminase	B-GENE
apparently	O
interacts	O
with	O
this	O
gp20	B-GENE
portal	I-GENE
peptide	I-GENE
,	O
polyclonal	O
antibody	O
against	O
the	O
portal	O
peptide	O
appears	O
unable	O
to	O
access	O
it	O
in	O
the	O
native	O
structure	O
,	O
suggesting	O
intimate	O
association	O
of	O
gp20	B-GENE
and	O
gp17	B-GENE
possibly	O
internalizes	O
terminase	B-GENE
regions	I-GENE
within	O
the	O
portal	O
in	O
the	O
packasome	O
complex	O
.	O

cDNA	O
and	O
structural	O
organization	O
of	O
the	O
gene	B-GENE
Pole1	I-GENE
for	O
the	O
mouse	B-GENE
DNA	I-GENE
polymerase	I-GENE
epsilon	I-GENE
catalytic	I-GENE
subunit	I-GENE
.	O

A	O
liquid	O
chromatographic	O
method	O
is	O
described	O
for	O
analysis	O
of	O
beta	O
-	O
carotene	O
in	O
medical	O
food	O
.	O

The	O
FCMS	O
conditions	O
were	O
as	O
follows	O
:	O
2	O
kW	O
maximum	O
electrical	O
power	O
consumption	O
,	O
800	O
V	O
maximum	O
capacitor	O
voltage	O
,	O
720	O
microseconds	O
pulsewidth	O
(	O
180	O
microseconds	O
rise	O
time	O
)	O
,	O
and	O
5	O
-	O
30	O
Hz	O
frequency	O
.	O

Severe	O
hemolysis	O
resulted	O
in	O
statistically	O
significant	O
changes	O
in	O
the	O
mean	O
values	O
of	O
the	O
above	O
analytes	O
in	O
addition	O
to	O
the	O
following	O
increases	O
:	O
alanine	B-GENE
aminotransferase	I-GENE
,	O
calcium	O
,	O
and	O
serum	B-GENE
globulins	I-GENE
(	O
P	O
<	O
0	O
.	O
001	O
)	O
and	O
albumin	B-GENE
and	O
total	O
protein	O
(	O
P	O
<	O
0	O
.	O
01	O
)	O
.	O

Optimal	O
monitoring	O
of	O
ODA	O
remains	O
undefined	O
.	O

The	O
exon	O
:	O
intron	O
structure	O
of	O
chicken	B-GENE
IL8	I-GENE
corresponds	O
almost	O
exactly	O
to	O
that	O
of	O
human	B-GENE
IL8	I-GENE
and	O
differs	O
from	O
those	O
of	O
other	O
known	O
mammalian	B-GENE
CXC	I-GENE
chemokine	I-GENE
genes	I-GENE
.	O

The	O
Aa	B-GENE
-	I-GENE
Pri2	I-GENE
gene	I-GENE
,	O
specifically	O
expressed	O
during	O
basidiocarp	O
differentiation	O
of	O
the	O
mushroom	O
Agrocybe	O
aegerita	O
,	O
was	O
cloned	O
.	O

The	O
main	O
causes	O
of	O
liver	O
disease	O
in	O
the	O
patients	O
with	O
HCC	O
were	O
hepatitis	O
C	O
virus	O
(	O
HCV	O
)	O
(	O
77	O
%	O
)	O
,	O
alcohol	O
abuse	O
(	O
73	O
%	O
)	O
,	O
and	O
the	O
combination	O
of	O
HCV	O
and	O
alcohol	O
abuse	O
(	O
50	O
%	O
)	O
.	O

Three	O
new	O
aromatase	B-GENE
inhibitors	O
have	O
recently	O
completed	O
phase	O
III	O
evaluation	O
as	O
treatment	O
of	O
metastatic	O
breast	O
cancer	O
in	O
post	O
-	O
menopausal	O
women	O
whose	O
disease	O
has	O
progressed	O
despite	O
tamoxifen	O
therapy	O
:	O
anastrozole	O
(	O
ARIMIDEX	O
,	O
Zeneca	O
)	O
,	O
letrozole	O
(	O
FEMARA	O
,	O
Novartis	O
)	O
and	O
vorozole	O
(	O
RIVIZOR	O
,	O
Janssen	O
)	O
.	O

Of	O
those	O
injuries	O
,	O
143	O
cases	O
were	O
snowboard	O
related	O
and	O
158	O
cases	O
were	O
ski	O
related	O
.	O

The	O
femoral	O
artery	O
/	O
vein	O
and	O
the	O
soleus	O
and	O
gastrocnemius	O
muscles	O
were	O
examined	O
in	O
healthy	O
human	O
male	O
volunteers	O
.	O

SRFDelta5	B-GENE
acts	O
as	O
a	O
naturally	O
occurring	O
dominant	O
negative	O
regulatory	O
mutant	O
that	O
blocks	O
SRF	B-GENE
-	O
dependent	O
skeletal	B-GENE
alpha	I-GENE
-	I-GENE
actin	I-GENE
,	O
cardiac	B-GENE
alpha	I-GENE
-	I-GENE
actin	I-GENE
,	O
smooth	B-GENE
alpha	I-GENE
-	I-GENE
actin	I-GENE
,	O
SM22alpha	B-GENE
,	O
and	O
SRF	B-GENE
promoter	O
-	O
luciferase	B-GENE
reporter	O
activities	O
.	O

In	O
serum	O
-	O
free	O
media	O
,	O
p50E4F	B-GENE
accelerated	O
E1A	B-GENE
-	O
induced	O
apoptosis	O
.	O

Progression	O
after	O
first	O
-	O
line	O
chemotherapy	O
was	O
associated	O
with	O
significantly	O
worse	O
survival	O
for	O
patients	O
with	O
metastasis	O
.	O

Mutations	O
within	O
human	O
UTR1	O
modulate	O
NRF	B-GENE
-	I-GENE
1	I-GENE
expression	O
by	O
interfering	O
with	O
mRNA	O
translational	O
efficiency	O
in	O
transfected	O
cells	O
and	O
in	O
an	O
in	O
vitro	O
translation	O
system	O
.	O

As	O
is	O
deduced	O
from	O
the	O
nucleotide	O
sequence	O
of	O
the	O
cDNA	O
,	O
CBS	B-GENE
-	I-GENE
1	I-GENE
contains	O
an	O
open	O
reading	O
frame	O
consisting	O
of	O
182	O
amino	O
acids	O
,	O
with	O
a	O
molecular	O
weight	O
of	O
19	O
.	O
5kDa	O
.	O

Corticostriatal	O
and	O
corticosubthalamic	O
input	O
zones	O
from	O
the	O
presupplementary	O
motor	O
area	O
in	O
the	O
macaque	O
monkey	O
:	O
comparison	O
with	O
the	O
input	O
zones	O
from	O
the	O
supplementary	O
motor	O
area	O
.	O

Basic	B-GENE
fibroblast	I-GENE
growth	I-GENE
factor	I-GENE
(	O
bFGF	B-GENE
)	O
has	O
been	O
shown	O
to	O
induce	O
angiogenesis	O
in	O
various	O
animal	O
models	O
,	O
but	O
the	O
methods	O
of	O
administration	O
used	O
experimentally	O
are	O
not	O
clinically	O
feasible	O
.	O

Both	O
filters	O
equally	O
contributed	O
to	O
elevation	O
of	O
iliac	O
venous	O
pressure	O
(	O
median	O
,	O
9	O
.	O
3	O
and	O
7	O
.	O
2	O
mm	O
Hg	O
[	O
n	O
=	O
9	O
]	O
with	O
the	O
spring	O
filter	O
and	O
RF02	O
filter	O
,	O
respectively	O
)	O
.	O

12	O
healthy	O
women	O
(	O
age	O
18	O
-	O
38	O
years	O
)	O
were	O
examined	O
using	O
the	O
2	O
-	O
hour	O
'	O
s	O
method	O
of	O
passive	O
leg	O
rising	O
(	O
PLR	O
)	O
in	O
follicular	O
(	O
FP	O
)	O
and	O
luteal	O
(	O
LP	O
)	O
phases	O
of	O
normal	O
ovulatory	O
cycle	O
.	O

Thus	O
,	O
sgRNA2	B-GENE
has	O
the	O
3	O
'	O
TE	O
in	O
its	O
5	O
'	O
UTR	O
.	O

These	O
single	O
mutational	O
defects	O
in	O
the	O
eRF1	B-GENE
-	O
eRF3	B-GENE
interaction	O
became	O
evident	O
when	O
either	O
truncated	O
protein	O
eRF3C	B-GENE
or	O
C	O
-	O
terminally	O
altered	O
eRF1	B-GENE
proteins	O
were	O
used	O
for	O
the	O
authentic	O
protein	O
,	O
providing	O
further	O
support	O
for	O
the	O
presence	O
of	O
a	O
C	O
-	O
terminal	O
interaction	O
.	O

Removal	O
of	O
each	O
of	O
three	O
contiguous	O
segments	O
from	O
the	O
N	O
-	O
terminal	O
half	O
specifically	O
inhibits	O
the	O
formation	O
of	O
5	B-GENE
.	I-GENE
8Ss	I-GENE
rRNA	I-GENE
,	O
whereas	O
deleting	O
part	O
of	O
the	O
C	O
-	O
terminal	O
region	O
of	O
the	O
protein	O
only	O
blocks	O
the	O
production	O
of	O
18S	B-GENE
rRNA	I-GENE
.	O

Ras	B-GENE
is	O
not	O
associated	O
with	O
the	O
tegument	O
.	O

Green	O
fluorescent	O
protein	O
-	O
tagged	O
UNC	B-GENE
-	I-GENE
49B	I-GENE
and	O
UNC	B-GENE
-	I-GENE
49C	I-GENE
subunits	I-GENE
are	O
coexpressed	O
in	O
muscle	O
cells	O
and	O
are	O
colocalized	O
to	O
synaptic	O
regions	O
.	O

We	O
show	O
that	O
a	O
protein	O
,	O
UBC9	B-GENE
,	O
interacts	O
specifically	O
with	O
TEL	B-GENE
in	O
vitro	O
and	O
in	O
vivo	O
.	O

Molecules	O
of	O
NH3	O
are	O
capable	O
of	O
emitting	O
stimulated	O
radiation	O
(	O
MASER	O
)	O
.	O

The	O
major	O
findings	O
of	O
our	O
studies	O
are	O
as	O
follows	O
:	O
1	O
)	O
There	O
are	O
no	O
detectable	O
signals	O
around	O
GDF	B-GENE
-	I-GENE
9	I-GENE
-	O
deficient	O
follicles	O
for	O
several	O
theca	O
cell	O
layer	O
markers	O
[	O
i	O
.	O
e	O
.	O

Interestingly	O
,	O
highly	O
charged	O
residues	O
were	O
abundantly	O
possessed	O
in	O
the	O
carboxy	O
-	O
terminal	O
part	O
of	O
the	O
MDV2	B-GENE
UL10	I-GENE
protein	I-GENE
.	O

Identification	O
and	O
structure	O
of	O
the	O
Marek	B-GENE
'	I-GENE
s	I-GENE
disease	I-GENE
virus	I-GENE
serotype	I-GENE
2	I-GENE
glycoprotein	I-GENE
M	I-GENE
gene	I-GENE
:	O
comparison	O
with	O
glycoprotein	B-GENE
M	I-GENE
genes	I-GENE
of	O
Herpesviridae	O
family	O
.	O

OBJECTIVE	O
:	O
To	O
perform	O
a	O
cost	O
-	O
effectiveness	O
analysis	O
(	O
CEA	O
)	O
between	O
a	O
standard	O
antiemetic	O
regimen	O
-	O
chlorpromazine	O
+	O
dexamethasone	O
(	O
CPM	O
-	O
DEX	O
)	O
-	O
and	O
a	O
5	B-GENE
-	I-GENE
HT3	I-GENE
receptor	I-GENE
antagonist	O
-	O
tropisetron	O
(	O
TROP	O
)	O
-	O
-	O
in	O
the	O
control	O
of	O
acute	O
emesis	O
induced	O
by	O
highly	O
emetogenic	O
chemotherapy	O
in	O
children	O
,	O
considering	O
two	O
analytic	O
perspectives	O
:	O
hospital	O
and	O
patients	O
.	O

Baseline	O
data	O
were	O
obtained	O
from	O
10	O
adults	O
.	O

A	O
comparison	O
of	O
the	O
nucleotide	O
and	O
deduced	O
amino	O
acid	O
sequences	O
of	O
the	O
core	O
regions	O
of	O
the	O
RNA	B-GENE
-	I-GENE
dependent	I-GENE
RNA	I-GENE
polymerase	I-GENE
domains	I-GENE
found	O
in	O
these	O
three	O
dsRNAs	O
suggested	O
that	O
these	O
dsRNAs	O
probably	O
evolved	O
independently	O
within	O
each	O
host	O
plant	O
from	O
a	O
common	O
ancestor	O
.	O

Consistent	O
with	O
this	O
possibility	O
,	O
a	O
non	O
-	O
MBD	B-GENE
region	O
of	O
Bin1	B-GENE
was	O
sufficient	O
to	O
recruit	O
a	O
repression	O
function	O
to	O
DNA	O
that	O
was	O
unrelated	O
to	O
histone	B-GENE
deacetylase	I-GENE
.	O

Forty	O
-	O
eight	O
sequences	O
,	O
30	O
not	O
previously	O
identified	O
as	O
IR	O
-	O
responsive	O
,	O
were	O
significantly	O
regulated	O
by	O
IR	O
.	O

A	O
recently	O
described	O
protein	O
,	O
metaxin	B-GENE
1	I-GENE
,	O
serves	O
as	O
a	O
component	O
of	O
a	O
preprotein	O
import	O
complex	O
in	O
the	O
outer	O
membrane	O
of	O
the	O
mammalian	O
mitochondrion	O
.	O

Molecular	O
cloning	O
of	O
rat	B-GENE
SH2	I-GENE
-	I-GENE
containing	I-GENE
inositol	I-GENE
phosphatase	I-GENE
2	I-GENE
(	O
SHIP2	B-GENE
)	O
and	O
its	O
role	O
in	O
the	O
regulation	O
of	O
insulin	B-GENE
signaling	O
.	O

Slp1	B-GENE
represses	O
transcription	O
via	O
this	O
binding	O
site	O
in	O
yeast	O
cells	O
,	O
consistent	O
with	O
its	O
role	O
as	O
a	O
direct	O
repressor	O
of	O
ftz	B-GENE
stripes	O
in	O
interstripe	O
regions	O
during	O
late	O
stages	O
of	O
embryogenesis	O
.	O

The	O
results	O
of	O
these	O
studies	O
support	O
a	O
model	O
in	O
which	O
VirB4	B-GENE
dimers	I-GENE
or	O
homomultimers	O
contribute	O
structural	O
information	O
for	O
the	O
assembly	O
of	O
a	O
transenvelope	O
channel	O
competent	O
for	O
bidirectional	O
DNA	O
transfer	O
,	O
whereas	O
an	O
ATP	O
-	O
dependent	O
activity	O
is	O
required	O
for	O
configuring	O
this	O
channel	O
as	O
a	O
dedicated	O
export	O
machine	O
.	O

The	O
penicillin	B-GENE
binding	I-GENE
proteins	I-GENE
(	O
PBPs	B-GENE
)	O
synthesize	O
and	O
remodel	O
peptidoglycan	O
,	O
the	O
structural	O
component	O
of	O
the	O
bacterial	O
cell	O
wall	O
.	O

TCR	B-GENE
alpha	I-GENE
(	O
TCRA	B-GENE
)	O
expression	O
was	O
examined	O
in	O
RNA	O
samples	O
from	O
PBMC	O
and	O
isolated	O
populations	O
of	O
CD4	B-GENE
+	I-GENE
,	O
CD8	B-GENE
+	I-GENE
,	O
and	O
DN	O
T	O
cells	O
from	O
15	O
healthy	O
individuals	O
.	O

Similar	O
results	O
were	O
obtained	O
with	O
xylitol	O
,	O
an	O
activator	O
of	O
the	O
pentose	O
phosphate	O
pathway	O
.	O

D3S1261	B-GENE
is	O
physically	O
located	O
at	O
or	O
near	O
the	O
MITF	B-GENE
locus	I-GENE
,	O
while	O
D3S2465	B-GENE
and	O
D3S1766	B-GENE
are	O
flanking	O
the	O
locus	O
at	O
about	O
17	O
.	O
5	O
cM	O
genetic	O
distance	O
each	O
side	O
.	O

The	O
percentages	O
of	O
recovery	O
decreased	O
with	O
storage	O
time	O
,	O
although	O
the	O
addition	O
of	O
dispersant	O
(	O
Tris	O
-	O
Tween	O
80	O
)	O
before	O
storage	O
appeared	O
to	O
partially	O
prevent	O
adhesion	O
.	O

Point	O
mutations	O
of	O
the	O
site	O
that	O
suppressed	O
Pit	B-GENE
-	I-GENE
1	I-GENE
binding	O
in	O
vitro	O
restored	O
full	O
tiGH	B-GENE
promoter	I-GENE
activity	O
.	O

A	O
human	B-GENE
Raf	I-GENE
-	I-GENE
responsive	I-GENE
zinc	I-GENE
-	I-GENE
finger	I-GENE
protein	I-GENE
that	O
binds	O
to	O
divergent	O
sequences	O
.	O

We	O
are	O
reporting	O
an	O
autopsy	O
case	O
of	O
so	O
-	O
called	O
"	O
acute	O
multiple	O
sclerosis	O
"	O
that	O
was	O
difficult	O
to	O
differentiate	O
from	O
a	O
brain	O
tumor	O
on	O
MRI	O
findings	O
.	O

Furthermore	O
,	O
MOM	B-GENE
-	I-GENE
4	I-GENE
and	O
TAK1	B-GENE
bind	O
related	O
proteins	O
that	O
promote	O
their	O
kinase	O
activities	O
.	O

BACKGROUND	O
:	O
The	O
MAZE	O
-	O
III	O
is	O
the	O
surgical	O
treatment	O
of	O
choice	O
for	O
medically	O
refractory	O
atrial	O
fibrillation	O
.	O

Gab2	B-GENE
,	O
a	O
new	O
pleckstrin	B-GENE
homology	O
domain	O
-	O
containing	O
adapter	O
protein	O
,	O
acts	O
to	O
uncouple	O
signaling	O
from	O
ERK	B-GENE
kinase	I-GENE
to	O
Elk	B-GENE
-	I-GENE
1	I-GENE
.	O

The	O
presence	O
of	O
cutaneous	O
xanthomas	O
with	O
normal	O
serum	O
lipid	O
levels	O
is	O
due	O
to	O
the	O
antibetalipoproteic	O
activity	O
of	O
the	O
monoclonal	B-GENE
immunoglobulin	I-GENE
.	O

In	O
an	O
attempt	O
to	O
reduce	O
the	O
incidence	O
of	O
NSAID	O
-	O
induced	O
gastrointestinal	O
lesions	O
,	O
the	O
following	O
approaches	O
have	O
been	O
proposed	O
:	O
(	O
i	O
)	O
use	O
of	O
the	O
prostaglandin	O
analogue	O
misoprostol	O
,	O
which	O
is	O
an	O
antiulcer	O
drug	O
which	O
has	O
been	O
proven	O
to	O
be	O
as	O
effective	O
in	O
the	O
prevention	O
of	O
NSAID	O
-	O
induced	O
gastric	O
and	O
duodenal	O
ulcers	O
as	O
in	O
the	O
reduction	O
of	O
serious	O
upper	O
gastrointestinal	O
complications	O
;	O
(	O
ii	O
)	O
histamine	B-GENE
H2	I-GENE
receptor	I-GENE
antagonists	O
(	O
H2	O
antagonists	O
)	O
,	O
e	O
.	O
g	O
.	O
ranitidine	O
,	O
cimetidine	O
and	O
famotidine	O
,	O
which	O
are	O
useful	O
in	O
the	O
prevention	O
of	O
NSAID	O
-	O
induced	O
duodenal	O
ulcers	O
during	O
long	O
term	O
treatment	O
,	O
but	O
not	O
in	O
the	O
prevention	O
of	O
NSAID	O
-	O
induced	O
gastric	O
ulcers	O
;	O
(	O
iii	O
)	O
proton	O
pump	O
inhibitors	O
,	O
e	O
.	O
g	O
omeprazole	O
,	O
and	O
pantoprazole	O
,	O
whose	O
efficacy	O
in	O
preventing	O
NSAID	O
-	O
associated	O
ulcers	O
has	O
been	O
recently	O
demonstrated	O
;	O
and	O
(	O
iv	O
)	O
barrier	O
agents	O
,	O
e	O
.	O
g	O
.	O
sucralfate	O
,	O
which	O
cannot	O
be	O
recommended	O
as	O
prophylactic	O
agents	O
to	O
prevent	O
NSAID	O
-	O
induced	O
gastropathy	O
.	O

Lung	O
mesenchyme	O
serves	O
as	O
a	O
'	O
compleat	O
'	O
inducer	O
of	O
lung	O
morphogenesis	O
by	O
secreting	O
soluble	O
peptide	O
growth	O
factors	O
.	O

The	O
activation	O
of	O
the	O
HIV	O
promoter	O
required	O
the	O
nuclear	O
localization	O
of	O
c	B-GENE
-	I-GENE
Abl	I-GENE
and	O
could	O
be	O
correlated	O
with	O
increased	O
tyrosine	O
phosphorylation	O
of	O
RNA	B-GENE
polymerase	I-GENE
II	I-GENE
.	O

The	O
bovine	B-GENE
papillomavirus	I-GENE
E2	I-GENE
protein	I-GENE
can	O
inhibit	O
the	O
proliferation	O
of	O
HT	O
-	O
3	O
cells	O
,	O
a	O
p53	B-GENE
-	O
negative	O
cervical	O
carcinoma	O
cell	O
line	O
containing	O
integrated	O
human	O
papillomavirus	O
type	O
30	O
DNA	O
.	O

E2	B-GENE
point	O
mutants	O
unable	O
to	O
inhibit	O
cell	O
growth	O
did	O
not	O
repress	O
cdc25A	B-GENE
and	O
cdc25B	B-GENE
expression	O
,	O
nor	O
did	O
the	O
cell	O
cycle	O
inhibitors	O
hydroxyurea	O
and	O
mimosine	O
.	O

BACKGROUND	O
/	O
PURPOSE	O
:	O
Anomalous	O
arrangement	O
of	O
the	O
pancreaticobiliary	O
duct	O
(	O
AAPBD	O
)	O
is	O
closely	O
related	O
to	O
congenital	O
biliary	O
dilatation	O
and	O
frequently	O
associated	O
with	O
biliary	O
tract	O
malignancy	O
.	O

Neurospora	O
crassa	O
CYT	B-GENE
-	I-GENE
18	I-GENE
,	O
can	O
rescue	O
the	O
exonic	O
trap	O
and	O
intron	O
mutants	O
which	O
cause	O
a	O
structural	O
defect	O
.	O

DDP1	B-GENE
also	O
localizes	O
to	O
heterochromatin	O
in	O
interphase	O
nuclei	O
of	O
larval	O
neuroblasts	O
.	O

In	O
a	O
reconstituted	O
human	O
DNA	O
repair	O
system	O
containing	O
DNA	B-GENE
polymerase	I-GENE
beta	I-GENE
and	O
DNA	B-GENE
ligase	I-GENE
III	I-GENE
-	O
XRCC1	B-GENE
,	O
accurate	O
rejoining	O
of	O
a	O
3	O
'	O
mismatched	O
base	O
residue	O
at	O
a	O
single	O
-	O
strand	O
break	O
is	O
dependent	O
on	O
addition	O
of	O
the	O
exonuclease	O
.	O

The	O
PAC	O
clone	O
with	O
an	O
insert	O
size	O
of	O
120kb	O
was	O
isolated	O
and	O
mapped	O
by	O
restriction	O
analysis	O
.	O

Sequence	O
of	O
10q24	B-GENE
locus	I-GENE
surrounding	O
the	O
HOX11	B-GENE
oncogene	I-GENE
reveals	O
a	O
new	O
gene	O
HUG1	B-GENE
expressed	O
in	O
a	O
T	O
-	O
ALL	O
cell	O
line	O
.	O

About	O
20	O
kb	O
upstream	O
of	O
LAMB2	B-GENE
we	O
found	O
a	O
gene	O
encoding	O
a	O
transcribed	O
,	O
non	O
-	O
processed	O
LAMB2	B-GENE
-	I-GENE
like	I-GENE
pseudogene	I-GENE
(	O
LAMB2L	B-GENE
)	O
.	O

Site	O
-	O
directed	O
mutagenesis	O
of	O
the	O
R2	B-GENE
protein	I-GENE
was	O
used	O
to	O
provide	O
evidence	O
that	O
this	O
motif	O
is	O
also	O
part	O
of	O
the	O
active	O
site	O
of	O
the	O
endonuclease	O
encoded	O
by	O
this	O
element	O
.	O

The	O
infected	B-GENE
cell	I-GENE
protein	I-GENE
no	I-GENE
.	I-GENE
0	I-GENE
(	O
ICP0	B-GENE
)	O
of	O
herpes	O
simplex	O
virus	O
1	O
is	O
a	O
promiscuous	O
transactivator	O
shown	O
to	O
enhance	O
the	O
expression	O
of	O
genes	O
introducted	O
into	O
cells	O
by	O
infection	O
or	O
transfection	O
.	O

Wrist	O
measurement	O
of	O
blood	O
pressure	O
:	O
some	O
critical	O
remarks	O
to	O
oscillometry	O
.	O

G	O
-	O
box	O
-	O
directed	O
expression	O
in	O
leaves	O
required	O
the	O
presence	O
of	O
an	O
enhancer	O
region	O
from	O
the	O
cauliflower	O
mosaic	O
virus	O
(	O
CaMV	O
)	O
35S	B-GENE
promoter	I-GENE
.	O

Another	O
element	O
necessary	O
for	O
augmenting	O
the	O
amplitude	O
of	O
the	O
oscillation	O
lies	O
between	O
-	O
178	O
and	O
-	O
264	O
.	O

This	O
scFv	O
was	O
therefore	O
used	O
as	O
control	O
in	O
experiments	O
where	O
another	O
anti	B-GENE
-	I-GENE
Ras	I-GENE
scFv	I-GENE
(	O
Y259	B-GENE
scFv	I-GENE
,	O
derived	O
from	O
the	O
neutralizing	O
anti	B-GENE
-	I-GENE
Ras	I-GENE
mAb	I-GENE
Y13	I-GENE
-	I-GENE
259	I-GENE
)	O
blocked	O
the	O
Ras	B-GENE
pathway	O
in	O
vitro	O
and	O
led	O
to	O
tumor	O
regression	O
in	O
a	O
nude	O
mouse	O
model	O
[	O
Cochet	O
,	O
O	O
.	O
,	O
Kenigsberg	O
,	O
M	O
.	O
,	O
Delumeau	O
,	O
I	O
.	O
,	O
Virone	O
-	O
Oddos	O
,	O
A	O
.	O
,	O
Multon	O
,	O
M	O
.	O
C	O
.	O
,	O
Fridman	O
,	O
W	O
.	O
H	O
.	O
,	O
Schweighoffer	O
,	O
F	O
.	O
,	O
Teillaud	O
,	O
J	O
.	O
L	O
.	O
,	O
Tocque	O
,	O
B	O
.	O
,	O
1998	O
.	O

There	O
was	O
no	O
competition	O
between	O
activin	B-GENE
A	I-GENE
and	O
OP	B-GENE
-	I-GENE
1	I-GENE
for	O
availability	O
of	O
Smad4	B-GENE
,	O
indicating	O
that	O
the	O
concentration	O
of	O
this	O
common	O
signal	O
transducer	O
is	O
not	O
limiting	O
for	O
generating	O
the	O
observed	O
biological	O
responses	O
.	O

Our	O
data	O
therefore	O
indicate	O
that	O
it	O
is	O
possible	O
to	O
engineer	O
the	O
HA	B-GENE
envelope	I-GENE
glycoprotein	I-GENE
by	O
fusing	O
ligands	O
to	O
its	O
amino	O
-	O
terminal	O
end	O
without	O
affecting	O
its	O
fusion	O
activity	O
.	O

However	O
,	O
the	O
favored	O
,	O
parallel	O
beta	O
helix	O
model	O
is	O
a	O
compact	O
coil	O
of	O
ten	O
helically	O
arranged	O
beta	O
strands	O
forming	O
two	O
parallel	O
beta	O
sheet	O
faces	O
.	O

This	O
is	O
predicted	O
to	O
encode	O
a	O
315	O
-	O
residue	O
protein	O
containing	O
seven	O
hydrophobic	O
helical	O
regions	O
and	O
a	O
17	O
amino	O
acid	O
motif	O
characteristic	O
of	O
the	O
R7G	B-GENE
family	I-GENE
of	O
G	B-GENE
-	I-GENE
protein	I-GENE
coupled	I-GENE
membrane	I-GENE
-	I-GENE
bound	I-GENE
receptors	I-GENE
.	O

Characterisation	O
of	O
the	O
chicken	B-GENE
apolipoprotein	I-GENE
A	I-GENE
-	I-GENE
I	I-GENE
gene	I-GENE
5	O
'	O
-	O
flanking	O
region	O
.	O

These	O
results	O
suggest	O
that	O
members	O
of	O
the	O
ATF	B-GENE
family	I-GENE
are	O
involved	O
in	O
mediating	O
the	O
transcriptional	O
regulation	O
of	O
the	O
KGF	B-GENE
gene	I-GENE
in	O
response	O
to	O
extracellular	O
stimuli	O
via	O
a	O
novel	O
CRE	O
regulatory	O
element	O
.	O

Moreover	O
,	O
a	O
high	O
proportion	O
of	O
blood	O
samples	O
from	O
a	O
random	O
sample	O
of	O
the	O
rest	O
of	O
the	O
suspects	O
tested	O
positive	O
for	O
trypanosome	O
-	O
specific	O
DNA	O
by	O
PCR	O
(	O
79	O
.	O
9	O
%	O
for	O
T	O
.	O
b	O
.	O
gambiense	O
and	O
13	O
.	O
9	O
%	O
for	O
T	O
.	O
b	O
.	O
rhodesiense	O
)	O
.	O

A	O
multi	O
-	O
centre	O
evaluation	O
of	O
the	O
card	O
indirect	O
agglutination	O
test	O
for	O
trypanosomiasis	O
(	O
TrypTect	O
CIATT	O
)	O
.	O

Results	O
for	O
men	O
who	O
drank	O
up	O
to	O
two	O
drinks	O
per	O
day	O
suggest	O
that	O
if	O
the	O
dependence	O
criteria	O
were	O
invalid	O
,	O
reductions	O
in	O
the	O
prevalence	O
of	O
specific	O
indicators	O
of	O
alcohol	O
dependence	O
would	O
range	O
from	O
0	O
.	O
3	O
%	O
to	O
5	O
.	O
2	O
%	O
.	O

Mutagenesis	O
of	O
the	O
CDE	O
/	O
CHR	O
elements	O
and	O
Sp1	B-GENE
sites	I-GENE
in	O
this	O
region	O
,	O
alone	O
or	O
in	O
combination	O
,	O
reduced	O
transcriptional	O
activity	O
by	O
40	O
-	O
60	O
%	O
in	O
asynchronously	O
growing	O
cells	O
and	O
abolished	O
cell	O
cycle	O
periodicity	O
in	O
G2	O
-	O
M	O
-	O
synchronized	O
cells	O
.	O

Using	O
Scheffe	O
'	O
s	O
procedure	O
as	O
an	O
illustration	O
,	O
comparisons	O
are	O
made	O
to	O
usual	O
sample	O
size	O
methods	O
that	O
incorrectly	O
ignore	O
the	O
stochastic	O
nature	O
of	O
S2p	O
.	O

The	O
crystal	O
structure	O
of	O
the	O
VP16	B-GENE
core	I-GENE
has	O
been	O
determined	O
at	O
2	O
.	O
1	O
A	O
resolution	O
.	O

The	O
latter	O
method	O
adds	O
clamping	O
of	O
the	O
inferior	O
vena	O
cava	O
,	O
which	O
results	O
in	O
hypotension	O
,	O
requiring	O
invasive	O
anesthetic	O
management	O
.	O

By	O
contrast	O
,	O
PvirE	B-GENE
or	O
Plac	B-GENE
promoter	I-GENE
constructs	I-GENE
yielded	O
functional	O
VirE2	B-GENE
only	O
if	O
virE1	B-GENE
was	O
coexpressed	O
with	O
virE2	B-GENE
.	O

Simian	O
parainfluenza	O
virus	O
5	O
(	O
SV5	O
)	O
is	O
a	O
prototype	O
of	O
the	O
Paramyxoviridae	O
family	O
of	O
nonsegmented	O
negative	O
-	O
sense	O
RNA	O
viruses	O
.	O

To	O
investigate	O
the	O
functions	O
of	O
GE	O
,	O
IG	O
,	O
and	O
GS	O
sequences	O
in	O
transcription	O
,	O
we	O
constructed	O
plasmids	O
containing	O
cDNAs	O
of	O
the	O
full	O
-	O
length	O
SV5	O
genome	O
in	O
which	O
the	O
gene	O
junction	O
sequences	O
(	O
GE	O
,	O
IG	O
,	O
and	O
GS	O
sequences	O
)	O
located	O
between	O
the	O
hemagglutinin	B-GENE
-	I-GENE
neuraminidase	I-GENE
(	O
HN	B-GENE
)	O
and	O
the	O
polymerase	B-GENE
(	I-GENE
L	I-GENE
)	I-GENE
genes	I-GENE
were	O
replaced	O
with	O
the	O
counterpart	O
sequences	O
from	O
other	O
gene	O
junctions	O
.	O

CXCR4	B-GENE
is	O
a	O
chemokine	O
receptor	O
and	O
a	O
coreceptor	O
for	O
T	O
-	O
cell	O
-	O
line	O
-	O
tropic	O
(	O
X4	O
)	O
and	O
dual	O
-	O
tropic	O
(	O
R5X4	O
)	O
human	O
immunodeficiency	O
virus	O
type	O
1	O
(	O
HIV	O
-	O
1	O
)	O
isolates	O
.	O

These	O
data	O
will	O
help	O
us	O
to	O
better	O
detail	O
the	O
CXCR4	B-GENE
structural	O
requirements	O
exhibited	O
by	O
different	O
HIV	O
-	O
1	O
strains	O
and	O
will	O
direct	O
further	O
mutagenesis	O
efforts	O
aimed	O
at	O
better	O
defining	O
the	O
domains	O
in	O
CXCR4	B-GENE
involved	O
in	O
the	O
HIV	O
-	O
1	O
Env	B-GENE
-	O
mediated	O
fusion	O
process	O
.	O

The	O
results	O
of	O
these	O
analyses	O
indicate	O
that	O
the	O
proteinase	O
cleaves	O
at	O
amino	O
acid	O
residues	O
E960	O
-	O
A961	O
,	O
E1071	O
-	O
S1072	O
,	O
E1345	O
-	O
T1346	O
,	O
and	O
E1419	O
-	O
G1420	O
;	O
however	O
,	O
the	O
cleavage	O
efficiency	O
is	O
varied	O
.	O

y	O
.	O

SM	B-GENE
is	O
also	O
shown	O
to	O
be	O
associated	O
in	O
vivo	O
with	O
other	O
components	O
of	O
the	O
CRM	B-GENE
1	I-GENE
export	O
pathway	O
,	O
including	O
the	O
small	B-GENE
GTPase	I-GENE
Ran	I-GENE
and	O
the	O
nucleoporin	O
CAN	B-GENE
/	O
Nup214	B-GENE
.	O

Identification	O
of	O
a	O
spliced	O
gene	O
from	O
Kaposi	O
'	O
s	O
sarcoma	O
-	O
associated	O
herpesvirus	O
encoding	O
a	O
protein	O
with	O
similarities	O
to	O
latent	B-GENE
membrane	I-GENE
proteins	I-GENE
1	I-GENE
and	I-GENE
2A	I-GENE
of	I-GENE
Epstein	I-GENE
-	I-GENE
Barr	I-GENE
virus	I-GENE
.	O

Auditory	O
clicks	O
were	O
given	O
at	O
a	O
rate	O
of	O
20	O
s	O
(	O
-	O
1	O
)	O
.	O

Myosin	B-GENE
light	I-GENE
chain	I-GENE
kinase	I-GENE
functions	O
downstream	O
of	O
Ras	B-GENE
/	O
ERK	B-GENE
to	O
promote	O
migration	O
of	O
urokinase	B-GENE
-	I-GENE
type	I-GENE
plasminogen	I-GENE
activator	I-GENE
-	O
stimulated	O
cells	O
in	O
an	O
integrin	B-GENE
-	O
selective	O
manner	O
.	O

The	O
inhibition	O
of	O
StAR	B-GENE
gene	I-GENE
transcription	O
by	O
DAX	B-GENE
-	I-GENE
1	I-GENE
was	O
dose	O
-	O
dependent	O
reducing	O
transcription	O
to	O
6	O
%	O
of	O
control	O
levels	O
.	O

In	O
a	O
prospective	O
randomized	O
study	O
,	O
287	O
patients	O
with	O
advanced	O
non	O
-	O
small	O
cell	O
lung	O
cancer	O
(	O
NSCLC	O
)	O
stage	O
IIIb	O
or	O
IV	O
with	O
ECOG	O
performance	O
status	O
(	O
PS	O
)	O
0	O
-	O
1	O
or	O
2	O
were	O
randomly	O
assigned	O
to	O
receive	O
either	O
best	O
supportive	O
care	O
(	O
BSC	O
)	O
or	O
supportive	O
care	O
plus	O
combination	O
chemotherapy	O
(	O
IEP	O
regimen	O
:	O
ifosfamide	O
3	O
gm	O
/	O
m2	O
IV	O
with	O
mesna	O
uroprotection	O
,	O
epirubicin	O
60	O
mg	O
/	O
m2	O
IV	O
on	O
day	O
1	O
and	O
cisplatin	O
60	O
mg	O
/	O
m2	O
IV	O
on	O
day	O
2	O
;	O
or	O
MVP	O
regimen	O
:	O
mitomycin	O
-	O
C	O
8	O
mg	O
/	O
m2	O
,	O
cisplatin	O
100	O
mg	O
/	O
m2	O
IV	O
on	O
day	O
1	O
,	O
vinblastine	O
4	O
mg	O
/	O
m2	O
IV	O
on	O
days	O
1	O
and	O
15	O
)	O
.	O

The	O
transcriptional	O
activities	O
of	O
the	O
full	O
-	O
length	O
promoter	O
(	O
-	O
295	O
to	O
+	O
85	O
)	O
and	O
of	O
three	O
deletion	O
constructs	O
(	O
-	O
197	O
,	O
-	O
154	O
and	O
-	O
74	O
to	O
+	O
85	O
)	O
were	O
significantly	O
down	O
-	O
regulated	O
in	O
resistant	O
cells	O
.	O

A	O
13	O
-	O
bp	O
cis	O
-	O
regulatory	O
element	O
in	O
the	O
LTR	O
promoter	O
of	O
the	O
tobacco	B-GENE
retrotransposon	I-GENE
Tto1	I-GENE
is	O
involved	O
in	O
responsiveness	O
to	O
tissue	O
culture	O
,	O
wounding	O
,	O
methyl	O
jasmonate	O
and	O
fungal	O
elicitors	O
.	O

In	O
this	O
study	O
we	O
describe	O
that	O
platelet	B-GENE
-	I-GENE
derived	I-GENE
growth	I-GENE
factor	I-GENE
(	O
PDGF	B-GENE
)	O
,	O
12	O
-	O
O	O
-	O
tetradecanoyl	O
-	O
phorbol	O
-	O
acetate	O
(	O
TPA	O
)	O
,	O
and	O
forskolin	O
induced	O
CREB	B-GENE
(	O
cAMP	B-GENE
-	I-GENE
responsive	I-GENE
element	I-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
)	O
Ser	O
-	O
133	O
phosphorylation	O
with	O
comparable	O
magnitude	O
and	O
kinetics	O
in	O
NIH	O
3T3	O
cells	O
.	O

This	O
constitutes	O
evidence	O
for	O
an	O
in	O
vivo	O
role	O
of	O
SRC	B-GENE
-	I-GENE
1	I-GENE
in	O
dimerization	O
-	O
induced	O
activation	O
by	O
OR1	B-GENE
/	O
RXRalpha	B-GENE
.	O

By	O
contrast	O
,	O
mTRAP100	B-GENE
coprecipitates	O
in	O
vivo	O
with	O
another	O
component	O
of	O
the	O
TRAP	B-GENE
complex	I-GENE
(	O
TRAP220	B-GENE
)	O
,	O
which	O
directly	O
contacts	O
TR	B-GENE
and	O
the	O
vitamin	B-GENE
D	I-GENE
receptor	I-GENE
in	O
a	O
ligand	O
-	O
dependent	O
manner	O
.	O

This	O
sequence	O
also	O
confers	O
VDR	B-GENE
and	O
vitamin	O
D	O
responsiveness	O
to	O
a	O
heterologous	O
promoter	O
.	O

Expression	O
of	O
GlcNAc	B-GENE
-	I-GENE
TI	I-GENE
mRNA	I-GENE
in	O
tobacco	O
leaves	O
was	O
detected	O
using	O
RT	O
-	O
PCR	O
.	O

Chemical	O
stability	O
tests	O
and	O
site	O
-	O
specific	O
mutagenesis	O
identified	O
amino	O
acids	O
H219	O
and	O
D63	O
of	O
RegS	B-GENE
and	O
RegR	B-GENE
,	O
respectively	O
,	O
as	O
the	O
phosphorylated	O
residues	O
.	O

An	O
overexpression	O
of	O
the	O
betaAPP	B-GENE
gene	I-GENE
in	O
certain	O
areas	O
of	O
the	O
AD	O
brain	O
has	O
been	O
suggested	O
to	O
be	O
an	O
important	O
factor	O
in	O
the	O
neuropathology	O
of	O
AD	O
.	O

For	O
functional	O
studies	O
,	O
two	O
promoter	O
regions	O
were	O
cloned	O
upstream	O
of	O
the	O
reporter	O
gene	O
,	O
chloramphenicol	B-GENE
acetyl	I-GENE
transferase	I-GENE
(	O
CAT	B-GENE
)	O
:	O
(	O
i	O
)	O
phbetaE	O
-	O
B	O
-	O
the	O
plasmid	O
that	O
contains	O
the	O
human	O
(	O
h	O
)	O
promoter	O
region	O
(	O
-	O
2832	O
to	O
+	O
101	O
)	O
including	O
URE	O
,	O
and	O
(	O
ii	O
)	O
prhbetaE	O
-	O
B	O
-	O
the	O
plasmid	O
that	O
contains	O
the	O
rhesus	O
(	O
rh	O
)	O
promoter	O
region	O
excluding	O
URE	O
as	O
it	O
lacks	O
a	O
270	O
bp	O
region	O
of	O
the	O
hbetaAPP	B-GENE
promoter	I-GENE
(	O
-	O
2435	O
to	O
-	O
2165	O
)	O
.	O

67	O
393	O
bp	O
of	O
contiguous	O
DNA	O
located	O
between	O
markers	O
cdc18	B-GENE
and	O
cdc14	B-GENE
on	O
the	O
right	O
arm	O
of	O
fission	O
yeast	O
chromosome	O
II	O
has	O
been	O
sequenced	O
as	O
part	O
of	O
the	O
European	O
Union	O
Schizosaccharomyces	O
pombe	O
genome	O
sequencing	O
project	O
.	O

67	O
393	O
bp	O
of	O
contiguous	O
DNA	O
located	O
between	O
markers	O
cdc18	B-GENE
and	O
cdc14	B-GENE
on	O
the	O
right	O
arm	O
of	O
fission	O
yeast	O
chromosome	O
II	O
has	O
been	O
sequenced	O
as	O
part	O
of	O
the	O
European	O
Union	O
Schizosaccharomyces	O
pombe	O
genome	O
sequencing	O
project	O
.	O

G	B-GENE
-	I-GENE
CSF	I-GENE
(	O
480	O
micrograms	O
subcutaneously	O
(	O
s	O
.	O
c	O
.	O
)	O
)	O
were	O
used	O
in	O
55	O
and	O
GM	B-GENE
-	I-GENE
CSF	I-GENE
(	O
400	O
micrograms	O
s	O
.	O
c	O
.	O
)	O
in	O
28	O
chemotherapeutic	O
cycles	O
.	O

Overexpression	O
of	O
H411	B-GENE
cDNA	I-GENE
in	O
the	O
RAW	O
264	O
.	O
7	O
macrophage	O
cell	O
line	O
promoted	O
an	O
increased	O
growth	O
rate	O
,	O
suggesting	O
that	O
expression	O
of	O
H411	B-GENE
is	O
part	O
of	O
the	O
proliferative	O
cell	O
response	O
to	O
LPS	O
.	O

Human	O
expressed	O
sequence	O
tag	O
clones	O
were	O
identified	O
by	O
sequence	O
similarity	O
to	O
mammalian	B-GENE
and	I-GENE
yeast	I-GENE
oligosaccharide	I-GENE
-	I-GENE
processing	I-GENE
mannosidases	I-GENE
,	O
and	O
the	O
full	O
-	O
length	O
coding	O
region	O
of	O
the	O
putative	O
mannosidase	B-GENE
homolog	I-GENE
was	O
isolated	O
by	O
a	O
combination	O
of	O
5	O
'	O
-	O
rapid	O
amplification	O
of	O
cDNA	O
ends	O
and	O
direct	O
polymerase	O
chain	O
reaction	O
from	O
human	O
placental	O
cDNA	O
.	O

Activation	O
of	O
ERK1	B-GENE
/	I-GENE
2	I-GENE
is	O
correlated	O
with	O
induction	O
of	O
the	O
immediate	B-GENE
-	I-GENE
early	I-GENE
response	I-GENE
genes	I-GENE
.	O

The	O
transcription	O
of	O
most	O
RP	B-GENE
genes	I-GENE
is	O
activated	O
by	O
two	O
Rap1p	B-GENE
binding	I-GENE
sites	I-GENE
,	O
250	O
to	O
400	O
bp	O
upstream	O
from	O
the	O
initiation	O
of	O
transcription	O
.	O

We	O
have	O
isolated	O
three	O
mutant	O
alleles	O
of	O
CDC4	B-GENE
(	O
cdc4	B-GENE
-	I-GENE
10	I-GENE
,	O
cdc4	B-GENE
-	I-GENE
11	I-GENE
,	O
and	O
cdc4	B-GENE
-	I-GENE
16	I-GENE
)	O
which	O
suppress	O
the	O
nuclear	O
division	O
defect	O
of	O
cdc20	B-GENE
-	I-GENE
1	I-GENE
cells	O
.	O

Role	O
of	O
secondary	O
structure	O
in	O
discrimination	O
between	O
constitutive	O
and	O
inducible	O
activators	O
.	O

In	O
summary	O
,	O
Ca	O
(	O
2	O
+	O
)	O
-	O
dependent	O
activation	O
of	O
NO	O
production	O
mediates	O
apoptosis	O
after	O
TG	B-GENE
exposure	O
in	O
JT	O
/	O
Neo	O
cells	O
.	O

Accumulation	O
of	O
the	O
U4	B-GENE
/	O
U6	B-GENE
duplex	O
was	O
relieved	O
by	O
overexpression	O
of	O
wild	B-GENE
-	I-GENE
type	I-GENE
Prp44p	I-GENE
.	O

Our	O
results	O
,	O
when	O
combined	O
with	O
previously	O
published	O
in	O
vitro	O
results	O
,	O
support	O
a	O
direct	O
role	O
for	O
Prp44p	B-GENE
in	O
unwinding	O
of	O
the	O
U4	B-GENE
/	O
U6	B-GENE
helix	O
.	O

This	O
approximately	O
125	O
-	O
nt	O
RNA	O
proved	O
to	O
arise	O
via	O
RNase	B-GENE
E	I-GENE
cleavage	O
from	O
the	O
3	O
'	O
-	O
terminal	O
region	O
of	O
the	O
mRNAs	O
bearing	O
the	O
terminator	O
.	O

The	O
mysteries	O
of	O
geographic	O
variability	O
in	O
nonmelanoma	O
skin	O
cancer	O
incidence	O
.	O

In	O
Saccharomyces	O
cerevisiae	O
the	O
cAMP	B-GENE
-	I-GENE
dependent	I-GENE
kinases	I-GENE
(	O
PKAs	B-GENE
)	O
promote	O
cytoplasmic	O
growth	O
and	O
modulate	O
the	O
growth	O
-	O
regulated	O
mechanism	O
triggering	O
the	O
begin	O
of	O
DNA	O
synthesis	O
.	O

A	O
recombinant	O
derivative	O
harboring	O
the	O
pMJ101	O
replication	O
region	O
proved	O
to	O
be	O
compatible	O
with	O
pJM1	O
,	O
a	O
plasmid	O
containing	O
the	O
iron	O
acquisition	O
system	O
required	O
for	O
the	O
virulence	O
of	O
V	O
.	O
anguillarum	O
775	O
,	O
another	O
important	O
pathogen	O
that	O
causes	O
vibriosis	O
.	O

FAK	B-GENE
localizes	O
to	O
sites	O
of	O
transmembrane	B-GENE
integrin	I-GENE
receptor	I-GENE
clustering	O
and	O
facilitates	O
intracellular	O
signaling	O
events	O
.	O

Expression	O
of	O
various	O
FAK	B-GENE
mutants	I-GENE
in	O
the	O
FAK	B-GENE
-	O
cells	O
showed	O
that	O
FAK	B-GENE
kinase	I-GENE
activity	O
,	O
the	O
Tyr	B-GENE
-	I-GENE
397	I-GENE
/	I-GENE
SH2	I-GENE
domain	I-GENE
binding	I-GENE
site	I-GENE
,	O
and	O
the	O
first	O
proline	O
-	O
rich	O
SH3	B-GENE
binding	I-GENE
region	I-GENE
in	O
the	O
FAK	B-GENE
C	I-GENE
-	I-GENE
terminal	I-GENE
domain	I-GENE
were	O
individually	O
needed	O
to	O
promote	O
full	O
FAK	B-GENE
-	O
mediated	O
FAK	B-GENE
-	O
cell	O
migration	O
to	O
FN	B-GENE
whereas	O
direct	O
paxillin	B-GENE
binding	O
to	O
FAK	B-GENE
was	O
not	O
required	O
.	O

This	O
dominant	O
-	O
negative	O
effect	O
of	O
FRNK	B-GENE
was	O
reversed	O
by	O
a	O
point	O
mutation	O
(	O
Leu	O
-	O
1034	O
to	O
Ser	O
)	O
which	O
prevented	O
FRNK	B-GENE
localization	O
to	O
focal	O
contact	O
sites	O
.	O

Fifty	O
six	O
young	O
patients	O
(	O
age	O
<	O
45	O
yr	O
)	O
with	O
doppler	O
-	O
proven	O
DVT	O
were	O
investigated	O
for	O
the	O
presence	O
of	O
resistance	O
to	O
activated	B-GENE
protein	I-GENE
C	I-GENE
(	O
APC	B-GENE
-	I-GENE
R	I-GENE
)	O
,	O
lupus	O
anticoagulant	O
(	O
LA	O
)	O
,	O
anticardiolipin	B-GENE
antibodies	I-GENE
and	O
deficiencies	O
of	O
protein	B-GENE
C	I-GENE
,	O
protein	B-GENE
S	I-GENE
,	O
ATIII	B-GENE
activities	O
.	O

DESIGN	O
:	O
Comparison	O
of	O
number	O
of	O
women	O
with	O
PKU	O
aged	O
15	O
-	O
44	O
years	O
on	O
the	O
NSW	O
PKU	O
database	O
(	O
observed	O
number	O
)	O
with	O
expected	O
number	O
derived	O
from	O
population	O
data	O
.	O

PURPOSE	O
:	O
The	O
purposes	O
of	O
the	O
present	O
study	O
were	O
to	O
assess	O
the	O
effects	O
of	O
a	O
12	O
-	O
wk	O
laboratory	O
based	O
aerobic	O
exercise	O
program	O
on	O
cardiopulmonary	O
function	O
,	O
CD4	B-GENE
cell	O
count	O
,	O
and	O
physician	O
-	O
assessed	O
health	O
status	O
among	O
symptomatic	O
pre	O
-	O
AIDS	O
HIV	O
-	O
infected	O
individuals	O
(	O
N	O
=	O
28	O
)	O
and	O
to	O
assess	O
the	O
degree	O
to	O
which	O
ill	O
health	O
was	O
associated	O
with	O
exercise	O
relapse	O
.	O

Epidemiologic	O
evidence	O
indicates	O
that	O
estrogen	O
replacement	O
therapy	O
after	O
menopause	O
increases	O
breast	O
cancer	O
risk	O
.	O

In	O
addition	O
to	O
its	O
elongation	O
activity	O
,	O
ELL	B-GENE
contains	O
a	O
novel	O
type	O
of	O
RNA	B-GENE
polymerase	I-GENE
II	I-GENE
interaction	I-GENE
domain	I-GENE
that	O
is	O
capable	O
of	O
repressing	O
polymerase	O
activity	O
in	O
promoter	O
-	O
specific	O
transcription	O
.	O

A	O
diagnosis	O
of	O
IgA	B-GENE
lambda	I-GENE
multiple	O
myeloma	O
with	O
peritoneal	O
involvement	O
was	O
made	O
.	O

The	O
radiation	O
burden	O
associated	O
with	O
the	O
majority	O
of	O
examinations	O
in	O
nuclear	O
medicine	O
expressed	O
as	O
the	O
effective	O
dose	O
is	O
comparable	O
with	O
the	O
radiation	O
burden	O
of	O
radiodiagnostic	O
examinations	O
,	O
only	O
after	O
administration	O
of	O
preparations	O
with	O
131I	O
,	O
201Tl	O
,	O
67Ga	O
and	O
111In	O
it	O
is	O
markedly	O
higher	O
.	O

Although	O
the	O
risk	O
of	O
malformation	O
in	O
children	O
born	O
after	O
ICSI	O
is	O
not	O
increased	O
there	O
is	O
an	O
increased	O
risk	O
to	O
transmit	O
genetic	O
abnormalities	O
in	O
case	O
of	O
NOA	O
(	O
such	O
as	O
the	O
rate	O
of	O
sex	O
chromosome	O
,	O
or	O
microdeletions	O
of	O
the	O
Y	O
chromosome	O
)	O
and	O
in	O
case	O
of	O
congenital	O
OA	O
(	O
mutations	O
of	O
the	O
cystic	B-GENE
fibrosis	I-GENE
gene	I-GENE
)	O
.	O

TaV	O
particles	O
have	O
a	O
buoyant	O
density	O
of	O
1	O
.	O
296	O
g	O
/	O
cm3	O
in	O
CsCl	O
and	O
consist	O
of	O
two	O
capsid	B-GENE
proteins	I-GENE
of	O
56	O
and	O
6	O
kDa	O
.	O

CONCLUSION	O
:	O
These	O
results	O
suggest	O
that	O
vibration	O
-	O
induced	O
neural	O
involvement	O
can	O
be	O
considered	O
neither	O
pure	O
digital	O
neuropathy	O
,	O
nor	O
definite	O
CTS	O
,	O
as	O
previously	O
described	O
.	O

In	O
about	O
770	O
bp	O
upstream	O
region	O
of	O
Spam1	B-GENE
that	O
has	O
been	O
cloned	O
and	O
sequenced	O
,	O
multiple	O
transcription	O
factor	O
binding	O
sites	O
including	O
a	O
CRE	O
(	O
cAMP	O
-	O
responsive	O
element	O
)	O
were	O
found	O
.	O

The	O
in	O
vitro	O
relaxivity	O
of	O
the	O
complex	O
is	O
16	O
.	O
24	O
s	O
(	O
-	O
1	O
)	O
mM	O
(	O
-	O
1	O
)	O
.	O

Bacterial	O
recovery	O
of	O
SA	O
from	O
the	O
liver	O
/	O
spleen	O
and	O
the	O
cecal	O
tonsil	O
in	O
contact	O
poults	O
and	O
SG	O
from	O
contact	O
chicks	O
treated	O
with	O
ILK	B-GENE
was	O
dramatically	O
reduced	O
when	O
compared	O
to	O
non	O
-	O
treated	O
contact	O
poults	O
and	O
chicks	O
.	O

The	O
results	O
of	O
the	O
ISIS	O
-	O
2	O
trial	O
and	O
the	O
data	O
from	O
the	O
Antiplatelet	O
Trialists	O
'	O
Collaboration	O
indicated	O
that	O
aspirin	O
is	O
mandatory	O
in	O
patients	O
with	O
acute	O
myocardial	O
infarction	O
and	O
for	O
secondary	O
prevention	O
.	O

This	O
study	O
was	O
performed	O
to	O
assess	O
the	O
role	O
of	O
additional	O
diagnostic	O
laparoscopy	O
in	O
the	O
preoperative	O
staging	O
of	O
patients	O
with	O
adenocarcinoma	O
of	O
the	O
esophagus	O
,	O
gastric	O
cancer	O
and	O
pancreatic	O
cancer	O
prior	O
to	O
intended	O
curative	O
surgery	O
.	O

This	O
report	O
presents	O
state	O
-	O
specific	O
MMRs	O
for	O
1987	O
-	O
1996	O
,	O
focusing	O
on	O
persistent	O
disparities	O
in	O
maternal	O
mortality	O
between	O
black	O
and	O
white	O
women	O
.	O

Preheparin	O
LPL	B-GENE
mass	O
level	O
did	O
not	O
significantly	O
differ	O
in	O
individuals	O
from	O
19	O
to	O
70	O
years	O
old	O
,	O
for	O
both	O
men	O
and	O
women	O
.	O

A	O
decrease	O
in	O
insulin	B-GENE
-	O
induced	O
receptor	O
kinase	O
activity	O
was	O
observed	O
for	O
solubilized	O
chimeric	O
receptors	O
.	O

Cat	B-GENE
-	I-GENE
1	I-GENE
is	O
identical	O
to	O
the	O
recently	O
identified	O
binding	O
partner	O
for	O
the	O
beta	B-GENE
-	I-GENE
adrenergic	I-GENE
receptor	I-GENE
kinase	I-GENE
(	O
betaARK	B-GENE
or	O
GRK	B-GENE
-	I-GENE
2	I-GENE
)	O
,	O
which	O
was	O
shown	O
to	O
have	O
Arf	B-GENE
-	O
GAP	B-GENE
activity	O
.	O

Cat	B-GENE
proteins	I-GENE
are	O
tyrosine	O
-	O
phosphorylated	O
when	O
co	O
-	O
expressed	O
in	O
cells	O
with	O
the	O
focal	B-GENE
adhesion	I-GENE
kinase	I-GENE
Fak	B-GENE
and	O
Src	B-GENE
.	O

Immunoprecipitation	O
experiments	O
using	O
DokR	B-GENE
-	I-GENE
specific	I-GENE
antibodies	I-GENE
revealed	O
an	O
interaction	O
between	O
endogenous	B-GENE
DokR	I-GENE
and	O
a	O
150	O
-	O
kDa	O
protein	O
that	O
is	O
tyrosine	O
-	O
phosphorylated	O
in	O
EGF	B-GENE
-	O
stimulated	O
BaF	O
/	O
3	O
cells	O
.	O

Expansins	B-GENE
are	O
a	O
family	O
of	O
proteins	O
that	O
catalyse	O
long	O
-	O
term	O
extension	O
of	O
isolated	O
plant	O
cell	O
walls	O
due	O
to	O
an	O
as	O
yet	O
unknown	O
biochemical	O
mechanism	O
.	O

This	O
review	O
summarizes	O
the	O
clinical	O
evidence	O
to	O
support	O
current	O
therapies	O
in	O
irritable	O
bowel	O
syndrome	O
(	O
IBS	O
)	O
.	O

The	O
responsive	O
region	O
of	O
the	O
alpha	B-GENE
2	I-GENE
(	I-GENE
V	I-GENE
)	I-GENE
collagen	I-GENE
gene	I-GENE
was	O
localized	O
to	O
a	O
fragment	O
including	O
100	O
bp	O
of	O
basal	O
promoter	O
and	O
150	O
bp	O
of	O
exon	O
1	O
sequences	O
,	O
which	O
contained	O
two	O
CRE	O
-	O
like	O
elements	O
.	O

Furthermore	O
,	O
addition	O
of	O
B	B-GENE
-	I-GENE
Myb	I-GENE
-	O
glutathionine	B-GENE
S	I-GENE
-	I-GENE
transferase	I-GENE
fusion	O
protein	O
inhibited	O
complex	O
formation	O
.	O

APOE	B-GENE
-	O
epsilon4	O
count	O
predicts	O
age	O
when	O
prevalence	O
of	O
AD	O
increases	O
,	O
then	O
declines	O
:	O
the	O
Cache	O
County	O
Study	O
.	O

A	O
new	O
DNA	B-GENE
repair	I-GENE
gene	I-GENE
from	O
Schizosaccharomyces	O
pombe	O
with	O
homology	O
to	O
RecA	B-GENE
was	O
identified	O
and	O
characterized	O
.	O

Among	O
mucus	O
-	O
secreting	O
cells	O
,	O
the	O
gastric	O
gland	O
mucous	O
cells	O
,	O
Brunner	O
'	O
s	O
glands	O
,	O
accessory	O
glands	O
of	O
pancreaticobiliary	O
tract	O
,	O
and	O
pancreatic	O
ducts	O
exhibiting	O
gastric	O
metaplasia	O
are	O
unique	O
in	O
that	O
they	O
express	O
class	B-GENE
III	I-GENE
mucin	I-GENE
identified	O
by	O
paradoxical	O
Con	B-GENE
A	I-GENE
staining	O
composed	O
of	O
periodate	O
oxidation	O
,	O
sodium	O
borohydride	O
reduction	O
,	O
Con	B-GENE
A	I-GENE
,	O
and	O
horseradish	B-GENE
peroxidase	I-GENE
reaction	O
.	O

The	O
C	O
-	O
terminal	O
mutants	O
were	O
strongly	O
dominant	O
over	O
TraR	B-GENE
,	O
suggesting	O
that	O
they	O
can	O
form	O
heteromultimers	O
with	O
the	O
wild	O
-	O
type	O
activator	O
.	O

The	O
data	O
imply	O
that	O
JAK	B-GENE
/	O
STAT	B-GENE
signaling	O
has	O
a	O
role	O
in	O
EBV	O
-	O
associated	O
malignancies	O
.	O

There	O
were	O
27	O
men	O
and	O
156	O
women	O
.	O

A	O
.	O
,	O
Bowers	O
,	O
K	O
.	O
E	O
,	O
and	O
Matthews	O
,	O
C	O
.	O

Spfkh1	B-GENE
is	O
transcribed	O
in	O
one	O
open	O
reading	O
frame	O
that	O
contains	O
the	O
DNA	O
binding	O
domain	O
,	O
nuclear	O
localization	O
signal	O
and	O
transactivation	O
domain	O
.	O

The	O
molecular	O
mechanism	O
of	O
Tax	B-GENE
-	O
mediated	O
trans	O
-	O
activation	O
has	O
been	O
well	O
investigated	O
.	O

METHODS	O
:	O
109	O
suspected	O
cases	O
with	O
SS	O
underwent	O
the	O
biopsies	O
.	O

We	O
also	O
identify	O
several	O
regulatory	O
domain	O
mutants	O
in	O
which	O
Cd	O
(	O
2	O
+	O
)	O
tolerance	O
of	O
the	O
mutant	O
strain	O
and	O
transport	O
activity	O
of	O
the	O
protein	O
are	O
dissociated	O
.	O

The	O
human	B-GENE
immunodeficiency	I-GENE
virus	I-GENE
type	I-GENE
-	I-GENE
1	I-GENE
(	I-GENE
HIV	I-GENE
-	I-GENE
1	I-GENE
)	I-GENE
Tat	I-GENE
protein	I-GENE
regulates	O
transcription	O
by	O
stimulating	O
RNA	B-GENE
polymerase	I-GENE
processivity	O
.	O

One	O
of	O
these	O
SEBPs	B-GENE
,	O
SEBP2	B-GENE
,	O
was	O
shown	O
to	O
be	O
the	O
product	O
of	O
the	O
homeotic	B-GENE
gene	I-GENE
fork	B-GENE
head	I-GENE
.	O

Identity	O
elements	O
in	O
tRNA	O
for	O
mono	O
-	O
and	O
dimethylation	O
reactions	O
by	O
the	O
recombinant	B-GENE
pfTrm1p	I-GENE
were	O
identified	O
using	O
in	O
vitro	O
T7	O
transcripts	O
of	O
33	O
variants	O
of	O
tRNA	B-GENE
(	I-GENE
Asp	I-GENE
)	I-GENE
and	O
tRNA	B-GENE
(	I-GENE
Phe	I-GENE
)	I-GENE
from	O
yeast	O
.	O

In	O
insulin	B-GENE
-	O
responsive	O
cells	O
,	O
Akt	B-GENE
phosphorylates	O
and	O
inactivates	O
the	O
serine	B-GENE
/	I-GENE
threonine	I-GENE
kinase	I-GENE
glycogen	B-GENE
synthase	I-GENE
kinase	I-GENE
-	I-GENE
3	I-GENE
(	O
GSK	B-GENE
-	I-GENE
3	I-GENE
)	O
.	O

The	O
B	B-GENE
cell	I-GENE
antigen	I-GENE
receptor	I-GENE
activates	O
the	O
Akt	B-GENE
(	O
protein	B-GENE
kinase	I-GENE
B	I-GENE
)	O
/	O
glycogen	B-GENE
synthase	I-GENE
kinase	I-GENE
-	I-GENE
3	I-GENE
signaling	O
pathway	O
via	O
phosphatidylinositol	B-GENE
3	I-GENE
-	I-GENE
kinase	I-GENE
.	O

Fewer	O
recombination	O
events	O
are	O
detected	O
in	O
four	O
different	O
B	O
and	O
T	O
cell	O
lines	O
that	O
do	O
not	O
undergo	O
switch	O
recombination	O
of	O
their	O
endogenous	O
genes	O
.	O

IL	B-GENE
-	I-GENE
1	I-GENE
and	O
TNF	B-GENE
increase	O
AND	B-GENE
-	I-GENE
34	I-GENE
transcript	I-GENE
levels	O
in	O
thymic	O
cortical	O
reticular	O
,	O
thymic	O
nurse	O
,	O
and	O
fibroblast	O
cell	O
lines	O
.	O

To	O
determine	O
what	O
role	O
eIF4E	B-GENE
might	O
play	O
in	O
c	B-GENE
-	I-GENE
myc	I-GENE
expression	O
,	O
the	O
c	B-GENE
-	I-GENE
myc	I-GENE
5	I-GENE
'	I-GENE
untranslated	I-GENE
region	I-GENE
(	I-GENE
UTR	I-GENE
)	I-GENE
was	O
fused	O
in	O
-	O
frame	O
to	O
CAT	B-GENE
reporters	I-GENE
,	O
and	O
several	O
more	O
derivative	O
constructs	O
were	O
made	O
.	O

Analysis	O
of	O
cell	O
cycle	O
proteins	O
showed	O
that	O
24	O
h	O
of	O
lovastatin	O
treatment	O
in	O
the	O
control	O
cells	O
caused	O
an	O
elevation	O
in	O
the	O
levels	O
of	O
the	O
cyclin	B-GENE
-	I-GENE
dependent	I-GENE
kinase	I-GENE
inhibitor	O
p27	B-GENE
(	O
kip1	B-GENE
)	O
,	O
inhibition	O
of	O
both	O
cyclin	B-GENE
E	I-GENE
-	I-GENE
and	I-GENE
cyclin	I-GENE
A	I-GENE
-	I-GENE
dependent	I-GENE
kinase	I-GENE
activity	O
,	O
and	O
decreased	O
levels	O
of	O
hyperphosphorylated	O
retinoblastoma	B-GENE
protein	I-GENE
(	O
pRb	B-GENE
)	O
.	O

RESULTS	O
:	O
Circulating	O
leptin	B-GENE
concentrations	O
in	O
AN	O
were	O
3	O
.	O
5	O
+	O
/	O
-	O
0	O
.	O
5	O
versus	O
7	O
.	O
6	O
+	O
/	O
-	O
1	O
.	O
2	O
ng	O
/	O
ml	O
in	O
control	O
subjects	O
.	O

Copyright	O
1999	O
Academic	O
Press	O
.	O

Oligonucleotide	O
probes	O
corresponding	O
to	O
wild	O
-	O
type	O
and	O
mutant	O
EpRE	O
sequences	O
were	O
used	O
in	O
gel	O
-	O
shift	O
and	O
super	O
-	O
shift	O
analyses	O
to	O
identify	O
proteins	O
binding	O
.	O

PKNbeta	B-GENE
had	O
high	O
sequence	O
homology	O
with	O
PKNalpha	B-GENE
,	O
originally	O
isolated	O
PKN	B-GENE
,	O
especially	O
in	O
the	O
repeats	O
of	O
charged	O
amino	O
acid	O
-	O
rich	O
region	O
with	O
leucine	O
-	O
zipper	O
like	O
sequences	O
(	O
CZ	O
region	O
/	O
HR1	O
)	O
,	O
in	O
the	O
carboxyl	O
-	O
terminal	O
catalytic	O
domain	O
,	O
and	O
in	O
approximately	O
130	O
amino	O
acid	O
stretch	O
(	O
D	O
region	O
/	O
HR2	O
)	O
,	O
located	O
between	O
CZ	O
region	O
/	O
HR1	O
and	O
the	O
catalytic	O
domain	O
.	O

At	O
baseline	O
,	O
serum	O
levels	O
of	O
lycopene	O
and	O
FLOP	O
were	O
abnormally	O
high	O
and	O
serum	O
FLOP	O
was	O
correlated	O
significantly	O
with	O
plasma	O
cyclosporine	O
levels	O
(	O
r	O
=	O
0	O
.	O
646	O
,	O
p	O
=	O
0	O
.	O
016	O
)	O
.	O

BACKGROUND	O
:	O
Chronic	O
alcohol	O
consumption	O
has	O
been	O
demonstrated	O
to	O
be	O
deleterious	O
to	O
bone	O
health	O
.	O

Interestingly	O
,	O
following	O
induction	O
of	O
stress	O
by	O
heat	O
shock	O
,	O
high	O
salt	O
,	O
or	O
ethanol	O
,	O
conditions	O
under	O
which	O
most	O
mRNA	O
export	O
is	O
blocked	O
,	O
Npl3p	B-GENE
is	O
still	O
exported	O
from	O
the	O
nucleus	O
.	O

For	O
symptomatic	O
relief	O
and	O
inhibition	O
of	O
the	O
growth	O
of	O
the	O
metastases	O
interferon	B-GENE
-	I-GENE
a	I-GENE
and	O
somatostatin	B-GENE
analogues	O
can	O
be	O
employed	O
.	O

In	O
summary	O
,	O
the	O
no	O
-	O
adverse	O
-	O
effect	O
-	O
level	O
for	O
this	O
study	O
was	O
determined	O
to	O
be	O
1000	O
ppm	O
,	O
based	O
on	O
decreased	O
weight	O
gain	O
in	O
female	O
rats	O
,	O
and	O
on	O
slight	O
organ	O
weight	O
changes	O
in	O
both	O
sexes	O
at	O
3000	O
ppm	O
.	O

Some	O
of	O
them	O
produce	O
gigantic	O
sperm	O
several	O
times	O
the	O
total	O
male	O
body	O
length	O
.	O

PDGF	B-GENE
A	I-GENE
-	I-GENE
chain	I-GENE
levels	O
increase	O
in	O
cultured	O
vascular	O
smooth	O
muscle	O
cells	O
(	O
SMCs	O
)	O
exposed	O
to	O
ATII	B-GENE
.	O

M	B-GENE
-	I-GENE
Ras	I-GENE
interacted	O
poorly	O
in	O
a	O
yeast	O
two	O
-	O
hybrid	O
assay	O
with	O
multiple	O
Ras	B-GENE
effectors	O
,	O
including	O
c	B-GENE
-	I-GENE
Raf	I-GENE
-	I-GENE
1	I-GENE
,	O
A	B-GENE
-	I-GENE
Raf	I-GENE
,	O
B	B-GENE
-	I-GENE
Raf	I-GENE
,	O
phosphoinositol	B-GENE
-	I-GENE
3	I-GENE
kinase	I-GENE
delta	I-GENE
,	O
RalGDS	B-GENE
,	O
and	O
Rin1	B-GENE
.	O

Deletion	O
mapping	O
of	O
the	O
human	B-GENE
presenilin	I-GENE
-	I-GENE
1	I-GENE
(	O
PS1	B-GENE
)	O
promoter	O
delineated	O
the	O
most	O
active	O
fragment	O
from	O
-	O
118	O
to	O
+	O
178	O
in	O
relation	O
to	O
the	O
transcription	O
start	O
site	O
mapped	O
in	O
this	O
study	O
,	O
in	O
both	O
human	O
neuroblastoma	O
SK	O
-	O
N	O
-	O
SH	O
and	O
hepatoma	O
HepG2	O
cells	O
.	O

Analysis	O
of	O
the	O
E2F1	B-GENE
gene	I-GENE
promoter	I-GENE
showed	O
that	O
the	O
-	O
146	O
to	O
-	O
54	O
region	O
was	O
required	O
for	O
E2	B-GENE
-	O
responsiveness	O
in	O
transient	O
transfection	O
assays	O
,	O
and	O
subsequent	O
deletion	O
/	O
mutation	O
analysis	O
showed	O
that	O
a	O
single	O
upstream	O
GC	O
-	O
rich	O
and	O
two	O
downstream	O
CCAAT	O
-	O
binding	O
sites	O
were	O
required	O
for	O
transactivation	O
by	O
E2	B-GENE
.	O

In	O
the	O
course	O
of	O
investigating	O
the	O
mechanisms	O
by	O
which	O
OF5	B-GENE
and	O
OF3	B-GENE
regulated	O
CYP11A1	B-GENE
transcription	O
,	O
we	O
found	O
that	O
OF5	B-GENE
and	O
OF3	B-GENE
bound	O
Sp1	B-GENE
and	O
Sp3	B-GENE
in	O
JEG	O
-	O
3	O
cells	O
.	O

In	O
contrast	O
,	O
the	O
differentiation	O
of	O
neoplastically	O
transformed	O
cells	O
does	O
not	O
repress	O
mitogenic	O
responsiveness	O
or	O
junB	B-GENE
or	O
c	B-GENE
-	I-GENE
fos	I-GENE
inducibility	O
.	O

Adipocyte	O
differentiation	O
of	O
nontransformed	O
cells	O
also	O
markedly	O
represses	O
the	O
ability	O
of	O
SRF	B-GENE
to	O
bind	O
to	O
the	O
junB	B-GENE
SRE	O
,	O
the	O
c	B-GENE
-	I-GENE
fos	I-GENE
SRE	O
,	O
and	O
other	O
SREs	O
,	O
as	O
determined	O
by	O
mobility	O
shift	O
and	O
gel	O
supershift	O
assays	O
,	O
without	O
affecting	O
the	O
DNA	O
binding	O
characteristics	O
of	O
the	O
nuclear	O
protein	O
SP	O
-	O
1	O
.	O

Transformation	O
blocks	O
differentiation	O
-	O
induced	O
inhibition	O
of	O
serum	B-GENE
response	I-GENE
factor	I-GENE
interactions	O
with	O
serum	O
response	O
elements	O
.	O

The	O
core	B-GENE
enzyme	I-GENE
is	O
homologous	O
to	O
those	O
of	O
bacteriophages	O
T3	O
,	O
T7	O
and	O
SP6	O
whereas	O
the	O
specificity	O
factor	O
shows	O
similarities	O
with	O
bacterial	B-GENE
sigma	I-GENE
factors	I-GENE
.	O

The	O
Cr	B-GENE
.	I-GENE
psbA	I-GENE
-	I-GENE
4	I-GENE
ORF	I-GENE
contains	O
an	O
H	O
-	O
N	O
-	O
H	O
motif	O
,	O
and	O
possibly	O
a	O
GIY	O
-	O
YIG	O
motif	O
.	O

The	O
interaction	O
of	O
zf4	B-GENE
-	I-GENE
6	I-GENE
with	O
full	B-GENE
-	I-GENE
length	I-GENE
5	I-GENE
S	I-GENE
RNA	I-GENE
was	O
far	O
more	O
sensitive	O
to	O
non	O
-	O
specific	O
competitor	O
concentration	O
than	O
was	O
the	O
zf4	B-GENE
-	I-GENE
7	I-GENE
:	O
5	B-GENE
S	I-GENE
RNA	I-GENE
interaction	O
,	O
suggesting	O
that	O
finger	O
seven	O
contributes	O
to	O
both	O
affinity	O
and	O
specificity	O
in	O
this	O
protein	O
:	O
RNA	O
interaction	O
.	O

The	O
STAT	B-GENE
protein	I-GENE
accumulation	O
resulting	O
from	O
C	B-GENE
/	I-GENE
EBP	I-GENE
expression	O
was	O
tightly	O
coupled	O
to	O
the	O
morphological	O
conversion	O
of	O
fibroblasts	O
to	O
adipocytes	O
and	O
represents	O
an	O
expression	O
profile	O
identical	O
to	O
that	O
reported	O
for	O
mature	O
adipocytes	O
in	O
vivo	O
.	O

The	O
median	O
durations	O
for	O
response	O
and	O
survival	O
time	O
in	O
the	O
late	O
phase	O
II	O
trial	O
were	O
2	O
.	O
3	O
months	O
and	O
5	O
.	O
8	O
months	O
,	O
respectively	O
.	O

The	O
role	O
of	O
'	O
scientific	O
psychiatry	O
'	O
in	O
understanding	O
patients	O
with	O
chronic	O
schizophrenia	O
or	O
severe	O
personality	O
disorder	O
.	O

Myocardial	O
antioxidant	O
enzymes	O
,	O
catalase	B-GENE
,	O
glutathione	B-GENE
peroxidase	I-GENE
and	O
superoxide	B-GENE
dismutase	I-GENE
,	O
in	O
the	O
MCT	O
-	O
treated	O
rats	O
were	O
not	O
different	O
compared	O
to	O
control	O
rats	O
.	O

The	O
second	O
goal	O
was	O
to	O
ascertain	O
the	O
somatotopic	O
arrangement	O
of	O
the	O
GPi	O
in	O
PD	O
.	O

These	O
overall	O
results	O
indicate	O
that	O
there	O
is	O
generally	O
one	O
PERV	O
copy	O
per	O
integration	O
site	O
.	O

OBJECTIVE	O
:	O
To	O
determine	O
whether	O
administration	O
of	O
misoprostol	O
prevents	O
gastric	O
hemorrhage	O
in	O
healthy	O
dogs	O
treated	O
with	O
high	O
doses	O
of	O
methylprednisolone	O
sodium	O
succinate	O
(	O
MPSS	O
)	O
.	O

Patients	O
were	O
assessed	O
for	O
cardiac	O
MIBG	O
uptake	O
,	O
circulating	O
norepinephrine	O
concentration	O
,	O
LVEF	O
,	O
peak	O
Vo2	O
,	O
x	O
-	O
ray	O
cardiothoracic	O
ratio	O
,	O
M	O
-	O
mode	O
echographic	O
end	O
-	O
diastolic	O
diameter	O
and	O
right	O
-	O
sided	O
heart	O
catheterization	O
parameters	O
.	O

Nuclear	O
hormone	O
receptors	O
(	O
NRs	O
)	O
are	O
ligand	O
-	O
inducible	O
transcription	O
factors	O
that	O
mediate	O
critical	O
functions	O
in	O
many	O
species	O
.	O

These	O
cells	O
were	O
able	O
to	O
present	O
influenza	O
virus	O
particles	O
to	O
HLA	B-GENE
-	I-GENE
DR1	I-GENE
-	O
restricted	O
T	O
cell	O
clones	O
.	O

Sequencing	O
of	O
zebrafish	O
(	O
Danio	O
rerio	O
)	O
bacterial	O
artificial	O
chromosome	O
and	O
P1	O
artificial	O
chromosome	O
genomic	O
clone	O
fragments	O
and	O
of	O
cDNA	O
clones	O
has	O
led	O
to	O
the	O
identification	O
of	O
five	O
new	O
loci	O
coding	O
for	O
beta	O
subunits	O
of	O
proteasomes	O
(	O
PSMB	B-GENE
)	O
.	O

In	O
addition	O
to	O
homologues	O
of	O
the	O
human	B-GENE
genes	I-GENE
PSMB5	I-GENE
through	O
PSMB9	B-GENE
,	O
two	O
new	O
genes	O
,	O
PSMB11	B-GENE
and	O
PSMB12	B-GENE
,	O
have	O
been	O
found	O
for	O
which	O
there	O
are	O
no	O
known	O
corresponding	O
genes	O
in	O
humans	O
.	O

It	O
applies	O
Udry	O
'	O
s	O
biosocial	O
perspective	O
,	O
which	O
attempts	O
to	O
reconcile	O
the	O
biological	O
and	O
sociological	O
models	O
of	O
premarital	O
sexual	O
and	O
reproductive	O
behaviour	O
.	O

Weight	O
and	O
height	O
z	O
-	O
scores	O
were	O
significantly	O
associated	O
with	O
BMD	O
z	O
-	O
scores	O
.	O

A	O
limited	O
sampling	O
strategy	O
was	O
used	O
based	O
on	O
a	O
bayesian	O
parameter	O
estimation	O
algorithm	O
that	O
is	O
part	O
of	O
the	O
ADAPT	O
II	O
software	O
package	O
.	O

The	O
amino	O
acid	O
changes	O
D206A	O
and	O
D208A	O
abolish	O
singly	O
or	O
in	O
combination	O
the	O
exonuclease	O
activity	O
in	O
vivo	O
.	O

Previous	O
experimental	O
evidence	O
had	O
indicated	O
that	O
Reg1	B-GENE
might	O
target	O
Glc7	B-GENE
to	O
nuclear	O
substrates	O
such	O
as	O
the	O
Snf1	B-GENE
kinase	I-GENE
complex	I-GENE
.	O

In	O
the	O
present	O
study	O
,	O
we	O
demonstrate	O
that	O
expression	O
of	O
TD	B-GENE
-	I-GENE
IkappaBalpha	I-GENE
blocked	O
phorbol	O
myristate	O
acetate	B-GENE
-	I-GENE
phytohemagglutinin	I-GENE
or	O
tumor	B-GENE
necrosis	I-GENE
factor	I-GENE
alpha	I-GENE
-	O
induced	O
IkappaBalpha	B-GENE
gene	I-GENE
transcription	O
and	O
abolished	O
NF	B-GENE
-	I-GENE
kappaB	I-GENE
DNA	O
binding	O
activity	O
,	O
due	O
to	O
the	O
continued	O
cytoplasmic	O
sequestration	O
of	O
RelA	B-GENE
(	O
p65	B-GENE
)	O
by	O
TD	B-GENE
-	I-GENE
IkappaBalpha	I-GENE
.	O

(	O
i	O
)	O
Complete	O
Grb10	B-GENE
expression	O
from	O
cDNA	O
with	O
an	O
ecdysone	O
-	O
regulated	O
transient	O
expression	O
system	O
stimulated	O
PDGF	B-GENE
-	I-GENE
BB	I-GENE
-	O
,	O
IGF	B-GENE
-	I-GENE
I	I-GENE
,	O
and	O
insulin	B-GENE
-	O
but	O
not	O
epidermal	B-GENE
growth	I-GENE
factor	I-GENE
(	O
EGF	B-GENE
)	O
-	O
induced	O
DNA	O
synthesis	O
in	O
an	O
ecdysone	O
dose	O
-	O
responsive	O
fashion	O
.	O

The	O
analysis	O
of	O
two	O
distinct	O
mitogen	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
kinase	I-GENE
pathways	O
shows	O
that	O
stress	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
kinase	I-GENE
-	O
Jun	B-GENE
N	I-GENE
-	I-GENE
terminal	I-GENE
kinase	I-GENE
activation	O
,	O
resulting	O
in	O
the	O
phosphorylation	O
of	O
ATF	B-GENE
-	I-GENE
2	I-GENE
,	O
c	B-GENE
-	I-GENE
Jun	I-GENE
,	O
and	O
JunD	B-GENE
,	O
is	O
required	O
not	O
only	O
for	O
the	O
IL	B-GENE
-	I-GENE
1	I-GENE
-	O
but	O
also	O
for	O
the	O
TPA	O
-	O
dependent	O
induction	O
,	O
while	O
the	O
extracellular	B-GENE
signal	I-GENE
-	I-GENE
related	I-GENE
kinase	I-GENE
1	I-GENE
(	O
ERK	B-GENE
-	I-GENE
1	I-GENE
)	O
and	O
ERK	B-GENE
-	I-GENE
2	I-GENE
activation	O
is	O
involved	O
in	O
the	O
TPA	O
-	O
but	O
not	O
in	O
the	O
IL	B-GENE
-	I-GENE
1	I-GENE
-	O
dependent	O
stimulation	O
of	O
the	O
uPA	B-GENE
enhancer	I-GENE
.	O

CONCLUSIONS	O
:	O
In	O
healthy	O
individuals	O
,	O
whole	O
body	O
insulin	B-GENE
sensitivity	O
is	O
related	O
,	O
or	O
"	O
coupled	O
,	O
"	O
to	O
the	O
anaerobic	O
threshold	O
.	O

Interdomain	O
signaling	O
in	O
a	O
two	O
-	O
domain	O
fragment	O
of	O
the	O
human	B-GENE
glucocorticoid	I-GENE
receptor	I-GENE
.	O

In	O
contrast	O
,	O
the	O
xtRNA	B-GENE
(	O
Sec	B-GENE
)	O
gene	O
needs	O
the	O
binding	O
of	O
the	O
seven	O
Staf	B-GENE
zinc	I-GENE
fingers	I-GENE
,	O
but	O
not	O
Oct	B-GENE
-	I-GENE
1	I-GENE
,	O
for	O
optimal	O
transcriptional	O
capacity	O
.	O

Collectively	O
,	O
these	O
results	O
show	O
that	O
the	O
differential	O
utilization	O
of	O
Staf	B-GENE
zinc	I-GENE
finger	I-GENE
1	I-GENE
represents	O
a	O
new	O
,	O
critical	O
determinant	O
of	O
the	O
transcriptional	O
activation	O
mechanism	O
for	O
the	O
Xenopus	B-GENE
tRNA	I-GENE
(	O
Sec	B-GENE
)	O
and	O
human	B-GENE
U6	I-GENE
snRNA	I-GENE
genes	I-GENE
.	O

In	O
B	O
cells	O
,	O
HEF1	B-GENE
is	O
phosphorylated	O
by	O
a	O
cytoskeleton	O
-	O
dependent	O
mechanism	O
that	O
is	O
triggered	O
by	O
integrin	B-GENE
ligation	O
.	O

The	O
calcitonin	B-GENE
-	O
induced	O
tyrosine	O
phosphorylation	O
of	O
HEF1	B-GENE
increased	O
in	O
a	O
time	O
-	O
and	O
dose	O
-	O
dependent	O
manner	O
.	O

Independent	O
protrudor	O
muscle	O
stimulation	O
increased	O
VI	O
,	O
max	O
(	O
peak	O
increase	O
61	O
%	O
,	O
P	O
<	O
0	O
.	O
05	O
)	O
,	O
did	O
not	O
change	O
Pcrit	O
,	O
and	O
decreased	O
Rn	O
(	O
peak	O
decrease	O
of	O
41	O
%	O
,	O
P	O
<	O
0	O
.	O
05	O
)	O
.	O

The	O
human	B-GENE
RAD30B	I-GENE
and	O
mouse	B-GENE
Rad30b	I-GENE
mRNA	I-GENE
transcripts	I-GENE
,	O
like	O
many	O
repair	O
proteins	O
,	O
are	O
highly	O
expressed	O
in	O
the	O
testis	O
.	O

Analysis	O
of	O
the	O
mouse	B-GENE
STAP	I-GENE
gene	I-GENE
isolated	O
from	O
the	O
genomic	O
library	O
revealed	O
that	O
the	O
STAP	B-GENE
gene	I-GENE
spans	O
a	O
region	O
of	O
over	O
11	O
kb	O
and	O
comprises	O
eight	O
exons	O
.	O

A	O
reduced	O
matrix	O
distribution	O
and	O
enhanced	O
cell	O
density	O
were	O
observed	O
as	O
the	O
biofilm	O
aged	O
.	O

After	O
10	O
months	O
of	O
treatment	O
with	O
the	O
conjugated	O
estrogen	O
,	O
both	O
his	O
height	O
and	O
weight	O
showed	O
improvement	O
,	O
while	O
his	O
bone	O
mineral	O
density	O
and	O
bone	O
age	O
were	O
increased	O
.	O

Viscosity	O
experiments	O
on	O
the	O
catalytic	O
fragment	O
kinase	O
reaction	O
demonstrated	O
that	O
the	O
chemical	O
(	O
phosphoryl	O
transfer	O
)	O
step	O
had	O
a	O
reduced	O
rate	O
.	O

Velocity	O
sedimentation	O
,	O
cross	O
-	O
linking	O
,	O
and	O
immunoprecipitation	O
analyses	O
of	O
detergent	O
-	O
solubilized	O
rat	O
brain	O
revealed	O
that	O
the	O
32	O
and	O
34	O
kDa	O
polypeptides	O
reside	O
within	O
heterotetramers	O
.	O

In	O
vitro	O
expression	O
levels	O
of	O
the	O
different	O
plasmids	O
differed	O
by	O
as	O
much	O
as	O
tenfold	O
.	O

In	O
EEG	O
only	O
single	O
slow	O
waves	O
above	O
left	O
temporal	O
region	O
were	O
revealed	O
.	O

Molecular	O
characterization	O
of	O
type	O
-	O
specific	O
capsular	O
polysaccharide	O
biosynthesis	O
genes	O
of	O
Streptococcus	O
agalactiae	O
type	O
Ia	O
.	O

(	O
1998	O
)	O
FASEB	O
J	O
.	O

IL	B-GENE
-	I-GENE
1beta	I-GENE
(	O
10	O
ng	O
/	O
ml	O
)	O
drastically	O
increased	O
both	O
PDGFalphaR	B-GENE
and	O
CCAAT	B-GENE
/	I-GENE
enhancer	I-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
delta	I-GENE
(	O
C	B-GENE
/	I-GENE
EBPdelta	I-GENE
)	O
mRNA	O
levels	O
in	O
a	O
time	O
dependent	O
manner	O
.	O

Transient	O
tyrosine	O
phosphorylation	O
of	O
Crk	B-GENE
in	O
fibroblast	B-GENE
growth	I-GENE
factor	I-GENE
-	I-GENE
2	I-GENE
-	O
stimulated	O
endothelial	O
cells	O
was	O
dependent	O
on	O
the	O
juxtamembrane	O
tyrosine	O
residue	O
463	O
in	O
FGFR	B-GENE
-	I-GENE
1	I-GENE
,	O
and	O
a	O
Crk	B-GENE
SH2	B-GENE
domain	I-GENE
precipitated	O
FGFR	B-GENE
-	I-GENE
1	I-GENE
via	O
phosphorylated	O
Tyr	O
-	O
463	O
,	O
indicating	O
direct	O
complex	O
formation	O
between	O
Crk	B-GENE
and	O
FGFR	B-GENE
-	I-GENE
1	I-GENE
.	O

Role	O
of	O
the	O
3	O
'	O
untranslated	O
region	O
of	O
baculovirus	B-GENE
p10	I-GENE
mRNA	I-GENE
in	O
high	O
-	O
level	O
expression	O
of	O
foreign	O
genes	O
.	O

The	O
intron	O
RNA	O
consists	O
of	O
2492	O
nucleotides	O
which	O
can	O
be	O
folded	O
into	O
a	O
secondary	O
structure	O
with	O
all	O
the	O
expected	O
sequence	O
motifs	O
of	O
subgroup	O
-	O
IIA1	O
introns	O
(	O
Michel	O
et	O
al	O
.	O

The	O
intron	O
is	O
capable	O
of	O
splicing	O
despite	O
the	O
fact	O
that	O
both	O
the	O
EBS1	B-GENE
/	O
IBS1	B-GENE
and	O
the	O
EBS2	B-GENE
/	O
IBS2	B-GENE
sequence	O
motifs	O
,	O
thought	O
to	O
be	O
necessary	O
for	O
correct	O
splicing	O
,	O
extend	O
over	O
5	O
instead	O
of	O
6	O
bp	O
.	O

The	O
Trk	B-GENE
/	I-GENE
Nerve	I-GENE
Growth	I-GENE
Factor	I-GENE
receptor	I-GENE
mediates	O
the	O
rapid	O
activation	O
of	O
a	O
number	O
of	O
intracellular	O
signaling	O
proteins	O
,	O
including	O
phosphatidylinositol	B-GENE
3	I-GENE
-	I-GENE
kinase	I-GENE
(	O
PI	B-GENE
3	I-GENE
-	I-GENE
kinase	I-GENE
)	O
.	O

Chemical	O
uptake	O
into	O
human	O
stratum	O
corneum	O
in	O
vivo	O
from	O
volatile	O
and	O
non	O
-	O
volatile	O
solvents	O
.	O

Like	O
DNA	O
binding	O
,	O
transcriptional	O
enhancement	O
required	O
amino	O
-	O
terminally	O
located	O
basic	O
amino	O
acid	O
residues	O
but	O
not	O
the	O
carboxyl	O
-	O
terminal	O
portion	O
of	O
Hap46	B-GENE
known	O
to	O
participate	O
in	O
hsp70	B-GENE
interaction	O
.	O

We	O
have	O
tested	O
the	O
function	O
of	O
two	O
potential	O
NF	B-GENE
-	I-GENE
kappaB	I-GENE
-	I-GENE
like	I-GENE
sites	I-GENE
present	O
in	O
the	O
PAI	B-GENE
-	I-GENE
2	I-GENE
proximal	I-GENE
promoter	I-GENE
for	O
responsiveness	O
to	O
TNFalpha	B-GENE
using	O
chloramphenicol	B-GENE
acetyl	I-GENE
transferase	I-GENE
reporter	I-GENE
gene	I-GENE
deletion	O
and	O
mutation	O
analyses	O
.	O

N	O
-	O
terminal	O
sequence	O
analysis	O
and	O
NMR	O
measurements	O
revealed	O
that	O
this	O
fragment	O
originates	O
from	O
the	O
C	O
-	O
terminal	O
80	O
residues	O
of	O
MBF1	B-GENE
and	O
form	O
a	O
well	O
structured	O
C	O
-	O
terminal	O
domain	O
of	O
MBF1	B-GENE
,	O
MBF1CTD	B-GENE
.	O

The	O
nucleosomal	O
response	O
associated	O
with	O
immediate	B-GENE
-	I-GENE
early	I-GENE
gene	I-GENE
induction	O
is	O
mediated	O
via	O
alternative	O
MAP	B-GENE
kinase	I-GENE
cascades	I-GENE
:	O
MSK1	B-GENE
as	O
a	O
potential	O
histone	B-GENE
H3	I-GENE
/	O
HMG	B-GENE
-	I-GENE
14	I-GENE
kinase	O
.	O

272	O
,	O
1904	O
]	O
.	O

Using	O
16	O
strains	O
of	O
C	O
.	O
trachomatis	O
in	O
triplicate	O
assays	O
,	O
we	O
found	O
the	O
RT	O
-	O
PCR	O
method	O
consistently	O
more	O
sensitive	O
than	O
the	O
conventional	O
technique	O
for	O
all	O
eight	O
antimicrobials	O
tested	O
,	O
with	O
resultant	O
MICs	O
determined	O
by	O
RT	O
-	O
PCR	O
ranging	O
from	O
1	O
.	O
6	O
-	O
fold	O
higher	O
(	O
erythromycin	O
)	O
to	O
>	O
/	O
=	O
195	O
-	O
fold	O
higher	O
(	O
amoxicillin	O
)	O
.	O

Recent	O
molecular	O
analysis	O
has	O
revealed	O
that	O
the	O
S	B-GENE
locus	I-GENE
is	O
highly	O
polymorphic	O
and	O
contains	O
several	O
genes	O
,	O
i	O
.	O
e	O
.	O
,	O
SLG	B-GENE
,	O
SRK	B-GENE
,	O
the	O
as	O
-	O
yet	O
-	O
unidentified	O
pollen	B-GENE
S	I-GENE
gene	I-GENE
(	I-GENE
s	I-GENE
)	I-GENE
,	O
and	O
other	O
linked	O
genes	O
.	O

A	O
cDNA	O
encoding	O
a	O
putative	O
RNA	B-GENE
and	I-GENE
/	I-GENE
or	I-GENE
DNA	I-GENE
helicase	I-GENE
has	O
been	O
isolated	O
from	O
Arabidopsis	O
thaliana	O
cDNA	O
libraries	O
.	O

In	O
vivo	O
,	O
MyoD	B-GENE
requires	O
this	O
tryptophan	O
motif	O
to	O
evoke	O
chromatin	O
remodeling	O
in	O
the	O
Myogenin	B-GENE
promoter	I-GENE
and	O
to	O
activate	O
Myogenin	B-GENE
transcription	O
.	O

Feed	O
intake	O
and	O
BW	O
gains	O
were	O
decreased	O
(	O
P	O
<	O
0	O
.	O
05	O
)	O
by	O
dietary	O
treatments	O
containing	O
M	O
.	O

The	O
N	O
terminus	O
of	O
beta	O
(	O
95	O
kDa	O
)	O
corresponds	O
to	O
alpha	O
with	O
the	O
integrase	B-GENE
domain	I-GENE
attached	O
to	O
the	O
C	O
terminus	O
(	O
32	O
kDa	O
)	O
.	O

Skn	B-GENE
-	I-GENE
1a	I-GENE
lacking	O
the	O
C	O
-	O
terminal	O
region	O
completely	O
lost	O
transactivation	O
ability	O
,	O
irrespective	O
of	O
the	O
promoter	O
tested	O
,	O
and	O
was	O
able	O
to	O
block	O
transactivation	O
by	O
normal	O
Skn	B-GENE
-	I-GENE
1a	I-GENE
in	O
competition	O
assays	O
.	O

In	O
early	O
Xenopus	O
embryos	O
,	O
the	O
transforming	B-GENE
growth	I-GENE
factor	I-GENE
-	I-GENE
beta	I-GENE
member	O
activin	B-GENE
induces	O
the	O
gene	B-GENE
Mix	I-GENE
.	I-GENE
2	I-GENE
by	O
stimulating	O
the	O
formation	O
of	O
a	O
multiprotein	O
complex	O
,	O
activin	B-GENE
-	I-GENE
responsive	I-GENE
factor	I-GENE
(	O
ARF	B-GENE
)	O
.	O

To	O
further	O
characterize	O
the	O
structure	O
and	O
evolutionary	O
synthesis	O
of	O
the	O
CMT1A	O
-	O
REP	O
repeat	O
,	O
fluorescent	O
in	O
situ	O
hybridization	O
(	O
FISH	O
)	O
analysis	O
and	O
heterologous	O
PCR	O
-	O
based	O
assays	O
were	O
carried	O
out	O
for	O
a	O
series	O
of	O
primates	O
.	O

Natl	O
.	O

In	O
the	O
face	O
of	O
the	O
outbreak	O
,	O
there	O
was	O
a	O
delay	O
before	O
vaccination	O
was	O
able	O
to	O
stop	O
deaths	O
.	O

Here	O
we	O
show	O
that	O
a	O
novel	O
isoform	O
of	O
Rapl	B-GENE
GTPase	I-GENE
-	I-GENE
activating	I-GENE
protein	I-GENE
,	O
called	O
rap1GAPII	B-GENE
,	O
binds	O
specifically	O
to	O
the	O
alpha	O
-	O
subunits	O
of	O
the	O
G	B-GENE
(	I-GENE
i	I-GENE
)	I-GENE
family	I-GENE
of	O
heterotrimeric	B-GENE
G	I-GENE
-	I-GENE
proteins	I-GENE
.	O

The	O
B	O
-	O
oligomer	O
of	O
pertussis	B-GENE
toxin	I-GENE
deactivates	O
CC	B-GENE
chemokine	I-GENE
receptor	I-GENE
5	I-GENE
and	O
blocks	O
entry	O
of	O
M	O
-	O
tropic	O
HIV	O
-	O
1	O
strains	O
.	O

Cross	O
-	O
linking	O
the	O
B	B-GENE
cell	I-GENE
Ag	I-GENE
receptor	I-GENE
(	O
BCR	B-GENE
)	O
to	O
surface	B-GENE
Fc	I-GENE
receptors	I-GENE
for	O
IgG	B-GENE
(	O
Fc	B-GENE
gamma	I-GENE
R	I-GENE
)	O
inhibits	O
G1	O
-	O
to	O
-	O
S	O
progression	O
;	O
the	O
mechanism	O
by	O
which	O
this	O
occurs	O
is	O
not	O
completely	O
known	O
.	O

Cross	O
-	O
linking	O
the	O
B	B-GENE
cell	I-GENE
Ag	I-GENE
receptor	I-GENE
(	O
BCR	B-GENE
)	O
to	O
surface	B-GENE
Fc	I-GENE
receptors	I-GENE
for	O
IgG	B-GENE
(	O
Fc	B-GENE
gamma	I-GENE
R	I-GENE
)	O
inhibits	O
G1	O
-	O
to	O
-	O
S	O
progression	O
;	O
the	O
mechanism	O
by	O
which	O
this	O
occurs	O
is	O
not	O
completely	O
known	O
.	O

TRAF2	B-GENE
is	O
a	O
potent	O
activator	O
of	O
a	O
95	B-GENE
-	I-GENE
kDa	I-GENE
serine	I-GENE
/	I-GENE
threonine	I-GENE
kinase	I-GENE
termed	O
germinal	B-GENE
center	I-GENE
kinase	I-GENE
related	I-GENE
(	O
GCKR	B-GENE
,	O
also	O
referred	O
to	O
as	O
KHS1	B-GENE
)	O
,	O
which	O
signals	O
activation	O
of	O
the	O
SAPK	B-GENE
pathway	O
.	O

An	O
activation	O
-	O
responsive	O
element	O
in	O
single	B-GENE
C	I-GENE
motif	I-GENE
-	I-GENE
1	I-GENE
/	O
lymphotactin	B-GENE
promoter	O
is	O
a	O
site	O
of	O
constitutive	O
and	O
inducible	O
DNA	O
-	O
protein	O
interactions	O
involving	O
nuclear	O
factor	O
of	O
activated	O
T	O
cell	O
.	O

A	O
portion	O
of	O
p193	B-GENE
is	O
nuclear	O
and	O
localizes	O
to	O
the	O
mitotic	O
spindle	O
.	O

The	O
main	O
issues	O
are	O
the	O
need	O
to	O
explain	O
a	O
number	O
of	O
still	O
unknown	O
mechanisms	O
,	O
to	O
determine	O
which	O
"	O
natural	O
diet	O
"	O
carries	O
the	O
minimum	O
coronary	O
risk	O
and	O
whether	O
"	O
new	O
"	O
foods	O
produced	O
by	O
modern	O
technology	O
are	O
really	O
needed	O
to	O
contrast	O
this	O
epidemic	O
.	O

Cotransfection	O
of	O
the	O
coactivator	O
CREB	B-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
relieved	O
the	O
transcriptional	O
repression	O
of	O
PPARalphawt	B-GENE
by	O
PPARalphatr	B-GENE
,	O
suggesting	O
that	O
the	O
dominant	O
negative	O
effect	O
of	O
PPARalphatr	B-GENE
might	O
occur	O
through	O
competition	O
for	O
essential	O
coactivators	O
.	O

SF	B-GENE
-	I-GENE
1	I-GENE
does	O
not	O
have	O
an	O
N	O
-	O
terminal	O
AF1	O
domain	O
.	O

We	O
discuss	O
these	O
results	O
in	O
terms	O
of	O
the	O
influence	O
that	O
time	O
and	O
nutritional	O
constraints	O
have	O
on	O
odonate	O
development	O
patterns	O
and	O
fitness	O
.	O

OBJECTIVE	O
:	O
1998	O
Surveillance	O
,	O
Epidemiology	O
,	O
and	O
End	O
Results	O
(	O
SEER	O
)	O
data	O
estimate	O
an	O
83	O
.	O
1	O
%	O
5	O
-	O
year	O
survival	O
rate	O
for	O
corpus	O
uteri	O
adenocarcinoma	O
FIGO	O
stage	O
II	O
.	O

A	O
novel	O
Drosophila	B-GENE
A	I-GENE
kinase	I-GENE
anchor	I-GENE
protein	I-GENE
,	O
Drosophila	B-GENE
A	I-GENE
kinase	I-GENE
anchor	I-GENE
protein	I-GENE
200	I-GENE
(	O
DAKAP200	B-GENE
)	O
,	O
is	O
predicted	O
to	O
be	O
involved	O
in	O
routing	O
,	O
mediating	O
,	O
and	O
integrating	O
signals	O
carried	O
by	O
cAMP	O
,	O
Ca	O
(	O
2	O
+	O
)	O
,	O
and	O
diacylglycerol	O
(	O
Li	O
,	O
Z	O
.	O
,	O
Rossi	O
,	O
E	O
.	O

In	O
vitro	O
transcription	O
results	O
indicate	O
that	O
this	O
5	O
'	O
structure	O
functions	O
in	O
the	O
attenuation	O
mechanism	O
,	O
since	O
deletion	O
of	O
the	O
stem	O
-	O
loop	O
caused	O
an	O
increase	O
in	O
transcription	O
readthrough	O
.	O

A	O
5	O
'	O
RNA	O
stem	O
-	O
loop	O
participates	O
in	O
the	O
transcription	O
attenuation	O
mechanism	O
that	O
controls	O
expression	O
of	O
the	O
Bacillus	B-GENE
subtilis	I-GENE
trpEDCFBA	I-GENE
operon	I-GENE
.	O

Single	O
-	O
alanine	O
-	O
substitution	O
mutations	O
had	O
minimal	O
,	O
if	O
any	O
,	O
effects	O
on	O
S	O
-	O
induced	O
cell	O
-	O
to	O
-	O
cell	O
fusion	O
.	O

Furthermore	O
,	O
we	O
demonstrate	O
that	O
transcription	O
from	O
the	O
MMTV	B-GENE
5	I-GENE
'	I-GENE
LTR	I-GENE
is	O
highly	O
active	O
in	O
the	O
absence	O
of	O
Stat5a	B-GENE
,	O
a	O
transcription	O
factor	O
that	O
had	O
been	O
shown	O
previously	O
to	O
be	O
required	O
for	O
transcription	O
from	O
the	O
MMTV	B-GENE
LTR	I-GENE
.	O

Regional	O
insertional	O
mutagenesis	O
of	O
specific	O
genes	O
on	O
the	O
CIC5F11	B-GENE
/	O
CIC2B9	B-GENE
locus	O
of	O
Arabidopsis	O
thaliana	O
chromosome	O
5	O
using	O
the	O
Ac	B-GENE
/	O
Ds	B-GENE
transposon	O
in	O
combination	O
with	O
the	O
cDNA	O
scanning	O
method	O
.	O

RESULTS	O
:	O
CK	B-GENE
-	O
MB	B-GENE
elevation	O
was	O
detected	O
in	O
313	O
patients	O
(	O
18	O
.	O
7	O
%	O
)	O
,	O
with	O
1	O
-	O
3x	O
in	O
12	O
.	O
8	O
%	O
,	O
3	O
-	O
5x	O
in	O
3	O
.	O
5	O
%	O
and	O
>	O
5x	O
normal	O
in	O
2	O
.	O
4	O
%	O
of	O
patients	O
.	O

Thus	O
,	O
NART	O
-	O
R	O
performance	O
may	O
not	O
be	O
a	O
valid	O
estimate	O
of	O
baseline	O
IQ	O
for	O
patients	O
with	O
neurologic	O
disorders	O
with	O
suspected	O
language	O
impairment	O
.	O

Activated	O
areas	O
have	O
been	O
identified	O
by	O
means	O
of	O
cross	O
-	O
correlation	O
analysis	O
.	O

Natural	O
Haemophilus	O
influenzae	O
type	O
b	O
capsular	O
polysaccharide	O
antibodies	O
in	O
412	O
infants	O
and	O
children	O
from	O
West	O
Africa	O
(	O
Burkina	O
-	O
Faso	O
)	O
and	O
France	O
:	O
a	O
cross	O
-	O
sectional	O
serosurvey	O
.	O

In	O
this	O
study	O
,	O
we	O
identified	O
Sp1	B-GENE
and	O
Sp3	B-GENE
as	O
major	O
factors	O
binding	O
to	O
the	O
Sp1	B-GENE
sites	I-GENE
of	O
the	O
p21	B-GENE
/	O
WAF1	B-GENE
/	O
Cip1	B-GENE
promoter	O
in	O
MG63	O
cells	O
through	O
electrophoretic	O
mobility	O
shift	O
assays	O
and	O
showed	O
that	O
TSA	O
treatment	O
did	O
not	O
change	O
their	O
binding	O
activities	O
.	O

Galoyan	O
has	O
summarized	O
the	O
results	O
of	O
his	O
discovery	O
of	O
cardioactive	O
neurohormones	O
.	O

To	O
study	O
the	O
regulation	O
of	O
its	O
expression	O
,	O
the	O
human	B-GENE
aldehyde	I-GENE
reductase	I-GENE
gene	I-GENE
and	O
promoter	O
were	O
cloned	O
and	O
characterized	O
.	O

The	O
C2C	B-GENE
-	O
Prx	B-GENE
is	O
encoded	O
as	O
a	O
preprotein	O
of	O
273	O
amino	O
acids	O
containing	O
a	O
putative	O
chloroplast	O
-	O
targeting	O
signal	O
of	O
65	O
amino	O
acids	O
at	O
its	O
N	O
-	O
terminus	O
.	O

Immediately	O
before	O
surgery	O
patients	O
received	O
either	O
intravenous	O
hydrocortisone	O
100	O
mg	O
or	O
placebo	O
in	O
random	O
,	O
double	O
-	O
blind	O
order	O
.	O

A	O
tyrosine	O
-	O
based	O
sorting	O
signal	O
in	O
the	O
beta2	B-GENE
integrin	I-GENE
cytoplasmic	I-GENE
domain	I-GENE
mediates	O
its	O
recycling	O
to	O
the	O
plasma	O
membrane	O
and	O
is	O
required	O
for	O
ligand	O
-	O
supported	O
migration	O
.	O

The	O
injection	O
of	O
XDRP1	B-GENE
protein	I-GENE
into	O
fertilized	O
Xenopus	O
eggs	O
blocked	O
embryonic	O
cell	O
division	O
.	O

Using	O
transgenic	O
Xenopus	O
embryos	O
,	O
we	O
demonstrate	O
that	O
the	O
integrity	O
of	O
these	O
two	O
sequences	O
is	O
necessary	O
for	O
correct	O
spatial	O
expression	O
of	O
a	O
Xbra2	B-GENE
promoter	I-GENE
-	I-GENE
driven	I-GENE
reporter	I-GENE
gene	I-GENE
.	O

In	O
order	O
to	O
screen	O
for	O
such	O
cofactors	O
,	O
we	O
have	O
used	O
a	O
transcriptionally	O
inactive	O
mutant	O
of	O
Xenopus	B-GENE
MEF2D	I-GENE
in	O
a	O
yeast	O
two	O
-	O
hybrid	O
screen	O
.	O

NuA4	B-GENE
has	O
an	O
apparent	O
molecular	O
mass	O
of	O
1	O
.	O
3	O
MDa	O
.	O

ATF1	B-GENE
transcription	O
is	O
negatively	O
regulated	O
by	O
unsaturated	O
fatty	O
acids	O
and	O
oxygen	O
.	O

Mutation	O
of	O
TTF	B-GENE
-	I-GENE
1	I-GENE
-	I-GENE
binding	I-GENE
sites	I-GENE
(	I-GENE
TBE	I-GENE
)	I-GENE
1	I-GENE
,	I-GENE
3	I-GENE
,	I-GENE
and	I-GENE
4	I-GENE
in	O
combination	O
markedly	O
decreased	O
transcriptional	O
activity	O
of	O
SP	B-GENE
-	I-GENE
A	I-GENE
promoter	O
-	O
chloramphenicol	B-GENE
acetyltransferase	I-GENE
constructs	O
containing	O
SP	B-GENE
-	I-GENE
A	I-GENE
gene	I-GENE
sequences	O
from	O
-	O
256	O
to	O
+	O
45	O
.	O

Insulin	B-GENE
-	I-GENE
like	I-GENE
growth	I-GENE
factor	I-GENE
-	I-GENE
I	I-GENE
induces	O
bcl	B-GENE
-	I-GENE
2	I-GENE
promoter	I-GENE
through	O
the	O
transcription	O
factor	O
cAMP	B-GENE
-	I-GENE
response	I-GENE
element	I-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
.	O

Synthesis	O
of	O
antisense	O
RNA	O
and	O
S	O
phase	O
-	O
dependent	O
binding	O
of	O
E2F	B-GENE
complexes	I-GENE
in	O
intron	O
1	O
.	O

Identification	O
of	O
eotaxin	B-GENE
-	I-GENE
3	I-GENE
will	O
further	O
promote	O
our	O
understanding	O
of	O
the	O
control	O
of	O
eosinophil	O
trafficking	O
and	O
other	O
CCR3	B-GENE
-	O
mediated	O
biological	O
phenomena	O
.	O

NF	B-GENE
-	I-GENE
kappaB	I-GENE
plays	O
a	O
critical	O
role	O
in	O
activation	O
of	O
HIV	O
-	O
1	O
gene	O
expression	O
by	O
cytokines	O
and	O
other	O
stimuli	O
,	O
but	O
the	O
signal	O
transduction	O
pathways	O
that	O
regulate	O
the	O
switch	O
from	O
latent	O
to	O
productive	O
infection	O
have	O
not	O
been	O
defined	O
.	O

These	O
studies	O
suggest	O
that	O
MAPK	B-GENE
acts	O
by	O
stimulating	O
AP	B-GENE
-	I-GENE
1	I-GENE
and	O
a	O
subsequent	O
physical	O
and	O
functional	O
interaction	O
of	O
AP	B-GENE
-	I-GENE
1	I-GENE
with	O
NF	B-GENE
-	I-GENE
kappaB	I-GENE
,	O
resulting	O
in	O
a	O
complex	O
that	O
synergistically	O
transactivates	O
the	O
HIV	B-GENE
-	I-GENE
1	I-GENE
LTR	I-GENE
.	O

ERK	B-GENE
MAP	B-GENE
kinase	I-GENE
links	O
cytokine	O
signals	O
to	O
activation	O
of	O
latent	O
HIV	O
-	O
1	O
infection	O
by	O
stimulating	O
a	O
cooperative	O
interaction	O
of	O
AP	B-GENE
-	I-GENE
1	I-GENE
and	O
NF	B-GENE
-	I-GENE
kappaB	I-GENE
.	O

A	O
human	O
nuclear	O
-	O
localized	O
chaperone	O
that	O
regulates	O
dimerization	O
,	O
DNA	O
binding	O
,	O
and	O
transcriptional	O
activity	O
of	O
bZIP	B-GENE
proteins	I-GENE
.	O

Clinical	O
differentiation	O
of	O
patients	O
with	O
mild	O
diplegic	O
cerebral	O
palsy	O
(	O
CP	O
)	O
and	O
idiopathic	O
toe	O
walking	O
(	O
ITW	O
)	O
can	O
be	O
difficult	O
.	O

Sputum	B-GENE
IL	I-GENE
-	I-GENE
8	I-GENE
and	O
MPO	B-GENE
were	O
significantly	O
increased	O
after	O
BPT	O
in	O
both	O
TDI	O
-	O
and	O
grain	O
dust	O
-	O
asthma	O
(	O
P	O
<	O
0	O
.	O
05	O
)	O
.	O

Montelukast	O
reduces	O
airway	O
eosinophilic	O
inflammation	O
in	O
asthma	O
:	O
a	O
randomized	O
,	O
controlled	O
trial	O
.	O

Here	O
,	O
we	O
demonstrate	O
that	O
kinase	O
-	O
dead	O
but	O
not	O
wild	O
-	O
type	O
forms	O
of	O
Fyn	B-GENE
,	O
Lck	B-GENE
,	O
and	O
ZAP	B-GENE
-	I-GENE
70	I-GENE
block	O
70Z	O
Cbl	B-GENE
-	O
mediated	O
NFAT	B-GENE
activation	O
.	O

Substitutions	O
of	O
region	O
I	O
with	O
synthetic	O
sequences	O
showed	O
that	O
no	O
specific	O
sequence	O
but	O
rather	O
repeats	O
of	O
three	O
or	O
more	O
consecutive	O
adenines	O
or	O
thymines	O
,	O
without	O
interruption	O
by	O
guanine	O
or	O
cytosine	O
,	O
are	O
required	O
for	O
the	O
ARS	O
activity	O
.	O

In	O
Saccharomyces	O
cerevisiae	O
,	O
PHO85	B-GENE
encodes	O
a	O
cyclin	B-GENE
-	I-GENE
dependent	I-GENE
protein	I-GENE
kinase	I-GENE
(	O
Cdk	B-GENE
)	O
catalytic	O
subunit	O
with	O
multiple	O
regulatory	O
roles	O
thought	O
to	O
be	O
specified	O
by	O
association	O
with	O
different	O
cyclin	B-GENE
partners	O
(	O
Pcls	B-GENE
)	O
.	O

Mutants	O
with	O
mild	O
lace	B-GENE
alleles	I-GENE
grow	O
to	O
become	O
adults	O
with	O
multiple	O
aberrant	O
morphologies	O
in	O
the	O
appendages	O
,	O
compound	O
eye	O
,	O
and	O
bristles	O
.	O

In	O
fact	O
,	O
SPT	B-GENE
activity	O
in	O
the	O
fly	O
expressing	O
epitope	O
-	O
tagged	O
Lace	B-GENE
was	O
absorbed	O
by	O
epitope	O
-	O
specific	O
antibody	O
.	O

These	O
results	O
show	O
that	O
targeting	O
of	O
Ras	B-GENE
-	O
GAP	B-GENE
could	O
represent	O
a	O
novel	O
anticancer	O
approach	O
.	O

EB	B-GENE
-	I-GENE
1	I-GENE
,	O
a	O
tyrosine	B-GENE
kinase	I-GENE
signal	I-GENE
transduction	I-GENE
gene	I-GENE
,	O
is	O
transcriptionally	O
activated	O
in	O
the	O
t	O
(	O
1	O
;	O
19	O
)	O
subset	O
of	O
pre	O
-	O
B	O
ALL	O
,	O
which	O
express	O
oncoprotein	O
E2a	B-GENE
-	O
Pbx1	B-GENE
.	O

BCL6	B-GENE
encodes	O
a	O
POZ	B-GENE
/	I-GENE
Zn	I-GENE
finger	I-GENE
protein	I-GENE
,	O
a	O
structure	O
similar	O
to	O
that	O
of	O
many	O
Drosophila	O
developmental	O
regulators	O
and	O
to	O
another	O
protein	O
involved	O
in	O
a	O
human	O
hematopoietic	O
malignancy	O
,	O
PLZF	B-GENE
.	O

Beta	B-GENE
1	I-GENE
integrin	I-GENE
-	O
and	O
proteoglycan	O
-	O
mediated	O
stimulation	O
of	O
T	O
lymphoma	O
cell	O
adhesion	O
and	O
mitogen	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
kinase	I-GENE
signaling	O
by	O
thrombospondin	B-GENE
-	I-GENE
1	I-GENE
and	O
thrombospondin	B-GENE
-	I-GENE
1	I-GENE
peptides	I-GENE
.	O

Optical	O
CD	O
,	O
and	O
spectral	O
and	O
activity	O
analyses	O
were	O
used	O
to	O
examine	O
reactivity	O
of	O
HO	B-GENE
isozymes	I-GENE
with	O
NO	O
species	O
produced	O
by	O
NO	O
donors	O
.	O

The	O
phosphotransferase	O
system	O
(	O
PTS	O
)	O
of	O
Streptomyces	O
coelicolor	O
identification	O
and	O
biochemical	O
analysis	O
of	O
a	O
histidine	B-GENE
phosphocarrier	I-GENE
protein	I-GENE
HPr	B-GENE
encoded	O
by	O
the	O
gene	O
ptsH	B-GENE
.	O

Serum	O
concentrations	O
of	O
bone	B-GENE
specific	I-GENE
alkaline	I-GENE
phosphatase	I-GENE
(	O
BALP	B-GENE
)	O
and	O
osteocalcin	B-GENE
(	O
bone	B-GENE
Gla	I-GENE
protein	I-GENE
,	O
BGP	B-GENE
)	O
,	O
urinary	O
levels	O
of	O
pyridinoline	O
(	O
Pyr	O
)	O
and	O
deoxypyridinoline	O
(	O
Dpyr	O
)	O
and	O
computed	O
tomography	O
(	O
CT	O
)	O
measurements	O
of	O
the	O
cross	O
-	O
sectional	O
areas	O
of	O
the	O
vertebrae	O
and	O
the	O
femurs	O
,	O
the	O
apparent	O
density	O
of	O
cancellous	O
bone	O
in	O
the	O
vertebrae	O
,	O
and	O
the	O
volume	O
and	O
the	O
material	O
density	O
of	O
cortical	O
bone	O
in	O
the	O
femurs	O
were	O
determined	O
in	O
126	O
boys	O
and	O
143	O
girls	O
,	O
ages	O
7	O
-	O
18	O
years	O
.	O

In	O
another	O
study	O
,	O
intravenous	O
administration	O
of	O
devazepide	O
,	O
a	O
specific	O
cholecystokinin	B-GENE
-	I-GENE
A	I-GENE
receptor	I-GENE
antagonist	O
,	O
at	O
a	O
dose	O
of	O
0	O
.	O
1	O
mg	O
/	O
kg	O
/	O
hr	O
was	O
begun	O
15	O
min	O
before	O
postprandial	O
saline	O
intake	O
and	O
continued	O
for	O
1	O
hr	O
.	O

This	O
cluster	O
consisted	O
of	O
four	O
apparently	O
unrelated	O
ESTs	O
and	O
two	O
genes	O
,	O
pregnancy	B-GENE
-	I-GENE
associated	I-GENE
plasma	I-GENE
protein	I-GENE
-	I-GENE
A	I-GENE
(	O
PAPP	B-GENE
-	I-GENE
A	I-GENE
)	O
and	O
a	O
novel	O
gene	O
(	O
tentatively	O
named	O
EST	B-GENE
-	I-GENE
YD1	I-GENE
)	O
.	O

Prognostic	O
value	O
of	O
a	O
treadmill	O
exercise	O
score	O
in	O
symptomatic	O
patients	O
with	O
nonspecific	O
ST	O
-	O
T	O
abnormalities	O
on	O
resting	O
ECG	O
.	O

Structural	O
changes	O
in	O
the	O
C	O
-	O
terminus	O
of	O
Ca2	O
+	O
-	O
bound	O
rat	B-GENE
S100B	I-GENE
(	O
beta	B-GENE
beta	I-GENE
)	O
upon	O
binding	O
to	O
a	O
peptide	O
derived	O
from	O
the	O
C	O
-	O
terminal	O
regulatory	O
domain	O
of	O
p53	B-GENE
.	O

We	O
propose	O
that	O
Gly84	O
is	O
part	O
of	O
a	O
putative	O
"	O
oxyanion	O
hole	O
"	O
involved	O
in	O
the	O
stabilization	O
of	O
the	O
transition	O
state	O
similar	O
to	O
the	O
C	B-GENE
group	I-GENE
of	O
the	O
esterase	B-GENE
/	O
lipase	B-GENE
family	O
.	O

The	O
solution	O
structure	O
of	O
the	O
adduct	O
derived	O
from	O
the	O
covalent	O
bonding	O
of	O
the	O
fjord	O
region	O
(	O
+	O
)	O
-	O
(	O
11S	O
,	O
12R	O
,	O
13R	O
,	O
14S	O
)	O
stereoisomer	O
of	O
anti	O
-	O
11	O
,	O
12	O
-	O
dihydroxy	O
-	O
13	O
,	O
14	O
-	O
epoxy	O
-	O
11	O
,	O
12	O
,	O
13	O
,	O
14	O
-	O
tetrahydrobenzo	O
[	O
g	O
]	O
chrysene	O
,	O
(	O
+	O
)	O
-	O
anti	O
-	O
B	O
[	O
g	O
]	O
CDE	O
,	O
to	O
the	O
exocyclic	O
N	O
(	O
6	O
)	O
amino	O
group	O
of	O
the	O
adenine	O
residue	O
dA6	O
,	O
(	O
designated	O
(	O
+	O
)	O
-	O
trans	O
-	O
anti	O
-	O
(	O
B	O
[	O
g	O
]	O
C	O
)	O
dA6	O
)	O
,	O
positioned	O
opposite	O
a	O
thymine	O
residue	O
dT17	O
in	O
the	O
DNA	O
sequence	O
context	O
d	O
(	O
C1	O
-	O
T2	O
-	O
C3	O
-	O
T4	O
-	O
C5	O
-	O
(	O
B	O
[	O
g	O
]	O
C	O
)	O
A6	O
-	O
C7	O
-	O
T8	O
-	O
T9	O
-	O
C10	O
-	O
C11	O
)	O
.	O
d	O
(	O
G12	O
-	O
G13	O
-	O
A14	O
-	O
A15	O
-	O
G16	O
-	O
T17	O
-	O
G18	O
-	O
A19	O
-	O
G20	O
+	O
+	O
+	O
-	O
A21	O
-	O
G22	O
)	O
(	O
designated	O
(	O
B	O
[	O
g	O
]	O
C	O
)	O
dA	O
.	O
dT	O
11	O
-	O
mer	O
duplex	O
)	O
,	O
has	O
been	O
studied	O
using	O
structural	O
information	O
derived	O
from	O
NMR	O
data	O
in	O
combination	O
with	O
molecular	O
dynamics	O
(	O
MD	O
)	O
calculations	O
.	O

Since	O
sildenafil	O
came	O
on	O
the	O
market	O
,	O
it	O
seems	O
that	O
the	O
place	O
of	O
MUSE	O
is	O
reduced	O
because	O
comparative	O
studies	O
give	O
better	O
results	O
for	O
sildenafil	O
than	O
MUSE	O
(	O
70	O
%	O
vs	O
40	O
%	O
)	O
and	O
of	O
course	O
with	O
a	O
better	O
acceptance	O
.	O

Serum	O
antibodies	O
were	O
detected	O
in	O
at	O
least	O
95	O
%	O
of	O
the	O
infected	O
guinea	O
pigs	O
between	O
4	O
-	O
30	O
WPI	O
and	O
rats	O
between	O
3	O
-	O
16	O
WPI	O
.	O

CONCLUSIONS	O
:	O
These	O
results	O
show	O
that	O
once	O
daily	O
oral	O
valganciclovir	O
can	O
produce	O
exposures	O
of	O
ganciclovir	O
(	O
AUC24	O
)	O
exceeding	O
those	O
attained	O
using	O
intravenous	O
ganciclovir	O
10	O
mg	O
/	O
kg	O
.	O

Except	O
for	O
nonperfusion	O
of	O
neurosensory	O
retinal	O
vessels	O
at	O
a	O
light	O
dose	O
of	O
150	O
J	O
/	O
cm2	O
,	O
no	O
other	O
adverse	O
events	O
were	O
of	O
concern	O
.	O

Except	O
for	O
nonperfusion	O
of	O
neurosensory	O
retinal	O
vessels	O
at	O
a	O
light	O
dose	O
of	O
150	O
J	O
/	O
cm2	O
,	O
no	O
other	O
adverse	O
events	O
were	O
of	O
concern	O
.	O

The	O
healing	O
rate	O
in	O
HIV	O
-	O
positive	O
patients	O
was	O
66	O
percent	O
after	O
14	O
weeks	O
and	O
100	O
percent	O
after	O
32	O
weeks	O
;	O
the	O
corresponding	O
figures	O
for	O
patients	O
with	O
acquired	O
immunodeficiency	O
syndrome	O
were	O
0	O
and	O
50	O
percent	O
.	O

The	O
P	B-GENE
mRNA	I-GENE
also	O
contains	O
a	O
third	O
ORF	O
for	O
the	O
V	B-GENE
protein	I-GENE
,	O
although	O
it	O
is	O
unclear	O
how	O
or	O
whether	O
this	O
ORF	O
is	O
accessed	O
.	O

A	O
genetic	O
screen	O
in	O
yeast	O
has	O
allowed	O
us	O
to	O
identify	O
a	O
novel	O
transcriptional	O
factor	O
binding	O
to	O
the	O
GlRE	O
,	O
i	O
.	O
e	O
.	O
the	O
chicken	B-GENE
ovalbumin	I-GENE
upstream	I-GENE
promoter	I-GENE
-	I-GENE
transcription	I-GENE
factor	I-GENE
II	I-GENE
(	O
COUP	B-GENE
-	I-GENE
TFII	I-GENE
)	O
.	O

We	O
have	O
cloned	O
the	O
single	O
-	O
copy	O
gene	O
for	O
the	O
trans	B-GENE
-	I-GENE
spliceosomal	I-GENE
U5	I-GENE
snRNA	I-GENE
from	O
the	O
trypanosomatid	O
species	O
Leptomonas	O
seymouri	O
,	O
using	O
U5	B-GENE
RNA	I-GENE
affinity	O
selection	O
and	O
cDNA	O
cloning	O
.	O

The	O
MMPI	O
-	O
A	O
(	O
Butcher	O
et	O
al	O
.	O
,	O
1992	O
)	O
,	O
like	O
the	O
older	O
MMPI	O
(	O
Hathaway	O
&	O
McKinley	O
,	O
1983	O
)	O
,	O
distinguishes	O
between	O
anorexia	O
and	O
bulimia	O
.	O

On	O
the	O
other	O
hand	O
,	O
phosphatidyl	O
inositol	O
4	O
,	O
5	O
bisphosphate	O
(	O
PIP2	O
)	O
hydrolysis	O
requires	O
direct	O
phosphorylation	O
at	O
tyrosine	O
residue	O
of	O
the	O
PLC	B-GENE
-	I-GENE
gamma1	I-GENE
isozyme	I-GENE
.	O

A	O
G22V	B-GENE
mutant	I-GENE
of	O
M	B-GENE
-	I-GENE
Ras	I-GENE
was	O
constitutively	O
active	O
and	O
its	O
expression	O
in	O
an	O
interleukin	B-GENE
-	I-GENE
3	I-GENE
(	O
IL	B-GENE
-	I-GENE
3	I-GENE
)	O
-	O
dependent	O
mast	O
cell	O
/	O
megakaryocyte	O
cell	O
line	O
resulted	O
in	O
increased	O
survival	O
in	O
the	O
absence	O
of	O
IL	B-GENE
-	I-GENE
3	I-GENE
,	O
increased	O
growth	O
in	O
IL	B-GENE
-	I-GENE
4	I-GENE
,	O
and	O
,	O
at	O
high	O
expression	O
levels	O
,	O
in	O
factor	O
-	O
independent	O
growth	O
.	O

Mammalian	B-GENE
M	I-GENE
-	I-GENE
Ras	I-GENE
and	O
a	O
Caenorhabditis	O
elegans	O
orthologue	O
exhibit	O
conserved	O
structural	O
features	O
,	O
and	O
these	O
are	O
likely	O
to	O
mediate	O
activation	O
of	O
distinctive	O
signaling	O
paths	O
that	O
function	O
in	O
parallel	O
to	O
those	O
downstream	O
of	O
p21	B-GENE
Ras	I-GENE
.	O

Taken	O
together	O
,	O
our	O
data	O
suggest	O
that	O
PecS	B-GENE
attenuates	O
pelD	B-GENE
and	O
pelE	B-GENE
expression	O
rather	O
than	O
acting	O
as	O
a	O
true	O
repressor	O
like	O
KdgR	B-GENE
.	O

These	O
observations	O
establish	O
that	O
RsmC	B-GENE
negatively	O
regulates	O
rsmB	B-GENE
transcription	O
but	O
positively	O
affects	O
RsmA	B-GENE
production	O
.	O

All	O
were	O
experienced	O
hearing	O
aid	O
users	O
who	O
wore	O
linear	O
Class	O
D	O
instruments	O
with	O
input	O
compression	O
limiting	O
at	O
the	O
time	O
of	O
their	O
enrollment	O
in	O
this	O
study	O
.	O

Ribonuclease	O
protection	O
assays	O
revealed	O
that	O
hmg1	B-GENE
and	O
hmg2	B-GENE
are	O
differentially	O
expressed	O
in	O
a	O
developmentally	O
-	O
and	O
spatially	O
-	O
modulated	O
manner	O
during	O
morphogenesis	O
of	O
specialized	O
terpenoid	O
-	O
containing	O
pigment	O
glands	O
in	O
embryos	O
.	O

Inactivation	O
of	O
the	O
Neurospora	B-GENE
crassa	I-GENE
mitochondrial	I-GENE
outer	I-GENE
membrane	I-GENE
protein	I-GENE
TOM70	I-GENE
by	O
repeat	O
-	O
induced	O
point	O
mutation	O
(	O
RIP	O
)	O
causes	O
defects	O
in	O
mitochondrial	O
protein	O
import	O
and	O
morphology	O
.	O

Recently	O
,	O
cell	O
-	O
surface	O
TRAIL	B-GENE
has	O
been	O
shown	O
to	O
be	O
expressed	O
by	O
activated	O
human	O
and	O
mouse	O
T	O
lymphocytes	O
,	O
raising	O
the	O
possibility	O
that	O
TRAIL	B-GENE
might	O
be	O
involved	O
in	O
T	O
cell	O
-	O
mediated	O
cytotoxicity	O
and	O
/	O
or	O
immune	O
regulation	O
.	O

A	O
panel	O
of	O
pharmacologic	O
inhibitors	O
was	O
used	O
to	O
investigate	O
the	O
signal	O
transduction	O
pathways	O
involved	O
in	O
TRAIL	B-GENE
gene	I-GENE
induction	O
following	O
T	O
lymphocyte	O
activation	O
.	O

Defective	O
provirus	O
genomes	O
of	O
human	O
T	O
-	O
cell	O
leukemia	O
virus	O
type	O
I	O
are	O
frequently	O
detected	O
in	O
lymphocytes	O
from	O
infected	O
individuals	O
and	O
in	O
infected	O
cell	O
lines	O
.	O

A	O
total	O
of	O
174	O
primer	O
pairs	O
gave	O
interpretable	O
banding	O
patterns	O
,	O
137	O
(	O
79	O
%	O
)	O
of	O
which	O
revealed	O
at	O
least	O
two	O
alleles	O
on	O
native	O
polyacrylamide	O
gels	O
.	O

A	O
population	O
pharmacokinetic	O
study	O
of	O
cyclosporin	O
in	O
organ	O
transplant	O
patients	O
,	O
including	O
elderly	O
allograft	O
recipients	O
up	O
to	O
75	O
years	O
of	O
age	O
,	O
did	O
not	O
identify	O
age	O
as	O
a	O
covariable	O
influencing	O
cyclosporin	O
pharmacokinetics	O
.	O

Immunofluoresence	O
data	O
indicated	O
that	O
once	O
bound	O
to	O
the	O
mutant	O
receptor	O
,	O
fluorescent	O
-	O
labeled	O
RAP	B-GENE
co	O
-	O
localized	O
with	O
markers	O
of	O
the	O
endosomal	O
pathway	O
,	O
whereas	O
,	O
in	O
cells	O
expressing	O
the	O
wild	O
-	O
type	O
receptor	O
,	O
RAP	B-GENE
fluorescence	O
co	O
-	O
localized	O
with	O
lysosomal	O
markers	O
.	O

Interleukin	B-GENE
-	I-GENE
12	I-GENE
(	O
IL	B-GENE
-	I-GENE
12	I-GENE
)	O
is	O
a	O
cytokine	O
produced	O
by	O
peripheral	O
blood	O
mononuclear	O
cells	O
(	O
PBMC	O
)	O
that	O
causes	O
interferon	B-GENE
-	I-GENE
gamma	I-GENE
(	O
IFN	B-GENE
-	I-GENE
gamma	I-GENE
)	O
production	O
and	O
enhancement	O
of	O
cell	O
-	O
mediated	O
cytotoxicity	O
.	O

IL	B-GENE
-	I-GENE
12	I-GENE
production	O
was	O
correlated	O
with	O
C3a	O
concentration	O
measured	O
at	O
the	O
outlet	O
of	O
hemodialyzer	O
after	O
15	O
min	O
of	O
dialysis	O
(	O
r	O
=	O
0	O
.	O
69	O
,	O
P	O
<	O
0	O
.	O
01	O
)	O
.	O

In	O
HeLa	O
cells	O
,	O
the	O
JNKK2	B-GENE
-	O
JNK1	B-GENE
fusion	O
protein	O
showed	O
significant	O
JNK	B-GENE
activity	O
,	O
which	O
was	O
comparable	O
with	O
that	O
of	O
JNK1	B-GENE
activated	O
by	O
many	O
stimuli	O
and	O
activators	O
,	O
including	O
EGF	B-GENE
,	O
TNF	B-GENE
-	I-GENE
alpha	I-GENE
,	O
anisomycin	O
,	O
UV	O
irradiation	O
,	O
MEKK1	B-GENE
,	O
and	O
small	B-GENE
GTP	I-GENE
binding	I-GENE
proteins	I-GENE
Rac1	I-GENE
and	O
Cdc42Hs	B-GENE
.	O

J	O
.	O

Our	O
results	O
implicate	O
TGF	B-GENE
-	I-GENE
beta	I-GENE
RII	I-GENE
as	O
a	O
direct	O
target	O
of	O
EWS	B-GENE
-	O
FLI1	B-GENE
.	O

The	O
reduction	O
in	O
saturated	O
fatty	O
acids	O
intake	O
led	O
to	O
modest	O
(	O
but	O
in	O
group	O
1	O
significant	O
)	O
0	O
.	O
15	O
mmol	O
/	O
l	O
(	O
2	O
.	O
5	O
%	O
)	O
reduction	O
in	O
total	O
serum	O
cholesterol	O
level	O
.	O

Secondly	O
,	O
an	O
ethanol	O
repression	O
autoregulation	O
(	O
ERA	O
)	O
/	O
twelve	O
-	O
fold	O
TA	O
repeat	O
(	O
TAB	O
)	O
repressor	O
element	O
was	O
identified	O
within	O
the	O
promoter	O
region	O
of	O
the	O
GLK1	B-GENE
gene	I-GENE
.	O

A	O
crucial	O
transcription	O
factor	O
in	O
this	O
process	O
is	O
STAT6	B-GENE
,	O
which	O
binds	O
to	O
a	O
specific	O
DNA	O
element	O
upon	O
cytokine	O
activation	O
.	O

CONCLUSIONS	O
:	O
Congenital	O
horizontal	O
tarsal	O
kink	O
is	O
rare	O
and	O
its	O
cause	O
is	O
unknown	O
.	O

A	O
local	O
,	O
high	O
-	O
density	O
,	O
single	O
-	O
nucleotide	O
polymorphism	O
map	O
used	O
to	O
clone	O
Caenorhabditis	B-GENE
elegans	I-GENE
cdf	I-GENE
-	I-GENE
1	I-GENE
.	O

This	O
machinery	O
involves	O
a	O
secondary	O
structure	O
,	O
SECIS	O
element	O
,	O
in	O
the	O
selenoprotein	B-GENE
-	O
encoding	O
mRNA	O
,	O
directing	O
selenocysteine	O
insertion	O
at	O
the	O
position	O
of	O
an	O
opal	O
(	O
UGA	O
)	O
codon	O
,	O
normally	O
conferring	O
termination	O
of	O
translation	O
.	O

High	O
-	O
level	O
expression	O
in	O
Escherichia	O
coli	O
of	O
selenocysteine	O
-	O
containing	O
rat	B-GENE
thioredoxin	I-GENE
reductase	I-GENE
utilizing	O
gene	O
fusions	O
with	O
engineered	O
bacterial	O
-	O
type	O
SECIS	O
elements	O
and	O
co	O
-	O
expression	O
with	O
the	O
selA	B-GENE
,	O
selB	B-GENE
and	O
selC	B-GENE
genes	I-GENE
.	O

In	O
Wnt	B-GENE
signaling	O
,	O
beta	B-GENE
-	I-GENE
catenin	I-GENE
and	O
plakoglobin	B-GENE
transduce	O
signals	O
to	O
the	O
nucleus	O
through	O
interactions	O
with	O
TCF	B-GENE
-	I-GENE
type	I-GENE
transcription	I-GENE
factors	I-GENE
.	O

Assembly	O
of	O
a	O
complex	O
between	O
FAK	B-GENE
and	O
Src	B-GENE
kinases	I-GENE
may	O
serve	O
to	O
regulate	O
the	O
subcellular	O
localization	O
and	O
the	O
enzymatic	O
activity	O
of	O
members	O
of	O
the	O
Src	B-GENE
family	I-GENE
of	O
kinases	O
.	O

Our	O
study	O
also	O
demonstrated	O
significant	O
increases	O
in	O
the	O
number	O
of	O
larger	O
myelinated	O
fibers	O
crossing	O
the	O
repair	O
site	O
in	O
comparison	O
with	O
the	O
neonatal	O
and	O
adult	O
groups	O
(	O
p	O
<	O
0	O
.	O
04	O
)	O
.	O

Cortical	O
dysplasias	O
,	O
genetics	O
,	O
and	O
epileptogenesis	O
.	O

In	O
the	O
work	O
reported	O
here	O
,	O
we	O
used	O
peptide	O
mapping	O
,	O
mass	O
spectrometry	O
,	O
and	O
site	O
-	O
directed	O
mutagenesis	O
to	O
identify	O
two	O
sets	O
of	O
pAP	B-GENE
phosphorylation	O
sites	O
.	O

Both	O
HERV	O
-	O
K	O
type	O
1	O
and	O
2	O
clones	O
were	O
isolated	O
.	O

Duch	O
,	O
and	O
F	O
.	O

At	O
all	O
time	O
-	O
points	O
,	O
most	O
patients	O
(	O
>	O
/	O
=	O
87	O
%	O
)	O
were	O
receiving	O
irbesartan	O
/	O
HCTZ	O
alone	O
.	O

Modification	O
of	O
dopamine	B-GENE
D2	I-GENE
receptor	I-GENE
activity	O
by	O
pergolide	O
in	O
Parkinson	O
'	O
s	O
disease	O
:	O
an	O
in	O
vivo	O
study	O
by	O
PET	O
.	O

High	O
-	O
affinity	O
binding	O
sites	O
for	O
both	O
GR	B-GENE
and	O
AP	B-GENE
-	I-GENE
1	I-GENE
nucleoproteins	I-GENE
were	O
identified	O
at	O
adjacent	O
elements	O
within	O
the	O
nGRE	O
.	O

When	O
the	O
73	O
-	O
bp	O
fragment	O
was	O
fused	O
to	O
an	O
alpha1	B-GENE
-	I-GENE
globin	I-GENE
promoter	O
-	O
CAT	B-GENE
construct	O
and	O
cotransfected	O
with	O
CCAAT	B-GENE
transcription	I-GENE
factor	I-GENE
1	I-GENE
(	O
CTF1	B-GENE
)	O
/	O
NF1	B-GENE
into	O
Drosophila	O
Schneider	O
SL2	O
insect	O
cells	O
(	O
which	O
lack	O
NF1	B-GENE
-	I-GENE
like	I-GENE
proteins	I-GENE
)	O
trans	O
-	O
activation	O
of	O
CAT	B-GENE
activity	O
was	O
observed	O
.	O

Western	O
blot	O
analysis	O
showed	O
a	O
rapid	O
corresponding	O
increase	O
in	O
p21WAF1	B-GENE
/	O
CIP1	B-GENE
protein	O
,	O
whereas	O
protein	O
levels	O
of	O
another	O
member	O
of	O
the	O
cyclin	B-GENE
-	I-GENE
dependent	I-GENE
kinase	I-GENE
inhibitor	I-GENE
family	I-GENE
,	O
p27kip1	B-GENE
,	O
were	O
unchanged	O
.	O

Aggregation	O
of	O
vHnf1	B-GENE
-	O
deficient	O
embryonic	O
stem	O
cells	O
with	O
wild	O
-	O
type	O
tetraploid	O
embryos	O
,	O
which	O
contribute	O
exclusively	O
to	O
extraembryonic	O
tissues	O
,	O
rescues	O
periimplantation	O
lethality	O
and	O
allows	O
development	O
to	O
progress	O
to	O
early	O
organogenesis	O
.	O

nos	B-GENE
-	I-GENE
1	I-GENE
and	O
nos	B-GENE
-	I-GENE
2	I-GENE
,	O
two	O
genes	O
related	O
to	O
Drosophila	B-GENE
nanos	I-GENE
,	O
regulate	O
primordial	O
germ	O
cell	O
development	O
and	O
survival	O
in	O
Caenorhabditis	O
elegans	O
.	O

Although	O
upstream	O
regulators	O
of	O
Tec	B-GENE
family	I-GENE
kinases	I-GENE
are	O
relatively	O
well	O
characterized	O
,	O
little	O
is	O
known	O
of	O
the	O
downstream	O
effectors	O
of	O
these	O
enzymes	O
.	O

Efficient	O
phosphorylation	O
of	O
BRDG1	B-GENE
by	O
Tec	B-GENE
required	O
the	O
PH	B-GENE
and	O
SH2	B-GENE
domains	I-GENE
as	O
well	O
as	O
the	O
kinase	O
domain	O
of	O
the	O
latter	O
.	O

CONCLUSION	O
:	O
These	O
findings	O
imply	O
that	O
eotaxin	O
either	O
is	O
mechanistically	O
involved	O
in	O
acute	O
asthma	O
or	O
serves	O
as	O
a	O
biomarker	O
for	O
activity	O
of	O
the	O
CCR3	B-GENE
receptor	I-GENE
ligand	I-GENE
system	O
,	O
which	O
is	O
functionally	O
linked	O
to	O
asthma	O
.	O

The	O
expression	O
analysis	O
of	O
the	O
KlHIS4	B-GENE
gene	I-GENE
under	O
phosphate	O
starvation	O
or	O
high	O
adenine	O
supply	O
shows	O
that	O
factors	O
,	O
such	O
as	O
Bas1	B-GENE
or	O
Bas2	B-GENE
,	O
involved	O
in	O
the	O
basal	O
control	O
may	O
also	O
operate	O
in	O
a	O
different	O
way	O
in	O
K	O
.	O
lactis	O
.	O

These	O
thyroid	O
hormone	O
changes	O
may	O
be	O
mediated	O
in	O
part	O
by	O
cytokines	O
or	O
other	O
inflammatory	O
mediators	O
,	O
acting	O
at	O
the	O
level	O
of	O
the	O
hypothalamus	O
and	O
pituitary	O
gland	O
,	O
the	O
thyroid	O
gland	O
,	O
and	O
the	O
hepatic	B-GENE
deiodinase	I-GENE
system	O
.	O

ESS	O
type	O
1	O
,	O
with	O
FT3	O
low	O
and	O
FT4	O
and	O
TSH	B-GENE
normal	O
,	O
is	O
the	O
most	O
frequent	O
form	O
.	O

METHODS	O
:	O
We	O
studied	O
20	O
symptomatic	O
patients	O
with	O
HOCM	O
(	O
12	O
men	O
)	O
,	O
mean	O
age	O
52	O
+	O
/	O
-	O
17	O
years	O
,	O
before	O
and	O
after	O
septal	O
reduction	O
using	O
echocardiography	O
and	O
electrocardiogram	O
(	O
ECG	O
)	O
.	O

Paleoceanographic	O
data	O
from	O
the	O
Laurentian	O
Fan	O
,	O
used	O
as	O
a	O
proxy	O
for	O
sea	O
surface	O
temperature	O
,	O
reveal	O
that	O
surface	O
slope	O
waters	O
north	O
of	O
the	O
Gulf	O
Stream	O
experienced	O
warming	O
during	O
the	O
Little	O
Ice	O
Age	O
of	O
the	O
16th	O
to	O
19th	O
centuries	O
and	O
support	O
the	O
notion	O
of	O
an	O
NAO	O
-	O
driven	O
coupled	O
system	O
.	O

This	O
effect	O
required	O
(	O
i	O
)	O
IR	B-GENE
activation	O
since	O
it	O
was	O
abrogated	O
by	O
IR	B-GENE
mutation	O
at	O
tyrosines	O
1162	O
and	O
1163	O
and	O
(	O
ii	O
)	O
NF	B-GENE
-	I-GENE
kappaB	I-GENE
activation	O
since	O
it	O
was	O
abolished	O
by	O
overexpression	O
of	O
dominant	B-GENE
-	I-GENE
negative	I-GENE
IkappaB	I-GENE
-	I-GENE
alpha	I-GENE
(	I-GENE
A32	I-GENE
/	I-GENE
36	I-GENE
)	I-GENE
and	O
mimicked	O
by	O
overexpression	O
of	O
the	O
NF	B-GENE
-	I-GENE
kappaB	I-GENE
c	B-GENE
-	I-GENE
Rel	I-GENE
subunit	I-GENE
.	O

The	O
factor	O
designated	O
B	O
formed	O
a	O
complex	O
centered	O
on	O
the	O
sequence	O
TGTGGT	O
,	O
a	O
core	O
motif	O
recognized	O
by	O
members	O
of	O
the	O
AML	B-GENE
/	I-GENE
CBFalpha	I-GENE
transcription	I-GENE
factor	I-GENE
family	I-GENE
.	O

Furthermore	O
,	O
overexpression	O
of	O
AML3	B-GENE
/	O
CBFalpha1	B-GENE
could	O
rescue	O
the	O
AML1	B-GENE
-	O
ETO	B-GENE
repression	O
.	O

We	O
examined	O
Akt	B-GENE
activation	O
in	O
Lyn	B-GENE
-	O
,	O
Syk	B-GENE
-	O
and	O
Btk	B-GENE
-	O
deficient	O
DT40	O
cells	O
and	O
B	O
cells	O
from	O
Lyn	B-GENE
(	I-GENE
-	I-GENE
/	I-GENE
-	I-GENE
)	I-GENE
mice	O
.	O

Regulators	O
of	O
G	B-GENE
protein	I-GENE
signaling	I-GENE
(	I-GENE
RGS	I-GENE
)	I-GENE
proteins	I-GENE
that	O
contain	O
DEP	B-GENE
(	O
disheveled	B-GENE
,	O
EGL	B-GENE
-	I-GENE
10	I-GENE
,	O
pleckstrin	B-GENE
)	O
and	O
GGL	B-GENE
(	O
G	B-GENE
protein	I-GENE
gamma	I-GENE
subunit	I-GENE
-	I-GENE
like	I-GENE
)	O
domains	O
form	O
a	O
subfamily	O
that	O
includes	O
the	O
mammalian	B-GENE
RGS	I-GENE
proteins	I-GENE
RGS6	B-GENE
,	O
RGS7	B-GENE
,	O
RGS9	B-GENE
,	O
and	O
RGS11	B-GENE
.	O

Cloning	O
and	O
expression	O
of	O
a	O
specific	O
human	B-GENE
alpha	I-GENE
1	I-GENE
,	I-GENE
2	I-GENE
-	I-GENE
mannosidase	I-GENE
that	O
trims	O
Man9GlcNAc2	O
to	O
Man8GlcNAc2	O
isomer	O
B	O
during	O
N	O
-	O
glycan	O
biosynthesis	O
.	O

The	O
ORs	O
of	O
GC	O
,	O
adjusted	O
for	O
age	O
and	O
sex	O
,	O
varied	O
from	O
17	O
.	O
1	O
,	O
for	O
those	O
with	O
baseline	O
diagnoses	O
of	O
superficial	O
intestinal	O
metaplasia	O
(	O
IM	O
)	O
,	O
to	O
29	O
.	O
3	O
,	O
for	O
those	O
with	O
deep	O
IM	O
or	O
mild	O
dysplasia	O
(	O
DYS	O
)	O
or	O
IM	O
with	O
glandular	O
atrophy	O
and	O
neck	O
hyperplasia	O
,	O
to	O
104	O
.	O
2	O
,	O
for	O
those	O
with	O
moderate	O
or	O
severe	O
DYS	O
,	O
as	O
compared	O
with	O
subjects	O
with	O
superficial	O
gastritis	O
(	O
SG	O
)	O
or	O
chronic	O
atrophic	O
gastritis	O
(	O
CAG	O
)	O
at	O
baseline	O
.	O

Here	O
we	O
report	O
that	O
Dbp5p	B-GENE
and	O
Rat7p	B-GENE
interact	O
through	O
their	O
Nterminal	O
domains	O
.	O

Thus	O
,	O
the	O
nematode	O
genes	O
could	O
be	O
the	O
homologs	B-GENE
of	I-GENE
Hh	I-GENE
molecules	I-GENE
in	O
other	O
phyla	O
.	O

A	O
subset	O
of	O
mutations	O
in	O
the	O
Psi	B-GENE
synthase	I-GENE
domain	I-GENE
impairs	O
association	O
of	O
the	O
altered	O
Cbf5p	B-GENE
proteins	I-GENE
with	O
selected	O
box	O
H	B-GENE
/	I-GENE
ACA	I-GENE
snoRNAs	I-GENE
,	O
suggesting	O
that	O
the	O
functional	O
catalytic	O
domain	O
is	O
essential	O
for	O
that	O
interaction	O
.	O

The	O
transcription	B-GENE
factor	I-GENE
CHOP	I-GENE
(	O
C	B-GENE
/	I-GENE
EBP	I-GENE
homologous	I-GENE
protein	I-GENE
10	I-GENE
)	O
is	O
a	O
bZIP	B-GENE
protein	I-GENE
induced	O
by	O
a	O
variety	O
of	O
stimuli	O
that	O
evoke	O
cellular	O
stress	O
responses	O
and	O
has	O
been	O
shown	O
to	O
arrest	O
cell	O
growth	O
and	O
to	O
promote	O
programmed	O
cell	O
death	O
.	O

Thus	O
,	O
CHOP	B-GENE
not	O
only	O
is	O
a	O
negative	O
or	O
a	O
positive	O
regulator	O
of	O
C	B-GENE
/	I-GENE
EBP	I-GENE
target	O
genes	O
but	O
also	O
,	O
when	O
tethered	O
to	O
AP	B-GENE
-	I-GENE
1	I-GENE
factors	I-GENE
,	O
can	O
activate	O
AP	B-GENE
-	I-GENE
1	I-GENE
target	O
genes	O
.	O

This	O
motif	O
,	O
first	O
described	O
for	O
the	O
Drosophila	B-GENE
homeobox	I-GENE
activator	I-GENE
DEAF	I-GENE
-	I-GENE
1	I-GENE
,	O
identifies	O
an	O
emerging	O
group	O
of	O
metazoan	O
transcriptional	O
modulators	O
.	O

RNase	B-GENE
MRP	I-GENE
is	O
a	O
ribonucleoprotein	O
endoribonuclease	O
that	O
has	O
been	O
shown	O
to	O
have	O
roles	O
in	O
both	O
mitochondrial	O
DNA	O
replication	O
and	O
nuclear	B-GENE
5	I-GENE
.	I-GENE
8S	I-GENE
rRNA	I-GENE
processing	O
.	O

We	O
have	O
examined	O
the	O
regulation	O
of	O
the	O
FGFR	B-GENE
-	I-GENE
1	I-GENE
gene	I-GENE
(	O
cek	B-GENE
-	I-GENE
1	I-GENE
)	O
in	O
avian	O
myogenic	O
cultures	O
by	O
immunocytochemistry	O
and	O
Northern	O
blot	O
analysis	O
.	O

Regulation	O
of	O
avian	B-GENE
fibroblast	I-GENE
growth	I-GENE
factor	I-GENE
receptor	I-GENE
1	I-GENE
(	O
FGFR	B-GENE
-	I-GENE
1	I-GENE
)	O
gene	O
expression	O
during	O
skeletal	O
muscle	O
differentiation	O
.	O

The	O
backbone	O
dynamics	O
of	O
residues	O
located	O
in	O
the	O
folded	O
part	O
of	O
CRP2	B-GENE
(	O
LIM2	B-GENE
)	O
R122A	B-GENE
have	O
been	O
characterized	O
by	O
proton	O
-	O
detected	O
(	O
15	O
)	O
N	O
NMR	O
spectroscopy	O
.	O

Rac	B-GENE
causes	O
uncapping	O
of	O
actin	B-GENE
filaments	I-GENE
(	O
F	B-GENE
-	I-GENE
actin	I-GENE
)	O
at	O
the	O
plus	O
-	O
ends	O
,	O
through	O
phosphatidylinositol	O
4	O
,	O
5	O
bisphosphate	O
(	O
PIP2	O
)	O
,	O
and	O
eventually	O
induces	O
membrane	O
ruffling	O
.	O

However	O
,	O
a	O
specific	O
ICE	B-GENE
/	O
caspase	B-GENE
-	I-GENE
1	I-GENE
inhibitor	O
called	O
N1445	O
completely	O
abolished	O
the	O
CK	B-GENE
-	O
induced	O
apoptosis	O
by	O
reactivating	O
PKB	B-GENE
,	O
but	O
without	O
affecting	O
the	O
CK	B-GENE
-	O
induced	O
suppression	O
of	O
Ras	B-GENE
transformation	O
.	O

OBJECTIVE	O
:	O
Although	O
the	O
preponderance	O
of	O
findings	O
offer	O
support	O
for	O
transient	O
(	O
where	O
is	O
it	O
?	O
)	O
as	O
opposed	O
to	O
sustained	O
(	O
what	O
is	O
it	O
?	O
)	O
deficit	O
,	O
a	O
need	O
remains	O
for	O
specific	O
depiction	O
of	O
the	O
deficit	O
.	O

The	O
AL	O
-	O
R8	O
SI	O
:	O
the	O
next	O
generation	O
staging	O
container	O
for	O
plutonium	O
pits	O
at	O
the	O
USDOE	O
Pantex	O
Plant	O
.	O

One	O
form	O
of	O
the	O
SBEI	B-GENE
gene	I-GENE
transcript	I-GENE
in	O
12	O
-	O
day	O
old	O
kernels	O
contained	O
the	O
exon	O
I	O
+	O
II	O
+	O
III	O
combination	O
at	O
the	O
5	O
'	O
end	O
,	O
whereas	O
other	O
forms	O
differed	O
by	O
inclusion	O
of	O
intron	O
1	O
or	O
exclusion	O
of	O
exon	O
II	O
sequences	O
.	O

In	O
PC	O
,	O
rare	O
MNGCs	O
had	O
intranuclear	O
inclusions	O
and	O
grooves	O
.	O

16	O
percent	O
,	O
P	O
<	O
0	O
.	O
001	O
)	O
,	O
and	O
sustained	O
normalization	O
of	O
serum	B-GENE
alanine	I-GENE
aminotransferase	I-GENE
levels	O
(	O
41	O
percent	O
vs	O
.	O

Its	O
C	O
-	O
terminal	O
catalytic	O
domain	O
was	O
found	O
to	O
be	O
highly	O
conserved	O
in	O
the	O
homologues	O
p140	B-GENE
(	O
ras	B-GENE
-	O
GRF	B-GENE
)	O
and	O
Sos	B-GENE
.	O

356	O
,	O
93	O
-	O
98	O
]	O
.	O

In	O
assays	O
with	O
purified	O
enzymes	O
,	O
wild	O
-	O
type	O
but	O
not	O
PTPS	B-GENE
-	O
S19A	B-GENE
was	O
a	O
specific	O
substrate	O
for	O
the	O
cGMP	B-GENE
-	I-GENE
dependent	I-GENE
protein	I-GENE
kinase	I-GENE
(	I-GENE
cGK	I-GENE
)	I-GENE
type	I-GENE
I	I-GENE
and	I-GENE
II	I-GENE
.	O

R	O
.	O
,	O
Fleischmann	O
,	O
R	O
.	O
,	O
Venter	O
,	O
J	O
.	O

The	O
N	O
-	O
terminal	O
domain	O
of	O
approximately	O
70	O
kDa	O
exhibits	O
11	O
imperfect	O
amino	O
acid	O
repeats	O
that	O
show	O
some	O
homology	O
to	O
promastigote	O
surface	O
glycoproteins	O
of	O
the	O
psa2	B-GENE
/	O
gp46	B-GENE
complex	O
.	O

In	O
contrast	O
to	O
previously	O
characterized	O
proteophosphoglycans	O
,	O
the	O
ppg1	B-GENE
gene	O
product	O
is	O
predominantly	O
membrane	O
-	O
associated	O
and	O
it	O
is	O
expressed	O
on	O
the	O
promastigote	O
cell	O
surface	O
.	O

Most	O
important	O
,	O
infection	O
of	O
the	O
cells	O
with	O
an	O
adenoviral	O
construct	O
expressing	O
this	O
mutant	O
inhibited	O
the	O
induction	O
of	O
VEGF	B-GENE
mRNA	I-GENE
under	O
conditions	O
that	O
mimic	O
hypoxia	O
.	O

Neuregulin	B-GENE
stimulates	O
ErbB2	B-GENE
,	O
ErbB3	B-GENE
,	O
and	O
ErbB4	B-GENE
,	O
members	O
of	O
the	O
ErbB	B-GENE
family	I-GENE
of	O
receptor	B-GENE
tyrosine	I-GENE
kinases	I-GENE
.	O

Our	O
results	O
suggest	O
that	O
Anu2p	B-GENE
is	O
the	O
yeast	B-GENE
homologue	I-GENE
of	I-GENE
mammalian	I-GENE
epsilon	I-GENE
-	I-GENE
COP	I-GENE
and	O
the	O
abrupt	O
accumulation	O
of	O
the	O
ER	O
membrane	O
caused	O
by	O
a	O
blockage	O
of	O
the	O
early	O
protein	O
transport	O
pathway	O
leads	O
to	O
alteration	O
of	O
nuclear	O
morphology	O
of	O
the	O
budding	O
yeast	O
cells	O
.	O

In	O
PC12	O
cells	O
,	O
nerve	B-GENE
growth	I-GENE
factor	I-GENE
induces	O
neuronal	O
differentiation	O
and	O
repressed	O
expression	O
of	O
nrg	B-GENE
-	I-GENE
1	I-GENE
.	O

In	O
a	O
PC12	O
cell	O
mutant	O
that	O
is	O
deficient	O
in	O
protein	B-GENE
kinase	I-GENE
A	I-GENE
activity	O
(	O
AB	O
.	O
11	O
)	O
,	O
all	O
three	O
differentiating	O
agents	O
were	O
unable	O
to	O
down	O
-	O
regulate	O
nrg	B-GENE
-	I-GENE
1	I-GENE
mRNA	I-GENE
.	O

TSC1	B-GENE
mutations	I-GENE
include	O
two	O
nonsense	O
mutations	O
,	O
four	O
insertions	O
,	O
and	O
three	O
splice	O
mutations	O
.	O

Twelve	O
patients	O
without	O
abnormalities	O
in	O
the	O
PTT	O
are	O
assumed	O
to	O
harbor	O
missense	O
mutations	O
,	O
probably	O
in	O
TSC2	B-GENE
.	O

The	O
first	O
algorithm	O
,	O
FOREPROJ	O
,	O
is	O
a	O
fast	O
-	O
forward	O
projection	O
algorithm	O
that	O
allows	O
calculation	O
of	O
the	O
3	O
-	O
D	O
attenuation	O
correction	O
factors	O
(	O
ACF	O
'	O
s	O
)	O
directly	O
from	O
a	O
two	O
-	O
dimensional	O
(	O
2	O
-	O
D	O
)	O
transmission	O
scan	O
,	O
without	O
first	O
reconstructing	O
the	O
attenuation	O
map	O
and	O
then	O
performing	O
a	O
3	O
-	O
D	O
forward	O
projection	O
.	O

The	O
RMR	O
was	O
measured	O
twice	O
in	O
each	O
phase	O
and	O
found	O
to	O
be	O
similar	O
(	O
F	O
(	O
1	O
,	O
18	O
)	O
=	O
0	O
.	O
863	O
)	O
across	O
the	O
follicular	O
(	O
5018	O
kJ	O
/	O
24	O
h	O
)	O
and	O
the	O
luteal	O
(	O
5098	O
kJ	O
/	O
24	O
h	O
)	O
phases	O
.	O

In	O
gel	O
mobility	O
shift	O
assays	O
,	O
we	O
found	O
no	O
evidence	O
for	O
VDR	B-GENE
-	O
TR	B-GENE
heterodimer	O
interaction	O
with	O
any	O
tested	O
element	O
.	O

The	O
relative	O
importance	O
of	O
these	O
two	O
mechanisms	O
differed	O
in	O
a	O
response	O
element	O
-	O
specific	O
manner	O
.	O

After	O
14	O
d	O
of	O
overfeeding	O
,	O
hepatic	O
PL	O
profiles	O
were	O
identical	O
in	O
the	O
two	O
breeds	O
and	O
similar	O
to	O
that	O
in	O
control	O
livers	O
;	O
choline	O
-	O
containing	O
PL	O
accounted	O
for	O
95	O
%	O
of	O
total	O
PL	O
.	O

C	O
-	O
SP	O
duration	O
was	O
significantly	O
reduced	O
in	O
ALS	O
patients	O
compared	O
to	O
controls	O
at	O
low	O
stimulation	O
intensity	O
corresponding	O
to	O
an	O
MEP	O
threshold	O
increased	O
by	O
15	O
%	O
.	O

These	O
data	O
show	O
that	O
the	O
spv	B-GENE
virulence	I-GENE
genes	I-GENE
belong	O
simultaneously	O
to	O
several	O
regulons	O
in	O
the	O
cell	O
,	O
raising	O
the	O
possibility	O
that	O
spv	B-GENE
expression	O
can	O
be	O
fine	O
-	O
tuned	O
in	O
response	O
to	O
multiple	O
environmental	O
inputs	O
.	O

Intensive	O
synthesis	O
of	O
PNA	B-GENE
in	O
the	O
cells	O
of	O
microvascular	O
wall	O
evidenced	O
of	O
their	O
high	O
functional	O
activity	O
,	O
and	O
the	O
synthesis	O
of	O
DNA	O
in	O
them	O
showed	O
their	O
ability	O
for	O
proliferation	O
,	O
i	O
.	O
g	O
.	O
-	O
-	O
for	O
growth	O
.	O

Tracheal	O
transsection	O
combined	O
with	O
hilar	O
ligation	O
(	O
TL	O
&	O
PL	O
)	O
effected	O
a	O
reduction	O
of	O
19	O
.	O
9	O
%	O
(	O
n	O
.	O
s	O
.	O
)	O
.	O

Kinase	O
-	O
deficient	O
erbB	B-GENE
proteins	I-GENE
reduced	O
epidermal	B-GENE
growth	I-GENE
factor	I-GENE
(	O
EGF	B-GENE
)	O
-	O
induced	O
tyrosine	O
phosphorylation	O
of	O
endogenous	O
Shc	B-GENE
proteins	I-GENE
and	O
also	O
reduced	O
immediate	O
and	O
sustained	O
EGF	B-GENE
-	I-GENE
induced	I-GENE
ERK	I-GENE
MAPK	I-GENE
activities	O
in	O
human	O
glioblastoma	O
cells	O
,	O
although	O
basal	O
ERK	B-GENE
MAPK	I-GENE
activities	O
were	O
unaffected	O
.	O

Using	O
immunolocalization	O
,	O
we	O
observe	O
that	O
ACE3	B-GENE
,	O
a	O
440	O
-	O
bp	O
chorion	O
element	O
that	O
contains	O
information	O
sufficient	O
to	O
drive	O
amplification	O
,	O
directs	O
DmORC	B-GENE
localization	O
in	O
follicle	O
cells	O
.	O

Therefore	O
,	O
homozygous	O
co	O
-	O
deletions	O
of	O
CDKN2A	B-GENE
and	O
CDKN2B	B-GENE
rather	O
than	O
mutations	O
targeting	O
individual	O
transcripts	O
are	O
frequently	O
selected	O
for	O
in	O
these	O
tumors	O
.	O

Here	O
,	O
we	O
show	O
that	O
aortic	O
explants	O
isolated	O
from	O
PPARalpha	B-GENE
-	O
null	O
mice	O
display	O
an	O
exacerbated	O
response	O
to	O
inflammatory	O
stimuli	O
,	O
such	O
as	O
lipopolysaccharide	O
(	O
LPS	O
)	O
,	O
as	O
demonstrated	O
by	O
increased	O
IL	B-GENE
-	I-GENE
6	I-GENE
secretion	O
.	O

Albumin	O
expression	O
is	O
maintained	O
in	O
the	O
liver	O
by	O
a	O
combination	O
of	O
liver	O
-	O
enriched	O
transcription	O
factors	O
such	O
as	O
CAAT	B-GENE
enhancer	I-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
(	I-GENE
C	I-GENE
/	I-GENE
EBP	I-GENE
)	I-GENE
alpha	I-GENE
and	O
C	B-GENE
/	I-GENE
EBPbeta	I-GENE
.	O

The	O
requirement	O
for	O
proteolytic	O
activity	O
of	O
both	O
FVIIa	B-GENE
and	O
FXa	B-GENE
suggests	O
that	O
protease	O
-	O
activated	O
receptors	O
may	O
be	O
involved	O
.	O

Amyloid	B-GENE
beta	I-GENE
-	I-GENE
protein	I-GENE
(	O
Abeta	B-GENE
)	O
is	O
the	O
main	O
constituent	O
of	O
amyloid	O
fibrils	O
found	O
in	O
senile	O
plaques	O
and	O
cerebral	O
vessels	O
in	O
Alzheimer	O
'	O
s	O
disease	O
(	O
AD	O
)	O
and	O
is	O
derived	O
by	O
proteolysis	O
from	O
the	O
beta	B-GENE
-	I-GENE
amyloid	I-GENE
precursor	I-GENE
protein	I-GENE
(	O
APP	B-GENE
)	O
.	O

The	O
importin	B-GENE
alpha	I-GENE
.	I-GENE
beta	I-GENE
heterodimer	I-GENE
mediates	O
nuclear	O
import	O
of	O
proteins	O
containing	O
classical	O
nuclear	O
localization	O
signals	O
.	O

The	O
expressed	O
G1	B-GENE
-	O
G2	B-GENE
bound	O
to	O
both	O
hyaluronan	O
and	O
link	B-GENE
protein	I-GENE
indicating	O
that	O
the	O
immunoglobulin	B-GENE
-	I-GENE
fold	I-GENE
motif	I-GENE
and	O
proteoglycan	O
tandem	O
repeat	O
loops	O
of	O
the	O
G1	B-GENE
domain	I-GENE
were	O
correctly	O
folded	O
.	O

The	O
results	O
suggest	O
that	O
the	O
presence	O
or	O
absence	O
per	O
se	O
of	O
keratan	O
sulfate	O
on	O
native	O
G1	O
-	O
G2	O
does	O
not	O
affect	O
the	O
activity	O
of	O
atrolysin	O
C	O
toward	O
the	O
two	O
sites	O
.	O

Despite	O
i	O
.	O
v	O
.	O
steroid	O
therapy	O
,	O
[	O
NOexh	O
]	O
remained	O
elevated	O
throughout	O
recovery	O
(	O
37	O
.	O
9	O
+	O
/	O
-	O
4	O
.	O
8	O
ppb	O
,	O
p	O
<	O
0	O
.	O
001	O
)	O
until	O
discharge	O
(	O
40	O
.	O
9	O
+	O
/	O
-	O
4	O
.	O
3	O
ppb	O
,	O
p	O
<	O
0	O
.	O
001	O
)	O
.	O

It	O
contains	O
binding	O
sites	O
for	O
several	O
transcription	O
factors	O
,	O
for	O
example	O
:	O
(	O
i	O
)	O
a	O
well	O
-	O
characterized	O
binding	O
site	O
for	O
rel	B-GENE
/	O
NF	B-GENE
-	I-GENE
kappaB	I-GENE
transcription	O
factors	O
in	O
its	O
3	O
'	O
-	O
end	O
(	O
the	O
H2TF1	B-GENE
or	O
kappaB1	B-GENE
element	I-GENE
)	O
,	O
(	O
ii	O
)	O
a	O
second	O
kappaB	B-GENE
site	I-GENE
(	O
the	O
kappaB2	B-GENE
element	I-GENE
)	O
,	O
which	O
is	O
located	O
immediately	O
adjacent	O
5	O
'	O
to	O
the	O
H2TF1	B-GENE
element	I-GENE
and	O
which	O
is	O
recognized	O
by	O
p65	B-GENE
/	O
relA	B-GENE
in	O
the	O
human	B-GENE
HLA	I-GENE
system	O
,	O
and	O
(	O
iii	O
)	O
an	O
AP	B-GENE
-	I-GENE
1	I-GENE
/	O
ATF	B-GENE
recognition	O
sequence	O
in	O
the	O
5	O
'	O
end	O
(	O
EnA	B-GENE
-	I-GENE
TRE	I-GENE
)	O
.	O

The	O
tumorigenic	O
E1A	B-GENE
+	O
cHa	B-GENE
-	I-GENE
ras	I-GENE
cells	O
are	O
characterized	O
by	O
high	O
and	O
constitutive	O
DNA	O
binding	O
activities	O
of	O
AP	B-GENE
-	I-GENE
1	I-GENE
,	O
in	O
contrast	O
to	O
nontransformed	O
cells	O
and	O
the	O
E1A	B-GENE
cells	O
.	O

The	O
yeast	O
C	B-GENE
-	I-GENE
type	I-GENE
cyclin	I-GENE
Ume3p	B-GENE
/	O
Srb11p	B-GENE
and	O
its	O
cyclin	B-GENE
-	I-GENE
dependent	I-GENE
kinase	I-GENE
(	O
Cdk	B-GENE
)	O
Ume5p	B-GENE
are	O
required	O
for	O
the	O
full	O
repression	O
of	O
genes	O
involved	O
in	O
the	O
stress	O
response	O
or	O
meiosis	O
.	O

In	O
particular	O
,	O
the	O
S1	B-GENE
'	I-GENE
specificity	I-GENE
site	I-GENE
is	O
a	O
deep	O
and	O
highly	O
hydrophobic	O
cavity	O
.	O

FZD4	B-GENE
is	O
homologous	O
to	O
FZD9	B-GENE
and	O
FZD10	B-GENE
,	O
and	O
overall	O
amino	O
acid	O
identity	O
is	O
as	O
follows	O
:	O
FZD4	B-GENE
vs	O
FZD9	B-GENE
,	O
51	O
.	O
6	O
%	O
;	O
FZD4	B-GENE
vs	O
FZD10	B-GENE
,	O
51	O
.	O
2	O
%	O
;	O
FZD9	B-GENE
vs	O
FZD10	B-GENE
,	O
65	O
.	O
7	O
%	O
.	O

The	O
NF	B-GENE
-	I-GENE
kappaB	I-GENE
responsive	O
reporter	O
construct	O
,	O
(	B-GENE
PRDII	I-GENE
)	I-GENE
(	I-GENE
4	I-GENE
)	I-GENE
-	O
CAT	B-GENE
,	O
was	O
used	O
to	O
explore	O
transcription	O
resulting	O
from	O
NF	B-GENE
-	I-GENE
kappaB	I-GENE
activated	O
by	O
Tat	B-GENE
.	O

The	O
RNA	O
transcripts	O
structurally	O
equivalent	O
to	O
I	B-GENE
(	I-GENE
2	I-GENE
)	I-GENE
sgRNAs	I-GENE
of	O
TMV	B-GENE
U1	I-GENE
and	O
crTMV	O
,	O
but	O
containing	O
a	O
hairpin	O
structure	O
(	O
H	O
)	O
immediately	O
upstream	O
of	O
IRES	B-GENE
(	I-GENE
MP	I-GENE
,	I-GENE
75	I-GENE
)	I-GENE
(	I-GENE
HIRES	I-GENE
(	I-GENE
MP	I-GENE
)	I-GENE
,	I-GENE
(	I-GENE
75	I-GENE
)	I-GENE
(	I-GENE
CR	I-GENE
)	I-GENE
-	I-GENE
MP	I-GENE
-	I-GENE
CP	I-GENE
-	I-GENE
3	I-GENE
'	I-GENE
UTR	I-GENE
;	O
HIRES	B-GENE
(	I-GENE
MP	I-GENE
,	I-GENE
75	I-GENE
)	I-GENE
(	I-GENE
U1	I-GENE
)	I-GENE
-	I-GENE
MP	I-GENE
-	I-GENE
CP	I-GENE
-	I-GENE
3	I-GENE
'	I-GENE
UTR	I-GENE
)	O
,	O
were	O
able	O
to	O
express	O
the	O
MP	B-GENE
gene	I-GENE
in	O
vitro	O
.	O

EIAV	B-GENE
LTR	I-GENE
sequence	I-GENE
variability	O
is	O
confined	O
mostly	O
to	O
a	O
small	O
portion	O
of	O
the	O
enhancer	O
within	O
the	O
U3	O
segment	O
of	O
the	O
LTR	O
.	O

The	O
core	O
of	O
this	O
enhancer	O
contains	O
two	O
evolutionarily	O
conserved	O
binding	O
sites	O
for	O
the	O
homeodomain	B-GENE
protein	I-GENE
Tinman	B-GENE
(	O
Tin	B-GENE
)	O
,	O
expressed	O
in	O
developing	O
cardiac	O
,	O
somatic	O
,	O
and	O
visceral	O
muscle	O
lineages	O
.	O

Furthermore	O
,	O
the	O
striking	O
ability	O
of	O
polyoma	B-GENE
middle	I-GENE
T	I-GENE
antigens	I-GENE
to	O
promote	O
retinoic	O
acid	O
-	O
induced	O
differentiation	O
appears	O
to	O
utilize	O
ERK	B-GENE
,	O
but	O
not	O
JNK	B-GENE
/	O
SPK	B-GENE
or	O
p38	B-GENE
signaling	O
.	O

All	O
loci	O
have	O
a	O
similar	O
organization	O
,	O
except	O
for	O
H1	B-GENE
.	I-GENE
8	I-GENE
that	O
harbors	O
two	O
TcP2beta	B-GENE
genes	I-GENE
arranged	O
in	O
tandem	O
and	O
separated	O
by	O
a	O
short	O
repetitive	O
sequence	O
,	O
named	O
SIRE	O
(	O
short	O
interspersed	O
repetitive	O
element	O
)	O
,	O
which	O
is	O
also	O
found	O
upstream	O
of	O
the	O
first	O
gene	O
of	O
the	O
tandem	O
and	O
downstream	O
of	O
the	O
second	O
.	O

A	O
proportion	O
of	O
APC	B-GENE
wild	O
-	O
type	O
colon	O
carcinomas	O
and	O
melanomas	O
also	O
contains	O
constitutive	O
nuclear	O
Tcf	B-GENE
-	I-GENE
4	I-GENE
/	O
beta	B-GENE
-	I-GENE
catenin	I-GENE
complexes	O
as	O
a	O
result	O
of	O
dominant	O
mutations	O
in	O
the	O
N	O
terminus	O
of	O
beta	B-GENE
-	I-GENE
catenin	I-GENE
that	O
render	O
it	O
insensitive	O
to	O
downregulation	O
by	O
APC	B-GENE
,	O
GSK3	B-GENE
beta	I-GENE
,	O
and	O
Axin	B-GENE
/	O
Conductin	B-GENE
.	O

Similar	O
mechanisms	O
leading	O
to	O
deregulation	O
of	O
Tcf	B-GENE
target	I-GENE
gene	I-GENE
activity	O
are	O
likely	O
to	O
be	O
involved	O
in	O
melanoma	O
and	O
other	O
forms	O
of	O
cancer	O
.	O

PATIENTS	O
AND	O
METHODS	O
:	O
Immediately	O
before	O
radical	O
prostatectomy	O
,	O
bone	O
marrow	O
aspirates	O
from	O
both	O
sides	O
of	O
the	O
iliac	O
crest	O
were	O
taken	O
from	O
287	O
patients	O
.	O

With	O
regard	O
to	O
nonhematologic	O
toxicities	O
,	O
diarrhea	O
,	O
infection	O
and	O
elevated	O
serum	B-GENE
alkaline	I-GENE
phosphatase	I-GENE
of	O
grade	O
3	O
or	O
over	O
were	O
observed	O
in	O
2	O
%	O
of	O
cycles	O
,	O
but	O
were	O
tolerable	O
and	O
reversible	O
.	O

LHbeta	B-GENE
is	O
expressed	O
in	O
pituitary	O
gonadotrope	O
cells	O
and	O
CGbeta	B-GENE
is	O
expressed	O
in	O
placental	O
trophoblast	O
cells	O
.	O

Regulation	O
of	O
HIV	O
-	O
1	O
transcription	O
.	O

Human	B-GENE
LTBP	I-GENE
-	I-GENE
1	I-GENE
is	O
known	O
to	O
exist	O
in	O
different	O
forms	O
.	O

In	O
an	O
earlier	O
study	O
(	O
Kimura	O
,	O
Y	O
.	O
,	O
Kurzydlowski	O
,	O
K	O
.	O
,	O
Tada	O
,	O
M	O
.	O
,	O
and	O
MacLennan	O
,	O
D	O
.	O

It	O
consists	O
of	O
2185	O
amino	O
acid	O
residues	O
encoded	O
by	O
a	O
9	O
-	O
kilobase	O
pair	O
mRNA	O
;	O
several	O
splice	O
variants	O
have	O
been	O
detected	O
in	O
human	O
and	O
rat	O
cDNA	O
libraries	O
.	O

Cyclic	B-GENE
AMP	I-GENE
-	I-GENE
dependent	I-GENE
protein	I-GENE
kinase	I-GENE
binding	O
to	O
A	B-GENE
-	I-GENE
kinase	I-GENE
anchoring	O
proteins	O
in	O
living	O
cells	O
by	O
fluorescence	O
resonance	O
energy	O
transfer	O
of	O
green	B-GENE
fluorescent	I-GENE
protein	I-GENE
fusion	O
proteins	O
.	O

Factor	B-GENE
XI	I-GENE
deficiency	O
is	O
a	O
rare	O
hereditary	O
bleeding	O
disorder	O
affecting	O
the	O
intrinsic	O
pathway	O
.	O

The	O
Ishasha	O
samples	O
show	O
a	O
range	O
encompassing	O
three	O
trophic	O
levels	O
.	O

The	O
more	O
traditional	O
SERMS	O
,	O
clomiphene	O
citrate	O
and	O
tamoxifen	O
,	O
will	O
be	O
reviewed	O
along	O
with	O
such	O
modern	O
drugs	O
as	O
raloxifene	O
and	O
faslodex	O
,	O
with	O
emphasis	O
upon	O
their	O
actions	O
on	O
breast	O
,	O
uterus	O
,	O
bone	O
and	O
lipids	O
.	O

Ti	O
exhibited	O
a	O
feather	O
-	O
like	O
morphology	O
.	O

This	O
organization	O
suggests	O
that	O
duplication	O
events	O
that	O
have	O
generated	O
the	O
primate	O
FUT3	B-GENE
-	O
FUT5	B-GENE
-	O
FUT6	B-GENE
cluster	O
might	O
have	O
occurred	O
through	O
a	O
long	O
-	O
interspersed	O
-	O
nuclear	O
-	O
element	O
-	O
based	O
mechanism	O
of	O
unequal	O
crossing	O
over	O
,	O
as	O
described	O
for	O
the	O
globin	B-GENE
cluster	I-GENE
.	O

S	O
.	O
,	O
Kim	O
,	O
S	O
.	O

The	O
cop	B-GENE
region	I-GENE
also	O
harbors	O
a	O
region	O
of	O
plasmid	O
incompatibility	O
,	O
inc	B-GENE
,	O
encompassing	O
a	O
stem	O
-	O
loop	O
structure	O
,	O
the	O
repA	B-GENE
promoter	I-GENE
,	O
Prep	B-GENE
,	O
as	O
well	O
as	O
two	O
distinct	O
RepA	B-GENE
binding	I-GENE
sites	I-GENE
,	O
BD	O
-	O
1	O
and	O
BD	O
-	O
2	O
.	O

WA	O
constructs	O
afforded	O
relaxed	O
and	O
positive	O
topoisomers	O
,	O
and	O
cyclization	O
kinetics	O
indicated	O
slow	O
interconversion	O
of	O
precursors	O
to	O
the	O
two	O
topoisomers	O
.	O

The	O
RFX	B-GENE
protein	I-GENE
family	I-GENE
includes	O
members	O
from	O
yeast	O
to	O
humans	O
,	O
which	O
function	O
in	O
various	O
biological	O
systems	O
,	O
and	O
share	O
a	O
DNA	O
-	O
binding	O
domain	O
and	O
a	O
conserved	O
C	O
-	O
terminal	O
region	O
.	O

Binding	O
to	O
sulphatides	O
and	O
the	O
alpha	B-GENE
-	I-GENE
dystroglycan	I-GENE
receptor	I-GENE
was	O
much	O
stronger	O
and	O
required	O
at	O
least	O
two	O
LG	B-GENE
modules	I-GENE
.	O

Here	O
,	O
we	O
propose	O
that	O
an	O
antagonistic	O
,	O
BMP	B-GENE
/	O
ALK2	B-GENE
/	O
Smad	B-GENE
-	O
mediated	O
signaling	O
pathway	O
is	O
active	O
on	O
the	O
right	O
side	O
of	O
the	O
Xenopus	O
embryo	O
.	O

Gentamicin	O
given	O
by	O
DPI	O
and	O
SVN	O
significantly	O
decreased	O
the	O
sputum	O
Psa	O
density	O
(	O
p	O
<	O
0	O
.	O
05	O
)	O
,	O
by	O
almost	O
one	O
order	O
of	O
magnitude	O
.	O

CONCLUSIONS	O
:	O
The	O
largest	O
value	O
of	O
the	O
joint	O
space	O
may	O
be	O
used	O
when	O
evaluating	O
rheumatoid	O
AC	O
joint	O
space	O
.	O

An	O
analysis	O
of	O
sequence	O
of	O
the	O
mutant	B-GENE
recN	I-GENE
gene	I-GENE
revealed	O
a	O
G	O
:	O
C	O
to	O
T	O
:	O
A	O
transversion	O
near	O
the	O
3	O
'	O
end	O
of	O
the	O
coding	O
region	O
.	O

Nevertheless	O
,	O
in	O
view	O
of	O
the	O
potential	O
transmission	O
rates	O
of	O
HGV	O
and	O
the	O
lack	O
of	O
effective	O
immunization	O
,	O
HGV	O
should	O
be	O
regarded	O
as	O
a	O
potential	O
occupational	O
hazard	O
for	O
medical	O
and	O
dental	O
staff	O
.	O

We	O
have	O
previously	O
identified	O
mouse	B-GENE
and	I-GENE
human	I-GENE
cDNAs	I-GENE
encoding	I-GENE
UNC	I-GENE
-	I-GENE
51	I-GENE
-	I-GENE
like	I-GENE
kinase	I-GENE
(	O
ULK1	B-GENE
)	O
.	O

ULKs	B-GENE
and	O
UNC	B-GENE
-	I-GENE
51	I-GENE
share	O
a	O
typical	O
domain	O
structure	O
of	O
an	O
amino	O
-	O
terminal	O
kinase	O
domain	O
,	O
a	O
central	O
proline	O
/	O
serine	O
rich	O
(	O
PS	O
)	O
domain	O
,	O
and	O
a	O
carboxy	O
-	O
terminal	O
(	O
C	O
)	O
domain	O
.	O

These	O
results	O
suggest	O
that	O
ULK2	B-GENE
is	O
involved	O
in	O
a	O
previously	O
uncharacterized	O
signaling	O
pathway	O
in	O
mammalian	O
cells	O
.	O

Connector	B-GENE
enhancer	I-GENE
of	I-GENE
KSR	I-GENE
(	O
CNK	B-GENE
)	O
is	O
a	O
multidomain	O
protein	O
required	O
for	O
RAS	B-GENE
signaling	O
.	O

In	O
simpler	O
organisms	O
,	O
the	O
ATP	B-GENE
sulfurylase	I-GENE
and	O
APS	B-GENE
kinase	I-GENE
reactions	O
are	O
catalyzed	O
by	O
separate	O
enzymes	O
encoded	O
by	O
two	O
or	O
three	O
genes	O
,	O
suggesting	O
that	O
a	O
fusion	O
of	O
separate	O
genes	O
during	O
the	O
course	O
of	O
evolution	O
generated	O
the	O
bifunctional	O
enzyme	O
.	O

Epstein	B-GENE
-	I-GENE
Barr	I-GENE
virus	I-GENE
(	I-GENE
EBV	I-GENE
)	I-GENE
latent	I-GENE
membrane	I-GENE
protein	I-GENE
1	I-GENE
(	O
LMP1	B-GENE
)	O
is	O
essential	O
for	O
EBV	O
-	O
mediated	O
transformation	O
of	O
primary	O
B	O
lymphocytes	O
.	O

The	O
amino	O
-	O
terminal	O
half	O
of	O
1a	B-GENE
is	O
a	O
distant	O
homolog	B-GENE
of	I-GENE
alphavirus	I-GENE
nonstructural	I-GENE
protein	I-GENE
nsP1	I-GENE
,	O
which	O
has	O
been	O
implicated	O
in	O
capping	O
viral	O
RNAs	O
.	O

Moreover	O
,	O
a	O
recombinant	O
Ad	O
expressing	O
Ad5	B-GENE
E4orf6	I-GENE
/	I-GENE
7	I-GENE
induced	O
apoptosis	O
in	O
rat	O
cells	O
when	O
coinfected	O
with	O
wild	O
-	O
type	O
p53	B-GENE
-	O
expressing	O
Ad	O
.	O

CONCLUSION	O
(	O
S	O
)	O
:	O
Measuring	O
urinary	O
LH	B-GENE
levels	O
is	O
an	O
excellent	O
method	O
for	O
determining	O
ovulation	O
.	O

PURPOSE	O
:	O
To	O
evaluate	O
the	O
disease	O
-	O
free	O
survival	O
(	O
DFS	O
)	O
and	O
overall	O
survival	O
(	O
OS	O
)	O
,	O
prognostic	O
factors	O
,	O
and	O
treatment	O
-	O
related	O
mortality	O
of	O
women	O
with	O
stage	O
IIIB	O
inflammatory	O
breast	O
cancer	O
(	O
IBC	O
)	O
treated	O
with	O
combined	O
modality	O
therapy	O
(	O
CMT	O
)	O
and	O
high	O
-	O
dose	O
chemotherapy	O
(	O
HDCT	O
)	O
with	O
autologous	O
stem	O
-	O
cell	O
transplantation	O
.	O

We	O
have	O
cloned	O
a	O
novel	O
100	O
-	O
kDa	O
mammalian	O
protein	O
,	O
which	O
was	O
recognized	O
by	O
an	O
anti	O
-	O
peptide	O
antibody	O
against	O
an	O
epitope	O
-	O
containing	O
nuclear	O
localization	O
signal	O
of	O
NF	B-GENE
-	I-GENE
kappaB	I-GENE
p65	B-GENE
subunit	I-GENE
.	O

Insulin	B-GENE
-	O
regulated	O
events	O
,	O
however	O
,	O
occur	O
in	O
all	O
cells	O
.	O

Regulatory	O
regions	O
in	O
the	O
promoter	O
and	O
third	O
intron	O
of	O
the	O
growth	B-GENE
hormone	I-GENE
gene	I-GENE
in	I-GENE
rainbow	I-GENE
trout	I-GENE
,	O
Oncorhynchus	O
mykiss	O
walbaum	O
.	O

Although	O
most	O
SFV	O
genes	O
have	O
homologs	O
encoded	O
by	O
other	O
Chordopoxvirinae	O
,	O
the	O
SFV	O
genome	O
lacks	O
a	O
key	O
gene	O
required	O
for	O
the	O
production	O
of	O
extracellular	O
enveloped	O
virus	O
.	O

In	O
addition	O
,	O
media	O
containing	O
F	B-GENE
beta	I-GENE
alpha	I-GENE
/	O
CG	B-GENE
beta	I-GENE
displayed	O
high	O
-	O
affinity	O
binding	O
to	O
both	O
CG	B-GENE
and	I-GENE
FSH	I-GENE
receptors	I-GENE
.	O

In	O
contrast	O
,	O
AP	B-GENE
-	I-GENE
2	I-GENE
binding	O
activity	O
was	O
significantly	O
greater	O
in	O
T47D	O
cells	O
,	O
and	O
Western	O
blots	O
confirmed	O
increased	O
AP	B-GENE
-	I-GENE
2	I-GENE
protein	I-GENE
levels	O
in	O
these	O
cells	O
.	O

N	O
.	O
van	O
Hoek	O
,	O
and	O
M	O
.	O

Here	O
,	O
we	O
describe	O
a	O
tyrosine	O
-	O
phosphorylated	O
nuclear	O
protein	O
,	O
YT521	B-GENE
-	I-GENE
B	I-GENE
,	O
and	O
show	O
that	O
it	O
interacts	O
with	O
the	O
nuclear	B-GENE
transcriptosomal	I-GENE
component	I-GENE
scaffold	I-GENE
attachment	I-GENE
factor	I-GENE
B	I-GENE
,	O
and	O
the	O
68	B-GENE
-	I-GENE
kDa	I-GENE
Src	I-GENE
substrate	O
associated	O
during	O
mitosis	O
,	O
Sam68	B-GENE
.	O

These	O
mutants	O
all	O
failed	O
to	O
interact	O
with	O
the	O
TraR	B-GENE
fusion	I-GENE
in	O
the	O
two	O
-	O
hybrid	O
system	O
.	O

PhoP	B-GENE
-	O
PhoQ	B-GENE
homologues	O
in	O
Pseudomonas	O
aeruginosa	O
regulate	O
expression	O
of	O
the	O
outer	B-GENE
-	I-GENE
membrane	I-GENE
protein	I-GENE
OprH	I-GENE
and	O
polymyxin	O
B	O
resistance	O
.	O

Deletion	O
of	O
fdsR	B-GENE
revealed	O
a	O
dual	O
regulatory	O
effect	O
of	O
FdsR	B-GENE
on	O
the	O
fds	B-GENE
operon	I-GENE
by	O
acting	O
as	O
transcriptional	O
activator	O
in	O
the	O
presence	O
of	O
formate	O
or	O
as	O
repressor	O
in	O
the	O
absence	O
of	O
formate	O
.	O

With	O
constructs	O
containing	O
the	O
binding	O
site	O
of	O
one	O
gene	O
fused	O
to	O
the	O
promoter	O
of	O
the	O
other	O
,	O
we	O
demonstrated	O
that	O
the	O
positional	O
requirements	O
are	O
a	O
function	O
of	O
the	O
specific	O
binding	O
site	O
,	O
not	O
the	O
promoter	O
.	O

In	O
addition	O
,	O
all	O
three	O
Opa	B-GENE
proteins	I-GENE
of	O
C751	O
bind	O
equally	O
well	O
to	O
HeLa	O
cells	O
transfected	O
with	O
cDNA	O
encoding	O
the	O
carcinoembryonic	B-GENE
antigen	I-GENE
[	O
CEA	B-GENE
(	O
CD66e	B-GENE
)	O
]	O
subgroup	O
of	O
the	O
CD66	B-GENE
family	I-GENE
,	O
but	O
show	O
distinct	O
tropism	O
for	O
CGM1	B-GENE
-	O
(	O
CD66d	B-GENE
)	O
and	O
NCA	B-GENE
(	O
CD66c	B-GENE
)	O
-	O
expressing	O
cells	O
.	O

The	O
effect	O
of	O
smoking	O
was	O
not	O
examined	O
in	O
this	O
study	O
,	O
as	O
such	O
data	O
were	O
not	O
available	O
.	O

BACKGROUND	O
:	O
Measurement	O
of	O
stereoacuity	O
at	O
varying	O
distances	O
,	O
by	O
real	O
or	O
simulated	O
depth	O
stereoacuity	O
tests	O
,	O
is	O
helpful	O
in	O
the	O
evaluation	O
of	O
patients	O
with	O
binocular	O
imbalance	O
or	O
strabismus	O
.	O

Additional	O
studies	O
revealed	O
that	O
bovine	B-GENE
brain	I-GENE
Galpha	I-GENE
(	I-GENE
q	I-GENE
/	I-GENE
11	I-GENE
)	I-GENE
could	O
also	O
bind	O
to	O
an	O
N	O
-	O
terminal	O
construct	O
of	O
GRK2	B-GENE
,	O
while	O
no	O
binding	O
of	O
Galpha	B-GENE
(	I-GENE
q	I-GENE
/	I-GENE
11	I-GENE
)	I-GENE
,	O
Galpha	B-GENE
(	I-GENE
s	I-GENE
)	I-GENE
,	O
Galpha	B-GENE
(	I-GENE
i	I-GENE
)	I-GENE
,	O
or	O
Galpha	B-GENE
(	I-GENE
12	I-GENE
/	I-GENE
13	I-GENE
)	I-GENE
to	O
comparable	O
constructs	O
of	O
GRK5	B-GENE
or	O
GRK6	B-GENE
was	O
observed	O
.	O

The	O
elm1	B-GENE
kinase	I-GENE
functions	O
in	O
a	O
mitotic	O
signaling	O
network	O
in	O
budding	O
yeast	O
.	O

Reverse	O
transcription	O
(	O
RT	O
)	O
-	O
PCR	O
products	O
were	O
synthesized	O
with	O
two	O
degenerate	O
primers	O
derived	O
from	O
the	O
conserved	O
motifs	O
of	O
various	O
tyrosine	B-GENE
kinases	I-GENE
.	O

In	O
addition	O
,	O
the	O
acetyltransferase	O
activity	O
of	O
p300	B-GENE
was	O
observed	O
to	O
be	O
distinct	O
from	O
the	O
broadly	O
essential	O
activation	O
function	O
of	O
the	O
CH3	B-GENE
domain	I-GENE
/	O
E1A	B-GENE
-	O
binding	O
region	O
.	O

The	O
proliferation	O
-	O
specific	O
HNF	B-GENE
-	I-GENE
3	I-GENE
/	O
fork	B-GENE
head	I-GENE
homolog	I-GENE
-	I-GENE
11B	I-GENE
protein	O
(	O
HFH	B-GENE
-	I-GENE
11B	I-GENE
;	O
also	O
known	O
as	O
Trident	B-GENE
and	O
Win	B-GENE
)	O
is	O
a	O
family	O
member	O
of	O
the	O
winged	B-GENE
helix	I-GENE
/	O
fork	B-GENE
head	I-GENE
transcription	O
factors	O
and	O
in	O
regenerating	O
liver	O
its	O
expression	O
is	O
reactivated	O
prior	O
to	O
hepatocyte	O
entry	O
into	O
DNA	O
replication	O
(	O
S	O
phase	O
)	O
.	O

In	O
the	O
mouse	O
,	O
CtBP1	B-GENE
is	O
expressed	O
from	O
embryo	O
to	O
adult	O
,	O
but	O
CtBP2	B-GENE
is	O
mainly	O
expressed	O
during	O
embryogenesis	O
.	O

The	O
multiple	O
functions	O
of	O
Pmt3p	B-GENE
described	O
here	O
suggest	O
that	O
several	O
nuclear	O
proteins	O
are	O
regulated	O
by	O
Pmt3p	B-GENE
conjugation	O
.	O

The	O
role	O
of	O
transport	O
by	O
sea	O
ice	O
from	O
the	O
Kara	O
Sea	O
into	O
the	O
Arctic	O
Ocean	O
was	O
assessed	O
by	O
a	O
small	O
subgroup	O
at	O
GEOMAR	O
.	O

We	O
determined	O
whether	O
a	O
single	O
injection	O
of	O
slow	O
-	O
release	O
estradiol	O
-	O
17beta	O
(	O
SRE2	O
)	O
would	O
induce	O
pseudopregnancy	O
in	O
gilts	O
and	O
whether	O
PGF2alpha	O
would	O
regress	O
the	O
corpora	O
lutea	O
(	O
CL	O
)	O
of	O
pseudopregnancy	O
.	O

Among	O
the	O
remaining	O
22	O
sites	O
,	O
six	O
are	O
in	O
the	O
promoters	O
of	O
known	O
alpha	O
-	O
specific	O
genes	O
and	O
two	O
other	O
sites	O
have	O
an	O
alpha2	B-GENE
-	O
Mcm1	B-GENE
-	O
dependent	O
role	O
in	O
determining	O
the	O
direction	O
of	O
mating	O
type	O
switching	O
.	O

Activation	O
of	O
T	O
cells	O
via	O
the	O
TCR	B-GENE
and	O
other	O
costimulatory	O
receptors	O
triggers	O
a	O
number	O
of	O
signaling	O
cascades	O
.	O

A	O
phylogenetic	O
analysis	O
with	O
the	O
TK	B-GENE
domains	I-GENE
from	O
these	O
sequences	O
and	O
a	O
fourth	O
,	O
from	O
a	O
novel	O
scavenger	B-GENE
RTK	I-GENE
(	O
all	O
domains	O
comprise	O
the	O
signature	O
for	O
the	O
TK	B-GENE
class	I-GENE
II	I-GENE
receptors	I-GENE
)	O
,	O
showed	O
that	O
they	O
are	O
distantly	O
related	O
to	O
the	O
insulin	B-GENE
and	O
insulin	B-GENE
-	I-GENE
like	I-GENE
receptors	I-GENE
.	O

Results	O
confirmed	O
that	O
stress	O
produced	O
CA3	O
dendritic	O
atrophy	O
and	O
tianeptine	O
prevented	O
it	O
.	O

We	O
have	O
isolated	O
a	O
binding	O
partner	O
for	O
the	O
Fanconi	B-GENE
anemia	I-GENE
group	I-GENE
C	I-GENE
protein	I-GENE
(	O
FANCC	B-GENE
)	O
by	O
yeast	O
two	O
-	O
hybrid	O
screening	O
.	O

These	O
results	O
suggest	O
that	O
both	O
transcription	O
activators	O
depend	O
on	O
or	O
interact	O
with	O
different	O
subunits	O
of	O
RNA	B-GENE
polymerase	I-GENE
,	O
although	O
their	O
role	O
in	O
formation	O
of	O
proper	O
DNA	O
geometry	O
may	O
also	O
be	O
crucial	O
.	O

Klebsiella	O
oxytoca	O
can	O
assimilate	O
nitrate	O
and	O
nitrite	O
by	O
using	O
enzymes	O
encoded	O
by	O
the	O
nasFEDCBA	B-GENE
operon	I-GENE
.	O

Marked	O
hemolysis	O
significantly	O
increased	O
plasma	O
values	O
of	O
potassium	O
,	O
phosphorus	O
,	O
total	O
protein	O
,	O
and	O
aspartate	B-GENE
aminotransferase	I-GENE
.	O

Studies	O
have	O
substantiated	O
the	O
involvement	O
of	O
numerous	O
loci	O
on	O
certain	O
chromosomes	O
;	O
in	O
excess	O
of	O
10	O
chromosomes	O
are	O
thought	O
to	O
be	O
involved	O
.	O

By	O
negatively	O
regulating	O
GRK	B-GENE
-	O
mediated	O
receptor	O
phosphorylation	O
,	O
beta	B-GENE
-	I-GENE
arrestin	I-GENE
-	O
mediated	O
processes	O
such	O
as	O
Src	B-GENE
recruitment	O
and	O
clathrin	B-GENE
-	O
mediated	O
internalization	O
,	O
which	O
are	O
required	O
for	O
GPCR	B-GENE
-	O
mediated	O
ERK	B-GENE
activation	O
,	O
are	O
inhibited	O
,	O
thus	O
dampening	O
further	O
ERK	B-GENE
activation	O
.	O

Based	O
on	O
subcellular	O
fractionation	O
,	O
the	O
47	B-GENE
-	I-GENE
kDa	I-GENE
P	I-GENE
-	I-GENE
CIP2	I-GENE
protein	I-GENE
is	O
mostly	O
cytosolic	O
.	O

Supershift	O
EMSAs	O
identified	O
that	O
upstream	B-GENE
stimulatory	I-GENE
factor	I-GENE
-	I-GENE
1	I-GENE
and	I-GENE
-	I-GENE
2	I-GENE
(	O
USF	B-GENE
-	I-GENE
1	I-GENE
and	I-GENE
-	I-GENE
2	I-GENE
)	O
were	O
part	O
of	O
these	O
complexes	O
.	O

Conversely	O
,	O
E1A	B-GENE
binding	O
to	O
only	O
p300	B-GENE
/	O
CBP	B-GENE
results	O
in	O
an	O
increase	O
in	O
PARP	B-GENE
enzyme	I-GENE
activity	O
and	O
consequently	O
in	O
cell	O
death	O
susceptibility	O
to	O
irradiation	O
,	O
which	O
is	O
effectively	O
counteracted	O
by	O
the	O
PARP	B-GENE
chemical	O
inhibitor	O
3	O
-	O
aminobenzamide	O
.	O

These	O
include	O
the	O
CACCC	O
and	O
CAAT	O
motifs	O
.	O

Skin	O
pH	O
changes	O
associated	O
with	O
iontophoresis	O
.	O

This	O
distinction	O
was	O
based	O
upon	O
whether	O
the	O
diagnosis	O
provided	O
a	O
straightforward	O
range	O
of	O
prognoses	O
or	O
an	O
ambiguous	O
clinical	O
implication	O
.	O

The	O
availability	O
of	O
potent	O
regulatory	O
DNA	O
cassettes	O
harboring	O
the	O
murine	B-GENE
D1A	I-GENE
gene	I-GENE
promoter	I-GENE
could	O
aid	O
testing	O
the	O
neuronal	O
-	O
specific	O
expression	O
of	O
transgenes	O
in	O
vivo	O
.	O

It	O
may	O
be	O
dependent	O
on	O
location	O
of	O
a	O
focus	O
(	O
according	O
to	O
EEG	O
)	O
as	O
well	O
as	O
on	O
the	O
character	O
and	O
manifestation	O
of	O
the	O
accompanying	O
neuropsychologic	O
symptomatology	O
.	O

The	O
results	O
of	O
these	O
studies	O
demonstrate	O
that	O
the	O
rat	O
HDL	O
receptor	O
SR	B-GENE
-	I-GENE
BI	I-GENE
promoter	O
contains	O
two	O
sterol	O
response	O
elements	O
(	O
pSRE	O
and	O
dSRE	O
)	O
through	O
which	O
SREBP	B-GENE
-	I-GENE
1a	I-GENE
can	O
bind	O
and	O
activate	O
transcription	O
of	O
this	O
gene	O
.	O

Of	O
these	O
patients	O
,	O
46	O
,	O
164	O
were	O
placed	O
on	O
a	O
waiting	O
list	O
for	O
transplantation	O
,	O
23	O
,	O
275	O
of	O
whom	O
received	O
a	O
first	O
cadaveric	O
transplant	O
between	O
1991	O
and	O
1997	O
.	O

In	O
electrophoretic	O
mobility	O
shift	O
assay	O
(	O
EMSA	O
)	O
,	O
this	O
GLUT4	B-GENE
repressor	I-GENE
element	I-GENE
(	O
G4RE	B-GENE
)	O
generated	O
specific	O
bands	O
with	O
nuclear	O
extracts	O
from	O
preadipocytes	O
,	O
but	O
not	O
from	O
adipocytes	O
.	O

Syndromes	O
of	O
abnormal	O
fat	O
redistribution	O
and	O
metabolic	O
complications	O
in	O
HIV	O
-	O
infected	O
patients	O
.	O

Cytoprotection	O
with	O
amifostine	O
in	O
radiotherapy	O
or	O
radio	O
-	O
chemotherapy	O
of	O
head	O
and	O
neck	O
tumors	O

Immunohistochemical	O
staining	O
was	O
positive	O
for	O
S	B-GENE
-	I-GENE
100	I-GENE
in	O
all	O
9	O
cases	O
stained	O
,	O
positive	O
for	O
HMB	B-GENE
-	I-GENE
45	I-GENE
in	O
9	O
(	O
90	O
%	O
)	O
of	O
10	O
,	O
and	O
negative	O
for	O
cytokeratin	B-GENE
in	O
all	O
9	O
cases	O
in	O
which	O
myxoid	O
melanoma	O
remained	O
in	O
the	O
block	O
after	O
previous	O
sections	O
.	O

Patients	O
with	O
types	O
I	O
and	O
III	O
MPGN	O
did	O
not	O
differ	O
in	O
age	O
at	O
apparent	O
onset	O
,	O
age	O
at	O
diagnosis	O
,	O
or	O
interval	O
from	O
apparent	O
onset	O
of	O
symptoms	O
to	O
diagnosis	O
(	O
biopsy	O
)	O
.	O

Residual	O
urinary	O
abnormalities	O
were	O
significantly	O
more	O
frequent	O
in	O
patients	O
with	O
type	O
III	O
than	O
type	O
I	O
MPGN	O
.	O

Taken	O
together	O
,	O
differences	O
in	O
signaling	O
and	O
tissue	O
expression	O
suggest	O
that	O
the	O
human	B-GENE
intermediate	I-GENE
PRLr	I-GENE
differs	O
from	O
the	O
long	B-GENE
PRLr	I-GENE
in	O
physiological	O
function	O
.	O

We	O
describe	O
here	O
a	O
Drosophila	B-GENE
melanogaster	I-GENE
FAK	I-GENE
homologue	I-GENE
,	O
DFak56	B-GENE
,	O
which	O
maps	O
to	O
band	O
56D	O
on	O
the	O
right	O
arm	O
of	O
the	O
second	O
chromosome	O
.	O

We	O
show	O
here	O
that	O
the	O
third	O
SH3	B-GENE
domain	I-GENE
binds	O
to	O
Sos	B-GENE
,	O
a	O
guanine	B-GENE
nucleotide	I-GENE
exchange	I-GENE
factor	I-GENE
for	O
Ras	B-GENE
and	O
Rac	B-GENE
,	O
both	O
in	O
vitro	O
and	O
in	O
vivo	O
.	O

Point	O
mutations	O
in	O
the	O
third	O
SH3	B-GENE
domain	I-GENE
abolished	O
the	O
vinexin	B-GENE
-	O
Sos	B-GENE
interaction	O
.	O

In	O
gel	O
mobility	O
shift	O
assays	O
,	O
low	O
binding	O
activity	O
of	O
CBF	B-GENE
to	O
the	O
wild	B-GENE
-	I-GENE
type	I-GENE
AtpC	I-GENE
promoter	I-GENE
sequence	I-GENE
was	O
observed	O
with	O
nuclear	O
extracts	O
from	O
tissue	O
with	O
low	O
AtpC	B-GENE
expression	O
levels	O
,	O
i	O
.	O
e	O
.	O
extracts	O
from	O
etiolated	O
and	O
photobleached	O
seedlings	O
,	O
whereas	O
high	O
binding	O
activity	O
was	O
detectable	O
with	O
extracts	O
from	O
tissues	O
with	O
high	O
AtpC	B-GENE
expression	O
levels	O
,	O
i	O
.	O
e	O
.	O
extracts	O
from	O
light	O
-	O
grown	O
seedlings	O
and	O
etiolated	O
seedlings	O
treated	O
with	O
cytokinin	B-GENE
.	O

They	O
are	O
subdivided	O
into	O
two	O
types	O
that	O
activate	O
transduction	O
pathways	O
via	O
different	O
cell	O
surface	O
receptors	O
.	O

We	O
report	O
here	O
that	O
out	O
of	O
the	O
major	O
pro	O
-	O
inflammatory	O
cytokines	O
examined	O
,	O
IL	B-GENE
-	I-GENE
1alpha	I-GENE
,	O
IL	B-GENE
-	I-GENE
1beta	I-GENE
,	O
TNF	B-GENE
-	I-GENE
alpha	I-GENE
and	O
IL	B-GENE
-	I-GENE
6	I-GENE
,	O
only	O
IL	B-GENE
-	I-GENE
6	I-GENE
was	O
generated	O
and	O
secreted	O
in	O
PKCeta	B-GENE
-	O
expressing	O
cells	O
without	O
any	O
additional	O
inducer	O
in	O
serum	O
-	O
supplemented	O
cultures	O
(	O
10	O
%	O
FCS	O
)	O
.	O

Demyelinating	O
diseases	O
involving	O
the	O
grey	O
matter	O
were	O
very	O
rare	O
,	O
but	O
we	O
must	O
consider	O
the	O
presence	O
of	O
symmetrical	O
thalamic	O
involvement	O
in	O
patients	O
with	O
ADEM	O
.	O

To	O
define	O
the	O
minimal	O
VDRE	O
binding	O
domain	O
for	O
human	B-GENE
VDR	I-GENE
(	O
hVDR	B-GENE
)	O
,	O
a	O
series	O
of	O
C	O
-	O
terminally	O
truncated	O
hVDR	B-GENE
mutants	I-GENE
(	O
Delta134	O
,	O
Delta113	O
,	O
Delta102	O
,	O
Delta90	O
,	O
Delta84	O
,	O
Delta80	O
,	O
and	O
Delta60	O
)	O
was	O
generated	O
and	O
expressed	O
in	O
bacteria	O
.	O

These	O
REPs	O
,	O
or	O
clusters	O
of	O
paralogous	O
loci	O
,	O
are	O
15	O
-	O
100	O
kb	O
and	O
harbor	O
at	O
least	O
four	O
ESTs	O
and	O
an	O
expressed	O
SH3GL	B-GENE
pseudogene	I-GENE
.	O

In	O
part	O
as	O
a	O
result	O
of	O
its	O
inability	O
to	O
sustain	O
radiative	O
loses	O
,	O
the	O
BB	O
resonator	O
has	O
extremely	O
low	O
RF	O
power	O
requirements	O
.	O

In	O
addition	O
,	O
narZ	B-GENE
expression	O
was	O
induced	O
approximately	O
20	O
-	O
fold	O
intracellularly	O
in	O
Madin	O
-	O
Darby	O
canine	O
kidney	O
epithelial	O
cells	O
and	O
16	O
-	O
fold	O
in	O
intracellular	O
salts	O
medium	O
,	O
which	O
is	O
believed	O
to	O
mimic	O
the	O
intracellular	O
milieu	O
.	O

However	O
,	O
mechanisms	O
underlying	O
HIV	O
-	O
1	O
gene	O
expression	O
in	O
the	O
CNS	O
are	O
poorly	O
understood	O
.	O

Is	O
radical	O
trachelectomy	O
a	O
safe	O
alternative	O
to	O
radical	O
hysterectomy	O
for	O
patients	O
with	O
stage	O
IA	O
-	O
B	O
carcinoma	O
of	O
the	O
cervix	O
?	O
BACKGROUND	O
:	O
The	O
prognosis	O
associated	O
with	O
lymph	O
node	O
negative	O
,	O
early	O
stage	O
carcinoma	O
of	O
the	O
cervix	O
is	O
excellent	O
,	O
with	O
5	O
-	O
year	O
survival	O
rates	O
greater	O
than	O
90	O
%	O
.	O

A	O
key	O
event	O
in	O
this	O
process	O
is	O
the	O
selective	O
recognition	O
of	O
the	O
target	O
membrane	O
by	O
the	O
vesicle	O
and	O
the	O
current	O
view	O
is	O
that	O
SNARE	B-GENE
protein	I-GENE
interactions	O
likely	O
play	O
a	O
central	O
role	O
in	O
vesicle	O
-	O
target	O
recognition	O
and	O
or	O
membrane	O
fusion	O
.	O

Scapulae	O
with	O
a	O
Type	O
I	O
configuration	O
were	O
found	O
to	O
have	O
low	O
values	O
for	O
the	O
coraco	O
-	O
glenoid	O
angle	O
and	O
coracoid	O
overlap	O
,	O
which	O
are	O
known	O
to	O
be	O
associated	O
with	O
a	O
short	O
coraco	O
-	O
humeral	O
distance	O
.	O

Measurements	O
in	O
the	O
LWS	O
p	O
.	O
a	O
.	O
,	O
LWS	O
lat	O
.	O
and	O
at	O
Ward	O
'	O
s	O
triangle	O
were	O
made	O
in	O
a	O
total	O
of	O
100	O
patients	O
.	O

A	O
group	O
of	O
66	O
DSM	O
-	O
IV	O
paranoid	O
schizophrenic	O
in	O
-	O
patients	O
were	O
assessed	O
three	O
times	O
using	O
the	O
SAPS	O
,	O
SANS	O
,	O
BPRS	O
and	O
PAS	O
.	O

Despite	O
the	O
high	O
frequency	O
of	O
natural	O
infection	O
,	O
the	O
seropositive	O
rates	O
of	O
JEV	O
antibody	O
still	O
correlated	O
well	O
with	O
the	O
dose	O
of	O
vaccine	O
received	O
,	O
i	O
.	O
e	O
.	O
,	O
67	O
%	O
(	O
1122	O
/	O
1664	O
)	O
,	O
66	O
%	O
(	O
65	O
/	O
97	O
)	O
,	O
33	O
%	O
(	O
4	O
/	O
12	O
)	O
and	O
40	O
%	O
(	O
19	O
/	O
47	O
)	O
for	O
children	O
receiving	O
3	O
,	O
2	O
,	O
1	O
,	O
and	O
0	O
dose	O
of	O
JE	O
vaccines	O
,	O
respectively	O
(	O
P	O
<	O
0	O
.	O
0001	O
Chi	O
-	O
square	O
for	O
trend	O
test	O
)	O
.	O

Furthermore	O
,	O
in	O
vivo	O
and	O
in	O
vitro	O
protein	O
-	O
protein	O
interaction	O
experiments	O
have	O
shown	O
that	O
SR33	B-GENE
protein	I-GENE
interacts	O
with	O
itself	O
and	O
with	O
SR45	B-GENE
protein	I-GENE
but	O
not	O
with	O
two	O
other	O
members	O
(	O
SRZ21	B-GENE
and	O
SRZ22	B-GENE
)	O
of	O
the	O
SR	B-GENE
family	I-GENE
that	O
are	O
known	O
to	O
interact	O
with	O
the	O
Arabidopsis	O
full	O
-	O
length	O
U	B-GENE
-	I-GENE
70K	I-GENE
only	O
.	O

In	O
summary	O
,	O
WT1	B-GENE
is	O
enriched	O
by	O
oligo	O
(	O
dT	O
)	O
chromatography	O
,	O
as	O
are	O
U2AF65	B-GENE
,	O
the	O
U5	B-GENE
small	I-GENE
nuclear	I-GENE
RNP	I-GENE
-	I-GENE
associated	I-GENE
protein	I-GENE
p116	B-GENE
and	O
hnRNP	O
A1	B-GENE
.	O

Six	O
out	O
of	O
ten	O
hearts	O
from	O
macerated	O
stillborn	O
infants	O
showed	O
varying	O
degrees	O
of	O
positive	O
staining	O
.	O

Tih1	B-GENE
maps	O
to	O
distal	O
mouse	O
Chr	O
1	O
and	O
human	O
Chr	O
1q31	O
,	O
chromosomal	O
regions	O
that	O
have	O
not	O
shown	O
evidence	O
for	O
imprinting	O
and	O
,	O
in	O
contrast	O
to	O
Ipl	B-GENE
,	O
Tih1	B-GENE
is	O
expressed	O
equally	O
from	O
both	O
parental	O
alleles	O
.	O

A	O
novel	O
pleckstrin	B-GENE
homology	I-GENE
-	I-GENE
related	I-GENE
gene	I-GENE
family	I-GENE
defined	O
by	O
Ipl	B-GENE
/	O
Tssc3	B-GENE
,	O
TDAG51	B-GENE
,	O
and	O
Tih1	B-GENE
:	O
tissue	O
-	O
specific	O
expression	O
,	O
chromosomal	O
location	O
,	O
and	O
parental	O
imprinting	O
.	O

The	O
potential	O
for	O
highly	O
reactive	O
nanoparticles	O
(	O
RNP	O
)	O
to	O
absorb	O
destructively	O
,	O
i	O
.	O
e	O
.	O
to	O
neutralize	O
highly	O
toxic	O
substances	O
such	O
as	O
the	O
warfare	O
agents	O
GA	O
,	O
GB	O
,	O
HD	O
and	O
VX	O
,	O
has	O
been	O
demonstrated	O
in	O
the	O
laboratory	O
.	O

There	O
were	O
minimal	O
negative	O
effects	O
on	O
hematological	O
parameters	O
,	O
acid	O
-	O
base	O
status	O
,	O
and	O
blood	O
gases	O
.	O

Twelve	O
out	O
of	O
43	O
renal	O
failure	O
patients	O
had	O
troponin	B-GENE
I	I-GENE
0	O
.	O
13	O
-	O
0	O
.	O
9	O
microg	O
/	O
l	O
using	O
Axsym	O
method	O
and	O
4	O
had	O
levels	O
of	O
0	O
.	O
07	O
-	O
0	O
.	O
13	O
microg	O
/	O
l	O
using	O
Immuno	O
1	O
.	O

Therefore	O
,	O
we	O
propose	O
that	O
p27	B-GENE
represents	O
a	O
crucial	O
molecule	O
in	O
HMBA	O
signaling	O
that	O
cannot	O
be	O
replaced	O
by	O
p21	B-GENE
.	O

Transient	O
,	O
high	O
-	O
level	O
Ras	B-GENE
-	O
expression	O
induces	O
transcriptional	O
activation	O
of	O
p21	B-GENE
mediated	O
by	O
a	O
GC	O
-	O
rich	O
region	O
in	O
p21	B-GENE
promoter	I-GENE
-	O
83	O
-	O
54	O
bp	O
relative	O
to	O
the	O
transcription	O
initiation	O
site	O
containing	O
binding	O
sites	O
for	O
Sp1	B-GENE
-	I-GENE
family	I-GENE
transcription	I-GENE
factors	I-GENE
.	O

The	O
RET	B-GENE
/	O
PTC3	B-GENE
rearrangement	O
is	O
formed	O
by	O
fusion	O
of	O
the	O
ELE1	B-GENE
and	O
RET	B-GENE
genes	I-GENE
,	O
and	O
is	O
highly	O
prevalent	O
in	O
radiation	O
-	O
induced	O
post	O
-	O
Chernobyl	O
papillary	O
thyroid	O
carcinomas	O
.	O

Apoptosis	O
of	O
small	O
cells	O
is	O
still	O
observed	O
after	O
co	O
-	O
transfection	O
of	O
JBD	B-GENE
and	O
LMP1	B-GENE
but	O
in	O
addition	O
a	O
few	O
apoptotic	O
HD	O
-	O
MyZ	O
cells	O
with	O
large	O
fused	O
nuclear	O
masses	O
are	O
identified	O
suggesting	O
that	O
specific	O
inhibition	O
of	O
JNK	B-GENE
leads	O
also	O
to	O
apoptosis	O
of	O
LMP1	B-GENE
induced	O
RS	O
cells	O
.	O

In	O
addition	O
to	O
the	O
bZIP	B-GENE
protein	I-GENE
Opaque2	I-GENE
(	O
O2	B-GENE
)	O
,	O
there	O
are	O
other	O
maize	O
endosperm	O
nuclear	O
proteins	O
that	O
recognize	O
the	O
O2	B-GENE
box	I-GENE
in	O
22	O
kDa	O
zein	B-GENE
gene	O
promoters	O
.	O

The	O
mEmBP	B-GENE
-	I-GENE
1	I-GENE
protein	I-GENE
can	O
activate	O
transcription	O
from	O
a	O
truncated	O
promoter	O
containing	O
a	O
pentamer	O
of	O
the	O
O2	B-GENE
site	I-GENE
in	O
yeast	O
cells	O
;	O
however	O
,	O
it	O
inhibited	O
regulated	O
transcription	O
of	O
a	O
22	B-GENE
kDa	I-GENE
zein	I-GENE
promoter	I-GENE
in	O
a	O
transient	O
expression	O
assay	O
using	O
cultured	O
maize	O
endosperm	O
cells	O
.	O

GHB	O
,	O
2	O
CB	O
,	O
HMB	O
,	O
are	O
some	O
of	O
these	O
recent	O
substances	O
.	O

There	O
were	O
15	O
deaths	O
,	O
seven	O
of	O
which	O
were	O
felt	O
to	O
be	O
avoidable	O
.	O

With	O
this	O
GH	B-GENE
and	O
estrogen	O
treatment	O
regimen	O
,	O
most	O
girls	O
with	O
TS	O
can	O
grow	O
and	O
develop	O
much	O
more	O
in	O
conformity	O
with	O
their	O
healthy	O
peers	O
.	O

We	O
propose	O
that	O
the	O
reduced	O
responsiveness	O
of	O
CYP3A2	B-GENE
is	O
the	O
result	O
of	O
preferential	O
binding	O
of	O
COUP	B-GENE
-	I-GENE
TF	I-GENE
at	O
the	O
CYP3A2	B-GENE
DexRE	I-GENE
-	I-GENE
1	I-GENE
site	I-GENE
.	O

Higher	O
CYP3A23	B-GENE
basal	O
activity	O
appears	O
to	O
be	O
due	O
to	O
an	O
E	O
-	O
box	O
in	O
3A23SiteA	B-GENE
that	O
interacts	O
with	O
USF1	B-GENE
,	O
a	O
ubiquitous	O
bHLH	B-GENE
/	I-GENE
leucine	I-GENE
zipper	I-GENE
transcription	I-GENE
factor	I-GENE
.	O

The	O
first	O
one	O
is	O
a	O
TPA	O
-	O
responsive	O
element	O
that	O
controls	O
the	O
base	O
-	O
line	O
ST3	B-GENE
promoter	I-GENE
activity	O
but	O
is	O
not	O
required	O
for	O
its	O
activation	O
.	O

To	O
understand	O
the	O
basis	O
for	O
the	O
increased	O
cell	O
surface	O
stability	O
compared	O
with	O
wild	O
-	O
type	O
peptide	O
and	O
to	O
understand	O
the	O
differences	O
in	O
T	O
cell	O
recognition	O
between	O
I1Y	B-GENE
and	O
I1F	B-GENE
,	O
we	O
determined	O
the	O
x	O
-	O
ray	O
crystal	O
structures	O
of	O
the	O
two	O
class	B-GENE
I	I-GENE
MHC	I-GENE
-	I-GENE
peptide	I-GENE
complexes	I-GENE
.	O

Redistribution	O
of	O
mannosidase	B-GENE
I	I-GENE
was	O
also	O
observed	O
in	O
cells	O
incubated	O
at	O
15	O
degrees	O
C	O
.	O

In	O
addition	O
,	O
using	O
biochemical	O
activity	O
assays	O
for	O
Rho	B-GENE
-	O
like	O
GTPases	B-GENE
,	O
we	O
show	O
that	O
the	O
expression	O
of	O
beta1A	B-GENE
,	O
beta1D	B-GENE
,	O
or	O
IL2R	B-GENE
-	O
beta1A	B-GENE
in	O
GE11	O
or	O
GD25	O
cells	O
triggers	O
activation	O
of	O
both	O
RhoA	B-GENE
and	O
Rac1	B-GENE
,	O
but	O
not	O
of	O
Cdc42	B-GENE
.	O

In	O
conclusion	O
,	O
our	O
data	O
do	O
not	O
support	O
a	O
role	O
for	O
IVIg	B-GENE
in	O
the	O
remyelination	O
of	O
stable	O
multiple	O
sclerosis	O
lesions	O
as	O
measured	O
by	O
central	O
conduction	O
time	O
.	O

The	O
rhabdomyosarcoma	O
R1H	O
growing	O
on	O
the	O
right	O
flank	O
of	O
male	O
WAG	O
/	O
Rij	O
rats	O
was	O
clamped	O
for	O
2	O
or	O
4	O
h	O
at	O
20	O
degrees	O
C	O
or	O
37	O
degrees	O
C	O
.	O

Relative	O
to	O
coherent	O
control	O
words	O
(	O
e	O
.	O
g	O
.	O
,	O
quick	O
)	O
,	O
these	O
discourse	O
-	O
dependent	O
semantic	O
anomalies	O
elicited	O
a	O
large	O
N400	O
effect	O
that	O
began	O
at	O
about	O
200	O
to	O
250	O
msec	O
after	O
word	O
onset	O
.	O

These	O
synergistic	O
effects	O
were	O
strongly	O
Jem	B-GENE
-	I-GENE
1	I-GENE
dose	O
-	O
dependent	O
.	O

Like	O
the	O
Tob	B-GENE
protein	I-GENE
,	O
Tob2	B-GENE
inhibited	O
cell	O
cycle	O
progression	O
from	O
the	O
G0	O
/	O
G1	O
to	O
S	O
phases	O
.	O

The	O
coordinate	O
increase	O
in	O
cyclin	B-GENE
D1	I-GENE
and	O
p21	B-GENE
had	O
the	O
effect	O
of	O
decreasing	O
the	O
specific	O
but	O
not	O
absolute	O
activity	O
of	O
cyclin	B-GENE
D1	I-GENE
/	O
cdk4	B-GENE
.	O
p53	B-GENE
was	O
not	O
involved	O
since	O
CSF	B-GENE
-	I-GENE
1	I-GENE
induction	O
of	O
p21	B-GENE
was	O
unaffected	O
by	O
dominant	B-GENE
-	I-GENE
negative	I-GENE
p53	I-GENE
expression	O
.	O

In	O
addition	O
,	O
SLK	B-GENE
displays	O
high	O
homology	O
to	O
microtubule	B-GENE
and	I-GENE
nuclear	I-GENE
associated	I-GENE
protein	I-GENE
(	O
M	B-GENE
-	I-GENE
NAP	I-GENE
)	O
and	O
AT1	B-GENE
-	I-GENE
46	I-GENE
,	O
both	O
of	O
unknown	O
function	O
.	O

In	O
this	O
study	O
26	O
patients	O
(	O
20	O
females	O
and	O
6	O
males	O
)	O
were	O
evaluated	O
.	O

The	O
signalling	O
molecules	O
Wnt1	B-GENE
and	O
Sonic	B-GENE
hedgehog	I-GENE
,	O
implicated	O
in	O
the	O
activation	O
of	O
Myf5	B-GENE
in	O
myogenic	O
progenitor	O
cells	O
in	O
the	O
somite	O
,	O
are	O
also	O
produced	O
in	O
the	O
viscinity	O
of	O
the	O
Myf5	B-GENE
expression	I-GENE
domain	I-GENE
in	O
the	O
mesencephalon	O
.	O

STUDY	O
DESIGN	O
AND	O
METHODS	O
:	O
A	O
study	O
was	O
initiated	O
to	O
compare	O
the	O
collection	O
of	O
PBPCs	O
with	O
the	O
new	O
device	O
,	O
the	O
AutoPBSC	O
(	O
version	O
[	O
V	O
]	O
6	O
.	O
0	O
with	O
AutoPBSC	O
tubing	O
set	O
)	O
,	O
and	O
that	O
with	O
the	O
MNC	O
(	O
mononuclear	O
cell	O
)	O
procedure	O
(	O
V4	O
.	O
7	O
with	O
white	O
cell	O
tubing	O
set	O
)	O
,	O
for	O
patients	O
and	O
healthy	O
donors	O
.	O

Albumin	B-GENE
dialysis	O
:	O
effective	O
removal	O
of	O
copper	O
in	O
a	O
patient	O
with	O
fulminant	O
Wilson	O
disease	O
and	O
successful	O
bridging	O
to	O
liver	O
transplantation	O
:	O
a	O
new	O
possibility	O
for	O
the	O
elimination	O
of	O
protein	O
-	O
bound	O
toxins	O
.	O

Some	O
artificial	O
promoter	O
constructs	O
containing	O
multiple	O
Sp1	B-GENE
sites	I-GENE
were	O
highly	O
responsive	O
to	O
ethanol	O
,	O
but	O
others	O
were	O
not	O
,	O
suggesting	O
that	O
the	O
organization	O
of	O
the	O
proximal	O
promoter	O
region	O
was	O
an	O
additional	O
factor	O
that	O
affected	O
the	O
ethanol	O
response	O
.	O

Overexpression	O
of	O
CDP	B-GENE
/	O
cut	B-GENE
in	O
ROS	O
17	O
/	O
2	O
.	O
8	O
osteosarcoma	O
cells	O
results	O
in	O
repression	O
of	O
OC	B-GENE
promoter	I-GENE
activity	O
;	O
this	O
repression	O
is	O
abrogated	O
by	O
mutating	O
OC	B-GENE
box	I-GENE
I	I-GENE
.	O

Injection	O
of	O
double	O
-	O
stranded	O
RNA	O
into	O
C	O
.	O
elegans	O
results	O
in	O
embryonic	O
lethality	O
;	O
thus	O
,	O
the	O
SF1	B-GENE
gene	I-GENE
is	O
essential	O
not	O
only	O
in	O
yeast	O
but	O
also	O
in	O
at	O
least	O
one	O
metazoan	O
.	O

Both	O
domains	O
were	O
required	O
for	O
specific	O
DNA	O
binding	O
to	O
the	O
beta	B-GENE
-	I-GENE
retinoic	I-GENE
acid	I-GENE
receptor	I-GENE
element	I-GENE
,	O
producing	O
a	O
DNase	B-GENE
I	I-GENE
footprint	O
covering	O
predominantly	O
one	O
strand	O
.	O

Snail	B-GENE
family	I-GENE
proteins	I-GENE
are	O
zinc	O
finger	O
transcriptional	O
regulators	O
first	O
identified	O
in	O
Drosophila	O
which	O
play	O
critical	O
roles	O
in	O
cell	O
fate	O
determination	O
.	O

Consistent	O
with	O
this	O
finding	O
,	O
beta	B-GENE
-	I-GENE
catenin	I-GENE
interacted	O
directly	O
with	O
the	O
RA	B-GENE
receptor	I-GENE
(	O
RAR	B-GENE
)	O
in	O
a	O
retinoid	O
-	O
dependent	O
manner	O
,	O
but	O
not	O
with	O
the	O
retinoid	B-GENE
X	I-GENE
receptor	I-GENE
(	O
RXR	B-GENE
)	O
,	O
and	O
RAR	B-GENE
competed	O
with	O
TCF	B-GENE
for	O
beta	B-GENE
-	I-GENE
catenin	I-GENE
binding	O
.	O

Thrombolysis	O
was	O
followed	O
by	O
a	O
similar	O
increase	O
of	O
platelet	O
activity	O
with	O
maximal	O
values	O
reached	O
at	O
the	O
3rd	O
hour	O
in	O
both	O
groups	O
(	O
196	O
+	O
/	O
-	O
43	O
IU	O
/	O
ml	O
in	O
Group	O
1	O
and	O
192	O
+	O
/	O
-	O
39	O
in	O
Group	O
2	O
:	O
p	O
&	O
lt	O
;	O
001versus	O
baseline	O
and	O
p	O
NS	O
between	O
the	O
groups	O
)	O
.	O

Similar	O
to	O
Hp140	B-GENE
,	O
isolated	O
Hp55	B-GENE
binds	O
DNA	O
with	O
moderate	O
strength	O
and	O
was	O
a	O
specificity	O
for	O
double	O
-	O
stranded	O
primer	O
-	O
template	O
DNA	O
.	O

Finally	O
,	O
three	O
new	O
missense	O
mutations	O
,	O
E138V	O
,	O
R254G	O
,	O
and	O
P362R	O
,	O
were	O
identified	O
in	O
the	O
human	B-GENE
AC	I-GENE
gene	I-GENE
from	O
FD	O
patients	O
.	O

These	O
data	O
indicate	O
that	O
the	O
interaction	O
of	O
eIF4A	B-GENE
with	O
the	O
middle	O
region	O
of	O
eIF4GI	B-GENE
is	O
necessary	O
for	O
translation	O
,	O
whereas	O
the	O
interaction	O
of	O
eIF4A	B-GENE
with	O
the	O
C	O
-	O
terminal	O
region	O
plays	O
a	O
modulatory	O
role	O
.	O

The	O
DAP5	B-GENE
/	O
p86	B-GENE
apoptotic	O
form	O
was	O
more	O
potent	O
than	O
DAP5	B-GENE
/	O
p97	B-GENE
in	O
these	O
functional	O
assays	O
.	O

12	O
:	O
2684	O
-	O
2697	O
,	O
1998	O
)	O
:	O
a	O
key	O
step	O
of	O
this	O
model	O
is	O
the	O
activation	O
of	O
the	O
MAPK	B-GENE
Fus3p	I-GENE
through	O
the	O
G	B-GENE
(	I-GENE
betagamma	I-GENE
)	I-GENE
-	O
dependent	O
relocalization	O
of	O
the	O
Ste5p	B-GENE
-	O
MAPK	B-GENE
cascade	O
to	O
the	O
plasma	O
membrane	O
.	O

Consistent	O
with	O
this	O
finding	O
,	O
wild	B-GENE
-	I-GENE
type	I-GENE
SAGA	I-GENE
inhibits	O
TBP	B-GENE
binding	O
to	O
the	O
HIS3	B-GENE
promoter	I-GENE
in	O
vitro	O
,	O
while	O
SAGA	B-GENE
lacking	O
Spt3	B-GENE
or	O
Spt8	B-GENE
is	O
not	O
inhibitory	O
.	O

Saccharomyces	O
cerevisiae	O
contains	O
a	O
genetically	O
and	O
biochemically	O
proven	O
CAK	B-GENE
gene	I-GENE
,	O
CAK1	B-GENE
,	O
that	O
encodes	O
a	O
monomeric	O
44	B-GENE
-	I-GENE
kDa	I-GENE
Cak1p	I-GENE
protein	I-GENE
unrelated	O
to	O
Cdk7	B-GENE
.	O

Northern	O
blot	O
and	O
reverse	O
transcription	O
-	O
PCR	O
analyses	O
of	O
human	O
mRNA	O
samples	O
demonstrate	O
that	O
RNR	B-GENE
is	O
expressed	O
exclusively	O
in	O
the	O
retina	O
,	O
with	O
transcripts	O
of	O
approximately	O
7	O
.	O
5	O
kb	O
,	O
approximately	O
3	O
.	O
0	O
kb	O
,	O
and	O
approximately	O
2	O
.	O
3	O
kb	O
by	O
Northern	O
blot	O
analysis	O
.	O

Particularly	O
striking	O
was	O
the	O
conservation	O
of	O
an	O
AP	B-GENE
-	I-GENE
4	I-GENE
binding	I-GENE
site	I-GENE
within	O
100	O
nucleotides	O
upstream	O
of	O
the	O
transcription	O
initiation	O
site	O
in	O
both	O
Aal	B-GENE
-	O
rpL34	B-GENE
and	O
Aal	B-GENE
-	O
rpL8	B-GENE
genes	O
.	O

CONCLUSIONS	O
:	O
Serum	O
levels	O
of	O
S	B-GENE
-	I-GENE
100beta	I-GENE
are	O
reliable	O
markers	O
for	O
adverse	O
neurologic	O
outcomes	O
after	O
cardiac	O
surgery	O
.	O

All	O
problems	O
were	O
associated	O
with	O
fractured	O
or	O
lost	O
screws	O
.	O

The	O
accumulated	O
products	O
of	O
ancient	O
duplication	O
events	O
can	O
be	O
readily	O
observed	O
among	O
the	O
genes	O
encoding	O
voltage	O
-	O
dependent	O
Ca	O
(	O
2	O
+	O
)	O
ion	O
channels	O
.	O

The	O
VirR	B-GENE
response	I-GENE
regulator	I-GENE
from	O
Clostridium	O
perfringens	O
binds	O
independently	O
to	O
two	O
imperfect	O
direct	O
repeats	O
located	O
upstream	O
of	O
the	O
pfoA	B-GENE
promoter	I-GENE
.	O

Cloning	O
and	O
sequencing	O
of	O
the	O
upstream	O
region	O
of	O
pepX	B-GENE
revealed	O
the	O
presence	O
of	O
two	O
ORFs	O
of	O
360	O
and	O
1	O
,	O
338	O
bp	O
that	O
were	O
shown	O
to	O
be	O
able	O
to	O
encode	O
proteins	O
with	O
high	O
homology	O
to	O
GlnR	B-GENE
and	O
GlnA	B-GENE
proteins	I-GENE
,	O
respectively	O
.	O

Objective	O
:	O
To	O
evaluate	O
endometrial	O
thickness	O
and	O
the	O
incidence	O
of	O
uterine	O
bleeding	O
in	O
postmenopausal	O
women	O
using	O
either	O
tibolone	O
2	O
.	O
5	O
mg	O
or	O
continuous	O
combined	O
2	O
mg	O
estradiol	O
and	O
1	O
mg	O
norethisterone	O
acetate	O
(	O
E	O
+	O
NETA	O
)	O
daily	O
as	O
hormone	O
replacement	O
therapy	O
.	O

Histological	O
analysis	O
showed	O
that	O
the	O
neuronal	O
loss	O
in	O
the	O
DHED	O
-	O
treated	O
group	O
was	O
notably	O
reduced	O
in	O
the	O
hippocampal	O
area	O
(	O
CA1	O
)	O
of	O
ischemic	O
rats	O
and	O
in	O
the	O
dentate	O
gyrus	O
and	O
hippocampal	O
area	O
(	O
CA1	O
and	O
CA3	O
)	O
of	O
EC	O
-	O
lesioned	O
rats	O
compared	O
with	O
the	O
nontreated	O
group	O
.	O

The	O
extents	O
of	O
phosphorylation	O
of	O
Ser44	O
and	O
Ser64	O
were	O
1	O
:	O
1	O
,	O
whereas	O
those	O
of	O
the	O
four	O
minor	O
sites	O
all	O
together	O
were	O
<	O
30	O
%	O
of	O
the	O
major	O
one	O
.	O

Serum	O
HBV	O
-	O
DNA	O
,	O
viral	O
serology	O
,	O
and	O
liver	O
enzymes	O
were	O
measured	O
sequentially	O
;	O
liver	O
histology	O
was	O
taken	O
before	O
and	O
during	O
treatment	O
in	O
12	O
patients	O
.	O

Chem	O
.	O

Maximum	O
induction	O
of	O
AP	B-GENE
-	I-GENE
1	I-GENE
was	O
reached	O
at	O
a	O
concentration	O
of	O
250	O
nmol	O
/	O
L	O
of	O
CalC	O
.	O

Rams	O
were	O
weighed	O
and	O
testis	O
size	O
was	O
estimated	O
by	O
orchimetry	O
at	O
each	O
time	O
period	O
.	O

Animal	O
studies	O
showed	O
that	O
beam	O
equalization	O
significantly	O
improved	O
fluoroscopic	O
and	O
angiographic	O
image	O
quality	O
.	O

Role	O
of	O
estrogen	B-GENE
receptor	I-GENE
ligand	O
and	O
estrogen	O
response	O
element	O
sequence	O
on	O
interaction	O
with	O
chicken	B-GENE
ovalbumin	I-GENE
upstream	I-GENE
promoter	I-GENE
transcription	I-GENE
factor	I-GENE
(	O
COUP	B-GENE
-	I-GENE
TF	I-GENE
)	O
.	O

CONCLUSION	O
:	O
In	O
Cdks	B-GENE
functioning	O
throughout	O
the	O
cell	O
cycle	O
,	O
tyrosine	O
phosphorylation	O
is	O
inhibitory	O
to	O
the	O
activation	O
of	O
kinase	O
,	O
whereas	O
the	O
phosphorylation	O
of	O
threonine	O
in	O
the	O
T	O
-	O
loop	O
is	O
essential	O
for	O
activation	O
.	O

We	O
also	O
report	O
that	O
AHR	B-GENE
interacts	O
with	O
COUP	B-GENE
-	I-GENE
TF	I-GENE
in	O
transfected	O
CV	O
-	O
1	O
cells	O
.	O

AB004534	B-GENE
.	O

The	O
prevalence	O
of	O
hepatitis	O
C	O
virus	O
(	O
HCV	O
)	O
infection	O
is	O
relatively	O
low	O
in	O
childhood	O
,	O
with	O
anti	B-GENE
-	I-GENE
HCV	I-GENE
prevalence	O
rates	O
of	O
0	O
.	O
1	O
-	O
0	O
.	O
4	O
%	O
in	O
the	O
Western	O
world	O
.	O

Clear	O
and	O
evidenced	O
-	O
based	O
information	O
should	O
be	O
provided	O
to	O
patients	O
as	O
to	O
the	O
means	O
of	O
prevention	O
with	O
special	O
attention	O
to	O
individual	O
risk	O
groups	O
such	O
as	O
IV	O
drug	O
abusers	O
.	O

During	O
latency	O
,	O
more	O
than	O
1	O
%	O
of	O
neurons	O
in	O
ganglia	O
that	O
innervate	O
the	O
footpad	O
expressed	O
beta	B-GENE
-	I-GENE
galactosidase	I-GENE
,	O
with	O
the	O
number	O
of	O
positive	O
cells	O
remaining	O
constant	O
for	O
at	O
least	O
5	O
months	O
.	O

As	O
an	O
alternative	O
approach	O
to	O
this	O
question	O
,	O
we	O
have	O
studied	O
the	O
effects	O
of	O
ectopically	O
expressed	O
SHIP	B-GENE
,	O
SHP	B-GENE
-	I-GENE
1	I-GENE
,	O
or	O
SHP	B-GENE
-	I-GENE
2	I-GENE
SH2	O
-	O
containing	O
decoy	O
proteins	O
on	O
Fc	B-GENE
gamma	I-GENE
RIIB1	I-GENE
signaling	O
.	O

Compared	O
to	O
those	O
with	O
normal	O
renal	O
functions	O
,	O
these	O
patients	O
were	O
older	O
(	O
P	O
<	O
or	O
=	O
0	O
.	O
01	O
)	O
,	O
had	O
significantly	O
elevated	O
blood	O
pressures	O
(	O
P	O
<	O
0	O
.	O
01	O
or	O
P	O
=	O
0	O
.	O
0001	O
)	O
,	O
and	O
in	O
the	O
case	O
of	O
Type	O
1	O
DM	O
,	O
with	O
a	O
higher	O
body	O
mass	O
index	O
(	O
P	O
=	O
0	O
.	O
0001	O
)	O
and	O
waist	O
-	O
hip	O
ratio	O
(	O
P	O
<	O
0	O
.	O
01	O
)	O
.	O

In	O
all	O
tissues	O
examined	O
only	O
transcripts	O
positive	O
for	O
insert	O
3	O
,	O
an	O
18	O
bp	O
insertion	O
in	O
repeat	O
21	O
,	O
were	O
amplified	O
,	O
even	O
under	O
conditions	O
in	O
which	O
a	O
30	O
%	O
level	O
of	O
insert	O
3	O
negative	O
transcript	O
could	O
be	O
easily	O
detected	O
in	O
artificially	O
prepared	O
control	O
samples	O
.	O

These	O
results	O
show	O
that	O
the	O
CAAT	O
-	O
region	O
is	O
involved	O
in	O
upregulating	O
the	O
MDR1	B-GENE
promoter	I-GENE
in	O
HL60	O
/	O
VCR	O
cells	O
.	O

Both	O
receptors	O
utilize	O
protein	B-GENE
tyrosine	I-GENE
kinases	I-GENE
(	O
PTKs	B-GENE
)	O
for	O
the	O
phosphorylation	O
of	O
various	O
signaling	O
molecules	O
,	O
a	O
process	O
that	O
is	O
critical	O
for	O
the	O
function	O
of	O
both	O
receptors	O
.	O

The	O
synergistic	O
effect	O
due	O
to	O
the	O
5	O
'	O
-	O
3	O
'	O
cooperation	O
was	O
at	O
least	O
fourfold	O
greater	O
than	O
the	O
sum	O
of	O
the	O
contributions	O
of	O
the	O
individual	O
UTRs	O
.	O

We	O
demonstrate	O
that	O
both	O
R	B-GENE
and	O
Z	B-GENE
activate	O
the	O
cellular	O
stress	O
mitogen	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
(	I-GENE
MAP	I-GENE
)	I-GENE
kinases	I-GENE
,	O
p38	B-GENE
and	O
JNK	B-GENE
,	O
resulting	O
in	O
phosphorylation	O
(	O
and	O
activation	O
)	O
of	O
the	O
cellular	B-GENE
transcription	I-GENE
factor	I-GENE
ATF2	I-GENE
.	O

Anatomy	O
of	O
the	O
uterine	O
artery	O
.	O

However	O
,	O
activation	O
of	O
the	O
cAMP	O
pathway	O
,	O
which	O
is	O
known	O
to	O
regulate	O
inhibin	B-GENE
alpha	I-GENE
expression	O
,	O
greatly	O
enhanced	O
the	O
actions	O
of	O
SF	B-GENE
-	I-GENE
1	I-GENE
.	O

Deletion	O
and	O
site	O
-	O
directed	O
mutagenesis	O
localized	O
a	O
novel	O
SF	B-GENE
-	I-GENE
1	I-GENE
regulatory	I-GENE
element	I-GENE
(	O
TCA	O
GGGCCA	O
;	O
-	O
137	O
to	O
-	O
129	O
)	O
adjacent	O
to	O
a	O
variant	O
cAMP	O
-	O
response	O
element	O
(	O
CRE	O
;	O
-	O
120	O
to	O
-	O
114	O
)	O
.	O

Synthetic	O
ligands	O
have	O
been	O
identified	O
that	O
reset	O
and	O
amplify	O
the	O
cycle	O
of	O
pulsatile	O
GH	B-GENE
secretion	O
by	O
interacting	O
with	O
the	O
orphan	B-GENE
GH	I-GENE
-	I-GENE
secretagogue	I-GENE
receptor	I-GENE
(	O
GHS	B-GENE
-	I-GENE
R	I-GENE
)	O
.	O

The	O
collection	O
of	O
mutants	O
displaying	O
TGN	O
sorting	O
defects	O
includes	O
members	O
with	O
mutations	O
in	O
previously	O
identified	O
vacuolar	B-GENE
protein	I-GENE
sorting	I-GENE
genes	I-GENE
(	O
VPS	B-GENE
)	O
,	O
including	O
the	O
dynamin	B-GENE
family	O
member	O
VPS1	B-GENE
.	O

Also	O
in	O
the	O
spectrum	O
of	O
mutants	O
with	O
TGN	O
sorting	O
defects	O
are	O
isolates	O
with	O
mutations	O
in	O
the	O
following	O
:	O
RIC1	B-GENE
,	O
encoding	O
a	O
product	O
originally	O
proposed	O
to	O
participate	O
in	O
ribosome	O
biogenesis	O
;	O
LUV1	B-GENE
,	O
encoding	O
a	O
product	O
potentially	O
involved	O
in	O
vacuole	O
and	O
microtubule	O
organization	O
;	O
and	O
INP53	B-GENE
,	O
encoding	O
a	O
synaptojanin	B-GENE
-	I-GENE
like	I-GENE
inositol	I-GENE
polyphosphate	I-GENE
5	I-GENE
-	I-GENE
phosphatase	I-GENE
.	O

The	O
single	O
strandedness	O
is	O
manifested	O
as	O
a	O
terminal	O
extension	O
of	O
the	O
G	O
-	O
rich	O
strand	O
(	O
G	O
tails	O
)	O
that	O
can	O
occur	O
independently	O
of	O
telomerase	B-GENE
,	O
suggesting	O
that	O
cdc17	B-GENE
/	O
pol1	B-GENE
mutants	O
exhibit	O
defects	O
in	O
telomeric	O
lagging	O
-	O
strand	O
synthesis	O
.	O

In	O
addition	O
,	O
CaMig1	B-GENE
formed	O
specific	O
complexes	O
with	O
the	O
URS1	O
region	O
of	O
the	O
S	B-GENE
.	I-GENE
cerevisiae	I-GENE
FBP1	I-GENE
gene	I-GENE
.	O

Furthermore	O
,	O
the	O
wide	O
distribution	O
of	O
the	O
GFP	B-GENE
-	O
POLO	B-GENE
protein	O
to	O
all	O
compartments	O
of	O
the	O
mitotic	O
apparatus	O
provides	O
a	O
valuable	O
tool	O
for	O
future	O
studies	O
on	O
cell	O
cycle	O
during	O
development	O
.	O

An	O
ASIC	O
-	O
chip	O
for	O
stereoscopic	O
depth	O
analysis	O
in	O
video	O
-	O
real	O
-	O
time	O
based	O
on	O
visual	O
cortical	O
cell	O
behavior	O
.	O

However	O
,	O
calphostin	O
C	O
,	O
a	O
specific	O
inhibitor	O
of	O
PKC	B-GENE
,	O
abolished	O
the	O
TPA	O
-	O
induced	O
increase	O
in	O
CFI	B-GENE
mRNA	I-GENE
levels	O
.	O

Preimmune	B-GENE
IgG	I-GENE
,	O
anti	B-GENE
-	I-GENE
GalT	I-GENE
Fab	I-GENE
fragments	I-GENE
,	O
irrelevant	O
polymers	O
and	O
monomeric	O
N	O
-	O
acetylglucosamine	O
had	O
no	O
effect	O
.	O

Downstream	O
of	O
the	O
G	O
-	O
A	O
anastomosis	O
,	O
the	O
RD	O
,	O
CC	O
,	O
E	O
(	O
p	O
)	O
and	O
loop	O
areas	O
were	O
significantly	O
different	O
from	O
REF	O
,	O
but	O
significantly	O
different	O
from	O
A	O
-	O
A	O
.	O

Induced	O
expression	O
of	O
c	B-GENE
-	I-GENE
myc	I-GENE
is	O
likely	O
to	O
contribute	O
to	O
the	O
proliferation	O
of	O
Stat1	B-GENE
-	O
null	O
cells	O
in	O
response	O
to	O
IFNs	B-GENE
.	O

Eastern	O
Cooperative	O
Oncology	O
Group	O
trial	O
E3186	O
was	O
initiated	O
to	O
explore	O
this	O
question	O
.	O

We	O
determined	O
how	O
DNA	O
repair	O
is	O
affected	O
by	O
TFA1	B-GENE
conditional	O
mutations	O
.	O

These	O
articles	O
both	O
report	O
the	O
results	O
of	O
multi	O
-	O
institutional	O
,	O
randomized	O
,	O
phase	O
3	O
trials	O
for	O
the	O
treatment	O
of	O
patients	O
with	O
localized	O
(	O
T1	O
-	O
3	O
N0	O
-	O
1	O
M0	O
)	O
esophageal	O
squamous	O
cell	O
carcinoma	O
(	O
SCC	O
)	O
or	O
esophageal	O
adenocarcinoma	O
.	O

Studies	O
of	O
MPO	B-GENE
gene	I-GENE
regulation	O
can	O
help	O
to	O
elucidate	O
the	O
mechanism	O
of	O
normal	O
and	O
abnormal	O
myeloid	O
differentiation	O
.	O

NDRF	B-GENE
/	O
NeuroD2	B-GENE
was	O
co	O
-	O
precipitated	O
with	O
PKN	B-GENE
from	O
the	O
lysate	O
of	O
COS	O
-	O
7	O
cells	O
transfected	O
with	O
both	O
expression	O
constructs	O
for	O
NDRF	B-GENE
/	O
NeuroD2	B-GENE
and	O
PKN	B-GENE
.	O

Transient	O
transfection	O
assays	O
using	O
P19	O
cells	O
revealed	O
that	O
expression	O
of	O
NDRF	B-GENE
/	O
NeuroD2	B-GENE
increased	O
the	O
transactivation	O
of	O
the	O
rat	B-GENE
insulin	I-GENE
promoter	I-GENE
element	I-GENE
3	I-GENE
(	O
RIPE3	B-GENE
)	O
enhancer	O
up	O
to	O
approximately	O
12	O
-	O
fold	O
and	O
that	O
co	O
-	O
expression	O
of	O
catalytically	O
active	O
form	O
of	O
PKN	B-GENE
,	O
but	O
not	O
kinase	O
-	O
deficient	O
derivative	O
,	O
resulted	O
in	O
a	O
further	O
threefold	O
increase	O
of	O
NDRF	B-GENE
/	O
NeuroD2	B-GENE
-	O
mediated	O
transcription	O
.	O

Two	O
Pax2	B-GENE
/	I-GENE
5	I-GENE
/	I-GENE
8	I-GENE
-	I-GENE
binding	I-GENE
sites	I-GENE
in	O
Engrailed2	B-GENE
are	O
required	O
for	O
proper	O
initiation	O
of	O
endogenous	O
mid	O
-	O
hindbrain	O
expression	O
.	O

AF154055	B-GENE
.	O

Alignment	O
of	O
the	O
cervical	O
spine	O
,	O
vertebral	O
abnormalities	O
,	O
and	O
disc	O
changes	O
also	O
were	O
evaluated	O
.	O

The	O
concomitant	O
interaction	O
of	O
mSTI1	B-GENE
with	O
hsp70	B-GENE
and	O
hsp90	B-GENE
at	O
its	O
N	O
-	O
and	O
C	O
-	O
termini	O
respectively	O
is	O
mediated	O
by	O
the	O
tetratricopeptide	O
repeat	O
(	O
TPR	O
)	O
motifs	O
in	O
these	O
regions	O
.	O

Competition	O
experiments	O
demonstrate	O
a	O
negative	O
allosteric	O
relationship	O
between	O
these	O
RGD	O
recognition	O
sites	O
.	O

Sequence	O
analysis	O
showed	O
that	O
the	O
5	O
'	O
-	O
flanking	O
region	O
upstream	O
to	O
the	O
ATG	O
codon	O
did	O
not	O
contain	O
a	O
conventional	O
TATA	O
box	O
.	O

After	O
i	O
.	O
v	O
.	O
administration	O
of	O
500	O
mg	O
acetazolamide	O
and	O
disinfection	O
of	O
the	O
conjunctiva	O
,	O
50	O
micrograms	O
rt	B-GENE
-	I-GENE
PA	I-GENE
in	O
0	O
.	O
1	O
ml	O
(	O
BSS	O
)	O
and	O
0	O
.	O
5	O
ml	O
SF6	O
were	O
injected	O
intravitreally	O
.	O

Differential	O
expression	O
and	O
regulation	O
by	O
20	O
-	O
hydroxyecdysone	O
of	O
mosquito	O
ultraspiracle	O
isoforms	O
.	O

The	O
three	O
isoforms	O
purified	O
with	O
anti	B-GENE
-	I-GENE
FLAG	I-GENE
antibody	I-GENE
affinity	O
column	O
transferred	O
sulfate	O
to	O
heparan	O
sulfate	O
and	O
heparin	O
but	O
not	O
to	O
other	O
glycosaminoglycans	O
.	O

The	O
differentiation	O
and	O
maintenance	O
of	O
a	O
neurotransmitter	O
phenotype	O
is	O
guided	O
by	O
the	O
interaction	O
of	O
exogenous	O
cues	O
with	O
intrinsic	O
genetic	O
machinery	O
.	O

Analysis	O
of	O
functional	O
domains	O
of	O
Arix	B-GENE
reveals	O
an	O
N	O
-	O
terminal	O
activation	O
domain	O
and	O
a	O
C	O
-	O
terminal	O
repression	O
domain	O
.	O

BACKGROUND	O
:	O
Left	O
ventricular	O
hypertrophy	O
is	O
a	O
heterogeneous	O
disorder	O
with	O
distinct	O
morphologies	O
.	O

Multivariate	O
predictors	O
were	O
concentric	O
remodeling	O
(	O
P	O
<	O
0	O
.	O
0001	O
;	O
odds	O
ratio	O
,	O
13	O
.	O
5	O
)	O
,	O
left	O
ventricular	O
ejection	O
fraction	O
>	O
2	O
SD	O
above	O
normal	O
(	O
P	O
<	O
0	O
.	O
0001	O
)	O
,	O
and	O
single	O
-	O
vessel	O
left	O
circumflex	O
disease	O
(	O
P	O
<	O
0	O
.	O
0007	O
;	O
odds	O
ratio	O
,	O
7	O
.	O
6	O
)	O
.	O

Overexpression	O
of	O
ICBP90	B-GENE
in	O
COS	O
-	O
1	O
-	O
transfected	O
cells	O
induced	O
an	O
enhanced	O
expression	O
of	O
endogenous	B-GENE
topoisomerase	I-GENE
IIalpha	I-GENE
.	O

The	O
RNA	O
aptamer	O
contains	O
three	O
stems	O
separated	O
by	O
a	O
pair	O
of	O
two	O
-	O
base	O
bulges	O
,	O
and	O
adopts	O
an	O
unanticipated	O
fold	O
in	O
which	O
both	O
junctional	O
sites	O
are	O
anchored	O
through	O
base	O
triple	O
formation	O
.	O

The	O
study	O
suggests	O
the	O
presence	O
of	O
an	O
anatomical	O
sphincter	O
at	O
the	O
RSJ	O
which	O
seems	O
to	O
regulate	O
the	O
passage	O
of	O
stools	O
from	O
the	O
sigmoid	O
colon	O
to	O
the	O
rectum	O
.	O

To	O
quantify	O
any	O
mechanical	O
inhibitory	O
effect	O
of	O
nasal	O
intermittent	O
positive	O
pressure	O
ventilation	O
(	O
IPPV	O
)	O
on	O
inspiratory	O
activity	O
of	O
the	O
diaphragm	O
we	O
ventilated	O
five	O
conscious	O
relaxed	O
subjects	O
on	O
two	O
occasions	O
at	O
respiratory	O
rates	O
similar	O
to	O
quiet	O
breathing	O
(	O
QB	O
)	O
and	O
at	O
three	O
levels	O
of	O
applied	O
pressure	O
(	O
Pappl	O
)	O
-	O
-	O
6	O
,	O
9	O
and	O
12	O
cmH2O	O
,	O
each	O
during	O
hypocapnia	O
(	O
P	O
(	O
CO2	O
)	O
allowed	O
to	O
decrease	O
)	O
and	O
eucapnia	O
(	O
CO2	O
added	O
to	O
inspired	O
gas	O
)	O
.	O

METHODS	O
:	O
Von	B-GENE
Willebrand	I-GENE
factor	I-GENE
(	O
vWF	B-GENE
)	O
and	O
the	O
fibrinolytic	O
factors	O
tissue	B-GENE
plasminogen	I-GENE
activator	I-GENE
(	O
tPA	B-GENE
)	O
,	O
measured	O
as	O
tPA	B-GENE
capacity	O
,	O
and	O
plasminogen	B-GENE
activator	I-GENE
inhibitor	I-GENE
1	I-GENE
(	O
PAI	B-GENE
-	I-GENE
1	I-GENE
)	O
,	O
platelets	O
,	O
fibrinogen	B-GENE
,	O
and	O
inflammatory	O
markers	O
were	O
measured	O
in	O
74	O
patients	O
with	O
active	O
seropositive	O
RA	O
.	O

Neuronal	O
signaling	O
properties	O
are	O
largely	O
determined	O
by	O
the	O
quantity	O
and	O
combination	O
of	O
ion	O
channels	O
expressed	O
.	O

Treatment	O
also	O
led	O
to	O
a	O
significant	O
dose	O
dependent	O
reduction	O
in	O
the	O
sum	O
of	O
ST	O
segment	O
depression	O
at	O
both	O
trough	O
and	O
peak	O
concentrations	O
.	O

We	O
have	O
investigated	O
the	O
contribution	O
of	O
specific	O
TATA	B-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
(	O
TBP	B-GENE
)	O
-	O
TATA	O
interactions	O
to	O
the	O
promoter	O
activity	O
of	O
a	O
constitutively	O
expressed	O
silkworm	B-GENE
tRNA	I-GENE
(	I-GENE
C	I-GENE
)	I-GENE
(	I-GENE
Ala	I-GENE
)	I-GENE
gene	I-GENE
and	O
have	O
also	O
asked	O
whether	O
the	O
lack	O
of	O
similar	O
interactions	O
accounts	O
for	O
the	O
low	O
promoter	O
activity	O
of	O
a	O
silk	B-GENE
gland	I-GENE
-	I-GENE
specific	I-GENE
tRNA	I-GENE
(	I-GENE
SG	I-GENE
)	I-GENE
(	I-GENE
Ala	I-GENE
)	I-GENE
gene	I-GENE
.	O

The	O
sequences	O
showed	O
extensive	O
homologies	O
with	O
squalene	B-GENE
synthase	I-GENE
genes	I-GENE
and	O
enzymes	O
from	O
a	O
number	O
of	O
other	O
organisms	O
and	O
extreme	O
amino	O
acid	O
conservation	O
within	O
the	O
binding	O
and	O
catalytic	O
domains	O
.	O

Two	O
episodes	O
of	O
peritonitis	O
occurred	O
while	O
the	O
patient	O
received	O
CAPD	O
(	O
1	O
episode	O
/	O
3	O
.	O
5	O
patient	O
-	O
months	O
)	O
.	O

Copyright	O
2000	O
The	O
Royal	O
College	O
of	O
Radiologists	O
.	O

Two	O
estrogen	B-GENE
receptor	I-GENE
(	O
ER	B-GENE
)	O
isoforms	O
with	O
different	O
estrogen	O
dependencies	O
are	O
generated	O
from	O
the	O
trout	B-GENE
ER	I-GENE
gene	I-GENE
.	O

Induction	O
was	O
reversed	O
by	O
coexpression	O
of	O
A	B-GENE
-	I-GENE
Fos	I-GENE
,	O
a	O
dominant	O
negative	O
to	O
AP	B-GENE
-	I-GENE
1	I-GENE
.	O

In	O
myometrial	O
SMC	O
,	O
both	O
isoforms	O
of	O
the	O
progesterone	B-GENE
receptor	I-GENE
,	O
PR	B-GENE
-	I-GENE
B	I-GENE
and	O
PR	B-GENE
-	I-GENE
A	I-GENE
,	O
caused	O
a	O
ligand	O
-	O
dependent	O
activation	O
of	O
PGDH	B-GENE
-	I-GENE
2368	I-GENE
/	O
luc3	B-GENE
.	O

Element	O
B	O
(	O
-	O
249	O
/	O
-	O
229	O
)	O
shows	O
more	O
than	O
80	O
%	O
homology	O
to	O
a	O
consensus	B-GENE
c	I-GENE
-	I-GENE
myb	I-GENE
element	I-GENE
,	O
but	O
formed	O
two	O
specific	O
complexes	O
that	O
differed	O
from	O
that	O
of	O
c	B-GENE
-	I-GENE
myb	I-GENE
in	O
the	O
electrophoretic	O
mobility	O
shift	O
assay	O
.	O

Stable	O
transfection	O
of	O
the	O
truncated	O
reduced	B-GENE
folate	I-GENE
carrier	I-GENE
cDNA	I-GENE
into	O
mouse	O
L1210	O
leukemia	O
cells	O
:	O
increased	O
folate	O
accumulation	O
,	O
decreased	O
their	O
leucovorin	O
and	O
folic	O
acid	O
growth	O
requirements	O
,	O
and	O
increased	O
their	O
sensitivity	O
to	O
methotrexate	O
.	O

Characterization	O
of	O
a	O
human	B-GENE
alternatively	I-GENE
spliced	I-GENE
truncated	I-GENE
reduced	I-GENE
folate	I-GENE
carrier	I-GENE
increasing	O
folate	O
accumulation	O
in	O
parental	O
leukemia	O
cells	O
.	O

Electron	O
microscopic	O
and	O
enzymatic	O
analyses	O
revealed	O
that	O
the	O
A118	O
genome	O
is	O
a	O
linear	O
,	O
circularly	O
permuted	O
,	O
terminally	O
redundant	O
collection	O
of	O
double	O
-	O
stranded	O
DNA	O
molecules	O
.	O

Moreover	O
,	O
increasing	O
the	O
dosage	O
of	O
wild	B-GENE
-	I-GENE
type	I-GENE
Fus3	I-GENE
intensifies	O
the	O
inhibition	O
of	O
both	O
Ty1	B-GENE
transposition	O
and	O
invasive	O
growth	O
.	O

Consistently	O
,	O
activation	O
of	O
c	B-GENE
-	I-GENE
Jun	I-GENE
N	I-GENE
-	I-GENE
terminal	I-GENE
kinase	I-GENE
downstream	O
of	O
Rho	B-GENE
family	I-GENE
GTP	I-GENE
-	I-GENE
binding	I-GENE
proteins	I-GENE
was	O
also	O
enhanced	O
when	O
Dbl	B-GENE
was	O
tyrosine	O
-	O
phosphorylated	O
.	O

However	O
,	O
its	O
participation	O
in	O
collagen	B-GENE
binding	O
has	O
not	O
been	O
shown	O
.	O

Together	O
,	O
these	O
data	O
suggest	O
that	O
the	O
carboxyl	O
terminus	O
of	O
CFTR	B-GENE
contains	O
a	O
tyrosine	O
-	O
based	O
internalization	O
signal	O
that	O
interacts	O
with	O
the	O
endocytic	O
adaptor	O
complex	O
AP	B-GENE
-	I-GENE
2	I-GENE
to	O
facilitate	O
efficient	O
entry	O
of	O
CFTR	B-GENE
into	O
clathrin	B-GENE
-	O
coated	O
vesicles	O
.	O

The	O
insulin	B-GENE
therapy	O
regimen	O
did	O
not	O
affect	O
the	O
evolution	O
of	O
the	O
patients	O
and	O
no	O
significant	O
relationship	O
existed	O
between	O
the	O
age	O
at	O
diagnosis	O
,	O
duration	O
of	O
diabetes	O
,	O
daily	O
insulin	B-GENE
dosage	O
or	O
metabolic	O
control	O
and	O
height	O
or	O
BMI	O
.	O

Scmh1	B-GENE
maps	O
to	O
4D1	O
-	O
D2	O
.	O
1	O
in	O
mice	O
.	O

The	O
applicability	O
of	O
laparoscopic	O
donor	O
nephrectomy	O
(	O
LDN	O
)	O
has	O
not	O
been	O
assessed	O
in	O
the	O
obese	O
donor	O
.	O

Hyaluronan	O
treatment	O
stimulated	O
collagen	B-GENE
remodeling	O
in	O
the	O
peripheral	O
region	O
and	O
inhibited	O
swelling	O
of	O
the	O
meniscus	O
repaired	O
in	O
the	O
inner	O
region	O
.	O

We	O
have	O
addressed	O
these	O
issues	O
by	O
reconstituting	O
and	O
characterizing	O
the	O
KRAB	B-GENE
:	O
KAP	B-GENE
-	I-GENE
1	I-GENE
-	O
RBCC	B-GENE
interaction	O
using	O
purified	O
components	O
.	O

The	O
RING	O
finger	O
,	O
B2	O
box	O
,	O
and	O
coiled	O
-	O
coil	O
region	O
are	O
required	O
for	O
oligomerization	O
of	O
KAP	B-GENE
-	I-GENE
1	I-GENE
-	O
RBCC	B-GENE
and	O
KRAB	B-GENE
binding	O
,	O
as	O
mutations	O
in	O
these	O
domains	O
concomitantly	O
abolished	O
these	O
functions	O
.	O

JPEG	O
53	O
,	O
resulting	O
in	O
a	O
compression	O
ratio	O
of	O
1	O
:	O
21	O
,	O
does	O
not	O
compromise	O
the	O
diagnostic	O
performance	O
in	O
general	O
.	O

We	O
critically	O
assess	O
current	O
systematic	O
uncertainties	O
and	O
determine	O
the	O
primordial	O
Li	O
abundance	O
within	O
new	O
,	O
much	O
tighter	O
limits	O
:	O
&	O
amp	O
;	O
parl0	O
;	O
Li	O
&	O
amp	O
;	O
solm0	O
;	O
H	O
&	O
amp	O
;	O
parr0	O
;	O
p	O
=	O
1	O
.	O
23	O
+	O
0	O
.	O
68	O
-	O
0	O
.	O
32x10	O
-	O
10	O
.	O

Like	O
their	O
yeast	O
counterpart	O
,	O
the	O
mouse	O
GCN2	B-GENE
isoforms	O
contain	O
HisRS	B-GENE
-	I-GENE
related	I-GENE
sequences	I-GENE
juxtaposed	O
to	O
the	O
kinase	O
catalytic	O
domain	O
.	O

Five	O
women	O
(	O
15	O
.	O
6	O
%	O
)	O
met	O
criteria	O
for	O
PMS	O
.	O

MBI	O
and	O
MMBI	O
showed	O
similar	O
Cmax	O
values	O
,	O
but	O
the	O
former	O
disappeared	O
slower	O
in	O
the	O
serum	O
than	O
the	O
latter	O
and	O
resulted	O
in	O
its	O
larger	O
AUC	O
values	O
.	O

Another	O
long	O
insertion	O
in	O
the	O
cathepsin	B-GENE
X	I-GENE
amino	I-GENE
acid	I-GENE
sequence	I-GENE
forms	O
a	O
beta	O
-	O
hairpin	O
pointing	O
away	O
from	O
the	O
active	O
site	O
.	O

Transfection	O
experiments	O
demonstrated	O
that	O
the	O
5	O
'	O
-	O
flanking	O
region	O
(	O
-	O
1894	O
to	O
+	O
37	O
)	O
of	O
the	O
mStaf	B-GENE
gene	I-GENE
drives	O
transcription	O
in	O
mouse	O
NMuMG	O
cells	O
and	O
that	O
a	O
construct	O
containing	O
a	O
fragment	O
from	O
-	O
387	O
to	O
+	O
37	O
showed	O
the	O
highest	O
transcriptional	O
activity	O
.	O

Further	O
studies	O
in	O
T	O
-	O
24	O
cells	O
demonstrated	O
that	O
HA	O
fragments	O
also	O
induced	O
I	B-GENE
kappa	I-GENE
B	I-GENE
alpha	I-GENE
phosphorylation	O
and	O
degradation	O
,	O
kappa	B-GENE
B	I-GENE
-	I-GENE
linked	I-GENE
reporter	I-GENE
gene	I-GENE
expression	O
,	O
and	O
ICAM	B-GENE
-	I-GENE
1	I-GENE
promoter	I-GENE
activity	O
in	O
an	O
NF	B-GENE
-	I-GENE
kappa	I-GENE
B	I-GENE
-	O
dependent	O
manner	O
.	O

Pretreatment	O
of	O
cells	O
or	O
mouse	O
skin	O
with	O
antisense	O
oligonucleotides	O
of	O
PKCzeta	B-GENE
impaired	O
UV	O
-	O
induced	O
activation	O
of	O
AP	B-GENE
-	I-GENE
1	I-GENE
in	O
JB6	O
cells	O
as	O
well	O
as	O
in	O
AP	B-GENE
-	I-GENE
1	I-GENE
-	O
luciferase	B-GENE
transgenic	O
mice	O
.	O

The	O
level	O
of	O
subclinical	O
infection	O
was	O
75	O
%	O
among	O
seropositive	O
dogs	O
.	O

Desmethylferrochloroquine	O
1a	O
and	O
didesmethylferrochloroquine	O
2	O
would	O
be	O
more	O
potent	O
against	O
schizontocides	O
than	O
CQ	O
in	O
vitro	O
against	O
two	O
strains	O
(	O
HB3	O
and	O
Dd2	O
)	O
of	O
Plasmodium	O
falciparum	O
.	O

The	O
rrd1	B-GENE
,	I-GENE
2delta	I-GENE
mutant	I-GENE
was	O
partially	O
rescued	O
by	O
inactivation	O
of	O
HOG1	B-GENE
or	O
PBS2	B-GENE
,	O
suggesting	O
an	O
interaction	O
between	O
the	O
RRD	B-GENE
genes	I-GENE
and	O
the	O
Hog1p	B-GENE
signal	I-GENE
transduction	I-GENE
pathway	I-GENE
.	O

Members	O
of	O
the	O
JAK	B-GENE
/	O
Tyk	B-GENE
family	O
of	O
tyrosine	B-GENE
kinases	I-GENE
mediate	O
phosphorylation	O
of	O
STAT3	B-GENE
at	O
Tyr705	O
during	O
CNTF	B-GENE
signaling	O
;	O
however	O
,	O
the	O
kinase	O
responsible	O
for	O
phosphorylation	O
at	O
STAT3	B-GENE
Tyr727	O
appears	O
to	O
depend	O
on	O
both	O
the	O
extracellular	O
stimulus	O
and	O
the	O
cellular	O
context	O
.	O

In	O
vivo	O
,	O
CARbeta	B-GENE
/	O
RXRalpha	B-GENE
activated	O
transcription	O
from	O
an	O
HD	B-GENE
-	O
PPRE	O
luciferase	B-GENE
reporter	I-GENE
construct	I-GENE
.	O

Thus	O
,	O
SOX8	B-GENE
is	O
a	O
good	O
candidate	O
gene	O
contributing	O
to	O
the	O
mental	O
retardation	O
phenotype	O
seen	O
in	O
ATR	O
-	O
16	O
patients	O
.	O

Patch	O
test	O
results	O
obtained	O
with	O
corticosteroid	O
allergic	O
patients	O
tested	O
with	O
a	O
large	O
corticosteroid	O
series	O
validated	O
the	O
earlier	O
classification	O
of	O
corticosteroid	O
molecules	O
in	O
four	O
groups	O
of	O
cross	O
-	O
reacting	O
molecules	O
:	O
i	O
.	O
e	O
.	O
,	O
group	O
A	O
(	O
hydrocortisone	O
type	O
)	O
,	O
group	O
B	O
(	O
acetonides	O
)	O
,	O
group	O
C	O
(	O
betamethasone	O
type	O
-	O
non	O
esterified	O
)	O
and	O
group	O
D	O
(	O
esters	O
)	O
.	O

An	O
increase	O
in	O
the	O
level	O
of	O
serum	O
enzymes	O
,	O
such	O
as	O
aspartate	B-GENE
transaminase	I-GENE
,	O
alkaline	B-GENE
phosphatase	I-GENE
,	O
creatine	B-GENE
phosphokinase	I-GENE
,	O
lactate	B-GENE
dehydrogenase	I-GENE
after	O
D	O
.	O
russelli	O
venom	O
injection	O
in	O
albino	O
rats	O
is	O
indicative	O
of	O
cell	O
or	O
tissue	O
damage	O
.	O

The	O
partial	O
farm	O
budget	O
highlighted	O
the	O
importance	O
of	O
reducing	O
sub	O
-	O
clinical	O
lesions	O
in	O
a	O
feedlot	O
.	O

Surprisingly	O
,	O
3	O
full	B-GENE
-	I-GENE
length	I-GENE
murine	I-GENE
survivin	I-GENE
cDNA	I-GENE
clones	O
were	O
isolated	O
,	O
predicting	O
the	O
existence	O
of	O
3	O
distinct	O
survivin	B-GENE
proteins	I-GENE
.	O

Thus	O
,	O
the	O
induction	O
of	O
E2F	B-GENE
binding	O
to	O
the	O
E2F	B-GENE
-	I-GENE
1	I-GENE
promoter	I-GENE
by	O
the	O
E4	B-GENE
-	I-GENE
6	I-GENE
/	I-GENE
7	I-GENE
protein	I-GENE
observed	O
in	O
vitro	O
correlates	O
with	O
transactivation	O
of	O
E2F	B-GENE
-	I-GENE
1	I-GENE
promoter	I-GENE
activity	O
in	O
vivo	O
.	O

We	O
show	O
that	O
stabilization	O
of	O
the	O
hairpin	O
reduced	O
the	O
amount	O
of	O
tRNA	O
primer	O
that	O
is	O
annealed	O
to	O
the	O
PBS	O
.	O

Ischemia	O
-	O
induced	O
biphasic	O
arrhythmias	O
were	O
suppressed	O
in	O
both	O
zatebradine	O
and	O
propranolol	O
groups	O
.	O

ZK7	B-GENE
and	O
HZF16	B-GENE
genes	I-GENE
appear	O
to	O
be	O
the	O
splice	O
variants	O
transcribed	O
from	O
the	O
same	O
gene	O
.	O

CONCLUSION	O
:	O
Presence	O
of	O
APOE	B-GENE
epsilon4	I-GENE
/	I-GENE
*	I-GENE
seems	O
to	O
increase	O
the	O
risk	O
for	O
dementia	O
and	O
AD	O
independently	O
of	O
its	O
effect	O
on	O
dyslipidemia	O
and	O
atherogenesis	O
.	O

No	O
definite	O
conclusions	O
are	O
possible	O
because	O
of	O
the	O
small	O
number	O
of	O
patients	O
involved	O
in	O
this	O
phase	O
II	O
trial	O
.	O

Two	O
distinct	O
Salmonella	B-GENE
fimbrins	I-GENE
,	O
AgfA	B-GENE
and	O
SefA	B-GENE
,	O
comprising	O
thin	O
aggregative	O
fimbriae	O
SEF17	B-GENE
and	O
SEF14	B-GENE
,	O
respectively	O
,	O
were	O
each	O
genetically	O
engineered	O
to	O
carry	O
PT3	B-GENE
,	O
an	O
alpha	O
-	O
helical	O
16	O
-	O
amino	O
acid	O
Leishmania	O
T	O
-	O
cell	O
epitope	O
derived	O
from	O
the	O
metalloprotease	B-GENE
gp63	B-GENE
.	O

In	O
marked	O
contrast	O
to	O
AgfA	B-GENE
,	O
none	O
of	O
the	O
chimeric	B-GENE
SefA	I-GENE
proteins	I-GENE
were	O
expressed	O
or	O
assembled	O
into	O
fimbriae	O
.	O

Productive	O
growth	O
of	O
phage	O
P22	O
in	O
wild	O
-	O
type	O
Salmonella	O
typhimurium	O
correlates	O
with	O
the	O
presence	O
of	O
Abc2	B-GENE
,	O
but	O
is	O
independent	O
of	O
the	O
absolute	O
level	O
of	O
ATP	B-GENE
-	I-GENE
dependent	I-GENE
nuclease	I-GENE
activity	O
,	O
suggesting	O
a	O
qualitative	O
change	O
in	O
the	O
nature	O
of	O
Abc2	B-GENE
-	O
modified	O
RecBCD	B-GENE
nuclease	I-GENE
activity	O
relative	O
to	O
the	O
native	O
enzyme	O
.	O

In	O
this	O
study	O
,	O
we	O
investigated	O
the	O
molecular	O
mechanisms	O
underlying	O
the	O
inducible	O
expression	O
of	O
the	O
flt	B-GENE
-	I-GENE
1	I-GENE
gene	I-GENE
during	O
the	O
activation	O
of	O
THP	O
-	O
1	O
cells	O
.	O

There	O
was	O
a	O
2	O
.	O
4	O
-	O
fold	O
difference	O
in	O
CAT	B-GENE
produced	O
from	O
these	O
transcripts	O
in	O
HeLa	O
cells	O
,	O
which	O
contain	O
a	O
greater	O
natural	O
abundance	O
of	O
PTB	B-GENE
.	O

Multiple	O
mitogen	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
kinase	I-GENE
signaling	O
pathways	O
connect	O
the	O
cot	B-GENE
oncoprotein	I-GENE
to	O
the	O
c	B-GENE
-	I-GENE
jun	I-GENE
promoter	I-GENE
and	O
to	O
cellular	O
transformation	O
.	O

4	O
.	O

In	O
the	O
present	O
study	O
we	O
have	O
investigated	O
the	O
regulatory	O
mechanism	O
for	O
CD95L	B-GENE
expression	O
.	O

Protein	O
sequence	O
analysis	O
reveals	O
that	O
MAN1	B-GENE
shares	O
a	O
conserved	O
globular	O
domain	O
of	O
approximately	O
40	O
amino	O
acids	O
,	O
which	O
we	O
term	O
the	O
LEM	B-GENE
module	I-GENE
,	O
with	O
inner	O
nuclear	O
membrane	O
proteins	O
lamina	B-GENE
-	I-GENE
associated	I-GENE
polypeptide	I-GENE
2	I-GENE
and	O
emerin	B-GENE
.	O

The	O
encoded	O
amino	O
acid	O
sequences	O
in	O
the	O
full	O
-	O
length	O
bovine	O
and	O
porcine	O
cDNAs	O
were	O
identical	O
,	O
consisting	O
of	O
209	O
amino	O
acid	O
residues	O
,	O
and	O
were	O
nearly	O
the	O
same	O
as	O
the	O
published	O
sequence	O
determined	O
by	O
Edman	O
degradation	O
.	O

With	O
chemical	O
shift	O
imaging	O
,	O
the	O
signal	O
intensity	O
decreased	O
on	O
the	O
out	O
-	O
of	O
-	O
phase	O
images	O
in	O
six	O
of	O
seven	O
(	O
86	O
%	O
)	O
patients	O
with	O
APA	O
and	O
in	O
eight	O
of	O
nine	O
(	O
89	O
%	O
)	O
patients	O
with	O
BAH	O
.	O

For	O
each	O
night	O
,	O
the	O
diary	O
allowed	O
the	O
subjective	O
measurement	O
of	O
bedtime	O
,	O
wake	O
time	O
,	O
time	O
in	O
bed	O
(	O
TIB	O
)	O
,	O
sleep	O
efficiency	O
,	O
number	O
of	O
minutes	O
of	O
wake	O
after	O
sleep	O
onset	O
(	O
WASO	O
)	O
,	O
alertness	O
on	O
awakening	O
,	O
and	O
percentage	O
of	O
morning	O
needing	O
an	O
alarm	O
(	O
or	O
a	O
person	O
functioning	O
as	O
one	O
)	O
.	O

Acad	O
.	O

Copyright	O
2000	O
Academic	O
Press	O
.	O

These	O
data	O
suggest	O
that	O
combined	O
lesions	O
of	O
cholinergic	O
and	O
serotonergic	O
neurons	O
in	O
the	O
rat	O
brain	O
do	O
not	O
alter	O
olfactory	O
perception	O
or	O
olfactory	O
short	O
-	O
term	O
memory	O
.	O

Extreme	O
potency	O
of	O
botulinum	B-GENE
toxin	I-GENE
.	O

In	O
contrast	O
,	O
c	B-GENE
-	I-GENE
Src	I-GENE
activated	O
by	O
isoproterenol	O
led	O
to	O
tyrosine	O
phosphorylation	O
of	O
Shc	B-GENE
and	O
subsequent	O
Erk	B-GENE
activation	O
,	O
but	O
not	O
tyrosine	O
phosphorylation	O
of	O
cortactin	B-GENE
or	O
Stat3	B-GENE
.	O

For	O
wild	O
type	O
MutT	B-GENE
and	O
its	O
E53D	B-GENE
and	O
E44D	B-GENE
mutants	I-GENE
,	O
plots	O
of	O
log	O
(	O
k	O
(	O
cat	O
)	O
)	O
versus	O
pH	O
exhibited	O
a	O
limiting	O
slope	O
of	O
1	O
on	O
the	O
ascending	O
limb	O
and	O
then	O
a	O
hump	O
,	O
i	O
.	O
e	O
.	O
,	O
a	O
sharply	O
defined	O
maximum	O
near	O
pH	O
8	O
followed	O
by	O
a	O
plateau	O
,	O
yielding	O
apparent	O
pK	O
(	O
a	O
)	O
values	O
of	O
7	O
.	O
6	O
+	O
/	O
-	O
0	O
.	O
3	O
and	O
8	O
.	O
4	O
+	O
/	O
-	O
0	O
.	O
4	O
for	O
an	O
essential	O
base	O
and	O
a	O
nonessential	O
acid	O
catalyst	O
,	O
respectively	O
,	O
in	O
the	O
active	O
quaternary	O
MutT	B-GENE
-	O
Mg	O
(	O
2	O
+	O
)	O
-	O
dGTP	O
-	O
Mg	O
(	O
2	O
+	O
)	O
complex	O
.	O

Structural	O
changes	O
in	O
the	O
kinetically	O
more	O
damaged	O
E44D	O
mutant	O
detected	O
in	O
(	O
1	O
)	O
H	O
-	O
(	O
15	O
)	O
N	O
HSQC	O
spectra	O
were	O
largely	O
limited	O
to	O
the	O
loop	O
I	O
-	O
helix	O
I	O
motif	O
,	O
suggesting	O
that	O
Glu	O
-	O
44	O
stabilizes	O
the	O
active	O
site	O
region	O
.	O

In	O
vitro	O
expression	O
of	O
four	O
different	O
naturally	O
occurring	O
nonsense	O
and	O
missense	O
mutations	O
revealed	O
a	O
dramatically	O
altered	O
subcellular	O
location	O
of	O
the	O
protein	O
in	O
cultured	O
cells	O
.	O

After	O
i	O
.	O
v	O
.	O

Immunity	O
acquired	O
by	O
mice	O
during	O
I	O
.	O
scapularis	O
nymphal	O
activity	O
in	O
early	O
summer	O
may	O
exclude	O
a	O
large	O
proportion	O
of	O
the	O
mouse	O
population	O
from	O
maintaining	O
E	O
.	O
phagocytophila	O
during	O
the	O
period	O
of	O
larval	O
activity	O
later	O
in	O
the	O
season	O
.	O

The	O
emerging	O
view	O
based	O
on	O
studies	O
in	O
yeast	O
is	O
that	O
each	O
class	O
of	O
snoRNPs	O
is	O
composed	O
of	O
a	O
unique	O
set	O
of	O
proteins	O
.	O

BCR	B-GENE
cross	O
-	O
linking	O
also	O
led	O
to	O
increased	O
MAPK	B-GENE
-	O
activated	O
protein	B-GENE
kinase	I-GENE
-	I-GENE
2	I-GENE
activity	O
,	O
an	O
enzyme	O
that	O
lies	O
immediately	O
downstream	O
from	O
p38	B-GENE
MAPK	I-GENE
;	O
MAPK	B-GENE
-	O
activated	O
protein	B-GENE
kinase	I-GENE
-	I-GENE
2	I-GENE
immune	O
complexes	O
phosphorylated	O
a	O
peptide	O
substrate	O
containing	O
the	O
CREB	B-GENE
serine	I-GENE
133	I-GENE
phosphoacceptor	I-GENE
motif	I-GENE
.	O

Activation	O
of	O
a	O
CRE	O
-	O
dependent	O
junB	B-GENE
promoter	I-GENE
/	O
chloramphenicol	B-GENE
acetyltransferase	I-GENE
(	O
CAT	B-GENE
)	O
reporter	O
gene	O
by	O
the	O
BCR	B-GENE
was	O
also	O
blocked	O
by	O
SB203580	O
.	O

We	O
present	O
evidence	O
that	O
the	O
upstream	O
open	O
reading	O
frame	O
(	O
uORF	O
)	O
represses	O
the	O
translation	O
of	O
the	O
downstream	O
major	O
open	O
reading	O
frame	O
(	O
mORF	O
)	O
.	O

METHODS	O
:	O
TBN	O
measurements	O
were	O
performed	O
in	O
31	O
female	O
outpatients	O
with	O
breast	O
carcinoma	O
who	O
were	O
undergoing	O
standard	O
cyclophosphamide	O
,	O
methotrexate	O
,	O
and	O
5	O
-	O
fluorouracil	O
(	O
CMF	O
)	O
-	O
based	O
chemotherapy	O
(	O
median	O
age	O
,	O
48	O
years	O
;	O
range	O
,	O
26	O
-	O
77	O
years	O
)	O
.	O

A	O
385	O
bp	O
Glucocorticoid	O
Response	O
Unit	O
(	O
GRU	O
)	O
was	O
identified	O
whose	O
glucocorticoid	O
induction	O
was	O
enhanced	O
by	O
dibutyryl	O
-	O
cAMP	O
and	O
reduced	O
by	O
phorbol	O
esters	O
.	O

No	O
somatic	O
mutations	O
were	O
found	O
in	O
any	O
of	O
the	O
samples	O
,	O
suggesting	O
that	O
ING1	B-GENE
is	O
not	O
a	O
tumor	O
suppressor	O
gene	O
target	O
in	O
head	O
and	O
neck	O
cancer	O
.	O

Ras	B-GENE
-	O
GRF1	B-GENE
transiently	O
expressed	O
with	O
v	B-GENE
-	I-GENE
Src	I-GENE
was	O
tyrosine	O
-	O
phosphorylated	O
and	O
showed	O
significant	O
GEF	B-GENE
activity	O
toward	O
Rac	B-GENE
,	O
but	O
not	O
Rho	B-GENE
and	O
Cdc42	B-GENE
,	O
which	O
was	O
comparable	O
with	O
that	O
induced	O
by	O
Gbetagamma	B-GENE
.	O

EMSA	O
showed	O
that	O
nuclear	O
proteins	O
from	O
PC12	O
but	O
not	O
C6	O
or	O
Rat2	O
cells	O
bind	O
the	O
CRE	O
as	O
a	O
complex	O
containing	O
activating	B-GENE
transcription	I-GENE
factor	I-GENE
(	I-GENE
ATF	I-GENE
)	I-GENE
-	I-GENE
4	I-GENE
and	O
CCAAT	B-GENE
enhancer	I-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
beta	I-GENE
,	O
while	O
both	O
PC12	O
and	O
C6	O
cell	O
nuclear	O
extracts	O
were	O
recruited	O
by	O
the	O
CCAAT	O
-	O
box	O
as	O
a	O
complex	O
containing	O
nuclear	B-GENE
factor	I-GENE
Y	I-GENE
.	O

EMSA	O
showed	O
that	O
nuclear	O
proteins	O
from	O
PC12	O
but	O
not	O
C6	O
or	O
Rat2	O
cells	O
bind	O
the	O
CRE	O
as	O
a	O
complex	O
containing	O
activating	B-GENE
transcription	I-GENE
factor	I-GENE
(	I-GENE
ATF	I-GENE
)	I-GENE
-	I-GENE
4	I-GENE
and	O
CCAAT	B-GENE
enhancer	I-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
beta	I-GENE
,	O
while	O
both	O
PC12	O
and	O
C6	O
cell	O
nuclear	O
extracts	O
were	O
recruited	O
by	O
the	O
CCAAT	O
-	O
box	O
as	O
a	O
complex	O
containing	O
nuclear	B-GENE
factor	I-GENE
Y	I-GENE
.	O

Despite	O
resolution	O
of	O
the	O
solid	O
portion	O
of	O
the	O
tumor	O
,	O
serial	O
MRI	O
showed	O
enlargement	O
of	O
a	O
bilobar	O
tumor	O
cyst	O
3	O
years	O
after	O
the	O
original	O
diagnosis	O
.	O

LPO	O
and	O
SOD	B-GENE
levels	O
were	O
measured	O
at	O
five	O
points	O
before	O
and	O
during	O
the	O
operation	O
.	O

Sustained	O
ventricular	O
tachycardia	O
and	O
its	O
successful	O
prophylaxis	O
during	O
high	O
-	O
dose	O
bolus	O
interleukin	B-GENE
-	I-GENE
2	I-GENE
therapy	O
for	O
metastatic	O
renal	O
cell	O
carcinoma	O
.	O

Second	O
,	O
when	O
the	O
NBF1	B-GENE
+	I-GENE
R	I-GENE
protein	I-GENE
,	O
the	O
NBF2	B-GENE
protein	I-GENE
,	O
and	O
a	O
mixture	O
of	O
the	O
two	O
proteins	O
were	O
folded	O
separately	O
and	O
analyzed	O
by	O
molecular	O
sieve	O
chomatography	O
,	O
the	O
mixture	O
was	O
found	O
to	O
elute	O
prior	O
to	O
either	O
NBF1	B-GENE
+	I-GENE
R	I-GENE
or	O
NBF2	B-GENE
.	O

Collectively	O
,	O
these	O
experiments	O
demonstrate	O
that	O
CFTR	B-GENE
'	I-GENE
s	I-GENE
NBF1	I-GENE
+	I-GENE
R	I-GENE
region	I-GENE
and	O
its	O
NBF2	B-GENE
domain	I-GENE
,	O
after	O
folding	O
separately	O
as	O
distinct	O
units	O
,	O
have	O
a	O
strong	O
propensity	O
to	O
interact	O
and	O
that	O
this	O
interaction	O
is	O
stable	O
in	O
the	O
absence	O
of	O
added	O
nucleotides	O
or	O
exogenously	O
induced	O
phosphorylation	O
.	O

Copyright	O
2000	O
Academic	O
Press	O
.	O

Sulfhydryl	O
titration	O
with	O
iodoacetamide	O
,	O
monitored	O
by	O
quantitating	O
the	O
residual	O
thiols	O
after	O
reaction	O
with	O
a	O
maleimide	O
derivative	O
of	O
biotin	O
,	O
revealed	O
a	O
striking	O
difference	O
in	O
the	O
apparent	O
pK	O
(	O
a	O
)	O
values	O
of	O
the	O
cysteines	O
at	O
the	O
two	O
splice	O
junctions	O
.	O

After	O
nitric	O
oxide	O
inhalation	O
,	O
the	O
results	O
showed	O
moderate	O
increases	O
in	O
PaO2	O
and	O
SaO2	O
(	O
P	O
>	O
0	O
.	O
05	O
)	O
and	O
a	O
significant	O
decrease	O
in	O
Qs	O
/	O
Q	O
tau	O
ratio	O
(	O
P	O
<	O
0	O
.	O
01	O
)	O
.	O

The	O
results	O
showed	O
that	O
MIP	O
,	O
MMIF	O
,	O
FIC	O
,	O
Wimax	O
,	O
P0	O
.	O
1	O
and	O
minute	O
ventilation	O
(	O
Vr	O
)	O
were	O
significantly	O
increased	O
after	O
administration	O
of	O
methylphenidatum	O
and	O
aminophylline	O
.	O

It	O
has	O
also	O
been	O
shown	O
that	O
a	O
variety	O
of	O
extracellular	O
factors	O
stimulate	O
a	O
pair	O
of	O
MAPK	O
p44	B-GENE
and	O
MAPK	O
p42	B-GENE
of	O
MAPK	B-GENE
family	I-GENE
members	I-GENE
.	O

Covalent	O
modification	O
of	O
the	O
transactivator	O
protein	O
IE2	B-GENE
-	O
p86	B-GENE
of	O
human	O
cytomegalovirus	O
by	O
conjugation	O
to	O
the	O
ubiquitin	B-GENE
-	I-GENE
homologous	I-GENE
proteins	I-GENE
SUMO	B-GENE
-	I-GENE
1	I-GENE
and	O
hSMT3b	B-GENE
.	O

73	O
:	O
658	O
-	O
666	O
,	O
1999	O
)	O
.	O

The	O
interaction	O
between	O
U	O
(	O
L	O
)	O
3	O
.	O

Protamine	B-GENE
and	O
heparin	O
doses	O
,	O
their	O
sum	O
(	O
Sigma	O
-	O
dose	O
)	O
and	O
differential	O
(	O
Delta	O
-	O
dose	O
)	O
doses	O
,	O
and	O
activated	O
clotting	O
times	O
were	O
tabulated	O
.	O

In	O
this	O
study	O
,	O
a	O
common	O
mechanism	O
has	O
been	O
identified	O
to	O
coordinate	O
the	O
growth	O
-	O
and	O
FC	O
-	O
dependent	O
expression	O
of	O
caveolin	B-GENE
.	O

Comparison	O
of	O
the	O
plant	O
nuclear	O
tRNA	O
3	O
'	O
processing	O
enzyme	O
with	O
the	O
plant	O
mitochondrial	O
one	O
suggests	O
that	O
both	O
activities	O
are	O
different	O
enzymes	O
.	O

NKX2	B-GENE
.	I-GENE
1	I-GENE
is	O
a	O
member	O
of	O
the	O
NK2	B-GENE
family	I-GENE
of	O
homeodomain	B-GENE
-	I-GENE
containing	I-GENE
transcription	I-GENE
factors	I-GENE
whose	O
targeted	O
disruption	O
in	O
mouse	O
results	O
in	O
the	O
absence	O
of	O
thyroid	O
tissue	O
and	O
a	O
severely	O
abnormal	O
lung	O
phenotype	O
.	O

National	O
abortion	O
laws	O
usually	O
do	O
not	O
allow	O
abortion	O
when	O
a	O
foetus	O
is	O
independently	O
viable	O
,	O
i	O
.	O
e	O
.	O
from	O
a	O
gestational	O
age	O
of	O
about	O
24	O
weeks	O
.	O

Deglutition	O
is	O
considered	O
to	O
be	O
immature	O
in	O
infants	O
and	O
to	O
mature	O
postnatally	O
.	O

This	O
repression	O
does	O
not	O
require	O
the	O
PU	B-GENE
.	I-GENE
1	I-GENE
transactivation	O
or	O
PEST	O
domains	O
and	O
cannot	O
be	O
reversed	O
by	O
p300	B-GENE
expression	O
.	O

First	O
,	O
human	O
erythroid	O
K562	O
cells	O
stably	O
integrated	O
with	O
various	O
HS	B-GENE
-	I-GENE
40	I-GENE
mutants	I-GENE
cis	O
linked	O
to	O
a	O
human	B-GENE
alpha	I-GENE
-	I-GENE
globin	I-GENE
promoter	I-GENE
-	O
growth	B-GENE
hormone	I-GENE
hybrid	O
gene	O
were	O
analyzed	O
by	O
genomic	O
footprinting	O
and	O
expression	O
analysis	O
.	O

Interestingly	O
,	O
addition	O
of	O
purified	O
CBP	B-GENE
to	O
the	O
nuclear	O
extracts	O
of	O
T47D	O
cells	O
markedly	O
stimulated	O
progesterone	O
-	O
and	O
PR	B-GENE
-	O
dependent	O
transcription	O
from	O
a	O
nucleosome	O
-	O
free	O
,	O
progesterone	O
response	O
element	O
(	O
PRE	O
)	O
-	O
linked	O
reporter	O
DNA	O
template	O
.	O

Its	O
cognate	O
binding	O
protein	O
,	O
REST	B-GENE
/	O
NRSF	B-GENE
,	O
is	O
an	O
essential	O
transcription	O
factor	O
;	O
its	O
null	O
mutations	O
result	O
in	O
embryonic	O
lethality	O
,	O
and	O
its	O
dominant	O
negative	O
mutants	O
produce	O
aberrant	O
expression	O
of	O
neuron	O
-	O
specific	O
genes	O
.	O

Removal	O
of	O
all	O
core	B-GENE
histone	I-GENE
tail	O
domains	O
by	O
limited	O
trypsin	B-GENE
proteolysis	O
or	O
acetylation	O
of	O
the	O
core	B-GENE
histone	I-GENE
tails	O
significantly	O
relieves	O
this	O
inhibition	O
and	O
allows	O
TFIIIA	B-GENE
to	O
exhibit	O
high	O
-	O
affinity	O
binding	O
to	O
nucleosomal	O
DNA	O
.	O

OUTCOME	O
:	O
Acetylcholine	B-GENE
receptor	I-GENE
antibodies	I-GENE
and	O
single	O
-	O
fibre	O
electromyogram	O
were	O
useful	O
in	O
the	O
diagnosis	O
of	O
myasthenia	O
gravis	O
.	O

Characterization	O
of	O
the	O
5	O
'	O
-	O
flanking	O
region	O
of	O
the	O
human	B-GENE
multidrug	I-GENE
resistance	I-GENE
protein	I-GENE
2	I-GENE
(	O
MRP2	B-GENE
)	O
gene	O
and	O
its	O
regulation	O
in	O
comparison	O
withthe	O
multidrug	B-GENE
resistance	I-GENE
protein	I-GENE
3	I-GENE
(	O
MRP3	B-GENE
)	O
gene	O
.	O

These	O
results	O
suggest	O
that	O
the	O
M	O
.	O
jannaschii	O
as	O
well	O
as	O
related	O
archaeal	B-GENE
20S	I-GENE
proteasomes	I-GENE
require	O
a	O
nucleotidase	O
complex	O
such	O
as	O
PAN	B-GENE
to	O
mediate	O
the	O
energy	O
-	O
dependent	O
hydrolysis	O
of	O
folded	O
-	O
substrate	O
proteins	O
and	O
that	O
the	O
N	O
-	O
terminal	O
73	O
amino	O
acid	O
residues	O
of	O
PAN	B-GENE
are	O
not	O
absolutely	O
required	O
for	O
this	O
reaction	O
.	O

The	O
transcription	O
factor	O
E2F	B-GENE
plays	O
an	O
important	O
role	O
in	O
G	O
(	O
1	O
)	O
to	O
S	O
phase	O
transition	O
in	O
the	O
higher	O
eukaryotic	O
cell	O
cycle	O
.	O

In	O
two	O
-	O
field	O
nodal	O
dissection	O
,	O
two	O
components	O
are	O
included	O
with	O
(	O
modern	O
two	O
-	O
field	O
)	O
or	O
without	O
(	O
traditional	O
two	O
-	O
field	O
)	O
nodal	O
dissection	O
around	O
both	O
recurrent	O
laryngeal	O
nerve	O
chains	O
in	O
the	O
upper	O
mediastinum	O
.	O

Of	O
the	O
153	O
patients	O
studied	O
,	O
CK	B-GENE
-	I-GENE
MB	I-GENE
results	O
were	O
positive	O
in	O
91	O
(	O
59	O
%	O
)	O
patients	O
;	O
ECG	O
revealed	O
AMI	O
in	O
72	O
(	O
47	O
%	O
)	O
patients	O
.	O

The	O
effect	O
of	O
MIB	O
on	O
the	O
dose	O
-	O
response	O
curve	O
of	O
externally	O
applied	O
noradrenaline	O
was	O
also	O
studied	O
.	O

The	O
regional	O
blockade	O
of	O
H1R	B-GENE
was	O
observed	O
mainly	O
in	O
the	O
frontal	O
,	O
temporal	O
and	O
anterior	O
cingulate	O
cortices	O
,	O
and	O
the	O
intravenous	O
administration	O
of	O
d	O
-	O
chlorpheniramine	O
as	O
a	O
therapeutic	O
dose	O
(	O
2	O
mg	O
)	O
blocked	O
over	O
60	O
%	O
of	O
H1R	B-GENE
in	O
the	O
frontal	O
cortices	O
.	O

Linearized	O
overall	O
infection	O
rates	O
(	O
events	O
/	O
100	O
patient	O
-	O
days	O
)	O
were	O
2	O
.	O
05	O
+	O
/	O
-	O
0	O
.	O
33	O
(	O
heart	O
-	O
lung	O
)	O
and	O
2	O
.	O
34	O
+	O
/	O
-	O
0	O
.	O
34	O
(	O
double	O
-	O
lung	O
;	O
P	O
=	O
NS	O
)	O
at	O
3	O
months	O
.	O

Static	O
and	O
dynamic	O
compliance	O
was	O
measured	O
after	O
induction	O
of	O
anesthesia	O
,	O
before	O
and	O
immediately	O
after	O
filtration	O
in	O
the	O
operating	O
theater	O
,	O
1	O
hour	O
after	O
return	O
to	O
the	O
pediatric	O
intensive	O
care	O
unit	O
,	O
and	O
24	O
hours	O
after	O
the	O
operation	O
.	O

Antipyretic	O
therapy	O
:	O
physiologic	O
rationale	O
,	O
diagnostic	O
implications	O
,	O
and	O
clinical	O
consequences	O
.	O

There	O
is	O
no	O
correlation	O
between	O
C2	O
-	O
C3	O
disk	O
morphology	O
and	O
the	O
diskographically	O
provoked	O
response	O
.	O

KFC	B-GENE
,	O
a	O
Ste20	B-GENE
-	I-GENE
like	I-GENE
kinase	I-GENE
with	O
mitogenic	O
potential	O
and	O
capability	O
to	O
activate	O
the	O
SAPK	B-GENE
/	O
JNK	B-GENE
pathway	O
.	O

We	O
have	O
mapped	O
the	O
human	B-GENE
STAG3	I-GENE
gene	I-GENE
to	O
the	O
7q22	O
region	O
of	O
chromosome	O
7	O
;	O
six	O
human	B-GENE
STAG3	I-GENE
-	I-GENE
related	I-GENE
genes	I-GENE
have	O
also	O
been	O
mapped	O
:	O
two	O
at	O
7q22	O
near	O
the	O
functional	O
gene	O
,	O
one	O
at	O
7q11	O
.	O
22	O
,	O
and	O
three	O
at	O
7q11	O
.	O
23	O
,	O
two	O
of	O
them	O
flanking	O
the	O
breakpoints	O
commonly	O
associated	O
with	O
the	O
Williams	B-GENE
-	I-GENE
Beuren	I-GENE
syndrome	I-GENE
(	I-GENE
WBS	I-GENE
)	I-GENE
deletion	I-GENE
.	O

Reaction	O
time	O
(	O
RT	O
)	O
and	O
P300	O
were	O
collected	O
simultaneously	O
.	O

In	O
experiment	O
2	O
the	O
rats	O
had	O
free	O
access	O
to	O
two	O
bottles	O
,	O
one	O
of	O
which	O
contained	O
tap	O
water	O
,	O
and	O
the	O
other	O
contained	O
either	O
an	O
ethanol	O
(	O
6	O
%	O
)	O
or	O
a	O
sucrose	O
(	O
5	O
%	O
)	O
solution	O
.	O

Furthermore	O
,	O
Zelen	O
'	O
s	O
method	O
is	O
used	O
to	O
balance	O
the	O
number	O
of	O
patients	O
allocated	O
to	O
the	O
two	O
groups	O
within	O
each	O
institution	O
(	O
M	O
.	O

RESULTS	O
:	O
In	O
this	O
group	O
of	O
patients	O
,	O
male	O
gender	O
(	O
P	O
=	O
0	O
.	O

Selective	O
visual	O
attention	O
involves	O
dynamic	O
interplay	O
between	O
attentional	O
control	O
systems	O
and	O
sensory	O
brain	O
structures	O
.	O

The	O
patient	O
had	O
developed	O
left	O
-	O
sided	O
low	O
-	O
frequency	O
tremor	O
and	O
hemidystonia	O
after	O
a	O
severe	O
head	O
trauma	O
sustained	O
at	O
15	O
years	O
of	O
age	O
.	O

However	O
,	O
the	O
a1	O
isoform	O
is	O
expressed	O
most	O
heavily	O
in	O
brain	O
and	O
heart	O
,	O
a2	O
in	O
liver	O
and	O
kidney	O
,	O
and	O
a3	O
in	O
liver	O
,	O
lung	O
,	O
heart	O
,	O
brain	O
,	O
spleen	O
,	O
and	O
kidney	O
.	O

During	O
the	O
cloning	O
by	O
reverse	B-GENE
transcriptase	I-GENE
-	O
polymerase	O
chain	O
reaction	O
of	O
the	O
human	B-GENE
HIF	I-GENE
-	I-GENE
1alpha	I-GENE
subunit	I-GENE
,	O
we	O
isolated	O
two	O
cDNA	O
clones	O
which	O
corresponded	O
to	O
alternative	O
splicing	O
of	O
the	O
HIF	B-GENE
-	I-GENE
1alpha	I-GENE
gene	I-GENE
.	O

To	O
assess	O
the	O
relationship	O
between	O
G	B-GENE
(	I-GENE
q	I-GENE
)	I-GENE
/	O
G	B-GENE
(	I-GENE
11	I-GENE
)	I-GENE
function	O
with	O
the	O
phosphatidylinositol	B-GENE
3	I-GENE
-	I-GENE
kinase	I-GENE
dependent	O
pathway	O
,	O
expression	O
of	O
a	O
dominant	O
-	O
interfering	O
p85	B-GENE
regulatory	I-GENE
subunit	I-GENE
,	O
as	O
well	O
as	O
wortmannin	O
treatment	O
inhibited	O
insulin	B-GENE
-	O
stimulated	O
but	O
not	O
G	B-GENE
(	I-GENE
q	I-GENE
)	I-GENE
/	I-GENE
Q209L	I-GENE
-	O
stimulated	O
GLUT4	B-GENE
-	O
EGFP	B-GENE
translocation	O
.	O

In	O
endemic	O
BL	O
,	O
the	O
RB2	B-GENE
/	O
p130	B-GENE
gene	O
is	O
mutated	O
in	O
most	O
of	O
the	O
cases	O
,	O
and	O
the	O
protein	O
is	O
restricted	O
to	O
the	O
cytoplasm	O
.	O

Together	O
,	O
these	O
data	O
identify	O
ERK2	B-GENE
as	O
a	O
specific	O
and	O
direct	O
target	O
of	O
HePTP	B-GENE
and	O
are	O
consistent	O
with	O
a	O
model	O
in	O
which	O
HePTP	B-GENE
negatively	O
regulates	O
ERK2	B-GENE
activity	O
as	O
part	O
of	O
a	O
feedback	O
mechanism	O
.	O

Cross	O
-	O
reaction	O
between	O
a	O
monoclonal	O
antibody	O
and	O
two	O
alpha	B-GENE
beta	I-GENE
T	I-GENE
cell	I-GENE
receptors	I-GENE
.	O

Strontium	O
nitrate	O
mixed	O
with	O
glycolic	O
acid	O
,	O
in	O
comparison	O
with	O
glycolic	O
acid	O
alone	O
,	O
markedly	O
(	O
p	O
<	O
0	O
.	O
01	O
)	O
shortened	O
the	O
duration	O
of	O
the	O
irritation	O
sensation	O
from	O
24	O
.	O
4	O
+	O
/	O
-	O
4	O
.	O
1	O
(	O
mean	O
+	O
/	O
-	O
SEM	O
)	O
min	O
to	O
8	O
.	O
9	O
+	O
/	O
-	O
3	O
.	O
7	O
(	O
mean	O
+	O
/	O
-	O
SEM	O
)	O
min	O
,	O
and	O
significantly	O
(	O
p	O
<	O
0	O
.	O
05	O
)	O
reduced	O
the	O
mean	O
magnitude	O
of	O
the	O
irritation	O
sensation	O
at	O
all	O
time	O
points	O
(	O
overall	O
)	O
.	O

The	O
pCMBS	O
-	O
reactive	O
sulfhydryl	O
groups	O
were	O
located	O
exclusively	O
in	O
the	O
exofacial	O
half	O
of	O
the	O
plasma	O
membrane	O
and	O
,	O
when	O
presented	O
in	O
a	O
helical	O
model	O
,	O
lie	O
along	O
one	O
side	O
of	O
the	O
helices	O
.	O

Analysis	O
of	O
1	O
Mb	O
of	O
published	O
sequence	O
from	O
the	O
region	O
of	O
conserved	O
synteny	O
on	O
human	O
chromosome	O
5q31	O
-	O
q33	O
identified	O
45	O
gene	O
candidates	O
,	O
including	O
35	O
expressed	O
genes	O
in	O
the	O
human	B-GENE
IL	I-GENE
-	I-GENE
4	I-GENE
cytokine	I-GENE
gene	I-GENE
cluster	I-GENE
.	O

Human	B-GENE
AP	I-GENE
-	I-GENE
2rep	I-GENE
repressed	O
both	O
reporter	O
expression	O
from	O
a	O
transiently	O
transfected	O
AP	B-GENE
-	I-GENE
2alpha	I-GENE
promoter	I-GENE
and	O
the	O
endogenous	O
AP	B-GENE
-	I-GENE
2alpha	I-GENE
gene	I-GENE
and	O
inversely	O
was	O
negatively	O
regulated	O
by	O
AP	B-GENE
-	I-GENE
2alpha	I-GENE
.	O

In	O
order	O
to	O
gain	O
deeper	O
insight	O
into	O
the	O
role	O
of	O
the	O
amino	O
-	O
terminal	O
domain	O
of	O
the	O
p24	B-GENE
(	O
CA	B-GENE
)	O
protein	O
during	O
viral	O
replication	O
,	O
eight	O
highly	O
conserved	O
proline	O
residues	O
known	O
to	O
promote	O
turns	O
and	O
to	O
terminate	O
alpha	O
-	O
helices	O
within	O
the	O
p24	B-GENE
tertiary	O
structure	O
were	O
replaced	O
by	O
a	O
leucine	O
residue	O
(	O
P	O
-	O
position	O
-	O
L	O
)	O
.	O

Clb	B-GENE
/	O
Cdc28	B-GENE
kinases	O
promote	O
nuclear	O
export	O
of	O
the	O
replication	B-GENE
initiator	I-GENE
proteins	I-GENE
Mcm2	I-GENE
-	I-GENE
7	I-GENE
.	O

Cooperative	O
roles	O
of	O
Bozozok	B-GENE
/	O
Dharma	B-GENE
and	O
Nodal	B-GENE
-	I-GENE
related	I-GENE
proteins	I-GENE
in	O
the	O
formation	O
of	O
the	O
dorsal	O
organizer	O
in	O
zebrafish	O
.	O

Thiopentone	O
sodium	O
administered	O
at	O
30	O
and	O
10	O
min	O
before	O
or	O
5	O
,	O
10	O
and	O
15	O
min	O
after	O
exposure	O
to	O
NOC	O
-	O
5	O
,	O
but	O
not	O
thereafter	O
,	O
significantly	O
attenuated	O
NO	O
-	O
induced	O
neurotoxicity	O
compared	O
with	O
controls	O
.	O

We	O
also	O
show	O
that	O
zygotically	O
activated	O
Xretpos	O
transcripts	O
are	O
restricted	O
to	O
ventro	O
-	O
posterior	O
specific	O
regions	O
and	O
induced	O
by	O
UV	O
-	O
irradiation	O
and	O
BMP	B-GENE
-	I-GENE
4	I-GENE
overexpression	O
in	O
cycloheximide	O
-	O
dependent	O
way	O
.	O
genesis	O
26	O
:	O
198	O
-	O
207	O
,	O
2000	O
.	O

In	O
all	O
other	O
cases	O
,	O
vestibular	O
neurectomy	O
or	O
chemical	O
vestibular	O
labyrinthectomy	O
,	O
by	O
means	O
of	O
intratympanic	O
low	O
concentration	O
gentamicin	O
(	O
20	O
mg	O
/	O
mL	O
)	O
,	O
are	O
indicated	O
.	O

However	O
,	O
when	O
,	O
where	O
and	O
how	O
the	O
DSPP	B-GENE
is	O
cleaved	O
into	O
DSP	B-GENE
and	O
DPP	B-GENE
is	O
not	O
clear	O
.	O

It	O
has	O
a	O
grave	O
prognosis	O
with	O
>	O
70	O
%	O
mortality	O
in	O
3	O
months	O
,	O
despite	O
mechanical	O
ventilation	O
.	O

We	O
found	O
that	O
TCR	B-GENE
signaling	O
induces	O
AP	B-GENE
-	I-GENE
1	I-GENE
binding	O
to	O
this	O
site	O
and	O
regulates	O
the	O
fasl	B-GENE
promoter	I-GENE
function	O
in	O
a	O
fashion	O
dependent	O
on	O
NF	B-GENE
-	I-GENE
kappaB	I-GENE
binding	O
.	O

Thus	O
,	O
patients	O
with	O
metastatic	O
melanoma	O
are	O
not	O
tolerant	O
to	O
gp100	B-GENE
Ag	I-GENE
based	O
on	O
the	O
detection	O
of	O
CD8	B-GENE
+	I-GENE
T	O
cells	O
specific	O
for	O
multiple	O
HLA	B-GENE
-	I-GENE
A	I-GENE
*	I-GENE
0201	I-GENE
-	O
restricted	O
,	O
gp100	B-GENE
-	O
derived	O
epitopes	O
.	O

Following	O
the	O
observation	O
that	O
non	O
-	O
organ	O
-	O
specific	O
antibodies	O
are	O
related	O
with	O
pregnancy	O
loss	O
and	O
preeclampsia	O
,	O
the	O
role	O
of	O
organ	O
-	O
specific	O
antibodies	O
is	O
currently	O
being	O
extensively	O
investigated	O
.	O

The	O
Mif1	B-GENE
5	I-GENE
'	I-GENE
flanking	I-GENE
region	I-GENE
contains	O
a	O
functional	O
ER	O
stress	O
-	O
responsive	O
element	O
which	O
is	O
sufficient	O
for	O
induction	O
by	O
tunicamycin	O
.	O

Rigid	O
point	O
feature	O
registration	O
using	O
mutual	O
information	O
.	O

Methysergide	O
is	O
a	O
serotonin	O
antagonist	O
and	O
has	O
been	O
demonstrated	O
to	O
reduce	O
wound	O
blood	O
flow	O
and	O
edema	O
formation	O
.	O

Serum	O
leptin	B-GENE
concentrations	O
in	O
women	O
during	O
gonadotropin	B-GENE
stimulation	O
cycles	O
.	O

Valuing	O
families	O
:	O
social	O
work	O
practice	O
with	O
families	O
from	O
a	O
strengths	O
perspective	O
.	O

PURPOSE	O
:	O
A	O
two	O
-	O
generation	O
consanguineous	O
Pakistani	O
family	O
with	O
autosomal	O
recessive	O
Leber	O
congenital	O
amaurosis	O
(	O
LCA	O
,	O
MIM	O
204	O
,	O
000	O
)	O
and	O
keratoconus	O
was	O
identified	O
.	O

Ste18p	B-GENE
was	O
targeted	O
to	O
the	O
plasma	O
membrane	O
even	O
in	O
the	O
absence	O
of	O
prenylation	O
or	O
thioacylation	O
.	O

Here	O
,	O
we	O
show	O
that	O
IRF	B-GENE
-	I-GENE
1	I-GENE
is	O
degraded	O
via	O
the	O
ubiquitin	B-GENE
-	O
proteasome	O
pathway	O
.	O

Here	O
we	O
show	O
that	O
IIIa	O
pre	O
-	O
mRNA	O
splicing	O
is	O
activated	O
more	O
than	O
200	O
-	O
fold	O
in	O
nuclear	O
extracts	O
prepared	O
from	O
late	O
adenovirus	O
-	O
infected	O
cells	O
(	O
Ad	O
-	O
NE	O
)	O
compared	O
to	O
uninfected	O
HeLa	O
cell	O
nuclear	O
extracts	O
(	O
HeLa	O
-	O
NE	O
)	O
.	O

Inactivation	O
of	O
Ulp2	B-GENE
also	O
suppresses	O
several	O
ulp1	B-GENE
(	I-GENE
ts	I-GENE
)	I-GENE
defects	O
,	O
and	O
the	O
double	O
mutant	O
accumulates	O
far	O
fewer	O
Smt3	B-GENE
-	I-GENE
protein	I-GENE
conjugates	O
than	O
either	O
single	O
mutant	O
.	O

Cyclin	B-GENE
A	I-GENE
expression	O
is	O
repressed	O
in	O
quiescent	O
cells	O
by	O
E2F	B-GENE
acting	O
in	O
conjunction	O
with	O
its	O
pocket	O
protein	O
partners	O
Rb	B-GENE
,	O
p107	B-GENE
,	O
and	O
p130	B-GENE
;	O
however	O
,	O
v	B-GENE
-	I-GENE
Jun	I-GENE
overrides	O
this	O
control	O
,	O
causing	O
phosphorylated	O
Rb	B-GENE
and	O
proliferation	O
-	O
specific	O
E2F	B-GENE
-	O
p107	B-GENE
complexes	O
to	O
persist	O
after	O
mitogen	O
withdrawal	O
.	O

D	B-GENE
-	I-GENE
cyclin	I-GENE
-	O
cdk	B-GENE
activity	O
is	O
required	O
for	O
Rb	B-GENE
phosphorylation	O
in	O
v	B-GENE
-	I-GENE
Jun	I-GENE
-	O
transformed	O
cells	O
,	O
since	O
ectopic	O
expression	O
of	O
the	O
cdk4	B-GENE
-	O
and	O
cdk6	B-GENE
-	O
specific	O
inhibitor	O
p16	B-GENE
(	O
INK4A	B-GENE
)	O
inhibits	O
both	O
DNA	O
synthesis	O
and	O
cell	O
proliferation	O
.	O

CONCLUSION	O
:	O
A	O
valve	O
-	O
like	O
mechanism	O
formed	O
by	O
the	O
capsulorhexis	O
rim	O
partially	O
adhered	O
to	O
the	O
IOL	O
optic	O
can	O
occur	O
postoperatively	O
.	O

The	O
protein	O
first	O
identified	O
by	O
the	O
monoclonal	B-GENE
antibody	I-GENE
Q18	I-GENE
is	O
encoded	O
by	O
a	O
gene	O
located	O
in	O
57A	O
on	O
polytene	O
chromosomes	O
and	O
has	O
been	O
consequently	O
named	O
Hrb57A	B-GENE
.	O

3	O
'	O
RNA	O
boundary	O
experiments	O
indicate	O
that	O
the	O
5	O
'	O
structure	O
reduces	O
the	O
number	O
of	O
(	O
G	O
/	O
U	O
)	O
AG	O
repeats	O
required	O
for	O
stable	O
TRAP	B-GENE
-	O
trp	B-GENE
leader	O
RNA	O
association	O
.	O

Gene	O
silencing	O
associated	O
with	O
repeated	O
DNA	O
sequences	O
has	O
been	O
reported	O
for	O
many	O
eukaryotes	O
,	O
including	O
plants	O
.	O

Animals	O
received	O
a	O
dose	O
of	O
dexamethasone	O
(	O
10	O
mg	O
/	O
kg	O
i	O
.	O
p	O
.	O
)	O
prior	O
to	O
the	O
protein	O
-	O
free	O
surfactant	O
preparation	O
Exosurf	O
(	O
pure	O
phospholipids	O
containing	O
surfactant	O
,	O
Wellcome	O
GmbH	O
,	O
Burgwedel	O
,	O
Germany	O
)	O
and	O
a	O
rSP	O
-	O
C	O
based	O
surfactant	O
,	O
respectively	O
.	O

BACKGROUND	O
:	O
The	O
aim	O
of	O
this	O
study	O
was	O
to	O
determine	O
the	O
response	O
rates	O
and	O
toxicity	O
of	O
two	O
regimens	O
containing	O
granulocyte	B-GENE
-	I-GENE
macrophage	I-GENE
-	I-GENE
colony	I-GENE
stimulating	I-GENE
factor	I-GENE
(	O
GM	B-GENE
-	I-GENE
CSF	I-GENE
)	O
in	O
combination	O
with	O
interleukin	B-GENE
-	I-GENE
2	I-GENE
(	O
IL	B-GENE
-	I-GENE
2	I-GENE
)	O
in	O
the	O
treatment	O
of	O
patients	O
with	O
metastatic	O
renal	O
cell	O
carcinoma	O
.	O

We	O
show	O
,	O
by	O
injection	O
of	O
synthetic	O
mRNAs	O
,	O
that	O
the	O
cis	O
-	O
acting	O
sequences	O
responsible	O
for	O
repression	O
of	O
cyclin	B-GENE
B1	I-GENE
mRNA	I-GENE
reside	O
within	O
its	O
3	O
'	O
UTR	O
.	O

These	O
data	O
indicate	O
that	O
expansion	O
of	O
the	O
dodecamer	O
repeat	O
located	O
in	O
the	O
proximal	O
promoter	O
of	O
CSTB	B-GENE
severely	O
disrupts	O
the	O
function	O
of	O
the	O
promoter	O
and	O
thereby	O
reduces	O
transcription	O
of	O
CSTB	B-GENE
.	O

Thus	O
,	O
while	O
the	O
genomic	O
organization	O
of	O
mHuA	B-GENE
is	O
similar	O
to	O
the	O
neural	O
-	O
restricted	O
members	O
of	O
the	O
Elav	B-GENE
family	I-GENE
,	O
the	O
promoter	O
element	O
differs	O
substantially	O
both	O
by	O
sequence	O
analysis	O
and	O
transcriptional	O
activity	O
in	O
non	O
-	O
neural	O
cell	O
types	O
.	O

Analysis	O
of	O
the	O
5	O
'	O
end	O
of	O
the	O
mouse	B-GENE
Elavl1	I-GENE
(	O
mHuA	B-GENE
)	O
gene	O
reveals	O
a	O
transcriptional	O
regulatory	O
element	O
and	O
evidence	O
for	O
conserved	O
genomic	O
organization	O
.	O
mHuA	B-GENE
(	O
Elavl1	B-GENE
)	O
belongs	O
to	O
a	O
highly	O
conserved	O
family	O
of	O
genes	O
encoding	O
RNA	O
-	O
binding	O
proteins	O
and	O
has	O
been	O
linked	O
to	O
cell	O
growth	O
and	O
proliferation	O
through	O
its	O
regulation	O
of	O
mRNA	O
stability	O
.	O

Fgd3	B-GENE
and	O
FGD1	B-GENE
share	O
a	O
high	O
degree	O
of	O
sequence	O
identity	O
that	O
spans	O
>	O
560	O
contiguous	O
amino	O
acid	O
residues	O
.	O

Molecular	O
cloning	O
of	O
mouse	B-GENE
thioredoxin	I-GENE
reductases	I-GENE
.	O

The	O
HPLC	O
method	O
involves	O
an	O
octadecylsilane	O
column	O
at	O
55	O
degrees	O
C	O
,	O
a	O
mixture	O
of	O
water	O
-	O
acetonitrile	O
-	O
orthophosphoric	O
acid	O
(	O
779	O
:	O
220	O
:	O
1	O
,	O
v	O
/	O
v	O
)	O
as	O
mobile	O
phase	O
and	O
detection	O
at	O
226	O
nm	O
.	O

CYC2	B-GENE
encodes	O
a	O
24	O
-	O
kDa	O
protein	O
that	O
has	O
sequence	O
identity	O
to	O
the	O
Neurospora	B-GENE
crassa	I-GENE
PREG1	I-GENE
and	O
the	O
S	B-GENE
.	I-GENE
cerevisiae	I-GENE
PHO80	I-GENE
cyclin	I-GENE
.	O

To	O
determine	O
if	O
CYC2	B-GENE
is	O
found	O
in	O
a	O
complex	O
with	O
previously	O
identified	O
trypanosome	B-GENE
cdc2	I-GENE
-	I-GENE
related	I-GENE
kinases	I-GENE
(	O
CRKs	B-GENE
)	O
,	O
the	O
CYC2	B-GENE
gene	I-GENE
was	O
fused	O
to	O
the	O
TY	B-GENE
epitope	I-GENE
tag	O
,	O
integrated	O
into	O
the	O
trypanosome	O
genome	O
,	O
and	O
expressed	O
under	O
inducible	O
control	O
.	O

These	O
findings	O
indicate	O
the	O
involvement	O
of	O
Sp1	B-GENE
and	O
an	O
Inr	O
in	O
non	O
-	O
cell	O
-	O
specific	O
regulation	O
and	O
a	O
Kruppel	B-GENE
-	I-GENE
like	I-GENE
transcription	I-GENE
factor	I-GENE
and	O
Sp1	B-GENE
in	O
the	O
cell	O
-	O
specific	O
regulation	O
of	O
the	O
LTC	B-GENE
(	I-GENE
4	I-GENE
)	I-GENE
S	I-GENE
gene	I-GENE
.	O

Here	O
we	O
review	O
progress	O
to	O
date	O
in	O
this	O
area	O
.	O

Additionally	O
,	O
the	O
mouse	O
promoter	O
contains	O
22	O
copies	O
of	O
a	O
CT	O
dinucleotide	O
repeat	O
sequence	O
located	O
approximately	O
155	O
bp	O
5	O
'	O
to	O
exon	O
1	O
.	O

The	O
newly	O
defined	O
region	O
contains	O
an	O
intron	O
that	O
may	O
be	O
alternatively	O
spliced	O
and	O
seven	O
polyadenylation	O
signal	O
sequences	O
.	O

Depleted	O
and	O
enriched	O
U3O8	O
standard	O
reference	O
materials	O
were	O
used	O
to	O
calibrate	O
the	O
system	O
.	O

Therefore	O
,	O
the	O
positive	O
cAMP	O
control	O
of	O
the	O
hypoxic	O
SRP1	B-GENE
and	O
HEM13	B-GENE
genes	I-GENE
was	O
uncoupled	O
from	O
the	O
HOG	B-GENE
pathway	O
.	O

This	O
paper	O
reviews	O
the	O
middleware	O
-	O
based	O
approach	O
adopted	O
by	O
CEN	O
ENV	O
12967	O
-	O
1	O
and	O
the	O
specialisation	O
necessary	O
for	O
the	O
healthcare	O
record	O
based	O
on	O
CEN	O
ENV	O
12265	O
'	O
Electronic	O
Healthcare	O
Record	O
Architecture	O
'	O
.	O

Sequence	O
analyses	O
of	O
sos2	B-GENE
mutant	I-GENE
alleles	I-GENE
reveal	O
that	O
both	O
the	O
N	O
-	O
terminal	O
catalytic	O
domain	O
and	O
the	O
C	O
-	O
terminal	O
regulatory	O
domain	O
of	O
SOS2	B-GENE
are	O
functionally	O
essential	O
.	O

A	O
mutation	O
which	O
abrogates	O
the	O
binding	O
of	O
these	O
factors	O
reduces	O
Wp	B-GENE
reporter	I-GENE
activity	O
specifically	O
in	O
B	O
cell	O
lines	O
,	O
whereas	O
a	O
mutation	O
which	O
converts	O
the	O
site	O
to	O
a	O
consensus	O
CREB	B-GENE
-	I-GENE
binding	I-GENE
sequence	I-GENE
maintains	O
wild	O
-	O
type	O
promoter	O
function	O
.	O

Therefore	O
the	O
binding	O
sites	O
for	O
liver	O
-	O
enriched	O
factors	O
,	O
present	O
in	O
the	O
hamster	B-GENE
CYP7A1	I-GENE
proximal	I-GENE
promoter	I-GENE
in	O
close	O
vicinity	O
and	O
conserved	O
between	O
species	O
,	O
constitute	O
a	O
regulatory	O
unit	O
important	O
for	O
basal	O
hepatic	O
expression	O
and	O
tissue	O
restriction	O
of	O
the	O
action	O
of	O
hormones	O
such	O
as	O
insulin	B-GENE
.	O

The	O
kinase	O
activity	O
of	O
PfPK6	B-GENE
is	O
sensitive	O
to	O
CDK	B-GENE
inhibitors	O
such	O
as	O
olomoucine	O
and	O
roscovitine	O
.	O

Although	O
MAP	B-GENE
(	I-GENE
mitogen	I-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
)	I-GENE
kinases	I-GENE
are	O
implicated	O
in	O
cell	O
proliferation	O
and	O
differentiation	O
in	O
many	O
cell	O
types	O
,	O
the	O
role	O
of	O
MAP	B-GENE
kinases	I-GENE
in	O
cardiac	O
hypertrophy	O
remains	O
unclear	O
.	O

Transfection	O
with	O
a	O
CSF	B-GENE
-	I-GENE
1R	I-GENE
expression	O
plasmid	O
permitted	O
CSF	B-GENE
-	I-GENE
1	I-GENE
-	O
dependent	O
activation	O
of	O
the	O
signalling	O
pathway	O
targeting	O
an	O
Ets	B-GENE
/	O
AP1	B-GENE
(	O
activator	B-GENE
protein	I-GENE
1	I-GENE
)	O
element	O
in	O
the	O
uPA	B-GENE
promoter	I-GENE
that	O
has	O
been	O
shown	O
previously	O
to	O
be	O
a	O
target	O
of	O
oncogenic	B-GENE
ras	I-GENE
and	O
protein	O
kinase	O
C	O
pathways	O
.	O

Regulation	O
of	O
urokinase	B-GENE
plasminogen	I-GENE
activator	I-GENE
gene	I-GENE
transcription	O
in	O
the	O
RAW264	O
murine	O
macrophage	O
cell	O
line	O
by	O
macrophage	B-GENE
colony	I-GENE
-	I-GENE
stimulating	I-GENE
factor	I-GENE
(	O
CSF	B-GENE
-	I-GENE
1	I-GENE
)	O
is	O
dependent	O
upon	O
the	O
level	O
of	O
cell	O
-	O
surface	O
receptor	O
.	O

Molecule	O
(	O
s	O
)	O
secreted	O
by	O
neuronal	O
cultures	O
contribute	O
to	O
this	O
induction	O
of	O
GLT	B-GENE
-	I-GENE
1	I-GENE
,	O
but	O
little	O
is	O
known	O
about	O
the	O
signaling	O
pathways	O
mediating	O
this	O
regulation	O
.	O

Coactivation	O
of	O
endogenous	O
or	O
exogenous	O
G	B-GENE
(	I-GENE
q	I-GENE
)	I-GENE
-	I-GENE
coupled	I-GENE
receptors	I-GENE
with	O
the	O
delta	B-GENE
-	I-GENE
opioid	I-GENE
receptor	I-GENE
produced	O
strong	O
stimulations	O
of	O
PLCbeta	B-GENE
and	O
such	O
responses	O
could	O
be	O
partially	O
blocked	O
by	O
pertussis	B-GENE
toxin	I-GENE
.	O

Patients	O
enrolled	O
in	O
the	O
Integrilin	O
to	O
Minimize	O
Platelet	O
Aggregation	O
and	O
Coronary	O
Thrombosis	O
-	O
II	O
(	O
IMPACT	O
-	O
II	O
)	O
trial	O
were	O
analyzed	O
.	O

The	O
Wnt	B-GENE
signaling	O
pathway	O
functions	O
reiteratively	O
during	O
animal	O
development	O
to	O
control	O
cell	O
fate	O
decisions	O
.	O

This	O
mutation	O
no	O
longer	O
repressed	O
the	O
HPV	O
-	O
11	O
upstream	O
regulatory	O
region	O
-	O
controlled	O
reporter	O
expression	O
.	O

In	O
the	O
icosahaedral	O
MVMi	O
capsid	O
,	O
this	O
sequence	O
forms	O
the	O
carboxy	O
end	O
of	O
the	O
amphipathic	O
beta	O
-	O
strand	O
I	O
(	O
betaI	O
)	O
,	O
and	O
all	O
its	O
basic	O
residues	O
are	O
contiguously	O
positioned	O
at	O
the	O
face	O
that	O
in	O
the	O
unassembled	O
subunit	O
would	O
be	O
exposed	O
to	O
solvent	O
.	O

The	O
two	O
contiguous	O
IGF2	B-GENE
(	O
human	B-GENE
insulin	I-GENE
-	I-GENE
like	I-GENE
growth	I-GENE
factor	I-GENE
II	I-GENE
)	O
and	O
H19	B-GENE
genes	I-GENE
are	O
reciprocally	O
imprinted	O
in	O
both	O
human	O
and	O
mouse	O
.	O

The	O
asymmetric	O
methylation	O
was	O
associated	O
with	O
tissue	O
-	O
specific	O
disruption	O
of	O
H19	B-GENE
genomic	O
imprinting	O
in	O
fetal	O
brain	O
.	O

Early	O
treatment	O
mechanics	O
of	O
the	O
Class	O
II	O
division	O
2	O
malocclusion	O
.	O

The	O
consensus	O
highlights	O
the	O
importance	O
of	O
residues	O
other	O
than	O
the	O
eight	O
motifs	O
that	O
are	O
often	O
associated	O
with	O
DEAD	B-GENE
-	I-GENE
box	I-GENE
RNA	I-GENE
helicases	I-GENE
,	O
as	O
well	O
as	O
de	O
-	O
emphasising	O
the	O
importance	O
of	O
the	O
"	O
A	O
"	O
residue	O
within	O
the	O
"	O
DEAD	O
"	O
motif	O
.	O

In	O
transient	O
assays	O
,	O
using	O
rice	O
suspension	O
-	O
cultured	O
cells	O
transformed	O
by	O
particle	O
bombardment	O
,	O
we	O
showed	O
previously	O
that	O
Oshox1	B-GENE
can	O
transcriptionally	O
repress	O
the	O
activity	O
of	O
reporter	O
gene	O
constructs	O
with	O
upstream	O
HD	B-GENE
-	I-GENE
Zip	I-GENE
binding	O
sites	O
.	O

Results	O
of	O
two	O
-	O
hybrid	O
assays	O
and	O
electrophoretic	O
mobility	O
shift	O
assays	O
strongly	O
suggest	O
that	O
all	O
HD	B-GENE
-	I-GENE
Zip	I-GENE
proteins	I-GENE
of	O
families	O
I	O
and	O
II	O
can	O
form	O
homodimers	O
and	O
also	O
heterodimers	O
with	O
all	O
HD	B-GENE
-	I-GENE
Zip	I-GENE
proteins	I-GENE
of	O
the	O
same	O
family	O
.	O

Among	O
mammalian	B-GENE
HSFs	I-GENE
,	O
HSF1	B-GENE
has	O
been	O
shown	O
to	O
be	O
important	O
for	O
regulation	O
of	O
the	O
heat	O
-	O
induced	O
stress	O
gene	O
expression	O
,	O
whereas	O
the	O
function	O
of	O
HSF2	B-GENE
in	O
stress	O
response	O
is	O
unclear	O
.	O

Importantly	O
,	O
concomitant	O
expression	O
of	O
constitutive	O
activated	O
Raf	B-GENE
and	O
V12N38	B-GENE
Ras	I-GENE
results	O
in	O
almost	O
complete	O
loss	O
of	O
TTF	B-GENE
-	I-GENE
1	I-GENE
activity	O
.	O

They	O
share	O
many	O
downstream	O
targets	O
,	O
including	O
remodeling	O
of	O
the	O
actin	B-GENE
cytoskeleton	O
,	O
activation	O
of	O
p70	B-GENE
(	I-GENE
S6	I-GENE
)	I-GENE
kinase	I-GENE
and	O
c	B-GENE
-	I-GENE
jun	I-GENE
N	I-GENE
-	I-GENE
terminal	I-GENE
kinase	I-GENE
(	O
JNK	B-GENE
)	O
,	O
and	O
regulation	O
of	O
transcription	O
and	O
cell	O
proliferation	O
.	O

Expression	O
of	O
activated	O
Cdc42	B-GENE
results	O
in	O
the	O
translocation	O
of	O
PKClambda	B-GENE
from	O
the	O
nucleus	O
into	O
the	O
cytosol	O
,	O
and	O
Cdc42	B-GENE
and	O
PKClambda	B-GENE
colocalize	O
at	O
the	O
plasma	O
membrane	O
and	O
in	O
the	O
cytoplasm	O
.	O

Copyright	O
2000	O
Academic	O
Press	O
.	O

Southern	O
blotting	O
and	O
single	O
strand	O
conformation	O
polymorphism	O
analyses	O
did	O
not	O
show	O
tumor	O
-	O
specific	O
alterations	O
of	O
this	O
gene	O
in	O
gliomas	O
and	O
RT	O
-	O
PCR	O
studies	O
showed	O
expression	O
in	O
glioma	O
cell	O
lines	O
,	O
suggesting	O
that	O
ANOVA	B-GENE
is	O
not	O
the	O
chromosome	O
19q	O
glioma	O
tumor	O
suppressor	O
gene	O
.	O

Enzyme	B-GENE
I	I-GENE
of	O
the	O
phosphoenolpyruvate	B-GENE
:	I-GENE
sugar	I-GENE
phosphotransferase	I-GENE
system	O
.	O

Based	O
on	O
these	O
data	O
,	O
we	O
conclude	O
that	O
transcription	O
of	O
prgX	B-GENE
is	O
initiated	O
from	O
the	O
Qa	B-GENE
promoter	I-GENE
in	O
prgQ	B-GENE
,	O
and	O
PrgX	B-GENE
autoregulates	O
its	O
transcription	O
either	O
by	O
mediating	O
transcriptional	O
readthrough	O
or	O
increasing	O
mRNA	O
stability	O
.	O

It	O
was	O
established	O
that	O
intrathecal	O
or	O
intraperitoneal	O
PTFL	O
,	O
elevated	O
the	O
nociceptive	O
threshold	O
for	O
mechanical	O
stimuli	O
in	O
the	O
formalin	O
test	O
in	O
rats	O
.	O

Molecular	O
mimicry	O
of	O
human	O
cytokine	O
and	O
cytokine	O
response	O
pathway	O
genes	O
by	O
KSHV	O
.	O

Family	O
environment	O
was	O
an	O
important	O
influence	O
on	O
interpersonal	O
relationships	O
,	O
substance	O
use	O
,	O
and	O
social	O
support	O
.	O

By	O
electrophoresis	O
mobility	O
shift	O
assays	O
using	O
probes	O
corresponding	O
to	O
different	O
segments	O
of	O
the	O
putative	O
human	B-GENE
c	I-GENE
-	I-GENE
myb	I-GENE
intron	I-GENE
1	I-GENE
transcription	I-GENE
pause	I-GENE
region	I-GENE
and	O
nuclear	O
extracts	O
from	O
myeloid	O
leukemia	O
HL	O
60	O
and	O
fibroblast	O
WI	O
38	O
cells	O
,	O
we	O
detected	O
a	O
HL	O
-	O
60	O
-	O
specific	O
DNA	O
-	O
protein	O
complex	O
with	O
a	O
123	O
-	O
bp	O
fragment	O
containing	O
binding	O
sites	O
for	O
the	O
interferon	B-GENE
regulatory	I-GENE
factors	I-GENE
(	O
IRFs	B-GENE
)	O
nuclear	O
proteins	O
.	O

STUDY	O
DESIGN	O
:	O
Fine	O
needle	O
aspiration	O
cytologic	O
smears	O
from	O
21	O
cases	O
of	O
invasive	O
lobular	O
carcinoma	O
(	O
ILC	O
)	O
of	O
breast	O
were	O
subjected	O
to	O
detailed	O
cytomorphologic	O
analysis	O
.	O

Electrophile	O
Response	O
Elements	O
(	O
EpREs	O
)	O
,	O
located	O
in	O
5	O
'	O
-	O
flanking	O
sequences	O
of	O
both	O
the	O
GCSh	B-GENE
and	O
GCSl	B-GENE
subunit	I-GENE
genes	I-GENE
,	O
are	O
hypothesized	O
to	O
at	O
least	O
partially	O
mediate	O
gene	O
induction	O
following	O
xenobiotic	O
exposure	O
.	O

A	O
new	O
technique	O
to	O
create	O
an	O
artificial	O
stenosis	O
in	O
the	O
native	O
LAD	O
using	O
a	O
hemoclip	O
.	O

Dll3	B-GENE
is	O
mutated	O
in	O
the	O
X	O
-	O
ray	O
-	O
induced	O
mouse	B-GENE
mutant	I-GENE
pudgy	I-GENE
(	O
pu	B-GENE
)	O
,	O
causing	O
a	O
variety	O
of	O
vertebrocostal	O
defects	O
similar	O
to	O
SD	O
phenotypes	O
.	O

TbRAB31	B-GENE
behaviour	O
was	O
also	O
studied	O
during	O
the	O
cell	O
cycle	O
;	O
TbRAB31	B-GENE
always	O
localised	O
to	O
a	O
discrete	O
structure	O
that	O
duplicated	O
very	O
early	O
in	O
mitosis	O
and	O
relocated	O
to	O
daughter	O
cells	O
in	O
a	O
coordinate	O
manner	O
with	O
the	O
basal	O
body	O
and	O
kinetoplast	O
,	O
suggesting	O
the	O
involvement	O
of	O
microtubules	O
.	O

Invertases	B-GENE
are	O
responsible	O
for	O
the	O
breakdown	O
of	O
sucrose	O
to	O
fructose	O
and	O
glucose	O
.	O

To	O
investigate	O
the	O
molecular	O
mechanisms	O
of	O
this	O
Tax	B-GENE
-	O
mediated	O
inhibition	O
,	O
we	O
analyzed	O
its	O
effect	O
on	O
the	O
transcriptional	O
activity	O
of	O
the	O
myogenic	O
MyoD	B-GENE
protein	I-GENE
,	O
which	O
was	O
used	O
as	O
a	O
paradigm	O
of	O
bHLH	B-GENE
factors	I-GENE
.	O

The	O
human	B-GENE
T	I-GENE
cell	I-GENE
leukemia	I-GENE
/	I-GENE
lymphotropic	I-GENE
virus	I-GENE
type	I-GENE
1	I-GENE
Tax	I-GENE
protein	I-GENE
represses	O
MyoD	B-GENE
-	O
dependent	O
transcription	O
by	O
inhibiting	O
MyoD	B-GENE
-	O
binding	O
to	O
the	O
KIX	B-GENE
domain	I-GENE
of	O
p300	B-GENE
.	O

Phosphorylation	O
and	O
spindle	O
pole	O
body	O
localization	O
of	O
the	O
Cdc15p	B-GENE
mitotic	I-GENE
regulatory	I-GENE
protein	I-GENE
kinase	I-GENE
in	I-GENE
budding	I-GENE
yeast	I-GENE
.	O

Thus	O
,	O
both	O
the	O
hyperplasia	O
and	O
thrombotic	O
complications	O
which	O
often	O
follow	O
stenting	O
might	O
be	O
minimized	O
by	O
employing	O
gold	O
stents	O
,	O
which	O
have	O
a	O
greater	O
capacity	O
than	O
steel	O
in	O
supporting	O
a	O
functional	O
neo	O
-	O
endothelium	O
.	O

The	O
cell	O
cycle	O
and	O
transcriptional	O
defects	O
caused	O
by	O
taf17	B-GENE
(	O
slm7	B-GENE
-	I-GENE
1	I-GENE
)	O
are	O
consistent	O
with	O
the	O
role	O
of	O
TAF	B-GENE
(	I-GENE
II	I-GENE
)	I-GENE
s	I-GENE
as	O
modulators	O
of	O
transcriptional	O
activation	O
and	O
may	O
reflect	O
a	O
role	O
for	O
TAF17	B-GENE
in	O
regulating	O
activation	O
by	O
SBF	B-GENE
and	O
MBF	B-GENE
.	O

Proteolysis	O
of	O
Mbp1	B-GENE
and	O
Swi4	B-GENE
DNA	I-GENE
-	I-GENE
protein	I-GENE
complexes	I-GENE
has	O
revealed	O
the	O
extent	O
of	O
these	O
sequences	O
,	O
and	O
C	O
-	O
terminally	O
extended	O
molecules	O
with	O
substantially	O
enhanced	O
DNA	O
binding	O
activity	O
compared	O
to	O
the	O
core	O
domains	O
alone	O
have	O
been	O
produced	O
.	O

These	O
results	O
indicate	O
that	O
residue	O
266	O
serves	O
as	O
a	O
"	O
protein	O
sensor	O
"	O
of	O
altered	O
minor	O
groove	O
interactions	O
and	O
identifies	O
which	O
base	O
pair	O
interactions	O
are	O
altered	O
by	O
these	O
lesions	O
.	O

The	O
recombinant	O
enzymes	O
exist	O
as	O
monomers	O
.	O

A	O
pathway	O
for	O
regulation	O
of	O
B	B-GENE
lymphocyte	I-GENE
antigen	I-GENE
receptor	I-GENE
-	O
induced	O
calcium	O
flux	O
.	O

We	O
now	O
describe	O
a	O
second	O
RIM	B-GENE
protein	I-GENE
,	O
called	O
RIM2	B-GENE
,	O
that	O
is	O
highly	O
homologous	O
to	O
RIM1	B-GENE
and	O
also	O
expressed	O
primarily	O
in	O
brain	O
.	O

Inhibitor	B-GENE
-	I-GENE
1	I-GENE
(	O
I	B-GENE
-	I-GENE
1	I-GENE
)	O
and	O
inhibitor	B-GENE
-	I-GENE
2	I-GENE
(	O
I	B-GENE
-	I-GENE
2	I-GENE
)	O
selectively	O
inhibit	O
type	B-GENE
1	I-GENE
protein	I-GENE
serine	I-GENE
/	I-GENE
threonine	I-GENE
phosphatases	I-GENE
(	O
PP1	B-GENE
)	O
.	O

The	O
substrates	O
for	O
glycan	O
synthesis	O
in	O
the	O
lumen	O
of	O
the	O
Golgi	O
are	O
nucleotide	O
sugars	O
that	O
must	O
be	O
transported	O
from	O
the	O
cytosol	O
by	O
specific	O
membrane	O
-	O
bound	O
transporters	O
.	O

Synaptic	O
targeting	O
of	O
the	O
postsynaptic	B-GENE
density	I-GENE
protein	I-GENE
PSD	I-GENE
-	I-GENE
95	I-GENE
mediated	O
by	O
a	O
tyrosine	O
-	O
based	O
trafficking	O
signal	O
.	O

(	O
1998	O
)	O
J	O
.	O

Both	O
normal	O
and	O
transforming	O
PCPH	B-GENE
proteins	I-GENE
have	O
guanosine	B-GENE
diphosphatase	I-GENE
activity	O
but	O
only	O
the	O
oncoprotein	O
cooperates	O
with	O
Ras	B-GENE
in	O
activating	O
extracellular	B-GENE
signal	I-GENE
-	I-GENE
regulated	I-GENE
kinase	I-GENE
ERK1	B-GENE
.	O

These	O
results	O
indicate	O
that	O
virulence	O
-	O
associated	O
genes	O
and	O
their	O
overall	O
chromosomal	O
arrangement	O
are	O
relatively	O
well	O
conserved	O
between	O
B	O
.	O
henselae	O
and	O
other	O
gram	O
-	O
negative	O
bacteria	O
such	O
as	O
A	O
.	O
tumefaciens	O
.	O

An	O
important	O
mechanism	O
by	O
which	O
the	O
tumor	O
suppressor	O
p53	B-GENE
maintains	O
genomic	O
stability	O
is	O
to	O
induce	O
cell	O
cycle	O
arrest	O
through	O
activation	O
of	O
the	O
cyclin	B-GENE
-	I-GENE
dependent	I-GENE
kinase	I-GENE
inhibitor	O
p21	B-GENE
(	O
WAF1	B-GENE
/	O
Cip1	B-GENE
)	O
gene	O
.	O

Paxillin	B-GENE
acts	O
as	O
an	O
adaptor	O
molecule	O
in	O
integrin	B-GENE
signaling	O
.	O

Thus	O
,	O
growth	O
factor	O
activation	O
of	O
ER	B-GENE
can	O
mediate	O
transactivation	O
vs	O
ER	B-GENE
/	O
Sp1	B-GENE
binding	O
to	O
GC	O
-	O
rich	O
sites	O
and	O
represents	O
a	O
novel	O
pathway	O
for	O
ligand	O
-	O
independent	O
ER	B-GENE
action	O
.	O

Furthermore	O
,	O
analysis	O
of	O
deletion	O
promoter	O
-	O
reporter	O
constructs	O
found	O
that	O
the	O
basal	O
activity	O
of	O
P2	O
resided	O
in	O
the	O
proximal	O
region	O
of	O
P2	O
.	O

RESULTS	O
:	O
Auditory	O
thresholds	O
collected	O
during	O
audiometric	O
tests	O
increased	O
gradually	O
in	O
proportion	O
with	O
age	O
,	O
especially	O
in	O
the	O
hypertensive	O
group	O
(	O
p	O
<	O
0	O
.	O
05	O
)	O
.	O

In	O
addition	O
,	O
the	O
transcription	O
of	O
c	B-GENE
-	I-GENE
IAP2	I-GENE
promoter	I-GENE
was	O
strongly	O
up	O
-	O
regulated	O
when	O
CD40	B-GENE
or	O
Epstein	B-GENE
-	I-GENE
Barr	I-GENE
virus	I-GENE
latent	I-GENE
membrane	I-GENE
protein	I-GENE
1	I-GENE
was	O
overexpressed	O
.	O

A	O
variety	O
of	O
professional	O
and	O
self	O
-	O
applied	O
fluoride	O
products	O
are	O
available	O
and	O
new	O
fluoride	O
delivery	O
systems	O
have	O
recently	O
entered	O
the	O
market	O
.	O

These	O
studies	O
identify	O
several	O
of	O
the	O
signal	O
-	O
transduction	O
events	O
involved	O
in	O
the	O
apoptosis	O
of	O
malignant	O
B	O
cells	O
that	O
transpire	O
following	O
ligation	O
of	O
CD20	B-GENE
by	O
anti	B-GENE
-	I-GENE
CD20	I-GENE
antibodies	I-GENE
in	O
the	O
presence	O
of	O
Fc	B-GENE
-	I-GENE
receptor	I-GENE
-	O
expressing	O
cells	O
or	O
secondary	O
goat	O
anti	B-GENE
-	I-GENE
(	I-GENE
mouse	I-GENE
Ig	I-GENE
)	I-GENE
antibodies	I-GENE
and	O
which	O
may	O
contribute	O
to	O
the	O
tumor	O
regressions	O
observed	O
in	O
mouse	O
models	O
and	O
clinical	O
trials	O
.	O

Phenazone	O
potentiates	O
the	O
local	O
anaesthetic	O
effect	O
of	O
lidocaine	O
in	O
mice	O
.	O

The	O
solubility	O
of	O
all	O
the	O
mutated	O
proteins	O
was	O
remarkably	O
reduced	O
.	O

Recently	O
,	O
identical	O
RBE	B-GENE
sequences	I-GENE
have	O
been	O
identified	O
at	O
other	O
locations	O
in	O
the	O
human	O
genome	O
.	O

EM	O
analysis	O
demonstrated	O
that	O
only	O
one	O
Rep	B-GENE
-	I-GENE
DNA	I-GENE
complex	I-GENE
was	O
formed	O
on	O
ch	O
-	O
19	O
target	O
DNA	O
.	O

The	O
protein	O
was	O
associated	O
with	O
purified	O
vaccinia	O
virus	O
particles	O
and	O
with	O
membranes	O
of	O
immature	O
and	O
mature	O
virions	O
that	O
were	O
visualized	O
by	O
electron	O
microscopy	O
of	O
infected	O
cells	O
.	O

CONCLUSION	O
:	O
More	O
than	O
50	O
%	O
of	O
patients	O
with	O
perennial	O
rhinitis	O
and	O
CRS	O
do	O
not	O
improve	O
after	O
surgery	O
,	O
a	O
response	O
that	O
may	O
be	O
predicted	O
by	O
more	O
cells	O
expressing	O
IL	B-GENE
-	I-GENE
5	I-GENE
mRNA	I-GENE
in	O
the	O
ethmoid	O
sinuses	O
.	O

On	O
the	O
basis	O
of	O
size	O
,	O
the	O
CRS	O
sequence	O
to	O
which	O
it	O
binds	O
,	O
and	O
its	O
tentative	O
identification	O
as	O
a	O
zinc	B-GENE
finger	I-GENE
protein	I-GENE
,	O
Adx	B-GENE
factor	I-GENE
has	O
been	O
identified	O
as	O
a	O
Kruppel	B-GENE
-	I-GENE
like	I-GENE
zinc	I-GENE
finger	I-GENE
protein	I-GENE
(	O
a	O
mouse	B-GENE
ZBP	I-GENE
-	I-GENE
89	I-GENE
homologue	I-GENE
)	O
.	O

METHODS	O
:	O
The	O
most	O
distal	O
muscle	O
fibres	O
from	O
the	O
deep	O
and	O
superficial	O
finger	O
flexors	O
were	O
measured	O
relative	O
to	O
the	O
pisiform	O
bone	O
in	O
18	O
cadaveric	O
specimens	O
.	O

Here	O
we	O
report	O
on	O
the	O
isolation	O
of	O
ICK2	B-GENE
,	O
and	O
show	O
that	O
it	O
interacts	O
with	O
Cdc2aAt	B-GENE
,	O
but	O
not	O
with	O
a	O
second	O
CDK	B-GENE
from	I-GENE
Arabidopsis	I-GENE
,	O
Cdc2bAt	B-GENE
.	O

Systemic	O
impact	O
of	O
risk	O
-	O
sharing	O
arrangements	O
.	O

METHODS	O
:	O
We	O
determined	O
an	O
odds	O
ratio	O
(	O
OR	O
)	O
,	O
as	O
a	O
measure	O
of	O
the	O
relative	O
risk	O
of	O
being	O
exposed	O
to	O
a	O
potential	O
interaction	O
,	O
comparing	O
the	O
use	O
of	O
the	O
H2	B-GENE
-	I-GENE
receptor	I-GENE
antagonist	O
,	O
cimetidine	O
,	O
with	O
that	O
of	O
the	O
noninteracting	O
agents	O
ranitidine	O
,	O
famotidine	O
and	O
nizatidine	O
in	O
users	O
and	O
nonusers	O
of	O
warfarin	O
,	O
phenytoin	O
and	O
theophylline	O
.	O

The	O
prevalence	O
of	O
malnutrition	O
was	O
30	O
%	O
in	O
the	O
47	O
patients	O
without	O
CVD	O
and	O
was	O
significantly	O
higher	O
(	O
70	O
%	O
,	O
P	O
<	O
0	O
.	O
001	O
)	O
in	O
the	O
70	O
patients	O
with	O
CVD	O
,	O
who	O
also	O
had	O
lower	O
tHcy	O
,	O
SAlb	O
,	O
plasma	B-GENE
IGF	I-GENE
-	I-GENE
1	I-GENE
,	O
serum	O
creatinine	O
(	O
SCr	O
)	O
,	O
and	O
blood	B-GENE
hemoglobin	I-GENE
.	O

Our	O
data	O
suggest	O
that	O
,	O
at	O
least	O
at	O
high	O
temperature	O
,	O
a	O
critical	O
minimal	O
level	O
of	O
Ypt	B-GENE
protein	I-GENE
prenylation	O
is	O
required	O
for	O
maintaining	O
vesicle	O
polarization	O
.	O

The	O
second	O
functional	O
pair	O
of	O
CreA	B-GENE
sites	I-GENE
is	O
located	O
between	O
the	O
two	O
transcription	O
initiation	O
sites	O
.	O

A	O
distinct	O
staining	O
pattern	O
for	O
the	O
N	B-GENE
-	I-GENE
utrophin	I-GENE
was	O
not	O
detectable	O
,	O
although	O
it	O
was	O
expected	O
to	O
localise	O
at	O
the	O
actin	B-GENE
stress	O
fibers	O
.	O

The	O
'	O
Newcastle	O
'	O
model	O
,	O
which	O
is	O
based	O
on	O
Hotelling	O
'	O
s	O
T2	O
statistic	O
,	O
proved	O
to	O
be	O
more	O
sensitive	O
and	O
diagnosed	O
a	O
systematic	O
displacement	O
for	O
three	O
prostate	O
patients	O
.	O

The	O
MMA	B-GENE
,	I-GENE
DMA	I-GENE
,	I-GENE
and	I-GENE
TMA	I-GENE
methyltransferases	I-GENE
are	O
not	O
homologs	O
;	O
however	O
,	O
like	O
the	O
MMA	B-GENE
methyltransferase	I-GENE
gene	I-GENE
,	O
the	O
genes	O
encoding	O
the	O
DMA	B-GENE
and	I-GENE
TMA	I-GENE
methyltransferases	I-GENE
each	O
contain	O
a	O
single	O
in	O
-	O
frame	O
amber	O
codon	O
.	O

After	O
phosphorylation	O
,	O
STAT	B-GENE
proteins	I-GENE
are	O
transported	O
into	O
the	O
nucleus	O
and	O
exhibit	O
transcriptional	O
activity	O
.	O

Overexpression	O
of	O
mcl	B-GENE
-	I-GENE
1	I-GENE
is	O
sufficient	O
to	O
protect	O
against	O
apoptosis	O
,	O
while	O
transfection	O
of	O
a	O
mcl	B-GENE
-	I-GENE
1	I-GENE
antisense	O
plasmid	O
causes	O
cell	O
death	O
.	O

Thus	O
,	O
although	O
multiple	O
senescence	O
pathways	O
are	O
activated	O
in	O
response	O
to	O
a	O
ras	B-GENE
oncogene	I-GENE
,	O
inactivation	O
of	O
TGFbeta1	B-GENE
secretion	O
or	O
response	O
is	O
sufficient	O
to	O
block	O
the	O
senescence	O
program	O
.	O

In	O
this	O
study	O
,	O
the	O
abilities	O
of	O
constitutive	O
and	O
conditional	O
forms	O
of	O
the	O
three	O
Raf	B-GENE
kinases	I-GENE
to	O
abrogate	O
the	O
cytokine	O
dependency	O
of	O
FDC	O
-	O
P1	O
cells	O
were	O
examined	O
.	O

Application	O
of	O
the	O
method	O
to	O
a	O
representative	O
set	O
of	O
50	O
known	O
genes	O
from	O
Arabidopsis	O
thaliana	O
showed	O
significant	O
improvement	O
in	O
prediction	O
accuracy	O
compared	O
to	O
previous	O
spliced	O
alignment	O
methods	O
.	O

The	O
complete	O
cDNA	O
sequence	O
of	O
human	B-GENE
betaV	I-GENE
spectrin	I-GENE
is	O
available	O
from	O
GenBank	O
(	O
TM	O
)	O
as	O
accession	O
number	O
.	O

Transactivation	O
of	O
naturally	O
occurring	O
HIV	B-GENE
-	I-GENE
1	I-GENE
long	I-GENE
terminal	I-GENE
repeats	I-GENE
by	O
the	O
JNK	B-GENE
signaling	O
pathway	O
.	O

The	O
mode	O
of	O
resistance	O
to	O
quinupristin	O
/	O
dalfopristin	O
was	O
not	O
evident	O
(	O
sat	O
A	O
-	O
negative	O
by	O
PCR	O
)	O
;	O
and	O
these	O
cases	O
illustrate	O
the	O
existence	O
of	O
streptogramin	O
-	O
resistant	O
isolates	O
before	O
the	O
introduction	O
of	O
this	O
antimicrobial	O
class	O
into	O
human	O
clinical	O
practice	O
.	O

This	O
study	O
was	O
carried	O
out	O
to	O
analyze	O
PRL	B-GENE
secretion	O
in	O
metastatic	O
prostate	O
cancer	O
patients	O
both	O
at	O
basal	O
conditions	O
and	O
in	O
response	O
to	O
L	O
-	O
Dopa	O
and	O
metoclopramide	O
,	O
which	O
represents	O
the	O
most	O
classical	O
inhibitory	O
and	O
stimulatory	O
tests	O
for	O
PRL	B-GENE
secretion	O
,	O
respectively	O
.	O

Integrin	B-GENE
adhesion	I-GENE
receptors	I-GENE
transduce	O
signals	O
that	O
control	O
complex	O
cell	O
functions	O
which	O
require	O
the	O
regulation	O
of	O
gene	O
expression	O
,	O
such	O
as	O
proliferation	O
,	O
differentiation	O
and	O
survival	O
.	O

Recombination	O
,	O
replication	O
,	O
repair	O
:	O
from	O
complexity	O
to	O
harmony	O
.	O

Hex	B-GENE
is	O
expressed	O
in	O
the	O
developing	O
liver	O
coincident	O
with	O
the	O
forkhead	B-GENE
/	O
winged	B-GENE
helix	I-GENE
transcription	O
factor	O
,	O
Hepatocyte	B-GENE
Nuclear	I-GENE
Factor	I-GENE
3beta	I-GENE
(	O
HNF3beta	B-GENE
)	O
.	O

As	O
an	O
extension	O
of	O
our	O
structural	O
characterization	O
of	O
the	O
exon	O
-	O
intron	O
organization	O
of	O
the	O
mouse	B-GENE
Pkr	I-GENE
gene	I-GENE
,	O
we	O
now	O
have	O
isolated	O
and	O
characterized	O
the	O
mouse	B-GENE
Pkr	I-GENE
promoter	I-GENE
region	I-GENE
required	O
for	O
IFN	B-GENE
-	O
inducible	O
transcription	O
.	O

The	O
CRE	O
,	O
5	O
'	O
-	O
TGACGTCA	O
-	O
3	O
'	O
,	O
has	O
been	O
described	O
as	O
the	O
consensus	O
sequence	O
for	O
the	O
cis	O
-	O
element	O
that	O
directs	O
cAMP	O
-	O
regulated	O
gene	O
expression	O
.	O

Kidney	O
length	O
did	O
not	O
significantly	O
differ	O
between	O
right	O
and	O
left	O
,	O
however	O
,	O
kidney	O
width	O
,	O
cortical	O
thickness	O
and	O
size	O
did	O
(	O
p	O
<	O
0	O
.	O
05	O
)	O
.	O

The	O
clinical	O
stage	O
was	O
I	O
(	O
T1N0M0	O
)	O
,	O
and	O
S2	O
sleeve	O
segmentectomy	O
with	O
lymph	O
node	O
dissection	O
(	O
R	O
2	O
b	O
)	O
was	O
performed	O
.	O

Benztropine	O
for	O
venlafaxine	O
-	O
induced	O
night	O
sweats	O
.	O

The	O
physicians	O
in	O
charge	O
of	O
all	O
patients	O
with	O
evidence	O
of	O
acute	O
Q	O
fever	O
(	O
seroconversion	O
and	O
/	O
or	O
presence	O
of	O
IgM	B-GENE
)	O
or	O
chronic	O
Q	O
fever	O
(	O
prolonged	O
disease	O
and	O
/	O
or	O
IgG	B-GENE
antibody	I-GENE
titer	O
to	O
phase	O
I	O
of	O
Coxiella	O
burnetii	O
>	O
or	O
=	O
800	O
)	O
were	O
asked	O
to	O
complete	O
a	O
questionnaire	O
,	O
which	O
was	O
computerized	O
.	O

Copyright	O
2000	O
Academic	O
Press	O
.	O

Viral	O
cell	O
-	O
to	O
-	O
cell	O
movement	O
of	O
PVX	B-GENE
CP	I-GENE
mutant	I-GENE
was	O
complemented	O
in	O
Nicotiana	O
tabacum	O
cv	O
.	O

Induction	O
of	O
CD86	B-GENE
expression	O
by	O
stimulation	O
of	O
U937	O
cells	O
with	O
IFN	B-GENE
-	I-GENE
gamma	I-GENE
revealed	O
the	O
presence	O
of	O
two	O
functional	O
GAS	B-GENE
(	O
gamma	B-GENE
-	I-GENE
interferon	I-GENE
activation	I-GENE
site	I-GENE
)	O
elements	O
.	O

SNAP	B-GENE
-	I-GENE
23	I-GENE
plays	O
an	O
important	O
role	O
in	O
the	O
regulation	O
of	O
vesicle	O
trafficking	O
in	O
mammalian	O
cells	O
.	O

Ab	O
-	O
MLV	O
strains	O
expressing	O
P70	B-GENE
/	O
S2	B-GENE
failed	O
to	O
transform	O
NIH	O
3T3	O
cells	O
and	O
demonstrated	O
a	O
greatly	O
reduced	O
capacity	O
to	O
mediate	O
signaling	O
events	O
associated	O
with	O
the	O
Ras	B-GENE
-	O
dependent	O
mitogen	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
(	I-GENE
MAP	I-GENE
)	I-GENE
kinase	I-GENE
pathway	O
.	O

The	O
p53	B-GENE
-	I-GENE
homolog	I-GENE
p73beta	B-GENE
also	O
activated	O
the	O
PIG3	B-GENE
promoter	I-GENE
,	O
but	O
in	O
contrast	O
to	O
p53	B-GENE
,	O
the	O
proline	O
-	O
rich	O
domain	O
of	O
p73beta	B-GENE
(	I-GENE
residues	I-GENE
81	I-GENE
-	I-GENE
113	I-GENE
)	I-GENE
was	O
dispensable	O
to	O
induce	O
the	O
PIG3	B-GENE
promoter	I-GENE
.	O

Results	O
from	O
transient	O
assays	O
using	O
these	O
mutants	O
showed	O
that	O
the	O
DE1	O
received	O
signals	O
from	O
phytochromes	B-GENE
A	I-GENE
and	I-GENE
B	I-GENE
,	O
demonstrating	O
that	O
this	O
element	O
is	O
indeed	O
a	O
light	O
-	O
responsive	O
element	O
.	O

Co	O
-	O
immunoprecipitation	O
and	O
DNA	O
affinity	O
chromatography	O
prove	O
that	O
Sp1	B-GENE
heterodimerizes	O
with	O
ZBP	B-GENE
-	I-GENE
89	I-GENE
when	O
bound	O
to	O
the	O
silencer	O
element	O
to	O
yield	O
a	O
DNA	O
-	O
protein	O
complex	O
whose	O
mobility	O
is	O
indistinguishable	O
from	O
that	O
displayed	O
by	O
HeLa	O
nuclear	O
extract	O
in	O
band	O
shift	O
assays	O
.	O

The	O
ZNF274	B-GENE
gene	I-GENE
is	O
mapped	O
distal	O
to	O
marker	O
RP	O
S28	O
1	O
in	O
the	O
human	O
chromosome	O
19qter	O
region	O
,	O
by	O
RH	O
mapping	O
.	O

The	O
C	B-GENE
-	I-GENE
terminal	I-GENE
Cdk2	I-GENE
truncations	O
,	O
however	O
,	O
were	O
non	O
-	O
functional	O
in	O
these	O
strains	O
and	O
thus	O
dependent	O
for	O
activity	O
on	O
the	O
pho85	B-GENE
coding	I-GENE
region	I-GENE
which	O
remained	O
in	O
the	O
mutant	B-GENE
pho85	I-GENE
:	O
:	O
HIS3	B-GENE
chromosomal	I-GENE
locus	I-GENE
.	O

We	O
report	O
here	O
on	O
the	O
molecular	O
nature	O
of	O
an	O
EMS	O
-	O
induced	O
mutant	O
,	O
mn1	B-GENE
-	I-GENE
89	I-GENE
,	O
a	O
leaky	O
semidominant	O
allele	O
of	O
the	O
Miniature1	B-GENE
(	O
Mn1	B-GENE
)	O
seed	O
locus	O
that	O
encodes	O
a	O
seed	B-GENE
-	I-GENE
specific	I-GENE
cell	I-GENE
wall	I-GENE
invertase	I-GENE
,	O
INCW2	B-GENE
.	O

We	O
conclude	O
that	O
,	O
both	O
in	O
atrial	O
myocytes	O
and	O
in	O
Xenopus	O
oocytes	O
,	O
beta	O
-	O
adrenergic	O
stimulation	O
potentiates	O
the	O
ACh	O
-	O
evoked	O
GIRK	B-GENE
channels	I-GENE
via	O
a	O
pathway	O
that	O
involves	O
PKA	B-GENE
-	O
catalyzed	O
phosphorylation	O
downstream	O
from	O
beta	B-GENE
(	I-GENE
2	I-GENE
)	I-GENE
AR	I-GENE
.	O

Identification	O
of	O
a	O
novel	O
E2F3	B-GENE
product	I-GENE
suggests	O
a	O
mechanism	O
for	O
determining	O
specificity	O
of	O
repression	O
by	O
Rb	B-GENE
proteins	I-GENE
.	O

In	O
DNase	B-GENE
I	I-GENE
footprinting	O
protection	O
analysis	O
,	O
both	O
SFRE	B-GENE
and	O
ERE	O
regions	O
were	O
protected	O
by	O
glutathione	B-GENE
S	I-GENE
-	I-GENE
transferase	I-GENE
-	O
ERRalpha1	B-GENE
fusion	O
protein	O
.	O

Overexpressing	O
the	O
coactivator	O
,	O
SRC1a	B-GENE
or	O
GRIP1	B-GENE
,	O
further	O
enhances	O
ERRalpha1	B-GENE
-	O
induced	O
transcriptional	O
activity	O
.	O

Estrogen	B-GENE
receptor	I-GENE
-	I-GENE
related	I-GENE
receptor	I-GENE
alpha	I-GENE
1	I-GENE
interacts	O
with	O
coactivator	O
and	O
constitutively	O
activates	O
the	O
estrogen	O
response	O
elements	O
of	O
the	O
human	B-GENE
lactoferrin	I-GENE
gene	I-GENE
.	O

The	O
median	O
levels	O
of	O
particles	O
with	O
50	O
%	O
cut	O
-	O
off	O
aerodynamic	O
diameters	O
of	O
10	O
(	O
PM10	O
)	O
and	O
2	O
.	O
5	O
microm	O
(	O
PM2	O
.	O
5	O
)	O
were	O
170	O
(	O
range	O
103	O
-	O
613	O
)	O
and	O
95	O
(	O
range	O
61	O
-	O
218	O
)	O
micro	O
x	O
m	O
-	O
3	O
,	O
respectively	O
.	O

Specific	O
and	O
heritable	O
genetic	O
interference	O
by	O
double	O
-	O
stranded	O
RNA	O
in	O
Arabidopsis	O
thaliana	O
.	O

Comparison	O
of	O
sequences	O
from	O
-	O
215	O
to	O
+	O
1	O
bp	O
identified	O
consensus	O
binding	O
sites	O
for	O
the	O
homeodomain	B-GENE
transcription	I-GENE
factor	I-GENE
thyroid	B-GENE
transcription	I-GENE
factor	I-GENE
-	I-GENE
1	I-GENE
(	O
TTF	B-GENE
-	I-GENE
1	I-GENE
)	O
.	O

Two	O
additional	O
cis	O
-	O
acting	O
sequences	O
,	O
conserved	O
in	O
both	O
the	O
region	O
1	O
and	O
3	O
promoters	O
,	O
were	O
identified	O
,	O
suggesting	O
a	O
role	O
for	O
these	O
sequences	O
in	O
the	O
coordinate	O
regulation	O
of	O
transcription	O
from	O
these	O
promoters	O
.	O

Purple	O
photosynthetic	O
bacteria	O
are	O
capable	O
of	O
generating	O
cellular	O
energy	O
from	O
several	O
sources	O
,	O
including	O
photosynthesis	O
,	O
respiration	O
,	O
and	O
H	O
(	O
2	O
)	O
oxidation	O
.	O

An	O
analysis	O
of	O
synthetic	O
peptides	O
revealed	O
a	O
minimal	O
CTD	O
sequence	O
that	O
is	O
sufficient	O
to	O
bind	O
to	O
the	O
second	O
Rsp5	B-GENE
WW	I-GENE
domain	I-GENE
(	O
Rsp5	B-GENE
WW2	I-GENE
)	O
in	O
vitro	O
and	O
in	O
yeast	O
two	O
-	O
hybrid	O
assays	O
.	O

Furthermore	O
,	O
bone	O
marrow	O
-	O
derived	O
macrophages	O
from	O
LAT	B-GENE
-	O
deficient	O
mice	O
displayed	O
reduced	O
phagocytic	O
efficiency	O
in	O
comparison	O
to	O
the	O
macrophages	O
from	O
wild	O
-	O
type	O
mice	O
.	O

T1	O
-	O
weighted	O
MRI	O
on	O
the	O
49th	O
postoperative	O
day	O
demonstrated	O
bilateral	O
and	O
symmetrical	O
hyperintense	O
lesions	O
in	O
the	O
globus	O
pallidus	O
.	O

The	O
method	O
is	O
applied	O
to	O
determine	O
aberration	O
constants	O
of	O
a	O
CM300	O
FEG	O
/	O
UT	O
microscope	O
with	O
correction	O
of	O
the	O
three	O
-	O
fold	O
astigmatism	O
.	O

The	O
interaction	O
does	O
not	O
depend	O
on	O
the	O
presence	O
of	O
the	O
correct	O
amino	O
-	O
terminal	O
DNA	O
binding	O
domain	O
or	O
the	O
amino	O
acid	O
sequences	O
between	O
the	O
DNA	O
binding	O
domain	O
and	O
the	O
last	O
ten	O
amino	O
acids	O
.	O

METHOD	O
:	O
The	O
sample	O
of	O
subjects	O
was	O
drawn	O
from	O
the	O
Suffolk	O
County	O
Mental	O
Health	O
Project	O
,	O
a	O
longitudinal	O
epidemiologic	O
study	O
of	O
first	O
-	O
hospitalized	O
subjects	O
with	O
psychotic	O
disorders	O
;	O
the	O
present	O
study	O
focused	O
on	O
patients	O
with	O
schizophrenic	O
disorders	O
.	O

Marrow	O
dysplasia	O
is	O
a	O
major	O
characteristic	O
of	O
patients	O
with	O
myelodysplastic	O
syndrome	O
(	O
MDS	O
)	O
,	O
along	O
with	O
marrow	O
blastosis	O
,	O
cytopenia	O
and	O
cytogenetic	O
anomalies	O
.	O

Eight	O
of	O
the	O
non	O
-	O
acceptable	O
inlays	O
/	O
onlays	O
and	O
five	O
of	O
the	O
direct	O
restorations	O
were	O
replaced	O
,	O
while	O
the	O
other	O
ones	O
were	O
repaired	O
with	O
resin	O
composite	O
.	O

How	O
plants	O
respond	O
to	O
attack	O
by	O
the	O
range	O
of	O
herbivores	O
and	O
pathogens	O
that	O
confront	O
them	O
in	O
the	O
field	O
is	O
the	O
subject	O
of	O
considerable	O
research	O
by	O
both	O
molecular	O
biologists	O
and	O
ecologists	O
.	O

CONCLUSION	O
:	O
The	O
probability	O
of	O
cardiopulmonary	O
complications	O
increases	O
significantly	O
when	O
patients	O
develop	O
class	O
1	O
HELLP	O
syndrome	O
.	O

The	O
rate	O
-	O
limiting	O
step	O
for	O
telomerase	B-GENE
activity	O
seems	O
to	O
be	O
the	O
expression	O
of	O
the	O
catalytic	O
subunit	O
of	O
the	O
enzyme	O
,	O
encoded	O
by	O
the	O
human	B-GENE
telomerase	I-GENE
reverse	I-GENE
transcriptase	I-GENE
(	O
hTERT	B-GENE
)	O
gene	O
.	O

In	O
the	O
control	O
group	O
,	O
platelet	O
markers	O
increased	O
1	O
h	O
after	O
surgery	O
.	O

However	O
,	O
the	O
element	O
proximal	O
to	O
the	O
transcription	O
start	O
site	O
is	O
dependent	O
on	O
the	O
SRE	O
-	O
1	O
.	O

Since	O
proteins	O
containing	O
TPR	O
elements	O
are	O
typically	O
involved	O
in	O
multiple	O
protein	O
-	O
protein	O
interactions	O
,	O
we	O
suggest	O
that	O
the	O
102kD	O
protein	O
interacts	O
within	O
the	O
tri	O
-	O
snRNP	O
with	O
both	O
the	O
U5	B-GENE
and	O
U4	B-GENE
/	O
U6	B-GENE
snRNPs	O
,	O
thus	O
bridging	O
the	O
two	O
particles	O
.	O

Antibodies	O
raised	O
against	O
a	O
C	O
-	O
terminal	O
portion	O
of	O
Sec31A	B-GENE
co	O
-	O
precipitate	O
Sec13	B-GENE
and	O
inhibit	O
ER	O
-	O
Golgi	O
transport	O
of	O
temperature	O
-	O
arrested	O
vesicular	O
stomatitis	B-GENE
G	I-GENE
protein	I-GENE
in	O
a	O
semi	O
-	O
intact	O
cell	O
assay	O
.	O

Regulation	O
of	O
mitochondrial	O
single	O
-	O
stranded	O
DNA	O
-	O
binding	O
protein	O
gene	O
expression	O
links	O
nuclear	O
and	O
mitochondrial	O
DNA	O
replication	O
in	O
drosophila	O
.	O

Genetic	O
and	O
molecular	O
complexity	O
of	O
the	O
position	O
effect	O
variegation	O
modifier	O
mod	B-GENE
(	O
mdg4	B-GENE
)	O
in	O
Drosophila	O
.	O
mod	B-GENE
(	O
mdg4	B-GENE
)	O
,	O
also	O
known	O
as	O
E	B-GENE
(	I-GENE
var	I-GENE
)	I-GENE
3	I-GENE
-	I-GENE
93D	I-GENE
,	O
is	O
involved	O
in	O
a	O
variety	O
of	O
processes	O
,	O
such	O
as	O
gene	O
silencing	O
in	O
position	O
effect	O
variegation	O
(	O
PEV	O
)	O
,	O
the	O
control	O
of	O
gypsy	B-GENE
insulator	I-GENE
sequences	I-GENE
,	O
regulation	O
of	O
homeotic	B-GENE
gene	I-GENE
expression	O
,	O
and	O
programmed	O
cell	O
death	O
.	O

They	O
are	O
present	O
in	O
many	O
kinds	O
of	O
living	O
things	O
,	O
but	O
their	O
functions	O
,	O
especially	O
those	O
in	O
humans	O
,	O
are	O
unclear	O
.	O

This	O
tendency	O
is	O
likely	O
due	O
to	O
the	O
biased	O
nucleotide	O
composition	O
of	O
the	O
asparagus	O
genome	O
,	O
rather	O
than	O
to	O
the	O
translational	O
selection	O
for	O
specific	O
codons	O
.	O

Transduction	O
of	O
the	O
human	O
leukemic	O
cell	O
line	O
K562	O
showed	O
that	O
viral	O
MRP1	B-GENE
-	O
PG13	O
supernatants	O
routinely	O
transfer	O
the	O
MRP1	B-GENE
gene	I-GENE
to	O
approximately	O
35	O
%	O
of	O
target	O
K562	O
cells	O
,	O
of	O
which	O
at	O
least	O
one	O
third	O
are	O
capable	O
of	O
proliferating	O
in	O
the	O
presence	O
of	O
otherwise	O
toxic	O
concentrations	O
of	O
etoposide	O
.	O

Regulation	O
of	O
pituitary	O
vasopressin	B-GENE
V1b	I-GENE
receptors	I-GENE
plays	O
a	O
critical	O
role	O
in	O
regulating	O
pituitary	B-GENE
adrenocorticotropic	I-GENE
hormone	I-GENE
(	O
ACTH	B-GENE
)	O
secretion	O
during	O
adaptation	O
to	O
stress	O
.	O

Identification	O
of	O
an	O
AfsA	B-GENE
homologue	I-GENE
(	O
BarX	B-GENE
)	O
from	O
Streptomyces	O
virginiae	O
as	O
a	O
pleiotropic	O
regulator	O
controlling	O
autoregulator	O
biosynthesis	O
,	O
virginiamycin	O
biosynthesis	O
and	O
virginiamycin	O
M1	O
resistance	O
.	O

Given	O
its	O
relative	O
longevity	O
on	O
the	O
Web	O
,	O
TIE	O
researchers	O
have	O
been	O
in	O
a	O
unique	O
position	O
to	O
observe	O
trends	O
in	O
telemedicine	O
.	O

Cerebral	O
vasculitis	O
secondary	O
to	O
Crohn	O
'	O
s	O
disease	O
seems	O
to	O
be	O
a	O
very	O
rare	O
phenomenon	O
.	O

To	O
test	O
the	O
hypothesis	O
that	O
progestin	O
-	O
mediated	O
increases	O
in	O
resting	O
core	O
temperature	O
and	O
the	O
core	O
temperature	O
threshold	O
for	O
sweating	O
onset	O
are	O
counteracted	O
by	O
estrogen	O
,	O
we	O
studied	O
eight	O
women	O
(	O
24	O
+	O
/	O
-	O
2	O
yr	O
)	O
at	O
27	O
degrees	O
C	O
rest	O
,	O
during	O
20	O
min	O
of	O
passive	O
heating	O
(	O
35	O
degrees	O
C	O
)	O
,	O
and	O
during	O
40	O
min	O
of	O
exercise	O
at	O
35	O
degrees	O
C	O
.	O

Our	O
data	O
show	O
also	O
that	O
phagocytic	O
killing	O
of	O
meningococci	O
is	O
probably	O
a	O
more	O
consistent	O
assay	O
than	O
antibody	O
titer	O
levels	O
for	O
antimeningococcal	O
immunity	O
,	O
especially	O
in	O
LCC	O
-	O
deficient	O
patients	O
.	O

These	O
studies	O
suggest	O
an	O
additional	O
component	O
or	O
cellular	O
environment	O
is	O
required	O
for	O
SPRK	B-GENE
activation	O
by	O
Cdc42	B-GENE
.	O

M	O
.	O

Jkappa	B-GENE
DNA	I-GENE
-	I-GENE
binding	I-GENE
sites	I-GENE
were	O
not	O
required	O
for	O
this	O
activation	O
,	O
and	O
a	O
mutant	B-GENE
EBNA	I-GENE
-	I-GENE
3C	I-GENE
protein	I-GENE
unable	O
to	O
bind	O
Jkappa	B-GENE
activated	O
transcription	O
as	O
efficiently	O
as	O
wild	B-GENE
-	I-GENE
type	I-GENE
EBNA	I-GENE
-	I-GENE
3C	I-GENE
,	O
indicating	O
that	O
EBNA	B-GENE
-	I-GENE
3C	I-GENE
can	O
regulate	O
transcription	O
through	O
a	O
mechanism	O
that	O
is	O
independent	O
of	O
Jkappa	B-GENE
.	O

Thus	O
,	O
both	O
YY1	B-GENE
and	O
CDP	B-GENE
appear	O
to	O
be	O
negative	O
regulators	O
of	O
the	O
differentiation	O
-	O
induced	O
HPV	B-GENE
-	I-GENE
6	I-GENE
E1	I-GENE
promoter	I-GENE
and	O
thereby	O
the	O
HPV	O
life	O
cycle	O
.	O

Sequential	O
cleavage	O
by	O
metallopeptidases	B-GENE
and	O
proteasomes	O
is	O
involved	O
in	O
processing	O
HIV	B-GENE
-	I-GENE
1	I-GENE
ENV	I-GENE
epitope	I-GENE
for	O
endogenous	O
MHC	B-GENE
class	I-GENE
I	I-GENE
antigen	I-GENE
presentation	O
.	O

Cloning	O
and	O
characterization	O
of	O
human	B-GENE
Lnk	I-GENE
,	O
an	O
adaptor	O
protein	O
with	O
pleckstrin	B-GENE
homology	O
and	O
Src	B-GENE
homology	I-GENE
2	I-GENE
domains	I-GENE
that	O
can	O
inhibit	O
T	O
cell	O
activation	O
.	O

Vancomycin	O
data	O
were	O
analyzed	O
according	O
to	O
a	O
one	O
-	O
compartment	O
open	O
model	O
with	O
use	O
of	O
NONMEM	O
population	O
pharmacokinetic	O
software	O
.	O

Finally	O
,	O
Cas	B-GENE
existed	O
mainly	O
in	O
cytosol	O
and	O
membrane	O
cytoskeleton	O
fractions	O
in	O
the	O
resting	O
state	O
,	O
and	O
remained	O
unchanged	O
during	O
platelet	O
aggregation	O
,	O
when	O
FAK	B-GENE
translocated	O
to	O
the	O
cytoskeletal	O
fraction	O
.	O

Transcriptional	O
regulation	O
of	O
the	O
yeast	B-GENE
PHO8	I-GENE
promoter	I-GENE
in	O
comparison	O
to	O
the	O
coregulated	O
PHO5	B-GENE
promoter	I-GENE
.	O

The	O
Siglecs	B-GENE
are	O
a	O
subfamily	O
of	O
I	B-GENE
-	I-GENE
type	I-GENE
lectins	I-GENE
(	O
immunoglobulin	B-GENE
superfamily	I-GENE
proteins	I-GENE
that	O
bind	O
sugars	O
)	O
that	O
specifically	O
recognize	O
sialic	O
acids	O
.	O

Our	O
data	O
provide	O
a	O
biochemical	O
explanation	O
for	O
the	O
similarity	O
in	O
phenotype	O
between	O
A	O
-	O
T	O
and	O
NBS	O
.	O

PATIENTS	O
OR	O
OTHER	O
PARTICIPANTS	O
:	O
Twenty	O
children	O
met	O
the	O
criteria	O
for	O
being	O
learning	O
disabled	O
.	O

Update	O
on	O
maternal	O
-	O
fetal	O
infections	O
by	O
hepatitis	O
C	O
,	O
HIV	O
and	O
cytomegalovirus	O

In	O
the	O
present	O
study	O
,	O
we	O
characterized	O
cis	O
-	O
elements	O
of	O
the	O
human	B-GENE
PCI	I-GENE
gene	I-GENE
required	O
for	O
expression	O
in	O
the	O
hepatoma	O
-	O
derived	O
cell	O
line	O
,	O
HepG2	O
cells	O
,	O
and	O
also	O
evaluated	O
rat	B-GENE
PCI	I-GENE
mRNA	I-GENE
expression	O
,	O
particularly	O
on	O
the	O
effect	O
of	O
androgen	O
in	O
rat	O
reproductive	O
tissues	O
.	O

In	O
the	O
study	O
on	O
PCI	B-GENE
mRNA	I-GENE
expression	O
in	O
the	O
reproductive	O
organs	O
,	O
we	O
first	O
cloned	O
rat	B-GENE
PCI	I-GENE
cDNA	I-GENE
and	O
then	O
evaluated	O
the	O
effect	O
of	O
androgen	O
on	O
the	O
PCI	B-GENE
mRNA	I-GENE
expression	O
.	O

The	O
stoichiometry	O
of	O
the	O
complexes	O
formed	O
with	O
the	O
dodeca	O
-	O
satellite	O
C	O
strand	O
suggests	O
that	O
,	O
in	O
DDP1	B-GENE
,	O
the	O
15	O
consecutive	O
KH	O
domains	O
are	O
organized	O
such	O
that	O
they	O
define	O
two	O
nucleic	O
acid	O
binding	O
surfaces	O
.	O

Mutational	O
analysis	O
of	O
mammalian	B-GENE
translation	I-GENE
initiation	I-GENE
factor	I-GENE
5	I-GENE
(	O
eIF5	B-GENE
)	O
:	O
role	O
of	O
interaction	O
between	O
the	O
beta	O
subunit	O
of	O
eIF2	B-GENE
and	O
eIF5	B-GENE
in	O
eIF5	B-GENE
function	O
in	O
vitro	O
and	O
in	O
vivo	O
.	O

Much	O
evidence	O
indicates	O
that	O
p38	B-GENE
is	O
an	O
activator	O
of	O
MyoD	B-GENE
:	O
(	O
i	O
)	O
p38	B-GENE
kinase	I-GENE
activity	O
is	O
required	O
for	O
the	O
expression	O
of	O
MyoD	B-GENE
-	O
responsive	O
genes	O
,	O
(	O
ii	O
)	O
enforced	O
induction	O
of	O
p38	B-GENE
stimulates	O
the	O
transcriptional	O
activity	O
of	O
a	O
Gal4	B-GENE
-	O
MyoD	B-GENE
fusion	O
protein	O
and	O
allows	O
efficient	O
activation	O
of	O
chromatin	O
-	O
integrated	O
reporters	O
by	O
MyoD	B-GENE
,	O
and	O
(	O
iii	O
)	O
MyoD	B-GENE
-	O
dependent	O
myogenic	O
conversion	O
is	O
reduced	O
in	O
mouse	O
embryonic	O
fibroblasts	O
derived	O
from	O
p38alpha	B-GENE
(	I-GENE
-	I-GENE
/	I-GENE
-	I-GENE
)	I-GENE
embryos	O
.	O

This	O
activity	O
is	O
stimulated	O
by	O
complex	O
formation	O
with	O
the	O
other	O
eIF2B	B-GENE
subunits	I-GENE
.	O

Our	O
analysis	O
of	O
nonsense	O
mutations	O
indicates	O
that	O
the	O
C	O
terminus	O
of	O
eIF2Bepsilon	B-GENE
(	I-GENE
residues	I-GENE
518	I-GENE
to	I-GENE
712	I-GENE
)	I-GENE
is	O
required	O
for	O
both	O
catalytic	O
activity	O
and	O
interaction	O
with	O
eIF2	B-GENE
.	O

In	O
contrast	O
,	O
mutations	O
affecting	O
the	O
other	O
two	O
Nim1p	B-GENE
-	I-GENE
related	I-GENE
kinases	I-GENE
in	O
S	O
.	O
cerevisiae	O
,	O
Hsl1p	B-GENE
and	O
Kcc4p	B-GENE
,	O
produce	O
no	O
detectable	O
effect	O
on	O
septin	B-GENE
organization	O
.	O

CONCLUSIONS	O
:	O
Physiologic	O
pacing	O
provides	O
little	O
benefit	O
over	O
ventricular	O
pacing	O
for	O
the	O
prevention	O
of	O
stroke	O
or	O
death	O
due	O
to	O
cardiovascular	O
causes	O
.	O

Among	O
non	O
-	O
cirrhotics	O
,	O
lack	O
of	O
portal	O
vein	O
visualisation	O
had	O
a	O
90	O
%	O
sensitivity	O
,	O
88	O
%	O
specificity	O
,	O
94	O
%	O
negative	O
predictive	O
value	O
,	O
and	O
83	O
%	O
positive	O
predictive	O
value	O
in	O
the	O
diagnosis	O
of	O
pre	O
-	O
sinusoidal	O
portal	O
hypertension	O
.	O

The	O
serine	B-GENE
-	I-GENE
threonine	I-GENE
kinase	I-GENE
gene	I-GENE
is	O
likely	O
functional	O
,	O
whereas	O
the	O
zinc	O
finger	O
motif	O
is	O
likely	O
nonfunctional	O
.	O

Stat	B-GENE
activation	O
in	O
response	O
to	O
GH	B-GENE
and	O
IL	B-GENE
-	I-GENE
6	I-GENE
was	O
determined	O
by	O
reporter	O
gene	O
induction	O
.	O

HFA	O
134a	O
had	O
a	O
greater	O
tendency	O
to	O
take	O
up	O
moisture	O
from	O
the	O
environment	O
than	O
did	O
HFA	O
227	O
.	O

RESULTS	O
:	O
Abnormal	O
color	O
perception	O
was	O
found	O
in	O
32	O
%	O
of	O
the	O
epilepsy	O
patients	O
treated	O
with	O
vigabatrin	O
monotherapy	O
and	O
28	O
%	O
of	O
the	O
epilepsy	O
patients	O
treated	O
with	O
carbamazepine	O
monotherapy	O
.	O

In	O
the	O
SPP2	O
screening	O
test	O
,	O
a	O
few	O
plates	O
were	O
not	O
seen	O
in	O
both	O
groups	O
.	O

Mitogen	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
(	I-GENE
MAP	I-GENE
)	I-GENE
kinase	I-GENE
phosphatase	I-GENE
-	I-GENE
3	I-GENE
(	O
MKP	B-GENE
-	I-GENE
3	I-GENE
)	O
is	O
a	O
dual	O
specificity	O
phosphatase	O
that	O
inactivates	O
extracellular	B-GENE
signal	I-GENE
-	I-GENE
regulated	I-GENE
kinase	I-GENE
(	O
ERK	B-GENE
)	O
MAP	B-GENE
kinases	I-GENE
.	O

Consistent	O
with	O
this	O
,	O
we	O
show	O
that	O
peptides	O
representing	O
docking	O
sites	O
within	O
the	O
target	O
substrates	O
Elk	B-GENE
-	I-GENE
1	I-GENE
and	O
p90	B-GENE
(	O
rsk	B-GENE
)	O
inhibit	O
ERK	B-GENE
-	O
dependent	O
activation	O
of	O
MKP	B-GENE
-	I-GENE
3	I-GENE
.	O

HPLC	O
phosphopeptide	O
mapping	O
,	O
amino	O
acid	O
sequencing	O
,	O
and	O
site	O
-	O
directed	O
mutagenesis	O
determined	O
that	O
NCLK	B-GENE
phosphorylates	O
Ser	O
(	O
67	O
)	O
of	O
I	B-GENE
-	I-GENE
1	I-GENE
.	O

When	O
the	O
entire	O
diet	O
consisted	O
of	O
SBF	O
,	O
voluntary	O
feed	O
intake	O
was	O
reduced	O
,	O
indicating	O
that	O
SBF	O
should	O
not	O
be	O
fed	O
to	O
ponies	O
as	O
the	O
sole	O
dietary	O
ingredient	O
.	O

Hepatitis	O
C	O
virus	O
infection	O
and	O
lymphoproliferative	O
diseases	O
in	O
France	O
:	O
a	O
national	O
study	O
.	O

Interestingly	O
,	O
a	O
decreased	O
transcription	O
from	O
the	O
endogenous	O
c	B-GENE
-	I-GENE
Myb	I-GENE
promoter	I-GENE
was	O
observed	O
in	O
several	O
HTLV	O
-	O
I	O
transformed	O
T	O
-	O
cell	O
lines	O
.	O

H19	B-GENE
and	O
Igf2	B-GENE
monoallelic	O
expression	O
is	O
regulated	O
in	O
two	O
distinct	O
ways	O
by	O
a	O
shared	O
cis	O
acting	O
regulatory	O
region	O
upstream	O
of	O
H19	B-GENE
.	O

C	O
.	O
elegans	O
KLP	B-GENE
-	I-GENE
11	I-GENE
/	O
OSM	B-GENE
-	I-GENE
3	I-GENE
/	O
KAP	B-GENE
-	I-GENE
1	I-GENE
:	O
orthologs	O
of	O
the	O
sea	B-GENE
urchin	I-GENE
kinesin	I-GENE
-	I-GENE
II	I-GENE
,	O
and	O
mouse	O
KIF3A	B-GENE
/	O
KIFB	B-GENE
/	O
KAP3	B-GENE
kinesin	B-GENE
complexes	O
.	O

BACKGROUND	O
:	O
Hepatic	O
encephalopathy	O
is	O
a	O
neuropsychiatric	O
syndrome	O
associated	O
with	O
acute	O
liver	O
failure	O
,	O
chronic	O
parenchymal	O
liver	O
disease	O
or	O
portal	O
systemic	O
anastomosis	O
.	O

These	O
natural	O
antisense	O
S	B-GENE
transcripts	I-GENE
co	O
-	O
exist	O
with	O
several	O
less	O
abundant	O
sense	O
S	B-GENE
transcripts	I-GENE
.	O

Nor	O
is	O
such	O
adjustment	O
possible	O
unless	O
one	O
posits	O
a	O
model	O
that	O
relates	O
the	O
missing	O
observations	O
to	O
other	O
observed	O
information	O
for	O
each	O
subject	O
-	O
models	O
that	O
are	O
inherently	O
untestable	O
.	O

However	O
,	O
the	O
presence	O
of	O
effacement	O
seems	O
to	O
be	O
a	O
more	O
reliable	O
and	O
practical	O
parameter	O
that	O
will	O
be	O
preferred	O
in	O
that	O
prediction	O
.	O

The	O
data	O
are	O
compatible	O
with	O
the	O
idea	O
that	O
YLL031c	B-GENE
transfers	O
the	O
ethanolaminephosphate	O
to	O
the	O
inner	O
alpha1	O
-	O
2	O
-	O
linked	O
mannose	O
,	O
i	O
.	O
e	O
.	O
the	O
group	O
that	O
links	O
the	O
GPI	O
lipid	O
anchor	O
to	O
proteins	O
,	O
whereas	O
Mcd4p	B-GENE
and	O
Gpi7p	B-GENE
transfer	O
ethanolaminephosphate	O
onto	O
the	O
alpha1	O
-	O
4	O
-	O
and	O
alpha1	O
-	O
6	O
-	O
linked	O
mannoses	O
of	O
the	O
GPI	O
anchor	O
,	O
respectively	O
.	O

The	O
C	O
terminus	O
of	O
TRBP	B-GENE
binds	O
to	O
CBP	B-GENE
/	O
p300	B-GENE
and	O
DRIP130	B-GENE
,	O
a	O
component	O
of	O
the	O
DRIP	B-GENE
/	O
TRAP	B-GENE
/	O
ARC	B-GENE
complex	O
,	O
which	O
suggests	O
that	O
TRBP	B-GENE
may	O
activate	O
transcription	O
by	O
means	O
of	O
such	O
interactions	O
.	O

The	O
patients	O
who	O
presented	O
with	O
mucocutaneous	O
disease	O
also	O
had	O
low	O
CD4	B-GENE
+	I-GENE
T	O
lymphocyte	O
counts	O
,	O
and	O
most	O
of	O
them	O
had	O
AIDS	O
defining	O
illnesses	O
.	O

Increased	O
dietary	O
energy	O
decreased	O
PAB	O
and	O
the	O
use	O
of	O
added	O
dietary	O
CO	O
rather	O
than	O
PF	O
decreased	O
PSHL	O
in	O
broiler	O
breeders	O
between	O
26	O
and	O
47	O
wk	O
of	O
age	O
.	O

The	O
gene	O
amplification	O
model	O
of	O
Coquelle	O
et	O
al	O
.	O

Hierarchy	O
of	O
protein	B-GENE
tyrosine	I-GENE
kinases	I-GENE
in	O
interleukin	B-GENE
-	I-GENE
2	I-GENE
(	O
IL	B-GENE
-	I-GENE
2	I-GENE
)	O
signaling	O
:	O
activation	O
of	O
syk	B-GENE
depends	O
on	O
Jak3	B-GENE
;	O
however	O
,	O
neither	O
Syk	B-GENE
nor	O
Lck	B-GENE
is	O
required	O
for	O
IL	B-GENE
-	I-GENE
2	I-GENE
-	O
mediated	O
STAT	B-GENE
activation	O
.	O

Immobilized	O
dimers	O
of	O
N	B-GENE
-	I-GENE
cadherin	I-GENE
-	O
Fc	B-GENE
chimera	O
mimic	O
cadherin	O
-	O
mediated	O
cell	O
contact	O
formation	O
:	O
contribution	O
of	O
both	O
outside	O
-	O
in	O
and	O
inside	O
-	O
out	O
signals	O
.	O

The	O
monoclonal	O
immunoglobulin	B-GENE
products	O
of	O
plasma	O
cell	O
neoplasm	O
can	O
give	O
rise	O
to	O
a	O
variety	O
of	O
manifestations	O
including	O
hyperviscosity	O
,	O
amyloidosis	O
,	O
cryoglobulinemia	O
,	O
neuropathy	O
,	O
and	O
renal	O
failure	O
.	O

Investigation	O
of	O
the	O
structural	O
basis	O
of	O
the	O
interaction	O
between	O
human	B-GENE
Igs	I-GENE
and	O
gp120	B-GENE
shows	O
that	O
the	O
viral	B-GENE
gp120	I-GENE
SAg	I-GENE
can	O
interact	O
only	O
with	O
a	O
subset	O
of	O
human	B-GENE
V	I-GENE
(	I-GENE
H	I-GENE
)	I-GENE
3	I-GENE
+	I-GENE
Igs	I-GENE
.	O

Double	O
-	O
blind	O
,	O
placebo	O
-	O
controlled	O
trial	O
.	O

Here	O
,	O
it	O
is	O
shown	O
that	O
TAFII250	B-GENE
,	O
the	O
largest	O
subunit	O
of	O
TFIID	B-GENE
,	O
contains	O
two	O
tandem	O
bromodomain	O
modules	O
that	O
bind	O
selectively	O
to	O
multiply	O
acetylated	O
histone	B-GENE
H4	I-GENE
peptides	I-GENE
.	O

Endostatin	O
treatment	O
for	O
10	O
minutes	O
or	O
24	O
hours	O
induced	O
tyrosine	O
phosphorylation	O
of	O
Shb	B-GENE
and	O
formation	O
of	O
multiprotein	O
complexes	O
.	O

The	O
transcript	O
was	O
initially	O
identified	O
as	O
a	O
partial	O
cDNA	O
sequence	O
in	O
the	O
course	O
of	O
constructing	O
a	O
transcript	O
map	O
of	O
the	O
region	O
between	O
markers	O
D11S1765	B-GENE
and	O
uteroglobin	B-GENE
known	O
to	O
encompass	O
the	O
gene	O
causing	O
Best	O
disease	O
.	O

The	O
real	O
challenge	O
for	O
the	O
future	O
will	O
be	O
the	O
management	O
of	O
patients	O
who	O
do	O
not	O
respond	O
to	O
first	O
-	O
line	O
treatment	O
.	O

Iodine	O
deficiency	O
disorders	O
in	O
Bangladesh	O
.	O

RESULTS	O
:	O
Soluble	O
CD23	B-GENE
levels	O
were	O
significantly	O
higher	O
in	O
women	O
with	O
endometriosis	O
before	O
treatment	O
than	O
in	O
ten	O
normal	O
controls	O
.	O

CONCLUSION	O
:	O
Our	O
findings	O
suggest	O
that	O
endometriosis	O
increases	O
soluble	O
CD23	B-GENE
levels	O
,	O
which	O
can	O
be	O
suppressed	O
with	O
either	O
danazol	O
or	O
leuprolide	O
acetate	O
injection	O
.	O

To	O
isolate	O
this	O
gene	O
,	O
a	O
P	O
-	O
1	O
artificial	O
chromosome	O
(	O
PAC	O
)	O
library	O
was	O
screened	O
with	O
a	O
full	B-GENE
length	I-GENE
UGT2B7	I-GENE
probe	O
and	O
a	O
clone	O
of	O
approximately	O
100	O
kb	O
in	O
length	O
was	O
isolated	O
.	O

Age	O
>	O
/	O
=	O
50	O
years	O
(	O
odds	O
ratio	O
[	O
OR	O
]	O
,	O
14	O
.	O
1	O
)	O
,	O
BMI	O
>	O
/	O
=	O
28	O
kg	O
/	O
m	O
(	O
2	O
)	O
(	O
OR	O
,	O
5	O
.	O
7	O
)	O
,	O
triglycerides	O
>	O
/	O
=	O
1	O
.	O
7	O
mmol	O
/	O
L	O
(	O
OR	O
,	O
5	O
)	O
,	O
and	O
alanine	B-GENE
aminotransferase	I-GENE
(	O
ALT	B-GENE
)	O
>	O
/	O
=	O
2N	O
(	O
OR	O
,	O
4	O
.	O
6	O
)	O
were	O
independently	O
associated	O
with	O
septal	O
fibrosis	O
.	O

However	O
,	O
the	O
elderly	O
group	O
showed	O
significantly	O
longer	O
mean	O
residence	O
times	O
(	O
MRTs	O
)	O
and	O
lower	O
plasma	O
clearance	O
of	O
lidocaine	O
during	O
the	O
period	O
compared	O
with	O
the	O
adult	O
group	O
(	O
P	O
<	O
.	O
05	O
)	O
.	O

Here	O
,	O
we	O
show	O
that	O
the	O
zinc	B-GENE
finger	I-GENE
protein	I-GENE
Gis1	I-GENE
acts	O
as	O
a	O
dosage	O
-	O
dependent	O
suppressor	O
of	O
the	O
rim15Delta	B-GENE
defect	O
in	O
nutrient	O
limitation	O
-	O
induced	O
transcriptional	O
derepression	O
of	O
SSA3	B-GENE
.	O

The	O
so	O
-	O
called	O
"	B-GENE
SH3	I-GENE
"	I-GENE
segment	I-GENE
of	O
the	O
linker	O
domain	O
,	O
in	O
contrast	O
,	O
shows	O
species	O
-	O
specific	O
sequence	O
identity	O
in	O
all	O
but	O
one	O
amino	O
acid	O
residues	O
in	O
both	O
factors	O
,	O
in	O
cattle	O
,	O
human	O
,	O
and	O
mouse	O
.	O

No	O
differences	O
in	O
total	O
cholesterol	O
levels	O
were	O
observed	O
between	O
mapuches	O
and	O
aymaras	O
.	O

Up	O
to	O
95	O
%	O
of	O
the	O
total	O
UV	O
exposure	O
received	O
is	O
in	O
the	O
UV	O
-	O
A	O
waveband	O
(	O
320	O
-	O
400	O
nm	O
)	O
.	O

To	O
begin	O
to	O
characterize	O
the	O
role	O
of	O
the	O
RNA	O
subunits	O
in	O
enzyme	O
function	O
and	O
substrate	O
specificity	O
,	O
we	O
swapped	O
two	O
hairpin	O
structures	O
(	O
MRP3	O
and	O
P3	O
)	O
between	O
RNase	B-GENE
MRP	I-GENE
RNA	I-GENE
and	O
RNase	B-GENE
P	I-GENE
RNA	I-GENE
of	I-GENE
S	I-GENE
.	I-GENE
cerevisiae	I-GENE
.	O

Among	O
genes	O
induced	O
by	O
added	O
pMesogenin1	B-GENE
is	O
Xwnt	B-GENE
-	I-GENE
8	I-GENE
,	O
a	O
signaling	O
factor	O
that	O
induces	O
a	O
similar	O
repertoire	O
of	O
marker	O
genes	O
and	O
a	O
similar	O
cellular	O
phenotype	O
.	O

Accordingly	O
,	O
no	O
Ha	B-GENE
-	I-GENE
ras	I-GENE
codon	I-GENE
12	I-GENE
mutations	O
are	O
found	O
in	O
the	O
EtNU	O
-	O
induced	O
mammary	O
tumors	O
.	O

False	O
positive	O
PET	O
FDG	O
corresponded	O
to	O
lung	O
infection	O
,	O
degenerative	O
bone	O
disease	O
,	O
and	O
reconstruction	O
artifact	O
.	O

Tumor	O
stages	O
were	O
IIB	O
(	O
T3	O
N0	O
)	O
in	O
52	O
%	O
,	O
IIIA	O
in	O
15	O
%	O
,	O
and	O
IIIB	O
in	O
27	O
%	O
of	O
patients	O
.	O

Similarly	O
,	O
comparison	O
of	O
percentage	O
reductions	O
of	O
heart	O
rate	O
at	O
supine	O
,	O
sitting	O
and	O
exercise	O
by	O
repeated	O
measure	O
analysis	O
showed	O
the	O
Malays	O
to	O
have	O
significantly	O
higher	O
change	O
compared	O
to	O
the	O
Chinese	O
(	O
p	O
=	O
0	O
.	O
040	O
)	O
.	O

Consistent	O
with	O
our	O
model	O
,	O
CTCF	B-GENE
binding	O
is	O
abolished	O
by	O
DNA	O
methylation	O
.	O

OBJECTIVE	O
:	O
To	O
determine	O
the	O
efficacy	O
and	O
safety	O
of	O
amphotericin	O
B	O
oral	O
suspension	O
(	O
ABOS	O
)	O
for	O
the	O
treatment	O
of	O
fluconazole	O
refractory	O
oral	O
candidiasis	O
in	O
persons	O
with	O
HIV	O
infection	O
.	O

The	O
experimentally	O
mapped	O
regions	O
of	O
RPB5	B-GENE
involved	O
in	O
these	O
interactions	O
correspond	O
to	O
distinct	O
and	O
surface	O
-	O
exposed	O
alpha	O
-	O
helical	O
structures	O
.	O

The	O
model	O
indicates	O
that	O
a	O
0	O
.	O
076	O
%	O
reduction	O
in	O
cigarette	O
consumption	O
is	O
associated	O
with	O
the	O
availability	O
of	O
nicotine	O
patches	O
after	O
1992	O
.	O

Paper	O
alert	O
.	O

The	O
tryptase	B-GENE
locus	I-GENE
also	O
contains	O
at	O
least	O
four	O
tryptase	B-GENE
-	I-GENE
like	I-GENE
pseudogenes	I-GENE
,	O
including	O
mastin	B-GENE
,	O
a	O
gene	O
expressed	O
in	O
dogs	O
but	O
not	O
in	O
humans	O
.	O

The	O
cellular	O
part	O
of	O
the	O
third	O
chimeric	O
clone	O
shows	O
significant	O
homology	O
to	O
an	O
exon	O
of	O
the	O
human	B-GENE
tyrosine	I-GENE
phosphatase	I-GENE
1	I-GENE
gene	I-GENE
,	O
although	O
oriented	O
in	O
the	O
antisense	O
direction	O
compared	O
to	O
the	O
adjacent	O
LTR	O
.	O

OBJECTIVE	O
:	O
This	O
study	O
was	O
conducted	O
to	O
assess	O
the	O
relative	O
roles	O
of	O
99mTc	O
-	O
sestamibi	O
scintimammography	O
and	O
sonography	O
in	O
the	O
evaluation	O
of	O
breast	O
lesions	O
that	O
are	O
indeterminate	O
or	O
suspicious	O
on	O
mammography	O
or	O
clinical	O
examination	O
.	O

Mutational	O
analyses	O
showed	O
that	O
in	O
-	O
frame	O
stop	O
codons	O
introduced	O
into	O
five	O
of	O
seven	O
RNA	B-GENE
2	I-GENE
ORFs	I-GENE
did	O
not	O
affect	O
accumulation	O
of	O
progeny	O
LIYV	B-GENE
RNA	I-GENE
1	I-GENE
or	O
RNA	B-GENE
2	I-GENE
,	O
confirming	O
that	O
RNA	B-GENE
2	I-GENE
does	O
not	O
encode	O
proteins	O
necessary	O
for	O
LIYV	O
RNA	O
replication	O
.	O

Role	O
of	O
NH	O
(	O
2	O
)	O
-	O
and	O
COOH	O
-	O
terminal	O
domains	O
of	O
the	O
P	B-GENE
protein	I-GENE
of	O
human	O
parainfluenza	O
virus	O
type	O
3	O
in	O
transcription	O
and	O
replication	O
.	O

Phosphorylation	O
of	O
tyrosine	O
residues	O
in	O
the	O
kinase	O
domain	O
and	O
juxtamembrane	O
region	O
regulates	O
the	O
biological	O
and	O
catalytic	O
activities	O
of	O
Eph	B-GENE
receptors	I-GENE
.	O

RESULTS	O
:	O
Fournier	O
'	O
s	O
gangrene	O
occurs	O
worldwide	O
.	O

Genomic	O
DNA	O
sequencing	O
in	O
the	O
vicinity	O
of	O
methylmalonyl	B-GENE
-	I-GENE
CoA	I-GENE
mutase	I-GENE
gene	I-GENE
(	O
mutAB	B-GENE
)	O
from	O
a	O
rifamycin	O
SV	O
-	O
producing	O
Amycolatopsis	O
mediterranei	O
U32	O
allowed	O
us	O
to	O
clone	O
,	O
sequence	O
,	O
and	O
identify	O
a	O
gene	O
encoding	O
a	O
novel	O
serine	B-GENE
/	I-GENE
threonine	I-GENE
protein	I-GENE
kinase	I-GENE
(	O
amk	B-GENE
)	O
.	O

IL	B-GENE
-	I-GENE
2	I-GENE
is	O
accepted	O
as	O
a	O
standard	O
treatment	O
used	O
alone	O
,	O
or	O
in	O
combination	O
with	O
chemotherapy	O
or	O
biotherapy	O
in	O
the	O
management	O
of	O
metastatic	O
melanoma	O
and	O
metastatic	O
renal	O
cell	O
carcinoma	O
.	O

Moreover	O
,	O
expression	O
of	O
antisense	B-GENE
Ha	I-GENE
-	I-GENE
Ras	I-GENE
or	O
dominant	B-GENE
negative	I-GENE
Raf	I-GENE
-	I-GENE
1	I-GENE
abrogated	O
the	O
mitogenic	O
effect	O
of	O
TGF	B-GENE
-	I-GENE
beta1	I-GENE
in	O
TSU	O
-	O
Pr1	O
,	O
and	O
the	O
TGF	B-GENE
-	I-GENE
beta1	I-GENE
inhibition	O
of	O
DU145	O
was	O
switched	O
to	O
stimulation	O
by	O
V12Ha	B-GENE
-	I-GENE
Ras	I-GENE
transfection	O
.	O

Taken	O
together	O
,	O
our	O
data	O
suggest	O
that	O
prostate	O
carcinomas	O
with	O
the	O
Ras	B-GENE
/	O
MAPK	B-GENE
pathway	O
activation	O
might	O
have	O
a	O
selective	O
growth	O
advantage	O
by	O
autocrine	O
TGF	B-GENE
-	I-GENE
beta1	I-GENE
production	O
.	O

Vbeta	B-GENE
segments	O
are	O
appended	O
to	O
DJbeta	B-GENE
rearrangements	O
,	O
with	O
little	O
or	O
no	O
direct	O
Vbeta	B-GENE
to	O
Jbeta	B-GENE
joining	O
,	O
despite	O
12	O
/	O
23	O
compatibility	O
of	O
Vbeta	B-GENE
23	I-GENE
-	I-GENE
RSSs	I-GENE
and	O
Jbeta12	B-GENE
-	I-GENE
RSSs	I-GENE
.	O

For	O
oral	O
administration	O
,	O
AUC0	O
-	O
infinity	O
was	O
58	O
.	O
47	O
+	O
/	O
-	O
16	O
.	O
37	O
microg	O
x	O
h	O
/	O
ml	O
,	O
t1	O
/	O
2beta	O
was	O
18	O
.	O
39	O
+	O
/	O
-	O
0	O
.	O
06	O
hours	O
,	O
maximum	O
concentration	O
(	O
Cmax	O
)	O
was	O
2	O
.	O
12	O
+	O
/	O
-	O
00	O
.	O
51	O
microg	O
/	O
ml	O
,	O
time	O
to	O
Cmax	O
was	O
2	O
.	O
20	O
+	O
/	O
-	O
2	O
.	O
17	O
hours	O
,	O
mean	O
absorption	O
time	O
was	O
2	O
.	O
09	O
+	O
/	O
-	O
0	O
.	O
51	O
hours	O
,	O
and	O
bioavailability	O
was	O
42	O
+	O
/	O
-	O
0	O
.	O
42	O
%	O
.	O

In	O
experiment	O
2	O
,	O
no	O
difference	O
in	O
gastric	O
emptying	O
of	O
40	O
%	O
peptone	O
or	O
25	O
%	O
glucose	O
was	O
found	O
between	O
rats	O
receiving	O
TPN	O
and	O
those	O
receiving	O
intragastric	O
nutrition	O
for	O
10	O
to	O
12	O
days	O
.	O

In	O
contrast	O
,	O
H	B-GENE
-	I-GENE
NS	I-GENE
negative	O
regulation	O
operated	O
only	O
in	O
the	O
absence	O
of	O
Fur	B-GENE
.	O

Thus	O
,	O
SAG	B-GENE
appears	O
to	O
control	O
cell	O
cycle	O
progression	O
in	O
yeast	O
by	O
promoting	O
ubiquitination	O
and	O
degradation	O
of	O
cell	O
cycle	O
regulatory	O
proteins	O
.	O

It	O
brings	O
about	O
fatigue	O
,	O
negative	O
moods	O
,	O
and	O
impaired	O
health	O
,	O
sleep	O
,	O
safety	O
,	O
and	O
working	O
capacity	O
.	O

This	O
demonstrates	O
that	O
treatment	O
of	O
the	O
graft	O
recipient	O
for	O
a	O
relatively	O
short	O
period	O
during	O
and	O
after	O
surgery	O
has	O
a	O
favorable	O
effect	O
on	O
the	O
survival	O
of	O
grafted	O
dopaminergic	O
neurons	O
.	O

The	O
relationships	O
among	O
blood	O
concentrations	O
of	O
thyroid	O
hormones	O
and	O
selenium	O
,	O
zinc	O
,	O
retinol	O
,	O
and	O
alpha	O
-	O
tocopherol	O
were	O
studied	O
in	O
44	O
healthy	O
Northern	O
Italian	O
oldest	O
-	O
old	O
subjects	O
(	O
age	O
range	O
,	O
90	O
-	O
107	O
yr	O
)	O
,	O
selected	O
by	O
the	O
criteria	O
of	O
the	O
SENIEUR	O
protocol	O
.	O

Chinese	O
Spring	O
(	O
CS	O
)	O
carrying	O
the	O
Q	B-GENE
gene	I-GENE
to	O
those	O
of	O
a	O
chromosome	O
deletion	O
line	O
of	O
CS	O
,	O
namely	O
,	O
q5	O
,	O
which	O
lacks	O
15	O
%	O
of	O
5AL	O
including	O
the	O
Q	B-GENE
gene	I-GENE
.	O

Investigations	O
using	O
hippocampal	O
slices	O
maintained	O
in	O
vitro	O
have	O
demonstrated	O
that	O
bursts	O
of	O
oscillatory	O
field	O
potentials	O
in	O
the	O
gamma	O
frequency	O
range	O
(	O
30	O
-	O
80	O
Hz	O
)	O
are	O
followed	O
by	O
a	O
slower	O
oscillation	O
in	O
the	O
beta	O
1	O
range	O
(	O
12	O
-	O
20	O
Hz	O
)	O
.	O

Karger	O
AG	O
,	O
Basel	O

During	O
surgery	O
bone	O
cysts	O
were	O
excised	O
and	O
filled	O
by	O
bone	O
grafts	O
.	O

Urinary	O
LTE4	O
increased	O
after	O
both	O
challenges	O
the	O
rise	O
being	O
higher	O
following	O
oral	O
as	O
compared	O
to	O
inhalation	O
provocation	O
(	O
p	O
=	O
0	O
.	O
0001	O
)	O
.	O

Basal	O
FVR	O
was	O
reduced	O
by	O
approximately	O
18	O
%	O
by	O
ERT	O
and	O
HRT	O
,	O
but	O
FVR	O
responses	O
to	O
noradrenaline	O
,	O
angiotensin	B-GENE
II	I-GENE
,	O
acetylcholine	O
and	O
nitroprusside	O
were	O
unaffected	O
.	O

Three	O
FGF	B-GENE
-	I-GENE
AS	I-GENE
cDNAs	I-GENE
were	O
isolated	O
;	O
the	O
full	B-GENE
-	I-GENE
length	I-GENE
FGF	I-GENE
-	I-GENE
AS	I-GENE
mRNA	I-GENE
and	O
two	O
alternative	O
splice	O
variants	O
lacking	O
exon	O
2	O
or	O
exons	O
2	O
and	O
3	O
of	O
the	O
FGF	B-GENE
-	I-GENE
AS	I-GENE
sequence	I-GENE
.	O

Characterization	O
of	O
polymorphic	O
TNRs	O
in	O
novel	O
and	O
even	O
known	O
genes	O
expressed	O
in	O
human	O
spinal	O
cord	O
is	O
likely	O
to	O
help	O
in	O
the	O
identification	O
of	O
new	O
candidates	O
for	O
genes	O
involved	O
in	O
neurodegenerative	O
disorders	O
.	O

Finally	O
,	O
in	O
situ	O
RNA	O
hybridization	O
studies	O
revealed	O
a	O
very	O
specific	O
pattern	O
of	O
EphA8	B-GENE
gene	I-GENE
expression	O
restricted	O
to	O
the	O
rostral	O
region	O
of	O
midbrain	O
tectum	O
during	O
embryonic	O
development	O
.	O

Transfection	O
of	O
cDNAs	O
for	O
three	O
mutant	O
enzymes	O
into	O
FPGS	B-GENE
-	O
null	O
Chinese	O
hamster	O
ovary	O
cells	O
restored	O
a	O
reduced	O
level	O
of	O
clonal	O
growth	O
,	O
whereas	O
a	O
T339I	O
mutant	O
supported	O
growth	O
at	O
a	O
level	O
comparable	O
to	O
that	O
of	O
the	O
wild	O
-	O
type	O
enzyme	O
.	O

SETTING	O
:	O
University	O
of	O
Paris	O
VII	O
hospital	O
.	O
Patient	O
(	O
s	O
)	O
:	O
Nine	O
women	O
had	O
embolization	O
for	O
symptomatic	O
myoma	O
,	O
with	O
12	O
pregnancies	O
observed	O
.	O

Improving	O
fissure	O
sealant	O
quality	O
:	O
mechanical	O
preparation	O
and	O
filling	O
level	O
.	O

The	O
Menopause	O
-	O
Rating	O
-	O
Scale	O
(	O
MRS	O
I	O
)	O
was	O
used	O
in	O
clinical	O
practice	O
since	O
1992	O
.	O

The	O
MRS	O
II	O
meets	O
a	O
high	O
methodological	O
standard	O
as	O
an	O
instrument	O
standardized	O
in	O
the	O
population	O
.	O

The	O
protein	O
encoded	O
by	O
the	O
fruA	B-GENE
transcript	I-GENE
is	O
well	O
conserved	O
with	O
the	O
D	B-GENE
.	I-GENE
melanogaster	I-GENE
type	I-GENE
A	I-GENE
protein	I-GENE
,	O
particularly	O
the	O
BTB	B-GENE
protein	I-GENE
-	O
protein	O
-	O
binding	O
domain	O
,	O
which	O
is	O
encoded	O
by	O
exons	O
I	O
and	O
II	O
and	O
is	O
100	O
%	O
conserved	O
.	O

In	O
addition	O
,	O
the	O
mouse	O
ortholog	O
(	O
Mharp	B-GENE
/	O
Smarcal1	B-GENE
)	O
was	O
cloned	O
,	O
and	O
the	O
Caenorhabditis	O
elegans	O
ortholog	O
(	O
CEHARP	B-GENE
)	O
was	O
identified	O
in	O
the	O
GenBank	O
database	O
.	O

Sparfloxacin	O
and	O
clinafloxacin	O
were	O
evaluated	O
against	O
Enterococcus	O
faecium	O
SF2149	O
and	O
Enterococcus	O
faecalis	O
WH245	O
,	O
respectively	O
.	O

ECP	B-GENE
and	O
tryptase	B-GENE
levels	O
in	O
serum	O
were	O
measured	O
before	O
and	O
after	O
the	O
last	O
oral	O
challenge	O
.	O

Tolterodine	O
users	O
were	O
7	O
.	O
5	O
times	O
more	O
likely	O
to	O
have	O
received	O
another	O
spasmolytic	O
drug	O
(	O
RR	O
7	O
.	O
5	O
,	O
95	O
%	O
CI	O
4	O
.	O
8	O
to	O
11	O
.	O
9	O
)	O
.	O

For	O
an	O
unsupervised	O
program	O
,	O
the	O
costs	O
were	O
estimated	O
at	O
$	O
311	O
for	O
the	O
first	O
year	O
and	O
$	O
73	O
for	O
all	O
additional	O
years	O
.	O

The	O
presence	O
of	O
such	O
a	O
putative	O
RNA	O
-	O
binding	O
domain	O
suggests	O
a	O
mechanism	O
for	O
the	O
observed	O
autoregulation	O
of	O
bacteriophage	O
T4	B-GENE
DNA	I-GENE
polymerase	I-GENE
synthesis	O
by	O
binding	O
to	O
its	O
own	O
mRNA	O
.	O

Deletion	O
and	O
mutational	O
analyses	O
revealed	O
two	O
positive	O
cis	O
-	O
regulatory	O
elements	O
in	O
this	O
region	O
that	O
are	O
essential	O
for	O
CSX1	B-GENE
expression	O
in	O
cardiomyocytes	O
.	O

Functional	O
studies	O
which	O
introduced	O
a	O
mutation	O
in	O
the	O
AP2	B-GENE
core	I-GENE
binding	I-GENE
region	I-GENE
as	O
well	O
as	O
cotransfection	O
experiments	O
using	O
an	O
AP2	B-GENE
expression	O
vector	O
revealed	O
that	O
AP2	B-GENE
exerts	O
a	O
repressive	O
role	O
on	O
the	O
HGF	B-GENE
gene	I-GENE
promoter	I-GENE
activity	O
.	O

In	O
reconstitution	O
experiments	O
,	O
we	O
first	O
showed	O
that	O
expression	O
in	O
the	O
RAW	O
264	O
.	O
7	O
cell	O
line	O
of	O
C	B-GENE
-	I-GENE
terminal	I-GENE
Src	I-GENE
kinase	I-GENE
(	O
Csk	B-GENE
)	O
inhibited	O
and	O
that	O
of	O
a	O
membrane	O
-	O
anchored	O
,	O
gain	O
-	O
of	O
-	O
function	O
Csk	B-GENE
abolished	O
the	O
Fc	B-GENE
gamma	I-GENE
R	I-GENE
-	O
mediated	O
signaling	O
that	O
leads	O
to	O
phagocytosis	O
in	O
a	O
kinase	O
-	O
dependent	O
manner	O
.	O

In	O
contrast	O
,	O
c	B-GENE
-	I-GENE
Src	I-GENE
-	I-GENE
derived	I-GENE
construct	I-GENE
(	O
a	B-GENE
-	I-GENE
Src	I-GENE
)	O
,	O
that	O
was	O
excluded	O
from	O
detergent	O
-	O
resistant	O
membranes	O
,	O
could	O
not	O
restore	O
the	O
series	O
of	O
phagocytosis	O
signaling	O
.	O

The	O
pJR	O
vectors	O
differ	O
among	O
them	O
in	O
:	O
(	O
a	O
)	O
the	O
selectable	O
marker	O
(	O
Saccharomyces	O
cerevisiae	O
LEU	B-GENE
2	I-GENE
gene	I-GENE
,	O
which	O
complements	O
S	B-GENE
.	I-GENE
pombe	I-GENE
leu1	I-GENE
-	I-GENE
gene	I-GENE
and	O
S	O
.	O
pombe	O
ura4	B-GENE
+	I-GENE
and	O
his3	B-GENE
+	I-GENE
genes	I-GENE
)	O
;	O
(	O
b	O
)	O
the	O
thiamine	O
-	O
repressible	O
nmt1	B-GENE
promoter	I-GENE
(	O
3X	O
,	O
41X	O
and	O
81X	O
with	O
extremely	O
high	O
,	O
moderate	O
or	O
low	O
transcription	O
efficiency	O
,	O
respectively	O
)	O
;	O
and	O
(	O
c	O
)	O
the	O
multiple	O
cloning	O
site	O
(	O
two	O
multiple	O
cloning	O
sites	O
,	O
with	O
12	O
restriction	O
sites	O
each	O
)	O
.	O

(	O
GUT	O
)	O
Sera	O
of	O
30	O
montoux	O
negative	O
healthy	O
adults	O
(	O
age	O
/	O
sex	O
matched	O
)	O
were	O
taken	O
as	O
control	O
by	O
detecting	O
IgG	B-GENE
anti	I-GENE
bodies	I-GENE
to	O
A60	B-GENE
antigen	I-GENE
.	O

Franz	O
Schubert	O
-	O
-	O
his	O
life	O
,	O
music	O
and	O
diseases	O

These	O
results	O
demonstrate	O
that	O
N	O
-	O
glycans	O
flanking	O
the	O
receptor	O
-	O
binding	O
site	O
of	O
the	O
HA	B-GENE
molecule	I-GENE
are	O
potent	O
regulators	O
of	O
influenza	O
virus	O
growth	O
,	O
with	O
the	O
glycan	O
at	O
Asn149	O
being	O
dominant	O
and	O
that	O
at	O
Asn123	O
being	O
less	O
effective	O
.	O

RESULTS	O
:	O
The	O
introduction	O
of	O
the	O
PAIP	O
resulted	O
in	O
a	O
significant	O
(	O
p	O
<	O
0	O
.	O
001	O
)	O
reduction	O
in	O
contaminating	O
WBCs	O
(	O
median	O
,	O
30	O
,	O
000	O
)	O
from	O
the	O
numbers	O
seen	O
with	O
FIP	O
(	O
median	O
,	O
2	O
,	O
300	O
,	O
000	O
)	O
while	O
maintaining	O
the	O
separation	O
efficacy	O
(	O
47	O
%	O
)	O
and	O
separation	O
time	O
.	O

All	O
were	O
tested	O
for	O
serum	O
ferritin	B-GENE
(	O
SF	B-GENE
)	O
,	O
hemoglobin	B-GENE
(	O
Hb	B-GENE
)	O
level	O
and	O
asked	O
for	O
detailed	O
histories	O
of	O
donations	O
and	O
iron	O
supplementation	O
.	O

Vascular	B-GENE
endothelial	I-GENE
growth	I-GENE
factor	I-GENE
(	O
VEGF	B-GENE
)	O
,	O
a	O
potent	O
agonist	O
secreted	O
by	O
virtually	O
all	O
cells	O
,	O
controls	O
migration	O
and	O
division	O
of	O
vascular	O
endothelial	O
cells	O
.	O

The	O
antioxidant	O
agent	O
pyrrolidine	O
dithiocarbamate	O
(	O
PDTC	O
)	O
has	O
been	O
shown	O
to	O
protect	O
endothelial	O
cells	O
(	O
EC	O
)	O
from	O
pro	O
-	O
inflammatory	O
-	O
induced	O
and	O
pro	O
-	O
oxidant	O
-	O
induced	O
NF	B-GENE
-	I-GENE
kappaB	I-GENE
activation	O
.	O

We	O
further	O
studied	O
the	O
effects	O
of	O
SIE	B-GENE
-	I-GENE
1	I-GENE
hypermethylation	O
on	O
p21WAF1	B-GENE
induction	O
by	O
STAT	B-GENE
activation	O
.	O

In	O
the	O
pRb	B-GENE
(	I-GENE
-	I-GENE
)	I-GENE
SAOS	O
-	O
2	O
cell	O
line	O
transiently	O
transfected	O
with	O
a	O
reporter	O
plasmid	O
containing	O
six	O
tal	B-GENE
-	I-GENE
1	I-GENE
binding	I-GENE
site	I-GENE
,	O
pRb	B-GENE
enhances	O
the	O
transcriptional	O
activity	O
of	O
tal	B-GENE
-	I-GENE
1	I-GENE
-	O
E12	B-GENE
-	O
Lmo2	B-GENE
and	O
tal	B-GENE
-	I-GENE
1	I-GENE
-	O
E12	B-GENE
-	O
Lmo2	B-GENE
-	O
Ldb1	B-GENE
complexes	O
but	O
not	O
that	O
of	O
a	O
tal	B-GENE
-	I-GENE
1	I-GENE
-	O
E12	B-GENE
heterodimer	O
.	O

This	O
effect	O
was	O
not	O
seen	O
in	O
conjunction	O
with	O
oxycodone	O
,	O
a	O
morphine	B-GENE
-	I-GENE
like	I-GENE
mu	I-GENE
-	I-GENE
receptor	I-GENE
agonist	O
.	O

Neurofibromatosis	O
of	O
the	O
breast	O
in	O
a	O
patient	O
with	O
Morbus	O
von	O
Recklinghausen	O

In	O
the	O
premating	O
period	O
male	O
rate	O
of	O
aggression	O
was	O
not	O
significantly	O
correlated	O
with	O
testosterone	O
level	O
.	O

These	O
results	O
support	O
the	O
hypothesis	O
that	O
in	O
the	O
presence	O
of	O
tryptophan	O
the	O
ribosome	O
translating	O
tnaC	B-GENE
blocks	O
Rho	B-GENE
'	O
s	O
access	O
to	O
the	O
boxA	B-GENE
and	O
rut	B-GENE
sites	I-GENE
,	O
thereby	O
preventing	O
transcription	O
termination	O
.	O

In	O
situ	O
hybridization	O
with	O
the	O
antisense	O
RNA	O
probes	O
further	O
supported	O
the	O
expression	O
changes	O
of	O
these	O
six	O
clones	O
and	O
localized	O
the	O
changes	O
in	O
multiple	O
germ	O
cell	O
stages	O
as	O
well	O
as	O
other	O
cell	O
types	O
(	O
Sertoli	O
,	O
interstitial	O
and	O
peritubular	O
cells	O
)	O
.	O

The	O
administration	O
of	O
the	O
GnRH	B-GENE
agonist	O
reduced	O
the	O
bone	O
mineral	O
density	O
in	O
the	O
whole	O
femur	O
to	O
91	O
.	O
0	O
%	O
of	O
that	O
in	O
the	O
control	O
group	O
.	O

This	O
study	O
shows	O
that	O
C	B-GENE
/	I-GENE
EBPbeta	I-GENE
is	O
the	O
predominant	O
C	B-GENE
/	I-GENE
EBP	I-GENE
isoform	I-GENE
found	O
in	O
activated	O
stellate	O
cells	O
and	O
that	O
increased	O
C	B-GENE
/	I-GENE
EBPbeta	I-GENE
protein	I-GENE
and	O
C	B-GENE
/	I-GENE
EBPbeta	I-GENE
binding	O
to	O
a	O
proximal	O
C	B-GENE
/	I-GENE
EBP	I-GENE
binding	I-GENE
site	I-GENE
in	O
the	O
promoter	O
mediates	O
the	O
activating	O
effect	O
of	O
acetaldehyde	O
.	O

As	O
with	O
VP16	B-GENE
,	O
the	O
transactivation	O
function	O
of	O
Luman	B-GENE
is	O
also	O
regulated	O
by	O
HCF	B-GENE
.	O

After	O
two	O
successive	O
rounds	O
of	O
selection	O
by	O
focus	O
formation	O
assay	O
,	O
a	O
transforming	O
ribozyme	O
(	O
Rz007	B-GENE
)	O
was	O
identified	O
.	O

G	O
.	O
,	O
and	O
Hyde	O
,	O
C	O
.	O

The	O
ATR	O
-	O
X	O
syndrome	O
results	O
from	O
mutations	O
of	O
the	O
XH2	B-GENE
gene	I-GENE
,	O
located	O
on	O
the	O
X	O
chromosome	O
(	O
Xq13	O
.	O
3	O
)	O
and	O
coding	O
for	O
a	O
transacting	O
factor	O
which	O
regulates	O
gene	O
expression	O
.	O

AIMS	O
:	O
To	O
evaluate	O
the	O
role	O
of	O
environmental	O
intra	O
-	O
uterine	O
factors	O
in	O
determining	O
the	O
birthweights	O
of	O
twins	O
with	O
increased	O
susceptibility	O
to	O
diabetes	O
and	O
discordant	O
for	O
abnormal	O
responses	O
to	O
the	O
oral	O
glucose	O
tolerance	O
test	O
(	O
OGTT	O
)	O
and	O
verify	O
the	O
possible	O
association	O
of	O
within	O
-	O
pair	O
birthweight	O
differences	O
and	O
metabolic	O
abnormalities	O
in	O
adult	O
life	O
.	O

In	O
NASCIS	O
III	O
,	O
a	O
randomization	O
imbalance	O
occurred	O
that	O
allocated	O
a	O
disproportionate	O
number	O
of	O
patients	O
with	O
no	O
motor	O
deficit	O
(	O
and	O
therefore	O
no	O
chance	O
for	O
recovery	O
)	O
to	O
the	O
lower	O
dose	O
control	O
group	O
.	O

Penicillin	B-GENE
acylase	I-GENE
(	O
PA	B-GENE
)	O
from	O
Escherichia	O
coli	O
ATCC11105	O
is	O
a	O
periplasmic	O
heterodimer	O
consisting	O
of	O
a	O
24	O
kDa	O
small	O
subunit	O
and	O
a	O
65	O
kDa	O
large	O
subunit	O
.	O

A	O
murine	O
expressed	O
sequence	O
tag	O
(	O
EST	O
)	O
showing	O
homology	O
with	O
erythropoietin	B-GENE
receptor	I-GENE
(	O
EPOR	B-GENE
)	O
was	O
identified	O
in	O
the	O
EST	O
database	O
.	O

When	O
the	O
LCx	O
was	O
partially	O
occluded	O
,	O
mild	O
PM	O
-	O
induced	O
tachycardia	O
resulted	O
in	O
decreased	O
AoP	O
(	O
P	O
=	O
0	O
.	O
045	O
)	O
as	O
well	O
as	O
in	O
decreased	O
SV	O
(	O
P	O
=	O
0	O
.	O
048	O
)	O
;	O
the	O
LVEDP	O
remained	O
high	O
(	O
P	O
=	O
0	O
.	O
002	O
)	O
.	O

Activation	O
of	O
nuclear	B-GENE
factor	I-GENE
(	I-GENE
NF	I-GENE
)	I-GENE
-	I-GENE
kappaB	I-GENE
and	O
subsequent	O
proinflammatory	O
gene	O
expression	O
in	O
human	O
airway	O
epithelial	O
cells	O
can	O
be	O
evoked	O
by	O
oxidative	O
stress	O
.	O

GAP	O
JUNCTIONS	O
IN	O
THE	O
BRAIN	O
:	O
PREFACE	O
.	O

We	O
have	O
isolated	O
and	O
functionally	O
characterized	O
the	O
mouse	O
gene	O
for	O
the	O
C2	O
subunit	O
of	O
the	O
20S	B-GENE
proteasome	I-GENE
.	O

Furthermore	O
,	O
as	O
in	O
the	O
human	O
gene	O
,	O
the	O
3	O
'	O
end	O
of	O
the	O
Cacna1f	B-GENE
gene	I-GENE
maps	O
within	O
5	O
kb	O
of	O
the	O
5	O
'	O
end	O
of	O
the	O
mouse	B-GENE
synaptophysin	I-GENE
gene	I-GENE
in	O
a	O
region	O
orthologous	O
to	O
Xp11	O
.	O
23	O
.	O

With	O
the	O
human	B-GENE
Rhotekin	I-GENE
cDNA	I-GENE
as	O
a	O
probe	O
,	O
Northern	O
hybridization	O
revealed	O
that	O
a	O
4	O
.	O
0	O
-	O
kb	O
transcript	O
was	O
expressed	O
at	O
a	O
high	O
level	O
in	O
prostate	O
and	O
at	O
a	O
middle	O
level	O
in	O
13	O
of	O
16	O
tissues	O
examined	O
,	O
but	O
it	O
cannot	O
be	O
detected	O
in	O
liver	O
and	O
lung	O
tissues	O
.	O

Similarly	O
,	O
co	O
-	O
expression	O
of	O
a	O
dominant	O
-	O
negative	O
mutant	O
of	O
p38alpha	B-GENE
,	O
but	O
not	O
of	O
ERK1	B-GENE
,	O
ERK2	B-GENE
,	O
JNK1	B-GENE
,	O
or	O
JNK2	B-GENE
,	O
reduces	O
basal	O
and	O
cadmium	O
-	O
induced	O
pE1	B-GENE
-	I-GENE
luc	I-GENE
activity	O
.	O

BACKGROUND	O
:	O
Gamma	O
knife	O
radiosurgery	O
(	O
GKR	O
)	O
is	O
a	O
safe	O
and	O
effective	O
alternative	O
to	O
surgery	O
for	O
intracranial	O
lesions	O
.	O

It	O
is	O
mainly	O
transcribed	O
in	O
neural	O
structures	O
and	O
in	O
developing	O
organs	O
characterized	O
by	O
epithelial	O
-	O
mesenchymal	O
interactions	O
.	O

CONCLUSION	O
:	O
The	O
alpha2	O
-	O
adrenergic	O
antagonist	O
idazoxan	O
increases	O
glucose	O
-	O
induced	O
sympathetic	O
activity	O
but	O
not	O
energy	O
expenditure	O
in	O
obese	O
subjects	O
.	O

Next	O
,	O
we	O
show	O
that	O
two	O
EMS	O
-	O
induced	O
mutations	O
,	O
previously	O
shown	O
to	O
interact	O
genetically	O
with	O
zipper	O
(	O
Ebr	B-GENE
)	O
,	O
disrupt	O
the	O
RhoA	B-GENE
locus	I-GENE
.	O

Therefore	O
,	O
the	O
results	O
indicate	O
that	O
repeated	O
exposure	O
to	O
amphetamine	O
or	O
apomorphine	O
overcomes	O
the	O
context	O
-	O
dependent	O
component	O
of	O
sensitization	O
of	O
amphetamine	O
-	O
or	O
apomorphine	O
-	O
induced	O
stereotyped	O
behavior	O
.	O

Testing	O
for	O
serum	B-GENE
IgM	I-GENE
binding	O
to	O
GM1	O
ganglioside	O
in	O
clinical	O
practice	O
.	O

Objective	O
responses	O
also	O
occurred	O
in	O
studies	O
that	O
explored	O
sequential	O
use	O
of	O
exemestane	O
after	O
failure	O
of	O
aminoglutethimide	O
(	O
26	O
%	O
with	O
exemestane	O
200	O
mg	O
/	O
day	O
)	O
or	O
other	O
nonsteroidal	O
aromatase	B-GENE
inhibitors	O
(	O
6	O
.	O
6	O
%	O
with	O
exemestane	O
25	O
mg	O
/	O
day	O
)	O
.	O

The	O
science	O
of	O
tissue	O
engineering	O
.	O

Endonuclease	B-GENE
III	I-GENE
(	O
Nth	B-GENE
)	O
of	O
Escherichia	O
coli	O
is	O
a	O
DNA	B-GENE
glycosylase	I-GENE
essential	O
for	O
the	O
removal	O
of	O
oxidised	O
pyrimidine	O
base	O
residues	O
from	O
DNA	O
.	O

The	O
duration	O
of	O
reactive	O
hyperemia	O
decreased	O
with	O
aging	O
,	O
but	O
the	O
difference	O
between	O
males	O
and	O
females	O
was	O
not	O
significant	O
at	O
any	O
age	O
.	O

Acquired	O
bile	O
duct	O
blockage	O
:	O
entry	O
of	O
hepatobiliary	O
agent	O
into	O
an	O
intrahepatic	O
abscess	O
.	O

Furthermore	O
,	O
this	O
study	O
looks	O
at	O
the	O
impact	O
of	O
synthesis	O
conditions	O
on	O
block	O
length	O
and	O
crystallinity	O
,	O
and	O
the	O
impact	O
of	O
the	O
blocking	O
on	O
both	O
,	O
crystallinity	O
and	O
solubility	O
of	O
the	O
polymers	O
.	O

However	O
,	O
little	O
was	O
understood	O
about	O
the	O
normal	O
function	O
of	O
CREB	B-GENE
-	I-GENE
2	I-GENE
in	O
mammalian	O
development	O
or	O
organ	O
physiology	O
.	O

Both	O
the	O
MVBF	O
and	O
the	O
maximum	O
EMG	O
activity	O
in	O
the	O
right	O
masseter	O
and	O
the	O
left	O
anterior	O
temporalis	O
muscles	O
were	O
significantly	O
decreased	O
during	O
muscle	O
pain	O
when	O
the	O
subjects	O
bit	O
on	O
the	O
painful	O
side	O
.	O

The	O
total	O
alkaloids	O
contained	O
in	O
the	O
peel	O
of	O
Atzimba	O
,	O
Lopez	O
,	O
Marciana	O
,	O
Montsama	O
,	O
Murca	O
,	O
and	O
Puebla	O
was	O
lower	O
than	O
the	O
limits	O
recommended	O
for	O
food	O
safety	O
.	O

The	O
detection	O
success	O
rate	O
was	O
determined	O
for	O
different	O
markers	O
using	O
this	O
MEK	B-GENE
.	O

Herein	O
,	O
we	O
show	O
that	O
Smad3	B-GENE
physically	O
interacts	O
with	O
the	O
HMG	B-GENE
box	O
domain	O
of	O
LEF1	B-GENE
and	O
that	O
TGFbeta	B-GENE
and	O
Wnt	B-GENE
pathways	O
synergize	O
to	O
activate	O
transcription	O
of	O
the	O
Xenopus	O
homeobox	O
gene	O
twin	B-GENE
(	O
Xtwn	B-GENE
)	O
.	O

The	O
transmembrane	O
topology	O
of	O
Na	O
(	O
+	O
)	O
/	O
H	O
(	O
+	O
)	O
exchanger	O
NHE3	B-GENE
has	O
been	O
studied	O
using	O
in	O
vitro	O
transcription	O
/	O
translation	O
of	O
two	O
types	O
of	O
fusion	O
vectors	O
designed	O
to	O
test	O
membrane	O
insertion	O
properties	O
of	O
cDNA	O
sequences	O
encoding	O
putative	O
NHE3	B-GENE
membrane	O
spanning	O
domains	O
(	O
msds	O
)	O
.	O

Members	O
of	O
the	O
titin	B-GENE
/	O
myosin	B-GENE
light	I-GENE
chain	I-GENE
kinase	I-GENE
family	O
play	O
an	O
essential	O
role	O
in	O
the	O
organization	O
of	O
the	O
actin	B-GENE
/	O
myosin	B-GENE
cytoskeleton	O
,	O
especially	O
in	O
sarcomere	O
assembly	O
and	O
function	O
.	O

Furthermore	O
,	O
a	O
pTyr317	B-GENE
Shc	I-GENE
phosphopeptide	I-GENE
selectively	O
recognized	O
Grb2	B-GENE
,	O
Sos1	B-GENE
,	O
SHIP	B-GENE
,	O
and	O
the	O
p85	B-GENE
subunit	I-GENE
of	O
phosphatidylinositol	B-GENE
3	I-GENE
'	I-GENE
kinase	I-GENE
from	O
mast	O
cells	O
,	O
as	O
characterized	O
by	O
mass	O
spectrometry	O
.	O

Although	O
increased	O
expression	O
of	O
the	O
HMG	B-GENE
-	I-GENE
I	I-GENE
/	I-GENE
Y	I-GENE
proteins	I-GENE
is	O
associated	O
with	O
cellular	O
proliferation	O
,	O
neoplastic	O
transformation	O
,	O
and	O
several	O
human	O
cancers	O
,	O
the	O
role	O
of	O
these	O
proteins	O
in	O
the	O
pathogenesis	O
of	O
malignancy	O
remains	O
unclear	O
.	O

The	O
naltrexone	O
/	O
lofexidine	O
combination	O
was	O
associated	O
with	O
a	O
more	O
rapid	O
resolution	O
of	O
the	O
opiate	O
withdrawal	O
syndrome	O
than	O
a	O
7	O
-	O
day	O
lofexidine	O
-	O
only	O
treatment	O
schedule	O
,	O
without	O
substantial	O
increases	O
in	O
withdrawal	O
symptoms	O
or	O
hypotensive	O
side	O
-	O
effects	O
.	O

The	O
unfolded	O
protein	O
response	O
regulates	O
multiple	O
aspects	O
of	O
secretory	O
and	O
membrane	O
protein	O
biogenesis	O
and	O
endoplasmic	O
reticulum	O
quality	O
control	O
.	O

PNRC	B-GENE
:	O
a	O
proline	O
-	O
rich	O
nuclear	O
receptor	O
coregulatory	O
protein	O
that	O
modulates	O
transcriptional	O
activation	O
of	O
multiple	O
nuclear	O
receptors	O
including	O
orphan	O
receptors	O
SF1	B-GENE
(	O
steroidogenic	B-GENE
factor	I-GENE
1	I-GENE
)	O
and	O
ERRalpha1	B-GENE
(	O
estrogen	B-GENE
related	I-GENE
receptor	I-GENE
alpha	I-GENE
-	I-GENE
1	I-GENE
)	O
.	O

Studies	O
using	O
a	O
reporter	O
plasmid	O
with	O
a	O
functionally	O
disrupted	O
sterol	O
-	O
responsive	O
element	O
(	O
SRE	O
)	O
-	O
1	O
revealed	O
a	O
reduced	O
stimulatory	O
response	O
to	O
IL	B-GENE
-	I-GENE
6	I-GENE
.	O

However	O
,	O
there	O
is	O
still	O
a	O
subset	O
of	O
tumors	O
that	O
displayed	O
no	O
changes	O
in	O
these	O
genes	O
.	O

Bailey	O
Instruments	O
and	O
Owen	O
Mumford	O
filaments	O
were	O
the	O
most	O
accurate	O
with	O
100	O
%	O
buckling	O
within	O
+	O
/	O
-	O
1	O
.	O
0	O
g	O
of	O
10	O
g	O
.	O

PARTICIPANTS	O
:	O
Convenience	O
sample	O
of	O
ambulatory	O
outpatients	O
with	O
hereditary	O
motor	O
and	O
sensory	O
neuropathy	O
,	O
type	O
I	O
(	O
n	O
=	O
9	O
)	O
,	O
myotonic	O
muscular	O
dystrophy	O
(	O
n	O
=	O
10	O
)	O
,	O
and	O
able	O
-	O
bodied	O
controls	O
(	O
n	O
=	O
11	O
)	O
.	O

The	O
effect	O
of	O
water	O
deprivation	O
for	O
19	O
h	O
on	O
renal	O
Na	O
excretion	O
of	O
conscious	O
adrenalectomized	O
(	O
ADX	O
)	O
sheep	O
maintained	O
on	O
a	O
constant	O
intravenous	O
infusion	O
of	O
aldosterone	O
and	O
cortisol	O
(	O
ADX	O
-	O
constant	O
steroid	O
sheep	O
)	O
was	O
investigated	O
.	O

Neither	O
is	O
it	O
a	O
major	O
cause	O
of	O
rehydration	O
-	O
induced	O
renal	O
Na	O
retention	O
.	O

CONCLUSION	O
:	O
Rheumatic	O
fever	O
in	O
the	O
Nazareth	O
area	O
is	O
still	O
manifest	O
.	O

Antithrombin	B-GENE
III	I-GENE
deficiency	O
:	O
when	O
substitute	O
,	O
when	O
heparin	O
?	O
Thrombosis	O
ABC	O
,	O
3	O
:	O
The	O
role	O
of	O
antithrombin	B-GENE
III	I-GENE

Specific	O
class	B-GENE
I	I-GENE
and	I-GENE
II	I-GENE
histone	I-GENE
deacetylases	I-GENE
(	O
HDACs	B-GENE
)	O
interact	O
in	O
vivo	O
with	O
BCoR	B-GENE
,	O
suggesting	O
that	O
BCoR	B-GENE
may	O
functionally	O
link	O
these	O
two	O
classes	O
of	O
HDACs	B-GENE
.	O

This	O
is	O
the	O
first	O
example	O
of	O
a	O
eukaryotic	O
transcription	O
factor	O
complex	O
containing	O
both	O
a	O
MADS	B-GENE
-	I-GENE
box	I-GENE
and	O
a	O
forkhead	B-GENE
protein	I-GENE
,	O
and	O
it	O
has	O
important	O
implications	O
for	O
the	O
regulation	O
of	O
mammalian	O
gene	O
expression	O
.	O

After	O
screening	O
the	O
Berkeley	O
Drosophila	O
Genome	O
Project	O
database	O
with	O
sequences	O
from	O
a	O
recently	O
characterized	O
Leu	B-GENE
-	I-GENE
rich	I-GENE
repeats	I-GENE
-	I-GENE
containing	I-GENE
G	I-GENE
protein	I-GENE
-	I-GENE
coupled	I-GENE
receptor	I-GENE
(	O
LGR	B-GENE
)	O
from	O
Drosophila	O
(	O
DLGR	B-GENE
-	I-GENE
1	I-GENE
)	O
,	O
we	O
identified	O
a	O
second	O
gene	O
for	O
a	O
different	O
LGR	B-GENE
(	O
DLGR	B-GENE
-	I-GENE
2	I-GENE
)	O
and	O
cloned	O
its	O
cDNA	O
.	O

Degenerate	O
primers	O
homologous	O
to	O
highly	O
conserved	O
regions	O
of	O
known	O
CYP3A	B-GENE
sequences	I-GENE
were	O
used	O
for	O
initial	O
RT	O
-	O
PCRs	O
.	O

When	O
cells	O
were	O
microinjected	O
with	O
TFOs	O
designed	O
to	O
bind	O
to	O
a	O
30	O
-	O
bp	O
polypurine	O
site	O
situated	O
between	O
the	O
two	O
TK	B-GENE
genes	I-GENE
,	O
recombination	O
was	O
observed	O
at	O
frequencies	O
in	O
the	O
range	O
of	O
1	O
%	O
,	O
2	O
,	O
500	O
-	O
fold	O
above	O
the	O
background	O
.	O

Methyllevamisole	O
was	O
used	O
as	O
the	O
internal	O
standard	O
.	O

Only	O
transcripts	O
specific	O
for	O
TSGF	B-GENE
-	I-GENE
2	I-GENE
are	O
detected	O
in	O
ovary	O
and	O
testes	O
tissues	O
of	O
adults	O
as	O
well	O
as	O
in	O
puparia	O
,	O
while	O
neither	O
gene	O
is	O
expressed	O
during	O
the	O
larval	O
developmental	O
stages	O
.	O

In	O
a	O
gel	O
retardation	O
assay	O
using	O
HepG2	O
nuclear	O
extracts	O
,	O
the	O
5	O
'	O
flanking	O
sequence	O
from	O
-	O
74	O
to	O
-	O
46	O
showed	O
a	O
shifted	O
band	O
.	O

Coimmunoprecipitation	O
experiments	O
performed	O
in	O
transfected	O
cells	O
showed	O
that	O
BCMA	B-GENE
associates	O
with	O
TNFR	B-GENE
-	I-GENE
associated	I-GENE
factor	I-GENE
(	I-GENE
TRAF	I-GENE
)	I-GENE
1	I-GENE
,	O
TRAF2	B-GENE
,	O
and	O
TRAF3	B-GENE
adaptor	I-GENE
proteins	I-GENE
.	O

Since	O
the	O
RINX	B-GENE
gene	I-GENE
is	O
likely	O
an	O
ortholog	O
of	O
the	O
goldfish	B-GENE
Vsx1	I-GENE
gene	I-GENE
,	O
it	O
has	O
been	O
named	O
VSX1	B-GENE
by	O
the	O
Human	O
Gene	O
Nomenclature	O
Committee	O
.	O

The	O
chromosomal	O
localization	O
on	O
distal	O
chromosome	O
7	O
places	O
it	O
in	O
a	O
cluster	O
of	O
imprinted	O
genes	O
,	O
flanked	O
by	O
the	O
previously	O
described	O
Tapa1	B-GENE
and	O
Kcnq1	B-GENE
genes	I-GENE
.	O

The	O
present	O
study	O
was	O
designed	O
to	O
evaluate	O
the	O
sensitivity	O
and	O
specificity	O
of	O
AMP	O
CT	O
(	O
Gen	O
-	O
Probe	O
Incorporated	O
,	O
San	O
Diego	O
,	O
CA	O
,	O
USA	O
)	O
on	O
urogenital	O
specimens	O
taken	O
from	O
symptomatic	O
patients	O
and	O
on	O
first	O
void	O
urine	O
(	O
FVU	O
)	O
specimens	O
from	O
asymptomatic	O
patients	O
.	O

The	O
linear	O
plasmid	O
pCLU1	O
from	O
the	O
yeast	O
Kluyveromyces	O
lactis	O
normally	O
replicates	O
in	O
the	O
cytoplasm	O
,	O
with	O
the	O
aid	O
of	O
the	O
helper	O
linear	O
plasmid	O
pGKL2	O
,	O
using	O
terminal	B-GENE
protein	I-GENE
(	O
TP	B-GENE
)	O
as	O
a	O
primer	O
.	O

The	O
repetitive	O
ETn	B-GENE
(	O
early	B-GENE
transposon	I-GENE
)	O
family	O
of	O
sequences	O
represents	O
an	O
active	O
"	O
mobile	O
mutagen	O
"	O
in	O
the	O
mouse	O
genome	O
.	O

The	O
two	O
main	O
experimental	O
variables	O
were	O
the	O
attended	O
hemifield	O
(	O
left	O
or	O
right	O
)	O
and	O
the	O
proportion	O
of	O
trials	O
requiring	O
a	O
shift	O
within	O
that	O
hemifield	O
(	O
20	O
%	O
or	O
80	O
%	O
)	O
.	O

The	O
measurement	O
of	O
NO	O
in	O
biological	O
systems	O
using	O
chemiluminescence	O
.	O

Biochemical	O
examinations	O
of	O
calcium	O
-	O
phosphorus	O
metabolism	O
included	O
ions	O
and	O
PTH	B-GENE
concentrations	O
in	O
blood	O
serum	O
,	O
and	O
the	O
activity	O
of	O
bone	O
isoenzyme	O
of	O
AP	B-GENE
.	O

Atorvastatin	O
was	O
the	O
most	O
cost	O
-	O
effective	O
HMG	B-GENE
-	I-GENE
CoA	I-GENE
reductase	I-GENE
inhibitor	O
.	O

Pharmacoeconomic	O
assessment	O
of	O
HMG	B-GENE
-	I-GENE
CoA	I-GENE
reductase	I-GENE
inhibitor	O
therapy	O
:	O
an	O
analysis	O
based	O
on	O
the	O
CURVES	O
study	O
.	O

Interestingly	O
,	O
although	O
E	O
domains	O
of	O
these	O
two	O
receptors	O
are	O
much	O
less	O
conserved	O
,	O
replacement	O
of	O
this	O
domain	O
in	O
rtER	B-GENE
by	O
its	O
human	O
counterpart	O
resulted	O
in	O
higher	O
estradiol	O
sensitivity	O
but	O
no	O
increase	O
in	O
the	O
magnitude	O
of	O
transactivation	O
.	O

G	O
-	O
DNA	O
is	O
a	O
four	O
-	O
stranded	O
DNA	O
structure	O
with	O
diverse	O
putative	O
biological	O
roles	O
.	O

The	O
effectiveness	O
of	O
NRT	O
appears	O
to	O
be	O
largely	O
independent	O
of	O
the	O
intensity	O
of	O
additional	O
support	O
provided	O
to	O
the	O
smoker	O
.	O

8	O
%	O
(	O
95	O
%	O
CI	O
,	O
21	O
.	O
3	O
-	O
44	O
.	O
3	O
%	O
)	O
.	O

In	O
contrast	O
,	O
the	O
action	O
of	O
GLP	B-GENE
-	I-GENE
1	I-GENE
at	O
the	O
CRE	O
was	O
not	O
blocked	O
by	O
cotransfection	O
with	O
M1	B-GENE
-	I-GENE
CREB	I-GENE
,	O
an	O
isoform	O
that	O
lacks	O
a	O
consensus	O
serine	O
residue	O
serving	O
as	O
substrate	O
for	O
PKA	B-GENE
-	O
mediated	O
phosphorylation	O
.	O

Because	O
all	O
PDGFbetaR	B-GENE
fusions	I-GENE
described	O
thus	O
far	O
result	O
in	O
splicing	O
to	O
a	O
common	O
exon	O
of	O
this	O
gene	O
,	O
we	O
performed	O
5	O
'	O
-	O
rapid	O
amplification	O
of	O
cDNA	O
ends	O
PCR	O
on	O
patient	O
RNA	O
.	O

CONCLUSIONS	O
:	O
In	O
essential	O
hypertension	O
an	O
acute	O
protein	O
load	O
induces	O
a	O
decrease	O
in	O
GFR	O
that	O
may	O
normalize	O
under	O
antihypertensive	O
treatment	O
.	O

This	O
finding	O
suggested	O
that	O
the	O
PI3K	B-GENE
-	O
Akt	B-GENE
activation	O
pathway	O
plays	O
some	O
role	O
in	O
the	O
antiapoptotic	O
effect	O
of	O
EPO	B-GENE
.	O

Nine	O
DNA	O
fragments	O
that	O
were	O
specifically	O
recognized	O
and	O
bound	O
by	O
histidine	O
-	O
tagged	O
AdpA	B-GENE
were	O
isolated	O
by	O
cycles	O
of	O
a	O
gel	O
mobility	O
shift	O
-	O
PCR	O
method	O
.	O

To	O
determine	O
whether	O
the	O
NTP	O
-	O
binding	O
motif	O
is	O
important	O
for	O
Rad24	B-GENE
function	O
,	O
we	O
mutated	O
the	O
conserved	O
lysine	O
(	O
115	O
)	O
residue	O
in	O
this	O
motif	O
.	O

The	O
carboxyl	O
-	O
terminal	O
proline	O
-	O
rich	O
domain	O
of	O
SOS1	B-GENE
is	O
involved	O
in	O
the	O
interaction	O
with	O
the	O
PLC	B-GENE
-	I-GENE
gamma1	I-GENE
SH3	B-GENE
domain	I-GENE
.	O

From	O
transient	O
expression	O
studies	O
,	O
we	O
could	O
demonstrate	O
that	O
the	O
SH3	B-GENE
domain	I-GENE
of	O
PLC	B-GENE
-	I-GENE
gamma1	I-GENE
is	O
necessary	O
for	O
the	O
association	O
with	O
SOS1	B-GENE
in	O
vivo	O
.	O

Wnt	B-GENE
-	I-GENE
1	I-GENE
overexpression	O
in	O
mammary	O
epithelial	O
cells	O
induced	O
cyclin	B-GENE
D1	I-GENE
mRNA	I-GENE
and	O
targeted	O
overexpression	O
of	O
Wnt	B-GENE
-	I-GENE
1	I-GENE
in	O
the	O
mammary	O
gland	O
of	O
transgenic	O
mice	O
increased	O
both	O
ILK	B-GENE
activity	O
and	O
cyclin	B-GENE
D1	I-GENE
levels	O
.	O

Intravenous	O
versus	O
oral	O
administration	O
of	O
amitriptyline	O
in	O
patients	O
with	O
major	O
depression	O
.	O

Deletion	O
of	O
the	O
RVH	B-GENE
domain	I-GENE
resulted	O
in	O
loss	O
of	O
Ca	O
(	O
2	O
+	O
)	O
-	O
dependent	O
activation	O
.	O

Logistic	O
regression	O
analysis	O
revealed	O
that	O
physicians	O
were	O
3	O
.	O
6	O
times	O
more	O
likely	O
to	O
detect	O
thin	O
lesions	O
(	O
<	O
/	O
=	O
0	O
.	O
75	O
mm	O
)	O
compared	O
with	O
nonphysician	O
detectors	O
(	O
95	O
%	O
confidence	O
interval	O
[	O
95	O
%	O
CI	O
]	O
,	O
2	O
.	O
1	O
,	O
6	O
.	O
5	O
;	O
P	O
=	O
0	O
.	O
0001	O
)	O
.	O

Erythema	O
exsudativum	O
multiforme	O
induced	O
by	O
granulocyte	B-GENE
colony	I-GENE
-	I-GENE
stimulating	I-GENE
factor	I-GENE
in	O
an	O
allogeneic	O
peripheral	O
blood	O
stem	O
cell	O
donor	O
.	O

VaI	O
and	O
VaII	O
co	O
-	O
immunoprecipitated	O
with	O
ErbB2	B-GENE
,	O
but	O
not	O
with	O
ErbB1	B-GENE
,	O
ErbB3	B-GENE
,	O
or	O
ErbB4	B-GENE
.	O

While	O
interactions	O
of	O
WT	O
and	O
variant	O
TGF	B-GENE
-	I-GENE
alpha	I-GENE
with	O
the	O
ErbBs	B-GENE
all	O
result	O
in	O
ErbB2	B-GENE
activation	O
,	O
they	O
produce	O
different	O
biological	O
consequences	O
,	O
suggesting	O
that	O
the	O
various	O
TGF	B-GENE
-	I-GENE
alpha	I-GENE
precursors	I-GENE
differentially	O
modulate	O
ErbB	B-GENE
signaling	O
.	O

In	O
contrast	O
to	O
full	B-GENE
-	I-GENE
length	I-GENE
E2F	I-GENE
-	I-GENE
3	I-GENE
,	O
which	O
is	O
expressed	O
only	O
at	O
the	O
G1	O
/	O
S	O
boundary	O
,	O
E2F	B-GENE
-	I-GENE
3B	I-GENE
is	O
detected	O
throughout	O
the	O
cell	O
cycle	O
with	O
peak	O
levels	O
in	O
GO	O
where	O
it	O
is	O
associated	O
with	O
Rb	B-GENE
.	O

Developmental	O
toxicity	O
of	O
the	O
class	O
III	O
antiarrhythmic	O
agent	O
almokalant	O
in	O
mice	O
.	O

In	O
addition	O
to	O
its	O
effect	O
in	O
augmenting	O
the	O
neutrophil	O
response	O
to	O
eccentric	O
exercise	O
,	O
vitamin	O
E	O
causes	O
a	O
greater	O
increase	O
in	O
circulating	O
creatine	B-GENE
kinase	I-GENE
activity	O
,	O
perhaps	O
indicating	O
increased	O
skeletal	O
muscle	O
repair	O
.	O

CONCLUSION	O
:	O
The	O
authors	O
emphasize	O
that	O
the	O
initial	O
management	O
of	O
primary	O
STS	O
should	O
be	O
adequate	O
and	O
suggest	O
that	O
safty	O
margin	O
of	O
>	O
or	O
=	O
2	O
cm	O
should	O
be	O
adhered	O
to	O
.	O

Measurements	O
were	O
compared	O
with	O
two	O
computerised	O
treatment	O
planning	O
systems	O
-	O
-	O
Theraplan	O
VO5B	O
and	O
ADAC	O
Pinnacle3	O
V4	O
.	O
0b	O
.	O

Activation	O
was	O
biphasic	O
;	O
peaking	O
at	O
5	O
-	O
10	O
min	O
and	O
24	O
h	O
after	O
treatment	O
.	O

Whereas	O
MARTA1	B-GENE
is	O
clearly	O
detectable	O
in	O
crude	O
lysates	O
,	O
cytosolic	O
and	O
ribosomal	O
salt	O
-	O
wash	O
fractions	O
,	O
and	O
in	O
nuclear	O
extracts	O
,	O
MARTA2	B-GENE
is	O
preferentially	O
found	O
in	O
the	O
ribosomal	O
salt	O
-	O
wash	O
preparation	O
.	O

Five	O
of	O
the	O
PDP1	B-GENE
isoforms	I-GENE
differ	O
by	O
the	O
substitution	O
or	O
insertion	O
of	O
amino	O
acids	O
at	O
or	O
near	O
the	O
N	O
-	O
terminal	O
of	O
the	O
protein	O
.	O

The	O
optimum	O
technique	O
for	O
the	O
pathological	O
examination	O
of	O
sentinel	O
lymph	O
nodes	O
(	O
SLNs	O
)	O
is	O
still	O
under	O
debate	O
.	O

Partial	O
correction	O
of	O
anemia	O
with	O
recombinant	B-GENE
human	I-GENE
erythropoietin	I-GENE
likely	O
reduces	O
left	O
ventricular	O
mass	O
and	O
volume	O
.	O

This	O
study	O
demonstrated	O
that	O
the	O
PFA	O
-	O
100	O
analyzer	O
can	O
accurately	O
assess	O
vWF	B-GENE
-	O
dependent	O
platelet	O
function	O
and	O
detect	O
other	O
platelet	O
defects	O
under	O
high	O
shear	O
stress	O
in	O
complex	O
patient	O
populations	O
.	O

We	O
recently	O
reported	O
the	O
molecular	O
cloning	O
of	O
a	O
PL	B-GENE
scramblase	I-GENE
of	O
human	O
(	O
HuPLSCR1	B-GENE
)	O
and	O
mouse	O
origin	O
,	O
respectively	O
.	O

To	O
analyze	O
the	O
regulatory	O
activity	O
of	O
Gtx	B-GENE
,	O
we	O
first	O
identified	O
the	O
optimal	O
Gtx	B-GENE
-	I-GENE
binding	I-GENE
sequence	I-GENE
using	O
an	O
in	O
vitro	O
DNA	O
-	O
binding	O
assay	O
.	O

Using	O
an	O
oligomer	O
duplex	O
5	O
'	O
-	O
A	O
(	O
GGGTTA	O
)	O
(	O
5	O
)	O
-	O
3	O
'	O
/	O
5	O
'	O
-	O
(	O
TAACCC	O
)	O
(	O
5	O
)	O
T	O
-	O
3	O
'	O
as	O
a	O
template	O
-	O
primer	O
,	O
we	O
show	O
that	O
both	O
the	O
Klenow	B-GENE
fragment	I-GENE
of	I-GENE
Escherichia	I-GENE
coli	I-GENE
DNA	I-GENE
polymerase	I-GENE
I	I-GENE
and	O
HIV	B-GENE
reverse	I-GENE
transcriptase	I-GENE
could	O
expand	O
telomere	O
DNA	O
sequences	O
as	O
well	O
,	O
giving	O
products	O
greater	O
than	O
the	O
size	O
of	O
the	O
template	O
DNA	O
.	O

Cdk2	B-GENE
and	O
MAPK	B-GENE
precipitates	O
from	O
untreated	O
tumor	O
lysates	O
phosphorylated	O
recombinant	B-GENE
wild	I-GENE
-	I-GENE
type	I-GENE
p27	I-GENE
but	O
not	O
the	O
T187A	O
mutant	O
in	O
vitro	O
.	O

The	O
loss	O
of	O
avirulence	O
activity	O
because	O
of	O
mutations	O
in	O
the	O
acidic	O
transcriptional	O
activation	O
domain	O
was	O
restored	O
by	O
addition	O
of	O
the	O
activation	O
domain	O
from	O
the	O
herpes	B-GENE
simplex	I-GENE
viral	I-GENE
protein	I-GENE
VP16	I-GENE
.	O

Mutations	O
in	O
the	O
RP2	B-GENE
locus	I-GENE
at	I-GENE
Xp11	I-GENE
.	I-GENE
3	I-GENE
were	O
found	O
in	O
a	O
further	O
10	O
-	O
20	O
%	O
of	O
XLRP	O
patients	O
,	O
as	O
predicted	O
from	O
linkage	O
studies	O
.	O

Subsequently	O
,	O
HD	O
inhibited	O
healing	O
because	O
it	O
significantly	O
delayed	O
epithelialization	O
and	O
caused	O
protracted	O
inflammation	O
.	O

The	O
effectiveness	O
of	O
the	O
haemodialysate	O
Solcoseryl	O
for	O
second	O
-	O
intention	O
wound	O
healing	O
in	O
horses	O
and	O
ponies	O
.	O

Although	O
there	O
is	O
little	O
evidence	O
that	O
diet	O
composition	O
plays	O
a	O
clinically	O
important	O
role	O
in	O
the	O
absorption	O
or	O
expenditure	O
of	O
energy	O
,	O
it	O
does	O
appear	O
to	O
play	O
a	O
role	O
in	O
food	O
intake	O
.	O

These	O
findings	O
were	O
reinforced	O
by	O
an	O
analysis	O
that	O
was	O
restricted	O
to	O
living	O
donor	O
transplants	O
without	O
acute	O
rejection	O
.	O

The	O
genome	O
of	O
the	O
human	O
herpesvirus	O
8	O
(	O
HHV	O
-	O
8	O
)	O
contains	O
a	O
cluster	O
of	O
open	O
reading	O
frames	O
(	O
ORFs	O
)	O
encoding	O
proteins	O
with	O
homology	O
to	O
the	O
cellular	O
transcription	O
factors	O
of	O
the	O
interferon	B-GENE
regulatory	I-GENE
factor	I-GENE
(	O
IRF	B-GENE
)	O
family	O
.	O

Despite	O
these	O
limitations	O
the	O
CHIME	O
monitor	O
provides	O
an	O
opportunity	O
to	O
record	O
physiological	O
data	O
previously	O
unavailable	O
in	O
the	O
home	O
.	O

DATA	O
SYNTHESIS	O
:	O
Intracoronary	O
ultrasound	O
has	O
been	O
shown	O
to	O
improve	O
upon	O
demonstrated	O
weaknesses	O
of	O
coronary	O
angiography	O
.	O

TB	O
bone	O
area	O
(	O
p	O
<	O
0	O
.	O
001	O
)	O
,	O
height	O
(	O
p	O
<	O
0	O
.	O
01	O
)	O
,	O
years	O
in	O
present	O
colony	O
(	O
p	O
=	O
0	O
.	O
03	O
)	O
,	O
and	O
menses	O
(	O
p	O
<	O
0	O
.	O
01	O
)	O
predicted	O
TB	O
BMC	O
.	O

CREST	O
syndrome	O
;	O
a	O
changing	O
clinical	O
significance	O

Troglitazone	O
also	O
induced	O
an	O
endogenous	B-GENE
PPARgamma	I-GENE
target	I-GENE
gene	I-GENE
in	O
T24	O
cells	O
,	O
adipocyte	B-GENE
-	I-GENE
type	I-GENE
fatty	I-GENE
acid	I-GENE
binding	I-GENE
protein	I-GENE
(	O
A	B-GENE
-	I-GENE
FABP	I-GENE
)	O
,	O
the	O
expression	O
of	O
which	O
correlates	O
with	O
bladder	O
cancer	O
differentiation	O
.	O

The	O
RS447	B-GENE
human	B-GENE
megasatellite	I-GENE
tandem	I-GENE
repetitive	I-GENE
sequence	I-GENE
encodes	O
a	O
novel	O
deubiquitinating	O
enzyme	O
with	O
a	O
functional	O
promoter	O
.	O

Previous	O
experience	O
and	O
contextual	O
cues	O
are	O
essential	O
elements	O
in	O
the	O
generation	O
of	O
a	O
subjective	O
prediction	O
.	O

To	O
characterize	O
this	O
effect	O
,	O
we	O
looked	O
for	O
targets	O
of	O
NS1	B-GENE
influenza	I-GENE
virus	I-GENE
protein	I-GENE
among	O
cellular	O
translation	O
factors	O
.	O

Collectively	O
,	O
these	O
and	O
previously	O
published	O
data	O
suggest	O
a	O
model	O
where	O
NS1	B-GENE
recruits	O
eIF4GI	B-GENE
specifically	O
to	O
the	O
5	O
'	O
untranslated	O
region	O
(	O
5	O
'	O
UTR	O
)	O
of	O
the	O
viral	O
mRNA	O
,	O
allowing	O
for	O
the	O
preferential	O
translation	O
of	O
the	O
influenza	O
virus	O
messengers	O
.	O

Eukaryotic	B-GENE
translation	I-GENE
initiation	I-GENE
factor	I-GENE
4GI	I-GENE
is	O
a	O
cellular	O
target	O
for	O
NS1	B-GENE
protein	I-GENE
,	O
a	O
translational	O
activator	O
of	O
influenza	O
virus	O
.	O

(	O
iii	O
)	O
In	O
these	O
cells	O
,	O
PKCbeta	B-GENE
plays	O
a	O
unique	O
Ras	B-GENE
-	O
independent	O
role	O
in	O
mediating	O
insulin	B-GENE
but	O
not	O
EGF	B-GENE
or	O
other	O
growth	O
factor	O
mitogenic	O
signals	O
.	O

However	O
,	O
it	O
is	O
not	O
known	O
whether	O
the	O
recently	O
identified	O
isoforms	O
Vav2	B-GENE
and	O
Vav3	B-GENE
,	O
which	O
are	O
broadly	O
expressed	O
,	O
can	O
couple	O
with	O
similar	O
classes	O
of	O
receptors	O
,	O
nor	O
is	O
it	O
known	O
whether	O
all	O
Vav	B-GENE
isoforms	I-GENE
possess	O
identical	O
functional	O
activities	O
.	O

Transcriptional	O
regulation	O
of	O
fbp1	B-GENE
promoter	I-GENE
constructs	I-GENE
containing	O
only	O
UAS1	O
or	O
UAS2	O
confirms	O
that	O
the	O
PKA	B-GENE
and	O
MAPK	B-GENE
regulation	O
is	O
targeted	O
to	O
both	O
sites	O
.	O

X	O
-	O
ray	O
crystallographic	O
data	O
show	O
that	O
the	O
PLZF	B-GENE
BTB	B-GENE
/	O
POZ	O
domain	O
forms	O
an	O
obligate	O
homodimer	O
via	O
an	O
extensive	O
interface	O
.	O

The	O
ability	O
of	O
SMRT	B-GENE
to	O
associate	O
with	O
these	O
transcription	O
factors	O
and	O
thereby	O
to	O
mediate	O
repression	O
is	O
strongly	O
inhibited	O
by	O
activation	O
of	O
tyrosine	B-GENE
kinase	I-GENE
signaling	O
pathways	O
,	O
such	O
as	O
that	O
represented	O
by	O
the	O
epidermal	B-GENE
growth	I-GENE
factor	I-GENE
receptor	I-GENE
.	O

In	O
addition	O
,	O
the	O
ketamine	O
-	O
treated	O
rats	O
had	O
more	O
neurons	O
and	O
glial	O
cells	O
surrounding	O
the	O
ventricles	O
.	O

The	O
differences	O
were	O
as	O
follows	O
:	O
for	O
overall	O
response	O
rate	O
p	O
=	O
0	O
.	O
004	O
;	O
power	O
(	O
for	O
p	O
=	O
0	O
.	O
05	O
)	O
85	O
%	O
;	O
for	O
survival	O
p	O
=	O
0	O
.	O
09	O
;	O
for	O
grade	O
IV	O
granulocytopenia	O
p	O
=	O
0	O
.	O
3	O
;	O
and	O
for	O
febrile	O
neutropenia	O
p	O
=	O
0	O
.	O
61	O
.	O

Patients	O
were	O
randomly	O
assigned	O
to	O
treatment	O
with	O
the	O
ACE	B-GENE
inhibitor	O
perindopril	O
(	O
and	O
the	O
diuretic	O
indapamide	O
for	O
those	O
with	O
no	O
definite	O
indication	O
for	O
or	O
contraindication	O
to	O
treatment	O
with	O
a	O
diuretic	O
)	O
or	O
matching	O
placebo	O
(	O
s	O
)	O
.	O

The	O
results	O
indicate	O
that	O
the	O
open	O
-	O
section	O
effect	O
decreases	O
the	O
torsional	O
stiffness	O
and	O
stress	O
concentration	O
effects	O
decrease	O
the	O
torsional	O
strength	O
of	O
a	O
long	O
bone	O
with	O
a	O
longitudinal	O
defect	O
.	O

These	O
regions	O
may	O
be	O
differentially	O
involved	O
in	O
tissue	O
-	O
specificity	O
,	O
and	O
/	O
or	O
circadian	O
regulation	O
,	O
of	O
the	O
human	B-GENE
hPer1	I-GENE
gene	I-GENE
transcription	O
.	O

Additionally	O
,	O
putative	O
CF1	B-GENE
/	O
USP	B-GENE
and	O
Broad	B-GENE
Complex	I-GENE
Z2	I-GENE
transcription	O
factor	O
elements	O
were	O
found	O
in	O
the	O
upstream	O
regions	O
of	O
MIH	B-GENE
and	O
MO	B-GENE
-	I-GENE
IH	I-GENE
genes	O
respectively	O
.	O

Sequence	O
analysis	O
reveals	O
that	O
the	O
newly	O
discovered	O
oasA2	B-GENE
gene	I-GENE
represents	O
a	O
pseudogene	O
that	O
is	O
still	O
transcribed	O
,	O
but	O
is	O
not	O
functionally	O
translated	O
.	O

Genomic	O
and	O
functional	O
characterization	O
of	O
the	O
oas	B-GENE
gene	I-GENE
family	I-GENE
encoding	O
O	B-GENE
-	I-GENE
acetylserine	I-GENE
(	I-GENE
thiol	I-GENE
)	I-GENE
lyases	I-GENE
,	O
enzymes	O
catalyzing	O
the	O
final	O
step	O
in	O
cysteine	O
biosynthesis	O
in	O
Arabidopsis	O
thaliana	O
.	O

Two	O
distinct	O
recessive	O
susceptibility	O
loci	O
for	O
vasculitis	O
were	O
mapped	O
on	O
chromosome	O
(	O
Chr	O
)	O
4	O
at	O
D4Mit89	B-GENE
and	O
D4Mit147	B-GENE
in	O
both	O
progenies	O
.	O

Further	O
characterization	O
of	O
these	O
putative	O
Hoxa	B-GENE
-	I-GENE
1	I-GENE
target	I-GENE
genes	I-GENE
will	O
aid	O
in	O
delineating	O
the	O
functions	O
of	O
the	O
Hoxa	B-GENE
-	I-GENE
1	I-GENE
protein	I-GENE
in	O
the	O
differentiation	O
processes	O
which	O
occur	O
during	O
embryogenesis	O
.	O

The	O
ability	O
of	O
U6	B-GENE
-	O
U57	B-GENE
mutants	O
to	O
influence	O
the	O
fidelity	O
of	O
both	O
branch	O
site	O
and	O
3	O
'	O
splice	O
site	O
recognition	O
suggests	O
that	O
this	O
nucleotide	O
may	O
participate	O
in	O
the	O
formation	O
of	O
the	O
active	O
site	O
(	O
s	O
)	O
of	O
the	O
spliceosome	O
.	O

We	O
have	O
determined	O
the	O
structure	O
of	O
the	O
WNT	B-GENE
-	I-GENE
2B	I-GENE
gene	I-GENE
.	O

The	O
role	O
of	O
daunorubicin	O
in	O
induction	O
therapy	O
for	O
adult	O
acute	O
myeloid	O
leukemia	O

TNF	B-GENE
-	I-GENE
alpha	I-GENE
induced	O
a	O
dose	O
-	O
and	O
time	O
-	O
dependent	O
increase	O
in	O
cyclooxygenase	B-GENE
-	I-GENE
2	I-GENE
(	O
COX	B-GENE
-	I-GENE
2	I-GENE
)	O
expression	O
and	O
PGE2	O
formation	O
in	O
human	O
NCI	O
-	O
H292	O
epithelial	O
cells	O
.	O

The	O
therapy	O
time	O
to	O
deliver	O
the	O
NCS	O
therapeutic	O
dose	O
of	O
10000	O
RBE	O
-	O
cGy	O
,	O
is	O
27	O
times	O
longer	O
when	O
157Gd	O
is	O
used	O
instead	O
of	O
10B	O
.	O

Mis3	B-GENE
is	O
needed	O
for	O
the	O
formation	O
of	O
18S	B-GENE
ribosome	I-GENE
RNA	I-GENE
,	O
and	O
may	O
hence	O
direct	O
the	O
level	O
of	O
proteins	O
required	O
for	O
the	O
coupling	O
.	O

Losartan	O
Intervention	O
For	O
Endpoint	O
.	O

CONCLUSION	O
:	O
Vitrectomy	O
for	O
vitreous	O
hemorrhage	O
in	O
Terson	O
syndrome	O
is	O
a	O
safe	O
and	O
effective	O
procedure	O
,	O
offering	O
a	O
rapid	O
and	O
prolonged	O
improvement	O
in	O
vision	O
.	O

RNA	O
in	O
situ	O
hybridization	O
on	O
brain	O
sections	O
of	O
normal	O
human	O
embryos	O
revealed	O
a	O
strong	O
labeling	O
in	O
restricted	O
areas	O
of	O
the	O
cerebral	O
cortex	O
.	O

To	O
facilitate	O
manipulation	O
of	O
large	O
genomic	O
sequences	O
,	O
we	O
developed	O
a	O
method	O
of	O
converting	O
Escherichia	O
coli	O
P1	O
artificial	O
chromosomes	O
(	O
PACs	O
)	O
into	O
yeast	O
artificial	O
chromosomes	O
(	O
YACs	O
)	O
.	O

After	O
gamma	O
-	O
irradiation	O
,	O
the	O
majority	O
of	O
F9	O
cells	O
undergo	O
apoptosis	O
implying	O
that	O
wt	B-GENE
-	I-GENE
p53	I-GENE
likely	O
triggers	O
pro	O
-	O
apoptotic	O
gene	O
expression	O
in	O
DNA	O
damaged	O
cells	O
.	O

Mobilization	O
with	O
cyclophosphamide	O
and	O
granulocyte	B-GENE
-	I-GENE
colony	I-GENE
stimulating	I-GENE
factor	I-GENE
was	O
effective	O
in	O
terms	O
of	O
CD34	B-GENE
+	I-GENE
cell	O
shift	O
to	O
peripheral	O
blood	O
and	O
the	O
good	O
quality	O
autograft	O
reliably	O
led	O
to	O
haematopoetic	O
recovery	O
after	O
megachemotherapy	O
.	O

This	O
suggests	O
that	O
cardiovascular	O
magnetic	O
resonance	O
is	O
the	O
preferred	O
technique	O
for	O
volume	O
and	O
ejection	O
fraction	O
estimation	O
in	O
heart	O
failure	O
patients	O
,	O
because	O
of	O
its	O
3D	O
approach	O
for	O
non	O
-	O
symmetric	O
ventricles	O
and	O
superior	O
image	O
quality	O
.	O

A	O
degenerate	O
DNA	O
transposon	O
,	O
Pat	B-GENE
,	O
was	O
identified	O
in	O
the	O
genomes	O
of	O
various	O
wild	O
-	O
type	O
strains	O
of	O
the	O
filamentous	O
fungus	O
Podospora	O
anserina	O
.	O

However	O
,	O
the	O
presence	O
of	O
Tax	B-GENE
I	I-GENE
increased	O
the	O
extent	O
and	O
altered	O
the	O
profile	O
of	O
proteins	O
binding	O
TRE	B-GENE
-	I-GENE
2	I-GENE
in	O
vivo	O
.	O

We	O
have	O
also	O
identified	O
a	O
functional	O
domain	O
in	O
the	O
ORF	O
50	O
protein	O
,	O
an	O
immediate	B-GENE
-	I-GENE
early	I-GENE
gene	I-GENE
product	I-GENE
that	O
is	O
mainly	O
encoded	O
by	O
ORF	O
50	O
.	O

A	O
2	O
.	O
3	O
-	O
kb	O
full	O
-	O
length	O
cDNA	O
clone	O
of	O
an	O
Atlantic	B-GENE
halibut	I-GENE
Mx	I-GENE
gene	I-GENE
was	O
isolated	O
from	O
a	O
liver	O
cDNA	O
library	O
.	O

PLUS	O
-	O
3	O
is	O
a	O
new	O
Swedish	O
protocol	O
of	O
natural	O
speech	O
in	O
3	O
-	O
year	O
-	O
old	O
children	O
.	O

Once	O
HIT	O
II	O
is	O
suspected	O
,	O
heparin	O
(	O
and	O
low	O
-	O
molecular	O
-	O
weight	O
heparins	O
)	O
should	O
be	O
stopped	O
immediately	O
.	O

The	O
reduced	O
efficiency	O
in	O
the	O
glycosylase	B-GENE
activity	O
is	O
also	O
reflected	O
in	O
a	O
reduced	O
ability	O
of	O
S120K	B-GENE
MutY	I-GENE
to	O
prevent	O
DNA	O
mutations	O
in	O
vivo	O
.	O

METHODS	O
AND	O
RESULTS	O
:	O
We	O
prospectively	O
compared	O
the	O
automated	O
measurements	O
of	O
left	O
ventricular	O
ejection	O
fraction	O
(	O
LVEF	O
)	O
and	O
volumes	O
from	O
rest	O
-	O
injected	O
gated	O
Technetium	O
99m	O
(	O
Tc99m	O
)	O
perfusion	O
SPECT	O
with	O
equilibrium	O
radionuclide	O
angiocardiography	O
(	O
ERNA	O
)	O
in	O
62	O
patients	O
and	O
the	O
assessment	O
of	O
regional	O
function	O
with	O
echocardiography	O
in	O
22	O
patients	O
.	O

This	O
intracellular	O
signaling	O
,	O
known	O
as	O
the	O
unfolded	O
protein	O
response	O
(	O
UPR	O
)	O
,	O
is	O
mediated	O
by	O
the	O
cis	O
-	O
acting	O
ER	O
stress	O
response	O
element	O
(	O
ERSE	O
)	O
in	O
mammals	O
.	O

A	O
Y	B-GENE
.	I-GENE
lipolytica	I-GENE
Kar2p	I-GENE
mutant	I-GENE
was	O
isolated	O
that	O
restored	O
interaction	O
with	O
an	O
Sls1p	B-GENE
mutant	I-GENE
,	O
suggesting	O
that	O
the	O
interaction	O
with	O
Sls1p	B-GENE
could	O
be	O
nucleotide	O
and	O
/	O
or	O
conformation	O
dependent	O
.	O

We	O
have	O
carried	O
out	O
a	O
comprehensive	O
and	O
systematic	O
mutagenesis	O
of	O
the	O
Cse4p	B-GENE
N	I-GENE
terminus	I-GENE
to	O
analyze	O
its	O
function	O
.	O

The	O
spacing	O
of	O
the	O
essential	O
N	O
-	O
terminal	O
domain	O
(	O
END	O
)	O
relative	O
to	O
the	O
HFD	B-GENE
can	O
be	O
changed	O
significantly	O
without	O
an	O
apparent	O
effect	O
on	O
Cse4p	B-GENE
function	O
.	O

The	O
bases	O
of	O
this	O
comparison	O
are	O
reviewed	O
and	O
discussed	O
.	O

In	O
invertebrates	O
,	O
Fhit	B-GENE
is	O
encoded	O
as	O
a	O
fusion	O
protein	O
with	O
Nit	B-GENE
,	O
a	O
member	O
of	O
the	O
nitrilase	B-GENE
superfamily	I-GENE
.	O

The	O
manifestations	O
often	O
include	O
a	O
moderate	O
thrombocytopenia	O
and	O
,	O
less	O
commonly	O
,	O
hemolysis	O
.	O

A	O
beta2	B-GENE
RARE	I-GENE
reporter	I-GENE
construct	I-GENE
in	O
which	O
the	O
methylation	O
-	O
susceptible	O
cytosines	O
in	O
the	O
sense	O
strand	O
were	O
replaced	O
by	O
thymine	O
displayed	O
marked	O
loss	O
of	O
activity	O
in	O
a	O
replicated	O
chromatin	O
-	O
dependent	O
manner	O
.	O

Non	O
-	O
poliomyelitis	O
AFP	O
rate	O
had	O
increased	O
from	O
0	O
.	O
9	O
in	O
1997	O
to	O
2	O
.	O
8	O
in	O
1998	O
.	O

Consciousness	O
is	O
connected	O
with	O
attention	O
,	O
working	O
memory	O
and	O
perception	O
.	O

Multiparity	O
had	O
a	O
protective	O
effect	O
with	O
0	O
.	O
66	O
less	O
risk	O
(	O
95	O
%	O
CI	O
0	O
.	O
44	O
-	O
0	O
.	O
99	O
)	O
.	O

Picture	O
the	O
smell	O
.	O

Only	O
two	O
of	O
27	O
participants	O
(	O
7	O
.	O
4	O
%	O
)	O
with	O
definite	O
POAG	O
had	O
been	O
previously	O
diagnosed	O
and	O
treated	O
,	O
and	O
66	O
.	O
7	O
%	O
of	O
the	O
previously	O
undiagnosed	O
had	O
IOP	O
less	O
than	O
22	O
mmHg	O
.	O

Taken	O
together	O
,	O
they	O
uphold	O
the	O
emerging	O
concern	O
that	O
women	O
with	O
ER	B-GENE
(	I-GENE
+	I-GENE
)	I-GENE
cancers	O
may	O
not	O
benefit	O
significantly	O
from	O
endocrine	O
treatment	O
if	O
the	O
tumors	O
also	O
overexpress	O
HER	B-GENE
-	I-GENE
2	I-GENE
.	O

Promoter	O
activity	O
was	O
dose	O
-	O
dependently	O
inhibited	O
by	O
cotransfection	O
with	O
either	O
ras	B-GENE
or	O
mos	B-GENE
oncogenes	I-GENE
,	O
but	O
oncogene	O
inhibition	O
was	O
reversed	O
and	O
the	O
overall	O
activity	O
increased	O
when	O
cells	O
were	O
treated	O
with	O
the	O
MAP	B-GENE
kinase	I-GENE
kinase	I-GENE
(	O
MKK	B-GENE
)	O
inhibitor	O
PD98059	O
.	O

Our	O
results	O
indicate	O
that	O
the	O
expression	O
of	O
Cktsf1b1	B-GENE
,	O
a	O
gene	O
associated	O
with	O
early	O
development	O
and	O
cell	O
transformation	O
,	O
is	O
sensitive	O
to	O
MKK	B-GENE
levels	O
and	O
may	O
be	O
regulated	O
via	O
multiple	O
transcription	O
factor	O
complexes	O
.	O

INTERVENTIONS	O
:	O
Subcutaneous	O
tissue	O
PO2	O
and	O
PCO2	O
tensions	O
were	O
measured	O
directly	O
in	O
patients	O
with	O
necrotising	O
fasciitis	O
and	O
in	O
healthy	O
volunteers	O
during	O
normobaric	O
and	O
hyperbaric	O
conditions	O
.	O

Because	O
GH	B-GENE
-	O
induced	O
Akt	B-GENE
activation	O
was	O
completely	O
inhibited	O
in	O
both	O
cells	O
by	O
the	O
same	O
concentration	O
of	O
LY294002	O
,	O
these	O
findings	O
indicate	O
that	O
the	O
wortmannin	O
sensitivity	O
of	O
both	O
the	O
IRS	B-GENE
-	I-GENE
1	I-GENE
-	O
independent	O
and	O
-	O
dependent	O
GH	B-GENE
-	O
induced	O
MAP	B-GENE
kinase	I-GENE
activation	O
may	O
reflect	O
the	O
activity	O
of	O
another	O
wortmannin	O
-	O
sensitive	O
target	O
(	O
s	O
)	O
in	O
addition	O
to	O
PI3K	B-GENE
in	O
mediation	O
of	O
GH	B-GENE
-	O
induced	O
MAP	B-GENE
kinase	I-GENE
activation	O
in	O
these	O
cells	O
.	O

Insulin	B-GENE
receptor	I-GENE
substrate	I-GENE
-	I-GENE
1	I-GENE
-	O
mediated	O
enhancement	O
of	O
growth	B-GENE
hormone	I-GENE
-	O
induced	O
mitogen	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
kinase	I-GENE
activation	O
.	O

Functional	O
magnetic	O
resonance	O
imaging	O
(	O
fMRI	O
)	O
has	O
been	O
increasingly	O
used	O
in	O
studying	O
human	O
brain	O
function	O
given	O
its	O
non	O
-	O
invasive	O
feature	O
and	O
good	O
spatial	O
resolution	O
.	O

After	O
declamping	O
of	O
the	O
aorta	O
,	O
there	O
were	O
also	O
severe	O
edema	O
,	O
local	O
fibre	O
necrosis	O
,	O
and	O
adhesion	O
of	O
leucocytes	O
,	O
whereas	O
muscle	O
fibre	O
areas	O
became	O
3	O
,	O
935	O
.	O
18	O
micro	O
531	O
microm	O
(	O
2	O
)	O
for	O
type	O
I	O
and	O
5	O
,	O
804	O
+	O
/	O
-	O
1	O
,	O
075	O
microm	O
(	O
2	O
)	O
for	O
type	O
II	O
.	O

It	O
was	O
found	O
that	O
increase	O
in	O
the	O
RH	O
level	O
boosts	O
the	O
current	O
values	O
by	O
2	O
-	O
3	O
orders	O
of	O
magnitude	O
;	O
contrariwise	O
,	O
the	O
voltage	O
values	O
rise	O
by	O
about	O
three	O
times	O
with	O
drop	O
in	O
the	O
RH	O
.	O

Genomic	O
libraries	O
were	O
stored	O
as	O
frozen	O
cultures	O
in	O
a	O
96	O
-	O
well	O
format	O
,	O
each	O
well	O
containing	O
approximately	O
300	O
-	O
600	O
colonies	O
(	O
12	O
plates	O
for	O
small	O
library	O
,	O
four	O
for	O
medium	O
-	O
size	O
library	O
and	O
four	O
for	O
large	O
library	O
)	O
.	O

In	O
several	O
cell	O
lines	O
,	O
mTOR	B-GENE
or	O
its	O
downstream	O
targets	O
can	O
be	O
regulated	O
by	O
phosphatidylinositol	B-GENE
(	I-GENE
PI	I-GENE
)	I-GENE
3	I-GENE
-	I-GENE
kinase	I-GENE
;	O
protein	B-GENE
kinases	I-GENE
A	I-GENE
,	I-GENE
B	I-GENE
,	I-GENE
and	I-GENE
C	I-GENE
;	O
heterotrimeric	B-GENE
G	I-GENE
-	I-GENE
proteins	I-GENE
;	O
a	O
PD98059	O
-	O
sensitive	O
kinase	O
or	O
calcium	O
;	O
as	O
well	O
as	O
by	O
amino	O
acids	O
.	O

The	O
importance	O
of	O
this	O
new	O
epidemiological	O
profile	O
of	O
schistosomiasis	O
in	O
the	O
State	O
of	O
Pernambuco	O
relies	O
on	O
the	O
fact	O
that	O
it	O
can	O
be	O
related	O
with	O
the	O
drastic	O
human	O
interference	O
on	O
the	O
environment	O
.	O

RESULTS	O
:	O
No	O
significant	O
deformation	O
in	O
vertebral	O
artery	O
flow	O
was	O
noted	O
in	O
the	O
flexion	O
-	O
distraction	O
Stage	O
I	O
injuries	O
within	O
the	O
physiologic	O
range	O
of	O
cervical	O
flexion	O
.	O

We	O
screened	O
a	O
K562	O
cDNA	O
library	O
and	O
identified	O
novel	O
transcripts	O
,	O
MZF1B	B-GENE
and	O
MZF1C	B-GENE
.	O

The	O
human	O
cDNA	O
clone	O
NFBD1	O
(	O
previously	O
designated	O
KIAA0170	O
)	O
encodes	O
a	O
novel	O
protein	O
(	O
2089	O
amino	O
acids	O
in	O
length	O
;	O
calculated	O
molecular	O
mass	O
226	O
,	O
440	O
D	O
)	O
with	O
possible	O
BRCT	B-GENE
domains	I-GENE
at	O
its	O
carboxy	O
terminus	O
(	O
amino	O
acid	O
residues	O
1894	O
-	O
2089	O
)	O
.	O

RESULTS	O
:	O
Neither	O
basal	O
FSH	B-GENE
level	O
nor	O
stimulated	O
FSH	B-GENE
level	O
alone	O
were	O
statistically	O
significant	O
predictors	O
of	O
IVF	O
success	O
;	O
however	O
,	O
no	O
patient	O
with	O
a	O
day	O
3	O
FSH	B-GENE
level	O
>	O
11	O
.	O
1	O
mIU	O
/	O
ml	O
or	O
a	O
stimulated	O
day	O
10	O
FSH	B-GENE
level	O
>	O
13	O
.	O
5	O
mIU	O
/	O
ml	O
conceived	O
and	O
carried	O
a	O
pregnancy	O
.	O

Parathyroid	B-GENE
hormone	I-GENE
regulation	O
of	O
bone	B-GENE
sialoprotein	I-GENE
(	O
BSP	B-GENE
)	O
gene	O
transcription	O
is	O
mediated	O
through	O
a	O
pituitary	B-GENE
-	I-GENE
specific	I-GENE
transcription	I-GENE
factor	I-GENE
-	I-GENE
1	I-GENE
(	O
Pit	B-GENE
-	I-GENE
1	I-GENE
)	O
motif	O
in	O
the	O
rat	B-GENE
BSP	I-GENE
gene	I-GENE
promoter	I-GENE
.	O

Recent	O
target	O
BP	O
goals	O
promulgated	O
by	O
the	O
Sixth	O
Report	O
from	O
the	O
Joint	O
National	O
Committee	O
(	O
JNC	O
VI	O
)	O
are	O
based	O
on	O
the	O
premise	O
that	O
the	O
intensity	O
of	O
treatment	O
directly	O
corresponds	O
to	O
the	O
magnitude	O
of	O
pretreatment	O
risk	O
.	O

Linking	O
continuous	O
community	O
-	O
based	O
morbidity	O
recording	O
of	O
influenza	O
-	O
like	O
illness	O
(	O
ILI	O
)	O
with	O
virological	O
sampling	O
has	O
consistently	O
proved	O
its	O
value	O
as	O
one	O
of	O
the	O
earliest	O
indicators	O
of	O
circulating	O
influenza	O
activity	O
.	O

These	O
include	O
NPF	O
repeats	O
,	O
a	O
leucine	O
heptad	O
repeat	O
enriched	O
in	O
charged	O
residues	O
,	O
and	O
a	O
proline	O
-	O
rich	O
SH3	B-GENE
-	I-GENE
like	I-GENE
and	O
/	O
or	O
WW	O
domain	O
-	O
binding	O
site	O
in	O
the	O
N	O
-	O
terminal	O
domain	O
,	O
which	O
is	O
followed	O
by	O
a	O
membrane	O
core	O
containing	O
four	O
putative	O
transmembrane	O
spans	O
and	O
three	O
amphiphilic	O
segments	O
that	O
are	O
the	O
most	O
highly	O
conserved	O
structural	O
elements	O
.	O

We	O
show	O
here	O
that	O
this	O
difference	O
is	O
due	O
to	O
the	O
presence	O
of	O
a	O
Mot3	B-GENE
binding	I-GENE
site	I-GENE
in	O
OpA	B-GENE
.	O

The	O
article	O
deals	O
with	O
the	O
diagnosing	O
and	O
correction	O
of	O
reversible	O
ischemia	O
of	O
the	O
intestine	O
.	O

Functional	O
recognition	O
of	O
5	O
'	O
splice	O
site	O
by	O
U4	B-GENE
/	O
U6	B-GENE
.	O
U5	B-GENE
tri	O
-	O
snRNP	O
defines	O
a	O
novel	O
ATP	O
-	O
dependent	O
step	O
in	O
early	O
spliceosome	O
assembly	O
.	O

As	O
control	O
,	O
the	O
cells	O
were	O
transfected	O
with	O
DNA	O
mixtures	O
containing	O
vector	O
mU6	O
-	O
C1	O
or	O
mU6	O
-	O
C2	O
.	O

In	O
this	O
regard	O
,	O
we	O
have	O
recently	O
observed	O
that	O
a	O
constitutively	O
active	O
G	B-GENE
protein	I-GENE
-	I-GENE
coupled	I-GENE
receptor	I-GENE
(	O
GPCR	B-GENE
)	O
encoded	O
by	O
the	O
Kaposi	O
'	O
s	O
sarcoma	O
-	O
associated	O
herpes	O
virus	O
(	O
KSHV	O
)	O
/	O
human	O
herpes	O
virus	O
8	O
is	O
oncogenic	O
and	O
stimulates	O
angiogenesis	O
by	O
increasing	O
the	O
secretion	O
of	O
vascular	B-GENE
endothelial	I-GENE
growth	I-GENE
factor	I-GENE
(	O
VEGF	B-GENE
)	O
,	O
which	O
is	O
a	O
key	O
angiogenic	O
stimulator	O
and	O
a	O
critical	O
mitogen	O
for	O
the	O
development	O
of	O
Kaposi	O
'	O
s	O
sarcoma	O
.	O

No	O
specific	O
subgroup	O
of	O
clients	O
benefited	O
more	O
from	O
URD	O
,	O
although	O
a	O
prospective	O
study	O
employing	O
random	O
assignment	O
might	O
be	O
more	O
successful	O
in	O
identifying	O
such	O
a	O
group	O
.	O

In	O
the	O
lattice	O
,	O
23	O
%	O
of	O
the	O
sites	O
are	O
occupied	O
,	O
95	O
%	O
of	O
the	O
atoms	O
are	O
in	O
the	O
lowest	O
energy	O
magnetic	O
sublevel	O
,	O
and	O
37	O
%	O
are	O
in	O
the	O
lowest	O
3D	O
vibrational	O
state	O
.	O

Coexisting	O
vertical	O
and	O
horizontal	O
one	O
and	O
a	O
half	O
syndromes	O
.	O

As	O
in	O
the	O
other	O
three	O
members	O
whose	O
gene	O
expression	O
is	O
altered	O
during	O
tumorigenesis	O
,	O
PI12	B-GENE
expression	O
was	O
found	O
to	O
be	O
down	O
-	O
regulated	O
in	O
tumor	O
brain	O
tissues	O
and	O
in	O
two	O
brain	O
cancer	O
cell	O
lines	O
:	O
U	O
-	O
87	O
MG	O
and	O
H4	O
.	O

This	O
slope	O
was	O
further	O
significantly	O
decreased	O
at	O
5	O
min	O
ischemia	O
(	O
-	O
26	O
.	O
5	O
+	O
/	O
-	O
8	O
.	O
8	O
microm	O
/	O
mmHg	O
)	O
but	O
returned	O
toward	O
control	O
values	O
in	O
short	O
-	O
term	O
hibernating	O
myocardium	O
at	O
90	O
min	O
ischemia	O
(	O
-	O
17	O
.	O
2	O
+	O
/	O
-	O
6	O
.	O
6	O
microm	O
/	O
mmHg	O
)	O
.	O

Whereas	O
both	O
MAP	O
and	O
MSNA	O
increase	O
during	O
SHG	O
,	O
the	O
transition	O
from	O
SHG	O
to	O
PHI	O
is	O
characterized	O
by	O
a	O
transient	O
reduction	O
in	O
MAP	O
but	O
sustained	O
elevation	O
in	O
MSNA	O
,	O
facilitating	O
separation	O
of	O
these	O
factors	O
in	O
vivo	O
.	O

We	O
have	O
recently	O
discovered	O
that	O
CCAAAT	B-GENE
/	I-GENE
enhancer	I-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
-	I-GENE
beta	I-GENE
(	O
C	B-GENE
/	I-GENE
EBP	I-GENE
-	I-GENE
beta	I-GENE
)	O
induces	O
gene	O
transcription	O
through	O
a	O
novel	O
IFN	B-GENE
response	I-GENE
element	I-GENE
called	O
the	O
gamma	B-GENE
-	I-GENE
IFN	I-GENE
-	I-GENE
activated	I-GENE
transcriptional	I-GENE
element	I-GENE

Northern	O
blot	O
analysis	O
demonstrated	O
that	O
the	O
STORP	B-GENE
gene	I-GENE
has	O
a	O
ubiquitous	O
pattern	O
of	O
expression	O
similar	O
to	O
that	O
of	O
the	O
PML	B-GENE
gene	I-GENE
.	O

In	O
the	O
TLE	O
patients	O
the	O
NAA	O
:	O
Cr	O
ratios	O
were	O
reduced	O
in	O
the	O
seizure	O
focus	O
,	O
while	O
in	O
the	O
FLE	O
patients	O
they	O
were	O
not	O
always	O
reduced	O
in	O
the	O
seizure	O
focus	O
.	O

The	O
psychologic	O
factors	O
associated	O
wth	O
serious	O
illness	O
,	O
terminal	O
prognoses	O
,	O
and	O
dying	O
complicate	O
the	O
scenario	O
even	O
more	O
as	O
compared	O
with	O
that	O
of	O
nonmalignant	O
pain	O
.	O

However	O
,	O
if	O
the	O
spatial	O
resolution	O
is	O
not	O
critical	O
and	O
interest	O
is	O
to	O
compare	O
a	O
pathologic	O
area	O
with	O
a	O
contralateral	O
VOI	O
,	O
then	O
the	O
acquisition	O
of	O
two	O
single	O
-	O
voxel	O
spectra	O
may	O
be	O
preferred	O
.	O

Quantitative	O
evaluation	O
of	O
magneto	O
-	O
optical	O
parameters	O
is	O
necessary	O
in	O
order	O
to	O
apply	O
scanning	O
near	O
-	O
field	O
optical	O
microscope	O
(	O
SNOM	O
)	O
technology	O
to	O
the	O
study	O
of	O
magnetism	O
on	O
the	O
mesoscopic	O
scale	O
.	O

We	O
found	O
that	O
the	O
amplitude	O
of	O
the	O
cortical	O
evoked	O
potentials	O
(	O
amplitude	O
of	O
the	O
N2	O
/	O
P2	O
peak	O
)	O
increased	O
from	O
5	O
.	O
1	O
+	O
/	O
-	O
0	O
.	O
7	O
microV	O
at	O
5	O
mA	O
to	O
16	O
.	O
3	O
+	O
/	O
-	O
1	O
.	O
1	O
microV	O
at	O
20	O
mA	O
.	O

LMP	B-GENE
-	I-GENE
1	I-GENE
is	O
targeted	O
to	O
the	O
plasma	O
membrane	O
,	O
where	O
it	O
binds	O
TRAF	B-GENE
,	O
TRADD	B-GENE
,	O
and	O
JAK	B-GENE
molecules	I-GENE
to	O
activate	O
NF	B-GENE
-	I-GENE
kappaB	I-GENE
-	O
,	O
AP	B-GENE
-	I-GENE
1	I-GENE
-	O
,	O
and	O
STAT	B-GENE
-	O
dependent	O
pathways	O
as	O
does	O
CD40	B-GENE
.	O

Identification	O
of	O
an	O
enhancer	O
and	O
an	O
alternative	O
promoter	O
in	O
the	O
first	O
intron	O
of	O
the	O
alpha	B-GENE
-	I-GENE
fetoprotein	I-GENE
gene	I-GENE
.	O

Studying	O
intracellular	O
signaling	O
pathways	O
,	O
which	O
may	O
be	O
involved	O
in	O
malignant	O
transformation	O
of	O
Ret	B-GENE
-	I-GENE
9bp	I-GENE
expressing	O
NIH3T3	O
cells	O
,	O
we	O
could	O
demonstrate	O
Ret	B-GENE
-	I-GENE
9bp	I-GENE
dependent	O
phosphorylation	O
of	O
insulin	B-GENE
receptor	I-GENE
substrate	I-GENE
-	I-GENE
2	I-GENE
(	O
IRS	B-GENE
-	I-GENE
2	I-GENE
)	O
with	O
consecutive	O
activation	O
of	O
phosphatidylinositol	B-GENE
3	I-GENE
-	I-GENE
kinase	I-GENE
(	O
PI	B-GENE
3	I-GENE
-	I-GENE
kinase	I-GENE
)	O
and	O
protein	B-GENE
kinase	I-GENE
B	I-GENE
(	O
PKB	B-GENE
/	O
AKT	B-GENE
)	O
.	O

METHODS	O
:	O
In	O
the	O
current	O
study	O
the	O
authors	O
reported	O
on	O
PPB	O
cases	O
from	O
a	O
national	O
retrospective	O
search	O
performed	O
in	O
18	O
Italian	O
Associations	O
for	O
Pediatric	O
Hematology	O
and	O
Oncology	O
centers	O
.	O

Phylogenetic	O
analysis	O
showed	O
that	O
the	O
ToLCV	O
isolates	O
from	O
Bangalore	O
constitute	O
a	O
group	O
of	O
viruses	O
separated	O
from	O
those	O
of	O
Northern	O
India	O
.	O

Mutating	O
the	O
Fcp1p	B-GENE
-	O
binding	O
motif	O
KEFGK	O
in	O
the	O
RAP74	B-GENE
(	O
Tfg1p	B-GENE
)	O
subunit	O
of	O
TFIIF	B-GENE
to	O
EEFGE	O
led	O
to	O
both	O
synthetic	O
phenotypes	O
in	O
certain	O
fcp1	B-GENE
tfg1	B-GENE
double	O
mutants	O
and	O
a	O
reduced	O
ability	O
of	O
Fcp1p	B-GENE
to	O
activate	O
transcription	O
when	O
it	O
is	O
artificially	O
tethered	O
to	O
a	O
promoter	O
.	O

Deletion	O
of	O
an	O
intergenic	O
DNA	O
-	O
binding	O
site	O
for	O
this	O
complex	O
from	O
a	O
human	B-GENE
beta	I-GENE
-	I-GENE
globin	I-GENE
locus	I-GENE
construct	I-GENE
results	O
in	O
delayed	O
human	B-GENE
gamma	I-GENE
-	I-GENE
to	I-GENE
beta	I-GENE
-	I-GENE
globin	I-GENE
switching	O
in	O
transgenic	O
mice	O
,	O
suggesting	O
that	O
the	O
PYR	B-GENE
complex	I-GENE
acts	O
to	O
facilitate	O
the	O
switch	O
.	O

The	O
product	O
of	O
rat	B-GENE
gene	I-GENE
33	I-GENE
was	O
identified	O
as	O
an	O
ErbB	B-GENE
-	I-GENE
2	I-GENE
-	I-GENE
interacting	I-GENE
protein	I-GENE
in	O
a	O
two	O
-	O
hybrid	O
screen	O
employing	O
the	O
ErbB	B-GENE
-	I-GENE
2	I-GENE
juxtamembrane	I-GENE
and	I-GENE
kinase	I-GENE
domains	I-GENE
as	O
bait	O
.	O

Studies	O
suggest	O
that	O
the	O
DGOR	O
without	O
acid	O
reflux	O
may	O
result	O
in	O
symptoms	O
but	O
unless	O
acid	O
reflux	O
is	O
present	O
simultaneously	O
,	O
it	O
does	O
not	O
cause	O
oesophagitis	O
.	O

OBJECTIVE	O
:	O
To	O
evaluate	O
the	O
relationship	O
between	O
blood	O
flow	O
in	O
the	O
tumor	O
assessed	O
by	O
color	O
Doppler	O
ultrasound	O
,	O
microvessel	O
density	O
,	O
and	O
vascular	B-GENE
endothelial	I-GENE
growth	I-GENE
factor	I-GENE
levels	O
in	O
endometrial	O
carcinoma	O
.	O

These	O
results	O
demonstrate	O
Ras	B-GENE
-	O
and	O
Raf	B-GENE
-	O
independent	O
ERK	B-GENE
MAPK	O
activation	O
maintains	O
cell	O
viability	O
following	O
heat	O
shock	O
.	O

Three	O
cDNAs	O
encoding	O
basic	B-GENE
leucine	I-GENE
zipper	I-GENE
(	I-GENE
bZIP	I-GENE
)	I-GENE
-	I-GENE
type	I-GENE
ABRE	I-GENE
-	I-GENE
binding	I-GENE
proteins	I-GENE
were	O
isolated	O
by	O
using	O
the	O
yeast	O
one	O
-	O
hybrid	O
system	O
and	O
were	O
designated	O
AREB1	B-GENE
,	O
AREB2	B-GENE
,	O
and	O
AREB3	B-GENE
(	O
ABA	B-GENE
-	I-GENE
responsive	I-GENE
element	I-GENE
binding	I-GENE
protein	I-GENE
)	O
.	O

Recombinant	O
AROM	B-GENE
-	O
p64	B-GENE
displayed	O
high	O
binding	O
to	O
single	O
-	O
stranded	O
DNA	O
and	O
poly	O
(	O
A	O
)	O
homopolymers	O
suggesting	O
that	O
this	O
protein	O
could	O
play	O
a	O
role	O
in	O
mRNA	O
maturation	O
/	O
metabolism	O
.	O

The	O
protein	B-GENE
-	I-GENE
tyrosine	I-GENE
kinase	I-GENE
fer	B-GENE
associates	O
with	O
signaling	O
complexes	O
containing	O
insulin	B-GENE
receptor	I-GENE
substrate	I-GENE
-	I-GENE
1	I-GENE
and	O
phosphatidylinositol	B-GENE
3	I-GENE
-	I-GENE
kinase	I-GENE
.	O

In	O
the	O
PMR	O
target	O
area	O
but	O
not	O
in	O
the	O
nontreated	O
area	O
an	O
improvement	O
in	O
regional	O
myocardial	O
flow	O
reserve	O
occurs	O
in	O
wall	O
segments	O
with	O
initially	O
severely	O
or	O
moderately	O
reduced	O
stress	O
perfusion	O
.	O

Analysis	O
of	O
intron	O
/	O
exon	O
boundaries	O
of	O
the	O
genomic	O
BAC	O
clones	O
demonstrate	O
that	O
junctin	B-GENE
,	O
junctate	B-GENE
,	O
and	O
aspartyl	B-GENE
beta	I-GENE
-	I-GENE
hydroxylase	I-GENE
result	O
from	O
alternative	O
splicing	O
of	O
the	O
same	O
gene	O
.	O

The	O
growth	B-GENE
factor	I-GENE
receptor	I-GENE
-	I-GENE
bound	I-GENE
protein	I-GENE
2	I-GENE
(	O
Grb2	B-GENE
)	O
adaptor	O
when	O
complexed	O
with	O
Sos	B-GENE
(	O
Son	B-GENE
of	I-GENE
sevenless	I-GENE
)	O
,	O
the	O
exchange	O
factor	O
of	O
Ras	B-GENE
,	O
conveys	O
the	O
signal	O
induced	O
by	O
tyrosine	B-GENE
kinase	I-GENE
-	I-GENE
activated	I-GENE
receptor	I-GENE
to	O
Ras	B-GENE
by	O
recruiting	O
Sos	B-GENE
to	O
the	O
membrane	O
,	O
allowing	O
activation	O
of	O
Ras	B-GENE
.	O

Mutations	O
in	O
genes	O
encoding	O
PR65	B-GENE
/	I-GENE
A	I-GENE
subunits	I-GENE
have	O
been	O
identified	O
in	O
several	O
different	O
human	O
cancers	O
and	O
the	O
PP2A	B-GENE
inhibitor	O
,	O
termed	O
fostriecin	O
,	O
is	O
being	O
tested	O
as	O
an	O
anticancer	O
drug	O
.	O

For	O
this	O
purpose	O
,	O
a	O
segment	O
of	O
dxr	B-GENE
was	O
amplified	O
from	O
Synechococcus	O
leopoliensis	O
SAUG	O
1402	O
-	O
1	O
DNA	O
via	O
PCR	O
using	O
oligonucleotides	O
for	O
conserved	O
regions	O
.	O

Perceptual	O
learning	O
for	O
a	O
pattern	O
discrimination	O
task	O
.	O

While	O
this	O
Saccharomyces	O
cerevisiae	O
SIN4	B-GENE
gene	I-GENE
product	I-GENE
is	O
a	O
component	O
of	O
a	O
mediator	O
complex	O
associated	O
with	O
RNA	B-GENE
polymerase	I-GENE
II	I-GENE
,	O
various	O
studies	O
suggest	O
the	O
involvement	O
of	O
Sin4	B-GENE
in	O
the	O
alteration	O
of	O
higher	O
-	O
order	O
chromatin	O
structure	O
.	O

Src	B-GENE
activation	O
induced	O
by	O
FGF1	B-GENE
was	O
blocked	O
by	O
the	O
SH2	B-GENE
domain	I-GENE
of	O
Src	B-GENE
and	O
PP2	B-GENE
,	O
a	O
specific	O
inhibitor	O
of	O
Src	B-GENE
.	O

The	O
use	O
of	O
the	O
PLCgamma	B-GENE
inhibitory	I-GENE
peptide	I-GENE
,	O
neomycin	O
and	O
the	O
calcium	O
chelator	O
BAPTA	O
-	O
AM	O
on	O
oocytes	O
expressing	O
FGFR1	B-GENE
or	O
the	O
stimulation	O
by	O
PDGF	B-GENE
-	I-GENE
BB	I-GENE
of	O
oocytes	O
expressing	O
PDGFR	B-GENE
-	O
FGFR1	B-GENE
mutated	O
on	O
the	O
PLCgamma	B-GENE
binding	I-GENE
site	I-GENE
,	O
prevented	O
GVBD	O
and	O
ERK2	B-GENE
phosphorylation	O
.	O

Multiple	O
transcription	O
start	O
sites	O
were	O
revealed	O
by	O
primer	O
extension	O
analysis	O
of	O
the	O
mouse	O
gene	O
,	O
and	O
transfection	O
constructs	O
containing	O
the	O
prospective	O
promoter	O
generated	O
transcriptional	O
activity	O
comparable	O
to	O
that	O
of	O
the	O
SV40	B-GENE
promoter	I-GENE
.	O

To	O
determine	O
whether	O
interaction	O
of	O
arsenite	O
with	O
the	O
hormone	O
-	O
binding	O
domain	O
results	O
in	O
receptor	O
activation	O
,	O
COS	O
-	O
1	O
cells	O
were	O
transiently	O
cotransfected	O
with	O
the	O
chimeric	B-GENE
receptors	I-GENE
GAL	I-GENE
-	I-GENE
ER	I-GENE
,	O
which	O
contains	O
the	O
hormone	O
-	O
binding	O
domain	O
of	O
ERalpha	B-GENE
and	O
the	O
DNA	O
-	O
binding	O
domain	O
of	O
the	O
transcription	O
factor	O
GAL4	B-GENE
,	O
and	O
a	O
GAL4	B-GENE
-	O
responsive	O
CAT	B-GENE
reporter	I-GENE
gene	I-GENE
.	O

The	O
mean	O
day	O
of	O
diagnosis	O
of	O
periventricular	O
echodensities	O
was	O
3	O
+	O
/	O
-	O
2	O
days	O
(	O
range	O
1	O
-	O
11	O
days	O
)	O
,	O
and	O
of	O
cystic	O
PVL	O
21	O
+	O
/	O
-	O
8	O
days	O
(	O
range	O
2	O
-	O
47	O
days	O
)	O
.	O

The	O
LAMMER	B-GENE
protein	O
kinase	O
encoded	O
by	O
the	O
Doa	B-GENE
locus	I-GENE
of	O
Drosophila	O
is	O
required	O
in	O
both	O
somatic	O
and	O
germline	O
cells	O
and	O
is	O
expressed	O
as	O
both	O
nuclear	O
and	O
cytoplasmic	O
isoforms	O
throughout	O
development	O
.	O

We	O
have	O
mutated	O
to	O
cysteine	O
,	O
one	O
at	O
a	O
time	O
,	O
21	O
consecutive	O
residues	O
in	O
the	O
fourth	O
TMS	O
(	O
TM4	O
)	O
.	O

(	O
1995	O
)	O
J	O
.	O

HYPOTHESIS	O
:	O
The	O
aim	O
of	O
this	O
study	O
was	O
to	O
investigate	O
the	O
oxidative	O
susceptibility	O
of	O
apolipoprotein	B-GENE
B	I-GENE
-	I-GENE
containing	I-GENE
lipoproteins	I-GENE
and	O
antioxidant	O
status	O
in	O
patients	O
with	O
acute	O
coronary	O
syndromes	O
and	O
chronic	O
stable	O
angina	O
pectoris	O
.	O

In	O
group	O
B	O
37	O
MBq	O
in	O
150	O
microL	O
of	O
99mTc	O
-	O
HSA	O
nanocolloid	O
was	O
additionally	O
injected	O
intradermally	O
18	O
h	O
before	O
surgery	O
(	O
3	O
-	O
6	O
aliquots	O
injected	O
perilesionally	O
)	O
.	O

Post	O
-	O
operative	O
functional	O
outcome	O
is	O
related	O
to	O
pre	O
-	O
operative	O
functional	O
status	O
.	O

We	O
cloned	O
a	O
DNA	O
fragment	O
encoding	O
the	O
N	O
-	O
terminal	O
part	O
of	O
a	O
protein	O
with	O
significant	O
similarity	O
to	O
members	O
of	O
the	O
LysR	B-GENE
family	I-GENE
of	I-GENE
transcriptional	I-GENE
regulators	I-GENE
(	O
LTTRs	B-GENE
)	O
.	O

AGO1	B-GENE
is	O
similar	O
to	O
QDE	B-GENE
-	I-GENE
2	I-GENE
required	O
for	O
quelling	O
and	O
RDE	B-GENE
-	I-GENE
1	I-GENE
required	O
for	O
RNAi	O
.	O

We	O
could	O
demonstrate	O
the	O
involvement	O
of	O
cAMP	B-GENE
-	I-GENE
dependent	I-GENE
protein	I-GENE
kinase	I-GENE
(	O
PKA	B-GENE
)	O
in	O
the	O
phosphorylation	O
of	O
CDC25Mm	B-GENE
in	O
fibroblasts	O
overexpressing	O
this	O
RasGEF	B-GENE
as	O
well	O
as	O
in	O
mouse	O
brain	O
synaptosomal	O
membranes	O
.	O

We	O
find	O
that	O
3T1	O
-	O
3T2	O
mixing	O
has	O
a	O
pronounced	O
effect	O
on	O
the	O
line	O
shape	O
and	O
radiative	O
decay	O
rate	O
of	O
emission	O
from	O
the	O
3T2	O
state	O
and	O
that	O
the	O
extent	O
of	O
mixing	O
depends	O
critically	O
on	O
the	O
magnitude	O
of	O
nontetrahedral	O
distortions	O
.	O

A	O
total	O
of	O
576	O
1	O
-	O
day	O
-	O
old	O
Ross	O
broiler	O
chicks	O
were	O
housed	O
in	O
six	O
treatment	O
groups	O
[	O
six	O
replicates	O
of	O
16	O
each	O
;	O
control	O
,	O
CLI	O
(	O
15	O
g	O
kg	O
(	O
-	O
1	O
)	O
diet	O
)	O
,	O
50	O
parts	O
per	O
billion	O
(	O
ppb	O
)	O
AF	B-GENE
,	O
50	O
ppb	O
AF	B-GENE
plus	O
CLI	O
,	O
100	O
ppb	O
AF	B-GENE
,	O
100	O
ppb	O
AF	B-GENE
plus	O
CLI	O
]	O
for	O
42	O
days	O
.	O

The	O
cost	O
per	O
test	O
is	O
less	O
than	O
those	O
for	O
CC	O
,	O
kEIA	O
and	O
PACE2	O
.	O

Concurrently	O
,	O
we	O
monitored	O
weather	O
conditions	O
and	O
used	O
time	O
-	O
activity	O
budget	O
data	O
of	O
free	O
-	O
living	O
birds	O
and	O
laboratory	O
data	O
on	O
resting	O
metabolic	O
rate	O
to	O
construct	O
time	O
-	O
activity	O
laboratory	O
(	O
TAL	O
)	O
estimates	O
of	O
daily	O
energy	O
expenditure	O
(	O
DEE	O
)	O
and	O
to	O
partition	O
the	O
verdins	O
'	O
energy	O
budget	O
into	O
thermoregulatory	O
,	O
activity	O
and	O
basal	O
components	O
.	O

L	O
/	O
H	O
>	O
0	O
.	O
61	O
(	O
chi	O
(	O
2	O
)	O
=	O
10	O
.	O
8	O
;	O
P	O
:	O
<	O
0	O
.	O
001	O
)	O
and	O
a	O
restrictive	O
filling	O
pattern	O
(	O
chi	O
(	O
2	O
)	O
=	O
3	O
.	O
6	O
;	O
P	O
:	O
<	O
0	O
.	O
05	O
)	O
were	O
independent	O
predictors	O
of	O
events	O
.	O

The	O
high	O
selectivity	O
of	O
arrestins	B-GENE
for	O
this	O
particular	O
functional	O
form	O
of	O
receptor	O
ensures	O
their	O
timely	O
binding	O
and	O
dissociation	O
.	O

When	O
cotransfected	O
in	O
fibroblasts	O
with	O
a	O
C	B-GENE
/	I-GENE
EBP	I-GENE
alpha	I-GENE
expression	O
vector	O
,	O
reporter	O
gene	O
expression	O
increased	O
3	O
-	O
fold	O
only	O
in	O
the	O
wild	O
-	O
type	O
constructs	O
.	O

Expression	O
of	O
a	O
dominant	B-GENE
negative	I-GENE
Smad2	I-GENE
significantly	O
reduces	O
the	O
level	O
of	O
luciferase	B-GENE
reporter	I-GENE
activity	O
induced	O
by	O
nodal	O
treatment	O
.	O

Normal	O
alpha1	B-GENE
(	I-GENE
I	I-GENE
)	I-GENE
collagen	I-GENE
mRNA	I-GENE
showed	O
no	O
significant	O
reduction	O
when	O
AR	O
or	O
IR	O
was	O
expressed	O
from	O
the	O
pHbetaAPr	O
-	O
1	O
-	O
neo	O
vector	O
and	O
a	O
small	O
(	O
10	O
-	O
20	O
%	O
)	O
but	O
significant	O
reduction	O
when	O
either	O
ribozyme	O
was	O
expressed	O
from	O
the	O
pCI	O
.	O
neo	O
vector	O
.	O

Nature	O
398	O
,	O
828	O
-	O
830	O
)	O
that	O
the	O
amino	O
acid	O
sequences	O
of	O
peptide	O
fragments	O
obtained	O
from	O
a	O
polypeptide	O
found	O
in	O
a	O
complex	O
of	O
proteins	O
that	O
alters	O
chromatin	O
structure	O
(	O
ARC	B-GENE
)	O
are	O
identical	O
to	O
portions	O
of	O
the	O
deduced	O
open	O
reading	O
frame	O
of	O
TIG	B-GENE
-	I-GENE
1	I-GENE
mRNA	I-GENE
.	O

Abnormalities	O
of	O
plasma	B-GENE
cholecystokinin	I-GENE
were	O
observed	O
only	O
in	O
patients	O
with	O
delayed	O
gastric	O
emptying	O
.	O

5	O
(	O
Sunset	O
Yellow	O
FCF	O
)	O
were	O
determined	O
using	O
liquid	O
chromatography	O
/	O
mass	O
spectrometry	O
(	O
LC	O
/	O
MS	O
)	O
with	O
electrospray	O
ionization	O
.	O

Cam	B-GENE
kinase	I-GENE
II	I-GENE
induces	O
in	O
vivo	O
phosphorylation	O
of	O
Smad2	B-GENE
and	O
Smad4	B-GENE
and	O
,	O
to	O
a	O
lesser	O
extent	O
,	O
Smad3	B-GENE
.	O

This	O
interaction	O
inhibits	O
the	O
histone	B-GENE
acetyltransferase	I-GENE
activity	O
of	O
p300	B-GENE
,	O
resulting	O
in	O
drastic	O
reduction	O
of	O
nucleosomal	O
histone	B-GENE
acetylation	O
and	O
alteration	O
of	O
chromatin	O
structure	O
.	O

Recombinant	B-GENE
BRI1	I-GENE
-	I-GENE
KD	I-GENE
autophosphorylated	O
on	O
serine	O
(	O
Ser	O
)	O
and	O
threonine	O
(	O
Thr	O
)	O
residues	O
with	O
p	O
-	O
Ser	O
predominating	O
.	O

Flow	O
cytomery	O
was	O
used	O
for	O
cell	O
cycle	O
analysis	O
.	O

Further	O
research	O
is	O
required	O
to	O
better	O
measure	O
treatment	O
effects	O
,	O
modification	O
of	O
MS	O
natural	O
history	O
,	O
and	O
net	O
societal	O
costs	O
of	O
IFN	B-GENE
beta	I-GENE
-	I-GENE
1b	I-GENE
in	O
RRMS	O
.	O

Cost	O
-	O
effectiveness	O
of	O
interferon	B-GENE
beta	I-GENE
-	I-GENE
1b	I-GENE
in	O
slowing	O
multiple	O
sclerosis	O
disability	O
progression	O
.	O

Both	O
the	O
Cmax	O
and	O
AUC	O
values	O
were	O
almost	O
doubled	O
with	O
doubling	O
the	O
dose	O
.	O

Hyperactivation	O
of	O
Cdc2	B-GENE
in	O
fission	O
yeast	O
causes	O
cells	O
to	O
undergo	O
a	O
lethal	O
premature	O
mitosis	O
called	O
mitotic	O
catastrophe	O
.	O

Diary	O
.	O

Cells	O
differentiate	O
in	O
response	O
to	O
various	O
extracellular	O
stimuli	O
.	O

Transforming	B-GENE
growth	I-GENE
factor	I-GENE
-	I-GENE
beta1	I-GENE
(	O
TGF	B-GENE
-	I-GENE
beta1	I-GENE
)	O
can	O
act	O
as	O
a	O
tumor	O
suppressor	O
or	O
a	O
tumor	O
promoter	O
depending	O
on	O
the	O
characteristics	O
of	O
the	O
malignant	O
cell	O
.	O

Mn2	O
+	O
increased	O
both	O
the	O
junction	O
binding	O
and	O
cleaving	O
activities	O
of	O
the	O
mutant	O
proteins	O
.	O

While	O
Pt	B-GENE
;	I-GENE
cycH	I-GENE
;	I-GENE
1	I-GENE
and	O
Os	B-GENE
;	I-GENE
cycH	I-GENE
;	I-GENE
1	I-GENE
were	O
expressed	O
in	O
all	O
tissues	O
examined	O
,	O
the	O
transcripts	O
accumulated	O
abundantly	O
in	O
dividing	O
cells	O
.	O

Moreover	O
,	O
an	O
in	O
vitro	O
pull	O
-	O
down	O
assay	O
showed	O
that	O
Os	B-GENE
;	I-GENE
CycH	I-GENE
;	I-GENE
1	I-GENE
specifically	O
bound	O
to	O
R2	B-GENE
but	O
not	O
to	O
other	O
rice	B-GENE
CDKs	I-GENE
.	O

In	O
transient	O
analysis	O
using	O
particle	O
bombardment	O
of	O
tobacco	O
leaf	O
sections	O
,	O
a	O
tetramer	O
of	O
the	O
distB	O
ABRE	O
(	O
abscisic	O
acid	O
-	O
responsive	O
element	O
)	O
mediated	O
transactivation	O
by	O
ABI3	B-GENE
and	O
ABI3	B-GENE
-	O
dependent	O
response	O
to	O
ABA	O
,	O
whereas	O
a	O
tetramer	O
of	O
the	O
composite	O
RY	O
/	O
G	O
complex	O
,	O
containing	O
RY	O
repeats	O
and	O
a	O
G	O
-	O
box	O
,	O
mediated	O
only	O
ABA	O
-	O
independent	O
transactivation	O
by	O
ABI3	B-GENE
.	O

The	O
major	O
neurological	O
manifestations	O
of	O
brain	O
injury	O
in	O
these	O
babies	O
are	O
spastic	O
motor	O
deficits	O
.	O

Spores	O
from	O
Rhizopus	O
stolonifer	O
were	O
suspended	O
in	O
distilled	O
water	O
(	O
1	O
x	O
10	O
(	O
6	O
)	O
spores	O
/	O
mL	O
)	O
and	O
used	O
as	O
starter	O
.	O

The	O
LMW	B-GENE
FGF	I-GENE
-	I-GENE
2	I-GENE
up	O
-	O
regulated	O
the	O
PKC	B-GENE
epsilon	I-GENE
levels	O
by	O
1	O
.	O
6	O
-	O
fold	O
;	O
by	O
contrast	O
the	O
HMW	B-GENE
isoform	I-GENE
down	O
-	O
regulated	O
the	O
level	O
of	O
this	O
PKC	B-GENE
isotype	I-GENE
by	O
about	O
3	O
-	O
fold	O
and	O
increased	O
the	O
amount	O
of	O
PKC	B-GENE
delta	I-GENE
by	O
1	O
.	O
7	O
-	O
fold	O
.	O

Helicobacter	O
pylori	O
and	O
stomach	O
diseases	O
:	O
from	O
clinical	O
point	O
of	O
view	O

For	O
this	O
purpose	O
,	O
the	O
writhing	O
test	O
,	O
capsaicin	O
and	O
formalin	O
induced	O
-	O
pain	O
in	O
mice	O
were	O
used	O
.	O

2000	O
update	O
of	O
recommendations	O
for	O
the	O
use	O
of	O
hematopoietic	B-GENE
colony	I-GENE
-	I-GENE
stimulating	I-GENE
factors	I-GENE
:	O
evidence	O
-	O
based	O
,	O
clinical	O
practice	O
guidelines	O
.	O

Prominent	O
findings	O
were	O
chronic	O
pancreatitis	O
with	O
acinar	O
and	O
ductal	O
plugs	O
,	O
granulomatous	O
and	O
necrotizing	O
peripancreatic	O
steatitis	O
,	O
degenerative	O
myopathy	O
,	O
testicular	O
atrophy	O
,	O
candidiasis	O
and	O
bacterial	O
necrotizing	O
glossitis	O
.	O

Taken	O
together	O
,	O
our	O
data	O
indicate	O
that	O
multiple	O
survival	O
pathways	O
are	O
triggered	O
via	O
this	O
receptor	O
,	O
whereas	O
NF	B-GENE
-	I-GENE
kappaB	I-GENE
/	O
Rel	B-GENE
and	O
PI	B-GENE
-	I-GENE
3K	I-GENE
are	O
crucial	O
for	O
CD40	B-GENE
-	O
induced	O
proliferation	O
.	O

In	O
vitro	O
,	O
Arix	B-GENE
and	O
NBPhox	B-GENE
form	O
DNA	O
-	O
independent	O
multimers	O
and	O
exhibit	O
cooperative	O
binding	O
to	O
the	O
DB1	B-GENE
regulatory	I-GENE
element	I-GENE
,	O
which	O
contains	O
two	O
homeodomain	B-GENE
recognition	I-GENE
sites	I-GENE
.	O

We	O
conclude	O
from	O
this	O
study	O
that	O
Arix	B-GENE
and	O
NBPhox	B-GENE
exhibit	O
indistinguishable	O
and	O
independent	O
transcriptional	O
regulatory	O
properties	O
on	O
the	O
DBH	B-GENE
promoter	I-GENE
.	O

METHODS	O
AND	O
RESULTS	O
:	O
Studies	O
were	O
undertaken	O
in	O
9	O
isolated	O
guinea	O
pig	O
hearts	O
,	O
which	O
demonstrated	O
reverse	O
use	O
-	O
dependent	O
prolongation	O
of	O
cardiac	O
repolarization	O
by	O
100	O
nmol	O
/	O
L	O
domperidone	O
.	O

OBJECTIVE	O
:	O
To	O
evaluate	O
the	O
overall	O
performance	O
of	O
a	O
new	O
oscillometric	O
wrist	O
blood	O
pressure	O
monitor	O
(	O
Braun	O
PrecisionSensor	O
,	O
Braun	O
GmbH	O
,	O
Kronberg	O
,	O
Germany	O
)	O
as	O
defined	O
by	O
the	O
ANSI	O
/	O
AAMI	O
SP10	O
-	O
1992	O
guidelines	O
,	O
and	O
to	O
analyze	O
the	O
data	O
for	O
the	O
optimized	O
selection	O
of	O
the	O
algorithm	O
that	O
derives	O
the	O
blood	O
pressure	O
values	O
from	O
the	O
oscillometric	O
blood	O
pressure	O
curves	O
.	O

Following	O
the	O
results	O
of	O
toxicological	O
experiments	O
in	O
the	O
target	O
animals	O
"	O
Toxicological	O
Drinking	O
Water	O
Standards	O
for	O
Animals	O
"	O
can	O
be	O
established	O
.	O

An	O
increase	O
in	O
hypothalamic	O
expression	O
of	O
at	O
least	O
two	O
of	O
the	O
erbB	B-GENE
receptors	I-GENE
is	O
initiated	O
before	O
the	O
pubertal	O
augmentation	O
of	O
gonadal	O
steroid	O
secretion	O
and	O
is	O
completed	O
on	O
the	O
day	O
of	O
the	O
first	O
preovulatory	O
surge	O
of	O
gonadotropins	B-GENE
.	O

Dsh	B-GENE
is	O
required	O
for	O
two	O
different	O
pathways	O
,	O
the	O
Wnt	B-GENE
pathway	O
and	O
planar	O
polarity	O
pathway	O
in	O
Drosophila	O
.	O

Catch	O
-	O
up	O
growth	O
and	O
craniofacial	O
dimensions	O
following	O
administration	O
of	O
the	O
antineoplastic	O
agent	O
vincristine	O
to	O
young	O
rats	O
.	O

CONCLUSIONS	O
:	O
LSCC	O
malformation	O
,	O
like	O
other	O
inner	O
ear	O
malformations	O
such	O
as	O
large	O
vestibular	O
aqueduct	O
and	O
X	O
-	O
linked	O
mixed	O
deafness	O
with	O
perilymph	O
gusher	O
,	O
can	O
be	O
associated	O
with	O
CHL	O
,	O
SNHL	O
,	O
or	O
normal	O
hearing	O
.	O

Escalation	O
to	O
180	O
mg	O
/	O
m2	O
was	O
to	O
be	O
carried	O
out	O
if	O
white	O
blood	O
cell	O
nadir	O
count	O
was	O
>	O
2	O
.	O
0	O
x	O
10	O
(	O
9	O
)	O
/	O
l	O
and	O
platelet	O
nadir	O
count	O
was	O
>	O
75	O
x	O
10	O
(	O
9	O
)	O
/	O
l	O
.	O

Methyl	O
formate	O
was	O
used	O
as	O
the	O
solvent	O
of	O
biodegradable	O
oligoesters	O
for	O
the	O
fabrication	O
of	O
microspheres	O
with	O
encapsulated	O
bovine	B-GENE
serum	I-GENE
albumin	I-GENE
(	O
BSA	B-GENE
)	O
.	O

The	O
small	B-GENE
monomeric	I-GENE
GTP	I-GENE
-	I-GENE
binding	I-GENE
proteins	I-GENE
of	O
the	O
RAB	B-GENE
subfamily	I-GENE
are	O
key	O
regulatory	O
elements	O
of	O
the	O
machinery	O
that	O
controls	O
membrane	O
traffic	O
in	O
eukaryotic	O
cells	O
.	O

Furthermore	O
,	O
loss	O
of	O
methylation	O
also	O
greatly	O
reduced	O
the	O
association	O
of	O
another	O
yeast	O
B	O
-	O
type	O
subunit	O
,	O
Rts1p	B-GENE
.	O

Thus	O
,	O
methylation	O
of	O
Pph21p	B-GENE
is	O
important	O
for	O
formation	O
of	O
PP2A	B-GENE
trimeric	I-GENE
and	I-GENE
dimeric	I-GENE
complexes	I-GENE
,	O
and	O
consequently	O
,	O
for	O
PP2A	B-GENE
function	O
.	O

The	O
purpose	O
of	O
this	O
study	O
was	O
to	O
analyze	O
the	O
temporal	O
characteristics	O
and	O
the	O
spatial	O
mapping	O
of	O
the	O
independent	O
components	O
identified	O
by	O
ICA	O
when	O
the	O
subject	O
performs	O
a	O
finger	O
-	O
tapping	O
task	O
.	O

The	O
authors	O
present	O
the	O
only	O
two	O
studies	O
that	O
have	O
proved	O
successful	O
in	O
treating	O
animal	O
models	O
of	O
osteoarthritis	O
using	O
gene	O
therapy	O
,	O
and	O
propose	O
an	O
overview	O
of	O
several	O
strategies	O
for	O
the	O
development	O
of	O
gene	O
therapy	O
in	O
osteoarthritis	O
treatment	O
in	O
the	O
future	O
.	O

Together	O
,	O
these	O
results	O
indicate	O
that	O
IL	B-GENE
-	I-GENE
1	I-GENE
beta	I-GENE
induces	O
VEGF	B-GENE
gene	I-GENE
expression	O
at	O
both	O
transcriptional	O
and	O
post	O
-	O
transcriptional	O
levels	O
,	O
and	O
IL	B-GENE
-	I-GENE
1	I-GENE
beta	I-GENE
evokes	O
p38	B-GENE
MAPK	O
and	O
JNK	B-GENE
signalings	O
,	O
which	O
in	O
turn	O
stimulate	O
the	O
transcription	O
of	O
the	O
VEGF	B-GENE
gene	I-GENE
through	O
Sp1	B-GENE
-	I-GENE
binding	I-GENE
sites	I-GENE
.	O

Binding	O
of	O
NusA	B-GENE
to	O
RNA	O
in	O
the	O
presence	O
of	O
alpha	O
or	O
N	O
involves	O
an	O
amino	B-GENE
-	I-GENE
terminal	I-GENE
S1	I-GENE
homology	I-GENE
region	I-GENE
that	O
is	O
otherwise	O
inactive	O
in	O
full	B-GENE
-	I-GENE
length	I-GENE
NusA	I-GENE
.	O

The	O
subjects	O
were	O
diagnosed	O
on	O
the	O
basis	O
of	O
DSM	O
-	O
IV	O
pathological	O
gambling	O
criteria	O
and	O
completed	O
the	O
Turkish	O
Version	O
of	O
South	O
Oaks	O
Gambling	O
Screen	O
(	O
SOGS	O
)	O
.	O

Lys	O
(	O
193	O
)	O
and	O
Arg	O
(	O
194	O
)	O
,	O
located	O
at	O
the	O
COOH	O
-	O
terminal	O
end	O
of	O
HD	B-GENE
,	O
are	O
essential	O
for	O
dimerization	O
.	O

Elevation	O
of	O
intracellular	O
Ca	O
(	O
2	O
+	O
)	O
levels	O
are	O
also	O
involved	O
because	O
treatment	O
with	O
receptor	O
-	O
associated	O
protein	O
,	O
nifedipine	O
,	O
MK801	O
,	O
removal	O
of	O
Ca	O
(	O
2	O
+	O
)	O
from	O
the	O
medium	O
and	O
dantrolene	O
all	O
served	O
to	O
inhibit	O
calcium	O
elevation	O
and	O
attenuate	O
the	O
activation	O
of	O
CREB	B-GENE
.	O

The	O
present	O
study	O
shows	O
that	O
phosphatidylinositol	B-GENE
3	I-GENE
-	I-GENE
kinase	I-GENE
-	O
dependent	O
p38	B-GENE
kinase	I-GENE
activation	O
regulates	O
Akt	B-GENE
phosphorylation	O
and	O
activity	O
in	O
human	O
neutrophils	O
.	O

When	O
BFDS	O
was	O
taken	O
as	O
the	O
reference	O
,	O
W	O
/	O
A	O
Z	O
scores	O
showed	O
consistent	O
positive	O
increments	O
,	O
from	O
birth	O
in	O
girls	O
and	O
1	O
mo	O
in	O
boys	O
.	O

Using	O
purified	O
recombinant	B-GENE
HMG	I-GENE
I	I-GENE
,	O
we	O
have	O
identified	O
several	O
high	O
-	O
affinity	O
binding	O
sites	O
which	O
overlap	O
important	O
transcription	O
factor	O
binding	O
sites	O
.	O

High	B-GENE
-	I-GENE
mobility	I-GENE
-	I-GENE
group	I-GENE
protein	I-GENE
I	I-GENE
can	O
modulate	O
binding	O
of	O
transcription	O
factors	O
to	O
the	O
U5	B-GENE
region	I-GENE
of	O
the	O
human	B-GENE
immunodeficiency	I-GENE
virus	I-GENE
type	I-GENE
1	I-GENE
proviral	I-GENE
promoter	I-GENE
.	O

Leptinaemia	O
does	O
not	O
correlate	O
with	O
the	O
actual	O
or	O
mean	O
blood	O
pressure	O
reading	O
nor	O
with	O
stage	O
of	O
hypertension	O
according	O
to	O
the	O
WHO	O
classification	O
.	O

Thus	O
,	O
diamide	O
treatment	O
of	O
nuclear	O
extracts	O
strongly	O
reduces	O
the	O
binding	O
of	O
NFI	B-GENE
proteins	I-GENE
,	O
and	O
the	O
addition	O
of	O
higher	O
concentrations	O
of	O
dithiothreitol	O
to	O
nuclear	O
extracts	O
from	O
TG	B-GENE
-	O
treated	O
cells	O
restores	O
NFI	B-GENE
-	I-GENE
DNA	I-GENE
binding	O
to	O
levels	O
in	O
extracts	O
from	O
untreated	O
cells	O
.	O

LMP2A	B-GENE
enhances	O
Lyn	B-GENE
and	O
Syk	B-GENE
ubiquitination	O
in	O
vivo	O
in	O
a	O
fashion	O
that	O
depends	O
on	O
the	O
activity	O
of	O
Nedd4	B-GENE
family	O
members	O
and	O
correlates	O
with	O
destabilization	O
of	O
the	O
Lyn	B-GENE
tyrosine	I-GENE
kinase	I-GENE
.	O

Further	O
,	O
Tax	B-GENE
-	O
mediated	O
apoptosis	O
was	O
effectively	O
prevented	O
by	O
ectopic	O
expression	O
of	O
the	O
p300	B-GENE
coactivator	I-GENE
.	O

Our	O
results	O
,	O
however	O
,	O
were	O
obtained	O
for	O
Z	O
itself	O
and	O
not	O
for	O
[	O
Z	O
]	O
.	O

Fisher	O
'	O
s	O
exact	O
test	O
or	O
Pearson	O
'	O
s	O
chi2	O
test	O
were	O
used	O
for	O
statistical	O
analysis	O
.	O

RESULTS	O
:	O
In	O
the	O
pregnant	O
group	O
,	O
serum	O
PP14	B-GENE
concentrations	O
were	O
markedly	O
increased	O
after	O
ET	O
,	O
and	O
a	O
significant	O
difference	O
between	O
the	O
pregnant	O
group	O
and	O
the	O
nonpregnant	O
group	O
was	O
observed	O
8	O
days	O
following	O
ET	O
(	O
p	O
<	O
0	O
.	O
01	O
)	O
.	O

High	O
expression	O
of	O
the	O
peroxisome	B-GENE
proliferator	I-GENE
-	I-GENE
activated	I-GENE
receptor	I-GENE
alpha	I-GENE
(	O
PPARalpha	B-GENE
)	O
differentiates	O
brown	O
fat	O
from	O
white	O
,	O
and	O
is	O
related	O
to	O
its	O
high	O
capacity	O
of	O
lipid	O
oxidation	O
.	O

This	O
-	O
2485	O
/	O
-	O
2458	O
element	O
bound	O
PPARalpha	B-GENE
and	O
PPARgamma	B-GENE
from	O
brown	O
fat	O
nuclei	O
.	O

These	O
results	O
provide	O
direct	O
evidence	O
for	O
differential	O
susceptibility	O
to	O
endonuclease	O
-	O
mediated	O
mRNA	O
decay	O
resulting	O
from	O
the	O
differential	O
affinity	O
of	O
a	O
RNA	O
-	O
binding	O
protein	O
for	O
cis	O
-	O
acting	O
stability	O
determinants	O
.	O

RESULTS	O
:	O
Twenty	O
-	O
two	O
(	O
26	O
%	O
)	O
patients	O
had	O
PHG	O
before	O
(	O
group	O
A	O
)	O
and	O
64	O
(	O
74	O
%	O
)	O
developed	O
PHG	O
after	O
variceal	O
eradication	O
(	O
group	O
B	O
)	O
.	O

Response	O
was	O
extremely	O
poor	O
in	O
African	O
Americans	O
and	O
those	O
with	O
HCV	O
genotype	O
1	O
.	O

Aspirin	O
causes	O
peptic	O
ulcers	O
predominately	O
by	O
reducing	O
gastric	B-GENE
mucosal	I-GENE
cyclooxygenase	I-GENE
(	O
COX	B-GENE
)	O
activity	O
and	O
prostaglandin	O
synthesis	O
.	O

A	O
total	O
of	O
1060	O
clones	O
were	O
randomly	O
selected	O
for	O
sequencing	O
of	O
one	O
end	O
.	O

CONCLUSIONS	O
:	O
The	O
surgical	O
or	O
multimodality	O
treatment	O
of	O
MSGT	O
has	O
provided	O
a	O
good	O
locoregional	O
control	O
(	O
78	O
%	O
)	O
and	O
68	O
%	O
10	O
-	O
year	O
survival	O
in	O
a	O
series	O
of	O
patients	O
treated	O
at	O
the	O
oncology	O
department	O
of	O
a	O
general	O
hospital	O
in	O
Quito	O
,	O
Ecuador	O
.	O

The	O
gene	O
is	O
separated	O
into	O
four	O
exons	O
by	O
three	O
short	O
introns	O
,	O
and	O
the	O
open	O
reading	O
frame	O
consists	O
of	O
6660	O
base	O
pairs	O
(	O
bp	O
)	O
capable	O
of	O
encoding	O
a	O
polypeptide	O
of	O
2220	O
amino	O
acid	O
residues	O
.	O

Like	O
the	O
p190	B-GENE
-	I-GENE
B	I-GENE
exon	O
,	O
the	O
first	O
exon	O
of	O
p190	B-GENE
-	I-GENE
A	I-GENE
is	O
extremely	O
large	O
(	O
3	O
.	O
7	O
kb	O
in	O
length	O
)	O
,	O
encoding	O
both	O
the	O
GTPase	B-GENE
and	O
middle	O
domains	O
(	O
residues	O
1	O
-	O
1228	O
)	O
,	O
but	O
not	O
the	O
remaining	O
GAP	B-GENE
domain	I-GENE
,	O
suggesting	O
a	O
high	O
conservation	O
of	O
genomic	O
structure	O
between	O
two	O
p190	B-GENE
genes	I-GENE
.	O

The	O
entire	O
human	B-GENE
teneurin	I-GENE
-	I-GENE
1	I-GENE
(	O
TEN1	B-GENE
)	O
gene	O
is	O
contained	O
in	O
eight	O
PAC	O
clones	O
representing	O
part	O
of	O
the	O
chromosomal	O
locus	O
Xq25	O
.	O

The	O
plexiform	O
neurofibroma	O
and	O
multiple	O
localized	O
neurofibromas	O
are	O
characteristic	O
of	O
NF1	B-GENE
.	O

In	O
general	O
lookback	O
,	O
all	O
patients	O
who	O
received	O
blood	O
before	O
being	O
tested	O
for	O
hepatitis	O
C	O
are	O
advised	O
to	O
undergo	O
testing	O
.	O

The	O
proposed	O
algorithm	O
consists	O
of	O
several	O
steps	O
.	O

It	O
contained	O
seven	O
extra	O
amino	O
acids	O
of	O
FVVLNLQ	O
;	O
this	O
short	O
stretch	O
of	O
extra	O
sequence	O
was	O
found	O
between	O
Gln	O
(	O
421	O
)	O
and	O
Phe	O
(	O
422	O
)	O
within	O
the	O
SET	B-GENE
(	O
Suvar3	B-GENE
-	I-GENE
9	I-GENE
,	O
Enhancer	B-GENE
-	I-GENE
of	I-GENE
-	I-GENE
zeste	I-GENE
,	O
Trithorax	B-GENE
)	O
interacting	O
domain	O
(	O
SID	O
)	O
of	O
rMTM	B-GENE
.	O

MED1	B-GENE
has	O
a	O
weak	O
glycosylase	B-GENE
activity	O
on	O
the	O
mutagenic	O
adduct	O
3	O
,	O
N	O
(	O
4	O
)	O
-	O
ethenocytosine	O
,	O
a	O
metabolite	O
of	O
vinyl	O
chloride	O
and	O
ethyl	O
carbamate	O
.	O

There	O
were	O
no	O
instances	O
of	O
major	O
flap	O
necrosis	O
although	O
two	O
flaps	O
showed	O
tip	O
ischaemia	O
.	O

These	O
results	O
suggest	O
that	O
XAB1	B-GENE
is	O
a	O
novel	O
cytoplasmic	B-GENE
GTPase	I-GENE
involved	O
in	O
nuclear	O
localization	O
of	O
XPA	B-GENE
.	O

One	O
of	O
these	O
factors	O
,	O
IRF	B-GENE
-	I-GENE
2	I-GENE
,	O
was	O
initially	O
cloned	O
as	O
an	O
antagonistic	O
counterpart	O
to	O
IRF	B-GENE
-	I-GENE
1	I-GENE
with	O
oncogenic	O
potential	O
.	O

Among	O
the	O
total	O
CDSs	O
,	O
8	O
.	O
8	O
%	O
match	O
sequences	O
of	O
proteins	O
found	O
only	O
in	O
Bacillus	O
subtilis	O
and	O
66	O
.	O
7	O
%	O
are	O
widely	O
conserved	O
in	O
comparison	O
with	O
the	O
proteins	O
of	O
various	O
organisms	O
,	O
including	O
B	O
.	O
subtilis	O
.	O

Tobramycin	O
-	O
loaded	O
SLN	O
administered	O
i	O
.	O
v	O
.	O
showed	O
a	O
prolonged	O
circulation	O
time	O
compared	O
to	O
the	O
i	O
.	O
v	O
.	O
administered	O
tobramycin	O
solution	O
.	O

Bacteriol	O
.	O

Terminal	B-GENE
deoxynucleotidyl	I-GENE
transferase	I-GENE
-	O
mediated	O
nick	O
end	O
labeling	O
assays	O
revealed	O
that	O
hormonal	O
activation	O
of	O
the	O
PAX3	B-GENE
repressors	I-GENE
induced	O
extensive	O
apoptosis	O
that	O
correlated	O
with	O
down	O
-	O
regulation	O
of	O
BCL	B-GENE
-	I-GENE
X	I-GENE
(	I-GENE
L	I-GENE
)	I-GENE
expression	O
.	O

VEGF	B-GENE
promoter	I-GENE
activity	O
in	O
transient	O
transfections	O
was	O
decreased	O
by	O
either	O
pharmacological	O
or	O
genetic	O
inhibition	O
of	O
EGFR	B-GENE
,	O
Ras	B-GENE
,	O
or	O
phosphatidylinositol	B-GENE
3	I-GENE
'	I-GENE
-	I-GENE
kinase	I-GENE
[	B-GENE
PI	I-GENE
(	I-GENE
3	I-GENE
)	I-GENE
kinase	I-GENE
]	I-GENE
.	O

Epidermal	B-GENE
growth	I-GENE
factor	I-GENE
receptor	I-GENE
transcriptionally	O
up	O
-	O
regulates	O
vascular	B-GENE
endothelial	I-GENE
growth	I-GENE
factor	I-GENE
expression	O
in	O
human	O
glioblastoma	O
cells	O
via	O
a	O
pathway	O
involving	O
phosphatidylinositol	B-GENE
3	I-GENE
'	I-GENE
-	I-GENE
kinase	I-GENE
and	O
distinct	O
from	O
that	O
induced	O
by	O
hypoxia	O
.	O

Thus	O
,	O
IHHNV	O
is	O
closely	O
related	O
to	O
densoviruses	O
of	O
the	O
genus	O
Brevidensovirus	O
in	O
the	O
family	O
Parvoviridae	O
,	O
and	O
we	O
therefore	O
propose	O
to	O
rename	O
this	O
virus	O
Penaeus	O
stylirostris	O
densovirus	O
(	O
PstDNV	O
)	O
.	O

Stress	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
kinase	I-GENE
1	I-GENE
(	O
SAPK1	B-GENE
)	O
,	O
also	O
called	O
c	B-GENE
-	I-GENE
Jun	I-GENE
N	I-GENE
-	I-GENE
terminal	I-GENE
kinase	I-GENE
(	O
JNK	B-GENE
)	O
,	O
becomes	O
activated	O
in	O
vivo	O
in	O
response	O
to	O
pro	O
-	O
inflammatory	O
cytokines	O
or	O
cellular	O
stresses	O
.	O

Catalytic	O
activation	O
of	O
mitogen	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
(	I-GENE
MAP	I-GENE
)	I-GENE
kinase	I-GENE
phosphatase	I-GENE
-	I-GENE
1	I-GENE
by	O
binding	O
to	O
p38	B-GENE
MAP	I-GENE
kinase	I-GENE
:	O
critical	O
role	O
of	O
the	O
p38	B-GENE
C	I-GENE
-	I-GENE
terminal	I-GENE
domain	I-GENE
in	O
its	O
negative	O
regulation	O
.	O

Thus	O
,	O
the	O
class	B-GENE
C	I-GENE
-	O
Vps	B-GENE
complex	O
directs	O
multiple	O
reactions	O
during	O
the	O
docking	O
and	O
fusion	O
of	O
vesicles	O
with	O
the	O
vacuole	O
,	O
each	O
of	O
which	O
contributes	O
to	O
the	O
overall	O
specificity	O
and	O
efficiency	O
of	O
this	O
transport	O
process	O
.	O

Combined	O
intravenous	O
and	O
intra	O
-	O
arterial	O
recombinant	O
tissue	B-GENE
plasminogen	I-GENE
activator	I-GENE
in	O
acute	O
ischemic	O
stroke	O
.	O

Signal	O
transduction	O
via	O
modulation	O
of	O
phosphorylation	O
after	O
selective	O
inhibition	O
of	O
protein	B-GENE
phosphatase	I-GENE
(	I-GENE
PP	I-GENE
)	I-GENE
1	I-GENE
and	O
/	O
or	O
PP2A	B-GENE
appears	O
to	O
play	O
a	O
role	O
in	O
okadaic	O
acid	O
(	O
OA	O
)	O
-	O
mediated	O
effects	O
.	O

Exon	O
A	O
is	O
located	O
approximately	O
7	O
kb	O
5	O
'	O
to	O
the	O
HSL	B-GENE
translation	I-GENE
start	I-GENE
site	I-GENE
.	O

NF	B-GENE
-	I-GENE
kappaB	I-GENE
is	O
a	O
redox	O
-	O
sensitive	O
transcription	O
factor	O
known	O
to	O
be	O
activated	O
by	O
oxidative	O
stress	O
as	O
well	O
as	O
chemical	O
and	O
biological	O
reductants	O
.	O

Cardiovascular	O
risk	O
factors	O
and	O
antihypertensive	O
treatment	O
.	O

What	O
to	O
look	O
for	O
during	O
a	O
compliance	O
review	O
:	O
10	O
common	O
mistakes	O
made	O
by	O
SNFs	O
.	O

CONCLUSIONS	O
:	O
EBCT	O
technology	O
allows	O
minimally	O
invasive	O
evaluation	O
of	O
intramyocardial	O
microcirculatory	O
function	O
and	O
permits	O
assessment	O
of	O
microvascular	O
BV	O
distribution	O
in	O
different	O
functional	O
components	O
.	O

These	O
two	O
mAbs	O
used	O
the	O
same	O
V	O
(	O
H	O
)	O
and	O
J	O
(	O
H	O
)	O
gene	O
segments	O
,	O
but	O
different	O
D	O
,	O
Vkappa	O
,	O
and	O
Jkappa	O
genes	O
.	O

SSF	O
experiments	O
were	O
carried	O
out	O
in	O
bench	O
-	O
scale	O
bioreactors	O
(	O
equipped	O
with	O
CO2	O
and	O
volatile	O
organic	O
traps	O
)	O
containing	O
a	O
mixture	O
of	O
lignocellulosic	O
materials	O
and	O
a	O
radiolabeled	O
pesticide	O
.	O

Characterization	O
of	O
a	O
Xenopus	B-GENE
laevis	I-GENE
CXC	I-GENE
chemokine	I-GENE
receptor	I-GENE
4	I-GENE
:	O
implications	O
for	O
hematopoietic	O
cell	O
development	O
in	O
the	O
vertebrate	O
embryo	O
.	O

Patients	O
had	O
to	O
have	O
adequate	O
liver	O
,	O
renal	O
,	O
and	O
marrow	O
functions	O
.	O

Inhibition	O
of	O
RNA2	B-GENE
translation	O
was	O
selective	O
,	O
with	O
no	O
effect	O
on	O
general	O
cellular	O
translation	O
or	O
translation	O
of	O
BMV	O
RNA1	B-GENE
-	O
encoded	O
replication	B-GENE
factor	I-GENE
1a	I-GENE
,	O
and	O
was	O
independent	O
of	O
p20	B-GENE
,	O
a	O
cellular	O
antagonist	O
of	O
DED1	B-GENE
function	O
in	O
translation	O
.	O

Abbreviations	O
:	O
CAS	B-GENE
,	O
CRK	B-GENE
-	I-GENE
associated	I-GENE
substrate	I-GENE
;	O
CH	B-GENE
,	O
calponin	B-GENE
-	I-GENE
homology	I-GENE
domain	I-GENE
;	O
CSK	B-GENE
,	O
C	B-GENE
-	I-GENE
terminal	I-GENE
SRC	I-GENE
kinase	I-GENE
;	O
E6	B-GENE
,	O
Papillomavirus	B-GENE
E6	I-GENE
protein	I-GENE
;	O
FAK	B-GENE
,	O
focal	B-GENE
adhesion	I-GENE
kinase	I-GENE
;	O
GIT	B-GENE
,	O
GRK	B-GENE
interacter	I-GENE
;	O
GPCR	B-GENE
,	O
heterotrimeric	B-GENE
-	I-GENE
G	I-GENE
-	I-GENE
protein	I-GENE
-	I-GENE
coupled	I-GENE
receptor	I-GENE
;	O
GRK	B-GENE
,	O
G	B-GENE
-	I-GENE
protein	I-GENE
-	I-GENE
coupled	I-GENE
-	I-GENE
receptor	I-GENE
kinase	I-GENE
;	O
MAPK	B-GENE
,	O
mitogen	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
kinase	I-GENE
(	O
ERK	B-GENE
,	O
p38	B-GENE
,	O
JNK	B-GENE
)	O
;	O
PAK	B-GENE
,	O
p21	B-GENE
-	I-GENE
activated	I-GENE
kinase	I-GENE
;	O
PBS	B-GENE
,	O
paxillin	B-GENE
-	I-GENE
binding	I-GENE
subdomain	I-GENE
;	O
PIX	B-GENE
,	O
PAK	B-GENE
-	I-GENE
interacting	I-GENE
exchange	I-GENE
factor	I-GENE
;	O
PKL	B-GENE
,	O
paxillin	B-GENE
kinase	I-GENE
linker	I-GENE
;	O
POR1	B-GENE
,	O
partner	B-GENE
of	I-GENE
Rac	I-GENE
;	O
PS	O
,	O
phosphoserine	O
;	O
PT	O
,	O
phosphothreonine	O
;	O
PY	O
,	O
phosphotyrosine	O
;	O
RTK	B-GENE
,	O
growth	B-GENE
factor	I-GENE
receptor	I-GENE
tyrosine	I-GENE
kinase	I-GENE
;	O
SH	B-GENE
,	O
SRC	B-GENE
-	I-GENE
homology	I-GENE
domain	I-GENE
.	O

In	O
15	O
ventilator	O
-	O
dependent	O
,	O
SB	O
,	O
and	O
actively	O
expiring	O
patients	O
,	O
we	O
found	O
that	O
the	O
difference	O
PEEP	O
(	O
i	O
)	O
,	O
dyn	O
-	O
Pga	O
,	O
total	O
decay	O
(	O
mean	O
+	O
/	O
-	O
SD	O
,	O
5	O
.	O
7	O
+	O
/	O
-	O
1	O
.	O
9	O
cm	O
H	O
(	O
2	O
)	O
O	O
)	O
was	O
quite	O
similar	O
to	O
PEEP	O
(	O
i	O
)	O
,	O
dyn	O
ref	O
(	O
5	O
.	O
3	O
+	O
/	O
-	O
1	O
.	O
9	O
cm	O
H	O
(	O
2	O
)	O
O	O
)	O
.	O

Of	O
208	O
eligible	O
subjects	O
,	O
82	O
received	O
supervised	O
IPT	O
at	O
a	O
dose	O
of	O
900	O
mg	O
twice	O
weekly	O
for	O
6	O
mo	O
(	O
Regimen	O
A	O
)	O
,	O
73	O
received	O
unsupervised	O
IPT	O
900	O
mg	O
twice	O
weekly	O
for	O
6	O
mo	O
(	O
Regimen	O
B	O
)	O
,	O
and	O
53	O
received	O
unsupervised	O
IPT	O
300	O
mg	O
daily	O
for	O
6	O
mo	O
(	O
Regimen	O
C	O
)	O
.	O

There	O
were	O
122	O
cases	O
of	O
tuberculosis	O
over	O
an	O
average	O
10	O
.	O
3	O
yr	O
of	O
follow	O
-	O
up	O
(	O
crude	O
annual	O
incidence	O
,	O
76	O
.	O
2	O
/	O
100	O
,	O
000	O
)	O
.	O

These	O
results	O
suggested	O
that	O
BACH1t	B-GENE
recruits	O
BACH1	B-GENE
to	O
the	O
nucleus	O
through	O
BTB	B-GENE
domain	O
-	O
mediated	O
interaction	O
.	O

Transcription	O
of	O
the	O
six	O
EBNA	B-GENE
genes	I-GENE
,	O
which	O
are	O
expressed	O
in	O
EBV	O
-	O
immortalized	O
primary	O
B	O
cells	O
,	O
arises	O
from	O
one	O
of	O
two	O
promoters	O
,	O
Cp	B-GENE
and	O
Wp	B-GENE
,	O
located	O
near	O
the	O
left	O
end	O
of	O
the	O
viral	O
genome	O
.	O

Thus	O
,	O
blocks	O
in	O
the	O
RARalpha	B-GENE
-	O
specific	O
pathway	O
of	O
retinoid	O
-	O
induced	O
differentiation	O
may	O
be	O
bypassed	O
during	O
retinoid	O
induction	O
of	O
FR	B-GENE
-	I-GENE
beta	I-GENE
expression	O
.	O

Is	O
more	O
better	O
?	O
About	O
dose	O
levels	O
of	O
ACE	B-GENE
inhibitors	O
in	O
chronic	O
heart	O
failure	O
.	O

To	O
test	O
whether	O
or	O
not	O
SOCS	B-GENE
-	I-GENE
3	I-GENE
also	O
binds	O
to	O
the	O
IGFIR	B-GENE
,	O
we	O
cloned	O
human	B-GENE
SOCS	I-GENE
-	I-GENE
3	I-GENE
by	O
reverse	O
transcription	O
-	O
polymerase	O
chain	O
reaction	O
from	O
human	O
skeletal	O
muscle	O
mRNA	O
.	O

A	O
protein	O
lacking	O
the	O
SH2	B-GENE
and	O
RING	O
finger	O
domains	O
has	O
no	O
activity	O
,	O
but	O
a	O
chimeric	O
protein	O
with	O
the	O
SH2	B-GENE
and	O
RING	O
finger	O
domains	O
of	O
SLI	B-GENE
-	I-GENE
1	I-GENE
replaced	O
by	O
the	O
equivalent	O
domains	O
of	O
c	B-GENE
-	I-GENE
Cbl	I-GENE
has	O
activity	O
.	O

To	O
evaluate	O
the	O
effects	O
of	O
HRT	O
on	O
those	O
factors	O
in	O
end	O
-	O
stage	O
renal	O
disease	O
(	O
ESRD	O
)	O
patients	O
,	O
we	O
evaluated	O
the	O
changes	O
of	O
lipid	O
profile	O
,	O
coagulation	O
and	O
fibrinolysis	O
markers	O
,	O
and	O
plasma	O
homocysteine	O
levels	O
after	O
treatment	O
.	O

There	O
was	O
a	O
weak	O
significant	O
correlation	O
between	O
TGF	B-GENE
beta	I-GENE
1	I-GENE
levels	O
and	O
normal	O
cell	O
radiosensitivity	O
(	O
lymphocyte	O
SF2	O
)	O
.	O

Acute	O
feasibility	O
and	O
safety	O
of	O
a	O
smoking	O
reduction	O
strategy	O
for	O
smokers	O
with	O
schizophrenia	O
.	O

Tightly	O
ordered	O
proteasomal	O
degradation	O
of	O
proteins	O
critical	O
for	O
cell	O
cycle	O
control	O
implies	O
a	O
role	O
of	O
the	O
proteasome	O
in	O
maintaining	O
cell	O
proliferation	O
and	O
cell	O
survival	O
.	O

The	O
sixth	O
nucleotide	O
was	O
bulged	O
out	O
to	O
allow	O
stacking	O
of	O
this	O
U	O
.	O
G	O
pair	O
on	O
the	O
adjacent	O
helical	O
region	O
.	O

Functional	O
analysis	O
of	O
the	O
mutant	B-GENE
desmin	I-GENE
in	O
SW13	O
(	O
vim	B-GENE
-	O
)	O
cells	O
showed	O
aggregation	O
of	O
abnormal	O
coarse	O
clumps	O
of	O
desmin	B-GENE
positive	O
material	O
dispersed	O
throughout	O
the	O
cytoplasm	O
.	O

Patients	O
with	O
lesions	O
affecting	O
the	O
PRC	O
but	O
sparing	O
the	O
PHC	O
,	O
and	O
patients	O
with	O
lesions	O
affecting	O
both	O
PRC	O
and	O
PHC	O
,	O
performed	O
an	O
oculomotor	O
delayed	O
response	O
task	O
with	O
unpredictably	O
varied	O
memory	O
delays	O
of	O
up	O
to	O
30	O
s	O
.	O

In	O
addition	O
,	O
26	O
amino	O
acid	O
residues	O
,	O
K69	O
,	O
D88	O
,	O
E94	O
,	O
D134	O
,	O
R154	O
,	O
K169	O
,	O
H197	O
,	O
D233	O
,	O
G235	O
,	O
G236	O
,	O
G237	O
,	O
F238	O
,	O
E274	O
,	O
G276	O
,	O
R277	O
,	O
Y278	O
,	O
K294	O
,	O
Y323	O
,	O
Y331	O
,	O
D332	O
,	O
C360	O
,	O
D361	O
,	O
D364	O
,	O
G387	O
,	O
Y389	O
,	O
and	O
F397	O
(	O
mouse	O
ODC	B-GENE
numbering	O
)	O
,	O
all	O
of	O
which	O
are	O
implicated	O
in	O
the	O
formation	O
of	O
the	O
pyridoxal	O
phosphate	O
-	O
binding	O
domain	O
and	O
the	O
substrate	O
-	O
binding	O
domain	O
and	O
in	O
dimer	O
stabilization	O
with	O
the	O
eukaryotic	O
ODCs	B-GENE
,	O
were	O
also	O
conserved	O
in	O
S	O
.	O
ruminantium	O
LDC	B-GENE
.	O

The	O
Psc2	B-GENE
cDNA	I-GENE
contained	O
an	O
open	O
reading	O
frame	O
homologous	O
to	O
CP2	B-GENE
family	I-GENE
proteins	I-GENE
.	O

Our	O
results	O
indicate	O
that	O
Shh	B-GENE
can	O
drive	O
continued	O
cycling	O
in	O
immature	O
,	O
proliferating	O
CGNPs	O
.	O

The	O
QT	O
interval	O
was	O
related	O
to	O
various	O
components	O
of	O
the	O
insulin	B-GENE
resistance	O
syndrome	O
,	O
including	O
BP	O
and	O
insulin	B-GENE
sensitivity	O
.	O

The	O
wavenumbers	O
corresponding	O
to	O
the	O
normal	O
modes	O
of	O
vibration	O
were	O
calculated	O
using	O
the	O
DFT	O
(	O
B3LYP	O
/	O
6	O
-	O
31G	O
*	O
*	O
)	O
approximation	O
and	O
their	O
agreement	O
with	O
the	O
measured	O
values	O
improved	O
after	O
scaling	O
of	O
the	O
associated	O
force	O
field	O
.	O

The	O
data	O
provide	O
strong	O
evidence	O
that	O
ThlA	B-GENE
is	O
involved	O
in	O
the	O
metabolism	O
of	O
both	O
acid	O
and	O
solvent	O
formation	O
,	O
whereas	O
the	O
physiological	O
function	O
of	O
ThlB	B-GENE
has	O
yet	O
to	O
be	O
elucidated	O
.	O

In	O
addition	O
,	O
npm3	B-GENE
,	O
which	O
is	O
usually	O
coactivated	O
with	O
fgf8	B-GENE
by	O
MMTV	O
insertion	O
,	O
was	O
not	O
up	O
-	O
regulated	O
by	O
androgens	O
in	O
SC	O
-	O
3	O
cells	O
.	O

Experiments	O
with	O
epitope	O
-	O
tagged	O
proteins	O
show	O
that	O
UEV1A	B-GENE
is	O
a	O
nuclear	O
protein	O
,	O
whereas	O
both	O
Kua	B-GENE
and	O
Kua	B-GENE
-	O
UEV	B-GENE
localize	O
to	O
cytoplasmic	O
structures	O
,	O
indicating	O
that	O
the	O
Kua	B-GENE
domain	I-GENE
determines	O
the	O
cytoplasmic	O
localization	O
of	O
Kua	B-GENE
-	O
UEV	B-GENE
.	O

Stoichiometric	O
phosphorylation	O
of	O
human	B-GENE
p53	I-GENE
at	O
Ser315	O
stimulates	O
p53	B-GENE
-	O
dependent	O
transcription	O
.	O
p53	B-GENE
protein	I-GENE
activity	O
as	O
a	O
transcription	O
factor	O
can	O
be	O
activated	O
in	O
vivo	O
by	O
antibodies	O
that	O
target	O
its	O
C	O
-	O
terminal	O
negative	O
regulatory	O
domain	O
suggesting	O
that	O
cellular	O
enzymes	O
that	O
target	O
this	O
domain	O
may	O
play	O
a	O
role	O
in	O
stimulating	O
p53	B-GENE
-	O
dependent	O
gene	O
expression	O
.	O

Interestingly	O
,	O
this	O
mutant	O
cell	O
line	O
lacks	O
expression	O
of	O
the	O
IKK	B-GENE
regulatory	I-GENE
protein	I-GENE
,	O
IKKgamma	B-GENE
.	O

The	O
Tax	B-GENE
/	O
IKKgamma	B-GENE
interaction	O
serves	O
to	O
recruit	O
Tax	B-GENE
to	O
the	O
IKK	B-GENE
catalytic	I-GENE
subunits	I-GENE
,	O
IKKalpha	B-GENE
and	O
IKKbeta	B-GENE
,	O
and	O
this	O
recruitment	O
appears	O
to	O
be	O
an	O
essential	O
mechanism	O
by	O
which	O
Tax	B-GENE
stimulates	O
the	O
activity	O
of	O
IKK	B-GENE
.	O

An	O
anchored	O
AFLP	O
-	O
and	O
retrotransposon	O
-	O
based	O
map	O
of	O
diploid	O
Avena	O
.	O

In	O
addition	O
,	O
we	O
identified	O
a	O
novel	O
type	O
of	O
inhibitory	O
domain	O
in	O
the	O
N	O
-	O
terminal	O
60	O
amino	O
acids	O
of	O
IRF	B-GENE
-	I-GENE
1	I-GENE
which	O
strongly	O
inhibits	O
its	O
transcriptional	O
activity	O
.	O

Simultaneous	O
determination	O
of	O
theophylline	O
and	O
its	O
metabolites	O
by	O
HPLC	O
]	O
A	O
high	O
performance	O
liquid	O
chromatography	O
(	O
HPLC	O
)	O
method	O
has	O
been	O
developed	O
for	O
the	O
simultaneous	O
determination	O
of	O
theophylline	O
and	O
its	O
metabolites	O
,	O
with	O
caffeine	O
and	O
its	O
metabolites	O
.	O

Ten	O
males	O
performed	O
both	O
test	O
conditions	O
and	O
oxygen	O
uptake	O
VO2	O
,	O
heart	O
rate	O
,	O
minute	O
ventilation	O
VE	O
,	O
perceived	O
exertion	O
and	O
spinal	O
shrinkage	O
were	O
recorded	O
.	O

CONCLUSION	O
:	O
SPT	O
is	O
more	O
useful	O
than	O
WST	O
in	O
differentiating	O
patients	O
predisposed	O
to	O
aspiration	O
.	O

Studied	O
groups	O
were	O
(	O
1	O
)	O
untreated	O
control	O
,	O
n	O
=	O
12	O
;	O
(	O
2	O
)	O
FK	O
-	O
1	O
,	O
n	O
=	O
8	O
;	O
(	O
3	O
)	O
FK	O
-	O
3	O
,	O
n	O
=	O
8	O
.	O

DNA	O
binding	O
and	O
glutathione	B-GENE
S	I-GENE
-	I-GENE
transferase	I-GENE
pull	O
-	O
down	O
assays	O
demonstrate	O
that	O
binding	O
requires	O
Elk	B-GENE
-	I-GENE
1	I-GENE
(	I-GENE
1	I-GENE
-	I-GENE
212	I-GENE
)	I-GENE
but	O
not	O
the	O
C	O
-	O
terminal	O
transactivation	O
domain	O
.	O

Unexpectedly	O
,	O
ALK7	B-GENE
signaling	O
produced	O
a	O
remarkable	O
change	O
in	O
cell	O
morphology	O
characterized	O
by	O
cell	O
flattening	O
and	O
elaboration	O
of	O
blunt	O
,	O
short	O
cell	O
processes	O
.	O

The	O
swa2	B-GENE
-	I-GENE
1	I-GENE
allele	I-GENE
recovered	O
from	O
the	O
original	O
screen	O
carries	O
a	O
point	O
mutation	O
in	O
its	O
tetratricopeptide	O
repeat	O
(	O
TPR	O
)	O
domain	O
,	O
a	O
motif	O
not	O
found	O
in	O
auxilin	B-GENE
but	O
known	O
in	O
other	O
proteins	O
to	O
mediate	O
interaction	O
with	O
heat	B-GENE
-	I-GENE
shock	I-GENE
proteins	I-GENE
.	O

In	O
slightly	O
older	O
embryos	O
,	O
the	O
expression	O
was	O
skewed	O
to	O
one	O
side	O
of	O
the	O
embryo	O
and	O
by	O
E6	O
.	O
5	O
,	O
at	O
the	O
onset	O
of	O
gastrulation	O
,	O
expression	O
was	O
seen	O
in	O
the	O
epiblast	O
,	O
visceral	O
endoderm	O
,	O
nascent	O
mesoderm	O
,	O
and	O
the	O
primitive	O
streak	O
.	O

The	O
authors	O
proposed	O
that	O
the	O
highly	O
convergent	O
inputs	O
to	O
the	O
entorhinal	O
cortex	O
indicate	O
this	O
region	O
may	O
be	O
particularly	O
important	O
for	O
selecting	O
or	O
compressing	O
information	O
.	O

Influence	O
of	O
oil	O
emulsions	O
and	O
diphenyl	O
on	O
post	O
-	O
harvest	O
physiconutritional	O
changes	O
in	O
Kagzi	O
limes	O
(	O
Citrus	O
aurantifolia	O
)	O
was	O
studied	O
.	O

Detailed	O
analysis	O
of	O
alpha1	B-GENE
,	I-GENE
3GT	I-GENE
transcripts	I-GENE
revealed	O
two	O
major	O
alternative	O
splicing	O
patterns	O
in	O
the	O
5	O
'	O
-	O
untranslated	O
region	O
(	O
5	O
'	O
-	O
UTR	O
)	O
and	O
evidence	O
for	O
minor	O
splicing	O
activity	O
that	O
occurs	O
in	O
a	O
tissue	O
-	O
specific	O
manner	O
.	O

A	O
thermal	O
Kubo	O
-	O
Martin	O
-	O
Schwinger	O
condition	O
arises	O
due	O
to	O
the	O
coupling	O
of	O
a	O
computer	O
to	O
a	O
strong	O
periodic	O
source	O
,	O
namely	O
,	O
the	O
daily	O
and	O
weekly	O
usage	O
patterns	O
of	O
the	O
system	O
.	O

The	O
non	O
-	O
homologous	O
sequences	O
in	O
the	O
5	O
'	O
untranslated	O
regions	O
might	O
be	O
acquired	O
at	O
or	O
after	O
transcription	O
during	O
retrotransposition	O
of	O
the	O
ATLN	O
elements	O
.	O

The	O
time	O
course	O
of	O
RNA1	B-GENE
replication	O
and	O
RNA3	B-GENE
synthesis	O
in	O
induced	O
yeast	O
paralleled	O
that	O
in	O
yeast	O
transfected	O
with	O
natural	O
FHV	O
virion	O
RNA	O
.	O

The	O
transcription	O
and	O
alternative	O
splicing	O
of	O
human	B-GENE
ORL1	I-GENE
and	O
GAIP	B-GENE
are	O
cell	O
-	O
type	O
specific	O
.	O

The	O
extraction	O
was	O
subsequently	O
rated	O
as	O
'	O
easy	O
'	O
or	O
'	O
difficult	O
'	O
.	O
Taking	O
Pell	O
-	O
Gregory	O
class	O
C	O
as	O
a	O
predictor	O
of	O
a	O
'	O
difficult	O
'	O
extraction	O
,	O
specificity	O
was	O
88	O
%	O
but	O
sensitivity	O
was	O
low	O
at	O
15	O
%	O
.	O

In	O
addition	O
,	O
our	O
results	O
show	O
that	O
ERKs	B-GENE
and	O
PI3Ks	B-GENE
can	O
synergise	O
to	O
convert	O
ectoderm	O
into	O
mesoderm	O
.	O

Nevertheless	O
,	O
protein	B-GENE
kinase	I-GENE
A	I-GENE
stimulation	O
induces	O
CREMalpha	B-GENE
to	O
activate	O
the	O
complex	O
native	O
promoter	O
in	O
the	O
phosphoenolpyruvate	B-GENE
carboxykinase	I-GENE
(	O
PEPCK	B-GENE
)	O
gene	O
.	O

Another	O
putative	O
HNF3	B-GENE
site	I-GENE
in	O
close	O
apposition	O
to	O
a	O
NF1	B-GENE
/	O
CTF	B-GENE
site	O
was	O
localized	O
upstream	O
of	O
the	O
silencer	O
-	O
like	O
element	O
.	O

A	O
recently	O
reported	O
new	O
member	O
of	O
the	O
Vav	B-GENE
family	I-GENE
proteins	I-GENE
,	O
Vav3	B-GENE
has	O
been	O
identified	O
as	O
a	O
Ros	B-GENE
receptor	B-GENE
protein	I-GENE
tyrosine	I-GENE
kinase	I-GENE
(	O
RPTK	B-GENE
)	O
interacting	O
protein	O
by	O
yeast	O
two	O
-	O
hybrid	O
screening	O
.	O

Subsequently	O
,	O
we	O
show	O
that	O
the	O
reexpression	O
of	O
the	O
r	B-GENE
-	I-GENE
PTPeta	I-GENE
gene	I-GENE
in	O
highly	O
malignant	O
rat	O
thyroid	O
cells	O
transformed	O
by	O
retroviruses	O
carrying	O
the	O
v	B-GENE
-	I-GENE
mos	I-GENE
and	O
v	B-GENE
-	I-GENE
ras	I-GENE
-	I-GENE
Ki	I-GENE
oncogenes	I-GENE
suppresses	O
their	O
malignant	O
phenotype	O
.	O

Induced	O
expression	O
of	O
Rnd3	B-GENE
is	O
associated	O
with	O
transformation	O
of	O
polarized	O
epithelial	O
cells	O
by	O
the	O
Raf	B-GENE
-	O
MEK	B-GENE
-	O
extracellular	O
signal	O
-	O
regulated	O
kinase	O
pathway	O
.	O

The	O
activity	O
of	O
the	O
transcription	B-GENE
factor	I-GENE
CREB	I-GENE
is	O
regulated	O
by	O
extracellular	O
stimuli	O
that	O
result	O
in	O
its	O
phosphorylation	O
at	O
a	O
critical	O
serine	O
residue	O
,	O
Ser133	O
.	O

When	O
10	O
fields	O
were	O
analysed	O
,	O
a	O
strong	O
relationship	O
was	O
found	O
between	O
the	O
presence	O
of	O
bacteria	O
on	O
Gram	O
staining	O
and	O
the	O
final	O
diagnosis	O
of	O
VAP	O
(	O
for	O
PSB	O
and	O
PTC	O
respectively	O
:	O
sensitivity	O
74	O
and	O
81	O
%	O
,	O
specificity	O
94	O
and	O
100	O
%	O
,	O
positive	O
predictive	O
value	O
91	O
and	O
100	O
%	O
,	O
negative	O
predictive	O
value	O
82	O
and	O
88	O
%	O
)	O
.	O

Tranilast	O
in	O
the	O
Therapy	O
of	O
Coronary	O
Artery	O
Disease	O
.	O

This	O
study	O
is	O
a	O
further	O
and	O
more	O
extensive	O
validation	O
of	O
the	O
clinician	O
rated	O
NIMH	O
-	O
LCM	O
-	O
p	O
.	O

The	O
Aie1	B-GENE
locus	I-GENE
was	O
mapped	O
to	O
mouse	O
chromosome	O
7A2	O
-	O
A3	O
by	O
fluorescent	O
in	O
situ	O
hybridization	O
.	O

Psychiatric	O
disorders	O
in	O
children	O
and	O
adolescents	O
carry	O
considerable	O
morbidity	O
,	O
impede	O
development	O
,	O
and	O
carry	O
a	O
significant	O
mortality	O
by	O
suicide	O
.	O

Thyrotoxicosis	O
due	O
to	O
amiodarone	O
is	O
difficult	O
to	O
treat	O
and	O
is	O
further	O
complicated	O
by	O
the	O
pro	O
-	O
arrhythmic	O
potential	O
of	O
thyrotoxicosis	O
and	O
the	O
fading	O
antiarrhythmic	O
effect	O
after	O
amiodarone	O
withdrawal	O
.	O

Chaperones	O
/	O
HSPs	B-GENE
thus	O
play	O
important	O
roles	O
within	O
cell	O
cycle	O
processes	O
.	O

This	O
study	O
allows	O
us	O
to	O
draw	O
conclusions	O
about	O
the	O
identity	O
of	O
proteins	O
required	O
for	O
the	O
development	O
of	O
the	O
nervous	O
system	O
in	O
Drosophila	O
and	O
provides	O
an	O
example	O
of	O
a	O
molecular	O
approach	O
to	O
characterize	O
en	O
masse	O
transposon	O
-	O
tagged	O
mutations	O
identified	O
in	O
genetic	O
screens	O
.	O

Children	O
with	O
ADD	O
showed	O
an	O
attenuated	O
frontal	O
CNV	O
-	O
1	O
amplitude	O
and	O
a	O
trend	O
towards	O
increased	O
CNV	O
-	O
1	O
and	O
CNV	O
-	O
2	O
occipital	O
amplitudes	O
.	O

Where	O
UMDNJ	O
is	O
headed	O
.	O

Overexpression	O
of	O
c	B-GENE
-	I-GENE
Myc	I-GENE
in	O
serum	O
-	O
starved	O
human	O
or	O
mouse	O
embryonic	O
cells	O
leads	O
to	O
apoptosis	O
which	O
is	O
significantly	O
reduced	O
in	O
the	O
presence	O
of	O
growth	O
factor	O
-	O
containing	O
serum	O
.	O
c	B-GENE
-	I-GENE
Myc	I-GENE
-	O
induced	O
apoptosis	O
appears	O
to	O
be	O
deficient	O
in	O
bax	B-GENE
-	O
null	O
as	O
compared	O
with	O
bax	B-GENE
-	O
wild	O
-	O
type	O
mouse	O
embryonic	O
fibroblasts	O
.	O

METHODS	O
:	O
T2	O
*	O
-	O
weighted	O
,	O
three	O
-	O
dimensional	O
gradient	O
-	O
echo	O
images	O
were	O
acquired	O
by	O
exploiting	O
the	O
magnetic	O
susceptibility	O
difference	O
between	O
oxygenated	O
and	O
deoxygenated	O
hemoglobin	B-GENE
in	O
the	O
vasculature	O
and	O
microvasculature	O
.	O

In	O
the	O
COPD	O
patients	O
,	O
the	O
variability	O
of	O
Delta	O
-	O
inst	O
Rrs	O
(	O
30	O
%	O
)	O
was	O
greater	O
than	O
that	O
of	O
FOT	O
Rrs	O
(	O
21	O
%	O
)	O
.	O

Thus	O
,	O
Pet111p	B-GENE
could	O
play	O
dual	O
roles	O
in	O
both	O
membrane	O
localization	O
and	O
regulation	O
of	O
Cox2p	B-GENE
synthesis	O
within	O
mitochondria	O
.	O

The	O
determination	O
of	O
the	O
double	O
bounds	O
in	O
blood	O
serum	O
lipids	O
by	O
titration	O
with	O
ozone	O
:	O
the	O
pathophysiology	O
and	O
diagnostic	O
significance	O
]	O
In	O
this	O
article	O
the	O
method	O
of	O
definition	O
of	O
double	O
binders	O
in	O
lipids	O
of	O
blood	O
serum	O
in	O
patients	O
with	O
different	O
diseases	O
basically	O
atherosclerosis	O
and	O
ischemic	O
heart	O
disease	O
,	O
with	O
use	O
titration	O
by	O
ozone	O
is	O
given	O
.	O

Ang	B-GENE
II	I-GENE
-	O
induced	O
fibronectin	B-GENE
mRNA	O
was	O
not	O
affected	O
by	O
PKC	B-GENE
inhibitors	O
or	O
PKC	B-GENE
depletion	O
,	O
whereas	O
specific	O
inhibition	O
of	O
EGF	B-GENE
-	I-GENE
R	I-GENE
function	O
by	O
a	O
dominant	B-GENE
negative	I-GENE
EGF	I-GENE
-	I-GENE
R	I-GENE
mutant	I-GENE
and	O
tyrphostin	O
AG1478	O
abolished	O
induction	O
of	O
fibronectin	B-GENE
mRNA	I-GENE
.	O

Acoust	O
.	O

Video	O
images	O
of	O
the	O
nostrils	O
were	O
captured	O
and	O
then	O
analyzed	O
for	O
area	O
,	O
perimeter	O
,	O
centroid	O
,	O
principal	O
axis	O
,	O
moments	O
about	O
the	O
major	O
and	O
minor	O
axes	O
(	O
I11	O
,	O
I22	O
)	O
,	O
anisometry	O
,	O
bulkiness	O
,	O
lateral	O
offset	O
,	O
internostril	O
angle	O
,	O
and	O
rotational	O
angle	O
.	O

Young	O
fish	O
(	O
Oreochromis	O
mossambicus	O
)	O
were	O
exposed	O
to	O
microgravity	O
(	O
micro	O
g	O
)	O
for	O
9	O
to	O
10	O
days	O
during	O
space	O
missions	O
STS	O
-	O
55	O
and	O
STS	O
-	O
84	O
,	O
or	O
to	O
hypergravity	O
(	O
hg	O
)	O
for	O
9	O
days	O
.	O

S6K2	B-GENE
is	O
highly	O
homologous	O
to	O
S6K1	B-GENE
in	O
the	O
core	O
kinase	O
and	O
linker	O
regulatory	O
domains	O
but	O
differs	O
from	O
S6K1	B-GENE
in	O
the	O
N	O
-	O
and	O
C	O
-	O
terminal	O
regions	O
and	O
is	O
differently	O
localized	O
primarily	O
to	O
the	O
nucleus	O
because	O
of	O
a	O
C	O
-	O
terminal	O
nuclear	O
localization	O
signal	O
unique	O
to	O
S6K2	B-GENE
.	O

Pretreatment	O
of	O
cells	O
with	O
the	O
mitogen	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
-	I-GENE
extracellular	I-GENE
signal	I-GENE
-	I-GENE
regulated	I-GENE
kinase	I-GENE
kinase	I-GENE
(	O
MEK	B-GENE
)	O
inhibitor	O
U0126	O
inhibited	O
S6K2	B-GENE
activation	O
to	O
a	O
greater	O
extent	O
than	O
S6K1	B-GENE
.	O

T	O
cells	O
express	O
two	O
isoforms	O
of	O
S6k1	B-GENE
:	O
a	O
70	O
kDa	O
cytoplasmic	O
kinase	O
and	O
an	O
85	O
kDa	O
isoform	O
that	O
has	O
a	O
classic	O
nuclear	O
localisation	O
.	O

Ketanserin	O
,	O
a	O
hypotensive	O
drug	O
with	O
5	B-GENE
-	I-GENE
HT2	I-GENE
receptor	I-GENE
antagonism	O
,	O
when	O
administered	O
by	O
topical	O
infusion	O
of	O
a	O
0	O
.	O
25	O
%	O
w	O
/	O
v	O
solution	O
by	O
corneal	O
and	O
scleral	O
applications	O
,	O
was	O
found	O
to	O
lower	O
intraocular	O
pressure	O
with	O
four	O
times	O
more	O
activity	O
than	O
its	O
metabolite	O
,	O
ketanserinol	O
.	O

A	O
prospectively	O
gated	O
2D	O
axial	O
sequence	O
with	O
velocity	O
encoding	O
in	O
the	O
craniocaudal	O
direction	O
in	O
the	O
cervical	O
region	O
was	O
set	O
at	O
a	O
velocity	O
of	O
+	O
/	O
-	O
10	O
cm	O
/	O
s	O
.	O

It	O
was	O
subsequently	O
shown	O
that	O
Tip60	B-GENE
had	O
histone	B-GENE
acetyltransferase	I-GENE
(	O
HAT	B-GENE
)	O
activity	O
.	O

Our	O
data	O
show	O
that	O
multiple	O
MLSN1	B-GENE
transcripts	I-GENE
,	O
both	O
constitutively	O
expressed	O
and	O
inducible	O
,	O
are	O
present	O
in	O
cultured	O
pigmented	O
melanoma	O
cells	O
,	O
and	O
suggest	O
that	O
MLSN1	B-GENE
expression	O
can	O
be	O
regulated	O
at	O
the	O
level	O
of	O
both	O
transcription	O
and	O
mRNA	O
processing	O
.	O

These	O
results	O
also	O
suggest	O
the	O
involvement	O
of	O
additional	O
elements	O
in	O
the	O
UPR	O
.	O

We	O
show	O
that	O
in	O
contrast	O
to	O
SRC1	B-GENE
,	O
direct	O
binding	O
of	O
CBP	B-GENE
to	O
the	O
estrogen	B-GENE
receptor	I-GENE
is	O
weak	O
,	O
suggesting	O
that	O
SRC1	B-GENE
functions	O
primarily	O
as	O
an	O
adaptor	O
to	O
recruit	O
CBP	B-GENE
and	O
p300	B-GENE
.	O

Remarkably	O
,	O
a	O
construct	O
corresponding	O
to	O
residues	O
631	O
to	O
970	O
,	O
which	O
contains	O
only	O
the	O
LXXLL	O
motifs	O
and	O
the	O
AD1	O
region	O
of	O
SRC1	B-GENE
,	O
retained	O
strong	O
coactivator	O
activity	O
in	O
our	O
assays	O
.	O

Since	O
MEK	B-GENE
acts	O
as	O
a	O
cytoplasmic	O
anchor	O
for	O
the	O
ERKs	B-GENE
,	O
the	O
lack	O
of	O
a	O
MEK	B-GENE
interaction	O
resulted	O
in	O
the	O
aberrant	O
nuclear	O
localization	O
of	O
ERK2	B-GENE
-	O
Delta19	B-GENE
-	I-GENE
25	I-GENE
mutants	O
in	O
serum	O
-	O
starved	O
cells	O
.	O

Pmt2	B-GENE
is	O
a	O
member	O
of	O
a	O
six	O
-	O
protein	O
family	O
in	O
yeast	O
that	O
catalyzes	O
the	O
first	O
step	O
in	O
O	O
mannosylation	O
of	O
target	O
proteins	O
.	O

Of	O
the	O
21	O
quadrants	O
positive	O
in	O
the	O
controls	O
,	O
17	O
were	O
correlated	O
with	O
previously	O
detected	O
jaw	O
pathoses	O
.	O

Four	O
cases	O
of	O
synovial	O
chondromatosis	O
are	O
presented	O
.	O

Previous	O
studies	O
have	O
shown	O
that	O
the	O
pro	O
-	O
inflammatory	O
cytokines	O
tumor	B-GENE
necrosis	I-GENE
factor	I-GENE
alpha	I-GENE
and	O
interferon	B-GENE
gamma	I-GENE
reduce	O
the	O
expression	O
of	O
the	O
cystic	B-GENE
fibrosis	I-GENE
transmembrane	I-GENE
conductance	I-GENE
regulator	I-GENE
(	O
CFTR	B-GENE
)	O
gene	O
(	O
CFTR	B-GENE
)	O
in	O
HT	O
-	O
29	O
and	O
T84	O
cells	O
by	O
acting	O
post	O
-	O
transcriptionally	O
.	O

Regulation	O
of	O
RhoA	B-GENE
is	O
required	O
to	O
maintain	O
adhesion	O
in	O
stationary	O
cells	O
,	O
but	O
is	O
also	O
critical	O
for	O
cell	O
spreading	O
and	O
migration	O
[	O
3	O
]	O
.	O

Here	O
we	O
show	O
in	O
mouse	O
fibroblasts	O
stably	O
transformed	O
by	O
v	B-GENE
-	I-GENE
Src	I-GENE
that	O
mRNA	O
and	O
protein	O
levels	O
of	O
p21	B-GENE
(	O
WAF1	B-GENE
/	O
CIP1	B-GENE
)	O
,	O
cyclin	B-GENE
D1	I-GENE
,	O
and	O
cyclin	B-GENE
E	I-GENE
are	O
elevated	O
.	O

ORFA	O
and	O
ccdA	B-GENE
were	O
constitutively	O
cotranscribed	O
as	O
determined	O
by	O
primer	O
extension	O
analysis	O
.	O

Mouse	B-GENE
Impact	I-GENE
is	O
a	O
paternally	O
expressed	O
gene	O
encoding	O
an	O
evolutionarily	O
conserved	O
protein	O
of	O
unknown	O
function	O
.	O

Coexpression	O
studies	O
indicate	O
that	O
insulin	B-GENE
and	O
PKB	B-GENE
suppress	O
transactivation	O
by	O
C	B-GENE
/	I-GENE
EBPbeta	I-GENE
,	O
but	O
not	O
C	B-GENE
/	I-GENE
EBPalpha	I-GENE
,	O
and	O
that	O
N	O
-	O
terminal	O
transactivation	O
domains	O
in	O
C	B-GENE
/	I-GENE
EBPbeta	I-GENE
are	O
required	O
.	O

Among	O
eight	O
graminaceous	O
species	O
tested	O
,	O
Ids3	B-GENE
expression	O
was	O
observed	O
only	O
in	O
Fe	O
-	O
deficient	O
roots	O
of	O
H	O
.	O
vulgare	O
and	O
Secale	O
cereale	O
.	O
which	O
not	O
only	O
secrete	O
2	O
'	O
-	O
deoxymugineic	O
acid	O
(	O
DMA	O
)	O
,	O
but	O
also	O
mugineic	O
acid	O
(	O
MA	O
)	O
and	O
3	O
-	O
epihydroxymugineic	O
acid	O
(	O
epiHMA	O
,	O
H	O
.	O
vulgare	O
)	O
,	O
and	O
3	O
-	O
hydroxymugineic	O
acid	O
(	O
HMA	O
,	O
S	O
.	O
cereale	O
)	O
.	O

In	O
contrast	O
,	O
high	O
COUP	B-GENE
-	I-GENE
TFI	I-GENE
expression	O
impeded	O
the	O
neuronal	O
differentiation	O
of	O
P19	O
cells	O
induced	O
with	O
RA	O
,	O
resulting	O
in	O
cell	O
cultures	O
lacking	O
neurons	O
.	O

Because	O
PET	O
is	O
also	O
useful	O
for	O
the	O
pretreatment	O
and	O
follow	O
-	O
up	O
evaluation	O
,	O
the	O
use	O
of	O
stereotactic	O
PET	O
in	O
these	O
patients	O
can	O
enable	O
an	O
accurate	O
comparison	O
of	O
PET	O
-	O
based	O
metabolic	O
data	O
with	O
MR	O
-	O
based	O
anatomical	O
data	O
.	O

Therefore	O
,	O
in	O
our	O
in	O
vitro	O
model	O
,	O
the	O
localization	O
of	O
the	O
mutation	O
in	O
the	O
K	B-GENE
-	I-GENE
ras	I-GENE
gene	I-GENE
predisposes	O
to	O
a	O
different	O
level	O
of	O
aggressiveness	O
in	O
the	O
transforming	O
phenotype	O
.	O

Here	O
,	O
we	O
describe	O
the	O
isolation	O
of	O
MdPin1	B-GENE
,	O
a	O
Pin1	B-GENE
homologue	O
from	O
the	O
plant	O
species	O
apple	O
(	O
Malus	O
domestica	O
)	O
and	O
show	O
that	O
it	O
has	O
the	O
same	O
phosphorylation	O
-	O
specific	O
substrate	O
specificity	O
and	O
can	O
be	O
inhibited	O
by	O
juglone	O
in	O
vitro	O
,	O
as	O
is	O
the	O
case	O
for	O
Pin1	B-GENE
.	O

These	O
and	O
other	O
data	O
presented	O
suggest	O
that	O
TAg	B-GENE
'	O
re	O
-	O
models	O
'	O
host	O
cell	O
transcription	O
factors	O
that	O
are	O
used	O
early	O
in	O
viral	O
infection	O
,	O
and	O
thereby	O
mimics	O
an	O
event	O
that	O
naturally	O
occurs	O
during	O
transformation	O
.	O

This	O
sensitivity	O
analysis	O
showed	O
that	O
the	O
practical	O
limits	O
of	O
the	O
accuracy	O
of	O
the	O
used	O
screening	O
test	O
jeopardize	O
the	O
estimation	O
of	O
the	O
true	O
herd	O
prevalence	O
within	O
reasonable	O
confidence	O
limits	O
,	O
because	O
the	O
within	O
-	O
herd	O
PTB	O
true	O
prevalence	O
was	O
low	O
.	O
For	O
this	O
reason	O
we	O
augmented	O
the	O
herd	O
specificity	O
for	O
herds	O
with	O
larger	O
adult	O
herd	O
size	O
(	O
>	O
5	O
)	O
.	O

ORFK10	B-GENE
.	I-GENE
5	I-GENE
encodes	O
a	O
protein	O
,	O
latency	B-GENE
-	I-GENE
associated	I-GENE
nuclear	I-GENE
antigen	I-GENE
2	I-GENE
(	O
LANA2	B-GENE
)	O
,	O
which	O
is	O
expressed	O
in	O
KSHV	O
-	O
infected	O
hematopoietic	O
tissues	O
,	O
including	O
PEL	O
and	O
CD	O
but	O
not	O
KS	O
lesions	O
.	O

In	O
Xenopus	O
,	O
BMPs	B-GENE
act	O
as	O
epidermal	O
inducers	O
and	O
also	O
as	O
negative	O
regulators	O
of	O
neurogenesis	O
.	O

Presently	O
four	O
unique	O
variants	O
carrying	O
distinct	O
GAF	B-GENE
sequences	I-GENE
in	O
the	O
N	O
-	O
terminal	O
region	O
have	O
been	O
identified	O
.	O

Genomic	O
organization	O
of	O
the	O
human	O
phosphodiesterase	B-GENE
PDE11A	I-GENE
gene	I-GENE
.	O

The	O
present	O
findings	O
revealed	O
that	O
the	O
rib	B-GENE
-	I-GENE
2	I-GENE
protein	I-GENE
was	O
a	O
unique	O
alpha1	B-GENE
,	I-GENE
4	I-GENE
-	I-GENE
N	I-GENE
-	I-GENE
acetylglucosaminyltransferase	I-GENE
involved	O
in	O
the	O
biosynthetic	O
initiation	O
and	O
elongation	O
of	O
heparan	O
sulfate	O
.	O

Inhibition	O
of	O
the	O
Mek	B-GENE
/	O
Erk	B-GENE
pathway	O
in	O
Rat1	O
/	O
ras	B-GENE
cells	O
,	O
using	O
the	O
Mek	B-GENE
inhibitor	O
,	O
PD98059	O
,	O
resulted	O
in	O
complete	O
cytoskeletal	O
recovery	O
,	O
indistinguishable	O
from	O
that	O
induced	O
by	O
HR12	O
.	O

The	O
transcription	O
factor	O
CHOP	B-GENE
/	O
GADD153	B-GENE
gene	O
is	O
induced	O
by	O
cellular	O
stress	O
and	O
is	O
involved	O
in	O
mediating	O
apoptosis	O
.	O

Addition	O
of	O
synthetic	O
tyrosine	O
-	O
phosphorylated	O
peptides	O
derived	O
from	O
betac	O
cytoplasmic	O
tyrosines	O
prior	O
to	O
GM	B-GENE
-	I-GENE
CSF	I-GENE
stimulation	O
inhibited	O
the	O
in	O
vitro	O
activation	O
of	O
STAT5	B-GENE
.	O

MAIN	O
OUTCOME	O
MEASURES	O
:	O
Percentage	O
change	O
in	O
the	O
apnea	O
-	O
hypopnea	O
index	O
(	O
AHI	O
;	O
apnea	O
events	O
+	O
hypopnea	O
events	O
per	O
hour	O
of	O
sleep	O
)	O
and	O
odds	O
of	O
developing	O
moderate	O
-	O
to	O
-	O
severe	O
SDB	O
(	O
defined	O
by	O
an	O
AHI	O
>	O
or	O
=	O
15	O
events	O
per	O
hour	O
of	O
sleep	O
)	O
,	O
with	O
respect	O
to	O
change	O
in	O
weight	O
.	O

Paraneoplastic	O
rheumatic	O
syndromes	O
.	O

This	O
article	O
reviews	O
recent	O
information	O
on	O
the	O
frequency	O
,	O
characteristics	O
,	O
and	O
possible	O
pathogenic	O
mechanisms	O
of	O
the	O
vasculitides	O
occurring	O
in	O
patients	O
with	O
the	O
main	O
connective	O
tissue	O
diseases	O
.	O

Tec	B-GENE
kinase	I-GENE
signaling	O
in	O
T	O
cells	O
is	O
regulated	O
by	O
phosphatidylinositol	B-GENE
3	I-GENE
-	I-GENE
kinase	I-GENE
and	O
the	O
Tec	B-GENE
pleckstrin	B-GENE
homology	I-GENE
domain	I-GENE
.	O

Current	O
evidence	O
for	O
this	O
type	O
of	O
DNA	O
supercoiling	O
-	O
dependent	O
transcriptional	O
coupling	O
,	O
based	O
largely	O
on	O
the	O
in	O
vivo	O
activities	O
of	O
promoters	O
contained	O
in	O
engineered	O
DNA	O
constructs	O
,	O
suggests	O
that	O
the	O
transcription	O
complex	O
must	O
be	O
physically	O
hindered	O
to	O
generate	O
DNA	O
supercoils	O
and	O
to	O
prevent	O
their	O
diffusion	O
throughout	O
the	O
DNA	O
duplex	O
.	O

The	O
structure	O
of	O
the	O
free	O
SH2	B-GENE
domain	I-GENE
has	O
been	O
compared	O
to	O
that	O
of	O
the	O
SH2	B-GENE
complexed	O
with	O
a	O
doubly	O
phosphorylated	O
peptide	O
derived	O
from	O
polyomavirus	B-GENE
middle	I-GENE
T	I-GENE
antigen	I-GENE
(	O
MT	B-GENE
)	O
.	O

We	O
have	O
identified	O
three	O
binding	O
sites	O
for	O
protein	O
complexes	O
:	O
a	O
palindrome	O
,	O
a	O
direct	O
repeat	O
,	O
and	O
a	O
C	O
+	O
T	O
sequence	O
that	O
corresponds	O
to	O
seven	O
GAGA	O
motifs	O
on	O
the	O
transcribed	O
strand	O
.	O

Copyright	O
2000	O
Academic	O
Press	O
.	O

Patients	O
underwent	O
pretreatment	O
cystoscopy	O
and	O
detailed	O
tumor	O
mapping	O
,	O
and	O
were	O
treated	O
with	O
75	O
mg	O
.	O
/	O
m	O
.	O
2	O
cisplatin	O
on	O
day	O
1	O
and	O
1	O
gm	O
.	O
/	O
m	O
.	O
2	O
daily	O
,	O
5	O
-	O
fluorouracil	O
on	O
days	O
1	O
to	O
4	O
and	O
definitive	O
radiotherapy	O
.	O

All	O
9	O
untreated	O
patients	O
underwent	O
laparoscopy	O
,	O
which	O
identified	O
3	O
intra	O
-	O
abdominal	O
,	O
3	O
vanished	O
and	O
2	O
peeping	O
testes	O
,	O
and	O
1	O
atrophic	O
testis	O
in	O
the	O
inguinal	O
canal	O
.	O

This	O
philosophy	O
was	O
instituted	O
for	O
the	O
compound	O
RP	O
73401	O
,	O
a	O
specific	O
phosphodiesterase	B-GENE
IV	I-GENE
inhibitor	O
,	O
that	O
was	O
being	O
developed	O
simultaneously	O
for	O
delivery	O
by	O
both	O
oral	O
and	O
pulmonary	O
routes	O
of	O
administration	O
.	O

Increased	O
levels	O
of	O
anticardiolipin	B-GENE
immunoglobulin	I-GENE
G	I-GENE
may	O
also	O
cause	O
bleeding	O
.	O

RESULTS	O
:	O
Prevalence	O
of	O
obesity	O
(	O
BMI	O
SDS	O
>	O
2	O
.	O
0	O
)	O
was	O
<	O
2	O
%	O
at	O
diagnosis	O
,	O
but	O
increased	O
to	O
16	O
%	O
at	O
3y	O
.	O

One	O
of	O
the	O
sequelae	O
of	O
the	O
antiphospholipid	O
-	O
antibodies	O
is	O
an	O
impaired	O
uteroplacental	O
circulation	O
.	O

Bupropion	O
to	O
aid	O
smoking	O
cessation	O
.	O

Using	O
a	O
natural	O
dominant	O
negative	O
for	O
AP	B-GENE
-	I-GENE
1	I-GENE
transcriptional	O
activity	O
in	O
ROS	O
17	O
/	O
2	O
.	O
8	O
cells	O
,	O
we	O
then	O
showed	O
that	O
AP	B-GENE
-	I-GENE
1	I-GENE
transcription	I-GENE
factors	I-GENE
mediated	O
TGF	B-GENE
-	I-GENE
beta1	I-GENE
-	O
and	O
BMP	B-GENE
-	I-GENE
2	I-GENE
-	O
regulated	O
expression	O
of	O
the	O
(	B-GENE
alpha1	I-GENE
)	I-GENE
collagen	I-GENE
I	I-GENE
gene	I-GENE
as	O
well	O
as	O
TGF	B-GENE
-	I-GENE
beta1	I-GENE
-	O
regulated	O
expression	O
of	O
the	O
parathyroid	B-GENE
hormone	I-GENE
(	O
PTH	B-GENE
)	O
/	O
PTH	B-GENE
-	I-GENE
related	I-GENE
peptide	I-GENE
(	I-GENE
PTHrP	I-GENE
)	I-GENE
receptor	I-GENE
.	O

PM	O
12	O
or	O
18	O
mg	O
/	O
kg	O
daily	O
plus	O
a	O
standard	O
dose	O
of	O
SB	O
for	O
21	O
days	O
was	O
statistically	O
more	O
effective	O
than	O
SB	O
in	O
producing	O
a	O
final	O
cure	O
for	O
patients	O
with	O
VL	O
in	O
Bihar	O
,	O
India	O
.	O

There	O
were	O
significant	O
differences	O
(	O
p	O
<	O
0	O
.	O
05	O
)	O
between	O
the	O
fracture	O
and	O
nonfracture	O
groups	O
in	O
the	O
total	O
femur	O
BMD	O
(	O
13	O
%	O
)	O
,	O
trabecular	O
BMD	O
in	O
the	O
distal	O
radius	O
(	O
4	O
%	O
)	O
,	O
and	O
the	O
fractal	O
dimension	O
in	O
the	O
radiographs	O
(	O
FD2	O
)	O
(	O
3	O
%	O
)	O
.	O

BACKGROUND	O
:	O
The	O
aim	O
of	O
this	O
study	O
was	O
to	O
determine	O
and	O
compare	O
interleukin	B-GENE
-	I-GENE
6	I-GENE
(	O
IL	B-GENE
-	I-GENE
6	I-GENE
)	O
levels	O
in	O
gingival	O
crevicular	O
fluid	O
(	O
GCF	O
)	O
and	O
clinical	O
periodontal	O
findings	O
in	O
patients	O
with	O
rheumatoid	O
arthritis	O
(	O
RA	O
)	O
and	O
adult	O
periodontitis	O
(	O
AP	O
)	O
.	O

In	O
a	O
prospective	O
,	O
multicentre	O
trial	O
the	O
efficacy	O
of	O
an	O
Vitex	O
agnus	O
castus	O
L	O
extract	O
Ze	O
440	O
was	O
investigated	O
in	O
50	O
patients	O
with	O
pre	O
-	O
menstrual	O
syndrome	O
(	O
PMS	O
)	O
.	O

Studies	O
are	O
necessary	O
to	O
assess	O
the	O
source	O
of	O
contamination	O
and	O
potential	O
role	O
of	O
MRSA	O
-	O
contaminated	O
milk	O
in	O
the	O
transmission	O
of	O
MRSA	O
to	O
neonates	O
.	O

Depending	O
on	O
treatment	O
exposures	O
,	O
this	O
at	O
-	O
risk	O
population	O
may	O
experience	O
life	O
-	O
threatening	O
late	O
effects	O
,	O
such	O
as	O
cirrhosis	O
secondary	O
to	O
hepatitis	O
C	O
or	O
late	O
-	O
onset	O
anthracycline	O
-	O
induced	O
cardiomyopathy	O
,	O
or	O
life	O
-	O
changing	O
late	O
effects	O
,	O
such	O
as	O
cognitive	O
dysfunction	O
.	O

The	O
presence	O
of	O
locus	O
-	O
specific	O
residues	O
throughout	O
the	O
entire	O
promoter	O
region	O
strongly	O
suggests	O
that	O
the	O
various	O
HLA	B-GENE
class	I-GENE
I	I-GENE
loci	I-GENE
are	O
differentially	O
regulated	O
.	O

Because	O
the	O
number	O
of	O
parameters	O
required	O
by	O
a	O
Volterra	O
series	O
grows	O
rapidly	O
with	O
both	O
the	O
length	O
of	O
its	O
memory	O
and	O
the	O
order	O
of	O
its	O
nonlinearity	O
,	O
methods	O
for	O
identifying	O
these	O
models	O
from	O
measurements	O
of	O
input	O
/	O
output	O
data	O
are	O
limited	O
to	O
low	O
-	O
order	O
systems	O
with	O
relatively	O
short	O
memories	O
.	O

The	O
standard	O
method	O
for	O
calculating	O
the	O
composite	O
score	O
on	O
the	O
S	O
-	O
B	O
IV	O
excludes	O
subtests	O
with	O
a	O
raw	O
score	O
of	O
0	O
,	O
which	O
overestimates	O
cognitive	O
functioning	O
in	O
young	O
biologically	O
high	O
risk	O
children	O
.	O

NiCl	O
(	O
2	O
)	O
-	O
induced	O
MCP	B-GENE
-	I-GENE
1	I-GENE
synthesis	O
required	O
activation	O
of	O
NF	B-GENE
-	I-GENE
kappaB	I-GENE
since	O
mutation	O
of	O
NF	B-GENE
-	I-GENE
kappaB	I-GENE
-	I-GENE
binding	I-GENE
sites	I-GENE
in	O
the	O
promoter	O
resulted	O
in	O
complete	O
loss	O
of	O
inducible	O
promoter	O
activity	O
.	O

Engagement	O
of	O
human	B-GENE
CD2	I-GENE
by	O
mitogenic	O
pairs	O
of	O
anti	B-GENE
-	I-GENE
CD2	I-GENE
mAb	I-GENE
induces	O
tyrosine	O
phosphorylation	O
of	O
a	O
number	O
of	O
intracellular	O
proteins	O
including	O
a	O
120	O
kDa	O
phosphoprotein	O
that	O
we	O
identify	O
as	O
the	O
proto	B-GENE
-	I-GENE
oncogene	I-GENE
c	I-GENE
-	I-GENE
Cbl	I-GENE
.	O

Validity	O
of	O
NIR	O
spectroscopy	O
for	O
quantitatively	O
measuring	O
muscle	O
oxidative	O
metabolic	O
rate	O
in	O
exercise	O
.	O

Previous	O
studies	O
have	O
demonstrated	O
that	O
tissue	O
-	O
restricted	O
transcription	O
factors	O
including	O
PU	B-GENE
.	I-GENE
1	I-GENE
and	O
PU	B-GENE
.	I-GENE
1	I-GENE
interaction	I-GENE
partner	I-GENE
(	O
PIP	B-GENE
)	O
function	O
synergistically	O
with	O
c	B-GENE
-	I-GENE
Fos	I-GENE
plus	O
c	B-GENE
-	I-GENE
Jun	I-GENE
to	O
stimulate	O
the	O
kappaE3	B-GENE
'	I-GENE
-	I-GENE
enhancer	I-GENE
in	O
3T3	O
cells	O
.	O

The	O
murine	B-GENE
int	I-GENE
-	I-GENE
6	I-GENE
locus	I-GENE
,	O
identified	O
as	O
a	O
frequent	O
integration	O
site	O
of	O
mouse	O
mammary	O
tumor	O
viruses	O
,	O
encodes	O
the	O
48	B-GENE
-	I-GENE
kDa	I-GENE
eIF3e	I-GENE
subunit	I-GENE
of	I-GENE
translation	I-GENE
initiation	I-GENE
factor	I-GENE
eIF3	I-GENE
.	O

An	O
int6	B-GENE
deletion	I-GENE
(	O
int6Delta	B-GENE
)	O
mutant	O
was	O
viable	O
but	O
grew	O
slowly	O
in	O
minimal	O
medium	O
.	O

We	O
produced	O
transgenic	O
plants	O
expressing	O
the	O
antisense	B-GENE
Arabidopsis	I-GENE
HD	I-GENE
(	O
AtHD1	B-GENE
)	O
gene	O
.	O

Four	O
transcription	O
initiation	O
sites	O
have	O
been	O
identified	O
by	O
full	O
-	O
length	O
RNA	B-GENE
ligase	I-GENE
-	O
mediated	O
rapid	O
amplification	O
of	O
cDNA	O
ends	O
(	O
RLM	O
-	O
RACE	O
)	O
between	O
-	O
61	O
and	O
-	O
32	O
bp	O
from	O
the	O
translation	O
initiation	O
codon	O
.	O
Reverse	O
transcription	O
-	O
PCR	O
analysis	O
revealed	O
that	O
PFK	B-GENE
-	I-GENE
A	I-GENE
,	O
PFK	B-GENE
-	I-GENE
B	I-GENE
and	O
PFK	B-GENE
-	I-GENE
C	I-GENE
genes	I-GENE
were	O
expressed	O
,	O
in	O
all	O
mouse	O
tissues	O
tested	O
,	O
at	O
varying	O
levels	O
.	O

PFK	B-GENE
-	I-GENE
A	I-GENE
mRNA	O
was	O
more	O
abundantly	O
expressed	O
in	O
all	O
tissues	O
than	O
were	O
the	O
PFK	B-GENE
-	I-GENE
B	I-GENE
and	O
PFK	B-GENE
-	I-GENE
C	I-GENE
genes	I-GENE
.	O

We	O
used	O
the	O
Toshiba	O
IIDR	O
system	O
,	O
which	O
is	O
composed	O
of	O
an	O
X	O
-	O
ray	O
TV	O
system	O
and	O
a	O
digital	O
image	O
managing	O
circuit	O
.	O

In	O
whole	O
sardine	O
,	O
domoic	O
acid	O
was	O
detected	O
in	O
levels	O
exceeding	O
sometimes	O
the	O
regulatory	O
limit	O
.	O

Closeup	O
:	O
a	O
resource	O
for	O
nurses	O
who	O
smoke	O
.	O

[	O
18F	O
]	O
(	O
+	O
)	O
-	O
4	O
-	O
fluorobenzyltrozamicol	O
(	O
FBT	O
)	O
,	O
which	O
selectively	O
binds	O
to	O
the	O
vesicular	O
acetylcholine	B-GENE
transporter	I-GENE
in	O
the	O
presynaptic	O
cholinergic	O
neuron	O
,	O
has	O
previously	O
been	O
shown	O
to	O
be	O
a	O
useful	O
ligand	O
for	O
the	O
study	O
of	O
cholinergic	O
terminal	O
density	O
in	O
the	O
basal	O
ganglia	O
with	O
PET	O
.	O

We	O
demonstrate	O
that	O
the	O
protein	O
is	O
a	O
murine	B-GENE
homologue	I-GENE
of	I-GENE
SAF	I-GENE
-	I-GENE
A	I-GENE
which	O
has	O
been	O
shown	O
to	O
bind	O
selectively	O
to	O
MARs	O
and	O
is	O
responsible	O
for	O
the	O
satMa	B-GENE
-	O
binding	O
activity	O
in	O
the	O
chromatographic	O
fractions	O
.	O

The	O
molecular	O
associations	O
dictating	O
INCENP	B-GENE
behavior	O
during	O
mitosis	O
are	O
currently	O
unknown	O
.	O

Ang	B-GENE
II	I-GENE
significantly	O
induced	O
Ang2	B-GENE
mRNA	I-GENE
accumulations	O
without	O
affecting	O
Ang1	B-GENE
or	O
Tie2	B-GENE
expression	O
,	O
which	O
was	O
inhibited	O
by	O
protein	B-GENE
kinase	I-GENE
C	I-GENE
inhibitors	O
and	O
by	O
intracellular	O
Ca	O
(	O
2	O
+	O
)	O
chelating	O
agents	O
.	O

Promoter	O
analysis	O
demonstrated	O
that	O
the	O
sequence	O
identical	O
to	O
consensus	O
cAMP	O
-	O
responsive	O
element	O
(	O
CRE	O
)	O
located	O
at	O
-	O
481	O
of	O
the	O
SMemb	B-GENE
promoter	I-GENE
was	O
critical	O
for	O
Hex	B-GENE
responsiveness	O
.	O

LH	B-GENE
/	I-GENE
CG	I-GENE
receptor	I-GENE
activation	O
of	O
ARNO	B-GENE
is	O
not	O
mediated	O
by	O
activation	O
of	O
phosphatidylinositol	B-GENE
3	I-GENE
-	I-GENE
kinase	I-GENE
(	O
PI	B-GENE
3	I-GENE
-	I-GENE
kinase	I-GENE
)	O
or	O
by	O
G	B-GENE
protein	I-GENE
beta	I-GENE
gamma	I-GENE
subunits	I-GENE
.	O

Deletion	O
analysis	O
showed	O
that	O
the	O
-	O
321	O
/	O
+	O
41	O
sequence	O
was	O
sufficient	O
for	O
both	O
the	O
constitutive	O
promoter	O
activity	O
and	O
auto	O
-	O
activation	O
and	O
electrophoretic	O
mobility	O
shift	O
assays	O
identified	O
the	O
interaction	O
of	O
C	B-GENE
/	I-GENE
EBPs	I-GENE
and	O
Sp1	B-GENE
to	O
this	O
region	O
.	O

Termination	O
of	O
induced	O
VT	O
on	O
the	O
first	O
attempt	O
was	O
comparable	O
with	O
BV	O
pacing	O
(	O
87	O
.	O
4	O
%	O
)	O
versus	O
RV	O
pacing	O
(	O
89	O
.	O
6	O
%	O
)	O
.	O

We	O
compare	O
the	O
results	O
of	O
this	O
algorithm	O
with	O
the	O
results	O
obtained	O
with	O
two	O
other	O
algorithms	O
,	O
the	O
optimal	O
algorithm	O
for	O
monochannel	O
nonoverlapping	O
noise	O
and	O
the	O
optimal	O
algorithm	O
for	O
multichannel	O
additive	O
noise	O
,	O
and	O
we	O
show	O
that	O
in	O
both	O
cases	O
improvement	O
can	O
be	O
obtained	O
.	O

Changes	O
in	O
stimulation	O
levels	O
over	O
time	O
in	O
nucleus	O
22	O
cochlear	O
implant	O
users	O
.	O

A	O
marked	O
decrease	O
in	O
the	O
type	B-GENE
1	I-GENE
insulin	I-GENE
-	I-GENE
like	I-GENE
growth	I-GENE
factor	I-GENE
(	I-GENE
IGF	I-GENE
)	I-GENE
receptor	I-GENE
(	O
IGF	B-GENE
-	I-GENE
IR	I-GENE
)	O
occurs	O
in	O
prostate	O
epithelial	O
cells	O
during	O
transformation	O
from	O
the	O
benign	O
to	O
the	O
metastatic	O
state	O
.	O

The	O
P69	O
cell	O
line	O
was	O
derived	O
by	O
immortalization	O
of	O
human	O
primary	O
prostate	O
epithelial	O
cells	O
with	O
simian	B-GENE
virus	I-GENE
-	I-GENE
40	I-GENE
T	I-GENE
antigen	I-GENE
and	O
is	O
rarely	O
tumorigenic	O
.	O

We	O
determined	O
whether	O
the	O
human	B-GENE
StAR	I-GENE
promoter	I-GENE
is	O
responsive	O
to	O
sterol	B-GENE
regulatory	I-GENE
element	I-GENE
-	I-GENE
binding	I-GENE
proteins	I-GENE
(	O
SREBPs	B-GENE
)	O
.	O

Expression	O
of	O
SREBP	B-GENE
-	I-GENE
1a	I-GENE
stimulated	O
StAR	B-GENE
promoter	I-GENE
activity	O
in	O
the	O
context	O
of	O
COS	O
-	O
1	O
cells	O
and	O
human	O
granulosa	O
-	O
lutein	O
cells	O
.	O

Because	O
the	O
high	B-GENE
-	I-GENE
density	I-GENE
lipoprotein	I-GENE
receptor	I-GENE
(	O
HDL	B-GENE
-	I-GENE
R	I-GENE
)	O
is	O
a	O
key	O
element	O
in	O
cholesterol	O
homeostasis	O
and	O
a	O
potential	O
therapeutic	O
target	O
for	O
hypercholesterolemic	O
drugs	O
,	O
an	O
understanding	O
of	O
HDL	B-GENE
-	I-GENE
R	I-GENE
regulation	O
is	O
essential	O
.	O

IFN	B-GENE
-	I-GENE
stimulated	I-GENE
gene	I-GENE
factor	I-GENE
-	I-GENE
3	I-GENE
and	O
STAT1	B-GENE
homodimers	I-GENE
formed	O
and	O
bound	O
an	O
IFN	B-GENE
-	I-GENE
stimulated	I-GENE
response	I-GENE
element	I-GENE
(	O
ISRE	B-GENE
)	O
and	O
gamma	B-GENE
-	I-GENE
activated	I-GENE
sequence	I-GENE
(	O
GAS	B-GENE
)	O
element	O
,	O
respectively	O
.	O

We	O
have	O
therefore	O
studied	O
the	O
molecular	O
mechanisms	O
of	O
TGF	B-GENE
-	I-GENE
beta1	I-GENE
action	O
on	O
thyroglobulin	B-GENE
(	O
TG	B-GENE
)	O
gene	O
expression	O
by	O
focusing	O
our	O
attention	O
on	O
TGF	B-GENE
-	I-GENE
beta1	I-GENE
regulation	O
of	O
thyroid	O
-	O
specific	O
transcription	O
factors	O
.	O

The	O
epitope	O
-	O
protected	O
lysine	O
(	O
K	O
)	O
was	O
present	O
in	O
a	O
30	B-GENE
-	I-GENE
aa	I-GENE
TPO	I-GENE
fragment	I-GENE
that	O
,	O
by	O
N	O
-	O
terminal	O
sequencing	O
,	O
was	O
found	O
to	O
be	O
K713	O
.	O

To	O
understand	O
the	O
molecular	O
regulation	O
of	O
these	O
genes	O
in	O
thyroid	O
cells	O
,	O
the	O
effect	O
of	O
thyroid	B-GENE
transcription	I-GENE
factor	I-GENE
1	I-GENE
(	O
TTF	B-GENE
-	I-GENE
1	I-GENE
)	O
and	O
the	O
paired	B-GENE
domain	I-GENE
-	I-GENE
containing	I-GENE
protein	I-GENE
8	I-GENE
(	O
Pax	B-GENE
-	I-GENE
8	I-GENE
)	O
on	O
the	O
transcriptional	O
activity	O
of	O
the	O
deiodinase	B-GENE
promoters	I-GENE
were	O
studied	O
.	O

Regional	O
blood	O
blow	O
was	O
measured	O
by	O
means	O
of	O
microspheres	O
in	O
predefined	O
regions	O
of	O
the	O
C6	O
,	O
T11	O
,	O
and	O
L6	O
vertebrae	O
.	O

Activation	O
of	O
transcription	O
through	O
the	O
AP	B-GENE
-	I-GENE
1	I-GENE
site	I-GENE
in	O
Jurkat	O
cells	O
by	O
JunD	B-GENE
and	O
/	O
or	O
Fra	B-GENE
-	I-GENE
2	I-GENE
was	O
weak	O
.	O
c	B-GENE
-	I-GENE
Jun	I-GENE
,	O
JunB	B-GENE
,	O
and	O
c	B-GENE
-	I-GENE
Fos	I-GENE
activation	O
was	O
greater	O
,	O
although	O
the	O
level	O
was	O
still	O
less	O
than	O
that	O
with	O
Tax	B-GENE
.	O

The	O
mechanism	O
of	O
ligand	O
-	O
activated	O
estrogen	B-GENE
receptor	I-GENE
alpha	I-GENE
(	O
ERalpha	B-GENE
)	O
-	O
dependent	O
activation	O
of	O
gene	O
expression	O
through	O
the	O
SRE	O
was	O
determined	O
by	O
mutational	O
analysis	O
of	O
the	O
promoter	O
,	O
analysis	O
of	O
mitogen	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
kinase	I-GENE
(	O
MAPK	B-GENE
)	O
pathway	O
activation	O
by	O
E2	O
,	O
and	O
transforming	B-GENE
growth	I-GENE
factor	I-GENE
alpha	I-GENE
(	O
TGF	B-GENE
-	I-GENE
alpha	I-GENE
)	O
as	O
a	O
positive	O
control	O
.	O

CONCLUSIONS	O
:	O
Under	O
current	O
immunization	O
practices	O
,	O
the	O
authors	O
estimate	O
that	O
nearly	O
13	O
,	O
000	O
Asian	O
and	O
Pacific	O
Islander	O
children	O
living	O
in	O
the	O
United	O
States	O
today	O
will	O
become	O
infected	O
with	O
HBV	O
in	O
the	O
future	O
,	O
resulting	O
in	O
more	O
than	O
600	O
liver	O
carcinoma	O
deaths	O
.	O

We	O
observed	O
NP	B-GENE
/	O
NMP4	B-GENE
/	O
CIZ	B-GENE
expression	O
in	O
osteocytes	O
,	O
osteoblasts	O
,	O
and	O
chondrocytes	O
in	O
rat	O
bone	O
.	O

Chlamydia	O
and	O
cervical	O
cancer	O
:	O
a	O
real	O
association	O
?	O

A	O
novel	O
approach	O
was	O
developed	O
for	O
identifying	O
transcription	O
factor	O
activities	O
associated	O
with	O
NGF	B-GENE
-	O
activated	O
,	O
but	O
not	O
EGF	B-GENE
-	O
activated	O
,	O
signaling	O
,	O
using	O
random	O
oligonucleotide	O
clones	O
from	O
a	O
DNA	O
recognition	O
library	O
to	O
isolate	O
specific	O
DNA	O
binding	O
proteins	O
from	O
PC12	O
nuclear	O
extracts	O
.	O

NGF	B-GENE
elicits	O
a	O
more	O
delayed	O
and	O
sustained	O
ERK	B-GENE
phosphorylation	O
than	O
EGF	B-GENE
,	O
consistent	O
with	O
previous	O
reports	O
.	O

NGF	B-GENE
,	O
but	O
not	O
EGF	B-GENE
,	O
enhances	O
the	O
upper	O
bands	O
,	O
corresponding	O
to	O
phosphorylated	B-GENE
Fra	I-GENE
-	I-GENE
2	I-GENE
.	O

The	O
actA	B-GENE
gene	I-GENE
is	O
present	O
as	O
a	O
single	O
copy	O
in	O
the	O
genome	O
of	O
A	O
.	O
chrysogenum	O
;	O
and	O
its	O
expression	O
level	O
,	O
opposite	O
to	O
pcbC	B-GENE
and	O
cefEF	B-GENE
cephalosporin	I-GENE
biosynthetic	I-GENE
genes	I-GENE
,	O
was	O
steady	O
during	O
cephalosporin	O
fermentation	O
,	O
showing	O
a	O
single	O
1	O
.	O
4	O
-	O
kb	O
transcript	O
.	O

Adding	O
10	O
mmol	O
SDS	O
/	O
l	O
led	O
to	O
transient	O
inhibition	O
of	O
acidification	O
,	O
metal	O
solubilization	O
and	O
sulfur	O
oxidation	O
.	O

We	O
have	O
investigated	O
the	O
role	O
of	O
NGF	B-GENE
in	O
regulating	O
gene	O
transcription	O
in	O
PC12	O
and	O
INS	O
-	O
1	O
cells	O
,	O
in	O
order	O
to	O
define	O
if	O
there	O
are	O
NGF	B-GENE
-	O
regulated	O
genes	O
per	O
se	O
.	O

Nine	O
animals	O
served	O
as	O
control	O
animals	O
,	O
whereas	O
20	O
animals	O
received	O
a	O
focal	O
arachnoid	O
scar	O
at	O
C1	O
-	O
C2	O
,	O
which	O
was	O
produced	O
by	O
placement	O
of	O
a	O
kaolin	O
-	O
soaked	O
fibrin	B-GENE
sponge	O
on	O
the	O
posterior	O
surface	O
of	O
the	O
spinal	O
cord	O
.	O

The	O
Schistosoma	B-GENE
mansoni	I-GENE
homologue	I-GENE
(	O
SmSmad2	B-GENE
)	O
was	O
overexpressed	O
in	O
bacteria	O
as	O
a	O
Sj26	B-GENE
-	O
GST	B-GENE
fusion	O
protein	O
and	O
used	O
to	O
raise	O
specific	O
antibodies	O
.	O

These	O
data	O
indicate	O
that	O
the	O
SmSmad2	B-GENE
responds	O
to	O
the	O
TGF	B-GENE
-	I-GENE
beta	I-GENE
signals	O
by	O
interaction	O
with	O
receptor	B-GENE
I	I-GENE
,	O
which	O
phosphorylates	O
it	O
,	O
whereupon	O
it	O
translocates	O
into	O
the	O
nucleus	O
presumably	O
to	O
regulate	O
target	O
gene	O
transcription	O
and	O
consequently	O
elicit	O
a	O
specific	O
TGF	B-GENE
-	I-GENE
beta	I-GENE
effect	O
.	O

Intact	O
Flag	O
-	O
tagged	O
protein	O
products	O
from	O
all	O
six	O
were	O
produced	O
from	O
genomic	O
expression	O
vectors	O
,	O
although	O
the	O
ORF40	O
/	O
41	O
transcript	O
encoding	O
a	O
primase	B-GENE
-	O
helicase	B-GENE
component	O
proved	O
to	O
be	O
spliced	O
with	O
a	O
127	O
-	O
bp	O
intron	O
.	O

Expression	O
of	O
the	O
src	B-GENE
homology	I-GENE
3	I-GENE
(	O
SH3	B-GENE
)	O
-	O
encoding	O
,	O
expressed	O
in	O
tumorigenic	O
astrocytes	O
(	O
SETA	B-GENE
)	O
gene	O
is	O
associated	O
with	O
astrocyte	O
transformation	O
in	O
culture	O
and	O
tumors	O
in	O
the	O
adult	O
brain	O
.	O

METHODS	O
:	O
One	O
hundred	O
fourteen	O
consecutive	O
patients	O
(	O
mean	O
age	O
61	O
years	O
)	O
with	O
focal	O
pancreatic	O
masses	O
,	O
detected	O
on	O
CT	O
,	O
underwent	O
EUS	O
-	O
FNA	O
by	O
using	O
a	O
linear	O
-	O
array	O
echoendoscope	O
and	O
22	O
-	O
gauge	O
needles	O
.	O

METHODS	O
:	O
Thyroid	O
status	O
was	O
measured	O
at	O
baseline	O
(	O
1990	O
-	O
93	O
)	O
,	O
through	O
assessment	O
of	O
serum	O
antibodies	O
to	O
thyroid	B-GENE
peroxidase	I-GENE
(	O
TPO	B-GENE
-	I-GENE
Abs	I-GENE
,	O
positive	O
:	O
>	O
10	O
IU	O
/	O
ml	O
)	O
,	O
serum	B-GENE
TSH	I-GENE
levels	O
,	O
and	O
when	O
TSH	B-GENE
was	O
abnormal	O
(	O
<	O
0	O
.	O
4	O
or	O
>	O
4	O
.	O
0	O
mU	O
/	O
l	O
)	O
,	O
serum	B-GENE
thyroxin	I-GENE
levels	O
(	O
T4	O
)	O
.	O

We	O
suggest	O
that	O
ventriculopleural	O
shunting	O
should	O
be	O
considered	O
as	O
the	O
preferred	O
alternative	O
to	O
peritoneal	O
drainage	O
in	O
children	O
with	O
intra	O
-	O
abdominal	O
adhesions	O
or	O
with	O
a	O
history	O
of	O
recent	O
peritoneal	O
infection	O
.	O

TBARS	O
levels	O
,	O
oxygen	O
-	O
radical	O
absorbing	O
capacity	O
assay	O
and	O
AFR	O
release	O
assessed	O
by	O
electron	O
paramagnetic	O
resonance	O
(	O
EPR	O
)	O
were	O
used	O
to	O
explore	O
the	O
existence	O
of	O
oxidative	O
stress	O
in	O
diabetes	O
.	O

Long	O
-	O
range	O
comparison	O
of	O
human	B-GENE
and	I-GENE
mouse	I-GENE
SCL	I-GENE
loci	I-GENE
:	O
localized	O
regions	O
of	O
sensitivity	O
to	O
restriction	O
endonucleases	O
correspond	O
precisely	O
with	O
peaks	O
of	O
conserved	O
noncoding	O
sequences	O
.	O

To	O
account	O
for	O
this	O
observation	O
,	O
other	O
possible	O
causes	O
include	O
increased	O
CSF	O
pulsation	O
in	O
children	O
creating	O
motion	O
artifact	O
,	O
changes	O
in	O
arterial	O
oxygen	O
concentration	O
intrinsic	O
to	O
propofol	O
or	O
related	O
to	O
the	O
supplemental	O
oxygen	O
normally	O
administered	O
,	O
or	O
changes	O
in	O
CSF	O
protein	O
levels	O
related	O
to	O
propofol	O
binding	O
to	O
proteins	O
for	O
uptake	O
into	O
CSF	O
.	O

The	O
utilities	O
measured	O
in	O
our	O
study	O
can	O
be	O
applied	O
directly	O
to	O
quality	O
-	O
of	O
-	O
life	O
determinations	O
in	O
clinical	O
trials	O
of	O
adjuvant	O
IFN	B-GENE
alpha	I-GENE
-	I-GENE
2b	I-GENE
to	O
measure	O
the	O
net	O
benefit	O
of	O
therapy	O
.	O

Serum	B-GENE
PTH	I-GENE
tended	O
to	O
increase	O
in	O
the	O
WL	O
group	O
but	O
not	O
in	O
the	O
WM	O
group	O
(	O
P	O
<	O
0	O
.	O
06	O
)	O
.	O

Structure	O
of	O
the	O
EMAPII	B-GENE
domain	I-GENE
of	O
human	B-GENE
aminoacyl	I-GENE
-	I-GENE
tRNA	I-GENE
synthetase	I-GENE
complex	I-GENE
reveals	O
evolutionary	O
dimer	O
mimicry	O
.	O

METHODS	O
:	O
The	O
passive	O
and	O
active	O
transport	O
of	O
fluorescein	O
through	O
the	O
BRB	O
was	O
quantitated	O
by	O
vitreous	O
fluorometry	O
.	O

Nerve	B-GENE
growth	I-GENE
factor	I-GENE
(	O
NGF	B-GENE
)	O
and	O
retinoic	O
acid	O
(	O
RA	O
)	O
exert	O
important	O
actions	O
on	O
PC12	O
cells	O
.	O

The	O
region	O
containing	O
both	O
serines	O
is	O
homologous	O
to	O
the	O
N	O
-	O
terminal	O
destruction	O
box	O
of	O
IkappaBalpha	B-GENE
,	I-GENE
-	I-GENE
beta	I-GENE
,	I-GENE
and	I-GENE
-	I-GENE
epsilon	I-GENE
.	O

This	O
function	O
requires	O
not	O
only	O
the	O
kinase	O
domain	O
of	O
Csk	B-GENE
,	O
but	O
also	O
its	O
Src	B-GENE
homology	I-GENE
3	I-GENE
(	O
SH3	B-GENE
)	O
and	O
SH2	B-GENE
regions	O
.	O

Furthermore	O
,	O
we	O
showed	O
that	O
ERSF	B-GENE
including	O
NF	B-GENE
-	I-GENE
Y	I-GENE
and	O
ATF6alpha	B-GENE
and	I-GENE
/	I-GENE
or	I-GENE
beta	I-GENE
and	O
capable	O
of	O
binding	O
to	O
ERSE	O
is	O
indeed	O
formed	O
when	O
the	O
cellular	O
UPR	O
is	O
activated	O
.	O

These	O
effects	O
were	O
not	O
seen	O
with	O
SHIP2	B-GENE
possessing	O
a	O
mutation	O
in	O
the	O
SH2	B-GENE
domain	I-GENE
(	O
R47G	B-GENE
)	O
.	O

The	O
gonadotrope	O
-	O
specific	O
and	O
regulated	O
expression	O
of	O
the	O
GnRH	B-GENE
receptor	I-GENE
(	O
GnRH	B-GENE
-	I-GENE
R	I-GENE
)	O
gene	O
is	O
dependent	O
on	O
multiple	O
transcription	O
factors	O
that	O
interact	O
with	O
the	O
noncanonical	B-GENE
GnRH	I-GENE
-	I-GENE
R	I-GENE
activating	I-GENE
sequence	I-GENE
(	O
GRAS	B-GENE
)	O
,	O
the	O
activator	B-GENE
protein	I-GENE
-	I-GENE
1	I-GENE
(	O
AP	B-GENE
-	I-GENE
1	I-GENE
)	O
element	O
,	O
and	O
the	O
steroidogenic	B-GENE
factor	I-GENE
-	I-GENE
1	I-GENE
(	O
SF	B-GENE
-	I-GENE
1	I-GENE
)	O
binding	O
site	O
.	O

METHODS	O
:	O
A	O
structured	O
interview	O
was	O
undertaken	O
at	O
the	O
time	O
of	O
initial	O
consultation	O
and	O
at	O
subsequent	O
1	O
-	O
year	O
intervals	O
regarding	O
type	O
of	O
BHS	O
,	O
frequency	O
of	O
spells	O
,	O
associated	O
phenomenon	O
,	O
sequelae	O
,	O
family	O
history	O
,	O
and	O
age	O
at	O
termination	O
of	O
spells	O
.	O

In	O
three	O
cases	O
(	O
21	O
.	O
4	O
%	O
)	O
,	O
the	O
MR	O
imaging	O
was	O
interpreted	O
as	O
negative	O
,	O
but	O
microscopic	O
tumor	O
was	O
shown	O
around	O
seroma	O
on	O
reexcision	O
.	O

Methylation	O
at	O
both	O
cytosine	O
residues	O
in	O
the	O
E2F	B-GENE
element	O
(	O
(	O
m	O
)	O
CG	O
(	O
m	O
)	O
CG	O
)	O
generated	O
a	O
new	O
methylcytosine	O
-	O
specific	O
DNA	O
-	O
protein	O
complex	O
.	O

These	O
mutations	O
,	O
when	O
placed	O
in	O
a	O
wild	B-GENE
-	I-GENE
type	I-GENE
fliF	I-GENE
background	O
,	O
had	O
no	O
mutant	O
phenotype	O
.	O

As	O
well	O
,	O
IFN	B-GENE
-	I-GENE
gamma	I-GENE
-	O
induced	O
expression	O
of	O
IRF	B-GENE
-	I-GENE
1	I-GENE
and	O
its	O
binding	O
to	O
the	O
IRF	B-GENE
element	I-GENE
is	O
inhibited	O
.	O

This	O
molecule	O
,	O
wH22xeGFP	B-GENE
,	O
consists	O
of	O
the	O
entire	B-GENE
humanized	I-GENE
anti	I-GENE
-	I-GENE
FcgammaRI	I-GENE
mAb	I-GENE
H22	B-GENE
with	O
eGFP	B-GENE
genetically	O
fused	O
to	O
the	O
C	O
-	O
terminal	O
end	O
of	O
each	O
CH3	B-GENE
domain	I-GENE
.	O
wH22xeGFP	B-GENE
binds	O
within	O
the	O
ligand	O
-	O
binding	O
region	O
by	O
its	O
Fc	B-GENE
end	O
,	O
as	O
well	O
as	O
outside	O
the	O
ligand	O
-	O
binding	O
region	O
by	O
its	O
Fab	B-GENE
ends	O
,	O
thereby	O
cross	O
-	O
linking	O
FcgammaRI	B-GENE
.	O

This	O
interaction	O
is	O
reciprocal	O
,	O
since	O
C	B-GENE
/	I-GENE
EBP	I-GENE
dimer	I-GENE
binding	O
to	O
a	O
strong	O
C	B-GENE
/	I-GENE
EBP	I-GENE
site	I-GENE
leads	O
to	O
enhanced	O
CREB	B-GENE
-	I-GENE
1	I-GENE
recruitment	O
to	O
ATF	B-GENE
/	O
CREB	B-GENE
sites	O
that	O
are	O
weakly	O
bound	O
by	O
CREB	B-GENE
.	O

The	O
metabolic	O
events	O
occurring	O
at	O
or	O
near	O
that	O
structure	O
and	O
involving	O
cyclin	B-GENE
D3	I-GENE
cause	O
the	O
translocation	O
of	O
ICP0	B-GENE
to	O
the	O
cytoplasm	O
.	O

Transient	O
transfections	O
showed	O
that	O
a	O
single	O
mutation	O
(	O
556M	O
)	O
decreased	O
TBLV	B-GENE
enhancer	I-GENE
activity	O
at	O
least	O
20	O
-	O
fold	O
in	O
two	O
different	O
T	O
-	O
cell	O
lines	O
.	O

Vector	O
stocks	O
containing	O
envelope	B-GENE
proteins	I-GENE
from	O
three	O
different	O
SIVmac	O
clones	O
,	O
namely	O
,	O
SIVmac239	O
(	O
T	O
-	O
lymphocyte	O
tropic	O
[	O
T	O
-	O
tropic	O
]	O
)	O
,	O
SIVmac316	O
(	O
macrophage	O
tropic	O
[	O
M	O
-	O
tropic	O
]	O
)	O
,	O
and	O
SIVmac1A11	O
(	O
dualtropic	O
)	O
,	O
were	O
tested	O
.	O

Quantitative	O
PCR	O
studies	O
indicated	O
that	O
synthesis	O
and	O
transport	O
of	O
vector	O
DNA	O
into	O
the	O
nucleus	O
were	O
similar	O
for	O
macrophages	O
infected	O
with	O
the	O
clone	O
239	O
and	O
316	O
pseudotypes	O
,	O
suggesting	O
that	O
the	O
restriction	O
for	O
SIVmac239	O
infection	O
is	O
after	O
reverse	O
transcription	O
and	O
nuclear	O
import	O
of	O
viral	O
DNA	O
.	O

Thus	O
,	O
the	O
anti	B-GENE
-	I-GENE
interferon	I-GENE
functions	O
of	O
vIRF	B-GENE
-	I-GENE
2	I-GENE
may	O
contribute	O
to	O
the	O
establishment	O
of	O
a	O
chronic	O
or	O
latent	O
infection	O
.	O

Interestingly	O
,	O
the	O
activity	O
of	O
IkappaB	B-GENE
kinase	I-GENE
(	O
IKK	B-GENE
-	I-GENE
beta	I-GENE
)	O
,	O
which	O
plays	O
an	O
essential	O
role	O
in	O
NF	B-GENE
-	I-GENE
kappaB	I-GENE
activation	O
through	O
IkappaB	B-GENE
phosphorylation	O
,	O
was	O
largely	O
enhanced	O
in	O
paclitaxel	O
-	O
treated	O
cells	O
,	O
detected	O
as	O
IkappaBalpha	B-GENE
phosphorylation	O
.	O

We	O
propose	O
that	O
TFOs	O
represent	O
a	O
therapeutic	O
potential	O
to	O
specifically	O
diminish	O
the	O
expression	O
of	O
c	B-GENE
-	I-GENE
sis	I-GENE
/	O
PDGF	B-GENE
-	I-GENE
B	I-GENE
proto	O
-	O
oncogene	O
in	O
various	O
pathologic	O
settings	O
where	O
constitutive	O
expression	O
of	O
this	O
gene	O
has	O
been	O
observed	O
.	O

Rapid	O
evolution	O
of	O
the	O
DNA	O
-	O
binding	O
site	O
in	O
LAGLIDADG	B-GENE
homing	I-GENE
endonucleases	I-GENE
.	O

Copyright	O
2001	O
Academic	O
Press	O
.	O

Interestingly	O
,	O
the	O
similarities	O
with	O
the	O
endophilin	B-GENE
proteins	I-GENE
cover	O
the	O
entire	O
sequence	O
of	O
the	O
SH3GLB	B-GENE
family	I-GENE
,	O
suggesting	O
a	O
common	O
fold	O
and	O
presumably	O
a	O
common	O
mode	O
of	O
action	O
.	O

Mental	O
rotation	O
of	O
paired	O
figures	O
engendered	O
activation	O
in	O
the	O
left	O
superior	O
parietal	O
lobule	O
and	O
the	O
right	O
frontal	O
medial	O
gyrus	O
.	O

We	O
also	O
reported	O
the	O
identification	O
of	O
three	O
corresponding	O
alternative	O
first	O
exons	O
and	O
an	O
intronic	O
promoter	O
in	O
the	O
human	B-GENE
PDE5A	I-GENE
gene	I-GENE
.	O

The	O
glucose	O
/	O
insulin	B-GENE
stimulation	O
was	O
inhibited	O
by	O
the	O
addition	O
of	O
polyunsaturated	O
fatty	O
acids	O
.	O

In	O
the	O
present	O
work	O
,	O
the	O
complete	O
genome	O
sequences	O
of	O
Pyrococcus	O
horikoshii	O
and	O
Pyrococcus	O
abyssi	O
,	O
two	O
species	O
in	O
a	O
genus	O
of	O
hyperthermophilic	O
archaeon	O
(	O
archaebacterium	O
)	O
,	O
were	O
compared	O
to	O
detect	O
large	O
genome	O
polymorphisms	O
linked	O
with	O
restriction	O
-	O
modification	O
gene	O
homologs	O
.	O

This	O
animal	O
model	O
of	O
dystonia	O
appears	O
to	O
be	O
a	O
model	O
of	O
NAD	O
in	O
man	O
from	O
the	O
viewpoint	O
of	O
treatment	O
-	O
response	O
.	O

Peripheral	O
and	O
preemptive	O
opioid	O
antinociception	O
in	O
a	O
mouse	O
visceral	O
pain	O
model	O
.	O

Twenty	O
-	O
six	O
(	O
55	O
%	O
)	O
(	O
95	O
%	O
CI	O
,	O
41	O
-	O
69	O
%	O
)	O
patients	O
experienced	O
>	O
or	O
=	O
grade	O
3	O
acute	O
toxicity	O
(	O
RTOG	O
)	O
.	O

No	O
'	O
TATA	O
'	O
motif	O
was	O
identified	O
near	O
either	O
the	O
GABPalpha	B-GENE
or	O
ATPsynCF6	B-GENE
transcription	O
start	O
sites	O
.	O

Significantly	O
higher	O
lung	O
function	O
parameters	O
were	O
obtained	O
in	O
extubated	O
recipients	O
of	O
LPD	O
preserved	O
grafts	O
2	O
weeks	O
after	O
TX	O
.	O

Acquired	O
antithrombin	B-GENE
deficiency	O
in	O
sepsis	O
.	O

In	O
addition	O
,	O
we	O
have	O
isolated	O
a	O
genomic	O
fragment	O
containing	O
the	O
most	O
distal	O
5	O
'	O
sequences	O
of	O
the	O
major	O
GGT	B-GENE
mRNA	I-GENE
in	O
HepG2	O
cells	O
.	O

(	O
1997	O
)	O
Nature	O
387	O
,	O
370	O
-	O
376	O
)	O
]	O
,	O
we	O
suggest	O
that	O
the	O
metal	O
fluoride	O
ions	O
replaced	O
phosphate	O
at	O
the	O
two	O
ATP	O
-	O
binding	O
sites	O
of	O
the	O
iron	O
protein	O
,	O
Kp2	B-GENE
.	O

Expression	O
of	O
herpes	B-GENE
simplex	I-GENE
virus	I-GENE
type	I-GENE
2	I-GENE
US3	I-GENE
affects	O
the	O
Cdc42	B-GENE
/	O
Rac	B-GENE
pathway	O
and	O
attenuates	O
c	B-GENE
-	I-GENE
Jun	I-GENE
N	I-GENE
-	I-GENE
terminal	I-GENE
kinase	I-GENE
activation	O
.	O

If	O
you	O
think	O
education	O
is	O
expensive	O
-	O
-	O
try	O
ignorance	O
-	O
-	O
Bok	O
'	O
s	O
Law	O
.	O

To	O
study	O
the	O
in	O
vivo	O
role	O
of	O
p16	B-GENE
.	I-GENE
7	I-GENE
,	O
a	O
phi29	O
mutant	O
containing	O
a	O
suppressible	O
mutation	O
in	O
gene	B-GENE
16	I-GENE
.	I-GENE
7	I-GENE
was	O
constructed	O
.	O

To	O
the	O
best	O
of	O
our	O
knowledge	O
,	O
SNTCS	O
is	O
highly	O
malignant	O
.	O

The	O
extraordinary	O
stability	O
of	O
peptide	B-GENE
-	I-GENE
-	I-GENE
gp96	I-GENE
complexes	I-GENE
and	O
the	O
plasticity	O
of	O
the	O
peptide	O
-	O
binding	O
pocket	O
support	O
the	O
proposed	O
relay	O
of	O
diverse	O
peptides	O
to	O
MHC	B-GENE
and	O
/	O
or	O
other	O
molecules	O
via	O
molecular	O
recognition	O
.	O

High	O
-	O
affinity	O
binding	O
of	O
NF	B-GENE
-	I-GENE
1	I-GENE
to	O
PSE	B-GENE
-	I-GENE
B	I-GENE
,	O
but	O
not	O
to	O
PSE	B-GENE
-	I-GENE
A	I-GENE
,	O
was	O
confirmed	O
by	O
competition	O
of	O
DNA	O
-	O
protein	O
interactions	O
by	O
using	O
NF	B-GENE
-	I-GENE
1	I-GENE
DNA	O
elements	O
and	O
antibodies	O
.	O

Coexpression	O
of	O
the	O
p120	B-GENE
(	O
ctn	B-GENE
)	O
protein	O
with	O
an	O
N	O
-	O
terminal	O
deletion	O
,	O
which	O
eliminates	O
some	O
potential	O
tyrosine	O
phosphorylation	O
sites	O
,	O
or	O
the	O
protein	O
with	O
a	O
single	O
amino	O
acid	O
substitution	O
(	O
tyrosine	O
at	O
217	O
to	O
phenylalanine	O
)	O
resulted	O
in	O
an	O
increase	O
in	O
the	O
aggregation	O
of	O
v	B-GENE
-	I-GENE
Src	I-GENE
-	O
transformed	O
EL	O
and	O
EalphaCL	O
cells	O
.	O

We	O
show	O
that	O
p73	B-GENE
can	O
transcriptionally	O
inhibit	O
a	O
number	O
of	O
cellular	O
and	O
viral	O
promoters	O
.	O

RESULTS	O
:	O
Of	O
the	O
24	O
patients	O
,	O
6	O
had	O
Grade	O
1	O
pneumonitis	O
,	O
and	O
13	O
had	O
Grade	O
2	O
pneumonitis	O
.	O

In	O
contrast	O
,	O
we	O
did	O
not	O
detect	O
a	O
significant	O
correlation	O
between	O
plasma	B-GENE
TNFalpha	I-GENE
and	O
radiation	O
pneumonitis	O
.	O

METHODS	O
:	O
Sixteen	O
pigs	O
were	O
assigned	O
randomly	O
to	O
control	O
and	O
shock	O
groups	O
.	O

Identification	O
of	O
pulmonary	O
vein	O
stenosis	O
after	O
radiofrequency	O
ablation	O
for	O
atrial	O
fibrillation	O
using	O
MRI	O
.	O

Tumor	O
cell	O
lines	O
transduced	O
at	O
an	O
MOI	O
of	O
8	O
for	O
3	O
days	O
led	O
to	O
>	O
90	O
%	O
gene	O
transfer	O
efficiency	O
.	O

Treatment	O
includes	O
both	O
medical	O
and	O
surgical	O
options	O
,	O
with	O
medical	O
therapy	O
further	O
subclassified	O
into	O
pharmacologic	O
and	O
pneumatic	O
dilation	O
.	O

Finally	O
,	O
we	O
compared	O
the	O
differential	O
screening	O
techniques	O
in	O
terms	O
of	O
sensitivity	O
,	O
efficiency	O
and	O
occurrence	O
of	O
false	O
positives	O
.	O

Serial	O
US	O
images	O
were	O
obtained	O
before	O
and	O
20	O
,	O
30	O
,	O
40	O
,	O
50	O
,	O
60	O
,	O
90	O
,	O
120	O
,	O
150	O
,	O
180	O
,	O
240	O
,	O
and	O
300	O
s	O
after	O
intravenous	O
injection	O
of	O
2	O
g	O
of	O
contrast	O
agent	O
using	O
conventional	O
and	O
harmonic	O
PD	O
US	O
.	O

To	O
investigate	O
the	O
effects	O
of	O
exogenous	O
hyaluronic	O
acid	O
,	O
the	O
development	O
of	O
port	O
-	O
site	O
metastasis	O
was	O
examined	O
using	O
mouse	O
adenocarcinoma	O
cell	O
-	O
line	O
colon	O
26	O
cells	O
.	O

Cytomegalovirus	O
,	O
Chlamydia	O
pneumoniae	O
,	O
and	O
Helicobacter	O
pylori	O
IgG	B-GENE
antibodies	I-GENE
and	O
restenosis	O
after	O
stent	O
implantation	O
:	O
an	O
angiographic	O
and	O
intravascular	O
ultrasound	O
study	O
.	O

Responses	O
of	O
single	O
-	O
unit	O
carotid	O
body	O
chemoreceptors	O
in	O
adult	O
rats	O
.	O

Architecture	O
and	O
anatomy	O
of	O
the	O
genomic	O
locus	O
encoding	O
the	O
human	O
leukemia	O
-	O
associated	O
transcription	O
factor	O
RUNX1	B-GENE
/	O
AML1	B-GENE
.	O

Therefore	O
,	O
we	O
suggested	O
that	O
both	O
proteins	O
might	O
belong	O
to	O
the	O
PLTP	B-GENE
family	I-GENE
.	O

In	O
this	O
paper	O
the	O
tyrosine	O
dephosphorylating	O
enzymes	O
,	O
the	O
protein	B-GENE
-	I-GENE
tyrosine	I-GENE
phosphatases	I-GENE
(	O
PTPs	B-GENE
)	O
,	O
are	O
studied	O
which	O
can	O
be	O
grouped	O
into	O
two	O
subfamilies	O
,	O
the	O
soluble	B-GENE
PTPs	I-GENE
and	O
the	O
receptor	B-GENE
PTPs	I-GENE
(	O
RPTPs	B-GENE
)	O
.	O

The	O
Ig	B-GENE
-	O
related	O
,	O
typical	O
metazoan	O
,	O
module	O
is	O
classified	O
to	O
the	O
disulphide	O
lacking	O
Ig	B-GENE
members	I-GENE
and	O
represents	O
the	O
phylogenetic	O
earliest	O
member	O
of	O
this	O
group	O
.	O

The	O
Sox	B-GENE
gene	I-GENE
family	I-GENE
(	O
Sry	B-GENE
like	I-GENE
HMG	I-GENE
box	I-GENE
gene	I-GENE
)	O
is	O
characterised	O
by	O
a	O
conserved	O
DNA	O
sequence	O
encoding	O
a	O
domain	O
of	O
approximately	O
80	O
amino	O
acids	O
which	O
is	O
responsible	O
for	O
sequence	O
specific	O
DNA	O
binding	O
.	O

While	O
these	O
results	O
are	O
consistent	O
with	O
previously	O
reported	O
effects	O
of	O
the	O
C	O
-	O
terminal	O
domain	O
on	O
nucleotide	O
binding	O
,	O
they	O
also	O
demonstrate	O
that	O
interactions	O
with	O
the	O
N	O
-	O
terminal	O
domains	O
are	O
necessary	O
to	O
inhibit	O
proton	O
transport	O
.	O

Respiratory	O
parameters	O
suggested	O
that	O
M6G	O
produced	O
less	O
respiratory	O
depression	O
than	O
morphine	O
.	O

This	O
supports	O
previous	O
arguments	O
for	O
the	O
improbability	O
of	O
biological	O
effects	O
at	O
UHF	O
frequencies	O
unless	O
a	O
mechanism	O
can	O
be	O
found	O
for	O
accumulating	O
energy	O
over	O
time	O
and	O
space	O
and	O
focussing	O
it	O
.	O

To	O
assess	O
the	O
maximum	O
oxygen	O
uptake	O
(	O
V	O
'	O
O2	O
max	O
)	O
of	O
Hong	O
Kong	O
Chinese	O
children	O
and	O
to	O
explore	O
its	O
association	O
with	O
respiratory	O
illnesses	O
,	O
we	O
conducted	O
the	O
Multistage	O
Fitness	O
Test	O
(	O
MFT	O
)	O
,	O
a	O
20	O
-	O
m	O
shuttle	O
run	O
test	O
,	O
in	O
1	O
,	O
427	O
schoolchildren	O
aged	O
between	O
8	O
-	O
12	O
years	O
.	O

By	O
analyzing	O
5	O
'	O
-	O
deletion	O
insulin	B-GENE
promoter	I-GENE
-	I-GENE
reporter	I-GENE
constructs	I-GENE
in	O
transient	O
transfections	O
of	O
clonal	O
INS	B-GENE
-	I-GENE
1	I-GENE
beta	I-GENE
-	O
cells	O
,	O
we	O
located	O
activating	O
Hh	B-GENE
-	O
responsive	O
regions	O
within	O
the	O
rat	B-GENE
insulin	I-GENE
I	I-GENE
promoter	I-GENE
that	O
include	O
the	O
glucose	O
-	O
response	O
elements	O
Far	O
(	O
E2	O
)	O
and	O
Flat	O
(	O
A2	O
/	O
A3	O
)	O
.	O

The	O
androgen	B-GENE
receptor	I-GENE
(	O
AR	B-GENE
)	O
amino	O
-	O
terminus	O
imposes	O
androgen	O
-	O
specific	O
regulation	O
of	O
AR	B-GENE
gene	I-GENE
expression	O
via	O
an	O
exonic	O
enhancer	O
.	O

A	O
major	O
mechanism	O
by	O
which	O
estrogens	O
prevent	O
osteoporosis	O
seems	O
to	O
be	O
repression	O
of	O
transcription	O
of	O
NF	B-GENE
-	I-GENE
kappa	I-GENE
B	I-GENE
target	I-GENE
genes	I-GENE
,	O
such	O
as	O
the	O
osteoclast	O
-	O
activating	O
cytokines	O
interleukin	B-GENE
-	I-GENE
6	I-GENE
and	O
interleukin	B-GENE
-	I-GENE
1	I-GENE
.	O

To	O
identify	O
the	O
important	O
cis	O
-	O
DNA	O
regulatory	O
element	O
(	O
s	O
)	O
involved	O
in	O
the	O
tissue	O
-	O
,	O
region	O
-	O
,	O
and	O
cell	O
-	O
specific	O
expression	O
of	O
the	O
mE	B-GENE
-	I-GENE
RABP	I-GENE
gene	I-GENE
,	O
the	O
5	O
-	O
kb	O
DNA	O
fragment	O
was	O
sequenced	O
.	O

In	O
the	O
mouse	O
,	O
both	O
genes	O
reside	O
in	O
the	O
syntenic	O
region	O
8E1	O
on	O
chromosome	O
8	O
.	O

Analysis	O
of	O
the	O
genome	O
sequence	O
revealed	O
26	O
,	O
588	O
protein	O
-	O
encoding	O
transcripts	O
for	O
which	O
there	O
was	O
strong	O
corroborating	O
evidence	O
and	O
an	O
additional	O
approximately	O
12	O
,	O
000	O
computationally	O
derived	O
genes	O
with	O
mouse	O
matches	O
or	O
other	O
weak	O
supporting	O
evidence	O
.	O

The	O
corresponding	O
genotype	O
was	O
determined	O
with	O
a	O
restriction	O
enzyme	O
-	O
based	O
assay	O
.	O

By	O
Caveman	O
.	O

Multistage	O
models	O
and	O
the	O
A	O
-	O
bomb	O
survivor	O
data	O
:	O
implications	O
for	O
carcinogenic	O
mechanisms	O
?	O

The	O
revitalization	O
of	O
surgery	O
for	O
Parkinson	O
'	O
s	O
disease	O
(	O
PD	O
)	O
has	O
fueled	O
discussion	O
about	O
the	O
best	O
methodology	O
to	O
define	O
the	O
target	O
.	O

Corneal	O
scrapping	O
and	O
deep	O
stromal	O
biopsy	O
were	O
obtained	O
and	O
stained	O
for	O
microscopic	O
evaluation	O
with	O
periodic	O
acid	O
-	O
Schiff	O
,	O
Giemsa	O
,	O
and	O
Gomori	O
'	O
s	O
methenamine	O
silver	O
stains	O
.	O

These	O
results	O
indicate	O
that	O
BACM	O
has	O
antiplaque	O
and	O
stronger	O
antidegradation	O
effects	O
than	O
GLCM	O
.	O

Multidrug	O
resistance	O
in	O
Saccharomyces	O
cerevisiae	O
mainly	O
results	O
from	O
the	O
overexpression	O
of	O
genes	O
coding	O
for	O
the	O
membrane	O
efflux	O
pumps	O
,	O
the	O
major	O
facilitators	O
and	O
the	O
ABC	B-GENE
binding	I-GENE
cassette	I-GENE
transporters	I-GENE
,	O
under	O
the	O
control	O
of	O
key	O
transcription	O
regulators	O
encoded	O
by	O
the	O
PDR1	B-GENE
and	O
PDR3	B-GENE
genes	I-GENE
.	O

Susceptibility	O
to	O
ischemia	O
-	O
induced	O
arrhythmias	O
was	O
lower	O
in	O
1	O
-	O
week	O
diabetics	O
:	O
only	O
42	O
%	O
of	O
diabetic	O
hearts	O
exhibited	O
ventricular	O
tachycardia	O
(	O
VT	O
)	O
and	O
16	O
%	O
had	O
short	O
episodes	O
of	O
ventricular	O
fibrillation	O
(	O
VF	O
)	O
as	O
compared	O
to	O
VT	O
100	O
%	O
and	O
VF	O
70	O
%	O
(	O
including	O
sustained	O
VF	O
36	O
%	O
)	O
in	O
the	O
non	O
-	O
diabetics	O
(	O
P	O
<	O
0	O
.	O
05	O
)	O
.	O

A	O
picture	O
is	O
emerging	O
showing	O
a	O
gradient	O
of	O
function	O
among	O
p53	B-GENE
,	O
p73	B-GENE
,	O
p63	B-GENE
ranging	O
from	O
tumor	O
suppression	O
to	O
development	O
.	O

This	O
could	O
lead	O
to	O
subsequent	O
outbreaks	O
if	O
Babesia	O
carrier	O
animals	O
were	O
to	O
be	O
introduced	O
into	O
the	O
herd	O
.	O

Contagious	O
bovine	O
pleuropneumonia	O
is	O
a	O
major	O
threat	O
for	O
cattle	O
in	O
Africa	O
.	O

Baseline	O
BMD	O
values	O
were	O
significantly	O
lower	O
in	O
the	O
oligo	O
-	O
amenorrheic	O
group	O
than	O
in	O
the	O
two	O
others	O
at	O
the	O
level	O
of	O
lumbar	O
spine	O
(	O
anteroposterior	O
view	O
:	O
0	O
.	O
941	O
+	O
/	O
-	O
0	O
.	O
039	O
in	O
oligo	O
-	O
amenorrheic	O
vs	O
1	O
.	O
077	O
+	O
/	O
-	O
0	O
.	O
029	O
or	O
1	O
.	O
051	O
+	O
/	O
-	O
0	O
.	O
017	O
g	O
x	O
cm	O
(	O
-	O
2	O
)	O
,	O
P	O
<	O
0	O
.	O
005	O
,	O
in	O
the	O
eumenorrheic	O
and	O
contraceptive	O
user	O
groups	O
,	O
respectively	O
)	O
but	O
not	O
in	O
weight	O
-	O
bearing	O
bone	O
such	O
as	O
proximal	O
and	O
midshaft	O
femur	O
.	O

The	O
distribution	O
of	O
red	O
rice	O
cultivation	O
in	O
Sri	O
Lanka	O
is	O
coincident	O
with	O
the	O
HIDD	O
villages	O
.	O

The	O
increase	O
in	O
number	O
of	O
terminal	O
hairs	O
,	O
which	O
are	O
defined	O
as	O
hairs	O
more	O
than	O
60	O
microm	O
in	O
diameter	O
,	O
in	O
the	O
designated	O
area	O
(	O
0	O
.	O
5	O
cm	O
square	O
=	O
0	O
.	O
25	O
cm2	O
area	O
)	O
of	O
the	O
procyanidin	O
B	O
-	O
2	O
group	O
subjects	O
after	O
the	O
6	O
-	O
month	O
trial	O
was	O
significantly	O
greater	O
than	O
that	O
of	O
the	O
placebo	O
control	O
group	O
subjects	O
(	O
procyanidin	O
B	O
-	O
2	O
,	O
1	O
.	O
99	O
+	O
/	O
-	O
2	O
.	O
58	O
(	O
mean	O
+	O
/	O
-	O
SD	O
)	O
/	O
0	O
.	O
25	O
cm2	O
;	O
placebo	O
,	O
-	O
0	O
.	O
82	O
+	O
/	O
-	O
3	O
.	O
40	O
(	O
mean	O
+	O
/	O
-	O
SD	O
)	O
/	O
0	O
.	O
25	O
cm2	O
;	O
P	O
<	O
0	O
.	O
02	O
,	O
two	O
-	O
sample	O
t	O
test	O
)	O
.	O

Ectopic	O
expression	O
of	O
the	O
dominant	B-GENE
mutant	I-GENE
Lg3	I-GENE
allele	I-GENE
is	O
believed	O
to	O
cause	O
the	O
phenotype	O
.	O

High	O
plasma	B-GENE
AVP	I-GENE
levels	O
observed	O
in	O
the	O
two	O
cases	O
suggest	O
that	O
SSRIs	O
stimulate	O
AVP	B-GENE
secretion	O
,	O
thereby	O
causing	O
SIADH	O
.	O

Thus	O
,	O
in	O
T47D	O
breast	O
carcinoma	O
cells	O
,	O
IL	B-GENE
-	I-GENE
6	I-GENE
acts	O
in	O
synergy	O
with	O
EGF	B-GENE
receptor	I-GENE
autocrine	O
activity	O
to	O
signal	O
through	O
the	O
MAPK	B-GENE
/	O
PI3K	B-GENE
pathways	O
.	O

Human	B-GENE
homologue	I-GENE
of	I-GENE
yeast	I-GENE
Rad23	I-GENE
protein	I-GENE
A	I-GENE
interacts	O
with	O
p300	B-GENE
/	O
cyclic	B-GENE
AMP	I-GENE
-	I-GENE
responsive	I-GENE
element	I-GENE
binding	I-GENE
(	I-GENE
CREB	I-GENE
)	I-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
to	O
down	O
-	O
regulate	O
transcriptional	O
activity	O
of	O
p53	B-GENE
.	O

Most	O
patients	O
harboring	O
metronidazole	O
-	O
and	O
clarithromycin	O
-	O
resistant	O
strains	O
were	O
eradicated	O
at	O
an	O
equal	O
rate	O
by	O
each	O
of	O
the	O
three	O
regimens	O
.	O

Binding	O
of	O
cell	O
type	O
-	O
specific	O
nuclear	O
proteins	O
to	O
the	O
5	O
'	O
-	O
flanking	O
region	O
of	O
maize	B-GENE
C4	I-GENE
phosphoenolpyruvate	I-GENE
carboxylase	I-GENE
gene	I-GENE
confers	O
its	O
differential	O
transcription	O
in	O
mesophyll	O
cells	O
.	O

RESULTS	O
:	O
During	O
the	O
stabilization	O
period	O
,	O
PaCO2	O
(	O
mean	O
+	O
/	O
-	O
SD	O
)	O
was	O
33	O
+	O
/	O
-	O
5	O
mm	O
Hg	O
,	O
and	O
arrhythmias	O
were	O
not	O
detected	O
.	O

BACKGROUND	O
:	O
Previous	O
studies	O
have	O
indicated	O
that	O
the	O
60	O
-	O
,	O
30	O
-	O
,	O
28	O
-	O
and	O
12	O
-	O
item	O
versions	O
of	O
the	O
General	O
Health	O
Questionnaire	O
(	O
GHQ	O
)	O
are	O
liable	O
to	O
retest	O
effects	O
,	O
especially	O
when	O
administered	O
multiple	O
times	O
with	O
short	O
intervals	O
.	O

Acute	O
effects	O
of	O
LI	O
160	O
(	O
extract	O
of	O
Hypericum	O
perforatum	O
,	O
St	O
John	O
'	O
s	O
wort	O
)	O
and	O
two	O
of	O
its	O
constituents	O
on	O
neuroendocrine	O
responses	O
in	O
the	O
rat	O
.	O

Decreased	O
serum	B-GENE
ceruloplasmin	I-GENE
and	O
copper	O
levels	O
in	O
cervical	O
dystonia	O
.	O

A	O
microsporidian	O
,	O
Nosema	O
algerae	O
Vavra	O
and	O
undeen	O
,	O
was	O
found	O
parasitizing	O
larvae	O
and	O
adults	O
of	O
a	O
laboratory	O
colony	O
of	O
Culex	O
pipiens	O
L	O
.	O
originated	O
from	O
Gharbia	O
Governorate	O
.	O

Molecular	O
cloning	O
and	O
characterization	O
of	O
OsPSK	B-GENE
,	O
a	O
gene	O
encoding	O
a	O
precursor	O
for	O
phytosulfokine	B-GENE
-	I-GENE
alpha	I-GENE
,	O
required	O
for	O
rice	O
cell	O
proliferation	O
.	O

Plasma	O
DHE	O
concentration	O
rose	O
promptly	O
above	O
5	O
ng	O
/	O
ml	O
after	O
the	O
application	O
of	O
the	O
PSA	O
tape	O
onto	O
the	O
damaged	O
skin	O
in	O
hairless	O
rat	O
.	O

Implications	O
in	O
biomonitoring	O
of	O
the	O
observed	O
accumulation	O
patterns	O
,	O
especially	O
in	O
the	O
different	O
tissues	O
of	O
Posidonia	O
oceanica	O
,	O
are	O
discussed	O
.	O

Thus	O
,	O
Xlim	B-GENE
-	I-GENE
1	I-GENE
not	O
only	O
contains	O
a	O
unique	O
tyrosine	O
-	O
rich	O
activation	O
domain	O
but	O
also	O
contains	O
a	O
negative	O
regulatory	O
domain	O
in	O
CT239	O
-	O
403	O
,	O
suggesting	O
a	O
complex	O
regulatory	O
mechanism	O
underlying	O
the	O
transcriptional	O
activity	O
of	O
Xlim	B-GENE
-	I-GENE
1	I-GENE
in	O
the	O
organizer	O
.	O

After	O
allowing	O
time	O
for	O
absorption	O
,	O
participants	O
completed	O
a	O
bridge	O
simulator	O
task	O
.	O

Functional	O
analysis	O
of	O
various	O
PTP	B-GENE
-	O
deficient	O
DT40	O
B	O
cell	O
lines	O
stably	O
expressing	O
wild	O
-	O
type	O
chimeric	O
Fc	B-GENE
gamma	I-GENE
RIIB1	I-GENE
-	I-GENE
PECAM	I-GENE
-	I-GENE
1	I-GENE
receptor	I-GENE
indicated	O
that	O
cytoplasmic	B-GENE
Src	I-GENE
homology	I-GENE
2	I-GENE
-	I-GENE
domain	I-GENE
-	I-GENE
containing	I-GENE
phosphatases	I-GENE
,	O
SHP	B-GENE
-	I-GENE
1	I-GENE
and	O
SHP	B-GENE
-	I-GENE
2	I-GENE
,	O
were	O
both	O
necessary	O
and	O
sufficient	O
to	O
deliver	O
inhibitory	O
negative	O
regulation	O
upon	O
coligation	O
of	O
BCR	B-GENE
complex	I-GENE
with	O
inhibitory	O
receptor	O
.	O

Substitutions	O
in	O
the	O
YFV	B-GENE
Ag	B-GENE
-	I-GENE
binding	I-GENE
region	I-GENE
(	O
ABR	B-GENE
)	O
occur	O
at	O
four	O
of	O
the	O
eight	O
highly	O
conserved	O
residues	O
that	O
are	O
essential	O
for	O
binding	O
of	O
peptide	O
-	O
Ag	O
in	O
the	O
class	O
Ia	O
molecules	O
.	O

Similarly	O
,	O
curcumin	O
(	O
diferuloylmethane	O
)	O
,	O
an	O
anti	O
-	O
inflammatory	O
agent	O
,	O
suppressed	O
OSM	B-GENE
-	O
stimulated	O
STAT1	B-GENE
phosphorylation	O
,	O
DNA	O
-	O
binding	O
activity	O
of	O
STAT1	B-GENE
,	O
and	O
c	B-GENE
-	I-GENE
Jun	I-GENE
N	I-GENE
-	I-GENE
terminal	I-GENE
kinase	I-GENE
activation	O
without	O
affecting	O
JAK1	B-GENE
,	O
JAK2	B-GENE
,	O
JAK3	B-GENE
,	O
ERK1	B-GENE
/	I-GENE
2	I-GENE
,	O
and	O
p38	B-GENE
phosphorylation	O
.	O

In	O
contrast	O
,	O
the	O
failure	O
of	O
the	O
QKTT	O
motif	O
and	O
TGN46	O
cytoplasmic	O
tail	O
to	O
induce	O
steady	O
-	O
state	O
ER	O
localization	O
of	O
vesicular	B-GENE
stomatitis	I-GENE
virus	I-GENE
glycoprotein	I-GENE
(	O
VSVG	B-GENE
)	O
chimeras	O
in	O
HeLa	O
and	O
NRK	O
cells	O
indicates	O
that	O
significant	O
differences	O
in	O
early	O
secretory	O
trafficking	O
also	O
exist	O
.	O

A	O
cDNA	O
clone	O
encoding	O
C2H2	B-GENE
-	I-GENE
type	I-GENE
zinc	I-GENE
finger	I-GENE
protein	I-GENE
,	O
SCOF	B-GENE
-	I-GENE
1	I-GENE
,	O
was	O
isolated	O
from	O
soybean	O
.	O

Consistent	O
with	O
the	O
specificity	O
observed	O
for	O
the	O
interaction	O
of	O
DmCKIIalpha	B-GENE
with	O
these	O
bHLH	B-GENE
proteins	I-GENE
,	O
sequence	O
alignment	O
suggests	O
that	O
only	O
m5	B-GENE
,	O
m7	B-GENE
,	O
and	O
m8	B-GENE
contain	O
a	O
consensus	O
site	O
for	O
phosphorylation	O
by	O
CKII	B-GENE
within	O
a	O
subdomain	O
unique	O
to	O
these	O
three	O
proteins	O
.	O

Apart	O
from	O
antimicrobial	O
properties	O
,	O
recent	O
data	O
indicate	O
that	O
PMN	O
also	O
exert	O
anti	O
-	O
inflammatory	O
effects	O
by	O
stimulation	O
and	O
release	O
of	O
cytokine	O
antagonists	O
such	O
as	O
interleukin	B-GENE
-	I-GENE
1	I-GENE
receptor	I-GENE
antagonist	I-GENE
(	O
IL	B-GENE
-	I-GENE
1ra	I-GENE
)	O
.	O

The	O
purpose	O
of	O
this	O
investigation	O
was	O
to	O
study	O
the	O
morphological	O
characteristics	O
of	O
the	O
fibrous	O
tissue	O
capsule	O
resulting	O
from	O
the	O
implantation	O
of	O
aluminum	O
calcium	O
phosphate	O
(	O
ALCAP	O
)	O
and	O
hydroxyapetite	O
(	O
HA	O
)	O
bioceramics	O
.	O

Sevelamer	O
hydrochloride	O
(	O
Renagel	O
)	O
is	O
a	O
nonabsorbed	O
phosphate	O
-	O
binding	O
polymer	O
marketed	O
for	O
the	O
treatment	O
of	O
hyperphosphatemia	O
in	O
adult	O
patients	O
receiving	O
hemodialysis	O
.	O

The	O
pharmacokinetic	O
profiles	O
of	O
digoxin	O
and	O
warfarin	O
were	O
not	O
altered	O
by	O
the	O
simultaneous	O
and	O
continued	O
administration	O
of	O
sevelamer	O
.	O

Before	O
PO3	O
administration	O
,	O
more	O
than	O
half	O
(	O
57	O
.	O
4	O
%	O
)	O
of	O
the	O
patients	O
received	O
only	O
1	O
or	O
2	O
antituberculous	O
drugs	O
(	O
ethambutole	O
and	O
ethionamide	O
or	O
ethambutole	O
and	O
oprofloxacin	O
)	O
.	O

Can	O
survival	O
be	O
prolonged	O
for	O
patients	O
with	O
hormone	O
-	O
resistant	O
prostate	O
cancer	O
?	O

Patients	O
were	O
divided	O
into	O
two	O
group	O
;	O
Control	O
group	O
A	O
in	O
which	O
a	O
hot	O
-	O
water	O
circulating	O
system	O
was	O
used	O
and	O
group	O
B	O
in	O
which	O
a	O
transtracheal	O
heating	O
and	O
humidification	O
system	O
by	O
ANAMED	O
HUMITUBE	O
was	O
used	O
,	O
during	O
gastric	O
cancer	O
operation	O
.	O

The	O
present	O
data	O
also	O
demonstrate	O
that	O
ectopic	O
expression	O
of	O
blr1	B-GENE
increased	O
JNK	B-GENE
/	O
SAPK	B-GENE
activity	O
,	O
but	O
JNK	B-GENE
/	O
SAPK	B-GENE
activation	O
was	O
not	O
needed	O
for	O
accelerated	O
RA	O
-	O
induced	O
differentiation	O
and	O
growth	O
arrest	O
.	O

RESULTS	O
:	O
The	O
parameters	O
SF2	O
and	O
plating	O
efficiency	O
were	O
stable	O
throughout	O
the	O
4	O
-	O
year	O
test	O
period	O
.	O

Also	O
,	O
small	O
,	O
sense	O
and	O
antisense	O
approximately	O
22	O
nt	O
RNAs	O
,	O
derived	O
from	O
the	O
satRNA	O
,	O
were	O
associated	O
with	O
the	O
replicating	O
satellite	O
.	O

VE	O
-	O
DEF	O
animals	O
had	O
significantly	O
higher	O
(	O
p	O
<	O
0	O
.	O
05	O
)	O
levels	O
of	O
myocardial	O
lipid	O
peroxidation	O
and	O
lower	O
(	O
p	O
<	O
0	O
.	O
05	O
)	O
protein	O
thiols	O
following	O
I	O
-	O
R	O
compared	O
to	O
the	O
CON	O
animals	O
.	O

Grippers	O
with	O
integrated	O
piezoresistive	O
force	O
sensors	O
and	O
with	O
attached	O
strain	O
gauges	O
have	O
been	O
reported	O
.	O

The	O
child	O
left	O
behind	O
.	O

Transition	O
between	O
P	O
-	O
and	O
H	O
-	O
BPPV	O
was	O
found	O
in	O
6	O
cases	O
.	O

The	O
contrasting	O
effects	O
of	O
dopaminergic	O
stimulation	O
on	O
the	O
motor	O
performance	O
and	O
on	O
some	O
aspects	O
of	O
cognitive	O
processing	O
suggest	O
the	O
existence	O
of	O
complex	O
interactions	O
within	O
pre	O
-	O
and	O
postsynaptic	O
brain	B-GENE
dopamine	I-GENE
receptors	I-GENE
,	O
and	O
an	O
intervention	O
of	O
segregated	O
basal	O
ganglia	O
-	O
prefrontal	O
cortex	O
loops	O
in	O
motor	O
and	O
cognitive	O
behaviour	O
.	O

HexA71	B-GENE
negatively	O
affects	O
RpoS	B-GENE
,	O
as	O
the	O
levels	O
of	O
this	O
alternative	O
sigma	B-GENE
factor	I-GENE
are	O
higher	O
in	O
the	O
HexA	B-GENE
-	I-GENE
mutant	I-GENE
than	O
in	O
the	O
HexA	B-GENE
+	I-GENE
strain	O
.	O

Multiple	O
copies	O
of	O
rsmB	B-GENE
+	I-GENE
DNA	I-GENE
,	O
on	O
the	O
other	O
hand	O
,	O
stimulate	O
exoenzyme	O
production	O
by	O
relieving	O
the	O
negative	O
effects	O
of	O
a	O
chromosomal	O
copy	O
of	O
hexA	B-GENE
+	I-GENE
.	O

0	O
%	O
)	O
and	O
IL	B-GENE
-	I-GENE
12	I-GENE
(	O
42	O
.	O
6	O
%	O
vs	O
.	O

Systematic	O
review	O
of	O
diagnostic	O
tests	O
for	O
vaginal	O
trichomoniasis	O
.	O

CHAP	O
and	O
the	O
Department	O
of	O
Veterans	O
Affairs	O
.	O

More	O
importantly	O
,	O
this	O
fusion	O
converted	O
a	O
less	O
effective	O
vaccine	O
into	O
one	O
with	O
significant	O
potency	O
against	O
established	O
E7	B-GENE
-	O
expressing	O
metastatic	O
tumors	O
.	O

We	O
compared	O
previously	O
the	O
methylation	O
status	O
between	O
normal	O
liver	O
and	O
liver	O
tumors	O
in	O
SV40	B-GENE
T	I-GENE
/	I-GENE
t	I-GENE
antigen	I-GENE
transgenic	O
mice	O
(	O
MT	O
-	O
D2	O
mice	O
)	O
using	O
Restriction	O
Landmark	O
Genomic	O
Scanning	O
for	O
Methylation	O
(	O
RLGS	O
-	O
M	O
)	O
and	O
identified	O
several	O
loci	O
/	O
spots	O
that	O
appeared	O
to	O
be	O
methylated	O
frequently	O
in	O
liver	O
tumors	O
.	O

The	O
Genescan	O
program	O
predicted	O
an	O
open	O
reading	O
frame	O
of	O
a	O
novel	O
,	O
intron	O
-	O
less	O
gene	O
adjacent	O
to	O
the	O
B236	O
spot	O
that	O
encodes	O
a	O
putative	O
493	O
-	O
amino	O
acid	O
protein	O
containing	O
the	O
SNAG	O
repressor	O
motif	O
in	O
the	O
NH2	O
-	O
terminal	O
region	O
and	O
five	O
C2H2	O
-	O
type	O
zinc	O
finger	O
motifs	O
in	O
the	O
COOH	O
-	O
terminal	O
half	O
.	O

Northern	O
blot	O
analysis	O
revealed	O
that	O
mlt	B-GENE
1	I-GENE
is	O
normally	O
expressed	O
in	O
brain	O
,	O
spleen	O
,	O
stom	O
ach	O
,	O
and	O
liver	O
.	O

Treatment	O
of	O
N18TG	O
-	O
2	O
cells	O
with	O
a	O
demethylating	O
agent	O
,	O
5	O
-	O
aza	O
-	O
deoxycytidine	O
,	O
resulted	O
in	O
an	O
expression	O
of	O
mlt	B-GENE
1	I-GENE
,	O
indicating	O
that	O
the	O
repression	O
of	O
mlt	B-GENE
1	I-GENE
is	O
attributable	O
to	O
methylation	O
Thus	O
,	O
mlt	B-GENE
1	I-GENE
is	O
a	O
novel	O
target	O
gene	O
that	O
is	O
silenced	O
by	O
methylation	O
during	O
liver	O
tumorigenesis	O
initiated	O
by	O
SV40	B-GENE
T	I-GENE
antigen	I-GENE
.	O

These	O
results	O
suggested	O
a	O
critical	O
role	O
for	O
tyrosine	O
residue	O
1229	O
in	O
the	O
regulation	O
of	O
L1	B-GENE
endocytosis	O
.	O

Folate	O
metabolism	O
in	O
the	O
human	O
malaria	O
parasite	O
Plasmodium	O
falciparum	O
is	O
an	O
essential	O
activity	O
for	O
cell	O
growth	O
and	O
replication	O
,	O
and	O
the	O
target	O
of	O
an	O
important	O
class	O
of	O
therapeutic	O
agents	O
in	O
widespread	O
use	O
.	O

The	O
BFA	O
System	O
reads	O
a	O
text	O
file	O
with	O
flows	O
,	O
measured	O
with	O
fluorescent	O
microsphere	O
technique	O
,	O
and	O
constructs	O
the	O
lung	O
anatomy	O
with	O
volumetric	O
pixels	O
showing	O
the	O
flows	O
with	O
a	O
color	O
schema	O
.	O

Retinoids	O
participate	O
in	O
the	O
onset	O
of	O
differentiation	O
,	O
apoptosis	O
and	O
the	O
inhibition	O
of	O
growth	O
in	O
a	O
wide	O
variety	O
of	O
normal	O
and	O
cancerous	O
cells	O
.	O

These	O
results	O
indicate	O
that	O
evaluation	O
of	O
exposure	O
to	O
S	O
.	O
neurona	O
by	O
WB	O
analysis	O
of	O
serum	O
may	O
be	O
misleading	O
in	O
young	O
horses	O
.	O

Drosophila	B-GENE
Menin1	I-GENE
gene	I-GENE
transcripts	I-GENE
use	O
alternative	O
polyadenylation	O
sites	O
resulting	O
in	O
4	O
.	O
3	O
and	O
5	O
-	O
kb	O
messages	O
.	O

Sequence	O
analysis	O
indicates	O
that	O
RBP21	B-GENE
shares	O
homology	O
with	O
other	O
retinoblastoma	B-GENE
-	I-GENE
binding	I-GENE
proteins	I-GENE
in	O
the	O
pRb	B-GENE
-	I-GENE
binding	I-GENE
motif	I-GENE
LxCxE	O
at	O
the	O
C	O
-	O
terminal	O
region	O
.	O

In	O
addition	O
,	O
the	O
consensus	O
amino	O
acid	O
motif	O
for	O
serine	B-GENE
threonine	I-GENE
receptor	I-GENE
kinases	I-GENE
was	O
also	O
present	O
.	O

We	O
have	O
also	O
isolated	O
and	O
analyzed	O
the	O
5	O
'	O
flanking	O
region	O
of	O
the	O
pea	O
33RNP	B-GENE
gene	I-GENE
.	O

OsBBPI	B-GENE
was	O
found	O
to	O
be	O
rapidly	O
induced	O
in	O
rice	O
seedling	O
leaf	O
in	O
response	O
to	O
cut	B-GENE
,	O
exogenous	O
jasmonic	O
acid	O
(	O
JA	O
)	O
,	O
and	O
two	O
potent	O
protein	B-GENE
phosphatase	I-GENE
2A	I-GENE
(	O
PP2A	B-GENE
)	O
inhibitors	O
,	O
cantharidin	O
(	O
CN	O
)	O
and	O
endothall	O
(	O
EN	O
)	O
,	O
in	O
a	O
light	O
/	O
dark	O
-	O
,	O
time	O
-	O
and	O
dose	O
-	O
dependent	O
manner	O
;	O
this	O
induction	O
was	O
completely	O
inhibited	O
by	O
cycloheximide	O
(	O
CHX	O
)	O
,	O
indicating	O
a	O
requirement	O
for	O
de	O
novo	O
protein	O
synthesis	O
in	O
its	O
induction	O
.	O

The	O
effects	O
of	O
chlordiazepoxide	O
(	O
2	O
.	O
5	O
-	O
15	O
.	O
0mg	O
/	O
kg	O
)	O
,	O
a	O
full	O
benzodiazepine	B-GENE
receptor	I-GENE
agonist	O
,	O
and	O
bretazenil	O
(	O
5	O
.	O
0	O
-	O
30	O
.	O
0mg	O
/	O
kg	O
)	O
,	O
a	O
partial	O
benzodiazepine	B-GENE
receptor	I-GENE
agonist	O
,	O
were	O
examined	O
in	O
the	O
murine	O
elevated	O
plus	O
-	O
maze	O
paradigm	O
.	O

However	O
,	O
plasmids	O
carrying	O
the	O
yeast	B-GENE
TyrRS	I-GENE
gene	I-GENE
could	O
not	O
be	O
stably	O
maintained	O
in	O
E	O
.	O
coli	O
.	O

In	O
mammalian	O
tissue	O
culture	O
cells	O
,	O
overexpression	O
of	O
any	O
of	O
the	O
four	O
mouse	O
deltex	O
homologs	O
suppressed	O
the	O
transcriptional	O
activity	O
of	O
E47	B-GENE
,	O
a	O
basic	B-GENE
helix	I-GENE
-	I-GENE
loop	I-GENE
-	I-GENE
helix	I-GENE
(	I-GENE
bHLH	I-GENE
)	I-GENE
protein	I-GENE
,	O
in	O
a	O
manner	O
similar	O
to	O
suppression	O
by	O
an	O
activated	O
form	O
of	O
human	B-GENE
Notch1	I-GENE
or	O
human	B-GENE
DTX1	I-GENE
.	O

Multiparous	O
women	O
presented	O
higher	O
BMI	O
(	O
P	O
=	O
0	O
.	O
01	O
)	O
and	O
PBF	O
(	O
P	O
=	O
0	O
.	O
03	O
)	O
compared	O
with	O
primi	O
-	O
and	O
nulliparous	O
groups	O
.	O

The	O
authors	O
did	O
not	O
detect	O
any	O
significant	O
correlations	O
between	O
parameters	O
of	O
the	O
lipids	O
of	O
bone	O
marrow	O
and	O
leptin	B-GENE
levels	O
in	O
serum	O
and	O
bone	O
marrow	O
.	O

The	O
position	O
of	O
the	O
analyst	O
as	O
expert	O
:	O
yesterday	O
and	O
today	O
.	O

Our	O
results	O
suggest	O
that	O
the	O
central	O
role	O
of	O
the	O
Notch	B-GENE
-	O
CBF1	B-GENE
/	O
RBP	B-GENE
-	I-GENE
Jkappa	I-GENE
signaling	O
pathway	O
in	O
cell	O
fate	O
decisions	O
renders	O
it	O
susceptible	O
to	O
pathways	O
of	O
viral	O
replication	O
and	O
oncogenic	O
conversion	O
.	O

Using	O
a	O
novel	O
method	O
combining	O
chromatin	O
immunoprecipitation	O
and	O
genomic	O
array	O
hybridization	O
,	O
we	O
have	O
identified	O
a	O
460	B-GENE
-	I-GENE
kb	I-GENE
CENP	I-GENE
-	I-GENE
A	I-GENE
-	I-GENE
binding	I-GENE
DNA	I-GENE
domain	I-GENE
of	O
a	O
neocentromere	O
derived	O
from	O
the	O
20p12	O
region	O
of	O
an	O
invdup	O
(	O
20p	O
)	O
human	O
marker	O
chromosome	O
.	O

We	O
describe	O
a	O
total	O
of	O
39	O
DEAH	B-GENE
helicases	I-GENE
in	O
these	O
four	O
species	O
.	O

Two	O
cases	O
with	O
marked	O
chronic	O
arm	O
lymphoedema	O
reported	O
major	O
and	O
persistent	O
improvements	O
in	O
arm	O
volume	O
for	O
at	O
least	O
12	O
months	O
after	O
treatment	O
with	O
HBO2	O
.	O

The	O
sensitivity	O
of	O
human	O
neuroblastoma	O
cells	O
SK	O
-	O
N	O
-	O
SH	O
to	O
undergo	O
apoptosis	O
induced	O
by	O
thapsigargin	O
was	O
examined	O
.	O

Prophylactic	O
lymph	O
node	O
dissection	O
or	O
radiation	O
therapy	O
to	O
the	O
nodal	O
chain	O
may	O
decrease	O
local	O
recurrence	O
but	O
does	O
not	O
consistently	O
affect	O
overall	O
survival	O
.	O

Currently	O
,	O
the	O
clinical	O
use	O
of	O
5	O
-	O
aminolaevulinic	O
acid	O
(	O
ALA	O
)	O
induced	O
protoporphyrin	B-GENE
IX	I-GENE
(	O
PPIX	B-GENE
)	O
for	O
photodynamic	O
therapy	O
(	O
PDT	O
)	O
is	O
limited	O
by	O
the	O
maximum	O
tolerated	O
oral	O
ALA	O
dose	O
(	O
60	O
mg	O
/	O
kg	O
)	O
.	O

We	O
can	O
classify	O
antibiotics	O
into	O
two	O
groups	O
based	O
on	O
initial	O
bactericidal	O
activity	O
against	O
P	O
.	O
aeruginosa	O
;	O
one	O
class	O
is	O
antibiotics	O
having	O
rapid	O
initial	O
killing	O
such	O
as	O
AMK	O
,	O
IPM	O
and	O
PAPM	O
,	O
the	O
other	O
is	O
CAZ	O
,	O
MEPM	O
showing	O
slow	O
initial	O
killing	O
.	O

Managing	O
HIV	O
.	O

In	O
Klinefelter	O
'	O
s	O
syndrome	O
(	O
47XXY	O
)	O
,	O
serum	O
testosterone	O
levels	O
are	O
at	O
the	O
lower	O
end	O
of	O
the	O
normal	O
range	O
and	O
dihydrotestosterone	O
levels	O
are	O
low	O
.	O

The	O
histamine	B-GENE
H1	I-GENE
receptor	I-GENE
antagonists	O
(	O
antihistamines	O
)	O
are	O
an	O
important	O
class	O
of	O
medications	O
used	O
for	O
the	O
relief	O
of	O
common	O
symptoms	O
associated	O
with	O
hyperhistaminic	O
conditions	O
occurring	O
in	O
children	O
and	O
adults	O
.	O

Conclusion	O
:	O
The	O
Lp	B-GENE
(	I-GENE
a	I-GENE
)	I-GENE
levels	O
in	O
these	O
children	O
were	O
the	O
lower	O
ever	O
reported	O
.	O

A	O
subset	O
of	O
patients	O
(	O
n	O
=	O
30	O
)	O
underwent	O
multichannel	O
pressure	O
flow	O
studies	O
,	O
which	O
demonstrated	O
that	O
transrectal	O
HIFU	O
reduces	O
bladder	O
outflow	O
obstruction	O
.	O

AIMS	O
:	O
To	O
establish	O
a	O
baseline	O
and	O
intraindividual	O
fluctuations	O
of	O
the	O
tumour	O
markers	O
CEA	B-GENE
,	O
CA	B-GENE
50	I-GENE
and	O
CA	B-GENE
242	I-GENE
in	O
patients	O
cured	O
from	O
colorectal	O
cancer	O
,	O
and	O
to	O
test	O
the	O
hypothesis	O
that	O
serum	O
concentrations	O
and	O
intraindividual	O
fluctuations	O
do	O
not	O
differ	O
from	O
the	O
concentrations	O
in	O
cancer	O
-	O
free	O
individuals	O
.	O

The	O
homologous	O
active	O
-	O
site	O
framework	O
of	O
these	O
enzymes	O
with	O
distinct	O
structures	O
suggests	O
convergent	O
evolution	O
of	O
a	O
common	O
catalytic	O
mechanism	O
.	O

We	O
found	O
that	O
RhoA	B-GENE
can	O
initiate	O
a	O
linear	O
kinase	O
cascade	O
leading	O
to	O
the	O
activation	O
of	O
ERK6	B-GENE
(	O
p38	B-GENE
gamma	I-GENE
)	O
,	O
a	O
recently	O
identified	O
member	O
of	O
the	O
p38	B-GENE
family	I-GENE
of	O
MAPKs	O
.	O

We	O
show	O
that	O
several	O
heme	O
-	O
responsive	O
mechanisms	O
combine	O
to	O
regulate	O
DAN	B-GENE
/	O
TIR	B-GENE
gene	O
expression	O
.	O

In	O
strains	O
lacking	O
tup11	B-GENE
and	O
tup12	B-GENE
,	O
the	O
atf1	B-GENE
-	O
pcr1	B-GENE
transcriptional	O
activator	O
continues	O
to	O
play	O
a	O
central	O
role	O
in	O
fbp1	B-GENE
-	O
lacZ	B-GENE
expression	O
;	O
however	O
,	O
spc1	B-GENE
MAPK	I-GENE
phosphorylation	O
of	O
atf1	B-GENE
is	O
no	O
longer	O
essential	O
for	O
its	O
activation	O
.	O

In	O
vitro	O
binding	O
studies	O
demonstrate	O
that	O
eIF	B-GENE
-	I-GENE
5A	I-GENE
is	O
required	O
for	O
efficient	O
interaction	O
of	O
Rev	B-GENE
-	O
NES	B-GENE
with	O
CRM1	B-GENE
/	O
exportin1	B-GENE
and	O
that	O
eIF	B-GENE
-	I-GENE
5A	I-GENE
interacts	O
with	O
the	O
nucleoporins	O
CAN	B-GENE
/	O
nup214	B-GENE
,	O
nup153	B-GENE
,	O
nup98	B-GENE
,	O
and	O
nup62	B-GENE
.	O

Structural	O
studies	O
have	O
shown	O
that	O
class	B-GENE
I	I-GENE
major	I-GENE
histocompatibility	I-GENE
complex	I-GENE
(	O
MHC	B-GENE
)	O
-	O
restricted	O
peptide	O
-	O
specific	O
T	B-GENE
cell	I-GENE
receptor	I-GENE
(	I-GENE
TCR	I-GENE
)	I-GENE
-	I-GENE
alpha	I-GENE
/	I-GENE
betas	I-GENE
make	O
multiple	O
contacts	O
with	O
the	O
alpha1	O
and	O
alpha2	O
helices	O
of	O
the	O
MHC	B-GENE
,	O
but	O
it	O
is	O
unclear	O
which	O
or	O
how	O
many	O
of	O
these	O
interactions	O
contribute	O
to	O
functional	O
binding	O
.	O

Mice	O
homozygous	O
for	O
the	O
dlg	B-GENE
mutation	O
exhibit	O
growth	O
retardation	O
in	O
utero	O
,	O
have	O
hypoplasia	O
of	O
the	O
premaxilla	O
and	O
mandible	O
,	O
have	O
a	O
cleft	O
secondary	O
palate	O
,	O
and	O
die	O
perinatally	O
.	O

Moreover	O
,	O
a	O
complex	O
containing	O
PTP	B-GENE
phi	I-GENE
,	O
paxillin	B-GENE
,	O
and	O
a	O
paxillin	B-GENE
-	I-GENE
associated	I-GENE
tyrosine	I-GENE
kinase	I-GENE
,	O
Pyk2	B-GENE
,	O
can	O
be	O
immunoprecipitated	O
from	O
macrophage	O
lysates	O
,	O
and	O
the	O
catalytic	O
domain	O
of	O
PTP	B-GENE
phi	I-GENE
selectively	O
binds	O
paxillin	B-GENE
and	O
Pyk2	B-GENE
in	O
vitro	O
.	O

A	O
single	O
base	O
change	O
(	O
A8G	O
)	O
in	O
either	O
sequence	O
reduces	O
hnRNP	B-GENE
A2	I-GENE
binding	O
and	O
,	O
in	O
the	O
case	O
of	O
A2RE	B-GENE
-	I-GENE
2	I-GENE
,	O
inhibits	O
RNA	O
transport	O
.	O

Baseline	O
variables	O
associated	O
with	O
CD	O
included	O
a	O
less	O
frequent	O
use	O
of	O
prestroke	O
aspirin	O
and	O
a	O
higher	O
incidence	O
of	O
early	O
CT	O
changes	O
of	O
edema	O
or	O
mass	O
effect	O
or	O
dense	O
middle	O
cerebral	O
artery	O
sign	O
.	O

IL	B-GENE
-	I-GENE
1beta	I-GENE
was	O
significantly	O
higher	O
in	O
endometrioma	O
than	O
in	O
lesions	O
of	O
other	O
localizations	O
.	O

A	O
complete	O
drug	O
history	O
was	O
compiled	O
,	O
specifying	O
the	O
amount	O
and	O
duration	O
of	O
VGB	O
medication	O
.	O

The	O
mutant	O
receptors	O
,	O
as	O
well	O
as	O
sBMPR	B-GENE
-	I-GENE
IA	I-GENE
,	O
were	O
expressed	O
as	O
fusion	O
proteins	O
with	O
thioredoxin	B-GENE
in	O
Escherichia	O
coli	O
,	O
and	O
purified	O
using	O
reverse	O
phase	O
high	O
performance	O
liquid	O
chromatography	O
(	O
RP	O
-	O
HPLC	O
)	O
after	O
digestion	O
with	O
enterokinase	B-GENE
.	O

The	O
authors	O
undertook	O
a	O
retrospective	O
analysis	O
of	O
pathology	O
with	O
quantification	O
of	O
the	O
percentage	O
of	O
papillary	O
serous	O
component	O
(	O
%	O
PSC	O
)	O
and	O
p53	B-GENE
expression	O
.	O

For	O
this	O
purpose	O
,	O
the	O
immediate	O
and	O
the	O
final	O
(	O
after	O
swelling	O
)	O
fixation	O
strengths	O
of	O
two	O
variations	O
of	O
the	O
swellable	O
bone	O
anchor	O
designs	O
(	O
a	O
smooth	O
anchor	O
and	O
a	O
screw	O
anchor	O
)	O
were	O
measured	O
in	O
two	O
different	O
foams	O
(	O
used	O
to	O
simulate	O
bone	O
)	O
with	O
different	O
densities	O
.	O

Constitutive	O
phosphorylation	O
and	O
nuclear	O
localization	O
of	O
Smad3	B-GENE
are	O
correlated	O
with	O
increased	O
collagen	B-GENE
gene	I-GENE
transcription	O
in	O
activated	O
hepatic	O
stellate	O
cells	O
.	O

Cloning	O
and	O
characterization	O
of	O
the	O
murine	B-GENE
beta	I-GENE
(	I-GENE
3	I-GENE
)	I-GENE
integrin	I-GENE
gene	I-GENE
promoter	O
:	O
identification	O
of	O
an	O
interleukin	B-GENE
-	I-GENE
4	I-GENE
responsive	I-GENE
element	I-GENE
and	O
regulation	O
by	O
STAT	B-GENE
-	I-GENE
6	I-GENE
.	O

CONCLUSIONS	O
:	O
Although	O
the	O
levels	O
of	O
oxLDL	B-GENE
antibodies	I-GENE
might	O
be	O
modified	O
in	O
early	O
hypertension	O
,	O
once	O
advanced	O
coronary	O
artery	O
disease	O
has	O
developed	O
the	O
presence	O
of	O
hypertension	O
does	O
not	O
affect	O
anti	B-GENE
-	I-GENE
oxLDL	I-GENE
levels	O
.	O

GafChromic	O
(	O
MD	O
-	O
55	O
-	O
2	O
)	O
radiochromic	O
film	O
has	O
become	O
increasingly	O
popular	O
for	O
medical	O
applications	O
and	O
has	O
proven	O
to	O
be	O
useful	O
for	O
brachytherapy	O
dosimetry	O
.	O

RESULTS	O
:	O
Within	O
7	O
days	O
,	O
all	O
groups	O
re	O
-	O
acquired	O
responding	O
for	O
heroin	O
under	O
CRF	O
at	O
rates	O
similar	O
to	O
their	O
pre	O
-	O
lesion	O
performance	O
.	O

Cis	O
-	O
acting	O
CCAAT	O
elements	O
are	O
frequently	O
found	O
in	O
eukaryotic	O
promoter	O
regions	O
.	O

Twenty	O
-	O
five	O
patients	O
also	O
received	O
PET	O
examinations	O
during	O
the	O
staging	O
procedures	O
.	O

The	O
Gap69C	B-GENE
is	O
a	O
single	O
-	O
copy	O
gene	O
producing	O
a	O
major	O
2	O
.	O
1	O
-	O
kb	O
mRNA	O
throughout	O
development	O
,	O
but	O
its	O
amount	O
is	O
decreased	O
in	O
larvae	O
.	O

Cases	O
of	O
lung	O
cancer	O
with	O
intramedullary	O
metastasis	O
are	O
rare	O
,	O
especially	O
those	O
diagnosed	O
before	O
death	O
.	O

A	O
novel	O
growth	O
-	O
related	O
nuclear	O
protein	O
binds	O
and	O
inhibits	O
rat	O
aldolase	B-GENE
B	I-GENE
gene	I-GENE
promoter	O
.	O

OBJECTIVE	O
:	O
To	O
investigate	O
the	O
association	O
between	O
complete	O
congenital	O
heart	O
block	O
(	O
CCHB	O
)	O
in	O
the	O
fetus	O
and	O
adult	O
disease	O
.	O

This	O
study	O
examined	O
the	O
role	O
of	O
cholesteryl	O
ester	O
transfer	O
(	O
CET	O
)	O
,	O
cholesteryl	B-GENE
ester	I-GENE
transfer	I-GENE
protein	I-GENE
(	O
CETP	B-GENE
)	O
activity	O
,	O
and	O
phospholipid	B-GENE
transfer	I-GENE
protein	I-GENE
(	O
PLTP	B-GENE
)	O
activity	O
in	O
the	O
increased	O
prevalence	O
of	O
coronary	O
artery	O
calcification	O
(	O
CAC	O
)	O
in	O
diabetic	O
subjects	O
compared	O
with	O
nondiabetic	O
subjects	O
and	O
in	O
the	O
loss	O
of	O
the	O
sex	O
difference	O
in	O
CAC	O
in	O
diabetes	O
.	O

Two	O
families	O
with	O
concordant	O
inheritance	O
of	O
DNAH9	B-GENE
alleles	I-GENE
in	O
affected	O
individuals	O
were	O
observed	O
.	O

Efficacy	O
of	O
first	O
-	O
generation	O
Cavermap	O
to	O
verify	O
location	O
and	O
function	O
of	O
cavernous	O
nerves	O
during	O
radical	O
prostatectomy	O
:	O
a	O
multi	O
-	O
institutional	O
evaluation	O
by	O
experienced	O
surgeons	O
.	O

The	O
(	O
two	O
-	O
motif	O
)	O
domain	O
fold	O
contains	O
a	O
pair	O
of	O
calcium	O
binding	O
sites	O
very	O
similar	O
to	O
those	O
found	O
in	O
a	O
two	B-GENE
-	I-GENE
domain	I-GENE
prokaryotic	I-GENE
betagamma	I-GENE
-	I-GENE
crystallin	I-GENE
fold	I-GENE
family	I-GENE
member	I-GENE
,	O
Protein	B-GENE
S	I-GENE
.	O

Deletional	O
analyses	O
of	O
VDR	B-GENE
indicated	O
that	O
GRIP1	B-GENE
and	O
RAC3	B-GENE
required	O
an	O
intact	O
VDR	B-GENE
activation	O
function	O
(	O
AF	O
-	O
2	O
)	O
domain	O
for	O
efficient	O
interaction	O
as	O
well	O
as	O
additional	O
but	O
distinct	O
regions	O
of	O
the	O
VDR	B-GENE
.	O

Mechanism	O
in	O
the	O
sequential	O
control	O
of	O
cell	O
morphology	O
and	O
S	O
phase	O
entry	O
by	O
epidermal	B-GENE
growth	I-GENE
factor	I-GENE
involves	O
distinct	O
MEK	B-GENE
/	O
ERK	B-GENE
activations	O
.	O

3D	O
image	O
-	O
processing	O
permits	O
to	O
analyse	O
ultrasound	O
data	O
interactively	O
in	O
three	O
orthogonal	O
planes	O
(	O
section	O
mode	O
)	O
or	O
in	O
realistic	O
3D	O
views	O
(	O
rendering	O
mode	O
)	O
.	O

Direct	O
superoxide	O
scavenging	O
activity	O
of	O
nonsteroidal	O
anti	O
-	O
inflammatory	O
drugs	O
:	O
determination	O
by	O
electron	O
spin	O
resonance	O
using	O
the	O
spin	O
trap	O
method	O
.	O

BACKGROUND	O
:	O
Dermoscopy	O
is	O
a	O
noninvasive	O
technique	O
that	O
increases	O
the	O
diagnostic	O
accuracy	O
of	O
pigmented	O
skin	O
lesions	O
,	O
particularly	O
improving	O
the	O
diagnosis	O
of	O
patients	O
with	O
cutaneous	O
melanoma	O
in	O
situ	O
(	O
CMIS	O
)	O
and	O
early	O
invasive	O
melanoma	O
.	O

Moreover	O
,	O
PTax	B-GENE
expressed	O
higher	O
background	O
activities	O
than	O
PTF	B-GENE
,	O
indicating	O
that	O
the	O
sequence	O
of	O
the	O
synthetic	O
regulatory	O
region	O
can	O
influence	O
background	O
levels	O
.	O

However	O
,	O
the	O
promoter	O
region	O
contains	O
several	O
potential	O
cis	O
-	O
regulatory	O
elements	O
such	O
as	O
Sp1	B-GENE
,	O
early	B-GENE
growth	I-GENE
response	I-GENE
-	I-GENE
1	I-GENE
,	O
activator	B-GENE
protein	I-GENE
-	I-GENE
2	I-GENE
,	O
MyoD	B-GENE
,	O
p300	B-GENE
,	O
nuclear	B-GENE
factor	I-GENE
-	I-GENE
kappaB	I-GENE
,	O
myeloid	B-GENE
zinc	I-GENE
finger	I-GENE
protein	I-GENE
-	I-GENE
1	I-GENE
,	O
caudal	B-GENE
-	I-GENE
related	I-GENE
homeobox	I-GENE
(	I-GENE
Cdx	I-GENE
)	I-GENE
gene	I-GENE
A	I-GENE
,	O
and	O
Cdx	B-GENE
protein	I-GENE
-	I-GENE
2	I-GENE
binding	I-GENE
sites	I-GENE
.	O

Thus	O
,	O
the	O
interaction	O
of	O
Tat	B-GENE
with	O
the	O
components	O
of	O
this	O
rel	B-GENE
/	O
AP1	B-GENE
cooperative	O
complex	O
seems	O
to	O
induce	O
quantitative	O
and	O
qualitative	O
alterations	O
of	O
this	O
complex	O
as	O
activation	O
progresses	O
,	O
resulting	O
in	O
a	O
decrease	O
of	O
IL	B-GENE
-	I-GENE
2	I-GENE
gene	I-GENE
transcription	O
.	O

2001	O
.	O

Unlike	O
other	O
progenitor	O
cells	O
of	O
the	O
brain	O
,	O
SVZa	O
progenitor	O
cells	O
have	O
the	O
capacity	O
to	O
divide	O
even	O
though	O
they	O
express	O
a	O
neuronal	O
phenotype	O
.	O

A	O
minimal	O
ER3	O
sequence	O
of	O
DNA	O
was	O
further	O
demonstrated	O
to	O
function	O
as	O
a	O
FXR	B-GENE
HRE	I-GENE
and	O
was	O
bound	O
in	O
vitro	O
by	O
FXR	B-GENE
-	O
expressing	O
yeast	O
extracts	O
.	O

OBJECTIVE	O
:	O
To	O
determine	O
the	O
association	O
of	O
depressive	O
symptoms	O
with	O
HIV	O
-	O
related	O
mortality	O
and	O
decline	O
in	O
CD4	B-GENE
lymphocyte	O
counts	O
among	O
women	O
with	O
HIV	O
.	O

An	O
economic	O
analysis	O
using	O
West	O
of	O
Scotland	O
Coronary	O
Prevention	O
Study	O
(	O
WOSCOPS	O
)	O
findings	O
indicates	O
that	O
statin	B-GENE
treatment	O
would	O
have	O
prevented	O
318	O
events	O
per	O
10	O
,	O
000	O
patients	O
in	O
a	O
population	O
similar	O
to	O
that	O
in	O
WOSCOPS	O
(	O
average	O
1	O
.	O
5	O
%	O
annual	O
risk	O
of	O
a	O
cardiovascular	O
event	O
)	O
at	O
a	O
discounted	O
cost	O
per	O
life	O
-	O
year	O
gained	O
of	O
20	O
,	O
375	O
pounds	O
(	O
$	O
31	O
,	O
818	O
)	O
.	O

Furthermore	O
,	O
the	O
soluble	O
forms	O
of	O
ATF6	B-GENE
and	O
the	O
G13	B-GENE
gene	I-GENE
product	I-GENE
are	O
unable	O
to	O
bind	O
to	O
several	O
point	O
mutants	O
of	O
the	O
cis	O
-	O
acting	O
ER	O
stress	O
response	O
element	O
in	O
vitro	O
that	O
hardly	O
respond	O
to	O
ER	O
stress	O
in	O
vivo	O
.	O

The	O
present	O
study	O
was	O
initiated	O
to	O
explore	O
the	O
potential	O
of	O
a	O
hybrid	O
biological	O
reactor	O
,	O
combining	O
trickling	O
filter	O
(	O
TF	O
)	O
and	O
activated	O
sludge	O
process	O
(	O
ASP	O
)	O
,	O
to	O
treat	O
wastewater	O
containing	O
trichloroethylene	O
(	O
TCE	O
)	O
at	O
ambient	O
temperature	O
at	O
different	O
hydraulic	O
retention	O
time	O
(	O
HRT	O
)	O
.	O

In	O
DNA	O
strand	O
exchange	O
reactions	O
using	O
oligonucleotides	O
,	O
we	O
found	O
that	O
Rec2	B-GENE
exhibited	O
a	O
pairing	O
bias	O
that	O
is	O
opposite	O
that	O
of	O
RecA	B-GENE
.	O

Forskolin	O
treatment	O
(	O
10	O
microM	O
)	O
of	O
the	O
transfected	O
cells	O
for	O
3	O
-	O
-	O
6	O
h	O
maximally	O
induced	O
luciferase	B-GENE
threefold	O
.	O

Analysis	O
of	O
ace2Delta	O
cells	O
reveals	O
that	O
Ace2p	B-GENE
is	O
required	O
for	O
cell	O
separation	O
but	O
not	O
for	O
polarized	O
growth	O
.	O

The	O
results	O
presented	O
here	O
show	O
that	O
AR1	B-GENE
of	O
the	O
promoter	O
-	O
proximal	O
CAP	B-GENE
subunit	I-GENE
was	O
required	O
for	O
papBA	B-GENE
transcription	O
even	O
in	O
the	O
absence	O
of	O
the	O
histone	B-GENE
-	I-GENE
like	I-GENE
protein	I-GENE
H	B-GENE
-	I-GENE
NS	I-GENE
.	O

A	O
.	O
,	O
Slatkin	O
,	O
D	O
.	O

RESULTS	O
:	O
A	O
significant	O
correlation	O
(	O
p	O
<	O
0	O
.	O
001	O
)	O
was	O
observed	O
for	O
mean	O
wall	O
thickness	O
and	O
vessel	O
wall	O
area	O
between	O
MRI	O
and	O
histopathology	O
(	O
r	O
=	O
0	O
.	O
87	O
and	O
r	O
=	O
0	O
.	O
85	O
,	O
respectively	O
)	O
.	O

Our	O
data	O
indicate	O
that	O
SIP1	B-GENE
is	O
required	O
to	O
confine	O
XBra	B-GENE
gene	I-GENE
expression	O
to	O
the	O
mesoderm	O
.	O

SIP1	B-GENE
(	O
Smad	B-GENE
interacting	I-GENE
protein	I-GENE
1	I-GENE
)	O
and	O
deltaEF1	B-GENE
(	O
delta	B-GENE
-	I-GENE
crystallin	I-GENE
enhancer	I-GENE
binding	I-GENE
factor	I-GENE
)	O
are	O
structurally	O
similar	O
transcriptional	O
repressors	O
.	O

B	B-GENE
-	I-GENE
myb	I-GENE
is	O
essential	O
for	O
G1	O
/	O
S	O
transition	O
and	O
has	O
been	O
shown	O
to	O
be	O
phosphorylated	O
by	O
the	O
cyclin	B-GENE
A2	I-GENE
/	O
cdk2	B-GENE
complex	O
.	O

Nucleotide	O
sequence	O
,	O
transcription	O
map	O
,	O
and	O
mutation	O
analysis	O
of	O
the	O
13q14	O
chromosomal	O
region	O
deleted	O
in	O
B	O
-	O
cell	O
chronic	O
lymphocytic	O
leukemia	O
.	O

Human	B-GENE
T	I-GENE
-	I-GENE
cell	I-GENE
leukemia	I-GENE
virus	I-GENE
type	I-GENE
I	I-GENE
(	I-GENE
HTLV	I-GENE
-	I-GENE
I	I-GENE
)	I-GENE
Tax	I-GENE
is	O
a	O
potent	O
transcriptional	O
regulator	O
that	O
can	O
activate	O
or	O
repress	O
specific	O
cellular	O
genes	O
and	O
that	O
has	O
been	O
proposed	O
to	O
contribute	O
to	O
leukemogenesis	O
in	O
adult	O
T	O
-	O
cell	O
leukemia	O
.	O

Requirements	O
for	O
the	O
nuclear	O
-	O
cytoplasmic	O
translocation	O
of	O
infected	B-GENE
-	I-GENE
cell	I-GENE
protein	I-GENE
0	I-GENE
of	O
herpes	O
simplex	O
virus	O
1	O
.	O

The	O
Novacor	O
Left	O
Ventricular	O
Assist	O
System	O
(	O
LVAS	O
)	O
(	O
Novacor	O
Corp	O
,	O
Oakland	O
,	O
CA	O
)	O
was	O
initially	O
console	O
-	O
based	O
and	O
has	O
been	O
available	O
since	O
1993	O
in	O
a	O
wearable	O
configuration	O
.	O

Atheroma	O
appears	O
as	O
a	O
very	O
low	O
signal	O
intensity	O
area	O
on	O
2	O
-	O
dimensional	O
time	O
-	O
of	O
-	O
flight	O
(	O
TOF	O
)	O
magnetic	O
resonance	O
(	O
MR	O
)	O
images	O
,	O
and	O
its	O
components	O
have	O
various	O
signal	O
intensities	O
on	O
spin	O
-	O
echo	O
(	O
SE	O
)	O
images	O
.	O

Body	O
fat	O
distribution	O
was	O
determined	O
by	O
abdominal	O
computed	O
tomography	O
.	O

The	O
flux	O
rates	O
of	O
p	O
-	O
toluidine	O
decreased	O
as	O
the	O
pH	O
value	O
in	O
the	O
donor	O
solution	O
increased	O
.	O

The	O
protein	O
is	O
composed	O
of	O
two	O
major	O
domains	O
separated	O
by	O
a	O
hydrophobic	O
linker	O
region	O
of	O
20	O
amino	O
acid	O
residues	O
.	O

We	O
performed	O
the	O
present	O
study	O
to	O
clarify	O
the	O
relationship	O
between	O
the	O
DOX	O
binding	O
ability	O
(	O
%	O
DB	O
)	O
and	O
the	O
histologic	O
response	O
,	O
rate	O
of	O
decrease	O
in	O
tumor	O
volume	O
of	O
malignant	O
soft	O
tissue	O
tumors	O
after	O
preoperative	O
chemotherapy	O
and	O
prognosis	O
.	O

To	O
avoid	O
misinterpretations	O
,	O
special	O
reference	O
values	O
should	O
be	O
applied	O
for	O
preadolescents	O
,	O
at	O
least	O
with	O
regard	O
to	O
FVC	O
and	O
FEV1	O
.	O

Nephrotoxicity	O
after	O
orthotopic	O
liver	O
transplantation	O
in	O
cyclosporin	O
A	O
and	O
FK	O
506	O
-	O
treated	O
patients	O
.	O

Compared	O
with	O
normal	O
control	O
subjects	O
,	O
all	O
74	O
TOF	O
patients	O
had	O
decreased	O
systolic	O
and	O
diastolic	O
myocardial	O
velocities	O
and	O
a	O
longer	O
isovolumic	O
relaxation	O
time	O
.	O

Acetoin	O
can	O
be	O
reused	O
by	O
the	O
bacteria	O
during	O
stationary	O
phase	O
when	O
other	O
carbon	O
sources	O
have	O
been	O
depleted	O
.	O

Mutational	O
analysis	O
showed	O
that	O
the	O
U	O
-	O
box	O
,	O
like	O
the	O
RING	O
finger	O
in	O
other	O
proteins	O
,	O
forms	O
the	O
physical	O
basis	O
for	O
the	O
interaction	O
with	O
E2	B-GENE
enzymes	I-GENE
.	O

Thus	O
,	O
our	O
studies	O
define	O
Rac	B-GENE
/	O
Cdc42	B-GENE
/	O
Pak	B-GENE
as	O
a	O
module	O
upstream	O
of	O
Raf	B-GENE
-	I-GENE
1	I-GENE
during	O
its	O
activation	O
by	O
microtubule	O
disruption	O
.	O

Nrf2	B-GENE
regulates	O
expression	O
of	O
genes	O
encoding	O
enzymes	O
with	O
antioxidant	O
(	O
e	O
.	O
g	O
.	O
heme	B-GENE
oxygenase	I-GENE
-	I-GENE
1	I-GENE
(	O
HO	B-GENE
-	I-GENE
1	I-GENE
)	O
)	O
or	O
xenobiotic	O
detoxification	O
(	O
e	O
.	O
g	O
.	O

These	O
results	O
indicate	O
that	O
ATF4	B-GENE
regulates	O
basal	O
and	O
CdCl	O
(	O
2	O
)	O
-	O
induced	O
expression	O
of	O
the	O
ho	B-GENE
-	I-GENE
1	I-GENE
gene	I-GENE
in	O
a	O
cell	O
-	O
specific	O
manner	O
and	O
possibly	O
in	O
a	O
complex	O
with	O
Nrf2	B-GENE
.	O

On	O
the	O
other	O
hand	O
,	O
forced	O
overexpression	O
of	O
the	O
wild	O
type	O
,	O
but	O
not	O
the	O
kinase	O
-	O
inactivated	O
mutant	O
of	O
nm23H1	B-GENE
,	O
converted	O
the	O
GDP	O
-	O
bound	O
forms	O
of	O
Rac1	B-GENE
,	O
Cdc42	B-GENE
,	O
and	O
RhoA	B-GENE
to	O
their	O
GTP	O
-	O
bound	O
forms	O
in	O
vitro	O
by	O
its	O
nucleoside	B-GENE
diphosphate	I-GENE
kinase	I-GENE
activity	O
,	O
but	O
nm23H1	B-GENE
alone	O
apparently	O
did	O
not	O
produce	O
the	O
GTP	O
-	O
bound	O
form	O
of	O
these	O
GTPases	B-GENE
in	O
vivo	O
.	O

This	O
effect	O
was	O
observed	O
in	O
the	O
absence	O
of	O
de	O
novo	O
protein	O
synthesis	O
and	O
was	O
independent	O
of	O
histone	B-GENE
deacetylase	I-GENE
activity	O
.	O

Deletion	O
of	O
the	O
potential	O
initiator	O
element	O
does	O
not	O
affect	O
repression	O
of	O
the	O
p21	B-GENE
promoter	I-GENE
by	O
c	B-GENE
-	I-GENE
Myc	I-GENE
.	O

Fetal	O
lung	O
volume	O
:	O
estimation	O
at	O
MR	O
imaging	O
-	O
initial	O
results	O
.	O

Of	O
its	O
gene	O
products	O
,	O
E6	B-GENE
binds	O
to	O
and	O
inactivates	O
p53	B-GENE
tumor	I-GENE
suppressor	I-GENE
protein	I-GENE
by	O
ubiquitin	B-GENE
/	O
proteasome	O
-	O
dependent	O
degradation	O
.	O

In	O
mouse	O
,	O
Mmip1	B-GENE
(	O
Mad	B-GENE
member	I-GENE
interacting	I-GENE
protein	I-GENE
1	I-GENE
)	O
and	O
Smc3	B-GENE
share	O
99	O
%	O
sequence	O
identity	O
and	O
are	O
products	O
of	O
the	O
same	O
gene	O
.	O

An	O
element	O
within	O
the	O
5	O
'	O
untranslated	O
region	O
of	O
human	B-GENE
Hsp70	I-GENE
mRNA	I-GENE
which	O
acts	O
as	O
a	O
general	O
enhancer	O
of	O
mRNA	O
translation	O
.	O

In	O
SN	O
-	O
48	O
neuronal	O
cells	O
that	O
express	O
MR	B-GENE
,	O
GR	B-GENE
,	O
and	O
5	B-GENE
-	I-GENE
HT1A	I-GENE
receptors	I-GENE
,	O
deletion	O
or	O
inactivation	O
of	O
the	O
nGRE	O
(	O
negative	O
GRE	O
)	O
eliminated	O
negative	O
regulation	O
of	O
the	O
rat	B-GENE
5	I-GENE
-	I-GENE
HT1A	I-GENE
or	O
heterologous	O
promoters	O
by	O
corticosteroids	O
,	O
whereas	O
its	O
inclusion	O
conferred	O
corticosteroid	O
-	O
induced	O
inhibition	O
to	O
a	O
heterologous	O
promoter	O
.	O

Corticosteroid	O
-	O
mediated	O
transcriptional	O
inhibition	O
was	O
greater	O
for	O
MR	B-GENE
/	O
GR	B-GENE
in	O
combination	O
than	O
for	O
MR	B-GENE
or	O
GR	B-GENE
alone	O
.	O

Whereas	O
Smad2	B-GENE
was	O
rapidly	O
phosphorylated	O
by	O
TGF	B-GENE
-	I-GENE
beta	I-GENE
and	O
involved	O
in	O
the	O
initial	O
activation	O
of	O
Agc	B-GENE
expression	O
in	O
confluent	O
cells	O
,	O
Smad2	B-GENE
activation	O
was	O
not	O
required	O
for	O
maintaining	O
the	O
high	O
level	O
of	O
Agc	B-GENE
expression	O
.	O

Reverse	B-GENE
transcriptase	I-GENE
-	O
polymerase	O
chain	O
reaction	O
assays	O
showed	O
that	O
PKRDeltaE7	B-GENE
is	O
expressed	O
in	O
a	O
broad	O
range	O
of	O
human	O
tissues	O
at	O
variable	O
levels	O
.	O

Both	O
pancreatic	O
and	O
intestinal	O
cell	O
lines	O
were	O
found	O
to	O
express	O
a	O
number	O
of	O
POU	B-GENE
(	O
OCT	B-GENE
binding	O
)	O
homeodomain	O
proteins	O
examined	O
by	O
electrophoretic	O
mobility	O
shift	O
assay	O
.	O

SV1	B-GENE
has	O
a	O
33	O
-	O
amino	O
acid	O
insert	O
in	O
the	O
S1	O
transmembrane	O
domain	O
that	O
does	O
not	O
alter	O
S1	O
overall	O
hydrophobicity	O
,	O
but	O
makes	O
the	O
S0	O
-	O
S1	O
linker	O
longer	O
.	O

Polyclonal	O
antibodies	O
against	O
the	O
N	O
-	O
terminal	O
part	O
(	O
amino	O
acids	O
12	O
-	O
363	O
)	O
and	O
the	O
C	O
-	O
terminal	O
part	O
(	O
amino	O
acids	O
330	O
-	O
730	O
)	O
of	O
rainbow	B-GENE
trout	I-GENE
HIF	I-GENE
-	I-GENE
1alpha	I-GENE
protein	I-GENE
recognized	O
rainbow	B-GENE
trout	I-GENE
and	I-GENE
chinook	I-GENE
salmon	I-GENE
HIF	I-GENE
-	I-GENE
1alpha	I-GENE
protein	I-GENE
in	O
Western	O
blot	O
analysis	O
.	O

The	O
v	B-GENE
-	I-GENE
Src	I-GENE
SH3	B-GENE
domain	I-GENE
facilitates	O
a	O
cell	O
adhesion	O
-	O
independent	O
association	O
with	O
focal	B-GENE
adhesion	I-GENE
kinase	I-GENE
.	O

Mutagenesis	O
of	O
SNT1	B-GENE
(	O
IRS	B-GENE
)	O
CX	B-GENE
identified	O
three	O
classes	O
of	O
effector	O
motifs	O
within	O
SNT	B-GENE
critical	O
for	O
both	O
sustained	O
ERK	B-GENE
activation	O
and	O
neuronal	O
differentiation	O
:	O
1	O
)	O
four	O
phosphotyrosine	O
motifs	O
that	O
mediate	O
recruitment	O
of	O
Grb2	B-GENE
,	O
2	O
)	O
two	O
phosphotyrosine	O
motifs	O
that	O
mediate	O
recruitment	O
of	O
Shp2	B-GENE
,	O
and	O
3	O
)	O
a	O
C	O
-	O
terminal	O
motif	O
that	O
functions	O
by	O
helping	O
to	O
recruit	O
Sos	B-GENE
.	O

Exchanging	O
the	O
human	O
propeptide	O
in	O
this	O
chimera	O
with	O
either	O
the	O
murine	B-GENE
MIC	I-GENE
-	I-GENE
1	I-GENE
or	O
TGF	B-GENE
-	I-GENE
beta1	I-GENE
propeptide	I-GENE
resulted	O
in	O
secretion	O
of	O
the	O
unprocessed	O
,	O
monomeric	O
chimera	O
,	O
suggesting	O
a	O
specific	O
interaction	O
between	O
the	O
human	B-GENE
MIC	I-GENE
-	I-GENE
1	I-GENE
propeptide	I-GENE
and	O
mature	O
peptide	O
.	O

Radiolabeled	O
biantennary	O
N	O
-	O
glycans	O
synthesized	O
by	O
Pro	O
(	O
-	O
)	O
5Lec20	O
were	O
proportionately	O
less	O
ricin	O
-	O
bound	O
than	O
similar	O
species	O
from	O
parental	O
CHO	O
cells	O
,	O
and	O
Lec20	O
cell	O
extracts	O
had	O
a	O
markedly	O
reduced	O
ability	O
to	O
transfer	O
Gal	O
to	O
GlcNAc	O
-	O
terminating	O
acceptors	O
.	O

We	O
found	O
that	O
the	O
SOCS	B-GENE
box	I-GENE
interacted	O
with	O
Cullin	B-GENE
-	I-GENE
2	I-GENE
and	O
promoted	O
ubiquitination	O
of	O
TEL	B-GENE
-	O
JAK2	B-GENE
.	O

Neuron	B-GENE
-	I-GENE
specific	I-GENE
Bcl	I-GENE
-	I-GENE
2	I-GENE
homology	I-GENE
3	I-GENE
domain	I-GENE
-	I-GENE
only	I-GENE
splice	I-GENE
variant	I-GENE
of	O
Bak	B-GENE
is	O
anti	O
-	O
apoptotic	O
in	O
neurons	O
,	O
but	O
pro	O
-	O
apoptotic	O
in	O
non	O
-	O
neuronal	O
cells	O
.	O

Sequence	O
comparison	O
and	O
binding	O
studies	O
of	O
the	O
18	B-GENE
-	I-GENE
bp	I-GENE
MOK2	I-GENE
-	I-GENE
binding	I-GENE
sites	I-GENE
present	O
in	O
intron	O
2	O
of	O
human	O
,	O
bovine	O
,	O
and	O
mouse	B-GENE
IRBP	I-GENE
genes	I-GENE
show	O
that	O
the	O
3	O
'	O
-	O
half	O
sequence	O
is	O
the	O
essential	O
core	O
element	O
for	O
MOK2	B-GENE
binding	O
.	O

Furthermore	O
,	O
SB203580	O
inhibited	O
LPS	O
-	O
induced	O
activation	O
of	O
Sp1	B-GENE
,	O
as	O
well	O
as	O
the	O
promoter	O
activity	O
in	O
cells	O
transfected	O
with	O
a	O
plasmid	O
containing	O
the	O
Sp1	B-GENE
consensus	O
sequence	O
.	O

We	O
confirmed	O
the	O
interaction	O
between	O
TLS	B-GENE
and	O
p65	B-GENE
by	O
the	O
pull	O
-	O
down	O
assay	O
in	O
vitro	O
and	O
by	O
a	O
coimmunoprecipitation	O
experiment	O
followed	O
by	O
Western	O
blot	O
of	O
the	O
cultured	O
cell	O
in	O
vivo	O
.	O

Based	O
on	O
mutational	O
data	O
and	O
possible	O
mRNA	O
structure	O
,	O
we	O
hypothesized	O
about	O
the	O
effect	O
of	O
mRNA	O
structure	O
on	O
translation	O
of	O
the	O
two	O
major	O
C	B-GENE
/	I-GENE
EBPepsilon	I-GENE
isoforms	I-GENE
:	O
p32	B-GENE
and	O
p30	B-GENE
.	O

Binding	O
of	O
serum	B-GENE
response	I-GENE
factor	I-GENE
to	O
CArG	O
box	O
sequences	O
is	O
necessary	O
but	O
not	O
sufficient	O
to	O
restrict	O
gene	O
expression	O
to	O
arterial	O
smooth	O
muscle	O
cells	O
.	O

Together	O
,	O
these	O
results	O
identify	O
HPK1	B-GENE
as	O
a	O
new	O
component	O
of	O
TCR	B-GENE
signaling	O
.	O

The	O
size	O
of	O
the	O
infarct	O
was	O
determined	O
using	O
the	O
creatine	B-GENE
kinase	I-GENE
integral	O
method	O
.	O

A	O
new	O
echocardiographic	O
technique	O
is	O
described	O
with	O
a	O
conventional	O
M	O
mode	O
,	O
digitalised	O
2D	O
and	O
tissular	O
Doppler	O
which	O
has	O
a	O
comparable	O
ability	O
to	O
identify	O
the	O
anomalous	O
pathways	O
of	O
electric	O
conduction	O
using	O
a	O
non	O
-	O
invasive	O
method	O
.	O

SELECTION	O
CRITERIA	O
:	O
Randomised	O
controlled	O
trials	O
of	O
cabergoline	O
versus	O
placebo	O
in	O
patients	O
with	O
a	O
clinical	O
diagnosis	O
of	O
idiopathic	O
Parkinson	O
'	O
s	O
disease	O
and	O
long	O
-	O
term	O
complications	O
of	O
levodopa	O
therapy	O
.	O

Deterministic	O
effects	O
.	O

Unusual	O
two	B-GENE
-	I-GENE
domain	I-GENE
arginine	I-GENE
kinases	I-GENE
(	O
AKs	B-GENE
)	O
arose	O
independently	O
at	O
least	O
two	O
times	O
during	O
molecular	O
evolution	O
of	O
phosphagen	B-GENE
kinases	I-GENE
:	O
AKs	B-GENE
from	O
the	O
primitive	O
sea	O
anemone	O
Anthopleurura	O
japonicus	O
and	O
from	O
the	O
clam	O
Pseudocardium	O
sachalinensis	O
.	O

The	O
mouse	B-GENE
platelet	I-GENE
-	I-GENE
derived	I-GENE
growth	I-GENE
factor	I-GENE
(	I-GENE
PDGF	I-GENE
)	I-GENE
beta	I-GENE
-	I-GENE
receptor	I-GENE
promoter	I-GENE
contains	O
a	O
CCAAT	O
motif	O
,	O
and	O
NF	B-GENE
-	I-GENE
Y	I-GENE
plays	O
an	O
essential	O
role	O
in	O
its	O
transcription	O
.	O

Baseline	O
MBF	O
in	O
females	O
was	O
significantly	O
(	O
P	O
<	O
0	O
.	O
001	O
)	O
higher	O
than	O
in	O
males	O
.	O

No	O
preferential	O
VH	B-GENE
/	O
VL	B-GENE
-	O
chains	O
correlated	O
with	O
any	O
of	O
the	O
12	O
different	O
antigen	O
reactivities	O
,	O
even	O
for	O
mAbs	O
with	O
nearly	O
identical	O
cross	O
-	O
reactivities	O
.	O

Recently	O
,	O
it	O
was	O
shown	O
that	O
purified	O
RAG1	B-GENE
/	I-GENE
2	I-GENE
proteins	I-GENE
can	O
cleave	O
DNA	O
hairpins	O
in	O
vitro	O
,	O
but	O
the	O
same	O
activity	O
was	O
also	O
described	O
for	O
a	O
protein	O
complex	O
of	O
the	O
DNA	O
repair	O
proteins	O
Nbs1	B-GENE
/	O
Mre11	B-GENE
/	O
Rad50	B-GENE
.	O

In	O
addition	O
,	O
we	O
did	O
not	O
detect	O
significant	O
differences	O
in	O
CDR3	B-GENE
sequences	I-GENE
of	O
endogenous	B-GENE
Ig	I-GENE
lambdaL	I-GENE
and	O
kappaL	B-GENE
chain	I-GENE
gene	I-GENE
loci	I-GENE
cloned	O
from	O
peripheral	O
blood	O
lymphocytes	O
of	O
an	O
NBS	O
patient	O
and	O
of	O
healthy	O
individuals	O
.	O

Phase	O
II	O
study	O
of	O
paclitaxel	O
and	O
oral	O
etoposide	O
in	O
patients	O
with	O
locally	O
advanced	O
or	O
metastatic	O
non	O
-	O
small	O
cell	O
lung	O
cancer	O
.	O

Oral	O
supplementation	O
of	O
L	O
-	O
arginine	O
significantly	O
increased	O
plasma	O
L	O
-	O
citrulline	O
,	O
which	O
indicated	O
enhancement	O
of	O
NO	O
production	O
.	O

This	O
activation	O
was	O
then	O
blocked	O
by	O
CGS	O
12066A	O
.	O

Two	O
independent	O
transgenic	O
lines	O
were	O
produced	O
,	O
and	O
both	O
showed	O
expression	O
of	O
the	O
Gus	B-GENE
gene	I-GENE
specifically	O
in	O
the	O
endosperm	O
during	O
mid	O
-	O
development	O
(	O
first	O
detected	O
10	O
-	O
12	O
d	O
after	O
anthesis	O
)	O
.	O

Here	O
we	O
demonstrate	O
that	O
native	B-GENE
MRCK	I-GENE
exists	O
in	O
high	O
-	O
molecular	O
-	O
weight	O
complexes	O
.	O

Regression	O
analyses	O
showed	O
that	O
SOREMP	O
dream	O
occurrences	O
were	O
significantly	O
related	O
to	O
the	O
amount	O
of	O
REM	O
sleep	O
,	O
while	O
NREMP	O
dream	O
occurrences	O
were	O
related	O
to	O
arousals	O
from	O
NREM	O
sleep	O
.	O

Instead	O
,	O
TRPS1	B-GENE
potently	O
and	O
specifically	O
represses	O
transcriptional	O
activation	O
mediated	O
by	O
other	O
GATA	B-GENE
factors	I-GENE
.	O

9	O
.	O
7	O
(	O
95	O
%	O
CI	O
:	O
9	O
.	O
6	O
-	O
9	O
.	O
7	O
)	O
micromol	O
/	O
L	O
among	O
women	O
(	O
P	O
=	O
0	O
.	O
003	O
)	O
.	O

Three	O
patients	O
received	O
additional	O
cycles	O
of	O
5	O
-	O
fluorouracil	O
+	O
/	O
-	O
leucovorin	O
as	O
maintenance	O
chemotherapy	O
.	O
RESULTS	O
:	O
Thirty	O
males	O
and	O
21	O
females	O
with	O
a	O
median	O
age	O
of	O
55	O
years	O
(	O
range	O
31	O
-	O
-	O
73	O
years	O
)	O
were	O
treated	O
.	O

Secretion	O
of	O
interleukin	B-GENE
-	I-GENE
8	I-GENE
,	O
RANTES	B-GENE
,	O
macrophage	B-GENE
inflammatory	I-GENE
protein	I-GENE
1alpha	I-GENE
,	O
and	O
10	B-GENE
-	I-GENE
kappaDa	I-GENE
IFN	I-GENE
-	I-GENE
gamma	I-GENE
-	I-GENE
inducible	I-GENE
protein	I-GENE
were	O
increased	O
in	O
differentiating	O
keratinocytes	O
by	O
E6	B-GENE
.	O

Another	O
mutant	O
,	O
T255A	O
,	O
lost	O
the	O
ability	O
to	O
bind	O
E4orf6	B-GENE
,	O
but	O
unexpectedly	O
,	O
viral	O
late	O
-	O
gene	O
expression	O
was	O
not	O
affected	O
.	O

Herein	O
PPARgamma	B-GENE
,	O
liganded	O
by	O
either	O
natural	O
(	O
15d	O
-	O
PGJ	O
(	O
2	O
)	O
and	O
PGD	O
(	O
2	O
)	O
)	O
or	O
synthetic	O
ligands	O
(	O
BRL49653	O
and	O
troglitazone	O
)	O
,	O
selectively	O
inhibited	O
expression	O
of	O
the	O
cyclin	B-GENE
D1	I-GENE
gene	I-GENE
.	O

Here	O
we	O
demonstrate	O
that	O
the	O
Ras	B-GENE
-	O
activated	O
Raf	B-GENE
-	O
MEK	B-GENE
-	O
extracellular	B-GENE
signal	I-GENE
-	I-GENE
regulated	I-GENE
kinase	I-GENE
(	O
ERK	B-GENE
)	O
signaling	O
pathway	O
can	O
specifically	O
control	O
the	O
expression	O
of	O
individual	O
integrin	B-GENE
subunits	I-GENE
in	O
a	O
variety	O
of	O
human	O
and	O
mouse	O
cell	O
lines	O
.	O

Children	O
who	O
developed	O
lower	O
respiratory	O
tract	O
infections	O
or	O
PCP	O
had	O
increased	O
rates	O
of	O
decline	O
of	O
CD4	B-GENE
cell	O
counts	O
during	O
the	O
first	O
6	O
months	O
of	O
life	O
.	O

The	O
reproductive	O
effects	O
of	O
the	O
administration	O
of	O
4	O
-	O
chloro	O
-	O
2	O
-	O
methylphenoxyacetic	O
acid	O
(	O
MCPA	O
)	O
to	O
rats	O
were	O
evaluated	O
through	O
two	O
generations	O
,	O
from	O
prior	O
to	O
mating	O
,	O
throughout	O
mating	O
,	O
to	O
gestation	O
and	O
lactation	O
.	O

Coexposure	O
to	O
FP	O
also	O
resulted	O
in	O
a	O
more	O
pronounced	O
and	O
sustained	O
activation	O
of	O
the	O
mitogen	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
kinase	I-GENE
kinase	I-GENE
/	O
extracellular	B-GENE
signal	I-GENE
-	I-GENE
regulated	I-GENE
protein	I-GENE
kinase	I-GENE
cascade	O
after	O
PMA	O
treatment	O
,	O
although	O
disruption	O
of	O
this	O
pathway	O
by	O
the	O
mitogen	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
kinase	I-GENE
kinase	I-GENE
1	I-GENE
inhibitor	O
U0126	O
did	O
not	O
prevent	O
potentiation	O
of	O
apoptosis	O
.	O

Also	O
,	O
the	O
EWS	B-GENE
protein	I-GENE
stimulates	O
transcription	O
mediated	O
by	O
the	O
COOH	O
-	O
terminal	O
transactivation	O
domain	O
of	O
the	O
cofactor	O
CREB	B-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
(	O
CBP	B-GENE
)	O
.	O

In	O
the	O
present	O
study	O
,	O
we	O
have	O
determined	O
the	O
ICBP90	B-GENE
gene	I-GENE
structure	O
by	O
screening	O
of	O
a	O
human	O
placenta	O
genomic	O
library	O
and	O
PCR	O
analysis	O
.	O

Tumor	O
-	O
like	O
accumulation	O
on	O
Tl	O
-	O
201	O
SPECT	O
in	O
subacute	O
hemorrhagic	O
cerebral	O
infarction	O
.	O

METHODS	O
:	O
126	O
patients	O
with	O
histologically	O
confirmed	O
MFH	O
were	O
analyzed	O
.	O

It	O
is	O
surprising	O
that	O
dnaE173	O
,	O
a	O
potent	O
mutator	O
mutation	O
specific	O
for	O
sequence	O
substitution	O
as	O
well	O
as	O
single	O
-	O
base	O
frameshift	O
,	O
did	O
not	O
enhance	O
the	O
frequency	O
of	O
the	O
hot	O
-	O
spot	O
frameshift	O
mutation	O
.	O

Its	O
transcription	O
in	O
vitro	O
by	O
pol	B-GENE
III	I-GENE
requires	O
the	O
same	O
factors	O
as	O
the	O
U6	B-GENE
gene	I-GENE
with	O
the	O
major	O
exception	O
that	O
the	O
modified	O
TATA	O
-	O
box	O
of	O
this	O
construct	O
only	O
interacts	O
with	O
a	O
TATA	B-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
(	O
TBP	B-GENE
)	O
mutant	O
(	O
TBP	B-GENE
-	I-GENE
DR2	I-GENE
)	O
but	O
not	O
with	O
TBP	B-GENE
wild	I-GENE
-	I-GENE
type	I-GENE
(	O
TBPwt	B-GENE
)	O
.	O

HSF	B-GENE
binds	O
DNA	O
as	O
a	O
trimer	O
,	O
and	O
additional	O
trimers	O
can	O
bind	O
DNA	O
co	O
-	O
operatively	O
.	O

We	O
also	O
demonstrate	O
that	O
the	O
spo20	B-GENE
(	I-GENE
+	I-GENE
)	I-GENE
gene	I-GENE
product	I-GENE
is	O
structurally	O
homologous	O
to	O
Saccharomyces	B-GENE
cerevisiae	I-GENE
Sec14	I-GENE
,	O
the	O
major	O
phosphatidylinositol	O
transfer	O
protein	O
of	O
budding	O
yeast	O
.	O

There	O
was	O
no	O
evidence	O
of	O
linkage	O
disequilibrium	O
between	O
the	O
polymorphic	O
site	O
in	O
the	O
B	O
cell	O
specific	O
promoter	O
and	O
those	O
in	O
the	O
3	O
'	O
UTR	O
.	O

Their	O
numbers	O
have	O
regularly	O
increased	O
since	O
the	O
mid	O
-	O
1970s	O
.	O

Specimen	O
mass	O
reduction	O
increased	O
with	O
irradiance	O
from	O
19	O
to	O
72	O
%	O
of	O
the	O
initial	O
mass	O
for	O
9	O
-	O
-	O
31	O
W	O
/	O
cm	O
(	O
2	O
)	O
,	O
respectively	O
.	O

In	O
conclusion	O
,	O
tube	O
size	O
estimated	O
by	O
Cole	O
'	O
s	O
formula	O
tends	O
to	O
be	O
smaller	O
than	O
practically	O
appropriate	O
tube	O
size	O
for	O
pediatric	O
cardiac	O
anesthesia	O
,	O
and	O
therefore	O
we	O
suggest	O
new	O
formula	O
to	O
estimate	O
the	O
tube	O
size	O
.	O

An	O
F222W	B-GENE
:	I-GENE
W21F	I-GENE
rGST	I-GENE
A1	I-GENE
-	I-GENE
1	I-GENE
double	I-GENE
mutant	I-GENE
provides	O
a	O
direct	O
fluorescence	O
probe	O
of	O
changes	O
in	O
the	O
environment	O
of	O
the	O
C	O
-	O
terminal	O
residue	O
.	O

The	O
recessive	O
hos1	B-GENE
mutation	O
causes	O
enhanced	O
induction	O
of	O
the	O
CBF	B-GENE
transcription	I-GENE
factors	I-GENE
by	O
low	O
temperature	O
as	O
well	O
as	O
of	O
their	O
downstream	O
cold	O
-	O
responsive	O
genes	O
.	O

Stable	O
transfection	O
of	O
human	B-GENE
CHOP	I-GENE
cDNA	I-GENE
into	O
mammary	O
carcinoma	O
cells	O
demonstrated	O
that	O
CHOP	B-GENE
functioned	O
not	O
as	O
a	O
mediator	O
of	O
hGH	B-GENE
-	O
stimulated	O
mitogenesis	O
but	O
rather	O
enhanced	O
the	O
protection	O
from	O
apoptosis	O
afforded	O
by	O
hGH	B-GENE
in	O
a	O
p38	B-GENE
MAPK	O
-	O
dependent	O
manner	O
.	O

A	O
comparison	O
of	O
the	O
duplicated	O
Vkappa	B-GENE
genes	I-GENE
suggests	O
positive	O
selection	O
on	O
the	O
complementarity	O
-	O
determining	O
regions	O
of	O
the	O
duplicated	O
genes	O
by	O
point	O
mutations	O
.	O

In	O
contrast	O
,	O
the	O
ubiquitous	O
expression	O
of	O
p19	B-GENE
(	O
INK4d	B-GENE
)	O
has	O
not	O
been	O
previously	O
described	O
in	O
human	O
or	O
murine	O
B	O
-	O
lineage	O
cells	O
.	O

The	O
results	O
show	O
that	O
cognitive	O
stimulation	O
enhanced	O
performance	O
on	O
the	O
Boston	O
Naming	O
Test	O
and	O
a	O
Word	O
List	O
Recognition	O
Task	O
;	O
physical	O
intervention	O
,	O
however	O
,	O
did	O
not	O
reach	O
statistical	O
significance	O
.	O

Instead	O
,	O
affective	O
flattening	O
was	O
associated	O
with	O
both	O
dopamine	B-GENE
receptor	I-GENE
sensitivity	O
and	O
psychomotor	O
slowing	O
.	O

Homo	O
-	O
oligomerisation	O
and	O
nuclear	O
localisation	O
of	O
mouse	B-GENE
histone	I-GENE
deacetylase	I-GENE
1	I-GENE
.	O

With	O
NEU	B-GENE
overexpression	O
,	O
nodal	O
control	O
decreased	O
from	O
72	O
%	O
to	O
34	O
%	O
(	O
p	O
=	O
.	O
008	O
)	O
.	O

At	O
the	O
time	O
of	O
the	O
blind	O
therapeutic	O
doses	O
,	O
Tg	B-GENE
-	O
off	O
values	O
ranged	O
from	O
8	O
to	O
608	O
microg	O
/	O
l	O
.	O

Effects	O
of	O
a	O
booster	O
dose	O
of	O
tetanus	O
toxoid	O
after	O
different	O
primary	O
courses	O
of	O
vaccination	O
:	O
implications	O
on	O
the	O
use	O
of	O
immune	B-GENE
globulin	I-GENE
.	O

Using	O
RACE	O
techniques	O
we	O
have	O
cloned	O
and	O
sequenced	O
one	O
of	O
the	O
hamster	O
liver	O
3	B-GENE
-	I-GENE
hydroxy	I-GENE
-	I-GENE
hexobarbital	I-GENE
dehydrogenases	I-GENE
which	O
catalyze	O
not	O
only	O
cyclic	O
alcohols	O
but	O
also	O
17beta	O
-	O
hydroxy	O
-	O
steroids	O
and	O
3alpha	O
-	O
hydroxysteroids	O
.	O

An	O
association	O
was	O
demonstrated	O
between	O
the	O
expression	O
of	O
aberrantly	O
and	O
/	O
or	O
alternatively	O
spliced	O
mdm2	B-GENE
mRNAs	I-GENE
and	O
a	O
lack	O
of	O
progesterone	B-GENE
receptor	I-GENE
.	O

Histological	O
examination	O
showed	O
lichenoid	O
changes	O
,	O
acantholytic	O
blister	O
formation	O
and	O
apoptotic	O
keratinocytes	O
.	O

We	O
find	O
that	O
our	O
response	O
function	O
is	O
well	O
approximated	O
by	O
the	O
GSER	O
only	O
within	O
a	O
particular	O
frequency	O
range	O
determined	O
by	O
the	O
material	O
parameters	O
of	O
both	O
the	O
bead	O
and	O
the	O
network	O
.	O

It	O
is	O
shown	O
that	O
,	O
for	O
any	O
periodic	O
input	O
,	O
the	O
map	O
representing	O
the	O
relation	O
between	O
input	O
phases	O
at	O
consecutive	O
discharge	O
times	O
can	O
be	O
restricted	O
to	O
a	O
piecewise	O
continuous	O
,	O
orientation	O
preserving	O
circle	O
map	O
.	O

Nine	O
strains	O
were	O
subtyped	O
as	O
Camp	O
.	O
jejuni	O
subsp	O
.	O
jejuni	O
biotype	O
II	O
and	O
the	O
remaining	O
ones	O
as	O
biotype	O
I	O
.	O

Analysis	O
of	O
mCTR	B-GENE
mRNAs	I-GENE
has	O
revealed	O
that	O
the	O
three	O
alternative	O
promoters	O
give	O
rise	O
to	O
at	O
least	O
seven	O
mCTR	B-GENE
isoforms	I-GENE
in	O
the	O
5	O
'	O
region	O
of	O
the	O
gene	O
and	O
generate	O
5	O
'	O
-	O
untranslated	O
regions	O
of	O
very	O
different	O
lengths	O
.	O

Effects	O
of	O
3	O
'	O
terminus	O
modifications	O
on	O
mRNA	O
functional	O
decay	O
during	O
in	O
vitro	O
protein	O
synthesis	O
.	O

A	O
comprehensive	O
neuropsychological	O
battery	O
was	O
administered	O
to	O
48	O
veterans	O
with	O
Gulf	O
War	O
Illness	O
(	O
GWI	O
)	O
characterized	O
by	O
severe	O
fatigue	O
(	O
GV	O
-	O
F	O
)	O
and	O
39	O
healthy	O
veterans	O
(	O
GV	O
-	O
H	O
)	O
.	O

Reverse	O
transcription	O
-	O
PCR	O
analysis	O
of	O
mRNA	O
from	O
patients	O
shows	O
that	O
each	O
of	O
these	O
five	O
mutations	O
results	O
in	O
aberrant	O
splicing	O
.	O

RESULTS	O
:	O
Coronary	O
mortality	O
during	O
the	O
median	O
follow	O
-	O
up	O
time	O
of	O
17	O
months	O
was	O
6	O
-	O
fold	O
higher	O
in	O
the	O
highest	O
tertile	O
for	O
CRP	B-GENE
and	O
IL	B-GENE
-	I-GENE
6	I-GENE
and	O
3	O
.	O
5	O
-	O
fold	O
higher	O
in	O
the	O
highest	O
tertile	O
for	O
fibrinogen	B-GENE
and	O
TNF	B-GENE
-	I-GENE
alpha	I-GENE
than	O
in	O
the	O
respective	O
combined	O
lower	O
tertiles	O
.	O

The	O
relationship	O
of	O
the	O
factor	B-GENE
V	I-GENE
Leiden	I-GENE
mutation	I-GENE
or	O
the	O
deletion	O
-	O
deletion	O
polymorphism	O
of	O
the	O
angiotensin	B-GENE
converting	I-GENE
enzyme	I-GENE
to	O
postoperative	O
thromboembolic	O
events	O
following	O
total	O
joint	O
arthroplasty	O
.	O

To	O
examine	O
transcriptional	O
regulation	O
of	O
the	O
rat	B-GENE
eIF4E	I-GENE
gene	I-GENE
,	O
2	O
.	O
1	O
kB	O
of	O
the	O
rat	B-GENE
eIF4E	I-GENE
promoter	I-GENE
region	I-GENE
was	O
cloned	O
and	O
the	O
contribution	O
of	O
specific	O
elements	O
in	O
regulating	O
transcription	O
was	O
determined	O
in	O
primary	O
cultures	O
of	O
rat	O
cardiocytes	O
and	O
in	O
a	O
murine	O
C	O
(	O
2	O
)	O
C	O
(	O
12	O
)	O
myoblast	O
cell	O
line	O
.	O

In	O
the	O
remaining	O
case	O
,	O
the	O
aneurysm	O
originated	O
from	O
the	O
proximal	O
end	O
of	O
the	O
associated	O
A1	O
fenestration	O
.	O

GABA	B-GENE
(	I-GENE
B	I-GENE
)	I-GENE
R1g	I-GENE
was	O
expressed	O
in	O
both	O
brain	O
and	O
peripheral	O
tissues	O
.	O

Raes	O
,	O
P	O
.	O

NF	B-GENE
-	I-GENE
kappaB	I-GENE
pathway	O
activation	O
occurs	O
during	O
transformation	O
induced	O
by	O
a	O
number	O
of	O
classical	O
oncogenes	O
,	O
including	O
Bcr	B-GENE
/	O
Abl	B-GENE
,	O
Ras	B-GENE
and	O
Rac	B-GENE
,	O
and	O
is	O
necessary	O
for	O
full	O
transforming	O
potential	O
.	O

We	O
used	O
a	O
rev	B-GENE
-	O
and	O
RRE	B-GENE
-	O
defective	O
HIV	O
type	O
1	O
(	O
HIV	O
-	O
1	O
)	O
molecular	O
clone	O
in	O
complementation	O
experiments	O
to	O
establish	O
a	O
method	O
for	O
the	O
rapid	O
isolation	O
of	O
posttranscriptional	O
regulatory	O
elements	O
from	O
the	O
mammalian	O
genome	O
by	O
selecting	O
for	O
rescue	O
of	O
virus	O
replication	O
.	O

Copyright	O
2001	O
Academic	O
Press	O
.	O

A	O
novel	O
myeloid	O
-	O
restricted	O
zebrafish	O
CCAAT	B-GENE
/	I-GENE
enhancer	I-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
with	O
a	O
potent	O
transcriptional	O
activation	O
domain	O
.	O

Recently	O
,	O
we	O
discovered	O
that	O
alanine	O
substitutions	O
of	O
the	O
active	O
center	O
cleft	O
residues	O
significantly	O
impair	O
the	O
depurinating	O
and	O
ribosome	O
inhibitory	O
activity	O
of	O
PAP	B-GENE
.	O

SH2D1A	B-GENE
protein	I-GENE
levels	O
are	O
up	O
-	O
regulated	O
by	O
CD40	B-GENE
cross	O
-	O
linking	O
and	O
down	O
-	O
regulated	O
by	O
B	B-GENE
cell	I-GENE
receptor	I-GENE
ligation	O
.	O

Cross	O
-	O
linking	O
FcalphaR	B-GENE
on	O
wt	B-GENE
-	I-GENE
ITAM	I-GENE
or	O
IIA	B-GENE
-	I-GENE
ITAM	I-GENE
cells	O
triggered	O
equivalent	O
PI	B-GENE
3	I-GENE
-	I-GENE
kinase	I-GENE
-	O
dependent	O
activation	O
of	O
PKBalpha	B-GENE
.	O

RPM	B-GENE
/	O
RGL3	B-GENE
resembled	O
AF	B-GENE
-	I-GENE
6	I-GENE
and	O
Nore1	B-GENE
in	O
interacting	O
strongly	O
with	O
constitutively	O
active	O
M	B-GENE
-	I-GENE
Ras	I-GENE
and	O
p21	B-GENE
Ras	I-GENE
.	O

A	O
novel	O
potential	O
effector	O
of	O
M	B-GENE
-	I-GENE
Ras	I-GENE
and	O
p21	B-GENE
Ras	I-GENE
negatively	O
regulates	O
p21	B-GENE
Ras	I-GENE
-	O
mediated	O
gene	O
induction	O
and	O
cell	O
growth	O
.	O

The	O
mice	O
are	O
phenotypically	O
normal	O
and	O
do	O
not	O
develop	O
spontaneous	O
tumors	O
at	O
an	O
early	O
age	O
,	O
in	O
contrast	O
to	O
knock	O
-	O
out	O
(	O
p53	B-GENE
(	I-GENE
-	I-GENE
/	I-GENE
-	I-GENE
)	I-GENE
)	O
strains	O
with	O
a	O
defective	O
p53	B-GENE
gene	I-GENE
.	O

Cyclins	B-GENE
are	O
one	O
of	O
the	O
pivotal	O
determinants	O
regulating	O
cell	O
cycle	O
progression	O
.	O

Evidence	O
-	O
based	O
care	O
:	O
a	O
new	O
formula	O
for	O
an	O
old	O
problem	O
?	O

Further	O
,	O
the	O
osteo	O
-	O
retentive	O
ability	O
of	O
the	O
hydroxyapatite	O
in	O
the	O
sockets	O
was	O
seen	O
to	O
be	O
close	O
to	O
significance	O
(	O
after	O
six	O
months	O
width	O
differences	O
,	O
in	O
the	O
canine	O
region	O
:	O
P	O
=	O
0	O
.	O
059	O
,	O
LHS	O
,	O
and	O
P	O
=	O
0	O
.	O
065	O
,	O
RHS	O
)	O
.	O

The	O
cleavage	O
site	O
between	O
VPg	B-GENE
and	O
RNA	B-GENE
dependent	I-GENE
RNA	I-GENE
polymerase	I-GENE
was	O
predicted	O
to	O
be	O
E445	O
-	O
T446	O
based	O
on	O
the	O
amino	O
acid	O
sequence	O
analysis	O
of	O
the	O
polyprotein	O
from	O
different	O
sobemoviruses	O
.	O

The	O
%	O
SVend	O
of	O
HCM	O
-	O
I	O
was	O
significantly	O
lower	O
than	O
the	O
respective	O
values	O
of	O
the	O
HCM	O
-	O
II	O
and	O
Control	O
groups	O
.	O

Nearly	O
all	O
isolates	O
of	O
S	O
.	O
intermedius	O
and	O
most	O
isolates	O
of	O
S	O
.	O
constellatus	O
,	O
but	O
only	O
19	O
%	O
of	O
those	O
of	O
S	O
.	O
anginosus	O
,	O
were	O
associated	O
with	O
abscess	O
.	O

DESIGN	O
:	O
Retrospective	O
study	O
.	O

Human	O
brain	O
cDNA	O
library	O
screening	O
and	O
5	O
'	O
rapid	O
amplification	O
of	O
cDNA	O
ends	O
yielded	O
full	B-GENE
-	I-GENE
length	I-GENE
DENTT	I-GENE
cDNA	I-GENE
containing	O
an	O
1899	O
-	O
bp	O
open	O
reading	O
frame	O
encoding	O
a	O
predicted	O
633	O
-	O
amino	O
-	O
acid	O
protein	O
with	O
four	O
potential	O
nuclear	O
localization	O
signals	O
(	O
NLSs	O
)	O
and	O
two	O
coiled	O
-	O
coil	O
regions	O
.	O

Transfection	O
of	O
EGFP	B-GENE
-	O
tagged	O
DENTT	B-GENE
NLS	O
deletion	O
constructs	O
lacking	O
the	O
bipartite	O
NLS	B-GENE
-	I-GENE
1	I-GENE
were	O
excluded	O
from	O
the	O
nucleolus	O
.	O

These	O
genes	O
encode	O
a	O
tryptophanyl	B-GENE
tRNA	I-GENE
,	O
the	O
protein	B-GENE
translocase	I-GENE
component	O
SecE	B-GENE
,	O
the	O
antiterminator	B-GENE
protein	I-GENE
NusG	I-GENE
,	O
and	O
the	O
ribosomal	O
proteins	O
L11	B-GENE
and	O
L1	B-GENE
in	O
addition	O
to	O
PkwR	B-GENE
,	O
a	O
putative	O
regulatory	O
protein	O
of	O
the	O
LacI	B-GENE
-	O
GalR	B-GENE
family	O
.	O

Rapamycin	O
(	O
FRAP	B-GENE
/	O
mTOR	B-GENE
inhibitor	O
)	O
blocked	O
4E	B-GENE
-	I-GENE
BP1	I-GENE
phosphorylation	O
causing	O
a	O
predominance	O
of	O
the	O
alpha	O
(	O
hypophosphorylated	O
)	O
band	O
.	O

Sixteen	O
out	O
of	O
52	O
seropositive	O
MS	O
patients	O
(	O
30	O
.	O
8	O
%	O
)	O
showed	O
intrathecal	O
synthesis	O
of	O
C	B-GENE
.	I-GENE
pneumoniae	I-GENE
-	I-GENE
specific	I-GENE
IgG	I-GENE
but	O
only	O
one	O
of	O
43	O
seropositive	O
controls	O
(	O
2	O
.	O
3	O
%	O
)	O
.	O

Far	O
Western	O
blot	O
analysis	O
suggested	O
that	O
the	O
tandem	O
SH2	B-GENE
domains	I-GENE
of	O
SHP2	B-GENE
bind	O
to	O
Gab1	B-GENE
in	O
a	O
specific	O
orientation	O
,	O
in	O
which	O
the	O
N	B-GENE
-	I-GENE
SH2	I-GENE
domain	I-GENE
binds	O
to	O
phosphotyrosine	O
(	O
Tyr	O
(	O
P	O
)	O
)	O
-	O
627	O
and	O
the	O
C	B-GENE
-	I-GENE
SH2	I-GENE
domain	I-GENE
binds	O
to	O
Tyr	O
(	O
P	O
)	O
-	O
659	O
.	O

Molecular	O
cloning	O
,	O
genomic	O
mapping	O
,	O
and	O
expression	O
of	O
two	O
secretor	B-GENE
blood	I-GENE
group	I-GENE
alpha	I-GENE
(	I-GENE
1	I-GENE
,	I-GENE
2	I-GENE
)	I-GENE
fucosyltransferase	I-GENE
genes	I-GENE
differentially	O
regulated	O
in	O
mouse	O
uterine	O
epithelium	O
and	O
gastrointestinal	O
tract	O
.	O

The	O
UBA	B-GENE
domains	I-GENE
of	O
RAD23	B-GENE
and	O
DDI1	B-GENE
are	O
required	O
for	O
these	O
interactions	O
.	O

It	O
was	O
found	O
that	O
intrathecal	O
administration	O
(	O
i	O
.	O
t	O
.	O
)	O
of	O
D2	B-GENE
receptor	I-GENE
agonist	O
LY171555	O
or	O
D1	B-GENE
/	I-GENE
D2	I-GENE
receptor	I-GENE
agonist	O
apomorphine	O
increased	O
pain	O
threshold	O
and	O
had	O
a	O
potentiating	O
effect	O
on	O
AA	O
.	O

The	O
R2	O
between	O
MFI	O
of	O
fresh	O
and	O
frozen	O
muscle	O
was	O
0	O
.	O
94	O
and	O
0	O
.	O
92	O
for	O
lamb	O
and	O
pork	O
longissimus	O
,	O
respectively	O
.	O

After	O
all	O
doses	O
of	O
d	O
-	O
amphetamine	O
,	O
responding	O
occurred	O
largely	O
on	O
the	O
saline	O
key	O
under	O
both	O
schedules	O
.	O

Intravenous	O
L	O
-	O
carnitine	O
treatment	O
increased	O
plasma	O
carnitine	O
concentrations	O
,	O
improved	O
patient	O
-	O
assessed	O
fatigue	O
,	O
and	O
may	O
prevent	O
the	O
decline	O
in	O
peak	O
exercise	O
capacity	O
in	O
hemodialysis	O
patients	O
.	O

Elevated	O
expression	O
of	O
full	B-GENE
-	I-GENE
length	I-GENE
UhpB	I-GENE
or	O
of	O
a	O
soluble	O
hybrid	O
protein	O
,	O
GST	B-GENE
-	O
Bc	B-GENE
,	O
which	O
is	O
glutathione	B-GENE
S	I-GENE
-	I-GENE
transferase	I-GENE
(	O
GST	B-GENE
)	O
fused	O
to	O
the	O
cytoplasmic	O
C	O
-	O
terminal	O
portion	O
of	O
UhpB	B-GENE
,	O
results	O
in	O
complete	O
blockage	O
of	O
uhpT	B-GENE
expression	O
in	O
a	O
uhp	B-GENE
(	I-GENE
+	I-GENE
)	I-GENE
strain	O
.	O

Here	O
we	O
show	O
that	O
PKC	B-GENE
and	O
p44	B-GENE
/	O
p42MAPK	B-GENE
signalings	O
are	O
required	O
for	O
the	O
HBx	B-GENE
-	O
induced	O
Sp1	B-GENE
-	O
mediated	O
IGF	B-GENE
-	I-GENE
II	I-GENE
P4	I-GENE
transcriptional	O
activity	O
since	O
(	O
i	O
)	O
PKC	B-GENE
activation	O
by	O
PMA	O
or	O
PKC	B-GENE
expression	O
vector	O
increases	O
Sp1	B-GENE
phosphorylation	O
and	O
P4	B-GENE
activity	O
in	O
HBx	B-GENE
-	O
transfected	O
HepG2	O
cells	O
;	O
(	O
ii	O
)	O
PKC	B-GENE
inhibition	O
by	O
PKC	B-GENE
inhibitor	O
Go6976	O
reduces	O
Sp1	B-GENE
phosphorylation	O
,	O
P4	B-GENE
activity	O
,	O
and	O
IGF	B-GENE
-	I-GENE
II	I-GENE
mRNA	I-GENE
in	O
HBx	B-GENE
-	O
transfected	O
HepG2	O
cells	O
;	O
and	O
(	O
iii	O
)	O
the	O
inhibition	O
of	O
MEK	B-GENE
activation	O
by	O
U0126	O
reduces	O
Sp1	B-GENE
phosphorylation	O
,	O
P4	B-GENE
activity	O
and	O
IGF	B-GENE
-	I-GENE
II	I-GENE
mRNA	I-GENE
in	O
HBx	B-GENE
-	O
transfected	O
HepG2	O
cells	O
.	O

Through	O
two	O
novel	O
mechanisms	O
,	O
Arf	B-GENE
inhibits	O
the	O
oncoprotein	B-GENE
Hdm2	I-GENE
,	O
a	O
negative	O
regulator	O
of	O
p53	B-GENE
.	O

In	O
the	O
free	O
-	O
swimming	O
rotatory	O
test	O
mice	O
spend	O
most	O
of	O
the	O
time	O
swimming	O
close	O
to	O
the	O
wall	O
of	O
the	O
container	O
attempting	O
to	O
escape	O
from	O
an	O
aversive	O
test	O
situation	O
.	O

Examination	O
of	O
various	O
promoter	O
deletion	O
mutants	O
indicated	O
that	O
SF	B-GENE
-	I-GENE
1	I-GENE
acts	O
through	O
the	O
proximal	O
promoter	O
region	O
and	O
upstream	O
promoter	O
sequences	O
.	O

Prrp	B-GENE
can	O
also	O
associate	O
with	O
the	O
EVH1	B-GENE
domain	I-GENE
of	O
Mena	B-GENE
,	O
another	O
microfilament	O
-	O
associated	O
protein	O
.	O

Srb10	B-GENE
is	O
a	O
physiological	O
regulator	O
of	O
Gcn4	B-GENE
stability	O
because	O
both	O
phosphorylation	O
and	O
turnover	O
of	O
Gcn4	B-GENE
are	O
diminished	O
in	O
srb10	B-GENE
mutants	I-GENE
.	O

A	O
new	O
intron	O
of	O
476	O
base	O
pairs	O
was	O
found	O
in	O
the	O
middle	O
of	O
the	O
5	O
'	O
-	O
untranslated	O
leader	O
sequence	O
and	O
was	O
shown	O
to	O
robustly	O
enhance	O
the	O
promoter	O
activity	O
.	O

Based	O
on	O
this	O
analysis	O
,	O
we	O
propose	O
that	O
the	O
interactions	O
of	O
Sos	B-GENE
with	O
the	O
switch	O
1	O
and	O
switch	O
2	O
regions	O
of	O
Ras	B-GENE
have	O
distinct	O
functional	O
consequences	O
:	O
the	O
interaction	O
with	O
switch	O
2	O
mediates	O
the	O
anchoring	O
of	O
Ras	B-GENE
to	O
Sos	B-GENE
,	O
whereas	O
the	O
interaction	O
with	O
switch	O
1	O
leads	O
to	O
disruption	O
of	O
the	O
nucleotide	O
-	O
binding	O
site	O
and	O
GDP	O
dissociation	O
.	O

A	O
log	O
-	O
linear	O
dose	O
-	O
response	O
was	O
obtained	O
for	O
the	O
average	O
increase	O
in	O
FEV1	O
up	O
to	O
6	O
h	O
(	O
AUC0	O
-	O
6	O
h	O
)	O
and	O
peak	O
FEV1	O
across	O
the	O
dose	O
range	O
administered	O
by	O
Respimat	O
.	O

Bandshift	O
experiments	O
demonstrate	O
that	O
BmHR3A	B-GENE
binds	O
specifically	O
to	O
RORE	B-GENE
(	O
Retinoic	B-GENE
acid	I-GENE
-	I-GENE
related	I-GENE
Orphan	I-GENE
receptor	I-GENE
Response	I-GENE
Element	I-GENE
)	O
-	O
like	O
sequences	O
in	O
the	O
promoters	O
of	O
both	O
genes	O
,	O
thus	O
suggesting	O
a	O
direct	O
role	O
for	O
BmHR3A	B-GENE
in	O
regulating	O
the	O
expression	O
of	O
BmGATAbeta	B-GENE
and	O
ESP	B-GENE
genes	I-GENE
during	O
vitellogenesis	O
.	O

This	O
was	O
most	O
pronounced	O
during	O
the	O
initial	O
phase	O
of	O
Erk	B-GENE
activation	O
.	O

The	O
iterative	O
method	O
proposed	O
by	O
Bengtsson	O
[	O
Appl	O
.	O

The	O
COD	O
and	O
color	O
removals	O
were	O
both	O
more	O
than	O
90	O
%	O
when	O
FeCl3	O
was	O
used	O
as	O
the	O
coagulation	O
(	O
dosages	O
of	O
two	O
-	O
step	O
coagulation	O
were	O
0	O
.	O
031	O
and	O
0	O
.	O
012	O
mol	O
/	O
L	O
respectively	O
)	O
after	O
a	O
ferrous	O
hydrogen	O
peroxide	O
oxidation	O
pretreatment	O
at	O
a	O
H2O2	O
dosage	O
of	O
0	O
.	O
06	O
mol	O
/	O
L	O
.	O

Although	O
there	O
was	O
a	O
high	O
correlation	O
between	O
sap	O
flux	O
densities	O
registered	O
by	O
the	O
old	O
and	O
new	O
sensors	O
,	O
significant	O
differences	O
in	O
sap	O
flux	O
densities	O
between	O
the	O
duplicated	O
sensors	O
were	O
detected	O
.	O

Three	O
of	O
the	O
proteins	O
involved	O
in	O
checkpoint	O
signaling	O
,	O
Rad1	B-GENE
,	O
Hus1	B-GENE
,	O
and	O
Rad9	B-GENE
,	O
have	O
been	O
shown	O
to	O
interact	O
by	O
immunoprecipitation	O
and	O
yeast	O
two	O
-	O
hybrid	O
studies	O
.	O

Based	O
on	O
the	O
hypothesis	O
that	O
evolutionarily	O
conserved	O
regions	O
are	O
functionally	O
important	O
and	O
likely	O
to	O
interact	O
with	O
coactivators	O
,	O
we	O
compared	O
the	O
amino	O
acid	O
sequence	O
of	O
C	B-GENE
/	I-GENE
EBPalpha	I-GENE
from	O
different	O
species	O
(	O
frog	O
to	O
human	O
)	O
and	O
identified	O
four	O
highly	O
conserved	O
regions	O
(	O
CR1	O
-	O
CR4	O
)	O
within	O
the	O
transactivation	O
domain	O
.	O

Tolerance	O
to	O
ADAL	O
-	O
2	O
was	O
similar	O
to	O
that	O
of	O
Vicryl	O
suture	O
and	O
tolerance	O
to	O
ADAL	O
-	O
2	O
was	O
superior	O
to	O
that	O
to	O
Tisuacryl	O
.	O

Of	O
the	O
patients	O
in	O
each	O
regimen	O
who	O
reached	O
study	O
end	O
points	O
,	O
17	O
of	O
29	O
(	O
59	O
%	O
)	O
were	O
in	O
regimen	O
A	O
,	O
11	O
of	O
20	O
(	O
55	O
%	O
)	O
were	O
in	O
regimen	O
B	O
,	O
and	O
28	O
of	O
43	O
(	O
65	O
%	O
)	O
were	O
in	O
regimen	O
C	O
met	O
the	O
treatment	O
success	O
criterion	O
.	O

SAMPLE	O
POPULATION	O
:	O
MCB	O
from	O
7	O
racing	O
Greyhounds	O
euthanatized	O
for	O
reasons	O
unrelated	O
to	O
MCB	O
abnormalities	O
.	O

CONCLUSIONS	O
AND	O
CLINICAL	O
RELEVANCE	O
:	O
Increased	O
cortical	O
thickness	O
and	O
geometric	O
properties	O
of	O
left	O
MCB	O
-	O
IV	O
and	O
-	O
V	O
of	O
Greyhounds	O
,	O
together	O
with	O
altered	O
turnover	O
and	O
orientation	O
of	O
osteons	O
in	O
the	O
dorsal	O
quadrants	O
of	O
left	O
MCB	O
,	O
are	O
site	O
-	O
specific	O
adaptive	O
responses	O
associated	O
with	O
asymmetric	O
cyclic	O
loading	O
as	O
a	O
result	O
of	O
racing	O
on	O
circular	O
tracks	O
.	O

METHODS	O
AND	O
RESULTS	O
:	O
Palmaz	O
-	O
Schatz	O
stents	O
were	O
dip	O
-	O
coated	O
with	O
paclitaxel	O
(	O
0	O
,	O
0	O
.	O
2	O
,	O
15	O
,	O
or	O
187	O
microgram	O
/	O
stent	O
)	O
by	O
immersion	O
in	O
ethanolic	O
paclitaxel	O
and	O
evaporation	O
of	O
the	O
solvent	O
.	O

Percentages	O
of	O
recovery	O
for	O
overload	O
and	O
dilution	O
tests	O
were	O
between	O
87	O
and	O
120	O
%	O
.	O

One	O
of	O
the	O
conserved	O
RNA	O
subdomains	O
,	O
designated	O
P3	B-GENE
,	O
has	O
previously	O
been	O
shown	O
to	O
be	O
required	O
for	O
nucleolar	O
localization	O
.	O

In	O
Cd	O
-	O
spiked	O
OECD	O
soil	O
,	O
internal	O
Cd	O
levels	O
were	O
linearly	O
related	O
to	O
external	O
Cd	O
concentrations	O
,	O
whereas	O
the	O
springtails	O
maintained	O
fixed	O
internal	O
levels	O
of	O
Cu	O
and	O
Zn	O
regardless	O
of	O
spiked	O
concentrations	O
.	O

Nutritional	O
status	O
in	O
adults	O
on	O
an	O
alternative	O
or	O
traditional	O
diet	O
]	O
BACKGROUND	O
:	O
Plant	O
food	O
lacks	O
vitamin	O
B12	O
,	O
vitamin	O
D	O
and	O
higher	O
n	O
-	O
3	O
polyunsaturated	O
fatty	O
acids	O
.	O

It	O
is	O
useful	O
as	O
an	O
adjunct	O
to	O
mammography	O
in	O
those	O
patients	O
with	O
radiographically	O
dense	O
breasts	O
for	O
the	O
characterization	O
of	O
palpable	O
masses	O
.	O

Measurements	O
were	O
obtained	O
:	O
(	O
i	O
)	O
just	O
after	O
the	O
traumatic	O
exposure	O
(	O
D0	O
)	O
;	O
(	O
ii	O
)	O
3	O
days	O
after	O
this	O
first	O
measurement	O
(	O
D3	O
)	O
;	O
and	O
(	O
iii	O
)	O
30	O
days	O
after	O
(	O
D30	O
)	O
.	O

Changes	O
of	O
the	O
DB	O
sequence	O
without	O
affecting	O
the	O
postulated	O
stem	O
structure	O
led	O
to	O
drastic	O
losses	O
of	O
translation	O
efficiency	O
.	O

It	O
has	O
been	O
suggested	O
that	O
members	O
of	O
this	O
protein	O
family	O
exhibit	O
both	O
prolyl	B-GENE
isomerase	I-GENE
and	O
chaperone	O
activity	O
.	O

Inhibition	O
of	O
the	O
Raf	B-GENE
-	I-GENE
1	I-GENE
target	I-GENE
ERK	B-GENE
kinase	I-GENE
(	O
MEK	B-GENE
)	O
either	O
attenuated	O
or	O
abolished	O
Rp	O
-	O
cAMPS	O
-	O
and	O
PKI	B-GENE
-	O
induced	O
ERK	B-GENE
activation	O
,	O
caldesmon	B-GENE
phosphorylation	O
,	O
and	O
stress	O
fiber	O
formation	O
.	O

PACAP	B-GENE
mRNA	I-GENE
was	O
widely	O
expressed	O
in	O
most	O
human	O
tissues	O
;	O
in	O
transfected	O
cells	O
,	O
PACAP	B-GENE
was	O
diffusely	O
expressed	O
in	O
the	O
cytoplasm	O
.	O

The	O
radial	O
forearm	O
flap	O
is	O
used	O
most	O
commonly	O
,	O
however	O
the	O
lateral	O
arm	O
flap	O
may	O
be	O
the	O
flap	O
of	O
choice	O
in	O
certain	O
situations	O
.	O

By	O
comparison	O
,	O
in	O
nontumorigenic	O
Ad5	O
cells	O
,	O
class	O
I	O
expression	O
is	O
high	O
due	O
to	O
negligible	O
binding	O
of	O
COUP	B-GENE
-	I-GENE
TF	I-GENE
and	O
strong	O
binding	O
of	O
NF	B-GENE
-	I-GENE
kappaB	I-GENE
.	O

As	O
an	O
application	O
of	O
reverse	O
genetics	O
,	O
we	O
introduced	O
one	O
nucleotide	O
change	O
(	O
UCU	O
to	O
ACU	O
)	O
to	O
immediate	O
downstream	O
of	O
the	O
RNA	O
-	O
editing	O
site	O
of	O
the	O
V	B-GENE
gene	I-GENE
in	O
the	O
full	O
-	O
length	O
hPIV2	O
cDNA	O
and	O
were	O
able	O
to	O
obtain	O
infectious	O
viruses	O
[	O
rPIV2V	O
(	O
-	O
)	O
]	O
from	O
the	O
cDNA	O
.	O

The	O
frameshift	O
initiated	O
by	O
ADEx2	O
is	O
believed	O
to	O
alter	O
the	O
regular	O
coding	O
sequence	O
,	O
acting	O
as	O
a	O
loss	O
-	O
of	O
-	O
function	O
ASIP	B-GENE
mutation	I-GENE
.	O

In	O
regards	O
to	O
the	O
latter	O
activity	O
,	O
it	O
has	O
been	O
shown	O
that	O
S3	B-GENE
contains	O
vigorous	O
N	B-GENE
-	I-GENE
glycosylase	I-GENE
activity	O
for	O
the	O
removal	O
of	O
8	O
-	O
oxoguanine	O
residues	O
in	O
DNA	O
that	O
leaves	O
baseless	O
sites	O
in	O
their	O
places	O
.	O

Here	O
we	O
report	O
the	O
isolation	O
and	O
characterization	O
of	O
the	O
forkhead	B-GENE
homologue	I-GENE
in	I-GENE
rhabdomyosarcoma	I-GENE
(	O
FKHR	B-GENE
)	O
,	O
a	O
recently	O
described	O
member	O
of	O
the	O
hepatocyte	B-GENE
nuclear	I-GENE
factor	I-GENE
3	I-GENE
/	O
forkhead	B-GENE
homeotic	B-GENE
gene	I-GENE
family	I-GENE
,	O
as	O
a	O
nuclear	B-GENE
hormone	I-GENE
receptor	I-GENE
(	O
NR	B-GENE
)	O
intermediary	O
protein	O
.	O

The	O
improved	O
CSF	O
outflow	O
conductance	O
may	O
increase	O
the	O
intracranial	O
compliance	O
and	O
thereby	O
dampen	O
a	O
pathological	O
ICP	O
waveform	O
.	O

A	O
new	O
species	O
of	O
Euspondylus	O
is	O
described	O
based	O
on	O
a	O
female	O
(	O
taken	O
within	O
a	O
bromeliad	O
)	O
from	O
Cerro	O
El	O
Humo	O
,	O
Sucre	O
,	O
northeastern	O
Venezuela	O
.	O

The	O
cyclins	B-GENE
bind	O
to	O
and	O
activate	O
the	O
CDK	B-GENE
,	O
which	O
leads	O
to	O
phosphorylation	O
(	O
and	O
then	O
inhibition	O
)	O
of	O
the	O
tumor	O
suppressor	O
protein	O
,	O
pRb	B-GENE
.	O
pRb	B-GENE
controls	O
commitment	O
to	O
progress	O
from	O
the	O
G1	O
to	O
S	O
phase	O
,	O
at	O
least	O
in	O
part	O
by	O
repressing	O
the	O
activity	O
of	O
the	O
E2F	B-GENE
transcription	I-GENE
factors	I-GENE
known	O
to	O
promote	O
cell	O
proliferation	O
.	O

Additional	O
education	O
and	O
research	O
is	O
needed	O
to	O
provide	O
further	O
direction	O
for	O
intervention	O
and	O
incorporation	O
into	O
practice	O
.	O

Proliferative	O
vasculopathy	O
and	O
cutaneous	O
hemorrhages	O
in	O
porcine	O
neonates	O
infected	O
with	O
the	O
porcine	O
reproductive	O
and	O
respiratory	O
syndrome	O
virus	O
.	O

The	O
difference	O
of	O
hardness	O
over	O
time	O
of	O
composite	O
specimens	O
was	O
measured	O
using	O
Knoop	O
hardness	O
measurements	O
taken	O
at	O
the	O
top	O
and	O
bottom	O
surfaces	O
of	O
resin	O
specimens	O
made	O
in	O
a	O
Teflon	O
mold	O
the	O
same	O
dimensions	O
as	O
the	O
cavity	O
prepared	O
in	O
dentin	O
.	O

An	O
18	O
-	O
kb	O
genomic	O
clone	O
including	O
sequences	O
encoding	O
for	O
the	O
two	O
GHS	B-GENE
-	I-GENE
R	I-GENE
variants	I-GENE
was	O
isolated	O
.	O

Saccharomyces	O
cerevisiae	O
activates	O
a	O
regulatory	O
network	O
called	O
"	O
general	O
control	O
"	O
that	O
provides	O
the	O
cell	O
with	O
sufficient	O
amounts	O
of	O
protein	O
precursors	O
during	O
amino	O
acid	O
starvation	O
.	O

In	O
Ka13	O
cells	O
,	O
CoCl	O
(	O
2	O
)	O
stimulated	O
expression	O
of	O
a	O
luciferase	B-GENE
reporter	I-GENE
gene	I-GENE
under	O
the	O
control	O
of	O
a	O
15	B-GENE
-	I-GENE
kilobase	I-GENE
pair	I-GENE
mouse	I-GENE
ho	I-GENE
-	I-GENE
1	I-GENE
promoter	I-GENE
(	O
pHO15luc	B-GENE
)	O
.	O

Mutation	O
analyses	O
identified	O
the	O
cobalt	O
-	O
responsive	O
sequences	O
as	O
the	O
stress	O
-	O
response	O
elements	O
(	O
StREs	O
)	O
.	O

Members	O
of	O
the	O
AP	B-GENE
-	I-GENE
1	I-GENE
superfamily	I-GENE
of	I-GENE
basic	I-GENE
-	I-GENE
leucine	I-GENE
zipper	I-GENE
factors	I-GENE
bind	O
to	O
the	O
StRE	O
.	O

Descriptions	O
of	O
this	O
locus	O
would	O
allow	O
comparison	O
with	O
functionally	O
relevant	O
molecular	O
genetic	O
features	O
of	O
other	O
species	O
'	O
homologous	O
loci	O
including	O
the	O
single	O
-	O
copy	O
equid	O
LH	B-GENE
/	O
CGbeta	B-GENE
gene	O
and	O
the	O
primate	O
LHbeta	B-GENE
-	O
CGbeta	B-GENE
gene	O
cluster	O
locus	O
.	O

Like	O
the	O
consensus	B-GENE
mammalian	I-GENE
LHbeta	I-GENE
gene	I-GENE
,	O
the	O
5	O
'	O
-	O
flanking	O
region	O
of	O
the	O
gpLH	B-GENE
/	O
CGbeta	B-GENE
gene	O
contains	O
a	O
single	O
TATA	O
sequence	O
37	O
bp	O
upstream	O
of	O
the	O
translation	O
start	O
codon	O
.	O

This	O
shows	O
that	O
in	O
situations	O
of	O
separated	O
breaks	O
,	O
NHEJ	O
deficiency	O
leads	O
to	O
genomic	O
rearrangements	O
,	O
in	O
agreement	O
with	O
chromosomal	O
studies	O
.	O

Foxp1	B-GENE
and	O
Foxp2	B-GENE
are	O
expressed	O
at	O
high	O
levels	O
in	O
the	O
lung	O
as	O
early	O
as	O
E12	O
.	O
5	O
of	O
mouse	O
development	O
with	O
Foxp2	B-GENE
expression	O
restricted	O
to	O
the	O
airway	O
epithelium	O
.	O

Immunological	O
and	O
biochemical	O
characterization	O
of	O
streptococcal	B-GENE
pyrogenic	I-GENE
exotoxins	I-GENE
I	I-GENE
and	I-GENE
J	I-GENE
(	O
SPE	B-GENE
-	I-GENE
I	I-GENE
and	O
SPE	B-GENE
-	I-GENE
J	I-GENE
)	O
from	O
Streptococcus	O
pyogenes	O
.	O

Several	O
dozen	O
HIF	B-GENE
-	I-GENE
1	I-GENE
targets	I-GENE
are	O
known	O
,	O
including	O
the	O
gene	O
encoding	O
vascular	B-GENE
endothelial	I-GENE
growth	I-GENE
factor	I-GENE
(	O
VEGF	B-GENE
)	O
.	O

We	O
previously	O
reported	O
that	O
Tax	B-GENE
induced	O
cell	O
cycle	O
progression	O
from	O
G0	O
/	O
G1	O
phase	O
to	O
S	O
and	O
G2	O
/	O
M	O
phases	O
in	O
human	O
T	O
-	O
cell	O
line	O
Kit	O
225	O
cells	O
.	O

Most	O
yeast	B-GENE
peroxisomal	I-GENE
matrix	I-GENE
proteins	I-GENE
contain	O
a	O
type	O
1C	O
-	O
terminal	O
peroxisomal	O
targeting	O
signal	O
(	O
PTS1	O
)	O
consisting	O
of	O
the	O
tripeptide	O
SKL	O
or	O
a	O
conservative	O
variant	O
thereof	O
.	O

Here	O
,	O
the	O
PEX5	B-GENE
-	O
TPR	O
domains	O
from	O
human	O
,	O
tobacco	O
,	O
and	O
nematode	O
were	O
inserted	O
into	O
a	O
TPR	O
-	O
less	O
yeast	O
Pex5p	B-GENE
construct	O
to	O
generate	O
Pex5p	B-GENE
chimaeras	O
.	O

HIV	O
-	O
1	O
and	O
hepatitis	O
B	O
virus	O
infections	O
in	O
adolescents	O
lodged	O
in	O
security	O
institutes	O
of	O
Buenos	O
Aires	O
.	O

Immunofixation	O
experiments	O
of	O
C4A	B-GENE
and	O
C4B	B-GENE
demonstrate	O
>	O
41	O
allotypes	O
in	O
the	O
two	O
classes	O
of	O
proteins	O
.	O

However	O
,	O
C4B	B-GENE
proteins	I-GENE
encoded	O
by	O
monomodular	O
short	O
genes	O
may	O
have	O
relatively	O
higher	O
concentrations	O
than	O
those	O
from	O
long	B-GENE
C4A	I-GENE
genes	I-GENE
.	O

In	O
the	O
course	O
of	O
screening	O
for	O
transcription	O
factors	O
which	O
interact	O
with	O
the	O
human	B-GENE
myeloperoxidase	I-GENE
(	O
MPO	B-GENE
)	O
promoter	O
we	O
,	O
for	O
the	O
first	O
time	O
,	O
identified	O
and	O
cloned	O
the	O
cDNA	O
and	O
genomic	O
DNA	O
for	O
human	B-GENE
HBP1	I-GENE
(	O
HMG	B-GENE
-	I-GENE
Box	I-GENE
containing	I-GENE
protein	I-GENE
1	I-GENE
)	O
,	O
a	O
member	O
of	O
the	O
high	B-GENE
mobility	I-GENE
group	I-GENE
of	I-GENE
non	I-GENE
-	I-GENE
histone	I-GENE
chromosomal	I-GENE
proteins	I-GENE
.	O

The	O
human	O
protein	O
sequence	O
exhibits	O
a	O
putative	O
DNA	O
-	O
binding	O
domain	O
similar	O
to	O
that	O
seen	O
in	O
rat	B-GENE
HBP1	I-GENE
and	O
shows	O
homology	O
with	O
the	O
activation	O
and	O
repressor	O
domains	O
previously	O
demonstrated	O
in	O
the	O
rat	O
protein	O
.	O

Promoter	O
transcriptional	O
activity	O
was	O
determined	O
for	O
a	O
wide	O
5	O
'	O
portion	O
of	O
the	O
human	O
annexin	B-GENE
A5	I-GENE
gene	I-GENE
,	O
from	O
bp	O
-	O
1275	O
to	O
+	O
79	O
relative	O
to	O
the	O
most	O
5	O
'	O
of	O
several	O
discrete	O
transcription	O
start	O
points	O
.	O

In	O
contrast	O
the	O
human	O
and	O
mouse	B-GENE
BCNT	I-GENE
proteins	I-GENE
contain	O
one	O
repeat	O
unit	O
and	O
lack	O
the	O
RTE	B-GENE
-	I-GENE
1	I-GENE
-	O
derived	O
portion	O
.	O

Molecular	O
identification	O
of	O
smg	B-GENE
-	I-GENE
4	I-GENE
,	O
required	O
for	O
mRNA	O
surveillance	O
in	O
C	O
.	O
elegans	O
.	O

Two	O
remotely	O
situated	O
exons	O
within	O
the	O
complement	B-GENE
C3	I-GENE
gene	O
locus	O
encode	O
an	O
alternate	O
5	O
'	O
end	O
and	O
proximal	O
ORF	O
under	O
the	O
control	O
of	O
a	O
bidirectional	O
promoter	O
.	O

CONCLUSIONS	O
:	O
Adding	O
MMF	O
,	O
a	O
potent	O
topical	O
corticosteroid	O
,	O
to	O
an	O
emollient	O
cream	O
is	O
statistically	O
significantly	O
more	O
effective	O
than	O
emollient	O
cream	O
alone	O
in	O
reducing	O
acute	O
radiation	O
dermatitis	O
.	O

Recent	O
advances	O
have	O
shown	O
that	O
volatile	O
sulfur	O
is	O
a	O
result	O
of	O
ecological	O
interactions	O
and	O
transformation	O
processes	O
through	O
planktonic	O
food	O
webs	O
.	O

The	O
first	O
hypothesis	O
was	O
supported	O
in	O
the	O
sense	O
that	O
stimulus	O
differences	O
might	O
affect	O
behaviour	O
even	O
without	O
their	O
successful	O
attentive	O
processing	O
in	O
normal	O
participants	O
.	O

There	O
was	O
an	O
increase	O
in	O
protein	O
binding	O
onto	O
this	O
element	O
only	O
after	O
peptide	O
treatment	O
.	O

CSR	O
is	O
directed	O
to	O
specific	O
heavy	O
chain	O
isotypes	O
by	O
cytokines	O
and	O
B	O
cell	O
activators	O
that	O
induce	O
transcription	O
from	O
the	O
unrearranged	O
,	O
or	O
germline	O
(	O
GL	O
)	O
,	O
C	B-GENE
(	I-GENE
H	I-GENE
)	I-GENE
region	I-GENE
genes	I-GENE
.	O

In	O
this	O
manuscript	O
we	O
demonstrate	O
that	O
two	O
tandem	B-GENE
Ets	I-GENE
sites	I-GENE
in	O
the	O
mouse	B-GENE
GL	I-GENE
alpha	I-GENE
promoter	I-GENE
bind	O
the	O
transcription	B-GENE
factors	I-GENE
Elf	I-GENE
-	I-GENE
1	I-GENE
and	O
PU	B-GENE
.	I-GENE
1	I-GENE
,	O
and	O
that	O
the	O
3	O
'	O
site	O
is	O
essential	O
for	O
expression	O
of	O
a	O
luciferase	B-GENE
reporter	I-GENE
gene	I-GENE
driven	O
by	O
the	O
GL	B-GENE
alpha	I-GENE
promoter	I-GENE
.	O

Cell	O
.	O

The	O
mean	O
serum	O
creatinine	O
level	O
did	O
not	O
change	O
during	O
the	O
first	O
6	O
months	O
after	O
withdrawal	O
of	O
MMF	O
.	O

The	O
proportion	O
of	O
the	O
biopsies	O
found	O
to	O
be	O
seropositive	O
for	O
HBs	B-GENE
antigen	I-GENE
was	O
27	O
.	O
9	O
%	O
,	O
and	O
these	O
showed	O
either	O
MGN	O
or	O
MPGN	O
pattern	O
.	O

They	O
correspond	O
to	O
nucleotides	O
equivalent	O
to	O
base	O
-	O
pair	O
C1	O
-	O
G72	O
and	O
discriminator	O
base	O
A73	O
in	O
the	O
amino	O
acid	O
-	O
acceptor	O
branch	O
of	O
the	O
molecule	O
.	O

This	O
domain	O
without	O
the	O
canonical	O
anticodon	O
loop	O
or	O
the	O
tyrosine	O
anticodon	O
acts	O
as	O
an	O
anchor	O
for	O
TyrRS	B-GENE
interaction	O
leading	O
to	O
a	O
better	O
efficiency	O
of	O
tyrosylation	O
.	O

During	O
most	O
of	O
the	O
cell	O
cycle	O
,	O
separase	B-GENE
is	O
kept	O
inactive	O
by	O
binding	O
to	O
an	O
inhibitory	O
protein	O
called	O
securin	B-GENE
.	O

Mechanical	O
ventilation	O
in	O
control	O
lungs	O
produced	O
a	O
47	O
%	O
decrease	O
in	O
chord	O
compliance	O
,	O
an	O
increase	O
in	O
lung	O
lavage	O
levels	O
of	O
tumor	B-GENE
necrosis	I-GENE
factor	I-GENE
(	I-GENE
TNF	I-GENE
)	I-GENE
-	I-GENE
alpha	I-GENE
(	O
722	O
+	O
/	O
-	O
306	O
pg	O
/	O
ml	O
)	O
,	O
interleukin	B-GENE
(	I-GENE
IL	I-GENE
)	I-GENE
-	I-GENE
1beta	I-GENE
(	O
902	O
+	O
/	O
-	O
322	O
pg	O
/	O
ml	O
)	O
,	O
and	O
macrophage	B-GENE
inflammatory	I-GENE
protein	I-GENE
-	I-GENE
2	I-GENE
(	O
MIP	B-GENE
-	I-GENE
2	I-GENE
)	O
(	O
363	O
+	O
/	O
-	O
104	O
pg	O
/	O
ml	O
)	O
as	O
compared	O
with	O
low	O
levels	O
of	O
cytokines	O
detected	O
in	O
preventilation	O
data	O
,	O
and	O
no	O
change	O
in	O
percentage	O
of	O
surfactant	O
large	O
aggregates	O
(	O
LA	O
)	O
.	O

Maternal	O
p	O
,	O
p	O
'	O
DDE	O
and	O
beta	O
-	O
HCH	O
levels	O
were	O
also	O
associated	O
with	O
newborn	O
levels	O
,	O
but	O
levels	O
of	O
PCBs	O
were	O
not	O
.	O

Multiple	O
regression	O
analysis	O
performed	O
between	O
these	O
long	O
-	O
term	O
abiotic	O
factors	O
and	O
nymphal	O
abundance	O
in	O
positive	O
sites	O
showed	O
high	O
relationship	O
(	O
R2	O
coefficients	O
)	O
for	O
every	O
habitat	O
category	O
and	O
explained	O
>	O
50	O
%	O
of	O
the	O
variation	O
in	O
tick	O
abundance	O
.	O

In	O
summary	O
,	O
we	O
conclude	O
that	O
the	O
adenoviral	O
oncoprotein	O
E1A	B-GENE
activates	O
transcription	O
from	O
the	O
endogenous	O
AP	B-GENE
-	I-GENE
2alpha	I-GENE
gene	I-GENE
,	O
an	O
effect	O
that	O
involves	O
transcriptional	O
derepression	O
of	O
the	O
AP	B-GENE
-	I-GENE
2alpha	I-GENE
promoter	I-GENE
by	O
interaction	O
of	O
E1A	B-GENE
with	O
the	O
AP	B-GENE
-	I-GENE
2rep	I-GENE
corepressor	O
CtBP1	B-GENE
.	O

Additional	O
factors	O
such	O
as	O
advanced	O
age	O
,	O
concomitant	O
use	O
of	O
corticosteroids	O
or	O
anticoagulants	O
,	O
prior	O
ulcer	O
complications	O
and	O
co	O
-	O
morbid	O
diseases	O
may	O
further	O
increase	O
the	O
risk	O
of	O
bleeding	O
.	O

The	O
core	O
promoter	O
of	O
human	B-GENE
thioredoxin	I-GENE
reductase	I-GENE
1	I-GENE
:	O
cloning	O
,	O
transcriptional	O
activity	O
,	O
and	O
Oct	B-GENE
-	I-GENE
1	I-GENE
,	O
Sp1	B-GENE
,	O
and	O
Sp3	B-GENE
binding	O
reveal	O
a	O
housekeeping	O
-	O
type	O
promoter	O
for	O
the	O
AU	O
-	O
rich	O
element	O
-	O
regulated	O
gene	O
.	O

Here	O
we	O
show	O
that	O
phosphorylation	O
-	O
induced	O
loss	O
of	O
the	O
protein	O
kinase	O
activity	O
of	O
DNA	B-GENE
-	I-GENE
PK	I-GENE
is	O
restored	O
by	O
the	O
addition	O
of	O
the	O
purified	O
catalytic	O
subunit	O
of	O
either	O
protein	B-GENE
phosphatase	I-GENE
1	I-GENE
or	O
protein	B-GENE
phosphatase	I-GENE
2A	I-GENE
(	O
PP2A	B-GENE
)	O
and	O
that	O
this	O
reactivation	O
is	O
blocked	O
by	O
the	O
potent	O
protein	O
phosphatase	O
inhibitor	O
,	O
microcystin	O
.	O

The	O
first	O
exon	O
(	O
exon	O
1A	O
)	O
that	O
corresponded	O
to	O
the	O
5	O
'	O
-	O
untranslated	O
region	O
of	O
the	O
GHR	B-GENE
1A	I-GENE
mRNA	I-GENE
was	O
15	O
,	O
250	O
bp	O
upstream	O
from	O
exon	O
2	O
in	O
the	O
GHR	B-GENE
gene	I-GENE
.	O

FLP	B-GENE
and	O
Cre	B-GENE
recombinase	I-GENE
function	O
in	O
Xenopus	O
embryos	O
.	O

A	O
method	O
of	O
three	O
-	O
station	O
three	O
-	O
dimensional	O
magnetic	O
resonance	O
(	O
MR	O
)	O
angiography	O
of	O
the	O
lower	O
extremities	O
with	O
segmented	O
volume	O
acquisition	O
is	O
presented	O
.	O

A	O
single	O
nucleotide	O
polymorphism	O
(	O
SNP	O
)	O
in	O
exon	O
2	O
,	O
which	O
is	O
tightly	O
liked	O
to	O
another	O
SNP	O
(	O
GTG83	O
/	O
ATG83	O
)	O
,	O
creates	O
an	O
additional	O
alternative	O
in	O
-	O
frame	O
AUG	O
in	O
B	B-GENE
-	I-GENE
type	I-GENE
MTH1	I-GENE
mRNAs	I-GENE
yielding	O
the	O
fourth	O
MTH1	B-GENE
polypeptide	I-GENE
,	O
p26	B-GENE
that	O
possesses	O
an	O
additional	O
mitochondrial	O
targeting	O
signal	O
.	O

Our	O
previous	O
studies	O
have	O
shown	O
that	O
SHP	B-GENE
-	I-GENE
1	I-GENE
,	O
a	O
SH2	B-GENE
domain	I-GENE
-	I-GENE
containing	I-GENE
protein	I-GENE
-	I-GENE
tyrosine	I-GENE
phosphatase	I-GENE
,	O
is	O
expressed	O
not	O
only	O
in	O
cells	O
of	O
hematopoietic	O
lineages	O
,	O
but	O
also	O
in	O
many	O
non	O
-	O
hematopoietic	O
cells	O
under	O
the	O
control	O
of	O
an	O
alternative	O
tissue	O
-	O
specific	O
promoter	O
,	O
P1	O
.	O

Unexpectedly	O
,	O
Arg1	B-GENE
-	O
expressing	O
COS1	O
cells	O
showed	O
no	O
significant	O
proteinase	O
activity	O
to	O
various	O
synthesized	O
substrates	O
under	O
neutral	O
or	O
acidic	O
conditions	O
in	O
this	O
study	O
.	O

ORF1	O
(	O
1029	O
bp	O
;	O
EMBL	O
databank	O
,	O
Accession	O
No	O
.	O

In	O
the	O
meantime	O
,	O
one	O
has	O
succeeded	O
to	O
establish	O
the	O
deammonification	O
processes	O
in	O
a	O
continuous	O
flow	O
moving	O
-	O
bed	O
pilot	O
plant	O
.	O

The	O
purpose	O
of	O
this	O
study	O
was	O
to	O
evaluate	O
simplified	O
methods	O
for	O
estimation	O
of	O
Technetium	O
Tc	O
99m	O
(	O
99mTc	O
)	O
-	O
pentetate	O
and	O
orthoiodohippurate	O
I	O
131	O
(	O
131I	O
-	O
OIH	O
)	O
plasma	O
clearance	O
in	O
dogs	O
and	O
cats	O
with	O
1	O
and	O
2	O
blood	O
samples	O
.	O

Interventions	O
aimed	O
at	O
these	O
specific	O
mediators	O
and	O
processes	O
may	O
be	O
successful	O
in	O
reducing	O
the	O
very	O
significant	O
human	O
and	O
economic	O
costs	O
of	O
vascular	O
access	O
dysfunction	O
.	O

In	O
addition	O
,	O
stonin	B-GENE
2	I-GENE
binds	O
to	O
the	O
C2B	O
domains	O
of	O
synaptotagmins	B-GENE
I	I-GENE
and	I-GENE
II	I-GENE
.	O

This	O
partial	O
transection	O
could	O
permit	O
vasopressin	B-GENE
to	O
be	O
secreted	O
in	O
response	O
to	O
a	O
larger	O
rise	O
in	O
plasma	O
sodium	O
concentration	O
.	O

In	O
conclusion	O
,	O
USPIO	O
-	O
enhanced	O
MRI	O
data	O
were	O
capable	O
to	O
characterize	O
tumor	O
microvessel	O
properties	O
in	O
this	O
breast	O
cancer	O
model	O
:	O
microvascular	O
permeability	O
(	O
determined	O
using	O
USPIO	O
)	O
correlated	O
significantly	O
with	O
tumor	O
grade	O
.	O

However	O
,	O
the	O
N63S	O
mutation	O
in	O
the	O
wild	B-GENE
-	I-GENE
type	I-GENE
VP5	I-GENE
background	O
increased	O
the	O
interaction	O
,	O
as	O
judged	O
by	O
the	O
beta	B-GENE
-	I-GENE
galactosidase	I-GENE
activity	O
,	O
by	O
a	O
factor	O
of	O
9	O
relative	O
to	O
when	O
the	O
PR7	O
mutation	O
was	O
present	O
.	O

An	O
integrated	O
RTC	O
algorithm	O
for	O
the	O
urban	O
wastewater	O
system	O
is	O
formulated	O
,	O
the	O
parameters	O
of	O
which	O
are	O
optimized	O
using	O
various	O
global	O
optimization	O
routines	O
.	O

SKP1	B-GENE
-	O
SnRK	B-GENE
protein	O
kinase	O
interactions	O
mediate	O
proteasomal	O
binding	O
of	O
a	O
plant	O
SCF	B-GENE
ubiquitin	I-GENE
ligase	I-GENE
.	O

PATIENTS	O
AND	O
METHODS	O
:	O
Between	O
June	O
1991	O
and	O
December	O
1996	O
,	O
we	O
administered	O
the	O
nucleoside	O
analog	O
2	O
-	O
chlorodeoxyadenosine	O
(	O
2	O
-	O
CDA	O
)	O
to	O
73	O
children	O
with	O
primary	O
AML	O
and	O
20	O
children	O
with	O
secondary	O
AML	O
or	O
myelodysplastic	O
syndrome	O
(	O
MDS	O
)	O
.	O

The	O
severity	O
of	O
pathologic	O
changes	O
increased	O
with	O
the	O
magnitude	O
of	O
percussion	O
.	O

Experimental	O
study	O
of	O
ta	O
chengchi	O
tang	O
decoction	O
for	O
relieving	O
lung	O
injury	O
during	O
acute	O
necrotizing	O
pancreatitis	O
]	O
The	O
objectives	O
of	O
the	O
study	O
were	O
to	O
investigate	O
the	O
changes	O
of	O
leukocyte	O
adhesiveness	O
and	O
tumor	B-GENE
necrosis	I-GENE
factor	I-GENE
(	O
TNF	B-GENE
)	O
in	O
the	O
early	O
stage	O
of	O
acute	O
necrotizing	O
pancreatitis	O
(	O
ANP	O
)	O
,	O
to	O
go	O
further	O
into	O
the	O
relation	O
of	O
those	O
changes	O
to	O
lung	O
injury	O
of	O
ANP	O
,	O
and	O
to	O
evaluate	O
the	O
prohibitive	O
effect	O
of	O
ta	O
chengchi	O
tang	O
Decoction	O
on	O
leukocyte	O
adhesion	O
and	O
TNF	B-GENE
secretion	O
.	O

A	O
variety	O
of	O
receptor	O
-	O
mediated	O
signaling	O
pathways	O
are	O
controlled	O
by	O
both	O
positive	O
and	O
negative	O
extracellular	O
regulators	O
.	O

TT	O
cells	O
,	O
a	O
human	O
MTC	O
cell	O
line	O
expressing	O
MEN	B-GENE
2A	I-GENE
type	I-GENE
RET	I-GENE
,	O
display	O
transcriptionally	O
active	O
RelA	B-GENE
(	I-GENE
p65	I-GENE
)	I-GENE
in	O
the	O
nucleus	O
.	O

Inhibition	O
of	O
constitutive	O
NF	B-GENE
-	I-GENE
kappaB	I-GENE
activity	O
results	O
in	O
cell	O
death	O
of	O
TT	O
cells	O
and	O
blocks	O
focus	O
formation	O
induced	O
by	O
oncogenic	O
forms	O
of	O
RET	B-GENE
in	O
NIH	O
3T3	O
cells	O
.	O

Reciprocally	O
,	O
HMGI	B-GENE
-	I-GENE
C	I-GENE
expression	O
also	O
coordinately	O
enhances	O
PIAS3	B-GENE
-	O
mediated	O
repression	O
of	O
STAT3	B-GENE
-	O
dependent	O
transactivation	O
.	O

A	O
central	O
finding	O
is	O
the	O
identification	O
of	O
a	O
GC	O
-	O
rich	O
sequence	O
in	O
the	O
-	O
99	O
/	O
-	O
91	O
Cp	B-GENE
region	O
that	O
is	O
essential	O
for	O
oriPI	O
-	O
EBNA1	B-GENE
-	O
independent	O
as	O
well	O
as	O
oriPI	O
-	O
EBNA1	B-GENE
-	O
dependent	O
activity	O
of	O
the	O
promoter	O
.	O

Additional	O
deletion	O
mutations	O
revealed	O
a	O
new	O
,	O
67	O
-	O
amino	O
-	O
acid	O
functional	O
domain	O
within	O
the	O
proline	O
-	O
rich	O
region	O
of	O
SLP	B-GENE
-	I-GENE
76	I-GENE
,	O
which	O
we	O
have	O
termed	O
the	O
P	O
-	O
1	O
domain	O
.	O

Finally	O
,	O
profiling	O
of	O
a	O
gcn4Delta	B-GENE
mutant	I-GENE
uncovered	O
an	O
alternative	O
induction	O
pathway	O
operating	O
at	O
many	O
Gcn4p	B-GENE
target	I-GENE
genes	I-GENE
in	O
histidine	O
-	O
starved	O
cells	O
.	O

Evidence	O
from	O
a	O
Northern	O
hybridization	O
indicated	O
that	O
jadM	B-GENE
expression	O
is	O
correlated	O
with	O
jadomycin	B-GENE
B	I-GENE
synthesis	O
.	O

Right	O
LHR	O
(	O
R	O
-	O
LHR	O
)	O
provided	O
the	O
best	O
interobserver	O
and	O
intraobserver	O
reproducibility	O
.	O

CONCLUSIONS	O
:	O
The	O
methodology	O
of	O
LHR	O
measurement	O
significantly	O
influences	O
the	O
clinical	O
contribution	O
of	O
Tl	O
-	O
201	O
lung	O
uptake	O
evaluation	O
.	O

Mutation	O
of	O
the	O
NF	B-GENE
-	I-GENE
kappaB	I-GENE
site	I-GENE
in	O
the	O
Mdr1b	B-GENE
promoter	I-GENE
prevents	O
its	O
induction	O
by	O
TNF	B-GENE
-	I-GENE
alpha	I-GENE
.	O

To	O
determine	O
the	O
genomic	O
complexity	O
of	O
the	O
deleted	O
region	O
shared	O
among	O
tumors	O
,	O
we	O
assembled	O
a	O
physical	O
map	O
of	O
the	O
I	O
Mbp	O
SRO	O
consisting	O
predominantly	O
of	O
bacteriophage	O
P1	O
-	O
derived	O
artificial	O
chromosome	O
(	O
PAC	O
)	O
clones	O
.	O

Online	O
teaching	O
:	O
design	O
and	O
techniques	O
.	O

Data	O
were	O
obtained	O
from	O
2	O
undergraduate	O
student	O
samples	O
,	O
a	O
self	O
-	O
report	O
group	O
(	O
n	O
=	O
132	O
)	O
who	O
provided	O
NEO	O
-	O
PI	O
-	O
R	O
self	O
-	O
ratings	O
on	O
2	O
occasions	O
separated	O
by	O
a	O
7	O
-	O
to	O
14	O
-	O
day	O
interval	O
and	O
an	O
informant	O
group	O
(	O
n	O
=	O
109	O
)	O
who	O
provided	O
ratings	O
of	O
well	O
-	O
known	O
friends	O
or	O
relatives	O
on	O
2	O
occasions	O
separated	O
by	O
a	O
6	O
month	O
interval	O
.	O

Northern	O
blot	O
analysis	O
of	O
RNAs	O
from	O
a	O
number	O
of	O
mouse	O
tissues	O
reveals	O
that	O
Atp6i	B-GENE
is	O
expressed	O
predominantly	O
in	O
osteoclasts	O
,	O
and	O
this	O
predominant	O
expression	O
was	O
confirmed	O
by	O
reverse	O
-	O
transcription	O
polymerase	O
chain	O
reaction	O
(	O
RT	O
-	O
PCR	O
)	O
assay	O
and	O
immunohistochemical	O
analysis	O
.	O

Indeed	O
,	O
mutation	O
of	O
two	O
of	O
these	O
motifs	O
,	O
known	O
to	O
be	O
important	O
to	O
regulation	O
of	O
sid1	B-GENE
,	O
altered	O
the	O
differential	O
regulation	O
of	O
sid2	B-GENE
by	O
iron	O
.	O

The	O
described	O
results	O
show	O
that	O
DTD	O
is	O
fast	O
,	O
simple	O
,	O
and	O
easy	O
to	O
automate	O
;	O
requires	O
only	O
a	O
small	O
amount	O
of	O
sample	O
(	O
approximately	O
50	O
mg	O
)	O
;	O
and	O
affords	O
quantitative	O
information	O
about	O
the	O
main	O
groups	O
of	O
compounds	O
present	O
in	O
cheeses	O
.	O

Guidelines	O
for	O
performing	O
a	O
routine	O
spiral	O
assay	O
are	O
presented	O
,	O
and	O
alternative	O
test	O
methods	O
intended	O
to	O
overcome	O
a	O
variety	O
of	O
technical	O
difficulties	O
(	O
such	O
as	O
restricted	O
sample	O
availability	O
,	O
sample	O
viscosity	O
or	O
volatility	O
,	O
etc	O
.	O
)	O
are	O
recommended	O
.	O

In	O
conclusion	O
,	O
obesity	O
,	O
alcohol	O
intake	O
,	O
and	O
multimetabolic	O
disorders	O
were	O
determined	O
to	O
be	O
independent	O
predictors	O
for	O
the	O
development	O
of	O
hyperuricemia	O
.	O

Autoregulation	O
enables	O
different	O
pathways	O
to	O
control	O
CCAAT	B-GENE
/	I-GENE
enhancer	I-GENE
binding	I-GENE
protein	I-GENE
beta	I-GENE
(	O
C	B-GENE
/	I-GENE
EBP	I-GENE
beta	I-GENE
)	O
transcription	O
.	O

As	O
a	O
reflection	O
of	O
uncertainties	O
in	O
the	O
estimates	O
for	O
individual	O
sources	O
,	O
the	O
90th	O
percentiles	O
of	O
PCDD	O
/	O
F	O
releases	O
for	O
1999	O
ranged	O
up	O
to	O
4	O
.	O
1	O
g	O
I	O
-	O
TEQ	O
/	O
y	O
.	O

Gabapentin	O
for	O
opiod	O
-	O
related	O
myoclonus	O
in	O
cancer	O
patients	O
.	O

CONCLUSIONS	O
:	O
Our	O
meta	O
-	O
analysis	O
of	O
randomized	O
controlled	O
trials	O
of	O
HRT	O
noted	O
a	O
statistically	O
significant	O
reduction	O
in	O
nonvertebral	O
fractures	O
.	O

Newcastle	B-GENE
disease	I-GENE
antibody	I-GENE
titre	O
is	O
dependent	O
on	O
serum	O
calcium	O
concentration	O
.	O

A	O
total	O
of	O
25	O
patients	O
with	O
malignant	O
brain	O
tumours	O
were	O
investigated	O
.	O

Net	O
lift	O
and	O
combined	O
drag	O
from	O
all	O
8	O
bearings	O
of	O
the	O
4	O
-	O
bladed	O
impeller	O
are	O
compared	O
with	O
predictions	O
based	O
on	O
2	O
-	O
D	O
theory	O
.	O

Our	O
results	O
indicate	O
that	O
Gab1	B-GENE
is	O
involved	O
in	O
the	O
control	O
of	O
egr	B-GENE
-	I-GENE
1	I-GENE
expression	O
regulated	O
by	O
insulin	B-GENE
.	O

The	O
co	O
-	O
existence	O
of	O
TE	B-GENE
domains	I-GENE
within	O
modular	O
PKSs	B-GENE
along	O
with	O
physically	O
separated	O
,	O
monofunctional	O
TEs	B-GENE
(	O
TE	B-GENE
IIs	I-GENE
)	O
has	O
been	O
reported	O
for	O
a	O
number	O
of	O
modular	O
polyketide	O
and	O
non	B-GENE
-	I-GENE
ribosomal	I-GENE
peptide	I-GENE
synthases	I-GENE
(	O
NRPS	B-GENE
)	O
.	O

To	O
gain	O
an	O
understanding	O
of	O
the	O
mGSTM2	B-GENE
regulation	O
,	O
we	O
have	O
also	O
cloned	O
and	O
analyzed	O
its	O
promoter	O
region	O
.	O

10	O
.	O
0	O
+	O
/	O
-	O
2	O
.	O
0	O
pmol	O
/	O
24	O
h	O
,	O
P	O
<	O
0	O
.	O
01	O
)	O
and	O
remained	O
elevated	O
.	O

SELECTION	O
CRITERIA	O
:	O
All	O
randomised	O
controlled	O
trials	O
comparing	O
IUSs	O
with	O
other	O
forms	O
of	O
reversible	O
contraceptives	O
and	O
reporting	O
on	O
pre	O
-	O
determined	O
outcomes	O
in	O
women	O
of	O
reproductive	O
years	O
.	O

OBJECTIVES	O
:	O
The	O
objective	O
of	O
this	O
review	O
was	O
to	O
compare	O
the	O
effectiveness	O
,	O
safety	O
and	O
acceptability	O
of	O
the	O
diaphragm	O
with	O
and	O
without	O
spermicide	O
.	O

To	O
test	O
the	O
hypothesis	O
that	O
these	O
elements	O
are	O
required	O
for	O
promoter	O
activity	O
,	O
we	O
compared	O
the	O
reporter	O
expression	O
activity	O
of	O
segments	O
containing	O
mutations	O
of	O
these	O
elements	O
with	O
activity	O
of	O
the	O
parent	B-GENE
Hlx	I-GENE
promoter	I-GENE
sequence	I-GENE
.	O

In	O
all	O
of	O
these	O
cases	O
,	O
expression	O
of	O
the	O
implicated	O
genes	O
was	O
absent	O
.	O

CONCLUSIONS	O
:	O
Ketamine	O
-	O
induced	O
dissociative	O
anesthesia	O
produces	O
persistently	O
elevated	O
BIS	O
index	O
which	O
is	O
different	O
from	O
thiamylal	O
and	O
those	O
reported	O
with	O
other	O
conventional	O
anesthetic	O
agents	O
.	O

Our	O
results	O
are	O
reassuring	O
and	O
we	O
therefore	O
advise	O
that	O
in	O
patients	O
undergoing	O
free	O
jejunum	O
flap	O
reconstruction	O
of	O
the	O
hypopharyngo	O
-	O
esophageal	O
tract	O
voice	O
restoration	O
should	O
be	O
attempted	O
by	O
placing	O
a	O
voice	O
prosthesis	O
through	O
a	O
secondary	O
tracheo	O
-	O
esophageal	O
puncture	O
and	O
providing	O
intensive	O
speech	O
training	O
.	O

Hypercalcemia	O
associated	O
with	O
elevated	O
serum	B-GENE
PTH	I-GENE
concentration	O
indicating	O
primary	O
hyperparathyroidism	O
was	O
found	O
in	O
7	O
BC	O
patients	O
(	O
7	O
%	O
)	O
and	O
in	O
none	O
of	O
healthy	O
women	O
or	O
patients	O
with	O
thyroid	O
cancer	O
.	O

Positive	O
and	O
significant	O
correlations	O
were	O
found	O
between	O
the	O
weeks	O
of	O
pregnancy	O
and	O
Se	O
levels	O
in	O
kidney	O
(	O
r	O
=	O
0	O
.	O
433	O
,	O
P	O
=	O
0	O
.	O
023	O
)	O
and	O
heart	O
(	O
r	O
=	O
0	O
.	O
313	O
,	O
P	O
=	O
0	O
.	O
030	O
)	O
.	O

This	O
study	O
suggests	O
that	O
PSP	O
is	O
more	O
common	O
than	O
previously	O
considered	O
,	O
is	O
commonly	O
misdiagnosed	O
and	O
that	O
the	O
majority	O
of	O
cases	O
are	O
not	O
initially	O
referred	O
to	O
neurologists	O
.	O

In	O
Saccharomyces	O
cerevisiae	O
,	O
entry	O
into	O
mitosis	O
requires	O
activation	O
of	O
the	O
cyclin	B-GENE
-	I-GENE
dependent	I-GENE
kinase	I-GENE
Cdc28	B-GENE
in	O
its	O
cyclin	B-GENE
B	I-GENE
(	O
Clb	B-GENE
)	O
-	O
associated	O
form	O
.	O

We	O
investigated	O
the	O
production	O
of	O
hyaluronan	O
(	O
HA	O
)	O
and	O
its	O
effect	O
on	O
cell	O
motility	O
in	O
cells	O
expressing	O
the	O
v	B-GENE
-	I-GENE
src	I-GENE
mutants	I-GENE
.	O

Our	O
results	O
indicate	O
that	O
D	O
(	O
4	O
)	O
and	O
D	O
(	O
2L	O
)	O
receptors	O
activate	O
the	O
ERK	B-GENE
kinase	I-GENE
cascade	O
by	O
first	O
mobilizing	O
signaling	O
by	O
the	O
PDGF	B-GENE
receptor	I-GENE
,	O
followed	O
by	O
the	O
subsequent	O
activation	O
of	O
ERK1	B-GENE
/	I-GENE
2	I-GENE
by	O
pathways	O
associated	O
with	O
this	O
receptor	B-GENE
tyrosine	I-GENE
kinase	I-GENE
.	O

Karger	O
AG	O
,	O
Basel	O

NIRS	O
was	O
used	O
for	O
the	O
quantitative	O
measurement	O
of	O
muscle	O
O	O
(	O
2	O
)	O
consumption	O
(	O
mV	O
.	O
O	O
(	O
2	O
)	O
)	O
and	O
forearm	O
blood	O
flow	O
(	O
FBF	O
)	O
in	O
78	O
healthy	O
subjects	O
.	O

No	O
dominant	O
clinical	O
factor	O
of	O
risk	O
was	O
found	O
,	O
but	O
multiple	O
regression	O
analysis	O
identified	O
age	O
,	O
body	O
surface	O
area	O
,	O
valve	O
size	O
,	O
shop	O
order	O
fracture	O
rate	O
,	O
and	O
manufacturing	O
period	O
as	O
risk	O
factors	O
for	O
OSF	O
.	O

In	O
this	O
report	O
this	O
technique	O
was	O
applied	O
to	O
human	O
breast	O
carcinoma	O
MDA	O
-	O
MB231	O
cells	O
overexpressing	O
human	B-GENE
MPG	I-GENE
in	O
order	O
to	O
assess	O
whether	O
up	O
-	O
regulation	O
of	O
the	O
initial	O
step	O
in	O
BER	O
alters	O
the	O
activity	O
of	O
selected	O
other	O
BER	O
(	O
hOGG1	B-GENE
and	O
APE	B-GENE
/	O
ref	B-GENE
-	I-GENE
1	I-GENE
)	O
or	O
direct	O
reversal	O
(	O
MGMT	B-GENE
)	O
repair	O
activities	O
.	O

The	O
selective	O
alteration	O
of	O
the	O
genome	O
using	O
Cre	B-GENE
recombinase	I-GENE
to	O
target	O
the	O
rearrangement	O
of	O
genes	O
flanked	O
by	O
LOX	B-GENE
recognition	I-GENE
sequences	I-GENE
has	O
required	O
the	O
use	O
of	O
two	O
separate	O
genetic	O
constructs	O
in	O
trans	O
,	O
one	O
containing	O
cre	O
and	O
the	O
other	O
containing	O
the	O
gene	O
of	O
interest	O
flanked	O
by	O
LOX	B-GENE
sites	I-GENE
.	O

Influence	O
of	O
compression	O
therapy	O
on	O
symptoms	O
following	O
soft	O
tissue	O
injury	O
from	O
maximal	O
eccentric	O
exercise	O
.	O

Keratoconjunctivitis	O
sicca	O
appears	O
to	O
be	O
a	O
common	O
ocular	O
complication	O
and	O
all	O
children	O
with	O
JRA	O
should	O
be	O
screened	O
for	O
it	O
with	O
a	O
comprehensive	O
battery	O
of	O
tests	O
.	O

STAT5A	B-GENE
mutations	O
in	O
the	O
Src	B-GENE
homology	I-GENE
2	I-GENE
(	O
SH2	B-GENE
)	O
and	O
SH3	B-GENE
domains	I-GENE
did	O
not	O
alter	O
the	O
BTK	B-GENE
-	O
mediated	O
tyrosine	O
phosphorylation	O
.	O

In	O
conclusion	O
,	O
primary	O
chemotherapy	O
based	O
on	O
high	O
dose	O
MTX	O
and	O
ara	O
-	O
C	O
is	O
highly	O
efficient	O
in	O
PCNSL	O
.	O

Reovirus	O
mRNAs	O
are	O
efficiently	O
translated	O
within	O
host	O
cells	O
despite	O
the	O
absence	O
of	O
3	O
'	O
polyadenylated	O
tails	O
.	O

Analyses	O
revealed	O
that	O
scale	O
matters	O
above	O
and	O
beyond	O
the	O
effect	O
of	O
quadrat	O
area	O
.	O

Myasthenia	O
gravis	O
is	O
an	O
autoimmune	O
disease	O
resulting	O
from	O
the	O
production	O
of	O
antibodies	O
against	O
the	O
ACh	B-GENE
receptors	I-GENE
of	O
the	O
neuromuscular	O
synapse	O
.	O

Copyright	O
2001	O
Academic	O
Press	O
.	O

Using	O
the	O
postural	O
and	O
force	O
data	O
as	O
input	O
to	O
a	O
3	O
-	O
D	O
biomechanical	O
model	O
,	O
the	O
lumbosacral	O
spinal	O
compression	O
was	O
calculated	O
.	O

Angina	O
(	O
Q	O
)	O
persistence	O
showed	O
marked	O
associations	O
with	O
previous	O
myocardial	O
infarction	O
,	O
diagnosed	O
angina	O
,	O
electrocardiogram	O
ischemia	O
,	O
and	O
subsequent	O
major	O
ischemic	O
heart	O
disease	O
events	O
from	O
Q5	O
onward	O
.	O

In	O
the	O
past	O
decade	O
,	O
there	O
have	O
been	O
enormous	O
advances	O
in	O
the	O
use	O
of	O
Bayesian	O
methodology	O
for	O
analysis	O
of	O
epidemiologic	O
data	O
,	O
and	O
there	O
are	O
now	O
many	O
practical	O
advantages	O
to	O
the	O
Bayesian	O
approach	O
.	O

To	O
assess	O
more	O
specific	O
PKA	B-GENE
-	O
dependent	O
mediation	O
of	O
LH	B-GENE
'	I-GENE
s	I-GENE
contribution	O
to	O
combined	O
hormonal	O
drive	O
,	O
the	O
LDL	B-GENE
receptor	I-GENE
(	I-GENE
-	I-GENE
1076	I-GENE
to	I-GENE
+	I-GENE
11	I-GENE
bp	I-GENE
)	I-GENE
reporter	I-GENE
plasmid	O
was	O
cotransfected	O
with	O
a	O
full	B-GENE
-	I-GENE
sequence	I-GENE
rabbit	I-GENE
muscle	I-GENE
protein	I-GENE
kinase	I-GENE
inhibitor	I-GENE
(	O
PKI	B-GENE
)	O
minigene	O
driven	O
constitutively	O
by	O
a	O
Rous	B-GENE
sarcoma	I-GENE
virus	I-GENE
promoter	I-GENE
.	O

To	O
investigate	O
the	O
convergent	O
role	O
of	O
the	O
insulin	B-GENE
/	O
IGF	B-GENE
-	I-GENE
I	I-GENE
effector	O
pathway	O
mediating	O
bihormonal	O
stimulation	O
of	O
LDL	B-GENE
receptor	I-GENE
promoter	I-GENE
expression	O
,	O
transfected	O
granulosa	O
-	O
luteal	O
cells	O
were	O
pretreated	O
for	O
30	O
min	O
with	O
two	O
specific	O
inhibitors	O
of	O
phophatidylinositol	B-GENE
3	I-GENE
-	I-GENE
kinase	I-GENE
,	O
wortmannin	O
(	O
100	O
nM	O
)	O
and	O
LY	O
294002	O
(	O
10	O
microM	O
)	O
,	O
or	O
of	O
mitogen	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
kinase	I-GENE
kinase	I-GENE
,	O
PD	O
98059	O
(	O
50	O
microM	O
)	O
,	O
U0126	O
(	O
10	O
microM	O
)	O
,	O
or	O
the	O
latter	O
'	O
s	O
inactive	O
derivative	O
,	O
U0124	O
(	O
10	O
microM	O
)	O
.	O

Concerted	O
transcriptional	O
activation	O
of	O
the	O
low	B-GENE
density	I-GENE
lipoprotein	I-GENE
receptor	I-GENE
gene	I-GENE
by	O
insulin	B-GENE
and	O
luteinizing	B-GENE
hormone	I-GENE
in	O
cultured	O
porcine	O
granulosa	O
-	O
luteal	O
cells	O
:	O
possible	O
convergence	O
of	O
protein	B-GENE
kinase	I-GENE
a	I-GENE
,	O
phosphatidylinositol	B-GENE
3	I-GENE
-	I-GENE
kinase	I-GENE
,	O
and	O
mitogen	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
kinase	I-GENE
signaling	O
pathways	O
.	O

These	O
studies	O
demonstrate	O
that	O
site	O
-	O
specific	O
recognition	O
of	O
the	O
bxd	B-GENE
PRE	I-GENE
by	O
d	O
(	O
GA	O
)	O
(	O
n	O
)	O
repeat	O
binding	O
activities	O
mediates	O
PcG	B-GENE
-	O
dependent	O
silencing	O
.	O

Our	O
findings	O
further	O
our	O
understanding	O
of	O
how	O
ZBP	B-GENE
-	I-GENE
89	I-GENE
modulates	O
cell	O
proliferation	O
and	O
reveals	O
a	O
novel	O
mechanism	O
by	O
which	O
the	O
p53	B-GENE
protein	I-GENE
is	O
stabilized	O
.	O

A	O
computerized	O
method	O
of	O
determining	O
the	O
focal	O
point	O
of	O
electrical	O
activity	O
in	O
the	O
pallidum	O
of	O
parkinsonian	O
patients	O
was	O
developed	O
using	O
on	O
-	O
line	O
quantitative	O
physiological	O
data	O
analysis	O
.	O

Isolated	O
Systolic	O
Hypertension	O
:	O
An	O
Update	O
.	O

The	O
N	O
-	O
terminal	O
portion	O
of	O
Notch	B-GENE
(	I-GENE
IC	I-GENE
)	I-GENE
inhibited	O
p50	B-GENE
DNA	O
binding	O
and	O
interacted	O
specifically	O
with	O
p50	B-GENE
subunit	I-GENE
,	O
not	O
p65	B-GENE
of	O
NF	B-GENE
-	I-GENE
kappaB	I-GENE
.	O

Conformational	O
changes	O
of	O
the	O
ferric	B-GENE
uptake	I-GENE
regulation	I-GENE
protein	I-GENE
upon	O
metal	O
activation	O
and	O
DNA	O
binding	O
;	O
first	O
evidence	O
of	O
structural	O
homologies	O
with	O
the	O
diphtheria	B-GENE
toxin	I-GENE
repressor	I-GENE
.	O

As	O
a	O
complement	O
to	O
genome	O
-	O
wide	O
mapping	O
and	O
sequencing	O
efforts	O
,	O
it	O
is	O
often	O
important	O
to	O
generate	O
detailed	O
maps	O
and	O
sequence	O
data	O
for	O
specific	O
regions	O
of	O
interest	O
.	O

Granulocyte	B-GENE
colony	I-GENE
-	I-GENE
stimulating	I-GENE
factor	I-GENE
(	O
G	B-GENE
-	I-GENE
CSF	I-GENE
)	O
administration	O
in	O
vivo	O
has	O
been	O
shown	O
to	O
improve	O
the	O
defence	O
mechanisms	O
against	O
infection	O
by	O
different	O
microbes	O
.	O

Among	O
individuals	O
,	O
however	O
,	O
changes	O
were	O
strongly	O
correlated	O
with	O
ACR	O
levels	O
at	O
baseline	O
.	O

Thus	O
,	O
the	O
screen	O
for	O
toxic	O
p53	B-GENE
mutants	I-GENE
in	O
yeast	O
can	O
identify	O
novel	O
p53	B-GENE
variants	O
that	O
may	O
be	O
useful	O
in	O
dissecting	O
p53	B-GENE
regulated	O
cellular	O
responses	O
and	O
in	O
developing	O
p53	B-GENE
-	O
based	O
cancer	O
therapies	O
.	O

This	O
is	O
necessary	O
if	O
psychiatric	O
diagnoses	O
are	O
ultimately	O
going	O
to	O
be	O
refined	O
and	O
validated	O
against	O
biological	O
criteria	O
.	O

Since	O
the	O
latter	O
is	O
very	O
small	O
for	O
physiological	O
flows	O
,	O
the	O
result	O
is	O
that	O
alpha	O
<	O
1	O
even	O
at	O
relatively	O
high	O
values	O
of	O
the	O
Reynolds	O
number	O
(	O
i	O
.	O
e	O
.	O
,	O
for	O
non	O
-	O
negligible	O
inertia	O
)	O
and	O
we	O
validate	O
our	O
perturbation	O
theory	O
results	O
by	O
comparison	O
with	O
a	O
numerical	O
integration	O
of	O
the	O
full	O
model	O
.	O

Cells	O
lacking	O
p116	B-GENE
exhibit	O
a	O
striking	O
defect	O
in	O
the	O
formation	O
of	O
these	O
macropinocytic	O
structures	O
,	O
a	O
concomitant	O
reduction	O
in	O
the	O
rate	O
of	O
fluid	O
phase	O
pinocytosis	O
,	O
a	O
significant	O
decrease	O
in	O
the	O
efficiency	O
of	O
chemotactic	O
aggregation	O
,	O
and	O
a	O
decrease	O
in	O
cellular	O
F	B-GENE
-	I-GENE
actin	I-GENE
content	O
.	O

The	O
validity	O
of	O
the	O
FPS	O
-	O
R	O
was	O
further	O
supported	O
by	O
strong	O
positive	O
correlations	O
with	O
the	O
VAS	O
(	O
r	O
=	O
0	O
.	O
92	O
,	O
N	O
=	O
45	O
)	O
and	O
the	O
CAS	O
(	O
r	O
=	O
0	O
.	O
84	O
,	O
N	O
=	O
45	O
)	O
in	O
this	O
clinical	O
sample	O
.	O

The	O
susceptibility	O
of	O
Aspergillus	O
fumigatus	O
to	O
mulundocandin	O
,	O
an	O
echinocandin	O
-	O
like	O
compound	O
,	O
and	O
other	O
antifungal	O
agents	O
was	O
assessed	O
by	O
the	O
National	O
Committee	O
for	O
Clinical	O
Laboratory	O
Standards	O
(	O
NCCLS	O
)	O
M38	O
-	O
P	O
method	O
,	O
a	O
2	O
,	O
3	O
-	O
bis	O
(	O
2	O
-	O
methoxy	O
-	O
4	O
-	O
nitro	O
-	O
5	O
-	O
sulfophenyl	O
)	O
-	O
5	O
-	O
[	O
(	O
phenyl	O
-	O
amino	O
)	O
carbonyl	O
]	O
-	O
2H	O
-	O
tetrazolium	O
hydroxide	O
(	O
XTT	O
)	O
-	O
based	O
colorimetric	O
assay	O
,	O
and	O
determination	O
of	O
morphologic	O
alterations	O
by	O
microscopy	O
.	O

DESIGN	O
:	O
A	O
retrospective	O
chart	O
review	O
of	O
9	O
,	O
322	O
patients	O
undergoing	O
surgical	O
procedures	O
in	O
the	O
period	O
January	O
1993	O
to	O
December	O
1998	O
.	O

Pulmonary	O
vein	O
varix	O
in	O
association	O
with	O
bilateral	O
pulmonary	O
vein	O
stenosis	O
.	O

Biochemical	O
experiments	O
have	O
shown	O
that	O
CopG	B-GENE
co	O
-	O
operatively	O
associates	O
to	O
its	O
target	O
DNA	O
at	O
low	O
protein	O
:	O
DNA	O
ratios	O
,	O
completely	O
protecting	O
four	O
helical	O
turns	O
on	O
the	O
same	O
face	O
of	O
the	O
double	O
helix	O
in	O
both	O
directions	O
from	O
the	O
inverted	O
repeat	O
that	O
constitutes	O
the	O
CopG	B-GENE
primary	O
target	O
.	O

We	O
demonstrated	O
that	O
,	O
under	O
serum	O
-	O
starved	O
conditions	O
,	O
KMS	O
-	O
11	O
and	O
OPM	O
-	O
2	O
cells	O
express	O
appreciable	O
levels	O
of	O
phosphorylated	O
FGFR3	B-GENE
mutants	I-GENE
indicating	O
a	O
constitutive	O
activation	O
of	O
the	O
Y373C	B-GENE
and	I-GENE
K650E	I-GENE
receptors	I-GENE
;	O
the	O
addition	O
of	O
the	O
aFGF	B-GENE
ligand	I-GENE
further	O
increased	O
the	O
level	O
of	O
receptor	O
phosphorylation	O
.	O

[	O
figure	O
:	O
see	O
text	O
]	O
The	O
Stille	O
coupling	O
reaction	O
has	O
been	O
performed	O
in	O
1	O
-	O
butyl	O
-	O
3	O
-	O
methylimidazolium	O
tetrafluoroborate	O
(	O
BMIM	O
BF4	O
)	O
,	O
a	O
room	O
-	O
temperature	O
ionic	O
liquid	O
(	O
RTIL	O
)	O
.	O

Special	O
issues	O
devoted	O
to	O
the	O
biosynthesis	O
of	O
woody	O
plant	O
biopolymers	O
and	O
related	O
substances	O
.	O

Interactions	O
between	O
the	O
checkpoint	O
abrogator	O
UCN	O
-	O
01	O
and	O
several	O
pharmacological	O
inhibitors	O
of	O
the	O
mitogen	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
kinase	I-GENE
(	I-GENE
MAPK	I-GENE
)	I-GENE
kinase	I-GENE
(	O
MEK	B-GENE
)	O
/	O
MAPK	B-GENE
pathway	O
have	O
been	O
examined	O
in	O
a	O
variety	O
of	O
human	O
leukemia	O
cell	O
lines	O
.	O

Low	O
affinity	O
binding	O
of	O
Rab6A	B-GENE
-	I-GENE
GTP	I-GENE
was	O
also	O
observed	O
(	O
K	O
(	O
d	O
)	O
=	O
16	O
microm	O
)	O
,	O
whereas	O
Rab1B	B-GENE
,	I-GENE
-	I-GENE
5	I-GENE
,	I-GENE
-	I-GENE
7	I-GENE
,	I-GENE
-	I-GENE
8	I-GENE
,	I-GENE
or	I-GENE
-	I-GENE
11A	I-GENE
did	O
not	O
bind	O
.	O

The	O
students	O
who	O
had	O
abnormal	O
urine	O
screening	O
results	O
at	O
the	O
first	O
time	O
received	O
a	O
second	O
urine	O
analysis	O
10	O
to	O
15	O
days	O
later	O
to	O
confirm	O
the	O
abnormal	O
urine	O
analysis	O
.	O

Regulation	O
of	O
laminin	B-GENE
beta2	I-GENE
chain	I-GENE
gene	I-GENE
expression	O
in	O
human	O
cancer	O
cell	O
lines	O
.	O

Northern	O
and	O
Western	O
blot	O
analyses	O
demonstrated	O
that	O
Graf2	B-GENE
is	O
expressed	O
in	O
several	O
tissues	O
,	O
with	O
the	O
highest	O
expression	O
in	O
skeletal	O
muscle	O
.	O

However	O
,	O
when	O
directed	O
to	O
the	O
nucleosome	O
by	O
fusion	O
to	O
core	B-GENE
histone	I-GENE
H2A	I-GENE
or	O
H2B	B-GENE
,	O
the	O
non	O
-	O
histone	B-GENE
tail	O
forms	O
an	O
MCB	O
that	O
appears	O
identical	O
to	O
that	O
of	O
the	O
endogenous	O
protein	O
.	O

These	O
data	O
suggest	O
that	O
proper	O
direct	O
binding	O
of	O
Nhp2p	B-GENE
to	O
H	B-GENE
/	I-GENE
ACA	I-GENE
snoRNAs	I-GENE
is	O
required	O
for	O
the	O
assembly	O
of	O
H	B-GENE
/	I-GENE
ACA	I-GENE
snoRNPs	I-GENE
and	O
hence	O
for	O
the	O
stability	O
of	O
some	O
of	O
their	O
components	O
.	O

Telomerase	B-GENE
is	O
a	O
ribonucleoprotein	O
complex	O
that	O
synthesizes	O
telomeric	O
DNA	O
onto	O
chromosomes	O
using	O
its	O
RNA	O
component	O
as	O
template	O
.	O

SIT	B-GENE
(	O
SHP2	B-GENE
-	I-GENE
interacting	I-GENE
transmembrane	I-GENE
adaptor	I-GENE
protein	I-GENE
)	O
is	O
a	O
recently	O
identified	O
transmembrane	O
adaptor	O
protein	O
,	O
which	O
is	O
expressed	O
in	O
lymphocytes	O
.	O

Ileal	O
digestibilities	O
of	O
DM	O
,	O
OM	O
,	O
CP	O
,	O
total	O
dietary	O
fiber	O
(	O
TDF	O
)	O
,	O
fat	O
and	O
gross	O
energy	O
(	O
GE	O
)	O
were	O
lower	O
(	O
P	O
<	O
0	O
.	O
05	O
)	O
for	O
dogs	O
fed	O
diets	O
containing	O
supplemental	O
fiber	O
compared	O
with	O
dogs	O
fed	O
the	O
control	O
diet	O
.	O

Together	O
these	O
data	O
imply	O
that	O
the	O
HFV	B-GENE
R	I-GENE
region	I-GENE
acts	O
in	O
the	O
nucleus	O
to	O
modify	O
the	O
cytoplasmic	O
fate	O
of	O
target	O
HFV	O
mRNA	O
.	O

These	O
TxRE	B-GENE
contain	O
cyclic	O
AMP	O
-	O
responsive	O
elements	O
(	O
CRE	O
)	O
,	O
but	O
,	O
remarkably	O
,	O
the	O
"	O
TGACGTCA	O
"	O
consensus	O
is	O
never	O
strictly	O
conserved	O
in	O
any	O
viral	O
strain	O
(	O
e	O
.	O
g	O
.	O
,	O
AGACGTCA	O
,	O
TGACGGCA	O
,	O
TGACCTCA	O
)	O
.	O

And	O
,	O
most	O
importantly	O
,	O
reconstitution	O
of	O
a	O
consensus	O
CRE	O
,	O
within	O
the	O
21	O
-	O
bp	O
enhancers	O
increases	O
binding	O
of	O
CREB	B-GENE
/	O
ATF	B-GENE
proteins	O
but	O
abrogates	O
basal	O
repression	O
of	O
LTR	O
-	O
directed	O
transcription	O
in	O
vitro	O
.	O

Site	O
-	O
directed	O
mutagenesis	O
of	O
CAR	B-GENE
revealed	O
that	O
CAR	B-GENE
residues	O
Leu73	O
and	O
Lys121	O
and	O
/	O
or	O
Lys123	O
are	O
critical	O
contact	O
residues	O
,	O
with	O
Tyr80	O
and	O
Tyr83	O
being	O
peripherally	O
involved	O
in	O
the	O
binding	O
interaction	O
with	O
the	O
Ad5	B-GENE
,	I-GENE
Ad9	I-GENE
,	I-GENE
Ad12	I-GENE
,	I-GENE
and	I-GENE
Ad41L	I-GENE
fiber	I-GENE
knobs	I-GENE
.	O

This	O
subfamily	O
of	O
genes	O
all	O
have	O
a	O
single	O
ATP	O
-	O
binding	O
domain	O
at	O
the	O
N	O
-	O
terminus	O
and	O
a	O
single	O
C	O
-	O
terminal	O
set	O
of	O
transmembrane	O
segments	O
.	O

The	O
promoter	O
activity	O
of	O
the	O
proximal	O
region	O
was	O
found	O
to	O
be	O
restricted	O
to	O
a	O
subset	O
of	O
prestalk	O
cells	O
.	O

Substitution	O
of	O
serine	O
residues	O
at	O
the	O
C	O
-	O
terminus	O
indicated	O
that	O
loss	O
of	O
phosphorylation	O
sites	O
did	O
not	O
appear	O
to	O
have	O
any	O
effect	O
on	O
transcription	O
and	O
replication	O
.	O

Thus	O
,	O
replication	O
fork	O
movement	O
near	O
HML	B-GENE
pauses	O
at	O
a	O
silent	O
origin	O
which	O
is	O
competent	O
for	O
replication	O
initiation	O
but	O
kept	O
silent	O
through	O
Orc2p	B-GENE
,	O
a	O
component	O
of	O
the	O
replication	O
initiator	O
.	O

These	O
findings	O
suggest	O
that	O
the	O
adapter	O
Gab1	B-GENE
may	O
redirect	O
c	B-GENE
-	I-GENE
Met	I-GENE
signaling	O
through	O
PI3K	B-GENE
away	O
from	O
a	O
c	B-GENE
-	I-GENE
Akt	I-GENE
/	O
Pak1	B-GENE
cell	O
survival	O
pathway	O
.	O

We	O
have	O
cloned	O
a	O
novel	O
mouse	O
protein	O
,	O
TAF	B-GENE
(	I-GENE
II	I-GENE
)	I-GENE
140	I-GENE
,	O
containing	O
an	O
HFD	B-GENE
and	O
a	O
plant	B-GENE
homeodomain	I-GENE
(	O
PHD	B-GENE
)	O
finger	O
,	O
which	O
we	O
demonstrated	O
by	O
immunoprecipitation	O
to	O
be	O
a	O
mammalian	B-GENE
TFIID	I-GENE
component	I-GENE
.	O

The	O
other	O
inhibitor	O
was	O
a	O
single	O
TAR	B-GENE
decoy	O
,	O
driven	O
by	O
the	O
U6	B-GENE
small	I-GENE
nuclear	I-GENE
RNA	I-GENE
promoter	I-GENE
(	O
U6	B-GENE
-	I-GENE
P	I-GENE
)	O
.	O

In	O
contrast	O
to	O
MPc3	B-GENE
,	O
data	O
indicate	O
that	O
the	O
Pc	B-GENE
protein	I-GENE
M33	B-GENE
does	O
not	O
interact	O
with	O
AF9	B-GENE
.	O

Long	O
-	O
term	O
results	O
with	O
MACOP	O
-	O
B	O
and	O
radiation	O
therapy	O
for	O
aggressive	O
lymphomas	O
]	O
BACKGROUND	O
:	O
Long	O
-	O
term	O
results	O
are	O
needed	O
to	O
evaluate	O
chemotherapy	O
regimens	O
and	O
prognostic	O
factors	O
in	O
non	O
-	O
Hodgkin	O
'	O
s	O
lymphomas	O
(	O
NHL	O
)	O
.	O

At	O
20	O
days	O
(	O
D	O
)	O
and	O
at	O
3	O
months	O
post	O
-	O
TBI	O
,	O
irradiated	O
rats	O
had	O
a	O
significantly	O
lower	O
percentage	O
of	O
avoidance	O
than	O
controls	O
but	O
no	O
statistical	O
difference	O
was	O
found	O
at	O
5	O
months	O
post	O
-	O
TBI	O
.	O
b	O
/	O
Two	O
-	O
way	O
avoidance	O
test	O
:	O
this	O
test	O
was	O
performed	O
only	O
after	O
TBI	O
.	O

At	O
the	O
end	O
of	O
each	O
day	O
of	O
migration	O
the	O
pulmonary	O
hemolymph	O
PO2	O
decreased	O
by	O
1	O
-	O
2	O
.	O
5	O
kPa	O
,	O
but	O
the	O
hemocyanin	O
remained	O
saturated	O
with	O
O2	O
and	O
the	O
venous	O
reserve	O
was	O
largely	O
unchanged	O
(	O
O2	O
>	O
0	O
.	O
4	O
mmol	O
x	O
l	O
(	O
-	O
1	O
)	O
)	O
.	O

DESIGN	O
:	O
Prospective	O
cohort	O
study	O
with	O
a	O
20	O
y	O
follow	O
-	O
up	O
period	O
,	O
the	O
First	O
National	O
Health	O
and	O
Examination	O
Survey	O
(	O
NHANES	O
1	O
)	O
Epidemiologic	O
Follow	O
-	O
up	O
Study	O
(	O
NHEFS	O
)	O
.	O

Mean	O
Hg	O
concentrations	O
in	O
the	O
livers	O
of	O
mice	O
at	O
some	O
sites	O
in	O
Isle	O
Royale	O
are	O
not	O
significantly	O
lower	O
(	O
P	O
=	O
0	O
.	O
62	O
)	O
than	O
Hg	O
concentrations	O
considered	O
by	O
some	O
government	O
agencies	O
to	O
be	O
unhealthy	O
for	O
human	O
consumption	O
.	O

There	O
are	O
many	O
different	O
proposals	O
for	O
the	O
statistical	O
analysis	O
of	O
data	O
to	O
determine	O
early	O
onset	O
of	O
action	O
.	O

The	O
assay	O
herein	O
described	O
allows	O
the	O
comparison	O
of	O
relative	O
FGFR	B-GENE
expression	O
levels	O
,	O
both	O
within	O
a	O
single	O
RNA	O
pool	O
and	O
among	O
multiple	O
RNA	O
pool	O
samples	O
.	O

The	O
amount	O
of	O
drained	O
effusion	O
was	O
measured	O
,	O
and	O
fluid	O
was	O
sent	O
for	O
diagnostic	O
assessment	O
.	O

The	O
system	O
,	O
designed	O
to	O
exploit	O
the	O
relatively	O
constant	O
small	O
intestine	O
transit	O
time	O
,	O
consists	O
of	O
a	O
drug	O
-	O
containing	O
core	O
coated	O
with	O
a	O
polymeric	O
matrix	O
formed	O
by	O
a	O
channeling	O
agent	O
(	O
NaCl	O
,	O
mannitol	O
,	O
and	O
Emdex	O
)	O
and	O
an	O
inert	O
polymer	O
(	O
Eudragit	O
RS100	O
)	O
.	O

STUDY	O
OBJECTIVE	O
:	O
This	O
study	O
assessed	O
several	O
methodological	O
aspects	O
related	O
to	O
the	O
quality	O
of	O
published	O
controlled	O
clinical	O
trials	O
(	O
CCTs	O
)	O
in	O
relation	O
to	O
the	O
participation	O
of	O
an	O
epidemiologist	O
/	O
biostatistician	O
(	O
E	O
/	O
B	O
)	O
.	O

The	O
median	O
preoperative	O
best	O
-	O
corrected	O
visual	O
acuity	O
of	O
0	O
.	O
08	O
(	O
range	O
hand	O
motions	O
/	O
0	O
.	O
003	O
to	O
0	O
.	O
4	O
)	O
,	O
improved	O
by	O
5	O
lines	O
to	O
a	O
median	O
final	O
postoperative	O
best	O
-	O
corrected	O
visual	O
acuity	O
of	O
0	O
.	O
25	O
(	O
range	O
0	O
.	O
025	O
-	O
0	O
.	O
5	O
)	O
(	O
P	O
=	O
0	O
.	O
001	O
)	O
.	O

A	O
rare	O
case	O
of	O
primary	O
group	O
A	O
streptococcal	O
peritonitis	O
.	O

Gimpl	O
,	O
F	O
.	O

BACKGROUND	O
/	O
AIMS	O
:	O
Hepatitis	O
C	O
and	O
nonalcoholic	O
fatty	O
liver	O
disease	O
(	O
NAFL	O
)	O
are	O
the	O
two	O
most	O
common	O
forms	O
of	O
liver	O
disease	O
in	O
the	O
United	O
States	O
.	O

Statistical	O
Analysis	O
included	O
ANOVA	O
,	O
the	O
Pearson	O
Product	O
Moment	O
Correlation	O
Coefficient	O
,	O
Principal	O
Components	O
Analysis	O
and	O
Discriminant	O
Function	O
Analysis	O
and	O
the	O
calculation	O
of	O
Cronbach	O
'	O
s	O
alpha	O
(	O
alpha	O
)	O
RESULTS	O
:	O
Both	O
Sensitivity	O
and	O
specificity	O
exceed	O
90	O
.	O
00	O
at	O
23	O
/	O
24	O
,	O
Chronbach	O
'	O
s	O
alpha	O
for	O
the	O
total	O
scale	O
was	O
equal	O
to	O
0	O
.	O
95	O
.	O

The	O
titer	O
of	O
TSH	B-GENE
binding	I-GENE
inhibitor	I-GENE
immunoglobulin	I-GENE
(	O
TBII	B-GENE
)	O
,	O
which	O
had	O
been	O
8	O
.	O
6	O
%	O
at	O
initial	O
presentation	O
,	O
rose	O
to	O
14	O
.	O
9	O
%	O
in	O
2	O
weeks	O
.	O

Here	O
we	O
show	O
that	O
independent	O
of	O
uncertainties	O
in	O
the	O
models	O
,	O
terrestrial	O
planets	O
with	O
dense	O
atmosphere	O
like	O
Venus	O
can	O
evolve	O
into	O
one	O
of	O
only	O
four	O
possible	O
rotation	O
states	O
.	O

Enantiomer	O
separation	O
of	O
venlafaxine	O
and	O
O	O
-	O
desmethylvenlafaxine	O
in	O
human	O
plasma	O
.	O

TE	O
-	O
671	O
cells	O
that	O
were	O
transfected	O
with	O
cAMP	O
response	O
element	O
mutant	O
constructs	O
demonstrated	O
a	O
diminished	O
basal	O
activity	O
of	O
the	O
GnRH	B-GENE
-	I-GENE
II	I-GENE
promoter	I-GENE
.	O

They	O
consist	O
of	O
at	O
least	O
two	O
separable	O
components	O
,	O
one	O
heat	O
stable	O
and	O
the	O
other	O
heat	O
labile	O
.	O

Altogether	O
,	O
we	O
confirm	O
that	O
all	O
genes	O
of	O
the	O
Rad52	B-GENE
recombinational	O
repair	O
pathway	O
are	O
required	O
for	O
the	O
survival	O
of	O
rad27	B-GENE
Delta	I-GENE
strains	O
at	O
both	O
permissive	O
(	O
23	O
degrees	O
C	O
)	O
and	O
semipermissive	O
(	O
30	O
degrees	O
C	O
)	O
temperatures	O
for	O
growth	O
.	O

In	O
the	O
last	O
case	O
,	O
both	O
hydroxychloroquine	O
,	O
carbamazepine	O
and	O
fluvoxamine	O
had	O
a	O
common	O
imputability	O
which	O
was	O
plausible	O
.	O

We	O
investigate	O
the	O
reaction	O
kinetics	O
of	O
small	O
spherical	O
particles	O
with	O
inertia	O
,	O
obeying	O
coalescence	O
type	O
of	O
reaction	O
,	O
B	O
+	O
B	O
-	O
-	O
>	O
B	O
,	O
and	O
being	O
advected	O
by	O
hydrodynamical	O
flows	O
with	O
time	O
-	O
periodic	O
forcing	O
.	O

The	O
role	O
of	O
the	O
Vp1	B-GENE
DBD	I-GENE
during	O
infection	O
was	O
investigated	O
by	O
taking	O
advantage	O
of	O
NLS	O
phenotypic	O
complementation	O
(	O
N	O
.	O

2	O
were	O
nonviable	O
,	O
and	O
the	O
mutant	B-GENE
Vp1s	I-GENE
unexpectedly	O
failed	O
to	O
localize	O
to	O
the	O
nucleus	O
though	O
Vp2	B-GENE
and	O
Vp3	B-GENE
did	O
,	O
suggesting	O
that	O
the	O
mutated	B-GENE
NLS1	I-GENE
acted	O
as	O
a	O
dominant	O
signal	O
for	O
the	O
cytoplasmic	O
localization	O
of	O
Vp1	B-GENE
.	O

Fasting	O
gastrin	B-GENE
levels	O
(	O
normal	O
range	O
:	O
25	O
-	O
110	O
mU	O
/	O
L	O
)	O
varied	O
from	O
48	O
.	O
78	O
mU	O
/	O
L	O
-	O
168	O
.	O
20	O
(	O
mean	O
:	O
85	O
.	O
23	O
mU	O
/	O
L	O
)	O
.	O

Here	O
,	O
we	O
show	O
that	O
the	O
phorbol	O
ester	O
PMA	O
decreases	O
both	O
basal	O
and	O
dexamethasone	O
/	O
cAMP	O
-	O
induced	O
expression	O
of	O
a	O
luciferase	B-GENE
gene	I-GENE
under	O
the	O
control	O
of	O
the	O
G6Pase	B-GENE
promoter	I-GENE
in	O
transiently	O
transfected	O
H4IIE	O
hepatoma	O
cells	O
.	O

Through	O
deletion	O
mutagenesis	O
,	O
we	O
identify	O
amino	O
acids	O
2003	O
to	O
2212	O
of	O
CBP	B-GENE
,	O
which	O
we	O
call	O
carboxy	O
-	O
terminal	O
region	O
2	O
(	O
CR2	O
)	O
,	O
as	O
the	O
minimal	O
region	O
for	O
Tax	B-GENE
interaction	O
.	O

Such	O
knowledge	O
could	O
advance	O
diagnosis	O
and	O
treatment	O
of	O
the	O
patient	O
and	O
counseling	O
of	O
the	O
affected	O
family	O
.	O

BACKGROUND	O
:	O
There	O
is	O
increasing	O
interest	O
on	O
the	O
part	O
of	O
investigators	O
and	O
the	O
public	O
at	O
large	O
in	O
finding	O
ways	O
to	O
study	O
and	O
improve	O
treatments	O
for	O
the	O
seriously	O
mentally	O
ill	O
without	O
exposing	O
such	O
individuals	O
to	O
unnecessary	O
risks	O
.	O

In	O
the	O
next	O
week	O
,	O
the	O
beta	O
-	O
adrenergic	O
antagonist	O
atenolol	O
was	O
added	O
at	O
an	O
initial	O
dose	O
of	O
25	O
mg	O
/	O
day	O
and	O
titrated	O
to	O
50	O
mg	O
/	O
day	O
within	O
1	O
week	O
.	O

Lack	O
of	O
association	O
between	O
Kawasaki	O
syndrome	O
and	O
infection	O
with	O
Rickettsia	O
conorii	O
,	O
Rickettsia	O
typhi	O
,	O
Coxiella	O
burnetii	O
or	O
Ehrlichia	O
phagocytophila	O
group	O
.	O

The	O
presence	O
of	O
AS	O
-	O
oligo	O
had	O
no	O
further	O
effect	O
on	O
the	O
FSH	B-GENE
-	O
mediated	O
activation	O
of	O
the	O
EB	O
*	O
-	O
mTf	B-GENE
-	O
CAT	B-GENE
construct	O
but	O
reduced	O
cAMP	O
-	O
mediated	O
activation	O
.	O

This	O
is	O
a	O
challenging	O
task	O
insofar	O
as	O
direct	O
measures	O
of	O
ISF	O
glucose	O
are	O
not	O
readily	O
available	O
.	O

We	O
report	O
the	O
results	O
of	O
a	O
detailed	O
policy	O
analysis	O
comparing	O
2	O
CJD	O
-	O
related	O
decisions	O
:	O
a	O
1995	O
recall	O
of	O
blood	O
from	O
a	O
donor	O
with	O
classic	O
CJD	O
and	O
the	O
1999	O
decision	O
to	O
defer	O
donations	O
from	O
individuals	O
with	O
a	O
6	O
-	O
month	O
travel	O
history	O
to	O
the	O
UK	O
between	O
1980	O
and	O
1996	O
due	O
to	O
concerns	O
related	O
to	O
variant	O
CJD	O
.	O

At	O
visit	O
5	O
,	O
the	O
isokinetic	O
test	O
showed	O
impaired	O
muscle	O
function	O
recovery	O
from	O
23	O
%	O
to	O
32	O
%	O
,	O
while	O
the	O
manual	O
test	O
showed	O
almost	O
full	O
recovery	O
.	O

We	O
developed	O
a	O
system	O
for	O
domain	O
shuffling	O
to	O
establish	O
the	O
function	O
of	O
C1	B-GENE
domains	O
from	O
human	B-GENE
Raf	I-GENE
kinase	I-GENE
and	O
rat	B-GENE
PKC	I-GENE
eta	I-GENE
in	O
yeast	O
.	O

We	O
interpret	O
these	O
data	O
as	O
further	O
evidence	O
that	O
interaction	O
with	O
a	O
small	B-GENE
GTPase	I-GENE
is	O
the	O
main	O
regulatory	O
function	O
of	O
the	O
C1	B-GENE
domain	O
in	O
yeast	O
.	O

Breast	O
cancer	O
risk	O
assessment	O
:	O
Who	O
holds	O
the	O
magic	O
crystal	O
ball	O
?	O

Patients	O
with	O
type	O
III	O
SOD	O
may	O
have	O
visceral	O
hyperalgesia	O
;	O
a	O
trial	O
of	O
antidepressants	O
or	O
a	O
therapeutic	O
trial	O
with	O
botulinum	B-GENE
toxin	I-GENE
injection	O
into	O
the	O
ampulla	O
should	O
be	O
considered	O
prior	O
to	O
more	O
invasive	O
endoscopic	O
therapy	O
.	O

RESULTS	O
:	O
There	O
is	O
a	O
considerable	O
amount	O
of	O
variation	O
between	O
the	O
results	O
of	O
TRA1	O
and	O
TRA2	O
and	O
between	O
the	O
results	O
of	O
both	O
TRA	O
'	O
s	O
and	O
the	O
door	O
-	O
to	O
-	O
door	O
survey	O
.	O

In	O
addition	O
,	O
these	O
patients	O
show	O
both	O
quantitative	O
and	O
qualitative	O
differences	O
in	O
their	O
infectious	O
microbiological	O
spectrum	O
,	O
mainly	O
in	O
clean	O
-	O
contaminated	O
,	O
contaminated	O
and	O
dirty	O
surgical	O
procedures	O
.	O

CONCLUSION	O
:	O
Extrusion	O
cooking	O
is	O
effective	O
for	O
the	O
inactivation	O
of	O
DON	O
but	O
is	O
of	O
limited	O
value	O
for	O
AFB1	B-GENE
,	O
even	O
if	O
metabisulphite	O
is	O
added	O
.	O

The	O
differences	O
in	O
the	O
CPIgG	B-GENE
,	O
CRP	B-GENE
,	O
and	O
fibrinogen	B-GENE
levels	O
in	O
patients	O
who	O
were	O
diagnosed	O
with	O
ACS	O
versus	O
those	O
who	O
were	O
not	O
(	O
non	O
-	O
ACS	O
)	O
were	O
evaluated	O
.	O

NaeI	B-GENE
,	O
a	O
novel	O
DNA	B-GENE
endonuclease	I-GENE
,	O
shows	O
topoisomerase	B-GENE
and	O
recombinase	B-GENE
activities	O
when	O
a	O
Lys	O
residue	O
is	O
substituted	O
for	O
Leu	O
43	O
.	O

The	O
decrements	O
in	O
cerebrovascular	O
resistance	O
induced	O
by	O
hexamethonium	O
,	O
in	O
mm	O
Hg	O
ml	O
(	O
-	O
1	O
)	O
.	O
min	O
(	O
-	O
1	O
)	O
,	O
were	O
:	O
under	O
control	O
.	O

The	O
desirability	O
function	O
is	O
based	O
on	O
the	O
search	O
for	O
a	O
global	O
optimum	O
[	O
D	O
=	O
f	O
(	O
Y1	O
,	O
Y2	O
,	O
.	O
.	O
.	O
,	O
Yn	O
)	O
]	O
by	O
the	O
transformation	O
of	O
the	O
measured	O
property	O
to	O
a	O
dimensionless	O
scale	O
for	O
each	O
criterion	O
.	O

RESULTS	O
:	O
In	O
vivo	O
,	O
there	O
was	O
a	O
wide	O
distribution	O
with	O
the	O
coefficient	O
of	O
variation	O
(	O
SD	O
/	O
mean	O
x	O
100	O
%	O
)	O
for	O
different	O
valve	O
sizes	O
ranging	O
from	O
21	O
%	O
to	O
39	O
%	O
in	O
the	O
St	O
Jude	O
Medical	O
valve	O
and	O
from	O
25	O
%	O
to	O
33	O
%	O
in	O
the	O
Omnicarbon	O
valve	O
.	O

Even	O
if	O
the	O
electrocardiographic	O
signs	O
are	O
subdued	O
,	O
the	O
underlying	O
blockade	O
of	O
I	O
(	O
Kr	O
)	O
current	O
may	O
precipitate	O
the	O
occurrence	O
of	O
arrhythmia	O
.	O

The	O
production	O
of	O
ceramide	O
is	O
emerging	O
as	O
a	O
fixture	O
of	O
programmed	O
cell	O
death	O
.	O

We	O
randomly	O
assigned	O
1	O
,	O
219	O
subjects	O
to	O
receive	O
either	O
the	O
standard	O
three	O
-	O
times	O
-	O
weekly	O
(	O
TIW	O
)	O
interferon	B-GENE
alfa	I-GENE
-	I-GENE
2b	I-GENE
dose	O
(	O
3	O
MIU	O
)	O
or	O
the	O
once	O
-	O
weekly	O
(	O
QW	O
)	O
peginterferon	B-GENE
alfa	I-GENE
-	I-GENE
2b	I-GENE
(	O
0	O
.	O
5	O
,	O
1	O
.	O
0	O
,	O
or	O
1	O
.	O
5	O
microg	O
/	O
kg	O
)	O
.	O

At	O
cross	O
purposes	O
.	O

Among	O
the	O
transcription	O
factors	O
known	O
to	O
interact	O
with	O
Groucho	B-GENE
-	I-GENE
related	I-GENE
protein	I-GENE
,	O
only	O
RUNX1	B-GENE
was	O
appreciably	O
downregulated	O
by	O
E2A	B-GENE
-	O
HLF	B-GENE
.	O

The	O
combination	O
of	O
ifosfamide	O
,	O
epirubicin	O
and	O
etoposide	O
(	O
IEV	O
)	O
is	O
an	O
effective	O
salvage	O
regimen	O
for	O
lymphoproliferative	O
disease	O
.	O

A	O
prospective	O
trial	O
was	O
undertaken	O
to	O
determine	O
(	O
1	O
)	O
clinical	O
characteristics	O
of	O
patients	O
with	O
chest	O
pain	O
;	O
(	O
2	O
)	O
value	O
of	O
cardiac	O
markers	O
troponin	B-GENE
T	I-GENE
,	O
myoglobin	B-GENE
and	O
CK	B-GENE
-	O
MB	B-GENE
mass	O
in	O
differentiating	O
cardiac	O
and	O
noncardiac	O
chest	O
pain	O
;	O
(	O
3	O
)	O
the	O
proportion	O
of	O
patients	O
with	O
ACS	O
in	O
whom	O
these	O
markers	O
provided	O
helpful	O
additional	O
information	O
on	O
admission	O
and	O
afterwards	O
.	O

Cardiac	O
markers	O
troponin	B-GENE
T	I-GENE
,	O
CK	B-GENE
-	O
MB	B-GENE
mass	O
and	O
myoglobin	B-GENE
were	O
helpful	O
in	O
the	O
differential	O
diagnosis	O
of	O
chest	O
pain	O
,	O
even	O
when	O
the	O
ECG	O
was	O
unremarkable	O
or	O
nonspecific	O
.	O

At	O
termination	O
(	O
gd	O
20	O
)	O
,	O
confirmed	O
-	O
pregnant	O
females	O
(	O
21	O
to	O
25	O
per	O
group	O
)	O
were	O
evaluated	O
for	O
clinical	O
status	O
and	O
gestational	O
outcome	O
;	O
live	O
fetuses	O
were	O
examined	O
for	O
external	O
,	O
visceral	O
,	O
and	O
skeletal	O
malformations	O
.	O

One	O
maternal	O
death	O
,	O
reduced	O
body	O
weight	O
,	O
and	O
reduced	O
weight	O
gain	O
were	O
noted	O
at	O
the	O
high	O
dose	O
;	O
confirmed	O
pregnancy	O
rates	O
were	O
84	O
to	O
100	O
%	O
for	O
each	O
group	O
.	O

In	O
the	O
further	O
development	O
of	O
bladder	O
neck	O
suspension	O
according	O
to	O
Stamey	O
-	O
Pereyra	O
,	O
the	O
use	O
of	O
miniature	O
bone	O
anchors	O
received	O
considerable	O
support	O
.	O

Simulating	O
the	O
impact	O
during	O
human	O
jumping	O
by	O
means	O
of	O
a	O
4	O
-	O
degrees	O
-	O
of	O
-	O
freedom	O
model	O
with	O
time	O
-	O
dependent	O
properties	O
.	O

A	O
1	O
-	O
base	O
pair	O
mismatch	O
within	O
the	O
corresponding	O
region	O
of	O
the	O
CYP3A4	B-GENE
gene	I-GENE
was	O
sufficient	O
for	O
a	O
differential	O
enhancer	O
activity	O
.	O

The	O
authors	O
made	O
an	O
analysis	O
of	O
social	O
-	O
economical	O
conditions	O
limiting	O
the	O
possibilities	O
of	O
rendering	O
cardiosurgical	O
care	O
to	O
children	O
.	O

METHODS	O
:	O
93	O
female	O
and	O
43	O
male	O
patients	O
undergoing	O
thyroid	O
surgery	O
were	O
stratified	O
according	O
to	O
gender	O
and	O
then	O
randomised	O
to	O
receive	O
double	O
-	O
blind	O
one	O
of	O
four	O
antiemetic	O
regimes	O
:	O
50	O
mg	O
dolasetron	O
given	O
orally	O
45	O
minutes	O
prior	O
to	O
induction	O
of	O
anaesthesia	O
(	O
group	O
I	O
)	O
,	O
12	O
.	O
5	O
mg	O
dolasetron	O
given	O
intravenously	O
during	O
induction	O
of	O
anaesthesia	O
(	O
group	O
II	O
)	O
,	O
1	O
.	O
25	O
mg	O
DHB	B-GENE
given	O
intravenously	O
during	O
induction	O
of	O
anaesthesia	O
(	O
group	O
III	O
)	O
or	O
placebo	O
(	O
group	O
IV	O
)	O
.	O

This	O
slow	O
progression	O
through	O
the	O
early	O
G1	O
-	O
phase	O
resulted	O
in	O
decreased	O
phosphorylation	O
of	O
the	O
RB	B-GENE
protein	I-GENE
and	O
subsequent	O
delay	O
into	O
the	O
S	O
phase	O
transition	O
.	O

In	O
mammals	O
,	O
the	O
transcriptional	O
repressors	O
in	O
the	O
Wnt	B-GENE
pathway	O
are	O
not	O
well	O
defined	O
.	O

Despite	O
abundant	O
expression	O
of	O
NtmybAS	B-GENE
transcripts	I-GENE
in	O
mature	O
pollen	O
,	O
gPAL1	B-GENE
transcripts	I-GENE
were	O
not	O
detectable	O
in	O
pollen	O
.	O

Identical	O
effects	O
were	O
obtained	O
when	O
inhibitors	O
and	O
dominant	O
negative	O
mutants	O
were	O
tested	O
on	O
the	O
-	O
29	O
to	O
+	O
139	O
bp	O
region	O
of	O
the	O
cyclin	B-GENE
D1	I-GENE
promoter	I-GENE
.	O

These	O
findings	O
suggest	O
a	O
novel	O
ankyrin	B-GENE
-	O
independent	O
role	O
for	O
LAD	B-GENE
-	I-GENE
1	I-GENE
related	O
to	O
FGFR	B-GENE
signaling	O
.	O

Moreover	O
,	O
elderly	O
men	O
with	O
bioavailable	O
estradiol	O
levels	O
below	O
the	O
median	O
[	O
40	O
pmol	O
/	O
liter	O
(	O
11	O
pg	O
/	O
ml	O
)	O
]	O
had	O
significantly	O
higher	O
rates	O
of	O
bone	O
loss	O
and	O
levels	O
of	O
bone	O
resorption	O
markers	O
than	O
men	O
with	O
bioavailable	O
estradiol	O
levels	O
above	O
40	O
pmol	O
/	O
liter	O
.	O

Competition	O
electrophoretic	O
mobility	O
shift	O
and	O
immunoshift	O
assays	O
confirmed	O
that	O
NF1	B-GENE
factors	I-GENE
present	O
in	O
nuclear	O
extracts	O
of	O
HeLa	O
and	O
CV	O
-	O
1	O
cells	O
bind	O
to	O
the	O
BKV	B-GENE
-	I-GENE
MLP	I-GENE
.	O

This	O
study	O
demonstrates	O
that	O
inducible	O
expression	O
in	O
response	O
to	O
either	O
PMA	O
or	O
TPO	B-GENE
is	O
mediated	O
through	O
the	O
Ets	B-GENE
site	I-GENE
in	O
the	O
proximal	O
promoter	O
of	O
GPIX	B-GENE
and	O
is	O
dependent	O
upon	O
the	O
upstream	O
activation	O
of	O
MAPK	B-GENE
/	O
extracellular	B-GENE
signal	I-GENE
-	I-GENE
regulated	I-GENE
kinase	I-GENE
.	O

RESULTS	O
:	O
The	O
analyzed	O
fragment	O
has	O
significant	O
activity	O
in	O
EpCAM	B-GENE
positive	O
cells	O
,	O
and	O
it	O
is	O
regulated	O
negatively	O
by	O
tumor	B-GENE
necrosis	I-GENE
factor	I-GENE
alpha	I-GENE
(	O
TNFalpha	B-GENE
)	O
.	O

On	O
Cox	O
proportional	O
hazards	O
regression	O
adenocarcinoma	O
(	O
P	O
=	O
0	O
.	O
006	O
)	O
,	O
the	O
development	O
of	O
BPF	O
(	O
P	O
=	O
0	O
.	O
003	O
)	O
,	O
older	O
age	O
(	O
P	O
=	O
0	O
.	O
03	O
)	O
and	O
higher	O
pathological	O
stage	O
(	O
P	O
=	O
0	O
.	O
02	O
)	O
were	O
independent	O
adverse	O
predictors	O
of	O
survival	O
.	O

Phosphatidylinositol	B-GENE
3	I-GENE
-	I-GENE
kinase	I-GENE
potentiates	O
,	O
but	O
does	O
not	O
trigger	O
,	O
T	O
cell	O
proliferation	O
mediated	O
by	O
the	O
IL	B-GENE
-	I-GENE
2	I-GENE
receptor	I-GENE
.	O

In	O
the	O
stable	O
transfectants	O
(	O
BM3	O
cells	O
)	O
expressing	O
a	O
mutant	B-GENE
bacterial	I-GENE
P450	I-GENE
AA	I-GENE
epoxygenase	I-GENE
,	O
F87V	O
BM3	O
,	O
which	O
was	O
genetically	O
engineered	O
to	O
metabolize	O
arachidonic	O
acid	O
only	O
to	O
14	O
,	O
15	O
-	O
EET	O
,	O
AA	O
did	O
not	O
induce	O
apoptosis	O
and	O
protected	O
against	O
agonist	O
-	O
induced	O
apoptosis	O
.	O

The	O
loop	O
domain	O
of	O
heat	B-GENE
shock	I-GENE
transcription	I-GENE
factor	I-GENE
1	I-GENE
dictates	O
DNA	O
-	O
binding	O
specificity	O
and	O
responses	O
to	O
heat	O
stress	O
.	O

Progressive	O
study	O
and	O
robustness	O
test	O
of	O
QSAR	O
model	O
based	O
on	O
quantum	O
chemical	O
parameters	O
for	O
predicting	O
BCF	O
of	O
selected	O
polychlorinated	O
organic	O
compounds	O
(	O
PCOCs	O
)	O
.	O

Of	O
the	O
six	O
cases	O
of	O
malignant	O
polyposis	O
,	O
none	O
were	O
identified	O
using	O
CT	O
,	O
and	O
only	O
two	O
were	O
diagnosed	O
by	O
small	O
bowel	O
follow	O
-	O
through	O
.	O

Using	O
the	O
two	O
-	O
hybrid	O
system	O
,	O
we	O
show	O
that	O
nonprenylated	O
Rac1	B-GENE
interacts	O
very	O
weakly	O
with	O
Rho	B-GENE
-	I-GENE
GDI	I-GENE
,	O
pointing	O
to	O
the	O
predominant	O
role	O
of	O
protein	O
-	O
isoprene	O
interaction	O
in	O
complex	O
formation	O
.	O

The	O
patterns	O
of	O
early	O
mRNA	O
and	O
protein	O
expression	O
in	O
these	O
seven	O
mutants	O
were	O
examined	O
,	O
and	O
it	O
was	O
found	O
that	O
mutation	O
of	O
the	O
T	B-GENE
'	I-GENE
(	I-GENE
135	I-GENE
)	I-GENE
acceptor	O
site	O
resulted	O
in	O
the	O
utilization	O
of	O
cryptic	O
splice	O
sites	O
and	O
the	O
generation	O
of	O
new	O
T	B-GENE
'	I-GENE
species	O
.	O

Sixty	O
-	O
one	O
cases	O
of	O
cholera	O
,	O
all	O
caused	O
by	O
V	O
.	O
cholerae	O
O1	O
,	O
were	O
reported	O
.	O

Subsequently	O
,	O
these	O
coordinates	O
must	O
be	O
interpreted	O
to	O
define	O
particular	O
tissues	O
and	O
organs	O
.	O

Testing	O
was	O
associated	O
with	O
a	O
history	O
of	O
nonsexual	O
risk	O
behavior	O
,	O
increased	O
knowledge	O
of	O
the	O
hepatitis	O
C	O
virus	O
,	O
and	O
healthcare	O
provider	O
communication	O
.	O

Low	O
-	O
selenium	O
diet	O
has	O
a	O
human	O
unfavourable	O
impact	O
.	O

Thus	O
,	O
BALB	O
/	O
c	O
mice	O
appear	O
to	O
be	O
the	O
most	O
appropriate	O
strain	O
of	O
mice	O
to	O
perform	O
studies	O
on	O
the	O
possible	O
connection	O
between	O
infection	O
with	O
T	O
.	O
canis	O
and	O
allergic	O
asthma	O
.	O

Furthermore	O
,	O
hormonal	O
regulation	O
of	O
G	O
(	O
1	O
)	O
gene	O
transcription	O
can	O
occur	O
even	O
without	O
additional	O
activation	O
of	O
the	O
Mek	B-GENE
-	O
Erk1	B-GENE
/	I-GENE
2	I-GENE
pathway	O
by	O
estrogen	B-GENE
receptors	I-GENE
.	O

Therefore	O
,	O
to	O
understand	O
how	O
ErbB1	B-GENE
/	O
ErbB2	B-GENE
signaling	O
contributes	O
to	O
this	O
process	O
,	O
we	O
used	O
the	O
ErbB	B-GENE
kinase	I-GENE
inhibitor	O
AG1478in	O
ErbB2	B-GENE
-	O
dependent	O
BT	O
-	O
474	O
and	O
SKBR	O
-	O
3	O
human	O
breast	O
cancer	O
cells	O
.	O

This	O
plus	O
the	O
reduced	O
phosphorylation	O
of	O
p27	B-GENE
by	O
MAPK	B-GENE
enhanced	O
the	O
stability	O
of	O
p27	B-GENE
that	O
associated	O
with	O
nuclear	B-GENE
Cdk2	I-GENE
at	O
high	O
stoichiometry	O
and	O
inhibited	O
its	O
kinase	O
activity	O
.	O

ICA	O
in	O
the	O
reference	O
solution	O
was	O
characterised	O
by	O
LC	O
and	O
time	O
-	O
of	O
-	O
flight	O
(	O
TOF	O
)	O
MS	O
and	O
quantified	O
by	O
LC	O
chemiluminescent	O
nitrogen	O
detection	O
(	O
LC	O
-	O
CLND	O
)	O
.	O

Forced	O
expression	O
of	O
BZAP45	B-GENE
strongly	O
stimulates	O
H4	B-GENE
promoter	I-GENE
(	O
nt	O
-	O
215	O
to	O
-	O
1	O
)	O
/	O
CAT	B-GENE
reporter	O
gene	O
activity	O
.	O

Local	O
control	O
rates	O
were	O
91	O
%	O
for	O
metastatic	O
lung	O
cancer	O
,	O
89	O
%	O
for	O
primary	O
lung	O
cancer	O
and	O
85	O
%	O
for	O
T1	O
,	O
2N0M0	O
cases	O
.	O

Utility	O
of	O
OAE	O
screener	O
(	O
GSI	O
70	O
)	O
for	O
the	O
evaluation	O
of	O
distortion	O
product	O
otoacoustic	O
emissions	O
]	O
The	O
purpose	O
of	O
this	O
study	O
was	O
to	O
investigate	O
the	O
ability	O
of	O
the	O
OAE	O
screener	O
GSI	O
70	O
to	O
evaluate	O
of	O
cochlea	O
function	O
in	O
neonates	O
,	O
infants	O
and	O
adults	O
.	O

For	O
the	O
sample	O
of	O
systematic	O
reviews	O
drawn	O
from	O
ACP	O
Journal	O
Club	O
(	O
n	O
=	O
103	O
)	O
,	O
the	O
PubMed	O
strategy	O
achieved	O
a	O
sensitivity	O
of	O
97	O
%	O
(	O
CI	O
,	O
91	O
%	O
to	O
99	O
%	O
)	O
.	O

Inhibition	O
of	O
JNK1	B-GENE
and	O
ERK	B-GENE
kinase	O
activities	O
either	O
by	O
expression	O
of	O
the	O
dominant	O
negative	O
mutant	O
JNK1	B-GENE
or	O
by	O
treatment	O
with	O
a	O
selective	O
chemical	O
inhibitor	O
of	O
ERK	B-GENE
(	O
PD098059	O
)	O
substantially	O
abrogates	O
the	O
UV	O
induction	O
of	O
the	O
GADD45	B-GENE
promoter	I-GENE
.	O

With	O
a	O
GC	O
content	O
of	O
45	O
%	O
the	O
one	O
segment	O
would	O
correspond	O
to	O
"	B-GENE
isochore	I-GENE
H1	I-GENE
"	I-GENE
and	O
the	O
other	O
segment	O
(	O
39	O
%	O
GC	O
in	O
human	O
,	O
40	O
%	O
GC	O
in	O
mouse	O
)	O
to	O
"	O
isochore	O
L1	B-GENE
/	O
L2	B-GENE
"	O
.	O

No	O
mutation	O
of	O
the	O
NRL	B-GENE
gene	I-GENE
was	O
found	O
in	O
any	O
of	O
the	O
two	O
families	O
.	O

After	O
nerve	O
injury	O
,	O
the	O
nociceptive	O
responses	O
through	O
type	O
I	O
neurons	O
,	O
which	O
are	O
polymodal	O
C	O
-	O
fibers	O
and	O
drive	O
NK1	B-GENE
-	I-GENE
receptor	I-GENE
mechanisms	O
in	O
spinal	O
pain	O
transmission	O
,	O
were	O
completely	O
lost	O
,	O
but	O
without	O
changes	O
in	O
type	O
II	O
ones	O
,	O
which	O
are	O
polymodal	O
C	O
-	O
fibers	O
and	O
drive	O
NMDA	B-GENE
receptor	I-GENE
-	O
mechanisms	O
,	O
while	O
type	O
III	O
ones	O
,	O
which	O
are	O
capsaicin	O
-	O
insensitive	O
(	O
possibly	O
A	O
-	O
fibers	O
)	O
and	O
drive	O
NMDA	B-GENE
-	I-GENE
receptor	I-GENE
mechanisms	O
,	O
were	O
markedly	O
enhanced	O
.	O

This	O
article	O
reports	O
the	O
design	O
and	O
development	O
of	O
an	O
ECG	O
simulator	O
intended	O
for	O
use	O
in	O
the	O
testing	O
,	O
calibration	O
and	O
maintenance	O
of	O
electrocardiographic	O
equipment	O
.	O

Subacute	O
diencephalic	O
angioencephalopathy	O
(	O
SDAE	O
)	O
is	O
a	O
rare	O
and	O
fatal	O
disease	O
of	O
unknown	O
etiology	O
that	O
involves	O
the	O
thalami	O
bilaterally	O
.	O

Third	O
,	O
consistent	O
with	O
these	O
data	O
,	O
N	O
-	O
acetylcysteine	O
reduced	O
the	O
stimulatory	O
effect	O
of	O
HGF	B-GENE
on	O
stress	B-GENE
kinase	I-GENE
activities	O
,	O
while	O
p42	B-GENE
/	I-GENE
44	I-GENE
mitogen	O
activated	O
kinase	O
(	O
MAPK	O
)	O
was	O
unmodified	O
,	O
suggesting	O
an	O
involvement	O
of	O
c	B-GENE
-	I-GENE
Jun	I-GENE
-	I-GENE
N	I-GENE
-	I-GENE
terminal	I-GENE
kinase	I-GENE
(	O
JNK	B-GENE
)	O
and	O
p38	B-GENE
MAPK	O
in	O
HIF	B-GENE
-	I-GENE
1	I-GENE
activation	O
.	O

There	O
was	O
no	O
significant	O
difference	O
in	O
developmental	O
scores	O
at	O
9	O
or	O
18	O
months	O
,	O
although	O
PDF	O
infants	O
had	O
a	O
2	O
.	O
8	O
(	O
-	O
1	O
.	O
3	O
-	O
6	O
.	O
8	O
)	O
point	O
advantage	O
in	O
Bayley	O
motor	O
score	O
scales	O
.	O

In	O
the	O
single	O
case	O
the	O
restoration	O
of	O
a	O
structured	O
daily	O
routine	O
represents	O
the	O
presupposition	O
for	O
a	O
cognitive	O
therapy	O
.	O

However	O
these	O
search	O
engines	O
respond	O
with	O
such	O
cumbersome	O
results	O
that	O
domain	O
specific	O
experts	O
can	O
not	O
tolerate	O
.	O

The	O
binary	O
and	O
tertiary	O
combinations	O
of	O
plant	O
-	O
derived	O
molluscicides	O
Azadirachta	O
indica	O
and	O
Cedrus	O
deodara	O
oil	O
with	O
synergists	O
MGK	O
-	O
264	O
,	O
piperonyl	O
butoxide	O
(	O
PB	O
)	O
and	O
fruit	O
powder	O
of	O
Embelia	O
ribes	O
were	O
used	O
against	O
the	O
Lymnaea	O
acuminata	O
.	O

From	O
the	O
above	O
results	O
,	O
we	O
might	O
infer	O
that	O
the	O
seizure	O
type	O
of	O
TLE	O
and	O
a	O
high	O
frequency	O
of	O
seizure	O
are	O
two	O
major	O
independent	O
precipitate	O
factors	O
for	O
abnormal	O
latencies	O
of	O
P300	O
in	O
the	O
epileptic	O
patients	O
.	O

Audiological	O
findings	O
in	O
pregnancy	O
.	O

The	O
deubiquitinating	O
enzyme	O
DUB	B-GENE
-	I-GENE
2	I-GENE
is	O
induced	O
in	O
response	O
to	O
IL	B-GENE
-	I-GENE
2	I-GENE
but	O
as	O
yet	O
its	O
function	O
has	O
not	O
been	O
determined	O
.	O

The	O
isoform	O
,	O
designated	O
HDAC9a	B-GENE
,	O
is	O
132	O
aa	O
shorter	O
at	O
the	O
C	O
terminus	O
than	O
HDAC9	B-GENE
.	O

Pulmonary	O
embolectomy	O
and	O
lung	O
transplantation	O
are	O
the	O
main	O
indications	O
for	O
the	O
use	O
of	O
heart	O
-	O
lung	O
-	O
machine	O
.	O

The	O
NAUSICAA	O
system	O
gives	O
a	O
good	O
knowledge	O
of	O
LET	O
spectra	O
for	O
the	O
first	O
time	O
in	O
space	O
dosimetry	O
.	O

In	O
order	O
to	O
quantify	O
these	O
effects	O
,	O
tests	O
were	O
conducted	O
in	O
the	O
NASA	O
MSFC	O
Neutral	O
Buoyancy	O
Simulator	O
,	O
in	O
the	O
NASA	O
KC	O
-	O
135	O
in	O
parabolic	O
flight	O
,	O
and	O
in	O
space	O
with	O
the	O
EASE	O
program	O
during	O
the	O
Shuttle	O
Atlantis	O
mission	O
61	O
-	O
B	O
.	O

This	O
article	O
comparatively	O
evaluates	O
five	O
Generic	O
Systems	O
that	O
describe	O
the	O
basic	O
alternatives	O
to	O
composting	O
facility	O
design	O
and	O
control	O
.	O

Different	O
thermoluminescent	O
detectors	O
(	O
TLD	O
)	O
have	O
been	O
used	O
to	O
measure	O
the	O
contribution	O
of	O
the	O
low	O
linear	O
energy	O
transfer	O
component	O
(	O
LET	O
<	O
10	O
keV	O
/	O
micrometer	O
)	O
and	O
plastic	O
nuclear	O
track	O
detectors	O
(	O
PNTD	O
)	O
for	O
the	O
high	O
linear	O
energy	O
tranfer	O
(	O
LET	O
)	O
component	O
.	O

Responses	O
of	O
TLD	O
Mg2SiO4	O
:	O
Tb	O
and	O
radiophotoluminescent	O
glass	O
to	O
heavy	O
charged	O
particles	O
and	O
space	O
radiation	O
.	O

The	O
absorbed	O
dose	O
was	O
measured	O
by	O
combination	O
of	O
two	O
integrating	O
detectors	O
:	O
thermo	O
-	O
luminescent	O
dosemeter	O
of	O
Mg2SiO4	O
:	O
Tb	O
(	O
TDMS	O
)	O
and	O
plastic	O
nuclear	O
track	O
detector	O
(	O
PNTD	O
)	O
.	O

Thus	O
,	O
while	O
the	O
folds	O
of	O
all	O
Myb	B-GENE
domains	I-GENE
resemble	O
each	O
other	O
closely	O
,	O
the	O
function	O
of	O
each	O
Myb	B-GENE
domain	I-GENE
depends	O
on	O
the	O
amino	O
acid	O
residues	O
that	O
are	O
located	O
on	O
the	O
surface	O
of	O
each	O
protein	O
.	O

METHODS	O
:	O
Experiments	O
testing	O
the	O
new	O
catheter	O
and	O
comparing	O
it	O
to	O
the	O
existing	O
catheter	O
included	O
:	O
(	O
1	O
)	O
measurement	O
of	O
the	O
laser	O
output	O
beam	O
sizes	O
and	O
divergences	O
;	O
(	O
2	O
)	O
evaluation	O
of	O
particulate	O
matter	O
generation	O
during	O
ablation	O
of	O
atherosclerotic	O
tissue	O
;	O
(	O
3	O
)	O
measurement	O
of	O
ablation	O
hole	O
sizes	O
and	O
tissue	O
penetration	O
rates	O
;	O
(	O
4	O
)	O
histopathologic	O
examination	O
of	O
laser	O
-	O
induced	O
in	O
vivo	O
vessel	O
wall	O
injury	O
.	O

Overexpression	O
of	O
RORgamma	B-GENE
has	O
been	O
shown	O
to	O
inhibit	O
T	B-GENE
cell	I-GENE
receptor	I-GENE
-	O
mediated	O
apoptosis	O
in	O
T	O
cell	O
hybridomas	O
and	O
to	O
repress	O
the	O
induction	O
of	O
Fas	B-GENE
-	I-GENE
ligand	I-GENE
and	O
interleukin	B-GENE
2	I-GENE
.	O

Once	O
ICP	O
reaches	O
critical	O
values	O
(	O
>	O
30	O
mm	O
Hg	O
)	O
herniation	O
occurs	O
,	O
usually	O
within	O
2	O
to	O
5	O
days	O
.	O

Other	O
therapies	O
are	O
also	O
available	O
,	O
including	O
hypertonic	O
saline	O
solution	O
,	O
THAM	O
(	O
Tris	O
-	O
hydroxy	O
-	O
methyl	O
-	O
aminomethane	O
)	O
buffer	O
,	O
and	O
high	O
-	O
dose	O
barbiturates	O
.	O

CYP2C19	B-GENE
genotype	I-GENE
was	O
determined	O
by	O
the	O
polymerase	O
chain	O
reaction	O
-	O
restriction	O
fragment	O
length	O
polymorphism	O
method	O
.	O

The	O
results	O
indicate	O
that	O
a	O
more	O
differentiated	O
diagnosis	O
of	O
the	O
molar	O
relationship	O
will	O
allow	O
for	O
a	O
more	O
causally	O
directed	O
correction	O
of	O
Class	O
II	O
molar	O
relationship	O
.	O

Similar	O
data	O
were	O
also	O
obtained	O
when	O
either	O
dominant	O
negative	O
EGFR	B-GENE
-	O
CD533	B-GENE
or	O
dominant	B-GENE
negative	I-GENE
Ras	I-GENE
N17	I-GENE
were	O
used	O
to	O
block	O
MAPK	B-GENE
activation	O
.	O

These	O
analyses	O
re	O
-	O
open	O
the	O
question	O
whether	O
all	O
the	O
CesA	B-GENE
genes	I-GENE
encode	O
cellulose	B-GENE
synthases	I-GENE
or	O
whether	O
some	O
of	O
the	O
sub	O
-	O
class	O
members	O
may	O
encode	O
other	O
non	B-GENE
-	I-GENE
cellulosic	I-GENE
(	I-GENE
1	I-GENE
-	I-GENE
-	I-GENE
>	I-GENE
4	I-GENE
)	I-GENE
beta	I-GENE
-	I-GENE
glycan	I-GENE
synthases	I-GENE
in	O
plants	O
.	O

The	O
mutation	O
experiments	O
showed	O
that	O
the	O
most	O
critical	O
sequence	O
for	O
the	O
repression	O
of	O
PTH	B-GENE
was	O
5	O
'	O
-	O
GGGGGAGGGGAG	O
-	O
3	O
'	O
(	O
+	O
1	O
to	O
+	O
12	O
)	O
of	O
PTHSR	B-GENE
.	O

Cardiac	O
output	O
at	O
anaerobic	O
threshold	O
(	O
COAT	O
)	O
<	O
or	O
=	O
7	O
.	O
3	O
L	O
/	O
min	O
was	O
the	O
best	O
cutoff	O
value	O
for	O
identifying	O
multivessel	O
coronary	O
artery	O
disease	O
(	O
relative	O
risk	O
,	O
3	O
.	O
1	O
)	O
.	O

Experience	O
with	O
xylene	O
-	O
free	O
sections	O
since	O
1995	O
at	O
the	O
Vrinnevi	O
Hospital	O
is	O
favorable	O
.	O

A	O
randomized	O
mix	O
of	O
180	O
sections	O
(	O
10	O
samples	O
x	O
3	O
tissues	O
x	O
3	O
stains	O
x	O
2	O
)	O
gave	O
90	O
matched	O
pairs	O
.	O

Interestingly	O
,	O
the	O
CYP71D20	B-GENE
-	I-GENE
encoded	I-GENE
enzyme	I-GENE
activity	O
was	O
capable	O
of	O
converting	O
both	O
5	O
-	O
epi	O
-	O
aristolochene	O
and	O
1	O
-	O
deoxycapsidiol	O
to	O
capsidiol	O
in	O
vitro	O
,	O
consistent	O
with	O
the	O
notion	O
that	O
this	O
P450	B-GENE
enzyme	I-GENE
catalyzes	O
both	O
hydroxylations	O
of	O
its	O
hydrocarbon	O
substrate	O
.	O

In	O
conclusion	O
,	O
NF	B-GENE
-	I-GENE
Y	I-GENE
and	O
Sp1	B-GENE
binding	O
sites	O
play	O
a	O
decisive	O
role	O
in	O
the	O
basal	O
expression	O
of	O
the	O
rat	B-GENE
mrp2	I-GENE
gene	I-GENE
,	O
while	O
the	O
human	B-GENE
MRP2	I-GENE
gene	I-GENE
is	O
regulated	O
differently	O
.	O

Transcriptional	O
regulation	O
of	O
the	O
estrogen	O
-	O
inducible	O
pS2	B-GENE
breast	B-GENE
cancer	I-GENE
marker	I-GENE
gene	I-GENE
by	O
the	O
ERR	B-GENE
family	I-GENE
of	O
orphan	B-GENE
nuclear	I-GENE
receptors	I-GENE
.	O

NB	O
-	O
506	O
completely	O
inhibits	O
the	O
capacity	O
of	O
topoisomerase	B-GENE
I	I-GENE
to	O
phosphorylate	O
,	O
in	O
vitro	O
,	O
the	O
human	B-GENE
splicing	I-GENE
factor	I-GENE
2	I-GENE
/	O
alternative	B-GENE
splicing	I-GENE
factor	I-GENE
(	O
SF2	B-GENE
/	O
ASF	B-GENE
)	O
.	O

However	O
,	O
during	O
our	O
work	O
with	O
a	O
replication	O
-	O
deficient	O
virus	O
expressing	O
the	O
ASF	B-GENE
/	O
SF2	B-GENE
splicing	O
factor	O
from	O
a	O
progesterone	O
antagonist	O
-	O
inducible	O
gene	O
cassette	O
,	O
we	O
discovered	O
that	O
ASF	B-GENE
/	O
SF2	B-GENE
was	O
expressed	O
at	O
a	O
significant	O
level	O
in	O
the	O
293	O
producer	O
cell	O
line	O
,	O
even	O
in	O
the	O
absence	O
of	O
inducer	O
.	O

DNA	O
binding	O
assays	O
confirmed	O
the	O
interference	O
of	O
p30	B-GENE
(	I-GENE
II	I-GENE
)	I-GENE
with	O
the	O
assembly	O
of	O
CREB	B-GENE
-	O
Tax	B-GENE
-	O
p300	B-GENE
/	O
CBP	B-GENE
multiprotein	O
complexes	O
on	O
21	O
-	O
bp	O
repeat	O
oligonucleotides	O
in	O
vitro	O
.	O

Using	O
the	O
presented	O
categorical	O
structure	O
as	O
domain	O
model	O
a	O
prototype	O
DSS	O
for	O
dipslide	O
urine	O
cultures	O
has	O
been	O
developed	O
.	O

DNA	O
recognition	O
by	O
F	B-GENE
factor	I-GENE
TraI36	B-GENE
:	O
highly	O
sequence	O
-	O
specific	O
binding	O
of	O
single	O
-	O
stranded	O
DNA	O
.	O

E47	B-GENE
protein	I-GENE
levels	O
remain	O
high	O
until	O
the	O
double	O
positive	O
developmental	O
stage	O
,	O
at	O
which	O
point	O
they	O
drop	O
to	O
relatively	O
moderate	O
levels	O
,	O
and	O
are	O
further	O
downregulated	O
upon	O
transition	O
to	O
the	O
single	O
positive	O
stage	O
.	O

The	O
dual	O
specificity	O
kinases	O
mitogen	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
kinase	I-GENE
(	I-GENE
MAPK	I-GENE
)	I-GENE
kinase	I-GENE
(	I-GENE
MKK	I-GENE
)	I-GENE
7	I-GENE
and	O
MKK4	B-GENE
are	O
the	O
only	O
molecules	O
known	O
to	O
directly	O
activate	O
the	O
stress	O
kinases	O
stress	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
kinases	I-GENE
(	O
SAPKs	B-GENE
)	O
/	O
c	B-GENE
-	I-GENE
Jun	I-GENE
N	I-GENE
-	I-GENE
terminal	I-GENE
kinases	I-GENE
(	O
JNKs	B-GENE
)	O
in	O
response	O
to	O
environmental	O
or	O
mitogenic	O
stimuli	O
.	O

SAPK	B-GENE
/	O
JNK	B-GENE
activation	O
was	O
completely	O
abolished	O
in	O
the	O
absence	O
of	O
MKK7	B-GENE
,	O
even	O
though	O
expression	O
of	O
MKK4	B-GENE
was	O
strongly	O
upregulated	O
in	O
mkk7	B-GENE
(	I-GENE
-	I-GENE
/	I-GENE
-	I-GENE
)	I-GENE
mast	O
cell	O
lines	O
,	O
and	O
phosphorylation	O
of	O
MKK4	B-GENE
occurred	O
normally	O
in	O
response	O
to	O
multiple	O
stress	O
stimuli	O
.	O

Thus	O
,	O
MKK7	B-GENE
is	O
an	O
essential	O
and	O
specific	O
regulator	O
of	O
stress	O
-	O
induced	O
SAPK	B-GENE
/	O
JNK	B-GENE
activation	O
in	O
mast	O
cells	O
and	O
MKK7	B-GENE
negatively	O
regulates	O
growth	O
factor	O
and	O
antigen	O
receptor	O
-	O
driven	O
proliferation	O
in	O
hematopoietic	O
cells	O
.	O

When	O
mixed	O
with	O
aqueous	O
solutions	O
of	O
TMT	O
-	O
55	O
,	O
aqueous	O
solutions	O
of	O
either	O
reagent	O
-	O
grade	O
zinc	O
,	O
cadmium	O
,	O
or	O
lead	O
salts	O
precipitate	O
crystalline	O
"	O
Zn	O
-	O
TMT	O
"	O
,	O
amorphous	O
or	O
crystalline	O
"	O
Cd	O
-	O
TMT	O
"	O
or	O
amorphous	O
"	O
Pb	O
-	O
TMT	O
"	O
(	O
M3	O
[	O
S3C3N3	O
]	O
2	O
.	O
nH2O	O
,	O
where	O
M	O
=	O
Cd2	O
+	O
,	O
Pb2	O
+	O
,	O
and	O
Zn2	O
+	O
and	O
n	O
>	O
or	O
=	O
0	O
)	O
that	O
may	O
eventually	O
crystallize	O
if	O
stored	O
in	O
air	O
.	O

Many	O
of	O
the	O
important	O
genes	O
associated	O
with	O
G1	O
regulation	O
have	O
been	O
shown	O
to	O
play	O
a	O
key	O
role	O
in	O
proliferation	O
,	O
differentiation	O
and	O
oncogenic	O
transformation	O
and	O
programmed	O
cell	O
death	O
(	O
apoptosis	O
)	O
.	O

These	O
results	O
indicate	O
the	O
presence	O
of	O
TATA	O
-	O
unified	O
transcription	O
systems	O
in	O
contemporary	O
eukaryotes	O
and	O
provide	O
insight	O
into	O
the	O
residual	O
need	O
for	O
TBP	B-GENE
by	O
all	O
three	O
Pols	B-GENE
in	O
other	O
eukaryotes	O
despite	O
a	O
lack	O
of	O
TATA	O
elements	O
in	O
their	O
promoters	O
.	O

Thus	O
,	O
through	O
a	O
change	O
in	O
conformation	O
upon	O
repair	O
of	O
the	O
6RG	O
lesion	O
,	O
MGMT	B-GENE
switches	O
from	O
a	O
DNA	O
repair	O
factor	O
to	O
a	O
transcription	O
regulator	O
(	O
R	B-GENE
-	I-GENE
MGMT	I-GENE
)	O
,	O
enabling	O
the	O
cell	O
to	O
sense	O
as	O
well	O
as	O
respond	O
to	O
mutagens	O
.	O

A	O
split	O
motor	O
domain	O
in	O
a	O
cytoplasmic	B-GENE
dynein	I-GENE
.	O

In	O
hypertensive	O
nephrosclerosis	O
,	O
therapy	O
containing	O
an	O
ACEI	O
alone	O
or	O
in	O
combination	O
significantly	O
reduces	O
the	O
incidence	O
of	O
renal	O
events	O
.	O

Body	O
weight	O
reduction	O
increases	O
insulin	B-GENE
sensitivity	O
and	O
improves	O
both	O
blood	O
glucose	O
and	O
blood	O
pressure	O
control	O
.	O

Here	O
we	O
suggest	O
that	O
uvrA	B-GENE
and	O
the	O
nucleotide	O
excision	O
repair	O
pathway	O
are	O
involved	O
in	O
the	O
repair	O
of	O
acid	O
-	O
induced	O
DNA	O
damage	O
and	O
are	O
associated	O
with	O
successful	O
adaptation	O
of	O
S	O
.	O
mutans	O
to	O
low	O
pH	O
.	O

The	O
best	O
regression	O
model	O
for	O
predicting	O
changes	O
in	O
the	O
WCXR	O
included	O
time	O
to	O
first	O
positive	O
culture	O
and	O
antibody	O
titer	O
for	O
Pa	B-GENE
elastase	I-GENE
.	O

Temperature	O
measurement	O
in	O
microfluidic	O
systems	O
using	O
a	O
temperature	O
-	O
dependent	O
fluorescent	O
dye	O
.	O

APC	B-GENE
-	O
resistance	O
was	O
determined	O
with	O
a	O
functional	O
method	O
with	O
high	O
sensitivity	O
and	O
specificity	O
for	O
the	O
factor	B-GENE
V	I-GENE
Leiden	I-GENE
mutation	I-GENE
.	O

Zarix	O
expected	O
patient	O
enrollment	O
in	O
Canadian	O
clinical	O
sites	O
to	O
begin	O
in	O
Spring	O
2001	O
[	O
397955	O
]	O
,	O
[	O
405928	O
]	O
.	O

RESULTS	O
:	O
The	O
subjects	O
in	O
the	O
augmented	O
feedback	O
group	O
significantly	O
reduced	O
their	O
peak	O
vertical	O
ground	O
reaction	O
force	O
in	O
both	O
post	O
-	O
test	O
conditions	O
(	O
2	O
-	O
minute	O
post	O
-	O
test	O
reduction	O
,	O
0	O
.	O
85	O
+	O
/	O
-	O
0	O
.	O
62	O
;	O
1	O
-	O
week	O
post	O
-	O
test	O
reduction	O
,	O
0	O
.	O
74	O
+	O
/	O
-	O
0	O
.	O
58	O
)	O
as	O
compared	O
to	O
the	O
sensory	O
,	O
control	O
I	O
,	O
and	O
control	O
II	O
feedback	O
groups	O
.	O

Four	O
casein	B-GENE
kinase	I-GENE
I	I-GENE
isoforms	I-GENE
are	O
differentially	O
partitioned	O
between	O
nucleus	O
and	O
cytoplasm	O
.	O

Use	O
of	O
a	O
dual	O
-	O
pulse	O
lithotripter	O
to	O
generate	O
a	O
localized	O
and	O
intensified	O
cavitation	O
field	O
.	O

When	O
the	O
blood	O
clot	O
is	O
formed	O
in	O
the	O
vitreous	O
cavity	O
,	O
intravitreal	O
injection	O
of	O
t	B-GENE
-	I-GENE
PA	I-GENE
can	O
convert	O
plasminogen	B-GENE
to	O
plasmin	B-GENE
and	O
remove	O
the	O
clot	O
.	O

Management	O
of	O
postvitrectomy	O
diabetic	O
vitreous	O
hemorrhage	O
with	O
tissue	B-GENE
plasminogen	I-GENE
activator	I-GENE
(	O
t	B-GENE
-	I-GENE
PA	I-GENE
)	O
and	O
volume	O
homeostatic	O
fluid	O
-	O
fluid	O
exchanger	O
.	O

Effect	O
of	O
heat	O
treatments	O
on	O
the	O
meltability	O
of	O
cheeses	O
.	O

RESULTS	O
:	O
Sixty	O
per	O
cent	O
of	O
African	O
Americans	O
exposed	O
in	O
26	O
community	O
outbreaks	O
were	O
TST	O
positive	O
compared	O
to	O
only	O
40	O
%	O
of	O
whites	O
following	O
comparable	O
exposures	O
.	O

The	O
mean	O
waiting	O
time	O
to	O
receive	O
the	O
pancreas	O
transplant	O
was	O
244	O
days	O
for	O
SPK	O
and	O
167	O
days	O
for	O
PAK	O
recipients	O
(	O
P	O
=	O
0	O
.	O
001	O
)	O
.	O

Patients	O
with	O
antibody	O
peaks	O
,	O
defined	O
as	O
fivefold	O
or	O
higher	O
increase	O
in	O
antibody	O
titer	O
compared	O
to	O
the	O
lowest	O
antibody	O
titer	O
over	O
the	O
course	O
of	O
GBS	O
,	O
had	O
higher	O
disability	O
scores	O
during	O
the	O
first	O
two	O
weeks	O
of	O
GBS	O
and	O
a	O
worse	O
clinical	O
outcome	O
(	O
anti	B-GENE
-	I-GENE
GM1	I-GENE
IgG	I-GENE
and	O
anti	B-GENE
-	I-GENE
GD1a	I-GENE
IgM	I-GENE
antibody	I-GENE
peaks	O
)	O
and	O
axonal	O
damage	O
(	O
anti	B-GENE
-	I-GENE
GD1a	I-GENE
IgM	I-GENE
antibody	I-GENE
peaks	O
)	O
,	O
compared	O
to	O
patients	O
without	O
peak	O
antibody	O
titers	O
.	O

Following	O
baseline	O
clinical	O
examination	O
and	O
initial	O
periodontal	O
therapy	O
,	O
32	O
patients	O
received	O
mucogingival	O
surgery	O
with	O
free	O
gingival	O
grafts	O
for	O
treatment	O
of	O
insufficient	O
attached	O
gingiva	O
.	O

However	O
,	O
patients	O
with	O
isolated	O
office	O
hypertension	O
had	O
fewer	O
previous	O
cardiovascular	O
complications	O
.	O

In	O
the	O
TVD	O
-	O
patients	O
decreases	O
in	O
skin	O
blood	O
flow	O
were	O
similar	O
compared	O
with	O
the	O
healthy	O
controls	O
.	O

2	O
:	O
The	O
dynamic	O
moduli	O
of	O
microcrystalline	O
cellulose	O
.	O

These	O
findings	O
suggest	O
that	O
an	O
intracellular	O
WT	B-GENE
-	I-GENE
1	I-GENE
/	O
HSAL2	B-GENE
pathway	O
may	O
play	O
a	O
role	O
in	O
development	O
and	O
hematopoiesis	O
.	O

Phosphotyrosyl	O
peptides	O
block	O
Stat3	B-GENE
-	O
mediated	O
DNA	O
binding	O
activity	O
,	O
gene	O
regulation	O
,	O
and	O
cell	O
transformation	O
.	O

Plane	O
wave	O
geometry	O
is	O
impractical	O
for	O
clinical	O
use	O
but	O
the	O
results	O
of	O
this	O
work	O
encouraged	O
us	O
to	O
further	O
develop	O
the	O
P3	O
approximation	O
for	O
a	O
spherical	O
geometry	O
,	O
described	O
in	O
this	O
paper	O
.	O

The	O
diagnosis	O
of	O
HCV	O
arthritis	O
in	O
patients	O
with	O
positive	O
rheumatoid	B-GENE
factor	I-GENE
and	O
chronic	O
inflammatory	O
polyarthritis	O
may	O
be	O
difficult	O
.	O

METHODS	O
:	O
We	O
retrospectively	O
selected	O
13	O
TFCD	O
patients	O
who	O
underwent	O
surgery	O
for	O
intractable	O
epilepsy	O
with	O
the	O
aim	O
of	O
removing	O
the	O
magnetic	O
resonance	O
(	O
MR	O
)	O
-	O
detectable	O
lesion	O
and	O
/	O
or	O
the	O
epileptogenic	O
zone	O
defined	O
by	O
stereoelectroencephalographic	O
recordings	O
.	O

RESULTS	O
:	O
At	O
latest	O
examination	O
,	O
mean	O
UPDRS	O
II	O
and	O
III	O
scores	O
had	O
improved	O
by	O
30	O
%	O
(	O
on	O
stimulation	O
,	O
off	O
therapy	O
)	O
with	O
mean	O
50	O
%	O
reduction	O
in	O
daily	O
off	O
time	O
.	O

In	O
Exp	O
.	O

Several	O
distinct	O
apoptotic	O
stimuli	O
induce	O
the	O
expression	O
and	O
caspase	B-GENE
-	O
dependent	O
cleavage	O
of	O
hTAF	B-GENE
(	I-GENE
II	I-GENE
)	I-GENE
80	I-GENE
delta	I-GENE
.	O
hTAF	B-GENE
(	I-GENE
II	I-GENE
)	I-GENE
80	I-GENE
delta	I-GENE
,	O
unlike	O
hTAF	B-GENE
(	I-GENE
II	I-GENE
)	I-GENE
80	I-GENE
,	O
forms	O
a	O
TFIID	B-GENE
-	I-GENE
like	I-GENE
complex	I-GENE
lacking	O
hTAF	B-GENE
(	I-GENE
II	I-GENE
)	I-GENE
31	I-GENE
.	O

Endovascular	O
aneurysm	O
repair	O
with	O
the	O
AneuRx	O
stent	O
-	O
graft	O
is	O
safe	O
,	O
but	O
is	O
it	O
effective	O
?	O

Chronic	O
nutritional	O
diseases	O
of	O
infectious	O
origin	O
:	O
an	O
assessment	O
of	O
a	O
nascent	O
field	O
.	O

Drug	O
interactions	O
have	O
been	O
found	O
with	O
drugs	O
that	O
compete	O
for	O
the	O
same	O
CYP450	B-GENE
isoenzymes	I-GENE
as	O
statins	O
.	O

METHODS	O
:	O
We	O
studied	O
the	O
clinical	O
benefit	O
of	O
depth	O
-	O
dependent	O
RR	O
,	O
nonuniform	O
AC	O
using	O
a	O
scanning	O
line	O
source	O
,	O
and	O
scatter	O
correction	O
(	O
photon	O
energy	O
recovery	O
[	O
PER	O
]	O
)	O
compared	O
with	O
filtered	O
backprojection	O
alone	O
.	O

Because	O
of	O
differences	O
in	O
patient	O
characteristics	O
,	O
control	O
measurements	O
were	O
obtained	O
from	O
normal	O
muscle	O
in	O
all	O
patients	O
.	O

However	O
,	O
the	O
abi1	B-GENE
-	I-GENE
1	I-GENE
gene	I-GENE
product	I-GENE
has	O
no	O
effect	O
on	O
the	O
ABA	O
suppression	O
of	O
a	O
GA	O
-	O
responsive	O
alpha	B-GENE
-	I-GENE
amylase	I-GENE
gene	I-GENE
.	O

In	O
children	O
unable	O
to	O
perform	O
forced	O
expiratory	O
maneuvers	O
(	O
n	O
=	O
25	O
)	O
,	O
FOT	O
,	O
contrary	O
to	O
the	O
interrupter	O
technique	O
,	O
clearly	O
identified	O
a	O
subgroup	O
of	O
young	O
children	O
with	O
high	O
resistance	O
values	O
at	O
baseline	O
,	O
which	O
returned	O
to	O
normal	O
after	O
bronchodilation	O
.	O

In	O
budding	O
yeast	O
,	O
this	O
latter	O
checkpoint	O
response	O
involves	O
the	O
proteins	O
Mad1	B-GENE
,	I-GENE
2	I-GENE
,	I-GENE
3	I-GENE
,	O
Bub1	B-GENE
and	O
Bub3	B-GENE
,	O
whose	O
vertebrate	O
counterparts	O
localize	O
to	O
unattached	O
kinetochores	O
.	O

HTLV	O
-	O
1	O
decreases	O
Th2	O
type	O
of	O
immune	O
response	O
in	O
patients	O
with	O
strongyloidiasis	O
.	O

However	O
,	O
the	O
beta5L	O
splice	O
variant	O
was	O
found	O
only	O
in	O
the	O
retina	O
.	O

PROCEDURE	O
:	O
Cannulas	O
were	O
surgically	O
positioned	O
in	O
the	O
abomasal	O
body	O
and	O
pyloric	O
antrum	O
of	O
each	O
calf	O
.	O

METHODS	O
:	O
Humphrey	O
Field	O
Analyzer	O
model	O
630	O
(	O
HFA	O
I	O
,	O
program	O
30	O
-	O
2	O
with	O
a	O
rectangular	O
6	O
degrees	O
x	O
6	O
degrees	O
grid	O
)	O
was	O
used	O
as	O
the	O
conventional	O
perimetric	O
method	O
.	O

Transforming	B-GENE
growth	I-GENE
factor	I-GENE
-	I-GENE
beta	I-GENE
(	O
TGF	B-GENE
-	I-GENE
beta	I-GENE
)	O
induced	O
growth	O
arrest	O
of	O
cells	O
involves	O
regulation	O
of	O
the	O
activities	O
of	O
both	O
D	B-GENE
-	I-GENE
and	I-GENE
E	I-GENE
-	I-GENE
type	I-GENE
cyclin	I-GENE
kinase	I-GENE
complexes	I-GENE
thought	O
to	O
be	O
mediated	O
primarily	O
by	O
the	O
regulation	O
of	O
p15	B-GENE
(	O
Ink4b	B-GENE
)	O
and	O
p27	B-GENE
(	O
Kip1	B-GENE
)	O
cyclin	O
kinase	O
inhibitors	O
.	O

Alignment	O
of	O
different	O
cDNAs	O
of	O
the	O
NR5A2	B-GENE
(	O
hB1F	B-GENE
)	O
gene	O
with	O
the	O
genomic	O
sequence	O
facilitated	O
the	O
delineation	O
of	O
its	O
structural	O
organization	O
,	O
which	O
spans	O
over	O
150	O
kb	O
and	O
consists	O
of	O
eight	O
exons	O
interrupted	O
by	O
seven	O
introns	O
.	O

The	O
genomic	O
structure	O
of	O
the	O
human	B-GENE
SPEC1	I-GENE
gene	I-GENE
reveals	O
complex	O
splicing	O
and	O
close	O
promoter	O
proximity	O
to	O
the	O
AF1q	B-GENE
translocation	I-GENE
gene	I-GENE
.	O

Hp	O
positive	O
relatives	O
of	O
gastric	O
cancer	O
had	O
a	O
markedly	O
higher	O
prevalence	O
of	O
atrophy	O
than	O
those	O
with	O
Hp	O
negativity	O
without	O
cancer	O
relatives	O
(	O
29	O
vs	O
.	O

Peripheral	O
metabolism	O
of	O
androgens	O
takes	O
place	O
in	O
various	O
areas	O
within	O
the	O
pilosebaceous	O
unit	O
,	O
as	O
indicated	O
by	O
local	O
differences	O
in	O
the	O
activities	O
of	O
aromatase	B-GENE
,	O
5alpha	B-GENE
-	I-GENE
reductase	I-GENE
as	O
well	O
as	O
of	O
the	O
presence	O
of	O
the	O
androgen	B-GENE
receptors	I-GENE
.	O

The	O
uptake	O
of	O
fluorine	O
-	O
18	O
fluorodeoxyglucose	O
(	O
F	O
-	O
18	O
FDG	O
)	O
by	O
a	O
malignant	O
tumor	O
depends	O
on	O
the	O
blood	O
glucose	O
level	O
.	O

This	O
analysis	O
supports	O
the	O
use	O
of	O
fluticasone	O
propionate	O
88	O
microg	O
twice	O
daily	O
as	O
first	O
-	O
line	O
treatment	O
in	O
patients	O
with	O
persistent	O
asthma	O
previously	O
treated	O
with	O
short	O
-	O
acting	O
beta2	B-GENE
-	O
agonist	O
alone	O
.	O

By	O
using	O
space	O
-	O
discrete	O
/	O
continuous	O
metapopulation	O
dynamic	O
models	O
and	O
computer	O
simulations	O
,	O
we	O
show	O
that	O
there	O
can	O
be	O
two	O
principally	O
different	O
regimes	O
of	O
metapopulation	O
dynamics	O
.	O

Eight	O
CAD	O
patients	O
who	O
were	O
matched	O
to	O
the	O
treated	O
patients	O
for	O
age	O
(	O
+	O
/	O
-	O
3	O
years	O
)	O
,	O
baseline	O
low	B-GENE
density	I-GENE
lipoprotein	I-GENE
(	O
+	O
/	O
-	O
5	O
mg	O
/	O
dL	O
)	O
,	O
and	O
triglycerides	O
(	O
+	O
/	O
-	O
50	O
mg	O
/	O
dL	O
)	O
but	O
who	O
had	O
never	O
been	O
treated	O
with	O
lipid	O
-	O
lowering	O
drugs	O
were	O
selected	O
as	O
controls	O
.	O

RESULTS	O
:	O
A	O
novel	O
gene	O
was	O
cloned	O
.	O

The	O
moduli	O
of	O
elasticity	O
of	O
the	O
gray	O
and	O
white	O
matter	O
were	O
3	O
.	O
4	O
+	O
/	O
-	O
1	O
.	O
4	O
kPa	O
(	O
mean	O
+	O
/	O
-	O
standard	O
deviation	O
)	O
and	O
3	O
.	O
4	O
+	O
/	O
-	O
0	O
.	O
9	O
kPa	O
in	O
the	O
axial	O
section	O
,	O
3	O
+	O
/	O
-	O
0	O
.	O
3	O
kPa	O
and	O
3	O
.	O
5	O
+	O
/	O
-	O
0	O
.	O
5	O
kPa	O
in	O
the	O
frontal	O
section	O
,	O
and	O
3	O
.	O
5	O
+	O
/	O
-	O
0	O
.	O
9	O
kPa	O
and	O
2	O
.	O
8	O
+	O
/	O
-	O
0	O
.	O
4	O
kPa	O
in	O
the	O
sagittal	O
section	O
,	O
respectively	O
.	O

Direct	O
current	O
polarography	O
and	O
differential	O
pulse	O
polarographic	O
methods	O
have	O
been	O
developed	O
for	O
the	O
qualitative	O
as	O
well	O
as	O
quantitative	O
analysis	O
of	O
vitamin	O
B1	O
,	O
B2	O
and	O
B6	O
.	O

Against	O
gram	O
-	O
positive	O
organisms	O
,	O
E	O
-	O
4767	O
and	O
E	O
-	O
5065	O
were	O
,	O
in	O
general	O
,	O
eight	O
-	O
and	O
fourfold	O
more	O
active	O
than	O
tosufloxacin	O
,	O
which	O
is	O
the	O
most	O
potent	O
of	O
the	O
reference	O
compounds	O
.	O

However	O
,	O
most	O
produced	O
significant	O
alteration	O
of	O
small	O
intestinal	O
permeability	O
.	O

These	O
included	O
HNF	B-GENE
-	I-GENE
3	I-GENE
beta	I-GENE
,	O
HFH	B-GENE
-	I-GENE
1	I-GENE
,	O
HFH	B-GENE
-	I-GENE
2	I-GENE
,	O
HFH	B-GENE
-	I-GENE
3	I-GENE
,	O
C	B-GENE
/	I-GENE
EBP	I-GENE
,	O
and	O
C	B-GENE
/	I-GENE
EBP	I-GENE
beta	I-GENE
,	O
all	O
of	O
which	O
are	O
consistent	O
with	O
the	O
tissue	O
-	O
specific	O
expression	O
profiles	O
of	O
the	O
gene	O
.	O

Managing	O
vertigo	O
and	O
vertigo	O
syndromes	O
in	O
the	O
elderly	O

The	O
MABP	O
and	O
MCBFV	O
signals	O
were	O
bandpass	O
filtered	O
in	O
the	O
very	O
low	O
-	O
frequency	O
range	O
(	O
VLF	O
,	O
0	O
.	O
015	O
-	O
0	O
.	O
07	O
Hz	O
)	O
,	O
low	O
-	O
frequency	O
range	O
(	O
LF	O
,	O
0	O
.	O
07	O
-	O
0	O
.	O
15	O
Hz	O
)	O
and	O
high	O
-	O
frequency	O
range	O
(	O
HF	O
,	O
0	O
.	O
15	O
-	O
0	O
.	O
40	O
Hz	O
)	O
before	O
applying	O
CCF	O
for	O
the	O
purpose	O
of	O
studying	O
the	O
effect	O
of	O
different	O
bandwidths	O
on	O
the	O
resulting	O
mean	O
CCFs	O
.	O

Hepatitis	O
B	O
and	O
C	O
seroprevalence	O
rates	O
among	O
high	O
-	O
risk	O
adolescents	O
are	O
lower	O
in	O
El	O
Paso	O
than	O
in	O
other	O
similar	O
US	O
populations	O
,	O
presenting	O
an	O
ideal	O
climate	O
for	O
prevention	O
programs	O
.	O

A	O
twelfth	O
insertion	O
disrupts	O
two	O
genes	O
,	O
Nrk	B-GENE
,	O
a	O
"	B-GENE
neurospecific	I-GENE
"	I-GENE
receptor	I-GENE
tyrosine	I-GENE
kinase	I-GENE
,	O
and	O
Tpp	B-GENE
,	O
which	O
encodes	O
a	O
neuropeptidase	B-GENE
.	O

Not	O
Available	O

This	O
unique	O
work	O
needs	O
to	O
be	O
edited	O
critically	O
and	O
afterwards	O
translated	O
into	O
Urdu	O
and	O
other	O
languages	O
for	O
the	O
benefit	O
of	O
the	O
present	O
day	O
students	O
and	O
scholars	O
.	O

Comparison	O
of	O
German	O
language	O
versions	O
of	O
the	O
QWB	O
-	O
SA	O
and	O
SF	O
-	O
36	O
evaluating	O
outcomes	O
for	O
patients	O
with	O
prostate	O
disease	O
.	O

Disciplinary	O
action	O
for	O
DNA	O
violation	O
.	O

Epithelial	O
cytotoxicity	O
of	O
combined	O
antibiotics	O
was	O
additive	O
,	O
with	O
no	O
evidence	O
of	O
competition	O
or	O
synergism	O
.	O

Pro	O
-	O
inflammatory	O
cytokine	O
,	O
tumor	B-GENE
necrosis	I-GENE
factor	I-GENE
-	I-GENE
alpha	I-GENE
(	O
TNF	B-GENE
-	I-GENE
alpha	I-GENE
)	O
,	O
produced	O
from	O
adipose	O
tissues	O
in	O
obese	O
subjects	O
,	O
is	O
known	O
to	O
play	O
a	O
predominant	O
role	O
in	O
inducing	O
insulin	B-GENE
resistance	O
.	O

The	O
most	O
important	O
finding	O
,	O
however	O
,	O
was	O
that	O
IMT	O
values	O
were	O
related	O
with	O
24	O
h	O
SBP	O
or	O
PP	O
standard	O
deviation	O
(	O
P	O
<	O
0	O
.	O
001	O
)	O
,	O
a	O
measure	O
of	O
overall	O
SBP	O
or	O
PP	O
variability	O
.	O

The	O
difference	O
between	O
the	O
patients	O
and	O
the	O
controls	O
was	O
statistically	O
significant	O
(	O
p	O
=	O
0	O
.	O
03	O
)	O
.	O

The	O
effect	O
of	O
crude	O
oil	O
spillage	O
on	O
growth	O
,	O
productivity	O
and	O
nutrient	O
uptake	O
of	O
maize	O
(	O
Zea	O
mays	O
L	O
.	O
)	O
was	O
assessed	O
in	O
a	O
pot	O
experiment	O
using	O
an	O
Evwreni	O
manifold	O
sample	O
of	O
a	O
petroleum	O
development	O
company	O
,	O
which	O
had	O
a	O
specific	O
gravity	O
of	O
0	O
.	O
8778	O
.	O

NO	O
metabolites	O
were	O
determined	O
by	O
the	O
measurement	O
of	O
nitrate	O
/	O
nitrite	O
(	O
NOx	O
,	O
micromol	O
/	O
mmol	O
creatinine	O
)	O
and	O
cyclic	O
guanosine	O
monophosphate	O
(	O
cGMP	O
,	O
nmol	O
/	O
mmol	O
creatinine	O
)	O
in	O
plasma	O
and	O
urine	O
.	O

In	O
the	O
base	O
-	O
case	O
analysis	O
,	O
total	O
direct	O
costs	O
per	O
patient	O
were	O
$	O
728	O
for	O
zoledronic	O
acid	O
and	O
$	O
776	O
for	O
pamidronate	O
.	O

The	O
diet	O
of	O
migrants	O
showed	O
both	O
positive	O
(	O
macronutrients	O
)	O
and	O
negative	O
(	O
micronutrients	O
)	O
differences	O
with	O
the	O
general	O
Dutch	O
diet	O
.	O

C	O
.	O
elegans	O
embryogenesis	O
begins	O
with	O
a	O
stereotyped	O
sequence	O
of	O
asymmetric	O
cell	O
divisions	O
that	O
are	O
largely	O
responsible	O
for	O
establishing	O
the	O
nematode	O
body	O
plan	O
.	O

Finally	O
,	O
a	O
chromogenic	O
method	O
was	O
used	O
,	O
based	O
on	O
thrombin	B-GENE
inhibition	O
and	O
the	O
substrate	O
S	O
-	O
2238	O
.	O

[	O
Diabetologia	O
(	O
2001	O
)	O
44	O
[	O
Suppl	O
3	O
]	O
:	O
B37	O
-	O
B44	O
]	O

The	O
5	O
'	O
flanking	O
sequence	O
of	O
the	O
3B	B-GENE
gene	I-GENE
is	O
extremely	O
A	O
+	O
T	O
rich	O
but	O
contains	O
five	O
G	O
/	O
C	O
rich	O
stretches	O
,	O
each	O
approximately	O
7bp	O
long	O
,	O
which	O
have	O
strong	O
sequence	O
similarity	O
to	O
the	O
G	O
boxes	O
found	O
upstream	O
of	O
other	O
developmentally	O
regulated	O
Dictyostelium	O
genes	O
.	O

Considering	O
that	O
the	O
reactor	O
is	O
thoroughly	O
mixed	O
during	O
each	O
discharge	O
and	O
that	O
LD50	O
=	O
0	O
.	O
9	O
values	O
are	O
nearly	O
independent	O
of	O
E	O
.	O
coli	O
concentrations	O
in	O
the	O
range	O
of	O
2	O
x	O
10	O
(	O
3	O
)	O
<	O
or	O
=	O
E	O
coli	O
/	O
cfu	O
mL	O
(	O
-	O
1	O
)	O
<	O
or	O
=	O
3	O
x	O
10	O
(	O
6	O
)	O
,	O
we	O
ascribe	O
the	O
nonexponential	O
Pn	O
decay	O
of	O
single	O
-	O
strain	O
E	O
.	O
coli	O
colonies	O
to	O
a	O
shielding	O
phenomenon	O
where	O
inactive	O
cells	O
protect	O
the	O
successively	O
smaller	O
numbers	O
of	O
viable	O
cells	O
in	O
the	O
EHD	O
.	O

In	O
the	O
long	O
term	O
,	O
questions	O
still	O
remain	O
about	O
whether	O
pre	O
-	O
dialysis	O
rHu	B-GENE
EPO	I-GENE
either	O
speeds	O
up	O
or	O
delays	O
the	O
onset	O
of	O
dialysis	O
.	O

METHODS	O
:	O
This	O
retrospective	O
review	O
comprised	O
2711	O
eyes	O
that	O
had	O
LASIK	O
between	O
September	O
1996	O
and	O
September	O
1999	O
.	O

No	O
ISREs	B-GENE
could	O
be	O
identified	O
in	O
the	O
mouse	O
promoter	O
.	O

BACKGROUND	O
:	O
Ischemic	O
heart	O
disease	O
is	O
the	O
primary	O
cause	O
of	O
morbidity	O
and	O
mortality	O
among	O
diabetics	O
,	O
especially	O
those	O
who	O
became	O
ill	O
at	O
a	O
young	O
age	O
.	O

A	O
38	O
-	O
year	O
-	O
old	O
woman	O
with	O
ulcerative	O
colitis	O
subsequently	O
developed	O
sarcoidosis	O
.	O

Cholesteryl	B-GENE
ester	I-GENE
transfer	I-GENE
protein	I-GENE
and	O
atherosclerosis	O
in	O
Japanese	O
subjects	O
:	O
a	O
study	O
based	O
on	O
coronary	O
angiography	O
.	O

Electrophoretic	O
mobility	O
shift	O
assays	O
and	O
coimmunoprecipitation	O
studies	O
suggest	O
that	O
homo	O
-	O
and	O
heterodimerization	O
occurs	O
between	O
cKrox	B-GENE
family	I-GENE
members	I-GENE
.	O

The	O
hcKrox	B-GENE
gene	O
family	O
regulates	O
multiple	O
extracellular	O
matrix	O
genes	O
.	O

A	O
review	O
of	O
the	O
literature	O
identified	O
8	O
comprehensive	O
clinical	O
studies	O
,	O
all	O
of	O
which	O
failed	O
to	O
document	O
any	O
relationship	O
between	O
NF1	B-GENE
and	O
intracranial	O
aneurysms	O
.	O

These	O
utilisation	O
data	O
imply	O
annual	O
drug	O
costs	O
in	O
the	O
range	O
of	O
$	O
US	O
480	O
,	O
000	O
to	O
$	O
US	O
3	O
,	O
600	O
,	O
000	O
for	O
TNF	B-GENE
antagonists	O
for	O
RA	O
per	O
1	O
million	O
population	O
.	O

This	O
study	O
investigated	O
whether	O
boron	O
would	O
enhance	O
the	O
ability	O
of	O
17beta	O
-	O
estradiol	O
(	O
E2	O
)	O
or	O
parathyroid	B-GENE
hormone	I-GENE
(	O
PTH	B-GENE
)	O
to	O
improve	O
bone	O
quality	O
in	O
ovariectomized	O
OVX	O
rats	O
.	O

We	O
found	O
in	O
the	O
control	O
subjects	O
rCBF	O
increases	O
in	O
regions	O
associated	O
with	O
the	O
meso	O
-	O
striatal	O
and	O
meso	O
-	O
corticolimbic	O
circuits	O
in	O
response	O
to	O
both	O
monetary	O
reward	O
and	O
nonmonetary	O
reinforcement	O
.	O

Doxorubicin	O
(	O
DOX	O
)	O
is	O
commonly	O
used	O
for	O
the	O
treatment	O
of	O
hematological	O
and	O
solid	O
tumors	O
.	O

The	O
event	O
rate	O
in	O
patients	O
with	O
chronic	O
Irr	O
-	O
rMFP	O
or	O
Un	O
-	O
nrMFP	O
was	O
markedly	O
higher	O
than	O
it	O
was	O
in	O
those	O
with	O
Rev	O
-	O
rMFP	O
or	O
Sta	O
-	O
nrMFP	O
.	O

Subtraction	O
hybridization	O
identified	O
melanoma	B-GENE
differentiation	I-GENE
associated	I-GENE
gene	I-GENE
-	I-GENE
7	I-GENE
(	O
mda	B-GENE
-	I-GENE
7	I-GENE
)	O
,	O
as	O
a	O
gene	O
induced	O
during	O
these	O
physiological	O
changes	O
in	O
human	O
melanoma	O
cells	O
.	O

Therefore	O
,	O
vitamin	O
D3	O
analogues	O
have	O
a	O
substantial	O
antipsoriatic	O
effect	O
.	O

Hydrocoele	O
is	O
common	O
in	O
men	O
in	O
Wuchereria	O
bancrofti	O
-	O
endemic	O
areas	O
,	O
the	O
treatment	O
for	O
which	O
is	O
currently	O
surgical	O
intervention	O
.	O

Growth	B-GENE
hormone	I-GENE
and	O
insulin	B-GENE
-	I-GENE
like	I-GENE
growth	I-GENE
factor	I-GENE
I	I-GENE
receptors	I-GENE
in	O
the	O
temporomandibular	O
joint	O
of	O
the	O
rat	O
.	O

In	O
addition	O
to	O
that	O
,	O
she	O
received	O
hepatic	O
intra	O
-	O
arterial	O
infusion	O
of	O
levoforinate	O
(	O
l	O
-	O
LV	O
)	O
250	O
mg	O
and	O
5	O
-	O
fluorouracil	O
(	O
5	O
-	O
FU	O
)	O
500	O
mg	O
for	O
combined	O
multiple	O
hepatic	O
metastases	O
starting	O
on	O
postoperative	O
day	O
14	O
,	O
and	O
these	O
medications	O
were	O
administered	O
over	O
48	O
hours	O
once	O
weekly	O
by	O
infuser	O
pump	O
.	O

The	O
astronaut	O
crew	O
operates	O
the	O
payload	O
and	O
documents	O
its	O
operation	O
.	O

For	O
these	O
patients	O
the	O
introduction	O
of	O
a	O
separate	O
category	O
"	O
extended	O
oligoarthritis	O
at	O
onset	O
"	O
should	O
be	O
considered	O
to	O
establish	O
comparable	O
patient	O
groups	O
.	O

Phase	O
II	O
trial	O
of	O
the	O
anti	B-GENE
-	I-GENE
G	I-GENE
(	I-GENE
D2	I-GENE
)	I-GENE
monoclonal	I-GENE
antibody	I-GENE
3F8	I-GENE
and	O
granulocyte	B-GENE
-	I-GENE
macrophage	I-GENE
colony	I-GENE
-	I-GENE
stimulating	I-GENE
factor	I-GENE
for	O
neuroblastoma	O
.	O

Hepatitis	O
A	O
infected	O
food	O
handler	O
at	O
an	O
Edmonton	O
,	O
Alberta	O
retail	O
food	O
facility	O
:	O
public	O
health	O
protection	O
strategies	O
.	O

Hydrogels	O
for	O
tissue	O
engineering	O
.	O

Eliminating	O
any	O
subset	O
of	O
ASCUS	O
reduces	O
the	O
ASCUS	O
/	O
SIL	O
ratio	O
but	O
also	O
significantly	O
diminishes	O
the	O
sensitivity	O
of	O
the	O
Papanicolaou	O
test	O
.	O

Eliminating	O
any	O
subset	O
of	O
ASCUS	O
reduces	O
the	O
ASCUS	O
/	O
SIL	O
ratio	O
but	O
also	O
significantly	O
diminishes	O
the	O
sensitivity	O
of	O
the	O
Papanicolaou	O
test	O
.	O

Two	O
nuclear	O
medicine	O
physicians	O
blinded	O
to	O
the	O
surgical	O
findings	O
interpreted	O
all	O
available	O
images	O
and	O
various	O
Tc	O
-	O
99m	O
MIBI	O
image	O
combinations	O
at	O
15	O
minutes	O
alone	O
;	O
15	O
minutes	O
and	O
2	O
hours	O
,	O
15	O
minutes	O
and	O
4	O
hours	O
;	O
and	O
15	O
minutes	O
and	O
2	O
and	O
4	O
hours	O
each	O
with	O
and	O
without	O
correlative	O
pertechnetate	O
thyroid	O
imaging	O
.	O

Between	O
1967	O
and	O
1994	O
,	O
495	O
patients	O
underwent	O
surgery	O
for	O
primary	O
PTC	O
at	O
the	O
Department	O
of	O
Surgery	O
,	O
Helsinki	O
University	O
Central	O
Hospital	O
.	O

ISS	O
and	O
the	O
acute	O
physiology	O
and	O
chronic	O
health	O
evaluation	O
(	O
APACHE	O
II	O
)	O
calculated	O
on	O
admission	O
.	O

The	O
procedure	O
is	O
less	O
aggressive	O
and	O
painful	O
than	O
sternotomy	O
.	O

Paul	O
Monagle	O
addresses	O
the	O
epidemiology	O
of	O
neonatal	O
thrombosis	O
outside	O
of	O
the	O
central	O
nervous	O
system	O
in	O
both	O
arterial	O
and	O
venous	O
locations	O
,	O
and	O
those	O
that	O
occur	O
in	O
utero	O
.	O

[	O
Clinical	O
and	O
epidemiological	O
characteristics	O
of	O
squamous	O
cell	O
carcinoma	O
of	O
the	O
oral	O
cavity	O
in	O
women	O
]	O
BACKGROUND	O
:	O
Squamous	O
cell	O
carcinoma	O
(	O
SCC	O
)	O
of	O
the	O
oral	O
cavity	O
occurs	O
mainly	O
in	O
the	O
male	O
population	O
.	O

Regarding	O
gestational	O
risk	O
,	O
3	O
,	O
243	O
drugs	O
used	O
(	O
34	O
%	O
)	O
belonged	O
to	O
category	O
A	O
risk	O
,	O
1	O
,	O
923	O
(	O
22	O
.	O
6	O
%	O
)	O
to	O
category	O
B	O
,	O
3	O
,	O
798	O
(	O
39	O
.	O
7	O
%	O
)	O
to	O
category	O
C	O
,	O
289	O
(	O
3	O
.	O
0	O
%	O
)	O
to	O
category	O
D	O
,	O
and	O
55	O
(	O
0	O
.	O
6	O
%	O
)	O
to	O
category	O
X	O
.	O

The	O
process	O
has	O
been	O
applied	O
to	O
the	O
river	O
reclamation	O
in	O
Yangpu	O
District	O
of	O
Shanghai	O
City	O
,	O
China	O
.	O

Physical	O
principles	O
in	O
therapeutic	O
apheresis	O
.	O

Rind	O
et	O
al	O
.	O
'	O
s	O
study	O
'	O
s	O
main	O
conclusions	O
were	O
not	O
supported	O
by	O
the	O
original	O
data	O
.	O

Of	O
major	O
concern	O
to	O
food	O
processors	O
is	O
the	O
inadvertent	O
cross	O
-	O
contact	O
of	O
food	O
products	O
with	O
allergenic	O
residues	O
,	O
which	O
could	O
result	O
in	O
potentially	O
life	O
-	O
threatening	O
reactions	O
in	O
those	O
with	O
a	O
food	O
allergy	O
.	O

Lactate	O
accumulation	O
peak	O
was	O
unaffected	O
by	O
supplementation	O
(	O
HMB	O
,	O
8	O
.	O
1	O
+	O
/	O
-	O
1	O
.	O
1	O
mM	O
;	O
LEU	O
,	O
6	O
.	O
2	O
+	O
/	O
-	O
0	O
.	O
8	O
mM	O
;	O
CON	O
,	O
7	O
.	O
5	O
+	O
/	O
-	O
1	O
.	O
3	O
mM	O
)	O
.	O

The	O
increased	O
clearance	O
observed	O
in	O
young	O
infants	O
is	O
in	O
contrast	O
to	O
other	O
opioids	O
.	O

These	O
results	O
were	O
robust	O
to	O
changes	O
in	O
the	O
baseline	O
assumptions	O
of	O
the	O
model	O
.	O

CONCLUSION	O
:	O
The	O
training	O
of	O
novices	O
using	O
MIST	O
-	O
VR	O
yields	O
quantifiable	O
changes	O
in	O
skill	O
that	O
are	O
transferable	O
to	O
a	O
simple	O
real	O
task	O
and	O
are	O
similar	O
to	O
the	O
results	O
achieved	O
with	O
conventional	O
training	O
.	O

The	O
patients	O
and	O
their	O
families	O
were	O
closely	O
questioned	O
,	O
and	O
full	O
clinical	O
examination	O
included	O
a	O
test	O
for	O
orthostasia	O
.	O

They	O
have	O
not	O
been	O
previously	O
reported	O
as	O
a	O
reaction	O
to	O
i	O
.	O
v	O
.	O
contrast	O
material	O
.	O

There	O
was	O
a	O
statistically	O
significant	O
correlation	O
between	O
simultaneous	O
weekly	O
average	O
pollen	O
levels	O
in	O
Philadelphia	O
and	O
in	O
Cherry	O
Hill	O
(	O
Acer	O
,	O
r	O
(	O
p	O
)	O
=	O
0	O
.	O
987	O
,	O
Quercus	O
,	O
r	O
(	O
p	O
)	O
=	O
0	O
.	O
645	O
,	O
Betula	O
,	O
r	O
(	O
p	O
)	O
=	O
0	O
.	O
896	O
,	O
Pinus	O
,	O
r	O
(	O
p	O
)	O
=	O
0	O
.	O
732	O
,	O
Cupressaceae	O
,	O
r	O
(	O
p	O
)	O
=	O
0	O
.	O
695	O
,	O
Poaceae	O
,	O
r	O
(	O
p	O
)	O
=	O
0	O
.	O
950	O
,	O
Ambrosia	O
,	O
r	O
(	O
p	O
)	O
=	O
0	O
.	O
903	O
,	O
and	O
Rumex	O
,	O
r	O
(	O
p	O
)	O
=	O
0	O
.	O
572	O
,	O
P	O
<	O
0	O
.	O
001	O
)	O
.	O

Encouraged	O
by	O
a	O
Dutch	O
study	O
using	O
etidronate	O
/	O
fluoride	O
in	O
corticoid	O
-	O
induced	O
osteoporosis	O
,	O
we	O
performed	O
a	O
pilot	O
study	O
in	O
33	O
men	O
with	O
severe	O
established	O
primary	O
osteoporosis	O
giving	O
cyclically	O
etidronate	O
for	O
14	O
days	O
followed	O
by	O
fluoride	O
plus	O
calcium	O
/	O
vitamin	O
D	O
for	O
76	O
days	O
.	O

In	O
order	O
to	O
overcome	O
the	O
false	O
positive	O
readings	O
that	O
are	O
possible	O
in	O
sphincter	O
manometry	O
,	O
we	O
proposed	O
to	O
use	O
secretin	B-GENE
stimulated	O
endoscopic	O
ultrasound	O
(	O
SSEUS	O
)	O
to	O
measure	O
pancreatic	O
ductal	O
response	O
as	O
an	O
adjunctive	O
method	O
to	O
aid	O
and	O
supplement	O
the	O
diagnosis	O
.	O

The	O
cut	O
-	O
off	O
percentage	O
positivity	O
value	O
was	O
established	O
using	O
500	O
brucellosis	O
-	O
positive	O
and	O
500	O
brucellosis	O
-	O
negative	O
serum	O
samples	O
,	O
confirmed	O
with	O
reference	O
to	O
the	O
sample	O
data	O
using	O
the	O
indirect	O
ELISA	O
kit	O
.	O

An	O
analysis	O
of	O
the	O
dynamics	O
is	O
performed	O
of	O
exactly	O
solvable	O
models	O
for	O
fragile	O
and	O
strong	O
glasses	O
,	O
exploiting	O
the	O
partitioning	O
of	O
the	O
free	O
-	O
energy	O
landscape	O
in	O
inherent	O
structures	O
.	O

Fifty	O
-	O
six	O
semen	O
samples	O
were	O
included	O
in	O
this	O
study	O
;	O
18	O
were	O
subnormal	O
(	O
G1	O
)	O
and	O
38	O
were	O
normal	O
(	O
G2	O
)	O
based	O
on	O
World	O
Health	O
Organization	O
criteria	O
,	O
except	O
for	O
morphology	O
,	O
which	O
was	O
evaluated	O
according	O
to	O
strict	O
criteria	O
.	O

At	O
this	O
timepoint	O
,	O
many	O
leucocytes	O
in	O
the	O
ME	O
and	O
ET	O
mucosa	O
had	O
incorporated	O
BrdU	O
(	O
between	O
15	O
and	O
25	O
%	O
within	O
the	O
subsets	O
)	O
.	O

Their	O
chemical	O
structures	O
were	O
elucidated	O
as	O
1	O
alpha	O
,	O
2	O
alpha	O
-	O
diacetoxy	O
-	O
8	O
beta	O
-	O
isobutanoyloxy	O
-	O
9	O
alpha	O
-	O
benzoyloxy	O
-	O
13	O
-	O
(	O
alpha	O
-	O
methyl	O
)	O
butanoyloxy	O
-	O
4	O
beta	O
,	O
6	O
beta	O
-	O
dihydroxy	O
-	O
beta	O
-	O
dihydroagarofuran	O
(	O
1	O
)	O
,	O
1	O
alpha	O
,	O
2	O
alpha	O
-	O
diacetoxy	O
-	O
8	O
beta	O
-	O
(	O
beta	O
-	O
furancarbonyloxy	O
)	O
-	O
9	O
alpha	O
-	O
benzoyloxy	O
-	O
13	O
-	O
isobutanoyloxy	O
-	O
4	O
beta	O
,	O
6	O
beta	O
-	O
dihydroxy	O
-	O
beta	O
-	O
dihydroagarofuran	O
(	O
2	O
)	O
and	O
1	O
alpha	O
,	O
6	O
beta	O
,	O
8	O
alpha	O
,	O
13	O
-	O
tetraacetoxy	O
-	O
9	O
alpha	O
-	O
benzoyloxy	O
-	O
2	O
alpha	O
-	O
hydroxy	O
-	O
beta	O
-	O
dihydroagarofuran	O
(	O
3	O
)	O
mainly	O
by	O
analyses	O
NMR	O
and	O
MS	O
spectral	O
data	O
.	O

Saunders	O
Company	O
.	O

Acute	O
stress	O
in	O
7	O
rats	O
also	O
increased	O
the	O
mean	O
amount	O
of	O
IL	B-GENE
-	I-GENE
6	I-GENE
released	O
in	O
the	O
urine	O
by	O
31	O
.	O
5	O
%	O
from	O
775	O
.	O
9	O
+	O
/	O
-	O
69	O
.	O
2	O
to	O
1	O
,	O
021	O
.	O
1	O
+	O
/	O
-	O
93	O
.	O
3	O
pg	O
.	O
/	O
ml	O
.	O

Patients	O
with	O
CF	O
and	O
meconium	O
ileus	O
presented	O
a	O
poor	O
nutritional	O
status	O
at	O
diagnosis	O
and	O
a	O
lower	O
survival	O
rate	O
compared	O
to	O
the	O
general	O
CF	O
population	O
.	O

(	O
Cactaceae	O
)	O
waste	O
matter	O
.	O

Skin	O
cancers	O
,	O
followed	O
by	O
gastrointestinal	O
tract	O
and	O
male	O
genital	O
system	O
affected	O
mostly	O
older	O
age	O
patients	O
.	O

CONCLUSION	O
:	O
MMF	O
(	O
2	O
-	O
3	O
g	O
/	O
day	O
)	O
is	O
unable	O
to	O
control	O
the	O
signs	O
of	O
mucocutaneous	O
Adamantiades	O
-	O
Behcet	O
'	O
s	O
disease	O
.	O

In	O
the	O
treatment	O
of	O
opioid	O
naive	O
patients	O
who	O
underwent	O
surgery	O
and	O
received	O
opioids	O
for	O
acute	O
pain	O
,	O
oral	O
ADL	O
8	O
-	O
2698	O
(	O
6	O
.	O
0	O
mg	O
)	O
improved	O
the	O
management	O
of	O
postoperative	O
ileus	O
(	O
POI	O
)	O
by	O
shortening	O
the	O
time	O
to	O
achieve	O
normal	O
bowel	O
function	O
and	O
,	O
ultimately	O
,	O
hospital	O
stay	O
.	O

Evidence	O
suggests	O
that	O
PHACES	O
syndrome	O
is	O
not	O
a	O
random	O
association	O
but	O
a	O
true	O
phakomatosis	O
;	O
further	O
studies	O
are	O
awaited	O
to	O
shed	O
light	O
on	O
a	O
possible	O
genetic	O
background	O
.	O

Moreover	O
,	O
a	O
severe	O
decrease	O
of	O
antithrombin	B-GENE
activity	O
became	O
evident	O
during	O
both	O
experiments	O
(	O
eg	O
,	O
in	O
experiment	O
2	O
from	O
95	O
.	O
6	O
+	O
/	O
-	O
4	O
.	O
8	O
to	O
59	O
.	O
2	O
+	O
/	O
-	O
6	O
.	O
6	O
%	O
)	O
.	O

The	O
Penn	O
State	O
Worry	O
Questionnaire	O
for	O
Children	O
(	O
PSWQ	O
-	O
C	O
)	O
is	O
a	O
14	O
-	O
item	O
self	O
-	O
report	O
questionnaire	O
that	O
intends	O
to	O
measure	O
the	O
tendency	O
of	O
children	O
to	O
engage	O
in	O
excessive	O
,	O
generalized	O
,	O
and	O
uncontrollable	O
worry	O
(	O
Chorpita	O
et	O
al	O
.	O
,	O
Behav	O
.	O

Described	O
X	O
-	O
ray	O
projection	O
were	O
performed	O
in	O
70	O
patients	O
.	O

Pyrethroid	O
insecticides	O
are	O
widely	O
used	O
in	O
agriculture	O
and	O
private	O
households	O
.	O

The	O
sorption	O
mechanisms	O
changed	O
from	O
adsorption	O
to	O
partition	O
in	O
the	O
process	O
of	O
repetitious	O
sorption	O
.	O

Although	O
the	O
spatial	O
and	O
temporal	O
variability	O
of	O
LDF	O
signals	O
evoked	O
by	O
cerebrocortical	O
microflow	O
is	O
in	O
the	O
same	O
range	O
as	O
with	O
other	O
methods	O
and	O
in	O
other	O
organs	O
,	O
LDF	O
cerebrocortical	O
mapping	O
is	O
restricted	O
by	O
the	O
large	O
temporal	O
and	O
spatial	O
heterogeneity	O
of	O
the	O
cerebrocortical	O
vasculature	O
.	O

The	O
5	O
-	O
year	O
overall	O
survival	O
(	O
OS	O
)	O
and	O
progression	O
-	O
free	O
survival	O
(	O
PFS	O
)	O
rates	O
were	O
58	O
.	O
9	O
%	O
and	O
55	O
.	O
4	O
%	O
for	O
arm	O
A	O
and	O
44	O
.	O
5	O
%	O
and	O
41	O
.	O
3	O
%	O
for	O
arm	O
B	O
(	O
P	O
=	O
.	O
007	O
and	O
P	O
=	O
.	O
02	O
)	O
,	O
respectively	O
.	O

METHODS	O
:	O
P	B-GENE
-	I-GENE
selectin	I-GENE
expression	O
of	O
nonstimulated	O
and	O
ADP	O
-	O
stimulated	O
platelets	O
was	O
flow	O
cytometrically	O
measured	O
before	O
the	O
clopidogrel	O
loading	O
dose	O
and	O
on	O
3	O
consecutive	O
days	O
in	O
52	O
patients	O
with	O
coronary	O
artery	O
disease	O
:	O
21	O
patients	O
in	O
group	O
1	O
received	O
300	O
mg	O
of	O
clopidogrel	O
after	O
stent	O
implantation	O
and	O
11	O
patients	O
in	O
group	O
2	O
received	O
the	O
higher	O
450	O
-	O
mg	O
clopidogrel	O
loading	O
dose	O
followed	O
by	O
a	O
daily	O
dose	O
of	O
75	O
mg	O
of	O
clopidogrel	O
for	O
both	O
groups	O
.	O

Traditional	O
surgical	O
exploration	O
was	O
followed	O
by	O
survey	O
with	O
a	O
gamma	O
-	O
detecting	O
probe	O
.	O

No	O
effect	O
of	O
the	O
intervention	O
on	O
depression	O
scores	O
was	O
found	O
.	O

IV	O
.	O
combined	O
sclerosis	O
and	O
resorption	O
of	O
the	O
skull	O
base	O
(	O
6	O
cases	O
,	O
2	O
group	O
I	O
lesions	O
and	O
4	O
group	O
II	O
lesions	O
)	O
.	O

The	O
quantity	O
of	O
each	O
population	O
(	O
L	O
.	O
bulgaricus	O
,	O
S	O
.	O
thermophilus	O
)	O
was	O
then	O
estimated	O
in	O
the	O
pellet	O
by	O
PyMS	O
,	O
and	O
the	O
data	O
were	O
analysed	O
by	O
artificial	O
neural	O
networks	O
(	O
ANNs	O
)	O
.	O

AF	B-GENE
showed	O
a	O
mixed	O
nuclear	O
/	O
cytoplasmic	O
pattern	O
of	O
expression	O
in	O
the	O
epithelial	O
,	O
endothelial	O
,	O
and	O
stromal	O
component	O
of	O
the	O
normal	O
breast	O
and	O
benign	O
lesions	O
,	O
whereas	O
an	O
impressive	O
loss	O
of	O
AF	B-GENE
expression	O
was	O
noted	O
in	O
in	O
situ	O
and	O
invasive	O
breast	O
cancer	O
and	O
tumoral	O
stroma	O
.	O

We	O
derive	O
joint	O
probability	O
density	O
distributions	O
for	O
three	O
key	O
uncertain	O
properties	O
of	O
the	O
climate	O
system	O
,	O
using	O
an	O
optimal	O
fingerprinting	O
approach	O
to	O
compare	O
simulations	O
of	O
an	O
intermediate	O
complexity	O
climate	O
model	O
with	O
three	O
distinct	O
diagnostics	O
of	O
recent	O
climate	O
observations	O
.	O

Frequency	O
of	O
seeing	O
curves	O
were	O
examined	O
for	O
the	O
method	O
most	O
similar	O
to	O
FDT	O
.	O

Chronic	O
graft	O
-	O
versus	O
-	O
host	O
disease	O
(	O
cGVHD	O
)	O
is	O
a	O
major	O
complication	O
of	O
allogeneic	O
hematopoietic	O
cell	O
transplantation	O
.	O

Compared	O
to	O
white	O
-	O
on	O
-	O
white	O
(	O
W	O
-	O
W	O
)	O
perimetry	O
,	O
SWAP	O
is	O
limited	O
clinically	O
by	O
:	O
greater	O
variability	O
associated	O
with	O
the	O
estimation	O
of	O
threshold	O
,	O
ocular	O
media	O
absorption	O
,	O
increased	O
examination	O
duration	O
and	O
an	O
additional	O
learning	O
effect	O
.	O

Preservatives	O
are	O
an	O
important	O
component	O
of	O
ophthalmic	O
preparations	O
,	O
providing	O
antimicrobial	O
activity	O
in	O
the	O
bottle	O
and	O
preventing	O
decomposition	O
of	O
active	O
drug	O
.	O

Comparative	O
analysis	O
of	O
various	O
techniques	O
of	O
prostatic	O
drainage	O
in	O
patients	O
with	O
chronic	O
obstructive	O
prostatitis	O
]	O
The	O
efficacy	O
of	O
prostatic	O
drainage	O
using	O
transurethral	O
vacuum	O
aspiration	O
(	O
Introl	O
-	O
4	O
unit	O
)	O
and	O
transrectal	O
pneumovibromassage	O
(	O
PVM	O
-	O
R	O
-	O
01	O
)	O
was	O
compared	O
in	O
1511	O
patients	O
with	O
chronic	O
obstructive	O
prostatitis	O
.	O

Consumption	O
of	O
4	O
%	O
sucrose	O
was	O
not	O
affected	O
by	O
excitotoxic	O
lesions	O
of	O
the	O
PPTg	O
,	O
but	O
PPTg	O
lesioned	O
rats	O
consumed	O
significantly	O
more	O
12	O
%	O
and	O
20	O
%	O
sucrose	O
than	O
sham	O
controls	O
.	O

Actuarial	O
freedom	O
from	O
ventricular	O
arrhythmias	O
at	O
4	O
-	O
year	O
follow	O
-	O
up	O
was	O
74	O
.	O
1	O
+	O
/	O
-	O
6	O
.	O
0	O
%	O
in	O
group	O
A	O
vs	O
.	O

Mental	O
development	O
is	O
generally	O
normal	O
.	O

Influence	O
of	O
different	O
methods	O
of	O
chemical	O
disinfection	O
on	O
the	O
physical	O
properties	O
of	O
type	O
IV	O
and	O
V	O
gypsum	O
dies	O
]	O
Several	O
instruments	O
and	O
materials	O
frequently	O
used	O
in	O
prosthodontics	O
-	O
-	O
such	O
as	O
stone	O
casts	O
,	O
dental	O
impressions	O
,	O
interocclusal	O
records	O
-	O
-	O
are	O
classified	O
,	O
by	O
the	O
dental	O
literature	O
,	O
as	O
vehicles	O
of	O
transmission	O
of	O
infectious	O
diseases	O
to	O
those	O
who	O
handle	O
them	O
.	O

Vitrectomy	O
and	O
removal	O
of	O
retained	O
lens	O
fragments	O
restores	O
good	O
visual	O
acuity	O
and	O
reduces	O
secondary	O
glaucoma	O
in	O
the	O
majority	O
of	O
patients	O
.	O

CONCLUSIONS	O
:	O
The	O
mechanism	O
of	O
MIRI	O
is	O
Qi	O
deficiency	O
and	O
blood	O
stasis	O
in	O
TCM	O
,	O
its	O
treating	O
principles	O
should	O
be	O
promoting	O
Qi	O
and	O
removing	O
the	O
blood	O
stasis	O
.	O

Effects	O
of	O
activating	O
blood	O
circulation	O
to	O
remove	O
blood	O
stasis	O
on	O
barrier	O
action	O
of	O
gastric	O
wall	O
in	O
chronic	O
atrophic	O
gastritis	O

Proteomic	O
patterns	O
of	O
nipple	O
aspirate	O
fluids	O
obtained	O
by	O
SELDI	O
-	O
TOF	O
:	O
potential	O
for	O
new	O
biomarkers	O
to	O
aid	O
in	O
the	O
diagnosis	O
of	O
breast	O
cancer	O
.	O

According	O
to	O
the	O
laboratory	O
results	O
,	O
the	O
application	O
of	O
neural	O
network	O
can	O
solve	O
the	O
problem	O
successfully	O
.	O

A	O
high	O
-	O
efficiency	O
cross	O
-	O
flow	O
micronebulizer	O
interface	O
for	O
capillary	O
electrophoresis	O
and	O
inductively	O
coupled	O
plasma	O
mass	O
spectrometry	O
.	O

The	O
experimental	O
results	O
showed	O
that	O
the	O
coagulation	O
-	O
electrooxidation	O
process	O
could	O
efficiently	O
remove	O
the	O
color	O
and	O
the	O
COD	O
from	O
the	O
simulated	O
dye	O
wastewater	O
.	O

Cyclic	O
loading	O
of	O
bone	O
during	O
normal	O
daily	O
activity	O
leads	O
to	O
the	O
formation	O
of	O
microcracks	O
within	O
the	O
tissue	O
matrix	O
of	O
compact	O
bone	O
.	O

The	O
weight	O
-	O
bearing	O
surface	O
of	O
the	O
PE	O
head	O
became	O
smoother	O
with	O
time	O
after	O
THA	O
,	O
and	O
the	O
friction	O
coefficient	O
did	O
not	O
differ	O
significantly	O
from	O
that	O
of	O
an	O
unused	O
PE	O
head	O
.	O

OBJECTIVE	O
:	O
To	O
demonstrate	O
a	O
lack	O
of	O
effect	O
of	O
steady	O
-	O
state	O
concentrations	O
of	O
cilomilast	O
,	O
a	O
new	O
oral	O
phosphodiesterase	B-GENE
4	I-GENE
inhibitor	O
for	O
the	O
treatment	O
of	O
chronic	O
obstructive	O
pulmonary	O
disease	O
,	O
on	O
warfarin	O
-	O
induced	O
anticoagulation	O
.	O

Postdocs	O
face	O
hardship	O
across	O
mainland	O
Europe	O
.	O

The	O
design	O
principle	O
based	O
on	O
a	O
uniform	O
vibration	O
mode	O
is	O
presented	O
.	O

Dynamic	O
imaging	O
of	O
nuclear	O
wave	O
functions	O
with	O
ultrashort	O
UV	O
laser	O
pulses	O
.	O

Efficacy	O
and	O
safety	O
of	O
aspirin	O
in	O
the	O
long	O
-	O
term	O
management	O
of	O
atherothrombosis	O
.	O

The	O
General	O
Practice	O
Research	O
Database	O
(	O
GPRD	O
)	O
is	O
the	O
world	O
'	O
s	O
largest	O
computerized	O
database	O
of	O
anonymized	O
longitudinal	O
patient	O
records	O
from	O
general	O
practice	O
and	O
is	O
a	O
unique	O
public	O
health	O
research	O
tool	O
.	O

This	O
paper	O
reports	O
the	O
results	O
of	O
a	O
laboratory	O
study	O
on	O
aldicarb	O
and	O
its	O
main	O
metabolites	O
,	O
aldicarb	O
sulfone	O
and	O
aldicarb	O
sulfoxide	O
.	O

Only	O
one	O
DC	O
cardioversion	O
was	O
required	O
in	O
the	O
HBS	O
group	O
,	O
whereas	O
2	O
DC	O
in	O
the	O
CBC	O
group	O
and	O
total	O
7	O
DC	O
in	O
the	O
GIK	O
group	O
.	O

Since	O
August	O
1994	O
,	O
the	O
ENRP	O
has	O
retained	O
70	O
.	O
3	O
metric	O
tons	O
of	O
TP	O
that	O
otherwise	O
would	O
have	O
entered	O
the	O
Everglades	O
.	O

It	O
was	O
found	O
that	O
the	O
disappearance	O
of	O
BOD5	O
and	O
NH3	O
-	O
N	O
could	O
be	O
approximated	O
using	O
first	O
-	O
order	O
kinetics	O
,	O
but	O
the	O
kinetics	O
of	O
TP	O
removal	O
were	O
unclear	O
.	O

It	O
was	O
found	O
that	O
the	O
disappearance	O
of	O
BOD5	O
and	O
NH3	O
-	O
N	O
could	O
be	O
approximated	O
using	O
first	O
-	O
order	O
kinetics	O
,	O
but	O
the	O
kinetics	O
of	O
TP	O
removal	O
were	O
unclear	O
.	O

Losses	O
of	O
dichlofluanid	O
(	O
54	O
%	O
)	O
,	O
chlozolinate	O
(	O
22	O
%	O
)	O
,	O
and	O
etridiazole	O
(	O
40	O
%	O
)	O
,	O
previously	O
reported	O
to	O
occur	O
during	O
ambient	O
processing	O
of	O
apples	O
,	O
were	O
reduced	O
to	O
barely	O
significant	O
levels	O
(	O
10	O
,	O
17	O
,	O
and	O
14	O
%	O
,	O
respectively	O
)	O
by	O
cryogenic	O
processing	O
.	O

The	O
TB	O
incidence	O
in	O
the	O
"	O
AIRIN	O
"	O
area	O
,	O
where	O
about	O
20	O
%	O
TB	O
patients	O
are	O
homeless	O
,	O
shows	O
highest	O
rate	O
of	O
above	O
1	O
,	O
000	O
/	O
100	O
,	O
000	O
.	O

It	O
is	O
shown	O
that	O
the	O
displacement	O
distribution	O
measured	O
by	O
q	O
-	O
space	O
MRI	O
in	O
both	O
the	O
large	O
displacement	O
(	O
i	O
.	O
e	O
.	O
,	O
large	O
r	O
)	O
and	O
the	O
long	O
-	O
wavelength	O
(	O
i	O
.	O
e	O
.	O
,	O
small	O
q	O
)	O
limits	O
is	O
the	O
same	O
3D	O
Gaussian	O
displacement	O
distribution	O
assumed	O
in	O
DT	O
-	O
MRI	O
.	O

The	O
procedure	O
facilitated	O
the	O
retention	O
of	O
a	O
mandibular	O
molar	O
with	O
a	O
Class	O
III	O
FI	O
in	O
a	O
manner	O
acceptable	O
to	O
both	O
the	O
patient	O
and	O
the	O
clinician	O
.	O

The	O
results	O
of	O
our	O
ten	O
-	O
fold	O
cross	O
-	O
validation	O
experiments	O
show	O
that	O
,	O
on	O
the	O
average	O
,	O
the	O
system	O
increases	O
the	O
specificity	O
from	O
0	O
.	O
19	O
(	O
0	O
.	O
35	O
)	O
to	O
0	O
.	O
69	O
(	O
0	O
.	O
74	O
)	O
at	O
a	O
sensitivity	O
level	O
of	O
1	O
.	O
0	O
(	O
0	O
.	O
95	O
)	O
.	O

The	O
physical	O
characteristics	O
of	O
these	O
calls	O
vary	O
among	O
species	O
of	O
bat	O
,	O
and	O
variations	O
also	O
exist	O
in	O
the	O
timing	O
and	O
patterns	O
of	O
respiratory	O
muscle	O
recruitment	O
during	O
echolocation	O
.	O

Clicking	O
on	O
"	O
Examples	O
and	O
Explanations	O
of	O
APA	O
Form	O
"	O
provides	O
a	O
help	O
system	O
with	O
examples	O
of	O
the	O
various	O
sections	O
of	O
a	O
review	O
article	O
,	O
journal	O
article	O
that	O
has	O
one	O
experiment	O
,	O
or	O
journal	O
article	O
that	O
has	O
two	O
or	O
more	O
experiments	O
.	O

The	O
drug	O
packets	O
contained	O
acetyl	O
aspirin	O
,	O
acetaminophen	O
and	O
chloramphenicol	O
.	O

Karger	O
AG	O
,	O
Basel	O

AIM	O
:	O
To	O
understand	O
the	O
role	O
of	O
nutritional	O
status	O
in	O
cirrhotic	O
patients	O
without	O
clinical	O
porto	O
-	O
systemic	O
encephalopathy	O
(	O
PSE	O
)	O
.	O
METHODS	O
:	O
Fifty	O
-	O
one	O
non	O
-	O
alcoholic	O
patients	O
with	O
cirrhosis	O
without	O
PSE	O
were	O
studied	O
prospectively	O
and	O
compared	O
with	O
20	O
healthy	O
volunteers	O
.	O

MAIN	O
OUTCOME	O
MEASURE	O
(	O
S	O
)	O
:	O
Serum	O
levels	O
of	O
FSH	B-GENE
,	O
LH	B-GENE
,	O
and	O
inhibin	B-GENE
A	I-GENE
and	I-GENE
B	I-GENE
.	O

For	O
instance	O
,	O
a	O
total	O
SIP	O
score	O
of	O
an	O
individual	O
patient	O
of	O
28	O
.	O
3	O
%	O
(	O
which	O
is	O
taken	O
as	O
an	O
example	O
,	O
being	O
the	O
mean	O
score	O
in	O
the	O
study	O
population	O
)	O
should	O
decrease	O
by	O
at	O
least	O
9	O
.	O
26	O
%	O
or	O
approximately	O
13	O
items	O
,	O
before	O
any	O
improvement	O
beyond	O
reproducibility	O
noise	O
can	O
be	O
detected	O
.	O

Group	O
I	O
comprised	O
5	O
adult	O
Collies	O
that	O
received	O
at	O
least	O
400	O
microg	O
/	O
kg	O
ivermectin	O
p	O
.	O
o	O
.	O
and	O
were	O
presented	O
to	O
the	O
VMTH	O
3	O
hours	O
after	O
intoxication	O
.	O

No	O
increased	O
tumor	O
-	O
related	O
mortality	O
was	O
observed	O
after	O
a	O
mean	O
follow	O
-	O
up	O
of	O
44	O
months	O
.	O

Dissociable	O
effects	O
of	O
lidocaine	O
inactivation	O
of	O
the	O
rostral	O
and	O
caudal	O
basolateral	O
amygdala	O
on	O
the	O
maintenance	O
and	O
reinstatement	O
of	O
cocaine	O
-	O
seeking	O
behavior	O
in	O
rats	O
.	O

The	O
population	O
studied	O
comprised	O
4472	O
men	O
and	O
5212	O
women	O
aged	O
30	O
-	O
74	O
years	O
,	O
without	O
coronary	O
heart	O
disease	O
,	O
who	O
had	O
CRP	B-GENE
measurements	O
in	O
the	O
Third	O
National	O
Health	O
and	O
Nutrition	O
Examination	O
Survey	O
(	O
NHANES	O
III	O
)	O
.	O

Herceptin	O
,	O
which	O
recognizes	O
the	O
HER	B-GENE
-	I-GENE
2	I-GENE
/	O
neu	B-GENE
antigen	O
and	O
has	O
similar	O
size	O
(	O
10	O
nm	O
)	O
to	O
G6	O
-	O
(	O
1B4M	O
-	O
Gd	O
)	O
(	O
256	O
)	O
,	O
accumulated	O
and	O
internalized	O
in	O
the	O
WIBC	O
-	O
9	O
tumors	O
more	O
quickly	O
than	O
in	O
the	O
control	O
MC	O
-	O
5	O
tumors	O
that	O
progress	O
with	O
normal	O
angiogenesis	O
.	O

Forty	O
-	O
eight	O
pigs	O
were	O
removed	O
from	O
sows	O
at	O
1	O
d	O
of	O
age	O
and	O
randomly	O
assigned	O
to	O
one	O
of	O
three	O
treatments	O
:	O
1	O
)	O
control	O
with	O
lactose	O
as	O
the	O
carbohydrate	O
source	O
,	O
2	O
)	O
lactose	O
replaced	O
(	O
gram	O
for	O
gram	O
)	O
with	O
CSS	O
(	O
dextrose	O
equivalent	O
[	O
DE	O
]	O
-	O
20	O
)	O
,	O
and	O
3	O
)	O
lactose	O
replaced	O
with	O
DE	O
-	O
42	O
.	O

CONCLUSIONS	O
:	O
AMVT	O
is	O
rare	O
but	O
a	O
potentially	O
lethal	O
emergency	O
disease	O
.	O

Therefore	O
,	O
in	O
a	O
large	O
animal	O
model	O
of	O
permanent	O
focal	O
ischemia	O
in	O
which	O
transfusion	O
starts	O
30	O
min	O
after	O
ischemia	O
,	O
tetrameric	O
cross	O
-	O
linked	O
hemoglobin	B-GENE
transfusion	O
can	O
augment	O
oxygen	O
transport	O
to	O
the	O
ischemic	O
cortex	O
,	O
but	O
the	O
increase	O
can	O
be	O
delayed	O
and	O
not	O
necessarily	O
provide	O
protection	O
.	O

Since	O
the	O
early	O
1980s	O
there	O
has	O
been	O
increasing	O
awareness	O
of	O
the	O
importance	O
of	O
quantifying	O
health	O
-	O
related	O
quality	O
of	O
life	O
(	O
HRQL	O
)	O
in	O
patients	O
with	O
chronic	O
respiratory	O
disorders	O
included	O
in	O
clinical	O
trials	O
.	O

They	O
were	O
randomly	O
allocated	O
to	O
receive	O
either	O
625	O
mg	O
of	O
calcium	O
carbonate	O
(	O
250	O
mg	O
of	O
elemental	O
calcium	O
)	O
at	O
the	O
end	O
of	O
a	O
meal	O
three	O
times	O
a	O
day	O
(	O
group	O
A	O
,	O
n	O
=	O
26	O
)	O
or	O
calcium	O
carbonate	O
in	O
the	O
same	O
manner	O
plus	O
0	O
.	O
625	O
mg	O
/	O
day	O
of	O
conjugated	O
equine	O
estrogen	O
and	O
5	O
mg	O
medrogestone	O
acetate	O
from	O
day	O
1	O
-	O
12	O
each	O
month	O
(	O
group	O
B	O
,	O
n	O
=	O
30	O
)	O
.	O

The	O
two	O
-	O
wave	O
,	O
1995	O
-	O
1996	O
National	O
Longitudinal	O
Study	O
of	O
Adolescent	O
Health	O
uses	O
a	O
measure	O
of	O
depressive	O
symptomatology	O
across	O
a	O
12	O
-	O
month	O
interval	O
.	O

METHODS	O
:	O
9	O
cases	O
of	O
conventional	O
intermittent	O
tissue	O
expansion	O
(	O
CITE	O
)	O
and	O
9	O
cases	O
of	O
continuous	O
pressure	O
-	O
controlled	O
tissue	O
expansion	O
(	O
CPTE	O
)	O
were	O
chosen	O
for	O
the	O
study	O
.	O

Wegener	O
'	O
s	O
granulomatosis	O

There	O
was	O
a	O
significant	O
effect	O
of	O
hematocrit	O
on	O
the	O
General	O
Health	O
scale	O
on	O
the	O
SF	O
-	O
36	O
(	O
P	O
=	O
0	O
.	O
03	O
)	O
.	O

A	O
global	O
response	O
rate	O
was	O
17	O
%	O
(	O
95	O
%	O
confidence	O
interval	O
(	O
95	O
%	O
CI	O
)	O
:	O
2	O
%	O
-	O
32	O
%	O
)	O
and	O
the	O
median	O
overall	O
survival	O
was	O
12	O
months	O
.	O

We	O
also	O
studied	O
a	O
new	O
parameter	O
:	O
the	O
angle	O
to	O
maximal	O
peak	O
torque	O
(	O
APT	O
)	O
.	O

For	O
the	O
2	O
.	O
5	O
to	O
4	O
ng	O
/	O
mL	O
model	O
,	O
the	O
AUC	O
of	O
the	O
ANN	O
ROC	O
curve	O
was	O
significantly	O
higher	O
than	O
the	O
AUCs	O
for	O
percentage	O
of	O
free	O
PSA	B-GENE
(	O
P	O
=	O
.	O
0239	O
)	O
,	O
PSA	O
-	O
TZ	O
(	O
P	O
=	O
.	O
0204	O
)	O
,	O
and	O
PSA	B-GENE
density	O
and	O
total	O
prostate	O
volume	O
(	O
P	O
<	O
.	O
01	O
for	O
both	O
)	O
.	O

Potential	O
treatments	O
include	O
dobutamine	O
,	O
KATP	O
channel	O
activators	O
,	O
and	O
21	O
-	O
aminosteroids	O
.	O

Selenium	O
is	O
an	O
essential	O
element	O
for	O
humans	O
,	O
animals	O
and	O
some	O
species	O
of	O
microorganisms	O
.	O

The	O
GT	O
-	O
foreign	O
-	O
pictures	O
showed	O
that	O
the	O
judgment	O
of	O
other	O
subjects	O
changed	O
toward	O
hedonic	O
and	O
permeability	O
directions	O
.	O

RESULTS	O
:	O
The	O
target	O
dose	O
was	O
comparable	O
in	O
the	O
3D	O
-	O
CRT	O
and	O
IMRT	O
plans	O
,	O
although	O
improvements	O
were	O
seen	O
when	O
seven	O
and	O
nine	O
IMRT	O
fields	O
were	O
used	O
.	O

We	O
therefore	O
applied	O
a	O
radiolabelled	O
serumalbumin	B-GENE
method	O
to	O
determine	O
blood	O
volume	O
after	O
haemodilution	O
with	O
crosslinked	O
or	O
conjugated	O
haemoglobin	B-GENE
,	O
in	O
comparison	O
with	O
a	O
reference	O
solution	O
of	O
hydroxyethyl	O
starch	O
(	O
HES	O
)	O
.	O

The	O
equilibrium	O
phosphorus	O
content	O
(	O
EPC0	O
)	O
of	O
surface	O
soil	O
was	O
generally	O
higher	O
than	O
the	O
SRP	O
content	O
of	O
drainage	O
water	O
,	O
at	O
one	O
farm	O
by	O
1	O
order	O
of	O
magnitude	O
.	O

The	O
long	O
-	O
term	O
prediction	O
is	O
based	O
on	O
an	O
algorithm	O
for	O
R	O
-	O
R	O
interval	O
estimation	O
.	O

Despite	O
considerable	O
research	O
,	O
an	O
explanation	O
of	O
this	O
effect	O
has	O
been	O
elusive	O
.	O

The	O
structure	O
has	O
been	O
established	O
by	O
a	O
study	O
of	O
its	O
mono	O
-	O
and	O
bidimensional	O
NMR	O
spectra	O
and	O
mass	O
spectrometry	O
.	O

We	O
argue	O
that	O
this	O
is	O
the	O
general	O
property	O
of	O
QSAR	O
models	O
developed	O
using	O
LOO	O
cross	O
-	O
validation	O
.	O

We	O
compared	O
the	O
efficacy	O
and	O
costs	O
of	O
valacyclovir	O
in	O
preventing	O
HSV	O
reactivation	O
among	O
HSV	O
seropositive	O
autologous	O
progenitor	O
cell	O
transplantation	O
(	O
APCT	O
)	O
patients	O
with	O
historical	O
controls	O
in	O
whom	O
intravenous	O
acyclovir	O
or	O
no	O
HSV	O
prophylaxis	O
were	O
used	O
.	O

All	O
adults	O
attending	O
the	O
outpatient	O
clinics	O
of	O
a	O
dermatological	O
hospital	O
on	O
predetermined	O
days	O
were	O
given	O
the	O
12	O
-	O
item	O
General	O
Health	O
Questionnaire	O
.	O

Data	O
on	O
prosthesis	O
use	O
are	O
encouraging	O
,	O
although	O
a	O
follow	O
-	O
up	O
study	O
is	O
required	O
to	O
determine	O
the	O
functional	O
outcome	O
for	O
prosthesis	O
users	O
and	O
non	O
-	O
users	O
.	O

A	O
mail	O
survey	O
of	O
Georgia	O
members	O
of	O
the	O
American	O
College	O
of	O
Obstetricians	O
and	O
Gynecologists	O
was	O
conducted	O
.	O

HIV	O
-	O
1	O
C	O
subtype	O
in	O
IDUs	O
accounted	O
for	O
61	O
.	O
3	O
%	O
.	O

When	O
a	O
plateau	O
of	O
enhancement	O
was	O
reached	O
,	O
a	O
single	O
lesion	O
in	O
each	O
patient	O
was	O
imaged	O
using	O
five	O
different	O
continuous	O
scanning	O
modes	O
,	O
fundamental	O
grey	O
scale	O
(	O
FGS	O
)	O
;	O
fundamental	O
colour	O
Doppler	O
(	O
FCD	O
)	O
;	O
fundamental	O
power	O
Doppler	O
(	O
FPD	O
)	O
;	O
second	O
harmonic	O
grey	O
scale	O
(	O
HGS	O
)	O
;	O
and	O
pulse	O
inversion	O
mode	O
(	O
Pim	O
)	O
using	O
an	O
HDI5000	O
scanner	O
and	O
C5	O
-	O
2	O
probe	O
(	O
ATL	O
,	O
Bothell	O
,	O
WA	O
)	O
.	O

A	O
comparative	O
study	O
of	O
the	O
effects	O
of	O
carbamazepine	O
and	O
the	O
NMDA	B-GENE
receptor	I-GENE
antagonist	O
remacemide	O
on	O
road	O
tracking	O
and	O
car	O
-	O
following	O
performance	O
in	O
actual	O
traffic	O
.	O

We	O
find	O
that	O
the	O
measured	O
Nusselt	O
number	O
decreased	O
about	O
20	O
%	O
over	O
the	O
range	O
of	O
Pr	O
spanned	O
in	O
the	O
experiment	O
.	O

Viral	O
and	O
atypical	O
pathogens	O
as	O
causes	O
of	O
type	O
1	O
acute	O
exacerbations	O
of	O
chronic	O
bronchitis	O
.	O

Treatment	O
for	O
this	O
condition	O
often	O
involves	O
use	O
of	O
a	O
wax	O
softening	O
or	O
dispersing	O
agent	O
(	O
cerumenolytic	O
)	O
before	O
syringing	O
.	O

In	O
addition	O
,	O
benzocaine	O
and	O
2	O
-	O
phenoxyethanol	O
depressed	O
complement	O
activity	O
and	O
phagocytosis	O
,	O
while	O
MS222	O
and	O
quinaldine	O
sulphate	O
did	O
not	O
.	O

The	O
EC	O
(	O
50	O
)	O
for	O
suppression	O
of	O
long	O
-	O
term	O
memory	O
(	O
the	O
concentration	O
decreasing	O
memory	O
by	O
50	O
%	O
)	O
of	O
fear	O
conditioning	O
to	O
context	O
was	O
2	O
.	O
00	O
%	O
plus	O
/	O
minus	O
0	O
.	O
01	O
%	O
(	O
mean	O
plus	O
/	O
minus	O
SEM	O
)	O
,	O
and	O
for	O
fear	O
conditioning	O
to	O
tone	O
was	O
3	O
.	O
45	O
%	O
plus	O
/	O
minus	O
0	O
.	O
26	O
%	O
,	O
(	O
P	O
<	O
0	O
.	O
05	O
)	O
.	O

It	O
has	O
been	O
proposed	O
that	O
insulin	B-GENE
resistance	O
(	O
IR	O
)	O
underlies	O
a	O
cluster	O
of	O
cardiovascular	O
disease	O
(	O
CVD	O
)	O
risk	O
factors	O
constituting	O
a	O
"	O
metabolic	O
syndrome	O
.	O
"	O
CVD	O
is	O
a	O
leading	O
cause	O
of	O
premature	O
mortality	O
among	O
indigenous	O
Australians	O
.	O

Dementia	O
is	O
being	O
avoided	O
in	O
NHS	O
and	O
social	O
care	O
.	O

HIV	O
-	O
1	O
infection	O
in	O
rural	O
Africa	O
:	O
is	O
there	O
a	O
difference	O
in	O
median	O
time	O
to	O
AIDS	O
and	O
survival	O
compared	O
with	O
that	O
in	O
industrialized	O
countries	O
?	O
OBJECTIVES	O
:	O
To	O
describe	O
the	O
progression	O
times	O
of	O
HIV	O
-	O
1	O
infection	O
from	O
seroconversion	O
to	O
AIDS	O
and	O
to	O
death	O
,	O
and	O
time	O
from	O
first	O
developing	O
AIDS	O
to	O
death	O
in	O
rural	O
Uganda	O
.	O

The	O
use	O
of	O
highly	O
active	O
antiretroviral	O
therapy	O
(	O
HAART	O
)	O
has	O
resulted	O
in	O
significant	O
improvements	O
in	O
the	O
treatment	O
of	O
HIV	O
infection	O
,	O
including	O
a	O
decrease	O
in	O
the	O
incidence	O
and	O
severity	O
of	O
several	O
acquired	O
immune	O
deficiency	O
syndrome	O
(	O
AIDS	O
)	O
-	O
related	O
malignancies	O
.	O

Time	O
to	O
progression	O
was	O
6	O
months	O
(	O
5	O
-	O
7	O
months	O
)	O
with	O
a	O
median	O
survival	O
from	O
registration	O
of	O
9	O
.	O
6	O
months	O
(	O
95	O
%	O
CI	O
8	O
-	O
12	O
months	O
)	O
.	O

Heparin	O
(	O
100	O
U	O
.	O
kg	O
(	O
-	O
1	O
)	O
.	O
day	O
(	O
-	O
1	O
)	O
)	O
was	O
injected	O
subcutaneously	O
to	O
the	O
rats	O
in	O
H	O
group	O
while	O
normal	O
saline	O
to	O
those	O
in	O
N	O
group	O
once	O
a	O
day	O
.	O

MAIN	O
OUTCOME	O
MEASURE	O
:	O
A	O
positive	O
test	O
result	O
for	O
gonococcal	O
or	O
chlamydial	O
infection	O
by	O
the	O
ligase	B-GENE
chain	O
reaction	O
assay	O
;	O
secondary	O
outcome	O
measure	O
was	O
a	O
positive	O
test	O
result	O
for	O
human	O
immunodeficiency	O
virus	O
(	O
HIV	O
)	O
.	O

The	O
purpose	O
of	O
this	O
study	O
was	O
to	O
develop	O
a	O
reliable	O
and	O
culturally	O
meaningful	O
exercise	O
self	O
-	O
efficacy	O
questionnaire	O
for	O
older	O
Mexican	O
American	O
women	O
.	O

Neutrophil	O
:	O
lymphocyte	O
ratio	O
,	O
plasma	O
haptoglobin	B-GENE
,	O
and	O
CBG	B-GENE
levels	O
were	O
greater	O
(	O
P	O
<	O
0	O
.	O
01	O
)	O
during	O
the	O
INITIAL	O
period	O
than	O
during	O
the	O
PRE	O
or	O
POST	O
periods	O
but	O
did	O
not	O
differ	O
between	O
treatments	O
.	O

CD	O
was	O
determined	O
using	O
the	O
Farnsworth	O
D	O
-	O
15	O
method	O
.	O

Here	O
is	O
presented	O
the	O
monitoring	O
of	O
the	O
accidental	O
spill	O
on	O
vertical	O
distribution	O
of	O
heavy	O
metals	O
in	O
the	O
estuarine	O
sediments	O
.	O

The	O
large	O
fluxes	O
of	O
239	O
+	O
240Pu	O
might	O
be	O
attributed	O
to	O
episodic	O
lateral	O
transport	O
of	O
particles	O
that	O
flow	O
down	O
the	O
continental	O
slope	O
with	O
the	O
nepheloid	O
layer	O
which	O
was	O
considered	O
to	O
be	O
significant	O
for	O
239	O
+	O
240Pu	O
transport	O
on	O
the	O
continental	O
slope	O
in	O
the	O
East	O
China	O
Sea	O
.	O

Rigorous	O
treatment	O
protocols	O
for	O
diet	O
delivery	O
and	O
EEN	O
-	O
related	O
GI	O
adverse	O
effects	O
were	O
applied	O
.	O

The	O
range	O
of	O
200	O
000	O
-	O
300	O
000	O
spermatozoa	O
/	O
microl	O
appeared	O
to	O
be	O
a	O
reasonable	O
compromise	O
for	O
both	O
criteria	O
.	O

Gastritis	O
score	O
was	O
significantly	O
lower	O
in	O
nod	O
-	O
/	O
CagA	B-GENE
-	O
children	O
than	O
in	O
nod	O
+	O
/	O
CagA	B-GENE
-	O
(	O
p	O
=	O
.	O
004	O
)	O
,	O
nod	O
-	O
/	O
CagA	B-GENE
+	O
(	O
p	O
=	O
.	O
002	O
)	O
and	O
nod	O
+	O
/	O
CagA	B-GENE
+	O
(	O
p	O
<	O
.	O
001	O
)	O
,	O
both	O
in	O
the	O
antrum	O
and	O
corpus	O
.	O

The	O
mean	O
thickness	O
of	O
the	O
visceral	O
peritoneum	O
was	O
comparable	O
in	O
both	O
groups	O
of	O
animals	O
,	O
but	O
,	O
macroscopically	O
,	O
more	O
severe	O
fibrosis	O
was	O
found	O
in	O
the	O
peritoneum	O
of	O
rats	O
exposed	O
to	O
CAPD	O
3	O
as	O
compared	O
with	O
animals	O
treated	O
with	O
CAPD	O
3	O
Balance	O
(	O
p	O
<	O
0	O
.	O
05	O
)	O
.	O

A	O
further	O
analysis	O
has	O
been	O
performed	O
using	O
the	O
series	O
of	O
maximum	O
intensity	O
for	O
fixed	O
duration	O
(	O
1	O
,	O
3	O
,	O
6	O
,	O
12	O
,	O
24	O
hrs	O
)	O
and	O
annual	O
daily	O
maxima	O
.	O

BACKGROUND	O
:	O
We	O
hypothesized	O
that	O
the	O
postoperative	O
serum	O
level	O
of	O
TA90	B-GENE
-	I-GENE
IC	I-GENE
,	O
an	O
immune	O
complex	O
of	O
a	O
90	O
-	O
kDa	O
tumor	O
-	O
associated	O
antigen	O
and	O
its	O
antibody	O
,	O
might	O
have	O
a	O
significant	O
correlation	O
with	O
recurrence	O
and	O
survival	O
in	O
patients	O
with	O
thick	O
primary	O
melanomas	O
.	O

Genetics	O
Institute	O
has	O
developed	O
and	O
launched	O
oprelvekin	B-GENE
(	O
rhIL	B-GENE
-	I-GENE
11	I-GENE
;	O
Neumega	O
)	O
,	O
a	O
recombinant	O
form	O
of	O
human	B-GENE
IL	I-GENE
-	I-GENE
11	I-GENE
.	O

Patients	O
subsequently	O
returned	O
to	O
the	O
clinic	O
every	O
3	O
days	O
to	O
have	O
the	O
wounds	O
checked	O
and	O
dressings	O
changed	O
.	O

Elements	O
that	O
are	O
fundamental	O
to	O
the	O
safety	O
evaluation	O
of	O
flavor	O
ingredients	O
include	O
exposure	O
,	O
structural	O
analogy	O
,	O
metabolism	O
,	O
pharmacokinetics	O
and	O
toxicology	O
.	O

The	O
mass	O
-	O
specific	O
resting	O
minute	O
ventilation	O
(	O
E	O
)	O
and	O
the	O
ventilatory	O
equivalent	O
(	O
VE	O
/	O
(	O
O	O
(	O
2	O
)	O
)	O
)	O
were	O
approximately	O
the	O
same	O
at	O
the	O
two	O
ages	O
,	O
with	O
a	O
breathing	O
pattern	O
significantly	O
deeper	O
and	O
slower	O
at	O
day	O
1	O
.	O

INTERPRETATION	O
:	O
It	O
is	O
probable	O
that	O
the	O
cognitive	O
dissonance	O
created	O
by	O
more	O
health	O
information	O
on	O
smoking	O
after	O
1964	O
,	O
i	O
.	O
e	O
.	O
the	O
necessary	O
motivation	O
to	O
quit	O
,	O
was	O
reduced	O
as	O
a	O
result	O
of	O
strategic	O
changes	O
in	O
the	O
amount	O
and	O
content	O
of	O
advertising	O
.	O

Nine	O
cases	O
of	O
GBS	O
and	O
five	O
of	O
TM	O
reported	O
to	O
the	O
active	O
AFP	O
surveillance	O
were	O
not	O
found	O
in	O
the	O
hospital	O
searches	O
.	O

The	O
ability	O
of	O
rats	O
with	O
control	O
or	O
hippocampal	O
lesions	O
to	O
learn	O
an	O
object	O
-	O
place	O
,	O
odor	O
-	O
place	O
,	O
or	O
object	O
-	O
odor	O
paired	O
-	O
associate	O
task	O
was	O
assessed	O
in	O
a	O
cheeseboard	O
maze	O
apparatus	O
.	O

The	O
shift	O
in	O
the	O
earliest	O
activation	O
site	O
after	O
administration	O
of	O
esmolol	O
was	O
compared	O
with	O
the	O
shift	O
after	O
RFA	O
.	O
RESULTS	O
:	O
The	O
heart	O
rate	O
at	O
rest	O
and	O
in	O
drug	O
-	O
free	O
state	O
ranged	O
between	O
95	O
and	O
125	O
beats	O
/	O
min	O
(	O
mean	O
99	O
+	O
/	O
-	O
14	O
beats	O
/	O
min	O
)	O
.	O

Urine	O
samples	O
collected	O
after	O
the	O
administration	O
of	O
these	O
supplements	O
can	O
test	O
positive	O
.	O

CONCLUSIONS	O
:	O
Lymphoscintigraphy	O
of	O
the	O
cynomolgus	O
monkey	O
eyelids	O
reveals	O
discrete	O
lymphatic	O
drainage	O
pathways	O
for	O
the	O
upper	O
and	O
lower	O
eyelids	O
and	O
a	O
dual	O
pathway	O
for	O
the	O
central	O
upper	O
eyelid	O
.	O

Data	O
management	O
in	O
practice	O
-	O
based	O
research	O
.	O

We	O
have	O
previously	O
reported	O
reduced	O
levels	O
of	O
choline	B-GENE
acetyltransferase	I-GENE
activity	O
in	O
the	O
cerebral	O
cortex	O
of	O
patients	O
who	O
died	O
after	O
a	O
head	O
injury	O
,	O
demonstrating	O
that	O
there	O
is	O
a	O
loss	O
of	O
cortical	O
cholinergic	O
innervation	O
.	O

After	O
taking	O
smears	O
from	O
lesions	O
of	O
the	O
oral	O
mucosa	O
(	O
tongue	O
,	O
cheeks	O
,	O
palate	O
)	O
and	O
the	O
contiguous	O
denture	O
surface	O
by	O
cotton	O
wool	O
swabs	O
and	O
inoculating	O
them	O
onto	O
Sabouraud	O
glucose	O
agar	O
and	O
CHROMagar	O
Candida	O
,	O
individual	O
yeast	O
species	O
were	O
identified	O
by	O
a	O
germ	O
tube	O
,	O
filamentous	O
,	O
and	O
assimilation	O
tests	O
employing	O
the	O
commercial	O
kit	O
AuxaColor	O
.	O

The	O
effects	O
of	O
pharmacological	O
treatment	O
and	O
professional	O
care	O
and	O
support	O
may	O
improve	O
when	O
dementia	O
is	O
detected	O
in	O
an	O
early	O
stage	O
.	O

Sexually	O
conditioned	O
incentives	O
:	O
attenuation	O
of	O
motivational	O
impact	O
during	O
dopamine	B-GENE
receptor	I-GENE
antagonism	O
.	O

PATIENTS	O
AND	O
METHODS	O
:	O
This	O
study	O
is	O
a	O
retrospective	O
cohort	O
study	O
of	O
all	O
children	O
with	O
cancer	O
admitted	O
to	O
a	O
single	O
institution	O
with	O
fever	O
and	O
neutropenia	O
(	O
defined	O
as	O
an	O
absolute	O
neutrophil	O
count	O
<	O
500	O
cells	O
/	O
mm3	O
)	O
in	O
a	O
1	O
-	O
year	O
period	O
.	O

Concentrations	O
of	O
N	O
(	O
O3	O
-	O
)	O
-	O
N	O
and	O
N	O
(	O
H3	O
-	O
)	O
-	O
N	O
at	O
Deoprayag	O
varied	O
from	O
0	O
.	O
30	O
to	O
0	O
.	O
50	O
and	O
0	O
.	O
02	O
to	O
0	O
.	O
12	O
mg	O
/	O
L	O
,	O
respectively	O
,	O
depending	O
on	O
season	O
.	O

Steal	O
is	O
a	O
pathophysiological	O
process	O
in	O
which	O
increased	O
blood	O
flow	O
through	O
a	O
low	O
-	O
resistance	O
vascular	O
bed	O
is	O
sufficient	O
to	O
divert	O
flow	O
away	O
from	O
a	O
region	O
of	O
the	O
central	O
nervous	O
system	O
.	O

The	O
orientations	O
of	O
the	O
contact	O
surfaces	O
and	O
their	O
locations	O
relative	O
to	O
the	O
object	O
'	O
s	O
center	O
of	O
mass	O
were	O
varied	O
.	O

The	O
results	O
are	O
given	O
as	O
:	O
flux	O
,	O
number	O
of	O
stars	O
per	O
cm3	O
,	O
charge	O
of	O
the	O
ions	O
,	O
comparison	O
with	O
other	O
detectors	O
(	O
plastics	O
,	O
AgCl	O
crystals	O
,	O
LiF	O
)	O
,	O
energy	O
loss	O
,	O
hit	O
region	O
in	O
the	O
biological	O
objects	O
.	O

Nodal	O
domains	O
are	O
regions	O
where	O
a	O
function	O
has	O
definite	O
sign	O
.	O

DESIGN	O
:	O
Prospective	O
,	O
randomized	O
,	O
double	O
-	O
blind	O
,	O
controlled	O
trial	O
.	O

CONCLUSIONS	O
:	O
This	O
retrospective	O
uncontrolled	O
study	O
shows	O
that	O
in	O
patients	O
with	O
type	O
1	O
HRS	O
,	O
terlipressin	O
-	O
induced	O
improved	O
renal	O
function	O
is	O
associated	O
with	O
an	O
increase	O
in	O
survival	O
.	O

Calcimimetic	O
agents	O
directly	O
inhibit	O
PTH	B-GENE
secretion	O
by	O
activating	O
the	O
calcium	O
-	O
sensing	O
receptor	O
in	O
the	O
parathyroid	O
glands	O
,	O
but	O
clinical	O
experience	O
with	O
them	O
is	O
limited	O
.	O

The	O
subjects	O
were	O
shown	O
to	O
be	O
capable	O
of	O
assessing	O
integrally	O
the	O
value	O
of	O
accelerations	O
and	O
estimating	O
it	O
with	O
an	O
error	O
of	O
0	O
.	O
1	O
-	O
0	O
.	O
12	O
g	O
.	O

The	O
observed	O
incidence	O
rates	O
were	O
compared	O
to	O
expected	O
rates	O
in	O
the	O
general	O
population	O
.	O

The	O
only	O
predictor	O
of	O
response	O
to	O
tacrolimus	O
was	O
a	O
previous	O
response	O
to	O
cyclosporin	O
and	O
prednisone	O
,	O
either	O
as	O
a	O
complete	O
or	O
partial	O
remission	O
(	O
remission	O
rate	O
75	O
%	O
vs	O
15	O
.	O
3	O
;	O
P	O
=	O
0	O
.	O
036	O
)	O
.	O

Based	O
on	O
a	O
morphological	O
study	O
of	O
the	O
resin	O
-	O
dentine	O
interface	O
,	O
a	O
broad	O
selection	O
of	O
dentine	O
adhesive	O
systems	O
was	O
classified	O
following	O
their	O
adhesion	O
-	O
strategy	O
.	O

Copyright	O
2002	O
American	O
Cancer	O
Society	O
.	O
DOI	O
10	O
.	O
1002	O
/	O
cncr	O
.	O
10318	O

As	O
measured	O
by	O
the	O
PDQ	O
-	O
39	O
,	O
STN	O
-	O
DBS	O
significantly	O
improves	O
important	O
aspects	O
of	O
QoL	O
in	O
patients	O
with	O
advanced	O
PD	O
.	O

Selegiline	B-Chemical
-	O
induced	O
postural	B-Disease
hypotension	I-Disease
in	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
:	O
a	O
longitudinal	O
study	O
on	O
the	O
effects	O
of	O
drug	O
withdrawal	O
.	O

OBJECTIVES	O
:	O
The	O
United	O
Kingdom	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
Disease	I-Disease
Research	O
Group	O
(	O
UKPDRG	O
)	O
trial	O
found	O
an	O
increased	O
mortality	O
in	O
patients	O
with	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
(	O
PD	B-Disease
)	O
randomized	O
to	O
receive	O
10	O
mg	O
selegiline	B-Chemical
per	O
day	O
and	O
L	B-Chemical
-	I-Chemical
dopa	I-Chemical
compared	O
with	O
those	O
taking	O
L	B-Chemical
-	I-Chemical
dopa	I-Chemical
alone	O
.	O

Recently	O
,	O
we	O
found	O
that	O
therapy	O
with	O
selegiline	B-Chemical
and	O
L	B-Chemical
-	I-Chemical
dopa	I-Chemical
was	O
associated	O
with	O
selective	O
systolic	B-Disease
orthostatic	I-Disease
hypotension	I-Disease
which	O
was	O
abolished	O
by	O
withdrawal	O
of	O
selegiline	B-Chemical
.	O

This	O
unwanted	O
effect	O
on	O
postural	O
blood	O
pressure	O
was	O
not	O
the	O
result	O
of	O
underlying	O
autonomic	O
failure	O
.	O

The	O
aims	O
of	O
this	O
study	O
were	O
to	O
confirm	O
our	O
previous	O
findings	O
in	O
a	O
separate	O
cohort	O
of	O
patients	O
and	O
to	O
determine	O
the	O
time	O
course	O
of	O
the	O
cardiovascular	O
consequences	O
of	O
stopping	O
selegiline	B-Chemical
in	O
the	O
expectation	O
that	O
this	O
might	O
shed	O
light	O
on	O
the	O
mechanisms	O
by	O
which	O
the	O
drug	O
causes	O
orthostatic	B-Disease
hypotension	I-Disease
.	O

METHODS	O
:	O
The	O
cardiovascular	O
responses	O
to	O
standing	O
and	O
head	O
-	O
up	O
tilt	O
were	O
studied	O
repeatedly	O
in	O
PD	B-Disease
patients	O
receiving	O
selegiline	B-Chemical
and	O
as	O
the	O
drug	O
was	O
withdrawn	O
.	O

RESULTS	O
:	O
Head	O
-	O
up	O
tilt	O
caused	O
systolic	B-Disease
orthostatic	I-Disease
hypotension	I-Disease
which	O
was	O
marked	O
in	O
six	O
of	O
20	O
PD	B-Disease
patients	O
on	O
selegiline	B-Chemical
,	O
one	O
of	O
whom	O
lost	O
consciousness	O
with	O
unrecordable	O
blood	O
pressures	O
.	O

A	O
lesser	O
degree	O
of	O
orthostatic	B-Disease
hypotension	I-Disease
occurred	O
with	O
standing	O
.	O

Orthostatic	B-Disease
hypotension	I-Disease
was	O
ameliorated	O
4	O
days	O
after	O
withdrawal	O
of	O
selegiline	B-Chemical
and	O
totally	O
abolished	O
7	O
days	O
after	O
discontinuation	O
of	O
the	O
drug	O
.	O

Stopping	O
selegiline	B-Chemical
also	O
significantly	O
reduced	B-Disease
the	I-Disease
supine	I-Disease
systolic	I-Disease
and	I-Disease
diastolic	I-Disease
blood	I-Disease
pressures	I-Disease
consistent	O
with	O
a	O
previously	O
undescribed	O
supine	O
pressor	O
action	O
.	O

CONCLUSION	O
:	O
This	O
study	O
confirms	O
our	O
previous	O
finding	O
that	O
selegiline	B-Chemical
in	O
combination	O
with	O
L	B-Chemical
-	I-Chemical
dopa	I-Chemical
is	O
associated	O
with	O
selective	O
orthostatic	B-Disease
hypotension	I-Disease
.	O

The	O
possibilities	O
that	O
these	O
cardiovascular	O
findings	O
might	O
be	O
the	O
result	O
of	O
non	O
-	O
selective	O
inhibition	O
of	O
monoamine	O
oxidase	O
or	O
of	O
amphetamine	B-Chemical
and	O
metamphetamine	B-Chemical
are	O
discussed	O
.	O

Further	O
studies	O
on	O
effects	O
of	O
irrigation	O
solutions	O
on	O
rat	O
bladders	O
.	O

Further	O
studies	O
on	O
the	O
effects	O
of	O
certain	O
irrigating	O
fluids	O
on	O
the	O
rat	O
bladder	O
for	O
18	O
hours	O
are	O
reported	O
.	O

The	O
results	O
have	O
shown	O
that	O
the	O
degradation	O
product	O
p	B-Chemical
-	I-Chemical
choloroaniline	I-Chemical
is	O
not	O
a	O
significant	O
factor	O
in	O
chlorhexidine	B-Chemical
-	I-Chemical
digluconate	I-Chemical
associated	O
erosive	O
cystitis	B-Disease
.	O

A	O
high	O
percentage	O
of	O
kanamycin	B-Chemical
-	O
colistin	B-Chemical
and	O
povidone	B-Chemical
-	I-Chemical
iodine	I-Chemical
irrigations	O
were	O
associated	O
with	O
erosive	O
cystitis	B-Disease
and	O
suggested	O
a	O
possible	O
complication	O
with	O
human	O
usage	O
.	O

Picloxydine	B-Chemical
irrigations	O
appeared	O
to	O
have	O
a	O
lower	O
incidence	O
of	O
erosive	O
cystitis	B-Disease
but	O
further	O
studies	O
would	O
have	O
to	O
be	O
performed	O
before	O
it	O
could	O
be	O
recommended	O
for	O
use	O
in	O
urological	O
procedures	O
.	O

Effects	O
of	O
tetrandrine	B-Chemical
and	O
fangchinoline	B-Chemical
on	O
experimental	O
thrombosis	B-Disease
in	O
mice	O
and	O
human	O
platelet	B-Disease
aggregation	I-Disease
.	O

Tetrandrine	B-Chemical
(	O
TET	B-Chemical
)	O
and	O
fangchinoline	B-Chemical
(	O
FAN	B-Chemical
)	O
are	O
two	O
naturally	O
occurring	O
analogues	O
with	O
a	O
bisbenzylisoquinoline	B-Chemical
structure	O
.	O

The	O
present	O
study	O
was	O
undertaken	O
to	O
investigate	O
the	O
effects	O
of	O
TET	B-Chemical
and	O
FAN	B-Chemical
on	O
the	O
experimental	O
thrombosis	B-Disease
induced	O
by	O
collagen	O
plus	O
epinephrine	B-Chemical
(	O
EP	B-Chemical
)	O
in	O
mice	O
,	O
and	O
platelet	B-Disease
aggregation	I-Disease
and	O
blood	B-Disease
coagulation	I-Disease
in	O
vitro	O
.	O

In	O
the	O
in	O
vivo	O
study	O
,	O
the	O
administration	O
(	O
50	O
mg	O
/	O
kg	O
,	O
i	O
.	O
p	O
.	O
)	O
of	O
TET	B-Chemical
and	O
FAN	B-Chemical
in	O
mice	O
showed	O
the	O
inhibition	O
of	O
thrombosis	B-Disease
by	O
55	O
%	O
and	O
35	O
%	O
,	O
respectively	O
,	O
while	O
acetylsalicylic	B-Chemical
acid	I-Chemical
(	O
ASA	B-Chemical
,	O
50	O
mg	O
/	O
kg	O
,	O
i	O
.	O
p	O
.	O
)	O
,	O
a	O
positive	O
control	O
,	O
showed	O
only	O
30	O
%	O
inhibition	O
.	O

In	O
the	O
vitro	O
human	O
platelet	B-Disease
aggregations	I-Disease
induced	O
by	O
the	O
agonists	O
used	O
in	O
tests	O
,	O
TET	B-Chemical
and	O
FAN	B-Chemical
showed	O
the	O
inhibitions	O
dose	O
dependently	O
.	O

In	O
addition	O
,	O
neither	O
TET	B-Chemical
nor	O
FAN	B-Chemical
showed	O
any	O
anticoagulation	O
activities	O
in	O
the	O
measurement	O
of	O
the	O
activated	O
partial	O
thromboplastin	O
time	O
(	O
APTT	O
)	O
,	O
prothrombin	O
time	O
(	O
PT	O
)	O
and	O
thrombin	O
time	O
(	O
TT	O
)	O
using	O
human	O
-	O
citrated	O
plasma	O
.	O

These	O
results	O
suggest	O
that	O
antithrombosis	O
of	O
TET	B-Chemical
and	O
FAN	B-Chemical
in	O
mice	O
may	O
be	O
mainly	O
related	O
to	O
the	O
antiplatelet	O
aggregation	O
activities	O
.	O

Angioedema	B-Disease
due	O
to	O
ACE	B-Chemical
inhibitors	I-Chemical
:	O
common	O
and	O
inadequately	O
diagnosed	O
.	O

The	O
estimated	O
incidence	O
of	O
angioedema	B-Disease
during	O
angiotensin	B-Chemical
-	I-Chemical
converting	I-Chemical
enzyme	I-Chemical
(	I-Chemical
ACE	I-Chemical
)	I-Chemical
inhibitor	I-Chemical
treatment	O
is	O
between	O
1	O
and	O
7	O
per	O
thousand	O
patients	O
.	O

This	O
potentially	O
serious	O
adverse	O
effect	O
is	O
often	O
preceded	O
by	O
minor	O
manifestations	O
that	O
may	O
serve	O
as	O
a	O
warning	O
.	O

Cocaine	B-Chemical
-	O
induced	O
mood	B-Disease
disorder	I-Disease
:	O
prevalence	O
rates	O
and	O
psychiatric	B-Disease
symptoms	O
in	O
an	O
outpatient	O
cocaine	B-Chemical
-	O
dependent	O
sample	O
.	O

This	O
paper	O
attempts	O
to	O
examine	O
and	O
compare	O
prevalence	O
rates	O
and	O
symptom	O
patterns	O
of	O
DSM	O
substance	O
-	O
induced	O
and	O
other	O
mood	B-Disease
disorders	I-Disease
.	O

243	O
cocaine	B-Chemical
-	O
dependent	O
outpatients	O
with	O
cocaine	B-Chemical
-	O
induced	O
mood	B-Disease
disorder	I-Disease
(	O
CIMD	B-Disease
)	O
,	O
other	O
mood	B-Disease
disorders	I-Disease
,	O
or	O
no	O
mood	B-Disease
disorder	I-Disease
were	O
compared	O
on	O
measures	O
of	O
psychiatric	B-Disease
symptoms	O
.	O

The	O
prevalence	O
rate	O
for	O
CIMD	B-Disease
was	O
12	O
%	O
at	O
baseline	O
.	O

Introduction	O
of	O
the	O
DSM	O
-	O
IV	O
diagnosis	O
of	O
CIMD	B-Disease
did	O
not	O
substantially	O
affect	O
rates	O
of	O
the	O
other	O
depressive	B-Disease
disorders	I-Disease
.	O

Patients	O
with	O
CIMD	B-Disease
had	O
symptom	O
severity	O
levels	O
between	O
those	O
of	O
patients	O
with	O
and	O
without	O
a	O
mood	B-Disease
disorder	I-Disease
.	O

These	O
findings	O
suggest	O
some	O
validity	O
for	O
the	O
new	O
DSM	O
-	O
IV	O
diagnosis	O
of	O
CIMD	B-Disease
,	O
but	O
also	O
suggest	O
that	O
it	O
requires	O
further	O
specification	O
and	O
replication	O
.	O

Effect	O
of	O
fucoidan	B-Chemical
treatment	O
on	O
collagenase	O
-	O
induced	O
intracerebral	B-Disease
hemorrhage	I-Disease
in	O
rats	O
.	O

Inflammatory	O
cells	O
are	O
postulated	O
to	O
mediate	O
some	O
of	O
the	O
brain	B-Disease
damage	I-Disease
following	O
ischemic	B-Disease
stroke	I-Disease
.	O

Intracerebral	B-Disease
hemorrhage	I-Disease
is	O
associated	O
with	O
more	O
inflammation	B-Disease
than	O
ischemic	B-Disease
stroke	I-Disease
.	O

We	O
tested	O
the	O
sulfated	O
polysaccharide	O
fucoidan	B-Chemical
,	O
which	O
has	O
been	O
reported	O
to	O
reduce	O
inflammatory	O
brain	B-Disease
damage	I-Disease
,	O
in	O
a	O
rat	O
model	O
of	O
intracerebral	B-Disease
hemorrhage	I-Disease
induced	O
by	O
injection	O
of	O
bacterial	O
collagenase	O
into	O
the	O
caudate	O
nucleus	O
.	O

Rats	O
were	O
treated	O
with	O
seven	O
day	O
intravenous	O
infusion	O
of	O
fucoidan	B-Chemical
(	O
30	O
micrograms	O
h	O
-	O
1	O
)	O
or	O
vehicle	O
.	O

The	O
hematoma	B-Disease
was	O
assessed	O
in	O
vivo	O
by	O
magnetic	O
resonance	O
imaging	O
.	O

Motor	O
behavior	O
,	O
passive	O
avoidance	O
,	O
and	O
skilled	O
forelimb	O
function	O
were	O
tested	O
repeatedly	O
for	O
six	O
weeks	O
.	O

Fucoidan	B-Chemical
-	O
treated	O
rats	O
exhibited	O
evidence	O
of	O
impaired	B-Disease
blood	I-Disease
clotting	I-Disease
and	O
hemodilution	B-Disease
,	O
had	O
larger	O
hematomas	B-Disease
,	O
and	O
tended	O
to	O
have	O
less	O
inflammation	B-Disease
in	O
the	O
vicinity	O
of	O
the	O
hematoma	B-Disease
after	O
three	O
days	O
.	O

They	O
showed	O
significantly	O
more	O
rapid	O
improvement	O
of	O
motor	O
function	O
in	O
the	O
first	O
week	O
following	O
hemorrhage	B-Disease
and	O
better	O
memory	O
retention	O
in	O
the	O
passive	O
avoidance	O
test	O
.	O

Acute	O
white	B-Disease
matter	I-Disease
edema	I-Disease
and	O
eventual	O
neuronal	B-Disease
loss	I-Disease
in	O
the	O
striatum	O
adjacent	O
to	O
the	O
hematoma	B-Disease
did	O
not	O
differ	O
between	O
the	O
two	O
groups	O
.	O

Investigation	O
of	O
more	O
specific	O
anti	O
-	O
inflammatory	O
agents	O
and	O
hemodiluting	O
agents	O
are	O
warranted	O
in	O
intracerebral	B-Disease
hemorrhage	I-Disease
.	O

Recurarization	O
in	O
the	O
recovery	O
room	O
.	O

A	O
case	O
of	O
recurarization	O
in	O
the	O
recovery	O
room	O
is	O
reported	O
.	O

Accumulation	O
of	O
atracurium	B-Chemical
in	O
the	O
intravenous	O
line	O
led	O
to	O
recurarization	O
after	O
flushing	O
the	O
line	O
in	O
the	O
recovery	O
room	O
.	O

A	O
respiratory	B-Disease
arrest	I-Disease
with	O
severe	O
desaturation	B-Disease
and	O
bradycardia	B-Disease
occurred	O
.	O

Circumstances	O
leading	O
to	O
this	O
event	O
and	O
the	O
mechanisms	O
enabling	O
a	O
neuromuscular	B-Disease
blockade	I-Disease
to	O
occur	O
,	O
following	O
the	O
administration	O
of	O
a	O
small	O
dose	O
of	O
relaxant	O
,	O
are	O
discussed	O
.	O

The	O
haemodynamic	O
effects	O
of	O
propofol	B-Chemical
in	O
combination	O
with	O
ephedrine	B-Chemical
in	O
elderly	O
patients	O
(	O
ASA	O
groups	O
3	O
and	O
4	O
)	O
.	O

The	O
marked	O
vasodilator	O
and	O
negative	O
inotropic	O
effects	O
of	O
propofol	B-Chemical
are	O
disadvantages	O
in	O
frail	O
elderly	O
patients	O
.	O

We	O
investigated	O
the	O
safety	O
and	O
efficacy	O
of	O
adding	O
different	O
doses	O
of	O
ephedrine	B-Chemical
to	O
propofol	B-Chemical
in	O
order	O
to	O
obtund	O
the	O
hypotensive	B-Disease
response	O
.	O

The	O
haemodynamic	O
effects	O
of	O
adding	O
15	O
,	O
20	O
or	O
25	O
mg	O
of	O
ephedrine	B-Chemical
to	O
200	O
mg	O
of	O
propofol	B-Chemical
were	O
compared	O
to	O
control	O
in	O
40	O
ASA	O
3	O
/	O
4	O
patients	O
over	O
60	O
years	O
presenting	O
for	O
genito	O
-	O
urinary	O
surgery	O
.	O

The	O
addition	O
of	O
ephedrine	B-Chemical
to	O
propofol	B-Chemical
appears	O
to	O
be	O
an	O
effective	O
method	O
of	O
obtunding	O
the	O
hypotensive	B-Disease
response	O
to	O
propofol	B-Chemical
at	O
all	O
doses	O
used	O
in	O
this	O
study	O
.	O

However	O
,	O
marked	O
tachycardia	B-Disease
associated	O
with	O
the	O
use	O
of	O
ephedrine	B-Chemical
in	O
combination	O
with	O
propofol	B-Chemical
occurred	O
in	O
the	O
majority	O
of	O
patients	O
,	O
occasionally	O
reaching	O
high	O
levels	O
in	O
individual	O
patients	O
.	O

Due	O
to	O
the	O
risk	O
of	O
this	O
tachycardia	B-Disease
inducing	O
myocardial	B-Disease
ischemia	I-Disease
,	O
we	O
would	O
not	O
recommend	O
the	O
use	O
in	O
elderly	O
patients	O
of	O
any	O
of	O
the	O
ephedrine	B-Chemical
/	O
propofol	B-Chemical
/	O
mixtures	O
studied	O
.	O

Gemcitabine	B-Chemical
plus	O
vinorelbine	B-Chemical
in	O
nonsmall	B-Disease
cell	I-Disease
lung	I-Disease
carcinoma	I-Disease
patients	O
age	O
70	O
years	O
or	O
older	O
or	O
patients	O
who	O
cannot	O
receive	O
cisplatin	B-Chemical
.	O

Oncopaz	O
Cooperative	O
Group	O
.	O

BACKGROUND	O
:	O
Although	O
the	O
prevalence	O
of	O
nonsmall	B-Disease
cell	I-Disease
lung	I-Disease
carcinoma	I-Disease
(	O
NSCLC	B-Disease
)	O
is	O
high	O
among	O
elderly	O
patients	O
,	O
few	O
data	O
are	O
available	O
regarding	O
the	O
efficacy	O
and	O
toxicity	B-Disease
of	O
chemotherapy	O
in	O
this	O
group	O
of	O
patients	O
.	O

Recent	O
reports	O
indicate	O
that	O
single	O
agent	O
therapy	O
with	O
vinorelbine	B-Chemical
(	O
VNB	B-Chemical
)	O
or	O
gemcitabine	B-Chemical
(	O
GEM	B-Chemical
)	O
may	O
obtain	O
a	O
response	O
rate	O
of	O
20	O
-	O
30	O
%	O
in	O
elderly	O
patients	O
,	O
with	O
acceptable	O
toxicity	B-Disease
and	O
improvement	O
in	O
symptoms	O
and	O
quality	O
of	O
life	O
.	O

In	O
the	O
current	O
study	O
the	O
efficacy	O
and	O
toxicity	B-Disease
of	O
the	O
combination	O
of	O
GEM	B-Chemical
and	O
VNB	B-Chemical
in	O
elderly	O
patients	O
with	O
advanced	O
NSCLC	B-Disease
or	O
those	O
with	O
some	O
contraindication	O
to	O
receiving	O
cisplatin	B-Chemical
were	O
assessed	O
.	O

METHODS	O
:	O
Forty	O
-	O
nine	O
patients	O
with	O
advanced	O
NSCLC	B-Disease
were	O
included	O
,	O
38	O
of	O
whom	O
were	O
age	O
>	O
/	O
=	O
70	O
years	O
and	O
11	O
were	O
age	O
<	O
70	O
years	O
but	O
who	O
had	O
some	O
contraindication	O
to	O
receiving	O
cisplatin	B-Chemical
.	O

All	O
patients	O
were	O
evaluable	O
for	O
response	O
and	O
toxicity	B-Disease
.	O

Treatment	O
was	O
comprised	O
of	O
VNB	B-Chemical
,	O
25	O
mg	O
/	O
m	O
(	O
2	O
)	O
,	O
plus	O
GEM	B-Chemical
,	O
1000	O
mg	O
/	O
m	O
(	O
2	O
)	O
,	O
both	O
on	O
Days	O
1	O
,	O
8	O
,	O
and	O
15	O
every	O
28	O
days	O
.	O

Patients	O
received	O
a	O
minimum	O
of	O
three	O
courses	O
unless	O
progressive	O
disease	O
was	O
detected	O
.	O

RESULTS	O
:	O
One	O
hundred	O
sixty	O
-	O
five	O
courses	O
were	O
administered	O
,	O
with	O
a	O
median	O
of	O
3	O
.	O

6	O
courses	O
per	O
patient	O
.	O

The	O
overall	O
response	O
rate	O
was	O
26	O
%	O
(	O
95	O
%	O
confidence	O
interval	O
,	O
15	O
-	O
41	O
%	O
)	O
.	O

Two	O
patients	O
attained	O
a	O
complete	O
response	O
(	O
4	O
%	O
)	O
and	O
11	O
patients	O
(	O
22	O
%	O
)	O
achieved	O
a	O
partial	O
response	O
.	O

Eastern	O
Cooperative	O
Oncology	O
Group	O
performance	O
status	O
improved	O
in	O
35	O
%	O
of	O
those	O
patients	O
with	O
an	O
initial	O
value	O
>	O
0	O
,	O
whereas	O
relief	O
of	O
at	O
least	O
1	O
symptom	O
without	O
worsening	O
of	O
other	O
symptoms	O
was	O
noted	O
in	O
27	O
patients	O
(	O
55	O
%	O
)	O
.	O

The	O
median	O
time	O
to	O
progression	O
was	O
16	O
weeks	O
and	O
the	O
1	O
-	O
year	O
survival	O
rate	O
was	O
33	O
%	O
.	O

Toxicity	B-Disease
was	O
mild	O
.	O

Six	O
patients	O
(	O
12	O
%	O
)	O
had	O
World	O
Health	O
Organization	O
Grade	O
3	O
-	O
4	O
neutropenia	B-Disease
,	O
2	O
patients	O
(	O
4	O
%	O
)	O
had	O
Grade	O
3	O
-	O
4	O
thrombocytopenia	B-Disease
,	O
and	O
2	O
patients	O
(	O
4	O
%	O
)	O
had	O
Grade	O
3	O
neurotoxicity	B-Disease
.	O

Three	O
patients	O
with	O
severe	O
neutropenia	B-Disease
(	O
6	O
%	O
)	O
died	O
of	O
sepsis	B-Disease
.	O

The	O
median	O
age	O
of	O
those	O
patients	O
developing	O
Grade	O
3	O
-	O
4	O
neutropenia	B-Disease
was	O
significantly	O
higher	O
than	O
that	O
of	O
the	O
remaining	O
patients	O
(	O
75	O
years	O
vs	O
.	O
72	O
years	O
;	O
P	O
=	O
0	O
.	O
047	O
)	O
.	O

CONCLUSIONS	O
:	O
The	O
combination	O
of	O
GEM	B-Chemical
and	O
VNB	B-Chemical
is	O
moderately	O
active	O
and	O
well	O
tolerated	O
except	O
in	O
patients	O
age	O
>	O
/	O
=	O
75	O
years	O
.	O

This	O
age	O
group	O
had	O
an	O
increased	O
risk	O
of	O
myelosuppression	B-Disease
.	O

Therefore	O
the	O
prophylactic	O
use	O
of	O
granulocyte	O
-	O
colony	O
stimulating	O
factor	O
should	O
be	O
considered	O
with	O
this	O
treatment	O
.	O

New	O
chemotherapy	O
combinations	O
with	O
higher	O
activity	O
and	O
lower	O
toxicity	B-Disease
are	O
needed	O
for	O
elderly	O
patients	O
with	O
advanced	O
NSCLC	B-Disease
.	O

A	O
selective	O
dopamine	B-Chemical
D4	O
receptor	O
antagonist	O
,	O
NRA0160	B-Chemical
:	O
a	O
preclinical	O
neuropharmacological	O
profile	O
.	O

NRA0160	B-Chemical
,	O
5	B-Chemical
-	I-Chemical
[	I-Chemical
2	I-Chemical
-	I-Chemical
(	I-Chemical
4	I-Chemical
-	I-Chemical
(	I-Chemical
3	I-Chemical
-	I-Chemical
fluorobenzylidene	I-Chemical
)	I-Chemical
piperidin	I-Chemical
-	I-Chemical
1	I-Chemical
-	I-Chemical
yl	I-Chemical
)	I-Chemical
ethyl	I-Chemical
]	I-Chemical
-	I-Chemical
4	I-Chemical
-	I-Chemical
(	I-Chemical
4	I-Chemical
-	I-Chemical
fluorophenyl	I-Chemical
)	I-Chemical
thiazole	I-Chemical
-	I-Chemical
2	I-Chemical
-	I-Chemical
carboxamide	I-Chemical
,	O
has	O
a	O
high	O
affinity	O
for	O
human	O
cloned	O
dopamine	B-Chemical
D4	O
.	O
2	O
,	O
D4	O
.	O
4	O
and	O
D4	O
.	O
7	O
receptors	O
,	O
with	O
Ki	O
values	O
of	O
0	O
.	O
5	O
,	O
0	O
.	O
9	O
and	O
2	O
.	O
7	O
nM	O
,	O
respectively	O
.	O

NRA0160	B-Chemical
is	O
over	O
20	O
,	O
000fold	O
more	O
potent	O
at	O
the	O
dopamine	B-Chemical
D4	O
.	O
2	O
receptor	O
compared	O
with	O
the	O
human	O
cloned	O
dopamine	B-Chemical
D2L	O
receptor	O
.	O

NRA0160	B-Chemical
has	O
negligible	O
affinity	O
for	O
the	O
human	O
cloned	O
dopamine	B-Chemical
D3	O
receptor	O
(	O
Ki	O
=	O
39	O
nM	O
)	O
,	O
rat	O
serotonin	B-Chemical
(	O
5	B-Chemical
-	I-Chemical
HT	I-Chemical
)	O
2A	O
receptors	O
(	O
Ki	O
=	O
180	O
nM	O
)	O
and	O
rat	O
alpha1	O
adrenoceptor	O
(	O
Ki	O
=	O
237	O
nM	O
)	O
.	O

NRA0160	B-Chemical
and	O
clozapine	B-Chemical
antagonized	O
locomotor	O
hyperactivity	B-Disease
induced	O
by	O
methamphetamine	B-Chemical
(	O
MAP	B-Chemical
)	O
in	O
mice	O
.	O

NRA0160	B-Chemical
and	O
clozapine	B-Chemical
antagonized	O
MAP	B-Chemical
-	O
induced	O
stereotyped	O
behavior	O
in	O
mice	O
,	O
although	O
their	O
effects	O
did	O
not	O
exceed	O
50	O
%	O
inhibition	O
,	O
even	O
at	O
the	O
highest	O
dose	O
given	O
.	O

NRA0160	B-Chemical
and	O
clozapine	B-Chemical
significantly	O
induced	O
catalepsy	B-Disease
in	O
rats	O
,	O
although	O
their	O
effects	O
did	O
not	O
exceed	O
50	O
%	O
induction	O
even	O
at	O
the	O
highest	O
dose	O
given	O
.	O

NRA0160	B-Chemical
and	O
clozapine	B-Chemical
significantly	O
reversed	O
the	O
disruption	O
of	O
prepulse	O
inhibition	O
(	O
PPI	O
)	O
in	O
rats	O
produced	O
by	O
apomorphine	B-Chemical
.	O

NRA0160	B-Chemical
and	O
clozapine	B-Chemical
significantly	O
shortened	O
the	O
phencyclidine	B-Chemical
(	O
PCP	B-Chemical
)	O
-	O
induced	O
prolonged	O
swimming	O
latency	O
in	O
rats	O
in	O
a	O
water	O
maze	O
task	O
.	O

These	O
findings	O
suggest	O
that	O
NRA0160	B-Chemical
may	O
have	O
unique	O
antipsychotic	O
activities	O
without	O
the	O
liability	O
of	O
motor	O
side	O
effects	O
typical	O
of	O
classical	O
antipsychotics	O
.	O

Warfarin	B-Chemical
-	O
induced	O
artery	B-Disease
calcification	I-Disease
is	O
accelerated	O
by	O
growth	O
and	O
vitamin	B-Chemical
D	I-Chemical
.	O

The	O
present	O
studies	O
demonstrate	O
that	O
growth	O
and	O
vitamin	B-Chemical
D	I-Chemical
treatment	O
enhance	O
the	O
extent	O
of	O
artery	B-Disease
calcification	I-Disease
in	O
rats	O
given	O
sufficient	O
doses	O
of	O
Warfarin	B-Chemical
to	O
inhibit	O
gamma	O
-	O
carboxylation	O
of	O
matrix	O
Gla	O
protein	O
,	O
a	O
calcification	B-Disease
inhibitor	O
known	O
to	O
be	O
expressed	O
by	O
smooth	O
muscle	O
cells	O
and	O
macrophages	O
in	O
the	O
artery	O
wall	O
.	O

The	O
first	O
series	O
of	O
experiments	O
examined	O
the	O
influence	O
of	O
age	O
and	O
growth	O
status	O
on	O
artery	B-Disease
calcification	I-Disease
in	O
Warfarin	B-Chemical
-	O
treated	O
rats	O
.	O

Treatment	O
for	O
2	O
weeks	O
with	O
Warfarin	B-Chemical
caused	O
massive	O
focal	O
calcification	B-Disease
of	I-Disease
the	I-Disease
artery	I-Disease
media	O
in	O
20	O
-	O
day	O
-	O
old	O
rats	O
and	O
less	O
extensive	O
focal	O
calcification	B-Disease
in	O
42	O
-	O
day	O
-	O
old	O
rats	O
.	O

In	O
contrast	O
,	O
no	O
artery	B-Disease
calcification	I-Disease
could	O
be	O
detected	O
in	O
10	O
-	O
month	O
-	O
old	O
adult	O
rats	O
even	O
after	O
4	O
weeks	O
of	O
Warfarin	B-Chemical
treatment	O
.	O

To	O
directly	O
examine	O
the	O
importance	O
of	O
growth	O
to	O
Warfarin	B-Chemical
-	O
induced	O
artery	B-Disease
calcification	I-Disease
in	O
animals	O
of	O
the	O
same	O
age	O
,	O
20	O
-	O
day	O
-	O
old	O
rats	O
were	O
fed	O
for	O
2	O
weeks	O
either	O
an	O
ad	O
libitum	O
diet	O
or	O
a	O
6	O
-	O
g	O
/	O
d	O
restricted	O
diet	O
that	O
maintains	O
weight	O
but	O
prevents	O
growth	O
.	O

Concurrent	O
treatment	O
of	O
both	O
dietary	O
groups	O
with	O
Warfarin	B-Chemical
produced	O
massive	O
focal	O
calcification	B-Disease
of	I-Disease
the	I-Disease
artery	I-Disease
media	O
in	O
the	O
ad	O
libitum	O
-	O
fed	O
rats	O
but	O
no	O
detectable	O
artery	B-Disease
calcification	I-Disease
in	O
the	O
restricted	O
-	O
diet	O
,	O
growth	O
-	O
inhibited	O
group	O
.	O

Although	O
the	O
explanation	O
for	O
the	O
association	O
between	O
artery	B-Disease
calcification	I-Disease
and	O
growth	O
status	O
cannot	O
be	O
determined	O
from	O
the	O
present	O
study	O
,	O
there	O
was	O
a	O
relationship	O
between	O
higher	O
serum	O
phosphate	B-Chemical
and	O
susceptibility	O
to	O
artery	B-Disease
calcification	I-Disease
,	O
with	O
30	O
%	O
higher	O
levels	O
of	O
serum	O
phosphate	B-Chemical
in	O
young	O
,	O
ad	O
libitum	O
-	O
fed	O
rats	O
compared	O
with	O
either	O
of	O
the	O
groups	O
that	O
was	O
resistant	O
to	O
Warfarin	B-Chemical
-	O
induced	O
artery	B-Disease
calcification	I-Disease
,	O
ie	O
,	O
the	O
10	O
-	O
month	O
-	O
old	O
rats	O
and	O
the	O
restricted	O
-	O
diet	O
,	O
growth	O
-	O
inhibited	O
young	O
rats	O
.	O

This	O
observation	O
suggests	O
that	O
increased	O
susceptibility	O
to	O
Warfarin	B-Chemical
-	O
induced	O
artery	B-Disease
calcification	I-Disease
could	O
be	O
related	O
to	O
higher	O
serum	O
phosphate	B-Chemical
levels	O
.	O

The	O
second	O
set	O
of	O
experiments	O
examined	O
the	O
possible	O
synergy	O
between	O
vitamin	B-Chemical
D	I-Chemical
and	O
Warfarin	B-Chemical
in	O
artery	B-Disease
calcification	I-Disease
.	O

High	O
doses	O
of	O
vitamin	B-Chemical
D	I-Chemical
are	O
known	O
to	O
cause	O
calcification	B-Disease
of	I-Disease
the	I-Disease
artery	I-Disease
media	O
in	O
as	O
little	O
as	O
3	O
to	O
4	O
days	O
.	O

High	O
doses	O
of	O
the	O
vitamin	B-Chemical
K	I-Chemical
antagonist	O
Warfarin	B-Chemical
are	O
also	O
known	O
to	O
cause	O
calcification	B-Disease
of	I-Disease
the	I-Disease
artery	I-Disease
media	O
,	O
but	O
at	O
treatment	O
times	O
of	O
2	O
weeks	O
or	O
longer	O
yet	O
not	O
at	O
1	O
week	O
.	O

In	O
the	O
current	O
study	O
,	O
we	O
investigated	O
the	O
synergy	O
between	O
these	O
2	O
treatments	O
and	O
found	O
that	O
concurrent	O
Warfarin	B-Chemical
administration	O
dramatically	O
increased	O
the	O
extent	O
of	O
calcification	B-Disease
in	O
the	O
media	O
of	O
vitamin	B-Chemical
D	I-Chemical
-	O
treated	O
rats	O
at	O
3	O
and	O
4	O
days	O
.	O

There	O
was	O
a	O
close	O
parallel	O
between	O
the	O
effect	O
of	O
vitamin	B-Chemical
D	I-Chemical
dose	O
on	O
artery	B-Disease
calcification	I-Disease
and	O
the	O
effect	O
of	O
vitamin	B-Chemical
D	I-Chemical
dose	O
on	O
the	O
elevation	O
of	O
serum	O
calcium	B-Chemical
,	O
which	O
suggests	O
that	O
vitamin	B-Chemical
D	I-Chemical
may	O
induce	O
artery	B-Disease
calcification	I-Disease
through	O
its	O
effect	O
on	O
serum	O
calcium	B-Chemical
.	O

Because	O
Warfarin	B-Chemical
treatment	O
had	O
no	O
effect	O
on	O
the	O
elevation	O
in	O
serum	O
calcium	B-Chemical
produced	O
by	O
vitamin	B-Chemical
D	I-Chemical
,	O
the	O
synergy	O
between	O
Warfarin	B-Chemical
and	O
vitamin	B-Chemical
D	I-Chemical
is	O
probably	O
best	O
explained	O
by	O
the	O
hypothesis	O
that	O
Warfarin	B-Chemical
inhibits	O
the	O
activity	O
of	O
matrix	O
Gla	O
protein	O
as	O
a	O
calcification	B-Disease
inhibitor	O
.	O

High	O
levels	O
of	O
matrix	O
Gla	O
protein	O
are	O
found	O
at	O
sites	O
of	O
artery	B-Disease
calcification	I-Disease
in	O
rats	O
treated	O
with	O
vitamin	B-Chemical
D	I-Chemical
plus	O
Warfarin	B-Chemical
,	O
and	O
chemical	O
analysis	O
showed	O
that	O
the	O
protein	O
that	O
accumulated	O
was	O
indeed	O
not	O
gamma	B-Chemical
-	I-Chemical
carboxylated	I-Chemical
.	O

These	O
observations	O
indicate	O
that	O
although	O
the	O
gamma	B-Chemical
-	I-Chemical
carboxyglutamate	I-Chemical
residues	O
of	O
matrix	O
Gla	O
protein	O
are	O
apparently	O
required	O
for	O
its	O
function	O
as	O
a	O
calcification	B-Disease
inhibitor	O
,	O
they	O
are	O
not	O
required	O
for	O
its	O
accumulation	O
at	O
calcification	B-Disease
sites	O
.	O

Test	O
conditions	O
influence	O
the	O
response	O
to	O
a	O
drug	O
challenge	O
in	O
rodents	O
.	O

These	O
studies	O
were	O
conducted	O
to	O
examine	O
the	O
differential	O
response	O
to	O
a	O
drug	O
challenge	O
under	O
varied	O
experimental	O
test	O
conditions	O
routinely	O
employed	O
to	O
study	O
drug	O
-	O
induced	O
behavioral	O
and	O
neurophysiological	O
responses	O
in	O
rodents	O
.	O

Apomorphine	B-Chemical
,	O
a	O
nonselective	O
dopamine	B-Chemical
agonist	I-Chemical
,	O
was	O
selected	O
due	O
to	O
its	O
biphasic	O
behavioral	O
effects	O
,	O
its	O
ability	O
to	O
induce	O
hypothermia	B-Disease
,	O
and	O
to	O
produce	O
distinct	O
changes	O
to	O
dopamine	B-Chemical
turnover	O
in	O
the	O
rodent	O
brain	O
.	O

From	O
such	O
experiments	O
there	O
is	O
evidence	O
that	O
characterization	O
and	O
detection	O
of	O
apomorphine	B-Chemical
-	O
induced	O
activity	O
in	O
rodents	O
critically	O
depends	O
upon	O
the	O
test	O
conditions	O
employed	O
.	O

In	O
rats	O
,	O
detection	O
of	O
apomorphine	B-Chemical
-	O
induced	O
hyperactivity	B-Disease
was	O
facilitated	O
by	O
a	O
period	O
of	O
acclimatization	O
to	O
the	O
test	O
conditions	O
.	O

Moreover	O
,	O
test	O
conditions	O
can	O
impact	O
upon	O
other	O
physiological	O
responses	O
to	O
apomorphine	B-Chemical
such	O
as	O
drug	O
-	O
induced	O
hypothermia	B-Disease
.	O

In	O
mice	O
,	O
apomorphine	B-Chemical
produced	O
qualitatively	O
different	O
responses	O
under	O
novel	O
conditions	O
when	O
compared	O
to	O
those	O
behaviors	O
elicited	O
in	O
the	O
home	O
test	O
cage	O
.	O

Drug	O
-	O
induced	O
gross	O
activity	O
counts	O
were	O
increased	O
in	O
the	O
novel	O
exploratory	O
box	O
only	O
,	O
while	O
measures	O
of	O
stereotypic	O
behavior	O
were	O
similar	O
in	O
both	O
.	O

By	O
contrast	O
,	O
apomorphine	B-Chemical
-	O
induced	O
locomotion	O
was	O
more	O
prominent	O
in	O
the	O
novel	O
exploratory	O
box	O
.	O

Dopamine	B-Chemical
turnover	O
ratios	O
(	O
DOPAC	B-Chemical
:	O
DA	B-Chemical
and	O
HVA	B-Chemical
:	O
DA	B-Chemical
)	O
were	O
found	O
to	O
be	O
lower	O
in	O
those	O
animals	O
exposed	O
to	O
the	O
exploratory	O
box	O
when	O
compared	O
to	O
their	O
home	O
cage	O
counterparts	O
.	O

However	O
,	O
apomorphine	B-Chemical
-	O
induced	O
reductions	O
in	O
striatal	O
dopamine	B-Chemical
turnover	O
were	O
detected	O
in	O
both	O
novel	O
and	O
home	O
cage	O
environments	O
.	O

The	O
implications	O
of	O
these	O
findings	O
are	O
discussed	O
with	O
particular	O
emphasis	O
upon	O
conducting	O
psychopharmacological	O
challenge	O
tests	O
in	O
rodents	O
.	O

Hemolysis	B-Disease
of	O
human	O
erythrocytes	O
induced	O
by	O
tamoxifen	B-Chemical
is	O
related	O
to	O
disruption	O
of	O
membrane	O
structure	O
.	O

Tamoxifen	B-Chemical
(	O
TAM	B-Chemical
)	O
,	O
the	O
antiestrogenic	O
drug	O
most	O
widely	O
prescribed	O
in	O
the	O
chemotherapy	O
of	O
breast	B-Disease
cancer	I-Disease
,	O
induces	O
changes	O
in	O
normal	O
discoid	O
shape	O
of	O
erythrocytes	O
and	O
hemolytic	B-Disease
anemia	I-Disease
.	O

This	O
work	O
evaluates	O
the	O
effects	O
of	O
TAM	B-Chemical
on	O
isolated	O
human	O
erythrocytes	O
,	O
attempting	O
to	O
identify	O
the	O
underlying	O
mechanisms	O
on	O
TAM	B-Chemical
-	O
induced	O
hemolytic	B-Disease
anemia	I-Disease
and	O
the	O
involvement	O
of	O
biomembranes	O
in	O
its	O
cytostatic	O
action	O
mechanisms	O
.	O

TAM	B-Chemical
induces	O
hemolysis	B-Disease
of	O
erythrocytes	O
as	O
a	O
function	O
of	O
concentration	O
.	O

The	O
extension	O
of	O
hemolysis	B-Disease
is	O
variable	O
with	O
erythrocyte	O
samples	O
,	O
but	O
12	O
.	O
5	O
microM	O
TAM	B-Chemical
induces	O
total	O
hemolysis	B-Disease
of	O
all	O
tested	O
suspensions	O
.	O

Despite	O
inducing	O
extensive	O
erythrocyte	O
lysis	O
,	O
TAM	B-Chemical
does	O
not	O
shift	O
the	O
osmotic	O
fragility	O
curves	O
of	O
erythrocytes	O
.	O

The	O
hemolytic	B-Disease
effect	O
of	O
TAM	B-Chemical
is	O
prevented	O
by	O
low	O
concentrations	O
of	O
alpha	B-Chemical
-	I-Chemical
tocopherol	I-Chemical
(	O
alpha	B-Chemical
-	I-Chemical
T	I-Chemical
)	O
and	O
alpha	B-Chemical
-	I-Chemical
tocopherol	I-Chemical
acetate	I-Chemical
(	O
alpha	B-Chemical
-	I-Chemical
TAc	I-Chemical
)	O
(	O
inactivated	O
functional	O
hydroxyl	B-Chemical
)	O
indicating	O
that	O
TAM	B-Chemical
-	O
induced	O
hemolysis	B-Disease
is	O
not	O
related	O
to	O
oxidative	O
membrane	O
damage	O
.	O

This	O
was	O
further	O
evidenced	O
by	O
absence	O
of	O
oxygen	B-Chemical
consumption	O
and	O
hemoglobin	O
oxidation	O
both	O
determined	O
in	O
parallel	O
with	O
TAM	B-Chemical
-	O
induced	O
hemolysis	B-Disease
.	O

Furthermore	O
,	O
it	O
was	O
observed	O
that	O
TAM	B-Chemical
inhibits	O
the	O
peroxidation	O
of	O
human	O
erythrocytes	O
induced	O
by	O
AAPH	B-Chemical
,	O
thus	O
ruling	O
out	O
TAM	B-Chemical
-	O
induced	O
cell	O
oxidative	O
stress	O
.	O

Hemolysis	B-Disease
caused	O
by	O
TAM	B-Chemical
was	O
not	O
preceded	O
by	O
the	O
leakage	O
of	O
K	B-Chemical
(	O
+	O
)	O
from	O
the	O
cells	O
,	O
also	O
excluding	O
a	O
colloid	O
-	O
osmotic	O
type	O
mechanism	O
of	O
hemolysis	B-Disease
,	O
according	O
to	O
the	O
effects	O
on	O
osmotic	O
fragility	O
curves	O
.	O

However	O
,	O
TAM	B-Chemical
induces	O
release	O
of	O
peripheral	O
proteins	O
of	O
membrane	O
-	O
cytoskeleton	O
and	O
cytosol	O
proteins	O
essentially	O
bound	O
to	O
band	O
3	O
.	O

Either	O
alpha	B-Chemical
-	I-Chemical
T	I-Chemical
or	O
alpha	B-Chemical
-	I-Chemical
TAc	I-Chemical
increases	O
membrane	O
packing	O
and	O
prevents	O
TAM	B-Chemical
partition	O
into	O
model	O
membranes	O
.	O

These	O
effects	O
suggest	O
that	O
the	O
protection	O
from	O
hemolysis	B-Disease
by	O
tocopherols	B-Chemical
is	O
related	O
to	O
a	O
decreased	O
TAM	B-Chemical
incorporation	O
in	O
condensed	O
membranes	O
and	O
the	O
structural	O
damage	O
of	O
the	O
erythrocyte	O
membrane	O
is	O
consequently	O
avoided	O
.	O

Therefore	O
,	O
TAM	B-Chemical
-	O
induced	O
hemolysis	B-Disease
results	O
from	O
a	O
structural	O
perturbation	O
of	O
red	O
cell	O
membrane	O
,	O
leading	O
to	O
changes	O
in	O
the	O
framework	O
of	O
the	O
erythrocyte	O
membrane	O
and	O
its	O
cytoskeleton	O
caused	O
by	O
its	O
high	O
partition	O
in	O
the	O
membrane	O
.	O

These	O
defects	O
explain	O
the	O
abnormal	O
erythrocyte	O
shape	O
and	O
decreased	O
mechanical	O
stability	O
promoted	O
by	O
TAM	B-Chemical
,	O
resulting	O
in	O
hemolytic	B-Disease
anemia	I-Disease
.	O

Additionally	O
,	O
since	O
membrane	O
leakage	O
is	O
a	O
final	O
stage	O
of	O
cytotoxicity	O
,	O
the	O
disruption	O
of	O
the	O
structural	O
characteristics	O
of	O
biomembranes	O
by	O
TAM	B-Chemical
may	O
contribute	O
to	O
the	O
multiple	O
mechanisms	O
of	O
its	O
anticancer	O
action	O
.	O

Changes	O
of	O
sodium	B-Chemical
and	O
ATP	B-Chemical
affinities	O
of	O
the	O
cardiac	O
(	O
Na	B-Chemical
,	O
K	B-Chemical
)	O
-	O
ATPase	O
during	O
and	O
after	O
nitric	B-Chemical
oxide	I-Chemical
deficient	O
hypertension	B-Disease
.	O

In	O
the	O
cardiovascular	O
system	O
,	O
NO	B-Chemical
is	O
involved	O
in	O
the	O
regulation	O
of	O
a	O
variety	O
of	O
functions	O
.	O

Inhibition	O
of	O
NO	B-Chemical
synthesis	O
induces	O
sustained	O
hypertension	B-Disease
.	O

In	O
several	O
models	O
of	O
hypertension	B-Disease
,	O
elevation	O
of	O
intracellular	O
sodium	B-Chemical
level	O
was	O
documented	O
in	O
cardiac	O
tissue	O
.	O

To	O
assess	O
the	O
molecular	O
basis	O
of	O
disturbances	O
in	O
transmembraneous	O
transport	O
of	O
Na	B-Chemical
+	O
,	O
we	O
studied	O
the	O
response	O
of	O
cardiac	O
(	O
Na	B-Chemical
,	O
K	B-Chemical
)	O
-	O
ATPase	O
to	O
NO	B-Chemical
-	O
deficient	O
hypertension	B-Disease
induced	O
in	O
rats	O
by	O
NO	B-Chemical
-	O
synthase	O
inhibition	O
with	O
40	O
mg	O
/	O
kg	O
/	O
day	O
N	B-Chemical
(	I-Chemical
G	I-Chemical
)	I-Chemical
-	I-Chemical
nitro	I-Chemical
-	I-Chemical
L	I-Chemical
-	I-Chemical
arginine	I-Chemical
methyl	I-Chemical
ester	I-Chemical
(	O
L	B-Chemical
-	I-Chemical
NAME	I-Chemical
)	O
for	O
4	O
four	O
weeks	O
.	O

After	O
4	O
-	O
week	O
administration	O
of	O
L	B-Chemical
-	I-Chemical
NAME	I-Chemical
,	O
the	O
systolic	O
blood	O
pressure	O
(	O
SBP	O
)	O
increased	O
by	O
36	O
%	O
.	O

Two	O
weeks	O
after	O
terminating	O
the	O
treatment	O
,	O
the	O
SBP	O
recovered	O
to	O
control	O
value	O
.	O

When	O
activating	O
the	O
(	O
Na	B-Chemical
,	O
K	B-Chemical
)	O
-	O
ATPase	O
with	O
its	O
substrate	O
ATP	B-Chemical
,	O
no	O
changes	O
in	O
Km	O
and	O
Vmax	O
values	O
were	O
observed	O
in	O
NO	B-Chemical
-	O
deficient	O
rats	O
.	O

During	O
activation	O
with	O
Na	B-Chemical
+	O
,	O
the	O
Vmax	O
remained	O
unchanged	O
,	O
however	O
the	O
K	B-Chemical
(	O
Na	B-Chemical
)	O
increased	O
by	O
50	O
%	O
,	O
indicating	O
a	O
profound	O
decrease	O
in	O
the	O
affinity	O
of	O
the	O
Na	B-Chemical
+	O
-	O
binding	O
site	O
in	O
NO	B-Chemical
-	O
deficient	O
rats	O
.	O

After	O
recovery	O
from	O
hypertension	B-Disease
,	O
the	O
activity	O
of	O
(	O
Na	B-Chemical
,	O
K	B-Chemical
)	O
-	O
ATPase	O
increased	O
,	O
due	O
to	O
higher	O
affinity	O
of	O
the	O
ATP	B-Chemical
-	O
binding	O
site	O
,	O
as	O
revealed	O
from	O
the	O
lowered	O
Km	O
value	O
for	O
ATP	B-Chemical
.	O

The	O
K	B-Chemical
(	O
Na	B-Chemical
)	O
value	O
for	O
Na	B-Chemical
+	O
returned	O
to	O
control	O
value	O
.	O

Inhibition	O
of	O
NO	B-Chemical
-	O
synthase	O
induced	O
a	O
reversible	O
hypertension	B-Disease
accompanied	O
by	O
depressed	B-Disease
Na	B-Chemical
+	O
-	O
extrusion	O
from	O
cardiac	O
cells	O
as	O
a	O
consequence	O
of	O
deteriorated	O
Na	B-Chemical
+	O
-	O
binding	O
properties	O
of	O
the	O
(	O
Na	B-Chemical
,	O
K	B-Chemical
)	O
-	O
ATPase	O
.	O

After	O
recovery	O
of	O
blood	O
pressure	O
to	O
control	O
values	O
,	O
the	O
extrusion	O
of	O
Na	B-Chemical
+	O
from	O
cardiac	O
cells	O
was	O
normalized	O
,	O
as	O
revealed	O
by	O
restoration	O
of	O
the	O
(	O
Na	B-Chemical
,	O
K	B-Chemical
)	O
-	O
ATPase	O
activity	O
.	O

Effects	O
of	O
long	O
-	O
term	O
pretreatment	O
with	O
isoproterenol	B-Chemical
on	O
bromocriptine	B-Chemical
-	O
induced	O
tachycardia	B-Disease
in	O
conscious	O
rats	O
.	O

It	O
has	O
been	O
shown	O
that	O
bromocriptine	B-Chemical
-	O
induced	O
tachycardia	B-Disease
,	O
which	O
persisted	O
after	O
adrenalectomy	O
,	O
is	O
(	O
i	O
)	O
mediated	O
by	O
central	O
dopamine	B-Chemical
D2	O
receptor	O
activation	O
and	O
(	O
ii	O
)	O
reduced	O
by	O
5	O
-	O
day	O
isoproterenol	B-Chemical
pretreatment	O
,	O
supporting	O
therefore	O
the	O
hypothesis	O
that	O
this	O
effect	O
is	O
dependent	O
on	O
sympathetic	O
outflow	O
to	O
the	O
heart	O
.	O

This	O
study	O
was	O
conducted	O
to	O
examine	O
whether	O
prolonged	O
pretreatment	O
with	O
isoproterenol	B-Chemical
could	O
abolish	O
bromocriptine	B-Chemical
-	O
induced	O
tachycardia	B-Disease
in	O
conscious	O
rats	O
.	O

Isoproterenol	B-Chemical
pretreatment	O
for	O
15	O
days	O
caused	O
cardiac	B-Disease
hypertrophy	I-Disease
without	O
affecting	O
baseline	O
blood	O
pressure	O
and	O
heart	O
rate	O
.	O

In	O
control	O
rats	O
,	O
intravenous	O
bromocriptine	B-Chemical
(	O
150	O
microg	O
/	O
kg	O
)	O
induced	O
significant	O
hypotension	B-Disease
and	O
tachycardia	B-Disease
.	O

Bromocriptine	B-Chemical
-	O
induced	O
hypotension	B-Disease
was	O
unaffected	O
by	O
isoproterenol	B-Chemical
pretreatment	O
,	O
while	O
tachycardia	B-Disease
was	O
reversed	O
to	O
significant	O
bradycardia	B-Disease
,	O
an	O
effect	O
that	O
was	O
partly	O
reduced	O
by	O
i	O
.	O
v	O
.	O
domperidone	B-Chemical
(	O
0	O
.	O
5	O
mg	O
/	O
kg	O
)	O
.	O

Neither	O
cardiac	O
vagal	O
nor	O
sympathetic	O
tone	O
was	O
altered	O
by	O
isoproterenol	B-Chemical
pretreatment	O
.	O

In	O
isolated	O
perfused	O
heart	O
preparations	O
from	O
isoproterenol	B-Chemical
-	O
pretreated	O
rats	O
,	O
the	O
isoproterenol	B-Chemical
-	O
induced	O
maximal	O
increase	O
in	O
left	O
ventricular	O
systolic	O
pressure	O
was	O
significantly	O
reduced	O
,	O
compared	O
with	O
saline	O
-	O
pretreated	O
rats	O
(	O
the	O
EC50	O
of	O
the	O
isoproterenol	B-Chemical
-	O
induced	O
increase	O
in	O
left	O
ventricular	O
systolic	O
pressure	O
was	O
enhanced	O
approximately	O
22	O
-	O
fold	O
)	O
.	O

These	O
results	O
show	O
that	O
15	O
-	O
day	O
isoproterenol	B-Chemical
pretreatment	O
not	O
only	O
abolished	O
but	O
reversed	O
bromocriptine	B-Chemical
-	O
induced	O
tachycardia	B-Disease
to	O
bradycardia	B-Disease
,	O
an	O
effect	O
that	O
is	O
mainly	O
related	O
to	O
further	O
cardiac	O
beta	O
-	O
adrenoceptor	O
desensitization	O
rather	O
than	O
to	O
impairment	O
of	O
autonomic	O
regulation	O
of	O
the	O
heart	O
.	O

They	O
suggest	O
that	O
,	O
in	O
normal	O
conscious	O
rats	O
,	O
the	O
central	O
tachycardia	B-Disease
of	O
bromocriptine	B-Chemical
appears	O
to	O
predominate	O
and	O
to	O
mask	O
the	O
bradycardia	B-Disease
of	O
this	O
agonist	O
at	O
peripheral	O
dopamine	B-Chemical
D2	O
receptors	O
.	O

A	O
developmental	O
analysis	O
of	O
clonidine	B-Chemical
'	O
s	O
effects	O
on	O
cardiac	O
rate	O
and	O
ultrasound	O
production	O
in	O
infant	O
rats	O
.	O

Under	O
controlled	O
conditions	O
,	O
infant	O
rats	O
emit	O
ultrasonic	O
vocalizations	O
during	O
extreme	O
cold	O
exposure	O
and	O
after	O
administration	O
of	O
the	O
alpha	O
(	O
2	O
)	O
adrenoceptor	O
agonist	O
,	O
clonidine	B-Chemical
.	O

Previous	O
investigations	O
have	O
determined	O
that	O
,	O
in	O
response	O
to	O
clonidine	B-Chemical
,	O
ultrasound	O
production	O
increases	O
through	O
the	O
2nd	O
-	O
week	O
postpartum	O
and	O
decreases	O
thereafter	O
.	O

Given	O
that	O
sympathetic	O
neural	O
dominance	O
exhibits	O
a	O
similar	O
developmental	O
pattern	O
,	O
and	O
given	O
that	O
clonidine	B-Chemical
induces	O
sympathetic	O
withdrawal	O
and	O
bradycardia	B-Disease
,	O
we	O
hypothesized	O
that	O
clonidine	B-Chemical
'	O
s	O
developmental	O
effects	O
on	O
cardiac	O
rate	O
and	O
ultrasound	O
production	O
would	O
mirror	O
each	O
other	O
.	O

Therefore	O
,	O
in	O
the	O
present	O
experiment	O
,	O
the	O
effects	O
of	O
clonidine	B-Chemical
administration	O
(	O
0	O
.	O
5	O
mg	O
/	O
kg	O
)	O
on	O
cardiac	O
rate	O
and	O
ultrasound	O
production	O
were	O
examined	O
in	O
2	O
-	O
,	O
8	O
-	O
,	O
15	O
-	O
,	O
and	O
20	O
-	O
day	O
-	O
old	O
rats	O
.	O

Age	O
-	O
related	O
changes	O
in	O
ultrasound	O
production	O
corresponded	O
with	O
changes	O
in	O
cardiovascular	O
variables	O
,	O
including	O
baseline	O
cardiac	O
rate	O
and	O
clonidine	B-Chemical
-	O
induced	O
bradycardia	B-Disease
.	O

This	O
experiment	O
is	O
discussed	O
with	O
regard	O
to	O
the	O
hypothesis	O
that	O
ultrasound	O
production	O
is	O
the	O
acoustic	O
by	O
-	O
product	O
of	O
a	O
physiological	O
maneuver	O
that	O
compensates	O
for	O
clonidine	B-Chemical
'	O
s	O
detrimental	O
effects	O
on	O
cardiovascular	O
function	O
.	O

Recurrent	O
use	O
of	O
newer	O
oral	B-Chemical
contraceptives	I-Chemical
and	O
the	O
risk	O
of	O
venous	B-Disease
thromboembolism	I-Disease
.	O

The	O
epidemiological	O
studies	O
that	O
assessed	O
the	O
risk	O
of	O
venous	B-Disease
thromboembolism	I-Disease
(	O
VTE	B-Disease
)	O
associated	O
with	O
newer	O
oral	B-Chemical
contraceptives	I-Chemical
(	O
OC	B-Chemical
)	O
did	O
not	O
distinguish	O
between	O
patterns	O
of	O
OC	B-Chemical
use	O
,	O
namely	O
first	O
-	O
time	O
users	O
,	O
repeaters	O
and	O
switchers	O
.	O

Data	O
from	O
a	O
Transnational	O
case	O
-	O
control	O
study	O
were	O
used	O
to	O
assess	O
the	O
risk	O
of	O
VTE	B-Disease
for	O
the	O
latter	O
patterns	O
of	O
use	O
,	O
while	O
accounting	O
for	O
duration	O
of	O
use	O
.	O

Over	O
the	O
period	O
1993	O
-	O
1996	O
,	O
551	O
cases	O
of	O
VTE	B-Disease
were	O
identified	O
in	O
Germany	O
and	O
the	O
UK	O
along	O
with	O
2066	O
controls	O
.	O

Totals	O
of	O
128	O
cases	O
and	O
650	O
controls	O
were	O
analysed	O
for	O
repeat	O
use	O
and	O
135	O
cases	O
and	O
622	O
controls	O
for	O
switching	O
patterns	O
.	O

The	O
adjusted	O
rate	O
ratio	O
of	O
VTE	B-Disease
for	O
repeat	O
users	O
of	O
third	O
generation	O
OC	B-Chemical
was	O
0	O
.	O
6	O
(	O
95	O
%	O
CI	O
:	O
0	O
.	O
3	O
-	O
1	O
.	O
2	O
)	O
relative	O
to	O
repeat	O
users	O
of	O
second	O
generation	O
pills	O
,	O
whereas	O
it	O
was	O
1	O
.	O
3	O
(	O
95	O
%	O
CI	O
:	O
0	O
.	O
7	O
-	O
2	O
.	O
4	O
)	O
for	O
switchers	O
from	O
second	O
to	O
third	O
generation	O
pills	O
relative	O
to	O
switchers	O
from	O
third	O
to	O
second	O
generation	O
pills	O
.	O

We	O
conclude	O
that	O
second	O
and	O
third	O
generation	O
agents	O
are	O
associated	O
with	O
equivalent	O
risks	O
of	O
VTE	B-Disease
when	O
the	O
same	O
agent	O
is	O
used	O
repeatedly	O
after	O
interruption	O
periods	O
or	O
when	O
users	O
are	O
switched	O
between	O
the	O
two	O
generations	O
of	O
pills	O
.	O

These	O
analyses	O
suggest	O
that	O
the	O
higher	O
risk	O
observed	O
for	O
the	O
newer	O
OC	B-Chemical
in	O
other	O
studies	O
may	O
be	O
the	O
result	O
of	O
inadequate	O
comparisons	O
of	O
pill	O
users	O
with	O
different	O
patterns	O
of	O
pill	O
use	O
.	O

Differential	O
effects	O
of	O
systemically	O
administered	O
ketamine	B-Chemical
and	O
lidocaine	B-Chemical
on	O
dynamic	O
and	O
static	O
hyperalgesia	B-Disease
induced	O
by	O
intradermal	O
capsaicin	B-Chemical
in	O
humans	O
.	O

We	O
have	O
examined	O
the	O
effect	O
of	O
systemic	O
administration	O
of	O
ketamine	B-Chemical
and	O
lidocaine	B-Chemical
on	O
brush	O
-	O
evoked	O
(	O
dynamic	O
)	O
pain	B-Disease
and	O
punctate	O
-	O
evoked	O
(	O
static	O
)	O
hyperalgesia	B-Disease
induced	O
by	O
capsaicin	B-Chemical
.	O

In	O
a	O
randomized	O
,	O
double	O
-	O
blind	O
,	O
placebo	O
-	O
controlled	O
,	O
crossover	O
study	O
,	O
we	O
studied	O
12	O
volunteers	O
in	O
three	O
experiments	O
.	O

Capsaicin	B-Chemical
100	O
micrograms	O
was	O
injected	O
intradermally	O
on	O
the	O
volar	O
forearm	O
followed	O
by	O
an	O
i	O
.	O
v	O
.	O
infusion	O
of	O
ketamine	B-Chemical
(	O
bolus	O
0	O
.	O
1	O
mg	O
kg	O
-	O
1	O
over	O
10	O
min	O
followed	O
by	O
infusion	O
of	O
7	O
micrograms	O
kg	O
-	O
1	O
min	O
-	O
1	O
)	O
,	O
lidocaine	B-Chemical
5	O
mg	O
kg	O
-	O
1	O
or	O
saline	O
for	O
50	O
min	O
.	O

Infusion	O
started	O
15	O
min	O
after	O
injection	O
of	O
capsaicin	B-Chemical
.	O

The	O
following	O
were	O
measured	O
:	O
spontaneous	O
pain	B-Disease
,	O
pain	B-Disease
evoked	O
by	O
punctate	O
and	O
brush	O
stimuli	O
(	O
VAS	O
)	O
,	O
and	O
areas	O
of	O
brush	O
-	O
evoked	O
and	O
punctate	O
-	O
evoked	O
hyperalgesia	B-Disease
.	O

Ketamine	B-Chemical
reduced	O
both	O
the	O
area	O
of	O
brush	O
-	O
evoked	O
and	O
punctate	O
-	O
evoked	O
hyperalgesia	B-Disease
significantly	O
and	O
it	O
tended	O
to	O
reduce	O
brush	O
-	O
evoked	O
pain	B-Disease
.	O

Lidocaine	B-Chemical
reduced	O
the	O
area	O
of	O
punctate	O
-	O
evoked	O
hyperalgesia	B-Disease
significantly	O
.	O

It	O
tended	O
to	O
reduce	O
VAS	O
scores	O
of	O
spontaneous	O
pain	B-Disease
but	O
had	O
no	O
effect	O
on	O
evoked	O
pain	B-Disease
.	O

The	O
differential	O
effects	O
of	O
ketamine	B-Chemical
and	O
lidocaine	B-Chemical
on	O
static	O
and	O
dynamic	O
hyperalgesia	B-Disease
suggest	O
that	O
the	O
two	O
types	O
of	O
hyperalgesia	B-Disease
are	O
mediated	O
by	O
separate	O
mechanisms	O
and	O
have	O
a	O
distinct	O
pharmacology	O
.	O

Development	O
of	O
apomorphine	B-Chemical
-	O
induced	O
aggressive	B-Disease
behavior	I-Disease
:	O
comparison	O
of	O
adult	O
male	O
and	O
female	O
Wistar	O
rats	O
.	O

The	O
development	O
of	O
apomorphine	B-Chemical
-	O
induced	O
(	O
1	O
.	O
0	O
mg	O
/	O
kg	O
s	O
.	O
c	O
.	O
once	O
daily	O
)	O
aggressive	B-Disease
behavior	I-Disease
of	O
adult	O
male	O
and	O
female	O
Wistar	O
rats	O
obtained	O
from	O
the	O
same	O
breeder	O
was	O
studied	O
in	O
two	O
consecutive	O
sets	O
.	O

In	O
male	O
animals	O
,	O
repeated	O
apomorphine	B-Chemical
treatment	O
induced	O
a	O
gradual	O
development	O
of	O
aggressive	B-Disease
behavior	I-Disease
as	O
evidenced	O
by	O
the	O
increased	O
intensity	O
of	O
aggressiveness	B-Disease
and	O
shortened	O
latency	O
before	O
the	O
first	O
attack	O
toward	O
the	O
opponent	O
.	O

In	O
female	O
rats	O
,	O
only	O
a	O
weak	O
tendency	O
toward	O
aggressiveness	B-Disease
was	O
found	O
.	O

In	O
conclusion	O
,	O
the	O
present	O
study	O
demonstrates	O
gender	O
differences	O
in	O
the	O
development	O
of	O
the	O
apomorphine	B-Chemical
-	O
induced	O
aggressive	B-Disease
behavior	I-Disease
and	O
indicates	O
that	O
the	O
female	O
rats	O
do	O
not	O
fill	O
the	O
validation	O
criteria	O
for	O
use	O
in	O
this	O
method	O
.	O

Intracranial	B-Disease
aneurysms	I-Disease
and	O
cocaine	B-Disease
abuse	I-Disease
:	O
analysis	O
of	O
prognostic	O
indicators	O
.	O

OBJECTIVE	O
:	O
The	O
outcome	O
of	O
subarachnoid	B-Disease
hemorrhage	I-Disease
associated	O
with	O
cocaine	B-Disease
abuse	I-Disease
is	O
reportedly	O
poor	O
.	O

However	O
,	O
no	O
study	O
in	O
the	O
literature	O
has	O
reported	O
the	O
use	O
of	O
a	O
statistical	O
model	O
to	O
analyze	O
the	O
variables	O
that	O
influence	O
outcome	O
.	O

METHODS	O
:	O
A	O
review	O
of	O
admissions	O
during	O
a	O
6	O
-	O
year	O
period	O
revealed	O
14	O
patients	O
with	O
cocaine	B-Chemical
-	O
related	O
aneurysms	B-Disease
.	O

This	O
group	O
was	O
compared	O
with	O
a	O
control	O
group	O
of	O
135	O
patients	O
with	O
ruptured	B-Disease
aneurysms	I-Disease
and	O
no	O
history	O
of	O
cocaine	B-Disease
abuse	I-Disease
.	O

Age	O
at	O
presentation	O
,	O
time	O
of	O
ictus	O
after	O
intoxication	O
,	O
Hunt	O
and	O
Hess	O
grade	O
of	O
subarachnoid	B-Disease
hemorrhage	I-Disease
,	O
size	O
of	O
the	O
aneurysm	B-Disease
,	O
location	O
of	O
the	O
aneurysm	B-Disease
,	O
and	O
the	O
Glasgow	O
Outcome	O
Scale	O
score	O
were	O
assessed	O
and	O
compared	O
.	O

RESULTS	O
:	O
The	O
patients	O
in	O
the	O
study	O
group	O
were	O
significantly	O
younger	O
than	O
the	O
patients	O
in	O
the	O
control	O
group	O
(	O
P	O
<	O
0	O
.	O
002	O
)	O
.	O

In	O
patients	O
in	O
the	O
study	O
group	O
,	O
all	O
aneurysms	B-Disease
were	O
located	O
in	O
the	O
anterior	O
circulation	O
.	O

The	O
majority	O
of	O
these	O
aneurysms	B-Disease
were	O
smaller	O
than	O
those	O
of	O
the	O
control	O
group	O
(	O
8	O
+	O
/	O
-	O
6	O
.	O
08	O
mm	O
versus	O
11	O
+	O
/	O
-	O
5	O
.	O
4	O
mm	O
;	O
P	O
=	O
0	O
.	O
05	O
)	O
.	O

The	O
differences	O
in	O
mortality	O
and	O
morbidity	O
between	O
the	O
two	O
groups	O
were	O
not	O
significant	O
.	O

Hunt	O
and	O
Hess	O
grade	O
(	O
P	O
<	O
0	O
.	O
005	O
)	O
and	O
age	O
(	O
P	O
<	O
0	O
.	O
007	O
)	O
were	O
significant	O
predictors	O
of	O
outcome	O
for	O
the	O
patients	O
with	O
cocaine	B-Chemical
-	O
related	O
aneurysms	B-Disease
.	O

CONCLUSION	O
:	O
Cocaine	B-Chemical
use	O
predisposed	O
aneurysmal	B-Disease
rupture	I-Disease
at	O
a	O
significantly	O
earlier	O
age	O
and	O
in	O
much	O
smaller	O
aneurysms	B-Disease
.	O

Contrary	O
to	O
the	O
published	O
literature	O
,	O
this	O
group	O
did	O
reasonably	O
well	O
with	O
aggressive	O
management	O
.	O

Effect	O
of	O
intravenous	O
nimodipine	B-Chemical
on	O
blood	O
pressure	O
and	O
outcome	O
after	O
acute	B-Disease
stroke	I-Disease
.	O

BACKGROUND	O
AND	O
PURPOSE	O
:	O
The	O
Intravenous	O
Nimodipine	B-Chemical
West	O
European	O
Stroke	B-Disease
Trial	O
(	O
INWEST	O
)	O
found	O
a	O
correlation	O
between	O
nimodipine	B-Chemical
-	O
induced	O
reduction	B-Disease
in	I-Disease
blood	I-Disease
pressure	I-Disease
(	O
BP	O
)	O
and	O
an	O
unfavorable	O
outcome	O
in	O
acute	B-Disease
stroke	I-Disease
.	O

We	O
sought	O
to	O
confirm	O
this	O
correlation	O
with	O
and	O
without	O
adjustment	O
for	O
prognostic	O
variables	O
and	O
to	O
investigate	O
outcome	O
in	O
subgroups	O
with	O
increasing	O
levels	O
of	O
BP	B-Disease
reduction	I-Disease
.	O

METHODS	O
:	O
Patients	O
with	O
a	O
clinical	O
diagnosis	O
of	O
ischemic	B-Disease
stroke	I-Disease
(	O
within	O
24	O
hours	O
)	O
were	O
consecutively	O
allocated	O
to	O
receive	O
placebo	O
(	O
n	O
=	O
100	O
)	O
,	O
1	O
mg	O
/	O
h	O
(	O
low	O
-	O
dose	O
)	O
nimodipine	B-Chemical
(	O
n	O
=	O
101	O
)	O
,	O
or	O
2	O
mg	O
/	O
h	O
(	O
high	O
-	O
dose	O
)	O
nimodipine	B-Chemical
(	O
n	O
=	O
94	O
)	O
.	O

The	O
correlation	O
between	O
average	O
BP	O
change	O
during	O
the	O
first	O
2	O
days	O
and	O
the	O
outcome	O
at	O
day	O
21	O
was	O
analyzed	O
.	O

RESULTS	O
:	O
Two	O
hundred	O
sixty	O
-	O
five	O
patients	O
were	O
included	O
in	O
this	O
analysis	O
(	O
n	O
=	O
92	O
,	O
93	O
,	O
and	O
80	O
for	O
placebo	O
,	O
low	O
dose	O
,	O
and	O
high	O
dose	O
,	O
respectively	O
)	O
.	O

Nimodipine	B-Chemical
treatment	O
resulted	O
in	O
a	O
statistically	O
significant	O
reduction	B-Disease
in	I-Disease
systolic	I-Disease
BP	I-Disease
(	O
SBP	O
)	O
and	O
diastolic	O
BP	O
(	O
DBP	O
)	O
from	O
baseline	O
compared	O
with	O
placebo	O
during	O
the	O
first	O
few	O
days	O
.	O

In	O
multivariate	O
analysis	O
,	O
a	O
significant	O
correlation	O
between	O
DBP	B-Disease
reduction	I-Disease
and	O
worsening	O
of	O
the	O
neurological	O
score	O
was	O
found	O
for	O
the	O
high	O
-	O
dose	O
group	O
(	O
beta	O
=	O
0	O
.	O
49	O
,	O
P	O
=	O
0	O
.	O
048	O
)	O
.	O

Patients	O
with	O
a	O
DBP	B-Disease
reduction	I-Disease
of	O
>	O
or	O
=	O
20	O
%	O
in	O
the	O
high	O
-	O
dose	O
group	O
had	O
a	O
significantly	O
increased	O
adjusted	O
OR	O
for	O
the	O
compound	O
outcome	O
variable	O
death	B-Disease
or	O
dependency	O
(	O
Barthel	O
Index	O
<	O
60	O
)	O
(	O
n	O
/	O
N	O
=	O
25	O
/	O
26	O
,	O
OR	O
10	O
.	O
16	O
,	O
95	O
%	O
CI	O
1	O
.	O
02	O
to	O
101	O
.	O
74	O
)	O
and	O
death	B-Disease
alone	O
(	O
n	O
/	O
N	O
=	O
9	O
/	O
26	O
,	O
OR	O
4	O
.	O
336	O
,	O
95	O
%	O
CI	O
1	O
.	O
131	O
16	O
.	O
619	O
)	O
compared	O
with	O
all	O
placebo	O
patients	O
(	O
n	O
/	O
N	O
=	O
62	O
/	O
92	O
and	O
14	O
/	O
92	O
,	O
respectively	O
)	O
.	O

There	O
was	O
no	O
correlation	O
between	O
SBP	O
change	O
and	O
outcome	O
.	O

CONCLUSIONS	O
:	O
DBP	O
,	O
but	O
not	O
SBP	O
,	O
reduction	O
was	O
associated	O
with	O
neurological	O
worsening	O
after	O
the	O
intravenous	O
administration	O
of	O
high	O
-	O
dose	O
nimodipine	B-Chemical
after	O
acute	B-Disease
stroke	I-Disease
.	O

For	O
low	O
-	O
dose	O
nimodipine	B-Chemical
,	O
the	O
results	O
were	O
not	O
conclusive	O
.	O

These	O
results	O
do	O
not	O
confirm	O
or	O
exclude	O
a	O
neuroprotective	O
property	O
of	O
nimodipine	B-Chemical
.	O

Neonatal	O
pyridoxine	B-Chemical
responsive	O
convulsions	B-Disease
due	O
to	O
isoniazid	B-Chemical
therapy	O
.	O

A	O
17	O
-	O
day	O
-	O
old	O
infant	O
on	O
isoniazid	B-Chemical
therapy	O
13	O
mg	O
/	O
kg	O
daily	O
from	O
birth	O
because	O
of	O
maternal	O
tuberculosis	B-Disease
was	O
admitted	O
after	O
4	O
days	O
of	O
clonic	B-Disease
fits	I-Disease
.	O

No	O
underlying	O
infective	O
or	O
biochemical	O
cause	O
could	O
be	O
found	O
.	O

The	O
fits	B-Disease
ceased	O
within	O
4	O
hours	O
of	O
administering	O
intramuscular	O
pyridoxine	B-Chemical
,	O
suggesting	O
an	O
aetiology	O
of	O
pyridoxine	B-Chemical
deficiency	O
secondary	O
to	O
isoniazid	B-Chemical
medication	O
.	O

Ketamine	B-Chemical
sedation	O
for	O
the	O
reduction	O
of	O
children	O
'	O
s	O
fractures	B-Disease
in	O
the	O
emergency	O
department	O
.	O

BACKGROUND	O
:	O
There	O
recently	O
has	O
been	O
a	O
resurgence	O
in	O
the	O
utilization	O
of	O
ketamine	B-Chemical
,	O
a	O
unique	O
anesthetic	O
,	O
for	O
emergency	O
-	O
department	O
procedures	O
requiring	O
sedation	O
.	O

The	O
purpose	O
of	O
the	O
present	O
study	O
was	O
to	O
examine	O
the	O
safety	O
and	O
efficacy	O
of	O
ketamine	B-Chemical
for	O
sedation	O
in	O
the	O
treatment	O
of	O
children	O
'	O
s	O
fractures	B-Disease
in	O
the	O
emergency	O
department	O
.	O

METHODS	O
:	O
One	O
hundred	O
and	O
fourteen	O
children	O
(	O
average	O
age	O
,	O
5	O
.	O
3	O
years	O
;	O
range	O
,	O
twelve	O
months	O
to	O
ten	O
years	O
and	O
ten	O
months	O
)	O
who	O
underwent	O
closed	O
reduction	O
of	O
an	O
isolated	O
fracture	B-Disease
or	O
dislocation	B-Disease
in	O
the	O
emergency	O
department	O
at	O
a	O
level	O
-	O
I	O
trauma	B-Disease
center	O
were	O
prospectively	O
evaluated	O
.	O

Ketamine	B-Chemical
hydrochloride	I-Chemical
was	O
administered	O
intravenously	O
(	O
at	O
a	O
dose	O
of	O
two	O
milligrams	O
per	O
kilogram	O
of	O
body	O
weight	O
)	O
in	O
ninety	O
-	O
nine	O
of	O
the	O
patients	O
and	O
intramuscularly	O
(	O
at	O
a	O
dose	O
of	O
four	O
milligrams	O
per	O
kilogram	O
of	O
body	O
weight	O
)	O
in	O
the	O
other	O
fifteen	O
.	O

A	O
board	O
-	O
certified	O
emergency	O
physician	O
skilled	O
in	O
airway	O
management	O
supervised	O
administration	O
of	O
the	O
anesthetic	O
,	O
and	O
the	O
patients	O
were	O
monitored	O
by	O
a	O
registered	O
nurse	O
.	O

Any	O
pain	B-Disease
during	O
the	O
reduction	O
was	O
rated	O
by	O
the	O
orthopaedic	O
surgeon	O
treating	O
the	O
patient	O
according	O
to	O
the	O
Children	O
'	O
s	O
Hospital	O
of	O
Eastern	O
Ontario	O
Pain	B-Disease
Scale	O
(	O
CHEOPS	O
)	O
.	O

RESULTS	O
:	O
The	O
average	O
time	O
from	O
intravenous	O
administration	O
of	O
ketamine	B-Chemical
to	O
manipulation	O
of	O
the	O
fracture	B-Disease
or	O
dislocation	B-Disease
was	O
one	O
minute	O
and	O
thirty	O
-	O
six	O
seconds	O
(	O
range	O
,	O
twenty	O
seconds	O
to	O
five	O
minutes	O
)	O
,	O
and	O
the	O
average	O
time	O
from	O
intramuscular	O
administration	O
to	O
manipulation	O
was	O
four	O
minutes	O
and	O
forty	O
-	O
two	O
seconds	O
(	O
range	O
,	O
sixty	O
seconds	O
to	O
fifteen	O
minutes	O
)	O
.	O

The	O
average	O
score	O
according	O
to	O
the	O
Children	O
'	O
s	O
Hospital	O
of	O
Eastern	O
Ontario	O
Pain	B-Disease
Scale	O
was	O
6	O
.	O
4	O
points	O
(	O
range	O
,	O
5	O
to	O
10	O
points	O
)	O
,	O
reflecting	O
minimal	O
or	O
no	O
pain	B-Disease
during	O
fracture	B-Disease
reduction	O
.	O

Adequate	O
fracture	B-Disease
reduction	O
was	O
obtained	O
in	O
111	O
of	O
the	O
children	O
.	O

Ninety	O
-	O
nine	O
percent	O
(	O
sixty	O
-	O
eight	O
)	O
of	O
the	O
sixty	O
-	O
nine	O
parents	O
present	O
during	O
the	O
reduction	O
were	O
pleased	O
with	O
the	O
sedation	O
and	O
would	O
allow	O
it	O
to	O
be	O
used	O
again	O
in	O
a	O
similar	O
situation	O
.	O

Patency	O
of	O
the	O
airway	O
and	O
independent	O
respiration	O
were	O
maintained	O
in	O
all	O
of	O
the	O
patients	O
.	O

Blood	O
pressure	O
and	O
heart	O
rate	O
remained	O
stable	O
.	O

Minor	O
side	O
effects	O
included	O
nausea	B-Disease
(	O
thirteen	O
patients	O
)	O
,	O
emesis	B-Disease
(	O
eight	O
of	O
the	O
thirteen	O
patients	O
with	O
nausea	B-Disease
)	O
,	O
clumsiness	B-Disease
(	O
evident	O
as	O
ataxic	B-Disease
movements	I-Disease
in	O
ten	O
patients	O
)	O
,	O
and	O
dysphoric	B-Disease
reaction	I-Disease
(	O
one	O
patient	O
)	O
.	O

No	O
long	O
-	O
term	O
sequelae	O
were	O
noted	O
,	O
and	O
no	O
patients	O
had	O
hallucinations	B-Disease
or	O
nightmares	O
.	O

CONCLUSIONS	O
:	O
Ketamine	B-Chemical
reliably	O
,	O
safely	O
,	O
and	O
quickly	O
provided	O
adequate	O
sedation	O
to	O
effectively	O
facilitate	O
the	O
reduction	O
of	O
children	O
'	O
s	O
fractures	B-Disease
in	O
the	O
emergency	O
department	O
at	O
our	O
institution	O
.	O

Ketamine	B-Chemical
should	O
only	O
be	O
used	O
in	O
an	O
environment	O
such	O
as	O
the	O
emergency	O
department	O
,	O
where	O
proper	O
one	O
-	O
on	O
-	O
one	O
monitoring	O
is	O
used	O
and	O
board	O
-	O
certified	O
physicians	O
skilled	O
in	O
airway	O
management	O
are	O
directly	O
involved	O
in	O
the	O
care	O
of	O
the	O
patient	O
.	O

Cyclosporine	B-Chemical
and	O
tacrolimus	B-Chemical
-	O
associated	O
thrombotic	B-Disease
microangiopathy	I-Disease
.	O

The	O
development	O
of	O
thrombotic	B-Disease
microangiopathy	I-Disease
(	O
TMA	B-Disease
)	O
associated	O
with	O
the	O
use	O
of	O
cyclosporine	B-Chemical
has	O
been	O
well	O
documented	O
.	O

Treatments	O
have	O
included	O
discontinuation	O
or	O
reduction	O
of	O
cyclosporine	B-Chemical
dose	O
with	O
or	O
without	O
concurrent	O
plasma	O
exchange	O
,	O
plasma	O
infusion	O
,	O
anticoagulation	O
,	O
and	O
intravenous	O
immunoglobulin	O
G	O
infusion	O
.	O

However	O
,	O
for	O
recipients	O
of	O
organ	O
transplantation	O
,	O
removing	O
the	O
inciting	O
agent	O
is	O
not	O
without	O
the	O
attendant	O
risk	O
of	O
precipitating	O
acute	O
rejection	O
and	O
graft	O
loss	O
.	O

The	O
last	O
decade	O
has	O
seen	O
the	O
emergence	O
of	O
tacrolimus	B-Chemical
as	O
a	O
potent	O
immunosuppressive	O
agent	O
with	O
mechanisms	O
of	O
action	O
virtually	O
identical	O
to	O
those	O
of	O
cyclosporine	B-Chemical
.	O

As	O
a	O
result	O
,	O
switching	O
to	O
tacrolimus	B-Chemical
has	O
been	O
reported	O
to	O
be	O
a	O
viable	O
therapeutic	O
option	O
in	O
the	O
setting	O
of	O
cyclosporine	B-Chemical
-	O
induced	O
TMA	B-Disease
.	O

With	O
the	O
more	O
widespread	O
application	O
of	O
tacrolimus	B-Chemical
in	O
organ	O
transplantation	O
,	O
tacrolimus	B-Chemical
-	O
associated	O
TMA	B-Disease
has	O
also	O
been	O
recognized	O
.	O

However	O
,	O
literature	O
regarding	O
the	O
incidence	O
of	O
the	O
recurrence	O
of	O
TMA	B-Disease
in	O
patients	O
exposed	O
sequentially	O
to	O
cyclosporine	B-Chemical
and	O
tacrolimus	B-Chemical
is	O
limited	O
.	O

We	O
report	O
a	O
case	O
of	O
a	O
living	O
donor	O
renal	O
transplant	O
recipient	O
who	O
developed	O
cyclosporine	B-Chemical
-	O
induced	O
TMA	B-Disease
that	O
responded	O
to	O
the	O
withdrawal	O
of	O
cyclosporine	B-Chemical
in	O
conjunction	O
with	O
plasmapheresis	O
and	O
fresh	O
frozen	O
plasma	O
replacement	O
therapy	O
.	O

Introduction	O
of	O
tacrolimus	B-Chemical
as	O
an	O
alternative	O
immunosuppressive	O
agent	O
resulted	O
in	O
the	O
recurrence	O
of	O
TMA	B-Disease
and	O
the	O
subsequent	O
loss	O
of	O
the	O
renal	O
allograft	O
.	O

Patients	O
who	O
are	O
switched	O
from	O
cyclosporine	B-Chemical
to	O
tacrolimus	B-Chemical
or	O
vice	O
versa	O
should	O
be	O
closely	O
monitored	O
for	O
the	O
signs	O
and	O
symptoms	O
of	O
recurrent	O
TMA	B-Disease
.	O

Analgesic	O
effect	O
of	O
intravenous	O
ketamine	B-Chemical
in	O
cancer	B-Disease
patients	O
on	O
morphine	B-Chemical
therapy	O
:	O
a	O
randomized	O
,	O
controlled	O
,	O
double	O
-	O
blind	O
,	O
crossover	O
,	O
double	O
-	O
dose	O
study	O
.	O

Pain	B-Disease
not	O
responsive	O
to	O
morphine	B-Chemical
is	O
often	O
problematic	O
.	O

Animal	O
and	O
clinical	O
studies	O
have	O
suggested	O
that	O
N	B-Chemical
-	I-Chemical
methyl	I-Chemical
-	I-Chemical
D	I-Chemical
-	I-Chemical
aspartate	I-Chemical
(	O
NMDA	B-Chemical
)	O
antagonists	O
,	O
such	O
as	O
ketamine	B-Chemical
,	O
may	O
be	O
effective	O
in	O
improving	O
opioid	O
analgesia	O
in	O
difficult	O
pain	B-Disease
syndromes	O
,	O
such	O
as	O
neuropathic	B-Disease
pain	I-Disease
.	O

A	O
slow	O
bolus	O
of	O
subhypnotic	O
doses	O
of	O
ketamine	B-Chemical
(	O
0	O
.	O
25	O
mg	O
/	O
kg	O
or	O
0	O
.	O
50	O
mg	O
/	O
kg	O
)	O
was	O
given	O
to	O
10	O
cancer	B-Disease
patients	O
whose	O
pain	B-Disease
was	O
unrelieved	O
by	O
morphine	B-Chemical
in	O
a	O
randomized	O
,	O
double	O
-	O
blind	O
,	O
crossover	O
,	O
double	O
-	O
dose	O
study	O
.	O

Pain	B-Disease
intensity	O
on	O
a	O
0	O
to	O
10	O
numerical	O
scale	O
;	O
nausea	B-Disease
and	O
vomiting	B-Disease
,	O
drowsiness	O
,	O
confusion	B-Disease
,	O
and	O
dry	B-Disease
mouth	I-Disease
,	O
using	O
a	O
scale	O
from	O
0	O
to	O
3	O
(	O
not	O
at	O
all	O
,	O
slight	O
,	O
a	O
lot	O
,	O
awful	O
)	O
;	O
Mini	O
-	O
Mental	O
State	O
Examination	O
(	O
MMSE	O
)	O
(	O
0	O
-	O
30	O
)	O
;	O
and	O
arterial	O
pressure	O
were	O
recorded	O
before	O
administration	O
of	O
drugs	O
(	O
T0	O
)	O
and	O
after	O
30	O
minutes	O
(	O
T30	O
)	O
,	O
60	O
minutes	O
(	O
T60	O
)	O
,	O
120	O
minutes	O
(	O
T120	O
)	O
,	O
and	O
180	O
minutes	O
(	O
T180	O
)	O
.	O

Ketamine	B-Chemical
,	O
but	O
not	O
saline	O
solution	O
,	O
significantly	O
reduced	O
the	O
pain	B-Disease
intensity	O
in	O
almost	O
all	O
the	O
patients	O
at	O
both	O
doses	O
.	O

This	O
effect	O
was	O
more	O
relevant	O
in	O
patients	O
treated	O
with	O
higher	O
doses	O
.	O

Hallucinations	B-Disease
occurred	O
in	O
4	O
patients	O
,	O
and	O
an	O
unpleasant	O
sensation	O
(	O
"	O
empty	O
head	O
"	O
)	O
was	O
also	O
reported	O
by	O
2	O
patients	O
.	O

These	O
episodes	O
reversed	O
after	O
the	O
administration	O
of	O
diazepam	B-Chemical
1	O
mg	O
intravenously	O
.	O

Significant	O
increases	O
in	O
drowsiness	O
were	O
reported	O
in	O
patients	O
treated	O
with	O
ketamine	B-Chemical
in	O
both	O
groups	O
and	O
were	O
more	O
marked	O
with	O
ketamine	B-Chemical
0	O
.	O
50	O
mg	O
/	O
kg	O
.	O

A	O
significant	O
difference	O
in	O
MMSE	O
was	O
observed	O
at	O
T30	O
in	O
patients	O
who	O
received	O
0	O
.	O
50	O
mg	O
/	O
kg	O
of	O
ketamine	B-Chemical
.	O

Ketamine	B-Chemical
can	O
improve	O
morphine	B-Chemical
analgesia	O
in	O
difficult	O
pain	B-Disease
syndromes	O
,	O
such	O
as	O
neuropathic	B-Disease
pain	I-Disease
.	O

However	O
,	O
the	O
occurrence	O
of	O
central	O
adverse	O
effects	O
should	O
be	O
taken	O
into	O
account	O
,	O
especially	O
when	O
using	O
higher	O
doses	O
.	O

This	O
observation	O
should	O
be	O
tested	O
in	O
studies	O
of	O
prolonged	O
ketamine	B-Chemical
administration	O
.	O

Paclitaxel	B-Chemical
,	O
cisplatin	B-Chemical
,	O
and	O
gemcitabine	B-Chemical
combination	O
chemotherapy	O
within	O
a	O
multidisciplinary	O
therapeutic	O
approach	O
in	O
metastatic	O
nonsmall	B-Disease
cell	I-Disease
lung	I-Disease
carcinoma	I-Disease
.	O

BACKGROUND	O
:	O
Cisplatin	B-Chemical
-	O
based	O
chemotherapy	O
combinations	O
improve	O
quality	O
of	O
life	O
and	O
survival	O
in	O
advanced	O
nonsmall	B-Disease
cell	I-Disease
lung	I-Disease
carcinoma	I-Disease
(	O
NSCLC	B-Disease
)	O
.	O

The	O
emergence	O
of	O
new	O
active	O
drugs	O
might	O
translate	O
into	O
more	O
effective	O
regimens	O
for	O
the	O
treatment	O
of	O
this	O
disease	O
.	O

METHODS	O
:	O
The	O
objective	O
of	O
this	O
study	O
was	O
to	O
determine	O
the	O
feasibility	O
,	O
response	O
rate	O
,	O
and	O
toxicity	B-Disease
of	O
a	O
paclitaxel	B-Chemical
,	O
cisplatin	B-Chemical
,	O
and	O
gemcitabine	B-Chemical
combination	O
to	O
treat	O
metastatic	O
NSCLC	B-Disease
.	O

Thirty	O
-	O
five	O
consecutive	O
chemotherapy	O
-	O
naive	O
patients	O
with	O
Stage	O
IV	O
NSCLC	B-Disease
and	O
an	O
Eastern	O
Cooperative	O
Oncology	O
Group	O
performance	O
status	O
of	O
0	O
-	O
2	O
were	O
treated	O
with	O
a	O
combination	O
of	O
paclitaxel	B-Chemical
(	O
135	O
mg	O
/	O
m	O
(	O
2	O
)	O
given	O
intravenously	O
in	O
3	O
hours	O
)	O
on	O
Day	O
1	O
,	O
cisplatin	B-Chemical
(	O
120	O
mg	O
/	O
m	O
(	O
2	O
)	O
given	O
intravenously	O
in	O
6	O
hours	O
)	O
on	O
Day	O
1	O
,	O
and	O
gemcitabine	B-Chemical
(	O
800	O
mg	O
/	O
m	O
(	O
2	O
)	O
given	O
intravenously	O
in	O
30	O
minutes	O
)	O
on	O
Days	O
1	O
and	O
8	O
,	O
every	O
4	O
weeks	O
.	O

Although	O
responding	O
patients	O
were	O
scheduled	O
to	O
receive	O
consolidation	O
radiotherapy	O
and	O
24	O
patients	O
received	O
preplanned	O
second	O
-	O
line	O
chemotherapy	O
after	O
disease	O
progression	O
,	O
the	O
response	O
and	O
toxicity	B-Disease
rates	O
reported	O
refer	O
only	O
to	O
the	O
chemotherapy	O
regimen	O
given	O
.	O

RESULTS	O
:	O
All	O
the	O
patients	O
were	O
examined	O
for	O
toxicity	B-Disease
;	O
34	O
were	O
examinable	O
for	O
response	O
.	O

An	O
objective	O
response	O
was	O
observed	O
in	O
73	O
.	O
5	O
%	O
of	O
the	O
patients	O
(	O
95	O
%	O
confidence	O
interval	O
[	O
CI	O
]	O
,	O
55	O
.	O
6	O
-	O
87	O
.	O
1	O
%	O
)	O
,	O
including	O
4	O
complete	O
responses	O
(	O
11	O
.	O
7	O
%	O
)	O
.	O

According	O
to	O
intention	O
-	O
to	O
-	O
treat	O
,	O
the	O
overall	O
response	O
rate	O
was	O
71	O
.	O
4	O
%	O
(	O
95	O
%	O
CI	O
,	O
53	O
.	O
7	O
-	O
85	O
.	O
4	O
%	O
)	O
.	O

After	O
154	O
courses	O
of	O
therapy	O
,	O
the	O
median	O
dose	O
intensity	O
was	O
131	O
mg	O
/	O
m	O
(	O
2	O
)	O
for	O
paclitaxel	B-Chemical
(	O
97	O
.	O
3	O
%	O
)	O
,	O
117	O
mg	O
/	O
m	O
(	O
2	O
)	O
for	O
cisplatin	B-Chemical
(	O
97	O
.	O
3	O
%	O
)	O
,	O
and	O
1378	O
mg	O
/	O
m	O
(	O
2	O
)	O
for	O
gemcitabine	B-Chemical
(	O
86	O
.	O
2	O
%	O
)	O
.	O

World	O
Health	O
Organization	O
Grade	O
3	O
-	O
4	O
neutropenia	B-Disease
and	O
thrombocytopenia	B-Disease
occurred	O
in	O
39	O
.	O
9	O
%	O
and	O
11	O
.	O
4	O
%	O
of	O
patients	O
,	O
respectively	O
.	O

There	O
was	O
one	O
treatment	O
-	O
related	O
death	B-Disease
.	O

Nonhematologic	O
toxicities	B-Disease
were	O
mild	O
.	O

After	O
a	O
median	O
follow	O
-	O
up	O
of	O
22	O
months	O
,	O
the	O
median	O
progression	O
free	O
survival	O
rate	O
was	O
7	O
months	O
,	O
and	O
the	O
median	O
survival	O
time	O
was	O
16	O
months	O
.	O

CONCLUSIONS	O
:	O
The	O
combination	O
of	O
paclitaxel	B-Chemical
,	O
cisplatin	B-Chemical
,	O
and	O
gemcitabine	B-Chemical
is	O
well	O
tolerated	O
and	O
shows	O
high	O
activity	O
in	O
metastatic	O
NSCLC	B-Disease
.	O

This	O
treatment	O
merits	O
further	O
comparison	O
with	O
other	O
cisplatin	B-Chemical
-	O
based	O
regimens	O
.	O

Serotonergic	B-Chemical
antidepressants	I-Chemical
and	O
urinary	B-Disease
incontinence	I-Disease
.	O

Many	O
new	O
serotonergic	B-Chemical
antidepressants	I-Chemical
have	O
been	O
introduced	O
over	O
the	O
past	O
decade	O
.	O

Although	O
urinary	B-Disease
incontinence	I-Disease
is	O
listed	O
as	O
one	O
side	O
effect	O
of	O
these	O
drugs	O
in	O
their	O
package	O
inserts	O
there	O
is	O
only	O
one	O
report	O
in	O
the	O
literature	O
.	O

This	O
concerns	O
2	O
male	O
patients	O
who	O
experienced	O
incontinence	B-Disease
while	O
taking	O
venlafaxine	B-Chemical
.	O

In	O
the	O
present	O
paper	O
the	O
authors	O
describe	O
2	O
female	O
patients	O
who	O
developed	O
incontinence	B-Disease
secondary	O
to	O
the	O
selective	O
serotonin	B-Chemical
reuptake	O
inhibitors	O
paroxetine	B-Chemical
and	O
sertraline	B-Chemical
,	O
as	O
well	O
as	O
a	O
third	O
who	O
developed	O
this	O
side	O
effect	O
on	O
venlafaxine	B-Chemical
.	O

In	O
2	O
of	O
the	O
3	O
cases	O
the	O
patients	O
were	O
also	O
taking	O
lithium	B-Chemical
carbonate	I-Chemical
and	O
beta	O
-	O
blockers	O
,	O
both	O
of	O
which	O
could	O
have	O
contributed	O
to	O
the	O
incontinence	B-Disease
.	O

Animal	O
studies	O
suggest	O
that	O
incontinence	B-Disease
secondary	O
to	O
serotonergic	B-Chemical
antidepressants	I-Chemical
could	O
be	O
mediated	O
by	O
the	O
5HT4	O
receptors	O
found	O
on	O
the	O
bladder	O
.	O

Further	O
research	O
is	O
needed	O
to	O
delineate	O
the	O
frequency	O
of	O
this	O
troubling	O
side	O
effect	O
and	O
how	O
best	O
to	O
treat	O
it	O
.	O

Acute	O
cocaine	B-Chemical
-	O
induced	O
seizures	B-Disease
:	O
differential	O
sensitivity	O
of	O
six	O
inbred	O
mouse	O
strains	O
.	O

Mature	O
male	O
and	O
female	O
mice	O
from	O
six	O
inbred	O
stains	O
were	O
tested	O
for	O
susceptibility	O
to	O
behavioral	O
seizures	B-Disease
induced	O
by	O
a	O
single	O
injection	O
of	O
cocaine	B-Chemical
.	O

Cocaine	B-Chemical
was	O
injected	O
ip	O
over	O
a	O
range	O
of	O
doses	O
(	O
50	O
-	O
100	O
mg	O
/	O
kg	O
)	O
and	O
behavior	O
was	O
monitored	O
for	O
20	O
minutes	O
.	O

Seizure	B-Disease
end	O
points	O
included	O
latency	O
to	O
forelimb	O
or	O
hindlimb	O
clonus	O
,	O
latency	O
to	O
clonic	O
running	O
seizure	B-Disease
and	O
latency	O
to	O
jumping	O
bouncing	O
seizure	B-Disease
.	O

A	O
range	O
of	O
strain	O
specific	O
sensitivities	O
was	O
documented	O
with	O
A	O
/	O
J	O
and	O
SJL	O
mice	O
being	O
most	O
sensitive	O
and	O
C57BL	O
/	O
6J	O
most	O
resistant	O
.	O

DBA	O
/	O
2J	O
,	O
BALB	O
/	O
cByJ	O
and	O
NZW	O
/	O
LacJ	O
strains	O
exhibited	O
intermediate	O
sensitivity	O
.	O

EEG	O
recordings	O
were	O
made	O
in	O
SJL	O
,	O
A	O
/	O
J	O
and	O
C57BL	O
/	O
6J	O
mice	O
revealing	O
a	O
close	O
correspondence	O
between	O
electrical	O
activity	O
and	O
behavior	O
.	O

Additionally	O
,	O
levels	O
of	O
cocaine	B-Chemical
determined	O
in	O
hippocampus	O
and	O
cortex	O
were	O
not	O
different	O
between	O
sensitive	O
and	O
resistant	O
strains	O
.	O

Additional	O
studies	O
of	O
these	O
murine	O
strains	O
may	O
be	O
useful	O
for	O
investigating	O
genetic	O
influences	O
on	O
cocaine	B-Chemical
-	O
induced	O
seizures	B-Disease
.	O

Hypotension	B-Disease
following	O
the	O
initiation	O
of	O
tizanidine	B-Chemical
in	O
a	O
patient	O
treated	O
with	O
an	O
angiotensin	B-Chemical
converting	O
enzyme	O
inhibitor	O
for	O
chronic	O
hypertension	B-Disease
.	O

Centrally	O
acting	O
alpha	O
-	O
2	O
adrenergic	O
agonists	O
are	O
one	O
of	O
several	O
pharmacologic	O
agents	O
used	O
in	O
the	O
treatment	O
of	O
spasticity	B-Disease
related	O
to	O
disorders	B-Disease
of	I-Disease
the	I-Disease
central	I-Disease
nervous	I-Disease
system	I-Disease
.	O

In	O
addition	O
to	O
their	O
effects	O
on	O
spasticity	B-Disease
,	O
certain	O
adverse	O
cardiorespiratory	O
effects	O
have	O
been	O
reported	O
.	O

Adults	O
chronically	O
treated	O
with	O
angiotensin	B-Chemical
converting	O
enzyme	O
inhibitors	O
may	O
have	O
a	O
limited	O
ability	O
to	O
respond	O
to	O
hypotension	B-Disease
when	O
the	O
sympathetic	O
response	O
is	O
simultaneously	O
blocked	O
.	O

The	O
authors	O
present	O
a	O
10	O
-	O
year	O
-	O
old	O
boy	O
chronically	O
treated	O
with	O
lisinopril	B-Chemical
,	O
an	O
angiotensin	B-Chemical
converting	O
enzyme	O
inhibitor	O
,	O
to	O
control	O
hypertension	B-Disease
who	O
developed	O
hypotension	B-Disease
following	O
the	O
addition	O
of	O
tizanidine	B-Chemical
,	O
an	O
alpha	O
-	O
2	O
agonist	O
,	O
for	O
the	O
treatment	O
of	O
spasticity	B-Disease
.	O

The	O
possible	O
interaction	O
of	O
tizanidine	B-Chemical
and	O
other	O
antihypertensive	O
agents	O
should	O
be	O
kept	O
in	O
mind	O
when	O
prescribing	O
therapy	O
to	O
treat	O
either	O
hypertension	B-Disease
or	O
spasticity	B-Disease
in	O
such	O
patients	O
.	O

Two	O
mouse	O
lines	O
selected	O
for	O
differential	O
sensitivities	O
to	O
beta	B-Chemical
-	I-Chemical
carboline	I-Chemical
-	O
induced	O
seizures	B-Disease
are	O
also	O
differentially	O
sensitive	O
to	O
various	O
pharmacological	O
effects	O
of	O
other	O
GABA	B-Chemical
(	O
A	O
)	O
receptor	O
ligands	O
.	O

Two	O
mouse	O
lines	O
were	O
selectively	O
bred	O
according	O
to	O
their	O
sensitivity	O
(	O
BS	O
line	O
)	O
or	O
resistance	O
(	O
BR	O
line	O
)	O
to	O
seizures	B-Disease
induced	O
by	O
a	O
single	O
i	O
.	O
p	O
.	O
injection	O
of	O
methyl	B-Chemical
beta	I-Chemical
-	I-Chemical
carboline	I-Chemical
-	I-Chemical
3	I-Chemical
-	I-Chemical
carboxylate	I-Chemical
(	O
beta	B-Chemical
-	I-Chemical
CCM	I-Chemical
)	O
,	O
an	O
inverse	O
agonist	O
of	O
the	O
GABA	B-Chemical
(	O
A	O
)	O
receptor	O
benzodiazepine	B-Chemical
site	O
.	O

Our	O
aim	O
was	O
to	O
characterize	O
both	O
lines	O
'	O
sensitivities	O
to	O
various	O
physiological	O
effects	O
of	O
other	O
ligands	O
of	O
the	O
GABA	B-Chemical
(	O
A	O
)	O
receptor	O
.	O

We	O
measured	O
diazepam	B-Chemical
-	O
induced	O
anxiolysis	O
with	O
the	O
elevated	O
plus	O
-	O
maze	O
test	O
,	O
diazepam	B-Chemical
-	O
induced	O
sedation	O
by	O
recording	O
the	O
vigilance	O
states	O
,	O
and	O
picrotoxin	B-Chemical
-	O
and	O
pentylenetetrazol	B-Chemical
-	O
induced	O
seizures	B-Disease
after	O
i	O
.	O
p	O
.	O
injections	O
.	O

Results	O
presented	O
here	O
show	O
that	O
the	O
differential	O
sensitivities	O
of	O
BS	O
and	O
BR	O
lines	O
to	O
beta	B-Chemical
-	I-Chemical
CCM	I-Chemical
can	O
be	O
extended	O
to	O
diazepam	B-Chemical
,	O
picrotoxin	B-Chemical
,	O
and	O
pentylenetetrazol	B-Chemical
,	O
suggesting	O
a	O
genetic	O
selection	O
of	O
a	O
general	O
sensitivity	O
and	O
resistance	O
to	O
several	O
ligands	O
of	O
the	O
GABA	B-Chemical
(	O
A	O
)	O
receptor	O
.	O

Propylthiouracil	B-Chemical
-	O
induced	O
perinuclear	O
-	O
staining	O
antineutrophil	O
cytoplasmic	O
autoantibody	O
-	O
positive	O
vasculitis	B-Disease
in	O
conjunction	O
with	O
pericarditis	B-Disease
.	O

OBJECTIVE	O
:	O
To	O
describe	O
a	O
case	O
of	O
propylthiouracil	B-Chemical
-	O
induced	O
vasculitis	B-Disease
manifesting	O
with	O
pericarditis	B-Disease
.	O

METHODS	O
:	O
We	O
present	O
the	O
first	O
case	O
report	O
of	O
a	O
woman	O
with	O
hyperthyroidism	B-Disease
treated	O
with	O
propylthiouracil	B-Chemical
in	O
whom	O
a	O
syndrome	O
of	O
pericarditis	B-Disease
,	O
fever	B-Disease
,	O
and	O
glomerulonephritis	B-Disease
developed	O
.	O

Serologic	O
testing	O
and	O
immunologic	O
studies	O
were	O
done	O
,	O
and	O
a	O
pericardial	O
biopsy	O
was	O
performed	O
.	O

RESULTS	O
:	O
A	O
25	O
-	O
year	O
-	O
old	O
woman	O
with	O
Graves	B-Disease
'	I-Disease
disease	I-Disease
had	O
a	O
febrile	B-Disease
illness	I-Disease
and	O
evidence	O
of	O
pericarditis	B-Disease
,	O
which	O
was	O
confirmed	O
by	O
biopsy	O
.	O

Serologic	O
evaluation	O
revealed	O
the	O
presence	O
of	O
perinuclear	O
-	O
staining	O
antineutrophil	O
cytoplasmic	O
autoantibodies	O
(	O
pANCA	O
)	O
against	O
myeloperoxidase	O
(	O
MPO	O
)	O
.	O

Propylthiouracil	B-Chemical
therapy	O
was	O
withdrawn	O
,	O
and	O
she	O
was	O
treated	O
with	O
a	O
1	O
-	O
month	O
course	O
of	O
prednisone	B-Chemical
,	O
which	O
alleviated	O
her	O
symptoms	O
.	O

A	O
literature	O
review	O
revealed	O
no	O
prior	O
reports	O
of	O
pericarditis	B-Disease
in	O
anti	O
-	O
MPO	O
pANCA	O
-	O
positive	O
vasculitis	B-Disease
associated	O
with	O
propylthio	B-Chemical
-	I-Chemical
uracil	I-Chemical
therapy	O
.	O

CONCLUSION	O
:	O
Pericarditis	B-Disease
may	O
be	O
the	O
initial	O
manifestation	O
of	O
drug	O
-	O
induced	O
vasculitis	B-Disease
attributable	O
to	O
propylthio	B-Chemical
-	I-Chemical
uracil	I-Chemical
therapy	O
.	O

Repeated	O
transient	O
anuria	B-Disease
following	O
losartan	B-Chemical
administration	O
in	O
a	O
patient	O
with	O
a	O
solitary	O
kidney	O
.	O

We	O
report	O
the	O
case	O
of	O
a	O
70	O
-	O
year	O
-	O
old	O
hypertensive	B-Disease
man	O
with	O
a	O
solitary	O
kidney	O
and	O
chronic	B-Disease
renal	I-Disease
insufficiency	I-Disease
who	O
developed	O
two	O
episodes	O
of	O
transient	O
anuria	B-Disease
after	O
losartan	B-Chemical
administration	O
.	O

He	O
was	O
hospitalized	O
for	O
a	O
myocardial	B-Disease
infarction	I-Disease
with	O
pulmonary	B-Disease
edema	I-Disease
,	O
treated	O
with	O
high	O
-	O
dose	O
diuretics	O
.	O

Due	O
to	O
severe	O
systolic	B-Disease
dysfunction	I-Disease
losartan	B-Chemical
was	O
prescribed	O
.	O

Surprisingly	O
,	O
the	O
first	O
dose	O
of	O
50	O
mg	O
of	O
losartan	B-Chemical
resulted	O
in	O
a	O
sudden	O
anuria	B-Disease
,	O
which	O
lasted	O
eight	O
hours	O
despite	O
high	O
-	O
dose	O
furosemide	B-Chemical
and	O
amine	B-Chemical
infusion	O
.	O

One	O
week	O
later	O
,	O
by	O
mistake	O
,	O
losartan	B-Chemical
was	O
prescribed	O
again	O
and	O
after	O
the	O
second	O
dose	O
of	O
50	O
mg	O
,	O
the	O
patient	O
developed	O
a	O
second	O
episode	O
of	O
transient	O
anuria	B-Disease
lasting	O
10	O
hours	O
.	O

During	O
these	O
two	O
episodes	O
,	O
his	O
blood	O
pressure	O
diminished	O
but	O
no	O
severe	O
hypotension	B-Disease
was	O
noted	O
.	O

Ultimately	O
,	O
an	O
arteriography	O
showed	O
a	O
70	O
-	O
80	O
%	O
renal	B-Disease
artery	I-Disease
stenosis	I-Disease
.	O

In	O
this	O
patient	O
,	O
renal	B-Disease
artery	I-Disease
stenosis	I-Disease
combined	O
with	O
heart	B-Disease
failure	I-Disease
and	O
diuretic	O
therapy	O
certainly	O
resulted	O
in	O
a	O
strong	O
activation	O
of	O
the	O
renin	O
-	O
angiotensin	B-Chemical
system	O
(	O
RAS	O
)	O
.	O

Under	O
such	O
conditions	O
,	O
angiotensin	B-Chemical
II	I-Chemical
receptor	O
blockade	O
by	O
losartan	B-Chemical
probably	O
induced	O
a	O
critical	O
fall	O
in	O
glomerular	O
filtration	O
pressure	O
.	O

This	O
case	O
report	O
highlights	O
the	O
fact	O
that	O
the	O
angiotensin	B-Chemical
II	I-Chemical
receptor	O
antagonist	O
losartan	B-Chemical
can	O
cause	O
serious	O
unexpected	O
complications	O
in	O
patients	O
with	O
renovascular	B-Disease
disease	I-Disease
and	O
should	O
be	O
used	O
with	O
extreme	O
caution	O
in	O
this	O
setting	O
.	O

Calcineurin	O
-	O
inhibitor	O
induced	O
pain	B-Disease
syndrome	O
(	O
CIPS	B-Disease
)	O
:	O
a	O
severe	O
disabling	O
complication	O
after	O
organ	O
transplantation	O
.	O

Bone	O
pain	B-Disease
after	O
transplantation	O
is	O
a	O
frequent	O
complication	O
that	O
can	O
be	O
caused	O
by	O
several	O
diseases	O
.	O

Treatment	O
strategies	O
depend	O
on	O
the	O
correct	O
diagnosis	O
of	O
the	O
pain	B-Disease
.	O

Nine	O
patients	O
with	O
severe	O
pain	B-Disease
in	O
their	O
feet	O
,	O
which	O
was	O
registered	O
after	O
transplantation	O
,	O
were	O
investigated	O
.	O

Bone	O
scans	O
showed	O
an	O
increased	O
tracer	O
uptake	O
of	O
the	O
foot	O
bones	O
.	O

Magnetic	O
resonance	O
imaging	O
demonstrated	O
bone	B-Disease
marrow	I-Disease
oedema	I-Disease
in	O
the	O
painful	O
bones	O
.	O

Pain	B-Disease
was	O
not	O
explained	O
by	O
other	O
diseases	O
causing	O
foot	O
pain	B-Disease
,	O
like	O
reflex	B-Disease
sympathetic	I-Disease
dystrophy	I-Disease
,	O
polyneuropathy	B-Disease
,	O
Morton	B-Disease
'	I-Disease
s	I-Disease
neuralgia	I-Disease
,	O
gout	B-Disease
,	O
osteoporosis	B-Disease
,	O
avascular	B-Disease
necrosis	I-Disease
,	O
intermittent	B-Disease
claudication	I-Disease
,	O
orthopaedic	O
foot	B-Disease
deformities	I-Disease
,	O
stress	B-Disease
fractures	I-Disease
,	O
and	O
hyperparathyroidism	B-Disease
.	O

The	O
reduction	O
of	O
cyclosporine	B-Chemical
-	O
or	O
tacrolimus	B-Chemical
trough	O
levels	O
and	O
the	O
administration	O
of	O
calcium	B-Chemical
channel	O
blockers	O
led	O
to	O
relief	O
of	O
pain	B-Disease
.	O

The	O
Calcineurin	O
-	O
inhibitor	O
Induced	O
Pain	B-Disease
Syndrome	O
(	O
CIPS	B-Disease
)	O
is	O
a	O
rare	O
but	O
severe	O
side	O
effect	O
of	O
cyclosporine	B-Chemical
or	O
tacrolimus	B-Chemical
and	O
is	O
accurately	O
diagnosed	O
by	O
its	O
typical	O
presentation	O
,	O
magnetic	O
resonance	O
imaging	O
and	O
bone	O
scans	O
.	O

Incorrect	O
diagnosis	O
of	O
the	O
syndrome	O
will	O
lead	O
to	O
a	O
significant	O
reduction	O
of	O
life	O
quality	O
in	O
patients	O
suffering	O
from	O
CIPS	B-Disease
.	O

Brain	O
natriuretic	O
peptide	O
is	O
a	O
predictor	O
of	O
anthracycline	B-Chemical
-	O
induced	O
cardiotoxicity	B-Disease
.	O

Anthracyclines	B-Chemical
are	O
effective	O
antineoplastic	O
drugs	O
,	O
but	O
they	O
frequently	O
cause	O
dose	O
-	O
related	O
cardiotoxicity	B-Disease
.	O

The	O
cardiotoxicity	B-Disease
of	O
conventional	O
anthracycline	B-Chemical
therapy	O
highlights	O
a	O
need	O
to	O
search	O
for	O
methods	O
that	O
are	O
highly	O
sensitive	O
and	O
capable	O
of	O
predicting	O
cardiac	B-Disease
dysfunction	I-Disease
.	O

We	O
measured	O
the	O
plasma	O
level	O
of	O
brain	O
natriuretic	O
peptide	O
(	O
BNP	O
)	O
to	O
determine	O
whether	O
BNP	O
might	O
serve	O
as	O
a	O
simple	O
diagnostic	O
indicator	O
of	O
anthracycline	B-Chemical
-	O
induced	O
cardiotoxicity	B-Disease
in	O
patients	O
with	O
acute	B-Disease
leukemia	I-Disease
treated	O
with	O
a	O
daunorubicin	B-Chemical
(	O
DNR	B-Chemical
)	O
-	O
containing	O
regimen	O
.	O

Thirteen	O
patients	O
with	O
acute	B-Disease
leukemia	I-Disease
were	O
treated	O
with	O
a	O
DNR	B-Chemical
-	O
containing	O
regimen	O
.	O

Cardiac	O
functions	O
were	O
evaluated	O
with	O
radionuclide	O
angiography	O
before	O
chemotherapies	O
.	O

The	O
plasma	O
levels	O
of	O
atrial	O
natriuretic	O
peptide	O
(	O
ANP	O
)	O
and	O
BNP	O
were	O
measured	O
at	O
the	O
time	O
of	O
radionuclide	O
angiography	O
.	O

Three	O
patients	O
developed	O
congestive	B-Disease
heart	I-Disease
failure	I-Disease
after	O
the	O
completion	O
of	O
chemotherapy	O
.	O

Five	O
patients	O
were	O
diagnosed	O
as	O
having	O
subclinical	O
heart	B-Disease
failure	I-Disease
after	O
the	O
completion	O
of	O
chemotherapy	O
.	O

The	O
plasma	O
levels	O
of	O
BNP	O
in	O
all	O
the	O
patients	O
with	O
clinical	O
and	O
subclinical	O
heart	B-Disease
failure	I-Disease
increased	O
above	O
the	O
normal	O
limit	O
(	O
40	O
pg	O
/	O
ml	O
)	O
before	O
the	O
detection	O
of	O
clinical	O
or	O
subclinical	O
heart	B-Disease
failure	I-Disease
by	O
radionuclide	O
angiography	O
.	O

On	O
the	O
other	O
hand	O
,	O
BNP	O
did	O
not	O
increase	O
in	O
the	O
patients	O
without	O
heart	B-Disease
failure	I-Disease
given	O
DNR	B-Chemical
,	O
even	O
at	O
more	O
than	O
700	O
mg	O
/	O
m	O
(	O
2	O
)	O
.	O

The	O
plasma	O
level	O
of	O
ANP	O
did	O
not	O
always	O
increase	O
in	O
all	O
the	O
patients	O
with	O
clinical	O
and	O
subclinical	O
heart	B-Disease
failure	I-Disease
.	O

These	O
preliminary	O
results	O
suggest	O
that	O
BNP	O
may	O
be	O
useful	O
as	O
an	O
early	O
and	O
sensitive	O
indicator	O
of	O
anthracycline	B-Chemical
-	O
induced	O
cardiotoxicity	B-Disease
.	O

Nephrotoxicity	B-Disease
of	O
combined	O
cephalothin	B-Chemical
-	O
gentamicin	B-Chemical
regimen	O
.	O

Two	O
patients	O
developed	O
acute	B-Disease
tubular	I-Disease
necrosis	I-Disease
,	O
characterized	O
clinically	O
by	O
acute	O
oliguric	B-Disease
renal	I-Disease
failure	I-Disease
,	O
while	O
they	O
were	O
receiving	O
a	O
combination	O
of	O
cephalothin	B-Chemical
sodium	I-Chemical
and	O
gentamicin	B-Chemical
sulfate	I-Chemical
therapy	O
.	O

Patients	O
who	O
are	O
given	O
this	O
drug	O
regimen	O
should	O
be	O
observed	O
very	O
carefully	O
for	O
early	O
signs	O
of	O
nephrotoxicity	B-Disease
.	O

High	O
doses	O
of	O
this	O
antibiotic	O
combination	O
should	O
be	O
avoided	O
especially	O
in	O
elderly	O
patients	O
.	O

Patients	O
with	O
renal	B-Disease
insufficiency	I-Disease
should	O
not	O
be	O
given	O
this	O
regimen	O
.	O

In	O
vivo	O
protection	O
of	O
dna	O
damage	O
associated	O
apoptotic	O
and	O
necrotic	B-Disease
cell	O
deaths	O
during	O
acetaminophen	B-Chemical
-	O
induced	O
nephrotoxicity	B-Disease
,	O
amiodarone	B-Chemical
-	O
induced	O
lung	B-Disease
toxicity	I-Disease
and	O
doxorubicin	B-Chemical
-	O
induced	O
cardiotoxicity	B-Disease
by	O
a	O
novel	O
IH636	B-Chemical
grape	I-Chemical
seed	I-Chemical
proanthocyanidin	I-Chemical
extract	I-Chemical
.	O

Grape	B-Chemical
seed	I-Chemical
extract	I-Chemical
,	O
primarily	O
a	O
mixture	O
of	O
proanthocyanidins	B-Chemical
,	O
has	O
been	O
shown	O
to	O
modulate	O
a	O
wide	O
-	O
range	O
of	O
biological	O
,	O
pharmacological	O
and	O
toxicological	O
effects	O
which	O
are	O
mainly	O
cytoprotective	O
.	O

This	O
study	O
assessed	O
the	O
ability	O
of	O
IH636	B-Chemical
grape	I-Chemical
seed	I-Chemical
proanthocyanidin	I-Chemical
extract	I-Chemical
(	O
GSPE	B-Chemical
)	O
to	O
prevent	O
acetaminophen	B-Chemical
(	O
AAP	B-Chemical
)	O
-	O
induced	O
nephrotoxicity	B-Disease
,	O
amiodarone	B-Chemical
(	O
AMI	B-Chemical
)	O
-	O
induced	O
lung	B-Disease
toxicity	I-Disease
,	O
and	O
doxorubicin	B-Chemical
(	O
DOX	B-Chemical
)	O
-	O
induced	O
cardiotoxicity	B-Disease
in	O
mice	O
.	O

Experimental	O
design	O
consisted	O
of	O
four	O
groups	O
:	O
control	O
(	O
vehicle	O
alone	O
)	O
,	O
GSPE	B-Chemical
alone	O
,	O
drug	O
alone	O
and	O
GSPE	B-Chemical
+	O
drug	O
.	O

For	O
the	O
cytoprotection	O
study	O
,	O
animals	O
were	O
orally	O
gavaged	O
100	O
mg	O
/	O
Kg	O
GSPE	B-Chemical
for	O
7	O
-	O
10	O
days	O
followed	O
by	O
i	O
.	O
p	O
.	O
injections	O
of	O
organ	O
specific	O
three	O
drugs	O
(	O
AAP	B-Chemical
:	O
500	O
mg	O
/	O
Kg	O
for	O
24	O
h	O
;	O
AMI	B-Chemical
:	O
50	O
mg	O
/	O
Kg	O
/	O
day	O
for	O
four	O
days	O
;	O
DOX	B-Chemical
:	O
20	O
mg	O
/	O
Kg	O
for	O
48	O
h	O
)	O
.	O

Parameters	O
of	O
study	O
included	O
analysis	O
of	O
serum	O
chemistry	O
(	O
ALT	O
,	O
BUN	O
and	O
CPK	O
)	O
,	O
and	O
orderly	O
fragmentation	O
of	O
genomic	O
DNA	O
(	O
both	O
endonuclease	O
-	O
dependent	O
and	O
independent	O
)	O
in	O
addition	O
to	O
microscopic	O
evaluation	O
of	O
damage	O
and	O
/	O
or	O
protection	O
in	O
corresponding	O
PAS	O
stained	O
tissues	O
.	O

Results	O
indicate	O
that	O
GSPE	B-Chemical
preexposure	O
prior	O
to	O
AAP	B-Chemical
,	O
AMI	B-Chemical
and	O
DOX	B-Chemical
,	O
provided	O
near	O
complete	O
protection	O
in	O
terms	O
of	O
serum	O
chemistry	O
changes	O
(	O
ALT	O
,	O
BUN	O
and	O
CPK	O
)	O
,	O
and	O
significantly	O
reduced	O
DNA	O
fragmentation	O
.	O

Histopathological	O
examination	O
of	O
kidney	O
,	O
heart	O
and	O
lung	O
sections	O
revealed	O
moderate	O
to	O
massive	O
tissue	B-Disease
damage	I-Disease
with	O
a	O
variety	O
of	O
morphological	O
aberrations	O
by	O
all	O
the	O
three	O
drugs	O
in	O
the	O
absence	O
of	O
GSPE	B-Chemical
preexposure	O
than	O
in	O
its	O
presence	O
.	O

GSPE	B-Chemical
+	O
drug	O
exposed	O
tissues	O
exhibited	O
minor	O
residual	O
damage	O
or	O
near	O
total	O
recovery	O
.	O

Additionally	O
,	O
histopathological	O
alterations	O
mirrored	O
both	O
serum	O
chemistry	O
changes	O
and	O
the	O
pattern	O
of	O
DNA	O
fragmentation	O
.	O

Interestingly	O
,	O
all	O
the	O
drugs	O
,	O
such	O
as	O
,	O
AAP	B-Chemical
,	O
AMI	B-Chemical
and	O
DOX	B-Chemical
induced	O
apoptotic	O
death	O
in	O
addition	O
to	O
necrosis	B-Disease
in	O
the	O
respective	O
organs	O
which	O
was	O
very	O
effectively	O
blocked	O
by	O
GSPE	B-Chemical
.	O

Since	O
AAP	B-Chemical
,	O
AMI	B-Chemical
and	O
DOX	B-Chemical
undergo	O
biotransformation	O
and	O
are	O
known	O
to	O
produce	O
damaging	O
radicals	O
in	O
vivo	O
,	O
the	O
protection	O
by	O
GSPE	B-Chemical
may	O
be	O
linked	O
to	O
both	O
inhibition	O
of	O
metabolism	O
and	O
/	O
or	O
detoxification	O
of	O
cytotoxic	O
radicals	O
.	O

In	O
addition	O
,	O
its	O
'	O
presumed	O
contribution	O
to	O
DNA	O
repair	O
may	O
be	O
another	O
important	O
attribute	O
,	O
which	O
played	O
a	O
role	O
in	O
the	O
chemoprevention	O
process	O
.	O

Additionally	O
,	O
this	O
may	O
have	O
been	O
the	O
first	O
report	O
on	O
AMI	B-Chemical
-	O
induced	O
apoptotic	O
death	O
in	O
the	O
lung	O
tissue	O
.	O

Taken	O
together	O
,	O
these	O
events	O
undoubtedly	O
establish	O
GSPE	B-Chemical
'	O
s	O
abundant	O
bioavailability	O
,	O
and	O
the	O
power	O
to	O
defend	O
multiple	O
target	O
organs	O
from	O
toxic	O
assaults	O
induced	O
by	O
structurally	O
diverse	O
and	O
functionally	O
different	O
entities	O
in	O
vivo	O
.	O

Antidepressant	B-Chemical
-	O
induced	O
mania	B-Disease
in	O
bipolar	B-Disease
patients	O
:	O
identification	O
of	O
risk	O
factors	O
.	O

BACKGROUND	O
:	O
Concerns	O
about	O
possible	O
risks	O
of	O
switching	O
to	O
mania	B-Disease
associated	O
with	O
antidepressants	B-Chemical
continue	O
to	O
interfere	O
with	O
the	O
establishment	O
of	O
an	O
optimal	O
treatment	O
paradigm	O
for	O
bipolar	B-Disease
depression	I-Disease
.	O

METHOD	O
:	O
The	O
response	O
of	O
44	O
patients	O
meeting	O
DSM	O
-	O
IV	O
criteria	O
for	O
bipolar	B-Disease
disorder	I-Disease
to	O
naturalistic	O
treatment	O
was	O
assessed	O
for	O
at	O
least	O
6	O
weeks	O
using	O
the	O
Montgomery	O
-	O
Asberg	O
Depression	O
Rating	O
Scale	O
and	O
the	O
Bech	O
-	O
Rafaelson	O
Mania	O
Rating	O
Scale	O
.	O

Patients	O
who	O
experienced	O
a	O
manic	B-Disease
or	O
hypomanic	B-Disease
switch	O
were	O
compared	O
with	O
those	O
who	O
did	O
not	O
on	O
several	O
variables	O
including	O
age	O
,	O
sex	O
,	O
diagnosis	O
(	O
DSM	B-Disease
-	I-Disease
IV	I-Disease
bipolar	I-Disease
I	I-Disease
vs	O
.	O
bipolar	B-Disease
II	I-Disease
)	O
,	O
number	O
of	O
previous	O
manic	B-Disease
episodes	O
,	O
type	O
of	O
antidepressant	B-Chemical
therapy	O
used	O
(	O
electroconvulsive	O
therapy	O
vs	O
.	O
antidepressant	B-Chemical
drugs	O
and	O
,	O
more	O
particularly	O
,	O
selective	O
serotonin	B-Chemical
reuptake	I-Chemical
inhibitors	I-Chemical
[	O
SSRIs	B-Chemical
]	O
)	O
,	O
use	O
and	O
type	O
of	O
mood	O
stabilizers	O
(	O
lithium	B-Chemical
vs	O
.	O
anticonvulsants	O
)	O
,	O
and	O
temperament	O
of	O
the	O
patient	O
,	O
assessed	O
during	O
a	O
normothymic	O
period	O
using	O
the	O
hyperthymia	O
component	O
of	O
the	O
Semi	O
-	O
structured	O
Affective	O
Temperament	O
Interview	O
.	O

RESULTS	O
:	O
Switches	O
to	O
hypomania	B-Disease
or	O
mania	B-Disease
occurred	O
in	O
27	O
%	O
of	O
all	O
patients	O
(	O
N	O
=	O
12	O
)	O
(	O
and	O
in	O
24	O
%	O
of	O
the	O
subgroup	O
of	O
patients	O
treated	O
with	O
SSRIs	B-Chemical
[	O
8	O
/	O
33	O
]	O
)	O
;	O
16	O
%	O
(	O
N	O
=	O
7	O
)	O
experienced	O
manic	B-Disease
episodes	O
,	O
and	O
11	O
%	O
(	O
N	O
=	O
5	O
)	O
experienced	O
hypomanic	B-Disease
episodes	O
.	O

Sex	O
,	O
age	O
,	O
diagnosis	O
(	O
bipolar	B-Disease
I	I-Disease
vs	O
.	O
bipolar	B-Disease
II	I-Disease
)	O
,	O
and	O
additional	O
treatment	O
did	O
not	O
affect	O
the	O
risk	O
of	O
switching	O
.	O

The	O
incidence	O
of	O
mood	O
switches	O
seemed	O
not	O
to	O
differ	O
between	O
patients	O
receiving	O
an	O
anticonvulsant	O
and	O
those	O
receiving	O
no	O
mood	O
stabilizer	O
.	O

In	O
contrast	O
,	O
mood	O
switches	O
were	O
less	O
frequent	O
in	O
patients	O
receiving	O
lithium	B-Chemical
(	O
15	O
%	O
,	O
4	O
/	O
26	O
)	O
than	O
in	O
patients	O
not	O
treated	O
with	O
lithium	B-Chemical
(	O
44	O
%	O
,	O
8	O
/	O
18	O
;	O
p	O
=	O
.	O
04	O
)	O
.	O

The	O
number	O
of	O
previous	O
manic	B-Disease
episodes	O
did	O
not	O
affect	O
the	O
probability	O
of	O
switching	O
,	O
whereas	O
a	O
high	O
score	O
on	O
the	O
hyperthymia	O
component	O
of	O
the	O
Semistructured	O
Affective	O
Temperament	O
Interview	O
was	O
associated	O
with	O
a	O
greater	O
risk	O
of	O
switching	O
(	O
p	O
=	O
.	O
008	O
)	O
.	O

CONCLUSION	O
:	O
The	O
frequency	O
of	O
mood	O
switching	O
associated	O
with	O
acute	O
antidepressant	B-Chemical
therapy	O
may	O
be	O
reduced	O
by	O
lithium	B-Chemical
treatment	O
.	O

Particular	O
attention	O
should	O
be	O
paid	O
to	O
patients	O
with	O
a	O
hyperthymic	O
temperament	O
,	O
who	O
have	O
a	O
greater	O
risk	O
of	O
mood	O
switches	O
.	O

Peritubular	O
capillary	O
basement	O
membrane	O
reduplication	O
in	O
allografts	O
and	O
native	O
kidney	B-Disease
disease	I-Disease
:	O
a	O
clinicopathologic	O
study	O
of	O
278	O
consecutive	O
renal	O
specimens	O
.	O

BACKGROUND	O
:	O
An	O
association	O
has	O
been	O
found	O
between	O
transplant	B-Disease
glomerulopathy	I-Disease
(	O
TG	B-Disease
)	O
and	O
reduplication	O
of	O
peritubular	O
capillary	O
basement	O
membranes	O
(	O
PTCR	O
)	O
.	O

Although	O
such	O
an	O
association	O
is	O
of	O
practical	O
and	O
theoretical	O
importance	O
,	O
only	O
one	O
prospective	O
study	O
has	O
tried	O
to	O
confirm	O
it	O
.	O

METHODS	O
:	O
We	O
examined	O
278	O
consecutive	O
renal	O
specimens	O
(	O
from	O
135	O
transplants	O
and	O
143	O
native	O
kidneys	O
)	O
for	O
ultrastructural	O
evidence	O
of	O
PTCR	O
.	O

In	O
addition	O
to	O
renal	O
allografts	O
with	O
TG	B-Disease
,	O
we	O
also	O
examined	O
grafts	O
with	O
acute	O
rejection	O
,	O
recurrent	O
glomerulonephritis	B-Disease
,	O
chronic	B-Disease
allograft	I-Disease
nephropathy	I-Disease
and	O
stable	O
grafts	O
(	O
"	O
protocol	O
biopsies	O
"	O
)	O
.	O

Native	O
kidney	O
specimens	O
included	O
a	O
wide	O
range	O
of	O
glomerulopathies	B-Disease
as	O
well	O
as	O
cases	O
of	O
thrombotic	B-Disease
microangiopathy	I-Disease
,	O
malignant	B-Disease
hypertension	I-Disease
,	O
acute	O
interstitial	B-Disease
nephritis	I-Disease
,	O
and	O
acute	B-Disease
tubular	I-Disease
necrosis	I-Disease
.	O

RESULTS	O
:	O
We	O
found	O
PTCR	O
in	O
14	O
of	O
15	O
cases	O
of	O
TG	B-Disease
,	O
in	O
7	O
transplant	O
biopsy	O
specimens	O
without	O
TG	B-Disease
,	O
and	O
in	O
13	O
of	O
143	O
native	O
kidney	O
biopsy	O
specimens	O
.	O

These	O
13	O
included	O
cases	O
of	O
malignant	B-Disease
hypertension	I-Disease
,	O
thrombotic	B-Disease
microangiopathy	I-Disease
,	O
lupus	B-Disease
nephritis	I-Disease
,	O
Henoch	B-Disease
-	I-Disease
Schonlein	I-Disease
nephritis	I-Disease
,	O
crescentic	O
glomerulonephritis	B-Disease
,	O
and	O
cocaine	B-Chemical
-	O
related	O
acute	B-Disease
renal	I-Disease
failure	I-Disease
.	O

Mild	O
PTCR	O
in	O
allografts	O
without	O
TG	B-Disease
did	O
not	O
predict	O
renal	B-Disease
failure	I-Disease
or	O
significant	O
proteinuria	B-Disease
after	O
follow	O
-	O
up	O
periods	O
of	O
between	O
3	O
months	O
and	O
1	O
year	O
.	O

CONCLUSIONS	O
:	O
We	O
conclude	O
that	O
in	O
transplants	O
,	O
there	O
is	O
a	O
strong	O
association	O
between	O
well	O
-	O
developed	O
PTCR	O
and	O
TG	B-Disease
,	O
while	O
the	O
significance	O
of	O
mild	O
PTCR	O
and	O
its	O
predictive	O
value	O
in	O
the	O
absence	O
of	O
TG	B-Disease
is	O
unclear	O
.	O

PTCR	O
also	O
occurs	O
in	O
certain	O
native	O
kidney	B-Disease
diseases	I-Disease
,	O
though	O
the	O
association	O
is	O
not	O
as	O
strong	O
as	O
that	O
for	O
TG	B-Disease
.	O

We	O
suggest	O
that	O
repeated	O
endothelial	B-Disease
injury	I-Disease
,	O
including	O
immunologic	B-Disease
injury	I-Disease
,	O
may	O
be	O
the	O
cause	O
of	O
this	O
lesion	O
both	O
in	O
allografts	O
and	O
native	O
kidneys	O
.	O

Caffeine	B-Chemical
-	O
induced	O
cardiac	B-Disease
arrhythmia	I-Disease
:	O
an	O
unrecognised	O
danger	O
of	O
healthfood	O
products	O
.	O

We	O
describe	O
a	O
25	O
-	O
year	O
-	O
old	O
woman	O
with	O
pre	O
-	O
existing	O
mitral	B-Disease
valve	I-Disease
prolapse	I-Disease
who	O
developed	O
intractable	O
ventricular	B-Disease
fibrillation	I-Disease
after	O
consuming	O
a	O
"	O
natural	O
energy	O
"	O
guarana	O
health	O
drink	O
containing	O
a	O
high	O
concentration	O
of	O
caffeine	B-Chemical
.	O

This	O
case	O
highlights	O
the	O
need	O
for	O
adequate	O
labelling	O
and	O
regulation	O
of	O
such	O
products	O
.	O

Conformationally	O
restricted	O
analogs	O
of	O
BD1008	B-Chemical
and	O
an	O
antisense	O
oligodeoxynucleotide	B-Chemical
targeting	O
sigma1	O
receptors	O
produce	O
anti	O
-	O
cocaine	B-Chemical
effects	O
in	O
mice	O
.	O

Cocaine	B-Chemical
'	O
s	O
ability	O
to	O
interact	O
with	O
sigma	O
receptors	O
suggests	O
that	O
these	O
proteins	O
mediate	O
some	O
of	O
its	O
behavioral	O
effects	O
.	O

Therefore	O
,	O
three	O
novel	O
sigma	O
receptor	O
ligands	O
with	O
antagonist	O
activity	O
were	O
evaluated	O
in	O
Swiss	O
Webster	O
mice	O
:	O
BD1018	B-Chemical
(	O
3S	B-Chemical
-	I-Chemical
1	I-Chemical
-	I-Chemical
[	I-Chemical
2	I-Chemical
-	I-Chemical
(	I-Chemical
3	I-Chemical
,	I-Chemical
4	I-Chemical
-	I-Chemical
dichlorophenyl	I-Chemical
)	I-Chemical
ethyl	I-Chemical
]	I-Chemical
-	I-Chemical
1	I-Chemical
,	I-Chemical
4	I-Chemical
-	I-Chemical
diazabicyclo	I-Chemical
[	I-Chemical
4	I-Chemical
.	I-Chemical
3	I-Chemical
.	I-Chemical
0	I-Chemical
]	I-Chemical
nonane	I-Chemical
)	O
,	O
BD1063	B-Chemical
(	O
1	B-Chemical
-	I-Chemical
[	I-Chemical
2	I-Chemical
-	I-Chemical
(	I-Chemical
3	I-Chemical
,	I-Chemical
4	I-Chemical
-	I-Chemical
dichlorophenyl	I-Chemical
)	I-Chemical
ethyl	I-Chemical
]	I-Chemical
-	I-Chemical
4	I-Chemical
-	I-Chemical
methylpiperazine	I-Chemical
)	O
,	O
and	O
LR132	B-Chemical
(	O
1R	O
,	O
2S	O
-	O
(	O
+	O
)	O
-	O
cis	O
-	O
N	O
-	O
[	O
2	O
-	O
(	O
3	O
,	O
4	O
-	O
dichlorophenyl	O
)	O
ethyl	O
]	O
-	O
2	O
-	O
(	O
1	O
-	O
pyrrolidinyl	O
)	O
cyclohexylamine	O
)	O
.	O

Competition	O
binding	O
assays	O
demonstrated	O
that	O
all	O
three	O
compounds	O
have	O
high	O
affinities	O
for	O
sigma1	O
receptors	O
.	O

The	O
three	O
compounds	O
vary	O
in	O
their	O
affinities	O
for	O
sigma2	O
receptors	O
and	O
exhibit	O
negligible	O
affinities	O
for	O
dopamine	B-Chemical
,	O
opioid	O
,	O
GABA	B-Chemical
(	O
A	O
)	O
and	O
NMDA	B-Chemical
receptors	O
.	O

In	O
behavioral	O
studies	O
,	O
pre	O
-	O
treatment	O
of	O
mice	O
with	O
BD1018	B-Chemical
,	O
BD1063	B-Chemical
,	O
or	O
LR132	B-Chemical
significantly	O
attenuated	O
cocaine	B-Chemical
-	O
induced	O
convulsions	B-Disease
and	O
lethality	O
.	O

Moreover	O
,	O
post	O
-	O
treatment	O
with	O
LR132	B-Chemical
prevented	O
cocaine	B-Chemical
-	O
induced	O
lethality	O
in	O
a	O
significant	O
proportion	O
of	O
animals	O
.	O

In	O
contrast	O
to	O
the	O
protection	O
provided	O
by	O
the	O
putative	O
antagonists	O
,	O
the	O
well	O
-	O
characterized	O
sigma	O
receptor	O
agonist	O
di	B-Chemical
-	I-Chemical
o	I-Chemical
-	I-Chemical
tolylguanidine	I-Chemical
(	O
DTG	B-Chemical
)	O
and	O
the	O
novel	O
sigma	O
receptor	O
agonist	O
BD1031	B-Chemical
(	O
3R	B-Chemical
-	I-Chemical
1	I-Chemical
-	I-Chemical
[	I-Chemical
2	I-Chemical
-	I-Chemical
(	I-Chemical
3	I-Chemical
,	I-Chemical
4	I-Chemical
-	I-Chemical
dichlorophenyl	I-Chemical
)	I-Chemical
ethyl	I-Chemical
]	I-Chemical
-	I-Chemical
1	I-Chemical
,	I-Chemical
4	I-Chemical
-	I-Chemical
diazabicyclo	I-Chemical
[	I-Chemical
4	I-Chemical
.	I-Chemical
3	I-Chemical
.	I-Chemical
0	I-Chemical
]	I-Chemical
nonane	I-Chemical
)	O
each	O
worsened	O
the	O
behavioral	O
toxicity	B-Disease
of	O
cocaine	B-Chemical
.	O

At	O
doses	O
where	O
alone	O
,	O
they	O
produced	O
no	O
significant	O
effects	O
on	O
locomotion	O
,	O
BD1018	B-Chemical
,	O
BD1063	B-Chemical
and	O
LR132	B-Chemical
significantly	O
attenuated	O
the	O
locomotor	O
stimulatory	O
effects	O
of	O
cocaine	B-Chemical
.	O

To	O
further	O
validate	O
the	O
hypothesis	O
that	O
the	O
anti	O
-	O
cocaine	B-Chemical
effects	O
of	O
the	O
novel	O
ligands	O
involved	O
antagonism	O
of	O
sigma	O
receptors	O
,	O
an	O
antisense	O
oligodeoxynucleotide	B-Chemical
against	O
sigma1	O
receptors	O
was	O
also	O
shown	O
to	O
significantly	O
attenuate	O
the	O
convulsive	B-Disease
and	O
locomotor	O
stimulatory	O
effects	O
of	O
cocaine	B-Chemical
.	O

Together	O
,	O
the	O
data	O
suggests	O
that	O
functional	O
antagonism	O
of	O
sigma	O
receptors	O
is	O
capable	O
of	O
attenuating	O
a	O
number	O
of	O
cocaine	B-Chemical
-	O
induced	O
behaviors	O
.	O

Ranitidine	B-Chemical
-	O
induced	O
acute	O
interstitial	B-Disease
nephritis	I-Disease
in	O
a	O
cadaveric	O
renal	O
allograft	O
.	O

Ranitidine	B-Chemical
frequently	O
is	O
used	O
for	O
preventing	O
peptic	O
ulceration	O
after	O
renal	O
transplantation	O
.	O

This	O
drug	O
occasionally	O
has	O
been	O
associated	O
with	O
acute	O
interstitial	B-Disease
nephritis	I-Disease
in	O
native	O
kidneys	O
.	O

There	O
are	O
no	O
similar	O
reports	O
with	O
renal	O
transplantation	O
.	O

We	O
report	O
a	O
case	O
of	O
ranitidine	B-Chemical
-	O
induced	O
acute	O
interstitial	B-Disease
nephritis	I-Disease
in	O
a	O
recipient	O
of	O
a	O
cadaveric	O
renal	O
allograft	O
presenting	O
with	O
acute	O
allograft	O
dysfunction	O
within	O
48	O
hours	O
of	O
exposure	O
to	O
the	O
drug	O
.	O

The	O
biopsy	O
specimen	O
showed	O
pathognomonic	O
features	O
,	O
including	O
eosinophilic	O
infiltration	O
of	O
the	O
interstitial	O
compartment	O
.	O

Allograft	O
function	O
improved	O
rapidly	O
and	O
returned	O
to	O
baseline	O
after	O
stopping	O
the	O
drug	O
.	O

Liver	B-Disease
disease	I-Disease
caused	O
by	O
propylthiouracil	B-Chemical
.	O

This	O
report	O
presents	O
the	O
clinical	O
,	O
laboratory	O
,	O
and	O
light	O
and	O
electron	O
microscopic	O
observations	O
on	O
a	O
patient	O
with	O
chronic	B-Disease
active	I-Disease
(	I-Disease
aggressive	I-Disease
)	I-Disease
hepatitis	I-Disease
caused	O
by	O
the	O
administration	O
of	O
propylthiouracil	B-Chemical
.	O

This	O
is	O
an	O
addition	O
to	O
the	O
list	O
of	O
drugs	O
that	O
must	O
be	O
considered	O
in	O
the	O
evaluation	O
of	O
chronic	O
liver	B-Disease
disease	I-Disease
.	O

Withdrawal	B-Disease
-	I-Disease
emergent	I-Disease
rabbit	I-Disease
syndrome	I-Disease
during	O
dose	O
reduction	O
of	O
risperidone	B-Chemical
.	O

Rabbit	B-Disease
syndrome	I-Disease
(	O
RS	B-Disease
)	O
is	O
a	O
rare	O
extrapyramidal	O
side	O
effect	O
caused	O
by	O
prolonged	O
neuroleptic	O
medication	O
.	O

Here	O
we	O
present	O
a	O
case	O
of	O
withdrawal	B-Disease
-	I-Disease
emergent	I-Disease
RS	I-Disease
,	O
which	O
is	O
the	O
first	O
of	O
its	O
kind	O
to	O
be	O
reported	O
.	O

The	O
patient	O
developed	O
RS	B-Disease
during	O
dose	O
reduction	O
of	O
risperidone	B-Chemical
.	O

The	O
symptom	O
was	O
treated	O
successfully	O
with	O
trihexyphenidyl	B-Chemical
anticholinergic	O
therapy	O
.	O

The	O
underlying	O
mechanism	O
of	O
withdrawal	B-Disease
-	I-Disease
emergent	I-Disease
RS	I-Disease
in	O
the	O
present	O
case	O
may	O
have	O
been	O
related	O
to	O
the	O
pharmacological	O
profile	O
of	O
risperidone	B-Chemical
,	O
a	O
serotonin	B-Chemical
-	O
dopamine	B-Chemical
antagonist	O
,	O
suggesting	O
the	O
pathophysiologic	O
influence	O
of	O
the	O
serotonin	B-Chemical
system	O
in	O
the	O
development	O
of	O
RS	B-Disease
.	O

Pharmacokinetic	O
/	O
pharmacodynamic	O
assessment	O
of	O
the	O
effects	O
of	O
E4031	B-Chemical
,	O
cisapride	B-Chemical
,	O
terfenadine	B-Chemical
and	O
terodiline	B-Chemical
on	O
monophasic	O
action	O
potential	O
duration	O
in	O
dog	O
.	O

1	O
.	O

Torsades	B-Disease
de	I-Disease
pointes	I-Disease
(	O
TDP	B-Disease
)	O
is	O
a	O
potentially	O
fatal	O
ventricular	B-Disease
tachycardia	I-Disease
associated	O
with	O
increases	O
in	O
QT	O
interval	O
and	O
monophasic	O
action	O
potential	O
duration	O
(	O
MAPD	O
)	O
.	O

TDP	B-Disease
is	O
a	O
side	O
-	O
effect	O
that	O
has	O
led	O
to	O
withdrawal	O
of	O
several	O
drugs	O
from	O
the	O
market	O
(	O
e	O
.	O
g	O
.	O
terfenadine	B-Chemical
and	O
terodiline	B-Chemical
)	O
.	O

2	O
.	O

The	O
potential	O
of	O
compounds	O
to	O
cause	O
TDP	B-Disease
was	O
evaluated	O
by	O
monitoring	O
their	O
effects	O
on	O
MAPD	O
in	O
dog	O
.	O

Four	O
compounds	O
known	O
to	O
increase	O
QT	O
interval	O
and	O
cause	O
TDP	B-Disease
were	O
investigated	O
:	O
terfenadine	B-Chemical
,	O
terodiline	B-Chemical
,	O
cisapride	B-Chemical
and	O
E4031	B-Chemical
.	O

On	O
the	O
basis	O
that	O
only	O
free	O
drug	O
in	O
the	O
systemic	O
circulation	O
will	O
elicit	O
a	O
pharmacological	O
response	O
target	O
,	O
free	O
concentrations	O
in	O
plasma	O
were	O
selected	O
to	O
mimic	O
the	O
free	O
drug	O
exposures	O
in	O
man	O
.	O

Infusion	O
regimens	O
were	O
designed	O
that	O
rapidly	O
achieved	O
and	O
maintained	O
target	O
-	O
free	O
concentrations	O
of	O
these	O
drugs	O
in	O
plasma	O
and	O
data	O
on	O
the	O
relationship	O
between	O
free	O
concentration	O
and	O
changes	O
in	O
MAPD	O
were	O
obtained	O
for	O
these	O
compounds	O
.	O

3	O
.	O

These	O
data	O
indicate	O
that	O
the	O
free	O
ED50	O
in	O
plasma	O
for	O
terfenadine	B-Chemical
(	O
1	O
.	O
9	O
nM	O
)	O
,	O
terodiline	B-Chemical
(	O
76	O
nM	O
)	O
,	O
cisapride	B-Chemical
(	O
11	O
nM	O
)	O
and	O
E4031	B-Chemical
(	O
1	O
.	O
9	O
nM	O
)	O
closely	O
correlate	O
with	O
the	O
free	O
concentration	O
in	O
man	O
causing	O
QT	O
effects	O
.	O

For	O
compounds	O
that	O
have	O
shown	O
TDP	B-Disease
in	O
the	O
clinic	O
(	O
terfenadine	B-Chemical
,	O
terodiline	B-Chemical
,	O
cisapride	B-Chemical
)	O
there	O
is	O
little	O
differentiation	O
between	O
the	O
dog	O
ED50	O
and	O
the	O
efficacious	O
free	O
plasma	O
concentrations	O
in	O
man	O
(	O
<	O
10	O
-	O
fold	O
)	O
reflecting	O
their	O
limited	O
safety	O
margins	O
.	O

These	O
data	O
underline	O
the	O
need	O
to	O
maximize	O
the	O
therapeutic	O
ratio	O
with	O
respect	O
to	O
TDP	B-Disease
in	O
potential	O
development	O
candidates	O
and	O
the	O
importance	O
of	O
using	O
free	O
drug	O
concentrations	O
in	O
pharmacokinetic	O
/	O
pharmacodynamic	O
studies	O
.	O

Bladder	O
retention	B-Disease
of	I-Disease
urine	I-Disease
as	O
a	O
result	O
of	O
continuous	O
intravenous	O
infusion	O
of	O
fentanyl	B-Chemical
:	O
2	O
case	O
reports	O
.	O

Sedation	O
has	O
been	O
commonly	O
used	O
in	O
the	O
neonate	O
to	O
decrease	O
the	O
stress	O
and	O
pain	B-Disease
from	O
the	O
noxious	O
stimuli	O
and	O
invasive	O
procedures	O
in	O
the	O
neonatal	O
intensive	O
care	O
unit	O
,	O
as	O
well	O
as	O
to	O
facilitate	O
synchrony	O
between	O
ventilator	O
and	O
spontaneous	O
breaths	O
.	O

Fentanyl	B-Chemical
,	O
an	O
opioid	O
analgesic	O
,	O
is	O
frequently	O
used	O
in	O
the	O
neonatal	O
intensive	O
care	O
unit	O
setting	O
for	O
these	O
very	O
purposes	O
.	O

Various	O
reported	O
side	O
effects	O
of	O
fentanyl	B-Chemical
administration	O
include	O
chest	B-Disease
wall	I-Disease
rigidity	I-Disease
,	O
hypotension	B-Disease
,	O
respiratory	B-Disease
depression	I-Disease
,	O
and	O
bradycardia	B-Disease
.	O

Here	O
,	O
2	O
cases	O
of	O
urinary	B-Disease
bladder	I-Disease
retention	I-Disease
leading	O
to	O
renal	O
pelvocalyceal	O
dilatation	O
mimicking	O
hydronephrosis	B-Disease
as	O
a	O
result	O
of	O
continuous	O
infusion	O
of	O
fentanyl	B-Chemical
are	O
reported	O
.	O

Fatal	O
myeloencephalopathy	B-Disease
due	O
to	O
accidental	O
intrathecal	O
vincristin	B-Chemical
administration	O
:	O
a	O
report	O
of	O
two	O
cases	O
.	O

We	O
report	O
on	O
two	O
fatal	O
cases	O
of	O
accidental	O
intrathecal	O
vincristine	B-Chemical
instillation	O
in	O
a	O
5	O
-	O
year	O
old	O
girl	O
with	O
recurrent	O
acute	B-Disease
lymphoblastic	I-Disease
leucemia	I-Disease
and	O
a	O
57	O
-	O
year	O
old	O
man	O
with	O
lymphoblastic	B-Disease
lymphoma	I-Disease
.	O

The	O
girl	O
died	O
seven	O
days	O
,	O
the	O
man	O
four	O
weeks	O
after	O
intrathecal	O
injection	O
of	O
vincristine	B-Chemical
.	O

Clinically	O
,	O
the	O
onset	O
was	O
characterized	O
by	O
the	O
signs	O
of	O
opistothonus	B-Disease
,	I-Disease
sensory	I-Disease
and	I-Disease
motor	I-Disease
dysfunction	I-Disease
and	O
ascending	O
paralysis	B-Disease
.	O

Histological	O
and	O
immunohistochemical	O
investigations	O
(	O
HE	O
-	O
LFB	O
,	O
CD	O
-	O
68	O
,	O
Neurofilament	O
)	O
revealed	O
degeneration	B-Disease
of	I-Disease
myelin	I-Disease
and	I-Disease
axons	I-Disease
as	O
well	O
as	O
pseudocystic	B-Disease
transformation	I-Disease
in	O
areas	O
exposed	O
to	O
vincristine	B-Chemical
,	O
accompanied	O
by	O
secondary	O
changes	O
with	O
numerous	O
prominent	O
macrophages	O
.	O

The	O
clinical	O
course	O
and	O
histopathological	O
results	O
of	O
the	O
two	O
cases	O
are	O
presented	O
.	O

A	O
review	O
of	O
all	O
reported	O
cases	O
in	O
the	O
literature	O
is	O
given	O
.	O

A	O
better	O
controlled	O
regimen	O
for	O
administering	O
vincristine	B-Chemical
and	O
intrathecal	O
chemotherapy	O
is	O
recommended	O
.	O

Palpebral	B-Disease
twitching	I-Disease
in	O
a	O
depressed	B-Disease
adolescent	O
on	O
citalopram	B-Chemical
.	O

Current	O
estimates	O
suggest	O
that	O
between	O
0	O
.	O
4	O
%	O
and	O
8	O
.	O
3	O
%	O
of	O
children	O
and	O
adolescents	O
are	O
affected	O
by	O
major	B-Disease
depression	I-Disease
.	O

We	O
report	O
a	O
favorable	O
response	O
to	O
treatment	O
with	O
citalopram	B-Chemical
by	O
a	O
15	O
-	O
year	O
-	O
old	O
boy	O
with	O
major	B-Disease
depression	I-Disease
who	O
exhibited	O
palpebral	B-Disease
twitching	I-Disease
during	O
his	O
first	O
2	O
weeks	O
of	O
treatment	O
.	O

This	O
may	O
have	O
been	O
a	O
side	O
effect	O
of	O
citalopram	B-Chemical
as	O
it	O
remitted	O
with	O
redistribution	O
of	O
doses	O
.	O

The	O
3	O
-	O
week	O
sulphasalazine	B-Chemical
syndrome	O
strikes	O
again	O
.	O

A	O
34	O
-	O
year	O
-	O
old	O
lady	O
developed	O
a	O
constellation	O
of	O
dermatitis	B-Disease
,	O
fever	B-Disease
,	O
lymphadenopathy	B-Disease
and	O
hepatitis	B-Disease
,	O
beginning	O
on	O
the	O
17th	O
day	O
of	O
a	O
course	O
of	O
oral	O
sulphasalazine	B-Chemical
for	O
sero	O
-	O
negative	O
rheumatoid	B-Disease
arthritis	I-Disease
.	O

Cervical	O
and	O
inguinal	O
lymph	O
node	O
biopsies	O
showed	O
the	O
features	O
of	O
severe	O
necrotising	O
lymphadenitis	B-Disease
,	O
associated	O
with	O
erythrophagocytosis	O
and	O
prominent	O
eosinophilic	O
infiltrates	O
,	O
without	O
viral	O
inclusion	O
bodies	O
,	O
suggestive	O
of	O
an	O
adverse	B-Disease
drug	I-Disease
reaction	I-Disease
.	O
A	O
week	O
later	O
,	O
fulminant	O
drug	B-Disease
-	I-Disease
induced	I-Disease
hepatitis	I-Disease
,	O
associated	O
with	O
the	O
presence	O
of	O
anti	O
-	O
nuclear	O
autoantibodies	O
(	O
but	O
not	O
with	O
other	O
markers	O
of	O
autoimmunity	B-Disease
)	O
,	O
and	O
accompanied	O
by	O
multi	B-Disease
-	I-Disease
organ	I-Disease
failure	I-Disease
and	O
sepsis	B-Disease
,	O
supervened	O
.	O

She	O
subsequently	O
died	O
some	O
5	O
weeks	O
after	O
the	O
commencement	O
of	O
her	O
drug	O
therapy	O
.	O
Post	O
-	O
mortem	O
examination	O
showed	O
evidence	O
of	O
massive	B-Disease
hepatocellular	I-Disease
necrosis	I-Disease
,	O
acute	O
hypersensitivity	O
myocarditis	B-Disease
,	O
focal	O
acute	O
tubulo	O
-	O
interstitial	O
nephritis	B-Disease
and	O
extensive	O
bone	B-Disease
marrow	I-Disease
necrosis	I-Disease
,	O
with	O
no	O
evidence	O
of	O
malignancy	B-Disease
.	O

It	O
is	O
thought	O
that	O
the	O
clinico	O
-	O
pathological	O
features	O
and	O
chronology	O
of	O
this	O
case	O
bore	O
the	O
hallmarks	O
of	O
the	O
so	O
-	O
called	O
"	O
3	O
-	O
week	O
sulphasalazine	B-Chemical
syndrome	O
"	O
,	O
a	O
rare	O
,	O
but	O
often	O
fatal	O
,	O
immunoallergic	O
reaction	O
to	O
sulphasalazine	B-Chemical
.	O

Intravenous	O
administration	O
of	O
prochlorperazine	B-Chemical
by	O
15	O
-	O
minute	O
infusion	O
versus	O
2	O
-	O
minute	O
bolus	O
does	O
not	O
affect	O
the	O
incidence	O
of	O
akathisia	B-Disease
:	O
a	O
prospective	O
,	O
randomized	O
,	O
controlled	O
trial	O
.	O

STUDY	O
OBJECTIVE	O
:	O
We	O
sought	O
to	O
compare	O
the	O
rate	O
of	O
akathisia	B-Disease
after	O
administration	O
of	O
intravenous	O
prochlorperazine	B-Chemical
as	O
a	O
2	O
-	O
minute	O
bolus	O
or	O
15	O
-	O
minute	O
infusion	O
.	O

METHODS	O
:	O
We	O
conducted	O
a	O
prospective	O
,	O
randomized	O
,	O
double	O
-	O
blind	O
study	O
in	O
the	O
emergency	O
department	O
of	O
a	O
central	O
-	O
city	O
teaching	O
hospital	O
.	O

Patients	O
aged	O
18	O
years	O
or	O
older	O
treated	O
with	O
prochlorperazine	B-Chemical
for	O
headache	B-Disease
,	O
nausea	B-Disease
,	O
or	O
vomiting	B-Disease
were	O
eligible	O
for	O
inclusion	O
.	O

Study	O
participants	O
were	O
randomized	O
to	O
receive	O
10	O
mg	O
of	O
prochlorperazine	B-Chemical
administered	O
intravenously	O
by	O
means	O
of	O
2	O
-	O
minute	O
push	O
(	O
bolus	O
group	O
)	O
or	O
10	O
mg	O
diluted	O
in	O
50	O
mL	O
of	O
normal	O
saline	O
solution	O
administered	O
by	O
means	O
of	O
intravenous	O
infusion	O
during	O
a	O
15	O
-	O
minute	O
period	O
(	O
infusion	O
group	O
)	O
.	O

The	O
main	O
outcome	O
was	O
the	O
number	O
of	O
study	O
participants	O
experiencing	O
akathisia	B-Disease
within	O
60	O
minutes	O
of	O
administration	O
.	O

Akathisia	O
was	O
defined	O
as	O
either	O
a	O
spontaneous	O
report	O
of	O
restlessness	O
or	O
agitation	B-Disease
or	O
a	O
change	O
of	O
2	O
or	O
more	O
in	O
the	O
patient	O
-	O
reported	O
akathisia	B-Disease
rating	O
scale	O
and	O
a	O
change	O
of	O
at	O
least	O
1	O
in	O
the	O
investigator	O
-	O
observed	O
akathisia	B-Disease
rating	O
scale	O
.	O

The	O
intensity	O
of	O
headache	B-Disease
and	O
nausea	B-Disease
was	O
measured	O
with	O
a	O
100	O
-	O
mm	O
visual	O
analog	O
scale	O
.	O

RESULTS	O
:	O
One	O
hundred	O
patients	O
were	O
enrolled	O
.	O

One	O
study	O
participant	O
was	O
excluded	O
after	O
protocol	O
violation	O
.	O

Seventy	O
-	O
three	O
percent	O
(	O
73	O
/	O
99	O
)	O
of	O
the	O
study	O
participants	O
were	O
treated	O
for	O
headache	B-Disease
and	O
70	O
%	O
(	O
70	O
/	O
99	O
)	O
for	O
nausea	B-Disease
.	O

In	O
the	O
bolus	O
group	O
,	O
26	O
.	O
0	O
%	O
(	O
13	O
/	O
50	O
)	O
had	O
akathisia	B-Disease
compared	O
with	O
32	O
.	O
7	O
%	O
(	O
16	O
/	O
49	O
)	O
in	O
the	O
infusion	O
group	O
(	O
Delta	O
=	O
-	O
6	O
.	O
7	O
%	O
;	O
95	O
%	O
confidence	O
interval	O
[	O
CI	O
]	O
-	O
24	O
.	O
6	O
%	O
to	O
11	O
.	O
2	O
%	O
)	O
.	O

The	O
difference	O
between	O
the	O
bolus	O
and	O
infusion	O
groups	O
in	O
the	O
percentage	O
of	O
participants	O
who	O
saw	O
a	O
50	O
%	O
reduction	O
in	O
their	O
headache	B-Disease
intensity	O
within	O
30	O
minutes	O
was	O
11	O
.	O
8	O
%	O
(	O
95	O
%	O
CI	O
-	O
9	O
.	O
6	O
%	O
to	O
33	O
.	O
3	O
%	O
)	O
.	O

The	O
difference	O
in	O
the	O
percentage	O
of	O
patients	O
with	O
a	O
50	O
%	O
reduction	O
in	O
their	O
nausea	B-Disease
was	O
12	O
.	O
6	O
%	O
(	O
95	O
%	O
CI	O
-	O
4	O
.	O
6	O
%	O
to	O
29	O
.	O
8	O
%	O
)	O
.	O

CONCLUSION	O
:	O
A	O
50	O
%	O
reduction	O
in	O
the	O
incidence	O
of	O
akathisia	B-Disease
when	O
prochlorperazine	B-Chemical
was	O
administered	O
by	O
means	O
of	O
15	O
-	O
minute	O
intravenous	O
infusion	O
versus	O
a	O
2	O
-	O
minute	O
intravenous	O
push	O
was	O
not	O
detected	O
.	O

The	O
efficacy	O
of	O
prochlorperazine	B-Chemical
in	O
the	O
treatment	O
of	O
headache	B-Disease
and	O
nausea	B-Disease
likewise	O
did	O
not	O
appear	O
to	O
be	O
affected	O
by	O
the	O
rate	O
of	O
administration	O
,	O
although	O
no	O
formal	O
statistical	O
comparisons	O
were	O
made	O
.	O

Combined	O
antiretroviral	O
therapy	O
causes	O
cardiomyopathy	B-Disease
and	O
elevates	O
plasma	O
lactate	B-Chemical
in	O
transgenic	O
AIDS	B-Disease
mice	O
.	O

Highly	O
active	O
antiretroviral	O
therapy	O
(	O
HAART	O
)	O
is	O
implicated	O
in	O
cardiomyopathy	B-Disease
(	O
CM	B-Disease
)	O
and	O
in	O
elevated	O
plasma	O
lactate	B-Chemical
(	O
LA	B-Chemical
)	O
in	O
AIDS	B-Disease
through	O
mechanisms	O
of	O
mitochondrial	B-Disease
dysfunction	I-Disease
.	O

To	O
determine	O
mitochondrial	O
events	O
from	O
HAART	O
in	O
vivo	O
,	O
8	O
-	O
week	O
-	O
old	O
hemizygous	O
transgenic	O
AIDS	B-Disease
mice	O
(	O
NL4	O
-	O
3Delta	O
gag	O
/	O
pol	O
;	O
TG	O
)	O
and	O
wild	O
-	O
type	O
FVB	O
/	O
n	O
littermates	O
were	O
treated	O
with	O
the	O
HAART	O
combination	O
of	O
zidovudine	B-Chemical
,	O
lamivudine	B-Chemical
,	O
and	O
indinavir	B-Chemical
or	O
vehicle	O
control	O
for	O
10	O
days	O
or	O
35	O
days	O
.	O

At	O
termination	O
of	O
the	O
experiments	O
,	O
mice	O
underwent	O
echocardiography	O
,	O
quantitation	O
of	O
abundance	O
of	O
molecular	O
markers	O
of	O
CM	B-Disease
(	O
ventricular	O
mRNA	O
encoding	O
atrial	O
natriuretic	O
factor	O
[	O
ANF	O
]	O
and	O
sarcoplasmic	O
calcium	B-Chemical
ATPase	O
[	O
SERCA2	O
]	O
)	O
,	O
and	O
determination	O
of	O
plasma	O
LA	B-Chemical
.	O

Myocardial	O
histologic	O
features	O
were	O
analyzed	O
semiquantitatively	O
and	O
results	O
were	O
confirmed	O
by	O
transmission	O
electron	O
microscopy	O
.	O

After	O
35	O
days	O
in	O
the	O
TG	O
+	O
HAART	O
cohort	O
,	O
left	O
ventricular	O
mass	O
increased	O
160	O
%	O
by	O
echocardiography	O
.	O

Molecularly	O
,	O
ANF	O
mRNA	O
increased	O
250	O
%	O
and	O
SERCA2	O
mRNA	O
decreased	O
57	O
%	O
.	O

Biochemically	O
,	O
LA	B-Chemical
was	O
elevated	O
(	O
8	O
.	O
5	O
+	O
/	O
-	O
2	O
.	O
0	O
mM	O
)	O
.	O

Pathologically	O
,	O
granular	O
cytoplasmic	O
changes	O
were	O
found	O
in	O
cardiac	O
myocytes	O
,	O
indicating	O
enlarged	O
,	O
damaged	O
mitochondria	O
.	O

Findings	O
were	O
confirmed	O
ultrastructurally	O
.	O

No	O
changes	O
were	O
found	O
in	O
other	O
cohorts	O
.	O

After	O
10	O
days	O
,	O
only	O
ANF	O
was	O
elevated	O
,	O
and	O
only	O
in	O
the	O
TG	O
+	O
HAART	O
cohort	O
.	O

Results	O
show	O
that	O
cumulative	O
HAART	O
caused	O
mitochondrial	O
CM	B-Disease
with	O
elevated	O
LA	B-Chemical
in	O
AIDS	B-Disease
transgenic	O
mice	O
.	O

A	O
Phase	O
II	O
trial	O
of	O
cisplatin	B-Chemical
plus	O
WR	B-Chemical
-	I-Chemical
2721	I-Chemical
(	O
amifostine	B-Chemical
)	O
for	O
metastatic	O
breast	B-Disease
carcinoma	I-Disease
:	O
an	O
Eastern	O
Cooperative	O
Oncology	O
Group	O
Study	O
(	O
E8188	O
)	O
.	O

BACKGROUND	O
:	O
Cisplatin	B-Chemical
has	O
minimal	O
antitumor	O
activity	O
when	O
used	O
as	O
second	O
-	O
or	O
third	O
-	O
line	O
treatment	O
of	O
metastatic	O
breast	B-Disease
carcinoma	I-Disease
.	O

Older	O
reports	O
suggest	O
an	O
objective	O
response	O
rate	O
of	O
8	O
%	O
when	O
60	O
-	O
120	O
mg	O
/	O
m2	O
of	O
cisplatin	B-Chemical
is	O
administered	O
every	O
3	O
-	O
4	O
weeks	O
.	O

Although	O
a	O
dose	O
-	O
response	O
effect	O
has	O
been	O
observed	O
with	O
cisplatin	B-Chemical
,	O
the	O
dose	O
-	O
limiting	O
toxicities	B-Disease
associated	O
with	O
cisplatin	B-Chemical
(	O
e	O
.	O
g	O
.	O
,	O
nephrotoxicity	B-Disease
,	O
ototoxicity	B-Disease
,	O
and	O
neurotoxicity	B-Disease
)	O
have	O
limited	O
its	O
use	O
as	O
a	O
treatment	O
for	O
breast	B-Disease
carcinoma	I-Disease
.	O

WR	B-Chemical
-	I-Chemical
2721	I-Chemical
or	O
amifostine	B-Chemical
initially	O
was	O
developed	O
to	O
protect	O
military	O
personnel	O
in	O
the	O
event	O
of	O
nuclear	O
war	O
.	O

Amifostine	B-Chemical
subsequently	O
was	O
shown	O
to	O
protect	O
normal	O
tissues	O
from	O
the	O
toxic	O
effects	O
of	O
alkylating	B-Chemical
agents	I-Chemical
and	O
cisplatin	B-Chemical
without	O
decreasing	O
the	O
antitumor	O
effect	O
of	O
the	O
chemotherapy	O
.	O

Early	O
trials	O
of	O
cisplatin	B-Chemical
and	O
amifostine	B-Chemical
also	O
suggested	O
that	O
the	O
incidence	O
and	O
severity	O
of	O
cisplatin	B-Chemical
-	O
induced	O
nephrotoxicity	B-Disease
,	O
ototoxicity	B-Disease
,	O
and	O
neuropathy	B-Disease
were	O
reduced	O
.	O

METHODS	O
:	O
A	O
Phase	O
II	O
study	O
of	O
the	O
combination	O
of	O
cisplatin	B-Chemical
plus	O
amifostine	B-Chemical
was	O
conducted	O
in	O
patients	O
with	O
progressive	O
metastatic	O
breast	B-Disease
carcinoma	I-Disease
who	O
had	O
received	O
one	O
,	O
but	O
not	O
more	O
than	O
one	O
,	O
chemotherapy	O
regimen	O
for	O
metastatic	O
disease	O
.	O

Patients	O
received	O
amifostine	B-Chemical
,	O
910	O
mg	O
/	O
m2	O
intravenously	O
over	O
15	O
minutes	O
.	O

After	O
completion	O
of	O
the	O
amifostine	B-Chemical
infusion	O
,	O
cisplatin	B-Chemical
120	O
mg	O
/	O
m2	O
was	O
administered	O
over	O
30	O
minutes	O
.	O

Intravenous	O
hydration	O
and	O
mannitol	B-Chemical
was	O
administered	O
before	O
and	O
after	O
cisplatin	B-Chemical
.	O

Treatment	O
was	O
administered	O
every	O
3	O
weeks	O
until	O
disease	O
progression	O
.	O

RESULTS	O
:	O
Forty	O
-	O
four	O
patients	O
were	O
enrolled	O
in	O
the	O
study	O
of	O
which	O
7	O
(	O
16	O
%	O
)	O
were	O
ineligible	O
.	O

A	O
median	O
of	O
2	O
cycles	O
of	O
therapy	O
was	O
administered	O
to	O
the	O
37	O
eligible	O
patients	O
.	O

Six	O
partial	O
responses	O
were	O
observed	O
for	O
an	O
overall	O
response	O
rate	O
of	O
16	O
%	O
.	O

Most	O
patients	O
(	O
57	O
%	O
)	O
stopped	O
treatment	O
because	O
of	O
disease	O
progression	O
.	O

Neurologic	B-Disease
toxicity	I-Disease
was	O
reported	O
in	O
52	O
%	O
of	O
patients	O
.	O

Seven	O
different	O
life	O
-	O
threatening	O
toxicities	B-Disease
were	O
observed	O
in	O
patients	O
while	O
receiving	O
treatment	O
.	O

CONCLUSIONS	O
:	O
The	O
combination	O
of	O
cisplatin	B-Chemical
and	O
amifostine	B-Chemical
in	O
this	O
study	O
resulted	O
in	O
an	O
overall	O
response	O
rate	O
of	O
16	O
%	O
.	O

Neither	O
a	O
tumor	B-Disease
-	O
protective	O
effect	O
nor	O
reduced	O
toxicity	B-Disease
to	O
normal	O
tissues	O
was	O
observed	O
with	O
the	O
addition	O
of	O
amifostine	B-Chemical
to	O
cisplatin	B-Chemical
in	O
this	O
trial	O
.	O

Oral	B-Chemical
contraceptives	I-Chemical
and	O
the	O
risk	O
of	O
myocardial	B-Disease
infarction	I-Disease
.	O

BACKGROUND	O
:	O
An	O
association	O
between	O
the	O
use	O
of	O
oral	B-Chemical
contraceptives	I-Chemical
and	O
the	O
risk	O
of	O
myocardial	B-Disease
infarction	I-Disease
has	O
been	O
found	O
in	O
some	O
,	O
but	O
not	O
all	O
,	O
studies	O
.	O

We	O
investigated	O
this	O
association	O
,	O
according	O
to	O
the	O
type	O
of	O
progestagen	B-Chemical
included	O
in	O
third	O
-	O
generation	O
(	O
i	O
.	O
e	O
.	O
,	O
desogestrel	B-Chemical
or	O
gestodene	B-Chemical
)	O
and	O
second	O
-	O
generation	O
(	O
i	O
.	O
e	O
.	O
,	O
levonorgestrel	B-Chemical
)	O
oral	B-Chemical
contraceptives	I-Chemical
,	O
the	O
dose	O
of	O
estrogen	B-Chemical
,	O
and	O
the	O
presence	O
or	O
absence	O
of	O
prothrombotic	O
mutations	O
METHODS	O
:	O
In	O
a	O
nationwide	O
,	O
population	O
-	O
based	O
,	O
case	O
-	O
control	O
study	O
,	O
we	O
identified	O
and	O
enrolled	O
248	O
women	O
18	O
through	O
49	O
years	O
of	O
age	O
who	O
had	O
had	O
a	O
first	O
myocardial	B-Disease
infarction	I-Disease
between	O
1990	O
and	O
1995	O
and	O
925	O
control	O
women	O
who	O
had	O
not	O
had	O
a	O
myocardial	B-Disease
infarction	I-Disease
and	O
who	O
were	O
matched	O
for	O
age	O
,	O
calendar	O
year	O
of	O
the	O
index	O
event	O
,	O
and	O
area	O
of	O
residence	O
.	O

Subjects	O
supplied	O
information	O
on	O
oral	B-Chemical
-	I-Chemical
contraceptive	I-Chemical
use	O
and	O
major	O
cardiovascular	O
risk	O
factors	O
.	O

An	O
analysis	O
for	O
factor	O
V	O
Leiden	O
and	O
the	O
G20210A	O
mutation	O
in	O
the	O
prothrombin	O
gene	O
was	O
conducted	O
in	O
217	O
patients	O
and	O
763	O
controls	O
RESULTS	O
:	O
The	O
odds	O
ratio	O
for	O
myocardial	B-Disease
infarction	I-Disease
among	O
women	O
who	O
used	O
any	O
type	O
of	O
combined	O
oral	B-Chemical
contraceptive	I-Chemical
,	O
as	O
compared	O
with	O
nonusers	O
,	O
was	O
2	O
.	O
0	O
(	O
95	O
percent	O
confidence	O
interval	O
,	O
1	O
.	O
5	O
to	O
2	O
.	O
8	O
)	O
.	O

The	O
adjusted	O
odds	O
ratio	O
was	O
2	O
.	O
5	O
(	O
95	O
percent	O
confidence	O
interval	O
,	O
1	O
.	O
5	O
to	O
4	O
.	O
1	O
)	O
among	O
women	O
who	O
used	O
second	O
-	O
generation	O
oral	B-Chemical
contraceptives	I-Chemical
and	O
1	O
.	O
3	O
(	O
95	O
percent	O
confidence	O
interval	O
,	O
0	O
.	O
7	O
to	O
2	O
.	O
5	O
)	O
among	O
those	O
who	O
used	O
third	O
-	O
generation	O
oral	B-Chemical
contraceptives	I-Chemical
.	O

Among	O
women	O
who	O
used	O
oral	B-Chemical
contraceptives	I-Chemical
,	O
the	O
odds	O
ratio	O
was	O
2	O
.	O
1	O
(	O
95	O
percent	O
confidence	O
interval	O
,	O
1	O
.	O
5	O
to	O
3	O
.	O
0	O
)	O
for	O
those	O
without	O
a	O
prothrombotic	O
mutation	O
and	O
1	O
.	O
9	O
(	O
95	O
percent	O
confidence	O
interval	O
,	O
0	O
.	O
6	O
to	O
5	O
.	O
5	O
)	O
for	O
those	O
with	O
a	O
mutation	O
CONCLUSIONS	O
:	O
The	O
risk	O
of	O
myocardial	B-Disease
infarction	I-Disease
was	O
increased	O
among	O
women	O
who	O
used	O
second	O
-	O
generation	O
oral	B-Chemical
contraceptives	I-Chemical
.	O

The	O
results	O
with	O
respect	O
to	O
the	O
use	O
of	O
third	O
-	O
generation	O
oral	B-Chemical
contraceptives	I-Chemical
were	O
inconclusive	O
but	O
suggested	O
that	O
the	O
risk	O
was	O
lower	O
than	O
the	O
risk	O
associated	O
with	O
second	O
-	O
generation	O
oral	B-Chemical
contraceptives	I-Chemical
.	O

The	O
risk	O
of	O
myocardial	B-Disease
infarction	I-Disease
was	O
similar	O
among	O
women	O
who	O
used	O
oral	B-Chemical
contraceptives	I-Chemical
whether	O
or	O
not	O
they	O
had	O
a	O
prothrombotic	O
mutation	O
.	O

End	B-Disease
-	I-Disease
stage	I-Disease
renal	I-Disease
disease	I-Disease
(	O
ESRD	B-Disease
)	O
after	O
orthotopic	O
liver	O
transplantation	O
(	O
OLTX	O
)	O
using	O
calcineurin	O
-	O
based	O
immunotherapy	O
:	O
risk	O
of	O
development	O
and	O
treatment	O
.	O

BACKGROUND	O
:	O
The	O
calcineurin	O
inhibitors	O
cyclosporine	B-Chemical
and	O
tacrolimus	B-Chemical
are	O
both	O
known	O
to	O
be	O
nephrotoxic	B-Disease
.	O

Their	O
use	O
in	O
orthotopic	O
liver	O
transplantation	O
(	O
OLTX	O
)	O
has	O
dramatically	O
improved	O
success	O
rates	O
.	O

Recently	O
,	O
however	O
,	O
we	O
have	O
had	O
an	O
increase	O
of	O
patients	O
who	O
are	O
presenting	O
after	O
OLTX	O
with	O
end	B-Disease
-	I-Disease
stage	I-Disease
renal	I-Disease
disease	I-Disease
(	O
ESRD	B-Disease
)	O
.	O

This	O
retrospective	O
study	O
examines	O
the	O
incidence	O
and	O
treatment	O
of	O
ESRD	B-Disease
and	O
chronic	B-Disease
renal	I-Disease
failure	I-Disease
(	O
CRF	B-Disease
)	O
in	O
OLTX	O
patients	O
.	O

METHODS	O
:	O
Patients	O
receiving	O
an	O
OLTX	O
only	O
from	O
June	O
1985	O
through	O
December	O
of	O
1994	O
who	O
survived	O
6	O
months	O
postoperatively	O
were	O
studied	O
(	O
n	O
=	O
834	O
)	O
.	O

Our	O
prospectively	O
collected	O
database	O
was	O
the	O
source	O
of	O
information	O
.	O

Patients	O
were	O
divided	O
into	O
three	O
groups	O
:	O
Controls	O
,	O
no	O
CRF	B-Disease
or	O
ESRD	B-Disease
,	O
n	O
=	O
748	O
;	O
CRF	B-Disease
,	O
sustained	O
serum	O
creatinine	B-Chemical
>	O
2	O
.	O
5	O
mg	O
/	O
dl	O
,	O
n	O
=	O
41	O
;	O
and	O
ESRD	B-Disease
,	O
n	O
=	O
45	O
.	O

Groups	O
were	O
compared	O
for	O
preoperative	O
laboratory	O
variables	O
,	O
diagnosis	O
,	O
postoperative	O
variables	O
,	O
survival	O
,	O
type	O
of	O
ESRD	B-Disease
therapy	O
,	O
and	O
survival	O
from	O
onset	O
of	O
ESRD	B-Disease
.	O

RESULTS	O
:	O
At	O
13	O
years	O
after	O
OLTX	O
,	O
the	O
incidence	O
of	O
severe	O
renal	B-Disease
dysfunction	I-Disease
was	O
18	O
.	O
1	O
%	O
(	O
CRF	B-Disease
8	O
.	O
6	O
%	O
and	O
ESRD	B-Disease
9	O
.	O
5	O
%	O
)	O
.	O

Compared	O
with	O
control	O
patients	O
,	O
CRF	B-Disease
and	O
ESRD	B-Disease
patients	O
had	O
higher	O
preoperative	O
serum	O
creatinine	B-Chemical
levels	O
,	O
a	O
greater	O
percentage	O
of	O
patients	O
with	O
hepatorenal	B-Disease
syndrome	I-Disease
,	O
higher	O
percentage	O
requirement	O
for	O
dialysis	O
in	O
the	O
first	O
3	O
months	O
postoperatively	O
,	O
and	O
a	O
higher	O
1	O
-	O
year	O
serum	O
creatinine	B-Chemical
.	O

Multivariate	O
stepwise	O
logistic	O
regression	O
analysis	O
using	O
preoperative	O
and	O
postoperative	O
variables	O
identified	O
that	O
an	O
increase	O
of	O
serum	O
creatinine	B-Chemical
compared	O
with	O
average	O
at	O
1	O
year	O
,	O
3	O
months	O
,	O
and	O
4	O
weeks	O
postoperatively	O
were	O
independent	O
risk	O
factors	O
for	O
the	O
development	O
of	O
CRF	B-Disease
or	O
ESRD	B-Disease
with	O
odds	O
ratios	O
of	O
2	O
.	O
6	O
,	O
2	O
.	O
2	O
,	O
and	O
1	O
.	O
6	O
,	O
respectively	O
.	O

Overall	O
survival	O
from	O
the	O
time	O
of	O
OLTX	O
was	O
not	O
significantly	O
different	O
among	O
groups	O
,	O
but	O
by	O
year	O
13	O
,	O
the	O
survival	O
of	O
the	O
patients	O
who	O
had	O
ESRD	B-Disease
was	O
only	O
28	O
.	O
2	O
%	O
compared	O
with	O
54	O
.	O
6	O
%	O
in	O
the	O
control	O
group	O
.	O

Patients	O
developing	O
ESRD	B-Disease
had	O
a	O
6	O
-	O
year	O
survival	O
after	O
onset	O
of	O
ESRD	B-Disease
of	O
27	O
%	O
for	O
the	O
patients	O
receiving	O
hemodialysis	O
versus	O
71	O
.	O
4	O
%	O
for	O
the	O
patients	O
developing	O
ESRD	B-Disease
who	O
subsequently	O
received	O
kidney	O
transplants	O
.	O

CONCLUSIONS	O
:	O
Patients	O
who	O
are	O
more	O
than	O
10	O
years	O
post	O
-	O
OLTX	O
have	O
CRF	B-Disease
and	O
ESRD	B-Disease
at	O
a	O
high	O
rate	O
.	O

The	O
development	O
of	O
ESRD	B-Disease
decreases	O
survival	O
,	O
particularly	O
in	O
those	O
patients	O
treated	O
with	O
dialysis	O
only	O
.	O

Patients	O
who	O
develop	O
ESRD	B-Disease
have	O
a	O
higher	O
preoperative	O
and	O
1	O
-	O
year	O
serum	O
creatinine	B-Chemical
and	O
are	O
more	O
likely	O
to	O
have	O
hepatorenal	B-Disease
syndrome	I-Disease
.	O

However	O
,	O
an	O
increase	O
of	O
serum	O
creatinine	B-Chemical
at	O
various	O
times	O
postoperatively	O
is	O
more	O
predictive	O
of	O
the	O
development	O
of	O
CRF	B-Disease
or	O
ESRD	B-Disease
.	O

New	O
strategies	O
for	O
long	O
-	O
term	O
immunosuppression	O
may	O
be	O
needed	O
to	O
decrease	O
this	O
complication	O
.	O

Epileptic	B-Disease
seizures	I-Disease
following	O
cortical	O
application	O
of	O
fibrin	O
sealants	O
containing	O
tranexamic	B-Chemical
acid	I-Chemical
in	O
rats	O
.	O

BACKGROUND	O
:	O
Fibrin	O
sealants	O
(	O
FS	O
)	O
derived	O
from	O
human	O
plasma	O
are	O
frequently	O
used	O
in	O
neurosurgery	O
.	O

In	O
order	O
to	O
increase	O
clot	O
stability	O
,	O
FS	O
typically	O
contain	O
aprotinin	O
,	O
a	O
natural	O
fibrinolysis	O
inhibitor	O
.	O

Recently	O
,	O
synthetic	O
fibrinolysis	O
inhibitors	O
such	O
as	O
tranexamic	B-Chemical
acid	I-Chemical
(	O
tAMCA	B-Chemical
)	O
have	O
been	O
considered	O
as	O
substitutes	O
for	O
aprotinin	O
.	O

However	O
,	O
tAMCA	B-Chemical
has	O
been	O
shown	O
to	O
cause	O
epileptic	B-Disease
seizures	I-Disease
.	O

We	O
wanted	O
to	O
study	O
whether	O
tAMCA	B-Chemical
retains	O
its	O
convulsive	B-Disease
action	O
if	O
incorporated	O
into	O
a	O
FS	O
.	O

METHOD	O
:	O
FS	O
containing	O
aprotinin	O
or	O
different	O
concentrations	O
of	O
tAMCA	B-Chemical
(	O
0	O
.	O
5	O
-	O
47	O
.	O
5	O
mg	O
/	O
ml	O
)	O
were	O
applied	O
to	O
the	O
pial	O
surface	O
of	O
the	O
cortex	O
of	O
anaesthetized	O
rats	O
.	O

The	O
response	O
of	O
the	O
animals	O
was	O
evaluated	O
using	O
electroencephalography	O
and	O
by	O
monitoring	O
the	O
clinical	O
behaviour	O
during	O
and	O
after	O
recovery	O
from	O
anaesthesia	O
.	O

FINDINGS	O
:	O
FS	O
containing	O
tAMCA	B-Chemical
caused	O
paroxysmal	O
brain	O
activity	O
which	O
was	O
associated	O
with	O
distinct	O
convulsive	B-Disease
behaviours	O
.	O

The	O
degree	O
of	O
these	O
seizures	B-Disease
increased	O
with	O
increasing	O
concentration	O
of	O
tAMCA	B-Chemical
.	O

Thus	O
,	O
FS	O
containing	O
47	O
.	O
5	O
mg	O
/	O
ml	O
tAMCA	B-Chemical
evoked	O
generalized	B-Disease
seizures	I-Disease
in	O
all	O
tested	O
rats	O
(	O
n	O
=	O
6	O
)	O
while	O
the	O
lowest	O
concentration	O
of	O
tAMCA	B-Chemical
(	O
0	O
.	O
5	O
mg	O
/	O
ml	O
)	O
only	O
evoked	O
brief	O
episodes	O
of	O
jerk	O
-	O
correlated	O
convulsive	B-Disease
potentials	O
in	O
1	O
of	O
6	O
rats	O
.	O

In	O
contrast	O
,	O
FS	O
containing	O
aprotinin	O
did	O
not	O
evoke	O
any	O
paroxysmal	O
activity	O
.	O

INTERPRETATION	O
:	O
Tranexamic	B-Chemical
acid	I-Chemical
retains	O
its	O
convulsive	B-Disease
action	O
within	O
FS	O
.	O

Thus	O
,	O
use	O
of	O
FS	O
containing	O
tAMCA	B-Chemical
for	O
surgery	O
within	O
or	O
close	O
to	O
the	O
CNS	O
may	O
pose	O
a	O
substantial	O
risk	O
to	O
the	O
patient	O
.	O

Sequential	O
observations	O
of	O
exencephaly	B-Disease
and	O
subsequent	O
morphological	O
changes	O
by	O
mouse	O
exo	O
utero	O
development	O
system	O
:	O
analysis	O
of	O
the	O
mechanism	O
of	O
transformation	O
from	O
exencephaly	B-Disease
to	O
anencephaly	B-Disease
.	O

Anencephaly	B-Disease
has	O
been	O
suggested	O
to	O
develop	O
from	O
exencephaly	B-Disease
;	O
however	O
,	O
there	O
is	O
little	O
direct	O
experimental	O
evidence	O
to	O
support	O
this	O
,	O
and	O
the	O
mechanism	O
of	O
transformation	O
remains	O
unclear	O
.	O

We	O
examined	O
this	O
theory	O
using	O
the	O
exo	O
utero	O
development	O
system	O
that	O
allows	O
direct	O
and	O
sequential	O
observations	O
of	O
mid	O
-	O
to	O
late	O
-	O
gestation	O
mouse	O
embryos	O
.	O

We	O
observed	O
the	O
exencephaly	B-Disease
induced	O
by	O
5	B-Chemical
-	I-Chemical
azacytidine	I-Chemical
at	O
embryonic	O
day	O
13	O
.	O
5	O
(	O
E13	O
.	O
5	O
)	O
,	O
let	O
the	O
embryos	O
develop	O
exo	O
utero	O
until	O
E18	O
.	O
5	O
,	O
and	O
re	O
-	O
observed	O
the	O
same	O
embryos	O
at	O
E18	O
.	O
5	O
.	O

We	O
confirmed	O
several	O
cases	O
of	O
transformation	O
from	O
exencephaly	B-Disease
to	O
anencephaly	B-Disease
.	O

However	O
,	O
in	O
many	O
cases	O
,	O
the	O
exencephalic	B-Disease
brain	O
tissue	O
was	O
preserved	O
with	O
more	O
or	O
less	O
reduction	O
during	O
this	O
period	O
.	O

To	O
analyze	O
the	O
transformation	O
patterns	O
,	O
we	O
classified	O
the	O
exencephaly	B-Disease
by	O
size	O
and	O
shape	O
of	O
the	O
exencephalic	B-Disease
tissue	O
into	O
several	O
types	O
at	O
E13	O
.	O
5	O
and	O
E18	O
.	O
5	O
.	O

It	O
was	O
found	O
that	O
the	O
transformation	O
of	O
exencephalic	B-Disease
tissue	O
was	O
not	O
simply	O
size	O
-	O
dependent	O
,	O
and	O
all	O
cases	O
of	O
anencephaly	B-Disease
at	O
E18	O
.	O
5	O
resulted	O
from	O
embryos	O
with	O
a	O
large	O
amount	O
of	O
exencephalic	B-Disease
tissue	O
at	O
E13	O
.	O
5	O
.	O

Microscopic	O
observation	O
showed	O
the	O
configuration	O
of	O
exencephaly	B-Disease
at	O
E13	O
.	O
5	O
,	O
frequent	O
hemorrhaging	B-Disease
and	O
detachment	O
of	O
the	O
neural	O
plate	O
from	O
surface	O
ectoderm	O
in	O
the	O
exencephalic	B-Disease
head	O
at	O
E15	O
.	O
5	O
,	O
and	O
multiple	O
modes	O
of	O
reduction	O
in	O
the	O
exencephalic	B-Disease
tissue	O
at	O
E18	O
.	O
5	O
.	O

From	O
observations	O
of	O
the	O
vasculature	O
,	O
altered	O
distribution	O
patterns	O
of	O
vessels	O
were	O
identified	O
in	O
the	O
exencephalic	B-Disease
head	O
.	O

These	O
findings	O
suggest	O
that	O
overgrowth	O
of	O
the	O
exencephalic	B-Disease
neural	O
tissue	O
causes	O
the	O
altered	O
distribution	O
patterns	O
of	O
vessels	O
,	O
subsequent	O
peripheral	O
circulatory	B-Disease
failure	I-Disease
and	O
/	O
or	O
hemorrhaging	B-Disease
in	O
various	O
parts	O
of	O
the	O
exencephalic	B-Disease
head	O
,	O
leading	O
to	O
the	O
multiple	O
modes	O
of	O
tissue	O
reduction	O
during	O
transformation	O
from	O
exencephaly	B-Disease
to	O
anencephaly	B-Disease
.	O

99mTc	B-Chemical
-	I-Chemical
glucarate	I-Chemical
for	O
detection	O
of	O
isoproterenol	B-Chemical
-	O
induced	O
myocardial	B-Disease
infarction	I-Disease
in	O
rats	O
.	O

Infarct	B-Disease
-	O
avid	O
radiopharmaceuticals	O
are	O
necessary	O
for	O
rapid	O
and	O
timely	O
diagnosis	O
of	O
acute	O
myocardial	B-Disease
infarction	I-Disease
.	O

The	O
animal	O
model	O
used	O
to	O
produce	O
infarction	B-Disease
implies	O
artery	O
ligation	O
but	O
chemical	O
induction	O
can	O
be	O
easily	O
obtained	O
with	O
isoproterenol	B-Chemical
.	O

A	O
new	O
infarct	B-Disease
-	O
avid	O
radiopharmaceutical	O
based	O
on	O
glucaric	B-Chemical
acid	I-Chemical
was	O
prepared	O
in	O
the	O
hospital	O
radiopharmacy	O
of	O
the	O
INCMNSZ	O
.	O

99mTc	B-Chemical
-	I-Chemical
glucarate	I-Chemical
was	O
easy	O
to	O
prepare	O
,	O
stable	O
for	O
96	O
h	O
and	O
was	O
used	O
to	O
study	O
its	O
biodistribution	O
in	O
rats	O
with	O
isoproterenol	B-Chemical
-	O
induced	O
acute	O
myocardial	B-Disease
infarction	I-Disease
.	O

Histological	O
studies	O
demonstrated	O
that	O
the	O
rats	O
developed	O
an	O
infarct	B-Disease
18	O
h	O
after	O
isoproterenol	B-Chemical
administration	O
.	O

The	O
rat	O
biodistribution	O
studies	O
showed	O
a	O
rapid	O
blood	O
clearance	O
via	O
the	O
kidneys	O
.	O

Thirty	O
minutes	O
after	O
99mTc	B-Chemical
-	I-Chemical
glucarate	I-Chemical
administration	O
the	O
standardised	O
heart	O
uptake	O
value	O
S	O
(	O
h	O
)	O
UV	O
was	O
4	O
.	O
7	O
in	O
infarcted	O
rat	O
heart	O
which	O
is	O
six	O
times	O
more	O
than	O
in	O
normal	O
rats	O
.	O

ROIs	O
drawn	O
over	O
the	O
gamma	O
camera	O
images	O
showed	O
a	O
ratio	O
of	O
4	O
.	O
4	O
.	O

The	O
high	O
image	O
quality	O
suggests	O
that	O
high	O
contrast	O
images	O
can	O
be	O
obtained	O
in	O
humans	O
and	O
the	O
96	O
h	O
stability	O
makes	O
it	O
an	O
ideal	O
agent	O
to	O
detect	O
,	O
in	O
patients	O
,	O
early	O
cardiac	B-Disease
infarction	I-Disease
.	O

Bupropion	B-Chemical
(	O
Zyban	B-Chemical
)	O
toxicity	B-Disease
.	O

Bupropion	B-Chemical
is	O
a	O
monocyclic	O
antidepressant	B-Chemical
structurally	O
related	O
to	O
amphetamine	B-Chemical
.	O

Zyban	B-Chemical
,	O
a	O
sustained	O
-	O
release	O
formulation	O
of	O
bupropion	B-Chemical
hydrochloride	I-Chemical
,	O
was	O
recently	O
released	O
in	O
Ireland	O
,	O
as	O
a	O
smoking	O
cessation	O
aid	O
.	O

In	O
the	O
initial	O
6	O
months	O
since	O
it	O
'	O
s	O
introduction	O
,	O
12	O
overdose	B-Disease
cases	O
have	O
been	O
reported	O
to	O
The	O
National	O
Poisons	O
Information	O
Centre	O
.	O

8	O
patients	O
developed	O
symptoms	O
of	O
toxicity	B-Disease
.	O

Common	O
features	O
included	O
tachycardia	B-Disease
,	O
drowsiness	O
,	O
hallucinations	B-Disease
and	O
convulsions	B-Disease
.	O

Two	O
patients	O
developed	O
severe	O
cardiac	B-Disease
arrhythmias	I-Disease
,	O
including	O
one	O
patient	O
who	O
was	O
resuscitated	O
following	O
a	O
cardiac	B-Disease
arrest	I-Disease
.	O

All	O
patients	O
recovered	O
without	O
sequelae	O
.	O

We	O
report	O
a	O
case	O
of	O
a	O
31	O
year	O
old	O
female	O
who	O
required	O
admission	O
to	O
the	O
Intensive	O
Care	O
Unit	O
for	O
ventilation	O
and	O
full	O
supportive	O
therapy	O
,	O
following	O
ingestion	O
of	O
13	O
.	O
5g	O
bupropion	B-Chemical
.	O

Recurrent	O
seizures	B-Disease
were	O
treated	O
with	O
diazepam	B-Chemical
and	O
broad	O
complex	O
tachycardia	B-Disease
was	O
successfully	O
treated	O
with	O
adenosine	B-Chemical
.	O

Zyban	B-Chemical
caused	O
significant	O
neurological	B-Disease
and	I-Disease
cardiovascular	I-Disease
toxicity	I-Disease
in	O
overdose	B-Disease
.	O

The	O
potential	O
toxic	O
effects	O
should	O
be	O
considered	O
when	O
prescribing	O
it	O
as	O
a	O
smoking	O
cessation	O
aid	O
.	O

GLEPP1	O
receptor	O
tyrosine	B-Chemical
phosphatase	O
(	O
Ptpro	O
)	O
in	O
rat	O
PAN	B-Chemical
nephrosis	B-Disease
.	O

A	O
marker	O
of	O
acute	O
podocyte	O
injury	O
.	O

Glomerular	O
epithelial	O
protein	O
1	O
(	O
GLEPP1	O
)	O
is	O
a	O
podocyte	O
receptor	O
membrane	O
protein	O
tyrosine	B-Chemical
phosphatase	O
located	O
on	O
the	O
apical	O
cell	O
membrane	O
of	O
visceral	O
glomerular	O
epithelial	O
cell	O
and	O
foot	O
processes	O
.	O

This	O
receptor	O
plays	O
a	O
role	O
in	O
regulating	O
the	O
structure	O
and	O
function	O
of	O
podocyte	O
foot	O
process	O
.	O

To	O
better	O
understand	O
the	O
utility	O
of	O
GLEPP1	O
as	O
a	O
marker	O
of	O
glomerular	B-Disease
injury	I-Disease
,	O
the	O
amount	O
and	O
distribution	O
of	O
GLEPP1	O
protein	O
and	O
mRNA	O
were	O
examined	O
by	O
immunohistochemistry	O
,	O
Western	O
blot	O
and	O
RNase	O
protection	O
assay	O
in	O
a	O
model	O
of	O
podocyte	O
injury	O
in	O
the	O
rat	O
.	O

Puromycin	B-Chemical
aminonucleoside	I-Chemical
nephrosis	B-Disease
was	O
induced	O
by	O
single	O
intraperitoneal	O
injection	O
of	O
puromycin	B-Chemical
aminonucleoside	I-Chemical
(	O
PAN	B-Chemical
,	O
20	O
mg	O
/	O
100g	O
BW	O
)	O
.	O

Tissues	O
were	O
analyzed	O
at	O
0	O
,	O
5	O
,	O
7	O
,	O
11	O
,	O
21	O
,	O
45	O
,	O
80	O
and	O
126	O
days	O
after	O
PAN	B-Chemical
injection	O
so	O
as	O
to	O
include	O
both	O
the	O
acute	O
phase	O
of	O
proteinuria	B-Disease
associated	O
with	O
foot	O
process	O
effacement	O
(	O
days	O
5	O
-	O
11	O
)	O
and	O
the	O
chronic	O
phase	O
of	O
proteinuria	B-Disease
associated	O
with	O
glomerulosclerosis	B-Disease
(	O
days	O
45	O
-	O
126	O
)	O
.	O

At	O
day	O
5	O
,	O
GLEPP1	O
protein	O
and	O
mRNA	O
were	O
reduced	O
from	O
the	O
normal	O
range	O
(	O
265	O
.	O
2	O
+	O
/	O
-	O
79	O
.	O
6	O
x	O
10	O
(	O
6	O
)	O
moles	O
/	O
glomerulus	O
and	O
100	O
%	O
)	O
to	O
15	O
%	O
of	O
normal	O
(	O
41	O
.	O
8	O
+	O
/	O
-	O
4	O
.	O
8	O
x	O
10	O
(	O
6	O
)	O
moles	O
/	O
glomerulus	O
,	O
p	O
<	O
0	O
.	O
005	O
)	O
.	O

This	O
occurred	O
in	O
association	O
with	O
an	O
increase	O
in	O
urinary	O
protein	O
content	O
from	O
1	O
.	O
8	O
+	O
/	O
-	O
1	O
to	O
99	O
.	O
0	O
+	O
/	O
-	O
61	O
mg	O
/	O
day	O
(	O
p	O
<	O
0	O
.	O
001	O
)	O
.	O

In	O
contrast	O
,	O
podocalyxin	O
did	O
not	O
change	O
significantly	O
at	O
this	O
time	O
.	O

By	O
day	O
11	O
,	O
GLEPP1	O
protein	O
and	O
mRNA	O
had	O
begun	O
to	O
return	O
towards	O
baseline	O
.	O

By	O
day	O
45	O
-	O
126	O
,	O
at	O
a	O
time	O
when	O
glomerular	O
scarring	O
was	O
present	O
,	O
GLEPP1	O
was	O
absent	O
from	O
glomerulosclerotic	O
areas	O
although	O
the	O
total	O
glomerular	O
content	O
of	O
GLEPP1	O
was	O
not	O
different	O
from	O
normal	O
.	O

We	O
conclude	O
that	O
GLEPP1	O
expression	O
,	O
unlike	O
podocalyxin	O
,	O
reflects	O
podocyte	O
injury	O
induced	O
by	O
PAN	B-Chemical
.	O

GLEPP1	O
expression	O
may	O
be	O
a	O
useful	O
marker	O
of	O
podocyte	O
injury	O
.	O

Antithymocyte	B-Chemical
globulin	I-Chemical
in	O
the	O
treatment	O
of	O
D	B-Chemical
-	I-Chemical
penicillamine	I-Chemical
-	O
induced	O
aplastic	B-Disease
anemia	I-Disease
.	O

A	O
patient	O
who	O
received	O
antithymocyte	B-Chemical
globulin	I-Chemical
therapy	O
for	O
aplastic	B-Disease
anemia	I-Disease
due	O
to	O
D	B-Chemical
-	I-Chemical
penicillamine	I-Chemical
therapy	O
is	O
described	O
.	O

Bone	O
marrow	O
recovery	O
and	O
peripheral	O
blood	O
recovery	O
were	O
complete	O
1	O
month	O
and	O
3	O
months	O
,	O
respectively	O
,	O
after	O
treatment	O
,	O
and	O
blood	O
transfusion	O
or	O
other	O
therapies	O
were	O
not	O
necessary	O
in	O
a	O
follow	O
-	O
up	O
period	O
of	O
more	O
than	O
2	O
years	O
.	O

Use	O
of	O
antithymocyte	B-Chemical
globulin	I-Chemical
may	O
be	O
the	O
optimal	O
treatment	O
of	O
D	B-Chemical
-	I-Chemical
penicillamine	I-Chemical
-	O
induced	O
aplastic	B-Disease
anemia	I-Disease
.	O

Metamizol	B-Chemical
potentiates	O
morphine	B-Chemical
antinociception	O
but	O
not	O
constipation	B-Disease
after	O
chronic	O
treatment	O
.	O

This	O
work	O
evaluates	O
the	O
antinociceptive	O
and	O
constipating	B-Disease
effects	O
of	O
the	O
combination	O
of	O
3	O
.	O
2	O
mg	O
/	O
kg	O
s	O
.	O
c	O
.	O
morphine	B-Chemical
with	O
177	O
.	O
8	O
mg	O
/	O
kg	O
s	O
.	O
c	O
.	O
metamizol	B-Chemical
in	O
acutely	O
and	O
chronically	O
treated	O
(	O
once	O
a	O
day	O
for	O
12	O
days	O
)	O
rats	O
.	O

On	O
the	O
13th	O
day	O
,	O
antinociceptive	O
effects	O
were	O
assessed	O
using	O
a	O
model	O
of	O
inflammatory	O
nociception	O
,	O
pain	B-Disease
-	O
induced	O
functional	O
impairment	O
model	O
,	O
and	O
the	O
charcoal	B-Chemical
meal	O
test	O
was	O
used	O
to	O
evaluate	O
the	O
intestinal	O
transit	O
.	O

Simultaneous	O
administration	O
of	O
morphine	B-Chemical
with	O
metamizol	B-Chemical
resulted	O
in	O
a	O
markedly	O
antinociceptive	O
potentiation	O
and	O
an	O
increasing	O
of	O
the	O
duration	O
of	O
action	O
after	O
a	O
single	O
(	O
298	O
+	O
/	O
-	O
7	O
vs	O
.	O
139	O
+	O
/	O
-	O
36	O
units	O
area	O
(	O
ua	O
)	O
;	O
P	O
<	O
0	O
.	O
001	O
)	O
and	O
repeated	O
administration	O
(	O
280	O
+	O
/	O
-	O
17	O
vs	O
.	O
131	O
+	O
/	O
-	O
22	O
ua	O
;	O
P	O
<	O
0	O
.	O
001	O
)	O
.	O

Antinociceptive	O
effect	O
of	O
morphine	B-Chemical
was	O
reduced	O
in	O
chronically	O
treated	O
rats	O
(	O
39	O
+	O
/	O
-	O
10	O
vs	O
.	O
18	O
+	O
/	O
-	O
5	O
au	O
)	O
while	O
the	O
combination	O
-	O
induced	O
antinociception	O
was	O
remained	O
similar	O
as	O
an	O
acute	O
treatment	O
(	O
298	O
+	O
/	O
-	O
7	O
vs	O
.	O
280	O
+	O
/	O
-	O
17	O
au	O
)	O
.	O

Acute	O
antinociceptive	O
effects	O
of	O
the	O
combination	O
were	O
partially	O
prevented	O
by	O
3	O
.	O
2	O
mg	O
/	O
kg	O
naloxone	B-Chemical
s	O
.	O
c	O
.	O

(	O
P	O
<	O
0	O
.	O
05	O
)	O
,	O
suggesting	O
the	O
partial	O
involvement	O
of	O
the	O
opioidergic	O
system	O
in	O
the	O
synergism	O
observed	O
.	O

In	O
independent	O
groups	O
,	O
morphine	B-Chemical
inhibited	O
the	O
intestinal	O
transit	O
in	O
48	O
+	O
/	O
-	O
4	O
%	O
and	O
38	O
+	O
/	O
-	O
4	O
%	O
after	O
acute	O
and	O
chronic	O
treatment	O
,	O
respectively	O
,	O
suggesting	O
that	O
tolerance	O
did	O
not	O
develop	O
to	O
the	O
constipating	B-Disease
effects	O
.	O

The	O
combination	O
inhibited	O
intestinal	O
transit	O
similar	O
to	O
that	O
produced	O
by	O
morphine	B-Chemical
regardless	O
of	O
the	O
time	O
of	O
treatment	O
,	O
suggesting	O
that	O
metamizol	B-Chemical
did	O
not	O
potentiate	O
morphine	B-Chemical
-	O
induced	O
constipation	B-Disease
.	O

These	O
findings	O
show	O
a	O
significant	O
interaction	O
between	O
morphine	B-Chemical
and	O
metamizol	B-Chemical
in	O
chronically	O
treated	O
rats	O
,	O
suggesting	O
that	O
this	O
combination	O
could	O
be	O
useful	O
for	O
the	O
treatment	O
of	O
chronic	B-Disease
pain	I-Disease
.	O

Ifosfamide	B-Chemical
encephalopathy	B-Disease
presenting	O
with	O
asterixis	B-Disease
.	O

CNS	O
toxic	O
effects	O
of	O
the	O
antineoplastic	O
agent	O
ifosfamide	B-Chemical
(	O
IFX	B-Chemical
)	O
are	O
frequent	O
and	O
include	O
a	O
variety	O
of	O
neurological	O
symptoms	O
that	O
can	O
limit	O
drug	O
use	O
.	O

We	O
report	O
a	O
case	O
of	O
a	O
51	O
-	O
year	O
-	O
old	O
man	O
who	O
developed	O
severe	O
,	O
disabling	O
negative	O
myoclonus	B-Disease
of	O
the	O
upper	O
and	O
lower	O
extremities	O
after	O
the	O
infusion	O
of	O
ifosfamide	B-Chemical
for	O
plasmacytoma	B-Disease
.	O

He	O
was	O
awake	O
,	O
revealed	O
no	O
changes	O
of	O
mental	O
status	O
and	O
at	O
rest	O
there	O
were	O
no	O
further	O
motor	O
symptoms	O
.	O

Cranial	O
magnetic	O
resonance	O
imaging	O
and	O
extensive	O
laboratory	O
studies	O
failed	O
to	O
reveal	O
structural	B-Disease
lesions	I-Disease
of	I-Disease
the	I-Disease
brain	I-Disease
and	O
metabolic	B-Disease
abnormalities	I-Disease
.	O

An	O
electroencephalogram	O
showed	O
continuous	O
,	O
generalized	O
irregular	O
slowing	O
with	O
admixed	O
periodic	O
triphasic	O
waves	O
indicating	O
symptomatic	O
encephalopathy	B-Disease
.	O

The	O
administration	O
of	O
ifosfamide	B-Chemical
was	O
discontinued	O
and	O
within	O
12	O
h	O
the	O
asterixis	B-Disease
resolved	O
completely	O
.	O

In	O
the	O
patient	O
described	O
,	O
the	O
presence	O
of	O
asterixis	B-Disease
during	O
infusion	O
of	O
ifosfamide	B-Chemical
,	O
normal	O
laboratory	O
findings	O
and	O
imaging	O
studies	O
and	O
the	O
resolution	O
of	O
symptoms	O
following	O
the	O
discontinuation	O
of	O
the	O
drug	O
suggest	O
that	O
negative	O
myoclonus	B-Disease
is	O
associated	O
with	O
the	O
use	O
of	O
IFX	B-Chemical
.	O

Antagonism	O
between	O
interleukin	O
3	O
and	O
erythropoietin	O
in	O
mice	O
with	O
azidothymidine	B-Chemical
-	O
induced	O
anemia	B-Disease
and	O
in	O
bone	O
marrow	O
endothelial	O
cells	O
.	O

Azidothymidine	B-Chemical
(	O
AZT	B-Chemical
)	O
-	O
induced	O
anemia	B-Disease
in	O
mice	O
can	O
be	O
reversed	O
by	O
the	O
administration	O
of	O
IGF	O
-	O
IL	O
-	O
3	O
(	O
fusion	O
protein	O
of	O
insulin	O
-	O
like	O
growth	O
factor	O
II	O
(	O
IGF	O
II	O
)	O
and	O
interleukin	O
3	O
)	O
.	O

Although	O
interleukin	O
3	O
(	O
IL	O
-	O
3	O
)	O
and	O
erythropoietin	O
(	O
EPO	O
)	O
are	O
known	O
to	O
act	O
synergistically	O
on	O
hematopoietic	O
cell	O
proliferation	O
in	O
vitro	O
,	O
injection	O
of	O
IGF	O
-	O
IL	O
-	O
3	O
and	O
EPO	O
in	O
AZT	B-Chemical
-	O
treated	O
mice	O
resulted	O
in	O
a	O
reduction	O
of	O
red	O
cells	O
and	O
an	O
increase	O
of	O
plasma	O
EPO	O
levels	O
as	O
compared	O
to	O
animals	O
treated	O
with	O
IGF	O
-	O
IL	O
-	O
3	O
or	O
EPO	O
alone	O
.	O

We	O
tested	O
the	O
hypothesis	O
that	O
the	O
antagonistic	O
effect	O
of	O
IL	O
-	O
3	O
and	O
EPO	O
on	O
erythroid	O
cells	O
may	O
be	O
mediated	O
by	O
endothelial	O
cells	O
.	O

Bovine	O
liver	O
erythroid	O
cells	O
were	O
cultured	O
on	O
monolayers	O
of	O
human	O
bone	O
marrow	O
endothelial	O
cells	O
previously	O
treated	O
with	O
EPO	O
and	O
IGF	O
-	O
IL	O
-	O
3	O
.	O

There	O
was	O
a	O
significant	O
reduction	O
of	O
thymidine	B-Chemical
incorporation	O
into	O
both	O
erythroid	O
and	O
endothelial	O
cells	O
in	O
cultures	O
pre	O
-	O
treated	O
with	O
IGF	O
-	O
IL	O
-	O
3	O
and	O
EPO	O
.	O

Endothelial	O
cell	O
culture	O
supernatants	O
separated	O
by	O
ultrafiltration	O
and	O
ultracentrifugation	O
from	O
cells	O
treated	O
with	O
EPO	O
and	O
IL	O
-	O
3	O
significantly	O
reduced	O
thymidine	B-Chemical
incorporation	O
into	O
erythroid	O
cells	O
as	O
compared	O
to	O
identical	O
fractions	O
obtained	O
from	O
the	O
media	O
of	O
cells	O
cultured	O
with	O
EPO	O
alone	O
.	O

These	O
results	O
suggest	O
that	O
endothelial	O
cells	O
treated	O
simultaneously	O
with	O
EPO	O
and	O
IL	O
-	O
3	O
have	O
a	O
negative	O
effect	O
on	O
erythroid	O
cell	O
production	O
.	O

The	O
relationship	O
between	O
hippocampal	O
acetylcholine	B-Chemical
release	O
and	O
cholinergic	O
convulsant	O
sensitivity	O
in	O
withdrawal	O
seizure	B-Disease
-	O
prone	O
and	O
withdrawal	O
seizure	B-Disease
-	O
resistant	O
selected	O
mouse	O
lines	O
.	O

BACKGROUND	O
:	O
The	O
septo	O
-	O
hippocampal	O
cholinergic	O
pathway	O
has	O
been	O
implicated	O
in	O
epileptogenesis	O
,	O
and	O
genetic	O
factors	O
influence	O
the	O
response	O
to	O
cholinergic	O
agents	O
,	O
but	O
limited	O
data	O
are	O
available	O
on	O
cholinergic	O
involvement	O
in	O
alcohol	B-Chemical
withdrawal	O
severity	O
.	O

Thus	O
,	O
the	O
relationship	O
between	O
cholinergic	O
activity	O
and	O
responsiveness	O
and	O
alcohol	B-Chemical
withdrawal	O
was	O
investigated	O
in	O
a	O
genetic	O
animal	O
model	O
of	O
ethanol	B-Chemical
withdrawal	O
severity	O
.	O

METHODS	O
:	O
Cholinergic	O
convulsant	O
sensitivity	O
was	O
examined	O
in	O
alcohol	B-Chemical
-	O
na	O
ve	O
Withdrawal	O
Seizure	B-Disease
-	O
Prone	O
(	O
WSP	O
)	O
and	O
-	O
Resistant	O
(	O
WSR	O
)	O
mice	O
.	O

Animals	O
were	O
administered	O
nicotine	B-Chemical
,	O
carbachol	B-Chemical
,	O
or	O
neostigmine	B-Chemical
via	O
timed	O
tail	O
vein	O
infusion	O
,	O
and	O
the	O
latencies	O
to	O
onset	O
of	O
tremor	B-Disease
and	O
clonus	O
were	O
recorded	O
and	O
converted	O
to	O
threshold	O
dose	O
.	O

We	O
also	O
used	O
microdialysis	O
to	O
measure	O
basal	O
and	O
potassium	B-Chemical
-	O
stimulated	O
acetylcholine	B-Chemical
(	O
ACh	B-Chemical
)	O
release	O
in	O
the	O
CA1	O
region	O
of	O
the	O
hippocampus	O
.	O

Potassium	B-Chemical
was	O
applied	O
by	O
reverse	O
dialysis	O
twice	O
,	O
separated	O
by	O
75	O
min	O
.	O

Hippocampal	O
ACh	B-Chemical
also	O
was	O
measured	O
during	O
testing	O
for	O
handling	O
-	O
induced	O
convulsions	B-Disease
.	O

RESULTS	O
:	O
Sensitivity	O
to	O
several	O
convulsion	B-Disease
endpoints	O
induced	O
by	O
nicotine	B-Chemical
,	O
carbachol	B-Chemical
,	O
and	O
neostigmine	B-Chemical
were	O
significantly	O
greater	O
in	O
WSR	O
versus	O
WSP	O
mice	O
.	O

In	O
microdialysis	O
experiments	O
,	O
the	O
lines	O
did	O
not	O
differ	O
in	O
basal	O
release	O
of	O
ACh	B-Chemical
,	O
and	O
50	O
mM	O
KCl	B-Chemical
increased	O
ACh	B-Chemical
output	O
in	O
both	O
lines	O
of	O
mice	O
.	O

However	O
,	O
the	O
increase	O
in	O
release	O
of	O
ACh	B-Chemical
produced	O
by	O
the	O
first	O
application	O
of	O
KCl	B-Chemical
was	O
2	O
-	O
fold	O
higher	O
in	O
WSP	O
versus	O
WSR	O
mice	O
.	O

When	O
hippocampal	O
ACh	B-Chemical
was	O
measured	O
during	O
testing	O
for	O
handling	O
-	O
induced	O
convulsions	B-Disease
,	O
extracellular	O
ACh	B-Chemical
was	O
significantly	O
elevated	O
(	O
192	O
%	O
)	O
in	O
WSP	O
mice	O
,	O
but	O
was	O
nonsignificantly	O
elevated	O
(	O
59	O
%	O
)	O
in	O
WSR	O
mice	O
.	O

CONCLUSIONS	O
:	O
These	O
results	O
suggest	O
that	O
differences	O
in	O
cholinergic	O
activity	O
and	O
postsynaptic	O
sensitivity	O
to	O
cholinergic	O
convulsants	B-Disease
may	O
be	O
associated	O
with	O
ethanol	B-Chemical
withdrawal	O
severity	O
and	O
implicate	O
cholinergic	O
mechanisms	O
in	O
alcohol	B-Chemical
withdrawal	O
.	O

Specifically	O
,	O
WSP	O
mice	O
may	O
have	O
lower	O
sensitivity	O
to	O
cholinergic	O
convulsants	B-Disease
compared	O
with	O
WSR	O
because	O
of	O
postsynaptic	O
receptor	O
desensitization	O
brought	O
on	O
by	O
higher	O
activity	O
of	O
cholinergic	O
neurons	O
.	O

Capsaicin	B-Chemical
-	O
induced	O
muscle	B-Disease
pain	I-Disease
alters	O
the	O
excitability	O
of	O
the	O
human	O
jaw	O
-	O
stretch	O
reflex	O
.	O

The	O
pathophysiology	O
of	O
painful	O
temporomandibular	B-Disease
disorders	I-Disease
is	O
not	O
fully	O
understood	O
,	O
but	O
evidence	O
suggests	O
that	O
muscle	B-Disease
pain	I-Disease
modulates	O
motor	O
function	O
in	O
characteristic	O
ways	O
.	O

This	O
study	O
tested	O
the	O
hypothesis	O
that	O
activation	O
of	O
nociceptive	B-Disease
muscle	I-Disease
afferent	O
fibers	O
would	O
be	O
linked	O
to	O
an	O
increased	O
excitability	O
of	O
the	O
human	O
jaw	O
-	O
stretch	O
reflex	O
and	O
whether	O
this	O
process	O
would	O
be	O
sensitive	O
to	O
length	O
and	O
velocity	O
of	O
the	O
stretch	O
.	O

Capsaicin	B-Chemical
(	O
10	O
micro	O
g	O
)	O
was	O
injected	O
into	O
the	O
masseter	O
muscle	O
to	O
induce	O
pain	B-Disease
in	O
11	O
healthy	O
volunteers	O
.	O

Short	O
-	O
latency	O
reflex	O
responses	O
were	O
evoked	O
in	O
the	O
masseter	O
and	O
temporalis	O
muscles	O
by	O
a	O
stretch	O
device	O
with	O
different	O
velocities	O
and	O
displacements	O
before	O
,	O
during	O
,	O
and	O
after	O
the	O
pain	B-Disease
.	O

The	O
normalized	O
reflex	O
amplitude	O
increased	O
with	O
an	O
increase	O
in	O
velocity	O
at	O
a	O
given	O
displacement	O
,	O
but	O
remained	O
constant	O
with	O
different	O
displacements	O
at	O
a	O
given	O
velocity	O
.	O

The	O
normalized	O
reflex	O
amplitude	O
was	O
significantly	O
higher	O
during	O
pain	B-Disease
,	O
but	O
only	O
at	O
faster	O
stretches	O
in	O
the	O
painful	B-Disease
muscle	I-Disease
.	O

Increased	O
sensitivity	O
of	O
the	O
fusimotor	O
system	O
during	O
acute	O
muscle	B-Disease
pain	I-Disease
could	O
be	O
one	O
likely	O
mechanism	O
to	O
explain	O
the	O
findings	O
.	O

Effects	O
of	O
5	O
-	O
HT1B	O
receptor	O
ligands	O
microinjected	O
into	O
the	O
accumbal	O
shell	O
or	O
core	O
on	O
the	O
cocaine	B-Chemical
-	O
induced	O
locomotor	B-Disease
hyperactivity	I-Disease
in	O
rats	O
.	O

The	O
present	O
study	O
was	O
designed	O
to	O
examine	O
the	O
effect	O
of	O
5	O
-	O
HT1B	O
receptor	O
ligands	O
microinjected	O
into	O
the	O
subregions	O
of	O
the	O
nucleus	O
accumbens	O
(	O
the	O
shell	O
and	O
the	O
core	O
)	O
on	O
the	O
locomotor	B-Disease
hyperactivity	I-Disease
induced	O
by	O
cocaine	B-Chemical
in	O
rats	O
.	O

Male	O
Wistar	O
rats	O
were	O
implanted	O
bilaterally	O
with	O
cannulae	O
into	O
the	O
accumbens	O
shell	O
or	O
core	O
,	O
and	O
then	O
were	O
locally	O
injected	O
with	O
GR	B-Chemical
55562	I-Chemical
(	O
an	O
antagonist	O
of	O
5	O
-	O
HT1B	O
receptors	O
)	O
or	O
CP	B-Chemical
93129	I-Chemical
(	O
an	O
agonist	O
of	O
5	O
-	O
HT1B	O
receptors	O
)	O
.	O

Given	O
alone	O
to	O
any	O
accumbal	O
subregion	O
,	O
GR	B-Chemical
55562	I-Chemical
(	O
0	O
.	O
1	O
-	O
10	O
microg	O
/	O
side	O
)	O
or	O
CP	B-Chemical
93129	I-Chemical
(	O
0	O
.	O
1	O
-	O
10	O
microg	O
/	O
side	O
)	O
did	O
not	O
change	O
basal	O
locomotor	O
activity	O
.	O

Systemic	O
cocaine	B-Chemical
(	O
10	O
mg	O
/	O
kg	O
)	O
significantly	O
increased	O
the	O
locomotor	O
activity	O
of	O
rats	O
.	O

GR	B-Chemical
55562	I-Chemical
(	O
0	O
.	O
1	O
-	O
10	O
microg	O
/	O
side	O
)	O
,	O
administered	O
intra	O
-	O
accumbens	O
shell	O
prior	O
to	O
cocaine	B-Chemical
,	O
dose	O
-	O
dependently	O
attenuated	O
the	O
psychostimulant	O
-	O
induced	O
locomotor	B-Disease
hyperactivity	I-Disease
.	O

Such	O
attenuation	O
was	O
not	O
found	O
in	O
animals	O
which	O
had	O
been	O
injected	O
with	O
GR	B-Chemical
55562	I-Chemical
into	O
the	O
accumbens	O
core	O
.	O

When	O
injected	O
into	O
the	O
accumbens	O
shell	O
(	O
but	O
not	O
the	O
core	O
)	O
before	O
cocaine	B-Chemical
,	O
CP	B-Chemical
93129	I-Chemical
(	O
0	O
.	O
1	O
-	O
10	O
microg	O
/	O
side	O
)	O
enhanced	O
the	O
locomotor	O
response	O
to	O
cocaine	B-Chemical
;	O
the	O
maximum	O
effect	O
being	O
observed	O
after	O
10	O
microg	O
/	O
side	O
of	O
the	O
agonist	O
.	O

The	O
later	O
enhancement	O
was	O
attenuated	O
after	O
intra	O
-	O
accumbens	O
shell	O
treatment	O
with	O
GR	B-Chemical
55562	I-Chemical
(	O
1	O
microg	O
/	O
side	O
)	O
.	O

Our	O
findings	O
indicate	O
that	O
cocaine	B-Chemical
induced	O
hyperlocomotion	B-Disease
is	O
modified	O
by	O
5	O
-	O
HT1B	O
receptor	O
ligands	O
microinjected	O
into	O
the	O
accumbens	O
shell	O
,	O
but	O
not	O
core	O
,	O
this	O
modification	O
consisting	O
in	O
inhibitory	O
and	O
facilitatory	O
effects	O
of	O
the	O
5	O
-	O
HT1B	O
receptor	O
antagonist	O
(	O
GR	B-Chemical
55562	I-Chemical
)	O
and	O
agonist	O
(	O
CP	B-Chemical
93129	I-Chemical
)	O
,	O
respectively	O
.	O

In	O
other	O
words	O
,	O
the	O
present	O
results	O
suggest	O
that	O
the	O
accumbal	O
shell	O
5	O
-	O
HT1B	O
receptors	O
play	O
a	O
permissive	O
role	O
in	O
the	O
behavioural	O
response	O
to	O
the	O
psychostimulant	O
.	O

Cocaine	B-Chemical
related	O
chest	B-Disease
pain	I-Disease
:	O
are	O
we	O
seeing	O
the	O
tip	O
of	O
an	O
iceberg	O
?	O

The	O
recreational	O
use	O
of	O
cocaine	B-Chemical
is	O
on	O
the	O
increase	O
.	O

The	O
emergency	O
nurse	O
ought	O
to	O
be	O
familiar	O
with	O
some	O
of	O
the	O
cardiovascular	O
consequences	O
of	O
cocaine	B-Chemical
use	O
.	O

In	O
particular	O
,	O
the	O
tendency	O
of	O
cocaine	B-Chemical
to	O
produce	O
chest	B-Disease
pain	I-Disease
ought	O
to	O
be	O
in	O
the	O
mind	O
of	O
the	O
emergency	O
nurse	O
when	O
faced	O
with	O
a	O
young	O
victim	O
of	O
chest	B-Disease
pain	I-Disease
who	O
is	O
otherwise	O
at	O
low	O
risk	O
.	O

The	O
mechanism	O
of	O
chest	B-Disease
pain	I-Disease
related	O
to	O
cocaine	B-Chemical
use	O
is	O
discussed	O
and	O
treatment	O
dilemmas	O
are	O
discussed	O
.	O

Finally	O
,	O
moral	O
issues	O
relating	O
to	O
the	O
testing	O
of	O
potential	O
cocaine	B-Chemical
users	O
will	O
be	O
addressed	O
.	O

Crossover	O
comparison	O
of	O
efficacy	O
and	O
preference	O
for	O
rizatriptan	B-Chemical
10	O
mg	O
versus	O
ergotamine	B-Chemical
/	O
caffeine	B-Chemical
in	O
migraine	B-Disease
.	O

Rizatriptan	B-Chemical
is	O
a	O
selective	O
5	B-Chemical
-	I-Chemical
HT	I-Chemical
(	O
1B	O
/	O
1D	O
)	O
receptor	O
agonist	O
with	O
rapid	O
oral	O
absorption	O
and	O
early	O
onset	O
of	O
action	O
in	O
the	O
acute	O
treatment	O
of	O
migraine	B-Disease
.	O

This	O
randomized	O
double	O
-	O
blind	O
crossover	O
outpatient	O
study	O
assessed	O
the	O
preference	O
for	O
1	O
rizatriptan	B-Chemical
10	O
mg	O
tablet	O
to	O
2	O
ergotamine	B-Chemical
1	O
mg	O
/	O
caffeine	B-Chemical
100	O
mg	O
tablets	O
in	O
439	O
patients	O
treating	O
a	O
single	O
migraine	B-Disease
attack	O
with	O
each	O
therapy	O
.	O

Of	O
patients	O
expressing	O
a	O
preference	O
(	O
89	O
.	O
1	O
%	O
)	O
,	O
more	O
than	O
twice	O
as	O
many	O
preferred	O
rizatriptan	B-Chemical
to	O
ergotamine	B-Chemical
/	O
caffeine	B-Chemical
(	O
69	O
.	O
9	O
vs	O
.	O
30	O
.	O
1	O
%	O
,	O
p	O
<	O
or	O
=	O
0	O
.	O
001	O
)	O
.	O

Faster	O
relief	O
of	O
headache	B-Disease
was	O
the	O
most	O
important	O
reason	O
for	O
preference	O
,	O
cited	O
by	O
67	O
.	O
3	O
%	O
of	O
patients	O
preferring	O
rizatriptan	B-Chemical
and	O
54	O
.	O
2	O
%	O
of	O
patients	O
who	O
preferred	O
ergotamine	B-Chemical
/	O
caffeine	B-Chemical
.	O

The	O
co	O
-	O
primary	O
endpoint	O
of	O
being	O
pain	B-Disease
free	O
at	O
2	O
h	O
was	O
also	O
in	O
favor	O
of	O
rizatriptan	B-Chemical
.	O

Forty	O
-	O
nine	O
percent	O
of	O
patients	O
were	O
pain	B-Disease
free	O
2	O
h	O
after	O
rizatriptan	B-Chemical
,	O
compared	O
with	O
24	O
.	O
3	O
%	O
treated	O
with	O
ergotamine	B-Chemical
/	O
caffeine	B-Chemical
(	O
p	O
<	O
or	O
=	O
0	O
.	O
001	O
)	O
,	O
rizatriptan	B-Chemical
being	O
superior	O
within	O
1	O
h	O
of	O
treatment	O
.	O

Headache	B-Disease
relief	O
at	O
2	O
h	O
was	O
75	O
.	O
9	O
%	O
for	O
rizatriptan	B-Chemical
and	O
47	O
.	O
3	O
%	O
for	O
ergotamine	B-Chemical
/	O
caffeine	B-Chemical
(	O
p	O
<	O
or	O
=	O
0	O
.	O
001	O
)	O
,	O
with	O
rizatriptan	B-Chemical
being	O
superior	O
to	O
ergotamine	B-Chemical
/	O
caffeine	B-Chemical
within	O
30	O
min	O
of	O
dosing	O
.	O

Almost	O
36	O
%	O
of	O
patients	O
taking	O
rizatriptan	B-Chemical
were	O
pain	B-Disease
free	O
at	O
2	O
h	O
and	O
had	O
no	O
recurrence	O
or	O
need	O
for	O
additional	O
medication	O
within	O
24	O
h	O
,	O
compared	O
to	O
20	O
%	O
of	O
patients	O
on	O
ergotamine	B-Chemical
/	O
caffeine	B-Chemical
(	O
p	O
<	O
or	O
=	O
0	O
.	O
001	O
)	O
.	O

Rizatriptan	B-Chemical
was	O
also	O
superior	O
to	O
ergotamine	B-Chemical
/	O
caffeine	B-Chemical
in	O
the	O
proportions	O
of	O
patients	O
with	O
no	O
nausea	B-Disease
,	O
vomiting	B-Disease
,	O
phonophobia	B-Disease
or	O
photophobia	B-Disease
and	O
for	O
patients	O
with	O
normal	O
function	O
2	O
h	O
after	O
drug	O
intake	O
(	O
p	O
<	O
or	O
=	O
0	O
.	O
001	O
)	O
.	O

More	O
patients	O
were	O
(	O
completely	O
,	O
very	O
or	O
somewhat	O
)	O
satisfied	O
2	O
h	O
after	O
treatment	O
with	O
rizatriptan	B-Chemical
(	O
69	O
.	O
8	O
%	O
)	O
than	O
at	O
2	O
h	O
after	O
treatment	O
with	O
ergotamine	B-Chemical
/	O
caffeine	B-Chemical
(	O
38	O
.	O
6	O
%	O
,	O
p	O
<	O
or	O
=	O
0	O
.	O
001	O
)	O
.	O

Recurrence	O
rates	O
were	O
31	O
.	O
4	O
%	O
with	O
rizatriptan	B-Chemical
and	O
15	O
.	O
3	O
%	O
with	O
ergotamine	B-Chemical
/	O
caffeine	B-Chemical
.	O

Both	O
active	O
treatments	O
were	O
well	O
tolerated	O
.	O

The	O
most	O
common	O
adverse	O
events	O
(	O
incidence	O
>	O
or	O
=	O
5	O
%	O
in	O
one	O
group	O
)	O
after	O
rizatriptan	B-Chemical
and	O
ergotamine	B-Chemical
/	O
caffeine	B-Chemical
,	O
respectively	O
,	O
were	O
dizziness	B-Disease
(	O
6	O
.	O
7	O
and	O
5	O
.	O
3	O
%	O
)	O
,	O
nausea	B-Disease
(	O
4	O
.	O
2	O
and	O
8	O
.	O
5	O
%	O
)	O
and	O
somnolence	B-Disease
(	O
5	O
.	O
5	O
and	O
2	O
.	O
3	O
%	O
)	O
.	O

Severe	O
ocular	B-Disease
and	I-Disease
orbital	I-Disease
toxicity	I-Disease
after	O
intracarotid	O
injection	O
of	O
carboplatin	B-Chemical
for	O
recurrent	O
glioblastomas	B-Disease
.	O

BACKGROUND	O
:	O
Glioblastoma	B-Disease
is	O
a	O
malignant	B-Disease
tumor	I-Disease
that	O
occurs	O
in	O
the	O
cerebrum	O
during	O
adulthood	O
.	O

With	O
current	O
treatment	O
regimens	O
including	O
combined	O
surgery	O
,	O
radiation	O
and	O
chemotherapy	O
,	O
the	O
average	O
life	O
expectancy	O
of	O
the	O
patients	O
is	O
limited	O
to	O
approximately	O
1	O
year	O
.	O

Therefore	O
,	O
patients	O
with	O
glioblastoma	B-Disease
sometimes	O
have	O
intracarotid	O
injection	O
of	O
carcinostatics	O
added	O
to	O
the	O
treatment	O
regimen	O
.	O

Generally	O
,	O
carboplatin	B-Chemical
is	O
said	O
to	O
have	O
milder	O
side	O
effects	O
than	O
cisplatin	B-Chemical
,	O
whose	O
ocular	B-Disease
and	I-Disease
orbital	I-Disease
toxicity	I-Disease
are	O
well	O
known	O
.	O

However	O
,	O
we	O
experienced	O
a	O
case	O
of	O
severe	O
ocular	B-Disease
and	I-Disease
orbital	I-Disease
toxicity	I-Disease
after	O
intracarotid	O
injection	O
of	O
carboplatin	B-Chemical
,	O
which	O
is	O
infrequently	O
reported	O
.	O

CASE	O
:	O
A	O
58	O
-	O
year	O
-	O
old	O
man	O
received	O
an	O
intracarotid	O
injection	O
of	O
carboplatin	B-Chemical
for	O
recurrent	O
glioblastomas	B-Disease
in	O
his	O
left	O
temporal	O
lobe	O
.	O

He	O
complained	O
of	O
pain	B-Disease
and	I-Disease
visual	I-Disease
disturbance	I-Disease
in	I-Disease
the	I-Disease
ipsilateral	I-Disease
eye	I-Disease
30	O
h	O
after	O
the	O
injection	O
.	O

Various	O
ocular	O
symptoms	O
and	O
findings	O
caused	O
by	O
carboplatin	B-Chemical
toxicity	B-Disease
were	O
seen	O
.	O

RESULTS	O
:	O
He	O
was	O
treated	O
with	O
intravenous	O
administration	O
of	O
corticosteroids	O
and	O
glycerin	B-Chemical
for	O
6	O
days	O
after	O
the	O
injection	O
.	O

Although	O
the	O
intraocular	O
pressure	O
elevation	O
caused	O
by	O
secondary	O
acute	O
angle	O
-	O
closure	O
glaucoma	B-Disease
decreased	O
and	O
ocular	B-Disease
pain	I-Disease
diminished	O
,	O
inexorable	O
papilledema	B-Disease
and	O
exudative	O
retinal	B-Disease
detachment	I-Disease
continued	O
for	O
3	O
weeks	O
.	O

Finally	O
,	O
6	O
weeks	O
later	O
,	O
diffuse	O
chorioretinal	B-Disease
atrophy	I-Disease
with	O
optic	B-Disease
atrophy	I-Disease
occurred	O
and	O
the	O
vision	O
in	O
his	O
left	O
eye	O
was	O
lost	O
.	O

CONCLUSION	O
:	O
When	O
performing	O
intracarotid	O
injection	O
of	O
carboplatin	B-Chemical
,	O
we	O
must	O
be	O
aware	O
of	O
its	O
potentially	O
blinding	O
ocular	B-Disease
toxicity	I-Disease
.	O

It	O
is	O
recommended	O
that	O
further	O
studies	O
and	O
investigations	O
are	O
undertaken	O
in	O
the	O
effort	O
to	O
minimize	O
such	O
severe	O
side	O
effects	O
.	O

Visual	B-Disease
hallucinations	I-Disease
associated	O
with	O
zonisamide	B-Chemical
.	O

Zonisamide	B-Chemical
is	O
a	O
broad	O
-	O
spectrum	O
antiepileptic	O
drug	O
used	O
to	O
treat	O
various	O
types	O
of	O
seizures	B-Disease
.	O

Although	O
visual	B-Disease
hallucinations	I-Disease
have	O
not	O
been	O
reported	O
as	O
an	O
adverse	O
effect	O
of	O
this	O
agent	O
,	O
we	O
describe	O
three	O
patients	O
who	O
experienced	O
complex	O
visual	B-Disease
hallucinations	I-Disease
and	O
altered	O
mental	O
status	O
after	O
zonisamide	B-Chemical
treatment	O
was	O
begun	O
or	O
its	O
dosage	O
increased	O
.	O

All	O
three	O
had	O
been	O
diagnosed	O
earlier	O
with	O
epilepsy	B-Disease
,	O
and	O
their	O
electroencephalogram	O
(	O
EEG	O
)	O
findings	O
were	O
abnormal	O
.	O

During	O
monitoring	O
,	O
visual	B-Disease
hallucinations	I-Disease
did	O
not	O
correlate	O
with	O
EEG	O
readings	O
,	O
nor	O
did	O
video	O
recording	O
capture	O
any	O
of	O
the	O
described	O
events	O
.	O

None	O
of	O
the	O
patients	O
had	O
experienced	O
visual	B-Disease
hallucinations	I-Disease
before	O
this	O
event	O
.	O

The	O
only	O
recent	O
change	O
in	O
their	O
treatment	O
was	O
the	O
introduction	O
or	O
increased	O
dosage	O
of	O
zonisamide	B-Chemical
.	O

With	O
either	O
discontinuation	O
or	O
decreased	O
dosage	O
of	O
the	O
drug	O
the	O
symptoms	O
disappeared	O
and	O
did	O
not	O
recur	O
.	O

Further	O
observations	O
and	O
reports	O
will	O
help	O
clarify	O
this	O
adverse	O
effect	O
.	O

Until	O
then	O
,	O
clinicians	O
need	O
to	O
be	O
aware	O
of	O
this	O
possible	O
complication	O
associated	O
with	O
zonisamide	B-Chemical
.	O

Anti	O
-	O
epileptic	B-Disease
drugs	O
-	O
induced	O
de	O
novo	O
absence	B-Disease
seizures	I-Disease
.	O

The	O
authors	O
present	O
three	O
patients	O
with	O
de	O
novo	O
absence	B-Disease
epilepsy	I-Disease
after	O
administration	O
of	O
carbamazepine	B-Chemical
and	O
vigabatrin	B-Chemical
.	O

Despite	O
the	O
underlying	O
diseases	O
,	O
the	O
prognosis	O
for	O
drug	O
-	O
induced	O
de	O
novo	O
absence	B-Disease
seizure	I-Disease
is	O
good	O
because	O
it	O
subsides	O
rapidly	O
after	O
discontinuing	O
the	O
use	O
of	O
the	O
offending	O
drugs	O
.	O

The	O
gamma	B-Chemical
-	I-Chemical
aminobutyric	I-Chemical
acid	I-Chemical
-	O
transmitted	O
thalamocortical	O
circuitry	O
accounts	O
for	O
a	O
major	O
part	O
of	O
the	O
underlying	O
neurophysiology	O
of	O
the	O
absence	B-Disease
epilepsy	I-Disease
.	O

Because	O
drug	O
-	O
induced	O
de	O
novo	O
absence	B-Disease
seizure	I-Disease
is	O
rare	O
,	O
pro	O
-	O
absence	O
drugs	O
can	O
only	O
be	O
considered	O
a	O
promoting	O
factor	O
.	O

The	O
underlying	O
epileptogenecity	O
of	O
the	O
patients	O
or	O
the	O
synergistic	O
effects	O
of	O
the	O
accompanying	O
drugs	O
is	O
required	O
to	O
trigger	O
the	O
de	O
novo	O
absence	B-Disease
seizure	I-Disease
.	O

The	O
possibility	O
of	O
drug	O
-	O
induced	O
aggravation	O
should	O
be	O
considered	O
whenever	O
an	O
unexpected	O
increase	O
in	O
seizure	B-Disease
frequency	O
and	O
/	O
or	O
new	O
seizure	B-Disease
types	O
appear	O
following	O
a	O
change	O
in	O
drug	O
treatment	O
.	O

By	O
understanding	O
the	O
underlying	O
mechanism	O
of	O
absence	B-Disease
epilepsy	I-Disease
,	O
we	O
can	O
avoid	O
the	O
inappropriate	O
use	O
of	O
anticonvulsants	O
in	O
children	O
with	O
epilepsy	B-Disease
and	O
prevent	O
drug	O
-	O
induced	O
absence	B-Disease
seizures	I-Disease
.	O

Prenatal	O
dexamethasone	B-Chemical
programs	O
hypertension	B-Disease
and	O
renal	B-Disease
injury	I-Disease
in	O
the	O
rat	O
.	O

Dexamethasone	O
is	O
frequently	O
administered	O
to	O
the	O
developing	O
fetus	O
to	O
accelerate	O
pulmonary	O
development	O
.	O

The	O
purpose	O
of	O
the	O
present	O
study	O
was	O
to	O
determine	O
if	O
prenatal	O
dexamethasone	B-Chemical
programmed	O
a	O
progressive	O
increase	B-Disease
in	I-Disease
blood	I-Disease
pressure	I-Disease
and	O
renal	B-Disease
injury	I-Disease
in	O
rats	O
.	O

Pregnant	O
rats	O
were	O
given	O
either	O
vehicle	O
or	O
2	O
daily	O
intraperitoneal	O
injections	O
of	O
dexamethasone	B-Chemical
(	O
0	O
.	O
2	O
mg	O
/	O
kg	O
body	O
weight	O
)	O
on	O
gestational	O
days	O
11	O
and	O
12	O
,	O
13	O
and	O
14	O
,	O
15	O
and	O
16	O
,	O
17	O
and	O
18	O
,	O
or	O
19	O
and	O
20	O
.	O

Offspring	O
of	O
rats	O
administered	O
dexamethasone	B-Chemical
on	O
days	O
15	O
and	O
16	O
gestation	O
had	O
a	O
20	O
%	O
reduction	B-Disease
in	I-Disease
glomerular	I-Disease
number	I-Disease
compared	O
with	O
control	O
at	O
6	O
to	O
9	O
months	O
of	O
age	O
(	O
22	O
527	O
+	O
/	O
-	O
509	O
versus	O
28	O
050	O
+	O
/	O
-	O
561	O
,	O
P	O
<	O
0	O
.	O
05	O
)	O
,	O
which	O
was	O
comparable	O
to	O
the	O
percent	O
reduction	O
in	O
glomeruli	O
measured	O
at	O
3	O
weeks	O
of	O
age	O
.	O

Six	O
-	O
to	O
9	O
-	O
month	O
old	O
rats	O
receiving	O
prenatal	O
dexamethasone	B-Chemical
on	O
days	O
17	O
and	O
18	O
of	O
gestation	O
had	O
a	O
17	O
%	O
reduction	O
in	O
glomeruli	O
(	O
23	O
380	O
+	O
/	O
-	O
587	O
)	O
compared	O
with	O
control	O
rats	O
(	O
P	O
<	O
0	O
.	O
05	O
)	O
.	O

Male	O
rats	O
that	O
received	O
prenatal	O
dexamethasone	B-Chemical
on	O
days	O
15	O
and	O
16	O
,	O
17	O
and	O
18	O
,	O
and	O
13	O
and	O
14	O
of	O
gestation	O
had	O
elevated	B-Disease
blood	I-Disease
pressures	I-Disease
at	O
6	O
months	O
of	O
age	O
;	O
the	O
latter	O
group	O
did	O
not	O
have	O
a	O
reduction	B-Disease
in	I-Disease
glomerular	I-Disease
number	I-Disease
.	O

Adult	O
rats	O
given	O
dexamethasone	B-Chemical
on	O
days	O
15	O
and	O
16	O
of	O
gestation	O
had	O
more	O
glomeruli	O
with	O
glomerulosclerosis	B-Disease
than	O
control	O
rats	O
.	O

This	O
study	O
shows	O
that	O
prenatal	O
dexamethasone	B-Chemical
in	O
rats	O
results	O
in	O
a	O
reduction	B-Disease
in	I-Disease
glomerular	I-Disease
number	I-Disease
,	O
glomerulosclerosis	B-Disease
,	O
and	O
hypertension	B-Disease
when	O
administered	O
at	O
specific	O
points	O
during	O
gestation	O
.	O

Hypertension	B-Disease
was	O
observed	O
in	O
animals	O
that	O
had	O
a	O
reduction	O
in	O
glomeruli	O
as	O
well	O
as	O
in	O
a	O
group	O
that	O
did	O
not	O
have	O
a	O
reduction	B-Disease
in	I-Disease
glomerular	I-Disease
number	I-Disease
,	O
suggesting	O
that	O
a	O
reduction	B-Disease
in	I-Disease
glomerular	I-Disease
number	I-Disease
is	O
not	O
the	O
sole	O
cause	O
for	O
the	O
development	O
of	O
hypertension	B-Disease
.	O

Kidney	O
function	O
and	O
morphology	O
after	O
short	O
-	O
term	O
combination	O
therapy	O
with	O
cyclosporine	B-Chemical
A	I-Chemical
,	O
tacrolimus	B-Chemical
and	O
sirolimus	B-Chemical
in	O
the	O
rat	O
.	O

BACKGROUND	O
:	O
Sirolimus	B-Chemical
(	O
SRL	B-Chemical
)	O
may	O
supplement	O
calcineurin	O
inhibitors	O
in	O
clinical	O
organ	O
transplantation	O
.	O

These	O
are	O
nephrotoxic	B-Disease
,	O
but	O
SRL	B-Chemical
seems	O
to	O
act	O
differently	O
displaying	O
only	O
minor	O
nephrotoxic	B-Disease
effects	O
,	O
although	O
this	O
question	O
is	O
still	O
open	O
.	O

In	O
a	O
number	O
of	O
treatment	O
protocols	O
where	O
SRL	B-Chemical
was	O
combined	O
with	O
a	O
calcineurin	O
inhibitor	O
indications	O
of	O
a	O
synergistic	O
nephrotoxic	B-Disease
effect	O
were	O
described	O
.	O

The	O
aim	O
of	O
this	O
study	O
was	O
to	O
examine	O
further	O
the	O
renal	O
function	O
,	O
including	O
morphological	O
analysis	O
of	O
the	O
kidneys	O
of	O
male	O
Sprague	O
-	O
Dawley	O
rats	O
treated	O
with	O
either	O
cyclosporine	B-Chemical
A	I-Chemical
(	O
CsA	B-Chemical
)	O
,	O
tacrolimus	B-Chemical
(	O
FK506	B-Chemical
)	O
or	O
SRL	B-Chemical
as	O
monotherapies	O
or	O
in	O
different	O
combinations	O
.	O

METHODS	O
:	O
For	O
a	O
period	O
of	O
2	O
weeks	O
,	O
CsA	B-Chemical
15	O
mg	O
/	O
kg	O
/	O
day	O
(	O
given	O
orally	O
)	O
,	O
FK506	B-Chemical
3	O
.	O
0	O
mg	O
/	O
kg	O
/	O
day	O
(	O
given	O
orally	O
)	O
or	O
SRL	B-Chemical
0	O
.	O
4	O
mg	O
/	O
kg	O
/	O
day	O
(	O
given	O
intraperitoneally	O
)	O
was	O
administered	O
once	O
a	O
day	O
as	O
these	O
doses	O
have	O
earlier	O
been	O
found	O
to	O
achieve	O
a	O
significant	O
immunosuppressive	O
effect	O
in	O
Sprague	O
-	O
Dawley	O
rats	O
.	O

In	O
the	O
'	O
conscious	O
catheterized	O
rat	O
'	O
model	O
,	O
the	O
glomerular	O
filtration	O
rate	O
(	O
GFR	O
)	O
was	O
measured	O
as	O
the	O
clearance	O
of	O
Cr	O
(	O
EDTA	O
)	O
.	O

The	O
morphological	O
analysis	O
of	O
the	O
kidneys	O
included	O
a	O
semi	O
-	O
quantitative	O
scoring	O
system	O
analysing	O
the	O
degree	O
of	O
striped	O
fibrosis	B-Disease
,	O
subcapsular	O
fibrosis	B-Disease
and	O
the	O
number	O
of	O
basophilic	O
tubules	O
,	O
plus	O
an	O
additional	O
stereological	O
analysis	O
of	O
the	O
total	O
grade	O
of	O
fibrosis	B-Disease
in	O
the	O
cortex	O
stained	O
with	O
Sirius	O
Red	O
.	O

RESULTS	O
:	O
CsA	B-Chemical
,	O
FK506	B-Chemical
and	O
SRL	B-Chemical
all	O
significantly	O
decreased	O
the	O
GFR	O
.	O

A	O
further	O
deterioration	O
was	O
seen	O
when	O
CsA	B-Chemical
was	O
combined	O
with	O
either	O
FK506	B-Chemical
or	O
SRL	B-Chemical
,	O
whereas	O
the	O
GFR	O
remained	O
unchanged	O
in	O
the	O
group	O
treated	O
with	O
FK506	B-Chemical
plus	O
SRL	B-Chemical
when	O
compared	O
with	O
treatment	O
with	O
any	O
of	O
the	O
single	O
substances	O
.	O

The	O
morphological	O
changes	O
presented	O
a	O
similar	O
pattern	O
.	O

The	O
semi	O
-	O
quantitative	O
scoring	O
was	O
significantly	O
worst	O
in	O
the	O
group	O
treated	O
with	O
CsA	B-Chemical
plus	O
SRL	B-Chemical
(	O
P	O
<	O
0	O
.	O
001	O
compared	O
with	O
controls	O
)	O
and	O
the	O
analysis	O
of	O
the	O
total	O
grade	O
of	O
fibrosis	B-Disease
also	O
showed	O
the	O
highest	O
proportion	O
in	O
the	O
same	O
group	O
and	O
was	O
significantly	O
different	O
from	O
controls	O
(	O
P	O
<	O
0	O
.	O
02	O
)	O
.	O

The	O
FK506	B-Chemical
plus	O
SRL	B-Chemical
combination	O
showed	O
only	O
a	O
marginally	O
higher	O
degree	O
of	O
fibrosis	B-Disease
as	O
compared	O
with	O
controls	O
(	O
P	O
=	O
0	O
.	O
05	O
)	O
.	O

CONCLUSION	O
:	O
This	O
rat	O
study	O
demonstrated	O
a	O
synergistic	O
nephrotoxic	B-Disease
effect	O
of	O
CsA	B-Chemical
plus	O
SRL	B-Chemical
,	O
whereas	O
FK506	B-Chemical
plus	O
SRL	B-Chemical
was	O
better	O
tolerated	O
.	O

Evaluation	O
of	O
cardiac	O
troponin	O
I	O
and	O
T	O
levels	O
as	O
markers	O
of	O
myocardial	B-Disease
damage	I-Disease
in	O
doxorubicin	B-Chemical
-	O
induced	O
cardiomyopathy	B-Disease
rats	O
,	O
and	O
their	O
relationship	O
with	O
echocardiographic	O
and	O
histological	O
findings	O
.	O

BACKGROUND	O
:	O
Cardiac	O
troponins	O
I	O
(	O
cTnI	O
)	O
and	O
T	O
(	O
cTnT	O
)	O
have	O
been	O
shown	O
to	O
be	O
highly	O
sensitive	O
and	O
specific	O
markers	O
of	O
myocardial	B-Disease
cell	I-Disease
injury	I-Disease
.	O

We	O
investigated	O
the	O
diagnostic	O
value	O
of	O
cTnI	O
and	O
cTnT	O
for	O
the	O
diagnosis	O
of	O
myocardial	B-Disease
damage	I-Disease
in	O
a	O
rat	O
model	O
of	O
doxorubicin	B-Chemical
(	O
DOX	B-Chemical
)	O
-	O
induced	O
cardiomyopathy	B-Disease
,	O
and	O
we	O
examined	O
the	O
relationship	O
between	O
serial	O
cTnI	O
and	O
cTnT	O
with	O
the	O
development	O
of	O
cardiac	B-Disease
disorders	I-Disease
monitored	O
by	O
echocardiography	O
and	O
histological	O
examinations	O
in	O
this	O
model	O
.	O

METHODS	O
:	O
Thirty	O
-	O
five	O
Wistar	O
rats	O
were	O
given	O
1	O
.	O
5	O
mg	O
/	O
kg	O
DOX	B-Chemical
,	O
i	O
.	O
v	O
.	O
,	O
weekly	O
for	O
up	O
to	O
8	O
weeks	O
for	O
a	O
total	O
cumulative	O
dose	O
of	O
12	O
mg	O
/	O
kg	O
BW	O
.	O

Ten	O
rats	O
received	O
saline	O
as	O
a	O
control	O
group	O
.	O

cTnI	O
was	O
measured	O
with	O
Access	O
(	O
R	O
)	O
(	O
ng	O
/	O
ml	O
)	O
and	O
a	O
research	O
immunoassay	O
(	O
pg	O
/	O
ml	O
)	O
,	O
and	O
compared	O
with	O
cTnT	O
,	O
CK	O
-	O
MB	O
mass	O
and	O
CK	O
.	O

By	O
using	O
transthoracic	O
echocardiography	O
,	O
anterior	O
and	O
posterior	O
wall	O
thickness	O
,	O
LV	O
diameters	O
and	O
LV	O
fractional	O
shortening	O
(	O
FS	O
)	O
were	O
measured	O
in	O
all	O
rats	O
before	O
DOX	B-Chemical
or	O
saline	O
,	O
and	O
at	O
weeks	O
6	O
and	O
9	O
after	O
treatment	O
in	O
all	O
surviving	O
rats	O
.	O

Histology	O
was	O
performed	O
in	O
DOX	B-Chemical
-	O
rats	O
at	O
6	O
and	O
9	O
weeks	O
after	O
the	O
last	O
DOX	B-Chemical
dose	O
and	O
in	O
all	O
controls	O
.	O

RESULTS	O
:	O
Eighteen	O
of	O
the	O
DOX	B-Chemical
rats	O
died	O
prematurely	O
of	O
general	O
toxicity	B-Disease
during	O
the	O
9	O
-	O
week	O
period	O
.	O

End	O
-	O
diastolic	O
(	O
ED	O
)	O
and	O
end	O
-	O
systolic	O
(	O
ES	O
)	O
LV	O
diameters	O
/	O
BW	O
significantly	O
increased	O
,	O
whereas	O
LV	O
FS	O
was	O
decreased	O
after	O
9	O
weeks	O
in	O
the	O
DOX	B-Chemical
group	O
(	O
p	O
<	O
0	O
.	O
001	O
)	O
.	O

These	O
parameters	O
remained	O
unchanged	O
in	O
controls	O
.	O

Histological	O
evaluation	O
of	O
hearts	O
from	O
all	O
rats	O
given	O
DOX	B-Chemical
revealed	O
significant	O
slight	O
degrees	O
of	O
perivascular	O
and	O
interstitial	O
fibrosis	B-Disease
.	O

In	O
7	O
of	O
the	O
18	O
rats	O
,	O
degeneration	O
and	O
myocyte	O
vacuolisation	O
were	O
found	O
.	O

Only	O
five	O
of	O
the	O
controls	O
exhibited	O
evidence	O
of	O
very	O
slight	O
perivascular	O
fibrosis	B-Disease
.	O

A	O
significant	O
rise	O
in	O
cTnT	O
was	O
found	O
in	O
DOX	B-Chemical
rats	O
after	O
cumulative	O
doses	O
of	O
7	O
.	O
5	O
and	O
12	O
mg	O
/	O
kg	O
in	O
comparison	O
with	O
baseline	O
(	O
p	O
<	O
0	O
.	O
05	O
)	O
.	O

cTnT	O
found	O
in	O
rats	O
after	O
12	O
mg	O
/	O
kg	O
were	O
significantly	O
greater	O
than	O
that	O
found	O
after	O
7	O
.	O
5	O
mg	O
/	O
kg	O
DOX	B-Chemical
.	O

Maximal	O
cTnI	O
(	O
pg	O
/	O
ml	O
)	O
and	O
cTnT	O
levels	O
were	O
significantly	O
increased	O
in	O
DOX	B-Chemical
rats	O
compared	O
with	O
controls	O
(	O
p	O
=	O
0	O
.	O
006	O
,	O
0	O
.	O
007	O
)	O
.	O

cTnI	O
(	O
ng	O
/	O
ml	O
)	O
,	O
CK	O
-	O
MB	O
mass	O
and	O
CK	O
remained	O
unchanged	O
in	O
DOX	B-Chemical
rats	O
compared	O
with	O
controls	O
.	O

All	O
markers	O
remained	O
stable	O
in	O
controls	O
.	O

Analysis	O
of	O
data	O
revealed	O
a	O
significant	O
correlation	O
between	O
maximal	O
cTnT	O
and	O
ED	O
and	O
ES	O
LV	O
diameters	O
/	O
BW	O
(	O
r	O
=	O
0	O
.	O
81	O
and	O
0	O
.	O
65	O
;	O
p	O
<	O
0	O
.	O
0001	O
)	O
.	O

A	O
significant	O
relationship	O
was	O
observed	O
between	O
maximal	O
cTnT	O
and	O
the	O
extent	O
of	O
myocardial	O
morphological	O
changes	O
,	O
and	O
between	O
LV	O
diameters	O
/	O
BW	O
and	O
histological	O
findings	O
.	O

CONCLUSIONS	O
:	O
Among	O
markers	O
of	O
ischemic	B-Disease
injury	I-Disease
after	O
DOX	B-Chemical
in	O
rats	O
,	O
cTnT	O
showed	O
the	O
greatest	O
ability	O
to	O
detect	O
myocardial	B-Disease
damage	I-Disease
assessed	O
by	O
echocardiographic	O
detection	O
and	O
histological	O
changes	O
.	O

Although	O
there	O
was	O
a	O
discrepancy	O
between	O
the	O
amount	O
of	O
cTnI	O
and	O
cTnT	O
after	O
DOX	B-Chemical
,	O
probably	O
due	O
to	O
heterogeneity	O
in	O
cross	O
-	O
reactivities	O
of	O
mAbs	O
to	O
various	O
cTnI	O
and	O
cTnT	O
forms	O
,	O
it	O
is	O
likely	O
that	O
cTnT	O
in	O
rats	O
after	O
DOX	B-Chemical
indicates	O
cell	O
damage	O
determined	O
by	O
the	O
magnitude	O
of	O
injury	O
induced	O
and	O
that	O
cTnT	O
should	O
be	O
a	O
useful	O
marker	O
for	O
the	O
prediction	O
of	O
experimentally	O
induced	O
cardiotoxicity	B-Disease
and	O
possibly	O
for	O
cardioprotective	O
experiments	O
.	O

Octreotide	B-Chemical
-	O
induced	O
hypoxemia	B-Disease
and	O
pulmonary	B-Disease
hypertension	I-Disease
in	O
premature	O
neonates	O
.	O

The	O
authors	O
report	O
2	O
cases	O
of	O
premature	O
neonates	O
who	O
had	O
enterocutaneous	O
fistula	B-Disease
complicating	O
necrotizing	B-Disease
enterocolitis	I-Disease
.	O

Pulmonary	B-Disease
hypertension	I-Disease
developed	O
after	O
administration	O
of	O
a	O
somatostatin	O
analogue	O
,	O
octreotide	B-Chemical
,	O
to	O
enhance	O
resolution	O
of	O
the	O
fistula	B-Disease
.	O

The	O
authors	O
discuss	O
the	O
mechanism	O
of	O
the	O
occurrence	O
of	O
this	O
complication	O
and	O
recommend	O
caution	O
of	O
its	O
use	O
in	O
high	O
-	O
risk	O
premature	O
neonates	O
.	O

The	O
risk	O
of	O
venous	B-Disease
thromboembolism	I-Disease
in	O
women	O
prescribed	O
cyproterone	B-Chemical
acetate	I-Chemical
in	O
combination	O
with	O
ethinyl	B-Chemical
estradiol	I-Chemical
:	O
a	O
nested	O
cohort	O
analysis	O
and	O
case	O
-	O
control	O
study	O
.	O

BACKGROUND	O
:	O
Cyproterone	B-Chemical
acetate	I-Chemical
combined	O
with	O
ethinyl	B-Chemical
estradiol	I-Chemical
(	O
CPA	B-Chemical
/	O
EE	B-Chemical
)	O
is	O
licensed	O
in	O
the	O
UK	O
for	O
the	O
treatment	O
of	O
women	O
with	O
acne	B-Disease
and	O
hirsutism	B-Disease
and	O
is	O
also	O
a	O
treatment	O
option	O
for	O
polycystic	B-Disease
ovary	I-Disease
syndrome	I-Disease
(	O
PCOS	B-Disease
)	O
.	O

Previous	O
studies	O
have	O
demonstrated	O
an	O
increased	O
risk	O
of	O
venous	B-Disease
thromboembolism	I-Disease
(	O
VTE	B-Disease
)	O
associated	O
with	O
CPA	B-Chemical
/	O
EE	B-Chemical
compared	O
with	O
conventional	O
combined	O
oral	B-Chemical
contraceptives	I-Chemical
(	O
COCs	O
)	O
.	O

We	O
believe	O
the	O
results	O
of	O
those	O
studies	O
may	O
have	O
been	O
affected	O
by	O
residual	O
confounding	O
.	O

METHODS	O
:	O
Using	O
the	O
General	O
Practice	O
Research	O
Database	O
we	O
conducted	O
a	O
cohort	O
analysis	O
and	O
case	O
-	O
control	O
study	O
nested	O
within	O
a	O
population	O
of	O
women	O
aged	O
between	O
15	O
and	O
39	O
years	O
with	O
acne	B-Disease
,	O
hirsutism	B-Disease
or	O
PCOS	B-Disease
to	O
estimate	O
the	O
risk	O
of	O
VTE	B-Disease
associated	O
with	O
CPA	B-Chemical
/	O
EE	B-Chemical
.	O

RESULTS	O
:	O
The	O
age	O
-	O
adjusted	O
incidence	O
rate	O
ratio	O
for	O
CPA	B-Chemical
/	O
EE	B-Chemical
versus	O
conventional	O
COCs	O
was	O
2	O
.	O
20	O
[	O
95	O
%	O
confidence	O
interval	O
(	O
CI	O
)	O
1	O
.	O
35	O
-	O
3	O
.	O
58	O
]	O
.	O

Using	O
as	O
the	O
reference	O
group	O
women	O
who	O
were	O
not	O
using	O
oral	O
contraception	O
,	O
had	O
no	O
recent	O
pregnancy	O
or	O
menopausal	O
symptoms	O
,	O
the	O
case	O
-	O
control	O
analysis	O
gave	O
an	O
adjusted	O
odds	O
ratio	O
(	O
OR	O
(	O
adj	O
)	O
)	O
of	O
7	O
.	O
44	O
(	O
95	O
%	O
CI	O
3	O
.	O
67	O
-	O
15	O
.	O
08	O
)	O
for	O
CPA	B-Chemical
/	O
EE	B-Chemical
use	O
compared	O
with	O
an	O
OR	O
(	O
adj	O
)	O
of	O
2	O
.	O
58	O
(	O
95	O
%	O
CI	O
1	O
.	O
60	O
-	O
4	O
.	O
18	O
)	O
for	O
use	O
of	O
conventional	O
COCs	O
.	O

CONCLUSIONS	O
:	O
We	O
have	O
demonstrated	O
an	O
increased	O
risk	O
of	O
VTE	B-Disease
associated	O
with	O
the	O
use	O
of	O
CPA	B-Chemical
/	O
EE	B-Chemical
in	O
women	O
with	O
acne	B-Disease
,	O
hirsutism	B-Disease
or	O
PCOS	B-Disease
although	O
residual	O
confounding	O
by	O
indication	O
cannot	O
be	O
excluded	O
.	O

The	O
effect	O
of	O
treatment	O
with	O
gum	B-Chemical
Arabic	I-Chemical
on	O
gentamicin	B-Chemical
nephrotoxicity	B-Disease
in	O
rats	O
:	O
a	O
preliminary	O
study	O
.	O

In	O
the	O
present	O
work	O
we	O
assessed	O
the	O
effect	O
of	O
treatment	O
of	O
rats	O
with	O
gum	B-Chemical
Arabic	I-Chemical
on	O
acute	B-Disease
renal	I-Disease
failure	I-Disease
induced	O
by	O
gentamicin	B-Chemical
(	O
GM	B-Chemical
)	O
nephrotoxicity	B-Disease
.	O

Rats	O
were	O
treated	O
with	O
the	O
vehicle	O
(	O
2	O
mL	O
/	O
kg	O
of	O
distilled	O
water	O
and	O
5	O
%	O
w	O
/	O
v	O
cellulose	O
,	O
10	O
days	O
)	O
,	O
gum	B-Chemical
Arabic	I-Chemical
(	O
2	O
mL	O
/	O
kg	O
of	O
a	O
10	O
%	O
w	O
/	O
v	O
aqueous	O
suspension	O
of	O
gum	B-Chemical
Arabic	I-Chemical
powder	O
,	O
orally	O
for	O
10	O
days	O
)	O
,	O
or	O
gum	B-Chemical
Arabic	I-Chemical
concomitantly	O
with	O
GM	B-Chemical
(	O
80mg	O
/	O
kg	O
/	O
day	O
intramuscularly	O
,	O
during	O
the	O
last	O
six	O
days	O
of	O
the	O
treatment	O
period	O
)	O
.	O

Nephrotoxicity	B-Disease
was	O
assessed	O
by	O
measuring	O
the	O
concentrations	O
of	O
creatinine	B-Chemical
and	O
urea	B-Chemical
in	O
the	O
plasma	O
and	O
reduced	O
glutathione	B-Chemical
(	O
GSH	B-Chemical
)	O
in	O
the	O
kidney	O
cortex	O
,	O
and	O
by	O
light	O
microscopic	O
examination	O
of	O
kidney	O
sections	O
.	O

The	O
results	O
indicated	O
that	O
concomitant	O
treatment	O
with	O
gum	B-Chemical
Arabic	I-Chemical
and	O
GM	B-Chemical
significantly	O
increased	O
creatinine	B-Chemical
and	O
urea	B-Chemical
by	O
about	O
183	O
and	O
239	O
%	O
,	O
respectively	O
(	O
compared	O
to	O
432	O
and	O
346	O
%	O
,	O
respectively	O
,	O
in	O
rats	O
treated	O
with	O
cellulose	O
and	O
GM	B-Chemical
)	O
,	O
and	O
decreased	O
that	O
of	O
cortical	O
GSH	B-Chemical
by	O
21	O
%	O
(	O
compared	O
to	O
27	O
%	O
in	O
the	O
cellulose	O
plus	O
GM	B-Chemical
group	O
)	O
The	O
GM	B-Chemical
-	O
induced	O
proximal	O
tubular	B-Disease
necrosis	I-Disease
appeared	O
to	O
be	O
slightly	O
less	O
severe	O
in	O
rats	O
given	O
GM	B-Chemical
together	O
with	O
gum	B-Chemical
Arabic	I-Chemical
than	O
in	O
those	O
given	O
GM	B-Chemical
and	O
cellulose	O
.	O

It	O
could	O
be	O
inferred	O
that	O
gum	B-Chemical
Arabic	I-Chemical
treatment	O
has	O
induced	O
a	O
modest	O
amelioration	O
of	O
some	O
of	O
the	O
histological	O
and	O
biochemical	O
indices	O
of	O
GM	B-Chemical
nephrotoxicity	B-Disease
.	O

Further	O
work	O
is	O
warranted	O
on	O
the	O
effect	O
of	O
the	O
treatments	O
on	O
renal	O
functional	O
aspects	O
in	O
models	O
of	O
chronic	B-Disease
renal	I-Disease
failure	I-Disease
,	O
and	O
on	O
the	O
mechanism	O
(	O
s	O
)	O
involved	O
.	O

Increased	O
frequency	O
of	O
venous	B-Disease
thromboembolism	I-Disease
with	O
the	O
combination	O
of	O
docetaxel	B-Chemical
and	O
thalidomide	B-Chemical
in	O
patients	O
with	O
metastatic	O
androgen	O
-	O
independent	O
prostate	B-Disease
cancer	I-Disease
.	O

STUDY	O
OBJECTIVE	O
:	O
To	O
evaluate	O
the	O
frequency	O
of	O
venous	B-Disease
thromboembolism	I-Disease
(	O
VTE	B-Disease
)	O
in	O
patients	O
with	O
advanced	O
androgen	O
-	O
independent	O
prostate	B-Disease
cancer	I-Disease
who	O
were	O
treated	O
with	O
docetaxel	B-Chemical
alone	O
or	O
in	O
combination	O
with	O
thalidomide	B-Chemical
.	O

DESIGN	O
:	O
Retrospective	O
analysis	O
of	O
a	O
randomized	O
phase	O
II	O
trial	O
.	O

SETTING	O
:	O
National	O
Institutes	O
of	O
Health	O
clinical	O
research	O
center	O
.	O

PATIENTS	O
:	O
Seventy	O
men	O
,	O
aged	O
50	O
-	O
80	O
years	O
,	O
with	O
advanced	O
androgen	O
-	O
independent	O
prostate	B-Disease
cancer	I-Disease
.	O

INTERVENTION	O
:	O
Each	O
patient	O
received	O
either	O
intravenous	O
docetaxel	B-Chemical
30	O
mg	O
/	O
m2	O
/	O
week	O
for	O
3	O
consecutive	O
weeks	O
,	O
followed	O
by	O
1	O
week	O
off	O
,	O
or	O
the	O
combination	O
of	O
continuous	O
oral	O
thalidomide	B-Chemical
200	O
mg	O
every	O
evening	O
plus	O
the	O
same	O
docetaxel	B-Chemical
regimen	O
.	O

This	O
4	O
-	O
week	O
cycle	O
was	O
repeated	O
until	O
there	O
was	O
evidence	O
of	O
excessive	O
toxicity	B-Disease
or	O
disease	O
progression	O
.	O

MEASUREMENTS	O
AND	O
MAIN	O
RESULTS	O
:	O
None	O
of	O
23	O
patients	O
who	O
received	O
docetaxel	B-Chemical
alone	O
developed	O
VTE	B-Disease
,	O
whereas	O
9	O
of	O
47	O
patients	O
(	O
19	O
%	O
)	O
who	O
received	O
docetaxel	B-Chemical
plus	O
thalidomide	B-Chemical
developed	O
VTE	B-Disease
(	O
p	O
=	O
0	O
.	O
025	O
)	O
.	O

CONCLUSION	O
:	O
The	O
addition	O
of	O
thalidomide	B-Chemical
to	O
docetaxel	B-Chemical
in	O
the	O
treatment	O
of	O
prostate	B-Disease
cancer	I-Disease
significantly	O
increases	O
the	O
frequency	O
of	O
VTE	B-Disease
.	O

Clinicians	O
should	O
be	O
aware	O
of	O
this	O
potential	O
complication	O
when	O
adding	O
thalidomide	B-Chemical
to	O
chemotherapeutic	O
regimens	O
.	O

Ticlopidine	B-Chemical
-	O
induced	O
cholestatic	B-Disease
hepatitis	I-Disease
.	O

OBJECTIVE	O
:	O
To	O
report	O
2	O
cases	O
of	O
ticlopidine	B-Chemical
-	O
induced	O
cholestatic	B-Disease
hepatitis	I-Disease
,	O
investigate	O
its	O
mechanism	O
,	O
and	O
compare	O
the	O
observed	O
main	O
characteristics	O
with	O
those	O
of	O
the	O
published	O
cases	O
.	O

CASE	O
SUMMARIES	O
:	O
Two	O
patients	O
developed	O
prolonged	O
cholestatic	B-Disease
hepatitis	I-Disease
after	O
receiving	O
ticlopidine	B-Chemical
following	O
percutaneous	O
coronary	O
angioplasty	O
,	O
with	O
complete	O
remission	O
during	O
the	O
follow	O
-	O
up	O
period	O
.	O

T	O
-	O
cell	O
stimulation	O
by	O
therapeutic	O
concentration	O
of	O
ticlopidine	B-Chemical
was	O
demonstrated	O
in	O
vitro	O
in	O
the	O
patients	O
,	O
but	O
not	O
in	O
healthy	O
controls	O
.	O

DISCUSSION	O
:	O
Cholestatic	B-Disease
hepatitis	I-Disease
is	O
a	O
rare	O
complication	O
of	O
the	O
antiplatelet	O
agent	O
ticlopidine	B-Chemical
;	O
several	O
cases	O
have	O
been	O
reported	O
but	O
few	O
in	O
the	O
English	O
literature	O
.	O

Our	O
patients	O
developed	O
jaundice	B-Disease
following	O
treatment	O
with	O
ticlopidine	B-Chemical
and	O
showed	O
the	O
clinical	O
and	O
laboratory	O
characteristics	O
of	O
cholestatic	B-Disease
hepatitis	I-Disease
,	O
which	O
resolved	O
after	O
discontinuation	O
of	O
the	O
drug	O
.	O

Hepatitis	B-Disease
may	O
develop	O
weeks	O
after	O
discontinuation	O
of	O
the	O
drug	O
and	O
may	O
run	O
a	O
prolonged	O
course	O
,	O
but	O
complete	O
remission	O
was	O
observed	O
in	O
all	O
reported	O
cases	O
.	O

An	O
objective	O
causality	O
assessment	O
revealed	O
that	O
the	O
adverse	O
drug	O
event	O
was	O
probably	O
related	O
to	O
the	O
use	O
of	O
ticlopidine	B-Chemical
.	O

The	O
mechanisms	O
of	O
this	O
ticlopidine	B-Chemical
-	O
induced	O
cholestasis	B-Disease
are	O
unclear	O
.	O

Immune	O
mechanisms	O
may	O
be	O
involved	O
in	O
the	O
drug	O
'	O
s	O
hepatotoxicity	B-Disease
,	O
as	O
suggested	O
by	O
the	O
T	O
-	O
cell	O
stimulation	O
study	O
reported	O
here	O
.	O

CONCLUSIONS	O
:	O
Cholestatic	B-Disease
hepatitis	I-Disease
is	O
a	O
rare	O
adverse	O
effect	O
of	O
ticlopidine	B-Chemical
that	O
may	O
be	O
immune	O
mediated	O
.	O

Patients	O
receiving	O
the	O
drug	O
should	O
be	O
monitored	O
with	O
liver	O
function	O
tests	O
along	O
with	O
complete	O
blood	O
cell	O
counts	O
.	O

This	O
complication	O
will	O
be	O
observed	O
even	O
less	O
often	O
in	O
the	O
future	O
as	O
ticlopidine	B-Chemical
is	O
being	O
replaced	O
by	O
the	O
newer	O
antiplatelet	O
agent	O
clopidogrel	B-Chemical
.	O

Epithelial	O
sodium	B-Chemical
channel	O
(	O
ENaC	O
)	O
subunit	O
mRNA	O
and	O
protein	O
expression	O
in	O
rats	O
with	O
puromycin	B-Chemical
aminonucleoside	I-Chemical
-	O
induced	O
nephrotic	B-Disease
syndrome	I-Disease
.	O

In	O
experimental	O
nephrotic	B-Disease
syndrome	I-Disease
,	O
urinary	O
sodium	B-Chemical
excretion	O
is	O
decreased	O
during	O
the	O
early	O
phase	O
of	O
the	O
disease	O
.	O

The	O
molecular	O
mechanism	O
(	O
s	O
)	O
leading	O
to	O
salt	O
retention	O
has	O
not	O
been	O
completely	O
elucidated	O
.	O

The	O
rate	O
-	O
limiting	O
constituent	O
of	O
collecting	O
duct	O
sodium	B-Chemical
transport	O
is	O
the	O
epithelial	O
sodium	B-Chemical
channel	O
(	O
ENaC	O
)	O
.	O

We	O
examined	O
the	O
abundance	O
of	O
ENaC	O
subunit	O
mRNAs	O
and	O
proteins	O
in	O
puromycin	B-Chemical
aminonucleoside	I-Chemical
(	O
PAN	B-Chemical
)	O
-	O
induced	O
nephrotic	B-Disease
syndrome	I-Disease
.	O

The	O
time	O
courses	O
of	O
urinary	O
sodium	B-Chemical
excretion	O
,	O
plasma	O
aldosterone	B-Chemical
concentration	O
and	O
proteinuria	B-Disease
were	O
studied	O
in	O
male	O
Sprague	O
-	O
Dawley	O
rats	O
treated	O
with	O
a	O
single	O
dose	O
of	O
either	O
PAN	B-Chemical
or	O
vehicle	O
.	O

The	O
relative	O
amounts	O
of	O
alphaENaC	O
,	O
betaENaC	O
and	O
gammaENaC	O
mRNAs	O
were	O
determined	O
in	O
kidneys	O
from	O
these	O
rats	O
by	O
real	O
-	O
time	O
quantitative	O
TaqMan	O
PCR	O
,	O
and	O
the	O
amounts	O
of	O
proteins	O
by	O
Western	O
blot	O
.	O

The	O
kinetics	O
of	O
urinary	O
sodium	B-Chemical
excretion	O
and	O
the	O
appearance	O
of	O
proteinuria	B-Disease
were	O
comparable	O
with	O
those	O
reported	O
previously	O
.	O

Sodium	B-Chemical
retention	O
occurred	O
on	O
days	O
2	O
,	O
3	O
and	O
6	O
after	O
PAN	B-Chemical
injection	O
.	O

A	O
significant	O
up	O
-	O
regulation	O
of	O
alphaENaC	O
and	O
betaENaC	O
mRNA	O
abundance	O
on	O
days	O
1	O
and	O
2	O
preceded	O
sodium	B-Chemical
retention	O
on	O
days	O
2	O
and	O
3	O
.	O

Conversely	O
,	O
down	O
-	O
regulation	O
of	O
alphaENaC	O
,	O
betaENaC	O
and	O
gammaENaC	O
mRNA	O
expression	O
on	O
day	O
3	O
occurred	O
in	O
the	O
presence	O
of	O
high	O
aldosterone	B-Chemical
concentrations	O
,	O
and	O
was	O
followed	O
by	O
a	O
return	O
of	O
sodium	B-Chemical
excretion	O
to	O
control	O
values	O
.	O

The	O
amounts	O
of	O
alphaENaC	O
,	O
betaENaC	O
and	O
gammaENaC	O
proteins	O
were	O
not	O
increased	O
during	O
PAN	B-Chemical
-	O
induced	O
sodium	B-Chemical
retention	O
.	O

In	O
conclusion	O
,	O
ENaC	O
mRNA	O
expression	O
,	O
especially	O
alphaENaC	O
,	O
is	O
increased	O
in	O
the	O
very	O
early	O
phase	O
of	O
the	O
experimental	O
model	O
of	O
PAN	B-Chemical
-	O
induced	O
nephrotic	B-Disease
syndrome	I-Disease
in	O
rats	O
,	O
but	O
appears	O
to	O
escape	O
from	O
the	O
regulation	O
by	O
aldosterone	B-Chemical
after	O
day	O
3	O
.	O

Sub	O
-	O
chronic	O
low	O
dose	O
gamma	B-Chemical
-	I-Chemical
vinyl	I-Chemical
GABA	I-Chemical
(	O
vigabatrin	B-Chemical
)	O
inhibits	O
cocaine	B-Chemical
-	O
induced	O
increases	O
in	O
nucleus	O
accumbens	O
dopamine	B-Chemical
.	O

RATIONALE	O
:	O
gamma	B-Chemical
-	I-Chemical
Vinyl	I-Chemical
GABA	I-Chemical
(	O
GVG	B-Chemical
)	O
irreversibly	O
inhibits	O
GABA	B-Chemical
-	O
transaminase	O
.	O

This	O
non	O
-	O
receptor	O
mediated	O
inhibition	O
requires	O
de	O
novo	O
synthesis	O
for	O
restoration	O
of	O
functional	O
GABA	B-Chemical
catabolism	O
.	O

OBJECTIVES	O
:	O
Given	O
its	O
preclinical	O
success	O
for	O
treating	O
substance	B-Disease
abuse	I-Disease
and	O
the	O
increased	O
risk	O
of	O
visual	B-Disease
field	I-Disease
defects	I-Disease
(	O
VFD	B-Disease
)	O
associated	O
with	O
cumulative	O
lifetime	O
exposure	O
,	O
we	O
explored	O
the	O
effects	O
of	O
sub	O
-	O
chronic	O
low	O
dose	O
GVG	B-Chemical
on	O
cocaine	B-Chemical
-	O
induced	O
increases	O
in	O
nucleus	O
accumbens	O
(	O
NAcc	O
)	O
dopamine	B-Chemical
(	O
DA	B-Chemical
)	O
.	O

METHODS	O
:	O
Using	O
in	O
vivo	O
microdialysis	O
,	O
we	O
compared	O
acute	O
exposure	O
(	O
450	O
mg	O
/	O
kg	O
)	O
to	O
an	O
identical	O
sub	O
-	O
chronic	O
exposure	O
(	O
150	O
mg	O
/	O
kg	O
per	O
day	O
for	O
3	O
days	O
)	O
,	O
followed	O
by	O
1	O
-	O
or	O
3	O
-	O
day	O
washout	O
.	O

Finally	O
,	O
we	O
examined	O
the	O
low	O
dose	O
of	O
150	O
mg	O
/	O
kg	O
(	O
50	O
mg	O
/	O
kg	O
per	O
day	O
)	O
using	O
a	O
similar	O
washout	O
period	O
.	O

RESULTS	O
:	O
Sub	O
-	O
chronic	O
GVG	B-Chemical
exposure	O
inhibited	O
the	O
effect	O
of	O
cocaine	B-Chemical
for	O
3	O
days	O
,	O
which	O
exceeded	O
in	O
magnitude	O
and	O
duration	O
the	O
identical	O
acute	O
dose	O
.	O

CONCLUSIONS	O
:	O
Sub	O
-	O
chronic	O
low	O
dose	O
GVG	B-Chemical
potentiates	O
and	O
extends	O
the	O
inhibition	O
of	O
cocaine	B-Chemical
-	O
induced	O
increases	O
in	O
dopamine	B-Chemical
,	O
effectively	O
reducing	O
cumulative	O
exposures	O
and	O
the	O
risk	O
for	O
VFDS	O
.	O

MR	O
imaging	O
with	O
quantitative	O
diffusion	O
mapping	O
of	O
tacrolimus	B-Chemical
-	O
induced	O
neurotoxicity	B-Disease
in	O
organ	O
transplant	O
patients	O
.	O

Our	O
objective	O
was	O
to	O
investigate	O
brain	O
MR	O
imaging	O
findings	O
and	O
the	O
utility	O
of	O
diffusion	O
-	O
weighted	O
(	O
DW	O
)	O
imaging	O
in	O
organ	O
transplant	O
patients	O
who	O
developed	O
neurologic	O
symptoms	O
during	O
tacrolimus	B-Chemical
therapy	O
.	O

Brain	O
MR	O
studies	O
,	O
including	O
DW	O
imaging	O
,	O
were	O
prospectively	O
performed	O
in	O
14	O
organ	O
transplant	O
patients	O
receiving	O
tacrolimus	B-Chemical
who	O
developed	O
neurologic	B-Disease
complications	I-Disease
.	O

In	O
each	O
patient	O
who	O
had	O
abnormalities	O
on	O
the	O
initial	O
MR	O
study	O
,	O
a	O
follow	O
-	O
up	O
MR	O
study	O
was	O
performed	O
1	O
month	O
later	O
.	O

Apparent	O
diffusion	O
coefficient	O
(	O
ADC	O
)	O
values	O
on	O
the	O
initial	O
MR	O
study	O
were	O
correlated	O
with	O
reversibility	O
of	O
the	O
lesions	O
.	O

Of	O
the	O
14	O
patients	O
,	O
5	O
(	O
35	O
.	O
7	O
%	O
)	O
had	O
white	B-Disease
matter	I-Disease
abnormalities	I-Disease
,	O
1	O
(	O
7	O
.	O
1	O
%	O
)	O
had	O
putaminal	B-Disease
hemorrhage	I-Disease
,	O
and	O
8	O
(	O
57	O
.	O
1	O
%	O
)	O
had	O
normal	O
findings	O
on	O
initial	O
MR	O
images	O
.	O

Among	O
the	O
5	O
patients	O
with	O
white	B-Disease
matter	I-Disease
abnormalities	I-Disease
,	O
4	O
patients	O
(	O
80	O
.	O
0	O
%	O
)	O
showed	O
higher	O
than	O
normal	O
ADC	O
values	O
on	O
initial	O
MR	O
images	O
,	O
and	O
all	O
showed	O
complete	O
resolution	O
on	O
follow	O
-	O
up	O
images	O
.	O

The	O
remaining	O
1	O
patient	O
(	O
20	O
.	O
0	O
%	O
)	O
showed	O
lower	O
than	O
normal	O
ADC	O
value	O
and	O
showed	O
incomplete	O
resolution	O
with	O
cortical	B-Disease
laminar	I-Disease
necrosis	I-Disease
.	O

Diffusion	O
-	O
weighted	O
imaging	O
may	O
be	O
useful	O
in	O
predicting	O
the	O
outcomes	O
of	O
the	O
lesions	O
of	O
tacrolimus	B-Chemical
-	O
induced	O
neurotoxicity	B-Disease
.	O

L	B-Chemical
-	I-Chemical
arginine	I-Chemical
transport	O
in	O
humans	O
with	O
cortisol	B-Chemical
-	O
induced	O
hypertension	B-Disease
.	O

A	O
deficient	O
L	B-Chemical
-	I-Chemical
arginine	I-Chemical
-	O
nitric	B-Chemical
oxide	I-Chemical
system	O
is	O
implicated	O
in	O
cortisol	B-Chemical
-	O
induced	O
hypertension	B-Disease
.	O

We	O
investigate	O
whether	O
abnormalities	O
in	O
L	B-Chemical
-	I-Chemical
arginine	I-Chemical
uptake	O
contribute	O
to	O
this	O
deficiency	O
.	O

Eight	O
healthy	O
men	O
were	O
recruited	O
.	O

Hydrocortisone	B-Chemical
acetate	I-Chemical
(	O
50	O
mg	O
)	O
was	O
given	O
orally	O
every	O
6	O
hours	O
for	O
24	O
hours	O
after	O
a	O
5	O
-	O
day	O
fixed	O
-	O
salt	O
diet	O
(	O
150	O
mmol	O
/	O
d	O
)	O
.	O

Crossover	O
studies	O
were	O
performed	O
2	O
weeks	O
apart	O
.	O

Thirty	O
milliliters	O
of	O
blood	O
was	O
obtained	O
for	O
isolation	O
of	O
peripheral	O
blood	O
mononuclear	O
cells	O
after	O
each	O
treatment	O
period	O
.	O

L	B-Chemical
-	I-Chemical
arginine	I-Chemical
uptake	O
was	O
assessed	O
in	O
mononuclear	O
cells	O
incubated	O
with	O
L	B-Chemical
-	I-Chemical
arginine	I-Chemical
(	O
1	O
to	O
300	O
micromol	O
/	O
L	O
)	O
,	O
incorporating	O
100	O
nmol	O
/	O
L	O
[	B-Chemical
3H	I-Chemical
]	I-Chemical
-	I-Chemical
l	I-Chemical
-	I-Chemical
arginine	I-Chemical
for	O
a	O
period	O
of	O
5	O
minutes	O
at	O
37	O
degrees	O
C	O
.	O

Forearm	O
[	B-Chemical
3H	I-Chemical
]	I-Chemical
-	I-Chemical
L	I-Chemical
-	I-Chemical
arginine	I-Chemical
extraction	O
was	O
calculated	O
after	O
infusion	O
of	O
[	B-Chemical
3H	I-Chemical
]	I-Chemical
-	I-Chemical
L	I-Chemical
-	I-Chemical
arginine	I-Chemical
into	O
the	O
brachial	O
artery	O
at	O
a	O
rate	O
of	O
100	O
nCi	O
/	O
min	O
for	O
80	O
minutes	O
.	O

Deep	O
forearm	O
venous	O
samples	O
were	O
collected	O
for	O
determination	O
of	O
L	B-Chemical
-	I-Chemical
arginine	I-Chemical
extraction	O
.	O

Plasma	O
cortisol	B-Chemical
concentrations	O
were	O
significantly	O
raised	O
during	O
the	O
active	O
phase	O
(	O
323	O
+	O
/	O
-	O
43	O
to	O
1082	O
+	O
/	O
-	O
245	O
mmol	O
/	O
L	O
,	O
P	O
<	O
0	O
.	O
05	O
)	O
.	O

Systolic	O
blood	O
pressure	O
was	O
elevated	O
by	O
an	O
average	O
of	O
7	O
mm	O
Hg	O
.	O

Neither	O
L	B-Chemical
-	I-Chemical
arginine	I-Chemical
transport	O
into	O
mononuclear	O
cells	O
(	O
placebo	O
vs	O
active	O
,	O
26	O
.	O
3	O
+	O
/	O
-	O
3	O
.	O
6	O
vs	O
29	O
.	O
0	O
+	O
/	O
-	O
2	O
.	O
1	O
pmol	O
/	O
10	O
000	O
cells	O
per	O
5	O
minutes	O
,	O
respectively	O
,	O
at	O
an	O
l	B-Chemical
-	I-Chemical
arginine	I-Chemical
concentration	O
of	O
300	O
micromol	O
/	O
L	O
)	O
nor	O
L	B-Chemical
-	I-Chemical
arginine	I-Chemical
extraction	O
in	O
the	O
forearm	O
(	O
at	O
80	O
minutes	O
,	O
placebo	O
vs	O
active	O
,	O
1	O
868	O
904	O
+	O
/	O
-	O
434	O
962	O
vs	O
2	O
013	O
910	O
+	O
/	O
-	O
770	O
619	O
disintegrations	O
per	O
minute	O
)	O
was	O
affected	O
by	O
cortisol	B-Chemical
treatment	O
;	O
ie	O
,	O
that	O
L	B-Chemical
-	I-Chemical
arginine	I-Chemical
uptake	O
is	O
not	O
affected	O
by	O
short	O
-	O
term	O
cortisol	B-Chemical
treatment	O
.	O

We	O
conclude	O
that	O
cortisol	B-Chemical
-	O
induced	O
increases	B-Disease
in	I-Disease
blood	I-Disease
pressure	I-Disease
are	O
not	O
associated	O
with	O
abnormalities	O
in	O
the	O
l	B-Chemical
-	I-Chemical
arginine	I-Chemical
transport	O
system	O
.	O

Amount	O
of	O
bleeding	B-Disease
and	O
hematoma	B-Disease
size	O
in	O
the	O
collagenase	O
-	O
induced	O
intracerebral	B-Disease
hemorrhage	I-Disease
rat	O
model	O
.	O

The	O
aggravated	O
risk	O
on	O
intracerebral	B-Disease
hemorrhage	I-Disease
(	O
ICH	B-Disease
)	O
with	O
drugs	O
used	O
for	O
stroke	B-Disease
patients	O
should	O
be	O
estimated	O
carefully	O
.	O

We	O
therefore	O
established	O
sensitive	O
quantification	O
methods	O
and	O
provided	O
a	O
rat	O
ICH	B-Disease
model	O
for	O
detection	O
of	O
ICH	B-Disease
deterioration	O
.	O

In	O
ICH	B-Disease
intrastriatally	O
induced	O
by	O
0	O
.	O
014	O
-	O
unit	O
,	O
0	O
.	O
070	O
-	O
unit	O
,	O
and	O
0	O
.	O
350	O
-	O
unit	O
collagenase	O
,	O
the	O
amount	O
of	O
bleeding	B-Disease
was	O
measured	O
using	O
a	O
hemoglobin	O
assay	O
developed	O
in	O
the	O
present	O
study	O
and	O
was	O
compared	O
with	O
the	O
morphologically	O
determined	O
hematoma	B-Disease
volume	O
.	O

The	O
blood	O
amounts	O
and	O
hematoma	B-Disease
volumes	O
were	O
significantly	O
correlated	O
,	O
and	O
the	O
hematoma	B-Disease
induced	O
by	O
0	O
.	O
014	O
-	O
unit	O
collagenase	O
was	O
adequate	O
to	O
detect	O
ICH	B-Disease
deterioration	O
.	O

In	O
ICH	B-Disease
induction	O
using	O
0	O
.	O
014	O
-	O
unit	O
collagenase	O
,	O
heparin	B-Chemical
enhanced	O
the	O
hematoma	B-Disease
volume	O
3	O
.	O
4	O
-	O
fold	O
over	O
that	O
seen	O
in	O
control	O
ICH	B-Disease
animals	O
and	O
the	O
bleeding	B-Disease
7	O
.	O
6	O
-	O
fold	O
.	O

Data	O
suggest	O
that	O
this	O
sensitive	O
hemoglobin	O
assay	O
is	O
useful	O
for	O
ICH	B-Disease
detection	O
,	O
and	O
that	O
a	O
model	O
with	O
a	O
small	O
ICH	B-Disease
induced	O
with	O
a	O
low	O
-	O
dose	O
collagenase	O
should	O
be	O
used	O
for	O
evaluation	O
of	O
drugs	O
that	O
may	O
affect	O
ICH	B-Disease
.	O

Estradiol	B-Chemical
reduces	O
seizure	B-Disease
-	O
induced	O
hippocampal	B-Disease
injury	I-Disease
in	O
ovariectomized	O
female	O
but	O
not	O
in	O
male	O
rats	O
.	O

Estrogens	O
protect	O
ovariectomized	O
rats	O
from	O
hippocampal	B-Disease
injury	I-Disease
induced	O
by	O
kainic	B-Chemical
acid	I-Chemical
-	O
induced	O
status	B-Disease
epilepticus	I-Disease
(	O
SE	B-Disease
)	O
.	O

We	O
compared	O
the	O
effects	O
of	O
17beta	B-Chemical
-	I-Chemical
estradiol	I-Chemical
in	O
adult	O
male	O
and	O
ovariectomized	O
female	O
rats	O
subjected	O
to	O
lithium	B-Chemical
-	O
pilocarpine	B-Chemical
-	O
induced	O
SE	B-Disease
.	O

Rats	O
received	O
subcutaneous	O
injections	O
of	O
17beta	B-Chemical
-	I-Chemical
estradiol	I-Chemical
(	O
2	O
microg	O
/	O
rat	O
)	O
or	O
oil	O
once	O
daily	O
for	O
four	O
consecutive	O
days	O
.	O

SE	B-Disease
was	O
induced	O
20	O
h	O
following	O
the	O
second	O
injection	O
and	O
terminated	O
3	O
h	O
later	O
.	O

The	O
extent	O
of	O
silver	B-Chemical
-	O
stained	O
CA3	O
and	O
CA1	O
hippocampal	O
neurons	O
was	O
evaluated	O
2	O
days	O
after	O
SE	B-Disease
.	O

17beta	B-Chemical
-	I-Chemical
Estradiol	I-Chemical
did	O
not	O
alter	O
the	O
onset	O
of	O
first	O
clonus	O
in	O
ovariectomized	O
rats	O
but	O
accelerated	O
it	O
in	O
males	O
.	O

17beta	B-Chemical
-	I-Chemical
Estradiol	I-Chemical
reduced	O
the	O
argyrophilic	O
neurons	O
in	O
the	O
CA1	O
and	O
CA3	O
-	O
C	O
sectors	O
of	O
ovariectomized	O
rats	O
.	O

In	O
males	O
,	O
estradiol	B-Chemical
increased	O
the	O
total	O
damage	O
score	O
.	O

These	O
findings	O
suggest	O
that	O
the	O
effects	O
of	O
estradiol	B-Chemical
on	O
seizure	B-Disease
threshold	O
and	O
damage	O
may	O
be	O
altered	O
by	O
sex	O
-	O
related	O
differences	O
in	O
the	O
hormonal	O
environment	O
.	O

Pseudoacromegaly	B-Disease
induced	O
by	O
the	O
long	O
-	O
term	O
use	O
of	O
minoxidil	B-Chemical
.	O

Acromegaly	B-Disease
is	O
an	O
endocrine	B-Disease
disorder	I-Disease
caused	O
by	O
chronic	O
excessive	O
growth	O
hormone	O
secretion	O
from	O
the	O
anterior	O
pituitary	O
gland	O
.	O

Significant	O
disfiguring	O
changes	O
occur	O
as	O
a	O
result	O
of	O
bone	O
,	O
cartilage	O
,	O
and	O
soft	O
tissue	O
hypertrophy	B-Disease
,	O
including	O
the	O
thickening	O
of	O
the	O
skin	O
,	O
coarsening	O
of	O
facial	O
features	O
,	O
and	O
cutis	B-Disease
verticis	I-Disease
gyrata	I-Disease
.	O

Pseudoacromegaly	B-Disease
,	O
on	O
the	O
other	O
hand	O
,	O
is	O
the	O
presence	O
of	O
similar	O
acromegaloid	O
features	O
in	O
the	O
absence	O
of	O
elevated	O
growth	O
hormone	O
or	O
insulin	O
-	O
like	O
growth	O
factor	O
levels	O
.	O

We	O
present	O
a	O
patient	O
with	O
pseudoacromegaly	B-Disease
that	O
resulted	O
from	O
the	O
long	O
-	O
term	O
use	O
of	O
minoxidil	B-Chemical
at	O
an	O
unusually	O
high	O
dose	O
.	O

This	O
is	O
the	O
first	O
case	O
report	O
of	O
pseudoacromegaly	B-Disease
as	O
a	O
side	O
effect	O
of	O
minoxidil	B-Chemical
use	O
.	O

Combined	O
androgen	O
blockade	O
-	O
induced	O
anemia	B-Disease
in	O
prostate	B-Disease
cancer	I-Disease
patients	O
without	O
bone	O
involvement	O
.	O

BACKGROUND	O
:	O
To	O
determine	O
the	O
onset	O
and	O
extent	O
of	O
combined	O
androgen	O
blockade	O
(	O
CAB	O
)	O
-	O
induced	O
anemia	B-Disease
in	O
prostate	B-Disease
cancer	I-Disease
patients	O
without	O
bone	O
involvement	O
.	O

PATIENTS	O
AND	O
METHODS	O
:	O
Forty	O
-	O
two	O
patients	O
with	O
biopsy	O
-	O
proven	O
prostatic	B-Disease
adenocarcinoma	I-Disease
[	O
26	O
with	O
stage	O
C	O
(	O
T3N0M0	O
)	O
and	O
16	O
with	O
stage	O
D1	O
(	O
T3N1M0	O
)	O
]	O
were	O
included	O
in	O
this	O
study	O
.	O

All	O
patients	O
received	O
CAB	O
[	O
leuprolide	B-Chemical
acetate	I-Chemical
(	O
LHRH	B-Chemical
-	I-Chemical
A	I-Chemical
)	O
3	O
.	O
75	O
mg	O
,	O
intramuscularly	O
,	O
every	O
28	O
days	O
plus	O
250	O
mg	O
flutamide	B-Chemical
,	O
tid	O
,	O
per	O
Os	O
]	O
and	O
were	O
evaluated	O
for	O
anemia	B-Disease
by	O
physical	O
examination	O
and	O
laboratory	O
tests	O
at	O
baseline	O
and	O
4	O
subsequent	O
intervals	O
(	O
1	O
,	O
2	O
,	O
3	O
and	O
6	O
months	O
post	O
-	O
CAB	O
)	O
.	O

Hb	O
,	O
PSA	O
and	O
Testosterone	B-Chemical
measurements	O
were	O
recorded	O
.	O

Patients	O
with	O
stage	O
D2	O
-	O
3	O
disease	O
,	O
abnormal	O
hemoglobin	O
level	O
or	O
renal	O
and	O
liver	O
function	O
tests	O
that	O
were	O
higher	O
than	O
the	O
upper	O
limits	O
were	O
excluded	O
from	O
the	O
study	O
.	O

The	O
duration	O
of	O
the	O
study	O
was	O
six	O
months	O
.	O

RESULTS	O
:	O
The	O
mean	O
hemoglobin	O
(	O
Hb	O
)	O
levels	O
were	O
significantly	O
declined	O
in	O
all	O
patients	O
from	O
baseline	O
of	O
14	O
.	O
2	O
g	O
/	O
dl	O
to	O
14	O
.	O
0	O
g	O
/	O
dl	O
,	O
13	O
.	O
5	O
g	O
/	O
dl	O
,	O
13	O
.	O
2	O
g	O
/	O
dl	O
and	O
12	O
.	O
7	O
g	O
/	O
dl	O
at	O
1	O
,	O
2	O
,	O
3	O
and	O
6	O
months	O
post	O
-	O
CAB	O
,	O
respectively	O
.	O

Severe	O
and	O
clinically	O
evident	O
anemia	B-Disease
of	O
Hb	O
<	O
11	O
g	O
/	O
dl	O
with	O
clinical	O
symptoms	O
was	O
detected	O
in	O
6	O
patients	O
(	O
14	O
.	O
3	O
%	O
)	O
.	O

This	O
CAB	O
-	O
induced	O
anemia	B-Disease
was	O
normochromic	O
and	O
normocytic	O
.	O

At	O
six	O
months	O
post	O
-	O
CAB	O
,	O
patients	O
with	O
severe	O
anemia	B-Disease
had	O
a	O
Hb	O
mean	O
value	O
of	O
10	O
.	O
2	O
+	O
/	O
-	O
0	O
.	O
1	O
g	O
/	O
dl	O
(	O
X	O
+	O
/	O
-	O
SE	O
)	O
,	O
whereas	O
the	O
other	O
patients	O
had	O
mild	O
anemia	B-Disease
with	O
Hb	O
mean	O
value	O
of	O
13	O
.	O
2	O
+	O
/	O
-	O
0	O
.	O
17	O
(	O
X	O
+	O
/	O
-	O
SE	O
)	O
.	O

The	O
development	O
of	O
severe	O
anemia	B-Disease
at	O
6	O
months	O
post	O
-	O
CAB	O
was	O
predictable	O
by	O
the	O
reduction	O
of	O
Hb	O
baseline	O
value	O
of	O
more	O
than	O
2	O
.	O
5	O
g	O
/	O
dl	O
after	O
3	O
months	O
of	O
CAB	O
(	O
p	O
=	O
0	O
.	O
01	O
)	O
.	O

The	O
development	O
of	O
severe	O
CAB	O
-	O
induced	O
anemia	B-Disease
in	O
prostate	B-Disease
cancer	I-Disease
patients	O
did	O
not	O
correlate	O
with	O
T	O
baseline	O
values	O
(	O
T	O
<	O
3	O
ng	O
/	O
ml	O
versus	O
T	O
>	O
or	O
=	O
3	O
ng	O
/	O
ml	O
)	O
,	O
with	O
age	O
(	O
<	O
76	O
yrs	O
versus	O
>	O
or	O
=	O
76	O
yrs	O
)	O
,	O
and	O
clinical	O
stage	O
(	O
stage	O
C	O
versus	O
stage	O
D1	O
)	O
.	O

Severe	O
and	O
clinically	O
evident	O
anemia	B-Disease
was	O
easily	O
corrected	O
by	O
subcutaneous	O
injections	O
(	O
3	O
times	O
/	O
week	O
for	O
1	O
month	O
)	O
of	O
recombinant	O
erythropoietin	O
(	O
rHuEPO	O
-	O
beta	O
)	O
.	O

CONCLUSION	O
:	O
Our	O
data	O
suggest	O
that	O
rHuEPO	O
-	O
beta	O
correctable	O
CAB	O
-	O
induced	O
anemia	B-Disease
occurs	O
in	O
14	O
.	O
3	O
%	O
of	O
prostate	B-Disease
cancer	I-Disease
patients	O
after	O
6	O
months	O
of	O
therapy	O
.	O

Delirium	B-Disease
during	O
clozapine	B-Chemical
treatment	O
:	O
incidence	O
and	O
associated	O
risk	O
factors	O
.	O

BACKGROUND	O
:	O
Incidence	O
and	O
risk	O
factors	O
for	O
delirium	B-Disease
during	O
clozapine	B-Chemical
treatment	O
require	O
further	O
clarification	O
.	O

METHODS	O
:	O
We	O
used	O
computerized	O
pharmacy	O
records	O
to	O
identify	O
all	O
adult	O
psychiatric	B-Disease
inpatients	O
treated	O
with	O
clozapine	B-Chemical
(	O
1995	O
-	O
96	O
)	O
,	O
reviewed	O
their	O
medical	O
records	O
to	O
score	O
incidence	O
and	O
severity	O
of	O
delirium	B-Disease
,	O
and	O
tested	O
associations	O
with	O
potential	O
risk	O
factors	O
.	O

RESULTS	O
:	O
Subjects	O
(	O
n	O
=	O
139	O
)	O
were	O
72	O
women	O
and	O
67	O
men	O
,	O
aged	O
40	O
.	O
8	O
+	O
/	O
-	O
12	O
.	O
1	O
years	O
,	O
hospitalized	O
for	O
24	O
.	O
9	O
+	O
/	O
-	O
23	O
.	O
3	O
days	O
,	O
and	O
given	O
clozapine	B-Chemical
,	O
gradually	O
increased	O
to	O
an	O
average	O
daily	O
dose	O
of	O
282	O
+	O
/	O
-	O
203	O
mg	O
(	O
3	O
.	O
45	O
+	O
/	O
-	O
2	O
.	O
45	O
mg	O
/	O
kg	O
)	O
for	O
18	O
.	O
9	O
+	O
/	O
-	O
16	O
.	O
4	O
days	O
.	O

Delirium	B-Disease
was	O
diagnosed	O
in	O
14	O
(	O
10	O
.	O
1	O
%	O
incidence	O
,	O
or	O
1	O
.	O
48	O
cases	O
/	O
person	O
-	O
years	O
of	O
exposure	O
)	O
;	O
71	O
.	O
4	O
%	O
of	O
cases	O
were	O
moderate	O
or	O
severe	O
.	O

Associated	O
factors	O
were	O
co	O
-	O
treatment	O
with	O
other	O
centrally	O
antimuscarinic	O
agents	O
,	O
poor	O
clinical	O
outcome	O
,	O
older	O
age	O
,	O
and	O
longer	O
hospitalization	O
(	O
by	O
17	O
.	O
5	O
days	O
,	O
increasing	O
cost	O
)	O
;	O
sex	O
,	O
diagnosis	O
or	O
medical	O
co	O
-	O
morbidity	O
,	O
and	O
daily	O
clozapine	B-Chemical
dose	O
,	O
which	O
fell	O
with	O
age	O
,	O
were	O
unrelated	O
.	O

CONCLUSIONS	O
:	O
Delirium	B-Disease
was	O
found	O
in	O
10	O
%	O
of	O
clozapine	B-Chemical
-	O
treated	O
inpatients	O
,	O
particularly	O
in	O
older	O
patients	O
exposed	O
to	O
other	O
central	O
anticholinergics	O
.	O

Delirium	B-Disease
was	O
inconsistently	O
recognized	O
clinically	O
in	O
milder	O
cases	O
and	O
was	O
associated	O
with	O
increased	O
length	O
-	O
of	O
-	O
stay	O
and	O
higher	O
costs	O
,	O
and	O
inferior	O
clinical	O
outcome	O
.	O

Neuroprotective	O
action	O
of	O
MPEP	B-Chemical
,	O
a	O
selective	O
mGluR5	O
antagonist	O
,	O
in	O
methamphetamine	B-Chemical
-	O
induced	O
dopaminergic	O
neurotoxicity	B-Disease
is	O
associated	O
with	O
a	O
decrease	O
in	O
dopamine	B-Chemical
outflow	O
and	O
inhibition	O
of	O
hyperthermia	B-Disease
in	O
rats	O
.	O

The	O
aim	O
of	O
this	O
study	O
was	O
to	O
examine	O
the	O
role	O
of	O
metabotropic	O
glutamate	B-Chemical
receptor	O
5	O
(	O
mGluR5	O
)	O
in	O
the	O
toxic	O
action	O
of	O
methamphetamine	B-Chemical
on	O
dopaminergic	O
neurones	O
in	O
rats	O
.	O

Methamphetamine	B-Chemical
(	O
10	O
mg	O
/	O
kg	O
sc	O
)	O
,	O
administered	O
five	O
times	O
,	O
reduced	O
the	O
levels	O
of	O
dopamine	B-Chemical
and	O
its	O
metabolites	O
in	O
striatal	O
tissue	O
when	O
measured	O
72	O
h	O
after	O
the	O
last	O
injection	O
.	O

A	O
selective	O
antagonist	O
of	O
mGluR5	O
,	O
2	B-Chemical
-	I-Chemical
methyl	I-Chemical
-	I-Chemical
6	I-Chemical
-	I-Chemical
(	I-Chemical
phenylethynyl	I-Chemical
)	I-Chemical
pyridine	I-Chemical
(	O
MPEP	B-Chemical
;	O
5	O
mg	O
/	O
kg	O
ip	O
)	O
,	O
when	O
administered	O
five	O
times	O
immediately	O
before	O
each	O
methamphetamine	B-Chemical
injection	O
reversed	O
the	O
above	O
-	O
mentioned	O
methamphetamine	B-Chemical
effects	O
.	O

A	O
single	O
MPEP	B-Chemical
(	O
5	O
mg	O
/	O
kg	O
ip	O
)	O
injection	O
reduced	O
the	O
basal	O
extracellular	O
dopamine	B-Chemical
level	O
in	O
the	O
striatum	O
,	O
as	O
well	O
as	O
dopamine	B-Chemical
release	O
stimulated	O
either	O
by	O
methamphetamine	B-Chemical
(	O
10	O
mg	O
/	O
kg	O
sc	O
)	O
or	O
by	O
intrastriatally	O
administered	O
veratridine	B-Chemical
(	O
100	O
microM	O
)	O
.	O

Moreover	O
,	O
it	O
transiently	O
diminished	O
the	O
methamphetamine	B-Chemical
(	O
10	O
mg	O
/	O
kg	O
sc	O
)	O
-	O
induced	O
hyperthermia	B-Disease
and	O
reduced	O
basal	O
body	O
temperature	O
.	O

MPEP	B-Chemical
administered	O
into	O
the	O
striatum	O
at	O
high	O
concentrations	O
(	O
500	O
microM	O
)	O
increased	O
extracellular	O
dopamine	B-Chemical
levels	O
,	O
while	O
lower	O
concentrations	O
(	O
50	O
-	O
100	O
microM	O
)	O
were	O
devoid	O
of	O
any	O
effect	O
.	O

The	O
results	O
of	O
this	O
study	O
suggest	O
that	O
the	O
blockade	O
of	O
mGluR5	O
by	O
MPEP	B-Chemical
may	O
protect	O
dopaminergic	O
neurones	O
against	O
methamphetamine	B-Chemical
-	O
induced	O
toxicity	B-Disease
.	O

Neuroprotection	O
rendered	O
by	O
MPEP	B-Chemical
may	O
be	O
associated	O
with	O
the	O
reduction	O
of	O
the	O
methamphetamine	B-Chemical
-	O
induced	O
dopamine	B-Chemical
efflux	O
in	O
the	O
striatum	O
due	O
to	O
the	O
blockade	O
of	O
extrastriatal	O
mGluR5	O
,	O
and	O
with	O
a	O
decrease	O
in	O
hyperthermia	B-Disease
.	O

Protective	O
efficacy	O
of	O
neuroactive	O
steroids	B-Chemical
against	O
cocaine	B-Chemical
kindled	O
-	O
seizures	B-Disease
in	O
mice	O
.	O

Neuroactive	O
steroids	B-Chemical
demonstrate	O
pharmacological	O
actions	O
that	O
have	O
relevance	O
for	O
a	O
host	O
of	O
neurological	B-Disease
and	I-Disease
psychiatric	I-Disease
disorders	I-Disease
.	O

They	O
offer	O
protection	O
against	O
seizures	B-Disease
in	O
a	O
range	O
of	O
models	O
and	O
seem	O
to	O
inhibit	O
certain	O
stages	O
of	O
drug	B-Disease
dependence	I-Disease
in	O
preclinical	O
assessments	O
.	O

The	O
present	O
study	O
was	O
designed	O
to	O
evaluate	O
two	O
endogenous	O
and	O
one	O
synthetic	O
neuroactive	O
steroid	B-Chemical
that	O
positively	O
modulate	O
the	O
gamma	B-Chemical
-	I-Chemical
aminobutyric	I-Chemical
acid	I-Chemical
(	O
GABA	B-Chemical
(	O
A	O
)	O
)	O
receptor	O
against	O
the	O
increase	O
in	O
sensitivity	O
to	O
the	O
convulsant	O
effects	O
of	O
cocaine	B-Chemical
engendered	O
by	O
repeated	O
cocaine	B-Chemical
administration	O
(	O
seizure	B-Disease
kindling	O
)	O
.	O

Allopregnanolone	B-Chemical
(	O
3alpha	B-Chemical
-	I-Chemical
hydroxy	I-Chemical
-	I-Chemical
5alpha	I-Chemical
-	I-Chemical
pregnan	I-Chemical
-	I-Chemical
20	I-Chemical
-	I-Chemical
one	I-Chemical
)	O
,	O
pregnanolone	B-Chemical
(	O
3alpha	B-Chemical
-	I-Chemical
hydroxy	I-Chemical
-	I-Chemical
5beta	I-Chemical
-	I-Chemical
pregnan	I-Chemical
-	I-Chemical
20	I-Chemical
-	I-Chemical
one	I-Chemical
)	O
and	O
ganaxolone	B-Chemical
(	O
a	O
synthetic	O
derivative	O
of	O
allopregnanolone	B-Chemical
3alpha	B-Chemical
-	I-Chemical
hydroxy	I-Chemical
-	I-Chemical
3beta	I-Chemical
-	I-Chemical
methyl	I-Chemical
-	I-Chemical
5alpha	I-Chemical
-	I-Chemical
pregnan	I-Chemical
-	I-Chemical
20	I-Chemical
-	I-Chemical
one	I-Chemical
)	O
were	O
tested	O
for	O
their	O
ability	O
to	O
suppress	O
the	O
expression	O
(	O
anticonvulsant	O
effect	O
)	O
and	O
development	O
(	O
antiepileptogenic	O
effect	O
)	O
of	O
cocaine	B-Chemical
-	O
kindled	O
seizures	B-Disease
in	O
male	O
,	O
Swiss	O
-	O
Webster	O
mice	O
.	O

Kindled	O
seizures	B-Disease
were	O
induced	O
by	O
daily	O
administration	O
of	O
60	O
mg	O
/	O
kg	O
cocaine	B-Chemical
for	O
5	O
days	O
.	O

All	O
of	O
these	O
positive	O
GABA	B-Chemical
(	O
A	O
)	O
modulators	O
suppressed	O
the	O
expression	O
of	O
kindled	O
seizures	B-Disease
,	O
whereas	O
only	O
allopregnanolone	B-Chemical
and	O
ganaxolone	B-Chemical
inhibited	O
the	O
development	O
of	O
kindling	O
.	O

Allopregnanolone	B-Chemical
and	O
pregnanolone	B-Chemical
,	O
but	O
not	O
ganaxolone	B-Chemical
,	O
also	O
reduced	O
cumulative	O
lethality	O
associated	O
with	O
kindling	O
.	O

These	O
findings	O
demonstrate	O
that	O
some	O
neuroactive	O
steroids	B-Chemical
attenuate	O
convulsant	O
and	O
sensitizing	O
properties	O
of	O
cocaine	B-Chemical
and	O
add	O
to	O
a	O
growing	O
literature	O
on	O
their	O
potential	O
use	O
in	O
the	O
modulation	O
of	O
effects	O
of	O
drugs	O
of	O
abuse	O
.	O

Effect	O
of	O
humoral	O
modulators	O
of	O
morphine	B-Chemical
-	O
induced	O
increase	B-Disease
in	I-Disease
locomotor	I-Disease
activity	I-Disease
of	O
mice	O
.	O

The	O
effect	O
of	O
humoral	O
modulators	O
on	O
the	O
morphine	B-Chemical
-	O
induced	O
increase	B-Disease
in	I-Disease
locomotor	I-Disease
activity	I-Disease
of	O
mice	O
was	O
studied	O
.	O

The	O
subcutaneous	O
administration	O
of	O
10	O
mg	O
/	O
kg	O
of	O
morphine	B-Chemical
-	O
HC1	O
produced	O
a	O
marked	O
increase	B-Disease
in	I-Disease
locomotor	I-Disease
activity	I-Disease
in	O
mice	O
.	O

The	O
morphine	B-Chemical
-	O
induced	O
hyperactivity	B-Disease
was	O
potentiated	O
by	O
scopolamine	B-Chemical
and	O
attenuated	O
by	O
physostigmine	B-Chemical
.	O

In	O
contrast	O
,	O
both	O
methscopolamine	B-Chemical
and	O
neostigmine	B-Chemical
,	O
which	O
do	O
not	O
penetrate	O
the	O
blood	O
-	O
brain	O
barrier	O
,	O
had	O
no	O
effect	O
on	O
the	O
hyperactivity	B-Disease
produced	O
by	O
morphine	B-Chemical
.	O

Pretreatment	O
of	O
mice	O
with	O
alpha	B-Chemical
-	I-Chemical
methyltyrosine	I-Chemical
(	O
20	O
mg	O
/	O
kg	O
i	O
.	O
p	O
.	O
,	O
one	O
hour	O
)	O
,	O
an	O
inhibitor	O
of	O
tyrosine	B-Chemical
hydroxylase	O
,	O
significantly	O
decreased	O
the	O
activity	O
-	O
increasing	O
effects	O
of	O
morphine	B-Chemical
.	O

On	O
the	O
other	O
hand	O
,	O
pretreatment	O
with	O
p	B-Chemical
-	I-Chemical
chlorophenylalamine	I-Chemical
(	O
3	O
X	O
320	O
mg	O
/	O
kg	O
i	O
.	O
p	O
.	O
,	O
24	O
hr	O
)	O
,	O
a	O
serotonin	B-Chemical
depletor	O
,	O
caused	O
no	O
significant	O
change	O
in	O
the	O
hyperactivity	B-Disease
.	O

The	O
study	O
suggests	O
that	O
the	O
activity	O
-	O
increasing	O
effects	O
of	O
morphine	B-Chemical
are	O
mediated	O
by	O
the	O
release	O
of	O
catecholamines	B-Chemical
from	O
adrenergic	O
neurons	O
in	O
the	O
brain	O
.	O

And	O
the	O
results	O
are	O
consistent	O
with	O
the	O
hypothesis	O
that	O
morphine	B-Chemical
acts	O
by	O
retarding	O
the	O
release	O
of	O
acetylcholine	B-Chemical
at	O
some	O
central	O
cholinergic	O
synapses	O
.	O

It	O
is	O
also	O
suggested	O
from	O
collected	O
evidence	O
that	O
the	O
activity	O
-	O
increasing	O
effects	O
of	O
morphine	B-Chemical
in	O
mice	O
are	O
mediated	O
by	O
mechanisms	O
different	O
from	O
those	O
which	O
mediate	O
the	O
activity	O
-	O
increasing	O
effects	O
of	O
morphine	B-Chemical
in	O
rats	O
.	O

Effects	O
of	O
uninephrectomy	O
and	O
high	O
protein	O
feeding	O
on	O
lithium	B-Chemical
-	O
induced	O
chronic	B-Disease
renal	I-Disease
failure	I-Disease
in	O
rats	O
.	O

Rats	O
with	O
lithium	B-Chemical
-	O
induced	O
nephropathy	B-Disease
were	O
subjected	O
to	O
high	O
protein	O
(	O
HP	O
)	O
feeding	O
,	O
uninephrectomy	O
(	O
NX	O
)	O
or	O
a	O
combination	O
of	O
these	O
,	O
in	O
an	O
attempt	O
to	O
induce	O
glomerular	O
hyperfiltration	O
and	O
further	O
progression	O
of	O
renal	B-Disease
failure	I-Disease
.	O

Newborn	O
female	O
Wistar	O
rats	O
were	O
fed	O
a	O
lithium	B-Chemical
-	O
containing	O
diet	O
(	O
50	O
mmol	O
/	O
kg	O
)	O
for	O
8	O
weeks	O
and	O
then	O
randomized	O
to	O
normal	O
diet	O
,	O
HP	O
diet	O
(	O
40	O
vs	O
.	O
19	O
%	O
)	O
,	O
NX	O
or	O
HP	O
+	O
NX	O
for	O
another	O
8	O
weeks	O
.	O

Corresponding	O
non	O
-	O
lithium	B-Chemical
pretreated	O
groups	O
were	O
generated	O
.	O

When	O
comparing	O
all	O
lithium	B-Chemical
treated	O
versus	O
non	O
-	O
lithium	B-Chemical
-	O
treated	O
groups	O
,	O
lithium	B-Chemical
caused	O
a	O
reduction	O
in	O
glomerular	O
filtration	O
rate	O
(	O
GFR	O
)	O
without	O
significant	O
changes	O
in	O
effective	O
renal	O
plasma	O
flow	O
(	O
as	O
determined	O
by	O
a	O
marker	O
secreted	O
into	O
the	O
proximal	O
tubules	O
)	O
or	O
lithium	B-Chemical
clearance	O
.	O

Consequently	O
,	O
lithium	B-Chemical
pretreatment	O
caused	O
a	O
fall	O
in	O
filtration	O
fraction	O
and	O
an	O
increase	O
in	O
fractional	O
Li	B-Chemical
excretion	O
.	O

Lithium	B-Chemical
also	O
caused	O
proteinuria	B-Disease
and	O
systolic	O
hypertension	B-Disease
in	O
absence	O
of	O
glomerulosclerosis	B-Disease
.	O

HP	O
failed	O
to	O
accentuante	O
progression	O
of	O
renal	B-Disease
failure	I-Disease
and	O
in	O
fact	O
tended	O
to	O
increase	O
GFR	O
and	O
decrease	O
plasma	O
creatinine	B-Chemical
levels	O
in	O
lithium	B-Chemical
pretreated	O
rats	O
.	O

NX	O
caused	O
an	O
additive	O
deterioration	O
in	O
GFR	O
which	O
,	O
however	O
,	O
was	O
ameliorated	O
by	O
HP	O
.	O

NX	O
+	O
HP	O
caused	O
a	O
further	O
rise	O
in	O
blood	O
pressure	O
in	O
Li	B-Chemical
-	O
pretreated	O
rats	O
.	O

The	O
results	O
indicate	O
that	O
Li	B-Chemical
-	O
induced	O
nephropathy	B-Disease
,	O
even	O
when	O
the	O
GFR	O
is	O
only	O
modestly	O
reduced	O
,	O
is	O
associated	O
with	O
proteinuria	B-Disease
and	O
arterial	O
systolic	O
hypertension	B-Disease
.	O

In	O
this	O
model	O
of	O
chronic	B-Disease
renal	I-Disease
failure	I-Disease
the	O
decline	O
in	O
GFR	O
is	O
not	O
accompanied	O
by	O
a	O
corresponding	O
fall	O
in	O
effective	O
renal	O
plasma	O
flow	O
,	O
which	O
may	O
be	O
the	O
functional	O
expression	O
of	O
the	O
formation	O
of	O
nonfiltrating	O
atubular	O
glomeruli	O
.	O

The	O
fractional	O
reabsorption	O
of	O
tubular	O
fluid	O
by	O
the	O
proximal	O
tubules	O
is	O
reduced	O
,	O
leaving	O
the	O
distal	O
delivery	O
unchanged	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
250	O
WORDS	O
)	O

Treatment	O
of	O
Crohn	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
with	O
fusidic	B-Chemical
acid	I-Chemical
:	O
an	O
antibiotic	O
with	O
immunosuppressive	O
properties	O
similar	O
to	O
cyclosporin	B-Chemical
.	O

Fusidic	O
acid	O
is	O
an	O
antibiotic	O
with	O
T	O
-	O
cell	O
specific	O
immunosuppressive	O
effects	O
similar	O
to	O
those	O
of	O
cyclosporin	B-Chemical
.	O

Because	O
of	O
the	O
need	O
for	O
the	O
development	O
of	O
new	O
treatments	O
for	O
Crohn	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
,	O
a	O
pilot	O
study	O
was	O
undertaken	O
to	O
estimate	O
the	O
pharmacodynamics	O
and	O
tolerability	O
of	O
fusidic	B-Chemical
acid	I-Chemical
treatment	O
in	O
chronic	O
active	O
,	O
therapy	O
-	O
resistant	O
patients	O
.	O

Eight	O
Crohn	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
patients	O
were	O
included	O
.	O

Fusidic	B-Chemical
acid	I-Chemical
was	O
administered	O
orally	O
in	O
a	O
dose	O
of	O
500	O
mg	O
t	O
.	O
d	O
.	O
s	O
.	O
and	O
the	O
treatment	O
was	O
planned	O
to	O
last	O
8	O
weeks	O
.	O

The	O
disease	O
activity	O
was	O
primarily	O
measured	O
by	O
a	O
modified	O
individual	O
grading	O
score	O
.	O

Five	O
of	O
8	O
patients	O
(	O
63	O
%	O
)	O
improved	O
during	O
fusidic	B-Chemical
acid	I-Chemical
treatment	O
:	O
3	O
at	O
two	O
weeks	O
and	O
2	O
after	O
four	O
weeks	O
.	O

There	O
were	O
no	O
serious	O
clinical	O
side	O
effects	O
,	O
but	O
dose	O
reduction	O
was	O
required	O
in	O
two	O
patients	O
because	O
of	O
nausea	B-Disease
.	O

Biochemically	O
,	O
an	O
increase	O
in	O
alkaline	O
phosphatases	O
was	O
noted	O
in	O
5	O
of	O
8	O
cases	O
(	O
63	O
%	O
)	O
,	O
and	O
the	O
greatest	O
increases	O
were	O
seen	O
in	O
those	O
who	O
had	O
elevated	O
levels	O
prior	O
to	O
treatment	O
.	O

All	O
reversed	O
to	O
pre	O
-	O
treatment	O
levels	O
after	O
cessation	O
of	O
treatment	O
.	O

The	O
results	O
of	O
this	O
pilot	O
study	O
suggest	O
that	O
fusidic	B-Chemical
acid	I-Chemical
may	O
be	O
of	O
benefit	O
in	O
selected	O
chronic	O
active	O
Crohn	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
patients	O
in	O
whom	O
conventional	O
treatment	O
is	O
ineffective	O
.	O

Because	O
there	O
seems	O
to	O
exist	O
a	O
scientific	O
rationale	O
for	O
the	O
use	O
of	O
fusidic	B-Chemical
acid	I-Chemical
at	O
the	O
cytokine	O
level	O
in	O
inflammatory	B-Disease
bowel	I-Disease
disease	I-Disease
,	O
we	O
suggest	O
that	O
the	O
role	O
of	O
this	O
treatment	O
should	O
be	O
further	O
investigated	O
.	O

Changes	O
in	O
depressive	B-Disease
status	O
associated	O
with	O
topical	O
beta	O
-	O
blockers	O
.	O

Depression	B-Disease
and	O
sexual	B-Disease
dysfunction	I-Disease
have	O
been	O
related	O
to	O
side	O
effects	O
of	O
topical	O
beta	O
-	O
blockers	O
.	O

We	O
performed	O
a	O
preliminary	O
study	O
in	O
order	O
to	O
determine	O
any	O
difference	O
between	O
a	O
non	O
selective	O
beta	O
-	O
blocker	O
(	O
timolol	B-Chemical
)	O
and	O
a	O
selective	O
beta	O
-	O
blocker	O
(	O
betaxolol	B-Chemical
)	O
regarding	O
CNS	O
side	O
effects	O
.	O

Eight	O
glaucomatous	B-Disease
patients	O
chronically	O
treated	O
with	O
timolol	B-Chemical
0	O
.	O
5	O
%	O
/	O
12h	O
,	O
suffering	O
from	O
depression	B-Disease
diagnosed	O
through	O
DMS	O
-	O
III	O
-	O
R	O
criteria	O
,	O
were	O
included	O
in	O
the	O
study	O
.	O

During	O
the	O
six	O
-	O
month	O
follow	O
up	O
,	O
depression	B-Disease
was	O
quantified	O
through	O
the	O
Beck	O
and	O
Zung	O
-	O
Conde	O
scales	O
every	O
two	O
months	O
.	O

In	O
a	O
double	O
blind	O
cross	O
-	O
over	O
study	O
with	O
control	O
group	O
,	O
the	O
patients	O
under	O
timolol	B-Chemical
treatment	O
presented	O
higher	O
depression	B-Disease
values	O
measured	O
through	O
the	O
Beck	O
and	O
the	O
Zung	O
-	O
Conde	O
scales	O
(	O
p	O
<	O
0	O
.	O
001	O
vs	O
control	O
)	O
.	O

These	O
results	O
suggest	O
that	O
betaxolol	B-Chemical
could	O
be	O
less	O
of	O
a	O
depression	B-Disease
-	O
inducer	O
than	O
timolol	B-Chemical
in	O
predisposed	O
patients	O
.	O

Protection	O
against	O
amphetamine	B-Chemical
-	O
induced	O
neurotoxicity	B-Disease
toward	O
striatal	O
dopamine	B-Chemical
neurons	O
in	O
rodents	O
by	O
LY274614	B-Chemical
,	O
an	O
excitatory	O
amino	B-Chemical
acid	I-Chemical
antagonist	O
.	O

LY274614	B-Chemical
,	O
3SR	B-Chemical
,	I-Chemical
4aRS	I-Chemical
,	I-Chemical
6SR	I-Chemical
,	I-Chemical
8aRS	I-Chemical
-	I-Chemical
6	I-Chemical
-	I-Chemical
[	I-Chemical
phosphonomethyl	I-Chemical
]	I-Chemical
decahydr	I-Chemical
oisoquinoline	I-Chemical
-	I-Chemical
3	I-Chemical
-	I-Chemical
carboxylic	I-Chemical
acid	I-Chemical
,	O
has	O
been	O
described	O
as	O
a	O
potent	O
antagonist	O
of	O
the	O
N	B-Chemical
-	I-Chemical
methyl	I-Chemical
-	I-Chemical
D	I-Chemical
-	I-Chemical
aspartate	I-Chemical
(	O
NMDA	B-Chemical
)	O
subtype	O
of	O
glutamate	B-Chemical
receptor	O
.	O

Here	O
its	O
ability	O
to	O
antagonize	O
the	O
prolonged	O
depletion	O
of	O
dopamine	B-Chemical
in	O
the	O
striatum	O
by	O
amphetamine	B-Chemical
in	O
iprindole	B-Chemical
-	O
treated	O
rats	O
is	O
reported	O
.	O

A	O
single	O
18	O
.	O
4	O
mg	O
/	O
kg	O
(	O
i	O
.	O
p	O
.	O
)	O
dose	O
of	O
(	O
+	O
/	O
-	O
)	O
-	O
amphetamine	B-Chemical
hemisulfate	O
,	O
given	O
to	O
rats	O
pretreated	O
with	O
iprindole	B-Chemical
,	O
resulted	O
in	O
persistent	O
depletion	O
of	O
dopamine	B-Chemical
in	O
the	O
striatum	O
1	O
week	O
later	O
.	O

This	O
prolonged	O
depletion	O
of	O
dopamine	B-Chemical
in	O
the	O
striatum	O
was	O
antagonized	O
by	O
dizocilpine	B-Chemical
(	O
MK	B-Chemical
-	I-Chemical
801	I-Chemical
,	O
a	O
non	O
-	O
competitive	O
antagonist	O
of	O
NMDA	B-Chemical
receptors	O
)	O
or	O
by	O
LY274614	B-Chemical
(	O
a	O
competitive	O
antagonist	O
of	O
NMDA	B-Chemical
receptors	O
)	O
.	O

The	O
protective	O
effect	O
of	O
LY274614	B-Chemical
was	O
dose	O
-	O
dependent	O
,	O
being	O
maximum	O
at	O
10	O
-	O
40	O
mgkg	O
(	O
i	O
.	O
p	O
.	O
)	O
.	O

A	O
10	O
mg	O
/	O
kg	O
dose	O
of	O
LY274614	B-Chemical
was	O
effective	O
in	O
antagonizing	O
the	O
depletion	O
of	O
dopamine	B-Chemical
in	O
the	O
striatum	O
,	O
when	O
given	O
as	O
long	O
as	O
8	O
hr	O
prior	O
to	O
amphetamine	B-Chemical
but	O
not	O
when	O
given	O
24	O
hr	O
prior	O
to	O
amphetamine	B-Chemical
.	O

Depletion	O
of	O
dopamine	B-Chemical
in	O
the	O
striatum	O
was	O
also	O
antagonized	O
when	O
LY274614	B-Chemical
was	O
given	O
after	O
the	O
injection	O
of	O
amphetamine	B-Chemical
;	O
LY274614	B-Chemical
protected	O
when	O
given	O
up	O
to	O
4	O
hr	O
after	O
but	O
not	O
when	O
given	O
8	O
or	O
24	O
hr	O
after	O
amphetamine	B-Chemical
.	O

The	O
prolonged	O
depletion	O
of	O
dopamine	B-Chemical
in	O
the	O
striatum	O
in	O
mice	O
,	O
given	O
multiple	O
injections	O
of	O
methamphetamine	B-Chemical
,	O
was	O
also	O
antagonized	O
dose	O
-	O
dependently	O
and	O
completely	O
by	O
LY274614	B-Chemical
.	O

The	O
data	O
strengthen	O
the	O
evidence	O
that	O
the	O
neurotoxic	B-Disease
effect	O
of	O
amphetamine	B-Chemical
and	O
related	O
compounds	O
toward	O
nigrostriatal	O
dopamine	B-Chemical
neurons	O
involves	O
NMDA	B-Chemical
receptors	O
and	O
that	O
LY274614	B-Chemical
is	O
an	O
NMDA	B-Chemical
receptor	O
antagonist	O
with	O
long	O
-	O
lasting	O
in	O
vivo	O
effects	O
in	O
rats	O
.	O

Ketoconazole	B-Chemical
-	O
induced	O
neurologic	B-Disease
sequelae	I-Disease
.	O

A	O
77	O
-	O
y	O
-	O
old	O
patient	O
developed	O
weakness	B-Disease
of	I-Disease
extremities	I-Disease
,	O
legs	B-Disease
paralysis	I-Disease
,	O
dysarthria	B-Disease
and	O
tremor	B-Disease
1	O
h	O
after	O
ingestion	O
of	O
200	O
mg	O
ketoconazole	B-Chemical
for	O
the	O
first	O
time	O
in	O
his	O
life	O
.	O

All	O
complaints	O
faded	O
away	O
within	O
24	O
h	O
.	O

Few	O
days	O
later	O
,	O
the	O
patient	O
used	O
another	O
200	O
mg	O
ketoconazole	B-Chemical
tablet	O
,	O
and	O
within	O
an	O
hour	O
experienced	O
a	O
similar	O
clinical	O
picture	O
,	O
which	O
resolved	O
again	O
spontaneously	O
within	O
hours	O
.	O

Laboratory	O
evaluations	O
,	O
including	O
head	O
CT	O
scan	O
,	O
were	O
normal	O
.	O

This	O
case	O
illustrates	O
the	O
need	O
for	O
close	O
vigilance	O
in	O
adverse	B-Disease
drug	I-Disease
reactions	I-Disease
,	O
particularly	O
in	O
the	O
elderly	O
.	O

Development	O
of	O
levodopa	B-Chemical
-	O
induced	O
dyskinesias	B-Disease
in	O
parkinsonian	B-Disease
monkeys	O
may	O
depend	O
upon	O
rate	O
of	O
symptom	O
onset	O
and	O
/	O
or	O
duration	O
of	O
symptoms	O
.	O

Levodopa	B-Chemical
-	O
induced	O
dyskinesias	B-Disease
(	O
LIDs	B-Disease
)	O
present	O
a	O
major	O
problem	O
for	O
the	O
long	O
-	O
term	O
management	O
of	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
(	O
PD	B-Disease
)	O
patients	O
.	O

Due	O
to	O
the	O
interdependence	O
of	O
risk	O
factors	O
in	O
clinical	O
populations	O
,	O
it	O
is	O
difficult	O
to	O
independently	O
examine	O
factors	O
that	O
may	O
influence	O
the	O
development	O
of	O
LIDs	B-Disease
.	O

Using	O
macaque	O
monkeys	O
with	O
different	O
types	O
of	O
MPTP	B-Chemical
-	O
induced	O
parkinsonism	B-Disease
,	O
the	O
current	O
study	O
evaluated	O
the	O
degree	O
to	O
which	O
rate	O
of	O
symptom	O
progression	O
,	O
symptom	O
severity	O
,	O
and	O
response	O
to	O
and	O
duration	O
of	O
levodopa	B-Chemical
therapy	O
may	O
be	O
involved	O
in	O
the	O
development	O
of	O
LIDs	B-Disease
.	O

Monkeys	O
with	O
acute	O
(	O
short	O
-	O
term	O
)	O
MPTP	B-Chemical
exposure	O
,	O
rapid	O
symptom	O
onset	O
and	O
short	O
symptom	O
duration	O
prior	O
to	O
initiation	O
of	O
levodopa	B-Chemical
therapy	O
developed	O
dyskinesia	B-Disease
between	O
11	O
and	O
24	O
days	O
of	O
daily	O
levodopa	B-Chemical
administration	O
.	O

In	O
contrast	O
,	O
monkeys	O
with	O
long	O
-	O
term	O
MPTP	B-Chemical
exposure	O
,	O
slow	O
symptom	O
progression	O
and	O
/	O
or	O
long	O
symptom	O
duration	O
prior	O
to	O
initiation	O
of	O
levodopa	B-Chemical
therapy	O
were	O
more	O
resistant	O
to	O
developing	O
LIDs	B-Disease
(	O
e	O
.	O
g	O
.	O
,	O
dyskinesia	B-Disease
developed	O
no	O
sooner	O
than	O
146	O
days	O
of	O
chronic	O
levodopa	B-Chemical
administration	O
)	O
.	O

All	O
animals	O
were	O
similarly	O
symptomatic	O
at	O
the	O
start	O
of	O
levodopa	B-Chemical
treatment	O
and	O
had	O
similar	O
therapeutic	O
responses	O
to	O
the	O
drug	O
.	O

These	O
data	O
suggest	O
distinct	O
differences	O
in	O
the	O
propensity	O
to	O
develop	O
LIDs	B-Disease
in	O
monkeys	O
with	O
different	O
rates	O
of	O
symptom	O
progression	O
or	O
symptom	O
durations	O
prior	O
to	O
levodopa	B-Chemical
and	O
demonstrate	O
the	O
value	O
of	O
these	O
models	O
for	O
further	O
studying	O
the	O
pathophysiology	O
of	O
LIDs	B-Disease
.	O

A	O
diet	O
promoting	O
sugar	B-Disease
dependency	I-Disease
causes	O
behavioral	B-Disease
cross	I-Disease
-	I-Disease
sensitization	I-Disease
to	O
a	O
low	O
dose	O
of	O
amphetamine	B-Chemical
.	O

Previous	O
research	O
in	O
this	O
laboratory	O
has	O
shown	O
that	O
a	O
diet	O
of	O
intermittent	O
excessive	O
sugar	O
consumption	O
produces	O
a	O
state	O
with	O
neurochemical	O
and	O
behavioral	O
similarities	O
to	O
drug	B-Disease
dependency	I-Disease
.	O

The	O
present	O
study	O
examined	O
whether	O
female	O
rats	O
on	O
various	O
regimens	O
of	O
sugar	O
access	O
would	O
show	O
behavioral	B-Disease
cross	I-Disease
-	I-Disease
sensitization	I-Disease
to	O
a	O
low	O
dose	O
of	O
amphetamine	B-Chemical
.	O

After	O
a	O
30	O
-	O
min	O
baseline	O
measure	O
of	O
locomotor	O
activity	O
(	O
day	O
0	O
)	O
,	O
animals	O
were	O
maintained	O
on	O
a	O
cyclic	O
diet	O
of	O
12	O
-	O
h	O
deprivation	O
followed	O
by	O
12	O
-	O
h	O
access	O
to	O
10	O
%	O
sucrose	B-Chemical
solution	O
and	O
chow	O
pellets	O
(	O
12	O
h	O
access	O
starting	O
4	O
h	O
after	O
onset	O
of	O
the	O
dark	O
period	O
)	O
for	O
21	O
days	O
.	O

Locomotor	O
activity	O
was	O
measured	O
again	O
for	O
30	O
min	O
at	O
the	O
beginning	O
of	O
days	O
1	O
and	O
21	O
of	O
sugar	O
access	O
.	O

Beginning	O
on	O
day	O
22	O
,	O
all	O
rats	O
were	O
maintained	O
on	O
ad	O
libitum	O
chow	O
.	O

Nine	O
days	O
later	O
locomotor	O
activity	O
was	O
measured	O
in	O
response	O
to	O
a	O
single	O
low	O
dose	O
of	O
amphetamine	B-Chemical
(	O
0	O
.	O
5	O
mg	O
/	O
kg	O
)	O
.	O

The	O
animals	O
that	O
had	O
experienced	O
cyclic	O
sucrose	B-Chemical
and	O
chow	O
were	O
hyperactive	B-Disease
in	O
response	O
to	O
amphetamine	B-Chemical
compared	O
with	O
four	O
control	O
groups	O
(	O
ad	O
libitum	O
10	O
%	O
sucrose	B-Chemical
and	O
chow	O
followed	O
by	O
amphetamine	B-Chemical
injection	O
,	O
cyclic	O
chow	O
followed	O
by	O
amphetamine	B-Chemical
injection	O
,	O
ad	O
libitum	O
chow	O
with	O
amphetamine	B-Chemical
,	O
or	O
cyclic	O
10	O
%	O
sucrose	B-Chemical
and	O
chow	O
with	O
a	O
saline	O
injection	O
)	O
.	O

These	O
results	O
suggest	O
that	O
a	O
diet	O
comprised	O
of	O
alternating	O
deprivation	O
and	O
access	O
to	O
a	O
sugar	O
solution	O
and	O
chow	O
produces	O
bingeing	O
on	O
sugar	O
that	O
leads	O
to	O
a	O
long	O
lasting	O
state	O
of	O
increased	O
sensitivity	O
to	O
amphetamine	B-Chemical
,	O
possibly	O
due	O
to	O
a	O
lasting	O
alteration	O
in	O
the	O
dopamine	B-Chemical
system	O
.	O

Reversible	O
dilated	B-Disease
cardiomyopathy	I-Disease
related	O
to	O
amphotericin	B-Chemical
B	I-Chemical
therapy	O
.	O

We	O
describe	O
a	O
patient	O
who	O
developed	O
dilated	B-Disease
cardiomyopathy	I-Disease
and	O
clinical	O
congestive	O
heart	B-Disease
failure	I-Disease
after	O
2	O
months	O
of	O
therapy	O
with	O
amphotericin	B-Chemical
B	I-Chemical
(	O
AmB	B-Chemical
)	O
for	O
disseminated	O
coccidioidomycosis	B-Disease
.	O

His	O
echocardiographic	O
abnormalities	O
and	O
heart	B-Disease
failure	I-Disease
resolved	O
after	O
posaconazole	B-Chemical
was	O
substituted	O
for	O
AmB	B-Chemical
.	O

It	O
is	O
important	O
to	O
recognize	O
the	O
rare	O
and	O
potentially	O
reversible	O
toxicity	B-Disease
of	O
AmB	B-Chemical
.	O

NO	B-Chemical
-	O
induced	O
migraine	B-Disease
attack	O
:	O
strong	O
increase	O
in	O
plasma	O
calcitonin	B-Chemical
gene	I-Chemical
-	I-Chemical
related	I-Chemical
peptide	I-Chemical
(	O
CGRP	B-Chemical
)	O
concentration	O
and	O
negative	O
correlation	O
with	O
platelet	O
serotonin	B-Chemical
release	O
.	O

The	O
aim	O
of	O
the	O
present	O
study	O
was	O
to	O
investigate	O
changes	O
in	O
the	O
plasma	O
calcitonin	B-Chemical
gene	I-Chemical
-	I-Chemical
related	I-Chemical
peptide	I-Chemical
(	O
CGRP	B-Chemical
)	O
concentration	O
and	O
platelet	O
serotonin	B-Chemical
(	O
5	B-Chemical
-	I-Chemical
hydroxytriptamine	I-Chemical
,	O
5	B-Chemical
-	I-Chemical
HT	I-Chemical
)	O
content	O
during	O
the	O
immediate	O
headache	B-Disease
and	O
the	O
delayed	O
genuine	O
migraine	B-Disease
attack	O
provoked	O
by	O
nitroglycerin	B-Chemical
.	O

Fifteen	O
female	O
migraineurs	B-Disease
(	I-Disease
without	I-Disease
aura	I-Disease
)	I-Disease
and	O
eight	O
controls	O
participated	O
in	O
the	O
study	O
.	O

Sublingual	O
nitroglycerin	B-Chemical
(	O
0	O
.	O
5	O
mg	O
)	O
was	O
administered	O
.	O

Blood	O
was	O
collected	O
from	O
the	O
antecubital	O
vein	O
four	O
times	O
:	O
60	O
min	O
before	O
and	O
after	O
the	O
nitroglycerin	B-Chemical
application	O
,	O
and	O
60	O
and	O
120	O
min	O
after	O
the	O
beginning	O
of	O
the	O
migraine	B-Disease
attack	O
(	O
mean	O
344	O
and	O
404	O
min	O
;	O
12	O
subjects	O
)	O
.	O

In	O
those	O
subjects	O
who	O
had	O
no	O
migraine	B-Disease
attack	O
(	O
11	O
subjects	O
)	O
a	O
similar	O
time	O
schedule	O
was	O
used	O
.	O

Plasma	O
CGRP	B-Chemical
concentration	O
increased	O
significantly	O
(	O
P	O
<	O
0	O
.	O
01	O
)	O
during	O
the	O
migraine	B-Disease
attack	O
and	O
returned	O
to	O
baseline	O
after	O
the	O
cessation	O
of	O
the	O
migraine	B-Disease
.	O

In	O
addition	O
,	O
both	O
change	O
and	O
peak	O
,	O
showed	O
significant	O
positive	O
correlations	O
with	O
migraine	B-Disease
headache	B-Disease
intensity	O
(	O
P	O
<	O
0	O
.	O
001	O
)	O
.	O

However	O
,	O
plasma	O
CGRP	B-Chemical
concentrations	O
failed	O
to	O
change	O
during	O
immediate	O
headache	B-Disease
and	O
in	O
the	O
subjects	O
with	O
no	O
migraine	B-Disease
attack	O
.	O

Basal	O
CGRP	B-Chemical
concentration	O
was	O
significantly	O
higher	O
and	O
platelet	O
5	B-Chemical
-	I-Chemical
HT	I-Chemical
content	O
tended	O
to	O
be	O
lower	O
in	O
subjects	O
who	O
experienced	O
a	O
migraine	B-Disease
attack	O
.	O

Platelet	O
serotonin	B-Chemical
content	O
decreased	O
significantly	O
(	O
P	O
<	O
0	O
.	O
01	O
)	O
after	O
nitroglycerin	B-Chemical
in	O
subjects	O
with	O
no	O
migraine	B-Disease
attack	O
but	O
no	O
consistent	O
change	O
was	O
observed	O
in	O
patients	O
with	O
migraine	B-Disease
attack	O
.	O

In	O
conclusion	O
,	O
the	O
fact	O
that	O
plasma	O
CGRP	B-Chemical
concentration	O
correlates	O
with	O
the	O
timing	O
and	O
severity	O
of	O
a	O
migraine	B-Disease
headache	B-Disease
suggests	O
a	O
direct	O
relationship	O
between	O
CGRP	B-Chemical
and	O
migraine	B-Disease
.	O

In	O
contrast	O
,	O
serotonin	B-Chemical
release	O
from	O
platelets	O
does	O
not	O
provoke	O
migraine	B-Disease
,	O
it	O
may	O
even	O
counteract	O
the	O
headache	B-Disease
and	O
the	O
concomitant	O
CGRP	B-Chemical
release	O
in	O
this	O
model	O
.	O

Hyperbaric	O
oxygen	B-Chemical
therapy	O
for	O
control	O
of	O
intractable	O
cyclophosphamide	B-Chemical
-	O
induced	O
hemorrhagic	B-Disease
cystitis	I-Disease
.	O

We	O
report	O
a	O
case	O
of	O
intractable	O
hemorrhagic	B-Disease
cystitis	I-Disease
due	O
to	O
cyclophosphamide	B-Chemical
therapy	O
for	O
Wegener	B-Disease
'	I-Disease
s	I-Disease
granulomatosis	I-Disease
.	O

Conservative	O
treatment	O
,	O
including	O
bladder	O
irrigation	O
with	O
physiological	O
saline	O
and	O
instillation	O
of	O
prostaglandin	B-Chemical
F2	I-Chemical
alpha	I-Chemical
,	O
failed	O
to	O
totally	O
control	O
hemorrhage	B-Disease
.	O

We	O
then	O
used	O
hyperbaric	O
oxygen	B-Chemical
at	O
an	O
absolute	O
pressure	O
of	O
2	O
atm	O
,	O
5	O
days	O
a	O
week	O
for	O
8	O
consecutive	O
weeks	O
.	O

The	O
bleeding	B-Disease
ceased	O
completely	O
by	O
the	O
end	O
of	O
treatment	O
and	O
the	O
patient	O
remained	O
free	O
of	O
hematuria	B-Disease
thereafter	O
.	O

No	O
side	O
effect	O
was	O
noted	O
during	O
the	O
course	O
of	O
therapy	O
.	O

In	O
future	O
,	O
this	O
form	O
of	O
therapy	O
can	O
offer	O
a	O
safe	O
alternative	O
in	O
the	O
treatment	O
of	O
cyclophosphamide	B-Chemical
-	O
induced	O
hemorrhagic	B-Disease
cystitis	I-Disease
.	O

Acute	B-Disease
psychosis	I-Disease
due	O
to	O
treatment	O
with	O
phenytoin	B-Chemical
in	O
a	O
nonepileptic	O
patient	O
.	O

The	O
development	O
of	O
psychosis	B-Disease
related	O
to	O
antiepileptic	O
drug	O
treatment	O
is	O
usually	O
attributed	O
to	O
the	O
interaction	O
between	O
the	O
epileptic	B-Disease
brain	O
substratum	O
and	O
the	O
antiepileptic	O
drugs	O
.	O

The	O
case	O
of	O
a	O
nonepileptic	O
patient	O
who	O
developed	O
psychosis	B-Disease
following	O
phenytoin	B-Chemical
treatment	O
for	O
trigeminal	B-Disease
neuralgia	I-Disease
is	O
described	O
.	O

This	O
case	O
suggests	O
that	O
the	O
psychotic	B-Disease
symptoms	I-Disease
that	O
occur	O
following	O
phenytoin	B-Chemical
treatment	O
in	O
some	O
epileptic	B-Disease
patients	O
may	O
be	O
the	O
direct	O
result	O
of	O
medication	O
,	O
unrelated	O
to	O
seizures	B-Disease
.	O

Risks	O
of	O
the	O
consumption	O
of	O
beverages	O
containing	O
quinine	B-Chemical
.	O

Although	O
the	O
United	O
States	O
Food	O
and	O
Drug	O
Administration	O
banned	O
its	O
use	O
for	O
nocturnal	B-Disease
leg	I-Disease
cramps	I-Disease
due	O
to	O
lack	O
of	O
safety	O
and	O
efficacy	O
,	O
quinine	B-Chemical
is	O
widely	O
available	O
in	O
beverages	O
including	O
tonic	O
water	O
and	O
bitter	O
lemon	O
.	O

Numerous	O
anecdotal	O
reports	O
suggest	O
that	O
products	O
containing	O
quinine	B-Chemical
may	O
produce	O
neurological	B-Disease
complications	I-Disease
,	O
including	O
confusion	B-Disease
,	O
altered	O
mental	O
status	O
,	O
seizures	B-Disease
,	O
and	O
coma	B-Disease
,	O
particularly	O
in	O
older	O
women	O
.	O

Psychologists	O
need	O
to	O
inquire	O
about	O
consumption	O
of	O
quinine	B-Chemical
-	O
containing	O
beverages	O
as	O
part	O
of	O
an	O
evaluation	O
process	O
.	O

Transient	O
platypnea	B-Disease
-	I-Disease
orthodeoxia	I-Disease
-	I-Disease
like	I-Disease
syndrome	I-Disease
induced	O
by	O
propafenone	B-Chemical
overdose	B-Disease
in	O
a	O
young	O
woman	O
with	O
Ebstein	B-Disease
'	I-Disease
s	I-Disease
anomaly	I-Disease
.	O

In	O
this	O
report	O
we	O
describe	O
the	O
case	O
of	O
a	O
37	O
-	O
year	O
-	O
old	O
white	O
woman	O
with	O
Ebstein	B-Disease
'	I-Disease
s	I-Disease
anomaly	I-Disease
,	O
who	O
developed	O
a	O
rare	O
syndrome	O
called	O
platypnea	B-Disease
-	I-Disease
orthodeoxia	I-Disease
,	O
characterized	O
by	O
massive	O
right	O
-	O
to	O
-	O
left	O
interatrial	O
shunting	O
with	O
transient	O
profound	O
hypoxia	B-Disease
and	O
cyanosis	B-Disease
.	O

This	O
shunt	O
of	O
blood	O
via	O
a	O
patent	B-Disease
foramen	I-Disease
ovale	I-Disease
occurred	O
in	O
the	O
presence	O
of	O
a	O
normal	O
pulmonary	O
artery	O
pressure	O
,	O
and	O
was	O
probably	O
precipitated	O
by	O
a	O
propafenone	B-Chemical
overdose	B-Disease
.	O

This	O
drug	O
caused	O
biventricular	B-Disease
dysfunction	I-Disease
,	O
due	O
to	O
its	O
negative	O
inotropic	O
effect	O
,	O
and	O
hypotension	B-Disease
,	O
due	O
to	O
its	O
peripheral	O
vasodilatory	O
effect	O
.	O

These	O
effects	O
gave	O
rise	O
to	O
an	O
increase	O
in	O
the	O
right	O
atrial	O
pressure	O
and	O
a	O
decrease	O
in	O
the	O
left	O
one	O
with	O
a	O
consequent	O
stretching	O
of	O
the	O
foramen	O
ovale	O
and	O
the	O
creation	O
of	O
massive	O
right	O
-	O
to	O
-	O
left	O
shunting	O
.	O

In	O
our	O
case	O
this	O
interatrial	O
shunt	O
was	O
very	O
accurately	O
detected	O
at	O
bubble	O
contrast	O
echocardiography	O
.	O

Noxious	O
chemical	O
stimulation	O
of	O
rat	O
facial	O
mucosa	O
increases	O
intracranial	O
blood	O
flow	O
through	O
a	O
trigemino	O
-	O
parasympathetic	O
reflex	O
-	O
-	O
an	O
experimental	O
model	O
for	O
vascular	B-Disease
dysfunctions	I-Disease
in	O
cluster	B-Disease
headache	I-Disease
.	O

Cluster	B-Disease
headache	I-Disease
is	O
characterized	O
by	O
typical	O
autonomic	O
dysfunctions	O
including	O
facial	O
and	O
intracranial	B-Disease
vascular	I-Disease
disturbances	I-Disease
.	O

Both	O
the	O
trigeminal	O
and	O
the	O
cranial	O
parasympathetic	O
systems	O
may	O
be	O
involved	O
in	O
mediating	O
these	O
dysfunctions	O
.	O

An	O
experimental	O
model	O
was	O
developed	O
in	O
the	O
rat	O
to	O
measure	O
changes	O
in	O
lacrimation	O
and	O
intracranial	O
blood	O
flow	O
following	O
noxious	O
chemical	O
stimulation	O
of	O
facial	O
mucosa	O
.	O

Blood	O
flow	O
was	O
monitored	O
in	O
arteries	O
of	O
the	O
exposed	O
cranial	O
dura	O
mater	O
and	O
the	O
parietal	O
cortex	O
using	O
laser	O
Doppler	O
flowmetry	O
.	O

Capsaicin	B-Chemical
(	O
0	O
.	O
01	O
-	O
1	O
mm	O
)	O
applied	O
to	O
oral	O
or	O
nasal	O
mucosa	O
induced	O
increases	B-Disease
in	I-Disease
dural	I-Disease
and	I-Disease
cortical	I-Disease
blood	I-Disease
flow	I-Disease
and	O
provoked	O
lacrimation	O
.	O

These	O
responses	O
were	O
blocked	O
by	O
systemic	O
pre	O
-	O
administration	O
of	O
hexamethonium	B-Chemical
chloride	I-Chemical
(	O
20	O
mg	O
/	O
kg	O
)	O
.	O

The	O
evoked	O
increases	B-Disease
in	I-Disease
dural	I-Disease
blood	I-Disease
flow	I-Disease
were	O
also	O
abolished	O
by	O
topical	O
pre	O
-	O
administration	O
of	O
atropine	B-Chemical
(	O
1	O
mm	O
)	O
and	O
[	O
Lys1	O
,	O
Pro2	O
,	O
5	O
,	O
Arg3	O
,	O
4	O
,	O
Tyr6	O
]	O
-	O
VIP	O
(	O
0	O
.	O
1	O
mm	O
)	O
,	O
a	O
vasoactive	O
intestinal	O
polypeptide	O
(	O
VIP	O
)	O
antagonist	O
,	O
onto	O
the	O
exposed	O
dura	O
mater	O
.	O

We	O
conclude	O
that	O
noxious	O
stimulation	O
of	O
facial	O
mucosa	O
increases	O
intracranial	O
blood	O
flow	O
and	O
lacrimation	O
via	O
a	O
trigemino	O
-	O
parasympathetic	O
reflex	O
.	O

The	O
blood	O
flow	O
responses	O
seem	O
to	O
be	O
mediated	O
by	O
the	O
release	O
of	O
acetylcholine	B-Chemical
and	O
VIP	O
within	O
the	O
meninges	O
.	O

Similar	O
mechanisms	O
may	O
be	O
involved	O
in	O
the	O
pathogenesis	O
of	O
cluster	B-Disease
headache	I-Disease
.	O

Organophosphate	B-Chemical
-	O
induced	O
convulsions	B-Disease
and	O
prevention	O
of	O
neuropathological	B-Disease
damages	I-Disease
.	O

Such	O
organophosphorus	B-Chemical
(	O
OP	B-Chemical
)	O
compounds	O
as	O
diisopropylfluorophosphate	B-Chemical
(	O
DFP	B-Chemical
)	O
,	O
sarin	B-Chemical
and	O
soman	B-Chemical
are	O
potent	O
inhibitors	O
of	O
acetylcholinesterases	O
(	O
AChEs	O
)	O
and	O
butyrylcholinesterases	O
(	O
BChEs	O
)	O
.	O

The	O
acute	O
toxicity	B-Disease
of	O
OPs	B-Chemical
is	O
the	O
result	O
of	O
their	O
irreversible	O
binding	O
with	O
AChEs	O
in	O
the	O
central	O
nervous	O
system	O
(	O
CNS	O
)	O
,	O
which	O
elevates	O
acetylcholine	B-Chemical
(	O
ACh	B-Chemical
)	O
levels	O
.	O

The	O
protective	O
action	O
of	O
subcutaneously	O
(	O
SC	O
)	O
administered	O
antidotes	O
or	O
their	O
combinations	O
in	O
DFP	B-Chemical
(	O
2	O
.	O
0	O
mg	O
/	O
kg	O
BW	O
)	O
intoxication	O
was	O
studied	O
in	O
9	O
-	O
10	O
-	O
weeks	O
-	O
old	O
Han	O
-	O
Wistar	O
male	O
rats	O
.	O

The	O
rats	O
received	O
AChE	O
reactivator	O
pralidoxime	B-Chemical
-	I-Chemical
2	I-Chemical
-	I-Chemical
chloride	I-Chemical
(	O
2PAM	B-Chemical
)	O
(	O
30	O
.	O
0	O
mg	O
/	O
kg	O
BW	O
)	O
,	O
anticonvulsant	O
diazepam	B-Chemical
(	O
2	O
.	O
0	O
mg	O
/	O
kg	O
BW	O
)	O
,	O
A	O
(	O
1	O
)	O
-	O
adenosine	B-Chemical
receptor	O
agonist	O
N	B-Chemical
(	I-Chemical
6	I-Chemical
)	I-Chemical
-	I-Chemical
cyclopentyl	I-Chemical
adenosine	I-Chemical
(	O
CPA	B-Chemical
)	O
(	O
2	O
.	O
0	O
mg	O
/	O
kg	O
BW	O
)	O
,	O
NMDA	B-Chemical
-	O
receptor	O
antagonist	O
dizocilpine	B-Chemical
maleate	I-Chemical
(	O
+	O
-	O
MK801	O
hydrogen	O
maleate	O
)	O
(	O
2	O
.	O
0	O
mg	O
/	O
kg	O
BW	O
)	O
or	O
their	O
combinations	O
with	O
cholinolytic	O
drug	O
atropine	B-Chemical
sulfate	I-Chemical
(	O
50	O
.	O
0	O
mg	O
/	O
kg	O
BW	O
)	O
immediately	O
or	O
30	O
min	O
after	O
the	O
single	O
SC	O
injection	O
of	O
DFP	B-Chemical
.	O

The	O
control	O
rats	O
received	O
atropine	B-Chemical
sulfate	I-Chemical
,	O
but	O
also	O
saline	O
and	O
olive	O
oil	O
instead	O
of	O
other	O
antidotes	O
and	O
DFP	B-Chemical
,	O
respectively	O
.	O

All	O
rats	O
were	O
terminated	O
either	O
24	O
h	O
or	O
3	O
weeks	O
after	O
the	O
DFP	B-Chemical
injection	O
.	O

The	O
rats	O
treated	O
with	O
DFP	B-Chemical
-	O
atropine	B-Chemical
showed	O
severe	O
typical	O
OP	B-Chemical
-	O
induced	O
toxicity	B-Disease
signs	O
.	O

When	O
CPA	B-Chemical
,	O
diazepam	B-Chemical
or	O
2PAM	B-Chemical
was	O
given	O
immediately	O
after	O
DFP	B-Chemical
-	O
atropine	B-Chemical
,	O
these	O
treatments	O
prevented	O
,	O
delayed	O
or	O
shortened	O
the	O
occurrence	O
of	O
serious	O
signs	O
of	O
poisoning	B-Disease
.	O

Atropine	B-Chemical
-	O
MK801	B-Chemical
did	O
not	O
offer	O
any	O
additional	O
protection	O
against	O
DFP	B-Chemical
toxicity	B-Disease
.	O

In	O
conclusion	O
,	O
CPA	B-Chemical
,	O
diazepam	B-Chemical
and	O
2PAM	B-Chemical
in	O
combination	O
with	O
atropine	B-Chemical
prevented	O
the	O
occurrence	O
of	O
serious	O
signs	O
of	O
poisoning	B-Disease
and	O
thus	O
reduced	O
the	O
toxicity	B-Disease
of	O
DFP	B-Chemical
in	O
rat	O
.	O

A	O
pyridoxine	B-Chemical
-	O
dependent	O
behavioral	B-Disease
disorder	I-Disease
unmasked	O
by	O
isoniazid	B-Chemical
.	O

A	O
3	O
-	O
year	O
-	O
old	O
girl	O
had	O
behavioral	B-Disease
deterioration	I-Disease
,	O
with	O
hyperkinesis	B-Disease
,	O
irritability	B-Disease
,	O
and	O
sleeping	B-Disease
difficulties	I-Disease
after	O
the	O
therapeutic	O
administration	O
of	O
isoniazid	B-Chemical
.	O

The	O
administration	O
of	O
pharmacologic	O
doses	O
of	O
pyridoxine	B-Chemical
hydrochloride	I-Chemical
led	O
to	O
a	O
disappearance	O
of	O
symptoms	O
.	O

After	O
discontinuing	O
isoniazid	B-Chemical
therapy	O
a	O
similar	O
pattern	O
of	O
behavior	O
was	O
noted	O
that	O
was	O
controlled	O
by	O
pyridoxine	B-Chemical
.	O

A	O
placebo	O
had	O
no	O
effect	O
,	O
but	O
niacinamide	B-Chemical
was	O
as	O
effective	O
as	O
pyridoxine	B-Chemical
.	O

Periodic	O
withdrawal	O
of	O
pyridoxine	B-Chemical
was	O
associated	O
with	O
return	O
of	O
the	O
hyperkinesis	B-Disease
.	O

The	O
level	O
of	O
pyridoxal	B-Chemical
in	O
the	O
blood	O
was	O
normal	O
during	O
the	O
periods	O
of	O
relapse	O
.	O

Metabolic	O
studies	O
suggested	O
a	O
block	O
in	O
the	O
kynurenine	B-Chemical
pathway	O
of	O
tryptophan	B-Chemical
metabolism	O
.	O

The	O
patient	O
has	O
been	O
followed	O
for	O
six	O
years	O
and	O
has	O
required	O
pharmacologic	O
doses	O
of	O
pyridoxine	B-Chemical
to	O
control	O
her	O
behavior	O
.	O

Recurrent	O
excitation	O
in	O
the	O
dentate	O
gyrus	O
of	O
a	O
murine	O
model	O
of	O
temporal	B-Disease
lobe	I-Disease
epilepsy	I-Disease
.	O

Similar	O
to	O
rats	O
,	O
systemic	O
pilocarpine	B-Chemical
injection	O
causes	O
status	B-Disease
epilepticus	I-Disease
(	O
SE	B-Disease
)	O
and	O
the	O
eventual	O
development	O
of	O
spontaneous	O
seizures	B-Disease
and	O
mossy	O
fiber	O
sprouting	O
in	O
C57BL	O
/	O
6	O
and	O
CD1	O
mice	O
,	O
but	O
the	O
physiological	O
correlates	O
of	O
these	O
events	O
have	O
not	O
been	O
identified	O
in	O
mice	O
.	O

Population	O
responses	O
in	O
granule	O
cells	O
of	O
the	O
dentate	O
gyrus	O
were	O
examined	O
in	O
transverse	O
slices	O
of	O
the	O
ventral	O
hippocampus	O
from	O
pilocarpine	B-Chemical
-	O
treated	O
and	O
untreated	O
mice	O
.	O

In	O
Mg	B-Chemical
(	O
2	O
+	O
)	O
-	O
free	O
bathing	O
medium	O
containing	O
bicuculline	B-Chemical
,	O
conditions	O
designed	O
to	O
increase	O
excitability	O
in	O
the	O
slices	O
,	O
electrical	O
stimulation	O
of	O
the	O
hilus	O
resulted	O
in	O
a	O
single	O
population	O
spike	O
in	O
granule	O
cells	O
from	O
control	O
mice	O
and	O
pilocarpine	B-Chemical
-	O
treated	O
mice	O
that	O
did	O
not	O
experience	O
SE	B-Disease
.	O

In	O
SE	B-Disease
survivors	O
,	O
similar	O
stimulation	O
resulted	O
in	O
a	O
population	O
spike	O
followed	O
,	O
at	O
a	O
variable	O
latency	O
,	O
by	O
negative	O
DC	O
shifts	O
and	O
repetitive	O
afterdischarges	O
of	O
3	O
-	O
60	O
s	O
duration	O
,	O
which	O
were	O
blocked	O
by	O
ionotropic	O
glutamate	B-Chemical
receptor	O
antagonists	O
.	O

Focal	O
glutamate	B-Chemical
photostimulation	O
of	O
the	O
granule	O
cell	O
layer	O
at	O
sites	O
distant	O
from	O
the	O
recording	O
pipette	O
resulted	O
in	O
population	O
responses	O
of	O
1	O
-	O
30	O
s	O
duration	O
in	O
slices	O
from	O
SE	B-Disease
survivors	O
but	O
not	O
other	O
groups	O
.	O

These	O
data	O
support	O
the	O
hypothesis	O
that	O
SE	B-Disease
-	O
induced	O
mossy	O
fiber	O
sprouting	O
and	O
synaptic	O
reorganization	O
are	O
relevant	O
characteristics	O
of	O
seizure	B-Disease
development	O
in	O
these	O
murine	O
strains	O
,	O
resembling	O
rat	O
models	O
of	O
human	O
temporal	B-Disease
lobe	I-Disease
epilepsy	I-Disease
.	O

Urinary	B-Disease
bladder	I-Disease
cancer	I-Disease
in	O
Wegener	B-Disease
'	I-Disease
s	I-Disease
granulomatosis	I-Disease
:	O
risks	O
and	O
relation	O
to	O
cyclophosphamide	B-Chemical
.	O

OBJECTIVE	O
:	O
To	O
assess	O
and	O
characterise	O
the	O
risk	O
of	O
bladder	B-Disease
cancer	I-Disease
,	O
and	O
its	O
relation	O
to	O
cyclophosphamide	B-Chemical
,	O
in	O
patients	O
with	O
Wegener	B-Disease
'	I-Disease
s	I-Disease
granulomatosis	I-Disease
.	O

METHODS	O
:	O
In	O
the	O
population	O
based	O
,	O
nationwide	O
Swedish	O
Inpatient	O
Register	O
a	O
cohort	O
of	O
1065	O
patients	O
with	O
Wegener	B-Disease
'	I-Disease
s	I-Disease
granulomatosis	I-Disease
,	O
1969	O
-	O
95	O
,	O
was	O
identified	O
.	O

Through	O
linkage	O
with	O
the	O
Swedish	O
Cancer	B-Disease
Register	O
,	O
all	O
subjects	O
in	O
this	O
cohort	O
diagnosed	O
with	O
bladder	B-Disease
cancer	I-Disease
were	O
identified	O
.	O

Nested	O
within	O
the	O
cohort	O
,	O
a	O
matched	O
case	O
-	O
control	O
study	O
was	O
performed	O
to	O
estimate	O
the	O
association	O
between	O
cyclophosphamide	B-Chemical
and	O
bladder	B-Disease
cancer	I-Disease
using	O
odds	O
ratios	O
(	O
ORs	O
)	O
as	O
relative	O
risk	O
.	O

In	O
the	O
cohort	O
the	O
cumulative	O
risk	O
of	O
bladder	B-Disease
cancer	I-Disease
after	O
Wegener	B-Disease
'	I-Disease
s	I-Disease
granulomatosis	I-Disease
,	O
and	O
the	O
relative	O
prevalence	O
of	O
a	O
history	O
of	O
bladder	B-Disease
cancer	I-Disease
at	O
the	O
time	O
of	O
diagnosis	O
of	O
Wegener	B-Disease
'	I-Disease
s	I-Disease
granulomatosis	I-Disease
,	O
were	O
also	O
estimated	O
.	O

RESULTS	O
:	O
The	O
median	O
cumulative	O
doses	O
of	O
cyclophosphamide	B-Chemical
among	O
cases	O
(	O
n	O
=	O
11	O
)	O
and	O
controls	O
(	O
n	O
=	O
25	O
)	O
were	O
113	O
g	O
and	O
25	O
g	O
,	O
respectively	O
.	O

The	O
risk	O
of	O
bladder	B-Disease
cancer	I-Disease
doubled	O
for	O
every	O
10	O
g	O
increment	O
in	O
cyclophosphamide	B-Chemical
(	O
OR	O
=	O
2	O
.	O
0	O
,	O
95	O
%	O
confidence	O
interval	O
(	O
CI	O
)	O
0	O
.	O
8	O
to	O
4	O
.	O
9	O
)	O
.	O

Treatment	O
duration	O
longer	O
than	O
1	O
year	O
was	O
associated	O
with	O
an	O
eightfold	O
increased	O
risk	O
(	O
OR	O
=	O
7	O
.	O
7	O
,	O
95	O
%	O
CI	O
0	O
.	O
9	O
to	O
69	O
)	O
.	O

The	O
absolute	O
risk	O
for	O
bladder	B-Disease
cancer	I-Disease
in	O
the	O
cohort	O
reached	O
10	O
%	O
16	O
years	O
after	O
diagnosis	O
of	O
Wegener	B-Disease
'	I-Disease
s	I-Disease
granulomatosis	I-Disease
,	O
and	O
a	O
history	O
of	O
bladder	B-Disease
cancer	I-Disease
was	O
(	O
non	O
-	O
significantly	O
)	O
twice	O
as	O
common	O
as	O
expected	O
at	O
the	O
time	O
of	O
diagnosis	O
of	O
Wegener	B-Disease
'	I-Disease
s	I-Disease
granulomatosis	I-Disease
.	O

CONCLUSION	O
:	O
The	O
results	O
indicate	O
a	O
dose	O
-	O
response	O
relationship	O
between	O
cyclophosphamide	B-Chemical
and	O
the	O
risk	O
of	O
bladder	B-Disease
cancer	I-Disease
,	O
high	O
cumulative	O
risks	O
in	O
the	O
entire	O
cohort	O
,	O
and	O
also	O
the	O
possibility	O
of	O
risk	O
factors	O
operating	O
even	O
before	O
Wegener	B-Disease
'	I-Disease
s	I-Disease
granulomatosis	I-Disease
.	O

Differential	O
modulation	O
by	O
estrogen	B-Chemical
of	O
alpha2	O
-	O
adrenergic	O
and	O
I1	O
-	O
imidazoline	B-Chemical
receptor	O
-	O
mediated	O
hypotension	B-Disease
in	O
female	O
rats	O
.	O

We	O
have	O
recently	O
shown	O
that	O
estrogen	B-Chemical
negatively	O
modulates	O
the	O
hypotensive	B-Disease
effect	O
of	O
clonidine	B-Chemical
(	O
mixed	O
alpha2	O
-	O
/	O
I1	O
-	O
receptor	O
agonist	O
)	O
in	O
female	O
rats	O
and	O
implicates	O
the	O
cardiovascular	O
autonomic	O
control	O
in	O
this	O
interaction	O
.	O

The	O
present	O
study	O
investigated	O
whether	O
this	O
effect	O
of	O
estrogen	B-Chemical
involves	O
interaction	O
with	O
alpha2	O
-	O
and	O
/	O
or	O
I1	O
-	O
receptors	O
.	O

Changes	O
evoked	O
by	O
a	O
single	O
intraperitoneal	O
injection	O
of	O
rilmenidine	B-Chemical
(	O
600	O
microg	O
/	O
kg	O
)	O
or	O
alpha	B-Chemical
-	I-Chemical
methyldopa	I-Chemical
(	O
100	O
mg	O
/	O
kg	O
)	O
,	O
selective	O
I1	O
-	O
and	O
alpha2	O
-	O
receptor	O
agonists	O
,	O
respectively	O
,	O
in	O
blood	O
pressure	O
,	O
hemodynamic	O
variability	O
,	O
and	O
locomotor	O
activity	O
were	O
assessed	O
in	O
radiotelemetered	O
sham	O
-	O
operated	O
and	O
ovariectomized	O
(	O
Ovx	O
)	O
Sprague	O
-	O
Dawley	O
female	O
rats	O
with	O
or	O
without	O
12	O
-	O
wk	O
estrogen	B-Chemical
replacement	O
.	O

Three	O
time	O
domain	O
indexes	O
of	O
hemodynamic	O
variability	O
were	O
employed	O
:	O
the	O
standard	O
deviation	O
of	O
mean	O
arterial	O
pressure	O
as	O
a	O
measure	O
of	O
blood	O
pressure	O
variability	O
and	O
the	O
standard	O
deviation	O
of	O
beat	O
-	O
to	O
-	O
beat	O
intervals	O
(	O
SDRR	O
)	O
and	O
the	O
root	O
mean	O
square	O
of	O
successive	O
differences	O
in	O
R	O
-	O
wave	O
-	O
to	O
-	O
R	O
-	O
wave	O
intervals	O
as	O
measures	O
of	O
heart	O
rate	O
variability	O
.	O

In	O
sham	O
-	O
operated	O
rats	O
,	O
rilmenidine	B-Chemical
or	O
alpha	B-Chemical
-	I-Chemical
methyldopa	I-Chemical
elicited	O
similar	O
hypotension	B-Disease
that	O
lasted	O
at	O
least	O
5	O
h	O
and	O
was	O
associated	O
with	O
reductions	O
in	O
standard	O
deviation	O
of	O
mean	O
arterial	O
pressure	O
.	O

SDRR	O
was	O
reduced	O
only	O
by	O
alpha	B-Chemical
-	I-Chemical
methyldopa	I-Chemical
.	O

Ovx	O
significantly	O
enhanced	O
the	O
hypotensive	B-Disease
response	O
to	O
alpha	B-Chemical
-	I-Chemical
methyldopa	I-Chemical
,	O
in	O
contrast	O
to	O
no	O
effect	O
on	O
rilmenidine	B-Chemical
hypotension	B-Disease
.	O

The	O
enhanced	O
alpha	B-Chemical
-	I-Chemical
methyldopa	I-Chemical
hypotension	B-Disease
in	O
Ovx	O
rats	O
was	O
paralleled	O
with	O
further	O
reduction	O
in	O
SDRR	O
and	O
a	B-Disease
reduced	I-Disease
locomotor	I-Disease
activity	I-Disease
.	O

Estrogen	O
replacement	O
(	O
17beta	B-Chemical
-	I-Chemical
estradiol	I-Chemical
subcutaneous	O
pellet	O
,	O
14	O
.	O
2	O
microg	O
/	O
day	O
,	O
12	O
wk	O
)	O
of	O
Ovx	O
rats	O
restored	O
the	O
hemodynamic	O
and	O
locomotor	O
effects	O
of	O
alpha	B-Chemical
-	I-Chemical
methyldopa	I-Chemical
to	O
sham	O
-	O
operated	O
levels	O
.	O

These	O
findings	O
suggest	O
that	O
estrogen	B-Chemical
downregulates	O
alpha2	O
-	O
but	O
not	O
I1	O
-	O
receptor	O
-	O
mediated	O
hypotension	B-Disease
and	O
highlight	O
a	O
role	O
for	O
the	O
cardiac	O
autonomic	O
control	O
in	O
alpha	B-Chemical
-	I-Chemical
methyldopa	I-Chemical
-	O
estrogen	B-Chemical
interaction	O
.	O

Severe	O
reversible	O
left	B-Disease
ventricular	I-Disease
systolic	I-Disease
and	I-Disease
diastolic	I-Disease
dysfunction	I-Disease
due	O
to	O
accidental	O
iatrogenic	O
epinephrine	B-Chemical
overdose	B-Disease
.	O

Catecholamine	B-Chemical
-	O
induced	O
cardiomyopathy	B-Disease
due	O
to	O
chronic	O
excess	O
of	O
endogenous	O
catecholamines	B-Chemical
has	O
been	O
recognized	O
for	O
decades	O
as	O
a	O
clinical	O
phenomenon	O
.	O

In	O
contrast	O
,	O
reports	O
of	O
myocardial	B-Disease
dysfunction	I-Disease
due	O
to	O
acute	O
iatrogenic	O
overdose	B-Disease
are	O
rare	O
.	O

A	O
35	O
-	O
year	O
-	O
old	O
woman	O
whose	O
cervix	O
uteri	O
was	O
inadvertently	O
injected	O
with	O
8	O
mg	O
of	O
epinephrine	B-Chemical
developed	O
myocardial	B-Disease
stunning	I-Disease
that	O
was	O
characterized	O
by	O
severe	O
hemodynamic	O
compromise	O
,	O
profound	O
,	O
albeit	O
transient	O
,	O
left	B-Disease
ventricular	I-Disease
systolic	I-Disease
and	I-Disease
diastolic	I-Disease
dysfunction	I-Disease
,	O
and	O
only	O
modestly	O
elevated	O
biochemical	O
markers	O
of	O
myocardial	B-Disease
necrosis	I-Disease
.	O

Our	O
case	O
illustrates	O
the	O
serious	O
consequences	O
of	O
medical	O
errors	O
that	O
can	O
be	O
avoided	O
through	O
improved	O
medication	O
labeling	O
and	O
staff	O
supervision	O
.	O

Cardioprotective	O
effect	O
of	O
tincture	B-Chemical
of	I-Chemical
Crataegus	I-Chemical
on	O
isoproterenol	B-Chemical
-	O
induced	O
myocardial	B-Disease
infarction	I-Disease
in	O
rats	O
.	O

Tincture	B-Chemical
of	I-Chemical
Crataegus	I-Chemical
(	O
TCR	B-Chemical
)	O
,	O
an	O
alcoholic	B-Chemical
extract	I-Chemical
of	I-Chemical
the	I-Chemical
berries	I-Chemical
of	I-Chemical
hawthorn	I-Chemical
(	O
Crataegus	B-Chemical
oxycantha	I-Chemical
)	O
,	O
is	O
used	O
in	O
herbal	O
and	O
homeopathic	O
medicine	O
.	O

The	O
present	O
study	O
was	O
done	O
to	O
investigate	O
the	O
protective	O
effect	O
of	O
TCR	B-Chemical
on	O
experimentally	O
induced	O
myocardial	B-Disease
infarction	I-Disease
in	O
rats	O
.	O

Pretreatment	O
of	O
TCR	B-Chemical
,	O
at	O
a	O
dose	O
of	O
0	O
.	O
5	O
mL	O
/	O
100	O
g	O
bodyweight	O
per	O
day	O
,	O
orally	O
for	O
30	O
days	O
,	O
prevented	O
the	O
increase	O
in	O
lipid	O
peroxidation	O
and	O
activity	O
of	O
marker	O
enzymes	O
observed	O
in	O
isoproterenol	B-Chemical
-	O
induced	O
rats	O
(	O
85	O
mg	O
kg	O
(	O
-	O
1	O
)	O
s	O
.	O
c	O
.	O
for	O
2	O
days	O
at	O
an	O
interval	O
of	O
24	O
h	O
)	O
.	O

TCR	B-Chemical
prevented	O
the	O
isoproterenol	B-Chemical
-	O
induced	O
decrease	O
in	O
antioxidant	O
enzymes	O
in	O
the	O
heart	O
and	O
increased	O
the	O
rate	O
of	O
ADP	B-Chemical
-	O
stimulated	O
oxygen	B-Chemical
uptake	O
and	O
respiratory	O
coupling	O
ratio	O
.	O

TCR	B-Chemical
protected	O
against	O
pathological	O
changes	O
induced	O
by	O
isoproterenol	B-Chemical
in	O
rat	O
heart	O
.	O

The	O
results	O
show	O
that	O
pretreatment	O
with	O
TCR	B-Chemical
may	O
be	O
useful	O
in	O
preventing	O
the	O
damage	O
induced	O
by	O
isoproterenol	B-Chemical
in	O
rat	O
heart	O
.	O

Treatment	O
of	O
tinnitus	B-Disease
by	O
intratympanic	O
instillation	O
of	O
lignocaine	B-Chemical
(	O
lidocaine	B-Chemical
)	O
2	O
per	O
cent	O
through	O
ventilation	O
tubes	O
.	O

Idiopathic	B-Disease
subjective	I-Disease
tinnitus	I-Disease
(	O
IST	B-Disease
)	O
is	O
one	O
of	O
the	O
most	O
obscure	O
otological	O
pathologies	O
.	O

This	O
paper	O
presents	O
the	O
results	O
of	O
treating	O
IST	B-Disease
by	O
intratympanic	O
instillation	O
of	O
lignocaine	B-Chemical
(	O
lidocaine	B-Chemical
)	O
2	O
per	O
cent	O
through	O
a	O
grommet	O
,	O
for	O
five	O
weekly	O
courses	O
.	O

Fifty	O
-	O
two	O
patients	O
suffering	O
from	O
intractable	O
tinnitus	B-Disease
entered	O
this	O
therapeutic	O
trial	O
,	O
but	O
only	O
nine	O
finished	O
all	O
five	O
courses	O
.	O

In	O
one	O
patient	O
,	O
the	O
tinnitus	B-Disease
was	O
almost	O
completely	O
abolished	O
,	O
but	O
in	O
all	O
the	O
nine	O
patients	O
the	O
decompensated	O
tinnitus	B-Disease
changed	O
to	O
a	O
compensated	O
one	O
.	O

We	O
suggest	O
this	O
mode	O
of	O
treatment	O
for	O
patients	O
that	O
were	O
previously	O
treated	O
by	O
drugs	O
,	O
acupuncture	O
and	O
biofeedback	O
,	O
with	O
disappointing	O
results	O
.	O

Patients	O
should	O
be	O
warned	O
about	O
the	O
side	O
effects	O
of	O
vertigo	B-Disease
and	O
vomiting	B-Disease
,	O
which	O
subsides	O
gradually	O
with	O
every	O
new	O
instillation	O
,	O
and	O
that	O
the	O
tinnitus	B-Disease
may	O
not	O
disappear	O
but	O
will	O
be	O
alleviated	O
,	O
enabling	O
them	O
to	O
cope	O
more	O
easily	O
with	O
the	O
disease	O
and	O
lead	O
a	O
more	O
normal	O
life	O
.	O

The	O
alpha3	O
and	O
beta4	O
nicotinic	O
acetylcholine	B-Chemical
receptor	O
subunits	O
are	O
necessary	O
for	O
nicotine	B-Chemical
-	O
induced	O
seizures	B-Disease
and	O
hypolocomotion	B-Disease
in	O
mice	O
.	O

Binding	O
of	O
nicotine	B-Chemical
to	O
nicotinic	O
acetylcholine	B-Chemical
receptors	O
(	O
nAChRs	O
)	O
elicits	O
a	O
series	O
of	O
dose	O
-	O
dependent	O
behaviors	O
that	O
go	O
from	O
altered	O
exploration	O
,	O
sedation	O
,	O
and	O
tremors	B-Disease
,	O
to	O
seizures	B-Disease
and	O
death	B-Disease
.	O

nAChRs	O
are	O
pentameric	O
ion	O
channels	O
usually	O
composed	O
of	O
alpha	O
and	O
beta	O
subunits	O
.	O

A	O
gene	O
cluster	O
comprises	O
the	O
alpha3	O
,	O
alpha5	O
and	O
beta4	O
subunits	O
,	O
which	O
coassemble	O
to	O
form	O
functional	O
receptors	O
.	O

We	O
examined	O
the	O
role	O
of	O
the	O
beta4	O
subunits	O
in	O
nicotine	B-Chemical
-	O
induced	O
seizures	B-Disease
and	O
hypolocomotion	B-Disease
in	O
beta4	O
homozygous	O
null	O
(	O
beta4	O
-	O
/	O
-	O
)	O
and	O
alpha3	O
heterozygous	O
(	O
+	O
/	O
-	O
)	O
mice	O
.	O

beta4	O
-	O
/	O
-	O
mice	O
were	O
less	O
sensitive	O
to	O
the	O
effects	O
of	O
nicotine	B-Chemical
both	O
at	O
low	O
doses	O
,	O
measured	O
as	O
decreased	O
exploration	O
in	O
an	O
open	O
field	O
,	O
and	O
at	O
high	O
doses	O
,	O
measured	O
as	O
sensitivity	O
to	O
nicotine	B-Chemical
-	O
induced	O
seizures	B-Disease
.	O

Using	O
in	O
situ	O
hybridization	O
probes	O
for	O
the	O
alpha3	O
and	O
alpha5	O
subunits	O
,	O
we	O
showed	O
that	O
alpha5	O
mRNA	O
levels	O
are	O
unchanged	O
,	O
whereas	O
alpha3	O
mRNA	O
levels	O
are	O
selectively	O
decreased	O
in	O
the	O
mitral	O
cell	O
layer	O
of	O
the	O
olfactory	O
bulb	O
,	O
and	O
the	O
inferior	O
and	O
the	O
superior	O
colliculus	O
of	O
beta4	O
-	O
/	O
-	O
brains	O
.	O

alpha3	O
+	O
/	O
-	O
mice	O
were	O
partially	O
resistant	O
to	O
nicotine	B-Chemical
-	O
induced	O
seizures	B-Disease
when	O
compared	O
to	O
wild	O
-	O
type	O
littermates	O
.	O

mRNA	O
levels	O
for	O
the	O
alpha5	O
and	O
the	O
beta4	O
subunits	O
were	O
unchanged	O
in	O
alpha3	O
+	O
/	O
-	O
brains	O
.	O

Together	O
,	O
these	O
results	O
suggest	O
that	O
the	O
beta4	O
and	O
the	O
alpha3	O
subunits	O
are	O
mediators	O
of	O
nicotine	B-Chemical
-	O
induced	O
seizures	B-Disease
and	O
hypolocomotion	B-Disease
.	O

The	O
effects	O
of	O
sevoflurane	B-Chemical
on	O
lidocaine	B-Chemical
-	O
induced	O
convulsions	B-Disease
.	O

The	O
influence	O
of	O
sevoflurane	B-Chemical
on	O
lidocaine	B-Chemical
-	O
induced	O
convulsions	B-Disease
was	O
studied	O
in	O
cats	O
.	O

The	O
convulsive	B-Disease
threshold	O
(	O
mean	O
+	O
/	O
-	O
SD	O
)	O
was	O
41	O
.	O
4	O
+	O
/	O
-	O
6	O
.	O
5	O
mg	O
.	O

l	O
(	O
-	O
1	O
)	O
with	O
lidocaine	B-Chemical
infusion	O
(	O
6	O
mg	O
.	O
kg	O
(	O
-	O
1	O
)	O
.	O
min	O
(	O
-	O
1	O
)	O
)	O
,	O
increasing	O
significantly	O
to	O
66	O
.	O
6	O
+	O
/	O
-	O
10	O
.	O
9	O
mg	O
.	O

l	O
(	O
-	O
1	O
)	O
when	O
the	O
end	O
-	O
tidal	O
concentration	O
of	O
sevoflurane	B-Chemical
was	O
0	O
.	O
8	O
%	O
.	O

However	O
,	O
the	O
threshold	O
(	O
61	O
.	O
6	O
+	O
/	O
-	O
8	O
.	O
7	O
mg	O
.	O
l	O
(	O
-	O
1	O
)	O
)	O
during	O
1	O
.	O
6	O
%	O
sevoflurane	B-Chemical
was	O
not	O
significant	O
from	O
that	O
during	O
0	O
.	O
8	O
%	O
sevoflurane	B-Chemical
,	O
indicating	O
a	O
celling	O
effect	O
.	O

There	O
was	O
no	O
significant	O
difference	O
in	O
the	O
convulsive	B-Disease
threshold	O
between	O
sevoflurane	B-Chemical
and	O
enflurane	B-Chemical
.	O

The	O
rise	O
in	O
blood	O
pressure	O
became	O
less	O
marked	O
when	O
higher	O
concentrations	O
of	O
sevoflurane	B-Chemical
or	O
enflurane	B-Chemical
were	O
administered	O
and	O
the	O
blood	O
pressure	O
at	O
convulsions	B-Disease
decreased	O
significantly	O
in	O
1	O
.	O
6	O
%	O
sevoflurane	B-Chemical
,	O
and	O
in	O
0	O
.	O
8	O
%	O
and	O
1	O
.	O
6	O
%	O
enflurane	B-Chemical
.	O

However	O
,	O
there	O
was	O
no	O
significant	O
difference	O
in	O
the	O
lidocaine	B-Chemical
concentrations	O
measured	O
when	O
the	O
systolic	O
blood	O
pressure	O
became	O
70	O
mmHg	O
.	O

Apamin	B-Chemical
,	O
a	O
selective	O
blocker	O
of	O
calcium	B-Chemical
-	O
dependent	O
potassium	B-Chemical
channels	O
,	O
was	O
administered	O
intracerebroventricularly	O
in	O
rats	O
anesthetized	O
with	O
0	O
.	O
8	O
%	O
sevoflurane	B-Chemical
to	O
investigate	O
the	O
mechanism	O
of	O
the	O
anticonvulsive	O
effects	O
.	O

Apamin	B-Chemical
(	O
10	O
ng	O
)	O
had	O
a	O
tendency	O
to	O
decrease	O
the	O
convulsive	B-Disease
threshold	O
(	O
21	O
.	O
6	O
+	O
/	O
-	O
2	O
.	O
2	O
to	O
19	O
.	O
9	O
+	O
/	O
-	O
2	O
.	O
5	O
mg	O
.	O
l	O
(	O
-	O
1	O
)	O
)	O
but	O
this	O
was	O
not	O
statistically	O
significant	O
.	O

It	O
is	O
suggested	O
that	O
sevoflurane	B-Chemical
reduces	O
the	O
convulsive	B-Disease
effect	O
of	O
lidocaine	B-Chemical
toxicity	B-Disease
but	O
carries	O
some	O
risk	O
due	O
to	O
circulatory	O
depression	B-Disease
.	O

Cardiac	B-Disease
toxicity	I-Disease
observed	O
in	O
association	O
with	O
high	O
-	O
dose	O
cyclophosphamide	B-Chemical
-	O
based	O
chemotherapy	O
for	O
metastatic	O
breast	B-Disease
cancer	I-Disease
.	O

INTRODUCTION	O
:	O
Cyclophosphamide	B-Chemical
is	O
an	O
alkylating	O
agent	O
given	O
frequently	O
as	O
a	O
component	O
of	O
many	O
conditioning	O
regimens	O
.	O

In	O
high	O
doses	O
,	O
its	O
nonhematological	O
dose	O
-	O
limiting	O
toxicity	B-Disease
is	O
cardiomyopathy	B-Disease
.	O

STUDY	O
DESIGN	O
:	O
We	O
combined	O
paclitaxel	B-Chemical
,	O
melphalan	B-Chemical
and	O
high	O
-	O
dose	O
cyclophosphamide	B-Chemical
,	O
thiotepa	B-Chemical
,	O
and	O
carboplatin	B-Chemical
in	O
a	O
triple	O
sequential	O
high	O
-	O
dose	O
regimen	O
for	O
patients	O
with	O
metastatic	O
breast	B-Disease
cancer	I-Disease
.	O

Analysis	O
was	O
performed	O
on	O
61	O
women	O
with	O
chemotherapy	O
-	O
responsive	O
metastatic	O
breast	B-Disease
cancer	I-Disease
receiving	O
96	O
-	O
h	O
infusional	O
cyclophosphamide	B-Chemical
as	O
part	O
of	O
a	O
triple	O
sequential	O
high	O
-	O
dose	O
regimen	O
to	O
assess	O
association	O
between	O
presence	O
of	O
peritransplant	O
congestive	B-Disease
heart	I-Disease
failure	I-Disease
(	O
CHF	B-Disease
)	O
and	O
the	O
following	O
pretreatment	O
characteristics	O
:	O
presence	O
of	O
electrocardiogram	O
(	O
EKG	O
)	O
abnormalities	O
,	O
age	O
,	O
hypertension	B-Disease
,	O
prior	O
cardiac	O
history	O
,	O
smoking	O
,	O
diabetes	B-Disease
mellitus	I-Disease
,	O
prior	O
use	O
of	O
anthracyclines	B-Chemical
,	O
and	O
left	O
-	O
sided	O
chest	O
irradiation	O
.	O

RESULTS	O
:	O
Six	O
of	O
61	O
women	O
(	O
10	O
%	O
)	O
developed	O
clinically	O
reversible	O
grade	O
3	O
CHF	B-Disease
following	O
infusional	O
cyclophosphamide	B-Chemical
with	O
a	O
median	O
percent	O
decline	O
in	O
ejection	O
fraction	O
of	O
31	O
%	O
.	O

Incidence	O
of	O
transient	O
cyclophosphamide	B-Chemical
-	O
related	O
cardiac	B-Disease
toxicity	I-Disease
(	O
10	O
%	O
)	O
is	O
comparable	O
to	O
previous	O
recorded	O
literature	O
.	O

Older	O
age	O
was	O
significantly	O
correlated	O
with	O
the	O
CHF	B-Disease
development	O
;	O
with	O
median	O
ages	O
for	O
the	O
entire	O
group	O
and	O
for	O
patients	O
developing	O
CHF	B-Disease
of	O
45	O
and	O
59	O
,	O
respectively	O
.	O

No	O
association	O
was	O
found	O
with	O
other	O
pretreatment	O
characteristics	O
.	O

CONCLUSIONS	O
:	O
As	O
a	O
result	O
of	O
these	O
findings	O
,	O
oncologists	O
should	O
carefully	O
monitor	O
fluid	O
balance	O
in	O
older	O
patients	O
.	O

Routine	O
EKG	O
monitoring	O
during	O
infusional	O
cyclophosphamide	B-Chemical
did	O
not	O
predict	O
CHF	B-Disease
development	O
.	O

Tremor	B-Disease
side	O
effects	O
of	O
salbutamol	B-Chemical
,	O
quantified	O
by	O
a	O
laser	O
pointer	O
technique	O
.	O

OBJECTIVE	O
:	O
To	O
study	O
tremor	B-Disease
side	O
effects	O
of	O
salbutamol	B-Chemical
an	O
easily	O
applicable	O
,	O
quick	O
and	O
low	O
-	O
priced	O
method	O
is	O
needed	O
.	O

A	O
new	O
method	O
using	O
a	O
commercially	O
available	O
,	O
pen	O
-	O
shaped	O
laser	O
pointer	O
was	O
developed	O
.	O

Aim	O
of	O
the	O
study	O
was	O
to	O
determine	O
sensitivity	O
,	O
reproducibility	O
,	O
reference	O
values	O
and	O
the	O
agreement	O
with	O
a	O
questionnaire	O
.	O

METHODS	O
:	O
Tremor	B-Disease
was	O
measured	O
using	O
a	O
laser	O
pointer	O
technique	O
.	O

To	O
determine	O
sensitivity	O
we	O
assessed	O
tremor	B-Disease
in	O
44	O
patients	O
with	O
obstructive	B-Disease
lung	I-Disease
disease	I-Disease
after	O
administration	O
of	O
cumulative	O
doses	O
of	O
salbutamol	B-Chemical
.	O

Subjects	O
were	O
asked	O
to	O
aim	O
at	O
the	O
centre	O
of	O
a	O
target	O
,	O
subdivided	O
in	O
concentric	O
circles	O
,	O
from	O
5	O
m	O
distance	O
.	O

The	O
circle	O
in	O
which	O
the	O
participant	O
succeeded	O
to	O
aim	O
was	O
recorded	O
in	O
millimetres	O
radius	O
.	O

In	O
another	O
series	O
of	O
measurements	O
,	O
reproducibility	O
and	O
reference	O
values	O
of	O
the	O
tremor	B-Disease
was	O
assessed	O
in	O
65	O
healthy	O
subjects	O
in	O
three	O
sessions	O
,	O
at	O
9	O
a	O
.	O
m	O
.	O
,	O
4	O
p	O
.	O
m	O
.	O
and	O
9	O
a	O
.	O
m	O
.	O
,	O
respectively	O
,	O
1	O
week	O
later	O
.	O

Postural	O
tremor	B-Disease
was	O
measured	O
with	O
the	O
arm	O
horizontally	O
outstretched	O
rest	O
tremor	B-Disease
with	O
the	O
arm	O
supported	O
by	O
an	O
armrest	O
and	O
finally	O
tremor	B-Disease
was	O
measured	O
after	O
holding	O
a	O
2	O
-	O
kg	O
weight	O
until	O
exhaustion	O
.	O

Inter	O
-	O
observer	O
variability	O
was	O
measured	O
in	O
a	O
series	O
of	O
10	O
healthy	O
subjects	O
.	O

Tremor	B-Disease
was	O
measured	O
simultaneously	O
by	O
two	O
independent	O
observers	O
.	O

RESULTS	O
:	O
Salbutamol	B-Chemical
significantly	O
increased	O
tremor	B-Disease
severity	O
in	O
patients	O
in	O
a	O
dose	O
-	O
dependent	O
way	O
.	O

Within	O
healthy	O
adults	O
no	O
age	O
-	O
dependency	O
could	O
be	O
found	O
(	O
b	O
=	O
0	O
.	O
262	O
mm	O
/	O
year	O
;	O
P	O
=	O
0	O
.	O
72	O
)	O
.	O

There	O
was	O
no	O
agreement	O
between	O
the	O
questionnaire	O
and	O
tremor	B-Disease
severity	O
(	O
r	O
=	O
0	O
.	O
093	O
;	O
P	O
=	O
0	O
.	O
53	O
)	O
.	O

Postural	O
tremor	B-Disease
showed	O
no	O
significant	O
difference	O
between	O
the	O
first	O
and	O
third	O
session	O
(	O
P	O
=	O
0	O
.	O
07	O
)	O
.	O

Support	O
of	O
the	O
arm	O
decreased	O
tremor	B-Disease
severity	O
,	O
exhaustion	O
increased	O
tremor	B-Disease
severity	O
significantly	O
.	O

A	O
good	O
agreement	O
was	O
found	O
between	O
two	O
independent	O
observers	O
(	O
interclass	O
correlation	O
coefficient	O
0	O
.	O
72	O
)	O
.	O

DISCUSSION	O
:	O
Quantifying	O
tremor	B-Disease
by	O
using	O
an	O
inexpensive	O
laser	O
pointer	O
is	O
,	O
with	O
the	O
exception	O
of	O
children	O
(	O
<	O
12	O
years	O
)	O
a	O
sensitive	O
and	O
reproducible	O
method	O
.	O

Safety	O
and	O
adverse	O
effects	O
associated	O
with	O
raloxifene	B-Chemical
:	O
multiple	O
outcomes	O
of	O
raloxifene	B-Chemical
evaluation	O
.	O

OBJECTIVE	O
:	O
To	O
examine	O
the	O
effect	O
of	O
raloxifene	B-Chemical
on	O
major	O
adverse	O
events	O
that	O
occur	O
with	O
postmenopausal	O
estrogen	B-Chemical
therapy	O
or	O
tamoxifen	B-Chemical
.	O

METHODS	O
:	O
The	O
Multiple	O
Outcomes	O
of	O
Raloxifene	B-Chemical
Evaluation	O
,	O
a	O
multicenter	O
,	O
randomized	O
,	O
double	O
-	O
blind	O
trial	O
,	O
enrolled	O
7	O
,	O
705	O
postmenopausal	O
women	O
with	O
osteoporosis	B-Disease
.	O

Women	O
were	O
randomly	O
assigned	O
to	O
raloxifene	B-Chemical
60	O
mg	O
/	O
d	O
or	O
120	O
mg	O
/	O
d	O
or	O
placebo	O
.	O

Outcomes	O
included	O
venous	B-Disease
thromboembolism	I-Disease
,	O
cataracts	B-Disease
,	O
gallbladder	B-Disease
disease	I-Disease
,	O
and	O
endometrial	B-Disease
hyperplasia	I-Disease
or	I-Disease
cancer	I-Disease
.	O

RESULTS	O
:	O
During	O
a	O
mean	O
follow	O
-	O
up	O
of	O
3	O
.	O
3	O
years	O
,	O
raloxifene	B-Chemical
was	O
associated	O
with	O
an	O
increased	O
risk	O
for	O
venous	B-Disease
thromboembolism	I-Disease
(	O
relative	O
risk	O
[	O
RR	O
]	O
2	O
.	O
1	O
;	O
95	O
%	O
confidence	O
interval	O
[	O
CI	O
]	O
1	O
.	O
2	O
-	O
3	O
.	O
8	O
)	O
.	O

The	O
excess	O
event	O
rate	O
was	O
1	O
.	O
8	O
per	O
1	O
,	O
000	O
woman	O
-	O
years	O
(	O
95	O
%	O
CI	O
-	O
0	O
.	O
5	O
-	O
4	O
.	O
1	O
)	O
,	O
and	O
the	O
number	O
needed	O
to	O
treat	O
to	O
cause	O
1	O
event	O
was	O
170	O
(	O
95	O
%	O
CI	O
100	O
-	O
582	O
)	O
over	O
3	O
.	O
3	O
years	O
.	O

Risk	O
in	O
the	O
raloxifene	B-Chemical
group	O
was	O
higher	O
than	O
in	O
the	O
placebo	O
group	O
for	O
the	O
first	O
2	O
years	O
,	O
but	O
decreased	O
to	O
about	O
the	O
same	O
rate	O
as	O
in	O
the	O
placebo	O
group	O
thereafter	O
.	O

Raloxifene	B-Chemical
did	O
not	O
increase	O
risk	O
for	O
cataracts	B-Disease
(	O
RR	O
0	O
.	O
9	O
;	O
95	O
%	O
CI	O
0	O
.	O
8	O
-	O
1	O
.	O
1	O
)	O
,	O
gallbladder	B-Disease
disease	I-Disease
(	O
RR	O
1	O
.	O
0	O
;	O
95	O
%	O
CI	O
0	O
.	O
7	O
-	O
1	O
.	O
3	O
)	O
,	O
endometrial	B-Disease
hyperplasia	I-Disease
(	O
RR	O
1	O
.	O
3	O
;	O
95	O
%	O
CI	O
0	O
.	O
4	O
-	O
5	O
.	O
1	O
)	O
,	O
or	O
endometrial	B-Disease
cancer	I-Disease
(	O
RR	O
0	O
.	O
9	O
;	O
95	O
%	O
CI	O
0	O
.	O
3	O
-	O
2	O
.	O
7	O
)	O
.	O

CONCLUSION	O
:	O
Raloxifene	B-Chemical
was	O
associated	O
with	O
an	O
increased	O
risk	O
for	O
venous	B-Disease
thromboembolism	I-Disease
,	O
but	O
there	O
was	O
no	O
increased	O
risk	O
for	O
cataracts	B-Disease
,	O
gallbladder	B-Disease
disease	I-Disease
,	O
endometrial	B-Disease
hyperplasia	I-Disease
,	O
or	O
endometrial	B-Disease
cancer	I-Disease
.	O

LEVEL	O
OF	O
EVIDENCE	O
:	O
I	O

Optimization	O
of	O
levodopa	B-Chemical
therapy	O
.	O

While	O
there	O
is	O
no	O
single	O
correct	O
starting	O
dose	O
for	O
levodopa	B-Chemical
therapy	O
,	O
many	O
individuals	O
can	O
be	O
started	O
on	O
either	O
the	O
25	O
/	O
100	O
or	O
controlled	O
-	O
release	O
formula	O
,	O
following	O
the	O
general	O
rule	O
not	O
to	O
attempt	O
to	O
titrate	O
carbidopa	B-Chemical
-	O
levodopa	B-Chemical
to	O
the	O
point	O
of	O
"	O
normality	O
,	O
"	O
which	O
can	O
lead	O
to	O
toxicity	B-Disease
.	O

The	O
physician	O
should	O
also	O
determine	O
the	O
proper	O
use	O
of	O
any	O
adjunctive	O
medications	O
;	O
such	O
combined	O
therapy	O
has	O
become	O
the	O
standard	O
approach	O
to	O
treatment	O
.	O

Following	O
the	O
initial	O
period	O
of	O
therapy	O
,	O
emerging	O
difficulties	O
require	O
a	O
reassessment	O
of	O
therapeutic	O
approaches	O
,	O
such	O
as	O
dosage	O
adjustment	O
or	O
introduction	O
of	O
a	O
dopamine	B-Chemical
agonist	O
.	O

Other	O
possible	O
adverse	O
effects	O
-	O
-	O
such	O
as	O
gastrointestinal	B-Disease
disorders	I-Disease
,	O
orthostatic	B-Disease
hypotension	I-Disease
,	O
levodopa	B-Chemical
-	O
induced	O
psychosis	B-Disease
,	O
sleep	B-Disease
disturbances	I-Disease
or	O
parasomnias	B-Disease
,	O
or	O
drug	O
interactions	O
-	O
-	O
also	O
require	O
carefully	O
monitored	O
individual	O
treatment	O
.	O

Nonpharmacologic	O
concerns	O
can	O
help	O
the	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
patient	O
achieve	O
and	O
maintain	O
optimal	O
functioning	O
,	O
including	O
daily	O
exercise	O
,	O
physical	O
therapy	O
,	O
and	O
involvement	O
with	O
support	O
groups	O
.	O

Long	O
term	O
audiological	O
evaluation	O
of	O
beta	B-Disease
-	I-Disease
thalassemic	I-Disease
patients	O
.	O

OBJECTIVE	O
:	O
The	O
objective	O
of	O
this	O
study	O
was	O
to	O
identify	O
the	O
incidence	O
and	O
to	O
monitor	O
the	O
progression	O
of	O
hearing	B-Disease
loss	I-Disease
in	O
children	O
and	O
young	O
adults	O
with	O
beta	B-Disease
-	I-Disease
thalassemia	I-Disease
major	O
.	O

METHODS	O
:	O
One	O
hundred	O
and	O
four	O
(	O
104	O
)	O
patients	O
aged	O
6	O
-	O
35	O
years	O
(	O
mean	O
17	O
,	O
2	O
years	O
)	O
participated	O
in	O
the	O
study	O
.	O

All	O
patients	O
were	O
on	O
a	O
regular	O
transfusion	O
-	O
chelation	O
program	O
maintaining	O
a	O
mean	O
hemoglobin	O
level	O
of	O
9	O
.	O
5	O
gr	O
/	O
dl	O
.	O

Subjects	O
were	O
receiving	O
desferrioxamine	B-Chemical
(	O
DFO	B-Chemical
)	O
chelation	O
treatment	O
with	O
a	O
mean	O
daily	O
dose	O
of	O
50	O
-	O
60	O
mg	O
/	O
kg	O
,	O
5	O
-	O
6	O
days	O
a	O
week	O
during	O
the	O
first	O
six	O
years	O
of	O
the	O
study	O
,	O
which	O
was	O
then	O
reduced	O
to	O
40	O
-	O
50	O
mg	O
/	O
kg	O
for	O
the	O
following	O
eight	O
years	O
.	O

Patients	O
were	O
followed	O
for	O
8	O
-	O
14	O
years	O
.	O

RESULTS	O
:	O
Overall	O
,	O
21	O
out	O
of	O
104	O
patients	O
(	O
20	O
.	O
2	O
%	O
)	O
presented	O
with	O
high	O
frequency	O
sensorineural	B-Disease
hearing	I-Disease
loss	I-Disease
(	O
SNHL	B-Disease
)	O
,	O
either	O
unilateral	O
or	O
bilateral	O
.	O

No	O
ototoxic	B-Disease
factor	O
,	O
other	O
than	O
DFO	B-Chemical
,	O
was	O
present	O
in	O
any	O
of	O
the	O
patients	O
.	O

Patients	O
with	O
SNHL	B-Disease
presented	O
with	O
relatively	O
lower	O
serum	O
ferritin	O
levels	O
than	O
those	O
with	O
normal	O
hearing	O
,	O
however	O
,	O
no	O
statistically	O
significant	O
difference	O
was	O
observed	O
.	O

Subjects	O
with	O
SNHL	B-Disease
were	O
submitted	O
to	O
DFO	B-Chemical
reduction	O
or	O
temporary	O
withdrawal	O
.	O

Following	O
intervention	O
,	O
7	O
out	O
of	O
21	O
affected	O
patients	O
recovered	O
,	O
10	O
remained	O
stable	O
and	O
4	O
demonstrated	O
aggravation	O
.	O

CONCLUSION	O
:	O
The	O
findings	O
are	O
indicative	O
of	O
DFO	B-Chemical
'	O
s	O
contributing	O
role	O
in	O
the	O
development	O
of	O
hearing	B-Disease
impairment	I-Disease
.	O

Regular	O
audiologic	O
evaluation	O
is	O
imperative	O
in	O
all	O
thalassemic	B-Disease
patients	O
so	O
that	O
early	O
changes	O
may	O
be	O
recognized	O
and	O
treatment	O
may	O
be	O
judiciously	O
adjusted	O
in	O
order	O
to	O
prevent	O
or	O
reverse	O
hearing	B-Disease
impairment	I-Disease
.	O

Individual	O
differences	O
in	O
renal	O
ACE	O
activity	O
in	O
healthy	O
rats	O
predict	O
susceptibility	O
to	O
adriamycin	B-Chemical
-	O
induced	O
renal	B-Disease
damage	I-Disease
.	O

BACKGROUND	O
:	O
In	O
man	O
,	O
differences	O
in	O
angiotensin	B-Chemical
-	O
converting	O
enzyme	O
(	O
ACE	O
)	O
levels	O
,	O
related	O
to	O
ACE	O
(	O
I	O
/	O
D	O
)	O
genotype	O
,	O
are	O
associated	O
with	O
renal	O
prognosis	O
.	O

This	O
raises	O
the	O
hypothesis	O
that	O
individual	O
differences	O
in	O
renal	O
ACE	O
activity	O
are	O
involved	O
in	O
renal	O
susceptibility	O
to	O
inflicted	O
damage	O
.	O

Therefore	O
,	O
we	O
studied	O
the	O
predictive	O
effect	O
of	O
renal	O
ACE	O
activity	O
for	O
the	O
severity	O
of	O
renal	B-Disease
damage	I-Disease
induced	O
by	O
a	O
single	O
injection	O
of	O
adriamycin	B-Chemical
in	O
rats	O
.	O

METHODS	O
:	O
Renal	O
ACE	O
activity	O
(	O
Hip	B-Chemical
-	I-Chemical
His	I-Chemical
-	I-Chemical
Leu	I-Chemical
cleavage	O
by	O
cortical	O
homogenates	O
)	O
was	O
determined	O
by	O
renal	O
biopsy	O
in	O
27	O
adult	O
male	O
Wistar	O
rats	O
.	O

After	O
1	O
week	O
of	O
recovery	O
,	O
proteinuria	B-Disease
was	O
induced	O
by	O
adriamycin	B-Chemical
[	O
1	O
.	O
5	O
mg	O
/	O
kg	O
intravenously	O
(	O
i	O
.	O
v	O
.	O
)	O
n	O
=	O
18	O
;	O
controls	O
,	O
saline	O
i	O
.	O
v	O
.	O
n	O
=	O
9	O
]	O
.	O

Proteinuria	B-Disease
was	O
measured	O
every	O
2	O
weeks	O
.	O

After	O
12	O
weeks	O
,	O
rats	O
were	O
sacrificed	O
and	O
their	O
kidneys	O
harvested	O
.	O

RESULTS	O
:	O
As	O
anticipated	O
,	O
adriamycin	B-Chemical
elicited	O
nephrotic	B-Disease
range	O
proteinuria	B-Disease
,	O
renal	B-Disease
interstitial	I-Disease
damage	I-Disease
and	O
mild	O
focal	B-Disease
glomerulosclerosis	I-Disease
.	O

Baseline	O
renal	O
ACE	O
positively	O
correlated	O
with	O
the	O
relative	O
rise	O
in	O
proteinuria	B-Disease
after	O
adriamycin	B-Chemical
(	O
r	O
=	O
0	O
.	O
62	O
,	O
P	O
<	O
0	O
.	O
01	O
)	O
,	O
renal	O
interstitial	O
alpha	O
-	O
smooth	O
muscle	O
actin	O
(	O
r	O
=	O
0	O
.	O
49	O
,	O
P	O
<	O
0	O
.	O
05	O
)	O
,	O
interstitial	O
macrophage	O
influx	O
(	O
r	O
=	O
0	O
.	O
56	O
,	O
P	O
<	O
0	O
.	O
05	O
)	O
,	O
interstitial	O
collagen	O
III	O
(	O
r	O
=	O
0	O
.	O
53	O
,	O
P	O
<	O
0	O
.	O
05	O
)	O
,	O
glomerular	O
alpha	O
-	O
smooth	O
muscle	O
actin	O
(	O
r	O
=	O
0	O
.	O
74	O
,	O
P	O
<	O
0	O
.	O
01	O
)	O
and	O
glomerular	O
desmin	O
(	O
r	O
=	O
0	O
.	O
48	O
,	O
P	O
<	O
0	O
.	O
05	O
)	O
.	O

Baseline	O
renal	O
ACE	O
did	O
not	O
correlate	O
with	O
focal	B-Disease
glomerulosclerosis	I-Disease
(	O
r	O
=	O
0	O
.	O
22	O
,	O
NS	O
)	O
.	O

In	O
controls	O
,	O
no	O
predictive	O
values	O
for	O
renal	O
parameters	O
were	O
observed	O
.	O

CONCLUSION	O
:	O
Individual	O
differences	O
in	O
renal	O
ACE	O
activity	O
predict	O
the	O
severity	O
of	O
adriamycin	B-Chemical
-	O
induced	O
renal	B-Disease
damage	I-Disease
in	O
this	O
outbred	O
rat	O
strain	O
.	O

This	O
supports	O
the	O
assumption	O
that	O
differences	O
in	O
renal	O
ACE	O
activity	O
predispose	O
to	O
a	O
less	O
favourable	O
course	O
of	O
renal	B-Disease
damage	I-Disease
.	O

Recurrent	O
acute	O
interstitial	B-Disease
nephritis	I-Disease
induced	O
by	O
azithromycin	B-Chemical
.	O

A	O
14	O
-	O
year	O
-	O
old	O
girl	O
is	O
reported	O
with	O
recurrent	O
,	O
azithromycin	B-Chemical
-	O
induced	O
,	O
acute	O
interstitial	B-Disease
nephritis	I-Disease
.	O

The	O
second	O
episode	O
was	O
more	O
severe	O
than	O
the	O
first	O
;	O
and	O
although	O
both	O
were	O
treated	O
with	O
intensive	O
corticosteroid	O
therapy	O
,	O
renal	O
function	O
remained	O
impaired	O
.	O

Although	O
most	O
cases	O
of	O
antibiotic	O
induced	O
acute	O
interstitial	B-Disease
nephritis	I-Disease
are	O
benign	O
and	O
self	O
-	O
limited	O
,	O
some	O
patients	O
are	O
at	O
risk	O
for	O
permanent	O
renal	B-Disease
injury	I-Disease
.	O

Spironolactone	B-Chemical
-	O
induced	O
renal	B-Disease
insufficiency	I-Disease
and	O
hyperkalemia	B-Disease
in	O
patients	O
with	O
heart	B-Disease
failure	I-Disease
.	O

BACKGROUND	O
:	O
A	O
previous	O
randomized	O
controlled	O
trial	O
evaluating	O
the	O
use	O
of	O
spironolactone	B-Chemical
in	O
heart	B-Disease
failure	I-Disease
patients	O
reported	O
a	O
low	O
risk	O
of	O
hyperkalemia	B-Disease
(	O
2	O
%	O
)	O
and	O
renal	B-Disease
insufficiency	I-Disease
(	O
0	O
%	O
)	O
.	O

Because	O
treatments	O
for	O
heart	B-Disease
failure	I-Disease
have	O
changed	O
since	O
the	O
benefits	O
of	O
spironolactone	B-Chemical
were	O
reported	O
,	O
the	O
prevalence	O
of	O
these	O
complications	O
may	O
differ	O
in	O
current	O
clinical	O
practice	O
.	O

We	O
therefore	O
sought	O
to	O
determine	O
the	O
prevalence	O
and	O
clinical	O
associations	O
of	O
hyperkalemia	B-Disease
and	O
renal	B-Disease
insufficiency	I-Disease
in	O
heart	B-Disease
failure	I-Disease
patients	O
treated	O
with	O
spironolactone	B-Chemical
.	O

METHODS	O
:	O
We	O
performed	O
a	O
case	O
control	O
study	O
of	O
heart	B-Disease
failure	I-Disease
patients	O
treated	O
with	O
spironolactone	B-Chemical
in	O
our	O
clinical	O
practice	O
.	O

Cases	O
were	O
patients	O
who	O
developed	O
hyperkalemia	B-Disease
(	O
K	B-Chemical
(	O
+	O
)	O
>	O
5	O
.	O
0	O
mEq	O
/	O
L	O
)	O
or	O
renal	B-Disease
insufficiency	I-Disease
(	O
Cr	B-Chemical
>	O
or	O
=	O
2	O
.	O
5	O
mg	O
/	O
dL	O
)	O
,	O
and	O
they	O
were	O
compared	O
to	O
2	O
randomly	O
selected	O
controls	O
per	O
case	O
.	O

Clinical	O
characteristics	O
,	O
medications	O
,	O
and	O
serum	O
chemistries	O
at	O
baseline	O
and	O
follow	O
-	O
up	O
time	O
periods	O
were	O
compared	O
.	O

RESULTS	O
:	O
Sixty	O
-	O
seven	O
of	O
926	O
patients	O
(	O
7	O
.	O
2	O
%	O
)	O
required	O
discontinuation	O
of	O
spironolactone	B-Chemical
due	O
to	O
hyperkalemia	B-Disease
(	O
n	O
=	O
33	O
)	O
or	O
renal	B-Disease
failure	I-Disease
(	O
n	O
=	O
34	O
)	O
.	O

Patients	O
who	O
developed	O
hyperkalemia	B-Disease
were	O
older	O
and	O
more	O
likely	O
to	O
have	O
diabetes	B-Disease
,	O
had	O
higher	O
baseline	O
serum	O
potassium	B-Chemical
levels	O
and	O
lower	O
baseline	O
potassium	B-Chemical
supplement	O
doses	O
,	O
and	O
were	O
more	O
likely	O
to	O
be	O
treated	O
with	O
beta	O
-	O
blockers	O
than	O
controls	O
(	O
n	O
=	O
134	O
)	O
.	O

Patients	O
who	O
developed	O
renal	B-Disease
insufficiency	I-Disease
had	O
lower	O
baseline	O
body	O
weight	O
and	O
higher	O
baseline	O
serum	O
creatinine	B-Chemical
,	O
required	O
higher	O
doses	O
of	O
loop	O
diuretics	O
,	O
and	O
were	O
more	O
likely	O
to	O
be	O
treated	O
with	O
thiazide	B-Chemical
diuretics	O
than	O
controls	O
.	O

CONCLUSIONS	O
:	O
Spironolactone	B-Chemical
-	O
induced	O
hyperkalemia	B-Disease
and	O
renal	B-Disease
insufficiency	I-Disease
are	O
more	O
common	O
in	O
our	O
clinical	O
experience	O
than	O
reported	O
previously	O
.	O

This	O
difference	O
is	O
explained	O
by	O
patient	O
comorbidities	O
and	O
more	O
frequent	O
use	O
of	O
beta	O
-	O
blockers	O
.	O

Acute	O
reserpine	B-Chemical
and	O
subchronic	O
haloperidol	B-Chemical
treatments	O
change	O
synaptosomal	O
brain	O
glutamate	B-Chemical
uptake	O
and	O
elicit	O
orofacial	B-Disease
dyskinesia	I-Disease
in	O
rats	O
.	O

Reserpine	B-Chemical
-	O
and	O
haloperidol	B-Chemical
-	O
induced	O
orofacial	B-Disease
dyskinesia	I-Disease
are	O
putative	O
animal	O
models	O
of	O
tardive	B-Disease
dyskinesia	I-Disease
(	O
TD	B-Disease
)	O
whose	O
pathophysiology	O
has	O
been	O
related	O
to	O
free	O
radical	O
generation	O
and	O
oxidative	O
stress	O
.	O

In	O
the	O
present	O
study	O
,	O
the	O
authors	O
induced	O
orofacial	B-Disease
dyskinesia	I-Disease
by	O
acute	O
reserpine	B-Chemical
and	O
subchronic	O
haloperidol	B-Chemical
administration	O
to	O
rats	O
.	O

Reserpine	B-Chemical
injection	O
(	O
one	O
dose	O
of	O
1	O
mg	O
/	O
kg	O
s	O
.	O
c	O
.	O
)	O
every	O
other	O
day	O
for	O
3	O
days	O
caused	O
a	O
significant	O
increase	O
in	O
vacuous	O
chewing	O
,	O
tongue	O
protrusion	O
and	O
duration	O
of	O
facial	O
twitching	O
,	O
compared	O
to	O
the	O
control	O
.	O

Haloperidol	B-Chemical
administration	O
(	O
one	O
dose	O
of	O
12	O
mg	O
/	O
kg	O
once	O
a	O
week	O
s	O
.	O
c	O
.	O
)	O
for	O
4	O
weeks	O
caused	O
an	O
increase	O
in	O
vacuous	O
chewing	O
,	O
tongue	O
protrusion	O
and	O
duration	O
of	O
facial	O
twitching	O
observed	O
in	O
four	O
weekly	O
evaluations	O
.	O

After	O
the	O
treatments	O
and	O
behavioral	O
observation	O
,	O
glutamate	B-Chemical
uptake	O
by	O
segments	O
of	O
the	O
brain	O
was	O
analyzed	O
.	O

A	O
decreased	O
glutamate	B-Chemical
uptake	O
was	O
observed	O
in	O
the	O
subcortical	O
parts	O
of	O
animals	O
treated	O
with	O
reserpine	B-Chemical
and	O
haloperidol	B-Chemical
,	O
compared	O
to	O
the	O
control	O
.	O

Importantly	O
,	O
a	O
decrease	O
in	O
glutamate	B-Chemical
uptake	O
correlates	O
negatively	O
with	O
an	O
increase	O
in	O
the	O
incidence	O
of	O
orofacial	B-Disease
diskinesia	I-Disease
.	O

These	O
results	O
indicate	O
that	O
early	O
changes	O
in	O
glutamate	B-Chemical
transport	O
may	O
be	O
related	O
to	O
the	O
development	O
of	O
vacuous	O
chewing	O
movements	O
in	O
rats	O
.	O

Ceftriaxone	B-Chemical
-	O
associated	O
biliary	B-Disease
pseudolithiasis	I-Disease
in	O
paediatric	O
surgical	O
patients	O
.	O

It	O
is	O
well	O
known	O
that	O
ceftriaxone	B-Chemical
leads	O
to	O
pseudolithiasis	B-Disease
in	O
some	O
patients	O
.	O

Clinical	O
and	O
experimental	O
studies	O
also	O
suggest	O
that	O
situations	O
causing	O
gallbladder	B-Disease
dysfunction	I-Disease
,	O
such	O
as	O
fasting	O
,	O
may	O
have	O
a	O
role	O
for	O
the	O
development	O
of	O
pseudolithiasis	B-Disease
.	O

In	O
this	O
study	O
,	O
we	O
prospectively	O
evaluated	O
the	O
incidence	O
and	O
clinical	O
importance	O
of	O
pseudolithiasis	B-Disease
in	O
paediatric	O
surgical	O
patients	O
receiving	O
ceftriaxone	B-Chemical
treatment	O
,	O
who	O
often	O
had	O
to	O
fast	O
in	O
the	O
post	O
-	O
operative	O
period	O
.	O

Fifty	O
children	O
who	O
were	O
given	O
ceftriaxone	B-Chemical
were	O
evaluated	O
by	O
serial	O
abdominal	O
sonograms	O
.	O

Of	O
those	O
,	O
13	O
(	O
26	O
%	O
)	O
developed	O
biliary	O
pathology	O
.	O

Comparison	O
of	O
the	O
patients	O
with	O
or	O
without	O
pseudolithiasis	B-Disease
revealed	O
no	O
significant	O
difference	O
with	O
respect	O
to	O
age	O
,	O
sex	O
,	O
duration	O
of	O
the	O
treatment	O
and	O
starvation	O
variables	O
.	O

After	O
cessation	O
of	O
the	O
treatment	O
,	O
pseudolithiasis	B-Disease
resolved	O
spontaneously	O
within	O
a	O
short	O
period	O
.	O

The	O
incidence	O
of	O
pseudolithiasis	B-Disease
is	O
not	O
affected	O
by	O
fasting	O
.	O

Coronary	B-Disease
aneurysm	I-Disease
after	O
implantation	O
of	O
a	O
paclitaxel	B-Chemical
-	O
eluting	O
stent	O
.	O

Formation	O
of	O
coronary	B-Disease
aneurysm	I-Disease
is	O
a	O
rare	O
complication	O
of	O
stenting	O
with	O
bare	O
metal	O
stents	O
,	O
but	O
based	O
on	O
experimental	O
studies	O
drug	O
-	O
eluting	O
stents	O
may	O
induce	O
toxic	O
effects	O
on	O
the	O
vessel	O
wall	O
with	O
incomplete	O
stent	O
apposition	O
,	O
aneurysm	B-Disease
formation	O
and	O
with	O
the	O
potential	O
of	O
stent	O
thrombosis	B-Disease
or	O
vessel	B-Disease
rupture	I-Disease
.	O

We	O
present	O
a	O
43	O
-	O
year	O
-	O
old	O
man	O
who	O
developed	O
a	O
coronary	B-Disease
aneurysm	I-Disease
in	O
the	O
right	O
coronary	O
artery	O
6	O
months	O
after	O
receiving	O
a	O
paclitaxel	B-Chemical
-	O
eluting	O
stent	O
.	O

The	O
patient	O
was	O
asymptomatic	O
and	O
the	O
aneurysm	B-Disease
was	O
detected	O
in	O
a	O
routine	O
control	O
.	O

Angiography	O
and	O
intracoronary	O
ultrasound	O
demonstrated	O
lack	O
of	O
contact	O
between	O
stent	O
and	O
vessel	O
wall	O
in	O
a	O
15	O
-	O
mm	O
long	O
segment	O
with	O
maximal	O
aneurysm	B-Disease
diameter	O
of	O
6	O
.	O
0	O
mm	O
.	O

The	O
patient	O
was	O
successfully	O
treated	O
with	O
a	O
graft	O
stent	O
.	O

Causes	O
of	O
acute	O
thrombotic	B-Disease
microangiopathy	I-Disease
in	O
patients	O
receiving	O
kidney	O
transplantation	O
.	O

OBJECTIVES	O
:	O
Thrombotic	B-Disease
microangiopathy	I-Disease
is	O
a	O
well	O
-	O
known	O
problem	O
in	O
patients	O
following	O
renal	O
transplantation	O
.	O

In	O
postrenal	O
transplantation	O
,	O
thrombotic	B-Disease
microangiopathy	I-Disease
is	O
often	O
a	O
reflection	O
of	O
hemolytic	B-Disease
uremic	I-Disease
syndrome	I-Disease
.	O

We	O
aimed	O
to	O
determine	O
the	O
causes	O
of	O
thrombotic	B-Disease
microangiopathy	I-Disease
in	O
a	O
population	O
of	O
renal	O
transplantation	O
recipients	O
and	O
discuss	O
the	O
literature	O
.	O

MATERIALS	O
AND	O
METHODS	O
:	O
We	O
investigated	O
the	O
causes	O
of	O
thrombotic	B-Disease
microangiopathy	I-Disease
during	O
a	O
1	O
-	O
year	O
period	O
,	O
from	O
June	O
2003	O
to	O
June	O
2004	O
,	O
at	O
the	O
King	O
Fahad	O
National	O
Guard	O
Hospital	O
in	O
Riyadh	O
,	O
Saudi	O
Arabia	O
,	O
by	O
reviewing	O
the	O
slides	O
of	O
all	O
transplant	O
biopsies	O
(	O
n	O
=	O
25	O
)	O
performed	O
during	O
this	O
interval	O
.	O

Pre	O
-	O
and	O
posttransplant	O
crossmatching	O
was	O
done	O
when	O
possible	O
.	O

RESULTS	O
:	O
Five	O
cases	O
of	O
thrombotic	B-Disease
microangiopathy	I-Disease
were	O
found	O
.	O

Three	O
of	O
these	O
cases	O
were	O
from	O
the	O
25	O
transplantations	O
performed	O
at	O
King	O
Fahad	O
National	O
Guard	O
Hospital	O
,	O
while	O
the	O
other	O
2	O
transplantations	O
had	O
been	O
performed	O
abroad	O
and	O
were	O
referred	O
to	O
us	O
for	O
follow	O
-	O
up	O
.	O

Three	O
cases	O
were	O
related	O
to	O
cyclosporine	B-Chemical
,	O
and	O
1	O
case	O
was	O
secondary	O
to	O
both	O
cyclosporine	B-Chemical
and	O
tacrolimus	B-Chemical
.	O

The	O
fifth	O
case	O
had	O
features	O
of	O
thrombotic	B-Disease
microangiopathy	I-Disease
related	O
to	O
an	O
antiphospholipid	B-Disease
syndrome	I-Disease
in	O
a	O
patient	O
with	O
systemic	B-Disease
lupus	I-Disease
erythematosus	I-Disease
.	O

CONCLUSIONS	O
:	O
In	O
the	O
literature	O
,	O
the	O
most	O
-	O
frequent	O
cause	O
of	O
hemolytic	B-Disease
uremic	I-Disease
syndrome	I-Disease
in	O
patients	O
following	O
renal	O
transplantation	O
is	O
recurrence	O
of	O
the	O
hemolytic	B-Disease
uremic	I-Disease
syndrome	I-Disease
.	O

Other	O
causes	O
include	O
drug	O
-	O
related	O
(	O
cyclosporine	B-Chemical
,	O
tacrolimus	B-Chemical
)	O
toxicity	B-Disease
,	O
procoagulant	O
status	O
,	O
and	O
antibody	O
-	O
mediated	O
rejection	O
.	O

We	O
found	O
that	O
the	O
most	O
-	O
frequent	O
cause	O
of	O
thrombotic	B-Disease
microangiopathy	I-Disease
was	O
drug	O
related	O
,	O
secondary	O
mainly	O
to	O
cyclosporine	B-Chemical
.	O

In	O
the	O
current	O
study	O
,	O
the	O
frequency	O
of	O
thrombotic	B-Disease
microangiopathy	I-Disease
was	O
similar	O
to	O
the	O
percentage	O
reported	O
in	O
the	O
literature	O
(	O
20	O
%	O
)	O
.	O

Comparison	O
of	O
developmental	O
toxicity	B-Disease
of	O
selective	O
and	O
non	O
-	O
selective	O
cyclooxygenase	O
-	O
2	O
inhibitors	O
in	O
CRL	O
:	O
(	O
WI	O
)	O
WUBR	O
Wistar	O
rats	O
-	O
-	O
DFU	B-Chemical
and	O
piroxicam	B-Chemical
study	O
.	O

BACKGROUND	O
:	O
Cyclooxygenase	O
(	O
COX	O
)	O
inhibitors	O
are	O
one	O
of	O
the	O
most	O
often	O
ingested	O
drugs	O
during	O
pregnancy	O
.	O

Unlike	O
general	O
toxicity	B-Disease
data	O
,	O
their	O
prenatal	O
toxic	O
effects	O
were	O
not	O
extensively	O
studied	O
before	O
.	O

The	O
aim	O
of	O
the	O
experiment	O
was	O
to	O
evaluate	O
the	O
developmental	O
toxicity	B-Disease
of	O
the	O
non	O
-	O
selective	O
(	O
piroxicam	B-Chemical
)	O
and	O
selective	O
(	O
DFU	B-Chemical
;	O
5	B-Chemical
,	I-Chemical
5	I-Chemical
-	I-Chemical
dimethyl	I-Chemical
-	I-Chemical
3	I-Chemical
-	I-Chemical
(	I-Chemical
3	I-Chemical
-	I-Chemical
fluorophenyl	I-Chemical
)	I-Chemical
-	I-Chemical
4	I-Chemical
-	I-Chemical
(	I-Chemical
4	I-Chemical
-	I-Chemical
methylsulphonyl	I-Chemical
)	I-Chemical
phenyl	I-Chemical
-	I-Chemical
2	I-Chemical
(	I-Chemical
5H	I-Chemical
)	I-Chemical
-	I-Chemical
furanon	I-Chemical
)	O
COX	O
-	O
2	O
inhibitors	O
.	O

METHODS	O
:	O
Drugs	O
were	O
separately	O
,	O
orally	O
once	O
daily	O
dosed	O
to	O
pregnant	O
rats	O
from	O
day	O
8	O
to	O
21	O
(	O
GD1	O
=	O
plug	O
day	O
)	O
.	O

Doses	O
were	O
set	O
at	O
0	O
.	O
3	O
,	O
3	O
.	O
0	O
and	O
30	O
.	O
0mg	O
/	O
kg	O
for	O
piroxicam	B-Chemical
and	O
0	O
.	O
2	O
,	O
2	O
.	O
0	O
and	O
20	O
.	O
0mg	O
/	O
kg	O
for	O
DFU	B-Chemical
.	O

Fetuses	O
were	O
delivered	O
on	O
GD	O
21	O
and	O
routinely	O
examined	O
.	O

Comprehensive	O
clinical	O
and	O
developmental	O
measurements	O
were	O
done	O
.	O

The	O
pooled	O
statistical	O
analysis	O
for	O
ventricular	B-Disease
septal	I-Disease
(	I-Disease
VSD	I-Disease
)	I-Disease
and	I-Disease
midline	I-Disease
(	I-Disease
MD	I-Disease
)	I-Disease
defects	I-Disease
was	O
performed	O
for	O
rat	O
fetuses	O
exposed	O
to	O
piroxicam	B-Chemical
,	O
selective	O
and	O
non	O
-	O
selective	O
COX	O
-	O
2	O
inhibitor	O
based	O
on	O
present	O
and	O
historic	O
data	O
.	O

RESULTS	O
:	O
Maternal	O
toxicity	B-Disease
,	O
intrauterine	B-Disease
growth	I-Disease
retardation	I-Disease
,	O
and	O
increase	B-Disease
of	I-Disease
external	I-Disease
and	I-Disease
skeletal	I-Disease
variations	I-Disease
were	O
found	O
in	O
rats	O
treated	O
with	O
the	O
highest	O
dose	O
of	O
piroxicam	B-Chemical
.	O

Decrease	O
of	O
fetal	O
length	O
was	O
the	O
only	O
signs	O
of	O
the	O
DFU	B-Chemical
developmental	O
toxicity	B-Disease
observed	O
in	O
pups	O
exposed	O
to	O
the	O
highest	O
compound	O
dose	O
.	O

Lack	O
of	O
teratogenicity	O
was	O
found	O
in	O
piroxicam	B-Chemical
and	O
DFU	B-Chemical
-	O
exposed	O
groups	O
.	O

Prenatal	O
exposure	O
to	O
non	O
-	O
selective	O
COX	O
inhibitors	O
increases	O
the	O
risk	O
of	O
VSD	O
and	O
MD	O
when	O
compared	O
to	O
historic	O
control	O
but	O
not	O
with	O
selective	O
COX	O
-	O
2	O
inhibitors	O
.	O

CONCLUSION	O
:	O
Both	O
selective	O
and	O
non	O
-	O
selective	O
COX	O
-	O
2	O
inhibitors	O
were	O
toxic	O
for	O
rats	O
fetuses	O
when	O
administered	O
in	O
the	O
highest	O
dose	O
.	O

Unlike	O
DFU	B-Chemical
,	O
piroxicam	B-Chemical
was	O
also	O
highly	O
toxic	O
to	O
the	O
dams	O
.	O

Prenatal	O
exposure	O
to	O
selective	O
COX	O
-	O
2	O
inhibitors	O
does	O
not	O
increase	O
the	O
risk	O
of	O
ventricular	B-Disease
septal	I-Disease
and	I-Disease
midline	I-Disease
defects	I-Disease
in	O
rat	O
when	O
compared	O
to	O
non	O
-	O
selective	O
drugs	O
and	O
historic	O
control	O
.	O

Lone	O
atrial	B-Disease
fibrillation	I-Disease
associated	O
with	O
creatine	B-Chemical
monohydrate	O
supplementation	O
.	O

Atrial	B-Disease
fibrillation	I-Disease
in	O
young	O
patients	O
without	O
structural	O
heart	B-Disease
disease	I-Disease
is	O
rare	O
.	O

Therefore	O
,	O
when	O
the	O
arrhythmia	B-Disease
is	O
present	O
in	O
this	O
population	O
,	O
reversible	O
causes	O
must	O
be	O
identified	O
and	O
resolved	O
.	O

Thyroid	B-Disease
disorders	I-Disease
,	O
illicit	O
drug	O
or	O
stimulant	O
use	O
,	O
and	O
acute	B-Disease
alcohol	I-Disease
intoxication	I-Disease
are	O
among	O
these	O
causes	O
.	O

We	O
report	O
the	O
case	O
of	O
a	O
30	O
-	O
year	O
-	O
old	O
Caucasian	O
man	O
who	O
came	O
to	O
the	O
emergency	O
department	O
in	O
atrial	B-Disease
fibrillation	I-Disease
with	O
rapid	O
ventricular	O
response	O
.	O

His	O
medical	O
history	O
was	O
unremarkable	O
,	O
except	O
for	O
minor	O
fractures	B-Disease
of	O
the	O
fingers	O
and	O
foot	O
.	O

Thyroid	O
-	O
stimulating	O
hormone	O
,	O
magnesium	B-Chemical
,	O
and	O
potassium	B-Chemical
levels	O
were	O
within	O
normal	O
limits	O
,	O
urine	O
drug	O
screen	O
was	O
negative	O
,	O
and	O
alcohol	B-Chemical
use	O
was	O
denied	O
.	O

However	O
,	O
when	O
the	O
patient	O
was	O
questioned	O
about	O
use	O
of	O
herbal	O
products	O
and	O
supplements	O
,	O
the	O
use	O
of	O
creatine	B-Chemical
monohydrate	O
was	O
revealed	O
.	O

The	O
patient	O
was	O
admitted	O
to	O
the	O
hospital	O
,	O
anticoagulated	O
with	O
unfractionated	O
heparin	B-Chemical
,	O
and	O
given	O
intravenous	O
diltiazem	B-Chemical
for	O
rate	O
control	O
and	O
intravenous	O
amiodarone	B-Chemical
for	O
rate	O
and	O
rhythm	O
control	O
.	O

When	O
discharged	O
less	O
than	O
24	O
hours	O
later	O
,	O
he	O
was	O
receiving	O
metoprolol	B-Chemical
and	O
aspirin	B-Chemical
,	O
with	O
follow	O
-	O
up	O
plans	O
for	O
echocardiography	O
and	O
nuclear	O
imaging	O
to	O
assess	O
perfusion	O
.	O

Exogenous	O
creatine	B-Chemical
is	O
used	O
by	O
athletes	O
to	O
theoretically	O
improve	O
exercise	O
performance	O
.	O

Vegetarians	O
may	O
also	O
take	O
creatine	B-Chemical
to	O
replace	O
what	O
they	O
are	O
not	O
consuming	O
from	O
meat	O
,	O
fish	O
,	O
and	O
other	O
animal	O
products	O
.	O

Previous	O
anecdotal	O
reports	O
have	O
linked	O
creatine	B-Chemical
to	O
the	O
development	O
of	O
arrhythmia	B-Disease
.	O

Clinicians	O
must	O
be	O
diligent	O
when	O
interviewing	O
patients	O
about	O
their	O
drug	O
therapy	O
histories	O
and	O
include	O
questions	O
about	O
their	O
use	O
of	O
herbal	O
products	O
and	O
dietary	O
supplements	O
.	O

In	O
addition	O
,	O
it	O
is	O
important	O
to	O
report	O
adverse	O
effects	O
associated	O
with	O
frequently	O
consumed	O
supplements	O
and	O
herbal	O
products	O
to	O
the	O
Food	O
and	O
Drug	O
Administration	O
and	O
in	O
the	O
literature	O
.	O

Seizures	B-Disease
induced	O
by	O
the	O
cocaine	B-Chemical
metabolite	O
benzoylecgonine	B-Chemical
in	O
rats	O
.	O

The	O
half	O
-	O
life	O
(	O
t1	O
/	O
2	O
)	O
of	O
cocaine	B-Chemical
is	O
relatively	O
short	O
,	O
but	O
some	O
of	O
the	O
consequences	O
of	O
its	O
use	O
,	O
such	O
as	O
seizures	B-Disease
and	O
strokes	B-Disease
,	O
can	O
occur	O
hours	O
after	O
exposure	O
.	O

This	O
led	O
us	O
to	O
hypothesize	O
that	O
a	O
metabolite	O
of	O
cocaine	B-Chemical
may	O
be	O
responsible	O
for	O
some	O
of	O
those	O
delayed	O
sequelae	O
.	O

We	O
evaluated	O
the	O
potential	O
of	O
the	O
major	O
metabolite	O
of	O
cocaine	B-Chemical
,	O
benzoylecgonine	B-Chemical
(	O
BE	B-Chemical
)	O
,	O
to	O
cause	O
seizures	B-Disease
.	O

Two	O
separate	O
equimolar	O
doses	O
(	O
0	O
.	O
2	O
and	O
0	O
.	O
4	O
mumol	O
)	O
of	O
either	O
cocaine	B-Chemical
or	O
BE	B-Chemical
were	O
injected	O
ventricularly	O
in	O
unanesthetized	O
juvenile	O
rats	O
.	O

Treated	O
rats	O
were	O
then	O
evaluated	O
for	O
incidence	O
,	O
latency	O
,	O
and	O
seizure	B-Disease
pattern	O
or	O
for	O
locomotor	O
activity	O
in	O
animals	O
without	O
seizures	B-Disease
.	O

BE	B-Chemical
-	O
Induced	O
seizures	B-Disease
occurred	O
more	O
frequently	O
and	O
had	O
significantly	O
longer	O
latencies	O
than	O
those	O
induced	O
by	O
equimolar	O
amounts	O
of	O
cocaine	B-Chemical
.	O

Whereas	O
cocaine	B-Chemical
-	O
induced	O
seizures	B-Disease
were	O
best	O
characterized	O
as	O
brief	O
,	O
generalized	O
,	O
and	O
tonic	O
and	O
resulted	O
in	O
death	B-Disease
,	O
those	O
induced	O
by	O
BE	B-Chemical
were	O
prolonged	O
,	O
often	O
multiple	O
and	O
mixed	O
in	O
type	O
,	O
and	O
rarely	O
resulted	O
in	O
death	B-Disease
.	O

Electrical	O
recordings	O
from	O
the	O
hippocampus	O
showed	O
a	O
rhythmic	O
progression	O
in	O
EEG	O
frequency	O
and	O
voltage	O
with	O
clinical	O
seizure	B-Disease
expression	O
.	O

BE	B-Chemical
-	O
Injected	O
rats	O
that	O
did	O
not	O
have	O
seizures	B-Disease
had	O
significantly	O
more	O
locomotor	O
activity	O
than	O
cocaine	B-Chemical
-	O
injected	O
animals	O
without	O
seizures	B-Disease
.	O

The	O
finding	O
that	O
cocaine	B-Chemical
-	O
and	O
BE	B-Chemical
-	O
induced	O
seizures	B-Disease
differ	O
in	O
several	O
respects	O
suggests	O
more	O
than	O
one	O
mechanism	O
for	O
cocaine	B-Chemical
-	O
induced	O
seizures	B-Disease
and	O
emphasizes	O
the	O
importance	O
of	O
a	O
cocaine	B-Chemical
metabolite	O
,	O
BE	B-Chemical
.	O

The	O
selective	O
5	O
-	O
HT6	O
receptor	O
antagonist	O
Ro4368554	B-Chemical
restores	O
memory	O
performance	O
in	O
cholinergic	O
and	O
serotonergic	O
models	O
of	O
memory	B-Disease
deficiency	I-Disease
in	O
the	O
rat	O
.	O

Antagonists	O
at	O
serotonin	B-Chemical
type	O
6	O
(	O
5	B-Chemical
-	I-Chemical
HT	I-Chemical
(	O
6	O
)	O
)	O
receptors	O
show	O
activity	O
in	O
models	O
of	O
learning	O
and	O
memory	O
.	O

Although	O
the	O
underlying	O
mechanism	O
(	O
s	O
)	O
are	O
not	O
well	O
understood	O
,	O
these	O
effects	O
may	O
involve	O
an	O
increase	O
in	O
acetylcholine	B-Chemical
(	O
ACh	B-Chemical
)	O
levels	O
.	O

The	O
present	O
study	O
sought	O
to	O
characterize	O
the	O
cognitive	O
-	O
enhancing	O
effects	O
of	O
the	O
5	B-Chemical
-	I-Chemical
HT	I-Chemical
(	O
6	O
)	O
antagonist	O
Ro4368554	B-Chemical
(	O
3	B-Chemical
-	I-Chemical
benzenesulfonyl	I-Chemical
-	I-Chemical
7	I-Chemical
-	I-Chemical
(	I-Chemical
4	I-Chemical
-	I-Chemical
methyl	I-Chemical
-	I-Chemical
piperazin	I-Chemical
-	I-Chemical
1	I-Chemical
-	I-Chemical
yl	I-Chemical
)	I-Chemical
1H	I-Chemical
-	I-Chemical
indole	I-Chemical
)	O
in	O
a	O
rat	O
object	O
recognition	O
task	O
employing	O
a	O
cholinergic	O
(	O
scopolamine	B-Chemical
pretreatment	O
)	O
and	O
a	O
serotonergic	O
-	O
(	O
tryptophan	B-Chemical
(	O
TRP	B-Chemical
)	O
depletion	O
)	O
deficient	O
model	O
,	O
and	O
compared	O
its	O
pattern	O
of	O
action	O
with	O
that	O
of	O
the	O
acetylcholinesterase	O
inhibitor	O
metrifonate	B-Chemical
.	O

Initial	O
testing	O
in	O
a	O
time	O
-	O
dependent	O
forgetting	O
task	O
employing	O
a	O
24	O
-	O
h	O
delay	O
between	O
training	O
and	O
testing	O
showed	O
that	O
metrifonate	B-Chemical
improved	O
object	O
recognition	O
(	O
at	O
10	O
and	O
30	O
mg	O
/	O
kg	O
,	O
p	O
.	O
o	O
.	O
)	O
,	O
whereas	O
Ro4368554	B-Chemical
was	O
inactive	O
.	O

Both	O
,	O
Ro4368554	B-Chemical
(	O
3	O
and	O
10	O
mg	O
/	O
kg	O
,	O
intraperitoneally	O
(	O
i	O
.	O
p	O
.	O
)	O
)	O
and	O
metrifonate	B-Chemical
(	O
10	O
mg	O
/	O
kg	O
,	O
p	O
.	O
o	O
.	O
,	O
respectively	O
)	O
reversed	O
memory	B-Disease
deficits	I-Disease
induced	O
by	O
scopolamine	B-Chemical
and	O
TRP	B-Chemical
depletion	O
(	O
10	O
mg	O
/	O
kg	O
,	O
i	O
.	O
p	O
.	O
,	O
and	O
3	O
mg	O
/	O
kg	O
,	O
p	O
.	O
o	O
.	O
,	O
respectively	O
)	O
.	O

In	O
conclusion	O
,	O
although	O
Ro4368554	B-Chemical
did	O
not	O
improve	O
a	O
time	O
-	O
related	O
retention	O
deficit	O
,	O
it	O
reversed	O
a	O
cholinergic	O
and	O
a	O
serotonergic	O
memory	B-Disease
deficit	I-Disease
,	O
suggesting	O
that	O
both	O
mechanisms	O
may	O
be	O
involved	O
in	O
the	O
facilitation	O
of	O
object	O
memory	O
by	O
Ro4368554	B-Chemical
and	O
,	O
possibly	O
,	O
other	O
5	B-Chemical
-	I-Chemical
HT	I-Chemical
(	O
6	O
)	O
receptor	O
antagonists	O
.	O

Evaluation	O
of	O
the	O
anticocaine	O
monoclonal	O
antibody	O
GNC92H2	B-Chemical
as	O
an	O
immunotherapy	O
for	O
cocaine	B-Disease
overdose	I-Disease
.	O

The	O
illicit	O
use	O
of	O
cocaine	B-Chemical
continues	O
in	O
epidemic	O
proportions	O
and	O
treatment	O
for	O
cocaine	B-Disease
overdose	I-Disease
remains	O
elusive	O
.	O

Current	O
protein	O
-	O
based	O
technology	O
offers	O
a	O
new	O
therapeutic	O
venue	O
by	O
which	O
antibodies	O
bind	O
the	O
drug	O
in	O
the	O
blood	O
stream	O
,	O
inactivating	O
its	O
toxic	O
effects	O
.	O

The	O
therapeutic	O
potential	O
of	O
the	O
anticocaine	O
antibody	O
GNC92H2	B-Chemical
was	O
examined	O
using	O
a	O
model	O
of	O
cocaine	B-Disease
overdose	I-Disease
.	O

Swiss	O
albino	O
mice	O
prepared	O
with	O
intrajugular	O
catheters	O
were	O
tested	O
in	O
photocell	O
cages	O
after	O
administration	O
of	O
93	O
mg	O
/	O
kg	O
(	O
LD50	O
)	O
of	O
cocaine	B-Chemical
and	O
GNC92H2	B-Chemical
infusions	O
ranging	O
from	O
30	O
to	O
190	O
mg	O
/	O
kg	O
.	O

GNC92H2	B-Chemical
was	O
delivered	O
30	O
min	O
before	O
,	O
concomitantly	O
or	O
3	O
min	O
after	O
cocaine	B-Chemical
treatment	O
.	O

Significant	O
blockade	O
of	O
cocaine	B-Chemical
toxicity	B-Disease
was	O
observed	O
with	O
the	O
higher	O
dose	O
of	O
GNC92H2	B-Chemical
(	O
190	O
mg	O
/	O
kg	O
)	O
,	O
where	O
premorbid	O
behaviors	O
were	O
reduced	O
up	O
to	O
40	O
%	O
,	O
seizures	B-Disease
up	O
to	O
77	O
%	O
and	O
death	B-Disease
by	O
72	O
%	O
.	O

Importantly	O
,	O
GNC92H2	B-Chemical
prevented	O
death	B-Disease
even	O
post	O
-	O
cocaine	B-Chemical
injection	O
.	O

The	O
results	O
support	O
the	O
important	O
potential	O
of	O
GNC92H2	B-Chemical
as	O
a	O
therapeutic	O
tool	O
against	O
cocaine	B-Disease
overdose	I-Disease
.	O

Electrocardiographic	O
evidence	O
of	O
myocardial	B-Disease
injury	I-Disease
in	O
psychiatrically	O
hospitalized	O
cocaine	B-Chemical
abusers	O
.	O

The	O
electrocardiograms	O
(	O
ECG	O
)	O
of	O
99	O
cocaine	B-Chemical
-	O
abusing	O
patients	O
were	O
compared	O
with	O
the	O
ECGs	O
of	O
50	O
schizophrenic	B-Disease
controls	O
.	O

Eleven	O
of	O
the	O
cocaine	B-Chemical
abusers	O
and	O
none	O
of	O
the	O
controls	O
had	O
ECG	O
evidence	O
of	O
significant	O
myocardial	B-Disease
injury	I-Disease
defined	O
as	O
myocardial	B-Disease
infarction	I-Disease
,	O
ischemia	B-Disease
,	O
and	O
bundle	B-Disease
branch	I-Disease
block	I-Disease
.	O

Behavioral	O
effects	O
of	O
urotensin	B-Chemical
-	I-Chemical
II	I-Chemical
centrally	O
administered	O
in	O
mice	O
.	O

Urotensin	B-Chemical
-	I-Chemical
II	I-Chemical
(	O
U	B-Chemical
-	I-Chemical
II	I-Chemical
)	O
receptors	O
are	O
widely	O
distributed	O
in	O
the	O
central	O
nervous	O
system	O
.	O

Intracerebroventricular	O
(	O
i	O
.	O
c	O
.	O
v	O
.	O
)	O
injection	O
of	O
U	B-Chemical
-	I-Chemical
II	I-Chemical
causes	O
hypertension	B-Disease
and	O
bradycardia	B-Disease
and	O
stimulates	O
prolactin	O
and	O
thyrotropin	O
secretion	O
.	O

However	O
,	O
the	O
behavioral	O
effects	O
of	O
centrally	O
administered	O
U	B-Chemical
-	I-Chemical
II	I-Chemical
have	O
received	O
little	O
attention	O
.	O

In	O
the	O
present	O
study	O
,	O
we	O
tested	O
the	O
effects	O
of	O
i	O
.	O
c	O
.	O
v	O
.	O
injections	O
of	O
U	B-Chemical
-	I-Chemical
II	I-Chemical
on	O
behavioral	O
,	O
metabolic	O
,	O
and	O
endocrine	O
responses	O
in	O
mice	O
.	O

Administration	O
of	O
graded	O
doses	O
of	O
U	B-Chemical
-	I-Chemical
II	I-Chemical
(	O
1	O
-	O
10	O
,	O
000	O
ng	O
/	O
mouse	O
)	O
provoked	O
:	O
(	O
1	O
)	O
a	O
dose	O
-	O
dependent	O
reduction	O
in	O
the	O
number	O
of	O
head	O
dips	O
in	O
the	O
hole	O
-	O
board	O
test	O
;	O
(	O
2	O
)	O
a	O
dose	O
-	O
dependent	O
reduction	O
in	O
the	O
number	O
of	O
entries	O
in	O
the	O
white	O
chamber	O
in	O
the	O
black	O
-	O
and	O
-	O
white	O
compartment	O
test	O
,	O
and	O
in	O
the	O
number	O
of	O
entries	O
in	O
the	O
central	O
platform	O
and	O
open	O
arms	O
in	O
the	O
plus	O
-	O
maze	O
test	O
;	O
and	O
(	O
3	O
)	O
a	O
dose	O
-	O
dependent	O
increase	O
in	O
the	O
duration	O
of	O
immobility	O
in	O
the	O
forced	O
-	O
swimming	O
test	O
and	O
tail	O
suspension	O
test	O
.	O

Intracerebroventricular	O
injection	O
of	O
U	B-Chemical
-	I-Chemical
II	I-Chemical
also	O
caused	O
an	O
increase	O
in	O
:	O
food	O
intake	O
at	O
doses	O
of	O
100	O
and	O
1	O
,	O
000	O
ng	O
/	O
mouse	O
,	O
water	O
intake	O
at	O
doses	O
of	O
100	O
-	O
10	O
,	O
000	O
ng	O
/	O
mouse	O
,	O
and	O
horizontal	O
locomotion	O
activity	O
at	O
a	O
dose	O
of	O
10	O
,	O
000	O
ng	O
/	O
mouse	O
.	O

Whatever	O
was	O
the	O
dose	O
,	O
the	O
central	O
administration	O
of	O
U	B-Chemical
-	I-Chemical
II	I-Chemical
had	O
no	O
effect	O
on	O
body	O
temperature	O
,	O
nociception	O
,	O
apomorphine	B-Chemical
-	O
induced	O
penile	B-Disease
erection	I-Disease
and	O
climbing	O
behavior	O
,	O
and	O
stress	O
-	O
induced	O
plasma	O
corticosterone	B-Chemical
level	O
.	O

Taken	O
together	O
,	O
the	O
present	O
study	O
demonstrates	O
that	O
the	O
central	O
injection	O
of	O
U	B-Chemical
-	I-Chemical
II	I-Chemical
at	O
doses	O
of	O
1	O
-	O
10	O
,	O
000	O
ng	O
/	O
mouse	O
induces	O
anxiogenic	O
-	O
and	O
depressant	O
-	O
like	O
effects	O
in	O
mouse	O
.	O

These	O
data	O
suggest	O
that	O
U	B-Chemical
-	I-Chemical
II	I-Chemical
may	O
be	O
involved	O
in	O
some	O
aspects	O
of	O
psychiatric	B-Disease
disorders	I-Disease
.	O

Learning	O
of	O
rats	O
under	O
amnesia	B-Disease
caused	O
by	O
pentobarbital	B-Chemical
.	O

Dissociated	O
learning	O
of	O
rats	O
in	O
the	O
normal	O
state	O
and	O
the	O
state	O
of	O
amnesia	B-Disease
produced	O
by	O
pentobarbital	B-Chemical
(	O
15	O
mg	O
/	O
kg	O
,	O
ip	O
)	O
was	O
carried	O
out	O
.	O

Rats	O
were	O
trained	O
to	O
approach	O
a	O
shelf	O
where	O
they	O
received	O
food	O
reinforcement	O
.	O

In	O
Group	O
1	O
the	O
rats	O
were	O
trained	O
under	O
the	O
influence	O
of	O
pentobarbital	B-Chemical
to	O
run	O
to	O
the	O
same	O
shelf	O
as	O
in	O
the	O
normal	O
state	O
.	O

In	O
Group	O
2	O
the	O
rats	O
were	O
trained	O
to	O
approach	O
different	O
shelves	O
in	O
different	O
drug	O
states	O
.	O

It	O
was	O
shown	O
that	O
memory	B-Disease
dissociation	I-Disease
occurred	O
in	O
both	O
groups	O
.	O

Differences	O
in	O
the	O
parameters	O
of	O
training	O
under	O
the	O
influence	O
of	O
pentobarbital	B-Chemical
between	O
Groups	O
1	O
and	O
2	O
were	O
revealed	O
.	O

These	O
findings	O
show	O
that	O
the	O
brain	O
-	O
dissociated	O
state	O
induced	O
by	O
pentobarbital	B-Chemical
is	O
formed	O
with	O
the	O
participation	O
of	O
the	O
mechanisms	O
of	O
information	O
perception	O
.	O

The	O
effects	O
of	O
short	O
-	O
term	O
raloxifene	B-Chemical
therapy	O
on	O
fibrinolysis	O
markers	O
:	O
TAFI	O
,	O
tPA	O
,	O
and	O
PAI	O
-	O
1	O
.	O

BACKGROUND	O
:	O
Markers	O
of	O
fibrinolysis	O
,	O
thrombin	O
-	O
activatable	O
fibrinolysis	O
inhibitor	O
(	O
TAFI	O
)	O
,	O
tissue	O
-	O
type	O
plasminogen	O
activator	O
(	O
tPA	O
)	O
,	O
and	O
plasminogen	O
activator	O
inhibitor	O
-	O
1	O
(	O
PAI	O
-	O
1	O
)	O
levels	O
were	O
studied	O
for	O
the	O
evaluation	O
of	O
short	O
-	O
term	O
effects	O
of	O
raloxifene	B-Chemical
administration	O
in	O
postmenopausal	O
women	O
.	O

METHODS	O
:	O
Thirty	O
-	O
nine	O
postmenopausal	O
women	O
with	O
osteopenia	B-Disease
or	O
osteoporosis	B-Disease
were	O
included	O
in	O
this	O
prospective	O
,	O
controlled	O
clinical	O
study	O
.	O

Twenty	O
-	O
five	O
women	O
were	O
given	O
raloxifene	B-Chemical
hydrochloride	I-Chemical
(	O
60	O
mg	O
/	O
day	O
)	O
plus	O
calcium	B-Chemical
(	O
500	O
mg	O
/	O
day	O
)	O
.	O

Age	O
-	O
matched	O
controls	O
(	O
n	O
=	O
14	O
)	O
were	O
given	O
only	O
calcium	B-Chemical
.	O

Plasma	O
TAFI	O
,	O
tPA	O
,	O
and	O
PAI	O
-	O
1	O
antigen	O
levels	O
were	O
measured	O
at	O
baseline	O
and	O
after	O
3	O
months	O
of	O
treatment	O
by	O
commercially	O
available	O
ELISA	O
kits	O
.	O

Variations	O
of	O
individuals	O
were	O
assessed	O
by	O
Wilcoxon	O
'	O
s	O
test	O
.	O

Relationship	O
between	O
those	O
markers	O
and	O
demographic	O
characteristics	O
were	O
investigated	O
.	O

RESULTS	O
:	O
Three	O
months	O
of	O
raloxifene	B-Chemical
treatment	O
was	O
associated	O
with	O
a	O
significant	O
decrease	O
in	O
the	O
plasma	O
TAFI	O
antigen	O
concentrations	O
(	O
16	O
%	O
change	O
,	O
P	O
<	O
0	O
.	O
01	O
)	O
,	O
and	O
a	O
significant	O
increase	O
in	O
tPA	O
antigen	O
concentrations	O
(	O
25	O
%	O
change	O
,	O
P	O
<	O
0	O
.	O
05	O
)	O
.	O

A	O
significant	O
correlation	O
was	O
found	O
between	O
baseline	O
TAFI	O
antigen	O
concentrations	O
and	O
the	O
duration	O
of	O
amenorrhea	B-Disease
(	O
P	O
<	O
0	O
.	O
05	O
;	O
r	O
=	O
0	O
.	O
33	O
)	O
.	O

CONCLUSION	O
:	O
We	O
suggest	O
that	O
the	O
increased	O
risk	O
of	O
venous	B-Disease
thromboembolism	I-Disease
due	O
to	O
raloxifene	B-Chemical
treatment	O
may	O
be	O
related	O
to	O
increased	O
tPA	O
levels	O
,	O
but	O
not	O
TAFI	O
levels	O
.	O

Valproate	B-Chemical
-	O
induced	O
encephalopathy	B-Disease
.	O

Valproate	B-Chemical
-	O
induced	O
encephalopathy	B-Disease
is	O
a	O
rare	O
syndrome	O
that	O
may	O
manifest	O
in	O
otherwise	O
normal	O
epileptic	B-Disease
individuals	O
.	O

It	O
may	O
even	O
present	O
in	O
patients	O
who	O
have	O
tolerated	O
this	O
medicine	O
well	O
in	O
the	O
past	O
.	O

It	O
is	O
usually	O
but	O
not	O
necessarily	O
associated	O
with	O
hyperammonemia	B-Disease
.	O

The	O
EEG	O
shows	O
characteristic	O
triphasic	O
waves	O
in	O
most	O
patients	O
with	O
this	O
complication	O
.	O

A	O
case	O
of	O
valproate	B-Chemical
-	O
induced	O
encephalopathy	B-Disease
is	O
presented	O
.	O

The	O
problems	O
in	O
diagnosing	O
this	O
condition	O
are	O
subsequently	O
discussed	O
.	O

Recurrent	O
dysphonia	B-Disease
and	O
acitretin	B-Chemical
.	O

We	O
report	O
the	O
case	O
of	O
a	O
woman	O
complaining	O
of	O
dysphonia	B-Disease
while	O
she	O
was	O
treated	O
by	O
acitretin	B-Chemical
.	O

Her	O
symptoms	O
totally	O
regressed	O
after	O
drug	O
withdrawal	O
and	O
reappeared	O
when	O
acitretin	B-Chemical
was	O
reintroduced	O
.	O

To	O
our	O
knowledge	O
,	O
this	O
is	O
the	O
first	O
case	O
of	O
acitretin	B-Chemical
-	O
induced	O
dysphonia	B-Disease
.	O

This	O
effect	O
may	O
be	O
related	O
to	O
the	O
pharmacological	O
effect	O
of	O
this	O
drug	O
on	O
mucous	O
membranes	O
.	O

Nitro	B-Chemical
-	I-Chemical
L	I-Chemical
-	I-Chemical
arginine	I-Chemical
methyl	I-Chemical
ester	I-Chemical
:	O
a	O
potential	O
protector	O
against	O
gentamicin	B-Chemical
ototoxicity	B-Disease
.	O

The	O
nitric	B-Chemical
oxide	I-Chemical
(	O
NO	B-Chemical
)	O
inhibitor	O
nitro	B-Chemical
-	I-Chemical
L	I-Chemical
-	I-Chemical
arginine	I-Chemical
methyl	I-Chemical
ester	I-Chemical
(	O
L	B-Chemical
-	I-Chemical
NAME	I-Chemical
)	O
may	O
act	O
as	O
an	O
otoprotectant	O
against	O
high	B-Disease
-	I-Disease
frequency	I-Disease
hearing	I-Disease
loss	I-Disease
caused	O
by	O
gentamicin	B-Chemical
,	O
but	O
further	O
studies	O
are	O
needed	O
to	O
confirm	O
this	O
.	O
Aminoglycoside	B-Chemical
antibiotics	O
are	O
still	O
widely	O
used	O
by	O
virtue	O
of	O
their	O
efficacy	O
and	O
low	O
cost	O
.	O

Their	O
ototoxicity	B-Disease
is	O
a	O
serious	O
health	O
problem	O
and	O
,	O
as	O
their	O
ototoxic	B-Disease
mechanism	O
involves	O
the	O
production	O
of	O
NO	B-Chemical
,	O
we	O
need	O
to	O
assess	O
the	O
use	O
of	O
NO	B-Chemical
inhibitors	O
for	O
the	O
prevention	O
of	O
aminoglycoside	B-Chemical
-	O
induced	O
sensorineural	B-Disease
hearing	I-Disease
loss	I-Disease
.	O

In	O
this	O
experimental	O
study	O
we	O
used	O
30	O
Sprague	O
-	O
Dawley	O
rats	O
,	O
27	O
of	O
which	O
had	O
gentamicin	B-Chemical
instilled	O
into	O
the	O
middle	O
ear	O
.	O

The	O
otoprotectant	O
L	B-Chemical
-	I-Chemical
NAME	I-Chemical
was	O
administered	O
topically	O
to	O
12	O
/	O
27	O
animals	O
.	O

Its	O
effect	O
was	O
determined	O
in	O
terms	O
of	O
attenuation	O
of	O
hearing	B-Disease
loss	I-Disease
,	O
measured	O
by	O
shifts	O
in	O
the	O
auditory	O
brainstem	O
response	O
threshold	O
.	O

L	B-Chemical
-	I-Chemical
NAME	I-Chemical
reduced	O
gentamicin	B-Chemical
-	O
induced	O
hearing	B-Disease
loss	I-Disease
in	O
the	O
high	O
-	O
frequency	O
range	O
,	O
but	O
gave	O
no	O
protection	O
in	O
the	O
middle	O
or	O
low	O
frequencies	O
.	O

Safety	O
profile	O
of	O
a	O
nicotine	B-Chemical
lozenge	O
compared	O
with	O
that	O
of	O
nicotine	B-Chemical
gum	O
in	O
adult	O
smokers	O
with	O
underlying	O
medical	O
conditions	O
:	O
a	O
12	O
-	O
week	O
,	O
randomized	O
,	O
open	O
-	O
label	O
study	O
.	O

BACKGROUND	O
:	O
Nicotine	B-Chemical
polacrilex	O
lozenges	O
deliver	O
25	O
%	O
to	O
27	O
%	O
more	O
nicotine	B-Chemical
compared	O
with	O
equivalent	O
doses	O
of	O
nicotine	B-Chemical
polacrilex	O
gum	O
.	O

The	O
increased	O
nicotine	B-Chemical
exposure	O
from	O
the	O
lozenge	O
has	O
raised	O
questions	O
about	O
the	O
relative	O
safety	O
of	O
the	O
lozenge	O
and	O
gum	O
.	O

OBJECTIVE	O
:	O
The	O
objective	O
of	O
this	O
study	O
was	O
to	O
compare	O
the	O
safety	O
profiles	O
of	O
the	O
4	O
-	O
mg	O
nicotine	B-Chemical
lozenge	O
and	O
4	O
-	O
mg	O
nicotine	B-Chemical
gum	O
in	O
smokers	O
with	O
selected	O
label	O
-	O
restricted	O
diseases	O
.	O

METHODS	O
:	O
This	O
was	O
a	O
multicenter	O
,	O
randomized	O
,	O
open	O
-	O
label	O
study	O
in	O
adult	O
smokers	O
with	O
heart	B-Disease
disease	I-Disease
,	O
hypertension	B-Disease
not	O
controlled	O
by	O
medication	O
,	O
and	O
/	O
or	O
diabetes	B-Disease
mellitus	I-Disease
.	O

Patients	O
were	O
randomized	O
in	O
a	O
1	O
:	O
1	O
ratio	O
to	O
receive	O
the	O
4	O
-	O
mg	O
nicotine	B-Chemical
lozenge	O
or	O
4	O
-	O
mg	O
nicotine	B-Chemical
gum	O
.	O

Safety	O
assessments	O
were	O
made	O
at	O
baseline	O
and	O
at	O
2	O
,	O
4	O
,	O
6	O
,	O
and	O
12	O
weeks	O
after	O
the	O
start	O
of	O
product	O
use	O
.	O

RESULTS	O
:	O
Nine	O
hundred	O
one	O
patients	O
were	O
randomized	O
to	O
treatment	O
,	O
447	O
who	O
received	O
the	O
lozenge	O
and	O
454	O
who	O
received	O
the	O
gum	O
(	O
safety	O
population	O
)	O
.	O

The	O
majority	O
were	O
women	O
(	O
52	O
.	O
7	O
%	O
)	O
.	O

Patients	O
'	O
mean	O
age	O
was	O
53	O
.	O
9	O
years	O
,	O
their	O
mean	O
weight	O
was	O
193	O
.	O
9	O
pounds	O
,	O
and	O
they	O
smoked	O
a	O
mean	O
of	O
25	O
.	O
2	O
cigarettes	O
per	O
day	O
at	O
baseline	O
.	O

Five	O
hundred	O
fifty	O
-	O
three	O
patients	O
,	O
264	O
taking	O
the	O
lozenge	O
and	O
289	O
taking	O
the	O
gum	O
,	O
used	O
the	O
study	O
product	O
for	O
>	O
or	O
=	O
4	O
days	O
per	O
week	O
during	O
the	O
first	O
2	O
weeks	O
(	O
evaluable	O
population	O
)	O
.	O

The	O
nicotine	B-Chemical
lozenge	O
and	O
nicotine	B-Chemical
gum	O
were	O
equally	O
well	O
tolerated	O
,	O
despite	O
increased	O
nicotine	B-Chemical
exposure	O
from	O
the	O
lozenge	O
.	O

The	O
incidence	O
of	O
adverse	O
events	O
in	O
the	O
2	O
groups	O
was	O
similar	O
during	O
the	O
first	O
2	O
weeks	O
of	O
product	O
use	O
(	O
evaluation	O
population	O
:	O
55	O
.	O
3	O
%	O
lozenge	O
,	O
54	O
.	O
7	O
%	O
gum	O
)	O
,	O
as	O
well	O
as	O
during	O
the	O
entire	O
study	O
(	O
safety	O
population	O
:	O
63	O
.	O
8	O
%	O
and	O
58	O
.	O
6	O
%	O
,	O
respectively	O
)	O
.	O

Stratification	O
of	O
patients	O
by	O
sex	O
,	O
age	O
,	O
extent	O
of	O
concurrent	O
smoking	O
,	O
extent	O
of	O
product	O
use	O
,	O
and	O
severity	O
of	O
adverse	O
events	O
revealed	O
no	O
clinically	O
significant	O
differences	O
between	O
the	O
lozenge	O
and	O
gum	O
.	O

The	O
most	O
common	O
adverse	O
events	O
were	O
nausea	B-Disease
(	O
17	O
.	O
2	O
%	O
and	O
16	O
.	O
1	O
%	O
;	O
95	O
%	O
CI	O
,	O
-	O
3	O
.	O
7	O
to	O
6	O
.	O
0	O
)	O
,	O
hiccups	B-Disease
(	O
10	O
.	O
7	O
%	O
and	O
6	O
.	O
6	O
%	O
;	O
95	O
%	O
CI	O
,	O
0	O
.	O
5	O
to	O
7	O
.	O
8	O
)	O
,	O
and	O
headache	B-Disease
(	O
8	O
.	O
7	O
%	O
and	O
9	O
.	O
9	O
%	O
;	O
95	O
%	O
Cl	O
,	O
-	O
5	O
.	O
0	O
to	O
2	O
.	O
6	O
)	O
.	O

Serious	O
adverse	O
events	O
were	O
reported	O
in	O
11	O
and	O
13	O
patients	O
in	O
the	O
respective	O
groups	O
.	O

Fewer	O
than	O
6	O
%	O
of	O
patients	O
in	O
either	O
group	O
were	O
considered	O
by	O
the	O
investigator	O
to	O
have	O
a	O
worsening	O
of	O
their	O
overall	O
disease	O
condition	O
during	O
the	O
study	O
.	O

The	O
majority	O
of	O
patients	O
(	O
>	O
60	O
%	O
)	O
experienced	O
no	O
change	O
in	O
their	O
disease	O
status	O
from	O
baseline	O
.	O

CONCLUSION	O
:	O
The	O
4	O
-	O
mg	O
nicotine	B-Chemical
lozenge	O
and	O
4	O
-	O
mg	O
nicotine	B-Chemical
gum	O
had	O
comparable	O
safety	O
profiles	O
in	O
these	O
patients	O
with	O
label	O
-	O
restricted	O
medical	O
conditions	O
.	O

Pharmacological	O
modulation	O
of	O
pain	B-Disease
-	O
related	O
brain	O
activity	O
during	O
normal	O
and	O
central	O
sensitization	O
states	O
in	O
humans	O
.	O

Abnormal	O
processing	O
of	O
somatosensory	O
inputs	O
in	O
the	O
central	O
nervous	O
system	O
(	O
central	O
sensitization	O
)	O
is	O
the	O
mechanism	O
accounting	O
for	O
the	O
enhanced	O
pain	B-Disease
sensitivity	O
in	O
the	O
skin	O
surrounding	O
tissue	B-Disease
injury	I-Disease
(	O
secondary	B-Disease
hyperalgesia	I-Disease
)	O
.	O

Secondary	B-Disease
hyperalgesia	I-Disease
shares	O
clinical	O
characteristics	O
with	O
neurogenic	B-Disease
hyperalgesia	I-Disease
in	O
patients	O
with	O
neuropathic	B-Disease
pain	I-Disease
.	O

Abnormal	O
brain	O
responses	O
to	O
somatosensory	O
stimuli	O
have	O
been	O
found	O
in	O
patients	O
with	O
hyperalgesia	B-Disease
as	O
well	O
as	O
in	O
normal	O
subjects	O
during	O
experimental	O
central	O
sensitization	O
.	O

The	O
aim	O
of	O
this	O
study	O
was	O
to	O
assess	O
the	O
effects	O
of	O
gabapentin	B-Chemical
,	O
a	O
drug	O
effective	O
in	O
neuropathic	B-Disease
pain	I-Disease
patients	O
,	O
on	O
brain	O
processing	O
of	O
nociceptive	O
information	O
in	O
normal	O
and	O
central	O
sensitization	O
states	O
.	O

Using	O
functional	O
magnetic	O
resonance	O
imaging	O
(	O
fMRI	O
)	O
in	O
normal	O
volunteers	O
,	O
we	O
studied	O
the	O
gabapentin	B-Chemical
-	O
induced	O
modulation	O
of	O
brain	O
activity	O
in	O
response	O
to	O
nociceptive	O
mechanical	O
stimulation	O
of	O
normal	O
skin	O
and	O
capsaicin	B-Chemical
-	O
induced	O
secondary	B-Disease
hyperalgesia	I-Disease
.	O

The	O
dose	O
of	O
gabapentin	B-Chemical
was	O
1	O
,	O
800	O
mg	O
per	O
os	O
,	O
in	O
a	O
single	O
administration	O
.	O

We	O
found	O
that	O
(	O
i	O
)	O
gabapentin	B-Chemical
reduced	O
the	O
activations	O
in	O
the	O
bilateral	O
operculoinsular	O
cortex	O
,	O
independently	O
of	O
the	O
presence	O
of	O
central	O
sensitization	O
;	O
(	O
ii	O
)	O
gabapentin	B-Chemical
reduced	O
the	O
activation	O
in	O
the	O
brainstem	O
,	O
only	O
during	O
central	O
sensitization	O
;	O
(	O
iii	O
)	O
gabapentin	B-Chemical
suppressed	O
stimulus	O
-	O
induced	O
deactivations	O
,	O
only	O
during	O
central	O
sensitization	O
;	O
this	O
effect	O
was	O
more	O
robust	O
than	O
the	O
effect	O
on	O
brain	O
activation	O
.	O

The	O
observed	O
drug	O
-	O
induced	O
effects	O
were	O
not	O
due	O
to	O
changes	O
in	O
the	O
baseline	O
fMRI	O
signal	O
.	O

These	O
findings	O
indicate	O
that	O
gabapentin	B-Chemical
has	O
a	O
measurable	O
antinociceptive	O
effect	O
and	O
a	O
stronger	O
antihyperalgesic	O
effect	O
most	O
evident	O
in	O
the	O
brain	O
areas	O
undergoing	O
deactivation	O
,	O
thus	O
supporting	O
the	O
concept	O
that	O
gabapentin	B-Chemical
is	O
more	O
effective	O
in	O
modulating	O
nociceptive	O
transmission	O
when	O
central	O
sensitization	O
is	O
present	O
.	O

Investigation	O
of	O
mitochondrial	O
involvement	O
in	O
the	O
experimental	O
model	O
of	O
epilepsy	B-Disease
induced	O
by	O
pilocarpine	B-Chemical
.	O

Mitochondrial	B-Disease
abnormalities	I-Disease
have	O
been	O
associated	O
with	O
several	O
aspects	O
of	O
epileptogenesis	O
,	O
such	O
as	O
energy	O
generation	O
,	O
control	O
of	O
cell	O
death	B-Disease
,	O
neurotransmitter	O
synthesis	O
,	O
and	O
free	O
radical	O
(	O
FR	O
)	O
production	O
.	O

Increased	O
production	O
of	O
FRs	O
may	O
cause	O
mtDNA	O
damage	O
leading	O
to	O
decreased	O
activities	O
of	O
oxidative	O
phosphorylation	O
complexes	O
containing	O
mtDNA	O
-	O
encoded	O
subunits	O
.	O

In	O
this	O
study	O
,	O
we	O
investigated	O
whether	O
increased	O
generation	O
of	O
FR	O
during	O
status	B-Disease
epilepticus	I-Disease
would	O
be	O
sufficient	O
to	O
provoke	O
abnormalities	O
in	O
mtDNA	O
and	O
in	O
the	O
expression	O
and	O
activity	O
of	O
cytochrome	O
c	O
oxidase	O
(	O
CCO	O
)	O
,	O
complex	O
IV	O
of	O
the	O
respiratory	O
chain	O
,	O
in	O
the	O
chronic	O
phase	O
of	O
the	O
pilocarpine	B-Chemical
model	O
of	O
temporal	B-Disease
lobe	I-Disease
epilepsy	I-Disease
.	O

DNA	O
analysis	O
revealed	O
low	O
amounts	O
of	O
a	O
4	O
.	O
8	O
kb	O
mtDNA	O
deletion	O
but	O
with	O
no	O
differences	O
in	O
frequency	O
or	O
quantity	O
in	O
the	O
control	O
and	O
experimental	O
groups	O
.	O

We	O
did	O
not	O
find	O
abnormalities	O
in	O
the	O
expression	O
and	O
distribution	O
of	O
an	O
mtDNA	O
-	O
encoded	O
subunit	O
of	O
CCO	O
(	O
CCO	O
-	O
I	O
)	O
or	O
a	O
relative	O
decrease	O
in	O
CCO	O
-	O
I	O
when	O
compared	O
with	O
nuclear	O
-	O
encoded	O
subunits	O
(	O
CCO	O
-	O
IV	O
and	O
SDH	O
-	O
fp	O
)	O
.	O

No	O
abnormality	O
in	O
CCO	O
activity	O
was	O
observed	O
through	O
histochemistry	O
.	O

Although	O
evidences	O
of	O
mitochondrial	B-Disease
abnormalities	I-Disease
were	O
found	O
in	O
previously	O
published	O
studies	O
,	O
our	O
results	O
do	O
not	O
suggest	O
that	O
the	O
FRs	O
,	O
generated	O
during	O
the	O
acute	O
phase	O
,	O
determined	O
important	O
abnormalities	O
in	O
mtDNA	O
,	O
in	O
expression	O
of	O
CCO	O
-	O
I	O
,	O
and	O
in	O
CCO	O
activity	O
.	O

Adverse	O
effect	O
of	O
the	O
calcium	B-Chemical
channel	O
blocker	O
nitrendipine	B-Chemical
on	O
nephrosclerosis	B-Disease
in	O
rats	O
with	O
renovascular	B-Disease
hypertension	I-Disease
.	O

The	O
effect	O
of	O
a	O
6	O
-	O
week	O
treatment	O
with	O
the	O
calcium	B-Chemical
channel	O
blocker	O
nitrendipine	B-Chemical
or	O
the	O
angiotensin	B-Chemical
converting	O
enzyme	O
inhibitor	O
enalapril	B-Chemical
on	O
blood	O
pressure	O
,	O
albuminuria	B-Disease
,	O
renal	O
hemodynamics	O
,	O
and	O
morphology	O
of	O
the	O
nonclipped	O
kidney	O
was	O
studied	O
in	O
rats	O
with	O
two	O
-	O
kidney	O
,	O
one	O
clip	O
renovascular	B-Disease
hypertension	I-Disease
.	O

Six	O
weeks	O
after	O
clipping	O
of	O
one	O
renal	O
artery	O
,	O
hypertensive	B-Disease
rats	O
(	O
178	O
+	O
/	O
-	O
4	O
mm	O
Hg	O
)	O
were	O
randomly	O
assigned	O
to	O
three	O
groups	O
:	O
untreated	O
hypertensive	B-Disease
controls	O
(	O
n	O
=	O
8	O
)	O
,	O
enalapril	B-Chemical
-	O
treated	O
(	O
n	O
=	O
8	O
)	O
,	O
or	O
nitrendipine	B-Chemical
-	O
treated	O
(	O
n	O
=	O
10	O
)	O
.	O

Sham	O
-	O
operated	O
rats	O
served	O
as	O
normotensive	O
controls	O
(	O
128	O
+	O
/	O
-	O
3	O
mm	O
Hg	O
,	O
n	O
=	O
8	O
)	O
.	O

After	O
6	O
weeks	O
of	O
treatment	O
,	O
renal	O
hemodynamics	O
(	O
glomerular	O
filtration	O
rate	O
and	O
renal	O
plasma	O
flow	O
)	O
were	O
measured	O
in	O
the	O
anesthetized	O
rats	O
.	O

Renal	O
tissue	O
was	O
obtained	O
for	O
determination	O
of	O
glomerular	O
size	O
and	O
sclerosis	O
.	O

Enalapril	B-Chemical
but	O
not	O
nitrendipine	B-Chemical
reduced	O
blood	O
pressure	O
significantly	O
.	O

After	O
6	O
weeks	O
of	O
therapy	O
,	O
glomerular	O
filtration	O
rate	O
was	O
not	O
different	O
among	O
the	O
studied	O
groups	O
.	O

Renal	O
plasma	O
flow	O
increased	O
,	O
but	O
albumin	O
excretion	O
and	O
glomerulosclerosis	B-Disease
did	O
not	O
change	O
after	O
enalapril	B-Chemical
treatment	O
.	O

In	O
contrast	O
,	O
in	O
the	O
nitrendipine	B-Chemical
-	O
treated	O
group	O
albuminuria	B-Disease
increased	O
from	O
12	O
.	O
8	O
+	O
/	O
-	O
2	O
progressively	O
to	O
163	O
+	O
/	O
-	O
55	O
compared	O
with	O
19	O
.	O
2	O
+	O
/	O
-	O
9	O
mg	O
/	O
24	O
hr	O
in	O
the	O
hypertensive	B-Disease
controls	O
.	O

Furthermore	O
,	O
glomerulosclerosis	B-Disease
index	O
was	O
significantly	O
increased	O
in	O
the	O
nitrendipine	B-Chemical
-	O
treated	O
group	O
compared	O
with	O
the	O
hypertensive	B-Disease
controls	O
(	O
0	O
.	O
38	O
+	O
/	O
-	O
0	O
.	O
1	O
versus	O
0	O
.	O
13	O
+	O
/	O
-	O
0	O
.	O
04	O
)	O
.	O

In	O
addition	O
,	O
glomerular	O
size	O
was	O
higher	O
in	O
the	O
nitrendipine	B-Chemical
-	O
treated	O
group	O
(	O
14	O
.	O
9	O
+	O
/	O
-	O
0	O
.	O
17	O
10	O
(	O
-	O
3	O
)	O
mm2	O
)	O
but	O
lower	O
in	O
the	O
enalapril	B-Chemical
-	O
treated	O
group	O
(	O
11	O
.	O
5	O
+	O
/	O
-	O
0	O
.	O
15	O
10	O
(	O
-	O
3	O
)	O
mm2	O
)	O
compared	O
with	O
the	O
hypertensive	B-Disease
controls	O
(	O
12	O
.	O
1	O
+	O
/	O
-	O
0	O
.	O
17	O
10	O
(	O
-	O
3	O
)	O
mm2	O
)	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
250	O
WORDS	O
)	O

Ketoconazole	B-Chemical
induced	O
torsades	B-Disease
de	I-Disease
pointes	I-Disease
without	O
concomitant	O
use	O
of	O
QT	O
interval	O
-	O
prolonging	O
drug	O
.	O

Ketoconazole	B-Chemical
is	O
not	O
known	O
to	O
be	O
proarrhythmic	O
without	O
concomitant	O
use	O
of	O
QT	O
interval	O
-	O
prolonging	O
drugs	O
.	O

We	O
report	O
a	O
woman	O
with	O
coronary	B-Disease
artery	I-Disease
disease	I-Disease
who	O
developed	O
a	O
markedly	O
prolonged	B-Disease
QT	I-Disease
interval	I-Disease
and	O
torsades	B-Disease
de	I-Disease
pointes	I-Disease
(	O
TdP	B-Disease
)	O
after	O
taking	O
ketoconazole	B-Chemical
for	O
treatment	O
of	O
fungal	B-Disease
infection	I-Disease
.	O

Her	O
QT	O
interval	O
returned	O
to	O
normal	O
upon	O
withdrawal	O
of	O
ketoconazole	B-Chemical
.	O

Genetic	O
study	O
did	O
not	O
find	O
any	O
mutation	O
in	O
her	O
genes	O
that	O
encode	O
cardiac	O
IKr	O
channel	O
proteins	O
.	O

We	O
postulate	O
that	O
by	O
virtue	O
of	O
its	O
direct	O
blocking	O
action	O
on	O
IKr	O
,	O
ketoconazole	B-Chemical
alone	O
may	O
prolong	O
QT	O
interval	O
and	O
induce	O
TdP	B-Disease
.	O

This	O
calls	O
for	O
attention	O
when	O
ketoconazole	B-Chemical
is	O
administered	O
to	O
patients	O
with	O
risk	O
factors	O
for	O
acquired	O
long	B-Disease
QT	I-Disease
syndrome	I-Disease
.	O

Cerebral	B-Disease
vasculitis	I-Disease
following	O
oral	O
methylphenidate	B-Chemical
intake	O
in	O
an	O
adult	O
:	O
a	O
case	O
report	O
.	O

Methylphenidate	B-Chemical
is	O
structurally	O
and	O
functionally	O
similar	O
to	O
amphetamine	B-Chemical
.	O

Cerebral	B-Disease
vasculitis	I-Disease
associated	O
with	O
amphetamine	B-Disease
abuse	I-Disease
is	O
well	O
documented	O
,	O
and	O
in	O
rare	O
cases	O
ischaemic	B-Disease
stroke	I-Disease
has	O
been	O
reported	O
after	O
methylphenidate	B-Chemical
intake	O
in	O
children	O
.	O

We	O
report	O
the	O
case	O
of	O
a	O
63	O
-	O
year	O
-	O
old	O
female	O
who	O
was	O
treated	O
with	O
methylphenidate	B-Chemical
due	O
to	O
hyperactivity	B-Disease
and	O
suffered	O
from	O
multiple	O
ischaemic	B-Disease
strokes	I-Disease
.	O

We	O
consider	O
drug	O
-	O
induced	O
cerebral	B-Disease
vasculitis	I-Disease
as	O
the	O
most	O
likely	O
cause	O
of	O
recurrent	O
ischaemic	B-Disease
strokes	I-Disease
in	O
the	O
absence	O
of	O
any	O
pathological	O
findings	O
during	O
the	O
diagnostic	O
work	O
-	O
up	O
.	O

We	O
conclude	O
that	O
methylphenidate	B-Chemical
mediated	O
vasculitis	B-Disease
should	O
be	O
considered	O
in	O
patients	O
with	O
neurological	O
symptoms	O
and	O
a	O
history	O
of	O
methylphenidate	B-Chemical
therapy	O
.	O

This	O
potential	O
side	O
-	O
effect	O
,	O
though	O
very	O
rare	O
,	O
represents	O
one	O
more	O
reason	O
to	O
be	O
very	O
restrictive	O
in	O
the	O
use	O
of	O
methylphenidate	B-Chemical
.	O

MDMA	B-Chemical
polydrug	O
users	O
show	O
process	O
-	O
specific	O
central	O
executive	O
impairments	O
coupled	O
with	O
impaired	B-Disease
social	I-Disease
and	I-Disease
emotional	I-Disease
judgement	I-Disease
processes	I-Disease
.	O

In	O
recent	O
years	O
working	O
memory	B-Disease
deficits	I-Disease
have	O
been	O
reported	O
in	O
users	O
of	O
MDMA	B-Chemical
(	O
3	B-Chemical
,	I-Chemical
4	I-Chemical
-	I-Chemical
methylenedioxymethamphetamine	I-Chemical
,	O
ecstasy	B-Chemical
)	O
.	O

The	O
current	O
study	O
aimed	O
to	O
assess	O
the	O
impact	O
of	O
MDMA	B-Chemical
use	O
on	O
three	O
separate	O
central	O
executive	O
processes	O
(	O
set	O
shifting	O
,	O
inhibition	O
and	O
memory	O
updating	O
)	O
and	O
also	O
on	O
"	O
prefrontal	O
"	O
mediated	O
social	O
and	O
emotional	O
judgement	O
processes	O
.	O

Fifteen	O
polydrug	O
ecstasy	B-Chemical
users	O
and	O
15	O
polydrug	O
non	O
-	O
ecstasy	B-Chemical
user	O
controls	O
completed	O
a	O
general	O
drug	O
use	O
questionnaire	O
,	O
the	O
Brixton	O
Spatial	O
Anticipation	O
task	O
(	O
set	O
shifting	O
)	O
,	O
Backward	O
Digit	O
Span	O
procedure	O
(	O
memory	O
updating	O
)	O
,	O
Inhibition	O
of	O
Return	O
(	O
inhibition	O
)	O
,	O
an	O
emotional	O
intelligence	O
scale	O
,	O
the	O
Tromso	O
Social	O
Intelligence	O
Scale	O
and	O
the	O
Dysexecutive	O
Questionnaire	O
(	O
DEX	O
)	O
.	O

Compared	O
with	O
MDMA	B-Chemical
-	O
free	O
polydrug	O
controls	O
,	O
MDMA	B-Chemical
polydrug	O
users	O
showed	O
impairments	O
in	O
set	O
shifting	O
and	O
memory	O
updating	O
,	O
and	O
also	O
in	O
social	O
and	O
emotional	O
judgement	O
processes	O
.	O

The	O
latter	O
two	O
deficits	O
remained	O
significant	O
after	O
controlling	O
for	O
other	O
drug	O
use	O
.	O

These	O
data	O
lend	O
further	O
support	O
to	O
the	O
proposal	O
that	O
cognitive	O
processes	O
mediated	O
by	O
the	O
prefrontal	O
cortex	O
may	O
be	O
impaired	O
by	O
recreational	O
ecstasy	B-Chemical
use	O
.	O

Phase	O
II	O
study	O
of	O
the	O
amsacrine	B-Chemical
analogue	O
CI	B-Chemical
-	I-Chemical
921	I-Chemical
(	O
NSC	B-Chemical
343499	I-Chemical
)	O
in	O
non	B-Disease
-	I-Disease
small	I-Disease
cell	I-Disease
lung	I-Disease
cancer	I-Disease
.	O

CI	B-Chemical
-	I-Chemical
921	I-Chemical
(	O
NSC	B-Chemical
343499	I-Chemical
;	O
9	B-Chemical
-	I-Chemical
[	I-Chemical
[	I-Chemical
2	I-Chemical
-	I-Chemical
methoxy	I-Chemical
-	I-Chemical
4	I-Chemical
-	I-Chemical
[	I-Chemical
(	I-Chemical
methylsulphonyl	I-Chemical
)	I-Chemical
amino	I-Chemical
]	I-Chemical
phenyl	I-Chemical
]	I-Chemical
amino	I-Chemical
]	I-Chemical
-	I-Chemical
N	I-Chemical
,	I-Chemical
5	I-Chemical
-	I-Chemical
dimethyl	I-Chemical
-	I-Chemical
4	I-Chemical
-	I-Chemical
acridinecarboxamide	I-Chemical
)	O
is	O
a	O
topoisomerase	O
II	O
poison	O
with	O
high	O
experimental	O
antitumour	O
activity	O
.	O

It	O
was	O
administered	O
by	O
15	O
min	O
infusion	O
to	O
16	O
evaluable	O
patients	O
with	O
non	B-Disease
-	I-Disease
small	I-Disease
cell	I-Disease
lung	I-Disease
cancer	I-Disease
(	O
NSCLC	B-Disease
)	O
(	O
7	O
with	O
no	O
prior	O
treatment	O
,	O
9	O
patients	O
in	O
relapse	O
following	O
surgery	O
/	O
radiotherapy	O
)	O
at	O
a	O
dose	O
(	O
648	O
mg	O
/	O
m2	O
divided	O
over	O
3	O
days	O
,	O
repeated	O
every	O
3	O
weeks	O
)	O
determined	O
by	O
phase	O
I	O
trial	O
.	O

Patients	O
had	O
a	O
median	O
performance	O
status	O
of	O
1	O
(	O
WHO	O
)	O
,	O
and	O
median	O
age	O
of	O
61	O
years	O
.	O

The	O
histology	O
comprised	O
squamous	B-Disease
carcinoma	I-Disease
(	O
11	O
)	O
,	O
adenocarcinoma	B-Disease
(	O
1	O
)	O
,	O
mixed	O
histology	O
(	O
2	O
)	O
,	O
bronchio	B-Disease
-	I-Disease
alveolar	I-Disease
carcinoma	I-Disease
(	O
1	O
)	O
and	O
large	O
cell	O
undifferentiated	B-Disease
carcinoma	I-Disease
(	O
1	O
)	O
.	O

Neutropenia	B-Disease
grade	O
greater	O
than	O
or	O
equal	O
to	O
3	O
was	O
seen	O
in	O
15	O
patients	O
,	O
infections	B-Disease
with	O
recovery	O
in	O
3	O
,	O
and	O
grand	O
mal	O
seizures	B-Disease
in	O
1	O
patient	O
.	O

Grade	O
less	O
than	O
or	O
equal	O
to	O
2	O
nausea	B-Disease
and	O
vomiting	B-Disease
occurred	O
in	O
66	O
%	O
courses	O
and	O
phlebitis	B-Disease
in	O
the	O
infusion	O
arm	O
in	O
37	O
%	O
.	O

1	O
patient	O
with	O
squamous	B-Disease
cell	I-Disease
carcinoma	I-Disease
achieved	O
a	O
partial	O
response	O
lasting	O
5	O
months	O
.	O

Further	O
testing	O
in	O
this	O
and	O
other	O
tumour	B-Disease
types	O
using	O
multiple	O
daily	O
schedules	O
is	O
warranted	O
.	O

Pharmacokinetics	O
of	O
desipramine	B-Chemical
HCl	I-Chemical
when	O
administered	O
with	O
cinacalcet	B-Chemical
HCl	I-Chemical
.	O

OBJECTIVE	O
:	O
In	O
vitro	O
work	O
has	O
demonstrated	O
that	O
cinacalcet	B-Chemical
is	O
a	O
strong	O
inhibitor	O
of	O
cytochrome	O
P450	O
isoenzyme	O
(	O
CYP	O
)	O
2D6	O
.	O

The	O
purpose	O
of	O
this	O
study	O
was	O
to	O
evaluate	O
the	O
effect	O
of	O
cinacalcet	B-Chemical
on	O
CYP2D6	O
activity	O
,	O
using	O
desipramine	B-Chemical
as	O
a	O
probe	O
substrate	O
,	O
in	O
healthy	O
subjects	O
.	O

METHODS	O
:	O
Seventeen	O
subjects	O
who	O
were	O
genotyped	O
as	O
CYP2D6	O
extensive	O
metabolizers	O
were	O
enrolled	O
in	O
this	O
randomized	O
,	O
open	O
-	O
label	O
,	O
crossover	O
study	O
to	O
receive	O
a	O
single	O
oral	O
dose	O
of	O
desipramine	B-Chemical
(	O
50	O
mg	O
)	O
on	O
two	O
separate	O
occasions	O
,	O
once	O
alone	O
and	O
once	O
after	O
multiple	O
doses	O
of	O
cinacalcet	B-Chemical
(	O
90	O
mg	O
for	O
7	O
days	O
)	O
.	O

Blood	O
samples	O
were	O
obtained	O
predose	O
and	O
up	O
to	O
72	O
h	O
postdose	O
.	O

RESULTS	O
:	O
Fourteen	O
subjects	O
completed	O
both	O
treatment	O
arms	O
.	O

Relative	O
to	O
desipramine	B-Chemical
alone	O
,	O
mean	O
AUC	O
and	O
C	O
(	O
max	O
)	O
of	O
desipramine	B-Chemical
increased	O
3	O
.	O
6	O
-	O
and	O
1	O
.	O
8	O
-	O
fold	O
when	O
coadministered	O
with	O
cinacalcet	B-Chemical
.	O

The	O
t	O
(	O
1	O
/	O
2	O
,	O
z	O
)	O
of	O
desipramine	B-Chemical
was	O
longer	O
when	O
desipramine	B-Chemical
was	O
coadministered	O
with	O
cinacalcet	B-Chemical
(	O
21	O
.	O
0	O
versus	O
43	O
.	O
3	O
hs	O
)	O
.	O

The	O
t	O
(	O
max	O
)	O
was	O
similar	O
between	O
the	O
regimens	O
.	O

Fewer	O
subjects	O
reported	O
adverse	O
events	O
following	O
treatment	O
with	O
desipramine	B-Chemical
alone	O
than	O
when	O
receiving	O
desipramine	B-Chemical
with	O
cinacalcet	B-Chemical
(	O
33	O
versus	O
86	O
%	O
)	O
,	O
the	O
most	O
frequent	O
of	O
which	O
(	O
nausea	B-Disease
and	O
headache	B-Disease
)	O
have	O
been	O
reported	O
for	O
patients	O
treated	O
with	O
either	O
desipramine	B-Chemical
or	O
cinacalcet	B-Chemical
.	O

CONCLUSION	O
:	O
This	O
study	O
demonstrates	O
that	O
cinacalcet	B-Chemical
is	O
a	O
strong	O
inhibitor	O
of	O
CYP2D6	O
.	O

These	O
data	O
suggest	O
that	O
during	O
concomitant	O
treatment	O
with	O
cinacalcet	B-Chemical
,	O
dose	O
adjustment	O
may	O
be	O
necessary	O
for	O
drugs	O
that	O
demonstrate	O
a	O
narrow	O
therapeutic	O
index	O
and	O
are	O
metabolized	O
by	O
CYP2D6	O
.	O

Case	O
report	O
:	O
acute	O
unintentional	O
carbachol	B-Chemical
intoxication	O
.	O

INTRODUCTION	O
:	O
Intoxications	O
with	O
carbachol	B-Chemical
,	O
a	O
muscarinic	O
cholinergic	O
receptor	O
agonist	O
are	O
rare	O
.	O

We	O
report	O
an	O
interesting	O
case	O
investigating	O
a	O
(	O
near	O
)	O
fatal	O
poisoning	B-Disease
.	O

METHODS	O
:	O
The	O
son	O
of	O
an	O
84	O
-	O
year	O
-	O
old	O
male	O
discovered	O
a	O
newspaper	O
report	O
stating	O
clinical	O
success	O
with	O
plant	O
extracts	O
in	O
Alzheimer	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
.	O

The	O
mode	O
of	O
action	O
was	O
said	O
to	O
be	O
comparable	O
to	O
that	O
of	O
the	O
synthetic	O
compound	O
'	O
carbamylcholin	B-Chemical
'	O
;	O
that	O
is	O
,	O
carbachol	B-Chemical
.	O

He	O
bought	O
25	O
g	O
of	O
carbachol	B-Chemical
as	O
pure	O
substance	O
in	O
a	O
pharmacy	O
,	O
and	O
the	O
father	O
was	O
administered	O
400	O
to	O
500	O
mg	O
.	O

Carbachol	B-Chemical
concentrations	O
in	O
serum	O
and	O
urine	O
on	O
day	O
1	O
and	O
2	O
of	O
hospital	O
admission	O
were	O
analysed	O
by	O
HPLC	O
-	O
mass	O
spectrometry	O
.	O

RESULTS	O
:	O
Minutes	O
after	O
oral	O
administration	O
,	O
the	O
patient	O
developed	O
nausea	B-Disease
,	O
sweating	O
and	O
hypotension	B-Disease
,	O
and	O
finally	O
collapsed	O
.	O

Bradycardia	B-Disease
,	O
cholinergic	O
symptoms	O
and	O
asystole	B-Disease
occurred	O
.	O

Initial	O
cardiopulmonary	O
resuscitation	O
and	O
immediate	O
treatment	O
with	O
adrenaline	B-Chemical
(	O
epinephrine	B-Chemical
)	O
,	O
atropine	B-Chemical
and	O
furosemide	B-Chemical
was	O
successful	O
.	O

On	O
hospital	O
admission	O
,	O
blood	O
pressure	O
of	O
the	O
intubated	O
,	O
bradyarrhythmic	O
patient	O
was	O
100	O
/	O
65	O
mmHg	O
.	O

Further	O
signs	O
were	O
hyperhidrosis	B-Disease
,	O
hypersalivation	B-Disease
,	O
bronchorrhoea	B-Disease
,	O
and	O
severe	O
miosis	B-Disease
;	O
the	O
electrocardiographic	O
finding	O
was	O
atrio	B-Disease
-	I-Disease
ventricular	I-Disease
dissociation	I-Disease
.	O

High	O
doses	O
of	O
atropine	B-Chemical
(	O
up	O
to	O
50	O
mg	O
per	O
24	O
hours	O
)	O
,	O
adrenaline	B-Chemical
and	O
dopamine	B-Chemical
were	O
necessary	O
.	O

The	O
patient	O
was	O
extubated	O
1	O
week	O
later	O
.	O

However	O
,	O
increased	O
dyspnoea	B-Disease
and	O
bronchospasm	B-Disease
necessitated	O
reintubation	O
.	O

Respiratory	B-Disease
insufficiency	I-Disease
was	O
further	O
worsened	O
by	O
Proteus	B-Disease
mirabilis	I-Disease
infection	I-Disease
and	O
severe	O
bronchoconstriction	O
.	O

One	O
week	O
later	O
,	O
the	O
patient	O
was	O
again	O
extubated	O
and	O
3	O
days	O
later	O
was	O
transferred	O
to	O
a	O
peripheral	O
ward	O
.	O

On	O
the	O
next	O
day	O
he	O
died	O
,	O
probably	O
as	O
a	O
result	O
of	O
heart	B-Disease
failure	I-Disease
.	O

Serum	O
samples	O
from	O
the	O
first	O
and	O
second	O
days	O
contained	O
3	O
.	O
6	O
and	O
1	O
.	O
9	O
mg	O
/	O
l	O
carbachol	B-Chemical
,	O
respectively	O
.	O

The	O
corresponding	O
urine	O
concentrations	O
amounted	O
to	O
374	O
and	O
554	O
mg	O
/	O
l	O
.	O

CONCLUSION	O
:	O
This	O
case	O
started	O
with	O
a	O
media	O
report	O
in	O
a	O
popular	O
newspaper	O
,	O
initiated	O
by	O
published	O
,	O
peer	O
-	O
reviewed	O
research	O
on	O
herbals	O
,	O
and	O
involved	O
human	O
failure	O
in	O
a	O
case	O
history	O
,	O
medical	O
examination	O
and	O
clinical	O
treatment	O
.	O

For	O
the	O
first	O
time	O
,	O
an	O
analytical	O
method	O
for	O
the	O
determination	O
of	O
carbachol	B-Chemical
in	O
plasma	O
and	O
urine	O
has	O
been	O
developed	O
.	O

The	O
analysed	O
carbachol	B-Chemical
concentration	O
exceeded	O
the	O
supposed	O
serum	O
level	O
resulting	O
from	O
a	O
therapeutic	O
dose	O
by	O
a	O
factor	O
of	O
130	O
to	O
260	O
.	O

Especially	O
in	O
old	O
patients	O
,	O
intensivists	O
should	O
consider	O
intoxications	O
(	O
with	O
cholinergics	O
)	O
as	O
a	O
cause	O
of	O
acute	B-Disease
cardiovascular	I-Disease
failure	I-Disease
.	O

Pharmacological	O
evidence	O
for	O
the	O
potential	O
of	O
Daucus	O
carota	O
in	O
the	O
management	O
of	O
cognitive	B-Disease
dysfunctions	I-Disease
.	O

The	O
present	O
study	O
was	O
aimed	O
at	O
investigating	O
the	O
effects	O
of	O
Daucus	O
carota	O
seeds	O
on	O
cognitive	O
functions	O
,	O
total	O
serum	O
cholesterol	B-Chemical
levels	O
and	O
brain	O
cholinesterase	O
activity	O
in	O
mice	O
.	O

The	O
ethanolic	O
extract	B-Chemical
of	I-Chemical
Daucus	I-Chemical
carota	I-Chemical
seeds	I-Chemical
(	O
DCE	B-Chemical
)	O
was	O
administered	O
orally	O
in	O
three	O
doses	O
(	O
100	O
,	O
200	O
,	O
400	O
mg	O
/	O
kg	O
)	O
for	O
seven	O
successive	O
days	O
to	O
different	O
groups	O
of	O
young	O
and	O
aged	O
mice	O
.	O

Elevated	O
plus	O
maze	O
and	O
passive	O
avoidance	O
apparatus	O
served	O
as	O
the	O
exteroceptive	O
behavioral	O
models	O
for	O
testing	O
memory	O
.	O

Diazepam	B-Chemical
-	O
,	O
scopolamine	B-Chemical
-	O
and	O
ageing	O
-	O
induced	O
amnesia	B-Disease
served	O
as	O
the	O
interoceptive	O
behavioral	O
models	O
.	O

DCE	B-Chemical
(	O
200	O
,	O
400	O
mg	O
/	O
kg	O
,	O
p	O
.	O
o	O
.	O
)	O
showed	O
significant	O
improvement	O
in	O
memory	O
scores	O
of	O
young	O
and	O
aged	O
mice	O
.	O

The	O
extent	O
of	O
memory	O
improvement	O
evoked	O
by	O
DCE	B-Chemical
was	O
23	O
%	O
at	O
the	O
dose	O
of	O
200	O
mg	O
/	O
kg	O
and	O
35	O
%	O
at	O
the	O
dose	O
of	O
400	O
mg	O
/	O
kg	O
in	O
young	O
mice	O
using	O
elevated	O
plus	O
maze	O
.	O

Similarly	O
,	O
significant	O
improvements	O
in	O
memory	O
scores	O
were	O
observed	O
using	O
passive	O
avoidance	O
apparatus	O
and	O
aged	O
mice	O
.	O

Furthermore	O
,	O
DCE	B-Chemical
reversed	O
the	O
amnesia	B-Disease
induced	O
by	O
scopolamine	B-Chemical
(	O
0	O
.	O
4	O
mg	O
/	O
kg	O
,	O
i	O
.	O
p	O
.	O
)	O
and	O
diazepam	B-Chemical
(	O
1	O
mg	O
/	O
kg	O
,	O
i	O
.	O
p	O
.	O
)	O
.	O

Daucus	B-Chemical
carota	I-Chemical
extract	I-Chemical
(	O
200	O
,	O
400	O
mg	O
/	O
kg	O
,	O
p	O
.	O
o	O
.	O
)	O
reduced	O
significantly	O
the	O
brain	O
acetylcholinesterase	O
activity	O
and	O
cholesterol	B-Chemical
levels	O
in	O
young	O
and	O
aged	O
mice	O
.	O

The	O
extent	O
of	O
inhibition	O
of	O
brain	O
cholinesterase	O
activity	O
evoked	O
by	O
DCE	B-Chemical
at	O
the	O
dose	O
of	O
400	O
mg	O
/	O
kg	O
was	O
22	O
%	O
in	O
young	O
and	O
19	O
%	O
in	O
aged	O
mice	O
.	O

There	O
was	O
a	O
remarkable	O
reduction	O
in	O
total	O
cholesterol	B-Chemical
level	O
as	O
well	O
,	O
to	O
the	O
extent	O
of	O
23	O
%	O
in	O
young	O
and	O
21	O
%	O
in	O
aged	O
animals	O
with	O
this	O
dose	O
of	O
DCE	B-Chemical
.	O

Therefore	O
,	O
DCE	B-Chemical
may	O
prove	O
to	O
be	O
a	O
useful	O
remedy	O
for	O
the	O
management	O
of	O
cognitive	B-Disease
dysfunctions	I-Disease
on	O
account	O
of	O
its	O
multifarious	O
beneficial	O
effects	O
such	O
as	O
,	O
memory	O
improving	O
property	O
,	O
cholesterol	B-Chemical
lowering	O
property	O
and	O
anticholinesterase	O
activity	O
.	O

Valproic	B-Chemical
acid	I-Chemical
induced	O
encephalopathy	B-Disease
-	O
-	O
19	O
new	O
cases	O
in	O
Germany	O
from	O
1994	O
to	O
2003	O
-	O
-	O
a	O
side	O
effect	O
associated	O
to	O
VPA	B-Chemical
-	O
therapy	O
not	O
only	O
in	O
young	O
children	O
.	O

Valproic	B-Chemical
acid	I-Chemical
(	O
VPA	B-Chemical
)	O
is	O
a	O
broad	O
-	O
spectrum	O
antiepileptic	O
drug	O
and	O
is	O
usually	O
well	O
-	O
tolerated	O
.	O

Rare	O
serious	O
complications	O
may	O
occur	O
in	O
some	O
patients	O
,	O
including	O
haemorrhagic	O
pancreatitis	B-Disease
,	O
bone	B-Disease
marrow	I-Disease
suppression	I-Disease
,	O
VPA	B-Chemical
-	O
induced	O
hepatotoxicity	B-Disease
and	O
VPA	B-Chemical
-	O
induced	O
encephalopathy	B-Disease
.	O

The	O
typical	O
signs	O
of	O
VPA	B-Chemical
-	O
induced	O
encephalopathy	B-Disease
are	O
impaired	B-Disease
consciousness	I-Disease
,	O
sometimes	O
marked	O
EEG	O
background	O
slowing	O
,	O
increased	O
seizure	B-Disease
frequency	O
,	O
with	O
or	O
without	O
hyperammonemia	B-Disease
.	O

There	O
is	O
still	O
no	O
proof	O
of	O
causative	O
effect	O
of	O
VPA	B-Chemical
in	O
patients	O
with	O
encephalopathy	B-Disease
,	O
but	O
only	O
of	O
an	O
association	O
with	O
an	O
assumed	O
causal	O
relation	O
.	O

We	O
report	O
19	O
patients	O
with	O
VPA	B-Chemical
-	O
associated	O
encephalopathy	B-Disease
in	O
Germany	O
from	O
the	O
years	O
1994	O
to	O
2003	O
,	O
none	O
of	O
whom	O
had	O
been	O
published	O
previously	O
.	O

Cerebral	B-Disease
haemorrhage	I-Disease
induced	O
by	O
warfarin	B-Chemical
-	O
the	O
influence	O
of	O
drug	O
-	O
drug	O
interactions	O
.	O

PURPOSE	O
:	O
To	O
evaluate	O
the	O
frequency	O
,	O
severity	O
and	O
preventability	O
of	O
warfarin	B-Chemical
-	O
induced	O
cerebral	B-Disease
haemorrhages	I-Disease
due	O
to	O
warfarin	B-Chemical
and	O
warfarin	B-Chemical
-	O
drug	O
interactions	O
in	O
patients	O
living	O
in	O
the	O
county	O
of	O
Osterg	O
tland	O
,	O
Sweden	O
.	O

METHODS	O
:	O
All	O
patients	O
with	O
a	O
diagnosed	O
cerebral	B-Disease
haemorrhage	I-Disease
at	O
three	O
hospitals	O
during	O
the	O
period	O
2000	O
-	O
2002	O
were	O
identified	O
.	O

Medical	O
records	O
were	O
studied	O
retrospectively	O
to	O
evaluate	O
whether	O
warfarin	B-Chemical
and	O
warfarin	B-Chemical
-	O
drug	O
interactions	O
could	O
have	O
caused	O
the	O
cerebral	B-Disease
haemorrhage	I-Disease
.	O

The	O
proportion	O
of	O
possibly	O
avoidable	O
cases	O
due	O
to	O
drug	O
interactions	O
was	O
estimated	O
.	O

RESULTS	O
:	O
Among	O
593	O
patients	O
with	O
cerebral	B-Disease
haemorrhage	I-Disease
,	O
59	O
(	O
10	O
%	O
)	O
were	O
assessed	O
as	O
related	O
to	O
warfarin	B-Chemical
treatment	O
.	O

This	O
imply	O
an	O
incidence	O
of	O
1	O
.	O
7	O
/	O
100	O
,	O
000	O
treatment	O
years	O
.	O

Of	O
the	O
59	O
cases	O
,	O
26	O
(	O
44	O
%	O
)	O
had	O
a	O
fatal	O
outcome	O
,	O
compared	O
to	O
136	O
(	O
25	O
%	O
)	O
among	O
the	O
non	O
-	O
warfarin	B-Chemical
patients	O
(	O
p	O
<	O
0	O
.	O
01	O
)	O
.	O

A	O
warfarin	B-Chemical
-	O
drug	O
interaction	O
could	O
have	O
contributed	O
to	O
the	O
haemorrhage	B-Disease
in	O
24	O
(	O
41	O
%	O
)	O
of	O
the	O
warfarin	B-Chemical
patients	O
and	O
in	O
7	O
of	O
these	O
(	O
12	O
%	O
)	O
the	O
bleeding	B-Disease
complication	O
was	O
considered	O
being	O
possible	O
to	O
avoid	O
.	O

CONCLUSIONS	O
:	O
Warfarin	B-Chemical
-	O
induced	O
cerebral	B-Disease
haemorrhages	I-Disease
are	O
a	O
major	O
clinical	O
problem	O
with	O
a	O
high	O
fatality	O
rate	O
.	O

Almost	O
half	O
of	O
the	O
cases	O
was	O
related	O
to	O
a	O
warfarin	B-Chemical
-	O
drug	O
interaction	O
.	O

A	O
significant	O
proportion	O
of	O
warfarin	B-Chemical
-	O
related	O
cerebral	B-Disease
haemorrhages	I-Disease
might	O
have	O
been	O
prevented	O
if	O
greater	O
caution	O
had	O
been	O
taken	O
when	O
prescribing	O
drugs	O
known	O
to	O
interact	O
with	O
warfarin	B-Chemical
.	O

Antipsychotic	O
-	O
like	O
profile	O
of	O
thioperamide	B-Chemical
,	O
a	O
selective	O
H3	O
-	O
receptor	O
antagonist	O
in	O
mice	O
.	O

Experimental	O
and	O
clinical	O
evidence	O
points	O
to	O
a	O
role	O
of	O
central	O
histaminergic	O
system	O
in	O
the	O
pathogenesis	O
of	O
schizophrenia	B-Disease
.	O

The	O
present	O
study	O
was	O
designed	O
to	O
study	O
the	O
effect	O
of	O
histamine	B-Chemical
H	O
(	O
3	O
)	O
-	O
receptor	O
ligands	O
on	O
neuroleptic	O
-	O
induced	O
catalepsy	B-Disease
,	O
apomorphine	B-Chemical
-	O
induced	O
climbing	O
behavior	O
and	O
amphetamine	B-Chemical
-	O
induced	O
locomotor	O
activities	O
in	O
mice	O
.	O

Catalepsy	B-Disease
was	O
induced	O
by	O
haloperidol	B-Chemical
(	O
2	O
mg	O
/	O
kg	O
p	O
.	O
o	O
.	O
)	O
,	O
while	O
apomorphine	B-Chemical
(	O
1	O
.	O
5	O
mg	O
/	O
kg	O
s	O
.	O
c	O
.	O
)	O
and	O
amphetamine	B-Chemical
(	O
2	O
mg	O
/	O
kg	O
s	O
.	O
c	O
.	O
)	O
were	O
used	O
for	O
studying	O
climbing	O
behavior	O
and	O
locomotor	O
activities	O
,	O
respectively	O
.	O

(	B-Chemical
R	I-Chemical
)	I-Chemical
-	I-Chemical
alpha	I-Chemical
-	I-Chemical
methylhistamine	I-Chemical
(	O
RAMH	B-Chemical
)	O
(	O
5	O
microg	O
i	O
.	O
c	O
.	O
v	O
.	O
)	O
and	O
thioperamide	B-Chemical
(	O
THP	B-Chemical
)	O
(	O
15	O
mg	O
/	O
kg	O
i	O
.	O
p	O
.	O
)	O
,	O
per	O
se	O
did	O
not	O
cause	O
catalepsy	B-Disease
.	O

Administration	O
of	O
THP	B-Chemical
(	O
3	O
.	O
75	O
,	O
7	O
.	O
5	O
and	O
15	O
mg	O
/	O
kg	O
i	O
.	O
p	O
.	O
)	O
1	O
h	O
prior	O
to	O
haloperidol	B-Chemical
resulted	O
in	O
a	O
dose	O
-	O
dependent	O
increase	O
in	O
the	O
catalepsy	B-Disease
times	O
(	O
P	O
<	O
0	O
.	O
05	O
)	O
.	O

However	O
,	O
pretreatment	O
with	O
RAMH	B-Chemical
significantly	O
reversed	O
such	O
an	O
effect	O
of	O
THP	B-Chemical
(	O
15	O
mg	O
/	O
kg	O
i	O
.	O
p	O
.	O
)	O
.	O

RAMH	B-Chemical
per	O
se	O
showed	O
significant	O
reduction	O
in	O
locomotor	O
time	O
,	O
distance	O
traveled	O
and	O
average	O
speed	O
but	O
THP	B-Chemical
(	O
15	O
mg	O
/	O
kg	O
i	O
.	O
p	O
.	O
)	O
per	O
se	O
had	O
no	O
effect	O
on	O
these	O
parameters	O
.	O

On	O
amphetamine	B-Chemical
-	O
induced	O
hyperactivity	B-Disease
,	O
THP	B-Chemical
(	O
3	O
.	O
75	O
and	O
7	O
.	O
5	O
mg	O
/	O
kg	O
i	O
.	O
p	O
.	O
)	O
reduced	O
locomotor	O
time	O
,	O
distance	O
traveled	O
and	O
average	O
speed	O
(	O
P	O
<	O
0	O
.	O
05	O
)	O
.	O

Pretreatment	O
with	O
RAMH	B-Chemical
(	O
5	O
microg	O
i	O
.	O
c	O
.	O
v	O
.	O
)	O
could	O
partially	O
reverse	O
such	O
effects	O
of	O
THP	B-Chemical
(	O
3	O
.	O
75	O
mg	O
/	O
kg	O
i	O
.	O
p	O
.	O
)	O
.	O

Climbing	O
behavior	O
induced	O
by	O
apomorphine	B-Chemical
was	O
reduced	O
in	O
animals	O
treated	O
with	O
THP	B-Chemical
.	O

Such	O
an	O
effect	O
was	O
,	O
however	O
,	O
reversed	O
in	O
presence	O
of	O
RAMH	B-Chemical
.	O

THP	B-Chemical
exhibited	O
an	O
antipsychotic	O
-	O
like	O
profile	O
by	O
potentiating	O
haloperidol	B-Chemical
-	O
induced	O
catalepsy	B-Disease
,	O
reducing	O
amphetamine	B-Chemical
-	O
induced	O
hyperactivity	B-Disease
and	O
reducing	O
apomorphine	B-Chemical
-	O
induced	O
climbing	O
in	O
mice	O
.	O

Such	O
effects	O
of	O
THP	B-Chemical
were	O
reversed	O
by	O
RAMH	B-Chemical
indicating	O
the	O
involvement	O
of	O
histamine	B-Chemical
H	O
(	O
3	O
)	O
-	O
receptors	O
.	O

Findings	O
suggest	O
a	O
potential	O
for	O
H	O
(	O
3	O
)	O
-	O
receptor	O
antagonists	O
in	O
improving	O
the	O
refractory	O
cases	O
of	O
schizophrenia	B-Disease
.	O

Cauda	B-Disease
equina	I-Disease
syndrome	I-Disease
after	O
epidural	O
steroid	B-Chemical
injection	O
:	O
a	O
case	O
report	O
.	O

OBJECTIVE	O
:	O
Conventional	O
treatment	O
methods	O
of	O
lumbusacral	O
radiculopathy	B-Disease
are	O
physical	O
therapy	O
,	O
epidural	O
steroid	B-Chemical
injections	O
,	O
oral	O
medications	O
,	O
and	O
spinal	O
manipulative	O
therapy	O
.	O

Cauda	B-Disease
equina	I-Disease
syndrome	I-Disease
is	O
a	O
rare	O
complication	O
of	O
epidural	O
anesthesia	O
.	O

The	O
following	O
case	O
is	O
a	O
report	O
of	O
cauda	B-Disease
equina	I-Disease
syndrome	I-Disease
possibly	O
caused	O
by	O
epidural	O
injection	O
of	O
triamcinolone	B-Chemical
and	O
bupivacaine	B-Chemical
.	O

CLINICAL	O
FEATURES	O
:	O
A	O
50	O
-	O
year	O
-	O
old	O
woman	O
with	O
low	B-Disease
back	I-Disease
and	I-Disease
right	I-Disease
leg	I-Disease
pain	I-Disease
was	O
scheduled	O
for	O
epidural	O
steroid	B-Chemical
injection	O
.	O

INTERVENTION	O
AND	O
OUTCOME	O
:	O
An	O
18	O
-	O
gauge	O
Touhy	O
needle	O
was	O
inserted	O
until	O
loss	O
of	O
resistance	O
occurred	O
at	O
the	O
L4	O
-	O
5	O
level	O
.	O

Spread	O
of	O
the	O
contrast	O
medium	O
within	O
the	O
epidural	O
space	O
was	O
determined	O
by	O
radiographic	O
imaging	O
.	O

After	O
verifying	O
the	O
epidural	O
space	O
,	O
bupivacaine	B-Chemical
and	O
triamcinolone	B-Chemical
diacetate	I-Chemical
were	O
injected	O
.	O

After	O
the	O
injection	O
,	O
there	O
was	O
a	O
reduction	O
in	O
radicular	O
symptoms	O
.	O

Three	O
hours	O
later	O
,	O
she	O
complained	O
of	O
perineal	O
numbness	B-Disease
and	O
lower	B-Disease
extremity	I-Disease
weakness	I-Disease
.	O

The	O
neurologic	O
evaluation	O
revealed	O
loss	B-Disease
of	I-Disease
sensation	I-Disease
in	O
the	O
saddle	O
area	O
and	O
medial	O
aspect	O
of	O
her	O
right	O
leg	O
.	O

There	O
was	O
a	O
decrease	O
in	O
the	O
perception	O
of	O
pinprick	O
test	O
.	O

Deep	O
-	O
tendon	O
reflexes	O
were	O
decreased	O
especially	O
in	O
the	O
right	O
leg	O
.	O

She	O
was	O
unable	O
to	O
urinate	O
.	O

The	O
patient	O
'	O
s	O
symptoms	O
improved	O
slightly	O
over	O
the	O
next	O
few	O
hours	O
.	O

She	O
had	O
a	O
gradual	O
return	O
of	O
motor	O
function	O
and	O
ability	O
of	O
feeling	O
Foley	O
catheter	O
.	O

All	O
of	O
the	O
symptoms	O
were	O
completely	O
resolved	O
over	O
the	O
next	O
8	O
hours	O
.	O

CONCLUSION	O
:	O
Complications	O
associated	O
with	O
epidural	O
steroid	B-Chemical
injections	O
are	O
rare	O
.	O

Clinical	O
examination	O
and	O
continued	O
vigilance	O
for	O
neurologic	B-Disease
deterioration	I-Disease
after	O
epidural	O
steroid	B-Chemical
injections	O
is	O
important	O
.	O

High	O
-	O
dose	O
testosterone	B-Chemical
is	O
associated	O
with	O
atherosclerosis	B-Disease
in	O
postmenopausal	O
women	O
.	O

OBJECTIVES	O
:	O
To	O
study	O
the	O
long	O
-	O
term	O
effects	O
of	O
androgen	O
treatment	O
on	O
atherosclerosis	B-Disease
in	O
postmenopausal	O
women	O
.	O

METHODS	O
:	O
In	O
a	O
population	O
-	O
based	O
study	O
in	O
513	O
naturally	O
postmenopausal	O
women	O
aged	O
54	O
-	O
67	O
years	O
,	O
we	O
studied	O
the	O
association	O
between	O
self	O
-	O
reported	O
intramuscularly	O
administered	O
high	O
-	O
dose	O
estrogen	B-Chemical
-	O
testosterone	B-Chemical
therapy	O
(	O
estradiol	B-Chemical
-	I-Chemical
and	I-Chemical
testosterone	I-Chemical
esters	I-Chemical
)	O
and	O
aortic	O
atherosclerosis	B-Disease
.	O

Aortic	O
atherosclerosis	B-Disease
was	O
diagnosed	O
by	O
radiographic	O
detection	O
of	O
calcified	O
deposits	O
in	O
the	O
abdominal	O
aorta	O
,	O
which	O
have	O
been	O
shown	O
to	O
reflect	O
intima	O
atherosclerosis	B-Disease
.	O

Hormone	O
therapy	O
users	O
were	O
compared	O
with	O
never	O
users	O
.	O

RESULTS	O
:	O
Intramuscular	O
hormone	O
therapy	O
use	O
for	O
1	O
year	O
or	O
longer	O
was	O
reported	O
by	O
25	O
women	O
.	O

In	O
almost	O
half	O
of	O
these	O
women	O
severe	O
atherosclerosis	B-Disease
of	O
the	O
aorta	O
was	O
present	O
(	O
n	O
=	O
11	O
)	O
,	O
while	O
in	O
women	O
without	O
hormone	O
use	O
severe	O
atherosclerosis	B-Disease
of	O
the	O
aorta	O
was	O
present	O
in	O
less	O
than	O
20	O
%	O
(	O
OR	O
3	O
.	O
1	O
;	O
95	O
%	O
CI	O
,	O
1	O
.	O
1	O
-	O
8	O
.	O
5	O
,	O
adjusted	O
for	O
age	O
,	O
years	O
since	O
menopause	O
,	O
smoking	O
,	O
and	O
body	O
mass	O
index	O
)	O
.	O

The	O
association	O
remained	O
after	O
additional	O
adjustment	O
for	O
diabetes	B-Disease
,	O
cholesterol	B-Chemical
level	O
,	O
systolic	O
blood	O
pressure	O
,	O
or	O
alcohol	B-Chemical
use	O
.	O

No	O
association	O
was	O
found	O
for	O
hormone	O
use	O
less	O
than	O
1	O
year	O
.	O

CONCLUSION	O
:	O
Our	O
results	O
suggest	O
that	O
high	O
-	O
dose	O
testosterone	B-Chemical
therapy	O
may	O
adversely	O
affect	O
atherosclerosis	B-Disease
in	O
postmenopausal	O
women	O
and	O
indicate	O
that	O
androgen	O
replacement	O
in	O
these	O
women	O
may	O
not	O
be	O
harmless	O
.	O

Optimising	O
stroke	B-Disease
prevention	O
in	O
non	O
-	O
valvular	O
atrial	B-Disease
fibrillation	I-Disease
.	O

Atrial	B-Disease
fibrillation	I-Disease
is	O
associated	O
with	O
substantial	O
morbidity	O
and	O
mortality	O
.	O

Pooled	O
data	O
from	O
trials	O
comparing	O
antithrombotic	O
treatment	O
with	O
placebo	O
have	O
shown	O
that	O
warfarin	B-Chemical
reduces	O
the	O
risk	O
of	O
stroke	B-Disease
by	O
62	O
%	O
,	O
and	O
that	O
aspirin	B-Chemical
alone	O
reduces	O
the	O
risk	O
by	O
22	O
%	O
.	O

Overall	O
,	O
in	O
high	O
-	O
risk	O
patients	O
,	O
warfarin	B-Chemical
is	O
superior	O
to	O
aspirin	B-Chemical
in	O
preventing	O
strokes	B-Disease
,	O
with	O
a	O
relative	O
risk	O
reduction	O
of	O
36	O
%	O
.	O

Ximelagatran	B-Chemical
,	O
an	O
oral	O
direct	O
thrombin	O
inhibitor	O
,	O
was	O
found	O
to	O
be	O
as	O
efficient	O
as	O
vitamin	B-Chemical
K	I-Chemical
antagonist	O
drugs	O
in	O
the	O
prevention	O
of	O
embolic	B-Disease
events	I-Disease
,	O
but	O
has	O
been	O
recently	O
withdrawn	O
because	O
of	O
abnormal	B-Disease
liver	I-Disease
function	I-Disease
tests	O
.	O

The	O
ACTIVE	O
-	O
W	O
(	O
Atrial	B-Disease
Fibrillation	I-Disease
Clopidogrel	B-Chemical
Trial	O
with	O
Irbesartan	B-Chemical
for	O
Prevention	O
of	O
Vascular	O
Events	O
)	O
study	O
has	O
demonstrated	O
that	O
warfarin	B-Chemical
is	O
superior	O
to	O
platelet	O
therapy	O
(	O
clopidogrel	B-Chemical
plus	O
aspirin	B-Chemical
)	O
in	O
the	O
prevention	O
af	O
embolic	B-Disease
events	I-Disease
.	O

Idraparinux	B-Chemical
,	O
a	O
Factor	O
Xa	O
inhibitor	O
,	O
is	O
being	O
evaluated	O
in	O
patients	O
with	O
atrial	B-Disease
fibrillation	I-Disease
.	O

Angiotensin	B-Chemical
-	O
converting	O
enzyme	O
inhibitors	O
and	O
angiotensin	B-Chemical
II	I-Chemical
receptor	O
-	O
blocking	O
drugs	O
hold	O
promise	O
in	O
atrial	B-Disease
fibrillation	I-Disease
through	O
cardiac	B-Disease
remodelling	I-Disease
.	O

Preliminary	O
studies	O
suggest	O
that	O
statins	B-Chemical
could	O
interfere	O
with	O
the	O
risk	O
of	O
recurrence	O
after	O
electrical	O
cardioversion	O
.	O

Finally	O
,	O
percutaneous	O
methods	O
for	O
the	O
exclusion	O
of	O
left	O
atrial	O
appendage	O
are	O
under	O
investigation	O
in	O
high	O
-	O
risk	O
patients	O
.	O

Anti	O
-	O
oxidant	O
effects	O
of	O
atorvastatin	B-Chemical
in	O
dexamethasone	B-Chemical
-	O
induced	O
hypertension	B-Disease
in	O
the	O
rat	O
.	O

1	O
.	O

Dexamethasone	B-Chemical
(	O
Dex	B-Chemical
)	O
-	O
induced	O
hypertension	B-Disease
is	O
characterized	O
by	O
endothelial	O
dysfunction	O
associated	O
with	O
nitric	B-Chemical
oxide	I-Chemical
(	O
NO	B-Chemical
)	O
deficiency	O
and	O
increased	O
superoxide	B-Chemical
(	O
O2	B-Chemical
-	I-Chemical
)	O
production	O
.	O

Atorvastatin	B-Chemical
(	O
Ato	B-Chemical
)	O
possesses	O
pleiotropic	O
properties	O
that	O
have	O
been	O
reported	O
to	O
improve	O
endothelial	O
function	O
through	O
increased	O
availability	O
of	O
NO	B-Chemical
and	O
reduced	O
O2	B-Chemical
-	I-Chemical
production	O
in	O
various	O
forms	O
of	O
hypertension	B-Disease
.	O

In	O
the	O
present	O
study	O
,	O
we	O
investigated	O
whether	O
50	O
mg	O
/	O
kg	O
per	O
day	O
,	O
p	O
.	O
o	O
.	O
,	O
Ato	B-Chemical
could	O
prevent	O
endothelial	O
NO	B-Chemical
synthase	O
(	O
eNOS	O
)	O
downregulation	O
and	O
the	O
increase	O
in	O
O2	B-Chemical
-	I-Chemical
in	O
Sprague	O
-	O
Dawley	O
(	O
SD	O
)	O
rats	O
,	O
thereby	O
reducing	O
blood	O
pressure	O
.	O

2	O
.	O

Male	O
SD	O
rats	O
(	O
n	O
=	O
30	O
)	O
were	O
treated	O
with	O
Ato	B-Chemical
(	O
50	O
mg	O
/	O
kg	O
per	O
day	O
in	O
drinking	O
water	O
)	O
or	O
tap	O
water	O
for	O
15	O
days	O
.	O

Dexamethasone	B-Chemical
(	O
10	O
microg	O
/	O
kg	O
per	O
day	O
,	O
s	O
.	O
c	O
.	O
)	O
or	O
saline	O
was	O
started	O
after	O
4	O
days	O
in	O
Ato	B-Chemical
-	O
treated	O
and	O
non	O
-	O
treated	O
rats	O
and	O
continued	O
for	O
11	O
-	O
13	O
days	O
.	O

Systolic	O
blood	O
pressure	O
(	O
SBP	O
)	O
was	O
measured	O
on	O
alternate	O
days	O
using	O
the	O
tail	O
-	O
cuff	O
method	O
.	O

Endothelial	O
function	O
was	O
assessed	O
by	O
acetylcholine	B-Chemical
-	O
induced	O
vasorelaxation	O
and	O
phenylephrine	B-Chemical
-	O
induced	O
vasoconstriction	O
in	O
aortic	O
segments	O
.	O

Vascular	O
eNOS	O
mRNA	O
was	O
assessed	O
by	O
semi	O
-	O
quantitative	O
reverse	O
transcription	O
-	O
polymerase	O
chain	O
reaction	O
.	O

3	O
.	O

In	O
rats	O
treated	O
with	O
Dex	B-Chemical
alone	O
,	O
SBP	O
was	O
increased	O
from	O
109	O
+	O
/	O
-	O
2	O
to	O
133	O
+	O
/	O
-	O
2	O
mmHg	O
on	O
Days	O
4	O
and	O
Day	O
14	O
,	O
respectively	O
(	O
P	O
<	O
0	O
.	O
001	O
)	O
.	O

In	O
the	O
Ato	B-Chemical
+	O
Dex	B-Chemical
group	O
,	O
SBP	O
was	O
increased	O
from	O
113	O
+	O
/	O
-	O
2	O
to	O
119	O
+	O
/	O
-	O
2	O
mmHg	O
on	O
Days	O
4	O
to	O
14	O
,	O
respectively	O
(	O
P	O
<	O
0	O
.	O
001	O
)	O
,	O
but	O
was	O
significantly	O
lower	O
than	O
SBP	O
in	O
the	O
group	O
treated	O
with	O
Dex	B-Chemical
alone	O
(	O
P	O
<	O
0	O
.	O
05	O
)	O
.	O

Endothelial	O
-	O
dependent	O
relaxation	O
and	O
eNOS	O
mRNA	O
expression	O
were	O
greater	O
in	O
the	O
Dex	B-Chemical
+	O
Ato	B-Chemical
group	O
than	O
in	O
the	O
Dex	B-Chemical
only	O
group	O
(	O
P	O
<	O
0	O
.	O
05	O
and	O
P	O
<	O
0	O
.	O
0001	O
,	O
respectively	O
)	O
.	O

Aortic	O
superoxide	B-Chemical
production	O
was	O
lower	O
in	O
the	O
Dex	B-Chemical
+	O
Ato	B-Chemical
group	O
compared	O
with	O
the	O
group	O
treated	O
with	O
Dex	B-Chemical
alone	O
(	O
P	O
<	O
0	O
.	O
0001	O
)	O
.	O

4	O
.	O

Treatment	O
with	O
Ato	B-Chemical
improved	O
endothelial	O
function	O
,	O
reduced	O
superoxide	B-Chemical
production	O
and	O
reduced	O
SBP	O
in	O
Dex	B-Chemical
-	O
treated	O
SD	O
rats	O
.	O

Severe	O
citrate	B-Chemical
toxicity	B-Disease
complicating	O
volunteer	O
apheresis	O
platelet	O
donation	O
.	O

We	O
report	O
a	O
case	O
of	O
severe	O
citrate	B-Chemical
toxicity	B-Disease
during	O
volunteer	O
donor	O
apheresis	O
platelet	O
collection	O
.	O

The	O
donor	O
was	O
a	O
40	O
-	O
year	O
-	O
old	O
female	O
,	O
first	O
-	O
time	O
apheresis	O
platelet	O
donor	O
.	O

Past	O
medical	O
history	O
was	O
remarkable	O
for	O
hypertension	B-Disease
,	O
hyperlipidemia	B-Disease
,	O
and	O
depression	B-Disease
.	O

Reported	O
medications	O
included	O
bumetanide	B-Chemical
,	O
pravastatin	B-Chemical
,	O
and	O
paroxetine	B-Chemical
.	O

Thirty	O
minutes	O
from	O
the	O
start	O
of	O
the	O
procedure	O
,	O
the	O
donor	O
noted	O
tingling	O
around	O
the	O
mouth	O
,	O
hands	O
,	O
and	O
feet	O
.	O

She	O
then	O
very	O
rapidly	O
developed	O
acute	O
onset	O
of	O
severe	O
facial	O
and	O
extremity	O
tetany	B-Disease
.	O

Empirical	O
treatment	O
with	O
intravenous	O
calcium	B-Chemical
gluconate	I-Chemical
was	O
initiated	O
,	O
and	O
muscle	B-Disease
contractions	I-Disease
slowly	O
subsided	O
over	O
approximately	O
10	O
to	O
15	O
minutes	O
.	O

The	O
events	O
are	O
consistent	O
with	O
a	O
severe	O
reaction	O
to	O
calcium	B-Chemical
chelation	O
by	O
sodium	B-Chemical
citrate	I-Chemical
anticoagulant	O
resulting	O
in	O
symptomatic	O
systemic	O
hypocalcemia	B-Disease
.	O

Upon	O
additional	O
retrospective	O
analysis	O
,	O
it	O
was	O
noted	O
that	O
bumetanide	B-Chemical
is	O
a	O
loop	B-Chemical
diuretic	I-Chemical
that	O
may	O
cause	O
significant	O
hypocalcemia	B-Disease
.	O

We	O
conclude	O
that	O
careful	O
screening	O
for	O
medications	O
and	O
underlying	O
conditions	O
predisposing	O
to	O
hypocalcemia	B-Disease
is	O
recommended	O
to	O
help	O
prevent	O
severe	O
reactions	O
due	O
to	O
citrate	B-Chemical
toxicity	B-Disease
.	O

Laboratory	O
measurement	O
of	O
pre	O
-	O
procedure	O
serum	O
calcium	B-Chemical
levels	O
in	O
selected	O
donors	O
may	O
identify	O
cases	O
requiring	O
heightened	O
vigilance	O
.	O

The	O
case	O
also	O
illustrates	O
the	O
importance	O
of	O
maintaining	O
preparedness	O
for	O
managing	O
rare	O
but	O
serious	O
reactions	O
in	O
volunteer	O
apheresis	O
blood	O
donors	O
.	O

Sirolimus	B-Chemical
-	O
associated	O
proteinuria	B-Disease
and	O
renal	B-Disease
dysfunction	I-Disease
.	O

Sirolimus	B-Chemical
is	O
a	O
novel	O
immunosuppressant	O
with	O
potent	O
antiproliferative	O
actions	O
through	O
its	O
ability	O
to	O
inhibit	O
the	O
raptor	O
-	O
containing	O
mammalian	O
target	O
of	O
rapamycin	B-Chemical
protein	O
kinase	O
.	O

Sirolimus	B-Chemical
represents	O
a	O
major	O
therapeutic	O
advance	O
in	O
the	O
prevention	O
of	O
acute	O
renal	O
allograft	O
rejection	O
and	O
chronic	O
allograft	O
nephropathy	B-Disease
.	O

Its	O
role	O
in	O
the	O
therapy	O
of	O
glomerulonephritis	B-Disease
,	O
autoimmunity	B-Disease
,	O
cystic	B-Disease
renal	I-Disease
diseases	I-Disease
and	O
renal	B-Disease
cancer	I-Disease
is	O
under	O
investigation	O
.	O

Because	O
sirolimus	B-Chemical
does	O
not	O
share	O
the	O
vasomotor	O
renal	O
adverse	O
effects	O
exhibited	O
by	O
calcineurin	O
inhibitors	O
,	O
it	O
has	O
been	O
designated	O
a	O
'	O
non	O
-	O
nephrotoxic	B-Disease
drug	O
'	O
.	O

However	O
,	O
clinical	O
reports	O
suggest	O
that	O
,	O
under	O
some	O
circumstances	O
,	O
sirolimus	B-Chemical
is	O
associated	O
with	O
proteinuria	B-Disease
and	O
acute	B-Disease
renal	I-Disease
dysfunction	I-Disease
.	O

A	O
common	O
risk	O
factor	O
appears	O
to	O
be	O
presence	O
of	O
pre	O
-	O
existing	O
chronic	B-Disease
renal	I-Disease
damage	I-Disease
.	O

The	O
mechanisms	O
of	O
sirolimus	B-Chemical
-	O
associated	O
proteinuria	B-Disease
are	O
multifactorial	O
and	O
may	O
be	O
due	O
to	O
an	O
increase	O
in	O
glomerular	O
capillary	O
pressure	O
following	O
calcineurin	O
inhibitor	O
withdrawal	O
.	O

It	O
has	O
also	O
been	O
suggested	O
that	O
sirolimus	B-Chemical
directly	O
causes	O
increased	O
glomerular	O
permeability	O
/	O
injury	O
,	O
but	O
evidence	O
for	O
this	O
mechanism	O
is	O
currently	O
inconclusive	O
.	O

The	O
acute	B-Disease
renal	I-Disease
dysfunction	I-Disease
associated	O
with	O
sirolimus	B-Chemical
(	O
such	O
as	O
in	O
delayed	O
graft	O
function	O
)	O
may	O
be	O
due	O
to	O
suppression	O
of	O
compensatory	O
renal	O
cell	O
proliferation	O
and	O
survival	O
/	O
repair	O
processes	O
.	O

Although	O
these	O
adverse	O
effects	O
occur	O
in	O
some	O
patients	O
,	O
their	O
occurrence	O
could	O
be	O
minimised	O
by	O
knowledge	O
of	O
the	O
molecular	O
effects	O
of	O
sirolimus	B-Chemical
on	O
the	O
kidney	O
,	O
the	O
use	O
of	O
sirolimus	B-Chemical
in	O
appropriate	O
patient	O
populations	O
,	O
close	O
monitoring	O
of	O
proteinuria	B-Disease
and	O
renal	O
function	O
,	O
use	O
of	O
angiotensin	B-Chemical
-	O
converting	O
enzyme	O
inhibitors	O
or	O
angiotensin	B-Chemical
II	I-Chemical
receptor	O
blockers	O
if	O
proteinuria	B-Disease
occurs	O
and	O
withdrawal	O
if	O
needed	O
.	O

Further	O
long	O
-	O
term	O
analysis	O
of	O
renal	O
allograft	O
studies	O
using	O
sirolimus	B-Chemical
as	O
de	O
novo	O
immunosuppression	O
along	O
with	O
clinical	O
and	O
laboratory	O
studies	O
will	O
refine	O
these	O
issues	O
in	O
the	O
future	O
.	O

Proteinuria	B-Disease
after	O
conversion	O
to	O
sirolimus	B-Chemical
in	O
renal	O
transplant	O
recipients	O
.	O

Sirolimus	B-Chemical
(	O
SRL	B-Chemical
)	O
is	O
a	O
new	O
,	O
potent	O
immunosuppressive	O
agent	O
.	O

More	O
recently	O
,	O
proteinuria	B-Disease
has	O
been	O
reported	O
as	O
a	O
consequence	O
of	O
sirolimus	B-Chemical
therapy	O
,	O
although	O
the	O
mechanism	O
has	O
remained	O
unclear	O
.	O

We	O
retrospectively	O
examined	O
the	O
records	O
of	O
25	O
renal	O
transplant	O
patients	O
,	O
who	O
developed	O
or	O
displayed	O
increased	O
proteinuria	B-Disease
after	O
SRL	B-Chemical
conversion	O
.	O

The	O
patient	O
cohort	O
(	O
14	O
men	O
,	O
11	O
women	O
)	O
was	O
treated	O
with	O
SRL	B-Chemical
as	O
conversion	O
therapy	O
,	O
due	O
to	O
chronic	B-Disease
allograft	I-Disease
nephropathy	I-Disease
(	O
CAN	B-Disease
)	O
(	O
n	O
=	O
15	O
)	O
neoplasia	B-Disease
(	O
n	O
=	O
8	O
)	O
;	O
Kaposi	B-Disease
'	I-Disease
s	I-Disease
sarcoma	I-Disease
,	O
Four	O
skin	B-Disease
cancers	I-Disease
,	O
One	O
intestinal	B-Disease
tumors	I-Disease
,	O
One	O
renal	B-Disease
cell	I-Disease
carsinom	I-Disease
)	O
or	O
BK	O
virus	O
nephropathy	B-Disease
(	O
n	O
=	O
2	O
)	O
.	O

SRL	B-Chemical
was	O
started	O
at	O
a	O
mean	O
of	O
78	O
+	O
/	O
-	O
42	O
(	O
15	O
to	O
163	O
)	O
months	O
after	O
transplantation	O
.	O

Mean	O
follow	O
-	O
up	O
on	O
SRL	B-Chemical
therapy	O
was	O
20	O
+	O
/	O
-	O
12	O
(	O
6	O
to	O
43	O
)	O
months	O
.	O

Proteinuria	B-Disease
increased	O
from	O
0	O
.	O
445	O
(	O
0	O
to	O
1	O
.	O
5	O
)	O
g	O
/	O
d	O
before	O
conversion	O
to	O
3	O
.	O
2	O
g	O
/	O
dL	O
(	O
0	O
.	O
2	O
to	O
12	O
)	O
after	O
conversion	O
(	O
P	O
=	O
0	O
.	O
001	O
)	O
.	O

Before	O
conversion	O
8	O
(	O
32	O
%	O
)	O
patients	O
had	O
no	O
proteinuria	B-Disease
,	O
whereas	O
afterwards	O
all	O
patients	O
had	O
proteinuria	B-Disease
.	O

In	O
28	O
%	O
of	O
patients	O
proteinuria	B-Disease
remained	O
unchanged	O
,	O
whereas	O
it	O
increased	O
in	O
68	O
%	O
of	O
patients	O
.	O

In	O
40	O
%	O
it	O
increased	O
by	O
more	O
than	O
100	O
%	O
.	O

Twenty	O
-	O
eight	O
percent	O
of	O
patients	O
showed	O
increased	O
proteinuria	B-Disease
to	O
the	O
nephrotic	B-Disease
range	O
.	O

Biopsies	O
performed	O
in	O
five	O
patients	O
revealed	O
new	O
pathological	O
changes	O
:	O
One	O
membranoproliferative	B-Disease
glomerulopathy	I-Disease
and	O
interstitial	B-Disease
nephritis	I-Disease
.	O

These	O
patients	O
showed	O
persistently	O
good	O
graft	O
function	O
.	O

Serum	O
creatinine	B-Chemical
values	O
did	O
not	O
change	O
significantly	O
:	O
1	O
.	O
98	O
+	O
/	O
-	O
0	O
.	O
8	O
mg	O
/	O
dL	O
before	O
SRL	B-Chemical
therapy	O
and	O
2	O
.	O
53	O
+	O
/	O
-	O
1	O
.	O
9	O
mg	O
/	O
dL	O
at	O
last	O
follow	O
-	O
up	O
(	O
P	O
=	O
.	O
14	O
)	O
.	O

Five	O
grafts	O
were	O
lost	O
and	O
the	O
patients	O
returned	O
to	O
dialysis	O
.	O

Five	O
patients	O
displayed	O
CAN	B-Disease
and	O
Kaposi	B-Disease
'	I-Disease
s	I-Disease
sarcoma	I-Disease
.	O

Mean	O
urinary	O
protein	O
of	O
patients	O
who	O
returned	O
to	O
dialysis	O
was	O
1	O
.	O
26	O
(	O
0	O
.	O
5	O
to	O
3	O
.	O
5	O
)	O
g	O
/	O
d	O
before	O
and	O
4	O
.	O
7	O
(	O
3	O
to	O
12	O
)	O
g	O
/	O
d	O
after	O
conversion	O
(	O
P	O
=	O
.	O
01	O
)	O
.	O

Mean	O
serum	O
creatinine	B-Chemical
level	O
before	O
conversion	O
was	O
2	O
.	O
21	O
mg	O
/	O
dL	O
and	O
thereafter	O
,	O
4	O
.	O
93	O
mg	O
/	O
dL	O
(	O
P	O
=	O
.	O
02	O
)	O
.	O

Heavy	O
proteinuria	B-Disease
was	O
common	O
after	O
the	O
use	O
of	O
SRL	B-Chemical
as	O
rescue	O
therapy	O
for	O
renal	O
transplantation	O
.	O

Therefore	O
,	O
conversion	O
should	O
be	O
considered	O
for	O
patients	O
who	O
have	O
not	O
developed	O
advanced	O
CAN	B-Disease
and	O
proteinuria	B-Disease
.	O

The	O
possibility	O
of	O
de	O
novo	O
glomerular	O
pathology	O
under	O
SRL	B-Chemical
treatment	O
requires	O
further	O
investigation	O
by	O
renal	O
biopsy	O
.	O

Long	O
-	O
term	O
follow	O
-	O
up	O
of	O
ifosfamide	B-Chemical
renal	B-Disease
toxicity	I-Disease
in	O
children	O
treated	O
for	O
malignant	B-Disease
mesenchymal	I-Disease
tumors	I-Disease
:	O
an	O
International	O
Society	O
of	O
Pediatric	O
Oncology	O
report	O
.	O

The	O
renal	O
function	O
of	O
74	O
children	O
with	O
malignant	B-Disease
mesenchymal	I-Disease
tumors	I-Disease
in	O
complete	O
remission	O
and	O
who	O
have	O
received	O
the	O
same	O
ifosfamide	B-Chemical
chemotherapy	O
protocol	O
(	O
International	O
Society	O
of	O
Pediatric	O
Oncology	O
Malignant	B-Disease
Mesenchymal	I-Disease
Tumor	I-Disease
Study	O
84	O
[	O
SIOP	O
MMT	O
84	O
]	O
)	O
were	O
studied	O
1	O
year	O
after	O
the	O
completion	O
of	O
treatment	O
.	O

Total	O
cumulative	O
doses	O
were	O
36	O
or	O
60	O
g	O
/	O
m2	O
of	O
ifosfamide	B-Chemical
(	O
six	O
or	O
10	O
cycles	O
of	O
ifosfamide	B-Chemical
,	I-Chemical
vincristine	I-Chemical
,	I-Chemical
and	I-Chemical
dactinomycin	I-Chemical
[	O
IVA	B-Chemical
]	O
)	O
.	O

None	O
of	O
them	O
had	O
received	O
cisplatin	B-Chemical
chemotherapy	O
.	O

Ages	O
ranged	O
from	O
4	O
months	O
to	O
17	O
years	O
;	O
58	O
patients	O
were	O
males	O
and	O
42	O
females	O
.	O

The	O
most	O
common	O
primary	O
tumor	B-Disease
site	O
was	O
the	O
head	O
and	O
neck	O
.	O

Renal	O
function	O
was	O
investigated	O
by	O
measuring	O
plasma	O
and	O
urinary	O
electrolytes	O
,	O
glucosuria	B-Disease
,	O
proteinuria	B-Disease
,	O
aminoaciduria	B-Disease
,	O
urinary	O
pH	O
,	O
osmolarity	O
,	O
creatinine	B-Chemical
clearance	O
,	O
phosphate	B-Chemical
tubular	O
reabsorption	O
,	O
beta	O
2	O
microglobulinuria	O
,	O
and	O
lysozymuria	O
.	O

Fifty	O
-	O
eight	O
patients	O
(	O
78	O
%	O
)	O
had	O
normal	O
renal	O
tests	O
,	O
whereas	O
16	O
patients	O
(	O
22	O
%	O
)	O
had	O
renal	B-Disease
abnormalities	I-Disease
.	O

Two	O
subsets	O
of	O
patients	O
were	O
identified	O
from	O
this	O
latter	O
group	O
:	O
the	O
first	O
included	O
four	O
patients	O
(	O
5	O
%	O
of	O
the	O
total	O
population	O
)	O
who	O
developed	O
major	O
toxicity	B-Disease
resulting	O
in	O
Fanconi	B-Disease
'	I-Disease
s	I-Disease
syndrome	I-Disease
(	O
TDFS	B-Disease
)	O
;	O
and	O
the	O
second	O
group	O
included	O
five	O
patients	O
with	O
elevated	O
beta	O
2	O
microglobulinuria	O
and	O
low	O
phosphate	B-Chemical
reabsorption	O
.	O

The	O
remaining	O
seven	O
patients	O
had	O
isolated	O
beta	O
2	O
microglobulinuria	O
.	O

Severe	O
toxicity	B-Disease
was	O
correlated	O
with	O
the	O
higher	O
cumulative	O
dose	O
of	O
60	O
g	O
/	O
m2	O
of	O
ifosfamide	B-Chemical
,	O
a	O
younger	O
age	O
(	O
less	O
than	O
2	O
1	O
/	O
2	O
years	O
old	O
)	O
,	O
and	O
a	O
predominance	O
of	O
vesicoprostatic	O
tumor	B-Disease
involvement	O
.	O

This	O
low	O
percentage	O
(	O
5	O
%	O
)	O
of	O
TDFS	O
must	O
be	O
evaluated	O
with	O
respect	O
to	O
the	O
efficacy	O
of	O
ifosfamide	B-Chemical
in	O
the	O
treatment	O
of	O
mesenchymal	B-Disease
tumors	I-Disease
in	O
children	O
.	O

Progressive	O
myopathy	B-Disease
with	O
up	O
-	O
regulation	O
of	O
MHC	O
-	O
I	O
associated	O
with	O
statin	B-Chemical
therapy	O
.	O

Statins	B-Chemical
can	O
cause	O
a	O
necrotizing	O
myopathy	B-Disease
and	O
hyperCKaemia	B-Disease
which	O
is	O
reversible	O
on	O
cessation	O
of	O
the	O
drug	O
.	O

What	O
is	O
less	O
well	O
known	O
is	O
a	O
phenomenon	O
whereby	O
statins	B-Chemical
may	O
induce	O
a	O
myopathy	B-Disease
,	O
which	O
persists	O
or	O
may	O
progress	O
after	O
stopping	O
the	O
drug	O
.	O

We	O
investigated	O
the	O
muscle	O
pathology	O
in	O
8	O
such	O
cases	O
.	O

All	O
had	O
myofibre	O
necrosis	B-Disease
but	O
only	O
3	O
had	O
an	O
inflammatory	O
infiltrate	O
.	O

In	O
all	O
cases	O
there	O
was	O
diffuse	O
or	O
multifocal	O
up	O
-	O
regulation	O
of	O
MHC	O
-	O
I	O
expression	O
even	O
in	O
non	O
-	O
necrotic	B-Disease
fibres	O
.	O

Progressive	O
improvement	O
occurred	O
in	O
7	O
cases	O
after	O
commencement	O
of	O
prednisolone	B-Chemical
and	O
methotrexate	B-Chemical
,	O
and	O
in	O
one	O
case	O
spontaneously	O
.	O

These	O
observations	O
suggest	O
that	O
statins	B-Chemical
may	O
initiate	O
an	O
immune	O
-	O
mediated	O
myopathy	B-Disease
that	O
persists	O
after	O
withdrawal	O
of	O
the	O
drug	O
and	O
responds	O
to	O
immunosuppressive	O
therapy	O
.	O

The	O
mechanism	O
of	O
this	O
myopathy	B-Disease
is	O
uncertain	O
but	O
may	O
involve	O
the	O
induction	O
by	O
statins	B-Chemical
of	O
an	O
endoplasmic	O
reticulum	O
stress	O
response	O
with	O
associated	O
up	O
-	O
regulation	O
of	O
MHC	O
-	O
I	O
expression	O
and	O
antigen	O
presentation	O
by	O
muscle	O
fibres	O
.	O

Use	O
of	O
chromosome	O
substitution	O
strains	O
to	O
identify	O
seizure	B-Disease
susceptibility	O
loci	O
in	O
mice	O
.	O

Seizure	B-Disease
susceptibility	O
varies	O
among	O
inbred	O
mouse	O
strains	O
.	O

Chromosome	O
substitution	O
strains	O
(	O
CSS	O
)	O
,	O
in	O
which	O
a	O
single	O
chromosome	O
from	O
one	O
inbred	O
strain	O
(	O
donor	O
)	O
has	O
been	O
transferred	O
onto	O
a	O
second	O
strain	O
(	O
host	O
)	O
by	O
repeated	O
backcrossing	O
,	O
may	O
be	O
used	O
to	O
identify	O
quantitative	O
trait	O
loci	O
(	O
QTLs	O
)	O
that	O
contribute	O
to	O
seizure	B-Disease
susceptibility	O
.	O

QTLs	O
for	O
susceptibility	O
to	O
pilocarpine	B-Chemical
-	O
induced	O
seizures	B-Disease
,	O
a	O
model	O
of	O
temporal	B-Disease
lobe	I-Disease
epilepsy	I-Disease
,	O
have	O
not	O
been	O
reported	O
,	O
and	O
CSS	O
have	O
not	O
previously	O
been	O
used	O
to	O
localize	O
seizure	B-Disease
susceptibility	O
genes	O
.	O

We	O
report	O
QTLs	O
identified	O
using	O
a	O
B6	O
(	O
host	O
)	O
x	O
A	O
/	O
J	O
(	O
donor	O
)	O
CSS	O
panel	O
to	O
localize	O
genes	O
involved	O
in	O
susceptibility	O
to	O
pilocarpine	B-Chemical
-	O
induced	O
seizures	B-Disease
.	O

Three	O
hundred	O
fifty	O
-	O
five	O
adult	O
male	O
CSS	O
mice	O
,	O
58	O
B6	O
,	O
and	O
39	O
A	O
/	O
J	O
were	O
tested	O
for	O
susceptibility	O
to	O
pilocarpine	B-Chemical
-	O
induced	O
seizures	B-Disease
.	O

Highest	O
stage	O
reached	O
and	O
latency	O
to	O
each	O
stage	O
were	O
recorded	O
for	O
all	O
mice	O
.	O

B6	O
mice	O
were	O
resistant	O
to	O
seizures	B-Disease
and	O
slower	O
to	O
reach	O
stages	O
compared	O
to	O
A	O
/	O
J	O
mice	O
.	O

The	O
CSS	O
for	O
Chromosomes	O
10	O
and	O
18	O
progressed	O
to	O
the	O
most	O
severe	O
stages	O
,	O
diverging	O
dramatically	O
from	O
the	O
B6	O
phenotype	O
.	O

Latencies	O
to	O
stages	O
were	O
also	O
significantly	O
shorter	O
for	O
CSS10	O
and	O
CSS18	O
mice	O
.	O

CSS	O
mapping	O
suggests	O
seizure	B-Disease
susceptibility	O
loci	O
on	O
mouse	O
Chromosomes	O
10	O
and	O
18	O
.	O

This	O
approach	O
provides	O
a	O
framework	O
for	O
identifying	O
potentially	O
novel	O
homologous	O
candidate	O
genes	O
for	O
human	O
temporal	B-Disease
lobe	I-Disease
epilepsy	I-Disease
.	O

In	O
vitro	O
characterization	O
of	O
parasympathetic	O
and	O
sympathetic	O
responses	O
in	O
cyclophosphamide	B-Chemical
-	O
induced	O
cystitis	B-Disease
in	O
the	O
rat	O
.	O

In	O
cyclophosphamide	B-Chemical
-	O
induced	O
cystitis	B-Disease
in	O
the	O
rat	O
,	O
detrusor	O
function	O
is	O
impaired	O
and	O
the	O
expression	O
and	O
effects	O
of	O
muscarinic	O
receptors	O
altered	O
.	O

Whether	O
or	O
not	O
the	O
neuronal	O
transmission	O
may	O
be	O
affected	O
by	O
cystitis	B-Disease
was	O
presently	O
investigated	O
.	O

Responses	O
of	O
urinary	O
strip	O
preparations	O
from	O
control	O
and	O
cyclophosphamide	B-Chemical
-	O
pretreated	O
rats	O
to	O
electrical	O
field	O
stimulation	O
and	O
to	O
agonists	O
were	O
assessed	O
in	O
the	O
absence	O
and	O
presence	O
of	O
muscarinic	O
,	O
adrenergic	O
and	O
purinergic	O
receptor	O
antagonists	O
.	O

Generally	O
,	O
atropine	B-Chemical
reduced	O
contractions	O
,	O
but	O
in	O
contrast	O
to	O
controls	O
,	O
it	O
also	O
reduced	O
responses	O
to	O
low	O
electrical	O
field	O
stimulation	O
intensity	O
(	O
1	O
-	O
5	O
Hz	O
)	O
in	O
inflamed	O
preparations	O
.	O

In	O
both	O
types	O
,	O
purinoceptor	O
desensitization	O
with	O
alpha	B-Chemical
,	I-Chemical
beta	I-Chemical
-	I-Chemical
methylene	I-Chemical
adenosine	I-Chemical
-	I-Chemical
5	I-Chemical
'	I-Chemical
-	I-Chemical
triphosphate	I-Chemical
(	O
alpha	B-Chemical
,	I-Chemical
beta	I-Chemical
-	I-Chemical
meATP	I-Chemical
)	O
caused	O
further	O
reductions	O
at	O
low	O
frequencies	O
(	O
<	O
10	O
Hz	O
)	O
.	O

The	O
muscarinic	O
receptor	O
antagonists	O
atropine	B-Chemical
,	O
4	B-Chemical
-	I-Chemical
diphenylacetoxy	I-Chemical
-	I-Chemical
N	I-Chemical
-	I-Chemical
methylpiperidine	I-Chemical
(	O
4	B-Chemical
-	I-Chemical
DAMP	I-Chemical
)	O
(	O
'	O
M	O
(	O
1	O
)	O
/	O
M	O
(	O
3	O
)	O
/	O
M	O
(	O
5	O
)	O
-	O
selective	O
'	O
)	O
,	O
methoctramine	B-Chemical
(	O
'	O
M	O
(	O
2	O
)	O
-	O
selective	O
'	O
)	O
and	O
pirenzepine	B-Chemical
(	O
'	O
M	O
(	O
1	O
)	O
-	O
selective	O
'	O
)	O
antagonized	O
the	O
tonic	O
component	O
of	O
the	O
electrical	O
field	O
stimulation	O
-	O
evoked	O
contractile	O
response	O
more	O
potently	O
than	O
the	O
phasic	O
component	O
.	O

4	B-Chemical
-	I-Chemical
DAMP	I-Chemical
inhibited	O
the	O
tonic	O
contractions	O
in	O
controls	O
more	O
potently	O
than	O
methoctramine	B-Chemical
and	O
pirenzepine	B-Chemical
.	O

In	O
inflamed	O
preparations	O
,	O
the	O
muscarinic	O
receptor	O
antagonism	O
on	O
the	O
phasic	O
component	O
of	O
the	O
electrical	O
field	O
stimulation	O
-	O
evoked	O
contraction	O
was	O
decreased	O
and	O
the	O
pirenzepine	B-Chemical
and	O
4	B-Chemical
-	I-Chemical
DAMP	I-Chemical
antagonism	O
on	O
the	O
tonic	O
component	O
was	O
much	O
less	O
efficient	O
than	O
in	O
controls	O
.	O

In	O
contrast	O
to	O
controls	O
,	O
methoctramine	B-Chemical
increased	O
-	O
-	O
instead	O
of	O
decreased	O
-	O
-	O
the	O
tonic	O
responses	O
at	O
high	O
frequencies	O
.	O

While	O
contractions	O
to	O
carbachol	B-Chemical
and	O
ATP	B-Chemical
were	O
the	O
same	O
in	O
inflamed	O
and	O
in	O
control	O
strips	O
when	O
related	O
to	O
a	O
reference	O
potassium	B-Chemical
response	O
,	O
isoprenaline	B-Chemical
-	O
induced	O
relaxations	O
were	O
smaller	O
in	O
inflamed	O
strips	O
.	O

Thus	O
,	O
in	O
cystitis	B-Disease
substantial	O
changes	O
of	O
the	O
efferent	O
functional	O
responses	O
occur	O
.	O

While	O
postjunctional	O
beta	O
-	O
adrenoceptor	O
-	O
mediated	O
relaxations	O
are	O
reduced	O
,	O
effects	O
by	O
prejunctional	O
inhibitory	O
muscarinic	O
receptors	O
may	O
be	O
increased	O
.	O

Direct	O
inhibition	O
of	O
cardiac	O
hyperpolarization	O
-	O
activated	O
cyclic	B-Chemical
nucleotide	I-Chemical
-	O
gated	O
pacemaker	O
channels	O
by	O
clonidine	B-Chemical
.	O

BACKGROUND	O
:	O
Inhibition	O
of	O
cardiac	O
sympathetic	O
tone	O
represents	O
an	O
important	O
strategy	O
for	O
treatment	O
of	O
cardiovascular	B-Disease
disease	I-Disease
,	O
including	O
arrhythmia	B-Disease
,	O
coronary	B-Disease
heart	I-Disease
disease	I-Disease
,	O
and	O
chronic	O
heart	B-Disease
failure	I-Disease
.	O

Activation	O
of	O
presynaptic	O
alpha2	O
-	O
adrenoceptors	O
is	O
the	O
most	O
widely	O
accepted	O
mechanism	O
of	O
action	O
of	O
the	O
antisympathetic	O
drug	O
clonidine	B-Chemical
;	O
however	O
,	O
other	O
target	O
proteins	O
have	O
been	O
postulated	O
to	O
contribute	O
to	O
the	O
in	O
vivo	O
actions	O
of	O
clonidine	B-Chemical
.	O

METHODS	O
AND	O
RESULTS	O
:	O
To	O
test	O
whether	O
clonidine	B-Chemical
elicits	O
pharmacological	O
effects	O
independent	O
of	O
alpha2	O
-	O
adrenoceptors	O
,	O
we	O
have	O
generated	O
mice	O
with	O
a	O
targeted	O
deletion	O
of	O
all	O
3	O
alpha2	O
-	O
adrenoceptor	O
subtypes	O
(	O
alpha2ABC	O
-	O
/	O
-	O
)	O
.	O

Alpha2ABC	O
-	O
/	O
-	O
mice	O
were	O
completely	O
unresponsive	O
to	O
the	O
analgesic	O
and	O
hypnotic	O
effects	O
of	O
clonidine	B-Chemical
;	O
however	O
,	O
clonidine	B-Chemical
significantly	O
lowered	O
heart	O
rate	O
in	O
alpha2ABC	O
-	O
/	O
-	O
mice	O
by	O
up	O
to	O
150	O
bpm	O
.	O

Clonidine	B-Chemical
-	O
induced	O
bradycardia	B-Disease
in	O
conscious	O
alpha2ABC	O
-	O
/	O
-	O
mice	O
was	O
32	O
.	O
3	O
%	O
(	O
10	O
microg	O
/	O
kg	O
)	O
and	O
26	O
.	O
6	O
%	O
(	O
100	O
microg	O
/	O
kg	O
)	O
of	O
the	O
effect	O
in	O
wild	O
-	O
type	O
mice	O
.	O

A	O
similar	O
bradycardic	O
effect	O
of	O
clonidine	B-Chemical
was	O
observed	O
in	O
isolated	O
spontaneously	O
beating	O
right	O
atria	O
from	O
alpha2ABC	O
-	O
knockout	O
and	O
wild	O
-	O
type	O
mice	O
.	O

Clonidine	B-Chemical
inhibited	O
the	O
native	O
pacemaker	O
current	O
(	O
I	O
(	O
f	O
)	O
)	O
in	O
isolated	O
sinoatrial	O
node	O
pacemaker	O
cells	O
and	O
the	O
I	O
(	O
f	O
)	O
-	O
generating	O
hyperpolarization	O
-	O
activated	O
cyclic	B-Chemical
nucleotide	I-Chemical
-	O
gated	O
(	O
HCN	O
)	O
2	O
and	O
HCN4	O
channels	O
in	O
transfected	O
HEK293	O
cells	O
.	O

As	O
a	O
consequence	O
of	O
blocking	O
I	O
(	O
f	O
)	O
,	O
clonidine	B-Chemical
reduced	O
the	O
slope	O
of	O
the	O
diastolic	O
depolarization	O
and	O
the	O
frequency	O
of	O
pacemaker	O
potentials	O
in	O
sinoatrial	O
node	O
cells	O
from	O
wild	O
-	O
type	O
and	O
alpha2ABC	O
-	O
knockout	O
mice	O
.	O

CONCLUSIONS	O
:	O
Direct	O
inhibition	O
of	O
cardiac	O
HCN	O
pacemaker	O
channels	O
contributes	O
to	O
the	O
bradycardic	O
effects	O
of	O
clonidine	B-Chemical
gene	O
-	O
targeted	O
mice	O
in	O
vivo	O
,	O
and	O
thus	O
,	O
clonidine	B-Chemical
-	O
like	O
drugs	O
represent	O
novel	O
structures	O
for	O
future	O
HCN	O
channel	O
inhibitors	O
.	O

Granulomatous	B-Disease
hepatitis	I-Disease
due	O
to	O
combination	B-Chemical
of	I-Chemical
amoxicillin	I-Chemical
and	I-Chemical
clavulanic	I-Chemical
acid	I-Chemical
.	O

We	O
report	O
the	O
case	O
of	O
a	O
patient	O
with	O
amoxicillin	B-Chemical
-	I-Chemical
clavulanic	I-Chemical
acid	I-Chemical
-	O
induced	O
hepatitis	B-Disease
with	O
histologic	O
multiple	O
granulomas	B-Disease
.	O

This	O
type	O
of	O
lesion	O
broadens	O
the	O
spectrum	O
of	O
liver	B-Disease
injury	I-Disease
due	O
to	O
this	O
drug	O
combination	O
,	O
mainly	O
represented	O
by	O
a	O
benign	O
cholestatic	B-Disease
syndrome	I-Disease
.	O

The	O
association	O
of	O
granulomas	B-Disease
and	O
eosinophilia	B-Disease
favor	O
an	O
immunoallergic	O
mechanism	O
.	O

As	O
penicillin	B-Chemical
derivatives	O
and	O
amoxicillin	B-Chemical
alone	O
are	O
known	O
to	O
induce	O
such	O
types	O
of	O
lesions	O
,	O
the	O
amoxicillin	B-Chemical
component	O
,	O
with	O
or	O
without	O
a	O
potentiating	O
effect	O
of	O
clavulanic	B-Chemical
acid	I-Chemical
,	O
might	O
have	O
a	O
major	O
role	O
.	O

Dobutamine	B-Chemical
stress	O
echocardiography	O
:	O
a	O
sensitive	O
indicator	O
of	O
diminished	O
myocardial	O
function	O
in	O
asymptomatic	O
doxorubicin	B-Chemical
-	O
treated	O
long	O
-	O
term	O
survivors	O
of	O
childhood	O
cancer	B-Disease
.	O

Doxorubicin	B-Chemical
is	O
an	O
effective	O
anticancer	O
chemotherapeutic	O
agent	O
known	O
to	O
cause	O
acute	O
and	O
chronic	O
cardiomyopathy	B-Disease
.	O

To	O
develop	O
a	O
more	O
sensitive	O
echocardiographic	O
screening	O
test	O
for	O
cardiac	B-Disease
damage	I-Disease
due	O
to	O
doxorubicin	B-Chemical
,	O
a	O
cohort	O
study	O
was	O
performed	O
using	O
dobutamine	B-Chemical
infusion	O
to	O
differentiate	O
asymptomatic	O
long	O
-	O
term	O
survivors	O
of	O
childhood	O
cancer	B-Disease
treated	O
with	O
doxorubicin	B-Chemical
from	O
healthy	O
control	O
subjects	O
.	O

Echocardiographic	O
data	O
from	O
the	O
experimental	O
group	O
of	O
21	O
patients	O
(	O
mean	O
age	O
16	O
+	O
/	O
-	O
5	O
years	O
)	O
treated	O
from	O
1	O
.	O
6	O
to	O
14	O
.	O
3	O
years	O
(	O
median	O
5	O
.	O
3	O
)	O
before	O
this	O
study	O
with	O
27	O
to	O
532	O
mg	O
/	O
m2	O
of	O
doxorubicin	B-Chemical
(	O
mean	O
196	O
)	O
were	O
compared	O
with	O
echocardiographic	O
data	O
from	O
12	O
normal	O
age	O
-	O
matched	O
control	O
subjects	O
.	O

Graded	O
dobutamine	B-Chemical
infusions	O
of	O
0	O
.	O
5	O
,	O
2	O
.	O
5	O
,	O
5	O
and	O
10	O
micrograms	O
/	O
kg	O
per	O
min	O
were	O
administered	O
.	O

Echocardiographic	O
Doppler	O
studies	O
were	O
performed	O
before	O
infusion	O
and	O
after	O
15	O
min	O
of	O
infusion	O
at	O
each	O
rate	O
.	O

Dobutamine	B-Chemical
infusion	O
at	O
10	O
micrograms	O
/	O
kg	O
per	O
min	O
was	O
discontinued	O
after	O
six	O
studies	O
secondary	O
to	O
a	O
50	O
%	O
incidence	O
rate	O
of	O
adverse	O
symptoms	O
.	O

The	O
most	O
important	O
findings	O
were	O
that	O
compared	O
with	O
values	O
in	O
control	O
subjects	O
,	O
end	O
-	O
systolic	O
left	O
ventricular	O
posterior	O
wall	O
dimension	O
and	O
percent	O
of	O
left	O
ventricular	O
posterior	O
wall	O
thickening	O
in	O
doxorubicin	B-Chemical
-	O
treated	O
patients	O
were	O
decreased	O
at	O
baseline	O
study	O
and	O
these	O
findings	O
were	O
more	O
clearly	O
delineated	O
with	O
dobutamine	B-Chemical
stimulation	O
.	O

End	O
-	O
systolic	O
left	O
ventricular	O
posterior	O
wall	O
dimension	O
at	O
baseline	O
for	O
the	O
doxorubicin	B-Chemical
-	O
treated	O
group	O
was	O
11	O
+	O
/	O
-	O
1	O
.	O
9	O
mm	O
versus	O
13	O
.	O
1	O
+	O
/	O
-	O
1	O
.	O
5	O
mm	O
for	O
control	O
subjects	O
(	O
p	O
less	O
than	O
0	O
.	O
01	O
)	O
.	O

End	O
-	O
systolic	O
left	O
ventricular	O
posterior	O
wall	O
dimension	O
at	O
the	O
5	O
-	O
micrograms	O
/	O
kg	O
per	O
min	O
dobutamine	B-Chemical
infusion	O
for	O
the	O
doxorubicin	B-Chemical
-	O
treated	O
group	O
was	O
14	O
.	O
1	O
+	O
/	O
-	O
2	O
.	O
4	O
mm	O
versus	O
19	O
.	O
3	O
+	O
/	O
-	O
2	O
.	O
6	O
mm	O
for	O
control	O
subjects	O
(	O
p	O
less	O
than	O
0	O
.	O
01	O
)	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
250	O
WORDS	O
)	O

Influence	O
of	O
smoking	B-Chemical
on	O
developing	O
cochlea	O
.	O

Does	O
smoking	B-Chemical
during	O
pregnancy	O
affect	O
the	O
amplitudes	O
of	O
transient	O
evoked	O
otoacoustic	O
emissions	O
in	O
newborns	O
?	O

OBJECTIVE	O
:	O
Maternal	O
tobacco	O
smoking	B-Chemical
has	O
negative	O
effects	O
on	O
fetal	O
growth	O
.	O

The	O
influence	O
of	O
smoking	B-Chemical
during	O
pregnancy	O
on	O
the	O
developing	O
cochlea	O
has	O
not	O
been	O
estimated	O
,	O
although	O
smoking	B-Chemical
has	O
been	O
positively	O
associated	O
with	O
hearing	B-Disease
loss	I-Disease
in	O
adults	O
.	O

The	O
objective	O
of	O
this	O
study	O
was	O
to	O
determine	O
the	O
effects	O
of	O
maternal	O
smoking	B-Chemical
on	O
transient	O
evoked	O
otoacoustic	O
emissions	O
(	O
TEOAEs	O
)	O
of	O
healthy	O
neonates	O
.	O

METHODS	O
:	O
This	O
study	O
was	O
undertaken	O
as	O
part	O
of	O
neonatal	O
screening	O
for	O
hearing	B-Disease
impairment	I-Disease
and	O
involved	O
both	O
ears	O
of	O
200	O
newborns	O
.	O

Newborns	O
whose	O
mothers	O
reported	O
smoking	B-Chemical
during	O
pregnancy	O
(	O
n	O
=	O
200	O
ears	O
)	O
were	O
compared	O
to	O
a	O
control	O
group	O
of	O
newborns	O
(	O
n	O
=	O
200	O
ears	O
)	O
,	O
whose	O
mothers	O
were	O
non	O
-	O
smokers	O
.	O

Exposure	O
to	O
tobacco	O
was	O
characterized	O
as	O
low	O
(	O
<	O
5	O
cigarettes	O
per	O
day	O
,	O
n	O
=	O
88	O
ears	O
)	O
,	O
moderate	O
(	O
5	O
<	O
or	O
=	O
cigarettes	O
per	O
day	O
<	O
10	O
,	O
n	O
=	O
76	O
)	O
or	O
high	O
(	O
>	O
or	O
=	O
10	O
cigarettes	O
per	O
day	O
,	O
n	O
=	O
36	O
)	O
.	O

RESULTS	O
:	O
In	O
exposed	O
neonates	O
,	O
TEOAEs	O
mean	O
response	O
(	O
across	O
frequency	O
)	O
and	O
mean	O
amplitude	O
at	O
4000Hz	O
was	O
significantly	O
lower	O
than	O
in	O
non	O
-	O
exposed	O
neonates	O
.	O

Comparisons	O
between	O
exposed	O
newborns	O
'	O
subgroups	O
revealed	O
no	O
significant	O
differences	O
.	O

However	O
,	O
by	O
comparing	O
each	O
subgroup	O
to	O
control	O
group	O
,	O
we	O
found	O
statistically	O
significant	O
decreases	B-Disease
of	I-Disease
TEOAEs	I-Disease
amplitudes	I-Disease
at	O
4000Hz	O
for	O
all	O
three	O
groups	O
.	O

Mean	O
TEOAEs	O
responses	O
of	O
highly	O
exposed	O
newborns	O
were	O
also	O
significantly	O
lower	O
in	O
comparison	O
to	O
our	O
control	O
group	O
.	O

CONCLUSION	O
:	O
In	O
utero	O
,	O
exposure	O
to	O
tobacco	O
smoking	B-Chemical
seems	O
to	O
have	O
a	O
small	O
impact	O
on	O
outer	O
hair	O
cells	O
.	O

These	O
effects	O
seem	O
to	O
be	O
equally	O
true	O
for	O
all	O
exposed	O
newborns	O
,	O
regardless	O
of	O
the	O
degree	O
of	O
exposure	O
.	O

Further	O
studies	O
are	O
needed	O
in	O
order	O
to	O
establish	O
a	O
potential	O
negative	O
effect	O
of	O
maternal	O
smoking	B-Chemical
on	O
the	O
neonate	O
'	O
s	O
hearing	O
acuity	O
.	O

Simvastatin	B-Chemical
-	O
induced	O
bilateral	O
leg	O
compartment	B-Disease
syndrome	I-Disease
and	O
myonecrosis	B-Disease
associated	O
with	O
hypothyroidism	B-Disease
.	O

A	O
54	O
-	O
year	O
-	O
old	O
hypothyroid	B-Disease
male	O
taking	O
thyroxine	B-Chemical
and	O
simvastatin	B-Chemical
presented	O
with	O
bilateral	O
leg	O
compartment	B-Disease
syndrome	I-Disease
and	O
myonecrosis	B-Disease
.	O

Urgent	O
fasciotomies	O
were	O
performed	O
and	O
the	O
patient	O
made	O
an	O
uneventful	O
recovery	O
with	O
the	O
withdrawal	O
of	O
simvastatin	B-Chemical
.	O

It	O
is	O
likely	O
that	O
this	O
complication	O
will	O
be	O
seen	O
more	O
often	O
with	O
the	O
increased	O
worldwide	O
use	O
of	O
this	O
drug	O
and	O
its	O
approval	O
for	O
all	O
arteriopathic	B-Disease
patients	O
.	O

Neuroinflammation	B-Disease
and	O
behavioral	B-Disease
abnormalities	I-Disease
after	O
neonatal	O
terbutaline	B-Chemical
treatment	O
in	O
rats	O
:	O
implications	O
for	O
autism	B-Disease
.	O

Autism	B-Disease
is	O
a	O
neurodevelopmental	B-Disease
disorder	I-Disease
presenting	O
before	O
3	O
years	O
of	O
age	O
with	O
deficits	B-Disease
in	I-Disease
communication	I-Disease
and	I-Disease
social	I-Disease
skills	I-Disease
and	O
repetitive	B-Disease
behaviors	I-Disease
.	O

In	O
addition	O
to	O
genetic	O
influences	O
,	O
recent	O
studies	O
suggest	O
that	O
prenatal	O
drug	O
or	O
chemical	O
exposures	O
are	O
risk	O
factors	O
for	O
autism	B-Disease
.	O

Terbutaline	B-Chemical
,	O
a	O
beta2	O
-	O
adrenoceptor	O
agonist	O
used	O
to	O
arrest	O
preterm	B-Disease
labor	I-Disease
,	O
has	O
been	O
associated	O
with	O
increased	O
concordance	O
for	O
autism	B-Disease
in	O
dizygotic	O
twins	O
.	O

We	O
studied	O
the	O
effects	O
of	O
terbutaline	B-Chemical
on	O
microglial	O
activation	O
in	O
different	O
brain	O
regions	O
and	O
behavioral	O
outcomes	O
in	O
developing	O
rats	O
.	O

Newborn	O
rats	O
were	O
given	O
terbutaline	B-Chemical
(	O
10	O
mg	O
/	O
kg	O
)	O
daily	O
on	O
postnatal	O
days	O
(	O
PN	O
)	O
2	O
to	O
5	O
or	O
PN	O
11	O
to	O
14	O
and	O
examined	O
24	O
h	O
after	O
the	O
last	O
dose	O
and	O
at	O
PN	O
30	O
.	O

Immunohistochemical	O
studies	O
showed	O
that	O
administration	O
of	O
terbutaline	B-Chemical
on	O
PN	O
2	O
to	O
5	O
produced	O
a	O
robust	O
increase	O
in	O
microglial	O
activation	O
on	O
PN	O
30	O
in	O
the	O
cerebral	O
cortex	O
,	O
as	O
well	O
as	O
in	O
cerebellar	O
and	O
cerebrocortical	O
white	O
matter	O
.	O

None	O
of	O
these	O
effects	O
occurred	O
in	O
animals	O
given	O
terbutaline	B-Chemical
on	O
PN	O
11	O
to	O
14	O
.	O

In	O
behavioral	O
tests	O
,	O
animals	O
treated	O
with	O
terbutaline	B-Chemical
on	O
PN	O
2	O
to	O
5	O
showed	O
consistent	O
patterns	O
of	O
hyper	O
-	O
reactivity	O
to	O
novelty	O
and	O
aversive	O
stimuli	O
when	O
assessed	O
in	O
a	O
novel	O
open	O
field	O
,	O
as	O
well	O
as	O
in	O
the	O
acoustic	O
startle	O
response	O
test	O
.	O

Our	O
findings	O
indicate	O
that	O
beta2	O
-	O
adrenoceptor	O
overstimulation	O
during	O
an	O
early	O
critical	O
period	O
results	O
in	O
microglial	O
activation	O
associated	O
with	O
innate	O
neuroinflammatory	O
pathways	O
and	O
behavioral	B-Disease
abnormalities	I-Disease
,	O
similar	O
to	O
those	O
described	O
in	O
autism	B-Disease
.	O

This	O
study	O
provides	O
a	O
useful	O
animal	O
model	O
for	O
understanding	O
the	O
neuropathological	O
processes	O
underlying	O
autism	B-Disease
spectrum	I-Disease
disorders	I-Disease
.	O

Upregulation	O
of	O
brain	O
expression	O
of	O
P	O
-	O
glycoprotein	O
in	O
MRP2	O
-	O
deficient	O
TR	O
(	O
-	O
)	O
rats	O
resembles	O
seizure	B-Disease
-	O
induced	O
up	O
-	O
regulation	O
of	O
this	O
drug	O
efflux	O
transporter	O
in	O
normal	O
rats	O
.	O

PURPOSE	O
:	O
The	O
multidrug	O
resistance	O
protein	O
2	O
(	O
MRP2	O
)	O
is	O
a	O
drug	O
efflux	O
transporter	O
that	O
is	O
expressed	O
predominantly	O
at	O
the	O
apical	O
domain	O
of	O
hepatocytes	O
but	O
seems	O
also	O
to	O
be	O
expressed	O
at	O
the	O
apical	O
membrane	O
of	O
brain	O
capillary	O
endothelial	O
cells	O
that	O
form	O
the	O
blood	O
-	O
brain	O
barrier	O
(	O
BBB	O
)	O
.	O

MRP2	O
is	O
absent	O
in	O
the	O
transport	O
-	O
deficient	O
(	O
TR	O
(	O
-	O
)	O
)	O
Wistar	O
rat	O
mutant	O
,	O
so	O
that	O
this	O
rat	O
strain	O
was	O
very	O
helpful	O
in	O
defining	O
substrates	O
of	O
MRP2	O
by	O
comparing	O
tissue	O
concentrations	O
or	O
functional	O
activities	O
of	O
compounds	O
in	O
MRP2	O
-	O
deficient	O
rats	O
with	O
those	O
in	O
transport	O
-	O
competent	O
Wistar	O
rats	O
.	O

By	O
using	O
this	O
strategy	O
to	O
study	O
the	O
involvement	O
of	O
MRP2	O
in	O
brain	O
access	O
of	O
antiepileptic	O
drugs	O
(	O
AEDs	O
)	O
,	O
we	O
recently	O
reported	O
that	O
phenytoin	B-Chemical
is	O
a	O
substrate	O
for	O
MRP2	O
in	O
the	O
BBB	O
.	O

However	O
,	O
one	O
drawback	O
of	O
such	O
studies	O
in	O
genetically	O
deficient	O
rats	O
is	O
the	O
fact	O
that	O
compensatory	O
changes	O
with	O
upregulation	O
of	O
other	O
transporters	O
can	O
occur	O
.	O

This	O
prompted	O
us	O
to	O
study	O
the	O
brain	O
expression	O
of	O
P	O
-	O
glycoprotein	O
(	O
Pgp	O
)	O
,	O
a	O
major	O
drug	O
efflux	O
transporter	O
in	O
many	O
tissues	O
,	O
including	O
the	O
BBB	O
,	O
in	O
TR	O
(	O
-	O
)	O
rats	O
compared	O
with	O
nonmutant	O
(	O
wild	O
-	O
type	O
)	O
Wistar	O
rats	O
.	O

METHODS	O
:	O
The	O
expression	O
of	O
MRP2	O
and	O
Pgp	O
in	O
brain	O
and	O
liver	O
sections	O
of	O
TR	O
(	O
-	O
)	O
rats	O
and	O
normal	O
Wistar	O
rats	O
was	O
determined	O
with	O
immunohistochemistry	O
,	O
by	O
using	O
a	O
novel	O
,	O
highly	O
selective	O
monoclonal	O
MRP2	O
antibody	O
and	O
the	O
monoclonal	O
Pgp	O
antibody	O
C219	O
,	O
respectively	O
.	O

RESULTS	O
:	O
Immunofluorescence	O
staining	O
with	O
the	O
MRP2	O
antibody	O
was	O
found	O
to	O
label	O
a	O
high	O
number	O
of	O
microvessels	O
throughout	O
the	O
brain	O
in	O
normal	O
Wistar	O
rats	O
,	O
whereas	O
such	O
labeling	O
was	O
absent	O
in	O
TR	O
(	O
-	O
)	O
rats	O
.	O

TR	O
(	O
-	O
)	O
rats	O
exhibited	O
a	O
significant	O
up	O
-	O
regulation	O
of	O
Pgp	O
in	O
brain	O
capillary	O
endothelial	O
cells	O
compared	O
with	O
wild	O
-	O
type	O
controls	O
.	O

No	O
such	O
obvious	O
upregulation	O
of	O
Pgp	O
was	O
observed	O
in	O
liver	O
sections	O
.	O

A	O
comparable	O
overexpression	O
of	O
Pgp	O
in	O
the	O
BBB	O
was	O
obtained	O
after	O
pilocarpine	B-Chemical
-	O
induced	O
seizures	B-Disease
in	O
wild	O
-	O
type	O
Wistar	O
rats	O
.	O

Experiments	O
with	O
systemic	O
administration	O
of	O
the	O
Pgp	O
substrate	O
phenobarbital	B-Chemical
and	O
the	O
selective	O
Pgp	O
inhibitor	O
tariquidar	B-Chemical
in	O
TR	O
(	O
-	O
)	O
rats	O
substantiated	O
that	O
Pgp	O
is	O
functional	O
and	O
compensates	O
for	O
the	O
lack	O
of	O
MRP2	O
in	O
the	O
BBB	O
.	O

CONCLUSIONS	O
:	O
The	O
data	O
on	O
TR	O
(	O
-	O
)	O
rats	O
indicate	O
that	O
Pgp	O
plays	O
an	O
important	O
role	O
in	O
the	O
compensation	O
of	O
MRP2	O
deficiency	O
in	O
the	O
BBB	O
.	O

Because	O
such	O
a	O
compensatory	O
mechanism	O
most	O
likely	O
occurs	O
to	O
reduce	O
injury	B-Disease
to	I-Disease
the	I-Disease
brain	I-Disease
from	O
cytotoxic	O
compounds	O
,	O
the	O
present	O
data	O
substantiate	O
the	O
concept	O
that	O
MRP2	O
performs	O
a	O
protective	O
role	O
in	O
the	O
BBB	O
.	O

Furthermore	O
,	O
our	O
data	O
suggest	O
that	O
TR	O
(	O
-	O
)	O
rats	O
are	O
an	O
interesting	O
tool	O
to	O
study	O
consequences	O
of	O
overexpression	O
of	O
Pgp	O
in	O
the	O
BBB	O
on	O
access	O
of	O
drugs	O
in	O
the	O
brain	O
,	O
without	O
the	O
need	O
of	O
inducing	O
seizures	B-Disease
or	O
other	O
Pgp	O
-	O
enhancing	O
events	O
for	O
this	O
purpose	O
.	O

Role	O
of	O
xanthine	B-Chemical
oxidase	O
in	O
dexamethasone	B-Chemical
-	O
induced	O
hypertension	B-Disease
in	O
rats	O
.	O

1	O
.	O

Glucocorticoid	O
-	O
induced	O
hypertension	B-Disease
(	O
GC	O
-	O
HT	B-Disease
)	O
in	O
the	O
rat	O
is	O
associated	O
with	O
nitric	B-Chemical
oxide	I-Chemical
-	O
redox	O
imbalance	O
.	O

2	O
.	O

We	O
studied	O
the	O
role	O
of	O
xanthine	B-Chemical
oxidase	O
(	O
XO	O
)	O
,	O
which	O
is	O
implicated	O
in	O
the	O
production	O
of	O
reactive	O
oxygen	O
species	O
,	O
in	O
dexamethasone	B-Chemical
-	O
induced	O
hypertension	B-Disease
(	O
dex	B-Chemical
-	O
HT	B-Disease
)	O
.	O

3	O
.	O

Thirty	O
male	O
Sprague	O
-	O
Dawley	O
rats	O
were	O
divided	O
randomly	O
into	O
four	O
treatment	O
groups	O
:	O
saline	O
,	O
dexamethasone	B-Chemical
(	O
dex	B-Chemical
)	O
,	O
allopurinol	B-Chemical
plus	O
saline	O
,	O
and	O
allopurinol	B-Chemical
plus	O
dex	B-Chemical
.	O

4	O
.	O

Systolic	O
blood	O
pressures	O
(	O
SBP	O
)	O
and	O
bodyweights	O
were	O
recorded	O
each	O
alternate	O
day	O
.	O

Thymus	O
weight	O
was	O
used	O
as	O
a	O
marker	O
of	O
glucocorticoid	O
activity	O
,	O
and	O
serum	O
urate	B-Chemical
to	O
assess	O
XO	O
inhibition	O
.	O

5	O
.	O

Dex	B-Chemical
increased	B-Disease
SBP	I-Disease
(	O
110	O
+	O
/	O
-	O
2	O
-	O
126	O
+	O
/	O
-	O
3	O
mmHg	O
;	O
P	O
<	O
0	O
.	O
001	O
)	O
and	O
decreased	B-Disease
thymus	I-Disease
(	I-Disease
P	I-Disease
<	I-Disease
0	I-Disease
.	I-Disease
001	I-Disease
)	I-Disease
and	I-Disease
bodyweights	I-Disease
(	O
P	O
"	O
<	O
0	O
.	O
01	O
)	O
.	O

Allopurinol	B-Chemical
decreased	O
serum	O
urate	B-Chemical
from	O
76	O
+	O
/	O
-	O
5	O
to	O
30	O
+	O
/	O
-	O
3	O
micromol	O
/	O
L	O
(	O
P	O
<	O
0	O
.	O
001	O
)	O
in	O
saline	O
and	O
from	O
84	O
+	O
/	O
-	O
13	O
to	O
28	O
+	O
/	O
-	O
2	O
micromol	O
/	O
L	O
in	O
dex	B-Chemical
-	O
treated	O
(	O
P	O
<	O
0	O
.	O
01	O
)	O
groups	O
.	O

6	O
.	O

Allopurinol	B-Chemical
did	O
not	O
prevent	O
dex	B-Chemical
-	O
HT	B-Disease
.	O

This	O
,	O
together	O
with	O
our	O
previous	O
findings	O
that	O
allopurinol	B-Chemical
failed	O
to	O
prevent	O
adrenocorticotrophic	O
hormone	O
induced	O
hypertension	B-Disease
,	O
suggests	O
that	O
XO	O
activity	O
is	O
not	O
a	O
major	O
determinant	O
of	O
GC	O
-	O
HT	B-Disease
in	O
the	O
rat	O
.	O

Side	O
effects	O
of	O
postoperative	O
administration	O
of	O
methylprednisolone	B-Chemical
and	O
gentamicin	B-Chemical
into	O
the	O
posterior	O
sub	O
-	O
Tenon	O
'	O
s	O
space	O
.	O

PURPOSE	O
:	O
To	O
assess	O
the	O
incidence	O
of	O
postoperative	O
emetic	O
side	O
effects	O
after	O
the	O
administration	O
of	O
methylprednisolone	B-Chemical
and	O
gentamicin	B-Chemical
into	O
the	O
posterior	O
sub	O
-	O
Tenon	O
'	O
s	O
space	O
at	O
the	O
end	O
of	O
routine	O
cataract	B-Disease
surgery	O
.	O

SETTING	O
:	O
St	O
.	O

Luke	O
'	O
s	O
Hospital	O
,	O
Gwardamangia	O
,	O
Malta	O
.	O

METHODS	O
:	O
A	O
double	O
-	O
blind	O
double	O
-	O
armed	O
prospective	O
study	O
comprised	O
40	O
patients	O
who	O
had	O
uneventful	O
sutureless	O
phacoemulsification	O
under	O
sub	O
-	O
Tenon	O
'	O
s	O
local	O
infiltration	O
of	O
3	O
mL	O
of	O
plain	O
lignocaine	B-Chemical
.	O

At	O
the	O
end	O
of	O
the	O
procedure	O
,	O
Group	O
A	O
(	O
n	O
=	O
20	O
)	O
had	O
20	O
mg	O
/	O
0	O
.	O
5	O
mL	O
of	O
methylprednisolone	B-Chemical
and	O
10	O
mg	O
/	O
0	O
.	O
5	O
mL	O
of	O
gentamicin	B-Chemical
injected	O
into	O
the	O
posterior	O
sub	O
-	O
Tenon	O
'	O
s	O
space	O
and	O
Group	O
B	O
(	O
n	O
=	O
20	O
)	O
had	O
the	O
same	O
combination	O
injected	O
into	O
the	O
anterior	O
sub	O
-	O
Tenon	O
'	O
s	O
space	O
.	O

Postoperatively	O
,	O
all	O
patients	O
were	O
assessed	O
for	O
symptoms	O
of	O
nausea	B-Disease
,	I-Disease
vomiting	I-Disease
,	O
and	O
headache	B-Disease
.	O

A	O
chi	O
-	O
square	O
test	O
was	O
used	O
to	O
assess	O
the	O
statistical	O
significance	O
of	O
results	O
.	O

RESULTS	O
:	O
Sixty	O
percent	O
in	O
Group	O
A	O
developed	O
postoperative	B-Disease
emetic	I-Disease
symptoms	I-Disease
,	O
headache	B-Disease
,	O
or	O
both	O
;	O
1	O
patient	O
in	O
Group	O
B	O
developed	O
symptoms	O
.	O

CONCLUSIONS	O
:	O
The	O
administration	O
of	O
methylprednisolone	B-Chemical
and	O
gentamicin	B-Chemical
in	O
the	O
posterior	O
sub	O
-	O
Tenon	O
'	O
s	O
space	O
was	O
related	O
to	O
a	O
high	O
incidence	O
of	O
side	O
effects	O
including	O
nausea	B-Disease
,	I-Disease
vomiting	I-Disease
,	O
and	O
headache	B-Disease
.	O

All	O
adverse	O
effects	O
were	O
self	O
-	O
limiting	O
.	O

Assessment	O
of	O
a	O
new	O
non	O
-	O
invasive	O
index	O
of	O
cardiac	O
performance	O
for	O
detection	O
of	O
dobutamine	B-Chemical
-	O
induced	O
myocardial	B-Disease
ischemia	I-Disease
.	O

BACKGROUND	O
:	O
Electrocardiography	O
has	O
a	O
very	O
low	O
sensitivity	O
in	O
detecting	O
dobutamine	B-Chemical
-	O
induced	O
myocardial	B-Disease
ischemia	I-Disease
.	O

OBJECTIVES	O
:	O
To	O
assess	O
the	O
added	O
diagnostic	O
value	O
of	O
a	O
new	O
cardiac	O
performance	O
index	O
(	O
dP	O
/	O
dtejc	O
)	O
measurement	O
,	O
based	O
on	O
brachial	O
artery	O
flow	O
changes	O
,	O
as	O
compared	O
to	O
standard	O
12	O
-	O
lead	O
ECG	O
,	O
for	O
detecting	O
dobutamine	B-Chemical
-	O
induced	O
myocardial	B-Disease
ischemia	I-Disease
,	O
using	O
Tc99m	B-Chemical
-	I-Chemical
Sestamibi	I-Chemical
single	O
-	O
photon	O
emission	O
computed	O
tomography	O
as	O
the	O
gold	O
standard	O
of	O
comparison	O
to	O
assess	O
the	O
presence	O
or	O
absence	O
of	O
ischemia	B-Disease
.	O

METHODS	O
:	O
The	O
study	O
group	O
comprised	O
40	O
patients	O
undergoing	O
Sestamibi	B-Chemical
-	O
SPECT	O
/	O
dobutamine	B-Chemical
stress	O
test	O
.	O

Simultaneous	O
measurements	O
of	O
ECG	O
and	O
brachial	O
artery	O
dP	O
/	O
dtejc	O
were	O
performed	O
at	O
each	O
dobutamine	B-Chemical
level	O
.	O

In	O
19	O
of	O
the	O
40	O
patients	O
perfusion	O
defects	O
compatible	O
with	O
ischemia	B-Disease
were	O
detected	O
on	O
SPECT	O
.	O

The	O
increase	O
in	O
dP	O
/	O
dtejc	O
during	O
infusion	O
of	O
dobutamine	B-Chemical
in	O
this	O
group	O
was	O
severely	O
impaired	O
as	O
compared	O
to	O
the	O
non	O
-	O
ischemic	O
group	O
.	O

dP	O
/	O
dtejc	O
outcome	O
was	O
combined	O
with	O
the	O
ECG	O
results	O
,	O
giving	O
an	O
ECG	O
-	O
enhanced	O
value	O
,	O
and	O
compared	O
to	O
ECG	O
alone	O
.	O

RESULTS	O
:	O
The	O
sensitivity	O
improved	O
dramatically	O
from	O
16	O
%	O
to	O
79	O
%	O
,	O
positive	O
predictive	O
value	O
increased	O
from	O
60	O
%	O
to	O
68	O
%	O
and	O
negative	O
predictive	O
value	O
from	O
54	O
%	O
to	O
78	O
%	O
,	O
and	O
specificity	O
decreased	O
from	O
90	O
%	O
to	O
67	O
%	O
.	O

CONCLUSIONS	O
:	O
If	O
ECG	O
alone	O
is	O
used	O
for	O
specificity	O
,	O
the	O
combination	O
with	O
dP	O
/	O
dtejc	O
improved	O
the	O
sensitivity	O
of	O
the	O
test	O
and	O
could	O
be	O
a	O
cost	O
-	O
savings	O
alternative	O
to	O
cardiac	O
imaging	O
or	O
perfusion	O
studies	O
to	O
detect	O
myocardial	B-Disease
ischemia	I-Disease
,	O
especially	O
in	O
patients	O
unable	O
to	O
exercise	O
.	O

Cocaine	B-Chemical
-	O
induced	O
myocardial	B-Disease
infarction	I-Disease
:	O
clinical	O
observations	O
and	O
pathogenetic	O
considerations	O
.	O

Clinical	O
and	O
experimental	O
data	O
published	O
to	O
date	O
suggest	O
several	O
possible	O
mechanisms	O
by	O
which	O
cocaine	B-Chemical
may	O
result	O
in	O
acute	B-Disease
myocardial	I-Disease
infarction	I-Disease
.	O

In	O
individuals	O
with	O
preexisting	O
,	O
high	O
-	O
grade	O
coronary	O
arterial	O
narrowing	O
,	O
acute	B-Disease
myocardial	I-Disease
infarction	I-Disease
may	O
result	O
from	O
an	O
increase	O
in	O
myocardial	O
oxygen	B-Chemical
demand	O
associated	O
with	O
cocaine	B-Chemical
-	O
induced	O
increase	O
in	O
rate	O
-	O
pressure	O
product	O
.	O

In	O
other	O
individuals	O
with	O
no	O
underlying	O
atherosclerotic	B-Disease
obstruction	I-Disease
,	O
coronary	B-Disease
occlusion	I-Disease
may	O
be	O
due	O
to	O
spasm	B-Disease
,	O
thrombus	B-Disease
,	O
or	O
both	O
.	O

With	O
regard	O
to	O
spasm	B-Disease
,	O
the	O
clinical	O
findings	O
are	O
largely	O
circumstantial	O
,	O
and	O
the	O
locus	O
of	O
cocaine	B-Chemical
-	O
induced	O
vasoconstriction	O
remains	O
speculative	O
.	O

Although	O
certain	O
clinical	O
and	O
experimental	O
findings	O
support	O
the	O
hypothesis	O
that	O
spasm	B-Disease
involves	O
the	O
epicardial	O
,	O
medium	O
-	O
size	O
vessels	O
,	O
other	O
data	O
suggest	O
intramural	O
vasoconstriction	O
.	O

Diffuse	O
intramural	O
vasoconstriction	O
is	O
not	O
consistent	O
with	O
reports	O
of	O
segmental	O
,	O
discrete	O
infarction	B-Disease
.	O

Whereas	O
certain	O
in	O
vivo	O
data	O
suggest	O
that	O
these	O
effects	O
are	O
alpha	O
-	O
mediated	O
,	O
other	O
in	O
vitro	O
data	O
suggest	O
the	O
opposite	O
.	O

The	O
finding	O
of	O
cocaine	B-Chemical
-	O
induced	O
vasoconstriction	O
in	O
segments	O
of	O
(	O
noninnervated	O
)	O
human	O
umbilical	O
artery	O
suggests	O
that	O
the	O
presence	O
or	O
absence	O
of	O
intact	O
innervation	O
is	O
not	O
sufficient	O
to	O
explain	O
the	O
discrepant	O
data	O
involving	O
the	O
possibility	O
of	O
alpha	O
-	O
mediated	O
effects	O
.	O

Finally	O
,	O
the	O
contribution	O
of	O
a	O
primary	O
,	O
thrombotic	B-Disease
effect	O
of	O
cocaine	B-Chemical
has	O
not	O
been	O
excluded	O
.	O

Proteomic	O
analysis	O
of	O
striatal	O
proteins	O
in	O
the	O
rat	O
model	O
of	O
L	B-Chemical
-	I-Chemical
DOPA	I-Chemical
-	O
induced	O
dyskinesia	B-Disease
.	O

L	B-Chemical
-	I-Chemical
DOPA	I-Chemical
-	O
induced	O
dyskinesia	B-Disease
(	O
LID	B-Disease
)	O
is	O
among	O
the	O
motor	O
complications	O
that	O
arise	O
in	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
(	O
PD	B-Disease
)	O
patients	O
after	O
a	O
prolonged	O
treatment	O
with	O
L	B-Chemical
-	I-Chemical
DOPA	I-Chemical
.	O

To	O
this	O
day	O
,	O
transcriptome	O
analysis	O
has	O
been	O
performed	O
in	O
a	O
rat	O
model	O
of	O
LID	B-Disease
[	O
Neurobiol	O
.	O
Dis	O
.	O
,	O
17	O
(	O
2004	O
)	O
,	O
219	O
]	O
but	O
information	O
regarding	O
the	O
proteome	O
is	O
still	O
lacking	O
.	O

In	O
the	O
present	O
study	O
,	O
we	O
investigated	O
the	O
changes	O
occurring	O
at	O
the	O
protein	O
level	O
in	O
striatal	O
samples	O
obtained	O
from	O
the	O
unilaterally	O
6	B-Chemical
-	I-Chemical
hydroxydopamine	I-Chemical
-	O
lesion	O
rat	O
model	O
of	O
PD	B-Disease
treated	O
with	O
saline	O
,	O
L	B-Chemical
-	I-Chemical
DOPA	I-Chemical
or	O
bromocriptine	B-Chemical
using	O
two	O
-	O
dimensional	O
difference	O
gel	O
electrophoresis	O
and	O
mass	O
spectrometry	O
(	O
MS	O
)	O
.	O

Rats	O
treated	O
with	O
L	B-Chemical
-	I-Chemical
DOPA	I-Chemical
were	O
allocated	O
to	O
two	O
groups	O
based	O
on	O
the	O
presence	O
or	O
absence	O
of	O
LID	B-Disease
.	O

Among	O
the	O
2000	O
spots	O
compared	O
for	O
statistical	O
difference	O
,	O
67	O
spots	O
were	O
significantly	O
changed	O
in	O
abundance	O
and	O
identified	O
using	O
matrix	O
-	O
assisted	O
laser	O
desorption	O
/	O
ionization	O
time	O
-	O
of	O
-	O
flight	O
MS	O
,	O
atmospheric	O
pressure	O
matrix	O
-	O
assisted	O
laser	O
desorption	O
/	O
ionization	O
and	O
HPLC	O
coupled	O
tandem	O
MS	O
(	O
LC	O
/	O
MS	O
/	O
MS	O
)	O
.	O

Out	O
of	O
these	O
67	O
proteins	O
,	O
LID	B-Disease
significantly	O
changed	O
the	O
expression	O
level	O
of	O
five	O
proteins	O
:	O
alphabeta	O
-	O
crystalin	O
,	O
gamma	O
-	O
enolase	O
,	O
guanidoacetate	O
methyltransferase	O
,	O
vinculin	O
,	O
and	O
proteasome	O
alpha	O
-	O
2	O
subunit	O
.	O

Complementary	O
techniques	O
such	O
as	O
western	O
immunoblotting	O
and	O
immunohistochemistry	O
were	O
performed	O
to	O
investigate	O
the	O
validity	O
of	O
the	O
data	O
obtained	O
using	O
the	O
proteomic	O
approach	O
.	O

In	O
conclusion	O
,	O
this	O
study	O
provides	O
new	O
insights	O
into	O
the	O
protein	O
changes	O
occurring	O
in	O
LID	B-Disease
.	O

Cardiac	O
Angiography	O
in	O
Renally	O
Impaired	O
Patients	O
(	O
CARE	O
)	O
study	O
:	O
a	O
randomized	O
double	O
-	O
blind	O
trial	O
of	O
contrast	O
-	O
induced	O
nephropathy	B-Disease
in	O
patients	O
with	O
chronic	B-Disease
kidney	I-Disease
disease	I-Disease
.	O

BACKGROUND	O
:	O
No	O
direct	O
comparisons	O
exist	O
of	O
the	O
renal	O
tolerability	O
of	O
the	O
low	O
-	O
osmolality	O
contrast	B-Chemical
medium	I-Chemical
iopamidol	B-Chemical
with	O
that	O
of	O
the	O
iso	O
-	O
osmolality	O
contrast	B-Chemical
medium	I-Chemical
iodixanol	B-Chemical
in	O
high	O
-	O
risk	O
patients	O
.	O

METHODS	O
AND	O
RESULTS	O
:	O
The	O
present	O
study	O
is	O
a	O
multicenter	O
,	O
randomized	O
,	O
double	O
-	O
blind	O
comparison	O
of	O
iopamidol	B-Chemical
and	O
iodixanol	B-Chemical
in	O
patients	O
with	O
chronic	B-Disease
kidney	I-Disease
disease	I-Disease
(	O
estimated	O
glomerular	O
filtration	O
rate	O
,	O
20	O
to	O
59	O
mL	O
/	O
min	O
)	O
who	O
underwent	O
cardiac	O
angiography	O
or	O
percutaneous	O
coronary	O
interventions	O
.	O

Serum	O
creatinine	B-Chemical
(	O
SCr	O
)	O
levels	O
and	O
estimated	O
glomerular	O
filtration	O
rate	O
were	O
assessed	O
at	O
baseline	O
and	O
2	O
to	O
5	O
days	O
after	O
receiving	O
medications	O
.	O

The	O
primary	O
outcome	O
was	O
a	O
postdose	O
SCr	O
increase	O
>	O
or	O
=	O
0	O
.	O
5	O
mg	O
/	O
dL	O
(	O
44	O
.	O
2	O
micromol	O
/	O
L	O
)	O
over	O
baseline	O
.	O

Secondary	O
outcomes	O
were	O
a	O
postdose	O
SCr	O
increase	O
>	O
or	O
=	O
25	O
%	O
,	O
a	O
postdose	O
estimated	O
glomerular	O
filtration	O
rate	O
decrease	O
of	O
>	O
or	O
=	O
25	O
%	O
,	O
and	O
the	O
mean	O
peak	O
change	O
in	O
SCr	O
.	O

In	O
414	O
patients	O
,	O
contrast	O
volume	O
,	O
presence	O
of	O
diabetes	B-Disease
mellitus	I-Disease
,	O
use	O
of	O
N	B-Chemical
-	I-Chemical
acetylcysteine	I-Chemical
,	O
mean	O
baseline	O
SCr	O
,	O
and	O
estimated	O
glomerular	O
filtration	O
rate	O
were	O
comparable	O
in	O
the	O
2	O
groups	O
.	O

SCr	O
increases	O
>	O
or	O
=	O
0	O
.	O
5	O
mg	O
/	O
dL	O
occurred	O
in	O
4	O
.	O
4	O
%	O
(	O
9	O
of	O
204	O
patients	O
)	O
after	O
iopamidol	B-Chemical
and	O
6	O
.	O
7	O
%	O
(	O
14	O
of	O
210	O
patients	O
)	O
after	O
iodixanol	B-Chemical
(	O
P	O
=	O
0	O
.	O
39	O
)	O
,	O
whereas	O
rates	O
of	O
SCr	O
increases	O
>	O
or	O
=	O
25	O
%	O
were	O
9	O
.	O
8	O
%	O
and	O
12	O
.	O
4	O
%	O
,	O
respectively	O
(	O
P	O
=	O
0	O
.	O
44	O
)	O
.	O

In	O
patients	O
with	O
diabetes	B-Disease
,	O
SCr	O
increases	O
>	O
or	O
=	O
0	O
.	O
5	O
mg	O
/	O
dL	O
were	O
5	O
.	O
1	O
%	O
(	O
4	O
of	O
78	O
patients	O
)	O
with	O
iopamidol	B-Chemical
and	O
13	O
.	O
0	O
%	O
(	O
12	O
of	O
92	O
patients	O
)	O
with	O
iodixanol	B-Chemical
(	O
P	O
=	O
0	O
.	O
11	O
)	O
,	O
whereas	O
SCr	O
increases	O
>	O
or	O
=	O
25	O
%	O
were	O
10	O
.	O
3	O
%	O
and	O
15	O
.	O
2	O
%	O
,	O
respectively	O
(	O
P	O
=	O
0	O
.	O
37	O
)	O
.	O

Mean	O
post	O
-	O
SCr	O
increases	O
were	O
significantly	O
less	O
with	O
iopamidol	B-Chemical
(	O
all	O
patients	O
:	O
0	O
.	O
07	O
versus	O
0	O
.	O
12	O
mg	O
/	O
dL	O
,	O
6	O
.	O
2	O
versus	O
10	O
.	O
6	O
micromol	O
/	O
L	O
,	O
P	O
=	O
0	O
.	O
03	O
;	O
patients	O
with	O
diabetes	B-Disease
:	O
0	O
.	O
07	O
versus	O
0	O
.	O
16	O
mg	O
/	O
dL	O
,	O
6	O
.	O
2	O
versus	O
14	O
.	O
1	O
micromol	O
/	O
L	O
,	O
P	O
=	O
0	O
.	O
01	O
)	O
.	O

CONCLUSIONS	O
:	O
The	O
rate	O
of	O
contrast	O
-	O
induced	O
nephropathy	B-Disease
,	O
defined	O
by	O
multiple	O
end	O
points	O
,	O
is	O
not	O
statistically	O
different	O
after	O
the	O
intraarterial	O
administration	O
of	O
iopamidol	B-Chemical
or	O
iodixanol	B-Chemical
to	O
high	O
-	O
risk	O
patients	O
,	O
with	O
or	O
without	O
diabetes	B-Disease
mellitus	I-Disease
.	O

Any	O
true	O
difference	O
between	O
the	O
agents	O
is	O
small	O
and	O
not	O
likely	O
to	O
be	O
clinically	O
significant	O
.	O

A	O
novel	O
compound	O
,	O
maltolyl	B-Chemical
p	I-Chemical
-	I-Chemical
coumarate	I-Chemical
,	O
attenuates	O
cognitive	B-Disease
deficits	I-Disease
and	O
shows	O
neuroprotective	O
effects	O
in	O
vitro	O
and	O
in	O
vivo	O
dementia	B-Disease
models	O
.	O

To	O
develop	O
a	O
novel	O
and	O
effective	O
drug	O
that	O
could	O
enhance	O
cognitive	O
function	O
and	O
neuroprotection	O
,	O
we	O
newly	O
synthesized	O
maltolyl	B-Chemical
p	I-Chemical
-	I-Chemical
coumarate	I-Chemical
by	O
the	O
esterification	O
of	O
maltol	B-Chemical
and	O
p	B-Chemical
-	I-Chemical
coumaric	I-Chemical
acid	I-Chemical
.	O

In	O
the	O
present	O
study	O
,	O
we	O
investigated	O
whether	O
maltolyl	B-Chemical
p	I-Chemical
-	I-Chemical
coumarate	I-Chemical
could	O
improve	O
cognitive	B-Disease
decline	I-Disease
in	O
scopolamine	B-Chemical
-	O
injected	O
rats	O
and	O
in	O
amyloid	B-Chemical
beta	I-Chemical
peptide	I-Chemical
(	I-Chemical
1	I-Chemical
-	I-Chemical
42	I-Chemical
)	I-Chemical
-	O
infused	O
rats	O
.	O

Maltolyl	B-Chemical
p	I-Chemical
-	I-Chemical
coumarate	I-Chemical
was	O
found	O
to	O
attenuate	O
cognitive	B-Disease
deficits	I-Disease
in	O
both	O
rat	O
models	O
using	O
passive	O
avoidance	O
test	O
and	O
to	O
reduce	O
apoptotic	O
cell	O
death	O
observed	O
in	O
the	O
hippocampus	O
of	O
the	O
amyloid	B-Chemical
beta	I-Chemical
peptide	I-Chemical
(	I-Chemical
1	I-Chemical
-	I-Chemical
42	I-Chemical
)	I-Chemical
-	O
infused	O
rats	O
.	O

We	O
also	O
examined	O
the	O
neuroprotective	O
effects	O
of	O
maltolyl	B-Chemical
p	I-Chemical
-	I-Chemical
coumarate	I-Chemical
in	O
vitro	O
using	O
SH	O
-	O
SY5Y	O
cells	O
.	O

Cells	O
were	O
pretreated	O
with	O
maltolyl	B-Chemical
p	I-Chemical
-	I-Chemical
coumarate	I-Chemical
,	O
before	O
exposed	O
to	O
amyloid	B-Chemical
beta	I-Chemical
peptide	I-Chemical
(	I-Chemical
1	I-Chemical
-	I-Chemical
42	I-Chemical
)	I-Chemical
,	O
glutamate	B-Chemical
or	O
H2O2	B-Chemical
.	O

We	O
found	O
that	O
maltolyl	B-Chemical
p	I-Chemical
-	I-Chemical
coumarate	I-Chemical
significantly	O
decreased	O
apoptotic	O
cell	O
death	O
and	O
reduced	O
reactive	O
oxygen	O
species	O
,	O
cytochrome	O
c	O
release	O
,	O
and	O
caspase	O
3	O
activation	O
.	O

Taking	O
these	O
in	O
vitro	O
and	O
in	O
vivo	O
results	O
together	O
,	O
our	O
study	O
suggests	O
that	O
maltolyl	B-Chemical
p	I-Chemical
-	I-Chemical
coumarate	I-Chemical
is	O
a	O
potentially	O
effective	O
candidate	O
against	O
Alzheimer	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
that	O
is	O
characterized	O
by	O
wide	O
spread	O
neuronal	B-Disease
death	I-Disease
and	O
progressive	O
decline	B-Disease
of	I-Disease
cognitive	I-Disease
function	I-Disease
.	O

Attenuation	O
of	O
methamphetamine	B-Chemical
-	O
induced	O
nigrostriatal	O
dopaminergic	O
neurotoxicity	B-Disease
in	O
mice	O
by	O
lipopolysaccharide	B-Chemical
pretreatment	O
.	O

Immunological	O
activation	O
has	O
been	O
proposed	O
to	O
play	O
a	O
role	O
in	O
methamphetamine	B-Chemical
-	O
induced	O
dopaminergic	B-Disease
terminal	I-Disease
damage	I-Disease
.	O

In	O
this	O
study	O
,	O
we	O
examined	O
the	O
roles	O
of	O
lipopolysaccharide	B-Chemical
,	O
a	O
pro	O
-	O
inflammatory	O
and	O
inflammatory	O
factor	O
,	O
treatment	O
in	O
modulating	O
the	O
methamphetamine	B-Chemical
-	O
induced	O
nigrostriatal	O
dopamine	B-Chemical
neurotoxicity	B-Disease
.	O

Lipopolysaccharide	B-Chemical
pretreatment	O
did	O
not	O
affect	O
the	O
basal	O
body	O
temperature	O
or	O
methamphetamine	B-Chemical
-	O
elicited	O
hyperthermia	B-Disease
three	O
days	O
later	O
.	O

Such	O
systemic	O
lipopolysaccharide	B-Chemical
treatment	O
mitigated	O
methamphetamine	B-Chemical
-	O
induced	O
striatal	O
dopamine	B-Chemical
and	O
3	B-Chemical
,	I-Chemical
4	I-Chemical
-	I-Chemical
dihydroxyphenylacetic	I-Chemical
acid	I-Chemical
depletions	O
in	O
a	O
dose	O
-	O
dependent	O
manner	O
.	O

As	O
the	O
most	O
potent	O
dose	O
(	O
1	O
mg	O
/	O
kg	O
)	O
of	O
lipopolysaccharide	B-Chemical
was	O
administered	O
two	O
weeks	O
,	O
one	O
day	O
before	O
or	O
after	O
the	O
methamphetamine	B-Chemical
dosing	O
regimen	O
,	O
methamphetamine	B-Chemical
-	O
induced	O
striatal	O
dopamine	B-Chemical
and	O
3	B-Chemical
,	I-Chemical
4	I-Chemical
-	I-Chemical
dihydroxyphenylacetic	I-Chemical
acid	I-Chemical
depletions	O
remained	O
unaltered	O
.	O

Moreover	O
,	O
systemic	O
lipopolysaccharide	B-Chemical
pretreatment	O
(	O
1	O
mg	O
/	O
kg	O
)	O
attenuated	O
local	O
methamphetamine	B-Chemical
infusion	O
-	O
produced	O
dopamine	B-Chemical
and	O
3	B-Chemical
,	I-Chemical
4	I-Chemical
-	I-Chemical
dihydroxyphenylacetic	I-Chemical
acid	I-Chemical
depletions	O
in	O
the	O
striatum	O
,	O
indicating	O
that	O
the	O
protective	O
effect	O
of	O
lipopolysaccharide	B-Chemical
is	O
less	O
likely	O
due	O
to	O
interrupted	O
peripheral	O
distribution	O
or	O
metabolism	O
of	O
methamphetamine	B-Chemical
.	O

We	O
concluded	O
a	O
critical	O
time	O
window	O
for	O
systemic	O
lipopolysaccharide	B-Chemical
pretreatment	O
in	O
exerting	O
effective	O
protection	O
against	O
methamphetamine	B-Chemical
-	O
induced	O
nigrostriatal	O
dopamine	B-Chemical
neurotoxicity	B-Disease
.	O

Acute	O
myocarditis	B-Disease
associated	O
with	O
clozapine	B-Chemical
.	O

OBJECTIVE	O
:	O
A	O
case	O
of	O
acute	O
myocarditis	B-Disease
associated	O
with	O
the	O
commencement	O
of	O
clozapine	B-Chemical
is	O
described	O
,	O
highlighting	O
the	O
onset	O
,	O
course	O
and	O
possible	O
contributing	O
factors	O
.	O

There	O
is	O
an	O
urgent	O
need	O
to	O
raise	O
awareness	O
about	O
this	O
potentially	O
fatal	O
complication	O
of	O
clozapine	B-Chemical
use	O
.	O

RESULTS	O
:	O
A	O
20	O
-	O
year	O
-	O
old	O
male	O
with	O
schizophrenia	B-Disease
developed	O
a	O
sudden	O
onset	O
of	O
myocarditis	B-Disease
after	O
commencement	O
of	O
clozapine	B-Chemical
.	O

The	O
patient	O
recovered	O
with	O
intensive	O
medical	O
support	O
.	O

The	O
symptoms	O
occurred	O
around	O
2	O
weeks	O
after	O
starting	O
clozapine	B-Chemical
in	O
an	O
inpatient	O
setting	O
.	O

Possible	O
contributing	O
factors	O
may	O
have	O
been	O
concomitant	O
antidepressant	B-Chemical
use	O
and	O
unaccustomed	O
physical	O
activity	O
.	O

CONCLUSIONS	O
:	O
Myocarditis	B-Disease
is	O
an	O
increasingly	O
recognized	O
complication	O
associated	O
with	O
the	O
use	O
of	O
clozapine	B-Chemical
.	O

It	O
can	O
be	O
fatal	O
if	O
not	O
recognized	O
and	O
treated	O
early	O
.	O

Considering	O
that	O
clozapine	B-Chemical
remains	O
the	O
gold	O
standard	O
in	O
treatment	O
of	O
resistant	O
psychosis	B-Disease
,	O
there	O
is	O
an	O
urgent	O
need	O
to	O
raise	O
awareness	O
among	O
medical	O
and	O
paramedical	O
staff	O
involved	O
in	O
the	O
care	O
of	O
these	O
patients	O
.	O

There	O
are	O
also	O
implications	O
for	O
recommendations	O
and	O
regulations	O
regarding	O
the	O
use	O
of	O
clozapine	B-Chemical
.	O

Severe	O
rhabdomyolysis	B-Disease
and	O
acute	B-Disease
renal	I-Disease
failure	I-Disease
secondary	O
to	O
concomitant	O
use	O
of	O
simvastatin	B-Chemical
,	O
amiodarone	B-Chemical
,	O
and	O
atazanavir	B-Chemical
.	O

OBJECTIVE	O
:	O
To	O
report	O
a	O
case	O
of	O
a	O
severe	O
interaction	O
between	O
simvastatin	B-Chemical
,	O
amiodarone	B-Chemical
,	O
and	O
atazanavir	B-Chemical
resulting	O
in	O
rhabdomyolysis	B-Disease
and	O
acute	B-Disease
renal	I-Disease
failure	I-Disease
.	O

BACKGROUND	O
:	O
A	O
72	O
-	O
year	O
-	O
old	O
white	O
man	O
with	O
underlying	O
human	B-Disease
immunodeficiency	I-Disease
virus	I-Disease
,	O
atrial	B-Disease
fibrillation	I-Disease
,	O
coronary	B-Disease
artery	I-Disease
disease	I-Disease
,	O
and	O
hyperlipidemia	B-Disease
presented	O
with	O
generalized	O
pain	B-Disease
,	O
fatigue	B-Disease
,	O
and	O
dark	O
orange	O
urine	O
for	O
3	O
days	O
.	O

The	O
patient	O
was	O
taking	O
80	O
mg	O
simvastatin	B-Chemical
at	O
bedtime	O
(	O
initiated	O
27	O
days	O
earlier	O
)	O
;	O
amiodarone	B-Chemical
at	O
a	O
dose	O
of	O
400	O
mg	O
daily	O
for	O
7	O
days	O
,	O
then	O
200	O
mg	O
daily	O
(	O
initiated	O
19	O
days	O
earlier	O
)	O
;	O
and	O
400	O
mg	O
atazanavir	B-Chemical
daily	O
(	O
initiated	O
at	O
least	O
2	O
years	O
previously	O
)	O
.	O

Laboratory	O
evaluation	O
revealed	O
66	O
,	O
680	O
U	O
/	O
L	O
creatine	B-Chemical
kinase	O
,	O
93	O
mg	O
/	O
dL	O
blood	B-Chemical
urea	I-Chemical
nitrogen	I-Chemical
,	O
4	O
.	O
6	O
mg	O
/	O
dL	O
creatinine	B-Chemical
,	O
1579	O
U	O
/	O
L	O
aspartate	B-Chemical
aminotransferase	O
,	O
and	O
738	O
U	O
/	O
L	O
alanine	B-Chemical
aminotransferase	O
.	O

Simvastatin	B-Chemical
,	O
amiodarone	B-Chemical
,	O
and	O
the	O
patient	O
'	O
s	O
human	B-Disease
immunodeficiency	I-Disease
virus	I-Disease
medications	O
were	O
all	O
temporarily	O
discontinued	O
and	O
the	O
patient	O
was	O
given	O
forced	O
alkaline	O
diuresis	O
and	O
started	O
on	O
dialysis	O
.	O

Nine	O
days	O
later	O
the	O
patient	O
'	O
s	O
creatine	B-Chemical
kinase	O
had	O
dropped	O
to	O
1695	O
U	O
/	O
L	O
and	O
creatinine	B-Chemical
was	O
3	O
.	O
3	O
mg	O
/	O
dL	O
.	O

The	O
patient	O
was	O
discharged	O
and	O
continued	O
outpatient	O
dialysis	O
for	O
1	O
month	O
until	O
his	O
renal	O
function	O
recovered	O
.	O

DISCUSSION	O
:	O
The	O
risk	O
of	O
rhabdomyolysis	B-Disease
is	O
increased	O
in	O
the	O
presence	O
of	O
concomitant	O
drugs	O
that	O
inhibit	O
simvastatin	B-Chemical
metabolism	O
.	O

Simvastatin	B-Chemical
is	O
metabolized	O
by	O
CYP3A4	O
.	O

Amiodarone	B-Chemical
and	O
atazanavir	B-Chemical
are	O
recognized	O
CYP3A4	O
inhibitors	O
.	O

CONCLUSIONS	O
:	O
Pharmacokinetic	O
differences	O
in	O
statins	B-Chemical
are	O
an	O
important	O
consideration	O
for	O
assessing	O
the	O
risk	O
of	O
potential	O
drug	O
interactions	O
.	O

In	O
patients	O
requiring	O
the	O
concurrent	O
use	O
of	O
statins	B-Chemical
and	O
CYP3A4	O
inhibitors	O
,	O
pravastatin	B-Chemical
,	O
fluvastatin	B-Chemical
,	O
and	O
rosuvastatin	B-Chemical
carry	O
the	O
lowest	O
risk	O
of	O
drug	O
interactions	O
;	O
atorvastatin	B-Chemical
carries	O
moderate	O
risk	O
,	O
whereas	O
simvastatin	B-Chemical
and	O
lovastatin	B-Chemical
have	O
the	O
highest	O
risk	O
and	O
should	O
be	O
avoided	O
in	O
patients	O
taking	O
concomitant	O
CYP3A4	O
inhibitors	O
.	O

Interaction	O
between	O
warfarin	B-Chemical
and	O
levofloxacin	B-Chemical
:	O
case	O
series	O
.	O

Warfarin	B-Chemical
is	O
the	O
most	O
widely	O
used	O
oral	O
anticoagulant	O
and	O
is	O
indicated	O
for	O
many	O
clinical	O
conditions	O
.	O

Levofloxacin	B-Chemical
,	O
a	O
fluoroquinolone	B-Chemical
,	O
is	O
one	O
of	O
the	O
most	O
commonly	O
prescribed	O
antibiotics	O
in	O
clinical	O
practice	O
and	O
is	O
effective	O
against	O
Gram	O
-	O
positive	O
,	O
Gram	O
-	O
negative	O
,	O
and	O
atypical	O
bacteria	O
.	O

While	O
small	O
prospective	O
studies	O
have	O
not	O
revealed	O
any	O
significant	O
drug	O
-	O
drug	O
interaction	O
between	O
warfarin	B-Chemical
and	O
levofloxacin	B-Chemical
,	O
several	O
case	O
reports	O
have	O
indicated	O
that	O
levofloxacin	B-Chemical
may	O
significantly	O
potentiate	O
the	O
anticoagulation	O
effect	O
of	O
warfarin	B-Chemical
.	O

We	O
report	O
3	O
cases	O
of	O
serious	O
bleeding	B-Disease
complications	O
that	O
appear	O
to	O
be	O
the	O
result	O
of	O
the	O
interaction	O
between	O
warfarin	B-Chemical
and	O
levofloxacin	B-Chemical
.	O

Physicians	O
should	O
be	O
aware	O
of	O
this	O
potential	O
interaction	O
and	O
use	O
caution	O
when	O
prescribing	O
levofloxacin	B-Chemical
to	O
patients	O
taking	O
warfarin	B-Chemical
.	O

Mutations	O
associated	O
with	O
lamivudine	B-Chemical
-	O
resistance	O
in	O
therapy	O
-	O
na	B-Chemical
ve	O
hepatitis	B-Disease
B	I-Disease
virus	I-Disease
(	I-Disease
HBV	I-Disease
)	I-Disease
infected	I-Disease
patients	O
with	O
and	O
without	O
HIV	B-Disease
co	I-Disease
-	I-Disease
infection	I-Disease
:	O
implications	O
for	O
antiretroviral	O
therapy	O
in	O
HBV	B-Disease
and	I-Disease
HIV	I-Disease
co	I-Disease
-	I-Disease
infected	I-Disease
South	O
African	O
patients	O
.	O

This	O
was	O
an	O
exploratory	O
study	O
to	O
investigate	O
lamivudine	B-Chemical
-	O
resistant	O
hepatitis	B-Disease
B	I-Disease
virus	O
(	O
HBV	O
)	O
strains	O
in	O
selected	O
lamivudine	B-Chemical
-	O
na	B-Chemical
ve	O
HBV	O
carriers	O
with	O
and	O
without	O
human	B-Disease
immunodeficiency	I-Disease
virus	I-Disease
(	I-Disease
HIV	I-Disease
)	I-Disease
co	I-Disease
-	I-Disease
infection	I-Disease
in	O
South	O
African	O
patients	O
.	O

Thirty	O
-	O
five	O
lamivudine	B-Chemical
-	O
na	B-Chemical
ve	O
HBV	B-Disease
infected	I-Disease
patients	O
with	O
or	O
without	O
HIV	B-Disease
co	I-Disease
-	I-Disease
infection	I-Disease
were	O
studied	O
:	O
15	O
chronic	O
HBV	B-Disease
mono	I-Disease
-	I-Disease
infected	I-Disease
patients	O
and	O
20	O
HBV	B-Disease
-	I-Disease
HIV	I-Disease
co	I-Disease
-	I-Disease
infected	I-Disease
patients	O
.	O

The	O
latter	O
group	O
was	O
further	O
sub	O
-	O
divided	O
into	O
13	O
occult	O
HBV	O
(	O
HBsAg	B-Chemical
-	O
negative	O
)	O
and	O
7	O
overt	O
HBV	O
(	O
HBsAg	B-Chemical
-	O
positive	O
)	O
patients	O
.	O

HBsAg	B-Chemical
,	O
anti	O
-	O
HBs	O
,	O
anti	O
-	O
HBc	O
,	O
and	O
anti	O
-	O
HIV	O
1	O
/	O
2	O
were	O
determined	O
as	O
part	O
of	O
routine	O
diagnosis	O
using	O
Axsym	O
assays	O
(	O
Abbott	O
Laboratories	O
,	O
North	O
Chicago	O
,	O
IL	O
)	O
.	O

Serum	O
samples	O
were	O
PCR	O
amplified	O
with	O
HBV	O
reverse	O
transcriptase	O
(	O
RT	O
)	O
primers	O
,	O
followed	O
by	O
direct	O
sequencing	O
across	O
the	O
tyrosine	B-Chemical
-	O
methionine	B-Chemical
-	O
aspartate	B-Chemical
-	O
aspartate	B-Chemical
(	O
YMDD	O
)	O
motif	O
of	O
the	O
major	O
catalytic	O
region	O
in	O
the	O
C	O
domain	O
of	O
the	O
HBV	O
RT	O
enzyme	O
.	O

HBV	O
viral	O
load	O
was	O
performed	O
with	O
Amplicor	O
HBV	O
Monitor	O
test	O
v2	O
.	O
0	O
(	O
Roche	O
Diagnostics	O
,	O
Penzberg	O
,	O
Germany	O
)	O
.	O

HBV	O
lamivudine	B-Chemical
-	O
resistant	O
strains	O
were	O
detected	O
in	O
3	O
of	O
15	O
mono	O
-	O
infected	O
chronic	O
hepatitis	B-Disease
B	I-Disease
patients	O
and	O
10	O
of	O
20	O
HBV	B-Disease
-	I-Disease
HIV	I-Disease
co	I-Disease
-	I-Disease
infected	I-Disease
patients	O
.	O

To	O
the	O
best	O
of	O
our	O
knowledge	O
,	O
this	O
constitutes	O
the	O
first	O
report	O
of	O
HBV	O
lamivudine	B-Chemical
-	O
resistant	O
strains	O
in	O
therapy	O
-	O
na	B-Chemical
ve	O
HBV	B-Disease
-	I-Disease
HIV	I-Disease
co	I-Disease
-	I-Disease
infected	I-Disease
patients	O
.	O

The	O
HBV	O
viral	O
loads	O
for	O
mono	O
-	O
infected	O
and	O
co	O
-	O
infected	O
patients	O
ranged	O
from	O
3	O
.	O
32	O
x	O
10	O
(	O
2	O
)	O
to	O
3	O
.	O
82	O
x	O
10	O
(	O
7	O
)	O
and	O
<	O
200	O
to	O
4	O
.	O
40	O
x	O
10	O
(	O
3	O
)	O
copies	O
/	O
ml	O
,	O
respectively	O
.	O

It	O
remains	O
to	O
be	O
seen	O
whether	O
such	O
pre	O
-	O
existing	O
antiviral	O
mutations	O
could	O
result	O
in	O
widespread	O
emergence	O
of	O
HBV	O
resistant	O
strains	O
when	O
lamivudine	B-Chemical
-	O
containing	O
highly	O
active	O
antiretroviral	O
(	O
ARV	O
)	O
treatment	O
(	O
HAART	O
)	O
regimens	O
become	O
widely	O
applied	O
in	O
South	O
Africa	O
,	O
as	O
this	O
is	O
likely	O
to	O
have	O
potential	O
implications	O
in	O
the	O
management	O
of	O
HBV	B-Disease
-	I-Disease
HIV	I-Disease
co	I-Disease
-	I-Disease
infected	I-Disease
patients	O
.	O

Rabbit	B-Disease
syndrome	I-Disease
,	O
antidepressant	B-Chemical
use	O
,	O
and	O
cerebral	O
perfusion	O
SPECT	O
scan	O
findings	O
.	O

The	O
rabbit	B-Disease
syndrome	I-Disease
is	O
an	O
extrapyramidal	O
side	O
effect	O
associated	O
with	O
chronic	O
neuroleptic	O
therapy	O
.	O

Its	O
occurrence	O
in	O
a	O
patient	O
being	O
treated	O
with	O
imipramine	B-Chemical
is	O
described	O
,	O
representing	O
the	O
first	O
reported	O
case	O
of	O
this	O
syndrome	O
in	O
conjunction	O
with	O
antidepressants	B-Chemical
.	O

Repeated	O
cerebral	O
perfusion	O
SPECT	O
scans	O
revealed	O
decreased	B-Disease
basal	I-Disease
ganglia	I-Disease
perfusion	I-Disease
while	O
the	O
movement	B-Disease
disorder	I-Disease
was	O
present	O
,	O
and	O
a	O
return	O
to	O
normal	O
perfusion	O
when	O
the	O
rabbit	B-Disease
syndrome	I-Disease
resolved	O
.	O

Estrogen	O
prevents	O
cholesteryl	B-Chemical
ester	I-Chemical
accumulation	O
in	O
macrophages	O
induced	O
by	O
the	O
HIV	O
protease	O
inhibitor	O
ritonavir	B-Chemical
.	O

Individuals	O
with	O
HIV	O
can	O
now	O
live	O
long	O
lives	O
with	O
drug	O
therapy	O
that	O
often	O
includes	O
protease	O
inhibitors	O
such	O
as	O
ritonavir	B-Chemical
.	O

Many	O
patients	O
,	O
however	O
,	O
develop	O
negative	O
long	O
-	O
term	O
side	O
effects	O
such	O
as	O
premature	B-Disease
atherosclerosis	I-Disease
.	O

We	O
have	O
previously	O
demonstrated	O
that	O
ritonavir	B-Chemical
treatment	O
increases	O
atherosclerotic	B-Disease
lesion	I-Disease
formation	O
in	O
male	O
mice	O
to	O
a	O
greater	O
extent	O
than	O
in	O
female	O
mice	O
.	O

Furthermore	O
,	O
peripheral	O
blood	O
monocytes	O
isolated	O
from	O
ritonavir	B-Chemical
-	O
treated	O
females	O
had	O
less	O
cholesteryl	B-Chemical
ester	I-Chemical
accumulation	O
.	O

In	O
the	O
present	O
study	O
,	O
we	O
have	O
investigated	O
the	O
molecular	O
mechanisms	O
by	O
which	O
female	O
hormones	O
influence	O
cholesterol	B-Chemical
metabolism	O
in	O
macrophages	O
in	O
response	O
to	O
the	O
HIV	O
protease	O
inhibitor	O
ritonavir	B-Chemical
.	O

We	O
have	O
utilized	O
the	O
human	O
monocyte	O
cell	O
line	O
,	O
THP	O
-	O
1	O
as	O
a	O
model	O
to	O
address	O
this	O
question	O
.	O

Briefly	O
,	O
cells	O
were	O
differentiated	O
for	O
72	O
h	O
with	O
100	O
nM	O
PMA	O
to	O
obtain	O
a	O
macrophage	O
-	O
like	O
phenotype	O
in	O
the	O
presence	O
or	O
absence	O
of	O
1	O
nM	O
17beta	B-Chemical
-	I-Chemical
estradiol	I-Chemical
(	O
E2	B-Chemical
)	O
,	O
100	O
nM	O
progesterone	B-Chemical
or	O
vehicle	O
(	O
0	O
.	O
01	O
%	O
ethanol	B-Chemical
)	O
.	O

Cells	O
were	O
then	O
treated	O
with	O
30	O
ng	O
/	O
ml	O
ritonavir	B-Chemical
or	O
vehicle	O
in	O
the	O
presence	O
of	O
aggregated	O
LDL	O
for	O
24	O
h	O
.	O

Cell	O
extracts	O
were	O
harvested	O
,	O
and	O
lipid	O
or	O
total	O
RNA	O
was	O
isolated	O
.	O

E2	B-Chemical
decreased	O
the	O
accumulation	O
of	O
cholesteryl	B-Chemical
esters	I-Chemical
in	O
macrophages	O
following	O
ritonavir	B-Chemical
treatment	O
.	O

Ritonavir	B-Chemical
increased	O
the	O
expression	O
of	O
the	O
scavenger	O
receptor	O
,	O
CD36	O
mRNA	O
,	O
responsible	O
for	O
the	O
uptake	O
of	O
LDL	O
.	O

Additionally	O
,	O
ritonavir	B-Chemical
treatment	O
selectively	O
increased	O
the	O
relative	O
levels	O
of	O
PPARgamma	O
mRNA	O
,	O
a	O
transcription	O
factor	O
responsible	O
for	O
the	O
regulation	O
of	O
CD36	O
mRNA	O
expression	O
.	O

Treatment	O
with	O
E2	B-Chemical
,	O
however	O
,	O
failed	O
to	O
prevent	O
these	O
increases	O
at	O
the	O
mRNA	O
level	O
.	O

E2	B-Chemical
did	O
,	O
however	O
,	O
significantly	O
suppress	O
CD36	O
protein	O
levels	O
as	O
measured	O
by	O
fluorescent	O
immunocytochemistry	O
.	O

This	O
data	O
suggests	O
that	O
E2	B-Chemical
modifies	O
the	O
expression	O
of	O
CD36	O
at	O
the	O
level	O
of	O
protein	O
expression	O
in	O
monocyte	O
-	O
derived	O
macrophages	O
resulting	O
in	O
reduced	O
cholesteryl	B-Chemical
ester	I-Chemical
accumulation	O
following	O
ritonavir	B-Chemical
treatment	O
.	O

Acute	O
hepatitis	B-Disease
attack	O
after	O
exposure	O
to	O
telithromycin	B-Chemical
.	O

INTRODUCTION	O
:	O
Antibiotic	O
-	O
associated	O
hepatotoxicity	B-Disease
is	O
rare	O
.	O

With	O
widespread	O
use	O
of	O
antimicrobial	O
agents	O
,	O
however	O
,	O
hepatic	B-Disease
injury	I-Disease
occurs	O
frequently	O
,	O
and	O
among	O
adverse	B-Disease
drug	I-Disease
reactions	I-Disease
,	O
idiosyncratic	O
reactions	O
are	O
the	O
most	O
serious	O
.	O

CASE	O
SUMMARY	O
:	O
A	O
25	O
-	O
year	O
-	O
old	O
male	O
patient	O
,	O
with	O
a	O
height	O
of	O
175	O
cm	O
and	O
weight	O
of	O
72	O
kg	O
presented	O
to	O
Marmara	O
University	O
Hospital	O
Emergency	O
Department	O
,	O
Istanbul	O
,	O
Turkey	O
,	O
with	O
5	O
days	O
'	O
history	O
of	O
jaundice	B-Disease
,	O
malaise	O
,	O
nausea	B-Disease
,	O
and	O
vomiting	B-Disease
.	O

He	O
had	O
been	O
prescribed	O
telithromycin	B-Chemical
400	O
mg	O
/	O
d	O
PO	O
to	O
treat	O
an	O
upper	B-Disease
respiratory	I-Disease
tract	I-Disease
infection	I-Disease
7	O
days	O
prior	O
.	O

Admission	O
laboratory	O
tests	O
were	O
as	O
follows	O
:	O
alanine	B-Chemical
aminotransferase	O
,	O
67	O
U	O
/	O
L	O
(	O
reference	O
range	O
,	O
10	O
-	O
37	O
U	O
/	O
L	O
)	O
;	O
aspartate	B-Chemical
aminotransferase	O
,	O
98	O
U	O
/	O
L	O
(	O
10	O
-	O
40	O
U	O
/	O
L	O
)	O
;	O
alkaline	O
phosphatase	O
,	O
513	O
U	O
/	O
L	O
(	O
0	O
-	O
270	O
U	O
/	O
L	O
)	O
;	O
gamma	O
-	O
glutamyltransferase	O
,	O
32	O
U	O
/	O
L	O
(	O
7	O
-	O
49	O
U	O
/	O
L	O
)	O
;	O
amylase	O
,	O
46	O
U	O
/	O
L	O
(	O
0	O
-	O
220	O
U	O
/	O
L	O
)	O
;	O
total	O
bilirubin	B-Chemical
,	O
20	O
.	O
1	O
mg	O
/	O
dL	O
(	O
0	O
.	O
2	O
-	O
1	O
.	O
0	O
mg	O
/	O
dL	O
)	O
;	O
direct	O
bilirubin	B-Chemical
,	O
14	O
.	O
8	O
mg	O
/	O
dL	O
(	O
0	O
-	O
0	O
.	O
3	O
mg	O
/	O
dL	O
)	O
;	O
and	O
albumin	O
,	O
4	O
.	O
7	O
mg	O
/	O
dL	O
(	O
3	O
.	O
5	O
-	O
5	O
.	O
4	O
mg	O
/	O
dL	O
)	O
.	O

No	O
toxin	O
,	O
alcohol	B-Chemical
,	O
or	O
other	O
drugs	O
were	O
reported	O
.	O

The	O
patient	O
had	O
suffered	O
a	O
previous	O
episode	O
of	O
"	O
acute	O
hepatitis	B-Disease
of	O
unknown	O
origin	O
,	O
"	O
that	O
occurred	O
after	O
telithromycin	B-Chemical
usage	O
.	O

Both	O
incidents	O
occurred	O
within	O
a	O
year	O
.	O

DISCUSSION	O
:	O
Telithromycin	B-Chemical
is	O
the	O
first	O
of	O
the	O
ketolide	O
antibacterials	O
to	O
receive	O
US	O
Food	O
and	O
Drug	O
Administration	O
approval	O
for	O
clinical	O
use	O
.	O

It	O
has	O
been	O
associated	O
with	O
infrequent	O
and	O
usually	O
reversible	O
severe	O
hepatic	B-Disease
dysfunction	I-Disease
.	O

Based	O
on	O
a	O
score	O
of	O
8	O
on	O
the	O
Naranjo	O
adverse	B-Disease
drug	I-Disease
reaction	I-Disease
probability	O
scale	O
,	O
telithromycin	B-Chemical
was	O
the	O
probable	O
cause	O
of	O
acute	O
hepatitis	B-Disease
in	O
this	O
patient	O
,	O
and	O
pathological	O
findings	O
suggested	O
drug	O
-	O
induced	O
toxic	B-Disease
hepatitis	I-Disease
.	O

Recurrence	O
of	O
hepatitis	B-Disease
attack	O
might	O
have	O
been	O
avoided	O
if	O
the	O
initial	O
incident	O
had	O
been	O
communicated	O
to	O
the	O
attending	O
physician	O
who	O
prescribed	O
telithromycin	B-Chemical
the	O
second	O
time	O
.	O

CONCLUSION	O
:	O
Here	O
we	O
report	O
a	O
case	O
of	O
acute	O
hepatitis	B-Disease
probably	O
associated	O
with	O
the	O
administration	O
of	O
telithromycin	B-Chemical
.	O

A	O
study	O
on	O
the	O
effect	O
of	O
the	O
duration	O
of	O
subcutaneous	O
heparin	B-Chemical
injection	O
on	O
bruising	B-Disease
and	O
pain	B-Disease
.	O

AIM	O
:	O
This	O
study	O
was	O
carried	O
out	O
to	O
determine	O
the	O
effect	O
of	O
injection	O
duration	O
on	O
bruising	B-Disease
and	O
pain	B-Disease
following	O
the	O
administration	O
of	O
the	O
subcutaneous	O
injection	O
of	O
heparin	B-Chemical
.	O

BACKGROUND	O
:	O
Although	O
different	O
methods	O
to	O
prevent	O
bruising	B-Disease
and	O
pain	B-Disease
following	O
the	O
subcutaneous	O
injection	O
of	O
heparin	B-Chemical
have	O
been	O
widely	O
studied	O
and	O
described	O
,	O
the	O
effect	O
of	O
injection	O
duration	O
on	O
the	O
occurrence	O
of	O
bruising	B-Disease
and	O
pain	B-Disease
is	O
little	O
documented	O
.	O

DESIGN	O
:	O
This	O
study	O
was	O
designed	O
as	O
within	O
-	O
subject	O
,	O
quasi	O
-	O
experimental	O
research	O
.	O

METHOD	O
:	O
The	O
sample	O
for	O
the	O
study	O
consisted	O
of	O
50	O
patients	O
to	O
whom	O
subcutaneous	O
heparin	B-Chemical
was	O
administered	O
.	O

Heparin	B-Chemical
was	O
injected	O
over	O
10	O
seconds	O
on	O
the	O
right	O
abdominal	O
site	O
and	O
30	O
seconds	O
on	O
the	O
left	O
abdominal	O
site	O
.	O

Injections	O
areas	O
were	O
assessed	O
for	O
the	O
presence	O
of	O
bruising	B-Disease
at	O
48	O
and	O
72	O
hours	O
after	O
each	O
injection	O
.	O

Dimensions	O
of	O
the	O
bruising	B-Disease
on	O
the	O
heparin	B-Chemical
applied	O
areas	O
were	O
measured	O
using	O
transparent	O
millimetric	O
measuring	O
paper	O
.	O

The	O
visual	O
analog	O
scale	O
(	O
VAS	O
)	O
was	O
used	O
to	O
measure	O
pain	B-Disease
intensity	O
and	O
a	O
stop	O
-	O
watch	O
was	O
used	O
to	O
time	O
the	O
pain	B-Disease
period	O
.	O

Data	O
were	O
analysed	O
using	O
chi	O
-	O
square	O
test	O
,	O
Mann	O
-	O
Whitney	O
U	O
,	O
Wilcoxon	O
signed	O
ranks	O
tests	O
and	O
correlation	O
.	O

RESULTS	O
:	O
The	O
percentage	O
of	O
bruising	B-Disease
occurrence	O
was	O
64	O
%	O
with	O
the	O
injection	O
of	O
10	O
seconds	O
duration	O
and	O
42	O
%	O
in	O
the	O
30	O
-	O
second	O
injection	O
.	O

It	O
was	O
determined	O
that	O
the	O
size	O
of	O
the	O
bruising	B-Disease
was	O
smaller	O
in	O
the	O
30	O
-	O
second	O
injection	O
.	O

Pain	B-Disease
intensity	O
and	O
pain	B-Disease
period	O
were	O
statistically	O
significantly	O
lower	O
for	O
the	O
30	O
-	O
second	O
injection	O
than	O
for	O
the	O
10	O
-	O
second	O
injection	O
.	O

CONCLUSIONS	O
:	O
It	O
was	O
determined	O
that	O
injection	O
duration	O
had	O
an	O
effect	O
on	O
bruising	B-Disease
and	O
pain	B-Disease
following	O
the	O
subcutaneous	O
administration	O
of	O
heparin	B-Chemical
.	O

This	O
study	O
should	O
be	O
repeated	O
on	O
a	O
larger	O
sample	O
.	O

RELEVANCE	O
TO	O
CLINICAL	O
PRACTICE	O
:	O
When	O
administering	O
subcutaneous	O
heparin	B-Chemical
injections	O
,	O
it	O
is	O
important	O
to	O
extend	O
the	O
duration	O
of	O
the	O
injection	O
.	O

Acute	B-Disease
liver	I-Disease
failure	I-Disease
in	O
two	O
patients	O
with	O
regular	O
alcohol	B-Chemical
consumption	O
ingesting	O
paracetamol	B-Chemical
at	O
therapeutic	O
dosage	O
.	O

BACKGROUND	O
:	O
The	O
possible	O
role	O
of	O
alcohol	B-Chemical
in	O
the	O
development	O
of	O
hepatotoxicity	B-Disease
associated	O
with	O
therapeutic	O
doses	O
of	O
paracetamol	B-Chemical
(	O
acetaminophen	B-Chemical
)	O
is	O
currently	O
debated	O
.	O

CASE	O
REPORT	O
:	O
We	O
describe	O
2	O
patients	O
who	O
were	O
regular	O
consumers	O
of	O
alcohol	B-Chemical
and	O
who	O
developed	O
liver	B-Disease
failure	I-Disease
within	O
3	O
-	O
5	O
days	O
after	O
hospitalization	O
and	O
stopping	O
alcohol	B-Chemical
consumption	O
while	O
being	O
treated	O
with	O
4	O
g	O
paracetamol	B-Chemical
/	O
day	O
.	O

A	O
paracetamol	B-Chemical
serum	O
level	O
obtained	O
in	O
one	O
of	O
these	O
patients	O
was	O
not	O
in	O
the	O
toxic	O
range	O
.	O

Possible	O
risk	O
factors	O
for	O
the	O
development	O
of	O
hepatotoxicity	B-Disease
in	O
patients	O
treated	O
with	O
therapeutic	O
doses	O
of	O
paracetamol	B-Chemical
are	O
discussed	O
.	O

CONCLUSION	O
:	O
In	O
patients	O
with	O
risk	O
factors	O
,	O
e	O
.	O
g	O
.	O
regular	O
consumption	O
of	O
alcohol	B-Chemical
,	O
liver	B-Disease
failure	I-Disease
is	O
possible	O
when	O
therapeutic	O
doses	O
are	O
ingested	O
.	O

We	O
propose	O
that	O
the	O
paracetamol	B-Chemical
dose	O
should	O
not	O
exceed	O
2	O
g	O
/	O
day	O
in	O
such	O
patients	O
and	O
that	O
their	O
liver	O
function	O
should	O
be	O
monitored	O
closely	O
while	O
being	O
treated	O
with	O
paracetamol	B-Chemical
.	O

Associations	O
between	O
use	O
of	O
benzodiazepines	B-Chemical
or	O
related	O
drugs	O
and	O
health	O
,	O
physical	O
abilities	O
and	O
cognitive	O
function	O
:	O
a	O
non	O
-	O
randomised	O
clinical	O
study	O
in	O
the	O
elderly	O
.	O

OBJECTIVE	O
:	O
To	O
describe	O
associations	O
between	O
the	O
use	O
of	O
benzodiazepines	B-Chemical
or	O
related	O
drugs	O
(	O
BZDs	B-Chemical
/	O
RDs	O
)	O
and	O
health	O
,	O
functional	O
abilities	O
and	O
cognitive	O
function	O
in	O
the	O
elderly	O
.	O

METHODS	O
:	O
A	O
non	O
-	O
randomised	O
clinical	O
study	O
of	O
patients	O
aged	O
>	O
or	O
=	O
65	O
years	O
admitted	O
to	O
acute	O
hospital	O
wards	O
during	O
1	O
month	O
.	O

164	O
patients	O
(	O
mean	O
age	O
+	O
/	O
-	O
standard	O
deviation	O
[	O
SD	O
]	O
81	O
.	O
6	O
+	O
/	O
-	O
6	O
.	O
8	O
years	O
)	O
were	O
admitted	O
.	O

Of	O
these	O
,	O
nearly	O
half	O
(	O
n	O
=	O
78	O
)	O
had	O
used	O
BZDs	B-Chemical
/	O
RDs	O
before	O
admission	O
,	O
and	O
the	O
remainder	O
(	O
n	O
=	O
86	O
)	O
were	O
non	O
-	O
users	O
.	O

Cognitive	O
ability	O
was	O
assessed	O
by	O
the	O
Mini	O
-	O
Mental	O
State	O
Examination	O
(	O
MMSE	O
)	O
.	O

Patients	O
scoring	O
>	O
or	O
=	O
20	O
MMSE	O
sum	O
points	O
were	O
interviewed	O
(	O
n	O
=	O
79	O
)	O
and	O
questioned	O
regarding	O
symptoms	O
and	O
functional	O
abilities	O
during	O
the	O
week	O
prior	O
to	O
admission	O
.	O

Data	O
on	O
use	O
of	O
BZDs	B-Chemical
/	O
RDs	O
before	O
admission	O
,	O
current	O
medications	O
and	O
discharge	O
diagnoses	O
were	O
collected	O
from	O
medical	O
records	O
.	O

Health	O
,	O
physical	O
abilities	O
and	O
cognitive	O
function	O
were	O
compared	O
between	O
BZD	O
/	O
RD	O
users	O
and	O
non	O
-	O
users	O
,	O
and	O
adjustments	O
were	O
made	O
for	O
confounding	O
variables	O
.	O

The	O
residual	O
serum	O
concentrations	O
of	O
oxazepam	B-Chemical
,	O
temazepam	B-Chemical
and	O
zopiclone	B-Chemical
were	O
analysed	O
.	O

RESULTS	O
:	O
The	O
mean	O
+	O
/	O
-	O
SD	O
duration	O
of	O
BZD	O
/	O
RD	O
use	O
was	O
7	O
+	O
/	O
-	O
7	O
years	O
(	O
range	O
1	O
-	O
31	O
)	O
.	O

Two	O
or	O
three	O
BZDs	B-Chemical
/	O
RDs	O
were	O
concomitantly	O
taken	O
by	O
26	O
%	O
of	O
users	O
(	O
n	O
=	O
20	O
)	O
.	O

Long	O
-	O
term	O
use	O
of	O
these	O
drugs	O
was	O
associated	O
with	O
female	O
sex	O
and	O
use	O
of	O
a	O
higher	O
number	O
of	O
drugs	O
with	O
effects	O
on	O
the	O
CNS	O
,	O
which	O
tended	O
to	O
be	O
related	O
to	O
diagnosed	O
dementia	B-Disease
.	O

After	O
adjustment	O
for	O
these	O
variables	O
as	O
confounders	O
,	O
use	O
of	O
BZDs	B-Chemical
/	O
RDs	O
was	O
not	O
associated	O
with	O
cognitive	O
function	O
as	O
measured	O
by	O
the	O
MMSE	O
.	O

However	O
,	O
use	O
of	O
BZDs	B-Chemical
/	O
RDs	O
was	O
associated	O
with	O
dizziness	B-Disease
,	O
inability	B-Disease
to	I-Disease
sleep	I-Disease
after	O
awaking	O
at	O
night	O
and	O
tiredness	B-Disease
in	O
the	O
mornings	O
during	O
the	O
week	O
prior	O
to	O
admission	O
and	O
with	O
stronger	O
depressive	B-Disease
symptoms	I-Disease
measured	O
at	O
the	O
beginning	O
of	O
the	O
hospital	O
stay	O
.	O

Use	O
of	O
BZDs	B-Chemical
/	O
RDs	O
tended	O
to	O
be	O
associated	O
with	O
a	O
reduced	O
ability	O
to	O
walk	O
and	O
shorter	O
night	O
-	O
time	O
sleep	O
during	O
the	O
week	O
prior	O
to	O
admission	O
.	O

A	O
higher	O
residual	O
serum	O
concentration	O
of	O
temazepam	B-Chemical
correlated	O
with	O
a	O
lower	O
MMSE	O
sum	O
score	O
after	O
adjustment	O
for	O
confounding	O
variables	O
.	O

CONCLUSIONS	O
:	O
Long	O
-	O
term	O
use	O
and	O
concomitant	O
use	O
of	O
more	O
than	O
one	O
BZD	O
/	O
RD	O
were	O
common	O
in	O
elderly	O
patients	O
hospitalised	O
because	O
of	O
acute	O
illnesses	O
.	O

Long	O
-	O
term	O
use	O
was	O
associated	O
with	O
daytime	O
and	O
night	O
-	O
time	O
symptoms	O
indicative	O
of	O
poorer	O
health	O
and	O
potentially	O
caused	O
by	O
the	O
adverse	O
effects	O
of	O
these	O
drugs	O
.	O

Acute	O
vocal	B-Disease
fold	I-Disease
palsy	I-Disease
after	O
acute	O
disulfiram	B-Chemical
intoxication	O
.	O

Acute	O
peripheral	B-Disease
neuropathy	I-Disease
caused	O
by	O
a	O
disulfiram	B-Chemical
overdose	B-Disease
is	O
very	O
rare	O
and	O
there	O
is	O
no	O
report	O
of	O
it	O
leading	O
to	O
vocal	B-Disease
fold	I-Disease
palsy	I-Disease
.	O

A	O
49	O
-	O
year	O
-	O
old	O
woman	O
was	O
transferred	O
to	O
our	O
department	O
because	O
of	O
quadriparesis	B-Disease
,	O
lancinating	O
pain	B-Disease
,	O
sensory	B-Disease
loss	I-Disease
,	O
and	O
paresthesia	B-Disease
of	O
the	O
distal	O
limbs	O
.	O

One	O
month	O
previously	O
,	O
she	O
had	O
taken	O
a	O
single	O
high	O
dose	O
of	O
disulfiram	B-Chemical
(	O
130	O
tablets	O
of	O
ALCOHOL	B-Chemical
STOP	O
TAB	O
,	O
Shin	O
-	O
Poong	O
Pharm	O
.	O
Co	O
.	O
,	O
Ansan	O
,	O
Korea	O
)	O
in	O
a	O
suicide	O
attempt	O
.	O

She	O
was	O
not	O
an	O
alcoholic	O
.	O

For	O
the	O
first	O
few	O
days	O
after	O
ingestion	O
,	O
she	O
was	O
in	O
a	O
confused	O
state	O
and	O
had	O
mild	O
to	O
moderate	O
ataxia	B-Disease
and	O
giddiness	B-Disease
.	O

She	O
noticed	O
hoarseness	B-Disease
and	O
distally	O
accentuated	O
motor	O
and	O
sensory	O
dysfunction	O
after	O
she	O
had	O
recovered	O
from	O
this	O
state	O
.	O

A	O
nerve	O
conduction	O
study	O
was	O
consistent	O
with	O
severe	O
sensorimotor	O
axonal	O
polyneuropathy	B-Disease
.	O

Laryngeal	O
electromyography	O
(	O
thyroarytenoid	O
muscle	O
)	O
showed	O
ample	O
denervation	O
potentials	O
.	O

Laryngoscopy	O
revealed	O
asymmetric	O
vocal	O
fold	O
movements	O
during	O
phonation	O
.	O

Her	O
vocal	O
change	O
and	O
weakness	O
began	O
to	O
improve	O
spontaneously	O
about	O
3	O
weeks	O
after	O
transfer	O
.	O

This	O
was	O
a	O
case	O
of	O
acute	O
palsy	B-Disease
of	O
the	O
recurrent	O
laryngeal	O
nerve	O
and	O
superimposed	O
severe	O
acute	O
sensorimotor	O
axonal	O
polyneuropathy	B-Disease
caused	O
by	O
high	O
-	O
dose	O
disulfiram	B-Chemical
intoxication	O
.	O

Encephalopathy	B-Disease
induced	O
by	O
levetiracetam	B-Chemical
added	O
to	O
valproate	B-Chemical
.	O

BACKGROUND	O
:	O
We	O
report	O
on	O
the	O
manifestation	O
of	O
a	O
levetiracetam	B-Chemical
(	O
LEV	B-Chemical
)	O
-	O
induced	O
encephalopathy	B-Disease
.	O

FINDINGS	O
:	O
A	O
28	O
-	O
year	O
-	O
old	O
man	O
suffering	O
from	O
idiopathic	B-Disease
epilepsy	I-Disease
with	O
generalized	O
seizures	B-Disease
was	O
treated	O
with	O
LEV	B-Chemical
(	O
3000	O
mg	O
)	O
added	O
to	O
valproate	B-Chemical
(	O
VPA	B-Chemical
)	O
(	O
2000	O
mg	O
)	O
.	O

Frequency	O
of	O
generalized	O
tonic	B-Disease
-	I-Disease
clonic	I-Disease
seizures	I-Disease
increased	O
from	O
one	O
per	O
6	O
months	O
to	O
two	O
per	O
month	O
.	O

Neuropsychological	O
testing	O
showed	O
impaired	B-Disease
word	I-Disease
fluency	I-Disease
,	I-Disease
psychomotor	I-Disease
speed	I-Disease
and	I-Disease
working	I-Disease
memory	I-Disease
.	O

The	O
interictal	O
electroencephalogram	O
(	O
EEG	O
)	O
showed	O
a	O
generalized	O
slowing	O
to	O
5	O
per	O
second	O
theta	O
rhythms	O
with	O
bilateral	O
generalized	O
high	O
-	O
amplitude	O
discharges	O
.	O

OUTCOME	O
:	O
Following	O
discontinuation	O
of	O
LEV	B-Chemical
,	O
EEG	O
and	O
neuropsychological	O
findings	O
improved	O
and	O
seizure	B-Disease
frequency	O
decreased	O
.	O

Norepinephrine	B-Chemical
signaling	O
through	O
beta	O
-	O
adrenergic	O
receptors	O
is	O
critical	O
for	O
expression	O
of	O
cocaine	B-Chemical
-	O
induced	O
anxiety	B-Disease
.	O

BACKGROUND	O
:	O
Cocaine	B-Chemical
is	O
a	O
widely	O
abused	O
psychostimulant	O
that	O
has	O
both	O
rewarding	O
and	O
aversive	O
properties	O
.	O

While	O
the	O
mechanisms	O
underlying	O
cocaine	B-Chemical
'	O
s	O
rewarding	O
effects	O
have	O
been	O
studied	O
extensively	O
,	O
less	O
attention	O
has	O
been	O
paid	O
to	O
the	O
unpleasant	O
behavioral	O
states	O
induced	O
by	O
cocaine	B-Chemical
,	O
such	O
as	O
anxiety	B-Disease
.	O

METHODS	O
:	O
In	O
this	O
study	O
,	O
we	O
evaluated	O
the	O
performance	O
of	O
dopamine	B-Chemical
beta	O
-	O
hydroxylase	O
knockout	O
(	O
Dbh	O
-	O
/	O
-	O
)	O
mice	O
,	O
which	O
lack	O
norepinephrine	B-Chemical
(	O
NE	B-Chemical
)	O
,	O
in	O
the	O
elevated	O
plus	O
maze	O
(	O
EPM	O
)	O
to	O
examine	O
the	O
contribution	O
of	O
noradrenergic	O
signaling	O
to	O
cocaine	B-Chemical
-	O
induced	O
anxiety	B-Disease
.	O

RESULTS	O
:	O
We	O
found	O
that	O
cocaine	B-Chemical
dose	O
-	O
dependently	O
increased	O
anxiety	B-Disease
-	O
like	O
behavior	O
in	O
control	O
(	O
Dbh	O
+	O
/	O
-	O
)	O
mice	O
,	O
as	O
measured	O
by	O
a	O
decrease	O
in	O
open	O
arm	O
exploration	O
.	O

The	O
Dbh	O
-	O
/	O
-	O
mice	O
had	O
normal	O
baseline	O
performance	O
in	O
the	O
EPM	O
but	O
were	O
completely	O
resistant	O
to	O
the	O
anxiogenic	O
effects	O
of	O
cocaine	B-Chemical
.	O

Cocaine	B-Chemical
-	O
induced	O
anxiety	B-Disease
was	O
also	O
attenuated	O
in	O
Dbh	O
+	O
/	O
-	O
mice	O
following	O
administration	O
of	O
disulfiram	B-Chemical
,	O
a	O
dopamine	B-Chemical
beta	O
-	O
hydroxylase	O
(	O
DBH	O
)	O
inhibitor	O
.	O

In	O
experiments	O
using	O
specific	O
adrenergic	O
antagonists	O
,	O
we	O
found	O
that	O
pretreatment	O
with	O
the	O
beta	O
-	O
adrenergic	O
receptor	O
antagonist	O
propranolol	B-Chemical
blocked	O
cocaine	B-Chemical
-	O
induced	O
anxiety	B-Disease
-	O
like	O
behavior	O
in	O
Dbh	O
+	O
/	O
-	O
and	O
wild	O
-	O
type	O
C57BL6	O
/	O
J	O
mice	O
,	O
while	O
the	O
alpha	O
(	O
1	O
)	O
antagonist	O
prazosin	B-Chemical
and	O
the	O
alpha	O
(	O
2	O
)	O
antagonist	O
yohimbine	B-Chemical
had	O
no	O
effect	O
.	O

CONCLUSIONS	O
:	O
These	O
results	O
indicate	O
that	O
noradrenergic	O
signaling	O
via	O
beta	O
-	O
adrenergic	O
receptors	O
is	O
required	O
for	O
cocaine	B-Chemical
-	O
induced	O
anxiety	B-Disease
in	O
mice	O
.	O

Hypothalamic	O
prolactin	O
receptor	O
messenger	O
ribonucleic	B-Chemical
acid	I-Chemical
levels	O
,	O
prolactin	O
signaling	O
,	O
and	O
hyperprolactinemic	B-Disease
inhibition	O
of	O
pulsatile	O
luteinizing	O
hormone	O
secretion	O
are	O
dependent	O
on	O
estradiol	B-Chemical
.	O

Hyperprolactinemia	B-Disease
can	O
reduce	O
fertility	O
and	O
libido	O
.	O

Although	O
central	O
prolactin	O
actions	O
are	O
thought	O
to	O
contribute	O
to	O
this	O
,	O
the	O
mechanisms	O
are	O
poorly	O
understood	O
.	O

We	O
first	O
tested	O
whether	O
chronic	O
hyperprolactinemia	B-Disease
inhibited	O
two	O
neuroendocrine	O
parameters	O
necessary	O
for	O
female	O
fertility	O
:	O
pulsatile	O
LH	O
secretion	O
and	O
the	O
estrogen	B-Chemical
-	O
induced	O
LH	O
surge	O
.	O

Chronic	O
hyperprolactinemia	B-Disease
induced	O
by	O
the	O
dopamine	B-Chemical
antagonist	O
sulpiride	B-Chemical
caused	O
a	O
40	O
%	O
reduction	O
LH	O
pulse	O
frequency	O
in	O
ovariectomized	O
rats	O
,	O
but	O
only	O
in	O
the	O
presence	O
of	O
chronic	O
low	O
levels	O
of	O
estradiol	B-Chemical
.	O

Sulpiride	B-Chemical
did	O
not	O
affect	O
the	O
magnitude	O
of	O
a	O
steroid	B-Chemical
-	O
induced	O
LH	O
surge	O
or	O
the	O
percentage	O
of	O
GnRH	O
neurons	O
activated	O
during	O
the	O
surge	O
.	O

Estradiol	B-Chemical
is	O
known	O
to	O
influence	O
expression	O
of	O
the	O
long	O
form	O
of	O
prolactin	O
receptors	O
(	O
PRL	O
-	O
R	O
)	O
and	O
components	O
of	O
prolactin	O
'	O
s	O
signaling	O
pathway	O
.	O

To	O
test	O
the	O
hypothesis	O
that	O
estrogen	B-Chemical
increases	O
PRL	O
-	O
R	O
expression	O
and	O
sensitivity	O
to	O
prolactin	O
,	O
we	O
next	O
demonstrated	O
that	O
estradiol	B-Chemical
greatly	O
augments	O
prolactin	O
-	O
induced	O
STAT5	O
activation	O
.	O

Lastly	O
,	O
we	O
measured	O
PRL	O
-	O
R	O
and	O
suppressor	O
of	O
cytokine	O
signaling	O
(	O
SOCS	O
-	O
1	O
and	O
-	O
3	O
and	O
CIS	O
,	O
which	O
reflect	O
the	O
level	O
of	O
prolactin	O
signaling	O
)	O
mRNAs	O
in	O
response	O
to	O
sulpiride	B-Chemical
and	O
estradiol	B-Chemical
.	O

Sulpiride	B-Chemical
induced	O
only	O
SOCS	O
-	O
1	O
in	O
the	O
medial	O
preoptic	O
area	O
,	O
where	O
GnRH	O
neurons	O
are	O
regulated	O
,	O
but	O
in	O
the	O
arcuate	O
nucleus	O
and	O
choroid	O
plexus	O
,	O
PRL	O
-	O
R	O
,	O
SOCS	O
-	O
3	O
,	O
and	O
CIS	O
mRNA	O
levels	O
were	O
also	O
induced	O
.	O

Estradiol	B-Chemical
enhanced	O
these	O
effects	O
on	O
SOCS	O
-	O
3	O
and	O
CIS	O
.	O

Interestingly	O
,	O
estradiol	B-Chemical
also	O
induced	O
PRL	O
-	O
R	O
,	O
SOCS	O
-	O
3	O
,	O
and	O
CIS	O
mRNA	O
levels	O
independently	O
.	O

These	O
data	O
show	O
that	O
GnRH	O
pulse	O
frequency	O
is	O
inhibited	O
by	O
chronic	O
hyperprolactinemia	B-Disease
in	O
a	O
steroid	B-Chemical
-	O
dependent	O
manner	O
.	O

They	O
also	O
provide	O
evidence	O
for	O
estradiol	B-Chemical
-	O
dependent	O
and	O
brain	O
region	O
-	O
specific	O
regulation	O
of	O
PRL	O
-	O
R	O
expression	O
and	O
signaling	O
responses	O
by	O
prolactin	O
.	O

Clonidine	B-Chemical
for	O
attention	B-Disease
-	I-Disease
deficit	I-Disease
/	I-Disease
hyperactivity	I-Disease
disorder	I-Disease
:	O
II	O
.	O

ECG	O
changes	O
and	O
adverse	O
events	O
analysis	O
.	O

OBJECTIVE	O
:	O
To	O
examine	O
the	O
safety	O
and	O
tolerability	O
of	O
clonidine	B-Chemical
used	O
alone	O
or	O
with	O
methylphenidate	B-Chemical
in	O
children	O
with	O
attention	B-Disease
-	I-Disease
deficit	I-Disease
/	I-Disease
hyperactivity	I-Disease
disorder	I-Disease
(	O
ADHD	B-Disease
)	O
.	O

METHOD	O
:	O
In	O
a	O
16	O
-	O
week	O
multicenter	O
,	O
double	O
-	O
blind	O
trial	O
,	O
122	O
children	O
with	O
ADHD	B-Disease
were	O
randomly	O
assigned	O
to	O
clonidine	B-Chemical
(	O
n	O
=	O
31	O
)	O
,	O
methylphenidate	B-Chemical
(	O
n	O
=	O
29	O
)	O
,	O
clonidine	B-Chemical
and	O
methylphenidate	B-Chemical
(	O
n	O
=	O
32	O
)	O
,	O
or	O
placebo	O
(	O
n	O
=	O
30	O
)	O
.	O

Doses	O
were	O
flexibly	O
titrated	O
up	O
to	O
0	O
.	O
6	O
mg	O
/	O
day	O
for	O
clonidine	B-Chemical
and	O
60	O
mg	O
/	O
day	O
for	O
methylphenidate	B-Chemical
(	O
both	O
with	O
divided	O
dosing	O
)	O
.	O

Groups	O
were	O
compared	O
regarding	O
adverse	O
events	O
and	O
changes	O
from	O
baseline	O
to	O
week	O
16	O
in	O
electrocardiograms	O
and	O
vital	O
signs	O
.	O

RESULTS	O
:	O
There	O
were	O
more	O
incidents	O
of	O
bradycardia	B-Disease
in	O
subjects	O
treated	O
with	O
clonidine	B-Chemical
compared	O
with	O
those	O
not	O
treated	O
with	O
clonidine	B-Chemical
(	O
17	O
.	O
5	O
%	O
versus	O
3	O
.	O
4	O
%	O
;	O
p	O
=	O
.	O
02	O
)	O
,	O
but	O
no	O
other	O
significant	O
group	O
differences	O
regarding	O
electrocardiogram	O
and	O
other	O
cardiovascular	O
outcomes	O
.	O

There	O
were	O
no	O
suggestions	O
of	O
interactions	O
between	O
clonidine	B-Chemical
and	O
methylphenidate	B-Chemical
regarding	O
cardiovascular	O
outcomes	O
.	O

Moderate	O
or	O
severe	O
adverse	O
events	O
were	O
more	O
common	O
in	O
subjects	O
on	O
clonidine	B-Chemical
(	O
79	O
.	O
4	O
%	O
versus	O
49	O
.	O
2	O
%	O
;	O
p	O
=	O
.	O
0006	O
)	O
but	O
not	O
associated	O
with	O
higher	O
rates	O
of	O
early	O
study	O
withdrawal	O
.	O

Drowsiness	B-Disease
was	O
common	O
on	O
clonidine	B-Chemical
,	O
but	O
generally	O
resolved	O
by	O
6	O
to	O
8	O
weeks	O
.	O

CONCLUSIONS	O
:	O
Clonidine	B-Chemical
,	O
used	O
alone	O
or	O
with	O
methylphenidate	B-Chemical
,	O
appears	O
safe	O
and	O
well	O
tolerated	O
in	O
childhood	O
ADHD	B-Disease
.	O

Physicians	O
prescribing	O
clonidine	B-Chemical
should	O
monitor	O
for	O
bradycardia	B-Disease
and	O
advise	O
patients	O
about	O
the	O
high	O
likelihood	O
of	O
initial	O
drowsiness	B-Disease
.	O

Renal	B-Disease
Fanconi	I-Disease
syndrome	I-Disease
and	O
myopathy	B-Disease
after	O
liver	O
transplantation	O
:	O
drug	O
-	O
related	O
mitochondrial	B-Disease
cytopathy	I-Disease
?	O

Advances	O
in	O
the	O
field	O
of	O
transplantation	O
provide	O
a	O
better	O
quality	O
of	O
life	O
and	O
allow	O
more	O
favorable	O
conditions	O
for	O
growth	O
and	O
development	O
in	O
children	O
.	O

However	O
,	O
combinations	O
of	O
different	O
therapeutic	O
regimens	O
require	O
consideration	O
of	O
potential	O
adverse	O
reactions	O
.	O

We	O
describe	O
a	O
15	O
-	O
yr	O
-	O
old	O
girl	O
who	O
had	O
orthotopic	O
liver	O
transplantation	O
because	O
of	O
Wilson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
.	O

Tacrolimus	B-Chemical
,	O
MMF	B-Chemical
,	O
and	O
steroids	B-Chemical
were	O
given	O
as	O
immunosuppressant	O
.	O

Lamivudine	B-Chemical
was	O
added	O
because	O
of	O
de	O
nova	O
hepatitis	B-Disease
B	I-Disease
infection	I-Disease
during	O
her	O
follow	O
-	O
up	O
.	O

Three	O
yr	O
after	O
transplantation	O
she	O
developed	O
renal	B-Disease
Fanconi	I-Disease
syndrome	I-Disease
with	O
severe	O
metabolic	B-Disease
acidosis	I-Disease
,	O
hypophosphatemia	B-Disease
,	O
glycosuria	B-Disease
,	O
and	O
aminoaciduria	B-Disease
.	O

Although	O
tacrolimus	B-Chemical
was	O
suspected	O
to	O
be	O
the	O
cause	O
of	O
late	O
post	O
-	O
transplant	O
renal	O
acidosis	B-Disease
and	O
was	O
replaced	O
by	O
sirolimus	B-Chemical
,	O
acidosis	B-Disease
,	O
and	O
electrolyte	O
imbalance	O
got	O
worse	O
.	O

Proximal	O
muscle	B-Disease
weakness	I-Disease
has	O
developed	O
during	O
her	O
follow	O
-	O
up	O
.	O

Fanconi	B-Disease
syndrome	I-Disease
,	O
as	O
well	O
as	O
myopathy	B-Disease
,	O
is	O
well	O
recognized	O
in	O
patients	O
with	O
mitochondrial	B-Disease
disorders	I-Disease
and	O
caused	O
by	O
depletion	O
of	O
mtDNA	O
.	O

We	O
suggest	O
that	O
our	O
patient	O
'	O
s	O
tubular	B-Disease
dysfunction	I-Disease
and	O
myopathy	B-Disease
may	O
have	O
resulted	O
from	O
mitochondrial	B-Disease
dysfunction	I-Disease
which	O
is	O
triggered	O
by	O
tacrolimus	B-Chemical
and	O
augmented	O
by	O
lamivudine	B-Chemical
.	O

Higher	O
optical	O
density	O
of	O
an	O
antigen	O
assay	O
predicts	O
thrombosis	B-Disease
in	O
patients	O
with	O
heparin	B-Chemical
-	O
induced	O
thrombocytopenia	B-Disease
.	O

OBJECTIVES	O
:	O
To	O
correlate	O
optical	O
density	O
and	O
percent	O
inhibition	O
of	O
a	O
two	O
-	O
step	O
heparin	B-Chemical
-	O
induced	O
thrombocytopenia	B-Disease
(	O
HIT	B-Disease
)	O
antigen	O
assay	O
with	O
thrombosis	B-Disease
;	O
the	O
assay	O
utilizes	O
reaction	O
inhibition	O
characteristics	O
of	O
a	O
high	O
heparin	B-Chemical
concentration	O
.	O

PATIENTS	O
AND	O
METHODS	O
:	O
Patients	O
with	O
more	O
than	O
50	O
%	O
decrease	O
in	O
platelet	O
count	O
or	O
thrombocytopenia	B-Disease
(	O
<	O
150	O
x	O
10	O
(	O
9	O
)	O
/	O
L	O
)	O
after	O
exposure	O
to	O
heparin	B-Chemical
,	O
who	O
had	O
a	O
positive	O
two	O
-	O
step	O
antigen	O
assay	O
[	O
optical	O
density	O
(	O
OD	O
)	O
>	O
0	O
.	O
4	O
and	O
>	O
50	O
inhibition	O
with	O
high	O
concentration	O
of	O
heparin	B-Chemical
]	O
were	O
included	O
in	O
the	O
study	O
.	O

RESULTS	O
:	O
Forty	O
of	O
94	O
HIT	B-Disease
patients	O
had	O
thrombosis	B-Disease
at	O
diagnosis	O
;	O
54	O
/	O
94	O
had	O
isolated	O
-	O
HIT	B-Disease
without	O
thrombosis	B-Disease
.	O

Eight	O
of	O
the	O
isolated	O
-	O
HIT	B-Disease
patients	O
developed	O
thrombosis	B-Disease
within	O
the	O
next	O
30	O
d	O
;	O
thus	O
,	O
a	O
total	O
of	O
48	O
patients	O
had	O
thrombosis	B-Disease
at	O
day	O
30	O
.	O

At	O
diagnosis	O
there	O
was	O
no	O
significant	O
difference	O
in	O
OD	O
between	O
HIT	B-Disease
patients	O
with	O
thrombosis	B-Disease
and	O
those	O
with	O
isolated	O
-	O
HIT	B-Disease
.	O

However	O
,	O
OD	O
was	O
significantly	O
higher	O
in	O
all	O
patients	O
with	O
thrombosis	B-Disease
(	O
n	O
=	O
48	O
,	O
1	O
.	O
34	O
+	O
/	O
-	O
0	O
.	O
89	O
)	O
,	O
including	O
isolated	O
-	O
HIT	B-Disease
patients	O
who	O
later	O
developed	O
thrombosis	B-Disease
within	O
30	O
d	O
(	O
n	O
=	O
8	O
,	O
1	O
.	O
84	O
+	O
/	O
-	O
0	O
.	O
64	O
)	O
as	O
compared	O
to	O
isolated	O
-	O
HIT	B-Disease
patients	O
who	O
did	O
not	O
develop	O
thrombosis	B-Disease
(	O
0	O
.	O
96	O
+	O
/	O
-	O
0	O
.	O
75	O
;	O
P	O
=	O
0	O
.	O
011	O
and	O
P	O
=	O
0	O
.	O
008	O
)	O
.	O

The	O
Receiver	O
Operative	O
Characteristic	O
Curve	O
showed	O
that	O
OD	O
>	O
1	O
.	O
27	O
in	O
the	O
isolated	O
-	O
HIT	B-Disease
group	O
had	O
a	O
significantly	O
higher	O
chance	O
of	O
developing	O
thrombosis	B-Disease
by	O
day	O
30	O
.	O

None	O
of	O
these	O
groups	O
showed	O
significant	O
difference	O
in	O
percent	O
inhibition	O
.	O

Multivariate	O
analysis	O
showed	O
a	O
2	O
.	O
8	O
-	O
fold	O
increased	O
risk	O
of	O
thrombosis	B-Disease
in	O
females	O
.	O

Similarly	O
,	O
thrombotic	B-Disease
risk	O
increased	O
with	O
age	O
and	O
OD	O
values	O
.	O

CONCLUSION	O
:	O
Higher	O
OD	O
is	O
associated	O
with	O
significant	O
risk	O
of	O
subsequent	O
thrombosis	B-Disease
in	O
patients	O
with	O
isolated	O
-	O
HIT	B-Disease
;	O
percent	O
inhibition	O
,	O
however	O
,	O
was	O
not	O
predictive	O
.	O

Thalidomide	B-Chemical
has	O
limited	O
single	O
-	O
agent	O
activity	O
in	O
relapsed	O
or	O
refractory	O
indolent	O
non	B-Disease
-	I-Disease
Hodgkin	I-Disease
lymphomas	I-Disease
:	O
a	O
phase	O
II	O
trial	O
of	O
the	O
Cancer	B-Disease
and	O
Leukemia	B-Disease
Group	O
B	O
.	O

Thalidomide	B-Chemical
is	O
an	O
immunomodulatory	O
agent	O
with	O
demonstrated	O
activity	O
in	O
multiple	B-Disease
myeloma	I-Disease
,	O
mantle	B-Disease
cell	I-Disease
lymphoma	I-Disease
and	O
lymphoplasmacytic	B-Disease
lymphoma	I-Disease
.	O

Its	O
activity	O
is	O
believed	O
to	O
be	O
due	O
modulation	O
of	O
the	O
tumour	B-Disease
milieu	O
,	O
including	O
downregulation	O
of	O
angiogenesis	O
and	O
inflammatory	O
cytokines	O
.	O

Between	O
July	O
2001	O
and	O
April	O
2004	O
,	O
24	O
patients	O
with	O
relapsed	O
/	O
refractory	O
indolent	O
lymphomas	B-Disease
received	O
thalidomide	B-Chemical
200	O
mg	O
daily	O
with	O
escalation	O
by	O
100	O
mg	O
daily	O
every	O
1	O
-	O
2	O
weeks	O
as	O
tolerated	O
,	O
up	O
to	O
a	O
maximum	O
of	O
800	O
mg	O
daily	O
.	O

Patients	O
had	O
received	O
a	O
median	O
of	O
2	O
(	O
range	O
,	O
1	O
-	O
4	O
)	O
prior	O
regimens	O
.	O

Of	O
24	O
evaluable	O
patients	O
,	O
two	O
achieved	O
a	O
complete	O
remission	O
and	O
one	O
achieved	O
a	O
partial	O
remission	O
for	O
an	O
overall	O
response	O
rate	O
of	O
12	O
.	O
5	O
%	O
(	O
95	O
%	O
confidence	O
interval	O
:	O
2	O
.	O
6	O
-	O
32	O
.	O
4	O
%	O
)	O
.	O

Eleven	O
patients	O
progressed	O
during	O
therapy	O
.	O

Grade	O
3	O
-	O
4	O
adverse	O
effects	O
included	O
myelosuppression	B-Disease
,	O
fatigue	B-Disease
,	O
somnolence	B-Disease
/	O
depressed	B-Disease
mood	I-Disease
,	O
neuropathy	B-Disease
and	O
dyspnea	B-Disease
.	O

Of	O
concern	O
was	O
the	O
occurrence	O
of	O
four	O
thromboembolic	B-Disease
events	O
.	O

Our	O
results	O
failed	O
to	O
demonstrate	O
an	O
important	O
response	O
rate	O
to	O
single	O
agent	O
thalidomide	B-Chemical
in	O
indolent	O
lymphomas	B-Disease
and	O
contrast	O
with	O
the	O
higher	O
activity	O
level	O
reported	O
with	O
the	O
second	O
generation	O
immunomodulatory	O
agent	O
,	O
lenalidomide	B-Chemical
.	O

Sex	O
differences	O
in	O
NMDA	B-Chemical
antagonist	O
enhancement	O
of	O
morphine	B-Chemical
antihyperalgesia	O
in	O
a	O
capsaicin	B-Chemical
model	O
of	O
persistent	O
pain	B-Disease
:	O
comparisons	O
to	O
two	O
models	O
of	O
acute	B-Disease
pain	I-Disease
.	O

In	O
acute	B-Disease
pain	I-Disease
models	O
,	O
N	B-Chemical
-	I-Chemical
methyl	I-Chemical
-	I-Chemical
D	I-Chemical
-	I-Chemical
aspartate	I-Chemical
(	O
NMDA	B-Chemical
)	O
antagonists	O
enhance	O
the	O
antinociceptive	O
effects	O
of	O
morphine	B-Chemical
to	O
a	O
greater	O
extent	O
in	O
males	O
than	O
females	O
.	O

The	O
purpose	O
of	O
this	O
investigation	O
was	O
to	O
extend	O
these	O
findings	O
to	O
a	O
persistent	O
pain	B-Disease
model	O
which	O
could	O
be	O
distinguished	O
from	O
acute	B-Disease
pain	I-Disease
models	O
on	O
the	O
basis	O
of	O
the	O
nociceptive	O
fibers	O
activated	O
,	O
neurochemical	O
substrates	O
,	O
and	O
duration	O
of	O
the	O
nociceptive	O
stimulus	O
.	O

To	O
this	O
end	O
,	O
persistent	O
hyperalgesia	B-Disease
was	O
induced	O
by	O
administration	O
of	O
capsaicin	B-Chemical
in	O
the	O
tail	O
of	O
gonadally	O
intact	O
F344	O
rats	O
,	O
following	O
which	O
the	O
tail	O
was	O
immersed	O
in	O
a	O
mildly	O
noxious	O
thermal	O
stimulus	O
,	O
and	O
tail	O
-	O
withdrawal	O
latencies	O
measured	O
.	O

For	O
comparison	O
,	O
tests	O
were	O
conducted	O
in	O
two	O
acute	B-Disease
pain	I-Disease
models	O
,	O
the	O
hotplate	O
and	O
warm	O
water	O
tail	O
-	O
withdrawal	O
procedures	O
.	O

In	O
males	O
,	O
the	O
non	O
-	O
competitive	O
NMDA	B-Chemical
antagonist	O
dextromethorphan	B-Chemical
enhanced	O
the	O
antihyperalgesic	O
effect	O
of	O
low	O
to	O
moderate	O
doses	O
of	O
morphine	B-Chemical
in	O
a	O
dose	O
-	O
and	O
time	O
-	O
dependent	O
manner	O
.	O

Across	O
the	O
doses	O
and	O
pretreatment	O
times	O
examined	O
,	O
enhancement	O
was	O
not	O
observed	O
in	O
females	O
.	O

Enhancement	O
of	O
morphine	B-Chemical
antinociception	O
by	O
dextromethorphan	B-Chemical
was	O
seen	O
in	O
both	O
males	O
and	O
females	O
in	O
the	O
acute	B-Disease
pain	I-Disease
models	O
,	O
with	O
the	O
magnitude	O
of	O
this	O
effect	O
being	O
greater	O
in	O
males	O
.	O

These	O
findings	O
demonstrate	O
a	O
sexually	O
-	O
dimorphic	O
interaction	O
between	O
NMDA	B-Chemical
antagonists	O
and	O
morphine	B-Chemical
in	O
a	O
persistent	O
pain	B-Disease
model	O
that	O
can	O
be	O
distinguished	O
from	O
those	O
observed	O
in	O
acute	B-Disease
pain	I-Disease
models	O
.	O

Development	O
of	O
proteinuria	B-Disease
after	O
switch	O
to	O
sirolimus	B-Chemical
-	O
based	O
immunosuppression	O
in	O
long	O
-	O
term	O
cardiac	O
transplant	O
patients	O
.	O

Calcineurin	O
-	O
inhibitor	O
therapy	O
can	O
lead	O
to	O
renal	B-Disease
dysfunction	I-Disease
in	O
heart	O
transplantation	O
patients	O
.	O

The	O
novel	O
immunosuppressive	O
(	O
IS	O
)	O
drug	O
sirolmus	B-Chemical
(	O
Srl	B-Chemical
)	O
lacks	O
nephrotoxic	B-Disease
effects	O
;	O
however	O
,	O
proteinuria	B-Disease
associated	O
with	O
Srl	B-Chemical
has	O
been	O
reported	O
following	O
renal	O
transplantation	O
.	O

In	O
cardiac	O
transplantation	O
,	O
the	O
incidence	O
of	O
proteinuria	B-Disease
associated	O
with	O
Srl	B-Chemical
is	O
unknown	O
.	O

In	O
this	O
study	O
,	O
long	O
-	O
term	O
cardiac	O
transplant	O
patients	O
were	O
switched	O
from	O
cyclosporine	B-Chemical
to	O
Srl	B-Chemical
-	O
based	O
IS	O
.	O

Concomitant	O
IS	O
consisted	O
of	O
mycophenolate	B-Chemical
mofetil	I-Chemical
+	O
/	O
-	O
steroids	B-Chemical
.	O

Proteinuria	O
increased	O
significantly	O
from	O
a	O
median	O
of	O
0	O
.	O
13	O
g	O
/	O
day	O
(	O
range	O
0	O
-	O
5	O
.	O
7	O
)	O
preswitch	O
to	O
0	O
.	O
23	O
g	O
/	O
day	O
(	O
0	O
-	O
9	O
.	O
88	O
)	O
at	O
24	O
months	O
postswitch	O
(	O
p	O
=	O
0	O
.	O
0024	O
)	O
.	O

Before	O
the	O
switch	O
,	O
11	O
.	O
5	O
%	O
of	O
patients	O
had	O
high	O
-	O
grade	O
proteinuria	B-Disease
(	O
>	O
1	O
.	O
0	O
g	O
/	O
day	O
)	O
;	O
this	O
increased	O
to	O
22	O
.	O
9	O
%	O
postswitch	O
(	O
p	O
=	O
0	O
.	O
006	O
)	O
.	O

ACE	B-Chemical
inhibitor	I-Chemical
and	O
angiotensin	B-Chemical
-	I-Chemical
releasing	I-Chemical
blocker	I-Chemical
(	O
ARB	B-Chemical
)	O
therapy	O
reduced	O
proteinuria	B-Disease
development	O
.	O

Patients	O
without	O
proteinuria	B-Disease
had	O
increased	O
renal	O
function	O
(	O
median	O
42	O
.	O
5	O
vs	O
.	O
64	O
.	O
1	O
,	O
p	O
=	O
0	O
.	O
25	O
)	O
,	O
whereas	O
patients	O
who	O
developed	O
high	O
-	O
grade	O
proteinuria	B-Disease
showed	O
decreased	O
renal	O
function	O
at	O
the	O
end	O
of	O
follow	O
-	O
up	O
(	O
median	O
39	O
.	O
6	O
vs	O
.	O
29	O
.	O
2	O
,	O
p	O
=	O
0	O
.	O
125	O
)	O
.	O

Thus	O
,	O
proteinuria	B-Disease
may	O
develop	O
in	O
cardiac	O
transplant	O
patients	O
after	O
switch	O
to	O
Srl	B-Chemical
,	O
which	O
may	O
have	O
an	O
adverse	O
effect	O
on	O
renal	O
function	O
in	O
these	O
patients	O
.	O

Srl	B-Chemical
should	O
be	O
used	O
with	O
ACEi	B-Chemical
/	O
ARB	B-Chemical
therapy	O
and	O
patients	O
monitored	O
for	O
proteinuria	B-Disease
and	O
increased	O
renal	B-Disease
dysfunction	I-Disease
.	O

Ginsenoside	B-Chemical
Rg1	I-Chemical
restores	O
the	O
impairment	B-Disease
of	I-Disease
learning	I-Disease
induced	O
by	O
chronic	O
morphine	B-Chemical
administration	O
in	O
rats	O
.	O

Rg1	B-Chemical
,	O
as	O
a	O
ginsenoside	B-Chemical
extracted	O
from	O
Panax	O
ginseng	O
,	O
could	O
ameliorate	O
spatial	O
learning	B-Disease
impairment	I-Disease
.	O

Previous	O
studies	O
have	O
demonstrated	O
that	O
Rg1	B-Chemical
might	O
be	O
a	O
useful	O
agent	O
for	O
the	O
prevention	O
and	O
treatment	O
of	O
the	O
adverse	O
effects	O
of	O
morphine	B-Chemical
.	O

The	O
aim	O
of	O
this	O
study	O
was	O
to	O
investigate	O
the	O
effect	O
of	O
Rg1	B-Chemical
on	O
learning	B-Disease
impairment	I-Disease
by	O
chronic	O
morphine	B-Chemical
administration	O
and	O
the	O
mechanism	O
responsible	O
for	O
this	O
effect	O
.	O

Male	O
rats	O
were	O
subcutaneously	O
injected	O
with	O
morphine	B-Chemical
(	O
10	O
mg	O
/	O
kg	O
)	O
twice	O
a	O
day	O
at	O
12	O
hour	O
intervals	O
for	O
10	O
days	O
,	O
and	O
Rg1	B-Chemical
(	O
30	O
mg	O
/	O
kg	O
)	O
was	O
intraperitoneally	O
injected	O
2	O
hours	O
after	O
the	O
second	O
injection	O
of	O
morphine	B-Chemical
once	O
a	O
day	O
for	O
10	O
days	O
.	O

Spatial	O
learning	O
capacity	O
was	O
assessed	O
in	O
the	O
Morris	O
water	O
maze	O
.	O

The	O
results	O
showed	O
that	O
rats	O
treated	O
with	O
Morphine	B-Chemical
/	O
Rg1	B-Chemical
decreased	O
escape	O
latency	O
and	O
increased	O
the	O
time	O
spent	O
in	O
platform	O
quadrant	O
and	O
entering	O
frequency	O
.	O

By	O
implantation	O
of	O
electrodes	O
and	O
electrophysiological	O
recording	O
in	O
vivo	O
,	O
the	O
results	O
showed	O
that	O
Rg1	B-Chemical
restored	O
the	O
long	O
-	O
term	O
potentiation	O
(	O
LTP	O
)	O
impaired	O
by	O
morphine	B-Chemical
in	O
both	O
freely	O
moving	O
and	O
anaesthetised	O
rats	O
.	O

The	O
electrophysiological	O
recording	O
in	O
vitro	O
showed	O
that	O
Rg1	B-Chemical
restored	O
the	O
LTP	O
in	O
slices	O
from	O
the	O
rats	O
treated	O
with	O
morphine	B-Chemical
,	O
but	O
not	O
changed	O
LTP	O
in	O
the	O
slices	O
from	O
normal	O
saline	O
-	O
or	O
morphine	B-Chemical
/	O
Rg1	B-Chemical
-	O
treated	O
rats	O
;	O
this	O
restoration	O
could	O
be	O
inhibited	O
by	O
N	B-Chemical
-	I-Chemical
methyl	I-Chemical
-	I-Chemical
D	I-Chemical
-	I-Chemical
aspartate	I-Chemical
(	O
NMDA	B-Chemical
)	O
receptor	O
antagonist	O
MK801	B-Chemical
.	O

We	O
conclude	O
that	O
Rg1	B-Chemical
may	O
significantly	O
improve	O
the	O
spatial	O
learning	O
capacity	O
impaired	O
by	O
chonic	O
morphine	B-Chemical
administration	O
and	O
restore	O
the	O
morphine	B-Chemical
-	O
inhibited	O
LTP	O
.	O

This	O
effect	O
is	O
NMDA	B-Chemical
receptor	O
dependent	O
.	O

Synthesis	O
of	O
N	B-Chemical
-	I-Chemical
pyrimidinyl	I-Chemical
-	I-Chemical
2	I-Chemical
-	I-Chemical
phenoxyacetamides	I-Chemical
as	O
adenosine	B-Chemical
A2A	O
receptor	O
antagonists	O
.	O

A	O
series	O
of	O
N	B-Chemical
-	I-Chemical
pyrimidinyl	I-Chemical
-	I-Chemical
2	I-Chemical
-	I-Chemical
phenoxyacetamide	I-Chemical
adenosine	B-Chemical
A	O
(	O
2A	O
)	O
antagonists	O
is	O
described	O
.	O

SAR	O
studies	O
led	O
to	O
compound	O
14	O
with	O
excellent	O
potency	O
(	O
K	O
(	O
i	O
)	O
=	O
0	O
.	O
4	O
nM	O
)	O
,	O
selectivity	O
(	O
A	O
(	O
1	O
)	O
/	O
A	O
(	O
2A	O
)	O
>	O
100	O
)	O
,	O
and	O
efficacy	O
(	O
MED	O
10	O
mg	O
/	O
kg	O
p	O
.	O
o	O
.	O
)	O
in	O
the	O
rat	O
haloperidol	B-Chemical
-	O
induced	O
catalepsy	B-Disease
model	O
for	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
.	O

Evidence	O
for	O
an	O
involvement	O
of	O
D1	O
and	O
D2	O
dopamine	B-Chemical
receptors	O
in	O
mediating	O
nicotine	B-Chemical
-	O
induced	O
hyperactivity	B-Disease
in	O
rats	O
.	O

Previous	O
studies	O
have	O
suggested	O
that	O
repeated	O
exposure	O
of	O
rats	O
to	O
the	O
drug	O
or	O
to	O
the	O
experimental	O
environment	O
is	O
necessary	O
to	O
observe	O
nicotine	B-Chemical
-	O
induced	O
locomotor	O
stimulation	O
.	O

In	O
the	O
present	O
study	O
the	O
role	O
of	O
habituation	O
to	O
the	O
experimental	O
environment	O
on	O
the	O
stimulant	O
effect	O
of	O
nicotine	B-Chemical
in	O
rats	O
was	O
examined	O
.	O

In	O
addition	O
,	O
the	O
role	O
of	O
dopamine	B-Chemical
receptors	O
in	O
mediating	O
nicotine	B-Chemical
-	O
induced	O
locomotor	O
stimulation	O
was	O
investigated	O
by	O
examining	O
the	O
effects	O
of	O
selective	O
D1	O
and	O
D2	O
dopamine	B-Chemical
receptor	O
antagonists	O
on	O
activity	O
induced	O
by	O
nicotine	B-Chemical
.	O

Locomotor	O
activity	O
was	O
assessed	O
in	O
male	O
Sprague	O
-	O
Dawley	O
rats	O
tested	O
in	O
photocell	O
cages	O
.	O

Nicotine	B-Chemical
(	O
1	O
.	O
0	O
mg	O
/	O
kg	O
)	O
caused	O
a	O
significant	O
increase	B-Disease
in	I-Disease
locomotor	I-Disease
activity	I-Disease
in	O
rats	O
that	O
were	O
habituated	O
to	O
the	O
test	O
environment	O
,	O
but	O
had	O
only	O
a	O
weak	O
and	O
delayed	O
stimulant	O
action	O
in	O
rats	O
that	O
were	O
unfamiliar	O
with	O
the	O
test	O
environment	O
.	O

The	O
stimulant	O
action	O
of	O
nicotine	B-Chemical
was	O
blocked	O
by	O
the	O
central	O
nicotinic	O
antagonist	O
mecamylamine	B-Chemical
but	O
not	O
by	O
the	O
peripheral	O
nicotinic	O
blocker	O
hexamethonium	B-Chemical
,	O
indicating	O
that	O
the	O
response	O
is	O
probably	O
mediated	O
by	O
central	O
nicotinic	O
receptors	O
.	O

Nicotine	B-Chemical
-	O
induced	O
hyperactivity	B-Disease
was	O
blocked	O
by	O
the	O
selective	O
D1	O
antagonist	O
SCH	B-Chemical
23390	I-Chemical
,	O
the	O
selective	O
D2	O
antagonist	O
raclopride	B-Chemical
and	O
the	O
D1	O
/	O
D2	O
antagonist	O
fluphenazine	B-Chemical
.	O

Pretreatment	O
with	O
the	O
D2	O
agonist	O
PHNO	B-Chemical
enhanced	O
nicotine	B-Chemical
-	O
induced	O
hyperactivity	B-Disease
,	O
whereas	O
the	O
D1	O
agonist	O
SKF	B-Chemical
38393	I-Chemical
had	O
no	O
effect	O
.	O

The	O
results	O
indicate	O
that	O
acute	O
nicotine	B-Chemical
injection	O
induces	O
a	O
pronounced	O
hyperactivity	B-Disease
in	O
rats	O
habituated	O
to	O
the	O
test	O
environment	O
.	O

The	O
effect	O
appears	O
to	O
be	O
mediated	O
by	O
central	O
nicotine	B-Chemical
receptors	O
,	O
possibly	O
located	O
on	O
dopaminergic	O
neurons	O
,	O
and	O
also	O
requires	O
the	O
activation	O
of	O
both	O
D1	O
and	O
D2	O
dopamine	B-Chemical
receptors	O
.	O

Central	O
retinal	B-Disease
vein	I-Disease
occlusion	I-Disease
associated	O
with	O
clomiphene	B-Chemical
-	O
induced	O
ovulation	O
.	O

OBJECTIVE	O
:	O
To	O
report	O
a	O
case	O
of	O
central	O
retinal	B-Disease
vein	I-Disease
occlusion	I-Disease
associated	O
with	O
clomiphene	B-Chemical
citrate	I-Chemical
(	O
CC	B-Chemical
)	O
.	O

DESIGN	O
:	O
Case	O
study	O
.	O

SETTING	O
:	O
Ophthalmology	O
clinic	O
of	O
an	O
academic	O
hospital	O
.	O

PATIENT	O
(	O
S	O
)	O
:	O
A	O
36	O
-	O
year	O
-	O
old	O
woman	O
referred	O
from	O
the	O
infertility	B-Disease
clinic	O
for	O
blurred	B-Disease
vision	I-Disease
.	O

INTERVENTION	O
(	O
S	O
)	O
:	O
Ophthalmic	O
examination	O
after	O
CC	B-Chemical
therapy	O
.	O

MAIN	O
OUTCOME	O
MEASURE	O
(	O
S	O
)	O
:	O
Central	O
retinal	B-Disease
vein	I-Disease
occlusion	I-Disease
after	O
ovulation	O
induction	O
with	O
CC	B-Chemical
.	O

RESULT	O
(	O
S	O
)	O
:	O
A	O
36	O
-	O
year	O
-	O
old	O
Chinese	O
woman	O
developed	O
central	O
retinal	B-Disease
vein	I-Disease
occlusion	I-Disease
after	O
eight	O
courses	O
of	O
CC	B-Chemical
.	O

A	O
search	O
of	O
the	O
literature	O
on	O
the	O
thromboembolic	B-Disease
complications	O
of	O
CC	B-Chemical
does	O
not	O
include	O
this	O
severe	O
ophthalmic	O
complication	O
,	O
although	O
mild	O
visual	B-Disease
disturbance	I-Disease
after	O
CC	B-Chemical
intake	O
is	O
not	O
uncommon	O
.	O

CONCLUSION	O
(	O
S	O
)	O
:	O
This	O
is	O
the	O
first	O
reported	O
case	O
of	O
central	O
retinal	B-Disease
vein	I-Disease
occlusion	I-Disease
after	O
treatment	O
with	O
CC	B-Chemical
.	O

Extra	O
caution	O
is	O
warranted	O
in	O
treating	O
infertility	B-Disease
patients	O
with	O
CC	B-Chemical
,	O
and	O
patients	O
should	O
be	O
well	O
informed	O
of	O
this	O
side	O
effect	O
before	O
commencement	O
of	O
therapy	O
.	O

Acute	O
bronchodilating	O
effects	O
of	O
ipratropium	B-Chemical
bromide	I-Chemical
and	O
theophylline	B-Chemical
in	O
chronic	B-Disease
obstructive	I-Disease
pulmonary	I-Disease
disease	I-Disease
.	O

The	O
bronchodilator	O
effects	O
of	O
a	O
single	O
dose	O
of	O
ipratropium	B-Chemical
bromide	I-Chemical
aerosol	O
(	O
36	O
micrograms	O
)	O
and	O
short	O
-	O
acting	O
theophylline	B-Chemical
tablets	O
(	O
dose	O
titrated	O
to	O
produce	O
serum	O
levels	O
of	O
10	O
-	O
20	O
micrograms	O
/	O
mL	O
)	O
were	O
compared	O
in	O
a	O
double	O
-	O
blind	O
,	O
placebo	O
-	O
controlled	O
crossover	O
study	O
in	O
21	O
patients	O
with	O
stable	O
,	O
chronic	B-Disease
obstructive	I-Disease
pulmonary	I-Disease
disease	I-Disease
.	O

Mean	O
peak	O
forced	O
expiratory	O
volume	O
in	O
1	O
second	O
(	O
FEV1	O
)	O
increases	O
over	O
baseline	O
and	O
the	O
proportion	O
of	O
patients	O
attaining	O
at	O
least	O
a	O
15	O
%	O
increase	O
in	O
the	O
FEV1	O
(	O
responders	O
)	O
were	O
31	O
%	O
and	O
90	O
%	O
,	O
respectively	O
,	O
for	O
ipratropium	B-Chemical
and	O
17	O
%	O
and	O
50	O
%	O
,	O
respectively	O
,	O
for	O
theophylline	B-Chemical
.	O

The	O
average	O
FEV1	O
increases	O
during	O
the	O
6	O
-	O
hour	O
observation	O
period	O
were	O
18	O
%	O
for	O
ipratropium	B-Chemical
and	O
8	O
%	O
for	O
theophylline	B-Chemical
.	O

The	O
mean	O
duration	O
of	O
action	O
was	O
3	O
.	O
8	O
hours	O
with	O
ipratropium	B-Chemical
and	O
2	O
.	O
4	O
hours	O
with	O
theophylline	B-Chemical
.	O

While	O
side	O
effects	O
were	O
rare	O
,	O
those	O
experienced	O
after	O
theophylline	B-Chemical
use	O
did	O
involve	O
the	O
cardiovascular	B-Disease
and	I-Disease
gastrointestinal	I-Disease
systems	I-Disease
.	O

These	O
results	O
show	O
that	O
ipratropium	B-Chemical
is	O
a	O
more	O
potent	O
bronchodilator	O
than	O
oral	O
theophylline	B-Chemical
in	O
patients	O
with	O
chronic	B-Disease
airflow	I-Disease
obstruction	I-Disease
.	O

Methamphetamine	B-Chemical
-	O
induced	O
neurotoxicity	B-Disease
and	O
microglial	O
activation	O
are	O
not	O
mediated	O
by	O
fractalkine	O
receptor	O
signaling	O
.	O

Methamphetamine	B-Chemical
(	O
METH	B-Chemical
)	O
damages	O
dopamine	B-Chemical
(	O
DA	B-Chemical
)	O
nerve	O
endings	O
by	O
a	O
process	O
that	O
has	O
been	O
linked	O
to	O
microglial	O
activation	O
but	O
the	O
signaling	O
pathways	O
that	O
mediate	O
this	O
response	O
have	O
not	O
yet	O
been	O
delineated	O
.	O

Cardona	O
et	O
al	O
.	O

[	O
Nat	O
.	O
Neurosci	O
.	O
9	O
(	O
2006	O
)	O
,	O
917	O
]	O
recently	O
identified	O
the	O
microglial	O
-	O
specific	O
fractalkine	O
receptor	O
(	O
CX3CR1	O
)	O
as	O
an	O
important	O
mediator	O
of	O
MPTP	B-Chemical
-	O
induced	O
neurodegeneration	B-Disease
of	O
DA	B-Chemical
neurons	O
.	O

Because	O
the	O
CNS	B-Disease
damage	I-Disease
caused	O
by	O
METH	B-Chemical
and	O
MPTP	B-Chemical
is	O
highly	O
selective	O
for	O
the	O
DA	B-Chemical
neuronal	O
system	O
in	O
mouse	O
models	O
of	O
neurotoxicity	B-Disease
,	O
we	O
hypothesized	O
that	O
the	O
CX3CR1	O
plays	O
a	O
role	O
in	O
METH	B-Chemical
-	O
induced	O
neurotoxicity	B-Disease
and	O
microglial	O
activation	O
.	O

Mice	O
in	O
which	O
the	O
CX3CR1	O
gene	O
has	O
been	O
deleted	O
and	O
replaced	O
with	O
a	O
cDNA	O
encoding	O
enhanced	O
green	O
fluorescent	O
protein	O
(	O
eGFP	O
)	O
were	O
treated	O
with	O
METH	B-Chemical
and	O
examined	O
for	O
striatal	O
neurotoxicity	B-Disease
.	O

METH	B-Chemical
depleted	O
DA	B-Chemical
,	O
caused	O
microglial	O
activation	O
,	O
and	O
increased	O
body	O
temperature	O
in	O
CX3CR1	O
knockout	O
mice	O
to	O
the	O
same	O
extent	O
and	O
over	O
the	O
same	O
time	O
course	O
seen	O
in	O
wild	O
-	O
type	O
controls	O
.	O

The	O
effects	O
of	O
METH	B-Chemical
in	O
CX3CR1	O
knockout	O
mice	O
were	O
not	O
gender	O
-	O
dependent	O
and	O
did	O
not	O
extend	O
beyond	O
the	O
striatum	O
.	O

Striatal	O
microglia	O
expressing	O
eGFP	O
constitutively	O
show	O
morphological	O
changes	O
after	O
METH	B-Chemical
that	O
are	O
characteristic	O
of	O
activation	O
.	O

This	O
response	O
was	O
restricted	O
to	O
the	O
striatum	O
and	O
contrasted	O
sharply	O
with	O
unresponsive	O
eGFP	O
-	O
microglia	O
in	O
surrounding	O
brain	O
areas	O
that	O
are	O
not	O
damaged	O
by	O
METH	B-Chemical
.	O

We	O
conclude	O
from	O
these	O
studies	O
that	O
CX3CR1	O
signaling	O
does	O
not	O
modulate	O
METH	B-Chemical
neurotoxicity	B-Disease
or	O
microglial	O
activation	O
.	O

Furthermore	O
,	O
it	O
appears	O
that	O
striatal	O
-	O
resident	O
microglia	O
respond	O
to	O
METH	B-Chemical
with	O
an	O
activation	O
cascade	O
and	O
then	O
return	O
to	O
a	O
surveying	O
state	O
without	O
undergoing	O
apoptosis	O
or	O
migration	O
.	O

Nicotine	B-Chemical
-	O
induced	O
nystagmus	B-Disease
correlates	O
with	O
midpontine	O
activation	O
.	O

The	O
pathomechanism	O
of	O
nicotine	B-Chemical
-	O
induced	O
nystagmus	B-Disease
(	O
NIN	B-Disease
)	O
is	O
unknown	O
.	O

The	O
aim	O
of	O
this	O
study	O
was	O
to	O
delineate	O
brain	O
structures	O
that	O
are	O
involved	O
in	O
NIN	B-Disease
generation	O
.	O

Eight	O
healthy	O
volunteers	O
inhaled	O
nicotine	B-Chemical
in	O
darkness	O
during	O
a	O
functional	O
magnetic	O
resonance	O
imaging	O
(	O
fMRI	O
)	O
experiment	O
;	O
eye	O
movements	O
were	O
registered	O
using	O
video	O
-	O
oculography	O
.	O

NIN	B-Disease
correlated	O
with	O
blood	O
oxygen	B-Chemical
level	O
-	O
dependent	O
(	O
BOLD	O
)	O
activity	O
levels	O
in	O
a	O
midpontine	O
site	O
in	O
the	O
posterior	O
basis	O
pontis	O
.	O

NIN	B-Disease
-	O
induced	O
midpontine	O
activation	O
may	O
correspond	O
to	O
activation	O
of	O
the	O
dorsomedial	O
pontine	O
nuclei	O
and	O
the	O
nucleus	O
reticularis	O
tegmenti	O
pontis	O
,	O
structures	O
known	O
to	O
participate	O
in	O
the	O
generation	O
of	O
multidirectional	O
saccades	O
and	O
smooth	O
pursuit	O
eye	O
movements	O
.	O

Acute	O
effects	O
of	O
N	B-Chemical
-	I-Chemical
(	I-Chemical
2	I-Chemical
-	I-Chemical
propylpentanoyl	I-Chemical
)	I-Chemical
urea	I-Chemical
on	O
hippocampal	O
amino	B-Chemical
acid	I-Chemical
neurotransmitters	O
in	O
pilocarpine	B-Chemical
-	O
induced	O
seizure	B-Disease
in	O
rats	O
.	O

The	O
present	O
study	O
aimed	O
to	O
investigate	O
the	O
anticonvulsant	O
activity	O
as	O
well	O
as	O
the	O
effects	O
on	O
the	O
level	O
of	O
hippocampal	O
amino	B-Chemical
acid	I-Chemical
neurotransmitters	O
(	O
glutamate	B-Chemical
,	O
aspartate	B-Chemical
,	O
glycine	B-Chemical
and	O
GABA	B-Chemical
)	O
of	O
N	B-Chemical
-	I-Chemical
(	I-Chemical
2	I-Chemical
-	I-Chemical
propylpentanoyl	I-Chemical
)	I-Chemical
urea	I-Chemical
(	O
VPU	B-Chemical
)	O
in	O
comparison	O
to	O
its	O
parent	O
compound	O
,	O
valproic	B-Chemical
acid	I-Chemical
(	O
VPA	B-Chemical
)	O
.	O

VPU	B-Chemical
was	O
more	O
potent	O
than	O
VPA	B-Chemical
,	O
exhibiting	O
the	O
median	O
effective	O
dose	O
(	O
ED	O
(	O
50	O
)	O
)	O
of	O
49	O
mg	O
/	O
kg	O
in	O
protecting	O
rats	O
against	O
pilocarpine	B-Chemical
-	O
induced	O
seizure	B-Disease
whereas	O
the	O
corresponding	O
value	O
for	O
VPA	B-Chemical
was	O
322	O
mg	O
/	O
kg	O
.	O

In	O
vivo	O
microdialysis	O
demonstrated	O
that	O
an	O
intraperitoneal	O
administration	O
of	O
pilocarpine	B-Chemical
induced	O
a	O
pronounced	O
increment	O
of	O
hippocampal	O
glutamate	B-Chemical
and	O
aspartate	B-Chemical
whereas	O
no	O
significant	O
change	O
was	O
observed	O
on	O
the	O
level	O
of	O
glycine	B-Chemical
and	O
GABA	B-Chemical
.	O

Pretreatment	O
with	O
either	O
VPU	B-Chemical
(	O
50	O
and	O
100	O
mg	O
/	O
kg	O
)	O
or	O
VPA	B-Chemical
(	O
300	O
and	O
600	O
mg	O
/	O
kg	O
)	O
completely	O
abolished	O
pilocarpine	B-Chemical
-	O
evoked	O
increases	O
in	O
extracellular	O
glutamate	B-Chemical
and	O
aspartate	B-Chemical
.	O

In	O
addition	O
,	O
a	O
statistically	O
significant	O
reduction	O
was	O
also	O
observed	O
on	O
the	O
level	O
of	O
GABA	B-Chemical
and	O
glycine	B-Chemical
but	O
less	O
than	O
a	O
drastic	O
reduction	O
of	O
glutamate	B-Chemical
and	O
aspartate	B-Chemical
level	O
.	O

Based	O
on	O
the	O
finding	O
that	O
VPU	B-Chemical
and	O
VPA	B-Chemical
could	O
protect	O
the	O
animals	O
against	O
pilocarpine	B-Chemical
-	O
induced	O
seizure	B-Disease
it	O
is	O
suggested	O
that	O
the	O
reduction	O
of	O
inhibitory	O
amino	B-Chemical
acid	I-Chemical
neurotransmitters	O
was	O
comparatively	O
minor	O
and	O
offset	O
by	O
a	O
pronounced	O
reduction	O
of	O
glutamate	B-Chemical
and	O
aspartate	B-Chemical
.	O

Therefore	O
,	O
like	O
VPA	B-Chemical
,	O
the	O
finding	O
that	O
VPU	B-Chemical
could	O
drastically	O
reduce	O
pilocarpine	B-Chemical
-	O
induced	O
increases	O
in	O
glutamate	B-Chemical
and	O
aspartate	B-Chemical
should	O
account	O
,	O
at	O
least	O
partly	O
,	O
for	O
its	O
anticonvulsant	O
activity	O
observed	O
in	O
pilocarpine	B-Chemical
-	O
induced	O
seizure	B-Disease
in	O
experimental	O
animals	O
.	O

Some	O
other	O
mechanism	O
than	O
those	O
being	O
reported	O
herein	O
should	O
be	O
further	O
investigated	O
.	O

Protective	O
effect	O
of	O
verapamil	B-Chemical
on	O
gastric	B-Disease
hemorrhagic	I-Disease
ulcers	B-Disease
in	O
severe	O
atherosclerotic	B-Disease
rats	O
.	O

Studies	O
concerning	O
with	O
pathogenesis	O
of	O
gastric	B-Disease
hemorrhage	I-Disease
and	O
mucosal	O
ulceration	O
produced	O
in	O
atherosclerotic	B-Disease
rats	O
are	O
lacking	O
.	O

The	O
aim	O
of	O
this	O
study	O
is	O
to	O
examine	O
the	O
role	O
of	O
gastric	O
acid	O
back	O
-	O
diffusion	O
,	O
mast	O
cell	O
histamine	B-Chemical
release	O
,	O
lipid	O
peroxide	O
(	O
LPO	O
)	O
generation	O
and	O
mucosal	O
microvascular	O
permeability	O
in	O
modulating	O
gastric	B-Disease
hemorrhage	I-Disease
and	O
ulcer	B-Disease
in	O
rats	O
with	O
atherosclerosis	B-Disease
induced	O
by	O
coadministration	O
of	O
vitamin	B-Chemical
D2	I-Chemical
and	O
cholesterol	B-Chemical
.	O

Additionally	O
,	O
the	O
protective	O
effect	O
of	O
verapamil	B-Chemical
on	O
this	O
ulcer	B-Disease
model	O
was	O
evaluated	O
.	O

Male	O
Wistar	O
rats	O
were	O
challenged	O
intragastrically	O
once	O
daily	O
for	O
9	O
days	O
with	O
1	O
.	O
0	O
ml	O
/	O
kg	O
of	O
corn	O
oil	O
containing	O
vitamin	B-Chemical
D2	I-Chemical
and	O
cholesterol	B-Chemical
to	O
induce	O
atherosclerosis	B-Disease
.	O

Control	O
rats	O
received	O
corn	O
oil	O
only	O
.	O

After	O
gastric	O
surgery	O
,	O
rat	O
stomachs	O
were	O
irrigated	O
for	O
3	O
h	O
with	O
either	O
simulated	O
gastric	O
juice	O
or	O
normal	O
saline	O
.	O

Gastric	O
acid	O
back	O
-	O
diffusion	O
,	O
mucosal	O
LPO	O
generation	O
,	O
histamine	B-Chemical
concentration	O
,	O
microvascular	O
permeability	O
,	O
luminal	B-Chemical
hemoglobin	O
content	O
and	O
ulcer	B-Disease
areas	O
were	O
determined	O
.	O

Elevated	O
atherosclerotic	B-Disease
parameters	O
,	O
such	O
as	O
serum	O
calcium	B-Chemical
,	O
total	O
cholesterol	B-Chemical
and	O
low	O
-	O
density	O
lipoprotein	O
concentration	O
were	O
obtained	O
in	O
atherosclerotic	B-Disease
rats	O
.	O

Severe	O
gastric	O
ulcers	B-Disease
accompanied	O
with	O
increased	O
ulcerogenic	O
factors	O
,	O
including	O
gastric	O
acid	O
back	O
-	O
diffusion	O
,	O
histamine	B-Chemical
release	O
,	O
LPO	O
generation	O
and	O
luminal	B-Chemical
hemoglobin	O
content	O
were	O
also	O
observed	O
in	O
these	O
rats	O
.	O

Moreover	O
,	O
a	O
positive	O
correlation	O
of	O
histamine	B-Chemical
to	O
gastric	B-Disease
hemorrhage	I-Disease
and	O
to	O
ulcer	B-Disease
was	O
found	O
in	O
those	O
atherosclerotic	B-Disease
rats	O
.	O

This	O
hemorrhagic	B-Disease
ulcer	B-Disease
and	O
various	O
ulcerogenic	O
parameters	O
were	O
dose	O
-	O
dependently	O
ameliorated	O
by	O
daily	O
intragastric	O
verapamil	B-Chemical
.	O

Atherosclerosis	B-Disease
could	O
produce	O
gastric	B-Disease
hemorrhagic	I-Disease
ulcer	B-Disease
via	O
aggravation	O
of	O
gastric	O
acid	O
back	O
-	O
diffusion	O
,	O
LPO	O
generation	O
,	O
histamine	B-Chemical
release	O
and	O
microvascular	O
permeability	O
that	O
could	O
be	O
ameliorated	O
by	O
verapamil	B-Chemical
in	O
rats	O
.	O

Lamivudine	B-Chemical
for	O
the	O
prevention	O
of	O
hepatitis	B-Disease
B	I-Disease
virus	O
reactivation	O
in	O
hepatitis	B-Chemical
-	I-Chemical
B	I-Chemical
surface	I-Chemical
antigen	I-Chemical
(	O
HBSAG	B-Chemical
)	O
seropositive	O
cancer	B-Disease
patients	O
undergoing	O
cytotoxic	O
chemotherapy	O
.	O

Hepatitis	B-Disease
B	I-Disease
virus	O
(	O
HBV	O
)	O
is	O
one	O
of	O
the	O
major	O
causes	O
of	O
chronic	O
liver	B-Disease
disease	I-Disease
worldwide	O
.	O

Cancer	B-Disease
patients	O
who	O
are	O
chronic	O
carriers	O
of	O
HBV	O
have	O
a	O
higher	O
hepatic	B-Disease
complication	I-Disease
rate	O
while	O
receiving	O
cytotoxic	O
chemotherapy	O
(	O
CT	O
)	O
and	O
this	O
has	O
mainly	O
been	O
attributed	O
to	O
HBV	O
reactivation	O
.	O

In	O
this	O
study	O
,	O
cancer	B-Disease
patients	O
who	O
have	O
solid	O
and	O
hematological	B-Disease
malignancies	I-Disease
with	O
chronic	O
HBV	B-Disease
infection	I-Disease
received	O
the	O
antiviral	O
agent	O
lamivudine	B-Chemical
prior	O
and	O
during	O
CT	O
compared	O
with	O
historical	O
control	O
group	O
who	O
did	O
not	O
receive	O
lamivudine	B-Chemical
.	O

The	O
objectives	O
were	O
to	O
assess	O
the	O
efficacy	O
of	O
lamivudine	B-Chemical
in	O
reducing	O
the	O
incidence	O
of	O
HBV	O
reactivation	O
,	O
and	O
diminishing	O
morbidity	O
and	O
mortality	O
during	O
CT	O
.	O

Two	O
groups	O
were	O
compared	O
in	O
this	O
study	O
.	O

The	O
prophylactic	O
lamivudin	B-Chemical
group	O
consisted	O
of	O
37	O
patients	O
who	O
received	O
prophylactic	O
lamivudine	B-Chemical
treatment	O
.	O

The	O
historical	O
controls	O
consisted	O
of	O
50	O
consecutive	O
patients	O
who	O
underwent	O
CT	O
without	O
prophylactic	O
lamivudine	B-Chemical
.	O

They	O
were	O
followed	O
up	O
during	O
and	O
for	O
8	O
weeks	O
after	O
CT	O
.	O

The	O
outcomes	O
were	O
compared	O
for	O
both	O
groups	O
.	O

Of	O
our	O
control	O
group	O
(	O
n	O
=	O
50	O
)	O
,	O
21	O
patients	O
(	O
42	O
%	O
)	O
were	O
established	O
hepatitis	B-Disease
.	O

Twelve	O
(	O
24	O
%	O
)	O
of	O
them	O
were	O
evaluated	O
as	O
severe	O
hepatitis	B-Disease
.	O

In	O
the	O
prophylactic	O
lamivudine	B-Chemical
group	O
severe	O
hepatitis	B-Disease
were	O
observed	O
only	O
in	O
1	O
patient	O
(	O
2	O
.	O
7	O
%	O
)	O
of	O
37	O
patients	O
(	O
p	O
<	O
0	O
.	O
006	O
)	O
.	O

Comparison	O
of	O
the	O
mean	O
ALT	O
values	O
revealed	O
significantly	O
higher	O
mean	O
alanine	B-Chemical
aminotransferase	O
(	O
ALT	O
)	O
values	O
in	O
the	O
control	O
group	O
than	O
the	O
prophylactic	O
lamivudine	B-Chemical
group	O
;	O
154	O
:	O
64	O
(	O
p	O
<	O
0	O
.	O
32	O
)	O
.	O

Our	O
study	O
suggests	O
that	O
prophylactic	O
lamivudine	B-Chemical
significantly	O
decreases	O
the	O
incidence	O
of	O
HBV	O
reactivation	O
and	O
overall	O
morbidity	O
in	O
cancer	B-Disease
patients	O
during	O
and	O
after	O
immunosuppressive	O
therapy	O
.	O

Further	O
studies	O
are	O
needed	O
to	O
determine	O
the	O
most	O
appropriate	O
nucleoside	B-Chemical
or	O
nucleotide	B-Chemical
analogue	O
for	O
antiviral	O
prophylaxis	O
during	O
CT	O
and	O
the	O
optimal	O
duration	O
of	O
administration	O
after	O
completion	O
of	O
CT	O
.	O

Recovery	O
of	O
tacrolimus	B-Chemical
-	O
associated	O
brachial	B-Disease
neuritis	I-Disease
after	O
conversion	O
to	O
everolimus	B-Chemical
in	O
a	O
pediatric	O
renal	O
transplant	O
recipient	O
-	O
-	O
case	O
report	O
and	O
review	O
of	O
the	O
literature	O
.	O

TAC	B-Chemical
has	O
been	O
shown	O
to	O
be	O
a	O
potent	O
immunosuppressive	O
agent	O
for	O
solid	O
organ	O
transplantation	O
in	O
pediatrics	O
.	O

Neurotoxicity	B-Disease
is	O
a	O
potentially	O
serious	O
toxic	O
effect	O
.	O

It	O
is	O
characterized	O
by	O
encephalopathy	B-Disease
,	O
headaches	B-Disease
,	O
seizures	B-Disease
,	O
or	O
neurological	B-Disease
deficits	I-Disease
.	O

Here	O
,	O
we	O
describe	O
an	O
eight	O
-	O
and	O
-	O
a	O
-	O
half	O
-	O
yr	O
-	O
old	O
male	O
renal	O
transplant	O
recipient	O
with	O
right	O
BN	O
.	O

MRI	O
demonstrated	O
hyperintense	O
T2	O
signals	O
in	O
the	O
cervical	O
cord	O
and	O
right	O
brachial	O
plexus	O
roots	O
indicative	O
of	O
both	O
myelitis	B-Disease
and	O
right	O
brachial	B-Disease
plexitis	I-Disease
.	O

Symptoms	O
persisted	O
for	O
three	O
months	O
despite	O
TAC	B-Chemical
dose	O
reduction	O
,	O
administration	O
of	O
IVIG	O
and	O
four	O
doses	O
of	O
methylprednisolone	B-Chemical
pulse	O
therapy	O
.	O

Improvement	O
and	O
eventually	O
full	O
recovery	O
only	O
occurred	O
after	O
TAC	B-Chemical
was	O
completely	O
discontinued	O
and	O
successfully	O
replaced	O
by	O
everolimus	B-Chemical
.	O

Omitting	O
fentanyl	B-Chemical
reduces	O
nausea	B-Disease
and	O
vomiting	B-Disease
,	O
without	O
increasing	O
pain	B-Disease
,	O
after	O
sevoflurane	B-Chemical
for	O
day	O
surgery	O
.	O

BACKGROUND	O
AND	O
OBJECTIVE	O
:	O
Despite	O
advantages	O
of	O
induction	O
and	O
maintenance	O
of	O
anaesthesia	O
with	O
sevoflurane	B-Chemical
,	O
postoperative	B-Disease
nausea	I-Disease
and	I-Disease
vomiting	I-Disease
occurs	O
frequently	O
.	O

Fentanyl	B-Chemical
is	O
a	O
commonly	O
used	O
supplement	O
that	O
may	O
contribute	O
to	O
this	O
,	O
although	O
it	O
may	O
also	O
improve	O
analgesia	O
.	O

METHODS	O
:	O
This	O
double	O
-	O
blind	O
study	O
examined	O
the	O
incidence	O
and	O
severity	O
of	O
postoperative	B-Disease
nausea	I-Disease
and	I-Disease
vomiting	I-Disease
and	O
pain	B-Disease
in	O
the	O
first	O
24	O
h	O
after	O
sevoflurane	B-Chemical
anaesthesia	O
in	O
216	O
adult	O
day	O
surgery	O
patients	O
.	O

Patients	O
were	O
randomly	O
allocated	O
to	O
either	O
receive	O
or	O
not	O
receive	O
1	O
1	O
fentanyl	B-Chemical
,	O
while	O
a	O
third	O
group	O
received	O
dexamethasone	B-Chemical
in	O
addition	O
to	O
fentanyl	B-Chemical
.	O

RESULTS	O
:	O
Omission	O
of	O
fentanyl	B-Chemical
did	O
not	O
reduce	O
the	O
overall	O
incidence	O
of	O
postoperative	B-Disease
nausea	I-Disease
and	I-Disease
vomiting	I-Disease
,	O
but	O
did	O
reduce	O
the	O
incidence	O
of	O
vomiting	B-Disease
and	O
/	O
or	O
moderate	O
to	O
severe	O
nausea	B-Disease
prior	O
to	O
discharge	O
from	O
20	O
%	O
and	O
17	O
%	O
with	O
fentanyl	B-Chemical
and	O
fentanyl	B-Chemical
-	O
dexamethasone	B-Chemical
,	O
respectively	O
,	O
to	O
5	O
%	O
(	O
P	O
=	O
0	O
.	O
013	O
)	O
.	O

Antiemetic	O
requirements	O
were	O
reduced	O
from	O
24	O
%	O
and	O
31	O
%	O
to	O
7	O
%	O
(	O
P	O
=	O
0	O
.	O
0012	O
)	O
.	O

Dexamethasone	B-Chemical
had	O
no	O
significant	O
effect	O
on	O
the	O
incidence	O
or	O
severity	O
of	O
postoperative	B-Disease
nausea	I-Disease
and	I-Disease
vomiting	I-Disease
.	O

Combining	O
the	O
two	O
fentanyl	B-Chemical
groups	O
revealed	O
further	O
significant	O
benefits	O
from	O
the	O
avoidance	O
of	O
opioids	O
,	O
reducing	O
postoperative	B-Disease
nausea	I-Disease
and	I-Disease
vomiting	I-Disease
and	O
nausea	B-Disease
prior	O
to	O
discharge	O
from	O
35	O
%	O
and	O
33	O
%	O
to	O
22	O
%	O
and	O
19	O
%	O
(	O
P	O
=	O
0	O
.	O
049	O
and	O
P	O
=	O
0	O
.	O
035	O
)	O
,	O
respectively	O
,	O
while	O
nausea	B-Disease
in	O
the	O
first	O
24	O
h	O
was	O
decreased	O
from	O
42	O
%	O
to	O
27	O
%	O
(	O
P	O
=	O
0	O
.	O
034	O
)	O
.	O

Pain	B-Disease
severity	O
and	O
analgesic	O
requirements	O
were	O
unaffected	O
by	O
the	O
omission	O
of	O
fentanyl	B-Chemical
.	O

Fentanyl	B-Chemical
did	O
reduce	O
minor	O
intraoperative	O
movement	O
but	O
had	O
no	O
sevoflurane	B-Chemical
-	O
sparing	O
effect	O
and	O
increased	O
respiratory	B-Disease
depression	I-Disease
,	O
hypotension	B-Disease
and	O
bradycardia	B-Disease
.	O

CONCLUSION	O
:	O
As	O
fentanyl	B-Chemical
exacerbated	O
postoperative	B-Disease
nausea	I-Disease
and	I-Disease
vomiting	I-Disease
without	O
an	O
improvement	O
in	O
postoperative	B-Disease
pain	I-Disease
and	O
also	O
had	O
adverse	O
cardiorespiratory	O
effects	O
,	O
it	O
appears	O
to	O
be	O
an	O
unnecessary	O
and	O
possibly	O
detrimental	O
supplement	O
to	O
sevoflurane	B-Chemical
in	O
day	O
surgery	O
.	O

Valvular	B-Disease
heart	I-Disease
disease	I-Disease
in	O
patients	O
with	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
treated	O
with	O
pergolide	B-Chemical
.	O

Course	O
following	O
treatment	O
modifications	O
.	O

Valvular	B-Disease
heart	I-Disease
abnormalities	I-Disease
have	O
been	O
reported	O
in	O
patients	O
with	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
(	O
PD	B-Disease
)	O
treated	O
with	O
pergolide	B-Chemical
.	O

However	O
,	O
the	O
incidence	O
and	O
severity	O
of	O
these	O
abnormalities	O
vary	O
from	O
study	O
to	O
study	O
and	O
their	O
course	O
after	O
drug	O
withdrawal	O
has	O
not	O
been	O
systematically	O
assessed	O
.	O

OBJECTIVES	O
:	O
To	O
estimate	O
the	O
frequency	O
and	O
severity	O
of	O
valvular	B-Disease
heart	I-Disease
abnormality	I-Disease
and	O
its	O
possible	O
reversibility	O
after	O
drug	O
withdrawal	O
in	O
a	O
case	O
-	O
control	O
study	O
.	O

METHODS	O
:	O
All	O
PD	B-Disease
patients	O
in	O
the	O
Amiens	O
area	O
treated	O
with	O
pergolide	B-Chemical
were	O
invited	O
to	O
attend	O
a	O
cardiologic	O
assessment	O
including	O
transthoracic	O
echocardiography	O
.	O

Thirty	O
PD	B-Disease
patients	O
participated	O
in	O
the	O
study	O
.	O

A	O
second	O
echocardiography	O
was	O
performed	O
(	O
median	O
interval	O
:	O
13	O
months	O
)	O
after	O
pergolide	B-Chemical
withdrawal	O
(	O
n	O
=	O
10	O
patients	O
)	O
.	O

Controls	O
were	O
age	O
-	O
and	O
sex	O
-	O
matched	O
non	O
-	O
PD	B-Disease
patients	O
referred	O
to	O
the	O
cardiology	O
department	O
.	O

RESULTS	O
:	O
Compared	O
to	O
controls	O
,	O
aortic	B-Disease
regurgitation	I-Disease
(	O
OR	O
:	O
3	O
.	O
1	O
;	O
95	O
%	O
IC	O
:	O
1	O
.	O
1	O
-	O
8	O
.	O
8	O
)	O
and	O
mitral	B-Disease
regurgitation	I-Disease
(	O
OR	O
:	O
10	O
.	O
7	O
;	O
95	O
%	O
IC	O
:	O
2	O
.	O
1	O
-	O
53	O
)	O
were	O
more	O
frequent	O
in	O
PD	B-Disease
patients	O
(	O
tricuspid	O
:	O
NS	O
)	O
.	O

The	O
number	O
of	O
affected	O
valves	O
(	O
n	O
=	O
2	O
.	O
4	O
+	O
/	O
-	O
0	O
.	O
7	O
)	O
and	O
the	O
sum	O
of	O
regurgitation	O
grades	O
(	O
n	O
=	O
2	O
.	O
8	O
+	O
/	O
-	O
1	O
.	O
09	O
)	O
were	O
higher	O
(	O
p	O
=	O
0	O
.	O
008	O
and	O
p	O
=	O
0	O
.	O
006	O
,	O
respectively	O
)	O
in	O
the	O
pergolide	B-Chemical
group	O
.	O

Severity	O
of	O
regurgitation	O
was	O
not	O
correlated	O
with	O
pergolide	B-Chemical
cumulative	O
dose	O
.	O

A	O
restrictive	O
pattern	O
of	O
valvular	B-Disease
regurgitation	I-Disease
,	O
suggestive	O
of	O
the	O
role	O
of	O
pergolide	B-Chemical
,	O
was	O
observed	O
in	O
12	O
/	O
30	O
(	O
40	O
%	O
)	O
patients	O
including	O
two	O
with	O
heart	B-Disease
failure	I-Disease
.	O

Pergolide	B-Chemical
was	O
discontinued	O
in	O
10	O
patients	O
with	O
valvular	B-Disease
heart	I-Disease
disease	I-Disease
,	O
resulting	O
in	O
a	O
lower	O
regurgitation	O
grade	O
(	O
p	O
=	O
0	O
.	O
01	O
)	O
at	O
the	O
second	O
transthoracic	O
echocardiography	O
and	O
the	O
two	O
patients	O
with	O
heart	B-Disease
failure	I-Disease
returned	O
to	O
nearly	O
normal	O
clinical	O
examination	O
.	O

This	O
study	O
supports	O
the	O
high	O
frequency	O
of	O
restrictive	O
valve	B-Disease
regurgitation	I-Disease
in	O
PD	B-Disease
patients	O
treated	O
with	O
pergolide	B-Chemical
and	O
reveals	O
that	O
a	O
significant	O
improvement	O
is	O
usual	O
when	O
the	O
treatment	O
is	O
converted	O
to	O
non	O
-	O
ergot	O
dopamine	B-Chemical
agonists	O
.	O

Adriamycin	B-Chemical
-	O
induced	O
autophagic	O
cardiomyocyte	O
death	B-Disease
plays	O
a	O
pathogenic	O
role	O
in	O
a	O
rat	O
model	O
of	O
heart	B-Disease
failure	I-Disease
.	O

BACKGROUND	O
:	O
The	O
mechanisms	O
underlying	O
heart	B-Disease
failure	I-Disease
induced	O
by	O
adriamycin	B-Chemical
are	O
very	O
complicated	O
and	O
still	O
unclear	O
.	O

The	O
aim	O
of	O
this	O
study	O
was	O
to	O
investigate	O
whether	O
autophagy	O
was	O
involved	O
in	O
the	O
progression	O
of	O
heart	B-Disease
failure	I-Disease
induced	O
by	O
adriamycin	B-Chemical
,	O
so	O
that	O
we	O
can	O
develop	O
a	O
novel	O
treatment	O
strategy	O
for	O
heart	B-Disease
failure	I-Disease
.	O

METHODS	O
:	O
3	B-Chemical
-	I-Chemical
methyladenine	I-Chemical
(	O
3MA	B-Chemical
)	O
,	O
a	O
specific	O
inhibitor	O
on	O
autophagy	O
was	O
used	O
in	O
a	O
heart	B-Disease
failure	I-Disease
model	O
of	O
rats	O
induced	O
by	O
adriamycin	B-Chemical
.	O

Neonatal	O
cardiomyocytes	O
were	O
isolated	O
from	O
Sprague	O
-	O
Dawley	O
rat	O
hearts	O
and	O
randomly	O
divided	O
into	O
controls	O
,	O
an	O
adriamycin	B-Chemical
-	O
treated	O
group	O
,	O
and	O
a	O
3MA	B-Chemical
plus	O
adriamycin	B-Chemical
-	O
treated	O
group	O
.	O

We	O
then	O
examined	O
the	O
morphology	O
,	O
expression	O
of	O
beclin	O
1	O
gene	O
,	O
mitochondrial	O
permeability	O
transition	O
(	O
MPT	O
)	O
,	O
and	O
Na	O
+	O
-	O
K	B-Chemical
+	O
ATPase	O
activity	O
in	O
vivo	O
.	O

We	O
also	O
assessed	O
cell	O
viability	O
,	O
mitochondrial	O
membrane	O
potential	O
changes	O
and	O
counted	O
autophagic	O
vacuoles	O
in	O
cultured	O
cardiomyocytes	O
.	O

In	O
addition	O
,	O
we	O
analyzed	O
the	O
expression	O
of	O
autophagy	O
associated	O
gene	O
,	O
beclin	O
1	O
using	O
RT	O
-	O
PCR	O
and	O
Western	O
blotting	O
in	O
an	O
animal	O
model	O
.	O

RESULTS	O
:	O
3MA	B-Chemical
significantly	O
improved	O
cardiac	O
function	O
and	O
reduced	O
mitochondrial	O
injury	O
.	O

Furthermore	O
,	O
adriamycin	B-Chemical
induced	O
the	O
formation	O
of	O
autophagic	O
vacuoles	O
,	O
and	O
3MA	B-Chemical
strongly	O
downregulated	O
the	O
expression	O
of	O
beclin	O
1	O
in	O
adriamycin	B-Chemical
-	O
induced	O
failing	O
heart	O
and	O
inhibited	O
the	O
formation	O
of	O
autophagic	O
vacuoles	O
.	O

CONCLUSION	O
:	O
Autophagic	O
cardiomyocyte	O
death	B-Disease
plays	O
an	O
important	O
role	O
in	O
the	O
pathogenesis	O
of	O
heart	B-Disease
failure	I-Disease
in	O
rats	O
induced	O
by	O
adriamycin	B-Chemical
.	O

Mitochondrial	O
injury	O
may	O
be	O
involved	O
in	O
the	O
progression	O
of	O
heart	B-Disease
failure	I-Disease
caused	O
by	O
adriamycin	B-Chemical
via	O
the	O
autophagy	O
pathway	O
.	O

mToR	O
inhibitors	O
-	O
induced	O
proteinuria	B-Disease
:	O
mechanisms	O
,	O
significance	O
,	O
and	O
management	O
.	O

Massive	O
urinary	O
protein	O
excretion	O
has	O
been	O
observed	O
after	O
conversion	O
from	O
calcineurin	O
inhibitors	O
to	O
mammalian	O
target	O
of	O
rapamycin	B-Chemical
(	O
mToR	O
)	O
inhibitors	O
,	O
especially	O
sirolimus	B-Chemical
,	O
in	O
renal	O
transplant	O
recipients	O
with	O
chronic	B-Disease
allograft	I-Disease
nephropathy	I-Disease
.	O

Because	O
proteinuria	B-Disease
is	O
a	O
major	O
predictive	O
factor	O
of	O
poor	O
transplantation	O
outcome	O
,	O
many	O
studies	O
focused	O
on	O
this	O
adverse	O
event	O
during	O
the	O
past	O
years	O
.	O

Whether	O
proteinuria	B-Disease
was	O
due	O
to	O
sirolimus	B-Chemical
or	O
only	O
a	O
consequence	O
of	O
calcineurin	O
inhibitors	O
withdrawal	O
remained	O
unsolved	O
until	O
high	O
range	O
proteinuria	B-Disease
has	O
been	O
observed	O
during	O
sirolimus	B-Chemical
therapy	O
in	O
islet	O
transplantation	O
and	O
in	O
patients	O
who	O
received	O
sirolimus	B-Chemical
de	O
novo	O
.	O

Podocyte	O
injury	O
and	O
focal	O
segmental	O
glomerulosclerosis	B-Disease
have	O
been	O
related	O
to	O
mToR	O
inhibition	O
in	O
some	O
patients	O
,	O
but	O
the	O
pathways	O
underlying	O
these	O
lesions	O
remain	O
hypothetic	O
.	O

We	O
discuss	O
herein	O
the	O
possible	O
mechanisms	O
and	O
the	O
significance	O
of	O
mToR	O
blockade	O
-	O
induced	O
proteinuria	B-Disease
.	O

Neuropsychiatric	O
side	O
effects	O
after	O
the	O
use	O
of	O
mefloquine	B-Chemical
.	O

This	O
study	O
describes	O
neuropsychiatric	O
side	O
effects	O
in	O
patients	O
after	O
treatment	O
with	O
mefloquine	B-Chemical
.	O

Reactions	O
consisted	O
mainly	O
of	O
seizures	B-Disease
,	O
acute	O
psychoses	B-Disease
,	O
anxiety	B-Disease
neurosis	I-Disease
,	O
and	O
major	O
disturbances	B-Disease
of	I-Disease
sleep	I-Disease
-	I-Disease
wake	I-Disease
rhythm	I-Disease
.	O

Side	O
effects	O
occurred	O
after	O
both	O
therapeutic	O
and	O
prophylactic	O
intake	O
and	O
were	O
graded	O
from	O
moderate	O
to	O
severe	O
.	O

In	O
a	O
risk	O
analysis	O
of	O
neuropsychiatric	O
side	O
effects	O
in	O
Germany	O
,	O
it	O
is	O
estimated	O
that	O
one	O
of	O
8	O
,	O
000	O
mefloquine	B-Chemical
users	O
suffers	O
from	O
such	O
reactions	O
.	O

The	O
incidence	O
calculation	O
revealed	O
that	O
one	O
of	O
215	O
therapeutic	O
users	O
had	O
reactions	O
,	O
compared	O
with	O
one	O
of	O
13	O
,	O
000	O
in	O
the	O
prophylaxis	O
group	O
,	O
making	O
the	O
risk	O
of	O
neuropsychiatric	O
reactions	O
after	O
mefloquine	B-Chemical
treatment	O
60	O
times	O
higher	O
than	O
after	O
prophylaxis	O
.	O

Therefore	O
,	O
certain	O
limitations	O
for	O
malaria	B-Disease
prophylaxis	O
and	O
treatment	O
with	O
mefloquine	B-Chemical
are	O
recommended	O
.	O

Prenatal	O
protein	O
deprivation	O
alters	O
dopamine	B-Chemical
-	O
mediated	O
behaviors	O
and	O
dopaminergic	O
and	O
glutamatergic	O
receptor	O
binding	O
.	O

Epidemiological	O
evidence	O
indicates	O
that	O
prenatal	O
nutritional	O
deprivation	O
may	O
increase	O
the	O
risk	O
of	O
schizophrenia	B-Disease
.	O

The	O
goal	O
of	O
these	O
studies	O
was	O
to	O
use	O
an	O
animal	O
model	O
to	O
examine	O
the	O
effects	O
of	O
prenatal	O
protein	O
deprivation	O
on	O
behaviors	O
and	O
receptor	O
binding	O
with	O
relevance	O
to	O
schizophrenia	B-Disease
.	O

We	O
report	O
that	O
prenatally	O
protein	O
deprived	O
(	O
PD	O
)	O
female	O
rats	O
showed	O
an	O
increased	O
stereotypic	O
response	O
to	O
apomorphine	B-Chemical
and	O
an	O
increased	O
locomotor	O
response	O
to	O
amphetamine	B-Chemical
in	O
adulthood	O
.	O

These	O
differences	O
were	O
not	O
observed	O
during	O
puberty	O
.	O

No	O
changes	O
in	O
haloperidol	B-Chemical
-	O
induced	O
catalepsy	B-Disease
or	O
MK	B-Chemical
-	I-Chemical
801	I-Chemical
-	O
induced	O
locomotion	O
were	O
seen	O
following	O
PD	O
.	O

In	O
addition	O
,	O
PD	O
female	O
rats	O
showed	O
increased	O
(	O
3	O
)	O
H	B-Chemical
-	O
MK	B-Chemical
-	I-Chemical
801	I-Chemical
binding	O
in	O
the	O
striatum	O
and	O
hippocampus	O
,	O
but	O
not	O
in	O
the	O
cortex	O
.	O

PD	O
female	O
rats	O
also	O
showed	O
increased	O
(	O
3	O
)	O
H	B-Chemical
-	O
haloperidol	B-Chemical
binding	O
and	O
decreased	O
dopamine	B-Chemical
transporter	O
binding	O
in	O
striatum	O
.	O

No	O
statistically	O
significant	O
changes	O
in	O
behavior	O
or	O
receptor	O
binding	O
were	O
found	O
in	O
PD	O
males	O
with	O
the	O
exception	O
of	O
increased	O
(	O
3	O
)	O
H	B-Chemical
-	O
MK	B-Chemical
-	I-Chemical
801	I-Chemical
binding	O
in	O
cortex	O
.	O

This	O
animal	O
model	O
may	O
be	O
useful	O
to	O
explore	O
the	O
mechanisms	O
by	O
which	O
prenatal	O
nutritional	B-Disease
deficiency	I-Disease
enhances	O
risk	O
for	O
schizophrenia	B-Disease
in	O
humans	O
and	O
may	O
also	O
have	O
implications	O
for	O
developmental	O
processes	O
leading	O
to	O
differential	O
sensitivity	O
to	O
drugs	O
of	O
abuse	O
.	O

Adverse	O
effects	O
of	O
topical	O
papaverine	B-Chemical
on	O
auditory	O
nerve	O
function	O
.	O

BACKGROUND	O
:	O
Papaverine	B-Chemical
hydrochloride	I-Chemical
is	O
a	O
direct	O
-	O
acting	O
vasodilator	O
used	O
to	O
manage	O
vasospasm	B-Disease
during	O
various	O
neurosurgical	O
operations	O
.	O

Transient	O
cranial	B-Disease
nerve	I-Disease
dysfunction	I-Disease
has	O
been	O
described	O
in	O
a	O
few	O
cases	O
with	O
topical	O
papaverine	B-Chemical
.	O

This	O
study	O
supports	O
previous	O
reports	O
and	O
provides	O
neurophysiological	O
evidence	O
of	O
an	O
adverse	O
effect	O
on	O
the	O
auditory	O
nerve	O
.	O

METHODS	O
:	O
We	O
conducted	O
a	O
retrospective	O
review	O
of	O
70	O
consecutive	O
microvascular	O
decompression	O
operations	O
and	O
studied	O
those	O
patients	O
who	O
received	O
topical	O
papaverine	B-Chemical
for	O
vasospasm	B-Disease
.	O

Topical	O
papaverine	B-Chemical
was	O
used	O
as	O
a	O
direct	O
therapeutic	O
action	O
to	O
manage	O
vasospasm	B-Disease
in	O
a	O
total	O
of	O
11	O
patients	O
.	O

The	O
timing	O
of	O
papaverine	B-Chemical
application	O
and	O
ongoing	O
operative	O
events	O
was	O
reviewed	O
relative	O
to	O
changes	O
in	O
neurophysiological	O
recordings	O
.	O

Brainstem	O
auditory	O
evoked	O
potentials	O
(	O
BAEPs	O
)	O
were	O
routinely	O
used	O
to	O
monitor	O
cochlear	O
nerve	O
function	O
during	O
these	O
operations	O
.	O

FINDINGS	O
:	O
A	O
temporal	O
relationship	O
was	O
found	O
between	O
topical	O
papaverine	B-Chemical
and	O
BAEP	O
changes	O
leading	O
to	O
complete	O
waveform	O
loss	O
.	O

The	O
average	O
temporal	O
delay	O
between	O
papaverine	B-Chemical
and	O
the	O
onset	O
of	O
an	O
adverse	O
BAEP	O
change	O
was	O
5	O
min	O
.	O

In	O
10	O
of	O
11	O
patients	O
,	O
BAEP	O
waves	O
II	O
/	O
III	O
-	O
V	O
completely	O
disappeared	O
within	O
2	O
to	O
25	O
min	O
after	O
papaverine	B-Chemical
.	O

Eight	O
of	O
these	O
10	O
patients	O
had	O
complete	O
loss	O
of	O
BAEP	O
waveforms	O
within	O
10	O
min	O
.	O

One	O
patient	O
showed	O
no	O
recovery	O
of	O
later	O
waves	O
and	O
a	O
delayed	O
profound	O
sensorineural	B-Disease
hearing	I-Disease
loss	I-Disease
.	O

The	O
average	O
recovery	O
time	O
of	O
BAEP	O
waveforms	O
to	O
pre	O
-	O
papaverine	B-Chemical
baseline	O
values	O
was	O
39	O
min	O
.	O

CONCLUSIONS	O
:	O
Topical	O
papaverine	B-Chemical
for	O
the	O
treatment	O
of	O
vasospasm	B-Disease
was	O
associated	O
with	O
the	O
onset	O
of	O
a	O
transient	O
disturbance	O
in	O
neurophysiological	O
function	O
of	O
the	O
ascending	O
auditory	O
brainstem	O
pathway	O
.	O

The	O
complete	O
disappearance	O
of	O
BAEP	O
waveforms	O
with	O
a	O
consistent	O
temporal	O
delay	O
suggests	O
a	O
possible	O
adverse	B-Disease
effect	I-Disease
on	I-Disease
the	I-Disease
proximal	I-Disease
eighth	I-Disease
nerve	I-Disease
.	O

Recommendations	O
to	O
avoid	O
potential	O
cranial	B-Disease
nerve	I-Disease
deficits	I-Disease
from	O
papaverine	B-Chemical
are	O
provided	O
.	O

Simvastatin	B-Chemical
-	I-Chemical
ezetimibe	I-Chemical
-	O
induced	O
hepatic	B-Disease
failure	I-Disease
necessitating	O
liver	O
transplantation	O
.	O

Abstract	O
Serum	O
aminotransferase	O
elevations	O
are	O
a	O
commonly	O
known	O
adverse	O
effect	O
of	O
3	O
-	O
hydroxy	O
-	O
3	O
-	O
methylglutaryl	O
coenzyme	O
A	O
reductase	O
inhibitor	O
(	O
statin	B-Chemical
)	O
therapy	O
.	O

However	O
,	O
hepatotoxic	B-Disease
events	O
have	O
not	O
been	O
widely	O
published	O
with	O
ezetimibe	B-Chemical
or	O
the	O
combination	O
agent	O
simvastatin	B-Chemical
-	I-Chemical
ezetimibe	I-Chemical
.	O

We	O
describe	O
a	O
70	O
-	O
year	O
-	O
old	O
Hispanic	O
woman	O
who	O
developed	O
fulminant	B-Disease
hepatic	I-Disease
failure	I-Disease
necessitating	O
liver	O
transplantation	O
10	O
weeks	O
after	O
conversion	O
from	O
simvastatin	B-Chemical
40	O
mg	O
/	O
day	O
to	O
simvastatin	B-Chemical
10	I-Chemical
mg	I-Chemical
-	I-Chemical
ezetimibe	I-Chemical
40	I-Chemical
mg	I-Chemical
/	O
day	O
.	O

The	O
patient	O
'	O
s	O
lipid	O
panel	O
had	O
been	O
maintained	O
with	O
simvastatin	B-Chemical
for	O
18	O
months	O
before	O
the	O
conversion	O
without	O
evidence	O
of	O
hepatotoxicity	B-Disease
.	O

A	O
routine	O
laboratory	O
work	O
-	O
up	O
10	O
weeks	O
after	O
conversion	O
revealed	O
elevated	O
serum	O
aminotransferase	O
levels	O
.	O

Simvastatinezetimibe	B-Chemical
and	O
escitalopram	B-Chemical
(	O
which	O
she	O
was	O
taking	O
for	O
depression	B-Disease
)	O
were	O
discontinued	O
,	O
and	O
other	O
potential	O
causes	O
of	O
hepatotoxicity	B-Disease
were	O
excluded	O
.	O

A	O
repeat	O
work	O
-	O
up	O
revealed	O
further	O
elevations	O
in	O
aminotransferase	O
levels	O
,	O
and	O
liver	O
biopsy	O
revealed	O
evidence	O
of	O
moderate	O
-	O
to	O
-	O
severe	O
drug	B-Disease
toxicity	I-Disease
.	O

She	O
underwent	O
liver	O
transplantation	O
with	O
an	O
uneventful	O
postoperative	O
course	O
.	O

Her	O
aminotransferase	O
levels	O
returned	O
to	O
normal	O
by	O
postoperative	O
day	O
23	O
,	O
and	O
her	O
2	O
-	O
year	O
follow	O
-	O
up	O
showed	O
no	O
adverse	O
events	O
.	O

Ezetimibe	B-Chemical
undergoes	O
extensive	O
glucuronidation	O
by	O
uridine	B-Chemical
diphosphate	I-Chemical
glucoronosyltransferases	O
(	O
UGT	O
)	O
in	O
the	O
intestine	O
and	O
liver	O
and	O
may	O
have	O
inhibited	O
the	O
glucuronidation	O
of	O
simvastatin	B-Chemical
hydroxy	I-Chemical
acid	I-Chemical
,	O
resulting	O
in	O
increased	O
simvastatin	B-Chemical
exposure	O
and	O
subsequent	O
hepatotoxicity	B-Disease
.	O

To	O
our	O
knowledge	O
,	O
this	O
is	O
the	O
first	O
case	O
report	O
of	O
simvastatin	B-Chemical
-	I-Chemical
ezetimibe	I-Chemical
-	O
induced	O
liver	B-Disease
failure	I-Disease
that	O
resulted	O
in	O
liver	O
transplantation	O
.	O

We	O
postulate	O
that	O
the	O
mechanism	O
of	O
the	O
simvastatinezetimibe	B-Chemical
-	O
induced	O
hepatotoxicity	B-Disease
is	O
the	O
increased	O
simvastatin	B-Chemical
exposure	O
by	O
ezetimibe	B-Chemical
inhibition	O
of	O
UGT	O
enzymes	O
.	O

Clinicians	O
should	O
be	O
aware	O
of	O
potential	O
hepatotoxicity	B-Disease
with	O
simvastatin	B-Chemical
-	I-Chemical
ezetimibe	I-Chemical
especially	O
in	O
elderly	O
patients	O
and	O
should	O
carefully	O
monitor	O
serum	O
aminotransferase	O
levels	O
when	O
starting	O
therapy	O
and	O
titrating	O
the	O
dosage	O
.	O

Massive	O
proteinuria	B-Disease
and	O
acute	B-Disease
renal	I-Disease
failure	I-Disease
after	O
oral	O
bisphosphonate	B-Chemical
(	O
alendronate	B-Chemical
)	O
administration	O
in	O
a	O
patient	O
with	O
focal	B-Disease
segmental	I-Disease
glomerulosclerosis	I-Disease
.	O

A	O
61	O
-	O
year	O
-	O
old	O
Japanese	O
man	O
with	O
nephrotic	B-Disease
syndrome	I-Disease
due	O
to	O
focal	B-Disease
segmental	I-Disease
glomerulosclerosis	I-Disease
was	O
initially	O
responding	O
well	O
to	O
steroid	B-Chemical
therapy	O
.	O

The	O
amount	O
of	O
daily	O
urinary	O
protein	O
decreased	O
from	O
15	O
.	O
6	O
to	O
2	O
.	O
8	O
g	O
.	O

Within	O
14	O
days	O
of	O
the	O
oral	O
bisphosphonate	B-Chemical
(	O
alendronate	B-Chemical
sodium	I-Chemical
)	O
administration	O
,	O
the	O
amount	O
of	O
daily	O
urinary	O
protein	O
increased	O
rapidly	O
up	O
to	O
12	O
.	O
8	O
g	O
with	O
acute	B-Disease
renal	I-Disease
failure	I-Disease
.	O

After	O
discontinuing	O
the	O
oral	O
alendronate	B-Chemical
,	O
the	O
patient	O
underwent	O
six	O
cycles	O
of	O
hemodialysis	O
and	O
four	O
cycles	O
of	O
LDL	O
apheresis	O
.	O

Urinary	O
volume	O
and	O
serum	O
creatinine	B-Chemical
levels	O
recovered	O
to	O
the	O
normal	O
range	O
,	O
with	O
urinary	O
protein	O
disappearing	O
completely	O
within	O
40	O
days	O
.	O

This	O
report	O
demonstrates	O
that	O
not	O
only	O
intravenous	O
,	O
but	O
also	O
oral	O
bisphosphonates	B-Chemical
can	O
aggravate	O
proteinuria	B-Disease
and	O
acute	B-Disease
renal	I-Disease
failure	I-Disease
.	O

Serum	O
-	O
and	O
glucocorticoid	O
-	O
inducible	O
kinase	O
1	O
in	O
doxorubicin	B-Chemical
-	O
induced	O
nephrotic	B-Disease
syndrome	I-Disease
.	O

Doxorubicin	B-Chemical
-	O
induced	O
nephropathy	B-Disease
leads	O
to	O
epithelial	O
sodium	B-Chemical
channel	O
(	O
ENaC	O
)	O
-	O
dependent	O
volume	B-Disease
retention	I-Disease
and	O
renal	O
fibrosis	B-Disease
.	O

The	O
aldosterone	B-Chemical
-	O
sensitive	O
serum	O
-	O
and	O
glucocorticoid	O
-	O
inducible	O
kinase	O
SGK1	O
has	O
been	O
shown	O
to	O
participate	O
in	O
the	O
stimulation	O
of	O
ENaC	O
and	O
to	O
mediate	O
renal	O
fibrosis	B-Disease
following	O
mineralocorticoid	O
and	O
salt	O
excess	O
.	O

The	O
present	O
study	O
was	O
performed	O
to	O
elucidate	O
the	O
role	O
of	O
SGK1	O
in	O
the	O
volume	B-Disease
retention	I-Disease
and	O
fibrosis	B-Disease
during	O
nephrotic	B-Disease
syndrome	I-Disease
.	O

To	O
this	O
end	O
,	O
doxorubicin	B-Chemical
(	O
15	O
mug	O
/	O
g	O
body	O
wt	O
)	O
was	O
injected	O
intravenously	O
into	O
gene	O
-	O
targeted	O
mice	O
lacking	O
SGK1	O
(	O
sgk1	O
(	O
-	O
/	O
-	O
)	O
)	O
and	O
their	O
wild	O
-	O
type	O
littermates	O
(	O
sgk1	O
(	O
+	O
/	O
+	O
)	O
)	O
.	O

Doxorubicin	B-Chemical
treatment	O
resulted	O
in	O
heavy	O
proteinuria	B-Disease
(	O
>	O
100	O
mg	O
protein	O
/	O
mg	O
crea	O
)	O
in	O
15	O
/	O
44	O
of	O
sgk1	O
(	O
+	O
/	O
+	O
)	O
and	O
15	O
/	O
44	O
of	O
sgk1	O
(	O
-	O
/	O
-	O
)	O
mice	O
leading	O
to	O
severe	O
nephrotic	B-Disease
syndrome	I-Disease
with	O
ascites	B-Disease
,	O
lipidemia	B-Disease
,	O
and	O
hypoalbuminemia	B-Disease
in	O
both	O
genotypes	O
.	O

Plasma	O
aldosterone	B-Chemical
levels	O
increased	O
in	O
nephrotic	B-Disease
mice	O
of	O
both	O
genotypes	O
and	O
was	O
followed	O
by	O
increased	O
SGK1	O
protein	O
expression	O
in	O
sgk1	O
(	O
+	O
/	O
+	O
)	O
mice	O
.	O

Urinary	O
sodium	B-Chemical
excretion	O
reached	O
signficantly	O
lower	O
values	O
in	O
sgk1	O
(	O
+	O
/	O
+	O
)	O
mice	O
(	O
15	O
+	O
/	O
-	O
5	O
mumol	O
/	O
mg	O
crea	O
)	O
than	O
in	O
sgk1	O
(	O
-	O
/	O
-	O
)	O
mice	O
(	O
35	O
+	O
/	O
-	O
5	O
mumol	O
/	O
mg	O
crea	O
)	O
and	O
was	O
associated	O
with	O
a	O
significantly	O
higher	O
body	O
weight	B-Disease
gain	I-Disease
in	O
sgk1	O
(	O
+	O
/	O
+	O
)	O
compared	O
with	O
sgk1	O
(	O
-	O
/	O
-	O
)	O
mice	O
(	O
+	O
6	O
.	O
6	O
+	O
/	O
-	O
0	O
.	O
7	O
vs	O
.	O
+	O
4	O
.	O
1	O
+	O
/	O
-	O
0	O
.	O
8	O
g	O
)	O
.	O

During	O
the	O
course	O
of	O
nephrotic	B-Disease
syndrome	I-Disease
,	O
serum	O
urea	B-Chemical
concentrations	O
increased	O
significantly	O
faster	O
in	O
sgk1	O
(	O
-	O
/	O
-	O
)	O
mice	O
than	O
in	O
sgk1	O
(	O
+	O
/	O
+	O
)	O
mice	O
leading	O
to	O
uremia	B-Disease
and	O
a	O
reduced	O
median	O
survival	O
in	O
sgk1	O
(	O
-	O
/	O
-	O
)	O
mice	O
(	O
29	O
vs	O
.	O
40	O
days	O
in	O
sgk1	O
(	O
+	O
/	O
+	O
)	O
mice	O
)	O
.	O

In	O
conclusion	O
,	O
gene	O
-	O
targeted	O
mice	O
lacking	O
SGK1	O
showed	O
blunted	O
volume	B-Disease
retention	I-Disease
,	O
yet	O
were	O
not	O
protected	O
against	O
renal	O
fibrosis	B-Disease
during	O
experimental	O
nephrotic	B-Disease
syndrome	I-Disease
.	O

Severe	O
thrombocytopenia	B-Disease
and	O
haemolytic	B-Disease
anaemia	I-Disease
associated	O
with	O
ciprofloxacin	B-Chemical
:	O
a	O
case	O
report	O
with	O
fatal	O
outcome	O
.	O

Haematological	O
adverse	O
reactions	O
associated	O
with	O
fatal	O
outcome	O
are	O
rare	O
during	O
treatment	O
with	O
ciprofloxacin	B-Chemical
.	O

A	O
30	O
-	O
year	O
old	O
Caucasian	O
man	O
reported	O
with	O
abdominal	B-Disease
pain	I-Disease
and	O
jaundice	B-Disease
after	O
3	O
-	O
day	O
administration	O
of	O
oral	O
ciprofloxacin	B-Chemical
for	O
a	O
suspect	O
of	O
urinary	B-Disease
tract	I-Disease
infection	I-Disease
.	O

Clinical	O
evaluations	O
suggested	O
an	O
initial	O
diagnosis	O
of	O
severe	O
thrombocytopenia	B-Disease
and	O
haemolysis	B-Disease
.	O

The	O
patient	O
progressively	O
developed	O
petechiae	B-Disease
and	O
purpura	B-Disease
on	O
thorax	O
and	O
lower	O
limbs	O
.	O

Despite	O
pharmacological	O
and	O
supportive	O
interventions	O
,	O
laboratory	O
parameters	O
worsened	O
and	O
the	O
patient	O
died	O
17	O
hours	O
after	O
admission	O
.	O

An	O
accurate	O
autopsy	O
revealed	O
most	O
organs	O
with	O
diffuse	O
petechial	O
haemorrhages	B-Disease
.	O

No	O
signs	O
of	O
bone	B-Disease
marrow	I-Disease
depression	I-Disease
were	O
found	O
.	O

No	O
thrombi	B-Disease
or	O
signs	O
of	O
microangiopathies	B-Disease
were	O
observed	O
in	O
arterial	O
vessels	O
.	O

Blood	O
and	O
urine	O
cultures	O
did	O
not	O
show	O
any	O
bacterial	O
growth	O
.	O

This	O
case	O
report	O
shows	O
that	O
ciprofloxacin	B-Chemical
may	O
precipitate	O
life	O
-	O
threatening	O
thrombocytopenia	B-Disease
and	O
haemolytic	B-Disease
anaemia	I-Disease
,	O
even	O
in	O
the	O
early	O
phases	O
of	O
treatment	O
and	O
without	O
apparent	O
previous	O
exposures	O
.	O

Alpha	B-Chemical
-	I-Chemical
lipoic	I-Chemical
acid	I-Chemical
prevents	O
mitochondrial	B-Disease
damage	I-Disease
and	O
neurotoxicity	B-Disease
in	O
experimental	O
chemotherapy	O
neuropathy	B-Disease
.	O

The	O
study	O
investigates	O
if	O
alpha	B-Chemical
-	I-Chemical
lipoic	I-Chemical
acid	I-Chemical
is	O
neuroprotective	O
against	O
chemotherapy	O
induced	O
neurotoxicity	B-Disease
,	O
if	O
mitochondrial	B-Disease
damage	I-Disease
plays	O
a	O
critical	O
role	O
in	O
toxic	B-Disease
neurodegenerative	I-Disease
cascade	I-Disease
,	O
and	O
if	O
neuroprotective	O
effects	O
of	O
alpha	B-Chemical
-	I-Chemical
lipoic	I-Chemical
acid	I-Chemical
depend	O
on	O
mitochondria	O
protection	O
.	O

We	O
used	O
an	O
in	O
vitro	O
model	O
of	O
chemotherapy	O
induced	O
peripheral	B-Disease
neuropathy	I-Disease
that	O
closely	O
mimic	O
the	O
in	O
vivo	O
condition	O
by	O
exposing	O
primary	O
cultures	O
of	O
dorsal	O
root	O
ganglion	O
(	O
DRG	O
)	O
sensory	O
neurons	O
to	O
paclitaxel	B-Chemical
and	O
cisplatin	B-Chemical
,	O
two	O
widely	O
used	O
and	O
highly	O
effective	O
chemotherapeutic	O
drugs	O
.	O

This	O
approach	O
allowed	O
investigating	O
the	O
efficacy	O
of	O
alpha	B-Chemical
-	I-Chemical
lipoic	I-Chemical
acid	I-Chemical
in	O
preventing	O
axonal	B-Disease
damage	I-Disease
and	O
apoptosis	O
and	O
the	O
function	O
and	O
ultrastructural	O
morphology	O
of	O
mitochondria	O
after	O
exposure	O
to	O
toxic	O
agents	O
and	O
alpha	B-Chemical
-	I-Chemical
lipoic	I-Chemical
acid	I-Chemical
.	O

Our	O
results	O
demonstrate	O
that	O
both	O
cisplatin	B-Chemical
and	O
paclitaxel	B-Chemical
cause	O
early	O
mitochondrial	B-Disease
impairment	I-Disease
with	O
loss	O
of	O
membrane	O
potential	O
and	O
induction	O
of	O
autophagic	O
vacuoles	O
in	O
neurons	O
.	O

Alpha	B-Chemical
-	I-Chemical
lipoic	I-Chemical
acid	I-Chemical
exerts	O
neuroprotective	O
effects	O
against	O
chemotherapy	O
induced	O
neurotoxicity	B-Disease
in	O
sensory	O
neurons	O
:	O
it	O
rescues	O
the	O
mitochondrial	B-Disease
toxicity	I-Disease
and	O
induces	O
the	O
expression	O
of	O
frataxin	O
,	O
an	O
essential	O
mitochondrial	O
protein	O
with	O
anti	O
-	O
oxidant	O
and	O
chaperone	O
properties	O
.	O

In	O
conclusion	O
mitochondrial	B-Disease
toxicity	I-Disease
is	O
an	O
early	O
common	O
event	O
both	O
in	O
paclitaxel	B-Chemical
and	O
cisplatin	B-Chemical
induced	O
neurotoxicity	B-Disease
.	O

Alpha	B-Chemical
-	I-Chemical
lipoic	I-Chemical
acid	I-Chemical
protects	O
sensory	O
neurons	O
through	O
its	O
anti	O
-	O
oxidant	O
and	O
mitochondrial	O
regulatory	O
functions	O
,	O
possibly	O
inducing	O
the	O
expression	O
of	O
frataxin	O
.	O

These	O
findings	O
suggest	O
that	O
alpha	B-Chemical
-	I-Chemical
lipoic	I-Chemical
acid	I-Chemical
might	O
reduce	O
the	O
risk	O
of	O
developing	O
peripheral	B-Disease
nerve	I-Disease
toxicity	I-Disease
in	O
patients	O
undergoing	O
chemotherapy	O
and	O
encourage	O
further	O
confirmatory	O
clinical	O
trials	O
.	O

Toxicity	B-Disease
in	O
rhesus	O
monkeys	O
following	O
administration	O
of	O
the	O
8	B-Chemical
-	I-Chemical
aminoquinoline	I-Chemical
8	B-Chemical
-	I-Chemical
[	I-Chemical
(	I-Chemical
4	I-Chemical
-	I-Chemical
amino	I-Chemical
-	I-Chemical
l	I-Chemical
-	I-Chemical
methylbutyl	I-Chemical
)	I-Chemical
amino	I-Chemical
]	I-Chemical
-	I-Chemical
5	I-Chemical
-	I-Chemical
(	I-Chemical
l	I-Chemical
-	I-Chemical
hexyloxy	I-Chemical
)	I-Chemical
-	I-Chemical
6	I-Chemical
-	I-Chemical
methoxy	I-Chemical
-	I-Chemical
4	I-Chemical
-	I-Chemical
methylquinoline	I-Chemical
(	O
WR242511	B-Chemical
)	O
.	O

INTRODUCTION	O
:	O
Many	O
substances	O
that	O
form	O
methemoglobin	O
(	O
MHb	O
)	O
effectively	O
counter	O
cyanide	O
(	O
CN	O
)	O
toxicity	B-Disease
.	O

Although	O
MHb	O
formers	O
are	O
generally	O
applied	O
as	O
treatments	O
for	O
CN	O
poisoning	B-Disease
,	O
it	O
has	O
been	O
proposed	O
that	O
a	O
stable	O
,	O
long	O
-	O
acting	O
MHb	O
former	O
could	O
serve	O
as	O
a	O
CN	O
pretreatment	O
.	O

Using	O
this	O
rationale	O
,	O
the	O
8	B-Chemical
-	I-Chemical
aminoquinoline	I-Chemical
WR242511	B-Chemical
,	O
a	O
potent	O
long	O
-	O
lasting	O
MHb	O
former	O
in	O
rodents	O
and	O
beagle	O
dogs	O
,	O
was	O
studied	O
in	O
the	O
rhesus	O
monkey	O
for	O
advanced	O
development	O
as	O
a	O
potential	O
CN	O
pretreatment	O
.	O

METHODS	O
:	O
In	O
this	O
study	O
,	O
WR242511	B-Chemical
was	O
administered	O
intravenously	O
(	O
IV	O
)	O
in	O
2	O
female	O
and	O
4	O
male	O
rhesus	O
monkeys	O
in	O
doses	O
of	O
3	O
.	O
5	O
and	O
/	O
or	O
7	O
.	O
0	O
mg	O
/	O
kg	O
;	O
a	O
single	O
male	O
also	O
received	O
WR242511	B-Chemical
orally	O
(	O
PO	O
)	O
at	O
7	O
.	O
0	O
mg	O
/	O
kg	O
.	O

Health	O
status	O
and	O
MHb	O
levels	O
were	O
monitored	O
following	O
exposure	O
.	O

RESULTS	O
:	O
The	O
selected	O
doses	O
of	O
WR242511	B-Chemical
,	O
which	O
produced	O
significant	O
methemoglobinemia	B-Disease
in	O
beagle	O
dogs	O
in	O
earlier	O
studies	O
conducted	O
elsewhere	O
,	O
produced	O
very	O
little	O
MHb	O
(	O
mean	O
<	O
2	O
.	O
0	O
%	O
)	O
in	O
the	O
rhesus	O
monkey	O
.	O

Furthermore	O
,	O
transient	O
hemoglobinuria	B-Disease
was	O
noted	O
approximately	O
60	O
minutes	O
postinjection	O
of	O
WR242511	B-Chemical
(	O
3	O
.	O
5	O
or	O
7	O
.	O
0	O
mg	O
/	O
kg	O
)	O
,	O
and	O
2	O
lethalities	O
occurred	O
(	O
one	O
IV	O
and	O
one	O
PO	O
)	O
following	O
the	O
7	O
.	O
0	O
mg	O
/	O
kg	O
dose	O
.	O

Myoglobinuria	B-Disease
was	O
also	O
observed	O
following	O
the	O
7	O
.	O
0	O
mg	O
/	O
kg	O
dose	O
.	O

Histopathology	O
analyses	O
in	O
the	O
2	O
animals	O
that	O
died	O
revealed	O
liver	B-Disease
and	I-Disease
kidney	I-Disease
toxicity	I-Disease
,	O
with	O
greater	O
severity	O
in	O
the	O
orally	O
-	O
treated	O
animal	O
.	O

CONCLUSIONS	O
:	O
These	O
data	O
demonstrate	O
direct	O
and	O
/	O
or	O
indirect	O
drug	O
-	O
induced	O
toxicity	B-Disease
.	O

It	O
is	O
concluded	O
that	O
WR242511	B-Chemical
should	O
not	O
be	O
pursued	O
as	O
a	O
pretreatment	O
for	O
CN	O
poisoning	B-Disease
unless	O
the	O
anti	O
-	O
CN	O
characteristics	O
of	O
this	O
compound	O
can	O
be	O
successfully	O
dissociated	O
from	O
those	O
producing	O
undesirable	O
toxicity	B-Disease
.	O

Repetitive	O
transcranial	O
magnetic	O
stimulation	O
for	O
levodopa	B-Chemical
-	O
induced	O
dyskinesias	B-Disease
in	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
.	O

In	O
a	O
placebo	O
-	O
controlled	O
,	O
single	O
-	O
blinded	O
,	O
crossover	O
study	O
,	O
we	O
assessed	O
the	O
effect	O
of	O
"	O
real	O
"	O
repetitive	O
transcranial	O
magnetic	O
stimulation	O
(	O
rTMS	O
)	O
versus	O
"	O
sham	O
"	O
rTMS	O
(	O
placebo	O
)	O
on	O
peak	O
dose	O
dyskinesias	B-Disease
in	O
patients	O
with	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
(	O
PD	B-Disease
)	O
.	O

Ten	O
patients	O
with	O
PD	B-Disease
and	O
prominent	O
dyskinesias	B-Disease
had	O
rTMS	O
(	O
1	O
,	O
800	O
pulses	O
;	O
1	O
Hz	O
rate	O
)	O
delivered	O
over	O
the	O
motor	O
cortex	O
for	O
4	O
consecutive	O
days	O
twice	O
,	O
once	O
real	O
stimuli	O
and	O
once	O
sham	O
stimulation	O
were	O
used	O
;	O
evaluations	O
were	O
done	O
at	O
the	O
baseline	O
and	O
1	O
day	O
after	O
the	O
end	O
of	O
each	O
of	O
the	O
treatment	O
series	O
.	O

Direct	O
comparison	O
between	O
sham	O
and	O
real	O
rTMS	O
effects	O
showed	O
no	O
significant	O
difference	O
in	O
clinician	O
-	O
assessed	O
dyskinesia	B-Disease
severity	O
.	O

However	O
,	O
comparison	O
with	O
the	O
baseline	O
showed	O
small	O
but	O
significant	O
reduction	O
in	O
dyskinesia	B-Disease
severity	O
following	O
real	O
rTMS	O
but	O
not	O
placebo	O
.	O

The	O
major	O
effect	O
was	O
on	O
dystonia	B-Disease
subscore	O
.	O

Similarly	O
,	O
in	O
patient	O
diaries	O
,	O
although	O
both	O
treatments	O
caused	O
reduction	O
in	O
subjective	O
dyskinesia	B-Disease
scores	O
during	O
the	O
days	O
of	O
intervention	O
,	O
the	O
effect	O
was	O
sustained	O
for	O
3	O
days	O
after	O
the	O
intervention	O
for	O
the	O
real	O
rTMS	O
only	O
.	O

Following	O
rTMS	O
,	O
no	O
side	O
effects	O
and	O
no	O
adverse	O
effects	O
on	O
motor	O
function	O
and	O
PD	B-Disease
symptoms	O
were	O
noted	O
.	O

The	O
results	O
suggest	O
the	O
existence	O
of	O
residual	O
beneficial	O
clinical	O
aftereffects	O
of	O
consecutive	O
daily	O
applications	O
of	O
low	O
-	O
frequency	O
rTMS	O
on	O
dyskinesias	B-Disease
in	O
PD	B-Disease
.	O

The	O
effects	O
may	O
be	O
further	O
exploited	O
for	O
potential	O
therapeutic	O
uses	O
.	O

Intracavernous	O
epinephrine	B-Chemical
:	O
a	O
minimally	O
invasive	O
treatment	O
for	O
priapism	B-Disease
in	O
the	O
emergency	O
department	O
.	O

Priapism	B-Disease
is	O
the	O
prolonged	O
erection	O
of	O
the	O
penis	O
in	O
the	O
absence	O
of	O
sexual	O
arousal	O
.	O

A	O
45	O
-	O
year	O
-	O
old	O
man	O
,	O
an	O
admitted	O
frequent	O
cocaine	B-Chemical
user	O
,	O
presented	O
to	O
the	O
Emergency	O
Department	O
(	O
ED	O
)	O
on	O
two	O
separate	O
occasions	O
with	O
a	O
history	O
of	O
priapism	B-Disease
after	O
cocaine	B-Chemical
use	O
.	O

The	O
management	O
options	O
in	O
the	O
ED	O
,	O
as	O
exemplified	O
by	O
four	O
individual	O
case	O
reports	O
,	O
in	O
particular	O
the	O
use	O
of	O
a	O
minimally	O
invasive	O
method	O
of	O
intracorporal	O
epinephrine	B-Chemical
instillation	O
,	O
are	O
discussed	O
.	O

Prophylactic	O
use	O
of	O
lamivudine	B-Chemical
with	O
chronic	O
immunosuppressive	O
therapy	O
for	O
rheumatologic	B-Disease
disorders	I-Disease
.	O

The	O
objective	O
of	O
this	O
study	O
was	O
to	O
report	O
our	O
experience	O
concerning	O
the	O
effectiveness	O
of	O
the	O
prophylactic	O
administration	O
of	O
lamivudine	B-Chemical
in	O
hepatitis	B-Chemical
B	I-Chemical
virus	I-Chemical
surface	I-Chemical
antigen	I-Chemical
(	O
HBs	B-Chemical
Ag	I-Chemical
)	O
positive	O
patients	O
with	O
rheumatologic	B-Disease
disease	I-Disease
.	O

From	O
June	O
2004	O
to	O
October	O
2006	O
,	O
11	O
HBs	B-Chemical
Ag	I-Chemical
positive	O
patients	O
with	O
rheumatologic	B-Disease
diseases	I-Disease
,	O
who	O
were	O
on	O
both	O
immunosuppressive	O
and	O
prophylactic	O
lamivudine	B-Chemical
therapies	O
,	O
were	O
retrospectively	O
assessed	O
.	O

Liver	O
function	O
tests	O
,	O
hepatitis	B-Disease
B	I-Disease
virus	O
(	O
HBV	O
)	O
serologic	O
markers	O
,	O
and	O
HBV	O
DNA	O
levels	O
of	O
the	O
patients	O
during	O
follow	O
-	O
up	O
were	O
obtained	O
from	O
hospital	O
file	O
records	O
.	O

Eleven	O
patients	O
(	O
six	O
male	O
)	O
with	O
median	O
age	O
47	O
years	O
(	O
range	O
27	O
-	O
73	O
)	O
,	O
median	O
disease	O
duration	O
50	O
months	O
(	O
range	O
9	O
-	O
178	O
)	O
and	O
median	O
follow	O
-	O
up	O
period	O
of	O
patients	O
13	O
.	O
8	O
months	O
(	O
range	O
5	O
-	O
27	O
)	O
were	O
enrolled	O
in	O
this	O
study	O
.	O

Lamivudine	B-Chemical
therapy	O
was	O
started	O
3	O
-	O
7	O
days	O
prior	O
to	O
immunosuppressive	O
therapy	O
in	O
all	O
patients	O
.	O

Baseline	O
,	O
liver	O
function	O
tests	O
were	O
elevated	O
in	O
two	O
patients	O
(	O
fourth	O
patient	O
:	O
ALT	O
:	O
122	O
IU	O
/	O
l	O
,	O
AST	O
:	O
111	O
IU	O
/	O
l	O
,	O
tenth	O
patient	O
:	O
ALT	O
:	O
294	O
IU	O
/	O
l	O
,	O
AST	O
:	O
274	O
IU	O
/	O
l	O
,	O
with	O
minimal	O
changes	O
in	O
the	O
liver	O
biopsy	O
in	O
both	O
)	O
.	O

Shortly	O
after	O
treatment	O
their	O
tests	O
normalized	O
and	O
during	O
follow	O
-	O
up	O
period	O
none	O
of	O
the	O
patients	O
had	O
abnormal	B-Disease
liver	I-Disease
function	I-Disease
tests	O
.	O

In	O
four	O
patients	O
HBV	O
DNA	O
levels	O
were	O
higher	O
than	O
normal	O
at	O
baseline	O
.	O

Two	O
of	O
these	O
normalized	O
and	O
the	O
others	O
increased	O
later	O
.	O

In	O
three	O
additional	O
patients	O
,	O
HBV	O
DNA	O
levels	O
were	O
increased	O
during	O
follow	O
-	O
up	O
.	O

None	O
of	O
the	O
patients	O
had	O
significant	O
clinical	O
sings	O
of	O
HBV	O
activation	O
.	O

Lamivudine	B-Chemical
was	O
well	O
tolerated	O
and	O
was	O
continued	O
in	O
all	O
patients	O
.	O

Prophylactic	O
administration	O
of	O
lamivudine	B-Chemical
in	O
patients	O
who	O
required	O
immunosuppressive	O
therapy	O
seems	O
to	O
be	O
safe	O
,	O
well	O
tolerated	O
and	O
effective	O
in	O
preventing	O
HBV	O
reactivation	O
.	O

Effect	O
of	O
green	B-Chemical
tea	I-Chemical
and	O
vitamin	B-Chemical
E	I-Chemical
combination	O
in	O
isoproterenol	B-Chemical
induced	O
myocardial	B-Disease
infarction	I-Disease
in	O
rats	O
.	O

The	O
present	O
study	O
was	O
aimed	O
to	O
investigate	O
the	O
combined	O
effects	O
of	O
green	B-Chemical
tea	I-Chemical
and	O
vitamin	B-Chemical
E	I-Chemical
on	O
heart	O
weight	O
,	O
body	O
weight	O
,	O
serum	O
marker	O
enzymes	O
,	O
lipid	O
peroxidation	O
,	O
endogenous	O
antioxidants	O
and	O
membrane	O
bound	O
ATPases	O
in	O
isoproterenol	B-Chemical
(	O
ISO	B-Chemical
)	O
-	O
induced	O
myocardial	B-Disease
infarction	I-Disease
in	O
rats	O
.	O

Adult	O
male	O
albino	O
rats	O
,	O
treated	O
with	O
ISO	B-Chemical
(	O
200	O
mg	O
/	O
kg	O
,	O
s	O
.	O
c	O
.	O
)	O
for	O
2	O
days	O
at	O
an	O
interval	O
of	O
24	O
h	O
caused	O
a	O
significant	O
(	O
P	O
<	O
0	O
.	O
05	O
)	O
elevation	O
of	O
heart	O
weight	O
,	O
serum	O
marker	O
enzymes	O
,	O
lipid	O
peroxidation	O
and	O
Ca	B-Chemical
+	O
2	O
ATPase	O
level	O
whereas	O
there	O
was	O
a	O
significant	O
(	O
P	O
<	O
0	O
.	O
05	O
)	O
decrease	O
in	O
body	O
weight	O
,	O
endogenous	O
antioxidants	O
,	O
Na	B-Chemical
+	O
/	O
K	B-Chemical
+	O
ATPase	O
and	O
Mg	B-Chemical
+	O
2	O
ATPase	O
levels	O
.	O

Administration	O
of	O
green	B-Chemical
tea	I-Chemical
(	O
100	O
mg	O
/	O
kg	O
/	O
day	O
,	O
p	O
.	O
o	O
.	O
)	O
and	O
vitamin	B-Chemical
E	I-Chemical
(	O
100	O
mg	O
/	O
kg	O
/	O
day	O
,	O
p	O
.	O
o	O
.	O
)	O
together	O
for	O
30	O
consecutive	O
days	O
and	O
challenged	O
with	O
ISO	B-Chemical
on	O
the	O
day	O
29th	O
and	O
30th	O
,	O
showed	O
a	O
significant	O
(	O
P	O
<	O
0	O
.	O
05	O
)	O
decrease	O
in	O
heart	O
weight	O
,	O
serum	O
marker	O
enzymes	O
,	O
lipid	O
peroxidation	O
,	O
Ca	B-Chemical
+	O
2	O
ATPase	O
and	O
a	O
significant	O
increase	O
in	O
the	O
body	O
weight	O
,	O
endogenous	O
antioxidants	O
,	O
Na	B-Chemical
+	O
/	O
K	B-Chemical
+	O
ATPase	O
and	O
Mg	B-Chemical
+	O
2	O
ATPase	O
when	O
compared	O
with	O
ISO	B-Chemical
treated	O
group	O
and	O
green	B-Chemical
tea	I-Chemical
or	O
vitamin	B-Chemical
E	I-Chemical
alone	O
treated	O
groups	O
.	O

These	O
findings	O
indicate	O
the	O
synergistic	O
protective	O
effect	O
of	O
green	B-Chemical
tea	I-Chemical
and	O
vitamin	B-Chemical
E	I-Chemical
during	O
ISO	B-Chemical
induced	O
myocardial	B-Disease
infarction	I-Disease
in	O
rats	O
.	O

Irreversible	O
damage	O
to	O
the	O
medullary	O
interstitium	O
in	O
experimental	O
analgesic	O
nephropathy	B-Disease
in	O
F344	O
rats	O
.	O

Renal	B-Disease
papillary	I-Disease
necrosis	I-Disease
(	O
RPN	B-Disease
)	O
and	O
a	O
decreased	O
urinary	O
concentrating	O
ability	O
developed	O
during	O
continuous	O
long	O
-	O
term	O
treatment	O
with	O
aspirin	B-Chemical
and	O
paracetamol	B-Chemical
in	O
female	O
Fischer	O
344	O
rats	O
.	O

Renal	O
structure	O
and	O
concentrating	O
ability	O
were	O
examined	O
after	O
a	O
recovery	O
period	O
of	O
up	O
to	O
18	O
weeks	O
,	O
when	O
no	O
analgesics	O
were	O
given	O
,	O
to	O
investigate	O
whether	O
the	O
analgesic	O
-	O
induced	O
changes	O
were	O
reversible	O
.	O

There	O
was	O
no	O
evidence	O
of	O
repair	O
to	O
the	O
damaged	O
medullary	O
interstitial	O
matrix	O
,	O
or	O
proliferation	O
of	O
remaining	O
undamaged	O
type	O
1	O
medullary	O
interstitial	O
cells	O
after	O
the	O
recovery	O
period	O
following	O
analgesic	O
treatment	O
.	O

The	O
recovery	O
of	O
urinary	O
concentrating	O
ability	O
was	O
related	O
to	O
the	O
length	O
of	O
analgesic	O
treatment	O
and	O
the	O
extent	O
of	O
the	O
resulting	O
inner	O
medullary	O
structural	O
damage	O
.	O

During	O
the	O
early	O
stages	O
of	O
analgesic	O
treatment	O
,	O
the	O
changes	O
in	O
urinary	O
concentrating	O
ability	O
were	O
reversible	O
,	O
but	O
after	O
prolonged	O
analgesic	O
treatment	O
,	O
maximum	O
urinary	O
concentrating	O
ability	O
failed	O
to	O
recover	O
.	O

This	O
study	O
shows	O
that	O
prolonged	O
analgesic	O
treatment	O
in	O
Fischer	O
344	O
rats	O
causes	O
progressive	O
and	O
irreversible	O
damage	O
to	O
the	O
interstitial	O
matrix	O
and	O
type	O
1	O
interstitial	O
cells	O
leading	O
to	O
RPN	B-Disease
.	O

The	O
associated	O
urinary	O
concentrating	O
defect	O
is	O
reversible	O
only	O
during	O
the	O
early	O
stages	O
of	O
structural	O
damage	O
to	O
the	O
inner	O
medulla	O
.	O

Testosterone	B-Chemical
-	O
dependent	O
hypertension	B-Disease
and	O
upregulation	O
of	O
intrarenal	O
angiotensinogen	O
in	O
Dahl	O
salt	B-Chemical
-	O
sensitive	O
rats	O
.	O

Blood	O
pressure	O
(	O
BP	O
)	O
is	O
more	O
salt	B-Chemical
sensitive	O
in	O
men	O
than	O
in	O
premenopausal	O
women	O
.	O

In	O
Dahl	O
salt	B-Chemical
-	O
sensitive	O
rats	O
(	O
DS	O
)	O
,	O
high	O
-	O
salt	B-Chemical
(	O
HS	O
)	O
diet	O
increases	O
BP	O
more	O
in	O
males	O
than	O
females	O
.	O

In	O
contrast	O
to	O
the	O
systemic	O
renin	O
-	O
angiotensin	B-Chemical
system	O
,	O
which	O
is	O
suppressed	O
in	O
response	O
to	O
HS	O
in	O
male	O
DS	O
,	O
intrarenal	O
angiotensinogen	O
expression	O
is	O
increased	O
,	O
and	O
intrarenal	O
levels	O
of	O
ANG	O
II	O
are	O
not	O
suppressed	O
.	O

In	O
this	O
study	O
,	O
the	O
hypothesis	O
was	O
tested	O
that	O
there	O
is	O
a	O
sexual	O
dimorphism	O
in	O
HS	O
-	O
induced	O
upregulation	O
of	O
intrarenal	O
angiotensinogen	O
mediated	O
by	O
testosterone	B-Chemical
that	O
also	O
causes	O
increases	O
in	O
BP	O
and	O
renal	B-Disease
injury	I-Disease
.	O

On	O
a	O
low	O
-	O
salt	B-Chemical
(	O
LS	O
)	O
diet	O
,	O
male	O
DS	O
had	O
higher	O
levels	O
of	O
intrarenal	O
angiotensinogen	O
mRNA	O
than	O
females	O
.	O

HS	O
diet	O
for	O
4	O
wk	O
increased	O
renal	O
cortical	O
angiotensinogen	O
mRNA	O
and	O
protein	O
only	O
in	O
male	O
DS	O
,	O
which	O
was	O
prevented	O
by	O
castration	O
.	O

Ovariectomy	O
of	O
female	O
DS	O
had	O
no	O
effect	O
on	O
intrarenal	O
angiotensinogen	O
expression	O
on	O
either	O
diet	O
.	O

Radiotelemetric	O
BP	O
was	O
similar	O
between	O
males	O
and	O
castrated	O
rats	O
on	O
LS	O
diet	O
.	O

HS	O
diet	O
for	O
4	O
wk	O
caused	O
a	O
progressive	O
increase	O
in	O
BP	O
,	O
protein	O
and	O
albumin	O
excretion	O
,	O
and	O
glomerular	B-Disease
sclerosis	I-Disease
in	O
male	O
DS	O
rats	O
,	O
which	O
were	O
attenuated	O
by	O
castration	O
.	O

Testosterone	B-Chemical
replacement	O
in	O
castrated	O
DS	O
rats	O
increased	O
BP	O
,	O
renal	B-Disease
injury	I-Disease
,	O
and	O
upregulation	O
of	O
renal	O
angiotensinogen	O
associated	O
with	O
HS	O
diet	O
.	O

Testosterone	B-Chemical
contributes	O
to	O
the	O
development	O
of	O
hypertension	B-Disease
and	O
renal	B-Disease
injury	I-Disease
in	O
male	O
DS	O
rats	O
on	O
HS	O
diet	O
possibly	O
through	O
upregulation	O
of	O
the	O
intrarenal	O
renin	O
-	O
angiotensin	B-Chemical
system	O
.	O

Explicit	O
episodic	O
memory	O
for	O
sensory	O
-	O
discriminative	O
components	O
of	O
capsaicin	B-Chemical
-	O
induced	O
pain	B-Disease
:	O
immediate	O
and	O
delayed	O
ratings	O
.	O

Pain	B-Disease
memory	O
is	O
thought	O
to	O
affect	O
future	O
pain	B-Disease
sensitivity	O
and	O
thus	O
contribute	O
to	O
clinical	O
pain	B-Disease
conditions	O
.	O

Systematic	O
investigations	O
of	O
the	O
human	O
capacity	O
to	O
remember	O
sensory	O
features	O
of	O
experimental	O
pain	B-Disease
are	O
sparse	O
.	O

In	O
order	O
to	O
address	O
long	O
-	O
term	O
pain	B-Disease
memory	O
,	O
nine	O
healthy	O
male	O
volunteers	O
received	O
intradermal	O
injections	O
of	O
three	O
doses	O
of	O
capsaicin	B-Chemical
(	O
0	O
.	O
05	O
,	O
1	O
and	O
20	O
microg	O
,	O
separated	O
by	O
15	O
min	O
breaks	O
)	O
,	O
each	O
given	O
three	O
times	O
in	O
a	O
balanced	O
design	O
across	O
three	O
sessions	O
at	O
one	O
week	O
intervals	O
.	O

Pain	B-Disease
rating	O
was	O
performed	O
using	O
a	O
computerized	O
visual	O
analogue	O
scale	O
(	O
0	O
-	O
100	O
)	O
digitized	O
at	O
1	O
/	O
s	O
,	O
either	O
immediately	O
online	O
or	O
one	O
hour	O
or	O
one	O
day	O
after	O
injection	O
.	O

Subjects	O
also	O
recalled	O
their	O
pains	B-Disease
one	O
week	O
later	O
.	O

Capsaicin	B-Chemical
injection	O
reliably	O
induced	O
a	O
dose	O
-	O
dependent	O
flare	O
(	O
p	O
<	O
0	O
.	O
001	O
)	O
without	O
any	O
difference	O
within	O
or	O
across	O
sessions	O
.	O

The	O
strong	O
burning	O
pain	B-Disease
decayed	O
exponentially	O
within	O
a	O
few	O
minutes	O
.	O

Subjects	O
were	O
able	O
to	O
reliably	O
discriminate	O
pain	B-Disease
magnitude	O
and	O
duration	O
across	O
capsaicin	B-Chemical
doses	O
(	O
both	O
p	O
<	O
0	O
.	O
001	O
)	O
,	O
regardless	O
of	O
whether	O
first	O
-	O
time	O
ratings	O
were	O
requested	O
immediately	O
,	O
after	O
one	O
hour	O
or	O
after	O
one	O
day	O
.	O

Pain	B-Disease
recall	O
after	O
one	O
week	O
was	O
similarly	O
precise	O
(	O
magnitude	O
:	O
p	O
<	O
0	O
.	O
01	O
,	O
duration	O
:	O
p	O
<	O
0	O
.	O
05	O
)	O
.	O

Correlation	O
with	O
rating	O
recall	O
after	O
one	O
week	O
was	O
best	O
when	O
first	O
-	O
time	O
ratings	O
were	O
requested	O
as	O
late	O
as	O
one	O
day	O
after	O
injection	O
(	O
R	O
(	O
2	O
)	O
=	O
0	O
.	O
79	O
)	O
indicating	O
that	O
both	O
rating	O
retrievals	O
utilized	O
similar	O
memory	O
traces	O
.	O

These	O
results	O
indicate	O
a	O
reliable	O
memory	O
for	O
magnitude	O
and	O
duration	O
of	O
experimentally	O
induced	O
pain	B-Disease
.	O

The	O
data	O
further	O
suggest	O
that	O
the	O
consolidation	O
of	O
this	O
memory	O
is	O
an	O
important	O
interim	O
stage	O
,	O
and	O
may	O
take	O
up	O
to	O
one	O
day	O
.	O

Severe	O
and	O
long	O
lasting	O
cholestasis	B-Disease
after	O
high	O
-	O
dose	O
co	B-Chemical
-	I-Chemical
trimoxazole	I-Chemical
treatment	O
for	O
Pneumocystis	B-Disease
pneumonia	I-Disease
in	O
HIV	B-Disease
-	I-Disease
infected	I-Disease
patients	O
-	O
-	O
a	O
report	O
of	O
two	O
cases	O
.	O

Pneumocystis	B-Disease
pneumonia	I-Disease
(	O
PCP	B-Disease
)	O
,	O
a	O
common	O
opportunistic	B-Disease
infection	I-Disease
in	O
HIV	B-Disease
-	I-Disease
infected	I-Disease
individuals	O
,	O
is	O
generally	O
treated	O
with	O
high	O
doses	O
of	O
co	B-Chemical
-	I-Chemical
trimoxazole	I-Chemical
.	O

However	O
,	O
treatment	O
is	O
often	O
limited	O
by	O
adverse	O
effects	O
.	O

Here	O
,	O
we	O
report	O
two	O
cases	O
of	O
severely	O
immunocompromised	O
HIV	B-Disease
-	I-Disease
infected	I-Disease
patients	O
who	O
developed	O
severe	O
intrahepatic	B-Disease
cholestasis	I-Disease
,	O
and	O
in	O
one	O
patient	O
lesions	O
mimicking	O
liver	B-Disease
abscess	I-Disease
formation	O
on	O
radiologic	O
exams	O
,	O
during	O
co	B-Chemical
-	I-Chemical
trimoxazole	I-Chemical
treatment	O
for	O
PCP	B-Disease
.	O

Whereas	O
patient	O
1	O
showed	O
lesions	O
of	O
up	O
to	O
1	O
cm	O
readily	O
detectable	O
on	O
magnetic	O
resonance	O
imaging	O
under	O
prolonged	O
co	B-Chemical
-	I-Chemical
trimoxazole	I-Chemical
treatment	O
,	O
therapy	O
of	O
patient	O
2	O
was	O
switched	O
early	O
.	O

Bradykinin	B-Chemical
receptors	O
antagonists	O
and	O
nitric	B-Chemical
oxide	I-Chemical
synthase	O
inhibitors	O
in	O
vincristine	B-Chemical
and	O
streptozotocin	B-Chemical
induced	O
hyperalgesia	B-Disease
in	O
chemotherapy	O
and	O
diabetic	B-Disease
neuropathy	I-Disease
rat	O
model	O
.	O

PURPOSE	O
:	O
The	O
influence	O
of	O
an	O
irreversible	O
inhibitor	O
of	O
constitutive	O
NO	B-Chemical
synthase	O
(	O
L	O
-	O
NOArg	O
;	O
1	O
.	O
0	O
mg	O
/	O
kg	O
ip	O
)	O
,	O
a	O
relatively	O
selective	O
inhibitor	O
of	O
inducible	O
NO	B-Chemical
synthase	O
(	O
L	O
-	O
NIL	O
;	O
1	O
.	O
0	O
mg	O
/	O
kg	O
ip	O
)	O
and	O
a	O
relatively	O
specific	O
inhibitor	O
of	O
neuronal	O
NO	B-Chemical
synthase	O
(	O
7	O
-	O
NI	O
;	O
0	O
.	O
1	O
mg	O
/	O
kg	O
ip	O
)	O
,	O
on	O
antihyperalgesic	O
action	O
of	O
selective	O
antagonists	O
of	O
B2	O
and	O
B1	O
receptors	O
:	O
D	O
-	O
Arg	O
-	O
[	O
Hyp3	O
,	O
Thi5	O
,	O
D	O
-	O
Tic7	O
,	O
Oic8	O
]	O
bradykinin	B-Chemical
(	O
HOE	B-Chemical
140	I-Chemical
;	O
70	O
nmol	O
/	O
kg	O
ip	O
)	O
or	O
des	B-Chemical
Arg10	I-Chemical
HOE	I-Chemical
140	I-Chemical
(	O
70	O
nmol	O
/	O
kg	O
ip	O
)	O
respectively	O
,	O
in	O
model	O
of	O
diabetic	B-Disease
(	I-Disease
streptozotocin	I-Disease
-	I-Disease
induced	I-Disease
)	I-Disease
and	I-Disease
toxic	I-Disease
(	I-Disease
vincristine	I-Disease
-	I-Disease
induced	I-Disease
)	I-Disease
neuropathy	I-Disease
was	O
investigated	O
.	O

METHODS	O
:	O
The	O
changes	O
in	O
pain	B-Disease
thresholds	O
were	O
determined	O
using	O
mechanical	O
stimuli	O
-	O
-	O
the	O
modification	O
of	O
the	O
classic	O
paw	O
withdrawal	O
test	O
described	O
by	O
Randall	O
-	O
Selitto	O
.	O

RESULTS	O
:	O
The	O
results	O
of	O
this	O
paper	O
confirm	O
that	O
inhibition	O
of	O
bradykinin	B-Chemical
receptors	O
and	O
inducible	O
NO	B-Chemical
synthase	O
but	O
not	O
neuronal	O
NO	B-Chemical
synthase	O
activity	O
reduces	O
diabetic	B-Disease
hyperalgesia	I-Disease
.	O

Pretreatment	O
with	O
L	O
-	O
NOArg	O
and	O
L	O
-	O
NIL	O
but	O
not	O
7	O
-	O
NI	O
,	O
significantly	O
increases	O
antihyperalgesic	O
activity	O
both	O
HOE	B-Chemical
140	I-Chemical
and	O
des	B-Chemical
Arg10	I-Chemical
HOE	I-Chemical
140	I-Chemical
.	O

It	O
was	O
also	O
shown	O
that	O
both	O
products	O
of	O
inducible	O
NO	B-Chemical
synthase	O
and	O
neuronal	O
NO	B-Chemical
synthase	O
activation	O
as	O
well	O
as	O
bradykinin	B-Chemical
are	O
involved	O
in	O
hyperalgesia	B-Disease
produced	O
by	O
vincristine	B-Chemical
.	O

Moreover	O
,	O
L	O
-	O
NOArg	O
and	O
7	O
-	O
NI	O
but	O
not	O
L	O
-	O
NIL	O
intensify	O
antihyperalgesic	O
activity	O
of	O
HOE	B-Chemical
140	I-Chemical
or	O
des	B-Chemical
-	I-Chemical
Arg10HOE	I-Chemical
140	I-Chemical
in	O
toxic	B-Disease
neuropathy	I-Disease
.	O

CONCLUSIONS	O
:	O
Results	O
of	O
these	O
studies	O
suggest	O
that	O
B1	O
and	O
B2	O
receptors	O
are	O
engaged	O
in	O
transmission	O
of	O
nociceptive	O
stimuli	O
in	O
both	O
diabetic	B-Disease
and	I-Disease
toxic	I-Disease
neuropathy	I-Disease
.	O

In	O
streptozotocin	B-Chemical
-	O
induced	O
hyperalgesia	B-Disease
,	O
inducible	O
NO	B-Chemical
synthase	O
participates	O
in	O
pronociceptive	O
activity	O
of	O
bradykinin	B-Chemical
,	O
whereas	O
in	O
vincristine	B-Chemical
-	O
induced	O
hyperalgesia	B-Disease
bradykinin	B-Chemical
seemed	O
to	O
activate	O
neuronal	O
NO	B-Chemical
synthase	O
pathway	O
.	O

Therefore	O
,	O
concomitant	O
administration	O
of	O
small	O
doses	O
of	O
bradykinin	B-Chemical
receptor	O
antagonists	O
and	O
NO	B-Chemical
synthase	O
inhibitors	O
can	O
be	O
effective	O
in	O
alleviation	O
of	O
neuropathic	B-Disease
pain	I-Disease
,	O
even	O
in	O
hospital	O
care	O
.	O

Confusion	B-Disease
,	O
a	O
rather	O
serious	O
adverse	O
drug	O
reaction	O
with	O
valproic	B-Chemical
acid	I-Chemical
:	O
a	O
review	O
of	O
the	O
French	O
Pharmacovigilance	O
database	O
.	O

INTRODUCTION	O
:	O
Confusion	B-Disease
is	O
an	O
adverse	O
drug	O
reaction	O
frequently	O
observed	O
with	O
valproic	B-Chemical
acid	I-Chemical
.	O

Some	O
case	O
reports	O
are	O
published	O
in	O
the	O
literature	O
but	O
no	O
systematic	O
study	O
from	O
a	O
sample	O
of	O
patients	O
has	O
been	O
published	O
.	O

We	O
performed	O
this	O
study	O
in	O
order	O
to	O
describe	O
the	O
main	O
characteristics	O
of	O
this	O
adverse	O
drug	O
reaction	O
.	O

METHODS	O
:	O
Using	O
the	O
French	O
Pharmacovigilance	O
database	O
,	O
we	O
selected	O
the	O
cases	O
of	O
confusion	B-Disease
reported	O
since	O
1985	O
with	O
valproic	B-Chemical
acid	I-Chemical
.	O

RESULTS	O
:	O
272	O
cases	O
of	O
confusion	B-Disease
were	O
reported	O
with	O
valproic	B-Chemical
acid	I-Chemical
:	O
153	O
women	O
and	O
119	O
men	O
.	O

Confusion	B-Disease
mostly	O
occurred	O
during	O
the	O
two	O
first	O
weeks	O
following	O
valproic	B-Chemical
acid	I-Chemical
exposure	O
(	O
39	O
.	O
7	O
%	O
)	O
.	O

It	O
was	O
"	O
serious	O
"	O
for	O
almost	O
2	O
/	O
3	O
of	O
the	O
patients	O
(	O
62	O
.	O
5	O
%	O
)	O
and	O
its	O
outcome	O
favourable	O
in	O
most	O
of	O
the	O
cases	O
(	O
82	O
%	O
)	O
.	O

The	O
occurrence	O
of	O
this	O
ADR	O
was	O
more	O
frequent	O
in	O
patients	O
aged	O
between	O
61	O
and	O
80	O
years	O
.	O

CONCLUSION	O
:	O
This	O
work	O
shows	O
that	O
confusion	B-Disease
with	O
valproic	B-Chemical
acid	I-Chemical
is	O
a	O
serious	O
,	O
rather	O
frequent	O
but	O
reversible	O
adverse	O
drug	O
reaction	O
.	O

It	O
occurs	O
especially	O
in	O
older	O
patients	O
and	O
during	O
the	O
first	O
two	O
weeks	O
of	O
treatment	O
.	O

Reversible	O
inferior	B-Disease
colliculus	I-Disease
lesion	I-Disease
in	O
metronidazole	B-Chemical
-	O
induced	O
encephalopathy	B-Disease
:	O
magnetic	O
resonance	O
findings	O
on	O
diffusion	O
-	O
weighted	O
and	O
fluid	O
attenuated	O
inversion	O
recovery	O
imaging	O
.	O

OBJECTIVE	O
:	O
This	O
is	O
to	O
present	O
reversible	O
inferior	B-Disease
colliculus	I-Disease
lesions	I-Disease
in	O
metronidazole	B-Chemical
-	O
induced	O
encephalopathy	B-Disease
,	O
to	O
focus	O
on	O
the	O
diffusion	O
-	O
weighted	O
imaging	O
(	O
DWI	O
)	O
and	O
fluid	O
attenuated	O
inversion	O
recovery	O
(	O
FLAIR	O
)	O
imaging	O
.	O

MATERIALS	O
AND	O
METHODS	O
:	O
From	O
November	O
2005	O
to	O
September	O
2007	O
,	O
8	O
patients	O
(	O
5	O
men	O
and	O
3	O
women	O
)	O
were	O
diagnosed	O
as	O
having	O
metronidazole	B-Chemical
-	O
induced	O
encephalopathy	B-Disease
(	O
age	O
range	O
;	O
43	O
-	O
78	O
years	O
)	O
.	O

They	O
had	O
been	O
taking	O
metronidazole	B-Chemical
(	O
total	O
dosage	O
,	O
45	O
-	O
120	O
g	O
;	O
duration	O
,	O
30	O
days	O
to	O
2	O
months	O
)	O
to	O
treat	O
the	O
infection	B-Disease
in	O
various	O
organs	O
.	O

Initial	O
brain	O
magnetic	O
resonance	O
imaging	O
(	O
MRI	O
)	O
were	O
obtained	O
after	O
the	O
hospitalization	O
,	O
including	O
DWI	O
(	O
8	O
/	O
8	O
)	O
,	O
apparent	O
diffusion	O
coefficient	O
(	O
ADC	O
)	O
map	O
(	O
4	O
/	O
8	O
)	O
,	O
FLAIR	O
(	O
7	O
/	O
8	O
)	O
,	O
and	O
T2	O
-	O
weighted	O
image	O
(	O
8	O
/	O
8	O
)	O
.	O

Follow	O
-	O
up	O
MRIs	O
were	O
performed	O
on	O
5	O
patients	O
from	O
third	O
to	O
14th	O
days	O
after	O
discontinuation	O
of	O
metronidazole	B-Chemical
administration	O
.	O

Findings	O
of	O
initial	O
and	O
follow	O
-	O
up	O
MRIs	O
were	O
retrospectively	O
evaluated	O
by	O
2	O
neuroradiologists	O
by	O
consensus	O
,	O
to	O
analyze	O
the	O
presence	O
of	O
abnormal	O
signal	O
intensities	O
,	O
their	O
locations	O
,	O
and	O
signal	O
changes	O
on	O
follow	O
-	O
up	O
images	O
.	O

RESULTS	O
:	O
Initial	O
MRIs	O
showed	O
abnormal	O
high	O
signal	O
intensities	O
on	O
DWI	O
and	O
FLAIR	O
(	O
or	O
T2	O
-	O
weighted	O
image	O
)	O
at	O
the	O
dentate	O
nucleus	O
(	O
8	O
/	O
8	O
)	O
,	O
inferior	O
colliculus	O
(	O
6	O
/	O
8	O
)	O
,	O
corpus	O
callosum	O
(	O
2	O
/	O
8	O
)	O
,	O
pons	O
(	O
2	O
/	O
8	O
)	O
,	O
medulla	O
(	O
1	O
/	O
8	O
)	O
,	O
and	O
bilateral	O
cerebral	O
white	O
matter	O
(	O
1	O
/	O
8	O
)	O
.	O

High	O
-	O
signal	O
intensity	O
lesions	O
on	O
DWI	O
tended	O
to	O
show	O
low	O
signal	O
intensity	O
on	O
ADC	O
map	O
(	O
3	O
/	O
4	O
)	O
,	O
but	O
in	O
one	O
patient	O
,	O
high	O
signal	O
intensity	O
was	O
shown	O
at	O
bilateral	O
dentate	O
nuclei	O
on	O
not	O
only	O
DWI	O
but	O
also	O
ADC	O
map	O
.	O

All	O
the	O
lesions	O
in	O
dentate	O
,	O
inferior	O
colliculus	O
,	O
pons	O
,	O
and	O
medullas	O
had	O
been	O
resolved	O
completely	O
on	O
follow	O
-	O
up	O
MRIs	O
in	O
5	O
patients	O
,	O
but	O
in	O
1	O
patient	O
of	O
them	O
,	O
corpus	O
callosal	B-Disease
lesion	I-Disease
persisted	O
.	O

CONCLUSIONS	O
:	O
Reversible	O
inferior	B-Disease
colliculus	I-Disease
lesions	I-Disease
could	O
be	O
considered	O
as	O
the	O
characteristic	O
for	O
metronidazole	B-Chemical
-	O
induced	O
encephalopathy	B-Disease
,	O
next	O
to	O
the	O
dentate	O
nucleus	O
involvement	O
.	O

Clinically	O
significant	O
proteinuria	B-Disease
following	O
the	O
administration	O
of	O
sirolimus	B-Chemical
to	O
renal	O
transplant	O
recipients	O
.	O

BACKGROUND	O
:	O
Sirolimus	B-Chemical
is	O
the	O
latest	O
immunosuppressive	O
agent	O
used	O
to	O
prevent	O
rejection	O
,	O
and	O
may	O
have	O
less	O
nephrotoxicity	B-Disease
than	O
calcineurin	O
inhibitor	O
(	O
CNI	O
)	O
-	O
based	O
regimens	O
.	O

To	O
date	O
there	O
has	O
been	O
little	O
documentation	O
of	O
clinically	O
significant	O
proteinuria	B-Disease
linked	O
with	O
the	O
use	O
of	O
sirolimus	B-Chemical
.	O

We	O
have	O
encountered	O
several	O
patients	O
who	O
developed	O
substantial	O
proteinuria	B-Disease
associated	O
with	O
sirolimus	B-Chemical
use	O
.	O

In	O
each	O
patient	O
,	O
the	O
close	O
temporal	O
association	O
between	O
the	O
commencement	O
of	O
sirolimus	B-Chemical
therapy	O
and	O
proteinuria	B-Disease
implicated	O
sirolimus	B-Chemical
as	O
the	O
most	O
likely	O
etiology	O
of	O
the	O
proteinuria	B-Disease
.	O

METHODS	O
:	O
We	O
analyzed	O
the	O
clinical	O
and	O
laboratory	O
information	O
available	O
for	O
all	O
119	O
patients	O
transplanted	O
at	O
the	O
Washington	O
Hospital	O
Center	O
between	O
1999	O
-	O
2003	O
for	O
whom	O
sirolimus	B-Chemical
was	O
a	O
component	O
of	O
their	O
immunosuppressant	O
regimen	O
.	O

In	O
these	O
patients	O
,	O
the	O
magnitude	O
of	O
proteinuria	B-Disease
was	O
assessed	O
on	O
morning	O
urine	O
samples	O
by	O
turbidometric	O
measurement	O
or	O
random	O
urine	O
protein	O
:	O
creatinine	B-Chemical
ratios	O
,	O
an	O
estimate	O
of	O
grams	O
of	O
proteinuria	B-Disease
/	O
day	O
.	O

Laboratory	O
results	O
were	O
compared	O
between	O
prior	O
,	O
during	O
and	O
following	O
sirolimus	B-Chemical
use	O
.	O

RESULTS	O
:	O
Twenty	O
-	O
eight	O
patients	O
(	O
24	O
%	O
)	O
developed	O
increased	O
proteinuria	B-Disease
from	O
baseline	O
during	O
their	O
post	O
-	O
transplantation	O
course	O
.	O

In	O
21	O
patients	O
an	O
alternative	O
cause	O
of	O
proteinuria	B-Disease
was	O
either	O
obvious	O
or	O
insufficient	O
data	O
was	O
available	O
to	O
be	O
conclusive	O
.	O

In	O
7	O
of	O
the	O
28	O
patients	O
there	O
was	O
a	O
striking	O
temporal	O
association	O
between	O
the	O
initiation	O
of	O
sirolimus	B-Chemical
and	O
the	O
development	O
of	O
nephrotic	B-Disease
-	O
range	O
proteinuria	B-Disease
.	O

Proteinuria	B-Disease
correlated	O
most	O
strongly	O
with	O
sirolimus	B-Chemical
therapy	O
when	O
compared	O
to	O
other	O
demographic	O
and	O
clinical	O
variables	O
.	O

In	O
most	O
patients	O
,	O
discontinuation	O
of	O
sirolimus	B-Chemical
resulted	O
in	O
a	O
decrease	O
,	O
but	O
not	O
resolution	O
,	O
of	O
proteinuria	B-Disease
.	O

CONCLUSIONS	O
:	O
Sirolimus	B-Chemical
induces	O
or	O
aggravates	O
pre	O
-	O
existing	O
proteinuria	B-Disease
in	O
an	O
unpredictable	O
subset	O
of	O
renal	O
allograft	O
recipients	O
.	O

Proteinuria	B-Disease
may	O
improve	O
,	O
but	O
does	O
not	O
resolve	O
,	O
when	O
sirolimus	B-Chemical
is	O
withdrawn	O
.	O

Components	O
of	O
lemon	O
essential	O
oil	O
attenuate	O
dementia	B-Disease
induced	O
by	O
scopolamine	B-Chemical
.	O

The	O
anti	O
-	O
dementia	B-Disease
effects	O
of	O
s	B-Chemical
-	I-Chemical
limonene	I-Chemical
and	O
s	B-Chemical
-	I-Chemical
perillyl	I-Chemical
alcohol	I-Chemical
were	O
observed	O
using	O
the	O
passive	O
avoidance	O
test	O
(	O
PA	O
)	O
and	O
the	O
open	O
field	O
habituation	O
test	O
(	O
OFH	O
)	O
.	O

These	O
lemon	O
essential	O
oils	O
showed	O
strong	O
ability	O
to	O
improve	O
memory	B-Disease
impaired	I-Disease
by	O
scopolamine	B-Chemical
;	O
however	O
,	O
s	B-Chemical
-	I-Chemical
perillyl	I-Chemical
alcohol	I-Chemical
relieved	O
the	O
deficit	B-Disease
of	I-Disease
associative	I-Disease
memory	I-Disease
in	O
PA	O
only	O
,	O
and	O
did	O
not	O
improve	O
non	O
-	O
associative	O
memory	O
significantly	O
in	O
OFH	O
.	O

Analysis	O
of	O
neurotransmitter	O
concentration	O
in	O
some	O
brain	O
regions	O
on	O
the	O
test	O
day	O
showed	O
that	O
dopamine	B-Chemical
concentration	O
of	O
the	O
vehicle	O
/	O
scopolamine	B-Chemical
group	O
was	O
significantly	O
lower	O
than	O
that	O
of	O
the	O
vehicle	O
/	O
vehicle	O
group	O
,	O
but	O
this	O
phenomenon	O
was	O
reversed	O
when	O
s	B-Chemical
-	I-Chemical
limonene	I-Chemical
or	O
s	B-Chemical
-	I-Chemical
perillyl	I-Chemical
alcohol	I-Chemical
were	O
administered	O
before	O
the	O
injection	O
of	O
scopolamine	B-Chemical
.	O

Simultaneously	O
,	O
we	O
found	O
that	O
these	O
two	O
lemon	O
essential	O
oil	O
components	O
could	O
inhibit	O
acetylcholinesterase	O
activity	O
in	O
vitro	O
using	O
the	O
Ellman	O
method	O
.	O

Attentional	O
modulation	O
of	O
perceived	O
pain	B-Disease
intensity	O
in	O
capsaicin	B-Chemical
-	O
induced	O
secondary	O
hyperalgesia	B-Disease
.	O

Perceived	O
pain	B-Disease
intensity	O
is	O
modulated	O
by	O
attention	O
.	O

However	O
,	O
it	O
is	O
not	O
known	O
that	O
how	O
pain	B-Disease
intensity	O
ratings	O
are	O
affected	O
by	O
attention	O
in	O
capsaicin	B-Chemical
-	O
induced	O
secondary	O
hyperalgesia	B-Disease
.	O

Here	O
we	O
show	O
that	O
perceived	O
pain	B-Disease
intensity	O
in	O
secondary	O
hyperalgesia	B-Disease
is	O
decreased	O
when	O
attention	O
is	O
distracted	O
away	O
from	O
the	O
painful	O
pinprick	O
stimulus	O
with	O
a	O
visual	O
task	O
.	O

Furthermore	O
,	O
it	O
was	O
found	O
that	O
the	O
magnitude	O
of	O
attentional	O
modulation	O
in	O
secondary	O
hyperalgesia	B-Disease
is	O
very	O
similar	O
to	O
that	O
of	O
capsaicin	B-Chemical
-	O
untreated	O
,	O
control	O
condition	O
.	O

Our	O
findings	O
,	O
showing	O
no	O
interaction	O
between	O
capsaicin	B-Chemical
treatment	O
and	O
attentional	O
modulation	O
suggest	O
that	O
capsaicin	B-Chemical
-	O
induced	O
secondary	O
hyperalgesia	B-Disease
and	O
attention	O
might	O
affect	O
mechanical	O
pain	B-Disease
through	O
independent	O
mechanisms	O
.	O

Cardioprotective	O
effect	O
of	O
salvianolic	B-Chemical
acid	I-Chemical
A	I-Chemical
on	O
isoproterenol	B-Chemical
-	O
induced	O
myocardial	B-Disease
infarction	I-Disease
in	O
rats	O
.	O

The	O
present	O
study	O
was	O
designed	O
to	O
evaluate	O
the	O
cardioprotective	O
potential	O
of	O
salvianolic	B-Chemical
acid	I-Chemical
A	I-Chemical
on	O
isoproterenol	B-Chemical
-	O
induced	O
myocardial	B-Disease
infarction	I-Disease
in	O
rats	O
.	O

Hemodynamic	O
parameters	O
and	O
lead	O
II	O
electrocardiograph	O
were	O
monitored	O
and	O
recorded	O
continuously	O
.	O

Cardiac	O
marker	O
enzymes	O
and	O
antioxidative	O
parameters	O
in	O
serum	O
and	O
heart	O
tissues	O
were	O
measured	O
.	O

Assay	O
for	O
mitochondrial	O
respiratory	O
function	O
and	O
histopathological	O
examination	O
of	O
heart	O
tissues	O
were	O
performed	O
.	O

Isoproterenol	B-Chemical
-	O
treated	O
rats	O
showed	O
significant	O
increases	O
in	O
the	O
levels	O
of	O
lactate	B-Chemical
dehydrogenase	O
,	O
aspartate	B-Chemical
transaminase	O
,	O
creatine	B-Chemical
kinase	O
and	O
malondialdehyde	B-Chemical
and	O
significant	O
decreases	O
in	O
the	O
activities	O
of	O
superoxide	B-Chemical
dismutase	O
,	O
catalase	O
and	O
glutathione	B-Chemical
peroxidase	O
in	O
serum	O
and	O
heart	O
.	O

These	O
rats	O
also	O
showed	O
declines	O
in	O
left	O
ventricular	O
systolic	O
pressure	O
,	O
maximum	O
and	O
minimum	O
rate	O
of	O
developed	O
left	O
ventricular	O
pressure	O
,	O
and	O
elevation	O
of	O
left	O
ventricular	O
end	O
-	O
diastolic	O
pressure	O
and	O
ST	O
-	O
segment	O
.	O

In	O
addition	O
,	O
mitochondrial	O
respiratory	B-Disease
dysfunction	I-Disease
characterized	O
by	O
decreased	O
respiratory	O
control	O
ratio	O
and	O
ADP	B-Chemical
/	O
O	O
was	O
observed	O
in	O
isoproterenol	B-Chemical
-	O
treated	O
rats	O
.	O

Administration	O
of	O
salvianolic	B-Chemical
acid	I-Chemical
A	I-Chemical
for	O
a	O
period	O
of	O
8	O
days	O
significantly	O
attenuated	O
isoproterenol	B-Chemical
-	O
induced	O
cardiac	B-Disease
dysfunction	I-Disease
and	O
myocardial	B-Disease
injury	I-Disease
and	O
improved	O
mitochondrial	O
respiratory	O
function	O
.	O

The	O
protective	O
role	O
of	O
salvianolic	B-Chemical
acid	I-Chemical
A	I-Chemical
against	O
isoproterenol	B-Chemical
-	O
induced	O
myocardial	B-Disease
damage	I-Disease
was	O
further	O
confirmed	O
by	O
histopathological	O
examination	O
.	O

The	O
results	O
of	O
our	O
study	O
suggest	O
that	O
salvianolic	B-Chemical
acid	I-Chemical
A	I-Chemical
possessing	O
antioxidant	O
activity	O
has	O
a	O
significant	O
protective	O
effect	O
against	O
isoproterenol	B-Chemical
-	O
induced	O
myocardial	B-Disease
infarction	I-Disease
.	O

Long	O
-	O
term	O
glutamate	B-Chemical
supplementation	O
failed	O
to	O
protect	O
against	O
peripheral	B-Disease
neurotoxicity	I-Disease
of	O
paclitaxel	B-Chemical
.	O

Toxic	O
peripheral	B-Disease
neuropathy	I-Disease
is	O
still	O
a	O
significant	O
limiting	O
factor	O
for	O
chemotherapy	O
with	O
paclitaxel	B-Chemical
(	O
PAC	B-Chemical
)	O
,	O
although	O
glutamate	B-Chemical
and	O
its	O
closely	O
related	O
amino	B-Chemical
acid	I-Chemical
glutamine	B-Chemical
were	O
claimed	O
to	O
ameliorate	O
PAC	B-Chemical
neurotoxicity	B-Disease
.	O

This	O
pilot	O
trial	O
aimed	O
to	O
evaluate	O
the	O
role	O
of	O
glutamate	B-Chemical
supplementation	O
for	O
preventing	O
PAC	B-Chemical
-	O
induced	O
peripheral	B-Disease
neuropathy	I-Disease
in	O
a	O
randomized	O
,	O
placebo	O
-	O
controlled	O
,	O
double	O
-	O
blinded	O
clinical	O
and	O
electro	O
-	O
diagnostic	O
study	O
.	O

Forty	O
-	O
three	O
ovarian	B-Disease
cancer	I-Disease
patients	O
were	O
available	O
for	O
analysis	O
following	O
six	O
cycles	O
of	O
the	O
same	O
PAC	B-Chemical
-	O
containing	O
regimen	O
:	O
23	O
had	O
been	O
supplemented	O
by	O
glutamate	B-Chemical
all	O
along	O
the	O
treatment	O
period	O
,	O
at	O
a	O
daily	O
dose	O
of	O
three	O
times	O
500	O
mg	O
(	O
group	O
G	O
)	O
,	O
and	O
20	O
had	O
received	O
a	O
placebo	O
(	O
group	O
P	O
)	O
.	O

Patients	O
were	O
evaluated	O
by	O
neurological	O
examinations	O
,	O
questionnaires	O
and	O
sensory	O
-	O
motor	O
nerve	O
conduction	O
studies	O
.	O

There	O
was	O
no	O
significant	O
difference	O
in	O
the	O
frequency	O
of	O
signs	O
or	O
symptoms	O
between	O
the	O
two	O
groups	O
although	O
neurotoxicity	B-Disease
symptoms	O
presented	O
mostly	O
with	O
lower	O
scores	O
of	O
severity	O
in	O
group	O
G	O
.	O

However	O
,	O
this	O
difference	O
reached	O
statistical	O
significance	O
only	O
with	O
regard	O
to	O
reported	O
pain	B-Disease
sensation	O
(	O
P	O
=	O
0	O
.	O
011	O
)	O
.	O

Also	O
the	O
frequency	O
of	O
abnormal	O
electro	O
-	O
diagnostic	O
findings	O
showed	O
similarity	O
between	O
the	O
two	O
groups	O
(	O
G	O
:	O
7	O
/	O
23	O
=	O
30	O
.	O
4	O
%	O
;	O
P	O
:	O
6	O
/	O
20	O
=	O
30	O
%	O
)	O
.	O

This	O
pilot	O
study	O
leads	O
to	O
the	O
conclusion	O
that	O
glutamate	B-Chemical
supplementation	O
at	O
the	O
chosen	O
regimen	O
fails	O
to	O
protect	O
against	O
peripheral	B-Disease
neurotoxicity	I-Disease
of	O
PAC	B-Chemical
.	O

Development	O
of	O
ocular	B-Disease
myasthenia	I-Disease
during	O
pegylated	B-Chemical
interferon	I-Chemical
and	O
ribavirin	B-Chemical
treatment	O
for	O
chronic	B-Disease
hepatitis	I-Disease
C	I-Disease
.	O

A	O
63	O
-	O
year	O
-	O
old	O
male	O
experienced	O
sudden	O
diplopia	B-Disease
after	O
9	O
weeks	O
of	O
administration	O
of	O
pegylated	B-Chemical
interferon	I-Chemical
(	I-Chemical
IFN	I-Chemical
)	I-Chemical
alpha	I-Chemical
-	I-Chemical
2b	I-Chemical
and	O
ribavirin	B-Chemical
for	O
chronic	B-Disease
hepatitis	I-Disease
C	I-Disease
(	O
CHC	B-Disease
)	O
.	O

Ophthalmologic	O
examinations	O
showed	O
ptosis	B-Disease
on	I-Disease
the	I-Disease
right	I-Disease
upper	I-Disease
lid	I-Disease
and	O
restricted	B-Disease
right	I-Disease
eye	I-Disease
movement	I-Disease
without	O
any	O
other	O
neurological	O
signs	O
.	O

A	O
brain	O
imaging	O
study	O
and	O
repetitive	O
nerve	O
stimulation	O
test	O
indicated	O
no	O
abnormality	O
.	O

The	O
acetylcholine	B-Chemical
receptor	O
antibody	O
titer	O
and	O
response	O
to	O
acetylcholinesterase	O
inhibitors	O
were	O
negative	O
,	O
and	O
the	O
results	O
of	O
thyroid	O
function	O
tests	O
were	O
normal	O
.	O

The	O
patient	O
'	O
s	O
ophthalmological	O
symptoms	O
improved	O
rapidly	O
3	O
weeks	O
after	O
discontinuation	O
of	O
pegylated	B-Chemical
IFN	I-Chemical
alpha	I-Chemical
-	I-Chemical
2b	I-Chemical
and	O
ribavirin	B-Chemical
.	O

The	O
ocular	B-Disease
myasthenia	I-Disease
associated	O
with	O
combination	O
therapy	O
of	O
pegylated	B-Chemical
IFN	I-Chemical
alpha	I-Chemical
-	I-Chemical
2b	I-Chemical
and	O
ribavirin	B-Chemical
for	O
CHC	B-Disease
is	O
very	O
rarely	O
reported	O
;	O
therefore	O
,	O
we	O
present	O
this	O
case	O
with	O
a	O
review	O
of	O
the	O
various	O
eye	O
complications	O
of	O
IFN	B-Chemical
therapy	O
.	O

Learning	B-Disease
and	I-Disease
memory	I-Disease
deficits	I-Disease
in	O
ecstasy	B-Chemical
users	O
and	O
their	O
neural	O
correlates	O
during	O
a	O
face	O
-	O
learning	O
task	O
.	O

It	O
has	O
been	O
consistently	O
shown	O
that	O
ecstasy	B-Chemical
users	O
display	O
impairments	B-Disease
in	I-Disease
learning	I-Disease
and	I-Disease
memory	I-Disease
performance	O
.	O

In	O
addition	O
,	O
working	O
memory	O
processing	O
in	O
ecstasy	B-Chemical
users	O
has	O
been	O
shown	O
to	O
be	O
associated	O
with	O
neural	O
alterations	O
in	O
hippocampal	O
and	O
/	O
or	O
cortical	O
regions	O
as	O
measured	O
by	O
functional	O
magnetic	O
resonance	O
imaging	O
(	O
fMRI	O
)	O
.	O

Using	O
functional	O
imaging	O
and	O
a	O
face	O
-	O
learning	O
task	O
,	O
we	O
investigated	O
neural	O
correlates	O
of	O
encoding	O
and	O
recalling	O
face	O
-	O
name	O
associations	O
in	O
20	O
recreational	O
drug	O
users	O
whose	O
predominant	O
drug	O
use	O
was	O
ecstasy	B-Chemical
and	O
20	O
controls	O
.	O

To	O
address	O
the	O
potential	O
confounding	O
effects	O
of	O
the	O
cannabis	B-Chemical
use	O
of	O
the	O
ecstasy	B-Chemical
using	O
group	O
,	O
a	O
second	O
analysis	O
included	O
14	O
previously	O
tested	O
cannabis	B-Chemical
users	O
(	O
Nestor	O
,	O
L	O
.	O
,	O
Roberts	O
,	O
G	O
.	O
,	O
Garavan	O
,	O
H	O
.	O
,	O
Hester	O
,	O
R	O
.	O
,	O
2008	O
.	O
Deficits	B-Disease
in	I-Disease
learning	I-Disease
and	I-Disease
memory	I-Disease
:	O
parahippocampal	O
hyperactivity	B-Disease
and	O
frontocortical	O
hypoactivity	O
in	O
cannabis	B-Chemical
users	O
.	O
Neuroimage	O
40	O
,	O
1328	O
-	O
1339	O
)	O
.	O

Ecstasy	B-Chemical
users	O
performed	O
significantly	O
worse	O
in	O
learning	O
and	O
memory	O
compared	O
to	O
controls	O
and	O
cannabis	B-Chemical
users	O
.	O

A	O
conjunction	O
analysis	O
of	O
the	O
encode	O
and	O
recall	O
phases	O
of	O
the	O
task	O
revealed	O
ecstasy	B-Chemical
-	O
specific	O
hyperactivity	B-Disease
in	O
bilateral	O
frontal	O
regions	O
,	O
left	O
temporal	O
,	O
right	O
parietal	O
,	O
bilateral	O
temporal	O
,	O
and	O
bilateral	O
occipital	O
brain	O
regions	O
.	O

Ecstasy	B-Chemical
-	O
specific	O
hypoactivity	O
was	O
evident	O
in	O
the	O
right	O
dorsal	O
anterior	O
cingulated	O
cortex	O
(	O
ACC	O
)	O
and	O
left	O
posterior	O
cingulated	O
cortex	O
.	O

In	O
both	O
ecstasy	B-Chemical
and	O
cannabis	B-Chemical
groups	O
brain	O
activation	O
was	O
decreased	O
in	O
the	O
right	O
medial	O
frontal	O
gyrus	O
,	O
left	O
parahippocampal	O
gyrus	O
,	O
left	O
dorsal	O
cingulate	O
gyrus	O
,	O
and	O
left	O
caudate	O
.	O

These	O
results	O
elucidated	O
ecstasy	B-Chemical
-	O
related	O
deficits	O
,	O
only	O
some	O
of	O
which	O
might	O
be	O
attributed	O
to	O
cannabis	B-Chemical
use	O
.	O

These	O
ecstasy	B-Chemical
-	O
specific	O
effects	O
may	O
be	O
related	O
to	O
the	O
vulnerability	O
of	O
isocortical	O
and	O
allocortical	O
regions	O
to	O
the	O
neurotoxic	B-Disease
effects	O
of	O
ecstasy	B-Chemical
.	O

Disulfiram	B-Chemical
-	O
like	O
syndrome	O
after	O
hydrogen	B-Chemical
cyanamide	I-Chemical
professional	O
skin	O
exposure	O
:	O
two	O
case	O
reports	O
in	O
France	O
.	O

Hydrogen	B-Chemical
cyanamide	I-Chemical
is	O
a	O
plant	O
growth	O
regulator	O
used	O
in	O
agriculture	O
to	O
induce	O
bud	O
break	O
in	O
fruit	O
trees	O
.	O

Contact	O
with	O
the	O
skin	O
can	O
result	O
in	O
percutaneous	O
absorption	O
of	O
the	O
substance	O
that	O
inhibits	O
aldehyde	B-Chemical
dehydrogenase	O
and	O
can	O
induce	O
acetaldehyde	B-Chemical
syndrome	O
in	O
case	O
of	O
alcohol	B-Chemical
use	O
.	O

The	O
purpose	O
of	O
this	O
report	O
is	O
to	O
describe	O
two	O
cases	O
of	O
a	O
disulfiram	B-Chemical
-	O
like	O
syndrome	O
following	O
occupational	O
exposure	O
to	O
hydrogen	B-Chemical
cyanamide	I-Chemical
.	O

The	O
first	O
case	O
involved	O
a	O
59	O
-	O
year	O
-	O
old	O
man	O
who	O
used	O
Dormex	B-Chemical
,	O
which	O
contains	O
hydrogen	B-Chemical
cyanamide	I-Chemical
,	O
without	O
protection	O
after	O
consuming	O
a	O
large	O
amount	O
of	O
alcohol	B-Chemical
during	O
a	O
meal	O
.	O

In	O
less	O
than	O
1	O
hour	O
after	O
the	O
ingestion	O
of	O
alcohol	B-Chemical
,	O
he	O
developed	O
malaise	O
with	O
flushing	B-Disease
of	I-Disease
the	I-Disease
face	I-Disease
,	O
tachycardia	B-Disease
,	O
and	O
dyspnea	B-Disease
.	O

Manifestations	O
regressed	O
spontaneously	O
under	O
surveillance	O
in	O
the	O
hospital	O
.	O

The	O
second	O
case	O
occurred	O
in	O
a	O
55	O
-	O
year	O
-	O
old	O
farmer	O
following	O
cutaneous	O
contact	O
with	O
Dormex	B-Chemical
.	O

Five	O
hours	O
after	O
exposure	O
,	O
he	O
developed	O
disulfiram	B-Chemical
-	O
like	O
syndrome	O
with	O
flushing	B-Disease
,	O
tachycardia	B-Disease
,	O
and	O
arterial	B-Disease
hypotension	I-Disease
after	O
consuming	O
three	O
glasses	O
of	O
wine	O
.	O

The	O
patient	O
recovered	O
spontaneously	O
in	O
3	O
hours	O
under	O
surveillance	O
in	O
the	O
hospital	O
.	O

These	O
cases	O
confirm	O
the	O
necessity	O
of	O
avoiding	O
alcohol	B-Chemical
consumption	O
as	O
recommended	O
in	O
the	O
instructions	O
for	O
use	O
of	O
Dormex	B-Chemical
and	O
of	O
preventing	O
cutaneous	O
contact	O
during	O
use	O
.	O

Sulpiride	B-Chemical
-	O
induced	O
tardive	B-Disease
dystonia	I-Disease
.	O

Sulpiride	B-Chemical
is	O
a	O
selective	O
D2	O
-	O
receptor	O
antagonist	O
with	O
antipsychotic	O
and	O
antidepressant	B-Chemical
properties	O
.	O

Although	O
initially	O
thought	O
to	O
be	O
free	O
of	O
extrapyramidal	O
side	O
effects	O
,	O
sulpiride	B-Chemical
-	O
induced	O
tardive	B-Disease
dyskinesia	I-Disease
and	O
parkinsonism	B-Disease
have	O
been	O
reported	O
occasionally	O
.	O

We	O
studied	O
a	O
37	O
-	O
year	O
-	O
old	O
man	O
who	O
developed	O
persistent	O
segmental	O
dystonia	B-Disease
within	O
2	O
months	O
after	O
starting	O
sulpiride	B-Chemical
therapy	O
.	O

We	O
could	O
not	O
find	O
any	O
previous	O
reports	O
of	O
sulpiride	B-Chemical
-	O
induced	O
tardive	B-Disease
dystonia	I-Disease
.	O

Comparative	O
cognitive	O
and	O
subjective	O
side	O
effects	O
of	O
immediate	O
-	O
release	O
oxycodone	B-Chemical
in	O
healthy	O
middle	O
-	O
aged	O
and	O
older	O
adults	O
.	O

This	O
study	O
measured	O
the	O
objective	O
and	O
subjective	O
neurocognitive	O
effects	O
of	O
a	O
single	O
10	O
-	O
mg	O
dose	O
of	O
immediate	O
-	O
release	O
oxycodone	B-Chemical
in	O
healthy	O
,	O
older	O
(	O
>	O
65	O
years	O
)	O
,	O
and	O
middle	O
-	O
aged	O
(	O
35	O
to	O
55	O
years	O
)	O
adults	O
who	O
were	O
not	O
suffering	O
from	O
chronic	O
or	O
significant	O
daily	O
pain	B-Disease
.	O

Seventy	O
-	O
one	O
participants	O
completed	O
2	O
separate	O
study	O
days	O
and	O
were	O
blind	O
to	O
medication	O
condition	O
(	O
placebo	O
,	O
10	O
-	O
mg	O
oxycodone	B-Chemical
)	O
.	O

Plasma	O
oxycodone	B-Chemical
concentration	O
peaked	O
between	O
60	O
and	O
90	O
minutes	O
postdose	O
(	O
P	O
<	O
.	O
01	O
)	O
and	O
pupil	O
size	O
,	O
an	O
indication	O
of	O
physiological	O
effects	O
of	O
the	O
medication	O
,	O
peaked	O
at	O
approximately	O
90	O
to	O
120	O
minutes	O
postdose	O
(	O
P	O
<	O
.	O
01	O
)	O
.	O

Significant	O
declines	B-Disease
in	I-Disease
simple	I-Disease
and	I-Disease
sustained	I-Disease
attention	I-Disease
,	I-Disease
working	I-Disease
memory	I-Disease
,	I-Disease
and	I-Disease
verbal	I-Disease
memory	I-Disease
were	O
observed	O
at	O
1	O
hour	O
postdose	O
compared	O
to	O
baseline	O
for	O
both	O
age	O
groups	O
with	O
a	O
trend	O
toward	O
return	O
to	O
baseline	O
by	O
5	O
hours	O
postdose	O
.	O

For	O
almost	O
all	O
cognitive	O
measures	O
,	O
there	O
were	O
no	O
medication	O
by	O
age	O
-	O
interaction	O
effects	O
,	O
which	O
indicates	O
that	O
the	O
2	O
age	O
groups	O
exhibited	O
similar	O
responses	O
to	O
the	O
medication	O
challenge	O
.	O

This	O
study	O
suggests	O
that	O
for	O
healthy	O
older	O
adults	O
who	O
are	O
not	O
suffering	O
from	O
chronic	B-Disease
pain	I-Disease
,	O
neurocognitive	O
and	O
pharmacodynamic	O
changes	O
in	O
response	O
to	O
a	O
10	O
-	O
mg	O
dose	O
of	O
immediate	O
-	O
release	O
oxycodone	B-Chemical
are	O
similar	O
to	O
those	O
observed	O
for	O
middle	O
-	O
aged	O
adults	O
.	O

PERSPECTIVE	O
:	O
Study	O
findings	O
indicate	O
that	O
the	O
metabolism	O
,	O
neurocognitive	O
effects	O
,	O
and	O
physical	O
side	O
effects	O
of	O
oral	O
oxycodone	B-Chemical
are	O
similar	O
for	O
healthy	O
middle	O
-	O
aged	O
and	O
older	O
adults	O
.	O

Therefore	O
,	O
clinicians	O
should	O
not	O
avoid	O
prescribing	O
oral	O
opioids	O
to	O
older	O
adults	O
based	O
on	O
the	O
belief	O
that	O
older	O
adults	O
are	O
at	O
higher	O
risk	O
for	O
side	O
effects	O
than	O
younger	O
adults	O
.	O

The	O
glycine	B-Chemical
transporter	O
-	O
1	O
inhibitor	O
SSR103800	B-Chemical
displays	O
a	O
selective	O
and	O
specific	O
antipsychotic	O
-	O
like	O
profile	O
in	O
normal	O
and	O
transgenic	O
mice	O
.	O

Schizophrenia	B-Disease
has	O
been	O
initially	O
associated	O
with	O
dysfunction	O
in	O
dopamine	B-Chemical
neurotransmission	O
.	O

However	O
,	O
the	O
observation	O
that	O
antagonists	O
of	O
the	O
glutamate	B-Chemical
N	B-Chemical
-	I-Chemical
methyl	I-Chemical
-	I-Chemical
D	I-Chemical
-	I-Chemical
aspartate	I-Chemical
(	O
NMDA	B-Chemical
)	O
receptor	O
produce	O
schizophrenic	B-Disease
-	O
like	O
symptoms	O
in	O
humans	O
has	O
led	O
to	O
the	O
idea	O
of	O
a	O
dysfunctioning	O
of	O
the	O
glutamatergic	O
system	O
via	O
its	O
NMDA	B-Chemical
receptor	O
.	O

As	O
a	O
result	O
,	O
there	O
is	O
a	O
growing	O
interest	O
in	O
the	O
development	O
of	O
pharmacological	O
agents	O
with	O
potential	O
antipsychotic	O
properties	O
that	O
enhance	O
the	O
activity	O
of	O
the	O
glutamatergic	O
system	O
via	O
a	O
modulation	O
of	O
the	O
NMDA	B-Chemical
receptor	O
.	O

Among	O
them	O
are	O
glycine	B-Chemical
transporter	O
-	O
1	O
(	O
GlyT1	O
)	O
inhibitors	O
such	O
as	O
SSR103800	B-Chemical
,	O
which	O
indirectly	O
enhance	O
NMDA	B-Chemical
receptor	O
function	O
by	O
increasing	O
the	O
glycine	B-Chemical
(	O
a	O
co	O
-	O
agonist	O
for	O
the	O
NMDA	B-Chemical
receptor	O
)	O
levels	O
in	O
the	O
synapse	O
.	O

This	O
study	O
aimed	O
at	O
investigating	O
the	O
potential	O
antipsychotic	O
-	O
like	O
properties	O
of	O
SSR103800	B-Chemical
,	O
with	O
a	O
particular	O
focus	O
on	O
models	O
of	O
hyperactivity	B-Disease
,	O
involving	O
either	O
drug	O
challenge	O
(	O
ie	O
,	O
amphetamine	B-Chemical
and	O
MK	B-Chemical
-	I-Chemical
801	I-Chemical
)	O
or	O
transgenic	O
mice	O
(	O
ie	O
,	O
NMDA	B-Chemical
Nr1	O
(	O
neo	O
-	O
/	O
-	O
)	O
and	O
DAT	O
(	O
-	O
/	O
-	O
)	O
)	O
.	O

Results	O
showed	O
that	O
SSR103800	B-Chemical
(	O
10	O
-	O
30	O
mg	O
/	O
kg	O
p	O
.	O
o	O
.	O
)	O
blocked	O
hyperactivity	B-Disease
induced	O
by	O
the	O
non	O
-	O
competitive	O
NMDA	B-Chemical
receptor	O
antagonist	O
,	O
MK	B-Chemical
-	I-Chemical
801	I-Chemical
and	O
partially	O
reversed	O
spontaneous	O
hyperactivity	B-Disease
of	O
NMDA	B-Chemical
Nr1	O
(	O
neo	O
-	O
/	O
-	O
)	O
mice	O
.	O

In	O
contrast	O
,	O
SSR103800	B-Chemical
failed	O
to	O
affect	O
hyperactivity	B-Disease
induced	O
by	O
amphetamine	B-Chemical
or	O
naturally	O
observed	O
in	O
dopamine	B-Chemical
transporter	O
(	O
DAT	O
(	O
-	O
/	O
-	O
)	O
)	O
knockout	O
mice	O
(	O
10	O
-	O
30	O
mg	O
/	O
kg	O
p	O
.	O
o	O
.	O
)	O
.	O

Importantly	O
,	O
both	O
classical	O
(	O
haloperidol	B-Chemical
)	O
and	O
atypical	O
(	O
olanzapine	B-Chemical
,	O
clozapine	B-Chemical
and	O
aripiprazole	B-Chemical
)	O
antipsychotics	O
were	O
effective	O
in	O
all	O
these	O
models	O
of	O
hyperactivity	B-Disease
.	O

However	O
,	O
unlike	O
these	O
latter	O
,	O
SSR103800	B-Chemical
did	O
not	O
produce	O
catalepsy	B-Disease
(	O
retention	O
on	O
the	O
bar	O
test	O
)	O
up	O
to	O
30	O
mg	O
/	O
kg	O
p	O
.	O
o	O
.	O

Together	O
these	O
findings	O
show	O
that	O
the	O
GlyT1	O
inhibitor	O
,	O
SSR103800	B-Chemical
,	O
produces	O
antipsychotic	O
-	O
like	O
effects	O
,	O
which	O
differ	O
from	O
those	O
observed	O
with	O
compounds	O
primarily	O
targeting	O
the	O
dopaminergic	O
system	O
,	O
and	O
has	O
a	O
reduced	O
side	O
-	O
effect	O
potential	O
as	O
compared	O
with	O
these	O
latter	O
drugs	O
.	O

Pyrrolidine	B-Chemical
dithiocarbamate	I-Chemical
protects	O
the	O
piriform	O
cortex	O
in	O
the	O
pilocarpine	B-Chemical
status	B-Disease
epilepticus	I-Disease
model	O
.	O

Pyrrolidine	B-Chemical
dithiocarbamate	I-Chemical
(	O
PDTC	B-Chemical
)	O
has	O
a	O
dual	O
mechanism	O
of	O
action	O
as	O
an	O
antioxidant	O
and	O
an	O
inhibitor	O
of	O
the	O
transcription	O
factor	O
kappa	O
-	O
beta	O
.	O

Both	O
,	O
production	O
of	O
reactive	O
oxygen	B-Chemical
species	O
as	O
well	O
as	O
activation	O
of	O
NF	O
-	O
kappaB	O
have	O
been	O
implicated	O
in	O
severe	O
neuronal	B-Disease
damage	I-Disease
in	O
different	O
sub	O
-	O
regions	O
of	O
the	O
hippocampus	O
as	O
well	O
as	O
in	O
the	O
surrounding	O
cortices	O
.	O

The	O
effect	O
of	O
PDTC	B-Chemical
on	O
status	B-Disease
epilepticus	I-Disease
-	O
associated	O
cell	O
loss	O
in	O
the	O
hippocampus	O
and	O
piriform	O
cortex	O
was	O
evaluated	O
in	O
the	O
rat	O
fractionated	O
pilocarpine	B-Chemical
model	O
.	O

Treatment	O
with	O
150	O
mg	O
/	O
kg	O
PDTC	B-Chemical
before	O
and	O
following	O
status	B-Disease
epilepticus	I-Disease
significantly	O
increased	O
the	O
mortality	O
rate	O
to	O
100	O
%	O
.	O

Administration	O
of	O
50	O
mg	O
/	O
kg	O
PDTC	B-Chemical
(	O
low	O
-	O
dose	O
)	O
did	O
not	O
exert	O
major	O
effects	O
on	O
the	O
development	O
of	O
a	O
status	B-Disease
epilepticus	I-Disease
or	O
the	O
mortality	O
rate	O
.	O

In	O
vehicle	O
-	O
treated	O
rats	O
,	O
status	B-Disease
epilepticus	I-Disease
caused	O
pronounced	O
neuronal	B-Disease
damage	I-Disease
in	O
the	O
piriform	O
cortex	O
comprising	O
both	O
pyramidal	O
cells	O
and	O
interneurons	O
.	O

Low	O
-	O
dose	O
PDTC	B-Chemical
treatment	O
almost	O
completely	O
protected	O
from	O
lesions	O
in	O
the	O
piriform	O
cortex	O
.	O

A	O
significant	O
decrease	O
in	O
neuronal	O
density	O
of	O
the	O
hippocampal	O
hilar	O
formation	O
was	O
identified	O
in	O
vehicle	O
-	O
and	O
PDTC	B-Chemical
-	O
treated	O
rats	O
following	O
status	B-Disease
epilepticus	I-Disease
.	O

In	O
conclusion	O
,	O
the	O
NF	O
-	O
kappaB	O
inhibitor	O
and	O
antioxidant	O
PDTC	B-Chemical
protected	O
the	O
piriform	O
cortex	O
,	O
whereas	O
it	O
did	O
not	O
affect	O
hilar	O
neuronal	B-Disease
loss	I-Disease
.	O

These	O
data	O
might	O
indicate	O
that	O
the	O
generation	O
of	O
reactive	O
oxygen	B-Chemical
species	O
and	O
activation	O
of	O
NF	O
-	O
kappaB	O
plays	O
a	O
more	O
central	O
role	O
in	O
seizure	B-Disease
-	O
associated	O
neuronal	B-Disease
damage	I-Disease
in	O
the	O
temporal	O
cortex	O
as	O
compared	O
to	O
the	O
hippocampal	O
hilus	O
.	O

However	O
,	O
future	O
investigations	O
are	O
necessary	O
to	O
exactly	O
analyze	O
the	O
biochemical	O
mechanisms	O
by	O
which	O
PDTC	B-Chemical
exerted	O
its	O
beneficial	O
effects	O
in	O
the	O
piriform	O
cortex	O
.	O

Anaesthetists	O
'	O
nightmare	O
:	O
masseter	B-Disease
spasm	I-Disease
after	O
induction	O
in	O
an	O
undiagnosed	O
case	O
of	O
myotonia	B-Disease
congenita	I-Disease
.	O

We	O
report	O
an	O
undiagnosed	O
case	O
of	O
myotonia	B-Disease
congenita	I-Disease
in	O
a	O
24	O
-	O
year	O
-	O
old	O
previously	O
healthy	O
primigravida	O
,	O
who	O
developed	O
life	O
threatening	O
masseter	B-Disease
spasm	I-Disease
following	O
a	O
standard	O
dose	O
of	O
intravenous	O
suxamethonium	B-Chemical
for	O
induction	O
of	O
anaesthesia	O
.	O

Neither	O
the	O
patient	O
nor	O
the	O
anaesthetist	O
was	O
aware	O
of	O
the	O
diagnosis	O
before	O
this	O
potentially	O
lethal	O
complication	O
occurred	O
.	O

Twin	O
preterm	O
neonates	O
with	O
cardiac	B-Disease
toxicity	I-Disease
related	O
to	O
lopinavir	B-Chemical
/	I-Chemical
ritonavir	I-Chemical
therapy	O
.	O

We	O
report	O
twin	O
neonates	O
who	O
were	O
born	O
prematurely	O
at	O
32	O
weeks	O
of	O
gestation	O
to	O
a	O
mother	O
with	O
human	B-Disease
immunodeficiency	I-Disease
virus	I-Disease
infection	I-Disease
.	O

One	O
of	O
the	O
twins	O
developed	O
complete	O
heart	B-Disease
block	I-Disease
and	O
dilated	B-Disease
cardiomyopathy	I-Disease
related	O
to	O
lopinavir	B-Chemical
/	I-Chemical
ritonavir	I-Chemical
therapy	O
,	O
a	O
boosted	O
protease	O
-	O
inhibitor	O
agent	O
,	O
while	O
the	O
other	O
twin	O
developed	O
mild	O
bradycardia	B-Disease
.	O

We	O
recommend	O
caution	O
in	O
the	O
use	O
of	O
lopinavir	B-Chemical
/	I-Chemical
ritonavir	I-Chemical
in	O
the	O
immediate	O
neonatal	O
period	O
.	O

When	O
drugs	O
disappear	O
from	O
the	O
patient	O
:	O
elimination	O
of	O
intravenous	O
medication	O
by	O
hemodiafiltration	O
.	O

Twenty	O
-	O
three	O
hours	O
after	O
heart	O
transplantation	O
,	O
life	O
-	O
threatening	O
acute	O
right	B-Disease
heart	I-Disease
failure	I-Disease
was	O
diagnosed	O
in	O
a	O
patient	O
requiring	O
continuous	O
venovenous	O
hemodiafiltration	O
(	O
CVVHDF	O
)	O
.	O

Increasing	O
doses	O
of	O
catecholamines	B-Chemical
,	O
sedatives	O
,	O
and	O
muscle	O
relaxants	O
administered	O
through	O
a	O
central	O
venous	O
catheter	O
were	O
ineffective	O
.	O

However	O
,	O
a	O
bolus	O
of	O
epinephrine	B-Chemical
injected	O
through	O
an	O
alternative	O
catheter	O
provoked	O
a	O
hypertensive	B-Disease
crisis	O
.	O

Thus	O
,	O
interference	O
with	O
the	O
central	O
venous	O
infusion	O
by	O
the	O
dialysis	O
catheter	O
was	O
suspected	O
.	O

The	O
catheters	O
were	O
changed	O
,	O
and	O
hemodynamics	O
stabilized	O
at	O
lower	O
catecholamine	B-Chemical
doses	O
.	O

When	O
the	O
effects	O
of	O
IV	O
drugs	O
are	O
inadequate	O
in	O
patients	O
receiving	O
CVVHDF	O
,	O
interference	O
with	O
adjacent	O
catheters	O
resulting	O
in	O
elimination	O
of	O
the	O
drug	O
by	O
CVVHDF	O
should	O
be	O
suspected	O
.	O

Less	O
frequent	O
lithium	B-Chemical
administration	O
and	O
lower	O
urine	O
volume	O
.	O

OBJECTIVE	O
:	O
This	O
study	O
was	O
designed	O
to	O
determine	O
whether	O
patients	O
maintained	O
on	O
a	O
regimen	O
of	O
lithium	B-Chemical
on	O
a	O
once	O
-	O
per	O
-	O
day	O
schedule	O
have	O
lower	O
urine	O
volumes	O
than	O
do	O
patients	O
receiving	O
multiple	O
doses	O
per	O
day	O
.	O

METHOD	O
:	O
This	O
was	O
a	O
cross	O
-	O
sectional	O
study	O
of	O
85	O
patients	O
from	O
a	O
lithium	B-Chemical
clinic	O
who	O
received	O
different	O
dose	O
schedules	O
.	O

Patients	O
were	O
admitted	O
to	O
the	O
hospital	O
for	O
measurement	O
of	O
lithium	B-Chemical
level	O
,	O
creatinine	B-Chemical
clearance	O
,	O
urine	O
volume	O
,	O
and	O
maximum	O
osmolality	O
.	O

RESULTS	O
:	O
Multiple	O
daily	O
doses	O
of	O
lithium	B-Chemical
were	O
associated	O
with	O
higher	O
urine	O
volumes	O
.	O

The	O
dosing	O
schedule	O
,	O
duration	O
of	O
lithium	B-Chemical
treatment	O
,	O
and	O
daily	O
dose	O
of	O
lithium	B-Chemical
did	O
not	O
affect	O
maximum	O
osmolality	O
or	O
creatinine	B-Chemical
clearance	O
.	O

CONCLUSIONS	O
:	O
Urine	O
volume	O
can	O
be	O
reduced	O
by	O
giving	O
lithium	B-Chemical
once	O
daily	O
and	O
/	O
or	O
by	O
lowering	O
the	O
total	O
daily	O
dose	O
.	O

Lithium	B-Chemical
-	O
induced	O
polyuria	B-Disease
seems	O
to	O
be	O
related	O
to	O
extrarenal	O
as	O
well	O
as	O
to	O
renal	O
effects	O
.	O

Antibacterial	O
medication	O
use	O
during	O
pregnancy	O
and	O
risk	O
of	O
birth	B-Disease
defects	I-Disease
:	O
National	O
Birth	B-Disease
Defects	I-Disease
Prevention	O
Study	O
.	O

OBJECTIVE	O
:	O
To	O
estimate	O
the	O
association	O
between	O
antibacterial	O
medications	O
and	O
selected	O
birth	B-Disease
defects	I-Disease
.	O

DESIGN	O
,	O
SETTING	O
,	O
AND	O
PARTICIPANTS	O
:	O
Population	O
-	O
based	O
,	O
multisite	O
,	O
case	O
-	O
control	O
study	O
of	O
women	O
who	O
had	O
pregnancies	O
affected	O
by	O
1	O
of	O
more	O
than	O
30	O
eligible	O
major	O
birth	B-Disease
defects	I-Disease
identified	O
via	O
birth	B-Disease
defect	I-Disease
surveillance	O
programs	O
in	O
10	O
states	O
(	O
n	O
=	O
13	O
155	O
)	O
and	O
control	O
women	O
randomly	O
selected	O
from	O
the	O
same	O
geographical	O
regions	O
(	O
n	O
=	O
4941	O
)	O
.	O

MAIN	O
EXPOSURE	O
:	O
Reported	O
maternal	O
use	O
of	O
antibacterials	O
(	O
1	O
month	O
before	O
pregnancy	O
through	O
the	O
end	O
of	O
the	O
first	O
trimester	O
)	O
.	O

MAIN	O
OUTCOME	O
MEASURE	O
:	O
Odds	O
ratios	O
(	O
ORs	O
)	O
measuring	O
the	O
association	O
between	O
antibacterial	O
use	O
and	O
selected	O
birth	B-Disease
defects	I-Disease
adjusted	O
for	O
potential	O
confounders	O
.	O

RESULTS	O
:	O
The	O
reported	O
use	O
of	O
antibacterials	O
increased	O
during	O
pregnancy	O
,	O
peaking	O
during	O
the	O
third	O
month	O
.	O

Sulfonamides	B-Chemical
were	O
associated	O
with	O
anencephaly	B-Disease
(	O
adjusted	O
OR	O
[	O
AOR	O
]	O
=	O
3	O
.	O
4	O
;	O
95	O
%	O
confidence	O
interval	O
[	O
CI	O
]	O
,	O
1	O
.	O
3	O
-	O
8	O
.	O
8	O
)	O
,	O
hypoplastic	B-Disease
left	I-Disease
heart	I-Disease
syndrome	I-Disease
(	O
AOR	O
=	O
3	O
.	O
2	O
;	O
95	O
%	O
CI	O
,	O
1	O
.	O
3	O
-	O
7	O
.	O
6	O
)	O
,	O
coarctation	B-Disease
of	I-Disease
the	I-Disease
aorta	I-Disease
(	O
AOR	O
=	O
2	O
.	O
7	O
;	O
95	O
%	O
CI	O
,	O
1	O
.	O
3	O
-	O
5	O
.	O
6	O
)	O
,	O
choanal	B-Disease
atresia	I-Disease
(	O
AOR	O
=	O
8	O
.	O
0	O
;	O
95	O
%	O
CI	O
,	O
2	O
.	O
7	O
-	O
23	O
.	O
5	O
)	O
,	O
transverse	B-Disease
limb	I-Disease
deficiency	I-Disease
(	O
AOR	O
=	O
2	O
.	O
5	O
;	O
95	O
%	O
CI	O
,	O
1	O
.	O
0	O
-	O
5	O
.	O
9	O
)	O
,	O
and	O
diaphragmatic	B-Disease
hernia	I-Disease
(	O
AOR	O
=	O
2	O
.	O
4	O
;	O
95	O
%	O
CI	O
,	O
1	O
.	O
1	O
-	O
5	O
.	O
4	O
)	O
.	O

Nitrofurantoins	B-Chemical
were	O
associated	O
with	O
anophthalmia	B-Disease
or	O
microphthalmos	B-Disease
(	O
AOR	O
=	O
3	O
.	O
7	O
;	O
95	O
%	O
CI	O
,	O
1	O
.	O
1	O
-	O
12	O
.	O
2	O
)	O
,	O
hypoplastic	B-Disease
left	I-Disease
heart	I-Disease
syndrome	I-Disease
(	O
AOR	O
=	O
4	O
.	O
2	O
;	O
95	O
%	O
CI	O
,	O
1	O
.	O
9	O
-	O
9	O
.	O
1	O
)	O
,	O
atrial	B-Disease
septal	I-Disease
defects	I-Disease
(	O
AOR	O
=	O
1	O
.	O
9	O
;	O
95	O
%	O
CI	O
,	O
1	O
.	O
1	O
-	O
3	O
.	O
4	O
)	O
,	O
and	O
cleft	B-Disease
lip	I-Disease
with	O
cleft	B-Disease
palate	I-Disease
(	O
AOR	O
=	O
2	O
.	O
1	O
;	O
95	O
%	O
CI	O
,	O
1	O
.	O
2	O
-	O
3	O
.	O
9	O
)	O
.	O

Other	O
antibacterial	O
agents	O
that	O
showed	O
associations	O
included	O
erythromycins	B-Chemical
(	O
2	O
defects	O
)	O
,	O
penicillins	B-Chemical
(	O
1	O
defect	O
)	O
,	O
cephalosporins	B-Chemical
(	O
1	O
defect	O
)	O
,	O
and	O
quinolones	B-Chemical
(	O
1	O
defect	O
)	O
.	O

CONCLUSIONS	O
:	O
Reassuringly	O
,	O
penicillins	B-Chemical
,	O
erythromycins	B-Chemical
,	O
and	O
cephalosporins	B-Chemical
,	O
although	O
used	O
commonly	O
by	O
pregnant	O
women	O
,	O
were	O
not	O
associated	O
with	O
many	O
birth	B-Disease
defects	I-Disease
.	O

Sulfonamides	B-Chemical
and	O
nitrofurantoins	B-Chemical
were	O
associated	O
with	O
several	O
birth	B-Disease
defects	I-Disease
,	O
indicating	O
a	O
need	O
for	O
additional	O
scrutiny	O
.	O

Differential	O
impact	O
of	O
immune	O
escape	O
mutations	O
G145R	O
and	O
P120T	O
on	O
the	O
replication	O
of	O
lamivudine	B-Chemical
-	O
resistant	O
hepatitis	B-Chemical
B	I-Chemical
virus	I-Chemical
e	I-Chemical
antigen	I-Chemical
-	O
positive	O
and	O
-	O
negative	O
strains	O
.	O

Immune	O
escape	O
variants	O
of	O
the	O
hepatitis	B-Disease
B	I-Disease
virus	O
(	O
HBV	O
)	O
represent	O
an	O
emerging	O
clinical	O
challenge	O
,	O
because	O
they	O
can	O
be	O
associated	O
with	O
vaccine	O
escape	O
,	O
HBV	O
reactivation	O
,	O
and	O
failure	O
of	O
diagnostic	O
tests	O
.	O

Recent	O
data	O
suggest	O
a	O
preferential	O
selection	O
of	O
immune	O
escape	O
mutants	O
in	O
distinct	O
peripheral	O
blood	O
leukocyte	O
compartments	O
of	O
infected	O
individuals	O
.	O

We	O
therefore	O
systematically	O
analyzed	O
the	O
functional	O
impact	O
of	O
the	O
most	O
prevalent	O
immune	O
escape	O
variants	O
,	O
the	O
sG145R	O
and	O
sP120T	O
mutants	O
,	O
on	O
the	O
viral	O
replication	O
efficacy	O
and	O
antiviral	O
drug	O
susceptibility	O
of	O
common	O
treatment	O
-	O
associated	O
mutants	O
with	O
resistance	O
to	O
lamivudine	B-Chemical
(	O
LAM	B-Chemical
)	O
and	O
/	O
or	O
HBeAg	B-Chemical
negativity	O
.	O

Replication	O
-	O
competent	O
HBV	O
strains	O
with	O
sG145R	O
or	O
sP120T	O
and	O
LAM	B-Chemical
resistance	O
(	O
rtM204I	O
or	O
rtL180M	O
/	O
rtM204V	O
)	O
were	O
generated	O
on	O
an	O
HBeAg	B-Chemical
-	O
positive	O
and	O
an	O
HBeAg	B-Chemical
-	O
negative	O
background	O
with	O
precore	O
(	O
PC	O
)	O
and	O
basal	O
core	O
promoter	O
(	O
BCP	O
)	O
mutants	O
.	O

The	O
sG145R	O
mutation	O
strongly	O
reduced	O
HBsAg	B-Chemical
levels	O
and	O
was	O
able	O
to	O
fully	O
restore	O
the	O
impaired	O
replication	O
of	O
LAM	B-Chemical
-	O
resistant	O
HBV	O
mutants	O
to	O
the	O
levels	O
of	O
wild	O
-	O
type	O
HBV	O
,	O
and	O
PC	O
or	O
BCP	O
mutations	O
further	O
enhanced	O
viral	O
replication	O
.	O

Although	O
the	O
sP120T	O
substitution	O
also	O
impaired	O
HBsAg	B-Chemical
secretion	O
,	O
it	O
did	O
not	O
enhance	O
the	O
replication	O
of	O
LAM	B-Chemical
-	O
resistant	O
clones	O
.	O

However	O
,	O
the	O
concomitant	O
occurrence	O
of	O
HBeAg	B-Chemical
negativity	O
(	O
PC	O
/	O
BCP	O
)	O
,	O
sP120T	O
,	O
and	O
LAM	B-Chemical
resistance	O
resulted	O
in	O
the	O
restoration	O
of	O
replication	O
to	O
levels	O
of	O
wild	O
-	O
type	O
HBV	O
.	O

In	O
all	O
clones	O
with	O
combined	O
immune	O
escape	O
and	O
LAM	B-Chemical
resistance	O
mutations	O
,	O
the	O
nucleotide	B-Chemical
analogues	O
adefovir	B-Chemical
and	O
tenofovir	B-Chemical
remained	O
effective	O
in	O
suppressing	O
viral	O
replication	O
in	O
vitro	O
.	O

These	O
findings	O
reveal	O
the	O
differential	O
impact	O
of	O
immune	O
escape	O
variants	O
on	O
the	O
replication	O
and	O
drug	O
susceptibility	O
of	O
complex	O
HBV	O
mutants	O
,	O
supporting	O
the	O
need	O
of	O
close	O
surveillance	O
and	O
treatment	O
adjustment	O
in	O
response	O
to	O
the	O
selection	O
of	O
distinct	O
mutational	O
patterns	O
.	O

Hemolytic	B-Disease
anemia	I-Disease
associated	O
with	O
the	O
use	O
of	O
omeprazole	B-Chemical
.	O

Omeprazole	B-Chemical
is	O
the	O
first	O
drug	O
designed	O
to	O
block	O
the	O
final	O
step	O
in	O
the	O
acid	O
secretory	O
process	O
within	O
the	O
parietal	O
cell	O
.	O

It	O
has	O
been	O
shown	O
to	O
be	O
extremely	O
effective	O
in	O
the	O
treatment	O
of	O
peptic	B-Disease
ulcer	I-Disease
disease	I-Disease
,	O
reflux	B-Disease
esophagitis	I-Disease
,	O
and	O
the	O
Zollinger	B-Disease
-	I-Disease
Ellison	I-Disease
syndrome	I-Disease
.	O

Although	O
clinical	O
experience	O
with	O
omeprazole	B-Chemical
is	O
still	O
limited	O
,	O
many	O
controlled	O
studies	O
have	O
established	O
the	O
short	O
-	O
term	O
safety	O
of	O
this	O
drug	O
.	O

We	O
report	O
the	O
first	O
case	O
of	O
a	O
serious	O
short	O
-	O
term	O
adverse	O
reaction	O
with	O
the	O
use	O
of	O
omeprazole	B-Chemical
:	O
hemolytic	B-Disease
anemia	I-Disease
.	O

The	O
patient	O
developed	O
weakness	O
,	O
lethargy	B-Disease
,	O
and	O
shortness	B-Disease
of	I-Disease
breath	I-Disease
2	O
days	O
after	O
starting	O
therapy	O
with	O
omeprazole	B-Chemical
.	O

Two	O
weeks	O
after	O
the	O
initiation	O
of	O
therapy	O
,	O
her	O
hematocrit	O
had	O
decreased	O
from	O
44	O
.	O
1	O
%	O
to	O
20	O
.	O
4	O
%	O
,	O
and	O
she	O
had	O
a	O
positive	O
direct	O
Coombs	O
antiglobulin	O
test	O
and	O
an	O
elevated	O
indirect	O
bilirubin	B-Chemical
.	O

After	O
she	O
discontinued	O
the	O
omeprazole	B-Chemical
,	O
her	O
hemoglobin	O
and	O
hematocrit	O
gradually	O
returned	O
to	O
normal	O
.	O

The	O
mechanism	O
by	O
which	O
omeprazole	B-Chemical
caused	O
the	O
patient	O
'	O
s	O
hemolytic	B-Disease
anemia	I-Disease
is	O
uncertain	O
,	O
but	O
physicians	O
should	O
be	O
alerted	O
to	O
this	O
possible	O
adverse	O
effect	O
.	O

Phenylephrine	B-Chemical
but	O
not	O
ephedrine	B-Chemical
reduces	B-Disease
frontal	I-Disease
lobe	I-Disease
oxygenation	I-Disease
following	O
anesthesia	O
-	O
induced	O
hypotension	B-Disease
.	O

BACKGROUND	O
:	O
Vasopressor	O
agents	O
are	O
used	O
to	O
correct	O
anesthesia	O
-	O
induced	O
hypotension	B-Disease
.	O

We	O
describe	O
the	O
effect	O
of	O
phenylephrine	B-Chemical
and	O
ephedrine	B-Chemical
on	O
frontal	O
lobe	O
oxygenation	O
(	O
S	O
(	O
c	O
)	O
O	O
(	O
2	O
)	O
)	O
following	O
anesthesia	O
-	O
induced	O
hypotension	B-Disease
.	O

METHODS	O
:	O
Following	O
induction	O
of	O
anesthesia	O
by	O
fentanyl	B-Chemical
(	O
0	O
.	O
15	O
mg	O
kg	O
(	O
-	O
1	O
)	O
)	O
and	O
propofol	B-Chemical
(	O
2	O
.	O
0	O
mg	O
kg	O
(	O
-	O
1	O
)	O
)	O
,	O
13	O
patients	O
received	O
phenylephrine	B-Chemical
(	O
0	O
.	O
1	O
mg	O
iv	O
)	O
and	O
12	O
patients	O
received	O
ephedrine	B-Chemical
(	O
10	O
mg	O
iv	O
)	O
to	O
restore	O
mean	O
arterial	O
pressure	O
(	O
MAP	O
)	O
.	O

Heart	O
rate	O
(	O
HR	O
)	O
,	O
MAP	O
,	O
stroke	B-Disease
volume	O
(	O
SV	O
)	O
,	O
cardiac	O
output	O
(	O
CO	O
)	O
,	O
and	O
frontal	O
lobe	O
oxygenation	O
(	O
S	O
(	O
c	O
)	O
O	O
(	O
2	O
)	O
)	O
were	O
registered	O
.	O

RESULTS	O
:	O
Induction	O
of	O
anesthesia	O
was	O
followed	O
by	O
a	B-Disease
decrease	I-Disease
in	I-Disease
MAP	I-Disease
,	I-Disease
HR	I-Disease
,	I-Disease
SV	I-Disease
,	I-Disease
and	I-Disease
CO	I-Disease
concomitant	O
with	O
an	O
elevation	O
in	O
S	O
(	O
c	O
)	O
O	O
(	O
2	O
)	O
.	O

After	O
administration	O
of	O
phenylephrine	B-Chemical
,	O
MAP	O
increased	O
(	O
51	O
+	O
/	O
-	O
12	O
to	O
81	O
+	O
/	O
-	O
13	O
mmHg	O
;	O
P	O
<	O
0	O
.	O
001	O
;	O
mean	O
+	O
/	O
-	O
SD	O
)	O
.	O

However	O
,	O
a	O
14	O
%	O
(	O
from	O
70	O
+	O
/	O
-	O
8	O
%	O
to	O
60	O
+	O
/	O
-	O
7	O
%	O
)	O
reduction	O
in	O
S	O
(	O
c	O
)	O
O	O
(	O
2	O
)	O
(	O
P	O
<	O
0	O
.	O
05	O
)	O
followed	O
with	O
no	O
change	O
in	O
CO	O
(	O
3	O
.	O
7	O
+	O
/	O
-	O
1	O
.	O
1	O
to	O
3	O
.	O
4	O
+	O
/	O
-	O
0	O
.	O
9	O
l	O
min	O
(	O
-	O
1	O
)	O
)	O
.	O

The	O
administration	O
of	O
ephedrine	B-Chemical
led	O
to	O
a	O
similar	O
increase	O
in	O
MAP	O
(	O
53	O
+	O
/	O
-	O
9	O
to	O
79	O
+	O
/	O
-	O
8	O
mmHg	O
;	O
P	O
<	O
0	O
.	O
001	O
)	O
,	O
restored	O
CO	O
(	O
3	O
.	O
2	O
+	O
/	O
-	O
1	O
.	O
2	O
to	O
5	O
.	O
0	O
+	O
/	O
-	O
1	O
.	O
3	O
l	O
min	O
(	O
-	O
1	O
)	O
)	O
,	O
and	O
preserved	O
S	O
(	O
c	O
)	O
O	O
(	O
2	O
)	O
.	O

CONCLUSIONS	O
:	O
The	O
utilization	O
of	O
phenylephrine	B-Chemical
to	O
correct	O
hypotension	B-Disease
induced	O
by	O
anesthesia	O
has	O
a	O
negative	O
impact	O
on	O
S	O
(	O
c	O
)	O
O	O
(	O
2	O
)	O
while	O
ephedrine	B-Chemical
maintains	O
frontal	O
lobe	O
oxygenation	O
potentially	O
related	O
to	O
an	O
increase	O
in	O
CO	O
.	O

Prolonged	O
elevation	O
of	O
plasma	O
argatroban	B-Chemical
in	O
a	O
cardiac	O
transplant	O
patient	O
with	O
a	O
suspected	O
history	O
of	O
heparin	B-Chemical
-	O
induced	O
thrombocytopenia	B-Disease
with	O
thrombosis	B-Disease
.	O

BACKGROUND	O
:	O
Direct	O
thrombin	O
inhibitors	O
(	O
DTIs	O
)	O
provide	O
an	O
alternative	O
method	O
of	O
anticoagulation	O
for	O
patients	O
with	O
a	O
history	O
of	O
heparin	B-Chemical
-	O
induced	O
thrombocytopenia	B-Disease
(	O
HIT	B-Disease
)	O
or	O
HIT	B-Disease
with	O
thrombosis	B-Disease
(	O
HITT	B-Disease
)	O
undergoing	O
cardiopulmonary	O
bypass	O
(	O
CPB	O
)	O
.	O

In	O
the	O
following	O
report	O
,	O
a	O
65	O
-	O
year	O
-	O
old	O
critically	B-Disease
ill	I-Disease
patient	O
with	O
a	O
suspected	O
history	O
of	O
HITT	B-Disease
was	O
administered	O
argatroban	B-Chemical
for	O
anticoagulation	O
on	O
bypass	O
during	O
heart	O
transplantation	O
.	O

The	O
patient	O
required	O
massive	O
transfusion	O
support	O
(	O
55	O
units	O
of	O
red	O
blood	O
cells	O
,	O
42	O
units	O
of	O
fresh	O
-	O
frozen	O
plasma	O
,	O
40	O
units	O
of	O
cryoprecipitate	O
,	O
40	O
units	O
of	O
platelets	O
,	O
and	O
three	O
doses	O
of	O
recombinant	O
Factor	O
VIIa	O
)	O
for	O
severe	O
intraoperative	B-Disease
and	I-Disease
postoperative	I-Disease
bleeding	I-Disease
.	O

STUDY	O
DESIGN	O
AND	O
METHODS	O
:	O
Plasma	O
samples	O
from	O
before	O
and	O
after	O
CPB	O
were	O
analyzed	O
postoperatively	O
for	O
argatroban	B-Chemical
concentration	O
using	O
a	O
modified	O
ecarin	O
clotting	O
time	O
(	O
ECT	O
)	O
assay	O
.	O

RESULTS	O
:	O
Unexpectedly	O
high	O
concentrations	O
of	O
argatroban	B-Chemical
were	O
measured	O
in	O
these	O
samples	O
(	O
range	O
,	O
0	O
-	O
32	O
microg	O
/	O
mL	O
)	O
,	O
and	O
a	O
prolonged	O
plasma	O
argatroban	B-Chemical
half	O
life	O
(	O
t	O
(	O
1	O
/	O
2	O
)	O
)	O
of	O
514	O
minutes	O
was	O
observed	O
(	O
published	O
elimination	O
t	O
(	O
1	O
/	O
2	O
)	O
is	O
39	O
-	O
51	O
minutes	O
[	O
<	O
or	O
=	O
181	O
minutes	O
with	O
hepatic	B-Disease
impairment	I-Disease
]	O
)	O
.	O

CONCLUSIONS	O
:	O
Correlation	O
of	O
plasma	O
argatroban	B-Chemical
concentration	O
versus	O
the	O
patient	O
'	O
s	O
coagulation	O
variables	O
and	O
clinical	O
course	O
suggest	O
that	O
prolonged	O
elevated	O
levels	O
of	O
plasma	O
argatroban	B-Chemical
may	O
have	O
contributed	O
to	O
the	O
patient	O
'	O
s	O
extended	O
coagulopathy	B-Disease
.	O

Because	O
DTIs	O
do	O
not	O
have	O
reversal	O
agents	O
,	O
surgical	O
teams	O
and	O
transfusion	O
services	O
should	O
remain	O
aware	O
of	O
the	O
possibility	O
of	O
massive	O
transfusion	O
events	O
during	O
anticoagulation	O
with	O
these	O
agents	O
.	O

This	O
is	O
the	O
first	O
report	O
to	O
measure	O
plasma	O
argatroban	B-Chemical
concentration	O
in	O
the	O
context	O
of	O
CPB	O
and	O
extended	O
coagulopathy	B-Disease
.	O

The	O
effects	O
of	O
the	O
adjunctive	O
bupropion	B-Chemical
on	O
male	O
sexual	B-Disease
dysfunction	I-Disease
induced	O
by	O
a	O
selective	B-Chemical
serotonin	I-Chemical
reuptake	I-Chemical
inhibitor	I-Chemical
:	O
a	O
double	O
-	O
blind	O
placebo	O
-	O
controlled	O
and	O
randomized	O
study	O
.	O

OBJECTIVE	O
:	O
To	O
determine	O
the	O
safety	O
and	O
efficacy	O
of	O
adjunctive	O
bupropion	B-Chemical
sustained	O
-	O
release	O
(	O
SR	O
)	O
on	O
male	O
sexual	B-Disease
dysfunction	I-Disease
(	O
SD	B-Disease
)	O
induced	O
by	O
a	O
selective	B-Chemical
serotonin	I-Chemical
reuptake	I-Chemical
inhibitor	I-Chemical
(	O
SSRI	B-Chemical
)	O
,	O
as	O
SD	B-Disease
is	O
a	O
common	O
side	O
-	O
effect	O
of	O
SSRIs	B-Chemical
and	O
the	O
most	O
effective	O
treatments	O
have	O
yet	O
to	O
be	O
determined	O
.	O

PATIENTS	O
AND	O
METHODS	O
:	O
The	O
randomized	O
sample	O
consisted	O
of	O
234	O
euthymic	O
men	O
who	O
were	O
receiving	O
some	O
type	O
of	O
SSRI	B-Chemical
.	O

The	O
men	O
were	O
randomly	O
assigned	O
to	O
bupropion	B-Chemical
SR	O
(	O
150	O
mg	O
twice	O
daily	O
,	O
117	O
)	O
or	O
placebo	O
(	O
twice	O
daily	O
,	O
117	O
)	O
for	O
12	O
weeks	O
.	O

Efficacy	O
was	O
evaluated	O
using	O
the	O
Clinical	O
Global	O
Impression	O
-	O
Sexual	O
Function	O
(	O
CGI	O
-	O
SF	O
;	O
the	O
primary	O
outcome	O
measure	O
)	O
,	O
the	O
International	O
Index	O
of	O
Erectile	O
Function	O
(	O
IIEF	O
)	O
,	O
Arizona	O
Sexual	O
Experience	O
Scale	O
(	O
ASEX	O
)	O
,	O
and	O
Erectile	B-Disease
Dysfunction	I-Disease
Inventory	O
of	O
Treatment	O
Satisfaction	O
(	O
EDITS	O
)	O
(	O
secondary	O
outcome	O
measures	O
)	O
.	O

Participants	O
were	O
followed	O
biweekly	O
during	O
study	O
period	O
.	O

RESULTS	O
:	O
After	O
12	O
weeks	O
of	O
treatment	O
,	O
the	O
mean	O
(	O
sd	O
)	O
scores	O
for	O
CGI	O
-	O
SF	O
were	O
significantly	O
lower	O
,	O
i	O
.	O
e	O
.	O
better	O
,	O
in	O
patients	O
on	O
bupropion	B-Chemical
SR	O
,	O
at	O
2	O
.	O
4	O
(	O
1	O
.	O
2	O
)	O
,	O
than	O
in	O
the	O
placebo	O
group	O
,	O
at	O
3	O
.	O
9	O
(	O
1	O
.	O
1	O
)	O
(	O
P	O
=	O
0	O
.	O
01	O
)	O
.	O

Men	O
who	O
received	O
bupropion	B-Chemical
had	O
a	O
significant	O
increase	O
in	O
the	O
total	O
IIEF	O
score	O
(	O
54	O
.	O
4	O
%	O
vs	O
1	O
.	O
2	O
%	O
;	O
P	O
=	O
0	O
.	O
003	O
)	O
,	O
and	O
in	O
the	O
five	O
different	O
domains	O
of	O
the	O
IIEF	O
.	O

Total	O
ASEX	O
scores	O
were	O
significantly	O
lower	O
,	O
i	O
.	O
e	O
.	O
better	O
,	O
among	O
men	O
who	O
received	O
bupropion	B-Chemical
than	O
placebo	O
,	O
at	O
15	O
.	O
5	O
(	O
4	O
.	O
3	O
)	O
vs	O
21	O
.	O
5	O
(	O
4	O
.	O
7	O
)	O
(	O
P	O
=	O
0	O
.	O
002	O
)	O
.	O

The	O
EDITS	O
scores	O
were	O
67	O
.	O
4	O
(	O
10	O
.	O
2	O
)	O
for	O
the	O
bupropion	B-Chemical
and	O
36	O
.	O
3	O
(	O
11	O
.	O
7	O
)	O
for	O
the	O
placebo	O
group	O
(	O
P	O
=	O
0	O
.	O
001	O
)	O
.	O

The	O
ASEX	O
score	O
and	O
CGI	O
-	O
SF	O
score	O
were	O
correlated	O
(	O
P	O
=	O
0	O
.	O
003	O
)	O
.	O

In	O
linear	O
regression	O
analyses	O
the	O
CGI	O
-	O
SF	O
score	O
was	O
not	O
affected	O
significantly	O
by	O
the	O
duration	O
of	O
SD	B-Disease
,	O
type	O
of	O
SSRI	B-Chemical
used	O
and	O
age	O
.	O

CONCLUSIONS	O
:	O
Bupropion	B-Chemical
is	O
an	O
effective	O
treatment	O
for	O
male	O
SD	B-Disease
induced	O
by	O
SSRIs	B-Chemical
.	O

These	O
results	O
provide	O
empirical	O
support	O
for	O
conducting	O
a	O
further	O
study	O
of	O
bupropion	B-Chemical
.	O

Prevention	O
of	O
seizures	B-Disease
and	O
reorganization	O
of	O
hippocampal	O
functions	O
by	O
transplantation	O
of	O
bone	O
marrow	O
cells	O
in	O
the	O
acute	O
phase	O
of	O
experimental	O
epilepsy	B-Disease
.	O

In	O
this	O
study	O
,	O
we	O
investigated	O
the	O
therapeutic	O
potential	O
of	O
bone	O
marrow	O
mononuclear	O
cells	O
(	O
BMCs	O
)	O
in	O
a	O
model	O
of	O
epilepsy	B-Disease
induced	O
by	O
pilocarpine	B-Chemical
in	O
rats	O
.	O

BMCs	O
obtained	O
from	O
green	O
fluorescent	O
protein	O
(	O
GFP	O
)	O
transgenic	O
mice	O
or	O
rats	O
were	O
transplanted	O
intravenously	O
after	O
induction	O
of	O
status	B-Disease
epilepticus	I-Disease
(	O
SE	B-Disease
)	O
.	O

Spontaneous	B-Disease
recurrent	I-Disease
seizures	I-Disease
(	O
SRS	B-Disease
)	O
were	O
monitored	O
using	O
Racine	O
'	O
s	O
seizure	B-Disease
severity	O
scale	O
.	O

All	O
of	O
the	O
rats	O
in	O
the	O
saline	O
-	O
treated	O
epileptic	B-Disease
control	O
group	O
developed	O
SRS	B-Disease
,	O
whereas	O
none	O
of	O
the	O
BMC	O
-	O
treated	O
epileptic	B-Disease
animals	O
had	O
seizures	B-Disease
in	O
the	O
short	O
term	O
(	O
15	O
days	O
after	O
transplantation	O
)	O
,	O
regardless	O
of	O
the	O
BMC	O
source	O
.	O

Over	O
the	O
long	O
-	O
term	O
chronic	O
phase	O
(	O
120	O
days	O
after	O
transplantation	O
)	O
,	O
only	O
25	O
%	O
of	O
BMC	O
-	O
treated	O
epileptic	B-Disease
animals	O
had	O
seizures	B-Disease
,	O
but	O
with	O
a	O
lower	O
frequency	O
and	O
duration	O
compared	O
to	O
the	O
epileptic	B-Disease
control	O
group	O
.	O

The	O
density	O
of	O
hippocampal	O
neurons	O
in	O
the	O
brains	O
of	O
animals	O
treated	O
with	O
BMCs	O
was	O
markedly	O
preserved	O
.	O

At	O
hippocampal	O
Schaeffer	O
collateral	O
-	O
CA1	O
synapses	O
,	O
long	O
-	O
term	O
potentiation	O
was	O
preserved	O
in	O
BMC	O
-	O
transplanted	O
rats	O
compared	O
to	O
epileptic	B-Disease
controls	O
.	O

The	O
donor	O
-	O
derived	O
GFP	O
(	O
+	O
)	O
cells	O
were	O
rarely	O
found	O
in	O
the	O
brains	O
of	O
transplanted	O
epileptic	B-Disease
rats	O
.	O

In	O
conclusion	O
,	O
treatment	O
with	O
BMCs	O
can	O
prevent	O
the	O
development	O
of	O
chronic	O
seizures	B-Disease
,	O
reduce	O
neuronal	B-Disease
loss	I-Disease
,	O
and	O
influence	O
the	O
reorganization	O
of	O
the	O
hippocampal	O
neuronal	O
network	O
.	O

Normalizing	O
effects	O
of	O
modafinil	B-Chemical
on	O
sleep	O
in	O
chronic	O
cocaine	B-Chemical
users	O
.	O

OBJECTIVE	O
:	O
The	O
purpose	O
of	O
the	O
present	O
study	O
was	O
to	O
determine	O
the	O
effect	O
of	O
morning	O
-	O
dosed	O
modafinil	B-Chemical
on	O
sleep	O
and	O
daytime	B-Disease
sleepiness	I-Disease
in	O
chronic	O
cocaine	B-Chemical
users	O
.	O

METHOD	O
:	O
Twenty	O
cocaine	B-Chemical
-	O
dependent	O
participants	O
were	O
randomly	O
assigned	O
to	O
receive	O
modafinil	B-Chemical
,	O
400	O
mg	O
(	O
N	O
=	O
10	O
)	O
,	O
or	O
placebo	O
(	O
N	O
=	O
10	O
)	O
every	O
morning	O
at	O
7	O
:	O
30	O
a	O
.	O
m	O
.	O
for	O
16	O
days	O
in	O
an	O
inpatient	O
,	O
double	O
-	O
blind	O
randomized	O
trial	O
.	O

Participants	O
underwent	O
polysomnographic	O
sleep	O
recordings	O
on	O
days	O
1	O
to	O
3	O
,	O
7	O
to	O
9	O
,	O
and	O
14	O
to	O
16	O
(	O
first	O
,	O
second	O
,	O
and	O
third	O
weeks	O
of	O
abstinence	O
)	O
.	O

The	O
Multiple	O
Sleep	O
Latency	O
Test	O
was	O
performed	O
at	O
11	O
:	O
30	O
a	O
.	O
m	O
.	O
,	O
2	O
:	O
00	O
p	O
.	O
m	O
.	O
,	O
and	O
4	O
:	O
30	O
p	O
.	O
m	O
.	O
on	O
days	O
2	O
,	O
8	O
,	O
and	O
15	O
.	O

For	O
comparison	O
of	O
sleep	O
architecture	O
variables	O
,	O
12	O
healthy	O
comparison	O
participants	O
underwent	O
a	O
single	O
night	O
of	O
experimental	O
polysomnography	O
that	O
followed	O
1	O
night	O
of	O
accommodation	O
polysomnography	O
.	O

RESULTS	O
:	O
Progressive	O
abstinence	O
from	O
cocaine	B-Chemical
was	O
associated	O
with	O
worsening	O
of	O
all	O
measured	O
polysomnographic	O
sleep	O
outcomes	O
.	O

Compared	O
with	O
placebo	O
,	O
modafinil	B-Chemical
decreased	O
nighttime	O
sleep	O
latency	O
and	O
increased	O
slow	O
-	O
wave	O
sleep	O
time	O
in	O
cocaine	B-Chemical
-	O
dependent	O
participants	O
.	O

The	O
effect	O
of	O
modafinil	B-Chemical
interacted	O
with	O
the	O
abstinence	O
week	O
and	O
was	O
associated	O
with	O
longer	O
total	O
sleep	O
time	O
and	O
shorter	O
REM	O
sleep	O
latency	O
in	O
the	O
third	O
week	O
of	O
abstinence	O
.	O

Comparison	O
of	O
slow	O
-	O
wave	O
sleep	O
time	O
,	O
total	O
sleep	O
time	O
,	O
and	O
sleep	O
latency	O
in	O
cocaine	B-Chemical
-	O
dependent	O
and	O
healthy	O
participants	O
revealed	O
a	O
normalizing	O
effect	O
of	O
modafinil	B-Chemical
in	O
cocaine	B-Chemical
-	O
dependent	O
participants	O
.	O

Modafinil	B-Chemical
was	O
associated	O
with	O
increased	O
daytime	O
sleep	O
latency	O
,	O
as	O
measured	O
by	O
the	O
Multiple	O
Sleep	O
Latency	O
Test	O
,	O
and	O
a	O
nearly	O
significant	O
decrease	O
in	O
subjective	O
daytime	B-Disease
sleepiness	I-Disease
.	O

CONCLUSIONS	O
:	O
Morning	O
-	O
dosed	O
modafinil	B-Chemical
promotes	O
nocturnal	O
sleep	O
,	O
normalizes	O
sleep	O
architecture	O
,	O
and	O
decreases	O
daytime	B-Disease
sleepiness	I-Disease
in	O
abstinent	O
cocaine	B-Chemical
users	O
.	O

These	O
effects	O
may	O
be	O
relevant	O
in	O
the	O
treatment	O
of	O
cocaine	B-Chemical
dependence	O
.	O

Safety	O
of	O
transesophageal	O
echocardiography	O
in	O
adults	O
:	O
study	O
in	O
a	O
multidisciplinary	O
hospital	O
.	O

BACKGROUND	O
:	O
TEE	O
is	O
a	O
semi	O
-	O
invasive	O
tool	O
broadly	O
used	O
and	O
its	O
utilization	O
associated	O
to	O
sedatives	O
drugs	O
might	O
to	O
affect	O
the	O
procedure	O
safety	O
.	O

OBJECTIVE	O
:	O
to	O
analyze	O
aspects	O
of	O
TEE	O
safety	O
associated	O
to	O
the	O
use	O
of	O
Midazolan	B-Chemical
(	O
MZ	B-Chemical
)	O
and	O
Flumazenil	B-Chemical
(	O
FL	B-Chemical
)	O
and	O
the	O
influence	O
of	O
the	O
clinical	O
variables	O
on	O
the	O
event	O
rate	O
.	O

METHOD	O
:	O
prospective	O
study	O
with	O
137	O
patients	O
that	O
underwent	O
TEE	O
with	O
MZ	B-Chemical
associated	O
to	O
moderate	O
sedation	O
.	O

We	O
analyzed	O
the	O
following	O
events	O
:	O
complications	O
related	O
with	O
the	O
topical	O
anesthesia	O
,	O
with	O
MZ	B-Chemical
use	O
and	O
with	O
the	O
procedure	O
.	O

Uni	O
-	O
and	O
multivariate	O
analyses	O
were	O
used	O
to	O
test	O
the	O
influence	O
of	O
the	O
clinical	O
variables	O
:	O
age	O
,	O
sex	O
,	O
stroke	B-Disease
,	O
myocardiopathy	B-Disease
(	O
MP	B-Disease
)	O
,	O
duration	O
of	O
the	O
test	O
,	O
mitral	B-Disease
regurgitation	I-Disease
(	O
MR	B-Disease
)	O
and	O
the	O
MZ	B-Chemical
dose	O
.	O

RESULTS	O
:	O
All	O
patients	O
(	O
65	O
+	O
/	O
-	O
16	O
yrs	O
;	O
58	O
%	O
males	O
)	O
finished	O
the	O
examination	O
.	O

The	O
mean	O
doses	O
of	O
MZ	B-Chemical
and	O
FL	B-Chemical
were	O
4	O
.	O
3	O
+	O
/	O
-	O
1	O
.	O
9	O
mg	O
and	O
0	O
.	O
28	O
+	O
/	O
-	O
0	O
.	O
2	O
mg	O
,	O
respectively	O
.	O

The	O
duration	O
of	O
the	O
examination	O
and	O
the	O
mean	O
ejection	O
fraction	O
(	O
EF	O
)	O
were	O
16	O
.	O
4	O
+	O
/	O
-	O
6	O
.	O
1	O
minutes	O
and	O
60	O
+	O
/	O
-	O
9	O
%	O
,	O
respectively	O
.	O

Mild	O
hypoxia	B-Disease
(	O
SO2	O
<	O
90	O
%	O
)	O
was	O
the	O
most	O
common	O
event	O
(	O
11	O
patients	O
)	O
;	O
3	O
patients	O
(	O
2	O
%	O
)	O
presented	O
transient	O
hypoxia	B-Disease
due	O
to	O
upper	O
airway	B-Disease
obstruction	I-Disease
by	O
probe	O
introduction	O
and	O
8	O
(	O
5	O
.	O
8	O
%	O
)	O
due	O
to	O
hypoxia	B-Disease
caused	O
by	O
MZ	B-Chemical
use	O
.	O

Transient	O
hypotension	B-Disease
(	O
SAP	O
<	O
90mmHg	O
)	O
occurred	O
in	O
1	O
patient	O
(	O
0	O
.	O
7	O
%	O
)	O
.	O

The	O
multivariate	O
analysis	O
showed	O
that	O
severe	O
MR	B-Disease
,	O
MP	B-Disease
(	O
EF	O
<	O
45	O
%	O
)	O
and	O
high	O
doses	O
of	O
MZ	B-Chemical
(	O
>	O
5mg	O
)	O
were	O
associated	O
with	O
events	O
(	O
p	O
<	O
0	O
.	O
001	O
)	O
.	O

The	O
EF	O
was	O
40	O
%	O
,	O
in	O
the	O
group	O
with	O
MP	B-Disease
and	O
44	O
%	O
in	O
the	O
group	O
with	O
severe	O
MR	B-Disease
and	O
it	O
can	O
be	O
a	O
factor	O
associated	O
with	O
clinical	O
events	O
in	O
the	O
last	O
group	O
.	O

CONCLUSION	O
:	O
TEE	O
with	O
sedation	O
presents	O
a	O
low	O
rate	O
of	O
events	O
.	O

There	O
were	O
no	O
severe	O
events	O
and	O
there	O
was	O
no	O
need	O
to	O
interrupt	O
the	O
examinations	O
.	O

Effect	O
of	O
direct	O
intracoronary	O
administration	O
of	O
methylergonovine	B-Chemical
in	O
patients	O
with	O
and	O
without	O
variant	B-Disease
angina	I-Disease
.	O

The	O
effects	O
of	O
intracoronary	O
administration	O
of	O
methylergonovine	B-Chemical
were	O
studied	O
in	O
21	O
patients	O
with	O
variant	B-Disease
angina	I-Disease
and	O
22	O
patients	O
with	O
atypical	O
chest	B-Disease
pain	I-Disease
and	O
in	O
others	O
without	O
angina	B-Disease
pectoris	I-Disease
(	O
control	O
group	O
)	O
.	O

Methylergonovine	B-Chemical
was	O
administered	O
continuously	O
at	O
a	O
rate	O
of	O
10	O
micrograms	O
/	O
min	O
up	O
to	O
50	O
micrograms	O
.	O

In	O
all	O
patients	O
with	O
variant	B-Disease
angina	I-Disease
,	O
coronary	B-Disease
spasm	I-Disease
was	O
provoked	O
at	O
a	O
mean	O
dose	O
of	O
28	O
+	O
/	O
-	O
13	O
micrograms	O
(	O
mean	O
+	O
/	O
-	O
SD	O
)	O
.	O

In	O
the	O
control	O
group	O
neither	O
ischemic	O
ST	O
change	O
nor	O
localized	O
spasm	B-Disease
occurred	O
.	O

The	O
basal	O
tone	O
of	O
the	O
right	O
coronary	O
artery	O
was	O
significantly	O
lower	O
than	O
that	O
of	O
the	O
left	O
coronary	O
artery	O
.	O

The	O
percentage	O
of	O
vasoconstriction	O
of	O
the	O
right	O
coronary	O
artery	O
was	O
significantly	O
higher	O
than	O
that	O
of	O
the	O
left	O
coronary	O
artery	O
.	O

These	O
results	O
suggest	O
that	O
spasm	B-Disease
provocation	O
tests	O
,	O
which	O
use	O
an	O
intracoronary	O
injection	O
of	O
a	O
relatively	O
low	O
dose	O
of	O
methylergonovine	B-Chemical
,	O
have	O
a	O
high	O
sensitivity	O
in	O
variant	B-Disease
angina	I-Disease
and	O
the	O
vasoreactivity	O
of	O
the	O
right	O
coronary	O
artery	O
may	O
be	O
greater	O
than	O
that	O
of	O
the	O
other	O
coronary	O
arteries	O
.	O

Oral	O
manifestations	O
of	O
"	O
meth	B-Disease
mouth	I-Disease
"	O
:	O
a	O
case	O
report	O
.	O

AIM	O
:	O
The	O
aim	O
of	O
the	O
documentation	O
of	O
this	O
clinical	O
case	O
is	O
to	O
make	O
clinicians	O
aware	O
of	O
"	O
meth	B-Disease
mouth	I-Disease
"	O
and	O
the	O
medical	O
risks	O
associated	O
with	O
this	O
serious	O
condition	O
.	O

BACKGROUND	O
:	O
Methamphetamine	B-Chemical
is	O
a	O
very	O
addictive	O
,	O
powerful	O
stimulant	O
that	O
increases	O
wakefulness	O
and	O
physical	O
activity	O
and	O
can	O
produce	O
other	O
effects	O
such	O
as	O
cardiac	B-Disease
dysrhythmias	I-Disease
,	O
hypertension	B-Disease
,	O
hallucinations	B-Disease
,	O
and	O
violent	B-Disease
behavior	I-Disease
.	O

Dental	O
patients	O
abusing	O
methamphetamine	B-Chemical
can	O
present	O
with	O
poor	O
oral	O
hygiene	O
,	O
xerostomia	B-Disease
,	O
rampant	O
caries	B-Disease
(	O
"	O
meth	B-Disease
mouth	I-Disease
"	O
)	O
,	O
and	O
excessive	O
tooth	B-Disease
wear	I-Disease
.	O

Oral	O
rehabilitation	O
of	O
patients	O
using	O
methamphetamine	B-Chemical
can	O
be	O
challenging	O
.	O

CASE	O
DESCRIPTION	O
:	O
A	O
30	O
-	O
year	O
-	O
old	O
Caucasian	O
woman	O
presented	O
with	O
dental	O
pain	B-Disease
,	O
bad	B-Disease
breath	I-Disease
,	O
and	O
self	O
-	O
reported	O
poor	O
esthetics	O
.	O

A	O
comprehensive	O
examination	O
including	O
her	O
medical	O
history	O
,	O
panoramic	O
radiograph	O
,	O
and	O
intraoral	O
examination	O
revealed	O
19	O
carious	B-Disease
lesions	I-Disease
,	O
which	O
is	O
not	O
very	O
common	O
for	O
a	O
healthy	O
adult	O
.	O

She	O
reported	O
her	O
use	O
of	O
methamphetamine	B-Chemical
for	O
five	O
years	O
and	O
had	O
not	O
experienced	O
any	O
major	O
carious	B-Disease
episodes	I-Disease
before	O
she	O
started	O
using	O
the	O
drug	O
.	O

SUMMARY	O
:	O
The	O
patient	O
'	O
s	O
medical	O
and	O
dental	O
histories	O
along	O
with	O
radiographic	O
and	O
clinical	O
findings	O
lead	O
to	O
a	O
diagnosis	O
of	O
"	O
meth	B-Disease
mouth	I-Disease
.	O
"	O
Although	O
three	O
different	O
dental	O
treatment	O
modalities	O
(	O
either	O
conventional	O
or	O
implant	O
-	O
supported	O
)	O
have	O
been	O
offered	O
to	O
the	O
patient	O
since	O
August	O
2007	O
,	O
the	O
patient	O
has	O
yet	O
to	O
initiate	O
any	O
treatment	O
.	O

CLINICAL	O
SIGNIFICANCE	O
:	O
This	O
clinical	O
case	O
showing	O
oral	O
manifestations	O
of	O
meth	B-Disease
mouth	I-Disease
was	O
presented	O
to	O
help	O
dental	O
practitioners	O
recognize	O
and	O
manage	O
patients	O
who	O
may	O
be	O
abusing	O
methamphetamines	B-Chemical
.	O

Dental	O
practitioners	O
also	O
may	O
be	O
skeptical	O
about	O
the	O
reliability	O
of	O
appointment	O
keeping	O
by	O
these	O
patients	O
,	O
as	O
they	O
frequently	O
miss	O
their	O
appointments	O
without	O
reasonable	O
justification	O
.	O

Antituberculosis	B-Chemical
therapy	O
-	O
induced	O
acute	B-Disease
liver	I-Disease
failure	I-Disease
:	O
magnitude	O
,	O
profile	O
,	O
prognosis	O
,	O
and	O
predictors	O
of	O
outcome	O
.	O

Antituberculosis	B-Chemical
therapy	O
(	O
ATT	O
)	O
-	O
associated	O
acute	B-Disease
liver	I-Disease
failure	I-Disease
(	O
ATT	O
-	O
ALF	B-Disease
)	O
is	O
the	O
commonest	O
drug	O
-	O
induced	O
ALF	B-Disease
in	O
South	O
Asia	O
.	O

Prospective	O
studies	O
on	O
ATT	O
-	O
ALF	B-Disease
are	O
lacking	O
.	O

The	O
current	O
study	O
prospectively	O
evaluated	O
the	O
magnitude	O
,	O
clinical	O
course	O
,	O
outcome	O
,	O
and	O
prognostic	O
factors	O
in	O
ATT	O
-	O
ALF	B-Disease
.	O

From	O
January	O
1986	O
to	O
January	O
2009	O
,	O
1223	O
consecutive	O
ALF	B-Disease
patients	O
were	O
evaluated	O
:	O
ATT	O
alone	O
was	O
the	O
cause	O
in	O
70	O
(	O
5	O
.	O
7	O
%	O
)	O
patients	O
.	O

Another	O
15	O
(	O
1	O
.	O
2	O
%	O
)	O
had	O
ATT	O
and	O
simultaneous	O
hepatitis	B-Disease
virus	I-Disease
infection	I-Disease
.	O

In	O
44	O
(	O
62	O
.	O
8	O
%	O
)	O
patients	O
,	O
ATT	O
was	O
prescribed	O
empirically	O
without	O
definitive	O
evidence	O
of	O
tuberculosis	B-Disease
.	O

ATT	O
-	O
ALF	B-Disease
patients	O
were	O
younger	O
(	O
32	O
.	O
87	O
[	O
+	O
/	O
-	O
15	O
.	O
8	O
]	O
years	O
)	O
,	O
and	O
49	O
(	O
70	O
%	O
)	O
of	O
them	O
were	O
women	O
.	O

Most	O
had	O
hyperacute	O
presentation	O
;	O
the	O
median	O
icterus	B-Disease
encephalopathy	B-Disease
interval	O
was	O
4	O
.	O
5	O
(	O
0	O
-	O
30	O
)	O
days	O
.	O

The	O
median	O
duration	O
of	O
ATT	O
before	O
ALF	B-Disease
was	O
30	O
(	O
7	O
-	O
350	O
)	O
days	O
.	O

At	O
presentation	O
,	O
advanced	O
encephalopathy	B-Disease
and	O
cerebral	B-Disease
edema	I-Disease
were	O
present	O
in	O
51	O
(	O
76	O
%	O
)	O
and	O
29	O
(	O
41	O
.	O
4	O
%	O
)	O
patients	O
,	O
respectively	O
.	O

Gastrointestinal	B-Disease
bleed	I-Disease
,	O
seizures	B-Disease
,	O
infection	B-Disease
,	O
and	O
acute	B-Disease
renal	I-Disease
failure	I-Disease
were	O
documented	O
in	O
seven	O
(	O
10	O
%	O
)	O
,	O
five	O
(	O
7	O
.	O
1	O
%	O
)	O
,	O
26	O
(	O
37	O
.	O
1	O
%	O
)	O
,	O
and	O
seven	O
(	O
10	O
%	O
)	O
patients	O
,	O
respectively	O
.	O

Compared	O
with	O
hepatitis	B-Disease
E	I-Disease
virus	O
(	O
HEV	O
)	O
and	O
non	O
-	O
A	O
non	O
-	O
E	O
-	O
induced	O
ALF	B-Disease
,	O
ATT	O
-	O
ALF	B-Disease
patients	O
had	O
nearly	O
similar	O
presentations	O
except	O
for	O
older	O
age	O
and	O
less	O
elevation	O
of	O
liver	O
enzymes	O
.	O

The	O
mortality	O
rate	O
among	O
patients	O
with	O
ATT	O
-	O
ALF	B-Disease
was	O
high	O
(	O
67	O
.	O
1	O
%	O
,	O
n	O
=	O
47	O
)	O
,	O
and	O
only	O
23	O
(	O
32	O
.	O
9	O
%	O
)	O
patients	O
recovered	O
with	O
medical	O
treatment	O
.	O

In	O
multivariate	O
analysis	O
,	O
three	O
factors	O
independently	O
predicted	O
mortality	O
:	O
serum	O
bilirubin	B-Chemical
(	O
>	O
or	O
=	O
10	O
.	O
8	O
mg	O
/	O
dL	O
)	O
,	O
prothrombin	O
time	O
(	O
PT	O
)	O
prolongation	O
(	O
>	O
or	O
=	O
26	O
seconds	O
)	O
,	O
and	O
grade	O
III	O
/	O
IV	O
encephalopathy	B-Disease
at	O
presentation	O
.	O

CONCLUSION	O
:	O
ATT	O
-	O
ALF	B-Disease
constituted	O
5	O
.	O
7	O
%	O
of	O
ALF	B-Disease
at	O
our	O
center	O
and	O
had	O
a	O
high	O
mortality	O
rate	O
.	O

Because	O
the	O
mortality	O
rate	O
is	O
so	O
high	O
,	O
determining	O
which	O
factors	O
are	O
predictors	O
is	O
less	O
important	O
.	O

A	O
high	O
proportion	O
of	O
patients	O
had	O
consumed	O
ATT	O
empirically	O
,	O
which	O
could	O
have	O
been	O
prevented	O
.	O

Design	O
and	O
analysis	O
of	O
the	O
HYPREN	O
-	O
trial	O
:	O
safety	O
of	O
enalapril	B-Chemical
and	O
prazosin	B-Chemical
in	O
the	O
initial	O
treatment	O
phase	O
of	O
patients	O
with	O
congestive	B-Disease
heart	I-Disease
failure	I-Disease
.	O

Since	O
the	O
introduction	O
of	O
angiotensin	B-Chemical
converting	I-Chemical
enzyme	I-Chemical
(	I-Chemical
ACE	I-Chemical
)	I-Chemical
inhibitors	I-Chemical
into	O
the	O
adjunctive	O
treatment	O
of	O
patients	O
with	O
congestive	B-Disease
heart	I-Disease
failure	I-Disease
,	O
cases	O
of	O
severe	O
hypotension	B-Disease
,	O
especially	O
on	O
the	O
first	O
day	O
of	O
treatment	O
,	O
have	O
occasionally	O
been	O
reported	O
.	O

To	O
assess	O
the	O
safety	O
of	O
the	O
ACE	B-Chemical
inhibitor	I-Chemical
enalapril	B-Chemical
a	O
multicenter	O
,	O
randomized	O
,	O
prazosin	B-Chemical
-	O
controlled	O
trial	O
was	O
designed	O
that	O
compared	O
the	O
incidence	O
and	O
severity	O
of	O
symptomatic	O
hypotension	B-Disease
on	O
the	O
first	O
day	O
of	O
treatment	O
.	O

Trial	O
medication	O
was	O
2	O
.	O
5	O
mg	O
enalapril	B-Chemical
or	O
0	O
.	O
5	O
prazosin	B-Chemical
.	O

Subjects	O
were	O
1210	O
inpatients	O
with	O
New	O
York	O
Heart	O
Association	O
(	O
NYHA	O
)	O
functional	O
class	O
II	O
and	O
III	O
.	O

Patients	O
who	O
received	O
enalapril	B-Chemical
experienced	O
clinically	O
and	O
statistically	O
significantly	O
less	O
symptomatic	O
hypotension	B-Disease
(	O
5	O
.	O
2	O
%	O
)	O
than	O
the	O
patients	O
who	O
received	O
prazosin	B-Chemical
(	O
12	O
.	O
9	O
%	O
)	O
.	O

All	O
patients	O
recovered	O
.	O

It	O
was	O
concluded	O
that	O
treatment	O
with	O
enalapril	B-Chemical
was	O
well	O
tolerated	O
and	O
it	O
is	O
,	O
therefore	O
,	O
unreasonable	O
to	O
restrict	O
the	O
initiation	O
of	O
treatment	O
with	O
enalapril	B-Chemical
to	O
inpatients	O
.	O

Central	B-Disease
nervous	I-Disease
system	I-Disease
complications	I-Disease
during	O
treatment	O
of	O
acute	B-Disease
lymphoblastic	I-Disease
leukemia	I-Disease
in	O
a	O
single	O
pediatric	O
institution	O
.	O

Central	B-Disease
nervous	I-Disease
system	I-Disease
(	I-Disease
CNS	I-Disease
)	I-Disease
complications	I-Disease
during	O
treatment	O
of	O
childhood	O
acute	B-Disease
lymphoblastic	I-Disease
leukemia	I-Disease
(	O
ALL	B-Disease
)	O
remain	O
a	O
challenging	O
clinical	O
problem	O
.	O

Outcome	O
improvement	O
with	O
more	O
intensive	O
chemotherapy	O
has	O
significantly	O
increased	O
the	O
incidence	O
and	O
severity	O
of	O
adverse	O
events	O
.	O

This	O
study	O
analyzed	O
the	O
incidence	O
of	O
neurological	B-Disease
complications	I-Disease
during	O
ALL	B-Disease
treatment	O
in	O
a	O
single	O
pediatric	O
institution	O
,	O
focusing	O
on	O
clinical	O
,	O
radiological	O
,	O
and	O
electrophysiological	O
findings	O
.	O

Exclusion	O
criteria	O
included	O
CNS	O
leukemic	B-Disease
infiltration	I-Disease
at	O
diagnosis	O
,	O
therapy	O
-	O
related	O
peripheral	B-Disease
neuropathy	I-Disease
,	O
late	O
-	O
onset	O
encephalopathy	B-Disease
,	O
or	O
long	O
-	O
term	O
neurocognitive	B-Disease
defects	I-Disease
.	O

During	O
a	O
9	O
-	O
year	O
period	O
,	O
we	O
retrospectively	O
collected	O
27	O
neurological	O
events	O
(	O
11	O
%	O
)	O
in	O
as	O
many	O
patients	O
,	O
from	O
253	O
children	O
enrolled	O
in	O
the	O
ALL	B-Disease
front	O
-	O
line	O
protocol	O
.	O

CNS	O
complications	O
included	O
posterior	O
reversible	O
leukoencephalopathy	B-Disease
syndrome	O
(	O
n	O
=	O
10	O
)	O
,	O
stroke	B-Disease
(	O
n	O
=	O
5	O
)	O
,	O
temporal	B-Disease
lobe	I-Disease
epilepsy	I-Disease
(	O
n	O
=	O
2	O
)	O
,	O
high	O
-	O
dose	O
methotrexate	B-Chemical
toxicity	B-Disease
(	O
n	O
=	O
2	O
)	O
,	O
syndrome	O
of	O
inappropriate	B-Disease
antidiuretic	I-Disease
hormone	I-Disease
secretion	I-Disease
(	O
n	O
=	O
1	O
)	O
,	O
and	O
other	O
unclassified	O
events	O
(	O
n	O
=	O
7	O
)	O
.	O

In	O
conclusion	O
,	O
CNS	O
complications	O
are	O
frequent	O
events	O
during	O
ALL	B-Disease
therapy	O
,	O
and	O
require	O
rapid	O
detection	O
and	O
prompt	O
treatment	O
to	O
limit	O
permanent	O
damage	O
.	O

Cocaine	B-Chemical
causes	O
memory	B-Disease
and	I-Disease
learning	I-Disease
impairments	I-Disease
in	O
rats	O
:	O
involvement	O
of	O
nuclear	O
factor	O
kappa	O
B	O
and	O
oxidative	O
stress	O
,	O
and	O
prevention	O
by	O
topiramate	B-Chemical
.	O

Different	O
mechanisms	O
have	O
been	O
suggested	O
for	O
cocaine	B-Chemical
toxicity	B-Disease
including	O
an	O
increase	O
in	O
oxidative	O
stress	O
but	O
the	O
association	O
between	O
oxidative	O
status	O
in	O
the	O
brain	O
and	O
cocaine	B-Chemical
induced	O
-	O
behaviour	O
is	O
poorly	O
understood	O
.	O

Nuclear	O
factor	O
kappa	O
B	O
(	O
NFkappaB	O
)	O
is	O
a	O
sensor	O
of	O
oxidative	O
stress	O
and	O
participates	O
in	O
memory	O
formation	O
that	O
could	O
be	O
involved	O
in	O
drug	O
toxicity	B-Disease
and	O
addiction	O
mechanisms	O
.	O

Therefore	O
NFkappaB	O
activity	O
,	O
oxidative	O
stress	O
,	O
neuronal	O
nitric	B-Chemical
oxide	I-Chemical
synthase	O
(	O
nNOS	O
)	O
activity	O
,	O
spatial	O
learning	O
and	O
memory	O
as	O
well	O
as	O
the	O
effect	O
of	O
topiramate	B-Chemical
,	O
a	O
previously	O
proposed	O
therapy	O
for	O
cocaine	B-Disease
addiction	I-Disease
,	O
were	O
evaluated	O
in	O
an	O
experimental	O
model	O
of	O
cocaine	B-Chemical
administration	O
in	O
rats	O
.	O

NFkappaB	O
activity	O
was	O
decreased	O
in	O
the	O
frontal	O
cortex	O
of	O
cocaine	B-Chemical
treated	O
rats	O
,	O
as	O
well	O
as	O
GSH	B-Chemical
concentration	O
and	O
glutathione	B-Chemical
peroxidase	O
activity	O
in	O
the	O
hippocampus	O
,	O
whereas	O
nNOS	O
activity	O
in	O
the	O
hippocampus	O
was	O
increased	O
.	O

Memory	O
retrieval	O
of	O
experiences	O
acquired	O
prior	O
to	O
cocaine	B-Chemical
administration	O
was	O
impaired	O
and	O
negatively	O
correlated	O
with	O
NFkappaB	O
activity	O
in	O
the	O
frontal	O
cortex	O
.	O

In	O
contrast	O
,	O
learning	O
of	O
new	O
tasks	O
was	O
enhanced	O
and	O
correlated	O
with	O
the	O
increase	O
of	O
nNOS	O
activity	O
and	O
the	O
decrease	O
of	O
glutathione	B-Chemical
peroxidase	O
.	O

These	O
results	O
provide	O
evidence	O
for	O
a	O
possible	O
mechanistic	O
role	O
of	O
oxidative	O
and	O
nitrosative	O
stress	O
and	O
NFkappaB	O
in	O
the	O
alterations	O
induced	O
by	O
cocaine	B-Chemical
.	O

Topiramate	B-Chemical
prevented	O
all	O
the	O
alterations	O
observed	O
,	O
showing	O
novel	O
neuroprotective	O
properties	O
.	O

Efficacy	O
and	O
safety	O
of	O
asenapine	B-Chemical
in	O
a	O
placebo	O
-	O
and	O
haloperidol	B-Chemical
-	O
controlled	O
trial	O
in	O
patients	O
with	O
acute	O
exacerbation	O
of	O
schizophrenia	B-Disease
.	O

Asenapine	B-Chemical
is	O
approved	O
by	O
the	O
Food	O
and	O
Drugs	O
Administration	O
in	O
adults	O
for	O
acute	O
treatment	O
of	O
schizophrenia	B-Disease
or	O
of	O
manic	B-Disease
or	O
mixed	O
episodes	O
associated	O
with	O
bipolar	B-Disease
I	I-Disease
disorder	I-Disease
with	O
or	O
without	O
psychotic	B-Disease
features	O
.	O

In	O
a	O
double	O
-	O
blind	O
6	O
-	O
week	O
trial	O
,	O
458	O
patients	O
with	O
acute	O
schizophrenia	B-Disease
were	O
randomly	O
assigned	O
to	O
fixed	O
-	O
dose	O
treatment	O
with	O
asenapine	B-Chemical
at	O
5	O
mg	O
twice	O
daily	O
(	O
BID	O
)	O
,	O
asenapine	B-Chemical
at	O
10	O
mg	O
BID	O
,	O
placebo	O
,	O
or	O
haloperidol	B-Chemical
at	O
4	O
mg	O
BID	O
(	O
to	O
verify	O
assay	O
sensitivity	O
)	O
.	O

With	O
last	O
observations	O
carried	O
forward	O
(	O
LOCF	O
)	O
,	O
mean	O
Positive	O
and	O
Negative	O
Syndrome	O
Scale	O
total	O
score	O
reductions	O
from	O
baseline	O
to	O
endpoint	O
were	O
significantly	O
greater	O
with	O
asenapine	B-Chemical
at	O
5	O
mg	O
BID	O
(	O
-	O
16	O
.	O
2	O
)	O
and	O
haloperidol	B-Chemical
(	O
-	O
15	O
.	O
4	O
)	O
than	O
placebo	O
(	O
-	O
10	O
.	O
7	O
;	O
both	O
P	O
<	O
0	O
.	O
05	O
)	O
;	O
using	O
mixed	O
model	O
for	O
repeated	O
measures	O
(	O
MMRM	O
)	O
,	O
changes	O
at	O
day	O
42	O
were	O
significantly	O
greater	O
with	O
asenapine	B-Chemical
at	O
5	O
and	O
10	O
mg	O
BID	O
(	O
-	O
21	O
.	O
3	O
and	O
-	O
19	O
.	O
4	O
,	O
respectively	O
)	O
and	O
haloperidol	B-Chemical
(	O
-	O
20	O
.	O
0	O
)	O
than	O
placebo	O
(	O
-	O
14	O
.	O
6	O
;	O
all	O
P	O
<	O
0	O
.	O
05	O
)	O
.	O

On	O
the	O
Positive	O
and	O
Negative	O
Syndrome	O
Scale	O
positive	O
subscale	O
,	O
all	O
treatments	O
were	O
superior	O
to	O
placebo	O
with	O
LOCF	O
and	O
MMRM	O
;	O
asenapine	B-Chemical
at	O
5	O
mg	O
BID	O
was	O
superior	O
to	O
placebo	O
on	O
the	O
negative	O
subscale	O
with	O
MMRM	O
and	O
on	O
the	O
general	O
psychopathology	O
subscale	O
with	O
LOCF	O
and	O
MMRM	O
.	O

Treatment	O
-	O
related	O
adverse	O
events	O
(	O
AEs	O
)	O
occurred	O
in	O
44	O
%	O
and	O
52	O
%	O
,	O
57	O
%	O
,	O
and	O
41	O
%	O
of	O
the	O
asenapine	B-Chemical
at	O
5	O
and	O
10	O
mg	O
BID	O
,	O
haloperidol	B-Chemical
,	O
and	O
placebo	O
groups	O
,	O
respectively	O
.	O

Extrapyramidal	B-Disease
symptoms	I-Disease
reported	O
as	O
AEs	O
occurred	O
in	O
15	O
%	O
and	O
18	O
%	O
,	O
34	O
%	O
,	O
and	O
10	O
%	O
of	O
the	O
asenapine	B-Chemical
at	O
5	O
and	O
10	O
mg	O
BID	O
,	O
haloperidol	B-Chemical
,	O
and	O
placebo	O
groups	O
,	O
respectively	O
.	O

Across	O
all	O
groups	O
,	O
no	O
more	O
than	O
5	O
%	O
of	O
patients	O
had	O
clinically	O
significant	O
weight	O
change	O
.	O

Post	O
hoc	O
analyses	O
indicated	O
that	O
efficacy	O
was	O
similar	O
with	O
asenapine	B-Chemical
and	O
haloperidol	B-Chemical
;	O
greater	O
contrasts	O
were	O
seen	O
in	O
AEs	O
,	O
especially	O
extrapyramidal	B-Disease
symptoms	I-Disease
.	O

Salvage	O
therapy	O
with	O
nelarabine	B-Chemical
,	O
etoposide	B-Chemical
,	O
and	O
cyclophosphamide	B-Chemical
in	O
relapsed	O
/	O
refractory	O
paediatric	O
T	B-Disease
-	I-Disease
cell	I-Disease
lymphoblastic	I-Disease
leukaemia	I-Disease
and	I-Disease
lymphoma	I-Disease
.	O

A	O
combination	O
of	O
5	O
d	O
of	O
nelarabine	B-Chemical
(	O
AraG	B-Chemical
)	O
with	O
5	O
d	O
of	O
etoposide	B-Chemical
(	O
VP	B-Chemical
)	O
and	O
cyclophosphamide	B-Chemical
(	O
CPM	B-Chemical
)	O
and	O
prophylactic	O
intrathecal	O
chemotherapy	O
was	O
used	O
as	O
salvage	O
therapy	O
in	O
seven	O
children	O
with	O
refractory	O
or	O
relapsed	O
T	B-Disease
-	I-Disease
cell	I-Disease
leukaemia	I-Disease
or	I-Disease
lymphoma	I-Disease
.	O

The	O
most	O
common	O
side	O
effects	O
attributable	O
to	O
the	O
AraG	B-Chemical
included	O
Grade	O
2	O
and	O
3	O
sensory	O
and	O
motor	O
neuropathy	B-Disease
and	O
musculoskeletal	B-Disease
pain	I-Disease
.	O

Haematological	B-Disease
toxicity	I-Disease
was	O
greater	O
for	O
the	O
combination	O
than	O
AraG	B-Chemical
alone	O
,	O
although	O
median	O
time	O
to	O
neutrophil	O
and	O
platelet	O
recovery	O
was	O
consistent	O
with	O
other	O
salvage	O
therapies	O
.	O

All	O
patients	O
had	O
some	O
response	O
to	O
the	O
combined	O
therapy	O
and	O
five	O
of	O
the	O
seven	O
went	O
into	O
complete	O
remission	O
after	O
one	O
or	O
two	O
courses	O
of	O
AraG	B-Chemical
/	O
VP	B-Chemical
/	O
CPM	B-Chemical
.	O

Our	O
experience	O
supports	O
the	O
safety	O
of	O
giving	O
AraG	B-Chemical
as	O
salvage	O
therapy	O
in	O
synchrony	O
with	O
etoposide	B-Chemical
and	O
cyclophosphamide	B-Chemical
,	O
although	O
neurological	B-Disease
toxicity	I-Disease
must	O
be	O
closely	O
monitored	O
.	O

Effect	O
of	O
adriamycin	B-Chemical
combined	O
with	O
whole	O
body	O
hyperthermia	B-Disease
on	O
tumor	B-Disease
and	O
normal	O
tissues	O
.	O

Thermal	O
enhancement	O
of	O
Adriamycin	B-Chemical
-	O
mediated	O
antitumor	O
activity	O
and	O
normal	O
tissue	O
toxicities	B-Disease
by	O
whole	O
body	O
hyperthermia	B-Disease
were	O
compared	O
using	O
a	O
F344	O
rat	O
model	O
.	O

Antitumor	O
activity	O
was	O
studied	O
using	O
a	O
tumor	B-Disease
growth	O
delay	O
assay	O
.	O

Acute	O
normal	O
tissue	O
toxicities	B-Disease
(	O
i	O
.	O
e	O
.	O
,	O
leukopenia	B-Disease
and	O
thrombocytopenia	B-Disease
)	O
and	O
late	O
normal	O
tissue	O
toxicities	B-Disease
(	O
i	O
.	O
e	O
.	O
,	O
myocardial	B-Disease
and	I-Disease
kidney	I-Disease
injury	I-Disease
)	O
were	O
evaluated	O
by	O
functional	O
/	O
physiological	O
assays	O
and	O
by	O
morphological	O
techniques	O
.	O

Whole	O
body	O
hyperthermia	B-Disease
(	O
120	O
min	O
at	O
41	O
.	O
5	O
degrees	O
C	O
)	O
enhanced	O
both	O
Adriamycin	B-Chemical
-	O
mediated	O
antitumor	O
activity	O
and	O
toxic	O
side	O
effects	O
.	O

The	O
thermal	O
enhancement	O
ratio	O
calculated	O
for	O
antitumor	O
activity	O
was	O
1	O
.	O
6	O
.	O

Thermal	O
enhancement	O
ratios	O
estimated	O
for	O
"	O
acute	O
"	O
hematological	O
changes	O
were	O
1	O
.	O
3	O
,	O
whereas	O
those	O
estimated	O
for	O
"	O
late	O
"	O
damage	O
(	O
based	O
on	O
morphological	O
cardiac	B-Disease
and	I-Disease
renal	I-Disease
lesions	I-Disease
)	O
varied	O
between	O
2	O
.	O
4	O
and	O
4	O
.	O
3	O
.	O

Thus	O
,	O
while	O
whole	O
body	O
hyperthermia	B-Disease
enhances	O
Adriamycin	B-Chemical
-	O
mediated	O
antitumor	O
effect	O
,	O
normal	O
tissue	O
toxicity	B-Disease
is	O
also	O
increased	O
,	O
and	O
the	O
potential	O
therapeutic	O
gain	O
of	O
the	O
combined	O
modality	O
treatment	O
is	O
eroded	O
.	O

Permeability	O
,	O
ultrastructural	O
changes	O
,	O
and	O
distribution	O
of	O
novel	O
proteins	O
in	O
the	O
glomerular	O
barrier	O
in	O
early	O
puromycin	B-Chemical
aminonucleoside	I-Chemical
nephrosis	B-Disease
.	O

BACKGROUND	O
/	O
AIMS	O
:	O
It	O
is	O
still	O
unclear	O
what	O
happens	O
in	O
the	O
glomerulus	O
when	O
proteinuria	B-Disease
starts	O
.	O

Using	O
puromycin	B-Chemical
aminonucleoside	I-Chemical
nephrosis	B-Disease
(	O
PAN	O
)	O
rats	O
,	O
we	O
studied	O
early	O
ultrastructural	O
and	O
permeability	O
changes	O
in	O
relation	O
to	O
the	O
expression	O
of	O
the	O
podocyte	O
-	O
associated	O
molecules	O
nephrin	O
,	O
a	O
-	O
actinin	O
,	O
dendrin	O
,	O
and	O
plekhh2	O
,	O
the	O
last	O
two	O
of	O
which	O
were	O
only	O
recently	O
discovered	O
in	O
podocytes	O
.	O

METHODS	O
:	O
Using	O
immune	O
stainings	O
,	O
semiquantitative	O
measurement	O
was	O
performed	O
under	O
the	O
electron	O
microscope	O
.	O

Permeability	O
was	O
assessed	O
using	O
isolated	O
kidney	O
perfusion	O
with	O
tracers	O
.	O

Possible	O
effects	O
of	O
ACE	O
inhibition	O
were	O
tested	O
.	O

RESULTS	O
:	O
By	O
day	O
2	O
,	O
some	O
patchy	O
foot	O
process	O
effacement	O
,	O
but	O
no	O
proteinuria	B-Disease
,	O
appeared	O
.	O

The	O
amount	O
of	O
nephrin	O
was	O
reduced	O
in	O
both	O
diseased	O
and	O
normal	O
areas	O
.	O

The	O
other	O
proteins	O
showed	O
few	O
changes	O
,	O
which	O
were	O
limited	O
to	O
diseased	O
areas	O
.	O

By	O
day	O
4	O
,	O
foot	O
process	O
effacement	O
was	O
complete	O
and	O
proteinuria	B-Disease
appeared	O
in	O
parallel	O
with	O
signs	O
of	O
size	O
barrier	O
damage	O
.	O

Nephrin	O
decreased	O
further	O
,	O
while	O
dendrin	O
and	O
plekhh2	O
also	O
decreased	O
but	O
a	O
-	O
actinin	O
remained	O
unchanged	O
.	O

ACE	O
inhibition	O
had	O
no	O
significant	O
protective	O
effect	O
.	O

CONCLUSIONS	O
:	O
PAN	O
glomeruli	O
already	O
showed	O
significant	O
pathology	O
by	O
day	O
4	O
,	O
despite	O
relatively	O
mild	O
proteinuria	B-Disease
.	O

This	O
was	O
preceded	O
by	O
altered	O
nephrin	O
expression	O
,	O
supporting	O
its	O
pivotal	O
role	O
in	O
podocyte	O
morphology	O
.	O

The	O
novel	O
proteins	O
dendrin	O
and	O
plekhh2	O
were	O
both	O
reduced	O
,	O
suggesting	O
roles	O
in	O
PAN	O
,	O
whereas	O
a	O
-	O
actinin	O
was	O
unchanged	O
.	O

A	O
novel	O
,	O
multiple	O
symptom	O
model	O
of	O
obsessive	B-Disease
-	I-Disease
compulsive	I-Disease
-	I-Disease
like	I-Disease
behaviors	I-Disease
in	O
animals	O
.	O

BACKGROUND	O
:	O
Current	O
animal	O
models	O
of	O
obsessive	B-Disease
-	I-Disease
compulsive	I-Disease
disorder	I-Disease
(	O
OCD	B-Disease
)	O
typically	O
involve	O
acute	O
,	O
drug	O
-	O
induced	O
symptom	O
provocation	O
or	O
a	O
genetic	O
association	O
with	O
stereotypies	O
or	O
anxiety	B-Disease
.	O

None	O
of	O
these	O
current	O
models	O
demonstrate	O
multiple	O
OCD	B-Disease
-	O
like	O
behaviors	O
.	O

METHODS	O
:	O
Neonatal	O
rats	O
were	O
treated	O
with	O
the	O
tricyclic	O
antidepressant	B-Chemical
clomipramine	B-Chemical
or	O
vehicle	O
between	O
days	O
9	O
and	O
16	O
twice	O
daily	O
and	O
behaviorally	O
tested	O
in	O
adulthood	O
.	O

RESULTS	O
:	O
Clomipramine	B-Chemical
exposure	O
in	O
immature	O
rats	O
produced	O
significant	O
behavioral	O
and	O
biochemical	O
changes	O
that	O
include	O
enhanced	O
anxiety	B-Disease
(	O
elevated	O
plus	O
maze	O
and	O
marble	O
burying	O
)	O
,	O
behavioral	B-Disease
inflexibility	I-Disease
(	O
perseveration	O
in	O
the	O
spontaneous	O
alternation	O
task	O
and	O
impaired	O
reversal	O
learning	O
)	O
,	O
working	O
memory	B-Disease
impairment	I-Disease
(	O
e	O
.	O
g	O
.	O
,	O
win	O
-	O
shift	O
paradigm	O
)	O
,	O
hoarding	B-Disease
,	O
and	O
corticostriatal	B-Disease
dysfunction	I-Disease
.	O

Dopamine	B-Chemical
D2	O
receptors	O
were	O
elevated	O
in	O
the	O
striatum	O
,	O
whereas	O
serotonin	B-Chemical
2C	O
,	O
but	O
not	O
serotonin	B-Chemical
1A	O
,	O
receptors	O
were	O
elevated	O
in	O
the	O
orbital	O
frontal	O
cortex	O
.	O

CONCLUSIONS	O
:	O
This	O
is	O
the	O
first	O
demonstration	O
of	O
multiple	O
symptoms	O
consistent	O
with	O
an	O
OCD	B-Disease
-	O
like	O
profile	O
in	O
animals	O
.	O

Moreover	O
,	O
these	O
behaviors	O
are	O
accompanied	O
by	O
biochemical	O
changes	O
in	O
brain	O
regions	O
previously	O
identified	O
as	O
relevant	O
to	O
OCD	B-Disease
.	O

This	O
novel	O
model	O
of	O
OCD	B-Disease
demonstrates	O
that	O
drug	O
exposure	O
during	O
a	O
sensitive	O
period	O
can	O
program	O
disease	O
-	O
like	O
systems	O
permanently	O
,	O
which	O
could	O
have	O
implications	O
for	O
current	O
and	O
future	O
therapeutic	O
strategies	O
for	O
this	O
and	O
other	O
psychiatric	B-Disease
disorders	I-Disease
.	O

Elevation	O
of	O
ADAM10	O
,	O
ADAM17	O
,	O
MMP	O
-	O
2	O
and	O
MMP	O
-	O
9	O
expression	O
with	O
media	O
degeneration	O
features	O
CaCl2	B-Chemical
-	O
induced	O
thoracic	B-Disease
aortic	I-Disease
aneurysm	I-Disease
in	O
a	O
rat	O
model	O
.	O

PURPOSE	O
:	O
This	O
study	O
was	O
designed	O
to	O
establish	O
a	O
rat	O
model	O
of	O
thoracic	B-Disease
aortic	I-Disease
aneurysm	I-Disease
(	O
TAA	B-Disease
)	O
by	O
calcium	B-Chemical
chloride	I-Chemical
(	O
CaCl	B-Chemical
(	I-Chemical
2	I-Chemical
)	I-Chemical
)	O
-	O
induced	O
arterial	B-Disease
injury	I-Disease
and	O
to	O
explore	O
the	O
potential	O
role	O
of	O
a	O
disintegrin	O
and	O
metalloproteinase	O
(	O
ADAM	O
)	O
,	O
matrix	O
metalloproteinases	O
(	O
MMPs	O
)	O
and	O
their	O
endogenous	O
inhibitors	O
(	O
TIMPs	O
)	O
in	O
TAA	B-Disease
formation	O
.	O

METHODS	O
:	O
Thoracic	O
aorta	O
of	O
male	O
Sprague	O
-	O
Dawley	O
rats	O
was	O
exposed	O
to	O
0	O
.	O
5M	O
CaCl	B-Chemical
(	I-Chemical
2	I-Chemical
)	I-Chemical
or	O
normal	O
saline	O
(	O
NaCl	B-Chemical
)	O
.	O

After	O
12weeks	O
,	O
animals	O
were	O
euthanized	O
,	O
and	O
CaCl	B-Chemical
(	I-Chemical
2	I-Chemical
)	I-Chemical
-	O
treated	O
,	O
CaCl	B-Chemical
(	I-Chemical
2	I-Chemical
)	I-Chemical
-	O
untreated	O
(	O
n	O
=	O
12	O
)	O
and	O
NaCl	B-Chemical
-	O
treated	O
aortic	O
segments	O
(	O
n	O
=	O
12	O
)	O
were	O
collected	O
for	O
histological	O
and	O
molecular	O
assessments	O
.	O

MMP	O
-	O
TIMP	O
and	O
ADAM	O
mRNAs	O
were	O
semi	O
-	O
quantitatively	O
analyzed	O
and	O
protein	O
expressions	O
were	O
determined	O
by	O
immunohistochemistry	O
.	O

RESULTS	O
:	O
Despite	O
similar	O
external	O
diameters	O
among	O
CaCl	B-Chemical
(	I-Chemical
2	I-Chemical
)	I-Chemical
-	O
treated	O
,	O
non	O
-	O
CaCl	B-Chemical
(	I-Chemical
2	I-Chemical
)	I-Chemical
-	O
treated	O
and	O
NaCl	B-Chemical
-	O
treated	O
segments	O
,	O
aneurymal	O
alteration	O
(	O
n	O
=	O
6	O
,	O
50	O
%	O
)	O
,	O
media	O
degeneration	O
with	O
regional	O
disruption	O
,	O
fragmentation	O
of	O
elastic	O
fiber	O
,	O
and	O
increased	O
collagen	O
deposition	O
(	O
n	O
=	O
12	O
,	O
100	O
%	O
)	O
were	O
demonstrated	O
in	O
CaCl	B-Chemical
(	I-Chemical
2	I-Chemical
)	I-Chemical
-	O
treated	O
segments	O
.	O

MMP	O
-	O
2	O
,	O
MMP	O
-	O
9	O
,	O
ADAM	O
-	O
10	O
and	O
ADAM	O
-	O
17	O
mRNA	O
levels	O
were	O
increased	O
in	O
CaCl	B-Chemical
(	I-Chemical
2	I-Chemical
)	I-Chemical
-	O
treated	O
segments	O
(	O
all	O
p	O
<	O
0	O
.	O
01	O
)	O
,	O
with	O
trends	O
of	O
elevation	O
in	O
CaCl	B-Chemical
(	I-Chemical
2	I-Chemical
)	I-Chemical
-	O
untreated	O
segments	O
,	O
as	O
compared	O
with	O
NaCl	B-Chemical
-	O
treated	O
segments	O
.	O

Immunohistochemistry	O
displayed	O
significantly	O
increased	O
expressions	O
of	O
MMP	O
-	O
2	O
,	O
MMP	O
-	O
9	O
,	O
ADAM	O
-	O
10	O
and	O
ADAM	O
-	O
17	O
(	O
all	O
p	O
<	O
0	O
.	O
01	O
)	O
in	O
intima	O
and	O
media	O
for	O
CaCl	B-Chemical
(	I-Chemical
2	I-Chemical
)	I-Chemical
-	O
treated	O
segments	O
.	O

TIMP	O
mRNA	O
and	O
tissue	O
levels	O
did	O
not	O
differ	O
obviously	O
among	O
the	O
three	O
aortic	O
segments	O
.	O

CONCLUSION	O
:	O
This	O
study	O
establishes	O
a	O
TAA	B-Disease
model	O
by	O
periarterial	O
CaCl	B-Chemical
(	I-Chemical
2	I-Chemical
)	I-Chemical
exposure	O
in	O
rats	O
,	O
and	O
demonstrates	O
a	O
significant	O
elevation	O
of	O
expression	O
of	O
MMP	O
-	O
2	O
,	O
MMP	O
-	O
9	O
,	O
ADAM10	O
and	O
ADAM17	O
in	O
the	O
pathogenesis	O
of	O
vascular	O
remodeling	O
.	O

Suxamethonium	B-Chemical
induced	O
prolonged	O
apnea	B-Disease
in	O
a	O
patient	O
receiving	O
electroconvulsive	O
therapy	O
.	O

Suxamethonium	B-Chemical
causes	O
prolonged	O
apnea	B-Disease
in	O
patients	O
in	O
whom	O
pseudocholinesterase	O
enzyme	O
gets	O
deactivated	O
by	O
organophosphorus	B-Chemical
(	I-Chemical
OP	I-Chemical
)	I-Chemical
poisons	I-Chemical
.	O

Here	O
,	O
we	O
present	O
a	O
similar	O
incident	O
in	O
a	O
severely	O
depressed	B-Disease
patient	O
who	O
received	O
electroconvulsive	O
therapy	O
(	O
ECT	O
)	O
.	O

Prolonged	O
apnea	B-Disease
in	O
our	O
case	O
ensued	O
because	O
the	O
information	O
about	O
suicidal	O
attempt	O
by	O
OP	B-Chemical
compound	I-Chemical
was	O
concealed	O
from	O
the	O
treating	O
team	O
.	O

Curcumin	B-Chemical
ameliorates	O
cognitive	B-Disease
dysfunction	I-Disease
and	O
oxidative	O
damage	O
in	O
phenobarbitone	B-Chemical
and	O
carbamazepine	B-Chemical
administered	O
rats	O
.	O

The	O
antiepileptic	O
drugs	O
,	O
phenobarbitone	B-Chemical
and	O
carbamazepine	B-Chemical
are	O
well	O
known	O
to	O
cause	O
cognitive	B-Disease
impairment	I-Disease
on	O
chronic	O
use	O
.	O

The	O
increase	O
in	O
free	O
radical	O
generation	O
has	O
been	O
implicated	O
as	O
one	O
of	O
the	O
important	O
mechanisms	O
of	O
cognitive	B-Disease
impairment	I-Disease
by	O
antiepileptic	O
drugs	O
.	O

Curcumin	B-Chemical
has	O
shown	O
antioxidant	O
,	O
anti	O
-	O
inflammatory	O
and	O
neuro	O
-	O
protective	O
properties	O
.	O

Therefore	O
,	O
the	O
present	O
study	O
was	O
carried	O
out	O
to	O
investigate	O
the	O
effect	O
of	O
chronic	O
curcumin	B-Chemical
administration	O
on	O
phenobarbitone	B-Chemical
-	O
and	O
carbamazepine	B-Chemical
-	O
induced	O
cognitive	B-Disease
impairment	I-Disease
and	O
oxidative	O
stress	O
in	O
rats	O
.	O

Pharmacokinetic	O
interactions	O
of	O
curcumin	B-Chemical
with	O
phenobarbitone	B-Chemical
and	O
carbamazepine	B-Chemical
were	O
also	O
studied	O
.	O

Vehicle	O
/	O
drugs	O
were	O
administered	O
daily	O
for	O
21days	O
to	O
male	O
Wistar	O
rats	O
.	O

Passive	O
avoidance	O
paradigm	O
and	O
elevated	O
plus	O
maze	O
test	O
were	O
used	O
to	O
assess	O
cognitive	O
function	O
.	O

At	O
the	O
end	O
of	O
study	O
period	O
,	O
serum	O
phenobarbitone	B-Chemical
and	O
carbamazepine	B-Chemical
,	O
whole	O
brain	O
malondialdehyde	B-Chemical
and	O
reduced	O
glutathione	B-Chemical
levels	O
were	O
estimated	O
.	O

The	O
administration	O
of	O
phenobarbitone	B-Chemical
and	O
carbamazepine	B-Chemical
for	O
21days	O
caused	O
a	O
significant	O
impairment	B-Disease
of	I-Disease
learning	I-Disease
and	I-Disease
memory	I-Disease
as	O
well	O
as	O
an	O
increased	O
oxidative	O
stress	O
.	O

Concomitant	O
curcumin	B-Chemical
administration	O
prevented	O
the	O
cognitive	B-Disease
impairment	I-Disease
and	O
decreased	O
the	O
increased	O
oxidative	O
stress	O
induced	O
by	O
these	O
antiepileptic	O
drugs	O
.	O

Curcumin	B-Chemical
co	O
-	O
administration	O
did	O
not	O
cause	O
any	O
significant	O
alteration	O
in	O
the	O
serum	O
concentrations	O
of	O
both	O
phenobarbitone	B-Chemical
as	O
well	O
as	O
carbamazepine	B-Chemical
.	O

These	O
results	O
show	O
that	O
curcumin	B-Chemical
has	O
beneficial	O
effect	O
in	O
mitigating	O
the	O
deterioration	B-Disease
of	I-Disease
cognitive	I-Disease
functions	I-Disease
and	O
oxidative	O
damage	O
in	O
rats	O
treated	O
with	O
phenobarbitone	B-Chemical
and	O
carbamazepine	B-Chemical
without	O
significantly	O
altering	O
their	O
serum	O
concentrations	O
.	O

The	O
findings	O
suggest	O
that	O
curcumin	B-Chemical
can	O
be	O
considered	O
as	O
a	O
potential	O
safe	O
and	O
effective	O
adjuvant	O
to	O
phenobarbitone	B-Chemical
and	O
carbamazepine	B-Chemical
therapy	O
in	O
preventing	O
cognitive	B-Disease
impairment	I-Disease
associated	O
with	O
these	O
drugs	O
.	O

Can	O
angiogenesis	O
be	O
a	O
target	O
of	O
treatment	O
for	O
ribavirin	B-Chemical
associated	O
hemolytic	B-Disease
anemia	I-Disease
?	O

BACKGROUND	O
/	O
AIMS	O
:	O
Recently	O
ribavirin	B-Chemical
has	O
been	O
found	O
to	O
inhibit	O
angiogenesis	O
and	O
a	O
number	O
of	O
angiogenesis	O
inhibitors	O
such	O
as	O
sunitinib	B-Chemical
and	O
sorafenib	B-Chemical
have	O
been	O
found	O
to	O
cause	O
acute	O
hemolysis	B-Disease
.	O

We	O
aimed	O
to	O
investigate	O
whether	O
there	O
is	O
a	O
relation	O
between	O
hemoglobin	O
,	O
haptoglobin	O
and	O
angiogenesis	O
soluble	O
markers	O
which	O
are	O
modifiable	O
and	O
can	O
help	O
in	O
developing	O
strategies	O
against	O
anemia	B-Disease
.	O

METHODS	O
:	O
Fourteen	O
patients	O
chronically	B-Disease
infected	I-Disease
with	I-Disease
hepatitis	I-Disease
C	I-Disease
virus	I-Disease
were	O
treated	O
by	O
pegylated	B-Chemical
interferon	I-Chemical
alpha	I-Chemical
2a	I-Chemical
and	O
ribavirin	B-Chemical
.	O

Serum	O
hemoglobin	O
,	O
haptoglobin	O
and	O
angiogenesis	O
markers	O
of	O
vascular	O
endothelial	O
growth	O
factor	O
and	O
angiopoetin	O
-	O
2	O
were	O
investigated	O
before	O
and	O
after	O
therapy	O
.	O

RESULTS	O
:	O
We	O
observed	O
a	O
significant	O
decrease	O
in	O
haptoglobin	O
levels	O
at	O
the	O
end	O
of	O
the	O
treatment	O
period	O
.	O

Hemoglobin	O
levels	O
also	O
decreased	O
but	O
insignificantly	O
by	O
treatment	O
.	O

In	O
contrast	O
with	O
the	O
literature	O
,	O
serum	O
levels	O
of	O
angiogenesis	O
factors	O
did	O
not	O
change	O
significantly	O
by	O
pegylated	B-Chemical
interferon	I-Chemical
and	O
ribavirin	B-Chemical
therapy	O
.	O

We	O
found	O
no	O
correlation	O
of	O
angiogenesis	O
soluble	O
markers	O
with	O
either	O
hemoglobin	O
or	O
haptoglobin	O
.	O

CONCLUSION	O
:	O
This	O
is	O
the	O
first	O
study	O
in	O
the	O
literature	O
investigating	O
a	O
link	O
between	O
angiogenesis	O
soluble	O
markers	O
and	O
ribavirin	B-Chemical
induced	O
anemia	B-Disease
in	O
patients	O
with	O
hepatitis	B-Disease
C	I-Disease
and	O
we	O
could	O
not	O
find	O
any	O
relation	O
.	O

Future	O
research	O
with	O
larger	O
number	O
of	O
patients	O
is	O
needed	O
to	O
find	O
out	O
modifiable	O
factors	O
that	O
will	O
improve	O
the	O
safety	O
of	O
ribavirin	B-Chemical
therapy	O
.	O

Reduction	O
in	O
injection	O
pain	B-Disease
using	O
buffered	O
lidocaine	B-Chemical
as	O
a	O
local	O
anesthetic	O
before	O
cardiac	O
catheterization	O
.	O

Previous	O
reports	O
have	O
suggested	O
that	O
pain	B-Disease
associated	O
with	O
the	O
injection	O
of	O
lidocaine	B-Chemical
is	O
related	O
to	O
the	O
acidic	O
pH	O
of	O
the	O
solution	O
.	O

To	O
determine	O
if	O
the	O
addition	O
of	O
a	O
buffering	O
solution	O
to	O
adjust	O
the	O
pH	O
of	O
lidocaine	B-Chemical
into	O
the	O
physiologic	O
range	O
would	O
reduce	O
pain	B-Disease
during	O
injection	O
,	O
we	O
performed	O
a	O
blinded	O
randomized	O
study	O
in	O
patients	O
undergoing	O
cardiac	O
catheterization	O
.	O

Twenty	O
patients	O
were	O
asked	O
to	O
quantify	O
the	O
severity	O
of	O
pain	B-Disease
after	O
receiving	O
standard	O
lidocaine	B-Chemical
in	O
one	O
femoral	O
area	O
and	O
buffered	O
lidocaine	B-Chemical
in	O
the	O
opposite	O
femoral	O
area	O
.	O

The	O
mean	O
pain	B-Disease
score	O
for	O
buffered	O
lidocaine	B-Chemical
was	O
significantly	O
lower	O
than	O
the	O
mean	O
score	O
for	O
standard	O
lidocaine	B-Chemical
(	O
2	O
.	O
7	O
+	O
/	O
-	O
1	O
.	O
9	O
vs	O
.	O
3	O
.	O
8	O
+	O
/	O
-	O
2	O
.	O
2	O
,	O
P	O
=	O
0	O
.	O
03	O
)	O
.	O

The	O
pH	O
adjustment	O
of	O
standard	O
lidocaine	B-Chemical
can	O
be	O
accomplished	O
easily	O
in	O
the	O
catheterization	O
laboratory	O
before	O
injection	O
and	O
results	O
in	O
a	O
reduction	O
of	O
the	O
pain	B-Disease
occurring	O
during	O
the	O
infiltration	O
of	O
tissues	O
.	O

Effect	O
of	O
L	B-Chemical
-	I-Chemical
alpha	I-Chemical
-	I-Chemical
glyceryl	I-Chemical
-	I-Chemical
phosphorylcholine	I-Chemical
on	O
amnesia	B-Disease
caused	O
by	O
scopolamine	B-Chemical
.	O

The	O
present	O
study	O
was	O
carried	O
out	O
to	O
test	O
the	O
effects	O
of	O
L	B-Chemical
-	I-Chemical
alpha	I-Chemical
-	I-Chemical
glycerylphosphorylcholine	I-Chemical
(	O
L	B-Chemical
-	I-Chemical
alpha	I-Chemical
-	I-Chemical
GFC	I-Chemical
)	O
on	O
memory	B-Disease
impairment	I-Disease
induced	O
by	O
scopolamine	B-Chemical
in	O
man	O
.	O

Thirty	O
-	O
two	O
healthy	O
young	O
volunteers	O
were	O
randomly	O
allocated	O
to	O
four	O
different	O
groups	O
.	O

They	O
were	O
given	O
a	O
ten	O
day	O
pretreatment	O
with	O
either	O
L	B-Chemical
-	I-Chemical
alpha	I-Chemical
-	I-Chemical
GFC	I-Chemical
or	O
placebo	O
,	O
p	O
.	O
o	O
.	O
,	O
and	O
on	O
the	O
eleventh	O
day	O
either	O
scopolamine	B-Chemical
or	O
placebo	O
,	O
i	O
.	O
m	O
.	O

Before	O
and	O
0	O
.	O
5	O
,	O
1	O
,	O
2	O
,	O
3	O
,	O
and	O
6	O
h	O
after	O
injection	O
the	O
subjects	O
were	O
given	O
attention	O
and	O
mnemonic	O
tests	O
.	O

The	O
findings	O
of	O
this	O
study	O
indicate	O
that	O
the	O
drug	O
is	O
able	O
to	O
antagonize	O
impairment	B-Disease
of	I-Disease
attention	I-Disease
and	I-Disease
memory	I-Disease
induced	O
by	O
scopolamine	B-Chemical
.	O

Safety	O
of	O
capecitabine	B-Chemical
:	O
a	O
review	O
.	O

IMPORTANCE	O
OF	O
THE	O
FIELD	O
:	O
Fluoropyrimidines	B-Chemical
,	O
in	O
particular	O
5	B-Chemical
-	I-Chemical
fluorouracil	I-Chemical
(	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
)	O
,	O
have	O
been	O
the	O
mainstay	O
of	O
treatment	O
for	O
several	O
solid	O
tumors	B-Disease
,	O
including	O
colorectal	B-Disease
,	I-Disease
breast	I-Disease
and	I-Disease
head	I-Disease
and	I-Disease
neck	I-Disease
cancers	I-Disease
,	O
for	O
>	O
40	O
years	O
.	O

AREAS	O
COVERED	O
IN	O
THIS	O
REVIEW	O
:	O
This	O
article	O
reviews	O
the	O
pharmacology	O
and	O
efficacy	O
of	O
capecitabine	B-Chemical
with	O
a	O
special	O
emphasis	O
on	O
its	O
safety	O
.	O

WHAT	O
THE	O
READER	O
WILL	O
GAIN	O
:	O
The	O
reader	O
will	O
gain	O
better	O
insight	O
into	O
the	O
safety	O
of	O
capecitabine	B-Chemical
in	O
special	O
populations	O
such	O
as	O
patients	O
with	O
advanced	O
age	O
,	O
renal	B-Disease
and	I-Disease
kidney	I-Disease
disease	I-Disease
.	O

We	O
also	O
explore	O
different	O
dosing	O
and	O
schedules	O
of	O
capecitabine	B-Chemical
administration	O
.	O

TAKE	O
HOME	O
MESSAGE	O
:	O
Capecitabine	B-Chemical
is	O
an	O
oral	O
prodrug	O
of	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
and	O
was	O
developed	O
to	O
fulfill	O
the	O
need	O
for	O
a	O
more	O
convenient	O
therapy	O
and	O
provide	O
an	O
improved	O
safety	O
/	O
efficacy	O
profile	O
.	O

It	O
has	O
shown	O
promising	O
results	O
alone	O
or	O
in	O
combination	O
with	O
other	O
chemotherapeutic	O
agents	O
in	O
colorectal	B-Disease
,	I-Disease
breast	I-Disease
,	I-Disease
pancreaticobiliary	I-Disease
,	I-Disease
gastric	I-Disease
,	I-Disease
renal	I-Disease
cell	I-Disease
and	I-Disease
head	I-Disease
and	I-Disease
neck	I-Disease
cancers	I-Disease
.	O

The	O
most	O
commonly	O
reported	O
toxic	O
effects	O
of	O
capecitabine	B-Chemical
are	O
diarrhea	B-Disease
,	O
nausea	B-Disease
,	O
vomiting	B-Disease
,	O
stomatitis	B-Disease
and	O
hand	B-Disease
-	I-Disease
foot	I-Disease
syndrome	I-Disease
.	O

Capecitabine	B-Chemical
has	O
a	O
well	O
-	O
established	O
safety	O
profile	O
and	O
can	O
be	O
given	O
safely	O
to	O
patients	O
with	O
advanced	O
age	O
,	O
hepatic	B-Disease
and	I-Disease
renal	I-Disease
dysfunctions	I-Disease
.	O

Levodopa	B-Chemical
-	O
induced	O
dyskinesias	B-Disease
in	O
patients	O
with	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
:	O
filling	O
the	O
bench	O
-	O
to	O
-	O
bedside	O
gap	O
.	O

Levodopa	B-Chemical
is	O
the	O
most	O
effective	O
drug	O
for	O
the	O
treatment	O
of	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
.	O

However	O
,	O
the	O
long	O
-	O
term	O
use	O
of	O
this	O
dopamine	B-Chemical
precursor	O
is	O
complicated	O
by	O
highly	O
disabling	O
fluctuations	O
and	O
dyskinesias	B-Disease
.	O

Although	O
preclinical	O
and	O
clinical	O
findings	O
suggest	O
pulsatile	O
stimulation	O
of	O
striatal	O
postsynaptic	O
receptors	O
as	O
a	O
key	O
mechanism	O
underlying	O
levodopa	B-Chemical
-	O
induced	O
dyskinesias	B-Disease
,	O
their	O
pathogenesis	O
is	O
still	O
unclear	O
.	O

In	O
recent	O
years	O
,	O
evidence	O
from	O
animal	O
models	O
of	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
has	O
provided	O
important	O
information	O
to	O
understand	O
the	O
effect	O
of	O
specific	O
receptor	O
and	O
post	O
-	O
receptor	O
molecular	O
mechanisms	O
underlying	O
the	O
development	O
of	O
dyskinetic	B-Disease
movements	I-Disease
.	O

Recent	O
preclinical	O
and	O
clinical	O
data	O
from	O
promising	O
lines	O
of	O
research	O
focus	O
on	O
the	O
differential	O
role	O
of	O
presynaptic	O
versus	O
postsynaptic	O
mechanisms	O
,	O
dopamine	B-Chemical
receptor	O
subtypes	O
,	O
ionotropic	O
and	O
metabotropic	O
glutamate	B-Chemical
receptors	O
,	O
and	O
non	O
-	O
dopaminergic	O
neurotransmitter	O
systems	O
in	O
the	O
pathophysiology	O
of	O
levodopa	B-Chemical
-	O
induced	O
dyskinesias	B-Disease
.	O

Effects	O
of	O
pallidal	O
neurotensin	B-Chemical
on	O
haloperidol	B-Chemical
-	O
induced	O
parkinsonian	B-Disease
catalepsy	I-Disease
:	O
behavioral	O
and	O
electrophysiological	O
studies	O
.	O

OBJECTIVE	O
:	O
The	O
globus	O
pallidus	O
plays	O
a	O
critical	O
role	O
in	O
movement	O
regulation	O
.	O

Previous	O
studies	O
have	O
indicated	O
that	O
the	O
globus	O
pallidus	O
receives	O
neurotensinergic	O
innervation	O
from	O
the	O
striatum	O
,	O
and	O
systemic	O
administration	O
of	O
a	O
neurotensin	B-Chemical
analog	O
could	O
produce	O
antiparkinsonian	O
effects	O
.	O

The	O
present	O
study	O
aimed	O
to	O
investigate	O
the	O
effects	O
of	O
pallidal	O
neurotensin	B-Chemical
on	O
haloperidol	B-Chemical
-	O
induced	O
parkinsonian	B-Disease
symptoms	I-Disease
.	O

METHODS	O
:	O
Behavioral	O
experiments	O
and	O
electrophysiological	O
recordings	O
were	O
performed	O
in	O
the	O
present	O
study	O
.	O

RESULTS	O
:	O
Bilateral	O
infusions	O
of	O
neurotensin	B-Chemical
into	O
the	O
globus	O
pallidus	O
reversed	O
haloperidol	B-Chemical
-	O
induced	O
parkinsonian	B-Disease
catalepsy	I-Disease
in	O
rats	O
.	O

Electrophysiological	O
recordings	O
showed	O
that	O
microinjection	O
of	O
neurotensin	B-Chemical
induced	O
excitation	O
of	O
pallidal	O
neurons	O
in	O
the	O
presence	O
of	O
systemic	O
haloperidol	B-Chemical
administration	O
.	O

The	O
neurotensin	B-Chemical
type	I-Chemical
-	I-Chemical
1	I-Chemical
receptor	I-Chemical
antagonist	I-Chemical
SR48692	B-Chemical
blocked	O
both	O
the	O
behavioral	O
and	O
the	O
electrophysiological	O
effects	O
induced	O
by	O
neurotensin	B-Chemical
.	O

CONCLUSION	O
:	O
Activation	O
of	O
pallidal	O
neurotensin	B-Chemical
receptors	O
may	O
be	O
involved	O
in	O
neurotensin	B-Chemical
-	O
induced	O
antiparkinsonian	O
effects	O
.	O

Carmofur	B-Chemical
-	O
induced	O
organic	B-Disease
mental	I-Disease
disorders	I-Disease
.	O

Organic	B-Disease
mental	I-Disease
disorder	I-Disease
was	O
observed	O
in	O
a	O
29	O
-	O
year	O
-	O
old	O
female	O
in	O
the	O
prognostic	O
period	O
after	O
the	O
onset	O
of	O
carmofur	B-Chemical
-	O
induced	O
leukoencephalopathy	B-Disease
.	O

Symptoms	O
such	O
as	O
euphoria	O
,	O
emotional	O
lability	O
and	O
puerile	O
attitude	O
noted	O
in	O
the	O
patient	O
were	O
diagnosed	O
as	O
organic	B-Disease
personality	I-Disease
syndrome	I-Disease
according	O
to	O
the	O
criteria	O
defined	O
in	O
the	O
DSM	O
-	O
III	O
-	O
R	O
.	O

It	O
is	O
referred	O
to	O
as	O
a	O
frontal	B-Disease
lobe	I-Disease
syndrome	I-Disease
.	O

Brain	O
CT	O
revealed	O
a	O
periventricular	O
low	O
density	O
area	O
in	O
the	O
frontal	O
white	O
matter	O
and	O
moderate	O
dilatation	O
of	O
the	O
lateral	O
ventricles	O
especially	O
at	O
the	O
bilateral	O
anterior	O
horns	O
.	O

Consequently	O
,	O
carmofur	B-Chemical
-	O
induced	O
leukoencephalopathy	B-Disease
may	O
uncommonly	O
result	O
in	O
organic	B-Disease
personality	I-Disease
syndrome	I-Disease
in	O
the	O
residual	O
state	O
.	O

It	O
may	O
be	O
attributed	O
to	O
the	O
structural	B-Disease
damage	I-Disease
to	I-Disease
the	I-Disease
frontal	I-Disease
lobe	I-Disease
.	O

Butyrylcholinesterase	O
gene	O
mutations	O
in	O
patients	O
with	O
prolonged	O
apnea	B-Disease
after	O
succinylcholine	B-Chemical
for	O
electroconvulsive	O
therapy	O
.	O

BACKGROUND	O
:	O
patients	O
undergoing	O
electroconvulsive	O
therapy	O
(	O
ECT	O
)	O
often	O
receive	O
succinylcholine	B-Chemical
as	O
part	O
of	O
the	O
anesthetic	O
procedure	O
.	O

The	O
duration	O
of	O
action	O
may	O
be	O
prolonged	O
in	O
patients	O
with	O
genetic	O
variants	O
of	O
the	O
butyrylcholinesterase	O
enzyme	O
(	O
BChE	O
)	O
,	O
the	O
most	O
common	O
being	O
the	O
K	O
-	O
and	O
the	O
A	O
-	O
variants	O
.	O

The	O
aim	O
of	O
the	O
study	O
was	O
to	O
assess	O
the	O
clinical	O
significance	O
of	O
genetic	O
variants	O
in	O
butyrylcholinesterase	O
gene	O
(	O
BCHE	O
)	O
in	O
patients	O
with	O
a	O
suspected	O
prolonged	O
duration	O
of	O
action	O
of	O
succinylcholine	B-Chemical
after	O
ECT	O
.	O

METHODS	O
:	O
a	O
total	O
of	O
13	O
patients	O
were	O
referred	O
to	O
the	O
Danish	O
Cholinesterase	O
Research	O
Unit	O
after	O
ECT	O
during	O
38	O
months	O
.	O

We	O
determined	O
the	O
BChE	O
activity	O
and	O
the	O
BCHE	O
genotype	O
using	O
molecular	O
genetic	O
methods	O
,	O
the	O
duration	O
of	O
apnea	B-Disease
,	O
time	O
to	O
sufficient	O
spontaneous	O
ventilation	O
and	O
whether	O
neuromuscular	O
monitoring	O
was	O
used	O
.	O

The	O
duration	O
of	O
apnea	B-Disease
was	O
compared	O
with	O
published	O
data	O
on	O
normal	O
subjects	O
.	O

RESULTS	O
:	O
in	O
11	O
patients	O
,	O
mutations	O
were	O
found	O
in	O
the	O
BCHE	O
gene	O
,	O
the	O
K	O
-	O
variant	O
being	O
the	O
most	O
frequent	O
.	O

The	O
duration	O
of	O
apnea	B-Disease
was	O
5	O
-	O
15	O
min	O
compared	O
with	O
3	O
-	O
5	O
.	O
3	O
min	O
from	O
the	O
literature	O
.	O

Severe	O
distress	O
was	O
noted	O
in	O
the	O
recovery	O
phase	O
in	O
two	O
patients	O
.	O

Neuromuscular	O
monitoring	O
was	O
used	O
in	O
two	O
patients	O
.	O

CONCLUSION	O
:	O
eleven	O
of	O
13	O
patients	O
with	O
a	O
prolonged	O
duration	O
of	O
action	O
of	O
succinylcholine	B-Chemical
had	O
mutations	O
in	O
BCHE	O
,	O
indicating	O
that	O
this	O
is	O
the	O
possible	O
reason	O
for	O
a	O
prolonged	O
period	O
of	O
apnea	B-Disease
.	O

We	O
recommend	O
objective	O
neuromuscular	O
monitoring	O
during	O
the	O
first	O
ECT	O
.	O

Perhexiline	B-Chemical
maleate	I-Chemical
and	O
peripheral	B-Disease
neuropathy	I-Disease
.	O

Peripheral	B-Disease
neuropathy	I-Disease
has	O
been	O
noted	O
as	O
a	O
complication	O
of	O
therapy	O
with	O
perhexiline	B-Chemical
maleate	I-Chemical
,	O
a	O
drug	O
widely	O
used	O
in	O
France	O
(	O
and	O
in	O
clinical	O
trials	O
in	O
the	O
United	O
States	O
)	O
for	O
the	O
prophylactic	O
treatment	O
of	O
angina	B-Disease
pectoris	I-Disease
.	O

In	O
24	O
patients	O
with	O
this	O
complication	O
,	O
the	O
marked	O
slowing	O
of	O
motor	O
nerve	O
conduction	O
velocity	O
and	O
the	O
electromyographic	O
changes	O
imply	O
mainly	O
a	O
demyelinating	B-Disease
disorder	I-Disease
.	O

Improvement	O
was	O
noted	O
with	O
cessation	O
of	O
therapy	O
.	O

In	O
a	O
few	O
cases	O
the	O
presence	O
of	O
active	O
denervation	O
signified	O
a	O
poor	O
prognosis	O
,	O
with	O
only	O
slight	O
improvement	O
.	O

The	O
underlying	O
mechanism	O
causing	O
the	O
neuropathy	B-Disease
is	O
not	O
yet	O
fully	O
known	O
,	O
although	O
some	O
evidence	O
indicates	O
that	O
it	O
may	O
be	O
a	O
lipid	O
storage	O
process	O
.	O

A	O
phase	O
I	O
study	O
of	O
4	B-Chemical
'	I-Chemical
-	I-Chemical
0	I-Chemical
-	I-Chemical
tetrahydropyranyladriamycin	I-Chemical
.	O

Clinical	O
pharmacology	O
and	O
pharmacokinetics	O
.	O

A	O
Phase	O
I	O
study	O
of	O
intravenous	O
(	O
IV	O
)	O
bolus	O
4	B-Chemical
'	I-Chemical
-	I-Chemical
0	I-Chemical
-	I-Chemical
tetrahydropyranyladriamycin	I-Chemical
(	O
Pirarubicin	B-Chemical
)	O
was	O
done	O
in	O
55	O
patients	O
in	O
good	O
performance	O
status	O
with	O
refractory	O
tumors	B-Disease
.	O

Twenty	O
-	O
six	O
had	O
minimal	O
prior	O
therapy	O
(	O
good	O
risk	O
)	O
,	O
23	O
had	O
extensive	O
prior	O
therapy	O
(	O
poor	O
risk	O
)	O
,	O
and	O
six	O
had	O
renal	B-Disease
and	I-Disease
/	I-Disease
or	I-Disease
hepatic	I-Disease
dysfunction	I-Disease
.	O

A	O
total	O
of	O
167	O
courses	O
at	O
doses	O
of	O
15	O
to	O
70	O
mg	O
/	O
m2	O
were	O
evaluable	O
.	O

Maximum	O
tolerated	O
dose	O
in	O
good	O
-	O
risk	O
patients	O
was	O
70	O
mg	O
/	O
m2	O
,	O
and	O
in	O
poor	O
-	O
risk	O
patients	O
,	O
60	O
mg	O
/	O
m2	O
.	O

The	O
dose	O
-	O
limiting	O
toxic	O
effect	O
was	O
transient	O
noncumulative	O
granulocytopenia	B-Disease
.	O

Granulocyte	O
nadir	O
was	O
on	O
day	O
14	O
(	O
range	O
,	O
4	O
-	O
22	O
)	O
.	O

Less	O
frequent	O
toxic	O
effects	O
included	O
thrombocytopenia	B-Disease
,	O
anemia	B-Disease
,	O
nausea	B-Disease
,	O
mild	O
alopecia	B-Disease
,	O
phlebitis	B-Disease
,	O
and	O
mucositis	B-Disease
.	O

Myelosuppression	B-Disease
was	O
more	O
in	O
patients	O
with	O
hepatic	B-Disease
dysfunction	I-Disease
.	O

Pharmacokinetic	O
analyses	O
in	O
21	O
patients	O
revealed	O
Pirarubicin	B-Chemical
plasma	O
T	O
1	O
/	O
2	O
alpha	O
(	O
+	O
/	O
-	O
SE	O
)	O
of	O
2	O
.	O
5	O
+	O
/	O
-	O
0	O
.	O
85	O
minutes	O
,	O
T	O
beta	O
1	O
/	O
2	O
of	O
25	O
.	O
6	O
+	O
/	O
-	O
6	O
.	O
5	O
minutes	O
,	O
and	O
T	O
1	O
/	O
2	O
gamma	O
of	O
23	O
.	O
6	O
+	O
/	O
-	O
7	O
.	O
6	O
hours	O
.	O

The	O
area	O
under	O
the	O
curve	O
was	O
537	O
+	O
/	O
-	O
149	O
ng	O
/	O
ml	O
x	O
hours	O
,	O
volume	O
of	O
distribution	O
(	O
Vd	O
)	O
3504	O
+	O
/	O
-	O
644	O
l	O
/	O
m2	O
,	O
and	O
total	O
clearance	O
(	O
ClT	O
)	O
was	O
204	O
+	O
39	O
.	O
3	O
l	O
/	O
hour	O
/	O
m2	O
.	O

Adriamycinol	B-Chemical
,	O
doxorubicin	B-Chemical
,	O
adriamycinone	B-Chemical
,	O
and	O
tetrahydropyranyladriamycinol	B-Chemical
were	O
the	O
metabolites	O
detected	O
in	O
plasma	O
and	O
the	O
amount	O
of	O
doxorubicin	B-Chemical
was	O
less	O
than	O
or	O
equal	O
to	O
10	O
%	O
of	O
the	O
total	O
metabolites	O
.	O

Urinary	O
excretion	O
of	O
Pirarubicin	B-Chemical
in	O
the	O
first	O
24	O
hours	O
was	O
less	O
than	O
or	O
equal	O
to	O
10	O
%	O
.	O

Activity	O
was	O
noted	O
in	O
mesothelioma	B-Disease
,	O
leiomyosarcoma	B-Disease
,	O
and	O
basal	B-Disease
cell	I-Disease
carcinoma	I-Disease
.	O

The	O
recommended	O
starting	O
dose	O
for	O
Phase	O
II	O
trials	O
is	O
60	O
mg	O
/	O
m2	O
IV	O
bolus	O
every	O
3	O
weeks	O
.	O

Ocular	B-Disease
and	I-Disease
auditory	I-Disease
toxicity	I-Disease
in	O
hemodialyzed	O
patients	O
receiving	O
desferrioxamine	B-Chemical
.	O

During	O
an	O
18	O
-	O
month	O
period	O
of	O
study	O
41	O
hemodialyzed	O
patients	O
receiving	O
desferrioxamine	B-Chemical
(	O
10	O
-	O
40	O
mg	O
/	O
kg	O
BW	O
/	O
3	O
times	O
weekly	O
)	O
for	O
the	O
first	O
time	O
were	O
monitored	O
for	O
detection	O
of	O
audiovisual	B-Disease
toxicity	I-Disease
.	O

6	O
patients	O
presented	O
clinical	O
symptoms	O
of	O
visual	B-Disease
or	I-Disease
auditory	I-Disease
toxicity	I-Disease
.	O

Moreover	O
,	O
detailed	O
ophthalmologic	O
and	O
audiologic	O
studies	O
disclosed	O
abnormalities	O
in	O
7	O
more	O
asymptomatic	O
patients	O
.	O

Visual	B-Disease
toxicity	I-Disease
was	O
of	O
retinal	O
origin	O
and	O
was	O
characterized	O
by	O
a	O
tritan	O
-	O
type	O
dyschromatopsy	B-Disease
,	O
sometimes	O
associated	O
with	O
a	B-Disease
loss	I-Disease
of	I-Disease
visual	I-Disease
acuity	I-Disease
and	O
pigmentary	B-Disease
retinal	I-Disease
deposits	I-Disease
.	O

Auditory	B-Disease
toxicity	I-Disease
was	O
characterized	O
by	O
a	O
mid	O
-	O
to	O
high	O
-	O
frequency	O
neurosensorial	B-Disease
hearing	I-Disease
loss	I-Disease
and	O
the	O
lesion	O
was	O
of	O
the	O
cochlear	O
type	O
.	O

Desferrioxamine	B-Chemical
withdrawal	O
resulted	O
in	O
a	O
complete	O
recovery	O
of	O
visual	O
function	O
in	O
1	O
patient	O
and	O
partial	O
recovery	O
in	O
3	O
,	O
and	O
a	O
complete	O
reversal	O
of	O
hearing	B-Disease
loss	I-Disease
in	O
3	O
patients	O
and	O
partial	O
recovery	O
in	O
3	O
.	O

This	O
toxicity	B-Disease
appeared	O
in	O
patients	O
receiving	O
the	O
higher	O
doses	O
of	O
desferrioxamine	B-Chemical
or	O
coincided	O
with	O
the	O
normalization	O
of	O
ferritin	O
or	O
aluminium	B-Chemical
serum	O
levels	O
.	O

The	O
data	O
indicate	O
that	O
audiovisual	B-Disease
toxicity	I-Disease
is	O
not	O
an	O
infrequent	O
complication	O
in	O
hemodialyzed	O
patients	O
receiving	O
desferrioxamine	B-Chemical
.	O

Periodical	O
audiovisual	O
monitoring	O
should	O
be	O
performed	O
on	O
hemodialyzed	O
patients	O
receiving	O
the	O
drug	O
in	O
order	O
to	O
detect	O
adverse	O
effects	O
as	O
early	O
as	O
possible	O
.	O

Serial	O
epilepsy	B-Disease
caused	O
by	O
levodopa	B-Chemical
/	I-Chemical
carbidopa	I-Chemical
administration	O
in	O
two	O
patients	O
on	O
hemodialysis	O
.	O

Two	O
patients	O
with	O
similar	O
clinical	O
features	O
are	O
presented	O
:	O
both	O
patients	O
had	O
chronic	B-Disease
renal	I-Disease
failure	I-Disease
,	O
on	O
hemodialysis	O
for	O
many	O
years	O
but	O
recently	O
begun	O
on	O
a	O
high	O
-	O
flux	O
dialyzer	O
;	O
both	O
had	O
been	O
receiving	O
a	O
carbidopa	B-Chemical
/	I-Chemical
levodopa	I-Chemical
preparation	O
;	O
and	O
both	O
had	O
the	O
onset	O
of	O
hallucinosis	B-Disease
and	O
recurrent	O
seizures	B-Disease
,	O
which	O
were	O
refractory	O
to	O
anticonvulsants	O
.	O

The	O
first	O
patient	O
died	O
without	O
a	O
diagnosis	O
;	O
the	O
second	O
patient	O
had	O
a	O
dramatic	O
recovery	O
following	O
the	O
administration	O
of	O
vitamin	B-Chemical
B6	I-Chemical
.	O

Neither	O
patient	O
was	O
considered	O
to	O
have	O
a	O
renal	O
state	O
sufficiently	O
severe	O
enough	O
to	O
explain	O
their	O
presentation	O
.	O

Randomized	O
,	O
double	O
-	O
blind	O
trial	O
of	O
mazindol	B-Chemical
in	O
Duchenne	B-Disease
dystrophy	I-Disease
.	O

There	O
is	O
evidence	O
that	O
growth	O
hormone	O
may	O
be	O
related	O
to	O
the	O
progression	O
of	O
weakness	B-Disease
in	O
Duchenne	B-Disease
dystrophy	I-Disease
.	O

We	O
conducted	O
a	O
12	O
-	O
month	O
controlled	O
trial	O
of	O
mazindol	B-Chemical
,	O
a	O
putative	O
growth	O
hormone	O
secretion	O
inhibitor	O
,	O
in	O
83	O
boys	O
with	O
Duchenne	B-Disease
dystrophy	I-Disease
.	O

Muscle	O
strength	O
,	O
contractures	O
,	O
functional	O
ability	O
and	O
pulmonary	O
function	O
were	O
tested	O
at	O
baseline	O
,	O
and	O
6	O
and	O
12	O
months	O
after	O
treatment	O
with	O
mazindol	B-Chemical
(	O
3	O
mg	O
/	O
d	O
)	O
or	O
placebo	O
.	O

The	O
study	O
was	O
designed	O
to	O
have	O
a	O
power	O
of	O
greater	O
than	O
0	O
.	O
90	O
to	O
detect	O
a	O
slowing	O
to	O
25	O
%	O
of	O
the	O
expected	O
rate	O
of	O
progression	O
of	O
weakness	B-Disease
at	O
P	O
less	O
than	O
0	O
.	O
05	O
.	O

Mazindol	B-Chemical
did	O
not	O
benefit	O
strength	O
at	O
any	O
point	O
in	O
the	O
study	O
.	O

Side	O
effects	O
attributable	O
to	O
mazindol	B-Chemical
included	O
decreased	B-Disease
appetite	I-Disease
(	O
36	O
%	O
)	O
,	O
dry	B-Disease
mouth	I-Disease
(	O
10	O
%	O
)	O
,	O
behavioral	O
change	O
(	O
22	O
%	O
)	O
,	O
and	O
gastrointestinal	B-Disease
symptoms	I-Disease
(	O
18	O
%	O
)	O
;	O
mazindol	B-Chemical
dosage	O
was	O
reduced	O
in	O
43	O
%	O
of	O
patients	O
.	O

The	O
effect	O
of	O
mazindol	B-Chemical
on	O
GH	O
secretion	O
was	O
estimated	O
indirectly	O
by	O
comparing	O
the	O
postabsorptive	O
IGF	O
-	O
I	O
levels	O
obtained	O
following	O
3	O
,	O
6	O
,	O
9	O
,	O
and	O
12	O
months	O
in	O
the	O
mazindol	B-Chemical
treated	O
to	O
those	O
in	O
the	O
placebo	O
groups	O
.	O

Although	O
mazindol	B-Chemical
-	O
treated	O
patients	O
gained	O
less	O
weight	O
and	O
height	O
than	O
placebo	O
-	O
treated	O
patients	O
,	O
no	O
significant	O
effect	O
on	O
IGF	O
-	O
I	O
levels	O
was	O
observed	O
.	O

Mazindol	B-Chemical
doses	O
not	O
slow	O
the	O
progression	O
of	O
weakness	B-Disease
in	O
Duchenne	B-Disease
dystrophy	I-Disease
.	O

Facilitation	O
of	O
memory	O
retrieval	O
by	O
pre	O
-	O
test	O
morphine	B-Chemical
and	O
its	O
state	O
dependency	O
in	O
the	O
step	O
-	O
through	O
type	O
passive	O
avoidance	O
learning	O
test	O
in	O
mice	O
.	O

Amnesia	B-Disease
produced	O
by	O
scopolamine	B-Chemical
and	O
cycloheximide	B-Chemical
were	O
reversed	O
by	O
morphine	B-Chemical
given	O
30	O
min	O
before	O
the	O
test	O
trial	O
(	O
pre	O
-	O
test	O
)	O
,	O
and	O
pre	O
-	O
test	O
morphine	B-Chemical
also	O
facilitated	O
the	O
memory	O
retrieval	O
in	O
the	O
animals	O
administered	O
naloxone	B-Chemical
during	O
the	O
training	O
trial	O
.	O

Similarly	O
,	O
pre	O
-	O
test	O
scopolamine	B-Chemical
partially	O
reversed	O
the	O
scopolamine	B-Chemical
-	O
induced	O
amnesia	B-Disease
,	O
but	O
not	O
significantly	O
;	O
and	O
pre	O
-	O
test	O
cycloheximide	B-Chemical
failed	O
to	O
reverse	O
the	O
cycloheximide	B-Chemical
-	O
induced	O
amnesia	B-Disease
.	O

These	O
results	O
suggest	O
that	O
the	O
facilitation	O
of	O
memory	O
retrieval	O
by	O
pre	O
-	O
test	O
morphine	B-Chemical
might	O
be	O
the	O
direct	O
action	O
of	O
morphine	B-Chemical
rather	O
than	O
a	O
state	O
dependent	O
effect	O
.	O

Naloxone	B-Chemical
reverses	O
the	O
antihypertensive	O
effect	O
of	O
clonidine	B-Chemical
.	O

In	O
unanesthetized	O
,	O
spontaneously	O
hypertensive	B-Disease
rats	O
the	O
decrease	O
in	O
blood	O
pressure	O
and	O
heart	O
rate	O
produced	O
by	O
intravenous	O
clonidine	B-Chemical
,	O
5	O
to	O
20	O
micrograms	O
/	O
kg	O
,	O
was	O
inhibited	O
or	O
reversed	O
by	O
nalozone	B-Chemical
,	O
0	O
.	O
2	O
to	O
2	O
mg	O
/	O
kg	O
.	O

The	O
hypotensive	B-Disease
effect	O
of	O
100	O
mg	O
/	O
kg	O
alpha	B-Chemical
-	I-Chemical
methyldopa	I-Chemical
was	O
also	O
partially	O
reversed	O
by	O
naloxone	B-Chemical
.	O

Naloxone	B-Chemical
alone	O
did	O
not	O
affect	O
either	O
blood	O
pressure	O
or	O
heart	O
rate	O
.	O

In	O
brain	O
membranes	O
from	O
spontaneously	O
hypertensive	B-Disease
rats	O
clonidine	B-Chemical
,	O
10	O
(	O
-	O
8	O
)	O
to	O
10	O
(	O
-	O
5	O
)	O
M	O
,	O
did	O
not	O
influence	O
stereoselective	O
binding	O
of	O
[	B-Chemical
3H	I-Chemical
]	I-Chemical
-	I-Chemical
naloxone	I-Chemical
(	O
8	O
nM	O
)	O
,	O
and	O
naloxone	B-Chemical
,	O
10	O
(	O
-	O
8	O
)	O
to	O
10	O
(	O
-	O
4	O
)	O
M	O
,	O
did	O
not	O
influence	O
clonidine	B-Chemical
-	O
suppressible	O
binding	O
of	O
[	B-Chemical
3H	I-Chemical
]	I-Chemical
-	I-Chemical
dihydroergocryptine	I-Chemical
(	O
1	O
nM	O
)	O
.	O

These	O
findings	O
indicate	O
that	O
in	O
spontaneously	O
hypertensive	B-Disease
rats	O
the	O
effects	O
of	O
central	O
alpha	O
-	O
adrenoceptor	O
stimulation	O
involve	O
activation	O
of	O
opiate	O
receptors	O
.	O

As	O
naloxone	B-Chemical
and	O
clonidine	B-Chemical
do	O
not	O
appear	O
to	O
interact	O
with	O
the	O
same	O
receptor	O
site	O
,	O
the	O
observed	O
functional	O
antagonism	O
suggests	O
the	O
release	O
of	O
an	O
endogenous	O
opiate	O
by	O
clonidine	B-Chemical
or	O
alpha	B-Chemical
-	I-Chemical
methyldopa	I-Chemical
and	O
the	O
possible	O
role	O
of	O
the	O
opiate	O
in	O
the	O
central	O
control	O
of	O
sympathetic	O
tone	O
.	O

Neurotoxicity	B-Disease
of	O
halogenated	B-Chemical
hydroxyquinolines	I-Chemical
:	O
clinical	O
analysis	O
of	O
cases	O
reported	O
outside	O
Japan	O
.	O

An	O
analysis	O
is	O
presented	O
of	O
220	O
cases	O
of	O
possible	O
neurotoxic	B-Disease
reactions	O
to	O
halogenated	B-Chemical
hydroxyquinolines	I-Chemical
reported	O
from	O
outside	O
Japan	O
.	O

In	O
80	O
cases	O
insufficient	O
information	O
was	O
available	O
for	O
adequate	O
comment	O
and	O
in	O
29	O
a	O
relationship	O
to	O
the	O
administration	O
of	O
clioquinol	B-Chemical
could	O
be	O
excluded	O
.	O

Of	O
the	O
remainder	O
,	O
a	O
relationship	O
to	O
clioquinol	B-Chemical
was	O
considered	O
probable	O
in	O
42	O
and	O
possible	O
in	O
69	O
cases	O
.	O

In	O
six	O
of	O
the	O
probable	O
cases	O
the	O
neurological	B-Disease
disturbance	I-Disease
consisted	O
of	O
an	O
acute	O
reversible	O
encephalopathy	B-Disease
usually	O
related	O
to	O
the	O
ingestion	O
of	O
a	O
high	O
dose	O
of	O
clioquinol	B-Chemical
over	O
a	O
short	O
period	O
.	O

The	O
most	O
common	O
manifestation	O
,	O
observed	O
in	O
15	O
further	O
cases	O
,	O
was	O
isolated	O
optic	B-Disease
atrophy	I-Disease
.	O

This	O
was	O
most	O
frequently	O
found	O
in	O
children	O
,	O
many	O
of	O
whom	O
had	O
received	O
clioquinol	B-Chemical
as	O
treatment	O
for	O
acrodermatitis	B-Disease
enteropathica	I-Disease
.	O

In	O
the	O
remaining	O
cases	O
,	O
a	O
combination	O
of	O
myelopathy	B-Disease
,	O
visual	B-Disease
disturbance	I-Disease
,	O
and	O
peripheral	B-Disease
neuropathy	I-Disease
was	O
the	O
most	O
common	O
manifestation	O
.	O

Isolated	O
myelopathy	B-Disease
or	O
peripheral	B-Disease
neuropathy	I-Disease
,	O
or	O
these	O
manifestations	O
occurring	O
together	O
,	O
were	O
infrequent	O
.	O

The	O
onset	O
of	O
all	O
manifestations	O
(	O
except	O
toxic	O
encephalopathy	B-Disease
)	O
was	O
usually	O
subacute	O
,	O
with	O
subsequent	O
partial	O
recovery	O
.	O

Older	O
subjects	O
tended	O
to	O
display	O
more	O
side	O
effects	O
.	O

The	O
full	O
syndrome	O
of	O
subacute	O
myelo	B-Disease
-	I-Disease
optic	I-Disease
neuropathy	I-Disease
was	O
more	O
frequent	O
in	O
women	O
,	O
but	O
they	O
tended	O
to	O
have	O
taken	O
greater	O
quantities	O
of	O
the	O
drug	O
.	O

Prazosin	B-Chemical
-	O
induced	O
stress	B-Disease
incontinence	I-Disease
.	O

A	O
case	O
of	O
genuine	O
stress	B-Disease
incontinence	I-Disease
due	O
to	O
prazosin	B-Chemical
,	O
a	O
common	O
antihypertensive	O
drug	O
,	O
is	O
presented	O
.	O

Prazosin	B-Chemical
exerts	O
its	O
antihypertensive	O
effects	O
through	O
vasodilatation	O
caused	O
by	O
selective	O
blockade	O
of	O
postsynaptic	O
alpha	O
-	O
1	O
adrenergic	O
receptors	O
.	O

As	O
an	O
alpha	O
-	O
blocker	O
,	O
it	O
also	O
exerts	O
a	O
significant	O
relaxant	O
effect	O
on	O
the	O
bladder	O
neck	O
and	O
urethra	O
.	O

The	O
patient	O
'	O
s	O
clinical	O
course	O
is	O
described	O
and	O
correlated	O
with	O
initial	O
urodynamic	O
studies	O
while	O
on	O
prazosin	B-Chemical
and	O
subsequent	O
studies	O
while	O
taking	O
verapamil	B-Chemical
.	O

Her	O
incontinence	B-Disease
resolved	O
with	O
the	O
change	O
of	O
medication	O
.	O

The	O
restoration	O
of	O
continence	O
was	O
accompanied	O
by	O
a	O
substantial	O
rise	O
in	O
maximum	O
urethral	O
pressure	O
,	O
maximum	O
urethral	O
closure	O
pressure	O
,	O
and	O
functional	O
urethral	O
length	O
.	O

Patients	O
who	O
present	O
with	O
stress	B-Disease
incontinence	I-Disease
while	O
taking	O
prazosin	B-Chemical
should	O
change	O
their	O
antihypertensive	O
medication	O
before	O
considering	O
surgery	O
,	O
because	O
their	O
incontinence	B-Disease
may	O
resolve	O
spontaneously	O
with	O
a	O
change	O
in	O
drug	O
therapy	O
.	O

Myocardial	B-Disease
infarction	I-Disease
following	O
sublingual	O
administration	O
of	O
isosorbide	B-Chemical
dinitrate	I-Chemical
.	O

A	O
78	O
-	O
year	O
-	O
old	O
with	O
healed	O
septal	O
necrosis	B-Disease
suffered	O
a	O
recurrent	O
myocardial	B-Disease
infarction	I-Disease
of	O
the	O
anterior	O
wall	O
following	O
the	O
administration	O
of	O
isosorbide	B-Chemical
dinitrate	I-Chemical
5	O
mg	O
sublingually	O
.	O

After	O
detailing	O
the	O
course	O
of	O
events	O
,	O
we	O
discuss	O
the	O
role	O
of	O
paradoxical	O
coronary	O
spasm	B-Disease
and	O
hypotension	B-Disease
-	O
mediated	O
myocardial	B-Disease
ischemia	I-Disease
occurring	O
downstream	O
to	O
significant	O
coronary	B-Disease
arterial	I-Disease
stenosis	I-Disease
in	O
the	O
pathophysiology	O
of	O
acute	B-Disease
coronary	I-Disease
insufficiency	I-Disease
.	O

Comparison	O
of	O
the	O
respiratory	O
effects	O
of	O
i	O
.	O
v	O
.	O
infusions	O
of	O
morphine	B-Chemical
and	O
regional	O
analgesia	O
by	O
extradural	O
block	O
.	O

The	O
incidence	O
of	O
postoperative	O
respiratory	O
apnoea	B-Disease
was	O
compared	O
between	O
five	O
patients	O
receiving	O
a	O
continuous	O
i	O
.	O
v	O
.	O
infusion	O
of	O
morphine	B-Chemical
(	O
mean	O
73	O
.	O
6	O
mg	O
)	O
and	O
five	O
patients	O
receiving	O
a	O
continuous	O
extradural	O
infusion	O
of	O
0	O
.	O
25	O
%	O
bupivacaine	B-Chemical
(	O
mean	O
192	O
mg	O
)	O
in	O
the	O
24	O
-	O
h	O
period	O
following	O
upper	O
abdominal	O
surgery	O
.	O

Monitoring	O
consisted	O
of	O
airflow	O
detection	O
by	O
a	O
carbon	B-Chemical
dioxide	I-Chemical
analyser	O
,	O
chest	O
wall	O
movement	O
detected	O
by	O
pneumatic	O
capsules	O
,	O
and	O
continuous	O
electrocardiograph	O
recorded	O
with	O
a	O
Holter	O
ambulatory	O
monitor	O
.	O

Both	O
obstructive	B-Disease
(	I-Disease
P	I-Disease
less	I-Disease
than	I-Disease
0	I-Disease
.	I-Disease
05	I-Disease
)	I-Disease
and	I-Disease
central	I-Disease
apnoea	I-Disease
(	O
P	O
less	O
than	O
0	O
.	O
05	O
)	O
occurred	O
more	O
frequently	O
in	O
patients	O
who	O
had	O
a	O
morphine	B-Chemical
infusion	O
.	O

There	O
was	O
also	O
a	O
higher	O
incidence	O
of	O
tachyarrhythmias	B-Disease
(	O
P	O
less	O
than	O
0	O
.	O
05	O
)	O
and	O
ventricular	B-Disease
ectopic	I-Disease
beats	I-Disease
(	O
P	O
less	O
than	O
0	O
.	O
05	O
)	O
in	O
the	O
morphine	B-Chemical
infusion	O
group	O
.	O

Effects	O
of	O
aminophylline	B-Chemical
on	O
the	O
threshold	O
for	O
initiating	O
ventricular	B-Disease
fibrillation	I-Disease
during	O
respiratory	B-Disease
failure	I-Disease
.	O

Cardiac	B-Disease
arrhythmias	I-Disease
have	O
frequently	O
been	O
reported	O
in	O
association	O
with	O
respiratory	B-Disease
failure	I-Disease
.	O

The	O
possible	O
additive	O
role	O
of	O
pharmacologic	O
agents	O
in	O
precipitating	O
cardiac	B-Disease
disturbances	I-Disease
in	O
patients	O
with	O
respiratory	B-Disease
failure	I-Disease
has	O
only	O
recently	O
been	O
emphasized	O
.	O

The	O
effects	O
of	O
aminophylline	B-Chemical
on	O
the	O
ventricular	B-Disease
fibrillation	I-Disease
threshold	O
during	O
normal	O
acid	O
-	O
base	O
conditions	O
and	O
during	O
respiratory	B-Disease
failure	I-Disease
were	O
studied	O
in	O
anesthetized	O
open	O
chest	O
dogs	O
.	O

The	O
ventricular	B-Disease
fibrillation	I-Disease
threshold	O
was	O
measured	O
by	O
passing	O
a	O
gated	O
train	O
of	O
12	O
constant	O
current	O
pulses	O
through	O
the	O
ventricular	O
myocardium	O
during	O
the	O
vulnerable	O
period	O
of	O
the	O
cardiac	O
cycle	O
.	O

During	O
the	O
infusion	O
of	O
aminophylline	B-Chemical
,	O
the	O
ventricular	B-Disease
fibrillation	I-Disease
threshold	O
was	O
reduced	O
by	O
30	O
to	O
40	O
percent	O
of	O
the	O
control	O
when	O
pH	O
and	O
partial	O
pressures	O
of	O
oxygen	B-Chemical
(	O
PO2	B-Chemical
)	O
and	O
carbon	B-Chemical
dioxide	I-Chemical
(	O
CO2	B-Chemical
)	O
were	O
kept	O
within	O
normal	O
limits	O
.	O

When	O
respiratory	B-Disease
failure	I-Disease
was	O
produced	O
by	O
hypoventilation	B-Disease
(	O
pH	O
7	O
.	O
05	O
to	O
7	O
.	O
25	O
;	O
PC02	O
70	O
to	O
100	O
mm	O
Hg	O
:	O
P02	O
20	O
to	O
40	O
mm	O
Hg	O
)	O
,	O
infusion	O
of	O
aminophylline	B-Chemical
resulted	O
in	O
an	O
even	O
greater	O
decrease	O
in	O
ventricular	B-Disease
fibrillation	I-Disease
threshold	O
to	O
60	O
percent	O
of	O
the	O
control	O
level	O
.	O

These	O
experiments	O
suggest	O
that	O
although	O
many	O
factors	O
may	O
contribute	O
to	O
the	O
increased	O
incidence	O
of	O
ventricular	B-Disease
arrhythmias	I-Disease
in	O
respiratory	B-Disease
failure	I-Disease
,	O
pharmacologic	O
agents	O
,	O
particularly	O
aminophylline	B-Chemical
,	O
may	O
play	O
a	O
significant	O
role	O
.	O

Pentoxifylline	B-Chemical
(	O
Trental	B-Chemical
)	O
does	O
not	O
inhibit	O
dipyridamole	B-Chemical
-	O
induced	O
coronary	O
hyperemia	B-Disease
:	O
implications	O
for	O
dipyridamole	B-Chemical
-	O
thallium	B-Chemical
-	O
201	O
myocardial	O
imaging	O
.	O

Dipyridamole	B-Chemical
-	O
thallium	B-Chemical
-	O
201	O
imaging	O
is	O
often	O
performed	O
in	O
patients	O
unable	O
to	O
exercise	O
because	O
of	O
peripheral	B-Disease
vascular	I-Disease
disease	I-Disease
.	O

Many	O
of	O
these	O
patients	O
are	O
taking	O
pentoxifylline	B-Chemical
(	O
Trental	B-Chemical
)	O
,	O
a	O
methylxanthine	B-Chemical
derivative	O
which	O
may	O
improve	O
intermittent	B-Disease
claudication	I-Disease
.	O

Whether	O
pentoxifylline	B-Chemical
inhibits	O
dipyridamole	B-Chemical
-	O
induced	O
coronary	O
hyperemia	B-Disease
like	O
other	O
methylxanthines	B-Chemical
such	O
as	O
theophylline	B-Chemical
and	O
should	O
be	O
stopped	O
prior	O
to	O
dipyridamole	B-Chemical
-	O
thallium	B-Chemical
-	O
201	O
imaging	O
is	O
unknown	O
.	O

Therefore	O
,	O
we	O
studied	O
the	O
hyperemic	O
response	O
to	O
dipyridamole	B-Chemical
in	O
seven	O
open	O
-	O
chest	O
anesthetized	O
dogs	O
after	O
pretreatment	O
with	O
either	O
pentoxifylline	B-Chemical
(	O
0	O
,	O
7	O
.	O
5	O
,	O
or	O
15	O
mg	O
/	O
kg	O
i	O
.	O
v	O
.	O
)	O
or	O
theophylline	B-Chemical
(	O
3	O
mg	O
/	O
kg	O
i	O
.	O
v	O
.	O
)	O
.	O

Baseline	O
circumflex	O
coronary	O
blood	O
flows	O
did	O
not	O
differ	O
significantly	O
among	O
treatment	O
groups	O
.	O

Dipyridamole	B-Chemical
significantly	O
increased	O
coronary	O
blood	O
flow	O
before	O
and	O
after	O
7	O
.	O
5	O
or	O
15	O
mm	O
/	O
kg	O
i	O
.	O
v	O
.	O
pentoxifylline	B-Chemical
(	O
p	O
less	O
than	O
0	O
.	O
002	O
)	O
.	O

Neither	O
dose	O
of	O
pentoxifylline	B-Chemical
significantly	O
decreased	O
the	O
dipyridamole	B-Chemical
-	O
induced	O
hyperemia	B-Disease
,	O
while	O
peak	O
coronary	O
blood	O
flow	O
was	O
significantly	O
lower	O
after	O
theophylline	B-Chemical
(	O
p	O
less	O
than	O
0	O
.	O
01	O
)	O
.	O

We	O
conclude	O
that	O
pentoxyifylline	B-Chemical
does	O
not	O
inhibit	O
dipyridamole	B-Chemical
-	O
induced	O
coronary	O
hyperemia	B-Disease
even	O
at	O
high	O
doses	O
.	O

Cause	O
of	O
death	B-Disease
among	O
patients	O
with	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
:	O
a	O
rare	O
mortality	O
due	O
to	O
cerebral	B-Disease
haemorrhage	I-Disease
.	O

Causes	O
of	O
death	B-Disease
,	O
with	O
special	O
reference	O
to	O
cerebral	B-Disease
haemorrhage	I-Disease
,	O
among	O
240	O
patients	O
with	O
pathologically	O
verified	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
were	O
investigated	O
using	O
the	O
Annuals	O
of	O
the	O
Pathological	O
Autopsy	O
Cases	O
in	O
Japan	O
from	O
1981	O
to	O
1985	O
.	O

The	O
leading	O
causes	O
of	O
death	B-Disease
were	O
pneumonia	B-Disease
and	O
bronchitis	B-Disease
(	O
44	O
.	O
1	O
%	O
)	O
,	O
malignant	O
neoplasms	B-Disease
(	O
11	O
.	O
6	O
%	O
)	O
,	O
heart	B-Disease
diseases	I-Disease
(	O
4	O
.	O
1	O
%	O
)	O
,	O
cerebral	B-Disease
infarction	I-Disease
(	O
3	O
.	O
7	O
%	O
)	O
and	O
septicaemia	B-Disease
(	O
3	O
.	O
3	O
%	O
)	O
.	O

Cerebral	B-Disease
haemorrhage	I-Disease
was	O
the	O
11th	O
most	O
frequent	O
cause	O
of	O
death	B-Disease
,	O
accounting	O
for	O
only	O
0	O
.	O
8	O
%	O
of	O
deaths	B-Disease
among	O
the	O
patients	O
,	O
whereas	O
it	O
was	O
the	O
5th	O
most	O
common	O
cause	O
of	O
death	B-Disease
among	O
the	O
Japanese	O
general	O
population	O
in	O
1985	O
.	O

The	O
low	O
incidence	O
of	O
cerebral	B-Disease
haemorrhage	I-Disease
as	O
a	O
cause	O
of	O
death	B-Disease
in	O
patients	O
with	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
may	O
reflect	O
the	O
hypotensive	B-Disease
effect	O
of	O
levodopa	B-Chemical
and	O
a	O
hypotensive	B-Disease
mechanism	O
due	O
to	O
reduced	O
noradrenaline	B-Chemical
levels	O
in	O
the	O
parkinsonian	B-Disease
brain	O
.	O

Possible	O
intramuscular	O
midazolam	B-Chemical
-	O
associated	O
cardiorespiratory	B-Disease
arrest	I-Disease
and	O
death	B-Disease
.	O

Midazolam	B-Chemical
hydrochloride	I-Chemical
is	O
commonly	O
used	O
for	O
dental	O
or	O
endoscopic	O
procedures	O
.	O

Although	O
generally	O
consisted	O
safe	O
when	O
given	O
intramuscularly	O
,	O
intravenous	O
administration	O
is	O
known	O
to	O
cause	O
respiratory	B-Disease
and	I-Disease
cardiovascular	I-Disease
depression	I-Disease
.	O

This	O
report	O
describes	O
the	O
first	O
published	O
case	O
of	O
cardiorespiratory	B-Disease
arrest	I-Disease
and	O
death	B-Disease
associated	O
with	O
intramuscular	O
administration	O
of	O
midazolam	B-Chemical
.	O

Information	O
regarding	O
midazolam	B-Chemical
use	O
is	O
reviewed	O
to	O
provide	O
recommendation	O
for	O
safe	O
administration	O
.	O

Myasthenia	B-Disease
gravis	I-Disease
presenting	O
as	O
weakness	O
after	O
magnesium	B-Chemical
administration	O
.	O

We	O
studied	O
a	O
patient	O
with	O
no	O
prior	O
history	O
of	O
neuromuscular	B-Disease
disease	I-Disease
who	O
became	O
virtually	O
quadriplegic	B-Disease
after	O
parenteral	O
magnesium	B-Chemical
administration	O
for	O
preeclampsia	B-Disease
.	O

The	O
serum	O
magnesium	B-Chemical
concentration	O
was	O
3	O
.	O
0	O
mEq	O
/	O
L	O
,	O
which	O
is	O
usually	O
well	O
tolerated	O
.	O

The	O
magnesium	B-Chemical
was	O
stopped	O
and	O
she	O
recovered	O
over	O
a	O
few	O
days	O
.	O

While	O
she	O
was	O
weak	O
,	O
2	O
-	O
Hz	O
repetitive	O
stimulation	O
revealed	O
a	O
decrement	O
without	O
significant	O
facilitation	O
at	O
rapid	O
rates	O
or	O
after	O
exercise	O
,	O
suggesting	O
postsynaptic	B-Disease
neuromuscular	I-Disease
blockade	I-Disease
.	O

After	O
her	O
strength	O
returned	O
,	O
repetitive	O
stimulation	O
was	O
normal	O
,	O
but	O
single	O
fiber	O
EMG	O
revealed	O
increased	O
jitter	O
and	O
blocking	O
.	O

Her	O
acetylcholine	B-Chemical
receptor	O
antibody	O
level	O
was	O
markedly	O
elevated	O
.	O

Although	O
paralysis	B-Disease
after	O
magnesium	B-Chemical
administration	O
has	O
been	O
described	O
in	O
patients	O
with	O
known	O
myasthenia	B-Disease
gravis	I-Disease
,	O
it	O
has	O
not	O
previously	O
been	O
reported	O
to	O
be	O
the	O
initial	O
or	O
only	O
manifestation	O
of	O
the	O
disease	O
.	O

Patients	O
who	O
are	O
unusually	O
sensitive	O
to	O
the	O
neuromuscular	O
effects	O
of	O
magnesium	B-Chemical
should	O
be	O
suspected	O
of	O
having	O
an	O
underlying	O
disorder	B-Disease
of	I-Disease
neuromuscular	I-Disease
transmission	I-Disease
.	O

No	O
enhancement	O
by	O
phenobarbital	B-Chemical
of	O
the	O
hepatocarcinogenicity	O
of	O
a	O
choline	B-Chemical
-	O
devoid	O
diet	O
in	O
the	O
rat	O
.	O

An	O
experiment	O
was	O
performed	O
to	O
test	O
whether	O
inclusion	O
of	O
phenobarbital	B-Chemical
in	O
a	O
choline	B-Chemical
-	O
devoid	O
diet	O
would	O
increase	O
the	O
hepatocarcinogenicity	O
of	O
the	O
diet	O
.	O

Groups	O
of	O
5	O
-	O
week	O
old	O
male	O
Fischer	O
-	O
344	O
rats	O
were	O
fed	O
for	O
7	O
-	O
25	O
months	O
semipurified	O
choline	B-Chemical
-	O
devoid	O
or	O
choline	B-Chemical
-	O
supplemented	O
diets	O
,	O
containing	O
or	O
not	O
0	O
.	O
06	O
%	O
phenobarbital	B-Chemical
.	O

No	O
hepatic	O
preneoplastic	O
nodules	O
or	O
hepatocellular	B-Disease
carcinomas	I-Disease
developed	O
in	O
rats	O
fed	O
the	O
plain	O
choline	B-Chemical
-	O
supplemented	O
diet	O
,	O
while	O
one	O
preneoplastic	O
nodule	O
and	O
one	O
hepatocellular	B-Disease
carcinoma	I-Disease
developed	O
in	O
two	O
rats	O
fed	O
the	O
same	O
diet	O
containing	O
phenobarbital	B-Chemical
.	O

The	O
incidence	O
of	O
preneoplastic	O
nodules	O
and	O
of	O
hepatocellular	B-Disease
carcinomas	I-Disease
was	O
10	O
%	O
and	O
37	O
%	O
,	O
respectively	O
,	O
in	O
rats	O
fed	O
the	O
plain	O
choline	B-Chemical
-	O
devoid	O
diet	O
,	O
and	O
17	O
%	O
and	O
30	O
%	O
,	O
in	O
rats	O
fed	O
the	O
phenobarbital	B-Chemical
-	O
containing	O
choline	B-Chemical
-	O
devoid	O
diet	O
.	O

The	O
results	O
evinced	O
no	O
enhancement	O
of	O
the	O
hepatocarcinogenicity	O
of	O
the	O
choline	B-Chemical
-	O
devoid	O
diet	O
by	O
phenobarbital	B-Chemical
.	O

Sporadic	O
neoplastic	O
lesions	O
were	O
observed	O
in	O
organs	O
other	O
than	O
the	O
liver	O
of	O
some	O
of	O
the	O
animals	O
,	O
irrespective	O
of	O
the	O
diet	O
fed	O
.	O

On	O
two	O
paradoxical	O
side	O
-	O
effects	O
of	O
prednisolone	B-Chemical
in	O
rats	O
,	O
ribosomal	O
RNA	O
biosyntheses	O
,	O
and	O
a	O
mechanism	O
of	O
action	O
.	O

Liver	B-Disease
enlargement	I-Disease
and	O
muscle	B-Disease
wastage	I-Disease
occurred	O
in	O
Wistar	O
rats	O
following	O
the	O
subcutaneous	O
administration	O
of	O
prednisolone	B-Chemical
.	O

In	O
the	O
liver	O
both	O
the	O
content	O
of	O
RNA	O
and	O
the	O
biosynthesis	O
of	O
ribosomal	O
RNA	O
increased	O
while	O
both	O
the	O
RNA	O
content	O
and	O
ribosomal	O
RNA	O
biosynthesis	O
were	O
reduced	O
in	O
the	O
gastrocnemius	O
muscle	O
.	O

It	O
is	O
suggested	O
that	O
the	O
drug	O
acted	O
in	O
a	O
selective	O
and	O
tissue	O
-	O
specific	O
manner	O
to	O
enhance	O
ribosomal	O
RNA	O
synthesis	O
in	O
the	O
liver	O
and	O
depress	O
such	O
synthesis	O
in	O
the	O
muscle	O
.	O

This	O
view	O
supports	O
the	O
contention	O
that	O
the	O
liver	O
and	O
muscle	O
are	O
independent	O
sites	O
of	O
prednisolone	B-Chemical
action	O
.	O

Differential	O
effects	O
of	O
gamma	B-Chemical
-	I-Chemical
hexachlorocyclohexane	I-Chemical
(	O
lindane	B-Chemical
)	O
on	O
pharmacologically	O
-	O
induced	O
seizures	B-Disease
.	O

Gamma	B-Chemical
-	I-Chemical
hexachlorocyclohexane	I-Chemical
(	O
gamma	B-Chemical
-	I-Chemical
HCH	I-Chemical
)	O
,	O
the	O
active	O
ingredient	O
of	O
the	O
insecticide	O
lindane	B-Chemical
,	O
has	O
been	O
shown	O
to	O
decrease	O
seizure	B-Disease
threshold	O
to	O
pentylenetrazol	O
(	O
PTZ	B-Chemical
)	O
3	O
h	O
after	O
exposure	O
to	O
gamma	B-Chemical
-	I-Chemical
HCH	I-Chemical
and	O
conversely	O
increase	O
threshold	O
to	O
PTZ	B-Chemical
-	O
induced	O
seizures	B-Disease
24	O
h	O
after	O
exposure	O
to	O
gamma	B-Chemical
-	I-Chemical
HCH	I-Chemical
(	O
Vohland	O
et	O
al	O
.	O
1981	O
)	O
.	O

In	O
this	O
study	O
,	O
the	O
severity	O
of	O
response	O
to	O
other	O
seizure	B-Disease
-	O
inducing	O
agents	O
was	O
tested	O
in	O
mice	O
1	O
and	O
24	O
h	O
after	O
intraperitoneal	O
administration	O
of	O
80	O
mg	O
/	O
kg	O
gamma	B-Chemical
-	I-Chemical
HCH	I-Chemical
.	O

One	O
hour	O
after	O
the	O
administration	O
of	O
gamma	B-Chemical
-	I-Chemical
HCH	I-Chemical
,	O
the	O
activity	O
of	O
seizure	B-Disease
-	O
inducing	O
agents	O
was	O
increased	O
,	O
regardless	O
of	O
their	O
mechanism	O
,	O
while	O
24	O
h	O
after	O
gamma	B-Chemical
-	I-Chemical
HCH	I-Chemical
a	O
differential	O
response	O
was	O
observed	O
.	O

Seizure	B-Disease
activity	O
due	O
to	O
PTZ	B-Chemical
and	O
picrotoxin	B-Chemical
(	O
PTX	B-Chemical
)	O
was	O
significantly	O
decreased	O
;	O
however	O
,	O
seizure	B-Disease
activity	O
due	O
to	O
3	B-Chemical
-	I-Chemical
mercaptopropionic	I-Chemical
acid	I-Chemical
(	O
MPA	B-Chemical
)	O
,	O
bicuculline	B-Chemical
(	O
BCC	B-Chemical
)	O
,	O
methyl	B-Chemical
6	I-Chemical
,	I-Chemical
7	I-Chemical
-	I-Chemical
dimethoxy	I-Chemical
-	I-Chemical
4	I-Chemical
-	I-Chemical
ethyl	I-Chemical
-	I-Chemical
B	I-Chemical
-	I-Chemical
carboline	I-Chemical
-	I-Chemical
3	I-Chemical
-	I-Chemical
carboxylate	I-Chemical
(	O
DMCM	B-Chemical
)	O
,	O
or	O
strychnine	B-Chemical
(	O
STR	B-Chemical
)	O
was	O
not	O
different	O
from	O
control	O
.	O

In	O
vitro	O
,	O
gamma	B-Chemical
-	I-Chemical
HCH	I-Chemical
,	O
pentylenetetrazol	B-Chemical
and	O
picrotoxin	B-Chemical
were	O
shown	O
to	O
inhibit	O
3H	B-Chemical
-	I-Chemical
TBOB	I-Chemical
binding	O
in	O
mouse	O
whole	O
brain	O
,	O
with	O
IC50	O
values	O
of	O
4	O
.	O
6	O
,	O
404	O
and	O
9	O
.	O
4	O
microM	O
,	O
respectively	O
.	O

MPA	B-Chemical
,	O
BCC	B-Chemical
,	O
DMCM	B-Chemical
,	O
and	O
STR	B-Chemical
showed	O
no	O
inhibition	O
of	O
3H	B-Chemical
-	I-Chemical
TBOB	I-Chemical
(	O
t	B-Chemical
-	I-Chemical
butyl	I-Chemical
bicyclo	I-Chemical
-	I-Chemical
orthobenzoate	I-Chemical
)	O
binding	O
at	O
concentrations	O
of	O
100	O
micron	O
.	O

The	O
pharmacological	O
challenge	O
data	O
suggest	O
that	O
tolerance	O
may	O
occur	O
to	O
seizure	B-Disease
activity	O
induced	O
by	O
PTZ	B-Chemical
and	O
PTX	B-Chemical
24	O
h	O
after	O
gamma	B-Chemical
-	I-Chemical
HCH	I-Chemical
,	O
since	O
the	O
response	O
to	O
only	O
these	O
two	O
seizure	B-Disease
-	O
inducing	O
agents	O
is	O
decreased	O
.	O

The	O
in	O
vitro	O
data	O
suggest	O
that	O
the	O
site	O
responsible	O
for	O
the	O
decrease	O
in	O
seizure	B-Disease
activity	O
24	O
h	O
after	O
gamma	B-Chemical
-	I-Chemical
HCH	I-Chemical
may	O
be	O
the	O
GABA	B-Chemical
-	O
A	O
receptor	O
-	O
linked	O
chloride	O
channel	O
.	O

Tolerance	O
and	O
antiviral	O
effect	O
of	O
ribavirin	B-Chemical
in	O
patients	O
with	O
Argentine	B-Disease
hemorrhagic	I-Disease
fever	I-Disease
.	O

Tolerance	O
and	O
antiviral	O
effect	O
of	O
ribavirin	B-Chemical
was	O
studied	O
in	O
6	O
patients	O
with	O
Argentine	B-Disease
hemorrhagic	I-Disease
fever	I-Disease
(	O
AHF	B-Disease
)	O
of	O
more	O
than	O
8	O
days	O
of	O
evolution	O
.	O

Administration	O
of	O
ribavirin	B-Chemical
resulted	O
in	O
a	O
neutralization	O
of	O
viremia	B-Disease
and	O
a	O
drop	O
of	O
endogenous	O
interferon	O
titers	O
.	O

The	O
average	O
time	O
of	O
death	B-Disease
was	O
delayed	O
.	O

A	O
reversible	O
anemia	B-Disease
was	O
the	O
only	O
adverse	O
effect	O
observed	O
.	O

From	O
these	O
results	O
,	O
we	O
conclude	O
that	O
ribavirin	B-Chemical
has	O
an	O
antiviral	O
effect	O
in	O
advanced	O
cases	O
of	O
AHF	B-Disease
,	O
and	O
that	O
anemia	B-Disease
,	O
the	O
only	O
secondary	O
reaction	O
observed	O
,	O
can	O
be	O
easily	O
managed	O
.	O

The	O
possible	O
beneficial	O
effect	O
of	O
ribavirin	B-Chemical
during	O
the	O
initial	O
days	O
of	O
AHF	B-Disease
is	O
discussed	O
.	O

Is	O
the	O
treatment	O
of	O
scabies	B-Disease
hazardous	O
?	O

Treatment	O
for	O
scabies	B-Disease
is	O
usually	O
initiated	O
by	O
general	O
practitioners	O
;	O
most	O
consider	O
lindane	B-Chemical
(	O
gamma	B-Chemical
benzene	I-Chemical
hexachloride	I-Chemical
)	O
the	O
treatment	O
of	O
choice	O
.	O

Lindane	B-Chemical
is	O
also	O
widely	O
used	O
as	O
an	O
agricultural	O
and	O
industrial	O
pesticide	O
,	O
and	O
as	O
a	O
result	O
the	O
toxic	O
profile	O
of	O
this	O
insecticide	O
is	O
well	O
understood	O
.	O

Evidence	O
is	O
accumulating	O
that	O
lindane	B-Chemical
can	O
be	O
toxic	B-Disease
to	I-Disease
the	I-Disease
central	I-Disease
nervous	I-Disease
system	I-Disease
and	O
may	O
be	O
associated	O
with	O
aplastic	B-Disease
anaemia	I-Disease
.	O

Preparations	O
containing	O
lindane	B-Chemical
continue	O
to	O
be	O
sold	O
over	O
the	O
counter	O
and	O
may	O
represent	O
a	O
hazard	O
to	O
poorly	O
informed	O
patients	O
.	O

This	O
literature	O
review	O
suggests	O
that	O
general	O
practitioners	O
should	O
prescribe	O
scabicides	O
with	O
increased	O
caution	O
for	O
certain	O
at	O
-	O
risk	O
groups	O
,	O
and	O
give	O
adequate	O
warnings	O
regarding	O
potential	O
toxicity	B-Disease
.	O

Mouse	O
strain	O
-	O
dependent	O
effect	O
of	O
amantadine	B-Chemical
on	O
motility	O
and	O
brain	O
biogenic	O
amines	B-Chemical
.	O

The	O
effect	O
of	O
amantadine	B-Chemical
hydrochloride	I-Chemical
,	O
injected	O
i	O
.	O
p	O
.	O
in	O
6	O
increments	O
of	O
100	O
mg	O
/	O
kg	O
each	O
over	O
30	O
hr	O
,	O
on	O
mouse	O
motility	O
and	O
whole	O
brain	O
content	O
of	O
selected	O
biogenic	O
amines	B-Chemical
and	O
major	O
metabolites	O
was	O
studied	O
in	O
4	O
strains	O
of	O
mice	O
.	O

These	O
were	O
the	O
albino	O
Sprague	O
-	O
Dawley	O
ICR	O
and	O
BALB	O
/	O
C	O
,	O
the	O
black	O
C57BL	O
/	O
6	O
and	O
the	O
brown	O
CDF	O
-	O
I	O
mouse	O
strains	O
.	O

Amantadine	B-Chemical
treatment	O
produced	O
a	O
biphasic	O
effect	O
on	O
mouse	O
motility	O
.	O

The	O
initial	O
dose	O
of	O
amantadine	B-Chemical
depressed	B-Disease
locomotor	O
activity	O
in	O
all	O
mouse	O
strains	O
studied	O
with	O
the	O
BALB	O
/	O
C	O
mice	O
being	O
the	O
most	O
sensitive	O
.	O

Subsequent	O
amantadine	B-Chemical
treatments	O
produced	O
enhancement	O
of	O
motility	O
from	O
corresponding	O
control	O
in	O
all	O
mouse	O
strains	O
with	O
the	O
BALB	O
/	O
C	O
mice	O
being	O
the	O
least	O
sensitive	O
.	O

The	O
locomotor	O
activity	O
was	O
decreased	O
from	O
corresponding	O
controls	O
in	O
all	O
strains	O
studied	O
,	O
except	O
for	O
the	O
ICR	O
mice	O
,	O
during	O
an	O
overnight	O
drug	O
-	O
free	O
period	O
following	O
the	O
fourth	O
amantadine	B-Chemical
treatment	O
.	O

Readministration	O
of	O
amantadine	B-Chemical
,	O
after	O
a	O
drug	O
-	O
free	O
overnight	O
period	O
,	O
increased	O
motility	O
from	O
respective	O
saline	O
control	O
in	O
all	O
strains	O
with	O
exception	O
of	O
the	O
BALB	O
/	O
C	O
mice	O
where	O
suppression	B-Disease
of	I-Disease
motility	I-Disease
occurred	O
.	O

Treatment	O
with	O
amantadine	B-Chemical
did	O
not	O
alter	O
whole	O
brain	O
dopamine	B-Chemical
levels	O
but	O
decreased	O
the	O
amounts	O
of	O
3	B-Chemical
,	I-Chemical
4	I-Chemical
-	I-Chemical
dihydroxyphenylacetic	I-Chemical
acid	I-Chemical
in	O
the	O
BALB	O
/	O
C	O
mice	O
compared	O
to	O
saline	O
control	O
.	O

Conversely	O
,	O
brain	O
normetanephrine	B-Chemical
concentration	O
was	O
increased	O
from	O
saline	O
control	O
by	O
amantadine	B-Chemical
in	O
the	O
BALB	O
/	O
C	O
mice	O
.	O

The	O
results	O
suggest	O
a	O
strain	O
-	O
dependent	O
effect	O
of	O
amantadine	B-Chemical
on	O
motility	O
and	O
indicate	O
a	O
differential	O
response	O
to	O
the	O
acute	O
and	O
multiple	O
dose	O
regimens	O
used	O
.	O

The	O
BALB	O
/	O
C	O
mouse	O
was	O
the	O
most	O
sensitive	O
strain	O
and	O
could	O
serve	O
as	O
the	O
strain	O
of	O
choice	O
for	O
evaluating	O
the	O
side	O
effects	O
of	O
amantadine	B-Chemical
.	O

The	O
biochemical	O
results	O
of	O
brain	O
biogenic	O
amines	B-Chemical
of	O
BALB	O
/	O
C	O
mouse	O
strain	O
suggest	O
a	O
probable	O
decrease	O
of	O
catecholamine	B-Chemical
turnover	O
rate	O
and	O
/	O
or	O
metabolism	O
by	O
monoamine	O
oxidase	O
and	O
a	O
resulting	O
increase	O
in	O
O	O
-	O
methylation	O
of	O
norepinephrine	B-Chemical
which	O
may	O
account	O
for	O
a	O
behavioral	B-Disease
depression	I-Disease
caused	O
by	O
amantadine	B-Chemical
in	O
the	O
BALB	O
/	O
C	O
mice	O
.	O

Chloroacetaldehyde	B-Chemical
and	O
its	O
contribution	O
to	O
urotoxicity	O
during	O
treatment	O
with	O
cyclophosphamide	B-Chemical
or	O
ifosfamide	B-Chemical
.	O

An	O
experimental	O
study	O
/	O
short	O
communication	O
.	O

Based	O
on	O
clinical	O
data	O
,	O
indicating	O
that	O
chloroacetaldehyde	B-Chemical
(	O
CAA	B-Chemical
)	O
is	O
an	O
important	O
metabolite	O
of	O
oxazaphosphorine	O
cytostatics	O
,	O
an	O
experimental	O
study	O
was	O
carried	O
out	O
in	O
order	O
to	O
elucidate	O
the	O
role	O
of	O
CAA	B-Chemical
in	O
the	O
development	O
of	O
hemorrhagic	B-Disease
cystitis	I-Disease
.	O

The	O
data	O
demonstrate	O
that	O
CAA	B-Chemical
after	O
i	O
.	O
v	O
.	O
administration	O
does	O
not	O
contribute	O
to	O
bladder	B-Disease
damage	I-Disease
.	O

When	O
instilled	O
directly	O
into	O
the	O
bladder	O
,	O
CAA	B-Chemical
exerts	O
urotoxic	O
effects	O
,	O
it	O
is	O
,	O
however	O
,	O
susceptible	O
to	O
detoxification	O
with	O
mesna	B-Chemical
.	O

Source	O
of	O
pain	B-Disease
and	O
primitive	O
dysfunction	O
in	O
migraine	B-Disease
:	O
an	O
identical	O
site	O
?	O

Twenty	O
common	O
migraine	B-Disease
patients	O
received	O
a	O
one	O
sided	O
frontotemporal	O
application	O
of	O
nitroglycerin	B-Chemical
(	O
10	O
patients	O
)	O
or	O
placebo	O
ointment	O
(	O
10	O
patients	O
)	O
in	O
a	O
double	O
blind	O
study	O
.	O

Early	O
onset	O
migraine	B-Disease
attacks	O
were	O
induced	O
by	O
nitroglycerin	B-Chemical
in	O
seven	O
out	O
of	O
10	O
patients	O
versus	O
no	O
patient	O
in	O
the	O
placebo	O
group	O
.	O

Subsequently	O
20	O
migraine	B-Disease
patients	O
,	O
who	O
developed	O
an	O
early	O
onset	O
attack	O
with	O
frontotemporal	O
nitroglycerin	B-Chemical
,	O
received	O
the	O
drug	O
in	O
a	O
second	O
induction	O
test	O
at	O
other	O
body	O
areas	O
.	O

No	O
early	O
onset	O
migraine	B-Disease
was	O
observed	O
.	O

Thus	O
the	O
migraine	B-Disease
-	O
inducing	O
effect	O
of	O
nitroglycerin	B-Chemical
seems	O
to	O
depend	O
on	O
direct	O
stimulation	O
of	O
the	O
habitual	O
site	O
of	O
pain	B-Disease
,	O
suggesting	O
that	O
the	O
frontotemporal	O
region	O
is	O
of	O
crucial	O
importance	O
in	O
the	O
development	O
of	O
a	O
migraine	B-Disease
crisis	O
.	O

This	O
is	O
not	O
consistent	O
with	O
a	O
CNS	O
origin	O
of	O
migraine	B-Disease
attack	O
.	O

Hypersensitivity	B-Disease
to	O
carbamazepine	B-Chemical
presenting	O
with	O
a	O
leukemoid	B-Disease
reaction	I-Disease
,	O
eosinophilia	B-Disease
,	O
erythroderma	B-Disease
,	O
and	O
renal	B-Disease
failure	I-Disease
.	O

We	O
report	O
a	O
patient	O
in	O
whom	O
hypersensitivity	B-Disease
to	O
carbamazepine	B-Chemical
presented	O
with	O
generalized	O
erythroderma	B-Disease
,	O
a	O
severe	O
leukemoid	B-Disease
reaction	I-Disease
,	O
eosinophilia	B-Disease
,	O
hyponatremia	B-Disease
,	O
and	O
renal	B-Disease
failure	I-Disease
.	O

This	O
is	O
the	O
first	O
report	O
of	O
such	O
an	O
unusual	O
reaction	O
to	O
carbamazepine	B-Chemical
.	O

Fluoxetine	B-Chemical
-	O
induced	O
akathisia	B-Disease
:	O
clinical	O
and	O
theoretical	O
implications	O
.	O

Five	O
patients	O
receiving	O
fluoxetine	B-Chemical
for	O
the	O
treatment	O
of	O
obsessive	B-Disease
compulsive	I-Disease
disorder	I-Disease
or	O
major	B-Disease
depression	I-Disease
developed	O
akathisia	B-Disease
.	O

The	O
typical	O
fluoxetine	B-Chemical
-	O
induced	O
symptoms	O
of	O
restlessness	O
,	O
constant	O
pacing	O
,	O
purposeless	O
movements	O
of	O
the	O
feet	O
and	O
legs	O
,	O
and	O
marked	O
anxiety	B-Disease
were	O
indistinguishable	O
from	O
those	O
of	O
neuroleptic	O
-	O
induced	O
akathisia	B-Disease
.	O

Three	O
patients	O
who	O
had	O
experienced	O
neuroleptic	O
-	O
induced	O
akathisia	B-Disease
in	O
the	O
past	O
reported	O
that	O
the	O
symptoms	O
of	O
fluoxetine	B-Chemical
-	O
induced	O
akathisia	B-Disease
were	O
identical	O
,	O
although	O
somewhat	O
milder	O
.	O

Akathisia	B-Disease
appeared	O
to	O
be	O
a	O
common	O
side	O
effect	O
of	O
fluoxetine	B-Chemical
and	O
generally	O
responded	O
well	O
to	O
treatment	O
with	O
the	O
beta	O
-	O
adrenergic	O
antagonist	O
propranolol	B-Chemical
,	O
dose	O
reduction	O
,	O
or	O
both	O
.	O

The	O
authors	O
suggest	O
that	O
fluoxetine	B-Chemical
-	O
induced	O
akathisia	B-Disease
may	O
be	O
caused	O
by	O
serotonergically	O
mediated	O
inhibition	O
of	O
dopaminergic	O
neurotransmission	O
and	O
that	O
the	O
pathophysiology	O
of	O
fluoxetine	B-Chemical
-	O
induced	O
akathisia	B-Disease
and	O
tricyclic	O
antidepressant	B-Chemical
-	O
induced	O
"	O
jitteriness	O
"	O
may	O
be	O
identical	O
.	O

Effect	O
of	O
converting	O
enzyme	O
inhibition	O
on	O
the	O
course	O
of	O
adriamycin	B-Chemical
-	O
induced	O
nephropathy	B-Disease
.	O

The	O
effect	O
of	O
the	O
converting	O
enzyme	O
inhibitor	O
(	O
CEI	O
)	O
enalapril	B-Chemical
was	O
assessed	O
in	O
Munich	O
-	O
Wistar	O
rats	O
with	O
established	O
adriamycin	B-Chemical
nephrosis	B-Disease
.	O

Rats	O
were	O
given	O
a	O
single	O
dose	O
of	O
adriamycin	B-Chemical
and	O
one	O
month	O
later	O
divided	O
into	O
four	O
groups	O
matched	O
for	O
albuminuria	B-Disease
,	O
blood	O
pressure	O
,	O
and	O
plasma	O
albumin	O
concentration	O
.	O

Groups	O
1	O
and	O
3	O
remained	O
untreated	O
while	O
groups	O
2	O
and	O
4	O
received	O
enalapril	B-Chemical
.	O

Groups	O
1	O
and	O
2	O
underwent	O
micropuncture	O
studies	O
after	O
10	O
days	O
.	O

These	O
short	O
-	O
term	O
studies	O
showed	O
that	O
enalapril	B-Chemical
reduced	O
arterial	O
blood	O
pressure	O
(	O
101	O
+	O
/	O
-	O
2	O
vs	O
.	O
124	O
+	O
/	O
-	O
3	O
mm	O
Hg	O
,	O
group	O
2	O
vs	O
.	O
1	O
,	O
P	O
less	O
than	O
0	O
.	O
05	O
)	O
and	O
glomerular	O
capillary	O
pressure	O
(	O
54	O
+	O
/	O
-	O
1	O
vs	O
.	O
61	O
+	O
/	O
-	O
2	O
mm	O
Hg	O
,	O
P	O
less	O
than	O
0	O
.	O
05	O
)	O
without	O
reducing	O
albuminuria	B-Disease
(	O
617	O
+	O
/	O
-	O
50	O
vs	O
.	O
570	O
+	O
/	O
-	O
47	O
mg	O
/	O
day	O
)	O
or	O
GFR	O
(	O
1	O
.	O
03	O
+	O
/	O
-	O
0	O
.	O
04	O
vs	O
.	O
1	O
.	O
04	O
+	O
/	O
-	O
0	O
.	O
11	O
ml	O
/	O
min	O
)	O
.	O

Groups	O
3	O
and	O
4	O
were	O
studied	O
at	O
four	O
and	O
at	O
six	O
months	O
to	O
assess	O
the	O
effect	O
of	O
enalapril	B-Chemical
on	O
progression	O
of	O
renal	B-Disease
injury	I-Disease
in	O
adriamycin	B-Chemical
nephrosis	B-Disease
.	O

Chronic	O
enalapril	B-Chemical
treatment	O
reduced	O
blood	O
pressure	O
without	O
reducing	O
albuminuria	B-Disease
in	O
group	O
4	O
.	O

Untreated	O
group	O
3	O
rats	O
exhibited	O
a	O
progressive	O
reduction	O
in	O
GFR	O
(	O
0	O
.	O
35	O
+	O
/	O
-	O
0	O
.	O
08	O
ml	O
/	O
min	O
at	O
4	O
months	O
,	O
0	O
.	O
27	O
+	O
/	O
-	O
0	O
.	O
07	O
ml	O
/	O
min	O
at	O
6	O
months	O
)	O
.	O

Enalapril	B-Chemical
treatment	O
blunted	O
but	O
did	O
not	O
prevent	O
reduction	O
in	O
GFR	O
in	O
group	O
4	O
(	O
0	O
.	O
86	O
+	O
/	O
-	O
0	O
.	O
15	O
ml	O
/	O
min	O
at	O
4	O
months	O
,	O
0	O
.	O
69	O
+	O
/	O
-	O
0	O
.	O
13	O
ml	O
/	O
min	O
at	O
6	O
months	O
,	O
both	O
P	O
less	O
than	O
0	O
.	O
05	O
vs	O
.	O
group	O
3	O
)	O
.	O

Reduction	O
in	O
GFR	O
was	O
associated	O
with	O
the	O
development	O
of	O
glomerular	B-Disease
sclerosis	I-Disease
in	O
both	O
treated	O
and	O
untreated	O
rats	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
250	O
WORDS	O
)	O

Clotiazepam	B-Chemical
-	O
induced	O
acute	O
hepatitis	B-Disease
.	O

We	O
report	O
the	O
case	O
of	O
a	O
patient	O
who	O
developed	O
acute	O
hepatitis	B-Disease
with	O
extensive	B-Disease
hepatocellular	I-Disease
necrosis	I-Disease
,	O
7	O
months	O
after	O
the	O
onset	O
of	O
administration	O
of	O
clotiazepam	B-Chemical
,	O
a	O
thienodiazepine	B-Chemical
derivative	O
.	O

Clotiazepam	B-Chemical
withdrawal	O
was	O
followed	O
by	O
prompt	O
recovery	O
.	O

The	O
administration	O
of	O
several	O
benzodiazepines	B-Chemical
,	O
chemically	O
related	O
to	O
clotiazepam	B-Chemical
,	O
did	O
not	O
interfere	O
with	O
recovery	O
and	O
did	O
not	O
induce	O
any	O
relapse	O
of	O
hepatitis	B-Disease
.	O

This	O
observation	O
shows	O
that	O
clotiazepam	B-Chemical
can	O
induce	O
acute	O
hepatitis	B-Disease
and	O
suggests	O
that	O
there	O
is	O
no	O
cross	O
hepatotoxicity	B-Disease
between	O
clotiazepam	B-Chemical
and	O
several	O
benzodiazepines	B-Chemical
.	O

5	B-Chemical
-	I-Chemical
azacytidine	I-Chemical
potentiates	O
initiation	B-Disease
induced	I-Disease
by	I-Disease
carcinogens	I-Disease
in	O
rat	O
liver	O
.	O

To	O
test	O
the	O
validity	O
of	O
the	O
hypothesis	O
that	O
hypomethylation	O
of	O
DNA	O
plays	O
an	O
important	O
role	O
in	O
the	O
initiation	B-Disease
of	I-Disease
carcinogenic	I-Disease
process	I-Disease
,	O
5	B-Chemical
-	I-Chemical
azacytidine	I-Chemical
(	O
5	B-Chemical
-	I-Chemical
AzC	I-Chemical
)	O
(	O
10	O
mg	O
/	O
kg	O
)	O
,	O
an	O
inhibitor	O
of	O
DNA	O
methylation	O
,	O
was	O
given	O
to	O
rats	O
during	O
the	O
phase	O
of	O
repair	O
synthesis	O
induced	O
by	O
the	O
three	O
carcinogens	O
,	O
benzo	B-Chemical
[	I-Chemical
a	I-Chemical
]	I-Chemical
-	I-Chemical
pyrene	I-Chemical
(	O
200	O
mg	O
/	O
kg	O
)	O
,	O
N	B-Chemical
-	I-Chemical
methyl	I-Chemical
-	I-Chemical
N	I-Chemical
-	I-Chemical
nitrosourea	I-Chemical
(	O
60	O
mg	O
/	O
kg	O
)	O
and	O
1	B-Chemical
,	I-Chemical
2	I-Chemical
-	I-Chemical
dimethylhydrazine	I-Chemical
(	O
1	B-Chemical
,	I-Chemical
2	I-Chemical
-	I-Chemical
DMH	I-Chemical
)	O
(	O
100	O
mg	O
/	O
kg	O
)	O
.	O

The	O
initiated	O
hepatocytes	O
in	O
the	O
liver	O
were	O
assayed	O
as	O
the	O
gamma	O
-	O
glutamyltransferase	O
(	O
gamma	O
-	O
GT	O
)	O
positive	O
foci	O
formed	O
following	O
a	O
2	O
-	O
week	O
selection	O
regimen	O
consisting	O
of	O
dietary	O
0	O
.	O
02	O
%	O
2	B-Chemical
-	I-Chemical
acetylaminofluorene	I-Chemical
coupled	O
with	O
a	O
necrogenic	O
dose	O
of	O
CCl4	B-Chemical
.	O

The	O
results	O
obtained	O
indicate	O
that	O
with	O
all	O
three	O
carcinogens	O
,	O
administration	O
of	O
5	B-Chemical
-	I-Chemical
AzC	I-Chemical
during	O
repair	O
synthesis	O
increased	O
the	O
incidence	O
of	O
initiated	O
hepatocytes	O
,	O
for	O
example	O
10	O
-	O
20	O
foci	O
/	O
cm2	O
in	O
5	B-Chemical
-	I-Chemical
AzC	I-Chemical
and	O
carcinogen	O
-	O
treated	O
rats	O
compared	O
with	O
3	O
-	O
5	O
foci	O
/	O
cm2	O
in	O
rats	O
treated	O
with	O
carcinogen	O
only	O
.	O

Administration	O
of	O
[	B-Chemical
3H	I-Chemical
]	I-Chemical
-	I-Chemical
5	I-Chemical
-	I-Chemical
azadeoxycytidine	I-Chemical
during	O
the	O
repair	O
synthesis	O
induced	O
by	O
1	B-Chemical
,	I-Chemical
2	I-Chemical
-	I-Chemical
DMH	I-Chemical
further	O
showed	O
that	O
0	O
.	O
019	O
mol	O
%	O
of	O
cytosine	B-Chemical
residues	O
in	O
DNA	O
were	O
substituted	O
by	O
the	O
analogue	O
,	O
indicating	O
that	O
incorporation	O
of	O
5	B-Chemical
-	I-Chemical
AzC	I-Chemical
occurs	O
during	O
repair	O
synthesis	O
.	O

In	O
the	O
absence	O
of	O
the	O
carcinogen	O
,	O
5	B-Chemical
-	I-Chemical
AzC	I-Chemical
given	O
after	O
a	O
two	O
thirds	O
partial	O
hepatectomy	O
,	O
when	O
its	O
incorporation	O
should	O
be	O
maximum	O
,	O
failed	O
to	O
induce	O
any	O
gamma	O
-	O
GT	O
positive	O
foci	O
.	O

The	O
results	O
suggest	O
that	O
hypomethylation	O
of	O
DNA	O
per	O
se	O
may	O
not	O
be	O
sufficient	O
for	O
initiation	O
.	O

Perhaps	O
two	O
events	O
might	O
be	O
necessary	O
for	O
initiation	O
,	O
the	O
first	O
caused	O
by	O
the	O
carcinogen	O
and	O
a	O
second	O
involving	O
hypomethylation	O
of	O
DNA	O
.	O

Antihypertensive	O
drugs	O
and	O
depression	B-Disease
:	O
a	O
reappraisal	O
.	O

Eighty	O
-	O
nine	O
new	O
referral	O
hypertensive	B-Disease
out	O
-	O
patients	O
and	O
46	O
new	O
referral	O
non	O
-	O
hypertensive	B-Disease
chronically	O
physically	O
ill	O
out	O
-	O
patients	O
completed	O
a	O
mood	O
rating	O
scale	O
at	O
regular	O
intervals	O
for	O
one	O
year	O
.	O

The	O
results	O
showed	O
a	O
high	O
prevalence	O
of	O
depression	B-Disease
in	O
both	O
groups	O
of	O
patients	O
,	O
with	O
no	O
preponderance	O
in	O
the	O
hypertensive	B-Disease
group	O
.	O

Hypertensive	B-Disease
patients	O
with	O
psychiatric	B-Disease
histories	O
had	O
a	O
higher	O
prevalence	O
of	O
depression	B-Disease
than	O
the	O
comparison	O
patients	O
.	O

This	O
was	O
accounted	O
for	O
by	O
a	O
significant	O
number	O
of	O
depressions	B-Disease
occurring	O
in	O
methyl	B-Chemical
dopa	I-Chemical
treated	O
patients	O
with	O
psychiatric	B-Disease
histories	O
.	O

Chronic	B-Disease
active	I-Disease
hepatitis	I-Disease
associated	O
with	O
diclofenac	B-Chemical
sodium	I-Chemical
therapy	O
.	O

Diclofenac	B-Chemical
sodium	I-Chemical
(	O
Voltarol	B-Chemical
,	O
Geigy	O
Pharmaceuticals	O
)	O
is	O
a	O
non	O
-	O
steroidal	O
anti	O
-	O
inflammatory	O
derivative	O
of	O
phenylacetic	B-Chemical
acid	I-Chemical
.	O

Although	O
generally	O
well	O
-	O
tolerated	O
,	O
asymptomatic	O
abnormalities	B-Disease
of	I-Disease
liver	I-Disease
function	I-Disease
have	O
been	O
recorded	O
and	O
,	O
less	O
commonly	O
,	O
severe	O
hepatitis	B-Disease
induced	O
by	O
diclofenac	B-Chemical
.	O

The	O
patient	O
described	O
developed	O
chronic	B-Disease
active	I-Disease
hepatitis	I-Disease
after	O
six	O
months	O
therapy	O
with	O
diclofenac	B-Chemical
sodium	I-Chemical
which	O
progressed	O
despite	O
the	O
withdrawal	O
of	O
the	O
drug	O
,	O
a	O
finding	O
not	O
previously	O
reported	O
.	O

Arterial	O
hypertension	B-Disease
as	O
a	O
complication	O
of	O
prolonged	O
ketoconazole	B-Chemical
treatment	O
.	O

Two	O
of	O
14	O
patients	O
with	O
Cushing	B-Disease
'	I-Disease
s	I-Disease
syndrome	I-Disease
treated	O
on	O
a	O
long	O
-	O
term	O
basis	O
with	O
ketoconazole	B-Chemical
developed	O
sustained	O
hypertension	B-Disease
.	O

In	O
both	O
cases	O
normal	O
plasma	O
and	O
urinary	O
free	O
cortisol	B-Chemical
levels	O
had	O
been	O
achieved	O
following	O
ketoconazole	B-Chemical
therapy	O
,	O
yet	O
continuous	O
blood	O
pressure	O
monitoring	O
demonstrated	O
hypertension	B-Disease
31	O
(	O
patient	O
1	O
)	O
and	O
52	O
weeks	O
(	O
patient	O
2	O
)	O
after	O
treatment	O
.	O

In	O
patient	O
1	O
,	O
plasma	O
levels	O
of	O
deoxycorticosterone	B-Chemical
and	O
11	B-Chemical
-	I-Chemical
deoxycortisol	I-Chemical
were	O
elevated	O
.	O

In	O
patient	O
2	O
,	O
in	O
addition	O
to	O
an	O
increase	O
in	O
both	O
deoxycorticosterone	B-Chemical
and	O
11	B-Chemical
-	I-Chemical
deoxycortisol	I-Chemical
levels	O
,	O
plasma	O
aldosterone	B-Chemical
values	O
were	O
raised	O
,	O
with	O
a	O
concomitant	O
suppression	O
of	O
renin	O
levels	O
.	O

Our	O
findings	O
show	O
that	O
long	O
-	O
term	O
treatment	O
with	O
high	O
doses	O
of	O
ketoconazole	B-Chemical
may	O
induce	O
enzyme	O
blockade	O
leading	O
to	O
mineralocorticoid	O
-	O
related	O
hypertension	B-Disease
.	O

Effects	O
of	O
an	O
inhibitor	O
of	O
angiotensin	B-Chemical
converting	O
enzyme	O
(	O
Captopril	B-Chemical
)	O
on	O
pulmonary	B-Disease
and	I-Disease
renal	I-Disease
insufficiency	I-Disease
due	O
to	O
intravascular	B-Disease
coagulation	I-Disease
in	O
the	O
rat	O
.	O

Induction	O
of	O
intravascular	B-Disease
coagulation	I-Disease
and	O
inhibition	O
of	O
fibrinolysis	O
by	O
injection	O
of	O
thrombin	O
and	O
tranexamic	B-Chemical
acid	I-Chemical
(	O
AMCA	B-Chemical
)	O
in	O
the	O
rat	O
gives	O
rise	O
to	O
pulmonary	B-Disease
and	I-Disease
renal	I-Disease
insufficiency	I-Disease
resembling	O
that	O
occurring	O
after	O
trauma	B-Disease
or	O
sepsis	B-Disease
in	O
man	O
.	O

Injection	O
of	O
Captopril	B-Chemical
(	O
1	O
mg	O
/	O
kg	O
)	O
,	O
an	O
inhibitor	O
of	O
angiotensin	B-Chemical
converting	O
enzyme	O
(	O
ACE	O
)	O
,	O
reduced	O
both	O
pulmonary	B-Disease
and	I-Disease
renal	I-Disease
insufficiency	I-Disease
in	O
this	O
rat	O
model	O
.	O

The	O
lung	O
weights	O
were	O
lower	O
and	O
PaO2	O
was	O
improved	O
in	O
rats	O
given	O
this	O
enzyme	O
-	O
blocking	O
agent	O
.	O

The	O
contents	O
of	O
albumin	O
in	O
the	O
lungs	O
were	O
not	O
changed	O
,	O
indicating	O
that	O
Captopril	B-Chemical
did	O
not	O
influence	O
the	O
extravasation	O
of	O
protein	O
.	O

Renal	B-Disease
damage	I-Disease
as	O
reflected	O
by	O
an	O
increase	O
in	O
serum	O
urea	B-Chemical
and	O
in	O
kidney	O
weight	O
was	O
prevented	O
by	O
Captopril	B-Chemical
.	O

The	O
amount	O
of	O
fibrin	O
in	O
the	O
kidneys	O
was	O
also	O
considerably	O
lower	O
than	O
in	O
animals	O
which	O
received	O
thrombin	O
and	O
AMCA	B-Chemical
alone	O
.	O

It	O
is	O
suggested	O
that	O
the	O
effects	O
of	O
Captopril	B-Chemical
on	O
the	O
lungs	O
may	O
be	O
attributable	O
to	O
a	O
vasodilatory	O
effect	O
due	O
to	O
a	O
reduction	O
in	O
the	O
circulating	O
level	O
of	O
Angiotension	B-Chemical
II	I-Chemical
and	O
an	O
increase	O
in	O
prostacyclin	B-Chemical
(	O
secondary	O
to	O
an	O
increase	O
in	O
bradykinin	B-Chemical
)	O
.	O

Captopril	B-Chemical
may	O
,	O
by	O
the	O
same	O
mechanism	O
,	O
reduce	O
the	O
increase	O
in	O
glomerular	O
filtration	O
that	O
is	O
known	O
to	O
occur	O
after	O
an	O
injection	O
of	O
thrombin	O
,	O
thereby	O
diminishing	O
the	O
aggregation	O
of	O
fibrin	O
monomers	O
in	O
the	O
glomeruli	O
,	O
with	O
the	O
result	O
that	O
less	O
fibrin	O
will	O
be	O
deposited	O
and	O
thus	O
less	O
kidney	B-Disease
damage	I-Disease
will	O
be	O
produced	O
.	O

Stroke	B-Disease
associated	O
with	O
cocaine	B-Chemical
use	O
.	O

We	O
describe	O
eight	O
patients	O
in	O
whom	O
cocaine	B-Chemical
use	O
was	O
related	O
to	O
stroke	B-Disease
and	O
review	O
39	O
cases	O
from	O
the	O
literature	O
.	O

Among	O
these	O
47	O
patients	O
the	O
mean	O
(	O
+	O
/	O
-	O
SD	O
)	O
age	O
was	O
32	O
.	O
5	O
+	O
/	O
-	O
12	O
.	O
1	O
years	O
;	O
76	O
%	O
(	O
34	O
/	O
45	O
)	O
were	O
men	O
.	O

Stroke	B-Disease
followed	O
cocaine	B-Chemical
use	O
by	O
inhalation	O
,	O
intranasal	O
,	O
intravenous	O
,	O
and	O
intramuscular	O
routes	O
.	O

Intracranial	B-Disease
aneurysms	I-Disease
or	O
arteriovenous	B-Disease
malformations	I-Disease
were	O
present	O
in	O
17	O
of	O
32	O
patients	O
studied	O
angiographically	O
or	O
at	O
autopsy	O
;	O
cerebral	B-Disease
vasculitis	I-Disease
was	O
present	O
in	O
two	O
patients	O
.	O

Cerebral	B-Disease
infarction	I-Disease
occurred	O
in	O
10	O
patients	O
(	O
22	O
%	O
)	O
,	O
intracerebral	B-Disease
hemorrhage	I-Disease
in	O
22	O
(	O
49	O
%	O
)	O
,	O
and	O
subarachnoid	B-Disease
hemorrhage	I-Disease
in	O
13	O
(	O
29	O
%	O
)	O
.	O

These	O
data	O
indicate	O
that	O
(	O
1	O
)	O
the	O
apparent	O
incidence	O
of	O
stroke	B-Disease
related	O
to	O
cocaine	B-Chemical
use	O
is	O
increasing	O
;	O
(	O
2	O
)	O
cocaine	B-Chemical
-	O
associated	O
stroke	B-Disease
occurs	O
primarily	O
in	O
young	O
adults	O
;	O
(	O
3	O
)	O
stroke	B-Disease
may	O
follow	O
any	O
route	O
of	O
cocaine	B-Chemical
administration	O
;	O
(	O
4	O
)	O
stroke	B-Disease
after	O
cocaine	B-Chemical
use	O
is	O
frequently	O
associated	O
with	O
intracranial	B-Disease
aneurysms	I-Disease
and	O
arteriovenous	B-Disease
malformations	I-Disease
;	O
and	O
(	O
5	O
)	O
in	O
cocaine	B-Chemical
-	O
associated	O
stroke	B-Disease
,	O
the	O
frequency	O
of	O
intracranial	B-Disease
hemorrhage	I-Disease
exceeds	O
that	O
of	O
cerebral	B-Disease
infarction	I-Disease
.	O

A	O
randomized	O
comparison	O
of	O
labetalol	B-Chemical
and	O
nitroprusside	B-Chemical
for	O
induced	O
hypotension	B-Disease
.	O

In	O
a	O
randomized	O
study	O
,	O
labetalol	B-Chemical
-	O
induced	O
hypotension	B-Disease
and	O
nitroprusside	B-Chemical
-	O
induced	O
hypotension	B-Disease
were	O
compared	O
in	O
20	O
patients	O
(	O
10	O
in	O
each	O
group	O
)	O
scheduled	O
for	O
major	O
orthopedic	O
procedures	O
.	O

Each	O
patient	O
was	O
subjected	O
to	O
an	O
identical	O
anesthetic	O
protocol	O
and	O
similar	O
drug	O
-	O
induced	O
reductions	B-Disease
in	I-Disease
mean	I-Disease
arterial	I-Disease
blood	I-Disease
pressure	I-Disease
(	O
BP	O
)	O
(	O
50	O
to	O
55	O
mmHg	O
)	O
.	O

Nitroprusside	O
infusion	O
was	O
associated	O
with	O
a	O
significant	O
(	O
p	O
less	O
than	O
0	O
.	O
05	O
)	O
increase	B-Disease
in	I-Disease
heart	I-Disease
rate	I-Disease
and	I-Disease
cardiac	I-Disease
output	I-Disease
;	O
rebound	O
hypertension	B-Disease
was	O
observed	O
in	O
three	O
patients	O
after	O
discontinuation	O
of	O
nitroprusside	B-Chemical
.	O

Labetalol	B-Chemical
administration	O
was	O
not	O
associated	O
with	O
any	O
of	O
these	O
findings	O
.	O

Arterial	O
PO2	B-Chemical
decreased	O
in	O
both	O
groups	O
.	O

It	O
was	O
concluded	O
that	O
labetalol	B-Chemical
offers	O
advantages	O
over	O
nitroprusside	B-Chemical
.	O

Sodium	B-Chemical
status	O
influences	O
chronic	O
amphotericin	B-Chemical
B	I-Chemical
nephrotoxicity	B-Disease
in	O
rats	O
.	O

The	O
nephrotoxic	B-Disease
potential	O
of	O
amphotericin	B-Chemical
B	I-Chemical
(	O
5	O
mg	O
/	O
kg	O
per	O
day	O
intraperitoneally	O
for	O
3	O
weeks	O
)	O
has	O
been	O
investigated	O
in	O
salt	O
-	O
depleted	O
,	O
normal	O
-	O
salt	O
,	O
and	O
salt	O
-	O
loaded	O
rats	O
.	O

In	O
salt	O
-	O
depleted	O
rats	O
,	O
amphotericin	B-Chemical
B	I-Chemical
decreased	O
creatinine	B-Chemical
clearance	O
linearly	O
with	O
time	O
,	O
with	O
an	O
85	O
%	O
reduction	O
by	O
week	O
3	O
.	O

In	O
contrast	O
,	O
in	O
normal	O
-	O
salt	O
rats	O
creatinine	B-Chemical
clearance	O
was	O
decreased	O
but	O
to	O
a	O
lesser	O
extent	O
at	O
week	O
2	O
and	O
3	O
,	O
and	O
in	O
salt	O
-	O
loaded	O
rats	O
creatinine	B-Chemical
clearance	O
did	O
not	O
change	O
for	O
2	O
weeks	O
and	O
was	O
decreased	O
by	O
43	O
%	O
at	O
week	O
3	O
.	O

All	O
rats	O
in	O
the	O
sodium	B-Chemical
-	O
depleted	O
group	O
had	O
histopathological	O
evidence	O
of	O
patchy	O
tubular	O
cytoplasmic	O
degeneration	O
in	O
tubules	O
that	O
was	O
not	O
observed	O
in	O
any	O
normal	O
-	O
salt	O
or	O
salt	O
-	O
loaded	O
rat	O
.	O

Concentrations	O
of	O
amphotericin	B-Chemical
B	I-Chemical
in	O
plasma	O
were	O
not	O
significantly	O
different	O
among	O
the	O
three	O
groups	O
at	O
any	O
time	O
during	O
the	O
study	O
.	O

However	O
,	O
at	O
the	O
end	O
of	O
3	O
weeks	O
,	O
amphotericin	B-Chemical
B	I-Chemical
levels	O
in	O
the	O
kidneys	O
and	O
liver	O
were	O
significantly	O
higher	O
in	O
salt	O
-	O
depleted	O
and	O
normal	O
-	O
salt	O
rats	O
than	O
those	O
in	O
salt	O
-	O
loaded	O
rats	O
,	O
with	O
plasma	O
/	O
kidney	O
ratios	O
of	O
21	O
,	O
14	O
,	O
and	O
8	O
in	O
salt	O
-	O
depleted	O
,	O
normal	O
-	O
salt	O
,	O
and	O
salt	O
-	O
loaded	O
rats	O
,	O
respectively	O
.	O

In	O
conclusion	O
,	O
reductions	O
in	O
creatinine	B-Chemical
clearance	O
and	O
renal	O
amphotericin	B-Chemical
B	I-Chemical
accumulation	O
after	O
chronic	O
amphotericin	B-Chemical
B	I-Chemical
administration	O
were	O
enhanced	O
by	O
salt	O
depletion	O
and	O
attenuated	O
by	O
sodium	B-Chemical
loading	O
in	O
rats	O
.	O

Flestolol	B-Chemical
:	O
an	O
ultra	O
-	O
short	O
-	O
acting	O
beta	O
-	O
adrenergic	O
blocking	O
agent	O
.	O

Flestolol	B-Chemical
(	O
ACC	B-Chemical
-	I-Chemical
9089	I-Chemical
)	O
is	O
a	O
nonselective	O
,	O
competitive	O
,	O
ultra	O
-	O
short	O
-	O
acting	O
beta	O
-	O
adrenergic	O
blocking	O
agent	O
,	O
without	O
any	O
intrinsic	O
sympathomimetic	O
activity	O
.	O

Flestolol	B-Chemical
is	O
metabolized	O
by	O
plasma	O
esterases	O
and	O
has	O
an	O
elimination	O
half	O
-	O
life	O
of	O
approximately	O
6	O
.	O
5	O
minutes	O
.	O

This	O
agent	O
was	O
well	O
tolerated	O
in	O
healthy	O
volunteers	O
at	O
doses	O
up	O
to	O
100	O
micrograms	O
/	O
kg	O
/	O
min	O
.	O

In	O
long	O
-	O
term	O
infusion	O
studies	O
,	O
flestolol	B-Chemical
was	O
well	O
tolerated	O
at	O
the	O
effective	O
beta	O
-	O
blocking	O
dose	O
(	O
5	O
micrograms	O
/	O
kg	O
/	O
min	O
)	O
for	O
up	O
to	O
seven	O
days	O
.	O

Flestolol	B-Chemical
blood	O
concentrations	O
increased	O
linearly	O
with	O
increasing	O
dose	O
and	O
good	O
correlation	O
exists	O
between	O
blood	O
concentrations	O
of	O
flestolol	B-Chemical
and	O
beta	O
-	O
adrenergic	O
blockade	O
.	O

Flestolol	B-Chemical
produced	O
a	O
dose	O
-	O
dependent	O
attenuation	O
of	O
isoproterenol	B-Chemical
-	O
induced	O
tachycardia	B-Disease
.	O

Electrophysiologic	O
and	O
hemodynamic	O
effects	O
of	O
flestolol	B-Chemical
are	O
similar	O
to	O
those	O
of	O
other	O
beta	O
blockers	O
.	O

In	O
contrast	O
with	O
other	O
beta	O
blockers	O
,	O
flestolol	B-Chemical
-	O
induced	O
effects	O
reverse	O
rapidly	O
(	O
within	O
30	O
minutes	O
)	O
following	O
discontinuation	O
because	O
of	O
its	O
short	O
half	O
-	O
life	O
.	O

Flestolol	B-Chemical
effectively	O
reduced	O
heart	O
rate	O
in	O
patients	O
with	O
supraventricular	B-Disease
tachyarrhythmia	I-Disease
.	O

In	O
patients	O
with	O
unstable	B-Disease
angina	I-Disease
,	O
flestolol	B-Chemical
infusion	O
was	O
found	O
to	O
be	O
safe	O
and	O
effective	O
in	O
controlling	O
chest	B-Disease
pain	I-Disease
.	O

It	O
is	O
concluded	O
that	O
flestolol	B-Chemical
is	O
a	O
potent	O
,	O
well	O
-	O
tolerated	O
,	O
ultra	O
-	O
short	O
-	O
acting	O
beta	O
-	O
adrenergic	O
blocking	O
agent	O
.	O

Use	O
of	O
flestolol	B-Chemical
in	O
the	O
critical	O
care	O
setting	O
is	O
currently	O
undergoing	O
investigation	O
.	O

Immunohistochemical	O
,	O
electron	O
microscopic	O
and	O
morphometric	O
studies	O
of	O
estrogen	B-Chemical
-	O
induced	O
rat	O
prolactinomas	B-Disease
after	O
bromocriptine	B-Chemical
treatment	O
.	O

To	O
clarify	O
the	O
effects	O
of	O
bromocriptine	B-Chemical
on	O
prolactinoma	B-Disease
cells	O
in	O
vivo	O
,	O
immunohistochemical	O
,	O
ultrastructural	O
and	O
morphometrical	O
analyses	O
were	O
applied	O
to	O
estrogen	B-Chemical
-	O
induced	O
rat	O
prolactinoma	B-Disease
cells	O
1	O
h	O
and	O
6	O
h	O
after	O
injection	O
of	O
bromocriptine	B-Chemical
(	O
3	O
mg	O
/	O
kg	O
of	O
body	O
weight	O
)	O
.	O

One	O
h	O
after	O
treatment	O
,	O
serum	O
prolactin	O
levels	O
decreased	O
markedly	O
.	O

Electron	O
microscopy	O
disclosed	O
many	O
secretory	O
granules	O
,	O
slightly	O
distorted	O
rough	O
endoplasmic	O
reticulum	O
,	O
and	O
partially	O
dilated	O
Golgi	O
cisternae	O
in	O
the	O
prolactinoma	B-Disease
cells	O
.	O

Morphometric	O
analysis	O
revealed	O
that	O
the	O
volume	O
density	O
of	O
secretory	O
granules	O
increased	O
,	O
while	O
the	O
volume	O
density	O
of	O
cytoplasmic	O
microtubules	O
decreased	O
.	O

These	O
findings	O
suggest	O
that	O
lowered	O
serum	O
prolactin	O
levels	O
in	O
the	O
early	O
phase	O
of	O
bromocriptine	B-Chemical
treatment	O
may	O
result	O
from	O
an	O
impaired	O
secretion	O
of	O
prolactin	O
due	O
to	O
decreasing	O
numbers	O
of	O
cytoplasmic	O
microtubules	O
.	O

At	O
6	O
h	O
after	O
injection	O
,	O
serum	O
prolactin	O
levels	O
were	O
still	O
considerably	O
lower	O
than	O
in	O
controls	O
.	O

The	O
prolactinoma	B-Disease
cells	O
at	O
this	O
time	O
were	O
well	O
granulated	O
,	O
with	O
vesiculated	O
rough	O
endoplasmic	O
reticulum	O
and	O
markedly	O
dilated	O
Golgi	O
cisternae	O
.	O

Electron	O
microscopical	O
immunohistochemistry	O
revealed	O
positive	O
reaction	O
products	O
noted	O
on	O
the	O
secretory	O
granules	O
,	O
Golgi	O
cisternae	O
,	O
and	O
endoplasmic	O
reticulum	O
of	O
the	O
untreated	O
rat	O
prolactinoma	B-Disease
cells	O
.	O

However	O
,	O
only	O
secretory	O
granules	O
showed	O
the	O
positive	O
reaction	O
products	O
for	O
prolactin	O
6	O
h	O
after	O
bromocriptine	B-Chemical
treatment	O
of	O
the	O
adenoma	B-Disease
cells	O
.	O

An	O
increase	O
in	O
the	O
volume	O
density	O
of	O
secretory	O
granules	O
and	O
a	O
decrease	O
in	O
the	O
volume	O
densities	O
of	O
rough	O
endoplasmic	O
reticulum	O
and	O
microtubules	O
was	O
determined	O
by	O
morphometric	O
analysis	O
,	O
suggesting	O
that	O
bromocriptine	B-Chemical
inhibits	O
protein	O
synthesis	O
as	O
well	O
as	O
bringing	O
about	O
a	O
disturbance	O
of	O
the	O
prolactin	O
secretion	O
.	O

Sulfasalazine	B-Chemical
-	O
induced	O
lupus	B-Disease
erythematosus	I-Disease
.	O

Pneumonitis	B-Disease
,	O
bilateral	O
pleural	B-Disease
effusions	I-Disease
,	O
echocardiographic	O
evidence	O
of	O
cardiac	B-Disease
tamponade	I-Disease
,	O
and	O
positive	O
autoantibodies	O
developed	O
in	O
a	O
43	O
-	O
year	O
-	O
old	O
man	O
,	O
who	O
was	O
receiving	O
long	O
-	O
term	O
sulfasalazine	B-Chemical
therapy	O
for	O
chronic	O
ulcerative	B-Disease
colitis	I-Disease
.	O

After	O
cessation	O
of	O
the	O
sulfasalazine	B-Chemical
and	O
completion	O
of	O
a	O
six	O
-	O
week	O
course	O
of	O
corticosteroids	O
,	O
these	O
problems	O
resolved	O
over	O
a	O
period	O
of	O
four	O
to	O
six	O
months	O
.	O

It	O
is	O
suggested	O
that	O
the	O
patient	O
had	O
sulfasalazine	B-Chemical
-	O
induced	O
lupus	B-Disease
,	O
which	O
manifested	O
with	O
serositis	B-Disease
and	O
pulmonary	O
parenchymal	O
involvement	O
in	O
the	O
absence	O
of	O
joint	O
symptoms	O
.	O

Physicians	O
who	O
use	O
sulfasalazine	B-Chemical
to	O
treat	O
patients	O
with	O
inflammatory	B-Disease
bowel	I-Disease
disease	I-Disease
should	O
be	O
aware	O
of	O
the	O
signs	O
of	O
sulfasalazine	B-Chemical
-	O
induced	O
lupus	B-Disease
syndrome	I-Disease
.	O

Chronic	O
carbamazepine	B-Chemical
treatment	O
in	O
the	O
rat	O
:	O
efficacy	O
,	O
toxicity	B-Disease
,	O
and	O
effect	O
on	O
plasma	O
and	O
tissue	O
folate	B-Chemical
concentrations	O
.	O

Folate	B-Chemical
depletion	O
has	O
often	O
been	O
a	O
problem	O
in	O
chronic	O
antiepileptic	O
drug	O
(	O
AED	O
)	O
therapy	O
.	O

Carbamazepine	B-Chemical
(	O
CBZ	B-Chemical
)	O
,	O
a	O
commonly	O
used	O
AED	O
,	O
has	O
been	O
implicated	O
in	O
some	O
clinical	O
studies	O
.	O

A	O
rat	O
model	O
was	O
developed	O
to	O
examine	O
the	O
effects	O
of	O
chronic	O
CBZ	B-Chemical
treatment	O
on	O
folate	B-Chemical
concentrations	O
in	O
the	O
rat	O
.	O

In	O
the	O
course	O
of	O
developing	O
this	O
model	O
,	O
a	O
common	O
vehicle	O
,	O
propylene	B-Chemical
glycol	I-Chemical
,	O
by	O
itself	O
in	O
high	O
doses	O
,	O
was	O
found	O
to	O
exhibit	O
protective	O
properties	O
against	O
induced	O
seizures	B-Disease
and	O
inhibited	O
weight	B-Disease
gain	I-Disease
.	O

Seizures	B-Disease
induced	O
by	O
hexafluorodiethyl	B-Chemical
ether	I-Chemical
(	O
HFDE	B-Chemical
)	O
were	O
also	O
found	O
to	O
be	O
a	O
more	O
sensitive	O
measure	O
of	O
protection	O
by	O
CBZ	B-Chemical
than	O
seizures	B-Disease
induced	O
by	O
maximal	O
electroshock	O
(	O
MES	O
)	O
.	O

Oral	O
administration	O
of	O
CBZ	B-Chemical
as	O
an	O
aqueous	O
suspension	O
every	O
8	O
h	O
at	O
a	O
dose	O
of	O
250	O
mg	O
/	O
kg	O
was	O
continuously	O
protective	O
against	O
HFDE	B-Chemical
-	O
induced	O
seizures	B-Disease
and	O
was	O
minimally	O
toxic	O
as	O
measured	O
by	O
weight	B-Disease
gain	I-Disease
over	O
8	O
weeks	O
of	O
treatment	O
.	O

The	O
CBZ	B-Chemical
levels	O
measured	O
in	O
plasma	O
and	O
brain	O
of	O
these	O
animals	O
,	O
however	O
,	O
were	O
below	O
those	O
normally	O
considered	O
protective	O
.	O

This	O
treatment	O
with	O
CBZ	B-Chemical
had	O
no	O
apparent	O
adverse	O
effect	O
on	O
folate	B-Chemical
concentrations	O
in	O
the	O
rat	O
,	O
and	O
,	O
indeed	O
,	O
the	O
folate	B-Chemical
concentration	O
increased	O
in	O
liver	O
after	O
6	O
weeks	O
of	O
treatment	O
and	O
in	O
plasma	O
at	O
8	O
weeks	O
of	O
treatment	O
.	O

Dipyridamole	B-Chemical
-	O
induced	O
myocardial	B-Disease
ischemia	I-Disease
.	O

Angina	B-Disease
and	O
ischemic	O
electrocardiographic	O
changes	O
occurred	O
after	O
administration	O
of	O
oral	O
dipyridamole	B-Chemical
in	O
four	O
patients	O
awaiting	O
urgent	O
myocardial	O
revascularization	O
procedures	O
.	O

To	O
our	O
knowledge	O
,	O
this	O
has	O
not	O
previously	O
been	O
reported	O
as	O
a	O
side	O
effect	O
of	O
preoperative	O
dipyridamole	B-Chemical
therapy	O
,	O
although	O
dipyridamole	B-Chemical
-	O
induced	O
myocardial	B-Disease
ischemia	I-Disease
has	O
been	O
demonstrated	O
to	O
occur	O
in	O
animals	O
and	O
humans	O
with	O
coronary	B-Disease
artery	I-Disease
disease	I-Disease
.	O

Epicardial	O
coronary	O
collateral	O
vessels	O
were	O
demonstrated	O
in	O
all	O
four	O
patients	O
;	O
a	O
coronary	O
"	O
steal	O
"	O
phenomenon	O
may	O
be	O
the	O
mechanism	O
of	O
the	O
dipyridamole	B-Chemical
-	O
induced	O
ischemia	B-Disease
observed	O
.	O

Inhibition	O
of	O
sympathoadrenal	O
activity	O
by	O
atrial	O
natriuretic	O
factor	O
in	O
dogs	O
.	O

In	O
six	O
conscious	O
,	O
trained	O
dogs	O
,	O
maintained	O
on	O
a	O
normal	O
sodium	B-Chemical
intake	O
of	O
2	O
to	O
4	O
mEq	O
/	O
kg	O
/	O
day	O
,	O
sympathetic	O
activity	O
was	O
assessed	O
as	O
the	O
release	O
rate	O
of	O
norepinephrine	B-Chemical
and	O
epinephrine	B-Chemical
during	O
15	O
-	O
minute	O
i	O
.	O
v	O
.	O
infusions	O
of	O
human	O
alpha	O
-	O
atrial	O
natriuretic	O
factor	O
.	O

Mean	O
arterial	O
pressure	O
(	O
as	O
a	O
percentage	O
of	O
control	O
+	O
/	O
-	O
SEM	O
)	O
during	O
randomized	O
infusions	O
of	O
0	O
.	O
03	O
,	O
0	O
.	O
1	O
,	O
0	O
.	O
3	O
,	O
or	O
1	O
.	O
0	O
microgram	O
/	O
kg	O
/	O
min	O
was	O
99	O
+	O
/	O
-	O
1	O
,	O
95	O
+	O
/	O
-	O
1	O
(	O
p	O
less	O
than	O
0	O
.	O
05	O
)	O
,	O
93	O
+	O
/	O
-	O
1	O
(	O
p	O
less	O
than	O
0	O
.	O
01	O
)	O
,	O
or	O
79	O
+	O
/	O
-	O
6	O
%	O
(	O
p	O
less	O
than	O
0	O
.	O
001	O
)	O
,	O
respectively	O
,	O
but	O
no	O
tachycardia	B-Disease
and	O
no	O
augmentation	O
of	O
the	O
norepinephrine	B-Chemical
release	O
rate	O
(	O
up	O
to	O
0	O
.	O
3	O
microgram	O
/	O
kg	O
/	O
min	O
)	O
were	O
observed	O
,	O
which	O
is	O
in	O
contrast	O
to	O
comparable	O
hypotension	B-Disease
induced	O
by	O
hydralazine	B-Chemical
or	O
nitroglycerin	B-Chemical
.	O

The	O
release	O
rate	O
of	O
epinephrine	B-Chemical
(	O
control	O
,	O
6	O
.	O
7	O
+	O
/	O
-	O
0	O
.	O
6	O
ng	O
/	O
kg	O
/	O
min	O
)	O
declined	O
immediately	O
during	O
infusions	O
of	O
atrial	O
natriuretic	O
factor	O
to	O
a	O
minimum	O
of	O
49	O
+	O
/	O
-	O
5	O
%	O
of	O
control	O
(	O
p	O
less	O
than	O
0	O
.	O
001	O
)	O
during	O
0	O
.	O
1	O
microgram	O
/	O
kg	O
/	O
min	O
and	O
to	O
63	O
+	O
/	O
-	O
5	O
%	O
(	O
0	O
.	O
1	O
greater	O
than	O
p	O
greater	O
than	O
0	O
.	O
05	O
)	O
or	O
95	O
+	O
/	O
-	O
13	O
%	O
(	O
not	O
significant	O
)	O
during	O
0	O
.	O
3	O
or	O
1	O
.	O
0	O
microgram	O
/	O
kg	O
/	O
min	O
.	O

Steady	O
state	O
arterial	O
plasma	O
concentrations	O
of	O
atrial	O
natriuretic	O
factor	O
were	O
39	O
+	O
/	O
-	O
10	O
pg	O
/	O
ml	O
(	O
n	O
=	O
6	O
)	O
during	O
infusions	O
of	O
saline	O
and	O
284	O
+	O
/	O
-	O
24	O
pg	O
/	O
ml	O
(	O
n	O
=	O
6	O
)	O
and	O
1520	O
+	O
/	O
-	O
300	O
pg	O
/	O
ml	O
(	O
n	O
=	O
9	O
)	O
during	O
0	O
.	O
03	O
and	O
0	O
.	O
1	O
microgram	O
/	O
kg	O
/	O
min	O
infusions	O
of	O
the	O
factor	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
250	O
WORDS	O
)	O

Inhibition	O
of	O
immunoreactive	O
corticotropin	O
-	O
releasing	O
factor	O
secretion	O
into	O
the	O
hypophysial	O
-	O
portal	O
circulation	O
by	O
delayed	O
glucocorticoid	O
feedback	O
.	O

Nitroprusside	B-Chemical
-	O
induced	O
hypotension	B-Disease
evokes	O
ACTH	O
secretion	O
which	O
is	O
primarily	O
mediated	O
by	O
enhanced	O
secretion	O
of	O
immunoreactive	O
corticotropin	O
-	O
releasing	O
factor	O
(	O
irCRF	O
)	O
into	O
the	O
hypophysial	O
-	O
portal	O
circulation	O
.	O

Portal	O
plasma	O
concentrations	O
of	O
neither	O
arginine	B-Chemical
vasopressin	I-Chemical
nor	O
oxytocin	B-Chemical
are	O
significantly	O
altered	O
in	O
this	O
paradigm	O
.	O

Application	O
of	O
a	O
delayed	O
feedback	O
signal	O
,	O
in	O
the	O
form	O
of	O
a	O
2	O
-	O
h	O
systemic	O
corticosterone	B-Chemical
infusion	O
in	O
urethane	B-Chemical
-	O
anesthetized	O
rats	O
with	O
pharmacological	O
blockade	O
of	O
glucocorticoid	O
synthesis	O
,	O
is	O
without	O
effect	O
on	O
the	O
resting	O
secretion	O
of	O
arginine	B-Chemical
vasopressin	I-Chemical
and	O
oxytocin	B-Chemical
at	O
any	O
corticosterone	B-Chemical
feedback	O
dose	O
tested	O
.	O

Resting	O
irCRF	O
levels	O
are	O
suppressed	O
only	O
at	O
the	O
highest	O
corticosterone	B-Chemical
infusion	O
rate	O
,	O
which	O
resulted	O
in	O
systemic	O
corticosterone	B-Chemical
levels	O
of	O
40	O
micrograms	O
/	O
dl	O
.	O

Suppression	O
of	O
irCRF	O
secretion	O
in	O
response	O
to	O
nitroprusside	B-Chemical
-	O
induced	O
hypotension	B-Disease
is	O
observed	O
and	O
occurs	O
at	O
a	O
plasma	O
corticosterone	B-Chemical
level	O
between	O
8	O
-	O
12	O
micrograms	O
/	O
dl	O
.	O

These	O
studies	O
provide	O
further	O
evidence	O
for	O
a	O
strong	O
central	O
component	O
of	O
the	O
delayed	O
feedback	O
process	O
which	O
is	O
mediated	O
by	O
modulation	O
of	O
irCRF	O
release	O
.	O

Noradrenergic	O
involvement	O
in	O
catalepsy	B-Disease
induced	O
by	O
delta	B-Chemical
9	I-Chemical
-	I-Chemical
tetrahydrocannabinol	I-Chemical
.	O

In	O
order	O
to	O
elucidate	O
the	O
role	O
of	O
the	O
catecholaminergic	O
system	O
in	O
the	O
cataleptogenic	O
effect	O
of	O
delta	B-Chemical
9	I-Chemical
-	I-Chemical
tetrahydrocannabinol	I-Chemical
(	O
THC	B-Chemical
)	O
,	O
the	O
effect	O
of	O
pretreatment	O
with	O
6	B-Chemical
-	I-Chemical
hydroxydopamine	I-Chemical
(	O
6	B-Chemical
-	I-Chemical
OHDA	I-Chemical
)	O
or	O
with	O
desipramine	B-Chemical
and	O
6	B-Chemical
-	I-Chemical
OHDA	I-Chemical
and	O
lesions	O
of	O
the	O
locus	O
coeruleus	O
were	O
investigated	O
in	O
rats	O
.	O

The	O
cataleptogenic	O
effect	O
of	O
THC	B-Chemical
was	O
significantly	O
reduced	O
in	O
rats	O
treated	O
with	O
6	B-Chemical
-	I-Chemical
OHDA	I-Chemical
and	O
in	O
rats	O
with	O
lesions	O
of	O
the	O
locus	O
coeruleus	O
but	O
not	O
in	O
rats	O
treated	O
with	O
desipramine	B-Chemical
and	O
6	B-Chemical
-	I-Chemical
OHDA	I-Chemical
,	O
as	O
compared	O
with	O
control	O
rats	O
.	O

On	O
the	O
contrary	O
,	O
the	O
cataleptogenic	O
effect	O
of	O
haloperidol	B-Chemical
was	O
significantly	O
reduced	O
in	O
rats	O
treated	O
with	O
desipramine	B-Chemical
and	O
6	B-Chemical
-	I-Chemical
OHDA	I-Chemical
but	O
not	O
in	O
rats	O
treated	O
with	O
6	B-Chemical
-	I-Chemical
OHDA	I-Chemical
or	O
in	O
rats	O
with	O
lesions	O
of	O
the	O
locus	O
coeruleus	O
.	O

These	O
results	O
indicate	O
that	O
noradrenergic	O
neurons	O
have	O
an	O
important	O
role	O
in	O
the	O
manifestation	O
of	O
catalepsy	B-Disease
induced	O
by	O
THC	B-Chemical
,	O
whereas	O
dopaminergic	O
neurons	O
are	O
important	O
in	O
catalepsy	B-Disease
induced	O
by	O
haloperidol	B-Chemical
.	O

Reversibility	O
of	O
captopril	B-Chemical
-	O
induced	O
renal	B-Disease
insufficiency	I-Disease
after	O
prolonged	O
use	O
in	O
an	O
unusual	O
case	O
of	O
renovascular	B-Disease
hypertension	I-Disease
.	O

We	O
report	O
a	O
case	O
of	O
severe	O
hypertension	B-Disease
with	O
an	O
occluded	O
renal	O
artery	O
to	O
a	O
solitary	O
kidney	O
,	O
who	O
developed	O
sudden	B-Disease
deterioration	I-Disease
of	I-Disease
renal	I-Disease
function	I-Disease
following	O
treatment	O
with	O
captopril	B-Chemical
.	O

His	O
renal	O
function	O
remained	O
impaired	O
but	O
stable	O
during	O
2	O
years	O
'	O
treatment	O
with	O
captopril	B-Chemical
but	O
returned	O
to	O
pre	O
-	O
treatment	O
levels	O
soon	O
after	O
cessation	O
of	O
the	O
drug	O
.	O

This	O
indicates	O
reversibility	O
in	O
captopril	B-Chemical
-	O
induced	O
renal	B-Disease
failure	I-Disease
even	O
after	O
its	O
prolonged	O
use	O
and	O
suggests	O
that	O
no	O
organic	O
damage	O
occurs	O
to	O
glomerular	O
arterioles	O
following	O
chronic	O
ACE	O
inhibition	O
.	O

HMG	O
CoA	O
reductase	O
inhibitors	O
.	O

Current	O
clinical	O
experience	O
.	O

Lovastatin	B-Chemical
and	O
simvastatin	B-Chemical
are	O
the	O
2	O
best	O
-	O
known	O
members	O
of	O
the	O
class	O
of	O
hypolipidaemic	O
agents	O
known	O
as	O
HMG	O
CoA	O
reductase	O
inhibitors	O
.	O

Clinical	O
experience	O
with	O
lovastatin	B-Chemical
includes	O
over	O
5000	O
patients	O
,	O
700	O
of	O
whom	O
have	O
been	O
treated	O
for	O
2	O
years	O
or	O
more	O
,	O
and	O
experience	O
with	O
simvastatin	B-Chemical
includes	O
over	O
3500	O
patients	O
,	O
of	O
whom	O
350	O
have	O
been	O
treated	O
for	O
18	O
months	O
or	O
more	O
.	O

Lovastatin	B-Chemical
has	O
been	O
marketed	O
in	O
the	O
United	O
States	O
for	O
over	O
6	O
months	O
.	O

Both	O
agents	O
show	O
substantial	O
clinical	O
efficacy	O
,	O
with	O
reductions	O
in	O
total	O
cholesterol	B-Chemical
of	O
over	O
30	O
%	O
and	O
in	O
LDL	O
-	O
cholesterol	B-Chemical
of	O
40	O
%	O
in	O
clinical	O
studies	O
.	O

Modest	O
increases	O
in	O
HDL	O
-	O
cholesterol	B-Chemical
levels	O
of	O
about	O
10	O
%	O
are	O
also	O
reported	O
.	O

Clinical	O
tolerability	O
of	O
both	O
agents	O
has	O
been	O
good	O
,	O
with	O
fewer	O
than	O
3	O
%	O
of	O
patients	O
withdrawn	O
from	O
treatment	O
because	O
of	O
clinical	O
adverse	O
experiences	O
.	O

Ophthalmological	O
examinations	O
in	O
over	O
1100	O
patients	O
treated	O
with	O
one	O
or	O
the	O
other	O
agent	O
have	O
revealed	O
no	O
evidence	O
of	O
significant	O
short	O
term	O
(	O
up	O
to	O
2	O
years	O
)	O
cataractogenic	O
potential	O
.	O

One	O
to	O
2	O
%	O
of	O
patients	O
have	O
elevations	O
of	O
serum	O
transaminases	O
to	O
greater	O
than	O
3	O
times	O
the	O
upper	O
limit	O
of	O
normal	O
.	O

These	O
episodes	O
are	O
asymptomatic	O
and	O
reversible	O
when	O
therapy	O
is	O
discontinued	O
.	O

Minor	O
elevations	O
of	O
creatine	B-Chemical
kinase	O
levels	O
are	O
reported	O
in	O
about	O
5	O
%	O
of	O
patients	O
.	O

Myopathy	B-Disease
,	O
associated	O
in	O
some	O
cases	O
with	O
myoglobinuria	B-Disease
,	O
and	O
in	O
2	O
cases	O
with	O
transient	O
renal	B-Disease
failure	I-Disease
,	O
has	O
been	O
rarely	O
reported	O
with	O
lovastatin	B-Chemical
,	O
especially	O
in	O
patients	O
concomitantly	O
treated	O
with	O
cyclosporin	B-Chemical
,	O
gemfibrozil	B-Chemical
or	O
niacin	B-Chemical
.	O

Lovastatin	B-Chemical
and	O
simvastatin	B-Chemical
are	O
both	O
effective	O
and	O
well	O
-	O
tolerated	O
agents	O
for	O
lowering	O
elevated	O
levels	O
of	O
serum	O
cholesterol	B-Chemical
.	O

As	O
wider	O
use	O
confirms	O
their	O
safety	O
profile	O
,	O
they	O
will	O
gain	O
increasing	O
importance	O
in	O
the	O
therapeutic	O
approach	O
to	O
hypercholesterolaemia	B-Disease
and	O
its	O
consequences	O
.	O

Hepatic	O
reactions	O
associated	O
with	O
ketoconazole	B-Chemical
in	O
the	O
United	O
Kingdom	O
.	O

Ketoconazole	B-Chemical
was	O
introduced	O
in	O
the	O
United	O
Kingdom	O
in	O
1981	O
.	O

By	O
November	O
1984	O
the	O
Committee	O
on	O
Safety	O
of	O
Medicines	O
had	O
received	O
82	O
reports	O
of	O
possible	O
hepatotoxicity	B-Disease
associated	O
with	O
the	O
drug	O
,	O
including	O
five	O
deaths	B-Disease
.	O

An	O
analysis	O
of	O
the	O
75	O
cases	O
that	O
had	O
been	O
adequately	O
followed	O
up	O
suggested	O
that	O
16	O
,	O
including	O
three	O
deaths	B-Disease
,	O
were	O
probably	O
related	O
to	O
treatment	O
with	O
the	O
drug	O
.	O

Of	O
the	O
remainder	O
,	O
48	O
were	O
possibly	O
related	O
to	O
treatment	O
,	O
five	O
were	O
unlikely	O
to	O
be	O
so	O
,	O
and	O
six	O
were	O
unclassifiable	O
.	O

The	O
mean	O
age	O
of	O
patients	O
in	O
the	O
16	O
probable	O
cases	O
was	O
57	O
.	O
9	O
,	O
with	O
hepatotoxicity	B-Disease
being	O
more	O
common	O
in	O
women	O
.	O

The	O
average	O
duration	O
of	O
treatment	O
before	O
the	O
onset	O
of	O
jaundice	B-Disease
was	O
61	O
days	O
.	O

None	O
of	O
these	O
well	O
validated	O
cases	O
occurred	O
within	O
the	O
first	O
10	O
days	O
after	O
treatment	O
.	O

The	O
results	O
of	O
serum	O
liver	O
function	O
tests	O
suggested	O
hepatocellular	B-Disease
injury	I-Disease
in	O
10	O
(	O
63	O
%	O
)	O
;	O
the	O
rest	O
showed	O
a	O
mixed	O
pattern	O
.	O

In	O
contrast	O
,	O
the	O
results	O
of	O
histological	O
examination	O
of	O
the	O
liver	O
often	O
showed	O
evidence	O
of	O
cholestasis	B-Disease
.	O

The	O
characteristics	O
of	O
the	O
48	O
patients	O
in	O
the	O
possible	O
cases	O
were	O
similar	O
.	O

Allergic	O
manifestations	O
such	O
as	O
rash	B-Disease
and	O
eosinophilia	B-Disease
were	O
rare	O
.	O

Hepatitis	B-Disease
was	O
usually	O
reversible	O
when	O
treatment	O
was	O
stopped	O
,	O
with	O
the	O
results	O
of	O
liver	O
function	O
tests	O
returning	O
to	O
normal	O
after	O
an	O
average	O
of	O
3	O
.	O
1	O
months	O
.	O

In	O
two	O
of	O
the	O
three	O
deaths	B-Disease
probably	O
associated	O
with	O
ketoconazole	B-Chemical
treatment	O
the	O
drug	O
had	O
been	O
continued	O
after	O
the	O
onset	O
of	O
jaundice	B-Disease
and	O
other	O
symptoms	O
of	O
hepatitis	B-Disease
.	O

Clinical	O
and	O
biochemical	O
monitoring	O
at	O
regular	O
intervals	O
for	O
evidence	O
of	O
hepatitis	B-Disease
is	O
advised	O
during	O
long	O
term	O
treatment	O
with	O
ketoconazole	B-Chemical
to	O
prevent	O
possible	O
serious	O
hepatic	B-Disease
injury	I-Disease
.	O

Glyburide	B-Chemical
-	O
induced	O
hepatitis	B-Disease
.	O

Drug	O
-	O
induced	O
hepatotoxicity	B-Disease
,	O
although	O
common	O
,	O
has	O
been	O
reported	O
only	O
infrequently	O
with	O
sulfonylureas	B-Chemical
.	O

For	O
glyburide	B-Chemical
,	O
a	O
second	O
-	O
generation	O
sulfonylurea	B-Chemical
,	O
only	O
two	O
brief	O
reports	O
of	O
hepatotoxicity	B-Disease
exist	O
.	O

Two	O
patients	O
with	O
type	B-Disease
II	I-Disease
diabetes	I-Disease
mellitus	I-Disease
developed	O
an	O
acute	B-Disease
hepatitis	I-Disease
-	I-Disease
like	I-Disease
syndrome	I-Disease
soon	O
after	O
initiation	O
of	O
glyburide	B-Chemical
therapy	O
.	O

There	O
was	O
no	O
serologic	O
evidence	O
of	O
viral	B-Disease
infection	I-Disease
,	O
and	O
a	O
liver	O
biopsy	O
sample	O
showed	O
a	O
histologic	O
pattern	O
consistent	O
with	O
drug	B-Disease
-	I-Disease
induced	I-Disease
hepatitis	I-Disease
.	O

Both	O
patients	O
recovered	O
quickly	O
after	O
stopping	O
glyburide	B-Chemical
therapy	O
and	O
have	O
remained	O
well	O
for	O
a	O
follow	O
-	O
up	O
period	O
of	O
1	O
year	O
.	O

Glyburide	B-Chemical
can	O
produce	O
an	O
acute	B-Disease
hepatitis	I-Disease
-	I-Disease
like	I-Disease
illness	I-Disease
in	O
some	O
persons	O
.	O

Intracranial	O
pressure	O
increases	O
during	O
alfentanil	B-Chemical
-	O
induced	O
rigidity	B-Disease
.	O

Intracranial	O
pressure	O
(	O
ICP	O
)	O
was	O
measured	O
during	O
alfentanil	B-Chemical
-	O
induced	O
rigidity	B-Disease
in	O
rats	O
.	O

Ten	O
rats	O
had	O
arterial	O
,	O
central	O
venous	O
(	O
CVP	O
)	O
,	O
and	O
subdural	O
cannulae	O
inserted	O
under	O
halothane	B-Chemical
anesthesia	O
.	O

The	O
animals	O
were	O
mechanically	O
ventilated	O
to	O
achieve	O
normocarbia	O
(	O
PCO2	O
=	O
42	O
+	O
/	O
-	O
1	O
mmHg	O
,	O
mean	O
+	O
/	O
-	O
SE	O
)	O
.	O

Following	O
instrumentation	O
,	O
halothane	B-Chemical
was	O
discontinued	O
and	O
alfentanil	B-Chemical
(	O
125	O
mu	O
/	O
kg	O
)	O
administered	O
iv	O
during	O
emergence	O
from	O
halothane	B-Chemical
anesthesia	O
.	O

In	O
the	O
five	O
rats	O
that	O
developed	O
somatic	B-Disease
rigidity	I-Disease
,	O
ICP	O
and	O
CVP	O
increased	O
significantly	O
above	O
baseline	O
(	O
delta	O
ICP	O
7	O
.	O
5	O
+	O
/	O
-	O
1	O
.	O
0	O
mmHg	O
,	O
delta	O
CVP	O
5	O
.	O
9	O
+	O
/	O
-	O
1	O
.	O
3	O
mmHg	O
)	O
.	O

These	O
variables	O
returned	O
to	O
baseline	O
when	O
rigidity	B-Disease
was	O
abolished	O
with	O
metocurine	B-Chemical
.	O

In	O
five	O
rats	O
that	O
did	O
not	O
become	O
rigid	O
,	O
ICP	O
and	O
CVP	O
did	O
not	O
change	O
following	O
alfentanil	B-Chemical
.	O

These	O
observations	O
suggest	O
that	O
rigidity	B-Disease
should	O
be	O
prevented	O
when	O
alfentanil	B-Chemical
,	O
and	O
,	O
presumably	O
,	O
other	O
opiates	O
,	O
are	O
used	O
in	O
the	O
anesthetic	O
management	O
of	O
patients	O
with	O
ICP	O
problems	O
.	O

Verapamil	B-Chemical
withdrawal	O
as	O
a	O
possible	O
cause	O
of	O
myocardial	B-Disease
infarction	I-Disease
in	O
a	O
hypertensive	B-Disease
woman	O
with	O
a	O
normal	O
coronary	O
angiogram	O
.	O

Verapamil	B-Chemical
is	O
an	O
effective	O
and	O
relatively	O
-	O
safe	O
antihypertensive	O
drug	O
.	O

Serious	O
adverse	O
effects	O
are	O
uncommon	O
and	O
mainly	O
have	O
been	O
related	O
to	O
the	O
depression	B-Disease
of	O
cardiac	O
contractility	O
and	O
conduction	O
,	O
especially	O
when	O
the	O
drug	O
is	O
combined	O
with	O
beta	O
-	O
blocking	O
agents	O
.	O

We	O
report	O
a	O
case	O
in	O
which	O
myocardial	B-Disease
infarction	I-Disease
coincided	O
with	O
the	O
introduction	O
of	O
captopril	B-Chemical
and	O
the	O
withdrawal	O
of	O
verapamil	B-Chemical
in	O
a	O
previously	O
asymptomatic	O
woman	O
with	O
severe	O
hypertension	B-Disease
.	O

Possible	O
mechanisms	O
that	O
involve	O
a	O
verapamil	B-Chemical
-	O
related	O
increase	O
in	O
platelet	O
and	O
/	O
or	O
vascular	O
alpha	O
2	O
-	O
adrenoreceptor	O
affinity	O
for	O
catecholamines	B-Chemical
are	O
discussed	O
.	O

Haemolytic	B-Disease
-	I-Disease
uraemic	I-Disease
syndrome	I-Disease
after	O
treatment	O
with	O
metronidazole	B-Chemical
.	O

This	O
paper	O
describes	O
the	O
clinical	O
features	O
of	O
six	O
children	O
who	O
developed	O
the	O
haemolytic	B-Disease
-	I-Disease
uraemic	I-Disease
syndrome	I-Disease
after	O
treatment	O
with	O
metronidazole	B-Chemical
.	O

These	O
children	O
were	O
older	O
and	O
were	O
more	O
likely	O
to	O
have	O
undergone	O
recent	O
bowel	O
surgery	O
than	O
are	O
other	O
children	O
with	O
this	O
condition	O
.	O

While	O
the	O
involvement	O
of	O
metronidazole	B-Chemical
in	O
the	O
aetiology	O
of	O
the	O
haemolytic	B-Disease
-	I-Disease
uraemic	I-Disease
syndrome	I-Disease
is	O
not	O
established	O
firmly	O
,	O
the	O
action	O
of	O
this	O
drug	O
in	O
sensitizing	O
tissues	O
to	O
oxidation	O
injury	O
and	O
the	O
reported	O
evidence	O
of	O
oxidation	O
changes	O
in	O
the	O
haemolytic	B-Disease
-	I-Disease
uraemic	I-Disease
syndrome	I-Disease
suggest	O
a	O
possible	O
link	O
between	O
metronidazole	B-Chemical
treatment	O
and	O
some	O
cases	O
of	O
the	O
haemolytic	B-Disease
-	I-Disease
uraemic	I-Disease
syndrome	I-Disease
.	O

Adverse	O
cardiac	O
effects	O
during	O
induction	O
chemotherapy	O
treatment	O
with	O
cis	B-Chemical
-	I-Chemical
platin	I-Chemical
and	O
5	B-Chemical
-	I-Chemical
fluorouracil	I-Chemical
.	O

Survival	O
for	O
patients	O
with	O
advanced	O
head	B-Disease
and	I-Disease
neck	I-Disease
carcinoma	I-Disease
and	O
esophageal	B-Disease
carcinoma	I-Disease
is	O
poor	O
with	O
radiotherapy	O
and	O
/	O
or	O
surgery	O
.	O

Obviously	O
,	O
there	O
is	O
a	O
need	O
for	O
effective	O
chemotherapy	O
.	O

In	O
the	O
present	O
study	O
,	O
cis	B-Chemical
-	I-Chemical
platin	I-Chemical
(	O
80	O
-	O
120	O
mg	O
/	O
m2BSA	O
)	O
and	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
(	O
1000	O
mg	O
/	O
m2BSA	O
daily	O
as	O
a	O
continuous	O
infusion	O
during	O
5	O
days	O
)	O
were	O
given	O
to	O
76	O
patients	O
before	O
radiotherapy	O
and	O
surgery	O
.	O

The	O
aim	O
of	O
the	O
study	O
was	O
to	O
clarify	O
the	O
incidence	O
and	O
severity	O
of	O
adverse	O
cardiac	O
effects	O
to	O
this	O
treatment	O
.	O

Before	O
treatment	O
all	O
patients	O
had	O
a	O
cardiac	O
evaluation	O
and	O
during	O
treatment	O
serial	O
ECG	O
recordings	O
were	O
performed	O
.	O

In	O
the	O
pre	O
-	O
treatment	O
evaluation	O
,	O
signs	O
of	O
cardiovascular	B-Disease
disease	I-Disease
were	O
found	O
in	O
33	O
patients	O
(	O
43	O
%	O
)	O
.	O

During	O
treatment	O
,	O
adverse	O
cardiac	O
effects	O
were	O
observed	O
in	O
14	O
patients	O
(	O
18	O
%	O
)	O
.	O

The	O
mean	O
age	O
of	O
these	O
patients	O
was	O
the	O
same	O
as	O
for	O
the	O
entire	O
group	O
,	O
64	O
years	O
.	O

The	O
incidence	O
of	O
cardiotoxicity	B-Disease
was	O
not	O
higher	O
in	O
patients	O
with	O
signs	O
of	O
cardiovascular	B-Disease
disease	I-Disease
than	O
in	O
those	O
without	O
in	O
the	O
pre	O
-	O
treatment	O
evaluation	O
.	O

The	O
most	O
common	O
signs	O
of	O
cardiotoxicity	B-Disease
were	O
chest	B-Disease
pain	I-Disease
,	O
ST	O
-	O
T	O
wave	O
changes	O
and	O
atrial	B-Disease
fibrillation	I-Disease
.	O

This	O
was	O
followed	O
by	O
ventricular	B-Disease
fibrillation	I-Disease
in	O
one	O
patient	O
and	O
sudden	B-Disease
death	I-Disease
in	O
another	O
.	O

It	O
is	O
concluded	O
that	O
patients	O
on	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
treatment	O
should	O
be	O
under	O
close	O
supervision	O
and	O
that	O
the	O
treatment	O
should	O
be	O
discontinued	O
if	O
chest	B-Disease
pain	I-Disease
or	O
tachyarrhythmia	B-Disease
is	O
observed	O
.	O

Death	B-Disease
from	O
chemotherapy	O
in	O
gestational	B-Disease
trophoblastic	I-Disease
disease	I-Disease
.	O

Multiple	O
cytotoxic	O
drug	O
administration	O
is	O
the	O
generally	O
accepted	O
treatment	O
of	O
patients	O
with	O
a	O
high	O
-	O
risk	O
stage	O
of	O
choriocarcinoma	B-Disease
.	O

Based	O
on	O
this	O
principle	O
a	O
27	O
-	O
year	O
old	O
woman	O
,	O
classified	O
as	O
being	O
in	O
the	O
high	O
-	O
risk	O
group	O
(	O
Goldstein	O
and	O
Berkowitz	O
score	O
:	O
11	O
)	O
,	O
was	O
treated	O
with	O
multiple	O
cytotoxic	O
drugs	O
.	O

The	O
multiple	O
drug	O
schema	O
consisted	O
of	O
:	O
Etoposide	B-Chemical
16	O
.	O
213	O
,	O
Methotrexate	B-Chemical
,	O
Cyclophosphamide	B-Chemical
,	O
Actomycin	B-Chemical
-	I-Chemical
D	I-Chemical
,	O
and	O
Cisplatin	B-Chemical
.	O

On	O
the	O
first	O
day	O
of	O
the	O
schedule	O
,	O
moderate	O
high	O
doses	O
of	O
Methotrexate	B-Chemical
,	O
Etoposide	B-Chemical
and	O
Cyclophosphamide	B-Chemical
were	O
administered	O
.	O

Within	O
8	O
hours	O
after	O
initiation	O
of	O
therapy	O
the	O
patient	O
died	O
with	O
a	O
clinical	O
picture	O
resembling	O
massive	O
pulmonary	B-Disease
obstruction	I-Disease
due	O
to	O
choriocarcinomic	O
tissue	O
plugs	O
,	O
probably	O
originating	O
from	O
the	O
uterus	O
.	O

Formation	O
of	O
these	O
plugs	O
was	O
probably	O
due	O
to	O
extensive	O
tumor	B-Disease
necrosis	B-Disease
at	O
the	O
level	O
of	O
the	O
walls	O
of	O
the	O
major	O
uterine	O
veins	O
,	O
which	O
resulted	O
in	O
an	O
open	O
exchange	O
of	O
tumor	B-Disease
plugs	O
to	O
the	O
vascular	O
spaces	O
;	O
decrease	O
in	O
tumor	B-Disease
tissue	O
coherence	O
secondary	O
to	O
chemotherapy	O
may	O
have	O
further	O
contributed	O
to	O
the	O
formation	O
of	O
tumor	B-Disease
emboli	O
.	O

In	O
view	O
of	O
the	O
close	O
time	O
association	O
between	O
the	O
start	O
of	O
chemotherapy	O
and	O
the	O
acute	O
onset	O
of	O
massive	O
embolism	B-Disease
other	O
explanations	O
,	O
such	O
as	O
spontaneous	O
necrosis	B-Disease
,	O
must	O
be	O
considered	O
less	O
likely	O
.	O

Patients	O
with	O
large	O
pelvic	B-Disease
tumor	I-Disease
loads	O
are	O
,	O
according	O
to	O
existing	O
classifications	O
,	O
at	O
high	O
risk	O
to	O
die	O
and	O
to	O
develop	O
drug	O
resistance	O
.	O

Notwithstanding	O
these	O
facts	O
our	O
findings	O
suggest	O
that	O
these	O
patients	O
might	O
benefit	O
from	O
relatively	O
mild	O
initial	O
treatment	O
,	O
especially	O
true	O
for	O
patients	O
not	O
previously	O
exposed	O
to	O
this	O
drug	O
.	O

Close	O
observation	O
of	O
the	O
response	O
status	O
both	O
clinically	O
and	O
with	O
beta	O
-	O
hCG	O
values	O
may	O
indicate	O
whether	O
and	O
when	O
more	O
agressive	O
combination	O
chemotherapy	O
should	O
be	O
started	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
250	O
WORDS	O
)	O

Pulmonary	O
shunt	O
and	O
cardiovascular	O
responses	O
to	O
CPAP	O
during	O
nitroprusside	B-Chemical
-	O
induced	O
hypotension	B-Disease
.	O

The	O
effects	O
of	O
continuous	O
positive	O
airway	O
pressure	O
(	O
CPAP	O
)	O
on	O
cardiovascular	O
dynamics	O
and	O
pulmonary	O
shunt	O
(	O
QS	O
/	O
QT	O
)	O
were	O
investigated	O
in	O
12	O
dogs	O
before	O
and	O
during	O
sodium	B-Chemical
nitroprusside	I-Chemical
infusion	O
that	O
decreased	O
mean	O
arterial	O
blood	O
pressure	O
40	O
-	O
50	O
per	O
cent	O
.	O

Before	O
nitroprusside	B-Chemical
infusion	O
,	O
5	O
cm	O
H2O	B-Chemical
CPAP	O
significantly	O
,	O
P	O
less	O
than	O
.	O
05	O
,	O
decreased	O
arterial	O
blood	O
pressure	O
,	O
but	O
did	O
not	O
significantly	O
alter	O
heart	O
rate	O
,	O
cardiac	O
output	O
,	O
systemic	O
vascular	O
resistance	O
,	O
or	O
QS	O
/	O
QT	O
.	O

Ten	O
cm	O
H2O	B-Chemical
CPAP	O
before	O
nitroprusside	B-Chemical
infusion	O
produced	O
a	O
further	O
decrease	B-Disease
in	I-Disease
arterial	I-Disease
blood	I-Disease
pressure	I-Disease
and	O
significantly	O
increased	O
heart	O
rate	O
and	O
decreased	B-Disease
cardiac	I-Disease
output	I-Disease
and	O
QS	O
/	O
QT	O
.	O

Nitroprusside	B-Chemical
caused	O
significant	O
decreases	B-Disease
in	I-Disease
arterial	I-Disease
blood	I-Disease
pressure	I-Disease
and	O
systemic	O
vascular	O
resistance	O
and	O
increases	O
in	O
heart	O
rate	O
,	O
but	O
did	O
not	O
change	O
cardiac	O
output	O
or	O
QS	O
/	O
QT	O
.	O

Five	O
cm	O
H2O	B-Chemical
CPAP	O
during	O
nitroprusside	B-Chemical
did	O
not	O
further	O
alter	O
any	O
of	O
the	O
above	O
-	O
mentioned	O
variables	O
.	O

However	O
,	O
10	O
cm	O
H2O	B-Chemical
CPAP	O
decreased	O
arterial	O
blood	O
pressure	O
,	O
cardiac	O
output	O
,	O
and	O
QS	O
/	O
QT	O
.	O

These	O
data	O
indicate	O
that	O
nitroprusside	B-Chemical
infusion	O
rates	O
that	O
decrease	O
mean	O
arterial	O
blood	O
pressure	O
by	O
40	O
-	O
50	O
per	O
cent	O
do	O
not	O
change	O
cardiac	O
output	O
or	O
QS	O
/	O
QT	O
.	O

During	O
nitroprusside	B-Chemical
infusion	O
low	O
levels	O
of	O
CPAP	O
do	O
not	O
markedly	O
alter	O
cardiovascular	O
dynamics	O
,	O
but	O
high	O
levels	O
of	O
CPAP	O
(	O
10	O
cm	O
H2O	B-Chemical
)	O
,	O
while	O
decreasing	O
QS	O
/	O
QT	O
,	O
produce	O
marked	O
decreases	B-Disease
in	I-Disease
arterial	I-Disease
blood	I-Disease
pressure	I-Disease
and	I-Disease
cardiac	I-Disease
output	I-Disease
.	O

Systolic	O
pressure	O
variation	O
is	O
greater	O
during	O
hemorrhage	B-Disease
than	O
during	O
sodium	B-Chemical
nitroprusside	I-Chemical
-	O
induced	O
hypotension	B-Disease
in	O
ventilated	O
dogs	O
.	O

The	O
systolic	O
pressure	O
variation	O
(	O
SPV	O
)	O
,	O
which	O
is	O
the	O
difference	O
between	O
the	O
maximal	O
and	O
minimal	O
values	O
of	O
the	O
systolic	O
blood	O
pressure	O
(	O
SBP	O
)	O
after	O
one	O
positive	O
-	O
pressure	O
breath	O
,	O
was	O
studied	O
in	O
ventilated	O
dogs	O
subjected	O
to	O
hypotension	B-Disease
.	O

Mean	O
arterial	O
pressure	O
was	O
decreased	O
to	O
50	O
mm	O
Hg	O
for	O
30	O
minutes	O
either	O
by	O
hemorrhage	B-Disease
(	O
HEM	B-Disease
,	O
n	O
=	O
7	O
)	O
or	O
by	O
continuous	O
infusion	O
of	O
sodium	B-Chemical
nitroprusside	I-Chemical
(	O
SNP	B-Chemical
,	O
n	O
=	O
7	O
)	O
.	O

During	O
HEM	B-Disease
-	O
induced	O
hypotension	B-Disease
the	O
cardiac	O
output	O
was	O
significantly	O
lower	O
and	O
systemic	O
vascular	O
resistance	O
higher	O
compared	O
with	O
that	O
in	O
the	O
SNP	B-Chemical
group	O
.	O

The	O
systemic	O
,	O
central	O
venous	O
,	O
pulmonary	O
capillary	O
wedge	O
pressures	O
,	O
and	O
heart	O
rates	O
,	O
were	O
similar	O
in	O
the	O
two	O
groups	O
.	O

Analysis	O
of	O
the	O
respiratory	O
changes	O
in	O
the	O
arterial	O
pressure	O
waveform	O
enabled	O
differentiation	O
between	O
the	O
two	O
groups	O
.	O

The	O
SPV	O
during	O
hypotension	B-Disease
was	O
15	O
.	O
7	O
+	O
/	O
-	O
6	O
.	O
7	O
mm	O
Hg	O
in	O
the	O
HEM	B-Disease
group	O
,	O
compared	O
with	O
9	O
.	O
1	O
+	O
/	O
-	O
2	O
.	O
0	O
mm	O
Hg	O
in	O
the	O
SNP	B-Chemical
group	O
(	O
P	O
less	O
than	O
0	O
.	O
02	O
)	O
.	O

The	O
delta	O
down	O
,	O
which	O
is	O
the	O
measure	O
of	O
decrease	O
of	O
SBP	O
after	O
a	O
mechanical	O
breath	O
,	O
was	O
20	O
.	O
3	O
+	O
/	O
-	O
8	O
.	O
4	O
and	O
10	O
.	O
1	O
+	O
/	O
-	O
3	O
.	O
8	O
mm	O
Hg	O
in	O
the	O
HEM	B-Disease
and	O
SNP	B-Chemical
groups	O
,	O
respectively	O
,	O
during	O
hypotension	B-Disease
(	O
P	O
less	O
than	O
0	O
.	O
02	O
)	O
.	O

It	O
is	O
concluded	O
that	O
increases	O
in	O
the	O
SPV	O
and	O
the	O
delta	O
down	O
are	O
characteristic	O
of	O
a	O
hypotensive	B-Disease
state	O
due	O
to	O
a	O
predominant	O
decrease	O
in	O
preload	O
.	O

They	O
are	O
thus	O
more	O
important	O
during	O
absolute	O
hypovolemia	B-Disease
than	O
during	O
deliberate	O
hypotension	B-Disease
.	O

Ventricular	B-Disease
tachyarrhythmias	I-Disease
during	O
cesarean	O
section	O
after	O
ritodrine	B-Chemical
therapy	O
:	O
interaction	O
with	O
anesthetics	O
.	O

This	O
case	O
illustrates	O
that	O
patients	O
receiving	O
ritodrine	B-Chemical
for	O
preterm	B-Disease
labor	I-Disease
may	O
risk	O
interactions	O
between	O
the	O
residual	O
betamimetic	O
effects	O
of	O
ritodrine	B-Chemical
and	O
the	O
effects	O
of	O
anesthetics	O
during	O
cesarean	O
section	O
.	O

Such	O
interactions	O
may	O
result	O
in	O
serious	O
cardiovascular	B-Disease
complications	I-Disease
even	O
after	O
cessation	O
of	O
an	O
infusion	O
of	O
ritodrine	B-Chemical
.	O

Preoperative	O
assessment	O
should	O
focus	O
on	O
cardiovascular	O
status	O
and	O
serum	O
potassium	B-Chemical
level	O
.	O

Delaying	O
induction	O
of	O
anesthesia	O
should	O
be	O
considered	O
whenever	O
possible	O
.	O

Careful	O
fluid	O
administration	O
and	O
cautious	O
use	O
of	O
titrated	O
doses	O
of	O
ephedrine	B-Chemical
are	O
advised	O
.	O

After	O
delivery	O
of	O
the	O
infant	O
,	O
there	O
should	O
be	O
no	O
contraindication	O
to	O
the	O
use	O
of	O
an	O
alpha	O
-	O
adrenergic	O
vasopressor	O
such	O
as	O
phenylephrine	B-Chemical
to	O
treat	O
hypotensive	B-Disease
patients	O
with	O
tachycardia	B-Disease
.	O

Verapamil	B-Chemical
-	O
induced	O
carbamazepine	B-Chemical
neurotoxicity	B-Disease
.	O

A	O
report	O
of	O
two	O
cases	O
.	O

Two	O
patients	O
with	O
signs	O
of	O
carbamazepine	B-Chemical
neurotoxicity	B-Disease
after	O
combined	O
treatment	O
with	O
verapamil	B-Chemical
showed	O
complete	O
recovery	O
after	O
discontinuation	O
of	O
the	O
calcium	B-Chemical
entry	O
blocker	O
.	O

Use	O
of	O
verapamil	B-Chemical
in	O
combination	O
with	O
carbamazepine	B-Chemical
should	O
either	O
be	O
avoided	O
or	O
prescribed	O
only	O
with	O
appropriate	O
adjustment	O
of	O
the	O
carbamazepine	B-Chemical
dose	O
(	O
usually	O
reduction	O
of	O
the	O
carbamazepine	B-Chemical
dose	O
by	O
one	O
half	O
)	O
.	O

Paracetamol	B-Chemical
-	O
associated	O
coma	B-Disease
,	O
metabolic	B-Disease
acidosis	I-Disease
,	O
renal	B-Disease
and	I-Disease
hepatic	I-Disease
failure	I-Disease
.	O

A	O
case	O
of	O
metabolic	B-Disease
acidosis	I-Disease
,	O
acute	B-Disease
renal	I-Disease
failure	I-Disease
and	I-Disease
hepatic	I-Disease
failure	I-Disease
following	O
paracetamol	B-Chemical
ingestion	O
is	O
presented	O
.	O

The	O
diagnostic	O
difficulty	O
at	O
presentation	O
is	O
highlighted	O
.	O

Continuous	O
arteriovenous	O
haemofiltration	O
proved	O
a	O
valuable	O
means	O
of	O
maintaining	O
fluid	O
and	O
electrolyte	O
balance	O
.	O

The	O
patient	O
recovered	O
.	O

Sexual	B-Disease
dysfunction	I-Disease
among	O
patients	O
with	O
arthritis	B-Disease
.	O

The	O
relationship	O
of	O
arthritis	B-Disease
and	O
sexual	B-Disease
dysfunction	I-Disease
was	O
investigated	O
among	O
169	O
patients	O
with	O
rheumatoid	B-Disease
arthritis	I-Disease
,	O
osteoarthritis	B-Disease
and	O
spondyloarthropathy	B-Disease
,	O
130	O
of	O
whom	O
were	O
pair	O
-	O
matched	O
to	O
controls	O
.	O

Assessments	O
of	O
marital	O
happiness	O
and	O
depressed	B-Disease
mood	I-Disease
were	O
also	O
made	O
using	O
the	O
CES	O
-	O
D	O
and	O
the	O
Azrin	O
Marital	O
Happiness	O
Scale	O
(	O
AMHS	O
)	O
.	O

Sexual	B-Disease
dysfunctions	I-Disease
were	O
found	O
to	O
be	O
common	O
among	O
patients	O
and	O
controls	O
,	O
the	O
majority	O
in	O
both	O
groups	O
reporting	O
one	O
or	O
more	O
dysfunctions	O
.	O

Impotence	B-Disease
was	O
more	O
common	O
among	O
male	O
patients	O
than	O
controls	O
and	O
was	O
found	O
to	O
be	O
associated	O
with	O
co	O
-	O
morbidity	O
and	O
the	O
taking	O
of	O
methotrexate	B-Chemical
.	O

Depressed	B-Disease
mood	I-Disease
was	O
more	O
common	O
among	O
patients	O
and	O
was	O
associated	O
with	O
certain	O
sexual	O
difficulties	O
,	O
but	O
not	O
with	O
impotence	B-Disease
.	O

Marital	O
unhappiness	O
,	O
as	O
indicated	O
by	O
AMHS	O
scores	O
,	O
was	O
not	O
associated	O
with	O
arthritis	B-Disease
but	O
was	O
associated	O
with	O
sexual	B-Disease
dysfunction	I-Disease
,	O
sexual	O
dissatisfaction	O
and	O
being	O
female	O
.	O

Does	O
paracetamol	B-Chemical
cause	O
urothelial	B-Disease
cancer	I-Disease
or	O
renal	B-Disease
papillary	I-Disease
necrosis	I-Disease
?	O

The	O
risk	O
of	O
developing	O
renal	B-Disease
papillary	I-Disease
necrosis	I-Disease
or	O
cancer	B-Disease
of	I-Disease
the	I-Disease
renal	I-Disease
pelvis	I-Disease
,	I-Disease
ureter	I-Disease
or	I-Disease
bladder	I-Disease
associated	O
with	O
consumption	O
of	O
either	O
phenacetin	B-Chemical
or	O
paracetamol	B-Chemical
was	O
calculated	O
from	O
data	O
acquired	O
by	O
questionnaire	O
from	O
381	O
cases	O
and	O
808	O
controls	O
.	O

The	O
risk	O
of	O
renal	B-Disease
papillary	I-Disease
necrosis	I-Disease
was	O
increased	O
nearly	O
20	O
-	O
fold	O
by	O
consumption	O
of	O
phenacetin	B-Chemical
,	O
which	O
also	O
increased	O
the	O
risk	O
for	O
cancer	B-Disease
of	I-Disease
the	I-Disease
renal	I-Disease
pelvis	I-Disease
and	I-Disease
bladder	I-Disease
but	O
not	O
for	O
ureteric	B-Disease
cancer	I-Disease
.	O

By	O
contrast	O
,	O
we	O
were	O
unable	O
to	O
substantiate	O
an	O
increased	O
risk	O
from	O
paracetamol	B-Chemical
consumption	O
for	O
renal	B-Disease
papillary	I-Disease
necrosis	I-Disease
or	O
any	O
of	O
these	O
cancers	B-Disease
although	O
there	O
was	O
a	O
suggestion	O
of	O
an	O
association	O
with	O
cancer	B-Disease
of	I-Disease
the	I-Disease
ureter	I-Disease
.	O

Dapsone	B-Chemical
-	O
associated	O
Heinz	O
body	O
hemolytic	B-Disease
anemia	I-Disease
in	O
a	O
Cambodian	O
woman	O
with	O
hemoglobin	O
E	O
trait	O
.	O

A	O
Cambodian	O
woman	O
with	O
hemoglobin	O
E	O
trait	O
(	O
AE	O
)	O
and	O
leprosy	B-Disease
developed	O
a	O
Heinz	O
body	O
hemolytic	B-Disease
anemia	I-Disease
while	O
taking	O
a	O
dose	O
of	O
dapsone	B-Chemical
(	O
50	O
mg	O
/	O
day	O
)	O
not	O
usually	O
associated	O
with	O
clinical	O
hemolysis	B-Disease
.	O

Her	O
red	O
blood	O
cells	O
(	O
RBCs	O
)	O
had	O
increased	O
incubated	O
Heinz	O
body	O
formation	O
,	O
decreased	O
reduced	O
glutathione	B-Chemical
(	O
GSH	B-Chemical
)	O
,	O
and	O
decreased	O
GSH	B-Chemical
stability	O
.	O

The	O
pentose	B-Chemical
phosphate	I-Chemical
shunt	O
activity	O
of	O
the	O
dapsone	B-Chemical
-	O
exposed	O
AE	O
RBCs	O
was	O
increased	O
compared	O
to	O
normal	O
RBCs	O
.	O

Although	O
the	O
AE	O
RBCs	O
from	O
an	O
individual	O
not	O
taking	O
dapsone	B-Chemical
had	O
increased	O
incubated	O
Heinz	O
body	O
formation	O
,	O
the	O
GSH	B-Chemical
content	O
and	O
GSH	B-Chemical
stability	O
were	O
normal	O
.	O

The	O
pentose	B-Chemical
phosphate	I-Chemical
shunt	O
activity	O
of	O
the	O
non	O
-	O
dapsone	B-Chemical
-	O
exposed	O
AE	O
RBCs	O
was	O
decreased	O
compared	O
to	O
normal	O
RBCs	O
.	O

Thus	O
,	O
AE	O
RBCs	O
appear	O
to	O
have	O
an	O
increased	O
sensitivity	O
to	O
oxidant	O
stress	O
both	O
in	O
vitro	O
and	O
in	O
vivo	O
,	O
since	O
dapsone	B-Chemical
does	O
not	O
cause	O
hemolytic	B-Disease
anemia	I-Disease
at	O
this	O
dose	O
in	O
hematologically	O
normal	O
individuals	O
.	O

Given	O
the	O
influx	O
of	O
Southeast	O
Asians	O
into	O
the	O
United	O
States	O
,	O
oxidant	O
medications	O
should	O
be	O
used	O
with	O
caution	O
,	O
especially	O
if	O
an	O
infection	B-Disease
is	O
present	O
,	O
in	O
individuals	O
of	O
ethnic	O
backgrounds	O
that	O
have	O
an	O
increased	O
prevalence	O
of	O
hemoglobin	O
E	O
.	O

Severe	O
complications	O
of	O
antianginal	O
drug	O
therapy	O
in	O
a	O
patient	O
identified	O
as	O
a	O
poor	O
metabolizer	O
of	O
metoprolol	B-Chemical
,	O
propafenone	B-Chemical
,	O
diltiazem	B-Chemical
,	O
and	O
sparteine	B-Chemical
.	O

A	O
47	O
-	O
year	O
-	O
old	O
patient	O
suffering	O
from	O
coronary	B-Disease
artery	I-Disease
disease	I-Disease
was	O
admitted	O
to	O
the	O
CCU	O
in	O
shock	B-Disease
with	O
III	O
.	O

AV	B-Disease
block	I-Disease
,	O
severe	O
hypotension	B-Disease
,	O
and	O
impairment	B-Disease
of	I-Disease
ventricular	I-Disease
function	I-Disease
.	O

One	O
week	O
prior	O
to	O
admission	O
a	O
therapy	O
with	O
standard	O
doses	O
of	O
metoprolol	B-Chemical
(	O
100	O
mg	O
t	O
.	O
i	O
.	O
d	O
.	O
and	O
then	O
100	O
mg	O
b	O
.	O
i	O
.	O
d	O
.	O
)	O
had	O
been	O
initiated	O
.	O

Two	O
days	O
before	O
admission	O
diltiazem	B-Chemical
(	O
60	O
mg	O
b	O
.	O
i	O
.	O
d	O
.	O
)	O
was	O
prescribed	O
in	O
addition	O
.	O

Analyses	O
of	O
a	O
blood	O
sample	O
revealed	O
unusually	O
high	O
plasma	O
concentrations	O
of	O
metoprolol	B-Chemical
(	O
greater	O
than	O
3000	O
ng	O
/	O
ml	O
)	O
and	O
diltiazem	B-Chemical
(	O
526	O
ng	O
/	O
ml	O
)	O
.	O

The	O
patient	O
recovered	O
within	O
1	O
week	O
following	O
discontinuation	O
of	O
antianginal	O
therapy	O
.	O

Three	O
months	O
later	O
the	O
patient	O
was	O
exposed	O
to	O
a	O
single	O
dose	O
of	O
metoprolol	B-Chemical
,	O
diltiazem	B-Chemical
,	O
propafenone	B-Chemical
(	O
since	O
he	O
had	O
received	O
this	O
drug	O
in	O
the	O
past	O
)	O
,	O
and	O
sparteine	B-Chemical
(	O
as	O
a	O
probe	O
for	O
the	O
debrisoquine	B-Chemical
/	O
sparteine	B-Chemical
type	O
polymorphism	O
of	O
oxidative	O
drug	O
metabolism	O
)	O
.	O

It	O
was	O
found	O
that	O
he	O
was	O
a	O
poor	O
metabolizer	O
of	O
all	O
four	O
drugs	O
,	O
indicating	O
that	O
their	O
metabolism	O
is	O
under	O
the	O
same	O
genetic	O
control	O
.	O

Therefore	O
,	O
patients	O
belonging	O
to	O
the	O
poor	O
-	O
metabolizer	O
phenotype	O
of	O
sparteine	B-Chemical
/	O
debrisoquine	B-Chemical
polymorphism	O
in	O
drug	O
metabolism	O
,	O
which	O
constitutes	O
6	O
.	O
4	O
%	O
of	O
the	O
German	O
population	O
,	O
may	O
experience	O
adverse	B-Disease
drug	I-Disease
reactions	I-Disease
when	O
treated	O
with	O
standard	O
doses	O
of	O
one	O
of	O
these	O
drugs	O
alone	O
.	O

Moreover	O
,	O
the	O
coadministration	O
of	O
these	O
frequently	O
used	O
drugs	O
is	O
expected	O
to	O
be	O
especially	O
harmful	O
in	O
this	O
subgroup	O
of	O
patients	O
.	O

Clinical	O
experiences	O
in	O
an	O
open	O
and	O
a	O
double	O
-	O
blind	O
trial	O
.	O

A	O
total	O
of	O
sixty	O
patients	O
were	O
trated	O
with	O
bromperidol	B-Chemical
first	O
in	O
open	O
conditions	O
(	O
20	O
patients	O
)	O
,	O
then	O
on	O
a	O
double	O
blind	O
basis	O
(	O
40	O
patients	O
)	O
with	O
haloperidol	B-Chemical
as	O
the	O
reference	O
substance	O
.	O

The	O
open	O
study	O
lasted	O
for	O
four	O
weeks	O
;	O
the	O
drug	O
was	O
administrated	O
in	O
the	O
form	O
of	O
1	O
mg	O
tablets	O
.	O

The	O
daily	O
dose	O
(	O
initial	O
dose	O
:	O
1	O
mg	O
;	O
mean	O
dose	O
at	O
the	O
end	O
of	O
the	O
trial	O
:	O
4	O
.	O
47	O
mg	O
)	O
was	O
always	O
administered	O
in	O
one	O
single	O
dose	O
.	O

Nineteen	O
patients	O
finished	O
the	O
trial	O
,	O
and	O
in	O
18	O
cases	O
the	O
therapeutic	O
result	O
was	O
considered	O
very	O
good	O
to	O
good	O
.	O

These	O
results	O
were	O
confirmed	O
by	O
statistical	O
analysis	O
.	O

Nine	O
patients	O
exhibited	O
mild	O
to	O
moderate	O
extrapyramidal	B-Disease
concomitant	I-Disease
symptoms	I-Disease
;	O
no	O
other	O
side	O
effects	O
were	O
observed	O
.	O

The	O
results	O
of	O
detailed	O
laboratory	O
tests	O
and	O
evaluations	O
of	O
various	O
quantitative	O
and	O
qualitative	O
tolerability	O
parameters	O
were	O
not	O
indicative	O
of	O
toxic	O
effects	O
.	O

In	O
the	O
double	O
blind	O
study	O
with	O
haloperidol	B-Chemical
,	O
both	O
substances	O
were	O
found	O
to	O
be	O
highly	O
effective	O
in	O
the	O
treatment	O
of	O
psychotic	B-Disease
syndromes	I-Disease
belonging	I-Disease
predominantly	I-Disease
to	I-Disease
the	I-Disease
schizophrenia	I-Disease
group	I-Disease
.	O

Certain	O
clues	O
,	O
including	O
the	O
onset	O
of	O
action	O
,	O
seem	O
to	O
be	O
indicative	O
of	O
the	O
superiority	O
of	O
bromperidol	B-Chemical
.	O

No	O
differences	O
were	O
observed	O
with	O
respect	O
to	O
side	O
effects	O
and	O
general	O
tolerability	O
.	O

Prolonged	O
cholestasis	B-Disease
after	O
troleandomycin	B-Chemical
-	O
induced	O
acute	O
hepatitis	B-Disease
.	O

We	O
report	O
the	O
case	O
of	O
a	O
patient	O
in	O
whom	O
troleandomycin	B-Chemical
-	O
induced	O
hepatitis	B-Disease
was	O
followed	O
by	O
prolonged	O
anicteric	O
cholestasis	B-Disease
.	O

Jaundice	B-Disease
occurred	O
after	O
administration	O
of	O
troleandomycin	B-Chemical
for	O
7	O
days	O
and	O
was	O
associated	O
with	O
hypereosinophilia	B-Disease
.	O

Jaundice	B-Disease
disappeared	O
within	O
3	O
months	O
but	O
was	O
followed	O
by	O
prolonged	O
anicteric	O
cholestasis	B-Disease
marked	O
by	O
pruritus	B-Disease
and	O
high	O
levels	O
of	O
alkaline	O
phosphatase	O
and	O
gammaglutamyltransferase	O
activities	O
.	O

Finally	O
,	O
pruritus	B-Disease
disappeared	O
within	O
19	O
months	O
,	O
and	O
liver	O
tests	O
returned	O
to	O
normal	O
27	O
months	O
after	O
the	O
onset	O
of	O
hepatitis	B-Disease
.	O

This	O
observation	O
demonstrates	O
that	O
prolonged	O
cholestasis	B-Disease
can	O
follow	O
troleandomycin	B-Chemical
-	O
induced	O
acute	O
hepatitis	B-Disease
.	O

Serial	O
studies	O
of	O
auditory	B-Disease
neurotoxicity	I-Disease
in	O
patients	O
receiving	O
deferoxamine	B-Chemical
therapy	O
.	O

Visual	B-Disease
and	I-Disease
auditory	I-Disease
neurotoxicity	I-Disease
was	O
previously	O
documented	O
in	O
42	O
of	O
89	O
patients	O
with	O
transfusion	O
-	O
dependent	O
anemia	B-Disease
who	O
were	O
receiving	O
iron	B-Chemical
chelation	O
therapy	O
with	O
daily	O
subcutaneous	O
deferoxamine	B-Chemical
.	O

Twenty	O
-	O
two	O
patients	O
in	O
the	O
affected	O
group	O
had	O
abnormal	B-Disease
audiograms	I-Disease
with	I-Disease
deficits	I-Disease
mostly	I-Disease
in	I-Disease
the	I-Disease
high	I-Disease
frequency	I-Disease
range	I-Disease
of	I-Disease
4	I-Disease
,	I-Disease
000	I-Disease
to	I-Disease
8	I-Disease
,	I-Disease
000	I-Disease
Hz	I-Disease
and	O
in	O
the	O
hearing	O
threshold	O
levels	O
of	O
30	O
to	O
100	O
decibels	O
.	O

When	O
deferoxamine	B-Chemical
therapy	O
was	O
discontinued	O
and	O
serial	O
studies	O
were	O
performed	O
,	O
audiograms	O
in	O
seven	O
cases	O
reverted	O
to	O
normal	O
or	O
near	O
normal	O
within	O
two	O
to	O
three	O
weeks	O
,	O
and	O
nine	O
of	O
13	O
patients	O
with	O
symptoms	O
became	O
asymptomatic	O
.	O

Audiograms	O
from	O
15	O
patients	O
remained	O
abnormal	O
and	O
four	O
patients	O
required	O
hearing	O
aids	O
because	O
of	O
permanent	B-Disease
disability	I-Disease
.	O

Since	O
18	O
of	O
the	O
22	O
patients	O
were	O
initially	O
receiving	O
deferoxamine	B-Chemical
doses	O
in	O
excess	O
of	O
the	O
commonly	O
recommended	O
50	O
mg	O
/	O
kg	O
per	O
dose	O
,	O
therapy	O
was	O
restarted	O
with	O
lower	O
doses	O
,	O
usually	O
50	O
mg	O
/	O
kg	O
per	O
dose	O
or	O
less	O
depending	O
on	O
the	O
degree	O
of	O
auditory	B-Disease
abnormality	I-Disease
,	O
and	O
with	O
the	O
exception	O
of	O
two	O
cases	O
no	O
further	O
toxicity	B-Disease
was	O
demonstrated	O
.	O

Auditory	O
deterioration	O
and	O
improvement	O
,	O
demonstrated	O
serially	O
in	O
individual	O
patients	O
receiving	O
and	O
not	O
receiving	O
deferoxamine	B-Chemical
,	O
respectively	O
,	O
provided	O
convincing	O
evidence	O
for	O
a	O
cause	O
-	O
and	O
-	O
effect	O
relation	O
between	O
deferoxamine	B-Chemical
administration	O
and	O
ototoxicity	B-Disease
.	O

Based	O
on	O
these	O
data	O
,	O
a	O
plan	O
of	O
management	O
was	O
developed	O
that	O
allows	O
effective	O
yet	O
safe	O
administration	O
of	O
deferoxamine	B-Chemical
.	O

A	O
dose	O
of	O
50	O
mg	O
/	O
kg	O
is	O
recommended	O
in	O
those	O
without	O
audiogram	O
abnormalities	O
.	O

With	O
mild	O
toxicity	B-Disease
,	O
a	O
reduction	O
to	O
30	O
or	O
40	O
mg	O
/	O
kg	O
per	O
dose	O
should	O
result	O
in	O
a	O
reversal	O
of	O
the	O
abnormal	O
results	O
to	O
normal	O
within	O
four	O
weeks	O
.	O

Moderate	O
abnormalities	O
require	O
a	O
reduction	O
of	O
deferoxamine	B-Chemical
to	O
25	O
mg	O
/	O
kg	O
per	O
dose	O
with	O
careful	O
monitoring	O
.	O

In	O
those	O
with	O
symptoms	O
of	O
hearing	B-Disease
loss	I-Disease
,	O
the	O
drug	O
should	O
be	O
stopped	O
for	O
four	O
weeks	O
,	O
and	O
when	O
the	O
audiogram	O
is	O
stable	O
or	O
improved	O
,	O
therapy	O
should	O
be	O
restarted	O
at	O
10	O
to	O
25	O
mg	O
/	O
kg	O
per	O
dose	O
.	O

Serial	O
audiograms	O
should	O
be	O
performed	O
every	O
six	O
months	O
in	O
those	O
without	O
problems	O
and	O
more	O
frequently	O
in	O
young	O
patients	O
with	O
normal	O
serum	O
ferritin	O
values	O
and	O
in	O
those	O
with	O
auditory	B-Disease
dysfunction	I-Disease
.	O

Lidocaine	B-Chemical
-	O
induced	O
cardiac	B-Disease
asystole	I-Disease
.	O

Intravenous	O
administration	O
of	O
a	O
single	O
50	O
-	O
mg	O
bolus	O
of	O
lidocaine	B-Chemical
in	O
a	O
67	O
-	O
year	O
-	O
old	O
man	O
resulted	O
in	O
profound	O
depression	B-Disease
of	O
the	O
activity	O
of	O
the	O
sinoatrial	O
and	O
atrioventricular	O
nodal	O
pacemakers	O
.	O

The	O
patient	O
had	O
no	O
apparent	O
associated	O
conditions	O
which	O
might	O
have	O
predisposed	O
him	O
to	O
the	O
development	O
of	O
bradyarrhythmias	B-Disease
;	O
and	O
,	O
thus	O
,	O
this	O
probably	O
represented	O
a	O
true	O
idiosyncrasy	O
to	O
lidocaine	B-Chemical
.	O

Flurbiprofen	B-Chemical
in	O
the	O
treatment	O
of	O
juvenile	B-Disease
rheumatoid	I-Disease
arthritis	I-Disease
.	O

Thirty	O
-	O
four	O
patients	O
with	O
juvenile	B-Disease
rheumatoid	I-Disease
arthritis	I-Disease
,	O
who	O
were	O
treated	O
with	O
flurbiprofen	B-Chemical
at	O
a	O
maximum	O
dose	O
of	O
4	O
mg	O
/	O
kg	O
/	O
day	O
,	O
had	O
statistically	O
significant	O
decreases	O
from	O
baseline	O
in	O
6	O
arthritis	B-Disease
indices	O
after	O
12	O
weeks	O
of	O
treatment	O
.	O

Improvements	O
were	O
seen	O
in	O
the	O
number	O
of	O
tender	B-Disease
joints	I-Disease
,	O
the	O
severity	O
of	O
swelling	B-Disease
and	O
tenderness	B-Disease
,	O
the	O
time	O
of	O
walk	O
50	O
feet	O
,	O
the	O
duration	O
of	O
morning	B-Disease
stiffness	I-Disease
and	O
the	O
circumference	O
of	O
the	O
left	O
knee	O
.	O

The	O
most	O
frequently	O
observed	O
side	O
effect	O
was	O
fecal	B-Disease
occult	I-Disease
blood	I-Disease
(	O
25	O
%	O
of	O
patients	O
)	O
;	O
however	O
,	O
there	O
was	O
no	O
other	O
evidence	O
of	O
gastrointestinal	B-Disease
(	I-Disease
GI	I-Disease
)	I-Disease
bleeding	I-Disease
in	O
these	O
patients	O
.	O

One	O
patient	O
was	O
prematurely	O
discontinued	O
from	O
the	O
study	O
for	O
severe	O
headache	B-Disease
and	O
abdominal	B-Disease
pain	I-Disease
.	O

Most	O
side	O
effects	O
were	O
mild	O
and	O
related	O
to	O
the	O
GI	O
tract	O
.	O

Hyperkalemia	B-Disease
associated	O
with	O
sulindac	B-Chemical
therapy	O
.	O

Hyperkalemia	B-Disease
has	O
recently	O
been	O
recognized	O
as	O
a	O
complication	O
of	O
nonsteroidal	O
antiinflammatory	O
agents	O
(	O
NSAID	O
)	O
such	O
as	O
indomethacin	B-Chemical
.	O

Several	O
recent	O
studies	O
have	O
stressed	O
the	O
renal	O
sparing	O
features	O
of	O
sulindac	B-Chemical
,	O
owing	O
to	O
its	O
lack	O
of	O
interference	O
with	O
renal	O
prostacyclin	B-Chemical
synthesis	O
.	O

We	O
describe	O
4	O
patients	O
in	O
whom	O
hyperkalemia	B-Disease
ranging	O
from	O
6	O
.	O
1	O
to	O
6	O
.	O
9	O
mEq	O
/	O
l	O
developed	O
within	O
3	O
to	O
8	O
days	O
of	O
sulindac	B-Chemical
administration	O
.	O

In	O
all	O
of	O
them	O
normal	O
serum	O
potassium	B-Chemical
levels	O
reached	O
within	O
2	O
to	O
4	O
days	O
of	O
stopping	O
sulindac	B-Chemical
.	O

As	O
no	O
other	O
medications	O
known	O
to	O
effect	O
serum	O
potassium	B-Chemical
had	O
been	O
given	O
concomitantly	O
,	O
this	O
course	O
of	O
events	O
is	O
suggestive	O
of	O
a	O
cause	O
-	O
and	O
-	O
effect	O
relationship	O
between	O
sulindac	B-Chemical
and	O
hyperkalemia	B-Disease
.	O

These	O
observations	O
indicate	O
that	O
initial	O
hopes	O
that	O
sulindac	B-Chemical
may	O
not	O
be	O
associated	O
with	O
the	O
adverse	O
renal	O
effects	O
of	O
other	O
NSAID	O
are	O
probably	O
not	O
justified	O
.	O

Drug	O
-	O
induced	O
arterial	O
spasm	B-Disease
relieved	O
by	O
lidocaine	B-Chemical
.	O

Case	O
report	O
.	O

Following	O
major	O
intracranial	O
surgery	O
in	O
a	O
35	O
-	O
year	O
-	O
old	O
man	O
,	O
sodium	B-Chemical
pentothal	I-Chemical
was	O
intravenously	O
infused	O
to	O
minimize	O
cerebral	B-Disease
ischaemia	I-Disease
.	O

Intense	O
vasospasm	B-Disease
with	O
threatened	O
gangrene	B-Disease
arose	O
in	O
the	O
arm	O
used	O
for	O
the	O
infusion	O
.	O

Since	O
the	O
cranial	O
condition	O
precluded	O
use	O
of	O
more	O
usual	O
methods	O
,	O
lidocaine	B-Chemical
was	O
given	O
intra	O
-	O
arterially	O
,	O
with	O
careful	O
cardiovascular	O
monitoring	O
,	O
to	O
counteract	O
the	O
vasospasm	B-Disease
.	O

The	O
treatment	O
was	O
rapidly	O
successful	O
.	O

Regional	O
localization	O
of	O
the	O
antagonism	O
of	O
amphetamine	B-Chemical
-	O
induced	O
hyperactivity	B-Disease
by	O
intracerebral	O
calcitonin	B-Chemical
injections	O
.	O

Calcitonin	B-Chemical
receptors	O
are	O
found	O
in	O
the	O
brain	O
,	O
and	O
intracerebral	O
infusions	O
of	O
calcitonin	B-Chemical
can	O
produce	O
behavioral	O
effects	O
.	O

Among	O
these	O
behavioral	O
effects	O
are	O
decreases	O
in	O
food	O
intake	O
and	O
decreases	O
in	O
amphetamine	B-Chemical
-	O
induced	O
locomotor	O
activity	O
.	O

In	O
previous	O
experiments	O
we	O
found	O
that	O
decreases	O
in	O
food	O
intake	O
were	O
induced	O
by	O
local	O
administration	O
of	O
calcitonin	B-Chemical
into	O
several	O
hypothalamic	O
sites	O
and	O
into	O
the	O
nucleus	O
accumbens	O
.	O

In	O
the	O
present	O
experiment	O
calcitonin	B-Chemical
decreased	O
locomotor	O
activity	O
when	O
locally	O
injected	O
into	O
the	O
same	O
sites	O
where	O
it	O
decreases	O
food	O
intake	O
.	O

The	O
areas	O
where	O
calcitonin	B-Chemical
is	O
most	O
effective	O
in	O
decreasing	O
locomotor	O
activity	O
are	O
located	O
in	O
the	O
hypothalamus	O
and	O
nucleus	O
accumbens	O
,	O
suggesting	O
that	O
these	O
areas	O
are	O
the	O
major	O
sites	O
of	O
action	O
of	O
calcitonin	B-Chemical
in	O
inhibiting	O
amphetamine	B-Chemical
-	O
induced	O
locomotor	O
activity	O
.	O

The	O
hematologic	O
effects	O
of	O
cefonicid	B-Chemical
and	O
cefazedone	B-Chemical
in	O
the	O
dog	O
:	O
a	O
potential	O
model	O
of	O
cephalosporin	B-Chemical
hematotoxicity	B-Disease
in	O
man	O
.	O

Cephalosporin	B-Chemical
antibiotics	O
cause	O
a	O
variety	O
of	O
hematologic	B-Disease
disturbances	I-Disease
in	O
man	O
,	O
the	O
pathogeneses	O
and	O
hematopathology	O
of	O
which	O
remain	O
poorly	O
characterized	O
.	O

There	O
is	O
a	O
need	O
for	O
a	O
well	O
-	O
defined	O
animal	O
model	O
in	O
which	O
these	O
blood	B-Disease
dyscrasias	I-Disease
can	O
be	O
studied	O
.	O

In	O
four	O
subacute	O
toxicity	B-Disease
studies	O
,	O
the	O
intravenous	O
administration	O
of	O
cefonicid	B-Chemical
or	O
cefazedone	B-Chemical
to	O
beagle	O
dogs	O
caused	O
a	O
dose	O
-	O
dependent	O
incidence	O
of	O
anemia	B-Disease
,	O
neutropenia	B-Disease
,	O
and	O
thrombocytopenia	B-Disease
after	O
1	O
-	O
3	O
months	O
of	O
treatment	O
.	O

A	O
nonregenerative	O
anemia	B-Disease
was	O
the	O
most	O
compromising	O
of	O
the	O
cytopenias	B-Disease
and	O
occurred	O
in	O
approximately	O
50	O
%	O
of	O
dogs	O
receiving	O
400	O
-	O
500	O
mg	O
/	O
kg	O
cefonicid	B-Chemical
or	O
540	O
-	O
840	O
mg	O
/	O
kg	O
cefazedone	B-Chemical
.	O

All	O
three	O
cytopenias	B-Disease
were	O
completely	O
reversible	O
following	O
cessation	O
of	O
treatment	O
;	O
the	O
time	O
required	O
for	O
recovery	O
of	O
the	O
erythron	O
(	O
approximately	O
1	O
month	O
)	O
was	O
considerably	O
longer	O
than	O
that	O
of	O
the	O
granulocytes	O
and	O
platelets	O
(	O
hours	O
to	O
a	O
few	O
days	O
)	O
.	O

Upon	O
rechallenge	O
with	O
either	O
cephalosporin	B-Chemical
,	O
the	O
hematologic	B-Disease
syndrome	I-Disease
was	O
reproduced	O
in	O
most	O
dogs	O
tested	O
;	O
cefonicid	B-Chemical
(	O
but	O
not	O
cefazedone	B-Chemical
)	O
-	O
treated	O
dogs	O
showed	O
a	O
substantially	O
reduced	O
induction	O
period	O
(	O
15	O
+	O
/	O
-	O
5	O
days	O
)	O
compared	O
to	O
that	O
of	O
the	O
first	O
exposure	O
to	O
the	O
drug	O
(	O
61	O
+	O
/	O
-	O
24	O
days	O
)	O
.	O

This	O
observation	O
,	O
along	O
with	O
the	O
rapid	O
rate	O
of	O
decline	O
in	O
red	O
cell	O
mass	O
parameters	O
of	O
affected	O
dogs	O
,	O
suggests	O
that	O
a	O
hemolytic	B-Disease
component	O
complicated	O
the	O
red	O
cell	O
production	O
problem	O
and	O
that	O
multiple	O
toxicologic	O
mechanisms	O
contributed	O
to	O
the	O
cytopenia	B-Disease
.	O

We	O
conclude	O
that	O
the	O
administration	O
of	O
high	O
doses	O
of	O
cefonicid	B-Chemical
or	O
cefazedone	B-Chemical
to	O
dogs	O
can	O
induce	O
hematotoxicity	B-Disease
similar	O
to	O
the	O
cephalosporin	B-Chemical
-	O
induced	O
blood	B-Disease
dyscrasias	I-Disease
described	O
in	O
man	O
and	O
thus	O
provides	O
a	O
useful	O
model	O
for	O
studying	O
the	O
mechanisms	O
of	O
these	O
disorders	O
.	O

Cerebral	O
blood	O
flow	O
and	O
metabolism	O
during	O
isoflurane	B-Chemical
-	O
induced	O
hypotension	B-Disease
in	O
patients	O
subjected	O
to	O
surgery	O
for	O
cerebral	B-Disease
aneurysms	I-Disease
.	O

Cerebral	O
blood	O
flow	O
and	O
cerebral	O
metabolic	O
rate	O
for	O
oxygen	B-Chemical
were	O
measured	O
during	O
isoflurane	B-Chemical
-	O
induced	O
hypotension	B-Disease
in	O
10	O
patients	O
subjected	O
to	O
craniotomy	O
for	O
clipping	O
of	O
a	O
cerebral	B-Disease
aneurysm	I-Disease
.	O

Flow	O
and	O
metabolism	O
were	O
measured	O
5	O
-	O
13	O
days	O
after	O
the	O
subarachnoid	B-Disease
haemorrhage	I-Disease
by	O
a	O
modification	O
of	O
the	O
classical	O
Kety	O
-	O
Schmidt	O
technique	O
using	O
xenon	B-Chemical
-	O
133	O
i	O
.	O
v	O
.	O
Anaesthesia	O
was	O
maintained	O
with	O
an	O
inspired	O
isoflurane	B-Chemical
concentration	O
of	O
0	O
.	O
75	O
%	O
(	O
plus	O
67	O
%	O
nitrous	B-Chemical
oxide	I-Chemical
in	O
oxygen	B-Chemical
)	O
,	O
during	O
which	O
CBF	O
and	O
CMRO2	O
were	O
34	O
.	O
3	O
+	O
/	O
-	O
2	O
.	O
1	O
ml	O
/	O
100	O
g	O
min	O
-	O
1	O
and	O
2	O
.	O
32	O
+	O
/	O
-	O
0	O
.	O
16	O
ml	O
/	O
100	O
g	O
min	O
-	O
1	O
at	O
PaCO2	O
4	O
.	O
1	O
+	O
/	O
-	O
0	O
.	O
1	O
kPa	O
(	O
mean	O
+	O
/	O
-	O
SEM	O
)	O
.	O

Controlled	O
hypotension	B-Disease
to	O
an	O
average	O
MAP	O
of	O
50	O
-	O
55	O
mm	O
Hg	B-Chemical
was	O
induced	O
by	O
increasing	O
the	O
dose	O
of	O
isoflurane	B-Chemical
,	O
and	O
maintained	O
at	O
an	O
inspired	O
concentration	O
of	O
2	O
.	O
2	O
+	O
/	O
-	O
0	O
.	O
2	O
%	O
.	O

This	O
resulted	O
in	O
a	O
significant	O
decrease	O
in	O
CMRO2	O
(	O
to	O
1	O
.	O
73	O
+	O
/	O
-	O
0	O
.	O
16	O
ml	O
/	O
100	O
g	O
min	O
-	O
1	O
)	O
,	O
while	O
CBF	O
was	O
unchanged	O
.	O

After	O
the	O
clipping	O
of	O
the	O
aneurysm	B-Disease
the	O
isoflurane	B-Chemical
concentration	O
was	O
reduced	O
to	O
0	O
.	O
75	O
%	O
.	O

There	O
was	O
a	O
significant	O
increase	O
in	O
CBF	O
,	O
although	O
CMRO2	O
was	O
unchanged	O
,	O
compared	O
with	O
pre	O
-	O
hypotensive	B-Disease
values	O
.	O

These	O
changes	O
might	O
offer	O
protection	O
to	O
brain	O
tissue	O
during	O
periods	O
of	O
induced	O
hypotension	B-Disease
.	O

Triazolam	B-Chemical
-	O
induced	O
brief	O
episodes	O
of	O
secondary	O
mania	B-Disease
in	O
a	O
depressed	B-Disease
patient	O
.	O

Large	O
doses	O
of	O
triazolam	B-Chemical
repeatedly	O
induced	O
brief	O
episodes	O
of	O
mania	B-Disease
in	O
a	O
depressed	B-Disease
elderly	O
woman	O
.	O

Features	O
of	O
organic	B-Disease
mental	I-Disease
disorder	I-Disease
(	O
delirium	B-Disease
)	O
were	O
not	O
present	O
.	O

Manic	B-Disease
excitement	O
was	O
coincident	O
with	O
the	O
duration	O
of	O
action	O
of	O
triazolam	B-Chemical
.	O

The	O
possible	O
contribution	O
of	O
the	O
triazolo	B-Chemical
group	O
to	O
changes	O
in	O
affective	O
status	O
is	O
discussed	O
.	O

The	O
correlation	O
between	O
neurotoxic	B-Disease
esterase	O
inhibition	O
and	O
mipafox	B-Chemical
-	O
induced	O
neuropathic	B-Disease
damage	I-Disease
in	O
rats	O
.	O

The	O
correlation	O
between	O
neuropathic	B-Disease
damage	I-Disease
and	O
inhibition	O
of	O
neurotoxic	B-Disease
esterase	O
or	O
neuropathy	B-Disease
target	O
enzyme	O
(	O
NTE	O
)	O
was	O
examined	O
in	O
rats	O
acutely	O
exposed	O
to	O
Mipafox	B-Chemical
(	O
N	B-Chemical
,	I-Chemical
N	I-Chemical
'	I-Chemical
-	I-Chemical
diisopropylphosphorodiamidofluoridate	I-Chemical
)	O
,	O
a	O
neurotoxic	B-Disease
organophosphate	B-Chemical
.	O

Brain	O
and	O
spinal	O
cord	O
NTE	O
activities	O
were	O
measured	O
in	O
Long	O
-	O
Evans	O
male	O
rats	O
1	O
hr	O
post	O
-	O
exposure	O
to	O
various	O
dosages	O
of	O
Mipafox	B-Chemical
(	O
ip	O
,	O
1	O
-	O
15	O
mg	O
/	O
kg	O
)	O
.	O

These	O
data	O
were	O
correlated	O
with	O
histologically	O
scored	O
cervical	O
cord	B-Disease
damage	I-Disease
in	O
a	O
separate	O
group	O
of	O
similarly	O
dosed	O
rats	O
sampled	O
14	O
-	O
21	O
days	O
post	O
-	O
exposure	O
.	O

Those	O
dosages	O
(	O
greater	O
than	O
or	O
equal	O
to	O
10	O
mg	O
/	O
kg	O
)	O
that	O
inhibited	O
mean	O
NTE	O
activity	O
in	O
the	O
spinal	O
cord	O
greater	O
than	O
or	O
equal	O
to	O
73	O
%	O
and	O
brain	O
greater	O
than	O
or	O
equal	O
to	O
67	O
%	O
of	O
control	O
values	O
produced	O
severe	O
(	O
greater	O
than	O
or	O
equal	O
to	O
3	O
)	O
cervical	O
cord	O
pathology	O
in	O
85	O
%	O
of	O
the	O
rats	O
.	O

In	O
contrast	O
,	O
dosages	O
of	O
Mipafox	B-Chemical
(	O
less	O
than	O
or	O
equal	O
to	O
5	O
mg	O
/	O
kg	O
)	O
which	O
inhibited	O
mean	O
NTE	O
activity	O
in	O
spinal	O
cord	O
less	O
than	O
or	O
equal	O
to	O
61	O
%	O
and	O
brain	O
less	O
than	O
or	O
equal	O
to	O
60	O
%	O
produced	O
this	O
degree	O
of	O
cord	B-Disease
damage	I-Disease
in	O
only	O
9	O
%	O
of	O
the	O
animals	O
.	O

These	O
data	O
indicate	O
that	O
a	O
critical	O
percentage	O
of	O
NTE	O
inhibition	O
in	O
brain	O
and	O
spinal	O
cord	O
sampled	O
shortly	O
after	O
Mipafox	B-Chemical
exposure	O
can	O
predict	O
neuropathic	B-Disease
damage	I-Disease
in	O
rats	O
several	O
weeks	O
later	O
.	O

Allergic	B-Disease
reaction	I-Disease
to	O
5	B-Chemical
-	I-Chemical
fluorouracil	I-Chemical
infusion	O
.	O

An	O
allergic	B-Disease
reaction	I-Disease
consisting	O
of	O
angioneurotic	B-Disease
edema	I-Disease
secondary	O
to	O
continuous	O
infusion	O
5	B-Chemical
-	I-Chemical
fluorouracil	I-Chemical
occurred	O
in	O
a	O
patient	O
with	O
recurrent	O
carcinoma	B-Disease
of	I-Disease
the	I-Disease
oral	I-Disease
cavity	I-Disease
,	O
cirrhosis	B-Disease
,	O
and	O
cisplatin	B-Chemical
-	O
induced	O
impaired	B-Disease
renal	I-Disease
function	I-Disease
.	O

This	O
reaction	O
occurred	O
during	O
the	O
sixth	O
and	O
seventh	O
courses	O
of	O
infusional	O
chemotherapy	O
.	O

Oral	O
diphenhydramine	B-Chemical
and	O
prednisone	B-Chemical
were	O
ineffective	O
in	O
preventing	O
the	O
recurrence	O
of	O
the	O
allergic	B-Disease
reaction	I-Disease
.	O

Discontinuance	O
of	O
effective	O
chemotherapy	O
in	O
this	O
patient	O
during	O
partial	O
remission	O
resulted	O
in	O
fatal	O
disease	O
progression	O
.	O

Myasthenia	B-Disease
gravis	I-Disease
caused	O
by	O
penicillamine	B-Chemical
and	O
chloroquine	B-Chemical
therapy	O
for	O
rheumatoid	B-Disease
arthritis	I-Disease
.	O

We	O
have	O
described	O
a	O
unique	O
patient	O
who	O
had	O
reversible	O
and	O
dose	O
-	O
related	O
myasthenia	B-Disease
gravis	I-Disease
after	O
penicillamine	B-Chemical
and	O
chloroquine	B-Chemical
therapy	O
for	O
rheumatoid	B-Disease
arthritis	I-Disease
.	O

Although	O
acetylcholine	B-Chemical
receptor	O
antibodies	O
were	O
not	O
detectable	O
,	O
the	O
time	O
course	O
was	O
consistent	O
with	O
an	O
autoimmune	O
process	O
.	O

On	O
the	O
mechanisms	O
of	O
the	O
development	O
of	O
tolerance	O
to	O
the	O
muscular	B-Disease
rigidity	I-Disease
produced	O
by	O
morphine	B-Chemical
in	O
rats	O
.	O

The	O
development	O
of	O
tolerance	O
to	O
the	O
muscular	B-Disease
rigidity	I-Disease
produced	O
by	O
morphine	B-Chemical
was	O
studied	O
in	O
rats	O
.	O

Saline	O
-	O
pretreated	O
controls	O
given	O
a	O
test	O
dose	O
of	O
morphine	B-Chemical
(	O
20	O
mg	O
/	O
kg	O
i	O
.	O
p	O
.	O
)	O
showed	O
a	O
pronounced	O
rigidity	B-Disease
recorded	O
as	O
tonic	O
activity	O
in	O
the	O
electromyogram	O
.	O

Rats	O
treated	O
for	O
11	O
days	O
with	O
morphine	B-Chemical
and	O
withdrawn	O
for	O
36	O
-	O
40	O
h	O
showed	O
differences	O
in	O
the	O
development	O
of	O
tolerance	O
:	O
about	O
half	O
of	O
the	O
animals	O
showed	O
a	O
rigidity	B-Disease
after	O
the	O
test	O
dose	O
of	O
morphine	B-Chemical
that	O
was	O
not	O
significantly	O
less	O
than	O
in	O
the	O
controls	O
and	O
were	O
akinetic	B-Disease
(	O
A	O
group	O
)	O
.	O

The	O
other	O
rats	O
showed	O
a	O
strong	O
decrease	O
in	O
the	O
rigidity	B-Disease
and	O
the	O
occurrence	O
of	O
stereotyped	O
(	O
S	O
)	O
licking	O
and	O
/	O
or	O
gnawing	O
in	O
presence	O
of	O
akinetic	B-Disease
or	O
hyperkinetic	B-Disease
(	O
K	O
)	O
behaviour	O
(	O
AS	O
/	O
KS	O
group	O
)	O
,	O
suggesting	O
signs	O
of	O
dopaminergic	O
activation	O
.	O

The	O
rigidity	B-Disease
was	O
considerably	O
decreased	O
in	O
both	O
groups	O
after	O
20	O
days	O
'	O
treatment	O
.	O

In	O
a	O
further	O
series	O
of	O
experiments	O
,	O
haloperidol	B-Chemical
(	O
0	O
.	O
2	O
mg	O
/	O
kg	O
i	O
.	O
p	O
.	O
)	O
was	O
used	O
in	O
order	O
to	O
block	O
the	O
dopaminergic	O
activation	O
and	O
to	O
estimate	O
the	O
real	O
degree	O
of	O
the	O
tolerance	O
to	O
the	O
rigidity	B-Disease
without	O
any	O
dopaminergic	O
interference	O
.	O

Haloperidol	B-Chemical
enhanced	O
the	O
rigidity	B-Disease
in	O
the	O
A	O
group	O
.	O

However	O
,	O
the	O
level	O
in	O
the	O
AS	O
/	O
KS	O
group	O
remained	O
considerably	O
lower	O
than	O
in	O
the	O
A	O
group	O
.	O

The	O
results	O
suggest	O
that	O
rigidity	B-Disease
,	O
which	O
is	O
assumed	O
to	O
be	O
due	O
to	O
an	O
action	O
of	O
morphine	B-Chemical
in	O
the	O
striatum	O
,	O
can	O
be	O
antagonized	O
by	O
another	O
process	O
leading	O
to	O
dopaminergic	O
activation	O
in	O
the	O
striatum	O
.	O

Nevertheless	O
,	O
there	O
occurs	O
some	O
real	O
tolerance	O
to	O
this	O
effect	O
.	O

The	O
rapid	O
alternations	O
of	O
rigidity	B-Disease
and	O
the	O
signs	O
of	O
dopaminergic	O
activation	O
observed	O
in	O
the	O
animals	O
of	O
the	O
AS	O
/	O
KS	O
group	O
might	O
be	O
due	O
to	O
rapid	O
shifts	O
in	O
the	O
predominance	O
of	O
various	O
DA	O
-	O
innervated	O
structures	O
.	O

A	O
case	O
of	O
massive	O
rhabdomyolysis	B-Disease
following	O
molindone	B-Chemical
administration	O
.	O

Rhabdomyolysis	B-Disease
is	O
a	O
potentially	O
lethal	O
syndrome	O
that	O
psychiatric	B-Disease
patients	O
seem	O
predisposed	O
to	O
develop	O
.	O

The	O
clinical	O
signs	O
and	O
symptoms	O
,	O
typical	O
laboratory	O
features	O
,	O
and	O
complications	O
of	O
rhabdomyolysis	B-Disease
are	O
presented	O
.	O

The	O
case	O
of	O
a	O
schizophrenic	B-Disease
patient	O
is	O
reported	O
to	O
illustrate	O
massive	O
rhabdomyolysis	B-Disease
and	O
subsequent	O
acute	B-Disease
renal	I-Disease
failure	I-Disease
following	O
molindone	B-Chemical
administration	O
.	O

Physicians	O
who	O
prescribe	O
molindone	B-Chemical
should	O
be	O
aware	O
of	O
this	O
reaction	O
.	O

Compression	B-Disease
neuropathy	I-Disease
of	I-Disease
the	I-Disease
radial	I-Disease
nerve	I-Disease
due	O
to	O
pentazocine	B-Chemical
-	O
induced	O
fibrous	B-Disease
myopathy	I-Disease
.	O

Fibrous	B-Disease
myopathy	I-Disease
is	O
a	O
common	O
,	O
well	O
-	O
known	O
side	O
effect	O
of	O
repeated	O
pentazocine	B-Chemical
injection	O
.	O

However	O
,	O
compression	B-Disease
neuropathy	I-Disease
due	O
to	O
fibrotic	O
muscle	O
affected	O
by	O
pentazocine	B-Chemical
-	O
induced	O
myopathy	B-Disease
has	O
not	O
previously	O
been	O
reported	O
.	O

In	O
a	O
37	O
-	O
year	O
-	O
old	O
woman	O
with	O
documented	O
pentazocine	B-Chemical
-	O
induced	O
fibrous	B-Disease
myopathy	I-Disease
of	O
triceps	O
and	O
deltoid	O
muscles	O
bilaterally	O
and	O
a	O
three	O
-	O
week	O
history	O
of	O
right	O
wrist	O
drop	O
,	O
electrodiagnostic	O
examination	O
showed	O
a	O
severe	O
but	O
partial	O
lesion	O
of	O
the	O
right	O
radial	O
nerve	O
distal	O
to	O
the	O
branches	O
to	O
the	O
triceps	O
,	O
in	O
addition	O
to	O
the	O
fibrous	B-Disease
myopathy	I-Disease
.	O

Surgery	O
revealed	O
the	O
right	O
radial	O
nerve	O
to	O
be	O
severely	O
compressed	O
by	O
the	O
densely	O
fibrotic	O
lateral	O
head	O
of	O
the	O
triceps	O
.	O

Decompression	O
and	O
neurolysis	O
were	O
performed	O
with	O
good	O
subsequent	O
recovery	O
of	O
function	O
.	O

Recurrent	O
reversible	O
acute	B-Disease
renal	I-Disease
failure	I-Disease
from	O
amphotericin	B-Chemical
.	O

A	O
patient	O
with	O
cryptogenic	O
cirrhosis	B-Disease
and	O
disseminated	O
sporotrichosis	B-Disease
developed	O
acute	B-Disease
renal	I-Disease
failure	I-Disease
immediately	O
following	O
the	O
administration	O
of	O
amphotericin	B-Chemical
B	I-Chemical
on	O
four	O
separate	O
occasions	O
.	O

The	O
abruptness	O
of	O
the	O
renal	B-Disease
failure	I-Disease
and	O
its	O
reversibility	O
within	O
days	O
suggests	O
that	O
there	O
was	O
a	O
functional	O
component	O
to	O
the	O
renal	B-Disease
dysfunction	I-Disease
.	O

We	O
propose	O
that	O
amphotericin	B-Chemical
,	O
in	O
the	O
setting	O
of	O
reduced	O
effective	O
arterial	O
volume	O
,	O
may	O
activate	O
tubuloglomerular	O
feedback	O
,	O
thereby	O
contributing	O
to	O
acute	B-Disease
renal	I-Disease
failure	I-Disease
.	O

Cerebral	B-Disease
infarction	I-Disease
with	O
a	O
single	O
oral	O
dose	O
of	O
phenylpropanolamine	B-Chemical
.	O

Phenylpropanolamine	B-Chemical
(	O
PPA	B-Chemical
)	O
,	O
a	O
synthetic	O
sympathomimetic	O
that	O
is	O
structurally	O
similar	O
to	O
amphetamine	B-Chemical
,	O
is	O
available	O
over	O
the	O
counter	O
in	O
anorectics	O
,	O
nasal	O
congestants	O
,	O
and	O
cold	O
preparations	O
.	O

Its	O
prolonged	O
use	O
or	O
overuse	O
has	O
been	O
associated	O
with	O
seizures	B-Disease
,	O
intracerebral	B-Disease
hemorrhage	I-Disease
,	O
neuropsychiatric	B-Disease
symptoms	I-Disease
,	O
and	O
nonhemorrhagic	O
cerebral	B-Disease
infarction	I-Disease
.	O

We	O
report	O
the	O
case	O
of	O
a	O
young	O
woman	O
who	O
suffered	O
a	O
cerebral	B-Disease
infarction	I-Disease
after	O
taking	O
a	O
single	O
oral	O
dose	O
of	O
PPA	B-Chemical
.	O

Remission	O
induction	O
of	O
meningeal	B-Disease
leukemia	I-Disease
with	O
high	O
-	O
dose	O
intravenous	O
methotrexate	B-Chemical
.	O

Twenty	O
children	O
with	O
acute	B-Disease
lymphoblastic	I-Disease
leukemia	I-Disease
who	O
developed	O
meningeal	B-Disease
disease	I-Disease
were	O
treated	O
with	O
a	O
high	O
-	O
dose	O
intravenous	O
methotrexate	B-Chemical
regimen	O
that	O
was	O
designed	O
to	O
achieve	O
and	O
maintain	O
CSF	O
methotrexate	B-Chemical
concentrations	O
of	O
10	O
(	O
-	O
5	O
)	O
mol	O
/	O
L	O
without	O
the	O
need	O
for	O
concomitant	O
intrathecal	O
dosing	O
.	O

The	O
methotrexate	B-Chemical
was	O
administered	O
as	O
a	O
loading	O
dose	O
of	O
6	O
,	O
000	O
mg	O
/	O
m2	O
for	O
a	O
period	O
of	O
one	O
hour	O
followed	O
by	O
an	O
infusion	O
of	O
1	O
,	O
200	O
mg	O
/	O
m2	O
/	O
h	O
for	O
23	O
hours	O
.	O

Leucovorin	B-Chemical
rescue	O
was	O
initiated	O
12	O
hours	O
after	O
the	O
end	O
of	O
the	O
infusion	O
with	O
a	O
loading	O
dose	O
of	O
200	O
mg	O
/	O
m2	O
followed	O
by	O
12	O
mg	O
/	O
m2	O
every	O
three	O
hours	O
for	O
six	O
doses	O
and	O
then	O
every	O
six	O
hours	O
until	O
the	O
plasma	O
methotrexate	B-Chemical
level	O
decreased	O
to	O
less	O
than	O
1	O
X	O
10	O
(	O
-	O
7	O
)	O
mol	O
/	O
L	O
.	O

The	O
mean	O
steady	O
-	O
state	O
plasma	O
and	O
CSF	O
methotrexate	B-Chemical
concentrations	O
achieved	O
were	O
1	O
.	O
1	O
X	O
10	O
(	O
-	O
3	O
)	O
mol	O
/	O
L	O
and	O
3	O
.	O
6	O
X	O
10	O
(	O
-	O
5	O
)	O
mol	O
/	O
L	O
,	O
respectively	O
.	O

All	O
20	O
patients	O
responded	O
to	O
this	O
regimen	O
,	O
16	O
/	O
20	O
(	O
80	O
%	O
)	O
achieved	O
a	O
complete	O
remission	O
,	O
and	O
20	O
%	O
obtained	O
a	O
partial	O
remission	O
.	O

The	O
most	O
common	O
toxicities	B-Disease
encountered	O
were	O
transient	O
serum	O
transaminase	O
and	O
bilirubin	B-Chemical
elevations	O
,	O
neutropenia	B-Disease
,	O
and	O
mucositis	B-Disease
.	O

One	O
patient	O
had	O
focal	O
seizures	B-Disease
and	O
transient	B-Disease
hemiparesis	I-Disease
but	O
recovered	O
completely	O
.	O

High	O
-	O
dose	O
intravenous	O
methotrexate	B-Chemical
is	O
an	O
effective	O
treatment	O
for	O
the	O
induction	O
of	O
remission	O
after	O
meningeal	O
relapse	O
in	O
acute	B-Disease
lymphoblastic	I-Disease
leukemia	I-Disease
.	O

Interaction	O
of	O
cyclosporin	B-Chemical
A	I-Chemical
with	O
antineoplastic	O
agents	O
.	O

A	O
synergistic	O
effect	O
of	O
etoposide	B-Chemical
and	O
cyclosporin	B-Chemical
A	I-Chemical
was	O
observed	O
in	O
a	O
patient	O
with	O
acute	B-Disease
T	I-Disease
-	I-Disease
lymphocytic	I-Disease
leukemia	I-Disease
in	O
relapse	O
.	O

The	O
concomitant	O
administration	O
of	O
etoposide	B-Chemical
and	O
cyclosporin	B-Chemical
A	I-Chemical
resulted	O
in	O
eradication	O
of	O
hitherto	O
refractory	O
leukemic	B-Disease
infiltration	I-Disease
of	O
bone	O
marrow	O
.	O

Severe	O
side	O
effects	O
in	O
terms	O
of	O
mental	O
confusion	B-Disease
and	O
progressive	O
hyperbilirubinemia	B-Disease
,	O
however	O
,	O
point	O
to	O
an	O
enhancement	O
not	O
only	O
of	O
antineoplastic	O
effects	O
but	O
also	O
of	O
toxicity	B-Disease
in	O
normal	O
tissues	O
.	O

This	O
report	O
demonstrates	O
for	O
the	O
first	O
time	O
that	O
the	O
pharmacodynamic	O
properties	O
of	O
cyclosporin	B-Chemical
A	I-Chemical
may	O
not	O
be	O
confined	O
strictly	O
to	O
suppression	O
of	O
normal	O
T	O
-	O
cell	O
functions	O
.	O

Incidence	O
of	O
neoplasms	B-Disease
in	O
patients	O
with	O
rheumatoid	B-Disease
arthritis	I-Disease
exposed	O
to	O
different	O
treatment	O
regimens	O
.	O

Immunosuppressive	O
drugs	O
have	O
been	O
used	O
during	O
the	O
last	O
30	O
years	O
in	O
treatment	O
of	O
patients	O
with	O
severe	O
rheumatoid	B-Disease
arthritis	I-Disease
.	O

The	O
drugs	O
commonly	O
used	O
are	O
cyclophosphamide	B-Chemical
and	O
chlorambucil	B-Chemical
(	O
alkylating	B-Chemical
agents	I-Chemical
)	O
,	O
azathioprine	B-Chemical
(	O
purine	B-Chemical
analogue	O
)	O
,	O
and	O
methotrexate	B-Chemical
(	O
folic	B-Chemical
acid	I-Chemical
analogue	O
)	O
.	O

There	O
is	O
evidence	O
that	O
all	O
four	O
immunosuppressive	O
drugs	O
can	O
reduce	O
synovitis	B-Disease
,	O
but	O
disease	O
activity	O
almost	O
always	O
recurs	O
after	O
therapy	O
is	O
stopped	O
.	O

Since	O
adverse	O
reactions	O
are	O
frequent	O
,	O
less	O
than	O
50	O
percent	O
of	O
patients	O
are	O
able	O
to	O
continue	O
a	O
particular	O
drug	O
for	O
more	O
than	O
one	O
year	O
.	O

Since	O
it	O
takes	O
three	O
to	O
12	O
months	O
to	O
achieve	O
maximal	O
effects	O
,	O
those	O
patients	O
who	O
are	O
unable	O
to	O
continue	O
the	O
drug	O
receive	O
little	O
benefit	O
from	O
it	O
.	O

Patients	O
treated	O
with	O
alkylating	B-Chemical
agents	I-Chemical
have	O
an	O
increased	O
risk	O
of	O
development	O
of	O
acute	B-Disease
nonlymphocytic	I-Disease
leukemia	I-Disease
,	O
and	O
both	O
alkylating	B-Chemical
agents	I-Chemical
and	O
azathioprine	B-Chemical
are	O
associated	O
with	O
the	O
development	O
of	O
non	B-Disease
-	I-Disease
Hodgkin	I-Disease
'	I-Disease
s	I-Disease
lymphoma	I-Disease
.	O

Cyclophosphamide	B-Chemical
therapy	O
increases	O
the	O
risk	O
of	O
carcinoma	B-Disease
of	I-Disease
the	I-Disease
bladder	I-Disease
.	O

There	O
have	O
been	O
several	O
long	O
-	O
term	O
studies	O
of	O
patients	O
with	O
rheumatoid	B-Disease
arthritis	I-Disease
treated	O
with	O
azathioprine	B-Chemical
and	O
cyclophosphamide	B-Chemical
and	O
the	O
incidence	O
of	O
most	O
of	O
the	O
common	O
cancers	B-Disease
is	O
not	O
increased	O
.	O

Data	O
on	O
the	O
possible	O
increased	O
risk	O
of	O
malignancy	B-Disease
in	O
rheumatoid	B-Disease
arthritis	I-Disease
are	O
still	O
being	O
collected	O
,	O
and	O
until	O
further	O
information	O
is	O
available	O
,	O
the	O
use	O
of	O
immunosuppressive	O
drugs	O
,	O
particularly	O
alkylating	B-Chemical
agents	I-Chemical
,	O
in	O
the	O
treatment	O
of	O
rheumatoid	B-Disease
arthritis	I-Disease
should	O
be	O
reserved	O
for	O
patients	O
with	O
severe	O
progressive	O
disease	O
or	O
life	O
-	O
threatening	O
complications	O
.	O

Warfarin	B-Chemical
-	O
induced	O
iliopsoas	O
hemorrhage	B-Disease
with	O
subsequent	O
femoral	B-Disease
nerve	I-Disease
palsy	I-Disease
.	O

We	O
present	O
the	O
case	O
of	O
a	O
28	O
-	O
year	O
-	O
old	O
man	O
on	O
chronic	O
warfarin	B-Chemical
therapy	O
who	O
sustained	O
a	O
minor	O
muscle	B-Disease
tear	I-Disease
and	O
developed	O
increasing	O
pain	B-Disease
and	O
a	O
flexure	O
contracture	B-Disease
of	O
the	O
right	O
hip	O
.	O

Surgical	O
exploration	O
revealed	O
an	O
iliopsoas	O
hematoma	B-Disease
and	O
femoral	O
nerve	B-Disease
entrapment	I-Disease
,	O
resulting	O
in	O
a	O
femoral	B-Disease
nerve	I-Disease
palsy	I-Disease
and	O
partial	B-Disease
loss	I-Disease
of	I-Disease
quadriceps	I-Disease
functions	I-Disease
.	O

Anticoagulant	O
-	O
induced	O
femoral	B-Disease
nerve	I-Disease
palsy	I-Disease
represents	O
the	O
most	O
common	O
form	O
of	O
warfarin	B-Chemical
-	O
induced	O
peripheral	B-Disease
neuropathy	I-Disease
;	O
it	O
is	O
characterized	O
by	O
severe	O
pain	B-Disease
in	O
the	O
inguinal	O
region	O
,	O
varying	O
degrees	O
of	O
motor	B-Disease
and	I-Disease
sensory	I-Disease
impairment	I-Disease
,	O
and	O
flexure	O
contracture	B-Disease
of	O
the	O
involved	O
extremity	O
.	O

Pneumonitis	O
with	O
pleural	B-Disease
and	I-Disease
pericardial	I-Disease
effusion	I-Disease
and	O
neuropathy	B-Disease
during	O
amiodarone	B-Chemical
therapy	O
.	O

A	O
patient	O
with	O
sinuatrial	B-Disease
disease	I-Disease
and	O
implanted	O
pacemaker	O
was	O
treated	O
with	O
amiodarone	B-Chemical
(	O
maximum	O
dose	O
1000	O
mg	O
,	O
maintenance	O
dose	O
800	O
mg	O
daily	O
)	O
for	O
10	O
months	O
,	O
for	O
control	O
of	O
supraventricular	B-Disease
tachyarrhythmias	I-Disease
.	O

He	O
developed	O
pneumonitis	B-Disease
,	O
pleural	B-Disease
and	I-Disease
pericardial	I-Disease
effusions	I-Disease
,	O
and	O
a	O
predominantly	O
proximal	B-Disease
motor	I-Disease
neuropathy	I-Disease
.	O

Immediate	O
but	O
gradual	O
improvement	O
followed	O
withdrawal	O
of	O
amiodarone	B-Chemical
and	O
treatment	O
with	O
prednisolone	B-Chemical
.	O

Review	O
of	O
this	O
and	O
previously	O
reported	O
cases	O
indicates	O
the	O
need	O
for	O
early	O
diagnosis	O
of	O
amiodarone	B-Chemical
pneumonitis	B-Disease
,	O
immediate	O
withdrawal	O
of	O
amiodarone	B-Chemical
,	O
and	O
prompt	O
but	O
continued	O
steroid	B-Chemical
therapy	O
to	O
ensure	O
full	O
recovery	O
.	O

Amiodarone	B-Chemical
-	O
induced	O
sinoatrial	B-Disease
block	I-Disease
.	O

We	O
observed	O
sinoatrial	B-Disease
block	I-Disease
due	O
to	O
chronic	O
amiodarone	B-Chemical
administration	O
in	O
a	O
5	O
-	O
year	O
-	O
old	O
boy	O
with	O
primary	B-Disease
cardiomyopathy	I-Disease
,	O
Wolff	B-Disease
-	I-Disease
Parkinson	I-Disease
-	I-Disease
White	I-Disease
syndrome	I-Disease
and	O
supraventricular	B-Disease
tachycardia	I-Disease
.	O

Reduction	O
in	O
the	O
dosage	O
of	O
amiodarone	B-Chemical
resulted	O
in	O
the	O
disappearance	O
of	O
the	O
sinoatrial	B-Disease
block	I-Disease
and	O
the	O
persistence	O
of	O
asymptomatic	O
sinus	B-Disease
bradycardia	I-Disease
.	O

Desipramine	B-Chemical
-	O
induced	O
delirium	B-Disease
at	O
"	O
subtherapeutic	O
"	O
concentrations	O
:	O
a	O
case	O
report	O
.	O

An	O
elderly	O
patient	O
treated	O
with	O
low	O
dose	O
Desipramine	B-Chemical
developed	O
a	O
delirium	B-Disease
while	O
her	O
plasma	O
level	O
was	O
in	O
the	O
"	O
subtherapeutic	O
"	O
range	O
.	O

Delirium	B-Disease
,	O
which	O
may	O
be	O
induced	O
by	O
tricyclic	O
drug	O
therapy	O
in	O
the	O
elderly	O
,	O
can	O
be	O
caused	O
by	O
tricyclics	O
with	O
low	O
anticholinergic	O
potency	O
.	O

Therapeutic	O
ranges	O
for	O
antidepressants	B-Chemical
that	O
have	O
been	O
derived	O
from	O
general	O
adult	O
population	O
studies	O
may	O
not	O
be	O
appropriate	O
for	O
the	O
elderly	O
.	O

Further	O
studies	O
of	O
specifically	O
elderly	O
patients	O
are	O
now	O
required	O
to	O
establish	O
safer	O
and	O
more	O
appropriate	O
guidelines	O
for	O
drug	O
therapy	O
.	O

Indomethacin	B-Chemical
-	O
induced	O
renal	B-Disease
insufficiency	I-Disease
:	O
recurrence	O
on	O
rechallenge	O
.	O

We	O
have	O
reported	O
a	O
case	O
of	O
acute	O
oliguric	O
renal	B-Disease
failure	I-Disease
with	O
hyperkalemia	B-Disease
in	O
a	O
patient	O
with	O
cirrhosis	B-Disease
,	O
ascites	B-Disease
,	O
and	O
cor	B-Disease
pulmonale	I-Disease
after	O
indomethacin	B-Chemical
therapy	O
.	O

Prompt	O
restoration	O
of	O
renal	O
function	O
followed	O
drug	O
withdrawal	O
,	O
while	O
re	O
-	O
exposure	O
to	O
a	O
single	O
dose	O
of	O
indomethacin	B-Chemical
caused	O
recurrence	O
of	O
acute	O
reversible	O
oliguria	B-Disease
.	O

Our	O
case	O
supports	O
the	O
hypothesis	O
that	O
endogenous	O
renal	O
prostaglandins	B-Chemical
play	O
a	O
role	O
in	O
the	O
maintenance	O
of	O
renal	O
blood	O
flow	O
when	O
circulating	O
plasma	O
volume	O
is	O
diminished	O
.	O

Since	O
nonsteroidal	O
anti	O
-	O
inflammatory	O
agents	O
interfere	O
with	O
this	O
compensatory	O
mechanism	O
and	O
may	O
cause	O
acute	B-Disease
renal	I-Disease
failure	I-Disease
,	O
they	O
should	O
be	O
used	O
with	O
caution	O
in	O
such	O
patients	O
.	O

Patterns	O
of	O
hepatic	B-Disease
injury	I-Disease
induced	O
by	O
methyldopa	B-Chemical
.	O

Twelve	O
patients	O
with	O
liver	B-Disease
disease	I-Disease
related	O
to	O
methyldopa	B-Chemical
were	O
seen	O
between	O
1967	O
and	O
1977	O
.	O

Illness	O
occurred	O
within	O
1	O
-	O
-	O
9	O
weeks	O
of	O
commencement	O
of	O
therapy	O
in	O
9	O
patients	O
,	O
the	O
remaining	O
3	O
patients	O
having	O
received	O
the	O
drug	O
for	O
13	O
months	O
,	O
15	O
months	O
and	O
7	O
years	O
before	O
experiencing	O
symptoms	O
.	O

Jaundice	B-Disease
with	O
tender	O
hepatomegaly	B-Disease
,	O
usually	O
preceded	O
by	O
symptoms	O
of	O
malaise	O
,	O
anorexia	B-Disease
,	O
nausea	B-Disease
and	O
vomiting	B-Disease
,	O
and	O
associated	O
with	O
upper	O
abdominal	B-Disease
pain	I-Disease
,	O
was	O
an	O
invariable	O
finding	O
in	O
all	O
patients	O
.	O

Biochemical	O
liver	O
function	O
tests	O
indicated	O
hepatocellular	O
necrosis	B-Disease
and	O
correlated	O
with	O
histopathological	O
evidence	O
of	O
hepatic	B-Disease
injury	I-Disease
,	O
the	O
spectrum	O
of	O
which	O
ranged	O
from	O
fatty	B-Disease
change	I-Disease
and	O
focal	O
hepatocellular	O
necrosis	B-Disease
to	O
massive	B-Disease
hepatic	I-Disease
necrosis	I-Disease
.	O

Most	O
patients	O
showed	O
moderate	O
to	O
severe	O
acute	B-Disease
hepatitis	I-Disease
or	O
chronic	B-Disease
active	I-Disease
hepatitis	I-Disease
with	O
associated	O
cholestasis	B-Disease
.	O

The	O
drug	O
was	O
withdrawn	O
on	O
presentation	O
to	O
hospital	O
in	O
11	O
patients	O
,	O
with	O
rapid	O
clinical	O
improvement	O
in	O
9	O
.	O

One	O
patient	O
died	O
,	O
having	O
presented	O
in	O
hepatic	B-Disease
failure	I-Disease
,	O
and	O
another	O
,	O
who	O
had	O
been	O
taking	O
methyldopa	B-Chemical
for	O
7	O
years	O
,	O
showed	O
slower	O
clinical	O
and	O
biochemical	O
resolution	O
over	O
a	O
period	O
of	O
several	O
months	O
.	O

The	O
remaining	O
patient	O
in	O
the	O
series	O
developed	O
fulminant	B-Disease
hepatitis	I-Disease
when	O
the	O
drug	O
was	O
accidentally	O
recommenced	O
1	O
year	O
after	O
a	O
prior	O
episode	O
of	O
methyldopa	B-Chemical
-	O
induced	O
hepatitis	B-Disease
.	O

In	O
this	O
latter	O
patient	O
,	O
and	O
in	O
2	O
others	O
,	O
the	O
causal	O
relationship	O
between	O
methyldopa	B-Chemical
and	O
hepatic	B-Disease
dysfunction	I-Disease
was	O
proved	O
with	O
the	O
recurrence	O
of	O
hepatitis	B-Disease
within	O
2	O
weeks	O
of	O
re	O
-	O
exposure	O
to	O
the	O
drug	O
.	O

Suxamethonium	B-Chemical
infusion	O
rate	O
and	O
observed	O
fasciculations	B-Disease
.	O

A	O
dose	O
-	O
response	O
study	O
.	O

Suxamethonium	B-Chemical
chloride	I-Chemical
(	O
Sch	B-Chemical
)	O
was	O
administered	O
i	O
.	O
v	O
.	O
to	O
36	O
adult	O
males	O
at	O
six	O
rates	O
:	O
0	O
.	O
25	O
mg	O
s	O
-	O
1	O
to	O
20	O
mg	O
s	O
-	O
1	O
.	O

The	O
infusion	O
was	O
discontinued	O
either	O
when	O
there	O
was	O
no	O
muscular	O
response	O
to	O
tetanic	B-Disease
stimulation	O
of	O
the	O
ulnar	O
nerve	O
or	O
when	O
Sch	B-Chemical
120	O
mg	O
was	O
exceeded	O
.	O

Six	O
additional	O
patients	O
received	O
a	O
30	O
-	O
mg	O
i	O
.	O
v	O
.	O
bolus	O
dose	O
.	O

Fasciculations	B-Disease
in	O
six	O
areas	O
of	O
the	O
body	O
were	O
scored	O
from	O
0	O
to	O
3	O
and	O
summated	O
as	O
a	O
total	O
fasciculation	B-Disease
score	O
.	O

The	O
times	O
to	O
first	O
fasciculation	B-Disease
,	O
twitch	B-Disease
suppression	O
and	O
tetanus	B-Disease
suppression	O
were	O
inversely	O
related	O
to	O
the	O
infusion	O
rates	O
.	O

Fasciculations	B-Disease
in	O
the	O
six	O
areas	O
and	O
the	O
total	O
fasciculation	B-Disease
score	O
were	O
related	O
directly	O
to	O
the	O
rate	O
of	O
infusion	O
.	O

Total	O
fasciculation	B-Disease
scores	O
in	O
the	O
30	O
-	O
mg	O
bolus	O
group	O
and	O
the	O
5	O
-	O
mg	O
s	O
-	O
1	O
and	O
20	O
-	O
mg	O
s	O
-	O
1	O
infusion	O
groups	O
were	O
not	O
significantly	O
different	O
.	O

Treatment	O
of	O
psoriasis	B-Disease
with	O
azathioprine	B-Chemical
.	O

Azathioprine	B-Chemical
treatment	O
benefited	O
19	O
(	O
66	O
%	O
)	O
out	O
of	O
29	O
patients	O
suffering	O
from	O
severe	O
psoriasis	B-Disease
.	O

Haematological	O
complications	O
were	O
not	O
troublesome	O
and	O
results	O
of	O
biochemical	O
liver	O
function	O
tests	O
remained	O
normal	O
.	O

Minimal	O
cholestasis	B-Disease
was	O
seen	O
in	O
two	O
cases	O
and	O
portal	O
fibrosis	B-Disease
of	O
a	O
reversible	O
degree	O
in	O
eight	O
.	O

Liver	O
biopsies	O
should	O
be	O
undertaken	O
at	O
regular	O
intervals	O
if	O
azathioprine	B-Chemical
therapy	O
is	O
continued	O
so	O
that	O
structural	O
liver	B-Disease
damage	I-Disease
may	O
be	O
detected	O
at	O
an	O
early	O
and	O
reversible	O
stage	O
.	O

Angiosarcoma	B-Disease
of	I-Disease
the	I-Disease
liver	I-Disease
associated	O
with	O
diethylstilbestrol	B-Chemical
.	O

Angiosarcoma	B-Disease
of	I-Disease
the	I-Disease
liver	I-Disease
occurred	O
in	O
a	O
76	O
-	O
year	O
-	O
old	O
man	O
who	O
had	O
been	O
treated	O
for	O
a	O
well	O
-	O
differentiated	O
adenocarcinoma	B-Disease
of	I-Disease
the	I-Disease
liver	I-Disease
with	O
diethylstilbestrol	B-Chemical
for	O
13	O
years	O
.	O

Angiosarcoma	B-Disease
was	O
also	O
present	O
within	O
pulmonary	O
and	O
renal	O
arteries	O
.	O

The	O
possibility	O
that	O
the	O
intraarterial	B-Disease
lesions	I-Disease
might	O
represent	O
independent	O
primary	O
tumors	B-Disease
is	O
considered	O
.	O

Galanthamine	B-Chemical
hydrobromide	I-Chemical
,	O
a	O
longer	O
acting	O
anticholinesterase	O
drug	O
,	O
in	O
the	O
treatment	O
of	O
the	O
central	O
effects	O
of	O
scopolamine	B-Chemical
(	O
Hyoscine	B-Chemical
)	O
.	O

Galanthamine	B-Chemical
hydrobromide	I-Chemical
,	O
an	O
anticholinesterase	O
drug	O
capable	O
of	O
penetrating	O
the	O
blood	O
-	O
brain	O
barrier	O
,	O
was	O
used	O
in	O
a	O
patient	O
demonstrating	O
central	O
effects	O
of	O
scopolamine	B-Chemical
(	O
hyoscine	B-Chemical
)	O
overdosage	B-Disease
.	O

It	O
is	O
longer	O
acting	O
than	O
physostigmine	B-Chemical
and	O
is	O
used	O
in	O
anaesthesia	O
to	O
reverse	O
the	O
non	O
-	O
depolarizing	O
neuromuscular	O
block	O
.	O

However	O
,	O
studies	O
into	O
the	O
dose	O
necessary	O
to	O
combating	O
scopolamine	B-Chemical
intoxication	O
are	O
indicated	O
.	O

Comparison	O
of	O
the	O
subjective	O
effects	O
and	O
plasma	O
concentrations	O
following	O
oral	O
and	O
i	O
.	O
m	O
.	O
administration	O
of	O
flunitrazepam	B-Chemical
in	O
volunteers	O
.	O

Flunitrazepam	B-Chemical
0	O
.	O
5	O
,	O
1	O
.	O
0	O
or	O
2	O
.	O
0	O
mg	O
was	O
given	O
by	O
the	O
oral	O
or	O
i	O
.	O
m	O
.	O
routes	O
to	O
groups	O
of	O
volunteers	O
and	O
its	O
effects	O
compared	O
.	O

Plasma	O
concentrations	O
of	O
the	O
drug	O
were	O
estimated	O
by	O
gas	O
-	O
liquid	O
chromatography	O
,	O
in	O
a	O
smaller	O
number	O
of	O
the	O
subjects	O
.	O

The	O
most	O
striking	O
effect	O
was	O
sedation	O
which	O
increased	O
with	O
the	O
dose	O
,	O
2	O
mg	O
producing	O
deep	O
sleep	O
although	O
the	O
subjects	O
could	O
still	O
be	O
aroused	O
.	O

The	O
effects	O
of	O
i	O
.	O
m	O
.	O
administration	O
were	O
apparent	O
earlier	O
and	O
sometimes	O
lasted	O
longer	O
than	O
those	O
following	O
oral	O
administration	O
.	O

Dizziness	B-Disease
was	O
less	O
marked	O
than	O
sedation	O
,	O
but	O
increased	O
with	O
the	O
dose	O
.	O

There	O
was	O
pain	B-Disease
on	O
i	O
.	O
m	O
.	O
injection	O
of	O
flunitrazepam	B-Chemical
significantly	O
more	O
often	O
than	O
with	O
isotonic	O
saline	O
.	O

Plasma	O
concentrations	O
varied	O
with	O
dose	O
and	O
route	O
and	O
corresponded	O
qualitatively	O
with	O
the	O
subjective	O
effects	O
.	O

The	O
drug	O
was	O
still	O
present	O
in	O
measurable	O
quantities	O
after	O
24	O
h	O
even	O
with	O
the	O
smallest	O
dose	O
.	O

Possible	O
teratogenicity	O
of	O
sulphasalazine	B-Chemical
.	O

Three	O
infants	O
,	O
born	O
of	O
two	O
mothers	O
with	O
inflammatory	B-Disease
bowel	I-Disease
disease	I-Disease
who	O
received	O
treatment	O
with	O
sulphasalazine	B-Chemical
throughout	O
pregnancy	O
,	O
were	O
found	O
to	O
have	O
major	O
congenital	B-Disease
anomalies	I-Disease
.	O

In	O
the	O
singleton	O
pregnancy	O
,	O
the	O
mother	O
had	O
ulcerative	B-Disease
colitis	I-Disease
,	O
and	O
the	O
infant	O
,	O
a	O
male	O
,	O
had	O
coarctation	B-Disease
of	I-Disease
the	I-Disease
aorta	I-Disease
and	O
a	O
ventricular	B-Disease
septal	I-Disease
defect	I-Disease
.	O

In	O
the	O
twin	O
pregnancy	O
,	O
the	O
mother	O
had	O
Crohn	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
.	O

The	O
first	O
twin	O
,	O
a	O
female	O
,	O
had	O
a	O
left	O
Potter	B-Disease
-	I-Disease
type	I-Disease
IIa	I-Disease
polycystic	I-Disease
kidney	I-Disease
and	O
a	O
rudimentary	B-Disease
left	I-Disease
uterine	I-Disease
cornu	I-Disease
.	O

The	O
second	O
twin	O
,	O
a	O
male	O
,	O
had	O
some	O
features	O
of	O
Potter	B-Disease
'	I-Disease
s	I-Disease
facies	I-Disease
,	O
hypoplastic	B-Disease
lungs	I-Disease
,	O
absent	B-Disease
kidneys	I-Disease
and	I-Disease
ureters	I-Disease
,	O
and	O
talipes	B-Disease
equinovarus	I-Disease
.	O

Despite	O
reports	O
to	O
the	O
contrary	O
,	O
it	O
is	O
suggested	O
that	O
sulphasalazine	B-Chemical
may	O
be	O
teratogenic	O
.	O

Thrombotic	B-Disease
microangiopathy	I-Disease
and	O
renal	B-Disease
failure	I-Disease
associated	O
with	O
antineoplastic	O
chemotherapy	O
.	O

Five	O
patients	O
with	O
carcinoma	B-Disease
developed	O
thrombotic	B-Disease
microangiopathy	I-Disease
(	O
characterized	O
by	O
renal	B-Disease
insufficiency	I-Disease
,	O
microangiopathic	B-Disease
hemolytic	I-Disease
anemia	I-Disease
,	O
and	O
usually	O
thrombocytopenia	B-Disease
)	O
after	O
treatment	O
with	O
cisplatin	B-Chemical
,	O
bleomycin	B-Chemical
,	O
and	O
a	O
vinca	B-Chemical
alkaloid	I-Chemical
.	O

One	O
patient	O
had	O
thrombotic	B-Disease
thrombocytopenic	I-Disease
purpura	I-Disease
,	O
three	O
the	O
hemolytic	B-Disease
-	I-Disease
uremic	I-Disease
syndrome	I-Disease
,	O
and	O
one	O
an	O
apparent	O
forme	O
fruste	O
of	O
one	O
of	O
these	O
disorders	O
.	O

Histologic	O
examination	O
of	O
the	O
renal	O
tissue	O
showed	O
evidence	O
of	O
intravascular	B-Disease
coagulation	I-Disease
,	O
primarily	O
affecting	O
the	O
small	O
arteries	O
,	O
arterioles	O
,	O
and	O
glomeruli	O
.	O

Because	O
each	O
patient	O
was	O
tumor	B-Disease
-	O
free	O
or	O
had	O
only	O
a	O
small	O
tumor	B-Disease
at	O
the	O
onset	O
of	O
this	O
syndrome	O
,	O
the	O
thrombotic	B-Disease
microangiopathy	I-Disease
may	O
have	O
been	O
induced	O
by	O
chemotherapy	O
.	O

Diagnosis	O
of	O
this	O
potentially	O
fatal	O
complication	O
may	O
be	O
delayed	O
or	O
missed	O
if	O
renal	O
tissue	O
or	O
the	O
peripheral	O
blood	O
smear	O
is	O
not	O
examined	O
,	O
because	O
renal	B-Disease
failure	I-Disease
may	O
be	O
ascribed	O
to	O
cisplatin	B-Chemical
nephrotoxicity	B-Disease
and	O
the	O
anemia	B-Disease
and	O
thrombocytopenia	B-Disease
to	O
drug	O
-	O
induced	O
bone	B-Disease
marrow	I-Disease
suppression	I-Disease
.	O

International	O
mexiletine	B-Chemical
and	O
placebo	O
antiarrhythmic	O
coronary	O
trial	O
:	O
I	O
.	O

Report	O
on	O
arrhythmia	B-Disease
and	O
other	O
findings	O
.	O

Impact	O
Research	O
Group	O
.	O

The	O
antiarrhythmic	O
effects	O
of	O
the	O
sustained	O
release	O
form	O
of	O
mexiletine	B-Chemical
(	O
Mexitil	B-Chemical
-	I-Chemical
Perlongets	I-Chemical
)	O
were	O
evaluated	O
in	O
a	O
double	O
-	O
blind	O
placebo	O
trial	O
in	O
630	O
patients	O
with	O
recent	O
documented	O
myocardial	B-Disease
infarction	I-Disease
.	O

The	O
primary	O
response	O
variable	O
was	O
based	O
on	O
central	O
reading	O
of	O
24	O
hour	O
ambulatory	O
electrocardiographic	O
recordings	O
and	O
was	O
defined	O
as	O
the	O
occurrence	O
of	O
30	O
or	O
more	O
single	O
premature	O
ventricular	O
complexes	O
in	O
any	O
two	O
consecutive	O
30	O
minute	O
blocks	O
or	O
one	O
or	O
more	O
runs	O
of	O
two	O
or	O
more	O
premature	O
ventricular	O
complexes	O
in	O
the	O
entire	O
24	O
hour	O
electrocardiographic	O
recording	O
.	O

Large	O
differences	O
,	O
regarded	O
as	O
statistically	O
significant	O
,	O
between	O
the	O
mexiletine	B-Chemical
and	O
placebo	O
groups	O
were	O
noted	O
in	O
that	O
end	O
point	O
at	O
months	O
1	O
and	O
4	O
,	O
but	O
only	O
trends	O
were	O
observed	O
at	O
month	O
12	O
.	O

These	O
differences	O
were	O
observed	O
even	O
though	O
the	O
serum	O
mexiletine	B-Chemical
levels	O
obtained	O
in	O
this	O
study	O
were	O
generally	O
lower	O
than	O
those	O
observed	O
in	O
studies	O
that	O
have	O
used	O
the	O
regular	O
form	O
of	O
the	O
drug	O
.	O

There	O
were	O
more	O
deaths	B-Disease
in	O
the	O
mexiletine	B-Chemical
group	O
(	O
7	O
.	O
6	O
%	O
)	O
than	O
in	O
the	O
placebo	O
group	O
(	O
4	O
.	O
8	O
%	O
)	O
;	O
the	O
difference	O
was	O
not	O
statistically	O
significant	O
.	O

The	O
incidence	O
of	O
coronary	O
events	O
was	O
similar	O
in	O
both	O
groups	O
.	O

Previously	O
recognized	O
side	O
effects	O
,	O
particularly	O
tremor	B-Disease
and	O
gastrointestinal	B-Disease
problems	I-Disease
,	O
were	O
more	O
frequent	O
in	O
the	O
mexiletine	B-Chemical
group	O
than	O
in	O
the	O
placebo	O
group	O
.	O

Changes	O
in	O
heart	O
size	O
during	O
long	O
-	O
term	O
timolol	B-Chemical
treatment	O
after	O
myocardial	B-Disease
infarction	I-Disease
.	O

The	O
effect	O
of	O
long	O
-	O
term	O
timolol	B-Chemical
treatment	O
on	O
heart	O
size	O
after	O
myocardial	B-Disease
infarction	I-Disease
was	O
evaluated	O
by	O
X	O
-	O
ray	O
in	O
a	O
double	O
-	O
blind	O
study	O
including	O
241	O
patients	O
(	O
placebo	O
126	O
,	O
timolol	B-Chemical
115	O
)	O
.	O

The	O
follow	O
-	O
up	O
period	O
was	O
12	O
months	O
.	O

The	O
timolol	B-Chemical
-	O
treated	O
patients	O
showed	O
a	O
small	O
but	O
significant	O
increase	O
in	O
heart	O
size	O
from	O
baseline	O
in	O
contrast	O
to	O
a	O
decrease	O
in	O
the	O
placebo	O
group	O
.	O

These	O
differences	O
may	O
be	O
caused	O
by	O
timolol	B-Chemical
-	O
induced	O
bradycardia	B-Disease
and	O
a	O
compensatory	O
increase	O
in	O
end	O
-	O
diastolic	O
volume	O
.	O

The	O
timolol	B-Chemical
-	O
related	O
increase	O
in	O
heart	O
size	O
was	O
observed	O
only	O
in	O
patients	O
with	O
normal	O
and	O
borderline	O
heart	O
size	O
.	O

In	O
patients	O
with	O
cardiomegaly	B-Disease
,	O
the	O
increase	O
in	O
heart	O
size	O
was	O
similar	O
in	O
both	O
groups	O
.	O

After	O
re	O
-	O
infarction	B-Disease
,	O
heart	O
size	O
increased	O
in	O
the	O
placebo	O
group	O
and	O
remained	O
unchanged	O
in	O
the	O
timolol	B-Chemical
group	O
.	O

Vitamin	B-Chemical
D3	I-Chemical
toxicity	B-Disease
in	O
dairy	O
cows	O
.	O

Large	O
parenteral	O
doses	O
of	O
vitamin	B-Chemical
D3	I-Chemical
(	O
15	O
to	O
17	O
.	O
5	O
x	O
10	O
(	O
6	O
)	O
IU	O
vitamin	B-Chemical
D3	I-Chemical
)	O
were	O
associated	O
with	O
prolonged	O
hypercalcemia	B-Disease
,	O
hyperphosphatemia	B-Disease
,	O
and	O
large	O
increases	O
of	O
vitamin	B-Chemical
D3	I-Chemical
and	O
its	O
metabolites	O
in	O
the	O
blood	O
plasma	O
of	O
nonlactating	O
nonpregnant	O
and	O
pregnant	O
Jersey	O
cows	O
.	O

Calcium	B-Chemical
concentrations	O
1	O
day	O
postpartum	O
were	O
higher	O
in	O
cows	O
treated	O
with	O
vitamin	B-Chemical
D3	I-Chemical
about	O
32	O
days	O
prepartum	O
(	O
8	O
.	O
8	O
mg	O
/	O
100	O
ml	O
)	O
than	O
in	O
control	O
cows	O
(	O
5	O
.	O
5	O
mg	O
/	O
100	O
ml	O
)	O
.	O

None	O
of	O
the	O
cows	O
treated	O
with	O
vitamin	B-Chemical
D3	I-Chemical
showed	O
signs	O
of	O
milk	B-Disease
fever	I-Disease
during	O
the	O
peripartal	O
period	O
;	O
however	O
,	O
22	O
%	O
of	O
the	O
control	O
cows	O
developed	O
clinical	O
signs	O
of	O
milk	B-Disease
fever	I-Disease
during	O
this	O
period	O
.	O

Signs	O
of	O
vitamin	B-Chemical
D3	I-Chemical
toxicity	B-Disease
were	O
not	O
observed	O
in	O
nonlactating	O
nonpregnant	O
cows	O
;	O
however	O
,	O
pregnant	O
cows	O
commonly	O
developed	O
severe	O
signs	O
of	O
vitamin	B-Chemical
D3	I-Chemical
toxicity	B-Disease
and	O
10	O
of	O
17	O
cows	O
died	O
.	O

There	O
was	O
widespread	O
metastatic	O
calcification	O
in	O
the	O
cows	O
that	O
died	O
.	O

Because	O
of	O
the	O
extreme	O
toxicity	B-Disease
of	O
vitamin	B-Chemical
D3	I-Chemical
in	O
pregnant	O
Jersey	O
cows	O
and	O
the	O
low	O
margin	O
of	O
safety	O
between	O
doses	O
of	O
vitamin	B-Chemical
D3	I-Chemical
that	O
prevent	O
milk	B-Disease
fever	I-Disease
and	O
doses	O
that	O
induce	O
milk	B-Disease
fever	I-Disease
,	O
we	O
concluded	O
that	O
vitamin	B-Chemical
D3	I-Chemical
cannot	O
be	O
used	O
practically	O
to	O
prevent	O
milk	B-Disease
fever	I-Disease
when	O
injected	O
several	O
weeks	O
prepartum	O
.	O

Diseases	B-Disease
of	I-Disease
peripheral	I-Disease
nerves	I-Disease
as	O
seen	O
in	O
the	O
Nigerian	O
African	O
.	O

The	O
anatomical	O
and	O
aetiological	O
diagnoses	O
of	O
peripheral	B-Disease
nerve	I-Disease
disease	I-Disease
excluding	O
its	O
primary	O
benign	O
and	O
malignant	O
disorders	O
,	O
as	O
seen	O
in	O
358	O
Nigerians	O
are	O
presented	O
.	O

There	O
is	O
a	O
male	O
preponderance	O
and	O
the	O
peak	O
incidence	O
is	O
in	O
the	O
fourth	O
decade	O
.	O

Sensori	B-Disease
-	I-Disease
motor	I-Disease
neuropathy	I-Disease
was	O
the	O
commonest	O
presentation	O
(	O
50	O
%	O
)	O
.	O

Guillain	B-Disease
-	I-Disease
Barr	I-Disease
syndrome	I-Disease
was	O
the	O
commonest	O
identifiable	O
cause	O
(	O
15	O
.	O
6	O
%	O
)	O
,	O
accounting	O
for	O
half	O
of	O
the	O
cases	O
with	O
motor	B-Disease
neuropathy	I-Disease
.	O

Peripheral	B-Disease
neuropathy	I-Disease
due	O
to	O
nutritional	B-Disease
deficiency	I-Disease
of	O
thiamine	B-Chemical
and	O
riboflavin	B-Chemical
was	O
common	O
(	O
10	O
.	O
1	O
%	O
)	O
and	O
presented	O
mainly	O
as	O
sensory	O
and	O
sensori	B-Disease
-	I-Disease
motor	I-Disease
neuropathy	I-Disease
.	O

Diabetes	B-Disease
mellitus	I-Disease
was	O
the	O
major	O
cause	O
of	O
autonomic	B-Disease
neuropathy	I-Disease
.	O

Isoniazid	B-Chemical
was	O
the	O
most	O
frequent	O
agent	O
in	O
drug	O
-	O
induced	O
neuropathy	B-Disease
.	O

Migraine	B-Disease
(	O
20	O
%	O
)	O
was	O
not	O
an	O
uncommon	O
cause	O
of	O
cranial	B-Disease
neuropathy	I-Disease
although	O
malignancies	B-Disease
arising	O
from	O
the	O
reticuloendothelial	O
system	O
or	O
related	O
structures	O
of	O
the	O
head	O
and	O
neck	O
were	O
more	O
frequent	O
(	O
26	O
%	O
)	O
.	O

In	O
26	O
.	O
5	O
%	O
of	O
all	O
the	O
cases	O
,	O
the	O
aetiology	O
of	O
the	O
neuropathy	B-Disease
was	O
undetermined	O
.	O

Heredofamilial	O
and	O
connective	B-Disease
tissue	I-Disease
disorders	I-Disease
were	O
rare	O
.	O

Some	O
of	O
the	O
factors	O
related	O
to	O
the	O
clinical	O
presentation	O
and	O
pathogenesis	O
of	O
the	O
neuropathies	B-Disease
are	O
briefly	O
discussed	O
.	O

Reduction	O
in	O
caffeine	B-Chemical
toxicity	B-Disease
by	O
acetaminophen	B-Chemical
.	O

A	O
patient	O
who	O
allegedly	O
consumed	O
100	O
tablets	O
of	O
an	O
over	O
-	O
the	O
-	O
counter	O
analgesic	O
containing	O
sodium	B-Chemical
acetylsalicylate	I-Chemical
,	O
caffeine	B-Chemical
,	O
and	O
acetaminophen	B-Chemical
displayed	O
no	O
significant	O
CNS	O
stimulation	O
despite	O
the	O
presence	O
of	O
175	O
micrograms	O
of	O
caffeine	B-Chemical
per	O
mL	O
of	O
serum	O
.	O

Because	O
salicylates	O
have	O
been	O
reported	O
to	O
augment	O
the	O
stimulatory	O
effects	O
of	O
caffeine	B-Chemical
on	O
the	O
CNS	O
,	O
attention	O
was	O
focused	O
on	O
the	O
possibility	O
that	O
the	O
presence	O
of	O
acetaminophen	B-Chemical
(	O
52	O
micrograms	O
/	O
mL	O
)	O
reduced	O
the	O
CNS	O
toxicity	B-Disease
of	O
caffeine	B-Chemical
.	O

Studies	O
in	O
DBA	O
/	O
2J	O
mice	O
showed	O
that	O
:	O
1	O
)	O
pretreatment	O
with	O
acetaminophen	B-Chemical
(	O
100	O
mg	O
/	O
kg	O
)	O
increased	O
the	O
interval	O
between	O
the	O
administration	O
of	O
caffeine	B-Chemical
(	O
300	O
to	O
450	O
mg	O
/	O
kg	O
IP	O
)	O
and	O
the	O
onset	O
of	O
fatal	O
convulsions	B-Disease
by	O
a	O
factor	O
of	O
about	O
two	O
;	O
and	O
2	O
)	O
pretreatment	O
with	O
acetaminophen	B-Chemical
(	O
75	O
mg	O
/	O
kg	O
)	O
reduced	O
the	O
incidence	O
of	O
audiogenic	O
seizures	B-Disease
produced	O
in	O
the	O
presence	O
of	O
caffeine	B-Chemical
(	O
12	O
.	O
5	O
to	O
75	O
mg	O
/	O
kg	O
IP	O
)	O
.	O

The	O
frequency	O
of	O
sound	O
-	O
induced	O
seizures	B-Disease
after	O
12	O
.	O
5	O
or	O
25	O
mg	O
/	O
kg	O
caffeine	B-Chemical
was	O
reduced	O
from	O
50	O
to	O
5	O
%	O
by	O
acetaminophen	B-Chemical
.	O

In	O
the	O
absence	O
of	O
caffeine	B-Chemical
,	O
acetaminophen	B-Chemical
(	O
up	O
to	O
300	O
mg	O
/	O
kg	O
)	O
did	O
not	O
modify	O
the	O
seizures	B-Disease
induced	O
by	O
maximal	O
electroshock	O
and	O
did	O
not	O
alter	O
the	O
convulsant	O
dose	O
of	O
pentylenetetrezol	B-Chemical
in	O
mice	O
(	O
tests	O
performed	O
by	O
the	O
Anticonvulsant	O
Screening	O
Project	O
of	O
NINCDS	O
)	O
.	O

Acetaminophen	B-Chemical
(	O
up	O
to	O
150	O
micrograms	O
/	O
mL	O
)	O
did	O
not	O
retard	O
the	O
incorporation	O
of	O
radioactive	O
adenosine	B-Chemical
into	O
ATP	B-Chemical
in	O
slices	O
of	O
rat	O
cerebral	O
cortex	O
.	O

Thus	O
the	O
mechanism	O
by	O
which	O
acetaminophen	B-Chemical
antagonizes	O
the	O
actions	O
of	O
caffeine	B-Chemical
in	O
the	O
CNS	O
remains	O
unknown	O
.	O

A	O
double	O
-	O
blind	O
study	O
of	O
the	O
efficacy	O
and	O
safety	O
of	O
dothiepin	B-Chemical
hydrochloride	I-Chemical
in	O
the	O
treatment	O
of	O
major	O
depressive	B-Disease
disorder	I-Disease
.	O

In	O
a	O
6	O
-	O
week	O
double	O
-	O
blind	O
parallel	O
treatment	O
study	O
,	O
dothiepin	B-Chemical
and	O
amitriptyline	B-Chemical
were	O
compared	O
to	O
placebo	O
in	O
the	O
treatment	O
of	O
33	O
depressed	B-Disease
outpatients	O
.	O

Dothiepin	B-Chemical
and	O
amitriptyline	B-Chemical
were	O
equally	O
effective	O
in	O
alleviating	O
the	O
symptoms	O
of	O
depressive	B-Disease
illness	I-Disease
,	O
and	O
both	O
were	O
significantly	O
superior	O
to	O
placebo	O
.	O

The	O
overall	O
incidence	O
of	O
side	O
effects	O
and	O
the	O
frequency	O
and	O
severity	O
of	O
blurred	B-Disease
vision	I-Disease
,	O
dry	B-Disease
mouth	I-Disease
,	O
and	O
drowsiness	O
were	O
significantly	O
less	O
with	O
dothiepin	B-Chemical
than	O
with	O
amitriptyline	B-Chemical
.	O

Dothiepin	B-Chemical
also	O
produced	O
fewer	O
CNS	O
and	O
cardiovascular	O
effects	O
.	O

There	O
were	O
no	O
clinically	O
important	O
changes	O
in	O
laboratory	O
parameters	O
.	O

Dothiepin	B-Chemical
thus	O
was	O
found	O
to	O
be	O
an	O
effective	O
antidepressant	B-Chemical
drug	O
associated	O
with	O
fewer	O
side	O
effects	O
than	O
amitriptyline	B-Chemical
in	O
the	O
treatment	O
of	O
depressed	B-Disease
outpatients	O
.	O

Behavioral	O
effects	O
of	O
diazepam	B-Chemical
and	O
propranolol	B-Chemical
in	O
patients	O
with	O
panic	B-Disease
disorder	I-Disease
and	O
agoraphobia	B-Disease
.	O

The	O
effects	O
of	O
oral	O
doses	O
of	O
diazepam	B-Chemical
(	O
single	O
dose	O
of	O
10	O
mg	O
and	O
a	O
median	O
dose	O
of	O
30	O
mg	O
/	O
day	O
for	O
2	O
weeks	O
)	O
and	O
propranolol	B-Chemical
(	O
single	O
dose	O
of	O
80	O
mg	O
and	O
a	O
median	O
dose	O
of	O
240	O
mg	O
/	O
day	O
for	O
2	O
weeks	O
)	O
on	O
psychological	O
performance	O
of	O
patients	O
with	O
panic	B-Disease
disorders	I-Disease
and	O
agoraphobia	B-Disease
were	O
investigated	O
in	O
a	O
double	O
-	O
blind	O
,	O
randomized	O
and	O
crossover	O
design	O
.	O

Both	O
drugs	O
impaired	B-Disease
immediate	I-Disease
free	I-Disease
recall	I-Disease
but	O
the	O
decrease	O
was	O
greater	O
for	O
diazepam	B-Chemical
than	O
propranolol	B-Chemical
.	O

Delayed	B-Disease
free	I-Disease
recall	I-Disease
was	I-Disease
also	I-Disease
impaired	I-Disease
but	O
the	O
two	O
drugs	O
did	O
not	O
differ	O
.	O

Patients	O
tapped	O
faster	O
after	O
propranolol	B-Chemical
than	O
diazepam	B-Chemical
and	O
they	O
were	O
more	O
sedated	O
after	O
diazepam	B-Chemical
than	O
propranolol	B-Chemical
.	O

After	O
2	O
weeks	O
of	O
treatment	O
,	O
patients	O
tested	O
5	O
-	O
8	O
h	O
after	O
the	O
last	O
dose	O
of	O
medication	O
did	O
not	O
show	O
any	O
decrement	O
of	O
performance	O
.	O

These	O
results	O
are	O
similar	O
to	O
those	O
previously	O
found	O
in	O
healthy	O
subjects	O
.	O

Accumulation	O
of	O
drugs	O
was	O
not	O
reflected	O
in	O
prolonged	O
behavioral	B-Disease
impairment	I-Disease
.	O

Comparison	O
of	O
i	O
.	O
v	O
.	O
glycopyrrolate	B-Chemical
and	O
atropine	B-Chemical
in	O
the	O
prevention	O
of	O
bradycardia	B-Disease
and	O
arrhythmias	B-Disease
following	O
repeated	O
doses	O
of	O
suxamethonium	B-Chemical
in	O
children	O
.	O

The	O
effectiveness	O
of	O
administration	O
of	O
glycopyrrolate	B-Chemical
5	O
and	O
10	O
micrograms	O
kg	O
-	O
1	O
and	O
atropine	B-Chemical
10	O
and	O
20	O
micrograms	O
kg	O
-	O
1	O
i	O
.	O
v	O
.	O
immediately	O
before	O
the	O
induction	O
of	O
anaesthesia	O
,	O
to	O
prevent	O
arrhythmia	B-Disease
and	O
bradycardia	B-Disease
following	O
repeated	O
doses	O
of	O
suxamethonium	B-Chemical
in	O
children	O
,	O
was	O
studied	O
.	O

A	O
control	O
group	O
was	O
included	O
for	O
comparison	O
with	O
the	O
lower	O
dose	O
range	O
of	O
glycopyrrolate	B-Chemical
and	O
atropine	B-Chemical
.	O

A	O
frequency	O
of	O
bradycardia	B-Disease
of	O
50	O
%	O
was	O
noted	O
in	O
the	O
control	O
group	O
,	O
but	O
this	O
was	O
not	O
significantly	O
different	O
from	O
the	O
frequency	O
with	O
the	O
active	O
drugs	O
.	O

Bradycardia	B-Disease
(	O
defined	O
as	O
a	O
decrease	O
in	O
heart	O
rate	O
to	O
less	O
than	O
50	O
beat	O
min	O
-	O
1	O
)	O
was	O
prevented	O
when	O
the	O
larger	O
dose	O
of	O
either	O
active	O
drug	O
was	O
used	O
.	O

It	O
is	O
recommended	O
that	O
either	O
glycopyrrolate	B-Chemical
10	O
micrograms	O
kg	O
-	O
1	O
or	O
atropine	B-Chemical
20	O
micrograms	O
kg	O
-	O
1	O
i	O
.	O
v	O
.	O
should	O
immediately	O
precede	O
induction	O
of	O
anaesthesia	O
,	O
in	O
children	O
,	O
if	O
the	O
repeated	O
administration	O
of	O
suxamethonium	B-Chemical
is	O
anticipated	O
.	O

Veno	B-Disease
-	I-Disease
occlusive	I-Disease
liver	I-Disease
disease	I-Disease
after	O
dacarbazine	B-Chemical
therapy	O
(	O
DTIC	B-Chemical
)	O
for	O
melanoma	B-Disease
.	O

A	O
case	O
of	O
veno	B-Disease
-	I-Disease
occlusive	I-Disease
disease	I-Disease
of	I-Disease
the	I-Disease
liver	I-Disease
with	O
fatal	O
outcome	O
after	O
dacarbazine	B-Chemical
(	O
DTIC	B-Chemical
)	O
therapy	O
for	O
melanoma	B-Disease
is	O
reported	O
.	O

There	O
was	O
a	O
fulminant	O
clinical	O
course	O
from	O
start	O
of	O
symptoms	O
until	O
death	B-Disease
.	O

At	O
autopsy	O
the	O
liver	O
was	O
enlarged	O
and	O
firm	O
with	O
signs	O
of	O
venous	B-Disease
congestion	I-Disease
.	O

Small	O
-	O
and	O
medium	O
-	O
sized	O
hepatic	O
veins	O
were	O
blocked	O
by	O
thrombosis	B-Disease
.	O

Eosinophilic	O
infiltrations	O
were	O
found	O
around	O
the	O
vessels	O
.	O

Published	O
cases	O
from	O
the	O
literature	O
are	O
reviewed	O
and	O
pertinent	O
features	O
discussed	O
.	O

Maternal	O
lithium	B-Chemical
and	O
neonatal	O
Ebstein	B-Disease
'	I-Disease
s	I-Disease
anomaly	I-Disease
:	O
evaluation	O
with	O
cross	O
-	O
sectional	O
echocardiography	O
.	O

Cross	O
-	O
sectional	O
echocardiography	O
was	O
used	O
to	O
evaluate	O
two	O
neonates	O
whose	O
mothers	O
ingested	O
lithium	B-Chemical
during	O
pregnancy	O
.	O

In	O
one	O
infant	O
,	O
Ebstein	B-Disease
'	I-Disease
s	I-Disease
anomaly	I-Disease
of	O
the	O
tricuspid	O
valve	O
was	O
identified	O
.	O

In	O
the	O
other	O
infant	O
cross	O
-	O
sectional	O
echocardiography	O
provided	O
reassurance	O
that	O
the	O
infant	O
did	O
not	O
have	O
Ebstein	B-Disease
'	I-Disease
s	I-Disease
anomaly	I-Disease
.	O

Cross	O
-	O
sectional	O
echocardiographic	O
screening	O
of	O
newborns	O
exposed	O
to	O
lithium	B-Chemical
during	O
gestation	O
can	O
provide	O
highly	O
accurate	O
,	O
noninvasive	O
assessment	O
of	O
the	O
presence	O
or	O
absence	O
of	O
lithium	B-Chemical
-	O
induced	O
cardiac	B-Disease
malformations	I-Disease
.	O

Effects	O
of	O
training	O
on	O
the	O
extent	O
of	O
experimental	O
myocardial	B-Disease
infarction	I-Disease
in	O
aging	O
rats	O
.	O

The	O
effects	O
of	O
exercise	O
on	O
the	O
severity	O
of	O
isoproterenol	B-Chemical
-	O
induced	O
myocardial	B-Disease
infarction	I-Disease
were	O
studied	O
in	O
female	O
albino	O
rats	O
of	O
20	O
,	O
40	O
,	O
60	O
and	O
80	O
weeks	O
of	O
age	O
.	O

The	O
rats	O
were	O
trained	O
to	O
swim	O
for	O
a	O
specific	O
duration	O
and	O
for	O
a	O
particular	O
period	O
.	O

The	O
occurrence	O
of	O
infarcts	B-Disease
were	O
confirmed	O
by	O
histological	O
methods	O
.	O

Elevations	O
in	O
the	O
serum	O
GOT	O
and	O
GPT	O
were	O
maximum	O
in	O
the	O
sedentary	O
-	O
isoproterenols	B-Chemical
and	O
minimum	O
in	O
the	O
exercise	O
-	O
controls	O
.	O

These	O
changes	O
in	O
the	O
serum	O
transaminases	O
were	O
associated	O
with	O
corresponding	O
depletions	O
in	O
the	O
cardiac	O
GOT	O
and	O
GPT	O
.	O

However	O
,	O
age	O
was	O
seen	O
to	O
interfere	O
with	O
the	O
responses	O
exhibited	O
by	O
the	O
young	O
and	O
old	O
rats	O
.	O

Studies	O
dealing	O
with	O
myocardial	B-Disease
infarction	I-Disease
are	O
more	O
informative	O
when	O
dealt	O
with	O
age	O
.	O

Effect	O
of	O
polyethylene	B-Chemical
glycol	I-Chemical
400	I-Chemical
on	O
adriamycin	B-Chemical
toxicity	B-Disease
in	O
mice	O
.	O

The	O
effect	O
of	O
a	O
widely	O
used	O
organic	O
solvent	O
,	O
polyethylene	B-Chemical
glycol	I-Chemical
400	I-Chemical
(	O
PEG	B-Chemical
400	I-Chemical
)	O
,	O
on	O
the	O
toxic	O
action	O
of	O
an	O
acute	O
or	O
chronic	O
treatment	O
with	O
adriamycin	B-Chemical
(	O
ADR	B-Chemical
)	O
was	O
evaluated	O
in	O
mice	O
.	O

PEG	B-Chemical
400	I-Chemical
impressively	O
decreased	O
both	O
acute	O
high	O
-	O
dose	O
and	O
chronic	O
low	O
-	O
dose	O
-	O
ADR	B-Chemical
-	O
associated	O
lethality	O
.	O

Light	O
microscopic	O
analysis	O
showed	O
a	O
significant	O
protection	O
against	O
ADR	B-Chemical
-	O
induced	O
cardiac	B-Disease
morphological	I-Disease
alterations	I-Disease
.	O

Such	O
treatment	O
did	O
not	O
diminish	O
the	O
ADR	B-Chemical
antitumor	O
activity	O
in	O
L1210	B-Disease
leukemia	I-Disease
and	O
in	O
Ehrlich	B-Disease
ascites	I-Disease
tumor	I-Disease
.	O

Sublingual	O
absorption	O
of	O
the	O
quaternary	B-Chemical
ammonium	I-Chemical
antiarrhythmic	O
agent	O
,	O
UM	B-Chemical
-	I-Chemical
272	I-Chemical
.	O

UM	B-Chemical
-	I-Chemical
272	I-Chemical
(	O
N	B-Chemical
,	I-Chemical
N	I-Chemical
-	I-Chemical
dimethylpropranolol	I-Chemical
)	O
,	O
a	O
quaternary	O
antiarrhythmic	O
agent	O
,	O
was	O
administered	O
sublingually	O
to	O
dogs	O
with	O
ouabain	B-Chemical
-	O
induced	O
ventricular	B-Disease
tachycardias	I-Disease
.	O

Both	O
anti	O
-	O
arrhythmic	O
efficacy	O
and	O
bioavailability	O
were	O
compared	O
to	O
oral	O
drug	O
.	O

Sublingual	O
UM	B-Chemical
-	I-Chemical
272	I-Chemical
converted	O
ventricular	B-Disease
tachycardia	I-Disease
to	O
sinus	O
rhythm	O
in	O
all	O
5	O
dogs	O
.	O

The	O
area	O
under	O
the	O
plasma	O
concentration	O
time	O
curve	O
at	O
90	O
min	O
was	O
4	O
-	O
12	O
times	O
greater	O
than	O
for	O
oral	O
drug	O
,	O
suggesting	O
the	O
existence	O
of	O
an	O
absorption	O
-	O
limiting	O
process	O
in	O
the	O
intestine	O
,	O
and	O
providing	O
an	O
alternate	O
form	O
of	O
administration	O
for	O
quaternary	O
drugs	O
.	O

Early	O
adjuvant	O
adriamycin	B-Chemical
in	O
superficial	O
bladder	B-Disease
carcinoma	I-Disease
.	O

A	O
multicenter	O
study	O
was	O
performed	O
in	O
110	O
patients	O
with	O
superficial	O
transitional	O
cell	O
carcinoma	B-Disease
of	I-Disease
the	I-Disease
bladder	I-Disease
.	O

Adriamycin	B-Chemical
(	O
50	O
mg	O
/	O
50	O
ml	O
)	O
was	O
administered	O
intravesically	O
within	O
24	O
h	O
after	O
transurethral	O
resection	O
of	O
TA	O
-	O
T1	O
(	O
O	O
-	O
A	O
)	O
bladder	B-Disease
tumors	I-Disease
.	O

Instillation	O
was	O
repeated	O
twice	O
during	O
the	O
first	O
week	O
,	O
then	O
weekly	O
during	O
the	O
first	O
month	O
and	O
afterwards	O
monthly	O
for	O
1	O
year	O
.	O

The	O
tolerance	O
was	O
evaluated	O
in	O
these	O
110	O
patients	O
,	O
and	O
29	O
patients	O
presented	O
with	O
local	O
side	O
-	O
effects	O
.	O

In	O
24	O
of	O
these	O
patients	O
chemical	O
cystitis	B-Disease
was	O
severe	O
enough	O
for	O
them	O
to	O
drop	O
out	O
of	O
the	O
study	O
.	O

No	O
systemic	O
side	O
-	O
effects	O
were	O
observed	O
.	O

Recurrence	O
was	O
studied	O
in	O
82	O
evaluable	O
patients	O
after	O
1	O
year	O
of	O
follow	O
-	O
up	O
and	O
in	O
72	O
patients	O
followed	O
for	O
2	O
-	O
3	O
years	O
(	O
mean	O
32	O
months	O
)	O
.	O

Of	O
the	O
82	O
patients	O
studied	O
after	O
1	O
year	O
,	O
23	O
had	O
primary	O
and	O
59	O
recurrent	O
disease	O
.	O

Of	O
the	O
82	O
evaluable	O
patients	O
,	O
50	O
did	O
not	O
show	O
any	O
recurrence	O
after	O
1	O
year	O
(	O
61	O
%	O
)	O
,	O
while	O
32	O
presented	O
with	O
one	O
or	O
more	O
recurrences	O
(	O
39	O
%	O
)	O
.	O

Of	O
these	O
recurrences	O
,	O
27	O
were	O
T1	O
tumors	B-Disease
while	O
five	O
progressed	O
to	O
more	O
highly	O
invasive	O
lesions	O
.	O

In	O
patients	O
that	O
were	O
free	O
of	O
recurrence	O
during	O
the	O
first	O
year	O
,	O
80	O
%	O
remained	O
tumor	B-Disease
-	O
free	O
during	O
the	O
2	O
-	O
to	O
3	O
-	O
year	O
follow	O
-	O
up	O
period	O
.	O

Of	O
the	O
patients	O
developing	O
one	O
or	O
more	O
recurrences	O
during	O
the	O
first	O
year	O
,	O
only	O
50	O
%	O
presented	O
with	O
further	O
recurrence	O
once	O
the	O
instillations	O
were	O
stopped	O
.	O

The	O
beneficial	O
effect	O
of	O
Adriamycin	B-Chemical
appears	O
obvious	O
and	O
might	O
be	O
related	O
to	O
the	O
drug	O
itself	O
,	O
the	O
early	O
and	O
repeated	O
instillations	O
after	O
TUR	O
,	O
or	O
both	O
.	O

D	B-Chemical
-	I-Chemical
penicillamine	I-Chemical
-	O
induced	O
angiopathy	B-Disease
in	O
rats	O
.	O

The	O
effect	O
of	O
high	O
dose	O
D	B-Chemical
-	I-Chemical
penicillamine	I-Chemical
treatment	O
on	O
aortic	O
permeability	O
to	O
albumin	O
and	O
on	O
the	O
ultrastructure	O
of	O
the	O
vessel	O
.	O

Male	O
Sprague	O
-	O
Dawley	O
rats	O
were	O
treated	O
with	O
D	B-Chemical
-	I-Chemical
penicillamine	I-Chemical
(	O
D	B-Chemical
-	I-Chemical
pen	I-Chemical
)	O
500	O
mg	O
/	O
kg	O
/	O
day	O
for	O
10	O
or	O
42	O
days	O
.	O

Pair	O
fed	O
rats	O
served	O
as	O
controls	O
.	O

Changes	O
in	O
aortic	O
morphology	O
were	O
examined	O
by	O
light	O
-	O
and	O
transmission	O
-	O
electron	O
microscopy	O
(	O
TEM	O
)	O
.	O

In	O
addition	O
,	O
the	O
endothelial	O
permeability	O
and	O
the	O
penetration	O
through	O
the	O
aortic	O
wall	O
of	O
albumin	O
were	O
studied	O
10	O
minutes	O
,	O
24	O
and	O
48	O
hours	O
after	O
i	O
.	O
v	O
.	O
injection	O
of	O
human	O
serum	O
131I	O
-	O
albumin	O
(	O
131I	O
-	O
HSA	O
)	O
.	O

TEM	O
revealed	O
extensive	O
elastolysis	O
in	O
the	O
arterial	O
wall	O
of	O
D	B-Chemical
-	I-Chemical
pen	I-Chemical
-	O
treated	O
rats	O
,	O
consistent	O
with	O
an	O
inhibitory	O
effect	O
on	O
crosslink	O
formation	O
.	O

In	O
experimental	O
animals	O
excess	O
deposition	O
of	O
collagen	O
and	O
glycoaminoglycans	O
was	O
observed	O
in	O
the	O
subendothelial	O
and	O
medial	O
layer	O
of	O
the	O
aortic	O
wall	O
,	O
together	O
with	O
prominent	O
basal	O
membrane	O
substance	O
around	O
aortic	O
smooth	O
muscle	O
cells	O
.	O

The	O
aorta	O
/	O
serum	O
-	O
ratio	O
and	O
the	O
radioactive	O
build	O
-	O
up	O
24	O
and	O
48	O
hours	O
after	O
injection	O
of	O
131I	O
-	O
HSA	O
was	O
reduced	O
in	O
animals	O
treated	O
with	O
D	B-Chemical
-	I-Chemical
pen	I-Chemical
for	O
42	O
days	O
,	O
indicating	O
an	O
impeded	O
transmural	O
transport	O
of	O
tracer	O
which	O
may	O
be	O
caused	O
by	O
a	O
steric	O
exclusion	O
effect	O
of	O
abundant	O
hyaluronate	B-Chemical
.	O

The	O
endothelial	O
ultrastructure	O
was	O
unaffected	O
by	O
D	B-Chemical
-	I-Chemical
pen	I-Chemical
,	O
and	O
no	O
differences	O
in	O
aortic	O
131I	O
-	O
HSA	O
radioactivity	O
or	O
aorta	O
/	O
serum	O
-	O
ratio	O
were	O
recorded	O
between	O
experimental	O
and	O
control	O
groups	O
10	O
minutes	O
after	O
tracer	O
injection	O
,	O
indicating	O
that	O
the	O
permeability	O
of	O
the	O
endothelial	O
barrier	O
to	O
albumin	O
remained	O
unaffected	O
by	O
D	B-Chemical
-	I-Chemical
pen	I-Chemical
treatment	O
.	O

These	O
observations	O
support	O
the	O
hypothesis	O
that	O
treatment	O
with	O
high	O
doses	O
of	O
D	B-Chemical
-	I-Chemical
pen	I-Chemical
may	O
induce	O
a	O
fibroproliferative	O
response	O
in	O
rat	O
aorta	O
,	O
possibly	O
by	O
an	O
inhibitory	O
effect	O
on	O
the	O
cross	O
-	O
linking	O
of	O
collagen	O
and	O
elastin	O
.	O

Effect	O
of	O
aspirin	B-Chemical
on	O
N	B-Chemical
-	I-Chemical
[	I-Chemical
4	I-Chemical
-	I-Chemical
(	I-Chemical
5	I-Chemical
-	I-Chemical
nitro	I-Chemical
-	I-Chemical
2	I-Chemical
-	I-Chemical
furyl	I-Chemical
)	I-Chemical
-	I-Chemical
2	I-Chemical
-	I-Chemical
thiazolyl	I-Chemical
]	I-Chemical
-	I-Chemical
formamide	I-Chemical
-	O
induced	O
epithelial	O
proliferation	O
in	O
the	O
urinary	O
bladder	O
and	O
forestomach	O
of	O
the	O
rat	O
.	O

The	O
co	O
-	O
administration	O
of	O
aspirin	B-Chemical
with	O
N	B-Chemical
-	I-Chemical
[	I-Chemical
4	I-Chemical
-	I-Chemical
(	I-Chemical
5	I-Chemical
-	I-Chemical
nitro	I-Chemical
-	I-Chemical
2	I-Chemical
-	I-Chemical
furyl	I-Chemical
)	I-Chemical
-	I-Chemical
2	I-Chemical
-	I-Chemical
thiazolyl	I-Chemical
]	I-Chemical
-	I-Chemical
formamide	I-Chemical
(	O
FANFT	B-Chemical
)	O
to	O
rats	O
resulted	O
in	O
a	O
reduced	O
incidence	O
of	O
FANFT	B-Chemical
-	O
induced	O
bladder	B-Disease
carcinomas	I-Disease
but	O
a	O
concomitant	O
induction	O
of	O
forestomach	B-Disease
tumors	I-Disease
.	O

An	O
autoradiographic	O
study	O
was	O
performed	O
on	O
male	O
F	O
-	O
344	O
rats	O
fed	O
diet	O
containing	O
FANFT	B-Chemical
at	O
a	O
level	O
of	O
0	O
.	O
2	O
%	O
and	O
/	O
or	O
aspirin	B-Chemical
at	O
a	O
level	O
of	O
0	O
.	O
5	O
%	O
to	O
evaluate	O
the	O
effect	O
of	O
aspirin	B-Chemical
on	O
the	O
increased	O
cell	O
proliferation	O
induced	O
by	O
FANFT	B-Chemical
in	O
the	O
forestomach	O
and	O
bladder	O
.	O

FANFT	B-Chemical
-	O
induced	O
cell	O
proliferation	O
in	O
the	O
bladder	O
was	O
significantly	O
suppressed	O
by	O
aspirin	B-Chemical
co	O
-	O
administration	O
after	O
4	O
weeks	O
but	O
not	O
after	O
12	O
weeks	O
.	O

In	O
the	O
forestomach	O
,	O
and	O
also	O
in	O
the	O
liver	O
,	O
aspirin	B-Chemical
did	O
not	O
affect	O
the	O
FANFT	B-Chemical
-	O
induced	O
increase	O
in	O
labeling	O
index	O
.	O

The	O
present	O
results	O
are	O
consistent	O
with	O
the	O
carcinogenicity	O
experiment	O
suggesting	O
that	O
different	O
mechanisms	O
are	O
involved	O
in	O
FANFT	B-Chemical
carcinogenesis	B-Disease
in	O
the	O
bladder	O
and	O
forestomach	O
,	O
and	O
that	O
aspirin	B-Chemical
'	O
s	O
effect	O
on	O
FANFT	B-Chemical
in	O
the	O
forestomach	O
is	O
not	O
due	O
to	O
an	O
irritant	O
effect	O
associated	O
with	O
increased	O
cell	O
proliferation	O
.	O

Also	O
,	O
there	O
appears	O
to	O
be	O
an	O
adaptation	O
by	O
the	O
rats	O
to	O
the	O
chronic	O
ingestion	O
of	O
aspirin	B-Chemical
.	O

A	O
case	O
of	O
tardive	B-Disease
dyskinesia	I-Disease
caused	O
by	O
metoclopramide	B-Chemical
.	O

Abnormal	B-Disease
involuntary	I-Disease
movements	I-Disease
appeared	O
in	O
the	O
mouth	O
,	O
tongue	O
,	O
neck	O
and	O
abdomen	O
of	O
a	O
64	O
-	O
year	O
-	O
old	O
male	O
patient	O
after	O
he	O
took	O
metoclopramide	B-Chemical
for	O
gastrointestinal	B-Disease
disorder	I-Disease
in	O
a	O
regimen	O
of	O
30	O
mg	O
per	O
day	O
for	O
a	O
total	O
of	O
about	O
260	O
days	O
.	O

The	O
symptoms	O
exacerbated	O
to	O
a	O
maximum	O
in	O
a	O
month	O
.	O

When	O
the	O
metoclopramide	B-Chemical
administration	O
was	O
discontinued	O
,	O
the	O
abnormal	B-Disease
movements	I-Disease
gradually	O
improved	O
to	O
a	O
considerable	O
extent	O
.	O

Attention	O
to	O
the	O
possible	O
induction	O
of	O
specific	O
tardive	B-Disease
dyskinesia	I-Disease
is	O
called	O
for	O
in	O
the	O
use	O
of	O
this	O
drug	O
.	O

Intra	O
-	O
arterial	O
BCNU	B-Chemical
chemotherapy	O
for	O
treatment	O
of	O
malignant	B-Disease
gliomas	I-Disease
of	O
the	O
central	O
nervous	O
system	O
.	O

Because	O
of	O
the	O
rapid	O
systemic	O
clearance	O
of	O
BCNU	B-Chemical
(	O
1	B-Chemical
,	I-Chemical
3	I-Chemical
-	I-Chemical
bis	I-Chemical
-	I-Chemical
(	I-Chemical
2	I-Chemical
-	I-Chemical
chloroethyl	I-Chemical
)	I-Chemical
-	I-Chemical
1	I-Chemical
-	I-Chemical
nitrosourea	I-Chemical
)	O
,	O
intra	O
-	O
arterial	O
administration	O
should	O
provide	O
a	O
substantial	O
advantage	O
over	O
intravenous	O
administration	O
for	O
the	O
treatment	O
of	O
malignant	B-Disease
gliomas	I-Disease
.	O

Thirty	O
-	O
six	O
patients	O
were	O
treated	O
with	O
BCNU	B-Chemical
every	O
6	O
to	O
8	O
weeks	O
,	O
either	O
by	O
transfemoral	O
catheterization	O
of	O
the	O
internal	O
carotid	O
or	O
vertebral	O
artery	O
or	O
through	O
a	O
fully	O
implantable	O
intracarotid	O
drug	O
delivery	O
system	O
,	O
beginning	O
with	O
a	O
dose	O
of	O
200	O
mg	O
/	O
sq	O
m	O
body	O
surface	O
area	O
.	O

Twelve	O
patients	O
with	O
Grade	O
III	O
or	O
IV	O
astrocytomas	B-Disease
were	O
treated	O
after	O
partial	O
resection	O
of	O
the	O
tumor	B-Disease
without	O
prior	O
radiation	O
therapy	O
.	O

After	O
two	O
to	O
seven	O
cycles	O
of	O
chemotherapy	O
,	O
nine	O
patients	O
showed	O
a	O
decrease	O
in	O
tumor	B-Disease
size	O
and	O
surrounding	O
edema	B-Disease
on	O
contrast	O
-	O
enhanced	O
computerized	O
tomography	O
scans	O
.	O

In	O
the	O
nine	O
responders	O
,	O
median	O
duration	O
of	O
chemotherapy	O
response	O
from	O
the	O
time	O
of	O
operation	O
was	O
25	O
weeks	O
(	O
range	O
12	O
to	O
more	O
than	O
91	O
weeks	O
)	O
.	O

The	O
median	O
duration	O
of	O
survival	O
in	O
the	O
12	O
patients	O
was	O
54	O
weeks	O
(	O
range	O
21	O
to	O
more	O
than	O
156	O
weeks	O
)	O
,	O
with	O
an	O
18	O
-	O
month	O
survival	O
rate	O
of	O
42	O
%	O
.	O

Twenty	O
-	O
four	O
patients	O
with	O
recurrent	O
Grade	O
I	O
to	O
IV	O
astrocytomas	B-Disease
,	O
whose	O
resection	O
and	O
irradiation	O
therapy	O
had	O
failed	O
,	O
received	O
two	O
to	O
eight	O
courses	O
of	O
intra	O
-	O
arterial	O
BCNU	B-Chemical
therapy	O
.	O

Seventeen	O
of	O
these	O
had	O
a	O
response	O
or	O
were	O
stable	O
for	O
a	O
median	O
of	O
20	O
weeks	O
(	O
range	O
6	O
to	O
more	O
than	O
66	O
weeks	O
)	O
.	O

The	O
catheterization	O
procedure	O
is	O
safe	O
,	O
with	O
no	O
immediate	O
complication	O
in	O
111	O
infusions	O
of	O
BCNU	B-Chemical
.	O

A	O
delayed	O
complication	O
in	O
nine	O
patients	O
has	O
been	O
unilateral	O
loss	B-Disease
of	I-Disease
vision	I-Disease
secondary	O
to	O
a	O
retinal	B-Disease
vasculitis	I-Disease
.	O

The	O
frequency	O
of	O
visual	B-Disease
loss	I-Disease
decreased	O
after	O
the	O
concentration	O
of	O
the	O
ethanol	B-Chemical
diluent	O
was	O
lowered	O
.	O

Provocation	O
of	O
postural	O
hypotension	B-Disease
by	O
nitroglycerin	B-Chemical
in	O
diabetic	B-Disease
autonomic	I-Disease
neuropathy	I-Disease
?	O

The	O
effect	O
of	O
nitroglycerin	B-Chemical
on	O
heart	O
rate	O
and	O
systolic	O
blood	O
pressure	O
was	O
compared	O
in	O
5	O
normal	O
subjects	O
,	O
12	O
diabetic	B-Disease
subjects	O
without	O
autonomic	B-Disease
neuropathy	I-Disease
,	O
and	O
5	O
diabetic	B-Disease
subjects	O
with	O
autonomic	B-Disease
neuropathy	I-Disease
.	O

The	O
magnitude	O
and	O
time	O
course	O
of	O
the	O
increase	O
in	O
heart	O
rate	O
and	O
the	O
decrease	O
in	O
systolic	O
blood	O
pressure	O
after	O
nitroglycerin	B-Chemical
were	O
similar	O
in	O
the	O
normal	O
and	O
diabetic	B-Disease
subjects	O
without	O
autonomic	B-Disease
neuropathy	I-Disease
,	O
whereas	O
a	O
lesser	O
increase	O
in	O
heart	O
rate	O
and	O
a	O
greater	O
decrease	O
in	O
systolic	O
blood	O
pressure	O
occurred	O
in	O
the	O
diabetic	B-Disease
subjects	O
with	O
autonomic	B-Disease
neuropathy	I-Disease
.	O

It	O
is	O
therefore	O
suggested	O
that	O
caution	O
should	O
be	O
exercised	O
when	O
prescribing	O
vasodilator	O
drugs	O
in	O
diabetic	B-Disease
patients	O
,	O
particularly	O
those	O
with	O
autonomic	B-Disease
neuropathy	I-Disease
.	O

Blood	O
pressure	O
response	O
to	O
chronic	O
low	O
-	O
dose	O
intrarenal	O
noradrenaline	B-Chemical
infusion	O
in	O
conscious	O
rats	O
.	O

Sodium	B-Chemical
chloride	I-Chemical
solution	O
(	O
0	O
.	O
9	O
%	O
)	O
or	O
noradrenaline	B-Chemical
in	O
doses	O
of	O
4	O
,	O
12	O
and	O
36	O
micrograms	O
h	O
-	O
1	O
kg	O
-	O
1	O
was	O
infused	O
for	O
five	O
consecutive	O
days	O
,	O
either	O
intrarenally	O
(	O
by	O
a	O
new	O
technique	O
)	O
or	O
intravenously	O
into	O
rats	O
with	O
one	O
kidney	O
removed	O
.	O

Intrarenal	O
infusion	O
of	O
noradrenaline	B-Chemical
caused	O
hypertension	B-Disease
at	O
doses	O
which	O
did	O
not	O
do	O
so	O
when	O
infused	O
intravenously	O
.	O

Intrarenal	O
compared	O
with	O
intravenous	O
infusion	O
of	O
noradrenaline	B-Chemical
caused	O
higher	O
plasma	O
noradrenaline	B-Chemical
concentrations	O
and	O
a	O
shift	O
of	O
the	O
plasma	O
noradrenaline	B-Chemical
concentration	O
-	O
blood	O
pressure	O
effect	O
curve	O
towards	O
lower	O
plasma	O
noradrenaline	B-Chemical
levels	O
.	O

These	O
results	O
suggest	O
that	O
hypertension	B-Disease
after	O
chronic	O
intrarenal	O
noradrenaline	B-Chemical
infusion	O
is	O
produced	O
by	O
relatively	O
higher	O
levels	O
of	O
circulating	O
noradrenaline	B-Chemical
and	O
by	O
triggering	O
of	O
an	O
additional	O
intrarenal	O
pressor	O
mechanism	O
.	O

Characterization	O
of	O
estrogen	B-Chemical
-	O
induced	O
adenohypophyseal	B-Disease
tumors	I-Disease
in	O
the	O
Fischer	O
344	O
rat	O
.	O

Pituitary	B-Disease
tumors	I-Disease
were	O
induced	O
in	O
F344	O
female	O
rats	O
by	O
chronic	O
treatment	O
with	O
diethylstilbestrol	B-Chemical
(	O
DES	B-Chemical
,	O
8	O
-	O
10	O
mg	O
)	O
implanted	O
subcutaneously	O
in	O
silastic	O
capsules	O
.	O

Over	O
a	O
range	O
of	O
1	O
-	O
150	O
days	O
of	O
DES	B-Chemical
treatment	O
,	O
pairs	O
of	O
control	O
and	O
DES	B-Chemical
-	O
treated	O
rats	O
were	O
sacrificed	O
,	O
and	O
their	O
pituitaries	O
dissociated	O
enzymatically	O
into	O
single	O
-	O
cell	O
preparations	O
.	O

The	O
cell	O
populations	O
were	O
examined	O
regarding	O
total	O
cell	O
recovery	O
correlated	O
with	O
gland	O
weight	O
,	O
intracellular	O
prolactin	O
(	O
PRL	O
)	O
content	O
and	O
subsequent	O
release	O
in	O
primary	O
culture	O
,	O
immunocytochemical	O
PRL	O
staining	O
,	O
density	O
and	O
/	O
or	O
size	O
alterations	O
via	O
separation	O
on	O
Ficoll	O
-	O
Hypaque	O
and	O
by	O
unit	O
gravity	O
sedimentation	O
,	O
and	O
cell	O
cycle	O
analysis	O
,	O
after	O
acriflavine	B-Chemical
DNA	O
staining	O
,	O
by	O
laser	O
flow	O
cytometry	O
.	O

Total	O
cell	O
yields	O
from	O
DES	B-Chemical
-	O
treated	O
pituitaries	O
increased	O
from	O
1	O
.	O
3	O
times	O
control	O
yields	O
at	O
8	O
days	O
of	O
treatment	O
to	O
58	O
.	O
9	O
times	O
control	O
values	O
by	O
day	O
150	O
.	O

Intracellular	O
PRL	O
content	O
ranged	O
from	O
1	O
.	O
9	O
to	O
9	O
.	O
4	O
times	O
control	O
levels	O
,	O
and	O
PRL	O
release	O
in	O
vitro	O
was	O
significantly	O
and	O
consistently	O
higher	O
than	O
controls	O
,	O
after	O
at	O
least	O
8	O
days	O
of	O
DES	B-Chemical
exposure	O
.	O

Beyond	O
8	O
days	O
of	O
DES	B-Chemical
exposure	O
,	O
the	O
immunochemically	O
PRL	O
-	O
positive	O
proportion	O
of	O
cells	O
increased	O
to	O
over	O
50	O
%	O
of	O
the	O
total	O
population	O
.	O

Increased	O
density	O
and	O
/	O
or	O
size	O
and	O
PRL	O
content	O
were	O
indicated	O
for	O
the	O
majority	O
of	O
the	O
PRL	O
cell	O
population	O
in	O
both	O
types	O
of	O
separation	O
protocols	O
.	O

All	O
these	O
effects	O
of	O
DES	B-Chemical
were	O
more	O
pronounced	O
among	O
previously	O
ovariectomized	O
animals	O
.	O

The	O
data	O
extend	O
the	O
findings	O
of	O
other	O
investigators	O
,	O
further	O
establishing	O
the	O
DES	B-Chemical
-	O
induced	O
tumor	B-Disease
as	O
a	O
model	O
for	O
study	O
of	O
PRL	O
cellular	O
control	O
mechanisms	O
.	O

Age	O
and	O
renal	O
clearance	O
of	O
cimetidine	B-Chemical
.	O

In	O
35	O
patients	O
(	O
ages	O
20	O
to	O
86	O
yr	O
)	O
receiving	O
cimetidine	B-Chemical
therapeutically	O
two	O
serum	O
samples	O
and	O
all	O
urine	O
formed	O
in	O
the	O
interim	O
were	O
collected	O
for	O
analysis	O
of	O
cimetidine	B-Chemical
by	O
high	O
-	O
pressure	O
liquid	O
chromatography	O
and	O
for	O
creatinine	B-Chemical
.	O

Cimetidine	B-Chemical
clearance	O
decreased	O
with	O
age	O
.	O

The	O
extrapolated	O
6	O
-	O
hr	O
serum	O
concentration	O
of	O
cimetidine	B-Chemical
per	O
unit	O
dose	O
,	O
after	O
intravenous	O
cimetidine	B-Chemical
,	O
increased	O
with	O
age	O
of	O
the	O
patients	O
.	O

The	O
ratio	O
of	O
cimetidine	B-Chemical
clearance	O
to	O
creatinine	B-Chemical
clearance	O
(	O
Rc	O
)	O
averaged	O
4	O
.	O
8	O
+	O
/	O
-	O
2	O
.	O
0	O
,	O
indicating	O
net	O
tubular	O
secretion	O
for	O
cimetidine	B-Chemical
.	O

Rc	O
seemed	O
to	O
be	O
independent	O
of	O
age	O
and	O
decreased	O
with	O
increasing	O
serum	O
concentration	O
of	O
cimetidine	B-Chemical
,	O
suggesting	O
that	O
secretion	O
of	O
cimetidine	B-Chemical
is	O
a	O
saturable	O
process	O
.	O

There	O
was	O
only	O
one	O
case	O
of	O
dementia	B-Disease
possibly	O
due	O
to	O
cimetidine	B-Chemical
(	O
with	O
a	O
drug	O
level	O
of	O
1	O
.	O
9	O
microgram	O
/	O
ml	O
6	O
hr	O
after	O
a	O
dose	O
)	O
in	O
a	O
group	O
of	O
13	O
patients	O
without	O
liver	B-Disease
or	I-Disease
kidney	I-Disease
disease	I-Disease
who	O
had	O
cimetidine	B-Chemical
levels	O
above	O
1	O
.	O
25	O
microgram	O
/	O
ml	O
.	O

Thus	O
,	O
high	O
cimetidine	B-Chemical
levels	O
alone	O
do	O
not	O
always	O
induce	O
dementia	B-Disease
.	O

Further	O
observations	O
on	O
the	O
electrophysiologic	O
effects	O
of	O
oral	O
amiodarone	B-Chemical
therapy	O
.	O

A	O
case	O
is	O
presented	O
of	O
a	O
reversible	O
intra	B-Disease
-	I-Disease
Hisian	I-Disease
block	I-Disease
occurring	O
under	O
amiodarone	B-Chemical
treatment	O
for	O
atrial	B-Disease
tachycardia	I-Disease
in	O
a	O
patient	O
without	O
clear	O
intraventricular	B-Disease
conduction	I-Disease
abnormalities	I-Disease
.	O

His	O
bundle	O
recordings	O
showed	O
an	O
atrial	B-Disease
tachycardia	I-Disease
with	O
intermittent	O
exit	O
block	O
and	O
greatly	O
prolonged	O
BH	O
and	O
HV	O
intervals	O
(	O
40	O
and	O
100	O
msec	O
,	O
respectively	O
)	O
.	O

Thirty	O
days	O
after	O
amiodarone	B-Chemical
discontinuation	O
,	O
His	O
bundle	O
electrograms	O
showed	O
atrial	B-Disease
flutter	I-Disease
without	O
intra	O
-	O
Hisian	O
or	O
infra	O
-	O
Hisian	O
delay	O
.	O

Amiodarone	B-Chemical
should	O
be	O
used	O
with	O
caution	O
during	O
long	O
-	O
term	O
oral	O
therapy	O
in	O
patients	O
with	O
or	O
without	O
clear	O
intraventricular	O
conduction	O
defects	O
.	O

Development	O
of	O
clear	B-Disease
cell	I-Disease
adenocarcinoma	I-Disease
in	O
DES	B-Chemical
-	O
exposed	O
offspring	O
under	O
observation	O
.	O

Two	O
cases	O
of	O
clear	B-Disease
cell	I-Disease
adenocarcinoma	I-Disease
of	I-Disease
the	I-Disease
vagina	I-Disease
detected	O
at	O
follow	O
-	O
up	O
in	O
young	O
women	O
exposed	O
in	O
utero	O
to	O
diethylstilbestrol	B-Chemical
are	O
reported	O
.	O

One	O
patient	O
,	O
aged	O
23	O
,	O
had	O
been	O
followed	O
for	O
2	O
years	O
before	O
carcinoma	B-Disease
was	O
diagnosed	O
;	O
the	O
second	O
patient	O
,	O
aged	O
22	O
,	O
had	O
been	O
seen	O
on	O
a	O
regular	O
basis	O
for	O
5	O
years	O
,	O
8	O
months	O
.	O

In	O
both	O
instances	O
,	O
suspicion	O
of	O
the	O
presence	O
of	O
carcinoma	B-Disease
was	O
aroused	O
by	O
the	O
palpation	O
of	O
a	O
small	O
nodule	O
in	O
the	O
vaginal	O
fornix	O
.	O

Hysterosalpingography	O
was	O
performed	O
on	O
both	O
patients	O
and	O
,	O
in	O
1	O
instance	O
,	O
an	O
abnormal	O
x	O
-	O
ray	O
film	O
was	O
reflected	O
by	O
the	O
gross	O
appearance	O
of	O
the	O
uterine	O
cavity	O
found	O
in	O
the	O
surgical	O
specimen	O
.	O

Neurologic	O
effects	O
of	O
subarachnoid	O
administration	O
of	O
2	B-Chemical
-	I-Chemical
chloroprocaine	I-Chemical
-	I-Chemical
CE	I-Chemical
,	O
bupivacaine	B-Chemical
,	O
and	O
low	O
pH	O
normal	O
saline	O
in	O
dogs	O
.	O

The	O
purpose	O
of	O
this	O
study	O
was	O
to	O
evaluate	O
the	O
neurologic	O
consequences	O
of	O
deliberate	O
subarachnoid	O
injection	O
of	O
large	O
volumes	O
of	O
2	B-Chemical
-	I-Chemical
chloroprocaine	I-Chemical
-	I-Chemical
CE	I-Chemical
in	O
experimental	O
animals	O
.	O

The	O
possible	O
role	O
of	O
low	O
pH	O
as	O
well	O
as	O
total	O
volume	O
as	O
potential	O
factors	O
in	O
causing	O
neurotoxicity	B-Disease
was	O
evaluated	O
.	O

The	O
65	O
dogs	O
in	O
the	O
study	O
received	O
injections	O
in	O
the	O
subarachnoid	O
space	O
as	O
follows	O
:	O
6	O
to	O
8	O
ml	O
of	O
bupivacaine	B-Chemical
(	O
N	O
=	O
15	O
)	O
,	O
2	B-Chemical
-	I-Chemical
chloroprocaine	I-Chemical
-	I-Chemical
CE	I-Chemical
(	O
N	O
=	O
20	O
)	O
,	O
low	O
pH	O
normal	O
saline	O
(	O
pH	O
3	O
.	O
0	O
)	O
(	O
N	O
=	O
20	O
)	O
,	O
or	O
normal	O
saline	O
(	O
N	O
=	O
10	O
)	O
.	O

Of	O
the	O
20	O
animals	O
that	O
received	O
subarachnoid	O
injection	O
of	O
2	B-Chemical
-	I-Chemical
chloroprocaine	I-Chemical
-	I-Chemical
CE	I-Chemical
seven	O
(	O
35	O
%	O
)	O
developed	O
hind	O
-	O
limb	O
paralysis	B-Disease
.	O

None	O
of	O
the	O
animals	O
that	O
received	O
bupivacaine	B-Chemical
,	O
normal	O
saline	O
,	O
or	O
normal	O
saline	O
titrated	O
to	O
a	O
pH	O
3	O
.	O
0	O
developed	O
hind	O
-	O
limb	O
paralysis	B-Disease
.	O

Of	O
the	O
15	O
spinal	O
cords	O
of	O
the	O
animals	O
that	O
received	O
2	B-Chemical
-	I-Chemical
chloroprocaine	I-Chemical
-	I-Chemical
CE	I-Chemical
,	O
13	O
showed	O
subpial	B-Disease
necrosis	I-Disease
;	O
the	O
nerve	O
roots	O
and	O
subarachnoid	O
vessels	O
were	O
normal	O
.	O

The	O
spinal	O
cords	O
of	O
the	O
animals	O
that	O
received	O
bupivacaine	B-Chemical
,	O
low	O
pH	O
normal	O
saline	O
(	O
pH	O
3	O
.	O
0	O
)	O
,	O
or	O
normal	O
saline	O
did	O
not	O
show	O
abnormal	O
findings	O
.	O

Procainamide	B-Chemical
-	O
induced	O
polymorphous	O
ventricular	B-Disease
tachycardia	I-Disease
.	O

Seven	O
cases	O
of	O
procainamide	B-Chemical
-	O
induced	O
polymorphous	O
ventricular	B-Disease
tachycardia	I-Disease
are	O
presented	O
.	O

In	O
four	O
patients	O
,	O
polymorphous	O
ventricular	B-Disease
tachycardia	I-Disease
appeared	O
after	O
intravenous	O
administration	O
of	O
200	O
to	O
400	O
mg	O
of	O
procainamide	B-Chemical
for	O
the	O
treatment	O
of	O
sustained	O
ventricular	B-Disease
tachycardia	I-Disease
.	O

In	O
the	O
remaining	O
three	O
patients	O
,	O
procainamide	B-Chemical
was	O
administered	O
orally	O
for	O
treatment	O
of	O
chronic	O
premature	B-Disease
ventricular	I-Disease
contractions	I-Disease
or	O
atrial	B-Disease
flutter	I-Disease
.	O

These	O
patients	O
had	O
Q	B-Disease
-	I-Disease
T	I-Disease
prolongation	I-Disease
and	O
recurrent	O
syncope	B-Disease
due	O
to	O
polymorphous	O
ventricular	B-Disease
tachycardia	I-Disease
.	O

In	O
four	O
patients	O
,	O
the	O
arrhythmia	B-Disease
was	O
rapidly	O
diagnosed	O
and	O
treated	O
with	O
disappearance	O
of	O
further	O
episodes	O
of	O
the	O
arrhythmia	B-Disease
.	O

In	O
two	O
patients	O
,	O
the	O
arrhythmia	B-Disease
degenerated	O
into	O
irreversible	O
ventricular	B-Disease
fibrillation	I-Disease
and	O
both	O
patients	O
died	O
.	O

In	O
the	O
seventh	O
patient	O
,	O
a	O
permanent	O
ventricular	O
pacemaker	O
was	O
inserted	O
and	O
,	O
despite	O
continuation	O
of	O
procainamide	B-Chemical
therapy	O
,	O
polymorphous	O
ventricular	B-Disease
tachycardia	I-Disease
did	O
not	O
reoccur	O
.	O

These	O
seven	O
cases	O
demonstrate	O
that	O
procainamide	B-Chemical
can	O
produce	O
an	O
acquired	O
prolonged	B-Disease
Q	I-Disease
-	I-Disease
T	I-Disease
syndrome	I-Disease
with	O
polymorphous	O
ventricular	B-Disease
tachycardia	I-Disease
.	O

Phenobarbitone	B-Chemical
-	O
induced	O
enlargement	B-Disease
of	I-Disease
the	I-Disease
liver	I-Disease
in	O
the	O
rat	O
:	O
its	O
relationship	O
to	O
carbon	B-Chemical
tetrachloride	I-Chemical
-	O
induced	O
cirrhosis	B-Disease
.	O

The	O
yield	O
of	O
severe	O
cirrhosis	B-Disease
of	I-Disease
the	I-Disease
liver	I-Disease
(	O
defined	O
as	O
a	O
shrunken	O
finely	O
nodular	O
liver	O
with	O
micronodular	O
histology	O
,	O
ascites	B-Disease
greater	O
than	O
30	O
ml	O
,	O
plasma	O
albumin	O
less	O
than	O
2	O
.	O
2	O
g	O
/	O
dl	O
,	O
splenomegaly	B-Disease
2	O
-	O
3	O
times	O
normal	O
,	O
and	O
testicular	O
atrophy	B-Disease
approximately	O
half	O
normal	O
weight	O
)	O
after	O
12	O
doses	O
of	O
carbon	B-Chemical
tetrachloride	I-Chemical
given	O
intragastrically	O
in	O
the	O
phenobarbitone	B-Chemical
-	O
primed	O
rat	O
was	O
increased	O
from	O
25	O
%	O
to	O
56	O
%	O
by	O
giving	O
the	O
initial	O
"	O
calibrating	O
"	O
dose	O
of	O
carbon	B-Chemical
tetrachloride	I-Chemical
at	O
the	O
peak	O
of	O
the	O
phenobarbitone	B-Chemical
-	O
induced	O
enlargement	B-Disease
of	I-Disease
the	I-Disease
liver	I-Disease
.	O

At	O
this	O
point	O
it	O
was	O
assumed	O
that	O
the	O
cytochrome	O
P450	O
/	O
CCl4	B-Chemical
toxic	O
state	O
was	O
both	O
maximal	O
and	O
stable	O
.	O

The	O
optimal	O
rat	O
size	O
to	O
begin	O
phenobarbitone	B-Chemical
was	O
determined	O
as	O
100	O
g	O
,	O
and	O
this	O
size	O
as	O
a	O
group	O
had	O
a	O
mean	O
maximum	O
relative	O
liver	O
weight	O
increase	O
47	O
%	O
greater	O
than	O
normal	O
rats	O
of	O
the	O
same	O
body	O
weight	O
.	O

The	O
optimal	O
time	O
for	O
the	O
initial	O
dose	O
of	O
carbon	B-Chemical
tetrachloride	I-Chemical
was	O
after	O
14	O
days	O
on	O
phenobarbitone	B-Chemical
.	O

Triamterene	B-Chemical
nephrolithiasis	B-Disease
complicating	O
dyazide	B-Chemical
therapy	O
.	O

A	O
case	O
of	O
triamterene	B-Chemical
nephrolithiasis	B-Disease
is	O
reported	O
in	O
a	O
man	O
after	O
4	O
years	O
of	O
hydrochlorothiazide	B-Chemical
-	I-Chemical
triamterene	I-Chemical
therapy	O
for	O
hypertension	B-Disease
.	O

The	O
stone	O
passed	O
spontaneously	O
and	O
was	O
found	O
to	O
contain	O
a	O
triamterene	B-Chemical
metabolite	O
admixed	O
with	O
uric	B-Chemical
acid	I-Chemical
salts	I-Chemical
.	O

Factors	O
affecting	O
triamterene	B-Chemical
nephrolithiasis	B-Disease
are	O
discussed	O
and	O
2	O
previously	O
reported	O
cases	O
are	O
reviewed	O
.	O

Busulfan	B-Chemical
-	O
induced	O
hemorrhagic	B-Disease
cystitis	I-Disease
.	O

A	O
case	O
of	O
a	O
busulfan	B-Chemical
-	O
induced	O
hemorrhage	B-Disease
cystitis	I-Disease
is	O
reported	O
.	O

Spontaneous	O
resolution	O
occurred	O
following	O
cessation	O
of	O
the	O
drug	O
.	O

The	O
similarity	O
between	O
the	O
histologic	O
appearances	O
of	O
busulfan	B-Chemical
cystitis	B-Disease
and	O
both	O
radiation	O
and	O
cyclophosphamide	B-Chemical
-	O
induced	O
cystitis	B-Disease
is	O
discussed	O
and	O
the	O
world	O
literature	O
reviewed	O
.	O

In	O
view	O
of	O
the	O
known	O
tendency	O
of	O
busulfan	B-Chemical
to	O
induce	O
cellular	O
atypia	O
and	O
carcinoma	B-Disease
in	O
other	O
sites	O
,	O
periodic	O
urinary	O
cytology	O
is	O
suggested	O
in	O
patients	O
on	O
long	O
-	O
term	O
therapy	O
.	O

Variant	O
ventricular	B-Disease
tachycardia	I-Disease
in	O
desipramine	B-Chemical
toxicity	B-Disease
.	O

We	O
report	O
a	O
case	O
of	O
variant	O
ventricular	B-Disease
tachycardia	I-Disease
induced	O
by	O
desipramine	B-Chemical
toxicity	B-Disease
.	O

Unusual	O
features	O
of	O
the	O
arrhythmia	B-Disease
are	O
repetitive	O
group	O
beating	O
,	O
progressive	O
shortening	O
of	O
the	O
R	O
-	O
R	O
interval	O
,	O
progressive	O
widening	O
of	O
the	O
QRS	O
complex	O
with	O
eventual	O
failure	O
of	O
intraventricular	O
conduction	O
,	O
and	O
changes	O
in	O
direction	O
of	O
the	O
QRS	O
axis	O
.	O

Recognition	O
of	O
variant	O
ventricular	B-Disease
tachycardia	I-Disease
is	O
important	O
because	O
therapy	O
differs	O
from	O
that	O
of	O
classic	O
ventricular	B-Disease
tachycardia	I-Disease
.	O

Rebound	O
hypertensive	B-Disease
after	O
sodium	B-Chemical
nitroprusside	I-Chemical
prevented	O
by	O
saralasin	B-Chemical
in	O
rats	O
.	O

The	O
role	O
of	O
the	O
renin	O
-	O
-	O
angiotensin	B-Chemical
system	O
in	O
the	O
maintenance	O
of	O
blood	O
pressure	O
during	O
halothane	B-Chemical
anesthesia	O
and	O
sodium	B-Chemical
nitroprusside	I-Chemical
(	O
SNP	B-Chemical
)	O
-	O
induced	O
hypotension	B-Disease
was	O
evaluated	O
.	O

Control	O
rats	O
received	O
halothane	B-Chemical
anesthesia	O
(	O
1	O
MAC	O
)	O
for	O
one	O
hour	O
,	O
followed	O
by	O
SNP	B-Chemical
infusion	O
,	O
40	O
microgram	O
/	O
kg	O
/	O
min	O
,	O
for	O
30	O
min	O
,	O
followed	O
by	O
a	O
30	O
-	O
min	O
recovery	O
period	O
.	O

A	O
second	O
group	O
of	O
rats	O
was	O
treated	O
identically	O
and	O
,	O
in	O
addition	O
,	O
received	O
an	O
infusion	O
of	O
saralasin	B-Chemical
(	O
a	O
competitive	O
inhibitor	O
of	O
angiotensin	B-Chemical
II	I-Chemical
)	O
throughout	O
the	O
experimental	O
period	O
.	O

In	O
each	O
group	O
,	O
SNP	B-Chemical
infusion	O
resulted	O
in	O
an	O
initial	O
decrease	O
in	O
blood	O
pressure	O
from	O
86	O
torr	O
and	O
83	O
torr	O
,	O
respectively	O
,	O
to	O
48	O
torr	O
.	O

During	O
the	O
SNP	B-Chemical
infusion	O
the	O
control	O
animals	O
demonstrated	O
a	O
progressive	O
increase	B-Disease
in	I-Disease
blood	I-Disease
pressure	I-Disease
to	O
61	O
torr	O
,	O
whereas	O
the	O
saralasin	B-Chemical
-	O
treated	O
animals	O
showed	O
no	O
change	O
.	O

Following	O
discontinuation	O
of	O
SNP	B-Chemical
,	O
blood	O
pressure	O
in	O
the	O
control	O
animals	O
rebounded	O
to	O
94	O
torr	O
,	O
as	O
compared	O
with	O
78	O
torr	O
in	O
the	O
saralasin	B-Chemical
-	O
treated	O
rats	O
.	O

This	O
study	O
indicates	O
that	O
with	O
stable	O
halothane	B-Chemical
anesthesia	O
,	O
the	O
partial	O
recovery	O
of	O
blood	O
pressure	O
during	O
SNP	B-Chemical
infusion	O
and	O
the	O
post	O
-	O
SNP	B-Chemical
rebound	O
of	O
blood	O
pressure	O
can	O
be	O
completely	O
blocked	O
by	O
saralasin	B-Chemical
.	O

This	O
demonstrates	O
the	O
participation	O
of	O
the	O
renin	O
-	O
-	O
angiotensin	B-Chemical
system	O
in	O
antagonizing	O
the	O
combined	O
hypotensive	B-Disease
effects	O
of	O
halothane	B-Chemical
and	O
SNP	B-Chemical
.	O

Clinical	O
nephrotoxicity	B-Disease
of	O
tobramycin	B-Chemical
and	O
gentamicin	B-Chemical
.	O

A	O
prospective	O
study	O
.	O

Nearly	O
3	O
.	O
2	O
million	O
people	O
in	O
this	O
country	O
receive	O
aminoglycoside	B-Chemical
antibiotics	O
annually	O
.	O

Gentamicin	B-Chemical
sulfate	I-Chemical
and	O
tobramycin	B-Chemical
sulfate	I-Chemical
continue	O
to	O
demonstrate	O
ototoxicity	B-Disease
and	O
nephrotoxicity	B-Disease
in	O
both	O
animal	O
and	O
clinical	O
studies	O
.	O

In	O
this	O
study	O
,	O
62	O
patients	O
with	O
confirmed	O
initial	O
normal	O
renal	O
function	O
and	O
treated	O
with	O
2	O
to	O
5	O
mg	O
/	O
kg	O
/	O
day	O
of	O
gentamicin	B-Chemical
sulfate	I-Chemical
or	O
tobramycin	B-Chemical
sulfate	I-Chemical
for	O
a	O
minimum	O
of	O
seven	O
days	O
were	O
followed	O
up	O
prospectively	O
for	O
the	O
development	O
of	O
aminoglycoside	B-Chemical
-	O
related	O
renal	B-Disease
failure	I-Disease
,	O
defined	O
as	O
at	O
least	O
a	O
one	O
-	O
third	O
reduction	O
in	O
renal	O
function	O
.	O

In	O
these	O
62	O
patients	O
,	O
no	O
other	O
causes	O
for	O
renal	B-Disease
failure	I-Disease
could	O
be	O
identified	O
.	O

Five	O
of	O
33	O
(	O
15	O
%	O
)	O
of	O
the	O
tobramycin	B-Chemical
-	O
treated	O
patients	O
and	O
16	O
of	O
29	O
(	O
55	O
.	O
2	O
%	O
)	O
of	O
the	O
gentamicin	B-Chemical
-	O
treated	O
patients	O
had	O
renal	B-Disease
failure	I-Disease
.	O

Thus	O
,	O
gentamicin	B-Chemical
was	O
associated	O
with	O
renal	B-Disease
failure	I-Disease
more	O
than	O
three	O
times	O
as	O
often	O
as	O
was	O
tobramycin	B-Chemical
.	O

Metabolic	O
involvement	O
in	O
adriamycin	B-Chemical
cardiotoxicity	B-Disease
.	O

The	O
cardiotoxic	B-Disease
effects	O
of	O
adriamycin	B-Chemical
were	O
studied	O
in	O
mammalian	O
myocardial	O
cells	O
in	O
culture	O
as	O
a	O
model	O
system	O
.	O

Adriamycin	B-Chemical
inhibited	O
cell	O
growth	O
and	O
the	O
rhythmic	O
contractions	O
characteristic	O
of	O
myocardial	O
cells	O
in	O
culture	O
.	O

A	O
possible	O
involvement	O
of	O
energy	O
metabolism	O
was	O
suggested	O
previously	O
,	O
and	O
in	O
this	O
study	O
the	O
adenylate	O
energy	O
charge	O
and	O
phosphorylcreatine	B-Chemical
mole	O
fraction	O
were	O
determined	O
in	O
the	O
adriamycin	B-Chemical
-	O
treated	O
cells	O
.	O

The	O
adenylate	O
energy	O
charge	O
was	O
found	O
to	O
be	O
significantly	O
decreased	O
,	O
while	O
the	O
phophorylcreatine	B-Chemical
mole	O
fraction	O
was	O
unchanged	O
.	O

Such	O
disparity	O
suggests	O
an	O
inhibition	O
of	O
creatine	B-Chemical
phosphokinase	O
.	O

The	O
addition	O
of	O
1	O
mM	O
adenosine	B-Chemical
to	O
the	O
myocardial	O
cell	O
cultures	O
markedly	O
increases	O
the	O
ATP	B-Chemical
concentration	O
through	O
a	O
pathway	O
reportedly	O
leading	O
to	O
a	O
compartmentalized	O
ATP	B-Chemical
pool	O
.	O

In	O
the	O
adriamycin	B-Chemical
-	O
treated	O
cells	O
,	O
the	O
addition	O
of	O
adenosine	B-Chemical
increased	O
the	O
adenylate	O
charge	O
and	O
,	O
concomitant	O
with	O
this	O
inrcease	O
,	O
the	O
cells	O
'	O
functional	O
integrity	O
,	O
in	O
terms	O
of	O
percentage	O
of	O
beating	O
cells	O
and	O
rate	O
of	O
contractions	O
,	O
was	O
maintained	O
.	O

Age	O
-	O
dependent	O
sensitivity	O
of	O
the	O
rat	O
to	O
neurotoxic	B-Disease
effects	O
of	O
streptomycin	B-Chemical
.	O

Streptomycin	B-Chemical
sulfate	O
(	O
300	O
mg	O
/	O
kg	O
s	O
.	O
c	O
.	O
)	O
was	O
injected	O
for	O
various	O
periods	O
into	O
preweanling	O
rats	O
and	O
for	O
3	O
weeks	O
into	O
weanling	O
rats	O
.	O

Beginning	O
at	O
8	O
days	O
of	O
age	O
,	O
body	O
movement	O
and	O
hearing	O
were	O
examined	O
for	O
6	O
and	O
up	O
to	O
17	O
weeks	O
,	O
respectively	O
.	O

Abnormal	B-Disease
movements	I-Disease
and	O
deafness	B-Disease
occurred	O
only	O
in	O
rats	O
treated	O
during	O
the	O
preweaning	O
period	O
;	O
within	O
this	O
period	O
the	O
greatest	O
sensitivities	O
for	O
these	O
abnormalities	O
occurred	O
from	O
2	O
to	O
11	O
-	O
17	O
and	O
5	O
to	O
11	O
days	O
of	O
age	O
,	O
respectively	O
,	O
indicating	O
that	O
the	O
cochlea	O
is	O
more	O
sensitive	O
to	O
streptomycin	B-Chemical
than	O
the	O
site	O
(	O
vestibular	O
or	O
central	O
)	O
responsible	O
for	O
the	O
dyskinesias	B-Disease
.	O

Late	O
,	O
late	O
doxorubicin	B-Chemical
cardiotoxicity	B-Disease
.	O

Cardiac	B-Disease
toxicity	I-Disease
is	O
a	O
major	O
complication	O
which	O
limits	O
the	O
use	O
of	O
adriamycin	B-Chemical
as	O
a	O
chemotherapeutic	O
agent	O
.	O

Cardiomyopathy	B-Disease
is	O
frequent	O
when	O
the	O
total	O
dose	O
exceeds	O
600	O
mg	O
/	O
m2	O
and	O
occurs	O
within	O
one	O
to	O
six	O
months	O
after	O
cessation	O
of	O
therapy	O
.	O

A	O
patient	O
is	O
reported	O
who	O
developed	O
progressive	O
cardiomyopathy	B-Disease
two	O
and	O
one	O
-	O
half	O
years	O
after	O
receiving	O
580	O
mg	O
/	O
m2	O
which	O
apparently	O
represents	O
late	O
,	O
late	O
cardiotoxicity	B-Disease
.	O

Attenuation	O
of	O
the	O
lithium	B-Chemical
-	O
induced	O
diabetes	B-Disease
-	I-Disease
insipidus	I-Disease
-	I-Disease
like	I-Disease
syndrome	I-Disease
by	O
amiloride	B-Chemical
in	O
rats	O
.	O

The	O
effect	O
of	O
amiloride	B-Chemical
on	O
lithium	B-Chemical
-	O
induced	O
polydipsia	B-Disease
and	O
polyuria	B-Disease
and	O
on	O
the	O
lithium	B-Chemical
concentration	O
in	O
the	O
plasma	O
,	O
brain	O
,	O
kidney	O
,	O
thyroid	O
and	O
red	O
blood	O
cells	O
was	O
investigated	O
in	O
rats	O
,	O
chronically	O
treated	O
with	O
LiCl	B-Chemical
.	O

Amiloride	B-Chemical
reduced	O
the	O
drinking	O
and	O
urine	O
volume	O
of	O
rats	O
in	O
an	O
acute	O
(	O
6	O
or	O
12	O
h	O
)	O
and	O
a	O
subacute	O
(	O
3	O
days	O
)	O
experiment	O
.	O

6	O
h	O
after	O
the	O
administration	O
of	O
amiloride	B-Chemical
,	O
a	O
reduction	O
was	O
observed	O
in	O
the	O
lithium	B-Chemical
content	O
of	O
the	O
renal	O
medulla	O
but	O
not	O
in	O
the	O
other	O
organs	O
studied	O
.	O

At	O
12	O
h	O
,	O
all	O
the	O
tissues	O
showed	O
a	O
slight	O
increase	O
in	O
lithium	B-Chemical
levels	O
.	O

After	O
3	O
days	O
of	O
combined	O
treatment	O
,	O
a	O
marked	O
elevation	O
in	O
plasma	O
and	O
tissue	O
lithium	B-Chemical
levels	O
accompanied	O
a	O
reduction	O
in	O
water	O
intake	O
.	O

In	O
all	O
the	O
experiments	O
,	O
the	O
attenuation	O
of	O
the	O
lithium	B-Chemical
-	O
induced	O
diabetes	B-Disease
-	I-Disease
insipidus	I-Disease
-	I-Disease
like	I-Disease
syndrome	I-Disease
by	O
amiloride	B-Chemical
was	O
accompanied	O
by	O
a	O
reduction	O
of	O
the	O
ratio	O
between	O
the	O
lithium	B-Chemical
concentration	O
in	O
the	O
renal	O
medulla	O
and	O
its	O
levels	O
in	O
the	O
blood	O
and	O
an	O
elevation	O
in	O
the	O
plasma	O
potassium	B-Chemical
level	O
.	O

It	O
is	O
concluded	O
that	O
acute	O
amiloride	B-Chemical
administration	O
to	O
lithium	B-Chemical
-	O
treated	O
patients	O
suffering	O
from	O
polydipsia	B-Disease
and	O
polyuria	B-Disease
might	O
relieve	O
these	O
patients	O
but	O
prolonged	O
amiloride	B-Chemical
supplementation	O
would	O
result	O
in	O
elevated	O
lithium	B-Chemical
levels	O
and	O
might	O
be	O
hazardous	O
.	O

Cardiovascular	B-Disease
complications	I-Disease
associated	O
with	O
terbutaline	B-Chemical
treatment	O
for	O
preterm	B-Disease
labor	I-Disease
.	O

Severe	O
cardiovascular	B-Disease
complications	I-Disease
occurred	O
in	O
eight	O
of	O
160	O
patients	O
treated	O
with	O
terbutaline	B-Chemical
for	O
preterm	B-Disease
labor	I-Disease
.	O

Associated	O
corticosteroid	O
therapy	O
and	O
twin	O
gestations	O
appear	O
to	O
be	O
predisposing	O
factors	O
.	O

Potential	O
mechanisms	O
of	O
the	O
pathophysiology	O
are	O
briefly	O
discussed	O
.	O

Toxic	B-Disease
hepatitis	I-Disease
induced	O
by	O
antithyroid	O
drugs	O
:	O
four	O
cases	O
including	O
one	O
with	O
cross	O
-	O
reactivity	O
between	O
carbimazole	B-Chemical
and	O
benzylthiouracil	B-Chemical
.	O

OBJECTIVE	O
:	O
This	O
study	O
was	O
conducted	O
to	O
assess	O
the	O
occurrence	O
of	O
hepatic	B-Disease
adverse	I-Disease
effects	I-Disease
encountered	O
with	O
antithyroid	O
drugs	O
.	O

METHODS	O
:	O
Retrospective	O
review	O
of	O
medical	O
records	O
of	O
236	O
patients	O
with	O
hyperthyroidism	B-Disease
admitted	O
in	O
our	O
department	O
(	O
in	O
-	O
or	O
out	O
-	O
patients	O
)	O
from	O
1986	O
to	O
1992	O
.	O

RESULTS	O
:	O
Four	O
patients	O
(	O
1	O
.	O
7	O
%	O
)	O
were	O
identified	O
with	O
toxic	B-Disease
hepatitis	I-Disease
which	O
could	O
reasonably	O
be	O
attributed	O
to	O
the	O
use	O
of	O
antithyroid	O
agent	O
.	O

Two	O
patients	O
had	O
a	O
cholestatic	B-Disease
hepatitis	I-Disease
induced	O
by	O
carbimazole	B-Chemical
(	O
N	B-Chemical
omercazole	I-Chemical
)	O
.	O

Two	O
others	O
had	O
a	O
mixed	O
(	O
cholestatic	B-Disease
and	O
cytolytic	O
)	O
hepatitis	B-Disease
following	O
carbimazole	B-Chemical
.	O

One	O
of	O
the	O
latter	O
two	O
patients	O
further	O
experienced	O
a	O
cytolytic	O
hepatitis	B-Disease
which	O
appeared	O
after	O
Benzylthiouracil	B-Chemical
(	O
Basd	B-Chemical
ne	I-Chemical
)	O
had	O
replaced	O
carbimazole	B-Chemical
.	O

Biological	O
features	O
of	O
hepatitis	B-Disease
disappeared	O
in	O
all	O
cases	O
after	O
cessation	O
of	O
the	O
incriminated	O
drug	O
,	O
while	O
biliary	O
,	O
viral	O
and	O
immunological	O
searches	O
were	O
negative	O
.	O

Only	O
2	O
patients	O
of	O
our	O
retrospective	O
study	O
experienced	O
a	O
mild	O
or	O
severe	O
neutropenia	B-Disease
.	O

CONCLUSION	O
:	O
Toxic	B-Disease
hepatitis	I-Disease
is	O
a	O
potential	O
adverse	O
effect	O
of	O
antithyroid	O
drugs	O
which	O
warrants	O
,	O
as	O
for	O
haematological	O
disturbances	O
,	O
a	O
pre	O
-	O
therapeutic	O
determination	O
and	O
a	O
careful	O
follow	O
-	O
up	O
of	O
relevant	O
biological	O
markers	O
.	O

Moreover	O
,	O
hepatotoxicity	B-Disease
may	O
not	O
be	O
restricted	O
to	O
one	O
class	O
of	O
antithyroid	O
agents	O
.	O

Interactive	O
effects	O
of	O
variations	O
in	O
[	O
Na	B-Chemical
]	O
o	O
and	O
[	O
Ca	B-Chemical
]	O
o	O
on	O
rat	O
atrial	O
spontaneous	O
frequency	O
.	O

The	O
effects	O
of	O
varying	O
the	O
extracellular	O
concentrations	O
of	O
Na	B-Chemical
and	O
Ca	B-Chemical
(	O
[	O
Na	B-Chemical
]	O
o	O
and	O
[	O
Ca	B-Chemical
]	O
o	O
)	O
on	O
both	O
,	O
the	O
spontaneous	O
beating	O
and	O
the	O
negative	O
chronotropic	O
action	O
of	O
verapamil	B-Chemical
,	O
were	O
studied	O
in	O
the	O
isolated	O
rat	O
atria	O
.	O

Basal	O
frequency	O
(	O
BF	O
)	O
evaluated	O
by	O
surface	O
electrogram	O
was	O
223	O
+	O
/	O
-	O
4	O
beats	O
/	O
min	O
.	O
in	O
control	O
Krebs	O
-	O
Ringer	O
containing	O
137	O
mM	O
Na	B-Chemical
and	O
1	O
.	O
35	O
mM	O
Ca	B-Chemical
(	O
N	O
)	O
.	O

It	O
decreased	O
by	O
16	O
+	O
/	O
-	O
3	O
%	O
by	O
lowering	O
[	O
Na	B-Chemical
]	O
o	O
to	O
78	O
mM	O
(	O
LNa	O
)	O
,	O
23	O
+	O
/	O
-	O
2	O
%	O
by	O
lowering	O
simultaneously	O
[	O
Na	B-Chemical
]	O
o	O
to	O
78	O
mM	O
and	O
[	O
Ca	B-Chemical
]	O
o	O
to	O
0	O
.	O
675	O
mM	O
(	O
LNa	O
+	O
LCa	O
)	O
and	O
31	O
+	O
/	O
-	O
5	O
%	O
by	O
lowering	O
[	O
Na	B-Chemical
]	O
o	O
to	O
78	O
mM	O
plus	O
increasing	O
[	O
Ca	B-Chemical
]	O
o	O
to	O
3	O
.	O
6	O
mM	O
(	O
LNa	O
+	O
HCa	O
)	O
.	O

At	O
normal	O
[	O
Na	B-Chemical
]	O
o	O
,	O
decrease	O
(	O
0	O
.	O
675	O
mM	O
)	O
or	O
increase	O
(	O
3	O
.	O
6	O
mM	O
)	O
of	O
[	O
Ca	B-Chemical
]	O
o	O
did	O
not	O
modify	O
BF	O
;	O
a	O
reduction	O
of	O
ten	O
times	O
(	O
0	O
.	O
135	O
mM	O
of	O
normal	O
[	O
Ca	B-Chemical
]	O
o	O
was	O
effective	O
to	O
reduce	O
BF	O
by	O
40	O
+	O
/	O
-	O
13	O
%	O
.	O

All	O
negative	O
chronotropic	O
effects	O
were	O
BF	O
-	O
dependent	O
.	O

Dose	O
-	O
dependent	O
bradycardia	B-Disease
induced	O
by	O
verapamil	B-Chemical
was	O
potentiated	O
by	O
LNa	O
,	O
LCa	O
,	O
and	O
HCa	O
.	O

Independent	O
but	O
not	O
additive	O
effects	O
of	O
Na	B-Chemical
and	O
Ca	B-Chemical
are	O
shown	O
by	O
decreases	O
in	O
the	O
values	O
of	O
[	O
verapamil	B-Chemical
]	O
o	O
needed	O
to	O
reduce	O
BF	O
by	O
30	O
%	O
(	O
IC30	O
)	O
with	O
the	O
following	O
order	O
of	O
inhibitory	O
potency	O
:	O
LNa	O
>	O
LCa	O
>	O
HCa	O
>	O
N	O
,	O
resulting	O
LNa	O
+	O
HCa	O
similar	O
to	O
LNa	O
.	O

The	O
[	O
verapamil	B-Chemical
]	O
o	O
that	O
arrested	O
atrial	O
beating	O
(	O
AC	O
)	O
was	O
also	O
potentiated	O
with	O
the	O
order	O
LNa	O
=	O
LNa	O
+	O
LCa	O
=	O
LNa	O
+	O
HCa	O
=	O
LCa	O
>	O
HCa	O
=	O
N	O
.	O

The	O
results	O
indicate	O
that	O
rat	O
atrial	O
spontaneous	O
beating	O
is	O
more	O
dependent	O
on	O
[	O
Na	B-Chemical
]	O
o	O
than	O
on	O
[	O
Ca	B-Chemical
]	O
o	O
in	O
a	O
range	O
of	O
+	O
/	O
-	O
50	O
%	O
of	O
their	O
normal	O
concentration	O
.	O

Also	O
the	O
enhancement	O
of	O
verapamil	B-Chemical
effects	O
on	O
atrial	O
beating	O
was	O
more	O
pronounced	O
at	O
LNa	O
than	O
at	O
LCa	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
250	O
WORDS	O
)	O

Pseudo	O
-	O
allergic	B-Disease
reactions	I-Disease
to	O
corticosteroids	B-Chemical
:	O
diagnosis	O
and	O
alternatives	O
.	O

Two	O
patients	O
treated	O
with	O
parenteral	O
paramethasone	B-Chemical
(	O
Triniol	O
)	O
and	O
dexamethasone	B-Chemical
(	O
Sedionbel	O
)	O
are	O
described	O
.	O

A	O
few	O
minutes	O
after	O
administration	O
of	O
the	O
drugs	O
,	O
they	O
presented	O
urticaria	B-Disease
(	O
patients	O
1	O
and	O
2	O
)	O
and	O
conjunctivitis	B-Disease
(	O
patient	O
1	O
)	O
.	O

The	O
purpose	O
of	O
our	O
study	O
was	O
to	O
determine	O
the	O
cause	O
of	O
the	O
patients	O
'	O
reactions	O
,	O
the	O
immunological	O
mechanisms	O
involved	O
and	O
whether	O
these	O
patients	O
would	O
be	O
able	O
to	O
tolerate	O
any	O
kind	O
of	O
corticoid	O
.	O

Clinical	O
examinations	O
and	O
skin	O
,	O
oral	O
and	O
parenteral	O
challenges	O
with	O
different	O
corticosteroids	B-Chemical
and	O
ELISA	O
tests	O
were	O
performed	O
.	O

In	O
the	O
two	O
patients	O
,	O
skin	O
and	O
ELISA	O
tests	O
with	O
paramethasone	B-Chemical
were	O
negative	O
,	O
as	O
was	O
the	O
prick	O
test	O
with	O
each	O
of	O
its	O
excipients	O
.	O

A	O
single	O
-	O
blind	O
parenteral	O
challenge	O
with	O
Triniol	O
was	O
positive	O
in	O
both	O
patients	O
after	O
the	O
administration	O
of	O
1	O
ml	O
of	O
the	O
drug	O
,	O
and	O
negative	O
with	O
its	O
excipients	O
.	O

We	O
also	O
carried	O
out	O
oral	O
and	O
parenteral	O
challenges	O
with	O
other	O
corticosteroids	B-Chemical
and	O
found	O
intolerance	O
to	O
some	O
of	O
them	O
.	O

These	O
results	O
suggest	O
that	O
paramethasone	B-Chemical
caused	O
pseudoallergic	O
reactions	O
in	O
our	O
patients	O
.	O

Corticosteroids	O
different	O
from	O
paramethasone	B-Chemical
also	O
produced	O
hypersensitivity	B-Disease
reactions	O
in	O
these	O
patients	O
;	O
however	O
,	O
a	O
few	O
of	O
them	O
were	O
tolerated	O
.	O

The	O
basic	O
mechanisms	O
of	O
those	O
reactions	O
are	O
not	O
yet	O
fully	O
understood	O
.	O

To	O
our	O
knowledge	O
,	O
this	O
is	O
the	O
first	O
report	O
of	O
a	O
pseudo	O
-	O
allergy	B-Disease
caused	O
by	O
paramethasone	B-Chemical
.	O

Study	O
of	O
the	O
role	O
of	O
vitamin	B-Chemical
B12	I-Chemical
and	O
folinic	B-Chemical
acid	I-Chemical
supplementation	O
in	O
preventing	O
hematologic	O
toxicity	B-Disease
of	O
zidovudine	B-Chemical
.	O

A	O
prospective	O
,	O
randomized	O
study	O
was	O
conducted	O
to	O
evaluate	O
the	O
role	O
of	O
vitamin	B-Chemical
B12	I-Chemical
and	O
folinic	B-Chemical
acid	I-Chemical
supplementation	O
in	O
preventing	O
zidovudine	B-Chemical
(	O
ZDV	B-Chemical
)	O
-	O
induced	O
bone	B-Disease
marrow	I-Disease
suppression	I-Disease
.	O

Seventy	O
-	O
five	O
human	B-Disease
immunodeficiency	I-Disease
virus	I-Disease
(	I-Disease
HIV	I-Disease
)	I-Disease
-	I-Disease
infected	I-Disease
patients	O
with	O
CD4	O
+	O
cell	O
counts	O
<	O
500	O
/	O
mm3	O
were	O
randomized	O
to	O
receive	O
either	O
ZDV	B-Chemical
(	O
500	O
mg	O
daily	O
)	O
alone	O
(	O
group	O
I	O
,	O
n	O
=	O
38	O
)	O
or	O
in	O
combination	O
with	O
folinic	B-Chemical
acid	I-Chemical
(	O
15	O
mg	O
daily	O
)	O
and	O
intramascular	O
vitamin	B-Chemical
B12	I-Chemical
(	O
1000	O
micrograms	O
monthly	O
)	O
(	O
group	O
II	O
,	O
n	O
=	O
37	O
)	O
.	O

Finally	O
,	O
15	O
patients	O
were	O
excluded	O
from	O
the	O
study	O
(	O
noncompliance	O
14	O
,	O
death	B-Disease
1	O
)	O
;	O
thus	O
,	O
60	O
patients	O
(	O
31	O
in	O
group	O
I	O
and	O
29	O
in	O
group	O
II	O
)	O
were	O
eligible	O
for	O
analysis	O
.	O

No	O
significant	O
differences	O
between	O
groups	O
were	O
found	O
at	O
enrollment	O
.	O

During	O
the	O
study	O
,	O
vitamin	B-Chemical
B12	I-Chemical
and	O
folate	B-Chemical
levels	O
were	O
significantly	O
higher	O
in	O
group	O
II	O
patients	O
;	O
however	O
,	O
no	O
differences	O
in	O
hemoglobin	O
,	O
hematocrit	O
,	O
mean	O
corpuscular	O
volume	O
,	O
and	O
white	O
-	O
cell	O
,	O
neutrophil	O
and	O
platelet	O
counts	O
were	O
observed	O
between	O
groups	O
at	O
3	O
,	O
6	O
,	O
9	O
and	O
12	O
months	O
.	O

Severe	O
hematologic	O
toxicity	B-Disease
(	O
neutrophil	O
count	O
<	O
1000	O
/	O
mm3	O
and	O
/	O
or	O
hemoglobin	O
<	O
8	O
g	O
/	O
dl	O
)	O
occurred	O
in	O
4	O
patients	O
assigned	O
to	O
group	O
I	O
and	O
7	O
assigned	O
to	O
group	O
II	O
.	O

There	O
was	O
no	O
correlation	O
between	O
vitamin	B-Chemical
B12	I-Chemical
or	O
folate	B-Chemical
levels	O
and	O
development	O
of	O
myelosuppression	B-Disease
.	O

Vitamin	B-Chemical
B12	I-Chemical
and	O
folinic	B-Chemical
acid	I-Chemical
supplementation	O
of	O
ZDV	B-Chemical
therapy	O
does	O
not	O
seem	O
useful	O
in	O
preventing	O
or	O
reducing	O
ZDV	B-Chemical
-	O
induced	O
myelotoxicity	B-Disease
in	O
the	O
overall	O
treated	O
population	O
,	O
although	O
a	O
beneficial	O
effect	O
in	O
certain	O
subgroups	O
of	O
patients	O
cannot	O
be	O
excluded	O
.	O

Safety	O
and	O
side	O
-	O
effects	O
of	O
alprazolam	B-Chemical
.	O

Controlled	O
study	O
in	O
agoraphobia	B-Disease
with	O
panic	B-Disease
disorder	I-Disease
.	O

BACKGROUND	O
:	O
The	O
widespread	O
use	O
of	O
benzodiazepines	B-Chemical
has	O
led	O
to	O
increasing	O
recognition	O
of	O
their	O
unwanted	O
effects	O
.	O

The	O
efficacy	O
of	O
alprazolam	B-Chemical
and	O
placebo	O
in	O
panic	B-Disease
disorder	I-Disease
with	O
agoraphobia	B-Disease
,	O
and	O
the	O
side	O
-	O
effect	O
and	O
adverse	O
effect	O
profiles	O
of	O
both	O
drug	O
groups	O
were	O
measured	O
.	O

METHOD	O
:	O
In	O
London	O
and	O
Toronto	O
154	O
patients	O
who	O
met	O
DSM	O
-	O
III	O
criteria	O
for	O
panic	B-Disease
disorder	I-Disease
with	O
agoraphobia	B-Disease
were	O
randomised	O
to	O
alprazolam	B-Chemical
or	O
placebo	O
.	O

Subjects	O
in	O
each	O
drug	O
group	O
also	O
received	O
either	O
exposure	O
or	O
relaxation	O
.	O

Treatment	O
was	O
from	O
weeks	O
0	O
to	O
8	O
and	O
was	O
then	O
tapered	O
from	O
weeks	O
8	O
to	O
16	O
.	O

RESULTS	O
:	O
Mean	O
alprazolam	B-Chemical
dose	O
was	O
5	O
mg	O
daily	O
.	O

Compared	O
with	O
placebo	O
subjects	O
,	O
alprazolam	B-Chemical
patients	O
developed	O
more	O
adverse	O
reactions	O
(	O
21	O
%	O
v	O
.	O
0	O
%	O
)	O
of	O
depression	B-Disease
,	O
enuresis	B-Disease
,	O
disinhibition	O
and	O
aggression	B-Disease
;	O
and	O
more	O
side	O
-	O
effects	O
,	O
particularly	O
sedation	O
,	O
irritability	B-Disease
,	O
impaired	B-Disease
memory	I-Disease
,	O
weight	B-Disease
loss	I-Disease
and	O
ataxia	B-Disease
.	O

Side	O
-	O
effects	O
tended	O
to	O
diminish	O
during	O
treatment	O
but	O
remained	O
significant	O
at	O
week	O
8	O
.	O

Despite	O
this	O
,	O
the	O
drop	O
-	O
out	O
rate	O
was	O
low	O
.	O

CONCLUSIONS	O
:	O
Alprazolam	B-Chemical
caused	O
side	O
-	O
effects	O
and	O
adverse	O
effects	O
during	O
treatment	O
but	O
many	O
patients	O
were	O
willing	O
to	O
accept	O
these	O
.	O

Crescentic	O
fibrillary	O
glomerulonephritis	B-Disease
associated	O
with	O
intermittent	O
rifampin	B-Chemical
therapy	O
for	O
pulmonary	B-Disease
tuberculosis	I-Disease
.	O

This	O
case	O
study	O
reveals	O
an	O
unusual	O
finding	O
of	O
rapidly	O
proliferative	O
crescentic	O
glomerulonephritis	B-Disease
in	O
a	O
patient	O
treated	O
with	O
rifampin	B-Chemical
who	O
had	O
no	O
other	O
identifiable	O
causes	O
for	O
developing	O
this	O
disease	O
.	O

This	O
patient	O
underwent	O
a	O
10	O
-	O
month	O
regimen	O
of	O
rifampin	B-Chemical
and	O
isoniazid	B-Chemical
for	O
pulmonary	B-Disease
tuberculosis	I-Disease
and	O
was	O
discovered	O
to	O
have	O
developed	O
signs	O
of	O
severe	O
renal	B-Disease
failure	I-Disease
five	O
weeks	O
after	O
completion	O
of	O
therapy	O
.	O

Renal	O
biopsy	O
revealed	O
severe	O
glomerulonephritis	B-Disease
with	O
crescents	O
,	O
electron	O
dense	O
fibrillar	O
deposits	O
and	O
moderate	O
lymphocytic	O
interstitial	O
infiltrate	O
.	O

Other	O
possible	O
causes	O
of	O
rapidly	O
progressive	O
glomerulonephritis	B-Disease
were	O
investigated	O
and	O
ruled	O
out	O
.	O

This	O
report	O
documents	O
the	O
unusual	O
occurrence	O
of	O
rapidly	O
progressive	O
glomerulonephritis	B-Disease
with	O
crescents	O
and	O
fibrillar	O
glomerulonephritis	B-Disease
in	O
a	O
patient	O
treated	O
with	O
rifampin	B-Chemical
.	O

Acute	O
confusion	B-Disease
induced	O
by	O
a	O
high	O
-	O
dose	O
infusion	O
of	O
5	B-Chemical
-	I-Chemical
fluorouracil	I-Chemical
and	O
folinic	B-Chemical
acid	I-Chemical
.	O

A	O
61	O
-	O
year	O
-	O
old	O
man	O
was	O
treated	O
with	O
combination	O
chemotherapy	O
incorporating	O
cisplatinum	B-Chemical
,	O
etoposide	B-Chemical
,	O
high	O
-	O
dose	O
5	B-Chemical
-	I-Chemical
fluorouracil	I-Chemical
(	O
2	O
,	O
250	O
mg	O
/	O
m2	O
/	O
24	O
hours	O
)	O
and	O
folinic	B-Chemical
acid	I-Chemical
for	O
an	O
inoperable	O
gastric	B-Disease
adenocarcinoma	I-Disease
.	O

He	O
developed	O
acute	O
neurologic	O
symptoms	O
of	O
mental	O
confusion	B-Disease
,	O
disorientation	B-Disease
and	O
irritability	B-Disease
,	O
and	O
then	O
lapsed	O
into	O
a	O
deep	O
coma	B-Disease
,	O
lasting	O
for	O
approximately	O
40	O
hours	O
during	O
the	O
first	O
dose	O
(	O
day	O
2	O
)	O
of	O
5	B-Chemical
-	I-Chemical
fluorouracil	I-Chemical
and	O
folinic	B-Chemical
acid	I-Chemical
infusion	O
.	O

This	O
complication	O
reappeared	O
on	O
day	O
25	O
during	O
the	O
second	O
dose	O
of	O
5	B-Chemical
-	I-Chemical
fluorouracil	I-Chemical
and	O
folinic	B-Chemical
acid	I-Chemical
,	O
which	O
were	O
then	O
the	O
only	O
drugs	O
given	O
.	O

Because	O
folinic	B-Chemical
acid	I-Chemical
was	O
unlikely	O
to	O
be	O
associated	O
with	O
this	O
condition	O
,	O
neurotoxicity	B-Disease
due	O
to	O
high	O
-	O
dose	O
5	B-Chemical
-	I-Chemical
fluorouracil	I-Chemical
was	O
highly	O
suspected	O
.	O

The	O
pathogenesis	O
of	O
5	B-Chemical
-	I-Chemical
fluorouracil	I-Chemical
neurotoxicity	B-Disease
may	O
be	O
due	O
to	O
a	O
Krebs	O
cycle	O
blockade	O
by	O
fluoroacetate	B-Chemical
and	O
fluorocitrate	B-Chemical
,	O
thiamine	B-Chemical
deficiency	O
,	O
or	O
dihydrouracil	B-Chemical
dehydrogenase	O
deficiency	O
.	O

High	O
-	O
dose	O
5	B-Chemical
-	I-Chemical
fluorouracil	I-Chemical
/	O
folinic	B-Chemical
acid	I-Chemical
infusion	O
therapy	O
has	O
recently	O
become	O
a	O
popular	O
regimen	O
for	O
various	O
cancers	B-Disease
.	O

It	O
is	O
necessary	O
that	O
both	O
oncologists	O
and	O
neurologists	O
be	O
fully	O
aware	O
of	O
this	O
unusual	O
complication	O
.	O

Effect	O
of	O
switching	O
carbamazepine	B-Chemical
to	O
oxcarbazepine	B-Chemical
on	O
the	O
plasma	O
levels	O
of	O
neuroleptics	O
.	O

A	O
case	O
report	O
.	O

Carbamazepine	B-Chemical
was	O
switched	O
to	O
its	O
10	O
-	O
keto	O
analogue	O
oxcarbazepine	B-Chemical
among	O
six	O
difficult	O
-	O
to	O
-	O
treat	O
schizophrenic	B-Disease
or	O
organic	B-Disease
psychotic	I-Disease
patients	O
using	O
concomitantly	O
haloperidol	B-Chemical
,	O
chlorpromazine	B-Chemical
or	O
clozapine	B-Chemical
.	O

This	O
change	O
resulted	O
within	O
2	O
-	O
4	O
weeks	O
in	O
the	O
50	O
-	O
200	O
%	O
increase	O
in	O
the	O
plasma	O
levels	O
of	O
these	O
neuroleptics	O
and	O
the	O
appearance	O
of	O
extrapyramidal	B-Disease
symptoms	I-Disease
.	O

None	O
of	O
the	O
patients	O
showed	O
any	O
clinical	O
deteriotation	O
during	O
the	O
following	O
3	O
-	O
6	O
months	O
.	O

The	O
results	O
of	O
this	O
case	O
report	O
support	O
the	O
idea	O
that	O
in	O
contrast	O
with	O
carbamazepine	B-Chemical
oxcarbazepine	B-Chemical
does	O
not	O
induce	O
the	O
hepatic	O
microsomal	O
enzyme	O
systems	O
regulating	O
the	O
inactivation	O
of	O
antipsychotic	O
drugs	O
.	O

Time	O
course	O
of	O
lipid	O
peroxidation	O
in	O
puromycin	B-Chemical
aminonucleoside	I-Chemical
-	O
induced	O
nephropathy	B-Disease
.	O

Reactive	O
oxygen	B-Chemical
species	O
have	O
been	O
implicated	O
in	O
the	O
pathogenesis	O
of	O
acute	O
puromycin	B-Chemical
aminonucleoside	I-Chemical
(	O
PAN	B-Chemical
)	O
-	O
induced	O
nephropathy	B-Disease
,	O
with	O
antioxidants	O
significantly	O
reducing	O
the	O
proteinuria	B-Disease
.	O

The	O
temporal	O
relationship	O
between	O
lipid	O
peroxidation	O
in	O
the	O
kidney	O
and	O
proteinuria	B-Disease
was	O
examined	O
in	O
this	O
study	O
.	O

Rats	O
were	O
treated	O
with	O
a	O
single	O
IV	O
injection	O
of	O
puromycin	B-Chemical
aminonucleoside	I-Chemical
,	O
(	O
PAN	B-Chemical
,	O
7	O
.	O
5	O
mg	O
/	O
kg	O
)	O
and	O
24	O
hour	O
urine	O
samples	O
were	O
obtained	O
prior	O
to	O
sacrifice	O
on	O
days	O
3	O
,	O
5	O
,	O
7	O
,	O
10	O
,	O
17	O
,	O
27	O
,	O
41	O
(	O
N	O
=	O
5	O
-	O
10	O
per	O
group	O
)	O
.	O

The	O
kidneys	O
were	O
removed	O
,	O
flushed	O
with	O
ice	O
cold	O
TRIS	O
buffer	O
.	O

Kidney	O
cortices	O
from	O
each	O
animal	O
were	O
used	O
to	O
prepare	O
homogenates	O
.	O

Tissue	O
lipid	O
peroxidation	O
was	O
measured	O
in	O
whole	O
homogenates	O
as	O
well	O
as	O
in	O
lipid	O
extracts	O
from	O
homogenates	O
as	O
thiobarbituric	B-Chemical
acid	I-Chemical
reactive	O
substances	O
.	O

Proteinuria	B-Disease
was	O
evident	O
at	O
day	O
5	O
,	O
peaked	O
at	O
day	O
7	O
and	O
persisted	O
to	O
day	O
27	O
.	O

Lipid	O
peroxidation	O
in	O
homogenates	O
was	O
maximal	O
at	O
day	O
3	O
and	O
declined	O
rapidly	O
to	O
control	O
levels	O
by	O
day	O
17	O
.	O

This	O
study	O
supports	O
the	O
role	O
of	O
lipid	O
peroxidation	O
in	O
mediating	O
the	O
proteinuric	B-Disease
injury	I-Disease
in	O
PAN	B-Chemical
nephropathy	B-Disease
.	O

Composition	O
of	O
gall	B-Disease
bladder	I-Disease
stones	I-Disease
associated	O
with	O
octreotide	B-Chemical
:	O
response	O
to	O
oral	O
ursodeoxycholic	B-Chemical
acid	I-Chemical
.	O

Octreotide	B-Chemical
,	O
an	O
effective	O
treatment	O
for	O
acromegaly	B-Disease
,	O
induces	O
gall	B-Disease
bladder	I-Disease
stones	I-Disease
in	O
13	O
-	O
60	O
%	O
of	O
patients	O
.	O

Because	O
knowledge	O
of	O
stone	O
composition	O
is	O
essential	O
for	O
studies	O
of	O
their	O
pathogenesis	O
,	O
treatment	O
,	O
and	O
prevention	O
,	O
this	O
was	O
investigated	O
by	O
direct	O
and	O
indirect	O
methods	O
in	O
14	O
octreotide	B-Chemical
treated	O
acromegalic	B-Disease
patients	O
with	O
gall	B-Disease
stones	I-Disease
.	O

Chemical	O
analysis	O
of	O
gall	B-Disease
stones	I-Disease
retrieved	O
at	O
cholecystectomy	O
from	O
two	O
patients	O
,	O
showed	O
that	O
they	O
contained	O
71	O
%	O
and	O
87	O
%	O
cholesterol	B-Chemical
by	O
weight	O
.	O

In	O
the	O
remaining	O
12	O
patients	O
,	O
localised	O
computed	O
tomography	O
of	O
the	O
gall	O
bladder	O
showed	O
that	O
eight	O
had	O
stones	O
with	O
maximum	O
attenuation	O
scores	O
of	O
<	O
100	O
Hounsfield	O
units	O
(	O
values	O
of	O
<	O
100	O
HU	O
predict	O
cholesterol	B-Chemical
rich	O
,	O
dissolvable	O
stones	O
)	O
.	O

Gall	O
bladder	O
bile	O
was	O
obtained	O
by	O
ultrasound	O
guided	O
,	O
fine	O
needle	O
puncture	O
from	O
six	O
patients	O
.	O

All	O
six	O
patients	O
had	O
supersaturated	O
bile	O
(	O
mean	O
(	O
SEM	O
)	O
cholesterol	B-Chemical
saturation	O
index	O
of	O
1	O
.	O
19	O
(	O
0	O
.	O
08	O
)	O
(	O
range	O
1	O
.	O
01	O
-	O
1	O
.	O
53	O
)	O
)	O
and	O
all	O
had	O
abnormally	O
rapid	O
cholesterol	B-Chemical
microcrystal	O
nucleation	O
times	O
(	O
<	O
4	O
days	O
(	O
range	O
1	O
-	O
4	O
)	O
)	O
,	O
whilst	O
in	O
four	O
,	O
the	O
bile	O
contained	O
cholesterol	B-Chemical
microcrystals	O
immediately	O
after	O
sampling	O
.	O

Of	O
the	O
12	O
patients	O
considered	O
for	O
oral	O
ursodeoxycholic	B-Chemical
acid	I-Chemical
(	O
UDCA	B-Chemical
)	O
treatment	O
,	O
two	O
had	O
a	O
blocked	O
cystic	O
duct	O
and	O
were	O
not	O
started	O
on	O
UDCA	B-Chemical
while	O
one	O
was	O
lost	O
to	O
follow	O
up	O
.	O

After	O
one	O
year	O
of	O
treatment	O
,	O
five	O
of	O
the	O
remaining	O
nine	O
patients	O
showed	O
either	O
partial	O
(	O
n	O
=	O
3	O
)	O
or	O
complete	O
(	O
n	O
=	O
2	O
)	O
gall	B-Disease
stone	I-Disease
dissolution	O
,	O
suggesting	O
that	O
their	O
stones	O
were	O
cholesterol	B-Chemical
rich	O
.	O

This	O
corresponds	O
,	O
by	O
actuarial	O
(	O
life	O
table	O
)	O
analysis	O
,	O
to	O
a	O
combined	O
gall	B-Disease
stone	I-Disease
dissolution	O
rate	O
of	O
58	O
.	O
3	O
(	O
15	O
.	O
9	O
%	O
)	O
.	O

In	O
conclusion	O
,	O
octreotide	B-Chemical
induced	O
gall	B-Disease
stones	I-Disease
are	O
generally	O
small	O
,	O
multiple	O
,	O
and	O
cholesterol	B-Chemical
rich	O
although	O
,	O
in	O
common	O
with	O
spontaneous	O
gall	B-Disease
stone	I-Disease
disease	I-Disease
,	O
at	O
presentation	O
some	O
patients	O
will	O
have	O
a	O
blocked	O
cystic	O
duct	O
and	O
some	O
gall	B-Disease
stones	I-Disease
containing	O
calcium	B-Chemical
.	O

Erythema	B-Disease
multiforme	I-Disease
and	O
hypersensitivity	B-Disease
myocarditis	I-Disease
caused	O
by	O
ampicillin	B-Chemical
.	O

OBJECTIVE	O
:	O
To	O
report	O
a	O
case	O
of	O
erythema	B-Disease
multiforme	I-Disease
and	O
hypersensitivity	B-Disease
myocarditis	I-Disease
caused	O
by	O
ampicillin	B-Chemical
.	O

CASE	O
SUMMARY	O
:	O
A	O
13	O
-	O
year	O
-	O
old	O
boy	O
was	O
treated	O
with	O
ampicillin	B-Chemical
and	O
gentamicin	B-Chemical
because	O
of	O
suspected	O
septicemia	B-Disease
.	O

Medications	O
were	O
discontinued	O
when	O
erythema	B-Disease
multiforme	I-Disease
and	O
congestive	B-Disease
heart	I-Disease
failure	I-Disease
caused	O
by	O
myocarditis	B-Disease
occurred	O
.	O

The	O
patient	O
was	O
treated	O
with	O
methylprednisolone	B-Chemical
and	O
gradually	O
improved	O
.	O

Macrophage	O
-	O
migration	O
inhibition	O
(	O
MIF	O
)	O
test	O
with	O
ampicillin	B-Chemical
was	O
positive	O
.	O

DISCUSSION	O
:	O
After	O
most	O
infections	B-Disease
causing	O
erythema	B-Disease
multiforme	I-Disease
and	O
myocarditis	B-Disease
were	O
ruled	O
out	O
,	O
a	O
drug	B-Disease
-	I-Disease
induced	I-Disease
allergic	I-Disease
reaction	I-Disease
was	O
suspected	O
.	O

Positive	O
MIF	O
test	O
for	O
ampicillin	B-Chemical
showed	O
sensitization	O
of	O
the	O
patient	O
'	O
s	O
lymphocytes	O
to	O
ampicillin	B-Chemical
.	O

CONCLUSIONS	O
:	O
Hypersensitivity	B-Disease
myocarditis	I-Disease
is	O
a	O
rare	O
and	O
dangerous	O
manifestation	O
of	O
allergy	B-Disease
to	O
penicillins	B-Chemical
.	O

Clomipramine	B-Chemical
-	O
induced	O
sleep	B-Disease
disturbance	I-Disease
does	O
not	O
impair	O
its	O
prolactin	O
-	O
releasing	O
action	O
.	O

The	O
present	O
study	O
was	O
undertaken	O
to	O
examine	O
the	O
role	O
of	O
sleep	B-Disease
disturbance	I-Disease
,	O
induced	O
by	O
clomipramine	B-Chemical
administration	O
,	O
on	O
the	O
secretory	O
rate	O
of	O
prolactin	O
(	O
PRL	O
)	O
in	O
addition	O
to	O
the	O
direct	O
drug	O
effect	O
.	O

Two	O
groups	O
of	O
supine	O
subjects	O
were	O
studied	O
under	O
placebo	O
-	O
controlled	O
conditions	O
,	O
one	O
during	O
the	O
night	O
,	O
when	O
sleeping	O
(	O
n	O
=	O
7	O
)	O
and	O
the	O
other	O
at	O
daytime	O
,	O
when	O
awake	O
(	O
n	O
=	O
6	O
)	O
.	O

Each	O
subject	O
received	O
a	O
single	O
50	O
mg	O
dose	O
of	O
clomipramine	B-Chemical
given	O
orally	O
2	O
hours	O
before	O
blood	O
collection	O
.	O

Plasma	O
PRL	O
concentrations	O
were	O
analysed	O
at	O
10	O
min	O
intervals	O
and	O
underlying	O
secretory	O
rates	O
calculated	O
by	O
a	O
deconvolution	O
procedure	O
.	O

For	O
both	O
experiments	O
the	O
drug	O
intake	O
led	O
to	O
significant	O
increases	O
in	O
PRL	O
secretion	O
,	O
acting	O
preferentially	O
on	O
tonic	O
secretion	O
as	O
pulse	O
amplitude	O
and	O
frequency	O
did	O
not	O
differ	O
significantly	O
from	O
corresponding	O
control	O
values	O
.	O

During	O
the	O
night	O
clomipramine	B-Chemical
ingestion	O
altered	O
the	O
complete	O
sleep	O
architecture	O
in	O
that	O
it	O
suppressed	O
REM	O
sleep	O
and	O
the	O
sleep	O
cycles	O
and	O
induced	O
increased	O
wakefulness	O
.	O

As	O
the	O
relative	O
increase	O
in	O
PRL	O
secretion	O
expressed	O
as	O
a	O
percentage	O
of	O
the	O
mean	O
did	O
not	O
significantly	O
differ	O
between	O
the	O
night	O
and	O
day	O
time	O
studies	O
(	O
46	O
+	O
/	O
-	O
19	O
%	O
vs	O
34	O
+	O
/	O
-	O
10	O
%	O
)	O
,	O
it	O
can	O
be	O
concluded	O
that	O
the	O
observed	O
sleep	B-Disease
disturbance	I-Disease
did	O
not	O
interfere	O
with	O
the	O
drug	O
action	O
per	O
se	O
.	O

The	O
presence	O
of	O
REM	O
sleep	O
was	O
shown	O
not	O
to	O
be	O
a	O
determining	O
factor	O
either	O
for	O
secretory	O
pulse	O
amplitude	O
and	O
frequency	O
,	O
as	O
,	O
for	O
both	O
,	O
mean	O
nocturnal	O
values	O
were	O
similar	O
with	O
and	O
without	O
prior	O
clomipramine	B-Chemical
ingestion	O
.	O

Survey	O
of	O
complications	O
of	O
indocyanine	B-Chemical
green	I-Chemical
angiography	O
in	O
Japan	O
.	O

PURPOSE	O
:	O
We	O
evaluated	O
the	O
safety	O
of	O
indocyanine	B-Chemical
green	I-Chemical
for	O
use	O
in	O
fundus	O
angiography	O
.	O

METHODS	O
:	O
We	O
sent	O
a	O
questionnaire	O
concerning	O
complications	O
of	O
indocyanine	B-Chemical
green	I-Chemical
to	O
32	O
institutions	O
in	O
Japan	O
,	O
which	O
were	O
selected	O
on	O
the	O
basis	O
of	O
the	O
client	O
list	O
from	O
the	O
Topcon	O
Company	O
,	O
which	O
manufactures	O
the	O
indocyanine	B-Chemical
green	I-Chemical
fundus	O
camera	O
.	O

RESULTS	O
:	O
Ophthalmologists	O
at	O
15	O
institutions	O
responded	O
,	O
reporting	O
a	O
total	O
of	O
3	O
,	O
774	O
indocyanine	B-Chemical
green	I-Chemical
angiograms	O
performed	O
on	O
2	O
,	O
820	O
patients	O
between	O
June	O
1984	O
and	O
September	O
1992	O
.	O

Before	O
angiography	O
,	O
intradermal	O
or	O
intravenous	O
indocyanine	B-Chemical
green	I-Chemical
testing	O
,	O
or	O
both	O
was	O
performed	O
at	O
13	O
of	O
15	O
institutions	O
.	O

For	O
three	O
patients	O
,	O
the	O
decision	O
was	O
made	O
not	O
to	O
proceed	O
with	O
angiography	O
after	O
positive	O
preangiographic	O
testing	O
.	O

The	O
dosage	O
of	O
indocyanine	B-Chemical
green	I-Chemical
used	O
for	O
angiography	O
varied	O
from	O
25	O
to	O
75	O
mg	O
,	O
depending	O
upon	O
the	O
institution	O
.	O

There	O
were	O
13	O
cases	O
of	O
adverse	O
reactions	O
(	O
0	O
.	O
34	O
%	O
)	O
,	O
ten	O
of	O
which	O
were	O
mild	O
reactions	O
such	O
as	O
nausea	B-Disease
,	O
exanthema	B-Disease
,	O
urtication	B-Disease
,	O
itchiness	B-Disease
,	O
and	O
urgency	O
to	O
defecate	O
,	O
and	O
did	O
not	O
require	O
treatment	O
.	O

Also	O
recorded	O
were	O
one	O
case	O
of	O
pain	B-Disease
of	O
the	O
vein	O
,	O
which	O
required	O
treatment	O
,	O
and	O
two	O
cases	O
of	O
hypotension	B-Disease
.	O

The	O
two	O
hypotensive	B-Disease
patients	O
required	O
treatment	O
for	O
shock	B-Disease
.	O

CONCLUSIONS	O
:	O
A	O
comparison	O
of	O
frequency	O
of	O
adverse	O
reactions	O
to	O
indocyanine	B-Chemical
green	I-Chemical
with	O
the	O
previously	O
reported	O
frequency	O
of	O
such	O
reactions	O
to	O
fluorescein	B-Chemical
sodium	I-Chemical
indicated	O
that	O
indocyanine	B-Chemical
green	I-Chemical
is	O
a	O
safe	O
as	O
fluorescein	B-Chemical
for	O
use	O
in	O
angiography	O
.	O

Angioedema	B-Disease
following	O
the	O
intravenous	O
administration	O
of	O
metoprolol	B-Chemical
.	O

A	O
72	O
-	O
year	O
-	O
old	O
woman	O
was	O
admitted	O
to	O
the	O
hospital	O
with	O
"	O
flash	O
"	O
pulmonary	B-Disease
edema	I-Disease
,	O
preceded	O
by	O
chest	B-Disease
pain	I-Disease
,	O
requiring	O
intubation	O
.	O

Her	O
medical	O
history	O
included	O
coronary	B-Disease
artery	I-Disease
disease	I-Disease
with	O
previous	O
myocardial	B-Disease
infarctions	I-Disease
,	O
hypertension	B-Disease
,	O
and	O
diabetes	B-Disease
mellitus	I-Disease
.	O

A	O
history	O
of	O
angioedema	B-Disease
secondary	O
to	O
lisinopril	B-Chemical
therapy	O
was	O
elicited	O
.	O

Current	O
medications	O
did	O
not	O
include	O
angiotensin	B-Chemical
-	O
converting	O
enzyme	O
inhibitors	O
or	O
beta	O
-	O
blockers	O
.	O

She	O
had	O
no	O
previous	O
beta	O
-	O
blocking	O
drug	O
exposure	O
.	O

During	O
the	O
first	O
day	O
of	O
hospitalization	O
(	O
while	O
intubated	O
)	O
,	O
intravenous	O
metoprolol	B-Chemical
was	O
given	O
,	O
resulting	O
in	O
severe	O
angioedema	B-Disease
.	O

The	O
angioedema	B-Disease
resolved	O
after	O
therapy	O
with	O
intravenous	O
steroids	B-Chemical
and	O
diphenhydramine	B-Chemical
hydrochloride	O
.	O

Effect	O
of	O
coniine	B-Chemical
on	O
the	O
developing	O
chick	O
embryo	O
.	O

Coniine	B-Chemical
,	O
an	O
alkaloid	O
from	O
Conium	O
maculatum	O
(	O
poison	O
hemlock	O
)	O
,	O
has	O
been	O
shown	O
to	O
be	O
teratogenic	O
in	O
livestock	O
.	O

The	O
major	O
teratogenic	O
outcome	O
is	O
arthrogryposis	B-Disease
,	O
presumably	O
due	O
to	O
nicotinic	O
receptor	O
blockade	O
.	O

However	O
,	O
coniine	B-Chemical
has	O
failed	O
to	O
produce	O
arthrogryposis	B-Disease
in	O
rats	O
or	O
mice	O
and	O
is	O
only	O
weakly	O
teratogenic	O
in	O
rabbits	O
.	O

The	O
purpose	O
of	O
this	O
study	O
was	O
to	O
evaluate	O
and	O
compare	O
the	O
effects	O
of	O
coniine	B-Chemical
and	O
nicotine	B-Chemical
in	O
the	O
developing	O
chick	O
.	O

Concentrations	O
of	O
coniine	B-Chemical
and	O
nicotine	B-Chemical
sulfate	O
were	O
0	O
.	O
015	O
%	O
,	O
0	O
.	O
03	O
%	O
,	O
0	O
.	O
075	O
%	O
,	O
0	O
.	O
15	O
%	O
,	O
0	O
.	O
75	O
%	O
,	O
1	O
.	O
5	O
%	O
,	O
3	O
%	O
,	O
and	O
6	O
%	O
and	O
1	O
%	O
,	O
5	O
%	O
,	O
and	O
10	O
%	O
,	O
respectively	O
.	O

Both	O
compounds	O
caused	O
deformations	B-Disease
and	O
lethality	O
in	O
a	O
dose	O
-	O
dependent	O
manner	O
.	O

All	O
concentrations	O
of	O
nicotine	B-Chemical
sulfate	O
caused	O
some	O
lethality	O
but	O
a	O
no	O
effect	O
level	O
for	O
coniine	B-Chemical
lethality	O
was	O
0	O
.	O
75	O
%	O
.	O

The	O
deformations	B-Disease
caused	O
by	O
both	O
coniine	B-Chemical
and	O
nicotine	B-Chemical
sulfate	O
were	O
excessive	B-Disease
flexion	I-Disease
or	I-Disease
extension	I-Disease
of	I-Disease
one	I-Disease
or	I-Disease
more	I-Disease
toes	I-Disease
.	O

No	O
histopathological	O
alterations	O
or	O
differences	O
in	O
bone	O
formation	O
were	O
seen	O
in	O
the	O
limbs	O
or	O
toes	O
of	O
any	O
chicks	O
from	O
any	O
group	O
;	O
however	O
,	O
extensive	O
cranial	B-Disease
hemorrhage	I-Disease
occurred	O
in	O
all	O
nicotine	B-Chemical
sulfate	O
-	O
treated	O
chicks	O
.	O

There	O
was	O
a	O
statistically	O
significant	O
(	O
P	O
<	O
or	O
=	O
0	O
.	O
01	O
)	O
decrease	O
in	O
movement	O
in	O
coniine	B-Chemical
and	O
nicotine	B-Chemical
sulfate	O
treated	O
chicks	O
as	O
determined	O
by	O
ultrasound	O
.	O

Control	O
chicks	O
were	O
in	O
motion	O
an	O
average	O
of	O
33	O
.	O
67	O
%	O
of	O
the	O
time	O
,	O
while	O
coniine	B-Chemical
-	O
treated	O
chicks	O
were	O
only	O
moving	O
8	O
.	O
95	O
%	O
of	O
a	O
5	O
-	O
min	O
interval	O
,	O
and	O
no	O
movement	O
was	O
observed	O
for	O
nicotine	B-Chemical
sulfate	O
treated	O
chicks	O
.	O

In	O
summary	O
,	O
the	O
chick	O
embryo	O
provides	O
a	O
reliable	O
and	O
simple	O
experimental	O
animal	O
model	O
of	O
coniine	B-Chemical
-	O
induced	O
arthrogryposis	B-Disease
.	O

Data	O
from	O
this	O
model	O
support	O
a	O
mechanism	O
involving	O
nicotinic	O
receptor	O
blockade	O
with	O
subsequent	O
decreased	O
fetal	O
movement	O
.	O

Immediate	O
allergic	B-Disease
reactions	I-Disease
to	O
amoxicillin	B-Chemical
.	O

A	O
large	O
group	O
of	O
patients	O
with	O
suspected	O
allergic	B-Disease
reactions	I-Disease
to	O
beta	B-Chemical
-	I-Chemical
lactam	I-Chemical
antibiotics	O
was	O
evaluated	O
.	O

A	O
detailed	O
clinical	O
history	O
,	O
together	O
with	O
skin	O
tests	O
,	O
RAST	O
(	O
radioallergosorbent	O
test	O
)	O
,	O
and	O
controlled	O
challenge	O
tests	O
,	O
was	O
used	O
to	O
establish	O
whether	O
patients	O
allergic	B-Disease
to	O
beta	B-Chemical
-	I-Chemical
lactam	I-Chemical
antibiotics	O
had	O
selective	O
immediate	O
allergic	B-Disease
responses	O
to	O
amoxicillin	B-Chemical
(	O
AX	B-Chemical
)	O
or	O
were	O
cross	O
-	O
reacting	O
with	O
other	O
penicillin	B-Chemical
derivatives	O
.	O

Skin	O
tests	O
were	O
performed	O
with	O
benzylpenicilloyl	B-Chemical
-	I-Chemical
poly	I-Chemical
-	I-Chemical
L	I-Chemical
-	I-Chemical
lysine	I-Chemical
(	O
BPO	B-Chemical
-	I-Chemical
PLL	I-Chemical
)	O
,	O
benzylpenicilloate	B-Chemical
,	O
benzylpenicillin	B-Chemical
(	O
PG	B-Chemical
)	O
,	O
ampicillin	B-Chemical
(	O
AMP	B-Chemical
)	O
,	O
and	O
AX	B-Chemical
.	O

RAST	O
for	O
BPO	B-Chemical
-	I-Chemical
PLL	I-Chemical
and	O
AX	B-Chemical
-	O
PLL	O
was	O
done	O
.	O

When	O
both	O
skin	O
test	O
and	O
RAST	O
for	O
BPO	B-Chemical
were	O
negative	O
,	O
single	O
-	O
blind	O
,	O
placebo	O
-	O
controlled	O
challenge	O
tests	O
were	O
done	O
to	O
ensure	O
tolerance	O
of	O
PG	B-Chemical
or	O
sensitivity	O
to	O
AX	B-Chemical
.	O

A	O
total	O
of	O
177	O
patients	O
were	O
diagnosed	O
as	O
allergic	B-Disease
to	O
beta	B-Chemical
-	I-Chemical
lactam	I-Chemical
antibiotics	O
.	O

We	O
selected	O
the	O
54	O
(	O
30	O
.	O
5	O
%	O
)	O
cases	O
of	O
immediate	O
AX	B-Chemical
allergy	B-Disease
with	O
good	O
tolerance	O
of	O
PG	B-Chemical
.	O

Anaphylaxis	B-Disease
was	O
seen	O
in	O
37	O
patients	O
(	O
69	O
%	O
)	O
,	O
the	O
other	O
17	O
(	O
31	O
%	O
)	O
having	O
urticaria	B-Disease
and	O
/	O
or	O
angioedema	B-Disease
.	O

All	O
the	O
patients	O
were	O
skin	O
test	O
negative	O
to	O
BPO	B-Chemical
;	O
49	O
of	O
51	O
(	O
96	O
%	O
)	O
were	O
also	O
negative	O
to	O
MDM	B-Disease
,	O
and	O
44	O
of	O
46	O
(	O
96	O
%	O
)	O
to	O
PG	B-Chemical
.	O

Skin	O
tests	O
with	O
AX	B-Chemical
were	O
positive	O
in	O
34	O
(	O
63	O
%	O
)	O
patients	O
.	O

RAST	O
was	O
positive	O
for	O
AX	B-Chemical
in	O
22	O
patients	O
(	O
41	O
%	O
)	O
and	O
to	O
BPO	B-Chemical
in	O
just	O
5	O
(	O
9	O
%	O
)	O
.	O

None	O
of	O
the	O
sera	O
with	O
negative	O
RAST	O
for	O
AX	B-Chemical
were	O
positive	O
to	O
BPO	B-Chemical
.	O

Challenge	O
tests	O
with	O
AX	B-Chemical
were	O
performed	O
in	O
23	O
subjects	O
(	O
43	O
%	O
)	O
to	O
establish	O
the	O
diagnosis	O
of	O
immediate	O
allergic	B-Disease
reaction	I-Disease
to	O
AX	B-Chemical
,	O
and	O
in	O
15	O
cases	O
(	O
28	O
%	O
)	O
both	O
skin	O
test	O
and	O
RAST	O
for	O
AX	B-Chemical
were	O
negative	O
.	O

PG	B-Chemical
was	O
well	O
tolerated	O
by	O
all	O
54	O
patients	O
.	O

We	O
describe	O
the	O
largest	O
group	O
of	O
AX	B-Chemical
-	O
allergic	B-Disease
patients	O
who	O
have	O
tolerated	O
PG	B-Chemical
reported	O
so	O
far	O
.	O

Diagnosis	O
of	O
these	O
patients	O
can	O
be	O
achieved	O
only	O
if	O
specific	O
AX	B-Chemical
-	O
related	O
reagents	O
are	O
employed	O
.	O

Further	O
studies	O
are	O
necessary	O
to	O
determine	O
the	O
exact	O
extent	O
of	O
this	O
problem	O
and	O
to	O
improve	O
the	O
efficacy	O
of	O
diagnostic	O
methods	O
.	O

Reversal	O
by	O
phenylephrine	B-Chemical
of	O
the	O
beneficial	O
effects	O
of	O
intravenous	O
nitroglycerin	B-Chemical
in	O
patients	O
with	O
acute	B-Disease
myocardial	I-Disease
infarction	I-Disease
.	O

Nitroglycerin	B-Chemical
has	O
been	O
shown	O
to	O
reduce	O
ST	O
-	O
segment	O
elevation	O
during	O
acute	B-Disease
myocardial	I-Disease
infarction	I-Disease
,	O
an	O
effect	O
potentiated	O
in	O
the	O
dog	O
by	O
agents	O
that	O
reverse	O
nitroglycerin	B-Chemical
-	O
induced	O
hypotension	B-Disease
.	O

Our	O
study	O
was	O
designed	O
to	O
determine	O
the	O
effects	O
of	O
combined	O
nitroglycerin	B-Chemical
and	O
phenylephrine	B-Chemical
therapy	O
.	O

Ten	O
patients	O
with	O
acute	O
transmural	O
myocardial	B-Disease
infarctions	I-Disease
received	O
intravenous	O
nitroglycerin	B-Chemical
,	O
sufficient	O
to	O
reduce	O
mean	O
arterial	O
pressure	O
from	O
107	O
+	O
/	O
-	O
6	O
to	O
85	O
+	O
/	O
-	O
6	O
mm	O
Hg	O
(	O
P	O
less	O
than	O
0	O
.	O
001	O
)	O
,	O
for	O
60	O
minutes	O
.	O

Left	O
ventricular	O
filling	O
pressure	O
decreased	O
from	O
19	O
+	O
/	O
-	O
2	O
to	O
11	O
+	O
/	O
-	O
2	O
mm	O
Hg	O
(	O
P	O
less	O
than	O
0	O
.	O
001	O
)	O
.	O

SigmaST	O
,	O
the	O
sum	O
of	O
ST	O
-	O
segment	O
elevations	O
in	O
16	O
precordial	O
leads	O
,	O
decreased	O
(	O
P	O
less	O
than	O
0	O
.	O
02	O
)	O
with	O
intravenous	O
nitroglycerin	B-Chemical
.	O

Subsequent	O
addition	O
of	O
phenylephrine	B-Chemical
infusion	O
,	O
sufficient	O
to	O
re	O
-	O
elevate	O
mean	O
arterial	O
pressure	O
to	O
106	O
+	O
/	O
-	O
4	O
mm	O
Hg	O
(	O
P	O
less	O
than	O
0	O
.	O
001	O
)	O
for	O
30	O
minutes	O
,	O
increased	O
left	O
ventricular	O
filling	O
pressure	O
to	O
17	O
+	O
/	O
-	O
2	O
mm	O
Hg	O
(	O
P	O
less	O
than	O
0	O
.	O
05	O
)	O
and	O
also	O
significantly	O
increased	O
sigmaST	O
(	O
P	O
less	O
than	O
0	O
.	O
05	O
)	O
.	O

Our	O
results	O
suggest	O
that	O
addition	O
of	O
phenylephrine	B-Chemical
to	O
nitroglycerin	B-Chemical
is	O
not	O
beneficial	O
in	O
the	O
treatment	O
of	O
patients	O
with	O
acute	B-Disease
myocardial	I-Disease
infarction	I-Disease
.	O

Acetazolamide	B-Chemical
-	O
induced	O
nephrolithiasis	B-Disease
:	O
implications	O
for	O
treatment	O
of	O
neuromuscular	B-Disease
disorders	I-Disease
.	O

Carbonic	O
anhydrase	O
inhibitors	O
can	O
cause	O
nephrolithiasis	B-Disease
.	O

We	O
studied	O
20	O
patients	O
receiving	O
long	O
-	O
term	O
carbonic	O
anhydrase	O
inhibitor	O
treatment	O
for	O
periodic	O
paralysis	B-Disease
and	O
myotonia	B-Disease
.	O

Three	O
patients	O
on	O
acetazolamide	B-Chemical
(	O
15	O
%	O
)	O
developed	O
renal	B-Disease
calculi	I-Disease
.	O

Extracorporeal	O
lithotripsy	O
successfully	O
removed	O
a	O
renal	B-Disease
calculus	I-Disease
in	O
one	O
patient	O
and	O
surgery	O
removed	O
a	O
staghorn	O
calculus	B-Disease
in	O
another	O
,	O
permitting	O
continued	O
treatment	O
.	O

Renal	O
function	O
remained	O
normal	O
in	O
all	O
patients	O
.	O

Nephrolithiasis	B-Disease
is	O
a	O
complication	O
of	O
acetazolamide	B-Chemical
but	O
does	O
not	O
preclude	O
its	O
use	O
.	O

Effects	O
of	O
calcium	B-Chemical
channel	O
blockers	O
on	O
bupivacaine	B-Chemical
-	O
induced	O
toxicity	B-Disease
.	O

The	O
purpose	O
of	O
this	O
study	O
was	O
to	O
investigate	O
the	O
influence	O
of	O
calcium	B-Chemical
channel	O
blockers	O
on	O
bupivacaine	B-Chemical
-	O
induced	O
acute	O
toxicity	B-Disease
.	O

For	O
each	O
of	O
the	O
three	O
tested	O
calcium	B-Chemical
channel	O
blockers	O
(	O
diltiazem	B-Chemical
,	O
verapamil	B-Chemical
and	O
bepridil	B-Chemical
)	O
6	O
groups	O
of	O
mice	O
were	O
treated	O
by	O
two	O
different	O
doses	O
,	O
i	O
.	O
e	O
.	O
2	O
and	O
10	O
mg	O
/	O
kg	O
/	O
i	O
.	O
p	O
.	O
,	O
or	O
an	O
equal	O
volume	O
of	O
saline	O
for	O
the	O
control	O
group	O
(	O
n	O
=	O
20	O
)	O
;	O
15	O
minutes	O
later	O
,	O
all	O
the	O
animals	O
were	O
injected	O
with	O
a	O
single	O
50	O
mg	O
/	O
kg	O
/	O
i	O
.	O
p	O
.	O
dose	O
of	O
bupivacaine	B-Chemical
.	O

The	O
convulsant	O
activity	O
,	O
the	O
time	O
of	O
latency	O
to	O
convulse	O
and	O
the	O
mortality	O
rate	O
were	O
assessed	O
in	O
each	O
group	O
.	O

The	O
local	O
anesthetic	O
-	O
induced	O
mortality	O
was	O
significantly	O
increased	O
by	O
the	O
three	O
different	O
calcium	B-Chemical
channel	O
blockers	O
.	O

The	O
convulsant	O
activity	O
of	O
bupivacaine	B-Chemical
was	O
not	O
significantly	O
modified	O
but	O
calcium	B-Chemical
channel	O
blockers	O
decreased	O
the	O
time	O
of	O
latency	O
to	O
obtain	O
bupivacaine	B-Chemical
-	O
induced	O
convulsions	B-Disease
;	O
this	O
effect	O
was	O
less	O
pronounced	O
with	O
bepridil	B-Chemical
.	O

Epidural	O
blood	O
flow	O
during	O
prostaglandin	B-Chemical
E1	I-Chemical
or	O
trimethaphan	B-Chemical
induced	O
hypotension	B-Disease
.	O

To	O
evaluate	O
the	O
effect	O
of	O
prostaglandin	B-Chemical
E1	I-Chemical
(	O
PGE1	B-Chemical
)	O
or	O
trimethaphan	B-Chemical
(	O
TMP	B-Chemical
)	O
induced	O
hypotension	B-Disease
on	O
epidural	O
blood	O
flow	O
(	O
EBF	O
)	O
during	O
spinal	O
surgery	O
,	O
EBF	O
was	O
measured	O
using	O
the	O
heat	O
clearance	O
method	O
in	O
30	O
patients	O
who	O
underwent	O
postero	O
-	O
lateral	O
interbody	O
fusion	O
under	O
isoflurane	B-Chemical
anaesthesia	O
.	O

An	O
initial	O
dose	O
of	O
0	O
.	O
1	O
microgram	O
.	O
kg	O
-	O
1	O
.	O
min	O
-	O
1	O
of	O
PGE1	B-Chemical
(	O
15	O
patients	O
)	O
,	O
or	O
10	O
micrograms	O
.	O
kg	O
-	O
1	O
.	O
min	O
-	O
1	O
of	O
TMP	B-Chemical
(	O
15	O
patients	O
)	O
was	O
administered	O
intravenously	O
after	O
the	O
dural	O
opening	O
and	O
the	O
dose	O
was	O
adjusted	O
to	O
maintain	O
the	O
mean	O
arterial	O
blood	O
pressure	O
(	O
MAP	O
)	O
at	O
about	O
60	O
mmHg	O
.	O

The	O
hypotensive	B-Disease
drug	O
was	O
discontinued	O
at	O
the	O
completion	O
of	O
the	O
operative	O
procedure	O
.	O

After	O
starting	O
PGE1	B-Chemical
or	O
TMP	B-Chemical
,	O
MAP	O
and	O
rate	O
pressure	O
product	O
(	O
RPP	O
)	O
decreased	O
significantly	O
compared	O
with	O
preinfusion	O
values	O
(	O
P	O
<	O
0	O
.	O
01	O
)	O
,	O
and	O
the	O
degree	O
of	O
hypotension	B-Disease
due	O
to	O
PGE1	B-Chemical
remained	O
constant	O
until	O
60	O
min	O
after	O
its	O
discontinuation	O
.	O

Heart	O
rate	O
(	O
HR	O
)	O
did	O
not	O
change	O
in	O
either	O
group	O
.	O

EBFF	O
did	O
not	O
change	O
during	O
PGE1	B-Chemical
infusion	O
whereas	O
in	O
the	O
TMP	B-Chemical
group	O
,	O
EBF	O
decreased	O
significantly	O
at	O
30	O
and	O
60	O
min	O
after	O
the	O
start	O
of	O
TMP	B-Chemical
(	O
preinfusion	O
:	O
45	O
.	O
9	O
+	O
/	O
-	O
13	O
.	O
9	O
ml	O
/	O
100g	O
/	O
min	O
.	O
30	O
min	O
:	O
32	O
.	O
3	O
+	O
/	O
-	O
9	O
.	O
9	O
ml	O
/	O
100	O
g	O
/	O
min	O
(	O
P	O
<	O
0	O
.	O
05	O
)	O
.	O
60	O
min	O
:	O
30	O
+	O
/	O
-	O
7	O
.	O
5	O
ml	O
/	O
100	O
g	O
/	O
min	O
(	O
P	O
<	O
0	O
.	O
05	O
)	O
)	O
.	O

These	O
results	O
suggest	O
that	O
PGE1	B-Chemical
may	O
be	O
preferable	O
to	O
TMP	B-Chemical
for	O
hypotensive	B-Disease
anaesthesia	O
in	O
spinal	O
surgery	O
because	O
TMP	B-Chemical
decreased	O
EBF	O
.	O

Dup	B-Chemical
753	I-Chemical
prevents	O
the	O
development	O
of	O
puromycin	B-Chemical
aminonucleoside	I-Chemical
-	O
induced	O
nephrosis	B-Disease
.	O

The	O
appearance	O
of	O
nephrotic	B-Disease
syndromes	I-Disease
such	O
as	O
proteinuria	B-Disease
,	O
hypoalbuminemia	B-Disease
,	O
hypercholesterolemia	B-Disease
and	O
increase	O
in	O
blood	B-Chemical
nitrogen	I-Chemical
urea	I-Chemical
,	O
induced	O
in	O
rats	O
by	O
injection	O
of	O
puromycin	B-Chemical
aminonucleoside	I-Chemical
was	O
markedly	O
inhibited	O
by	O
oral	O
administration	O
of	O
Dup	B-Chemical
753	I-Chemical
(	O
losartan	B-Chemical
)	O
,	O
a	O
novel	O
angiotensin	B-Chemical
II	I-Chemical
receptor	O
antagonist	O
,	O
at	O
a	O
dose	O
of	O
1	O
or	O
2	O
mg	O
/	O
kg	O
per	O
day	O
.	O

The	O
results	O
suggest	O
a	O
possible	O
involvement	O
of	O
the	O
renin	O
-	O
angiotensin	B-Chemical
system	O
in	O
the	O
development	O
of	O
puromycin	B-Chemical
aminonucleoside	I-Chemical
-	O
induced	O
nephrosis	B-Disease
.	O

Neuroplasticity	O
of	O
the	O
adult	O
primate	O
auditory	O
cortex	O
following	O
cochlear	O
hearing	B-Disease
loss	I-Disease
.	O

Tonotopic	O
organization	O
is	O
an	O
essential	O
feature	O
of	O
the	O
primary	O
auditory	O
area	O
(	O
A1	O
)	O
of	O
primate	O
cortex	O
.	O

In	O
A1	O
of	O
macaque	O
monkeys	O
,	O
low	O
frequencies	O
are	O
represented	O
rostrolaterally	O
and	O
high	O
frequencies	O
are	O
represented	O
caudomedially	O
.	O

The	O
purpose	O
of	O
this	O
study	O
was	O
to	O
determine	O
if	O
changes	O
occur	O
in	O
this	O
tonotopic	O
organization	O
following	O
cochlear	O
hearing	B-Disease
loss	I-Disease
.	O

Under	O
anesthesia	O
,	O
the	O
superior	O
temporal	O
gyrus	O
of	O
adult	O
macaque	O
monkeys	O
was	O
exposed	O
,	O
and	O
the	O
tonotopic	O
organization	O
of	O
A1	O
was	O
mapped	O
using	O
conventional	O
microelectrode	O
recording	O
techniques	O
.	O

Following	O
recovery	O
,	O
the	O
monkeys	O
were	O
selectively	O
deafened	O
for	O
high	O
frequencies	O
using	O
kanamycin	B-Chemical
and	O
furosemide	B-Chemical
.	O

The	O
actual	O
frequencies	O
deafened	O
were	O
determined	O
by	O
the	O
loss	O
of	O
tone	O
-	O
burst	O
elicited	O
auditory	O
brainstem	O
responses	O
.	O

Three	O
months	O
after	O
deafening	O
,	O
A1	O
was	O
remapped	O
.	O

Postmortem	O
cytoarchitectural	O
features	O
identifying	O
A1	O
were	O
correlated	O
with	O
the	O
electrophysiologic	O
data	O
.	O

The	O
results	O
indicate	O
that	O
the	O
deprived	O
area	O
of	O
A1	O
undergoes	O
extensive	O
reorganization	O
and	O
becomes	O
responsive	O
to	O
intact	O
cochlear	O
frequencies	O
.	O

The	O
region	O
of	O
cortex	O
that	O
represents	O
the	O
low	O
frequencies	O
was	O
not	O
obviously	O
affected	O
by	O
the	O
cochlear	O
hearing	B-Disease
loss	I-Disease
.	O

Sodium	B-Chemical
bicarbonate	I-Chemical
alleviates	O
penile	B-Disease
pain	I-Disease
induced	O
by	O
intracavernous	O
injections	O
for	O
erectile	B-Disease
dysfunction	I-Disease
.	O

In	O
an	O
attempt	O
to	O
determine	O
whether	O
penile	B-Disease
pain	I-Disease
associated	O
with	O
intracorporeal	O
injections	O
could	O
be	O
due	O
to	O
the	O
acidity	O
of	O
the	O
medication	O
,	O
we	O
performed	O
a	O
randomized	O
study	O
comparing	O
the	O
incidence	O
of	O
penile	B-Disease
pain	I-Disease
following	O
intracorporeal	O
injections	O
with	O
or	O
without	O
the	O
addition	O
of	O
sodium	B-Chemical
bicarbonate	I-Chemical
to	O
the	O
intracorporeal	O
medications	O
.	O

A	O
total	O
of	O
38	O
consecutive	O
patients	O
who	O
presented	O
to	O
our	O
clinic	O
with	O
impotence	B-Disease
received	O
0	O
.	O
2	O
ml	O
.	O
of	O
a	O
combination	O
of	O
3	O
drugs	O
:	O
6	O
mg	O
.	O
papaverine	B-Chemical
,	O
100	O
micrograms	O
.	O
phentolamine	B-Chemical
and	O
10	O
micrograms	O
.	O
prostaglandin	B-Chemical
E1	I-Chemical
with	O
(	O
pH	O
7	O
.	O
05	O
)	O
or	O
without	O
(	O
pH	O
4	O
.	O
17	O
)	O
the	O
addition	O
of	O
sodium	B-Chemical
bicarbonate	I-Chemical
(	O
0	O
.	O
03	O
mEq	O
.	O
)	O
.	O

Of	O
the	O
19	O
patients	O
without	O
sodium	B-Chemical
bicarbonate	I-Chemical
added	O
to	O
the	O
medication	O
11	O
(	O
58	O
%	O
)	O
complained	O
of	O
penile	B-Disease
pain	I-Disease
due	O
to	O
the	O
medication	O
,	O
while	O
only	O
1	O
of	O
the	O
19	O
men	O
(	O
5	O
%	O
)	O
who	O
received	O
sodium	B-Chemical
bicarbonate	I-Chemical
complained	O
of	O
penile	B-Disease
pain	I-Disease
.	O

From	O
these	O
data	O
we	O
conclude	O
that	O
the	O
penile	B-Disease
pain	I-Disease
following	O
intracorporeal	O
injections	O
is	O
most	O
likely	O
due	O
to	O
the	O
acidity	O
of	O
the	O
medication	O
,	O
which	O
can	O
be	O
overcome	O
by	O
elevating	O
the	O
pH	O
to	O
a	O
neutral	O
level	O
.	O

The	O
use	O
and	O
toxicity	B-Disease
of	O
didanosine	B-Chemical
(	O
ddI	B-Chemical
)	O
in	O
HIV	B-Disease
antibody	I-Disease
-	I-Disease
positive	I-Disease
individuals	O
intolerant	O
to	O
zidovudine	B-Chemical
(	O
AZT	B-Chemical
)	O

One	O
hundred	O
and	O
fifty	O
-	O
one	O
patients	O
intolerant	O
to	O
zidovudine	B-Chemical
(	O
AZT	B-Chemical
)	O
received	O
didanosine	B-Chemical
(	O
ddI	B-Chemical
)	O
to	O
a	O
maximum	O
dose	O
of	O
12	O
.	O
5	O
mg	O
/	O
kg	O
/	O
day	O
.	O

Patient	O
response	O
was	O
assessed	O
using	O
changes	O
in	O
CD4	O
+	O
lymphocyte	O
subset	O
count	O
,	O
HIV	O
p24	O
antigen	O
,	O
weight	O
,	O
and	O
quality	O
of	O
life	O
.	O

Seventy	O
patients	O
developed	O
major	O
opportunistic	B-Disease
infections	I-Disease
whilst	O
on	O
therapy	O
;	O
this	O
was	O
the	O
first	O
AIDS	B-Disease
diagnosis	O
in	O
17	O
.	O

Only	O
minor	O
changes	O
in	O
CD4	O
+	O
lymphocyte	O
subset	O
count	O
were	O
observed	O
in	O
AIDS	B-Disease
patients	O
,	O
although	O
a	O
more	O
significant	O
rise	O
occurred	O
in	O
those	O
with	O
earlier	O
stages	O
of	O
disease	O
.	O

Of	O
those	O
positive	O
for	O
p24	O
antigen	O
at	O
the	O
commencement	O
of	O
the	O
study	O
67	O
%	O
showed	O
a	O
positive	O
response	O
,	O
and	O
this	O
was	O
most	O
likely	O
in	O
those	O
with	O
CD4	O
+	O
lymphocyte	O
subset	O
counts	O
above	O
100	O
mm3	O
.	O

A	O
positive	O
weight	O
response	O
was	O
seen	O
in	O
16	O
%	O
of	O
patients	O
.	O

Most	O
patients	O
showed	O
improvement	O
in	O
individual	O
parameters	O
and	O
global	O
score	O
of	O
quality	O
of	O
life	O
.	O

Adverse	O
reactions	O
possibly	O
attributable	O
to	O
didanosine	B-Chemical
were	O
common	O
.	O

The	O
most	O
common	O
side	O
-	O
effect	O
was	O
diarrhoea	B-Disease
,	O
which	O
resulted	O
in	O
cessation	O
of	O
therapy	O
in	O
19	O
individuals	O
.	O

Peripheral	B-Disease
neuropathy	I-Disease
occurred	O
in	O
12	O
patients	O
and	O
pancreatitis	B-Disease
in	O
six	O
.	O

Thirteen	O
patients	O
developed	O
a	O
raised	O
serum	O
amylase	O
without	O
abdominal	B-Disease
pain	I-Disease
.	O

Seven	O
patients	O
developed	O
glucose	B-Disease
tolerance	I-Disease
curves	I-Disease
characteristic	O
of	O
diabetes	B-Disease
but	O
these	O
were	O
mild	O
,	O
did	O
not	O
require	O
treatment	O
and	O
returned	O
to	O
normal	O
on	O
ceasing	O
didanosine	B-Chemical
.	O

Immunohistochemical	O
studies	O
with	O
antibodies	O
to	O
neurofilament	O
proteins	O
on	O
axonal	B-Disease
damage	I-Disease
in	O
experimental	O
focal	O
lesions	O
in	O
rat	O
.	O

Immunohistochemistry	O
with	O
monoclonal	O
antibodies	O
against	O
neurofilament	O
(	O
NF	O
)	O
proteins	O
of	O
middle	O
and	O
high	O
molecular	O
weight	O
class	O
,	O
NF	O
-	O
M	O
and	O
NF	O
-	O
H	O
,	O
was	O
used	O
to	O
study	O
axonal	B-Disease
injury	I-Disease
in	O
the	O
borderzone	O
of	O
focal	O
lesions	O
in	O
rats	O
.	O

Focal	O
injury	B-Disease
in	I-Disease
the	I-Disease
cortex	I-Disease
was	O
produced	O
by	O
infusion	O
of	O
lactate	B-Chemical
at	O
acid	O
pH	O
or	O
by	O
stab	O
caused	O
by	O
needle	O
insertion	O
.	O

Infarcts	B-Disease
in	I-Disease
substantia	I-Disease
nigra	I-Disease
pars	I-Disease
reticulata	I-Disease
were	O
evoked	O
by	O
prolonged	O
pilocarpine	B-Chemical
-	O
induced	O
status	B-Disease
epilepticus	I-Disease
.	O

Immunohistochemical	O
staining	O
for	O
NFs	O
showed	O
characteristic	O
terminal	O
clubs	O
of	O
axons	O
in	O
the	O
borderzone	O
of	O
lesions	O
.	O

Differences	O
in	O
the	O
labelling	O
pattern	O
occurred	O
with	O
different	O
antibodies	O
which	O
apparently	O
depended	O
on	O
molecular	O
weight	O
class	O
of	O
NFs	O
and	O
phosphorylation	O
state	O
.	O

These	O
immunohistochemical	O
changes	O
of	O
NFs	O
can	O
serve	O
as	O
a	O
marker	O
for	O
axonal	B-Disease
damage	I-Disease
in	O
various	O
experimental	O
traumatic	B-Disease
or	O
ischemic	O
lesions	O
.	O

Pharmacokinetic	O
and	O
clinical	O
studies	O
in	O
patients	O
with	O
cimetidine	B-Chemical
-	O
associated	O
mental	O
confusion	B-Disease
.	O

15	O
cases	O
of	O
cimetidine	B-Chemical
-	O
associated	O
mental	O
confusion	B-Disease
have	O
been	O
reported	O
.	O

In	O
order	O
that	O
this	O
syndrome	O
might	O
be	O
investigated	O
changes	O
in	O
mental	O
status	O
(	O
M	O
.	O
S	O
.	O
)	O
were	O
correlated	O
with	O
serum	O
concentrations	O
and	O
renal	O
and	O
hepatic	O
function	O
in	O
36	O
patients	O
,	O
30	O
patients	O
had	O
no	O
M	O
.	O
S	O
.	O
change	O
on	O
cimetidine	B-Chemical
and	O
6	O
had	O
moderate	O
to	O
severe	O
changes	O
.	O

These	O
6	O
patients	O
had	O
both	O
renal	B-Disease
and	I-Disease
liver	I-Disease
dysfunction	I-Disease
(	O
P	O
less	O
than	O
0	O
.	O
05	O
)	O
,	O
as	O
well	O
as	O
cimetidine	B-Chemical
trough	O
-	O
concentrations	O
of	O
more	O
than	O
1	O
.	O
25	O
microgram	O
/	O
ml	O
(	O
P	O
less	O
than	O
0	O
.	O
05	O
)	O
.	O

The	O
severity	O
of	O
M	O
.	O
S	O
.	O
changes	O
increased	O
as	O
trough	O
-	O
concentrations	O
rose	O
,	O
5	O
patients	O
had	O
lumbar	O
puncture	O
.	O

The	O
cerebrospinal	O
fluid	O
:	O
serum	O
ratio	O
of	O
cimetidine	B-Chemical
concentrations	O
was	O
0	O
.	O
24	O
:	O
1	O
and	O
indicates	O
that	O
cimetidine	B-Chemical
passes	O
the	O
blood	O
-	O
brain	O
barrier	O
;	O
it	O
also	O
raises	O
the	O
possibility	O
that	O
M	O
.	O
S	O
.	O
changes	O
are	O
due	O
to	O
blockade	O
of	O
histamine	B-Chemical
H2	O
-	O
receptors	O
in	O
the	O
central	O
nervous	O
system	O
.	O

Patients	O
likely	O
to	O
have	O
both	O
raised	O
trough	O
-	O
concentrations	O
and	O
mental	O
confusion	B-Disease
are	O
those	O
with	O
both	O
severe	O
renal	B-Disease
and	I-Disease
hepatic	I-Disease
dysfunction	I-Disease
.	O

They	O
should	O
be	O
closely	O
observed	O
and	O
should	O
be	O
given	O
reduced	O
doses	O
of	O
cimetidine	B-Chemical
.	O

Prospective	O
study	O
of	O
the	O
long	O
-	O
term	O
effects	O
of	O
somatostatin	O
analog	O
(	O
octreotide	B-Chemical
)	O
on	O
gallbladder	O
function	O
and	O
gallstone	B-Disease
formation	O
in	O
Chinese	O
acromegalic	B-Disease
patients	O
.	O

This	O
article	O
reports	O
the	O
changes	O
in	O
gallbladder	O
function	O
examined	O
by	O
ultrasonography	O
in	O
20	O
Chinese	O
patients	O
with	O
active	O
acromegaly	B-Disease
treated	O
with	O
sc	O
injection	O
of	O
the	O
somatostatin	O
analog	O
octreotide	B-Chemical
in	O
dosages	O
of	O
300	O
-	O
1500	O
micrograms	O
/	O
day	O
for	O
a	O
mean	O
of	O
24	O
.	O
2	O
+	O
/	O
-	O
13	O
.	O
9	O
months	O
.	O

During	O
treatment	O
with	O
octreotide	B-Chemical
,	O
17	O
patients	O
developed	O
sludge	O
,	O
10	O
had	O
gallstones	B-Disease
,	O
and	O
1	O
developed	O
acute	B-Disease
cholecystitis	I-Disease
requiring	O
surgery	O
.	O

In	O
all	O
of	O
7	O
patients	O
examined	O
acutely	O
,	O
gallbladder	O
contractility	O
was	O
inhibited	O
after	O
a	O
single	O
100	O
-	O
micrograms	O
injection	O
.	O

In	O
8	O
patients	O
followed	O
for	O
24	O
weeks	O
,	O
gallbladder	O
contractility	O
remained	O
depressed	B-Disease
throughout	O
therapy	O
.	O

After	O
withdrawal	O
of	O
octreotide	B-Chemical
in	O
10	O
patients	O
without	O
gallstones	B-Disease
,	O
8	O
patients	O
assessed	O
had	O
return	O
of	O
normal	O
gallbladder	O
contractility	O
within	O
1	O
month	O
.	O

In	O
8	O
of	O
the	O
remaining	O
10	O
patients	O
who	O
developed	O
gallstones	B-Disease
during	O
treatment	O
,	O
gallbladder	O
contractility	O
normalized	O
in	O
5	O
patients	O
(	O
3	O
of	O
whom	O
has	O
disappearance	O
of	O
their	O
stones	O
within	O
3	O
weeks	O
)	O
,	O
and	O
remained	O
depressed	B-Disease
in	O
3	O
(	O
2	O
of	O
whom	O
had	O
stones	O
present	O
at	O
6	O
months	O
)	O
.	O

Our	O
results	O
suggest	O
that	O
the	O
suppression	O
of	O
gallbladder	O
contractility	O
is	O
the	O
cause	O
of	O
the	O
successive	O
formation	O
of	O
bile	O
sludge	O
,	O
gallstones	B-Disease
,	O
and	O
cholecystitis	B-Disease
during	O
octreotide	B-Chemical
therapy	O
in	O
Chinese	O
acromegalic	B-Disease
patients	O
.	O

It	O
is	O
therefore	O
very	O
important	O
to	O
follow	O
the	O
changes	O
of	O
gallbladder	O
function	O
during	O
long	O
-	O
term	O
octreotide	B-Chemical
therapy	O
of	O
acromegalic	B-Disease
patients	O
.	O

Increase	O
of	O
Parkinson	B-Disease
disability	I-Disease
after	O
fluoxetine	B-Chemical
medication	O
.	O

Depression	B-Disease
is	O
a	O
major	O
clinical	O
feature	O
of	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
.	O

We	O
report	O
the	O
increased	O
amount	O
of	O
motor	B-Disease
disability	I-Disease
in	O
four	O
patients	O
with	O
idiopathic	B-Disease
Parkinson	I-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
after	O
exposure	O
to	O
the	O
antidepressant	B-Chemical
fluoxetine	B-Chemical
.	O

The	O
possibility	O
of	O
a	O
clinically	O
relevant	O
dopamine	B-Chemical
-	O
antagonistic	O
capacity	O
of	O
fluoxetine	B-Chemical
in	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
patients	O
must	O
be	O
considered	O
.	O

Sinus	B-Disease
arrest	I-Disease
associated	O
with	O
continuous	O
-	O
infusion	O
cimetidine	B-Chemical
.	O

The	O
administration	O
of	O
intermittent	O
intravenous	O
infusions	O
of	O
cimetidine	B-Chemical
is	O
infrequently	O
associated	O
with	O
the	O
development	O
of	O
bradyarrhythmias	B-Disease
.	O

A	O
40	O
-	O
year	O
-	O
old	O
man	O
with	O
leukemia	B-Disease
and	O
no	O
history	O
of	O
cardiac	B-Disease
disease	I-Disease
developed	O
recurrent	O
,	O
brief	O
episodes	O
of	O
apparent	O
sinus	B-Disease
arrest	I-Disease
while	O
receiving	O
continuous	O
-	O
infusion	O
cimetidine	B-Chemical
50	O
mg	O
/	O
hour	O
.	O

The	O
arrhythmias	B-Disease
were	O
temporally	O
related	O
to	O
cimetidine	B-Chemical
administration	O
,	O
disappeared	O
after	O
dechallenge	O
,	O
and	O
did	O
not	O
recur	O
during	O
ranitidine	B-Chemical
treatment	O
.	O

This	O
is	O
the	O
first	O
reported	O
case	O
of	O
sinus	B-Disease
arrest	I-Disease
associated	O
with	O
continuous	O
-	O
infusion	O
cimetidine	B-Chemical
.	O

Phase	O
II	O
trial	O
of	O
vinorelbine	B-Chemical
in	O
metastatic	O
squamous	B-Disease
cell	I-Disease
esophageal	I-Disease
carcinoma	I-Disease
.	O

European	O
Organization	O
for	O
Research	O
and	O
Treatment	O
of	O
Cancer	B-Disease
Gastrointestinal	O
Treat	O
Cancer	B-Disease
Cooperative	O
Group	O
.	O

PURPOSE	O
:	O
To	O
evaluate	O
the	O
response	O
rate	O
and	O
toxic	O
effects	O
of	O
vinorelbine	B-Chemical
(	O
VNB	B-Chemical
)	O
administered	O
as	O
a	O
single	O
agent	O
in	O
metastatic	O
squamous	B-Disease
cell	I-Disease
esophageal	I-Disease
carcinoma	I-Disease
.	O

PATIENTS	O
AND	O
METHODS	O
:	O
Forty	O
-	O
six	O
eligible	O
patients	O
with	O
measurable	O
lesions	O
were	O
included	O
and	O
were	O
stratified	O
according	O
to	O
previous	O
chemotherapy	O
.	O

Thirty	O
patients	O
without	O
prior	O
chemotherapy	O
and	O
16	O
pretreated	O
with	O
cisplatin	B-Chemical
-	O
based	O
chemotherapy	O
were	O
assessable	O
for	O
toxicity	B-Disease
and	O
response	O
.	O

VNB	B-Chemical
was	O
administered	O
weekly	O
as	O
a	O
25	O
-	O
mg	O
/	O
m2	O
short	O
intravenous	O
(	O
i	O
.	O
v	O
.	O
)	O
infusion	O
.	O

RESULTS	O
:	O
Six	O
of	O
30	O
patients	O
(	O
20	O
%	O
)	O
without	O
prior	O
chemotherapy	O
achieved	O
a	O
partial	O
response	O
(	O
PR	O
)	O
(	O
95	O
%	O
confidence	O
interval	O
[	O
CI	O
]	O
,	O
8	O
%	O
to	O
39	O
%	O
)	O
.	O

The	O
median	O
duration	O
of	O
response	O
was	O
21	O
weeks	O
(	O
range	O
,	O
17	O
to	O
28	O
)	O
.	O

One	O
of	O
16	O
patients	O
(	O
6	O
%	O
)	O
with	O
prior	O
chemotherapy	O
had	O
a	O
complete	O
response	O
(	O
CR	O
)	O
of	O
31	O
weeks	O
'	O
duration	O
(	O
95	O
%	O
CI	O
,	O
0	O
%	O
to	O
30	O
%	O
)	O
.	O

The	O
overall	O
response	O
rate	O
(	O
World	O
Health	O
Organization	O
[	O
WHO	O
]	O
criteria	O
)	O
was	O
15	O
%	O
(	O
CR	O
,	O
2	O
%	O
;	O
PR	O
13	O
%	O
;	O
95	O
%	O
CI	O
,	O
6	O
%	O
to	O
29	O
%	O
)	O
.	O

The	O
median	O
dose	O
-	O
intensity	O
(	O
DI	O
)	O
was	O
20	O
mg	O
/	O
m2	O
/	O
wk	O
.	O

VNB	B-Chemical
was	O
well	O
tolerated	O
and	O
zero	O
instances	O
of	O
WHO	O
grade	O
4	O
nonhematologic	O
toxicity	B-Disease
occurred	O
.	O

At	O
least	O
one	O
episode	O
of	O
grade	O
3	O
or	O
4	O
granulocytopenia	B-Disease
was	O
seen	O
in	O
59	O
%	O
of	O
patients	O
.	O

A	O
grade	O
2	O
or	O
3	O
infection	B-Disease
occurred	O
in	O
16	O
%	O
of	O
patients	O
,	O
but	O
no	O
toxic	O
deaths	B-Disease
occurred	O
.	O

Other	O
side	O
effects	O
were	O
rare	O
,	O
and	O
peripheral	B-Disease
neurotoxicity	I-Disease
has	O
been	O
minor	O
(	O
26	O
%	O
grade	O
1	O
)	O
.	O

CONCLUSION	O
:	O
These	O
data	O
indicate	O
that	O
VNB	B-Chemical
is	O
an	O
active	O
agent	O
in	O
metastatic	O
esophageal	B-Disease
squamous	I-Disease
cell	I-Disease
carcinoma	I-Disease
.	O

Given	O
its	O
excellent	O
tolerance	O
profile	O
and	O
low	O
toxicity	B-Disease
,	O
further	O
evaluation	O
of	O
VNB	B-Chemical
in	O
combination	O
therapy	O
is	O
warranted	O
.	O

Evaluation	O
of	O
adverse	O
reactions	O
of	O
aponidine	B-Chemical
hydrochloride	I-Chemical
ophthalmic	O
solution	O
.	O

We	O
prospectively	O
evaluated	O
the	O
adverse	O
reactions	O
of	O
apraclonidine	B-Chemical
in	O
20	O
normal	O
volunteers	O
by	O
instilling	O
a	O
single	O
drop	O
of	O
1	O
%	O
apraclonidine	B-Chemical
in	O
their	O
right	O
eyes	O
.	O

Examinations	O
,	O
including	O
blood	O
pressure	O
,	O
pulse	O
rate	O
,	O
conjunctiva	O
and	O
cornea	O
,	O
intraocular	O
pressure	O
(	O
IOP	O
)	O
,	O
pupil	O
diameter	O
,	O
basal	O
tear	O
secretion	O
and	O
margin	O
reflex	O
distance	O
of	O
both	O
upper	O
and	O
lower	O
eyelids	O
,	O
were	O
performed	O
prior	O
to	O
entry	O
and	O
at	O
1	O
,	O
3	O
,	O
5	O
and	O
7	O
hours	O
after	O
instillation	O
.	O

The	O
ocular	B-Disease
hypotensive	I-Disease
effects	O
were	O
statistically	O
significant	O
for	O
apraclonidine	B-Chemical
-	O
treated	O
eyes	O
throughout	O
the	O
study	O
and	O
also	O
statistically	O
significant	O
for	O
contralateral	O
eyes	O
from	O
three	O
hours	O
after	O
topical	O
administration	O
of	O
1	O
%	O
apraclonidine	B-Chemical
.	O

Decreases	B-Disease
in	I-Disease
systolic	I-Disease
blood	I-Disease
pressure	I-Disease
were	O
statistically	O
,	O
but	O
not	O
clinically	O
,	O
significant	O
.	O

No	O
significant	O
changes	O
in	O
diastolic	O
blood	O
pressure	O
,	O
pulse	O
rate	O
and	O
basal	O
tear	O
secretion	O
were	O
noted	O
.	O

Conjunctival	B-Disease
blanching	I-Disease
and	O
mydriasis	B-Disease
were	O
commonly	O
found	O
.	O

Upper	O
lid	O
retraction	O
was	O
frequently	O
noted	O
.	O

While	O
the	O
elevations	O
of	O
the	O
upper	O
lid	O
margin	O
in	O
most	O
subjects	O
were	O
not	O
more	O
than	O
2	O
mm	O
and	O
did	O
not	O
cause	O
noticeable	O
change	O
in	O
appearance	O
,	O
one	O
subject	O
suffered	O
from	O
mechanical	O
entropion	B-Disease
and	O
marked	O
corneal	B-Disease
abrasion	I-Disease
3	O
hours	O
after	O
instillation	O
of	O
the	O
medication	O
.	O

This	O
may	O
well	O
be	O
a	O
particularly	O
notable	O
finding	O
in	O
Asian	O
people	O
.	O

Thiopentone	B-Chemical
pretreatment	O
for	O
propofol	B-Chemical
injection	O
pain	B-Disease
in	O
ambulatory	O
patients	O
.	O

This	O
study	O
investigated	O
propofol	B-Chemical
injection	O
pain	B-Disease
in	O
patients	O
undergoing	O
ambulatory	O
anaesthesia	O
.	O

In	O
a	O
randomized	O
,	O
double	O
-	O
blind	O
trial	O
,	O
90	O
women	O
were	O
allocated	O
to	O
receive	O
one	O
of	O
three	O
treatments	O
prior	O
to	O
induction	O
of	O
anaesthesia	O
with	O
propofol	B-Chemical
.	O

Patients	O
in	O
Group	O
C	O
received	O
2	O
ml	O
normal	O
saline	O
,	O
Group	O
L	O
,	O
2	O
ml	O
,	O
lidocaine	B-Chemical
2	O
%	O
(	O
40	O
mg	O
)	O
and	O
Group	O
T	O
,	O
2	O
ml	O
thiopentone	B-Chemical
2	O
.	O
5	O
%	O
(	O
50	O
mg	O
)	O
.	O

Venous	O
discomfort	O
was	O
assessed	O
with	O
a	O
visual	O
analogue	O
scale	O
(	O
VAS	O
)	O
5	O
-	O
15	O
sec	O
after	O
commencing	O
propofol	B-Chemical
administration	O
using	O
an	O
infusion	O
pump	O
(	O
rate	O
1000	O
micrograms	O
.	O
kg	O
-	O
1	O
.	O
min	O
-	O
1	O
)	O
.	O

Loss	B-Disease
of	I-Disease
consciousness	I-Disease
occurred	O
in	O
60	O
-	O
90	O
sec	O
.	O

Visual	O
analogue	O
scores	O
(	O
mean	O
+	O
/	O
-	O
SD	O
)	O
during	O
induction	O
were	O
lower	O
in	O
Groups	O
L	O
(	O
3	O
.	O
3	O
+	O
/	O
-	O
2	O
.	O
5	O
)	O
and	O
T	O
(	O
4	O
.	O
1	O
+	O
/	O
-	O
2	O
.	O
7	O
)	O
than	O
in	O
Group	O
C	O
(	O
5	O
.	O
6	O
+	O
/	O
-	O
2	O
.	O
3	O
)	O
;	O
P	O
=	O
0	O
.	O
0031	O
.	O

The	O
incidence	O
of	O
venous	O
discomfort	O
was	O
lower	O
in	O
Group	O
L	O
(	O
76	O
.	O
6	O
%	O
;	O
P	O
<	O
0	O
.	O
05	O
)	O
than	O
in	O
Group	O
C	O
(	O
100	O
%	O
)	O
but	O
not	O
different	O
from	O
Group	O
T	O
(	O
90	O
%	O
)	O
.	O

The	O
VAS	O
scores	O
for	O
recall	O
of	O
pain	B-Disease
in	O
the	O
recovery	O
room	O
were	O
correlated	O
with	O
the	O
VAS	O
scores	O
during	O
induction	O
(	O
r	O
=	O
0	O
.	O
7045	O
;	O
P	O
<	O
0	O
.	O
0001	O
)	O
.	O

Recovery	O
room	O
discharge	O
times	O
were	O
similar	O
:	O
C	O
(	O
75	O
.	O
9	O
+	O
/	O
-	O
19	O
.	O
4	O
min	O
)	O
;	O
L	O
73	O
.	O
6	O
+	O
/	O
-	O
21	O
.	O
6	O
min	O
)	O
;	O
T	O
(	O
77	O
.	O
1	O
+	O
/	O
-	O
18	O
.	O
9	O
min	O
)	O
.	O

Assessing	O
their	O
overall	O
satisfaction	O
,	O
89	O
.	O
7	O
%	O
would	O
choose	O
propofol	B-Chemical
anaesthesia	O
again	O
.	O

We	O
conclude	O
that	O
lidocaine	B-Chemical
reduces	O
the	O
incidence	O
and	O
severity	O
of	O
propofol	B-Chemical
injection	O
pain	B-Disease
in	O
ambulatory	O
patients	O
whereas	O
thiopentone	B-Chemical
only	O
reduces	O
its	O
severity	O
.	O

Persistent	O
paralysis	B-Disease
after	O
prolonged	O
use	O
of	O
atracurium	B-Chemical
in	O
the	O
absence	O
of	O
corticosteroids	O
.	O

Neuromuscular	O
blocking	O
agents	O
(	O
NMBAs	O
)	O
are	O
often	O
used	O
for	O
patients	O
requiring	O
prolonged	O
mechanical	O
ventilation	O
.	O

Reports	O
of	O
persistent	O
paralysis	B-Disease
after	O
the	O
discontinuance	O
of	O
these	O
drugs	O
have	O
most	O
often	O
involved	O
aminosteroid	O
-	O
based	O
NMBAs	O
such	O
as	O
vecuronium	B-Chemical
bromide	I-Chemical
,	O
especially	O
when	O
used	O
in	O
conjunction	O
with	O
corticosteroids	O
.	O

Atracurium	B-Chemical
besylate	I-Chemical
,	O
a	O
short	O
-	O
acting	O
benzylisoquinolinium	B-Chemical
NMBA	O
that	O
is	O
eliminated	O
independently	O
of	O
renal	O
or	O
hepatic	O
function	O
,	O
has	O
also	O
been	O
associated	O
with	O
persistent	O
paralysis	B-Disease
,	O
but	O
only	O
when	O
used	O
with	O
corticosteroids	O
.	O

We	O
report	O
a	O
case	O
of	O
atracurium	B-Chemical
-	O
related	O
paralysis	B-Disease
persisting	O
for	O
approximately	O
50	O
hours	O
in	O
a	O
patient	O
who	O
was	O
not	O
treated	O
with	O
corticosteroids	O
.	O

A	O
phase	O
I	O
/	O
II	O
study	O
of	O
paclitaxel	B-Chemical
plus	O
cisplatin	B-Chemical
as	O
first	O
-	O
line	O
therapy	O
for	O
head	B-Disease
and	I-Disease
neck	I-Disease
cancers	I-Disease
:	O
preliminary	O
results	O
.	O

Improved	O
outcomes	O
among	O
patients	O
with	O
head	B-Disease
and	I-Disease
neck	I-Disease
carcinomas	I-Disease
require	O
investigations	O
of	O
new	O
drugs	O
for	O
induction	O
therapy	O
.	O

Preliminary	O
results	O
of	O
an	O
Eastern	O
Cooperative	O
Oncology	O
Group	O
study	O
of	O
single	O
-	O
agent	O
paclitaxel	B-Chemical
(	O
Taxol	B-Chemical
;	O
Bristol	O
-	O
Myers	O
Squibb	O
Company	O
,	O
Princeton	O
,	O
NJ	O
)	O
reported	O
a	O
37	O
%	O
response	O
rate	O
in	O
patients	O
with	O
head	B-Disease
and	I-Disease
neck	I-Disease
cancer	I-Disease
,	O
and	O
the	O
paclitaxel	B-Chemical
/	O
cisplatin	B-Chemical
combination	O
has	O
been	O
used	O
successfully	O
and	O
has	O
significantly	O
improved	O
median	O
response	O
duration	O
in	O
ovarian	B-Disease
cancer	I-Disease
patients	O
.	O

We	O
initiated	O
a	O
phase	O
I	O
/	O
II	O
trial	O
to	O
determine	O
the	O
response	O
and	O
toxicity	B-Disease
of	O
escalating	O
paclitaxel	B-Chemical
doses	O
combined	O
with	O
fixed	O
-	O
dose	O
cisplatin	B-Chemical
with	O
granulocyte	O
colony	O
-	O
stimulating	O
factor	O
support	O
in	O
patients	O
with	O
untreated	O
locally	O
advanced	O
inoperable	O
head	B-Disease
and	I-Disease
neck	I-Disease
carcinoma	I-Disease
.	O

To	O
date	O
,	O
23	O
men	O
with	O
a	O
median	O
age	O
of	O
50	O
years	O
and	O
good	O
performance	O
status	O
have	O
entered	O
the	O
trial	O
.	O

Primary	O
tumor	B-Disease
sites	O
were	O
oropharynx	O
,	O
10	O
patients	O
;	O
hypopharynx	O
,	O
four	O
;	O
larynx	O
,	O
two	O
;	O
oral	O
cavity	O
,	O
three	O
;	O
unknown	O
primary	O
,	O
two	O
;	O
and	O
nasal	O
cavity	O
and	O
parotid	O
gland	O
,	O
one	O
each	O
.	O

Of	O
20	O
patients	O
evaluable	O
for	O
toxicity	B-Disease
,	O
four	O
had	O
stage	O
III	O
and	O
16	O
had	O
stage	O
IV	O
disease	O
.	O

Treatment	O
,	O
given	O
every	O
21	O
days	O
for	O
a	O
maximum	O
of	O
three	O
cycles	O
,	O
consisted	O
of	O
paclitaxel	B-Chemical
by	O
3	O
-	O
hour	O
infusion	O
followed	O
the	O
next	O
day	O
by	O
a	O
fixed	O
dose	O
of	O
cisplatin	B-Chemical
(	O
75	O
mg	O
/	O
m2	O
)	O
.	O

The	O
dose	O
levels	O
incorporate	O
escalating	O
paclitaxel	B-Chemical
doses	O
,	O
and	O
intrapatient	O
escalations	O
within	O
a	O
given	O
dose	O
level	O
are	O
permitted	O
if	O
toxicity	B-Disease
permits	O
.	O

At	O
the	O
time	O
of	O
this	O
writing	O
,	O
dose	O
level	O
4	O
(	O
260	O
,	O
270	O
,	O
and	O
280	O
mg	O
/	O
m2	O
)	O
is	O
being	O
evaluated	O
;	O
three	O
patients	O
from	O
this	O
level	O
are	O
evaluable	O
.	O

With	O
paclitaxel	B-Chemical
doses	O
of	O
200	O
mg	O
/	O
m2	O
and	O
higher	O
,	O
granulocyte	O
colony	O
-	O
stimulating	O
factor	O
5	O
micrograms	O
/	O
kg	O
/	O
d	O
is	O
given	O
(	O
days	O
4	O
through	O
12	O
)	O
.	O

Of	O
18	O
patients	O
evaluable	O
for	O
response	O
,	O
seven	O
(	O
39	O
%	O
)	O
achieved	O
a	O
complete	O
response	O
and	O
six	O
(	O
33	O
%	O
)	O
achieved	O
a	O
partial	O
response	O
.	O

Three	O
patients	O
had	O
no	O
change	O
and	O
disease	O
progressed	O
in	O
two	O
.	O

The	O
overall	O
response	O
rate	O
is	O
72	O
%	O
.	O

Eleven	O
responding	O
patients	O
had	O
subsequent	O
surgery	O
/	O
radiotherapy	O
or	O
radical	O
radiotherapy	O
.	O

Two	O
pathologic	O
complete	O
responses	O
were	O
observed	O
in	O
patients	O
who	O
had	O
achieved	O
clinical	O
complete	O
responses	O
.	O

Alopecia	B-Disease
,	O
paresthesias	B-Disease
,	O
and	O
arthralgias	B-Disease
/	O
myalgias	B-Disease
have	O
occurred	O
frequently	O
,	O
but	O
with	O
one	O
exception	O
(	O
a	O
grade	O
3	O
myalgia	B-Disease
)	O
they	O
have	O
been	O
grade	O
1	O
or	O
2	O
.	O

No	O
dose	O
-	O
limiting	O
hematologic	O
toxicity	B-Disease
has	O
been	O
seen	O
.	O

Paclitaxel	B-Chemical
/	O
cisplatin	B-Chemical
is	O
an	O
effective	O
first	O
-	O
line	O
regimen	O
for	O
locoregionally	O
advanced	O
head	B-Disease
and	I-Disease
neck	I-Disease
cancer	I-Disease
and	O
continued	O
study	O
is	O
warranted	O
.	O

Results	O
thus	O
far	O
suggest	O
no	O
dose	O
-	O
response	O
effect	O
for	O
paclitaxel	B-Chemical
doses	O
above	O
200	O
mg	O
/	O
m2	O
.	O

Improvement	O
of	O
levodopa	B-Chemical
-	O
induced	O
dyskinesia	B-Disease
by	O
propranolol	B-Chemical
in	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
.	O

Seven	O
patients	O
suffering	O
from	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
(	O
PD	B-Disease
)	O
with	O
severely	O
disabling	O
dyskinesia	B-Disease
received	O
low	O
-	O
dose	O
propranolol	B-Chemical
as	O
an	O
adjunct	O
to	O
the	O
currently	O
used	O
medical	O
treatment	O
.	O

There	O
was	O
a	O
significant	O
40	O
%	O
improvement	O
in	O
the	O
dyskinesia	B-Disease
score	O
without	O
increase	O
of	O
parkinsonian	B-Disease
motor	B-Disease
disability	I-Disease
.	O

Ballistic	O
and	O
choreic	O
dyskinesia	B-Disease
were	O
markedly	O
ameliorated	O
,	O
whereas	O
dystonia	B-Disease
was	O
not	O
.	O

This	O
study	O
suggests	O
that	O
administration	O
of	O
low	O
doses	O
of	O
beta	O
-	O
blockers	O
may	O
improve	O
levodopa	B-Chemical
-	O
induced	O
ballistic	O
and	O
choreic	O
dyskinesia	B-Disease
in	O
PD	B-Disease
.	O

Habitual	O
use	O
of	O
acetaminophen	B-Chemical
as	O
a	O
risk	O
factor	O
for	O
chronic	B-Disease
renal	I-Disease
failure	I-Disease
:	O
a	O
comparison	O
with	O
phenacetin	B-Chemical
.	O

Six	O
epidemiologic	O
studies	O
in	O
the	O
United	O
States	O
and	O
Europe	O
indicate	O
that	O
habitual	O
use	O
of	O
phenacetin	B-Chemical
is	O
associated	O
with	O
the	O
development	O
of	O
chronic	B-Disease
renal	I-Disease
failure	I-Disease
and	O
end	B-Disease
-	I-Disease
stage	I-Disease
renal	I-Disease
disease	I-Disease
(	O
ESRD	B-Disease
)	O
,	O
with	O
a	O
relative	O
risk	O
in	O
the	O
range	O
of	O
4	O
to	O
19	O
.	O

As	O
a	O
result	O
of	O
these	O
and	O
other	O
studies	O
,	O
phenacetin	B-Chemical
has	O
now	O
been	O
withdrawn	O
from	O
the	O
market	O
in	O
most	O
countries	O
.	O

However	O
,	O
three	O
case	O
control	O
studies	O
,	O
one	O
each	O
in	O
North	O
Carolina	O
,	O
northern	O
Maryland	O
,	O
and	O
West	O
Berlin	O
,	O
Germany	O
,	O
showed	O
that	O
habitual	O
use	O
of	O
acetaminophen	B-Chemical
is	O
also	O
associated	O
with	O
chronic	B-Disease
renal	I-Disease
failure	I-Disease
and	O
ESRD	B-Disease
,	O
with	O
a	O
relative	O
risk	O
in	O
the	O
range	O
of	O
2	O
to	O
4	O
.	O

These	O
studies	O
suggest	O
that	O
both	O
phenacetin	B-Chemical
and	O
acetaminophen	B-Chemical
may	O
contribute	O
to	O
the	O
burden	O
of	O
ESRD	B-Disease
,	O
with	O
the	O
risk	O
of	O
the	O
latter	O
being	O
somewhat	O
less	O
than	O
that	O
of	O
the	O
former	O
.	O

This	O
apparent	O
difference	O
in	O
risk	O
may	O
not	O
be	O
due	O
to	O
differences	O
in	O
nephrotoxic	B-Disease
potential	O
of	O
the	O
drugs	O
themselves	O
.	O

A	O
lower	O
relative	O
risk	O
would	O
be	O
expected	O
for	O
acetaminophen	B-Chemical
if	O
the	O
risk	O
of	O
both	O
drugs	O
in	O
combination	O
with	O
other	O
analgesics	O
was	O
higher	O
than	O
the	O
risk	O
of	O
either	O
agent	O
alone	O
.	O

Thus	O
,	O
acetaminophen	B-Chemical
has	O
been	O
used	O
both	O
as	O
a	O
single	O
agent	O
and	O
in	O
combination	O
with	O
other	O
analgesics	O
,	O
whereas	O
phenacetin	B-Chemical
was	O
available	O
only	O
in	O
combinations	O
.	O

The	O
possibility	O
that	O
habitual	O
use	O
of	O
acetaminophen	B-Chemical
alone	O
increases	O
the	O
risk	O
of	O
ESRD	B-Disease
has	O
not	O
been	O
clearly	O
demonstrated	O
,	O
but	O
cannot	O
be	O
dismissed	O
.	O

Acetaminophen	B-Chemical
-	O
induced	O
hypotension	B-Disease
.	O

Through	O
30	O
years	O
of	O
widespread	O
use	O
,	O
acetaminophen	B-Chemical
has	O
been	O
shown	O
to	O
be	O
a	O
remarkably	O
safe	O
medication	O
in	O
therapeutic	O
dosages	O
.	O

The	O
potential	O
for	O
acetaminophen	B-Chemical
to	O
produce	O
cardiovascular	B-Disease
toxicities	I-Disease
is	O
very	O
low	O
.	O

However	O
,	O
acetaminophen	B-Chemical
has	O
been	O
demonstrated	O
to	O
produce	O
symptoms	O
of	O
anaphylaxis	B-Disease
,	O
including	O
hypotension	B-Disease
,	O
in	O
sensitive	O
individuals	O
.	O

This	O
article	O
describes	O
two	O
critically	B-Disease
ill	I-Disease
patients	O
in	O
whom	O
transient	O
episodes	O
of	O
hypotension	B-Disease
reproducibly	O
developed	O
after	O
administration	O
of	O
acetaminophen	B-Chemical
.	O

Other	O
symptoms	O
of	O
allergic	B-Disease
reactions	I-Disease
were	O
not	O
clinically	O
detectable	O
.	O

The	O
hypotensive	B-Disease
episodes	O
were	O
severe	O
enough	O
to	O
require	O
vasopressor	O
administration	O
.	O

The	O
reports	O
illustrate	O
the	O
need	O
for	O
clinicians	O
to	O
consider	O
acetaminophen	B-Chemical
in	O
patients	O
with	O
hypotension	B-Disease
of	O
unknown	O
origin	O
.	O

Reduction	O
of	O
heparan	B-Chemical
sulphate	I-Chemical
-	O
associated	O
anionic	O
sites	O
in	O
the	O
glomerular	O
basement	O
membrane	O
of	O
rats	O
with	O
streptozotocin	B-Chemical
-	O
induced	O
diabetic	B-Disease
nephropathy	I-Disease
.	O

Heparan	B-Chemical
sulphate	I-Chemical
-	O
associated	O
anionic	O
sites	O
in	O
the	O
glomerular	O
basement	O
membrane	O
were	O
studied	O
in	O
rats	O
8	O
months	O
after	O
induction	O
of	O
diabetes	B-Disease
by	O
streptozotocin	B-Chemical
and	O
in	O
age	O
-	O
adn	O
sex	O
-	O
matched	O
control	O
rats	O
,	O
employing	O
the	O
cationic	O
dye	O
cuprolinic	B-Chemical
blue	I-Chemical
.	O

Morphometric	O
analysis	O
at	O
the	O
ultrastructural	O
level	O
was	O
performed	O
using	O
a	O
computerized	O
image	O
processor	O
.	O

The	O
heparan	B-Chemical
sulphate	I-Chemical
specificity	O
of	O
the	O
cuprolinic	B-Chemical
blue	I-Chemical
staining	O
was	O
demonstrated	O
by	O
glycosaminoglycan	B-Chemical
-	O
degrading	O
enzymes	O
,	O
showing	O
that	O
pretreatment	O
of	O
the	O
sections	O
with	O
heparitinase	O
abolished	O
all	O
staining	O
,	O
whereas	O
chondroitinase	O
ABC	O
had	O
no	O
effect	O
.	O

The	O
majority	O
of	O
anionic	O
sites	O
(	O
74	O
%	O
in	O
diabetic	B-Disease
and	O
81	O
%	O
in	O
control	O
rats	O
)	O
were	O
found	O
within	O
the	O
lamina	O
rara	O
externa	O
of	O
the	O
glomerular	O
basement	O
membrane	O
.	O

A	O
minority	O
of	O
anionic	O
sites	O
were	O
scattered	O
throughout	O
the	O
lamina	O
densa	O
and	O
lamina	O
rara	O
interna	O
,	O
and	O
were	O
significantly	O
smaller	O
than	O
those	O
in	O
the	O
lamina	O
rara	O
externa	O
of	O
the	O
glomerular	O
basement	O
membrane	O
(	O
p	O
<	O
0	O
.	O
001	O
and	O
p	O
<	O
0	O
.	O
01	O
for	O
diabetic	B-Disease
and	O
control	O
rats	O
,	O
respectively	O
)	O
.	O

Diabetic	B-Disease
rats	O
progressively	O
developed	O
albuminuria	B-Disease
reaching	O
40	O
.	O
3	O
(	O
32	O
.	O
2	O
-	O
62	O
.	O
0	O
)	O
mg	O
/	O
24	O
h	O
after	O
8	O
months	O
in	O
contrast	O
to	O
the	O
control	O
animals	O
(	O
0	O
.	O
8	O
(	O
0	O
.	O
2	O
-	O
0	O
.	O
9	O
)	O
mg	O
/	O
24	O
h	O
,	O
p	O
<	O
0	O
.	O
002	O
)	O
.	O

At	O
the	O
same	O
time	O
,	O
the	O
number	O
of	O
heparan	B-Chemical
sulphate	I-Chemical
anionic	O
sites	O
and	O
the	O
total	O
anionic	O
site	O
surface	O
(	O
number	O
of	O
anionic	O
sites	O
x	O
mean	O
anionic	O
site	O
surface	O
)	O
in	O
the	O
lamina	O
rara	O
externa	O
of	O
the	O
glomerular	O
basement	O
membrane	O
was	O
reduced	O
by	O
19	O
%	O
(	O
p	O
<	O
0	O
.	O
021	O
)	O
and	O
by	O
26	O
%	O
(	O
p	O
<	O
0	O
.	O
02	O
)	O
,	O
respectively	O
.	O

Number	O
and	O
total	O
anionic	O
site	O
surface	O
in	O
the	O
remaining	O
part	O
of	O
the	O
glomerular	O
basement	O
membrane	O
(	O
lamina	O
densa	O
and	O
lamina	O
rara	O
interna	O
)	O
were	O
not	O
significantly	O
changed	O
.	O

We	O
conclude	O
that	O
in	O
streptozotocin	B-Chemical
-	O
diabetic	B-Disease
rats	O
with	O
an	O
increased	O
urinary	O
albumin	O
excretion	O
,	O
a	O
reduced	O
heparan	B-Chemical
sulphate	I-Chemical
charge	O
barrier	O
/	O
density	O
is	O
found	O
at	O
the	O
lamina	O
rara	O
externa	O
of	O
the	O
glomerular	O
basement	O
membrane	O
.	O

Mediation	O
of	O
enhanced	O
reflex	O
vagal	O
bradycardia	B-Disease
by	O
L	B-Chemical
-	I-Chemical
dopa	I-Chemical
via	O
central	O
dopamine	B-Chemical
formation	O
in	O
dogs	O
.	O

L	B-Chemical
-	I-Chemical
Dopa	I-Chemical
(	O
5	O
mg	O
/	O
kg	O
i	O
.	O
v	O
.	O
)	O
decreased	O
blood	O
pressure	O
and	O
heart	O
rate	O
after	O
extracerebral	O
decarboxylase	O
inhibition	O
with	O
MK	B-Chemical
-	I-Chemical
486	I-Chemical
(	O
25	O
mg	O
/	O
kg	O
i	O
.	O
v	O
.	O
)	O
in	O
anesthetize	O
MAO	B-Chemical
-	O
inhibited	O
dogs	O
.	O

In	O
addition	O
,	O
reflex	O
bradycardia	B-Disease
caused	O
by	O
injected	O
norepinephrine	B-Chemical
was	O
significantly	O
enhanced	O
by	O
L	B-Chemical
-	I-Chemical
dopa	I-Chemical
,	O
DL	B-Chemical
-	I-Chemical
Threo	I-Chemical
-	I-Chemical
dihydroxyphenylserine	I-Chemical
had	O
no	O
effect	O
on	O
blood	O
pressure	O
,	O
heart	O
rate	O
or	O
reflex	O
responses	O
to	O
norepinephrine	B-Chemical
.	O

FLA	B-Chemical
-	I-Chemical
63	I-Chemical
,	O
a	O
dopamine	B-Chemical
-	O
beta	O
-	O
oxidase	O
inhibitor	O
,	O
did	O
not	O
have	O
any	O
effect	O
on	O
the	O
hypotension	B-Disease
,	O
bradycardia	B-Disease
or	O
reflex	O
-	O
enhancing	O
effect	O
of	O
L	B-Chemical
-	I-Chemical
dopa	I-Chemical
.	O

Pimozide	B-Chemical
did	O
not	O
affect	O
the	O
actions	O
of	O
L	B-Chemical
-	I-Chemical
dopa	I-Chemical
on	O
blood	O
pressure	O
and	O
heart	O
rate	O
but	O
completely	O
blocked	O
the	O
enhancement	O
of	O
reflexes	O
.	O

Removal	O
of	O
the	O
carotid	O
sinuses	O
caused	O
an	O
elevation	O
blood	O
pressure	O
and	O
heart	O
rate	O
and	O
abolished	O
the	O
negative	O
chronotropic	O
effect	O
of	O
norepinephrine	B-Chemical
.	O

However	O
,	O
L	B-Chemical
-	I-Chemical
dopa	I-Chemical
restored	O
the	O
bradycardia	B-Disease
caused	O
by	O
norepinephrine	B-Chemical
in	O
addition	O
to	O
decreasing	O
blood	O
pressure	O
and	O
heart	O
rate	O
.	O

5	B-Chemical
-	I-Chemical
HTP	I-Chemical
(	O
5	O
mg	O
/	O
kg	O
i	O
.	O
v	O
.	O
)	O
decreased	O
blood	O
pressure	O
and	O
heart	O
rate	O
and	O
decreased	O
the	O
reflex	O
bradycardia	B-Disease
to	O
norepinephrine	B-Chemical
.	O

It	O
is	O
concluded	O
that	O
L	B-Chemical
-	I-Chemical
dopa	I-Chemical
enhances	O
reflex	O
bradycardia	B-Disease
through	O
central	O
alpha	O
-	O
receptor	O
stimulation	O
.	O

Furthermore	O
,	O
the	O
effects	O
are	O
mediated	O
through	O
dopamine	B-Chemical
rather	O
than	O
norepinephrine	B-Chemical
and	O
do	O
not	O
require	O
the	O
carotid	O
sinus	O
baroreceptors	O
.	O

Microangiopathic	B-Disease
hemolytic	I-Disease
anemia	I-Disease
complicating	O
FK506	B-Chemical
(	O
tacrolimus	B-Chemical
)	O
therapy	O
.	O

We	O
describe	O
3	O
episodes	O
of	O
microangiopathic	B-Disease
hemolytic	I-Disease
anemia	I-Disease
(	O
MAHA	B-Disease
)	O
in	O
2	O
solid	O
organ	O
recipients	O
under	O
FK506	B-Chemical
(	O
tacrolimus	B-Chemical
)	O
therapy	O
.	O

In	O
both	O
cases	O
,	O
discontinuation	O
of	O
FK506	B-Chemical
and	O
treatment	O
with	O
plasma	O
exchange	O
,	O
fresh	O
frozen	O
plasma	O
replacement	O
,	O
corticosteroids	B-Chemical
,	O
aspirin	B-Chemical
,	O
and	O
dipyridamole	B-Chemical
led	O
to	O
resolution	O
of	O
MAHA	B-Disease
.	O

In	O
one	O
patient	O
,	O
reintroduction	O
of	O
FK506	B-Chemical
led	O
to	O
rapid	O
recurrence	O
of	O
MAHA	B-Disease
.	O

FK506	B-Chemical
-	O
associated	O
MAHA	B-Disease
is	O
probably	O
rare	O
but	O
physicians	O
must	O
be	O
aware	O
of	O
this	O
severe	O
complication	O
.	O

In	O
our	O
experience	O
and	O
according	O
to	O
the	O
literature	O
,	O
FK506	B-Chemical
does	O
not	O
seem	O
to	O
cross	O
-	O
react	O
with	O
cyclosporin	B-Chemical
A	I-Chemical
(	O
CyA	B-Chemical
)	O
,	O
an	O
immuno	O
-	O
suppressive	O
drug	O
already	O
known	O
to	O
induce	O
MAHA	B-Disease
.	O

Effect	O
of	O
some	O
anticancer	O
drugs	O
and	O
combined	O
chemotherapy	O
on	O
renal	B-Disease
toxicity	I-Disease
.	O

The	O
nephrotoxic	B-Disease
action	O
of	O
anticancer	O
drugs	O
such	O
as	O
nitrogranulogen	B-Chemical
(	O
NG	B-Chemical
)	O
,	O
methotrexate	B-Chemical
(	O
MTX	B-Chemical
)	O
,	O
5	B-Chemical
-	I-Chemical
fluorouracil	I-Chemical
(	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
)	O
and	O
cyclophosphamide	B-Chemical
(	O
CY	B-Chemical
)	O
administered	O
alone	O
or	O
in	O
combination	O
[	O
MTX	B-Chemical
+	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
+	O
CY	B-Chemical
(	O
CMF	O
)	O
]	O
was	O
evaluated	O
in	O
experiments	O
on	O
Wistar	O
rats	O
.	O

After	O
drug	O
administration	O
,	O
creatinine	B-Chemical
concentrations	O
in	O
the	O
plasma	O
and	O
in	O
the	O
urine	O
of	O
the	O
rats	O
were	O
determined	O
,	O
as	O
well	O
as	O
creatinine	B-Chemical
clearance	O
.	O

Histopathologic	O
evaluation	O
of	O
the	O
kidneys	O
was	O
also	O
performed	O
.	O

After	O
MTX	B-Chemical
administration	O
a	O
significant	O
increase	O
(	O
p	O
=	O
0	O
.	O
0228	O
)	O
in	O
the	O
plasma	O
creatinine	B-Chemical
concentration	O
and	O
a	O
significant	O
(	O
p	O
=	O
0	O
.	O
0001	O
)	O
decrease	O
in	O
creatinine	B-Chemical
clearance	O
was	O
noted	O
compared	O
to	O
controls	O
.	O

After	O
the	O
administration	O
of	O
NG	B-Chemical
,	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
and	O
CY	B-Chemical
neither	O
a	O
statistically	O
significant	O
increase	O
in	O
creatinine	B-Chemical
concentration	O
nor	O
an	O
increase	O
in	O
creatinine	B-Chemical
clearance	O
was	O
observed	O
compared	O
to	O
the	O
group	O
receiving	O
no	O
cytostatics	O
.	O

Following	O
polytherapy	O
according	O
to	O
the	O
CMF	O
regimen	O
,	O
a	O
statistically	O
significant	O
decrease	O
(	O
p	O
=	O
0	O
.	O
0343	O
)	O
in	O
creatinine	B-Chemical
clearance	O
was	O
found	O
,	O
but	O
creatinine	B-Chemical
concentration	O
did	O
not	O
increase	O
significantly	O
compared	O
to	O
controls	O
.	O

CY	B-Chemical
caused	O
hemorrhagic	B-Disease
cystitis	I-Disease
in	O
40	O
%	O
of	O
rats	O
,	O
but	O
it	O
did	O
not	O
cause	O
this	O
complication	O
when	O
combined	O
with	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
and	O
MTX	B-Chemical
.	O

Histologic	O
changes	O
were	O
found	O
in	O
rat	O
kidneys	O
after	O
administration	O
of	O
MTX	B-Chemical
,	O
CY	B-Chemical
and	O
NG	B-Chemical
,	O
while	O
no	O
such	O
change	O
was	O
observed	O
after	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
and	O
joint	O
administration	O
of	O
MTX	B-Chemical
+	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
+	O
CY	B-Chemical
compared	O
to	O
controls	O
.	O

Our	O
studies	O
indicate	O
that	O
nephrotoxicity	B-Disease
of	O
MTX	B-Chemical
+	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
+	O
CY	B-Chemical
administered	O
jointly	O
is	O
lower	O
than	O
in	O
monotherapy	O
.	O

The	O
interpeduncular	O
nucleus	O
regulates	O
nicotine	B-Chemical
'	O
s	O
effects	O
on	O
free	O
-	O
field	O
activity	O
.	O

Partial	O
lesions	O
were	O
made	O
with	O
kainic	B-Chemical
acid	I-Chemical
in	O
the	O
interpeduncular	O
nucleus	O
of	O
the	O
ventral	O
midbrain	O
of	O
the	O
rat	O
.	O

Compared	O
with	O
sham	O
-	O
operated	O
controls	O
,	O
lesions	O
significantly	O
(	O
p	O
<	O
0	O
.	O
25	O
)	O
blunted	O
the	O
early	O
(	O
<	O
60	O
min	O
)	O
free	O
-	O
field	O
locomotor	B-Disease
hypoactivity	I-Disease
caused	O
by	O
nicotine	B-Chemical
(	O
0	O
.	O
5	O
mg	O
kg	O
(	O
-	O
1	O
)	O
,	O
i	O
.	O
m	O
.	O
)	O
,	O
enhanced	O
the	O
later	O
(	O
60	O
-	O
120	O
min	O
)	O
nicotine	B-Chemical
-	O
induced	O
hyperactivity	B-Disease
,	O
and	O
raised	O
spontaneous	O
nocturnal	O
activity	O
.	O

Lesions	O
reduced	O
the	O
extent	O
of	O
immunohistological	O
staining	O
for	O
choline	B-Chemical
acetyltransferase	O
in	O
the	O
interpeduncular	O
nucleus	O
(	O
p	O
<	O
0	O
.	O
025	O
)	O
,	O
but	O
not	O
for	O
tyrosine	B-Chemical
hydroxylase	O
in	O
the	O
surrounding	O
catecholaminergic	O
A10	O
region	O
.	O

We	O
conclude	O
that	O
the	O
interpeduncular	O
nucleus	O
mediates	O
nicotinic	O
depression	B-Disease
of	O
locomotor	O
activity	O
and	O
dampens	O
nicotinic	O
arousal	O
mechanisms	O
located	O
elsewhere	O
in	O
the	O
brain	O
.	O

Lithium	B-Chemical
-	O
associated	O
cognitive	B-Disease
and	I-Disease
functional	I-Disease
deficits	I-Disease
reduced	O
by	O
a	O
switch	O
to	O
divalproex	B-Chemical
sodium	I-Chemical
:	O
a	O
case	O
series	O
.	O

BACKGROUND	O
:	O
Lithium	B-Chemical
remains	O
a	O
first	O
-	O
line	O
treatment	O
for	O
the	O
acute	O
and	O
maintenance	O
treatment	O
of	O
bipolar	B-Disease
disorder	I-Disease
.	O

Although	O
much	O
has	O
been	O
written	O
about	O
the	O
management	O
of	O
the	O
more	O
common	O
adverse	O
effects	O
of	O
lithium	B-Chemical
,	O
such	O
as	O
polyuria	B-Disease
and	O
tremor	B-Disease
,	O
more	O
subtle	O
lithium	B-Chemical
side	O
effects	O
such	O
as	O
cognitive	B-Disease
deficits	I-Disease
,	O
loss	B-Disease
of	I-Disease
creativity	I-Disease
,	O
and	O
functional	B-Disease
impairments	I-Disease
remain	O
understudied	O
.	O

This	O
report	O
summarizes	O
our	O
experience	O
in	O
switching	O
bipolar	B-Disease
patients	O
from	O
lithium	B-Chemical
to	O
divalproex	B-Chemical
sodium	I-Chemical
to	O
alleviate	O
such	O
cognitive	B-Disease
and	I-Disease
functional	I-Disease
impairments	I-Disease
.	O

METHOD	O
:	O
Open	O
,	O
case	O
series	O
design	O
.	O

RESULTS	O
:	O
We	O
report	O
seven	O
cases	O
where	O
substitution	O
of	O
lithium	B-Chemical
,	O
either	O
fully	O
or	O
partially	O
,	O
with	O
divalproex	B-Chemical
sodium	I-Chemical
was	O
extremely	O
helpful	O
in	O
reducing	O
the	O
cognitive	B-Disease
,	I-Disease
motivational	I-Disease
,	I-Disease
or	I-Disease
creative	I-Disease
deficits	I-Disease
attributed	O
to	O
lithium	B-Chemical
in	O
our	O
bipolar	B-Disease
patients	O
.	O

CONCLUSION	O
:	O
In	O
this	O
preliminary	O
report	O
,	O
divalproex	B-Chemical
sodium	I-Chemical
was	O
a	O
superior	O
alternative	O
to	O
lithium	B-Chemical
in	O
bipolar	B-Disease
patients	O
experiencing	O
cognitive	B-Disease
deficits	I-Disease
,	O
loss	B-Disease
of	I-Disease
creativity	I-Disease
,	O
and	O
functional	B-Disease
impairments	I-Disease
.	O

Effect	O
of	O
nifedipine	B-Chemical
on	O
renal	O
function	O
in	O
liver	O
transplant	O
recipients	O
receiving	O
tacrolimus	B-Chemical
.	O

The	O
effect	O
of	O
nifedipine	B-Chemical
on	O
renal	O
function	O
in	O
liver	O
transplant	O
recipients	O
who	O
were	O
receiving	O
tacrolimus	B-Chemical
was	O
evaluated	O
between	O
January	O
1992	O
and	O
January	O
1996	O
.	O

Two	O
groups	O
of	O
patients	O
receiving	O
tacrolimus	B-Chemical
were	O
compared	O
over	O
a	O
period	O
of	O
1	O
year	O
,	O
one	O
group	O
comprising	O
hypertensive	B-Disease
patients	O
who	O
were	O
receiving	O
nifedipine	B-Chemical
,	O
and	O
the	O
other	O
comprising	O
nonhypertensive	O
patients	O
not	O
receiving	O
nifedipine	B-Chemical
.	O

The	O
time	O
from	O
transplant	O
to	O
baseline	O
was	O
similar	O
in	O
all	O
patients	O
.	O

Nifedipine	B-Chemical
significantly	O
improved	O
kidney	O
function	O
as	O
indicated	O
by	O
a	O
significant	O
lowering	O
of	O
serum	O
creatinine	B-Chemical
levels	O
at	O
6	O
and	O
12	O
months	O
.	O

The	O
observed	O
positive	O
impact	O
of	O
nifedipine	B-Chemical
on	O
reducing	O
the	O
nephrotoxicity	B-Disease
associated	O
with	O
tacrolimus	B-Chemical
in	O
liver	O
transplant	O
recipients	O
should	O
be	O
an	O
important	O
factor	O
in	O
selecting	O
an	O
agent	O
to	O
treat	O
hypertension	B-Disease
in	O
this	O
population	O
.	O

Alpha	O
and	O
beta	O
coma	B-Disease
in	O
drug	O
intoxication	O
uncomplicated	O
by	O
cerebral	B-Disease
hypoxia	I-Disease
.	O

Four	O
patients	O
who	O
were	O
rendered	O
comatose	B-Disease
or	O
stuporous	B-Disease
by	O
drug	O
intoxication	O
,	O
but	O
who	O
were	O
not	O
hypoxic	O
,	O
are	O
described	O
.	O

Three	O
patients	O
received	O
high	O
doses	O
of	O
chlormethiazole	B-Chemical
for	O
alcohol	B-Chemical
withdrawal	B-Disease
symptoms	I-Disease
,	O
and	O
one	O
took	O
a	O
suicidal	O
overdose	B-Disease
of	O
nitrazepam	B-Chemical
.	O

The	O
patient	O
with	O
nitrazepam	B-Chemical
overdose	B-Disease
and	O
two	O
of	O
those	O
with	O
chlormethiazole	B-Chemical
intoxication	O
conformed	O
to	O
the	O
criteria	O
of	O
'	O
alpha	O
coma	B-Disease
'	O
,	O
showing	O
non	O
-	O
reactive	O
generalized	O
or	O
frontally	O
predominant	O
alpha	O
activity	O
in	O
the	O
EEG	O
.	O

The	O
fourth	O
patient	O
who	O
was	O
unconscious	O
after	O
chlormethiazole	B-Chemical
administration	O
exhibite	O
generalized	O
non	O
-	O
reactive	O
activity	O
in	O
the	O
slow	O
beta	O
range	O
.	O

All	O
four	O
recovered	O
completely	O
without	O
neurological	B-Disease
sequelae	I-Disease
following	O
the	O
withdrawal	O
of	O
the	O
offending	O
agents	O
.	O

The	O
similarities	O
between	O
the	O
effects	O
of	O
structural	O
lesions	O
and	O
pharmacological	O
depression	B-Disease
of	O
the	O
brain	O
stem	O
reticular	O
formation	O
are	O
discussed	O
.	O

It	O
is	O
suggested	O
that	O
in	O
both	O
situations	O
disturbed	O
reticulo	O
-	O
thalamic	O
interactions	O
are	O
important	O
in	O
the	O
pathogenesis	O
of	O
alpha	O
coma	B-Disease
.	O

It	O
is	O
concluded	O
that	O
when	O
this	O
electroencephalographic	O
and	O
behavioural	O
picture	O
is	O
seen	O
in	O
drug	O
intoxication	O
,	O
in	O
the	O
absence	O
of	O
significant	O
hypoxaemia	B-Disease
,	O
a	O
favourable	O
outcome	O
may	O
be	O
anticipated	O
.	O

Magnetic	O
resonance	O
volumetry	O
of	O
the	O
cerebellum	O
in	O
epileptic	B-Disease
patients	O
after	O
phenytoin	B-Chemical
overdosages	B-Disease
.	O

The	O
aim	O
of	O
this	O
study	O
was	O
to	O
evaluate	O
the	O
relationship	O
between	O
phenytoin	B-Chemical
medication	O
and	O
cerebellar	B-Disease
atrophy	I-Disease
in	O
patients	O
who	O
had	O
experienced	O
clinical	O
intoxication	O
.	O

Five	O
females	O
and	O
6	O
males	O
,	O
21	O
-	O
59	O
years	O
of	O
age	O
,	O
were	O
examined	O
with	O
a	O
1	O
.	O
5	O
-	O
T	O
whole	O
-	O
body	O
system	O
using	O
a	O
circular	O
polarized	O
head	O
coil	O
.	O

Conventional	O
spin	O
echo	O
images	O
were	O
acquired	O
in	O
the	O
sagittal	O
and	O
transverse	O
orientation	O
.	O

In	O
addition	O
,	O
we	O
performed	O
a	O
high	O
-	O
resolution	O
3D	O
gradient	O
echo	O
,	O
T1	O
-	O
weighted	O
sequences	O
at	O
a	O
1	O
-	O
mm	O
slice	O
thickness	O
.	O

The	O
images	O
were	O
subsequently	O
processed	O
to	O
obtain	O
volumetric	O
data	O
for	O
the	O
cerebellum	O
.	O

Cerebellar	O
volume	O
for	O
the	O
patient	O
group	O
ranged	O
between	O
67	O
.	O
66	O
and	O
131	O
.	O
08	O
ml	O
(	O
mean	O
108	O
.	O
9	O
ml	O
)	O
.	O

In	O
addition	O
3D	O
gradient	O
echo	O
data	O
sets	O
from	O
10	O
healthy	O
male	O
and	O
10	O
healthy	O
female	O
age	O
-	O
matched	O
volunteers	O
were	O
used	O
to	O
compare	O
cerebellar	O
volumes	O
.	O

Using	O
linear	O
regression	O
we	O
found	O
that	O
no	O
correlation	O
exists	O
between	O
seizure	B-Disease
duration	O
,	O
elevation	O
of	O
phenytoin	B-Chemical
serum	O
levels	O
and	O
cerebellar	O
volume	O
.	O

However	O
,	O
multiple	O
regression	O
for	O
the	O
daily	O
dosage	O
,	O
duration	O
of	O
phenytoin	B-Chemical
treatment	O
and	O
cerebellar	O
volume	O
revealed	O
a	O
correlation	O
of	O
these	O
parameters	O
.	O

We	O
conclude	O
that	O
phenytoin	B-Chemical
overdosage	B-Disease
does	O
not	O
necessarily	O
result	O
in	O
cerebellar	B-Disease
atrophy	I-Disease
and	O
it	O
is	O
unlikely	O
that	O
phenytoin	B-Chemical
medication	O
was	O
the	O
only	O
cause	O
of	O
cerebellar	B-Disease
atrophy	I-Disease
in	O
the	O
remaining	O
patients	O
.	O

Quantitative	O
morphometric	O
studies	O
of	O
the	O
cerebellum	O
provide	O
valuable	O
insights	O
into	O
the	O
pathogenesis	O
of	O
cerebellar	B-Disease
disorders	I-Disease
.	O

Late	O
recovery	O
of	O
renal	O
function	O
in	O
a	O
woman	O
with	O
the	O
hemolytic	B-Disease
uremic	I-Disease
syndrome	I-Disease
.	O

A	O
case	O
is	O
reported	O
of	O
the	O
hemolytic	B-Disease
uremic	I-Disease
syndrome	I-Disease
(	O
HUS	B-Disease
)	O
in	O
a	O
woman	O
taking	O
oral	B-Chemical
contraceptives	I-Chemical
.	O

She	O
was	O
treated	O
with	O
heparin	B-Chemical
,	O
dipyridamole	B-Chemical
and	O
hemodialysis	O
;	O
and	O
after	O
more	O
than	O
three	O
months	O
,	O
her	O
urinary	O
output	O
rose	O
above	O
500	O
ml	O
;	O
and	O
six	O
months	O
after	O
the	O
onset	O
of	O
anuria	B-Disease
,	O
dialysis	O
treatment	O
was	O
stopped	O
.	O

This	O
case	O
emphasizes	O
the	O
possibility	O
that	O
HUS	B-Disease
in	O
adults	O
is	O
not	O
invariably	O
irreversible	O
and	O
that	O
,	O
despite	O
prolonged	O
oliguria	B-Disease
,	O
recovery	O
of	O
renal	O
function	O
can	O
be	O
obtained	O
.	O

Therefore	O
,	O
in	O
adult	O
patients	O
affected	O
by	O
HUS	B-Disease
,	O
dialysis	O
should	O
not	O
be	O
discontinued	O
prematurely	O
;	O
moreover	O
,	O
bilateral	O
nephrectomy	O
,	O
for	O
treatment	O
of	O
severe	O
hypertension	B-Disease
and	O
microangiopathic	B-Disease
hemolytic	I-Disease
anemia	I-Disease
,	O
should	O
be	O
performed	O
with	O
caution	O
.	O

Morphological	O
features	O
of	O
encephalopathy	B-Disease
after	O
chronic	O
administration	O
of	O
the	O
antiepileptic	O
drug	O
valproate	B-Chemical
to	O
rats	O
.	O

A	O
transmission	O
electron	O
microscopic	O
study	O
of	O
capillaries	O
in	O
the	O
cerebellar	O
cortex	O
.	O

Long	O
-	O
term	O
intragastric	O
application	O
of	O
the	O
antiepileptic	O
drug	O
sodium	B-Chemical
valproate	I-Chemical
(	O
Vupral	O
"	O
Polfa	O
"	O
)	O
at	O
the	O
effective	O
dose	O
of	O
200	O
mg	O
/	O
kg	O
b	O
.	O

w	O
.	O
once	O
daily	O
to	O
rats	O
for	O
1	O
,	O
3	O
,	O
6	O
,	O
9	O
and	O
12	O
months	O
revealed	O
neurological	B-Disease
disorders	I-Disease
indicating	O
cerebellum	B-Disease
damage	I-Disease
(	O
"	O
valproate	B-Chemical
encephalopathy	B-Disease
"	O
)	O
.	O

The	O
first	O
ultrastructural	O
changes	O
in	O
structural	O
elements	O
of	O
the	O
blood	O
-	O
brain	O
-	O
barrier	O
(	O
BBB	O
)	O
in	O
the	O
cerebellar	O
cortex	O
were	O
detectable	O
after	O
3	O
months	O
of	O
the	O
experiment	O
.	O

They	O
became	O
more	O
severe	O
in	O
the	O
later	O
months	O
of	O
the	O
experiment	O
,	O
and	O
were	O
most	O
severe	O
after	O
12	O
months	O
,	O
located	O
mainly	O
in	O
the	O
molecular	O
layer	O
of	O
the	O
cerebellar	O
cortex	O
.	O

Lesions	O
of	O
the	O
capillary	O
included	O
necrosis	B-Disease
of	O
endothelial	O
cells	O
.	O

Organelles	O
of	O
these	O
cells	O
,	O
in	O
particular	O
the	O
mitochondria	O
(	O
increased	O
number	O
and	O
size	O
,	O
distinct	O
degeneration	O
of	O
their	O
matrix	O
and	O
cristae	O
)	O
and	O
Golgi	O
apparatus	O
were	O
altered	O
.	O

Reduced	O
size	O
of	O
capillary	O
lumen	O
and	O
occlusion	O
were	O
caused	O
by	O
swollen	O
endothelial	O
cells	O
which	O
had	O
luminal	B-Chemical
protrusions	O
and	O
swollen	O
microvilli	O
.	O

Pressure	O
on	O
the	O
vessel	O
wall	O
was	O
produced	O
by	O
enlarged	O
perivascular	O
astrocytic	O
processes	O
.	O

Fragments	O
of	O
necrotic	B-Disease
endothelial	O
cells	O
were	O
in	O
the	O
vascular	O
lumens	O
and	O
in	O
these	O
there	O
was	O
loosening	O
and	O
breaking	O
of	O
tight	O
cellular	O
junctions	O
.	O

Damage	O
to	O
the	O
vascular	O
basement	O
lamina	O
was	O
also	O
observed	O
.	O

Damage	O
to	O
the	O
capillary	O
was	O
accompanied	O
by	O
marked	O
damage	O
to	O
neuroglial	O
cells	O
,	O
mainly	O
to	O
perivascular	O
processes	O
of	O
astrocytes	O
.	O

The	O
proliferation	O
of	O
astrocytes	O
(	O
Bergmann	O
'	O
s	O
in	O
particular	O
)	O
and	O
occasionally	O
of	O
oligodendrocytes	O
was	O
found	O
.	O

Alterations	O
in	O
the	O
structural	O
elements	O
of	O
the	O
BBB	O
coexisted	O
with	O
marked	O
lesions	O
of	O
neurons	O
of	O
the	O
cerebellum	O
(	O
Purkinje	O
cells	O
are	O
earliest	O
)	O
.	O

In	O
electron	O
micrographs	O
both	O
luminal	B-Chemical
and	O
antiluminal	O
sides	O
of	O
the	O
BBB	O
of	O
the	O
cerebellar	O
cortex	O
had	O
similar	O
lesions	O
.	O

The	O
possible	O
influence	O
of	O
the	O
hepatic	B-Disease
damage	I-Disease
,	O
mainly	O
hyperammonemia	B-Disease
,	O
upon	O
the	O
development	O
of	O
valproate	B-Chemical
encephalopathy	B-Disease
is	O
discussed	O
.	O

Fatal	O
intracranial	B-Disease
bleeding	I-Disease
associated	O
with	O
prehospital	O
use	O
of	O
epinephrine	B-Chemical
.	O

We	O
present	O
a	O
case	O
of	O
paramedic	O
misjudgment	O
in	O
the	O
execution	O
of	O
a	O
protocol	O
for	O
the	O
treatment	O
of	O
allergic	B-Disease
reaction	I-Disease
in	O
a	O
case	O
of	O
pulmonary	B-Disease
edema	I-Disease
with	O
wheezing	B-Disease
.	O

The	O
sudden	O
onset	O
of	O
respiratory	B-Disease
distress	I-Disease
,	O
rash	B-Disease
,	O
and	O
a	O
history	O
of	O
a	O
new	O
medicine	O
led	O
the	O
two	O
paramedics	O
on	O
the	O
scene	O
to	O
administer	O
subcutaneous	O
epinephrine	B-Chemical
.	O

Subsequently	O
,	O
acute	O
cardiac	B-Disease
arrest	I-Disease
and	O
fatal	O
subarachnoid	B-Disease
hemorrhage	I-Disease
occurred	O
.	O

Epinephrine	B-Chemical
has	O
a	O
proven	O
role	O
in	O
cardiac	B-Disease
arrest	I-Disease
in	O
prehospital	O
care	O
;	O
however	O
,	O
use	O
by	O
paramedics	O
in	O
patients	O
with	O
suspected	O
allergic	B-Disease
reaction	I-Disease
and	O
severe	O
hypertension	B-Disease
should	O
be	O
viewed	O
with	O
caution	O
.	O

Role	O
of	O
activation	O
of	O
bradykinin	B-Chemical
B2	O
receptors	O
in	O
disruption	O
of	O
the	O
blood	O
-	O
brain	O
barrier	O
during	O
acute	O
hypertension	B-Disease
.	O

Cellular	O
mechanisms	O
which	O
account	O
for	O
disruption	O
the	O
blood	O
-	O
brain	O
barrier	O
during	O
acute	O
hypertension	B-Disease
are	O
not	O
clear	O
.	O

The	O
goal	O
of	O
this	O
study	O
was	O
to	O
determine	O
the	O
role	O
of	O
synthesis	O
/	O
release	O
of	O
bradykinin	B-Chemical
to	O
activate	O
B2	O
receptors	O
in	O
disruption	O
of	O
the	O
blood	O
-	O
brain	O
barrier	O
during	O
acute	O
hypertension	B-Disease
.	O

Permeability	O
of	O
the	O
blood	O
-	O
brain	O
barrier	O
was	O
quantitated	O
by	O
clearance	O
of	O
fluorescent	O
-	O
labeled	O
dextran	B-Chemical
before	O
and	O
during	O
phenylephrine	B-Chemical
-	O
induced	O
acute	O
hypertension	B-Disease
in	O
rats	O
treated	O
with	O
vehicle	O
and	O
Hoe	B-Chemical
-	I-Chemical
140	I-Chemical
(	O
0	O
.	O
1	O
microM	O
)	O
.	O

Phenylephrine	B-Chemical
infusion	O
increased	O
arterial	O
pressure	O
,	O
arteriolar	O
diameter	O
and	O
clearance	O
of	O
fluorescent	O
dextran	B-Chemical
by	O
a	O
similar	O
magnitude	O
in	O
both	O
groups	O
.	O

These	O
findings	O
suggest	O
that	O
disruption	O
of	O
the	O
blood	O
-	O
brain	O
barrier	O
during	O
acute	O
hypertension	B-Disease
is	O
not	O
related	O
to	O
the	O
synthesis	O
/	O
release	O
of	O
bradykinin	B-Chemical
to	O
activate	O
B2	O
receptors	O
.	O

Risk	O
factors	O
of	O
sensorineural	B-Disease
hearing	I-Disease
loss	I-Disease
in	O
preterm	O
infants	O
.	O

Among	O
547	O
preterm	O
infants	O
of	O
<	O
or	O
=	O
34	O
weeks	O
gestation	O
born	O
between	O
1987	O
and	O
1991	O
,	O
8	O
children	O
(	O
1	O
.	O
46	O
%	O
)	O
developed	O
severe	O
progressive	O
and	O
bilateral	O
sensorineural	B-Disease
hearing	I-Disease
loss	I-Disease
.	O

Perinatal	O
risk	O
factors	O
of	O
infants	O
with	O
hearing	B-Disease
loss	I-Disease
were	O
compared	O
with	O
those	O
of	O
two	O
control	O
groups	O
matched	O
for	O
gestation	O
and	O
birth	O
weight	O
and	O
for	O
perinatal	O
complications	O
.	O

Our	O
observations	O
demonstrated	O
an	O
association	O
of	O
hearing	B-Disease
loss	I-Disease
with	O
a	O
higher	O
incidence	O
of	O
perinatal	O
complications	O
.	O

Ototoxicity	B-Disease
appeared	O
closely	O
related	O
to	O
a	O
prolonged	O
administration	O
and	O
higher	O
total	O
dose	O
of	O
ototoxic	B-Disease
drugs	O
,	O
particularly	O
aminoglycosides	B-Chemical
and	O
furosemide	B-Chemical
.	O

Finally	O
,	O
we	O
strongly	O
recommend	O
to	O
prospectively	O
and	O
regularly	O
perform	O
audiologic	O
assessment	O
in	O
sick	O
preterm	O
children	O
as	O
hearing	B-Disease
loss	I-Disease
is	O
of	O
delayed	O
onset	O
and	O
in	O
most	O
cases	O
bilateral	O
and	O
severe	O
.	O

Seizure	B-Disease
resulting	O
from	O
a	O
venlafaxine	B-Chemical
overdose	B-Disease
.	O

OBJECTIVE	O
:	O
To	O
report	O
a	O
case	O
of	O
venlafaxine	B-Chemical
overdose	B-Disease
.	O

CASE	O
SUMMARY	O
:	O
A	O
40	O
-	O
year	O
-	O
old	O
woman	O
with	O
major	B-Disease
depression	I-Disease
took	O
an	O
overdose	B-Disease
of	O
venlafaxine	B-Chemical
in	O
an	O
apparent	O
suicide	O
attempt	O
.	O

After	O
the	O
ingestion	O
of	O
26	O
venlafaxine	B-Chemical
50	O
-	O
mg	O
tablets	O
,	O
the	O
patient	O
experienced	O
a	O
witnessed	O
generalized	O
seizure	B-Disease
.	O

She	O
was	O
admitted	O
to	O
the	O
medical	O
intensive	O
care	O
unit	O
,	O
venlafaxine	B-Chemical
was	O
discontinued	O
,	O
and	O
no	O
further	O
sequelae	O
were	O
seen	O
.	O

DISCUSSION	O
:	O
To	O
our	O
knowledge	O
,	O
this	O
is	O
the	O
first	O
reported	O
case	O
of	O
venlafaxine	B-Chemical
overdose	B-Disease
that	O
resulted	O
in	O
a	O
generalized	O
seizure	B-Disease
.	O

Based	O
on	O
nonoverdose	O
pharmacokinetics	O
and	O
pharmacodynamics	O
of	O
venlafaxine	B-Chemical
and	O
the	O
potential	O
risks	O
of	O
available	O
interventions	O
,	O
no	O
emergent	O
therapy	O
was	O
instituted	O
.	O

CONCLUSIONS	O
:	O
The	O
venlafaxine	B-Chemical
overdose	B-Disease
in	O
our	O
patient	O
resulted	O
in	O
a	O
single	O
episode	O
of	O
generalized	O
seizure	B-Disease
but	O
elicited	O
no	O
further	O
sequelae	O
.	O

Combined	O
effects	O
of	O
prolonged	O
prostaglandin	B-Chemical
E1	I-Chemical
-	O
induced	O
hypotension	B-Disease
and	O
haemodilution	B-Disease
on	O
human	O
hepatic	O
function	O
.	O

Combined	O
effects	O
of	O
prolonged	O
prostaglandin	B-Chemical
E1	I-Chemical
(	O
PGE1	B-Chemical
)	O
-	O
induced	O
hypotension	B-Disease
and	O
haemodilution	B-Disease
on	O
hepatic	O
function	O
were	O
studied	O
in	O
30	O
patients	O
undergoing	O
hip	O
surgery	O
.	O

The	O
patients	O
were	O
randomly	O
allocated	O
to	O
one	O
of	O
three	O
groups	O
;	O
those	O
in	O
group	O
A	O
(	O
n	O
=	O
10	O
)	O
were	O
subjected	O
to	O
controlled	O
hypotension	B-Disease
alone	O
,	O
those	O
in	O
group	O
B	O
(	O
n	O
=	O
10	O
)	O
to	O
haemodilution	B-Disease
alone	O
and	O
those	O
in	O
group	O
C	O
(	O
n	O
=	O
10	O
)	O
to	O
both	O
controlled	O
hypotension	B-Disease
and	O
haemodilution	B-Disease
.	O

Haemodilution	B-Disease
in	O
groups	O
B	O
and	O
C	O
was	O
produced	O
by	O
withdrawing	O
approximately	O
1000	O
mL	O
of	O
blood	O
and	O
replacing	O
it	O
with	O
the	O
same	O
amount	O
of	O
dextran	B-Chemical
solution	O
,	O
and	O
final	O
haematocrit	O
values	O
were	O
21	O
or	O
22	O
%	O
.	O

Controlled	O
hypotension	B-Disease
in	O
groups	O
A	O
and	O
C	O
was	O
induced	O
with	O
PGE1	B-Chemical
to	O
maintain	O
mean	O
arterial	O
blood	O
pressure	O
at	O
55	O
mmHg	O
for	O
180	O
min	O
.	O

Measurements	O
included	O
arterial	O
ketone	O
body	O
ratio	O
(	O
AKBR	O
,	O
aceto	B-Chemical
-	I-Chemical
acetate	I-Chemical
/	O
3	B-Chemical
-	I-Chemical
hydroxybutyrate	I-Chemical
)	O
and	O
clinical	O
hepatic	O
function	O
parameters	O
.	O

AKBR	O
and	O
biological	O
hepatic	O
function	O
tests	O
showed	O
no	O
change	O
throughout	O
the	O
time	O
course	O
in	O
groups	O
A	O
and	O
B	O
.	O

In	O
group	O
C	O
,	O
AKBR	O
showed	O
a	O
significant	O
decrease	O
at	O
120	O
min	O
(	O
-	O
40	O
%	O
)	O
and	O
at	O
180	O
min	O
(	O
-	O
49	O
%	O
)	O
after	O
the	O
start	O
of	O
hypotension	B-Disease
and	O
at	O
60	O
min	O
(	O
-	O
32	O
%	O
)	O
after	O
recovery	O
of	O
normotension	O
,	O
and	O
SGOT	O
,	O
SGPT	O
,	O
LDH	O
and	O
total	O
bilirubin	B-Chemical
showed	O
significant	O
increases	O
after	O
operation	O
.	O

The	O
results	O
suggest	O
that	O
a	O
prolonged	O
combination	O
of	O
more	O
than	O
120	O
min	O
of	O
PGE1	B-Chemical
-	O
induced	O
hypotension	B-Disease
and	O
moderate	O
haemodilution	B-Disease
would	O
cause	O
impairment	B-Disease
of	I-Disease
hepatic	I-Disease
function	I-Disease
.	O

Cardiovascular	B-Disease
alterations	I-Disease
in	O
rat	O
fetuses	O
exposed	O
to	O
calcium	B-Chemical
channel	O
blockers	O
.	O

Preclinical	O
toxicologic	O
investigation	O
suggested	O
that	O
a	O
new	O
calcium	B-Chemical
channel	O
blocker	O
,	O
Ro	B-Chemical
40	I-Chemical
-	I-Chemical
5967	I-Chemical
,	O
induced	O
cardiovascular	B-Disease
alterations	I-Disease
in	O
rat	O
fetuses	O
exposed	O
to	O
this	O
agent	O
during	O
organogenesis	O
.	O

The	O
present	O
study	O
was	O
designed	O
to	O
investigate	O
the	O
hypothesis	O
that	O
calcium	B-Chemical
channel	O
blockers	O
in	O
general	O
induce	O
cardiovascular	B-Disease
malformations	I-Disease
indicating	O
a	O
pharmacologic	O
class	O
effect	O
.	O

We	O
studied	O
three	O
calcium	B-Chemical
channel	O
blockers	O
of	O
different	O
structure	O
,	O
nifedipine	B-Chemical
,	O
diltiazem	B-Chemical
,	O
and	O
verapamil	B-Chemical
,	O
along	O
with	O
the	O
new	O
agent	O
.	O

Pregnant	O
rats	O
were	O
administered	O
one	O
of	O
these	O
calcium	B-Chemical
channel	O
blockers	O
during	O
the	O
period	O
of	O
cardiac	O
morphogenesis	O
and	O
the	O
offspring	O
examined	O
on	O
day	O
20	O
of	O
gestation	O
for	O
cardiovascular	B-Disease
malformations	I-Disease
.	O

A	O
low	O
incidence	O
of	O
cardiovascular	B-Disease
malformations	I-Disease
was	O
observed	O
after	O
exposure	O
to	O
each	O
of	O
the	O
four	O
calcium	B-Chemical
channel	O
blockers	O
,	O
but	O
this	O
incidence	O
was	O
statistically	O
significant	O
only	O
for	O
verapamil	B-Chemical
and	O
nifedipine	B-Chemical
.	O

All	O
four	O
agents	O
were	O
associated	O
with	O
aortic	O
arch	O
branching	O
variants	O
,	O
although	O
significantly	O
increased	O
only	O
for	O
Ro	B-Chemical
40	I-Chemical
-	I-Chemical
5967	I-Chemical
and	O
verapamil	B-Chemical
.	O

The	O
site	O
of	O
common	O
side	O
effects	O
of	O
sumatriptan	B-Chemical
.	O

Atypical	B-Disease
sensations	I-Disease
following	O
the	O
use	O
of	O
subcutaneous	O
sumatriptan	B-Chemical
are	O
common	O
,	O
but	O
of	O
uncertain	O
origin	O
.	O

They	O
are	O
almost	O
always	O
benign	O
,	O
but	O
can	O
be	O
mistaken	O
for	O
a	O
serious	O
adverse	O
event	O
by	O
the	O
patient	O
.	O

Two	O
patients	O
are	O
presented	O
with	O
tingling	B-Disease
or	I-Disease
burning	I-Disease
sensations	I-Disease
limited	O
to	O
areas	O
of	O
heat	O
exposure	O
or	O
sunburn	B-Disease
.	O

In	O
these	O
individuals	O
,	O
side	O
effects	O
are	O
most	O
likely	O
generated	O
superficially	O
in	O
the	O
skin	O
.	O

Macula	O
toxicity	B-Disease
after	O
intravitreal	O
amikacin	B-Chemical
.	O

BACKGROUND	O
:	O
Although	O
intravitreal	O
aminoglycosides	B-Chemical
have	O
substantially	O
improved	O
visual	O
prognosis	O
in	O
endophthalmitis	B-Disease
,	O
macular	O
infarction	B-Disease
may	O
impair	O
full	O
visual	O
recovery	O
.	O

METHODS	O
:	O
We	O
present	O
a	O
case	O
of	O
presumed	O
amikacin	B-Chemical
retinal	B-Disease
toxicity	I-Disease
following	O
treatment	O
with	O
amikacin	B-Chemical
and	O
vancomycin	B-Chemical
for	O
alpha	O
-	O
haemolytic	O
streptococcal	B-Disease
endophthalmitis	I-Disease
.	O

RESULTS	O
:	O
Endophthalmitis	B-Disease
resolved	O
with	O
improvement	O
in	O
visual	O
acuity	O
to	O
6	O
/	O
24	O
at	O
three	O
months	O
.	O

Fundus	O
fluorescein	B-Chemical
angiography	O
confirmed	O
macular	O
capillary	O
closure	O
and	O
telangiectasis	B-Disease
.	O

CONCLUSIONS	O
:	O
Currently	O
accepted	O
intravitreal	O
antibiotic	O
regimens	O
may	O
cause	O
retinal	B-Disease
toxicity	I-Disease
and	O
macular	O
ischaemia	B-Disease
.	O

Treatment	O
strategies	O
aimed	O
at	O
avoiding	O
retinal	B-Disease
toxicity	I-Disease
are	O
discussed	O
.	O

The	O
role	O
of	O
nicotine	B-Chemical
in	O
smoking	O
-	O
related	O
cardiovascular	B-Disease
disease	I-Disease
.	O

Nicotine	B-Chemical
activates	O
the	O
sympathetic	O
nervous	O
system	O
and	O
in	O
this	O
way	O
could	O
contribute	O
to	O
cardiovascular	B-Disease
disease	I-Disease
.	O

Animal	O
studies	O
and	O
mechanistic	O
studies	O
indicate	O
that	O
nicotine	B-Chemical
could	O
play	O
a	O
role	O
in	O
accelerating	O
atherosclerosis	B-Disease
,	O
but	O
evidence	O
among	O
humans	O
is	O
too	O
inadequate	O
to	O
be	O
definitive	O
about	O
such	O
an	O
effect	O
.	O

Almost	O
certainly	O
,	O
nicotine	B-Chemical
via	O
its	O
hemodynamic	O
effects	O
contributes	O
to	O
acute	O
cardiovascular	O
events	O
,	O
although	O
current	O
evidence	O
suggests	O
that	O
the	O
effects	O
of	O
nicotine	B-Chemical
are	O
much	O
less	O
important	O
than	O
are	O
the	O
prothrombotic	O
effects	O
of	O
cigarette	O
smoking	O
or	O
the	O
effects	O
of	O
carbon	B-Chemical
monoxide	I-Chemical
.	O

Nicotine	B-Chemical
does	O
not	O
appear	O
to	O
enhance	O
thrombosis	B-Disease
among	O
humans	O
.	O

Clinical	O
studies	O
of	O
pipe	O
smokers	O
and	O
people	O
using	O
transdermal	O
nicotine	B-Chemical
support	O
the	O
idea	O
that	O
toxins	O
other	O
than	O
nicotine	B-Chemical
are	O
the	O
most	O
important	O
causes	O
of	O
acute	O
cardiovascular	O
events	O
.	O

Finally	O
,	O
the	O
dose	O
response	O
for	O
cardiovascular	O
events	O
of	O
nicotine	B-Chemical
appears	O
to	O
be	O
flat	O
,	O
suggesting	O
that	O
if	O
nicotine	B-Chemical
is	O
involved	O
,	O
adverse	O
effects	O
might	O
be	O
seen	O
with	O
relatively	O
low	O
-	O
level	O
cigarette	O
exposures	O
.	O

Iatrogenically	O
induced	O
intractable	O
atrioventricular	B-Disease
reentrant	I-Disease
tachycardia	I-Disease
after	O
verapamil	B-Chemical
and	O
catheter	O
ablation	O
in	O
a	O
patient	O
with	O
Wolff	B-Disease
-	I-Disease
Parkinson	I-Disease
-	I-Disease
White	I-Disease
syndrome	I-Disease
and	O
idiopathic	B-Disease
dilated	I-Disease
cardiomyopathy	I-Disease
.	O

In	O
a	O
patient	O
with	O
WPW	B-Disease
syndrome	I-Disease
and	O
idiopathic	B-Disease
dilated	I-Disease
cardiomyopathy	I-Disease
,	O
intractable	O
atrioventricular	B-Disease
reentrant	I-Disease
tachycardia	I-Disease
(	O
AVRT	B-Disease
)	O
was	O
iatrogenically	O
induced	O
.	O

QRS	O
without	O
preexcitation	O
,	O
caused	O
by	O
junctional	O
escape	O
beats	O
after	O
verapamil	B-Chemical
or	O
unidirectional	O
antegrade	O
block	O
of	O
accessory	O
pathway	O
after	O
catheter	O
ablation	O
,	O
established	O
frequent	O
AVRT	B-Disease
attack	O
.	O

Epidemic	O
of	O
liver	B-Disease
disease	I-Disease
caused	O
by	O
hydrochlorofluorocarbons	B-Chemical
used	O
as	O
ozone	B-Chemical
-	O
sparing	O
substitutes	O
of	O
chlorofluorocarbons	B-Chemical
.	O

BACKGROUND	O
:	O
Hydrochlorofluorocarbons	B-Chemical
(	O
HCFCs	B-Chemical
)	O
are	O
used	O
increasingly	O
in	O
industry	O
as	O
substitutes	O
for	O
ozone	B-Chemical
-	O
depleting	O
chlorofluorocarbons	B-Chemical
(	O
CFCs	B-Chemical
)	O
.	O

Limited	O
studies	O
in	O
animals	O
indicate	O
potential	O
hepatotoxicity	B-Disease
of	O
some	O
of	O
these	O
compounds	O
.	O

We	O
investigated	O
an	O
epidemic	O
of	O
liver	B-Disease
disease	I-Disease
in	O
nine	O
industrial	O
workers	O
who	O
had	O
had	O
repeated	O
accidental	O
exposure	O
to	O
a	O
mixture	O
of	O
1	B-Chemical
,	I-Chemical
1	I-Chemical
-	I-Chemical
dichloro	I-Chemical
-	I-Chemical
2	I-Chemical
,	I-Chemical
2	I-Chemical
,	I-Chemical
2	I-Chemical
-	I-Chemical
trifluoroethane	I-Chemical
(	O
HCFC	B-Chemical
123	I-Chemical
)	O
and	O
1	B-Chemical
-	I-Chemical
chloro	I-Chemical
-	I-Chemical
1	I-Chemical
,	I-Chemical
2	I-Chemical
,	I-Chemical
2	I-Chemical
,	I-Chemical
2	I-Chemical
-	I-Chemical
tetrafluoroethane	I-Chemical
(	O
HCFC	B-Chemical
124	I-Chemical
)	O
.	O

All	O
nine	O
exposed	O
workers	O
were	O
affected	O
to	O
various	O
degrees	O
.	O

Both	O
compounds	O
are	O
metabolised	O
in	O
the	O
same	O
way	O
as	O
1	B-Chemical
-	I-Chemical
bromo	I-Chemical
-	I-Chemical
1	I-Chemical
-	I-Chemical
chloro	I-Chemical
-	I-Chemical
2	I-Chemical
,	I-Chemical
2	I-Chemical
,	I-Chemical
2	I-Chemical
-	I-Chemical
trifluoroethane	I-Chemical
(	O
halothane	B-Chemical
)	O
to	O
form	O
reactive	O
trifluoroacetyl	B-Chemical
halide	O
intermediates	O
,	O
which	O
have	O
been	O
implicated	O
in	O
the	O
hepatotoxicity	B-Disease
of	O
halothane	B-Chemical
.	O

We	O
aimed	O
to	O
test	O
whether	O
HCFCs	B-Chemical
123	I-Chemical
and	I-Chemical
124	I-Chemical
can	O
result	O
in	O
serious	O
liver	B-Disease
disease	I-Disease
.	O

METHODS	O
:	O
For	O
one	O
severely	O
affected	O
worker	O
liver	O
biopsy	O
and	O
immunohistochemical	O
stainings	O
for	O
the	O
presence	O
of	O
trifluoroacetyl	B-Chemical
protein	O
adducts	O
were	O
done	O
.	O

The	O
serum	O
of	O
six	O
affected	O
workers	O
and	O
five	O
controls	O
was	O
tested	O
for	O
autoantibodies	O
that	O
react	O
with	O
human	O
liver	O
cytochrome	O
-	O
P450	O
2E1	O
(	O
P450	O
2E1	O
)	O
and	O
P58	O
protein	O
disulphide	O
isomerase	O
isoform	O
(	O
P58	O
)	O
.	O

FINDINGS	O
:	O
The	O
liver	O
biopsy	O
sample	O
showed	O
hepatocellular	O
necrosis	B-Disease
which	O
was	O
prominent	O
in	O
perivenular	O
zone	O
three	O
and	O
extended	O
focally	O
from	O
portal	O
tracts	O
to	O
portal	O
tracts	O
and	O
centrilobular	O
areas	O
(	O
bridging	O
necrosis	B-Disease
)	O
.	O

Trifluoroacetyl	B-Chemical
-	O
adducted	O
proteins	O
were	O
detected	O
in	O
surviving	O
hepatocytes	O
.	O

Autoantibodies	O
against	O
P450	O
2E1	O
or	O
P58	O
,	O
previously	O
associated	O
with	O
halothane	B-Disease
hepatitis	I-Disease
,	O
were	O
detected	O
in	O
the	O
serum	O
of	O
five	O
affected	O
workers	O
.	O

INTERPRETATION	O
:	O
Repeated	O
exposure	O
of	O
human	O
beings	O
to	O
HCFCs	B-Chemical
123	I-Chemical
and	I-Chemical
124	I-Chemical
can	O
result	O
in	O
serious	O
liver	B-Disease
injury	I-Disease
in	O
a	O
large	O
proportion	O
of	O
the	O
exposed	O
population	O
.	O

Although	O
the	O
exact	O
mechanism	O
of	O
hepatotoxicity	B-Disease
of	O
these	O
agents	O
is	O
not	O
known	O
,	O
the	O
results	O
suggest	O
that	O
trifluoroacetyl	B-Chemical
-	O
altered	O
liver	O
proteins	O
are	O
involved	O
.	O

In	O
view	O
of	O
the	O
potentially	O
widespread	O
use	O
of	O
these	O
compounds	O
,	O
there	O
is	O
an	O
urgent	O
need	O
to	O
develop	O
safer	O
alternatives	O
.	O

Bile	B-Disease
duct	I-Disease
hamartoma	I-Disease
occurring	O
in	O
association	O
with	O
long	O
-	O
term	O
treatment	O
with	O
danazol	B-Chemical
.	O

We	O
report	O
a	O
case	O
of	O
bile	B-Disease
duct	I-Disease
hamartoma	I-Disease
which	O
developed	O
in	O
a	O
patient	O
who	O
had	O
been	O
on	O
long	O
-	O
term	O
danazol	B-Chemical
treatment	O
.	O

Such	O
patients	O
should	O
be	O
under	O
close	O
follow	O
-	O
up	O
,	O
preferably	O
with	O
periodic	O
ultrasound	O
examination	O
of	O
the	O
liver	O
.	O

If	O
the	O
patient	O
develops	O
a	O
liver	B-Disease
mass	I-Disease
,	O
because	O
of	O
non	O
-	O
specific	O
clinical	O
features	O
and	O
imaging	O
appearances	O
,	O
biopsy	O
may	O
be	O
the	O
only	O
way	O
to	O
achieve	O
a	O
definitive	O
diagnosis	O
.	O

Endocrine	O
screening	O
in	O
1	O
,	O
022	O
men	O
with	O
erectile	B-Disease
dysfunction	I-Disease
:	O
clinical	O
significance	O
and	O
cost	O
-	O
effective	O
strategy	O
.	O

PURPOSE	O
:	O
We	O
reviewed	O
the	O
results	O
of	O
serum	O
testosterone	B-Chemical
and	O
prolactin	O
determination	O
in	O
1	O
,	O
022	O
patients	O
referred	O
because	O
of	O
erectile	B-Disease
dysfunction	I-Disease
and	O
compared	O
the	O
data	O
with	O
history	O
,	O
results	O
of	O
physical	O
examination	O
,	O
other	O
etiological	O
investigations	O
and	O
effects	O
of	O
endocrine	O
therapy	O
to	O
refine	O
the	O
rules	O
of	O
cost	O
-	O
effective	O
endocrine	O
screening	O
and	O
to	O
pinpoint	O
actual	O
responsibility	O
for	O
hormonal	O
abnormalities	O
.	O

MATERIALS	O
AND	O
METHODS	O
:	O
Testosterone	B-Chemical
and	O
prolactin	O
were	O
determined	O
by	O
radioimmunoassay	O
.	O

Every	O
patient	O
was	O
screened	O
for	O
testosterone	B-Chemical
and	O
451	O
were	O
screened	O
for	O
prolactin	O
on	O
the	O
basis	O
of	O
low	B-Disease
sexual	I-Disease
desire	I-Disease
,	O
gynecomastia	B-Disease
or	O
testosterone	B-Chemical
less	O
than	O
4	O
ng	O
.	O
/	O
ml	O
.	O

Determination	O
was	O
repeated	O
in	O
case	O
of	O
abnormal	O
first	O
results	O
.	O

Prolactin	O
results	O
were	O
compared	O
with	O
those	O
of	O
a	O
previous	O
personal	O
cohort	O
of	O
1	O
,	O
340	O
patients	O
with	O
erectile	B-Disease
dysfunction	I-Disease
and	O
systematic	O
prolactin	O
determination	O
.	O

Main	O
clinical	O
criteria	O
tested	O
regarding	O
efficiency	O
in	O
hormone	O
determination	O
were	O
low	B-Disease
sexual	I-Disease
desire	I-Disease
,	O
small	O
testes	O
and	O
gynecomastia	B-Disease
.	O

Endocrine	O
therapy	O
consisted	O
of	O
testosterone	B-Chemical
heptylate	I-Chemical
or	O
human	O
chorionic	O
gonadotropin	O
for	O
hypogonadism	B-Disease
and	O
bromocriptine	B-Chemical
for	O
hyperprolactinemia	B-Disease
.	O

RESULTS	O
:	O
Testosterone	B-Chemical
was	O
less	O
than	O
3	O
ng	O
.	O
/	O
ml	O
.	O
in	O
107	O
patients	O
but	O
normal	O
in	O
40	O
%	O
at	O
repeat	O
determination	O
.	O

The	O
prevalence	O
of	O
repeatedly	O
low	O
testosterone	B-Chemical
increased	O
with	O
age	O
(	O
4	O
%	O
before	O
age	O
50	O
years	O
and	O
9	O
%	O
50	O
years	O
or	O
older	O
)	O
.	O

Two	O
pituitary	B-Disease
tumors	I-Disease
were	O
discovered	O
after	O
testosterone	B-Chemical
determination	O
.	O

Most	O
of	O
the	O
other	O
low	O
testosterone	B-Chemical
levels	O
seemed	O
to	O
result	O
from	O
nonorganic	O
hypothalamic	B-Disease
dysfunction	I-Disease
because	O
of	O
normal	O
serum	O
luteinizing	O
hormone	O
and	O
prolactin	O
and	O
to	O
have	O
only	O
a	O
small	O
role	O
in	O
erectile	B-Disease
dysfunction	I-Disease
(	O
definite	O
improvement	O
in	O
only	O
16	O
of	O
44	O
[	O
36	O
%	O
]	O
after	O
androgen	O
therapy	O
,	O
normal	O
morning	O
or	O
nocturnal	O
erections	O
in	O
30	O
%	O
and	O
definite	O
vasculogenic	O
contributions	O
in	O
42	O
%	O
)	O
.	O

Determining	O
testosterone	B-Chemical
only	O
in	O
cases	O
of	O
low	B-Disease
sexual	I-Disease
desire	I-Disease
or	O
abnormal	O
physical	O
examination	O
would	O
have	O
missed	O
40	O
%	O
of	O
the	O
cases	O
with	O
low	O
testosterone	B-Chemical
,	O
including	O
37	O
%	O
of	O
those	O
subsequently	O
improved	O
by	O
androgen	O
therapy	O
.	O

Prolactin	O
exceeded	O
20	O
ng	O
.	O
/	O
ml	O
.	O
in	O
5	O
men	O
and	O
was	O
normal	O
in	O
2	O
at	O
repeat	O
determination	O
.	O

Only	O
1	O
prolactinoma	B-Disease
was	O
discovered	O
.	O

These	O
data	O
are	O
lower	O
than	O
those	O
we	O
found	O
during	O
the	O
last	O
2	O
decades	O
(	O
overall	O
prolactin	O
greater	O
than	O
20	O
ng	O
.	O
/	O
ml	O
.	O
in	O
1	O
.	O
86	O
%	O
of	O
1	O
,	O
821	O
patients	O
,	O
prolactinomas	B-Disease
in	O
7	O
,	O
0	O
.	O
38	O
%	O
)	O
.	O

Bromocriptine	B-Chemical
was	O
definitely	O
effective	O
in	O
cases	O
with	O
prolactin	O
greater	O
than	O
35	O
ng	O
.	O
/	O
ml	O
.	O

(	O
8	O
of	O
12	O
compared	O
to	O
only	O
9	O
of	O
22	O
cases	O
with	O
prolactin	O
between	O
20	O
and	O
35	O
ng	O
.	O
/	O
ml	O
.	O
)	O
.	O

Testosterone	B-Chemical
was	O
low	O
in	O
less	O
than	O
50	O
%	O
of	O
cases	O
with	O
prolactin	O
greater	O
than	O
35	O
ng	O
.	O
/	O
ml	O
.	O

CONCLUSIONS	O
:	O
Low	O
prevalences	O
and	O
effects	O
of	O
low	O
testosterone	B-Chemical
and	O
high	O
prolactin	O
in	O
erectile	B-Disease
dysfunction	I-Disease
cannot	O
justify	O
their	O
routine	O
determination	O
.	O

However	O
,	O
cost	O
-	O
effective	O
screening	O
strategies	O
recommended	O
so	O
far	O
missed	O
40	O
to	O
50	O
%	O
of	O
cases	O
improved	O
with	O
endocrine	O
therapy	O
and	O
the	O
pituitary	B-Disease
tumors	I-Disease
.	O

We	O
now	O
advocate	O
that	O
before	O
age	O
50	O
years	O
testosterone	B-Chemical
be	O
determined	O
only	O
in	O
cases	O
of	O
low	B-Disease
sexual	I-Disease
desire	I-Disease
and	O
abnormal	O
physical	O
examination	O
but	O
that	O
it	O
be	O
measured	O
in	O
all	O
men	O
older	O
than	O
50	O
years	O
.	O

Prolactin	O
should	O
be	O
determined	O
only	O
in	O
cases	O
of	O
low	B-Disease
sexual	I-Disease
desire	I-Disease
,	O
gynecomastia	B-Disease
and	O
/	O
or	O
testosterone	B-Chemical
less	O
than	O
4	O
ng	O
.	O
/	O
ml	O
.	O

Extrapyramidal	O
side	O
effects	O
with	O
risperidone	B-Chemical
and	O
haloperidol	B-Chemical
at	O
comparable	O
D2	O
receptor	O
occupancy	O
levels	O
.	O

Risperidone	B-Chemical
is	O
an	O
antipsychotic	O
drug	O
with	O
high	O
affinity	O
at	O
dopamine	B-Chemical
D2	O
and	O
serotonin	B-Chemical
5	I-Chemical
-	I-Chemical
HT2	I-Chemical
receptors	O
.	O

Previous	O
clinical	O
studies	O
have	O
proposed	O
that	O
risperidone	B-Chemical
'	O
s	O
pharmacologic	O
profile	O
may	O
produce	O
improved	O
efficacy	O
for	O
negative	O
psychotic	B-Disease
symptoms	I-Disease
and	O
decreased	O
propensity	O
for	O
extrapyramidal	O
side	O
effects	O
;	O
features	O
shared	O
by	O
so	O
-	O
called	O
'	O
atypical	O
'	O
neuroleptics	O
.	O

To	O
determine	O
if	O
routine	O
risperidone	B-Chemical
treatment	O
is	O
associated	O
with	O
a	O
unique	O
degree	O
of	O
D2	O
receptor	O
occupancy	O
and	O
pattern	O
of	O
clinical	O
effects	O
,	O
we	O
used	O
[	O
123I	O
]	O
IBZM	O
SPECT	O
to	O
determine	O
D2	O
occupancy	O
in	O
subjects	O
treated	O
with	O
routine	O
clinical	O
doses	O
of	O
risperidone	B-Chemical
(	O
n	O
=	O
12	O
)	O
or	O
haloperidol	B-Chemical
(	O
n	O
=	O
7	O
)	O
.	O

Both	O
risperidone	B-Chemical
and	O
haloperidol	B-Chemical
produced	O
D2	O
occupancy	O
levels	O
between	O
approximately	O
60	O
and	O
90	O
%	O
at	O
standard	O
clinical	O
doses	O
.	O

There	O
was	O
no	O
significant	O
difference	O
between	O
occupancy	O
levels	O
obtained	O
with	O
haloperidol	B-Chemical
or	O
risperidone	B-Chemical
.	O

Drug	B-Disease
-	I-Disease
induced	I-Disease
parkinsonism	I-Disease
was	O
observed	O
in	O
subjects	O
treated	O
with	O
risperidone	B-Chemical
(	O
42	O
%	O
)	O
and	O
haloperidol	B-Chemical
(	O
29	O
%	O
)	O
and	O
was	O
observed	O
at	O
occupancy	O
levels	O
above	O
60	O
%	O
.	O

Based	O
on	O
these	O
observations	O
,	O
it	O
is	O
concluded	O
that	O
5	O
-	O
HT2	O
blockade	O
obtained	O
with	O
risperidone	B-Chemical
at	O
D2	O
occupancy	O
rates	O
of	O
60	O
%	O
and	O
above	O
does	O
not	O
appear	O
to	O
protect	O
against	O
the	O
risk	O
for	O
extrapyramidal	O
side	O
effects	O
.	O

Treatment	O
of	O
previously	O
treated	O
metastatic	O
breast	B-Disease
cancer	I-Disease
by	O
mitoxantrone	B-Chemical
and	O
48	O
-	O
hour	O
continuous	O
infusion	O
of	O
high	O
-	O
dose	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
and	O
leucovorin	B-Chemical
(	O
MFL	B-Chemical
)	O
:	O
low	O
palliative	O
benefit	O
and	O
high	O
treatment	O
-	O
related	O
toxicity	B-Disease
.	O

For	O
previously	O
treated	O
advanced	O
breast	B-Disease
cancer	I-Disease
,	O
there	O
is	O
no	O
standard	O
second	O
-	O
line	O
therapy	O
.	O

Combination	O
chemotherapy	O
with	O
mitoxantrone	B-Chemical
,	O
high	O
-	O
dose	O
5	B-Chemical
-	I-Chemical
fluorouracil	I-Chemical
(	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
)	O
and	O
leucovorin	B-Chemical
(	O
MFL	B-Chemical
regimen	I-Chemical
)	O
had	O
been	O
reported	O
as	O
an	O
effective	O
and	O
well	O
tolerated	O
regimen	O
.	O

From	O
October	O
1993	O
to	O
November	O
1995	O
,	O
we	O
treated	O
13	O
patients	O
with	O
previously	O
chemotherapy	O
-	O
treated	O
metastatic	O
breast	B-Disease
cancer	I-Disease
by	O
mitoxantrone	B-Chemical
,	O
12	O
mg	O
/	O
m2	O
,	O
on	O
day	O
1	O
and	O
continuous	O
infusion	O
of	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
,	O
3000	O
mg	O
/	O
m2	O
,	O
together	O
with	O
leucovorin	B-Chemical
,	O
300	O
mg	O
/	O
m2	O
,	O
for	O
48	O
h	O
from	O
day	O
1	O
to	O
2	O
.	O

Each	O
course	O
of	O
chemotherapy	O
was	O
given	O
every	O
4	O
weeks	O
.	O

Most	O
of	O
these	O
patients	O
had	O
more	O
than	O
two	O
metastatic	O
sites	O
,	O
with	O
lung	O
metastasis	O
predominant	O
.	O

Seven	O
patients	O
had	O
been	O
treated	O
with	O
anthracycline	B-Chemical
.	O

Seven	O
patients	O
had	O
previously	O
received	O
radiotherapy	O
and	O
seven	O
had	O
received	O
hormone	O
therapy	O
.	O

Median	O
number	O
of	O
courses	O
of	O
MFL	B-Chemical
regimen	I-Chemical
given	O
was	O
six	O
and	O
the	O
median	O
cumulative	O
dose	O
of	O
mitoxantrone	B-Chemical
was	O
68	O
.	O
35	O
mg	O
/	O
m2	O
.	O

One	O
patient	O
had	O
complete	O
response	O
,	O
seven	O
had	O
stable	O
disease	O
,	O
none	O
had	O
partial	O
response	O
and	O
five	O
had	O
progressive	O
disease	O
.	O

The	O
overall	O
objective	O
response	O
rate	O
was	O
7	O
.	O
6	O
%	O
.	O

The	O
median	O
follow	O
-	O
up	O
period	O
was	O
14	O
months	O
.	O

Median	O
survival	O
was	O
16	O
months	O
.	O

Median	O
progression	O
-	O
free	O
survival	O
was	O
5	O
months	O
.	O

A	O
complete	O
responder	O
had	O
relapse	O
-	O
free	O
survival	O
up	O
to	O
17	O
months	O
.	O

Major	O
toxicities	B-Disease
were	O
cardiotoxicity	B-Disease
and	O
leukopenia	B-Disease
.	O

Eight	O
patients	O
were	O
dead	O
in	O
the	O
last	O
follow	O
-	O
up	O
;	O
two	O
of	O
them	O
died	O
of	O
treatment	O
-	O
related	O
toxicity	B-Disease
.	O

The	O
MFL	B-Chemical
regimen	I-Chemical
achieves	O
little	O
palliative	O
benefit	O
and	O
induces	O
severe	O
toxicity	B-Disease
at	O
a	O
fairly	O
high	O
rate	O
.	O

Administration	O
of	O
this	O
regimen	O
to	O
breast	B-Disease
cancer	I-Disease
patients	O
who	O
have	O
been	O
treated	O
by	O
chemotherapy	O
and	O
those	O
with	O
impaired	B-Disease
heart	I-Disease
function	I-Disease
requires	O
careful	O
attention	O
.	O

Ticlopidine	B-Chemical
-	O
induced	O
aplastic	B-Disease
anemia	I-Disease
:	O
report	O
of	O
three	O
Chinese	O
patients	O
and	O
review	O
of	O
the	O
literature	O
.	O

In	O
this	O
study	O
,	O
three	O
Chinese	O
patients	O
with	O
ticlopidine	B-Chemical
-	O
induced	O
aplastic	B-Disease
anemia	I-Disease
were	O
reported	O
and	O
another	O
13	O
patients	O
in	O
the	O
English	O
literature	O
were	O
reviewed	O
.	O

We	O
attempted	O
to	O
find	O
underlying	O
similarities	O
,	O
evaluate	O
the	O
risk	O
factors	O
,	O
and	O
identify	O
appropriate	O
treatment	O
for	O
this	O
complication	O
.	O

All	O
but	O
one	O
of	O
the	O
patients	O
were	O
over	O
60	O
years	O
old	O
,	O
and	O
the	O
6	O
who	O
died	O
were	O
all	O
older	O
than	O
65	O
.	O

Therefore	O
,	O
old	O
age	O
may	O
be	O
a	O
risk	O
factor	O
for	O
developing	O
this	O
complication	O
.	O

Agranulocytosis	B-Disease
occurred	O
3	O
-	O
20	O
weeks	O
after	O
initiation	O
of	O
ticlopidine	B-Chemical
,	O
so	O
frequent	O
examination	O
of	O
white	O
cell	O
count	O
during	O
treatment	O
is	O
recommended	O
.	O

There	O
seemed	O
to	O
be	O
no	O
direct	O
correlation	O
between	O
the	O
dose	O
or	O
duration	O
used	O
and	O
the	O
severity	O
of	O
bone	B-Disease
marrow	I-Disease
suppression	I-Disease
.	O

Treatment	O
for	O
ticlopidine	B-Chemical
-	O
induced	O
aplastic	B-Disease
anemia	I-Disease
with	O
colony	O
-	O
stimulating	O
factors	O
seemed	O
to	O
have	O
little	O
effect	O
.	O

The	O
fact	O
that	O
5	O
of	O
the	O
6	O
patients	O
who	O
received	O
concurrent	O
calcium	B-Chemical
channel	O
blockers	O
died	O
,	O
should	O
alert	O
clinicians	O
to	O
be	O
more	O
cautious	O
when	O
using	O
these	O
two	O
drugs	O
simultaneously	O
.	O

Upregulation	O
of	O
the	O
expression	O
of	O
vasopressin	B-Chemical
gene	O
in	O
the	O
paraventricular	O
and	O
supraoptic	O
nuclei	O
of	O
the	O
lithium	B-Chemical
-	O
induced	O
diabetes	B-Disease
insipidus	I-Disease
rat	O
.	O

The	O
expression	O
of	O
arginine	B-Chemical
vasopressin	I-Chemical
(	O
AVP	B-Chemical
)	O
gene	O
in	O
the	O
paraventricular	O
(	O
PVN	O
)	O
and	O
supraoptic	O
nuclei	O
(	O
SON	O
)	O
was	O
investigated	O
in	O
rats	O
with	O
lithium	B-Chemical
(	O
Li	B-Chemical
)	O
-	O
induced	O
polyuria	B-Disease
,	O
using	O
in	O
situ	O
hybridization	O
histochemistry	O
and	O
radioimmunoassay	O
.	O

The	O
male	O
Wistar	O
rats	O
consuming	O
a	O
diet	O
that	O
contained	O
LiCl	B-Chemical
(	O
60	O
mmol	O
/	O
kg	O
)	O
for	O
4	O
weeks	O
developed	O
marked	O
polyuria	B-Disease
.	O

The	O
Li	B-Chemical
-	O
treated	O
rats	O
produced	O
a	O
large	O
volume	O
of	O
hypotonic	O
urine	O
with	O
low	O
ionic	O
concentrations	O
.	O

Plasma	O
sodium	B-Chemical
concentrations	O
were	O
found	O
to	O
be	O
slightly	O
increased	O
in	O
the	O
Li	B-Chemical
-	O
treated	O
rats	O
compared	O
with	O
those	O
in	O
controls	O
.	O

Plasma	O
concentration	O
of	O
AVP	B-Chemical
and	O
transcripts	O
of	O
AVP	B-Chemical
gene	O
in	O
the	O
PVN	O
and	O
SON	O
were	O
significantly	O
increased	O
in	O
the	O
Li	B-Chemical
-	O
treated	O
rats	O
compared	O
with	O
controls	O
.	O

These	O
results	O
suggest	O
that	O
dehydration	B-Disease
and	O
/	O
or	O
the	O
activation	O
of	O
visceral	O
afferent	O
inputs	O
may	O
contribute	O
to	O
the	O
elevation	O
of	O
plasma	O
AVP	B-Chemical
and	O
the	O
upregulation	O
of	O
AVP	B-Chemical
gene	O
expression	O
in	O
the	O
PVN	O
and	O
the	O
SON	O
of	O
the	O
Li	B-Chemical
-	O
induced	O
diabetes	B-Disease
insipidus	I-Disease
rat	O
.	O

Antinociceptive	O
and	O
antiamnesic	O
properties	O
of	O
the	O
presynaptic	O
cholinergic	O
amplifier	O
PG	B-Chemical
-	I-Chemical
9	I-Chemical
.	O

The	O
antinociceptive	O
effect	O
of	O
3	B-Chemical
alpha	I-Chemical
-	I-Chemical
tropyl	I-Chemical
2	I-Chemical
-	I-Chemical
(	I-Chemical
p	I-Chemical
-	I-Chemical
bromophenyl	I-Chemical
)	I-Chemical
propionate	I-Chemical
[	O
(	O
+	O
/	O
-	O
)	O
-	O
PG	B-Chemical
-	I-Chemical
9	I-Chemical
]	O
(	O
10	O
-	O
40	O
mg	O
kg	O
-	O
1	O
s	O
.	O
c	O
.	O
;	O
30	O
-	O
60	O
mg	O
kg	O
-	O
1	O
p	O
.	O
o	O
.	O
;	O
10	O
-	O
30	O
mg	O
kg	O
-	O
1	O
i	O
.	O
v	O
.	O
;	O
10	O
-	O
30	O
micrograms	O
/	O
mouse	O
i	O
.	O
c	O
.	O
v	O
.	O
)	O
was	O
examined	O
in	O
mice	O
,	O
rats	O
and	O
guinea	O
pigs	O
by	O
use	O
of	O
the	O
hot	O
-	O
plate	O
,	O
abdominal	O
-	O
constriction	O
,	O
tail	O
-	O
flick	O
and	O
paw	O
-	O
pressure	O
tests	O
.	O

(	O
+	O
/	O
-	O
)	O
-	O
PG	B-Chemical
-	I-Chemical
9	I-Chemical
antinociception	O
peaked	O
15	O
min	O
after	O
injection	O
and	O
then	O
slowly	O
diminished	O
.	O

The	O
antinociception	O
produced	O
by	O
(	O
+	O
/	O
-	O
)	O
-	O
PG	B-Chemical
-	I-Chemical
9	I-Chemical
was	O
prevented	O
by	O
the	O
unselective	O
muscarinic	O
antagonist	O
atropine	B-Chemical
,	O
the	O
M1	O
-	O
selective	O
antagonists	O
pirenzepine	B-Chemical
and	O
dicyclomine	B-Chemical
and	O
the	O
acetylcholine	B-Chemical
depletor	O
hemicholinium	B-Chemical
-	I-Chemical
3	I-Chemical
,	O
but	O
not	O
by	O
the	O
opioid	O
antagonist	O
naloxone	B-Chemical
,	O
the	O
gamma	B-Chemical
-	I-Chemical
aminobutyric	I-Chemical
acidB	I-Chemical
antagonist	O
3	B-Chemical
-	I-Chemical
aminopropyl	I-Chemical
-	I-Chemical
diethoxy	I-Chemical
-	I-Chemical
methyl	I-Chemical
-	I-Chemical
phosphinic	I-Chemical
acid	I-Chemical
,	O
the	O
H3	O
agonist	O
R	B-Chemical
-	I-Chemical
(	I-Chemical
alpha	I-Chemical
)	I-Chemical
-	I-Chemical
methylhistamine	I-Chemical
,	O
the	O
D2	O
antagonist	O
quinpirole	B-Chemical
,	O
the	O
5	B-Chemical
-	I-Chemical
hydroxytryptamine4	I-Chemical
antagonist	O
2	B-Chemical
-	I-Chemical
methoxy	I-Chemical
-	I-Chemical
4	I-Chemical
-	I-Chemical
amino	I-Chemical
-	I-Chemical
5	I-Chemical
-	I-Chemical
chlorobenzoic	I-Chemical
acid	I-Chemical
2	I-Chemical
-	I-Chemical
(	I-Chemical
diethylamino	I-Chemical
)	I-Chemical
ethyl	I-Chemical
ester	I-Chemical
hydrochloride	O
,	O
the	O
5	B-Chemical
-	I-Chemical
hydroxytryptamin1A	I-Chemical
antagonist	O
1	B-Chemical
-	I-Chemical
(	I-Chemical
2	I-Chemical
-	I-Chemical
methoxyphenyl	I-Chemical
)	I-Chemical
-	I-Chemical
4	I-Chemical
-	I-Chemical
[	I-Chemical
4	I-Chemical
-	I-Chemical
(	I-Chemical
2	I-Chemical
-	I-Chemical
phthalimido	I-Chemical
)	I-Chemical
butyl	I-Chemical
]	I-Chemical
piperazine	I-Chemical
hydrobromide	O
and	O
the	O
polyamines	O
depletor	O
reserpine	B-Chemical
.	O

Based	O
on	O
these	O
data	O
,	O
it	O
can	O
be	O
postulated	O
that	O
(	O
+	O
/	O
-	O
)	O
-	O
PG	B-Chemical
-	I-Chemical
9	I-Chemical
exerted	O
an	O
antinociceptive	O
effect	O
mediated	O
by	O
a	O
central	O
potentiation	O
of	O
cholinergic	O
transmission	O
.	O

(	O
+	O
/	O
-	O
)	O
-	O
PG	B-Chemical
-	I-Chemical
9	I-Chemical
(	O
10	O
-	O
40	O
mg	O
kg	O
-	O
1	O
i	O
.	O
p	O
.	O
)	O
was	O
able	O
to	O
prevent	O
amnesia	B-Disease
induced	O
by	O
scopolamine	B-Chemical
(	O
1	O
mg	O
kg	O
-	O
1	O
i	O
.	O
p	O
.	O
)	O
and	O
dicyclomine	B-Chemical
(	O
2	O
mg	O
kg	O
-	O
1	O
i	O
.	O
p	O
.	O
)	O
in	O
the	O
mouse	O
passive	O
-	O
avoidance	O
test	O
.	O

Affinity	O
profiles	O
of	O
(	O
+	O
/	O
-	O
)	O
-	O
PG	B-Chemical
-	I-Chemical
9	I-Chemical
for	O
muscarinic	O
receptor	O
subtypes	O
,	O
determined	O
by	O
functional	O
studies	O
(	O
rabbit	O
vas	O
deferens	O
for	O
M1	O
,	O
guinea	O
pig	O
atrium	O
for	O
M2	O
,	O
guinea	O
pig	O
ileum	O
for	O
M3	O
and	O
immature	O
guinea	O
pig	O
uterus	O
for	O
putative	O
M4	O
)	O
,	O
have	O
shown	O
an	O
M4	O
/	O
M1	O
selectivity	O
ratio	O
of	O
10	O
.	O
2	O
that	O
might	O
be	O
responsible	O
for	O
the	O
antinociception	O
and	O
the	O
anti	O
-	O
amnesic	B-Disease
effect	O
induced	O
by	O
(	O
+	O
/	O
-	O
)	O
-	O
PG	B-Chemical
-	I-Chemical
9	I-Chemical
through	O
an	O
increase	O
in	O
acetylcholine	B-Chemical
extracellular	O
levels	O
.	O

In	O
the	O
antinociceptive	O
and	O
antiamnesic	O
dose	O
range	O
,	O
(	O
+	O
/	O
-	O
)	O
-	O
PG	B-Chemical
-	I-Chemical
9	I-Chemical
did	O
not	O
impair	O
mouse	O
performance	O
evaluated	O
by	O
the	O
rota	O
-	O
rod	O
test	O
and	O
Animex	O
apparatus	O
.	O

The	O
effect	O
of	O
different	O
anaesthetic	O
agents	O
in	O
hearing	B-Disease
loss	I-Disease
following	O
spinal	O
anaesthesia	O
.	O

The	O
cause	O
of	O
hearing	B-Disease
loss	I-Disease
after	O
spinal	O
anaesthesia	O
is	O
unknown	O
.	O

Up	O
until	O
now	O
,	O
the	O
only	O
factor	O
studied	O
has	O
been	O
the	O
effect	O
of	O
the	O
diameter	O
of	O
the	O
spinal	O
needle	O
on	O
post	O
-	O
operative	O
sensorineural	B-Disease
hearing	I-Disease
loss	I-Disease
.	O

The	O
aim	O
of	O
this	O
study	O
was	O
to	O
describe	O
this	O
hearing	B-Disease
loss	I-Disease
and	O
to	O
investigate	O
other	O
factors	O
influencing	O
the	O
degree	O
of	O
hearing	B-Disease
loss	I-Disease
.	O

Two	O
groups	O
of	O
22	O
similar	O
patients	O
were	O
studied	O
:	O
one	O
group	O
received	O
6	O
mL	O
prilocaine	B-Chemical
2	O
%	O
;	O
and	O
the	O
other	O
received	O
3	O
mL	O
bupivacaine	B-Chemical
0	O
.	O
5	O
%	O
.	O

Patients	O
given	O
prilocaine	B-Chemical
were	O
more	O
likely	O
to	O
develop	O
hearing	B-Disease
loss	I-Disease
(	O
10	O
out	O
of	O
22	O
)	O
than	O
those	O
given	O
bupivacaine	B-Chemical
(	O
4	O
out	O
of	O
22	O
)	O
(	O
P	O
<	O
0	O
.	O
05	O
)	O
.	O

The	O
average	O
hearing	B-Disease
loss	I-Disease
for	O
speech	O
frequencies	O
was	O
about	O
10	O
dB	O
after	O
prilocaine	B-Chemical
and	O
15	O
dB	O
after	O
bupivacaine	B-Chemical
.	O

None	O
of	O
the	O
patients	O
complained	O
of	O
subjective	O
hearing	B-Disease
loss	I-Disease
.	O

Long	O
-	O
term	O
follow	O
-	O
up	O
of	O
the	O
patients	O
was	O
not	O
possible	O
.	O

A	O
transient	O
neurological	B-Disease
deficit	I-Disease
following	O
intrathecal	O
injection	O
of	O
1	O
%	O
hyperbaric	O
bupivacaine	B-Chemical
for	O
unilateral	O
spinal	O
anaesthesia	O
.	O

We	O
describe	O
a	O
case	O
of	O
transient	O
neurological	B-Disease
deficit	I-Disease
that	O
occurred	O
after	O
unilateral	O
spinal	O
anaesthesia	O
with	O
8	O
mg	O
of	O
1	O
%	O
hyperbaric	O
bupivacaine	B-Chemical
slowly	O
injected	O
through	O
a	O
25	O
-	O
gauge	O
pencil	O
-	O
point	O
spinal	O
needle	O
.	O

The	O
surgery	O
and	O
anaesthesia	O
were	O
uneventful	O
,	O
but	O
3	O
days	O
after	O
surgery	O
,	O
the	O
patient	O
reported	O
an	O
area	O
of	O
hypoaesthesia	O
over	O
L3	O
-	O
L4	O
dermatomes	O
of	O
the	O
leg	O
which	O
had	O
been	O
operated	O
on	O
(	O
loss	B-Disease
of	I-Disease
pinprick	I-Disease
sensation	I-Disease
)	O
without	O
reduction	O
in	O
muscular	O
strength	O
.	O

Sensation	O
in	O
this	O
area	O
returned	O
to	O
normal	O
over	O
the	O
following	O
2	O
weeks	O
.	O

Prospective	O
multicentre	O
studies	O
with	O
a	O
large	O
population	O
and	O
a	O
long	O
follow	O
-	O
up	O
should	O
be	O
performed	O
in	O
order	O
to	O
evaluate	O
the	O
incidence	O
of	O
this	O
unusual	O
side	O
effect	O
.	O

However	O
,	O
we	O
suggest	O
that	O
a	O
low	O
solution	O
concentration	O
should	O
be	O
preferred	O
for	O
unilateral	O
spinal	O
anaesthesia	O
with	O
a	O
hyperbaric	O
anaesthetic	O
solution	O
(	O
if	O
pencil	O
-	O
point	O
needle	O
and	O
slow	O
injection	O
rate	O
are	O
employed	O
)	O
,	O
in	O
order	O
to	O
minimize	O
the	O
risk	O
of	O
a	O
localized	O
high	O
peak	O
anaesthetic	O
concentration	O
,	O
which	O
might	O
lead	O
to	O
a	O
transient	O
neurological	B-Disease
deficit	I-Disease
.	O

Transient	B-Disease
neurologic	I-Disease
symptoms	I-Disease
after	O
spinal	O
anesthesia	O
:	O
a	O
lower	O
incidence	O
with	O
prilocaine	B-Chemical
and	O
bupivacaine	B-Chemical
than	O
with	O
lidocaine	B-Chemical
.	O

BACKGROUND	O
:	O
Recent	O
evidence	O
suggests	O
that	O
transient	B-Disease
neurologic	I-Disease
symptoms	I-Disease
(	O
TNSs	B-Disease
)	O
frequently	O
follow	O
lidocaine	B-Chemical
spinal	O
anesthesia	O
but	O
are	O
infrequent	O
with	O
bupivacaine	B-Chemical
.	O

However	O
,	O
identification	O
of	O
a	O
short	O
-	O
acting	O
local	O
anesthetic	O
to	O
substitute	O
for	O
lidocaine	B-Chemical
for	O
brief	O
surgical	O
procedures	O
remains	O
an	O
important	O
goal	O
.	O

Prilocaine	B-Chemical
is	O
an	O
amide	O
local	O
anesthetic	O
with	O
a	O
duration	O
of	O
action	O
similar	O
to	O
that	O
of	O
lidocaine	B-Chemical
.	O

Accordingly	O
,	O
the	O
present	O
,	O
prospective	O
double	O
-	O
blind	O
study	O
compares	O
prilocaine	B-Chemical
with	O
lidocaine	B-Chemical
and	O
bupivacaine	B-Chemical
with	O
respect	O
to	O
duration	O
of	O
action	O
and	O
relative	O
risk	O
of	O
TNSs	B-Disease
.	O

METHODS	O
:	O
Ninety	O
patients	O
classified	O
as	O
American	O
Society	O
of	O
Anesthesiologists	O
physical	O
status	O
I	O
or	O
II	O
who	O
were	O
scheduled	O
for	O
short	O
gynecologic	O
procedures	O
under	O
spinal	O
anesthesia	O
were	O
randomly	O
allocated	O
to	O
receive	O
2	O
.	O
5	O
ml	O
2	O
%	O
lidocaine	B-Chemical
in	O
7	O
.	O
5	O
%	O
glucose	B-Chemical
,	O
2	O
%	O
prilocaine	B-Chemical
in	O
7	O
.	O
5	O
%	O
glucose	B-Chemical
,	O
or	O
0	O
.	O
5	O
%	O
bupivacaine	B-Chemical
in	O
7	O
.	O
5	O
%	O
glucose	B-Chemical
.	O

All	O
solutions	O
were	O
provided	O
in	O
blinded	O
vials	O
by	O
the	O
hospital	O
pharmacy	O
.	O

Details	O
of	O
spinal	O
puncture	O
,	O
extension	O
and	O
regression	O
of	O
spinal	O
block	O
,	O
and	O
the	O
times	O
to	O
reach	O
discharge	O
criteria	O
were	O
noted	O
.	O

In	O
the	O
evening	O
of	O
postoperative	O
day	O
1	O
,	O
patients	O
were	O
evaluated	O
for	O
TNSs	B-Disease
by	O
a	O
physician	O
unaware	O
of	O
the	O
drug	O
administered	O
and	O
the	O
details	O
of	O
the	O
anesthetic	O
procedure	O
.	O

RESULTS	O
:	O
Nine	O
of	O
30	O
patients	O
receiving	O
lidocaine	B-Chemical
experienced	O
TNSs	B-Disease
,	O
1	O
of	O
30	O
patients	O
receiving	O
prilocaine	B-Chemical
(	O
P	O
=	O
0	O
.	O
03	O
)	O
had	O
them	O
,	O
and	O
none	O
of	O
30	O
patients	O
receiving	O
bupivacaine	B-Chemical
had	O
TNSs	B-Disease
.	O

Times	O
to	O
ambulate	O
and	O
to	O
void	O
were	O
similar	O
after	O
lidocaine	B-Chemical
and	O
prilocaine	B-Chemical
(	O
150	O
vs	O
.	O
165	O
min	O
and	O
238	O
vs	O
.	O
253	O
min	O
,	O
respectively	O
)	O
but	O
prolonged	O
after	O
bupivacaine	B-Chemical
(	O
200	O
and	O
299	O
min	O
,	O
respectively	O
;	O
P	O
<	O
0	O
.	O
05	O
)	O
.	O

CONCLUSIONS	O
:	O
Prilocaine	B-Chemical
may	O
be	O
preferable	O
to	O
lidocaine	B-Chemical
for	O
short	O
surgical	O
procedures	O
because	O
it	O
has	O
a	O
similar	O
duration	O
of	O
action	O
but	O
a	O
lower	O
incidence	O
of	O
TNSs	B-Disease
.	O

Suxamethonium	B-Chemical
-	O
induced	O
cardiac	B-Disease
arrest	I-Disease
and	O
death	B-Disease
following	O
5	O
days	O
of	O
immobilization	O
.	O

The	O
present	O
report	O
describes	O
a	O
case	O
of	O
cardiac	B-Disease
arrest	I-Disease
and	O
subsequent	O
death	B-Disease
as	O
a	O
result	O
of	O
hyperkalaemia	B-Disease
following	O
the	O
use	O
of	O
suxamethonium	B-Chemical
in	O
a	O
23	O
-	O
year	O
-	O
old	O
Malawian	O
woman	O
.	O

Five	O
days	O
after	O
the	O
onset	O
of	O
the	O
symptoms	O
of	O
meningitis	B-Disease
,	O
the	O
patient	O
aspirated	O
stomach	O
contents	O
and	O
needed	O
endotracheal	O
intubation	O
.	O

Forty	O
seconds	O
after	O
injection	O
of	O
suxamethonium	B-Chemical
,	O
bradycardia	B-Disease
and	O
cardiac	B-Disease
arrest	I-Disease
occurred	O
.	O

Attempts	O
to	O
resuscitate	O
the	O
patient	O
were	O
not	O
successful	O
.	O

The	O
serum	O
level	O
of	O
potassium	B-Chemical
was	O
observed	O
to	O
be	O
8	O
.	O
4	O
mequiv	O
L	O
-	O
1	O
.	O

Apart	O
from	O
the	O
reduction	O
in	O
the	O
patient	O
'	O
s	O
level	O
of	O
consciousness	O
,	O
there	O
were	O
no	O
signs	O
of	O
motor	O
neurone	O
damage	O
or	O
of	O
any	O
of	O
the	O
other	O
known	O
predisposing	O
conditions	O
for	O
hyperkalaemia	B-Disease
following	O
the	O
administration	O
of	O
suxamethonium	B-Chemical
.	O

It	O
is	O
postulated	O
that	O
her	O
death	B-Disease
was	O
caused	O
by	O
hypersensitivity	B-Disease
to	O
suxamethonium	B-Chemical
,	O
associated	O
with	O
her	O
5	O
-	O
day	O
immobilization	O
.	O

Acute	O
hepatitis	B-Disease
,	O
autoimmune	B-Disease
hemolytic	I-Disease
anemia	I-Disease
,	O
and	O
erythroblastocytopenia	B-Disease
induced	O
by	O
ceftriaxone	B-Chemical
.	O

An	O
80	O
-	O
yr	O
-	O
old	O
man	O
developed	O
acute	O
hepatitis	B-Disease
shortly	O
after	O
ingesting	O
oral	O
ceftriaxone	B-Chemical
.	O

Although	O
the	O
transaminases	O
gradually	O
returned	O
to	O
baseline	O
after	O
withholding	O
the	O
beta	B-Chemical
lactam	I-Chemical
antibiotic	O
,	O
there	O
was	O
a	O
gradual	O
increase	O
in	O
serum	O
bilirubin	B-Chemical
and	O
a	O
decrease	O
in	O
hemoglobin	O
concentration	O
caused	O
by	O
an	O
autoimmune	B-Disease
hemolytic	I-Disease
anemia	I-Disease
and	O
erythroblastocytopenia	B-Disease
.	O

These	O
responded	O
to	O
systemic	O
steroids	B-Chemical
and	O
immunoglobulins	O
.	O

Despite	O
the	O
widespread	O
use	O
of	O
these	O
agents	O
this	O
triad	O
of	O
side	O
effects	O
has	O
not	O
previously	O
been	O
reported	O
in	O
connection	O
with	O
beta	B-Chemical
lactam	I-Chemical
antibiotics	O
.	O

Thyroxine	B-Chemical
abuse	O
:	O
an	O
unusual	O
case	O
of	O
thyrotoxicosis	B-Disease
in	O
pregnancy	O
.	O

Eating	B-Disease
disorders	I-Disease
and	O
the	O
associated	O
behavioural	O
problems	O
and	O
drug	B-Disease
abuse	I-Disease
are	O
uncommon	O
in	O
pregnancy	O
.	O

When	O
they	O
do	O
occur	O
they	O
are	O
often	O
unrecognized	O
because	O
of	O
denial	O
but	O
when	O
significant	O
may	O
pose	O
a	O
risk	O
to	O
both	O
the	O
mother	O
and	O
her	O
fetus	O
.	O

This	O
case	O
illustrates	O
a	O
number	O
of	O
problems	O
that	O
may	O
be	O
encountered	O
in	O
women	O
with	O
eating	B-Disease
disorders	I-Disease
in	O
pregnancy	O
,	O
including	O
prolonged	O
and	O
recurrent	O
metabolic	O
disturbances	O
and	O
diuretic	O
abuse	O
.	O

In	O
particular	O
it	O
illustrates	O
the	O
derangements	O
of	O
thyroid	O
function	O
seen	O
in	O
pregnant	O
women	O
with	O
eating	B-Disease
disorders	I-Disease
and	O
reminds	O
us	O
that	O
when	O
a	O
cause	O
for	O
thyrotoxicosis	B-Disease
remains	O
obscure	O
,	O
thyroxine	B-Chemical
abuse	O
should	O
be	O
considered	O
and	O
explored	O
.	O

Repeated	O
trimipramine	B-Chemical
induces	O
dopamine	B-Chemical
D2	O
/	O
D3	O
and	O
alpha1	O
-	O
adrenergic	O
up	O
-	O
regulation	O
.	O

Trimipramine	B-Chemical
(	O
TRI	B-Chemical
)	O
,	O
which	O
shows	O
a	O
clinical	O
antidepressant	B-Chemical
activity	O
,	O
is	O
chemically	O
related	O
to	O
imipramine	B-Chemical
but	O
does	O
not	O
inhibit	O
the	O
reuptake	O
of	O
noradrenaline	B-Chemical
and	O
5	B-Chemical
-	I-Chemical
hydroxytryptamine	I-Chemical
,	O
nor	O
does	O
it	O
induce	O
beta	O
-	O
adrenergic	O
down	O
-	O
regulation	O
.	O

The	O
mechanism	O
of	O
its	O
antidepressant	B-Chemical
activity	O
is	O
still	O
unknown	O
.	O

The	O
aim	O
of	O
the	O
present	O
study	O
was	O
to	O
find	O
out	O
whether	O
TRI	B-Chemical
given	O
repeatedly	O
was	O
able	O
to	O
induce	O
adaptive	O
changes	O
in	O
the	O
dopaminergic	O
and	O
alpha1	O
-	O
adrenergic	O
systems	O
,	O
demonstrated	O
by	O
us	O
previously	O
for	O
various	O
antidepressants	B-Chemical
.	O

TRI	B-Chemical
was	O
given	O
to	O
male	O
Wistar	O
rats	O
and	O
male	O
Albino	O
Swiss	O
mice	O
perorally	O
twice	O
daily	O
for	O
14	O
days	O
.	O

In	O
the	O
acute	O
experiment	O
TRI	B-Chemical
(	O
given	O
i	O
.	O
p	O
.	O
)	O
does	O
not	O
antagonize	O
the	O
reserpine	B-Chemical
hypothermia	B-Disease
in	O
mice	O
and	O
does	O
not	O
potentiate	O
the	O
5	B-Chemical
-	I-Chemical
hydroxytryptophan	I-Chemical
head	O
twitches	O
in	O
rats	O
.	O

TRI	B-Chemical
given	O
repeatedly	O
to	O
rats	O
increases	O
the	O
locomotor	O
hyperactivity	B-Disease
induced	O
by	O
d	B-Chemical
-	I-Chemical
amphetamine	I-Chemical
,	O
quinpirole	B-Chemical
and	O
(	O
+	O
)	O
-	O
7	O
-	O
hydroxy	O
-	O
dipropyloaminotetralin	O
(	O
dopamine	B-Chemical
D2	O
and	O
D3	O
effects	O
)	O
.	O

The	O
stereotypies	O
induced	O
by	O
d	B-Chemical
-	I-Chemical
amphetamine	I-Chemical
or	O
apomorphine	B-Chemical
are	O
not	O
potentiated	O
by	O
TRI	B-Chemical
.	O

It	O
increases	O
the	O
behaviour	O
stimulation	O
evoked	O
by	O
phenylephrine	B-Chemical
(	O
given	O
intraventricularly	O
)	O
in	O
rats	O
,	O
evaluated	O
in	O
the	O
open	O
field	O
test	O
as	O
well	O
as	O
the	O
aggressiveness	B-Disease
evoked	O
by	O
clonidine	B-Chemical
in	O
mice	O
,	O
both	O
these	O
effects	O
being	O
mediated	O
by	O
an	O
alpha1	O
-	O
adrenergic	O
receptor	O
.	O

It	O
may	O
be	O
concluded	O
that	O
,	O
like	O
other	O
tricyclic	O
antidepressants	B-Chemical
studied	O
previously	O
,	O
TRI	B-Chemical
given	O
repeatedly	O
increases	O
the	O
responsiveness	O
of	O
brain	O
dopamine	B-Chemical
D2	O
and	O
D3	O
(	O
locomotor	O
activity	O
but	O
not	O
stereotypy	O
)	O
as	O
well	O
as	O
alpha1	O
-	O
adrenergic	O
receptors	O
to	O
their	O
agonists	O
.	O

A	O
question	O
arises	O
whether	O
the	O
reuptake	O
inhibition	O
is	O
of	O
any	O
importance	O
to	O
the	O
adaptive	O
changes	O
induced	O
by	O
repeated	O
antidepressants	B-Chemical
,	O
suggested	O
to	O
be	O
responsible	O
for	O
the	O
antidepressant	B-Chemical
activity	O
.	O

Pethidine	B-Chemical
-	O
associated	O
seizure	B-Disease
in	O
a	O
healthy	O
adolescent	O
receiving	O
pethidine	B-Chemical
for	O
postoperative	B-Disease
pain	I-Disease
control	O
.	O

A	O
healthy	O
17	O
-	O
year	O
-	O
old	O
male	O
received	O
standard	O
intermittent	O
doses	O
of	O
pethidine	B-Chemical
via	O
a	O
patient	O
-	O
controlled	O
analgesia	O
(	O
PCA	O
)	O
pump	O
for	O
management	O
of	O
postoperative	B-Disease
pain	I-Disease
control	O
.	O

Twenty	O
-	O
three	O
h	O
postoperatively	O
he	O
developed	O
a	O
brief	O
self	O
-	O
limited	O
seizure	B-Disease
.	O

Both	O
plasma	O
pethidine	B-Chemical
and	O
norpethidine	B-Chemical
were	O
elevated	O
in	O
the	O
range	O
associated	O
with	O
clinical	O
manifestations	O
of	O
central	O
nervous	O
system	O
excitation	O
.	O

No	O
other	O
risk	O
factors	O
for	O
CNS	O
toxicity	B-Disease
were	O
identified	O
.	O

This	O
method	O
allowed	O
frequent	O
self	O
-	O
dosing	O
of	O
pethidine	B-Chemical
at	O
short	O
time	O
intervals	O
and	O
rapid	O
accumulation	O
of	O
pethidine	B-Chemical
and	O
norpethidine	B-Chemical
.	O

The	O
routine	O
use	O
of	O
pethidine	B-Chemical
via	O
PCA	O
even	O
for	O
a	O
brief	O
postoperative	O
analgesia	O
should	O
be	O
reconsidered	O
.	O

An	O
unusual	O
toxic	O
reaction	O
to	O
axillary	O
block	O
by	O
mepivacaine	B-Chemical
with	O
adrenaline	B-Chemical
.	O

An	O
increase	B-Disease
in	I-Disease
blood	I-Disease
pressure	I-Disease
,	O
accompanied	O
by	O
atrial	B-Disease
fibrillation	I-Disease
,	O
agitation	B-Disease
,	O
incomprehensible	B-Disease
shouts	I-Disease
and	O
loss	B-Disease
of	I-Disease
consciousness	I-Disease
,	O
was	O
observed	O
in	O
an	O
elderly	O
,	O
ASA	O
classification	O
group	O
II	O
,	O
cardiovascularly	O
medicated	O
male	O
,	O
12	O
min	O
after	O
performance	O
of	O
axillary	O
block	O
with	O
mepivacaine	B-Chemical
850	O
mg	O
containing	O
adrenaline	B-Chemical
0	O
.	O
225	O
mg	O
,	O
for	O
correction	O
of	O
Dupuytren	B-Disease
'	I-Disease
s	I-Disease
contracture	I-Disease
.	O

After	O
intravenous	O
administration	O
of	O
labetalol	B-Chemical
,	O
metoprolol	B-Chemical
and	O
midazolam	B-Chemical
the	O
patient	O
'	O
s	O
condition	O
improved	O
,	O
and	O
15	O
min	O
later	O
he	O
woke	O
up	O
.	O

The	O
block	O
was	O
successful	O
and	O
surgery	O
was	O
conducted	O
as	O
scheduled	O
despite	O
persisting	O
atrial	B-Disease
fibrillation	I-Disease
.	O

Postoperatively	O
,	O
the	O
patient	O
refused	O
DC	O
cardioversion	O
and	O
was	O
treated	O
medically	O
.	O

Both	O
the	O
temporal	O
relationship	O
of	O
events	O
and	O
the	O
response	O
to	O
treatment	O
suggest	O
that	O
a	O
rapid	O
systemic	O
absorption	O
of	O
mepivacaine	B-Chemical
with	O
adrenaline	B-Chemical
and	O
/	O
or	O
interaction	O
of	O
these	O
drugs	O
with	O
the	O
patient	O
'	O
s	O
cardiovascular	O
medications	O
were	O
responsible	O
for	O
the	O
perioperative	O
complications	O
.	O

Drug	O
-	O
associated	O
acute	O
-	O
onset	O
vanishing	B-Disease
bile	I-Disease
duct	I-Disease
and	O
Stevens	B-Disease
-	I-Disease
Johnson	I-Disease
syndromes	I-Disease
in	O
a	O
child	O
.	O

Acute	O
vanishing	B-Disease
bile	I-Disease
duct	I-Disease
syndrome	O
is	O
a	O
rare	O
but	O
established	O
cause	O
of	O
progressive	O
cholestasis	B-Disease
in	O
adults	O
,	O
is	O
most	O
often	O
drug	O
or	O
toxin	O
related	O
,	O
and	O
is	O
of	O
unknown	O
pathogenesis	O
.	O

It	O
has	O
not	O
been	O
reported	O
previously	O
in	O
children	O
.	O

Stevens	B-Disease
-	I-Disease
Johnson	I-Disease
syndrome	I-Disease
is	O
a	O
well	O
-	O
recognized	O
immune	O
complex	O
-	O
mediated	O
hypersensitivity	B-Disease
reaction	O
that	O
affects	O
all	O
age	O
groups	O
,	O
is	O
drug	O
or	O
infection	B-Disease
induced	O
,	O
and	O
has	O
classic	O
systemic	O
,	O
mucosal	O
,	O
and	O
dermatologic	O
manifestations	O
.	O

A	O
previously	O
healthy	O
child	O
who	O
developed	O
acute	O
,	O
severe	O
,	O
rapidly	O
progressive	O
vanishing	B-Disease
bile	I-Disease
duct	I-Disease
syndrome	I-Disease
shortly	O
after	O
Stevens	B-Disease
-	I-Disease
Johnson	I-Disease
syndrome	I-Disease
is	O
described	O
;	O
this	O
was	O
temporally	O
associated	O
with	O
ibuprofen	B-Chemical
use	O
.	O

Despite	O
therapy	O
with	O
ursodeoxycholic	B-Chemical
acid	I-Chemical
,	O
prednisone	B-Chemical
,	O
and	O
then	O
tacrolimus	B-Chemical
,	O
her	O
cholestatic	B-Disease
disease	I-Disease
was	O
unrelenting	O
,	O
with	O
cirrhosis	B-Disease
shown	O
by	O
biopsy	O
6	O
months	O
after	O
presentation	O
.	O

This	O
case	O
documents	O
acute	O
drug	O
-	O
related	O
vanishing	B-Disease
bile	I-Disease
duct	I-Disease
syndrome	I-Disease
in	O
the	O
pediatric	O
age	O
group	O
and	O
suggests	O
shared	O
immune	O
mechanisms	O
in	O
the	O
pathogenesis	O
of	O
both	O
Stevens	B-Disease
-	I-Disease
Johnson	I-Disease
syndrome	I-Disease
and	O
vanishing	B-Disease
bile	I-Disease
duct	I-Disease
syndrome	I-Disease
.	O

High	O
incidence	O
of	O
primary	B-Disease
pulmonary	I-Disease
hypertension	I-Disease
associated	O
with	O
appetite	B-Chemical
suppressants	I-Chemical
in	O
Belgium	O
.	O

Primary	B-Disease
pulmonary	I-Disease
hypertension	I-Disease
is	O
a	O
rare	O
,	O
progressive	O
and	O
incurable	O
disease	O
,	O
which	O
has	O
been	O
associated	O
with	O
the	O
intake	O
of	O
appetite	B-Chemical
suppressant	I-Chemical
drugs	O
.	O

The	O
importance	O
of	O
this	O
association	O
was	O
evaluated	O
in	O
Belgium	O
while	O
this	O
country	O
still	O
had	O
no	O
restriction	O
on	O
the	O
prescription	O
of	O
appetite	B-Chemical
suppressants	I-Chemical
.	O

Thirty	O
-	O
five	O
patients	O
with	O
primary	B-Disease
pulmonary	I-Disease
hypertension	I-Disease
and	O
85	O
matched	O
controls	O
were	O
recruited	O
over	O
32	O
months	O
(	O
1992	O
-	O
1994	O
)	O
in	O
Belgium	O
.	O

Exposure	O
to	O
appetite	B-Chemical
-	I-Chemical
suppressants	I-Chemical
was	O
assessed	O
on	O
the	O
basis	O
of	O
hospital	O
records	O
and	O
standardized	O
interview	O
.	O

Twenty	O
-	O
three	O
of	O
the	O
patients	O
had	O
previously	O
taken	O
appetite	B-Chemical
suppressants	I-Chemical
,	O
mainly	O
fenfluramines	B-Chemical
,	O
as	O
compared	O
with	O
only	O
5	O
of	O
the	O
controls	O
(	O
66	O
versus	O
6	O
%	O
,	O
p	O
<	O
0	O
.	O
0001	O
)	O
.	O

Five	O
patients	O
died	O
before	O
the	O
interview	O
,	O
all	O
of	O
them	O
had	O
taken	O
appetite	B-Chemical
suppressants	I-Chemical
.	O

In	O
8	O
patients	O
the	O
diagnosis	O
of	O
primary	B-Disease
pulmonary	I-Disease
hypertension	I-Disease
was	O
uncertain	O
,	O
5	O
of	O
them	O
had	O
taken	O
appetite	B-Chemical
suppressants	I-Chemical
.	O

The	O
patients	O
who	O
had	O
been	O
exposed	O
to	O
appetite	B-Chemical
suppressants	I-Chemical
tended	O
to	O
be	O
on	O
average	O
more	O
severely	O
ill	O
,	O
and	O
to	O
have	O
a	O
shorter	O
median	O
delay	O
between	O
onset	O
of	O
symptoms	O
and	O
diagnosis	O
.	O

A	O
policy	O
of	O
unrestricted	O
prescription	O
of	O
appetite	B-Chemical
suppressants	I-Chemical
may	O
lead	O
to	O
a	O
high	O
incidence	O
of	O
associated	O
primary	B-Disease
pulmonary	I-Disease
hypertension	I-Disease
.	O

Intake	O
of	O
appetite	B-Chemical
suppressants	I-Chemical
may	O
accelerate	O
the	O
progression	O
of	O
the	O
disease	O
.	O

Inappropriate	O
use	O
of	O
carbamazepine	B-Chemical
and	O
vigabatrin	B-Chemical
in	O
typical	O
absence	B-Disease
seizures	I-Disease
.	O

Carbamazepine	B-Chemical
and	O
vigabatrin	B-Chemical
are	O
contraindicated	O
in	O
typical	O
absence	B-Disease
seizures	I-Disease
.	O

Of	O
18	O
consecutive	O
referrals	O
of	O
children	O
with	O
resistant	O
typical	O
absences	O
only	O
,	O
eight	O
were	O
erroneously	O
treated	O
with	O
carbamazepine	B-Chemical
either	O
as	O
monotherapy	O
or	O
as	O
an	O
add	O
-	O
on	O
.	O

Vigabatrin	B-Chemical
was	O
also	O
used	O
in	O
the	O
treatment	O
of	O
two	O
children	O
.	O

Frequency	O
of	O
absences	O
increased	O
in	O
four	O
children	O
treated	O
with	O
carbamazepine	B-Chemical
and	O
two	O
of	O
these	O
developed	O
myoclonic	B-Disease
jerks	I-Disease
,	O
which	O
resolved	O
on	O
withdrawal	O
of	O
carbamazepine	B-Chemical
.	O

Absences	O
were	O
aggravated	O
in	O
both	O
cases	O
where	O
vigabatrin	B-Chemical
was	O
added	O
on	O
to	O
concurrent	O
treatment	O
.	O

Optimal	O
control	O
of	O
the	O
absences	O
was	O
achieved	O
with	O
sodium	B-Chemical
valproate	I-Chemical
,	O
lamotrigine	B-Chemical
,	O
or	O
ethosuximide	B-Chemical
alone	O
or	O
in	O
combination	O
.	O

Choreoathetoid	B-Disease
movements	I-Disease
associated	O
with	O
rapid	O
adjustment	O
to	O
methadone	B-Chemical
.	O

Choreatiform	B-Disease
hyperkinesias	I-Disease
are	O
known	O
to	O
be	O
occasional	O
movement	B-Disease
abnormalities	I-Disease
during	O
intoxications	O
with	O
cocaine	B-Chemical
but	O
not	O
opiates	O
.	O

This	O
is	O
a	O
case	O
report	O
of	O
euphoria	O
and	O
choreoathetoid	B-Disease
movements	I-Disease
both	O
transiently	O
induced	O
by	O
rapid	O
adjustment	O
to	O
the	O
selective	O
mu	O
-	O
opioid	O
receptor	O
agonist	O
methadone	B-Chemical
in	O
an	O
inpatient	O
previously	O
abusing	O
heroine	B-Chemical
and	O
cocaine	B-Chemical
.	O

In	O
addition	O
,	O
minor	O
EEG	O
abnormalities	O
occurred	O
.	O

Possible	O
underlying	O
neurobiological	O
phenomena	O
are	O
discussed	O
.	O

Adverse	O
effects	O
of	O
the	O
atypical	O
antipsychotics	O
.	O

Collaborative	O
Working	O
Group	O
on	O
Clinical	O
Trial	O
Evaluations	O
.	O

Adverse	O
effects	O
of	O
antipsychotics	O
often	O
lead	O
to	O
noncompliance	O
.	O

Thus	O
,	O
clinicians	O
should	O
address	O
patients	O
'	O
concerns	O
about	O
adverse	O
effects	O
and	O
attempt	O
to	O
choose	O
medications	O
that	O
will	O
improve	O
their	O
patients	O
'	O
quality	O
of	O
life	O
as	O
well	O
as	O
overall	O
health	O
.	O

The	O
side	O
effect	O
profiles	O
of	O
the	O
atypical	O
antipsychotics	O
are	O
more	O
advantageous	O
than	O
those	O
of	O
the	O
conventional	O
neuroleptics	O
.	O

Conventional	O
agents	O
are	O
associated	O
with	O
unwanted	O
central	O
nervous	O
system	O
effects	O
,	O
including	O
extrapyramidal	B-Disease
symptoms	I-Disease
(	O
EPS	B-Disease
)	O
,	O
tardive	B-Disease
dyskinesia	I-Disease
,	O
sedation	O
,	O
and	O
possible	O
impairment	O
of	O
some	O
cognitive	O
measures	O
,	O
as	O
well	O
as	O
cardiac	O
effects	O
,	O
orthostatic	B-Disease
hypotension	I-Disease
,	O
hepatic	O
changes	O
,	O
anticholinergic	O
side	O
effects	O
,	O
sexual	B-Disease
dysfunction	I-Disease
,	O
and	O
weight	B-Disease
gain	I-Disease
.	O

The	O
newer	O
atypical	O
agents	O
have	O
a	O
lower	O
risk	O
of	O
EPS	B-Disease
,	O
but	O
are	O
associated	O
in	O
varying	O
degrees	O
with	O
sedation	O
,	O
cardiovascular	O
effects	O
,	O
anticholinergic	O
effects	O
,	O
weight	B-Disease
gain	I-Disease
,	O
sexual	B-Disease
dysfunction	I-Disease
,	O
hepatic	O
effects	O
,	O
lowered	O
seizure	B-Disease
threshold	O
(	O
primarily	O
clozapine	B-Chemical
)	O
,	O
and	O
agranulocytosis	B-Disease
(	O
clozapine	B-Chemical
only	O
)	O
.	O

Since	O
the	O
incidence	O
and	O
severity	O
of	O
specific	O
adverse	O
effects	O
differ	O
among	O
the	O
various	O
atypicals	O
,	O
the	O
clinician	O
should	O
carefully	O
consider	O
which	O
side	O
effects	O
are	O
most	O
likely	O
to	O
lead	O
to	O
the	O
individual	O
'	O
s	O
dissatisfaction	O
and	O
noncompliance	O
before	O
choosing	O
an	O
antipsychotic	O
for	O
a	O
particular	O
patient	O
.	O

A	O
randomized	O
,	O
placebo	O
-	O
controlled	O
dose	O
-	O
comparison	O
trial	O
of	O
haloperidol	B-Chemical
for	O
psychosis	B-Disease
and	O
disruptive	B-Disease
behaviors	I-Disease
in	O
Alzheimer	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
.	O

OBJECTIVE	O
:	O
The	O
goal	O
of	O
this	O
study	O
was	O
to	O
compare	O
the	O
efficacy	O
and	O
side	O
effects	O
of	O
two	O
doses	O
of	O
haloperidol	B-Chemical
and	O
placebo	O
in	O
the	O
treatment	O
of	O
psychosis	B-Disease
and	O
disruptive	B-Disease
behaviors	I-Disease
in	O
patients	O
with	O
Alzheimer	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
.	O

METHOD	O
:	O
In	O
a	O
6	O
-	O
week	O
random	O
-	O
assignment	O
,	O
double	O
-	O
blind	O
,	O
placebo	O
-	O
controlled	O
trial	O
(	O
phase	O
A	O
)	O
,	O
haloperidol	B-Chemical
,	O
2	O
-	O
3	O
mg	O
/	O
day	O
(	O
standard	O
dose	O
)	O
,	O
and	O
haloperidol	B-Chemical
,	O
0	O
.	O
50	O
-	O
0	O
.	O
75	O
mg	O
/	O
day	O
(	O
low	O
dose	O
)	O
,	O
were	O
compared	O
in	O
71	O
outpatients	O
with	O
Alzheimer	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
.	O

For	O
the	O
subsequent	O
6	O
-	O
week	O
double	O
-	O
blind	O
crossover	O
phase	O
(	O
phase	O
B	O
)	O
,	O
patients	O
taking	O
standard	O
-	O
or	O
low	O
-	O
dose	O
haloperidol	B-Chemical
were	O
switched	O
to	O
placebo	O
,	O
and	O
patients	O
taking	O
placebo	O
were	O
randomly	O
assigned	O
to	O
standard	O
-	O
or	O
low	O
-	O
dose	O
haloperidol	B-Chemical
.	O

RESULTS	O
:	O
For	O
the	O
60	O
patients	O
who	O
completed	O
phase	O
A	O
,	O
standard	O
-	O
dose	O
haloperidol	B-Chemical
was	O
efficacious	O
and	O
superior	O
to	O
both	O
low	O
-	O
dose	O
haloperidol	B-Chemical
and	O
placebo	O
for	O
scores	O
on	O
the	O
Brief	O
Psychiatric	O
Rating	O
Scale	O
psychosis	B-Disease
factor	O
and	O
on	O
psychomotor	B-Disease
agitation	I-Disease
.	O

Response	O
rates	O
according	O
to	O
three	O
sets	O
of	O
criteria	O
were	O
greater	O
with	O
the	O
standard	O
dose	O
(	O
55	O
%	O
-	O
60	O
%	O
)	O
than	O
the	O
low	O
dose	O
(	O
25	O
%	O
-	O
35	O
%	O
)	O
and	O
placebo	O
(	O
25	O
%	O
-	O
30	O
%	O
)	O
.	O

The	O
advantage	O
of	O
standard	O
dose	O
over	O
low	O
dose	O
was	O
replicated	O
in	O
phase	O
B	O
.	O

In	O
phase	O
A	O
,	O
extrapyramidal	B-Disease
signs	I-Disease
tended	O
to	O
be	O
greater	O
with	O
the	O
standard	O
dose	O
than	O
in	O
the	O
other	O
two	O
conditions	O
,	O
primarily	O
because	O
of	O
a	O
subgroup	O
(	O
20	O
%	O
)	O
who	O
developed	O
moderate	O
to	O
severe	O
signs	O
.	O

Low	O
-	O
dose	O
haloperidol	B-Chemical
did	O
not	O
differ	O
from	O
placebo	O
on	O
any	O
measure	O
of	O
efficacy	O
or	O
side	O
effects	O
.	O

CONCLUSIONS	O
:	O
The	O
results	O
indicated	O
a	O
favorable	O
therapeutic	O
profile	O
for	O
haloperidol	B-Chemical
in	O
doses	O
of	O
2	O
-	O
3	O
mg	O
/	O
day	O
,	O
although	O
a	O
subgroup	O
developed	O
moderate	O
to	O
severe	O
extrapyramidal	B-Disease
signs	I-Disease
.	O

A	O
starting	O
dose	O
of	O
1	O
mg	O
/	O
day	O
with	O
gradual	O
,	O
upward	O
dose	O
titration	O
is	O
recommended	O
.	O

The	O
narrow	O
therapeutic	O
window	O
observed	O
with	O
haloperidol	B-Chemical
may	O
also	O
apply	O
to	O
other	O
neuroleptics	O
used	O
in	O
Alzheimer	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
patients	O
with	O
psychosis	B-Disease
and	O
disruptive	B-Disease
behaviors	I-Disease
.	O

Effects	O
of	O
acetylsalicylic	B-Chemical
acid	I-Chemical
,	O
dipyridamole	B-Chemical
,	O
and	O
hydrocortisone	B-Chemical
on	O
epinephrine	B-Chemical
-	O
induced	O
myocardial	B-Disease
injury	I-Disease
in	O
dogs	O
.	O

A	O
reproducible	O
model	O
for	O
producing	O
diffuse	O
myocardial	B-Disease
injury	I-Disease
(	O
epinephrine	B-Chemical
infusion	O
)	O
has	O
been	O
developed	O
to	O
study	O
the	O
cardioprotective	O
effects	O
of	O
agents	O
or	O
maneuvers	O
which	O
might	O
alter	O
the	O
evolution	O
of	O
acute	O
myocardial	B-Disease
infarction	I-Disease
.	O

Infusions	O
of	O
epinephrine	B-Chemical
(	O
4	O
mug	O
per	O
kilogram	O
per	O
minute	O
for	O
6	O
hours	O
)	O
increased	O
radiocalcium	B-Chemical
uptakes	O
into	O
intact	O
myocardium	O
and	O
each	O
of	O
its	O
subcellular	O
components	O
with	O
the	O
mitochondrial	O
fraction	O
showing	O
the	O
most	O
consistent	O
changes	O
when	O
compared	O
to	O
saline	O
-	O
infused	O
control	O
animals	O
(	O
4	O
,	O
957	O
vs	O
.	O
827	O
counts	O
per	O
minute	O
per	O
gram	O
of	O
dried	O
tissue	O
or	O
fraction	O
)	O
.	O

Myocardial	O
concentrations	O
of	O
calcium	B-Chemical
also	O
increased	O
significantly	O
(	O
12	O
.	O
0	O
vs	O
.	O
5	O
.	O
0	O
mg	O
.	O
per	O
100	O
Gm	O
.	O
of	O
fat	O
-	O
free	O
dry	O
weight	O
)	O
.	O

Infusions	O
of	O
calcium	B-Chemical
chloride	I-Chemical
sufficient	O
to	O
raise	O
serum	O
calcium	B-Chemical
concentrations	O
2	O
mEq	O
.	O
per	O
liter	O
failed	O
to	O
increase	O
calcium	B-Chemical
influx	O
into	O
the	O
myocardial	O
cell	O
.	O

Mitochondrial	O
radiocalcium	B-Chemical
uptakes	O
were	O
significantly	O
decreased	O
in	O
animals	O
pretreated	O
with	O
acetylsalicylic	B-Chemical
acid	I-Chemical
or	O
dipyridamole	B-Chemical
or	O
when	O
hydrocortisone	B-Chemical
was	O
added	O
to	O
the	O
epinephrine	B-Chemical
infusion	O
(	O
2	O
,	O
682	O
,	O
2	O
,	O
803	O
,	O
and	O
3	O
,	O
424	O
counts	O
per	O
minute	O
per	O
gram	O
of	O
dried	O
fraction	O
,	O
respectively	O
)	O
.	O

Myocardial	O
calcium	B-Chemical
concentrations	O
also	O
were	O
decreased	O
(	O
11	O
.	O
2	O
,	O
8	O
.	O
3	O
,	O
and	O
8	O
.	O
9	O
mg	O
.	O
per	O
100	O
Gm	O
.	O
of	O
fat	O
-	O
free	O
dry	O
weight	O
,	O
respectively	O
)	O
in	O
the	O
three	O
treatment	O
groups	O
,	O
being	O
significantly	O
decreased	O
only	O
in	O
the	O
last	O
two	O
.	O

Evidence	O
of	O
microscopic	O
damage	O
was	O
graded	O
as	O
less	O
severe	O
in	O
the	O
three	O
treatment	O
groups	O
.	O

Acetylsalicylic	B-Chemical
acid	I-Chemical
,	O
dipyridamole	B-Chemical
,	O
and	O
hydrocortisone	B-Chemical
all	O
appear	O
to	O
have	O
cardioprotective	O
effects	O
when	O
tested	O
in	O
this	O
model	O
.	O

Clinical	O
and	O
histopathologic	O
examination	O
of	O
renal	O
allografts	O
treated	O
with	O
tacrolimus	B-Chemical
(	O
FK506	B-Chemical
)	O
for	O
at	O
least	O
one	O
year	O
.	O

BACKGROUND	O
:	O
We	O
clinically	O
and	O
pathologically	O
analyzed	O
renal	O
allografts	O
from	O
1	O
9	O
renal	O
transplant	O
patients	O
treated	O
with	O
tacrolimus	B-Chemical
(	O
FK506	B-Chemical
)	O
for	O
more	O
than	O
1	O
year	O
.	O

METHODS	O
:	O
Twenty	O
-	O
six	O
renal	O
allograft	O
biopsy	O
specimens	O
from	O
1	O
9	O
renal	O
transplant	O
patients	O
who	O
underwent	O
transplantations	O
between	O
1991	O
and	O
1993	O
were	O
evaluated	O
.	O

Thirteen	O
biopsies	O
were	O
performed	O
from	O
stable	O
functioning	O
renal	O
allografts	O
with	O
informed	O
consent	O
(	O
nonepisode	O
biopsy	O
)	O
and	O
the	O
other	O
13	O
were	O
from	O
dysfunctional	O
renal	O
allografts	O
with	O
a	O
clinical	O
indication	O
for	O
biopsy	O
(	O
episode	O
biopsy	O
)	O
.	O

RESULTS	O
:	O
The	O
main	O
pathologic	O
diagnoses	O
(	O
some	O
overlap	O
)	O
were	O
acute	O
rejection	O
(	O
AR	O
;	O
n	O
=	O
4	O
)	O
,	O
chronic	O
rejection	O
(	O
CR	O
;	O
n	O
=	O
5	O
)	O
,	O
AR	O
+	O
CR	O
(	O
n	O
=	O
4	O
)	O
,	O
recurrent	O
IgA	B-Disease
nephropathy	I-Disease
(	O
n	O
=	O
5	O
)	O
,	O
normal	O
findings	O
(	O
n	O
=	O
2	O
)	O
,	O
minimal	O
-	O
type	O
chronic	O
FK506	B-Chemical
nephropathy	B-Disease
(	O
n	O
=	O
9	O
)	O
,	O
and	O
mild	O
-	O
type	O
FK506	B-Chemical
nephropathy	B-Disease
(	O
n	O
=	O
11	O
)	O
.	O

Of	O
the	O
nonepisode	O
biopsies	O
,	O
7	O
and	O
4	O
biopsies	O
showed	O
minimal	O
-	O
type	O
and	O
mild	O
-	O
type	O
chronic	O
FK506	B-Chemical
nephropathy	B-Disease
,	O
respectively	O
.	O

Chronic	O
FK506	B-Chemical
nephropathy	B-Disease
consisted	O
of	O
rough	O
and	O
foamy	O
tubular	O
vacuolization	O
(	O
5	O
biopsies	O
)	O
,	O
arteriolopathy	O
(	O
angiodegeneration	O
of	O
the	O
arteriolar	O
wall	O
;	O
20	O
biopsies	O
)	O
,	O
focal	B-Disease
segmental	I-Disease
glomerulosclerosis	I-Disease
(	O
4	O
biopsies	O
)	O
and	O
the	O
striped	O
form	O
of	O
interstitial	B-Disease
fibrosis	I-Disease
(	O
11	O
biopsies	O
)	O
.	O

The	O
serum	O
creatinine	B-Chemical
levels	O
of	O
patients	O
in	O
the	O
mild	O
-	O
type	O
chronic	O
FK506	B-Chemical
nephropathy	B-Disease
group	O
,	O
which	O
included	O
7	O
episode	O
biopsies	O
,	O
were	O
statistically	O
higher	O
than	O
those	O
in	O
the	O
minimum	O
-	O
type	O
chronic	O
FK506	B-Chemical
-	O
nephropathy	B-Disease
group	O
(	O
P	O
<	O
0	O
.	O
001	O
)	O
.	O

CONCLUSIONS	O
:	O
This	O
study	O
demonstrates	O
that	O
chronic	O
FK506	B-Chemical
nephropathy	B-Disease
consists	O
primarily	O
of	O
arteriolopathy	O
manifesting	O
as	O
insudative	O
hyalinosis	O
of	O
the	O
arteriolar	O
wall	O
,	O
and	O
suggests	O
that	O
mild	O
-	O
type	O
chronic	O
FK506	B-Chemical
nephropathy	B-Disease
is	O
a	O
condition	O
which	O
may	O
lead	O
to	O
deterioration	O
of	O
renal	O
allograft	O
function	O
.	O

Different	O
lobular	O
distributions	O
of	O
altered	O
hepatocyte	O
tight	O
junctions	O
in	O
rat	O
models	O
of	O
intrahepatic	B-Disease
and	I-Disease
extrahepatic	I-Disease
cholestasis	I-Disease
.	O

Hepatocyte	O
tight	O
junctions	O
(	O
TJs	O
)	O
,	O
the	O
only	O
intercellular	O
barrier	O
between	O
the	O
sinusoidal	O
and	O
the	O
canalicular	O
spaces	O
,	O
play	O
a	O
key	O
role	O
in	O
bile	O
formation	O
.	O

Although	O
hepatocyte	O
TJs	O
are	O
impaired	O
in	O
cholestasis	B-Disease
,	O
attempts	O
to	O
localize	O
the	O
precise	O
site	O
of	O
hepatocyte	O
TJ	O
damage	O
by	O
freeze	O
-	O
fracture	O
electron	O
microscopy	O
have	O
produced	O
limited	O
information	O
.	O

Recently	O
,	O
several	O
TJ	O
-	O
associated	O
proteins	O
like	O
ZO	O
-	O
1	O
and	O
7H6	O
have	O
been	O
identified	O
and	O
characterized	O
.	O

Immunolocalization	O
of	O
7H6	O
appears	O
to	O
closely	O
correlate	O
with	O
paracellular	O
permeability	O
.	O

We	O
used	O
rat	O
models	O
of	O
intrahepatic	B-Disease
cholestasis	I-Disease
by	O
ethinyl	B-Chemical
estradiol	I-Chemical
(	O
EE	B-Chemical
)	O
treatment	O
and	O
extrahepatic	B-Disease
cholestasis	I-Disease
by	O
bile	O
duct	O
ligation	O
(	O
BDL	O
)	O
to	O
precisely	O
determine	O
the	O
site	O
of	O
TJ	O
damage	O
.	O

Alterations	O
in	O
hepatocyte	O
TJs	O
were	O
assessed	O
by	O
double	O
-	O
immunolabeling	O
for	O
7H6	O
and	O
ZO	O
-	O
1	O
using	O
a	O
confocal	O
laser	O
scanning	O
microscope	O
.	O

In	O
control	O
rats	O
,	O
immunostaining	O
for	O
7H6	O
and	O
ZO	O
-	O
1	O
colocalized	O
to	O
outline	O
bile	O
canaliculi	O
in	O
a	O
continuous	O
fashion	O
.	O

In	O
contrast	O
,	O
7H6	O
and	O
ZO	O
-	O
1	O
immunostaining	O
was	O
more	O
discontinuous	O
,	O
outlining	O
the	O
bile	O
canaliculi	O
after	O
BDL	O
.	O

Immunostaining	O
for	O
7H6	O
,	O
not	O
ZO	O
-	O
1	O
,	O
decreased	O
and	O
predominantly	O
appeared	O
as	O
discrete	O
signals	O
in	O
the	O
submembranous	O
cytoplasm	O
of	O
periportal	O
hepatocytes	O
after	O
BDL	O
.	O

After	O
EE	B-Chemical
treatment	O
,	O
changes	O
in	O
immunostaining	O
for	O
7H6	O
and	O
ZO	O
-	O
1	O
were	O
similar	O
to	O
those	O
seen	O
in	O
periportal	O
hepatocytes	O
after	O
BDL	O
,	O
but	O
distributed	O
more	O
diffusely	O
throughout	O
the	O
lobule	O
.	O

This	O
study	O
is	O
the	O
first	O
to	O
demonstrate	O
that	O
impairment	O
of	O
hepatocyte	O
TJs	O
occurs	O
heterogenously	O
in	O
the	O
liver	O
lobule	O
after	O
BDL	O
and	O
suggests	O
that	O
BDL	O
and	O
EE	B-Chemical
treatments	O
produce	O
different	O
lobular	O
distributions	O
of	O
increased	O
paracellular	O
permeability	O
.	O

Memory	O
facilitation	O
and	O
stimulation	O
of	O
endogenous	O
nerve	O
growth	O
factor	O
synthesis	O
by	O
the	O
acetylcholine	B-Chemical
releaser	O
PG	B-Chemical
-	I-Chemical
9	I-Chemical
.	O

The	O
effects	O
of	O
PG	B-Chemical
-	I-Chemical
9	I-Chemical
(	O
3alpha	B-Chemical
-	I-Chemical
tropyl	I-Chemical
2	I-Chemical
-	I-Chemical
(	I-Chemical
p	I-Chemical
-	I-Chemical
bromophenyl	I-Chemical
)	I-Chemical
propionate	I-Chemical
)	O
,	O
the	O
acetylcholine	B-Chemical
releaser	O
,	O
on	O
memory	O
processes	O
and	O
nerve	O
growth	O
factor	O
(	O
NGF	O
)	O
synthesis	O
were	O
evaluated	O
.	O

In	O
the	O
mouse	O
passive	O
-	O
avoidance	O
test	O
,	O
PG	B-Chemical
-	I-Chemical
9	I-Chemical
(	O
10	O
-	O
30	O
mg	O
/	O
kg	O
,	O
i	O
.	O
p	O
.	O
)	O
,	O
administered	O
20	O
min	O
before	O
the	O
training	O
session	O
,	O
prevented	O
amnesia	B-Disease
induced	O
by	O
both	O
the	O
non	O
selective	O
antimuscarinic	O
drug	O
scopolamine	B-Chemical
and	O
the	O
M1	O
-	O
selective	O
antagonist	O
S	B-Chemical
-	I-Chemical
(	I-Chemical
-	I-Chemical
)	I-Chemical
-	I-Chemical
ET	I-Chemical
-	I-Chemical
126	I-Chemical
.	O

In	O
the	O
same	O
experimental	O
conditions	O
,	O
PG	B-Chemical
-	I-Chemical
9	I-Chemical
(	O
5	O
-	O
20	O
microg	O
per	O
mouse	O
,	O
i	O
.	O
c	O
.	O
v	O
.	O
)	O
was	O
also	O
able	O
to	O
prevent	O
antimuscarine	O
-	O
induced	O
amnesia	B-Disease
,	O
demonstrating	O
a	O
central	O
localization	O
of	O
the	O
activity	O
.	O

At	O
the	O
highest	O
effective	O
doses	O
,	O
PG	B-Chemical
-	I-Chemical
9	I-Chemical
did	O
not	O
produce	O
any	O
collateral	O
symptoms	O
as	O
revealed	O
by	O
the	O
Irwin	O
test	O
,	O
and	O
it	O
did	O
not	O
modify	O
spontaneous	O
motility	O
and	O
inspection	O
activity	O
,	O
as	O
revealed	O
by	O
the	O
hole	O
-	O
board	O
test	O
.	O

PG	B-Chemical
-	I-Chemical
9	I-Chemical
was	O
also	O
able	O
to	O
increase	O
the	O
amount	O
of	O
NGF	O
secreted	O
in	O
vitro	O
by	O
astrocytes	O
in	O
a	O
dose	O
-	O
dependent	O
manner	O
.	O

The	O
maximal	O
NGF	O
contents	O
obtained	O
by	O
PG	B-Chemical
-	I-Chemical
9	I-Chemical
were	O
17	O
.	O
6	O
-	O
fold	O
of	O
the	O
control	O
value	O
.	O

During	O
culture	O
,	O
no	O
morphological	O
changes	O
were	O
found	O
at	O
effective	O
concentrations	O
of	O
PG	B-Chemical
-	I-Chemical
9	I-Chemical
.	O

The	O
current	O
work	O
indicates	O
the	O
ability	O
of	O
PG	B-Chemical
-	I-Chemical
9	I-Chemical
to	O
induce	O
beneficial	O
effects	O
on	O
cognitive	O
processes	O
and	O
stimulate	O
activity	O
of	O
NGF	O
synthesis	O
in	O
astroglial	O
cells	O
.	O

Therefore	O
,	O
PG	B-Chemical
-	I-Chemical
9	I-Chemical
could	O
represent	O
a	O
potential	O
useful	O
drug	O
able	O
to	O
improve	O
the	O
function	O
of	O
impaired	O
cognitive	O
processes	O
.	O

Mechanisms	O
of	O
FK	B-Chemical
506	I-Chemical
-	O
induced	O
hypertension	B-Disease
in	O
the	O
rat	O
.	O

-	O
Tacrolimus	B-Chemical
(	O
FK	B-Chemical
506	I-Chemical
)	O
is	O
a	O
powerful	O
,	O
widely	O
used	O
immunosuppressant	O
.	O

The	O
clinical	O
utility	O
of	O
FK	B-Chemical
506	I-Chemical
is	O
complicated	O
by	O
substantial	O
hypertension	B-Disease
and	O
nephrotoxicity	B-Disease
.	O

To	O
clarify	O
the	O
mechanisms	O
of	O
FK	B-Chemical
506	I-Chemical
-	O
induced	O
hypertension	B-Disease
,	O
we	O
studied	O
the	O
chronic	O
effects	O
of	O
FK	B-Chemical
506	I-Chemical
on	O
the	O
synthesis	O
of	O
endothelin	O
-	O
1	O
(	O
ET	O
-	O
1	O
)	O
,	O
the	O
expression	O
of	O
mRNA	O
of	O
ET	O
-	O
1	O
and	O
endothelin	O
-	O
converting	O
enzyme	O
-	O
1	O
(	O
ECE	O
-	O
1	O
)	O
,	O
the	O
endothelial	O
nitric	B-Chemical
oxide	I-Chemical
synthase	O
(	O
eNOS	O
)	O
activity	O
,	O
and	O
the	O
expression	O
of	O
mRNA	O
of	O
eNOS	O
and	O
C	O
-	O
type	O
natriuretic	O
peptide	O
(	O
CNP	O
)	O
in	O
rat	O
blood	O
vessels	O
.	O

In	O
addition	O
,	O
the	O
effect	O
of	O
the	O
specific	O
endothelin	O
type	O
A	O
receptor	O
antagonist	O
FR	B-Chemical
139317	I-Chemical
on	O
FK	B-Chemical
506	I-Chemical
-	O
induced	O
hypertension	B-Disease
in	O
rats	O
was	O
studied	O
.	O

FK	B-Chemical
506	I-Chemical
,	O
5	O
mg	O
.	O

kg	O
-	O
1	O
.	O

d	O
-	O
1	O
given	O
for	O
4	O
weeks	O
,	O
elevated	O
blood	O
pressure	O
from	O
102	O
+	O
/	O
-	O
13	O
to	O
152	O
+	O
/	O
-	O
15	O
mm	O
Hg	O
and	O
increased	O
the	O
synthesis	O
of	O
ET	O
-	O
1	O
and	O
the	O
levels	O
of	O
ET	O
-	O
1	O
mRNA	O
in	O
the	O
mesenteric	O
artery	O
(	O
240	O
%	O
and	O
230	O
%	O
,	O
respectively	O
)	O
.	O

Little	O
change	O
was	O
observed	O
in	O
the	O
expression	O
of	O
ECE	O
-	O
1	O
mRNA	O
and	O
CNP	O
mRNA	O
.	O

FK	B-Chemical
506	I-Chemical
decreased	O
eNOS	O
activity	O
and	O
the	O
levels	O
of	O
eNOS	O
mRNA	O
in	O
the	O
aorta	O
(	O
48	O
%	O
and	O
55	O
%	O
,	O
respectively	O
)	O
.	O

The	O
administration	O
of	O
FR	B-Chemical
139317	I-Chemical
(	O
10	O
mg	O
.	O
kg	O
-	O
1	O
.	O
d	O
-	O
1	O
)	O
prevented	O
FK	B-Chemical
506	I-Chemical
-	O
induced	O
hypertension	B-Disease
in	O
rats	O
.	O

These	O
results	O
indicate	O
that	O
FK	B-Chemical
506	I-Chemical
may	O
increase	O
blood	O
pressure	O
not	O
only	O
by	O
increasing	O
ET	O
-	O
1	O
production	O
but	O
also	O
by	O
decreasing	O
NO	B-Chemical
synthesis	O
in	O
the	O
vasculature	O
.	O

Scp160p	O
,	O
a	O
multiple	O
KH	O
-	O
domain	O
protein	O
,	O
is	O
a	O
component	O
of	O
mRNP	O
complexes	O
in	O
yeast	B

Abstract	O

Scp160p	O
is	O
a	O
160	O
kDa	O
protein	O
in	O
the	O
yeast	B
Saccharomyces	B
cerevisiae	I
that	O
contains	O
14	O
repeats	O
of	O
the	O
hnRNP	O
K	O
-	O
homology	O
(	O
KH	O
)	O
domain	O
,	O
and	O
demonstrates	O
significant	O
sequence	O
homology	O
to	O
a	O
family	O
of	O
proteins	O
collectively	O
known	O
as	O
vigilins	O
.	O

As	O
a	O
first	O
step	O
towards	O
defining	O
the	O
function	O
of	O
Scp160p	O
,	O
we	O
have	O
characterized	O
the	O
subcellular	O
distribution	O
and	O
in	O
vivo	O
interactions	O
of	O
this	O
protein	O
.	O

Using	O
sucrose	O
gradient	O
fractionation	O
studies	O
we	O
have	O
demonstrated	O
that	O
Scp160p	O
in	O
cytoplasmic	O
lysates	O
is	O
predominantly	O
associated	O
with	O
polyribosomes	O
.	O

Furthermore	O
,	O
we	O
have	O
found	O
that	O
Scp160p	O
is	O
released	O
from	O
polyribosomes	O
by	O
EDTA	O
in	O
the	O
form	O
of	O
a	O
large	O
complex	O
of	O
>	O
=	O
1300	O
kDa	O
that	O
is	O
sensitive	O
both	O
to	O
RNase	O
and	O
NaCl	O
.	O

Using	O
affinity	O
-	O
chromatography	O
to	O
isolate	O
these	O
complexes	O
,	O
we	O
have	O
identified	O
two	O
protein	O
components	O
other	O
than	O
Scp160p	O
:	O
poly	O
(	O
A	O
)	O
binding	O
protein	O
,	O
Pab1p	O
,	O
and	O
Bfr1p	O
.	O

The	O
presence	O
of	O
Pab1p	O
confirms	O
these	O
complexes	O
to	O
be	O
mRNPs	O
.	O

The	O
presence	O
of	O
Bfr1p	O
is	O
intriguing	O
because	O
the	O
null	O
phenotype	O
for	O
this	O
gene	O
is	O
essentially	O
the	O
same	O
as	O
that	O
reported	O
for	O
scp160	O
-	O
null	O
cells	O
:	O
increased	O
cell	O
size	O
and	O
aberrant	O
DNA	O
content	O
.	O

These	O
results	O
demonstrate	O
that	O
Scp160p	O
associates	O
with	O
polyribosome	O
-	O
bound	O
mRNP	O
complexes	O
in	O
vivo	O
,	O
implicating	O
a	O
role	O
for	O
this	O
protein	O
in	O
one	O
or	O
more	O
levels	O
of	O
mRNA	O
metabolism	O
in	O
yeast	B
.	O

INTRODUCTION	O

Scp160p	O
is	O
a	O
1222	O
amino	O
acid	O
Saccharomyces	B
cerevisiae	I
protein	O
that	O
contains	O
14	O
copies	O
of	O
the	O
hnRNP	O
K	O
homology	O
(	O
KH	O
)	O
domain	O
,	O
a	O
highly	O
conserved	O
motif	O
found	O
in	O
many	O
proteins	O
involved	O
in	O
RNA	O
metabolism	O
(	O
1	O
)	O
.	O

KH	O
domain	O
-	O
containing	O
proteins	O
appear	O
to	O
have	O
diverse	O
functions	O
and	O
have	O
been	O
identified	O
in	O
all	O
kingdoms	O
of	O
life	O
,	O
including	O
the	O
ribosomal	O
protein	O
S3	O
from	O
Escherichia	B
coli	I
(	O
1	O
)	O
,	O
Mer1p	O
from	O
S	B
.	I
cerevisiae	I
,	O
a	O
meiosis	O
-	O
specific	O
splicing	O
factor	O
(	O
1	O
)	O
,	O
MEX	O
-	O
3	O
from	O
Caenorhabditis	B
elegans	I
,	O
presumably	O
involved	O
in	O
mRNA	O
localization	O
during	O
development	O
(	O
2	O
)	O
,	O
and	O
FMRP	O
,	O
the	O
fragile	O
-	O
X	O
mental	O
retardation	O
protein	O
in	O
humans	B
(	O
3	O
)	O
.	O

A	O
partial	O
clone	O
of	O
Scp160p	O
,	O
known	O
as	O
HX	O
,	O
was	O
one	O
of	O
the	O
first	O
multiple	O
-	O
KH	O
proteins	O
identified	O
(	O
1	O
)	O
.	O

Whole	O
cell	O
immunofluorescence	O
studies	O
have	O
demonstrated	O
that	O
Scp160p	O
localizes	O
to	O
the	O
cytoplasm	O
,	O
with	O
enrichment	O
around	O
the	O
nuclear	O
envelope	O
,	O
and	O
what	O
appears	O
to	O
be	O
the	O
endoplasmic	O
reticulum	O
(	O
3	O
)	O
.	O

Deletion	O
of	O
the	O
SCP160	O
locus	O
in	O
yeast	B
is	O
not	O
lethal	O
,	O
but	O
results	O
in	O
a	O
complex	O
phenotype	O
,	O
including	O
increased	O
DNA	O
content	O
per	O
cell	O
,	O
missegregation	O
of	O
genetic	O
markers	O
during	O
sporulation	O
,	O
and	O
abnormal	O
cell	O
morphology	O
,	O
including	O
increased	O
size	O
and	O
irregular	O
shape	O
(	O
4	O
)	O
.	O

Observation	O
of	O
this	O
phenotype	O
led	O
to	O
the	O
hypothesis	O
that	O
Scp160p	O
may	O
function	O
in	O
regulating	O
ploidy	O
during	O
cell	O
division	O
.	O

More	O
recently	O
,	O
Weber	O
and	O
colleagues	O
demonstrated	O
in	O
vitro	O
RNA	O
binding	O
activity	O
of	O
Scp160p	O
using	O
northwestern	O
blot	O
analyses	O
;	O
the	O
protein	O
was	O
found	O
to	O
bind	O
efficiently	O
to	O
ribohomopolymers	O
and	O
rRNA	O
,	O
but	O
not	O
to	O
tRNA	O
(	O
5	O
)	O
.	O

Cell	O
fractionation	O
studies	O
revealed	O
that	O
a	O
large	O
percentage	O
of	O
Scp160p	O
associates	O
with	O
membrane	O
-	O
pellets	O
,	O
and	O
is	O
released	O
by	O
treatment	O
with	O
either	O
10	O
mM	O
EDTA	O
or	O
500	O
mM	O
NaCl	O
(	O
5	O
)	O
.	O

While	O
these	O
authors	O
interpreted	O
these	O
results	O
to	O
suggest	O
that	O
the	O
nuclear	O
envelope	O
/	O
ER	O
localization	O
of	O
Scp160p	O
was	O
due	O
primarily	O
to	O
interactions	O
of	O
the	O
protein	O
with	O
membrane	O
-	O
bound	O
polyribosomes	O
,	O
clear	O
evidence	O
of	O
this	O
association	O
has	O
not	O
been	O
reported	O
(	O
5	O
)	O
.	O

Currently	O
,	O
the	O
relationship	O
between	O
the	O
phenotype	O
of	O
scp160	O
null	O
mutants	O
and	O
the	O
RNA	O
-	O
binding	O
activity	O
of	O
Scp160p	O
remains	O
unclear	O
.	O

Scp160p	O
demonstrates	O
significant	O
sequence	O
homology	O
(	O
~	O
23	O
%	O
identity	O
and	O
~	O
40	O
%	O
similarity	O
at	O
the	O
amino	O
acid	O
level	O
)	O
to	O
a	O
class	O
of	O
vertebrate	O
KH	O
-	O
domain	O
proteins	O
collectively	O
known	O
as	O
vigilins	O
.	O

First	O
identified	O
in	O
chicken	B
,	O
vigilin	O
homologues	O
have	O
now	O
been	O
found	O
in	O
human	B
(	O
6	O
)	O
,	O
Xenopus	B
laevis	I
(	O
7	O
)	O
,	O
Drosophila	B
melanogaster	I
(	O
8	O
)	O
,	O
C	B
.	I
elegans	I
(	O
5	O
)	O
and	O
Schizosaccharomyces	B
pombe	I
.	O

While	O
all	O
of	O
the	O
vigilin	O
proteins	O
studied	O
to	O
date	O
are	O
reported	O
to	O
bind	O
nucleic	O
acid	O
,	O
both	O
the	O
type	O
of	O
nucleic	O
acid	O
bound	O
and	O
the	O
functional	O
significance	O
of	O
these	O
interactions	O
remain	O
unclear	O
.	O

For	O
example	O
,	O
Kruse	O
and	O
colleagues	O
reported	O
from	O
their	O
work	O
with	O
human	B
cells	O
in	O
culture	O
that	O
vigilin	O
may	O
be	O
involved	O
in	O
the	O
binding	O
and	O
transport	O
of	O
tRNA	O
(	O
9	O
-	O
11	O
)	O
.	O

In	O
contrast	O
,	O
Dodson	O
and	O
Shapiro	O
concluded	O
from	O
their	O
work	O
with	O
Xenopus	O
vigilin	O
that	O
,	O
in	O
response	O
to	O
estrogen	O
,	O
the	O
protein	O
bound	O
specifically	O
to	O
the	O
3	O
'	O
UTR	O
of	O
vitellogenin	O
mRNA	O
(	O
7	O
,	O
12	O
)	O
,	O
potentially	O
stabilizing	O
the	O
message	O
(	O
13	O
)	O
.	O

Lastly	O
,	O
DDP1	O
,	O
the	O
Drosophila	O
homolog	O
of	O
vigilin	O
,	O
was	O
reported	O
recently	O
to	O
interact	O
with	O
the	O
dodeca	O
-	O
satellite	O
repeat	O
regions	O
of	O
centromeric	O
heterochromatin	O
in	O
embryonic	O
and	O
larval	O
cell	O
nuclei	O
,	O
suggesting	O
a	O
possible	O
role	O
for	O
this	O
protein	O
in	O
heterochromatin	O
structure	O
(	O
8	O
)	O
.	O

The	O
goal	O
of	O
the	O
present	O
study	O
was	O
to	O
begin	O
elucidating	O
the	O
function	O
of	O
Scp160p	O
in	O
yeast	B
by	O
characterizing	O
the	O
subcellular	O
distribution	O
and	O
macromolecular	O
interactions	O
of	O
this	O
protein	O
.	O

We	O
have	O
demonstrated	O
that	O
Scp160p	O
in	O
cytoplasmic	O
lysates	O
is	O
associated	O
predominantly	O
with	O
polyribosomes	O
,	O
and	O
that	O
following	O
treatment	O
with	O
EDTA	O
,	O
Scp160p	O
remains	O
in	O
an	O
RNase	O
/	O
NaCl	O
-	O
sensitive	O
complex	O
of	O
apparent	O
molecular	O
weight	O
approximately	O
>	O
=	O
1300	O
kDa	O
.	O

Affinity	O
purification	O
of	O
this	O
complex	O
revealed	O
the	O
presence	O
of	O
poly	O
(	O
A	O
)	O
-	O
binding	O
protein	O
(	O
Pab1p	O
)	O
,	O
a	O
well	O
-	O
characterized	O
component	O
of	O
eukaryotic	O
mRNPs	O
(	O
14	O
,	O
15	O
)	O
.	O

Finally	O
,	O
a	O
third	O
abundant	O
protein	O
component	O
of	O
this	O
complex	O
was	O
identified	O
as	O
Bfr1p	O
,	O
a	O
protein	O
not	O
previously	O
reported	O
to	O
associate	O
with	O
mRNPs	O
.	O

While	O
the	O
function	O
of	O
Bfr1p	O
remains	O
unknown	O
,	O
gene	O
deletion	O
reportedly	O
leads	O
to	O
a	O
phenotype	O
remarkably	O
similar	O
to	O
that	O
of	O
scp160	O
deletion	O
(	O
16	O
)	O
.	O

These	O
results	O
indicate	O
a	O
role	O
for	O
Scp160p	O
in	O
mRNA	O
metabolism	O
in	O
yeast	B
,	O
and	O
by	O
extension	O
,	O
support	O
results	O
seen	O
with	O
Xenopus	O
vigilin	O
in	O
its	O
interactions	O
with	O
mRNA	O
.	O

To	O
our	O
knowledge	O
,	O
the	O
data	O
reported	O
here	O
demonstrate	O
Scp160p	O
to	O
be	O
the	O
first	O
example	O
of	O
a	O
KH	O
-	O
domain	O
protein	O
that	O
functions	O
as	O
a	O
component	O
of	O
polyribosome	O
-	O
associated	O
mRNP	O
complexes	O
in	O
the	O
yeast	B
,	O
S	B
.	I
cerevisiae	I
.	O

MATERIALS	O
AND	O
METHODS	O

Plasmids	O
,	O
yeast	B
strains	O
and	O
culture	O
conditions	O

All	O
recombinant	O
DNA	O
manipulations	O
were	O
performed	O
according	O
to	O
standard	O
techniques	O
and	O
utilized	O
E	B
.	I
coli	I
strain	O
XL1	O
-	O
Blue	O
(	O
Stratagene	O
)	O
.	O

The	O
yeast	B
strain	O
JFy1511	O
,	O
expressing	O
FLAG	O
-	O
Scp160p	O
,	O
was	O
derived	O
by	O
two	O
-	O
step	O
gene	O
replacement	O
from	O
strain	O
yJJ52	O
(	O
MAT	O
alpha	O
gal7	O
Delta	O
102	O
ura3	O
-	O
52	O
trp1	O
-	O
289	O
ade1	O
lys1	O
leu2	O
-	O
3	O
,	O
112	O
;	O
generously	O
donated	O
by	O
Drs	O
Mark	O
Parthun	O
and	O
Judith	O
Jaehning	O
,	O
University	O
of	O
Colorado	O
Health	O
Sciences	O
Center	O
)	O
,	O
and	O
confirmed	O
by	O
PCR	O
.	O

The	O
wild	O
-	O
type	O
SCP160	O
coding	O
sequence	O
was	O
obtained	O
by	O
PCR	O
amplification	O
from	O
a	O
genomic	O
DNA	O
preparation	O
from	O
yJFK1	O
(	O
MAT	O
alpha	O
gal7	O
Delta	O
102	O
ura3	O
-	O
52	O
trp1	O
-	O
289	O
ade1	O
lys1	O
leu2	O
-	O
3	O
,	O
112	O
Delta	O
GAL80	O
:	O
:	O
URA3	O
)	O
,	O
using	O
a	O
16	O
:	O
1	O
mixture	O
of	O
Taq	O
(	O
Fisher	O
Biotech	O
)	O
and	O
Pfu	O
(	O
Stratagene	O
)	O
DNA	O
polymerases	O
and	O
the	O
following	O
primers	O
:	O
Scp160F1	O
(	O
5	O
'	O
-	O
GCCGGTCGA	O
-	O
CTAACTGCAATGTCTGAAGA	O
-	O
3	O
'	O
)	O
and	O
Scp160R1	O
(	O
5	O
'	O
-	O
GCGCGTCGACGAGCTTGTCT	O
-	O
CTTAAGG	O
-	O
3	O
'	O
)	O
.	O

A	O
wild	O
-	O
type	O
SCP160	O
genomic	O
clone	O
,	O
containing	O
1	O
kb	O
upstream	O
and	O
300	O
bp	O
downstream	O
sequence	O
was	O
PCR	O
amplified	O
from	O
yJFK1	O
genomic	O
DNA	O
using	O
the	O
primers	O
Scp160F0	O
(	O
5	O
'	O
-	O
GCCGAGCTCACACCAGCTTT	O
-	O
3	O
'	O
)	O
and	O
Scp160R2	O
(	O
5	O
'	O
-	O
GCGCAAGCTTGTGCGGTA	O
-	O
TCCCAGTCTATG	O
-	O
3	O
'	O
)	O
.	O

The	O
resultant	O
clone	O
was	O
confirmed	O
by	O
dideoxy	O
sequencing	O
.	O

The	O
N	O
-	O
terminal	O
FLAG	O
and	O
HA	O
tags	O
were	O
added	O
using	O
PCR	O
with	O
the	O
primers	O
ScpFLAGF1	O
(	O
5	O
'	O
-	O
CCAT	O
-	O
TATAACTGCAATGGACTACA	O
-	O
AAGATGTCTGAAGAACAAAC	O
-	O
3	O
'	O
)	O
and	O
ScpHAF1	O
(	O
5	O
'	O
-	O
CCCCCTCCTGTCGACATTAT	O
-	O
TCACCATCACCATTCTGAAG	O
-	O
3	O
'	O
)	O
respectively	O
.	O

For	O
integration	O
,	O
constructs	O
containing	O
the	O
1	O
kb	O
upstream	O
and	O
300	O
bp	O
downstream	O
sequence	O
were	O
subcloned	O
into	O
the	O
plasmid	O
YIplac211	O
(	O
17	O
)	O
using	O
SacI	O
and	O
HindIII	O
restriction	O
sites	O
.	O

The	O
HA	O
-	O
tagged	O
construct	O
was	O
subcloned	O
into	O
the	O
low	O
copy	O
number	O
plasmid	O
,	O
YCplac22	O
using	O
SacI	O
and	O
HindIII	O
restriction	O
sites	O
.	O

The	O
SCP160	O
deletion	O
construct	O
was	O
made	O
by	O
removal	O
of	O
a	O
3	O
.	O
4	O
kb	O
ApaI	O
-	O
KpnI	O
fragment	O
from	O
the	O
coding	O
region	O
of	O
this	O
construct	O
,	O
followed	O
by	O
treatment	O
with	O
Klenow	O
fragment	O
and	O
re	O
-	O
ligation	O
following	O
attachment	O
of	O
BamHI	O
linker	O
oligonucleotides	O
.	O

Genomic	O
integration	O
of	O
the	O
plasmid	O
sequences	O
and	O
subsequent	O
removal	O
of	O
the	O
endogenous	O
SCP160	O
allele	O
were	O
achieved	O
by	O
standard	O
two	O
-	O
step	O
gene	O
replacement	O
techniques	O
(	O
18	O
)	O
and	O
confirmed	O
by	O
PCR	O
.	O

The	O
N	O
-	O
terminally	O
HA	O
-	O
tagged	O
allele	O
of	O
BFR1	O
was	O
generated	O
by	O
PCR	O
-	O
amplifiction	O
of	O
the	O
BFR1	O
locus	O
from	O
wild	O
-	O
type	O
(	O
W303	O
)	O
yeast	B
genomic	O
DNA	O
using	O
the	O
primers	O
BFR1HAF1	O
(	O
5	O
'	O
-	O
CCGCGGATCCATGTACC	O
-	O
CATACGACGTCCCAGACTAC	O
-	O
AACACAA	O
-	O
3	O
'	O
)	O
and	O
BFR1HINDR1	O
(	O
5	O
'	O
-	O
CCGCAAGCTTGTCG	O
-	O
ACTATTTCATATGCCACAGG	O
-	O
3	O
'	O
)	O
,	O
and	O
subcloned	O
into	O
YIPlac211	O
.	O

The	O
BFR1	O
promoter	O
region	O
was	O
PCR	O
-	O
amplified	O
in	O
a	O
similar	O
manner	O
using	O
the	O
primers	O
BFR1SACF1	O
(	O
5	O
'	O
-	O
CCGCGAG	O
-	O
CTCAGCATTAAGCATTCACG	O
-	O
3	O
'	O
)	O
and	O
BFR1BAMR1	O
(	O
5	O
'	O
-	O
CCGCGGATCCGGCAATGGCT	O
-	O
3	O
'	O
)	O
and	O
subcloned	O
into	O
the	O
appropriate	O
position	O
upstream	O
of	O
the	O
HA	O
-	O
Bfr1p	O
open	O
reading	O
frame	O
in	O
the	O
plasmid	O
backbone	O
.	O

The	O
entire	O
open	O
reading	O
frame	O
was	O
confirmed	O
by	O
dideoxy	O
sequencing	O
.	O

Finally	O
,	O
the	O
HA	O
-	O
BFR1	O
allele	O
was	O
substituted	O
into	O
the	O
yeast	B
genome	O
in	O
place	O
of	O
the	O
native	O
allele	O
using	O
linearization	O
with	O
SphI	O
and	O
standard	O
two	O
-	O
step	O
gene	O
replacement	O
techniques	O
.	O

All	O
yeast	B
transformations	O
and	O
culture	O
manipulations	O
were	O
performed	O
according	O
to	O
standard	O
protocols	O
as	O
described	O
elsewhere	O
(	O
19	O
)	O
.	O

Confirmation	O
of	O
genomic	O
integrations	O

All	O
genomic	O
integrations	O
were	O
confirmed	O
by	O
PCR	O
amplifications	O
from	O
purified	O
yeast	B
genomic	O
DNA	O
.	O

For	O
scp160	O
deletion	O
mutants	O
,	O
the	O
primers	O
Scp160PF	O
(	O
5	O
'	O
-	O
GATTTCCTAACTTTCC	O
-	O
GTCTA	O
-	O
3	O
'	O
)	O
and	O
Scp160R5	O
(	O
5	O
'	O
-	O
GCGCAAGCTTCACCGCCTTA	O
-	O
3	O
'	O
)	O
that	O
flanked	O
the	O
deleted	O
region	O
were	O
used	O
.	O

Similarly	O
,	O
epitope	O
tags	O
on	O
Scp160p	O
were	O
confirmed	O
by	O
PCR	O
using	O
primers	O
that	O
flanked	O
the	O
tag	O
sequence	O
.	O

Positive	O
clones	O
were	O
further	O
confirmed	O
by	O
western	O
blot	O
analysis	O
of	O
crude	O
cell	O
lysates	O
using	O
the	O
appropriate	O
anti	O
-	O
tag	O
antibodies	O
.	O

The	O
presence	O
of	O
HA	O
-	O
Bfr1p	O
in	O
cells	O
was	O
confirmed	O
by	O
western	O
blot	O
analysis	O
of	O
soluble	O
cell	O
lysates	O
using	O
12CA5	O
mAb	O
(	O
Boehringer	O
Mannheim	O
)	O
.	O

Polyribosome	O
isolation	O

Polyribosomes	O
were	O
isolated	O
using	O
a	O
combination	O
of	O
protocols	O
described	O
by	O
Stansfield	O
and	O
colleagues	O
(	O
20	O
)	O
and	O
by	O
Dr	O
Maurice	O
Swanson	O
(	O
personal	O
communication	O
)	O
.	O

In	O
brief	O
,	O
a	O
100	O
ml	O
culture	O
of	O
yeast	B
was	O
grown	O
in	O
either	O
YEPD	O
or	O
Hartwell	O
synthetic	O
medium	O
,	O
to	O
early	O
-	O
log	O
phase	O
(	O
OD600	O
=	O
1	O
.	O
0	O
)	O
,	O
at	O
which	O
time	O
cyclohexamide	O
(	O
Sigma	O
)	O
was	O
added	O
directly	O
to	O
the	O
culture	O
to	O
a	O
final	O
concentration	O
of	O
100	O
micro	O
g	O
/	O
ml	O
.	O

The	O
culture	O
was	O
incubated	O
on	O
ice	O
for	O
15	O
min	O
,	O
and	O
cells	O
were	O
harvested	O
by	O
centrifugation	O
(	O
4000	O
r	O
.	O
p	O
.	O
m	O
.	O
/	O
10	O
min	O
)	O
.	O

Following	O
two	O
washes	O
in	O
10	O
ml	O
of	O
water	O
containing	O
100	O
micro	O
g	O
/	O
ml	O
cyclohexamide	O
,	O
cells	O
were	O
lysed	O
by	O
vortex	O
agitation	O
with	O
an	O
equal	O
volume	O
of	O
glass	O
beads	O
in	O
1	O
ml	O
lysis	O
buffer	O
(	O
25	O
mM	O
Tris	O
pH	O
7	O
.	O
2	O
,	O
50	O
mM	O
KCl	O
,	O
30	O
mM	O
MgCl2	O
,	O
5	O
mM	O
beta	O
-	O
mercaptoethanol	O
,	O
200	O
micro	O
g	O
/	O
ml	O
cyclohexamide	O
,	O
2	O
micro	O
g	O
/	O
ml	O
aprotonin	O
,	O
1	O
mM	O
PMSF	O
,	O
0	O
.	O
5	O
micro	O
g	O
/	O
ml	O
leupeptin	O
,	O
2	O
.	O
9	O
micro	O
g	O
/	O
ml	O
E64	O
,	O
1	O
micro	O
g	O
/	O
ml	O
antipain	O
,	O
0	O
.	O
2	O
micro	O
g	O
/	O
ml	O
chymostatin	O
)	O
.	O

Lysate	O
was	O
transferred	O
to	O
a	O
clean	O
microfuge	O
tube	O
,	O
and	O
centrifuged	O
10	O
min	O
at	O
3000	O
g	O
at	O
4	O
degrees	O
C	O
.	O

The	O
supernatant	O
was	O
again	O
transferred	O
to	O
a	O
clean	O
microfuge	O
tube	O
and	O
centrifuged	O
at	O
12	O
000	O
g	O
for	O
15	O
min	O
at	O
4	O
degrees	O
C	O
,	O
and	O
then	O
assayed	O
for	O
absorbance	O
at	O
260	O
nm	O
.	O

Approximately	O
12	O
OD260	O
units	O
were	O
loaded	O
onto	O
a	O
11	O
ml	O
15	O
-	O
45	O
%	O
sucrose	O
gradient	O
made	O
in	O
10	O
mM	O
Tris	O
,	O
pH	O
7	O
.	O
4	O
,	O
70	O
mM	O
NH4Cl	O
,	O
4	O
mM	O
MgOAc	O
,	O
using	O
a	O
Gradient	O
Master	O
automatic	O
system	O
,	O
and	O
the	O
gradient	O
was	O
centrifuged	O
in	O
a	O
SW41ti	O
rotor	O
(	O
Beckman	O
)	O
at	O
39	O
000	O
r	O
.	O
p	O
.	O
m	O
.	O
for	O
2	O
.	O
5	O
h	O
.	O

0	O
.	O
5	O
ml	O
fractions	O
were	O
collected	O
using	O
an	O
Isco	O
gradient	O
fractionator	O
,	O
and	O
gradient	O
profiles	O
were	O
determined	O
by	O
monitoring	O
absorbance	O
at	O
254	O
nm	O
.	O

For	O
EDTA	O
controls	O
,	O
lysis	O
buffer	O
containing	O
5	O
mM	O
MgCl2	O
was	O
used	O
,	O
and	O
30	O
mM	O
EDTA	O
was	O
added	O
to	O
the	O
sample	O
before	O
loading	O
onto	O
the	O
gradient	O
.	O

Where	O
indicated	O
,	O
addition	O
of	O
50	O
U	O
/	O
ml	O
of	O
RNase	O
One	O
(	O
Promega	O
)	O
was	O
performed	O
prior	O
to	O
loading	O
the	O
sample	O
onto	O
the	O
gradient	O
.	O

Gel	O
filtration	O
chromatography	O

Gel	O
filtration	O
chromatography	O
was	O
performed	O
using	O
a	O
120	O
ml	O
Hi	O
-	O
Prep	O
S	O
-	O
300	O
Sephacryl	O
column	O
(	O
Pharmacia	O
)	O
with	O
a	O
cut	O
-	O
off	O
of	O
1300	O
kDa	O
,	O
attached	O
to	O
an	O
FPLC	O
system	O
(	O
Pharmacia	O
)	O
.	O

The	O
column	O
had	O
been	O
calibrated	O
previously	O
using	O
the	O
following	O
molecular	O
weight	O
standards	O
(	O
Sigma	O
)	O
:	O
blue	O
dextran	O
(	O
2000	O
kDa	O
)	O
,	O
thyroglobulin	O
(	O
669	O
kDa	O
)	O
,	O
apoferritin	O
(	O
443	O
kDa	O
)	O
,	O
alcohol	O
dehydrogenase	O
(	O
150	O
kDa	O
)	O
,	O
and	O
bovine	B
serum	O
albumin	O
(	O
66	O
kDa	O
)	O
.	O

Yeast	B
were	O
lysed	O
as	O
described	O
for	O
polyribosome	O
analysis	O
,	O
with	O
an	O
additional	O
clarification	O
by	O
passage	O
through	O
a	O
0	O
.	O
2	O
micro	O
m	O
syringe	O
-	O
tip	O
filter	O
(	O
Acrodisc	O
)	O
and	O
run	O
over	O
the	O
column	O
at	O
a	O
rate	O
of	O
0	O
.	O
5	O
ml	O
/	O
min	O
in	O
polyribosome	O
lysis	O
buffer	O
following	O
treatment	O
with	O
the	O
indicated	O
reagents	O
.	O

Fractions	O
(	O
2	O
.	O
0	O
ml	O
)	O
were	O
collected	O
,	O
from	O
which	O
12	O
micro	O
l	O
were	O
combined	O
with	O
sample	O
buffer	O
(	O
2	O
%	O
SDS	O
,	O
10	O
%	O
glycerol	O
,	O
100	O
mM	O
dithiothreitol	O
,	O
60	O
mM	O
Tris	O
pH	O
6	O
.	O
8	O
,	O
0	O
.	O
001	O
%	O
bromophenol	O
blue	O
)	O
and	O
analyzed	O
by	O
western	O
blot	O
using	O
the	O
indicated	O
antibodies	O
.	O

alpha	O
-	O
FLAG	O
affinity	O
chromatography	O

For	O
most	O
experiments	O
,	O
one	O
liter	O
yeast	B
cultures	O
were	O
grown	O
to	O
early	O
log	O
-	O
phase	O
and	O
harvested	O
by	O
centrifugation	O
.	O

Cells	O
were	O
washed	O
twice	O
in	O
T75	O
buffer	O
(	O
25	O
mM	O
Tris	O
pH	O
7	O
.	O
5	O
,	O
75	O
mM	O
NaCl	O
)	O
and	O
then	O
were	O
lysed	O
by	O
vortex	O
agitation	O
with	O
an	O
equal	O
volume	O
of	O
glass	O
beads	O
in	O
4	O
ml	O
T75	O
buffer	O
containing	O
30	O
mM	O
EDTA	O
.	O

Lysate	O
was	O
transferred	O
to	O
a	O
clean	O
microfuge	O
tube	O
,	O
and	O
centrifuged	O
for	O
10	O
min	O
at	O
3000	O
g	O
at	O
4	O
degrees	O
C	O
.	O

The	O
supernatant	O
was	O
again	O
transferred	O
to	O
a	O
clean	O
microfuge	O
tube	O
and	O
centrifuged	O
at	O
12	O
000	O
g	O
for	O
15	O
min	O
at	O
4	O
degrees	O
C	O
,	O
and	O
finally	O
passed	O
through	O
a	O
0	O
.	O
2	O
micro	O
m	O
syringe	O
filter	O
.	O

Lysate	O
was	O
then	O
pre	O
-	O
purified	O
by	O
running	O
over	O
the	O
S	O
-	O
300	O
gel	O
-	O
filtration	O
column	O
in	O
T75	O
buffer	O
,	O
with	O
pooling	O
of	O
the	O
void	O
volume	O
fractions	O
(	O
~	O
10	O
ml	O
total	O
)	O
.	O

For	O
several	O
experiments	O
(	O
Fig	O
.	O
5A	O
,	O
B	O
,	O
E	O
and	O
F	O
)	O
,	O
a	O
low	O
concentration	O
(	O
<	O
10	O
micro	O
g	O
/	O
ml	O
)	O
of	O
FLAG	O
peptide	O
(	O
N	O
-	O
DYKDDDDK	O
-	O
C	O
)	O
was	O
added	O
to	O
this	O
sample	O
.	O

This	O
void	O
material	O
was	O
then	O
loaded	O
onto	O
a	O
1	O
ml	O
M2	O
alpha	O
-	O
FLAG	O
column	O
(	O
Sigma	O
)	O
;	O
column	O
flow	O
-	O
through	O
was	O
passed	O
over	O
the	O
column	O
a	O
second	O
time	O
.	O

The	O
column	O
was	O
then	O
washed	O
extensively	O
with	O
75	O
ml	O
T75	O
buffer	O
;	O
material	O
bound	O
to	O
the	O
column	O
was	O
eluted	O
with	O
5	O
ml	O
T75	O
containing	O
184	O
mg	O
/	O
ml	O
FLAG	O
peptide	O
.	O

The	O
peptide	O
solution	O
was	O
allowed	O
to	O
incubate	O
on	O
the	O
column	O
for	O
20	O
min	O
prior	O
to	O
collection	O
of	O
the	O
first	O
1	O
ml	O
fraction	O
;	O
subsequent	O
fractions	O
were	O
collected	O
every	O
10	O
min	O
.	O

Samples	O
of	O
crude	O
material	O
,	O
S	O
-	O
300	O
void	O
,	O
alpha	O
-	O
FLAG	O
flow	O
-	O
through	O
,	O
first	O
and	O
last	O
wash	O
,	O
and	O
eluate	O
fractions	O
were	O
analyzed	O
by	O
western	O
blot	O
using	O
the	O
indicated	O
antibodies	O
.	O

For	O
Figure	O
5A	O
and	O
E	O
,	O
samples	O
of	O
first	O
and	O
last	O
wash	O
and	O
eluate	O
fractions	O
were	O
concentrated	O
,	O
run	O
on	O
SDS	O
-	O
PAGE	O
and	O
stained	O
with	O
colloidal	O
G250	O
Coomassie	O
.	O

Concentration	O
of	O
samples	O

Where	O
indicated	O
,	O
samples	O
were	O
concentrated	O
using	O
the	O
method	O
of	O
Traub	O
et	O
al	O
.	O

(	O
21	O
)	O
.	O

400	O
micro	O
l	O
of	O
sample	O
were	O
transferred	O
to	O
a	O
microfuge	O
tube	O
,	O
and	O
combined	O
with	O
400	O
micro	O
l	O
of	O
methanol	O
,	O
and	O
100	O
micro	O
l	O
of	O
chloroform	O
.	O

Samples	O
were	O
then	O
vortexed	O
vigorously	O
,	O
and	O
centrifuged	O
for	O
5	O
min	O
at	O
12	O
000	O
g	O
.	O

The	O
supernatant	O
was	O
discarded	O
,	O
leaving	O
the	O
interface	O
intact	O
,	O
and	O
an	O
additional	O
400	O
micro	O
l	O
of	O
methanol	O
was	O
added	O
to	O
each	O
tube	O
.	O

Samples	O
were	O
then	O
inverted	O
several	O
times	O
,	O
and	O
centrifuged	O
again	O
for	O
5	O
min	O
.	O

The	O
supernatant	O
was	O
discarded	O
,	O
and	O
the	O
protein	O
pellet	O
was	O
air	O
-	O
dried	O
and	O
resuspended	O
in	O
1	O
x	O
sample	O
buffer	O
.	O

Western	O
blot	O
analysis	O

Western	O
blot	O
analysis	O
was	O
performed	O
essentially	O
as	O
described	O
previously	O
(	O
19	O
)	O
.	O

Briefly	O
,	O
samples	O
to	O
be	O
analyzed	O
were	O
mixed	O
with	O
sample	O
buffer	O
,	O
boiled	O
,	O
electrophoresed	O
through	O
a	O
10	O
%	O
SDS	O
-	O
polyacrylamide	O
gel	O
,	O
and	O
electro	O
-	O
blotted	O
onto	O
nitrocellulose	O
(	O
Bio	O
-	O
Rad	O
)	O
.	O

FLAG	O
-	O
Scp160p	O
fusion	O
protein	O
was	O
detected	O
by	O
incubation	O
of	O
the	O
filter	O
with	O
mouse	B
M2	O
anti	O
-	O
FLAG	O
monoclonal	O
antibody	O
(	O
10	O
micro	O
g	O
/	O
ml	O
final	O
concentration	O
)	O
,	O
followed	O
by	O
HRP	O
-	O
conjugated	O
sheep	B
anti	O
-	O
mouse	B
secondary	O
antibody	O
(	O
Amersham	O
)	O
,	O
diluted	O
1	O
:	O
5000	O
as	O
per	O
the	O
manufacturer	O
'	O
s	O
instructions	O
,	O
and	O
ECL	O
reagent	O
(	O
Amersham	O
)	O
,	O
followed	O
by	O
exposure	O
to	O
X	O
-	O
ray	O
film	O
.	O

HA	O
-	O
tagged	O
Scp160p	O
and	O
HA	O
-	O
tagged	O
Bfr1p	O
were	O
detected	O
using	O
the	O
12CA5	O
mAb	O
(	O
Boehringer	O
Mannheim	O
)	O
at	O
a	O
final	O
concentration	O
of	O
0	O
.	O
8	O
micro	O
g	O
/	O
ml	O
;	O
Pab1p	O
and	O
Pub1p	O
were	O
detected	O
using	O
1G1	O
mAb	O
at	O
1	O
:	O
5000	O
,	O
and	O
4C3	O
mAb	O
at	O
1	O
:	O
1000	O
,	O
respectively	O
,	O
both	O
generous	O
gifts	O
from	O
Dr	O
Maurice	O
Swanson	O
(	O
22	O
,	O
23	O
)	O
.	O

Where	O
appropriate	O
,	O
films	O
were	O
analyzed	O
by	O
scanning	O
densitometry	O
(	O
Molecular	O
Dynamics	O
)	O
,	O
and	O
quantitated	O
using	O
ImageQuant	O
software	O
(	O
Molecular	O
Dynamics	O
)	O
.	O

Colloidal	O
G250	O
coomassie	O
staining	O

Procedure	O
used	O
was	O
that	O
of	O
Neuhoff	O
(	O
24	O
)	O
.	O

Briefly	O
,	O
a	O
one	O
liter	O
stock	O
of	O
staining	O
solution	O
was	O
prepared	O
containing	O
1	O
g	O
Coomassie	O
brilliant	O
blue	O
G	O
-	O
250	O
(	O
Sigma	O
)	O
,	O
100	O
g	O
ammonium	O
sulfate	O
(	O
Sigma	O
)	O
,	O
and	O
11	O
.	O
76	O
ml	O
85	O
%	O
phosphoric	O
acid	O
(	O
Fisher	O
)	O
.	O

Following	O
SDS	O
-	O
PAGE	O
,	O
gels	O
were	O
fixed	O
in	O
40	O
%	O
methanol	O
,	O
10	O
%	O
acetic	O
acid	O
for	O
10	O
min	O
.	O

Gels	O
were	O
then	O
rinsed	O
several	O
times	O
in	O
water	O
,	O
then	O
stained	O
using	O
40	O
ml	O
of	O
the	O
stock	O
staining	O
solution	O
mixed	O
with	O
10	O
ml	O
methanol	O
,	O
for	O
2	O
h	O
at	O
room	O
temperature	O
.	O

Stain	O
was	O
then	O
poured	O
off	O
,	O
and	O
residual	O
stain	O
was	O
removed	O
by	O
rinsing	O
in	O
water	O
.	O

By	O
performing	O
a	O
standard	O
analysis	O
using	O
bovine	B
serum	O
albumin	O
,	O
the	O
stain	O
was	O
able	O
to	O
detect	O
~	O
15	O
ng	O
total	O
protein	O
per	O
lane	O
.	O

Pichia	O
expression	O
system	O

An	O
N	O
-	O
terminally	O
HIS6	O
/	O
FLAG	O
-	O
tagged	O
allele	O
of	O
the	O
SCP160	O
coding	O
sequence	O
was	O
blunt	O
-	O
end	O
sub	O
-	O
cloned	O
into	O
the	O
BamHI	O
/	O
SnaBI	O
sites	O
of	O
the	O
Pichia	O
expression	O
vector	O
pPIC3	O
.	O
5K	O
(	O
Invitrogen	O
)	O
.	O

The	O
construct	O
was	O
then	O
linearized	O
using	O
SalI	O
and	O
integrated	O
into	O
the	O
genome	O
of	O
the	O
Pichia	O
strain	O
GS115	O
(	O
Invitrogen	O
)	O
.	O

High	O
expression	O
transformants	O
were	O
selected	O
initially	O
on	O
histidine	O
-	O
deficient	O
medium	O
followed	O
by	O
selection	O
on	O
increasing	O
concentrations	O
of	O
G418	O
(	O
US	O
Biological	O
)	O
.	O

Crude	O
lysates	O
of	O
the	O
resultant	O
transformants	O
were	O
then	O
confirmed	O
by	O
western	O
blot	O
analysis	O
with	O
the	O
anti	O
-	O
FLAG	O
antibody	O
M2	O
,	O
and	O
the	O
best	O
expressing	O
strain	O
was	O
cultured	O
in	O
a	O
fermenter	O
,	O
harvested	O
,	O
and	O
lysed	O
by	O
agitation	O
with	O
glass	O
beads	O
.	O

To	O
purify	O
Scp160p	O
,	O
2	O
ml	O
of	O
crude	O
lysate	O
was	O
first	O
diluted	O
to	O
10	O
ml	O
with	O
25	O
mM	O
Tris	O
,	O
pH	O
7	O
.	O
5	O
,	O
1	O
M	O
NaCl	O
,	O
then	O
twice	O
passed	O
over	O
a	O
1	O
ml	O
alpha	O
-	O
FLAG	O
affinity	O
column	O
.	O

The	O
column	O
was	O
then	O
washed	O
with	O
75	O
ml	O
of	O
25	O
mM	O
Tris	O
,	O
pH	O
7	O
.	O
5	O
,	O
1	O
M	O
NaCl	O
,	O
and	O
then	O
eluted	O
with	O
184	O
micro	O
g	O
/	O
ml	O
FLAG	O
peptide	O
prepared	O
in	O
the	O
same	O
buffer	O
.	O

RESULTS	O

Expression	O
of	O
tagged	O
Scp160p	O
in	O
yeast	B

An	O
N	O
-	O
terminal	O
FLAG	O
-	O
tagged	O
form	O
of	O
Scp160p	O
was	O
created	O
to	O
facilitate	O
detection	O
of	O
the	O
protein	O
in	O
cells	O
and	O
extracts	O
(	O
Fig	O
.	O
1A	O
)	O
.	O

To	O
probe	O
functionality	O
of	O
this	O
fusion	O
protein	O
,	O
we	O
used	O
two	O
-	O
step	O
gene	O
replacement	O
(	O
18	O
)	O
to	O
substitute	O
the	O
modified	O
allele	O
into	O
the	O
SCP160	O
locus	O
of	O
haploid	O
yeast	B
,	O
and	O
then	O
tested	O
the	O
morphological	O
phenotype	O
of	O
the	O
resultant	O
cells	O
.	O

All	O
strains	O
were	O
confirmed	O
by	O
PCR	O
analysis	O
of	O
the	O
SCP160	O
locus	O
with	O
appropriate	O
primers	O
(	O
Materials	O
and	O
Methods	O
)	O
,	O
and	O
expression	O
of	O
the	O
tagged	O
protein	O
was	O
confirmed	O
by	O
western	O
blot	O
analysis	O
with	O
the	O
appropriate	O
antibody	O
(	O
M2	O
alpha	O
FLAG	O
)	O
(	O
Fig	O
.	O
1B	O
)	O
.	O

In	O
all	O
cases	O
,	O
yeast	B
expressing	O
tagged	O
Scp160p	O
in	O
place	O
of	O
the	O
native	O
protein	O
appeared	O
indistinguishable	O
from	O
the	O
corresponding	O
wild	O
-	O
type	O
strains	O
(	O
data	O
not	O
shown	O
)	O
.	O

As	O
a	O
negative	O
control	O
,	O
we	O
also	O
deleted	O
almost	O
the	O
entire	O
SCP160	O
coding	O
region	O
from	O
the	O
genomes	O
of	O
these	O
yeast	B
strains	O
(	O
Fig	O
.	O
1A	O
)	O
,	O
and	O
confirmed	O
the	O
expected	O
mutant	O
phenotype	O
(	O
data	O
not	O
shown	O
)	O
.	O

Scp160p	O
associates	O
with	O
polyribosomes	O

To	O
test	O
the	O
hypothesis	O
that	O
Scp160p	O
associates	O
with	O
polyribosomes	O
we	O
used	O
sucrose	O
gradient	O
ultracentrifugation	O
to	O
size	O
-	O
fractionate	O
subcellular	O
components	O
of	O
lysates	O
prepared	O
from	O
yeast	B
expressing	O
the	O
N	O
-	O
terminal	O
FLAG	O
-	O
tagged	O
Scp160p	O
protein	O
.	O

Western	O
blot	O
analyses	O
of	O
gradient	O
fractions	O
with	O
an	O
alpha	O
-	O
FLAG	O
antibody	O
(	O
M2	O
,	O
Boehringer	O
Mannheim	O
)	O
,	O
revealed	O
a	O
160	O
kDa	O
band	O
that	O
was	O
most	O
abundant	O
in	O
the	O
denser	O
fractions	O
,	O
consistent	O
with	O
the	O
location	O
of	O
polyribosomes	O
(	O
>	O
80S	O
)	O
(	O
Fig	O
.	O
2A	O
,	O
solid	O
arrow	O
)	O
.	O

A	O
convenient	O
internal	O
control	O
for	O
these	O
gradients	O
was	O
provided	O
by	O
an	O
unknown	O
endogenous	O
yeast	B
cross	O
-	O
reacting	O
protein	O
at	O
~	O
100	O
kDa	O
,	O
that	O
exemplified	O
the	O
migration	O
pattern	O
of	O
a	O
free	O
protein	O
,	O
appearing	O
only	O
in	O
the	O
upper	O
fractions	O
of	O
the	O
gradient	O
(	O
Fig	O
.	O
2A	O
,	O
open	O
arrow	O
)	O
.	O

To	O
determine	O
whether	O
the	O
migration	O
pattern	O
of	O
Scp160p	O
in	O
these	O
sucrose	O
gradients	O
truly	O
reflected	O
association	O
with	O
yeast	B
polyribosomes	O
,	O
lysates	O
were	O
pre	O
-	O
treated	O
with	O
either	O
30	O
mM	O
EDTA	O
or	O
50	O
U	O
/	O
ml	O
RNase	O
One	O
(	O
Promega	O
)	O
immediately	O
prior	O
to	O
sucrose	O
gradient	O
fractionation	O
.	O

EDTA	O
chelates	O
Mg2	O
+	O
cations	O
,	O
resulting	O
in	O
the	O
dissociation	O
of	O
the	O
small	O
and	O
large	O
ribosomal	O
subunits	O
,	O
reflected	O
in	O
gradient	O
profiles	O
(	O
OD254	O
)	O
by	O
the	O
disappearance	O
of	O
80S	O
monosomes	O
and	O
polyribosomes	O
along	O
with	O
a	O
marked	O
increase	O
in	O
the	O
abundance	O
of	O
free	O
ribosomal	O
subunits	O
(	O
Fig	O
.	O
2B	O
)	O
.	O

Under	O
these	O
conditions	O
,	O
the	O
greatest	O
intensity	O
of	O
FLAG	O
-	O
Scp160p	O
signal	O
was	O
seen	O
only	O
in	O
the	O
upper	O
-	O
most	O
fractions	O
of	O
the	O
gradient	O
(	O
Fig	O
.	O
2B	O
)	O
.	O

Alternatively	O
,	O
pre	O
-	O
treatment	O
of	O
lysates	O
with	O
RNase	O
,	O
which	O
results	O
in	O
inter	O
-	O
ribosomal	O
severing	O
of	O
translating	O
messages	O
,	O
gave	O
rise	O
to	O
a	O
large	O
pool	O
of	O
single	O
80S	O
ribosomes	O
(	O
Fig	O
.	O
2C	O
)	O
.	O

Again	O
,	O
FLAG	O
-	O
Scp160p	O
was	O
shifted	O
to	O
the	O
uppermost	O
fractions	O
of	O
these	O
gradients	O
.	O

Although	O
some	O
of	O
the	O
Scp160p	O
signal	O
was	O
detected	O
in	O
fractions	O
larger	O
than	O
40S	O
,	O
the	O
migration	O
pattern	O
of	O
the	O
100	O
kDa	O
cross	O
-	O
reacting	O
protein	O
in	O
these	O
experiments	O
indicated	O
that	O
RNase	O
treatment	O
caused	O
an	O
apparent	O
diffusion	O
of	O
material	O
in	O
the	O
upper	O
portion	O
of	O
the	O
gradient	O
.	O

Characterization	O
of	O
Scp160p	O
-	O
containing	O
complexes	O
following	O
EDTA	O
and	O
RNase	O
treatment	O

Gel	O
-	O
filtration	O
chromatography	O
was	O
used	O
to	O
determine	O
the	O
apparent	O
molecular	O
weight	O
of	O
Scp160p	O
following	O
its	O
release	O
from	O
polyribosomes	O
by	O
both	O
EDTA	O
and	O
RNase	O
treatment	O
.	O

Lysates	O
were	O
prepared	O
as	O
described	O
above	O
for	O
sucrose	O
gradient	O
analysis	O
,	O
but	O
were	O
instead	O
size	O
fractionated	O
over	O
a	O
Sephacryl	O
S	O
-	O
300	O
Hi	O
-	O
Prep	O
column	O
,	O
with	O
an	O
inclusion	O
cut	O
-	O
off	O
of	O
1300	O
kDa	O
.	O

As	O
expected	O
,	O
Scp160p	O
from	O
untreated	O
lysates	O
eluted	O
in	O
the	O
void	O
volume	O
,	O
confirming	O
its	O
association	O
with	O
large	O
complexes	O
,	O
ostensibly	O
polyribosomes	O
(	O
Fig	O
.	O
3A	O
,	O
solid	O
arrow	O
)	O
.	O

In	O
EDTA	O
treated	O
lysates	O
,	O
all	O
Scp160p	O
signal	O
was	O
still	O
detected	O
in	O
the	O
void	O
volume	O
,	O
indicating	O
it	O
remained	O
in	O
a	O
complex	O
of	O
>	O
1300	O
kDa	O
(	O
Fig	O
.	O
3B	O
,	O
solid	O
arrow	O
)	O
.	O

In	O
contrast	O
,	O
limited	O
RNase	O
treatment	O
(	O
10	O
min	O
)	O
resulted	O
in	O
the	O
appearance	O
of	O
an	O
Scp160p	O
-	O
containing	O
species	O
of	O
~	O
450	O
kDa	O
,	O
in	O
addition	O
to	O
a	O
fraction	O
still	O
visible	O
in	O
the	O
void	O
(	O
Fig	O
.	O
3C	O
,	O
solid	O
arrow	O
)	O
.	O

More	O
extensive	O
RNase	O
treatment	O
(	O
30	O
min	O
)	O
led	O
to	O
complete	O
conversion	O
to	O
the	O
450	O
kDa	O
species	O
(	O
Fig	O
.	O
3D	O
,	O
solid	O
arrow	O
)	O
.	O

Sequential	O
treatment	O
,	O
first	O
with	O
RNase	O
,	O
then	O
with	O
EDTA	O
,	O
also	O
resulted	O
in	O
a	O
450	O
kDa	O
species	O
(	O
data	O
not	O
shown	O
)	O
,	O
suggesting	O
that	O
all	O
components	O
of	O
this	O
apparent	O
450	O
kDa	O
complex	O
were	O
also	O
present	O
following	O
EDTA	O
treatment	O
alone	O
.	O

As	O
before	O
,	O
the	O
100	O
kDa	O
,	O
endogenous	O
alpha	O
-	O
FLAG	O
cross	O
-	O
reacting	O
protein	O
(	O
Fig	O
.	O
3	O
,	O
open	O
arrows	O
)	O
served	O
as	O
a	O
convenient	O
internal	O
control	O
,	O
eluting	O
from	O
the	O
column	O
at	O
a	O
volume	O
consistent	O
with	O
its	O
expected	O
monomeric	O
size	O
.	O

To	O
characterize	O
further	O
the	O
stability	O
of	O
the	O
large	O
(	O
apparent	O
molecular	O
weight	O
>	O
1300	O
kDa	O
)	O
,	O
EDTA	O
-	O
resistant	O
complex	O
,	O
lysates	O
were	O
treated	O
with	O
increasing	O
concentrations	O
of	O
NaCl	O
prior	O
to	O
size	O
fractionation	O
(	O
Fig	O
.	O
3	O
,	O
panels	O
E	O
,	O
F	O
and	O
G	O
)	O
.	O

As	O
shown	O
in	O
Figure	O
3E	O
,	O
at	O
75	O
mM	O
NaCl	O
,	O
the	O
large	O
complex	O
remained	O
intact	O
.	O

However	O
,	O
at	O
a	O
NaCl	O
concentration	O
of	O
150	O
mM	O
,	O
the	O
Scp160p	O
complex	O
was	O
partially	O
reduced	O
to	O
450	O
kDa	O
,	O
with	O
some	O
signal	O
still	O
remaining	O
in	O
the	O
void	O
(	O
Fig	O
.	O
3F	O
,	O
solid	O
arrow	O
)	O
.	O

Following	O
treatment	O
with	O
1	O
M	O
NaCl	O
,	O
Scp160p	O
was	O
only	O
visible	O
as	O
the	O
450	O
kDa	O
species	O
(	O
Fig	O
.	O
3G	O
,	O
solid	O
arrow	O
)	O
.	O

The	O
fact	O
that	O
RNase	O
treatment	O
and	O
high	O
salt	O
both	O
generated	O
Scp160p	O
species	O
of	O
similar	O
apparent	O
molecular	O
weight	O
suggests	O
that	O
these	O
high	O
salt	O
concentrations	O
resulted	O
in	O
the	O
disassociation	O
of	O
RNA	O
,	O
and	O
perhaps	O
other	O
components	O
,	O
from	O
Scp160p	O
.	O

Pab1p	O
and	O
Bfr1p	O
are	O
present	O
in	O
EDTA	O
-	O
resistant	O
Scp160p	O
-	O
containing	O
complexes	O

To	O
determine	O
if	O
the	O
>	O
1300	O
kDa	O
Scp160p	O
-	O
containing	O
complexes	O
remaining	O
after	O
EDTA	O
treatment	O
were	O
mRNPs	O
,	O
we	O
assayed	O
for	O
the	O
presence	O
of	O
the	O
yeast	B
poly	O
(	O
A	O
)	O
binding	O
protein	O
,	O
Pab1p	O
,	O
following	O
alpha	O
-	O
FLAG	O
affinity	O
purification	O
as	O
illustrated	O
in	O
Figure	O
4	O
.	O

Pab1p	O
is	O
an	O
abundant	O
and	O
well	O
-	O
characterized	O
component	O
of	O
mRNP	O
complexes	O
in	O
yeast	B
,	O
as	O
well	O
as	O
higher	O
eukaryotes	O
(	O
14	O
,	O
15	O
,	O
25	O
)	O
.	O

As	O
seen	O
in	O
Figure	O
5A	O
and	O
B	O
,	O
Pab1p	O
did	O
co	O
-	O
purify	O
with	O
FLAG	O
-	O
Scp160p	O
;	O
moreover	O
,	O
treatment	O
with	O
RNase	O
immediately	O
prior	O
to	O
FLAG	O
-	O
purification	O
completely	O
abolished	O
this	O
interaction	O
(	O
Fig	O
.	O
5C	O
)	O
,	O
indicating	O
an	O
RNA	O
-	O
dependant	O
association	O
between	O
these	O
two	O
proteins	O
.	O

We	O
also	O
probed	O
the	O
isolated	O
complexes	O
for	O
the	O
presence	O
of	O
another	O
abundant	O
mRNP	O
-	O
component	O
protein	O
,	O
Pub1p	O
(	O
23	O
,	O
26	O
)	O
.	O

Pub1p	O
,	O
as	O
opposed	O
to	O
Pab1p	O
,	O
is	O
not	O
reported	O
to	O
associate	O
with	O
polyribosomes	O
,	O
and	O
is	O
hypothesized	O
to	O
bind	O
a	O
pool	O
of	O
non	O
-	O
translatable	O
mRNAs	O
(	O
23	O
)	O
.	O

As	O
predicted	O
,	O
Pub1p	O
did	O
not	O
co	O
-	O
purify	O
with	O
Scp160p	O
(	O
Fig	O
.	O
5D	O
)	O
.	O

The	O
absence	O
of	O
Pub1p	O
in	O
Scp160p	O
-	O
containing	O
complexes	O
served	O
as	O
a	O
negative	O
control	O
,	O
demonstrating	O
that	O
abundant	O
RNA	O
-	O
binding	O
proteins	O
did	O
not	O
co	O
-	O
purify	O
non	O
-	O
specifically	O
by	O
this	O
protocol	O
.	O

In	O
addition	O
,	O
we	O
performed	O
mock	O
purifications	O
using	O
lysates	O
from	O
yeast	B
expressing	O
the	O
wild	O
-	O
type	O
allele	O
of	O
SCP160	O
without	O
the	O
FLAG	O
epitope	O
(	O
Fig	O
.	O
5F	O
)	O
,	O
or	O
with	O
an	O
unrelated	O
FLAG	O
-	O
tagged	O
protein	O
,	O
human	B
galactose	O
1	O
-	O
phosphate	O
uridylyltransferase	O
(	O
GALT	O
)	O
(	O
Fig	O
.	O
5G	O
,	O
lower	O
panel	O
)	O
.	O

In	O
neither	O
case	O
did	O
Pab1p	O
bind	O
and	O
elute	O
from	O
the	O
FLAG	O
affinity	O
column	O
.	O

Finally	O
,	O
no	O
bands	O
were	O
visible	O
by	O
colloidal	O
G250	O
Coomassie	O
staining	O
of	O
samples	O
from	O
the	O
mock	O
(	O
wild	O
-	O
type	O
)	O
preparations	O
(	O
Fig	O
.	O
5E	O
)	O
,	O
further	O
demonstrating	O
the	O
specificity	O
of	O
this	O
procedure	O
.	O

By	O
colloidal	O
G250	O
Coomassie	O
staining	O
(	O
Materials	O
and	O
Methods	O
)	O
of	O
the	O
FLAG	O
-	O
purified	O
complex	O
,	O
we	O
observed	O
in	O
addition	O
to	O
Scp160p	O
,	O
two	O
major	O
bands	O
,	O
at	O
~	O
70	O
kDa	O
and	O
~	O
55	O
kDa	O
,	O
which	O
ostensibly	O
represent	O
co	O
-	O
purifying	O
proteins	O
(	O
Fig	O
.	O
5A	O
,	O
bottom	O
panel	O
)	O
.	O

Western	O
blot	O
analysis	O
suggested	O
that	O
the	O
~	O
70	O
kDa	O
species	O
is	O
Pab1p	O
.	O

To	O
identify	O
the	O
55	O
kDa	O
protein	O
,	O
that	O
band	O
was	O
excised	O
from	O
the	O
gel	O
,	O
and	O
sent	O
to	O
the	O
Keck	O
microchemical	O
facility	O
at	O
Yale	O
University	O
for	O
analysis	O
by	O
in	O
gel	O
tryptic	O
digestion	O
,	O
followed	O
by	O
MALDI	O
-	O
mass	O
spectrometry	O
.	O

The	O
results	O
of	O
these	O
analyses	O
clearly	O
identified	O
the	O
unknown	O
protein	O
as	O
Bfr1p	O
.	O

To	O
confirm	O
this	O
result	O
,	O
an	O
N	O
-	O
terminal	O
HA	O
tag	O
was	O
engineered	O
onto	O
the	O
genomic	O
BFR1	O
locus	O
in	O
strains	O
expressing	O
FLAG	O
-	O
tagged	O
or	O
wild	O
-	O
type	O
Scp160p	O
.	O

Scp160p	O
complexes	O
were	O
then	O
isolated	O
from	O
both	O
of	O
these	O
strains	O
using	O
the	O
protocol	O
described	O
above	O
.	O

As	O
seen	O
in	O
Figure	O
6	O
,	O
an	O
HA	O
-	O
tagged	O
protein	O
of	O
~	O
55	O
kDa	O
(	O
center	O
panel	O
)	O
appears	O
in	O
alpha	O
-	O
FLAG	O
column	O
elutions	O
only	O
when	O
FLAG	O
-	O
Scp160p	O
is	O
also	O
present	O
(	O
top	O
panel	O
)	O
.	O

No	O
signal	O
is	O
visible	O
in	O
mock	O
purifications	O
of	O
extracts	O
where	O
Scp160p	O
is	O
not	O
FLAG	O
-	O
tagged	O
(	O
bottom	O
panel	O
)	O
.	O

Monomeric	O
Scp160p	O
migrates	O
as	O
a	O
~	O
450	O
kDa	O
protein	O
under	O
native	O
conditions	O

As	O
a	O
first	O
step	O
to	O
characterize	O
the	O
post	O
RNase	O
/	O
NaCl	O
450	O
kDa	O
Scp160p	O
species	O
we	O
compared	O
it	O
with	O
Scp160p	O
over	O
-	O
expressed	O
and	O
purified	O
from	O
an	O
exogenous	O
host	O
,	O
the	O
yeast	B
Pichia	B
pastoris	I
.	O

The	O
purified	O
N	O
-	O
terminal	O
FLAG	O
/	O
hexahistidine	O
-	O
tagged	O
Scp160p	O
was	O
run	O
over	O
an	O
S300	O
gel	O
filtration	O
column	O
;	O
2	O
ml	O
fractions	O
were	O
collected	O
and	O
analyzed	O
by	O
alpha	O
-	O
FLAG	O
western	O
blot	O
.	O

As	O
seen	O
in	O
Figure	O
7A	O
,	O
purified	O
Scp160p	O
eluted	O
at	O
a	O
volume	O
consistent	O
with	O
a	O
>	O
443	O
kDa	O
protein	O
.	O

To	O
confirm	O
that	O
no	O
other	O
proteins	O
were	O
associated	O
with	O
the	O
purified	O
Scp160p	O
,	O
12	O
micro	O
l	O
of	O
the	O
protein	O
was	O
run	O
on	O
SDS	O
-	O
PAGE	O
and	O
subjected	O
to	O
colloidal	O
G250	O
Coomassie	O
staining	O
before	O
loading	O
on	O
the	O
S	O
-	O
300	O
column	O
(	O
Fig	O
.	O
7B	O
)	O
.	O

As	O
shown	O
,	O
no	O
bands	O
other	O
than	O
Scp160p	O
were	O
visible	O
.	O

Several	O
KH	O
-	O
domain	O
proteins	O
,	O
including	O
Sam68	O
and	O
FMRP	O
,	O
have	O
been	O
reported	O
to	O
form	O
homodimers	O
in	O
vivo	O
(	O
27	O
)	O
.	O

Therefore	O
,	O
we	O
explored	O
the	O
possibility	O
that	O
the	O
~	O
450	O
kDa	O
Scp160p	O
species	O
might	O
contain	O
two	O
or	O
more	O
copies	O
of	O
Scp160p	O
.	O

To	O
test	O
this	O
hypothesis	O
,	O
yeast	B
expressing	O
FLAG	O
-	O
Scp160p	O
were	O
transfected	O
with	O
a	O
centromeric	O
plasmid	O
,	O
YCplac22	O
-	O
HA	O
-	O
Scp160p	O
,	O
encoding	O
a	O
distinct	O
,	O
HA	O
-	O
tagged	O
allele	O
of	O
the	O
protein	O
.	O

The	O
functionality	O
of	O
this	O
tagged	O
protein	O
had	O
previously	O
been	O
demonstrated	O
by	O
polyribosome	O
association	O
as	O
well	O
as	O
complementation	O
of	O
the	O
null	O
morphological	O
phenotype	O
in	O
cells	O
expressing	O
only	O
HA	O
-	O
Scp160p	O
(	O
data	O
not	O
shown	O
)	O
.	O

As	O
seen	O
in	O
Figure	O
7C	O
,	O
when	O
yeast	B
co	O
-	O
expressing	O
the	O
two	O
alleles	O
were	O
lysed	O
and	O
the	O
FLAG	O
-	O
tagged	O
protein	O
was	O
isolated	O
as	O
described	O
above	O
,	O
no	O
HA	O
-	O
Scp160p	O
co	O
-	O
purified	O
with	O
the	O
FLAG	O
-	O
Scp160p	O
.	O

These	O
data	O
strongly	O
suggest	O
that	O
Scp160p	O
does	O
not	O
form	O
homo	O
-	O
dimers	O
or	O
higher	O
-	O
order	O
multimers	O
in	O
vivo	O
,	O
and	O
that	O
the	O
~	O
450	O
kDa	O
species	O
of	O
Scp160p	O
observed	O
is	O
simply	O
the	O
monomeric	O
protein	O
.	O

DISCUSSION	O

The	O
data	O
presented	O
here	O
demonstrate	O
two	O
main	O
points	O
regarding	O
the	O
biochemical	O
associations	O
and	O
function	O
of	O
Scp160p	O
in	O
yeast	B
.	O

First	O
,	O
the	O
sucrose	O
gradient	O
fractionation	O
data	O
clearly	O
demonstrate	O
that	O
Scp160p	O
exists	O
primarily	O
associated	O
with	O
large	O
complexes	O
,	O
likely	O
to	O
be	O
polyribosomes	O
.	O

To	O
our	O
knowledge	O
,	O
this	O
is	O
the	O
first	O
time	O
a	O
vigilin	O
family	O
member	O
has	O
been	O
shown	O
to	O
associate	O
with	O
polyribosomes	O
in	O
this	O
manner	O
.	O

Interestingly	O
,	O
Weber	O
and	O
colleagues	O
did	O
not	O
observe	O
sucrose	O
gradient	O
fractionation	O
data	O
consistent	O
with	O
polyribosome	O
association	O
of	O
Scp160p	O
(	O
5	O
)	O
.	O

These	O
authors	O
hypothesized	O
that	O
Scp160p	O
associates	O
only	O
with	O
membrane	O
-	O
bound	O
polyribosomes	O
,	O
and	O
that	O
Scp160p	O
is	O
not	O
found	O
complexed	O
with	O
cytosolic	O
polyribosomes	O
(	O
5	O
)	O
.	O

Our	O
data	O
do	O
not	O
support	O
this	O
hypothesis	O
,	O
since	O
unlike	O
Weber	O
and	O
colleagues	O
,	O
we	O
were	O
able	O
to	O
detect	O
significant	O
amounts	O
of	O
Scp160p	O
associated	O
with	O
polyribosomes	O
without	O
using	O
detergents	O
during	O
preparation	O
.	O

There	O
are	O
several	O
possible	O
explanations	O
for	O
this	O
discrepancy	O
.	O

First	O
,	O
the	O
lysate	O
buffer	O
utilized	O
by	O
that	O
group	O
contained	O
100	O
mM	O
NaCl	O
,	O
whereas	O
our	O
buffer	O
contained	O
50	O
mM	O
KCl	O
.	O

Our	O
data	O
shown	O
in	O
Figure	O
3	O
suggest	O
that	O
100	O
mM	O
NaCl	O
may	O
have	O
caused	O
an	O
instability	O
in	O
the	O
Scp160p	O
-	O
RNA	O
interaction	O
,	O
leading	O
to	O
release	O
from	O
polyribosomes	O
during	O
their	O
procedure	O
.	O

Secondly	O
,	O
Weber	O
'	O
s	O
lysate	O
buffer	O
reportedly	O
contained	O
heparin	O
to	O
inhibit	O
ribonucleases	O
;	O
a	O
number	O
of	O
reports	O
(	O
28	O
,	O
29	O
)	O
suggest	O
that	O
heparin	O
can	O
disrupt	O
RNA	O
-	O
protein	O
interactions	O
.	O

Although	O
we	O
have	O
not	O
in	O
the	O
past	O
included	O
heparin	O
in	O
any	O
of	O
our	O
experiments	O
,	O
we	O
have	O
observed	O
disruption	O
of	O
the	O
polyribosome	O
association	O
in	O
buffer	O
containing	O
residual	O
diethylpyrocarbonate	O
,	O
another	O
inhibitor	O
of	O
ribonucleases	O
(	O
data	O
not	O
shown	O
)	O
.	O

Second	O
,	O
our	O
data	O
provide	O
compelling	O
evidence	O
that	O
Scp160p	O
is	O
released	O
from	O
polyribosomes	O
as	O
a	O
component	O
of	O
an	O
mRNP	O
complex	O
.	O

Since	O
Scp160p	O
does	O
not	O
remain	O
associated	O
with	O
either	O
single	O
ribosomes	O
or	O
ribosomal	O
subunits	O
following	O
treatment	O
with	O
EDTA	O
or	O
RNase	O
,	O
it	O
seems	O
unlikely	O
that	O
Scp160p	O
is	O
a	O
constitutive	O
component	O
of	O
the	O
translational	O
machinery	O
.	O

Partial	O
purification	O
of	O
the	O
EDTA	O
-	O
resistant	O
Scp160p	O
complexes	O
allowed	O
us	O
to	O
demonstrate	O
the	O
presence	O
of	O
Pab1p	O
but	O
not	O
Pub1p	O
in	O
these	O
preparations	O
,	O
which	O
is	O
consistent	O
with	O
the	O
idea	O
that	O
Scp160p	O
associates	O
with	O
polyribosomes	O
as	O
a	O
component	O
of	O
mRNP	O
complexes	O
.	O

Previously	O
,	O
Scp160p	O
had	O
been	O
shown	O
to	O
bind	O
ribohomopolymers	O
and	O
rRNA	O
in	O
vitro	O
,	O
although	O
the	O
in	O
vivo	O
nucleic	O
acid	O
targets	O
of	O
Scp160p	O
were	O
unknown	O
(	O
5	O
)	O
.	O

The	O
presence	O
of	O
Pab1p	O
in	O
RNase	O
-	O
sensitive	O
Scp160p	O
complexes	O
indicates	O
that	O
Scp160p	O
is	O
primarily	O
bound	O
to	O
polyadenylated	O
RNAs	O
.	O

Whether	O
or	O
not	O
Scp160p	O
binds	O
only	O
specific	O
sets	O
of	O
mRNAs	O
will	O
be	O
the	O
subject	O
of	O
future	O
studies	O
.	O

In	O
addition	O
to	O
Scp160p	O
and	O
Pab1p	O
,	O
we	O
have	O
identified	O
a	O
third	O
component	O
of	O
the	O
complex	O
,	O
the	O
protein	O
Bfr1p	O
.	O

The	O
gene	O
,	O
BFR1	O
,	O
was	O
originally	O
identified	O
in	O
a	O
screen	O
for	O
high	O
-	O
copy	O
suppressors	O
of	O
Brefeldin	O
-	O
A	O
induced	O
lethality	O
,	O
suggesting	O
a	O
role	O
in	O
the	O
secretory	O
pathway	O
(	O
16	O
)	O
.	O

Interestingly	O
,	O
however	O
,	O
bfr1	O
null	O
mutants	O
do	O
not	O
demonstrate	O
any	O
defects	O
in	O
the	O
secretory	O
pathway	O
,	O
but	O
rather	O
display	O
similar	O
phenotypes	O
to	O
scp160	O
null	O
mutants	O
,	O
most	O
notably	O
increased	O
ploidy	O
and	O
increased	O
cell	O
size	O
(	O
16	O
)	O
.	O

It	O
is	O
therefore	O
unclear	O
whether	O
Bfr1p	O
is	O
capable	O
of	O
functioning	O
in	O
both	O
RNA	O
metabolism	O
and	O
secretion	O
directly	O
,	O
or	O
if	O
the	O
Scp160p	O
-	O
Bfr1p	O
complex	O
regulates	O
the	O
expression	O
of	O
one	O
or	O
more	O
secretory	O
genes	O
at	O
the	O
post	O
-	O
transcriptional	O
level	O
.	O

Additionally	O
,	O
two	O
-	O
hybrid	O
analysis	O
indicated	O
an	O
interaction	O
of	O
Bfr1p	O
with	O
the	O
protein	O
Bbp1p	O
,	O
a	O
component	O
of	O
the	O
mitotic	O
spindle	O
apparatus	O
(	O
30	O
)	O
.	O

While	O
Bbp1p	O
is	O
an	O
essential	O
gene	O
,	O
overexpression	O
leads	O
to	O
a	O
phenotype	O
similar	O
to	O
both	O
bfr1	O
and	O
scp160	O
null	O
strains	O
(	O
30	O
)	O
.	O

Future	O
work	O
will	O
address	O
the	O
functional	O
relationship	O
between	O
Scp160p	O
and	O
Bfr1p	O
including	O
the	O
possibility	O
that	O
these	O
proteins	O
represent	O
a	O
regulatory	O
mechanism	O
connecting	O
the	O
translational	O
machinery	O
with	O
cell	O
division	O
and	O
/	O
or	O
the	O
secretory	O
pathway	O
.	O

Following	O
treatment	O
with	O
either	O
RNase	O
or	O
>	O
150	O
mM	O
NaCl	O
,	O
Scp160p	O
remained	O
as	O
an	O
apparent	O
~	O
450	O
kDa	O
species	O
.	O

Considering	O
that	O
purified	O
Scp160p	O
alone	O
also	O
migrates	O
at	O
this	O
size	O
,	O
we	O
conclude	O
that	O
this	O
apparent	O
complex	O
may	O
consist	O
only	O
of	O
Scp160p	O
,	O
although	O
the	O
presence	O
of	O
other	O
small	O
components	O
cannot	O
be	O
ruled	O
out	O
at	O
this	O
time	O
.	O

Furthermore	O
,	O
by	O
utilizing	O
yeast	B
co	O
-	O
expressing	O
two	O
distinct	O
epitope	O
-	O
tagged	O
versions	O
of	O
Scp160p	O
,	O
we	O
have	O
ruled	O
out	O
the	O
possibility	O
of	O
self	O
-	O
association	O
of	O
Scp160p	O
.	O

Although	O
both	O
tagged	O
proteins	O
appear	O
functional	O
,	O
it	O
remains	O
a	O
formal	O
possibility	O
that	O
the	O
tags	O
somehow	O
prevented	O
formation	O
of	O
FLAG	O
-	O
HA	O
hetero	O
-	O
complexes	O
.	O

Nonetheless	O
,	O
it	O
seems	O
most	O
likely	O
that	O
native	O
Scp160p	O
monomers	O
may	O
simply	O
migrate	O
aberrantly	O
under	O
native	O
conditions	O
due	O
to	O
an	O
unusual	O
shape	O
or	O
some	O
other	O
physical	O
property	O
.	O

In	O
conclusion	O
we	O
have	O
shown	O
convincing	O
evidence	O
that	O
Scp160p	O
exists	O
in	O
yeast	B
cytoplasmic	O
extracts	O
primarily	O
associated	O
with	O
polyribosomes	O
.	O

We	O
have	O
purified	O
Scp160p	O
following	O
disruption	O
of	O
polyribosomes	O
with	O
EDTA	O
,	O
and	O
identified	O
two	O
associated	O
proteins	O
:	O
Pab1p	O
and	O
Bfr1p	O
.	O

The	O
presence	O
of	O
Pab1p	O
suggests	O
that	O
Scp160p	O
associates	O
with	O
polyribosomes	O
as	O
a	O
component	O
of	O
an	O
mRNP	O
,	O
demonstrating	O
Scp160p	O
to	O
be	O
the	O
first	O
S	B
.	I
cerevisiae	I
multiple	O
-	O
KH	O
domain	O
protein	O
characterized	O
to	O
function	O
in	O
this	O
way	O
.	O

HP1	O
modulates	O
the	O
transcription	O
of	O
cell	O
-	O
cycle	O
regulators	O
in	O
Drosophila	B
melanogaster	I

Abstract	O

Heterochromatin	O
protein	O
1	O
(	O
HP1	O
)	O
was	O
originally	O
described	O
as	O
a	O
non	O
-	O
histone	O
chromosomal	O
protein	O
and	O
is	O
required	O
for	O
transcriptional	O
gene	O
silencing	O
and	O
the	O
formation	O
of	O
heterochromatin	O
.	O

Although	O
it	O
is	O
localized	O
primarily	O
at	O
pericentric	O
heterochromatin	O
,	O
a	O
scattered	O
distribution	O
over	O
a	O
large	O
number	O
of	O
euchromatic	O
loci	O
is	O
also	O
evident	O
.	O

Here	O
,	O
we	O
provide	O
evidence	O
that	O
Drosophila	B
HP1	O
is	O
essential	O
for	O
the	O
maintenance	O
of	O
active	O
transcription	O
of	O
euchromatic	O
genes	O
functionally	O
involved	O
in	O
cell	O
-	O
cycle	O
progression	O
,	O
including	O
those	O
required	O
for	O
DNA	O
replication	O
and	O
mitosis	O
.	O

Depletion	O
of	O
HP1	O
in	O
proliferating	O
embryonic	O
cells	O
caused	O
aberrant	O
progression	O
of	O
the	O
cell	O
cycle	O
at	O
S	O
phase	O
and	O
G2	O
/	O
M	O
phase	O
,	O
linked	O
to	O
aberrant	O
chromosome	O
segregation	O
,	O
cytokinesis	O
,	O
and	O
an	O
increase	O
in	O
apoptosis	O
.	O

The	O
chromosomal	O
distribution	O
of	O
Aurora	O
B	O
,	O
and	O
the	O
level	O
of	O
phosphorylation	O
of	O
histone	O
H3	O
serine	O
10	O
were	O
also	O
altered	O
in	O
the	O
absence	O
of	O
HP1	O
.	O

Using	O
chromatin	O
immunoprecipitation	O
analysis	O
,	O
we	O
further	O
demonstrate	O
that	O
the	O
promoters	O
of	O
a	O
number	O
of	O
cell	O
-	O
cycle	O
regulator	O
genes	O
are	O
bound	O
to	O
HP1	O
,	O
supporting	O
a	O
direct	O
role	O
for	O
HP1	O
in	O
their	O
active	O
transcription	O
.	O

Overall	O
,	O
our	O
data	O
suggest	O
that	O
HP1	O
is	O
essential	O
for	O
the	O
maintenance	O
of	O
cell	O
-	O
cycle	O
progression	O
and	O
the	O
transcription	O
of	O
cell	O
-	O
cycle	O
regulatory	O
genes	O
.	O

The	O
results	O
also	O
support	O
the	O
view	O
that	O
HP1	O
is	O
a	O
positive	O
regulator	O
of	O
transcription	O
in	O
euchromatin	O
.	O

INTRODUCTION	O

Chromatin	O
in	O
higher	O
eukaryotes	O
is	O
subdivided	O
into	O
different	O
functional	O
compartments	O
termed	O
heterochromatin	O
and	O
euchromatin	O
(	O
1	O
)	O
.	O

Heterochromatin	O
differs	O
from	O
euchromatin	O
in	O
its	O
DNA	O
composition	O
,	O
replication	O
timing	O
,	O
condensation	O
throughout	O
the	O
cell	O
cycle	O
,	O
and	O
its	O
ability	O
to	O
silence	O
euchromatic	O
genes	O
placed	O
adjacent	O
to	O
or	O
within	O
its	O
territory	O
,	O
often	O
described	O
as	O
position	O
-	O
effect	O
-	O
variegation	O
(	O
PEV	O
)	O
(	O
2	O
)	O
.	O

Heterochromatin	O
protein	O
1	O
(	O
HP1	O
)	O
was	O
the	O
first	O
protein	O
identified	O
in	O
Drosophila	B
melanogaster	I
as	O
a	O
heterochromatin	O
-	O
associated	O
protein	O
(	O
3	O
)	O
;	O
the	O
corresponding	O
gene	O
has	O
been	O
cloned	O
from	O
a	O
number	O
of	O
organisms	O
and	O
is	O
highly	O
conserved	O
from	O
yeast	B
to	O
human	B
(	O
4	O
)	O
.	O

Polytene	O
chromosome	O
staining	O
showed	O
that	O
,	O
in	O
Drosophila	B
,	O
HP1	O
is	O
distributed	O
mainly	O
in	O
pericentric	O
heterochromatin	O
,	O
telomeric	O
heterochromatin	O
,	O
the	O
banded	O
small	O
fourth	O
chromosome	O
(	O
5	O
-	O
8	O
)	O
,	O
as	O
well	O
as	O
~	O
200	O
individual	O
loci	O
scattered	O
throughout	O
the	O
euchromatic	O
chromosomal	O
arms	O
(	O
5	O
)	O
.	O

The	O
gene	O
encoding	O
HP1	O
in	O
D	B
.	I
melanogaster	I
,	O
Su	O
(	O
var	O
)	O
2	O
-	O
5	O
,	O
was	O
isolated	O
as	O
a	O
suppressor	O
of	O
PEV	O
(	O
9	O
-	O
11	O
)	O
.	O

The	O
protein	O
contains	O
a	O
highly	O
conserved	O
motif	O
,	O
the	O
chromo	O
(	O
chromatin	O
organization	O
modifier	O
)	O
domain	O
,	O
similar	O
to	O
Polycomb	O
(	O
Pc	O
)	O
,	O
a	O
repressor	O
of	O
homeotic	O
genes	O
(	O
12	O
)	O
.	O

The	O
association	O
between	O
HP1	O
and	O
pericentric	O
heterochromatin	O
is	O
believed	O
to	O
occur	O
via	O
the	O
chromo	O
domain	O
of	O
HP1	O
and	O
the	O
N	O
-	O
terminal	O
tail	O
of	O
histone	O
H3	O
methylated	O
at	O
lysine	O
9	O
(	O
13	O
,	O
14	O
)	O
,	O
generated	O
by	O
histone	O
methyltransferase	O
-	O
Su	O
(	O
var	O
)	O
3	O
-	O
9	O
,	O
a	O
partner	O
of	O
HP1	O
in	O
pericentric	O
heterochromatin	O
(	O
15	O
)	O
.	O

The	O
C	O
-	O
terminal	O
chromo	O
'	O
shadow	O
'	O
domain	O
of	O
HP1	O
interacts	O
with	O
other	O
silencing	O
complexes	O
to	O
suppress	O
local	O
transcriptional	O
activity	O
(	O
15	O
-	O
18	O
)	O
.	O

However	O
,	O
studies	O
of	O
HP1	O
chromosomal	O
distribution	O
also	O
showed	O
that	O
HP1	O
does	O
not	O
always	O
co	O
-	O
localize	O
with	O
lysine	O
9	O
methylated	O
histone	O
H3	O
or	O
Su	O
(	O
var	O
)	O
3	O
-	O
9	O
,	O
especially	O
in	O
euchromatic	O
regions	O
(	O
19	O
-	O
21	O
)	O
;	O
in	O
some	O
cases	O
,	O
HP1	O
is	O
found	O
directly	O
bound	O
to	O
DNA	O
(	O
22	O
,	O
23	O
)	O
.	O

All	O
these	O
features	O
argue	O
for	O
distinct	O
roles	O
for	O
HP1	O
in	O
chromatin	O
and	O
in	O
epigenetic	O
gene	O
regulation	O
.	O

HP1	O
is	O
believed	O
to	O
be	O
an	O
essential	O
structural	O
protein	O
protecting	O
the	O
integrity	O
of	O
chromosomes	O
during	O
cell	O
division	O
(	O
8	O
,	O
24	O
)	O
.	O

Swi6	O
,	O
the	O
homolog	O
of	O
HP1	O
in	O
fission	B
yeast	I
,	O
is	O
dispensable	O
for	O
survival	O
,	O
but	O
its	O
deletion	O
results	O
in	O
lagging	O
chromosomes	O
during	O
anaphase	O
,	O
and	O
a	O
high	O
rate	O
of	O
chromosome	O
loss	O
(	O
25	O
,	O
26	O
)	O
.	O

Mutations	O
of	O
HP1	O
in	O
D	B
.	I
melanogaster	I
result	O
in	O
late	O
larval	O
lethality	O
,	O
chromosome	O
breakages	O
/	O
loss	O
,	O
telomere	O
fusion	O
and	O
a	O
high	O
frequency	O
of	O
cells	O
with	O
abnormal	O
anaphase	O
(	O
8	O
,	O
27	O
)	O
.	O

Null	O
alleles	O
of	O
the	O
HP1	O
functional	O
partner	O
in	O
mice	B
(	O
SUVAR39	O
)	O
also	O
showed	O
various	O
chromosomal	O
defects	O
(	O
28	O
)	O
,	O
supporting	O
a	O
conserved	O
role	O
for	O
heterochromatin	O
proteins	O
in	O
the	O
regulation	O
of	O
chromosome	O
dynamics	O
during	O
cell	O
-	O
cycle	O
progression	O
.	O

However	O
,	O
the	O
mechanism	O
(	O
s	O
)	O
involved	O
remains	O
to	O
be	O
understood	O
.	O

In	O
this	O
study	O
,	O
we	O
utilized	O
Drosophila	B
embryonic	O
Kc	O
cells	O
and	O
an	O
RNA	O
interference	O
(	O
RNAi	O
)	O
-	O
based	O
approach	O
to	O
demonstrate	O
that	O
HP1	O
plays	O
an	O
important	O
role	O
at	O
S	O
phase	O
and	O
G2	O
/	O
M	O
phases	O
during	O
the	O
cell	O
cycle	O
.	O

We	O
further	O
show	O
that	O
nearly	O
one	O
-	O
third	O
of	O
known	O
/	O
predicted	O
cell	O
-	O
cycle	O
regulators	O
require	O
HP1	O
to	O
maintain	O
their	O
active	O
transcription	O
.	O

These	O
genes	O
include	O
MCMs	O
,	O
Orc4	O
,	O
CDC45L	O
,	O
INCENP	O
,	O
Aurora	O
B	O
,	O
CAF1	O
,	O
Bub1	O
,	O
Bub3	O
and	O
a	O
few	O
other	O
cell	O
-	O
cycle	O
regulators	O
.	O

ChIP	O
analysis	O
suggests	O
that	O
HP1	O
plays	O
a	O
direct	O
role	O
in	O
their	O
transcription	O
.	O

Therefore	O
,	O
the	O
results	O
of	O
this	O
study	O
provide	O
an	O
alternative	O
explanation	O
for	O
the	O
specific	O
role	O
of	O
HP1	O
in	O
the	O
regulation	O
of	O
chromatin	O
dynamics	O
and	O
in	O
cell	O
-	O
cycle	O
progression	O
.	O

MATERIALS	O
AND	O
METHODS	O

RNAi	O
in	O
Kc	O
cells	O

Drosophila	B
Kc	O
cells	O
were	O
routinely	O
cultured	O
at	O
25	O
degrees	O
C	O
in	O
Schneider	O
Drosophila	B
medium	O
(	O
GIBCO	O
)	O
supplemented	O
with	O
10	O
%	O
fetal	O
calf	O
serum	O
,	O
160	O
mu	O
g	O
/	O
ml	O
penicillin	O
,	O
250	O
mu	O
g	O
/	O
ml	O
streptomycin	O
,	O
and	O
4	O
mM	O
l	O
-	O
glutamine	O
.	O

Double	O
-	O
stranded	O
RNA	O
(	O
dsRNA	O
)	O
of	O
HP1	O
was	O
generated	O
by	O
incubation	O
of	O
single	O
-	O
stranded	O
RNA	O
in	O
annealing	O
buffer	O
(	O
100	O
mM	O
potassium	O
acetate	O
,	O
30	O
mM	O
HEPES	O
-	O
KOH	O
,	O
pH	O
7	O
.	O
4	O
,	O
2	O
mM	O
magnesium	O
acetate	O
)	O
for	O
3	O
min	O
at	O
95	O
degrees	O
C	O
and	O
then	O
placed	O
in	O
a	O
beaker	O
with	O
water	O
at	O
75	O
degrees	O
C	O
and	O
allowed	O
to	O
cool	O
slowly	O
to	O
room	O
temperature	O
.	O

The	O
detailed	O
procedure	O
of	O
RNAi	O
was	O
carried	O
out	O
according	O
to	O
the	O
established	O
protocols	O
(	O
)	O
.	O

Briefly	O
,	O
Kc	O
cells	O
were	O
seeded	O
in	O
a	O
six	O
-	O
well	O
dish	O
using	O
serum	O
-	O
free	O
medium	O
at	O
1	O
x	O
106	O
cells	O
/	O
ml	O
.	O

HP1	O
dsRNA	O
(	O
5	O
mu	O
g	O
/	O
ml	O
)	O
was	O
added	O
to	O
the	O
cultured	O
Kc	O
cells	O
.	O

After	O
60	O
min	O
at	O
room	O
temperature	O
,	O
2	O
ml	O
of	O
medium	O
containing	O
10	O
%	O
serum	O
was	O
added	O
to	O
each	O
well	O
and	O
the	O
plates	O
transferred	O
to	O
25	O
degrees	O
C	O
for	O
up	O
to	O
8	O
days	O
.	O

Western	O
blotting	O
and	O
RT	O
-	O
PCR	O
were	O
carried	O
out	O
using	O
the	O
extract	O
/	O
total	O
RNA	O
isolated	O
from	O
control	O
and	O
dsRNA	O
-	O
treated	O
cells	O
on	O
days	O
2	O
,	O
6	O
and	O
8	O
.	O

Cell	O
-	O
cycle	O
and	O
apoptosis	O
analysis	O

The	O
procedure	O
for	O
flow	O
cytometric	O
analysis	O
of	O
Kc	O
cells	O
followed	O
that	O
in	O
the	O
manual	O
provided	O
with	O
the	O
BrdU	O
flow	O
kit	O
(	O
BD	O
PharMingen	O
)	O
.	O

The	O
cells	O
were	O
fed	O
with	O
BrdU	O
for	O
4	O
h	O
,	O
then	O
scraped	O
and	O
collected	O
.	O

Fluorescence	O
was	O
measured	O
using	O
a	O
FACSCalibur	O
(	O
Becton	O
Dickinson	O
)	O
.	O

Data	O
collection	O
and	O
analysis	O
were	O
performed	O
using	O
CellQuest	O
software	O
.	O

Electrophoresis	O
and	O
immunoblotting	O

Cell	O
extracts	O
(	O
15	O
mu	O
g	O
)	O
were	O
fractionated	O
by	O
10	O
%	O
SDS	O
-	O
PAGE	O
,	O
then	O
transferred	O
to	O
Hybond	O
-	O
P	O
PVDF	O
membranes	O
(	O
Amersham	O
)	O
and	O
probed	O
with	O
primary	O
antibodies	O
(	O
CIA9	O
)	O
,	O
and	O
secondary	O
antibodies	O
(	O
anti	O
-	O
rabbit	B
or	O
anti	O
-	O
mouse	B
horseradish	B
peroxidase	O
-	O
conjugated	O
IgG	O
)	O
,	O
obtained	O
from	O
Jackson	O
Immunoresearch	O
Laboratories	O
.	O

Enhanced	O
chemiluminescence	O
reagents	O
(	O
Amersham	O
Pharmacia	O
Biotech	O
)	O
were	O
used	O
for	O
signal	O
detection	O
.	O

For	O
the	O
analysis	O
of	O
H3	O
ser10	O
phosphorylation	O
,	O
we	O
used	O
whole	O
-	O
cell	O
extracts	O
from	O
700	O
000	O
Kc	O
cells	O
(	O
control	O
and	O
RNAi	O
at	O
day	O
8	O
)	O
.	O

Western	O
blotting	O
was	O
performed	O
using	O
polyclonal	O
antibodies	O
against	O
ser10	O
-	O
phosphorylated	O
histone	O
H3	O
at	O
a	O
dilution	O
of	O
1	O
:	O
1000	O
(	O
Upstate	O
)	O
.	O

Kc	O
control	O
cells	O
arrested	O
in	O
mitosis	O
by	O
incubation	O
in	O
25	O
micro	O
M	O
colchicine	O
(	O
Sigma	O
)	O
for	O
24	O
h	O
were	O
also	O
analyzed	O
for	O
comparison	O
.	O

Immunofluorescence	O

Kc	O
cells	O
were	O
seeded	O
onto	O
polylysine	O
slides	O
,	O
fixed	O
with	O
4	O
%	O
formaldehyde	O
for	O
15	O
min	O
and	O
permeabilized	O
with	O
0	O
.	O
5	O
%	O
Triton	O
X	O
-	O
100	O
for	O
5	O
min	O
.	O

The	O
incubation	O
with	O
primary	O
antibodies	O
was	O
carried	O
out	O
in	O
blocking	O
solution	O
for	O
1	O
h	O
.	O

For	O
staining	O
of	O
mitotic	O
cells	O
,	O
the	O
cells	O
were	O
permeabilized	O
using	O
PBST	O
(	O
PBS	O
containing	O
0	O
.	O
3	O
%	O
Triton	O
X	O
-	O
100	O
)	O
and	O
stained	O
with	O
polyclonal	O
antibody	O
against	O
Drosophila	B
Aurora	O
B	O
at	O
1	O
:	O
200	O
dilution	O
and	O
monoclonal	O
mouse	B
at	O
anti	O
-	O
beta	O
-	O
tubulin	O
1	O
:	O
300	O
dilution	O
(	O
Chemicon	O
International	O
)	O
as	O
primary	O
antibodies	O
.	O

Secondary	O
antibodies	O
were	O
anti	O
-	O
rabbit	B
coupled	O
with	O
Alexa	O
488	O
(	O
1	O
:	O
500	O
)	O
and	O
anti	O
-	O
mouse	B
coupled	O
to	O
Alexa	O
546	O
(	O
1	O
:	O
500	O
)	O
(	O
Molecular	O
Probes	O
,	O
Eugene	O
,	O
Oregon	O
)	O
.	O

Images	O
were	O
acquired	O
using	O
a	O
confocal	O
LSM510	O
META	O
microscope	O
(	O
Zeiss	O
)	O
.	O

Stacks	O
of	O
images	O
were	O
analyzed	O
using	O
the	O
IMARIS	O
4	O
.	O
0	O
program	O
(	O
Media	O
cybernetics	O
,	O
Carlsbad	O
,	O
CA	O
)	O
.	O

Antibodies	O

Affinity	O
-	O
purified	O
polyclonal	O
antibodies	O
of	O
HP1	O
(	O
rabbit	B
#	O
192	O
and	O
#	O
187	O
,	O
5	O
mu	O
g	O
)	O
and	O
5	O
mu	O
g	O
of	O
polyclonal	O
anti	O
-	O
HA	O
antibodies	O
(	O
Sigma	O
)	O
were	O
used	O
in	O
each	O
ChIP	O
reaction	O
.	O

The	O
specificity	O
of	O
the	O
HP1	O
polyclonal	O
antibodies	O
was	O
determined	O
using	O
various	O
approaches	O
,	O
including	O
western	O
blotting	O
assay	O
,	O
immunofluorescence	O
staining	O
and	O
immunoprecipitation	O
to	O
pull	O
down	O
HP1	O
(	O
data	O
not	O
shown	O
)	O
.	O

The	O
monoclonal	O
antibody	O
HP1	O
-	O
CIA9	O
(	O
5	O
)	O
was	O
used	O
at	O
a	O
dilution	O
of	O
1	O
:	O
20	O
in	O
immunoblotting	O
assays	O
.	O

Microarray	O
analysis	O
and	O
RT	O
-	O
PCR	O

Total	O
RNA	O
was	O
isolated	O
from	O
control	O
and	O
HP1	O
-	O
depleted	O
Kc	O
cells	O
at	O
day	O
8	O
using	O
an	O
RNeasy	O
kit	O
(	O
Qiagen	O
)	O
.	O

RNA	O
labeling	O
and	O
microarray	O
data	O
analysis	O
followed	O
the	O
standard	O
protocol	O
from	O
Affymetrix	O
.	O

We	O
used	O
ANOVA	O
(	O
P	O
<	O
0	O
.	O
001	O
)	O
to	O
assess	O
the	O
expression	O
confidence	O
for	O
each	O
gene	O
.	O

For	O
RT	O
-	O
PCR	O
analysis	O
,	O
poly	O
(	O
A	O
)	O
+	O
mRNA	O
was	O
purified	O
with	O
the	O
Oligotex	O
Direct	O
mRNA	O
kit	O
(	O
Qiagen	O
)	O
according	O
to	O
the	O
manufacturer	O
'	O
s	O
instructions	O
.	O

The	O
purified	O
poly	O
(	O
A	O
)	O
+	O
RNA	O
was	O
reverse	O
transcribed	O
using	O
the	O
Thermoscript	O
kit	O
(	O
Invitrogen	O
)	O
.	O

The	O
cDNA	O
was	O
then	O
used	O
for	O
PCR	O
amplification	O
for	O
35	O
cycles	O
with	O
gene	O
-	O
specific	O
primers	O
.	O

PCR	O
products	O
were	O
scanned	O
after	O
electrophoretic	O
separation	O
with	O
a	O
Typhoon	O
Scanner	O
,	O
quantified	O
using	O
ImageQuant	O
software	O
(	O
Amersham	O
Biosciences	O
)	O
and	O
normalized	O
for	O
amplification	O
of	O
the	O
Actin5c	O
transcript	O
.	O

The	O
sequence	O
of	O
primers	O
used	O
for	O
RT	O
-	O
PCR	O
and	O
ChIP	O
analysis	O
are	O
provided	O
in	O
the	O
Supplementary	O
Material	O
.	O

ChIP	O

ChIP	O
was	O
performed	O
according	O
to	O
Orlando	O
et	O
al	O
.	O

(	O
29	O
)	O
and	O
the	O
protocol	O
provided	O
by	O
Upstate	O
(	O
)	O
with	O
some	O
modifications	O
.	O

In	O
brief	O
,	O
1	O
-	O
2	O
x	O
108	O
Kc	O
cells	O
were	O
prepared	O
and	O
fixed	O
in	O
1	O
%	O
formaldehyde	O
.	O

Nuclei	O
were	O
isolated	O
according	O
to	O
a	O
standard	O
procedure	O
in	O
Current	O
Protocols	O
(	O
)	O
,	O
then	O
resuspended	O
in	O
1	O
.	O
7	O
ml	O
of	O
lysis	O
buffer	O
(	O
50	O
mM	O
Tris	O
,	O
pH	O
8	O
.	O
0	O
,	O
10	O
mM	O
EDTA	O
,	O
1	O
%	O
SDS	O
and	O
protease	O
inhibitors	O
)	O
and	O
sonicated	O
using	O
a	O
Branson	O
sonifier	O
250	O
.	O

Chromatin	O
fractions	O
in	O
the	O
size	O
range	O
0	O
.	O
2	O
-	O
0	O
.	O
8	O
kb	O
were	O
used	O
to	O
perform	O
immunoprecipitation	O
experiments	O
.	O

We	O
used	O
5	O
mu	O
g	O
affinity	O
-	O
purified	O
polyclonal	O
antibodies	O
(	O
#	O
192	O
and	O
#	O
182	O
for	O
HP1	O
;	O
HA	O
antibody	O
for	O
control	O
)	O
and	O
1	O
ml	O
of	O
salmon	O
sperm	O
DNA	O
/	O
protein	O
-	O
A	O
-	O
agarose	O
(	O
Upstate	O
)	O
pre	O
-	O
cleared	O
chromatin	O
lysate	O
in	O
each	O
reaction	O
.	O

The	O
mixture	O
was	O
then	O
rotated	O
at	O
4	O
degrees	O
C	O
overnight	O
and	O
the	O
recovered	O
beads	O
were	O
washed	O
twice	O
with	O
1	O
ml	O
of	O
Low	O
salt	O
buffer	O
(	O
Upstate	O
)	O
,	O
once	O
with	O
High	O
salt	O
buffer	O
(	O
Upstate	O
)	O
,	O
once	O
with	O
LiCl	O
buffer	O
(	O
Upstate	O
)	O
and	O
twice	O
with	O
TE	O
at	O
4	O
degrees	O
C	O
for	O
8	O
min	O
.	O

ChIP	O
DNA	O
was	O
extracted	O
according	O
to	O
the	O
standard	O
procedures	O
(	O
29	O
)	O
.	O

RESULTS	O

Depletion	O
of	O
HP1	O
in	O
Drosophila	B
Kc	O
cells	O

Various	O
chromosomal	O
defects	O
in	O
the	O
cell	O
cycle	O
have	O
been	O
observed	O
in	O
embryos	O
or	O
larval	O
tissues	O
of	O
Drosophila	B
HP1	O
mutants	O
(	O
8	O
,	O
27	O
)	O
.	O

However	O
,	O
the	O
presence	O
of	O
maternally	O
loaded	O
HP1	O
in	O
embryos	O
and	O
the	O
lethality	O
of	O
HP1	O
mutants	O
at	O
late	O
larval	O
stages	O
have	O
so	O
far	O
precluded	O
a	O
systematic	O
study	O
of	O
the	O
role	O
of	O
HP1	O
in	O
cell	O
-	O
cycle	O
regulation	O
.	O

Therefore	O
,	O
we	O
used	O
Drosophila	B
Kc	O
cells	O
,	O
a	O
cell	O
line	O
derived	O
from	O
Drosophila	B
embryos	O
,	O
as	O
a	O
model	O
system	O
to	O
address	O
this	O
problem	O
.	O

HP1	O
transcripts	O
were	O
depleted	O
using	O
an	O
RNAi	O
-	O
based	O
approach	O
(	O
see	O
Materials	O
and	O
Methods	O
)	O
.	O

The	O
reduction	O
in	O
HP1	O
expression	O
was	O
measured	O
both	O
by	O
RT	O
-	O
PCR	O
and	O
by	O
western	O
blotting	O
analysis	O
(	O
Figure	O
1A	O
)	O
.	O

A	O
significant	O
reduction	O
in	O
the	O
HP1	O
expression	O
was	O
already	O
evident	O
after	O
2	O
days	O
treatment	O
with	O
HP1	O
dsRNA	O
.	O

Cells	O
at	O
day	O
8	O
showed	O
a	O
reduction	O
in	O
HP1	O
of	O
~	O
90	O
%	O
(	O
Figure	O
1A	O
)	O
and	O
were	O
therefore	O
used	O
in	O
all	O
subsequent	O
experiments	O
.	O

Cell	O
-	O
cycle	O
progression	O
at	O
S	O
and	O
G2	O
/	O
M	O
phase	O
is	O
altered	O
in	O
the	O
absence	O
of	O
HP1	O

The	O
impact	O
of	O
HP1	O
loss	O
on	O
the	O
cell	O
cycle	O
of	O
Kc	O
cells	O
was	O
determined	O
using	O
cell	O
-	O
cycle	O
profile	O
analysis	O
of	O
HP1	O
-	O
depleted	O
and	O
control	O
cells	O
.	O

The	O
percentage	O
of	O
cells	O
in	O
S	O
phase	O
was	O
determined	O
by	O
BrdU	O
incorporation	O
,	O
and	O
total	O
DNA	O
content	O
by	O
7	O
-	O
amino	O
-	O
actinomycin	O
(	O
7	O
-	O
AAD	O
)	O
.	O

The	O
results	O
showed	O
that	O
the	O
depletion	O
of	O
HP1	O
(	O
day	O
8	O
)	O
caused	O
a	O
decrease	O
in	O
S	O
-	O
phase	O
cells	O
of	O
at	O
least	O
4	O
-	O
fold	O
,	O
and	O
a	O
2	O
-	O
fold	O
decrease	O
in	O
G2	O
/	O
M	O
-	O
phase	O
cells	O
(	O
Figure	O
1B	O
)	O
,	O
although	O
no	O
significant	O
effect	O
was	O
found	O
at	O
the	O
G1	O
phase	O
.	O

In	O
addition	O
,	O
depletion	O
of	O
HP1	O
caused	O
a	O
greater	O
than	O
7	O
-	O
fold	O
increase	O
in	O
the	O
number	O
of	O
apoptotic	O
cells	O
.	O

These	O
results	O
,	O
therefore	O
,	O
confirm	O
that	O
HP1	O
is	O
an	O
important	O
regulator	O
during	O
the	O
cell	O
cycle	O
,	O
especially	O
at	O
the	O
S	O
and	O
G2	O
/	O
M	O
phases	O
.	O

Cell	O
-	O
cycle	O
regulators	O
require	O
HP1	O
to	O
maintain	O
their	O
active	O
transcription	O

To	O
ask	O
whether	O
the	O
cell	O
-	O
cycle	O
defects	O
were	O
due	O
to	O
changes	O
in	O
the	O
transcription	O
of	O
genes	O
functionally	O
involved	O
in	O
S	O
phase	O
and	O
the	O
G2	O
/	O
M	O
phase	O
,	O
we	O
next	O
assessed	O
global	O
changes	O
in	O
gene	O
transcription	O
following	O
depletion	O
of	O
HP1	O
.	O

Expression	O
profile	O
analysis	O
was	O
performed	O
using	O
total	O
RNA	O
isolated	O
from	O
both	O
HP1	O
-	O
depleted	O
Kc	O
cells	O
and	O
control	O
Kc	O
cells	O
,	O
and	O
an	O
Affymetrix	O
Drosophila	B
chip	O
.	O

For	O
each	O
experiment	O
,	O
we	O
used	O
total	O
RNA	O
isolated	O
from	O
two	O
independent	O
HP1	O
-	O
depleted	O
and	O
control	O
samples	O
,	O
and	O
at	O
least	O
two	O
independent	O
experiments	O
were	O
performed	O
.	O

The	O
microarray	O
analysis	O
showed	O
that	O
loss	O
of	O
HP1	O
function	O
in	O
Kc	O
cells	O
resulted	O
in	O
alterations	O
in	O
transcription	O
of	O
>	O
500	O
genes	O
:	O
~	O
400	O
genes	O
were	O
down	O
-	O
regulated	O
and	O
~	O
120	O
genes	O
were	O
up	O
-	O
regulated	O
(	O
>	O
1	O
.	O
5	O
-	O
fold	O
,	O
ANOVA	O
)	O
.	O

The	O
function	O
of	O
these	O
genes	O
ranged	O
from	O
cellular	O
enzymes	O
,	O
signal	O
transduction	O
molecules	O
,	O
and	O
membrane	O
and	O
cell	O
structural	O
proteins	O
,	O
to	O
nucleic	O
acid	O
-	O
binding	O
proteins	O
and	O
cell	O
-	O
cycle	O
regulators	O
(	O
Figure	O
2A	O
)	O
.	O

At	O
the	O
chromosomal	O
level	O
,	O
the	O
genes	O
targeted	O
by	O
HP1	O
appeared	O
to	O
be	O
distributed	O
along	O
all	O
euchromatic	O
chromosomal	O
arms	O
(	O
data	O
not	O
shown	O
)	O
,	O
supporting	O
a	O
global	O
role	O
of	O
HP1	O
in	O
euchromatic	O
gene	O
regulation	O
(	O
20	O
)	O
.	O

Among	O
60	O
known	O
/	O
predicted	O
genes	O
associated	O
with	O
DNA	O
replication	O
function	O
,	O
15	O
were	O
down	O
-	O
regulated	O
in	O
the	O
absence	O
of	O
HP1	O
(	O
Figure	O
2B	O
)	O
.	O

These	O
included	O
McM2	O
,	O
McM5	O
,	O
McM6	O
and	O
CDC45L	O
,	O
which	O
are	O
required	O
for	O
processive	O
DNA	O
replication	O
and	O
correct	O
chromosome	O
condensation	O
(	O
30	O
-	O
32	O
)	O
.	O

Other	O
genes	O
involved	O
in	O
DNA	O
replication	O
,	O
such	O
as	O
components	O
of	O
the	O
origin	O
recognition	O
complex	O
(	O
Orc	O
)	O
-	O
-	O
Orc4	O
,	O
Caf1	O
,	O
Gnf1	O
,	O
Dref1	O
,	O
DNA	O
polymerase	O
-	O
gamma	O
and	O
Tam	O
-	O
-	O
were	O
also	O
down	O
-	O
regulated	O
(	O
Figure	O
2B	O
)	O
.	O

Aurora	O
B	O
and	O
inner	O
centromere	O
protein	O
(	O
INCENP	O
)	O
,	O
known	O
to	O
be	O
required	O
for	O
kinetochore	O
assembly	O
,	O
chromosome	O
condensation	O
and	O
bipolar	O
chromosome	O
attachment	O
during	O
mitosis	O
(	O
33	O
)	O
,	O
also	O
showed	O
a	O
reduction	O
in	O
transcription	O
.	O

A	O
similar	O
loss	O
of	O
transcription	O
was	O
observed	O
in	O
Bub1	O
and	O
Bub3	O
(	O
Figure	O
2B	O
)	O
,	O
encoding	O
mitotic	O
checkpoint	O
control	O
proteins	O
(	O
34	O
,	O
35	O
)	O
.	O

Loss	O
function	O
of	O
Bub1	O
has	O
been	O
shown	O
to	O
cause	O
chromatin	O
bridges	O
to	O
extend	O
between	O
the	O
two	O
separating	O
groups	O
of	O
chromosomes	O
,	O
and	O
extensive	O
chromosome	O
fragmentation	O
in	O
anaphase	O
cells	O
(	O
35	O
)	O
.	O

We	O
confirmed	O
the	O
changes	O
in	O
the	O
transcription	O
of	O
cell	O
-	O
cycle	O
regulators	O
using	O
semi	O
-	O
quantitative	O
RT	O
-	O
PCR	O
,	O
which	O
gave	O
results	O
consistent	O
with	O
the	O
microarray	O
analysis	O
.	O

In	O
addition	O
,	O
cell	O
-	O
cycle	O
regulator	O
genes	O
,	O
such	O
as	O
McM3	O
,	O
McM7	O
and	O
Asp	O
(	O
abnormal	O
spindle	O
)	O
,	O
were	O
also	O
confirmed	O
to	O
be	O
down	O
-	O
regulated	O
(	O
Figure	O
2C	O
)	O
.	O

Collectively	O
,	O
these	O
results	O
demonstrate	O
that	O
HP1	O
is	O
indeed	O
involved	O
in	O
the	O
regulation	O
of	O
transcription	O
of	O
cell	O
-	O
cycle	O
regulators	O
.	O

HP1	O
is	O
required	O
for	O
Aurora	O
B	O
distribution	O
and	O
histone	O
H3	O
phosphorylation	O

INCENP	O
is	O
localized	O
to	O
the	O
centromeric	O
region	O
of	O
chromosomes	O
at	O
metaphase	O
and	O
the	O
spindle	O
midzone	O
at	O
anaphase	O
,	O
which	O
then	O
targets	O
Aurora	O
B	O
,	O
a	O
kinase	O
essential	O
for	O
histone	O
H3	O
ser10	O
phosphorylation	O
,	O
to	O
these	O
sites	O
(	O
36	O
)	O
.	O

Loss	O
of	O
function	O
of	O
both	O
these	O
'	O
chromosomal	O
passenger	O
'	O
proteins	O
causes	O
abnormal	O
chromosomal	O
segregation	O
at	O
metaphase	O
,	O
as	O
well	O
as	O
certain	O
cytokinesis	O
defects	O
(	O
36	O
,	O
37	O
)	O
.	O

The	O
loss	O
of	O
transcription	O
of	O
both	O
INCENP	O
and	O
Aurora	O
B	O
after	O
depletion	O
of	O
HP1	O
,	O
therefore	O
,	O
raised	O
the	O
possibility	O
that	O
localization	O
of	O
Aurora	O
B	O
(	O
Figure	O
3	O
and	O
data	O
not	O
shown	O
)	O
may	O
be	O
altered	O
.	O

Staining	O
of	O
HP1	O
-	O
depleted	O
Kc	O
cells	O
with	O
anti	O
-	O
Aurora	O
B	O
antibodies	O
indeed	O
revealed	O
an	O
altered	O
localization	O
of	O
Aurora	O
B	O
and	O
,	O
in	O
a	O
number	O
of	O
cases	O
,	O
a	O
complete	O
loss	O
of	O
Aurora	O
B	O
(	O
Figure	O
3A	O
)	O
.	O

Consistent	O
with	O
the	O
loss	O
function	O
of	O
Aurora	O
B	O
,	O
the	O
spindles	O
in	O
the	O
metaphase	O
cells	O
were	O
also	O
disorganized	O
,	O
with	O
a	O
large	O
number	O
of	O
cells	O
showing	O
an	O
altered	O
prometaphase	O
chromosome	O
alignment	O
(	O
Figure	O
3A	O
)	O
.	O

Some	O
showed	O
extensive	O
chromosome	O
fragmentation	O
(	O
Figure	O
3B	O
)	O
,	O
or	O
the	O
presence	O
of	O
a	O
third	O
spindle	O
pole	O
-	O
like	O
structure	O
as	O
indicated	O
by	O
beta	O
-	O
tubulin	O
(	O
Figure	O
3A	O
)	O
.	O

At	O
telophase	O
,	O
we	O
observed	O
defective	O
separating	O
cells	O
with	O
an	O
extra	O
cell	O
envelope	O
-	O
like	O
structure	O
without	O
nuclei	O
(	O
Figure	O
3A	O
)	O
.	O

Chromatin	O
bridges	O
or	O
lagging	O
chromatids	O
at	O
telophase	O
were	O
also	O
evident	O
in	O
some	O
cells	O
(	O
Figure	O
3C	O
)	O
;	O
however	O
,	O
in	O
some	O
cases	O
,	O
localization	O
of	O
Aurora	O
B	O
appeared	O
not	O
to	O
be	O
affected	O
,	O
arguing	O
that	O
other	O
pathways	O
are	O
possibly	O
involved	O
.	O

We	O
next	O
analyzed	O
changes	O
in	O
histone	O
H3	O
serine	O
10	O
phosphorylation	O
,	O
since	O
the	O
loss	O
of	O
transcription	O
of	O
INCENP	O
is	O
known	O
to	O
affect	O
localization	O
of	O
Aurora	O
B	O
(	O
33	O
)	O
,	O
which	O
is	O
essential	O
in	O
the	O
regulation	O
of	O
histone	O
H3	O
phosphorylation	O
(	O
36	O
)	O
.	O

Total	O
cell	O
extracts	O
from	O
HP1	O
-	O
depleted	O
Kc	O
cells	O
were	O
analyzed	O
by	O
western	O
blotting	O
(	O
Figure	O
3D	O
)	O
.	O

The	O
results	O
indeed	O
showed	O
a	O
severalfold	O
reduction	O
in	O
H3	O
ser10	O
phosphorylation	O
after	O
depletion	O
of	O
HP1	O
,	O
consistent	O
with	O
the	O
functional	O
disruption	O
of	O
INCENP	O
and	O
Aurora	O
B	O
in	O
the	O
absence	O
of	O
HP1	O
.	O

HP1	O
directly	O
targets	O
genes	O
encoding	O
cell	O
-	O
cycle	O
regulators	O
in	O
euchromatin	O

To	O
test	O
whether	O
the	O
loss	O
of	O
transcription	O
of	O
genes	O
involved	O
in	O
DNA	O
replication	O
and	O
mitosis	O
was	O
a	O
direct	O
effect	O
of	O
the	O
loss	O
of	O
HP1	O
,	O
we	O
performed	O
a	O
ChIP	O
analysis	O
to	O
determine	O
whether	O
HP1	O
is	O
physically	O
associated	O
with	O
these	O
genes	O
.	O

Chromatin	O
lysates	O
from	O
formaldehyde	O
-	O
fixed	O
Kc	O
cells	O
were	O
sonicated	O
into	O
small	O
chromatin	O
fragments	O
(	O
0	O
.	O
2	O
-	O
0	O
.	O
8	O
kb	O
)	O
and	O
immunoprecipitated	O
with	O
polyclonal	O
antibodies	O
against	O
Drosophila	B
HP1	O
.	O

As	O
a	O
control	O
,	O
we	O
used	O
a	O
mock	O
precipitation	O
(	O
beads	O
only	O
)	O
and	O
polyclonal	O
antibodies	O
against	O
HA	O
.	O

Our	O
ChIP	O
results	O
showed	O
that	O
known	O
transposable	O
elements	O
distributed	O
in	O
heterochromatin	O
,	O
such	O
as	O
F	O
-	O
element	O
,	O
TART	O
and	O
1360	O
(	O
7	O
,	O
38	O
)	O
,	O
were	O
all	O
enriched	O
in	O
HP1	O
binding	O
(	O
Figure	O
4	O
)	O
,	O
which	O
is	O
also	O
consistent	O
with	O
a	O
previous	O
study	O
(	O
20	O
)	O
.	O

Using	O
the	O
same	O
ChIP	O
DNA	O
material	O
,	O
we	O
then	O
attempted	O
to	O
determine	O
whether	O
HP1	O
was	O
enriched	O
in	O
genes	O
involved	O
in	O
DNA	O
replication	O
.	O

Primers	O
were	O
designed	O
to	O
cover	O
the	O
promoter	O
regions	O
of	O
selected	O
genes	O
.	O

The	O
results	O
showed	O
that	O
McM3	O
,	O
McM5	O
and	O
Tam	O
were	O
all	O
enriched	O
in	O
HP1	O
binding	O
(	O
Figure	O
4	O
)	O
.	O

However	O
,	O
McM7	O
appeared	O
to	O
be	O
HP1	O
-	O
negative	O
,	O
although	O
its	O
transcription	O
was	O
also	O
affected	O
by	O
the	O
loss	O
of	O
HP1	O
function	O
.	O

Genes	O
essential	O
for	O
mitosis	O
,	O
such	O
as	O
Aurora	O
B	O
,	O
were	O
also	O
HP1	O
-	O
positive	O
(	O
Figure	O
4	O
)	O
.	O

These	O
results	O
demonstrate	O
that	O
these	O
cell	O
-	O
cycle	O
regulator	O
genes	O
are	O
directly	O
targeted	O
by	O
HP1	O
in	O
their	O
promoter	O
regions	O
.	O

DISCUSSION	O

In	O
this	O
study	O
,	O
we	O
used	O
microarray	O
and	O
RT	O
-	O
PCR	O
techniques	O
to	O
demonstrate	O
that	O
transcription	O
of	O
cell	O
-	O
cycle	O
regulators	O
is	O
misregulated	O
in	O
the	O
absence	O
of	O
HP1	O
.	O

Certain	O
defects	O
in	O
S	O
phase	O
may	O
be	O
a	O
direct	O
consequence	O
of	O
the	O
loss	O
of	O
transcription	O
of	O
DNA	O
replication	O
genes	O
such	O
as	O
McM2	O
,	O
McM5	O
,	O
McM6	O
,	O
CDC45L	O
,	O
Orc4	O
and	O
others	O
,	O
since	O
these	O
genes	O
have	O
been	O
functionally	O
implicated	O
in	O
the	O
initiation	O
of	O
DNA	O
replication	O
and	O
/	O
or	O
the	O
progression	O
of	O
replication	O
forks	O
(	O
39	O
)	O
.	O

Depletion	O
or	O
mutation	O
of	O
these	O
genes	O
has	O
been	O
shown	O
to	O
result	O
in	O
DNA	O
damage	O
(	O
32	O
)	O
,	O
the	O
blockage	O
of	O
replication	O
forks	O
(	O
39	O
)	O
,	O
increased	O
chromosome	O
loss	O
/	O
genome	O
instability	O
,	O
and	O
defective	O
condensation	O
(	O
30	O
)	O
.	O

The	O
reduction	O
in	O
the	O
number	O
of	O
cells	O
in	O
G2	O
/	O
M	O
phase	O
may	O
be	O
a	O
consequence	O
of	O
the	O
reduction	O
in	O
transcription	O
or	O
functional	O
disruption	O
of	O
INCENP	O
,	O
Aurora	O
B	O
,	O
Bub1	O
,	O
and	O
Bub3	O
(	O
34	O
,	O
36	O
)	O
.	O

Chromosome	O
segregation	O
defects	O
,	O
such	O
as	O
chromosome	O
fragmentation	O
and	O
chromatin	O
bridges	O
in	O
anaphase	O
/	O
telophase	O
cells	O
,	O
and	O
certain	O
cytokinesis	O
defects	O
in	O
HP1	O
-	O
depleted	O
cells	O
,	O
mimic	O
the	O
phenotype	O
of	O
cells	O
with	O
loss	O
function	O
of	O
INCENP	O
,	O
Aurora	O
B	O
or	O
Bub1	O
(	O
35	O
-	O
37	O
)	O
.	O

The	O
mislocalization	O
of	O
Aurora	O
B	O
in	O
the	O
absence	O
of	O
HP1	O
is	O
also	O
consistent	O
with	O
the	O
loss	O
of	O
transcription	O
and	O
functional	O
disruption	O
of	O
INCENP	O
(	O
37	O
)	O
,	O
and	O
the	O
reduction	O
in	O
Aurora	O
B	O
transcription	O
may	O
be	O
partially	O
responsible	O
for	O
the	O
observed	O
chromosomal	O
defects	O
,	O
including	O
loss	O
of	O
histone	O
H3	O
phosphorylation	O
at	O
serine	O
10	O
.	O

HP1	O
is	O
also	O
known	O
to	O
physically	O
interact	O
with	O
certain	O
components	O
of	O
replication	O
complexes	O
such	O
as	O
ORCs	O
and	O
MCMs	O
(	O
30	O
,	O
40	O
,	O
41	O
)	O
,	O
with	O
the	O
inner	O
centromere	O
protein	O
INCENP	O
(	O
42	O
)	O
and	O
the	O
chromatin	O
assembly	O
factor	O
CAF1	O
(	O
43	O
)	O
promoting	O
delivery	O
of	O
HP1	O
to	O
heterochromatin	O
sites	O
(	O
44	O
)	O
.	O

Loss	O
of	O
HP1	O
is	O
,	O
therefore	O
,	O
expected	O
to	O
cause	O
disruption	O
to	O
such	O
HP1	O
-	O
associated	O
complexes	O
,	O
and	O
will	O
partially	O
contribute	O
to	O
the	O
chromatin	O
/	O
chromosomal	O
defects	O
in	O
HP1	O
mutants	O
(	O
8	O
,	O
27	O
)	O
and	O
HP1	O
-	O
depleted	O
Kc	O
cells	O
.	O

It	O
is	O
therefore	O
well	O
possible	O
that	O
the	O
loss	O
of	O
transcription	O
of	O
these	O
cell	O
-	O
cycle	O
regulator	O
genes	O
,	O
and	O
consequent	O
disruption	O
of	O
HP1	O
functional	O
complexes	O
or	O
heterochromatin	O
structure	O
,	O
all	O
contributed	O
to	O
the	O
cell	O
-	O
cycle	O
defects	O
observed	O
.	O

The	O
ChIP	O
assay	O
supports	O
the	O
hypothesis	O
that	O
the	O
loss	O
of	O
transcription	O
of	O
cell	O
-	O
cycle	O
regulator	O
genes	O
is	O
a	O
direct	O
effect	O
of	O
the	O
lack	O
of	O
HP1	O
.	O

Aurora	O
B	O
,	O
McM3	O
,	O
and	O
McM5	O
were	O
all	O
bound	O
by	O
HP1	O
at	O
their	O
promoter	O
regions	O
,	O
although	O
other	O
cell	O
-	O
cycle	O
regulators	O
,	O
such	O
as	O
McM7	O
,	O
were	O
HP1	O
-	O
negative	O
,	O
implying	O
that	O
the	O
altered	O
transcription	O
in	O
these	O
genes	O
might	O
be	O
a	O
secondary	O
effect	O
of	O
the	O
loss	O
of	O
HP1	O
.	O

A	O
previous	O
study	O
in	O
Drosophila	B
Kc	O
cells	O
(	O
20	O
)	O
employed	O
an	O
approach	O
based	O
on	O
the	O
ectopic	O
expression	O
of	O
a	O
fusion	O
protein	O
of	O
HP1	O
with	O
a	O
prokaryotic	O
DNA	O
adenine	O
methyltransferase	O
and	O
identified	O
a	O
number	O
of	O
methylated	O
targets	O
in	O
the	O
genome	O
.	O

In	O
this	O
study	O
,	O
MCM3	O
and	O
MCM5	O
were	O
not	O
found	O
to	O
be	O
methylated	O
,	O
indicating	O
lack	O
of	O
association	O
with	O
HP1	O
.	O

On	O
the	O
other	O
hand	O
,	O
heterochromatin	O
repeats	O
,	O
such	O
F	O
-	O
element	O
and	O
1360	O
,	O
were	O
consistently	O
found	O
to	O
be	O
HP1	O
-	O
enriched	O
both	O
here	O
and	O
in	O
the	O
previous	O
study	O
.	O

It	O
remains	O
to	O
be	O
determined	O
whether	O
these	O
discrepancies	O
are	O
due	O
to	O
the	O
different	O
experimental	O
systems	O
used	O
.	O

However	O
,	O
we	O
note	O
that	O
the	O
previous	O
study	O
was	O
performed	O
using	O
a	O
cDNA	O
array	O
,	O
while	O
we	O
observe	O
binding	O
of	O
endogenous	O
HP1	O
at	O
the	O
promoter	O
of	O
these	O
genes	O
.	O

Similarly	O
,	O
another	O
study	O
using	O
chromatin	O
immunoprecipitation	O
in	O
larvae	O
also	O
showed	O
few	O
HP1	O
-	O
positive	O
genes	O
that	O
were	O
not	O
detected	O
in	O
Kc	O
cells	O
by	O
the	O
Dam	O
ID	O
approach	O
(	O
21	O
)	O
.	O

A	O
large	O
number	O
of	O
genes	O
affected	O
by	O
the	O
loss	O
of	O
D	B
.	I
melanogaster	I
HP1	O
in	O
larval	O
tissues	O
(	O
21	O
)	O
seem	O
to	O
be	O
different	O
from	O
that	O
in	O
embryonic	O
Kc	O
cells	O
.	O

The	O
change	O
in	O
the	O
transcription	O
of	O
Aurora	O
B	O
and	O
few	O
cell	O
-	O
cycle	O
regulators	O
reported	O
in	O
this	O
study	O
is	O
also	O
not	O
found	O
among	O
the	O
HP1	O
-	O
affected	O
genes	O
at	O
larval	O
stage	O
(	O
21	O
)	O
.	O

This	O
may	O
be	O
due	O
to	O
specific	O
role	O
(	O
s	O
)	O
of	O
HP1	O
in	O
different	O
stages	O
of	O
development	O
.	O

Alternatively	O
,	O
it	O
is	O
also	O
possible	O
that	O
the	O
impact	O
of	O
HP1	O
in	O
the	O
transcription	O
of	O
cell	O
-	O
cycle	O
regulators	O
in	O
proliferating	O
cells	O
is	O
underestimated	O
when	O
performing	O
the	O
analyses	O
on	O
larval	O
tissues	O
,	O
and	O
thus	O
on	O
mixed	O
populations	O
of	O
both	O
proliferating	O
and	O
differentiating	O
/	O
differentiated	O
cells	O
.	O

HP1	O
is	O
generally	O
known	O
as	O
a	O
transcriptional	O
repressor	O
,	O
as	O
supported	O
by	O
several	O
lines	O
of	O
evidence	O
:	O
silencing	O
of	O
a	O
euchromatic	O
reporter	O
gene	O
in	O
heterochromatin	O
requires	O
HP1	O
(	O
10	O
,	O
11	O
)	O
,	O
tethering	O
of	O
HP1	O
next	O
to	O
a	O
euchromatic	O
reporter	O
gene	O
causes	O
silencing	O
(	O
45	O
)	O
,	O
and	O
the	O
repression	O
of	O
genes	O
within	O
euchromatic	O
region	O
31	O
bound	O
by	O
HP1	O
is	O
relieved	O
in	O
the	O
absence	O
of	O
HP1	O
(	O
46	O
)	O
.	O

In	O
contrast	O
,	O
genes	O
in	O
heterochromatin	O
,	O
known	O
as	O
heterochromatic	O
genes	O
,	O
such	O
as	O
light	O
and	O
rolled	O
,	O
seem	O
to	O
require	O
HP1	O
to	O
maintain	O
their	O
active	O
transcription	O
(	O
47	O
,	O
48	O
)	O
.	O

The	O
level	O
of	O
transcription	O
of	O
heterochromatic	O
genes	O
was	O
dramatically	O
reduced	O
in	O
a	O
mutated	O
HP1	O
background	O
(	O
47	O
-	O
49	O
)	O
.	O

It	O
was	O
therefore	O
proposed	O
that	O
HP1	O
may	O
function	O
as	O
a	O
positive	O
regulator	O
of	O
transcription	O
of	O
these	O
genes	O
(	O
50	O
,	O
51	O
)	O
,	O
although	O
the	O
exact	O
regulation	O
mechanism	O
remains	O
unclear	O
.	O

A	O
study	O
of	O
heat	O
-	O
shock	O
genes	O
found	O
that	O
HP1	O
is	O
associated	O
with	O
RNA	O
transcripts	O
in	O
the	O
coding	O
region	O
,	O
and	O
is	O
also	O
a	O
positive	O
regulator	O
of	O
their	O
transcription	O
(	O
52	O
,	O
53	O
)	O
.	O

The	O
chromatin	O
association	O
of	O
HP1	O
at	O
the	O
promoter	O
region	O
of	O
active	O
euchromatic	O
genes	O
demonstrated	O
from	O
this	O
work	O
and	O
others	O
,	O
and	O
its	O
independence	O
from	O
histone	O
H3K9	O
methylation	O
(	O
21	O
)	O
,	O
all	O
suggest	O
that	O
mechanism	O
whereby	O
HP1	O
modulates	O
transcription	O
of	O
euchromatic	O
genes	O
is	O
potentially	O
distinct	O
from	O
its	O
role	O
in	O
heterochromatin	O
formation	O
.	O

Collectively	O
,	O
the	O
results	O
of	O
this	O
study	O
demonstrate	O
that	O
HP1	O
plays	O
an	O
essential	O
role	O
in	O
cell	O
-	O
cycle	O
progression	O
,	O
and	O
support	O
the	O
view	O
that	O
HP1	O
,	O
in	O
addition	O
to	O
its	O
role	O
in	O
heterochromatin	O
,	O
can	O
act	O
as	O
a	O
positive	O
transcriptional	O
regulator	O
of	O
euchromatic	O
genes	O
.	O

SUPPLEMENTARY	O
MATERIAL	O

Supplementary	O
Material	O
is	O
available	O
at	O
NAR	O
Online	O
.	O

Supplementary	O
Material	O

Structural	O
organization	O
and	O
interactions	O
of	O
transmembrane	O
domains	O
in	O
tetraspanin	O
proteins	O

Abstract	O

Background	O

Proteins	O
of	O
the	O
tetraspanin	O
family	O
contain	O
four	O
transmembrane	O
domains	O
(	O
TM1	O
-	O
4	O
)	O
linked	O
by	O
two	O
extracellular	O
loops	O
and	O
a	O
short	O
intracellular	O
loop	O
,	O
and	O
have	O
short	O
intracellular	O
N	O
-	O
and	O
C	O
-	O
termini	O
.	O

While	O
structure	O
and	O
function	O
analysis	O
of	O
the	O
larger	O
extracellular	O
loop	O
has	O
been	O
performed	O
,	O
the	O
organization	O
and	O
role	O
of	O
transmembrane	O
domains	O
have	O
not	O
been	O
systematically	O
assessed	O
.	O

Results	O

Among	O
28	O
human	B
tetraspanin	O
proteins	O
,	O
the	O
TM1	O
-	O
3	O
sequences	O
display	O
a	O
distinct	O
heptad	O
repeat	O
motif	O
(	O
abcdefg	O
)	O
n	O
.	O

In	O
TM1	O
,	O
position	O
a	O
is	O
occupied	O
by	O
structurally	O
conserved	O
bulky	O
residues	O
and	O
position	O
d	O
contains	O
highly	O
conserved	O
Asn	O
and	O
Gly	O
residues	O
.	O

In	O
TM2	O
,	O
position	O
a	O
is	O
occupied	O
by	O
conserved	O
small	O
residues	O
(	O
Gly	O
/	O
Ala	O
/	O
Thr	O
)	O
,	O
and	O
position	O
d	O
has	O
a	O
conserved	O
Gly	O
and	O
two	O
bulky	O
aliphatic	O
residues	O
.	O

In	O
TM3	O
,	O
three	O
a	O
positions	O
of	O
the	O
heptad	O
repeat	O
are	O
filled	O
by	O
two	O
leucines	O
and	O
a	O
glutamate	O
/	O
glutamine	O
residue	O
,	O
and	O
two	O
d	O
positions	O
are	O
occupied	O
by	O
either	O
Phe	O
/	O
Tyr	O
or	O
Val	O
/	O
Ile	O
/	O
Leu	O
residues	O
.	O

No	O
heptad	O
motif	O
is	O
apparent	O
in	O
TM4	O
sequences	O
.	O

Mutations	O
of	O
conserved	O
glycines	O
in	O
human	B
CD9	O
(	O
Gly25	O
and	O
Gly32	O
in	O
TM1	O
;	O
Gly67	O
and	O
Gly74	O
in	O
TM2	O
)	O
caused	O
aggregation	O
of	O
mutant	O
proteins	O
inside	O
the	O
cell	O
.	O

Modeling	O
of	O
the	O
TM1	O
-	O
TM2	O
interface	O
in	O
CD9	O
,	O
using	O
a	O
novel	O
algorithm	O
,	O
predicts	O
tight	O
packing	O
of	O
conserved	O
bulky	O
residues	O
against	O
conserved	O
Gly	O
residues	O
along	O
the	O
two	O
helices	O
.	O

The	O
homodimeric	O
interface	O
of	O
CD9	O
was	O
mapped	O
,	O
by	O
disulfide	O
cross	O
-	O
linking	O
of	O
single	O
-	O
cysteine	O
mutants	O
,	O
to	O
the	O
vicinity	O
of	O
residues	O
Leu14	O
and	O
Phe17	O
in	O
TM1	O
(	O
positions	O
g	O
and	O
c	O
)	O
and	O
Gly77	O
,	O
Gly80	O
and	O
Ala81	O
in	O
TM2	O
(	O
positions	O
d	O
,	O
g	O
and	O
a	O
,	O
respectively	O
)	O
.	O

Mutations	O
of	O
a	O
and	O
d	O
residues	O
in	O
both	O
TM1	O
and	O
TM2	O
(	O
Gly25	O
,	O
Gly32	O
,	O
Gly67	O
and	O
Gly74	O
)	O
,	O
involved	O
in	O
intramolecular	O
TM1	O
-	O
TM2	O
interaction	O
,	O
also	O
strongly	O
diminished	O
intermolecular	O
interaction	O
,	O
as	O
assessed	O
by	O
cross	O
-	O
linking	O
of	O
Cys80	O
.	O

Conclusion	O

Our	O
results	O
suggest	O
that	O
tetraspanin	O
intra	O
-	O
and	O
intermolecular	O
interactions	O
are	O
mediated	O
by	O
conserved	O
residues	O
in	O
adjacent	O
,	O
but	O
distinct	O
regions	O
of	O
TM1	O
and	O
TM2	O
.	O

A	O
key	O
structural	O
element	O
that	O
defines	O
TM1	O
-	O
TM2	O
interaction	O
in	O
tetraspanins	O
is	O
the	O
specific	O
packing	O
of	O
bulky	O
residues	O
against	O
small	O
residues	O
.	O

Background	O

Tetraspanins	O
constitute	O
a	O
large	O
family	O
of	O
integral	O
membrane	O
proteins	O
,	O
characteristically	O
containing	O
4	O
,	O
6	O
or	O
8	O
conserved	O
cysteine	O
residues	O
in	O
the	O
large	O
extracellular	O
loop	O
(	O
including	O
the	O
CCG	O
and	O
PxxCC	O
motifs	O
)	O
,	O
which	O
form	O
disulfide	O
bonds	O
,	O
and	O
several	O
conserved	O
polar	O
residues	O
in	O
the	O
intracellular	O
loop	O
and	O
transmembrane	O
regions	O
[	O
1	O
,	O
2	O
]	O
.	O

There	O
are	O
32	O
putative	O
tetraspanin	O
family	O
members	O
in	O
mammals	O
,	O
37	O
in	O
Drosophila	B
melanogaster	I
and	O
20	O
in	O
Caenorhabditis	B
elegans	I
.	O

Tetraspanins	O
play	O
diverse	O
roles	O
in	O
cell	O
adhesion	O
,	O
migration	O
and	O
fusion	O
processes	O
,	O
cellular	O
activation	O
and	O
signaling	O
(	O
reviewed	O
in	O
refs	O
.	O
[	O
2	O
-	O
4	O
]	O
)	O
.	O

Mammalian	O
tetraspanins	O
such	O
as	O
CD9	O
,	O
CD63	O
,	O
CD81	O
,	O
CD82	O
,	O
CD151	O
,	O
rds	O
/	O
peripherin	O
,	O
and	O
uroplakins	O
Ia	O
and	O
Ib	O
have	O
been	O
most	O
extensively	O
studied	O
,	O
with	O
mouse	B
knock	O
-	O
out	O
models	O
available	O
for	O
CD9	O
[	O
5	O
-	O
7	O
]	O
,	O
CD81	O
[	O
8	O
,	O
9	O
]	O
,	O
CD151	O
[	O
10	O
]	O
and	O
a	O
few	O
others	O
.	O

However	O
,	O
the	O
majority	O
of	O
tetraspanins	O
are	O
characterized	O
very	O
little	O
,	O
if	O
at	O
all	O
,	O
at	O
genetic	O
,	O
biochemical	O
or	O
structural	O
levels	O
.	O

The	O
large	O
extracellular	O
loop	O
(	O
LEL	O
)	O
of	O
tetraspanins	O
has	O
received	O
most	O
attention	O
,	O
since	O
it	O
contains	O
functionally	O
important	O
sites	O
.	O

Sequence	O
QRD	O
(	O
194	O
-	O
196	O
)	O
in	O
CD151	O
is	O
important	O
for	O
association	O
with	O
integrins	O
,	O
which	O
has	O
functional	O
consequences	O
for	O
integrin	O
-	O
dependent	O
cell	O
spreading	O
and	O
multicellular	O
cable	O
formation	O
[	O
11	O
]	O
.	O

A	O
site	O
in	O
the	O
LEL	O
of	O
CD9	O
,	O
SFQ	O
(	O
residues	O
173	O
-	O
175	O
)	O
,	O
is	O
essential	O
for	O
CD9	O
function	O
in	O
sperm	O
-	O
egg	O
fusion	O
[	O
12	O
]	O
.	O

The	O
crystal	O
structure	O
of	O
tetraspanin	O
CD81	O
LEL	O
revealed	O
five	O
alpha	O
-	O
helixes	O
,	O
A	O
-	O
E	O
[	O
13	O
]	O
.	O

Helices	O
A	O
,	O
B	O
and	O
E	O
form	O
a	O
relatively	O
conserved	O
region	O
in	O
tetraspanins	O
,	O
whereas	O
the	O
region	O
between	O
helices	O
B	O
and	O
E	O
is	O
the	O
most	O
variable	O
[	O
14	O
]	O
.	O

Interestingly	O
,	O
the	O
variable	O
region	O
contains	O
most	O
of	O
the	O
functionally	O
important	O
sites	O
involved	O
in	O
tetraspanin	O
protein	O
-	O
protein	O
interactions	O
.	O

A	O
remarkable	O
biochemical	O
property	O
of	O
tetraspanin	O
molecules	O
is	O
their	O
ability	O
to	O
associate	O
with	O
a	O
large	O
number	O
of	O
other	O
transmembrane	O
proteins	O
,	O
including	O
integrins	O
,	O
membrane	O
-	O
associated	O
growth	O
factors	O
and	O
receptors	O
,	O
MHC	O
class	O
II	O
molecules	O
,	O
Ig	O
superfamily	O
proteins	O
,	O
and	O
each	O
other	O
[	O
2	O
,	O
3	O
,	O
15	O
]	O
.	O

Several	O
of	O
these	O
lateral	O
associations	O
of	O
tetraspanins	O
are	O
detected	O
in	O
"	O
mild	O
"	O
detergents	O
(	O
Brij	O
series	O
,	O
CHAPS	O
)	O
,	O
but	O
are	O
disrupted	O
by	O
"	O
strong	O
"	O
detergents	O
such	O
as	O
Triton	O
X	O
-	O
100	O
or	O
SDS	O
.	O

Multiprotein	O
complexes	O
of	O
tetraspanins	O
and	O
associated	O
molecules	O
,	O
also	O
called	O
the	O
"	O
tetraspanin	O
web	O
"	O
[	O
16	O
]	O
,	O
may	O
represent	O
a	O
distinct	O
tetraspanin	O
-	O
enriched	O
membrane	O
microdomain	O
[	O
17	O
,	O
18	O
]	O
.	O

The	O
formation	O
of	O
this	O
microdomain	O
is	O
influenced	O
by	O
palmitoylation	O
of	O
several	O
conserved	O
juxtamembrane	O
cysteine	O
residues	O
in	O
tetraspanins	O
[	O
19	O
-	O
21	O
]	O
.	O

The	O
transmembrane	O
domains	O
,	O
encompassing	O
nearly	O
half	O
of	O
a	O
tetraspanin	O
protein	O
,	O
are	O
the	O
most	O
conserved	O
part	O
of	O
the	O
molecule	O
(	O
Stipp	O
et	O
al	O
.	O
[	O
1	O
]	O
and	O
this	O
study	O
)	O
.	O

However	O
,	O
very	O
little	O
functional	O
information	O
is	O
available	O
on	O
these	O
domains	O
.	O

The	O
differential	O
detergent	O
sensitivity	O
of	O
tetraspanin	O
-	O
tetraspanin	O
associations	O
suggests	O
that	O
hydrophobic	O
interactions	O
between	O
TM	O
helices	O
may	O
play	O
a	O
role	O
.	O

Indeed	O
,	O
when	O
the	O
large	O
extracellular	O
loop	O
(	O
LEL	O
)	O
of	O
CD151	O
is	O
deleted	O
,	O
the	O
molecule	O
is	O
still	O
able	O
to	O
associate	O
with	O
other	O
tetraspanins	O
[	O
22	O
]	O
.	O

Thus	O
,	O
TM	O
domains	O
are	O
strong	O
candidates	O
for	O
mediating	O
tetraspanin	O
-	O
tetraspanin	O
interactions	O
.	O

The	O
importance	O
of	O
TM	O
domain	O
interactions	O
in	O
intramolecular	O
organization	O
was	O
demonstrated	O
in	O
a	O
study	O
showing	O
that	O
CD82	O
fragment	O
TM2	O
-	O
4	O
,	O
lacking	O
TM1	O
,	O
was	O
retained	O
in	O
the	O
endoplasmic	O
reticulum	O
,	O
but	O
was	O
transported	O
to	O
the	O
cell	O
surface	O
upon	O
co	O
-	O
expression	O
of	O
TM1	O
[	O
23	O
]	O
.	O

This	O
in	O
vivo	O
reconstitution	O
experiment	O
demonstrated	O
a	O
strong	O
interaction	O
between	O
TM1	O
and	O
the	O
rest	O
of	O
the	O
molecule	O
.	O

Expression	O
of	O
a	O
truncated	O
CD9	O
molecule	O
(	O
TM3	O
-	O
LEL	O
-	O
TM4	O
)	O
results	O
in	O
intracellular	O
accumulation	O
of	O
the	O
protein	O
and	O
significant	O
misfolding	O
of	O
the	O
LEL	O
,	O
as	O
judged	O
by	O
inappropriate	O
disulfide	O
formation	O
and	O
diminished	O
antibody	O
reactivity	O
(	O
our	O
unpublished	O
data	O
)	O
.	O

Similarly	O
,	O
a	O
CD9	O
epitope	O
in	O
the	O
LEL	O
is	O
lost	O
in	O
molecules	O
lacking	O
either	O
TM2	O
+	O
TM3	O
or	O
just	O
TM4	O
[	O
24	O
]	O
.	O

Thus	O
,	O
TM	O
domain	O
interactions	O
and	O
packing	O
are	O
crucial	O
for	O
proper	O
folding	O
,	O
stability	O
and	O
transport	O
of	O
tetraspanin	O
molecules	O
.	O

In	O
a	O
previous	O
study	O
,	O
we	O
showed	O
that	O
covalent	O
cross	O
-	O
linking	O
of	O
membrane	O
-	O
proximal	O
cysteine	O
residues	O
can	O
be	O
used	O
as	O
a	O
tool	O
for	O
detection	O
of	O
tetraspanin	O
-	O
tetraspanin	O
associations	O
[	O
25	O
]	O
.	O

Inhibition	O
of	O
cysteine	O
palmitoylation	O
by	O
2	O
-	O
bromopalmitate	O
(	O
2	O
-	O
BP	O
)	O
made	O
cysteines	O
available	O
for	O
cross	O
-	O
linking	O
and	O
enabled	O
demonstration	O
of	O
specific	O
tetraspanin	O
homodimerization	O
and	O
low	O
levels	O
of	O
heterodimerization	O
.	O

We	O
concluded	O
that	O
tetraspanin	O
homodimers	O
,	O
formed	O
in	O
the	O
Golgi	O
,	O
may	O
be	O
a	O
fundamental	O
structural	O
unit	O
within	O
tetraspanin	O
microdomains	O
.	O

In	O
this	O
study	O
,	O
we	O
carried	O
out	O
detailed	O
sequence	O
analysis	O
of	O
human	B
tetraspanin	O
TM	O
domains	O
.	O

We	O
show	O
that	O
a	O
heptad	O
repeat	O
containing	O
conserved	O
glycine	O
,	O
asparagine	O
and	O
large	O
hydrophobic	O
residues	O
occurs	O
in	O
TM1	O
and	O
TM2	O
domains	O
,	O
and	O
predict	O
tight	O
intramolecular	O
association	O
of	O
these	O
two	O
domains	O
by	O
packing	O
of	O
the	O
large	O
residues	O
against	O
the	O
small	O
residues	O
.	O

Moreover	O
,	O
by	O
using	O
cysteine	O
cross	O
-	O
linking	O
we	O
map	O
a	O
dimerization	O
interface	O
in	O
the	O
human	B
CD9	O
protein	O
,	O
and	O
show	O
that	O
conserved	O
heptad	O
motif	O
glycine	O
residues	O
are	O
also	O
important	O
for	O
intermolecular	O
CD9	O
associations	O
.	O

Results	O

Sequence	O
analysis	O
of	O
tetraspanin	O
transmembrane	O
domains	O
:	O
presence	O
of	O
the	O
heptad	O
repeat	O
motif	O

We	O
focused	O
our	O
attention	O
on	O
28	O
human	B
tetraspanins	O
identified	O
from	O
the	O
SWISS	O
-	O
PROT	O
and	O
GenBank	O
databases	O
.	O

All	O
tetraspanins	O
have	O
in	O
common	O
four	O
hydrophobic	O
stretches	O
(	O
TM	O
domains	O
)	O
of	O
20	O
-	O
25	O
residues	O
,	O
and	O
contain	O
highly	O
conserved	O
residues	O
in	O
the	O
second	O
extracellular	O
loop	O
,	O
in	O
particular	O
the	O
Cys	O
-	O
Cys	O
-	O
Gly	O
(	O
CCG	O
)	O
motif	O
.	O

Detailed	O
analysis	O
of	O
the	O
large	O
extracellular	O
loop	O
sequences	O
[	O
14	O
]	O
,	O
and	O
dendrograms	O
based	O
on	O
full	O
-	O
length	O
alignment	O
can	O
be	O
found	O
in	O
earlier	O
studies	O
[	O
26	O
,	O
27	O
]	O
.	O

The	O
length	O
of	O
each	O
transmembrane	O
domain	O
was	O
established	O
based	O
on	O
previous	O
sequence	O
analysis	O
of	O
tetraspanin	O
sequences	O
[	O
27	O
,	O
28	O
]	O
,	O
and	O
on	O
annotations	O
to	O
the	O
database	O
entries	O
.	O

Manual	O
adjustments	O
based	O
on	O
sequence	O
homology	O
and	O
hydrophobicity	O
profiles	O
were	O
done	O
to	O
fully	O
delineate	O
the	O
TM	O
domains	O
.	O

The	O
resulting	O
lengths	O
of	O
TM	O
domains	O
were	O
:	O
TM1	O
-	O
23	O
residues	O
;	O
TM2	O
-	O
21	O
residues	O
;	O
TM3	O
-	O
25	O
residues	O
;	O
TM4	O
-	O
25	O
residues	O
.	O

Two	O
more	O
residues	O
could	O
be	O
added	O
onto	O
the	O
N	O
-	O
terminal	O
part	O
of	O
TM2	O
;	O
however	O
,	O
relatively	O
small	O
sequence	O
conservation	O
of	O
these	O
residues	O
among	O
tetraspanins	O
and	O
occurrence	O
of	O
polar	O
/	O
charged	O
side	O
chains	O
in	O
some	O
tetraspanins	O
precluded	O
us	O
from	O
doing	O
so	O
for	O
the	O
global	O
alignment	O
.	O

Figures	O
1	O
and	O
2	O
show	O
a	O
multiple	O
sequence	O
alignment	O
of	O
four	O
TM	O
domains	O
of	O
28	O
human	B
tetraspanins	O
.	O

For	O
each	O
position	O
within	O
the	O
domains	O
,	O
consensus	O
residues	O
were	O
determined	O
and	O
classified	O
(	O
with	O
individual	O
color	O
code	O
)	O
in	O
4	O
categories	O
:	O
1	O
)	O
large	O
hydrophobic	O
residues	O
(	O
including	O
Val	O
,	O
Met	O
,	O
Leu	O
,	O
Ile	O
,	O
Phe	O
,	O
Tyr	O
,	O
Trp	O
)	O
,	O
2	O
)	O
small	O
residues	O
(	O
Gly	O
,	O
Ala	O
,	O
Ser	O
and	O
Thr	O
)	O
,	O
3	O
)	O
Cys	O
,	O
and	O
4	O
)	O
Asn	O
.	O

When	O
more	O
than	O
two	O
types	O
of	O
residues	O
occupied	O
a	O
given	O
position	O
in	O
a	O
TM	O
,	O
a	O
dual	O
-	O
color	O
pattern	O
that	O
reflected	O
the	O
prevalence	O
of	O
the	O
particular	O
residue	O
type	O
was	O
used	O
(	O
Figure	O
1	O
)	O
.	O

Cysteine	O
residues	O
were	O
shown	O
separately	O
due	O
to	O
their	O
importance	O
as	O
palmitoylation	O
target	O
sites	O
.	O

The	O
highly	O
conserved	O
asparagine	O
residue	O
in	O
TM1	O
was	O
considered	O
separately	O
.	O

No	O
proline	O
residues	O
are	O
found	O
in	O
TM	O
domains	O
1	O
-	O
3	O
of	O
human	B
tetraspanins	O
.	O

An	O
inspection	O
of	O
the	O
multiple	O
sequence	O
alignment	O
reveals	O
a	O
repeating	O
heptad	O
amino	O
acid	O
pattern	O
,	O
(	O
abcdefg	O
)	O
n	O
,	O
in	O
TM1	O
,	O
2	O
and	O
3	O
(	O
Figure	O
1	O
,	O
2	O
)	O
.	O

Heptad	O
repeats	O
promote	O
helical	O
coiled	O
coil	O
interactions	O
in	O
multiple	O
soluble	O
and	O
membrane	O
-	O
spanning	O
proteins	O
[	O
29	O
-	O
31	O
]	O
.	O

In	O
the	O
heptad	O
repeat	O
,	O
hydrophobic	O
residues	O
in	O
positions	O
a	O
and	O
d	O
are	O
of	O
special	O
importance	O
,	O
as	O
they	O
directly	O
mediate	O
interhelical	O
contacts	O
by	O
creating	O
a	O
tight	O
knobs	O
-	O
into	O
-	O
holes	O
packing	O
in	O
the	O
coiled	O
coil	O
structure	O
[	O
32	O
]	O
.	O

For	O
instance	O
,	O
in	O
the	O
leucine	O
zipper	O
of	O
the	O
yeast	B
transcription	O
factor	O
GCN4	O
,	O
positions	O
a	O
and	O
d	O
contain	O
Val	O
and	O
Leu	O
residues	O
,	O
respectively	O
,	O
with	O
an	O
Asn	O
residue	O
in	O
a	O
single	O
a	O
position	O
forming	O
a	O
hydrogen	O
bond	O
across	O
the	O
GCN4	O
dimer	O
interface	O
[	O
33	O
]	O
.	O

In	O
TM1	O
of	O
tetraspanins	O
,	O
highly	O
conserved	O
Asn	O
,	O
Gly	O
and	O
Gly	O
residues	O
(	O
numbers	O
18	O
,	O
25	O
and	O
32	O
in	O
the	O
CD9	O
sequence	O
)	O
appear	O
at	O
d	O
positions	O
of	O
the	O
heptad	O
repeats	O
,	O
and	O
residues	O
14	O
,	O
21	O
and	O
28	O
are	O
at	O
a	O
positions	O
(	O
Figure	O
1	O
)	O
.	O

In	O
TM2	O
,	O
residues	O
67	O
,	O
74	O
and	O
81	O
(	O
consensus	O
Gly	O
,	O
Gly	O
and	O
Ala	O
,	O
respectively	O
)	O
occupy	O
a	O
positions	O
,	O
whereas	O
residues	O
63	O
,	O
70	O
and	O
77	O
are	O
at	O
d	O
positions	O
.	O

Another	O
highly	O
conserved	O
glycine	O
,	O
Gly80	O
,	O
occupies	O
the	O
3rd	O
g	O
position	O
in	O
TM2	O
.	O

In	O
TM3	O
,	O
the	O
conserved	O
pattern	O
consists	O
of	O
two	O
leucine	O
residues	O
(	O
Leu89	O
and	O
Leu96	O
)	O
and	O
a	O
glutamate	O
/	O
glutamine	O
residue	O
(	O
Glu	O
/	O
Gln103	O
)	O
in	O
a	O
positions	O
(	O
Figure	O
2	O
)	O
.	O

Two	O
d	O
positions	O
are	O
also	O
conserved	O
-	O
Phe	O
/	O
Tyr92	O
and	O
Ile	O
/	O
Val	O
/	O
Leu99	O
.	O

TM4	O
lacks	O
a	O
conserved	O
heptad	O
pattern	O
and	O
has	O
only	O
a	O
single	O
conserved	O
position	O
,	O
Glu	O
/	O
Gln209	O
(	O
with	O
four	O
exceptions	O
)	O
.	O

These	O
features	O
of	O
TM1	O
-	O
4	O
of	O
tetraspanins	O
are	O
displayed	O
on	O
helical	O
wheel	O
diagrams	O
(	O
Figure	O
3	O
)	O
.	O

Analysis	O
of	O
TM1	O
sequences	O

The	O
conserved	O
Asn	O
-	O
Gly	O
-	O
Gly	O
motif	O
,	O
occupying	O
designated	O
d	O
positions	O
of	O
the	O
heptad	O
repeat	O
,	O
is	O
the	O
most	O
prominent	O
structural	O
feature	O
of	O
TM1	O
.	O

We	O
also	O
compared	O
sequences	O
of	O
CD9	O
orthologs	O
from	O
10	O
different	O
organisms	O
(	O
the	O
most	O
available	O
for	O
any	O
tetraspanin	O
)	O
to	O
gain	O
further	O
insight	O
into	O
conservation	O
and	O
variability	O
of	O
the	O
TM1	O
sequence	O
.	O

As	O
shown	O
in	O
Figure	O
4	O
,	O
positions	O
a	O
,	O
d	O
and	O
g	O
in	O
TM1	O
are	O
among	O
the	O
most	O
conserved	O
(	O
0	O
,	O
1	O
and	O
1	O
substitution	O
,	O
respectively	O
)	O
,	O
while	O
interspecies	O
variability	O
tends	O
to	O
occur	O
in	O
other	O
positions	O
:	O
b	O
(	O
5	O
substitutions	O
)	O
,	O
c	O
(	O
4	O
substitutions	O
)	O
,	O
e	O
(	O
4	O
substitutions	O
)	O
and	O
f	O
(	O
4	O
substitutions	O
)	O
.	O

Thus	O
,	O
the	O
positions	O
typically	O
involved	O
in	O
coiled	O
coil	O
interactions	O
(	O
a	O
and	O
d	O
)	O
are	O
the	O
most	O
conserved	O
.	O

When	O
residues	O
of	O
TM1	O
are	O
plotted	O
as	O
a	O
helical	O
wheel	O
,	O
additional	O
structural	O
features	O
are	O
revealed	O
(	O
Figure	O
3	O
)	O
.	O

There	O
are	O
highly	O
conserved	O
aliphatic	O
and	O
aromatic	O
residues	O
in	O
the	O
first	O
three	O
a	O
positions	O
of	O
the	O
heptad	O
motif	O
(	O
Phe15	O
,	O
Trp22	O
and	O
Leu29	O
in	O
CD9	O
)	O
,	O
as	O
well	O
as	O
in	O
g	O
positions	O
(	O
Leu14	O
,	O
Phe21	O
,	O
Val28	O
in	O
CD9	O
)	O
.	O

The	O
"	O
ridges	O
"	O
formed	O
by	O
these	O
bulky	O
residues	O
are	O
flanking	O
the	O
"	O
groove	O
"	O
-	O
forming	O
Gly	O
residues	O
of	O
the	O
Asn	O
-	O
Gly	O
-	O
Gly	O
position	O
d	O
motif	O
.	O

In	O
contrast	O
,	O
b	O
,	O
c	O
,	O
e	O
and	O
f	O
positions	O
show	O
an	O
overall	O
higher	O
variability	O
among	O
tetraspanins	O
,	O
as	O
also	O
seen	O
in	O
the	O
comparison	O
of	O
CD9	O
orthologs	O
described	O
above	O
.	O

Analysis	O
of	O
TM2	O
sequences	O

A	O
landmark	O
feature	O
of	O
TM2	O
in	O
tetraspanins	O
is	O
the	O
presence	O
of	O
highly	O
conserved	O
glycine	O
residues	O
(	O
Gly67	O
,	O
74	O
,	O
77	O
and	O
80	O
in	O
CD9	O
,	O
Figure	O
1	O
)	O
.	O

Other	O
substitutions	O
at	O
these	O
positions	O
are	O
almost	O
exclusively	O
small	O
residues	O
,	O
such	O
as	O
Ala	O
or	O
Ser	O
.	O

In	O
addition	O
,	O
Ala	O
,	O
Ser	O
or	O
Thr	O
occupy	O
position	O
81	O
.	O

This	O
residue	O
,	O
together	O
with	O
Gly67	O
and	O
Gly74	O
,	O
forms	O
face	O
a	O
of	O
the	O
helix	O
.	O

Residue	O
Gly77	O
(	O
position	O
d	O
)	O
is	O
preceded	O
by	O
conserved	O
,	O
chiefly	O
large	O
hydrophobic	O
residues	O
on	O
the	O
same	O
helical	O
face	O
(	O
Leu63	O
and	O
Met70	O
in	O
CD9	O
)	O
.	O

Extremely	O
conserved	O
Gly80	O
falls	O
into	O
heptad	O
position	O
g	O
(	O
Figure	O
3	O
)	O
.	O

Among	O
CD9	O
orthologs	O
,	O
heptad	O
positions	O
a	O
and	O
d	O
are	O
absolutely	O
conserved	O
,	O
whereas	O
other	O
positions	O
have	O
the	O
following	O
number	O
of	O
substitutions	O
:	O
b	O
-	O
3	O
;	O
c	O
-	O
2	O
;	O
e	O
-	O
1	O
;	O
f	O
-	O
3	O
;	O
g	O
-	O
1	O
(	O
Figure	O
4	O
)	O
.	O

Two	O
of	O
the	O
f	O
position	O
residues	O
in	O
TM2	O
(	O
65	O
and	O
79	O
)	O
also	O
show	O
higher	O
variability	O
among	O
different	O
tetraspanins	O
(	O
Figures	O
1	O
,	O
3	O
)	O
.	O

Cysteine	O
residues	O
are	O
frequently	O
found	O
near	O
the	O
cytoplasmic	O
end	O
of	O
TM2	O
helix	O
at	O
positions	O
78	O
and	O
79	O
;	O
these	O
cysteines	O
are	O
likely	O
to	O
be	O
palmitoylated	O
.	O

Analysis	O
of	O
TM3	O
and	O
TM4	O
sequences	O

The	O
TM3	O
domain	O
provides	O
another	O
example	O
of	O
the	O
heptad	O
repeat	O
pattern	O
.	O

Position	O
a	O
is	O
occupied	O
by	O
two	O
highly	O
conserved	O
leucine	O
and	O
a	O
glutamate	O
/	O
glutamine	O
residue	O
(	O
Leu89	O
,	O
Leu96	O
and	O
Glu	O
/	O
Gln103	O
in	O
CD9	O
)	O
.	O

Furthermore	O
,	O
two	O
d	O
positions	O
are	O
conserved	O
-	O
Phe	O
/	O
Tyr92	O
(	O
aromatic	O
residue	O
)	O
and	O
Ile	O
/	O
Val99	O
(	O
beta	O
-	O
branched	O
aliphatic	O
residue	O
;	O
Figures	O
2	O
,	O
3	O
)	O
.	O

In	O
addition	O
,	O
residue	O
100	O
in	O
position	O
e	O
is	O
generally	O
Phe	O
or	O
Leu	O
.	O

Among	O
CD9	O
orthologs	O
,	O
position	O
a	O
has	O
1	O
substitution	O
,	O
positions	O
b	O
,	O
c	O
and	O
f	O
each	O
have	O
6	O
,	O
positions	O
d	O
and	O
e	O
each	O
have	O
2	O
,	O
and	O
g	O
has	O
4	O
.	O

Thus	O
,	O
as	O
for	O
TM1	O
and	O
TM2	O
,	O
positions	O
a	O
and	O
d	O
are	O
among	O
the	O
most	O
conserved	O
,	O
but	O
overall	O
TM3	O
has	O
more	O
variable	O
positions	O
than	O
TM1	O
or	O
TM2	O
(	O
Figure	O
3	O
)	O
.	O

Less	O
than	O
half	O
of	O
TM3	O
sequences	O
contain	O
cysteine	O
residues	O
,	O
and	O
those	O
tend	O
to	O
occur	O
at	O
the	O
internal	O
positions	O
of	O
the	O
helix	O
(	O
Figure	O
2	O
)	O
.	O

TM4	O
shows	O
less	O
conservation	O
among	O
various	O
tetraspanin	O
family	O
members	O
than	O
the	O
other	O
TM	O
domains	O
(	O
Figures	O
2	O
,	O
3	O
)	O
.	O

The	O
only	O
highly	O
conserved	O
feature	O
is	O
the	O
glutamate	O
/	O
glutamine	O
residue	O
in	O
position	O
209	O
.	O

In	O
addition	O
,	O
one	O
or	O
two	O
cysteine	O
residues	O
can	O
be	O
found	O
at	O
the	O
C	O
-	O
terminal	O
end	O
of	O
TM4	O
in	O
some	O
tetraspanins	O
(	O
e	O
.	O
g	O
.	O
CD9	O
,	O
CD81	O
,	O
CD151	O
)	O
,	O
and	O
many	O
sequences	O
contain	O
additional	O
polar	O
residues	O
(	O
Arg	O
,	O
Lys	O
,	O
His	O
,	O
Asn	O
,	O
Gln	O
)	O
.	O

No	O
conserved	O
heptad	O
motif	O
was	O
identified	O
in	O
TM4	O
,	O
as	O
also	O
confirmed	O
by	O
analysis	O
of	O
substitutions	O
in	O
CD9	O
orthologs	O
(	O
data	O
not	O
shown	O
)	O
.	O

Mutational	O
analysis	O
of	O
conserved	O
glycine	O
residues	O
in	O
TM1	O
and	O
TM2	O

The	O
conserved	O
nature	O
of	O
the	O
Asn	O
and	O
Gly	O
residues	O
in	O
TM1	O
and	O
TM2	O
prompted	O
an	O
analysis	O
of	O
their	O
functional	O
role	O
.	O

To	O
this	O
end	O
,	O
we	O
have	O
probed	O
whether	O
mutations	O
of	O
these	O
residues	O
destabilize	O
the	O
protein	O
molecule	O
.	O

We	O
expressed	O
a	O
construct	O
of	O
the	O
first	O
and	O
second	O
TMs	O
of	O
CD9	O
,	O
connected	O
by	O
the	O
small	O
extracellular	O
loop	O
,	O
and	O
tagged	O
with	O
a	O
C	O
-	O
terminal	O
green	O
fluorescent	O
protein	O
(	O
TM	O
(	O
1	O
+	O
2	O
)	O
-	O
GFP	O
molecule	O
)	O
.	O

In	O
human	B
rhabdomyosarcoma	O
RD	O
cells	O
,	O
the	O
wild	O
-	O
type	O
fusion	O
protein	O
localized	O
mostly	O
in	O
a	O
reticular	O
,	O
intracellular	O
pattern	O
,	O
without	O
forming	O
any	O
large	O
aggregates	O
(	O
Figure	O
5	O
,	O
panel	O
A	O
)	O
.	O

Remarkably	O
,	O
when	O
double	O
mutants	O
Gly25Leu	O
+	O
Gly32Leu	O
and	O
Gly67Leu	O
+	O
Gly74Leu	O
were	O
expressed	O
,	O
the	O
protein	O
formed	O
distinct	O
large	O
aggregates	O
in	O
a	O
high	O
proportion	O
of	O
cells	O
(	O
Figure	O
5	O
,	O
panels	O
C	O
and	O
E	O
)	O
.	O

In	O
contrast	O
,	O
double	O
mutant	O
Gly77Leu	O
+	O
Gly80Leu	O
did	O
not	O
form	O
such	O
aggregates	O
(	O
Figure	O
5	O
,	O
panel	O
G	O
)	O
.	O

Results	O
with	O
respective	O
single	O
mutants	O
were	O
similar	O
to	O
that	O
with	O
double	O
mutants	O
,	O
with	O
the	O
aggregation	O
being	O
somewhat	O
more	O
pronounced	O
for	O
Leu	O
substitutions	O
of	O
Gly67	O
and	O
Gly74	O
compared	O
to	O
Gly25	O
and	O
Gly32	O
mutations	O
.	O

No	O
aggregation	O
was	O
observed	O
for	O
Asn18Ser	O
and	O
Asn18Tyr	O
mutants	O
(	O
data	O
not	O
shown	O
)	O
.	O

Also	O
,	O
nearly	O
identical	O
results	O
were	O
obtained	O
with	O
human	B
HT1080	O
cells	O
(	O
data	O
not	O
shown	O
)	O
.	O

We	O
interpret	O
these	O
results	O
as	O
an	O
indication	O
that	O
aggregating	O
mutants	O
are	O
destabilized	O
or	O
misfolded	O
while	O
non	O
-	O
aggregating	O
mutants	O
retain	O
the	O
wild	O
-	O
type	O
conformation	O
.	O

Intriguingly	O
,	O
mutations	O
to	O
the	O
conserved	O
GG7	O
motifs	O
caused	O
protein	O
aggregation	O
while	O
the	O
mutation	O
of	O
other	O
glycines	O
had	O
no	O
detectable	O
effect	O
.	O

These	O
results	O
also	O
suggest	O
that	O
wild	O
-	O
type	O
GFP	O
,	O
which	O
has	O
weak	O
tendency	O
to	O
self	O
-	O
associate	O
,	O
could	O
enhance	O
non	O
-	O
specific	O
interactions	O
of	O
destabilized	O
mutant	O
TM	O
(	O
1	O
+	O
2	O
)	O
CD9	O
moieties	O
,	O
leading	O
to	O
their	O
aggregation	O
.	O

Consistent	O
with	O
this	O
hypothesis	O
,	O
the	O
aggregation	O
of	O
Gly25Leu	O
+	O
Gly32Leu	O
and	O
Gly67Leu	O
+	O
Gly74Leu	O
double	O
mutants	O
was	O
suppressed	O
when	O
monomeric	O
GFP	O
molecule	O
,	O
Leu221Lys	O
[	O
34	O
]	O
was	O
used	O
(	O
Figure	O
5	O
,	O
panels	O
D	O
and	O
F	O
)	O
.	O

The	O
use	O
of	O
monomeric	O
GFP	O
did	O
not	O
affect	O
intercellular	O
localization	O
of	O
wild	O
-	O
type	O
CD9	O
TM	O
(	O
1	O
+	O
2	O
)	O
(	O
Figure	O
5	O
,	O
panel	O
B	O
)	O
,	O
or	O
a	O
Gly77Leu	O
+	O
Gly80Leu	O
double	O
mutant	O
(	O
Figure	O
5	O
,	O
panel	O
H	O
)	O
.	O

In	O
summary	O
,	O
Leu	O
substitutions	O
of	O
Gly	O
residues	O
that	O
are	O
part	O
of	O
the	O
Asn	O
-	O
Gly	O
-	O
Gly	O
(	O
NGG7	O
)	O
motif	O
in	O
TM1	O
,	O
or	O
Gly	O
-	O
Gly	O
-	O
Ala	O
(	O
GGA7	O
)	O
motif	O
in	O
TM2	O
,	O
resulted	O
in	O
destabilization	O
and	O
aggregation	O
of	O
GFP	O
-	O
fused	O
TM	O
(	O
1	O
+	O
2	O
)	O
proteins	O
,	O
whereas	O
substitutions	O
of	O
Gly77	O
or	O
Gly80	O
,	O
which	O
are	O
not	O
part	O
of	O
these	O
motifs	O
(	O
Figure	O
3	O
)	O
,	O
failed	O
to	O
show	O
such	O
aggregation	O
.	O

Prediction	O
and	O
modelling	O
of	O
interaction	O
between	O
TM1	O
and	O
TM2	O

Consecutive	O
helices	O
in	O
polytopic	O
membrane	O
proteins	O
frequently	O
interact	O
[	O
35	O
]	O
.	O

Sequence	O
analysis	O
of	O
TM1	O
and	O
TM2	O
helices	O
of	O
tetraspanins	O
reveals	O
a	O
remarkable	O
complementarity	O
in	O
the	O
distribution	O
of	O
large	O
and	O
small	O
residues	O
at	O
heptad	O
positions	O
a	O
and	O
d	O
along	O
the	O
helical	O
axis	O
(	O
Figure	O
3	O
)	O
,	O
suggesting	O
that	O
these	O
residues	O
may	O
interact	O
.	O

To	O
further	O
elucidate	O
the	O
potential	O
for	O
TM1	O
-	O
TM2	O
interaction	O
,	O
the	O
putative	O
interface	O
was	O
modeled	O
using	O
a	O
novel	O
algorithm	O
that	O
considers	O
mutational	O
data	O
during	O
each	O
step	O
of	O
a	O
Monte	O
Carlo	O
simulated	O
annealing	O
cycle	O
(	O
see	O
Methods	O
for	O
details	O
)	O
.	O

Specifically	O
,	O
Gly25Leu	O
,	O
Gly32Leu	O
,	O
Gly67Leu	O
and	O
Gly74Leu	O
were	O
scored	O
as	O
disruptive	O
mutations	O
,	O
while	O
Asn18Ser	O
,	O
Gly77Leu	O
and	O
Gly80Leu	O
were	O
scored	O
as	O
silent	O
mutations	O
,	O
based	O
on	O
their	O
effects	O
on	O
protein	O
stability	O
(	O
Figure	O
5	O
and	O
data	O
not	O
shown	O
)	O
.	O

The	O
resulting	O
model	O
predicts	O
left	O
-	O
handed	O
crossing	O
of	O
TM1	O
and	O
TM2	O
helices	O
at	O
an	O
angle	O
of	O
+	O
28	O
degrees	O
.	O

The	O
key	O
element	O
of	O
the	O
structure	O
is	O
the	O
apposition	O
of	O
bulky	O
and	O
small	O
heptad	O
position	O
a	O
and	O
d	O
residues	O
,	O
as	O
follows	O
:	O
Gly32	O
-	O
Leu63	O
;	O
Gly67	O
-	O
Leu29	O
;	O
Gly25	O
-	O
Met70	O
;	O
Gly74	O
-	O
Trp22	O
;	O
Asn18	O
-	O
Gly77	O
;	O
Ala81	O
-	O
Phe15	O
(	O
Figure	O
6	O
)	O
.	O

Our	O
model	O
predicts	O
that	O
each	O
of	O
these	O
residue	O
pairs	O
are	O
in	O
van	O
der	O
Waals	O
contact	O
.	O

Additionally	O
,	O
two	O
potential	O
H	O
-	O
bonds	O
are	O
predicted	O
in	O
this	O
model	O
,	O
indicating	O
close	O
packing	O
:	O
Gly67	O
C	O
alpha	O
to	O
Gly25	O
carbonyl	O
oxygen	O
,	O
and	O
Trp22	O
C	O
alpha	O
to	O
Met70	O
carbonyl	O
oxygen	O
.	O

The	O
packing	O
is	O
tighter	O
in	O
the	O
ectodomain	O
-	O
proximal	O
portion	O
of	O
the	O
helices	O
(	O
Figure	O
6	O
,	O
panel	O
B	O
)	O
,	O
as	O
determined	O
by	O
C	O
alpha	O
-	O
C	O
alpha	O
distances	O
between	O
interacting	O
residue	O
pairs	O
.	O

The	O
key	O
elements	O
of	O
the	O
model	O
are	O
corroborated	O
by	O
the	O
presence	O
of	O
apparently	O
complementary	O
substitutions	O
in	O
TM1	O
and	O
TM2	O
sequences	O
of	O
different	O
tetraspanins	O
(	O
Figure	O
1	O
,	O
boxed	O
residues	O
)	O
.	O

For	O
example	O
,	O
Gly74	O
is	O
predicted	O
to	O
interact	O
with	O
Trp22	O
.	O

In	O
8	O
of	O
the	O
10	O
tetraspanins	O
that	O
contain	O
a	O
substitution	O
for	O
Gly74	O
,	O
a	O
compensatory	O
substitution	O
occurs	O
at	O
the	O
Trp22	O
position	O
(	O
Figure	O
1	O
)	O
.	O

Thus	O
,	O
a	O
larger	O
non	O
-	O
glycine	O
side	O
chain	O
at	O
position	O
74	O
may	O
necessitate	O
a	O
less	O
bulky	O
non	O
-	O
Trp	O
side	O
chain	O
in	O
position	O
22	O
.	O

Likewise	O
,	O
the	O
presence	O
of	O
a	O
C	O
beta	O
at	O
position	O
25	O
,	O
typically	O
occupied	O
by	O
glycine	O
,	O
necessitates	O
a	O
non	O
-	O
beta	O
-	O
branched	O
amino	O
acid	O
at	O
position	O
70	O
,	O
which	O
is	O
occupied	O
by	O
a	O
beta	O
-	O
branched	O
residue	O
in	O
nearly	O
half	O
of	O
all	O
cases	O
.	O

Indeed	O
,	O
we	O
find	O
that	O
in	O
each	O
of	O
5	O
cases	O
in	O
which	O
position	O
25	O
contains	O
a	O
C	O
beta	O
,	O
a	O
leucine	O
residue	O
occurs	O
in	O
position	O
70	O
.	O

This	O
analysis	O
is	O
consistent	O
with	O
our	O
molecular	O
model	O
that	O
suggests	O
Leu70	O
will	O
pack	O
most	O
favorably	O
against	O
a	O
C	O
beta	O
at	O
position	O
25	O
than	O
a	O
beta	O
-	O
branched	O
residue	O
or	O
a	O
methionine	O
.	O

Role	O
of	O
TM1	O
and	O
TM2	O
heptad	O
motif	O
residues	O
in	O
CD9	O
dimerization	O

To	O
probe	O
CD9	O
dimerization	O
,	O
we	O
used	O
a	O
cysteine	O
-	O
mediated	O
cross	O
-	O
linking	O
approach	O
.	O

We	O
established	O
previously	O
a	O
simple	O
and	O
efficient	O
method	O
for	O
cysteine	O
-	O
mediated	O
cross	O
-	O
linking	O
[	O
25	O
]	O
.	O

After	O
cells	O
are	O
pre	O
-	O
treated	O
with	O
2	O
-	O
BP	O
for	O
16	O
-	O
24	O
hours	O
to	O
expose	O
normally	O
palmitoylated	O
cysteines	O
,	O
the	O
cysteines	O
can	O
be	O
cross	O
-	O
linked	O
using	O
any	O
of	O
the	O
following	O
methods	O
:	O
a	O
)	O
Spontaneous	O
oxidation	O
in	O
Brij97	O
lysates	O
(	O
a	O
condition	O
that	O
preserves	O
tetraspanin	O
-	O
tetraspanin	O
associations	O
)	O
,	O
b	O
)	O
In	O
situ	O
cross	O
-	O
linking	O
,	O
by	O
pre	O
-	O
lysis	O
oxidation	O
of	O
cells	O
with	O
Cu2	O
+	O
-	O
phenanthroline	O
(	O
CuP	O
)	O
to	O
promote	O
disulfide	O
bond	O
formation	O
.	O

c	O
)	O
In	O
situ	O
cross	O
-	O
linking	O
with	O
thiol	O
-	O
reactive	O
cross	O
-	O
linking	O
agents	O
of	O
defined	O
length	O
(	O
e	O
.	O
g	O
.	O
DTME	O
,	O
BMB	O
)	O
.	O

The	O
first	O
two	O
approaches	O
produce	O
in	O
essence	O
"	O
zero	O
-	O
length	O
"	O
disulfides	O
,	O
indicative	O
of	O
close	O
proximity	O
of	O
target	O
cysteines	O
and	O
presumably	O
high	O
specificity	O
of	O
interaction	O
.	O

In	O
contrast	O
,	O
chemical	O
cross	O
-	O
linkers	O
with	O
6	O
-	O
20	O
A	O
spacer	O
arm	O
may	O
cross	O
-	O
link	O
with	O
higher	O
efficiency	O
,	O
but	O
not	O
necessarily	O
higher	O
specificity	O
.	O

However	O
,	O
they	O
provide	O
advantages	O
such	O
as	O
variable	O
membrane	O
permeability	O
,	O
and	O
potential	O
linkage	O
cleavability	O
.	O

For	O
tetraspanins	O
such	O
as	O
CD9	O
,	O
membrane	O
-	O
permeable	O
cross	O
-	O
linker	O
DTME	O
(	O
13	O
.	O
3	O
A	O
-	O
long	O
,	O
reducible	O
)	O
provides	O
highly	O
specific	O
and	O
efficient	O
cross	O
-	O
linking	O
[	O
25	O
]	O
.	O

Here	O
we	O
have	O
used	O
a	O
cysteine	O
cross	O
-	O
linking	O
strategy	O
,	O
in	O
combination	O
with	O
cysteine	O
-	O
scanning	O
mutagenesis	O
,	O
to	O
map	O
the	O
residues	O
from	O
TM1	O
and	O
TM2	O
contributing	O
to	O
the	O
CD9	O
dimerization	O
interface	O
.	O

For	O
subsequent	O
cross	O
-	O
linking	O
experiments	O
using	O
CD9	O
TM	O
(	O
1	O
+	O
2	O
)	O
-	O
GFP	O
protein	O
,	O
the	O
non	O
-	O
dimerizing	O
form	O
of	O
GFP	O
was	O
used	O
.	O

This	O
avoids	O
potential	O
GFP	O
-	O
dependent	O
dimerization	O
and	O
aggregation	O
that	O
can	O
be	O
observed	O
with	O
wild	O
-	O
type	O
GFP	O
,	O
especially	O
when	O
fusions	O
with	O
transmembrane	O
proteins	O
are	O
studied	O
[	O
36	O
]	O
.	O

Importantly	O
,	O
the	O
Leu221Lys	O
mutation	O
in	O
GFP	O
prevented	O
aggregation	O
of	O
mutant	O
forms	O
of	O
CD9	O
TM	O
(	O
1	O
+	O
2	O
)	O
,	O
which	O
was	O
observed	O
with	O
wild	O
-	O
type	O
GFP	O
fusion	O
(	O
Figure	O
5	O
)	O
.	O

The	O
TM	O
(	O
1	O
+	O
2	O
)	O
fragment	O
of	O
CD9	O
contains	O
three	O
native	O
cysteines	O
-	O
Cys9	O
,	O
Cys78	O
and	O
Cys79	O
.	O

Single	O
-	O
cysteine	O
mutants	O
of	O
TM	O
(	O
1	O
+	O
2	O
)	O
were	O
constructed	O
,	O
in	O
which	O
a	O
cysteine	O
was	O
placed	O
at	O
various	O
faces	O
of	O
TM1	O
or	O
TM2	O
while	O
all	O
of	O
the	O
wild	O
-	O
type	O
cysteines	O
were	O
simultaneously	O
replaced	O
by	O
serines	O
.	O

The	O
mutant	O
proteins	O
were	O
transiently	O
expressed	O
in	O
RD	O
cells	O
(	O
having	O
little	O
endogenous	O
CD9	O
)	O
,	O
which	O
were	O
then	O
treated	O
for	O
16	O
-	O
18	O
hours	O
with	O
2	O
-	O
BP	O
.	O

To	O
achieve	O
maximal	O
specificity	O
in	O
cross	O
-	O
linking	O
we	O
used	O
a	O
"	O
zero	O
-	O
length	O
"	O
agent	O
,	O
CuP	O
.	O

First	O
,	O
single	O
-	O
cysteine	O
replacements	O
were	O
constructed	O
for	O
residues	O
Leu14	O
,	O
Phe15	O
,	O
Gly16	O
,	O
Phe17	O
and	O
Asn18	O
,	O
covering	O
just	O
over	O
one	O
complete	O
helical	O
turn	O
at	O
the	O
beginning	O
of	O
TM1	O
.	O

While	O
residue	O
Asn18	O
is	O
highly	O
conserved	O
,	O
positions	O
14	O
,	O
15	O
and	O
17	O
are	O
occupied	O
by	O
bulky	O
hydrophobic	O
residues	O
in	O
most	O
tetraspanins	O
,	O
whereas	O
position	O
16	O
shows	O
less	O
conservation	O
(	O
Figures	O
1	O
,	O
4	O
)	O
.	O

All	O
of	O
the	O
single	O
-	O
cysteine	O
mutants	O
showed	O
diffused	O
pattern	O
of	O
protein	O
localization	O
,	O
without	O
any	O
signs	O
of	O
aggregation	O
.	O

As	O
shown	O
in	O
Figure	O
7A	O
,	O
the	O
highest	O
level	O
of	O
intermolecular	O
cross	O
-	O
linking	O
was	O
observed	O
for	O
Leu14Cys	O
and	O
Phe17Cys	O
mutants	O
,	O
a	O
lower	O
level	O
for	O
Phe15Cys	O
and	O
Gly16Cys	O
mutants	O
,	O
and	O
very	O
little	O
cross	O
-	O
linking	O
for	O
Asn18Cys	O
substitution	O
.	O

These	O
results	O
indicate	O
that	O
:	O
a	O
)	O
the	O
first	O
two	O
transmembrane	O
domains	O
of	O
CD9	O
alone	O
can	O
mediate	O
its	O
dimerization	O
,	O
and	O
b	O
)	O
the	O
g	O
and	O
c	O
residues	O
of	O
TM1	O
(	O
e	O
.	O
g	O
.	O
Leu14	O
and	O
Phe17	O
,	O
Figure	O
3	O
)	O
are	O
likely	O
to	O
be	O
part	O
of	O
the	O
intermolecular	O
interface	O
.	O

Similarly	O
,	O
single	O
-	O
cysteine	O
substitutions	O
were	O
made	O
for	O
residues	O
Gly77	O
,	O
Gly80	O
and	O
Ala81	O
in	O
TM2	O
;	O
in	O
addition	O
,	O
proteins	O
carrying	O
a	O
single	O
wild	O
-	O
type	O
cysteine	O
,	O
Cys9	O
,	O
Cys78	O
or	O
Cys79	O
,	O
were	O
tested	O
.	O

No	O
protein	O
aggregation	O
was	O
observed	O
for	O
any	O
of	O
these	O
single	O
-	O
cysteine	O
mutants	O
.	O

As	O
shown	O
in	O
Figure	O
7B	O
,	O
the	O
relatively	O
low	O
level	O
of	O
intermolecular	O
cross	O
-	O
linking	O
of	O
wild	O
-	O
type	O
CD9	O
TM	O
(	O
1	O
+	O
2	O
)	O
-	O
GFP	O
protein	O
was	O
enhanced	O
dramatically	O
in	O
single	O
-	O
cysteine	O
TM2	O
mutants	O
Gly80Cys	O
and	O
Ala81Cys	O
.	O

The	O
Gly77Cys	O
mutant	O
also	O
had	O
an	O
elevated	O
level	O
of	O
cross	O
-	O
linking	O
.	O

In	O
contrast	O
,	O
any	O
of	O
the	O
three	O
native	O
cysteines	O
(	O
9	O
,	O
78	O
and	O
79	O
)	O
produced	O
level	O
of	O
cross	O
-	O
linking	O
not	O
much	O
greater	O
than	O
the	O
wild	O
-	O
type	O
TM	O
(	O
1	O
+	O
2	O
)	O
protein	O
.	O

Similar	O
results	O
were	O
obtained	O
with	O
cysteine	O
-	O
reactive	O
cross	O
-	O
linker	O
BMB	O
(	O
data	O
not	O
shown	O
)	O
.	O

Likewise	O
,	O
comparable	O
results	O
were	O
obtained	O
with	O
single	O
-	O
cysteine	O
mutants	O
of	O
untagged	O
,	O
full	O
-	O
length	O
CD9	O
,	O
using	O
CuP	O
(	O
Figure	O
7C	O
)	O
as	O
well	O
as	O
DTME	O
cross	O
-	O
linker	O
(	O
data	O
not	O
shown	O
)	O
.	O

These	O
cross	O
-	O
linking	O
results	O
for	O
TM1	O
and	O
TM2	O
are	O
consistent	O
with	O
our	O
model	O
that	O
places	O
residues	O
Leu14	O
,	O
Phe17	O
and	O
Gly80	O
on	O
the	O
same	O
side	O
of	O
the	O
TM1	O
-	O
TM2	O
pair	O
(	O
Figure	O
6	O
,	O
panel	O
C	O
)	O
.	O

The	O
strong	O
cross	O
-	O
linking	O
with	O
Leu14Cys	O
,	O
Phe17Cys	O
and	O
Gly80Cys	O
places	O
the	O
intermolecular	O
interface	O
toward	O
the	O
c	O
and	O
g	O
phases	O
of	O
the	O
TM1	O
helix	O
,	O
and	O
the	O
g	O
phase	O
of	O
the	O
TM2	O
helix	O
,	O
away	O
from	O
its	O
e	O
and	O
f	O
faces	O
containing	O
wild	O
-	O
type	O
cysteines	O
78	O
and	O
79	O
.	O

Critical	O
residues	O
at	O
the	O
TM1	O
-	O
TM2	O
interface	O
also	O
affect	O
dimerization	O
indirectly	O
.	O

To	O
assess	O
specific	O
CD9	O
dimerization	O
,	O
we	O
used	O
a	O
Gly80Cys	O
substitution	O
at	O
the	O
intermolecular	O
interface	O
for	O
cross	O
-	O
linking	O
.	O

As	O
shown	O
in	O
Figure	O
8A	O
,	O
single	O
replacements	O
of	O
conserved	O
heptad	O
residues	O
in	O
positions	O
18	O
,	O
25	O
,	O
32	O
,	O
67	O
and	O
74	O
(	O
Asn18Ser	O
,	O
Gly25	O
/	O
32	O
/	O
67	O
/	O
74	O
-	O
-	O
>	O
Leu	O
)	O
strongly	O
decreased	O
the	O
cross	O
-	O
linking	O
mediated	O
by	O
Cys80	O
.	O

The	O
effect	O
was	O
most	O
pronounced	O
for	O
mutations	O
of	O
residues	O
,	O
Gly32	O
and	O
Gly67	O
,	O
located	O
in	O
the	O
tightly	O
packed	O
extracellular	O
end	O
of	O
TM	O
helices	O
(	O
Figure	O
6	O
)	O
.	O

In	O
contrast	O
,	O
mutations	O
of	O
residues	O
closer	O
to	O
the	O
cytoplasmic	O
end	O
of	O
TM2	O
(	O
Gly74	O
and	O
especially	O
Ala81	O
)	O
had	O
only	O
modest	O
to	O
very	O
little	O
effect	O
on	O
cross	O
-	O
linking	O
.	O

Relatively	O
low	O
efficiency	O
of	O
intermolecular	O
cross	O
-	O
linking	O
via	O
native	O
residues	O
Cys9	O
,	O
78	O
,	O
and	O
79	O
(	O
Figures	O
7B	O
,	O
C	O
)	O
correlates	O
well	O
with	O
the	O
predicted	O
location	O
of	O
Cys78	O
and	O
79	O
away	O
from	O
the	O
dimeric	O
interface	O
(	O
Figure	O
3	O
)	O
,	O
and	O
suggests	O
that	O
the	O
extramembrane	O
N	O
-	O
terminal	O
part	O
of	O
CD9	O
(	O
residues	O
1	O
-	O
13	O
)	O
does	O
not	O
self	O
-	O
associate	O
.	O

We	O
next	O
examined	O
whether	O
mutations	O
of	O
conserved	O
Asn	O
and	O
Gly	O
residues	O
in	O
TM1	O
and	O
TM2	O
decreased	O
low	O
-	O
level	O
background	O
cross	O
-	O
linking	O
via	O
native	O
cysteines	O
.	O

As	O
expected	O
,	O
these	O
mutations	O
had	O
virtually	O
no	O
effect	O
on	O
dimer	O
formation	O
of	O
CD9	O
TM	O
(	O
1	O
+	O
2	O
)	O
-	O
GFP	O
(	O
Figure	O
8B	O
)	O
.	O

The	O
level	O
of	O
covalent	O
dimer	O
formed	O
was	O
not	O
diminished	O
for	O
triple	O
Asn18Ser	O
+	O
Gly25Leu	O
+	O
Gly32Leu	O
and	O
double	O
Gly67Leu	O
+	O
Gly74Leu	O
mutants	O
,	O
compared	O
to	O
wild	O
-	O
type	O
TM	O
(	O
1	O
+	O
2	O
)	O
CD9	O
molecule	O
.	O

Similarly	O
,	O
the	O
same	O
triple	O
and	O
double	O
mutations	O
in	O
the	O
context	O
of	O
full	O
-	O
length	O
CD9	O
-	O
GFP	O
protein	O
(	O
with	O
six	O
cysteines	O
)	O
produced	O
wild	O
-	O
type	O
levels	O
of	O
cross	O
-	O
linking	O
(	O
Figure	O
8C	O
)	O
.	O

We	O
interpret	O
these	O
findings	O
as	O
evidence	O
for	O
at	O
least	O
two	O
types	O
of	O
associations	O
between	O
CD9	O
molecules	O
:	O
primary	O
,	O
involving	O
residues	O
14	O
,	O
17	O
and	O
80	O
,	O
and	O
dependent	O
on	O
integrity	O
of	O
conserved	O
heptad	O
residues	O
in	O
TM1	O
and	O
TM2	O
,	O
and	O
less	O
efficient	O
secondary	O
interactions	O
,	O
probably	O
representing	O
random	O
collision	O
events	O
,	O
and	O
independent	O
of	O
the	O
heptad	O
residues	O
(	O
see	O
Discussion	O
for	O
more	O
details	O
)	O
.	O

TM3	O
and	O
TM4	O
cysteine	O
residues	O
in	O
CD9	O
dimerization	O

After	O
identifying	O
the	O
roles	O
of	O
conserved	O
TM1	O
and	O
TM2	O
residues	O
in	O
CD9	O
dimerization	O
,	O
we	O
next	O
probed	O
whether	O
residues	O
proximal	O
to	O
TM	O
domains	O
3	O
and	O
4	O
are	O
also	O
involved	O
.	O

To	O
this	O
end	O
,	O
disulfide	O
cross	O
-	O
linking	O
of	O
full	O
-	O
length	O
CD9	O
molecules	O
containing	O
3	O
C	O
-	O
terminal	O
cysteines	O
(	O
87	O
,	O
just	O
before	O
TM3	O
;	O
218	O
and	O
219	O
in	O
TM4	O
)	O
or	O
3	O
N	O
-	O
terminal	O
cysteines	O
(	O
9	O
,	O
78	O
and	O
79	O
)	O
was	O
compared	O
(	O
Figure	O
9	O
)	O
.	O

We	O
found	O
that	O
the	O
C	O
-	O
terminal	O
cysteines	O
were	O
only	O
slightly	O
better	O
than	O
N	O
-	O
terminal	O
cysteines	O
with	O
respect	O
to	O
detection	O
of	O
CD9	O
dimers	O
.	O

However	O
,	O
markedly	O
more	O
trimers	O
and	O
tetramers	O
were	O
detected	O
using	O
C	O
-	O
terminal	O
cysteines	O
.	O

Thus	O
,	O
residues	O
87	O
,	O
218	O
and	O
219	O
at	O
TM3	O
and	O
TM4	O
in	O
CD9	O
can	O
together	O
form	O
contacts	O
across	O
the	O
dimeric	O
interface	O
and	O
also	O
additional	O
contacts	O
with	O
other	O
neighboring	O
CD9	O
molecules	O
.	O

Discussion	O

Here	O
we	O
provide	O
the	O
first	O
detailed	O
analysis	O
of	O
tetraspanin	O
protein	O
transmembrane	O
domains	O
.	O

First	O
,	O
we	O
show	O
1	O
)	O
the	O
presence	O
of	O
a	O
heptad	O
repeat	O
motif	O
in	O
TM1	O
and	O
TM2	O
,	O
containing	O
highly	O
conserved	O
Asn	O
and	O
Gly	O
residues	O
,	O
2	O
)	O
a	O
leucine	O
and	O
glutamate	O
/	O
glutamine	O
-	O
containing	O
heptad	O
motif	O
in	O
TM3	O
,	O
and	O
3	O
)	O
high	O
variability	O
and	O
absence	O
of	O
heptad	O
repeats	O
in	O
TM4	O
sequences	O
.	O

Second	O
,	O
we	O
provide	O
evidence	O
for	O
a	O
specific	O
,	O
intramolecular	O
interaction	O
between	O
TM1	O
and	O
TM2	O
domains	O
,	O
in	O
which	O
bulky	O
hydrophobic	O
residues	O
pack	O
against	O
GG7	O
motif	O
,	O
and	O
present	O
a	O
molecular	O
model	O
for	O
this	O
interaction	O
.	O

Third	O
,	O
experimental	O
mapping	O
of	O
the	O
CD9	O
dimerization	O
interface	O
firmly	O
establishes	O
an	O
additional	O
role	O
for	O
conserved	O
TM1	O
and	O
TM2	O
residues	O
in	O
dimeric	O
intermolecular	O
interactions	O
.	O

Fourth	O
,	O
preliminary	O
evidence	O
is	O
provided	O
to	O
suggest	O
that	O
TM3	O
and	O
TM4	O
domains	O
contribute	O
to	O
expansion	O
of	O
CD9	O
dimers	O
into	O
higher	O
order	O
multimers	O
.	O

Conserved	O
residues	O
in	O
TM1	O
and	O
TM2	O
of	O
tetraspanins	O
:	O
role	O
in	O
intramolecular	O
packing	O

We	O
hypothesized	O
that	O
the	O
first	O
two	O
transmembrane	O
domains	O
of	O
tetraspanins	O
might	O
interact	O
with	O
each	O
other	O
because	O
:	O
a	O
)	O
consecutive	O
TM	O
domains	O
frequently	O
associate	O
in	O
known	O
protein	O
3D	O
structures	O
[	O
35	O
]	O
,	O
and	O
b	O
)	O
they	O
both	O
contain	O
a	O
series	O
of	O
highly	O
conserved	O
amino	O
acids	O
-	O
several	O
Gly	O
residues	O
and	O
an	O
Asn	O
residue	O
(	O
Figure	O
1	O
)	O
.	O

Conserved	O
Gly	O
residues	O
are	O
a	O
frequent	O
theme	O
in	O
the	O
organization	O
of	O
interacting	O
transmembrane	O
domains	O
.	O

Analysis	O
of	O
3D	O
helix	O
packing	O
in	O
polytopic	O
membrane	O
proteins	O
reveals	O
that	O
Gly	O
residues	O
tend	O
to	O
localize	O
in	O
buried	O
positions	O
,	O
especially	O
at	O
the	O
helix	O
-	O
helix	O
interfaces	O
and	O
helix	O
crossing	O
points	O
[	O
37	O
,	O
38	O
]	O
.	O

Due	O
to	O
the	O
absence	O
of	O
a	O
side	O
chain	O
,	O
Gly	O
provides	O
a	O
flat	O
surface	O
for	O
packing	O
of	O
a	O
side	O
chain	O
from	O
another	O
residue	O
,	O
without	O
loss	O
of	O
side	O
-	O
chain	O
entropy	O
upon	O
interaction	O
.	O

The	O
most	O
common	O
Gly	O
-	O
containing	O
motif	O
is	O
GxxxG	O
[	O
39	O
,	O
40	O
]	O
.	O

In	O
glycophorin	O
A	O
(	O
GpA	O
)	O
,	O
the	O
major	O
glycoprotein	O
in	O
erythrocyte	O
cell	O
membranes	O
,	O
Gly79	O
and	O
Gly83	O
are	O
part	O
of	O
the	O
LIxxGVxxGVxxT	O
sequence	O
that	O
promotes	O
homodimerization	O
of	O
parallel	O
transmembrane	O
alpha	O
-	O
helixes	O
[	O
41	O
,	O
42	O
]	O
.	O

In	O
the	O
GpA	O
dimerization	O
motif	O
,	O
Gly	O
residues	O
allow	O
for	O
tight	O
packing	O
in	O
the	O
right	O
-	O
handed	O
helical	O
crossing	O
[	O
43	O
]	O
.	O

There	O
are	O
also	O
examples	O
of	O
left	O
-	O
handed	O
helical	O
crossing	O
in	O
the	O
context	O
of	O
a	O
GxxxG	O
motif	O
[	O
44	O
]	O
.	O

Other	O
membrane	O
proteins	O
that	O
use	O
the	O
GxxxG	O
motif	O
for	O
homo	O
-	O
or	O
heterodimerization	O
include	O
bacteriophage	B
M13	I
coat	O
proteins	O
[	O
45	O
]	O
,	O
yeast	B
alpha	O
factor	O
receptor	O
[	O
46	O
]	O
,	O
integrin	O
alpha	O
IIb	O
subunit	O
[	O
47	O
]	O
,	O
and	O
ErbB1	O
receptor	O
tyrosine	O
kinase	O
[	O
48	O
]	O
.	O

Other	O
small	O
residues	O
,	O
such	O
as	O
Ala	O
and	O
Ser	O
,	O
can	O
substitute	O
for	O
Gly	O
in	O
this	O
motif	O
[	O
49	O
]	O
.	O

A	O
protein	O
motif	O
in	O
which	O
Gly	O
residues	O
are	O
separated	O
by	O
6	O
other	O
residues	O
(	O
GG7	O
)	O
is	O
also	O
common	O
in	O
transmembrane	O
helices	O
,	O
especially	O
in	O
transporter	O
/	O
channel	O
-	O
like	O
membrane	O
proteins	O
[	O
50	O
]	O
.	O

However	O
,	O
the	O
structural	O
features	O
associated	O
with	O
this	O
motif	O
are	O
not	O
well	O
known	O
.	O

In	O
particular	O
,	O
it	O
is	O
unclear	O
whether	O
left	O
-	O
handed	O
GG7	O
heptad	O
repeat	O
motif	O
(	O
as	O
opposed	O
to	O
the	O
"	O
classic	O
"	O
right	O
-	O
handed	O
GxxxG	O
motif	O
)	O
can	O
drive	O
membrane	O
helix	O
association	O
.	O

In	O
a	O
recent	O
work	O
addressing	O
this	O
issue	O
,	O
Lear	O
et	O
al	O
.	O

[	O
51	O
]	O
showed	O
that	O
a	O
synthetic	O
peptide	O
containing	O
Gly	O
at	O
heptad	O
positions	O
a	O
and	O
d	O
could	O
self	O
-	O
associate	O
in	O
vitro	O
,	O
likely	O
in	O
an	O
antiparallel	O
orientation	O
.	O

Heptad	O
repeats	O
containing	O
conserved	O
Gly	O
residues	O
occur	O
in	O
TM	O
domains	O
of	O
alpha	O
and	O
beta	O
chains	O
of	O
MHC	O
class	O
II	O
proteins	O
,	O
and	O
mutations	O
of	O
the	O
Gly	O
residues	O
disrupt	O
the	O
alpha	O
beta	O
heterodimer	O
[	O
52	O
]	O
.	O

These	O
examples	O
demonstrate	O
that	O
Gly	O
-	O
based	O
heptad	O
motifs	O
may	O
be	O
used	O
for	O
both	O
intra	O
-	O
and	O
intermolecular	O
associations	O
.	O

In	O
this	O
work	O
,	O
we	O
identified	O
a	O
highly	O
conserved	O
GG7	O
motif	O
in	O
the	O
first	O
two	O
tetraspanin	O
TM	O
domains	O
.	O

The	O
GG7	O
sequence	O
in	O
tetraspanins	O
is	O
a	O
part	O
of	O
a	O
larger	O
motif	O
that	O
also	O
includes	O
a	O
conserved	O
Asn	O
residue	O
in	O
TM1	O
(	O
NGG7	O
)	O
and	O
an	O
Ala	O
/	O
Ser	O
/	O
Thr	O
residue	O
in	O
TM2	O
(	O
GGA7	O
)	O
.	O

The	O
seven	O
-	O
residue	O
periodicity	O
of	O
these	O
motifs	O
strongly	O
suggests	O
their	O
involvement	O
in	O
left	O
-	O
handed	O
coiled	O
coil	O
packing	O
reminiscent	O
of	O
the	O
leucine	O
zipper	O
,	O
rather	O
than	O
right	O
-	O
handed	O
packing	O
of	O
the	O
GpA	O
-	O
like	O
GxxxG	O
motif	O
.	O

For	O
antiparallel	O
helices	O
,	O
the	O
left	O
-	O
handed	O
crossing	O
is	O
in	O
fact	O
predominant	O
over	O
the	O
right	O
-	O
handed	O
in	O
known	O
TM	O
domain	O
structures	O
[	O
44	O
]	O
.	O

In	O
our	O
model	O
,	O
heptad	O
Gly	O
residues	O
in	O
NGG7	O
and	O
GGA7	O
sequences	O
provide	O
specific	O
packing	O
between	O
antiparallel	O
tetraspanin	O
TM1	O
and	O
TM2	O
helices	O
by	O
allowing	O
tight	O
van	O
der	O
Waals	O
interactions	O
with	O
large	O
hydrophobic	O
residues	O
(	O
Figure	O
6	O
)	O
.	O

Highly	O
efficient	O
packing	O
of	O
bulky	O
side	O
chains	O
against	O
glycine	O
residues	O
is	O
observed	O
in	O
known	O
transmembrane	O
protein	O
3D	O
structures	O
[	O
38	O
,	O
53	O
,	O
54	O
]	O
.	O

An	O
example	O
includes	O
packing	O
of	O
helices	O
M1	O
and	O
M2	O
in	O
potassium	O
channel	O
KcsA	O
,	O
where	O
Val91	O
in	O
M2	O
is	O
paired	O
with	O
Gly43	O
in	O
M1	O
,	O
and	O
Leu36	O
in	O
M1	O
contacts	O
Ala98	O
and	O
Gly99	O
in	O
helix	O
M2	O
[	O
54	O
,	O
55	O
]	O
.	O

In	O
addition	O
to	O
facilitating	O
helix	O
-	O
helix	O
packing	O
,	O
Gly	O
residues	O
frequently	O
provide	O
additional	O
C	O
alpha	O
H	O
.	O
.	O
.	O
O	O
hydrogen	O
bonds	O
between	O
two	O
helices	O
[	O
44	O
]	O
.	O

In	O
our	O
model	O
,	O
two	O
C	O
alpha	O
-	O
backbone	O
carbonyl	O
H	O
-	O
bonds	O
are	O
predicted	O
-	O
between	O
residues	O
Gly27	O
-	O
Gly67	O
,	O
and	O
Trp22	O
-	O
Met70	O
.	O

Although	O
polar	O
and	O
charged	O
amino	O
acid	O
residues	O
(	O
such	O
as	O
Asn	O
in	O
the	O
TM1	O
heptad	O
motif	O
)	O
are	O
infrequent	O
in	O
transmembrane	O
domains	O
,	O
they	O
are	O
functionally	O
important	O
.	O

Polar	O
residues	O
such	O
as	O
glutamine	O
,	O
glutamic	O
acid	O
,	O
aspartic	O
acid	O
and	O
asparagine	O
can	O
promote	O
strong	O
oligomerization	O
of	O
model	O
membrane	O
-	O
associated	O
helices	O
[	O
56	O
-	O
58	O
]	O
.	O

Ruan	O
et	O
al	O
.	O

[	O
59	O
]	O
used	O
asparagine	O
scanning	O
mutagenesis	O
to	O
probe	O
the	O
interface	O
of	O
self	O
-	O
associating	O
polyleucine	O
helices	O
by	O
detecting	O
their	O
enhanced	O
self	O
-	O
interaction	O
in	O
vitro	O
and	O
in	O
the	O
E	B
.	I
coli	I
-	O
based	O
ToxR	O
assay	O
.	O

Thus	O
,	O
a	O
hydrogen	O
bond	O
in	O
an	O
apolar	O
environment	O
can	O
result	O
in	O
strong	O
,	O
though	O
not	O
necessarily	O
specific	O
,	O
association	O
of	O
transmembrane	O
helices	O
.	O

In	O
fact	O
,	O
mutations	O
to	O
polar	O
residues	O
in	O
transmembrane	O
proteins	O
are	O
commonly	O
associated	O
with	O
disease	O
[	O
60	O
]	O
.	O

Because	O
of	O
this	O
potential	O
for	O
non	O
-	O
specific	O
interactions	O
,	O
polar	O
residues	O
tend	O
to	O
localize	O
at	O
buried	O
positions	O
in	O
TM	O
domains	O
.	O

In	O
our	O
case	O
,	O
the	O
conserved	O
Asn18	O
residue	O
in	O
CD9	O
is	O
predicted	O
to	O
be	O
a	O
part	O
of	O
the	O
TM1	O
-	O
TM2	O
interface	O
,	O
though	O
our	O
model	O
does	O
not	O
predict	O
any	O
electrostatic	O
interaction	O
between	O
Asn18	O
and	O
TM2	O
(	O
Figure	O
6	O
)	O
.	O

Consistently	O
,	O
substitution	O
such	O
as	O
Asn18Tyr	O
(	O
and	O
Gly77Leu	O
)	O
in	O
TM	O
(	O
1	O
+	O
2	O
)	O
-	O
GFP	O
protein	O
was	O
not	O
destabilizing	O
as	O
analyzed	O
by	O
protein	O
aggregation	O
.	O

Curiously	O
,	O
the	O
full	O
-	O
length	O
Asn18Ser	O
CD9	O
migrated	O
slightly	O
slower	O
on	O
SDS	O
-	O
PAGE	O
gel	O
(	O
data	O
not	O
shown	O
)	O
,	O
suggesting	O
that	O
Asn18	O
does	O
play	O
a	O
role	O
in	O
maintaining	O
conformation	O
of	O
the	O
molecule	O
.	O

The	O
Asn18Cys	O
single	O
-	O
cysteine	O
mutant	O
shows	O
very	O
little	O
intermolecular	O
cross	O
-	O
linking	O
(	O
Figure	O
7A	O
)	O
,	O
supporting	O
the	O
proposed	O
location	O
of	O
this	O
residue	O
at	O
the	O
intramolecular	O
interface	O
.	O

It	O
is	O
tempting	O
to	O
speculate	O
that	O
the	O
"	O
pocket	O
"	O
between	O
TM1	O
and	O
TM2	O
lined	O
by	O
Asn18	O
and	O
Gly77	O
might	O
be	O
important	O
for	O
accommodating	O
palmitate	O
moieties	O
that	O
target	O
Cys78	O
and	O
Cys79	O
residues	O
,	O
and	O
/	O
or	O
important	O
for	O
access	O
by	O
the	O
putative	O
palmitoyl	O
transferase	O
to	O
those	O
residues	O
.	O

Understanding	O
the	O
exact	O
role	O
of	O
these	O
highly	O
conserved	O
Asn18	O
and	O
Gly77	O
residues	O
in	O
tetraspanins	O
awaits	O
further	O
investigation	O
.	O

In	O
summary	O
,	O
we	O
identified	O
conserved	O
glycine	O
residues	O
of	O
TM1	O
and	O
TM2	O
of	O
tetraspanins	O
as	O
key	O
elements	O
required	O
for	O
intramolecular	O
packing	O
.	O

Mutations	O
of	O
these	O
key	O
residues	O
(	O
Gly25	O
,	O
Gly32	O
,	O
Gly67	O
and	O
Gly74	O
in	O
CD9	O
)	O
resulted	O
in	O
protein	O
destabilization	O
and	O
aggregation	O
.	O

There	O
is	O
ample	O
evidence	O
in	O
the	O
literature	O
for	O
mutations	O
in	O
transmembrane	O
proteins	O
that	O
lead	O
to	O
protein	O
destabilization	O
,	O
misassembly	O
and	O
pathologic	O
conditions	O
[	O
61	O
]	O
.	O

Thus	O
,	O
we	O
have	O
identified	O
conserved	O
heptad	O
Gly	O
residues	O
in	O
TM1	O
and	O
TM2	O
of	O
tetraspanins	O
as	O
plausible	O
targets	O
of	O
destabilizing	O
mutations	O
with	O
potential	O
functional	O
consequences	O
.	O

Intermolecular	O
interactions	O
in	O
tetraspanins	O

Tetraspanin	O
CD9	O
forms	O
mostly	O
homodimers	O
,	O
but	O
also	O
a	O
low	O
level	O
of	O
heterodimers	O
with	O
CD81	O
and	O
CD151	O
[	O
25	O
]	O
.	O

Thus	O
,	O
mapping	O
the	O
dimerization	O
interface	O
is	O
an	O
important	O
next	O
step	O
in	O
structure	O
-	O
function	O
analysis	O
of	O
tetraspanins	O
.	O

Disulfide	O
-	O
mediated	O
cross	O
-	O
linking	O
,	O
often	O
in	O
combination	O
with	O
cysteine	O
-	O
scanning	O
mutagenesis	O
,	O
is	O
a	O
common	O
strategy	O
to	O
probe	O
oligomerization	O
or	O
intersubunit	O
interactions	O
of	O
transmembrane	O
proteins	O
such	O
as	O
histidine	O
kinase	O
EnvZ	O
[	O
62	O
]	O
,	O
M	O
(	O
3	O
)	O
muscarinic	O
acetylcholine	O
receptor	O
[	O
63	O
]	O
,	O
E	B
.	I
coli	I
lactose	O
permease	O
[	O
64	O
]	O
,	O
synaptobrevin	O
[	O
65	O
]	O
,	O
integrins	O
[	O
66	O
]	O
and	O
many	O
others	O
.	O

In	O
tetraspanins	O
such	O
as	O
CD9	O
,	O
membrane	O
-	O
proximal	O
cysteine	O
residues	O
are	O
especially	O
useful	O
targets	O
for	O
disulfide	O
trapping	O
,	O
as	O
their	O
linkage	O
can	O
be	O
enhanced	O
by	O
pre	O
-	O
treating	O
cells	O
with	O
2	O
-	O
BP	O
.	O

While	O
the	O
ability	O
of	O
wild	O
-	O
type	O
cysteines	O
in	O
CD9	O
to	O
be	O
cross	O
-	O
linked	O
may	O
indicate	O
that	O
they	O
are	O
close	O
to	O
the	O
dimerization	O
interface	O
,	O
more	O
precise	O
mapping	O
was	O
achieved	O
here	O
using	O
cysteine	O
-	O
scanning	O
mutagenesis	O
.	O

Our	O
data	O
clearly	O
identify	O
regions	O
,	O
near	O
the	O
cytoplasmic	O
face	O
of	O
TM1	O
and	O
TM2	O
,	O
important	O
for	O
dimerization	O
.	O

Intermolecular	O
zero	O
-	O
length	O
cross	O
-	O
linking	O
was	O
highest	O
when	O
single	O
cysteines	O
were	O
placed	O
in	O
positions	O
14	O
,	O
17	O
,	O
77	O
,	O
80	O
and	O
81	O
in	O
TM	O
(	O
1	O
+	O
2	O
)	O
-	O
GFP	O
molecule	O
,	O
or	O
at	O
positions	O
77	O
,	O
80	O
or	O
81	O
in	O
the	O
full	O
-	O
length	O
CD9	O
protein	O
.	O

Positions	O
14	O
,	O
17	O
and	O
80	O
are	O
distinct	O
from	O
the	O
intramolecular	O
interface	O
and	O
are	O
on	O
the	O
same	O
side	O
of	O
the	O
TM1	O
-	O
TM2	O
pair	O
(	O
Figure	O
6	O
)	O
.	O

Thus	O
,	O
they	O
are	O
well	O
-	O
positioned	O
to	O
participate	O
in	O
an	O
interaction	O
with	O
another	O
molecule	O
.	O

At	O
the	O
same	O
time	O
,	O
the	O
model	O
predicts	O
that	O
wild	O
-	O
type	O
cysteines	O
(	O
Cys78	O
,	O
79	O
)	O
,	O
which	O
do	O
not	O
yield	O
very	O
efficient	O
zero	O
-	O
length	O
cross	O
-	O
linking	O
,	O
are	O
on	O
the	O
other	O
side	O
of	O
TM1	O
-	O
TM2	O
pair	O
.	O

While	O
using	O
the	O
cysteine	O
at	O
position	O
80	O
as	O
the	O
dimeric	O
interface	O
probe	O
,	O
mutations	O
of	O
conserved	O
residues	O
in	O
TM1	O
and	O
TM2	O
(	O
especially	O
Gly32	O
and	O
Gly67	O
to	O
Leu	O
)	O
clearly	O
reduced	O
intermolecular	O
cross	O
-	O
linking	O
.	O

We	O
do	O
not	O
suggest	O
that	O
those	O
residues	O
are	O
directly	O
involved	O
in	O
intermolecular	O
interaction	O
.	O

Rather	O
,	O
we	O
propose	O
that	O
destabilization	O
of	O
the	O
intramolecular	O
TM1	O
-	O
TM2	O
interaction	O
by	O
Gly	O
to	O
Leu	O
substitutions	O
(	O
discussed	O
above	O
)	O
causes	O
an	O
overall	O
conformational	O
change	O
that	O
reduces	O
dimer	O
formation	O
.	O

An	O
Ala81Leu	O
mutation	O
did	O
not	O
reduce	O
cross	O
-	O
linking	O
via	O
Cys80	O
,	O
even	O
though	O
single	O
-	O
cysteine	O
Ala81Cys	O
molecules	O
themselves	O
produced	O
a	O
high	O
level	O
of	O
cross	O
-	O
linking	O
.	O

These	O
results	O
,	O
together	O
with	O
data	O
on	O
Gly32Leu	O
and	O
Gly67Leu	O
mutations	O
,	O
are	O
consistent	O
with	O
our	O
model	O
predicting	O
that	O
helices	O
1	O
and	O
2	O
interact	O
more	O
tightly	O
near	O
the	O
extracellular	O
end	O
and	O
less	O
at	O
the	O
cytoplasmic	O
end	O
.	O

This	O
would	O
give	O
more	O
flexibility	O
to	O
a	O
cysteine	O
at	O
position	O
81	O
and	O
also	O
limit	O
the	O
effect	O
of	O
an	O
Ala81Leu	O
mutation	O
.	O

Location	O
of	O
this	O
residue	O
at	O
the	O
membrane	O
/	O
cytoplasmic	O
border	O
could	O
also	O
make	O
it	O
more	O
accessible	O
to	O
CuP	O
reagent	O
as	O
compared	O
to	O
residues	O
buried	O
in	O
TM	O
domain	O
,	O
thus	O
elevating	O
the	O
efficiency	O
of	O
disulfide	O
formation	O
of	O
the	O
Ala81Cys	O
mutant	O
.	O

Multiple	O
interfaces	O
in	O
tetraspanin	O
molecules	O

In	O
the	O
full	O
-	O
length	O
CD9	O
molecules	O
,	O
the	O
3	O
C	O
-	O
terminal	O
cysteines	O
(	O
Cys87	O
,	O
218	O
and	O
219	O
)	O
located	O
at	O
or	O
in	O
TM3	O
and	O
TM4	O
promoted	O
efficient	O
dimer	O
and	O
even	O
more	O
efficient	O
oligomer	O
formation	O
compared	O
to	O
the	O
3	O
N	O
-	O
terminal	O
cysteines	O
(	O
Figure	O
9	O
)	O
.	O

Cys87	O
alone	O
can	O
be	O
used	O
to	O
capture	O
CD9	O
dimers	O
[	O
25	O
]	O
.	O

These	O
results	O
suggest	O
the	O
existence	O
of	O
two	O
dimeric	O
interfaces	O
in	O
CD9	O
molecule	O
-	O
the	O
TM	O
1	O
-	O
2	O
/	O
1	O
-	O
2	O
interface	O
and	O
the	O
TM	O
3	O
-	O
4	O
/	O
3	O
-	O
4	O
interface	O
(	O
Figure	O
10	O
)	O
.	O

In	O
a	O
TM	O
(	O
1	O
+	O
2	O
)	O
molecule	O
,	O
the	O
destabilization	O
of	O
1	O
-	O
2	O
interaction	O
,	O
e	O
.	O
g	O
.	O
by	O
Gly	O
-	O
-	O
>	O
Leu	O
mutations	O
,	O
would	O
affect	O
the	O
1	O
-	O
2	O
/	O
1	O
-	O
2	O
interface	O
,	O
as	O
discussed	O
above	O
.	O

However	O
,	O
these	O
mutations	O
would	O
not	O
interfere	O
with	O
the	O
3	O
-	O
4	O
/	O
3	O
-	O
4	O
interface	O
in	O
a	O
full	O
-	O
length	O
molecule	O
,	O
which	O
includes	O
Cys87	O
,	O
218	O
and	O
219	O
.	O

Thus	O
,	O
cross	O
-	O
linking	O
of	O
full	O
-	O
length	O
molecules	O
,	O
containing	O
all	O
6	O
cysteine	O
residues	O
,	O
would	O
be	O
unaffected	O
,	O
as	O
seen	O
in	O
Figure	O
8C	O
.	O

Furthermore	O
,	O
wild	O
-	O
type	O
Cys9	O
,	O
Cys78	O
and	O
Cys79	O
are	O
apparently	O
not	O
at	O
the	O
primary	O
1	O
-	O
2	O
/	O
1	O
-	O
2	O
interface	O
.	O

Their	O
relative	O
inefficiency	O
in	O
cross	O
-	O
linking	O
CD9	O
TM	O
(	O
1	O
+	O
2	O
)	O
protein	O
likely	O
reflects	O
weak	O
secondary	O
contacts	O
between	O
the	O
molecules	O
,	O
or	O
possibly	O
random	O
collision	O
events	O
.	O

Such	O
events	O
should	O
be	O
independent	O
of	O
mutations	O
in	O
the	O
conserved	O
Gly	O
residues	O
in	O
TM1	O
and	O
TM2	O
,	O
as	O
was	O
demonstrated	O
in	O
Figure	O
8B	O
.	O

The	O
potential	O
existence	O
of	O
two	O
interfaces	O
in	O
tetraspanin	O
molecules	O
,	O
1	O
-	O
2	O
/	O
1	O
-	O
2	O
and	O
3	O
-	O
4	O
/	O
3	O
-	O
4	O
,	O
should	O
provide	O
enhanced	O
flexibility	O
for	O
forming	O
additional	O
intermolecular	O
contacts	O
.	O

Current	O
understanding	O
of	O
tetraspanin	O
microdomains	O
assumes	O
a	O
few	O
strong	O
,	O
primary	O
homotypic	O
and	O
heterotypic	O
tetraspanin	O
complexes	O
(	O
e	O
.	O
g	O
.	O
CD9	O
-	O
CD9	O
,	O
CD9	O
-	O
CD81	O
,	O
CD151	O
-	O
alpha	O
3	O
integrin	O
,	O
CD81	O
-	O
EWI2	O
)	O
that	O
help	O
bring	O
together	O
various	O
other	O
proteins	O
,	O
forming	O
secondary	O
-	O
type	O
associations	O
.	O

Such	O
properties	O
of	O
tetraspanins	O
may	O
bring	O
signaling	O
molecules	O
such	O
as	O
protein	O
kinase	O
C	O
or	O
phosphatidylinositol	O
4	O
-	O
kinase	O
to	O
the	O
vicinity	O
of	O
integrins	O
[	O
67	O
,	O
68	O
]	O
.	O

The	O
organization	O
of	O
the	O
TM3	O
domain	O
points	O
to	O
a	O
potential	O
role	O
in	O
protein	O
-	O
protein	O
interactions	O
.	O

A	O
motif	O
of	O
Leu	O
-	O
Leu	O
-	O
Glu	O
(	O
Gln	O
)	O
spaced	O
7	O
residues	O
apart	O
(	O
heptad	O
positions	O
a	O
)	O
,	O
with	O
highly	O
conserved	O
residues	O
in	O
two	O
consecutive	O
positions	O
d	O
,	O
poses	O
as	O
a	O
likely	O
interaction	O
module	O
.	O

If	O
responsible	O
for	O
heterologous	O
protein	O
-	O
protein	O
interactions	O
,	O
it	O
would	O
form	O
another	O
distinct	O
interface	O
of	O
tetraspanin	O
molecule	O
.	O

Our	O
preliminary	O
data	O
indicate	O
that	O
replacing	O
the	O
Leu	O
and	O
Glu	O
residues	O
in	O
TM3	O
of	O
CD9	O
with	O
Ala	O
has	O
no	O
effect	O
on	O
cell	O
surface	O
expression	O
of	O
the	O
protein	O
and	O
its	O
dimerization	O
(	O
data	O
not	O
shown	O
)	O
.	O

It	O
remains	O
to	O
be	O
tested	O
if	O
interactions	O
with	O
other	O
proteins	O
will	O
be	O
affected	O
.	O

Similarly	O
,	O
the	O
TM4	O
domain	O
may	O
provide	O
additional	O
contributions	O
to	O
lateral	O
tetraspanin	O
associations	O
.	O

Much	O
higher	O
sequence	O
variability	O
,	O
and	O
the	O
lack	O
of	O
a	O
distinct	O
heptad	O
pattern	O
suggests	O
that	O
TM4	O
is	O
a	O
major	O
contributor	O
to	O
diversity	O
among	O
tetraspanin	O
complexes	O
.	O

Structure	O
-	O
function	O
analysis	O
of	O
TM3	O
and	O
TM4	O
domains	O
in	O
tetraspanins	O
is	O
the	O
subject	O
of	O
ongoing	O
investigation	O
.	O

Conclusion	O

We	O
have	O
defined	O
the	O
TM1	O
-	O
TM2	O
intramolecular	O
interface	O
in	O
tetraspanin	O
CD9	O
,	O
providing	O
evidence	O
for	O
glycines	O
(	O
Gly25	O
and	O
Gly32	O
in	O
TM1	O
,	O
Gly67	O
and	O
Gly74	O
in	O
TM2	O
)	O
packing	O
against	O
apposing	O
bulky	O
aliphatic	O
residues	O
.	O

Second	O
,	O
we	O
mapped	O
an	O
intermolecular	O
CD9	O
interface	O
(	O
involved	O
in	O
CD9	O
homodimer	O
formation	O
)	O
to	O
the	O
vicinity	O
of	O
residues	O
Leu14	O
and	O
Phe17	O
in	O
TM1	O
and	O
Gly77	O
,	O
Gly80	O
and	O
Ala81	O
in	O
TM2	O
.	O

Finally	O
,	O
we	O
provide	O
preliminary	O
evidence	O
that	O
TM3	O
and	O
TM4	O
in	O
CD9	O
may	O
contribute	O
to	O
a	O
second	O
intermolecular	O
interface	O
.	O

Key	O
CD9	O
residues	O
involved	O
in	O
intra	O
-	O
and	O
intermolecular	O
interactions	O
are	O
highly	O
conserved	O
throughout	O
the	O
tetraspanin	O
family	O
,	O
thus	O
suggesting	O
that	O
our	O
findings	O
will	O
apply	O
to	O
most	O
tetraspanins	O
.	O

Methods	O

Materials	O

Cell	O
culture	O
reagents	O
were	O
from	O
Invitrogen	O
(	O
Carlsbad	O
,	O
CA	O
)	O
.	O

2	O
-	O
bromopalmitate	O
was	O
from	O
Fluka	O
(	O
Milwaukee	O
,	O
WI	O
)	O
,	O
N	O
-	O
ethylmaleimide	O
(	O
NEM	O
)	O
and	O
1	O
,	O
10	O
-	O
phenanthroline	O
were	O
from	O
Sigma	O
-	O
Aldrich	O
(	O
St	O
.	O
Louis	O
,	O
MO	O
)	O
,	O
and	O
chemical	O
cross	O
-	O
linkers	O
dithio	O
-	O
bis	O
-	O
maleimidoethane	O
(	O
DTME	O
)	O
and	O
1	O
,	O
4	O
-	O
Bis	O
-	O
maleimidobutane	O
(	O
BMB	O
)	O
were	O
purchased	O
from	O
Pierce	O
Endogen	O
(	O
Rockford	O
,	O
IL	O
)	O
.	O

Triton	O
X	O
-	O
100	O
,	O
protease	O
inhibitor	O
cocktail	O
and	O
FuGENE	O
6	O
transfection	O
reagent	O
were	O
obtained	O
from	O
Roche	O
(	O
Indianapolis	O
,	O
IN	O
)	O
.	O

Restriction	O
endonucleases	O
and	O
Pfu	O
DNA	O
polymerase	O
were	O
obtained	O
New	O
England	O
Biolabs	O
(	O
Beverly	O
,	O
MA	O
)	O
and	O
Stratagene	O
(	O
Carlsbad	O
,	O
CA	O
)	O
,	O
respectively	O
.	O

All	O
other	O
chemicals	O
were	O
purchased	O
from	O
Sigma	O
-	O
Aldrich	O
or	O
Fisher	O
Scientific	O
(	O
Pittsburg	O
,	O
PA	O
)	O
.	O

Sequence	O
analysis	O

Tetraspanin	O
sequences	O
were	O
obtained	O
from	O
SWISS	O
-	O
PROT	O
and	O
GenBank	O
databases	O
.	O

Locus	O
designations	O
,	O
accession	O
numbers	O
and	O
the	O
most	O
commonly	O
used	O
protein	O
names	O
are	O
summarized	O
in	O
Tables	O
1	O
and	O
2	O
.	O

TM	O
segments	O
were	O
delineated	O
by	O
inspection	O
of	O
hydrophobicity	O
profiles	O
,	O
using	O
database	O
annotations	O
and	O
previous	O
analyses	O
of	O
TM	O
sequences	O
as	O
a	O
guide	O
(	O
[	O
28	O
]	O
,	O
M	O
.	O
Hemler	O
,	O
unpublished	O
)	O
,	O
and	O
aligned	O
manually	O
.	O

Residue	O
numbers	O
in	O
human	B
CD9	O
sequence	O
are	O
used	O
a	O
reference	O
point	O
throughout	O
the	O
study	O
.	O

DNA	O
cloning	O
and	O
mutagenesis	O

Sequence	O
encoding	O
CD9	O
protein	O
was	O
cloned	O
into	O
vector	O
pcDNA3	O
(	O
Invitrogen	O
,	O
Carlsbad	O
,	O
CA	O
)	O
and	O
pEGFP	O
-	O
N1	O
(	O
Clontech	O
,	O
Palo	O
Alto	O
,	O
CA	O
)	O
,	O
for	O
expression	O
of	O
untagged	O
and	O
C	O
-	O
terminally	O
GFP	O
-	O
tagged	O
CD9	O
,	O
respectively	O
.	O

pEGFP	O
-	O
N1	O
encoding	O
CD9	O
TM	O
(	O
1	O
+	O
2	O
)	O
-	O
GFP	O
fusion	O
protein	O
was	O
constructed	O
by	O
subcloning	O
DNA	O
for	O
residues	O
1	O
-	O
83	O
of	O
CD9	O
into	O
HindIII	O
and	O
PstI	O
sites	O
of	O
the	O
vector	O
;	O
to	O
introduce	O
the	O
PstI	O
site	O
,	O
codon	O
GTG	O
for	O
Val82	O
was	O
changed	O
to	O
CTG	O
(	O
coding	O
for	O
Ala	O
)	O
.	O

In	O
the	O
resulting	O
fusion	O
protein	O
,	O
there	O
is	O
a	O
13	O
-	O
amino	O
acid	O
linker	O
(	O
with	O
no	O
cysteines	O
)	O
between	O
CD9	O
and	O
GFP	O
.	O

To	O
minimize	O
the	O
low	O
inherent	O
ability	O
of	O
GFP	O
to	O
homodimerize	O
,	O
which	O
could	O
potentially	O
influence	O
the	O
results	O
of	O
CD9	O
cross	O
-	O
linking	O
,	O
we	O
used	O
a	O
monomeric	O
GFP	O
mutant	O
,	O
Leu221	O
-	O
-	O
>	O
Lys	O
[	O
34	O
]	O
,	O
for	O
cross	O
-	O
linking	O
experiments	O
.	O

Mutations	O
were	O
introduced	O
in	O
full	O
-	O
length	O
and	O
TM	O
(	O
1	O
+	O
2	O
)	O
CD9	O
proteins	O
by	O
a	O
PCR	O
-	O
based	O
strategy	O
using	O
mutagenic	O
primers	O
and	O
Pfu	O
DNA	O
polymerase	O
.	O

All	O
mutations	O
were	O
confirmed	O
by	O
DNA	O
sequencing	O
.	O

Protein	O
expression	O
,	O
microscopy	O
,	O
cysteine	O
disulfide	O
cross	O
-	O
linking	O
and	O
Western	O
blotting	O

DNA	O
constructs	O
encoding	O
TM	O
(	O
1	O
+	O
2	O
)	O
-	O
GFP	O
or	O
full	O
-	O
length	O
CD9	O
proteins	O
were	O
transfected	O
into	O
human	B
rhabdomyosarcoma	O
RD	O
cells	O
using	O
the	O
FuGENE	O
6	O
reagent	O
.	O

Cells	O
expressing	O
GFP	O
fusion	O
proteins	O
were	O
analysed	O
by	O
fluorescence	O
microscopy	O
18	O
-	O
28	O
hours	O
post	O
-	O
transfection	O
.	O

Images	O
were	O
captured	O
using	O
Spot	O
1	O
.	O
4	O
.	O
0	O
camera	O
(	O
Diagnostic	O
Instruments	O
,	O
Sterling	O
Heights	O
,	O
MI	O
)	O
attached	O
to	O
Nikon	O
Eclipse	O
TE300	O
microscope	O
.	O

For	O
experiments	O
involving	O
cysteine	O
-	O
mediated	O
cross	O
-	O
linking	O
,	O
cells	O
were	O
treated	O
with	O
50	O
mu	O
M	O
2	O
-	O
BP	O
starting	O
24	O
-	O
26	O
hours	O
post	O
-	O
transfection	O
and	O
continuing	O
for	O
16	O
-	O
18	O
hours	O
.	O

Cross	O
-	O
linking	O
was	O
carried	O
out	O
by	O
incubating	O
cells	O
in	O
HBSM	O
buffer	O
(	O
25	O
mM	O
Hepes	O
-	O
NaOH	O
,	O
pH	O
7	O
.	O
2	O
,	O
150	O
mM	O
NaCl	O
,	O
2	O
mM	O
MgCl2	O
)	O
containing	O
either	O
a	O
)	O
0	O
.	O
6	O
mM	O
CuSO4	O
and	O
1	O
.	O
8	O
mM	O
1	O
,	O
10	O
-	O
phenanthroline	O
(	O
CuP	O
complex	O
)	O
or	O
b	O
)	O
0	O
.	O
2	O
mg	O
/	O
ml	O
homobifunctional	O
cysteine	O
-	O
reactive	O
cross	O
-	O
linker	O
(	O
e	O
.	O
g	O
.	O
DTME	O
)	O
,	O
diluted	O
from	O
fresh	O
10	O
mg	O
/	O
ml	O
solution	O
in	O
DMSO	O
.	O

After	O
incubation	O
for	O
10	O
-	O
15	O
minutes	O
(	O
with	O
CuP	O
)	O
or	O
30	O
-	O
45	O
minutes	O
(	O
with	O
cross	O
-	O
linker	O
)	O
,	O
cells	O
were	O
washed	O
twice	O
for	O
10	O
minutes	O
with	O
HBSM	O
containing	O
10	O
mM	O
NEM	O
to	O
block	O
residual	O
free	O
cysteines	O
.	O

Cells	O
were	O
lysed	O
in	O
HBSM	O
containing	O
1	O
%	O
Triton	O
X	O
-	O
100	O
,	O
0	O
.	O
1	O
%	O
SDS	O
and	O
a	O
cocktail	O
of	O
protease	O
inhibitors	O
with	O
1	O
mM	O
EDTA	O
at	O
4	O
degrees	O
C	O
for	O
45	O
-	O
60	O
minutes	O
.	O

Cell	O
lysate	O
was	O
clarified	O
by	O
centrifugation	O
at	O
14	O
,	O
000	O
x	O
g	O
for	O
15	O
minutes	O
,	O
an	O
aliquot	O
was	O
removed	O
,	O
and	O
proteins	O
from	O
it	O
were	O
precipitated	O
by	O
addition	O
of	O
trichloroacetic	O
acid	O
to	O
10	O
%	O
on	O
ice	O
followed	O
by	O
centrifugation	O
at	O
14	O
,	O
000	O
x	O
g	O
for	O
10	O
minutes	O
.	O

After	O
two	O
washes	O
with	O
ice	O
-	O
cold	O
acetone	O
,	O
protein	O
pellet	O
was	O
solubilized	O
in	O
SDS	O
-	O
PAGE	O
sample	O
buffer	O
without	O
a	O
reducing	O
agent	O
(	O
50	O
mM	O
Tris	O
-	O
HCl	O
,	O
pH	O
6	O
.	O
8	O
,	O
1	O
%	O
SDS	O
,	O
8	O
%	O
glycerol	O
)	O
.	O

In	O
some	O
experiments	O
,	O
CD9	O
protein	O
was	O
immunoprecipitated	O
using	O
monoclonal	O
antibody	O
Alb6	O
(	O
Immunotech	O
,	O
Marseille	O
,	O
France	O
)	O
.	O

Proteins	O
were	O
separated	O
by	O
SDS	O
-	O
PAGE	O
and	O
analyzed	O
by	O
Western	O
blotting	O
using	O
monoclonal	O
antibody	O
JL	O
-	O
8	O
(	O
Clontech	O
)	O
for	O
GFP	O
or	O
Alb6	O
for	O
CD9	O
.	O

Bands	O
from	O
X	O
-	O
ray	O
films	O
were	O
quantitated	O
using	O
GeneTools	O
(	O
TM	O
)	O
software	O
from	O
Syngene	O
(	O
Frederick	O
,	O
MD	O
)	O
.	O

Modeling	O
of	O
TM1	O
-	O
TM2	O
interaction	O

An	O
atomic	O
model	O
of	O
the	O
CD9	O
TM1	O
-	O
TM2	O
dimer	O
was	O
constructed	O
with	O
a	O
Monte	O
Carlo	O
-	O
simulated	O
annealing	O
(	O
MCSA	O
)	O
algorithm	O
[	O
69	O
]	O
.	O

Two	O
idealized	O
alpha	O
-	O
helices	O
corresponding	O
to	O
TM1	O
residues	O
Tyr12	O
through	O
Leu35	O
and	O
TM2	O
residues	O
Gly59	O
through	O
Val82	O
were	O
docked	O
with	O
six	O
orthogonal	O
parameters	O
:	O
three	O
rigid	O
body	O
translations	O
and	O
three	O
rotations	O
.	O

During	O
each	O
step	O
of	O
a	O
MCSA	O
cycle	O
,	O
there	O
was	O
an	O
equal	O
probability	O
of	O
changing	O
either	O
one	O
parameter	O
or	O
all	O
six	O
parameters	O
to	O
random	O
values	O
.	O

A	O
conformation	O
'	O
s	O
energy	O
was	O
calculated	O
in	O
vacuo	O
with	O
the	O
AMBER	O
united	O
-	O
atom	O
force	O
field	O
for	O
van	O
der	O
Waals	O
interactions	O
[	O
70	O
]	O
.	O

The	O
van	O
der	O
Waals	O
term	O
was	O
modified	O
as	O
described	O
by	O
Kuhlman	O
and	O
Baker	O
[	O
71	O
]	O
.	O

If	O
a	O
structure	O
had	O
favorable	O
dimerization	O
energy	O
,	O
the	O
energies	O
of	O
select	O
mutants	O
were	O
calculated	O
.	O

Structures	O
were	O
selected	O
with	O
a	O
novel	O
scoring	O
function	O
that	O
maximizes	O
the	O
Boltzmann	O
probability	O
of	O
dimerization	O
for	O
silent	O
mutations	O
while	O
minimizing	O
the	O
probability	O
for	O
disruptive	O
mutations	O
.	O

Asn18Ser	O
,	O
Gly77Leu	O
,	O
and	O
Gly80Leu	O
were	O
scored	O
as	O
silent	O
mutations	O
while	O
Gly25Leu	O
,	O
Gly32Leu	O
,	O
Gly67Leu	O
,	O
and	O
Gly74Leu	O
were	O
considered	O
to	O
be	O
disruptive	O
.	O

Each	O
MCSA	O
cycle	O
consisted	O
of	O
50	O
,	O
000	O
steps	O
with	O
an	O
exponential	O
temperature	O
decay	O
from	O
10	O
,	O
000	O
to	O
10	O
K	O
.	O

Ten	O
MCSA	O
cycles	O
through	O
global	O
sample	O
space	O
were	O
used	O
to	O
restrict	O
the	O
search	O
area	O
.	O

Parameters	O
were	O
restricted	O
to	O
+	O
/	O
-	O
2	O
standard	O
deviations	O
from	O
their	O
mean	O
value	O
for	O
structures	O
within	O
10	O
kcal	O
of	O
the	O
best	O
structure	O
.	O

MCSA	O
cycles	O
were	O
repeated	O
as	O
described	O
above	O
with	O
additional	O
optimization	O
of	O
chi	O
values	O
:	O
rotamers	O
at	O
the	O
protein	O
-	O
protein	O
interface	O
were	O
optimized	O
with	O
Dead	O
End	O
Elimination	O
[	O
72	O
]	O
,	O
and	O
chi	O
values	O
were	O
further	O
optimized	O
with	O
Monte	O
Carlo	O
.	O

All	O
MCSA	O
cycles	O
converged	O
upon	O
structures	O
that	O
were	O
within	O
a	O
root	O
mean	O
squared	O
deviation	O
(	O
RMSD	O
)	O
of	O
1	O
.	O
5	O
A	O
with	O
the	O
best	O
structure	O
,	O
and	O
structures	O
that	O
scored	O
within	O
5	O
kcal	O
of	O
the	O
best	O
score	O
had	O
an	O
RMSD	O
of	O
less	O
than	O
0	O
.	O
5	O
A	O
with	O
the	O
best	O
structure	O
.	O

List	O
of	O
abbreviations	O

2	O
-	O
BP	O
,	O
2	O
-	O
bromopalmitate	O
;	O
CuP	O
,	O
Cu2	O
+	O
-	O
phenanthroline	O
;	O
DTME	O
,	O
dithio	O
-	O
bis	O
-	O
maleimidoethane	O
;	O
LEL	O
,	O
large	O
extracellular	O
loop	O
;	O
NEM	O
,	O
N	O
-	O
ethylmaleimide	O
;	O
TM	O
,	O
transmembrane	O
(	O
domain	O
)	O
.	O

Authors	O
'	O
contributions	O

OVK	O
carried	O
out	O
sequence	O
comparisons	O
,	O
mutational	O
analysis	O
and	O
cross	O
-	O
linking	O
experiments	O
,	O
and	O
drafted	O
the	O
manuscript	O
.	O

DGM	O
built	O
the	O
TM1	O
-	O
TM2	O
interaction	O
model	O
and	O
contributed	O
to	O
the	O
manuscript	O
.	O

WFD	O
supervised	O
DGM	O
'	O
s	O
work	O
.	O

MEH	O
coordinated	O
the	O
whole	O
study	O
and	O
prepared	O
the	O
final	O
manuscript	O
.	O

Epigenetic	O
inactivation	O
and	O
aberrant	O
transcription	O
of	O
CSMD1	O
in	O
squamous	O
cell	O
carcinoma	O
cell	O
lines	O

Abstract	O

Background	O

The	O
p23	O
.	O
2	O
region	O
of	O
human	B
chromosome	O
8	O
is	O
frequently	O
deleted	O
in	O
several	O
types	O
of	O
epithelial	O
cancer	O
and	O
those	O
deletions	O
appear	O
to	O
be	O
associated	O
with	O
poor	O
prognosis	O
.	O

Cub	O
and	O
Sushi	O
Multiple	O
Domains	O
1	O
(	O
CSMD1	O
)	O
was	O
positionally	O
cloned	O
as	O
a	O
candidate	O
for	O
the	O
8p23	O
suppressor	O
but	O
point	O
mutations	O
in	O
this	O
gene	O
are	O
rare	O
relative	O
to	O
the	O
frequency	O
of	O
allelic	O
loss	O
.	O

In	O
an	O
effort	O
to	O
identify	O
alternative	O
mechanisms	O
of	O
inactivation	O
,	O
we	O
have	O
characterized	O
CSMD1	O
expression	O
and	O
epigenetic	O
modifications	O
in	O
head	O
and	O
neck	O
squamous	O
cell	O
carcinoma	O
cell	O
lines	O
.	O

Results	O

Only	O
one	O
of	O
the	O
20	O
cell	O
lines	O
examined	O
appears	O
to	O
express	O
a	O
structurally	O
normal	O
CSMD1	O
transcript	O
.	O

The	O
rest	O
express	O
transcripts	O
which	O
either	O
lack	O
internal	O
exons	O
,	O
terminate	O
abnormally	O
or	O
initiate	O
at	O
cryptic	O
promoters	O
.	O

None	O
of	O
these	O
truncated	O
transcripts	O
is	O
predicted	O
to	O
encode	O
a	O
functional	O
CSMD1	O
protein	O
.	O

Cell	O
lines	O
that	O
express	O
little	O
or	O
no	O
CSMD1	O
RNA	O
exhibit	O
DNA	O
methylation	O
of	O
a	O
specific	O
region	O
of	O
the	O
CpG	O
island	O
surrounding	O
CSMD1	O
'	O
s	O
first	O
exon	O
.	O

Conclusion	O

Correlating	O
methylation	O
patterns	O
and	O
expression	O
suggests	O
that	O
it	O
is	O
modification	O
of	O
the	O
genomic	O
DNA	O
preceding	O
the	O
first	O
exon	O
that	O
is	O
associated	O
with	O
gene	O
silencing	O
and	O
that	O
methylation	O
of	O
CpG	O
dinucleotides	O
further	O
3	O
'	O
does	O
not	O
contribute	O
to	O
inactivation	O
of	O
the	O
gene	O
.	O

Taken	O
together	O
,	O
the	O
cell	O
line	O
data	O
suggest	O
that	O
epigenetic	O
silencing	O
and	O
aberrant	O
splicing	O
rather	O
than	O
point	O
mutations	O
may	O
be	O
contributing	O
to	O
the	O
reduction	O
in	O
CSMD1	O
expression	O
in	O
squamous	O
cancers	O
.	O

These	O
mechanisms	O
can	O
now	O
serve	O
as	O
a	O
focus	O
for	O
further	O
analysis	O
of	O
primary	O
squamous	O
cancers	O
.	O

Background	O

CUB	O
and	O
Sushi	O
Multiple	O
Domains	O
1	O
(	O
CSMD1	O
)	O
was	O
cloned	O
as	O
a	O
candidate	O
tumor	O
suppressor	O
or	O
progression	O
gene	O
from	O
a	O
region	O
of	O
human	B
chromosome	O
8	O
deleted	O
in	O
tumors	O
of	O
the	O
upper	O
aerodigestive	O
tract	O
,	O
prostate	O
,	O
ovary	O
and	O
bladder	O
[	O
1	O
-	O
7	O
]	O
.	O

Deletion	O
of	O
8p23	O
.	O
2	O
or	O
reduced	O
expression	O
of	O
CSMD1	O
has	O
been	O
associated	O
with	O
poor	O
prognosis	O
in	O
head	O
and	O
neck	O
squamous	O
cell	O
carcinomas	O
and	O
in	O
prostate	O
cancers	O
[	O
2	O
,	O
5	O
,	O
8	O
]	O
.	O

CSMD1	O
,	O
consisting	O
of	O
70	O
exons	O
spread	O
over	O
two	O
megabases	O
of	O
8p23	O
.	O
2	O
,	O
encodes	O
a	O
rare	O
11	O
.	O
5	O
kb	O
transcript	O
most	O
abundantly	O
expressed	O
in	O
the	O
brain	O
[	O
1	O
]	O
.	O

It	O
is	O
the	O
founding	O
member	O
of	O
a	O
novel	O
,	O
evolutionarily	O
highly	O
conserved	O
gene	O
family	O
whose	O
proteins	O
contain	O
multiple	O
domains	O
thought	O
to	O
be	O
sites	O
of	O
protein	O
-	O
protein	O
or	O
protein	O
-	O
ligand	O
interactions	O
and	O
whose	O
structure	O
suggests	O
that	O
they	O
may	O
be	O
transmembrane	O
receptors	O
or	O
adhesion	O
proteins	O
[	O
9	O
,	O
10	O
]	O
.	O

Tumor	O
suppressor	O
genes	O
are	O
expected	O
to	O
be	O
inactivated	O
in	O
cancers	O
either	O
genetically	O
by	O
mutations	O
or	O
epigenetically	O
by	O
modification	O
of	O
their	O
promoters	O
.	O

While	O
CSMD1	O
transcripts	O
are	O
detectable	O
in	O
upper	O
aerodigestive	O
tract	O
epithelium	O
,	O
preliminary	O
analysis	O
of	O
several	O
head	O
and	O
neck	O
squamous	O
cell	O
carcinoma	O
cell	O
lines	O
suggested	O
that	O
CSMD1	O
expression	O
was	O
lost	O
in	O
these	O
lines	O
[	O
1	O
]	O
.	O

Although	O
the	O
region	O
containing	O
CSMD1	O
is	O
frequently	O
deleted	O
in	O
head	O
and	O
neck	O
squamous	O
cell	O
carcinomas	O
and	O
prostatic	O
adenocarcinomas	O
[	O
3	O
,	O
11	O
-	O
15	O
]	O
,	O
point	O
mutations	O
in	O
the	O
gene	O
are	O
relatively	O
rare	O
in	O
primary	O
squamous	O
cancers	O
[	O
16	O
]	O
and	O
in	O
squamous	O
cell	O
carcinoma	O
cell	O
lines	O
(	O
Schmidt	O
,	O
Richter	O
and	O
Scholnick	O
,	O
unpublished	O
)	O
.	O

Nonsense	O
or	O
splice	O
junction	O
mutations	O
in	O
CSMD1	O
have	O
not	O
been	O
reported	O
and	O
not	O
enough	O
is	O
known	O
about	O
the	O
function	O
of	O
the	O
protein	O
to	O
accurately	O
assess	O
the	O
effect	O
of	O
the	O
few	O
missense	O
mutations	O
that	O
have	O
been	O
detected	O
.	O

Thus	O
,	O
if	O
CSMD1	O
is	O
inactivated	O
in	O
tumors	O
,	O
alternative	O
mechanisms	O
for	O
gene	O
silencing	O
must	O
be	O
operating	O
.	O

In	O
this	O
paper	O
,	O
we	O
demonstrate	O
that	O
while	O
most	O
squamous	O
cell	O
carcinoma	O
cell	O
lines	O
do	O
not	O
express	O
full	O
length	O
CSMD1	O
transcripts	O
,	O
nearly	O
all	O
produce	O
abnormal	O
transcripts	O
unlikely	O
to	O
encode	O
functional	O
CSMD1	O
proteins	O
.	O

Methylation	O
of	O
the	O
DNA	O
preceding	O
CSMD1	O
'	O
s	O
first	O
exon	O
is	O
correlated	O
with	O
reduction	O
in	O
the	O
level	O
of	O
expression	O
and	O
cell	O
lines	O
expressing	O
at	O
low	O
levels	O
do	O
not	O
appear	O
to	O
elongate	O
the	O
full	O
11	O
.	O
5	O
kb	O
transcript	O
.	O

Other	O
anomalies	O
of	O
expression	O
include	O
incorrect	O
splicing	O
and	O
the	O
use	O
of	O
cryptic	O
promoters	O
.	O

Our	O
data	O
suggest	O
that	O
activation	O
of	O
these	O
promoters	O
may	O
result	O
from	O
the	O
global	O
demethylation	O
of	O
the	O
genome	O
associated	O
with	O
tumorigenesis	O
(	O
reviewed	O
by	O
Ehrlich	O
[	O
17	O
]	O
)	O
.	O

Taken	O
together	O
these	O
data	O
demonstrate	O
that	O
mechanisms	O
other	O
than	O
point	O
mutation	O
are	O
responsible	O
for	O
the	O
aberrant	O
CSMD1	O
expression	O
in	O
head	O
and	O
neck	O
squamous	O
cell	O
carcinoma	O
cell	O
lines	O
,	O
and	O
these	O
data	O
suggest	O
potential	O
targets	O
for	O
further	O
investigation	O
in	O
primary	O
tumors	O
.	O

Results	O

CSMD1	O
promoter	O
methylation	O
in	O
HNSCC	O
cell	O
lines	O
is	O
correlated	O
with	O
expression	O
levels	O

Preliminary	O
evidence	O
suggested	O
that	O
CSMD1	O
expression	O
is	O
lost	O
in	O
head	O
and	O
neck	O
squamous	O
cell	O
carcinomas	O
[	O
1	O
]	O
but	O
that	O
point	O
mutations	O
were	O
rare	O
[	O
[	O
16	O
]	O
,	O
and	O
Schmidt	O
,	O
Richter	O
and	O
Scholnick	O
,	O
unpublished	O
]	O
.	O

To	O
date	O
,	O
only	O
two	O
of	O
the	O
20	O
cell	O
lines	O
we	O
have	O
tested	O
for	O
CSMD1	O
expression	O
,	O
UPCI	O
:	O
SCC066	O
and	O
PCI	O
-	O
13	O
,	O
express	O
large	O
transcripts	O
initiated	O
at	O
the	O
normal	O
CSMD1	O
promoter	O
.	O

These	O
data	O
suggest	O
that	O
a	O
mechanism	O
(	O
s	O
)	O
other	O
than	O
point	O
mutation	O
must	O
be	O
responsible	O
for	O
the	O
loss	O
of	O
expression	O
.	O

CSMD1	O
'	O
s	O
first	O
exon	O
is	O
embedded	O
in	O
a	O
3	O
.	O
7	O
kb	O
CpG	O
island	O
(	O
data	O
from	O
the	O
UCSC	O
genome	O
browser	O
[	O
18	O
]	O
)	O
suggesting	O
that	O
promoter	O
methylation	O
might	O
epigenetically	O
silence	O
the	O
gene	O
.	O

To	O
test	O
this	O
hypothesis	O
,	O
we	O
surveyed	O
32	O
head	O
and	O
neck	O
cancer	O
cell	O
lines	O
for	O
CSMD1	O
promoter	O
methylation	O
using	O
the	O
Combined	O
Bisulfite	O
Restriction	O
Analysis	O
(	O
COBRA	O
)	O
technique	O
described	O
by	O
Xiong	O
and	O
Laird	O
(	O
Methods	O
)	O
[	O
19	O
]	O
.	O

COBRA	O
analysis	O
of	O
the	O
three	O
amplicons	O
diagrammed	O
in	O
Figure	O
1	O
suggested	O
that	O
28	O
of	O
the	O
cell	O
lines	O
(	O
87	O
%	O
)	O
had	O
more	O
promoter	O
methylation	O
than	O
did	O
normal	O
upper	O
aerodigestive	O
epithelium	O
(	O
data	O
not	O
shown	O
)	O
.	O

We	O
selected	O
nine	O
of	O
these	O
cell	O
lines	O
for	O
high	O
resolution	O
analysis	O
of	O
promoter	O
methylation	O
by	O
sequencing	O
of	O
clones	O
from	O
bisulfite	O
converted	O
genomic	O
DNA	O
.	O

This	O
approach	O
has	O
the	O
distinct	O
advantage	O
of	O
allowing	O
determination	O
of	O
the	O
state	O
of	O
all	O
the	O
CpG	O
dinucleotides	O
within	O
an	O
amplicon	O
on	O
an	O
allele	O
by	O
allele	O
basis	O
.	O

Amplicons	O
1	O
and	O
2	O
have	O
19	O
and	O
20	O
CpG	O
dinucleotides	O
,	O
respectively	O
.	O

Amplicon	O
3	O
could	O
not	O
be	O
examined	O
by	O
this	O
technique	O
because	O
it	O
is	O
unclonable	O
after	O
bisulfite	O
conversion	O
.	O

The	O
methylation	O
data	O
were	O
correlated	O
to	O
CSMD1	O
expression	O
levels	O
as	O
measured	O
by	O
quantitative	O
RT	O
-	O
PCR	O
using	O
an	O
amplicon	O
spanning	O
exons	O
1	O
and	O
2	O
(	O
Methods	O
)	O
.	O

A	O
pool	O
of	O
cDNA	O
from	O
five	O
normal	O
oropharyngeal	O
epithelium	O
specimens	O
served	O
as	O
a	O
basis	O
for	O
comparison	O
to	O
the	O
cell	O
lines	O
.	O

Our	O
data	O
from	O
amplicon	O
1	O
demonstrate	O
a	O
clear	O
relationship	O
between	O
methylation	O
and	O
the	O
level	O
of	O
expression	O
(	O
Figure	O
2	O
)	O
.	O

The	O
bisulfite	O
sequencing	O
data	O
confirm	O
that	O
there	O
is	O
relatively	O
little	O
promoter	O
methylation	O
in	O
normal	O
tissue	O
(	O
clones	O
1	O
-	O
20	O
,	O
Figure	O
2A	O
)	O
.	O

This	O
is	O
also	O
the	O
case	O
in	O
cell	O
line	O
UPCI	O
:	O
SCC066	O
which	O
expresses	O
a	O
large	O
CSMD1	O
transcript	O
from	O
the	O
normal	O
promoter	O
at	O
a	O
level	O
approximately	O
33	O
%	O
of	O
that	O
of	O
normal	O
tissue	O
(	O
clones	O
32	O
-	O
39	O
,	O
Figure	O
2B	O
)	O
.	O

PCI	O
-	O
13	O
,	O
our	O
highest	O
expressing	O
line	O
at	O
125	O
%	O
of	O
normal	O
epithelium	O
,	O
displays	O
two	O
distinct	O
patterns	O
of	O
promoter	O
methylation	O
with	O
some	O
clones	O
heavily	O
methylated	O
(	O
clones	O
21	O
-	O
24	O
,	O
and	O
30	O
)	O
and	O
others	O
with	O
no	O
methylation	O
(	O
clones	O
25	O
-	O
39	O
and	O
31	O
;	O
Figure	O
2B	O
)	O
.	O

This	O
pattern	O
is	O
consistent	O
with	O
either	O
heterozygosity	O
for	O
methylation	O
or	O
the	O
co	O
-	O
existence	O
of	O
2	O
distinct	O
populations	O
within	O
the	O
cell	O
line	O
,	O
one	O
heavily	O
methylated	O
and	O
one	O
unmethylated	O
.	O

We	O
cannot	O
distinguish	O
between	O
these	O
two	O
possibilities	O
using	O
the	O
currently	O
available	O
data	O
.	O

The	O
remaining	O
cell	O
lines	O
express	O
CSMD1	O
at	O
a	O
level	O
half	O
that	O
of	O
UPCI	O
:	O
SCC066	O
or	O
less	O
(	O
ranging	O
from	O
17	O
%	O
to	O
1	O
%	O
of	O
normal	O
epithelium	O
)	O
and	O
they	O
exhibit	O
considerably	O
greater	O
methylation	O
of	O
amplicon	O
1	O
(	O
clones	O
40	O
-	O
76	O
,	O
Figure	O
2C	O
)	O
.	O

Cell	O
lines	O
with	O
more	O
amplicon	O
1	O
methylation	O
tend	O
to	O
express	O
the	O
gene	O
at	O
lower	O
levels	O
but	O
the	O
relationship	O
is	O
not	O
strictly	O
quantitative	O
(	O
Figure	O
2C	O
)	O
.	O

In	O
contrast	O
,	O
our	O
data	O
revealed	O
no	O
relationship	O
between	O
expression	O
level	O
and	O
methylation	O
of	O
amplicon	O
2	O
(	O
located	O
towards	O
the	O
3	O
'	O
end	O
of	O
exon	O
1	O
,	O
Figure	O
1	O
)	O
.	O

For	O
example	O
,	O
all	O
of	O
the	O
10	O
clones	O
of	O
amplicon	O
2	O
sequenced	O
from	O
PCI	O
-	O
13	O
were	O
methylated	O
at	O
19	O
or	O
20	O
of	O
their	O
20	O
CpG	O
dinucleotides	O
.	O

UPCI	O
:	O
SCC066	O
,	O
on	O
the	O
other	O
hand	O
,	O
has	O
nearly	O
no	O
methylation	O
in	O
amplicon	O
2	O
with	O
only	O
a	O
single	O
methylated	O
CpG	O
dinucleotide	O
detected	O
in	O
one	O
clone	O
out	O
of	O
the	O
nine	O
sequenced	O
.	O

Amplicon	O
2	O
ranges	O
from	O
completely	O
unmethylated	O
to	O
heavily	O
methylated	O
in	O
the	O
seven	O
remaining	O
cell	O
lines	O
(	O
data	O
not	O
shown	O
)	O
.	O

Low	O
transcript	O
levels	O
are	O
accompanied	O
by	O
a	O
failure	O
to	O
elongate	O
the	O
full	O
CSMD1	O
transcript	O

On	O
the	O
surface	O
,	O
the	O
quantitative	O
RT	O
-	O
PCR	O
data	O
presented	O
in	O
Figure	O
2	O
suggest	O
that	O
the	O
cell	O
lines	O
we	O
consider	O
low	O
expressing	O
might	O
still	O
have	O
up	O
to	O
17	O
%	O
of	O
the	O
normal	O
level	O
of	O
CSMD1	O
transcript	O
.	O

A	O
survey	O
of	O
20	O
cell	O
lines	O
using	O
a	O
battery	O
of	O
RT	O
-	O
PCR	O
primer	O
pairs	O
located	O
throughout	O
the	O
11	O
.	O
5	O
kb	O
transcript	O
reveals	O
that	O
this	O
is	O
not	O
the	O
case	O
.	O

These	O
lines	O
included	O
OKF6	O
-	O
TERT1	O
,	O
a	O
TERT	O
immortalized	O
,	O
p16	O
deficient	O
but	O
untransformed	O
oral	O
keratinocyte	O
cell	O
line	O
[	O
20	O
]	O
.	O

Our	O
data	O
suggest	O
that	O
the	O
low	O
expressing	O
cell	O
lines	O
shown	O
in	O
Figure	O
2C	O
express	O
considerably	O
more	O
of	O
the	O
5	O
'	O
end	O
of	O
the	O
11	O
.	O
5	O
kb	O
transcript	O
than	O
they	O
do	O
exons	O
further	O
3	O
'	O
,	O
a	O
phenomenon	O
well	O
illustrated	O
by	O
cell	O
line	O
PCI	O
-	O
100	O
.	O

This	O
line	O
expresses	O
the	O
exon	O
1	O
/	O
exon	O
2	O
amplicon	O
at	O
approximately	O
15	O
%	O
of	O
the	O
level	O
of	O
normal	O
epithelium	O
.	O

In	O
contrast	O
,	O
we	O
had	O
previously	O
reported	O
that	O
CSMD1	O
transcripts	O
were	O
not	O
detectable	O
in	O
this	O
line	O
by	O
combined	O
RT	O
-	O
PCR	O
and	O
Southern	O
blotting	O
using	O
three	O
sets	O
of	O
intron	O
spanning	O
primers	O
[	O
1	O
]	O
.	O

The	O
most	O
5	O
'	O
of	O
those	O
amplicons	O
spans	O
exons	O
9	O
through	O
26	O
.	O

Analysis	O
with	O
additional	O
primer	O
pairs	O
resolves	O
this	O
apparent	O
paradox	O
by	O
demonstrating	O
that	O
the	O
amount	O
of	O
transcript	O
declines	O
sharply	O
and	O
reproducibly	O
as	O
one	O
examines	O
progressively	O
more	O
3	O
'	O
exons	O
(	O
Figure	O
3	O
)	O
.	O

The	O
same	O
effect	O
is	O
seen	O
using	O
either	O
oligo	O
-	O
dT	O
or	O
random	O
hexamer	O
primed	O
cDNA	O
.	O

No	O
transcript	O
of	O
this	O
structure	O
has	O
been	O
detected	O
in	O
normal	O
epithelium	O
nor	O
have	O
we	O
detected	O
any	O
sequence	O
alterations	O
in	O
PCI	O
-	O
100	O
that	O
would	O
explain	O
why	O
the	O
full	O
transcript	O
is	O
not	O
expressed	O
.	O

It	O
is	O
not	O
clear	O
whether	O
PCI	O
-	O
100	O
produces	O
a	O
small	O
number	O
of	O
discrete	O
size	O
classes	O
of	O
transcript	O
,	O
if	O
individual	O
transcripts	O
terminate	O
at	O
random	O
points	O
within	O
the	O
very	O
large	O
introns	O
in	O
this	O
part	O
of	O
the	O
gene	O
(	O
the	O
first	O
10	O
introns	O
average	O
~	O
150	O
kb	O
in	O
length	O
)	O
,	O
or	O
if	O
the	O
short	O
transcripts	O
result	O
from	O
the	O
elevated	O
activity	O
of	O
a	O
previously	O
undetected	O
posttranscriptional	O
control	O
mechanism	O
.	O

Inactivation	O
of	O
CSMD1	O
by	O
aberrant	O
splicing	O

Two	O
cell	O
lines	O
,	O
UPCI	O
:	O
SCC066	O
and	O
PCI	O
-	O
13	O
,	O
express	O
large	O
CSMD1	O
transcripts	O
initiated	O
at	O
the	O
normal	O
promoter	O
.	O

Subsequent	O
finer	O
scale	O
analysis	O
demonstrates	O
that	O
PCI	O
-	O
13	O
'	O
s	O
transcript	O
lacks	O
exons	O
4	O
and	O
5	O
,	O
resulting	O
in	O
a	O
frameshift	O
-	O
induced	O
nonsense	O
codon	O
in	O
exon	O
6	O
(	O
Figure	O
4	O
)	O
.	O

Sequencing	O
of	O
the	O
PCI	O
-	O
13	O
RT	O
-	O
PCR	O
product	O
demonstrates	O
the	O
direct	O
juxtaposition	O
of	O
wildtype	O
exons	O
3	O
and	O
6	O
and	O
that	O
the	O
transcript	O
contains	O
no	O
novel	O
sequences	O
or	O
splices	O
that	O
would	O
prevent	O
the	O
frameshift	O
.	O

UPCI	O
:	O
SCC066	O
produces	O
two	O
transcripts	O
,	O
a	O
normal	O
one	O
that	O
includes	O
exons	O
4	O
and	O
5	O
and	O
another	O
that	O
lacks	O
them	O
(	O
Figure	O
4	O
)	O
.	O

RT	O
-	O
PCR	O
of	O
human	B
fetal	O
brain	O
cDNA	O
reveals	O
very	O
low	O
levels	O
of	O
an	O
RT	O
-	O
PCR	O
product	O
corresponding	O
in	O
size	O
to	O
that	O
expected	O
from	O
the	O
internally	O
deleted	O
transcript	O
.	O

This	O
band	O
is	O
not	O
readily	O
visible	O
at	O
the	O
exposure	O
used	O
for	O
Figure	O
4A	O
.	O

We	O
have	O
not	O
detected	O
a	O
similar	O
sized	O
PCR	O
product	O
in	O
RNA	O
from	O
oropharyngeal	O
epithelium	O
but	O
this	O
may	O
reflect	O
the	O
fact	O
that	O
CSMD1	O
transcripts	O
are	O
~	O
10x	O
less	O
abundant	O
in	O
oropharyngeal	O
epithelium	O
than	O
they	O
are	O
in	O
fetal	O
brain	O
(	O
data	O
not	O
shown	O
)	O
.	O

The	O
transcripts	O
lacking	O
exons	O
4	O
and	O
5	O
appear	O
to	O
result	O
from	O
aberrant	O
splicing	O
rather	O
than	O
somatic	O
deletion	O
of	O
these	O
two	O
exons	O
or	O
mutations	O
of	O
their	O
splicing	O
consensus	O
sequences	O
.	O

Exons	O
4	O
and	O
5	O
can	O
be	O
amplified	O
from	O
PCI	O
-	O
13	O
genomic	O
DNA	O
and	O
sequencing	O
of	O
those	O
PCR	O
products	O
demonstrates	O
that	O
both	O
their	O
coding	O
sequences	O
and	O
consensus	O
splice	O
sites	O
are	O
wildtype	O
.	O

Activation	O
of	O
cryptic	O
promoters	O
in	O
cancer	O
cell	O
lines	O

The	O
RT	O
-	O
PCR	O
survey	O
revealed	O
a	O
second	O
transcriptional	O
anomaly	O
exhibited	O
by	O
4	O
cell	O
lines	O
:	O
SCC9	O
,	O
041	O
,	O
PCI	O
-	O
1	O
and	O
PCI	O
-	O
2	O
.	O

Like	O
PCI	O
-	O
100	O
,	O
these	O
lines	O
express	O
low	O
levels	O
of	O
the	O
very	O
5	O
'	O
end	O
of	O
the	O
transcript	O
and	O
even	O
lower	O
levels	O
of	O
more	O
3	O
'	O
exons	O
within	O
the	O
first	O
half	O
of	O
the	O
transcript	O
.	O

However	O
,	O
these	O
lines	O
are	O
distinct	O
in	O
expressing	O
higher	O
levels	O
of	O
the	O
3	O
'	O
half	O
of	O
the	O
transcript	O
,	O
suggesting	O
that	O
alternative	O
promoters	O
in	O
the	O
middle	O
of	O
the	O
gene	O
may	O
be	O
used	O
.	O

SCC9	O
was	O
chosen	O
for	O
further	O
study	O
because	O
it	O
expresses	O
the	O
3	O
'	O
half	O
of	O
the	O
transcript	O
at	O
a	O
level	O
dramatically	O
higher	O
than	O
normal	O
for	O
oropharyngeal	O
epithelium	O
.	O

Northern	O
blotting	O
detects	O
a	O
comparatively	O
abundant	O
6	O
.	O
4	O
kb	O
truncated	O
transcript	O
as	O
well	O
as	O
smaller	O
amounts	O
of	O
an	O
8	O
.	O
7	O
kb	O
transcript	O
in	O
SCC9	O
(	O
Figure	O
5A	O
)	O
.	O

The	O
other	O
three	O
cell	O
lines	O
express	O
their	O
truncated	O
CSMD1	O
transcripts	O
at	O
lower	O
levels	O
(	O
data	O
not	O
shown	O
)	O
.	O

Sequence	O
analysis	O
of	O
CSMD1	O
cDNA	O
clones	O
from	O
SCC9	O
demonstrates	O
that	O
many	O
transcripts	O
are	O
improperly	O
spliced	O
,	O
resulting	O
in	O
retention	O
of	O
intronic	O
sequences	O
and	O
/	O
or	O
deletion	O
of	O
exonic	O
sequences	O
(	O
data	O
not	O
shown	O
)	O
.	O

In	O
particular	O
,	O
retention	O
of	O
sequences	O
from	O
intron	O
40	O
is	O
common	O
.	O

The	O
high	O
frequency	O
of	O
faulty	O
splicing	O
may	O
explain	O
the	O
broadness	O
of	O
the	O
6	O
.	O
4	O
kb	O
CSMD1	O
band	O
in	O
Figure	O
5A	O
and	O
suggests	O
that	O
the	O
8	O
.	O
7	O
kb	O
transcript	O
may	O
also	O
be	O
incompletely	O
or	O
improperly	O
spliced	O
.	O

5	O
'	O
RACE	O
[	O
21	O
]	O
reveals	O
that	O
the	O
SCC9	O
message	O
is	O
initiated	O
just	O
upstream	O
of	O
an	O
Alu	O
element	O
in	O
intron	O
36	O
(	O
Figure	O
5B	O
)	O
.	O

Only	O
the	O
5	O
'	O
-	O
most	O
120	O
base	O
pairs	O
of	O
the	O
Alu	O
element	O
are	O
present	O
in	O
the	O
genome	O
.	O

RT	O
-	O
PCR	O
using	O
a	O
forward	O
primer	O
specific	O
for	O
the	O
novel	O
sequences	O
of	O
the	O
SCC9	O
transcript	O
(	O
prm1904	O
,	O
cgtttagttcgacacacttc	O
)	O
demonstrates	O
that	O
cell	O
lines	O
041	O
,	O
PCI	O
-	O
1	O
and	O
PCI	O
-	O
2	O
do	O
not	O
initiate	O
their	O
CSMD1	O
transcripts	O
at	O
the	O
same	O
point	O
,	O
suggesting	O
that	O
other	O
cryptic	O
promoters	O
are	O
active	O
in	O
these	O
lines	O
.	O

The	O
sequence	O
of	O
this	O
novel	O
exon	O
has	O
been	O
entered	O
in	O
Genbank	O
as	O
accession	O
number	O
DQ093422	O
.	O

DNA	O
methyltransferase	O
inhibitors	O
activate	O
the	O
same	O
cryptic	O
promoter	O
used	O
in	O
cell	O
line	O
SCC9	O

Expression	O
from	O
epigenetically	O
silenced	O
promoters	O
can	O
sometimes	O
be	O
restored	O
by	O
treatment	O
with	O
inhibitors	O
of	O
DNA	O
methyltransferase	O
or	O
histone	O
deacetylase	O
activity	O
(	O
[	O
22	O
]	O
)	O
.	O

We	O
selected	O
two	O
low	O
expressing	O
cell	O
lines	O
with	O
promoter	O
methylation	O
,	O
UPCI	O
:	O
SCC104	O
and	O
094	O
,	O
for	O
treatment	O
with	O
various	O
concentrations	O
of	O
5	O
-	O
azacytidine	O
or	O
5	O
-	O
aza	O
-	O
2	O
'	O
-	O
deoxycytidine	O
(	O
5	O
-	O
aza	O
-	O
dC	O
)	O
as	O
well	O
as	O
combinations	O
of	O
either	O
of	O
those	O
drugs	O
with	O
the	O
histone	O
deacetylase	O
inhibitor	O
trichostatin	O
A	O
.	O

These	O
treatments	O
did	O
not	O
reactivate	O
the	O
silenced	O
CSMD1	O
promoter	O
.	O

COBRA	O
analysis	O
of	O
genomic	O
DNA	O
from	O
the	O
treated	O
cells	O
suggested	O
that	O
the	O
drugs	O
did	O
not	O
robustly	O
affect	O
methylation	O
of	O
the	O
CSMD1	O
promoter	O
even	O
at	O
levels	O
high	O
enough	O
to	O
be	O
toxic	O
to	O
the	O
cells	O
.	O

These	O
experiments	O
did	O
however	O
shed	O
light	O
on	O
the	O
cryptic	O
promoter	O
used	O
in	O
SCC9	O
cells	O
and	O
on	O
the	O
interpretation	O
of	O
experiments	O
using	O
methyltransferase	O
inhibitors	O
.	O

Treatment	O
of	O
cell	O
line	O
094	O
with	O
relatively	O
high	O
doses	O
of	O
5aza	O
-	O
dC	O
results	O
in	O
the	O
expression	O
of	O
the	O
3	O
'	O
end	O
of	O
the	O
CSMD1	O
transcript	O
.	O

This	O
transcript	O
was	O
not	O
detected	O
in	O
control	O
094	O
cells	O
undergoing	O
mock	O
drug	O
treatment	O
(	O
Figure	O
6	O
)	O
nor	O
was	O
it	O
detected	O
in	O
094	O
cells	O
growing	O
under	O
normal	O
culture	O
conditions	O
(	O
data	O
not	O
shown	O
)	O
.	O

RT	O
-	O
PCR	O
of	O
cDNA	O
from	O
drug	O
-	O
treated	O
094	O
cells	O
using	O
the	O
primer	O
developed	O
from	O
the	O
novel	O
5	O
'	O
exon	O
of	O
SCC9	O
'	O
s	O
truncated	O
transcript	O
(	O
prm1904	O
,	O
see	O
above	O
)	O
yielded	O
a	O
product	O
identical	O
in	O
size	O
to	O
that	O
amplified	O
from	O
SCC9	O
cDNA	O
(	O
Figure	O
6	O
)	O
.	O

The	O
identity	O
of	O
the	O
product	O
was	O
confirmed	O
by	O
DNA	O
sequencing	O
which	O
also	O
revealed	O
that	O
the	O
drug	O
-	O
induced	O
094	O
transcript	O
was	O
more	O
faithfully	O
spliced	O
than	O
the	O
transcript	O
expressed	O
in	O
SCC9	O
(	O
data	O
not	O
shown	O
)	O
.	O

Discussion	O

Our	O
data	O
clearly	O
demonstrate	O
that	O
expression	O
of	O
normal	O
CSMD1	O
transcripts	O
is	O
rare	O
in	O
head	O
and	O
neck	O
squamous	O
cell	O
carcinoma	O
cell	O
lines	O
.	O

Of	O
the	O
HNSCC	O
cell	O
lines	O
examined	O
,	O
only	O
UPCI	O
:	O
SCC066	O
appears	O
to	O
express	O
a	O
normal	O
transcript	O
from	O
the	O
expected	O
promoter	O
.	O

Even	O
that	O
cell	O
line	O
produces	O
a	O
second	O
species	O
of	O
aberrantly	O
spliced	O
transcript	O
lacking	O
internal	O
exons	O
.	O

Our	O
data	O
suggest	O
that	O
epigenetic	O
modification	O
of	O
the	O
DNA	O
5	O
'	O
of	O
the	O
transcription	O
start	O
site	O
may	O
contribute	O
to	O
the	O
down	O
-	O
regulation	O
of	O
CSMD1	O
.	O

In	O
addition	O
,	O
a	O
low	O
level	O
of	O
expression	O
appears	O
to	O
be	O
associated	O
with	O
production	O
of	O
prematurely	O
terminated	O
transcripts	O
.	O

This	O
degree	O
of	O
complexity	O
might	O
be	O
expected	O
from	O
a	O
2	O
megabase	O
,	O
70	O
exon	O
gene	O
.	O

Methylation	O
of	O
a	O
specific	O
region	O
of	O
the	O
CpG	O
island	O
,	O
-	O
395	O
to	O
-	O
112	O
bp	O
relative	O
to	O
the	O
transcriptional	O
start	O
site	O
(	O
amplicon	O
1	O
)	O
,	O
appears	O
to	O
be	O
correlated	O
with	O
the	O
activity	O
of	O
the	O
normal	O
CSMD1	O
promoter	O
.	O

In	O
contrast	O
,	O
methylation	O
of	O
amplicon	O
2	O
,	O
located	O
within	O
the	O
first	O
exon	O
,	O
shows	O
no	O
such	O
relationship	O
.	O

Our	O
data	O
suggest	O
that	O
the	O
relationship	O
between	O
the	O
amount	O
of	O
methylation	O
in	O
amplicon	O
1	O
and	O
the	O
level	O
of	O
expression	O
may	O
not	O
be	O
strictly	O
quantitative	O
.	O

Differences	O
between	O
cell	O
lines	O
with	O
amplicon	O
1	O
methylation	O
could	O
arise	O
through	O
a	O
number	O
of	O
mechanisms	O
,	O
for	O
example	O
,	O
variations	O
in	O
the	O
levels	O
of	O
transcription	O
factors	O
between	O
cell	O
lines	O
.	O

In	O
cases	O
where	O
there	O
is	O
considerable	O
heterogeneity	O
in	O
the	O
methylation	O
pattern	O
within	O
a	O
cell	O
line	O
like	O
PCI	O
-	O
100	O
,	O
alleles	O
with	O
less	O
methylation	O
may	O
be	O
expressed	O
at	O
higher	O
levels	O
than	O
those	O
more	O
heavily	O
methylated	O
(	O
compare	O
clones	O
51	O
and	O
52	O
to	O
clone	O
58	O
in	O
Figure	O
2C	O
)	O
.	O

Alternatively	O
,	O
the	O
presence	O
of	O
methylation	O
in	O
amplicon	O
1	O
could	O
be	O
a	O
qualitative	O
but	O
not	O
strictly	O
quantitative	O
indicator	O
of	O
methylation	O
of	O
a	O
critical	O
segment	O
of	O
the	O
promoter	O
not	O
discovered	O
in	O
this	O
study	O
.	O

The	O
normal	O
CSMD1	O
promoter	O
was	O
not	O
reactivated	O
by	O
drugs	O
that	O
inhibit	O
DNA	O
methyltransferases	O
and	O
histone	O
deacetylases	O
,	O
nor	O
did	O
the	O
drugs	O
abolish	O
CSMD1	O
promoter	O
methylation	O
,	O
even	O
at	O
toxic	O
doses	O
.	O

Not	O
all	O
genes	O
with	O
promoter	O
methylation	O
respond	O
to	O
such	O
treatments	O
[	O
23	O
]	O
.	O

These	O
drug	O
treatments	O
did	O
,	O
however	O
,	O
provide	O
a	O
potential	O
explanation	O
for	O
the	O
use	O
of	O
a	O
normally	O
cryptic	O
promoter	O
by	O
cell	O
line	O
SCC9	O
.	O

The	O
CSMD1	O
transcript	O
in	O
this	O
line	O
is	O
initiated	O
near	O
a	O
partial	O
Alu	O
element	O
.	O

5	O
-	O
aza	O
-	O
dC	O
treatment	O
of	O
cell	O
line	O
094	O
activates	O
the	O
same	O
cryptic	O
promoter	O
.	O

This	O
suggests	O
that	O
cryptic	O
promoters	O
may	O
be	O
naturally	O
activated	O
by	O
general	O
hypomethylation	O
of	O
the	O
genome	O
in	O
cancer	O
cells	O
and	O
the	O
subsequent	O
release	O
of	O
repetitive	O
elements	O
from	O
epigenetic	O
repression	O
(	O
reviewed	O
by	O
Ehrlich	O
[	O
17	O
]	O
)	O
.	O

The	O
SCC9	O
transcript	O
does	O
not	O
appear	O
to	O
encode	O
a	O
functional	O
protein	O
but	O
,	O
with	O
a	O
very	O
large	O
gene	O
like	O
CSMD1	O
,	O
there	O
is	O
a	O
potential	O
for	O
some	O
abnormally	O
initiated	O
transcripts	O
to	O
encode	O
truncated	O
proteins	O
with	O
dominant	O
negative	O
properties	O
.	O

The	O
second	O
ramification	O
of	O
this	O
finding	O
is	O
for	O
the	O
interpretation	O
of	O
data	O
obtained	O
by	O
treating	O
cells	O
with	O
methyltransferase	O
inhibitors	O
.	O

Detection	O
of	O
CSMD1	O
transcripts	O
solely	O
with	O
primers	O
mapping	O
to	O
the	O
3	O
'	O
end	O
of	O
the	O
gene	O
could	O
have	O
been	O
erroneously	O
interpreted	O
as	O
representing	O
reactivation	O
of	O
the	O
normal	O
promoter	O
.	O

It	O
seems	O
imperative	O
that	O
such	O
experiments	O
demonstrate	O
that	O
transcripts	O
detected	O
after	O
drug	O
treatment	O
are	O
actually	O
initiated	O
at	O
the	O
normal	O
promoter	O
.	O

Aberrant	O
splicing	O
also	O
appears	O
to	O
play	O
a	O
role	O
in	O
the	O
production	O
of	O
defective	O
CSMD1	O
transcripts	O
.	O

Loss	O
of	O
splicing	O
fidelity	O
has	O
been	O
proposed	O
as	O
a	O
characteristic	O
of	O
cancer	O
cells	O
[	O
24	O
,	O
25	O
]	O
and	O
this	O
would	O
be	O
consistent	O
with	O
the	O
variety	O
of	O
misspliced	O
transcripts	O
we	O
detected	O
from	O
SCC9	O
.	O

However	O
,	O
the	O
removal	O
of	O
exons	O
4	O
and	O
5	O
from	O
the	O
CSMD1	O
transcript	O
in	O
PCI	O
-	O
13	O
may	O
reflect	O
a	O
more	O
specific	O
phenomenon	O
than	O
a	O
general	O
inability	O
to	O
splice	O
large	O
introns	O
;	O
this	O
line	O
is	O
still	O
capable	O
of	O
splicing	O
large	O
introns	O
as	O
evidenced	O
by	O
its	O
successful	O
splicing	O
of	O
exon	O
3	O
to	O
exon	O
6	O
,	O
eliminating	O
an	O
intron	O
of	O
over	O
666	O
kb	O
.	O

The	O
failure	O
to	O
include	O
exons	O
4	O
and	O
5	O
may	O
be	O
due	O
to	O
inactivation	O
of	O
a	O
splicing	O
enhancer	O
in	O
intron	O
3	O
,	O
or	O
to	O
less	O
efficient	O
splicing	O
due	O
to	O
the	O
fact	O
that	O
exons	O
4	O
and	O
5	O
do	O
not	O
begin	O
with	O
the	O
consensus	O
G	O
residue	O
(	O
Figure	O
4B	O
)	O
[	O
26	O
]	O
.	O

Conclusion	O

Taken	O
together	O
,	O
our	O
data	O
suggest	O
that	O
CSMD1	O
function	O
is	O
lost	O
in	O
head	O
and	O
neck	O
squamous	O
cell	O
carcinoma	O
cell	O
lines	O
through	O
a	O
variety	O
of	O
mechanisms	O
other	O
than	O
point	O
mutagenesis	O
.	O

Epigenetic	O
modifications	O
of	O
amplicon	O
1	O
and	O
defective	O
splicing	O
appear	O
to	O
be	O
fruitful	O
areas	O
to	O
explore	O
in	O
primary	O
head	O
and	O
neck	O
squamous	O
cancers	O
.	O

Methods	O

Cell	O
lines	O
and	O
tissue	O
samples	O

DNA	O
from	O
HNSCC	O
cell	O
lines	O
UMSCC9	O
,	O
UMSCC35	O
,	O
UMSCC37	O
,	O
UMSCC38	O
,	O
UMSCC45	O
,	O
UMSCC49	O
,	O
UMSCC65	O
,	O
UMSCC68	O
,	O
and	O
UMSCC76	O
was	O
provided	O
by	O
Dr	O
.	O
Thomas	O
Carey	O
,	O
University	O
of	O
Michigan	O
[	O
27	O
]	O
.	O

Dr	O
.	O
Ruud	O
Brakenhoff	O
,	O
Vrije	O
Universitat	O
,	O
provided	O
cell	O
lines	O
040	O
,	O
041	O
,	O
and	O
094	O
[	O
28	O
]	O
;	O
Dr	O
.	O
Theresa	O
Whiteside	O
,	O
University	O
of	O
Pittsburgh	O
,	O
provided	O
cell	O
lines	O
PCI	O
-	O
1	O
,	O
PCI	O
-	O
2	O
,	O
PCI	O
-	O
4B	O
,	O
PCI	O
-	O
13	O
,	O
PCI	O
-	O
30	O
,	O
PCI	O
-	O
50	O
,	O
PCI	O
-	O
51	O
,	O
PCI	O
-	O
52	O
,	O
PCI	O
-	O
100	O
[	O
29	O
]	O
,	O
SCC4	O
,	O
SCC9	O
[	O
30	O
,	O
31	O
]	O
,	O
and	O
UPCI	O
:	O
SCC068	O
,	O
UPCI	O
:	O
SCC74	O
,	O
UPCI	O
:	O
SCC104	O
,	O
UPCI	O
:	O
SCC182	O
,	O
UPCI	O
:	O
SCC203	O
,	O
and	O
UPCI	O
:	O
SCC220	O
[	O
developed	O
by	O
Dr	O
.	O
Susanne	O
Gollin	O
,	O
University	O
of	O
Pittsburgh	O
,	O
32	O
]	O
.	O

Dr	O
.	O
Gollin	O
provided	O
cell	O
lines	O
UPCI	O
:	O
SCC056	O
,	O
UPCI	O
:	O
SCC066	O
,	O
and	O
UPCI	O
:	O
SCC114	O
[	O
14	O
,	O
16	O
,	O
32	O
]	O
.	O

The	O
immortal	O
but	O
untransformed	O
keratinocyte	O
line	O
OKF6	O
-	O
TERT1	O
was	O
obtained	O
from	O
Dr	O
.	O
James	O
Rheinwald	O
,	O
Harvard	O
University	O
[	O
20	O
]	O
.	O

Normal	O
oropharyngeal	O
epithelium	O
was	O
isolated	O
from	O
discarded	O
tissue	O
from	O
uvulopalatopharyngop	O
(	O
UPPP	O
)	O
collected	O
anonymously	O
with	O
the	O
approval	O
of	O
the	O
Washington	O
University	O
Human	B
Studies	O
Committee	O
.	O

Cell	O
Culture	O
and	O
Tissue	O
Preparation	O

Squamous	O
cell	O
carcinoma	O
cell	O
lines	O
were	O
grown	O
in	O
DMEM	O
or	O
DMEM	O
:	O
F	O
-	O
12	O
,	O
1	O
:	O
1	O
Mixture	O
(	O
BioWhittaker	O
)	O
containing	O
10	O
%	O
fetal	O
bovine	B
serum	O
(	O
Sigma	O
)	O
.	O

DMEM	O
medium	O
was	O
supplemented	O
with	O
1X	O
MEM	O
Nonessential	O
Amino	O
Acids	O
(	O
BioWhittaker	O
)	O
.	O

Upper	O
aerodigestive	O
tract	O
epithelium	O
was	O
separated	O
from	O
the	O
rest	O
of	O
the	O
UPPP	O
specimen	O
by	O
digestion	O
with	O
Dispase	O
II	O
(	O
Roche	O
)	O
using	O
a	O
protocol	O
adapted	O
from	O
Oda	O
and	O
Watson	O
[	O
33	O
]	O
.	O

Nucleic	O
acid	O
preparation	O
and	O
bisulfite	O
conversion	O

Genomic	O
DNA	O
was	O
isolated	O
by	O
using	O
either	O
Nucleospin	O
Tissue	O
kits	O
(	O
Clontech	O
)	O
,	O
QIAamp	O
DNA	O
Blood	O
Mini	O
kits	O
(	O
Qiagen	O
)	O
or	O
Trizol	O
(	O
Invitrogen	O
)	O
according	O
to	O
the	O
manufacturers	O
'	O
instructions	O
.	O

Total	O
RNA	O
isolation	O
,	O
synthesis	O
of	O
first	O
strand	O
cDNA	O
,	O
RT	O
-	O
PCR	O
and	O
5	O
'	O
RACE	O
PCR	O
were	O
performed	O
essentially	O
as	O
previously	O
described	O
[	O
1	O
]	O
.	O

Poly	O
-	O
A	O
+	O
RNA	O
for	O
Northern	O
blotting	O
was	O
selected	O
from	O
total	O
RNA	O
using	O
Oligotex	O
beads	O
(	O
Qiagen	O
)	O
.	O

Northern	O
blotting	O
and	O
hybridization	O
were	O
performed	O
as	O
previously	O
described	O
[	O
1	O
]	O
.	O

cDNA	O
synthesis	O
was	O
primed	O
using	O
oligo	O
dT	O
or	O
random	O
primers	O
and	O
extended	O
by	O
either	O
Thermoscript	O
or	O
Superscript	O
III	O
reverse	O
transcriptase	O
(	O
Invitrogen	O
)	O
.	O

PCR	O
was	O
run	O
in	O
Perkin	O
-	O
Elmer	O
480	O
or	O
Applied	O
Biosystems	O
9700	O
thermal	O
cyclers	O
for	O
35	O
cycles	O
unless	O
otherwise	O
noted	O
.	O

Images	O
of	O
ethidium	O
bromide	O
stained	O
gels	O
were	O
captured	O
with	O
a	O
Gel	O
-	O
Doc	O
imaging	O
station	O
(	O
Biorad	O
)	O
.	O

Quantitative	O
PCR	O
was	O
run	O
in	O
an	O
Applied	O
Biosystems	O
5700	O
thermal	O
cycler	O
using	O
SYBR	O
Green	O
Master	O
Mix	O
(	O
Applied	O
Biosystems	O
)	O
.	O

Primers	O
prm2426	O
(	O
gtgtggagtatctgcagaca	O
)	O
and	O
prm2427	O
(	O
ctggactaagcctccacagt	O
)	O
were	O
used	O
to	O
amplify	O
a	O
132	O
base	O
segment	O
spanning	O
CSMD1	O
'	O
s	O
first	O
and	O
second	O
exons	O
.	O

An	O
amplicon	O
from	O
human	B
18S	O
RNA	O
was	O
used	O
as	O
a	O
basis	O
for	O
comparisons	O
across	O
cell	O
lines	O
(	O
primers	O
prm2396	O
,	O
ttcggaactgaggccatgat	O
and	O
prm2397	O
,	O
tttcgctctggtccgtcttg	O
)	O
.	O

Calculations	O
were	O
performed	O
using	O
the	O
Delta	O
Delta	O
Ct	O
method	O
in	O
GeneAmp	O
5700	O
SDS	O
software	O
(	O
version	O
1	O
.	O
3	O
)	O
and	O
Microsoft	O
Excel	O
.	O

Quantitation	O
was	O
based	O
on	O
the	O
average	O
values	O
obtained	O
from	O
duplicate	O
reactions	O
.	O

The	O
level	O
of	O
CSMD1	O
expression	O
in	O
normal	O
oropharyngeal	O
epithelium	O
was	O
determined	O
from	O
pooled	O
cDNA	O
from	O
five	O
UPPP	O
specimens	O
.	O

We	O
used	O
the	O
CpGenome	O
DNA	O
Modification	O
kit	O
(	O
Intergen	O
)	O
for	O
bisulfite	O
conversion	O
of	O
the	O
genomic	O
DNA	O
according	O
to	O
the	O
manufacturer	O
'	O
s	O
protocol	O
,	O
with	O
the	O
following	O
exception	O
.	O

Incubation	O
of	O
the	O
conversion	O
reaction	O
was	O
carried	O
out	O
in	O
a	O
thermal	O
cycler	O
for	O
six	O
cycles	O
each	O
consisting	O
of	O
three	O
minutes	O
at	O
94	O
degrees	O
C	O
followed	O
by	O
three	O
hours	O
at	O
50	O
degrees	O
C	O
(	O
Christina	O
Menke	O
and	O
Paul	O
Goodfellow	O
,	O
personal	O
communication	O
)	O
.	O

Analysis	O
of	O
CSMD1	O
Promoter	O
Methylation	O

Methylation	O
of	O
three	O
segments	O
of	O
the	O
CSMD1	O
CpG	O
island	O
was	O
examined	O
using	O
the	O
Combined	O
Bisulfite	O
Restriction	O
Analysis	O
technique	O
(	O
COBRA	O
)	O
[	O
19	O
]	O
.	O

All	O
three	O
segments	O
were	O
amplified	O
by	O
using	O
the	O
nested	O
primers	O
and	O
PCR	O
conditions	O
listed	O
in	O
Table	O
1	O
.	O

Amplicon	O
1	O
extends	O
from	O
-	O
395	O
to	O
-	O
112	O
bp	O
,	O
amplicon	O
2	O
from	O
+	O
175	O
to	O
+	O
396	O
bp	O
,	O
and	O
amplicon	O
3	O
from	O
+	O
398	O
to	O
+	O
718	O
bp	O
relative	O
to	O
the	O
first	O
base	O
of	O
the	O
transcript	O
.	O

A	O
small	O
region	O
surrounding	O
the	O
transcription	O
start	O
site	O
(	O
-	O
111	O
to	O
+	O
174	O
bp	O
)	O
could	O
not	O
be	O
examined	O
because	O
no	O
PCR	O
primers	O
could	O
be	O
designed	O
from	O
its	O
extremely	O
GC	O
-	O
rich	O
sequence	O
.	O

The	O
first	O
round	O
PCR	O
used	O
2	O
mu	O
l	O
of	O
bisulfite	O
converted	O
genomic	O
DNA	O
in	O
a	O
final	O
volume	O
of	O
10	O
mu	O
l	O
.	O

Subsequent	O
amplifications	O
with	O
nested	O
primers	O
used	O
4	O
mu	O
l	O
of	O
first	O
round	O
product	O
as	O
template	O
in	O
reactions	O
with	O
a	O
final	O
volume	O
of	O
20	O
mu	O
l	O
.	O

All	O
PCR	O
was	O
carried	O
out	O
for	O
35	O
cycles	O
.	O

A	O
portion	O
of	O
the	O
second	O
round	O
PCR	O
product	O
was	O
run	O
on	O
a	O
1	O
.	O
5	O
%	O
agarose	O
gel	O
,	O
stained	O
with	O
ethidium	O
bromide	O
,	O
and	O
quantified	O
using	O
the	O
ImageQuant	O
software	O
package	O
(	O
v1	O
.	O
2	O
for	O
Macintosh	O
,	O
Molecular	O
Dynamics	O
)	O
so	O
that	O
equal	O
amounts	O
of	O
each	O
could	O
be	O
used	O
in	O
restriction	O
digests	O
.	O

Restriction	O
digests	O
for	O
COBRA	O
were	O
performed	O
with	O
either	O
BstU	O
I	O
or	O
Taq	O
alpha	O
I	O
(	O
5	O
or	O
10	O
units	O
per	O
reaction	O
,	O
respectively	O
;	O
New	O
England	O
Biolabs	O
)	O
for	O
4	O
hours	O
in	O
a	O
final	O
volume	O
of	O
10	O
mu	O
l	O
.	O

Taq	O
alpha	O
I	O
digests	O
were	O
performed	O
only	O
when	O
no	O
methylation	O
was	O
detected	O
with	O
BstU	O
I	O
.	O

BstU	O
I	O
digests	O
also	O
included	O
an	O
internal	O
control	O
DNA	O
fragment	O
to	O
confirm	O
complete	O
digestion	O
.	O

This	O
DNA	O
fragment	O
contains	O
a	O
single	O
BstU	O
I	O
site	O
and	O
was	O
amplified	O
from	O
a	O
cloned	O
CSMD1	O
cDNA	O
using	O
primers	O
prm2020	O
(	O
agatcccccagtgtctccct	O
)	O
and	O
prm2021	O
(	O
actgctggtgccgtggtaat	O
)	O
.	O

The	O
control	O
PCR	O
product	O
is	O
1019	O
bp	O
long	O
and	O
is	O
digested	O
to	O
two	O
fragments	O
of	O
605	O
and	O
414	O
bp	O
by	O
BstU	O
I	O
.	O

Digestion	O
products	O
were	O
fractionated	O
on	O
a	O
10	O
%	O
polyacrylamide	O
gel	O
,	O
stained	O
with	O
ethidium	O
bromide	O
,	O
and	O
visualized	O
with	O
a	O
Gel	O
-	O
Doc	O
video	O
imaging	O
workstation	O
(	O
Bio	O
-	O
Rad	O
)	O
.	O

High	O
resolution	O
analysis	O
of	O
methylation	O
was	O
performed	O
by	O
sequence	O
analysis	O
of	O
individual	O
clones	O
from	O
amplicons	O
1	O
and	O
2	O
.	O

DNA	O
from	O
amplicon	O
3	O
proved	O
unclonable	O
and	O
gel	O
electrophoresis	O
suggests	O
that	O
its	O
very	O
AT	O
rich	O
sequence	O
results	O
in	O
a	O
bent	O
DNA	O
configuration	O
.	O

PCR	O
products	O
were	O
purified	O
using	O
the	O
Nucleospin	O
Extraction	O
columns	O
(	O
Clontech	O
)	O
and	O
inserted	O
into	O
the	O
pCR2	O
.	O
1	O
-	O
TOPO	O
vector	O
using	O
the	O
TOPO	O
TA	O
Cloning	O
kit	O
(	O
Invitrogen	O
)	O
according	O
to	O
the	O
manufacturer	O
'	O
s	O
instructions	O
.	O

Plasmid	O
DNA	O
from	O
individual	O
colonies	O
was	O
isolated	O
using	O
the	O
Nucleospin	O
Plus	O
Plasmid	O
Miniprep	O
kit	O
(	O
Clontech	O
)	O
and	O
sequenced	O
with	O
a	O
reverse	O
vector	O
primer	O
(	O
agcggataacaatttcacac	O
)	O
using	O
fluorescence	O
based	O
sequencing	O
with	O
Big	O
Dye	O
Terminator	O
mix	O
(	O
Applied	O
Biosystems	O
)	O
.	O

Treatment	O
of	O
cultured	O
cells	O
with	O
DNA	O
methyltransferase	O
inhibitors	O

Cell	O
line	O
094	O
was	O
treated	O
with	O
5	O
-	O
aza	O
-	O
2	O
'	O
-	O
deoxycytidine	O
(	O
5aza	O
-	O
dC	O
)	O
(	O
Sigma	O
)	O
dissolved	O
in	O
DMSO	O
.	O

Two	O
100	O
mm	O
cell	O
culture	O
dishes	O
containing	O
5	O
x	O
105	O
cells	O
were	O
established	O
for	O
each	O
of	O
the	O
drug	O
concentrations	O
tested	O
.	O

Cells	O
were	O
grown	O
for	O
72	O
hours	O
in	O
media	O
containing	O
DMEM	O
:	O
F	O
-	O
12	O
,	O
1	O
:	O
1	O
Mixture	O
(	O
BioWhittaker	O
)	O
with	O
1X	O
MEM	O
Nonessential	O
Amino	O
Acids	O
(	O
BioWhittaker	O
)	O
and	O
10	O
%	O
fetal	O
bovine	B
serum	O
and	O
then	O
switched	O
to	O
media	O
containing	O
5aza	O
-	O
dC	O
at	O
concentrations	O
of	O
0	O
mu	O
m	O
,	O
5	O
mu	O
M	O
,	O
25	O
mu	O
M	O
,	O
or	O
100	O
mu	O
M	O
.	O

Cells	O
were	O
fed	O
daily	O
for	O
4	O
-	O
5	O
days	O
and	O
then	O
both	O
plates	O
were	O
harvested	O
in	O
3	O
ml	O
of	O
Trizol	O
(	O
Invitrogen	O
)	O
for	O
isolation	O
of	O
RNA	O
and	O
DNA	O
according	O
to	O
the	O
manufacturer	O
'	O
s	O
instructions	O
.	O

RT	O
-	O
PCR	O
used	O
for	O
detection	O
of	O
CSMD1	O
transcripts	O
in	O
these	O
treated	O
cells	O
was	O
run	O
for	O
40	O
cycles	O
.	O

Abbreviations	O

5aza	O
-	O
dC	O
=	O
5	O
-	O
aza	O
-	O
2	O
'	O
deoxycytidine	O
,	O
COBRA	O
=	O
Combined	O
Bisulfite	O
Restriction	O
Analysis	O
,	O
CSMD1	O
=	O
Cub	O
and	O
sushi	O
multiple	O
domains	O
1	O
,	O
HNSCC	O
=	O
head	O
&	O
neck	O
squamous	O
cell	O
carcinoma	O
,	O
RT	O
-	O
PCR	O
=	O
reverse	O
transcription	O
-	O
polymerase	O
chain	O
reaction	O
,	O
SCC	O
=	O
squamous	O
cell	O
carcinoma	O
,	O
UPPP	O
=	O
uvulopalatopharyngop	O
.	O

Competing	O
interests	O

The	O
author	O
(	O
s	O
)	O
declare	O
that	O
they	O
have	O
no	O
competing	O
interests	O

Authors	O
'	O
contributions	O

TMR	O
performed	O
the	O
DNA	O
methylation	O
analysis	O
,	O
and	O
parts	O
of	O
the	O
transcript	O
survey	O
.	O

BDT	O
cloned	O
and	O
characterized	O
the	O
novel	O
first	O
exon	O
expressed	O
in	O
cell	O
line	O
SCC9	O
.	O

SBS	O
performed	O
parts	O
of	O
the	O
transcript	O
survey	O
and	O
characterized	O
the	O
deletion	O
of	O
exons	O
4	O
and	O
5	O
in	O
PCI	O
-	O
13	O
.	O

All	O
three	O
authors	O
participated	O
in	O
the	O
analysis	O
of	O
the	O
data	O
and	O
in	O
the	O
writing	O
of	O
the	O
manuscript	O
.	O

Plasma	O
D	O
-	O
dimer	O
concentration	O
in	O
patients	B
with	O
systemic	O
sclerosis	O

Abstract	O

Background	O

Systemic	O
sclerosis	O
(	O
SSc	O
)	O
is	O
an	O
autoimmune	O
disorder	O
of	O
the	O
connective	O
tissue	O
characterized	O
by	O
widespread	O
vascular	O
lesions	O
and	O
fibrosis	O
.	O

Little	O
is	O
known	O
so	O
far	O
on	O
the	O
activation	O
of	O
the	O
hemostatic	O
and	O
fibrinolytic	O
systems	O
in	O
SSc	O
,	O
and	O
most	O
preliminary	O
evidences	O
are	O
discordant	O
.	O

Methods	O

To	O
verify	O
whether	O
SSc	O
patients	B
might	O
display	O
a	O
prothrombotic	O
condition	O
,	O
plasma	O
D	O
-	O
dimer	O
was	O
assessed	O
in	O
28	O
consecutive	O
SSc	O
patients	B
and	O
in	O
33	O
control	O
subjects	O
,	O
matched	O
for	O
age	O
,	O
sex	O
and	O
environmental	O
habit	O
.	O

Results	O
and	O
discussion	O

When	O
compared	O
to	O
healthy	O
controls	O
,	O
geometric	O
mean	O
and	O
95	O
%	O
confidence	O
interval	O
(	O
IC95	O
%	O
)	O
of	O
plasma	O
D	O
-	O
dimer	O
were	O
significantly	O
increased	O
in	O
SSc	O
patients	B
(	O
362	O
ng	O
/	O
mL	O
,	O
IC	O
95	O
%	O
:	O
361	O
-	O
363	O
ng	O
/	O
mL	O
vs	O
229	O
ng	O
/	O
mL	O
,	O
IC95	O
%	O
:	O
228	O
-	O
231	O
ng	O
/	O
mL	O
,	O
p	O
=	O
0	O
.	O
005	O
)	O
.	O

After	O
stratifying	O
SSc	O
patients	B
according	O
to	O
disease	O
subset	O
,	O
no	O
significant	O
differences	O
were	O
observed	O
between	O
those	O
with	O
limited	O
cutaneous	O
pattern	O
and	O
controls	O
,	O
whereas	O
patients	B
with	O
diffuse	O
cutaneous	O
pattern	O
displayed	O
substantially	O
increased	O
values	O
.	O

No	O
correlation	O
was	O
found	O
between	O
plasma	O
D	O
-	O
dimer	O
concentration	O
and	O
age	O
,	O
sex	O
,	O
autoantibody	O
pattern	O
,	O
serum	O
creatinine	O
,	O
erythrosedimentation	O
rate	O
,	O
nailfold	O
videocapillaroscopic	O
pattern	O
and	O
pulmonary	O
involvement	O
.	O

Conclusion	O

We	O
demonstrated	O
that	O
SSc	O
patients	B
with	O
diffuse	O
subset	O
are	O
characterized	O
by	O
increased	O
plasma	O
D	O
-	O
dimer	O
values	O
,	O
reflecting	O
a	O
potential	O
activation	O
of	O
both	O
the	O
hemostatic	O
and	O
fibrinolytic	O
cascades	O
,	O
which	O
might	O
finally	O
predispose	O
these	O
patients	B
to	O
thrombotic	O
complications	O
.	O

Background	O

Systemic	O
sclerosis	O
(	O
SSc	O
)	O
is	O
an	O
autoimmune	O
disorder	O
of	O
the	O
connective	O
tissue	O
characterized	O
by	O
widespread	O
vascular	O
lesions	O
and	O
fibrosis	O
.	O

In	O
SSc	O
,	O
vasospasm	O
causes	O
frequent	O
episodes	O
of	O
reperfusion	O
injury	O
and	O
free	O
radical	O
-	O
mediated	O
endothelial	O
dysfunction	O
,	O
which	O
might	O
finally	O
influence	O
the	O
onset	O
of	O
local	O
thrombotic	O
complications	O
.	O

The	O
characteristic	O
vascular	O
involvement	O
affects	O
primarily	O
small	O
arteries	O
and	O
capillaries	O
,	O
causing	O
reduced	O
blood	O
flow	O
and	O
tissue	O
ischemia	O
and	O
supporting	O
the	O
typical	O
clinical	O
manifestations	O
of	O
this	O
unique	O
autoimmune	O
disorder	O
[	O
1	O
]	O
.	O

However	O
,	O
mechanisms	O
involved	O
in	O
the	O
endothelial	O
injury	O
are	O
as	O
yet	O
elusive	O
and	O
most	O
biochemical	O
evidences	O
are	O
often	O
inconclusive	O
or	O
controversial	O
.	O

Some	O
earlier	O
investigations	O
suggested	O
that	O
SSc	O
patients	B
might	O
be	O
characterized	O
by	O
a	O
procoagulant	O
state	O
,	O
reporting	O
depressed	O
basal	O
and	O
stimulated	O
fibrinolytic	O
activity	O
,	O
while	O
others	O
studies	O
have	O
reported	O
normal	O
plasma	O
fibrinolytic	O
activity	O
and	O
normal	O
skin	O
and	O
plasma	O
tissue	O
plasminogen	O
activator	O
(	O
tPA	O
)	O
levels	O
[	O
2	O
-	O
4	O
]	O
.	O

It	O
has	O
been	O
also	O
reported	O
that	O
the	O
lack	O
of	O
a	O
consistent	O
and	O
homogenous	O
increase	O
of	O
some	O
fibrinolytic	O
markers	O
,	O
in	O
the	O
presence	O
of	O
normal	O
levels	O
of	O
antithrombin	O
,	O
might	O
indirectly	O
highlight	O
an	O
impairment	O
of	O
the	O
heparan	O
sulphate	O
-	O
antithrombin	O
system	O
,	O
which	O
would	O
finally	O
promote	O
thrombin	O
generation	O
[	O
3	O
]	O
.	O

Conversely	O
,	O
Cerinic	O
and	O
colleagues	O
provided	O
evidence	O
that	O
fibrinolysis	O
might	O
be	O
impaired	O
in	O
SSc	O
,	O
as	O
shown	O
by	O
reduced	O
D	O
-	O
dimer	O
and	O
decreased	O
levels	O
of	O
plasminogen	O
activator	O
inhibitor	O
[	O
4	O
]	O
.	O

In	O
synthesis	O
,	O
there	O
are	O
no	O
conclusive	O
evidences	O
on	O
the	O
activity	O
of	O
the	O
hemostatic	O
and	O
fibrinolytic	O
pathways	O
in	O
SSc	O
so	O
far	O
.	O

D	O
-	O
dimer	O
,	O
a	O
breakdown	O
product	O
of	O
cross	O
-	O
linked	O
fibrin	O
,	O
was	O
proven	O
useful	O
for	O
the	O
diagnostic	O
evaluation	O
of	O
several	O
thrombotic	O
disorders	O
.	O

Moreover	O
,	O
an	O
increased	O
D	O
-	O
dimer	O
value	O
in	O
plasma	O
is	O
a	O
reliable	O
marker	O
of	O
a	O
systemic	O
prothrombotic	O
state	O
,	O
likely	O
superior	O
to	O
alternative	O
fibrinolytic	O
markers	O
,	O
and	O
its	O
measurement	O
might	O
be	O
helpful	O
in	O
predicting	O
or	O
preventing	O
thrombotic	O
events	O
in	O
the	O
single	O
patient	B
[	O
5	O
]	O
.	O

Therefore	O
,	O
to	O
investigate	O
whether	O
SSc	O
patients	B
might	O
be	O
characterized	O
by	O
a	O
potential	O
prothrombotic	O
condition	O
,	O
plasma	O
D	O
-	O
dimer	O
vales	O
were	O
measured	O
in	O
a	O
subset	O
of	O
SSc	O
patients	B
,	O
compared	O
with	O
those	O
of	O
a	O
healthy	O
matched	O
control	O
population	O
and	O
further	O
associated	O
with	O
SSc	O
disease	O
subset	O
.	O

Methods	O

Plasma	O
D	O
-	O
dimer	O
was	O
measured	O
in	O
28	O
consecutive	O
SSc	O
patients	B
(	O
2	O
males	O
and	O
26	O
females	O
;	O
mean	O
age	O
50	O
+	O
/	O
-	O
15	O
years	O
,	O
17	O
with	O
limited	O
and	O
11	O
with	O
diffuse	O
disease	O
patterns	O
)	O
,	O
who	O
fulfilled	O
the	O
American	O
Rheumatism	O
Association	O
'	O
s	O
criteria	O
for	O
the	O
diagnosis	O
of	O
SSc	O
[	O
6	O
]	O
and	O
in	O
33	O
control	O
subjects	O
,	O
matched	O
for	O
age	O
(	O
48	O
+	O
/	O
-	O
13	O
years	O
)	O
,	O
sex	O
(	O
3	O
males	O
,	O
30	O
females	O
)	O
and	O
environmental	O
habit	O
,	O
recruited	O
among	O
healthy	O
hospital	O
personnel	O
.	O

Samples	O
were	O
collected	O
in	O
the	O
morning	O
;	O
all	O
subjects	O
were	O
in	O
a	O
fasted	O
state	O
.	O

The	O
research	O
was	O
carried	O
out	O
according	O
to	O
the	O
principles	O
of	O
the	O
Declaration	O
of	O
Helsinki	O
and	O
an	O
informed	O
consent	O
for	O
testing	O
was	O
received	O
from	O
all	O
individuals	O
recruited	O
to	O
the	O
study	O
.	O

Blood	O
was	O
collected	O
after	O
an	O
overnight	O
fast	O
into	O
siliconized	O
vacuum	O
tubes	O
,	O
containing	O
0	O
.	O
105	O
mol	O
/	O
l	O
sodium	O
citrate	O
(	O
Becton	O
-	O
Dickinson	O
,	O
Oxford	O
,	O
UK	O
)	O
.	O

Samples	O
were	O
gently	O
mixed	O
and	O
centrifuged	O
for	O
10	O
min	O
at	O
15	O
degrees	O
C	O
at	O
1500	O
x	O
g	O
;	O
plasma	O
was	O
separated	O
and	O
stored	O
in	O
aliquots	O
at	O
-	O
70	O
degrees	O
C	O
until	O
measurement	O
.	O

Plasma	O
D	O
-	O
dimer	O
was	O
measured	O
employing	O
Vidas	O
DD	O
,	O
a	O
rapid	O
and	O
quantitative	O
automated	O
enzyme	O
linked	O
immunosorbent	O
assay	O
with	O
fluorescent	O
detection	O
,	O
on	O
the	O
Mini	O
Vidas	O
immunoanalyzer	O
(	O
bioMerieux	O
,	O
Marcy	O
l	O
'	O
Etoile	O
,	O
France	O
)	O
.	O

Analytical	O
imprecision	O
,	O
expressed	O
in	O
terms	O
of	O
mean	O
inter	O
-	O
assay	O
coefficient	O
of	O
variation	O
(	O
CV	O
)	O
,	O
was	O
quoted	O
by	O
the	O
manufacturer	O
as	O
being	O
lower	O
than	O
5	O
%	O
.	O

Significance	O
of	O
differences	O
between	O
samples	O
was	O
assessed	O
,	O
following	O
logarithmic	O
conversion	O
of	O
data	O
,	O
by	O
parametric	O
tests	O
(	O
Student	O
'	O
s	O
t	O
-	O
test	O
,	O
ANOVA	O
test	O
,	O
Pearson	O
'	O
s	O
correlation	O
)	O
;	O
the	O
level	O
of	O
statistical	O
significance	O
was	O
set	O
at	O
p	O
<	O
0	O
.	O
05	O
.	O

Results	O
and	O
discussion	O

When	O
compared	O
to	O
healthy	O
controls	O
,	O
geometric	O
mean	O
and	O
95	O
%	O
confidence	O
interval	O
(	O
IC95	O
%	O
)	O
of	O
plasma	O
D	O
-	O
dimer	O
concentration	O
appeared	O
significantly	O
increased	O
in	O
SSc	O
patients	B
(	O
362	O
ng	O
/	O
mL	O
,	O
IC	O
95	O
%	O
:	O
361	O
-	O
363	O
ng	O
/	O
mL	O
vs	O
229	O
ng	O
/	O
mL	O
,	O
IC95	O
%	O
:	O
228	O
-	O
231	O
ng	O
/	O
mL	O
,	O
p	O
=	O
0	O
.	O
005	O
)	O
.	O

After	O
stratifying	O
SSc	O
patients	B
according	O
to	O
disease	O
subset	O
,	O
no	O
significant	O
differences	O
were	O
observed	O
between	O
those	O
with	O
limited	O
cutaneous	O
pattern	O
(	O
lcSSc	O
)	O
and	O
controls	O
(	O
geometric	O
mean	O
plasma	O
D	O
-	O
dimer	O
:	O
283	O
ng	O
/	O
mL	O
,	O
IC95	O
%	O
:	O
282	O
-	O
285	O
ng	O
/	O
mL	O
;	O
p	O
=	O
0	O
.	O
61	O
)	O
,	O
whereas	O
patients	B
with	O
diffuse	O
cutaneous	O
pattern	O
(	O
dcSSc	O
)	O
displayed	O
substantially	O
increased	O
values	O
(	O
geometric	O
mean	O
plasma	O
D	O
-	O
dimer	O
:	O
538	O
ng	O
/	O
mL	O
,	O
IC95	O
%	O
:	O
536	O
-	O
539	O
ng	O
/	O
mL	O
;	O
p	O
<	O
0	O
.	O
001	O
)	O
.	O

Additionally	O
,	O
patients	B
with	O
active	O
disease	O
,	O
as	O
evaluated	O
according	O
to	O
the	O
European	O
Scleroderma	O
Study	O
Group	O
criteria	O
[	O
7	O
]	O
,	O
displayed	O
higher	O
D	O
-	O
dimer	O
levels	O
as	O
compared	O
to	O
patients	B
with	O
inactive	O
disease	O
(	O
p	O
=	O
0	O
.	O
027	O
)	O
.	O

As	O
further	O
shown	O
in	O
table	O
1	O
,	O
D	O
-	O
dimer	O
concentration	O
correlated	O
significantly	O
with	O
the	O
modified	O
Rodnan	O
total	O
skin	O
score	O
(	O
TSS	O
)	O
and	O
the	O
forced	O
vital	O
capacity	O
(	O
FVC	O
)	O
.	O

No	O
correlation	O
was	O
observed	O
between	O
plasma	O
D	O
-	O
dimer	O
concentration	O
and	O
age	O
,	O
sex	O
,	O
autoantibody	O
pattern	O
,	O
serum	O
creatinine	O
,	O
erythrosedimentation	O
rate	O
,	O
nailfold	O
videocapillaroscopic	O
pattern	O
and	O
pulmonary	O
involvement	O
,	O
ascertained	O
according	O
to	O
the	O
score	O
proposed	O
by	O
Medsger	O
et	O
al	O
[	O
8	O
]	O
.	O

The	O
pathogenesis	O
of	O
the	O
endothelial	O
injury	O
in	O
SSc	O
is	O
as	O
yet	O
elusive	O
and	O
most	O
biochemical	O
evidences	O
are	O
often	O
inconclusive	O
or	O
controversial	O
.	O

Although	O
endothelial	O
cell	O
apoptosis	O
and	O
impaired	O
angiogenesis	O
have	O
received	O
major	O
attention	O
among	O
the	O
mechanisms	O
involved	O
in	O
the	O
characteristic	O
vascular	O
dysfunction	O
,	O
recent	O
studies	O
provided	O
clear	O
evidence	O
of	O
a	O
significant	O
activation	O
of	O
the	O
coagulation	O
cascade	O
,	O
resulting	O
in	O
a	O
procoagulant	O
state	O
that	O
might	O
finally	O
raise	O
the	O
relative	O
risk	O
of	O
thrombotic	O
events	O
in	O
these	O
patients	B
.	O

In	O
SSc	O
,	O
the	O
peculiar	O
vascular	O
lesions	O
and	O
fibrosis	O
were	O
claimed	O
to	O
impair	O
endothelial	O
function	O
,	O
as	O
suggested	O
by	O
impairment	O
of	O
fibrinolysis	O
and	O
activation	O
of	O
the	O
coagulation	O
pathway	O
.	O

The	O
following	O
loss	O
of	O
the	O
balance	O
between	O
fibrinolysis	O
and	O
coagulation	O
might	O
finally	O
contribute	O
to	O
vessel	O
engulfment	O
with	O
fibrin	O
and	O
breakdown	O
of	O
vessel	O
patency	O
,	O
symptomatic	O
of	O
a	O
tendency	O
to	O
the	O
development	O
of	O
thrombotic	O
complications	O
in	O
this	O
particular	O
autoimmune	O
disorder	O
[	O
4	O
]	O
.	O

D	O
-	O
dimer	O
is	O
a	O
heterogeneous	O
class	O
of	O
end	O
-	O
stage	O
degradation	O
products	O
that	O
directly	O
reflect	O
the	O
level	O
of	O
lysed	O
cross	O
-	O
linked	O
fibrin	O
,	O
occurring	O
in	O
vivo	O
with	O
a	O
wide	O
range	O
of	O
molecular	O
weights	O
.	O

Therefore	O
,	O
D	O
-	O
dimer	O
is	O
a	O
well	O
-	O
recognized	O
marker	O
of	O
a	O
systemic	O
prothrombotic	O
state	O
[	O
5	O
,	O
9	O
]	O
and	O
appears	O
a	O
strong	O
,	O
consistent	O
predictor	O
of	O
cardiovascular	O
events	O
in	O
the	O
general	O
population	O
,	O
in	O
patients	B
with	O
cardiovascular	O
disease	O
and	O
in	O
other	O
pathologies	O
characterized	O
by	O
an	O
increased	O
risk	O
of	O
thrombosis	O
[	O
10	O
-	O
12	O
]	O
.	O

Accordingly	O
,	O
D	O
-	O
dimer	O
measurement	O
could	O
be	O
reliably	O
used	O
as	O
an	O
initial	O
screening	O
test	O
in	O
patients	B
with	O
clinically	O
suspected	O
thrombosis	O
,	O
as	O
its	O
high	O
negative	O
predictive	O
value	O
enables	O
to	O
validly	O
rule	O
out	O
ongoing	O
thrombotic	O
complications	O
[	O
12	O
]	O
.	O

Little	O
is	O
known	O
on	O
the	O
thrombotic	O
tendency	O
of	O
SSc	O
patients	B
so	O
far	O
[	O
13	O
]	O
.	O

At	O
variance	O
with	O
previous	O
investigations	O
[	O
2	O
-	O
4	O
]	O
,	O
we	O
demonstrated	O
that	O
SSc	O
patients	B
with	O
diffuse	O
subset	O
are	O
characterized	O
by	O
increased	O
plasma	O
D	O
-	O
dimer	O
values	O
,	O
reflecting	O
a	O
potential	O
activation	O
of	O
both	O
the	O
coagulation	O
and	O
fibrinolytic	O
pathways	O
.	O

Conclusion	O

Although	O
increased	O
D	O
-	O
dimer	O
values	O
in	O
SSc	O
patients	B
were	O
occasionally	O
observed	O
in	O
earlier	O
studies	O
,	O
the	O
association	O
between	O
plasma	O
D	O
-	O
dimer	O
and	O
disease	O
subset	O
is	O
likely	O
an	O
original	O
and	O
innovative	O
issue	O
.	O

The	O
significant	O
correlation	O
observed	O
with	O
disease	O
activity	O
,	O
cutaneous	O
involvement	O
and	O
forced	O
vital	O
capacity	O
,	O
further	O
suggests	O
that	O
SSc	O
patients	B
,	O
especially	O
those	O
with	O
diffuse	O
subset	O
,	O
display	O
a	O
hypercoagulable	O
state	O
,	O
which	O
might	O
finally	O
predispose	O
this	O
peculiar	O
subset	O
of	O
patients	B
to	O
the	O
development	O
of	O
thrombotic	O
complications	O
.	O

Authors	O
'	O
contributions	O

GL	O
:	O
conceived	O
of	O
the	O
study	O
,	O
participated	O
in	O
its	O
design	O
and	O
coordination	O
and	O
drafted	O
the	O
manuscript	O
;	O
AV	O
:	O
participated	O
in	O
the	O
design	O
of	O
the	O
study	O
,	O
performed	O
the	O
statistical	O
analysis	O
and	O
helped	O
to	O
draft	O
the	O
manuscript	O
;	O
PC	O
:	O
participated	O
in	O
the	O
design	O
and	O
coordination	O
of	O
the	O
study	O
;	O
GLS	O
:	O
participated	O
in	O
the	O
design	O
of	O
the	O
study	O
;	O
MM	O
:	O
participated	O
in	O
the	O
design	O
and	O
coordination	O
of	O
the	O
study	O
and	O
performed	O
the	O
measurement	O
;	O
GCG	O
:	O
participated	O
in	O
the	O
design	O
and	O
coordination	O
of	O
the	O
study	O
.	O

All	O
authors	O
read	O
and	O
approved	O
the	O
final	O
manuscript	O
.	O

The	O
authors	O
declare	O
that	O
they	O
have	O
no	O
competing	O
interests	O
.	O

Enp1	O
,	O
a	O
yeast	B
protein	O
associated	O
with	O
U3	O
and	O
U14	O
snoRNAs	O
,	O
is	O
required	O
for	O
pre	O
-	O
rRNA	O
processing	O
and	O
40S	O
subunit	O
synthesis	O

Abstract	O

ENP1	O
is	O
an	O
essential	O
Saccharomyces	B
cerevisiae	I
gene	O
encoding	O
a	O
483	O
amino	O
acid	O
polypeptide	O
.	O

Enp1	O
protein	O
is	O
localized	O
in	O
the	O
nucleus	O
and	O
concentrated	O
in	O
the	O
nucleolus	O
.	O

An	O
enp1	O
-	O
1	O
temperature	O
-	O
sensitive	O
mutant	O
inhibited	O
35S	O
pre	O
-	O
rRNA	O
early	O
processing	O
at	O
sites	O
A0	O
,	O
A1	O
and	O
A2	O
as	O
shown	O
by	O
northern	O
analysis	O
of	O
steady	O
state	O
levels	O
of	O
rRNA	O
precursors	O
.	O

Pulse	O
-	O
chase	O
analysis	O
further	O
revealed	O
that	O
the	O
enp1	O
-	O
1	O
strain	O
was	O
defective	O
in	O
the	O
synthesis	O
of	O
20S	O
pre	O
-	O
rRNA	O
and	O
hence	O
18S	O
rRNA	O
,	O
which	O
led	O
to	O
reduced	O
formation	O
of	O
40S	O
ribosomal	O
subunits	O
.	O

Co	O
-	O
precipitation	O
analysis	O
revealed	O
that	O
Enp1	O
was	O
associated	O
with	O
Nop1	O
protein	O
,	O
as	O
well	O
as	O
with	O
U3	O
and	O
U14	O
RNAs	O
,	O
two	O
snoRNAs	O
implicated	O
in	O
early	O
pre	O
-	O
rRNA	O
processing	O
steps	O
.	O

These	O
results	O
suggest	O
a	O
direct	O
role	O
for	O
Enp1	O
in	O
the	O
early	O
steps	O
of	O
rRNA	O
processing	O
.	O

INTRODUCTION	O

Ribosome	O
biogenesis	O
is	O
one	O
of	O
the	O
major	O
cellular	O
activities	O
in	O
eukaryotic	O
cells	O
.	O

It	O
takes	O
place	O
primarily	O
in	O
a	O
specialized	O
subnuclear	O
compartment	O
,	O
the	O
nucleolus	O
(	O
1	O
,	O
2	O
)	O
.	O

In	O
the	O
yeast	B
Saccharomyces	B
cerevisiae	I
,	O
each	O
rRNA	O
gene	O
is	O
transcribed	O
by	O
RNA	O
polymerase	O
I	O
into	O
a	O
35S	O
rRNA	O
precursor	O
,	O
consisting	O
of	O
18S	O
,	O
5	O
.	O
8S	O
and	O
25S	O
rRNA	O
sequences	O
flanked	O
by	O
two	O
external	O
transcribed	O
spacers	O
(	O
ETS	O
)	O
and	O
separated	O
by	O
two	O
internal	O
transcribed	O
spacers	O
(	O
ITS	O
)	O
(	O
Fig	O
.	O
1	O
)	O
.	O

This	O
35S	O
precursor	O
goes	O
through	O
a	O
series	O
of	O
modifications	O
and	O
processing	O
steps	O
to	O
generate	O
the	O
mature	O
18S	O
,	O
5	O
.	O
8S	O
and	O
25S	O
rRNAs	O
.	O

The	O
processing	O
occurs	O
first	O
at	O
sites	O
A0	O
,	O
A1	O
and	O
A2	O
,	O
resulting	O
in	O
the	O
20S	O
pre	O
-	O
rRNA	O
and	O
27SA2	O
pre	O
-	O
rRNA	O
.	O

The	O
20S	O
pre	O
-	O
rRNA	O
is	O
then	O
cleaved	O
,	O
leading	O
to	O
the	O
mature	O
18S	O
rRNA	O
found	O
in	O
the	O
40S	O
ribosomal	O
subunit	O
.	O

The	O
27SA2	O
pre	O
-	O
rRNA	O
is	O
processed	O
through	O
two	O
alternative	O
pathways	O
.	O

The	O
majority	O
of	O
27SA2	O
pre	O
-	O
rRNA	O
is	O
cleaved	O
at	O
sites	O
A3	O
and	O
B2	O
to	O
form	O
the	O
27SA3	O
pre	O
-	O
rRNA	O
,	O
which	O
is	O
subsequently	O
processed	O
to	O
produce	O
27SBS	O
.	O

Alternatively	O
,	O
27SA2	O
pre	O
-	O
rRNA	O
can	O
be	O
processed	O
at	O
sites	O
B1L	O
and	O
B2	O
to	O
generate	O
27SBL	O
pre	O
-	O
rRNA	O
.	O

Both	O
27SBS	O
and	O
27SBL	O
pre	O
-	O
rRNAs	O
are	O
then	O
cleaved	O
at	O
sites	O
C1	O
and	O
C2	O
to	O
generate	O
the	O
mature	O
25S	O
rRNA	O
,	O
and	O
7SS	O
or	O
7SL	O
intermediates	O
,	O
which	O
are	O
then	O
processed	O
to	O
mature	O
5	O
.	O
8SS	O
or	O
5	O
.	O
8SL	O
rRNAs	O
(	O
Fig	O
.	O
1	O
)	O
.	O

The	O
25S	O
rRNA	O
and	O
5	O
.	O
8S	O
rRNA	O
are	O
the	O
RNA	O
components	O
of	O
the	O
60S	O
ribosomal	O
subunit	O
(	O
3	O
)	O
.	O

During	O
the	O
course	O
of	O
rRNA	O
modification	O
and	O
processing	O
,	O
many	O
of	O
the	O
ribosomal	O
proteins	O
are	O
assembled	O
onto	O
the	O
rRNA	O
molecules	O
to	O
form	O
the	O
ribosome	O
complex	O
.	O

Ribosome	O
biogenesis	O
needs	O
a	O
large	O
number	O
of	O
trans	O
-	O
acting	O
factors	O
,	O
including	O
small	O
nucleolar	O
RNAs	O
(	O
snoRNAs	O
)	O
,	O
protein	O
components	O
of	O
the	O
snoRNP	O
complexes	O
,	O
rRNA	O
modifying	O
enzymes	O
,	O
endo	O
-	O
and	O
exonucleases	O
,	O
putative	O
RNA	O
helicases	O
and	O
other	O
protein	O
factors	O
(	O
3	O
,	O
4	O
)	O
.	O

In	O
yeast	B
cells	O
there	O
are	O
more	O
than	O
100	O
different	O
snoRNAs	O
playing	O
important	O
roles	O
in	O
rRNA	O
modification	O
and	O
processing	O
.	O

On	O
the	O
basis	O
of	O
their	O
structure	O
,	O
the	O
snoRNAs	O
can	O
be	O
divided	O
into	O
two	O
groups	O
:	O
the	O
box	O
C	O
/	O
D	O
family	O
and	O
box	O
H	O
/	O
ACA	O
family	O
.	O

Only	O
one	O
snoRNA	O
,	O
MRP	O
RNA	O
,	O
belongs	O
to	O
neither	O
family	O
(	O
5	O
-	O
7	O
)	O
.	O

While	O
the	O
majority	O
of	O
the	O
snoRNAs	O
participate	O
in	O
RNA	O
pseudouridylation	O
and	O
2	O
'	O
-	O
O	O
-	O
ribose	O
methylation	O
,	O
a	O
few	O
of	O
them	O
,	O
including	O
MRP	O
snoRNA	O
,	O
box	O
C	O
/	O
D	O
snoRNAs	O
U3	O
and	O
U14	O
,	O
and	O
box	O
H	O
/	O
ACA	O
snoRNAs	O
snR10	O
and	O
snR30	O
,	O
are	O
required	O
for	O
processing	O
of	O
the	O
pre	O
-	O
rRNA	O
(	O
8	O
-	O
12	O
)	O
.	O

Not	O
only	O
are	O
U3	O
,	O
U14	O
,	O
snR10	O
and	O
snR30	O
essential	O
for	O
early	O
cleavages	O
of	O
35S	O
pre	O
-	O
rRNA	O
to	O
18S	O
rRNA	O
,	O
the	O
proteins	O
associated	O
with	O
them	O
,	O
including	O
Nop1	O
,	O
Nop5	O
,	O
Gar1	O
and	O
Nop10	O
,	O
have	O
also	O
been	O
shown	O
to	O
be	O
required	O
for	O
18S	O
rRNA	O
synthesis	O
(	O
13	O
-	O
16	O
)	O
.	O

The	O
ENP1	O
(	O
Essential	O
Nuclear	O
Protein	O
1	O
)	O
gene	O
was	O
identified	O
in	O
a	O
genetic	O
screen	O
for	O
suppressors	O
of	O
an	O
ost4	O
mutation	O
(	O
oligosaccharide	O
transferase	O
4	O
)	O
(	O
17	O
)	O
.	O

However	O
,	O
in	O
subsequent	O
studies	O
it	O
was	O
found	O
not	O
to	O
be	O
involved	O
in	O
OST4	O
function	O
(	O
18	O
)	O
.	O

ENP1	O
is	O
an	O
essential	O
gene	O
encoding	O
a	O
483	O
amino	O
acid	O
polypeptide	O
.	O

The	O
Enp1	O
protein	O
is	O
highly	O
conserved	O
and	O
homologs	O
are	O
found	O
in	O
all	O
eukaryotes	O
.	O

The	O
yeast	B
protein	O
was	O
localized	O
to	O
the	O
nucleus	O
in	O
a	O
previous	O
study	O
(	O
18	O
)	O
.	O

On	O
the	O
other	O
hand	O
,	O
an	O
Enp1	O
human	B
homolog	O
,	O
called	O
bystin	O
,	O
was	O
reported	O
to	O
localize	O
to	O
the	O
cytoplasm	O
and	O
was	O
proposed	O
to	O
be	O
involved	O
in	O
cell	O
adhesion	O
(	O
19	O
)	O
.	O

In	O
this	O
study	O
,	O
we	O
report	O
that	O
the	O
Enp1	O
protein	O
not	O
only	O
is	O
nuclear	O
but	O
is	O
enriched	O
in	O
the	O
nucleolus	O
.	O

We	O
also	O
found	O
that	O
Enp1	O
is	O
required	O
for	O
the	O
synthesis	O
of	O
40S	O
ribosomal	O
subunits	O
,	O
and	O
its	O
presence	O
is	O
necessary	O
for	O
the	O
pre	O
-	O
rRNA	O
processing	O
to	O
form	O
20S	O
pre	O
-	O
rRNA	O
and	O
18S	O
rRNA	O
.	O

An	O
association	O
between	O
Enp1	O
and	O
U3	O
and	O
U14	O
snoRNAs	O
,	O
and	O
with	O
the	O
nucleolar	O
protein	O
Nop1	O
,	O
was	O
established	O
.	O

We	O
also	O
found	O
that	O
human	B
Enp1	O
,	O
expressed	O
in	O
yeast	B
,	O
was	O
located	O
in	O
the	O
nucleus	O
and	O
the	O
nucleolus	O
,	O
suggesting	O
that	O
the	O
function	O
of	O
this	O
protein	O
is	O
conserved	O
.	O

MATERIALS	O
AND	O
METHODS	O

Yeast	B
strains	O
and	O
media	O

The	O
S	B
.	I
cerevisiae	I
strains	O
used	O
in	O
this	O
study	O
are	O
all	O
derivatives	O
of	O
a	O
wild	O
-	O
type	O
diploid	O
strain	O
W303	O
(	O
MATa	O
/	O
MAT	O
alpha	O
ura3	O
-	O
1	O
/	O
ura3	O
-	O
1	O
leu2	O
-	O
3	O
,	O
112	O
/	O
leu2	O
-	O
3	O
,	O
112	O
trp1	O
-	O
1	O
/	O
trp1	O
-	O
1	O
his3	O
-	O
11	O
,	O
15	O
/	O
his3	O
-	O
11	O
,	O
15	O
ade2	O
-	O
1	O
/	O
ade2	O
-	O
1	O
can1	O
-	O
100	O
/	O
can1	O
-	O
100	O
)	O
except	O
for	O
strain	O
RS1938	O
.	O

Strain	O
JBY45	O
(	O
MATa	O
/	O
MAT	O
alpha	O
ENP1	O
/	O
Delta	O
enp1	O
:	O
:	O
his5	O
+	O
)	O
was	O
constructed	O
by	O
replacing	O
one	O
copy	O
of	O
the	O
ENP1	O
open	O
reading	O
frame	O
(	O
ORF	O
)	O
with	O
the	O
Schizosaccharomyces	B
pombe	I
his5	O
+	O
gene	O
(	O
18	O
)	O
.	O

Strain	O
JBY46	O
[	O
MATa	O
Delta	O
enp1	O
:	O
:	O
his5	O
+	O
/	O
pJB23	O
(	O
ENP1	O
,	O
URA3	O
,	O
CEN6	O
)	O
]	O
is	O
a	O
haploid	O
strain	O
derived	O
from	O
JBY45	O
with	O
wild	O
-	O
type	O
ENP1	O
on	O
a	O
low	O
copy	O
number	O
plasmid	O
.	O

Strain	O
JBY48	O
[	O
MATa	O
Delta	O
enp1	O
:	O
:	O
his5	O
+	O
/	O
pJB19	O
(	O
enp1	O
-	O
1	O
,	O
TRP1	O
,	O
CEN6	O
)	O
]	O
and	O
strain	O
JBY49	O
[	O
MATa	O
Delta	O
enp1	O
:	O
:	O
his5	O
+	O
/	O
pJB39	O
(	O
enp1	O
-	O
2	O
,	O
TRP1	O
,	O
CEN6	O
)	O
]	O
have	O
plasmids	O
with	O
enp1	O
temperature	O
-	O
sensitive	O
(	O
ts	O
)	O
mutations	O
.	O

Strain	O
JBY51	O
(	O
MATa	O
Delta	O
enp1	O
:	O
:	O
his5	O
+	O
TRP1	O
:	O
:	O
enp1	O
-	O
1	O
)	O
is	O
an	O
enp1	O
ts	O
strain	O
generated	O
by	O
integrating	O
the	O
enp1	O
-	O
1	O
gene	O
at	O
the	O
chromosomal	O
trp1	O
-	O
1	O
locus	O
.	O

Strain	O
CWY13	O
[	O
MATa	O
Delta	O
enp1	O
:	O
:	O
his5	O
+	O
/	O
pJB24	O
(	O
pMET25	O
-	O
GFP	O
-	O
ENP1	O
,	O
URA3	O
,	O
CEN6	O
)	O
]	O
has	O
GFP	O
-	O
ENP1	O
under	O
control	O
of	O
the	O
MET25	O
promoter	O
.	O

Strain	O
CWY14	O
(	O
MATa	O
ENP1	O
-	O
TAP	O
)	O
was	O
created	O
by	O
fusing	O
sequences	O
encoding	O
a	O
Tandem	O
Affinity	O
Purification	O
(	O
TAP	O
)	O
tag	O
(	O
20	O
,	O
21	O
)	O
to	O
the	O
3	O
'	O
end	O
of	O
ENP1	O
.	O

Strain	O
YRH39	O
(	O
MAT	O
alpha	O
HST2	O
-	O
TAP	O
)	O
was	O
created	O
by	O
fusing	O
sequences	O
encoding	O
a	O
TAP	O
tag	O
to	O
the	O
3	O
'	O
end	O
of	O
HST2	O
.	O

Strain	O
RS1938	O
(	O
Delta	O
nop1	O
:	O
:	O
URA3	O
pUN100	O
-	O
ProtA	O
-	O
NOP1	O
)	O
was	O
created	O
by	O
transforming	O
RS1935	O
(	O
MATa	O
/	O
alpha	O
leu2	O
/	O
leu2	O
ura3	O
/	O
ura3	O
lys2	O
/	O
lys2	O
ade2	O
/	O
ade2	O
Delta	O
nop1	O
:	O
:	O
URA3	O
/	O
NOP1	O
)	O
with	O
pUN100	O
-	O
ProtA	O
-	O
NOP1	O
(	O
strain	O
and	O
plasmid	O
supplied	O
by	O
T	O
.	O
Schafer	O
)	O
,	O
followed	O
by	O
tetrad	O
dissection	O
.	O

Strain	O
CWY15	O
[	O
MATa	O
/	O
pCW109	O
(	O
pMET25	O
-	O
GFP	O
-	O
hENP1	O
,	O
URA3	O
,	O
CEN6	O
)	O
]	O
has	O
a	O
human	B
homolog	O
of	O
Enp1	O
expressed	O
in	O
W303	O
-	O
1a	O
.	O

The	O
media	O
used	O
were	O
prepared	O
as	O
described	O
(	O
22	O
)	O
.	O

Cloning	O
of	O
ENP1	O

pRS426	O
-	O
MEG1	O
(	O
The	O
original	O
name	O
of	O
ENP1	O
)	O
was	O
a	O
gift	O
from	O
Dr	O
William	O
J	O
.	O
Lennarz	O
.	O

It	O
contains	O
the	O
ENP1	O
gene	O
within	O
a	O
2	O
.	O
6	O
kb	O
EcoRI	O
genomic	O
fragment	O
cloned	O
into	O
pRS426	O
(	O
18	O
)	O
.	O

The	O
EcoRI	O
fragment	O
was	O
subsequently	O
cloned	O
into	O
pRS314	O
(	O
TRP1	O
,	O
CEN6	O
)	O
,	O
pRS316	O
(	O
URA3	O
,	O
CEN6	O
)	O
and	O
pRS424	O
(	O
TRP1	O
,	O
2	O
micro	O
)	O
to	O
create	O
pJB20	O
,	O
pJB23	O
and	O
pJB21	O
,	O
respectively	O
.	O

pGFP	O
-	O
N	O
-	O
FUS	O
is	O
a	O
centromeric	O
plasmid	O
for	O
fusing	O
green	O
fluorescence	O
protein	O
(	O
GFP	O
)	O
to	O
a	O
polypeptide	O
'	O
s	O
N	O
-	O
terminus	O
under	O
control	O
of	O
the	O
MET25	O
promoter	O
(	O
23	O
)	O
.	O

Cloning	O
the	O
ENP1	O
ORF	O
into	O
pGFP	O
-	O
N	O
-	O
FUS	O
via	O
XbaI	O
and	O
SalI	O
sites	O
generated	O
plasmid	O
pJB24	O
.	O

pJB19	O
(	O
enp1	O
-	O
1	O
,	O
TRP1	O
,	O
CEN6	O
)	O
contains	O
the	O
enp1	O
-	O
1	O
mutant	O
gene	O
.	O

The	O
human	B
homolog	O
of	O
yeast	B
Enp1	O
was	O
PCR	O
amplified	O
from	O
a	O
human	B
cDNA	O
clone	O
BC007340	O
(	O
Research	O
Genetics	O
)	O
,	O
then	O
cloned	O
into	O
pGFP	O
-	O
N	O
-	O
FUS	O
,	O
p415	O
-	O
ADH	O
,	O
p415	O
-	O
GPD	O
and	O
p415	O
-	O
TEF	O
(	O
24	O
)	O
via	O
XbaI	O
and	O
SalI	O
sites	O
to	O
generate	O
pCW109	O
,	O
pCW113	O
,	O
pCW115	O
and	O
pCW117	O
,	O
respectively	O
.	O

The	O
fragment	O
of	O
the	O
human	B
Enp1	O
homolog	O
(	O
amino	O
acids	O
152	O
-	O
437	O
)	O
was	O
also	O
cloned	O
into	O
these	O
vectors	O
to	O
generate	O
pCW110	O
,	O
pCW114	O
,	O
pCW116	O
and	O
pCW118	O
.	O

Random	O
mutagenesis	O
of	O
ENP1	O
to	O
generate	O
enp1	O
ts	O
mutants	O

The	O
enp1	O
ts	O
mutants	O
were	O
generated	O
with	O
a	O
protocol	O
introducing	O
random	O
mutations	O
by	O
PCR	O
(	O
25	O
)	O
.	O

The	O
PCR	O
was	O
performed	O
with	O
oligonucleotides	O
ENP1	O
-	O
MUT5	O
'	O
(	O
5	O
'	O
-	O
GGTGGTGTCAGT	O
AGGGGA	O
-	O
3	O
'	O
)	O
,	O
ENP1	O
-	O
MUT3	O
'	O
(	O
5	O
'	O
-	O
CAGTCTGCAATATA	O
TGGAC	O
-	O
3	O
'	O
)	O
and	O
plasmid	O
template	O
pJB20	O
(	O
see	O
above	O
)	O
.	O

The	O
nucleotide	O
concentrations	O
in	O
the	O
reaction	O
were	O
1	O
mM	O
each	O
for	O
dATP	O
,	O
dGTP	O
,	O
dCTP	O
and	O
dTTP	O
.	O

After	O
strain	O
JBY46	O
was	O
transformed	O
with	O
the	O
PCR	O
product	O
and	O
with	O
pJB20	O
gapped	O
by	O
NheI	O
and	O
NsiI	O
,	O
the	O
transformants	O
were	O
replica	O
-	O
plated	O
onto	O
two	O
plates	O
containing	O
5	O
-	O
FOA	O
synthetic	O
medium	O
without	O
tryptophan	O
;	O
one	O
replica	O
was	O
incubated	O
at	O
23	O
degrees	O
C	O
and	O
the	O
other	O
at	O
37	O
degrees	O
C	O
.	O

Colonies	O
growing	O
at	O
23	O
degrees	O
C	O
but	O
not	O
at	O
37	O
degrees	O
C	O
were	O
picked	O
as	O
candidates	O
.	O

Since	O
approximately	O
10	O
%	O
of	O
the	O
colonies	O
were	O
inviable	O
at	O
both	O
temperatures	O
,	O
we	O
knew	O
that	O
10	O
%	O
of	O
the	O
ENP1	O
PCR	O
products	O
lost	O
their	O
function	O
after	O
the	O
PCR	O
mutagenesis	O
.	O

This	O
confirmed	O
the	O
effectiveness	O
of	O
the	O
mutagenesis	O
procedure	O
.	O

Two	O
candidates	O
showed	O
good	O
growth	O
at	O
23	O
degrees	O
C	O
but	O
no	O
growth	O
at	O
37	O
degrees	O
C	O
.	O

They	O
were	O
named	O
strains	O
JBY48	O
and	O
JBY49	O
and	O
contained	O
plasmids	O
with	O
the	O
enp1	O
-	O
1	O
and	O
enp1	O
-	O
2	O
mutations	O
,	O
respectively	O
.	O

The	O
mutated	O
enp1	O
-	O
1	O
gene	O
on	O
pJB19	O
was	O
cloned	O
into	O
an	O
integration	O
vector	O
,	O
pRS304	O
,	O
as	O
an	O
EcoRI	O
fragment	O
.	O

The	O
plasmid	O
was	O
subsequently	O
linearized	O
with	O
SnaBI	O
within	O
the	O
TRP1	O
marker	O
and	O
was	O
integrated	O
at	O
the	O
chromosomal	O
trp1	O
-	O
1	O
locus	O
of	O
strain	O
JBY46	O
.	O

Selection	O
on	O
5	O
-	O
FOA	O
was	O
used	O
to	O
remove	O
plasmid	O
pJB23	O
,	O
creating	O
strain	O
JBY51	O
.	O

Sucrose	O
gradient	O
analysis	O

Polyribosome	O
preparation	O
and	O
analysis	O
were	O
carried	O
out	O
essentially	O
as	O
described	O
(	O
26	O
)	O
.	O

Cells	O
grown	O
in	O
YPD	O
were	O
collected	O
at	O
mid	O
-	O
log	O
phase	O
(	O
OD600	O
0	O
.	O
8	O
-	O
1	O
.	O
0	O
)	O
and	O
were	O
broken	O
with	O
glass	O
beads	O
.	O

The	O
lysate	O
was	O
frozen	O
immediately	O
in	O
liquid	O
N2	O
and	O
was	O
stored	O
at	O
-	O
80	O
degrees	O
C	O
.	O

Lysate	O
(	O
30	O
U	O
of	O
absorbance	O
at	O
OD260	O
)	O
was	O
layered	O
over	O
a	O
7	O
-	O
47	O
%	O
(	O
w	O
/	O
v	O
)	O
sucrose	O
gradient	O
,	O
which	O
was	O
centrifuged	O
at	O
28	O
000	O
r	O
.	O
p	O
.	O
m	O
.	O
for	O
5	O
h	O
at	O
4	O
degrees	O
C	O
in	O
a	O
SW28	O
rotor	O
and	O
was	O
analyzed	O
with	O
an	O
ISCO	O
UA	O
-	O
5	O
gradient	O
UV	O
detection	O
system	O
on	O
absorbency	O
at	O
254	O
nm	O
.	O

Immunofluorescence	O

Immunofluorescence	O
analysis	O
was	O
carried	O
out	O
essentially	O
as	O
described	O
(	O
27	O
)	O
.	O

Cells	O
were	O
fixed	O
with	O
3	O
.	O
7	O
%	O
formaldehyde	O
at	O
room	O
temperature	O
for	O
1	O
.	O
5	O
h	O
.	O

Antibodies	O
included	O
a	O
mouse	B
monoclonal	O
anti	O
-	O
Nop1	O
(	O
a	O
gift	O
from	O
John	O
P	O
.	O
Aris	O
,	O
University	O
of	O
Florida	O
,	O
Gainesville	O
,	O
Florida	O
)	O
and	O
a	O
Texas	O
-	O
red	O
-	O
conjugated	O
donkey	B
-	O
anti	O
-	O
mouse	B
antibody	O
(	O
Jackson	O
Lab	O
)	O
,	O
both	O
used	O
at	O
1	O
:	O
500	O
dilution	O
.	O

Images	O
were	O
taken	O
on	O
a	O
Zeiss	O
Axioplan2	O
microscope	O
equipped	O
with	O
a	O
Zeiss	O
AxioCam	O
camera	O
.	O

Pulse	O
-	O
chase	O
labeling	O
analysis	O
of	O
rRNA	O

For	O
[	O
methyl	O
-	O
3H	O
]	O
methionine	O
pulse	O
-	O
chase	O
analysis	O
,	O
cells	O
were	O
grown	O
in	O
synthetic	O
medium	O
without	O
methionine	O
at	O
room	O
temperature	O
or	O
37	O
degrees	O
C	O
for	O
2	O
h	O
.	O

When	O
the	O
OD600	O
reached	O
1	O
.	O
0	O
,	O
6	O
ml	O
of	O
the	O
culture	O
were	O
pulse	O
-	O
labeled	O
with	O
250	O
micro	O
Ci	O
[	O
methyl	O
-	O
3H	O
]	O
methionine	O
(	O
Amersham	O
Pharmacia	O
)	O
for	O
3	O
min	O
and	O
chased	O
with	O
cold	O
methionine	O
(	O
500	O
micro	O
g	O
/	O
ml	O
)	O
for	O
2	O
,	O
4	O
or	O
12	O
min	O
.	O

For	O
each	O
time	O
point	O
of	O
the	O
chase	O
1	O
.	O
25	O
ml	O
of	O
culture	O
was	O
mixed	O
with	O
ice	O
and	O
collected	O
.	O

The	O
pellets	O
were	O
frozen	O
immediately	O
in	O
liquid	O
N2	O
and	O
stored	O
at	O
-	O
80	O
degrees	O
C	O
before	O
total	O
RNA	O
was	O
purified	O
using	O
a	O
hot	O
phenol	O
method	O
(	O
28	O
)	O
.	O

The	O
RNAs	O
were	O
separated	O
on	O
a	O
1	O
.	O
2	O
%	O
agarose	O
formaldehyde	O
gel	O
and	O
transferred	O
onto	O
Hybond	O
-	O
N	O
+	O
nylon	O
membranes	O
(	O
Amersham	O
Pharmacia	O
)	O
.	O

After	O
being	O
sprayed	O
with	O
EN3HANCE	O
(	O
Du	O
Pont	O
)	O
,	O
the	O
membranes	O
were	O
exposed	O
to	O
film	O
at	O
-	O
80	O
degrees	O
C	O
(	O
29	O
)	O
.	O

Northern	O
analysis	O

Cells	O
were	O
grown	O
inYPD	O
at	O
room	O
temperature	O
or	O
37	O
degrees	O
C	O
for	O
2	O
-	O
4	O
h	O
.	O

When	O
the	O
OD600	O
reached	O
1	O
.	O
0	O
,	O
10	O
ml	O
of	O
cells	O
were	O
collected	O
and	O
frozen	O
immediately	O
.	O

Total	O
RNA	O
was	O
extracted	O
as	O
described	O
(	O
28	O
)	O
.	O

Five	O
micrograms	O
of	O
RNA	O
were	O
separated	O
on	O
1	O
.	O
2	O
%	O
agarose	O
formaldehyde	O
gels	O
(	O
for	O
high	O
molecular	O
weight	O
RNA	O
)	O
or	O
on	O
6	O
%	O
polyacrylamide	O
7	O
M	O
urea	O
denaturing	O
gels	O
(	O
for	O
low	O
molecular	O
weight	O
RNA	O
)	O
for	O
each	O
sample	O
.	O

The	O
RNA	O
was	O
then	O
transferred	O
to	O
Zeta	O
-	O
Probe	O
GT	O
nylon	O
membranes	O
(	O
Bio	O
-	O
Rad	O
)	O
.	O

Probes	O
for	O
hybridyzation	O
were	O
specific	O
oligonucleotides	O
end	O
-	O
labeled	O
using	O
[	O
gamma	O
-	O
32P	O
]	O
ATP	O
.	O

After	O
hybridization	O
and	O
washes	O
,	O
membranes	O
were	O
exposed	O
to	O
phosphorimager	O
screens	O
or	O
X	O
-	O
ray	O
films	O
(	O
29	O
)	O
.	O

Oligonucleotides	O
specific	O
for	O
various	O
regions	O
of	O
35S	O
pre	O
-	O
rRNA	O
are	O
:	O
1	O
,	O
GGTCTCTCTGCTGCCG	O
GAAATG	O
;	O
3	O
,	O
AATGAGCCATTCGCAGTTTC	O
;	O
4	O
,	O
GCTCTCATGCTCTTGCCAAA	O
;	O
5	O
,	O
TGTTTGTTACCT	O
CTGGGCCCCG	O
;	O
6	O
,	O
TCCAGTTACGAAAATTCTTG	O
;	O
7	O
,	O
CGTATCGCATTTCGCTGCGT	O
;	O
8	O
,	O
GTTCGCCTAGAC	O
GCTCTCTCTTC	O
;	O
9	O
,	O
GCGAGATTCCCCTACCCAC	O
.	O

The	O
regions	O
complementary	O
to	O
these	O
oligonucleotides	O
are	O
shown	O
in	O
Figure	O
6A	O
.	O

The	O
oligonucleotides	O
probing	O
box	O
C	O
/	O
D	O
snoRNAs	O
are	O
:	O
U3	O
,	O
TTCGGTTTCTCACTCACTCT	O
;	O
U14	O
,	O
GGAACCAGTCTTTCATCACC	O
.	O

The	O
oligonucleotides	O
probing	O
box	O
H	O
/	O
ACA	O
snoRNAs	O
are	O
:	O
snoRNA10	O
,	O
CCTTG	O
CAACGGTCCTCATCCGGG	O
;	O
snoRNA30	O
,	O
GTCCGAAGC	O
GCCATCTAGATGA	O
.	O

RNA	O
and	O
protein	O
precipitation	O
analysis	O

Cells	O
were	O
grown	O
in	O
YPD	O
(	O
1	O
l	O
)	O
to	O
OD600	O
1	O
.	O
0	O
,	O
then	O
collected	O
,	O
washed	O
once	O
in	O
ice	O
-	O
cold	O
PBS	O
and	O
broken	O
using	O
glass	O
beads	O
in	O
10	O
ml	O
IPP150	O
buffer	O
(	O
10	O
mM	O
Tris	O
pH	O
8	O
.	O
0	O
,	O
150	O
mM	O
NaCl	O
and	O
0	O
.	O
1	O
%	O
NP	O
-	O
40	O
)	O
with	O
protease	O
inhibitors	O
.	O

The	O
lysates	O
were	O
mixed	O
with	O
200	O
micro	O
l	O
IgG	O
agarose	O
beads	O
for	O
2	O
h	O
at	O
4	O
degrees	O
C	O
.	O

After	O
several	O
washes	O
with	O
50	O
ml	O
IPP150	O
buffer	O
,	O
the	O
IgG	O
beads	O
were	O
collected	O
and	O
the	O
RNA	O
associated	O
with	O
the	O
beads	O
extracted	O
by	O
the	O
hot	O
phenol	O
method	O
(	O
28	O
)	O
.	O

One	O
-	O
tenth	O
of	O
the	O
precipitated	O
RNA	O
was	O
then	O
separated	O
on	O
6	O
%	O
polyacrylamide	O
7	O
M	O
urea	O
denaturing	O
gels	O
and	O
electro	O
-	O
transferred	O
to	O
Zeta	O
-	O
Probe	O
GT	O
nylon	O
membranes	O
.	O

They	O
were	O
probed	O
with	O
[	O
gamma	O
-	O
32P	O
]	O
ATP	O
labeled	O
oligonucleotides	O
.	O

For	O
the	O
lanes	O
showing	O
total	O
RNA	O
,	O
2	O
micro	O
g	O
RNA	O
prepared	O
from	O
exponentially	O
growing	O
cultures	O
were	O
loaded	O
.	O

For	O
co	O
-	O
precipitation	O
analysis	O
of	O
proteins	O
,	O
the	O
IgG	O
beads	O
were	O
resuspended	O
in	O
2	O
x	O
Laemmli	O
sample	O
buffer	O
,	O
boiled	O
for	O
5	O
min	O
and	O
separated	O
by	O
SDS	O
-	O
polyacrylamide	O
gel	O
electrophoresis	O
.	O

Approximately	O
1	O
%	O
of	O
the	O
precipitate	O
was	O
loaded	O
onto	O
each	O
lane	O
.	O

For	O
the	O
total	O
protein	O
,	O
0	O
.	O
1	O
%	O
of	O
the	O
extract	O
prior	O
to	O
precipitation	O
was	O
loaded	O
onto	O
each	O
lane	O
.	O

Following	O
electrophoresis	O
,	O
the	O
proteins	O
were	O
transferred	O
to	O
nitrocellulose	O
membranes	O
and	O
detected	O
using	O
anti	O
-	O
Nop1	O
antibody	O
at	O
1	O
:	O
3000	O
dilution	O
(	O
provided	O
by	O
J	O
.	O
Aris	O
)	O
and	O
anti	O
-	O
L3	O
antibody	O
(	O
provided	O
by	O
J	O
.	O
Warner	O
)	O
at	O
1	O
:	O
3000	O
dilution	O
followed	O
by	O
peroxidase	O
-	O
conjugated	O
anti	O
-	O
mouse	B
secondary	O
antibody	O
at	O
1	O
:	O
5000	O
dilution	O
.	O

The	O
antibody	O
complexes	O
were	O
detected	O
using	O
ECL	O
-	O
Plus	O
reagents	O
(	O
Amersham	O
Pharmacia	O
)	O
as	O
specified	O
by	O
the	O
manufacturer	O
.	O

RESULTS	O

Construction	O
and	O
analysis	O
of	O
ENP1	O
temperature	O
-	O
sensitive	O
alleles	O

ENP1	O
is	O
an	O
essential	O
yeast	B
gene	O
conserved	O
among	O
eukaryotes	O
(	O
18	O
)	O
.	O

To	O
study	O
its	O
functions	O
,	O
we	O
first	O
created	O
a	O
diploid	O
strain	O
,	O
JBY45	O
,	O
heterozygous	O
for	O
the	O
Delta	O
enp1	O
mutation	O
.	O

Then	O
two	O
enp1	O
ts	O
mutant	O
alleles	O
(	O
enp1	O
-	O
1	O
and	O
enp1	O
-	O
2	O
)	O
were	O
generated	O
by	O
random	O
PCR	O
mutagenesis	O
,	O
as	O
described	O
in	O
Materials	O
and	O
Methods	O
.	O

Both	O
mutant	O
alleles	O
were	O
recessive	O
to	O
the	O
wild	O
-	O
type	O
ENP1	O
gene	O
.	O

The	O
enp1	O
-	O
1	O
gene	O
was	O
integrated	O
into	O
the	O
chromosomal	O
trp1	O
-	O
1	O
locus	O
to	O
create	O
strain	O
JBY51	O
and	O
all	O
subsequent	O
experiments	O
were	O
done	O
with	O
this	O
enp1	O
allele	O
.	O

At	O
23	O
degrees	O
C	O
the	O
growth	O
of	O
JBY51	O
was	O
comparable	O
to	O
that	O
of	O
W303	O
-	O
1a	O
(	O
ENP1	O
)	O
,	O
but	O
at	O
37	O
degrees	O
C	O
it	O
did	O
not	O
grow	O
(	O
Fig	O
.	O
2	O
)	O
.	O

Sequence	O
analysis	O
revealed	O
that	O
enp1	O
-	O
1	O
contains	O
two	O
point	O
mutations	O
,	O
resulting	O
in	O
substitutions	O
of	O
two	O
amino	O
acids	O
:	O
W242	O
-	O
-	O
>	O
G	O
and	O
V415	O
-	O
-	O
>	O
A	O
.	O

No	O
attempt	O
was	O
made	O
to	O
determine	O
whether	O
both	O
mutations	O
were	O
required	O
for	O
the	O
ts	O
phenotype	O
.	O

Flow	O
cytometry	O
of	O
strain	O
JBY51	O
showed	O
DNA	O
content	O
profiles	O
similar	O
to	O
those	O
of	O
the	O
wild	O
-	O
type	O
strain	O
at	O
the	O
non	O
-	O
permissive	O
temperature	O
(	O
data	O
not	O
shown	O
)	O
,	O
suggesting	O
that	O
ENP1	O
is	O
not	O
involved	O
in	O
cell	O
cycle	O
regulation	O
.	O

Enp1	O
is	O
enriched	O
in	O
the	O
nucleolus	O

Enp1	O
tagged	O
at	O
the	O
C	O
-	O
terminus	O
with	O
the	O
myc	O
epitope	O
was	O
previously	O
found	O
to	O
localize	O
to	O
the	O
nucleus	O
(	O
18	O
)	O
.	O

To	O
expand	O
this	O
analysis	O
,	O
we	O
fused	O
GFP	O
to	O
the	O
N	O
-	O
terminus	O
of	O
Enp1	O
,	O
and	O
expressed	O
the	O
tagged	O
Enp1	O
protein	O
under	O
control	O
of	O
the	O
MET25	O
promoter	O
as	O
the	O
sole	O
source	O
of	O
Enp1	O
protein	O
in	O
the	O
cells	O
.	O

Cells	O
of	O
strain	O
CWY13	O
(	O
pMET25	O
-	O
GFP	O
-	O
ENP1	O
)	O
were	O
grown	O
in	O
media	O
with	O
methionine	O
(	O
transcription	O
partially	O
repressed	O
)	O
or	O
without	O
methionine	O
(	O
transcription	O
not	O
repressed	O
)	O
.	O

Growth	O
of	O
CWY13	O
was	O
comparable	O
to	O
that	O
of	O
wild	O
-	O
type	O
cells	O
in	O
both	O
media	O
(	O
data	O
not	O
shown	O
)	O
,	O
indicating	O
that	O
the	O
GFP	O
tagged	O
Enp1	O
protein	O
was	O
functional	O
.	O

In	O
cells	O
cultured	O
in	O
medium	O
without	O
methionine	O
,	O
in	O
which	O
the	O
ENP	O
transcription	O
was	O
not	O
repressed	O
,	O
the	O
GFP	O
-	O
Enp1	O
protein	O
was	O
expressed	O
at	O
a	O
high	O
level	O
and	O
showed	O
strong	O
green	O
fluorescence	O
distributed	O
throughout	O
the	O
nucleus	O
(	O
data	O
not	O
shown	O
)	O
,	O
consistent	O
with	O
the	O
original	O
observation	O
(	O
18	O
)	O
.	O

With	O
methionine	O
added	O
to	O
the	O
medium	O
,	O
however	O
,	O
the	O
fluorescent	O
signal	O
of	O
GFP	O
-	O
Enp1	O
was	O
weaker	O
and	O
surprisingly	O
showed	O
crescent	O
or	O
cap	O
-	O
like	O
patterns	O
typical	O
of	O
nucleolar	O
proteins	O
(	O
Fig	O
.	O
3A	O
)	O
.	O

This	O
nucleolar	O
enrichment	O
was	O
confirmed	O
by	O
its	O
co	O
-	O
localization	O
with	O
the	O
nucleolar	O
protein	O
Nop1	O
(	O
Fig	O
.	O
3B	O
)	O
.	O

ENP1	O
mutation	O
leads	O
to	O
reduced	O
levels	O
of	O
40S	O
ribosomal	O
subunits	O

The	O
nucleolar	O
enrichment	O
suggested	O
that	O
Enp1	O
might	O
play	O
some	O
role	O
in	O
ribosome	O
synthesis	O
.	O

To	O
test	O
this	O
possibility	O
,	O
cells	O
of	O
W303	O
-	O
1a	O
(	O
ENP1	O
)	O
,	O
JBY51	O
(	O
enp1	O
-	O
1	O
)	O
and	O
a	O
top2	O
ts	O
strain	O
RS191	O
(	O
30	O
)	O
were	O
grown	O
in	O
YPD	O
at	O
23	O
or	O
37	O
degrees	O
C	O
and	O
their	O
ribosome	O
profiles	O
analyzed	O
after	O
separation	O
on	O
sucrose	O
gradients	O
.	O

At	O
23	O
degrees	O
C	O
,	O
enp1	O
-	O
1	O
cells	O
showed	O
polysome	O
profiles	O
similar	O
to	O
those	O
of	O
the	O
wild	O
-	O
type	O
and	O
top2	O
-	O
1	O
strains	O
(	O
Fig	O
.	O
4A	O
-	O
C	O
)	O
.	O

In	O
contrast	O
,	O
after	O
incubation	O
at	O
the	O
non	O
-	O
permissive	O
temperature	O
(	O
37	O
degrees	O
C	O
)	O
for	O
40	O
min	O
(	O
data	O
not	O
shown	O
)	O
and	O
2	O
h	O
,	O
enp1	O
-	O
1	O
cells	O
had	O
reduced	O
levels	O
of	O
40S	O
ribosomal	O
subunits	O
,	O
80S	O
monosomes	O
and	O
polysomes	O
,	O
along	O
with	O
a	O
dramatic	O
increase	O
in	O
the	O
free	O
60S	O
subunit	O
peak	O
(	O
Fig	O
.	O
4F	O
)	O
,	O
while	O
the	O
wild	O
-	O
type	O
and	O
top2	O
-	O
1	O
cells	O
showed	O
little	O
change	O
in	O
polysome	O
profile	O
at	O
37	O
degrees	O
C	O
(	O
Fig	O
.	O
4D	O
and	O
E	O
)	O
.	O

These	O
results	O
demonstrate	O
that	O
the	O
changes	O
of	O
the	O
enp1	O
-	O
1	O
polysome	O
profile	O
were	O
due	O
to	O
specific	O
defects	O
caused	O
by	O
the	O
enp1	O
-	O
1	O
mutation	O
,	O
and	O
not	O
due	O
simply	O
to	O
the	O
shift	O
to	O
37	O
degrees	O
C	O
for	O
a	O
wild	O
-	O
type	O
or	O
ts	O
strain	O
.	O

The	O
processing	O
of	O
pre	O
-	O
rRNA	O
for	O
18S	O
rRNA	O
is	O
impaired	O
in	O
enp1	O
mutants	O

In	O
most	O
cases	O
reductions	O
in	O
ribosomal	O
subunit	O
levels	O
are	O
the	O
results	O
of	O
defects	O
in	O
pre	O
-	O
rRNA	O
processing	O
or	O
ribosome	O
assembly	O
or	O
both	O
(	O
3	O
)	O
.	O

To	O
study	O
the	O
mechanism	O
by	O
which	O
Enp1	O
affects	O
the	O
40S	O
subunit	O
,	O
we	O
analyzed	O
the	O
effects	O
of	O
enp1	O
mutations	O
on	O
processing	O
of	O
the	O
pre	O
-	O
rRNA	O
using	O
pulse	O
-	O
chase	O
labeling	O
.	O

[	O
methyl	O
-	O
3H	O
]	O
methionine	O
is	O
preferred	O
for	O
labeling	O
rRNAs	O
in	O
pulse	O
-	O
chase	O
analysis	O
because	O
rRNAs	O
are	O
specifically	O
methylated	O
during	O
the	O
early	O
steps	O
of	O
the	O
processing	O
.	O

Cells	O
of	O
W303	O
-	O
1a	O
(	O
ENP1	O
)	O
and	O
JBY51	O
(	O
enp1	O
-	O
1	O
)	O
were	O
grown	O
at	O
23	O
or	O
37	O
degrees	O
C	O
for	O
2	O
h	O
before	O
they	O
were	O
labeled	O
with	O
[	O
methyl	O
-	O
3H	O
]	O
methionine	O
for	O
3	O
min	O
and	O
chased	O
with	O
cold	O
methionine	O
for	O
2	O
,	O
4	O
and	O
12	O
min	O
.	O

In	O
wild	O
-	O
type	O
cells	O
,	O
the	O
labeled	O
35S	O
rRNA	O
precursor	O
,	O
27S	O
and	O
20S	O
rRNA	O
intermediates	O
were	O
rapidly	O
chased	O
into	O
mature	O
25S	O
and	O
18S	O
rRNAs	O
(	O
Fig	O
.	O
5	O
)	O
,	O
at	O
23	O
or	O
37	O
degrees	O
C	O
.	O

In	O
contrast	O
,	O
enp1	O
-	O
1	O
cells	O
showed	O
dramatic	O
changes	O
after	O
incubation	O
at	O
37	O
degrees	O
C	O
.	O

Although	O
at	O
23	O
degrees	O
C	O
the	O
synthesis	O
and	O
processing	O
were	O
comparable	O
to	O
those	O
of	O
wild	O
-	O
type	O
cells	O
,	O
cells	O
cultured	O
at	O
37	O
degrees	O
C	O
for	O
2	O
h	O
had	O
neither	O
20S	O
pre	O
-	O
rRNA	O
nor	O
18S	O
rRNA	O
,	O
while	O
25S	O
rRNA	O
was	O
generated	O
at	O
normal	O
levels	O
.	O

The	O
37	O
degrees	O
C	O
grown	O
enp1	O
-	O
1	O
cells	O
also	O
had	O
low	O
levels	O
of	O
aberrant	O
23S	O
and	O
possibly	O
21S	O
intermediates	O
(	O
Fig	O
.	O
5	O
)	O
.	O

The	O
defect	O
in	O
18S	O
rRNA	O
synthesis	O
was	O
further	O
supported	O
by	O
pulse	O
-	O
chase	O
experiments	O
carried	O
out	O
using	O
[	O
5	O
,	O
6	O
-	O
3H	O
]	O
uracil	O
.	O

The	O
results	O
obtained	O
were	O
essentially	O
the	O
same	O
;	O
no	O
20S	O
pre	O
-	O
rRNA	O
or	O
18S	O
rRNA	O
was	O
produced	O
,	O
while	O
processing	O
to	O
25S	O
rRNA	O
was	O
not	O
affected	O
(	O
data	O
not	O
shown	O
)	O
.	O

Taken	O
together	O
,	O
these	O
results	O
suggested	O
that	O
the	O
enp1	O
mutation	O
leads	O
to	O
specific	O
defects	O
in	O
the	O
processing	O
pathway	O
for	O
20S	O
pre	O
-	O
rRNA	O
and	O
18S	O
rRNA	O
,	O
resulting	O
in	O
reduced	O
40S	O
subunit	O
synthesis	O
and	O
a	O
lowered	O
level	O
of	O
the	O
40S	O
subunit	O
.	O

Enp1	O
is	O
required	O
for	O
pre	O
-	O
rRNA	O
processing	O
at	O
A0	O
,	O
A1	O
and	O
A2	O
sites	O

To	O
define	O
the	O
processing	O
steps	O
affected	O
by	O
the	O
enp1	O
mutation	O
,	O
the	O
steady	O
state	O
levels	O
of	O
rRNA	O
precursors	O
and	O
mature	O
RNAs	O
were	O
analyzed	O
by	O
northern	O
blotting	O
.	O

Total	O
RNAs	O
were	O
isolated	O
from	O
cells	O
of	O
W303	O
-	O
1a	O
(	O
ENP1	O
)	O
and	O
JBY51	O
(	O
enp1	O
-	O
1	O
)	O
grown	O
at	O
37	O
degrees	O
C	O
for	O
2	O
or	O
4	O
h	O
.	O

After	O
separation	O
on	O
formaldehyde	O
agarose	O
,	O
RNAs	O
were	O
transferred	O
onto	O
nylon	O
membranes	O
and	O
probed	O
with	O
radiolabeled	O
oligonucleotides	O
specific	O
to	O
various	O
regions	O
of	O
the	O
35S	O
pre	O
-	O
rRNA	O
(	O
Fig	O
.	O
6A	O
)	O
.	O

After	O
incubation	O
at	O
37	O
degrees	O
C	O
,	O
enp1	O
-	O
1	O
cells	O
had	O
wild	O
-	O
type	O
levels	O
of	O
25S	O
rRNA	O
,	O
but	O
reduced	O
levels	O
of	O
18S	O
rRNA	O
(	O
Fig	O
.	O
6B	O
)	O
.	O

A	O
probe	O
specific	O
to	O
ITS1	O
(	O
P5	O
)	O
further	O
revealed	O
that	O
enp1	O
-	O
1	O
cells	O
incubated	O
at	O
the	O
non	O
-	O
permissive	O
temperature	O
accumulated	O
two	O
aberrant	O
rRNAs	O
,	O
23S	O
and	O
21S	O
(	O
Fig	O
.	O
6C	O
)	O
.	O

Aberrant	O
rRNA	O
processing	O
products	O
of	O
similar	O
sizes	O
have	O
been	O
described	O
in	O
numerous	O
studies	O
(	O
14	O
,	O
31	O
-	O
34	O
)	O
and	O
result	O
from	O
defects	O
in	O
processing	O
at	O
A0	O
,	O
A1	O
and	O
A2	O
.	O

Additional	O
probes	O
were	O
used	O
to	O
verify	O
the	O
origins	O
of	O
the	O
23S	O
and	O
21S	O
RNAs	O
in	O
the	O
enp1	O
-	O
1	O
strain	O
.	O

The	O
23S	O
product	O
was	O
detected	O
by	O
oligos	O
1	O
,	O
2	O
,	O
4	O
and	O
5	O
,	O
but	O
not	O
by	O
oligos	O
6	O
,	O
7	O
or	O
8	O
(	O
Fig	O
.	O
6D	O
,	O
E	O
,	O
C	O
,	O
F	O
,	O
G	O
and	O
data	O
not	O
shown	O
)	O
.	O

Thus	O
this	O
RNA	O
extends	O
from	O
the	O
5	O
'	O
end	O
of	O
the	O
35S	O
rRNA	O
to	O
the	O
A3	O
site	O
.	O

The	O
21S	O
product	O
was	O
detected	O
by	O
oligos	O
4	O
and	O
5	O
,	O
but	O
not	O
by	O
oligos	O
1	O
,	O
2	O
,	O
6	O
,	O
7	O
and	O
8	O
(	O
Fig	O
.	O
6E	O
,	O
C	O
,	O
D	O
,	O
F	O
,	O
G	O
and	O
data	O
not	O
shown	O
)	O
,	O
indicating	O
that	O
it	O
extends	O
from	O
the	O
A1	O
to	O
the	O
A3	O
site	O
.	O

At	O
37	O
degrees	O
C	O
the	O
enp1	O
-	O
1	O
cells	O
also	O
had	O
less	O
32S	O
and	O
20S	O
rRNA	O
intermediates	O
(	O
Fig	O
.	O
6B	O
and	O
E	O
)	O
.	O

These	O
results	O
suggest	O
that	O
the	O
enp1	O
mutation	O
led	O
to	O
complete	O
or	O
nearly	O
complete	O
inhibition	O
of	O
processing	O
at	O
site	O
A0	O
and	O
A2	O
,	O
and	O
partial	O
inhibition	O
of	O
processing	O
at	O
site	O
A1	O
.	O

As	O
a	O
consequence	O
,	O
the	O
35S	O
pre	O
-	O
rRNA	O
was	O
cleaved	O
at	O
site	O
A3	O
instead	O
,	O
producing	O
23S	O
and	O
21S	O
rRNA	O
products	O
.	O

Consistent	O
with	O
this	O
theory	O
,	O
the	O
27SA2	O
rRNA	O
intermediate	O
level	O
was	O
greatly	O
reduced	O
in	O
enp1	O
cells	O
at	O
37	O
degrees	O
C	O
(	O
Fig	O
.	O
6C	O
)	O
due	O
to	O
the	O
inhibition	O
of	O
processing	O
at	O
A2	O
,	O
while	O
the	O
27SB	O
pre	O
-	O
rRNA	O
level	O
was	O
similar	O
to	O
wild	O
-	O
type	O
cells	O
(	O
Fig	O
.	O
6G	O
)	O
.	O

Moreover	O
,	O
no	O
difference	O
in	O
the	O
5	O
.	O
8	O
rRNA	O
level	O
was	O
observed	O
between	O
the	O
wild	O
-	O
type	O
cells	O
and	O
enp1	O
cells	O
(	O
Fig	O
.	O
6H	O
)	O
.	O

Enp1	O
is	O
associated	O
with	O
U3	O
and	O
U14	O
snoRNAs	O
and	O
with	O
Nop1	O

It	O
has	O
previously	O
been	O
shown	O
that	O
mutations	O
in	O
the	O
U3	O
,	O
U14	O
,	O
snR10	O
and	O
snR30	O
snoRNAs	O
and	O
in	O
their	O
associated	O
proteins	O
affect	O
processing	O
of	O
35S	O
pre	O
-	O
rRNA	O
at	O
A0	O
,	O
A1	O
and	O
A2	O
.	O

Because	O
of	O
the	O
similarity	O
with	O
the	O
processing	O
defects	O
of	O
enp1	O
-	O
1	O
strains	O
,	O
we	O
tested	O
the	O
association	O
between	O
Enp1	O
and	O
snoRNAs	O
.	O

To	O
do	O
this	O
,	O
we	O
created	O
a	O
strain	O
in	O
which	O
a	O
TAP	O
tag	O
was	O
fused	O
to	O
the	O
C	O
-	O
terminus	O
of	O
Enp1	O
.	O

The	O
TAP	O
tag	O
contains	O
Staphylococcus	B
aureus	I
Protein	O
A	O
as	O
well	O
as	O
calmodulin	O
-	O
binding	O
peptide	O
sequences	O
,	O
so	O
the	O
tagged	O
Enp1	O
binds	O
IgG	O
beads	O
with	O
high	O
specificity	O
.	O

Cells	O
grew	O
well	O
with	O
the	O
TAP	O
-	O
tagged	O
Enp1	O
as	O
the	O
only	O
source	O
of	O
Enp1	O
protein	O
,	O
showing	O
that	O
it	O
was	O
functional	O
.	O

As	O
a	O
control	O
,	O
we	O
used	O
a	O
TAP	O
tag	O
on	O
an	O
unrelated	O
cytoplasmic	O
protein	O
,	O
Hst2	O
.	O

Strain	O
CWY14	O
(	O
ENP1	O
-	O
TAP	O
)	O
and	O
the	O
Hst2	O
-	O
TAP	O
tagged	O
strain	O
were	O
grown	O
in	O
YPD	O
to	O
mid	O
-	O
exponential	O
phase	O
before	O
being	O
harvested	O
.	O

Extracts	O
were	O
prepared	O
and	O
mixed	O
with	O
IgG	O
agarose	O
beads	O
to	O
precipitate	O
Enp1	O
-	O
TAP	O
and	O
associated	O
RNAs	O
.	O

Total	O
RNAs	O
were	O
extracted	O
from	O
washed	O
IgG	O
beads	O
,	O
separated	O
on	O
6	O
%	O
polyacrylamide	O
denaturing	O
gels	O
,	O
transferred	O
to	O
nylon	O
membranes	O
and	O
probed	O
with	O
radiolabeled	O
oligonucleotides	O
.	O

Northern	O
analysis	O
revealed	O
that	O
Enp1	O
-	O
TAP	O
precipitates	O
were	O
enriched	O
with	O
U3	O
and	O
U14	O
snoRNAs	O
relative	O
to	O
precipitates	O
from	O
the	O
Hst2	O
-	O
tagged	O
strain	O
(	O
Fig	O
.	O
7A	O
)	O
.	O

The	O
Enp1	O
-	O
TAP	O
samples	O
were	O
not	O
enriched	O
with	O
snR30	O
snoRNA	O
(	O
Fig	O
.	O
7A	O
)	O
,	O
nor	O
with	O
U24	O
or	O
U18	O
snoRNAs	O
(	O
data	O
not	O
shown	O
)	O
.	O

We	O
found	O
no	O
change	O
in	O
the	O
levels	O
of	O
U3	O
,	O
U14	O
,	O
snR10	O
and	O
snR30	O
snoRNAs	O
in	O
the	O
enp1	O
mutant	O
,	O
indicating	O
that	O
the	O
mutation	O
did	O
not	O
affect	O
snoRNAs	O
levels	O
(	O
Fig	O
.	O
6I	O
)	O
.	O

The	O
results	O
indicate	O
that	O
Enp1	O
associates	O
in	O
vivo	O
with	O
U3	O
and	O
U14	O
snoRNAs	O
.	O

Much	O
less	O
U3	O
RNA	O
co	O
-	O
immunoprecipitated	O
with	O
Enp1	O
-	O
TAP	O
than	O
with	O
Protein	O
A	O
-	O
tagged	O
Nop1	O
,	O
which	O
is	O
known	O
to	O
associate	O
with	O
U3	O
and	O
U14	O
snoRNAs	O
(	O
Fig	O
.	O
7A	O
)	O
.	O

However	O
,	O
Protein	O
A	O
-	O
Nop1	O
was	O
much	O
more	O
efficiently	O
precipitated	O
than	O
was	O
the	O
Enp1	O
-	O
TAP	O
protein	O
(	O
data	O
not	O
shown	O
)	O
.	O

Therefore	O
,	O
it	O
is	O
likely	O
that	O
similar	O
amounts	O
of	O
RNAs	O
are	O
associated	O
with	O
the	O
two	O
proteins	O
and	O
that	O
the	O
proteins	O
are	O
part	O
of	O
the	O
same	O
complex	O
.	O

To	O
address	O
this	O
further	O
,	O
we	O
checked	O
for	O
the	O
presence	O
of	O
Nop1	O
in	O
the	O
Enp1	O
-	O
TAP	O
immunoprecipitates	O
.	O

Figure	O
7B	O
shows	O
that	O
Nop1	O
indeed	O
is	O
in	O
the	O
Enp1	O
precipitate	O
but	O
not	O
in	O
the	O
Hst2	O
control	O
,	O
whereas	O
an	O
abundant	O
ribosomal	O
protein	O
,	O
L3	O
,	O
is	O
in	O
neither	O
precipitate	O
.	O

U3	O
and	O
U14	O
snoRNAs	O
have	O
been	O
shown	O
to	O
interact	O
with	O
rRNA	O
precursors	O
and	O
these	O
interactions	O
are	O
required	O
for	O
pre	O
-	O
rRNA	O
processing	O
(	O
35	O
-	O
37	O
)	O
.	O

Using	O
an	O
in	O
vitro	O
system	O
,	O
U3	O
was	O
also	O
shown	O
to	O
be	O
associated	O
with	O
its	O
rRNA	O
substrate	O
and	O
processing	O
product	O
(	O
38	O
)	O
.	O

This	O
raised	O
the	O
possibility	O
that	O
Enp1	O
might	O
also	O
be	O
associated	O
with	O
rRNAs	O
since	O
its	O
function	O
in	O
rRNA	O
processing	O
appeared	O
linked	O
to	O
those	O
of	O
U3	O
and	O
U14	O
snoRNAs	O
.	O

To	O
test	O
this	O
possibility	O
,	O
we	O
further	O
analyzed	O
the	O
RNAs	O
that	O
co	O
-	O
precipiate	O
with	O
TAP	O
-	O
tagged	O
Enp1	O
.	O

The	O
RNAs	O
were	O
separated	O
on	O
1	O
.	O
2	O
%	O
agarose	O
formaldehyde	O
gels	O
or	O
on	O
polyacrylamide	O
denaturing	O
gels	O
,	O
transferred	O
to	O
nylon	O
membranes	O
and	O
probed	O
with	O
radiolabeled	O
oligonucleotides	O
for	O
pre	O
-	O
rRNAs	O
.	O

A	O
probe	O
(	O
P4	O
;	O
see	O
Fig	O
.	O
6	O
)	O
specific	O
to	O
20s	O
and	O
its	O
precursors	O
revealed	O
that	O
pre	O
-	O
rRNAs	O
35S	O
,	O
33S	O
,	O
32S	O
and	O
20S	O
specifically	O
co	O
-	O
precipitated	O
with	O
Enp1	O
-	O
TAP	O
(	O
Fig	O
.	O
7C	O
)	O
.	O

No	O
such	O
enrichment	O
was	O
found	O
using	O
a	O
probe	O
(	O
P8	O
;	O
see	O
Fig	O
.	O
6	O
)	O
specific	O
for	O
27S	O
RNAs	O
or	O
a	O
probe	O
for	O
5	O
.	O
8S	O
RNA	O
(	O
Fig	O
.	O
7C	O
)	O
.	O

These	O
results	O
clearly	O
demonstrated	O
that	O
Enp1	O
is	O
associated	O
with	O
substrates	O
and	O
products	O
of	O
the	O
early	O
steps	O
of	O
18S	O
rRNA	O
processing	O
.	O

Comparison	O
of	O
Enp1	O
with	O
homologs	O
in	O
other	O
organisms	O

Homologs	O
of	O
Enp1	O
protein	O
in	O
human	B
,	O
Drosophila	B
and	O
Caenorhabditis	B
elegans	I
have	O
been	O
reported	O
(	O
18	O
)	O
.	O

A	O
previously	O
described	O
human	B
homolog	O
,	O
bystin	O
,	O
was	O
only	O
306	O
amino	O
acids	O
in	O
length	O
,	O
and	O
lacked	O
sequences	O
corresponding	O
to	O
the	O
N	O
-	O
terminal	O
163	O
amino	O
acids	O
of	O
yeast	B
Enp1	O
(	O
19	O
)	O
.	O

In	O
contrast	O
,	O
we	O
identified	O
a	O
human	B
expressed	O
sequence	O
tag	O
(	O
EST	O
)	O
,	O
BC007340	O
in	O
a	O
Blast	O
search	O
that	O
revealed	O
an	O
ORF	O
of	O
1311	O
nucleotides	O
encoding	O
a	O
437	O
amino	O
acid	O
polypeptide	O
(	O
39	O
)	O
.	O

Comparison	O
of	O
this	O
437	O
amino	O
acid	O
polypeptide	O
with	O
human	B
bystin	O
(	O
19	O
)	O
showed	O
that	O
they	O
were	O
encoded	O
by	O
the	O
same	O
gene	O
on	O
human	B
chromosome	O
6	O
.	O

The	O
reported	O
sequence	O
for	O
human	B
bystin	O
is	O
a	O
fragment	O
of	O
the	O
437	O
amino	O
acid	O
human	B
Enp1	O
protein	O
,	O
due	O
to	O
a	O
truncated	O
cDNA	O
sequence	O
.	O

Also	O
,	O
a	O
sequence	O
discrepancy	O
at	O
the	O
C	O
-	O
terminus	O
is	O
due	O
to	O
inaccurate	O
DNA	O
sequence	O
of	O
the	O
human	B
bystin	O
,	O
as	O
confirmed	O
by	O
available	O
human	B
genome	O
and	O
EST	O
sequences	O
.	O

Searches	O
of	O
the	O
database	O
of	O
other	O
organisms	O
identified	O
Enp1	O
homologs	O
in	O
S	B
.	I
pombe	I
,	O
Arabidopsis	B
thaliana	I
,	O
C	B
.	I
elegans	I
,	O
Drosophila	B
melanogaster	I
and	O
mouse	B
.	O

The	O
alignment	O
of	O
the	O
homologs	O
showed	O
that	O
they	O
shared	O
homology	O
from	O
the	O
N	O
-	O
terminus	O
to	O
the	O
C	O
-	O
terminus	O
,	O
with	O
the	O
C	O
-	O
terminal	O
half	O
extremely	O
well	O
conserved	O
,	O
with	O
close	O
to	O
90	O
%	O
similarity	O
(	O
Fig	O
.	O
8	O
)	O
.	O

One	O
interesting	O
observation	O
is	O
that	O
the	O
two	O
amino	O
acids	O
changed	O
in	O
the	O
enp1	O
-	O
1	O
mutant	O
,	O
W242	O
and	O
V415	O
,	O
are	O
conserved	O
among	O
all	O
homologs	O
.	O

The	O
human	B
Enp1	O
homolog	O
was	O
cloned	O
and	O
expressed	O
in	O
yeast	B
and	O
tested	O
for	O
function	O
.	O

Expressed	O
under	O
the	O
control	O
of	O
ADH	O
,	O
TEF	O
or	O
GPD	O
promoter	O
,	O
the	O
human	B
Enp1	O
homolog	O
did	O
not	O
complement	O
a	O
yeast	B
enp1	O
null	O
mutant	O
.	O

However	O
,	O
a	O
GFP	O
fusion	O
to	O
the	O
N	O
-	O
terminus	O
of	O
human	B
Enp1	O
homolog	O
localized	O
to	O
the	O
nucleus	O
and	O
was	O
enriched	O
in	O
the	O
nucleolus	O
(	O
data	O
not	O
shown	O
)	O
.	O

DISCUSSION	O

ENP1	O
is	O
a	O
yeast	B
gene	O
first	O
identified	O
in	O
a	O
genetic	O
screen	O
for	O
complementation	O
of	O
mutations	O
in	O
ost4	O
,	O
which	O
encodes	O
a	O
subunit	O
of	O
oligosaccharide	O
transferase	O
(	O
17	O
)	O
,	O
although	O
subsequent	O
work	O
showed	O
that	O
it	O
is	O
unlikely	O
that	O
Enp1	O
has	O
any	O
connection	O
to	O
oligosaccharide	O
transferase	O
(	O
18	O
)	O
.	O

ENP1	O
was	O
shown	O
to	O
be	O
essential	O
for	O
viability	O
and	O
the	O
Enp1	O
protein	O
localized	O
to	O
the	O
nucleus	O
(	O
18	O
)	O
.	O

When	O
we	O
re	O
-	O
examined	O
the	O
localization	O
of	O
Enp1	O
,	O
we	O
observed	O
that	O
the	O
protein	O
was	O
enriched	O
in	O
the	O
nucleolus	O
.	O

This	O
finding	O
led	O
us	O
to	O
test	O
for	O
a	O
role	O
of	O
Enp1	O
in	O
ribosome	O
synthesis	O
.	O

Using	O
an	O
enp1	O
ts	O
mutant	O
,	O
we	O
found	O
that	O
depletion	O
of	O
Enp1	O
caused	O
a	O
40S	O
ribosomal	O
subunit	O
deficiency	O
.	O

Further	O
analysis	O
revealed	O
that	O
this	O
deficiency	O
was	O
not	O
due	O
to	O
a	O
change	O
of	O
the	O
subunit	O
'	O
s	O
stability	O
,	O
but	O
to	O
a	O
defect	O
in	O
the	O
synthesis	O
of	O
the	O
subunit	O
'	O
s	O
18S	O
rRNA	O
component	O
.	O

Pulse	O
-	O
chase	O
analysis	O
of	O
RNA	O
synthesis	O
in	O
an	O
enp1	O
-	O
1	O
strain	O
revealed	O
that	O
no	O
20S	O
pre	O
-	O
rRNA	O
or	O
18S	O
rRNA	O
was	O
made	O
at	O
the	O
non	O
-	O
permissive	O
temperature	O
,	O
while	O
levels	O
of	O
25S	O
rRNA	O
appeared	O
normal	O
.	O

Low	O
levels	O
of	O
precursors	O
to	O
18S	O
rRNA	O
were	O
detected	O
in	O
the	O
mutants	O
,	O
and	O
they	O
were	O
extremely	O
unstable	O
.	O

Northern	O
analysis	O
of	O
steady	O
state	O
RNA	O
levels	O
demonstrated	O
that	O
the	O
enp1	O
mutation	O
specifically	O
inhibited	O
the	O
pre	O
-	O
rRNA	O
early	O
cleavages	O
at	O
sites	O
A0	O
,	O
A1	O
and	O
A2	O
,	O
which	O
are	O
required	O
for	O
the	O
production	O
of	O
the	O
20S	O
pre	O
-	O
rRNA	O
and	O
the	O
18S	O
rRNA	O
.	O

These	O
defects	O
of	O
the	O
enp1	O
mutation	O
on	O
rRNA	O
processing	O
are	O
very	O
similar	O
to	O
those	O
caused	O
by	O
mutation	O
of	O
KRR1	O
,	O
another	O
essential	O
nucleolar	O
gene	O
required	O
for	O
synthesis	O
of	O
the	O
40S	O
,	O
but	O
not	O
the	O
60S	O
subunit	O
(	O
40	O
)	O
.	O

Co	O
-	O
precipitation	O
analyses	O
provided	O
strong	O
evidence	O
that	O
Enp1	O
is	O
directly	O
involved	O
in	O
pre	O
-	O
rRNA	O
processing	O
.	O

In	O
these	O
experiments	O
,	O
TAP	O
-	O
tagged	O
Enp1	O
bound	O
to	O
IgG	O
beads	O
specifically	O
co	O
-	O
precipitated	O
with	O
two	O
snoRNAs	O
,	O
U3	O
and	O
U14	O
,	O
and	O
with	O
the	O
35S	O
,	O
33S	O
,	O
32S	O
and	O
20S	O
pre	O
-	O
rRNAs	O
.	O

Among	O
the	O
more	O
than	O
100	O
snoRNAs	O
in	O
yeast	B
cells	O
,	O
U3	O
,	O
U14	O
,	O
snR10	O
,	O
snR30	O
and	O
MRP	O
RNA	O
are	O
the	O
only	O
ones	O
required	O
for	O
rRNA	O
processing	O
.	O

It	O
has	O
been	O
shown	O
that	O
mutations	O
in	O
U3	O
,	O
U14	O
,	O
snR10	O
and	O
snR30	O
snoRNAs	O
and	O
protein	O
components	O
of	O
the	O
snoRNPs	O
affect	O
processing	O
at	O
sites	O
A0	O
,	O
A1	O
or	O
A2	O
(	O
15	O
,	O
16	O
,	O
41	O
,	O
42	O
)	O
.	O

Enp1	O
'	O
s	O
interaction	O
with	O
U3	O
and	O
U14	O
snoRNAs	O
suggests	O
that	O
Enp1	O
'	O
s	O
function	O
in	O
rRNA	O
processing	O
involves	O
these	O
two	O
snoRNAs	O
.	O

The	O
fact	O
that	O
the	O
nucleolar	O
protein	O
,	O
Nop1	O
,	O
known	O
to	O
bind	O
to	O
U3	O
and	O
U14	O
RNAs	O
,	O
also	O
was	O
found	O
in	O
the	O
Enp1	O
precipitate	O
,	O
provides	O
additional	O
evidence	O
that	O
Enp1	O
is	O
part	O
of	O
a	O
complex	O
involved	O
in	O
processing	O
of	O
rRNA	O
.	O

Recently	O
,	O
a	O
genome	O
-	O
wide	O
study	O
of	O
yeast	B
protein	O
complexes	O
,	O
using	O
a	O
TAP	O
tag	O
method	O
similar	O
to	O
ours	O
,	O
reported	O
a	O
number	O
of	O
proteins	O
that	O
co	O
-	O
immunoprecipitated	O
with	O
Enp1	O
(	O
43	O
)	O
.	O

These	O
proteins	O
included	O
Imp4	O
,	O
Kre31	O
,	O
Kre33	O
,	O
Mpp10	O
,	O
Nop1	O
,	O
Nop14	O
and	O
Sof1	O
,	O
all	O
of	O
which	O
have	O
been	O
implicated	O
in	O
18S	O
RNA	O
processing	O
or	O
40S	O
biogenesis	O
.	O

Very	O
recently	O
(	O
after	O
the	O
studies	O
in	O
this	O
manuscript	O
were	O
concluded	O
)	O
Grandi	O
et	O
al	O
.	O
published	O
an	O
analysis	O
of	O
components	O
of	O
the	O
90s	O
preribosomal	O
particle	O
,	O
which	O
include	O
the	O
35S	O
pre	O
-	O
rRNA	O
,	O
U3	O
snoRNP	O
and	O
rRNA	O
processing	O
factors	O
for	O
the	O
40S	O
subunit	O
(	O
44	O
)	O
.	O

In	O
agreement	O
with	O
our	O
findings	O
,	O
they	O
found	O
that	O
Enp1	O
is	O
a	O
component	O
of	O
this	O
90s	O
complex	O
and	O
also	O
of	O
a	O
smaller	O
complex	O
containing	O
the	O
20S	O
pre	O
-	O
rRNA	O
.	O

Surprisingly	O
,	O
none	O
of	O
the	O
other	O
proteins	O
involved	O
in	O
processing	O
of	O
pre	O
-	O
rRNAs	O
that	O
were	O
tested	O
associated	O
with	O
the	O
20S	O
rRNA	O
,	O
suggesting	O
that	O
those	O
proteins	O
,	O
but	O
not	O
Enp1	O
,	O
are	O
released	O
prior	O
to	O
20S	O
pre	O
-	O
rRNA	O
formation	O
(	O
44	O
)	O
.	O

The	O
authors	O
also	O
showed	O
co	O
-	O
precipitation	O
of	O
Enp1	O
with	O
dimethylated	O
20S	O
pre	O
-	O
rRNA	O
,	O
which	O
is	O
formed	O
after	O
export	O
of	O
20S	O
to	O
the	O
cytoplasm	O
.	O

These	O
results	O
of	O
Grandi	O
et	O
al	O
.	O
suggest	O
that	O
Enp1	O
may	O
also	O
be	O
involved	O
in	O
later	O
steps	O
of	O
processing	O
or	O
nuclear	O
export	O
.	O

A	O
previous	O
study	O
on	O
the	O
Enp1	O
human	B
homolog	O
,	O
bystin	O
,	O
reported	O
that	O
the	O
protein	O
was	O
localized	O
in	O
the	O
cytoplasm	O
of	O
mammalian	O
cells	O
and	O
might	O
be	O
involved	O
in	O
cell	O
adhesion	O
(	O
19	O
)	O
.	O

Our	O
discovery	O
of	O
the	O
437	O
amino	O
acid	O
human	B
Enp1	O
homolog	O
revealed	O
that	O
the	O
bystin	O
studied	O
previously	O
was	O
from	O
a	O
truncated	O
library	O
cDNA	O
encoding	O
only	O
the	O
C	O
-	O
terminal	O
306	O
amino	O
acids	O
.	O

Although	O
the	O
human	B
homolog	O
of	O
Enp1	O
did	O
not	O
complement	O
a	O
yeast	B
Delta	O
enp1	O
mutant	O
,	O
we	O
did	O
show	O
that	O
it	O
was	O
localized	O
to	O
the	O
nucleus	O
and	O
enriched	O
in	O
the	O
nucleolus	O
(	O
data	O
not	O
shown	O
)	O
.	O

This	O
strongly	O
suggests	O
that	O
the	O
conserved	O
function	O
of	O
Enp1	O
is	O
in	O
rRNA	O
processing	O
.	O

The	O
cytoplasmic	O
localization	O
of	O
bystin	O
and	O
its	O
proposed	O
function	O
in	O
cell	O
adhesion	O
are	O
unlikely	O
to	O
reflect	O
the	O
actual	O
function	O
of	O
the	O
human	B
Enp1	O
homolog	O
.	O

It	O
will	O
be	O
important	O
to	O
study	O
the	O
nature	O
of	O
the	O
associations	O
between	O
Enp1	O
and	O
U3	O
and	O
U14	O
snoRNPs	O
,	O
and	O
to	O
learn	O
more	O
about	O
the	O
exact	O
role	O
of	O
Enp1	O
in	O
ribosomal	O
RNA	O
processing	O
.	O

Piezoelectric	O
osteotomy	O
in	O
hand	O
surgery	O
:	O
first	O
experiences	O
with	O
a	O
new	O
technique	O

Abstract	O

Background	O

In	O
hand	O
and	O
spinal	O
surgery	O
nerve	O
lesions	O
are	O
feared	O
complications	O
with	O
the	O
use	O
of	O
standard	O
oscillating	O
saws	O
.	O

Oral	O
surgeons	O
have	O
started	O
using	O
a	O
newly	O
developed	O
ultrasound	O
bone	O
scalpel	O
when	O
performing	O
precise	O
osteotomies	O
.	O

By	O
using	O
a	O
frequency	O
of	O
25	O
-	O
29	O
kHz	O
only	O
mineralized	O
tissue	O
is	O
cut	O
,	O
sparing	O
the	O
soft	O
tissue	O
.	O

This	O
reduces	O
the	O
risk	O
of	O
nerve	O
lesions	O
.	O

As	O
there	O
is	O
a	O
lack	O
of	O
experience	O
with	O
this	O
technique	O
in	O
the	O
field	O
of	O
orthopaedic	O
bone	O
surgery	O
,	O
we	O
performed	O
the	O
first	O
ultrasound	O
osteotomy	O
in	O
hand	O
surgery	O
.	O

Method	O

While	O
performing	O
a	O
correctional	O
osteotomy	O
of	O
the	O
5th	O
metacarpal	O
bone	O
we	O
used	O
the	O
Piezosurgery	O
(	O
R	O
)	O
Device	O
from	O
Mectron	O
[	O
Italy	O
]	O
instead	O
of	O
the	O
usual	O
oscillating	O
saw	O
.	O

We	O
will	O
report	O
on	O
our	O
experience	O
with	O
one	O
case	O
,	O
with	O
a	O
follow	O
up	O
time	O
of	O
one	O
year	O
.	O

Results	O

The	O
cut	O
was	O
highly	O
precise	O
and	O
there	O
were	O
no	O
vibrations	O
of	O
the	O
bone	O
.	O

The	O
time	O
needed	O
for	O
the	O
operation	O
was	O
slightly	O
longer	O
than	O
the	O
time	O
needed	O
while	O
using	O
the	O
usual	O
saw	O
.	O

Bone	O
healing	O
was	O
good	O
and	O
at	O
no	O
point	O
were	O
there	O
any	O
neurovascular	O
disturbances	O
.	O

Conclusion	O

The	O
Piezosurgery	O
(	O
R	O
)	O
Device	O
is	O
useful	O
for	O
small	O
long	O
bone	O
osteotomies	O
.	O

Using	O
the	O
fine	O
tip	O
enables	O
curved	O
cutting	O
and	O
provides	O
an	O
opportunity	O
for	O
new	O
osteotomy	O
techniques	O
.	O

As	O
the	O
device	O
selectively	O
cuts	O
bone	O
we	O
feel	O
that	O
this	O
device	O
has	O
great	O
potential	O
in	O
the	O
field	O
of	O
hand	O
-	O
and	O
spinal	O
surgery	O
.	O

Background	O

For	O
osteotomies	O
of	O
the	O
hand	O
oscillating	O
saws	O
are	O
usually	O
used	O
[	O
1	O
]	O
.	O

Even	O
though	O
they	O
are	O
varied	O
in	O
size	O
,	O
they	O
are	O
not	O
very	O
precise	O
for	O
use	O
in	O
the	O
vicinity	O
of	O
nerves	O
and	O
arteries	O
.	O

They	O
also	O
pose	O
problems	O
while	O
being	O
used	O
in	O
conjunction	O
with	O
magnification	O
,	O
as	O
one	O
'	O
s	O
range	O
of	O
sight	O
and	O
focus	O
is	O
restricted	O
when	O
wearing	O
magnifying	O
glasses	O
.	O

For	O
that	O
reason	O
oral	O
surgeons	O
have	O
moved	O
to	O
using	O
the	O
newly	O
developed	O
piezoelectrical	O
bone	O
scalpel	O
when	O
operating	O
in	O
the	O
near	O
vicinity	O
of	O
nerves	O
or	O
arteries	O
.	O

The	O
tip	O
of	O
this	O
instrument	O
oscillates	O
in	O
the	O
frequency	O
of	O
ultrasound	O
[	O
2	O
]	O
.	O

The	O
mechanism	O
of	O
this	O
device	O
is	O
based	O
on	O
the	O
so	O
called	O
Piezo	O
-	O
Effect	O
.	O

French	O
Physicists	O
Jean	O
and	O
Marie	O
Curie	O
first	O
mentioned	O
the	O
direct	O
Piezo	O
-	O
Effect	O
1880	O
,	O
whereby	O
certain	O
crystals	O
produce	O
electrical	O
current	O
while	O
under	O
mechanical	O
pressure	O
.	O

The	O
reciprocal	O
effect	O
,	O
by	O
which	O
the	O
crystals	O
are	O
deformed	O
when	O
under	O
electrical	O
current	O
,	O
was	O
then	O
discovered	O
a	O
while	O
later	O
.	O

This	O
is	O
the	O
effect	O
being	O
used	O
by	O
the	O
Piezosurgery	O
Device	O
(	O
R	O
)	O
.	O

In	O
this	O
device	O
,	O
the	O
electrical	O
field	O
is	O
located	O
in	O
the	O
handle	O
of	O
the	O
saw	O
[	O
3	O
]	O
.	O

Due	O
to	O
the	O
deformation	O
caused	O
by	O
the	O
electrical	O
current	O
,	O
a	O
cutting	O
-	O
hammering	O
movement	O
is	O
produced	O
at	O
the	O
tip	O
of	O
the	O
instrument	O
.	O

These	O
micro	O
movements	O
are	O
in	O
the	O
frequency	O
range	O
of	O
25	O
to	O
29	O
kHz	O
and	O
,	O
depending	O
on	O
the	O
insert	O
,	O
with	O
an	O
amplitude	O
of	O
60	O
to	O
210	O
mu	O
m	O
.	O

This	O
way	O
only	O
mineralized	O
tissue	O
is	O
selectively	O
cut	O
.	O

Neurovascular	O
tissue	O
and	O
other	O
soft	O
tissue	O
would	O
only	O
be	O
cut	O
by	O
a	O
frequency	O
of	O
above	O
50	O
kHz	O
[	O
3	O
-	O
5	O
]	O
.	O

Depending	O
on	O
the	O
strength	O
of	O
the	O
bone	O
and	O
the	O
blade	O
geometry	O
,	O
the	O
efficiency	O
of	O
the	O
cutting	O
can	O
be	O
regulated	O
by	O
the	O
frequency	O
modulator	O
and	O
the	O
power	O
level	O
.	O

For	O
cooling	O
there	O
is	O
an	O
integrated	O
pump	O
with	O
five	O
different	O
working	O
levels	O
.	O

This	O
pump	O
automatically	O
washes	O
physiological	O
solution	O
to	O
the	O
area	O
being	O
cut	O
.	O

The	O
cost	O
of	O
the	O
device	O
is	O
about	O
7	O
.	O
000	O
USD	O
.	O

Additional	O
costs	O
per	O
operation	O
are	O
for	O
the	O
cooling	O
liquid	O
and	O
are	O
in	O
the	O
range	O
of	O
a	O
few	O
dollars	O
.	O

We	O
have	O
used	O
the	O
Piezosurgery	O
Device	O
(	O
R	O
)	O
by	O
Mectron	O
[	O
Italy	O
]	O
[	O
3	O
]	O
for	O
the	O
first	O
time	O
in	O
osteotomies	O
of	O
the	O
long	O
bone	O
in	O
the	O
field	O
of	O
hand	O
surgery	O
.	O

We	O
will	O
report	O
on	O
our	O
experience	O
with	O
one	O
case	O
,	O
with	O
a	O
follow	O
up	O
time	O
of	O
one	O
year	O
.	O

Method	O

The	O
correctional	O
osteotomy	O
was	O
performed	O
on	O
a	O
23	O
year	O
old	O
worker	O
who	O
suffered	O
a	O
malunited	O
metacarpal	O
bone	O
fracture	O
of	O
the	O
fifth	O
finger	O
on	O
his	O
dominant	O
hand	O
.	O

The	O
X	O
-	O
ray	O
revealed	O
a	O
45	O
degree	O
angular	O
deformity	O
of	O
the	O
fifth	O
metacarpal	O
neck	O
with	O
internal	O
rotation	O
.	O

(	O
Figure	O
1	O
)	O
.	O

The	O
operation	O
was	O
performed	O
under	O
regional	O
anesthesia	O
.	O

A	O
longitudinal	O
incision	O
was	O
made	O
over	O
the	O
fifth	O
metacarpal	O
.	O

The	O
tendon	O
of	O
the	O
extensor	O
digiti	O
minimi	O
was	O
found	O
and	O
on	O
its	O
radial	O
side	O
the	O
periosteum	O
of	O
metacarpal	O
five	O
was	O
reached	O
.	O

The	O
periosteum	O
was	O
opened	O
longitudinally	O
over	O
the	O
defect	O
as	O
usual	O
.	O

For	O
the	O
correction	O
of	O
the	O
defect	O
of	O
45	O
degrees	O
,	O
a	O
bone	O
wedge	O
was	O
excised	O
.	O

Instead	O
of	O
using	O
the	O
traditional	O
oscillating	O
saw	O
,	O
the	O
Piezosurgery	O
Device	O
(	O
R	O
)	O
[	O
3	O
]	O
was	O
used	O
(	O
Figure	O
2	O
)	O
.	O

We	O
used	O
a	O
sharp	O
hardened	O
saw	O
coated	O
with	O
titannitrid	O
(	O
Figure	O
3	O
)	O
.	O

For	O
most	O
of	O
the	O
surgery	O
the	O
highest	O
power	O
level	O
,	O
the	O
boosted	O
burst	O
c	O
,	O
was	O
used	O
.	O

We	O
set	O
the	O
automatic	O
cooling	O
of	O
the	O
area	O
with	O
water	O
to	O
its	O
highest	O
level	O
.	O

The	O
angulation	O
and	O
rotation	O
was	O
corrected	O
and	O
fixed	O
with	O
a	O
1	O
.	O
5	O
mm	O
titanium	O
five	O
-	O
hole	O
plate	O
and	O
four	O
screws	O
.	O

Closure	O
of	O
the	O
wound	O
was	O
done	O
in	O
layers	O
.	O

Mobilization	O
was	O
started	O
on	O
the	O
10th	O
postoperative	O
day	O
.	O

The	O
overall	O
time	O
of	O
observation	O
was	O
one	O
year	O
.	O

Results	O
and	O
discussion	O

The	O
Piezosurgery	O
(	O
R	O
)	O
Device	O
is	O
ideally	O
sized	O
for	O
hand	O
surgery	O
.	O

The	O
cutting	O
was	O
very	O
precise	O
.	O

The	O
edges	O
of	O
the	O
osteotomy	O
were	O
all	O
sharp	O
to	O
the	O
edge	O
,	O
there	O
was	O
no	O
need	O
to	O
split	O
the	O
bone	O
with	O
a	O
chisel	O
,	O
nor	O
was	O
there	O
the	O
danger	O
of	O
a	O
break	O
out	O
.	O

During	O
the	O
osteotomy	O
there	O
were	O
no	O
disturbing	O
vibrations	O
in	O
the	O
area	O
of	O
operation	O
.	O

This	O
absence	O
of	O
vibration	O
is	O
very	O
practical	O
for	O
operations	O
using	O
a	O
magnifier	O
.	O

Vercellotti	O
mentions	O
that	O
to	O
overcome	O
any	O
problems	O
during	O
surgery	O
,	O
instead	O
of	O
increasing	O
pressure	O
on	O
the	O
hand	O
piece	O
,	O
as	O
in	O
traditional	O
techniques	O
,	O
it	O
is	O
necessary	O
to	O
find	O
the	O
correct	O
pressure	O
to	O
achieve	O
the	O
desired	O
result	O
.	O

With	O
piezoelectric	O
surgery	O
,	O
increasing	O
the	O
working	O
pressure	O
above	O
a	O
certain	O
limit	O
impedes	O
the	O
vibrations	O
of	O
the	O
insert	O
[	O
4	O
]	O
.	O

We	O
have	O
also	O
experienced	O
this	O
in	O
our	O
study	O
.	O

The	O
instrument	O
can	O
be	O
moved	O
in	O
all	O
directions	O
comparable	O
to	O
a	O
pen	O
.	O

The	O
tip	O
of	O
the	O
instrument	O
is	O
exchangeable	O
.	O

Using	O
the	O
fine	O
tip	O
enables	O
multiplanar	O
as	O
well	O
as	O
curved	O
cutting	O
.	O

Because	O
of	O
the	O
automatic	O
water	O
cooling	O
during	O
the	O
whole	O
procedure	O
,	O
there	O
is	O
always	O
a	O
clear	O
view	O
onto	O
the	O
object	O
.	O

This	O
is	O
something	O
oral	O
surgeons	O
found	O
especially	O
useful	O
[	O
6	O
]	O
.	O

The	O
authors	O
mention	O
that	O
the	O
downside	O
of	O
the	O
device	O
is	O
the	O
relative	O
slow	O
sawing	O
process	O
.	O

We	O
needed	O
about	O
30	O
seconds	O
for	O
one	O
cut	O
of	O
the	O
relatively	O
small	O
bone	O
.	O

This	O
is	O
about	O
20	O
seconds	O
longer	O
than	O
the	O
time	O
needed	O
for	O
cutting	O
with	O
the	O
usual	O
saw	O
.	O

Although	O
the	O
power	O
can	O
be	O
regulated	O
with	O
the	O
power	O
box	O
and	O
the	O
use	O
of	O
different	O
scalpels	O
,	O
we	O
agree	O
with	O
other	O
authors	O
that	O
the	O
optimal	O
use	O
of	O
this	O
device	O
is	O
in	O
surgeries	O
of	O
small	O
bones	O
where	O
precise	O
and	O
soft	O
tissue	O
friendly	O
cutting	O
is	O
required	O
[	O
7	O
]	O
.	O

As	O
other	O
literature	O
has	O
shown	O
,	O
the	O
device	O
selectively	O
cuts	O
bone	O
while	O
sparing	O
nerves	O
and	O
other	O
soft	O
tissue	O
[	O
2	O
,	O
3	O
]	O
.	O

This	O
allows	O
for	O
minimal	O
invasive	O
surgeries	O
with	O
limited	O
retraction	O
of	O
soft	O
tissue	O
and	O
minimal	O
stripping	O
of	O
the	O
periosteum	O
,	O
saves	O
time	O
and	O
might	O
have	O
a	O
positive	O
effect	O
on	O
the	O
healing	O
process	O
.	O

Our	O
aim	O
of	O
the	O
first	O
time	O
use	O
of	O
the	O
Piezosurgery	O
(	O
R	O
)	O
Device	O
in	O
hand	O
surgery	O
was	O
to	O
check	O
its	O
usability	O
in	O
osteotomies	O
of	O
tubular	O
bones	O
.	O

The	O
preparation	O
of	O
the	O
bone	O
was	O
done	O
in	O
the	O
usual	O
manner	O
as	O
is	O
done	O
when	O
cutting	O
with	O
an	O
oscillating	O
saw	O
.	O

The	O
reason	O
for	O
this	O
was	O
to	O
fully	O
visualize	O
the	O
cutting	O
process	O
using	O
this	O
new	O
device	O
,	O
although	O
in	O
the	O
future	O
,	O
it	O
should	O
be	O
possible	O
to	O
minimize	O
the	O
bony	O
exposure	O
.	O

In	O
our	O
patient	B
the	O
postoperative	O
healing	O
of	O
the	O
wound	O
and	O
the	O
bone	O
consolidation	O
(	O
Figure	O
4	O
)	O
were	O
smooth	O
.	O

The	O
duration	O
of	O
postoperative	O
sick	O
leave	O
was	O
four	O
weeks	O
which	O
is	O
more	O
rapid	O
than	O
the	O
usual	O
recovery	O
period	O
.	O

The	O
patient	B
regained	O
full	O
use	O
of	O
his	O
finger	O
according	O
to	O
the	O
state	O
before	O
the	O
fracture	O
.	O

At	O
no	O
point	O
was	O
there	O
any	O
loss	O
of	O
sensitivity	O
.	O

The	O
patient	B
as	O
well	O
as	O
the	O
surgeons	O
were	O
fully	O
satisfied	O
with	O
the	O
result	O
.	O

Conclusion	O

The	O
Piezosurgery	O
(	O
R	O
)	O
Device	O
is	O
a	O
useful	O
device	O
for	O
small	O
long	O
bone	O
osteotomies	O
.	O

We	O
feel	O
that	O
this	O
device	O
has	O
great	O
potential	O
in	O
the	O
field	O
of	O
hand	O
-	O
and	O
spinal	O
surgery	O
.	O

As	O
the	O
device	O
selectively	O
cuts	O
bone	O
,	O
considerable	O
nerve	O
lesions	O
can	O
be	O
avoided	O
and	O
minimal	O
invasive	O
surgeries	O
are	O
possible	O
.	O

Using	O
the	O
fine	O
tip	O
enables	O
curved	O
cutting	O
and	O
provides	O
an	O
opportunity	O
for	O
new	O
osteotomy	O
techniques	O
.	O

Competing	O
interests	O

The	O
author	O
(	O
s	O
)	O
declare	O
that	O
they	O
have	O
no	O
competing	O
interests	O
.	O

Authors	O
'	O
contributions	O

DJH	O
initiated	O
and	O
coordinated	O
the	O
new	O
application	O
of	O
Piezosurgery	O
(	O
R	O
)	O
device	O
and	O
wrote	O
the	O
publication	O
.	O

StSt	O
lead	O
the	O
osteotomy	O
as	O
he	O
was	O
experienced	O
with	O
this	O
tool	O
from	O
oral	O
surgery	O
.	O

He	O
played	O
a	O
major	O
part	O
in	O
writing	O
the	O
technical	O
aspects	O
.	O

OVK	O
was	O
the	O
treating	O
surgeon	O
,	O
performed	O
the	O
operation	O
and	O
evaluated	O
the	O
new	O
tool	O
.	O

SS	O
performed	O
a	O
literature	O
review	O
and	O
wrote	O
part	O
of	O
the	O
publication	O
.	O

PH	O
was	O
the	O
treating	O
chief	O
surgeon	O
,	O
evaluated	O
the	O
new	O
tool	O
and	O
lead	O
the	O
treatment	O
in	O
all	O
aspects	O
.	O

Consent	O

We	O
obtained	O
oral	O
consent	O
from	O
the	O
patient	B
but	O
could	O
not	O
obtain	O
written	O
consent	O
.	O

Pre	O
-	O
publication	O
history	O

The	O
pre	O
-	O
publication	O
history	O
for	O
this	O
paper	O
can	O
be	O
accessed	O
here	O
:	O

Molecular	O
cloning	O
of	O
four	O
novel	O
murine	B
ribonuclease	O
genes	O
:	O
unusual	O
expansion	O
within	O
the	O
ribonuclease	O
A	O
gene	O
family	O
.	O

Abstract	O

We	O
have	O
characterized	O
four	O
novel	O
murine	B
ribonuclease	O
genes	O
that	O
,	O
together	O
with	O
the	O
murine	B
eosinophil	O
-	O
associated	O
ribonucleases	O
1	O
and	O
2	O
,	O
form	O
a	O
distinct	O
and	O
unusual	O
cluster	O
within	O
the	O
RNase	O
A	O
gene	O
superfamily	O
.	O

Three	O
of	O
these	O
genes	O
(	O
mR	O
-	O
3	O
,	O
mR	O
-	O
4	O
,	O
mR	O
-	O
5	O
)	O
include	O
complete	O
open	O
reading	O
frames	O
,	O
encoding	O
ribonucleases	O
with	O
eight	O
cysteines	O
and	O
appropriately	O
spaced	O
histidines	O
(	O
His11	O
and	O
His124	O
)	O
and	O
lysine	O
(	O
Lys35	O
)	O
that	O
are	O
characteristic	O
of	O
this	O
enlarging	O
protein	O
family	O
;	O
the	O
fourth	O
sequence	O
encodes	O
a	O
non	O
-	O
functional	O
pseudogene	O
(	O
mR	O
-	O
6P	O
)	O
.	O

Although	O
the	O
amino	O
acid	O
sequence	O
similarities	O
among	O
these	O
murine	B
ribonucleases	O
varies	O
from	O
60	O
to	O
94	O
%	O
,	O
they	O
form	O
a	O
unique	O
cluster	O
,	O
as	O
each	O
sequence	O
is	O
found	O
to	O
be	O
more	O
closely	O
related	O
to	O
another	O
of	O
this	O
group	O
than	O
to	O
either	O
murine	B
angiogenin	O
or	O
to	O
murine	B
pancreatic	O
ribonuclease	O
.	O

Interestingly	O
,	O
the	O
relationship	O
between	O
the	O
six	O
genes	O
in	O
this	O
'	O
mR	O
cluster	O
'	O
and	O
the	O
defined	O
lineages	O
of	O
the	O
RNase	O
A	O
gene	O
family	O
could	O
not	O
be	O
determined	O
by	O
amino	O
acid	O
sequence	O
homology	O
,	O
suggesting	O
the	O
possibility	O
that	O
there	O
are	O
one	O
or	O
more	O
additional	O
ribonuclease	O
lineages	O
that	O
have	O
yet	O
to	O
be	O
defined	O
.	O

Although	O
the	O
nature	O
of	O
the	O
evolutionary	O
constraints	O
promoting	O
this	O
unusual	O
expansion	O
and	O
diversification	O
remain	O
unclear	O
,	O
the	O
implications	O
with	O
respect	O
to	O
function	O
are	O
intriguing	O
.	O

<	O
FFFD	O
>	O
1997	O
Oxford	O
University	O
Press	O

Nucleic	O
Acids	O
Research	O
,	O
1997	O
,	O
Vol	O
.	O

25	O
,	O
No	O
.	O
21	O

4235	O
<	O
FFFD	O
>	O
4239	O

Molecular	O
cloning	O
of	O
four	O
novel	O
murine	B
ribonuclease	O
genes	O
:	O
unusual	O
expansion	O
within	O
the	O
Ribonuclease	O
A	O
gene	O
family	O
Dean	O
Batten	O
+	O
,	O
Kimberly	O
D	O
.	O
Dyer	O
,	O
Joseph	O
B	O
.	O
Domachowske	O
<	O
FFFD	O
>	O
and	O
Helene	O
F	O
.	O
Rosenberg	O
*	O
The	O
Laboratory	O
of	O
Host	O
Defenses	O
,	O
Building	O
10	O
,	O
Room	O
11N104	O
,	O
National	O
Institute	O
of	O
Allergy	O
and	O
Infectious	O
Diseases	O
,	O
National	O
Institutes	O
of	O
Health	O
,	O
9000	O
Rockville	O
Pike	O
,	O
Bethesda	O
,	O
MD	O
20892	O
,	O
USA	O
Received	O
August	O
4	O
,	O
1997	O
;	O
Revised	O
and	O
Accepted	O
September	O
17	O
,	O
1997	O
DDBJ	O
/	O
EMBL	O
/	O
GenBank	O
accession	O
numbers	O
:	O
U72031	O
,	O
U72032	O
,	O
AF017258	O
<	O
FFFD	O
>	O
AF017261	O

ABSTRACT	O
We	O
have	O
characterized	O
four	O
novel	O
murine	B
ribonuclease	O
genes	O
that	O
,	O
together	O
with	O
the	O
murine	B
eosinophilassociated	O
ribonucleases	O
1	O
and	O
2	O
,	O
form	O
a	O
distinct	O
and	O
unusual	O
cluster	O
within	O
the	O
RNase	O
A	O
gene	O
superfamily	O
.	O

Three	O
of	O
these	O
genes	O
(	O
mR	O
-	O
3	O
,	O
mR	O
-	O
4	O
,	O
mR	O
-	O
5	O
)	O
include	O
complete	O
open	O
reading	O
frames	O
,	O
encoding	O
ribonucleases	O
with	O
eight	O
cysteines	O
and	O
appropriately	O
spaced	O
histidines	O
(	O
His11	O
and	O
His124	O
)	O
and	O
lysine	O
(	O
Lys35	O
)	O
that	O
are	O
characteristic	O
of	O
this	O
enlarging	O
protein	O
family	O
;	O
the	O
fourth	O
sequence	O
encodes	O
a	O
non	O
-	O
functional	O
pseudogene	O
(	O
mR	O
-	O
6P	O
)	O
.	O

Although	O
the	O
amino	O
acid	O
sequence	O
similarities	O
among	O
these	O
murine	B
ribonucleases	O
varies	O
from	O
60	O
to	O
94	O
%	O
,	O
they	O
form	O
a	O
unique	O
cluster	O
,	O
as	O
each	O
sequence	O
is	O
found	O
to	O
be	O
more	O
closely	O
related	O
to	O
another	O
of	O
this	O
group	O
than	O
to	O
either	O
murine	B
angiogenin	O
or	O
to	O
murine	B
pancreatic	O
ribonuclease	O
.	O

Interestingly	O
,	O
the	O
relationship	O
between	O
the	O
six	O
genes	O
in	O
this	O
`	O
mR	O
cluster	O
'	O
and	O
the	O
defined	O
lineages	O
of	O
the	O
RNase	O
A	O
gene	O
family	O
could	O
not	O
be	O
determined	O
by	O
amino	O
acid	O
sequence	O
homology	O
,	O
suggesting	O
the	O
possibility	O
that	O
there	O
are	O
one	O
or	O
more	O
additional	O
ribonuclease	O
lineages	O
that	O
have	O
yet	O
to	O
be	O
defined	O
.	O

Although	O
the	O
nature	O
of	O
the	O
evolutionary	O
constraints	O
promoting	O
this	O
unusual	O
expansion	O
and	O
diversification	O
remain	O
unclear	O
,	O
the	O
implications	O
with	O
respect	O
to	O
function	O
are	O
intriguing	O
.	O

INTRODUCTION	O
Ribonuclease	O
A	O
(	O
RNase	O
A	O
,	O
bovine	B
pancreatic	O
ribonuclease	O
)	O
is	O
the	O
prototype	O
of	O
an	O
enlarging	O
family	O
of	O
proteins	O
defined	O
by	O
distinctive	O
elements	O
of	O
conserved	O
primary	O
structure	O
and	O
enzymatic	O
activity	O
(	O
1	O
,	O
2	O
)	O
.	O

The	O
features	O
shared	O
by	O
all	O
members	O
of	O
the	O
RNase	O
A	O
family	O
include	O
six	O
to	O
eight	O
cysteines	O
and	O
specific	O
histidine	O
and	O
lysine	O
residues	O
that	O
form	O
the	O
ribonuclease	O
active	O
site	O
.	O

To	O
date	O
,	O
several	O
distinct	O
lineages	O
within	O
the	O
RNase	O
A	O
superfamily	O
have	O
been	O
identified	O
.	O

Pancreatic	O
ribonucleases	O
(	O
RNases	O
1	O
)	O
have	O
been	O
isolated	O
from	O
an	O
extensive	O
array	O
of	O
mammalian	O
species	O
(	O
3	O
,	O
4	O
)	O
,	O
and	O
mRNA	O
encoding	O
human	B
pancreatic	O
ribonuclease	O
has	O
been	O
detected	O
in	O

numerous	O
somatic	O
tissues	O
in	O
addition	O
to	O
pancreas	O
(	O
5	O
)	O
.	O

RNases	O
2	O
and	O
3	O
,	O
eosinophil	O
-	O
derived	O
neurotoxin	O
(	O
EDN	O
)	O
and	O
eosinophil	O
cationic	O
protein	O
(	O
ECP	O
)	O
,	O
respectively	O
,	O
have	O
been	O
characterized	O
primarily	O
with	O
respect	O
to	O
eosinophil	O
function	O
(	O
6	O
,	O
7	O
)	O
,	O
although	O
expression	O
of	O
EDN	O
[	O
also	O
known	O
as	O
RNase	O
Us	O
(	O
8	O
)	O
or	O
human	B
liver	O
ribonuclease	O
(	O
9	O
)	O
]	O
is	O
also	O
widespread	O
(	O
5	O
)	O
.	O

Angiogenin	O
(	O
RNase	O
5	O
)	O
,	O
a	O
structurally	O
atypical	O
member	O
of	O
this	O
family	O
,	O
was	O
originally	O
identified	O
as	O
an	O
agent	O
promoting	O
blood	O
vessel	O
growth	O
and	O
development	O
(	O
10	O
,	O
11	O
)	O
.	O

RNase	O
4	O
(	O
12	O
,	O
13	O
)	O
and	O
RNase	O
k6	O
(	O
14	O
)	O
are	O
also	O
members	O
of	O
the	O
RNase	O
A	O
superfamily	O
,	O
although	O
their	O
functions	O
are	O
currently	O
obscure	O
.	O

Recently	O
,	O
Larson	O
and	O
colleagues	O
(	O
15	O
)	O
described	O
cDNAs	O
encoding	O
two	O
highly	O
homologous	O
murine	B
ribonucleases	O
,	O
the	O
murine	B
eosinophil	O
-	O
associated	O
ribonucleases	O
(	O
mEAR	O
)	O
1	O
and	O
2	O
,	O
which	O
were	O
cloned	O
and	O
identified	O
via	O
tryptic	O
peptides	O
isolated	O
from	O
murine	B
eosinophil	O
proteins	O
.	O

Although	O
Southern	O
analysis	O
demonstrated	O
that	O
multiple	O
copies	O
of	O
sequence	O
homologous	O
to	O
mEAR	O
-	O
1	O
and	O
mEAR	O
-	O
2	O
were	O
present	O
in	O
murine	B
genomic	O
DNA	O
,	O
the	O
precise	O
nature	O
of	O
these	O
copies	O
-	O
-	O
as	O
pseudogenes	O
,	O
polymorphisms	O
,	O
or	O
distinct	O
functional	O
genes	O
-	O
-	O
was	O
unclear	O
.	O

In	O
this	O
work	O
,	O
we	O
have	O
identified	O
four	O
of	O
these	O
homologous	O
sequences	O
,	O
three	O
encoding	O
novel	O
ribonucleases	O
,	O
and	O
one	O
encoding	O
a	O
pseudogene	O
.	O

Together	O
with	O
mEAR	O
-	O
1	O
and	O
mEAR	O
-	O
2	O
,	O
these	O
six	O
ribonuclease	O
genes	O
form	O
an	O
`	O
mR	O
cluster	O
,	O
'	O
whose	O
members	O
are	O
more	O
closely	O
related	O
to	O
one	O
another	O
than	O
they	O
are	O
to	O
other	O
murine	B
ribonucleases	O
,	O
yet	O
whose	O
position	O
with	O
respect	O
to	O
the	O
defined	O
RNase	O
A	O
lineages	O
remains	O
unclear	O
.	O

MATERIALS	O
AND	O
METHODS	O
Isolation	O
of	O
genomic	O
fragments	O
encoding	O
murine	B
ribonucleases	O
by	O
polymerase	O
chain	O
reaction	O
(	O
PCR	O
)	O
Genomic	O
DNA	O
was	O
isolated	O
from	O
cells	O
of	O
the	O
murine	B
3T3	O
fibroblast	O
cell	O
line	O
.	O

The	O
mR	O
-	O
3	O
,	O
mR	O
-	O
5	O
and	O
mR	O
-	O
6P	O
sequences	O
were	O
amplified	O
using	O
oligonucleotide	O
primers	O
derived	O
from	O
the	O
published	O
coding	O
sequence	O
of	O
mEAR	O
-	O
1	O
as	O
follows	O
:	O
5	O
-	O
CAA	O
ACC	O
CTT	O
TCC	O
CAG	O
AAG	O
TTT	O
GCC	O
-	O
3	O
(	O
amino	O
acids	O
28	O
<	O
FFFD	O
>	O
33	O
)	O
;	O
5	O
-	O
AAA	O
TGT	O
CCC	O
ATC	O
CAA	O
GTG	O
AAC	O
TGG	O
ACC	O
-	O
3	O
(	O
amino	O
acids	O
156	O
<	O
FFFD	O
>	O
148	O
)	O
(	O
15	O
)	O
.	O

The	O
PCR	O
reactions	O
were	O
performed	O
as	O
described	O
previously	O
(	O
14	O
)	O
,	O
and	O
the	O
multiple	O
products	O
present	O
in	O
the	O
single	O
400	O
bp	O
product	O
were	O
identified	O
by	O
dideoxy	O

*	O
To	O
whom	O
correspondence	O
should	O
be	O
addressed	O
.	O

Tel	O
:	O
+	O
1	O
301	O
402	O
9131	O
;	O
Fax	O
:	O
+	O
1	O
301	O
402	O
4369	O
;	O
Email	O
:	O
hr2k	O
@	O
nih	O
.	O
gov	O
Present	O
addresses	O
:	O
+	O
Duke	O
University	O
School	O
of	O
Medicine	O
,	O
Durham	O
,	O
NC	O
27701	O
,	O
USA	O
and	O
<	O
FFFD	O
>	O
Department	O
of	O
Pediatrics	O
,	O
State	O
University	O
of	O
New	O
York	O
-	O
Health	O
Sciences	O
Center	O
at	O
Syracuse	O
,	O
Syracuse	O
,	O
NY	O
13210	O
,	O
USA	O

4236	O
Nucleic	O
Acids	O
Research	O
,	O
1997	O
,	O
Vol	O
.	O

25	O
,	O
No	O
.	O
21	O

Figure	O
1	O
.	O

(	O
A	O
)	O
Alignment	O
of	O
amino	O
acid	O
sequences	O
encoded	O
by	O
six	O
related	O
murine	B
ribonuclease	O
genes	O
.	O

Regions	O
of	O
amino	O
acid	O
sequence	O
identity	O
among	O
the	O
five	O
functional	O
genes	O
are	O
enclosed	O
in	O
boxes	O
;	O
the	O
boxes	O
enclosing	O
the	O
active	O
site	O
residues	O
(	O
His11	O
,	O
Lys35	O
,	O
His124	O
)	O
and	O
eight	O
cysteines	O
conserved	O
in	O
all	O
members	O
of	O
the	O
RNase	O
A	O
superfamily	O
are	O
shaded	O
.	O

(	O
B	O
)	O
Percent	O
similarities	O
between	O
amino	O
acid	O
sequences	O
determined	O
via	O
the	O
BESTFIT	O
algorithm	O
of	O
the	O
Wisconsin	O
Genetics	O
Computer	O
Group	O
(	O
WGCG	O
)	O
program	O
on	O
-	O
line	O
at	O
the	O
National	O
Institutes	O
of	O
Health	O
.	O

GenBank	O
accession	O
numbers	O
:	O
mEAR	O
(	O
murine	B
eosinophil	O
-	O
associated	O
ribonuclease	O
)	O
-	O
1	O
,	O
U72032	O
;	O
mEAR	O
-	O
2	O
,	O
U72031	O
;	O
mR	O
(	O
murine	B
ribonuclease	O
)	O
-	O
3	O
,	O
AF017258	O
;	O
mR	O
-	O
4	O
,	O
AF017259	O
;	O
mR	O
-	O
5	O
,	O
AF017260	O
;	O
mR	O
-	O
6P	O
(	O
pseudogene	O
)	O
,	O
AF017261	O
.	O

sequencing	O
of	O
individual	O
plasmids	O
after	O
subcloning	O
into	O
the	O
pCR	O
II	O
TA	O
cloning	O
vector	O
(	O
Invitrogen	O
,	O
San	O
Diego	O
,	O
CA	O
)	O
.	O

The	O
complete	O
open	O
reading	O
frames	O
were	O
obtained	O
by	O
extension	O
in	O
both	O
5	O
and	O
3	O
directions	O
by	O
uni	O
-	O
directional	O
PCR	O
(	O
Genome	O
Walker	O
kit	O
,	O
Clontech	O
,	O
Palo	O
Alto	O
,	O
CA	O
)	O
,	O
involving	O
two	O
amplifications	O
with	O
nested	O
primers	O
and	O
Tth	O
polymerase	O
as	O
described	O
previously	O
(	O
14	O
)	O
.	O

The	O
nested	O
gene	O
-	O
specific	O
primer	O
pairs	O
were	O
as	O
follows	O
:	O
for	O
5	O
extension	O
of	O
mR	O
-	O
3	O
,	O
5	O
-	O
CTG	O
GAA	O
CCA	O
CTG	O
GAT	O
ACG	O
TGG	O
GAC	O
TGT	O
CCT	O
-	O
3	O
and	O
5	O
-	O
ACG	O
TGG	O
GAC	O
TGT	O
CCT	O
GTG	O
GAG	O
TTC	O
TGG	O
GTT	O
-	O
3	O
;	O
for	O
3	O
extension	O
of	O
mR	O
-	O
3	O
,	O
5	O
-	O
ATG	O
CTG	O
TTG	O
GTG	O
TGT	O
GTG	O
GAA	O
ATC	O
CAA	O
GTG	O
-	O
3	O
and	O
5	O
-	O
GCT	O
TGT	O
GCA	O
GTG	O
ACA	O
ATA	O
TAA	O
GTC	O
AAA	O
ACT	O
-	O
3	O
;	O
for	O
5	O
extension	O
of	O
mR	O
-	O
5	O
,	O
5	O
-	O
GGT	O
GGG	O
ACG	O
GTC	O
CTT	O
TGG	O
AGT	O
TCT	O
GGG	O
GTT	O
ACA	O
-	O
3	O
and	O
5	O
-	O
GGG	O
GTT	O
ACA	O
GGC	O
AAC	O
TGT	O
GTA	O
GGA	O
CTT	O
CTT	O
TCC	O
-	O
3	O
;	O
for	O
3	O
extension	O
of	O
mR	O
-	O
5	O
,	O
5	O
-	O
GAT	O
GTT	O
GTC	O
CGT	O
GTG	O
TGT	O
CAC	O
AAT	O
CCA	O
CCC	O
-	O
3	O
and	O
5	O
-	O
AAG	O
ACT	O
TGC	O
AAA	O
GAC	O
GGG	O
ACA	O
AGT	O
CCA	O
AAT	O
-	O
3	O
;	O
for	O
5	O
extension	O
of	O
mR	O
-	O
6P	O
,	O
5	O
-	O
TTG	O
TTG	O
TTT	O
TGC	O
ATC	O
TGC	O
ATT	O
GTG	O
CAT	O
AAC	O
TGC	O
-	O
3	O
and	O
5	O
-	O
TTC	O
TGC	O
ATA	O
ACT	O
GCT	O
TGC	O
TGA	O
ACT	O
TGT	O
GAG	O
TGA	O
-	O
3	O
;	O
for	O
3	O
extension	O
of	O
mR	O
-	O
6P	O
,	O
5	O
-	O
ATG	O
TGA	O
TAA	O
TGC	O
AAT	O
GCT	O
GTC	O
TCT	O
TAG	O
CAG	O
TTA	O
-	O
3	O
and	O
5	O
-	O
TAC	O
AAG	O

AGT	O
ATG	O
TAA	O
GCC	O
ATT	O
GAA	O
TCA	O
TTT	O
TCT	O
-	O
3	O
.	O

The	O
products	O
of	O
these	O
reactions	O
were	O
likewise	O
subcloned	O
into	O
the	O
PCR	O
II	O
TA	O
vector	O
and	O
evaluated	O
by	O
dideoxy	O
-	O
sequencing	O
.	O

The	O
mR	O
-	O
4	O
sequence	O
was	O
amplified	O
with	O
a	O
36	O
bp	O
primer	O
derived	O
from	O
sequence	O
encoding	O
the	O
amino	O
-	O
terminal	O
signal	O
sequence	O
of	O
mEAR	O
-	O
1	O
;	O
5	O
-	O
ATG	O
GGT	O
CCG	O
AAG	O
CTG	O
CTT	O
GAG	O
TCC	O
CGA	O
CTT	O
TGT	O
CTC	O
-	O
3	O
with	O
the	O
carboxy	O
-	O
primer	O
described	O
above	O
.	O

Northern	O
analysis	O
The	O
murine	B
multi	O
-	O
tissue	O
Northern	O
blot	O
was	O
purchased	O
from	O
Clontech	O
,	O
and	O
pre	O
-	O
hybridized	O
and	O
hybridized	O
as	O
per	O
manufacturer	O
'	O
s	O
instructions	O
with	O
radiolabelled	O
oligonucleotide	O
probes	O
.	O

The	O
membrane	O
was	O
washed	O
with	O
5	O
<	O
FFFD	O
>	O
SSPE	O
with	O
0	O
.	O
1	O
%	O
SDS	O
for	O
1	O
h	O
at	O
37	O
_	O
C	O
and	O
the	O
autoradiogram	O
developed	O
after	O
exposure	O
to	O
film	O
at	O
<	O
FFFD	O
>	O
80	O
_	O
C	O
.	O

The	O
mEAR	O
-	O
1	O
/	O
mEAR	O
-	O
2	O
/	O
mR	O
-	O
3	O
probe	O
:	O
5	O
-	O
CTC	O
TTG	O
TCA	O
CTG	O
CAC	O
AAG	O
CCA	O
CTT	O
GGA	O
TTT	O
CC	O
-	O
3	O
,	O
the	O
mR	O
-	O
5	O
probe	O
:	O
5	O
-	O
GTC	O
CCG	O
TCT	O
TTG	O
CAA	O
GTC	O
TTG	O
GGT	O
GGA	O
TTG	O
TG	O
-	O
3	O
,	O
and	O
the	O
actin	O
probe	O
:	O
5	O
-	O
GCA	O
CAT	O
GCC	O
GGA	O
GCC	O
GTT	O
GTC	O
GAC	O
GAC	O
GAG	O
CGC	O
GGC	O
GAT	O
ATC	O
ATC	O
ATC	O
-	O
3	O
(	O
16	O
)	O
.	O

4237	O
Nucleic	O
Acids	O
Research	O
,	O
1997	O
,	O
Vol	O
.	O

25	O
,	O
No	O
.	O

Nucleic	O
Acids	O
Research	O
,	O
1994	O
,	O
Vol	O
.	O

22	O
,	O
No	O
.	O
121	O
4237	O

Figure	O
2	O
.	O

(	O
A	O
)	O
Dendrogram	O
depicting	O
relationships	O
among	O
the	O
eight	O
characterized	O
murine	B
ribonucleases	O
as	O
determined	O
by	O
a	O
modified	O
UPGMA	O
method	O
(	O
17	O
)	O
.	O

Abbreviations	O
are	O
as	O
in	O
Figure	O
1A	O
,	O
also	O
mPR	O
(	O
murine	B
pancreatic	O
ribonuclease	O
,	O
sw	O
:	O
rnp	O
_	O
mouse	B
)	O
,	O
mANG	O
(	O
murine	B
angiogenin	O
,	O
U72672	O
)	O
,	O
hEDN	O
(	O
human	B
eosinophil	O
-	O
derived	O
neurotoxin	O
,	O
M24157	O
)	O
,	O
hECP	O
(	O
human	B
eosinophil	O
cationic	O
protein	O
,	O
X15161	O
)	O
,	O
hRK6	O
(	O
human	B
ribonuclease	O
k6	O
,	O
U64998	O
)	O
,	O
pRK6	O
(	O
porcine	O
kidney	O
ribonuclease	O
(	O
24	O
)	O
,	O
and	O
bRK6	O
(	O
bovine	B
kidney	O
ribonuclease	O
,	O
sw	O
:	O
rnkd	O
_	O
bovin	O
)	O
.	O

(	O
B	O
)	O
Calculated	O
isoelectric	O
points	O
from	O
amino	O
acid	O
sequences	O
in	O
(	O
A	O
)	O
as	O
determined	O
via	O
the	O
PEPTIDESORT	O
algorithm	O
of	O
WGCG	O
.	O

Table	O
1	O
.	O

Amino	O
acid	O
sequence	O
comparisons	O
of	O
murine	B
and	O
human	B
ribonucleases	O

Sequence	O
analysis	O
All	O
DNA	O
sequence	O
analysis	O
and	O
comparisons	O
were	O
performed	O
with	O
the	O
assistance	O
of	O
the	O
Wisconsin	O
Genetics	O
Computer	O
Group	O
and	O
Sequencher	O
(	O
Gene	O
Codes	O
Corporation	O
)	O
programs	O
available	O
at	O
the	O
National	O
Institutes	O
of	O
Health	O
.	O

The	O
dendrogram	O
in	O
Figure	O
2A	O
was	O
constructed	O
by	O
a	O
modified	O
version	O
of	O
the	O
unweighted	O
pair	O
group	O
method	O
with	O
arithmetic	O
mean	O
(	O
UPGMA	O
)	O
(	O
17	O
)	O
,	O
constructed	O
using	O
four	O
initial	O
pairings	O
,	O
mEAR	O
-	O
2	O
to	O
mR	O
-	O
3	O
,	O
mR	O
-	O
5	O
to	O
mR	O
-	O
6P	O
,	O
hEDN	O
to	O
hECP	O
and	O
bRK6	O
to	O
pRK6	O
.	O

RESULTS	O
Isolation	O
of	O
genomic	O
fragments	O
encoding	O
novel	O
murine	B
ribonucleases	O
The	O
alignment	O
in	O
Figure	O
1A	O
displays	O
the	O
amino	O
acid	O
sequences	O
encoded	O
by	O
the	O
six	O
related	O
ribonuclease	O
genes	O
.	O

Murine	B
eosinophil	O
-	O
associated	O
ribonucleases	O
-	O
1	O
and	O
-	O
2	O
(	O
mEAR	O
-	O
1	O
and	O
mEAR	O
-	O
2	O
)	O
are	O
the	O
predicted	O
amino	O
acid	O
sequences	O
from	O
two	O
genes	O
described	O
previously	O
by	O
Larson	O
and	O
colleagues	O
(	O
15	O
)	O
;	O
murine	B
ribonucleases	O
3	O
,	O
4	O
,	O
5	O
and	O
6	O
-	O
pseudogene	O
(	O
mR	O
-	O
3	O
,	O
mR	O
-	O
4	O
,	O
mR	O
-	O
5	O
and	O
mR	O
-	O
6P	O
)	O
,	O
are	O
the	O
predicted	O
amino	O
acid	O
sequences	O
encoded	O
by	O
novel	O
DNA	O

hEDN	O
mEAR	O
-	O
1	O
mEAR	O
-	O
2	O
mR	O
-	O
3	O
mR	O
-	O
4	O
mR	O
-	O
5	O
mANG	O
mPR	O
56	O
56	O
54	O
60	O
60	O
43	O
53	O

hECP	O
59	O
59	O
57	O
59	O
58	O
49	O
52	O

hRK6	O
58	O
59	O
59	O
53	O
56	O
49	O
59	O

hPR	O
47	O
48	O
49	O
48	O
57	O
55	O
79	O

hR4	O
50	O
53	O
51	O
52	O
54	O
57	O
66	O

hANG	O
49	O
48	O
51	O
47	O
47	O
80	O
60	O

Values	O
are	O
expressed	O
as	O
percent	O
similarity	O
between	O
pairs	O
of	O
amino	O
acid	O
sequences	O
as	O
determined	O
by	O
the	O
BESTFIT	O
algorithm	O
of	O
the	O
Wisconsin	O
Genetics	O
Computer	O
Group	O
program	O
on	O
-	O
line	O
at	O
the	O
National	O
Institutes	O
of	O
Health	O
.	O

Value	O
representing	O
the	O
highest	O
degree	O
of	O
sequence	O
homology	O
in	O
each	O
row	O
is	O
indicated	O
in	O
boldface	O
.	O

Abbreviations	O
are	O
as	O
defined	O
in	O
Figures	O
1	O
and	O
2	O
,	O
and	O
also	O
include	O
hR4	O
(	O
human	B
ribonuclease	O
4	O
,	O
sw	O
:	O
rnl4	O
_	O
human	B
)	O
,	O
hANG	O
(	O
human	B
angiogenin	O
,	O
M11567	O
)	O
,	O
and	O
hPR	O
(	O
human	B
pancreatic	O
ribonuclease	O
,	O
X62946	O
)	O
.	O

4238	O
Nucleic	O
Acids	O
Research	O
,	O
1997	O
,	O
Vol	O
.	O

25	O
,	O
No	O
.	O
21	O
fragments	O
amplified	O
from	O
murine	B
genomic	O
DNA	O
.	O

All	O
five	O
functional	O
genes	O
encode	O
amino	O
acid	O
sequences	O
with	O
eight	O
cysteines	O
and	O
appropriately	O
spaced	O
catalytic	O
histidines	O
and	O
lysine	O
that	O
are	O
conserved	O
among	O
the	O
members	O
of	O
the	O
RNase	O
A	O
superfamily	O
.	O

The	O
predicted	O
coding	O
sequence	O
of	O
the	O
non	O
-	O
functional	O
pseudogene	O
(	O
mR	O
-	O
6P	O
)	O
includes	O
two	O
aberrant	O
stop	O
codons	O
(	O
positions	O
19	O
and	O
100	O
)	O
as	O
well	O
as	O
a	O
point	O
mutation	O
resulting	O
in	O
the	O
destruction	O
of	O
the	O
cysteine	O
at	O
position	O
78	O
.	O

Each	O
genomic	O
fragment	O
also	O
encodes	O
a	O
28	O
residue	O
amino	O
terminal	O
signal	O
sequence	O
(	O
not	O
shown	O
)	O
.	O

The	O
amino	O
acid	O
sequences	O
are	O
displayed	O
in	O
order	O
of	O
decreasing	O
similarity	O
to	O
mEAR	O
-	O
1	O
(	O
Fig	O
.	O
1B	O
)	O
.	O

Genomic	O
fragments	O
encoding	O
mEAR	O
-	O
1	O
and	O
mEAR	O
-	O
2	O
were	O
also	O
detected	O
.	O

Relationships	O
among	O
the	O
murine	B
ribonucleases	O
A	O
dendrogram	O
depicting	O
the	O
relationships	O
among	O
several	O
of	O
the	O
murine	B
and	O
human	B
ribonucleases	O
is	O
shown	O
in	O
Figure	O
2A	O
.	O

The	O
mEAR	O
-	O
1	O
,	O
mEAR	O
-	O
2	O
,	O
and	O
mR	O
-	O
3	O
sequences	O
form	O
a	O
closely	O
related	O
sub	O
-	O
group	O
,	O
with	O
only	O
nine	O
amino	O
acid	O
sequence	O
differences	O
noted	O
between	O
mEAR	O
-	O
2	O
and	O
mR	O
-	O
3	O
,	O
and	O
12	O
and	O
17	O
between	O
these	O
two	O
and	O
mEAR	O
-	O
1	O
,	O
respectively	O
.	O

The	O
mR	O
-	O
4	O
,	O
mR	O
-	O
5	O
,	O
and	O
mR	O
-	O
6P	O
sequences	O
diverge	O
from	O
this	O
subgroup	O
and	O
from	O
one	O
another	O
as	O
well	O
.	O

These	O
six	O
sequences	O
are	O
more	O
closely	O
related	O
to	O
one	O
another	O
than	O
they	O
are	O
to	O
either	O
murine	B
pancreatic	O
ribonuclease	O
(	O
mPR	O
)	O
or	O
to	O
murine	B
angiogenin	O
(	O
mANG	O
)	O
or	O
to	O
any	O
of	O
the	O
three	O
human	B
ribonucleases	O
shown	O
(	O
hEDN	O
,	O
hECP	O
or	O
hRK6	O
)	O
.	O

Isoelectric	O
points	O
The	O
isoelectric	O
points	O
of	O
all	O
six	O
related	O
ribonucleases	O
range	O
from	O
8	O
<	O
FFFD	O
>	O
11	O
,	O
as	O
is	O
typical	O
for	O
members	O
of	O
the	O
RNase	O
A	O
superfamily	O
(	O
Fig	O
.	O
2B	O
)	O
.	O

Interestingly	O
,	O
the	O
isoelectric	O
points	O
within	O
the	O
mEAR	O
-	O
1	O
/	O
mEAR	O
-	O
2	O
/	O
mR	O
-	O
3	O
subgroup	O
vary	O
by	O
a	O
full	O
1	O
.	O
0	O
unit	O
(	O
mEAR	O
-	O
1	O
at	O
9	O
.	O
2	O
to	O
mEAR	O
-	O
2	O
at	O
10	O
.	O
2	O
)	O
in	O
response	O
to	O
only	O
12	O
discrepancies	O
in	O
amino	O
acid	O
sequence	O
.	O

As	O
increased	O
charge	O
has	O
been	O
associated	O
with	O
increased	O
toxicity	O
in	O
other	O
branches	O
of	O
the	O
RNase	O
A	O
gene	O
family	O
(	O
18	O
)	O
,	O
this	O
finding	O
has	O
potential	O
consequences	O
with	O
respect	O
to	O
the	O
function	O
of	O
these	O
proteins	O
(	O
see	O
Discussion	O
)	O
.	O

Northern	O
analysis	O
Tissue	O
-	O
specific	O
expression	O
of	O
mRNA	O
encoding	O
these	O
murine	B
ribonucleases	O
is	O
shown	O
in	O
Figure	O
3	O
.	O

The	O
probe	O
complementary	O
to	O
all	O
three	O
sequences	O
of	O
the	O
mEAR	O
-	O
1	O
/	O
mEAR	O
-	O
2	O
/	O
mR	O
-	O
3	O
subgroup	O
hybridizes	O
to	O
an	O
1	O
.	O
4	O
kb	O
mRNA	O
isolated	O
from	O
renal	O
tissue	O
(	O
Fig	O
.	O
3A	O
)	O
.	O

As	O
the	O
probe	O
cannot	O
distinguish	O
among	O
the	O
three	O
genes	O
,	O
it	O
is	O
not	O
possible	O
to	O
conclude	O
whether	O
the	O
band	O
detected	O
represents	O
mRNA	O
encoding	O
one	O
,	O
two	O
,	O
or	O
all	O
three	O
of	O
the	O
ribonucleases	O
of	O
this	O
subgroup	O
.	O

In	O
contrast	O
,	O
the	O
probe	O
complementary	O
to	O
the	O
mR	O
-	O
5	O
genomic	O
fragment	O
hybridizes	O
to	O
two	O
prominent	O
mRNA	O
species	O
in	O
hepatic	O
tissue	O
,	O
one	O
at	O
1	O
.	O
4	O
kb	O
,	O
and	O
a	O
second	O
at	O
2	O
.	O
0	O
kb	O
.	O

A	O
prominent	O
mRNA	O
of	O
1	O
.	O
8	O
kb	O
was	O
also	O
detected	O
in	O
mRNA	O
isolated	O
from	O
murine	B
testicular	O
tissue	O
;	O
fainter	O
hybridizing	O
mRNAs	O
of	O
varying	O
size	O
were	O
detected	O
in	O
lung	O
and	O
skeletal	O
muscle	O
.	O

The	O
size	O
variation	O
may	O
represent	O
differential	O
splicing	O
of	O
the	O
mR	O
-	O
5	O
-	O
encoding	O
mRNA	O
,	O
or	O
may	O
represent	O
mRNAs	O
encoding	O
one	O
or	O
more	O
as	O
yet	O
undiscovered	O
murine	B
ribonucleases	O
that	O
are	O
more	O
closely	O
related	O
to	O
mR	O
-	O
5	O
than	O
those	O
whose	O
sequences	O
are	O
reported	O
here	O
.	O

Figure	O
3	O
.	O

(	O
A	O
)	O
Murine	B
RNA	O
probed	O
with	O
a	O
32	O
bp	O
oligonucleotide	O
complementary	O
to	O
mEAR	O
-	O
1	O
,	O
mEAR	O
-	O
2	O
and	O
mR	O
-	O
3	O
coding	O
sequences	O
.	O

Tissue	O
source	O
of	O
each	O
RNA	O
is	O
indicated	O
above	O
each	O
lane	O
.	O

(	O
B	O
)	O
Same	O
as	O
in	O
(	O
A	O
)	O
,	O
probed	O
with	O
a	O
32	O
bp	O
oligonucleotide	O
complementary	O
to	O
mR	O
-	O
5	O
.	O

(	O
C	O
)	O
Same	O
as	O
in	O
(	O
A	O
)	O
,	O
probed	O
with	O
a	O
48	O
bp	O
oligonucleotide	O
complementary	O
to	O
human	B
actin	O
(	O
16	O
)	O
,	O
demonstrating	O
relative	O
loading	O
of	O
each	O
lane	O
.	O

Relationship	O
to	O
human	B
ribonucleases	O
The	O
data	O
in	O
Table	O
1	O
denote	O
the	O
amino	O
acid	O
sequence	O
similarity	O
between	O
pairs	O
of	O
murine	B
and	O
human	B
ribonucleases	O
of	O
the	O
RNase	O
A	O
superfamily	O
.	O

Overall	O
,	O
the	O
similarities	O
within	O
the	O
identified	O
cluster	O
range	O
from	O
47	O
to	O
60	O
%	O
,	O
with	O
remarkably	O
little	O
variation	O
among	O
the	O
pairs	O
.	O

Although	O
the	O
sequences	O
of	O
the	O
mEAR	O
-	O
1	O
/	O
mEAR	O
-	O
2	O
/	O
mR	O
-	O
3	O
subgroup	O
are	O
slightly	O
more	O
similar	O
to	O
ECP	O
and	O
RNase	O
k6	O
,	O
and	O
mR	O
-	O
4	O
and	O
mR	O
-	O
5	O
,	O
to	O
EDN	O
and	O
ECP	O
,	O
the	O
orthologous	O
relationships	O
of	O
these	O
murine	B
ribonucleases	O
cannot	O
be	O
discerned	O
from	O
these	O
data	O
.	O

This	O
stands	O
in	O
direct	O
contrast	O
to	O
mPR	O
and	O
mANG	O
,	O
whose	O
human	B
orthologs	O
can	O
be	O
clearly	O
distinguished	O
on	O
the	O
basis	O
of	O
their	O
amino	O
acid	O
sequence	O
homologies	O
.	O

DISCUSSION	O
In	O
this	O
work	O
,	O
we	O
have	O
identified	O
four	O
novel	O
murine	B
ribonuclease	O
genes	O
that	O
,	O
together	O
with	O
mEAR	O
-	O
1	O
and	O
mEAR	O
-	O
2	O
defined	O
by	O
Larson	O
and	O
colleagues	O
(	O
15	O
)	O
,	O
form	O
an	O
unusual	O
cluster	O
within	O
the	O
RNase	O
A	O
gene	O
superfamily	O
.	O

The	O
six	O
genes	O
within	O
this	O
cluster	O
have	O
varying	O
amino	O
acid	O
sequence	O
homologies	O
to	O
one	O
another	O
,	O
but	O
are	O
clearly	O
more	O
closely	O
related	O
to	O
one	O
another	O
than	O
to	O
either	O
murine	B
pancreatic	O
ribonuclease	O
(	O
mPR	O
)	O
or	O
angiogenin	O
(	O
mANG	O
)	O
,	O
or	O
to	O
any	O
of	O
the	O
human	B
ribonucleases	O
of	O
the	O
RNase	O
A	O
family	O
.	O

These	O
results	O
suggest	O
that	O
the	O
`	O
mR	O
cluster	O
'	O
emerged	O
via	O
multiple	O
duplications	O
of	O
a	O
gene	O
that	O
had	O
already	O
diverged	O
from	O
those	O
encoding	O
the	O
other	O
murine	B
ribonucleases	O
.	O

Although	O
this	O
type	O
of	O
expansion	O
is	O
unusual	O
in	O
this	O
gene	O
family	O
,	O
it	O
is	O
actually	O
not	O
unique	O
;	O
similar	O
expansion	O
has	O
occurred	O
in	O
bovine	B
species	O
,	O
with	O
gene	O
duplication	O
resulting	O
in	O
the	O
three	O
closely	O
-	O
related	O
bovine	B
pancreatic	O
,	O
bovine	B
brain	O
(	O
19	O
,	O
20	O
)	O
and	O
bovine	B
seminal	O
(	O
21	O
)	O
ribonucleases	O
.	O

One	O
interesting	O
feature	O
of	O
the	O
mR	O
cluster	O
is	O
that	O
its	O
relationship	O
to	O
any	O
of	O
to	O
the	O
six	O
known	O
human	B
RNase	O
A	O
-	O
type	O
genes	O
cannot	O
be	O

4239	O
Nucleic	O
Acids	O
Research	O
,	O
1997	O
,	O
Vol	O
.	O

25	O
,	O
No	O
.	O

Nucleic	O
Acids	O
Research	O
,	O
1994	O
,	O
Vol	O
.	O

22	O
,	O
No	O
.	O
121	O
determined	O
from	O
their	O
respective	O
amino	O
acid	O
sequence	O
homologies	O
.	O

Although	O
the	O
amino	O
acid	O
sequences	O
encoded	O
by	O
mEAR	O
-	O
1	O
and	O
mEAR	O
-	O
2	O
match	O
those	O
of	O
tryptic	O
peptides	O
derived	O
from	O
murine	B
eosinophil	O
proteins	O
(	O
15	O
)	O
,	O
the	O
homology	O
data	O
do	O
not	O
stand	O
in	O
overwhelming	O
support	O
of	O
a	O
unique	O
relationship	O
between	O
any	O
of	O
the	O
mR	O
cluster	O
ribonucleases	O
and	O
the	O
human	B
eosinophil	O
ribonucleases	O
EDN	O
and	O
ECP	O
.	O

The	O
existence	O
of	O
an	O
additional	O
,	O
as	O
yet	O
unidentified	O
human	B
ribonuclease	O
(	O
or	O
ribonucleases	O
)	O
more	O
closely	O
related	O
to	O
those	O
of	O
the	O
mR	O
cluster	O
cannot	O
be	O
ruled	O
out	O
.	O

Perhaps	O
the	O
most	O
important	O
issue	O
raised	O
by	O
this	O
work	O
is	O
the	O
question	O
of	O
why	O
so	O
much	O
evolutionary	O
energy	O
has	O
been	O
devoted	O
to	O
enlarging	O
and	O
diversifying	O
the	O
RNase	O
A	O
gene	O
superfamily	O
.	O

To	O
date	O
,	O
this	O
superfamily	O
now	O
includes	O
several	O
distinct	O
lineages	O
,	O
two	O
species	O
-	O
limited	O
clusters	O
,	O
and	O
the	O
two	O
most	O
rapidly	O
evolving	O
functional	O
coding	O
sequences	O
known	O
among	O
primates	O
(	O
22	O
)	O
.	O

The	O
question	O
of	O
evolutionary	O
energy	O
takes	O
on	O
particular	O
significance	O
here	O
,	O
where	O
five	O
functional	O
ribonucleases	O
have	O
emerged	O
in	O
what	O
appears	O
to	O
be	O
a	O
remarkably	O
short	O
period	O
of	O
evolutionary	O
time	O
(	O
15	O
)	O
.	O

It	O
is	O
conceivable	O
that	O
each	O
of	O
these	O
ribonucleases	O
might	O
serve	O
a	O
unique	O
but	O
related	O
function	O
.	O

On	O
this	O
point	O
,	O
a	O
number	O
of	O
studies	O
have	O
suggested	O
a	O
distinct	O
role	O
for	O
the	O
human	B
ribonuclease	O
ECP	O
in	O
eosinophil	O
-	O
mediated	O
host	O
defense	O
(	O
6	O
,	O
7	O
)	O
;	O
in	O
addition	O
,	O
we	O
have	O
recently	O
shown	O
that	O
eosinophil	O
ribonucleases	O
can	O
inhibit	O
retroviral	O
transduction	O
of	O
human	B
target	O
cells	O
(	O
23	O
)	O
.	O

The	O
possibility	O
that	O
certain	O
ribonucleases	O
have	O
diverged	O
to	O
promote	O
distinct	O
and	O
specific	O
host	O
defense	O
-	O
related	O
activities	O
remains	O
an	O
intriguing	O
hypothesis	O
.	O

ACKNOWLEDGEMENTS	O
We	O
would	O
like	O
to	O
thank	O
Dr	O
Jianzhi	O
Zhang	O
for	O
helpful	O
discussions	O
,	O
and	O
Drs	O
Harry	O
L	O
.	O
Malech	O
and	O
John	O
I	O
.	O
Gallin	O
for	O
their	O
ongoing	O
suppport	O
of	O
the	O
work	O
in	O
our	O
laboratory	O
.	O

D	O
.	O
B	O
.	O

is	O
a	O
Howard	O
Hughes	O
Medical	O
Institute	O
-	O
National	O
Institutes	O
of	O
Health	O
Research	O
Scholar	O
REFERENCES	O
1	O
D	O
'	O
Alessio	O
,	O
G	O
.	O
and	O
Riordan	O
,	O
J	O
.	O
F	O
.	O

(	O
1997	O
)	O
In	O
D	O
'	O
Alessio	O
,	O
G	O
.	O
and	O
Riordan	O
,	O
J	O
.	O
F	O
.	O

(	O
eds	O
)	O
Ribonucleases	O
:	O
structure	O
and	O
function	O
.	O

Academic	O
Press	O
,	O
Inc	O
.	O
,	O
New	O
York	O
,	O
NY	O
.	O

2	O
Sorrentino	O
,	O
S	O
.	O
and	O
Libonati	O
,	O
M	O
.	O

(	O
1997	O
)	O
FEBS	O
Lett	O
.	O

404	O
,	O
1	O
<	O
FFFD	O
>	O
5	O
.	O

21	O
22	O
23	O
24	O
3	O
4	O
5	O
6	O
7	O
8	O
9	O
10	O
11	O
12	O
13	O
14	O
15	O
16	O
17	O
18	O
19	O
20	O

4239	O

Beintema	O
,	O
J	O
.	O
J	O
.	O
,	O
Breukelman	O
,	O
H	O
.	O
J	O
,	O
Carsana	O
,	O
A	O
.	O
,	O
and	O
Furia	O
,	O
A	O
.	O

(	O
1997	O
)	O
In	O
D	O
'	O
Alessio	O
,	O
G	O
.	O
and	O
Riordan	O
,	O
J	O
.	O
F	O
.	O

(	O
eds	O
)	O
Ribonucleases	O
:	O
structure	O
and	O
function	O
.	O

Academic	O
Press	O
,	O
Inc	O
.	O
,	O
New	O
York	O
,	O
NY	O
.	O

Confalone	O
,	O
E	O
.	O
,	O
Beintema	O
,	O
J	O
.	O
J	O
.	O
,	O
Sasso	O
,	O
M	O
.	O
P	O
.	O

Carsana	O
,	O
A	O
.	O
,	O
Palmieria	O
,	O
M	O
.	O
,	O
Vento	O
,	O
M	O
.	O
T	O
.	O
and	O
Furia	O
A	O
.	O

(	O
1995	O
)	O
J	O
.	O

Mol	O
.	O

Evol	O
.	O

41	O
,	O
850	O
<	O
FFFD	O
>	O
858	O
.	O

Futami	O
,	O
J	O
.	O
,	O
Tsushima	O
,	O
Y	O
.	O
,	O
Murato	O
,	O
U	O
,	O
Tada	O
,	O
H	O
.	O
,	O
Sasaki	O
,	O
J	O
.	O
,	O
Seno	O
,	O
M	O
.	O
,	O
and	O
Yamada	O
,	O
H	O
.	O

(	O
1997	O
)	O
DNA	O
Cell	O
Biol	O
.	O

16	O
,	O
413	O
<	O
FFFD	O
>	O
419	O
.	O

Ackerman	O
,	O
S	O
.	O
J	O
.	O

(	O
1993	O
)	O
In	O
Makino	O
,	O
S	O
.	O
and	O
Fukuda	O
,	O
T	O
.	O

(	O
eds	O
)	O
Eosinophils	O
:	O
biological	O
and	O
clinical	O
aspects	O
.	O

CRC	O
Press	O
,	O
Inc	O
.	O
,	O
Boca	O
Raton	O
,	O
FL	O
Spry	O
,	O
C	O
.	O
J	O
.	O
F	O
.	O

(	O
1988	O
)	O
Eosinophils	O
:	O
a	O
comprehensive	O
review	O
and	O
guide	O
to	O
the	O
scientific	O
and	O
medical	O
literature	O
.	O

Oxford	O
University	O
Press	O
,	O
Oxford	O
,	O
UK	O
.	O

Beintema	O
,	O
J	O
.	O
J	O
.	O
,	O
Hofsteenge	O
,	O
J	O
.	O
,	O
Iwama	O
,	O
M	O
.	O
,	O
Morita	O
,	O
T	O
.	O
,	O
Ohgi	O
,	O
K	O
.	O
,	O
Irie	O
,	O
M	O
.	O
,	O
Sugiyama	O
,	O
R	O
.	O
H	O
.	O
,	O
Schieven	O
G	O
.	O
L	O
.	O
,	O
Dekker	O
,	O
C	O
.	O
A	O
.	O
,	O
and	O
Glitz	O
,	O
D	O
.	O
G	O
.	O

(	O
1988	O
)	O
Biochemistry	O
27	O
,	O
4530	O
<	O
FFFD	O
>	O
4538	O
.	O

Sorrentino	O
,	O
S	O
.	O
,	O
Tucker	O
,	O
G	O
.	O
K	O
.	O
,	O
and	O
Glitz	O
,	O
D	O
.	O
G	O
.	O

(	O
1988	O
)	O
J	O
.	O

Biol	O
.	O

Chem	O
.	O

263	O
,	O
16125	O
<	O
FFFD	O
>	O
16131	O
.	O

Vallee	O
,	O
B	O
.	O
L	O
.	O
and	O
Riordan	O
,	O
J	O
.	O
F	O
.	O

(	O
1988	O
)	O
Adv	O
.	O

Exp	O
.	O

Med	O
.	O

Biol	O
.	O

234	O
,	O
41	O
<	O
FFFD	O
>	O
53	O
.	O

Moroianu	O
,	O
J	O
.	O
and	O
Riordan	O
,	O
J	O
.	O
F	O
.	O

(	O
1994	O
)	O
Proc	O
.	O

Natl	O
.	O

Acad	O
.	O

Sci	O
.	O

USA	O
91	O
,	O
1677	O
<	O
FFFD	O
>	O
1681	O
.	O

Seno	O
,	O
M	O
.	O
,	O
Futami	O
,	O
J	O
.	O
,	O
Tsushima	O
,	O
Y	O
.	O
,	O
Akutagawa	O
,	O
K	O
.	O
,	O
Kosaka	O
,	O
M	O
.	O
,	O
Tada	O
,	O
H	O
.	O
and	O
Yamada	O
,	O
H	O
.	O

(	O
1995	O
)	O
Bioch	O
.	O

Biophys	O
.	O

Acta	O
1261	O
,	O
424	O
<	O
FFFD	O
>	O
426	O
.	O

Rosenberg	O
,	O
H	O
.	O
F	O
.	O
and	O
Dyer	O
,	O
K	O
.	O
D	O
.	O

(	O
1995	O
)	O
Nucleic	O
Acids	O
Res	O
.	O

23	O
,	O
4290	O
<	O
FFFD	O
>	O
4295	O
.	O

Rosenberg	O
,	O
H	O
.	O
F	O
.	O
and	O
Dyer	O
,	O
K	O
.	O
D	O
.	O

(	O
1996	O
)	O
Nucleic	O
Acids	O
Res	O
.	O

24	O
,	O
3507	O
<	O
FFFD	O
>	O
3513	O
.	O

Larson	O
,	O
K	O
.	O
A	O
.	O
,	O
Olson	O
,	O
E	O
.	O
V	O
.	O
,	O
Madden	O
,	O
B	O
.	O
J	O
.	O
,	O
Gleich	O
,	O
G	O
.	O
J	O
.	O
,	O
Lee	O
,	O
N	O
.	O
A	O
.	O
and	O
Lee	O
,	O
J	O
.	O
J	O
.	O

(	O
1997	O
)	O
Proc	O
.	O

Natl	O
.	O

Acad	O
.	O

Sci	O
.	O

USA	O
93	O
,	O
12370	O
<	O
FFFD	O
>	O
12375	O
.	O

Nakajima	O
-	O
Iyima	O
,	O
S	O
.	O
,	O
Hamada	O
,	O
H	O
.	O
,	O
Reddy	O
,	O
P	O
.	O
and	O
Kakanaga	O
,	O
T	O
.	O

(	O
1985	O
)	O
Proc	O
.	O

Natl	O
.	O

Acad	O
.	O

Sci	O
.	O

USA	O
82	O
,	O
6133	O
<	O
FFFD	O
>	O
6137	O
.	O

Li	O
,	O
W	O
.	O
-	O
H	O
.	O
and	O
Graur	O
,	O
D	O
.	O

(	O
1991	O
)	O
Fundamentals	O
of	O
Molecular	O
Evolution	O
.	O

Sinauer	O
Associates	O
,	O
Sunderland	O
,	O
MA	O
.	O

Rosenberg	O
,	O
H	O
.	O
F	O
.	O
and	O
Dyer	O
,	O
K	O
.	O
D	O
.	O

(	O
1995	O
)	O
J	O
.	O

Biol	O
.	O

Chem	O
.	O

270	O
,	O
21539	O
<	O
FFFD	O
>	O
21544	O
.	O

Watanabe	O
,	O
H	O
.	O
,	O
Katoh	O
,	O
H	O
,	O
Ishii	O
,	O
M	O
.	O
,	O
Komoda	O
,	O
Y	O
.	O
,	O
Sanda	O
,	O
A	O
.	O
,	O
Takizawa	O
,	O
Y	O
.	O
,	O
Ohgi	O
,	O
K	O
.	O
and	O
Irie	O
,	O
M	O
.	O

(	O
1988	O
)	O
J	O
.	O

Biochem	O
.	O

104	O
,	O
939	O
<	O
FFFD	O
>	O
945	O
.	O

Sasso	O
,	O
M	O
.	O
P	O
.	O
,	O
Carsana	O
,	O
A	O
.	O
,	O
Confalone	O
,	O
E	O
.	O
,	O
Cosi	O
,	O
C	O
.	O
,	O
Sorrentino	O
,	O
S	O
.	O
,	O
Viola	O
,	O
M	O
.	O
,	O
Palmieri	O
,	O
M	O
.	O
,	O
Russo	O
,	O
E	O
.	O
and	O
Furia	O
,	O
A	O
.	O

(	O
1991	O
)	O
Nucleic	O
Acids	O
Res	O
.	O

19	O
,	O
6469	O
<	O
FFFD	O
>	O
6474	O
.	O

Palmieri	O
,	O
M	O
.	O
,	O
Carsana	O
,	O
A	O
.	O
,	O
Furia	O
,	O
A	O
.	O
and	O
Libonati	O
,	O
M	O
.	O

(	O
1985	O
)	O
Eur	O
.	O

J	O
.	O

Biochem	O
.	O

152	O
,	O
275	O
<	O
FFFD	O
>	O
277	O
.	O

Rosenberg	O
,	O
H	O
.	O
F	O
.	O
,	O
Dyer	O
,	O
K	O
.	O
D	O
.	O
,	O
Tiffany	O
,	O
H	O
.	O
L	O
.	O
and	O
Gonzalez	O
,	O
M	O
.	O

(	O
1995	O
)	O
Nature	O
Genet	O
.	O

10	O
,	O
219	O
<	O
FFFD	O
>	O
223	O
.	O

Domachowske	O
,	O
J	O
.	O
B	O
.	O
and	O
Rosenberg	O
,	O
H	O
.	O
F	O
.	O

(	O
1997	O
)	O
J	O
.	O

Leukoc	O
.	O

Biol	O
.	O
,	O
62	O
,	O
363	O
<	O
FFFD	O
>	O
368	O
.	O

Iwama	O
,	O
M	O
.	O
,	O
Sanda	O
,	O
A	O
.	O
,	O
Ohgi	O
,	O
K	O
.	O
,	O
Hofsteenge	O
,	O
J	O
.	O
,	O
and	O
Irie	O
,	O
M	O
.	O

(	O
1993	O
)	O
Biosci	O
.	O

Biotech	O
.	O

Biochem	O
.	O

57	O
,	O
2133	O
<	O
FFFD	O
>	O
2138	O
.	O

Physiological	O
and	O
chemical	O
characterization	O
of	O
cyanobacterial	B
metallothioneins	O
.	O

Abstract	O

Techniques	O
have	O
been	O
developed	O
for	O
detection	O
,	O
quantitation	O
,	O
and	O
isolation	O
of	O
bacterial	O
metallothioneins	O
(	O
MTs	O
)	O
from	O
cyanobacterial	O
species	O
.	O

These	O
methods	O
involve	O
differential	O
pulse	O
polarography	O
and	O
reverse	O
-	O
phase	O
high	O
-	O
performance	O
liquid	O
chromatography	O
(	O
HPLC	O
)	O
and	O
have	O
allowed	O
detection	O
of	O
picomole	O
quantities	O
of	O
these	O
high	O
sulfhydryl	O
content	O
proteins	O
.	O

The	O
prokaryotic	O
molecule	O
was	O
found	O
to	O
be	O
induced	O
in	O
the	O
presence	O
of	O
Cd	O
or	O
Zn	O
salts	O
with	O
regulation	O
at	O
the	O
level	O
of	O
transcription	O
.	O

Cu	O
was	O
not	O
found	O
to	O
induce	O
synthesis	O
of	O
the	O
prokaryotic	O
MT	O
.	O

Exposure	O
to	O
the	O
former	O
metals	O
resulted	O
in	O
a	O
growth	O
lag	O
followed	O
by	O
simultaneous	O
induction	O
of	O
MT	O
synthesis	O
and	O
onset	O
of	O
growth	O
.	O

Amino	O
acid	O
analysis	O
and	O
N	O
-	O
terminal	O
sequence	O
analysis	O
indicated	O
that	O
the	O
bacterial	O
MTs	O
from	O
cyanobacteria	O
are	O
unique	O
,	O
having	O
many	O
aromatic	O
and	O
aliphatic	O
residues	O
and	O
no	O
apparent	O
association	O
of	O
hydroxylated	O
or	O
basic	O
amino	O
acids	O
with	O
cysteines	O
.	O

Although	O
the	O
characteristic	O
Cys	O
-	O
X	O
-	O
Cys	O
sequences	O
were	O
present	O
,	O
no	O
apparent	O
amino	O
acid	O
sequence	O
homology	O
with	O
the	O
eukaryotic	O
MTs	O
was	O
found	O
in	O
the	O
first	O
42	O
residues	O
.	O

Environmental	O
Health	O
Perspectives	O
Vol	O
.	O

65	O
,	O
pp	O
.	O

71	O
-	O
75	O
,	O
1986	O

Physiological	O
and	O
Chemical	O

Characterization	O
of	O
Cyanobacterial	O
Metallothioneins	O

by	O
Robert	O
W	O
.	O
Olafson	O
*	O

Techniques	O
have	O
been	O
developed	O
for	O
detection	O
,	O
quantitation	O
,	O
and	O
isolation	O
of	O
bacterial	O
metallothioneins	O
(	O
MTs	O
)	O
from	O
cyanobacterial	O
species	O
.	O

These	O
methods	O
involve	O
differential	O
pulse	O
polarography	O
and	O
reverse	O
-	O
phase	O
high	O
-	O
performance	O
liquid	O
chromatography	O
(	O
HPLC	O
)	O
and	O
have	O
allowed	O
detection	O
of	O
picomole	O
quantities	O
of	O
these	O
high	O
sulfhydryl	O
content	O
proteins	O
.	O

The	O
prokaryotic	O
molecule	O
was	O
found	O
to	O
be	O
induced	O
in	O
the	O
presence	O
of	O
Cd	O
or	O
Zn	O
salts	O
with	O
regulation	O
at	O
the	O
level	O
of	O
transcription	O
.	O

Cu	O
was	O
not	O
found	O
to	O
induce	O
synthesis	O
of	O
the	O
prokaryotic	O
MT	O
.	O

Exposure	O
to	O
the	O
former	O
metals	O
resulted	O
in	O
a	O
growth	O
lag	O
followed	O
by	O
simultaneous	O
induction	O
of	O
MT	O
synthesis	O
and	O
onset	O
of	O
growth	O
.	O

Amino	O
acid	O
analysis	O
and	O
N	O
-	O
terminal	O
sequence	O
analysis	O
indicated	O
that	O
the	O
bacterial	O
MTs	O
from	O
cyanobacteria	O
are	O
unique	O
,	O
having	O
many	O
aromatic	O
and	O
aliphatic	O
residues	O
and	O
no	O
apparent	O
association	O
of	O
hydroxylated	O
or	O
basic	O
amino	O
acids	O
with	O
cysteines	O
.	O

Although	O
the	O
characteristic	O
CysX	O
-	O
Cys	O
sequences	O
were	O
present	O
,	O
no	O
apparent	O
amino	O
acid	O
sequence	O
homology	O
with	O
the	O
eukaryotic	O
MTs	O
was	O
found	O
in	O
the	O
first	O
42	O
residues	O
.	O

Introduction	O

Metallothioneins	O
have	O
now	O
been	O
isolated	O
and	O
characterized	O
from	O
a	O
large	O
variety	O
of	O
eukaryotic	O
organisms	O
(	O
1	O
)	O
and	O
shown	O
to	O
be	O
involved	O
in	O
heavy	O
metal	O
detoxification	O
and	O
/	O
or	O
homeostasis	O
(	O
2	O
-	O
4	O
)	O
.	O

These	O
proteins	O
are	O
highly	O
homologous	O
with	O
respect	O
to	O
amino	O
acid	O
sequence	O
and	O
complex	O
metals	O
in	O
characteristic	O
metal	O
-	O
thiolate	O
cluster	O
arrangements	O
,	O
the	O
structures	O
of	O
which	O
have	O
been	O
recently	O

investigated	O
by	O
113Cd	O
-	O
NMR	O
(	O
6	O
)	O
.	O

Although	O
metallothionein	O
(	O
MT	O
)	O
is	O
found	O
throughout	O
the	O
eukaryotic	O
world	O
,	O
few	O
reports	O
of	O
the	O
presence	O
of	O
this	O
type	O
of	O
high	O
sulfhydryl	O
content	O
metal	O
-	O
binding	O
protein	O
exist	O
for	O
prokaryotes	O
.	O

We	O
earlier	O
reported	O
the	O
presence	O
of	O
a	O
prokaryotic	O
MT	O
in	O
cyanobacteria	O
(	O
7	O
,	O
8	O
)	O
and	O
have	O
recently	O
provided	O
primary	O
sequence	O
evidence	O
substantiating	O
these	O
data	O
.	O

This	O
manuscript	O
is	O
intended	O
to	O
summarize	O
the	O
present	O
state	O
of	O
knowledge	O
regarding	O
the	O
physiological	O
and	O
chemical	O
characterization	O
of	O
these	O
bacterial	O
MTs	O
,	O
with	O
an	O
emphasis	O
on	O
the	O
techniques	O
employed	O
in	O
such	O
studies	O
.	O

Analytical	O
Procedure	O

In	O
order	O
to	O
facilitate	O
rapid	O
detection	O
,	O
isolation	O
,	O
and	O
quantitation	O
of	O
MT	O
from	O
various	O
sources	O
,	O
we	O
have	O
routinely	O
employed	O
a	O
differential	O
pulse	O
polarographic	O
tech	O

*	O
Department	O
of	O
Biochemistry	O
and	O
Microbiology	O
,	O
University	O
of	O
Victoria	O
,	O
Victoria	O
,	O
British	O
Columbia	O
V8W	O
2Y2	O
,	O
Canada	O
.	O

nique	O
first	O
described	O
by	O
Brdicka	O
(	O
9	O
-	O
11	O
)	O
.	O

This	O
procedure	O
avoids	O
use	O
of	O
radioisotopes	O
and	O
circumvents	O
problems	O
such	O
as	O
species	O
specificity	O
and	O
metal	O
stoichiometric	O
assumptions	O
associated	O
with	O
radioimmunoassays	O
and	O
metal	O
binding	O
assays	O
.	O

Figure	O
1	O
shows	O
a	O
typical	O
polarographic	O
wave	O
for	O
MT	O
using	O
the	O
Brdicka	O
procedure	O
.	O

Measurement	O
of	O
the	O
wave	O
height	O
can	O
be	O
performed	O
from	O
either	O
the	O

0	O
.	O
20	O

glJ	O
MT	O
-	O
1	O

O	O
0	O
.	O
15	O

E	O

0	O
0	O
.	O
10	O
0	O

E	O
0	O
.	O
05	O
_	O
_	O

-	O
1	O
.	O
35	O
-	O
1	O
.	O
45	O
-	O
1	O
.	O
55	O
-	O
1	O
.	O
65	O

V	O
vs	O
Agt	O
/	O
AgC1	O

FIGURE	O
1	O
.	O

Differential	O
pulse	O
polarographic	O
wave	O
for	O
murine	B
MT	O
-	O
1	O
.	O

Wave	O
heights	O
were	O
calculated	O
from	O
the	O
broken	O
tangent	O
line	O
between	O
minima	O
rather	O
than	O
the	O
supporting	O
electrolyte	O
baseline	O
at	O
the	O
bottom	O
of	O
the	O
figure	O
.	O

R	O
.	O

W	O
OLAFSON	O

supporting	O
electrolyte	O
baseline	O
or	O
a	O
tangent	O
to	O
the	O
minima	O
as	O
shown	O
in	O
the	O
preceding	O
figure	O
.	O

In	O
the	O
cobalt	O
hexaminechloride	O
supporting	O
electrolyte	O
,	O
the	O
half	O
-	O
wave	O
potential	O
for	O
all	O
MTs	O
studied	O
to	O
date	O
is	O
approximately	O
-	O
1	O
.	O
45	O
V	O
versus	O
a	O
Ag	O
/	O
AgCl	O
reference	O
electrode	O
.	O

This	O
electrochemical	O
reaction	O
results	O
in	O
highly	O
reproducible	O
and	O
linear	O
current	O
responses	O
which	O
can	O
be	O
used	O
with	O
samples	O
containing	O
picomole	O
levels	O
of	O
MT	O
(	O
Fig	O
.	O
2	O
)	O
.	O

Since	O
this	O
is	O
an	O
exceedingly	O
sensitive	O
instrument	O
,	O
attention	O
to	O
detail	O
is	O
particularly	O
important	O
for	O
successful	O
use	O
of	O
the	O
Brdicka	O
procedure	O
(	O
11	O
)	O
.	O

Routine	O
use	O
of	O
a	O
reference	O
standard	O
MT	O
is	O
highly	O
recommended	O
to	O
compensate	O
for	O
small	O
day	O
-	O
today	O
variations	O
in	O
response	O
.	O

For	O
absolute	O
values	O
,	O
standards	O
must	O
be	O
identical	O
to	O
the	O
species	O
of	O
protein	O
quantitated	O
;	O
otherwise	O
commercially	O
available	O
standard	O
is	O
adequate	O
.	O

Although	O
certain	O
tissues	O
and	O
cellular	O
types	O
can	O
be	O
shown	O
to	O
have	O
no	O
other	O
polarographically	O
active	O
material	O
other	O
than	O
MT	O
,	O
with	O
samples	O
from	O
new	O
species	O
,	O
it	O
is	O
necessary	O
to	O
evaluate	O
this	O
potential	O
problem	O
by	O
gelperneation	O
chromatography	O
and	O
,	O
if	O
necessary	O
,	O
take	O
steps	O
to	O
remove	O
contaminants	O
before	O
assaying	O
.	O

In	O
most	O
cases	O
,	O

0	O

E	O
i	O

m	O
0	O

0	O
E	O

0	O
.	O
31	O

0	O
.	O
11	O

O	O
0	O
.	O
1	O
0	O
.	O
3	O
0	O
.	O
5	O

MT	O
(	O
nanomoles	O
)	O

FIGURE	O
2	O
.	O

Standard	O
curve	O
for	O
polarographic	O
determination	O
of	O
me	O

tallothionein	O
.	O

FIGURE	O
3	O
.	O

Cyclic	O
voltamogram	O
obtained	O
by	O
equilibration	O
at	O
-	O
1	O
.	O
0	O
V	O

for	O
4	O
min	O
followed	O
by	O
cyclic	O
scanning	O
to	O
OV	O
and	O
-	O
1	O
.	O
4	O
V	O
at	O
a	O
scan	O
rate	O
of	O
200	O
mV	O
/	O
sec	O
with	O
a	O
PAR	O
Model	O
303	O
static	O
mercury	O
drop	O
electrode	O
in	O
the	O
hanging	O
drop	O
mode	O
.	O

The	O
mercury	O
drop	O
electrode	O
was	O
set	O
in	O
the	O
large	O
drop	O
position	O
producing	O
a	O
drop	O
of	O
0	O
.	O
0226	O
cm3	O
.	O

The	O
supporting	O
electrolyte	O
was	O
20	O
mM	O
HEPES	O
buffer	O
,	O
pH	O
7	O
.	O
3	O
.	O

The	O
dotted	O
line	O
is	O
the	O
equilibrium	O
trace	O
.	O

Adapted	O
Olafson	O
and	O
Sim	O
(	O
10	O
)	O
.	O

this	O
is	O
easily	O
managed	O
by	O
heat	O
denaturation	O
,	O
if	O
care	O
is	O
taken	O
to	O
assess	O
the	O
degree	O
of	O
MT	O
losses	O
due	O
to	O
coprecipitation	O
.	O

Such	O
losses	O
later	O
can	O
usually	O
be	O
minimized	O
to	O
less	O
than	O
10	O
%	O
by	O
adjustment	O
of	O
the	O
tissue	O
homogenate	O
density	O
prior	O
to	O
denaturation	O
.	O

It	O
should	O
be	O
indicated	O
that	O
additional	O
utility	O
can	O
be	O
found	O
with	O
a	O
polarographic	O
analyzer	O
beyond	O
application	O
of	O
the	O
Brdicka	O
procedure	O
.	O

For	O
example	O
,	O
metal	O
levels	O
can	O
be	O
readily	O
determined	O
by	O
using	O
differential	O
pulse	O
or	O
anodic	O
stripping	O
voltametry	O
procedures	O
(	O
10	O
)	O
,	O
while	O
Figure	O
3	O
shows	O
a	O
cyclic	O
voltamogram	O
of	O
bacterial	O
MT	O
.	O

The	O
latter	O
technique	O
is	O
potentially	O
useful	O
in	O
assessing	O
metal	O
speciation	O
and	O
integrity	O
of	O
the	O
protein	O
tertiary	O
structure	O
near	O
metal	O
clusters	O
,	O
particularly	O
after	O
metal	O
reconstitution	O
studies	O
.	O

E	O

'	O
C2A	O
-	O
E	O
24	O

0	O
30	O
40	O
E0	O

*	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O

o	O
C	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
C	O

Fraction	O
Number	O
(	O
18ml	O
)	O

FIGURE	O
4	O
.	O

Sephadex	O
G	O
-	O
75	O
chromatography	O
profile	O
of	O
bacterial	O
cell	O

lysate	O
applied	O
to	O
a	O
5	O
x	O
100	O
cm	O
column	O
and	O
eluted	O
with	O
10	O
mM	O
anunoium	O
bicarbonate	O
,	O
5	O
mM	O
mercaptoethanol	O
(	O
7	O
)	O
.	O

Elution	O
Time	O
(	O
min	O
)	O

FIGURE	O
5	O
.	O

Reverse	O
-	O
phase	O
high	O
-	O
performance	O
chromatography	O
profile	O

of	O
Sephadex	O
G	O
-	O
75	O
fractionated	O
bacterial	O
MT	O
.	O

The	O
300	O
A	O
pore	O
size	O
propyl	O
column	O
was	O
eluted	O
with	O
20	O
mM	O
triethylamine	O
phosphate	O
,	O
pH	O
7	O
.	O
0	O
,	O
by	O
using	O
an	O
acetonitrile	O
organic	O
modifier	O
(	O
phase	O
B	O
)	O
.	O

Column	O
effluent	O
was	O
monitored	O
at	O
250	O
nm	O
with	O
a	O
sensitivity	O
of	O
1	O
.	O
0	O
AUFS	O
(	O
12	O
)	O
.	O

72	O

CYANOBACTERIAL	B
METALLOTHIONEINS	O

Isolation	O
of	O
Cyanobacterial	O
MT	O

Synechococcus	B
strain	I
Tx	I
-	I
20	I
cyanobacteria	O
were	O
maintained	O
in	O
axenic	O
culture	O
on	O
BG	O
-	O
11	O
medium	O
(	O
7	O
)	O
and	O
harvested	O
from	O
aerated	O
20	O
L	O
cultures	O
grown	O
at	O
280C	O
under	O
fluorescent	O
light	O
.	O

Cells	O
were	O
broken	O
in	O
a	O
French	O
pressure	O
cell	O
at	O
0	O
?	O
C	O
in	O
0	O
.	O
5	O
M	O
Tris	O
-	O
HCI	O
,	O
pH	O
8	O
.	O
6	O
,	O
and	O
the	O
lysate	O
exposed	O
to	O
10	O
,	O
uCi	O
of	O
109CdCl	O
.	O

The	O
40	O
,	O
000g	O
supernatant	O
was	O
applied	O
to	O
a	O
Sephadex	O
G	O
-	O
75	O
column	O
developed	O
with	O
10	O
mM	O
ammonium	O
bicarbonate	O
and	O
5	O
mM	O
mercaptoethanol	O
resulting	O
in	O
the	O
profile	O
shown	O
in	O
Figure	O
4	O
.	O

Polarographic	O
activity	O
and	O
radionuclide	O
binding	O
were	O
coincident	O
with	O
a	O
10	O
,	O
000	O
MW	O
ultraviolet	O
absorbing	O
fraction	O
.	O

Further	O
purification	O
of	O
this	O
material	O
could	O
be	O
undertaken	O
by	O
DEAE	O
-	O
cellulose	O
chromatography	O
or	O
isoelectric	O
focusing	O
but	O
maximum	O
resolution	O
of	O
isoproteins	O
was	O
best	O
attained	O
by	O
reverse	O
-	O
phase	O
high	O
-	O
performance	O
liquid	O
chromatogra	O

0	O
5	O

DAYS	O

I0	O

5	O

phy	O
.	O

Figure	O
5	O
shows	O
such	O
a	O
separation	O
performed	O
on	O
a	O
300	O
A	O
pore	O
size	O
C	O
-	O
3	O
column	O
(	O
Beckman	O
Instruments	O
)	O
.	O

Four	O
baseline	O
resolved	O
MT	O
peaks	O
appear	O
between	O
40	O
and	O
70	O
min	O
.	O

Peaks	O
eluting	O
at	O
80	O
min	O
contain	O
at	O
least	O
four	O
additional	O
MT	O
components	O
resolvable	O
by	O
adjustment	O
of	O
the	O
applied	O
organic	O
modifier	O
ramp	O
.	O

Preliminary	O
evidence	O
indicates	O
that	O
these	O
isoproteins	O
are	O
microheterogeneous	O
with	O
respect	O
to	O
both	O
amino	O
acid	O
composition	O
and	O
metal	O
speciation	O
resulting	O
in	O
the	O
observed	O
reverse	O
-	O
phase	O
separation	O
.	O

Physiological	O
Characteristics	O
of	O
Cyanobacterial	O
MT	O

Using	O
the	O
Brdicka	O
polarographic	O
procedure	O
,	O
it	O
is	O
possible	O
to	O
measure	O
basal	O
MT	O
levels	O
in	O
Synechococcus	O
strain	O

5	O

DAYS	O

10	O

15	O

FIGURE	O
6	O
.	O

Cell	O
numbers	O
and	O
MT	O
concentrations	O
as	O
a	O
function	O
of	O
time	O
after	O
inoculation	O
of	O
wild	O
-	O
type	O
cyanobacteria	O
in	O
the	O
presence	O
and	O
absence	O

of	O
(	O
A	O
)	O
22	O
.	O
5	O
,	O
uM	O
CdCl2	O
;	O
(	O
B	O
)	O
control	O
;	O
(	O
C	O
)	O
50	O
,	O
uM	O
ZnSO4	O
;	O
(	O
D	O
)	O
50	O
,	O
uM	O
CuCl2	O
(	O
8	O
)	O
.	O

73	O

74	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
R	O
.	O

W	O
OLAFSON	O

Table	O
1	O
.	O

Amino	O
acid	O
compositions	O
of	O
cyanobacterial	O

metallothioneins	O
compared	O
with	O
eukaryotic	O
metallothioneins	O
.	O

Nearest	O
integer	O
residues	O
per	O
molecule	O
Human	B
(	O
MT	O
-	O
2	O
)	O
Crab	O
(	O
MT	O
-	O
2	O
)	O
Tx	O
-	O
20t	O
CysA	O
20	O
18	O
9	O
.	O
5	O
Asx	O
4	O
6	O
5	O
.	O
7	O
Thr	O
2	O
3	O
4	O
.	O
8	O
Ser	O
8	O
5	O
3	O
.	O
8	O
Glx	O
2	O
5	O
2	O
.	O
0	O
Gly	O
5	O
3	O
8	O
.	O
0	O
Ala	O
7	O
1	O
4	O
.	O
0	O
Val	O
1	O
-	O
2	O
.	O
3	O
Met	O
1	O
-	O

Ile	O
1	O
-	O
1	O
.	O
1	O

Leu	O
Tyr	O
Phe	O
His	O
Lys	O
Arg	O
Pro	O

8	O
2	O

8	O
2	O
6	O

2	O
.	O
9	O
2	O
.	O
3	O

2	O
.	O
8	O
2	O
.	O
6	O
1	O
.	O
0	O
1	O
.	O
9	O

RRIMP	O
NI	O
cells	O
cultured	O
in	O
the	O
absence	O
of	O
added	O
metal	O
,	O
as	O
shown	O
in	O
Figure	O
6B	O
(	O
8	O
)	O
.	O

Comparison	O
with	O
cultures	O
exposed	O
to	O
cadmium	O
chloride	O
(	O
Fig	O
.	O
6A	O
)	O
or	O
zinc	O
sulfate	O
(	O
Fig	O
.	O
6C	O
)	O
showed	O
that	O
introduction	O
of	O
metal	O
salts	O
resulted	O
in	O
a	O
growth	O
lag	O
and	O
that	O
resumption	O
of	O
growth	O
occurred	O
coincident	O
with	O
an	O
increase	O
in	O
cellular	O
levels	O
of	O
MT	O
.	O

In	O
addition	O
,	O
it	O
should	O
be	O
noted	O
that	O
,	O
like	O
mammalian	O
MT	O
,	O
cadmium	O
appears	O
to	O
be	O
a	O
more	O
potent	O
inducer	O
than	O
zinc	O
.	O

Twice	O
as	O
much	O
cadmium	O
-	O
thionein	O
was	O
synthesized	O
on	O
exposure	O
to	O
half	O
as	O
much	O
metal	O
as	O
was	O
used	O
in	O
the	O
zinc	O
induction	O
experiment	O
.	O

A	O
further	O
interesting	O
finding	O
was	O
that	O
copper	O
exposure	O
resulted	O
in	O
an	O
even	O
greater	O
growth	O
lag	O
than	O
observed	O
with	O
cadmium	O
,	O
but	O
on	O
resumption	O
of	O
growth	O
in	O
the	O
presence	O
copper	O
,	O
MT	O
synthesis	O
was	O
not	O
noted	O
(	O
Fig	O
.	O
6D	O
)	O
.	O

Recent	O
results	O
suggest	O
that	O
this	O
copper	O
resistance	O
is	O
manifest	O
via	O
a	O
membrane	O
exclusion	O
mechanism	O
(	O
unpublished	O
results	O
)	O
.	O

HOURS	O

FIGURE	O
7	O
.	O

Inhibition	O
of	O
cadmium	O
induced	O
synthesis	O
by	O
actinomycin	O

D	O
(	O
hatched	O
bar	O
)	O
and	O
chloramphenicol	O
(	O
solid	O
bar	O
)	O
.	O

Control	O
cells	O
are	O
shown	O
by	O
unmarked	O
bars	O
.	O

In	O
order	O
that	O
the	O
level	O
of	O
regulation	O
of	O
metal	O
induction	O
be	O
determined	O
for	O
cyanobacteria	O
,	O
logarithmically	O
growing	O
cultures	O
were	O
exposed	O
to	O
cadmium	O
and	O
MT	O
concentrations	O
measured	O
at	O
several	O
time	O
intervals	O
thereafter	O
.	O

Two	O
cultures	O
were	O
exposed	O
to	O
either	O
chloramphenicol	O
or	O
actinomycin	O
D	O
30	O
min	O
prior	O
to	O
introduction	O
of	O
metal	O
,	O
while	O
a	O
third	O
culture	O
was	O
used	O
as	O
a	O
control	O
.	O

The	O
results	O
of	O
this	O
experiment	O
are	O
shown	O
in	O
Figure	O
7	O
and	O
indicate	O
induction	O
at	O
the	O
level	O
of	O
transcription	O
,	O
as	O
was	O
found	O
in	O
eukaryotic	O
organisms	O
.	O

The	O
assumption	O
at	O
this	O
stage	O
in	O
these	O
investigations	O
was	O
that	O
the	O
growth	O
lag	O
observed	O
in	O
cultures	O
exposed	O
to	O

Table	O
2	O
.	O

Amino	O
acid	O
sequence	O
analysis	O
.	O

Amino	O
acid	O

1	O
10	O
20	O
30	O
Cyanobacteria	O
T	O
S	O
T	O
T	O
L	O
V	O
K	O
C	O
A	O
C	O
E	O
P	O
C	O
L	O
C	O
N	O
V	O
D	O
P	O
S	O
K	O
A	O
I	O
D	O
R	O
N	O
G	O
L	O
Y	O
Y	O
Scylla	O
P	O
DP	O
C	O
C	O
NDK	O
C	O
DC	O
K	O
EG	O
EC	O
KT	O
GC	O
K	O
CT	O
S	O
C	O
Human	B
Ac	O
MD	O
P	O
NC	O
S	O
C	O
AA	O
G	O
DS	O
CT	O
C	O
AG	O
S	O
C	O
KC	O
KE	O
C	O
KC	O
T	O
S	O
C	O

Neurospora	O

G	O
D	O
C	O
G	O
C	O
S	O
G	O
A	O
S	O
S	O
C	O
N	O
C	O
G	O
S	O
G	O
C	O
S	O
C	O
S	O
N	O

C	O
G	O
S	O
K	O

Table	O
2	O
.	O

Continued	O
.	O

Amino	O
acid	O

40	O
50	O
60	O
C	O
C	O
EAC	O
A	O
H	O
GHT	O
G	O
G	O

R	O
CP	O
PC	O
EQ	O
C	O
S	O
SGC	O
K	O
CA	O
NK	O
E	O
DC	O
RK	O
TC	O
SK	O
PC	O
SCC	O
P	O
K	O
K	O
SCC	O
S	O
CCP	O
V	O
GC	O
A	O
KCA	O
Q	O
BC	O
I	O
C	O
K	O
GA	O
SDK	O
C	O
S	O
CC	O
A	O

74	O

I	O

II	O

I	O
I	O

CYANOBACTERIAL	B
METALLOTHIONEINS	O
75	O

cadmium	O
or	O
zinc	O
was	O
due	O
to	O
a	O
rather	O
protracted	O
time	O
of	O
MT	O
induction	O
,	O
perhaps	O
associated	O
with	O
toxic	O
burden	O
.	O

If	O
the	O
above	O
cadmium	O
-	O
resistant	O
cells	O
were	O
transferred	O
into	O
fresh	O
media	O
in	O
the	O
absence	O
of	O
cadmium	O
and	O
allowed	O
to	O
grow	O
up	O
between	O
three	O
successive	O
transfers	O
,	O
levels	O
of	O
MT	O
dropped	O
to	O
near	O
basal	O
values	O
as	O
synthesis	O
was	O
repressed	O
in	O
the	O
absence	O
of	O
metal	O
.	O

However	O
,	O
when	O
these	O
cells	O
were	O
now	O
transferred	O
into	O
cadmium	O
-	O
containing	O
media	O
,	O
instead	O
of	O
the	O
predicted	O
growth	O
lag	O
,	O
they	O
grew	O
immediately	O
.	O

Thus	O
,	O
these	O
cells	O
were	O
truly	O
cadmium	O
resistant	O
.	O

Since	O
50	O
tubes	O
of	O
wild	O
-	O
type	O
cells	O
at	O
a	O
dilution	O
of	O
104	O
grew	O
,	O
after	O
the	O
usual	O
lag	O
on	O
exposure	O
to	O
cadmium	O
-	O
containing	O
media	O
,	O
the	O
acquisition	O
of	O
cadmium	O
resistance	O
in	O
this	O
strain	O
of	O
Synechococcus	O
was	O
therefore	O
considered	O
unlikely	O
to	O
be	O
related	O
to	O
a	O
chromosomal	O
mutational	O
event	O
.	O

Such	O
a	O
mutation	O
frequency	O
would	O
be	O
unreasonably	O
high	O
.	O

Although	O
no	O
direct	O
evidence	O
exists	O
at	O
this	O
time	O
,	O
this	O
metal	O
resistance	O
phenomenon	O
is	O
best	O
explained	O
by	O
the	O
amplification	O
of	O
an	O
extrachromosomal	O
gene	O
,	O
especially	O
since	O
this	O
strain	O
is	O
known	O
to	O
have	O
plasmids	O
.	O

Structure	O
of	O
Cyanobacterial	O
MT	O

The	O
structural	O
determination	O
of	O
cyanobacterial	B
MT	O
is	O
not	O
yet	O
complete	O
,	O
although	O
a	O
substantial	O
amount	O
of	O
information	O
is	O
now	O
known	O
.	O

For	O
example	O
,	O
Table	O
1	O
compares	O
the	O
amino	O
acid	O
composition	O
of	O
a	O
Synechococcus	B
TX	I
-	I
20	I
isoprotein	O
with	O
two	O
eukaryotic	O
MTs	O
.	O

These	O
data	O
indicate	O
that	O
the	O
bacterial	O
form	O
is	O
unique	O
.	O

While	O
cysteine	O
was	O
still	O
the	O
predominant	O
amino	O
acid	O
in	O
this	O
protein	O
,	O
levels	O
of	O
the	O
amino	O
acid	O
were	O
half	O
that	O
seen	O
in	O
the	O
eukaryotes	O
.	O

In	O
addition	O
,	O
the	O
bacterial	O
protein	O
had	O
two	O
tyrosines	O
,	O
three	O
histidines	O
,	O
and	O
five	O
long	O
-	O
chain	O
aliphatics	O
-	O
all	O
residues	O
rarely	O
found	O
in	O
eukaryotic	O
MTs	O
.	O

Thus	O
,	O
the	O
amino	O
acid	O
composition	O
indicates	O
that	O
prokaryotic	O
MTs	O
are	O
not	O
as	O
structurally	O
homologous	O
with	O
eukaryotes	O
as	O
they	O
are	O
physiologically	O
homologous	O
.	O

This	O
was	O
further	O
exemplified	O
on	O
amino	O
terminal	O
amino	O
acid	O
sequence	O
analysis	O
(	O
12	O
)	O
.	O

With	O
the	O
exception	O
of	O
the	O
typical	O
Cys	O
-	O
X	O
-	O
Cys	O
sequences	O
,	O
the	O
first	O
42	O
residues	O
of	O
the	O
prokaryotic	O
MT	O
were	O
essentially	O
without	O
homology	O
on	O
comparison	O
with	O
the	O
crab	B
(	O
Scylla	B
)	O
,	O
human	B
,	O
or	O
Neurospora	B
crassa	I
MTs	O
(	O
Table	O
2	O
)	O
.	O

Of	O
the	O
above	O
-	O
mentioned	O
uncommon	O
MT	O
residues	O
,	O
two	O
tyrosines	O
were	O
found	O
together	O
in	O
positions	O
29	O
and	O
30	O
,	O
all	O
five	O
of	O
the	O
long	O
-	O
chain	O
aliphatic	O
amino	O
acids	O
were	O
located	O
in	O
the	O
first	O
28	O
residues	O
,	O
and	O
two	O
histidines	O
were	O
situated	O
at	O
positions	O
37	O
and	O
39	O
.	O

Perhaps	O
of	O
greater	O
interest	O
was	O
the	O
complete	O
lack	O
of	O
association	O
of	O
basic	O
residues	O
or	O
hydroxylated	O
residues	O
with	O
cysteines	O
,	O
as	O
is	O
found	O
in	O
eukaryotes	O
(	O
11	O
)	O
.	O

Instead	O
,	O
a	O
block	O
of	O
four	O
hydroxylated	O
amino	O
acids	O
was	O
found	O
at	O
the	O
amino	O
terminus	O
.	O

The	O
sequence	O
of	O
this	O
unique	O
MT	O
is	O
now	O
nearing	O
completion	O
,	O
opening	O
the	O
way	O
for	O
an	O
X	O
-	O
ray	O
crystallographic	O
investigation	O
.	O

However	O
,	O
the	O
degree	O
of	O
similarity	O
between	O
the	O
metal	O
cluster	O
arrangement	O
of	O
these	O
bacterial	O
molecules	O
with	O
the	O
eukaryotic	O
structures	O
will	O
initially	O
be	O
undertaken	O
spectroscopically	O
.	O

Reliable	O
interpretation	O
of	O
the	O
113Cd	O
-	O
NMR	O
data	O
for	O
this	O
molecule	O
will	O
be	O
dependent	O
upon	O
adequate	O
isolation	O
of	O
isoproteins	O
using	O
RP	O
-	O
HPLC	O
and	O
assessment	O
of	O
conformational	O
integrity	O
of	O
metal	O
reconstituted	O
molecules	O
,	O
using	O
procedures	O
such	O
as	O
cyclic	O
voltametry	O
.	O

Studies	O
along	O
these	O
lines	O
are	O
presently	O
underway	O
in	O
this	O
laboratory	O

The	O
author	O
gratefully	O
acknowledges	O
the	O
financial	O
support	O
of	O
the	O
Australian	O
Institute	O
of	O
Marine	O
Science	O
and	O
the	O
National	O
Science	O
and	O
Engineering	O
Research	O
Council	O
of	O
Canada	O
.	O

Excellent	O
technical	O
assistance	O
was	O
provided	O
by	O
R	O
.	O

G	O
.	O

Sim	O
and	O
S	O
.	O

Kielland	O
in	O
carrying	O
out	O
the	O
polarographic	O
and	O
sequence	O
analyses	O
,	O
respectively	O
.	O

REFERENCES	O

1	O
.	O

Kagi	O
,	O
J	O
.	O

H	O
.	O

R	O
.	O
,	O
and	O
Nordberg	O
,	O
M	O
.	O

(	O
Eds	O
.	O
)	O
.	O

Metallothionein	O
.	O

Birk	O

hauser	O
Verlag	O
,	O
Basel	O
,	O
1979	O
,	O
pp	O
.	O

5	O
-	O
55	O
.	O

2	O
.	O

Olafson	O
,	O
R	O
.	O

W	O
Differential	O
pulse	O
polarographic	O
determination	O
of	O

murine	B
metallothionein	O
induction	O
kinetics	O
.	O

J	O
.	O

Biol	O
.	O

Chem	O
.	O

256	O
:	O
12631268	O
(	O
1981	O
)	O
.	O

3	O
.	O

Olafson	O
,	O
R	O
.	O

W	O
Intestinal	O
metallothionein	O
:	O
effect	O
of	O
parenteral	O
and	O

enteral	O
zinc	O
exposure	O
on	O
tissue	O
levels	O
of	O
mice	B
on	O
controlled	O
zinc	O
diets	O
.	O

J	O
.	O

Nutr	O
.	O

113	O
:	O
268	O
-	O
275	O
(	O
1983	O
)	O
.	O

4	O
.	O

McCarter	O
,	O
J	O
.	O
A	O
.	O
,	O
and	O
Roch	O
,	O
M	O
.	O

Chronic	O
exposure	O
of	O
Coho	B
salmon	I

to	O
sublethal	O
concentrations	O
of	O
copper	O
.	O

III	O
.	O

Kinetics	O
of	O
metabolism	O
of	O
metallothionein	O
.	O

Comp	O
.	O

Biochem	O
.	O

Physiol	O
.	O

77C	O
:	O
83	O
-	O
87	O
(	O
1984	O
)	O
.	O

5	O
.	O

Lerch	O
,	O
K	O
.	O
,	O
Ammer	O
,	O
D	O
.	O
,	O
and	O
Olafson	O
,	O
R	O
.	O

W	O
Crab	O
metallothionein	O

primary	O
structures	O
of	O
metallothioneins	O
1	O
and	O
2	O
.	O

J	O
.	O

Biol	O
.	O

Chem	O
.	O

257	O
:	O
2420	O
-	O
2426	O
(	O
1982	O
)	O
.	O

6	O
.	O

Otvos	O
,	O
J	O
.	O

D	O
.	O
,	O
Olafson	O
,	O
R	O
.	O
W	O
,	O
and	O
Armitage	O
,	O
I	O
.	O

M	O
.	O

Structure	O
of	O
an	O

invertebrate	O
metallothionein	O
from	O
Scylla	B
serrata	I
.	O

J	O
.	O

Biol	O
.	O

Chem	O
.	O

257	O
:	O
2427	O
-	O
2431	O
(	O
1982	O
)	O
.	O

7	O
.	O

Olafson	O
,	O
R	O
.	O

W	O
,	O
Abel	O
,	O
K	O
.	O
,	O
and	O
Sim	O
,	O
R	O
.	O

G	O
.	O

Prokaryotic	O
metallothi	O

onein	O
:	O
preliminary	O
characteristics	O
of	O
a	O
blue	O
-	O
green	O
alga	O
heavy	O
metalbinding	O
protein	O
.	O

Biochem	O
.	O

Biophys	O
.	O

Res	O
.	O

Commun	O
.	O

89	O
:	O
36	O
-	O
40	O
(	O
1979	O
)	O
.	O

8	O
.	O

Olafson	O
,	O
R	O
.	O

W	O
,	O
Loya	O
,	O
S	O
.	O
,	O
and	O
Sim	O
,	O
R	O
.	O

G	O
.	O

Physiological	O
parameters	O

of	O
prokaryotic	O
metallothionein	O
induction	O
.	O

Biochem	O
.	O

Biophys	O
.	O

Res	O
.	O

Commun	O
.	O

95	O
:	O
1495	O
-	O
1503	O
(	O
1980	O
)	O
.	O

9	O
.	O

Brdicka	O
,	O
R	O
.	O

Pblarographic	O
studies	O
with	O
the	O
dropping	O
mercury	O
ka	O

thode	O
.	O
-	O
Part	O
XXXI	O
.	O
-	O
A	O
new	O
test	O
for	O
proteins	O
in	O
the	O
presence	O
of	O
cobalt	O
salts	O
in	O
ammoniacal	O
solutions	O
of	O
ammonium	O
chloride	O
.	O

Collect	O
.	O

Czech	O
.	O

Chem	O
.	O

Commun	O
.	O

5	O
:	O
112	O
-	O
128	O
(	O
1933	O
)	O
.	O

10	O
.	O

Olafson	O
,	O
R	O
.	O

W	O
,	O
and	O
Sim	O
,	O
R	O
.	O

G	O
.	O

An	O
electrochemical	O
approach	O
to	O

quantitation	O
and	O
characterization	O
of	O
metallothionein	O
.	O

Anal	O
.	O

Biochem	O
.	O

100	O
:	O
343	O
-	O
351	O
(	O
1979	O
)	O
.	O

11	O
.	O

Olafson	O
,	O
R	O
.	O

W	O
Differential	O
pulse	O
polarographic	O
determination	O
of	O

murine	B
metallothionein	O
induction	O
kinetics	O
.	O

J	O
.	O

Biol	O
.	O

Chem	O
.	O

256	O
:	O
12631268	O
(	O
1981	O
)	O
.	O

12	O
.	O

Olafson	O
,	O
R	O
.	O

W	O
Prokaryotic	O
metallothionein	O
:	O
amino	O
terminal	O
se	O

quence	O
analysis	O
of	O
a	O
unique	O
metallothionein	O
.	O

Int	O
.	O

J	O
.	O

Peptide	O
Protein	O
Res	O
.	O

24	O
:	O
303	O
-	O
308	O
(	O
1984	O
)	O
.	O

Peculiarities	O
of	O
carcinogenesis	O
under	O
simultaneous	O
oral	O
administration	O
of	O
benzo	O
(	O
a	O
)	O
pyrene	O
and	O
o	O
-	O
cresol	O
in	O
mice	B
.	O

Abstract	O

A	O
modifying	O
influence	O
of	O
ortho	O
-	O
cresol	O
(	O
o	O
-	O
cresol	O
)	O
on	O
the	O
carcinogenic	O
effect	O
of	O
benzo	O
(	O
a	O
)	O
pyrene	O
(	O
BaP	O
)	O
with	O
combined	O
oral	O
administration	O
to	O
CC57Br	O
mice	B
had	O
been	O
found	O
.	O

During	O
simultaneous	O
administration	O
of	O
o	O
-	O
cresol	O
(	O
1	O
mg	O
)	O
and	O
BaP	O
(	O
1	O
mg	O
)	O
,	O
the	O
incidence	O
of	O
tumors	O
,	O
the	O
multiplicity	O
of	O
tumors	O
,	O
and	O
the	O
degree	O
of	O
malignancy	O
all	O
increased	O
,	O
but	O
the	O
latency	O
was	O
shortened	O
.	O

When	O
o	O
-	O
cresol	O
was	O
administered	O
before	O
or	O
after	O
BaP	O
(	O
in	O
identical	O
doses	O
)	O
,	O
the	O
carcinogenic	O
effect	O
was	O
weakened	O
.	O

When	O
o	O
-	O
cresol	O
(	O
10	O
mg	O
)	O
and	O
BaP	O
(	O
5	O
mg	O
)	O
were	O
administered	O
simultaneously	O
,	O
the	O
incidence	O
of	O
malignant	O
tumors	O
was	O
similar	O
to	O
controls	O
receiving	O
BaP	O
only	O
(	O
13	O
.	O
8	O
%	O
)	O
,	O
indicating	O
inhibition	O
of	O
carcinogenesis	O
.	O

Environnmental	O
Health	O
Perspectives	O
Supplements	O
Vol	O
.	O

101	O
(	O
Suppl	O
.	O
3	O
)	O
:	O
341	O
-	O
344	O
(	O
1993	O
)	O

Peculiarities	O
of	O
Carcinogenesis	O
under	O
Simultaneous	O
Oral	O
Administration	O
of	O

Benzo	O
(	O
a	O
)	O
Pyrene	O
and	O
o	O
-	O
Cresol	O
in	O
Mice	B

by	O
N	O
.	O

Ya	O
.	O

Yanysheva	O
,	O
'	O
N	O
.	O

V	O
.	O

Balenko	O
,	O
1	O
.	O

A	O
.	O

Chernichenko	O
,	O
1	O
and	O
V	O
.	O

F	O
.	O

Babiy	O
'	O

A	O
modifying	O
influence	O
of	O
ortho	O
-	O
cresol	O
(	O
o	O
-	O
cresol	O
)	O
on	O
the	O
carcinogenic	O
effect	O
of	O
benzo	O
(	O
a	O
)	O
pyrene	O
(	O
BaP	O
)	O
with	O
combined	O
oral	O
administration	O
to	O
CC57Br	O
mice	B
had	O
been	O
found	O
.	O

During	O
simultaneous	O
administration	O
of	O
o	O
-	O
cresol	O
(	O
1	O
mg	O
)	O
and	O
BaP	O
(	O
1	O
mg	O
)	O
,	O
the	O
incidence	O
of	O
tumors	O
,	O
the	O
multiplicity	O
of	O
tumors	O
,	O
and	O
the	O
degree	O
of	O
malignancy	O
all	O
increased	O
,	O
but	O
the	O
latency	O
was	O
shortened	O
.	O

When	O
o	O
-	O
cresol	O
was	O
administered	O
before	O
or	O
after	O
BaP	O
(	O
in	O
identical	O
doses	O
)	O
,	O
the	O
carcinogenic	O
effect	O
was	O
weakened	O
.	O

When	O
o	O
-	O
cresol	O
(	O
10	O
mg	O
)	O
and	O
BaP	O
(	O
5	O
mg	O
)	O
were	O
administered	O
simultaneously	O
,	O
the	O
incidence	O
of	O
malignant	O
tumors	O
was	O
similar	O
to	O
controls	O
receiving	O
BaP	O
only	O
(	O
13	O
.	O
8	O
%	O
)	O
,	O
indicating	O
inhibition	O
of	O
carcinogenesis	O
.	O

Introduction	O

Numerous	O
experiments	O
have	O
shown	O
a	O
modifying	O
influence	O
of	O
different	O
chemicals	O
on	O
benzo	O
(	O
a	O
)	O
pyrene	O
(	O
BaP	O
)	O
induced	O
carcinogenic	O
effects	O
.	O

Both	O
enhancing	O
or	O
weakening	O
effects	O
have	O
been	O
seen	O
(	O
1	O
-	O
12	O
)	O
.	O

In	O
some	O
experiments	O
ubiquitious	O
environmental	O
carcinogenic	O
and	O
toxic	O
chemical	O
pollutants	O
were	O
used	O
(	O
13	O
-	O
17	O
)	O
.	O

The	O
stimulating	O
effect	O
of	O
phenol	O
,	O
nitrogen	O
oxides	O
,	O
and	O
sulfur	O
dioxide	O
upon	O
BaP	O
'	O
s	O
blastogenic	O
action	O
on	O
the	O
respiratory	O
tract	O
and	O
phenol	O
on	O
the	O
digestive	O
tract	O
(	O
forestomach	O
)	O
have	O
been	O
reported	O
(	O
12	O
-	O
18	O
)	O
.	O

We	O
have	O
established	O
the	O
relationship	O
between	O
the	O
doses	O
of	O
carcinogenic	O
and	O
toxic	O
agents	O
and	O
their	O
modifying	O
effects	O
(	O
17	O
,	O
18	O
)	O
.	O

The	O
maximal	O
enhancing	O
effect	O
was	O
observed	O
after	O
BaP	O
(	O
2	O
.	O
5	O
mg	O
)	O
and	O
NO2	O
(	O
0	O
.	O
87	O
mg	O
/	O
m3	O
)	O
were	O
exposed	O
to	O
rat	B
respiratory	O
tract	O
.	O

The	O
effect	O
weakened	O
with	O
decreasing	O
dose	O
.	O

At	O
concentrations	O
at	O
the	O
MPC	O
level	O
(	O
MPC	O
BaP	O
,	O
1	O
ng	O
/	O
m3	O
,	O
MPC	O
NO2	O
,	O
0	O
.	O
04	O
mg	O
/	O
m3	O
)	O
no	O
effect	O
was	O
seen	O
.	O

Phenol	O
at	O
1	O
mg	O
orally	O
to	O
CC57Br	O
mice	B
enhanced	O
the	O
BaP	O
(	O
1	O
mg	O
)	O
effect	O
,	O
but	O
no	O
effect	O
was	O
seen	O
at	O
0	O
.	O
02	O
mg	O
.	O

Phenolic	O
compounds	O
showed	O
either	O
enhancing	O
or	O
inhibiting	O
effects	O
on	O
carcinogenesis	O
depending	O
on	O
their	O
chemical	O
structure	O
(	O
16	O
,	O
18	O
-	O
25	O
)	O
.	O

This	O
report	O
presents	O
the	O
results	O
of	O
combined	O
oral	O
administration	O
of	O
BaP	O
and	O
artho	O
-	O
cresol	O
(	O
o	O
-	O
cresol	O
)	O
in	O
mice	B
,	O

'	O
Ukrainian	O
State	O
Medical	O
Center	O
for	O
Environmental	O
Health	O
,	O
Kiev	O
,	O
Ukraine	O
.	O

Address	O
reprint	O
requests	O
to	O
N	O
.	O

Y	O
.	O

Yanysheva	O
,	O
Ukrainian	O
State	O
Medical	O
Center	O
for	O
Environmental	O
Health	O
,	O
Popudrenko	O
St	O
.	O

50	O
,	O
253660	O
Kiev	O
-	O
94	O
,	O
Ukraine	O
.	O

chemicals	O
commonly	O
found	O
in	O
ambient	O
water	O
because	O
of	O
their	O
industrial	O
use	O
(	O
coke	O
chemistry	O
,	O
oil	O
processing	O
,	O
shale	O
processing	O
,	O
and	O
other	O
industries	O
)	O
(	O
27	O
-	O
30	O
)	O
.	O

Materials	O
and	O
Methods	O

The	O
experiment	O
was	O
conducted	O
on	O
CC57Br	O
female	O
mice	B
weighing	O
12	O
-	O
14	O
g	O
.	O

Animals	O
were	O
divided	O
in	O
15	O
groups	O
.	O

This	O
experiment	O
included	O
three	O
types	O
of	O
sequential	O
combinations	O
for	O
the	O
introduction	O
of	O
compounds	O
:	O
a	O
)	O
simultaneous	O
BaP	O
and	O
o	O
-	O
cresol	O
administration	O
;	O
b	O
)	O
BaP	O
after	O
o	O
-	O
cresol	O
(	O
stage	O
1	O
)	O
;	O
and	O
c	O
)	O
BaP	O
before	O
o	O
-	O
cresol	O
(	O
stage	O
2	O
)	O
.	O

Appropriate	O
controls	O
were	O
included	O
(	O
Table	O
1	O
)	O
.	O

The	O
chemicals	O
were	O
administered	O
twice	O
per	O
week	O
(	O
for	O
a	O
total	O
of	O
10	O
,	O
20	O
,	O
and	O
40	O
doses	O
)	O
using	O
a	O
syringe	O
and	O
a	O
needle	O
with	O
a	O
soldered	O
olive	O
on	O
its	O
tip	O
.	O

BaP	O
(	O
1	O
or	O
5	O
mg	O
)	O
or	O
o	O
-	O
cresol	O
(	O
0	O
.	O
02	O
,	O
1	O
,	O
or	O
10	O
mg	O
)	O
was	O
placed	O
in	O
triethylene	O
glycol	O
(	O
TEG	O
)	O
and	O
administered	O
as	O
0	O
.	O
1	O
-	O
mL	O
water	O
solutions	O
.	O

The	O
evaluation	O
of	O
o	O
-	O
cresol	O
'	O
s	O
modifying	O
effect	O
on	O
the	O
incidence	O
of	O
tumors	O
,	O
especially	O
malignant	O
tumors	O
,	O
the	O
tumor	O
latency	O
period	O
(	O
tl	O
)	O
,	O
and	O
the	O
average	O
time	O
(	O
ta	O
)	O
of	O
the	O
appearance	O
of	O
tumors	O
,	O
as	O
well	O
as	O
the	O
multiplicity	O
index	O
,	O
M	O
(	O
the	O
average	O
number	O
of	O
tumors	O
per	O
animal	O
for	O
tumor	O
-	O
bearing	O
animals	O
)	O
was	O
recorded	O
.	O

Because	O
the	O
M	O
could	O
be	O
identified	O
at	O
the	O
initial	O
stage	O
of	O
carcinogenesis	O
by	O
the	O
third	O
month	O
after	O
the	O
beginning	O
of	O
the	O
trial	O
when	O
neoplasms	O
began	O
to	O
emerge	O
,	O
moribund	O
animals	O
were	O
killed	O
by	O
ether	O
inhalation	O
if	O
they	O
did	O
not	O
die	O
spontaneously	O
.	O

The	O
experiments	O
with	O
large	O
chemical	O
doses	O
(	O
BaP	O
,	O
5	O
mg	O
;	O
o	O
-	O
cresol	O
,	O
10	O
mg	O
)	O
lasted	O
for	O
30	O
weeks	O
.	O

Some	O
animals	O
were	O
killed	O
after	O
the	O
1st	O
,	O
3rd	O
,	O
5th	O
,	O
and	O
10th	O
procedures	O
for	O
the	O

YANYSHEVA	O
ET	O
AL	O
.	O

evaluation	O
of	O
initial	O
stages	O
of	O
carcinogenesis	O
;	O
others	O
were	O
killed	O
at	O
26	O
and	O
30	O
weeks	O
.	O

The	O
stomachs	O
were	O
distended	O
with	O
formalin	O
solution	O
and	O
the	O
mucosa	O
examined	O
macroscopically	O
.	O

All	O
tumors	O
>	O
1	O
mm	O
in	O
diameter	O
were	O
recorded	O
.	O

Organs	O
and	O
tissues	O
were	O
fised	O
in	O
10	O
%	O
neutral	O
formalin	O
solution	O
,	O
embedded	O
in	O
paraffin	O
and	O
routine	O
histological	O
slides	O
prepared	O
.	O

Microscopic	O
data	O
were	O
processed	O
according	O
to	O
Mostkovoy	O
(	O
30	O
)	O
.	O

Results	O

The	O
data	O
from	O
this	O
study	O
demonstrate	O
the	O
modifying	O
influence	O
of	O
o	O
-	O
cresol	O
on	O
BaP	O
-	O
induced	O
carcinogenesis	O
with	O
combined	O
oral	O
exposure	O
.	O

The	O
combined	O
exposure	O
and	O
BaP	O
alone	O
caused	O
benign	O
and	O
malignant	O
epithelial	O
tumors	O
of	O
the	O
forestomach	O
.	O

The	O
benign	O
neoplasms	O
were	O
papillomas	O
,	O
and	O
the	O
malignant	O
neoplasms	O
were	O
invasive	O
carcinomas	O
.	O

The	O
combined	O
administration	O
of	O
BaP	O
and	O
o	O
-	O
cresol	O
showed	O
different	O
results	O
depending	O
on	O
doses	O
and	O
sequential	O
combinations	O
of	O
both	O
chemicals	O
.	O

As	O
shown	O
in	O
Table	O
2	O
,	O
the	O
simultaneous	O
administration	O
of	O
BaP	O
(	O
1	O
mg	O
)	O
and	O
o	O
-	O
cresol	O
(	O
1	O
mg	O
)	O
affected	O
all	O
parameters	O
of	O
carcinogenesis	O
that	O
were	O
measured	O
.	O

This	O
included	O
a	O
significant	O
increase	O
in	O
the	O
incidence	O
of	O
tumors	O
,	O
shortening	O
of	O
the	O
time	O
to	O
the	O
appearance	O
of	O
the	O
first	O
tumor	O
,	O
and	O
the	O
mean	O
time	O
of	O
tumor	O

development	O
as	O
compared	O
to	O
animals	O
that	O
received	O
1	O
mg	O
of	O
BaP	O
alone	O
and	O
had	O
tumors	O
.	O

One	O
hundred	O
percent	O
of	O
the	O
mice	B
that	O
received	O
5	O
mg	O
of	O
BaP	O
alone	O
had	O
tumors	O
.	O

Shortening	O
of	O
the	O
time	O
to	O
appearance	O
of	O
malignant	O
tumors	O
was	O
also	O
observed	O
:	O
the	O
mice	B
with	O
forestomach	O
cancer	O
died	O
between	O
23	O
and	O
26	O
.	O
2	O
weeks	O
after	O
the	O
beginning	O
of	O
experiment	O
,	O
but	O
the	O
controls	O
survived	O
to	O
58	O
.	O
5	O
weeks	O
.	O

Muliple	O
small	O
metastases	O
in	O
the	O
lungs	O
and	O
mediastinum	O
were	O
found	O
in	O
42	O
.	O
8	O
%	O
of	O
mice	B
,	O
which	O
signifies	O
a	O
high	O
degree	O
of	O
malignancy	O
.	O

o	O
-	O
Cresol	O
at	O
0	O
.	O
02	O
mg	O
did	O
not	O
modify	O
carcinogenesis	O
in	O
comparison	O
to	O
the	O
control	O
.	O

o	O
-	O
Cresol	O
administration	O
before	O
or	O
after	O
BaP	O
did	O
not	O
modify	O
tumor	O
incidence	O
or	O
the	O
multiplicity	O
index	O
as	O
compared	O
to	O
control	O
,	O
but	O
the	O
latency	O
period	O
was	O
longer	O
(	O
Table	O
2	O
)	O
.	O

When	O
o	O
-	O
cresol	O
was	O
administered	O
after	O
BaP	O
(	O
stage	O
2	O
)	O
,	O
there	O
was	O
an	O
absence	O
of	O
malignant	O
tumors	O
.	O

Besides	O
the	O
quantitative	O
aspects	O
,	O
other	O
peculiarities	O
of	O
carcinogenesis	O
in	O
mice	B
simultaneously	O
administered	O
BaP	O
and	O
o	O
-	O
cresol	O
should	O
be	O
noted	O
.	O

The	O
combined	O
chemical	O
administration	O
resulted	O
in	O
diffuse	O
verrucosa	O
vegetations	O
over	O
the	O
forestomach	O
surface	O
,	O
especially	O
near	O
the	O
greater	O
curvature	O
.	O

Highly	O
aggressive	O
malignant	O
neoplasms	O
developed	O
earlier	O
with	O
more	O
metastases	O
as	O
compared	O
to	O
control	O
.	O

Many	O
mice	B
were	O
emaciated	O
,	O
and	O
the	O
tumors	O
could	O
be	O

Table	O
1	O
.	O

Scheme	O
of	O
BaP	O
and	O
o	O
-	O
cresol	O
combined	O
action	O
under	O
different	O
regimes	O
of	O
oral	O
administration	O
.	O

Theatmenta	O

No	O
.	O
of	O
mice	B
Stage	O
1	O
Stage	O
2	O

Groups	O
of	O
in	O
each	O
No	O
.	O
of	O
No	O
.	O
of	O

animals	O
group	O
Substances	O
Dose	O
,	O
mg	O
applications	O
Substances	O
Dose	O
,	O
mg	O
applications	O

1	O
55	O
BaP	O
,	O
o	O
-	O
cresol	O
5	O
+	O
10	O
10	O
-	O
-	O
2	O
45	O
BaP	O
5	O
10	O
-	O
-	O
3	O
40	O
TEG	O
la	O
10	O
-	O
-	O
4	O
45	O
TEG	O
,	O
o	O
-	O
cresol	O
1b	O
+	O
10	O
10	O
-	O
-	O
5	O
30	O
BaP	O
,	O
o	O
-	O
cresol	O
1	O
+	O
1	O
20	O
-	O
-	O
6	O
30	O
BaP	O
,	O
o	O
-	O
cresol	O
1	O
+	O
0	O
.	O
02	O
20	O
-	O
-	O
7	O
30	O
o	O
-	O
Cresol	O
1	O
20	O
BaP	O
1	O
20	O
8	O
30	O
BaP	O
1	O
20	O
o	O
-	O
Cresol	O
1	O
20	O
9	O
30	O
BaP	O
1	O
20	O
-	O
10	O
30	O
-	O
-	O
-	O
BaP	O
1	O
20	O
11	O
30	O
o	O
-	O
Cresol	O
1	O
20	O
-	O
12	O
30	O
-	O
-	O
-	O
o	O
-	O
Cresol	O
1	O
20	O
13	O
30	O
o	O
-	O
Cresol	O
+	O
TEG	O
1	O
+	O
2	O
'	O
20	O
-	O
14	O
30	O
o	O
-	O
Cresol	O
+	O
TEG	O
0	O
.	O
02	O
+	O
2b	O
20	O

15	O
30	O
TEG	O
2b	O
20	O
-	O
-	O
Abbreviations	O
:	O
BaP	O
,	O
benzo	O
[	O
a	O
]	O
pyrene	O
;	O
TEG	O
,	O
triethylene	O
glycol	O
.	O

Table	O
2	O
.	O

Occurrence	O
of	O
forestomach	O
tumors	O
in	O
CC57Br	O
mice	B
after	O
combined	O
oral	O
administration	O
of	O
BaP	O
and	O
o	O
-	O
cresol	O
.	O

Number	O
of	O
animals	O
with	O
forestomach	O
tumors	O

Order	O
of	O
administration	O
of	O
substances	O
Total	O
Benign	O
Malignant	O

(	O
dose	O
,	O
mg	O
)	O
Absolute	O
%	O
%	O
M	O
t	O
,	O
ta	O
%	O
t	O
,	O
ta	O
BaP	O
(	O
5	O
)	O
,	O
o	O
-	O
cresol	O
(	O
10	O
)	O
29	O
100	O
.	O
0	O
86	O
.	O
2	O
ND	O
ND	O
ND	O
13	O
.	O
8	O
ND	O
ND	O
BaP	O
(	O
1	O
)	O
,	O
o	O
-	O
cresol	O
(	O
1	O
)	O
19	O
95	O
.	O
0	O
60	O
.	O
0	O
9	O
.	O
6	O
10	O
.	O
7	O
16	O
.	O
3	O
35	O
.	O
0	O
23	O
.	O
0	O
25	O
.	O
2	O
BaP	O
(	O
1	O
)	O
,	O
o	O
-	O
cresol	O
(	O
0	O
.	O
02	O
)	O
7	O
35	O
.	O
0	O
30	O
.	O
0	O
1	O
.	O
6	O
13	O
.	O
5	O
19	O
.	O
8	O
5	O
.	O
0	O
56	O
.	O
8	O
56	O
.	O
8	O
BaP	O
(	O
1	O
)	O
,	O
stage	O
1	O
,	O
o	O
-	O
cresol	O
(	O
1	O
)	O
,	O
stage	O
2	O
7	O
31	O
.	O
8	O
31	O
.	O
8	O
1	O
.	O
4	O
16	O
.	O
2	O
31	O
.	O
1	O
0	O
0	O
0	O

BaP	O
(	O
1	O
)	O
,	O
stage	O
2	O
6	O
35	O
.	O
3	O
29	O
.	O
4	O
2	O
.	O
8	O
15	O
.	O
8	O
41	O
.	O
2	O
5	O
.	O
9	O
24	O
.	O
8	O
24	O
.	O
8	O
BaP	O
(	O
5	O
)	O
,	O
stage	O
1	O
18	O
100	O
.	O
0	O
50	O
.	O
0	O
ND	O
ND	O
ND	O
50	O
.	O
0	O
ND	O
ND	O
BaP	O
(	O
1	O
)	O
,	O
stage	O
1	O
8	O
33	O
.	O
3	O
28	O
.	O
7	O
1	O
.	O
4	O
14	O
.	O
0	O
21	O
.	O
3	O
4	O
.	O
6	O
58	O
.	O
5	O
58	O
.	O
5	O
BaP	O
(	O
1	O
)	O
,	O
stage	O
2	O
7	O
36	O
.	O
8	O
31	O
.	O
6	O
2	O
.	O
8	O
10	O
.	O
0	O
13	O
.	O
3	O
5	O
.	O
2	O
55	O
.	O
7	O
55	O
.	O
7	O

Abbreviations	O
:	O
BaP	O
,	O
benzo	O
[	O
a	O
]	O
pyrene	O
;	O
0	O
,	O
not	O
observed	O
;	O
ND	O
,	O
not	O
determined	O
;	O
t1	O
,	O
time	O
of	O
the	O
first	O
tumor	O
appearance	O
in	O
weeks	O
;	O
ta	O
,	O
mean	O
time	O
of	O
tumor	O
development	O
in	O
weeks	O
;	O
M	O
,	O
multiplicity	O
.	O

342	O

CARCINOGENESIS	O
OF	O
BaP	O
AND	O
o	O
-	O
CRESOL	O
343	O

palpated	O
through	O
the	O
abdominal	O
wall	O
.	O

At	O
autopsy	O
,	O
enlargement	O
of	O
the	O
stomach	O
with	O
tuberculous	O
white	O
superficial	O
vegetations	O
were	O
observed	O
.	O

The	O
forestomach	O
and	O
glandular	O
part	O
of	O
the	O
stomach	O
was	O
often	O
obliterated	O
by	O
tumor	O
masses	O
.	O

The	O
stomach	O
was	O
often	O
adhered	O
to	O
the	O
pancreas	O
,	O
liver	O
,	O
and	O
mesentery	O
.	O

Hemmorrhage	O
and	O
inflammation	O
were	O
found	O
in	O
tumors	O
foci	O
.	O

When	O
o	O
-	O
cresol	O
was	O
introduced	O
before	O
BaP	O
,	O
the	O
tumors	O
were	O
more	O
frequently	O
found	O
closer	O
to	O
the	O
small	O
curvature	O
of	O
the	O
stomach	O
between	O
the	O
forestomach	O
and	O
esophageal	O
entrance	O
.	O

Over	O
the	O
large	O
curvature	O
less	O
prominent	O
mucosal	O
folds	O
were	O
observed	O
.	O

Microscopically	O
,	O
a	O
decrease	O
in	O
mucosa	O
papillae	O
,	O
epithelial	O
atrophy	O
(	O
one	O
to	O
two	O
cullular	O
layers	O
)	O
,	O
decreased	O
keratonization	O
,	O
and	O
nuclear	O
pycnosis	O
were	O
observed	O
.	O

With	O
the	O
simultaneous	O
administration	O
of	O
large	O
doses	O
of	O
o	O
-	O
cresol	O
and	O
BaP	O
,	O
the	O
final	O
carcinogenic	O
effect	O
(	O
30	O
weeks	O
after	O
the	O
first	O
dose	O
)	O
was	O
similar	O
to	O
BaP	O
alone	O
but	O
differences	O
were	O
observed	O
at	O
the	O
earlier	O
stages	O
(	O
after	O
the	O
1st	O
,	O
3rd	O
,	O
5th	O
,	O
and	O
10th	O
exposures	O
)	O
.	O

In	O
the	O
BaP	O
control	O
,	O
multiple	O
forestomach	O
epithelial	O
proliferative	O
and	O
hyperplastic	O
changes	O
were	O
found	O
after	O
the	O
third	O
dose	O
.	O

Multiple	O
papillomas	O
occurred	O
(	O
9	O
-	O
15	O
in	O
each	O
mouse	B
)	O
.	O

The	O
stomach	O
'	O
s	O
mucosal	O
folds	O
appeared	O
thickened	O
diffusely	O
,	O
then	O
papillomas	O
appeared	O
and	O
finally	O
merged	O
together	O
.	O

Approximately	O
half	O
of	O
the	O
tumors	O
were	O
malignant	O
.	O

The	O
neoplasms	O
filled	O
almost	O
the	O
whole	O
forestomach	O
cavity	O
and	O
infiltrated	O
the	O
wall	O
with	O
tuberculous	O
vegetations	O
,	O
which	O
were	O
visible	O
on	O
the	O
serosal	O
surface	O
.	O

Thmor	O
infiltration	O
in	O
the	O
liver	O
,	O
pancreas	O
,	O
and	O
wide	O
dissemination	O
of	O
peritoneum	O
were	O
also	O
observed	O
.	O

In	O
mice	B
simultaneously	O
administered	O
BaP	O
and	O
o	O
-	O
cresol	O
,	O
the	O
proliferative	O
alterations	O
of	O
forestomach	O
epithelium	O
were	O
seen	O
after	O
the	O
third	O
dose	O
.	O

However	O
,	O
they	O
occurred	O
as	O
the	O
single	O
foci	O
at	O
damaged	O
mucosa	O
and	O
even	O
in	O
the	O
later	O
stages	O
were	O
not	O
diffuse	O
.	O

Adjacent	O
to	O
the	O
hyperplastic	O
foci	O
,	O
the	O
mucosa	O
was	O
atrophied	O
with	O
decreased	O
keratonization	O
.	O

The	O
epithelial	O
cells	O
also	O
showed	O
cytoplasm	O
coagulation	O
and	O
nuclear	O
pycnosis	O
.	O

Edema	O
,	O
inflammation	O
of	O
the	O
mucosa	O
,	O
submucosa	O
microabscesses	O
,	O
and	O
erosion	O
were	O
seen	O
.	O

There	O
were	O
fewer	O
papillomas	O
per	O
mouse	B
(	O
four	O
to	O
eight	O
in	O
each	O
mouse	B
)	O
than	O
in	O
the	O
control	O
group	O
.	O

Even	O
in	O
the	O
late	O
stages	O
the	O
papillomas	O
were	O
isolated	O
and	O
elevated	O
on	O
the	O
atrophied	O
mucosal	O
folds	O
.	O

In	O
the	O
final	O
experiment	O
the	O
papillomas	O
prevailed	O
as	O
compared	O
to	O
the	O
previous	O
experiments	O
.	O

Only	O
4	O
out	O
of	O
29	O
mice	B
(	O
13	O
.	O
8	O
%	O
)	O
developed	O
malignant	O
tumors	O
.	O

Neoplasms	O
were	O
smaller	O
and	O
appeared	O
as	O
single	O
verrucosa	O
vegetations	O
5	O
-	O
10	O
mm	O
in	O
diameter	O
.	O

Thus	O
,	O
the	O
toxic	O
dose	O
of	O
o	O
-	O
cresol	O
inhibits	O
the	O
carcinogenic	O
process	O
of	O
induced	O
forestomach	O
tumors	O
by	O
decreasing	O
multiplicity	O
,	O
frequency	O
,	O
and	O
percentage	O
of	O
malignant	O
tumors	O
.	O

Discussion	O

Our	O
results	O
and	O
the	O
literature	O
suggest	O
a	O
hypothesis	O
on	O
modifying	O
carcinogenesis	O
mechanisms	O
.	O

The	O
primary	O
effect	O
of	O
the	O
toxic	O
agents	O
,	O
including	O
carcinogenic	O
agents	O
,	O
may	O
relate	O
to	O
cellular	O
membrane	O
damage	O
with	O
the	O
subsequent	O
increased	O
permeability	O
(	O
31	O
-	O
35	O
)	O
,	O
which	O
may	O
be	O
the	O
mechanism	O
of	O
the	O
o	O
-	O
cresol	O
.	O

With	O
simultaneous	O
introduction	O
of	O
o	O
-	O
cresol	O
at	O
low	O
toxic	O
doses	O
and	O
BaP	O
there	O
may	O
be	O
increased	O
carcinogen	O
penetration	O
to	O
the	O
target	O
cells	O
.	O

In	O
addition	O
,	O
membrane	O
damage	O
may	O
alter	O
other	O
cellular	O
systems	O
responsible	O
for	O
energy	O
and	O
xenobiotic	O
detoxication	O
.	O

Damage	O
of	O
these	O
processes	O
may	O
activate	O
free	O
-	O
radical	O
reactions	O
,	O
glycolysis	O
,	O
or	O
alter	O
carcinogenic	O
metabolism	O
,	O
which	O
promotes	O
the	O
oncogenic	O
effect	O
.	O

The	O
o	O
-	O
cresol	O
effect	O
on	O
these	O
systems	O
was	O
confirmed	O
by	O
our	O
previous	O
investigations	O
on	O
cytochrome	O
P450	O
,	O
ferrosulfuric	O
nonhemic	O
proteins	O
,	O
and	O
semiquinon	O
radical	O
content	O
affected	O
by	O
the	O
combined	O
action	O
of	O
BaP	O
and	O
o	O
-	O
cresol	O
(	O
36	O
)	O
.	O

Another	O
effect	O
was	O
obtained	O
with	O
BaP	O
exposure	O
after	O
o	O
-	O
cresol	O
.	O

The	O
atrophic	O
alterations	O
in	O
the	O
stomach	O
induced	O
by	O
2	O
.	O
5	O
months	O
of	O
o	O
-	O
cresol	O
administration	O
might	O
decrease	O
the	O
natural	O
conditions	O
of	O
retention	O
(	O
muscosal	O
folds	O
,	O
frontier	O
torn	O
)	O
,	O
and	O
thus	O
shorten	O
the	O
contact	O
of	O
BaP	O
with	O
the	O
forestomach	O
.	O

In	O
our	O
opinion	O
,	O
this	O
explains	O
the	O
decreased	O
carcinogenic	O
effect	O
seen	O
after	O
o	O
-	O
cresol	O
exposure	O
.	O

Considering	O
the	O
toxic	O
effect	O
of	O
o	O
-	O
cresol	O
at	O
low	O
toxic	O
doses	O
(	O
1	O
mg	O
)	O
after	O
BaP	O
and	O
the	O
effect	O
of	O
a	O
super	O
toxic	O
dose	O
(	O
10	O
mg	O
)	O
simultaneously	O
with	O
BaP	O
administration	O
,	O
it	O
is	O
possible	O
that	O
the	O
inhibition	O
of	O
carcinogenesis	O
in	O
both	O
trials	O
was	O
related	O
to	O
the	O
toxic	O
effects	O
of	O
o	O
-	O
cresol	O
.	O

Cytotoxicity	O
may	O
not	O
only	O
hamper	O
tumor	O
growth	O
,	O
but	O
also	O
promote	O
the	O
regression	O
of	O
inducible	O
and	O
spontaneous	O
neoplasms	O
(	O
37	O
-	O
39	O
)	O
.	O

There	O
is	O
also	O
a	O
possibility	O
that	O
BaP	O
damages	O
metabolic	O
systems	O
and	O
decreases	O
resistance	O
to	O
carcinogenesis	O
.	O

Conclusions	O

The	O
data	O
obtained	O
demonstrate	O
that	O
simultaneous	O
administration	O
of	O
BaP	O
modifies	O
the	O
induced	O
carcinogenesis	O
depending	O
on	O
the	O
dose	O
and	O
the	O
sequence	O
of	O
administration	O
.	O

Administered	O
with	O
BaP	O
(	O
1	O
mg	O
)	O
,	O
a	O
low	O
toxic	O
o	O
-	O
cresol	O
dose	O
(	O
about	O
minimally	O
effective	O
)	O
produces	O
an	O
enhanced	O
cocarcinogenic	O
effect	O
reflected	O
in	O
the	O
incidence	O
,	O
frequency	O
,	O
multiplicity	O
,	O
and	O
degree	O
of	O
malignancy	O
of	O
forestomach	O
tumors	O
.	O

o	O
-	O
Cresol	O
administration	O
at	O
low	O
toxic	O
doses	O
before	O
or	O
after	O
BaP	O
at	O
the	O
same	O
dose	O
level	O
(	O
1	O
mg	O
)	O
and	O
its	O
administration	O
at	O
super	O
toxic	O
doses	O
(	O
10	O
mg	O
)	O
with	O
the	O
BaP	O
optimal	O
dose	O
(	O
5	O
mg	O
)	O
may	O
inhibit	O
carcinogenesis	O
.	O

Simultaneous	O
introduction	O
of	O
a	O
noneffective	O
o	O
-	O
cresol	O
dose	O
(	O
0	O
.	O
02	O
mg	O
)	O
with	O
the	O
BaP	O
(	O
1	O
mg	O
)	O
does	O
not	O
change	O
its	O
carcinogenic	O
activity	O
.	O

Controlling	O
both	O
chemicals	O
in	O
the	O
environment	O
is	O
the	O
most	O
effective	O
measure	O
of	O
preventing	O
potential	O
risk	O
and	O
is	O
undoubtedly	O
of	O
paramount	O
significance	O
.	O

REFERENCES	O

1	O
.	O

Bingham	O
,	O
E	O
.	O
,	O
and	O
Falk	O
,	O
H	O
.	O

L	O
.	O

Environmental	O
carcinogenesis	O
.	O

The	O

modifying	O
effect	O
of	O
cocarcinogens	O
on	O
the	O
threshold	O
response	O
.	O

Arch	O
.	O

Environ	O
.	O

Health	O
19	O
:	O
779	O
-	O
783	O
(	O
1969	O
)	O
.	O

2	O
.	O

Goldschmidt	O
,	O
B	O
.	O

M	O
.	O
,	O
Katz	O
,	O
C	O
.	O
,	O
and	O
Van	O
Duuren	O
,	O
B	O
.	O

L	O
.	O

The	O
cocar	O

cinogenic	O
activity	O
of	O
non	O
-	O
carcinogenic	O
aromatic	O
hydrocarbons	O
.	O

Proc	O
.	O

Am	O
.	O

Assoc	O
.	O

Cancer	O
Res	O
.	O

17	O
:	O
84	O
(	O
1973	O
)	O
.	O

3	O
.	O

Kaufman	O
,	O
D	O
.	O

C	O
.	O
,	O
and	O
Madison	O
,	O
R	O
.	O

M	O
.	O

Synergistic	O
effects	O
of	O

benzo	O
(	O
a	O
)	O
pyrene	O
and	O
N	O
-	O
methyl	O
-	O
N	O
-	O
nitrosourea	O
respirators	O
carcinogenesis	O
in	O
Syrian	B
golden	I
hamsters	I
.	O

In	O
:	O
Proceedings	O
of	O
the	O
Sym	O

344	O
YANYSHEVA	O
ET	O
AL	O
.	O

posium	O
on	O
Epithelial	O
Respiratory	O
Carcinogenesis	O
and	O
Bioassays	O
.	O

Batelle	O
Seattle	O
Research	O
Center	O
,	O
Seattle	O
,	O
WA	O
,	O
1974	O
,	O
p	O
.	O

17	O
.	O

4	O
.	O

Montesano	O
,	O
R	O
.	O
,	O
Saffiotti	O
,	O
U	O
,	O
Ferrero	O
,	O
A	O
,	O
and	O
Kaufman	O
,	O
D	O
.	O

Synergistic	O

effects	O
of	O
benzo	O
(	O
a	O
)	O
pyrene	O
and	O
diethylnitrosamine	O
on	O
respiratory	O
carcinogenesis	O
in	O
hamsters	O
.	O

J	O
.	O

Natl	O
.	O

Cancer	O
.	O

Inst	O
.	O

5	O
:	O
1395	O
-	O
1397	O
(	O
1974	O
)	O
.	O

5	O
.	O

Pfeiffer	O
,	O
E	O
.	O

H	O
.	O

Investigations	O
of	O
the	O
carcinogenic	O
burden	O
by	O
air	O

pollution	O
in	O
man	B
.	O

VII	O
.	O

Studies	O
on	O
the	O
ontogenetic	O
interaction	O
of	O
polycyclic	O
aromatic	O
hydrocarbons	O
.	O

Zbl	O
.	O

Bakteriol	O
.	O

Parasitenk	O
.	O

Infektion	O
.	O

Hyg	O
.	O

Abt	O
.	O

B	O
158	O
(	O
1	O
)	O
:	O
69	O
-	O
83	O
(	O
1973	O
)	O
.	O

6	O
.	O

Slaga	O
,	O
T	O
.	O

J	O
.	O
,	O
Jecker	O
,	O
L	O
.	O
,	O
Bracken	O
,	O
W	O
.	O

M	O
.	O
,	O
and	O
Weeks	O
,	O
C	O
.	O

E	O
.	O

The	O
effects	O
of	O

weak	O
or	O
non	O
-	O
carcinogenic	O
polycyclic	O
hydrocarbons	O
on	O
7	O
,	O
12	O
-	O
dimethylbenz	O
(	O
a	O
)	O
anthracene	O
and	O
benzo	O
(	O
a	O
)	O
pyrene	O
skin	O
tumor	O
-	O
initiation	O
.	O

Cancer	O
Lett	O
.	O

7	O
:	O
51	O
-	O
59	O
(	O
1979	O
)	O
.	O

7	O
.	O

Topping	O
,	O
D	O
.	O

C	O
.	O
,	O
Martin	O
,	O
D	O
.	O

H	O
.	O
,	O
and	O
Nettesheim	O
,	O
P	O
.	O

Determination	O
of	O

cocarcinogenic	O
activity	O
of	O
benzo	O
(	O
a	O
)	O
pyrene	O
for	O
respiratory	O
tract	O
mucosa	O
.	O

Cancer	O
Lett	O
.	O

11	O
:	O
315	O
-	O
321	O
(	O
1981	O
)	O
.	O

8	O
.	O

Ilnitsky	O
,	O
A	O
.	O

P	O
.	O
,	O
Voronin	O
,	O
V	O
.	O

M	O
.	O
,	O
and	O
Solenova	O
,	O
M	O
.	O

G	O
.	O

Carcinogenic	O
effect	O

of	O
benzo	O
(	O
a	O
)	O
pyrene	O
and	O
its	O
combinations	O
with	O
other	O
carbohydrates	O
at	O
their	O
oral	O
intake	O
[	O
in	O
Russian	O
]	O
.	O

Voprosy	O
Onkol	O
.	O

10	O
:	O
71	O
-	O
75	O
(	O
1974	O
)	O
.	O

9	O
.	O

Kurljandsky	O
,	O
B	O
.	O

A	O
.	O
,	O
Medvedovsky	O
,	O
A	O
.	O

G	O
.	O
,	O
and	O
Mashbits	O
,	O
F	O
.	O

D	O
.	O

On	O

cocarcinogenic	O
effect	O
of	O
toxic	O
factors	O
of	O
low	O
intensity	O
[	O
in	O
Russian	O
]	O
.	O

Gig	O
.	O

Sanit	O
.	O

10	O
:	O
83	O
-	O
85	O
(	O
1972	O
)	O
.	O

10	O
.	O

Thrusov	O
,	O
V	O
.	O

S	O
.	O
,	O
and	O
Andrianov	O
,	O
L	O
.	O

A	O
.	O

On	O
combined	O
effect	O
on	O
the	O
skin	O
of	O

single	O
application	O
of	O
7	O
,	O
12	O
-	O
dimethylbenz	O
(	O
a	O
)	O
anthracene	O
and	O
repeated	O
applications	O
of	O
benz	O
(	O
a	O
)	O
pyrene	O
[	O
in	O
Russian	O
]	O
.	O

Bull	O
.	O

Eksper	O
.	O

Biol	O
.	O

Med	O
.	O

3	O
:	O
80	O
-	O
83	O
(	O
1972	O
)	O
.	O

11	O
.	O

Yanysheva	O
,	O
N	O
.	O

Ya	O
.	O
,	O
Chernichenko	O
,	O
I	O
.	O

A	O
.	O
,	O
Balenko	O
,	O
N	O
.	O

V	O
,	O
and	O
Kireeva	O
,	O

I	O
.	O

S	O
.	O

Carcinogenic	O
substances	O
and	O
their	O
hygienic	O
standardization	O
in	O
the	O
environment	O
[	O
in	O
Russian	O
]	O
.	O

Zdorovja	O
,	O
Kiev	O
,	O
1977	O
.	O

12	O
.	O

Laskin	O
,	O
S	O
.	O
,	O
Kushner	O
,	O
M	O
.	O
,	O
and	O
Drew	O
,	O
R	O
.	O

T	O
.	O

Studies	O
in	O
pulmonary	O

careinogenesis	O
.	O

In	O
:	O
Inhalation	O
Carcinogenesis	O
(	O
M	O
.	O
G	O
.	O
Hanna	O
,	O
P	O
.	O
Nettesheim	O
,	O
and	O
J	O
.	O
R	O
.	O
Gillbert	O
,	O
Eds	O
.	O
)	O
U	O
.	O
S	O
.	O

Atomic	O
Energy	O
Commission	O
Symposium	O
,	O
Series	O
18	O
,	O
1970	O
,	O
p	O
.	O

321	O
.	O

13	O
.	O

Laskin	O
,	O
S	O
.	O
,	O
Kuschner	O
,	O
M	O
.	O
,	O
and	O
Drew	O
,	O
R	O
.	O

T	O
.	O

Inhalation	O
exposure	O
to	O

sulphur	O
dioxide	O
and	O
benzo	O
(	O
a	O
)	O
pyrene	O
.	O

Oak	O
Ridge	O
National	O
Laboratory	O
,	O
Gatlinburg	O
,	O
TN	O
,	O
1970	O
,	O
pp	O
.	O

322	O
-	O
351	O
.	O

14	O
.	O

Kuschner	O
,	O
M	O
.	O
,	O
and	O
Laskin	O
,	O
S	O
.	O

Experimental	O
models	O
in	O
environmental	O

carcinogenesis	O
.	O

Am	O
.	O

J	O
.	O

Pathol	O
.	O

1	O
:	O
183	O
-	O
196	O
(	O
1971	O
)	O
.	O

15	O
.	O

Komine	O
,	O
T	O
.	O

Influences	O
of	O
sulfur	O
dioxide	O
and	O
3	O
,	O
4	O
-	O
benzpyrene	O
on	O
the	O

respiratory	O
organ	O
of	O
rats	B
.	O

Hokkaido	O
Igaku	O
Zasshi	O
3	O
:	O
189	O
-	O
203	O
(	O
1977	O
)	O
.	O

16	O
.	O

Skvortsova	O
,	O
N	O
.	O

N	O
.	O

Role	O
of	O
some	O
common	O
atmospheric	O
pollutions	O
in	O

lung	O
blastomogenesis	O
[	O
in	O
Russian	O
]	O
.	O

In	O
:	O
Handbook	O
of	O
Hygiene	O
of	O
Atmospheric	O
Air	O
(	O
K	O
.	O
A	O
.	O
Bushtueva	O
,	O
Ed	O
.	O
)	O
,	O
Meditsina	O
,	O
Moscow	O
,	O
1976	O
,	O
pp	O
.	O

384	O
-	O
391	O
.	O

17	O
.	O

Yanysheva	O
,	O
N	O
.	O

Ya	O
.	O
,	O
Balenko	O
,	O
N	O
.	O

V	O
,	O
Chernichenko	O
,	O
I	O
.	O

A	O
,	O
and	O
Babiy	O
,	O
V	O
.	O

F	O
.	O

Quantitation	O
of	O
modified	O
effects	O
of	O
nitrogen	O
oxides	O
on	O
carcinogenicity	O
of	O
benz	O
(	O
a	O
)	O
pyrene	O
effect	O
[	O
in	O
Rusian	O
]	O
.	O

Gig	O
.	O

Sanit	O
.	O

7	O
:	O
7	O
-	O
9	O
(	O
1986	O
)	O
.	O

18	O
.	O

Yanysheva	O
,	O
N	O
.	O

Ya	O
.	O
,	O
Balenko	O
,	O
N	O
.	O

V	O
.	O
,	O
Chernichenko	O
,	O
I	O
.	O

A	O
.	O
,	O
Babiy	O
,	O
V	O
.	O

F	O
.	O
,	O

Bakanova	O
,	O
G	O
.	O

N	O
.	O
,	O
and	O
Lemeshko	O
,	O
L	O
.	O

P	O
.	O

Peculiarities	O
of	O
manifestation	O
of	O
carcinogenesis	O
at	O
combined	O
effect	O
of	O
benz	O
(	O
a	O
)	O
pyrene	O
and	O
phenol	O
depending	O
on	O
regimen	O
of	O
intake	O
into	O
the	O
organism	O
[	O
in	O
Russian	O
]	O
.	O

Gig	O
.	O

Sanit	O
.	O

4	O
:	O
29	O
-	O
33	O
(	O
1988	O
)	O
.	O

19	O
.	O

Van	O
Duuren	O
,	O
B	O
.	O

L	O
.	O
,	O
Katz	O
,	O
C	O
.	O
,	O
and	O
Goldschmidt	O
,	O
B	O
.	O

M	O
.	O

Brief	O
communica	O

tion	O
:	O
cocarcinogenic	O
agents	O
in	O
tobacco	B
carcinogenesis	O
.	O

J	O
.	O

Natl	O
.	O

Cancer	O
Inst	O
.	O

51	O
:	O
703	O
-	O
705	O
(	O
1973	O
)	O
.	O

20	O
.	O

Van	O
Duuren	O
,	O
B	O
.	O

L	O
.	O
,	O
and	O
Goldschmidt	O
,	O
B	O
.	O

M	O
.	O

Cocarcinogenic	O
and	O

tumor	O
-	O
promoting	O
agents	O
in	O
tobacco	B
carcinogenesis	O
.	O

J	O
.	O

Natl	O
.	O

Cancer	O
Inst	O
.	O

56	O
:	O
1237	O
-	O
1242	O
(	O
1976	O
)	O
.	O

21	O
.	O

Wattenberg	O
,	O
L	O
.	O

W	O
.	O
,	O
Coccia	O
,	O
J	O
.	O

B	O
.	O
,	O
and	O
Lam	O
,	O
L	O
.	O

K	O
.	O

Inhibitory	O
effects	O
of	O

phenolic	O
compounds	O
on	O
benzo	O
(	O
a	O
)	O
pyrene	O
-	O
induced	O
neoplasia	O
.	O

Cancer	O
Res	O
.	O

8	O
:	O
2820	O
-	O
2823	O
(	O
1980	O
)	O
.	O

22	O
.	O

Bogovski	O
,	O
P	O
.	O

A	O
,	O
and	O
Mirme	O
,	O
H	O
.	O

Yu	O
.	O

Cocarcinogenicity	O
of	O
phenols	O
from	O

Estonian	O
shale	O
tars	O
(	O
oils	O
)	O
.	O

Environ	O
.	O

Health	O
Perspect	O
.	O

30	O
:	O
177	O
-	O
178	O
(	O
1979	O
)	O
.	O

23	O
.	O

Gubergritz	O
,	O
M	O
.	O

Ya	O
.	O
,	O
and	O
Kirso	O
,	O
U	O
.	O

E	O
.	O

Carcinogenic	O
properties	O
,	O
struc	O

ture	O
and	O
reactive	O
capacity	O
of	O
phenols	O
[	O
in	O
Russian	O
]	O
.	O

Voprosy	O
Onkol	O
.	O

8	O
:	O
96	O
-	O
100	O
(	O
1970	O
)	O
.	O

24	O
.	O

Mirme	O
,	O
H	O
.	O

Yu	O
.	O

Modifying	O
effect	O
of	O
water	O
-	O
soluble	O
shale	O
phenols	O
upon	O

carcinogenesis	O
[	O
in	O
Russian	O
]	O
.	O

In	O
:	O
Problems	O
of	O
Prevention	O
of	O
Pollution	O
of	O
Environment	O
by	O
Carcinogenic	O
Substances	O
(	O
M	O
.	O
M	O
.	O
Shabad	O
,	O
Ed	O
.	O
)	O
,	O
Tallinn	O
,	O
Valgus	O
,	O
1972	O
,	O
pp	O
.	O

16	O
-	O
18	O
.	O

25	O
.	O

Kirso	O
,	O
U	O
.	O

E	O
.	O
,	O
Pashin	O
,	O
Yu	O
.	O

V	O
.	O
,	O
Bakhitova	O
,	O
L	O
.	O

M	O
.	O
,	O
and	O
Kjung	O
,	O
A	O
.	O

I	O
.	O

Effect	O

of	O
antioxidants	O
on	O
carcinogenic	O
and	O
mutagenic	O
activity	O
of	O
benzo	O
(	O
a	O
)	O
pyrene	O
[	O
in	O
Russian	O
]	O
.	O

Voprosy	O
Onkol	O
.	O

4	O
:	O
70	O
-	O
75	O
(	O
1985	O
)	O
.	O

26	O
.	O

Veldre	O
,	O
I	O
.	O

A	O
.	O

Comparative	O
assessment	O
of	O
toxic	O
effect	O
of	O
some	O
water	O

soluble	O
phenols	O
[	O
in	O
Russian	O
]	O
.	O

In	O
:	O
Proceedings	O
of	O
the	O
Scientific	O
Conference	O
on	O
Urgent	O
Problems	O
Related	O
with	O
Decrease	O
of	O
Infectious	O
Diseases	O
Morbidity	O
and	O
with	O
Hygienic	O
Problems	O
.	O

Tallinn	O
,	O
1968	O
,	O
pp	O
.	O

200	O
-	O
202	O
.	O

27	O
.	O

Substances	O
possessing	O
cocarcinogenic	O
effect	O
.	O

In	O
:	O
Carcinogenic	O
Sub	O

stances	O
in	O
the	O
Environment	O
of	O
Man	B
(	O
L	O
.	O
M	O
.	O
Shabad	O
and	O
A	O
.	O
P	O
.	O
Ilnitsky	O
,	O
Eds	O
.	O
)	O
,	O
Budapest	O
,	O
1979	O
,	O
pp	O
.	O

111	O
-	O
113	O
.	O

28	O
.	O

Djatlovitskaya	O
,	O
F	O
.	O

G	O
.	O
,	O
and	O
Maktas	O
,	O
E	O
.	O

D	O
.	O

Separate	O
determination	O
of	O
fly	O

phenols	O
in	O
water	O
using	O
thin	O
-	O
layer	O
chromatography	O
[	O
in	O
Russian	O
]	O
.	O

Gig	O
.	O

Sanit	O
.	O

6	O
:	O
60	O
-	O
63	O
(	O
1965	O
)	O
.	O

29	O
.	O

Kostovetsky	O
,	O
Ya	O
.	O

I	O
.	O
,	O
and	O
Zholdakova	O
,	O
Z	O
.	O

I	O
.	O

About	O
hygienic	O
rate	O
setting	O

of	O
phenol	O
in	O
the	O
water	O
of	O
waterpools	O
[	O
in	O
Russian	O
]	O
.	O

Gig	O
.	O

Sanit	O
.	O

7	O
:	O
7	O
-	O
10	O
(	O
1971	O
)	O
.	O

30	O
.	O

Mostkovoy	O
,	O
M	O
.	O

I	O
.	O

Practicum	O
on	O
variational	O
-	O
statistical	O
processing	O
of	O

clinical	O
material	O
[	O
in	O
Russian	O
]	O
.	O

Ashkhabad	O
,	O
1954	O
,	O
p	O
.	O

132	O
.	O

31	O
.	O

Weinstein	O
,	O
I	O
.	O

B	O
.	O

The	O
scientific	O
basis	O
for	O
carcinogen	O
detection	O
and	O

primary	O
cancer	O
prevention	O
.	O

Cancer	O
47	O
:	O
1133	O
-	O
1141	O
(	O
1981	O
)	O
.	O

32	O
.	O

Merkulov	O
,	O
A	O
.	O

I	O
,	O
and	O
Skvortsova	O
,	O
R	O
.	O

I	O
.	O

About	O
toxic	O
effect	O
of	O
phenol	O
[	O
in	O

Russian	O
]	O
.	O

Gig	O
.	O

Sanit	O
.	O

1	O
:	O
79	O
-	O
80	O
(	O
1984	O
)	O
.	O

33	O
.	O

Weinstein	O
,	O
I	O
.	O

B	O
.	O
,	O
Mufson	O
,	O
R	O
.	O

A	O
.	O
,	O
Lee	O
,	O
L	O
.	O

S	O
.	O
,	O
et	O
al	O
.	O

Membrane	O
and	O
other	O

biochemical	O
effects	O
of	O
the	O
phorbol	O
esters	O
and	O
their	O
relevance	O
to	O
tumor	O
promotion	O
.	O

In	O
:	O
Carcinogenesis	O
.	O

Fundamental	O
Mechanisms	O
and	O
Environmental	O
Effects	O
.	O

London	O
,	O
1980	O
,	O
pp	O
.	O

543	O
-	O
563	O
.	O

34	O
.	O

Yamasaki	O
,	O
H	O
.	O
,	O
and	O
Weinstein	O
,	O
I	O
.	O

B	O
.	O

Cellular	O
and	O
molecular	O
mecha	O

nisms	O
of	O
tumor	O
promotion	O
and	O
their	O
implications	O
for	O
risk	O
assessment	O
.	O

In	O
:	O
Methods	O
for	O
Estimating	O
Risk	O
of	O
Chemical	O
Injury	O
:	O
Human	B
and	O
Non	O
-	O
human	B
Biota	O
and	O
Ecosystems	O
(	O
V	O
.	O
B	O
.	O
Vouk	O
,	O
G	O
.	O
C	O
.	O
Butler	O
,	O
D	O
.	O
G	O
.	O
Hoel	O
,	O
and	O
D	O
.	O
B	O
.	O
Peakall	O
,	O
Eds	O
.	O
)	O
,	O
SCOPE	O
,	O
1985	O
,	O
pp	O
.	O

155	O
-	O
180	O
.	O

35	O
.	O

Karu	O
,	O
T	O
,	O
Kirso	O
,	O
U	O
.	O

E	O
.	O
,	O
and	O
Andrianov	O
,	O
L	O
.	O

A	O
.	O

Dynamics	O
of	O
resorption	O
of	O

3	O
,	O
4	O
-	O
benzpyrene	O
with	O
phenols	O
from	O
mouse	B
skin	O
[	O
in	O
Russian	O
]	O
.	O

Voprosy	O
Onkol	O
.	O

5	O
:	O
80	O
-	O
84	O
(	O
1973	O
)	O
.	O

36	O
.	O

Yanysheva	O
,	O
N	O
.	O

Ya	O
.	O
,	O
Yurkovskaya	O
,	O
T	O
.	O

N	O
.	O
,	O
Beregovskaya	O
,	O
N	O
.	O

N	O
.	O
,	O
et	O
al	O
.	O

Metalloenzymic	O
complexes	O
of	O
energetic	O
and	O
detoxicating	O
systems	O
of	O
cell	O
during	O
benz	O
(	O
a	O
)	O
pyrene	O
-	O
induced	O
carcinogenesis	O
.	O

In	O
:	O
Proceedings	O
of	O
the	O
4th	O
National	O
Congress	O
of	O
Oncology	O
with	O
International	O
Participation	O
.	O

Sofia	O
,	O
1985	O
,	O
p	O
.	O

102	O
.	O

37	O
.	O

Mizell	O
,	O
M	O
.	O

Anuran	O
(	O
Lucke	O
)	O
tumor	O
breakdown	O
in	O
regenerating	O
anuran	O

tadpole	O
tails	O
.	O

Anat	O
.	O

Res	O
.	O

137	O
:	O
382	O
-	O
383	O
(	O
1960	O
)	O
.	O

38	O
.	O

Sheremetieva	O
,	O
E	O
.	O

N	O
.	O

Spontaneous	O
melanoma	O
in	O
regenerating	O
tails	O
of	O

axolotis	O
.	O

J	O
.	O

Exp	O
.	O

Zool	O
.	O

158	O
:	O
101	O
-	O
122	O
(	O
1965	O
)	O
.	O

39	O
.	O

Tsonis	O
,	O
P	O
.	O

A	O
,	O
and	O
Eguchi	O
,	O
G	O
.	O

Carcinogens	O
on	O
regeneration	O
.	O

Effects	O
on	O

N	O
-	O
methyl	O
-	O
N	O
-	O
nitro	O
-	O
N	O
-	O
nitrosoguanidine	O
and	O
4	O
-	O
nitrogninoline	O
-	O
1	O
-	O
oxide	O
on	O
limb	O
regeneration	O
in	O
adult	O
newts	O
.	O

Differentiation	O
20	O
:	O
52	O
-	O
60	O
(	O
1981	O
)	O
.	O

B	O
lymphocyte	O
stimulator	O
(	O
BLyS	O
)	O
isoforms	O
in	O
systemic	O
lupus	O
erythematosus	O
:	O
disease	O
activity	O
correlates	O
better	O
with	O
blood	O
leukocyte	O
BLyS	O
mRNA	O
levels	O
than	O
with	O
plasma	O
BLyS	O
protein	O
levels	O

Abstract	O

Considerable	O
evidence	O
points	O
to	O
a	O
role	O
for	O
B	O
lymphocyte	O
stimulator	O
(	O
BLyS	O
)	O
overproduction	O
in	O
murine	B
and	O
human	B
systemic	O
lupus	O
erythematosus	O
(	O
SLE	O
)	O
.	O

Nevertheless	O
,	O
the	O
correlation	O
between	O
circulating	O
levels	O
of	O
BLyS	O
protein	O
and	O
disease	O
activity	O
in	O
human	B
SLE	O
is	O
modest	O
at	O
best	O
.	O

This	O
may	O
be	O
due	O
to	O
an	O
inadequacy	O
of	O
the	O
former	O
to	O
reflect	O
endogenous	O
BLyS	O
overproduction	O
faithfully	O
,	O
in	O
that	O
steady	O
-	O
state	O
protein	O
levels	O
are	O
affected	O
not	O
just	O
by	O
production	O
rates	O
but	O
also	O
by	O
rates	O
of	O
peripheral	O
utilization	O
and	O
excretion	O
.	O

Increased	O
levels	O
of	O
BLyS	O
mRNA	O
may	O
better	O
reflect	O
increased	O
in	O
vivo	O
BLyS	O
production	O
,	O
and	O
therefore	O
they	O
may	O
correlate	O
better	O
with	O
biologic	O
and	O
clinical	O
sequelae	O
of	O
BLyS	O
overexpression	O
than	O
do	O
circulating	O
levels	O
of	O
BLyS	O
protein	O
.	O

Accordingly	O
,	O
we	O
assessed	O
peripheral	O
blood	O
leukocyte	O
levels	O
of	O
BLyS	O
mRNA	O
isoforms	O
(	O
full	O
-	O
length	O
BLyS	O
and	O
Delta	O
BLyS	O
)	O
and	O
plasma	O
BLyS	O
protein	O
levels	O
in	O
patients	B
with	O
SLE	O
,	O
and	O
correlated	O
these	O
levels	O
with	O
laboratory	O
and	O
clinical	O
features	O
.	O

BLyS	O
protein	O
,	O
full	O
-	O
length	O
BLyS	O
mRNA	O
,	O
and	O
Delta	O
BLyS	O
mRNA	O
levels	O
were	O
greater	O
in	O
SLE	O
patients	B
(	O
n	O
=	O
60	O
)	O
than	O
in	O
rheumatoid	O
arthritis	O
patients	B
(	O
n	O
=	O
60	O
)	O
or	O
normal	O
control	O
individuals	O
(	O
n	O
=	O
30	O
)	O
.	O

Although	O
full	O
-	O
length	O
BLyS	O
and	O
Delta	O
BLyS	O
mRNA	O
levels	O
correlated	O
significantly	O
with	O
BLyS	O
protein	O
levels	O
in	O
the	O
SLE	O
cohort	O
,	O
BLyS	O
mRNA	O
levels	O
were	O
more	O
closely	O
associated	O
with	O
serum	O
immunoglobulin	O
levels	O
and	O
SLE	O
Disease	O
Activity	O
Index	O
scores	O
than	O
were	O
BLyS	O
protein	O
levels	O
.	O

Moreover	O
,	O
changes	O
in	O
SLE	O
Disease	O
Activity	O
Index	O
scores	O
were	O
more	O
closely	O
associated	O
with	O
changes	O
in	O
BLyS	O
mRNA	O
levels	O
than	O
with	O
changes	O
in	O
BLyS	O
protein	O
levels	O
among	O
the	O
37	O
SLE	O
patients	B
from	O
whom	O
repeat	O
blood	O
samples	O
were	O
obtained	O
.	O

Thus	O
,	O
full	O
-	O
length	O
BLyS	O
and	O
Delta	O
BLyS	O
mRNA	O
levels	O
are	O
elevated	O
in	O
SLE	O
and	O
are	O
more	O
closely	O
associated	O
with	O
disease	O
activity	O
than	O
are	O
BLyS	O
protein	O
levels	O
.	O

BLyS	O
mRNA	O
levels	O
may	O
be	O
a	O
helpful	O
biomarker	O
in	O
the	O
clinical	O
monitoring	O
of	O
SLE	O
patients	B
.	O

Introduction	O

B	O
lymphocyte	O
stimulator	O
(	O
BLyS	O
;	O
a	O
trademark	O
of	O
Human	B
Genome	O
Sciences	O
,	O
Inc	O
.	O
,	O
Rockville	O
,	O
MD	O
,	O
USA	O
)	O
is	O
a	O
285	O
-	O
amino	O
-	O
acid	O
member	O
of	O
the	O
tumor	O
necrosis	O
factor	O
ligand	O
superfamily	O
[	O
1	O
-	O
3	O
]	O
.	O

A	O
causal	O
relation	O
between	O
constitutive	O
overproduction	O
of	O
BLyS	O
and	O
development	O
of	O
systemic	O
lupus	O
erythematosus	O
(	O
SLE	O
)	O
-	O
like	O
illness	O
has	O
incontrovertibly	O
been	O
established	O
in	O
mice	B
.	O

BLyS	O
-	O
transgenic	O
mice	B
often	O
develop	O
SLE	O
-	O
like	O
features	O
as	O
they	O
age	O
[	O
3	O
-	O
5	O
]	O
,	O
and	O
SLE	O
-	O
prone	O
(	O
NZB	O
x	O
NZW	O
)	O
F1	O
(	O
BWF1	O
)	O
and	O
MRL	O
-	O
lpr	O
/	O
lpr	O
mice	B
respond	O
clinically	O
to	O
treatment	O
with	O
BLyS	O
antagonists	O
(	O
decreased	O
disease	O
progression	O
and	O
improved	O
survival	O
)	O
[	O
3	O
,	O
6	O
]	O
.	O

Considerable	O
inferential	O
evidence	O
points	O
to	O
a	O
role	O
for	O
BLyS	O
overproduction	O
in	O
human	B
SLE	O
as	O
well	O
.	O

Cross	O
-	O
sectional	O
studies	O
have	O
demonstrated	O
elevated	O
circulating	O
levels	O
of	O
BLyS	O
in	O
20	O
-	O
30	O
%	O
of	O
human	B
SLE	O
patients	B
tested	O
at	O
a	O
single	O
point	O
in	O
time	O
[	O
7	O
,	O
8	O
]	O
.	O

Moreover	O
,	O
a	O
12	O
-	O
month	O
longitudinal	O
study	O
documented	O
persistently	O
elevated	O
serum	O
BLyS	O
levels	O
in	O
about	O
25	O
%	O
of	O
SLE	O
patients	B
and	O
intermittently	O
elevated	O
serum	O
BLyS	O
levels	O
in	O
an	O
additional	O
25	O
%	O
of	O
patients	B
[	O
9	O
]	O
.	O

Remarkably	O
,	O
circulating	O
BLyS	O
levels	O
did	O
not	O
correlate	O
with	O
disease	O
activity	O
(	O
measured	O
using	O
the	O
SLE	O
Disease	O
Activity	O
Index	O
[	O
SLEDAI	O
]	O
)	O
in	O
these	O
cross	O
-	O
sectional	O
or	O
longitudinal	O
studies	O
[	O
7	O
-	O
9	O
]	O
.	O

Although	O
a	O
statistically	O
significant	O
correlation	O
between	O
circulating	O
BLyS	O
levels	O
and	O
SLEDAI	O
has	O
been	O
appreciated	O
in	O
a	O
more	O
recent	O
24	O
-	O
month	O
longitudinal	O
study	O
of	O
245	O
SLE	O
patients	B
(	O
with	O
>	O
1	O
,	O
700	O
plasma	O
samples	O
analyzed	O
)	O
[	O
10	O
]	O
,	O
the	O
correlation	O
remains	O
weak	O
.	O

The	O
limited	O
correlation	O
between	O
circulating	O
BLyS	O
protein	O
levels	O
and	O
disease	O
activity	O
in	O
these	O
studies	O
may	O
have	O
exposed	O
an	O
inadequacy	O
of	O
the	O
former	O
to	O
reflect	O
faithfully	O
endogenous	O
BLyS	O
overproduction	O
.	O

In	O
addition	O
to	O
the	O
rate	O
of	O
BLyS	O
protein	O
production	O
,	O
several	O
other	O
factors	O
(	O
for	O
example	O
,	O
utilization	O
and	O
excretion	O
)	O
can	O
affect	O
circulating	O
BLyS	O
protein	O
levels	O
.	O

Although	O
there	O
are	O
no	O
practicable	O
means	O
of	O
directly	O
measuring	O
in	O
vivo	O
BLyS	O
production	O
per	O
se	O
in	O
humans	B
,	O
the	O
level	O
of	O
BLyS	O
mRNA	O
may	O
serve	O
as	O
a	O
better	O
surrogate	O
marker	O
of	O
in	O
vivo	O
BLyS	O
production	O
than	O
does	O
the	O
level	O
of	O
BLyS	O
protein	O
.	O

Candidate	O
BLyS	O
mRNA	O
isoforms	O
include	O
the	O
full	O
-	O
length	O
BLyS	O
mRNA	O
isoform	O
,	O
which	O
encodes	O
the	O
full	O
-	O
length	O
protein	O
,	O
and	O
the	O
alternatively	O
spliced	O
Delta	O
BLyS	O
mRNA	O
isoform	O
,	O
which	O
encodes	O
a	O
protein	O
with	O
a	O
small	O
peptide	O
deletion	O
[	O
11	O
]	O
.	O

(	O
Delta	O
BLyS	O
does	O
not	O
bind	O
to	O
cells	O
expressing	O
BLyS	O
receptors	O
,	O
and	O
therefore	O
it	O
has	O
no	O
agonistic	O
activity	O
.	O
Moreover	O
,	O
Delta	O
BLyS	O
can	O
form	O
heterotrimers	O
with	O
full	O
-	O
length	O
BLyS	O
,	O
thereby	O
actually	O
functioning	O
as	O
a	O
dominant	O
-	O
negative	O
antagonist	O
of	O
BLyS	O
activity	O
.	O
)	O

In	O
this	O
report	O
we	O
demonstrate	O
that	O
peripheral	O
blood	O
leukocytes	O
from	O
SLE	O
patients	B
express	O
elevated	O
mRNA	O
levels	O
of	O
both	O
full	O
-	O
length	O
BLyS	O
and	O
Delta	O
BLyS	O
relative	O
to	O
those	O
levels	O
expressed	O
by	O
patients	B
with	O
rheumatoid	O
arthritis	O
(	O
RA	O
)	O
or	O
by	O
normal	O
control	O
individuals	O
.	O

In	O
the	O
SLE	O
patients	B
,	O
both	O
full	O
-	O
length	O
BLyS	O
and	O
Delta	O
BLyS	O
mRNA	O
levels	O
are	O
more	O
closely	O
associated	O
with	O
disease	O
activity	O
(	O
SLEDAI	O
)	O
than	O
are	O
BLyS	O
protein	O
levels	O
.	O

Accordingly	O
,	O
BLyS	O
mRNA	O
levels	O
may	O
be	O
a	O
helpful	O
biomarker	O
in	O
the	O
clinical	O
monitoring	O
of	O
SLE	O
patients	B
.	O

Materials	O
and	O
methods	O

General	O
details	O

This	O
study	O
was	O
approved	O
by	O
the	O
institutional	O
review	O
boards	O
of	O
the	O
University	O
of	O
Southern	O
California	O
and	O
the	O
Scripps	O
Research	O
Institute	O
.	O

All	O
participants	B
gave	O
their	O
written	O
informed	O
consent	O
before	O
participation	O
in	O
this	O
study	O
.	O

Participants	B

Patients	B
receiving	O
outpatient	O
medical	O
care	O
at	O
the	O
rheumatology	O
clinics	O
of	O
the	O
Los	O
Angeles	O
County	O
+	O
University	O
of	O
Southern	O
California	O
Medical	O
Center	O
were	O
recruited	O
into	O
the	O
study	O
.	O

Diagnoses	O
of	O
SLE	O
(	O
n	O
=	O
60	O
)	O
or	O
RA	O
(	O
n	O
=	O
60	O
)	O
were	O
based	O
on	O
established	O
clinical	O
criteria	O
[	O
12	O
]	O
.	O

Healthy	O
control	O
individuals	O
(	O
n	O
=	O
30	O
)	O
were	O
recruited	O
from	O
Los	O
Angeles	O
County	O
+	O
University	O
of	O
Southern	O
California	O
Medical	O
Center	O
and	O
University	O
of	O
Southern	O
California	O
Keck	O
School	O
of	O
Medicine	O
personnel	O
.	O

No	O
exclusions	O
were	O
made	O
on	O
any	O
basis	O
other	O
than	O
an	O
inability	O
to	O
give	O
informed	O
consent	O
.	O

Each	O
patient	B
'	O
s	O
sex	O
,	O
race	O
,	O
age	O
,	O
and	O
medications	O
at	O
the	O
time	O
of	O
the	O
phlebotomy	O
were	O
recorded	O
(	O
Table	O
1	O
)	O
.	O

Based	O
solely	O
on	O
the	O
patient	B
'	O
s	O
willingness	O
to	O
donate	O
a	O
second	O
blood	O
sample	O
,	O
repeat	O
blood	O
samples	O
were	O
collected	O
from	O
37	O
of	O
the	O
SLE	O
patients	B
147	O
-	O
511	O
days	O
(	O
median	O
371	O
days	O
)	O
after	O
collection	O
of	O
the	O
first	O
samples	O
.	O

These	O
patients	B
were	O
not	O
selected	O
on	O
the	O
basis	O
of	O
any	O
demographic	O
,	O
clinical	O
,	O
or	O
laboratory	O
feature	O
.	O

Clinical	O
disease	O
activity	O
for	O
the	O
SLE	O
patients	B
was	O
assessed	O
using	O
the	O
SLEDAI	O
[	O
13	O
]	O
and	O
using	O
a	O
modified	O
SLEDAI	O
that	O
excludes	O
the	O
contribution	O
of	O
anti	O
-	O
double	O
-	O
stranded	O
DNA	O
(	O
anti	O
-	O
dsDNA	O
)	O
antibodies	O
from	O
the	O
total	O
score	O
.	O

Each	O
patient	B
'	O
s	O
medical	O
chart	O
was	O
reviewed	O
for	O
results	O
of	O
standard	O
clinical	O
laboratory	O
tests	O
within	O
the	O
previous	O
or	O
subsequent	O
1	O
-	O
month	O
period	O
.	O

Plasma	O
BLyS	O
determination	O

Whole	O
venous	O
blood	O
was	O
centrifuged	O
to	O
yield	O
plasma	O
and	O
a	O
buffy	O
coat	O
.	O

The	O
plasma	O
was	O
harvested	O
,	O
stored	O
at	O
-	O
70	O
degrees	O
C	O
,	O
and	O
assayed	O
for	O
BLyS	O
levels	O
by	O
ELISA	O
[	O
8	O
,	O
14	O
]	O
using	O
Fab	O
fragments	O
of	O
the	O
capture	O
antibody	O
rather	O
than	O
the	O
whole	O
antibody	O
to	O
reduce	O
assay	O
interference	O
by	O
rheumatoid	O
factor	O
.	O

The	O
lower	O
limit	O
of	O
detection	O
in	O
this	O
assay	O
is	O
0	O
.	O
3	O
ng	O
/	O
ml	O
.	O

For	O
statistical	O
purposes	O
,	O
plasma	O
samples	O
with	O
BLyS	O
concentrations	O
below	O
the	O
lower	O
limit	O
of	O
detection	O
were	O
assigned	O
a	O
value	O
of	O
0	O
.	O
25	O
ng	O
/	O
ml	O
.	O

Blood	O
BLyS	O
mRNA	O
determination	O

The	O
buffy	O
coat	O
from	O
centrifuged	O
whole	O
blood	O
was	O
harvested	O
,	O
added	O
to	O
RNAlater	O
(	O
TM	O
)	O
(	O
Ambion	O
,	O
Austin	O
,	O
TX	O
,	O
USA	O
)	O
at	O
a	O
1	O
:	O
4	O
vol	O
/	O
vol	O
ratio	O
for	O
RNA	O
stabilization	O
,	O
stored	O
at	O
-	O
70	O
degrees	O
C	O
,	O
and	O
assayed	O
for	O
full	O
-	O
length	O
BLyS	O
and	O
Delta	O
BLyS	O
mRNA	O
levels	O
by	O
real	O
-	O
time	O
PCR	O
.	O

Total	O
RNA	O
was	O
purified	O
from	O
buffy	O
coat	O
samples	O
using	O
RNAeasy	O
miniprep	O
kits	O
(	O
Qiagen	O
,	O
Valencia	O
,	O
CA	O
,	O
USA	O
)	O
,	O
and	O
contaminating	O
genomic	O
DNA	O
was	O
removed	O
by	O
DNAse	O
-	O
I	O
digestion	O
.	O

One	O
-	O
tenth	O
volume	O
of	O
total	O
RNA	O
was	O
used	O
as	O
template	O
in	O
the	O
first	O
-	O
strand	O
cDNA	O
reaction	O
using	O
oligo	O
-	O
dT	O
and	O
the	O
Superscript	O
III	O
first	O
-	O
strand	O
synthesis	O
system	O
(	O
Invitrogen	O
,	O
Carlsbad	O
,	O
CA	O
,	O
USA	O
)	O
.	O

Duplicate	O
samples	O
of	O
cDNA	O
were	O
amplified	O
with	O
primers	O
against	O
beta	O
-	O
actin	O
,	O
full	O
-	O
length	O
BLyS	O
,	O
or	O
Delta	O
BLyS	O
:	O
beta	O
-	O
actin	O
sense	O
5	O
'	O
-	O
CGAGAAGATGACCCAGATCA	O
-	O
3	O
'	O
;	O
beta	O
-	O
actin	O
anti	O
-	O
sense	O
5	O
'	O
-	O
GGCATACCCCTCGTAGATGG	O
-	O
3	O
'	O
;	O
full	O
-	O
length	O
BLyS	O
sense	O
5	O
'	O
-	O
GCAGACAGTGAAACACCAAC	O
-	O
3	O
'	O
;	O
Delta	O
BLyS	O
sense	O
5	O
'	O
-	O
CAGAAGAAACAGGATCTTAC	O
-	O
3	O
'	O
;	O
and	O
full	O
-	O
length	O
BLyS	O
/	O
Delta	O
BLyS	O
anti	O
-	O
sense	O
5	O
'	O
-	O
TGCCAGCTGAATAGCAGGAA	O
-	O
3	O
'	O
.	O

A	O
165	O
bp	O
amplicon	O
for	O
beta	O
-	O
actin	O
was	O
PCR	O
-	O
amplified	O
using	O
the	O
7900	O
HT	O
ABI	O
Prism	O
machine	O
(	O
Qiagen	O
)	O
with	O
annealing	O
at	O
65	O
degrees	O
C	O
.	O

A	O
296	O
bp	O
amplicon	O
for	O
full	O
-	O
length	O
BLyS	O
was	O
PCR	O
-	O
amplified	O
,	O
with	O
annealing	O
at	O
64	O
degrees	O
C	O
.	O

A	O
270	O
bp	O
amplicon	O
for	O
Delta	O
BLyS	O
was	O
PCR	O
-	O
amplified	O
with	O
annealing	O
at	O
61	O
degrees	O
C	O
.	O

The	O
annealing	O
conditions	O
for	O
full	O
-	O
length	O
BLyS	O
and	O
Delta	O
BLyS	O
were	O
determined	O
so	O
that	O
each	O
primer	O
set	O
remained	O
specific	O
to	O
the	O
respective	O
BLyS	O
isoform	O
and	O
yielded	O
a	O
PCR	O
efficiency	O
similar	O
to	O
those	O
of	O
cloned	O
cDNA	O
standards	O
.	O

Melting	O
curve	O
analysis	O
revealed	O
a	O
single	O
peak	O
for	O
each	O
gene	O
amplified	O
.	O

The	O
threshold	O
cycle	O
(	O
Ct	O
)	O
values	O
for	O
each	O
reaction	O
were	O
determined	O
using	O
Sequence	O
Detection	O
System	O
software	O
(	O
Applied	O
Biosystems	O
,	O
Foster	O
City	O
,	O
CA	O
,	O
USA	O
)	O
.	O

Results	O
are	O
presented	O
as	O
ratios	O
of	O
full	O
-	O
length	O
BLyS	O
or	O
Delta	O
BLyS	O
mRNA	O
to	O
beta	O
-	O
actin	O
mRNA	O
,	O
which	O
were	O
calculated	O
using	O
the	O
following	O
formulae	O
:	O

2	O
exp	O
(	O
Ct	O
beta	O
-	O
actin	O
-	O
Ctfull	O
-	O
length	O
BLyS	O
)	O

2	O
exp	O
(	O
Ct	O
beta	O
-	O
actin	O
-	O
Ct	O
Delta	O
BLyS	O
)	O

Determination	O
of	O
anti	O
-	O
BLyS	O
autoantibodies	O

BLyS	O
was	O
bound	O
to	O
microtiter	O
plates	O
by	O
first	O
coating	O
the	O
plates	O
with	O
streptavidin	O
and	O
then	O
adding	O
biotinylated	O
recombinant	O
BLyS	O
.	O

Using	O
these	O
plates	O
as	O
the	O
capture	O
reagent	O
,	O
plasma	O
samples	O
were	O
incubated	O
,	O
and	O
horseradish	B
peroxidase	O
-	O
conjugated	O
anti	O
-	O
human	B
IgA	O
/	O
IgM	O
/	O
IgG	O
(	O
Southern	O
Biotechnology	O
Associates	O
,	O
Birmingham	O
,	O
AL	O
,	O
USA	O
;	O
1	O
:	O
20	O
,	O
000	O
final	O
dilution	O
)	O
or	O
horseradish	B
peroxidase	O
-	O
conjugated	O
anti	O
-	O
human	B
IgG	O
(	O
Southern	O
Biotechnology	O
;	O
1	O
:	O
10	O
,	O
000	O
final	O
dilution	O
)	O
were	O
used	O
as	O
the	O
detector	O
reagents	O
.	O

Statistical	O
analysis	O

All	O
analyses	O
were	O
performed	O
using	O
SigmaStat	O
software	O
(	O
SPSS	O
,	O
Chicago	O
,	O
IL	O
,	O
USA	O
)	O
.	O

Results	O
that	O
did	O
not	O
follow	O
a	O
normal	O
distribution	O
were	O
log	O
-	O
transformed	O
to	O
achieve	O
normality	O
.	O

Parametric	O
testing	O
between	O
two	O
matched	O
or	O
unmatched	O
groups	O
was	O
performed	O
using	O
the	O
paired	O
or	O
unpaired	O
t	O
test	O
,	O
respectively	O
.	O

Parametric	O
testing	O
among	O
three	O
or	O
more	O
groups	O
was	O
performed	O
using	O
one	O
-	O
way	O
analysis	O
of	O
variance	O
.	O

When	O
log	O
-	O
transformation	O
failed	O
to	O
generate	O
normally	O
distributed	O
data	O
or	O
the	O
equal	O
variance	O
test	O
was	O
not	O
satisfied	O
,	O
nonparametric	O
testing	O
was	O
performed	O
using	O
the	O
Mann	O
-	O
Whitney	O
rank	O
sum	O
test	O
between	O
two	O
groups	O
and	O
by	O
Kruskal	O
-	O
Wallis	O
one	O
-	O
way	O
analysis	O
of	O
variance	O
on	O
ranks	O
among	O
three	O
or	O
more	O
groups	O
.	O

Correlations	O
were	O
determined	O
using	O
Pearson	O
product	O
moment	O
correlation	O
for	O
interval	O
data	O
and	O
using	O
Spearman	O
rank	O
order	O
correlation	O
for	O
ordinal	O
data	O
or	O
for	O
interval	O
data	O
that	O
did	O
not	O
follow	O
a	O
normal	O
distribution	O
.	O

Nominal	O
data	O
were	O
analyzed	O
using	O
chi	O
2	O
analysis	O
-	O
of	O
-	O
contingency	O
tables	O
.	O

Results	O

Elevated	O
plasma	O
BLyS	O
levels	O
and	O
blood	O
levels	O
of	O
full	O
-	O
length	O
BLyS	O
and	O
Delta	O
BLyS	O
mRNA	O
isoforms	O
in	O
systemic	O
lupus	O
erythematosus	O
patients	B

Previous	O
reports	O
of	O
elevated	O
circulating	O
BLyS	O
levels	O
in	O
SLE	O
patients	B
were	O
based	O
on	O
a	O
BLyS	O
ELISA	O
that	O
utilized	O
a	O
whole	O
(	O
unfragmented	O
)	O
capture	O
anti	O
-	O
BLyS	O
monoclonal	O
antibody	O
[	O
7	O
-	O
9	O
]	O
.	O

Since	O
the	O
publication	O
of	O
these	O
reports	O
,	O
it	O
has	O
been	O
recognized	O
that	O
the	O
presence	O
of	O
rheumatoid	O
factor	O
can	O
potentially	O
interfere	O
with	O
the	O
assay	O
and	O
lead	O
to	O
spurious	O
overestimation	O
of	O
the	O
true	O
circulating	O
BLyS	O
levels	O
(	O
Human	B
Genome	O
Sciences	O
,	O
Inc	O
.	O
;	O
unpublished	O
observations	O
)	O
.	O

To	O
mitigate	O
potential	O
interference	O
from	O
rheumatoid	O
factor	O
,	O
the	O
BLyS	O
ELISA	O
has	O
been	O
modified	O
and	O
the	O
capture	O
anti	O
-	O
BLyS	O
monoclonal	O
antibody	O
is	O
now	O
utilized	O
as	O
a	O
Fab	O
fragment	O
.	O

Despite	O
the	O
changes	O
in	O
the	O
ELISA	O
format	O
,	O
our	O
findings	O
are	O
entirely	O
consistent	O
with	O
those	O
of	O
the	O
previous	O
reports	O
.	O

Plasma	O
BLyS	O
levels	O
were	O
significantly	O
greater	O
in	O
the	O
SLE	O
group	O
than	O
in	O
either	O
RA	O
or	O
normal	O
control	O
group	O
(	O
P	O
<	O
0	O
.	O
001	O
;	O
Figure	O
1a	O
)	O
.	O

Arbitrary	O
assignment	O
of	O
the	O
95th	O
percentile	O
value	O
among	O
the	O
normal	O
control	O
individuals	O
as	O
the	O
upper	O
limit	O
of	O
'	O
normal	O
'	O
revealed	O
that	O
two	O
of	O
the	O
30	O
normal	O
control	O
individuals	O
,	O
15	O
of	O
the	O
60	O
RA	O
patients	B
,	O
and	O
29	O
of	O
the	O
60	O
SLE	O
patients	B
harbored	O
elevated	O
plasma	O
BLyS	O
levels	O
(	O
P	O
<	O
0	O
.	O
001	O
)	O
.	O

Overexpression	O
of	O
BLyS	O
in	O
SLE	O
patients	B
was	O
also	O
established	O
by	O
measuring	O
BLyS	O
mRNA	O
levels	O
normalized	O
to	O
beta	O
-	O
actin	O
mRNA	O
levels	O
in	O
peripheral	O
blood	O
leukocytes	O
(	O
buffy	O
coats	O
)	O
.	O

The	O
geometric	O
mean	O
full	O
-	O
length	O
BLyS	O
mRNA	O
and	O
Delta	O
BLyS	O
mRNA	O
levels	O
among	O
the	O
SLE	O
patients	B
were	O
each	O
significantly	O
greater	O
than	O
those	O
among	O
the	O
RA	O
patients	B
and	O
normal	O
control	O
individuals	O
,	O
respectively	O
(	O
P	O
<	O
0	O
.	O
001	O
for	O
each	O
;	O
Figure	O
1b	O
,	O
c	O
)	O
.	O

Arbitrary	O
assignment	O
of	O
the	O
95th	O
percentile	O
values	O
for	O
full	O
-	O
length	O
BLyS	O
and	O
Delta	O
BLyS	O
mRNA	O
levels	O
among	O
the	O
normal	O
control	O
individuals	O
as	O
the	O
upper	O
limits	O
of	O
'	O
normal	O
'	O
revealed	O
that	O
two	O
of	O
the	O
30	O
normal	O
control	O
individuals	O
,	O
four	O
of	O
the	O
60	O
RA	O
patients	B
,	O
and	O
20	O
of	O
the	O
60	O
SLE	O
patients	B
had	O
elevated	O
full	O
-	O
length	O
BLyS	O
mRNA	O
levels	O
(	O
P	O
<	O
0	O
.	O
001	O
)	O
,	O
and	O
that	O
two	O
of	O
the	O
30	O
normal	O
control	O
individuals	O
,	O
three	O
of	O
the	O
60	O
RA	O
patients	B
,	O
and	O
19	O
of	O
the	O
60	O
SLE	O
patients	B
had	O
elevated	O
Delta	O
BLyS	O
mRNA	O
levels	O
(	O
P	O
<	O
0	O
.	O
001	O
)	O
.	O

Levels	O
of	O
full	O
-	O
length	O
BLyS	O
and	O
Delta	O
BLyS	O
mRNA	O
strongly	O
correlated	O
with	O
each	O
other	O
(	O
r	O
=	O
0	O
.	O
703	O
;	O
P	O
<	O
0	O
.	O
001	O
)	O
in	O
the	O
SLE	O
cohort	O
,	O
and	O
plasma	O
BLyS	O
levels	O
also	O
correlated	O
significantly	O
with	O
levels	O
of	O
each	O
BLyS	O
isoform	O
(	O
r	O
=	O
0	O
.	O
429	O
,	O
P	O
<	O
0	O
.	O
001	O
;	O
and	O
r	O
=	O
0	O
.	O
290	O
,	O
P	O
=	O
0	O
.	O
024	O
,	O
respectively	O
)	O
.	O

Among	O
these	O
SLE	O
patients	B
,	O
none	O
of	O
the	O
measured	O
BLyS	O
parameters	O
correlated	O
with	O
patient	B
age	O
,	O
sex	O
,	O
race	O
,	O
or	O
daily	O
dose	O
of	O
corticosteroids	O
(	O
data	O
not	O
shown	O
)	O
.	O

Because	O
the	O
racial	O
composition	O
of	O
the	O
normal	O
cohort	O
was	O
not	O
as	O
predominantly	O
Hispanic	O
as	O
were	O
those	O
of	O
the	O
RA	O
and	O
SLE	O
cohorts	O
,	O
we	O
assessed	O
the	O
BLyS	O
parameters	O
in	O
the	O
respective	O
Hispanic	O
subpopulations	O
.	O

As	O
for	O
the	O
entire	O
populations	O
,	O
values	O
for	O
SLE	O
were	O
significantly	O
greater	O
than	O
those	O
for	O
either	O
RA	O
or	O
normal	O
controls	O
(	O
P	O
<	O
=	O
0	O
.	O
004	O
;	O
data	O
not	O
shown	O
)	O
.	O

Correlations	O
between	O
BLyS	O
parameters	O
and	O
plasma	O
immunoglobulin	O
levels	O

BLyS	O
is	O
a	O
potent	O
B	O
cell	O
survival	O
factor	O
[	O
15	O
-	O
21	O
]	O
,	O
and	O
administration	O
of	O
exogenous	O
BLyS	O
to	O
mice	B
leads	O
to	O
B	O
cell	O
expansion	O
and	O
hypergammaglobulinem	O
[	O
1	O
]	O
.	O

Previous	O
studies	O
with	O
numbers	O
of	O
SLE	O
patients	B
greater	O
than	O
were	O
included	O
in	O
the	O
present	O
study	O
documented	O
a	O
modest	O
but	O
significant	O
correlation	O
between	O
serum	O
levels	O
of	O
BLyS	O
and	O
IgG	O
[	O
8	O
,	O
10	O
]	O
.	O

In	O
our	O
SLE	O
cohort	O
of	O
limited	O
size	O
,	O
plasma	O
BLyS	O
levels	O
failed	O
to	O
show	O
significant	O
correlations	O
with	O
plasma	O
levels	O
of	O
total	O
immunoglobulin	O
,	O
IgG	O
,	O
or	O
IgA	O
.	O

In	O
contrast	O
,	O
full	O
-	O
length	O
BLyS	O
and	O
Delta	O
BLyS	O
mRNA	O
levels	O
correlated	O
significantly	O
with	O
each	O
(	O
Figure	O
2	O
)	O
.	O

(	O
None	O
of	O
the	O
BLyS	O
parameters	O
correlated	O
with	O
plasma	O
IgM	O
levels	O
.	O
)	O
The	O
absence	O
of	O
significant	O
correlation	O
between	O
plasma	O
BLyS	O
levels	O
and	O
the	O
immunoglobulin	O
parameters	O
also	O
persisted	O
when	O
just	O
the	O
53	O
patients	B
with	O
detectable	O
plasma	O
BLyS	O
levels	O
were	O
considered	O
(	O
r	O
=	O
-	O
0	O
.	O
133	O
,	O
P	O
=	O
0	O
.	O
346	O
for	O
total	O
immunoglobulin	O
;	O
r	O
=	O
-	O
0	O
.	O
048	O
,	O
P	O
=	O
0	O
.	O
734	O
for	O
IgG	O
;	O
and	O
r	O
=	O
0	O
.	O
033	O
,	O
P	O
=	O
0	O
.	O
817	O
for	O
IgA	O
)	O
.	O

Correlations	O
between	O
BLyS	O
parameters	O
and	O
disease	O
activity	O

Previous	O
studies	O
either	O
have	O
failed	O
to	O
demonstrate	O
a	O
significant	O
correlation	O
between	O
disease	O
activity	O
and	O
circulating	O
BLyS	O
levels	O
[	O
7	O
-	O
9	O
]	O
or	O
have	O
detected	O
only	O
a	O
weak	O
correlation	O
between	O
the	O
two	O
[	O
10	O
]	O
.	O

Consonant	O
with	O
those	O
studies	O
,	O
we	O
identified	O
no	O
significant	O
correlation	O
between	O
plasma	O
BLyS	O
levels	O
and	O
SLEDAI	O
in	O
our	O
cohort	O
of	O
60	O
SLE	O
patients	B
(	O
Figure	O
3a	O
)	O
.	O

The	O
failure	O
to	O
demonstrate	O
a	O
significant	O
correlation	O
cannot	O
be	O
attributed	O
to	O
a	O
skewing	O
of	O
the	O
results	O
by	O
the	O
patients	B
in	O
whom	O
plasma	O
BLyS	O
levels	O
were	O
below	O
the	O
limit	O
of	O
detection	O
,	O
because	O
no	O
significant	O
correlation	O
was	O
detected	O
among	O
the	O
53	O
SLE	O
patients	B
in	O
whom	O
plasma	O
BLyS	O
levels	O
were	O
in	O
the	O
detectable	O
range	O
(	O
r	O
=	O
0	O
.	O
185	O
,	O
P	O
=	O
0	O
.	O
183	O
)	O
.	O

In	O
contrast	O
,	O
a	O
significant	O
correlation	O
between	O
SLEDAI	O
and	O
full	O
-	O
length	O
BLyS	O
mRNA	O
levels	O
was	O
readily	O
discernible	O
(	O
Figure	O
3b	O
)	O
.	O

A	O
trend	O
toward	O
a	O
correlation	O
between	O
SLEDAI	O
and	O
Delta	O
BLyS	O
mRNA	O
levels	O
was	O
also	O
observed	O
,	O
although	O
it	O
did	O
not	O
achieve	O
statistical	O
significance	O
(	O
Figure	O
3c	O
)	O
.	O

A	O
component	O
of	O
the	O
SLEDAI	O
is	O
the	O
presence	O
of	O
circulating	O
anti	O
-	O
dsDNA	O
antibodies	O
.	O

Because	O
circulating	O
BLyS	O
levels	O
may	O
affect	O
the	O
presence	O
and	O
/	O
or	O
titers	O
of	O
circulating	O
anti	O
-	O
dsDNA	O
antibodies	O
[	O
7	O
-	O
10	O
]	O
,	O
we	O
assessed	O
correlations	O
between	O
the	O
individual	O
BLyS	O
parameters	O
and	O
a	O
modified	O
SLEDAI	O
that	O
excludes	O
any	O
consideration	O
of	O
anti	O
-	O
dsDNA	O
antibodies	O
.	O

As	O
with	O
the	O
unmodified	O
SLEDAI	O
,	O
the	O
modified	O
SLEDAI	O
did	O
not	O
correlate	O
with	O
plasma	O
BLyS	O
levels	O
(	O
Figure	O
3d	O
)	O
either	O
among	O
the	O
SLE	O
cohort	O
overall	O
or	O
among	O
the	O
53	O
patients	B
in	O
whom	O
plasma	O
BLyS	O
levels	O
were	O
in	O
the	O
detectable	O
range	O
(	O
r	O
=	O
0	O
.	O
160	O
,	O
P	O
=	O
0	O
.	O
252	O
)	O
,	O
but	O
it	O
significantly	O
correlated	O
with	O
full	O
-	O
length	O
BLyS	O
mRNA	O
levels	O
(	O
Figure	O
3e	O
)	O
and	O
exhibited	O
a	O
trend	O
toward	O
correlation	O
with	O
Delta	O
BLyS	O
mRNA	O
levels	O
(	O
Figure	O
3f	O
)	O
.	O

Thus	O
,	O
the	O
stronger	O
correlations	O
between	O
BLyS	O
mRNA	O
levels	O
and	O
disease	O
activity	O
cannot	O
solely	O
be	O
explained	O
by	O
any	O
effects	O
that	O
BLyS	O
may	O
have	O
on	O
anti	O
-	O
dsDNA	O
antibodies	O
per	O
se	O
.	O

Moreover	O
,	O
among	O
the	O
37	O
SLE	O
patients	B
who	O
were	O
evaluated	O
on	O
two	O
separate	O
occasions	O
,	O
trends	O
toward	O
correlation	O
were	O
appreciated	O
between	O
changes	O
in	O
the	O
unmodified	O
or	O
modified	O
SLEDAI	O
and	O
changes	O
in	O
full	O
-	O
length	O
BLyS	O
or	O
Delta	O
BLyS	O
mRNA	O
levels	O
but	O
not	O
changes	O
in	O
plasma	O
BLyS	O
levels	O
(	O
Figure	O
4	O
)	O
.	O

These	O
results	O
cannot	O
be	O
ascribed	O
to	O
changes	O
in	O
medications	O
taken	O
by	O
the	O
patients	B
,	O
because	O
changes	O
in	O
neither	O
disease	O
activity	O
nor	O
in	O
any	O
of	O
the	O
BLyS	O
parameters	O
correlated	O
with	O
changes	O
in	O
the	O
doses	O
of	O
corticosteroids	O
or	O
cytotoxics	O
taken	O
by	O
the	O
patients	B
(	O
data	O
not	O
shown	O
)	O
.	O

The	O
failure	O
to	O
demonstrate	O
a	O
meaningful	O
association	O
between	O
changes	O
in	O
SLEDAI	O
score	O
and	O
changes	O
in	O
plasma	O
BLyS	O
protein	O
levels	O
cannot	O
be	O
attributed	O
to	O
a	O
skewing	O
of	O
the	O
results	O
by	O
the	O
patients	B
in	O
whom	O
plasma	O
BLyS	O
levels	O
were	O
below	O
the	O
limit	O
of	O
detection	O
,	O
because	O
the	O
absence	O
of	O
association	O
between	O
the	O
two	O
persisted	O
among	O
the	O
27	O
SLE	O
patients	B
in	O
whom	O
plasma	O
BLyS	O
levels	O
were	O
in	O
the	O
detectable	O
range	O
in	O
both	O
samples	O
(	O
r	O
=	O
-	O
0	O
.	O
069	O
,	O
P	O
=	O
0	O
.	O
727	O
for	O
plasma	O
BLyS	O
versus	O
unmodified	O
SLEDAI	O
;	O
r	O
=	O
-	O
0	O
.	O
020	O
,	O
P	O
=	O
0	O
.	O
919	O
for	O
plasma	O
BLyS	O
versus	O
modified	O
SLEDAI	O
)	O
.	O

Lack	O
of	O
correlation	O
between	O
levels	O
of	O
BLyS	O
mRNA	O
isoforms	O
and	O
percentages	O
of	O
individual	O
leukocyte	O
cell	O
types	O

Among	O
cells	O
in	O
peripheral	O
blood	O
,	O
BLyS	O
is	O
predominantly	O
expressed	O
by	O
cells	O
of	O
the	O
myeloid	O
lineage	O
(	O
monocytes	O
and	O
neutrophils	O
)	O
[	O
1	O
,	O
14	O
,	O
22	O
,	O
23	O
]	O
.	O

Accordingly	O
,	O
a	O
shift	O
in	O
the	O
differential	O
leukocyte	O
count	O
away	O
from	O
lymphocytes	O
to	O
monocytes	O
and	O
/	O
or	O
neutrophils	O
could	O
substantially	O
alter	O
BLyS	O
mRNA	O
results	O
.	O

Because	O
of	O
the	O
limited	O
amount	O
of	O
blood	O
we	O
were	O
permitted	O
to	O
obtain	O
from	O
the	O
SLE	O
patients	B
(	O
consequent	O
to	O
the	O
high	O
prevalence	O
of	O
anemia	O
among	O
these	O
patients	B
)	O
,	O
we	O
were	O
unable	O
to	O
purify	O
the	O
individual	O
leukocyte	O
populations	O
for	O
BLyS	O
mRNA	O
analysis	O
.	O

Nevertheless	O
,	O
to	O
demonstrate	O
that	O
the	O
elevated	O
BLyS	O
mRNA	O
levels	O
in	O
SLE	O
did	O
not	O
simply	O
reflect	O
a	O
shift	O
in	O
differential	O
leukocyte	O
count	O
,	O
we	O
assessed	O
the	O
correlations	O
between	O
the	O
individual	O
BLyS	O
parameters	O
on	O
the	O
one	O
hand	O
and	O
the	O
percentages	O
of	O
blood	O
neutrophils	O
,	O
monocytes	O
,	O
and	O
lymphocytes	O
on	O
the	O
other	O
.	O

No	O
correlations	O
were	O
appreciated	O
(	O
Figure	O
5	O
)	O
.	O

Presence	O
of	O
anti	O
-	O
BLyS	O
autoantibodies	O
in	O
patients	B
with	O
systemic	O
lupus	O
erythematosus	O

The	O
poorer	O
correlation	O
between	O
plasma	O
BLyS	O
protein	O
levels	O
and	O
disease	O
activity	O
compared	O
with	O
that	O
between	O
BLyS	O
mRNA	O
levels	O
and	O
disease	O
activity	O
was	O
striking	O
.	O

Patients	B
with	O
SLE	O
frequently	O
develop	O
autoantibodies	O
against	O
self	O
-	O
antigens	O
,	O
and	O
so	O
some	O
of	O
the	O
SLE	O
patients	B
might	O
have	O
harbored	O
autoantibodies	O
to	O
BLyS	O
.	O

Such	O
autoantibodies	O
could	O
have	O
complexed	O
with	O
BLyS	O
and	O
enhanced	O
its	O
clearance	O
,	O
thereby	O
masking	O
BLyS	O
overproduction	O
.	O

Alternatively	O
,	O
such	O
autoantibodies	O
might	O
have	O
sterically	O
blocked	O
the	O
epitopes	O
recognized	O
by	O
the	O
detecting	O
antibodies	O
in	O
the	O
in	O
vitro	O
ELISA	O
.	O

In	O
this	O
case	O
,	O
measured	O
BLyS	O
levels	O
would	O
have	O
been	O
spuriously	O
reduced	O
,	O
again	O
masking	O
BLyS	O
overproduction	O
.	O

In	O
our	O
cohort	O
,	O
IgA	O
/	O
IgM	O
/	O
IgG	O
anti	O
-	O
BLyS	O
antibodies	O
were	O
detected	O
in	O
six	O
out	O
of	O
the	O
60	O
SLE	O
patients	B
.	O

Such	O
autoantibodies	O
were	O
also	O
detected	O
in	O
two	O
out	O
of	O
60	O
RA	O
patients	B
and	O
in	O
one	O
out	O
of	O
30	O
normal	O
control	O
individuals	O
,	O
demonstrating	O
that	O
anti	O
-	O
BLyS	O
autoantibodies	O
are	O
not	O
restricted	O
to	O
SLE	O
patients	B
.	O

IgG	O
anti	O
-	O
BLyS	O
autoantibodies	O
were	O
detected	O
in	O
3	O
SLE	O
patients	B
but	O
in	O
no	O
RA	O
patients	B
or	O
normal	O
control	O
individuals	O
.	O

Discussion	O

Elevated	O
blood	O
levels	O
of	O
BLyS	O
protein	O
and	O
mRNA	O
are	O
well	O
described	O
features	O
of	O
human	B
SLE	O
[	O
7	O
-	O
9	O
]	O
.	O

We	O
confirmed	O
these	O
observations	O
in	O
our	O
study	O
and	O
extended	O
them	O
by	O
documenting	O
increases	O
not	O
just	O
in	O
levels	O
of	O
full	O
-	O
length	O
BLyS	O
mRNA	O
but	O
also	O
in	O
levels	O
of	O
Delta	O
BLyS	O
mRNA	O
(	O
Figure	O
1	O
)	O
.	O

Of	O
note	O
,	O
BLyS	O
mRNA	O
levels	O
were	O
elevated	O
in	O
SLE	O
but	O
not	O
in	O
RA	O
,	O
raising	O
the	O
possibility	O
that	O
BLyS	O
overproduction	O
in	O
SLE	O
is	O
systemic	O
whereas	O
BLyS	O
overproduction	O
in	O
RA	O
may	O
be	O
more	O
focused	O
to	O
the	O
affected	O
arthritic	O
joints	O
[	O
24	O
]	O
.	O

The	O
modestly	O
elevated	O
plasma	O
BLyS	O
protein	O
levels	O
in	O
RA	O
patients	B
may	O
reflect	O
,	O
at	O
least	O
in	O
part	O
,	O
release	O
of	O
locally	O
overproduced	O
BLyS	O
into	O
the	O
circulation	O
.	O

The	O
relationship	O
between	O
circulating	O
BLyS	O
protein	O
levels	O
and	O
disease	O
activity	O
was	O
addressed	O
in	O
several	O
previous	O
studies	O
,	O
but	O
significant	O
correlations	O
between	O
the	O
two	O
measures	O
did	O
not	O
emerge	O
[	O
7	O
-	O
9	O
]	O
.	O

In	O
the	O
largest	O
study	O
to	O
date	O
,	O
a	O
2	O
-	O
year	O
longitudinal	O
study	O
of	O
245	O
patients	B
in	O
which	O
more	O
than	O
1	O
,	O
700	O
plasma	O
samples	O
were	O
analyzed	O
,	O
a	O
significant	O
but	O
weak	O
correlation	O
between	O
the	O
two	O
was	O
appreciated	O
[	O
10	O
]	O
.	O

In	O
the	O
present	O
study	O
,	O
a	O
significant	O
correlation	O
between	O
plasma	O
BLyS	O
protein	O
levels	O
and	O
disease	O
activity	O
was	O
again	O
not	O
realized	O
(	O
Figure	O
3a	O
,	O
d	O
)	O
.	O

The	O
weak	O
,	O
at	O
best	O
,	O
correlation	O
between	O
circulating	O
BLyS	O
levels	O
and	O
disease	O
activity	O
is	O
seemingly	O
rather	O
surprising	O
.	O

There	O
is	O
a	O
clear	O
-	O
cut	O
association	O
in	O
BlyS	O
transgenic	O
mice	B
between	O
BLyS	O
overexpression	O
and	O
development	O
of	O
SLE	O
-	O
like	O
features	O
[	O
3	O
-	O
5	O
]	O
,	O
and	O
treatment	O
of	O
SLE	O
-	O
prone	O
mice	B
with	O
BLyS	O
antagonists	O
retards	O
the	O
progression	O
of	O
disease	O
and	O
improves	O
survival	O
[	O
3	O
,	O
6	O
]	O
.	O

Moreover	O
,	O
development	O
of	O
precocious	O
glomerular	O
pathology	O
in	O
autoimmune	O
-	O
prone	O
mice	B
correlates	O
strongly	O
with	O
circulating	O
BLyS	O
levels	O
[	O
25	O
]	O
.	O

The	O
likely	O
explanation	O
for	O
the	O
weak	O
correlation	O
between	O
circulating	O
BLyS	O
levels	O
and	O
disease	O
activity	O
in	O
human	B
SLE	O
is	O
not	O
that	O
disease	O
activity	O
in	O
SLE	O
patients	B
is	O
insensitive	O
to	O
the	O
degree	O
of	O
BLyS	O
overproduction	O
.	O

Rather	O
,	O
a	O
more	O
tenable	O
explanation	O
is	O
that	O
circulating	O
BLyS	O
levels	O
in	O
human	B
SLE	O
do	O
not	O
always	O
accurately	O
reflect	O
excessive	O
endogenous	O
BLyS	O
production	O
.	O

We	O
can	O
identify	O
at	O
least	O
three	O
nonmutually	O
exclusive	O
mechanisms	O
to	O
explain	O
a	O
dissociation	O
between	O
the	O
two	O
.	O

First	O
,	O
SLE	O
patients	B
frequently	O
develop	O
autoantibodies	O
to	O
a	O
myriad	O
of	O
self	O
-	O
targets	O
(	O
for	O
example	O
,	O
erythrocytes	O
,	O
lymphocytes	O
)	O
.	O

Indeed	O
,	O
we	O
detected	O
circulating	O
IgA	O
/	O
IgM	O
/	O
IgG	O
anti	O
-	O
BLyS	O
autoantibodies	O
in	O
10	O
%	O
(	O
6	O
/	O
60	O
)	O
of	O
the	O
tested	O
SLE	O
patients	B
,	O
and	O
we	O
detected	O
circulating	O
IgG	O
anti	O
-	O
BLyS	O
autoantibodies	O
in	O
5	O
%	O
(	O
3	O
/	O
60	O
)	O
.	O

These	O
percentages	O
may	O
be	O
underestimates	O
of	O
the	O
true	O
prevalence	O
of	O
anti	O
-	O
BLyS	O
autoantibodies	O
,	O
because	O
some	O
of	O
these	O
autoantibodies	O
may	O
be	O
saturated	O
in	O
vivo	O
with	O
circulating	O
BLyS	O
,	O
rendering	O
them	O
incapable	O
of	O
binding	O
to	O
BLyS	O
in	O
the	O
in	O
vitro	O
detection	O
assay	O
.	O

We	O
do	O
not	O
yet	O
know	O
whether	O
the	O
anti	O
-	O
BLyS	O
autoantibodies	O
are	O
functionally	O
neutralizing	O
but	O
,	O
regardless	O
,	O
such	O
autoantibodies	O
could	O
enhance	O
the	O
clearance	O
of	O
BLyS	O
and	O
/	O
or	O
interfere	O
with	O
in	O
vitro	O
detection	O
of	O
BLyS	O
,	O
thereby	O
masking	O
endogenous	O
BLyS	O
overproduction	O
.	O

Second	O
,	O
increased	O
urinary	O
excretion	O
of	O
BLyS	O
has	O
been	O
reported	O
in	O
SLE	O
patients	B
,	O
especially	O
among	O
those	O
with	O
clinically	O
overt	O
renal	O
involvement	O
[	O
26	O
]	O
.	O

At	O
least	O
four	O
of	O
the	O
patients	B
we	O
studied	O
manifested	O
nephrotic	O
-	O
range	O
proteinuria	O
(	O
>	O
=	O
3	O
g	O
/	O
24	O
hours	O
)	O
,	O
and	O
so	O
urinary	O
loss	O
of	O
BLyS	O
was	O
probably	O
substantial	O
in	O
at	O
least	O
these	O
patients	B
.	O

A	O
validated	O
assay	O
for	O
urinary	O
BLyS	O
detection	O
has	O
not	O
yet	O
been	O
developed	O
so	O
we	O
were	O
unable	O
to	O
quantify	O
urinary	O
BLyS	O
levels	O
.	O

Once	O
an	O
assay	O
for	O
urinary	O
BLyS	O
levels	O
is	O
validated	O
,	O
we	O
should	O
be	O
able	O
to	O
assess	O
the	O
effect	O
of	O
urinary	O
BLyS	O
excretion	O
on	O
circulating	O
BLyS	O
levels	O
.	O

Third	O
,	O
BLyS	O
promotes	O
in	O
vivo	O
expansion	O
of	O
B	O
cells	O
[	O
1	O
]	O
.	O

Freshly	O
isolated	O
SLE	O
B	O
cells	O
,	O
despite	O
intact	O
surface	O
expression	O
of	O
BLyS	O
receptors	O
,	O
bind	O
less	O
biotinylated	O
BLyS	O
ex	O
vivo	O
than	O
do	O
freshly	O
isolated	O
normal	O
B	O
cells	O
[	O
27	O
]	O
.	O

Although	O
other	O
interpretations	O
are	O
possible	O
,	O
the	O
most	O
likely	O
explanation	O
is	O
that	O
BLyS	O
receptors	O
on	O
B	O
cells	O
in	O
SLE	O
patients	B
are	O
occupied	O
in	O
vivo	O
by	O
soluble	O
BLyS	O
.	O

Accordingly	O
,	O
it	O
is	O
likely	O
that	O
BLyS	O
receptors	O
expressed	O
by	O
the	O
expanded	O
B	O
cell	O
population	O
do	O
bind	O
BLyS	O
and	O
remove	O
it	O
from	O
the	O
circulation	O
,	O
resulting	O
in	O
a	O
homeostatic	O
pathway	O
that	O
modulates	O
the	O
effects	O
of	O
BLyS	O
overproduction	O
on	O
circulating	O
BLyS	O
levels	O
.	O

Indeed	O
,	O
circulating	O
levels	O
of	O
BLyS	O
rise	O
with	O
peripheral	O
blood	O
B	O
cell	O
depletion	O
and	O
fall	O
with	O
re	O
-	O
emergence	O
of	O
peripheral	O
blood	O
B	O
cells	O
in	O
rituximab	O
-	O
treated	O
RA	O
or	O
SLE	O
patients	B
[	O
28	O
,	O
29	O
]	O
,	O
highlighting	O
this	O
inverse	O
relationship	O
between	O
circulating	O
BLyS	O
levels	O
and	O
B	O
cell	O
load	O
.	O

Moreover	O
,	O
one	O
of	O
the	O
hallmarks	O
of	O
active	O
disease	O
in	O
human	B
SLE	O
is	O
the	O
increased	O
percentages	O
of	O
activated	O
B	O
cells	O
and	O
plasma	O
cells	O
in	O
peripheral	O
blood	O
[	O
30	O
-	O
34	O
]	O
,	O
probably	O
reflecting	O
increased	O
systemic	O
numbers	O
of	O
activated	O
B	O
cells	O
and	O
plasma	O
cells	O
.	O

Although	O
not	O
yet	O
formally	O
tested	O
,	O
differential	O
BLyS	O
receptor	O
expression	O
by	O
these	O
cells	O
compared	O
with	O
expression	O
by	O
nonactivated	O
B	O
cells	O
may	O
result	O
in	O
increased	O
peripheral	O
BLyS	O
utilization	O
,	O
further	O
dampening	O
the	O
effects	O
of	O
BLyS	O
overproduction	O
on	O
circulating	O
protein	O
levels	O
.	O

To	O
circumvent	O
these	O
confounding	O
processes	O
,	O
we	O
used	O
BLyS	O
mRNA	O
levels	O
as	O
a	O
surrogate	O
marker	O
of	O
endogenous	O
BLyS	O
production	O
.	O

Overall	O
,	O
the	O
correlations	O
between	O
disease	O
activity	O
and	O
either	O
full	O
-	O
length	O
BLyS	O
or	O
Delta	O
BLyS	O
mRNA	O
levels	O
were	O
much	O
stronger	O
than	O
that	O
between	O
disease	O
activity	O
and	O
BLyS	O
protein	O
levels	O
(	O
Figures	O
3	O
and	O
4	O
)	O
.	O

This	O
was	O
the	O
case	O
regardless	O
of	O
whether	O
we	O
used	O
the	O
standard	O
SLEDAI	O
or	O
the	O
modified	O
SLEDAI	O
as	O
a	O
measure	O
of	O
disease	O
activity	O
.	O

These	O
correlations	O
were	O
not	O
spurious	O
ones	O
consequent	O
to	O
shifts	O
in	O
percentages	O
of	O
leukocyte	O
subpopulations	O
in	O
peripheral	O
blood	O
,	O
because	O
BLyS	O
mRNA	O
levels	O
did	O
not	O
correlate	O
with	O
percentages	O
of	O
blood	O
neutrophils	O
,	O
monocytes	O
,	O
or	O
lymphocytes	O
(	O
Figure	O
5	O
)	O
.	O

A	O
similar	O
pattern	O
was	O
observed	O
between	O
plasma	O
immunoglobulin	O
levels	O
and	O
the	O
BLyS	O
parameters	O
,	O
with	O
plasma	O
levels	O
of	O
total	O
immunoglobulin	O
,	O
IgG	O
,	O
and	O
IgA	O
correlating	O
significantly	O
with	O
full	O
-	O
length	O
BLyS	O
and	O
Delta	O
BLyS	O
mRNA	O
levels	O
but	O
not	O
with	O
plasma	O
BLyS	O
levels	O
(	O
Figure	O
2	O
)	O
.	O

These	O
significant	O
correlations	O
between	O
full	O
-	O
length	O
BLyS	O
or	O
Delta	O
BLyS	O
mRNA	O
levels	O
and	O
plasma	O
immunoglobulin	O
levels	O
again	O
highlight	O
the	O
greater	O
ability	O
of	O
BLyS	O
mRNA	O
levels	O
,	O
compared	O
with	O
plasma	O
BLyS	O
protein	O
levels	O
,	O
to	O
reflect	O
ongoing	O
BLyS	O
overproduction	O
.	O

At	O
present	O
,	O
it	O
is	O
not	O
known	O
whether	O
soluble	O
Delta	O
BLyS	O
protein	O
is	O
present	O
in	O
the	O
circulation	O
of	O
SLE	O
patients	B
or	O
of	O
normal	O
individuals	O
.	O

Although	O
full	O
-	O
length	O
BLyS	O
protein	O
is	O
readily	O
cleaved	O
and	O
released	O
from	O
cells	O
transfected	O
with	O
a	O
vector	O
containing	O
murine	B
full	O
-	O
length	O
BLyS	O
,	O
Delta	O
BLyS	O
protein	O
is	O
not	O
cleaved	O
or	O
released	O
from	O
murine	B
Delta	O
BLyS	O
transfectants	O
[	O
11	O
]	O
.	O

Given	O
the	O
strong	O
similarities	O
between	O
murine	B
and	O
human	B
full	O
-	O
length	O
BLyS	O
and	O
Delta	O
BLyS	O
,	O
it	O
is	O
likely	O
that	O
human	B
soluble	O
Delta	O
BLyS	O
protein	O
is	O
also	O
not	O
cleaved	O
from	O
the	O
cell	O
surface	O
and	O
released	O
into	O
the	O
circulation	O
.	O

Moreover	O
,	O
soluble	O
Delta	O
BLyS	O
protein	O
is	O
not	O
released	O
from	O
cells	O
transfected	O
with	O
a	O
vector	O
containing	O
just	O
the	O
extracellular	O
domain	O
of	O
human	B
Delta	O
BLyS	O
(	O
which	O
encodes	O
the	O
soluble	O
protein	O
;	O
A	O
.	O
L	O
.	O
Gavin	O
,	O
unpublished	O
observations	O
)	O
.	O

Whether	O
this	O
reflects	O
rapid	O
intracellular	O
degradation	O
of	O
soluble	O
Delta	O
BLyS	O
or	O
some	O
other	O
impediment	O
to	O
its	O
release	O
remains	O
unknown	O
.	O

Regardless	O
,	O
if	O
the	O
inability	O
to	O
release	O
soluble	O
Delta	O
BLyS	O
in	O
vitro	O
faithfully	O
recapitulates	O
in	O
vivo	O
biology	O
,	O
then	O
the	O
stronger	O
associations	O
between	O
SLE	O
disease	O
activity	O
and	O
full	O
-	O
length	O
BLyS	O
or	O
Delta	O
BLyS	O
mRNA	O
levels	O
compared	O
with	O
that	O
between	O
SLE	O
disease	O
activity	O
and	O
BLyS	O
protein	O
levels	O
could	O
not	O
be	O
attributable	O
to	O
interference	O
by	O
biologically	O
inactive	O
(	O
inhibitory	O
)	O
Delta	O
BLyS	O
protein	O
in	O
the	O
BLyS	O
protein	O
detection	O
ELISA	O
.	O

Importantly	O
,	O
even	O
if	O
soluble	O
Delta	O
BLyS	O
protein	O
is	O
present	O
in	O
the	O
circulation	O
and	O
is	O
detected	O
by	O
the	O
BLyS	O
protein	O
detection	O
ELISA	O
,	O
then	O
the	O
stronger	O
correlations	O
between	O
SLE	O
disease	O
activity	O
and	O
full	O
-	O
length	O
BLyS	O
or	O
Delta	O
BLyS	O
mRNA	O
levels	O
than	O
that	O
between	O
disease	O
activity	O
and	O
total	O
BLyS	O
(	O
including	O
Delta	O
BLyS	O
)	O
protein	O
levels	O
suggest	O
that	O
full	O
-	O
length	O
BLyS	O
and	O
/	O
or	O
Delta	O
BLyS	O
mRNA	O
levels	O
may	O
operationally	O
serve	O
as	O
useful	O
biomarkers	O
of	O
disease	O
activity	O
in	O
SLE	O
.	O

Although	O
the	O
complexity	O
and	O
labor	O
intensiveness	O
associated	O
with	O
quantitative	O
real	O
-	O
time	O
PCR	O
may	O
render	O
measurement	O
of	O
BLyS	O
mRNA	O
levels	O
impracticable	O
for	O
routine	O
clinical	O
practice	O
,	O
such	O
measurement	O
could	O
readily	O
be	O
incorporated	O
into	O
clinical	O
trials	O
and	O
yield	O
valuable	O
information	O
.	O

Longitudinal	O
observations	O
in	O
large	O
numbers	O
of	O
SLE	O
patients	B
will	O
be	O
necessary	O
to	O
establish	O
or	O
refute	O
the	O
utility	O
of	O
full	O
-	O
length	O
BLyS	O
and	O
/	O
or	O
Delta	O
BLyS	O
mRNA	O
to	O
subserve	O
this	O
clinically	O
vital	O
function	O
.	O

Although	O
expression	O
of	O
the	O
two	O
major	O
BLyS	O
isoforms	O
was	O
highly	O
coordinate	O
among	O
SLE	O
patients	B
,	O
there	O
were	O
several	O
patients	B
in	O
whom	O
Delta	O
BLyS	O
mRNA	O
levels	O
were	O
markedly	O
greater	O
than	O
or	O
less	O
than	O
the	O
expected	O
values	O
based	O
on	O
full	O
-	O
length	O
BLyS	O
mRNA	O
levels	O
(	O
data	O
not	O
shown	O
)	O
.	O

This	O
raises	O
the	O
possibility	O
that	O
dysregulation	O
of	O
Delta	O
BLyS	O
may	O
contribute	O
to	O
overall	O
BLyS	O
dysregulation	O
in	O
at	O
least	O
some	O
SLE	O
patients	B
.	O

It	O
is	O
known	O
that	O
interferon	O
-	O
gamma	O
,	O
interleukin	O
-	O
10	O
,	O
interferon	O
-	O
alpha	O
,	O
and	O
CD154	O
can	O
upregulate	O
full	O
-	O
length	O
BLyS	O
mRNA	O
levels	O
[	O
14	O
,	O
22	O
,	O
35	O
]	O
,	O
but	O
it	O
is	O
not	O
known	O
what	O
effects	O
these	O
or	O
other	O
cytokines	O
/	O
cell	O
-	O
surface	O
structures	O
have	O
on	O
Delta	O
BLyS	O
expression	O
.	O

Further	O
investigation	O
of	O
the	O
regulation	O
of	O
Delta	O
BLyS	O
and	O
the	O
differential	O
expression	O
of	O
BLyS	O
isoforms	O
is	O
certainly	O
warranted	O
.	O

Although	O
the	O
associations	O
between	O
full	O
-	O
length	O
BLyS	O
and	O
/	O
or	O
Delta	O
BLyS	O
mRNA	O
levels	O
and	O
disease	O
activity	O
in	O
SLE	O
were	O
usually	O
strong	O
when	O
the	O
SLE	O
cohort	O
was	O
analyzed	O
in	O
aggregate	O
,	O
there	O
were	O
several	O
SLE	O
patients	B
in	O
whom	O
BLyS	O
mRNA	O
levels	O
were	O
quite	O
high	O
despite	O
little	O
objective	O
ongoing	O
disease	O
activity	O
,	O
and	O
there	O
were	O
several	O
SLE	O
patients	B
in	O
whom	O
BLyS	O
mRNA	O
levels	O
were	O
low	O
despite	O
considerable	O
ongoing	O
disease	O
activity	O
.	O

One	O
must	O
recognize	O
that	O
the	O
bulk	O
of	O
the	O
pathogenic	O
autoimmune	O
responses	O
probably	O
takes	O
place	O
in	O
the	O
spleen	O
and	O
lymph	O
nodes	O
,	O
rather	O
than	O
in	O
the	O
peripheral	O
blood	O
,	O
where	O
myeloid	O
lineage	O
cells	O
(	O
for	O
example	O
,	O
dendritic	O
cells	O
)	O
produce	O
BLyS	O
and	O
support	O
B	O
cell	O
survival	O
and	O
expansion	O
[	O
36	O
]	O
.	O

Local	O
BLyS	O
production	O
in	O
the	O
secondary	O
lymphoid	O
tissues	O
will	O
be	O
more	O
important	O
to	O
the	O
development	O
and	O
maintenance	O
of	O
an	O
autoimmune	O
response	O
than	O
will	O
remote	O
BLyS	O
levels	O
in	O
the	O
circulation	O
.	O

Because	O
at	O
least	O
some	O
autoreactive	O
B	O
cells	O
may	O
be	O
more	O
sensitive	O
to	O
BLyS	O
-	O
mediated	O
survival	O
signals	O
than	O
non	O
-	O
autoreactive	O
B	O
cells	O
[	O
37	O
,	O
38	O
]	O
,	O
local	O
increases	O
in	O
BLyS	O
production	O
could	O
preferentially	O
promote	O
expansion	O
of	O
autoreactive	O
B	O
cells	O
.	O

These	O
cells	O
,	O
in	O
turn	O
,	O
could	O
activate	O
autoreactive	O
T	O
cells	O
by	O
presenting	O
autoantigen	O
to	O
them	O
,	O
and	O
some	O
of	O
the	O
autoreactive	O
B	O
cells	O
would	O
respond	O
to	O
T	O
cell	O
derived	O
signals	O
and	O
mature	O
into	O
(	O
pathogenic	O
)	O
autoantibody	O
secreting	O
plasma	O
cells	O
.	O

In	O
contrast	O
to	O
murine	B
studies	O
,	O
in	O
which	O
investigators	O
can	O
readily	O
harvest	O
and	O
analyze	O
lymphoid	O
and	O
myeloid	O
lineage	O
cells	O
from	O
any	O
site	O
(	O
for	O
example	O
,	O
spleen	O
,	O
bone	O
marrow	O
)	O
,	O
such	O
is	O
not	O
the	O
case	O
for	O
human	B
studies	O
.	O

Peripheral	O
blood	O
is	O
the	O
only	O
site	O
readily	O
accessible	O
for	O
human	B
studies	O
,	O
and	O
it	O
is	O
possible	O
that	O
,	O
at	O
least	O
in	O
some	O
patients	B
,	O
BLyS	O
mRNA	O
levels	O
in	O
circulating	O
leukocytes	O
do	O
not	O
reflect	O
local	O
BLyS	O
production	O
in	O
the	O
secondary	O
lymphoid	O
tissues	O
.	O

One	O
must	O
also	O
recognize	O
that	O
disease	O
activity	O
in	O
SLE	O
is	O
not	O
solely	O
driven	O
by	O
B	O
cells	O
.	O

Systemic	O
inflammation	O
and	O
SLE	O
flares	O
can	O
be	O
triggered	O
via	O
B	O
cell	O
independent	O
means	O
.	O

Not	O
all	O
SLE	O
patients	B
treated	O
with	O
a	O
B	O
cell	O
depleting	O
course	O
of	O
rituximab	O
experience	O
clinical	O
remission	O
[	O
39	O
]	O
,	O
strongly	O
pointing	O
to	O
the	O
importance	O
of	O
non	O
-	O
B	O
cells	O
in	O
disease	O
pathogenesis	O
/	O
maintenance	O
.	O

Conversely	O
,	O
not	O
all	O
pathogenic	O
B	O
cells	O
necessarily	O
require	O
high	O
levels	O
of	O
BLyS	O
to	O
effect	O
their	O
pathogenicity	O
.	O

Murine	O
studies	O
have	O
unequivocally	O
documented	O
B	O
cell	O
subpopulations	O
that	O
do	O
not	O
depend	O
upon	O
BLyS	O
for	O
their	O
survival	O
[	O
40	O
-	O
42	O
]	O
.	O

Although	O
mice	B
completely	O
devoid	O
of	O
BLyS	O
have	O
reduced	O
numbers	O
of	O
mature	O
B	O
cells	O
and	O
harbor	O
reduced	O
levels	O
of	O
immunoglobulin	O
,	O
these	O
reductions	O
are	O
incomplete	O
.	O

Thus	O
,	O
it	O
is	O
possible	O
that	O
some	O
SLE	O
patients	B
harbor	O
pathogenic	O
B	O
cells	O
that	O
are	O
relatively	O
insensitive	O
to	O
BLyS	O
and	O
could	O
drive	O
considerable	O
disease	O
activity	O
even	O
in	O
the	O
context	O
of	O
low	O
endogenous	O
BLyS	O
production	O
.	O

Conversely	O
,	O
patients	B
with	O
high	O
BLyS	O
mRNA	O
levels	O
may	O
be	O
those	O
patients	B
whose	O
disease	O
is	O
strongly	O
driven	O
by	O
BLyS	O
and	O
may	O
be	O
especially	O
helped	O
by	O
BLyS	O
antagonist	O
therapy	O
.	O

Future	O
clinical	O
trials	O
should	O
be	O
able	O
to	O
establish	O
whether	O
the	O
BLyS	O
mRNA	O
levels	O
are	O
good	O
predictors	O
of	O
response	O
to	O
such	O
agents	O
.	O

Conclusion	O

Plasma	O
total	O
immunoglobulin	O
,	O
IgG	O
,	O
and	O
IgA	O
levels	O
and	O
disease	O
activity	O
(	O
as	O
measured	O
by	O
SLEDAI	O
)	O
in	O
SLE	O
patients	B
correlate	O
more	O
closely	O
with	O
peripheral	O
blood	O
leukocyte	O
levels	O
of	O
BLyS	O
mRNA	O
than	O
with	O
plasma	O
levels	O
of	O
BLyS	O
protein	O
.	O

These	O
findings	O
suggest	O
that	O
BLyS	O
mRNA	O
levels	O
better	O
reflect	O
in	O
vivo	O
BLyS	O
production	O
than	O
do	O
circulating	O
BLyS	O
protein	O
levels	O
,	O
and	O
may	O
be	O
a	O
useful	O
biomarker	O
in	O
the	O
clinical	O
monitoring	O
of	O
SLE	O
patients	B
.	O

These	O
findings	O
also	O
support	O
the	O
premise	O
that	O
BLyS	O
overexpression	O
not	O
only	O
promotes	O
development	O
of	O
disease	O
but	O
also	O
actively	O
contributes	O
to	O
the	O
ongoing	O
maintenance	O
of	O
disease	O
in	O
SLE	O
patients	B
.	O

This	O
reinforces	O
the	O
rationale	O
underlying	O
clinical	O
trials	O
with	O
BLyS	O
antagonists	O
in	O
SLE	O
.	O

Abbreviations	O

anti	O
-	O
dsDNA	O
=	O
anti	O
-	O
double	O
-	O
stranded	O
DNA	O
;	O
BLyS	O
=	O
B	O
lymphocyte	O
stimulator	O
;	O
bp	O
=	O
base	O
pairs	O
;	O
Ct	O
=	O
threshold	O
cycle	O
;	O
ELISA	O
=	O
enzyme	O
-	O
linked	O
immunosorbent	O
assay	O
;	O
PCR	O
=	O
polymerase	O
chain	O
reaction	O
;	O
RA	O
=	O
rheumatoid	O
arthritis	O
;	O
SLE	O
=	O
systemic	O
lupus	O
erythematosus	O
;	O
SLEDAI	O
=	O
SLE	O
Disease	O
Activity	O
Index	O
.	O

Competing	O
interests	O

TSM	O
and	O
DMH	O
were	O
employees	O
of	O
Human	B
Genome	O
Sciences	O
(	O
HGS	O
)	O
at	O
the	O
time	O
the	O
investigation	O
was	O
conducted	O
.	O

(	O
DMH	O
has	O
since	O
left	O
the	O
company	O
.	O
)	O
WS	O
has	O
received	O
research	O
support	O
from	O
HGS	O
and	O
has	O
served	O
as	O
a	O
consultant	O
to	O
HGS	O
(	O
<	O
$	O
10	O
,	O
000	O
)	O
.	O

CEC	O
,	O
ALG	O
,	O
and	O
DN	O
declare	O
that	O
they	O
have	O
no	O
competing	O
interests	O
.	O

Authors	O
'	O
contributions	O

CEC	O
identified	O
and	O
recruited	O
all	O
participants	B
;	O
collected	O
all	O
the	O
blood	O
samples	O
and	O
reviewed	O
all	O
the	O
medical	O
charts	O
;	O
and	O
wrote	O
the	O
initial	O
working	O
draft	O
of	O
this	O
manuscript	O
.	O

ALG	O
developed	O
and	O
performed	O
all	O
the	O
real	O
-	O
time	O
PCR	O
assays	O
and	O
assisted	O
in	O
the	O
interpretation	O
of	O
the	O
results	O
and	O
in	O
writing	O
the	O
final	O
version	O
of	O
the	O
manuscript	O
.	O

TSM	O
performed	O
the	O
plasma	O
BLyS	O
protein	O
and	O
anti	O
-	O
BLyS	O
assays	O
and	O
assisted	O
in	O
the	O
interpretation	O
of	O
the	O
results	O
and	O
in	O
writing	O
the	O
final	O
version	O
of	O
the	O
manuscript	O
.	O

DMH	O
assisted	O
in	O
the	O
design	O
in	O
the	O
study	O
,	O
in	O
the	O
interpretation	O
of	O
the	O
results	O
,	O
and	O
in	O
writing	O
the	O
final	O
version	O
of	O
the	O
manuscript	O
.	O

DN	O
assisted	O
in	O
the	O
design	O
in	O
the	O
study	O
,	O
in	O
the	O
interpretation	O
of	O
the	O
results	O
,	O
and	O
in	O
writing	O
the	O
final	O
version	O
of	O
the	O
manuscript	O
.	O

WS	O
conceived	O
the	O
study	O
,	O
supervised	O
the	O
recruitment	O
of	O
participants	B
,	O
performed	O
the	O
statistical	O
analyses	O
,	O
assisted	O
in	O
the	O
interpretation	O
of	O
the	O
results	O
,	O
and	O
supervised	O
the	O
editing	O
of	O
the	O
manuscript	O
to	O
its	O
final	O
form	O
.	O

All	O
authors	O
read	O
and	O
approved	O
the	O
final	O
manuscript	O
version	O
.	O

Travel	O
-	O
Related	O
Venous	O
Thrombosis	O
:	O
Results	O
from	O
a	O
Large	O
Population	O
-	O
Based	O
Case	O
Control	O
Study	O
(	O
MEGA	O
Study	O
)	O

Abstract	O

Background	O

Recent	O
studies	O
have	O
indicated	O
an	O
increased	O
risk	O
of	O
venous	O
thrombosis	O
after	O
air	O
travel	O
.	O

Nevertheless	O
,	O
questions	O
on	O
the	O
magnitude	O
of	O
risk	O
,	O
the	O
underlying	O
mechanism	O
,	O
and	O
modifying	O
factors	O
remain	O
unanswered	O
.	O

Methods	O
and	O
Findings	O

We	O
studied	O
the	O
effect	O
of	O
various	O
modes	O
and	O
duration	O
of	O
travel	O
on	O
the	O
risk	O
of	O
venous	O
thrombosis	O
in	O
a	O
large	O
ongoing	O
case	O
-	O
control	O
study	O
on	O
risk	O
factors	O
for	O
venous	O
thrombosis	O
in	O
an	O
unselected	O
population	O
(	O
MEGA	O
study	O
)	O
.	O

We	O
also	O
assessed	O
the	O
combined	O
effect	O
of	O
travel	O
and	O
prothrombotic	O
mutations	O
,	O
body	O
mass	O
index	O
,	O
height	O
,	O
and	O
oral	O
contraceptive	O
use	O
.	O

Since	O
March	O
1999	O
,	O
consecutive	O
patients	B
younger	O
than	O
70	O
y	O
with	O
a	O
first	O
venous	O
thrombosis	O
have	O
been	O
invited	O
to	O
participate	O
in	O
the	O
study	O
,	O
with	O
their	O
partners	O
serving	O
as	O
matched	O
control	O
individuals	O
.	O

Information	O
has	O
been	O
collected	O
on	O
acquired	O
and	O
genetic	O
risk	O
factors	O
for	O
venous	O
thrombosis	O
.	O

Of	O
1	O
,	O
906	O
patients	B
,	O
233	O
had	O
traveled	O
for	O
more	O
than	O
4	O
h	O
in	O
the	O
8	O
wk	O
preceding	O
the	O
event	O
.	O

Traveling	O
in	O
general	O
was	O
found	O
to	O
increase	O
the	O
risk	O
of	O
venous	O
thrombosis	O
2	O
-	O
fold	O
(	O
odds	O
ratio	O
[	O
OR	O
]	O
2	O
.	O
1	O
;	O
95	O
%	O
confidence	O
interval	O
[	O
CI	O
]	O
1	O
.	O
5	O
-	O
3	O
.	O
0	O
)	O
.	O

The	O
risk	O
of	O
flying	O
was	O
similar	O
to	O
the	O
risks	O
of	O
traveling	O
by	O
car	O
,	O
bus	O
,	O
or	O
train	O
.	O

The	O
risk	O
was	O
highest	O
in	O
the	O
first	O
week	O
after	O
traveling	O
.	O

Travel	O
by	O
car	O
,	O
bus	O
,	O
or	O
train	O
led	O
to	O
a	O
high	O
relative	O
risk	O
of	O
thrombosis	O
in	O
individuals	O
with	O
factor	O
V	O
Leiden	O
(	O
OR	O
8	O
.	O
1	O
;	O
95	O
%	O
CI	O
2	O
.	O
7	O
-	O
24	O
.	O
7	O
)	O
,	O
in	O
those	O
who	O
had	O
a	O
body	O
mass	O
index	O
of	O
more	O
than	O
30	O
kg	O
/	O
m2	O
(	O
OR	O
9	O
.	O
9	O
;	O
95	O
%	O
CI	O
3	O
.	O
6	O
-	O
27	O
.	O
6	O
)	O
,	O
in	O
those	O
who	O
were	O
more	O
than	O
1	O
.	O
90	O
m	O
tall	O
(	O
OR	O
4	O
.	O
7	O
;	O
95	O
%	O
CI	O
1	O
.	O
4	O
-	O
15	O
.	O
4	O
)	O
,	O
and	O
in	O
those	O
who	O
used	O
oral	O
contraceptives	O
(	O
estimated	O
OR	O
>	O
20	O
)	O
.	O

For	O
air	O
travel	O
these	O
synergistic	O
findings	O
were	O
more	O
apparent	O
,	O
while	O
people	B
shorter	O
than	O
1	O
.	O
60	O
m	O
had	O
an	O
increased	O
risk	O
of	O
thrombosis	O
after	O
air	O
travel	O
(	O
OR	O
4	O
.	O
9	O
;	O
95	O
%	O
CI	O
0	O
.	O
9	O
-	O
25	O
.	O
6	O
)	O
as	O
well	O
.	O

Conclusions	O

The	O
risk	O
of	O
venous	O
thrombosis	O
after	O
travel	O
is	O
moderately	O
increased	O
for	O
all	O
modes	O
of	O
travel	O
.	O

Subgroups	O
exist	O
in	O
which	O
the	O
risk	O
is	O
highly	O
increased	O
.	O

Background	O
.	O

Recently	O
there	O
has	O
been	O
increasing	O
concern	O
that	O
blood	O
clots	O
(	O
thromboses	O
)	O
in	O
the	O
leg	O
or	O
lungs	O
occur	O
with	O
greater	O
frequency	O
after	O
air	O
travel	O
.	O

Several	O
theories	O
have	O
been	O
put	O
forward	O
to	O
explain	O
why	O
this	O
increase	O
might	O
happen	O
,	O
including	O
the	O
fact	O
that	O
air	O
passengers	O
tend	O
to	O
not	O
move	O
around	O
much	O
,	O
or	O
possibly	O
that	O
reduced	O
amounts	O
of	O
oxygen	O
in	O
the	O
blood	O
make	O
the	O
blood	O
more	O
likely	O
to	O
clot	O
.	O

Understanding	O
what	O
causes	O
such	O
clots	O
is	O
important	O
as	O
it	O
would	O
help	O
us	O
come	O
up	O
with	O
suggestions	O
of	O
ways	O
to	O
prevent	O
them	O
.	O

Why	O
Was	O
This	O
Study	O
Done	O
?	O

It	O
is	O
not	O
possible	O
to	O
test	O
in	O
a	O
controlled	O
trial	O
whether	O
travel	O
causes	O
an	O
increase	O
in	O
blood	O
clots	O
,	O
so	O
the	O
next	O
best	O
way	O
of	O
studying	O
this	O
problem	O
is	O
to	O
do	O
a	O
case	O
-	O
control	O
study	O
,	O
in	O
which	O
people	B
with	O
blood	O
clots	O
(	O
cases	O
)	O
are	O
compared	O
with	O
similar	O
people	B
who	O
don	O
'	O
t	O
have	O
a	O
blood	O
clot	O
(	O
controls	O
-	O
-	O
in	O
this	O
case	O
,	O
the	O
partners	O
of	O
the	O
cases	O
)	O
,	O
and	O
the	O
differences	O
in	O
a	O
number	O
of	O
contributing	O
factors	O
are	O
assessed	O
.	O

What	O
Did	O
the	O
Researchers	O
Do	O
and	O
Find	O
?	O

Since	O
1999	O
,	O
the	O
MEGA	O
(	O
Multiple	O
Environmental	O
and	O
Genetic	O
Assessment	O
of	O
Risk	O
Factors	O
for	O
Venous	O
Thrombosis	O
)	O
study	O
has	O
aimed	O
to	O
identify	O
all	O
people	B
in	O
an	O
area	O
of	O
the	O
Netherlands	O
who	O
develop	O
a	O
blood	O
clot	O
for	O
the	O
first	O
time	O
,	O
by	O
seeking	O
out	O
people	B
who	O
receive	O
treatment	O
for	O
blood	O
clots	O
.	O

At	O
the	O
time	O
of	O
this	O
report	O
,	O
1	O
,	O
906	O
people	B
with	O
clots	O
had	O
been	O
found	O
;	O
of	O
these	O
,	O
233	O
had	O
traveled	O
for	O
more	O
than	O
four	O
hours	O
in	O
the	O
eight	O
weeks	O
preceding	O
the	O
event	O
.	O

Traveling	O
in	O
general	O
was	O
found	O
to	O
increase	O
the	O
risk	O
of	O
clots	O
two	O
-	O
fold	O
,	O
and	O
the	O
risk	O
was	O
highest	O
in	O
the	O
week	O
after	O
traveling	O
.	O

The	O
risk	O
of	O
flying	O
was	O
similar	O
to	O
the	O
risk	O
of	O
traveling	O
by	O
car	O
,	O
bus	O
,	O
or	O
train	O
,	O
and	O
was	O
highest	O
in	O
the	O
first	O
week	O
after	O
traveling	O
.	O

Certain	O
other	O
factors	O
increased	O
the	O
risk	O
of	O
a	O
blood	O
clot	O
even	O
more	O
,	O
such	O
as	O
having	O
a	O
particular	O
mutation	O
(	O
known	O
as	O
factor	O
V	O
Leiden	O
)	O
in	O
a	O
gene	O
involved	O
in	O
blood	O
clotting	O
,	O
having	O
a	O
body	O
mass	O
index	O
of	O
more	O
than	O
30	O
kg	O
/	O
m2	O
(	O
over	O
30	O
kg	O
/	O
m2	O
is	O
defined	O
as	O
being	O
obese	O
)	O
,	O
being	O
more	O
than	O
1	O
.	O
90	O
meters	O
tall	O
,	O
and	O
using	O
oral	O
contraceptives	O
.	O

All	O
these	O
factors	O
made	O
the	O
risk	O
of	O
clots	O
especially	O
after	O
air	O
travel	O
worse	O
;	O
in	O
addition	O
,	O
people	B
shorter	O
than	O
1	O
.	O
60	O
meters	O
also	O
had	O
an	O
increased	O
risk	O
of	O
thrombosis	O
after	O
air	O
travel	O
.	O

However	O
,	O
it	O
should	O
be	O
borne	O
in	O
mind	O
that	O
the	O
number	O
of	O
cases	O
in	O
each	O
of	O
these	O
various	O
groups	O
was	O
quite	O
small	O
,	O
and	O
the	O
overall	O
risk	O
of	O
getting	O
a	O
thrombosis	O
is	O
still	O
low	O
.	O

What	O
Do	O
These	O
Findings	O
Mean	O
?	O

Since	O
the	O
risks	O
of	O
thrombosis	O
are	O
increased	O
for	O
all	O
types	O
of	O
long	O
travel	O
,	O
it	O
seems	O
that	O
the	O
main	O
factor	O
causing	O
the	O
thrombosis	O
is	O
immobility	O
.	O

However	O
,	O
since	O
the	O
risk	O
is	O
even	O
higher	O
for	O
air	O
travel	O
,	O
the	O
relative	O
lack	O
of	O
oxygen	O
may	O
also	O
play	O
a	O
part	O
.	O

One	O
interesting	O
aspect	O
of	O
this	O
study	O
is	O
that	O
the	O
researchers	O
used	O
partners	O
as	O
controls	O
;	O
in	O
order	O
to	O
be	O
sure	O
that	O
doing	O
this	O
did	O
not	O
make	O
the	O
results	O
invalid	O
,	O
the	O
researchers	O
had	O
to	O
carefully	O
adjust	O
for	O
differences	O
between	O
the	O
cases	O
and	O
controls	O
,	O
such	O
as	O
the	O
fact	O
that	O
partners	O
were	O
generally	O
of	O
the	O
opposite	O
sex	O
.	O

In	O
a	O
related	O
Perspective	O
(	O
DOI	O
:	O
10	O
.	O
1371	O
/	O
journal	O
.	O
pmed	O
.	O
0030300	O
)	O
,	O
Kenneth	O
Rothman	O
discusses	O
the	O
study	O
further	O
.	O

Additional	O
Information	O
.	O

Please	O
access	O
these	O
Web	O
sites	O
via	O
the	O
online	O
version	O
of	O
this	O
summary	O
at	O
http	O
:	O
/	O
/	O
dx	O
.	O
doi	O
.	O
org	O
/	O
10	O
.	O
1371	O
/	O
journal	O
.	O
pmed	O
.	O
0030307	O
.	O

Introduction	O

Interest	O
in	O
the	O
role	O
of	O
air	O
travel	O
in	O
the	O
pathogenesis	O
of	O
venous	O
thrombosis	O
has	O
heightened	O
in	O
the	O
past	O
5	O
y	O
[	O
1	O
-	O
5	O
]	O
.	O

Venous	O
thrombosis	O
was	O
first	O
linked	O
to	O
air	O
travel	O
in	O
1954	O
[	O
6	O
]	O
,	O
and	O
as	O
air	O
travel	O
has	O
become	O
more	O
and	O
more	O
common	O
,	O
many	O
case	O
reports	O
and	O
case	O
series	O
have	O
been	O
published	O
since	O
.	O

Several	O
clinical	O
studies	O
have	O
shown	O
an	O
association	O
between	O
air	O
travel	O
and	O
the	O
risk	O
of	O
venous	O
thrombosis	O
.	O

In	O
a	O
series	O
of	O
individuals	O
who	O
died	O
suddenly	O
at	O
Heathrow	O
Airport	O
,	O
death	O
occurred	O
far	O
more	O
often	O
in	O
the	O
arrival	O
than	O
in	O
the	O
departure	O
area	O
[	O
7	O
]	O
.	O

Two	O
similar	O
studies	O
described	O
a	O
"	O
dose	O
-	O
response	O
"	O
relation	O
:	O
the	O
risk	O
of	O
pulmonary	O
embolism	O
in	O
air	O
travelers	O
increased	O
with	O
the	O
distance	O
traveled	O
[	O
5	O
,	O
8	O
]	O
.	O

A	O
number	O
of	O
case	O
-	O
control	O
studies	O
,	O
however	O
,	O
have	O
shown	O
conflicting	O
results	O
[	O
9	O
-	O
11	O
]	O
.	O

More	O
recently	O
,	O
a	O
2	O
-	O
fold	O
increased	O
risk	O
in	O
patients	B
who	O
had	O
traveled	O
by	O
air	O
was	O
described	O
in	O
a	O
case	O
-	O
control	O
study	O
among	O
210	O
patients	B
and	O
210	O
controls	O
[	O
3	O
]	O
.	O

A	O
case	O
-	O
crossover	O
study	O
based	O
on	O
record	O
linking	O
in	O
Australia	O
described	O
a	O
4	O
-	O
fold	O
increased	O
risk	O
of	O
venous	O
thrombosis	O
in	O
the	O
first	O
2	O
wk	O
after	O
a	O
long	O
-	O
haul	O
flight	O
[	O
1	O
]	O
.	O

In	O
terms	O
of	O
absolute	O
risk	O
,	O
two	O
studies	O
found	O
similar	O
results	O
:	O
one	O
performed	O
in	O
New	O
Zealand	O
found	O
a	O
frequency	O
of	O
1	O
%	O
of	O
venous	O
thrombosis	O
in	O
878	O
individuals	O
who	O
had	O
traveled	O
by	O
air	O
for	O
at	O
least	O
10	O
h	O
[	O
2	O
]	O
,	O
and	O
a	O
German	O
study	O
found	O
venous	O
thrombotic	O
events	O
in	O
2	O
.	O
8	O
%	O
of	O
964	O
individuals	O
who	O
had	O
traveled	O
for	O
more	O
than	O
8	O
h	O
in	O
an	O
airplane	O
,	O
as	O
compared	O
to	O
1	O
%	O
in	O
1	O
,	O
213	O
controls	O
[	O
4	O
]	O
.	O

The	O
events	O
in	O
both	O
studies	O
were	O
mostly	O
asymptomatic	O
.	O

The	O
available	O
evidence	O
suggests	O
that	O
the	O
overall	O
risk	O
of	O
venous	O
thrombosis	O
is	O
moderately	O
increased	O
after	O
air	O
travel	O
.	O

Nevertheless	O
,	O
many	O
questions	O
remain	O
unanswered	O
:	O
the	O
exact	O
underlying	O
mechanism	O
is	O
still	O
unknown	O
,	O
and	O
,	O
related	O
to	O
this	O
,	O
it	O
is	O
not	O
clear	O
whether	O
the	O
risk	O
is	O
increased	O
after	O
air	O
travel	O
only	O
or	O
after	O
long	O
-	O
distance	O
travel	O
in	O
general	O
.	O

Furthermore	O
,	O
the	O
effect	O
of	O
the	O
combination	O
of	O
other	O
risk	O
factors	O
for	O
venous	O
thrombosis	O
and	O
travel	O
has	O
not	O
yet	O
been	O
systematically	O
studied	O
,	O
with	O
the	O
exception	O
of	O
a	O
study	O
by	O
Martinelli	O
et	O
al	O
.	O
,	O
who	O
found	O
an	O
additionally	O
increased	O
risk	O
in	O
patients	B
with	O
thrombophilia	O
and	O
patients	B
who	O
used	O
oral	O
contraceptives	O
[	O
3	O
]	O
.	O

The	O
Multiple	O
Environmental	O
and	O
Genetic	O
Assessment	O
(	O
MEGA	O
)	O
study	O
of	O
risk	O
factors	O
for	O
venous	O
thrombosis	O
is	O
a	O
large	O
ongoing	O
case	O
-	O
control	O
study	O
aimed	O
at	O
assessing	O
the	O
combined	O
effect	O
of	O
genetic	O
and	O
acquired	O
risk	O
factors	O
for	O
venous	O
thrombosis	O
.	O

Cases	O
and	O
control	O
individuals	O
are	O
questioned	O
about	O
-	O
-	O
among	O
many	O
other	O
items	O
-	O
-	O
travel	O
that	O
occurred	O
shortly	O
before	O
the	O
event	O
.	O

This	O
provides	O
an	O
opportunity	O
to	O
assess	O
the	O
effect	O
of	O
travel	O
on	O
the	O
risk	O
of	O
thrombosis	O
in	O
an	O
unselected	O
population	O
,	O
as	O
well	O
as	O
the	O
effect	O
of	O
the	O
combination	O
of	O
travel	O
with	O
several	O
other	O
risk	O
factors	O
for	O
thrombosis	O
.	O

Methods	O

Study	O
Design	O

Since	O
March	O
1999	O
,	O
consecutive	O
patients	B
younger	O
than	O
70	O
y	O
with	O
a	O
first	O
deep	O
-	O
vein	O
thrombosis	O
(	O
DVT	O
)	O
or	O
pulmonary	O
embolism	O
(	O
PE	O
)	O
have	O
been	O
identified	O
at	O
six	O
regional	O
anticoagulation	O
clinics	O
in	O
the	O
Netherlands	O
.	O

Anticoagulant	O
clinics	O
monitor	O
the	O
anticoagulant	O
therapy	O
of	O
all	O
patients	B
in	O
a	O
well	O
-	O
defined	O
geographical	O
area	O
,	O
allowing	O
us	O
to	O
identify	O
consecutive	O
and	O
unselected	O
patients	B
with	O
thrombosis	O
.	O

Patients	B
who	O
were	O
unable	O
to	O
fill	O
in	O
the	O
questionnaire	O
(	O
because	O
of	O
language	O
or	O
severe	O
psychiatric	O
problems	O
)	O
,	O
as	O
well	O
as	O
those	O
who	O
died	O
soon	O
after	O
the	O
venous	O
thrombosis	O
or	O
who	O
were	O
in	O
the	O
end	O
stage	O
of	O
a	O
disease	O
and	O
for	O
that	O
reason	O
did	O
not	O
participate	O
,	O
were	O
not	O
included	O
.	O

All	O
others	O
were	O
considered	O
eligible	O
.	O

Partners	O
of	O
these	O
patients	B
were	O
invited	O
as	O
control	O
individuals	O
,	O
and	O
the	O
same	O
exclusion	O
criteria	O
were	O
applied	O
.	O

All	O
participants	B
filled	O
in	O
a	O
detailed	O
standardized	O
questionnaire	O
on	O
general	O
demographic	O
and	O
anthropomorphic	O
characteristics	O
,	O
as	O
well	O
as	O
risk	O
factors	O
for	O
venous	O
thrombosis	O
.	O

The	O
questionnaire	O
was	O
sent	O
to	O
all	O
participants	B
within	O
a	O
few	O
weeks	O
after	O
the	O
event	O
and	O
covered	O
the	O
period	O
of	O
1	O
y	O
prior	O
to	O
the	O
date	O
of	O
the	O
thrombotic	O
event	O
(	O
index	O
date	O
)	O
.	O

When	O
the	O
participant	B
was	O
unable	O
to	O
fill	O
in	O
the	O
questionnaire	O
we	O
asked	O
questions	O
by	O
phone	O
,	O
using	O
a	O
standardized	O
mini	O
-	O
questionnaire	O
.	O

Three	O
months	O
after	O
the	O
patients	B
had	O
discontinued	O
their	O
oral	O
anticoagulant	O
therapy	O
,	O
they	O
were	O
invited	O
with	O
their	O
partners	O
to	O
the	O
anticoagulation	O
clinic	O
for	O
a	O
blood	O
sample	O
.	O

In	O
those	O
patients	B
who	O
continued	O
to	O
take	O
oral	O
anticoagulant	O
therapy	O
for	O
more	O
than	O
1	O
y	O
after	O
the	O
event	O
,	O
blood	O
was	O
drawn	O
during	O
therapy	O
.	O

If	O
participants	B
were	O
unable	O
to	O
come	O
to	O
the	O
clinic	O
,	O
a	O
buccal	O
swab	O
was	O
sent	O
by	O
mail	O
to	O
replace	O
the	O
blood	O
sample	O
for	O
DNA	O
extraction	O
.	O

The	O
study	O
protocol	O
was	O
approved	O
by	O
the	O
Ethics	O
Committee	O
of	O
the	O
Leiden	O
University	O
Medical	O
Center	O
.	O

Written	O
informed	O
consent	O
was	O
obtained	O
from	O
all	O
participants	B
[	O
12	O
]	O
.	O

Validation	O
Study	O
of	O
Thrombosis	O
Diagnosis	O

Discharge	O
letters	O
or	O
diagnostic	O
reports	O
of	O
the	O
venous	O
thrombotic	O
event	O
were	O
obtained	O
for	O
a	O
sample	O
of	O
742	O
patients	B
who	O
had	O
their	O
first	O
thrombosis	O
between	O
March	O
1999	O
and	O
March	O
2000	O
.	O

The	O
diagnostic	O
management	O
of	O
the	O
patients	B
was	O
compared	O
to	O
the	O
diagnostic	O
procedure	O
as	O
described	O
in	O
the	O
Dutch	O
consensus	O
[	O
13	O
]	O
.	O

Diagnosis	O
of	O
clinically	O
suspected	O
DVT	O
of	O
the	O
leg	O
is	O
based	O
on	O
a	O
clinical	O
score	O
,	O
serial	O
compression	O
ultrasonography	O
,	O
and	O
D	O
-	O
dimer	O
assay	O
.	O

Objective	O
testing	O
of	O
clinically	O
suspected	O
pulmonary	O
embolism	O
is	O
based	O
on	O
perfusion	O
and	O
ventilation	O
scintigraphy	O
,	O
ultrasonography	O
of	O
the	O
leg	O
veins	O
,	O
pulmonary	O
angiography	O
,	O
or	O
helical	O
computed	O
tomography	O
.	O

Out	O
of	O
395	O
patients	B
with	O
DVT	O
of	O
the	O
leg	O
,	O
384	O
(	O
97	O
%	O
)	O
were	O
objectively	O
diagnosed	O
,	O
while	O
out	O
of	O
347	O
patients	B
with	O
PE	O
,	O
271	O
(	O
78	O
%	O
)	O
were	O
confirmed	O
with	O
objective	O
testing	O
as	O
certainly	O
having	O
PE	O
.	O

Since	O
the	O
diagnosis	O
appears	O
to	O
be	O
made	O
by	O
objective	O
methods	O
in	O
virtually	O
all	O
cases	O
of	O
DVT	O
,	O
while	O
being	O
more	O
ambiguous	O
for	O
PE	O
,	O
we	O
also	O
analyzed	O
these	O
two	O
manifestations	O
of	O
venous	O
thrombosis	O
separately	O
.	O

Current	O
Analysis	O

For	O
the	O
current	O
analysis	O
we	O
were	O
interested	O
in	O
the	O
effects	O
of	O
travel	O
,	O
and	O
its	O
combined	O
effect	O
with	O
other	O
common	O
risk	O
factors	O
for	O
venous	O
thrombosis	O
.	O

Patients	B
with	O
a	O
solitary	O
arm	O
thrombosis	O
were	O
excluded	O
from	O
this	O
analysis	O
.	O

Of	O
3	O
,	O
902	O
eligible	O
cases	O
,	O
diagnosed	O
up	O
to	O
May	O
2002	O
,	O
656	O
did	O
not	O
participate	O
for	O
various	O
reasons	O
(	O
such	O
as	O
not	O
willing	O
or	O
not	O
reachable	O
)	O
,	O
leading	O
to	O
a	O
response	O
of	O
83	O
%	O
.	O

A	O
further	O
3	O
%	O
responded	O
only	O
to	O
the	O
mini	O
-	O
questionnaire	O
,	O
taken	O
by	O
phone	O
,	O
which	O
did	O
not	O
contain	O
questions	O
about	O
travel	O
.	O

Of	O
the	O
remaining	O
3	O
,	O
111	O
cases	O
,	O
78	O
%	O
had	O
a	O
partner	O
,	O
77	O
%	O
of	O
whom	O
were	O
willing	O
to	O
participate	O
,	O
which	O
left	O
1	O
,	O
867	O
couples	O
.	O

Additionally	O
,	O
229	O
partners	O
were	O
identified	O
for	O
whom	O
the	O
corresponding	O
patient	B
originally	O
participated	O
but	O
was	O
later	O
found	O
not	O
to	O
be	O
eligible	O
(	O
aged	O
over	O
70	O
y	O
,	O
or	O
not	O
a	O
first	O
thrombotic	O
event	O
)	O
.	O

These	O
control	O
individuals	O
were	O
matched	O
on	O
sex	O
and	O
5	O
-	O
y	O
age	O
groups	O
to	O
one	O
of	O
the	O
557	O
patients	B
whose	O
partner	O
did	O
not	O
want	O
to	O
participate	O
,	O
so	O
an	O
extra	O
229	O
pairs	O
were	O
included	O
,	O
making	O
a	O
total	O
of	O
4	O
,	O
192	O
participants	B
(	O
2	O
,	O
096	O
pairs	O
)	O
.	O

As	O
part	O
of	O
the	O
general	O
questionnaire	O
,	O
questions	O
had	O
been	O
asked	O
about	O
whether	O
or	O
not	O
respondents	O
had	O
traveled	O
for	O
more	O
than	O
4	O
h	O
in	O
the	O
3	O
mo	O
before	O
the	O
index	O
date	O
,	O
about	O
the	O
travel	O
date	O
,	O
and	O
about	O
mode	O
and	O
duration	O
of	O
travel	O
.	O

We	O
assessed	O
the	O
occurrence	O
of	O
thrombosis	O
in	O
relation	O
to	O
the	O
period	O
of	O
time	O
that	O
had	O
passed	O
since	O
traveling	O
.	O

Travel	O
was	O
defined	O
in	O
the	O
analysis	O
as	O
at	O
least	O
one	O
journey	O
with	O
a	O
duration	O
of	O
at	O
least	O
four	O
uninterrupted	O
hours	O
during	O
the	O
8	O
-	O
wk	O
period	O
before	O
the	O
event	O
.	O

During	O
the	O
analysis	O
it	O
appeared	O
that	O
some	O
individuals	O
had	O
provided	O
dates	O
of	O
travel	O
after	O
the	O
event	O
instead	O
of	O
before	O
.	O

As	O
there	O
was	O
only	O
one	O
opportunity	O
to	O
fill	O
in	O
such	O
a	O
date	O
,	O
we	O
had	O
no	O
information	O
about	O
the	O
period	O
before	O
the	O
event	O
.	O

This	O
was	O
the	O
case	O
in	O
88	O
cases	O
and	O
146	O
controls	O
.	O

We	O
excluded	O
these	O
individuals	O
and	O
their	O
partners	O
,	O
which	O
left	O
3	O
,	O
812	O
participants	B
(	O
1	O
,	O
906	O
pairs	O
)	O
for	O
the	O
analysis	O
.	O

Because	O
we	O
selected	O
the	O
partners	O
of	O
the	O
cases	O
as	O
control	O
individuals	O
,	O
and	O
because	O
it	O
turned	O
out	O
,	O
as	O
expected	O
,	O
that	O
couples	O
tend	O
to	O
travel	O
together	O
,	O
we	O
performed	O
a	O
conditional	O
logistic	O
regression	O
analysis	O
to	O
calculate	O
odds	O
ratios	O
(	O
ORs	O
)	O
for	O
the	O
relation	O
between	O
travel	O
and	O
venous	O
thrombosis	O
.	O

This	O
method	O
fully	O
takes	O
this	O
matching	O
into	O
account	O
,	O
and	O
leads	O
to	O
unbiased	O
estimates	O
,	O
with	O
adjustment	O
for	O
all	O
factors	O
in	O
which	O
cases	O
and	O
controls	O
tend	O
to	O
be	O
similar	O
,	O
e	O
.	O
g	O
.	O
,	O
socioeconomic	O
class	O
[	O
14	O
]	O
.	O

Details	O
of	O
this	O
method	O
can	O
be	O
found	O
in	O
Protocol	O
S1	O
.	O

The	O
95	O
%	O
confidence	O
intervals	O
(	O
CIs	O
)	O
were	O
derived	O
from	O
the	O
model	O
.	O

We	O
assessed	O
the	O
combined	O
effect	O
of	O
traveling	O
and	O
the	O
following	O
risk	O
factors	O
for	O
thrombosis	O
:	O
factor	O
V	O
Leiden	O
mutation	O
,	O
prothrombin	O
G20210A	O
mutation	O
,	O
body	O
mass	O
index	O
(	O
BMI	O
,	O
as	O
kg	O
/	O
m2	O
)	O
,	O
and	O
height	O
.	O

We	O
were	O
also	O
interested	O
in	O
the	O
combined	O
effect	O
of	O
oral	O
contraceptive	O
use	O
and	O
travel	O
.	O

However	O
,	O
as	O
the	O
control	O
individuals	O
were	O
nearly	O
always	O
of	O
the	O
opposite	O
sex	O
(	O
partners	O
of	O
the	O
cases	O
were	O
recruited	O
as	O
controls	O
)	O
,	O
it	O
was	O
not	O
possible	O
to	O
perform	O
a	O
matched	O
analysis	O
for	O
the	O
combination	O
of	O
oral	O
contraceptive	O
use	O
and	O
travel	O
.	O

Therefore	O
,	O
we	O
performed	O
a	O
case	O
-	O
only	O
analysis	O
[	O
15	O
]	O
.	O

This	O
method	O
allows	O
one	O
to	O
examine	O
the	O
association	O
between	O
two	O
exposures	O
among	O
case	O
individuals	O
only	O
.	O

ORs	O
are	O
interpreted	O
as	O
a	O
synergy	O
index	O
(	O
SI	O
)	O
on	O
a	O
multiplicative	O
scale	O
,	O
with	O
independence	O
assumed	O
between	O
the	O
exposures	O
.	O

As	O
this	O
analysis	O
depends	O
only	O
on	O
cases	O
,	O
it	O
was	O
possible	O
to	O
perform	O
it	O
in	O
all	O
consecutive	O
cases	O
,	O
therefore	O
also	O
including	O
those	O
without	O
a	O
partner	O
.	O

Laboratory	O
Measurements	O

Blood	O
was	O
collected	O
from	O
the	O
antecubital	O
vein	O
into	O
vacuum	O
tubes	O
containing	O
0	O
.	O
106	O
mol	O
/	O
l	O
trisodium	O
citrate	O
.	O

High	O
molecular	O
weight	O
DNA	O
was	O
isolated	O
from	O
leukocytes	O
using	O
a	O
standard	O
salting	O
-	O
out	O
procedure	O
[	O
16	O
]	O
and	O
stored	O
at	O
-	O
20	O
degrees	O
C	O
.	O

When	O
a	O
blood	O
sample	O
was	O
not	O
available	O
,	O
DNA	O
was	O
extracted	O
from	O
buccal	O
swabs	O
.	O

Three	O
large	O
cotton	B
swabs	O
in	O
a	O
total	O
of	O
6	O
ml	O
of	O
SDS	O
-	O
proteinase	O
K	O
solution	O
(	O
100	O
mM	O
NaCl	O
,	O
10	O
mM	O
EDTA	O
,	O
10	O
mM	O
Tris	O
-	O
HCl	O
[	O
pH	O
8	O
.	O
0	O
]	O
,	O
0	O
.	O
5	O
%	O
SDS	O
,	O
0	O
.	O
1	O
mg	O
/	O
ml	O
proteinase	O
K	O
)	O
were	O
obtained	O
.	O

Upon	O
arrival	O
,	O
the	O
proteinase	O
K	O
concentration	O
was	O
raised	O
to	O
0	O
.	O
2	O
mg	O
/	O
ml	O
,	O
and	O
the	O
sample	O
was	O
incubated	O
for	O
2	O
h	O
at	O
65	O
degrees	O
C	O
.	O

Subsequently	O
,	O
the	O
solute	O
was	O
recovered	O
by	O
centrifugation	O
.	O

Potassium	O
acetate	O
was	O
added	O
to	O
the	O
supernatant	O
to	O
a	O
final	O
concentration	O
of	O
1	O
.	O
6	O
M	O
.	O

After	O
15	O
min	O
incubation	O
on	O
ice	O
,	O
proteins	O
were	O
removed	O
using	O
chloroform	O
/	O
isomylalcohol	O
(	O
24	O
:	O
1	O
)	O
treatment	O
.	O

The	O
DNA	O
in	O
the	O
water	O
phase	O
was	O
subsequently	O
ethanol	O
precipitated	O
.	O

After	O
centrifugation	O
,	O
the	O
pellet	O
was	O
resuspended	O
in	O
200	O
mu	O
l	O
of	O
10	O
mM	O
Tris	O
-	O
HCl	O
and	O
10	O
mM	O
EDTA	O
(	O
pH	O
8	O
.	O
0	O
)	O
,	O
and	O
frozen	O
at	O
-	O
20	O
degrees	O
C	O
until	O
further	O
analysis	O
.	O

The	O
factor	O
V	O
Leiden	O
mutation	O
(	O
G1691A	O
)	O
and	O
the	O
prothrombin	O
mutation	O
(	O
G20210A	O
)	O
were	O
simultaneously	O
detected	O
by	O
duplex	O
polymerase	O
chain	O
reaction	O
[	O
17	O
,	O
18	O
]	O
.	O

The	O
technician	O
was	O
blinded	O
concerning	O
the	O
origin	O
of	O
the	O
sample	O
,	O
i	O
.	O
e	O
.	O
,	O
whether	O
it	O
was	O
from	O
a	O
patient	B
or	O
from	O
a	O
control	O
individual	O
.	O

Results	O

Venous	O
Thrombosis	O
in	O
Relation	O
to	O
Travel	O

Table	O
1	O
shows	O
general	O
characteristics	O
of	O
the	O
1	O
,	O
906	O
patients	B
.	O

They	O
ranged	O
in	O
age	O
from	O
18	O
to	O
69	O
y	O
(	O
median	O
50	O
.	O
4	O
y	O
)	O
;	O
51	O
%	O
were	O
men	B
.	O

Diagnosis	O
was	O
DVT	O
in	O
57	O
%	O
of	O
the	O
cases	O
,	O
PE	O
in	O
32	O
%	O
,	O
and	O
both	O
in	O
11	O
%	O
.	O

As	O
partners	O
of	O
the	O
cases	O
were	O
included	O
as	O
control	O
individuals	O
,	O
the	O
sex	O
distribution	O
of	O
the	O
control	O
individuals	O
was	O
the	O
opposite	O
;	O
the	O
age	O
distribution	O
differed	O
only	O
trivially	O
.	O

Of	O
the	O
patients	B
,	O
233	O
individuals	O
(	O
12	O
%	O
)	O
had	O
traveled	O
for	O
at	O
least	O
4	O
h	O
by	O
air	O
,	O
bus	O
,	O
car	O
,	O
or	O
train	O
within	O
the	O
8	O
wk	O
preceding	O
the	O
index	O
date	O
,	O
as	O
compared	O
to	O
182	O
of	O
the	O
control	O
individuals	O
(	O
9	O
.	O
5	O
%	O
)	O
.	O

As	O
the	O
cases	O
and	O
control	O
individuals	O
were	O
selected	O
as	O
couples	O
,	O
many	O
pairs	O
(	O
135	O
)	O
had	O
traveled	O
together	O
and	O
were	O
uninformative	O
:	O
as	O
a	O
consequence	O
,	O
145	O
pairs	O
in	O
which	O
either	O
the	O
patient	B
(	O
98	O
)	O
or	O
the	O
control	O
(	O
47	O
)	O
had	O
traveled	O
could	O
be	O
used	O
for	O
the	O
matched	O
analysis	O
(	O
Table	O
2	O
)	O
.	O

This	O
analysis	O
showed	O
a	O
2	O
-	O
fold	O
increased	O
risk	O
of	O
venous	O
thrombosis	O
for	O
all	O
modes	O
of	O
travel	O
combined	O
(	O
OR	O
2	O
.	O
1	O
;	O
95	O
%	O
CI	O
1	O
.	O
5	O
-	O
3	O
.	O
0	O
)	O
compared	O
to	O
not	O
traveling	O
.	O

For	O
air	O
travel	O
alone	O
,	O
49	O
individuals	O
(	O
31	O
cases	O
and	O
18	O
controls	O
)	O
had	O
traveled	O
without	O
their	O
partner	O
,	O
and	O
the	O
analysis	O
yielded	O
an	O
OR	O
of	O
1	O
.	O
7	O
(	O
95	O
%	O
CI	O
1	O
.	O
0	O
-	O
3	O
.	O
1	O
)	O
.	O

For	O
the	O
other	O
modes	O
of	O
travel	O
(	O
car	O
,	O
bus	O
,	O
and	O
train	O
)	O
the	O
relative	O
risks	O
were	O
essentially	O
similar	O
to	O
each	O
other	O
and	O
to	O
that	O
of	O
air	O
travel	O
(	O
Table	O
2	O
)	O
.	O

The	O
risk	O
of	O
venous	O
thrombosis	O
was	O
not	O
clearly	O
related	O
to	O
increased	O
duration	O
of	O
travel	O
(	O
Table	O
2	O
)	O
.	O

Of	O
the	O
233	O
events	O
that	O
occurred	O
within	O
8	O
wk	O
after	O
traveling	O
,	O
68	O
(	O
29	O
%	O
)	O
were	O
diagnosed	O
in	O
the	O
first	O
week	O
,	O
after	O
which	O
the	O
incidence	O
gradually	O
decreased	O
(	O
Figure	O
1	O
)	O
.	O

The	O
Effect	O
of	O
Other	O
Risk	O
Factors	O
Combined	O
with	O
Travel	O

Prothrombotic	O
mutations	O
.	O

Information	O
on	O
the	O
factor	O
V	O
Leiden	O
mutation	O
and	O
prothrombin	O
G20210A	O
genotype	O
was	O
available	O
for	O
1	O
,	O
713	O
patients	B
(	O
90	O
%	O
)	O
and	O
for	O
1	O
,	O
629	O
of	O
the	O
control	O
individuals	O
(	O
85	O
%	O
)	O
.	O

Factor	O
V	O
Leiden	O
was	O
present	O
in	O
259	O
cases	O
(	O
14	O
%	O
)	O
and	O
84	O
control	O
individuals	O
(	O
4	O
%	O
)	O
(	O
OR	O
3	O
.	O
1	O
;	O
95	O
%	O
CI	O
2	O
.	O
4	O
-	O
4	O
.	O
1	O
)	O
.	O

The	O
risk	O
of	O
venous	O
thrombosis	O
was	O
8	O
-	O
fold	O
increased	O
in	O
people	B
with	O
factor	O
V	O
Leiden	O
who	O
had	O
traveled	O
by	O
bus	O
,	O
car	O
,	O
or	O
train	O
(	O
modes	O
combined	O
)	O
as	O
compared	O
to	O
noncarriers	O
who	O
did	O
not	O
travel	O
(	O
OR	O
8	O
.	O
1	O
;	O
95	O
%	O
CI	O
2	O
.	O
7	O
-	O
24	O
.	O
7	O
)	O
.	O

For	O
the	O
combined	O
effect	O
of	O
air	O
travel	O
and	O
factor	O
V	O
Leiden	O
,	O
the	O
risk	O
seemed	O
even	O
slightly	O
higher	O
(	O
OR	O
13	O
.	O
6	O
;	O
95	O
%	O
CI	O
2	O
.	O
9	O
-	O
64	O
.	O
2	O
)	O
.	O

The	O
prothrombin	O
G20210A	O
mutation	O
was	O
found	O
in	O
83	O
cases	O
(	O
4	O
%	O
)	O
and	O
in	O
29	O
control	O
individuals	O
(	O
2	O
%	O
)	O
(	O
OR	O
2	O
.	O
7	O
;	O
95	O
%	O
CI	O
1	O
.	O
7	O
-	O
4	O
.	O
2	O
)	O
.	O

The	O
risk	O
in	O
individuals	O
with	O
this	O
mutation	O
who	O
had	O
traveled	O
was	O
difficult	O
to	O
interpret	O
because	O
of	O
the	O
small	O
numbers	O
but	O
appeared	O
not	O
to	O
increase	O
more	O
than	O
additively	O
(	O
Table	O
3	O
)	O
.	O

BMI	O
.	O

The	O
effect	O
of	O
BMI	O
was	O
studied	O
by	O
dividing	O
individuals	O
into	O
three	O
categories	O
with	O
the	O
following	O
BMI	O
values	O
:	O
<	O
25	O
,	O
25	O
-	O
30	O
,	O
and	O
>	O
30	O
kg	O
/	O
m2	O
[	O
19	O
]	O
.	O

A	O
BMI	O
of	O
25	O
-	O
30	O
kg	O
/	O
m2	O
was	O
associated	O
with	O
an	O
increased	O
risk	O
of	O
venous	O
thrombosis	O
(	O
OR	O
1	O
.	O
4	O
;	O
95	O
%	O
CI	O
1	O
.	O
2	O
-	O
1	O
.	O
7	O
)	O
,	O
and	O
the	O
risk	O
was	O
slightly	O
higher	O
in	O
patients	B
with	O
a	O
BMI	O
of	O
30	O
kg	O
/	O
m2	O
or	O
more	O
(	O
OR	O
1	O
.	O
7	O
;	O
95	O
%	O
CI	O
1	O
.	O
4	O
-	O
2	O
.	O
1	O
)	O
.	O

The	O
combined	O
effect	O
of	O
a	O
higher	O
BMI	O
and	O
travel	O
was	O
the	O
sum	O
of	O
the	O
individual	O
risks	O
(	O
Table	O
3	O
)	O
,	O
with	O
the	O
exception	O
of	O
people	B
with	O
a	O
BMI	O
of	O
more	O
than	O
30	O
kg	O
/	O
m2	O
who	O
traveled	O
by	O
car	O
,	O
bus	O
,	O
or	O
train	O
,	O
for	O
whom	O
the	O
risk	O
was	O
10	O
-	O
fold	O
increased	O
(	O
OR	O
9	O
.	O
9	O
;	O
95	O
%	O
CI	O
3	O
.	O
6	O
-	O
27	O
.	O
6	O
)	O
.	O

This	O
increase	O
in	O
risk	O
was	O
not	O
found	O
in	O
people	B
who	O
traveled	O
by	O
air	O
.	O

Height	O
.	O

Particularly	O
short	O
or	O
tall	O
people	B
may	O
be	O
subjected	O
during	O
travel	O
to	O
even	O
more	O
unnatural	O
sitting	O
positions	O
than	O
individuals	O
with	O
average	O
height	O
.	O

Therefore	O
,	O
we	O
assessed	O
the	O
effect	O
of	O
extremes	O
of	O
heights	O
in	O
combination	O
with	O
travel	O
on	O
the	O
risk	O
of	O
venous	O
thrombosis	O
by	O
comparing	O
short	O
(	O
less	O
than	O
1	O
.	O
60	O
m	O
)	O
and	O
tall	O
individuals	O
(	O
more	O
than	O
1	O
.	O
90	O
m	O
)	O
with	O
people	B
of	O
average	O
height	O
(	O
1	O
.	O
60	O
-	O
1	O
.	O
90	O
m	O
)	O
.	O

Compared	O
to	O
people	B
of	O
average	O
height	O
,	O
the	O
risk	O
of	O
venous	O
thrombosis	O
was	O
lower	O
for	O
short	O
people	B
(	O
OR	O
0	O
.	O
7	O
;	O
95	O
%	O
CI	O
0	O
.	O
5	O
-	O
0	O
.	O
9	O
)	O
and	O
did	O
not	O
differ	O
for	O
very	O
tall	O
individuals	O
(	O
OR	O
0	O
.	O
9	O
;	O
95	O
%	O
CI	O
0	O
.	O
7	O
-	O
1	O
.	O
1	O
)	O
.	O

The	O
risk	O
was	O
found	O
to	O
be	O
increased	O
in	O
people	B
of	O
more	O
than	O
1	O
.	O
90	O
m	O
who	O
traveled	O
(	O
OR	O
4	O
.	O
7	O
;	O
95	O
%	O
CI	O
1	O
.	O
4	O
-	O
15	O
.	O
4	O
for	O
travel	O
by	O
car	O
,	O
bus	O
,	O
or	O
train	O
;	O
OR	O
6	O
.	O
8	O
;	O
95	O
%	O
CI	O
0	O
.	O
8	O
-	O
60	O
.	O
6	O
for	O
air	O
travel	O
)	O
compared	O
to	O
non	O
-	O
traveling	O
people	B
of	O
average	O
height	O
.	O

Interestingly	O
,	O
the	O
risk	O
of	O
venous	O
thrombosis	O
was	O
also	O
increased	O
in	O
short	O
people	B
but	O
only	O
after	O
air	O
travel	O
(	O
OR	O
4	O
.	O
9	O
;	O
95	O
%	O
CI	O
0	O
.	O
9	O
-	O
25	O
.	O
6	O
)	O
,	O
not	O
after	O
other	O
modes	O
of	O
travel	O
(	O
OR	O
1	O
.	O
0	O
;	O
95	O
%	O
CI	O
0	O
.	O
3	O
-	O
2	O
.	O
8	O
,	O
all	O
relative	O
to	O
non	O
-	O
traveling	O
people	B
of	O
average	O
height	O
)	O
.	O

Oral	O
contraception	O
.	O

To	O
study	O
the	O
association	O
between	O
oral	O
contraceptive	O
use	O
,	O
travel	O
,	O
and	O
the	O
risk	O
of	O
venous	O
thrombosis	O
,	O
we	O
performed	O
a	O
case	O
-	O
only	O
analysis	O
in	O
all	O
female	O
patients	B
who	O
were	O
less	O
than	O
50	O
y	O
of	O
age	O
.	O

As	O
we	O
needed	O
only	O
cases	O
,	O
it	O
was	O
also	O
possible	O
to	O
include	O
women	B
without	O
a	O
partner	O
for	O
this	O
analysis	O
,	O
which	O
led	O
to	O
a	O
total	O
of	O
1	O
,	O
025	O
women	B
aged	O
under	O
50	O
.	O

Non	O
-	O
users	O
who	O
did	O
not	O
travel	O
were	O
used	O
as	O
the	O
reference	O
group	O
.	O

The	O
case	O
-	O
only	O
estimate	O
of	O
the	O
SI	O
for	O
women	B
who	O
traveled	O
by	O
car	O
,	O
bus	O
,	O
or	O
train	O
was	O
2	O
.	O
4	O
(	O
95	O
%	O
CI	O
1	O
.	O
5	O
-	O
3	O
.	O
7	O
)	O
.	O

This	O
indicates	O
that	O
the	O
OR	O
for	O
the	O
combination	O
of	O
travel	O
and	O
oral	O
contraceptive	O
use	O
is	O
2	O
.	O
4	O
times	O
the	O
product	O
of	O
the	O
separate	O
ORs	O
.	O

As	O
oral	O
contraceptive	O
use	O
generally	O
increases	O
the	O
risk	O
of	O
venous	O
thrombosis	O
about	O
4	O
-	O
fold	O
[	O
20	O
]	O
,	O
the	O
combination	O
with	O
travel	O
by	O
car	O
,	O
bus	O
,	O
or	O
train	O
would	O
lead	O
to	O
an	O
estimated	O
OR	O
of	O
about	O
20	O
(	O
4	O
x	O
2	O
x	O
2	O
.	O
4	O
)	O
.	O

A	O
clearly	O
stronger	O
interaction	O
of	O
travel	O
by	O
air	O
with	O
oral	O
contraceptive	O
use	O
was	O
found	O
:	O
the	O
case	O
-	O
only	O
estimate	O
of	O
the	O
SI	O
was	O
4	O
.	O
9	O
(	O
95	O
%	O
CI	O
2	O
.	O
1	O
-	O
11	O
.	O
4	O
)	O
,	O
which	O
would	O
result	O
in	O
an	O
OR	O
of	O
about	O
40	O
(	O
4	O
x	O
2	O
x	O
4	O
.	O
9	O
)	O
.	O

Effect	O
of	O
Risk	O
Factors	O
in	O
DVT	O
Patients	B
Only	O

Of	O
the	O
1	O
,	O
906	O
cases	O
,	O
1	O
,	O
082	O
were	O
diagnosed	O
with	O
DVT	O
.	O

As	O
the	O
diagnosis	O
was	O
more	O
unambiguous	O
in	O
these	O
patients	B
(	O
97	O
%	O
objectively	O
diagnosed	O
as	O
compared	O
to	O
78	O
%	O
of	O
the	O
PE	O
patients	B
)	O
,	O
we	O
repeated	O
the	O
analysis	O
in	O
these	O
patients	B
only	O
.	O

In	O
this	O
analysis	O
,	O
the	O
overall	O
effect	O
of	O
travel	O
on	O
the	O
risk	O
of	O
DVT	O
was	O
equal	O
to	O
the	O
effect	O
on	O
all	O
venous	O
thrombosis	O
(	O
DVT	O
and	O
PE	O
combined	O
)	O
.	O

However	O
,	O
here	O
we	O
found	O
a	O
stronger	O
risk	O
for	O
travel	O
by	O
air	O
(	O
OR	O
3	O
.	O
0	O
;	O
95	O
%	O
CI	O
1	O
.	O
3	O
-	O
7	O
.	O
1	O
)	O
then	O
for	O
travel	O
by	O
car	O
,	O
bus	O
,	O
or	O
train	O
(	O
OR	O
1	O
.	O
9	O
;	O
95	O
%	O
CI	O
1	O
.	O
1	O
-	O
3	O
.	O
2	O
)	O
(	O
Table	O
4	O
)	O
.	O

Also	O
,	O
the	O
analysis	O
of	O
the	O
combination	O
of	O
other	O
risk	O
factors	O
with	O
travel	O
resulted	O
in	O
more	O
clear	O
-	O
cut	O
effects	O
,	O
despite	O
the	O
smaller	O
number	O
of	O
cases	O
:	O
the	O
risk	O
of	O
DVT	O
was	O
still	O
clearly	O
synergistically	O
increased	O
in	O
patients	B
with	O
factor	O
V	O
Leiden	O
who	O
traveled	O
,	O
whereas	O
the	O
prothrombin	O
G20210A	O
mutation	O
did	O
not	O
further	O
increase	O
the	O
risk	O
of	O
travel	O
(	O
Table	O
4	O
)	O
.	O

Furthermore	O
,	O
a	O
BMI	O
of	O
more	O
than	O
30	O
kg	O
/	O
m2	O
in	O
combination	O
with	O
travel	O
yielded	O
high	O
ORs	O
for	O
DVT	O
both	O
in	O
people	B
who	O
traveled	O
by	O
car	O
,	O
bus	O
,	O
or	O
train	O
and	O
in	O
those	O
who	O
flew	O
.	O

Being	O
more	O
than	O
1	O
.	O
90	O
m	O
tall	O
in	O
combination	O
with	O
travel	O
resulted	O
in	O
higher	O
ORs	O
for	O
DVT	O
;	O
the	O
risk	O
for	O
short	O
people	B
was	O
more	O
increased	O
after	O
travel	O
by	O
air	O
(	O
OR	O
6	O
.	O
8	O
;	O
95	O
%	O
CI	O
1	O
.	O
1	O
-	O
43	O
.	O
5	O
)	O
(	O
Table	O
4	O
)	O
.	O

The	O
effect	O
of	O
oral	O
contraceptive	O
use	O
in	O
combination	O
with	O
travel	O
by	O
car	O
,	O
bus	O
,	O
or	O
train	O
on	O
the	O
risk	O
of	O
DVT	O
was	O
studied	O
in	O
589	O
women	B
and	O
was	O
somewhat	O
lower	O
than	O
the	O
effect	O
on	O
the	O
risk	O
of	O
all	O
venous	O
thrombosis	O
(	O
SI	O
1	O
.	O
9	O
;	O
95	O
%	O
CI	O
0	O
.	O
9	O
-	O
4	O
.	O
2	O
)	O
.	O

In	O
those	O
who	O
traveled	O
by	O
air	O
it	O
was	O
also	O
a	O
bit	O
lower	O
(	O
SI	O
3	O
.	O
4	O
;	O
95	O
%	O
CI	O
1	O
.	O
3	O
-	O
8	O
.	O
8	O
)	O
,	O
but	O
still	O
indicative	O
of	O
a	O
strong	O
synergistic	O
effect	O
.	O

Discussion	O

In	O
this	O
population	O
-	O
based	O
case	O
-	O
control	O
study	O
,	O
long	O
-	O
distance	O
traveling	O
increased	O
the	O
risk	O
of	O
venous	O
thrombosis	O
2	O
-	O
fold	O
.	O

Travel	O
by	O
air	O
increased	O
the	O
risk	O
to	O
the	O
same	O
extent	O
as	O
travel	O
by	O
car	O
,	O
bus	O
,	O
or	O
train	O
.	O

The	O
risk	O
was	O
highest	O
in	O
the	O
first	O
week	O
after	O
traveling	O
.	O

As	O
venous	O
thrombosis	O
is	O
a	O
disease	O
in	O
which	O
many	O
factors	O
(	O
genetic	O
and	O
acquired	O
)	O
interact	O
[	O
21	O
]	O
,	O
we	O
identified	O
groups	O
with	O
additional	O
risk	O
factors	O
in	O
which	O
the	O
risk	O
was	O
further	O
increased	O
.	O

This	O
was	O
the	O
case	O
for	O
individuals	O
with	O
factor	O
V	O
Leiden	O
,	O
obese	O
people	B
(	O
BMI	O
>	O
30	O
kg	O
/	O
m2	O
)	O
,	O
and	O
short	O
(	O
only	O
for	O
travel	O
by	O
air	O
)	O
and	O
tall	O
people	B
,	O
as	O
well	O
as	O
for	O
women	B
using	O
oral	O
contraceptives	O
.	O

Some	O
of	O
these	O
synergistic	O
effects	O
were	O
more	O
apparent	O
for	O
air	O
travel	O
.	O

Although	O
the	O
studies	O
that	O
have	O
been	O
published	O
so	O
far	O
have	O
not	O
yielded	O
entirely	O
consistent	O
results	O
,	O
those	O
that	O
did	O
report	O
an	O
increased	O
risk	O
of	O
venous	O
thrombosis	O
in	O
air	O
travelers	O
showed	O
similar	O
risk	O
estimates	O
of	O
a	O
2	O
-	O
to	O
3	O
-	O
fold	O
increased	O
risk	O
(	O
even	O
in	O
one	O
with	O
asymptomatic	O
events	O
only	O
[	O
4	O
]	O
)	O
.	O

The	O
occurrence	O
of	O
venous	O
thrombosis	O
was	O
highest	O
in	O
the	O
first	O
week	O
after	O
travel	O
,	O
and	O
slowly	O
declined	O
afterwards	O
,	O
a	O
pattern	O
that	O
was	O
also	O
described	O
in	O
a	O
recent	O
record	O
-	O
linking	O
study	O
from	O
Australia	O
[	O
1	O
]	O
,	O
supporting	O
a	O
causal	O
relation	O
.	O

As	O
a	O
possible	O
mechanism	O
for	O
an	O
extra	O
risk	O
in	O
travelers	O
who	O
fly	O
,	O
an	O
effect	O
of	O
hypobaric	O
hypoxia	O
on	O
the	O
coagulation	O
system	O
was	O
postulated	O
,	O
which	O
has	O
already	O
been	O
studied	O
a	O
number	O
of	O
times	O
,	O
mainly	O
in	O
hypobaric	O
chambers	O
,	O
with	O
unclear	O
results	O
so	O
far	O
.	O

Our	O
study	O
showed	O
an	O
increased	O
risk	O
in	O
all	O
types	O
of	O
travel	O
,	O
which	O
suggests	O
that	O
the	O
increased	O
risk	O
of	O
flying	O
is	O
caused	O
mainly	O
by	O
immobilization	O
.	O

Additionally	O
,	O
the	O
risk	O
is	O
further	O
increased	O
in	O
short	O
and	O
tall	O
people	B
,	O
who	O
are	O
likely	O
to	O
experience	O
more	O
immobilization	O
and	O
venous	O
compression	O
than	O
other	O
travelers	O
.	O

However	O
,	O
as	O
some	O
of	O
our	O
findings	O
were	O
more	O
pronounced	O
for	O
air	O
travel	O
,	O
we	O
cannot	O
exclude	O
an	O
additional	O
effect	O
of	O
hypobaric	O
hypoxia	O
,	O
possibly	O
in	O
risk	O
groups	O
only	O
.	O

This	O
possibility	O
is	O
supported	O
by	O
a	O
recent	O
study	O
of	O
our	O
group	O
[	O
22	O
]	O
in	O
which	O
we	O
found	O
that	O
thrombin	O
generation	O
occurred	O
in	O
some	O
healthy	O
volunteers	O
after	O
flying	O
for	O
8	O
h	O
but	O
happened	O
to	O
a	O
far	O
lesser	O
extent	O
after	O
being	O
immobilized	O
for	O
8	O
h	O
in	O
a	O
cinema	O
.	O

The	O
high	O
response	O
in	O
the	O
fliers	O
was	O
associated	O
with	O
the	O
presence	O
of	O
risk	O
factors	O
for	O
thrombosis	O
,	O
i	O
.	O
e	O
.	O
,	O
oral	O
contraceptive	O
use	O
,	O
the	O
factor	O
V	O
Leiden	O
mutation	O
,	O
and	O
the	O
combination	O
of	O
the	O
two	O
.	O

This	O
finding	O
indicates	O
an	O
effect	O
of	O
an	O
additional	O
factor	O
in	O
an	O
airplane	O
,	O
such	O
as	O
hypobaric	O
hypoxia	O
,	O
to	O
which	O
mainly	O
individuals	O
with	O
risk	O
factors	O
respond	O
.	O

None	O
of	O
the	O
studies	O
published	O
so	O
far	O
have	O
systematically	O
studied	O
the	O
effect	O
of	O
traveling	O
in	O
combination	O
with	O
other	O
risk	O
factors	O
,	O
with	O
the	O
exception	O
of	O
the	O
study	O
by	O
Martinelli	O
et	O
al	O
.	O

[	O
3	O
]	O
.	O

In	O
an	O
analysis	O
of	O
210	O
patients	B
,	O
they	O
found	O
a	O
16	O
-	O
fold	O
increased	O
risk	O
for	O
patients	B
who	O
traveled	O
by	O
air	O
and	O
had	O
some	O
form	O
of	O
thrombophilia	O
,	O
as	O
well	O
as	O
a	O
14	O
-	O
fold	O
increased	O
risk	O
in	O
women	B
who	O
flew	O
and	O
used	O
oral	O
contraceptives	O
,	O
findings	O
that	O
confirm	O
both	O
the	O
results	O
of	O
the	O
present	O
study	O
and	O
our	O
finding	O
of	O
activated	O
coagulation	O
in	O
individuals	O
with	O
risk	O
factors	O
after	O
flying	O
[	O
22	O
]	O
.	O

The	O
finding	O
that	O
taller	O
and	O
shorter	O
people	B
had	O
an	O
increased	O
risk	O
of	O
venous	O
thrombosis	O
after	O
traveling	O
should	O
be	O
interpreted	O
with	O
some	O
caution	O
,	O
as	O
the	O
numbers	O
were	O
small	O
in	O
these	O
strata	O
.	O

On	O
the	O
other	O
hand	O
,	O
it	O
is	O
biologically	O
plausible	O
:	O
very	O
tall	O
people	B
are	O
subjected	O
to	O
even	O
more	O
cramped	O
seating	O
than	O
average	O
-	O
height	O
individuals	O
,	O
and	O
very	O
short	O
people	B
'	O
s	O
feet	O
may	O
not	O
touch	O
the	O
floor	O
,	O
which	O
would	O
lead	O
to	O
extra	O
compression	O
of	O
the	O
popliteal	O
veins	O
.	O

Interestingly	O
,	O
the	O
increased	O
risk	O
for	O
short	O
people	B
was	O
only	O
found	O
in	O
people	B
who	O
traveled	O
by	O
air	O
.	O

This	O
may	O
have	O
to	O
do	O
with	O
the	O
fact	O
that	O
seats	O
in	O
cars	O
are	O
generally	O
lower	O
,	O
and	O
more	O
individually	O
adjustable	O
,	O
than	O
those	O
in	O
airplanes	O
.	O

As	O
the	O
diagnosis	O
of	O
DVT	O
is	O
usually	O
more	O
unambiguous	O
than	O
that	O
of	O
PE	O
[	O
23	O
]	O
,	O
as	O
was	O
the	O
case	O
in	O
our	O
study	O
population	O
as	O
well	O
,	O
we	O
repeated	O
the	O
analysis	O
using	O
only	O
DVT	O
as	O
the	O
outcome	O
of	O
interest	O
(	O
97	O
%	O
objectively	O
diagnosed	O
)	O
.	O

In	O
this	O
analysis	O
,	O
despite	O
using	O
smaller	O
numbers	O
,	O
most	O
findings	O
were	O
either	O
similar	O
or	O
appeared	O
more	O
evident	O
,	O
and	O
inconsistencies	O
that	O
were	O
found	O
when	O
using	O
both	O
DVT	O
and	O
PE	O
as	O
endpoints	O
disappeared	O
.	O

To	O
our	O
knowledge	O
,	O
this	O
is	O
the	O
first	O
large	O
population	O
-	O
based	O
case	O
-	O
control	O
study	O
in	O
which	O
the	O
effect	O
of	O
travel	O
on	O
the	O
risk	O
of	O
venous	O
thrombosis	O
has	O
been	O
studied	O
.	O

Because	O
the	O
control	O
individuals	O
were	O
closely	O
matched	O
,	O
being	O
partners	O
of	O
the	O
cases	O
,	O
and	O
couples	O
tend	O
to	O
travel	O
together	O
,	O
only	O
the	O
cases	O
and	O
control	O
individuals	O
who	O
had	O
not	O
traveled	O
together	O
could	O
be	O
used	O
for	O
the	O
analysis	O
.	O

Also	O
because	O
of	O
this	O
design	O
,	O
the	O
effect	O
of	O
sex	O
and	O
age	O
could	O
not	O
be	O
studied	O
.	O

It	O
has	O
to	O
be	O
noted	O
,	O
however	O
,	O
that	O
for	O
all	O
other	O
research	O
questions	O
on	O
the	O
effect	O
of	O
genetic	O
and	O
acquired	O
risk	O
factors	O
on	O
the	O
risk	O
of	O
venous	O
thrombosis	O
,	O
this	O
design	O
has	O
no	O
limitations	O
and	O
the	O
close	O
matching	O
of	O
cases	O
and	O
controls	O
renders	O
confounding	O
by	O
,	O
for	O
instance	O
,	O
lifestyle	O
and	O
socioeconomic	O
class	O
less	O
likely	O
than	O
in	O
previous	O
unmatched	O
studies	O
(	O
see	O
also	O
Protocol	O
S1	O
)	O
.	O

Another	O
advantage	O
of	O
this	O
approach	O
is	O
the	O
minimization	O
of	O
recall	O
bias	O
,	O
as	O
the	O
cases	O
and	O
controls	O
would	O
generally	O
fill	O
in	O
the	O
questionnaire	O
together	O
.	O

Many	O
questions	O
are	O
still	O
left	O
unanswered	O
that	O
necessitate	O
more	O
research	O
.	O

First	O
of	O
all	O
,	O
our	O
study	O
results	O
apply	O
only	O
to	O
people	B
younger	O
than	O
70	O
y	O
of	O
age	O
.	O

Furthermore	O
,	O
it	O
is	O
likely	O
that	O
other	O
characteristics	O
exist	O
that	O
also	O
increase	O
the	O
risk	O
-	O
-	O
person	B
-	O
specific	O
(	O
e	O
.	O
g	O
.	O
,	O
other	O
drug	O
use	O
)	O
,	O
behavioral	O
(	O
e	O
.	O
g	O
.	O
,	O
use	O
of	O
sleeping	O
pills	O
or	O
alcohol	O
consumption	O
)	O
,	O
and	O
flight	O
-	O
specific	O
(	O
e	O
.	O
g	O
.	O
,	O
class	O
or	O
seating	O
)	O
-	O
-	O
that	O
need	O
to	O
be	O
identified	O
.	O

These	O
further	O
variables	O
are	O
part	O
of	O
our	O
ongoing	O
study	O
as	O
part	O
of	O
the	O
World	O
Health	O
Organization	O
Research	O
Initiative	O
into	O
the	O
Global	O
Hazards	O
of	O
Travel	O
(	O
WRIGHT	O
study	O
)	O
.	O

For	O
those	O
who	O
have	O
an	O
increased	O
risk	O
,	O
such	O
as	O
oral	O
contraceptive	O
users	O
and	O
individuals	O
with	O
factor	O
V	O
Leiden	O
,	O
prevention	O
may	O
be	O
warranted	O
.	O

Prevention	O
may	O
vary	O
from	O
simple	O
measures	O
,	O
such	O
as	O
exercises	O
during	O
the	O
flight	O
,	O
to	O
measures	O
that	O
carry	O
a	O
risk	O
themselves	O
,	O
such	O
as	O
anticoagulants	O
.	O

Specific	O
studies	O
are	O
needed	O
to	O
assess	O
the	O
efficacy	O
of	O
these	O
measures	O
and	O
their	O
risk	O
-	O
benefit	O
ratio	O
.	O

It	O
can	O
be	O
concluded	O
that	O
the	O
risk	O
of	O
venous	O
thrombosis	O
is	O
2	O
-	O
fold	O
increased	O
for	O
all	O
travelers	O
and	O
to	O
the	O
same	O
extent	O
for	O
all	O
modes	O
of	O
travel	O
.	O

In	O
individuals	O
who	O
use	O
oral	O
contraceptives	O
,	O
are	O
carriers	O
of	O
the	O
factor	O
V	O
Leiden	O
mutation	O
,	O
or	O
are	O
particularly	O
tall	O
,	O
short	O
,	O
or	O
obese	O
,	O
this	O
risk	O
is	O
considerably	O
higher	O
,	O
to	O
such	O
an	O
extent	O
that	O
studies	O
into	O
the	O
efficacy	O
of	O
prophylactic	O
measures	O
are	O
required	O
.	O

Supporting	O
Information	O

The	O
role	O
of	O
the	O
muscarinic	O
system	O
in	O
regulating	O
estradiol	O
secretion	O
varies	O
during	O
the	O
estrous	O
cycle	O
:	O
the	O
hemiovariectomized	O
rat	B
model	O

Abstract	O

There	O
is	O
evidence	O
that	O
one	O
gonad	O
has	O
functional	O
predominance	O
.	O

The	O
present	O
study	O
analyzed	O
the	O
acute	O
effects	O
of	O
unilateral	O
ovariectomy	O
(	O
ULO	O
)	O
and	O
blocking	O
the	O
cholinergic	O
system	O
,	O
by	O
injecting	O
atropine	O
sulfate	O
(	O
ATR	O
)	O
,	O
on	O
estradiol	O
(	O
E2	O
)	O
serum	O
concentrations	O
during	O
the	O
estrous	O
cycle	O
.	O

The	O
results	O
indicate	O
that	O
ULO	O
effects	O
on	O
E2	O
concentrations	O
are	O
asymmetric	O
,	O
vary	O
during	O
the	O
estrous	O
cycle	O
,	O
and	O
partially	O
depend	O
on	O
the	O
cholinergic	O
innervation	O
.	O

Background	O

Estradiol	O
secretion	O
is	O
regulated	O
by	O
pituitary	O
[	O
follicle	O
stimulating	O
hormone	O
(	O
FSH	O
)	O
and	O
luteinizing	O
hormones	O
(	O
LH	O
)	O
,	O
prolactin	O
,	O
and	O
adrenocorticotropin	O
(	O
ACTH	O
)	O
]	O
.	O

The	O
effects	O
of	O
these	O
hormones	O
are	O
modulated	O
by	O
neurotransmitters	O
released	O
by	O
the	O
intrinsic	O
ovarian	O
innervation	O
near	O
the	O
follicular	O
wall	O
.	O

Acetylcholine	O
produced	O
by	O
the	O
follicle	O
may	O
be	O
one	O
of	O
the	O
neurotransmitters	O
participating	O
in	O
modulating	O
the	O
effects	O
of	O
pituitary	O
hormones	O
on	O
the	O
follicle	O
[	O
1	O
-	O
3	O
]	O
.	O

Evidence	O
suggesting	O
that	O
one	O
gonad	O
has	O
functional	O
predominance	O
in	O
mammals	O
and	O
birds	O
have	O
been	O
published	O
[	O
1	O
,	O
4	O
-	O
8	O
]	O
.	O

In	O
previous	O
studies	O
we	O
have	O
shown	O
that	O
unilateral	O
ovariectomy	O
(	O
ULO	O
)	O
modifies	O
progesterone	O
and	O
/	O
or	O
testosterone	O
serum	O
concentrations	O
,	O
and	O
that	O
the	O
effects	O
of	O
ULO	O
depend	O
on	O
both	O
,	O
the	O
stage	O
of	O
the	O
estrous	O
cycle	O
when	O
ULO	O
was	O
performed	O
and	O
the	O
ovary	O
(	O
left	O
or	O
right	O
)	O
remaining	O
in	O
situ	O
[	O
9	O
-	O
11	O
]	O
.	O

Asymmetry	O
in	O
ovarian	O
functions	O
has	O
been	O
explained	O
by	O
differences	O
in	O
the	O
ovarian	O
innervation	O
participating	O
in	O
modulating	O
the	O
effects	O
of	O
gonadotropin	O
on	O
the	O
ovarian	O
follicles	O
[	O
1	O
,	O
6	O
]	O
.	O

Kawakami	O
et	O
al	O
[	O
12	O
]	O
showed	O
that	O
electrical	O
stimulation	O
of	O
the	O
medial	O
basal	O
pre	O
-	O
chiasmatic	O
area	O
,	O
the	O
ventro	O
-	O
medial	O
hypothalamus	O
,	O
and	O
the	O
areas	O
in	O
the	O
mesencephalon	O
of	O
hypophysectomized	O
and	O
adrenalectomized	O
female	O
rats	B
resulted	O
in	O
a	O
significant	O
increase	O
of	O
estradiol	O
(	O
E2	O
)	O
and	O
progesterone	O
(	O
P4	O
)	O
plasma	O
concentrations	O
in	O
the	O
contra	O
-	O
lateral	O
ovarian	O
venous	O
blood	O
.	O

In	O
turn	O
,	O
stimulating	O
the	O
dorsal	O
hippocampus	O
,	O
the	O
lateral	O
amygdala	O
,	O
and	O
the	O
mesencephalic	O
areas	O
resulted	O
in	O
lower	O
E2	O
and	O
P4	O
concentrations	O
.	O

Ovarian	O
denervation	O
of	O
rats	B
in	O
proestrus	O
stage	O
blocks	O
E2	O
secretion	O
induced	O
by	O
stimulating	O
the	O
medial	O
basal	O
pre	O
-	O
chiasmatic	O
area	O
.	O

In	O
addition	O
,	O
the	O
electrochemical	O
stimulation	O
in	O
proestrus	O
day	O
of	O
the	O
medial	O
basal	O
pre	O
-	O
chiasmatic	O
area	O
of	O
untreated	O
rats	B
increased	O
E2	O
and	O
P4	O
concentrations	O
in	O
serum	O
.	O

This	O
effect	O
was	O
not	O
observed	O
when	O
stimulation	O
was	O
applied	O
to	O
the	O
pre	O
-	O
optic	O
supra	O
-	O
chiasmatic	O
area	O
.	O

According	O
to	O
the	O
authors	O
'	O
interpretation	O
of	O
the	O
results	O
,	O
the	O
efferent	O
neural	O
system	O
connecting	O
the	O
brain	O
and	O
the	O
ovaries	O
is	O
supplementary	O
to	O
the	O
brain	O
-	O
pituitary	O
-	O
ovarian	O
hormonal	O
mechanisms	O
regulating	O
ovarian	O
steroid	O
secretion	O
,	O
and	O
the	O
system	O
may	O
be	O
required	O
for	O
adjusting	O
ovarian	O
responsiveness	O
and	O
sensitivity	O
to	O
gonadotropins	O
[	O
12	O
,	O
13	O
]	O
.	O

Gerendai	O
et	O
al	O
.	O

[	O
14	O
]	O
described	O
a	O
multi	O
-	O
synaptic	O
neural	O
pathway	O
between	O
the	O
central	O
nervous	O
system	O
and	O
the	O
ovaries	O
,	O
with	O
the	O
vagus	O
nerve	O
being	O
one	O
of	O
the	O
main	O
neural	O
pathways	O
.	O

In	O
ULO	O
treated	O
rats	B
,	O
bi	O
-	O
lateral	O
sectioning	O
the	O
vagus	O
nerve	O
(	O
ventral	O
or	O
dorsal	O
)	O
results	O
in	O
lower	O
compensatory	O
ovarian	O
hypertrophy	O
.	O

The	O
effects	O
of	O
sectioning	O
the	O
left	O
vagus	O
nerve	O
depend	O
on	O
the	O
remaining	O
ovary	O
in	O
situ	O
:	O
rats	B
with	O
the	O
left	O
ovary	O
in	O
situ	O
had	O
a	O
larger	O
proportion	O
of	O
ovulating	O
animals	O
,	O
compensatory	O
ovarian	O
hypertrophy	O
and	O
number	O
of	O
ova	O
shed	O
.	O

In	O
turn	O
,	O
rats	B
with	O
the	O
right	O
ovary	O
in	O
situ	O
showed	O
a	O
decrease	O
in	O
all	O
parameters	O
studied	O
[	O
15	O
]	O
.	O

Based	O
on	O
available	O
information	O
,	O
the	O
present	O
study	O
aims	O
to	O
analyze	O
if	O
changes	O
in	O
E2	O
secretion	O
by	O
the	O
left	O
and	O
right	O
ovaries	O
vary	O
during	O
the	O
estrous	O
cycle	O
,	O
using	O
the	O
unilateral	O
ovariectomized	O
animal	O
as	O
a	O
model	O
of	O
study	O
.	O

We	O
also	O
investigated	O
if	O
,	O
throughout	O
estrous	O
cycle	O
diestrus	O
1	O
(	O
D1	O
)	O
,	O
diestrus	O
2	O
(	O
D2	O
)	O
and	O
proestrus	O
(	O
P	O
)	O
,	O
the	O
cholinergic	O
system	O
modulates	O
E2	O
secretion	O
in	O
an	O
asymmetric	O
way	O
.	O

For	O
this	O
purpose	O
,	O
we	O
analyzed	O
the	O
effects	O
of	O
injecting	O
ATR	O
at	O
13	O
.	O
00	O
h	O
to	O
rats	B
on	O
D1	O
,	O
D2	O
or	O
P	O
with	O
or	O
without	O
unilateral	O
or	O
bilateral	O
ovariectomy	O
.	O

Materials	O
and	O
methods	O

The	O
study	O
was	O
performed	O
with	O
virgin	O
adult	O
female	O
rats	B
(	O
195	O
-	O
225	O
-	O
g	O
body	O
weight	O
)	O
of	O
the	O
CIIZ	O
-	O
V	O
strain	O
from	O
our	O
own	O
stock	O
.	O

Animals	O
were	O
kept	O
under	O
controlled	O
lighting	O
conditions	O
(	O
lights	O
on	O
from	O
05	O
:	O
00	O
to	O
19	O
:	O
00	O
h	O
)	O
,	O
with	O
free	O
access	O
to	O
food	O
(	O
Purina	O
S	O
.	O
A	O
.	O
,	O
Mexico	O
)	O
and	O
tap	O
water	O
;	O
following	O
NIH	O
Guide	O
parameters	O
for	O
the	O
care	O
of	O
laboratory	O
animals	O
.	O

The	O
Committee	O
of	O
the	O
Facultad	O
de	O
Estudios	O
Superiores	O
Zaragoza	O
approved	O
the	O
experimental	O
protocols	O
.	O

Estrous	O
cycles	O
were	O
monitored	O
by	O
daily	O
vaginal	O
smears	O
.	O

Only	O
rats	B
showing	O
at	O
least	O
two	O
consecutive	O
4	O
-	O
day	O
cycles	O
were	O
used	O
in	O
the	O
experiment	O
.	O

All	O
surgeries	O
were	O
performed	O
under	O
ether	O
anesthesia	O
,	O
between	O
13	O
:	O
00	O
-	O
13	O
:	O
15	O
hours	O
.	O

Rats	B
were	O
sacrificed	O
by	O
decapitation	O
one	O
hour	O
after	O
treatment	O
.	O

Experimental	O
groups	O

Rats	B
were	O
randomly	O
allotted	O
to	O
one	O
of	O
the	O
experimental	O
groups	O
described	O
below	O
.	O

Animals	O
from	O
different	O
experimental	O
groups	O
were	O
treated	O
simultaneously	O
and	O
sacrificed	O
one	O
hour	O
after	O
surgery	O
.	O

The	O
number	O
of	O
animals	O
used	O
in	O
each	O
experimental	O
group	O
is	O
presented	O
in	O
Tables	O
1	O
,	O
2	O
and	O
3	O
.	O

Control	O
group	O
(	O
N	O
=	O
48	O
)	O
.	O

Non	O
-	O
treated	O
cyclic	O
rats	B
sacrificed	O
at	O
14	O
:	O
00	O
h	O
on	O
D1	O
(	O
17	O
rats	B
)	O
,	O
D2	O
(	O
19	O
rats	B
)	O
and	O
P	O
(	O
12	O
rats	B
)	O
.	O

Ether	O
anesthesia	O
(	O
N	O
=	O
24	O
)	O
:	O
Groups	O
of	O
rats	B
,	O
on	O
specific	O
stages	O
(	O
D1	O
,	O
D2	O
or	O
P	O
)	O
of	O
the	O
estrous	O
cycle	O
,	O
were	O
anesthetized	O
for	O
10	O
min	O
and	O
sacrificed	O
one	O
hour	O
later	O
.	O

Unilateral	O
peritoneal	O
perforation	O
(	O
sham	O
operation	O
)	O
(	O
N	O
=	O
53	O
)	O
:	O
A	O
unilateral	O
incision	O
was	O
performed	O
2	O
-	O
cm	O
below	O
the	O
last	O
rib	O
;	O
affecting	O
skin	O
,	O
muscle	O
,	O
and	O
peritoneum	O
.	O

The	O
ovaries	O
were	O
not	O
injured	O
or	O
manipulated	O
.	O

After	O
surgical	O
procedures	O
the	O
wound	O
was	O
sealed	O
.	O

Bilateral	O
peritoneal	O
perforation	O
(	O
sham	O
operation	O
2	O
)	O
(	O
N	O
=	O
27	O
)	O
.	O

A	O
bilateral	O
incision	O
below	O
the	O
last	O
rib	O
,	O
including	O
skin	O
and	O
muscle	O
,	O
was	O
performed	O
.	O

The	O
ovaries	O
were	O
not	O
injured	O
or	O
manipulated	O
.	O

After	O
surgical	O
procedures	O
the	O
wound	O
was	O
sealed	O
.	O

Unilateral	O
ovariectomy	O
(	O
ULO	O
)	O
(	O
N	O
=	O
50	O
)	O
:	O
A	O
unilateral	O
incision	O
below	O
the	O
last	O
rib	O
,	O
including	O
skin	O
and	O
muscle	O
was	O
performed	O
,	O
and	O
the	O
right	O
or	O
left	O
ovary	O
was	O
extirpated	O
.	O

The	O
wound	O
was	O
subsequently	O
sealed	O
.	O

Bilateral	O
ovariectomy	O
(	O
N	O
=	O
23	O
)	O
:	O
A	O
bilateral	O
incision	O
below	O
the	O
last	O
rib	O
,	O
including	O
skin	O
and	O
muscle	O
was	O
performed	O
,	O
and	O
the	O
ovaries	O
removed	O
.	O

The	O
wound	O
was	O
subsequently	O
sealed	O
.	O

Blocking	O
the	O
cholinergic	O
system	O

To	O
analyze	O
the	O
effects	O
of	O
blocking	O
the	O
cholinergic	O
system	O
,	O
groups	O
of	O
animals	O
were	O
injected	O
with	O
atropine	O
sulfate	O
(	O
ATR	O
,	O
Sigma	O
Chem	O
.	O
Co	O
.	O
St	O
.	O
Louis	O
,	O
Mo	O
.	O
)	O
.	O

ATR	O
was	O
injected	O
one	O
hour	O
before	O
surgery	O
at	O
doses	O
known	O
to	O
block	O
ovulation	O
:	O
in	O
D1	O
,	O
100	O
mg	O
/	O
kg	O
body	O
weight	O
(	O
b	O
.	O
w	O
.	O
)	O
;	O
in	O
D2	O
,	O
300	O
mg	O
/	O
kg	O
b	O
.	O
w	O
.	O
;	O
and	O
in	O
P	O
,	O
700	O
mg	O
/	O
kg	O
b	O
.	O
w	O
.	O

[	O
16	O
]	O
.	O

One	O
hour	O
after	O
ATR	O
treatment	O
,	O
rats	B
were	O
randomly	O
allotted	O
to	O
one	O
of	O
the	O
following	O
treatments	O
:	O
unilateral	O
peritoneal	O
perforation	O
,	O
bilateral	O
peritoneal	O
perforation	O
,	O
ULO	O
,	O
or	O
bilateral	O
ovariectomy	O
.	O

All	O
animals	O
were	O
sacrificed	O
one	O
hour	O
after	O
surgery	O
.	O

For	O
control	O
purposes	O
,	O
untreated	O
rats	B
,	O
on	O
D1	O
,	O
D2	O
or	O
P	O
,	O
were	O
injected	O
with	O
ATR	O
in	O
the	O
same	O
dose	O
as	O
in	O
their	O
corresponding	O
treatment	O
group	O
.	O

The	O
animals	O
were	O
sacrificed	O
two	O
hours	O
after	O
treatment	O
.	O

Autopsy	O
procedures	O

Animals	O
were	O
sacrificed	O
by	O
decapitation	O
.	O

The	O
blood	O
of	O
the	O
trunk	O
was	O
collected	O
in	O
a	O
test	O
tube	O
,	O
allowed	O
to	O
clot	O
at	O
room	O
temperature	O
for	O
30	O
minutes	O
and	O
centrifuged	O
at	O
3	O
,	O
000	O
rpm	O
for	O
15	O
minutes	O
.	O

Serum	O
was	O
stored	O
at	O
-	O
20	O
degrees	O
C	O
,	O
until	O
E2	O
concentrations	O
were	O
measured	O
.	O

Hormone	O
assay	O

Concentrations	O
of	O
E2	O
in	O
serum	O
were	O
measured	O
by	O
Radio	O
-	O
Immuno	O
-	O
Assay	O
(	O
RIA	O
)	O
;	O
using	O
kits	O
purchased	O
from	O
Diagnostic	O
Products	O
(	O
Los	O
Angeles	O
,	O
CA	O
)	O
.	O

Results	O
are	O
expressed	O
in	O
pg	O
/	O
ml	O
.	O

The	O
Intra	O
-	O
and	O
inter	O
-	O
assay	O
variation	O
coefficients	O
were	O
6	O
.	O
9	O
%	O
and	O
10	O
.	O
8	O
%	O
,	O
respectively	O
.	O

Statistics	O

Data	O
on	O
hormonal	O
concentrations	O
in	O
serum	O
were	O
analyzed	O
using	O
multivariate	O
analysis	O
of	O
variance	O
(	O
MANOVA	O
)	O
followed	O
by	O
Tukey	O
'	O
s	O
test	O
.	O

Differences	O
in	O
serum	O
hormone	O
concentrations	O
between	O
two	O
groups	O
were	O
analyzed	O
by	O
Student	O
'	O
s	O
t	O
-	O
test	O
.	O

A	O
probability	O
value	O
of	O
less	O
than	O
5	O
%	O
was	O
considered	O
significant	O
.	O

Results	O

Effects	O
of	O
ether	O
anesthesia	O
and	O
unilateral	O
or	O
bilateral	O
perforation	O
of	O
the	O
peritoneum	O

In	O
the	O
control	O
group	O
,	O
animals	O
sacrificed	O
on	O
P	O
showed	O
significantly	O
higher	O
E2	O
serum	O
concentration	O
than	O
animals	O
sacrificed	O
on	O
D1	O
or	O
D2	O
(	O
D1	O
:	O
55	O
.	O
3	O
+	O
/	O
-	O
8	O
.	O
0	O
;	O
D2	O
:	O
59	O
.	O
1	O
+	O
/	O
-	O
7	O
.	O
9	O
;	O
P	O
:	O
158	O
.	O
4	O
+	O
/	O
-	O
1	O
.	O
8	O
)	O
.	O

Compared	O
to	O
the	O
control	O
group	O
,	O
ether	O
anesthesia	O
treatment	O
did	O
not	O
modify	O
E2	O
serum	O
concentrations	O
(	O
D1	O
:	O
62	O
.	O
9	O
+	O
/	O
-	O
8	O
.	O
4	O
;	O
D2	O
:	O
69	O
.	O
5	O
+	O
/	O
-	O
12	O
.	O
0	O
;	O
P	O
:	O
164	O
.	O
1	O
+	O
/	O
-	O
17	O
.	O
6	O
)	O
.	O

Since	O
ether	O
anesthesia	O
did	O
not	O
modify	O
E2	O
serum	O
concentrations	O
,	O
treatment	O
results	O
are	O
compared	O
to	O
their	O
respective	O
control	O
group	O
.	O

The	O
effects	O
on	O
E2	O
serum	O
concentrations	O
of	O
unilaterally	O
or	O
bilaterally	O
perforating	O
the	O
peritoneum	O
depended	O
on	O
the	O
side	O
of	O
the	O
peritoneum	O
and	O
the	O
stage	O
of	O
the	O
estrous	O
cycle	O
when	O
perforation	O
surgery	O
was	O
performed	O
.	O

Perforating	O
the	O
left	O
peritoneum	O
on	O
D1	O
resulted	O
in	O
lower	O
E2	O
serum	O
concentrations	O
(	O
55	O
%	O
)	O
,	O
while	O
bilateral	O
perforation	O
,	O
or	O
perforating	O
the	O
right	O
side	O
of	O
the	O
peritoneum	O
,	O
had	O
no	O
apparent	O
effects	O
(	O
Table	O
1	O
)	O
.	O

Perforating	O
the	O
right	O
side	O
of	O
the	O
peritoneum	O
on	O
D2	O
day	O
resulted	O
in	O
E2	O
concentration	O
increases	O
(	O
184	O
%	O
)	O
,	O
while	O
perforating	O
the	O
left	O
side	O
resulted	O
in	O
a	O
decrease	O
(	O
51	O
%	O
)	O
of	O
E2	O
serum	O
concentrations	O
.	O

Bilateral	O
perforation	O
had	O
no	O
apparent	O
effects	O
on	O
hormone	O
concentrations	O
.	O

Perforating	O
the	O
peritoneum	O
on	O
P	O
phase	O
(	O
left	O
,	O
right	O
or	O
bilateral	O
)	O
resulted	O
in	O
hormone	O
serum	O
concentration	O
decreases	O
(	O
Left	O
30	O
%	O
;	O
Right	O
50	O
%	O
;	O
Bilateral	O
41	O
%	O
)	O
.	O

Results	O
are	O
summarized	O
in	O
Table	O
1	O
.	O

Effects	O
of	O
unilateral	O
or	O
bilateral	O
ovariectomy	O

When	O
surgery	O
was	O
performed	O
on	O
D1	O
,	O
no	O
significant	O
differences	O
in	O
E2	O
serum	O
concentrations	O
were	O
observed	O
between	O
rats	B
with	O
ULO	O
(	O
animals	O
with	O
intact	O
left	O
or	O
right	O
ovary	O
in	O
situ	O
)	O
or	O
perforation	O
of	O
the	O
peritoneum	O
(	O
Figure	O
1	O
)	O
.	O

Animals	O
with	O
the	O
left	O
intact	O
ovary	O
in	O
situ	O
showed	O
significantly	O
higher	O
E2	O
serum	O
concentrations	O
than	O
animals	O
with	O
the	O
right	O
intact	O
ovary	O
in	O
situ	O
(	O
61	O
.	O
5	O
+	O
/	O
-	O
9	O
.	O
4	O
vs	O
.	O
17	O
.	O
3	O
+	O
/	O
-	O
4	O
.	O
3	O
,	O
p	O
<	O
0	O
.	O
05	O
Student	O
'	O
s	O
t	O
test	O
)	O
.	O

Compared	O
to	O
animals	O
with	O
unilateral	O
perforation	O
of	O
the	O
peritoneum	O
,	O
animals	O
with	O
right	O
ULO	O
(	O
left	O
ovary	O
in	O
situ	O
)	O
performed	O
on	O
D2	O
had	O
lower	O
E2	O
serum	O
concentrations	O
(	O
55	O
%	O
)	O
.	O

Such	O
differences	O
were	O
not	O
observed	O
in	O
rats	B
with	O
left	O
ULO	O
(	O
Figure	O
1	O
)	O
.	O

As	O
in	O
rats	B
treated	O
on	O
D1	O
,	O
E2	O
serum	O
concentrations	O
were	O
significantly	O
higher	O
in	O
animals	O
treated	O
on	O
D2	O
with	O
the	O
left	O
ovary	O
in	O
situ	O
(	O
right	O
ULO	O
)	O
than	O
in	O
animals	O
with	O
the	O
right	O
ovary	O
in	O
situ	O
(	O
49	O
.	O
5	O
+	O
/	O
-	O
10	O
.	O
8	O
vs	O
.	O
26	O
.	O
0	O
+	O
/	O
-	O
6	O
.	O
9	O
)	O
.	O

In	O
animals	O
treated	O
on	O
P	O
,	O
right	O
ULO	O
(	O
left	O
ovary	O
in	O
situ	O
)	O
resulted	O
in	O
higher	O
E2	O
(	O
180	O
%	O
)	O
serum	O
concentrations	O
than	O
in	O
animals	O
with	O
unilateral	O
peritoneum	O
perforation	O
.	O

ULO	O
performed	O
on	O
the	O
left	O
side	O
(	O
right	O
ovary	O
in	O
situ	O
)	O
,	O
resulted	O
in	O
significantly	O
lower	O
(	O
45	O
%	O
)	O
E2	O
serum	O
concentrations	O
compared	O
to	O
rats	B
with	O
a	O
unilateral	O
perforation	O
of	O
the	O
peritoneum	O
(	O
Figure	O
1	O
)	O
.	O

As	O
observed	O
in	O
rats	B
treated	O
on	O
D1	O
or	O
D2	O
,	O
when	O
the	O
intact	O
left	O
ovary	O
remains	O
in	O
situ	O
,	O
estradiol	O
serum	O
concentrations	O
were	O
significantly	O
higher	O
than	O
in	O
animals	O
with	O
the	O
intact	O
right	O
ovary	O
in	O
situ	O
(	O
142	O
.	O
0	O
+	O
/	O
-	O
14	O
.	O
1	O
vs	O
.	O
61	O
.	O
5	O
+	O
/	O
-	O
6	O
.	O
0	O
)	O
.	O

Compared	O
to	O
animals	O
with	O
a	O
bilateral	O
perforation	O
of	O
the	O
peritoneum	O
,	O
bilateral	O
ovariectomy	O
resulted	O
in	O
significantly	O
lower	O
E2	O
serum	O
concentrations	O
,	O
regardless	O
of	O
the	O
stage	O
of	O
the	O
estrous	O
cycle	O
surgery	O
performed	O
(	O
D1	O
74	O
%	O
;	O
D2	O
73	O
%	O
;	O
P	O
84	O
%	O
)	O
.	O

Results	O
are	O
summarized	O
in	O
Table	O
2	O
.	O

Effects	O
of	O
blocking	O
the	O
cholinergic	O
system	O

Injecting	O
ATR	O
on	O
D1	O
or	O
P	O
resulted	O
in	O
E2	O
serum	O
concentrations	O
decreases	O
(	O
84	O
%	O
and	O
67	O
%	O
,	O
respectively	O
)	O
,	O
and	O
had	O
no	O
apparent	O
effects	O
on	O
E2	O
serum	O
concentrations	O
when	O
injected	O
on	O
D2	O
(	O
Table	O
3	O
)	O
.	O

Figure	O
2	O
shows	O
that	O
the	O
effects	O
of	O
blocking	O
the	O
cholinergic	O
system	O
of	O
rats	B
with	O
unilateral	O
perforation	O
of	O
the	O
peritoneum	O
depended	O
on	O
both	O
,	O
the	O
side	O
(	O
left	O
or	O
right	O
)	O
and	O
the	O
phase	O
of	O
the	O
estrous	O
when	O
surgery	O
was	O
performed	O
.	O

Injecting	O
ATR	O
on	O
D1	O
or	O
D2	O
resulted	O
in	O
a	O
significant	O
drop	O
in	O
E2	O
serum	O
concentrations	O
in	O
animals	O
with	O
sham	O
treatment	O
on	O
the	O
right	O
side	O
.	O

Blocking	O
the	O
cholinergic	O
system	O
of	O
rats	B
with	O
left	O
side	O
peritoneum	O
perforation	O
on	O
D1	O
or	O
P	O
resulted	O
in	O
a	O
drop	O
in	O
E2	O
serum	O
concentrations	O
(	O
52	O
%	O
;	O
47	O
%	O
,	O
respectively	O
)	O
,	O
while	O
the	O
same	O
treatment	O
performed	O
on	O
D2	O
resulted	O
in	O
a	O
significant	O
E2	O
concentrations	O
increase	O
(	O
157	O
%	O
)	O
.	O

Figure	O
3	O
shows	O
the	O
effects	O
of	O
blocking	O
the	O
cholinergic	O
system	O
of	O
rats	B
with	O
ULO	O
.	O

ATR	O
treatment	O
on	O
D1	O
or	O
P	O
stages	O
performed	O
on	O
rats	B
with	O
the	O
left	O
ovary	O
in	O
situ	O
resulted	O
in	O
a	O
significant	O
drop	O
of	O
E2	O
serum	O
concentrations	O
(	O
65	O
%	O
;	O
62	O
%	O
respectively	O
)	O
.	O

Such	O
effects	O
were	O
not	O
observed	O
in	O
rats	B
treated	O
on	O
D2	O
.	O

When	O
ATR	O
treatment	O
was	O
performed	O
on	O
rats	B
with	O
the	O
right	O
ovary	O
in	O
situ	O
on	O
D1	O
,	O
E2	O
serum	O
concentrations	O
were	O
lower	O
(	O
48	O
%	O
)	O
than	O
in	O
ULO	O
animals	O
.	O

Blocking	O
the	O
cholinergic	O
system	O
on	O
D2	O
resulted	O
in	O
E2	O
serum	O
concentrations	O
increase	O
(	O
159	O
%	O
)	O
.	O

When	O
the	O
treatment	O
was	O
performed	O
on	O
P	O
,	O
no	O
significant	O
differences	O
in	O
E2	O
serum	O
concentrations	O
were	O
observed	O
.	O

Compared	O
to	O
bilateral	O
treatment	O
,	O
perforation	O
of	O
the	O
peritoneum	O
or	O
bilateral	O
ovariectomy	O
,	O
ATR	O
treatment	O
on	O
D1	O
resulted	O
in	O
significant	O
E2	O
serum	O
concentrations	O
decreases	O
,	O
90	O
%	O
in	O
bilateral	O
peritoneal	O
perforation	O
and	O
60	O
%	O
in	O
bilateral	O
ovariectomized	O
animals	O
.	O

Blocking	O
the	O
cholinergic	O
system	O
on	O
D2	O
,	O
to	O
rats	B
with	O
bilateral	O
perforation	O
of	O
the	O
peritoneum	O
or	O
bilateral	O
ovariectomy	O
resulted	O
in	O
E2	O
serum	O
concentrations	O
increases	O
(	O
159	O
%	O
and	O
253	O
%	O
respectively	O
)	O
,	O
while	O
injecting	O
ATR	O
to	O
animals	O
treated	O
on	O
P	O
had	O
no	O
apparent	O
effects	O
(	O
Figure	O
4	O
)	O
.	O

Discussion	O

The	O
results	O
obtained	O
in	O
the	O
present	O
study	O
suggest	O
that	O
the	O
ability	O
to	O
compensate	O
the	O
secretion	O
of	O
E2	O
by	O
the	O
missing	O
ovary	O
is	O
different	O
between	O
the	O
right	O
and	O
left	O
ovaries	O
and	O
varies	O
during	O
the	O
estrous	O
cycle	O
.	O

Similarly	O
,	O
our	O
results	O
suggest	O
that	O
the	O
cholinergic	O
system	O
participates	O
in	O
regulating	O
E2	O
secretion	O
by	O
the	O
ovary	O
,	O
and	O
that	O
such	O
participation	O
varies	O
depending	O
on	O
the	O
ovary	O
remaining	O
in	O
situ	O
and	O
the	O
stage	O
of	O
the	O
estrous	O
cycle	O
when	O
the	O
surgical	O
procedure	O
was	O
performed	O
.	O

Previously	O
,	O
we	O
suggested	O
the	O
existence	O
of	O
a	O
neural	O
pathway	O
arising	O
from	O
the	O
peritoneum	O
that	O
participates	O
in	O
regulating	O
E2	O
[	O
9	O
]	O
,	O
P4	O
[	O
10	O
]	O
and	O
testosterone	O
secretion	O
[	O
11	O
]	O
.	O

In	O
the	O
rat	B
,	O
the	O
sensory	O
information	O
arising	O
from	O
the	O
peritoneum	O
is	O
sent	O
to	O
the	O
nucleus	O
tractus	O
solitarius	O
and	O
stimulates	O
neurokinine	O
-	O
B	O
receptors	O
[	O
17	O
]	O
.	O

Since	O
perforating	O
the	O
peritoneum	O
unilaterally	O
on	O
each	O
day	O
of	O
the	O
estrous	O
cycle	O
changed	O
E2	O
serum	O
concentrations	O
,	O
we	O
think	O
that	O
each	O
side	O
of	O
the	O
peritoneum	O
sends	O
different	O
neural	O
information	O
through	O
the	O
superior	O
ovarian	O
nerve	O
(	O
SON	O
)	O
to	O
the	O
ovary	O
and	O
the	O
central	O
nervous	O
system	O
,	O
perhaps	O
reaching	O
nuclei	O
related	O
to	O
the	O
vagus	O
nerve	O
.	O

A	O
study	O
analyzing	O
the	O
distribution	O
of	O
sensory	O
neurons	O
innervating	O
the	O
peritoneum	O
showed	O
that	O
when	O
tracer	O
was	O
placed	O
on	O
the	O
area	O
where	O
the	O
peritoneum	O
covers	O
the	O
abdominal	O
wall	O
,	O
labeled	O
neurons	O
were	O
observed	O
only	O
in	O
the	O
ipsilateral	O
dorsal	O
root	O
ganglia	O
[	O
18	O
]	O
.	O

The	O
authors	O
suggest	O
that	O
most	O
of	O
the	O
parietal	O
peritoneum	O
receives	O
sensory	O
nerves	O
from	O
dorsal	O
root	O
ganglia	O
,	O
and	O
visceral	O
peritoneum	O
from	O
both	O
,	O
the	O
spinal	O
and	O
vagus	O
nerves	O
.	O

According	O
to	O
Stener	O
-	O
Victorin	O
et	O
al	O
.	O

(	O
19	O
)	O
repeated	O
electro	O
-	O
acupunture	O
treatments	O
in	O
rats	B
with	O
polycystic	O
ovary	O
syndrome	O
(	O
PCO	O
)	O
,	O
induced	O
by	O
a	O
single	O
injection	O
of	O
estradiol	O
valerate	O
,	O
resulted	O
in	O
lower	O
nerve	O
growth	O
factor	O
(	O
NGF	O
)	O
concentrations	O
at	O
the	O
ovarian	O
level	O
than	O
in	O
non	O
-	O
electro	O
-	O
acupunture	O
treated	O
PCO	O
rats	B
.	O

In	O
our	O
experiments	O
,	O
perforating	O
the	O
peritoneum	O
affected	O
the	O
same	O
somatic	O
segments	O
employed	O
by	O
Stener	O
-	O
Victorin	O
et	O
.	O

al	O
.	O

[	O
19	O
]	O
.	O

We	O
presume	O
that	O
peritoneum	O
surgery	O
resulted	O
in	O
an	O
increase	O
of	O
NGF	O
concentrations	O
at	O
the	O
ovarian	O
level	O
,	O
which	O
in	O
turn	O
induced	O
hyper	O
-	O
androgenism	O
,	O
as	O
observed	O
in	O
women	O
with	O
PCO	O
[	O
20	O
]	O
.	O

Previously	O
,	O
we	O
showed	O
that	O
the	O
unilateral	O
perforation	O
of	O
the	O
peritoneum	O
results	O
in	O
a	O
significant	O
increase	O
in	O
testosterone	O
serum	O
concentrations	O
[	O
11	O
]	O
.	O

Because	O
E2	O
serum	O
concentrations	O
did	O
not	O
increase	O
after	O
left	O
or	O
bilateral	O
perforation	O
of	O
the	O
peritoneum	O
,	O
we	O
suppose	O
that	O
the	O
neural	O
information	O
originating	O
from	O
the	O
peritoneum	O
inhibits	O
the	O
mechanisms	O
regulating	O
aromatase	O
activity	O
within	O
the	O
follicle	O
.	O

One	O
of	O
the	O
ovaries	O
'	O
sources	O
of	O
catecholamines	O
arrives	O
through	O
the	O
SON	O
.	O

In	O
the	O
ovary	O
,	O
the	O
SON	O
fibers	O
are	O
mainly	O
distributed	O
in	O
the	O
peri	O
-	O
follicular	O
theca	O
layer	O
,	O
and	O
in	O
close	O
relation	O
with	O
the	O
cells	O
of	O
the	O
theca	O
interna	O
[	O
21	O
,	O
22	O
]	O
.	O

Sectioning	O
the	O
SON	O
of	O
rats	B
in	O
P	O
results	O
in	O
a	O
sudden	O
drop	O
of	O
P4	O
and	O
E2	O
concentrations	O
in	O
the	O
ovarian	O
vein	O
effluent	O
[	O
23	O
]	O
,	O
while	O
the	O
same	O
procedure	O
on	O
estrus	O
did	O
not	O
modify	O
E2	O
concentrations	O
[	O
24	O
]	O
.	O

Therefore	O
,	O
it	O
is	O
possible	O
that	O
perforating	O
the	O
peritoneum	O
modifies	O
the	O
type	O
and	O
/	O
or	O
rate	O
of	O
information	O
arriving	O
to	O
the	O
ovary	O
via	O
the	O
SON	O
.	O

Another	O
possibility	O
is	O
that	O
perforating	O
the	O
left	O
side	O
of	O
the	O
peritoneum	O
results	O
in	O
an	O
increase	O
release	O
of	O
ovarian	O
gamma	O
amino	O
butyric	O
acid	O
(	O
GABA	O
)	O
,	O
and	O
a	O
subsequent	O
increase	O
of	O
E2	O
concentrations	O
.	O

According	O
to	O
Erd	O
o	O
,	O
et	O
.	O

al	O
.	O

[	O
25	O
]	O
and	O
Laszlo	O
,	O
et	O
.	O

al	O
.	O

[	O
26	O
]	O
,	O
injecting	O
GABA	O
into	O
pseudo	O
-	O
pregnant	O
rats	B
increases	O
E2	O
concentration	O
in	O
the	O
blood	O
.	O

Present	O
results	O
indicate	O
that	O
injecting	O
ATR	O
,	O
before	O
unilateral	O
or	O
bilateral	O
perforation	O
of	O
the	O
peritoneum	O
,	O
to	O
rats	B
in	O
D1	O
or	O
P	O
,	O
results	O
in	O
lower	O
E2serum	O
concentrations	O
;	O
leading	O
us	O
to	O
think	O
that	O
some	O
of	O
the	O
neural	O
fibers	O
present	O
in	O
the	O
peritoneum	O
are	O
muscarinic	O
.	O

It	O
is	O
also	O
possible	O
that	O
blocking	O
the	O
cholinergic	O
innervation	O
,	O
by	O
ATR	O
treatment	O
,	O
results	O
in	O
lower	O
adrenaline	O
and	O
norepinephrine	O
release	O
by	O
the	O
adrenal	O
medulla	O
.	O

Our	O
results	O
,	O
and	O
those	O
of	O
others	O
,	O
suggest	O
that	O
stimulating	O
on	O
D2	O
the	O
sensory	O
receptors	O
located	O
on	O
the	O
left	O
side	O
of	O
the	O
peritoneum	O
triggers	O
an	O
E2	O
secretion	O
inhibitory	O
mechanism	O
,	O
that	O
the	O
sensory	O
pathway	O
arising	O
from	O
the	O
right	O
side	O
has	O
a	O
stimulatory	O
effect	O
,	O
and	O
that	O
both	O
are	O
mediated	O
by	O
the	O
cholinergic	O
muscarinic	O
system	O
.	O

Previously	O
,	O
we	O
showed	O
that	O
injecting	O
ATR	O
to	O
rats	B
in	O
D2	O
results	O
in	O
increases	O
of	O
P4	O
serum	O
concentrations	O
originating	O
from	O
the	O
adrenals	O
[	O
8	O
]	O
,	O
without	O
having	O
apparent	O
effects	O
on	O
testosterone	O
serum	O
concentrations	O
[	O
11	O
]	O
.	O

Since	O
P4	O
and	O
androgens	O
are	O
precursors	O
in	O
the	O
synthesis	O
of	O
E2	O
,	O
we	O
presume	O
that	O
this	O
mechanism	O
may	O
explain	O
the	O
increase	O
in	O
E2	O
serum	O
concentrations	O
observed	O
in	O
rats	B
with	O
peritoneum	O
perforation	O
previously	O
injected	O
with	O
ATR	O
.	O

Another	O
possibility	O
explaining	O
the	O
differences	O
on	O
E2	O
secretion	O
regulation	O
during	O
the	O
estrous	O
cycle	O
is	O
that	O
the	O
effects	O
of	O
the	O
cholinergic	O
system	O
take	O
place	O
through	O
changes	O
at	O
the	O
celiac	O
ganglion	O
level	O
.	O

According	O
to	O
Aguado	O
and	O
Ojeda	O
[	O
23	O
]	O
,	O
acetylcholine	O
inhibits	O
P4	O
secretion	O
in	O
the	O
celiac	O
ganglion	O
-	O
SON	O
-	O
ovary	O
preparation	O
obtained	O
from	O
rats	B
in	O
D1	O
or	O
D2	O
,	O
while	O
the	O
preparation	O
obtained	O
from	O
rats	B
in	O
P	O
resulted	O
in	O
only	O
a	O
moderate	O
stimulation	O
.	O

Since	O
there	O
is	O
evidence	O
that	O
fibers	O
from	O
the	O
vagus	O
nerve	O
innervate	O
neurons	O
in	O
the	O
celiac	O
ganglion	O
[	O
27	O
]	O
,	O
we	O
presume	O
that	O
the	O
cholinergic	O
system	O
modulates	O
the	O
sympathetic	O
post	O
-	O
ganglionar	O
activity	O
and	O
the	O
secretory	O
ability	O
of	O
the	O
ovaries	O
through	O
the	O
SON	O
.	O

Conclusion	O

Based	O
on	O
the	O
differences	O
in	O
E2	O
serum	O
concentrations	O
in	O
rats	B
with	O
ULO	O
,	O
present	O
results	O
suggest	O
that	O
the	O
capacity	O
to	O
release	O
E2	O
by	O
the	O
left	O
and	O
right	O
ovaries	O
varies	O
during	O
the	O
estrous	O
cycle	O
.	O

We	O
presume	O
that	O
the	O
left	O
ovary	O
releases	O
more	O
E2	O
than	O
the	O
right	O
one	O
.	O

As	O
previously	O
proposed	O
,	O
another	O
possibility	O
is	O
that	O
neural	O
communication	O
between	O
the	O
ovaries	O
modulates	O
E2	O
secretion	O
.	O

Case	O
report	O
:	O
rapidly	O
fatal	O
bowel	O
ischaemia	O
on	O
clozapine	O
treatment	O

Abstract	O

Background	O

There	O
have	O
been	O
previous	O
reported	O
deaths	O
due	O
to	O
clozapine	O
-	O
induced	O
constipation	O
.	O

In	O
all	O
these	O
cases	O
patients	B
have	O
experienced	O
prior	O
abdominal	O
symptoms	O
over	O
a	O
period	O
of	O
weeks	O
or	O
months	O
.	O

Case	O
presentation	O

We	O
report	O
the	O
sudden	O
death	O
due	O
to	O
constipation	O
of	O
a	O
healthy	O
young	O
male	O
patient	B
on	O
clozapine	O
without	O
any	O
known	O
history	O
of	O
prior	O
abdominal	O
symptoms	O
.	O

Conclusion	O

Psychiatrists	O
need	O
to	O
be	O
alert	O
to	O
the	O
medical	O
emergencies	O
which	O
can	O
occur	O
in	O
the	O
context	O
of	O
clozapine	O
treatment	O
and	O
also	O
need	O
to	O
make	O
other	O
clinicians	O
who	O
may	O
have	O
contact	O
with	O
their	O
patients	B
aware	O
of	O
these	O
.	O

Background	O

There	O
have	O
been	O
six	O
previously	O
published	O
cases	O
of	O
death	O
secondary	O
to	O
clozapine	O
-	O
induced	O
constipation	O
[	O
1	O
-	O
3	O
]	O
.	O

Of	O
these	O
,	O
two	O
patients	B
died	O
from	O
faecal	O
peritonitis	O
,	O
two	O
from	O
aspiration	O
of	O
faeculent	O
vomitus	O
as	O
a	O
result	O
of	O
bowel	O
obstruction	O
and	O
two	O
from	O
bowel	O
necrosis	O
.	O

In	O
all	O
these	O
cases	O
there	O
had	O
been	O
prior	O
complaints	O
of	O
constipation	O
and	O
/	O
or	O
other	O
abdominal	O
symptoms	O
for	O
weeks	O
to	O
months	O
before	O
the	O
fatal	O
event	O
.	O

Here	O
we	O
describe	O
a	O
case	O
of	O
constipation	O
,	O
presumably	O
clozapine	O
-	O
induced	O
,	O
where	O
death	O
from	O
bowel	O
ischaemia	O
occured	O
within	O
2	O
days	O
from	O
the	O
first	O
complaint	O
of	O
constipation	O
and	O
without	O
any	O
prior	O
reported	O
abdominal	O
symptoms	O
which	O
might	O
have	O
provided	O
a	O
warning	O
to	O
the	O
clinicians	O
involved	O
.	O

Case	O
presentation	O

A	O
20	O
-	O
year	O
-	O
old	O
male	O
with	O
a	O
year	O
long	O
history	O
of	O
schizophrenia	O
which	O
had	O
been	O
unresponsive	O
to	O
trials	O
of	O
two	O
atypical	O
antipsychotic	O
drugs	O
was	O
commenced	O
on	O
clozapine	O
.	O

The	O
dose	O
was	O
titrated	O
over	O
the	O
next	O
year	O
to	O
900	O
mg	O
daily	O
.	O

Due	O
to	O
persisting	O
negative	O
symptoms	O
amisulpiride	O
400	O
mg	O
twice	O
daily	O
was	O
added	O
with	O
good	O
response	O
after	O
one	O
month	O
.	O

The	O
patient	B
was	O
reviewed	O
regularly	O
over	O
the	O
next	O
year	O
,	O
continued	O
to	O
improve	O
and	O
did	O
not	O
report	O
any	O
side	O
effects	O
to	O
members	O
of	O
the	O
multidisciplinary	O
mental	O
health	O
team	O
working	O
to	O
support	O
him	O
in	O
the	O
community	O
.	O

He	O
appeared	O
to	O
be	O
fit	O
and	O
healthy	O
.	O

Although	O
he	O
usually	O
lived	O
in	O
supported	O
accommodation	O
he	O
was	O
staying	O
temporarily	O
with	O
his	O
family	O
and	O
from	O
their	O
account	O
he	O
complained	O
of	O
having	O
constipation	O
for	O
2	O
days	O
before	O
presenting	O
to	O
his	O
GP	O
with	O
severe	O
abdominal	O
pain	O
.	O

He	O
was	O
prescribed	O
medication	O
and	O
returned	O
home	O
but	O
his	O
condition	O
deteriorated	O
further	O
and	O
a	O
few	O
hours	O
later	O
an	O
ambulance	O
was	O
called	O
.	O

He	O
collapsed	O
and	O
died	O
before	O
reaching	O
hospital	O
.	O

Post	O
mortem	O
examination	O
revealed	O
that	O
he	O
had	O
impacted	O
faeces	O
which	O
had	O
pressed	O
against	O
the	O
bowel	O
wall	O
causing	O
ischaemia	O
.	O

This	O
had	O
led	O
to	O
infarction	O
of	O
this	O
part	O
of	O
the	O
bowel	O
.	O

Conclusion	O

This	O
case	O
demonstrates	O
that	O
death	O
can	O
occur	O
over	O
a	O
very	O
short	O
time	O
course	O
from	O
constipation	O
,	O
in	O
this	O
case	O
presumably	O
induced	O
by	O
clozapine	O
.	O

Death	O
from	O
constipation	O
and	O
subsequent	O
bowel	O
infarction	O
is	O
relatively	O
common	O
in	O
elderly	O
patients	B
and	O
infarction	O
causes	O
a	O
far	O
more	O
rapid	O
and	O
dangerous	O
deterioration	O
than	O
does	O
intestinal	O
obstruction	O
.	O

In	O
the	O
present	O
case	O
this	O
meant	O
that	O
this	O
patient	B
did	O
not	O
have	O
any	O
contact	O
with	O
psychiatric	O
services	O
between	O
the	O
onset	O
of	O
his	O
symptoms	O
and	O
his	O
rapid	O
demise	O
,	O
in	O
spite	O
of	O
regular	O
follow	O
-	O
up	O
.	O

Although	O
the	O
risk	O
of	O
neutropenia	O
is	O
relatively	O
well	O
-	O
known	O
,	O
it	O
should	O
be	O
borne	O
in	O
mind	O
that	O
clozapine	O
is	O
reported	O
to	O
be	O
associated	O
with	O
a	O
number	O
of	O
other	O
syndromes	O
which	O
may	O
be	O
rapidly	O
fatal	O
including	O
not	O
only	O
constipation	O
and	O
obstruction	O
but	O
also	O
cardiovascular	O
collapse	O
,	O
seizures	O
and	O
ketoacidosis	O
.	O

Psychiatrists	O
working	O
with	O
such	O
patients	B
should	O
not	O
only	O
themselves	O
be	O
vigilant	O
regarding	O
such	O
complications	O
but	O
should	O
take	O
steps	O
to	O
see	O
that	O
other	O
clinicians	O
to	O
whom	O
the	O
patient	B
may	O
present	O
are	O
also	O
aware	O
of	O
them	O
.	O

Competing	O
interests	O

The	O
author	O
(	O
s	O
)	O
declare	O
that	O
they	O
have	O
no	O
competing	O
interests	O
.	O

Authors	O
'	O
contributions	O

Both	O
authors	O
were	O
equally	O
involved	O
in	O
the	O
preparation	O
of	O
this	O
manuscript	O
.	O

Pre	O
-	O
publication	O
history	O

The	O
pre	O
-	O
publication	O
history	O
for	O
this	O
paper	O
can	O
be	O
accessed	O
here	O
:	O

A	O
disease	O
-	O
specific	O
measure	O
of	O
health	O
-	O
related	O
quality	O
of	O
life	O
for	O
use	O
in	O
adults	O
with	O
immune	O
thrombocytopenic	O
purpura	O
:	O
Its	O
development	O
and	O
validation	O

Abstract	O

Background	O

No	O
validated	O
disease	O
-	O
specific	O
measures	O
are	O
available	O
to	O
assess	O
health	O
-	O
related	O
quality	O
of	O
life	O
(	O
HRQoL	O
)	O
in	O
adult	O
subjects	O
with	O
immune	O
thrombocytopenic	O
purpura	O
(	O
ITP	O
)	O
.	O

Therefore	O
,	O
we	O
sought	O
to	O
develop	O
and	O
validate	O
the	O
ITP	O
-	O
Patient	B
Assessment	O
Questionnaire	O
(	O
ITP	O
-	O
PAQ	O
)	O
for	O
adult	O
subjects	O
with	O
ITP	O
.	O

Methods	O

Information	O
from	O
literature	O
reviews	O
,	O
focus	O
groups	O
with	O
subjects	O
,	O
and	O
clinicians	O
were	O
used	O
to	O
develop	O
50	O
ITP	O
-	O
PAQ	O
items	O
.	O

Factor	O
analyses	O
were	O
conducted	O
to	O
develop	O
the	O
scale	O
structure	O
and	O
reduce	O
the	O
number	O
of	O
items	O
.	O

The	O
final	O
44	O
-	O
item	O
ITP	O
-	O
PAQ	O
,	O
which	O
includes	O
ten	O
scales	O
[	O
Symptoms	O
(	O
S	O
)	O
,	O
Bother	O
-	O
Physical	O
Health	O
(	O
B	O
)	O
,	O
Fatigue	O
/	O
Sleep	O
(	O
FT	O
)	O
,	O
Activity	O
(	O
A	O
)	O
,	O
Fear	O
(	O
FR	O
)	O
,	O
Psychological	O
Health	O
(	O
PH	O
)	O
,	O
Work	O
(	O
W	O
)	O
,	O
Social	O
Activity	O
(	O
SA	O
)	O
,	O
Women	B
'	O
s	O
Reproductive	O
Health	O
(	O
RH	O
)	O
,	O
and	O
Overall	O
(	O
QoL	O
)	O
]	O
,	O
was	O
self	O
-	O
administered	O
to	O
adult	O
ITP	O
subjects	O
at	O
baseline	O
and	O
7	O
-	O
10	O
days	O
later	O
.	O

Test	O
-	O
retest	O
reliability	O
,	O
internal	O
consistency	O
reliability	O
,	O
construct	O
and	O
known	O
groups	O
validity	O
of	O
the	O
final	O
ITP	O
-	O
PAQ	O
were	O
evaluated	O
.	O

Results	O

Seventy	O
-	O
three	O
subjects	O
with	O
ITP	O
completed	O
the	O
questionnaire	O
twice	O
.	O

Test	O
-	O
retest	O
reliability	O
,	O
as	O
measured	O
by	O
the	O
intra	O
-	O
class	O
correlation	O
,	O
ranged	O
from	O
0	O
.	O
52	O
-	O
0	O
.	O
90	O
.	O

Internal	O
consistency	O
reliability	O
was	O
demonstrated	O
with	O
Cronbach	O
'	O
s	O
alpha	O
for	O
all	O
scales	O
above	O
the	O
acceptable	O
level	O
of	O
0	O
.	O
70	O
(	O
range	O
:	O
0	O
.	O
71	O
-	O
0	O
.	O
92	O
)	O
,	O
except	O
for	O
RH	O
(	O
0	O
.	O
66	O
)	O
.	O

Construct	O
validity	O
,	O
assessed	O
by	O
correlating	O
ITP	O
-	O
PAQ	O
scales	O
with	O
established	O
measures	O
(	O
Short	O
Form	O
-	O
36	O
v	O
.	O
1	O
,	O
SF	O
-	O
36	O
and	O
Center	O
for	O
Epidemiologic	O
Studies	O
Depression	O
Scale	O
,	O
CES	O
-	O
D	O
)	O
,	O
was	O
demonstrated	O
through	O
moderate	O
correlations	O
between	O
the	O
ITP	O
-	O
PAQ	O
SA	O
and	O
SF	O
-	O
36	O
Social	O
Function	O
scales	O
(	O
r	O
=	O
0	O
.	O
67	O
)	O
,	O
and	O
between	O
ITP	O
-	O
PAQ	O
PH	O
and	O
SF	O
-	O
36	O
Mental	O
Health	O
Scales	O
(	O
r	O
=	O
0	O
.	O
63	O
)	O
.	O

Moderate	O
to	O
strong	O
inter	O
-	O
scale	O
correlations	O
were	O
reported	O
between	O
ITP	O
-	O
PAQ	O
scales	O
and	O
the	O
CES	O
-	O
D	O
,	O
except	O
for	O
the	O
RH	O
scale	O
.	O

Known	O
groups	O
validity	O
was	O
evaluated	O
by	O
comparing	O
mean	O
scores	O
for	O
groups	O
that	O
differed	O
clinically	O
.	O

Statistically	O
significant	O
differences	O
(	O
p	O
<	O
0	O
.	O
01	O
)	O
were	O
observed	O
when	O
subjects	O
were	O
categorized	O
by	O
treatment	O
status	O
[	O
S	O
,	O
FT	O
,	O
B	O
,	O
A	O
,	O
PH	O
,	O
and	O
QoL	O
,	O
perceived	O
effectiveness	O
of	O
ITP	O
treatment	O
[	O
S	O
]	O
,	O
and	O
time	O
elapsed	O
since	O
ITP	O
diagnosis	O
[	O
PH	O
]	O
.	O

Conclusion	O

Results	O
provide	O
preliminary	O
evidence	O
of	O
the	O
reliability	O
and	O
validity	O
of	O
the	O
ITP	O
-	O
PAQ	O
in	O
adult	O
subjects	O
with	O
ITP	O
.	O

Further	O
work	O
should	O
be	O
conducted	O
to	O
assess	O
the	O
responsiveness	O
and	O
to	O
estimate	O
the	O
minimal	O
clinical	O
important	O
difference	O
of	O
the	O
ITP	O
-	O
PAQ	O
to	O
more	O
fully	O
understand	O
the	O
impact	O
of	O
ITP	O
and	O
its	O
treatments	O
on	O
HRQoL	O
.	O

Background	O

Immune	O
thrombocytopenic	O
purpura	O
(	O
ITP	O
)	O
is	O
a	O
disorder	O
characterized	O
by	O
autoimmune	O
-	O
mediated	O
platelet	O
destruction	O
and	O
suboptimal	O
platelet	O
production	O
[	O
1	O
-	O
3	O
]	O
that	O
results	O
in	O
a	O
decrease	O
in	O
the	O
number	O
of	O
circulating	O
platelets	O
and	O
increases	O
the	O
risk	O
of	O
bleeding	O
events	O
.	O

The	O
estimated	O
prevalence	O
rate	O
for	O
ITP	O
in	O
the	O
United	O
States	O
is	O
9	O
.	O
5	O
/	O
100	O
,	O
000	O
[	O
4	O
]	O
.	O

Adult	O
women	B
are	O
disproportionately	O
affected	O
by	O
the	O
disorder	O
,	O
with	O
a	O
female	O
to	O
male	O
ratio	O
of	O
nearly	O
two	O
to	O
one	O
[	O
5	O
]	O
.	O

The	O
disorder	O
rarely	O
remits	O
spontaneously	O
in	O
adult	O
subjects	O
[	O
1	O
]	O
.	O

The	O
mortality	O
rate	O
is	O
relatively	O
low	O
(	O
<	O
1	O
%	O
)	O
[	O
6	O
]	O
in	O
adults	O
less	O
than	O
65	O
years	O
of	O
age	O
.	O

Morbidity	O
increases	O
above	O
age	O
65	O
,	O
primarily	O
as	O
a	O
result	O
of	O
an	O
increase	O
in	O
age	O
-	O
related	O
major	O
bleeding	O
events	O
[	O
7	O
]	O
.	O

Initial	O
therapy	O
for	O
ITP	O
consists	O
of	O
some	O
combination	O
of	O
glucocorticoids	O
,	O
intravenous	O
immune	O
globulin	O
(	O
IVIg	O
)	O
or	O
anti	O
-	O
D	O
[	O
8	O
]	O
.	O

Splenectomy	O
is	O
often	O
considered	O
if	O
these	O
therapies	O
fail	O
.	O

Approximately	O
two	O
-	O
thirds	O
of	O
patients	B
treated	O
with	O
splenectomy	O
achieve	O
a	O
sustained	O
remission	O
[	O
1	O
,	O
5	O
,	O
9	O
]	O
.	O

Patients	B
who	O
fail	O
splenectomy	O
are	O
treated	O
with	O
a	O
wide	O
variety	O
of	O
agents	O
including	O
corticosteroids	O
,	O
danazol	O
,	O
and	O
chemotherapeutic	O
agents	O
.	O

Morbidity	O
and	O
mortality	O
in	O
these	O
refractory	O
patients	B
are	O
substantial	O
[	O
1	O
,	O
6	O
,	O
8	O
]	O
.	O

Patient	B
-	O
reported	O
outcomes	O
(	O
PRO	O
)	O
,	O
including	O
health	O
-	O
related	O
quality	O
of	O
life	O
(	O
HRQoL	O
)	O
measures	O
,	O
are	O
critical	O
components	O
for	O
evaluating	O
and	O
understanding	O
treatment	O
effects	O
from	O
the	O
subject	O
'	O
s	O
perspective	O
.	O

The	O
Food	O
and	O
Drug	O
Administration	O
(	O
FDA	O
)	O
indicates	O
that	O
PRO	O
measures	O
are	O
important	O
to	O
assess	O
because	O
they	O
may	O
:	O
1	O
)	O
detect	O
treatment	O
effects	O
known	O
only	O
to	O
the	O
subject	O
;	O
2	O
)	O
understand	O
the	O
subject	O
'	O
s	O
perspective	O
regarding	O
treatment	O
effect	O
;	O
or	O
3	O
)	O
provide	O
information	O
not	O
included	O
in	O
a	O
clinician	O
'	O
s	O
subject	O
notes	O
[	O
10	O
]	O
.	O

Furthermore	O
,	O
the	O
Committee	O
for	O
Medicinal	O
Products	O
for	O
Human	B
Use	O
of	O
the	O
European	O
Medicines	O
Agency	O
defines	O
HRQoL	O
as	O
"	O
the	O
subject	O
'	O
s	O
subjective	O
perception	O
of	O
the	O
impact	O
of	O
his	O
disease	O
and	O
its	O
treatment	O
(	O
s	O
)	O
on	O
his	O
daily	O
life	O
,	O
physical	O
,	O
psychological	O
and	O
social	O
functioning	O
and	O
well	O
-	O
being	O
"	O
[	O
11	O
]	O
.	O

Currently	O
,	O
limited	O
data	O
are	O
available	O
on	O
the	O
assessment	O
of	O
the	O
impact	O
of	O
symptoms	O
in	O
adult	O
subjects	O
with	O
ITP	O
.	O

Symptoms	O
of	O
ITP	O
,	O
such	O
as	O
spontaneous	O
bruising	O
,	O
menorrhagia	O
,	O
mucosal	O
bleeding	O
and	O
prolonged	O
bleeding	O
with	O
injury	O
,	O
may	O
significantly	O
affect	O
HRQoL	O
in	O
ITP	O
subjects	O
[	O
12	O
]	O
.	O

Treatments	O
for	O
chronic	O
ITP	O
can	O
also	O
be	O
associated	O
with	O
substantial	O
side	O
effects	O
[	O
5	O
,	O
8	O
]	O
.	O

In	O
addition	O
,	O
subjects	O
who	O
are	O
resistant	O
to	O
current	O
therapies	O
are	O
likely	O
to	O
experience	O
an	O
even	O
greater	O
decrement	O
to	O
their	O
HRQoL	O
than	O
responders	O
to	O
treatment	O
.	O

Thus	O
,	O
restoring	O
and	O
/	O
or	O
maintaining	O
quality	O
of	O
life	O
should	O
be	O
an	O
important	O
goal	O
of	O
treatment	O
.	O

While	O
the	O
primary	O
markers	O
for	O
ITP	O
include	O
hematologic	O
measures	O
such	O
as	O
platelet	O
counts	O
,	O
clinical	O
measures	O
typically	O
do	O
not	O
assess	O
a	O
subject	O
'	O
s	O
functioning	O
and	O
well	O
-	O
being	O
.	O

Therefore	O
,	O
subjects	O
and	O
physicians	O
may	O
want	O
to	O
weigh	O
the	O
impact	O
of	O
ITP	O
therapies	O
on	O
HRQoL	O
endpoints	O
when	O
making	O
treatment	O
decisions	O
.	O

Previously	O
,	O
no	O
validated	O
disease	O
-	O
specific	O
measures	O
were	O
available	O
to	O
evaluate	O
quality	O
of	O
life	O
in	O
adult	O
ITP	O
subjects	O
;	O
however	O
,	O
two	O
disease	O
-	O
specific	O
HRQoL	O
questionnaires	O
have	O
been	O
developed	O
for	O
use	O
in	O
children	B
with	O
ITP	O
[	O
13	O
,	O
14	O
]	O
.	O

Thus	O
,	O
we	O
sought	O
to	O
develop	O
a	O
questionnaire	O
that	O
would	O
be	O
appropriate	O
to	O
assess	O
the	O
impact	O
of	O
ITP	O
symptoms	O
and	O
its	O
treatments	O
on	O
HRQoL	O
in	O
adult	O
subjects	O
.	O

The	O
objective	O
of	O
this	O
current	O
manuscript	O
is	O
to	O
describe	O
the	O
development	O
and	O
initial	O
validation	O
of	O
a	O
newly	O
developed	O
HRQoL	O
questionnaire	O
for	O
use	O
in	O
adult	O
subjects	O
with	O
ITP	O
.	O

Methods	O

Overview	O

A	O
newly	O
developed	O
questionnaire	O
,	O
which	O
assesses	O
issues	O
of	O
importance	O
to	O
ITP	O
subjects	O
,	O
was	O
developed	O
based	O
on	O
available	O
published	O
literature	O
,	O
existing	O
questionnaires	O
,	O
expert	O
clinical	O
opinion	O
,	O
and	O
input	O
from	O
subjects	O
with	O
ITP	O
.	O

Subjects	O
and	O
Procedures	O

To	O
develop	O
the	O
questionnaire	O
,	O
three	O
focus	O
groups	O
with	O
ITP	O
subjects	O
were	O
conducted	O
in	O
geographically	O
diverse	O
locations	O
(	O
San	O
Diego	O
,	O
CA	O
,	O
New	O
York	O
,	O
NY	O
,	O
and	O
Oklahoma	O
City	O
,	O
OK	O
)	O
.	O

Each	O
of	O
the	O
three	O
sites	O
recruited	O
a	O
convenience	O
sample	O
of	O
five	O
to	O
eight	O
ITP	O
subjects	O
who	O
were	O
being	O
treated	O
on	O
an	O
outpatient	O
basis	O
.	O

To	O
be	O
eligible	O
,	O
subjects	O
were	O
required	O
to	O
have	O
active	O
disease	O
and	O
be	O
>	O
=	O
18	O
years	O
of	O
age	O
.	O

Although	O
platelet	O
count	O
data	O
were	O
not	O
required	O
for	O
participation	O
in	O
the	O
focus	O
groups	O
,	O
clinicians	O
at	O
each	O
site	O
considered	O
the	O
subjects	O
to	O
have	O
active	O
disease	O
,	O
usually	O
an	O
indication	O
that	O
platelet	O
levels	O
have	O
dropped	O
below	O
120	O
x	O
109L	O
and	O
the	O
subject	O
requires	O
treatment	O
and	O
/	O
or	O
more	O
frequent	O
monitoring	O
.	O

In	O
total	O
,	O
23	O
ITP	O
subjects	O
participated	O
in	O
the	O
focus	O
groups	O
after	O
providing	O
their	O
informed	O
consent	O
.	O

To	O
validate	O
the	O
questionnaire	O
,	O
a	O
convenience	O
sample	O
of	O
subjects	O
was	O
recruited	O
from	O
the	O
same	O
three	O
clinical	O
sites	O
in	O
New	O
York	O
,	O
NY	O
,	O
Oklahoma	O
City	O
,	O
OK	O
,	O
and	O
La	O
Jolla	O
,	O
CA	O
.	O

Subjects	O
were	O
eligible	O
if	O
they	O
were	O
>	O
=	O
18	O
years	O
of	O
age	O
,	O
had	O
active	O
disease	O
,	O
and	O
were	O
willing	O
to	O
complete	O
a	O
self	O
-	O
administered	O
questionnaire	O
at	O
two	O
time	O
points	O
.	O

Target	O
enrollment	O
was	O
roughly	O
72	O
subjects	O
(	O
24	O
subjects	O
from	O
each	O
site	O
)	O
.	O

The	O
study	O
protocol	O
was	O
approved	O
by	O
a	O
local	O
institutional	O
review	O
board	O
at	O
each	O
site	O
and	O
was	O
carried	O
out	O
in	O
accordance	O
with	O
Good	O
Clinical	O
Practice	O
and	O
International	O
Conference	O
on	O
Harmonization	O
guidelines	O
and	O
the	O
Declaration	O
of	O
Helsinki	O
.	O

Written	O
informed	O
consent	O
was	O
obtained	O
from	O
each	O
subject	O
prior	O
to	O
enrollment	O
.	O

Creation	O
of	O
Questionnaire	O
/	O
Item	O
Selection	O

A	O
trained	O
moderator	O
led	O
all	O
focus	O
groups	O
using	O
a	O
detailed	O
discussion	O
guide	O
.	O

Subjects	O
discussed	O
their	O
ITP	O
history	O
,	O
treatment	O
,	O
ITP	O
symptoms	O
,	O
and	O
the	O
impact	O
of	O
ITP	O
on	O
daily	O
activities	O
.	O

Each	O
focus	O
group	O
lasted	O
approximately	O
three	O
hours	O
,	O
and	O
subjects	O
were	O
provided	O
with	O
an	O
honorarium	O
for	O
their	O
time	O
.	O

Following	O
the	O
focus	O
group	O
session	O
,	O
all	O
subjects	O
completed	O
a	O
questionnaire	O
which	O
included	O
the	O
SF	O
-	O
36	O
v1	O
[	O
15	O
]	O
and	O
ITP	O
-	O
specific	O
questions	O
.	O

The	O
ITP	O
-	O
specific	O
items	O
were	O
developed	O
based	O
on	O
clinical	O
input	O
[	O
12	O
,	O
16	O
-	O
18	O
]	O
.	O

The	O
ITP	O
-	O
specific	O
items	O
assessed	O
the	O
impact	O
of	O
ITP	O
on	O
the	O
subject	O
'	O
s	O
overall	O
quality	O
of	O
life	O
,	O
relationships	O
,	O
ability	O
to	O
sleep	O
,	O
menstruation	O
/	O
gynecological	O
history	O
,	O
and	O
sexual	O
activity	O
.	O

The	O
ITP	O
-	O
specific	O
questions	O
also	O
assessed	O
the	O
subject	O
'	O
s	O
response	O
to	O
ITP	O
treatments	O
and	O
any	O
side	O
effects	O
.	O

Transcripts	O
of	O
the	O
focus	O
groups	O
were	O
summarized	O
and	O
reviewed	O
by	O
the	O
study	O
team	O
.	O

The	O
initial	O
draft	O
of	O
the	O
ITP	O
Subject	O
Assessment	O
Questionnaire	O
(	O
ITP	O
-	O
PAQ	O
)	O
was	O
developed	O
after	O
reviewing	O
information	O
from	O
the	O
literature	O
searches	O
,	O
existing	O
questionnaires	O
,	O
expert	O
opinion	O
,	O
focus	O
group	O
transcripts	O
,	O
and	O
the	O
questionnaire	O
responses	O
from	O
the	O
focus	O
group	O
subjects	O
.	O

The	O
initial	O
ITP	O
-	O
PAQ	O
consisted	O
of	O
50	O
items	O
that	O
assesses	O
the	O
impact	O
of	O
ITP	O
in	O
the	O
areas	O
of	O
physical	O
health	O
,	O
mental	O
health	O
,	O
work	O
,	O
social	O
activity	O
,	O
reproductive	O
health	O
(	O
relevant	O
for	O
women	B
only	O
)	O
,	O
and	O
overall	O
quality	O
of	O
life	O
.	O

Factor	O
analyses	O
were	O
conducted	O
which	O
yielded	O
six	O
unique	O
domains	O
.	O

The	O
impact	O
of	O
ITP	O
on	O
physical	O
health	O
was	O
measured	O
by	O
four	O
scales	O
that	O
evaluated	O
ITP	O
-	O
related	O
symptoms	O
,	O
Fatigue	O
/	O
Sleep	O
,	O
Bother	O
-	O
Physical	O
Health	O
,	O
and	O
Activity	O
.	O

Its	O
impact	O
on	O
mental	O
health	O
was	O
measured	O
by	O
two	O
scales	O
that	O
evaluated	O
psychological	O
distress	O
and	O
fear	O
.	O

A	O
copy	O
of	O
the	O
questionnaire	O
can	O
be	O
obtained	O
by	O
contacting	O
Janet	O
L	O
.	O
Nichol	O
and	O
sample	O
items	O
are	O
included	O
Table	O
2	O
.	O

Statistical	O
Analyses	O

A	O
validation	O
study	O
was	O
conducted	O
to	O
evaluate	O
the	O
psychometric	O
properties	O
of	O
the	O
newly	O
developed	O
ITP	O
-	O
PAQ	O
questionnaire	O
so	O
that	O
it	O
could	O
be	O
used	O
to	O
measure	O
the	O
impact	O
of	O
ITP	O
in	O
adult	O
subjects	O
in	O
future	O
studies	O
.	O

Standard	O
psychometric	O
methods	O
were	O
used	O
to	O
evaluate	O
the	O
reliability	O
and	O
validity	O
of	O
the	O
questionnaire	O
[	O
19	O
,	O
20	O
]	O
.	O

Eligible	O
subjects	O
completed	O
the	O
baseline	O
questionnaire	O
at	O
the	O
site	O
or	O
by	O
mail	O
after	O
providing	O
telephone	O
consent	O
.	O

An	O
informed	O
consent	O
form	O
and	O
baseline	O
questionnaire	O
was	O
mailed	O
to	O
those	O
subjects	O
who	O
gave	O
their	O
initial	O
consent	O
via	O
telephone	O
.	O

These	O
completed	O
documents	O
were	O
returned	O
by	O
mail	O
to	O
the	O
investigators	O
.	O

At	O
follow	O
up	O
,	O
each	O
subject	O
was	O
mailed	O
the	O
same	O
questionnaire	O
and	O
asked	O
to	O
complete	O
it	O
a	O
second	O
time	O
(	O
for	O
evaluating	O
test	O
-	O
retest	O
reliability	O
)	O
approximately	O
two	O
weeks	O
later	O
.	O

Additionally	O
,	O
subjects	O
completed	O
the	O
SF	O
-	O
36	O
and	O
the	O
CES	O
-	O
D	O
[	O
21	O
]	O
for	O
validation	O
purposes	O
at	O
both	O
assessments	O
.	O

Demographic	O
and	O
clinical	O
characteristics	O
were	O
also	O
solicited	O
in	O
order	O
to	O
more	O
fully	O
describe	O
the	O
study	O
population	O
.	O

Each	O
study	O
subject	O
received	O
an	O
honorarium	O
for	O
completing	O
the	O
questionnaires	O
.	O

Scale	O
creation	O
and	O
confirmatory	O
factor	O
analysis	O

Confirmatory	O
factor	O
analyses	O
were	O
conducted	O
to	O
test	O
the	O
hypothesized	O
structure	O
of	O
the	O
scales	O
.	O

Two	O
models	O
using	O
LISREL	O
version	O
8	O
were	O
tested	O
[	O
22	O
]	O
.	O

The	O
first	O
model	O
consisted	O
of	O
all	O
50	O
HRQoL	O
items	O
and	O
10	O
factors	O
,	O
whereas	O
the	O
second	O
model	O
consisted	O
of	O
a	O
subset	O
of	O
the	O
50	O
-	O
item	O
correlation	O
matrix	O
.	O

Only	O
women	B
respond	O
to	O
the	O
six	O
items	O
comprising	O
the	O
Reproductive	O
Health	O
scale	O
,	O
so	O
the	O
items	O
were	O
not	O
included	O
in	O
the	O
second	O
LISREL	O
model	O
to	O
avoid	O
estimation	O
biases	O
.	O

The	O
remaining	O
44	O
items	O
were	O
analyzed	O
.	O

Model	O
fit	O
was	O
evaluated	O
using	O
the	O
goodness	O
-	O
of	O
-	O
fit	O
(	O
GFI	O
)	O
,	O
the	O
normed	O
fit	O
index	O
(	O
NFI	O
)	O
,	O
the	O
non	O
-	O
normed	O
fit	O
index	O
(	O
NNFI	O
)	O
,	O
the	O
comparative	O
fit	O
index	O
(	O
CIF	O
)	O
,	O
and	O
the	O
root	O
mean	O
square	O
error	O
of	O
approximation	O
(	O
RMSEA	O
)	O
.	O

For	O
the	O
confirmatory	O
models	O
,	O
index	O
values	O
greater	O
than	O
0	O
.	O
95	O
indicate	O
better	O
fit	O
,	O
and	O
RMSEA	O
values	O
less	O
than	O
0	O
.	O
05	O
are	O
considered	O
evidence	O
of	O
adequate	O
fit	O
[	O
23	O
]	O
.	O

Reliability	O
and	O
stability	O

Two	O
forms	O
of	O
reliability	O
were	O
assessed	O
:	O
test	O
-	O
retest	O
reliability	O
and	O
internal	O
consistency	O
reliability	O
.	O

Test	O
-	O
retest	O
reliability	O
,	O
a	O
measure	O
of	O
the	O
degree	O
to	O
which	O
the	O
questionnaire	O
yields	O
stable	O
scores	O
over	O
a	O
short	O
period	O
of	O
time	O
(	O
assuming	O
there	O
is	O
no	O
underlying	O
change	O
)	O
,	O
was	O
measured	O
by	O
the	O
intra	O
-	O
class	O
correlation	O
coefficient	O
(	O
ICC	O
)	O
[	O
24	O
,	O
25	O
]	O
.	O

An	O
ICC	O
of	O
>	O
=	O
0	O
.	O
70	O
was	O
considered	O
acceptable	O
[	O
26	O
]	O
.	O

Internal	O
consistency	O
reliability	O
,	O
the	O
extent	O
to	O
which	O
items	O
within	O
each	O
scale	O
correlate	O
with	O
each	O
other	O
to	O
form	O
a	O
multi	O
-	O
item	O
scale	O
,	O
was	O
assessed	O
using	O
Cronbach	O
'	O
s	O
alpha	O
[	O
25	O
,	O
27	O
]	O
.	O

Data	O
from	O
both	O
assessments	O
were	O
used	O
to	O
evaluate	O
internal	O
consistency	O
reliability	O
.	O

An	O
alpha	O
coefficient	O
of	O
>	O
=	O
0	O
.	O
70	O
was	O
considered	O
acceptable	O
,	O
which	O
is	O
the	O
commonly	O
accepted	O
minimal	O
standard	O
for	O
reliability	O
coefficients	O
endorsed	O
by	O
the	O
Scientific	O
Advisory	O
Committee	O
of	O
the	O
Medical	O
Outcomes	O
Trust	O
[	O
26	O
]	O
.	O

Construct	O
Validity	O

Construct	O
validity	O
was	O
assessed	O
by	O
examining	O
the	O
inter	O
-	O
scale	O
correlations	O
between	O
the	O
ITP	O
-	O
PAQ	O
and	O
the	O
CES	O
-	O
D	O
and	O
the	O
ITP	O
-	O
PAQ	O
with	O
the	O
SF	O
-	O
36	O
and	O
by	O
examining	O
the	O
strength	O
of	O
the	O
within	O
ITP	O
-	O
PAQ	O
scale	O
correlations	O
[	O
25	O
,	O
28	O
]	O
.	O

For	O
both	O
inter	O
-	O
scale	O
and	O
intra	O
-	O
scale	O
correlations	O
,	O
we	O
made	O
a	O
priori	O
hypotheses	O
about	O
the	O
directionality	O
and	O
magnitude	O
of	O
the	O
correlation	O
and	O
observed	O
the	O
extent	O
to	O
which	O
hypothesized	O
relationships	O
held	O
.	O

For	O
example	O
,	O
we	O
hypothesized	O
that	O
the	O
scales	O
of	O
the	O
ITP	O
-	O
PAQ	O
would	O
be	O
negatively	O
correlated	O
with	O
the	O
CES	O
-	O
D	O
and	O
positively	O
correlated	O
with	O
those	O
of	O
the	O
SF	O
-	O
36	O
.	O

We	O
expected	O
the	O
Pearson	O
correlations	O
to	O
be	O
moderate	O
in	O
size	O
.	O

Known	O
Groups	O

Known	O
groups	O
validity	O
evaluates	O
the	O
ability	O
of	O
the	O
measure	O
to	O
discriminate	O
between	O
groups	O
known	O
to	O
be	O
clinically	O
different	O
[	O
28	O
]	O
.	O

We	O
only	O
collected	O
patient	B
-	O
reported	O
information	O
using	O
the	O
questionnaire	O
and	O
did	O
not	O
collect	O
clinical	O
information	O
such	O
as	O
platelet	O
counts	O
.	O

Therefore	O
,	O
the	O
following	O
four	O
criteria	O
were	O
identified	O
as	O
proxies	O
for	O
severity	O
:	O

*	O
Currently	O
on	O
treatment	O

*	O
Splenectomy	O
status	O

*	O
Subjects	O
'	O
self	O
-	O
perception	O
of	O
the	O
effectiveness	O
of	O
current	O
medication	O

*	O
Length	O
of	O
time	O
since	O
diagnosis	O

It	O
was	O
hypothesized	O
that	O
subjects	O
not	O
being	O
treated	O
,	O
who	O
did	O
not	O
have	O
a	O
splenectomy	O
,	O
who	O
perceived	O
their	O
medication	O
to	O
be	O
more	O
effective	O
,	O
and	O
who	O
had	O
been	O
diagnosed	O
with	O
ITP	O
for	O
a	O
longer	O
time	O
would	O
be	O
healthier	O
and	O
therefore	O
report	O
higher	O
HRQoL	O
scores	O
.	O

In	O
contrast	O
,	O
subjects	O
on	O
any	O
treatment	O
,	O
who	O
had	O
received	O
a	O
splenectomy	O
,	O
who	O
perceived	O
their	O
medication	O
to	O
be	O
less	O
effective	O
,	O
and	O
who	O
were	O
diagnosed	O
more	O
recently	O
would	O
report	O
worse	O
HRQoL	O
.	O

In	O
addition	O
,	O
subjects	O
were	O
also	O
categorized	O
by	O
gender	O
.	O

Subjects	O
were	O
categorized	O
into	O
two	O
groups	O
for	O
each	O
of	O
the	O
analyses	O
:	O
female	O
vs	O
.	O
male	O
,	O
intact	O
spleen	O
vs	O
.	O
removed	O
spleen	O
,	O
currently	O
on	O
ITP	O
treatment	O
vs	O
.	O
not	O
currently	O
on	O
ITP	O
treatment	O
,	O
subject	O
'	O
s	O
perception	O
of	O
the	O
effectiveness	O
of	O
their	O
current	O
ITP	O
medication	O
(	O
extremely	O
/	O
moderately	O
effective	O
vs	O
.	O
not	O
at	O
all	O
effective	O
)	O
,	O
and	O
ITP	O
diagnosis	O
less	O
than	O
one	O
year	O
ago	O
vs	O
.	O
ITP	O
diagnosis	O
more	O
than	O
one	O
year	O
ago	O
.	O

Results	O

Demographics	O
and	O
clinical	O
characteristics	O

Table	O
1	O
describes	O
the	O
demographic	O
and	O
clinical	O
characteristics	O
of	O
the	O
73	O
subjects	O
included	O
in	O
the	O
validation	O
analyses	O
.	O

The	O
majority	O
were	O
female	O
(	O
77	O
%	O
)	O
and	O
Caucasian	O
(	O
84	O
%	O
)	O
.	O

The	O
mean	O
age	O
was	O
45	O
years	O
(	O
SD	O
=	O
15	O
.	O
7	O
)	O
,	O
and	O
most	O
of	O
the	O
subjects	O
had	O
been	O
diagnosed	O
with	O
ITP	O
for	O
at	O
least	O
five	O
years	O
(	O
57	O
%	O
)	O
.	O

Fifty	O
-	O
two	O
percent	O
of	O
the	O
subjects	O
reported	O
that	O
they	O
were	O
currently	O
taking	O
medications	O
for	O
their	O
ITP	O
.	O

Furthermore	O
,	O
58	O
%	O
indicated	O
that	O
they	O
had	O
a	O
splenectomy	O
.	O

Among	O
the	O
42	O
subjects	O
who	O
had	O
a	O
splenectomy	O
,	O
55	O
%	O
reported	O
that	O
the	O
removal	O
of	O
their	O
spleen	O
did	O
not	O
cure	O
their	O
ITP	O
.	O

With	O
one	O
exception	O
,	O
the	O
remaining	O
subjects	O
did	O
not	O
provide	O
a	O
response	O
.	O

Confirmatory	O
factor	O
analysis	O

The	O
first	O
confirmatory	O
factor	O
analysis	O
of	O
the	O
50	O
-	O
item	O
and	O
ten	O
factors	O
model	O
converged	O
in	O
28	O
iterations	O
.	O

However	O
,	O
neither	O
the	O
inter	O
-	O
item	O
correlation	O
matrix	O
nor	O
the	O
inter	O
-	O
factor	O
correlation	O
matrix	O
was	O
positive	O
-	O
definite	O
,	O
which	O
suggests	O
that	O
the	O
proposed	O
model	O
is	O
wrong	O
for	O
the	O
data	O
or	O
the	O
data	O
are	O
inadequate	O
for	O
the	O
model	O
[	O
22	O
]	O
.	O

The	O
chi	O
-	O
square	O
value	O
of	O
the	O
model	O
was	O
316	O
.	O
64	O
with	O
1129	O
degrees	O
of	O
freedom	O
(	O
p	O
=	O
1	O
.	O
0	O
)	O
,	O
which	O
does	O
not	O
support	O
the	O
hypothesized	O
scale	O
structure	O
of	O
the	O
initial	O
ITP	O
-	O
PAQ	O
.	O

The	O
confirmatory	O
analysis	O
of	O
this	O
LISREL	O
model	O
indicate	O
that	O
computing	O
domain	O
scores	O
for	O
the	O
Physical	O
Health	O
and	O
Mental	O
Health	O
domains	O
is	O
not	O
appropriate	O
for	O
the	O
ITP	O
-	O
PAQ	O
.	O

The	O
second	O
LISREL	O
model	O
was	O
analyzed	O
to	O
confirm	O
the	O
scale	O
structure	O
,	O
excluding	O
the	O
Reproductive	O
Health	O
scale	O
.	O

For	O
this	O
model	O
,	O
126	O
parameters	O
were	O
estimated	O
:	O
46	O
factor	O
loadings	O
,	O
44	O
error	O
terms	O
,	O
and	O
36	O
inter	O
-	O
factor	O
correlations	O
.	O

The	O
model	O
converged	O
in	O
39	O
iterations	O
,	O
with	O
a	O
chi	O
-	O
square	O
value	O
of	O
1043	O
.	O
10	O
with	O
864	O
degrees	O
of	O
freedom	O
(	O
p	O
<	O
0	O
.	O
01	O
)	O
.	O

The	O
Goodness	O
of	O
Fit	O
Index	O
(	O
GFI	O
)	O
,	O
Normed	O
Fit	O
Index	O
(	O
NFI	O
)	O
,	O
Non	O
-	O
normed	O
Fit	O
Index	O
(	O
NNFI	O
)	O
,	O
and	O
Comparative	O
Fit	O
Index	O
(	O
CFI	O
)	O
was	O
0	O
.	O
60	O
,	O
0	O
.	O
63	O
,	O
0	O
.	O
91	O
,	O
and	O
0	O
.	O
92	O
,	O
respectively	O
,	O
and	O
the	O
RMSEA	O
was	O
0	O
.	O
05	O
[	O
90	O
%	O
CI	O
,	O
0	O
.	O
04	O
-	O
0	O
.	O
065	O
]	O
.	O

Furthermore	O
,	O
the	O
inter	O
-	O
factor	O
correlations	O
ranged	O
form	O
0	O
.	O
33	O
between	O
the	O
Symptoms	O
and	O
Work	O
scales	O
to	O
0	O
.	O
96	O
between	O
the	O
Bother	O
-	O
Physical	O
Health	O
and	O
Overall	O
QoL	O
scales	O
.	O

In	O
addition	O
to	O
the	O
confirmatory	O
factor	O
analyses	O
,	O
Cronbach	O
'	O
s	O
alphas	O
and	O
item	O
-	O
to	O
-	O
total	O
correlations	O
were	O
used	O
for	O
item	O
reduction	O
.	O

Items	O
with	O
low	O
factor	O
loadings	O
and	O
item	O
-	O
to	O
-	O
total	O
correlations	O
that	O
reduced	O
the	O
internal	O
consistency	O
were	O
eliminated	O
.	O

Although	O
initial	O
factor	O
analyses	O
identified	O
six	O
domains	O
for	O
future	O
use	O
,	O
the	O
final	O
version	O
of	O
the	O
ITP	O
-	O
PAQ	O
contained	O
44	O
items	O
that	O
included	O
the	O
following	O
ten	O
scales	O
:	O
Symptoms	O
,	O
Bother	O
-	O
Physical	O
Health	O
,	O
Fatigue	O
/	O
Sleep	O
,	O
Activity	O
,	O
Fear	O
,	O
Psychological	O
Health	O
,	O
Work	O
,	O
Social	O
Activity	O
,	O
Women	B
'	O
s	O
Reproductive	O
Health	O
,	O
and	O
Overall	O
QoL	O
.	O

Table	O
2	O
provides	O
information	O
on	O
the	O
number	O
of	O
items	O
,	O
item	O
variability	O
and	O
sample	O
items	O
from	O
each	O
scale	O
of	O
the	O
questionnaire	O
.	O

Each	O
scale	O
is	O
scored	O
from	O
0	O
to	O
100	O
,	O
with	O
higher	O
scores	O
representing	O
better	O
quality	O
of	O
life	O
.	O

Test	O
-	O
retest	O
reliability	O

Of	O
the	O
73	O
subjects	O
who	O
completed	O
the	O
first	O
administration	O
of	O
the	O
questionnaire	O
,	O
most	O
of	O
the	O
subjects	O
completed	O
the	O
second	O
questionnaire	O
within	O
a	O
15	O
-	O
day	O
period	O
(	O
75	O
%	O
)	O
,	O
during	O
which	O
subjects	O
were	O
expected	O
to	O
remain	O
clinically	O
stable	O
.	O

However	O
,	O
20	O
%	O
of	O
the	O
73	O
subjects	O
completed	O
the	O
questionnaire	O
within	O
three	O
weeks	O
following	O
the	O
first	O
administration	O
.	O

The	O
remaining	O
5	O
%	O
of	O
subjects	O
completed	O
it	O
between	O
four	O
and	O
nine	O
weeks	O
after	O
the	O
first	O
"	O
test	O
.	O
"	O
ICC	O
'	O
s	O
were	O
computed	O
for	O
the	O
entire	O
sample	O
(	O
n	O
=	O
73	O
)	O
and	O
for	O
a	O
sub	O
-	O
sample	O
of	O
respondents	O
who	O
completed	O
the	O
second	O
questionnaire	O
within	O
three	O
weeks	O
(	O
n	O
=	O
69	O
)	O
.	O

With	O
the	O
exception	O
of	O
the	O
Bother	O
-	O
Physical	O
Health	O
and	O
Activity	O
scales	O
,	O
all	O
scales	O
had	O
acceptable	O
test	O
-	O
retest	O
reliability	O
(	O
ICC	O
>	O
=	O
0	O
.	O
70	O
)	O
as	O
measured	O
by	O
the	O
ICC	O
(	O
Table	O
3	O
)	O
.	O

For	O
the	O
entire	O
sample	O
,	O
ICC	O
values	O
ranged	O
from	O
0	O
.	O
52	O
-	O
0	O
.	O
90	O
,	O
while	O
ICC	O
values	O
for	O
the	O
sub	O
-	O
sample	O
ranged	O
from	O
0	O
.	O
56	O
-	O
0	O
.	O
89	O
.	O

Internal	O
consistency	O
reliability	O

Internal	O
consistency	O
reliability	O
,	O
measured	O
by	O
Cronbach	O
'	O
s	O
alpha	O
,	O
ranged	O
from	O
0	O
.	O
66	O
to	O
0	O
.	O
92	O
(	O
Table	O
3	O
)	O
.	O

With	O
the	O
exception	O
of	O
the	O
Reproductive	O
Health	O
scale	O
,	O
Cronbach	O
'	O
s	O
alpha	O
coefficients	O
exceeded	O
the	O
acceptable	O
level	O
of	O
0	O
.	O
70	O
.	O

Cronbach	O
'	O
s	O
alpha	O
for	O
the	O
Symptoms	O
,	O
Bother	O
-	O
Physical	O
Health	O
,	O
Fatigue	O
/	O
Sleep	O
,	O
and	O
Activity	O
scales	O
ranged	O
from	O
0	O
.	O
71	O
-	O
0	O
.	O
89	O
,	O
while	O
Cronbach	O
'	O
s	O
alpha	O
for	O
the	O
Psychological	O
Health	O
and	O
Fear	O
scales	O
ranged	O
from	O
0	O
.	O
87	O
-	O
0	O
.	O
92	O
.	O

Additionally	O
,	O
Cronbach	O
'	O
s	O
alphas	O
for	O
the	O
Social	O
Activity	O
,	O
Work	O
,	O
Reproductive	O
Health	O
,	O
and	O
Overall	O
QoL	O
scales	O
were	O
0	O
.	O
72	O
,	O
0	O
.	O
86	O
,	O
0	O
.	O
66	O
,	O
and	O
0	O
.	O
89	O
,	O
respectively	O
.	O

Construct	O
validity	O

Table	O
4	O
displays	O
the	O
results	O
of	O
inter	O
-	O
scale	O
Pearson	O
correlation	O
coefficients	O
for	O
the	O
initial	O
test	O
administration	O
of	O
the	O
ITP	O
-	O
PAQ	O
.	O

As	O
expected	O
,	O
the	O
Symptoms	O
,	O
Bother	O
-	O
Physical	O
Health	O
,	O
Fatigue	O
/	O
Sleep	O
,	O
and	O
Activity	O
scales	O
were	O
moderately	O
to	O
strongly	O
inter	O
-	O
correlated	O
based	O
on	O
the	O
data	O
from	O
the	O
initial	O
administration	O
(	O
correlation	O
coefficients	O
ranged	O
from	O
0	O
.	O
56	O
-	O
0	O
.	O
75	O
;	O
p	O
<	O
0	O
.	O
05	O
)	O
.	O

The	O
Overall	O
QoL	O
scale	O
was	O
moderately	O
to	O
strongly	O
correlated	O
with	O
the	O
other	O
ITP	O
-	O
PAQ	O
scales	O
,	O
with	O
the	O
exception	O
of	O
the	O
Reproductive	O
Health	O
scale	O
.	O

In	O
addition	O
to	O
examining	O
the	O
correlations	O
within	O
the	O
ITP	O
-	O
PAQ	O
scales	O
,	O
construct	O
validity	O
was	O
also	O
assessed	O
by	O
comparing	O
the	O
ITP	O
-	O
PAQ	O
scale	O
scores	O
with	O
those	O
of	O
the	O
CES	O
-	O
D	O
and	O
the	O
SF	O
-	O
36	O
.	O

The	O
CES	O
-	O
D	O
was	O
negatively	O
correlated	O
with	O
all	O
ITP	O
-	O
PAQ	O
scales	O
,	O
except	O
for	O
the	O
Reproductive	O
Health	O
scale	O
.	O

Other	O
than	O
the	O
Reproductive	O
Health	O
scale	O
,	O
Pearson	O
correlations	O
ranged	O
from	O
-	O
0	O
.	O
37	O
to	O
-	O
0	O
.	O
70	O
(	O
p	O
<	O
0	O
.	O
05	O
)	O
(	O
data	O
not	O
shown	O
)	O
.	O

Most	O
of	O
the	O
ITP	O
-	O
PAQ	O
scales	O
were	O
moderately	O
correlated	O
with	O
the	O
SF	O
-	O
36	O
scales	O
;	O
however	O
,	O
the	O
Reproductive	O
Health	O
scale	O
was	O
not	O
significantly	O
correlated	O
with	O
any	O
of	O
the	O
SF	O
-	O
36	O
scales	O
.	O

The	O
mean	O
SF	O
-	O
36	O
scores	O
of	O
the	O
subjects	O
with	O
ITP	O
were	O
compared	O
to	O
those	O
of	O
the	O
general	O
U	O
.	O
S	O
.	O
population	O
norms	O
[	O
15	O
]	O
.	O

Results	O
from	O
t	O
-	O
tests	O
indicate	O
that	O
there	O
were	O
statistically	O
significant	O
differences	O
(	O
p	O
<	O
0	O
.	O
05	O
)	O
in	O
SF	O
-	O
36	O
mean	O
scores	O
between	O
subjects	O
with	O
ITP	O
(	O
range	O
,	O
43	O
.	O
04	O
-	O
72	O
.	O
86	O
)	O
and	O
the	O
general	O
U	O
.	O
S	O
.	O
population	O
(	O
range	O
,	O
60	O
.	O
86	O
-	O
84	O
.	O
15	O
)	O
.	O

Subjects	O
with	O
ITP	O
reported	O
lower	O
scores	O
on	O
each	O
SF	O
-	O
36	O
scale	O
compared	O
to	O
the	O
US	O
norm	O
(	O
data	O
not	O
shown	O
)	O
.	O

Known	O
groups	O
validity	O

Subjects	O
were	O
categorized	O
into	O
two	O
groups	O
according	O
to	O
gender	O
,	O
splenectomy	O
status	O
,	O
current	O
ITP	O
treatment	O
status	O
,	O
subject	O
'	O
s	O
perception	O
of	O
the	O
effectiveness	O
of	O
ITP	O
treatment	O
,	O
and	O
time	O
elapsed	O
since	O
ITP	O
diagnosis	O
.	O

When	O
subjects	O
were	O
grouped	O
according	O
to	O
gender	O
or	O
splenectomy	O
status	O
,	O
no	O
statistically	O
significant	O
differences	O
were	O
observed	O
for	O
any	O
of	O
the	O
ITP	O
-	O
PAQ	O
scales	O
(	O
data	O
not	O
shown	O
)	O
.	O

Subjects	O
who	O
were	O
currently	O
receiving	O
treatment	O
for	O
ITP	O
reported	O
lower	O
scores	O
on	O
all	O
ITP	O
-	O
PAQ	O
scales	O
compared	O
to	O
subjects	O
who	O
were	O
not	O
currently	O
receiving	O
treatment	O
.	O

Statistically	O
significant	O
differences	O
(	O
p	O
<	O
0	O
.	O
01	O
)	O
were	O
reported	O
for	O
the	O
following	O
ITP	O
-	O
PAQ	O
scales	O
when	O
subjects	O
were	O
categorized	O
by	O
treatment	O
status	O
:	O
Symptoms	O
,	O
Fatigue	O
/	O
Sleep	O
,	O
Bother	O
-	O
Physical	O
Health	O
,	O
Activity	O
,	O
Psychological	O
Health	O
,	O
and	O
Overall	O
QoL	O
(	O
Figure	O
1	O
)	O
.	O

When	O
subjects	O
were	O
categorized	O
by	O
effectiveness	O
of	O
ITP	O
treatment	O
,	O
statistically	O
significant	O
differences	O
(	O
p	O
<	O
0	O
.	O
05	O
)	O
were	O
observed	O
for	O
the	O
Symptoms	O
and	O
Activity	O
scales	O
(	O
Figure	O
1	O
)	O
,	O
while	O
statistically	O
significant	O
differences	O
were	O
only	O
found	O
for	O
the	O
Psychological	O
Health	O
scale	O
when	O
subjects	O
were	O
categorized	O
according	O
to	O
time	O
elapsed	O
since	O
ITP	O
diagnosis	O
(	O
data	O
not	O
shown	O
)	O
.	O

Subjects	O
who	O
had	O
been	O
diagnosed	O
with	O
ITP	O
for	O
<	O
1	O
year	O
had	O
a	O
lower	O
mean	O
score	O
on	O
the	O
Psychological	O
Health	O
scale	O
compared	O
to	O
subjects	O
who	O
had	O
been	O
diagnosed	O
with	O
ITP	O
for	O
at	O
least	O
one	O
year	O
(	O
50	O
.	O
38	O
vs	O
.	O
66	O
.	O
46	O
,	O
respectively	O
;	O
p	O
=	O
0	O
.	O
02	O
)	O
(	O
data	O
not	O
shown	O
)	O
.	O

Discussion	O

The	O
goal	O
of	O
this	O
study	O
was	O
to	O
develop	O
and	O
undertake	O
initial	O
validation	O
analyses	O
of	O
the	O
ITP	O
-	O
PAQ	O
as	O
a	O
tool	O
for	O
measuring	O
HRQoL	O
specifically	O
related	O
to	O
adult	O
subjects	O
with	O
ITP	O
.	O

The	O
results	O
of	O
this	O
study	O
provide	O
preliminary	O
evidence	O
of	O
the	O
reliability	O
and	O
validity	O
of	O
the	O
ITP	O
-	O
PAQ	O
in	O
this	O
population	O
.	O

The	O
results	O
indicate	O
that	O
,	O
with	O
the	O
exception	O
of	O
the	O
Reproductive	O
Health	O
scale	O
,	O
the	O
questionnaire	O
has	O
good	O
internal	O
consistency	O
.	O

The	O
Reproductive	O
Health	O
scale	O
may	O
not	O
have	O
reached	O
an	O
acceptable	O
level	O
because	O
the	O
items	O
could	O
in	O
fact	O
be	O
measuring	O
slightly	O
different	O
concepts	O
.	O

For	O
example	O
,	O
the	O
Reproductive	O
Health	O
scale	O
includes	O
items	O
that	O
assess	O
symptom	O
bother	O
related	O
to	O
menstruation	O
in	O
addition	O
to	O
items	O
that	O
ask	O
how	O
ITP	O
impacts	O
reproductive	O
choices	O
,	O
such	O
as	O
becoming	O
pregnant	O
,	O
giving	O
birth	O
,	O
and	O
adopting	O
children	B
.	O

Perhaps	O
,	O
the	O
symptom	O
bother	O
items	O
in	O
this	O
scale	O
may	O
fit	O
more	O
appropriately	O
with	O
the	O
Bother	O
-	O
Physical	O
Health	O
scale	O
,	O
and	O
the	O
reproductive	O
choice	O
items	O
could	O
comprise	O
a	O
separate	O
scale	O
.	O

Most	O
of	O
the	O
ITP	O
-	O
PAQ	O
scales	O
also	O
demonstrated	O
acceptable	O
test	O
-	O
retest	O
reliability	O
,	O
even	O
though	O
the	O
time	O
interval	O
between	O
test	O
and	O
retest	O
administrations	O
of	O
the	O
questionnaire	O
exceeded	O
the	O
targeted	O
time	O
interval	O
of	O
seven	O
to	O
ten	O
days	O
.	O

However	O
,	O
two	O
scales	O
,	O
the	O
Bother	O
-	O
Physical	O
Health	O
and	O
Activity	O
scales	O
,	O
reported	O
ICC	O
values	O
below	O
the	O
acceptable	O
value	O
of	O
0	O
.	O
70	O
.	O

In	O
addition	O
to	O
the	O
lag	O
between	O
the	O
two	O
administrations	O
of	O
the	O
questionnaire	O
,	O
subjects	O
may	O
have	O
experienced	O
an	O
increase	O
in	O
bother	O
and	O
/	O
or	O
a	O
decrease	O
in	O
activity	O
due	O
to	O
ITP	O
during	O
the	O
extended	O
time	O
interval	O
.	O

Additionally	O
,	O
the	O
comparatively	O
low	O
ICC	O
values	O
of	O
the	O
Bother	O
-	O
Physical	O
Health	O
and	O
Activity	O
scales	O
may	O
be	O
due	O
in	O
part	O
to	O
the	O
relatively	O
low	O
number	O
of	O
items	O
contained	O
in	O
each	O
of	O
these	O
scales	O
(	O
four	O
and	O
two	O
items	O
,	O
respectively	O
)	O
compared	O
to	O
the	O
Symptoms	O
scale	O
which	O
contains	O
six	O
items	O
.	O

In	O
general	O
,	O
the	O
construct	O
validity	O
of	O
the	O
questionnaire	O
was	O
supported	O
by	O
inter	O
-	O
scale	O
correlations	O
.	O

As	O
expected	O
,	O
the	O
Bother	O
-	O
Physical	O
Health	O
,	O
Symptoms	O
,	O
Fatigue	O
/	O
Sleep	O
,	O
and	O
Activity	O
scales	O
were	O
more	O
strongly	O
correlated	O
to	O
one	O
another	O
than	O
with	O
other	O
scales	O
.	O

However	O
,	O
the	O
Reproductive	O
Health	O
scale	O
had	O
a	O
lower	O
internal	O
consistency	O
reliability	O
and	O
it	O
was	O
weakly	O
correlated	O
with	O
the	O
ITP	O
-	O
PAQ	O
scales	O
,	O
the	O
SF	O
-	O
36	O
,	O
and	O
the	O
CES	O
-	O
D	O
,	O
possibly	O
due	O
to	O
the	O
differing	O
concepts	O
measured	O
by	O
the	O
items	O
within	O
this	O
scale	O
or	O
the	O
all	O
-	O
female	O
sample	O
.	O

Most	O
of	O
the	O
ITP	O
-	O
PAQ	O
scales	O
were	O
moderately	O
correlated	O
with	O
the	O
SF	O
-	O
36	O
scales	O
and	O
the	O
CES	O
-	O
D	O
;	O
however	O
,	O
correlations	O
between	O
some	O
of	O
the	O
scales	O
were	O
<	O
0	O
.	O
40	O
(	O
e	O
.	O
g	O
.	O
,	O
Fear	O
and	O
SF	O
-	O
36	O
Mental	O
Health	O
,	O
0	O
.	O
30	O
;	O
p	O
<	O
0	O
.	O
05	O
)	O
.	O

This	O
low	O
correlation	O
could	O
be	O
due	O
to	O
the	O
ITP	O
-	O
PAQ	O
assessing	O
fear	O
associated	O
with	O
ITP	O
(	O
e	O
.	O
g	O
.	O
,	O
fear	O
of	O
having	O
a	O
bleeding	O
episode	O
)	O
,	O
while	O
the	O
SF	O
-	O
36	O
provides	O
a	O
more	O
general	O
assessment	O
of	O
mental	O
health	O
issues	O
(	O
e	O
.	O
g	O
.	O
,	O
felt	O
downhearted	O
and	O
blue	O
)	O
.	O

The	O
known	O
-	O
groups	O
validity	O
results	O
indicate	O
that	O
some	O
of	O
the	O
ITP	O
-	O
PAQ	O
scales	O
(	O
Symptoms	O
,	O
Fatigue	O
/	O
Sleep	O
,	O
Bother	O
-	O
Physical	O
Health	O
,	O
Activity	O
,	O
Psychological	O
Health	O
,	O
and	O
Overall	O
QoL	O
scales	O
)	O
were	O
able	O
to	O
differentiate	O
ITP	O
subjects	O
who	O
were	O
currently	O
receiving	O
ITP	O
treatment	O
from	O
those	O
who	O
were	O
not	O
receiving	O
treatment	O
for	O
ITP	O
,	O
providing	O
preliminary	O
evidence	O
of	O
the	O
ITP	O
-	O
PAQ	O
'	O
s	O
ability	O
to	O
distinguish	O
between	O
groups	O
known	O
to	O
be	O
different	O
.	O

However	O
,	O
the	O
ITP	O
-	O
PAQ	O
scales	O
were	O
generally	O
unable	O
to	O
distinguish	O
between	O
subjects	O
when	O
they	O
were	O
grouped	O
by	O
gender	O
,	O
splenectomy	O
status	O
,	O
perceived	O
effectiveness	O
of	O
treatment	O
and	O
length	O
of	O
time	O
since	O
ITP	O
diagnosis	O
.	O

The	O
ITP	O
-	O
PAQ	O
may	O
not	O
be	O
able	O
to	O
differentiate	O
between	O
female	O
and	O
male	O
subjects	O
because	O
the	O
disorder	O
may	O
affect	O
females	O
and	O
males	O
similarly	O
.	O

Additionally	O
,	O
significant	O
differences	O
may	O
not	O
have	O
been	O
observed	O
between	O
subjects	O
who	O
have	O
undergone	O
splenectomy	O
and	O
subjects	O
who	O
have	O
not	O
because	O
55	O
%	O
of	O
subjects	O
who	O
had	O
a	O
splenectomy	O
indicated	O
that	O
it	O
did	O
not	O
cure	O
their	O
ITP	O
.	O

Specifically	O
,	O
the	O
known	O
-	O
groups	O
could	O
be	O
defined	O
as	O
'	O
subjects	O
without	O
a	O
splenectomy	O
'	O
versus	O
'	O
subjects	O
with	O
a	O
failed	O
splenectomy	O
'	O
(	O
for	O
whom	O
QoL	O
likely	O
worsened	O
)	O
versus	O
'	O
subjects	O
with	O
a	O
successful	O
splenectomy	O
'	O
(	O
for	O
whom	O
QoL	O
may	O
have	O
improved	O
)	O
.	O

In	O
the	O
future	O
,	O
to	O
assess	O
whether	O
the	O
ITP	O
-	O
PAQ	O
scales	O
can	O
differentiate	O
between	O
groups	O
of	O
subjects	O
,	O
it	O
may	O
be	O
worthwhile	O
to	O
categorize	O
subjects	O
by	O
a	O
more	O
clinically	O
relevant	O
measure	O
,	O
such	O
as	O
platelet	O
count	O
.	O

Several	O
limitations	O
should	O
be	O
considered	O
when	O
interpreting	O
our	O
findings	O
.	O

Subjects	O
were	O
drawn	O
from	O
a	O
convenience	O
sample	O
.	O

The	O
study	O
population	O
was	O
fairly	O
homogeneous	O
,	O
comprised	O
primarily	O
of	O
Caucasian	O
female	O
subjects	O
.	O

The	O
data	O
was	O
validated	O
using	O
only	O
patient	B
-	O
reported	O
data	O
collected	O
via	O
questionnaire	O
.	O

The	O
lack	O
of	O
clinical	O
data	O
in	O
this	O
initial	O
validation	O
study	O
will	O
be	O
addressed	O
in	O
on	O
-	O
going	O
pivotal	O
trials	O
that	O
will	O
collect	O
clinical	O
data	O
such	O
as	O
platelet	O
counts	O
and	O
platelet	O
response	O
.	O

In	O
addition	O
,	O
the	O
time	O
interval	O
between	O
the	O
initial	O
and	O
retest	O
administration	O
of	O
the	O
questionnaire	O
may	O
have	O
been	O
too	O
lengthy	O
to	O
properly	O
evaluate	O
the	O
test	O
-	O
retest	O
reliability	O
.	O

Because	O
25	O
%	O
of	O
subjects	O
did	O
not	O
complete	O
the	O
questionnaire	O
within	O
the	O
targeted	O
fifteen	O
day	O
interval	O
,	O
those	O
subjects	O
may	O
have	O
undergone	O
clinical	O
changes	O
that	O
may	O
have	O
affected	O
their	O
responses	O
.	O

In	O
future	O
validation	O
studies	O
platelet	O
counts	O
or	O
type	O
of	O
platelet	O
response	O
should	O
be	O
used	O
to	O
identify	O
a	O
stable	O
cohort	O
for	O
the	O
test	O
-	O
retest	O
analyses	O
.	O

Furthermore	O
,	O
the	O
criteria	O
used	O
to	O
categorize	O
the	O
subjects	O
for	O
the	O
known	O
groups	O
validity	O
evaluation	O
may	O
not	O
have	O
been	O
sufficient	O
to	O
allow	O
for	O
the	O
ITP	O
-	O
PAQ	O
scales	O
to	O
detect	O
differences	O
between	O
groups	O
.	O

Grouping	O
the	O
subjects	O
by	O
a	O
different	O
criterion	O
,	O
such	O
as	O
a	O
relevant	O
clinical	O
measure	O
,	O
may	O
bolster	O
the	O
findings	O
for	O
its	O
known	O
groups	O
validity	O
.	O

Conclusion	O

The	O
primary	O
goal	O
of	O
this	O
manuscript	O
was	O
to	O
describe	O
the	O
development	O
of	O
a	O
new	O
ITP	O
-	O
specific	O
HRQoL	O
questionnaire	O
for	O
adults	O
with	O
ITP	O
and	O
to	O
present	O
our	O
initial	O
findings	O
on	O
the	O
psychometric	O
properties	O
of	O
this	O
questionnaire	O
.	O

The	O
results	O
of	O
this	O
initial	O
validation	O
study	O
indicate	O
that	O
the	O
questionnaire	O
generally	O
has	O
acceptable	O
reliability	O
and	O
validity	O
.	O

We	O
plan	O
to	O
conduct	O
additional	O
analyses	O
using	O
more	O
objective	O
clinical	O
measures	O
such	O
as	O
platelet	O
counts	O
as	O
a	O
criterion	O
for	O
known	O
groups	O
validity	O
.	O

Further	O
validation	O
work	O
should	O
also	O
be	O
conducted	O
to	O
assess	O
its	O
responsiveness	O
and	O
to	O
estimate	O
its	O
minimal	O
clinical	O
important	O
difference	O
value	O
so	O
that	O
it	O
can	O
become	O
a	O
more	O
widely	O
used	O
HRQoL	O
measure	O
in	O
the	O
ITP	O
population	O
.	O

Competing	O
interests	O

The	O
validation	O
study	O
design	O
,	O
analysis	O
,	O
interpretation	O
of	O
results	O
,	O
and	O
the	O
writing	O
of	O
the	O
manuscript	O
represent	O
the	O
joint	O
collaboration	O
of	O
all	O
authors	O
of	O
this	O
study	O
,	O
which	O
was	O
funded	O
solely	O
by	O
Amgen	O
,	O
Inc	O
,	O
Thousand	O
Oaks	O
,	O
California	O
,	O
USA	O
.	O

Ovation	O
Research	O
Group	O
provided	O
no	O
additional	O
funding	O
for	O
this	O
study	O
.	O

The	O
decision	O
to	O
submit	O
this	O
manuscript	O
for	O
publication	O
was	O
subject	O
to	O
the	O
approval	O
of	O
Amgen	O
,	O
Inc	O
.	O
and	O
all	O
authors	O
.	O

Gary	O
Okano	O
and	O
Janet	O
Nichol	O
are	O
employees	O
of	O
Amgen	O
,	O
Inc	O
.	O

James	O
Bussel	O
is	O
an	O
employee	O
of	O
Weill	O
Cornell	O
Medical	O
Center	O
.	O

James	O
George	O
is	O
employed	O
by	O
the	O
University	O
of	O
Oklahoma	O
Health	O
Sciences	O
Center	O
.	O

Robert	O
McMillan	O
is	O
a	O
Professor	O
Emeritus	O
of	O
the	O
Scripps	O
Research	O
Institute	O
.	O

Susan	O
Mathias	O
is	O
an	O
employee	O
of	O
Ovation	O
Research	O
Group	O
.	O

Authors	O
'	O
contributions	O

SDM	O
supervised	O
the	O
interpretation	O
of	O
the	O
results	O
from	O
the	O
validation	O
study	O
,	O
and	O
drafted	O
the	O
manuscript	O
.	O

JBB	O
,	O
JNG	O
,	O
RM	O
,	O
and	O
JLN	O
provided	O
clinical	O
expertise	O
in	O
the	O
development	O
of	O
the	O
questionnaire	O
,	O
and	O
participated	O
in	O
the	O
design	O
and	O
execution	O
of	O
the	O
study	O
.	O

GJO	O
assisted	O
in	O
interpreting	O
the	O
results	O
and	O
drafting	O
the	O
manuscript	O
.	O

All	O
authors	O
read	O
and	O
approved	O
the	O
final	O
manuscript	O
.	O

Estrogen	O
receptor	O
alpha	O
(	O
ER	O
alpha	O
)	O
mRNA	O
copy	O
numbers	O
in	O
immunohistochemicall	O
ER	O
alpha	O
-	O
positive	O
-	O
,	O
and	O
negative	O
breast	O
cancer	O
tissues	O

Abstract	O

Background	O

The	O
presence	O
of	O
ER	O
alpha	O
is	O
the	O
basis	O
for	O
treating	O
breast	O
cancer	O
patients	B
with	O
targeted	O
molecular	O
therapies	O
that	O
block	O
estrogen	O
stimulation	O
of	O
breast	O
cancer	O
cell	O
division	O
.	O

To	O
select	O
patients	B
for	O
the	O
above	O
therapies	O
,	O
currently	O
,	O
the	O
ER	O
alpha	O
presence	O
in	O
breast	O
cancer	O
tissues	O
is	O
determined	O
in	O
clinical	O
laboratories	O
by	O
microscopically	O
scoring	O
the	O
slides	O
subjected	O
to	O
immunohistochemistry	O
(	O
IHC	O
)	O
.	O

This	O
method	O
is	O
not	O
quantitative	O
,	O
highly	O
subjective	O
and	O
requires	O
large	O
amount	O
of	O
tumor	O
tissue	O
,	O
therefore	O
,	O
cannot	O
be	O
applied	O
to	O
sterotactic	O
and	O
ultrasound	O
guided	O
biopsy	O
samples	O
.	O

To	O
circumvent	O
these	O
problems	O
,	O
we	O
previously	O
developed	O
quantitative	O
real	O
-	O
time	O
PCR	O
based	O
molecular	O
assay	O
that	O
can	O
be	O
applied	O
to	O
determine	O
mRNA	O
copies	O
of	O
ER	O
alpha	O
in	O
picogram	O
amounts	O
of	O
total	O
RNA	O
from	O
tumor	O
samples	O
.	O

However	O
,	O
it	O
is	O
not	O
known	O
how	O
the	O
mRNA	O
copy	O
numbers	O
correlate	O
to	O
IHC	O
positive	O
and	O
negative	O
status	O
.	O

Methods	O

In	O
the	O
current	O
study	O
we	O
determined	O
the	O
copy	O
numbers	O
of	O
ER	O
alpha	O
mRNA	O
by	O
Q	O
RTPCR	O
in	O
breast	O
cancer	O
tissues	O
that	O
were	O
graded	O
as	O
ER	O
alpha	O
-	O
positive	O
and	O
negative	O
by	O
1	O
)	O
IHC	O
and	O
2	O
)	O
functional	O
estrogen	O
binding	O
assay	O
and	O
statistically	O
analyzed	O
the	O
data	O
.	O

Results	O

We	O
demonstrate	O
here	O
that	O
ER	O
alpha	O
mRNA	O
copy	O
numbers	O
are	O
not	O
significantly	O
different	O
in	O
tissues	O
that	O
are	O
graded	O
as	O
positive	O
by	O
IHC	O
and	O
ligand	O
binding	O
assays	O
.	O

We	O
establish	O
here	O
a	O
cut	O
of	O
value	O
of	O
5	O
x	O
106	O
copies	O
per	O
1010	O
mRNA	O
copies	O
of	O
GAPDH	O
with	O
an	O
Odds	O
Radio	O
of	O
39	O
.	O
4	O
,	O
Sensitivity	O
of	O
0	O
.	O
81	O
and	O
Specificity	O
of	O
0	O
.	O
90	O
in	O
breast	O
cancer	O
tissues	O
that	O
are	O
negative	O
for	O
ER	O
alpha	O
protein	O
by	O
IHC	O
and	O
estrogen	O
binding	O
assays	O
.	O

ROC	O
analysis	O
of	O
the	O
data	O
gave	O
an	O
area	O
of	O
0	O
.	O
8967	O
under	O
the	O
curve	O
.	O

Conclusion	O

We	O
expect	O
that	O
the	O
cut	O
off	O
values	O
determined	O
here	O
will	O
be	O
highly	O
significant	O
for	O
applying	O
molecular	O
assay	O
in	O
the	O
place	O
of	O
IHC	O
in	O
clinical	O
laboratories	O
for	O
evaluating	O
the	O
presence	O
of	O
ER	O
alpha	O
for	O
prognostic	O
and	O
therapeutic	O
purposes	O
.	O

Background	O

Breast	O
cancer	O
is	O
the	O
most	O
diagnosed	O
and	O
the	O
second	O
leading	O
cause	O
of	O
cancer	O
deaths	O
for	O
women	B
in	O
the	O
United	O
States	O
striking	O
about	O
300	O
,	O
000	O
and	O
killing	O
about	O
40	O
,	O
000	O
women	B
a	O
year	O
[	O
1	O
]	O
.	O

A	O
substantial	O
body	O
of	O
epidemiological	O
,	O
experimental	O
and	O
clinical	O
evidence	O
indicated	O
that	O
unopposed	O
stimulation	O
of	O
breast	O
epithelial	O
cells	O
by	O
the	O
natural	O
hormone	O
,	O
estrogen	O
,	O
plays	O
a	O
major	O
role	O
in	O
the	O
progression	O
of	O
breast	O
cancers	O
[	O
2	O
]	O
.	O

Because	O
endogenous	O
estrogens	O
directly	O
promote	O
the	O
growth	O
of	O
breast	O
cancer	O
cells	O
,	O
estrogen	O
deprivation	O
either	O
by	O
inhibiting	O
its	O
biosynthesis	O
(	O
aromatase	O
inhibitors	O
)	O
or	O
blocking	O
estrogen	O
-	O
mediated	O
gene	O
transcription	O
(	O
tamoxifen	O
)	O
through	O
its	O
high	O
affinity	O
receptor	O
,	O
the	O
estrogen	O
receptor	O
alpha	O
(	O
ER	O
alpha	O
)	O
,	O
are	O
the	O
primary	O
lines	O
of	O
therapy	O
for	O
breast	O
cancer	O
patients	B
.	O

In	O
most	O
cases	O
,	O
the	O
efficacy	O
of	O
the	O
above	O
treatments	O
has	O
correlated	O
with	O
the	O
presence	O
of	O
ER	O
alpha	O
in	O
the	O
tumor	O
tissues	O
.	O

Currently	O
,	O
only	O
those	O
patients	B
who	O
express	O
ER	O
alpha	O
in	O
their	O
tumors	O
are	O
chosen	O
for	O
aromatase	O
inhibitor	O
or	O
tamoxifen	O
therapies	O
.	O

In	O
addition	O
to	O
being	O
a	O
therapeutic	O
target	O
,	O
ER	O
alpha	O
was	O
also	O
shown	O
to	O
be	O
the	O
most	O
important	O
factor	O
to	O
predict	O
breast	O
cancer	O
prognosis	O
.	O

The	O
patients	B
who	O
express	O
ER	O
alpha	O
in	O
their	O
tumors	O
have	O
an	O
overall	O
longer	O
cancer	O
-	O
free	O
survival	O
and	O
lower	O
recurrence	O
rates	O
than	O
patients	B
who	O
do	O
not	O
express	O
this	O
receptor	O
[	O
3	O
]	O
.	O

To	O
predict	O
prognosis	O
and	O
identify	O
patients	B
for	O
the	O
above	O
two	O
anti	O
-	O
estrogen	O
therapies	O
,	O
every	O
breast	O
cancer	O
tissue	O
is	O
currently	O
screened	O
for	O
the	O
presence	O
of	O
ER	O
alpha	O
before	O
a	O
treatment	O
regimen	O
is	O
selected	O
for	O
any	O
breast	O
cancer	O
patient	B
.	O

The	O
presence	O
of	O
ER	O
alpha	O
in	O
breast	O
tumors	O
was	O
originally	O
determined	O
in	O
clinical	O
labs	O
by	O
estrogen	O
binding	O
assay	O
for	O
about	O
20	O
years	O
.	O

However	O
,	O
when	O
the	O
tumors	O
were	O
detected	O
at	O
comparatively	O
smaller	O
sizes	O
and	O
highly	O
specific	O
monoclonal	O
antibodies	O
were	O
developed	O
that	O
could	O
detect	O
ER	O
alpha	O
both	O
in	O
the	O
fresh	O
frozen	O
as	O
well	O
as	O
formalin	O
fixed	O
paraffin	O
-	O
embedded	O
tissues	O
,	O
the	O
clinical	O
labs	O
switched	O
to	O
immunohistochemistry	O
(	O
IHC	O
)	O
from	O
estrogen	O
binding	O
assay	O
for	O
determining	O
the	O
presence	O
of	O
ER	O
alpha	O
.	O

Currently	O
ER	O
alpha	O
is	O
determined	O
in	O
the	O
clinical	O
laboratories	O
from	O
rough	O
estimates	O
yielded	O
by	O
microscopically	O
scoring	O
the	O
slides	O
subjected	O
to	O
IHC	O
technique	O
using	O
antibodies	O
against	O
the	O
N	O
-	O
terminal	O
A	O
/	O
B	O
region	O
of	O
ER	O
alpha	O
.	O

Although	O
this	O
procedure	O
is	O
used	O
for	O
over	O
ten	O
years	O
,	O
it	O
has	O
several	O
limitations	O
including	O
not	O
quantitative	O
,	O
highly	O
subjective	O
,	O
variations	O
due	O
to	O
antibody	O
preparations	O
,	O
variations	O
from	O
one	O
clinical	O
lab	O
to	O
other	O
and	O
comparatively	O
large	O
sample	O
size	O
requirement	O
.	O

In	O
recent	O
times	O
,	O
due	O
to	O
increased	O
awareness	O
and	O
substantially	O
improved	O
screening	O
methods	O
,	O
breast	O
cancers	O
are	O
detected	O
at	O
very	O
early	O
stages	O
and	O
excised	O
,	O
in	O
a	O
large	O
majority	O
of	O
cases	O
,	O
by	O
stereotactic	O
and	O
ultrasound	O
guided	O
techniques	O
.	O

In	O
these	O
cases	O
the	O
limited	O
amount	O
of	O
tumor	O
tissue	O
that	O
remains	O
after	O
histological	O
testing	O
restricts	O
determining	O
ER	O
alpha	O
status	O
for	O
prognostic	O
and	O
therapeutic	O
purposes	O
by	O
IHC	O
.	O

In	O
many	O
cases	O
,	O
ER	O
alpha	O
status	O
is	O
not	O
determined	O
due	O
to	O
insufficient	O
amount	O
of	O
tumor	O
tissue	O
.	O

For	O
these	O
reasons	O
there	O
is	O
an	O
urgent	O
need	O
to	O
switch	O
to	O
a	O
procedure	O
that	O
can	O
detect	O
ER	O
alpha	O
in	O
a	O
very	O
small	O
amount	O
of	O
tumor	O
tissue	O
obtained	O
by	O
the	O
above	O
methods	O
.	O

There	O
is	O
a	O
general	O
consensus	O
that	O
ER	O
alpha	O
mRNA	O
quantification	O
is	O
a	O
more	O
suited	O
technique	O
for	O
detecting	O
its	O
presence	O
in	O
tumor	O
tissues	O
.	O

Several	O
PCR	O
based	O
approaches	O
have	O
been	O
described	O
for	O
detecting	O
the	O
presence	O
of	O
ER	O
alpha	O
in	O
breast	O
cancer	O
tissues	O
[	O
4	O
,	O
5	O
]	O
.	O

We	O
recently	O
developed	O
a	O
highly	O
sensitive	O
real	O
-	O
time	O
PCR	O
based	O
quantitative	O
molecular	O
assay	O
that	O
can	O
detect	O
and	O
quantify	O
as	O
low	O
as	O
50	O
-	O
100	O
copies	O
of	O
ER	O
alpha	O
mRNA	O
from	O
as	O
small	O
as	O
40	O
picograms	O
of	O
total	O
RNA	O
from	O
breast	O
cancer	O
tissues	O
.	O

Because	O
quantitative	O
real	O
-	O
time	O
PCR	O
is	O
a	O
high	O
through	O
-	O
put	O
method	O
,	O
it	O
could	O
be	O
automated	O
to	O
apply	O
in	O
clinical	O
laboratories	O
.	O

However	O
,	O
it	O
is	O
not	O
known	O
how	O
the	O
ER	O
alpha	O
mRNA	O
copy	O
numbers	O
correlate	O
to	O
ER	O
alpha	O
positivity	O
and	O
negativity	O
by	O
IHC	O
assay	O
.	O

Establishing	O
a	O
cut	O
off	O
value	O
in	O
IHC	O
negative	O
tissues	O
is	O
required	O
for	O
the	O
application	O
of	O
molecular	O
assay	O
in	O
the	O
place	O
of	O
IHC	O
assay	O
.	O

To	O
determine	O
the	O
cut	O
off	O
value	O
,	O
we	O
have	O
profiled	O
ER	O
alpha	O
mRNA	O
copy	O
numbers	O
in	O
breast	O
cancer	O
tissues	O
which	O
have	O
been	O
graded	O
as	O
ER	O
alpha	O
positive	O
and	O
negative	O
by	O
IHC	O
and	O
estrogen	O
binding	O
assays	O
.	O

We	O
demonstrate	O
here	O
that	O
ER	O
alpha	O
mRNA	O
copy	O
numbers	O
are	O
not	O
significantly	O
different	O
in	O
tissues	O
that	O
were	O
graded	O
as	O
positive	O
by	O
IHC	O
and	O
ligand	O
binding	O
assays	O
.	O

However	O
,	O
ER	O
alpha	O
positive	O
tissues	O
,	O
either	O
by	O
IHC	O
or	O
estrogen	O
binding	O
assays	O
,	O
express	O
significantly	O
higher	O
mRNA	O
copy	O
numbers	O
than	O
the	O
negative	O
tissues	O
.	O

We	O
have	O
determined	O
the	O
cut	O
off	O
values	O
of	O
ER	O
alpha	O
mRNA	O
copy	O
numbers	O
by	O
molecular	O
assay	O
that	O
correlate	O
to	O
ER	O
alpha	O
negativity	O
by	O
both	O
IHC	O
and	O
ligand	O
binding	O
assays	O
using	O
CART	O
program	O
(	O
Classification	O
And	O
Regression	O
Tree	O
)	O
.	O

We	O
expect	O
that	O
the	O
cut	O
off	O
values	O
determined	O
here	O
will	O
be	O
highly	O
significant	O
for	O
applying	O
molecular	O
assay	O
in	O
the	O
place	O
of	O
IHC	O
in	O
clinical	O
laboratories	O
for	O
determining	O
the	O
ER	O
alpha	O
status	O
for	O
prognostic	O
and	O
therapeutic	O
purposes	O
.	O

Methods	O

All	O
the	O
primers	O
used	O
in	O
the	O
current	O
study	O
were	O
synthesized	O
by	O
Gibco	O
-	O
BRL	O
Life	O
Technologies	O
.	O

TaqMan	O
Universal	O
PCR	O
Master	O
Mix	O
(	O
Cat	O
#	O
4304437	O
)	O
was	O
from	O
Applied	O
Biosystems	O
.	O

5	O
'	O
FAM	O
and	O
3	O
'	O
TAMARA	O
labeled	O
oligonucleotide	O
probes	O
were	O
synthesized	O
by	O
Applied	O
Biosystems	O
and	O
available	O
from	O
previous	O
studies	O
.	O

PCR	O
quality	O
water	O
and	O
Tris	O
-	O
EDTA	O
buffer	O
were	O
from	O
BioWhittaker	O
.	O

Breast	O
tumor	O
samples	O

Breast	O
cancer	O
tissues	O
with	O
known	O
ER	O
alpha	O
status	O
by	O
IHC	O
and	O
ligand	O
binding	O
assay	O
were	O
available	O
from	O
previous	O
studies	O
[	O
6	O
-	O
9	O
]	O
.	O

Briefly	O
,	O
the	O
tumor	O
samples	O
were	O
collected	O
from	O
either	O
biopsy	O
or	O
mastectomies	O
immediately	O
after	O
surgery	O
and	O
stored	O
at	O
-	O
80	O
degrees	O
C	O
until	O
use	O
.	O

Fresh	O
tumor	O
tissue	O
samples	O
for	O
ER	O
alpha	O
quantification	O
were	O
routinely	O
harvested	O
immediately	O
adjacent	O
to	O
the	O
histologic	O
/	O
diagnostic	O
sections	O
and	O
considered	O
to	O
be	O
representative	O
of	O
the	O
tissue	O
used	O
for	O
diagnosis	O
.	O

All	O
the	O
samples	O
were	O
examined	O
by	O
a	O
pathologist	O
and	O
tissues	O
containing	O
>	O
80	O
%	O
cancer	O
cells	O
were	O
excised	O
and	O
used	O
for	O
ER	O
alpha	O
mRNA	O
quantification	O
.	O

The	O
ER	O
alpha	O
-	O
status	O
for	O
the	O
samples	O
used	O
in	O
this	O
study	O
was	O
determined	O
either	O
by	O
IHC	O
using	O
monoclonal	O
antibodies	O
against	O
NH2	O
-	O
terminal	O
portion	O
of	O
the	O
molecule	O
at	O
Oncotech	O
Laboratories	O
,	O
Irwine	O
,	O
CA	O
,	O
or	O
by	O
ligand	O
binding	O
assay	O
as	O
described	O
[	O
10	O
]	O
.	O

The	O
tumor	O
tissues	O
were	O
considered	O
positive	O
for	O
ER	O
alpha	O
by	O
IHC	O
if	O
>	O
5	O
%	O
of	O
cancer	O
cells	O
showed	O
positive	O
nuclear	O
staining	O
.	O

The	O
tumor	O
tissues	O
that	O
were	O
diagnosed	O
as	O
ER	O
alpha	O
positive	O
by	O
estrogen	O
binding	O
assay	O
had	O
>	O
3	O
fmol	O
of	O
ER	O
/	O
mg	O
of	O
total	O
tissue	O
extract	O
.	O

A	O
total	O
of	O
70	O
samples	O
positive	O
by	O
IHC	O
,	O
33	O
positive	O
by	O
estrogen	O
binding	O
assay	O
,	O
43	O
negative	O
by	O
IHC	O
and	O
20	O
negative	O
by	O
estrogen	O
binding	O
assay	O
were	O
included	O
in	O
the	O
current	O
study	O
(	O
Tables	O
1	O
,	O
2	O
,	O
3	O
and	O
4	O
respectively	O
)	O
.	O

The	O
tumor	O
tissues	O
were	O
processed	O
to	O
isolate	O
total	O
RNA	O
and	O
cDNAs	O
prepared	O
as	O
previously	O
described	O
[	O
6	O
-	O
9	O
]	O
.	O

Howard	O
University	O
Institutional	O
Review	O
Board	O
granted	O
the	O
ethical	O
approval	O
of	O
Tumor	O
collection	O
procedures	O
for	O
the	O
study	O
.	O

Absolute	O
quantification	O
of	O
ER	O
alpha	O
mRNA	O
copy	O
numbers	O
by	O
quantitative	O
real	O
-	O
time	O
PCR	O

Absolute	O
quantification	O
of	O
ER	O
alpha	O
transcript	O
copy	O
numbers	O
was	O
achieved	O
by	O
quantitative	O
real	O
-	O
time	O
PCR	O
in	O
ABI	O
Prism	O
GeneAmp	O
7900	O
HT	O
Sequence	O
Detection	O
System	O
as	O
described	O
previously	O
(	O
9	O
)	O
.	O

Briefly	O
,	O
a	O
typical	O
real	O
-	O
time	O
PCR	O
reaction	O
mixture	O
contained	O
cDNA	O
prepared	O
from	O
reverse	O
transcription	O
of	O
0	O
.	O
5	O
-	O
5	O
nanograms	O
of	O
tumor	O
tissue	O
total	O
RNA	O
,	O
0	O
.	O
04	O
micromolar	O
each	O
of	O
sense	O
and	O
anti	O
-	O
sense	O
primers	O
,	O
0	O
.	O
05	O
micromolar	O
5	O
'	O
FAM	O
and	O
3	O
'	O
TAMARA	O
labeled	O
oligonucleotide	O
probe	O
and	O
1	O
x	O
Taqman	O
Universal	O
PCR	O
Mix	O
in	O
a	O
total	O
volume	O
of	O
25	O
mu	O
l	O
.	O

PCR	O
conditions	O
were	O
initial	O
hold	O
at	O
50	O
degrees	O
C	O
for	O
two	O
minutes	O
,	O
followed	O
by	O
denaturation	O
for	O
ten	O
minutes	O
at	O
95	O
degrees	O
C	O
,	O
and	O
denaturation	O
for	O
15	O
seconds	O
at	O
95	O
degrees	O
C	O
in	O
the	O
subsequent	O
cycles	O
and	O
annealing	O
and	O
extension	O
for	O
1	O
min	O
at	O
60	O
degrees	O
C	O
for	O
40	O
cycles	O
.	O

The	O
ER	O
alpha	O
mRNA	O
copy	O
numbers	O
in	O
tumor	O
tissues	O
were	O
determined	O
in	O
comparison	O
with	O
a	O
standard	O
graph	O
constructed	O
simultaneously	O
using	O
102	O
,	O
103	O
,	O
104	O
,	O
105	O
,	O
106	O
,	O
107	O
,	O
108	O
,	O
and	O
109	O
copies	O
of	O
reverse	O
transcribed	O
cRNA	O
of	O
ER	O
alpha	O
.	O

All	O
the	O
samples	O
were	O
amplified	O
in	O
triplicate	O
and	O
real	O
-	O
time	O
PCRs	O
were	O
repeated	O
four	O
times	O
.	O

The	O
ER	O
alpha	O
mRNA	O
copy	O
numbers	O
in	O
tumor	O
tissues	O
were	O
normalized	O
to	O
mRNA	O
copy	O
numbers	O
of	O
the	O
house	O
keeping	O
gene	O
,	O
glyceraldehyde	O
3	O
-	O
phosphate	O
dehydrogenase	O
(	O
GAPDH	O
)	O
.	O

GAPDH	O
copy	O
numbers	O
were	O
determined	O
as	O
previously	O
described	O
[	O
11	O
,	O
12	O
]	O
.	O

The	O
sense	O
,	O
and	O
anti	O
-	O
sense	O
primers	O
and	O
probe	O
for	O
quantifying	O
the	O
mRNA	O
copy	O
numbers	O
of	O
ER	O
alpha	O
were	O
5	O
'	O
caagcccgctcatgatcaa	O
3	O
'	O
(	O
position	O
,	O
exon	O
4	O
,	O
bp	O
1110	O
-	O
1128	O
)	O
,	O
5	O
'	O
ctgatcatggagggtcaaat	O
'	O
(	O
position	O
,	O
exon	O
5	O
,	O
bp	O
1358	O
-	O
1338	O
)	O
and	O
FAM	O
5	O
'	O
agaacagcctggccttgtcc	O
'	O
TAMARA	O
(	O
position	O
,	O
exon	O
4	O
,	O
bp	O
1140	O
-	O
1162	O
)	O
respectively	O
.	O

The	O
sense	O
and	O
anti	O
-	O
sense	O
primers	O
and	O
probe	O
for	O
quantifying	O
GAPDH	O
mRNA	O
copy	O
numbers	O
were	O
5	O
'	O
ttccagg	O
agcgag	O
atccct3	O
'	O
(	O
position	O
,	O
bp	O
304	O
-	O
322	O
)	O
,	O
5	O
'	O
ggctgttgtcatacttctca	O
'	O
(	O
position	O
,	O
bp	O
483	O
-	O
505	O
)	O
and	O
FAM	O
5	O
'	O
tgctggcgctgagtacgtcg	O
'	O
TAMARA	O
(	O
position	O
,	O
bp	O
342	O
-	O
363	O
)	O
respectively	O
.	O

Primer	O
positions	O
of	O
ER	O
alpha	O
and	O
GAPDH	O
nucleotide	O
sequences	O
were	O
as	O
described	O
[	O
13	O
,	O
14	O
]	O
.	O

Statistical	O
analysis	O

Wilcoxon	O
-	O
rank	O
-	O
sum	O
test	O
and	O
standard	O
two	O
-	O
sample	O
t	O
-	O
test	O
were	O
used	O
to	O
determine	O
whether	O
the	O
mRNA	O
copy	O
numbers	O
were	O
significantly	O
different	O
in	O
breast	O
cancer	O
tissues	O
that	O
were	O
1	O
)	O
ER	O
alpha	O
-	O
positive	O
and	O
ER	O
alpha	O
-	O
negative	O
by	O
IHC	O
,	O
2	O
)	O
ER	O
alpha	O
-	O
positive	O
and	O
ER	O
alpha	O
-	O
negative	O
by	O
estrogen	O
binding	O
assays	O
,	O
3	O
)	O
ER	O
alpha	O
positive	O
by	O
IHC	O
and	O
estrogen	O
binding	O
assays	O
,	O
and	O
4	O
)	O
ER	O
alpha	O
-	O
negative	O
by	O
IHC	O
and	O
estrogen	O
binding	O
assays	O
.	O

Test	O
results	O
were	O
considered	O
significant	O
if	O
P	O
<	O
=	O
0	O
.	O

05	O
.	O

To	O
determine	O
the	O
cut	O
-	O
off	O
value	O
/	O
maximum	O
level	O
of	O
mRNA	O
copy	O
numbers	O
in	O
the	O
samples	O
which	O
were	O
negative	O
by	O
IHC	O
and	O
estrogen	O
binding	O
assays	O
,	O
we	O
used	O
CART	O
(	O
Classification	O
Regression	O
Tree	O
)	O
[	O
15	O
,	O
16	O
]	O
program	O
.	O

The	O
data	O
consisting	O
of	O
103	O
ER	O
alpha	O
positive	O
and	O
63	O
ER	O
alpha	O
negative	O
samples	O
which	O
had	O
a	O
predictive	O
variable	O
,	O
mRNA	O
copy	O
numbers	O
,	O
were	O
partitioned	O
into	O
two	O
groups	O
using	O
CART	O
program	O
.	O

This	O
program	O
determines	O
the	O
best	O
cut	O
-	O
off	O
value	O
copy	O
numbers	O
in	O
the	O
sense	O
that	O
the	O
OR	O
(	O
Odds	O
Ratio	O
,	O
ER	O
alpha	O
positive	O
to	O
ER	O
alpha	O
negative	O
in	O
our	O
case	O
)	O
of	O
the	O
two	O
groups	O
(	O
with	O
copy	O
number	O
greater	O
than	O
the	O
cut	O
-	O
off	O
value	O
in	O
one	O
group	O
and	O
less	O
or	O
equal	O
to	O
the	O
cut	O
-	O
off	O
value	O
in	O
the	O
other	O
)	O
is	O
maximized	O
.	O

Receiver	O
Operating	O
Characteristic	O
(	O
ROC	O
)	O
analysis	O
was	O
performed	O
to	O
determine	O
the	O
sensitivity	O
and	O
specificity	O
of	O
the	O
RNA	O
based	O
molecular	O
assay	O
.	O

The	O
ROC	O
curves	O
were	O
generated	O
by	O
connecting	O
all	O
the	O
points	O
determined	O
by	O
the	O
copy	O
numbers	O
in	O
all	O
the	O
samples	O
in	O
an	O
increasing	O
order	O
.	O

Since	O
data	O
on	O
IHC	O
grading	O
as	O
percent	O
positive	O
cells	O
were	O
available	O
on	O
some	O
of	O
the	O
samples	O
,	O
the	O
correlation	O
between	O
the	O
IHC	O
grading	O
and	O
the	O
mRNA	O
copy	O
number	O
was	O
determined	O
both	O
in	O
the	O
original	O
scale	O
and	O
in	O
logarithmic	O
transformations	O
scale	O
using	O
S	O
-	O
PLUS	O
software	O
.	O

Results	O

We	O
have	O
undertaken	O
the	O
current	O
study	O
to	O
determine	O
ER	O
alpha	O
mRNA	O
copy	O
numbers	O
in	O
breast	O
cancer	O
tissues	O
that	O
were	O
positive	O
and	O
negative	O
by	O
two	O
conventional	O
methods	O
of	O
assaying	O
ER	O
alpha	O
protein	O
,	O
IHC	O
and	O
estrogen	O
binding	O
.	O

The	O
rational	O
for	O
undertaking	O
this	O
study	O
is	O
that	O
once	O
we	O
establish	O
a	O
threshold	O
value	O
in	O
IHC	O
negative	O
tissues	O
,	O
then	O
the	O
molecular	O
assay	O
could	O
be	O
applied	O
in	O
clinical	O
laboratories	O
in	O
the	O
place	O
of	O
currently	O
used	O
IHC	O
assay	O
for	O
determining	O
the	O
status	O
of	O
ER	O
alpha	O
for	O
prognostic	O
and	O
therapeutic	O
purposes	O
.	O

Our	O
rational	O
for	O
establishing	O
a	O
cut	O
off	O
value	O
is	O
that	O
any	O
patient	B
who	O
expresses	O
above	O
the	O
cut	O
off	O
level	O
could	O
be	O
selected	O
as	O
a	O
candidate	O
for	O
anti	O
-	O
estrogen	O
therapies	O
and	O
could	O
be	O
considered	O
to	O
have	O
good	O
prognosis	O
.	O

We	O
first	O
profiled	O
ER	O
alpha	O
mRNA	O
copy	O
numbers	O
in	O
70	O
samples	O
positive	O
by	O
IHC	O
,	O
43	O
negative	O
by	O
IHC	O
,	O
33	O
positive	O
by	O
estrogen	O
binding	O
assay	O
and	O
20	O
negative	O
by	O
estrogen	O
binding	O
assay	O
.	O

The	O
data	O
are	O
presented	O
in	O
Tables	O
1	O
,	O
3	O
,	O
2	O
and	O
4	O
respectively	O
.	O

A	O
box	O
plot	O
drawn	O
for	O
the	O
copy	O
numbers	O
(	O
logarithm	O
base	O
2	O
scale	O
)	O
in	O
the	O
four	O
groups	O
(	O
positive	O
and	O
negative	O
by	O
IHC	O
and	O
by	O
estrogen	O
binding	O
assay	O
)	O
using	O
S	O
-	O
PLUS	O
software	O
is	O
shown	O
in	O
Figure	O
1	O
.	O

We	O
next	O
compared	O
the	O
quantitative	O
data	O
on	O
mRNA	O
copy	O
numbers	O
among	O
samples	O
as	O
described	O
below	O
.	O

1	O
)	O
We	O
tested	O
whether	O
the	O
two	O
conventional	O
assays	O
,	O
the	O
IHC	O
and	O
estrogen	O
binding	O
assays	O
,	O
correlate	O
in	O
terms	O
of	O
mRNA	O
copy	O
numbers	O
in	O
70	O
and	O
33	O
positive	O
tissues	O
(	O
Tables	O
1	O
and	O
2	O
respectively	O
)	O
using	O
Wilcoxon	O
-	O
rank	O
-	O
sum	O
test	O
and	O
standard	O
two	O
-	O
sample	O
t	O
-	O
tests	O
.	O

By	O
these	O
two	O
tests	O
,	O
we	O
did	O
not	O
find	O
significant	O
differences	O
in	O
the	O
ER	O
alpha	O
mRNA	O
copy	O
numbers	O
in	O
samples	O
that	O
were	O
ER	O
alpha	O
positive	O
by	O
IHC	O
and	O
estrogen	O
binding	O
assays	O
(	O
p	O
>	O
0	O
.	O
28	O
by	O
both	O
tests	O
)	O
.	O

2	O
)	O
We	O
also	O
compared	O
the	O
mRNA	O
copy	O
numbers	O
in	O
43	O
samples	O
negative	O
by	O
IHC	O
with	O
20	O
samples	O
negative	O
by	O
estrogen	O
binding	O
assay	O
and	O
did	O
not	O
find	O
significant	O
differences	O
(	O
Tables	O
3	O
and	O
4	O
respectively	O
)	O
(	O
p	O
>	O
0	O
.	O
25	O
by	O
the	O
above	O
two	O
tests	O
)	O
.	O

However	O
,	O
3	O
)	O
we	O
found	O
significant	O
differences	O
in	O
mRNA	O
copy	O
numbers	O
in	O
the	O
breast	O
tumors	O
that	O
were	O
IHC	O
positive	O
from	O
those	O
which	O
were	O
IHC	O
negative	O
(	O
Tables	O
1	O
and	O
3	O
respectively	O
)	O
(	O
p	O
=	O
1	O
.	O
3e	O
-	O
6	O
by	O
standard	O
two	O
-	O
sample	O
t	O
-	O
test	O
and	O
p	O
=	O
2	O
.	O
7e	O
-	O
18	O
by	O
Wilcoxon	O
-	O
rank	O
-	O
sum	O
test	O
)	O
.	O

And	O
4	O
)	O
we	O
also	O
found	O
significant	O
differences	O
in	O
the	O
samples	O
that	O
were	O
positive	O
and	O
negative	O
by	O
estrogen	O
binding	O
assay	O
(	O
Tables	O
2	O
and	O
4	O
respectively	O
)	O
(	O
p	O
=	O
7	O
.	O
6e	O
-	O
3	O
by	O
standard	O
two	O
-	O
sample	O
t	O
-	O
test	O
and	O
p	O
=	O
3	O
.	O
6e	O
-	O
7	O
by	O
Wilcoxon	O
-	O
rank	O
-	O
sum	O
test	O
)	O
.	O

After	O
establishing	O
that	O
ER	O
alpha	O
-	O
positive	O
tissues	O
express	O
significantly	O
higher	O
levels	O
of	O
mRNA	O
copy	O
numbers	O
compared	O
to	O
negative	O
tumor	O
samples	O
,	O
we	O
next	O
determined	O
the	O
maximum	O
level	O
of	O
expression	O
in	O
ER	O
alpha	O
-	O
negative	O
samples	O
using	O
CART	O
program	O
.	O

By	O
using	O
this	O
program	O
,	O
we	O
found	O
the	O
maximum	O
level	O
of	O
expression	O
of	O
mRNA	O
copy	O
numbers	O
/	O
cut	O
-	O
off	O
value	O
to	O
be	O
5	O
x	O
106	O
per	O
1010copies	O
of	O
GAPDH	O
mRNA	O
.	O

Of	O
the	O
total	O
106	O
positive	O
(	O
70	O
by	O
IHC	O
and	O
33	O
by	O
estrogen	O
binding	O
assay	O
)	O
samples	O
in	O
our	O
study	O
,	O
83	O
samples	O
showed	O
higher	O
level	O
of	O
expression	O
than	O
5	O
x	O
106	O
copies	O
per	O
1010	O
copies	O
of	O
GAPDH	O
.	O

It	O
is	O
possible	O
that	O
the	O
samples	O
that	O
showed	O
less	O
than	O
the	O
above	O
cut	O
off	O
value	O
copy	O
numbers	O
could	O
be	O
due	O
to	O
false	O
positivity	O
by	O
the	O
above	O
methods	O
.	O

In	O
a	O
total	O
of	O
63	O
negative	O
samples	O
(	O
43	O
by	O
IHC	O
and	O
20	O
by	O
estrogen	O
binding	O
assay	O
)	O
only	O
6	O
samples	O
showed	O
higher	O
expression	O
than	O
5	O
x	O
106	O
copies	O
per	O
1010GAPDH	O
copies	O
.	O

It	O
is	O
also	O
possible	O
that	O
the	O
samples	O
that	O
showed	O
higher	O
than	O
the	O
cut	O
off	O
copy	O
numbers	O
could	O
be	O
false	O
negative	O
.	O

The	O
OR	O
(	O
Odds	O
Ratio	O
)	O
in	O
the	O
two	O
groups	O
is	O
about	O
39	O
.	O
4	O
,	O
an	O
extremely	O
high	O
OR	O
value	O
.	O

The	O
counts	O
of	O
the	O
ER	O
alpha	O
-	O
positive	O
(	O
80	O
,	O
23	O
)	O
and	O
ER	O
alpha	O
-	O
negative	O
(	O
6	O
,	O
66	O
)	O
in	O
the	O
two	O
groups	O
produce	O
a	O
chi	O
-	O
square	O
value	O
of	O
88	O
.	O
2544	O
with	O
1	O
degree	O
of	O
freedom	O
,	O
which	O
is	O
consistent	O
with	O
our	O
T	O
-	O
test	O
and	O
Wilcoxon	O
-	O
rank	O
-	O
sum	O
test	O
results	O
.	O

We	O
applied	O
the	O
above	O
cut	O
off	O
value	O
and	O
determined	O
the	O
Sensitivity	O
(	O
percentage	O
of	O
samples	O
that	O
showed	O
higher	O
copy	O
numbers	O
than	O
the	O
cut	O
off	O
value	O
of	O
5	O
x	O
106	O
copies	O
per	O
1010	O
GAPDH	O
copies	O
in	O
IHC	O
positive	O
tissues	O
)	O
and	O
Specificity	O
(	O
percentage	O
of	O
samples	O
that	O
showed	O
less	O
than	O
5	O
x	O
106	O
copies	O
per	O
1010	O
GAPDH	O
copies	O
in	O
IHC	O
negative	O
tissues	O
)	O
and	O
the	O
values	O
obtained	O
were	O
0	O
.	O
81	O
and	O
0	O
.	O
90	O
respectively	O
.	O

We	O
also	O
determined	O
Receiver	O
Operating	O
Characteristics	O
using	O
S	O
-	O
PLUS	O
software	O
and	O
the	O
ROC	O
curve	O
generated	O
is	O
shown	O
in	O
Figure	O
2	O
.	O

The	O
area	O
under	O
the	O
ROC	O
curve	O
,	O
0	O
.	O
89675	O
,	O
shows	O
that	O
the	O
molecular	O
assay	O
clearly	O
distinguishes	O
the	O
positives	O
by	O
IHC	O
or	O
estrogen	O
binding	O
from	O
the	O
negative	O
tissues	O
.	O

Since	O
we	O
have	O
the	O
grading	O
score	O
as	O
percent	O
positive	O
cells	O
for	O
about	O
50	O
samples	O
(	O
Table	O
1	O
)	O
,	O
we	O
tested	O
if	O
a	O
correlation	O
exits	O
between	O
the	O
percent	O
positive	O
cells	O
by	O
IHC	O
and	O
the	O
mRNA	O
copy	O
numbers	O
using	O
S	O
-	O
PLUS	O
software	O
.	O

We	O
obtained	O
a	O
correlation	O
coefficient	O
of	O
0	O
.	O
02	O
.	O

When	O
we	O
used	O
the	O
logarithmic	O
transformations	O
scale	O
,	O
we	O
obtained	O
a	O
correlation	O
coefficient	O
of	O
0	O
.	O
037	O
.	O

These	O
results	O
indicated	O
that	O
there	O
is	O
no	O
correlation	O
between	O
the	O
percent	O
positive	O
cells	O
and	O
the	O
level	O
of	O
ER	O
alpha	O
mRNA	O
copy	O
numbers	O
.	O

These	O
observations	O
could	O
be	O
due	O
to	O
qualitative	O
nature	O
of	O
IHC	O
assay	O
.	O

The	O
IHC	O
data	O
only	O
show	O
the	O
number	O
of	O
positive	O
cells	O
but	O
not	O
quantitative	O
to	O
determine	O
the	O
level	O
of	O
ER	O
alpha	O
expression	O
.	O

The	O
molecular	O
assay	O
based	O
on	O
RNA	O
is	O
quantitative	O
to	O
determine	O
the	O
level	O
of	O
ER	O
alpha	O
expression	O
.	O

Discussion	O
and	O
conclusion	O

Previously	O
ER	O
alpha	O
mRNA	O
levels	O
in	O
immunohistochemicall	O
positive	O
and	O
negative	O
tissues	O
were	O
evaluated	O
in	O
breast	O
cancer	O
tissues	O
by	O
several	O
groups	O
using	O
conventional	O
RT	O
PCR	O
.	O

Cullen	O
et	O
al	O
[	O
17	O
]	O
determined	O
mRNA	O
levels	O
by	O
conventional	O
PCR	O
in	O
107	O
breast	O
cancer	O
tissues	O
.	O

They	O
reported	O
that	O
ER	O
alpha	O
mRNA	O
was	O
more	O
frequently	O
detected	O
in	O
ER	O
alpha	O
protein	O
positive	O
tissues	O
than	O
ER	O
alpha	O
protein	O
negative	O
tissues	O
.	O

Jarzabek	O
et	O
al	O
[	O
18	O
]	O
studied	O
ER	O
alpha	O
mRNA	O
levels	O
and	O
protein	O
levels	O
in	O
41	O
primary	O
breast	O
cancer	O
tissues	O
.	O

They	O
reported	O
the	O
presence	O
of	O
ER	O
alpha	O
mRNA	O
in	O
all	O
the	O
tissues	O
,	O
where	O
as	O
the	O
protein	O
was	O
present	O
only	O
in	O
70	O
%	O
of	O
tumor	O
tissues	O
by	O
Western	O
blotting	O
and	O
67	O
%	O
showed	O
positive	O
by	O
immunohistochemistry	O
.	O

They	O
concluded	O
that	O
lack	O
of	O
ER	O
alpha	O
protein	O
is	O
not	O
due	O
to	O
lack	O
of	O
ER	O
alpha	O
gene	O
expression	O
or	O
methylation	O
of	O
its	O
promoter	O
,	O
but	O
may	O
be	O
due	O
to	O
post	O
-	O
transcriptional	O
or	O
post	O
-	O
translational	O
mechanisms	O
.	O

Alkarain	O
et	O
al	O
[	O
19	O
]	O
reported	O
the	O
presence	O
of	O
ER	O
alpha	O
mRNA	O
in	O
immunohistochemicall	O
ER	O
alpha	O
-	O
negative	O
tissues	O
.	O

However	O
,	O
none	O
of	O
the	O
above	O
studies	O
has	O
evaluated	O
the	O
threshold	O
levels	O
of	O
ER	O
alpha	O
mRNA	O
levels	O
in	O
immunohistochemicall	O
negative	O
tissues	O
or	O
those	O
negative	O
by	O
ligand	O
binding	O
assays	O
.	O

Our	O
quantitative	O
analysis	O
of	O
ER	O
alpha	O
mRNA	O
copy	O
numbers	O
demonstrate	O
that	O
breast	O
cancer	O
tissues	O
that	O
are	O
negative	O
by	O
both	O
IHC	O
and	O
ligand	O
binding	O
express	O
significant	O
levels	O
of	O
ER	O
alpha	O
mRNA	O
.	O

The	O
reasons	O
why	O
the	O
mRNA	O
is	O
not	O
translated	O
to	O
detectable	O
protein	O
are	O
not	O
clear	O
.	O

Our	O
previous	O
studies	O
on	O
ER	O
beta	O
mRNA	O
copy	O
numbers	O
[	O
9	O
]	O
in	O
breast	O
cancer	O
tissues	O
have	O
shown	O
that	O
at	O
the	O
5	O
x	O
106	O
copies	O
per	O
1010	O
mRNA	O
copies	O
of	O
GAPDH	O
levels	O
ER	O
beta	O
protein	O
is	O
translated	O
.	O

It	O
is	O
possible	O
that	O
either	O
ER	O
alpha	O
mRNA	O
is	O
not	O
translated	O
or	O
the	O
translated	O
protein	O
is	O
degraded	O
to	O
undetectable	O
levels	O
in	O
these	O
tissues	O
.	O

The	O
results	O
and	O
the	O
analysis	O
presented	O
above	O
clearly	O
demonstrate	O
that	O
the	O
ER	O
alpha	O
positive	O
tissues	O
by	O
IHC	O
or	O
estrogen	O
binding	O
assay	O
express	O
significantly	O
higher	O
mRNA	O
copy	O
numbers	O
than	O
5	O
x	O
106	O
copies	O
per	O
1010	O
GAPDH	O
copies	O
.	O

An	O
extremely	O
high	O
Odds	O
Ratio	O
,	O
high	O
sensitivity	O
and	O
specificity	O
demonstrate	O
that	O
the	O
molecular	O
assay	O
could	O
be	O
used	O
in	O
the	O
place	O
of	O
currently	O
used	O
IHC	O
in	O
the	O
clinical	O
laboratories	O
.	O

Based	O
on	O
our	O
data	O
above	O
any	O
patient	B
who	O
has	O
more	O
than	O
5	O
x	O
106	O
copies	O
per	O
1010	O
GAPDH	O
copies	O
in	O
her	O
tumor	O
tissue	O
could	O
be	O
considered	O
positive	O
for	O
ER	O
alpha	O
,	O
could	O
be	O
selected	O
for	O
anti	O
-	O
estrogen	O
therapies	O
and	O
considered	O
to	O
have	O
good	O
prognosis	O
.	O

However	O
,	O
the	O
above	O
described	O
approach	O
has	O
some	O
limitations	O
in	O
that	O
it	O
needs	O
to	O
be	O
verified	O
on	O
a	O
defined	O
set	O
of	O
biopsy	O
samples	O
and	O
with	O
reference	O
to	O
another	O
house	O
keeping	O
gene	O
.	O

Therefore	O
,	O
the	O
results	O
should	O
be	O
interpreted	O
with	O
caution	O
and	O
undoubtedly	O
will	O
require	O
confirmation	O
by	O
a	O
larger	O
prospective	O
multi	O
-	O
centered	O
clinical	O
study	O
with	O
a	O
more	O
accurate	O
design	O
to	O
bring	O
the	O
technology	O
to	O
the	O
clinic	O
.	O

The	O
current	O
study	O
is	O
a	O
first	O
step	O
in	O
that	O
direction	O
.	O

We	O
expect	O
that	O
the	O
cost	O
effective	O
,	O
extremely	O
sensitive	O
,	O
high	O
though	O
-	O
put	O
molecular	O
assay	O
which	O
requires	O
only	O
a	O
few	O
cancer	O
cells	O
could	O
be	O
an	O
assay	O
of	O
choice	O
to	O
replace	O
IHC	O
in	O
clinical	O
labs	O
for	O
determining	O
ER	O
alpha	O
status	O
in	O
breast	O
cancer	O
tissues	O
once	O
established	O
in	O
a	O
multi	O
-	O
centered	O
prospective	O
clinical	O
study	O
.	O

Abbreviations	O

FAM	O
,	O
carboxy	O
-	O
fluorescein	O
;	O
TAMARA	O
,	O
6	O
-	O
carboxy	O
tetraethyl	O
-	O
rhodamine	O
;	O
GAPDH	O
,	O
Glyceraldehyde	O
-	O
3	O
phosphate	O
dehydrogenase	O
;	O
ER	O
alpha	O
,	O
estrogen	O
receptor	O
alpha	O
;	O
IHC	O
,	O
Immunohistochemistry	O
;	O
CART	O
,	O
Classification	O
And	O
Regression	O
Tree	O
;	O
and	O
OR	O
,	O
Odds	O
Ratio	O
and	O
ROC	O
,	O
Receiver	O
Operating	O
Characteristics	O
.	O

Competing	O
interests	O

The	O
author	O
(	O
s	O
)	O
declare	O
that	O
they	O
have	O
no	O
competing	O
interests	O
.	O

Authors	O
'	O
contributions	O

I	O
.	O

P	O
conceived	O
the	O
study	O
,	O
participated	O
in	O
the	O
design	O
of	O
the	O
study	O
,	O
performed	O
the	O
real	O
-	O
time	O
PCR	O
quantifications	O
of	O
ERalph	O
mRNA	O
copy	O
numbers	O
and	O
drafted	O
the	O
manuscript	O
.	O

Q	O
.	O
Y	O
participated	O
in	O
performing	O
the	O
statistical	O
analysis	O
of	O
the	O
data	O
.	O

Both	O
authors	O
read	O
and	O
approved	O
the	O
final	O
manuscript	O
.	O

Pre	O
-	O
publication	O
history	O

The	O
pre	O
-	O
publication	O
history	O
for	O
this	O
paper	O
can	O
be	O
accessed	O
here	O
:	O

Molecular	O
Basis	O
for	O
a	O
Lack	O
of	O
Correlation	O
between	O
Viral	O
Fitness	O
and	O
Cell	O
Killing	O
Capacity	O

Abstract	O

The	O
relationship	O
between	O
parasite	O
fitness	O
and	O
virulence	O
has	O
been	O
the	O
object	O
of	O
experimental	O
and	O
theoretical	O
studies	O
often	O
with	O
conflicting	O
conclusions	O
.	O

Here	O
,	O
we	O
provide	O
direct	O
experimental	O
evidence	O
that	O
viral	O
fitness	O
and	O
virulence	O
,	O
both	O
measured	O
in	O
the	O
same	O
biological	O
environment	O
provided	O
by	O
host	O
cells	O
in	O
culture	O
,	O
can	O
be	O
two	O
unrelated	O
traits	O
.	O

A	O
biological	O
clone	O
of	O
foot	B
-	I
and	I
-	I
mouth	I
disease	I
virus	I
acquired	O
high	O
fitness	O
and	O
virulence	O
(	O
cell	O
killing	O
capacity	O
)	O
upon	O
large	O
population	O
passages	O
in	O
cell	O
culture	O
.	O

However	O
,	O
subsequent	O
plaque	O
-	O
to	O
-	O
plaque	O
transfers	O
resulted	O
in	O
profound	O
fitness	O
loss	O
,	O
but	O
only	O
a	O
minimal	O
decrease	O
of	O
virulence	O
.	O

While	O
fitness	O
-	O
decreasing	O
mutations	O
have	O
been	O
mapped	O
throughout	O
the	O
genome	O
,	O
virulence	O
determinants	O
-	O
-	O
studied	O
here	O
with	O
mutant	O
and	O
chimeric	O
viruses	O
-	O
-	O
were	O
multigenic	O
,	O
but	O
concentrated	O
on	O
some	O
genomic	O
regions	O
.	O

Therefore	O
,	O
we	O
propose	O
a	O
model	O
in	O
which	O
viral	O
virulence	O
is	O
more	O
robust	O
to	O
mutation	O
than	O
viral	O
fitness	O
.	O

As	O
a	O
consequence	O
,	O
depending	O
on	O
the	O
passage	O
regime	O
,	O
viral	O
fitness	O
and	O
virulence	O
can	O
follow	O
different	O
evolutionary	O
trajectories	O
.	O

This	O
lack	O
of	O
correlation	O
is	O
relevant	O
to	O
current	O
models	O
of	O
attenuation	O
and	O
virulence	O
in	O
that	O
virus	O
de	O
-	O
adaptation	O
need	O
not	O
entail	O
a	O
decrease	O
of	O
virulence	O
.	O

Virulence	O
expresses	O
the	O
harm	O
that	O
parasites	O
inflict	O
upon	O
their	O
hosts	O
.	O

Many	O
studies	O
have	O
addressed	O
the	O
basis	O
of	O
virulence	O
and	O
its	O
effect	O
on	O
host	O
and	O
parasite	O
survival	O
.	O

It	O
has	O
generally	O
been	O
accepted	O
that	O
one	O
of	O
the	O
components	O
of	O
parasite	O
virulence	O
is	O
fitness	O
,	O
or	O
the	O
capacity	O
of	O
the	O
parasite	O
to	O
multiply	O
in	O
its	O
host	O
.	O

Some	O
models	O
have	O
equated	O
virulence	O
with	O
fitness	O
.	O

In	O
the	O
present	O
study	O
,	O
we	O
use	O
foot	B
-	I
and	I
-	I
mouth	I
disease	I
virus	I
(	O
FMDV	B
)	O
to	O
document	O
that	O
virulence	O
and	O
fitness	O
-	O
-	O
measured	O
in	O
the	O
same	O
biological	O
environment	O
provided	O
by	O
cells	O
in	O
culture	O
-	O
-	O
can	O
be	O
unrelated	O
traits	O
.	O

This	O
has	O
been	O
achieved	O
by	O
multiplying	O
the	O
virus	O
in	O
a	O
manner	O
that	O
mutations	O
accumulated	O
in	O
its	O
genome	O
.	O

Mutations	O
decreased	O
fitness	O
dramatically	O
,	O
but	O
not	O
virulence	O
.	O

Chimeric	O
and	O
mutant	O
viruses	O
were	O
constructed	O
to	O
show	O
that	O
virulence	O
is	O
influenced	O
by	O
only	O
some	O
of	O
the	O
FMDV	B
genes	O
,	O
while	O
fitness	O
is	O
influenced	O
by	O
the	O
entire	O
genome	O
.	O

For	O
this	O
reason	O
,	O
virulence	O
is	O
more	O
robust	O
(	O
"	O
resistant	O
"	O
)	O
than	O
fitness	O
to	O
the	O
effects	O
of	O
deleterious	O
mutations	O
.	O

The	O
fact	O
that	O
virulence	O
can	O
be	O
unrelated	O
to	O
fitness	O
has	O
implications	O
for	O
the	O
design	O
of	O
anti	O
-	O
viral	O
vaccines	O
because	O
it	O
suggests	O
that	O
it	O
may	O
be	O
possible	O
to	O
design	O
high	O
fitness	O
,	O
low	O
virulence	O
strains	O
to	O
stimulate	O
the	O
host	O
immune	O
response	O
.	O

Furthermore	O
,	O
in	O
modelling	O
studies	O
it	O
cannot	O
be	O
assumed	O
that	O
virulence	O
is	O
equal	O
to	O
fitness	O
.	O

Introduction	O

The	O
relationship	O
between	O
fitness	O
and	O
virulence	O
is	O
an	O
unsettled	O
question	O
,	O
and	O
sometimes	O
fitness	O
is	O
considered	O
a	O
component	O
of	O
the	O
virulence	O
phenotype	O
of	O
parasites	O
.	O

RNA	O
viruses	O
are	O
ideal	O
systems	O
to	O
address	O
this	O
important	O
question	O
because	O
of	O
their	O
high	O
mutability	O
and	O
fecundity	O
,	O
which	O
result	O
in	O
a	O
potential	O
for	O
rapid	O
evolution	O
,	O
and	O
also	O
because	O
of	O
the	O
availability	O
of	O
quantitative	O
fitness	O
and	O
virulence	O
assays	O
.	O

RNA	O
viruses	O
replicate	O
as	O
complex	O
and	O
dynamic	O
mutant	O
spectra	O
,	O
termed	O
viral	O
quasispecies	O
.	O

Key	O
to	O
quasispecies	O
dynamics	O
are	O
mutation	O
rates	O
in	O
the	O
range	O
of	O
10	O
-	O
3	O
to	O
10	O
-	O
5	O
substitutions	O
per	O
nucleotide	O
copied	O
,	O
and	O
competition	O
among	O
continuously	O
arising	O
variant	O
genomes	O
[	O
1	O
-	O
4	O
]	O
,	O
which	O
prompt	O
rapid	O
movements	O
in	O
sequence	O
space	O
,	O
with	O
corresponding	O
changes	O
of	O
position	O
in	O
the	O
fitness	O
landscape	O
[	O
5	O
]	O
.	O

Indeed	O
,	O
large	O
population	O
passages	O
of	O
RNA	O
viruses	O
in	O
cell	O
culture	O
permit	O
competitive	O
optimization	O
of	O
mutant	O
distributions	O
that	O
generally	O
result	O
in	O
fitness	O
gain	O
[	O
6	O
,	O
7	O
]	O
,	O
while	O
repeated	O
bottleneck	O
events	O
(	O
experimentally	O
realized	O
as	O
plaque	O
-	O
to	O
-	O
plaque	O
transfers	O
)	O
lead	O
to	O
random	O
accumulation	O
of	O
deleterious	O
mutations	O
(	O
operation	O
of	O
Muller	O
'	O
s	O
ratchet	O
[	O
8	O
]	O
)	O
and	O
result	O
in	O
average	O
fitness	O
decreases	O
[	O
9	O
-	O
13	O
]	O
.	O

Fitness	O
recovery	O
of	O
low	O
fitness	O
foot	B
-	I
and	I
-	I
mouth	I
disease	I
virus	I
(	O
FMDV	B
)	O
clones	O
occurs	O
mainly	O
with	O
introduction	O
of	O
mutations	O
along	O
the	O
genome	O
,	O
with	O
very	O
few	O
true	O
reversions	O
.	O

An	O
understanding	O
of	O
the	O
consequences	O
of	O
fitness	O
variation	O
for	O
viral	O
virulence	O
is	O
a	O
key	O
question	O
for	O
viral	O
pathogenesis	O
and	O
evolution	O
.	O

Here	O
,	O
we	O
approach	O
this	O
issue	O
with	O
FMDV	B
,	O
an	O
important	O
viral	O
pathogen	O
in	O
veterinary	O
medicine	O
[	O
14	O
]	O
,	O
and	O
one	O
that	O
fully	O
participates	O
of	O
quasispecies	O
dynamics	O
.	O

Our	O
laboratory	O
has	O
characterized	O
multiple	O
FMDV	B
variants	O
that	O
derive	O
from	O
one	O
original	O
biological	O
clone	O
,	O
and	O
that	O
occupy	O
widely	O
different	O
fitness	O
levels	O
when	O
replicating	O
in	O
a	O
defined	O
environment	O
in	O
cell	O
culture	O
.	O

We	O
define	O
fitness	O
as	O
the	O
replication	O
capacity	O
of	O
a	O
mutant	O
FMDV	B
,	O
relative	O
to	O
a	O
reference	O
FMDV	B
,	O
in	O
direct	O
growth	O
-	O
competition	O
upon	O
coinfection	O
of	O
baby	O
hamster	B
kidney	O
21	O
(	O
BHK	O
-	O
21	O
)	O
cells	O
[	O
15	O
-	O
17	O
]	O
.	O

Fitness	O
of	O
FMDV	B
in	O
BHK	O
-	O
21	O
cells	O
is	O
a	O
multigenic	O
trait	O
[	O
7	O
]	O
.	O

In	O
the	O
present	O
study	O
,	O
we	O
define	O
virulence	O
of	O
FMDV	B
as	O
the	O
capacity	O
of	O
the	O
virus	O
to	O
kill	O
BHK	O
-	O
21	O
cells	O
under	O
a	O
standard	O
set	O
of	O
cell	O
culture	O
conditions	O
[	O
18	O
]	O
.	O

Thus	O
,	O
the	O
FMDV	B
-	O
BHK	O
-	O
21	O
system	O
offered	O
a	O
means	O
to	O
investigate	O
in	O
a	O
direct	O
and	O
comparative	O
fashion	O
the	O
relationship	O
between	O
fitness	O
and	O
virulence	O
of	O
a	O
virus	O
,	O
measured	O
in	O
the	O
same	O
biological	O
environment	O
provided	O
by	O
BHK	O
-	O
21	O
cells	O
.	O

We	O
describe	O
the	O
behavior	O
of	O
an	O
FMDV	B
clone	O
(	O

)	O
,	O
which	O
has	O
a	O
history	O
of	O
repeated	O
serial	O
plaque	O
-	O
to	O
-	O
plaque	O
transfers	O
in	O
BHK	O
-	O
21	O
cells	O
[	O
11	O
]	O
,	O
that	O
attained	O
a	O
very	O
low	O
fitness	O
value	O
relative	O
to	O
its	O
parental	O
reference	O
virus	O
(	O
C	O
-	O
S8c1	O
)	O
,	O
and	O
yet	O
,	O
its	O
virulence	O
for	O
BHK	O
-	O
21	O
cells	O
was	O
significantly	O
higher	O
than	O
that	O
of	O
C	O
-	O
S8c1	O
.	O

A	O
comparative	O
study	O
of	O
the	O
capacity	O
to	O
kill	O
BHK	O
-	O
21	O
cells	O
of	O
chimeric	O
FMDVs	B
constructed	O
with	O
cDNA	O
copies	O
of	O
the	O
two	O
parental	O
FMDVs	B
indicates	O
that	O
the	O
enhanced	O
virulence	O
for	O
BHK	O
-	O
21	O
cells	O
of	O
the	O
low	O
fitness	O
clone	O
is	O
a	O
polygenic	O
trait	O
,	O
with	O
participation	O
of	O
the	O
regions	O
encoding	O
capsid	O
proteins	O
and	O
non	O
-	O
structural	O
proteins	O
2A	O
,	O
2B	O
,	O
and	O
2C	O
as	O
virulence	O
determinants	O
.	O

Three	O
specific	O
amino	O
acid	O
replacements	O
in	O
2C	O
have	O
been	O
identified	O
as	O
redundant	O
virulence	O
determinants	O
of	O
FMDV	B
for	O
BHK	O
-	O
21	O
cells	O
.	O

Thus	O
,	O
while	O
large	O
population	O
passages	O
of	O
the	O
virus	O
resulted	O
in	O
a	O
gain	O
of	O
both	O
fitness	O
and	O
virulence	O
,	O
subsequent	O
bottleneck	O
passages	O
resulted	O
in	O
a	O
decrease	O
of	O
fitness	O
but	O
not	O
of	O
virulence	O
.	O

The	O
results	O
suggest	O
that	O
fitness	O
is	O
very	O
vulnerable	O
to	O
mutation	O
in	O
any	O
genomic	O
region	O
.	O

In	O
contrast	O
,	O
because	O
of	O
the	O
involvement	O
of	O
several	O
(	O
but	O
not	O
all	O
)	O
viral	O
genes	O
in	O
virulence	O
,	O
and	O
the	O
redundant	O
effect	O
of	O
three	O
2C	O
substitutions	O
,	O
virulence	O
is	O
a	O
more	O
robust	O
phenotypic	O
trait	O
than	O
fitness	O
,	O
and	O
less	O
vulnerable	O
to	O
accumulation	O
of	O
mutations	O
.	O

Therefore	O
,	O
we	O
provide	O
direct	O
evidence	O
that	O
viral	O
fitness	O
and	O
capacity	O
to	O
kill	O
cells	O
can	O
(	O
in	O
some	O
cases	O
)	O
be	O
unrelated	O
traits	O
.	O

Furthermore	O
,	O
the	O
relationship	O
between	O
fitness	O
and	O
virulence	O
,	O
of	O
being	O
either	O
linked	O
or	O
unrelated	O
traits	O
,	O
depends	O
on	O
the	O
evolutionary	O
history	O
of	O
the	O
virus	O
.	O

This	O
observation	O
has	O
implications	O
for	O
viral	O
pathogenesis	O
,	O
and	O
sheds	O
light	O
on	O
models	O
of	O
virulence	O
proposed	O
on	O
the	O
basis	O
of	O
theoretical	O
and	O
experimental	O
studies	O
with	O
cellular	O
organisms	O
.	O

Results	O

Inability	O
of	O
FMDV	B

to	O
Establish	O
a	O
Persistent	O
Infection	O
in	O
BHK	O
-	O
21	O
Cells	O

Several	O
biological	O
clones	O
and	O
populations	O
were	O
obtained	O
by	O
passaging	O
FMDV	B
biological	O
clone	O
C	O
-	O
S8c1	O
[	O
19	O
-	O
22	O
]	O
in	O
BHK	O
-	O
21	O
cells	O
,	O
either	O
as	O
large	O
population	O
passages	O
or	O
plaque	O
-	O
to	O
-	O
plaque	O
transfers	O
(	O
Figure	O
1	O
)	O
.	O

The	O
biological	O
clones	O
and	O
populations	O
differed	O
up	O
to	O
236	O
-	O
fold	O
in	O
relative	O
fitness	O
(	O
Table	O
1	O
)	O
.	O

The	O
fitness	O
differences	O
found	O
are	O
expected	O
from	O
previous	O
results	O
on	O
fitness	O
gain	O
upon	O
large	O
population	O
passages	O
of	O
RNA	O
viruses	O
[	O
6	O
,	O
7	O
]	O
and	O
fitness	O
decrease	O
upon	O
plaque	O
-	O
to	O
-	O
plaque	O
(	O
bottleneck	O
)	O
transfers	O
[	O
9	O
-	O
13	O
]	O
.	O

The	O
initial	O
experiment	O
was	O
aimed	O
at	O
testing	O
whether	O

,	O
because	O
of	O
its	O
low	O
fitness	O
(	O
0	O
.	O
11	O
times	O
that	O
of	O
its	O
parental	O
C	O
-	O
S8c1	O
[	O
12	O
,	O
23	O
,	O
24	O
]	O
[	O
Table	O
1	O
]	O
)	O
,	O
had	O
an	O
advantage	O
in	O
establishing	O
a	O
persistent	O
non	O
-	O
cytopathic	O
infection	O
in	O
BHK	O
-	O
21	O
cells	O
as	O
compared	O
with	O
its	O
parental	O
clone	O
,	O
C	O
-	O
S8c1	O
(	O
Figure	O
1	O
)	O
.	O

A	O
persistent	O
FMDV	B
infection	O
is	O
established	O
by	O
growing	O
the	O
cells	O
that	O
survive	O
a	O
standard	O
cytolytic	O
infection	O
with	O
FMDV	B
[	O
25	O
]	O
.	O

Confluent	O
monolayers	O
of	O
BHK	O
-	O
21	O
cells	O
were	O
infected	O
either	O
with	O
C	O
-	O
S8c1	O
or	O
with	O

at	O
a	O
multiplicity	O
of	O
infection	O
(	O
MOI	O
)	O
of	O
0	O
.	O
02	O
-	O
0	O
.	O
1	O
plaque	O
-	O
forming	O
units	O
(	O
PFU	O
)	O
/	O
cell	O
(	O
2	O
x	O
106	O
cells	O
infected	O
with	O
4	O
x	O
104	O
-	O
2	O
x	O
105	O
PFU	O
)	O
.	O

Unexpectedly	O
,	O
at	O
24	O
h	O
postinfection	O
,	O
the	O
cells	O
infected	O
with	O

showed	O
extensive	O
cytopathology	O
,	O
and	O
at	O
48	O
h	O
postinfection	O
,	O
no	O
surviving	O
cells	O
were	O
observed	O
.	O

The	O
frequency	O
of	O
surviving	O
cells	O
in	O
parallel	O
infections	O
with	O
C	O
-	O
S8c1	O
was	O
5	O
x	O
10	O
-	O
3	O
-	O
9	O
x	O
10	O
-	O
3	O
,	O
which	O
is	O
consistent	O
with	O
previous	O
determinations	O
[	O
25	O
]	O
.	O

No	O
persistently	O
infected	O
BHK	O
-	O
21	O
cell	O
cultures	O
could	O
be	O
established	O
with	O

,	O
despite	O
several	O
attempts	O
.	O

Thus	O
,	O
C	O
-	O
S8c1	O
,	O
which	O
displays	O
a	O
9	O
-	O
fold	O
higher	O
relative	O
fitness	O
than	O

in	O
BHK	O
-	O
21	O
cells	O
,	O
showed	O
a	O
capacity	O
to	O
kill	O
BHK	O
-	O
21	O
cells	O
that	O
was	O
at	O
least	O
103	O
-	O
fold	O
lower	O
than	O
the	O
killing	O
capacity	O
of	O

in	O
the	O
infectivity	O
assay	O
intended	O
to	O
establish	O
a	O
persistent	O
FMDV	B
infection	O
.	O

FMDV	B
Fitness	O
and	O
Capacity	O
to	O
Kill	O
BHK	O
-	O
21	O
Cells	O
May	O
Not	O
Be	O
Positively	O
Correlated	O

The	O
capacity	O
of	O

to	O
kill	O
BHK	O
-	O
21	O
cells	O
despite	O
its	O
low	O
fitness	O
in	O
BHK	O
-	O
21	O
cells	O
led	O
us	O
to	O
quantitatively	O
examine	O
the	O
relationship	O
between	O
fitness	O
of	O
FMDV	B
and	O
its	O
capacity	O
to	O
kill	O
BHK	O
-	O
21	O
cells	O
.	O

To	O
this	O
aim	O
,	O
FMDV	B
clones	O
or	O
populations	O
were	O
compared	O
in	O
a	O
cell	O
killing	O
assay	O
,	O
consisting	O
in	O
determining	O
the	O
time	O
required	O
to	O
kill	O
104	O
BHK	O
-	O
21	O
cells	O
as	O
a	O
function	O
of	O
the	O
PFU	O
added	O
(	O
described	O
in	O
Materials	O
and	O
Methods	O
)	O
.	O

The	O
results	O
(	O
Figure	O
2A	O
)	O
indicate	O
that	O
over	O
the	O
time	O
range	O
of	O
12	O
h	O
to	O
48	O
h	O
postinfection	O
,	O
the	O
number	O
of	O
PFUs	O
needed	O
to	O
kill	O
104	O
BHK	O
-	O
21	O
cells	O
varied	O
logarithmically	O
as	O
a	O
function	O
of	O
time	O
.	O

Similar	O
quantifications	O
of	O
relative	O
virulence	O
were	O
obtained	O
by	O
measuring	O
the	O
PFU	O
needed	O
to	O
kill	O
104	O
cells	O
in	O
24	O
h	O
,	O
and	O
then	O
by	O
extrapolating	O
the	O
PFU	O
values	O
to	O
0	O
h	O
postinfection	O
(	O
Tables	O
1	O
and	O
S1	O
)	O
.	O

Virulence	O
of	O

was	O
29	O
to	O
35	O
times	O
higher	O
than	O
virulence	O
of	O
C	O
-	O
S8c1	O
,	O
despite	O
the	O
latter	O
displaying	O
a	O
9	O
-	O
fold	O
higher	O
fitness	O
(	O
Tables	O
1	O
and	O
S1	O
)	O
.	O

The	O
high	O
virulence	O
of	O

was	O
not	O
due	O
to	O
the	O
plaque	O
-	O
to	O
-	O
plaque	O
transfers	O
,	O
since	O
a	O
high	O
virulence	O
was	O
also	O
quantitated	O
for	O
its	O
parental	O
clone	O
,	O

,	O
and	O
for	O
population	O
C	O
-	O
S8p113	O
(	O
Figure	O
2B	O
;	O
Tables	O
1	O
,	O
2	O
,	O
and	O
S1	O
)	O
.	O

deviated	O
from	O
a	O
line	O
that	O
correlated	O
relative	O
fitness	O
of	O
FMDV	B
and	O
the	O
logarithm	O
of	O
cell	O
killing	O
capacity	O
,	O
as	O
reflected	O
in	O
the	O
decrease	O
of	O
the	O
regression	O
coefficient	O
(	O
R2	O
)	O
(	O
inset	O
in	O
Figure	O
2A	O
)	O
.	O

Probably	O
,	O
this	O
deviation	O
is	O
due	O
to	O
the	O
fact	O
that	O

lost	O
fitness	O
due	O
to	O
plaque	O
-	O
to	O
-	O
plaque	O
transfers	O
,	O
and	O
the	O
other	O
viruses	O
were	O
not	O
subjected	O
to	O
plaque	O
-	O
to	O
-	O
plaque	O
transfers	O
.	O

On	O
the	O
other	O
hand	O
,	O
virulence	O
determinants	O
were	O
acquired	O
during	O
the	O
large	O
population	O
passages	O
done	O
between	O
C	O
-	O
S8c1	O
and	O
C	O
-	O
S8c1p113	O
.	O

The	O
29	O
-	O
to	O
35	O
-	O
fold	O
higher	O
virulence	O
of	O

with	O
respect	O
to	O
C	O
-	O
S8c1	O
(	O
Tables	O
1	O
and	O
S1	O
)	O
,	O
despite	O
its	O
low	O
fitness	O
,	O
indicates	O
that	O
viral	O
fitness	O
and	O
virulence	O
can	O
be	O
two	O
unrelated	O
traits	O
.	O

Mapping	O
Virulence	O
Determinants	O
in	O
the	O

Genome	O

The	O
comparison	O
of	O
the	O
consensus	O
nucleotide	O
sequence	O
of	O
the	O

genome	O
with	O
that	O
of	O
C	O
-	O
S8c1	O
revealed	O
a	O
total	O
of	O
47	O
mutations	O
(	O
Table	O
S2	O
)	O
,	O
leading	O
to	O
21	O
amino	O
acid	O
replacements	O
affecting	O
structural	O
and	O
non	O
-	O
structural	O
proteins	O
(	O
Figure	O
3	O
)	O
.	O

To	O
identify	O
the	O
genomic	O
regions	O
associated	O
with	O
the	O
increased	O
virulence	O
of	O

with	O
respect	O
to	O
C	O
-	O
S8c1	O
,	O
we	O
measured	O
the	O
BHK	O
-	O
21	O
cell	O
killing	O
capacity	O
of	O
nine	O
chimeric	O
viruses	O
rescued	O
from	O
constructs	O
obtained	O
by	O
introducing	O
fragments	O
of	O
cDNA	O
of	O
the	O

genome	O
into	O
plasmid	O
pMT28	O
,	O
which	O
encodes	O
infectious	O
C	O
-	O
S8c1	O
RNA	O
[	O
21	O
]	O
(	O
Figure	O
4	O
)	O
.	O

The	O
results	O
(	O
Figure	O
5	O
;	O
Tables	O
2	O
and	O
S1	O
)	O
show	O
that	O
several	O
genomic	O
regions	O
contribute	O
to	O
the	O
virulence	O
of	O

for	O
BHK	O
-	O
21	O
cells	O
,	O
and	O
that	O
the	O
major	O
contributors	O
map	O
within	O
genomic	O
positions	O
2046	O
to	O
3760	O
(	O
residues	O
encoding	O
part	O
of	O
VP2	O
,	O
VP3	O
,	O
and	O
part	O
of	O
VP1	O
,	O
Figure	O
5A	O
)	O
and	O
3760	O
to	O
5839	O
(	O
residues	O
encoding	O
2A	O
,	O
2B	O
,	O
2C	O
,	O
and	O
3A	O
,	O
Figure	O
5B	O
)	O
.	O

The	O
results	O
exclude	O
the	O
internal	O
ribosome	O
entry	O
site	O
and	O
the	O
3C	O
-	O
and	O
3D	O
-	O
coding	O
regions	O
as	O
significant	O
virulence	O
determinants	O
of	O

for	O
BHK	O
-	O
21	O
cells	O
(	O
virulence	O
of	O
the	O
relevant	O
chimeric	O
viruses	O
<	O
=	O
2	O
.	O
5	O
,	O
relative	O
to	O
C	O
-	O
S8c1	O
;	O
Tables	O
2	O
and	O
S1	O
)	O
.	O

Infectious	O
progeny	O
production	O
by	O
each	O
chimeric	O
virus	O
was	O
intermediate	O
between	O
the	O
production	O
of	O
the	O
parental	O
viruses	O
pMT28	O
and	O

,	O
with	O
no	O
significant	O
differences	O
that	O
could	O
be	O
correlated	O
with	O
virulence	O
(	O
Table	O
2	O
)	O
.	O

Non	O
-	O
Structural	O
Protein	O
2C	O
Is	O
a	O
Determinant	O
of	O
the	O
Virulence	O
of	O
FMDV	B
for	O
BHK	O
-	O
21	O
Cells	O

Amino	O
acid	O
substitutions	O
in	O
human	B
rhinovirus	I
protein	O
2C	O
promoted	O
cytopathology	O
for	O
mouse	B
L	O
cells	O
[	O
26	O
]	O
.	O

Remarkably	O
,	O

shares	O
with	O
other	O
FMDV	B
clones	O
and	O
populations	O
,	O
notably	O
,	O
MARLS	O
and	O
C	O
-	O
S8p260p3d	O
(	O
the	O
two	O
viruses	O
showing	O
the	O
highest	O
virulence	O
for	O
BHK	O
-	O
21	O
cells	O
;	O
Figure	O
2A	O
;	O
Tables	O
1	O
and	O
S1	O
)	O
,	O
three	O
amino	O
acid	O
substitutions	O
in	O
2C	O
:	O
S80N	O
,	O
T256A	O
,	O
and	O
Q263H	O
.	O

In	O
addition	O
,	O
MARLS	O
and	O
CS8p260p3d	O
include	O
replacement	O
M283V	O
in	O
2C	O
,	O
relative	O
to	O
C	O
-	O
S8c1	O
[	O
27	O
,	O
28	O
]	O
.	O

To	O
test	O
whether	O
any	O
(	O
or	O
a	O
combination	O
)	O
of	O
the	O
three	O
shared	O
amino	O
acid	O
substitutions	O
in	O
2C	O
contributed	O
to	O
the	O
increased	O
virulence	O
of	O
FMDV	B
,	O
each	O
of	O
the	O
mutations	O
was	O
introduced	O
individually	O
into	O
plasmid	O
pMT28	O
by	O
site	O
-	O
directed	O
mutagenesis	O
,	O
as	O
described	O
in	O
Materials	O
and	O
Methods	O
.	O

Transcripts	O
of	O
the	O
three	O
mutants	O
,	O
termed	O
pMT28	O
(	O
SN	O
)	O
,	O
pMT28	O
(	O
TA	O
)	O
,	O
and	O
pMT28	O
(	O
QH	O
)	O
(	O
Figure	O
4	O
)	O
,	O
were	O
used	O
to	O
transfect	O
BHK	O
-	O
21	O
cells	O
,	O
and	O
the	O
viruses	O
obtained	O
were	O
tested	O
with	O
the	O
BHK	O
-	O
21	O
cell	O
killing	O
assay	O
.	O

Viruses	O
having	O
any	O
of	O
the	O
substitutions	O
in	O
2C	O
have	O
a	O
virulence	O
intermediate	O
between	O
that	O
of	O
C	O
-	O
S8c1	O
and	O

(	O
Figure	O
6A	O
)	O
.	O

To	O
test	O
whether	O
the	O
combination	O
of	O
the	O
three	O
substitutions	O
in	O
2C	O
could	O
produce	O
an	O
additional	O
increase	O
of	O
virulence	O
,	O
the	O
three	O
mutations	O
were	O
introduced	O
in	O
pMT28	O
to	O
rescue	O
the	O
triple	O
mutant	O
pMT28	O
(	O
SN	O
,	O
TA	O
,	O
QH	O
)	O
(	O
Figure	O
4	O
)	O
.	O

The	O
results	O
(	O
Figure	O
6B	O
)	O
show	O
that	O
the	O
virulence	O
of	O
the	O
triple	O
2C	O
mutant	O
is	O
similar	O
to	O
the	O
virulence	O
of	O
the	O
individual	O
2C	O
mutants	O
.	O

The	O
2C	O
mutations	O
did	O
not	O
significantly	O
affect	O
the	O
infectious	O
progeny	O
production	O
(	O
Table	O
2	O
)	O
.	O

A	O
testable	O
prediction	O
of	O
this	O
result	O
is	O
that	O
the	O
introduction	O
of	O
the	O
wild	O
-	O
type	O
2C	O
-	O
3A	O
-	O
coding	O
region	O
in	O
the	O
genetic	O
background	O
of	O

should	O
produce	O
a	O
virus	O
with	O
lower	O
virulence	O
than	O

.	O
Indeed	O
,	O
the	O
results	O
with	O
such	O
a	O
chimeric	O
virus	O
(	O
Figure	O
5D	O
)	O
indicate	O
that	O
the	O
presence	O
of	O
the	O
2C	O
-	O
and	O
3A	O
-	O
coding	O
region	O
as	O
the	O
only	O
genetic	O
region	O
of	O
the	O
pMT28	O
in	O
the	O
genetic	O
background	O
of	O

resulted	O
in	O
an	O
FMDV	B
with	O
a	O
2	O
.	O
4	O
-	O
to	O
4	O
.	O
8	O
-	O
fold	O
lower	O
virulence	O
than	O

.	O
We	O
conclude	O
that	O
mutations	O
in	O
2C	O
contribute	O
to	O
virulence	O
of	O
FMDV	B
for	O
BHK	O
-	O
21	O
cells	O
.	O

Thus	O
,	O
a	O
virus	O
that	O
evolves	O
towards	O
low	O
fitness	O
levels	O
due	O
to	O
the	O
operation	O
of	O
Muller	O
'	O
s	O
ratchet	O
may	O
nevertheless	O
maintain	O
its	O
capacity	O
to	O
kill	O
the	O
same	O
cells	O
in	O
which	O
it	O
displays	O
low	O
fitness	O
.	O

In	O
FMDV	B
,	O
the	O
enhanced	O
capacity	O
to	O
kill	O
BHK	O
-	O
21	O
cells	O
was	O
multigenic	O
,	O
including	O
participation	O
of	O
non	O
-	O
structural	O
protein	O
2C	O
with	O
three	O
amino	O
acid	O
substitutions	O
acting	O
in	O
a	O
redundant	O
fashion	O
.	O

In	O
conclusion	O
,	O
the	O
results	O
provide	O
a	O
molecular	O
interpretation	O
of	O
why	O
fitness	O
and	O
virulence	O
of	O
an	O
animal	O
virus	O
can	O
follow	O
disparate	O
evolutionary	O
trajectories	O
,	O
culminating	O
in	O
two	O
unrelated	O
traits	O
.	O

Discussion	O

The	O
capacity	O
of	O
a	O
virus	O
to	O
kill	O
cells	O
is	O
probably	O
influenced	O
by	O
several	O
steps	O
in	O
the	O
virus	O
life	O
cycle	O
,	O
including	O
receptor	O
affinity	O
(	O
which	O
may	O
trigger	O
signalling	O
pathways	O
and	O
alter	O
cell	O
functions	O
)	O
and	O
intracellular	O
viral	O
replication	O
that	O
may	O
lead	O
to	O
metabolic	O
alterations	O
such	O
as	O
transcriptional	O
or	O
translational	O
shut	O
-	O
off	O
[	O
29	O
]	O
.	O

A	O
parallel	O
increase	O
of	O
virulence	O
and	O
fitness	O
as	O
a	O
virus	O
improves	O
its	O
adaptation	O
to	O
a	O
host	O
cell	O
type	O
is	O
expected	O
,	O
since	O
a	O
key	O
parameter	O
that	O
should	O
contribute	O
to	O
the	O
fitness	O
level	O
of	O
a	O
cytophatic	O
virus	O
is	O
the	O
accumulation	O
of	O
infectious	O
particles	O
and	O
its	O
release	O
from	O
cells	O
,	O
which	O
are	O
events	O
often	O
associated	O
with	O
cell	O
killing	O
.	O

This	O
expectation	O
was	O
fulfilled	O
in	O
our	O
experiments	O
(	O
increase	O
of	O
both	O
fitness	O
and	O
cell	O
killing	O
following	O
large	O
population	O
passages	O
of	O
C	O
-	O
S8c1	O
[	O
Figure	O
2	O
]	O
)	O
,	O
and	O
also	O
in	O
other	O
virus	O
-	O
host	O
systems	O
.	O

In	O
a	O
comparison	O
of	O
two	O
genetically	O
divergent	O
isolates	O
of	O
the	O
whispovirus	O
white	O
spot	O
syndrome	O
virus	O
,	O
whose	O
virulence	O
for	O
the	O
shrimp	B
host	O
Penaeus	B
monodon	I
was	O
measured	O
by	O
in	O
vivo	O
cumulative	O
mortality	O
rates	O
,	O
virulence	O
correlated	O
with	O
competitive	O
fitness	O
in	O
vivo	O
[	O
30	O
]	O
.	O

The	O
onset	O
of	O
type	O
1	O
diabetes	O
by	O
coxsackievirus	O
B	O
strains	O
was	O
linked	O
to	O
the	O
viral	O
replication	O
rate	O
and	O
to	O
the	O
infectious	O
dose	O
[	O
31	O
]	O
.	O

In	O
engineered	O
alphavirus	O
replicons	O
,	O
a	O
direct	O
correlation	O
between	O
the	O
level	O
of	O
RNA	O
replication	O
and	O
cytopathogenicity	O
was	O
observed	O
[	O
32	O
]	O
.	O

At	O
an	O
epidemiological	O
level	O
,	O
a	O
greater	O
replicative	O
fitness	O
of	O
historical	O
versus	O
current	O
human	B
immunodeficiency	I
virus	I
type	I
1	I
(	O
HIV	B
-	I
1	I
)	O
isolates	O
was	O
taken	O
as	O
evidence	O
of	O
HIV	B
-	I
1	I
attenuation	O
over	O
time	O
,	O
assuming	O
a	O
direct	O
connection	O
between	O
fitness	O
and	O
virulence	O
[	O
33	O
]	O
.	O

In	O
vivo	O
,	O
viral	O
fitness	O
may	O
vary	O
among	O
specific	O
organs	O
,	O
and	O
virulence	O
may	O
be	O
affected	O
only	O
when	O
fitness	O
for	O
some	O
specific	O
target	O
tissues	O
is	O
affected	O
[	O
34	O
]	O
.	O

Replicative	O
fitness	O
is	O
,	O
however	O
,	O
but	O
one	O
of	O
several	O
factors	O
which	O
influence	O
the	O
progression	O
of	O
a	O
viral	O
infection	O
in	O
vivo	O
.	O

In	O
a	O
comparative	O
analysis	O
,	O
R5	O
-	O
tropic	O
and	O
X4	O
-	O
tropic	O
clones	O
of	O
HIV	B
-	I
1	I
showed	O
similar	O
replication	O
capacity	O
in	O
mitogen	O
-	O
activated	O
T	O
cells	O
.	O

However	O
,	O
X4	O
clones	O
were	O
transferred	O
more	O
efficiently	O
than	O
R5	O
clones	O
from	O
dendritic	O
cells	O
to	O
CD4	O
(	O
+	O
)	O
T	O
cells	O
,	O
a	O
fact	O
that	O
can	O
contribute	O
to	O
the	O
competitive	O
advantage	O
of	O
X4	O
viruses	O
in	O
AIDS	O
patients	B
[	O
35	O
]	O
.	O

Simian	B
immunodeficiency	I
virus	I
SIVmac239	B
infects	O
both	O
the	O
sooty	B
mangabey	I
and	O
the	O
rhesus	B
macaque	I
,	O
reaching	O
high	O
viral	O
loads	O
in	O
both	O
hosts	O
,	O
yet	O
it	O
is	O
only	O
virulent	O
for	O
the	O
rhesus	B
macaque	I
[	O
36	O
]	O
.	O

Deviations	O
of	O
a	O
positive	O
correlation	O
between	O
viral	O
fitness	O
and	O
virulence	O
were	O
observed	O
also	O
in	O
the	O
plant	O
viruses	O
cucumber	B
mosaic	I
virus	I
[	O
37	O
]	O
and	O
barley	B
stripe	I
mosaic	I
virus	I
[	O
38	O
]	O
.	O

A	O
study	O
of	O
the	O
effect	O
of	O
lysis	O
timing	O
on	O
bacteriophage	B
fitness	O
revealed	O
that	O
a	O
strain	O
with	O
an	O
intermediate	O
lysis	O
time	O
had	O
the	O
highest	O
fitness	O
[	O
39	O
]	O
.	O

The	O
time	O
of	O
transmission	O
may	O
also	O
affect	O
virulence	O
.	O

Nuclear	O
polyhedrosis	O
virus	O
transmitted	O
early	O
to	O
its	O
host	O
,	O
the	O
moth	O
Lymantria	B
dispar	I
,	O
was	O
more	O
virulent	O
than	O
virus	O
transmitted	O
late	O
,	O
although	O
the	O
latter	O
was	O
more	O
productive	O
because	O
the	O
virus	O
could	O
use	O
more	O
host	O
tissue	O
for	O
replication	O
[	O
40	O
]	O
.	O

In	O
a	O
study	O
of	O
the	O
susceptibility	O
of	O
North	O
American	O
and	O
non	O
-	O
North	O
American	O
breeds	O
of	O
Lymantria	O
to	O
several	O
isolates	O
of	O
the	O
fungus	O
Entomaphaga	B
maimaiga	I
,	O
mortality	O
was	O
scored	O
in	O
all	O
cases	O
.	O

However	O
,	O
virulence	O
of	O
the	O
fungus	O
,	O
quantitated	O
by	O
the	O
time	O
of	O
death	O
of	O
Lymantria	O
,	O
was	O
,	O
in	O
some	O
cases	O
,	O
inversely	O
proportional	O
to	O
fitness	O
,	O
quantitated	O
by	O
fungal	O
reproduction	O
in	O
the	O
moth	B
[	O
41	O
]	O
.	O

In	O
all	O
these	O
cases	O
,	O
the	O
molecular	O
basis	O
of	O
the	O
lack	O
of	O
positive	O
correlation	O
between	O
fitness	O
and	O
virulence	O
is	O
not	O
understood	O
.	O

Model	O
for	O
a	O
Lack	O
of	O
Correlation	O
between	O
Viral	O
Fitness	O
and	O
Virulence	O

The	O
results	O
with	O
FMDV	B
clones	O
H5	O
have	O
documented	O
that	O
both	O
fitness	O
-	O
enhancing	O
and	O
virulence	O
-	O
enhancing	O
mutations	O
can	O
be	O
incorporated	O
in	O
the	O
viral	O
genome	O
in	O
such	O
a	O
fashion	O
that	O
subsequent	O
fitness	O
-	O
decreasing	O
mutations	O
associated	O
with	O
bottleneck	O
(	O
plaque	O
-	O
to	O
-	O
plaque	O
)	O
transfers	O
produce	O
only	O
minimal	O
effects	O
on	O
virulence	O
(	O
Figure	O
2	O
)	O
.	O

The	O
dissection	O
of	O
accompanying	O
molecular	O
events	O
,	O
achieved	O
through	O
quantification	O
of	O
virulence	O
of	O
recombinant	O
and	O
mutant	O
genomes	O
(	O
Tables	O
2	O
and	O
S1	O
)	O
,	O
provides	O
an	O
interpretation	O
of	O
the	O
lack	O
of	O
positive	O
correlation	O
between	O
virulence	O
and	O
fitness	O
.	O

Multiple	O
fitness	O
-	O
decreasing	O
mutations	O
occur	O
in	O
the	O
course	O
of	O
plaque	O
-	O
to	O
-	O
plaque	O
transfers	O
,	O
distributed	O
throughout	O
the	O
FMDV	B
genome	O
[	O
11	O
]	O
.	O

In	O
contrast	O
,	O
determinants	O
of	O
virulence	O
for	O
BHK	O
-	O
21	O
cells	O
are	O
multigenic	O
,	O
but	O
concentrated	O
mainly	O
in	O
some	O
FMDV	B
genomic	O
regions	O
.	O

Similar	O
multigenic	O
but	O
discrete	O
virulence	O
determinants	O
have	O
been	O
described	O
also	O
in	O
other	O
virus	O
-	O
host	O
systems	O
[	O
42	O
,	O
43	O
]	O
.	O

To	O
decrease	O
virulence	O
,	O
mutations	O
occurring	O
randomly	O
in	O
the	O
course	O
of	O
plaque	O
-	O
to	O
-	O
plaque	O
transfers	O
should	O
affect	O
specific	O
genomic	O
sites	O
,	O
and	O
this	O
will	O
occur	O
with	O
a	O
lower	O
probability	O
than	O
fitness	O
-	O
decreasing	O
mutations	O
,	O
which	O
can	O
hit	O
any	O
of	O
the	O
multifunctional	O
picornaviral	O
proteins	O
and	O
regulatory	O
regions	O
[	O
11	O
]	O
.	O

This	O
model	O
is	O
reinforced	O
by	O
the	O
observation	O
that	O
three	O
amino	O
acid	O
substitutions	O
in	O
2C	O
(	O
S80N	O
,	O
T256A	O
,	O
and	O
Q263H	O
)	O
had	O
a	O
similar	O
effect	O
in	O
enhancing	O
FMDV	B
virulence	O
,	O
and	O
the	O
three	O
mutations	O
in	O
the	O
same	O
genome	O
had	O
an	O
effect	O
comparable	O
to	O
each	O
mutation	O
individually	O
(	O
Figure	O
6	O
;	O
Tables	O
2	O
and	O
S1	O
)	O
.	O

It	O
is	O
not	O
clear	O
what	O
the	O
basis	O
of	O
the	O
contribution	O
of	O
2C	O
to	O
virulence	O
for	O
BHK	O
-	O
21	O
could	O
be	O
.	O

2C	O
is	O
involved	O
in	O
RNA	O
synthesis	O
and	O
contains	O
a	O
nucleotide	O
-	O
binding	O
domain	O
,	O
although	O
none	O
of	O
the	O
substitutions	O
found	O
in	O

and	O

lie	O
within	O
such	O
a	O
domain	O
.	O

An	O
unlikely	O
triple	O
reversion	O
would	O
be	O
required	O
to	O
eliminate	O
the	O
virulence	O
-	O
enhancing	O
effect	O
of	O
the	O
three	O
mutations	O
in	O
2C	O
.	O

We	O
propose	O
that	O
a	O
higher	O
robustness	O
of	O
the	O
FMDV	B
genome	O
with	O
regard	O
to	O
virulence	O
for	O
BHK	O
-	O
21	O
cells	O
,	O
rather	O
than	O
to	O
replicative	O
fitness	O
in	O
the	O
same	O
cells	O
,	O
underlies	O
the	O
different	O
trajectories	O
followed	O
by	O
fitness	O
and	O
virulence	O
upon	O
subjecting	O
the	O
virus	O
to	O
repeated	O
bottleneck	O
transfers	O
.	O

Obviously	O
,	O
we	O
cannot	O
exclude	O
that	O
parameters	O
of	O
the	O
virus	O
life	O
cycle	O
,	O
other	O
than	O
fitness	O
as	O
measured	O
in	O
our	O
experiments	O
,	O
could	O
correlate	O
with	O
virulence	O
for	O
BHK	O
-	O
21	O
.	O

The	O
comparative	O
analysis	O
of	O
FMDV	B
clones	O
and	O
populations	O
shows	O
that	O
shifts	O
in	O
virulence	O
can	O
occur	O
even	O
through	O
the	O
evolution	O
of	O
a	O
single	O
viral	O
clone	O
(	O
C	O
-	O
S8c1	O
)	O
,	O
with	O
its	O
restricted	O
genetic	O
diversity	O
prompted	O
by	O
different	O
replication	O
regimes	O
in	O
the	O
same	O
host	O
cells	O
,	O
which	O
also	O
have	O
a	O
clonal	O
origin	O
(	O
see	O
Materials	O
and	O
Methods	O
)	O
.	O

We	O
conjecture	O
that	O
the	O
demonstration	O
that	O
fitness	O
and	O
virulence	O
can	O
follow	O
different	O
evolutionary	O
courses	O
has	O
been	O
possible	O
thanks	O
to	O
the	O
consequences	O
of	O
the	O
extreme	O
passage	O
regimes	O
to	O
which	O
the	O
viral	O
populations	O
were	O
subjected	O
:	O
competitive	O
evolution	O
of	O
an	O
ample	O
mutant	O
spectra	O
during	O
repeated	O
large	O
population	O
passages	O
,	O
and	O
accumulation	O
of	O
deleterious	O
(	O
with	O
regard	O
to	O
fitness	O
,	O
but	O
not	O
with	O
regard	O
to	O
virulence	O
)	O
mutations	O
upon	O
plaque	O
-	O
to	O
-	O
plaque	O
transfers	O
(	O
predominance	O
of	O
genetic	O
drift	O
and	O
operation	O
of	O
Muller	O
'	O
s	O
ratchet	O
)	O
[	O
12	O
,	O
15	O
]	O
.	O

Implications	O
for	O
Models	O
of	O
Virulence	O

It	O
must	O
be	O
emphasized	O
that	O
fitness	O
and	O
virulence	O
are	O
relative	O
values	O
that	O
pertain	O
to	O
a	O
defined	O
physical	O
and	O
biological	O
environment	O
.	O

Virulence	O
determinants	O
of	O
FMDV	B
,	O
identified	O
here	O
for	O
BHK	O
-	O
21	O
cells	O
,	O
need	O
not	O
apply	O
to	O
virulence	O
for	O
the	O
natural	O
animal	O
hosts	O
of	O
FMDV	B
[	O
44	O
]	O
.	O

However	O
,	O
the	O
observation	O
of	O
a	O
lack	O
of	O
correlation	O
between	O
fitness	O
and	O
virulence	O
in	O
a	O
FMDV	B
clone	O
is	O
relevant	O
to	O
current	O
models	O
of	O
attenuation	O
and	O
virulence	O
,	O
since	O
it	O
shows	O
that	O
more	O
virulent	O
forms	O
of	O
a	O
virus	O
need	O
not	O
have	O
a	O
reproductive	O
advantage	O
,	O
and	O
that	O
viral	O
virulence	O
is	O
not	O
necessarily	O
a	O
byproduct	O
of	O
viral	O
fitness	O
.	O

Even	O
if	O
virulence	O
is	O
regarded	O
as	O
an	O
unavoidable	O
consequence	O
of	O
parasite	O
adaptation	O
[	O
45	O
]	O
,	O
virus	O
de	O
-	O
adaptation	O
(	O
fitness	O
loss	O
)	O
need	O
not	O
entail	O
a	O
decrease	O
of	O
virulence	O
.	O

Most	O
current	O
definitions	O
of	O
virulence	O
include	O
both	O
the	O
ability	O
of	O
the	O
pathogen	O
to	O
multiply	O
and	O
to	O
cause	O
harm	O
to	O
its	O
host	O
;	O
some	O
authors	O
,	O
however	O
,	O
assume	O
a	O
direct	O
relationship	O
between	O
fitness	O
and	O
capacity	O
to	O
produce	O
disease	O
[	O
46	O
-	O
48	O
]	O
.	O

In	O
relating	O
the	O
results	O
with	O
FMDV	B
to	O
general	O
models	O
of	O
virulence	O
in	O
host	O
-	O
parasite	O
systems	O
,	O
it	O
must	O
be	O
considered	O
that	O
in	O
the	O
FMDV	B
system	O
,	O
evolution	O
of	O
the	O
host	O
BHK	O
-	O
21	O
cells	O
could	O
not	O
influence	O
FMDV	B
evolution	O
,	O
because	O
clonal	O
cell	O
populations	O
with	O
a	O
controlled	O
passage	O
history	O
were	O
supplied	O
in	O
constant	O
numbers	O
at	O
each	O
infection	O
event	O
(	O
see	O
Materials	O
and	O
Methods	O
)	O
.	O

Therefore	O
,	O
changes	O
in	O
host	O
density	O
,	O
or	O
mobility	O
,	O
as	O
well	O
as	O
pathogen	O
survival	O
in	O
the	O
external	O
environment	O
,	O
all	O
of	O
which	O
are	O
relevant	O
parameters	O
in	O
virulence	O
models	O
[	O
48	O
,	O
49	O
]	O
,	O
cannot	O
play	O
a	O
role	O
in	O
our	O
system	O
.	O

A	O
consistent	O
finding	O
in	O
serial	O
passage	O
experiments	O
is	O
that	O
virulence	O
of	O
a	O
parasite	O
increases	O
with	O
passage	O
number	O
in	O
a	O
new	O
host	O
[	O
50	O
]	O
.	O

The	O
results	O
with	O
FMDV	B
infecting	O
BHK	O
-	O
21	O
cells	O
cytolytically	O
imply	O
that	O
the	O
increase	O
of	O
virulence	O
can	O
be	O
conditioned	O
to	O
the	O
history	O
of	O
passage	O
regimes	O
undergone	O
by	O
a	O
virus	O
.	O

The	O
invariance	O
of	O
BHK	O
-	O
21	O
cells	O
in	O
the	O
course	O
of	O
serial	O
cytolytic	O
passages	O
of	O
FMDV	B
is	O
in	O
contrast	O
with	O
the	O
parallel	O
system	O
consisting	O
of	O
BHK	O
-	O
21	O
cells	O
persistently	O
infected	O
with	O
FMDV	B
C	O
-	O
S8c1	O
[	O
25	O
]	O
,	O
in	O
which	O
the	O
cells	O
are	O
passaged	O
and	O
coevolve	O
with	O
the	O
resident	O
virus	O
[	O
51	O
]	O
.	O

Host	O
-	O
virus	O
coevolution	O
has	O
generally	O
favored	O
a	O
decrease	O
of	O
viral	O
virulence	O
in	O
the	O
field	O
,	O
a	O
classical	O
example	O
being	O
myxoma	B
virus	I
and	O
myxomatosis	O
in	O
rabbits	B
[	O
52	O
]	O
.	O

Our	O
comparison	O
of	O
FMDV	B
clones	O
did	O
not	O
provide	O
evidence	O
of	O
clones	O
with	O
high	O
fitness	O
and	O
low	O
virulence	O
,	O
which	O
,	O
with	O
regard	O
to	O
natural	O
hosts	O
,	O
is	O
an	O
aim	O
of	O
biomedicine	O
to	O
obtain	O
vaccine	O
strains	O
.	O

Yet	O
,	O
the	O
existence	O
of	O
specific	O
mutations	O
that	O
differentially	O
affect	O
fitness	O
and	O
virulence	O
opens	O
the	O
way	O
to	O
engineer	O
candidate	O
vaccine	O
strains	O
unable	O
to	O
kill	O
the	O
host	O
,	O
while	O
maintaining	O
replicative	O
competence	O
.	O

Virulence	O
is	O
,	O
however	O
,	O
a	O
feature	O
of	O
the	O
host	O
-	O
parasite	O
relationship	O
[	O
46	O
]	O
,	O
and	O
the	O
mutations	O
needed	O
to	O
impair	O
virulence	O
are	O
expected	O
to	O
be	O
host	O
-	O
dependent	O
[	O
53	O
,	O
54	O
]	O
.	O

Materials	O
and	O
Methods	O

Cells	O
,	O
viruses	O
,	O
and	O
infections	O
.	O

The	O
BHK	O
-	O
21	O
cells	O
used	O
in	O
the	O
present	O
study	O
were	O
cloned	O
by	O
end	O
-	O
point	O
dilution	O
,	O
followed	O
by	O
preparation	O
of	O
a	O
cell	O
stock	O
from	O
a	O
single	O
cell	O
;	O
they	O
were	O
passaged	O
a	O
maximum	O
of	O
30	O
times	O
before	O
being	O
used	O
for	O
FMDV	B
infection	O
[	O
25	O
,	O
51	O
]	O
.	O

Procedures	O
for	O
cell	O
growth	O
,	O
infection	O
of	O
BHK	O
-	O
21	O
cell	O
monolayers	O
with	O
FMDV	B
in	O
liquid	O
medium	O
,	O
and	O
plaque	O
assays	O
in	O
semi	O
-	O
solid	O
agar	O
medium	O
were	O
carried	O
out	O
as	O
previously	O
described	O
[	O
11	O
,	O
19	O
,	O
25	O
,	O
27	O
]	O
.	O

Mock	O
-	O
infected	O
cells	O
were	O
handled	O
in	O
parallel	O
in	O
all	O
infectivity	O
and	O
plaque	O
assays	O
to	O
monitor	O
absence	O
of	O
viral	O
contamination	O
.	O

The	O
FMDVs	B
used	O
in	O
the	O
present	O
study	O
(	O
Figure	O
1	O
)	O
are	O
(	O
i	O
)	O
the	O
reference	O
clone	O
C	O
-	O
S8c1	O
,	O
which	O
has	O
been	O
assigned	O
a	O
relative	O
fitness	O
of	O
1	O
.	O
0	O
[	O
11	O
]	O
.	O

(	O
ii	O
)	O
MARLS	O
,	O
a	O
monoclonal	O
antibody	O
escape	O
mutant	O
isolated	O
from	O
population	O
C	O
-	O
S8c1p213	O
[	O
55	O
]	O
;	O
MARLS	O
has	O
a	O
fitness	O
of	O
25	O
relative	O
to	O
C	O
-	O
S8c1	O
[	O
24	O
]	O
.	O

(	O
iii	O
)	O
C	O
-	O
S8p260p3d	O
,	O
a	O
standard	O
FMDV	B
virus	O
rescued	O
by	O
low	O
MOI	O
passage	O
of	O
C	O
-	O
S8p260	O
.	O

The	O
latter	O
is	O
a	O
virus	O
that	O
evolved	O
by	O
passage	O
of	O
C	O
-	O
S8c1	O
at	O
a	O
high	O
MOI	O
,	O
which	O
resulted	O
in	O
dominance	O
of	O
two	O
defective	O
FMDV	B
genomes	O
(	O
both	O
including	O
internal	O
deletions	O
)	O
that	O
were	O
infectious	O
by	O
complementation	O
,	O
in	O
the	O
absence	O
of	O
standard	O
virus	O
[	O
22	O
,	O
24	O
,	O
28	O
]	O
;	O
C	O
-	O
S8p260p3d	O
has	O
a	O
relative	O
fitness	O
of	O
20	O
[	O
24	O
]	O
.	O

(	O
iv	O
)	O
REDpt60	O
,	O
obtained	O
after	O
60	O
successive	O
plaque	O
-	O
to	O
-	O
plaque	O
transfers	O
of	O
RED	O
(	O
a	O
monoclonal	O
antibody	O
escape	O
mutant	O
isolated	O
from	O
population	O
C	O
-	O
S8c1p100	O
)	O
[	O
20	O
]	O
;	O
REDpt60	O
has	O
a	O
fitness	O
of	O
1	O
.	O
9	O
relative	O
to	O
C	O
-	O
S8c1	O
.	O

(	O
v	O
)	O
C	O
-	O
S8c1p113	O
,	O
a	O
viral	O
population	O
obtained	O
after	O
113	O
serial	O
cytolytic	O
passages	O
of	O
C	O
-	O
S8c1	O
at	O
a	O
high	O
MOI	O
in	O
BHK	O
-	O
21	O
cells	O
(	O
2	O
x	O
106	O
BHK	O
-	O
21	O
cells	O
infected	O
with	O
the	O
virus	O
contained	O
in	O
200	O
mu	O
l	O
of	O
the	O
supernatant	O
from	O
the	O
previous	O
infection	O
)	O
.	O

(	O
vi	O
)	O
Clone	O

,	O
a	O
biological	O
clone	O
isolated	O
from	O
population	O
C	O
-	O
S8c1p113	O
[	O
11	O
]	O
;	O
its	O
relative	O
fitness	O
is	O
26	O
(	O
unpublished	O
data	O
)	O
.	O

(	O
vii	O
)	O
Clone	O

,	O
obtained	O
after	O
95	O
successive	O
plaque	O
-	O
to	O
-	O
plaque	O
transfers	O
of	O

[	O
11	O
]	O
;	O
its	O
relative	O
fitness	O
is	O
0	O
.	O
11	O
[	O
23	O
]	O
.	O

Cell	O
killing	O
assay	O
.	O

The	O
capacity	O
of	O
FMDV	B
to	O
kill	O
BHK	O
-	O
21	O
cells	O
was	O
measured	O
as	O
previously	O
described	O
[	O
18	O
,	O
22	O
]	O
.	O

The	O
assay	O
consists	O
in	O
determining	O
the	O
minimum	O
number	O
of	O
PFU	O
required	O
to	O
kill	O
104	O
BHK	O
-	O
21	O
cells	O
after	O
variable	O
times	O
of	O
infection	O
.	O

The	O
assay	O
was	O
performed	O
in	O
M96	O
multiwell	O
plates	O
with	O
monolayers	O
of	O
104	O
BHK	O
-	O
21	O
cells	O
per	O
well	O
infected	O
with	O
serial	O
dilutions	O
of	O
virus	O
.	O

At	O
different	O
times	O
postinfection	O
,	O
cells	O
were	O
fixed	O
with	O
2	O
%	O
formaldehyde	O
and	O
stained	O
with	O
2	O
%	O
crystal	O
violet	O
in	O
2	O
%	O
formaldehyde	O
.	O

Results	O
are	O
expressed	O
as	O
the	O
logarithm	O
of	O
the	O
number	O
of	O
PFUs	O
needed	O
for	O
complete	O
cell	O
killing	O
(	O
as	O
judged	O
by	O
cell	O
staining	O
with	O
crystal	O
violet	O
,	O
with	O
series	O
of	O
control	O
wells	O
with	O
known	O
numbers	O
of	O
cells	O
)	O
as	O
a	O
function	O
of	O
time	O
postinfection	O
[	O
18	O
,	O
22	O
]	O
.	O

Determination	O
of	O
relative	O
fitness	O
of	O

.	O

The	O
relative	O
fitness	O
of	O
FMDV	B

was	O
determined	O
by	O
growth	O
competition	O
in	O
BHK	O
-	O
21	O
cells	O
as	O
previously	O
described	O
[	O
7	O
,	O
10	O
,	O
11	O
,	O
24	O
,	O
56	O
]	O
.	O

FMDV	B

was	O
mixed	O
with	O
appropriate	O
proportions	O
of	O

,	O
which	O
was	O
used	O
as	O
reference	O
virus	O
.	O

This	O
virus	O
has	O
a	O
fitness	O
8	O
.	O
5	O
-	O
fold	O
higher	O
than	O
that	O
of	O
the	O
reference	O
clone	O
of	O
C	O
-	O
S8c1	O
in	O
BHK	O
-	O
21	O
cells	O
[	O
7	O
,	O
10	O
,	O
11	O
,	O
24	O
,	O
56	O
]	O
.	O

Four	O
serial	O
infections	O
were	O
carried	O
out	O
at	O
MOI	O
of	O
0	O
.	O
1	O
PFU	O
/	O
cell	O
.	O

The	O
proportion	O
of	O
the	O
two	O
competing	O
genomes	O
at	O
different	O
passages	O
was	O
determined	O
by	O
real	O
-	O
time	O
reverse	O
transcription	O
(	O
RT	O
)	O
-	O
PCR	O
,	O
employing	O
primers	O
5531wtnew	O
and	O

,	O
which	O
are	O
able	O
to	O
discriminate	O
FMDV	B

RNA	O
from	O

RNA	O
.	O

The	O
nucleotide	O
sequences	O
of	O
the	O
primers	O
will	O
be	O
provided	O
upon	O
request	O
.	O

The	O
fitness	O
vector	O
obtained	O
for	O

corresponded	O
to	O
the	O
equation	O
y	O
=	O
0	O
,	O
0206e1	O
,	O
1074x	O
;	O
R2	O
=	O
0	O
.	O
9507	O
.	O

The	O
antilogarithm	O
(	O
base	O
e	O
)	O
of	O
the	O
vector	O
slope	O
is	O
the	O
fitness	O
of	O
the	O
assayed	O
virus	O
relative	O
to	O
the	O
reference	O
virus	O
[	O
56	O
]	O
.	O

cDNA	O
synthesis	O
,	O
molecular	O
cloning	O
,	O
and	O
nucleotide	O
sequencing	O
.	O

Viral	O
RNA	O
was	O
extracted	O
by	O
treatment	O
with	O
Trizol	O
as	O
previously	O
described	O
[	O
57	O
]	O
.	O

Reverse	O
transcription	O
of	O
FMDV	B
RNA	O
was	O
carried	O
out	O
with	O
avian	B
myeloblastosis	I
virus	I
reverse	O
transcriptase	O
(	O
Promega	O
,	O
http	O
:	O
/	O
/	O
www	O
.	O
promega	O
.	O
com	O
)	O
or	O
Transcriptor	O
reverse	O
transcriptase	O
(	O
Roche	O
,	O
http	O
:	O
/	O
/	O
www	O
.	O
roche	O
.	O
com	O
)	O
,	O
and	O
PCR	O
amplification	O
was	O
performed	O
by	O
using	O
either	O
Ampli	O
-	O
Taq	O
polymerase	O
(	O
PerkinElmer	O
,	O
http	O
:	O
/	O
/	O
las	O
.	O
perkinelmer	O
.	O
com	O
)	O
or	O
an	O
Expand	O
High	O
Fidelity	O
polymerase	O
system	O
(	O
Roche	O
)	O
,	O
as	O
instructed	O
by	O
the	O
manufacturers	O
.	O

The	O
FMDV	B
genome	O
-	O
specific	O
oligonucleotide	O
primers	O
used	O
have	O
been	O
previously	O
described	O
[	O
22	O
,	O
58	O
]	O
.	O

In	O
all	O
RT	O
-	O
PCR	O
amplifications	O
,	O
negative	O
amplification	O
controls	O
,	O
including	O
all	O
reaction	O
components	O
except	O
template	O
RNA	O
,	O
were	O
run	O
in	O
parallel	O
to	O
monitor	O
absence	O
of	O
contamination	O
.	O

Chimeric	O
viruses	O
containing	O
selected	O
regions	O
of	O

in	O
the	O
genetic	O
background	O
of	O
C	O
-	O
S8c1	O
(	O
Figure	O
4	O
)	O
were	O
obtained	O
by	O
replacing	O
the	O
corresponding	O
DNA	O
fragment	O
of	O
pMT28	O
by	O
a	O
cDNA	O
copy	O
of	O

RNA	O
,	O
using	O
specific	O
restriction	O
sites	O
.	O

To	O
obtain	O
pMT28	O
/	O

(	O
436	O
-	O
2046	O
)	O
,	O
a	O
chimera	O
that	O
included	O
nucleotides	O
436	O
to	O
2046	O
of	O

(	O
the	O
residue	O
numbering	O
of	O
the	O
FMDV	B
genome	O
is	O
as	O
in	O
[	O
11	O
]	O
)	O
,	O

RNA	O
was	O
amplified	O
by	O
RT	O
-	O
PCR	O
using	O
primers	O
NR2	O
and	O
JH2	O
,	O
and	O
the	O
cDNA	O
was	O
digested	O
with	O
Hpa	O
I	O
(	O
position	O
436	O
)	O
and	O
Xba	O
I	O
(	O
2046	O
)	O
,	O
and	O
ligated	O
into	O
pMT28	O
DNA	O
digested	O
with	O
the	O
same	O
enzymes	O
.	O

To	O
obtain	O
pMT28	O
/	O

(	O
2046	O
-	O
3760	O
)	O
,	O

RNA	O
was	O
amplified	O
by	O
RT	O
-	O
PCR	O
using	O
primers	O
2R1New	O
and	O
pU	O
,	O
and	O
then	O
the	O
cDNA	O
was	O
digested	O
with	O
Xba	O
I	O
(	O
2046	O
)	O
and	O
Avr	O
II	O
(	O
3760	O
)	O
.	O

To	O
obtain	O
pMT28	O
/	O

(	O
3760	O
-	O
5839	O
)	O
,	O

RNA	O
was	O
amplified	O
by	O
RT	O
-	O
PCR	O
using	O
primers	O
3R2New	O
and	O
3CD1	O
,	O
and	O
then	O
the	O
cDNA	O
was	O
digested	O
with	O
Avr	O
II	O
(	O
3760	O
)	O
and	O
Rsr	O
II	O
(	O
5839	O
)	O
.	O

To	O
obtain	O
pMT28	O
/	O

(	O
5839	O
-	O
7427	O
)	O
,	O

RNA	O
was	O
amplified	O
by	O
RT	O
-	O
PCR	O
using	O
primers	O
5531	O
wt	O
new	O
and	O
C	O
-	O
Not	O
-	O
Pol	O
,	O
and	O
then	O
the	O
cDNA	O
was	O
digested	O
with	O
Rsr	O
II	O
(	O
5839	O
)	O
and	O
Bam	O
HI	O
(	O
7427	O
)	O
.	O

To	O
obtain	O
pMT28	O
/	O

(	O
436	O
-	O
3760	O
)	O
,	O

RNA	O
was	O
amplified	O
by	O
RT	O
-	O
PCR	O
using	O
primers	O
NR2	O
and	O
JH2	O
,	O
and	O
then	O
the	O
cDNA	O
was	O
digested	O
with	O
Hpa	O
I	O
(	O
position	O
436	O
)	O
and	O
Xba	O
I	O
(	O
2046	O
)	O
,	O
and	O
ligated	O
into	O
pMT28	O
/	O

(	O
2046	O
-	O
3760	O
)	O
DNA	O
digested	O
with	O
the	O
same	O
enzymes	O
.	O

To	O
obtain	O
pMT28	O
/	O

(	O
3760	O
-	O
7427	O
)	O
,	O

RNA	O
was	O
amplified	O
by	O
RT	O
-	O
PCR	O
using	O
primers	O
3R2New	O
and	O
3CD1	O
,	O
and	O
then	O
the	O
cDNA	O
was	O
digested	O
with	O
Avr	O
II	O
(	O
3760	O
)	O
and	O
Rsr	O
II	O
(	O
5839	O
)	O
,	O
and	O
ligated	O
into	O
pMT28	O
/	O

(	O
5839	O
-	O
7427	O
)	O
DNA	O
digested	O
with	O
the	O
same	O
enzymes	O
.	O

To	O
obtain	O
pMT28	O
/	O

(	O
2046	O
-	O
7427	O
)	O
,	O

RNA	O
was	O
amplified	O
by	O
RT	O
-	O
PCR	O
using	O
primers	O
2R1New	O
and	O
pU	O
,	O
and	O
then	O
the	O
cDNA	O
was	O
digested	O
with	O
Xba	O
I	O
(	O
2046	O
)	O
and	O
Avr	O
II	O
(	O
3760	O
)	O
,	O
and	O
ligated	O
into	O
pMT28	O
/	O

(	O
3760	O
-	O
7427	O
)	O
DNA	O
digested	O
with	O
the	O
same	O
enzymes	O
.	O

To	O
obtain	O
pMT28	O
/	O

(	O
436	O
-	O
7427	O
)	O
,	O

RNA	O
was	O
amplified	O
by	O
RT	O
-	O
PCR	O
using	O
primers	O
NR2	O
and	O
JH2	O
;	O
the	O
cDNA	O
was	O
digested	O
with	O
Hpa	O
I	O
(	O
position	O
436	O
)	O
and	O
Xba	O
I	O
(	O
2046	O
)	O
,	O
and	O
ligated	O
into	O
pMT28	O
/	O

(	O
2046	O
-	O
7427	O
)	O
DNA	O
digested	O
with	O
the	O
same	O
enzymes	O
.	O

To	O
obtain	O

/	O
2C	O
-	O
3A	O
(	O
pMT28	O
)	O
,	O
pMT28	O
was	O
digested	O
with	O
Bgl	O
II	O
(	O
4201	O
)	O
and	O
Rsr	O
II	O
(	O
5839	O
)	O
,	O
and	O
a	O
DNA	O
fragment	O
including	O
wild	O
-	O
type	O
2C	O
-	O
3A	O
-	O
coding	O
region	O
was	O
inserted	O
into	O
pMT28	O
/	O

(	O
436	O
-	O
7427	O
)	O
DNA	O
digested	O
with	O
the	O
same	O
enzymes	O
.	O

DNA	O
ligation	O
,	O
transformation	O
of	O
Escherichia	B
coli	I
DH5	O
alpha	O
,	O
isolation	O
of	O
DNA	O
from	O
bacterial	O
colonies	O
,	O
and	O
characterization	O
of	O
DNA	O
by	O
restriction	O
enzyme	O
digestion	O
were	O
performed	O
by	O
standard	O
procedures	O
[	O
59	O
]	O
.	O

The	O
primers	O
used	O
for	O
molecular	O
cloning	O
and	O
site	O
-	O
directed	O
mutagenesis	O
are	O
described	O
in	O
Table	O
S3	O
.	O

To	O
obtain	O
FMDV	B
C	O
-	O
S8c1	O
containing	O
the	O
mutations	O
found	O
in	O
gene	O
2C	O
of	O

,	O
plasmid	O
pMT28	O
was	O
subjected	O
to	O
site	O
-	O
directed	O
mutagenesis	O
using	O
an	O
oligonucleotide	O
including	O
the	O
required	O
nucleotide	O
replacement	O
,	O
and	O
3R2New	O
or	O
3CD1	O
as	O
external	O
oligonucleotide	O
primer	O
(	O
Table	O
S3	O
;	O
Figure	O
4	O
)	O
.	O

A	O
DNA	O
fragment	O
termed	O
A	O
was	O
obtained	O
by	O
subjecting	O
plasmid	O
pMT28	O
to	O
site	O
-	O
directed	O
mutagenesis	O
using	O
primers	O
(	O
reverse	O
)	O
mutSNu	O
,	O
mutTAu	O
,	O
and	O
mutQHu	O
(	O
to	O
introduce	O
mutations	O
S80N	O
,	O
T256A	O
,	O
and	O
Q263H	O
,	O
respectively	O
)	O
and	O
an	O
external	O
oligonucleotide	O
primer	O
(	O
3R2New	O
,	O
forward	O
)	O
.	O

A	O
DNA	O
fragment	O
termed	O
B	O
was	O
obtained	O
amplifying	O
pMT28	O
with	O
primers	O
(	O
forward	O
)	O
mutSNd	O
,	O
mutTAd	O
,	O
and	O
mutQHd	O
(	O
to	O
introduce	O
mutations	O
S80N	O
,	O
T256A	O
,	O
and	O
Q263H	O
,	O
respectively	O
)	O
and	O
an	O
external	O
oligonucleotide	O
primer	O
(	O
3CD1	O
,	O
reverse	O
)	O
.	O

DNA	O
fragments	O
A	O
and	O
B	O
,	O
including	O
the	O
desired	O
mutations	O
,	O
were	O
recombined	O
by	O
shuffling	O
PCR	O
using	O
equimolar	O
amounts	O
of	O
DNA	O
fragments	O
and	O
two	O
external	O
primers	O
(	O
3R2New	O
and	O
3CD1	O
)	O
.	O

The	O
DNA	O
with	O
the	O
desired	O
mutation	O
(	O
s	O
)	O
in	O
the	O
2C	O
gene	O
was	O
digested	O
with	O
Avr	O
II	O
(	O
genomic	O
position	O
3760	O
)	O
and	O
Rsr	O
II	O
(	O
position	O
5839	O
)	O
,	O
and	O
cloned	O
into	O
pMT28	O
to	O
generate	O
pMT28	O
(	O
SN	O
)	O
,	O
pMT28	O
(	O
TA	O
)	O
,	O
and	O
pMT28	O
(	O
QH	O
)	O
.	O

To	O
obtain	O
pMT28	O
(	O
SN	O
,	O
TA	O
,	O
QH	O
)	O
,	O
plasmid	O
pMT28	O
(	O
SN	O
)	O
was	O
subjected	O
to	O
site	O
-	O
directed	O
mutagenesis	O
to	O
introduce	O
mutation	O
T256A	O
in	O
a	O
similar	O
way	O
as	O
described	O
above	O
,	O
and	O
then	O
,	O
plasmid	O
pMT28	O
(	O
SN	O
,	O
TA	O
)	O
was	O
subjected	O
to	O
site	O
-	O
directed	O
mutagenesis	O
to	O
introduce	O
mutation	O
Q263H	O
.	O

All	O
chimeric	O
viruses	O
and	O
mutants	O
were	O
analyzed	O
by	O
nucleotide	O
sequencing	O
using	O
Big	O
Dye	O
Terminator	O
Cycle	O
Sequencing	O
kit	O
(	O
Abi	O
Prism	O
;	O
PerkinElmer	O
)	O
and	O
sequencer	O
ABI373	O
as	O
previously	O
described	O
[	O
58	O
]	O
.	O

Sequences	O
were	O
analyzed	O
using	O
DNASTAR	O
4	O
.	O
0	O
(	O
http	O
:	O
/	O
/	O
www	O
.	O
dnastar	O
.	O
com	O
)	O
,	O
GeneDoc	O
,	O
and	O
GCC	O
(	O
University	O
of	O
Wisconsin	O
)	O
.	O

Each	O
sequence	O
was	O
determined	O
at	O
least	O
twice	O
,	O
with	O
products	O
obtained	O
using	O
different	O
oligonucleotide	O
primers	O
.	O

DNA	O
from	O
pMT28	O
or	O
its	O
recombinant	O
and	O
mutant	O
derivatives	O
was	O
linearized	O
with	O
Nde	O
I	O
and	O
transcribed	O
with	O
SP6	O
RNA	O
polymerase	O
as	O
previously	O
described	O
[	O
22	O
,	O
27	O
]	O
.	O

Transcript	O
RNA	O
integrity	O
and	O
concentration	O
were	O
estimated	O
by	O
agarose	O
gel	O
electrophoresis	O
,	O
in	O
parallel	O
runs	O
with	O
known	O
amounts	O
of	O
standard	O
C	O
-	O
S8c1	O
RNA	O
.	O

BHK	O
-	O
21	O
cell	O
monolayers	O
(	O
70	O
%	O
confluent	O
,	O
about	O
1	O
x	O
106	O
cells	O
)	O
were	O
transfected	O
with	O
RNA	O
transcripts	O
(	O
1	O
mu	O
g	O
RNA	O
)	O
using	O
lipofectin	O
as	O
previously	O
described	O
[	O
59	O
]	O
.	O

Virus	O
was	O
collected	O
from	O
the	O
culture	O
supernatant	O
at	O
72	O
h	O
post	O
-	O
transfection	O
.	O

The	O
virus	O
obtained	O
by	O
transfection	O
was	O
passaged	O
twice	O
before	O
using	O
it	O
in	O
biological	O
studies	O
.	O

RNA	O
was	O
extracted	O
and	O
sequenced	O
to	O
ascertain	O
that	O
the	O
virus	O
maintained	O
the	O
genomic	O
structure	O
and	O
mutations	O
of	O
the	O
initial	O
transcript	O
.	O

Consensus	O
genomic	O
nucleotide	O
sequences	O
of	O
FMDV	B
clones	O
were	O
obtained	O
by	O
RT	O
-	O
PCR	O
amplification	O
of	O
virion	O
RNA	O
using	O
specific	O
primers	O
[	O
7	O
,	O
22	O
,	O
28	O
]	O
.	O

Supporting	O
Information	O

Accession	O
Numbers	O

The	O
GenBank	O
accession	O
numbers	O
for	O
the	O
C	O
-	O
S8c1	O
,	O

,	O

,	O
CS8p260p3d	O
,	O
and	O
MARLS	O
genomic	O
sequences	O
are	O
AJ133357	O
,	O
AM409190	O
,	O
AM409325	O
,	O
DQ409185	O
,	O
and	O
AF274010	O
,	O
respectively	O
.	O

Nucleotide	O
and	O
amino	O
acid	O
sequences	O
for	O
picornaviruses	O
can	O
be	O
found	O
at	O
http	O
:	O
/	O
/	O
www	O
.	O
iah	O
.	O
bbsrc	O
.	O
ac	O
.	O
uk	O
/	O
virus	O
/	O
picornaviridae	O
/	O
SequenceDatabase	O
/	O
3Ddatabase	O
/	O
3D	O
.	O
HTM	O
.	O

Human	B
growth	O
hormone	O
(	O
GH1	O
)	O
gene	O
polymorphism	O
map	O
in	O
a	O
normal	O
-	O
statured	O
adult	O
population	O

Abstract	O

Objective	O

GH1	O
gene	O
presents	O
a	O
complex	O
map	O
of	O
single	O
nucleotide	O
polymorphisms	O
(	O
SNPs	O
)	O
in	O
the	O
entire	O
promoter	O
,	O
coding	O
and	O
noncoding	O
regions	O
.	O

The	O
aim	O
of	O
the	O
study	O
was	O
to	O
establish	O
the	O
complete	O
map	O
of	O
GH1	O
gene	O
SNPs	O
in	O
our	O
control	O
normal	O
population	O
and	O
to	O
analyse	O
its	O
association	O
with	O
adult	O
height	O
.	O

Design	O
,	O
subjects	O
and	O
measurements	O

A	O
systematic	O
GH1	O
gene	O
analysis	O
was	O
designed	O
in	O
a	O
control	O
population	O
of	O
307	O
adults	O
of	O
both	O
sexes	O
with	O
height	O
normally	O
distributed	O
within	O
normal	O
range	O
for	O
the	O
same	O
population	O
:	O
-	O
2	O
standard	O
deviation	O
scores	O
(	O
SDS	O
)	O
to	O
+	O
2	O
SDS	O
.	O

An	O
analysis	O
was	O
performed	O
on	O
individual	O
and	O
combined	O
genotype	O
associations	O
with	O
adult	O
height	O
.	O

Results	O

Twenty	O
-	O
five	O
SNPs	O
presented	O
a	O
frequency	O
over	O
1	O
%	O
:	O
11	O
in	O
the	O
promoter	O
(	O
P1	O
to	O
P11	O
)	O
,	O
three	O
in	O
the	O
5	O
'	O
UTR	O
region	O
(	O
P12	O
to	O
P14	O
)	O
,	O
one	O
in	O
exon	O
1	O
(	O
P15	O
)	O
,	O
three	O
in	O
intron	O
1	O
(	O
P16	O
to	O
P18	O
)	O
,	O
two	O
in	O
intron	O
2	O
(	O
P19	O
and	O
P20	O
)	O
,	O
two	O
in	O
exon	O
4	O
(	O
P21	O
and	O
P22	O
)	O
and	O
three	O
in	O
intron	O
4	O
(	O
P23	O
to	O
P25	O
)	O
.	O

Twenty	O
-	O
nine	O
additional	O
changes	O
with	O
frequencies	O
under	O
1	O
%	O
were	O
found	O
in	O
29	O
subjects	O
.	O

P8	O
,	O
P19	O
,	O
P20	O
and	O
P25	O
had	O
not	O
been	O
previously	O
described	O
.	O

P6	O
,	O
P12	O
,	O
P17	O
and	O
P25	O
accounted	O
for	O
6	O
.	O
2	O
%	O
of	O
the	O
variation	O
in	O
adult	O
height	O
(	O
P	O
=	O
0	O
.	O
0007	O
)	O
in	O
this	O
population	O
with	O
genotypes	O
A	O
/	O
G	O
at	O
P6	O
,	O
G	O
/	O
G	O
at	O
P6	O
and	O
A	O
/	O
G	O
at	O
P12	O
decreasing	O
height	O
SDS	O
(	O
-	O
0	O
.	O
063	O
+	O
/	O
-	O
0	O
.	O
031	O
,	O
-	O
0	O
.	O
693	O
+	O
/	O
-	O
0	O
.	O
350	O
and	O
-	O
0	O
.	O
489	O
+	O
/	O
-	O
0	O
.	O
265	O
,	O
Mean	O
+	O
/	O
-	O
SE	O
)	O
and	O
genotypes	O
A	O
/	O
T	O
at	O
P17	O
and	O
T	O
/	O
G	O
at	O
P25	O
increasing	O
height	O
SDS	O
(	O
+	O
1	O
.	O
094	O
+	O
/	O
-	O
0	O
.	O
456	O
and	O
+	O
1	O
.	O
184	O
+	O
/	O
-	O
0	O
.	O
432	O
)	O
.	O

Conclusions	O

This	O
study	O
established	O
the	O
GH1	O
gene	O
sequence	O
variation	O
map	O
in	O
a	O
normal	O
adult	O
height	O
control	O
population	O
confirming	O
the	O
high	O
density	O
of	O
SNPs	O
in	O
a	O
relatively	O
small	O
gene	O
.	O

Our	O
study	O
shows	O
that	O
the	O
more	O
frequent	O
SNPs	O
did	O
not	O
significantly	O
contribute	O
to	O
height	O
determination	O
,	O
while	O
only	O
one	O
promoter	O
and	O
two	O
intronic	O
SNPs	O
contributed	O
significantly	O
to	O
it	O
.	O

Studies	O
in	O
larger	O
populations	O
will	O
have	O
to	O
confirm	O
the	O
associations	O
and	O
in	O
vitro	O
functional	O
studies	O
will	O
elucidate	O
the	O
mechanisms	O
involved	O
.	O

Systematic	O
GH1	O
gene	O
analysis	O
in	O
patients	B
with	O
growth	O
delay	O
and	O
suspected	O
GH	O
deficiency	O
/	O
insufficiency	O
will	O
clarify	O
whether	O
different	O
SNP	O
frequencies	O
and	O
/	O
or	O
the	O
presence	O
of	O
different	O
sequence	O
changes	O
may	O
be	O
associated	O
with	O
phenotypes	O
in	O
them	O
.	O

Introduction	O

Human	B
skeletal	O
growth	O
and	O
final	O
height	O
attainment	O
are	O
a	O
result	O
of	O
a	O
multifactorial	O
regulation	O
involving	O
systemic	O
and	O
local	O
hormones	O
,	O
growth	O
and	O
nutritional	O
factors	O
,	O
lifestyle	O
and	O
genetic	O
factors	O
.	O

Heritability	O
estimates1	O
and	O
genome	O
-	O
wide	O
linkage	O
analysis2	O
have	O
shown	O
that	O
genetic	O
factors	O
play	O
a	O
major	O
role	O
in	O
determining	O
stature	O
.	O

Among	O
these	O
factors	O
,	O
the	O
GH	O
-	O
IGF	O
-	O
I	O
axis	O
plays	O
an	O
important	O
role	O
during	O
postnatal	O
life	O
,	O
and	O
associations	O
between	O
structural	O
variations	O
in	O
its	O
genes	O
and	O
height	O
are	O
currently	O
under	O
study	O
.	O
3	O
Although	O
growth	O
hormone	O
(	O
GH	O
)	O
deficiency	O
is	O
a	O
well	O
-	O
known	O
cause	O
of	O
growth	O
retardation	O
,	O
which	O
responds	O
to	O
GH	O
replacement	O
therapy	O
,	O
the	O
diagnosis	O
and	O
physiopathological	O
mechanisms	O
for	O
the	O
so	O
-	O
called	O
'	O
idiopathic	O
isolated	O
GH	O
deficiency	O
'	O
(	O
IIGHD	O
)	O
require	O
further	O
clarification	O
.	O

In	O
addition	O
,	O
GH	O
secretion	O
levels	O
and	O
markers	O
of	O
GH	O
biological	O
activity	O
have	O
been	O
demonstrated	O
to	O
be	O
specific	O
and	O
sensitive	O
only	O
in	O
major	O
deficiency	O
states	O
.	O
4	O
,	O
5	O
Genetic	O
causes	O
of	O
GH	O
deficiency	O
within	O
the	O
GH1	O
gene	O
have	O
been	O
established	O
;	O
however	O
,	O
they	O
are	O
rarely	O
recognized	O
and	O
only	O
sought	O
in	O
major	O
GH	O
deficiency	O
states	O
during	O
childhood	O
and	O
in	O
family	O
studies	O
.	O
3	O
GH1	O
gene	O
,	O
located	O
at	O
17q22	O
-	O
24	O
,	O
is	O
a	O
component	O
of	O
the	O
GH	O
gene	O
cluster	O
in	O
which	O
five	O
genes	O
evolving	O
from	O
a	O
common	O
ancestor	O
are	O
91	O
-	O
99	O
%	O
sequence	O
conserved	O
(	O
paralogues	O
)	O
.	O
6	O
GH1	O
is	O
more	O
abundantly	O
expressed	O
in	O
pituitary	O
cells	O
,	O
while	O
the	O
other	O
four	O
genes	O
are	O
expressed	O
in	O
placental	O
tissue	O
.	O

Large	O
deletions	O
within	O
the	O
GH1	O
gene	O
cluster	O
were	O
described	O
first	O
followed	O
by	O
point	O
mutations	O
,	O
the	O
majority	O
of	O
which	O
affect	O
introns	O
3	O
or	O
4	O
,	O
provoke	O
skipping	O
of	O
exon	O
3	O
product	O
and	O
exert	O
a	O
dominant	O
effect	O
.	O
3	O
,	O
7	O
,	O
8	O
More	O
recently	O
,	O
the	O
presence	O
of	O
single	O
nucleotide	O
polymorphic	O
points	O
(	O
SNPs	O
)	O
in	O
the	O
promoter	O
region	O
or	O
in	O
intron	O
4	O
of	O
the	O
GH1	O
gene	O
have	O
been	O
described9	O
-	O
12	O
and	O
associations	O
with	O
promoter	O
allele	O
activities	O
or	O
with	O
GH	O
secretion	O
efficacy	O
and	O
circulating	O
IGF	O
-	O
I	O
levels	O
in	O
growth	O
-	O
retarded	O
patients	B
have	O
also	O
been	O
described	O
.	O
11	O
,	O
12	O
Other	O
studies	O
have	O
analysed	O
several	O
GH1	O
gene	O
SNP	O
genotypes	O
as	O
related	O
to	O
the	O
incidence	O
of	O
neoplasia	O
,	O
with	O
a	O
positive	O
association	O
with	O
colorectal	O
neoplasia	O
for	O
intron	O
4	O
SNP	O
,	O
13	O
a	O
negative	O
result	O
for	O
breast	O
carcinoma14	O
,	O
15	O
or	O
a	O
positive	O
one	O
for	O
breast	O
cancer	O
risk	O
.	O
16	O
,	O
17	O
In	O
addition	O
,	O
a	O
recent	O
study	O
in	O
a	O
cohort	O
of	O
adults	O
over	O
ages	O
60	O
years	O
detected	O
a	O
significant	O
association	O
between	O
genotypes	O
at	O
one	O
SNP	O
in	O
the	O
GH1	O
gene	O
promoter	O
region	O
and	O
at	O
the	O
intron	O
4	O
SNP	O
described	O
by	O
Hasegawa	O
et	O
al	O
.	O
11	O
with	O
baseline	O
bone	O
density	O
and	O
accelerated	O
bone	O
loss	O
together	O
with	O
an	O
interaction	O
with	O
weight	O
at	O
1	O
year	O
.	O
18	O
Intron	O
4	O
SNP	O
described	O
by	O
Hasegawa	O
et	O
al	O
.	O
11	O
has	O
also	O
been	O
associated	O
,	O
in	O
women	B
,	O
with	O
shorter	O
body	O
height	O
and	O
reduced	O
mortality	O
,	O
19	O
whereas	O
another	O
intron	O
4	O
SNP	O
(	O
T1169A	O
)	O
has	O
been	O
associated	O
in	O
both	O
sexes	O
with	O
a	O
favourable	O
metabolic	O
profile	O
.	O
20	O
A	O
systematic	O
SNP	O
study	O
was	O
conducted	O
by	O
Adkins	O
et	O
al	O
.	O
21	O
in	O
GH1	O
promoter	O
,	O
coding	O
and	O
noncoding	O
regions	O
in	O
DNAs	O
from	O
placental	O
tissues	O
,	O
and	O
analysis	O
of	O
associations	O
between	O
genotypes	O
and	O
birth	O
weight	O
revealed	O
an	O
association	O
between	O
an	O
alternate	O
nucleotide	O
at	O
-	O
1	O
and	O
+	O
3	O
of	O
translation	O
initiation	O
site	O
and	O
fetal	O
growth	O
restriction	O
.	O

However	O
,	O
no	O
systematic	O
GH1	O
gene	O
analysis	O
in	O
the	O
entire	O
promoter	O
,	O
coding	O
and	O
noncoding	O
regions	O
has	O
been	O
conducted	O
in	O
adults	O
to	O
establish	O
the	O
map	O
of	O
structural	O
variation	O
and	O
its	O
possible	O
association	O
with	O
height	O
.	O

The	O
relatively	O
short	O
size	O
of	O
the	O
entire	O
gene	O
permits	O
a	O
complete	O
analysis	O
which	O
is	O
,	O
nevertheless	O
,	O
hampered	O
by	O
the	O
need	O
to	O
avoid	O
amplification	O
of	O
any	O
other	O
of	O
the	O
GH	O
cluster	O
genes	O
(	O
paralogues	O
)	O
and	O
the	O
high	O
density	O
of	O
sequence	O
variations	O
.	O

To	O
obtain	O
normative	O
data	O
for	O
subsequent	O
analysis	O
of	O
GH1	O
gene	O
contribution	O
to	O
IIGHD	O
in	O
children	B
,	O
a	O
systematic	O
GH1	O
gene	O
structural	O
analysis	O
was	O
designed	O
in	O
a	O
normal	O
adult	O
control	O
population	O
to	O
establish	O
the	O
GH1	O
gene	O
SNP	O
map	O
in	O
adults	O
from	O
our	O
population	O
with	O
heights	O
within	O
the	O
normal	O
range	O
,	O
determine	O
the	O
genotype	O
frequencies	O
and	O
analyse	O
possible	O
associations	O
between	O
individual	O
and	O
combined	O
SNPs	O
with	O
height	O
.	O

Subjects	O
and	O
methods	O

Subjects	O

A	O
total	O
of	O
307	O
adult	O
subjects	O
of	O
both	O
sexes	O
(	O
164	O
women	B
and	O
143	O
men	B
)	O
were	O
recruited	O
from	O
hospital	O
personnel	O
and	O
parents	O
of	O
patients	B
with	O
no	O
history	O
of	O
growth	O
retardation	O
.	O

Subjects	O
had	O
to	O
fulfil	O
the	O
following	O
criteria	O
:	O
Iberian	O
Peninsular	O
(	O
except	O
Basque	O
)	O
family	O
origin	O
and	O
no	O
family	O
history	O
of	O
pathological	O
short	O
stature	O
.	O

A	O
single	O
subject	O
per	O
family	O
was	O
included	O
.	O

The	O
protocol	O
was	O
approved	O
by	O
the	O
Hospital	O
Vall	O
d	O
'	O
Hebron	O
Ethics	O
Committee	O
and	O
written	O
informed	O
consent	O
was	O
obtained	O
from	O
each	O
participant	B
.	O

Height	O
standard	O
deviation	O
scores	O
(	O
height	O
SDS	O
)	O
were	O
calculated	O
according	O
to	O
sex	O
-	O
specific	O
reference	O
growth	O
charts	O
for	O
the	O
Spanish	O
population	O
(	O
Carrascosa	O
et	O
al	O
.	O
22	O
charts	O
were	O
used	O
for	O
subjects	O
under	O
ages	O
30	O
years	O
and	O
Hern	O
a	O
ndez	O
et	O
al	O
.	O
23	O
for	O
subjects	O
aged	O
30	O
-	O
50	O
years	O
)	O
.	O

Only	O
individuals	O
with	O
height	O
SDS	O
between	O
-	O
2	O
and	O
+	O
2	O
SDS	O
were	O
included	O
in	O
the	O
study	O
(	O
mean	O
-	O
0	O
.	O
016	O
;	O
32	O
women	B
and	O
28	O
men	B
between	O
-	O
2	O
.	O
000	O
and	O
-	O
1	O
.	O
010	O
;	O
99	O
women	B
and	O
80	O
men	B
between	O
-	O
1	O
.	O
000	O
and	O
+	O
0	O
.	O
910	O
;	O
33	O
women	B
and	O
35	O
men	B
between	O
+	O
1	O
.	O
010	O
and	O
+	O
1	O
.	O
980	O
)	O
and	O
sample	O
size	O
was	O
adjusted	O
for	O
normal	O
sex	O
and	O
height	O
SDS	O
distribution	O
.	O

Height	O
and	O
weight	O
were	O
recorded	O
in	O
the	O
morning	O
by	O
a	O
single	O
observer	O
.	O

Height	O
was	O
measured	O
with	O
a	O
Harpenden	O
stadiometer	O
.	O

Four	O
millilitres	O
of	O
peripheral	O
venous	O
blood	O
were	O
drawn	O
into	O
EDTA	O
-	O
containing	O
tubes	O
for	O
molecular	O
genetic	O
analysis	O
.	O

Genomic	O
DNA	O
study	O

Genomic	O
DNA	O
was	O
obtained	O
from	O
peripheral	O
blood	O
following	O
the	O
method	O
described	O
by	O
Lahiri	O
and	O
Nurnberger	O
.	O
24	O
DNA	O
was	O
amplified	O
by	O
polymerase	O
chain	O
reaction	O
(	O
PCR	O
)	O
using	O
a	O
nested	O
strategy	O
.	O

Briefly	O
,	O
50	O
ng	O
of	O
genomic	O
DNA	O
were	O
added	O
to	O
a	O
10	O
micro	O
l	O
reaction	O
mixture	O
of	O
1	O
mm	O
Mg	O
(	O
OAc	O
)	O
2	O
,	O
0	O
.	O
6	O
mm	O
dNTPs	O
,	O
0	O
.	O
3	O
micro	O
m	O
of	O
each	O
primer	O
,	O
and	O
0	O
.	O
4	O
U	O
r	O
Tth	O
DNA	O
polymerase	O
XL	O
(	O
Applied	O
Biosystems	O
,	O
Foster	O
City	O
,	O
CA	O
,	O
USA	O
)	O
.	O

The	O
sense	O
and	O
antisense	O
primers	O
used	O
corresponded	O
to	O
nucleotides	O
4156	O
-	O
5	O
'	O
ACGGTCCGCCACTACGCCCA	O
-	O
3	O
'	O
and	O
the	O
complement	O
of	O
6948	O
-	O
5	O
'	O
TGCAGTGAGCCAAGATTGTG	O
-	O
3	O
'	O
of	O
the	O
GH	O
gene	O
cluster	O
.	O
6	O
The	O
PCR	O
reaction	O
mix	O
was	O
denatured	O
for	O
5	O
min	O
at	O
94	O
degrees	O
C	O
and	O
cycled	O
40	O
times	O
(	O
94	O
degrees	O
C	O
,	O
1	O
min	O
;	O
72	O
degrees	O
C	O
,	O
3	O
min	O
30	O
s	O
)	O
followed	O
by	O
a	O
7	O
-	O
min	O
extension	O
at	O
72	O
degrees	O
C	O
.	O

The	O
resulting	O
GH1	O
PCR	O
products	O
(	O
2893	O
bp	O
)	O
were	O
used	O
as	O
templates	O
for	O
five	O
nested	O
reactions	O
(	O
AN	O
,	O
BL	O
,	O
CK	O
,	O
DI	O
,	O
FP	O
)	O
,	O
carried	O
out	O
as	O
follows	O
:	O
1	O
micro	O
l	O
of	O
each	O
GH1	O
PCR	O
product	O
was	O
added	O
to	O
a	O
20	O
micro	O
l	O
reaction	O
mixture	O
of	O
1	O
.	O
5	O
mm	O
MgCl2	O
,	O
0	O
.	O
2	O
mm	O
dNTPs	O
,	O
0	O
.	O
3	O
micro	O
m	O
of	O
each	O
primer	O
and	O
0	O
.	O
4	O
U	O
Eco	O
Taq	O
DNA	O
polymerase	O
(	O
Ecogen	O
S	O
.	O
R	O
.	O
L	O
.	O
,	O
Barcelona	O
,	O
Spain	O
)	O
.	O

Reaction	O
mixtures	O
were	O
denatured	O
for	O
5	O
min	O
at	O
94	O
degrees	O
C	O
,	O
cycled	O
40	O
times	O
(	O
94	O
degrees	O
C	O
,	O
1	O
min	O
;	O
58	O
degrees	O
C	O
,	O
1	O
min	O
;	O
and	O
72	O
degrees	O
C	O
,	O
1	O
min	O
)	O
,	O
followed	O
by	O
a	O
7	O
-	O
min	O
extension	O
at	O
72	O
degrees	O
C	O
.	O

Sense	O
and	O
antisense	O
primers	O
were	O
as	O
follows	O
:	O

Sequencing	O
from	O
both	O
ends	O
was	O
performed	O
by	O
the	O
dideoxy	O
method	O
using	O
ABI	O
PRISM	O
BigDye	O
Terminator	O
version	O
3	O
.	O
1	O
Cycle	O
Sequencing	O
Kit	O
(	O
Applied	O
Biosystems	O
,	O
Foster	O
City	O
,	O
CA	O
,	O
USA	O
)	O
.	O

GH1	O
gene	O
nucleotide	O
sequence	O
published	O
by	O
Chen	O
et	O
al	O
.	O
6	O
was	O
used	O
as	O
control	O
.	O

For	O
each	O
DNA	O
,	O
the	O
five	O
segments	O
from	O
the	O
nested	O
PCR	O
were	O
assembled	O
with	O
the	O
SeqEscape	O
programme	O
(	O
Applied	O
Biosystems	O
)	O
and	O
interpretation	O
was	O
made	O
visually	O
and	O
simultaneously	O
by	O
two	O
observers	O
.	O

Antisense	O
sequencing	O
was	O
performed	O
to	O
confirm	O
each	O
nucleotide	O
sequence	O
change	O
up	O
to	O
the	O
establishment	O
of	O
the	O
more	O
frequent	O
SNP	O
map	O
(	O
frequency	O
over	O
1	O
%	O
)	O
,	O
whereas	O
less	O
frequent	O
single	O
or	O
multiple	O
nucleotide	O
changes	O
were	O
reconfirmed	O
in	O
each	O
DNA	O
by	O
antisense	O
sequence	O
and	O
resequencing	O
after	O
a	O
new	O
nested	O
PCR	O
from	O
original	O
DNA	O
was	O
performed	O
.	O

Single	O
nucleotide	O
polymorphism	O
(	O
SNP	O
)	O
genotyping	O

The	O
sequences	O
for	O
the	O
five	O
genes	O
of	O
the	O
GH	O
cluster	O
identified	O
by	O
Chen	O
et	O
al	O
.	O
6	O
and	O
reported	O
as	O
the	O
GI	O
sequence	O
183148	O
were	O
aligned	O
using	O
the	O
Multalin	O
program	O
.	O
25	O
SNPs	O
and	O
other	O
sequence	O
changes	O
identified	O
were	O
indicated	O
using	O
their	O
position	O
corresponding	O
to	O
GH1	O
.	O

Genotypes	O
were	O
deduced	O
by	O
the	O
combination	O
of	O
genetic	O
variation	O
at	O
the	O
polymorphic	O
positions	O
.	O

Statistical	O
analysis	O

Standardized	O
height	O
was	O
investigated	O
for	O
normal	O
distribution	O
(	O
Kolmogorov	O
-	O
Smirnov	O
test	O
:	O
c2	O
=	O
2	O
.	O
882	O
,	O
P	O
=	O
0	O
.	O
4733	O
)	O
.	O

Hardy	O
-	O
Weinberg	O
equilibrium	O
was	O
tested	O
for	O
SNPs	O
presenting	O
three	O
alternate	O
genotypes	O
according	O
to	O
standard	O
procedures	O
using	O
chi	O
2	O
-	O
analysis	O
.	O
anova	O
test	O
was	O
applied	O
to	O
investigate	O
individual	O
and	O
combined	O
SNP	O
association	O
with	O
adult	O
height	O
SDS	O
;	O
significance	O
assessment	O
was	O
adjusted	O
for	O
multiple	O
testing	O
using	O
Fisher	O
'	O
s	O
PLSD	O
test	O
setting	O
Pcritical	O
=	O
0	O
.	O
05	O
or	O
the	O
Bonferroni	O
-	O
Dunn	O
test	O
setting	O
Pcritical	O
=	O
0	O
.	O
05	O
/	O
n	O
(	O
n	O
=	O
number	O
of	O
comparisons	O
carried	O
out	O
)	O
.	O

Stepwise	O
regression	O
analysis	O
was	O
applied	O
to	O
predict	O
the	O
contribution	O
of	O
SNPs	O
to	O
adult	O
height	O
SDS	O
.	O

Statview	O
4	O
.	O
5	O
program	O
(	O
Abacus	O
Concepts	O
Inc	O
.	O
,	O
Berkeley	O
,	O
CA	O
,	O
USA	O
)	O
was	O
used	O
for	O
statistical	O
analyses	O
.	O

Results	O

GH1	O
gene	O
sequence	O
variation	O

GH1	O
gene	O
sequence	O
comparison	O
with	O
the	O
GI	O
-	O
183148	O
sequence	O
published	O
by	O
Chen	O
et	O
al	O
.	O
6	O
yielded	O
a	O
total	O
of	O
54	O
single	O
or	O
multiple	O
nucleotide	O
changes	O
.	O

Twenty	O
-	O
five	O
SNPs	O
presented	O
a	O
frequency	O
over	O
1	O
%	O
(	O
genotypes	O
and	O
frequencies	O
are	O
listed	O
in	O
Table	O
1	O
)	O
.	O

SNPs	O
which	O
presented	O
the	O
three	O
alternate	O
genotypes	O
(	O
P2	O
to	O
P4	O
,	O
P6	O
,	O
P7	O
,	O
P10	O
and	O
P24	O
)	O
were	O
in	O
Hardy	O
-	O
Weinberg	O
equilibrium	O
(	O
data	O
not	O
shown	O
)	O
.	O

Twenty	O
-	O
nine	O
additional	O
changes	O
were	O
found	O
with	O
a	O
frequency	O
under	O
1	O
%	O
or	O
involving	O
more	O
than	O
one	O
nucleotide	O
and	O
thus	O
could	O
be	O
considered	O
as	O
rare	O
variant	O
SNPs	O
(	O
R1	O
to	O
R29	O
)	O
(	O
Table	O
2	O
)	O
.	O

These	O
changes	O
were	O
found	O
in	O
29	O
of	O
307	O
subjects	O
(	O
9	O
.	O
4	O
%	O
)	O
,	O
all	O
in	O
heterozygosity	O
.	O

GH1	O
-	O
paralogue	O
alignment	O

A	O
sequence	O
alignment	O
was	O
performed	O
to	O
study	O
possible	O
sequence	O
recombinations	O
among	O
paralogues	O
of	O
the	O
five	O
GH1	O
-	O
gene	O
cluster	O
(	O
Fig	O
.	O
1	O
)	O
.	O

This	O
alignment	O
showed	O
that	O
9	O
of	O
25	O
SNPs	O
(	O
36	O
%	O
)	O
in	O
the	O
GH1	O
gene	O
did	O
not	O
correspond	O
to	O
any	O
of	O
the	O
paralogues	O
.	O

Among	O
the	O
29	O
rare	O
SNPs	O
found	O
,	O
six	O
(	O
20	O
.	O
7	O
%	O
)	O
did	O
not	O
correspond	O
to	O
any	O
of	O
the	O
paralogues	O
:	O
two	O
were	O
located	O
in	O
the	O
5	O
'	O
UTR	O
region	O
(	O
R9	O
and	O
R10	O
)	O
,	O
two	O
in	O
intron	O
1	O
(	O
positions	O
5300	O
=	O
R14	O
and	O
5302	O
=	O
R17	O
)	O
,	O
one	O
in	O
intron	O
2	O
(	O
position	O
5679	O
=	O
R21	O
)	O
and	O
one	O
in	O
intron	O
4	O
(	O
position	O
6344	O
=	O
R23	O
)	O
(	O
Table	O
2	O
)	O
.	O

Equivalence	O
with	O
previously	O
reported	O
GH1	O
changes	O

Equivalence	O
with	O
changes	O
and	O
SNPs	O
previously	O
reported	O
by	O
other	O
authors	O
are	O
shown	O
in	O
Table	O
3	O
.	O

The	O
majority	O
found	O
a	O
high	O
density	O
of	O
SNPs	O
in	O
the	O
promoter	O
and	O
5	O
'	O
UTR	O
regions	O
in	O
control	O
populations	O
.	O
10	O
,	O
12	O
,	O
21	O
Several	O
sequence	O
changes	O
have	O
been	O
reported	O
in	O
patients	B
with	O
familial	O
or	O
idiopathic	O
short	O
stature	O
,	O
11	O
,	O
26	O
,	O
27	O
whereas	O
P8	O
,	O
P19	O
,	O
P20	O
and	O
P25	O
(	O
at	O
positions	O
5165	O
,	O
5681	O
,	O
5686	O
and	O
6358	O
,	O
respectively	O
,	O
in	O
the	O
Genebank	O
accession	O
GI	O
183148	O
)	O
located	O
in	O
the	O
promoter	O
,	O
intron	O
2	O
and	O
intron	O
4	O
regions	O
,	O
respectively	O
,	O
had	O
not	O
been	O
previously	O
described	O
.	O

GH1	O
genotypes	O
and	O
associations	O
with	O
height	O
SDS	O

Associations	O
between	O
genotypes	O
and	O
standardized	O
height	O
were	O
first	O
studied	O
in	O
the	O
subpopulation	O
of	O
278	O
controls	O
carrying	O
only	O
the	O
25	O
most	O
frequent	O
SNPs	O
in	O
the	O
GH1	O
gene	O
(	O
c2	O
=	O
2	O
.	O
59	O
;	O
P	O
=	O
0	O
.	O
5458	O
for	O
normality	O
of	O
height	O
distribution	O
)	O
.	O

Three	O
individual	O
SNPs	O
showed	O
a	O
statistically	O
significant	O
association	O
with	O
height	O
SDS	O
:	O
at	O
positions	O
5286	O
(	O
P16	O
)	O
,	O
5290	O
(	O
P17	O
)	O
and	O
6358	O
(	O
P25	O
)	O
.	O

Subjects	O
with	O
heterozygous	O
genotypes	O
presented	O
statistically	O
significant	O
taller	O
stature	O
than	O
the	O
corresponding	O
homozygous	O
genotypes	O
(	O
P	O
=	O
0	O
.	O
016	O
for	O
P16	O
,	O
P	O
=	O
0	O
.	O
015	O
for	O
P17	O
and	O
P	O
=	O
0	O
.	O
023	O
for	O
P25	O
)	O
(	O
Fig	O
.	O
2a	O
,	O
b	O
,	O
c	O
)	O
.	O

P16	O
and	O
P17	O
were	O
in	O
linkage	O
disequilibrium	O
(	O
LD	O
)	O
(	O
r2	O
=	O
0	O
.	O
831	O
)	O
,	O
while	O
P25	O
was	O
carried	O
by	O
six	O
subjects	O
homozygous	O
at	O
P16	O
and	O
P17	O
.	O

GH1	O
gene	O
genotypes	O
were	O
defined	O
by	O
genetic	O
variation	O
in	O
the	O
25	O
polymorphic	O
positions	O
.	O

We	O
found	O
163	O
different	O
combinations	O
.	O

Only	O
two	O
genotypes	O
presented	O
a	O
frequency	O
over	O
5	O
%	O
(	O
Table	O
4	O
)	O
.	O

Height	O
SDS	O
in	O
the	O
two	O
more	O
frequent	O
genotypes	O
did	O
not	O
differ	O
significantly	O
and	O
covered	O
the	O
whole	O
height	O
range	O
.	O

Genotype	O
1	O
presented	O
four	O
heterozygous	O
variations	O
and	O
Genotype	O
2	O
was	O
the	O
corresponding	O
homozygous	O
genotype	O
.	O

Heterozygous	O
positions	O
corresponded	O
to	O
SNPs	O
with	O
the	O
highest	O
frequency	O
variation	O
(	O
4886	O
(	O
P4	O
)	O
,	O
5107	O
(	O
P7	O
)	O
,	O
5157	O
(	O
P10	O
)	O
and	O
6331	O
(	O
P24	O
)	O
)	O
.	O

In	O
addition	O
,	O
DNAs	O
exhibited	O
a	O
different	O
genotype	O
in	O
each	O
of	O
129	O
subjects	O
(	O
46	O
.	O
4	O
%	O
)	O
.	O

The	O
11	O
SNPs	O
found	O
in	O
the	O
promoter	O
region	O
(	O
Table	O
1	O
)	O
were	O
grouped	O
in	O
94	O
genotypes	O
and	O
analysed	O
for	O
association	O
with	O
adult	O
height	O
SDS	O
.	O

The	O
four	O
more	O
frequent	O
combinations	O
are	O
listed	O
in	O
Table	O
4	O
:	O
height	O
SDS	O
of	O
these	O
four	O
genotypes	O
did	O
not	O
differ	O
statistically	O
although	O
Genotype	O
3	O
tended	O
to	O
have	O
a	O
shorter	O
height	O
.	O

Genotype	O
3	O
differed	O
from	O
Genotype	O
1	O
in	O
the	O
SNP	O
located	O
at	O
position	O
5089	O
(	O
P6	O
)	O
,	O
corresponding	O
to	O
Pit	O
1	O
proximal	O
responsive	O
element	O
for	O
GH1	O
gene	O
promoter	O
.	O

Genotype	O
4	O
is	O
heterozygous	O
at	O
positions	O
4856	O
(	O
P2	O
)	O
,	O
4863	O
(	O
P3	O
)	O
and	O
5107	O
(	O
P7	O
)	O
.	O

In	O
addition	O
,	O
19	O
%	O
of	O
cases	O
exhibited	O
a	O
genotype	O
in	O
the	O
promoter	O
region	O
carried	O
by	O
only	O
one	O
subject	O
.	O

Combination	O
of	O
the	O
three	O
SNPs	O
in	O
the	O
5	O
'	O
UTR	O
region	O
of	O
GH1	O
gene	O
resulted	O
in	O
five	O
different	O
genotypes	O
.	O

SNPs	O
at	O
positions	O
5178	O
(	O
P12	O
)	O
and	O
5187	O
(	O
P13	O
)	O
were	O
in	O
LD	O
(	O
r2	O
=	O
0	O
.	O
88	O
)	O
.	O

Mean	O
height	O
SDS	O
comparison	O
among	O
these	O
genotypes	O
was	O
not	O
statistically	O
significant	O
,	O
although	O
mean	O
height	O
SDS	O
of	O
alternate	O
nucleotide	O
carriers	O
at	O
position	O
5178	O
(	O
P12	O
)	O
tended	O
to	O
be	O
shorter	O
(	O
Table	O
4	O
)	O
.	O

An	O
anova	O
analysis	O
was	O
conducted	O
to	O
investigate	O
the	O
interaction	O
between	O
two	O
or	O
more	O
SNPs	O
and	O
height	O
SDS	O
.	O

SNPs	O
at	O
positions	O
5286	O
(	O
P16	O
)	O
and	O
5290	O
(	O
P17	O
)	O
were	O
in	O
LD	O
(	O
r2	O
=	O
0	O
.	O
83	O
)	O
:	O
the	O
heterozygous	O
genotype	O
AG	O
/	O
AT	O
for	O
these	O
SNPs	O
was	O
associated	O
with	O
taller	O
stature	O
(	O
shown	O
above	O
)	O
.	O

SNP	O
at	O
position	O
6358	O
(	O
P25	O
)	O
increased	O
the	O
expected	O
height	O
SDS	O
for	O
individual	O
carriers	O
of	O
the	O
G	O
allele	O
at	O
5089	O
(	O
P6	O
)	O
SNP	O
as	O
shown	O
in	O
Fig	O
.	O

2	O
(	O
d	O
)	O
:	O
subjects	O
heterozygous	O
at	O
6358	O
(	O
P25	O
)	O
were	O
taller	O
than	O
the	O
mean	O
,	O
and	O
mean	O
height	O
SDS	O
of	O
subjects	O
with	O
GG	O
/	O
TG	O
combined	O
genotype	O
was	O
significantly	O
higher	O
than	O
the	O
corresponding	O
GG	O
/	O
TT	O
genotype	O
(	O
P	O
=	O
0	O
.	O
0021	O
)	O
,	O
suggesting	O
an	O
interaction	O
between	O
these	O
two	O
SNPs	O
as	O
they	O
were	O
not	O
in	O
LD	O
.	O

Analysis	O
of	O
height	O
SDS	O
association	O
with	O
the	O
most	O
frequent	O
single	O
and	O
combined	O
SNPs	O
and	O
with	O
rare	O
variant	O
SNPs	O
was	O
performed	O
in	O
the	O
29	O
individuals	O
carrying	O
the	O
rare	O
SNPs	O
(	O
Table	O
2	O
)	O
.	O

None	O
of	O
them	O
carried	O
any	O
of	O
the	O
three	O
SNPs	O
(	O
P16	O
,	O
P17	O
and	O
P25	O
)	O
related	O
to	O
taller	O
stature	O
in	O
the	O
population	O
of	O
278	O
controls	O
with	O
only	O
the	O
frequent	O
SNPs	O
.	O

In	O
these	O
29	O
,	O
mean	O
height	O
SDS	O
(	O
0	O
.	O
000	O
+	O
/	O
-	O
0	O
.	O
987	O
,	O
from	O
-	O
1	O
.	O
930	O
to	O
+	O
1	O
.	O
870	O
)	O
did	O
not	O
differ	O
from	O
that	O
of	O
the	O
278	O
controls	O
(	O
-	O
0	O
.	O
018	O
+	O
/	O
-	O
1	O
.	O
041	O
,	O
from	O
-	O
2	O
.	O
000	O
to	O
+	O
1	O
.	O
980	O
)	O
.	O

Analysis	O
of	O
associations	O
between	O
individual	O
SNP	O
genotypes	O
and	O
height	O
SDS	O
revealed	O
that	O
SNPs	O
at	O
positions	O
5089	O
(	O
P6	O
)	O
,	O
5178	O
(	O
P12	O
)	O
and	O
5187	O
(	O
P13	O
)	O
were	O
associated	O
with	O
significantly	O
shorter	O
stature	O
(	O
Fig	O
.	O
2e	O
)	O
.	O

Only	O
two	O
sequence	O
changes	O
considered	O
as	O
rare	O
SNPs	O
were	O
carried	O
by	O
individuals	O
in	O
the	O
lower	O
normal	O
height	O
range	O
(	O
between	O
-	O
1	O
.	O
500	O
and	O
-	O
2	O
.	O
000	O
SDS	O
)	O
(	O
Table	O
2	O
)	O
:	O
R4	O
(	O
4979	O
C	O
>	O
T	O
)	O
in	O
the	O
promoter	O
region	O
and	O
R14	O
(	O
5300	O
C	O
>	O
T	O
)	O
in	O
intron	O
1	O
.	O

Predicted	O
single	O
amino	O
acid	O
changes	O
located	O
in	O
exon	O
5	O
(	O
R25	O
to	O
R27	O
)	O
were	O
not	O
associated	O
with	O
short	O
stature	O
.	O

In	O
the	O
entire	O
population	O
of	O
307	O
controls	O
,	O
stepwise	O
regression	O
analysis	O
between	O
height	O
SDS	O
and	O
genotypes	O
at	O
the	O
25	O
SNPs	O
showed	O
that	O
genotypes	O
at	O
5089	O
(	O
P6	O
)	O
,	O
5178	O
(	O
P12	O
)	O
,	O
5290	O
(	O
P17	O
)	O
and	O
6358	O
(	O
P25	O
)	O
were	O
significantly	O
correlated	O
with	O
height	O
SDS	O
(	O
r2	O
=	O
0	O
.	O
062	O
,	O
P	O
=	O
0	O
.	O
0007	O
)	O
with	O
genotypes	O
A	O
/	O
G	O
at	O
P6	O
,	O
G	O
/	O
G	O
at	O
P6	O
and	O
A	O
/	O
G	O
at	O
P12	O
decreasing	O
height	O
SDS	O
(	O
-	O
0	O
.	O
063	O
+	O
/	O
-	O
0	O
.	O
031	O
,	O
-	O
0	O
.	O
693	O
+	O
/	O
-	O
0	O
.	O
350	O
and	O
-	O
0	O
.	O
489	O
+	O
/	O
-	O
0	O
.	O
265	O
,	O
respectively	O
,	O
Mean	O
+	O
/	O
-	O
SE	O
)	O
and	O
genotypes	O
A	O
/	O
T	O
at	O
P17	O
and	O
T	O
/	O
G	O
at	O
P25	O
increasing	O
height	O
SDS	O
(	O
+	O
1	O
.	O
094	O
+	O
/	O
-	O
0	O
.	O
456	O
and	O
+	O
1	O
.	O
184	O
+	O
/	O
-	O
0	O
.	O
432	O
,	O
respectively	O
)	O
.	O

Discussion	O

Genetic	O
variations	O
within	O
human	B
GH1	O
gene	O
have	O
been	O
described	O
by	O
several	O
authors	O
.	O
9	O
-	O
12	O
,	O
21	O
The	O
populations	O
described	O
to	O
date	O
comprised	O
small	O
numbers	O
of	O
normal	O
-	O
stature	O
individuals	O
,	O
9	O
male	O
adults	O
with	O
narrow	O
height	O
range12	O
or	O
growth	O
-	O
retarded	O
patients	B
with	O
/	O
without	O
GHD	O
before	O
achievement	O
of	O
adult	O
height	O
.	O
9	O
,	O
11	O
,	O
12	O
Our	O
study	O
was	O
designed	O
to	O
characterize	O
the	O
GH1	O
gene	O
sequence	O
variation	O
in	O
individuals	O
within	O
the	O
whole	O
range	O
of	O
normal	O
adult	O
height	O
(	O
between	O
-	O
2	O
and	O
+	O
2	O
SDS	O
)	O
according	O
to	O
the	O
standards	O
for	O
our	O
population	O
.	O

Height	O
was	O
normally	O
distributed	O
,	O
both	O
sexes	O
were	O
equally	O
represented	O
and	O
the	O
GI	O
-	O
183148	O
homozygous	O
sequence6	O
was	O
used	O
for	O
comparison	O
.	O

A	O
nested	O
PCR	O
with	O
specific	O
primers	O
for	O
GH1	O
gene	O
was	O
designed	O
,	O
thus	O
avoiding	O
amplification	O
of	O
any	O
other	O
GH	O
gene	O
paralogue	O
of	O
the	O
GH	O
gene	O
cluster	O
.	O

Our	O
results	O
establish	O
a	O
map	O
of	O
25	O
SNPs	O
as	O
present	O
in	O
over	O
1	O
%	O
of	O
individuals	O
,	O
whereas	O
29	O
other	O
sequence	O
changes	O
(	O
single	O
or	O
multiple	O
nucleotide	O
)	O
are	O
present	O
in	O
less	O
than	O
1	O
%	O
of	O
subjects	O
.	O

More	O
than	O
50	O
%	O
(	O
n	O
=	O
14	O
)	O
of	O
SNPs	O
are	O
located	O
in	O
the	O
promoter	O
and	O
5	O
'	O
UTR	O
regions	O
,	O
thus	O
confirming	O
previous	O
reports	O
:	O
Giordano	O
et	O
al	O
.	O
9	O
reported	O
eight	O
SNPs	O
in	O
the	O
promoter	O
and	O
5	O
'	O
UTR	O
regions	O
,	O
Wagner	O
et	O
al	O
.	O
10	O
16	O
SNPs	O
from	O
the	O
promoter	O
to	O
intron	O
1	O
and	O
Horan	O
et	O
al	O
.	O
12	O
identified	O
36	O
haplotypes	O
in	O
control	O
subjects	O
of	O
the	O
British	O
population	O
,	O
which	O
would	O
result	O
from	O
the	O
combination	O
of	O
15	O
of	O
the	O
previously	O
reported	O
SNPs	O
.	O

Our	O
results	O
confirm	O
the	O
presence	O
of	O
13	O
of	O
those	O
points	O
;	O
SNP	O
at	O
5165	O
(	O
R11	O
in	O
the	O
present	O
study	O
and	O
+	O
3	O
in	O
references9	O
,	O
12	O
)	O
was	O
present	O
in	O
less	O
than	O
1	O
%	O
of	O
subjects	O
and	O
a	O
new	O
SNP	O
is	O
described	O
(	O
P8	O
at	O
5116	O
in	O
the	O
VDR	O
/	O
RA	O
/	O
T3	O
responsive	O
element	O
sequence	O
)	O
.	O

The	O
remaining	O
SNPs	O
(	O
from	O
P15	O
to	O
P25	O
,	O
n	O
=	O
11	O
)	O
are	O
distributed	O
in	O
introns	O
1	O
,	O
2	O
and	O
4	O
,	O
and	O
among	O
coding	O
regions	O
only	O
exon	O
1	O
and	O
exon	O
4	O
bear	O
a	O
total	O
of	O
three	O
SNPs	O
,	O
two	O
of	O
which	O
predict	O
an	O
amino	O
acid	O
change	O
(	O
P15	O
and	O
P21	O
)	O
.	O

These	O
two	O
latter	O
SNPs	O
had	O
been	O
described	O
by	O
Millar	O
et	O
al	O
.	O
26	O
and	O
the	O
more	O
frequent	O
SNP	O
in	O
intron	O
4	O
(	O
P24	O
)	O
has	O
been	O
described	O
by	O
Hasegawa	O
et	O
al	O
.	O
11	O
together	O
with	O
the	O
two	O
more	O
frequent	O
SNPs	O
in	O
the	O
promoter	O
region	O
(	O
P4	O
and	O
P7	O
in	O
our	O
map	O
)	O
.	O

Three	O
new	O
SNPs	O
are	O
described	O
(	O
P19	O
and	O
P20	O
in	O
intron	O
2	O
and	O
P25	O
in	O
intron	O
4	O
)	O
,	O
all	O
outside	O
the	O
splice	O
sites	O
.	O

Only	O
SNPs	O
presenting	O
high	O
frequency	O
are	O
present	O
in	O
homozygous	O
alternate	O
state	O
and	O
this	O
accounts	O
mostly	O
for	O
the	O
majority	O
of	O
the	O
promoter	O
and	O
5	O
'	O
UTR	O
SNPs	O
and	O
in	O
the	O
intron	O
4	O
more	O
frequent	O
SNP	O
(	O
P24	O
)	O
described	O
by	O
Hasegawa	O
et	O
al	O
.	O
11	O
In	O
conclusion	O
,	O
in	O
the	O
entire	O
coding	O
and	O
noncoding	O
GH1	O
gene	O
sequence	O
,	O
only	O
P24	O
is	O
present	O
in	O
homozygous	O
alternate	O
state	O
.	O

Our	O
results	O
show	O
that	O
the	O
GI	O
183148	O
homozygous	O
sequence	O
is	O
present	O
in	O
our	O
population	O
except	O
for	O
SNP	O
P14	O
in	O
the	O
5	O
'	O
UTR	O
region	O
which	O
is	O
only	O
present	O
as	O
the	O
alternate	O
nucleotide	O
in	O
homozygous	O
or	O
heterozygous	O
states	O
.	O

As	O
described	O
by	O
several	O
authors9	O
,	O
10	O
,	O
12	O
,	O
21	O
several	O
promoter	O
SNPs	O
affected	O
functional	O
sequences	O
and	O
P6	O
is	O
located	O
in	O
the	O
Pit	O
1	O
proximal	O
responsive	O
element	O
,	O
P7	O
and	O
P8	O
in	O
the	O
VDR	O
/	O
RA	O
/	O
T3	O
responsive	O
element	O
and	O
P9	O
(	O
G	O
del	O
)	O
in	O
the	O
TATA	O
box	O
.	O

The	O
mechanisms	O
by	O
which	O
the	O
high	O
density	O
of	O
SNPs	O
in	O
the	O
GH1	O
gene	O
is	O
generated	O
has	O
been	O
proposed	O
to	O
be	O
recombination	O
and	O
gene	O
conversion	O
with	O
any	O
other	O
(	O
s	O
)	O
of	O
the	O
GH	O
cluster	O
genes	O
.	O
9	O
,	O
12	O
,	O
28	O
Alignment	O
of	O
the	O
25	O
SNPs	O
with	O
the	O
other	O
GH1	O
gene	O
paralogues	O
demonstrated	O
in	O
our	O
results	O
that	O
this	O
mechanism	O
is	O
possible	O
for	O
64	O
%	O
of	O
SNPs	O
.	O

Familial	O
SNP	O
transmission	O
pattern	O
analysis	O
will	O
be	O
of	O
interest	O
to	O
support	O
the	O
hypothesis	O
of	O
GH	O
gene	O
recombination	O
.	O

In	O
addition	O
,	O
29	O
of	O
307	O
individuals	O
(	O
9	O
.	O
4	O
%	O
)	O
bore	O
additional	O
GH1	O
sequence	O
changes	O
with	O
frequencies	O
under	O
1	O
%	O
.	O

As	O
for	O
SNPs	O
,	O
they	O
are	O
located	O
along	O
the	O
whole	O
gene	O
with	O
higher	O
density	O
in	O
the	O
promoter	O
and	O
5	O
'	O
UTR	O
regions	O
.	O

Interestingly	O
,	O
intron	O
3	O
and	O
exon	O
5	O
present	O
several	O
of	O
these	O
less	O
frequent	O
changes	O
.	O

Intron	O
3	O
has	O
been	O
shown	O
to	O
carry	O
the	O
majority	O
of	O
single	O
nucleotide	O
mutations	O
causing	O
the	O
dominant	O
form	O
of	O
GH	O
deficiency	O
.	O
3	O
The	O
two	O
single	O
nucleotide	O
changes	O
detected	O
in	O
intron	O
3	O
(	O
R15	O
at	O
6056	O
and	O
R16	O
at	O
6061	O
)	O
are	O
in	O
perfect	O
LD	O
(	O
r2	O
=	O
1	O
.	O
0	O
)	O
and	O
located	O
within	O
the	O
enhancer	O
splice	O
site	O
element	O
(	O
ESE	O
)	O
described	O
by	O
Ryther	O
et	O
al	O
.	O
29	O
,	O
30	O
Studies	O
in	O
additional	O
normal	O
or	O
growth	O
-	O
retarded	O
populations	O
will	O
permit	O
description	O
of	O
their	O
possible	O
clinical	O
implications	O
.	O

Five	O
single	O
nucleotide	O
changes	O
are	O
located	O
in	O
exon	O
5	O
;	O
of	O
these	O
five	O
,	O
three	O
predict	O
an	O
amino	O
acid	O
change	O
,	O
and	O
one	O
of	O
the	O
three	O
(	O
Ile179Met	O
)	O
has	O
been	O
described	O
by	O
Lewis	O
et	O
al	O
.	O
27	O
in	O
a	O
paediatric	O
patient	B
with	O
familial	O
short	O
stature	O
and	O
the	O
other	O
two	O
,	O
as	O
yet	O
undescribed	O
,	O
are	O
contiguous	O
in	O
a	O
single	O
individual	O
(	O
Pro133Hys	O
and	O
Arg134Leu	O
)	O
.	O

Polynucleotide	O
changes	O
are	O
mostly	O
located	O
in	O
the	O
promoter	O
region	O
corresponding	O
to	O
the	O
VDR	O
/	O
RA	O
/	O
T3	O
response	O
element	O
.	O

As	O
for	O
frequent	O
SNPs	O
,	O
the	O
majority	O
of	O
the	O
sequence	O
changes	O
with	O
frequencies	O
under	O
1	O
%	O
may	O
have	O
been	O
generated	O
by	O
recombination	O
within	O
the	O
GH	O
gene	O
cluster	O
as	O
19	O
of	O
24	O
(	O
79	O
%	O
)	O
may	O
correspond	O
to	O
one	O
or	O
more	O
of	O
the	O
GH1	O
gene	O
paralogues	O
.	O

Our	O
results	O
now	O
show	O
the	O
diversity	O
and	O
complexity	O
of	O
SNP	O
genotypes	O
,	O
as	O
previously	O
highlighted	O
by	O
other	O
authors9	O
,	O
10	O
,	O
12	O
,	O
21	O
in	O
a	O
normal	O
adult	O
height	O
control	O
population	O
.	O

Our	O
initial	O
aim	O
when	O
designing	O
the	O
present	O
study	O
was	O
to	O
establish	O
the	O
map	O
of	O
GH1	O
gene	O
SNPs	O
in	O
our	O
adult	O
control	O
population	O
with	O
heights	O
normally	O
distributed	O
within	O
the	O
entire	O
normal	O
range	O
for	O
further	O
comparison	O
with	O
genotypes	O
in	O
our	O
paediatric	O
population	O
with	O
growth	O
delay	O
,	O
variable	O
response	O
to	O
GH	O
secretion	O
tests	O
and	O
adequate	O
response	O
to	O
GH	O
therapy	O
.	O

Analysis	O
of	O
SNP	O
association	O
with	O
adult	O
height	O
was	O
subsequently	O
performed	O
to	O
establish	O
a	O
body	O
of	O
knowledge	O
useful	O
for	O
comparing	O
patient	B
genotypes	O
and	O
phenotypes	O
.	O

This	O
analysis	O
was	O
first	O
performed	O
in	O
controls	O
bearing	O
only	O
frequent	O
SNPs	O
(	O
90	O
.	O
5	O
%	O
of	O
the	O
total	O
population	O
)	O
.	O

We	O
demonstrate	O
that	O
the	O
four	O
SNPs	O
with	O
the	O
highest	O
allelic	O
variation	O
frequencies	O
(	O
P4	O
,	O
P7	O
,	O
P10	O
and	O
P24	O
)	O
do	O
not	O
significantly	O
contribute	O
to	O
adult	O
height	O
determination	O
,	O
with	O
the	O
heterozygous	O
genotype	O
being	O
the	O
most	O
frequent	O
followed	O
by	O
the	O
corresponding	O
homozygous	O
genotype	O
in	O
the	O
whole	O
sequence	O
,	O
and	O
heights	O
are	O
normally	O
distributed	O
over	O
the	O
entire	O
height	O
range	O
.	O

The	O
third	O
most	O
frequent	O
combined	O
genotype	O
in	O
the	O
promoter	O
region	O
in	O
our	O
population	O
presented	O
,	O
in	O
addition	O
,	O
in	O
heterozygosity	O
,	O
the	O
SNP	O
at	O
P6	O
in	O
the	O
sequence	O
regulated	O
by	O
Pit	O
1	O
and	O
although	O
mean	O
height	O
of	O
individuals	O
(	O
6	O
.	O
1	O
%	O
)	O
bearing	O
this	O
genotype	O
was	O
around	O
-	O
0	O
.	O
5	O
SDS	O
,	O
this	O
was	O
not	O
statistically	O
significant	O
.	O

Analysis	O
of	O
single	O
SNP	O
genotype	O
association	O
with	O
adult	O
height	O
yielded	O
few	O
clues	O
as	O
to	O
the	O
contribution	O
of	O
GH1	O
gene	O
variation	O
to	O
adult	O
height	O
determination	O
.	O

Only	O
three	O
SNPs	O
(	O
P16	O
,	O
P17	O
and	O
P25	O
)	O
,	O
present	O
with	O
low	O
frequency	O
and	O
only	O
in	O
heterozygous	O
state	O
,	O
were	O
individually	O
significantly	O
associated	O
with	O
taller	O
stature	O
and	O
none	O
was	O
individually	O
associated	O
with	O
shorter	O
stature	O
.	O

P16	O
and	O
P17	O
(	O
in	O
LD	O
,	O
r2	O
=	O
0	O
.	O
83	O
)	O
are	O
located	O
in	O
intron	O
1	O
and	O
P25	O
in	O
intron	O
4	O
.	O

The	O
resulting	O
sequence	O
for	O
the	O
presence	O
of	O
P16	O
and	O
P17	O
corresponded	O
to	O
the	O
paralogue	O
GH2	O
and	O
generated	O
a	O
responsive	O
element	O
for	O
a	O
core	O
-	O
binding	O
protein	O
(	O
Matinspector	O
Programme	O
,	O
Geometrix	O
Software	O
GmbH	O
,	O
M	O
u	O
nchen	O
,	O
Germany	O
)	O
with	O
three	O
Kruppel	O
-	O
type	O
zinc	O
fingers	O
which	O
could	O
increase	O
the	O
efficacy	O
of	O
GH1	O
gene	O
transcription	O
;	O
31	O
,	O
32	O
moreover	O
,	O
Kruppel	O
-	O
like	O
proteins	O
have	O
recently	O
been	O
described	O
in	O
the	O
brain	O
.	O
33	O
Stepwise	O
regression	O
analysis	O
demonstrated	O
that	O
P17	O
and	O
P25	O
contribute	O
,	O
separately	O
,	O
to	O
an	O
increase	O
of	O
almost	O
1	O
.	O
0	O
height	O
SDS	O
.	O

P16	O
and	O
P17	O
had	O
been	O
described	O
by	O
Adkins	O
et	O
al	O
.	O
21	O
although	O
they	O
found	O
no	O
association	O
with	O
fetal	O
growth	O
,	O
whereas	O
P25	O
had	O
not	O
previously	O
been	O
described	O
.	O

The	O
mechanisms	O
by	O
which	O
they	O
may	O
determine	O
taller	O
final	O
height	O
should	O
be	O
established	O
by	O
in	O
vitro	O
studies	O
analysing	O
GH1	O
gene	O
transcription	O
and	O
GH	O
protein	O
translation	O
efficiencies	O
.	O

Analysis	O
of	O
interaction	O
effect	O
between	O
SNPs	O
detected	O
that	O
variation	O
at	O
P25	O
masked	O
an	O
effect	O
of	O
P6	O
.	O

Individuals	O
homozygous	O
at	O
P25	O
(	O
TT	O
)	O
present	O
a	O
significant	O
association	O
between	O
P6	O
genotype	O
and	O
height	O
with	O
the	O
homozygous	O
alternate	O
genotype	O
at	O
P6	O
(	O
GG	O
)	O
being	O
associated	O
with	O
shorter	O
stature	O
.	O

This	O
was	O
further	O
confirmed	O
in	O
the	O
subpopulation	O
of	O
29	O
individuals	O
bearing	O
rare	O
SNPs	O
who	O
,	O
in	O
the	O
absence	O
of	O
heterozygous	O
change	O
at	O
P25	O
,	O
presented	O
significantly	O
shorter	O
stature	O
in	O
the	O
heterozygous	O
alternate	O
nucleotide	O
change	O
at	O
P6	O
(	O
AG	O
)	O
.	O

P6	O
,	O
located	O
at	O
Pit	O
1	O
proximal	O
responsive	O
element	O
of	O
the	O
GH1	O
gene	O
promoter	O
,	O
was	O
first	O
described	O
by	O
Wagner	O
et	O
al	O
.	O
10	O
and	O
Giordano	O
et	O
al	O
.	O
9	O
and	O
further	O
by	O
Horan	O
et	O
al	O
.	O
12	O
Six	O
of	O
nine	O
GH1	O
gene	O
promoter	O
haplotypes	O
bearing	O
the	O
alternate	O
G	O
at	O
P6	O
presented	O
lower	O
transcriptional	O
activities	O
and	O
electrophoretic	O
mobility	O
shift	O
assays	O
(	O
EMSA	O
)	O
detected	O
differential	O
protein	O
binding	O
strength	O
,	O
although	O
in	O
vitro	O
studies	O
were	O
unable	O
to	O
identify	O
this	O
SNP	O
as	O
a	O
major	O
determinant	O
of	O
GH1	O
gene	O
expression	O
level	O
.	O
12	O
A	O
recent	O
study	O
from	O
Giordano	O
et	O
al	O
.	O
34	O
has	O
shown	O
a	O
twofold	O
reduced	O
luciferase	O
activity	O
for	O
the	O
G	O
nucleotide	O
bearing	O
promoter	O
haplotype	O
in	O
transfected	O
rat	B
pituitary	O
cells	O
.	O

Genotypes	O
at	O
P6	O
had	O
also	O
been	O
associated	O
with	O
decreased	O
breast	O
cancer	O
risk	O
through	O
its	O
association	O
with	O
lower	O
GH	O
secretion	O
and	O
IGF	O
-	O
I	O
circulating	O
levels	O
.	O
16	O
,	O
17	O

In	O
our	O
results	O
,	O
GH1	O
gene	O
polymorphic	O
structural	O
variation	O
accounted	O
for	O
only	O
6	O
.	O
2	O
%	O
of	O
adult	O
height	O
determination	O
in	O
the	O
entire	O
adult	O
population	O
studied	O
and	O
genome	O
-	O
wide	O
linkage	O
analysis	O
of	O
stature	O
in	O
multiple	O
populations	O
revealed	O
no	O
linkage	O
with	O
chromosome	O
17	O
GH	O
gene	O
cluster	O
.	O
2	O
,	O
35	O
As	O
only	O
some	O
of	O
the	O
less	O
frequent	O
SNPs	O
are	O
statistically	O
associated	O
with	O
height	O
,	O
and	O
in	O
view	O
of	O
the	O
high	O
density	O
of	O
SNPs	O
,	O
our	O
study	O
may	O
be	O
hampered	O
by	O
selection	O
bias36	O
and	O
would	O
ideally	O
have	O
required	O
a	O
wider	O
sampling	O
of	O
some	O
2	O
000	O
individuals	O
;	O
however	O
,	O
this	O
was	O
a	O
highly	O
laborious	O
strategy	O
when	O
the	O
complete	O
sequencing	O
technique	O
is	O
applied	O
.	O

The	O
high	O
density	O
of	O
SNPs	O
and	O
their	O
proximity	O
hamper	O
other	O
genotyping	O
strategies	O
for	O
rapid	O
determination	O
of	O
the	O
complete	O
GH1	O
SNP	O
map	O
in	O
large	O
control	O
and	O
patient	B
populations	O
.	O

Individual	O
SNP	O
associations	O
with	O
height	O
or	O
other	O
GH	O
secretion	O
-	O
related	O
phenotypic	O
traits	O
will	O
require	O
further	O
confirmation	O
by	O
studies	O
in	O
larger	O
populations	O
and	O
by	O
in	O
vitro	O
functional	O
studies	O
.	O

In	O
conclusion	O
,	O
our	O
study	O
established	O
the	O
GH1	O
gene	O
sequence	O
variation	O
map	O
in	O
an	O
adult	O
control	O
population	O
with	O
heights	O
normally	O
distributed	O
within	O
the	O
normal	O
range	O
.	O

SNPs	O
and	O
other	O
sequence	O
change	O
contributions	O
to	O
skeletal	O
growth	O
as	O
observed	O
at	O
adult	O
height	O
demonstrated	O
that	O
,	O
despite	O
the	O
high	O
frequency	O
of	O
variation	O
and	O
diversity	O
and	O
complexity	O
of	O
combinations	O
,	O
only	O
some	O
of	O
the	O
less	O
frequent	O
SNPs	O
were	O
associated	O
with	O
taller	O
stature	O
(	O
P17	O
in	O
intron	O
1	O
and	O
P25	O
in	O
intron	O
4	O
)	O
,	O
even	O
masking	O
the	O
SNP	O
contribution	O
to	O
a	O
shorter	O
one	O
(	O
P6	O
in	O
the	O
promoter	O
and	O
P12	O
in	O
the	O
5	O
'	O
UTR	O
regions	O
,	O
respectively	O
)	O
.	O

Systematic	O
GH1	O
gene	O
analysis	O
in	O
patients	B
with	O
growth	O
delay	O
and	O
suspected	O
GH	O
deficiency	O
/	O
insufficiency	O
will	O
clarify	O
whether	O
different	O
SNP	O
frequencies	O
and	O
/	O
or	O
the	O
presence	O
of	O
different	O
sequence	O
changes	O
may	O
be	O
associated	O
with	O
phenotypes	O
in	O
them	O
.	O

Elevated	O
Blood	O
Lead	O
Levels	O
of	O
Children	B
in	O
Guiyu	O
,	O
an	O
Electronic	O
Waste	O
Recycling	O
Town	O
in	O
China	O

Abstract	O

Background	O

Electronic	O
waste	O
(	O
e	O
-	O
waste	O
)	O
recycling	O
has	O
remained	O
primitive	O
in	O
Guiyu	O
,	O
China	O
,	O
and	O
thus	O
may	O
contribute	O
to	O
the	O
elevation	O
of	O
blood	O
lead	O
levels	O
(	O
BLLs	O
)	O
in	O
children	B
living	O
in	O
the	O
local	O
environment	O
.	O

Objectives	O

We	O
compared	O
the	O
BLLs	O
in	O
children	B
living	O
in	O
the	O
e	O
-	O
waste	O
recycling	O
town	O
of	O
Guiyu	O
with	O
those	O
living	O
in	O
the	O
neighboring	O
town	O
of	O
Chendian	O
.	O

Methods	O

We	O
observed	O
the	O
processing	O
of	O
e	O
-	O
waste	O
recycling	O
in	O
Guiyu	O
and	O
studied	O
BLLs	O
in	O
a	O
cluster	O
sample	O
of	O
226	O
children	B
<	O
6	O
years	O
of	O
age	O
who	O
lived	O
in	O
Guiyu	O
and	O
Chendian	O
.	O

BLLs	O
were	O
determined	O
with	O
atomic	O
absorption	O
spectrophotometry	O
.	O

Hemoglobin	O
(	O
Hgb	O
)	O
and	O
physical	O
indexes	O
(	O
height	O
and	O
weight	O
,	O
head	O
and	O
chest	O
circumferences	O
)	O
were	O
also	O
measured	O
.	O

Results	O

BLLs	O
in	O
165	O
children	B
of	O
Guiyu	O
ranged	O
from	O
4	O
.	O
40	O
to	O
32	O
.	O
67	O
mu	O
g	O
/	O
dL	O
with	O
a	O
mean	O
of	O
15	O
.	O
3	O
mu	O
g	O
/	O
dL	O
,	O
whereas	O
BLLs	O
in	O
61	O
children	B
of	O
Chendian	O
were	O
from	O
4	O
.	O
09	O
to	O
23	O
.	O
10	O
mu	O
g	O
/	O
dL	O
with	O
a	O
mean	O
of	O
9	O
.	O
94	O
mu	O
g	O
/	O
dL	O
.	O

Statistical	O
analyses	O
showed	O
that	O
children	B
living	O
in	O
Guiyu	O
had	O
significantly	O
higher	O
BLLs	O
compared	O
with	O
those	O
living	O
in	O
Chendian	O
(	O
p	O
<	O
0	O
.	O
01	O
)	O
.	O

Of	O
children	B
in	O
Guiyu	O
,	O
81	O
.	O
8	O
%	O
(	O
135	O
of	O
165	O
)	O
had	O
BLLs	O
>	O
10	O
mu	O
g	O
/	O
dL	O
,	O
compared	O
with	O
37	O
.	O
7	O
%	O
of	O
children	B
(	O
23	O
of	O
61	O
)	O
in	O
Chendian	O
(	O
p	O
<	O
0	O
.	O
01	O
)	O
.	O

In	O
addition	O
,	O
we	O
observed	O
a	O
significant	O
increasing	O
trend	O
in	O
BLLs	O
with	O
increasing	O
age	O
in	O
Guiyu	O
(	O
p	O
<	O
0	O
.	O
01	O
)	O
.	O

It	O
appeared	O
that	O
there	O
was	O
correlation	O
between	O
the	O
BLLs	O
in	O
children	B
and	O
numbers	O
of	O
e	O
-	O
waste	O
workshops	O
.	O

However	O
,	O
no	O
significant	O
difference	O
in	O
Hgb	O
level	O
or	O
physical	O
indexes	O
was	O
found	O
between	O
the	O
two	O
towns	O
.	O

Conclusions	O

The	O
primitive	O
e	O
-	O
waste	O
recycling	O
activities	O
may	O
contribute	O
to	O
the	O
elevated	O
BLLs	O
in	O
children	B
living	O
in	O
Guiyu	O
.	O

Disposal	O
of	O
electronic	O
waste	O
,	O
or	O
e	O
-	O
waste	O
,	O
is	O
an	O
emerging	O
global	O
environmental	O
issue	O
,	O
as	O
these	O
wastes	O
have	O
become	O
the	O
most	O
rapidly	O
growing	O
segment	O
of	O
the	O
municipal	O
waste	O
stream	O
in	O
the	O
world	O
[	O
Dahl	O
2002	O
;	O
Halluite	O
et	O
al	O
.	O
2005	O
;	O
Jang	O
and	O
Townsend	O
2003	O
;	O
Schmidt	O
2002	O
;	O
Silicon	O
Valley	O
Toxics	O
Coalition	O
(	O
SVTC	O
)	O
2001	O
]	O
.	O

It	O
is	O
reported	O
that	O
approximately	O
500	O
million	O
computers	O
became	O
obsolete	O
between	O
1997	O
and	O
2007	O
in	O
the	O
United	O
States	O
(	O
National	O
Safety	O
Council	O
1999	O
)	O
.	O

Up	O
to	O
80	O
%	O
of	O
e	O
-	O
waste	O
from	O
the	O
United	O
States	O
has	O
seeped	O
into	O
Asia	O
and	O
Africa	O
(	O
Johnson	O
2006	O
;	O
Puckett	O
et	O
al	O
.	O
2002	O
;	O
Schmidt	O
2002	O
,	O
2006	O
;	O
SVTC	O
2001	O
)	O
.	O

It	O
is	O
noteworthy	O
that	O
the	O
United	O
States	O
is	O
the	O
only	O
developed	O
country	O
today	O
that	O
has	O
not	O
ratified	O
the	O
United	O
Nations	O
Basel	O
Convention	O
,	O
which	O
bans	O
the	O
export	O
of	O
hazardous	O
wastes	O
to	O
developing	O
countries	O
(	O
United	O
Nations	O
Environment	O
Programme	O
1992	O
,	O
2006	O
;	O
USA	O
Today	O
2002	O
)	O
.	O

Together	O
with	O
New	O
Delhi	O
in	O
India	O
,	O
Guiyu	O
in	O
Shantou	O
,	O
Guangdong	O
Province	O
,	O
China	O
(	O
Figure	O
1	O
)	O
,	O
is	O
one	O
of	O
the	O
popular	O
destinations	O
of	O
e	O
-	O
waste	O
(	O
Brigden	O
et	O
al	O
.	O
2005	O
;	O
Puckett	O
et	O
al	O
.	O
2002	O
)	O
.	O

Within	O
a	O
total	O
area	O
of	O
52	O
km2	O
and	O
local	O
population	O
of	O
132	O
,	O
000	O
(	O
in	O
2003	O
)	O
,	O
Guiyu	O
has	O
accommodated	O
millions	O
of	O
tons	O
of	O
e	O
-	O
waste	O
from	O
overseas	O
and	O
domestic	O
a	O
year	O
.	O

Nearly	O
60	O
-	O
80	O
%	O
of	O
families	O
in	O
the	O
town	O
have	O
engaged	O
in	O
e	O
-	O
waste	O
recycling	O
operations	O
conducted	O
by	O
small	O
scale	O
family	O
-	O
run	O
workshops	O
,	O
with	O
approximately	O
100	O
,	O
000	O
migrant	O
workers	O
employed	O
in	O
processing	O
e	O
-	O
waste	O
.	O

Because	O
the	O
implementation	O
of	O
a	O
clean	O
and	O
safe	O
high	O
-	O
tech	O
recovery	O
process	O
was	O
very	O
expensive	O
(	O
Allsopp	O
et	O
al	O
.	O
2006	O
)	O
,	O
the	O
processes	O
and	O
techniques	O
used	O
during	O
the	O
recycling	O
activities	O
in	O
Guiyu	O
were	O
very	O
primitive	O
.	O

The	O
result	O
was	O
that	O
many	O
tons	O
of	O
e	O
-	O
waste	O
material	O
and	O
process	O
residues	O
were	O
dumped	O
in	O
workshops	O
,	O
yards	O
,	O
roadsides	O
,	O
open	O
fields	O
,	O
irrigation	O
canals	O
,	O
riverbanks	O
,	O
ponds	O
,	O
and	O
rivers	O
.	O

Hazardous	O
chemicals	O
can	O
be	O
released	O
from	O
e	O
-	O
wastes	O
through	O
disposal	O
or	O
recycling	O
processes	O
,	O
threatening	O
the	O
health	O
of	O
local	O
residents	O
.	O

Several	O
studies	O
have	O
reported	O
the	O
soaring	O
levels	O
of	O
toxic	O
heavy	O
metals	O
and	O
organic	O
contaminants	O
in	O
samples	O
of	O
dust	O
,	O
soil	O
,	O
river	O
sediment	O
,	O
surface	O
water	O
,	O
and	O
groundwater	O
of	O
Guiyu	O
(	O
Brigden	O
et	O
al	O
.	O
2005	O
;	O
Puckett	O
et	O
al	O
.	O
2002	O
;	O
Wang	O
and	O
Guo	O
2006	O
;	O
Wang	O
et	O
al	O
.	O
2005	O
;	O
Wong	O
et	O
al	O
.	O
2006	O
;	O
Yu	O
et	O
al	O
.	O
2006	O
)	O
.	O

Previously	O
,	O
we	O
have	O
shown	O
that	O
the	O
residents	O
in	O
Guiyu	O
had	O
high	O
incidence	O
of	O
skin	O
damage	O
,	O
headaches	O
,	O
vertigo	O
,	O
nausea	O
,	O
chronic	O
gastritis	O
,	O
and	O
gastric	O
and	O
duodenal	O
ulcers	O
,	O
all	O
of	O
which	O
may	O
be	O
caused	O
by	O
the	O
primitive	O
recycling	O
processing	O
of	O
e	O
-	O
waste	O
(	O
Qiu	O
et	O
al	O
.	O
2004	O
)	O
.	O

Of	O
many	O
toxic	O
heavy	O
metals	O
,	O
lead	O
is	O
the	O
most	O
widely	O
used	O
in	O
electronic	O
devices	O
for	O
various	O
purposes	O
,	O
resulting	O
in	O
a	O
variety	O
of	O
health	O
hazards	O
due	O
to	O
environmental	O
contamination	O
(	O
Jang	O
and	O
Townsend	O
2003	O
;	O
Musson	O
et	O
al	O
.	O
2006	O
;	O
Vann	O
et	O
al	O
.	O
2006	O
)	O
.	O

Lead	O
enters	O
biological	O
systems	O
via	O
food	O
,	O
water	O
,	O
air	O
,	O
and	O
soil	O
.	O

Children	B
are	O
particularly	O
vulnerable	O
to	O
lead	O
poisoning	O
-	O
-	O
more	O
so	O
than	O
adults	O
because	O
they	O
absorb	O
more	O
lead	O
from	O
their	O
environments	O
(	O
Baghurst	O
et	O
al	O
.	O
1992	O
;	O
Grigg	O
2004	O
;	O
Guilarte	O
et	O
al	O
.	O
2003	O
;	O
Jain	O
and	O
Hu	O
2006	O
;	O
Needleman	O
2004	O
;	O
Safi	O
et	O
al	O
.	O
2006	O
;	O
Wasserman	O
et	O
al	O
.	O
1998	O
)	O
.	O

The	O
U	O
.	O
S	O
.	O

Centers	O
for	O
Disease	O
Control	O
and	O
Prevention	O
(	O
CDC	O
)	O
defined	O
elevated	O
blood	O
lead	O
levels	O
(	O
BLLs	O
)	O
as	O
those	O
>	O
=	O
10	O
mu	O
g	O
/	O
dL	O
in	O
children	B
<	O
=	O
6	O
years	O
of	O
age	O
(	O
CDC	O
1991	O
)	O
.	O

Nevertheless	O
,	O
studies	O
have	O
increasingly	O
shown	O
that	O
low	O
blood	O
lead	O
concentrations	O
,	O
even	O
<	O
10	O
mu	O
g	O
/	O
dL	O
,	O
were	O
inversely	O
associated	O
with	O
children	B
'	O
s	O
IQ	O
scores	O
and	O
academic	O
skills	O
(	O
Canfield	O
et	O
al	O
.	O
2003	O
;	O
Lanphear	O
et	O
al	O
.	O
2000	O
,	O
2005	O
;	O
Nevin	O
2000	O
;	O
Schnaas	O
et	O
al	O
.	O
2006	O
)	O
.	O

Therefore	O
,	O
no	O
safety	O
margin	O
at	O
existing	O
exposures	O
has	O
been	O
identified	O
(	O
Chiodo	O
et	O
al	O
.	O
2004	O
;	O
Koller	O
et	O
al	O
.	O
2004	O
)	O
.	O

Considering	O
the	O
potential	O
heavy	O
metal	O
contamination	O
in	O
the	O
local	O
living	O
environment	O
of	O
Guiyu	O
,	O
we	O
hypothesized	O
that	O
children	B
living	O
in	O
Guiyu	O
may	O
have	O
elevated	O
BLLs	O
and	O
thus	O
their	O
physical	O
and	O
mental	O
development	O
may	O
have	O
been	O
affected	O
.	O

In	O
this	O
study	O
,	O
we	O
evaluated	O
the	O
mean	O
BLLs	O
in	O
children	B
1	O
-	O
6	O
years	O
of	O
age	O
living	O
in	O
Guiyu	O
and	O
compared	O
them	O
with	O
those	O
living	O
in	O
the	O
neighboring	O
town	O
of	O
Chendian	O
,	O
where	O
no	O
e	O
-	O
waste	O
processing	O
was	O
taken	O
.	O

Materials	O
and	O
Methods	O

Geographic	O
location	O
and	O
site	O
description	O

There	O
are	O
28	O
villages	O
with	O
a	O
total	O
area	O
of	O
52	O
km2	O
and	O
a	O
resident	O
population	O
of	O
132	O
,	O
000	O
and	O
around	O
100	O
,	O
000	O
migrant	O
workers	O
in	O
Guiyu	O
(	O
Figure	O
1	O
)	O
.	O

We	O
chose	O
four	O
villages	O
for	O
their	O
differences	O
in	O
the	O
scale	O
and	O
type	O
of	O
e	O
-	O
waste	O
processing	O
.	O

Beilin	O
village	O
has	O
dense	O
e	O
-	O
waste	O
workshops	O
mainly	O
involved	O
in	O
equipment	O
dismantling	O
,	O
circuit	O
board	O
baking	O
,	O
and	O
acid	O
baths	O
;	O
Dutou	O
village	O
specializes	O
in	O
plastics	O
sorting	O
,	O
including	O
manually	O
stripping	O
plastic	O
materials	O
from	O
electronic	O
products	O
and	O
then	O
crudely	O
classifying	O
them	O
;	O
Huamei	O
village	O
had	O
workshops	O
similar	O
to	O
those	O
of	O
Beilin	O
,	O
but	O
they	O
are	O
fewer	O
and	O
scattered	O
;	O
and	O
Longgang	O
village	O
was	O
involved	O
in	O
plastic	O
reprocessing	O
in	O
which	O
plastics	O
collected	O
from	O
Dutou	O
and	O
other	O
villages	O
were	O
washed	O
and	O
smashed	O
into	O
tiny	O
pieces	O
of	O
recycled	O
plastic	O
.	O

We	O
used	O
the	O
neighboring	O
town	O
of	O
Chendian	O
as	O
a	O
control	O
because	O
the	O
local	O
residents	O
work	O
mainly	O
in	O
the	O
textiles	O
industry	O
,	O
not	O
in	O
e	O
-	O
waste	O
processing	O
.	O

The	O
population	O
,	O
traffic	O
density	O
,	O
lifestyle	O
,	O
and	O
socioeconomic	O
status	O
were	O
very	O
similar	O
to	O
those	O
of	O
Guiyu	O
.	O

Study	O
population	O

The	O
study	O
population	O
was	O
composed	O
of	O
children	B
<	O
=	O
6	O
years	O
of	O
age	O
.	O

No	O
children	B
involved	O
in	O
the	O
study	O
had	O
any	O
occupational	O
exposure	O
to	O
e	O
-	O
waste	O
.	O

A	O
cluster	O
sample	O
of	O
165	O
children	B
with	O
a	O
median	O
age	O
of	O
5	O
.	O
0	O
years	O
lived	O
in	O
the	O
four	O
villages	O
of	O
Guiyu	O
(	O
Figure	O
1	O
)	O
.	O

Sixty	O
-	O
one	O
children	B
with	O
a	O
median	O
age	O
of	O
4	O
.	O
0	O
years	O
resided	O
in	O
Chendian	O
were	O
included	O
in	O
the	O
study	O
for	O
comparison	O
.	O

After	O
written	O
informed	O
consent	O
was	O
obtained	O
from	O
the	O
parents	O
or	O
guardians	O
,	O
blood	O
samples	O
were	O
collected	O
from	O
the	O
children	B
at	O
village	O
kindergartens	O
.	O

To	O
facilitate	O
the	O
counseling	O
process	O
,	O
advice	O
on	O
dietary	O
and	O
eating	O
habits	O
to	O
minimize	O
lead	O
exposure	O
were	O
provided	O
to	O
the	O
local	O
residents	O
.	O

All	O
children	B
found	O
to	O
have	O
high	O
BLLs	O
were	O
advised	O
to	O
get	O
further	O
hospital	O
treatment	O
.	O

The	O
study	O
was	O
approved	O
by	O
the	O
Human	O
Ethics	O
Committee	O
of	O
Shantou	O
University	O
Medical	O
College	O
.	O

Measurement	O
of	O
BLLs	O
and	O
hemoglobin	O

Venipuncture	O
blood	O
samples	O
were	O
obtained	O
from	O
each	O
volunteer	O
at	O
the	O
kindergarten	O
,	O
and	O
collected	O
in	O
lead	O
-	O
free	O
tubes	O
by	O
trained	O
nurses	O
.	O

Lead	O
in	O
total	O
blood	O
was	O
analyzed	O
by	O
graphite	O
furnace	O
atomic	O
absorption	O
spectrometry	O
(	O
GFAAS	O
)	O
,	O
which	O
consisted	O
of	O
a	O
Shimadzu	O
AA	O
-	O
660	O
AAS	O
and	O
GFA	O
-	O
4B	O
graphite	O
furnace	O
atomizer	O
and	O
an	O
ACS	O
-	O
60G	O
autosampler	O
(	O
Shimadzu	O
Corporation	O
,	O
Kyoto	O
,	O
Japan	O
)	O
.	O

The	O
main	O
parameters	O
used	O
for	O
the	O
determination	O
were	O
a	O
wavelength	O
of	O
283	O
.	O
3	O
nm	O
,	O
current	O
of	O
8	O
mA	O
,	O
a	O
slit	O
width	O
of	O
1	O
.	O
00	O
nm	O
,	O
drying	O
at	O
150	O
degrees	O
C	O
,	O
ashing	O
at	O
325	O
degrees	O
C	O
,	O
and	O
atomization	O
at	O
1	O
,	O
400	O
degrees	O
C	O
.	O

The	O
accuracy	O
of	O
the	O
method	O
was	O
controlled	O
by	O
recoveries	O
between	O
95	O
%	O
and	O
107	O
%	O
from	O
the	O
spiked	O
blood	O
samples	O
.	O

Repeated	O
analyses	O
of	O
standard	O
solutions	O
confirmed	O
the	O
method	O
'	O
s	O
precision	O
.	O

The	O
BLLs	O
were	O
expressed	O
in	O
micrograms	O
per	O
deciliter	O
(	O
1	O
mu	O
g	O
/	O
dL	O
=	O
0	O
.	O
0484	O
mu	O
mol	O
/	O
L	O
)	O
.	O

Meanwhile	O
,	O
we	O
assessed	O
hemoglobin	O
(	O
Hgb	O
)	O
levels	O
by	O
hemoglobin	O
cyanide	O
method	O
with	O
hemoglobinometer	O
(	O
XK	O
-	O
2	O
,	O
JiangSu	O
,	O
China	O
)	O
.	O

Evaluation	O
of	O
physical	O
developmental	O
indexes	O

Children	B
'	O
s	O
physical	O
growth	O
and	O
development	O
,	O
such	O
as	O
body	O
height	O
,	O
weight	O
,	O
and	O
head	O
and	O
chest	O
circumferences	O
were	O
measured	O
when	O
blood	O
samples	O
were	O
collected	O
.	O

Weight	O
and	O
height	O
were	O
measured	O
using	O
a	O
weighing	O
and	O
height	O
scale	O
(	O
TZ120	O
;	O
Yuyao	O
Balance	O
Instrument	O
Factory	O
,	O
Yuyao	O
,	O
China	O
)	O
with	O
maximum	O
weight	O
of	O
120	O
kg	O
(	O
minimum	O
scale	O
,	O
50	O
g	O
)	O
and	O
minimum	O
height	O
of	O
70	O
cm	O
(	O
minimum	O
scale	O
,	O
0	O
.	O
5	O
cm	O
)	O
.	O

Head	O
and	O
chest	O
circumferences	O
were	O
measured	O
using	O
graduated	O
anthropometric	O
tapes	O
.	O

Statistical	O
analyses	O

We	O
performed	O
statistical	O
analyses	O
using	O
SPSS	O
version	O
10	O
.	O
0	O
software	O
(	O
SPSS	O
,	O
Chicago	O
,	O
IL	O
,	O
USA	O
)	O
.	O

We	O
used	O
independent	O
sample	O
t	O
-	O
tests	O
or	O
covariance	O
analyses	O
for	O
comparisons	O
of	O
mean	O
,	O
chi	O
-	O
square	O
analyses	O
for	O
test	O
of	O
frequency	O
data	O
,	O
and	O
linear	O
regression	O
analysis	O
for	O
the	O
association	O
between	O
BLLs	O
and	O
age	O
.	O

Differences	O
were	O
considered	O
significant	O
with	O
a	O
p	O
-	O
value	O
<	O
0	O
.	O
05	O
.	O

Results	O

Observation	O
of	O
e	O
-	O
waste	O
processing	O

The	O
primitive	O
e	O
-	O
waste	O
recycling	O
procedures	O
in	O
Guiyu	O
were	O
mainly	O
as	O
follows	O
:	O
a	O
)	O
Old	O
electronic	O
equipment	O
was	O
dismantled	O
(	O
Figure	O
2	O
)	O
with	O
electric	O
drill	O
,	O
cutter	O
,	O
hammer	O
,	O
and	O
screwdriver	O
into	O
component	O
parts	O
such	O
as	O
monitor	O
,	O
hard	O
drive	O
,	O
CD	O
driver	O
,	O
wires	O
,	O
cables	O
,	O
circuit	O
boards	O
,	O
transformer	O
,	O
charger	O
,	O
battery	O
,	O
and	O
plastic	O
or	O
metal	O
frame	O
that	O
are	O
sold	O
for	O
reuse	O
or	O
to	O
other	O
workshops	O
for	O
further	O
recycling	O
.	O

b	O
)	O
Circuit	O
boards	O
(	O
Figure	O
3	O
)	O
of	O
computers	O
and	O
other	O
large	O
appliances	O
were	O
heated	O
over	O
coal	O
fires	O
to	O
melt	O
the	O
solder	O
to	O
release	O
valuable	O
electronic	O
components	O
,	O
such	O
as	O
diodes	O
,	O
resistors	O
,	O
and	O
microchips	O
.	O

c	O
)	O
Circuit	O
boards	O
of	O
cell	O
phones	O
and	O
other	O
hand	O
-	O
held	O
devices	O
were	O
taken	O
apart	O
by	O
a	O
electrothermal	O
machine	O
(	O
Figure	O
4	O
)	O
,	O
which	O
was	O
a	O
particular	O
environmental	O
and	O
human	B
health	O
concern	O
in	O
the	O
processing	O
of	O
e	O
-	O
waste	O
in	O
Guiyu	O
.	O

d	O
)	O
In	O
acid	O
baths	O
(	O
Figure	O
5	O
)	O
,	O
some	O
microchips	O
and	O
computer	O
parts	O
were	O
soaked	O
to	O
extract	O
precious	O
gold	O
and	O
palladium	O
,	O
from	O
which	O
the	O
waste	O
acids	O
were	O
discharged	O
into	O
nearby	O
fields	O
and	O
streams	O
.	O

e	O
)	O
Wires	O
and	O
cables	O
were	O
stripped	O
or	O
simply	O
burnt	O
in	O
open	O
air	O
to	O
recover	O
metals	O
.	O

f	O
)	O
Printer	O
cartridges	O
were	O
ripped	O
apart	O
for	O
their	O
toner	O
and	O
recyclable	O
aluminum	O
,	O
steel	O
,	O
and	O
plastic	O
parts	O
.	O

g	O
)	O
Plastic	O
[	O
e	O
.	O
g	O
.	O
,	O
polyvinyl	O
chloride	O
(	O
PVC	O
)	O
,	O
acrylonitrile	O
butadiene	O
styrene	O
copolymer	O
(	O
ABS	O
)	O
,	O
high	O
-	O
density	O
polyethylene	O
(	O
HDPE	O
)	O
]	O
was	O
sorted	O
by	O
workers	O
according	O
to	O
rigidity	O
,	O
color	O
,	O
and	O
luster	O
.	O

Plastic	O
scraps	O
that	O
cannot	O
be	O
sorted	O
visually	O
must	O
be	O
burned	O
and	O
classified	O
by	O
burning	O
odor	O
.	O

Another	O
way	O
to	O
sort	O
different	O
plastics	O
was	O
gravitational	O
separation	O
into	O
ceramic	O
jugs	O
with	O
brine	O
(	O
Figure	O
6	O
)	O
,	O
after	O
which	O
the	O
pieces	O
were	O
spread	O
on	O
the	O
sidewalk	O
to	O
dry	O
;	O
h	O
)	O
For	O
reprocessing	O
,	O
after	O
sorting	O
plastic	O
scraps	O
were	O
fed	O
into	O
grinders	O
that	O
spit	O
out	O
tiny	O
pieces	O
of	O
plastic	O
.	O

i	O
)	O
For	O
metals	O
sorting	O
and	O
reprocessing	O
,	O
transformers	O
,	O
chargers	O
,	O
batteries	O
,	O
and	O
cathode	O
-	O
ray	O
tubes	O
were	O
separated	O
and	O
hammered	O
open	O
for	O
recycling	O
metals	O
such	O
as	O
copper	O
,	O
steel	O
,	O
silver	O
,	O
aluminum	O
,	O
which	O
were	O
then	O
reprocessed	O
to	O
raw	O
material	O
.	O

Although	O
the	O
methods	O
for	O
processing	O
e	O
-	O
waste	O
were	O
primitive	O
,	O
the	O
coordination	O
of	O
e	O
-	O
waste	O
recycling	O
in	O
Guiyu	O
was	O
very	O
well	O
organized	O
into	O
specific	O
tasks	O
.	O

Workshops	O
specializing	O
in	O
dismantled	O
equipment	O
would	O
not	O
conduct	O
circuit	O
board	O
baking	O
or	O
plastics	O
and	O
metals	O
reprocessing	O
.	O

The	O
chain	O
of	O
recycling	O
components	O
from	O
each	O
type	O
of	O
e	O
-	O
waste	O
was	O
well	O
established	O
in	O
the	O
town	O
.	O

BLLs	O
in	O
children	B

We	O
collected	O
blood	O
from	O
165	O
children	B
in	O
Guiyu	O
and	O
61	O
children	B
in	O
Chendian	O
and	O
measured	O
the	O
BLLs	O
in	O
these	O
children	B
.	O

Table	O
1	O
shows	O
that	O
the	O
BLLs	O
corresponded	O
to	O
the	O
children	B
'	O
s	O
age	O
,	O
sex	O
,	O
and	O
town	O
of	O
residence	O
.	O

As	O
expected	O
,	O
BLLs	O
among	O
Guiyu	O
children	B
were	O
much	O
higher	O
than	O
those	O
in	O
the	O
children	B
of	O
Chendian	O
(	O
p	O
<	O
0	O
.	O
01	O
)	O
.	O

Among	O
Guiyu	O
children	B
,	O
135	O
(	O
81	O
.	O
8	O
%	O
)	O
had	O
BLLs	O
>	O
10	O
mu	O
g	O
/	O
dL	O
,	O
whereas	O
23	O
(	O
37	O
.	O
7	O
%	O
)	O
in	O
Chendian	O
(	O
p	O
<	O
0	O
.	O
01	O
)	O
had	O
high	O
levels	O
.	O

Among	O
135	O
(	O
81	O
.	O
8	O
%	O
)	O
Guiyu	O
children	B
with	O
elevated	O
BLLs	O
,	O
61	O
.	O
8	O
%	O
and	O
20	O
%	O
had	O
BLLs	O
>	O
10	O
mu	O
g	O
/	O
dL	O
and	O
20	O
mu	O
g	O
/	O
dL	O
respectively	O
,	O
but	O
lead	O
levels	O
>	O
45	O
mu	O
g	O
/	O
dL	O
were	O
not	O
found	O
.	O

And	O
BLLs	O
of	O
Guiyu	O
increased	O
somewhat	O
with	O
age	O
(	O
p	O
<	O
0	O
.	O
01	O
)	O
;	O
older	O
children	B
tended	O
to	O
have	O
higher	O
BLLs	O
than	O
younger	O
ones	O
.	O

We	O
found	O
no	O
evidence	O
for	O
the	O
association	O
in	O
lead	O
concentrations	O
or	O
prevalence	O
of	O
elevated	O
BLLs	O
differentiated	O
by	O
sex	O
(	O
both	O
p	O
>	O
0	O
.	O
05	O
)	O
.	O

Table	O
2	O
presents	O
BLLs	O
for	O
165	O
exposed	O
children	B
in	O
the	O
four	O
villages	O
.	O

The	O
findings	O
showed	O
that	O
BLLs	O
from	O
different	O
villages	O
were	O
in	O
the	O
following	O
descending	O
order	O
:	O
Beilin	O
,	O
19	O
.	O
34	O
mu	O
g	O
/	O
dL	O
>	O
Dutou	O
,	O
17	O
.	O
86	O
mu	O
g	O
/	O
dL	O
>	O
Huamei	O
,	O
14	O
.	O
23	O
mu	O
g	O
/	O
dL	O
>	O
Longgang	O
,	O
13	O
.	O
13	O
mu	O
g	O
/	O
dL	O
(	O
Table	O
2	O
)	O
.	O

Children	B
living	O
in	O
Beilin	O
,	O
where	O
the	O
number	O
of	O
e	O
-	O
waste	O
workshops	O
specializing	O
in	O
equipment	O
dismantling	O
,	O
circuit	O
board	O
baking	O
,	O
and	O
acid	O
baths	O
,	O
had	O
the	O
highest	O
BLLs	O
.	O

Dutou	O
,	O
which	O
had	O
many	O
workshops	O
specializing	O
in	O
plastics	O
sorting	O
,	O
including	O
strip	O
plastic	O
materials	O
from	O
e	O
-	O
waste	O
,	O
had	O
the	O
second	O
highest	O
BLLs	O
in	O
children	B
.	O

Huamei	O
had	O
e	O
-	O
waste	O
workshops	O
similar	O
to	O
those	O
of	O
Beilin	O
,	O
but	O
fewer	O
and	O
less	O
centralized	O
;	O
the	O
BLLs	O
of	O
Huamei	O
children	B
were	O
much	O
lower	O
than	O
those	O
of	O
Beilin	O
and	O
Dutou	O
.	O

Longgang	O
,	O
a	O
village	O
specializing	O
in	O
reprocessing	O
plastics	O
collected	O
from	O
other	O
villages	O
that	O
had	O
no	O
workshops	O
directly	O
processing	O
e	O
-	O
waste	O
,	O
had	O
the	O
lowest	O
BLLs	O
.	O

There	O
was	O
a	O
significant	O
difference	O
in	O
BLLs	O
among	O
the	O
children	B
of	O
the	O
four	O
villages	O
(	O
p	O
<	O
0	O
.	O
01	O
)	O
.	O

In	O
Beilin	O
and	O
Dutou	O
,	O
88	O
.	O
8	O
%	O
and	O
100	O
%	O
children	B
had	O
elevated	O
BLLs	O
>	O
10	O
mu	O
g	O
/	O
dL	O
,	O
respectively	O
.	O

As	O
far	O
as	O
physical	O
indexes	O
and	O
Hgb	O
levels	O
were	O
concerned	O
,	O
there	O
was	O
no	O
significant	O
difference	O
between	O
Guiyu	O
and	O
Chendian	O
(	O
p	O
>	O
0	O
.	O
05	O
,	O
Table	O
3	O
)	O
.	O

Discussion	O

In	O
this	O
study	O
,	O
we	O
observed	O
that	O
the	O
processing	O
of	O
e	O
-	O
waste	O
in	O
Guiyu	O
was	O
very	O
primitive	O
and	O
the	O
recycling	O
industry	O
depended	O
mainly	O
on	O
manual	O
processing	O
methods	O
.	O

Despite	O
the	O
fact	O
that	O
the	O
coordination	O
of	O
the	O
e	O
-	O
waste	O
recycling	O
is	O
well	O
organized	O
in	O
family	O
-	O
based	O
small	O
business	O
units	O
,	O
the	O
manual	O
processing	O
methods	O
and	O
the	O
deposition	O
of	O
the	O
e	O
-	O
waste	O
have	O
contributed	O
to	O
the	O
contamination	O
by	O
heavy	O
metals	O
in	O
the	O
living	O
environment	O
.	O

Examination	O
of	O
the	O
possible	O
impact	O
of	O
the	O
e	O
-	O
waste	O
industry	O
on	O
the	O
BLLs	O
of	O
children	B
living	O
in	O
Guiyu	O
revealed	O
that	O
Guiyu	O
children	B
had	O
significantly	O
higher	O
BLLs	O
than	O
Chendian	O
children	B
.	O

Of	O
children	B
tested	O
in	O
Guiyu	O
,	O
81	O
.	O
8	O
%	O
had	O
BLLs	O
>	O
10	O
mu	O
g	O
/	O
dL	O
,	O
indicating	O
a	O
correlation	O
between	O
the	O
BLLs	O
in	O
children	B
and	O
the	O
numbers	O
of	O
e	O
-	O
waste	O
workshops	O
.	O

We	O
speculated	O
that	O
the	O
elevated	O
BLLs	O
in	O
Guiyu	O
children	B
may	O
be	O
directly	O
caused	O
by	O
the	O
contamination	O
of	O
the	O
lead	O
during	O
e	O
-	O
waste	O
recycling	O
.	O

However	O
,	O
further	O
study	O
should	O
be	O
conducted	O
to	O
determine	O
the	O
relationship	O
between	O
BLLs	O
in	O
Children	B
and	O
the	O
actual	O
lead	O
contamination	O
in	O
the	O
environment	O
.	O

Lead	O
is	O
considered	O
one	O
of	O
the	O
major	O
heavy	O
metal	O
contaminants	O
during	O
the	O
process	O
of	O
e	O
-	O
waste	O
recycling	O
.	O

A	O
cathode	O
ray	O
tube	O
inside	O
a	O
television	O
set	O
or	O
a	O
computer	O
monitor	O
contains	O
an	O
average	O
of	O
4	O
-	O
8	O
lb	O
lead	O
;	O
monitor	O
glass	O
contains	O
about	O
20	O
%	O
lead	O
by	O
weight	O
;	O
a	O
typical	O
battery	O
weighs	O
36	O
lb	O
and	O
contains	O
about	O
18	O
lb	O
of	O
lead	O
.	O

For	O
decades	O
,	O
lead	O
as	O
a	O
major	O
component	O
of	O
solders	O
has	O
been	O
used	O
to	O
attach	O
electronic	O
components	O
to	O
printed	O
circuit	O
boards	O
.	O

Lead	O
compounds	O
have	O
also	O
been	O
used	O
as	O
stabilizers	O
in	O
some	O
PVC	O
cables	O
and	O
other	O
products	O
.	O

Our	O
study	O
demonstrated	O
in	O
Guiyu	O
a	O
significant	O
increasing	O
trend	O
in	O
BLLs	O
with	O
increasing	O
age	O
;	O
older	O
children	B
tended	O
to	O
have	O
higher	O
BLLs	O
than	O
younger	O
ones	O
.	O

This	O
might	O
be	O
the	O
result	O
of	O
increasing	O
exposure	O
risk	O
because	O
older	O
children	B
might	O
have	O
more	O
outdoor	O
activities	O
.	O

In	O
addition	O
,	O
it	O
may	O
also	O
be	O
attributed	O
to	O
the	O
fact	O
that	O
the	O
heaviest	O
lead	O
-	O
contaminated	O
zone	O
in	O
air	O
after	O
the	O
burning	O
of	O
the	O
e	O
-	O
waste	O
was	O
75	O
-	O
100	O
cm	O
above	O
the	O
ground	O
(	O
Wang	O
and	O
Zhang	O
2006	O
)	O
,	O
which	O
was	O
the	O
height	O
range	O
for	O
normal	O
Chinese	O
children	B
5	O
-	O
6	O
years	O
of	O
age	O
.	O

In	O
China	O
,	O
the	O
mean	O
BLL	O
of	O
children	B
was	O
9	O
.	O
29	O
mu	O
g	O
/	O
dL	O
,	O
and	O
33	O
.	O
8	O
%	O
of	O
the	O
subjects	O
had	O
BLLs	O
>	O
10	O
mu	O
g	O
/	O
dL	O
;	O
boys	B
'	O
mean	O
BLL	O
was	O
9	O
.	O
64	O
mu	O
g	O
/	O
dL	O
,	O
significantly	O
higher	O
than	O
the	O
girls	B
'	O
mean	O
BLL	O
of	O
8	O
.	O
94	O
mu	O
g	O
/	O
dL	O
(	O
p	O
<	O
0	O
.	O
001	O
)	O
(	O
Wang	O
and	O
Zhang	O
2006	O
)	O
.	O

Generally	O
in	O
China	O
,	O
BLLs	O
of	O
children	B
living	O
in	O
industrial	O
and	O
urban	O
areas	O
were	O
significantly	O
higher	O
than	O
those	O
of	O
children	B
in	O
suburbs	O
and	O
rural	O
areas	O
(	O
Wang	O
and	O
Zhang	O
2006	O
)	O
.	O

In	O
Guiyu	O
,	O
the	O
BLLs	O
of	O
children	B
were	O
higher	O
than	O
the	O
mean	O
level	O
in	O
China	O
,	O
and	O
there	O
were	O
no	O
significant	O
different	O
between	O
boys	B
and	O
girls	B
.	O

Although	O
Guiyu	O
is	O
rural	O
,	O
the	O
children	B
'	O
s	O
BLLs	O
were	O
nearly	O
double	O
those	O
of	O
a	O
nearby	O
urban	O
area	O
,	O
Shantou	O
City	O
(	O
7	O
.	O
9	O
mu	O
g	O
/	O
dL	O
;	O
Luo	O
et	O
al	O
.	O
2003	O
)	O
.	O

Compared	O
with	O
results	O
from	O
studies	O
conducted	O
in	O
some	O
other	O
part	O
of	O
Guangdong	O
province	O
,	O
such	O
as	O
Zhongshan	O
City	O
(	O
7	O
.	O
45	O
mu	O
g	O
/	O
dL	O
;	O
Huang	O
et	O
al	O
.	O
2003	O
)	O
and	O
Shenzhen	O
City	O
(	O
9	O
.	O
06	O
mu	O
g	O
/	O
dL	O
;	O
Wang	O
et	O
al	O
.	O
2003	O
)	O
,	O
we	O
observed	O
higher	O
BLLs	O
not	O
only	O
in	O
Guiyu	O
children	B
,	O
but	O
also	O
in	O
Chendian	O
children	B
(	O
9	O
.	O
94	O
mu	O
g	O
/	O
dL	O
)	O
.	O

The	O
lead	O
contamination	O
may	O
have	O
spread	O
from	O
Guiyu	O
to	O
nearby	O
Chendian	O
by	O
dust	O
,	O
river	O
,	O
and	O
air	O
and	O
contributed	O
to	O
the	O
elevation	O
of	O
Chendian	O
children	B
'	O
s	O
BLLs	O
.	O

In	O
conclusion	O
,	O
elevated	O
BLLs	O
in	O
Guiyu	O
children	B
are	O
common	O
as	O
a	O
result	O
of	O
exposure	O
to	O
lead	O
contamination	O
caused	O
by	O
primitive	O
e	O
-	O
waste	O
recycling	O
activities	O
.	O

Lead	O
contamination	O
from	O
e	O
-	O
waste	O
processing	O
appears	O
to	O
have	O
reached	O
the	O
level	O
considered	O
to	O
be	O
a	O
serious	O
threat	O
to	O
children	B
'	O
s	O
health	O
around	O
the	O
e	O
-	O
waste	O
recycling	O
area	O
.	O

Based	O
on	O
these	O
threats	O
,	O
it	O
is	O
necessary	O
to	O
increase	O
public	O
awareness	O
about	O
the	O
effects	O
of	O
exposure	O
to	O
lead	O
from	O
e	O
-	O
waste	O
and	O
arouse	O
local	O
governments	O
'	O
interest	O
in	O
public	O
health	O
and	O
safety	O
,	O
so	O
that	O
an	O
infrastructure	O
for	O
safe	O
management	O
of	O
e	O
-	O
waste	O
can	O
be	O
established	O
.	O

More	O
important	O
,	O
responsible	O
management	O
strategies	O
should	O
be	O
undertaken	O
to	O
minimize	O
e	O
-	O
waste	O
production	O
and	O
make	O
e	O
-	O
waste	O
components	O
more	O
easily	O
recycled	O
and	O
reused	O
.	O

Correction	O

In	O
the	O
Abstract	O
and	O
Discussion	O
,	O
the	O
percentage	O
of	O
Guiyu	O
children	B
with	O
BLLs	O
>	O
10	O
mu	O
g	O
/	O
dL	O
has	O
been	O
corrected	O
from	O
88	O
%	O
in	O
the	O
original	O
manuscript	O
published	O
online	O
to	O
81	O
.	O
8	O
%	O
.	O

Dynein	O
Modifiers	O
in	O
C	B
.	I
elegans	I
:	O
Light	O
Chains	O
Suppress	O
Conditional	O
Heavy	O
Chain	O
Mutants	O

Abstract	O

Cytoplasmic	O
dynein	O
is	O
a	O
microtubule	O
-	O
dependent	O
motor	O
protein	O
that	O
functions	O
in	O
mitotic	O
cells	O
during	O
centrosome	O
separation	O
,	O
metaphase	O
chromosome	O
congression	O
,	O
anaphase	O
spindle	O
elongation	O
,	O
and	O
chromosome	O
segregation	O
.	O

Dynein	O
is	O
also	O
utilized	O
during	O
interphase	O
for	O
vesicle	O
transport	O
and	O
organelle	O
positioning	O
.	O

While	O
numerous	O
cellular	O
processes	O
require	O
cytoplasmic	O
dynein	O
,	O
the	O
mechanisms	O
that	O
target	O
and	O
regulate	O
this	O
microtubule	O
motor	O
remain	O
largely	O
unknown	O
.	O

By	O
screening	O
a	O
conditional	O
Caenorhabditis	B
elegans	I
cytoplasmic	O
dynein	O
heavy	O
chain	O
mutant	O
at	O
a	O
semipermissive	O
temperature	O
with	O
a	O
genome	O
-	O
wide	O
RNA	O
interference	O
library	O
to	O
reduce	O
gene	O
functions	O
,	O
we	O
have	O
isolated	O
and	O
characterized	O
twenty	O
dynein	O
-	O
specific	O
suppressor	O
genes	O
.	O

When	O
reduced	O
in	O
function	O
,	O
these	O
genes	O
suppress	O
dynein	O
mutants	O
but	O
not	O
other	O
conditionally	O
mutant	O
loci	O
,	O
and	O
twelve	O
of	O
the	O
20	O
specific	O
suppressors	O
do	O
not	O
exhibit	O
sterile	O
or	O
lethal	O
phenotypes	O
when	O
their	O
function	O
is	O
reduced	O
in	O
wild	O
-	O
type	O
worms	B
.	O

Many	O
of	O
the	O
suppressor	O
proteins	O
,	O
including	O
two	O
dynein	O
light	O
chains	O
,	O
localize	O
to	O
subcellular	O
sites	O
that	O
overlap	O
with	O
those	O
reported	O
by	O
others	O
for	O
the	O
dynein	O
heavy	O
chain	O
.	O

Furthermore	O
,	O
knocking	O
down	O
any	O
one	O
of	O
four	O
putative	O
dynein	O
accessory	O
chains	O
suppresses	O
the	O
conditional	O
heavy	O
chain	O
mutants	O
,	O
suggesting	O
that	O
some	O
accessory	O
chains	O
negatively	O
regulate	O
heavy	O
chain	O
function	O
.	O

We	O
also	O
identified	O
29	O
additional	O
genes	O
that	O
,	O
when	O
reduced	O
in	O
function	O
,	O
suppress	O
conditional	O
mutations	O
not	O
only	O
in	O
dynein	O
but	O
also	O
in	O
loci	O
required	O
for	O
unrelated	O
essential	O
processes	O
.	O

In	O
conclusion	O
,	O
we	O
have	O
identified	O
twenty	O
genes	O
that	O
in	O
many	O
cases	O
are	O
not	O
essential	O
themselves	O
but	O
are	O
conserved	O
and	O
when	O
reduced	O
in	O
function	O
can	O
suppress	O
conditionally	O
lethal	O
C	B
.	I
elegans	I
cytoplasmic	O
dynein	O
heavy	O
chain	O
mutants	O
.	O

We	O
conclude	O
that	O
conserved	O
but	O
nonessential	O
genes	O
contribute	O
to	O
dynein	O
function	O
during	O
the	O
essential	O
process	O
of	O
mitosis	O
.	O

Microtubules	O
and	O
microtubule	O
-	O
dependent	O
motor	O
proteins	O
segregate	O
chromosomes	O
during	O
mitosis	O
and	O
also	O
promote	O
cellular	O
organization	O
in	O
nondividing	O
cells	O
.	O

An	O
essential	O
motor	O
protein	O
complex	O
called	O
cytoplasmic	O
dynein	O
powers	O
many	O
aspects	O
of	O
microtubule	O
-	O
dependent	O
transport	O
,	O
but	O
it	O
is	O
currently	O
unclear	O
how	O
dynein	O
is	O
regulated	O
such	O
that	O
it	O
can	O
execute	O
different	O
processes	O
.	O

We	O
have	O
performed	O
a	O
genome	O
-	O
wide	O
screen	O
to	O
isolate	O
genes	O
that	O
are	O
involved	O
in	O
dynein	O
-	O
dependent	O
processes	O
.	O

We	O
determined	O
that	O
20	O
of	O
the	O
49	O
genes	O
we	O
identified	O
specifically	O
influenced	O
the	O
viability	O
of	O
dynein	O
mutant	O
strains	O
but	O
not	O
the	O
viability	O
of	O
other	O
C	B
.	I
elegans	I
mutants	O
.	O

Many	O
of	O
the	O
proteins	O
that	O
specifically	O
influence	O
dynein	O
localized	O
to	O
subcellular	O
sites	O
where	O
the	O
dynein	O
heavy	O
chain	O
has	O
been	O
reported	O
by	O
others	O
to	O
be	O
found	O
.	O

Additionally	O
,	O
we	O
identified	O
four	O
dynein	O
components	O
that	O
appear	O
to	O
negatively	O
regulate	O
the	O
force	O
-	O
generating	O
dynein	O
heavy	O
chain	O
.	O

The	O
identification	O
and	O
initial	O
characterization	O
of	O
this	O
group	O
of	O
genes	O
represents	O
a	O
route	O
to	O
identify	O
genes	O
that	O
are	O
not	O
themselves	O
essential	O
but	O
do	O
participate	O
in	O
essential	O
processes	O
.	O

Introduction	O

The	O
microtubule	O
motor	O
called	O
cytoplasmic	O
dynein	O
has	O
roles	O
in	O
diverse	O
cellular	O
processes	O
including	O
meiotic	O
and	O
mitotic	O
spindle	O
assembly	O
and	O
function	O
,	O
neuronal	O
transport	O
,	O
and	O
organelle	O
positioning	O
[	O
1	O
]	O
.	O

Cytoplasmic	O
dynein	O
is	O
composed	O
of	O
a	O
dimer	O
of	O
heavy	O
chains	O
(	O
HCs	O
)	O
,	O
along	O
with	O
several	O
accessory	O
chains	O
(	O
ACs	O
:	O
intermediate	O
,	O
light	O
intermediate	O
,	O
and	O
light	O
chains	O
)	O
.	O

Other	O
dynein	O
-	O
interacting	O
proteins	O
,	O
such	O
as	O
dynactin	O
and	O
LIS1	O
,	O
are	O
likely	O
present	O
at	O
substoichiometric	O
levels	O
and	O
further	O
modulate	O
dynein	O
function	O
.	O

The	O
HCs	O
contain	O
both	O
ATPase	O
and	O
microtubule	O
binding	O
activities	O
and	O
are	O
sufficient	O
for	O
microtubule	O
-	O
based	O
motility	O
in	O
vitro	O
,	O
moving	O
toward	O
the	O
minus	O
,	O
or	O
slow	O
-	O
growing	O
,	O
end	O
of	O
microtubules	O
[	O
2	O
]	O
.	O

The	O
dynein	O
ACs	O
provide	O
cargo	O
docking	O
sites	O
and	O
often	O
are	O
encoded	O
by	O
multigene	O
families	O
in	O
any	O
one	O
species	O
[	O
reviewed	O
in	O
1	O
,	O
3	O
]	O
.	O

In	O
C	B
.	I
elegans	I
,	O
a	O
single	O
gene	O
called	O
dhc	O
-	O
1	O
encodes	O
a	O
cytoplasmic	O
dynein	O
1	O
HC	O
,	O
while	O
11	O
other	O
genes	O
encode	O
five	O
classes	O
of	O
predicted	O
dynein	O
ACs	O
[	O
3	O
,	O
4	O
]	O
.	O

The	O
early	O
C	B
.	I
elegans	I
embryo	O
is	O
an	O
excellent	O
system	O
for	O
investigating	O
gene	O
contributions	O
for	O
essential	O
cellular	O
processes	O
,	O
including	O
cytoskeletal	O
functions	O
[	O
5	O
]	O
.	O

The	O
C	B
.	I
elegans	I
dynein	O
HC	O
DHC	O
-	O
1	O
is	O
essential	O
and	O
required	O
for	O
multiple	O
microtubule	O
-	O
dependent	O
events	O
during	O
early	O
embryogenesis	O
[	O
6	O
-	O
9	O
]	O
.	O

Depletion	O
of	O
DHC	O
-	O
1	O
by	O
RNA	O
interference	O
(	O
RNAi	O
)	O
in	O
early	O
C	B
.	I
elegans	I
embryos	O
produces	O
defects	O
in	O
female	O
meiotic	O
divisions	O
,	O
migration	O
of	O
the	O
oocyte	O
and	O
sperm	O
pronuclei	O
after	O
fertilization	O
,	O
and	O
centrosome	O
separation	O
during	O
mitotic	O
spindle	O
assembly	O
[	O
6	O
]	O
.	O

Analysis	O
of	O
fast	O
-	O
acting	O
dhc	O
-	O
1	O
temperature	O
-	O
sensitive	O
(	O
ts	O
)	O
mutants	O
has	O
further	O
revealed	O
that	O
dynein	O
is	O
required	O
for	O
chromosome	O
congression	O
to	O
the	O
metaphase	O
plate	O
during	O
mitosis	O
,	O
as	O
well	O
as	O
for	O
mitotic	O
spindle	O
positioning	O
[	O
10	O
]	O
.	O

While	O
many	O
requirements	O
for	O
cytoplasmic	O
dynein	O
are	O
known	O
,	O
our	O
knowledge	O
of	O
the	O
molecular	O
mechanisms	O
that	O
target	O
and	O
regulate	O
dynein	O
remains	O
limited	O
.	O

Clearly	O
,	O
the	O
multiple	O
ACs	O
can	O
couple	O
the	O
dynein	O
HC	O
to	O
particular	O
substrates	O
[	O
11	O
]	O
,	O
including	O
vesicles	O
,	O
nuclei	O
,	O
viruses	O
,	O
kinetochores	O
,	O
and	O
rhodopsin	O
[	O
see	O
table	O
in	O
1	O
]	O
.	O

However	O
,	O
reducing	O
the	O
function	O
of	O
only	O
four	O
of	O
the	O
eleven	O
dynein	O
ACs	O
in	O
C	B
.	I
elegans	I
produces	O
lethal	O
phenotypes	O
[	O
12	O
]	O
.	O

Thus	O
,	O
it	O
remains	O
unclear	O
how	O
ACs	O
influence	O
the	O
different	O
essential	O
requirements	O
for	O
dynein	O
.	O

Another	O
potential	O
route	O
for	O
dynein	O
regulation	O
involves	O
the	O
phosphorylation	O
state	O
of	O
the	O
different	O
dynein	O
chains	O
,	O
which	O
in	O
some	O
cases	O
confers	O
distinctive	O
functional	O
properties	O
to	O
the	O
motor	O
.	O

While	O
many	O
examples	O
of	O
dynein	O
phosphorylation	O
exist	O
,	O
and	O
cell	O
cycle	O
dependent	O
changes	O
in	O
phosphorylation	O
have	O
been	O
described	O
[	O
13	O
-	O
15	O
]	O
,	O
few	O
if	O
any	O
studies	O
have	O
demonstrated	O
a	O
requirement	O
for	O
such	O
modification	O
during	O
mitosis	O
.	O

Large	O
-	O
scale	O
forward	O
genetic	O
screens	O
have	O
identified	O
genes	O
with	O
requirements	O
similar	O
to	O
those	O
for	O
dynein	O
,	O
but	O
many	O
of	O
these	O
encode	O
core	O
components	O
of	O
the	O
microtubule	O
cytoskeleton	O
and	O
few	O
are	O
known	O
to	O
directly	O
influence	O
dynein	O
itself	O
[	O
12	O
,	O
16	O
]	O
.	O

Genes	O
that	O
do	O
influence	O
dynein	O
function	O
might	O
also	O
have	O
other	O
essential	O
roles	O
,	O
leading	O
to	O
pleiotropic	O
mutant	O
phenotypes	O
that	O
obscure	O
their	O
relationship	O
to	O
dynein	O
[	O
17	O
-	O
19	O
]	O
.	O

Moreover	O
,	O
redundancy	O
within	O
the	O
multigene	O
dynein	O
subunit	O
families	O
,	O
and	O
also	O
perhaps	O
between	O
the	O
different	O
ACs	O
,	O
may	O
complicate	O
the	O
identification	O
of	O
single	O
gene	O
requirements	O
that	O
are	O
important	O
for	O
dynein	O
function	O
.	O

Thus	O
far	O
,	O
reducing	O
the	O
function	O
of	O
individual	O
genes	O
has	O
not	O
provided	O
substantial	O
insight	O
into	O
the	O
mechanisms	O
that	O
regulate	O
and	O
mediate	O
the	O
many	O
different	O
requirements	O
for	O
cytoplasmic	O
dynein	O
during	O
mitosis	O
.	O

To	O
identify	O
potential	O
regulators	O
of	O
cytoplasmic	O
dynein	O
,	O
we	O
have	O
used	O
a	O
sensitized	O
genetic	O
background	O
to	O
conduct	O
a	O
genome	O
-	O
wide	O
screen	O
for	O
modifiers	O
of	O
dynein	O
function	O
in	O
C	B
.	I
elegans	I
.	O

Other	O
groups	O
have	O
successfully	O
used	O
RNAi	O
modifier	O
screens	O
to	O
identify	O
genes	O
that	O
function	O
in	O
particular	O
pathways	O
[	O
20	O
-	O
23	O
]	O
;	O
we	O
have	O
used	O
RNAi	O
to	O
screen	O
for	O
genes	O
that	O
,	O
when	O
reduced	O
in	O
function	O
,	O
suppress	O
the	O
embryonic	O
lethality	O
associated	O
with	O
a	O
temperature	O
-	O
sensitive	O
(	O
ts	O
)	O
allele	O
of	O
the	O
dhc	O
-	O
1	O
dynein	O
HC	O
gene	O
.	O

Using	O
the	O
dhc	O
-	O
1ts	O
genetic	O
background	O
,	O
we	O
found	O
49	O
genes	O
that	O
,	O
when	O
depleted	O
,	O
suppress	O
the	O
partial	O
loss	O
of	O
HC	O
function	O
.	O

Twenty	O
of	O
these	O
genes	O
suppress	O
conditional	O
dynein	O
HC	O
mutants	O
but	O
not	O
other	O
conditional	O
mutants	O
with	O
unrelated	O
defects	O
.	O

Finally	O
,	O
we	O
show	O
that	O
some	O
of	O
these	O
dynein	O
-	O
specific	O
suppressors	O
encode	O
proteins	O
that	O
may	O
overlap	O
with	O
the	O
dynein	O
HC	O
in	O
subcellular	O
localization	O
.	O

Results	O

To	O
identify	O
dynein	O
suppressors	O
,	O
we	O
used	O
three	O
different	O
conditional	O
and	O
recessive	O
dhc	O
-	O
1	O
mutants	O
that	O
were	O
identified	O
previously	O
[	O
7	O
]	O
.	O

These	O
ts	O
alleles	O
of	O
dhc	O
-	O
1	O
(	O
or195	O
,	O
or283	O
,	O
and	O
or352	O
)	O
produce	O
similar	O
defects	O
at	O
the	O
restrictive	O
temperature	O
of	O
26	O
degrees	O
C	O
,	O
including	O
incomplete	O
mitotic	O
spindle	O
assembly	O
in	O
one	O
-	O
cell	O
embryos	O
and	O
embryonic	O
lethality	O
[	O
7	O
]	O
.	O

We	O
sequenced	O
the	O
dhc	O
-	O
1	O
locus	O
in	O
the	O
three	O
mutants	O
.	O

The	O
independently	O
isolated	O
or195	O
and	O
or283	O
alleles	O
each	O
change	O
a	O
conserved	O
serine	O
to	O
leucine	O
at	O
codon	O
3200	O
,	O
within	O
the	O
coiled	O
-	O
coil	O
region	O
of	O
the	O
microtubule	O
-	O
binding	O
stalk	O
domain	O
(	O
Figure	O
1A	O
and	O
1C	O
)	O
.	O

The	O
or352	O
allele	O
replaces	O
a	O
conserved	O
glycine	O
with	O
aspartic	O
acid	O
at	O
codon	O
2158	O
,	O
in	O
the	O
ATP	O
-	O
binding	O
walker	O
A	O
motif	O
of	O
the	O
second	O
AAA	O
ATPase	O
domain	O
(	O
Figure	O
1B	O
and	O
1C	O
)	O
.	O

As	O
both	O
missense	O
mutations	O
affect	O
conserved	O
residues	O
,	O
they	O
may	O
prove	O
useful	O
for	O
engineering	O
ts	O
alleles	O
in	O
other	O
organisms	O
.	O

The	O
temperature	O
versus	O
viability	O
curves	O
of	O
the	O
dynein	O
ts	O
mutants	O
feature	O
a	O
steep	O
central	O
transition	O
zone	O
ideal	O
for	O
modifier	O
screening	O
because	O
subtle	O
changes	O
in	O
temperature	O
produce	O
large	O
changes	O
in	O
embryonic	O
viability	O
(	O
Figure	O
2A	O
)	O
.	O

To	O
identify	O
genes	O
that	O
,	O
when	O
reduced	O
in	O
function	O
,	O
can	O
suppress	O
conditional	O
dhc	O
-	O
1	O
mutants	O
,	O
we	O
developed	O
a	O
high	O
-	O
throughput	O
RNAi	O
-	O
based	O
screen	O
(	O
Figure	O
2B	O
)	O
.	O

To	O
reduce	O
gene	O
function	O
we	O
used	O
a	O
library	O
of	O
16	O
,	O
757	O
bacterial	O
strains	O
that	O
each	O
express	O
a	O
dsRNA	O
corresponding	O
to	O
exon	O
-	O
rich	O
gene	O
sequences	O
[	O
17	O
,	O
19	O
]	O
.	O

We	O
then	O
tested	O
over	O
99	O
%	O
of	O
the	O
bacterial	O
strains	O
in	O
this	O
library	O
for	O
RNAi	O
-	O
mediated	O
suppression	O
of	O
dhc	O
-	O
1	O
(	O
or195	O
)	O
embryonic	O
lethality	O
at	O
23	O
degrees	O
C	O
,	O
after	O
raising	O
synchronized	O
L1	O
larvae	O
to	O
adulthood	O
on	O
dsRNA	O
-	O
expressing	O
bacterial	O
lawns	O
in	O
48	O
-	O
well	O
agar	O
plates	O
.	O

This	O
screening	O
procedure	O
should	O
work	O
to	O
identify	O
nonessential	O
and	O
essential	O
suppressor	O
genes	O
,	O
because	O
RNAi	O
does	O
not	O
always	O
fully	O
reduce	O
gene	O
function	O
[	O
24	O
,	O
25	O
]	O
,	O
and	O
even	O
if	O
RNAi	O
does	O
produce	O
lethality	O
,	O
cosuppression	O
could	O
restore	O
viability	O
.	O

Nevertheless	O
,	O
essential	O
genes	O
may	O
be	O
missed	O
due	O
to	O
earlier	O
requirements	O
that	O
produce	O
strong	O
larval	O
arrest	O
,	O
sterile	O
,	O
or	O
embryonic	O
lethal	O
phenotypes	O
.	O

Using	O
this	O
screening	O
procedure	O
,	O
we	O
identified	O
49	O
bacterial	O
clones	O
that	O
consistently	O
increased	O
embryonic	O
viability	O
at	O
the	O
semipermissive	O
temperature	O
.	O

The	O
dsRNA	O
-	O
producing	O
plasmids	O
were	O
then	O
sequenced	O
to	O
verify	O
gene	O
identity	O
.	O

Quantification	O
of	O
embryonic	O
viability	O
using	O
dhc	O
-	O
1	O
(	O
or195	O
)	O
animals	O
showed	O
that	O
the	O
RNAi	O
-	O
mediated	O
depletion	O
of	O
suppressor	O
gene	O
function	O
increased	O
viability	O
to	O
5	O
%	O
-	O
100	O
%	O
,	O
compared	O
to	O
less	O
than	O
2	O
%	O
in	O
unsuppressed	O
controls	O
(	O
Figure	O
3A	O
;	O
Table	O
S1	O
)	O
.	O

The	O
proteins	O
encoded	O
by	O
the	O
suppressor	O
genes	O
we	O
identified	O
are	O
summarized	O
in	O
Figure	O
4	O
.	O

As	O
a	O
more	O
direct	O
assay	O
for	O
dynein	O
activity	O
in	O
the	O
suppressed	O
dhc	O
-	O
1	O
embryos	O
,	O
we	O
measured	O
spindle	O
length	O
and	O
cytokinesis	O
success	O
:	O
dhc	O
-	O
1	O
mutant	O
embryos	O
have	O
severe	O
spindle	O
assembly	O
defects	O
and	O
subsequent	O
cytokinesis	O
failures	O
[	O
6	O
,	O
7	O
,	O
10	O
]	O
.	O

We	O
shifted	O
dhc	O
-	O
1	O
adult	O
hermaphrodites	O
from	O
23	O
degrees	O
C	O
to	O
the	O
fully	O
restrictive	O
temperature	O
of	O
26	O
degrees	O
C	O
for	O
3	O
-	O
5	O
hours	O
and	O
made	O
time	O
-	O
lapse	O
video	O
micrographs	O
using	O
Nomarski	O
optics	O
to	O
monitor	O
the	O
first	O
embryonic	O
cell	O
division	O
.	O

This	O
procedure	O
results	O
in	O
dhc	O
-	O
1	O
(	O
or195	O
)	O
embryos	O
with	O
P0	O
spindles	O
30	O
%	O
the	O
length	O
of	O
wild	O
-	O
type	O
spindles	O
(	O
Figure	O
S1	O
)	O
.	O

In	O
the	O
suppressed	O
dhc	O
-	O
1	O
(	O
or195	O
)	O
backgrounds	O
,	O
spindle	O
lengths	O
ranged	O
from	O
30	O
%	O
-	O
83	O
%	O
of	O
wild	O
-	O
type	O
lengths	O
(	O
Figure	O
S1	O
)	O
.	O

Similarly	O
,	O
cytokinesis	O
failed	O
in	O
unsuppressed	O
dhc	O
-	O
1	O
(	O
or195	O
)	O
embryos	O
89	O
%	O
of	O
the	O
time	O
,	O
but	O
most	O
of	O
the	O
suppressors	O
rescued	O
this	O
phenotype	O
(	O
Figure	O
S1	O
)	O
.	O

These	O
results	O
indicate	O
that	O
most	O
of	O
the	O
suppressors	O
influence	O
dynein	O
-	O
dependent	O
cellular	O
processes	O
,	O
as	O
expected	O
given	O
their	O
ability	O
to	O
restore	O
viability	O
when	O
reduced	O
in	O
function	O
.	O

Specificity	O
of	O
Suppression	O

Because	O
RNAi	O
can	O
reduce	O
the	O
function	O
of	O
unintended	O
targets	O
(	O
so	O
-	O
called	O
"	O
off	O
-	O
target	O
effects	O
"	O
[	O
26	O
,	O
27	O
]	O
)	O
,	O
we	O
also	O
used	O
available	O
mutations	O
in	O
some	O
of	O
the	O
suppressor	O
genes	O
we	O
identified	O
to	O
reduce	O
their	O
function	O
.	O

We	O
constructed	O
double	O
mutant	O
strains	O
using	O
dhc	O
-	O
1	O
(	O
or195	O
)	O
and	O
viable	O
deletion	O
alleles	O
for	O
two	O
suppressor	O
genes	O
,	O
dylt	O
-	O
1	O
(	O
ok417	O
)	O
and	O
ufd	O
-	O
2	O
(	O
tm1380	O
)	O
,	O
and	O
examined	O
embryonic	O
viability	O
(	O
Figure	O
3B	O
)	O
.	O

The	O
deletion	O
alleles	O
of	O
dylt	O
-	O
1	O
(	O
encoding	O
a	O
Tctex1	O
-	O
type	O
dynein	O
light	O
chain	O
)	O
,	O
and	O
ufd	O
-	O
2	O
(	O
encoding	O
a	O
ubiquitin	O
conjugating	O
enzyme	O
)	O
both	O
recapitulated	O
the	O
suppression	O
produced	O
by	O
RNAi	O
knockdown	O
(	O
Figure	O
3B	O
)	O
.	O

The	O
dpy	O
-	O
3	O
(	O
e27	O
)	O
and	O
dpy	O
-	O
10	O
(	O
e128	O
)	O
point	O
mutation	O
alleles	O
[	O
28	O
]	O
also	O
suppressed	O
embryonic	O
lethality	O
in	O
double	O
mutants	O
(	O
Figure	O
3B	O
)	O
.	O

Based	O
on	O
this	O
small	O
sampling	O
,	O
and	O
because	O
RNAi	O
in	O
C	B
.	I
elegans	I
appears	O
to	O
be	O
highly	O
gene	O
specific	O
in	O
the	O
absence	O
of	O
close	O
paralogs	O
[	O
12	O
,	O
19	O
]	O
,	O
we	O
conclude	O
that	O
many	O
of	O
the	O
suppressors	O
we	O
have	O
identified	O
will	O
prove	O
to	O
be	O
suppressor	O
locus	O
specific	O
.	O

The	O
dsRNA	O
-	O
expressing	O
bacterial	O
clones	O
we	O
used	O
to	O
deplete	O
two	O
of	O
the	O
dynein	O
suppressors	O
(	O
tag	O
-	O
300	O
and	O
ZK1127	O
.	O
10	O
)	O
probably	O
also	O
knock	O
down	O
expression	O
of	O
one	O
close	O
paralog	O
for	O
each	O
locus	O
[	O
29	O
]	O
.	O

We	O
next	O
asked	O
whether	O
the	O
suppressors	O
are	O
specific	O
for	O
dynein	O
function	O
or	O
if	O
their	O
depletion	O
more	O
generally	O
stabilizes	O
ts	O
proteins	O
.	O

We	O
tested	O
for	O
specificity	O
using	O
two	O
conditional	O
mutants	O
with	O
cell	O
fate	O
patterning	O
defects	O
unrelated	O
to	O
dynein	O
function	O
,	O
lit	O
-	O
1	O
(	O
or131	O
)	O
and	O
spn	O
-	O
4	O
(	O
or191	O
)	O
.	O

The	O
lit	O
-	O
1	O
gene	O
encodes	O
a	O
MAP	O
kinase	O
-	O
related	O
protein	O
[	O
30	O
]	O
,	O
while	O
spn	O
-	O
4	O
encodes	O
a	O
protein	O
with	O
an	O
RNA	O
binding	O
motif	O
[	O
31	O
]	O
.	O

We	O
found	O
that	O
ten	O
of	O
the	O
dhc	O
-	O
1	O
-	O
interacting	O
genes	O
significantly	O
increased	O
embryonic	O
viability	O
in	O
both	O
lit	O
-	O
1	O
and	O
spn	O
-	O
4	O
mutants	O
,	O
while	O
18	O
others	O
suppressed	O
one	O
or	O
the	O
other	O
of	O
these	O
two	O
conditional	O
mutants	O
when	O
reduced	O
in	O
function	O
using	O
the	O
same	O
RNAi	O
protocol	O
as	O
that	O
used	O
for	O
dhc	O
-	O
1ts	O
mutants	O
(	O
Figure	O
4	O
,	O
right	O
two	O
columns	O
;	O
Table	O
S1	O
)	O
.	O

Therefore	O
,	O
about	O
half	O
of	O
the	O
suppressors	O
appear	O
to	O
act	O
nonspecifically	O
on	O
multiple	O
ts	O
mutants	O
to	O
restore	O
embryonic	O
viability	O
.	O

From	O
here	O
on	O
,	O
we	O
will	O
refer	O
to	O
the	O
suppressors	O
that	O
only	O
acted	O
on	O
dhc	O
-	O
1	O
,	O
and	O
not	O
on	O
lit	O
-	O
1	O
and	O
spn	O
-	O
4	O
ts	O
mutants	O
,	O
as	O
dynein	O
-	O
specific	O
suppressors	O
.	O

Because	O
many	O
ts	O
mutations	O
exert	O
their	O
effect	O
via	O
protein	O
assembly	O
or	O
unfolding	O
mechanisms	O
[	O
32	O
]	O
,	O
suppressor	O
genes	O
reduced	O
in	O
function	O
by	O
RNAi	O
might	O
not	O
be	O
expected	O
to	O
exhibit	O
allele	O
specificity	O
with	O
most	O
ts	O
mutations	O
.	O

To	O
determine	O
if	O
the	O
dynein	O
suppressors	O
are	O
either	O
allele	O
or	O
strain	O
specific	O
,	O
we	O
tested	O
the	O
two	O
other	O
conditional	O
dhc	O
-	O
1	O
strains	O
(	O
containing	O
the	O
or283	O
and	O
or352	O
alleles	O
)	O
.	O

Although	O
the	O
or283	O
allele	O
is	O
identical	O
to	O
or195	O
,	O
it	O
provides	O
a	O
useful	O
control	O
for	O
the	O
presence	O
of	O
background	O
mutations	O
because	O
the	O
two	O
strains	O
were	O
isolated	O
independently	O
.	O

In	O
most	O
cases	O
,	O
depletion	O
of	O
the	O
dynein	O
-	O
specific	O
suppressors	O
also	O
restored	O
viability	O
to	O
the	O
other	O
two	O
ts	O
dhc	O
-	O
1	O
alleles	O
.	O

Y40B1B	O
.	O
5	O
,	O
a	O
putative	O
translation	O
initiation	O
factor	O
,	O
suppressed	O
only	O
one	O
conditional	O
dhc	O
-	O
1	O
strain	O
,	O
and	O
we	O
consider	O
this	O
as	O
an	O
example	O
of	O
a	O
nonspecific	O
interaction	O
(	O
Figure	O
4	O
,	O
left	O
three	O
columns	O
;	O
Table	O
S1	O
)	O
.	O

Two	O
dsRNAs	O
that	O
do	O
not	O
suppress	O
lit	O
-	O
1	O
or	O
spn	O
-	O
4	O
mutants	O
produced	O
suppression	O
in	O
the	O
dhc	O
-	O
1	O
(	O
or195	O
)	O
and	O
dhc	O
-	O
1	O
(	O
or283	O
)	O
strains	O
,	O
but	O
not	O
in	O
the	O
dhc	O
-	O
1	O
(	O
or352	O
)	O
strain	O
,	O
perhaps	O
indicating	O
allele	O
specificity	O
or	O
variability	O
in	O
the	O
RNAi	O
treatments	O
.	O

We	O
conclude	O
that	O
strain	O
background	O
differences	O
are	O
relatively	O
rare	O
,	O
and	O
that	O
the	O
majority	O
of	O
the	O
suppressors	O
are	O
allele	O
-	O
independent	O
.	O

To	O
summarize	O
,	O
we	O
have	O
identified	O
20	O
genes	O
that	O
when	O
reduced	O
in	O
function	O
specifically	O
suppress	O
multiple	O
dynein	O
ts	O
strains	O
but	O
not	O
unrelated	O
ts	O
loci	O
.	O

Survey	O
of	O
Putative	O
Dynein	O
Accessory	O
Chains	O

We	O
were	O
surprised	O
to	O
discover	O
that	O
depleting	O
two	O
predicted	O
dynein	O
ACs	O
specifically	O
suppressed	O
the	O
partial	O
loss	O
of	O
HC	O
function	O
,	O
because	O
most	O
dynein	O
accessory	O
subunits	O
are	O
presumed	O
to	O
promote	O
dynein	O
function	O
by	O
aiding	O
dynein	O
complex	O
formation	O
or	O
mediating	O
cargo	O
attachment	O
[	O
3	O
,	O
11	O
,	O
33	O
]	O
.	O

Depletion	O
of	O
either	O
dylt	O
-	O
1	O
(	O
encoding	O
a	O
Tctex1	O
-	O
type	O
light	O
chain	O
)	O
or	O
dyrb	O
-	O
1	O
(	O
encoding	O
a	O
roadblock	O
-	O
type	O
light	O
chain	O
)	O
suppressed	O
embryonic	O
lethality	O
in	O
all	O
three	O
ts	O
dynein	O
HC	O
mutant	O
strains	O
(	O
Figure	O
4	O
)	O
.	O

To	O
extend	O
this	O
observation	O
,	O
we	O
surveyed	O
all	O
genes	O
encoding	O
predicted	O
dynein	O
components	O
for	O
suppression	O
of	O
the	O
three	O
ts	O
dhc	O
-	O
1	O
mutants	O
(	O
Figure	O
5A	O
;	O
Table	O
S2	O
)	O
.	O

We	O
reasoned	O
that	O
some	O
dynein	O
subunit	O
genes	O
could	O
have	O
been	O
missed	O
in	O
the	O
primary	O
screening	O
and	O
several	O
dynein	O
AC	O
genes	O
were	O
not	O
represented	O
in	O
the	O
E	B
.	I
coli	I
RNAi	O
library	O
.	O

After	O
using	O
RNAi	O
to	O
reduce	O
their	O
function	O
,	O
we	O
found	O
that	O
one	O
of	O
three	O
Tctex1	O
homologs	O
(	O
dylt	O
-	O
1	O
)	O
,	O
one	O
of	O
four	O
LC8	O
homologs	O
(	O
dlc	O
-	O
1	O
)	O
,	O
one	O
of	O
two	O
light	O
intermediate	O
chains	O
(	O
dli	O
-	O
1	O
)	O
,	O
as	O
well	O
as	O
the	O
sole	O
roadblock	O
homolog	O
(	O
dyrb	O
-	O
1	O
)	O
each	O
strongly	O
suppressed	O
the	O
three	O
conditional	O
dynein	O
mutants	O
.	O

Lower	O
-	O
level	O
suppression	O
was	O
also	O
seen	O
for	O
the	O
second	O
light	O
intermediate	O
chain	O
,	O
xbx	O
-	O
1	O
,	O
when	O
its	O
function	O
was	O
reduced	O
.	O

Thus	O
,	O
one	O
gene	O
of	O
each	O
of	O
four	O
subunit	O
classes	O
restores	O
viability	O
to	O
the	O
three	O
dhc	O
-	O
1	O
mutant	O
strains	O
when	O
depleted	O
by	O
RNAi	O
.	O

The	O
only	O
subunit	O
class	O
not	O
found	O
to	O
suppress	O
was	O
the	O
intermediate	O
chain	O
,	O
encoded	O
by	O
a	O
single	O
gene	O
in	O
C	B
.	I
elegans	I
,	O
dyci	O
-	O
1	O
.	O

When	O
reduced	O
in	O
function	O
by	O
RNAi	O
,	O
dyci	O
-	O
1	O
produces	O
a	O
larval	O
arrest	O
phenotype	O
like	O
that	O
observed	O
for	O
dhc	O
-	O
1	O
(	O
RNAi	O
)	O
;	O
this	O
phenotype	O
precludes	O
any	O
suppression	O
of	O
the	O
conditional	O
embryonic	O
lethality	O
(	O
shown	O
as	O
"	O
la	O
"	O
in	O
Figure	O
5A	O
)	O
.	O

In	O
contrast	O
,	O
knockdown	O
of	O
either	O
dlc	O
-	O
1	O
or	O
dli	O
-	O
1	O
suppresses	O
embryonic	O
lethality	O
in	O
the	O
dhc	O
-	O
1ts	O
mutants	O
,	O
even	O
though	O
reducing	O
their	O
function	O
in	O
otherwise	O
wild	O
-	O
type	O
embryos	O
produces	O
dhc	O
-	O
1	O
-	O
like	O
defects	O
,	O
including	O
embryonic	O
lethality	O
[	O
12	O
,	O
34	O
]	O
(	O
see	O
Figure	O
5B	O
and	O
Discussion	O
)	O
.	O

The	O
suppressing	O
cytoplasmic	O
dynein	O
subunits	O
and	O
DYCI	O
-	O
1	O
are	O
shown	O
in	O
a	O
putative	O
complex	O
in	O
Figure	O
5E	O
.	O

We	O
performed	O
several	O
genetic	O
assays	O
to	O
better	O
understand	O
how	O
the	O
suppressor	O
genes	O
may	O
be	O
operating	O
.	O

First	O
,	O
suppression	O
of	O
dhc	O
-	O
1	O
lethality	O
by	O
reducing	O
AC	O
function	O
may	O
indicate	O
that	O
our	O
dhc	O
-	O
1	O
alleles	O
express	O
a	O
neomorphic	O
and	O
toxic	O
DHC	O
-	O
1	O
protein	O
:	O
if	O
the	O
suppressor	O
dynein	O
AC	O
subunits	O
positively	O
function	O
in	O
dynein	O
processes	O
,	O
depleting	O
them	O
might	O
suppress	O
any	O
neomorphic	O
effects	O
.	O

This	O
explanation	O
is	O
perhaps	O
unlikely	O
,	O
because	O
the	O
dhc	O
-	O
1ts	O
alleles	O
are	O
all	O
recessive	O
,	O
but	O
remained	O
a	O
possibility	O
in	O
dhc	O
-	O
1	O
homozygotes	O
.	O

We	O
therefore	O
reduced	O
dynein	O
function	O
using	O
RNAi	O
in	O
animals	O
that	O
had	O
passed	O
through	O
the	O
larval	O
arrest	O
points	O
for	O
dhc	O
-	O
1	O
(	O
RNAi	O
)	O
and	O
dyci	O
-	O
1	O
(	O
RNAi	O
)	O
.	O

Specifically	O
,	O
we	O
transferred	O
dhc	O
-	O
1	O
(	O
or195	O
)	O
L4	O
hermaphrodites	O
to	O
plates	O
with	O
bacteria	O
expressing	O
dhc	O
-	O
1	O
or	O
dyci	O
-	O
1	O
dsRNA	O
.	O

As	O
control	O
we	O
performed	O
dylt	O
-	O
1	O
(	O
RNAi	O
)	O
using	O
the	O
same	O
procedure	O
.	O

We	O
observed	O
substantial	O
suppression	O
with	O
dylt	O
-	O
1	O
in	O
this	O
assay	O
,	O
but	O
we	O
saw	O
no	O
suppression	O
with	O
the	O
heavy	O
or	O
intermediate	O
chains	O
(	O
Figure	O
5C	O
)	O
.	O

This	O
suggests	O
that	O
the	O
DHC	O
-	O
1ts	O
protein	O
is	O
not	O
toxic	O
and	O
that	O
dyci	O
-	O
1	O
acts	O
more	O
like	O
dhc	O
-	O
1	O
than	O
the	O
other	O
suppressing	O
ACs	O
because	O
it	O
does	O
not	O
suppress	O
the	O
heavy	O
chain	O
mutant	O
.	O

To	O
further	O
examine	O
the	O
nature	O
of	O
the	O
AC	O
suppression	O
,	O
we	O
asked	O
if	O
depletion	O
of	O
the	O
suppressor	O
chains	O
could	O
bypass	O
the	O
requirement	O
for	O
dhc	O
-	O
1	O
.	O

We	O
transferred	O
wild	O
-	O
type	O
L4	O
larvae	O
to	O
plates	O
with	O
bacteria	O
expressing	O
dsRNA	O
corresponding	O
to	O
both	O
the	O
suppressor	O
ACs	O
and	O
dhc	O
-	O
1	O
.	O

We	O
did	O
not	O
observe	O
any	O
suppression	O
in	O
these	O
double	O
RNAi	O
assays	O
(	O
Figure	O
5D	O
)	O
,	O
suggesting	O
that	O
dhc	O
-	O
1ts	O
suppression	O
requires	O
the	O
residual	O
activity	O
of	O
the	O
defective	O
DHC	O
-	O
1	O
protein	O
.	O

We	O
conclude	O
that	O
the	O
dynein	O
AC	O
suppressors	O
inhibit	O
or	O
somehow	O
oppose	O
the	O
function	O
of	O
the	O
DHC	O
-	O
1ts	O
protein	O
,	O
and	O
that	O
the	O
dhc	O
-	O
1	O
(	O
or195ts	O
)	O
mutation	O
does	O
not	O
produce	O
a	O
toxic	O
gene	O
product	O
but	O
simply	O
reduces	O
DHC	O
-	O
1	O
activity	O
to	O
a	O
low	O
,	O
but	O
non	O
-	O
null	O
,	O
level	O
.	O

Localization	O
of	O
the	O
Dynein	O
Suppressor	O
Proteins	O

To	O
further	O
explore	O
how	O
the	O
suppressor	O
proteins	O
function	O
,	O
we	O
examined	O
the	O
subcellular	O
localization	O
of	O
nine	O
of	O
them	O
as	O
stably	O
expressed	O
N	O
-	O
terminal	O
GFP	O
:	O
:	O
S	O
fusions	O
.	O

We	O
chose	O
to	O
first	O
focus	O
on	O
the	O
suppressor	O
genes	O
that	O
were	O
conserved	O
but	O
poorly	O
characterized	O
in	O
any	O
system	O
,	O
or	O
were	O
conserved	O
but	O
uncharacterized	O
during	O
early	O
C	B
.	I
elegans	I
embryogenesis	O
.	O

Prior	O
dynein	O
immunocytochemistry	O
-	O
based	O
localization	O
studies	O
serve	O
as	O
a	O
comparison	O
[	O
6	O
,	O
10	O
,	O
35	O
]	O
.	O

As	O
in	O
other	O
species	O
,	O
C	B
.	I
elegans	I
DHC	O
-	O
1	O
is	O
associated	O
with	O
mitotic	O
spindles	O
,	O
centrosomes	O
,	O
the	O
nuclear	O
envelope	O
,	O
the	O
cell	O
cortex	O
,	O
the	O
midbody	O
,	O
and	O
throughout	O
the	O
cytoplasm	O
.	O

Most	O
of	O
the	O
suppressor	O
proteins	O
we	O
examined	O
localized	O
to	O
sites	O
where	O
DHC	O
-	O
1	O
is	O
known	O
to	O
act	O
or	O
localize	O
(	O
Figure	O
6	O
)	O
.	O

However	O
,	O
the	O
nearly	O
ubiquitous	O
distribution	O
of	O
DHC	O
-	O
1	O
in	O
early	O
embryonic	O
cells	O
makes	O
colocalization	O
likely	O
but	O
not	O
necessarily	O
meaningful	O
,	O
and	O
biochemical	O
studies	O
are	O
needed	O
to	O
conclusively	O
address	O
any	O
direct	O
or	O
indirect	O
physical	O
associations	O
.	O

Four	O
suppressor	O
GFP	O
fusion	O
proteins	O
localized	O
to	O
nuclear	O
membranes	O
and	O
to	O
spindle	O
poles	O
or	O
pericentrosomal	O
regions	O
.	O

The	O
DYLT	O
-	O
1	O
and	O
DYRB	O
-	O
1	O
dynein	O
light	O
chains	O
were	O
associated	O
with	O
nuclear	O
envelopes	O
and	O
centrosomes	O
,	O
as	O
well	O
as	O
meiotic	O
and	O
mitotic	O
spindle	O
poles	O
(	O
Figure	O
6A	O
-	O
6H	O
;	O
Videos	O
S1	O
and	O
S2	O
)	O
.	O

The	O
potential	O
coiled	O
-	O
coil	O
protein	O
K04F10	O
.	O
3	O
was	O
present	O
on	O
the	O
nuclear	O
envelope	O
and	O
in	O
a	O
pericentrosomal	O
position	O
during	O
mitosis	O
,	O
similar	O
to	O
endoplasmic	O
reticulum	O
proteins	O
[	O
36	O
]	O
(	O
Figure	O
6I	O
-	O
6L	O
;	O
Video	O
S3	O
)	O
.	O

K04F10	O
.	O
3	O
was	O
also	O
highly	O
enriched	O
at	O
meiotic	O
spindle	O
poles	O
(	O
Figure	O
6I	O
)	O
,	O
which	O
has	O
been	O
observed	O
for	O
other	O
endoplasmic	O
reticulum	O
proteins	O
[	O
36	O
]	O
.	O

The	O
NPP	O
-	O
22	O
transmembrane	O
nucleoporin	O
was	O
found	O
at	O
nuclear	O
envelopes	O
(	O
Figure	O
6M	O
-	O
6P	O
;	O
Video	O
S4	O
)	O
,	O
as	O
previously	O
reported	O
for	O
later	O
stage	O
embryos	O
[	O
37	O
]	O
,	O
and	O
it	O
also	O
surrounded	O
centrosomes	O
during	O
mitosis	O
.	O

Two	O
splice	O
isoforms	O
of	O
the	O
pleckstrin	O
homology	O
domain	O
-	O
containing	O
EFA	O
-	O
6	O
/	O
Y55D9A	O
.	O
1	O
,	O
an	O
ARF	O
guanine	O
nucleotide	O
exchange	O
factor	O
,	O
were	O
enriched	O
cortically	O
both	O
in	O
the	O
anterior	O
portion	O
of	O
the	O
one	O
-	O
cell	O
zygote	O
and	O
at	O
the	O
blastomere	O
boundary	O
in	O
two	O
-	O
cell	O
embryos	O
(	O
Figure	O
6Q	O
-	O
6T	O
;	O
Videos	O
S5	O
and	O
S6	O
)	O
.	O

The	O
conserved	O
Mo25	O
homolog	O
MOP	O
-	O
25	O
.	O
2	O
/	O
Y53C12A	O
.	O
4	O
was	O
found	O
enriched	O
in	O
a	O
single	O
spot	O
after	O
cytokinesis	O
that	O
appears	O
to	O
correspond	O
to	O
the	O
midbody	O
(	O
Figure	O
6U	O
-	O
6X	O
;	O
Video	O
S7	O
)	O
.	O

F10E7	O
.	O
8	O
,	O
a	O
highly	O
conserved	O
ortholog	O
of	O
S	B
.	I
cerevisiae	I
Far11	O
,	O
appears	O
nuclear	O
(	O
Figure	O
6Y	O
-	O
6B	O
'	O
and	O
Video	O
S8	O
)	O
.	O

Finally	O
,	O
the	O
nonspecific	O
suppressor	O
protein	O
STAR	O
-	O
2	O
,	O
a	O
predicted	O
RNA	O
binding	O
protein	O
,	O
appears	O
to	O
be	O
associated	O
with	O
P	O
-	O
granules	O
(	O
like	O
its	O
homolog	O
GLD	O
-	O
1	O
)	O
,	O
where	O
dynein	O
is	O
neither	O
localized	O
nor	O
known	O
to	O
function	O
(	O
Figure	O
6C	O
'	O
-	O
6F	O
'	O
)	O
.	O

DLYT	O
-	O
1	O
and	O
DYRB	O
-	O
1	O
:	O
Dynein	O
Light	O
Chain	O
Localization	O

The	O
C	B
.	I
elegans	I
dynein	O
HC	O
protein	O
weakly	O
localizes	O
to	O
spindle	O
poles	O
during	O
early	O
embryonic	O
cell	O
cycles	O
[	O
6	O
,	O
10	O
]	O
,	O
and	O
so	O
did	O
DYRB	O
-	O
1	O
and	O
DYLT	O
-	O
1	O
(	O
Videos	O
S9	O
and	O
S10	O
)	O
.	O

However	O
,	O
ts	O
mutant	O
forms	O
of	O
the	O
DHC	O
-	O
1	O
protein	O
(	O
including	O
DHC	O
-	O
1	O
encoded	O
by	O
the	O
or195	O
allele	O
)	O
strongly	O
localize	O
to	O
centrosomes	O
when	O
shifted	O
to	O
the	O
non	O
-	O
permissive	O
temperature	O
[	O
10	O
]	O
.	O

The	O
mechanism	O
underlying	O
this	O
enhanced	O
localization	O
is	O
not	O
known	O
,	O
but	O
it	O
may	O
represent	O
trapping	O
of	O
the	O
defective	O
protein	O
at	O
a	O
normally	O
transient	O
location	O
.	O

We	O
exploited	O
this	O
behavior	O
of	O
the	O
mutant	O
DHC	O
-	O
1	O
protein	O
to	O
determine	O
whether	O
redistribution	O
of	O
the	O
putative	O
DYRB	O
-	O
1	O
and	O
DYLT	O
-	O
1	O
dynein	O
light	O
chains	O
also	O
occurred	O
in	O
the	O
dhc	O
-	O
1	O
(	O
or195	O
)	O
background	O
.	O

We	O
found	O
that	O
the	O
cellular	O
distributions	O
of	O
DYRB	O
-	O
1	O
and	O
DYLT	O
-	O
1	O
were	O
dramatically	O
altered	O
in	O
dhc	O
-	O
1	O
(	O
or195	O
)	O
mutant	O
embryos	O
.	O

After	O
shifting	O
the	O
parental	O
worms	B
to	O
the	O
restrictive	O
temperature	O
for	O
3	O
-	O
5	O
h	O
prior	O
to	O
collecting	O
embryos	O
,	O
these	O
two	O
proteins	O
were	O
prominently	O
localized	O
to	O
centrosomes	O
and	O
to	O
spindle	O
poles	O
that	O
did	O
not	O
separate	O
in	O
one	O
-	O
cell	O
stage	O
embryos	O
(	O
Figure	O
7	O
;	O
Videos	O
S11	O
and	O
S12	O
)	O
.	O

The	O
spindle	O
pole	O
to	O
cytoplasmic	O
fluorescence	O
ratio	O
during	O
late	O
anaphase	O
was	O
5	O
-	O
fold	O
higher	O
in	O
both	O
of	O
the	O
dhc	O
-	O
1	O
homozygous	O
mutant	O
strains	O
when	O
compared	O
to	O
wild	O
-	O
type	O
embryos	O
expressing	O
the	O
GFP	O
fusions	O
.	O

We	O
also	O
assayed	O
localization	O
of	O
the	O
two	O
putative	O
dynein	O
light	O
chains	O
after	O
short	O
temperature	O
shifts	O
to	O
the	O
nonpermissive	O
temperature	O
in	O
the	O
dhc	O
-	O
1	O
(	O
or195	O
)	O
mutant	O
background	O
,	O
which	O
yields	O
mitotic	O
spindles	O
with	O
an	O
overall	O
wild	O
-	O
type	O
appearance	O
and	O
function	O
.	O

These	O
short	O
temperature	O
shifts	O
also	O
resulted	O
in	O
robust	O
localization	O
of	O
these	O
two	O
dynein	O
light	O
chains	O
to	O
centrosomes	O
(	O
unpublished	O
data	O
)	O
.	O

Finally	O
,	O
we	O
examined	O
the	O
localization	O
of	O
GFP	O
:	O
:	O
DYRB	O
-	O
1	O
and	O
GFP	O
:	O
:	O
DYLT	O
-	O
1	O
in	O
embryos	O
from	O
dhc	O
-	O
1	O
(	O
or195	O
)	O
-	O
/	O
+	O
worms	B
grown	O
at	O
the	O
dhc	O
-	O
1	O
(	O
or195	O
)	O
permissive	O
temperature	O
of	O
15	O
degrees	O
C	O
.	O

Even	O
though	O
embryos	O
from	O
mothers	O
heterozygous	O
for	O
this	O
recessive	O
mutation	O
are	O
viable	O
and	O
develop	O
normally	O
,	O
even	O
at	O
26	O
degrees	O
C	O
[	O
7	O
]	O
,	O
we	O
observed	O
a	O
substantial	O
increase	O
in	O
both	O
GFP	O
fusion	O
proteins	O
at	O
the	O
mitotic	O
spindle	O
poles	O
in	O
early	O
embryos	O
(	O
Figure	O
7	O
;	O
Videos	O
S13	O
and	O
S14	O
)	O
.	O

Importantly	O
,	O
localization	O
of	O
DYLT	O
-	O
1	O
and	O
DYRB	O
-	O
1	O
to	O
centrosomes	O
does	O
not	O
occur	O
in	O
embryos	O
depleted	O
for	O
DHC	O
-	O
1	O
with	O
RNAi	O
(	O
our	O
unpublished	O
results	O
)	O
,	O
indicating	O
that	O
these	O
proteins	O
require	O
the	O
mutant	O
DHC	O
-	O
1	O
polypeptide	O
for	O
centrosomal	O
targeting	O
in	O
the	O
dhc	O
-	O
1	O
(	O
or195	O
)	O
embryos	O
.	O

In	O
summary	O
,	O
the	O
DYRB	O
-	O
1	O
and	O
DYLT	O
-	O
1	O
proteins	O
localize	O
to	O
sites	O
where	O
the	O
DHC	O
-	O
1	O
HC	O
is	O
also	O
found	O
in	O
wild	O
-	O
type	O
embryos	O
,	O
and	O
all	O
three	O
proteins	O
respond	O
similarly	O
to	O
mutational	O
alterations	O
in	O
DHC	O
-	O
1	O
.	O

Genetic	O
Characterization	O
of	O
the	O
DYLT	O
-	O
1	O
and	O
DYRB	O
-	O
1	O
Dynein	O
Light	O
Chains	O

We	O
obtained	O
putative	O
null	O
alleles	O
to	O
determine	O
if	O
dylt	O
-	O
1	O
and	O
dyrb	O
-	O
1	O
function	O
in	O
dynein	O
-	O
dependent	O
processes	O
.	O

DYLT	O
-	O
1	O
is	O
40	O
%	O
identical	O
to	O
human	B
DYNLT3	O
and	O
38	O
%	O
identical	O
to	O
Drosophila	B
Dlc90F	O
(	O
see	O
alignment	O
in	O
Figure	O
8A	O
)	O
.	O

Two	O
other	O
C	B
.	I
elegans	I
genes	O
,	O
dylt	O
-	O
2	O
and	O
dylt	O
-	O
3	O
,	O
encode	O
more	O
divergent	O
members	O
of	O
this	O
protein	O
family	O
.	O

DYRB	O
-	O
1	O
is	O
49	O
%	O
identical	O
to	O
both	O
human	B
DYNLRB1	O
and	O
Drosophila	B
Robl	O
(	O
see	O
alignment	O
in	O
Figure	O
8A	O
)	O
.	O

There	O
do	O
not	O
appear	O
to	O
be	O
other	O
Roadblock	O
genes	O
in	O
the	O
C	B
.	I
elegans	I
genome	O
[	O
3	O
]	O
.	O

Deletion	O
alleles	O
for	O
both	O
dylt	O
-	O
1	O
and	O
dyrb	O
-	O
1	O
have	O
been	O
isolated	O
(	O
Figure	O
8B	O
)	O
.	O

The	O
dylt	O
-	O
1	O
(	O
ok417	O
)	O
deletion	O
removes	O
the	O
entire	O
DYLT	O
-	O
1	O
open	O
reading	O
frame	O
and	O
does	O
not	O
affect	O
adjacent	O
coding	O
regions	O
.	O

The	O
dyrb	O
-	O
1	O
(	O
tm2645	O
)	O
deletion	O
removes	O
69	O
%	O
of	O
the	O
dyrb	O
-	O
1	O
coding	O
region	O
,	O
leaving	O
29	O
predicted	O
N	O
-	O
terminal	O
amino	O
acids	O
,	O
and	O
does	O
not	O
affect	O
adjacent	O
coding	O
regions	O
.	O

Both	O
deletions	O
are	O
currently	O
annotated	O
as	O
homozygous	O
viable	O
[	O
29	O
]	O
.	O

However	O
,	O
we	O
found	O
that	O
the	O
dyrb	O
-	O
1	O
(	O
tm2645	O
)	O
strain	O
was	O
in	O
fact	O
heterozygous	O
for	O
the	O
deletion	O
and	O
that	O
most	O
embryos	O
produced	O
by	O
dyrb	O
-	O
1	O
(	O
tm2645	O
)	O
homozygous	O
animals	O
failed	O
to	O
hatch	O
(	O
Figure	O
8C	O
)	O
.	O

Homozygous	O
dyrb	O
-	O
1	O
(	O
tm2645	O
)	O
worms	B
also	O
showed	O
an	O
egg	O
-	O
laying	O
defect	O
and	O
produced	O
small	O
broods	O
(	O
unpublished	O
data	O
)	O
.	O

To	O
determine	O
if	O
the	O
dyrb	O
-	O
1	O
deletion	O
was	O
responsible	O
for	O
the	O
embryonic	O
lethality	O
,	O
we	O
crossed	O
the	O
GFP	O
:	O
:	O
dyrb	O
-	O
1	O
transgene	O
into	O
the	O
deletion	O
background	O
.	O

The	O
presence	O
of	O
the	O
transgene	O
fully	O
rescued	O
the	O
embryonic	O
lethality	O
(	O
Figure	O
8C	O
)	O
,	O
but	O
not	O
the	O
egg	O
-	O
laying	O
defect	O
:	O
the	O
transgene	O
is	O
driven	O
from	O
a	O
germline	O
-	O
specific	O
promoter	O
and	O
so	O
would	O
not	O
be	O
expected	O
to	O
rescue	O
zygotic	O
phenotypes	O
.	O

The	O
embryonic	O
lethality	O
exhibited	O
by	O
dyrb	O
-	O
1	O
(	O
tm2645	O
)	O
mutants	O
is	O
consistent	O
with	O
RNAi	O
studies	O
performed	O
by	O
injection	O
or	O
soaking	O
[	O
12	O
,	O
38	O
]	O
.	O

In	O
contrast	O
,	O
homozygous	O
dylt	O
-	O
1	O
deletion	O
mutants	O
did	O
not	O
exhibit	O
any	O
larval	O
or	O
embryonic	O
lethality	O
(	O
Figure	O
8C	O
)	O
.	O

To	O
determine	O
if	O
these	O
dynein	O
light	O
chain	O
mutants	O
exhibit	O
dynein	O
HC	O
-	O
like	O
phenotypes	O
,	O
we	O
observed	O
the	O
completion	O
of	O
meiotic	O
polar	O
body	O
extrusion	O
and	O
the	O
first	O
two	O
mitotic	O
cell	O
divisions	O
in	O
mutant	O
embryos	O
(	O
Figure	O
8D	O
)	O
.	O

The	O
dylt	O
-	O
1	O
embryos	O
appeared	O
wild	O
type	O
for	O
completion	O
of	O
meiosis	O
,	O
pronuclear	O
migration	O
,	O
and	O
spindle	O
assembly	O
and	O
function	O
.	O

However	O
,	O
the	O
dyrb	O
-	O
1	O
embryos	O
occasionally	O
contained	O
extra	O
female	O
pronuclei	O
(	O
observed	O
in	O
four	O
of	O
12	O
recordings	O
,	O
Figure	O
8D	O
)	O
,	O
suggesting	O
that	O
polar	O
body	O
extrusion	O
was	O
defective	O
,	O
and	O
pronuclear	O
migration	O
was	O
often	O
slow	O
compared	O
to	O
wild	O
-	O
type	O
embryos	O
.	O

Once	O
formed	O
,	O
spindles	O
appeared	O
functional	O
using	O
Nomarski	O
optics	O
,	O
although	O
they	O
were	O
frequently	O
positioned	O
improperly	O
and	O
had	O
large	O
spindle	O
poles	O
,	O
as	O
has	O
also	O
been	O
observed	O
after	O
RNAi	O
knockdown	O
[	O
12	O
]	O
.	O

Thus	O
,	O
these	O
two	O
genes	O
are	O
not	O
strictly	O
essential	O
,	O
but	O
the	O
DYRB	O
-	O
1	O
protein	O
clearly	O
is	O
required	O
for	O
dynein	O
-	O
dependent	O
processes	O
.	O

Discussion	O

By	O
using	O
the	O
suppressor	O
screening	O
method	O
outlined	O
in	O
Figure	O
2B	O
,	O
we	O
have	O
isolated	O
and	O
characterized	O
49	O
genes	O
that	O
when	O
reduced	O
in	O
function	O
can	O
suppress	O
a	O
partial	O
loss	O
of	O
dynein	O
HC	O
function	O
.	O

This	O
screening	O
procedure	O
takes	O
advantage	O
of	O
sensitized	O
genetic	O
backgrounds	O
using	O
conditional	O
mutants	O
,	O
can	O
be	O
completed	O
for	O
one	O
mutant	O
in	O
less	O
than	O
5	O
wk	O
,	O
and	O
is	O
scalable	O
so	O
that	O
many	O
mutants	O
can	O
be	O
screened	O
in	O
parallel	O
.	O

In	O
fact	O
,	O
we	O
have	O
performed	O
15	O
such	O
screens	O
in	O
different	O
sensitized	O
backgrounds	O
(	O
unpublished	O
data	O
)	O
.	O

By	O
using	O
three	O
dhc	O
-	O
1ts	O
mutant	O
strains	O
,	O
we	O
found	O
that	O
strain	O
background	O
differences	O
and	O
allele	O
specificity	O
are	O
minimal	O
because	O
most	O
of	O
these	O
genes	O
suppress	O
all	O
three	O
dynein	O
mutants	O
when	O
reduced	O
in	O
function	O
using	O
RNAi	O
.	O

Furthermore	O
,	O
by	O
using	O
two	O
unrelated	O
ts	O
mutants	O
to	O
assay	O
for	O
specificity	O
,	O
we	O
found	O
that	O
57	O
%	O
of	O
the	O
suppressor	O
genes	O
suppress	O
multiple	O
unrelated	O
mutant	O
loci	O
.	O

Thus	O
,	O
it	O
is	O
clear	O
that	O
assaying	O
the	O
specificity	O
of	O
suppression	O
is	O
critical	O
for	O
evaluating	O
the	O
functional	O
significance	O
of	O
these	O
RNAi	O
interactions	O
.	O

Eliminating	O
the	O
analysis	O
of	O
these	O
nonspecific	O
genes	O
in	O
future	O
screens	O
will	O
save	O
time	O
and	O
resources	O
.	O

Most	O
of	O
the	O
specific	O
suppressor	O
proteins	O
we	O
examined	O
appear	O
to	O
overlap	O
in	O
subcellular	O
localization	O
with	O
the	O
dynein	O
HC	O
,	O
based	O
on	O
previous	O
studies	O
of	O
DHC	O
-	O
1	O
,	O
while	O
one	O
nonspecific	O
suppressor	O
protein	O
,	O
STAR	O
-	O
2	O
,	O
localized	O
to	O
germline	O
P	O
-	O
granules	O
,	O
where	O
dynein	O
is	O
not	O
known	O
to	O
function	O
.	O

Many	O
of	O
the	O
20	O
genes	O
that	O
specifically	O
suppress	O
multiple	O
dhc	O
-	O
1ts	O
alleles	O
are	O
nonessential	O
in	O
C	B
.	I
elegans	I
but	O
well	O
conserved	O
nonetheless	O
.	O

Six	O
of	O
eight	O
deletion	O
alleles	O
available	O
for	O
the	O
20	O
specific	O
suppressor	O
genes	O
are	O
homozygous	O
viable	O
,	O
and	O
six	O
additional	O
specific	O
genes	O
do	O
not	O
display	O
lethal	O
phenotypes	O
when	O
reduced	O
in	O
function	O
by	O
RNAi	O
in	O
wild	O
-	O
type	O
worms	B
[	O
29	O
]	O
.	O

Thus	O
,	O
our	O
genetic	O
screening	O
has	O
identified	O
roles	O
in	O
an	O
essential	O
process	O
for	O
at	O
least	O
12	O
apparently	O
nonessential	O
genes	O
.	O

Fourteen	O
of	O
the	O
specific	O
dynein	O
suppressor	O
genes	O
have	O
human	B
orthologs	O
as	O
determined	O
by	O
best	O
reciprocal	O
BLAST	O
hits	O
(	O
Table	O
1	O
)	O
,	O
while	O
mop	O
-	O
25	O
.	O
2	O
has	O
a	O
conserved	O
human	B
homolog	O
but	O
also	O
a	O
paralog	O
in	O
C	B
.	I
elegans	I
.	O

Eleven	O
of	O
these	O
conserved	O
genes	O
are	O
nonessential	O
in	O
C	B
.	I
elegans	I
.	O

Interestingly	O
,	O
eight	O
of	O
the	O
conserved	O
genes	O
in	O
Table	O
1	O
have	O
been	O
implicated	O
in	O
human	B
disease	O
etiology	O
,	O
with	O
three	O
of	O
them	O
identified	O
as	O
the	O
causative	O
gene	O
[	O
39	O
-	O
41	O
]	O
.	O

Thus	O
,	O
using	O
sensitized	O
genetic	O
backgrounds	O
for	O
genome	O
-	O
wide	O
modifier	O
screens	O
can	O
identify	O
roles	O
for	O
nonessential	O
but	O
conserved	O
genes	O
and	O
thereby	O
provide	O
insights	O
into	O
human	B
disease	O
.	O

Nonspecific	O
Suppression	O
of	O
Conditional	O
Mutants	O

We	O
examined	O
the	O
predicted	O
molecular	O
functions	O
of	O
the	O
suppressor	O
proteins	O
to	O
better	O
understand	O
the	O
basis	O
for	O
the	O
nonspecific	O
suppression	O
phenomenon	O
.	O

Strikingly	O
,	O
many	O
of	O
the	O
nonspecific	O
suppressor	O
genes	O
encode	O
proteins	O
with	O
predicted	O
roles	O
in	O
mitochondrial	O
,	O
ribosomal	O
,	O
and	O
collagen	O
function	O
(	O
18	O
of	O
29	O
genes	O
,	O
or	O
62	O
%	O
)	O
,	O
while	O
only	O
two	O
such	O
genes	O
appeared	O
to	O
specifically	O
suppress	O
dhc	O
-	O
1	O
(	O
2	O
of	O
20	O
genes	O
or	O
10	O
%	O
)	O
.	O

It	O
is	O
possible	O
that	O
stress	O
produced	O
by	O
RNAi	O
knockdown	O
of	O
these	O
suppressor	O
genes	O
triggers	O
the	O
activity	O
of	O
molecular	O
chaperones	O
that	O
can	O
generally	O
restore	O
function	O
to	O
ts	O
proteins	O
.	O

Indeed	O
,	O
mutation	O
of	O
dpy	O
-	O
10	O
is	O
known	O
to	O
suppress	O
three	O
other	O
ts	O
mutants	O
:	O
glp	O
-	O
1	O
,	O
emb	O
-	O
5	O
,	O
and	O
mup	O
-	O
1	O
[	O
42	O
-	O
44	O
]	O
.	O

Furthermore	O
,	O
RNAi	O
reduction	O
of	O
dpy	O
-	O
10	O
,	O
star	O
-	O
2	O
,	O
osr	O
-	O
1	O
,	O
or	O
C50D2	O
.	O
1	O
(	O
all	O
suppressors	O
of	O
dhc	O
-	O
1	O
,	O
lit	O
-	O
1	O
,	O
and	O
spn	O
-	O
4	O
ts	O
alleles	O
)	O
induces	O
the	O
glycerol	O
biosynthetic	O
gene	O
gpdh	O
-	O
2	O
,	O
while	O
dpy	O
-	O
10	O
and	O
osr	O
-	O
1	O
mutants	O
exhibit	O
increased	O
glycerol	O
levels	O
,	O
a	O
condition	O
that	O
promotes	O
protein	O
stability	O
[	O
45	O
]	O
.	O

We	O
suggest	O
that	O
partial	O
loss	O
of	O
central	O
metabolic	O
processes	O
can	O
invoke	O
stress	O
responses	O
that	O
nonspecifically	O
alleviate	O
protein	O
-	O
folding	O
problems	O
in	O
ts	O
proteins	O
.	O

Filtering	O
out	O
these	O
nonspecific	O
interactions	O
by	O
testing	O
unrelated	O
conditional	O
mutants	O
increases	O
the	O
likelihood	O
that	O
the	O
remaining	O
suppressor	O
genes	O
are	O
more	O
directly	O
involved	O
with	O
dynein	O
function	O
.	O

However	O
,	O
ts	O
mutants	O
likely	O
differ	O
in	O
their	O
susceptibility	O
to	O
nonspecific	O
suppression	O
mechanisms	O
,	O
and	O
some	O
apparently	O
unrelated	O
ts	O
mutants	O
might	O
share	O
common	O
cofactors	O
such	O
that	O
both	O
mutants	O
are	O
suppressed	O
by	O
depletion	O
of	O
the	O
same	O
cofactor	O
.	O

Nevertheless	O
,	O
we	O
expect	O
that	O
more	O
extensive	O
testing	O
for	O
specificity	O
will	O
prove	O
very	O
useful	O
for	O
judging	O
the	O
significance	O
of	O
modifier	O
interactions	O
.	O

Possible	O
Relevance	O
of	O
Suppressor	O
Proteins	O
to	O
Dynein	O
Function	O

We	O
examined	O
the	O
localization	O
of	O
a	O
number	O
of	O
GFP	O
fusions	O
to	O
suppressor	O
proteins	O
to	O
gain	O
insight	O
into	O
their	O
functional	O
relationship	O
to	O
dynein	O
.	O

In	O
several	O
cases	O
,	O
the	O
subcellular	O
distribution	O
of	O
the	O
suppressor	O
proteins	O
overlapped	O
in	O
different	O
ways	O
with	O
the	O
known	O
and	O
nearly	O
ubiquitous	O
distribution	O
of	O
cytoplasmic	O
dynein	O
in	O
the	O
early	O
C	B
.	I
elegans	I
embryo	O
.	O

In	O
fact	O
,	O
the	O
only	O
specific	O
suppressor	O
that	O
did	O
not	O
display	O
dynein	O
-	O
like	O
localization	O
was	O
F10E7	O
.	O
8	O
,	O
a	O
homolog	O
of	O
yeast	B
Far11	O
of	O
unknown	O
function	O
[	O
46	O
]	O
,	O
which	O
was	O
nuclear	O
.	O

The	O
one	O
nonspecific	O
suppressor	O
protein	O
we	O
examined	O
did	O
not	O
show	O
any	O
dynein	O
-	O
like	O
localization	O
patterns	O
.	O

The	O
subcellular	O
localizations	O
of	O
the	O
GFP	O
:	O
:	O
suppressor	O
protein	O
fusions	O
are	O
intriguing	O
.	O

However	O
,	O
given	O
the	O
nearly	O
ubiquitous	O
distribution	O
of	O
dynein	O
in	O
early	O
embryonic	O
cells	O
,	O
biochemical	O
tests	O
for	O
direct	O
association	O
are	O
needed	O
to	O
address	O
the	O
significance	O
of	O
any	O
colocalization	O
detected	O
using	O
light	O
microscopy	O
.	O

We	O
are	O
particularly	O
interested	O
in	O
suppressor	O
proteins	O
that	O
localize	O
to	O
mitotic	O
spindle	O
poles	O
:	O
the	O
association	O
of	O
the	O
DYLT	O
-	O
1	O
and	O
DYRB	O
-	O
1	O
predicted	O
dynein	O
light	O
chains	O
with	O
centrosomes	O
and	O
spindle	O
poles	O
suggests	O
that	O
they	O
may	O
be	O
components	O
of	O
cytoplasmic	O
dynein	O
in	O
C	B
.	I
elegans	I
.	O

Localization	O
of	O
cytoplasmic	O
dynein	O
to	O
centrosomes	O
and	O
spindle	O
poles	O
is	O
well	O
established	O
[	O
47	O
,	O
48	O
]	O
,	O
and	O
the	O
inhibition	O
of	O
dynein	O
function	O
prevents	O
centrosome	O
separation	O
,	O
centrosome	O
attachment	O
to	O
nuclei	O
,	O
and	O
the	O
formation	O
of	O
bipolar	O
spindles	O
[	O
6	O
,	O
10	O
,	O
49	O
,	O
50	O
]	O
.	O

Moreover	O
,	O
the	O
centrosomal	O
localization	O
of	O
DHC	O
-	O
1	O
,	O
DYLT	O
-	O
1	O
,	O
and	O
DYRB	O
-	O
1	O
are	O
all	O
greatly	O
enhanced	O
in	O
dhc	O
-	O
1ts	O
mutant	O
embryos	O
:	O
this	O
dependence	O
of	O
the	O
light	O
chain	O
distribution	O
on	O
the	O
HC	O
further	O
suggests	O
they	O
reside	O
in	O
the	O
same	O
motor	O
complex	O
(	O
Figure	O
7	O
and	O
[	O
10	O
]	O
)	O
.	O

Furthermore	O
,	O
roadblock	O
light	O
chains	O
are	O
well	O
-	O
established	O
components	O
of	O
dynein	O
,	O
and	O
all	O
of	O
the	O
roadblock	O
protein	O
in	O
mammalian	O
liver	O
extracts	O
is	O
dynein	O
associated	O
[	O
51	O
,	O
52	O
]	O
.	O

Finally	O
,	O
a	O
DYLT	O
-	O
1	O
homolog	O
in	O
vertebrates	O
is	O
a	O
stoichiometric	O
subunit	O
of	O
cytoplasmic	O
dynein	O
[	O
53	O
]	O
.	O

The	O
presence	O
of	O
these	O
two	O
light	O
chains	O
in	O
a	O
dynein	O
complex	O
is	O
consistent	O
with	O
them	O
having	O
either	O
positive	O
or	O
negative	O
roles	O
in	O
the	O
regulation	O
of	O
HC	O
function	O
(	O
see	O
below	O
)	O
.	O

Cytoplasmic	O
dynein	O
is	O
found	O
on	O
the	O
nuclear	O
envelope	O
where	O
it	O
is	O
thought	O
to	O
regulate	O
nuclear	O
membrane	O
breakdown	O
during	O
mitosis	O
[	O
54	O
]	O
,	O
and	O
dynein	O
plays	O
roles	O
during	O
the	O
trafficking	O
of	O
endoplasmic	O
reticulum	O
components	O
[	O
55	O
,	O
56	O
]	O
.	O

Therefore	O
,	O
the	O
nuclear	O
envelope	O
/	O
endoplasmic	O
reticulum	O
proteins	O
NPP	O
-	O
22	O
and	O
K04F10	O
.	O
3	O
could	O
couple	O
dynein	O
activity	O
to	O
either	O
of	O
these	O
structures	O
.	O

The	O
anc	O
-	O
1	O
gene	O
was	O
also	O
isolated	O
in	O
our	O
screening	O
and	O
ANC	O
-	O
1	O
is	O
localized	O
to	O
the	O
nuclear	O
envelope	O
where	O
it	O
maintains	O
nuclear	O
positioning	O
in	O
postembryonic	O
cells	O
[	O
57	O
]	O
.	O

Reducing	O
the	O
function	O
of	O
these	O
three	O
genes	O
may	O
suppress	O
partial	O
loss	O
of	O
dynein	O
HC	O
mutants	O
by	O
reducing	O
the	O
need	O
for	O
dynein	O
during	O
nuclear	O
envelope	O
breakdown	O
,	O
through	O
constitutive	O
partial	O
destabilization	O
of	O
the	O
nuclear	O
envelope	O
.	O

The	O
distribution	O
of	O
the	O
cytoplasmic	O
dynein	O
HC	O
includes	O
sites	O
other	O
than	O
spindle	O
poles	O
and	O
nuclear	O
envelopes	O
in	O
C	B
.	I
elegans	I
,	O
for	O
example	O
,	O
at	O
the	O
cell	O
cortex	O
and	O
at	O
the	O
cell	O
division	O
remnant	O
called	O
the	O
midbody	O
[	O
6	O
,	O
10	O
]	O
.	O

The	O
MOP	O
-	O
25	O
.	O
2	O
protein	O
was	O
found	O
at	O
the	O
midbody	O
and	O
faintly	O
at	O
spindle	O
poles	O
.	O

The	O
MOP	O
-	O
25	O
.	O
2	O
ortholog	O
in	O
S	B
.	I
pombe	I
,	O
Pmo25	O
,	O
is	O
also	O
present	O
at	O
the	O
cell	O
division	O
site	O
and	O
on	O
spindle	O
poles	O
[	O
58	O
]	O
.	O

Mammalian	O
MOP	O
-	O
25	O
.	O
2	O
homologs	O
stimulate	O
the	O
kinase	O
activity	O
of	O
the	O
LKB1	O
tumor	O
suppressor	O
(	O
the	O
C	B
.	I
elegans	I
ortholog	O
is	O
PAR	O
-	O
4	O
)	O
,	O
which	O
in	O
turn	O
activates	O
MARK	O
microtubule	O
-	O
destabilizing	O
kinases	O
[	O
59	O
,	O
60	O
]	O
.	O

The	O
C	B
.	I
elegans	I
MARK	O
ortholog	O
,	O
PAR	O
-	O
1	O
,	O
controls	O
cell	O
polarity	O
during	O
embryogenesis	O
,	O
and	O
orthologs	O
have	O
been	O
implicated	O
in	O
regulation	O
of	O
microtubule	O
dynamics	O
from	O
yeast	B
to	O
humans	B
[	O
61	O
-	O
64	O
]	O
.	O

Lastly	O
,	O
the	O
two	O
splice	O
isoforms	O
of	O
EFA	O
-	O
6	O
were	O
associated	O
with	O
the	O
anterior	O
cell	O
cortex	O
in	O
late	O
one	O
-	O
cell	O
embryos	O
.	O

Cortically	O
localized	O
dynein	O
may	O
have	O
important	O
roles	O
in	O
applying	O
forces	O
to	O
astral	O
microtubules	O
that	O
influence	O
mitotic	O
spindle	O
positioning	O
and	O
chromosome	O
separation	O
during	O
anaphase	O
[	O
10	O
,	O
65	O
,	O
66	O
]	O
.	O

EFA6	O
ARF	O
guanine	O
nucleotide	O
exchange	O
factors	O
require	O
their	O
pleckstrin	O
homology	O
domain	O
for	O
cortical	O
targeting	O
,	O
and	O
are	O
known	O
to	O
regulate	O
cortical	O
actin	O
dynamics	O
in	O
vertebrate	O
cells	O
by	O
promoting	O
guanine	O
nucleotide	O
exchange	O
on	O
ARF6	O
[	O
67	O
,	O
68	O
]	O
.	O

Our	O
results	O
identifying	O
efa	O
-	O
6	O
as	O
a	O
dynein	O
HC	O
suppressor	O
suggest	O
a	O
functional	O
linkage	O
of	O
the	O
actin	O
and	O
microtubule	O
cytoskeletons	O
at	O
the	O
cell	O
cortex	O
.	O

Interestingly	O
,	O
two	O
yeast	B
pleckstrin	O
homology	O
domain	O
proteins	O
,	O
Num1	O
and	O
mcp5	O
+	O
,	O
localize	O
to	O
the	O
cell	O
cortex	O
and	O
direct	O
astral	O
microtubule	O
and	O
dynein	O
function	O
,	O
although	O
they	O
do	O
not	O
contain	O
a	O
Sec7	O
domain	O
like	O
EFA	O
-	O
6	O
does	O
[	O
69	O
-	O
71	O
]	O
.	O

Function	O
of	O
Dynein	O
Intermediate	O
,	O
Light	O
Intermediate	O
,	O
and	O
Light	O
Chains	O

The	O
dynein	O
chains	O
in	O
C	B
.	I
elegans	I
exhibit	O
strikingly	O
different	O
functional	O
requirements	O
.	O

The	O
DYRB	O
-	O
1	O
roadblock	O
light	O
chain	O
is	O
required	O
for	O
completion	O
of	O
meiosis	O
and	O
pronuclear	O
migration	O
,	O
but	O
an	O
at	O
least	O
partially	O
functional	O
mitotic	O
spindle	O
forms	O
in	O
the	O
absence	O
of	O
DYRB	O
-	O
1	O
(	O
Figure	O
8	O
)	O
.	O

The	O
DLI	O
-	O
1	O
light	O
intermediate	O
chain	O
is	O
required	O
for	O
multiple	O
dynein	O
-	O
dependent	O
functions	O
:	O
pronuclear	O
migration	O
,	O
centrosome	O
separation	O
,	O
and	O
meiotic	O
and	O
mitotic	O
spindle	O
function	O
[	O
12	O
,	O
34	O
]	O
.	O

DLI	O
-	O
1	O
may	O
promote	O
nuclear	O
envelope	O
targeting	O
of	O
both	O
centrosomes	O
and	O
DHC	O
-	O
1	O
by	O
interacting	O
with	O
the	O
nuclear	O
envelope	O
protein	O
ZYG	O
-	O
12	O
[	O
35	O
]	O
.	O

The	O
second	O
worm	O
light	O
intermediate	O
chain	O
gene	O
,	O
xbx	O
-	O
1	O
,	O
is	O
required	O
for	O
cilia	O
function	O
but	O
not	O
early	O
embryonic	O
development	O
[	O
12	O
,	O
72	O
]	O
.	O

RNAi	O
knockdown	O
of	O
DLC	O
-	O
1	O
,	O
one	O
of	O
three	O
LC8	O
proteins	O
in	O
C	B
.	I
elegans	I
,	O
produces	O
defects	O
similar	O
to	O
dli	O
-	O
1	O
but	O
knockdown	O
of	O
the	O
other	O
two	O
LC8	O
-	O
related	O
genes	O
does	O
not	O
result	O
in	O
any	O
phenotypes	O
[	O
12	O
]	O
.	O

RNAi	O
depletion	O
of	O
dyci	O
-	O
1	O
results	O
in	O
severe	O
meiotic	O
,	O
pronuclear	O
migration	O
,	O
and	O
mitotic	O
spindle	O
assembly	O
defects	O
[	O
12	O
]	O
and	O
in	O
our	O
feeding	O
RNAi	O
regimen	O
dyci	O
-	O
1	O
(	O
RNAi	O
)	O
produces	O
a	O
larval	O
arrest	O
phenotype	O
similar	O
to	O
that	O
observed	O
for	O
dhc	O
-	O
1	O
.	O

Finally	O
,	O
the	O
three	O
Tctex1	O
proteins	O
in	O
C	B
.	I
elegans	I
,	O
DYLT	O
-	O
1	O
,	O
2	O
,	O
and	O
3	O
,	O
are	O
not	O
essential	O
for	O
dynein	O
-	O
related	O
functions	O
[	O
12	O
]	O
.	O

As	O
the	O
dyrb	O
-	O
1	O
,	O
dlc	O
-	O
1	O
,	O
and	O
dli	O
-	O
1	O
dynein	O
AC	O
genes	O
display	O
some	O
dhc	O
-	O
1	O
-	O
like	O
requirements	O
,	O
they	O
positively	O
influence	O
dynein	O
function	O
.	O

However	O
,	O
because	O
reducing	O
their	O
function	O
suppresses	O
dhc	O
-	O
1ts	O
mutants	O
,	O
they	O
may	O
also	O
exert	O
negative	O
regulation	O
(	O
along	O
with	O
dylt	O
-	O
1	O
)	O
on	O
the	O
heavy	O
chain	O
.	O

Negative	O
Regulation	O
of	O
Dynein	O
HC	O
by	O
Light	O
Chain	O
Subunits	O

Finding	O
that	O
reducing	O
the	O
function	O
of	O
light	O
and	O
light	O
intermediate	O
dynein	O
chains	O
suppressed	O
the	O
partial	O
loss	O
of	O
HC	O
function	O
was	O
a	O
striking	O
result	O
.	O

One	O
member	O
of	O
each	O
of	O
four	O
subunit	O
classes	O
can	O
suppress	O
the	O
embryonic	O
lethality	O
associated	O
with	O
three	O
dhc	O
-	O
1	O
ts	O
mutants	O
(	O
Figure	O
5	O
)	O
.	O

We	O
have	O
considered	O
two	O
different	O
models	O
to	O
explain	O
how	O
RNAi	O
-	O
mediated	O
depletion	O
of	O
these	O
dynein	O
ACs	O
can	O
suppress	O
reduced	O
HC	O
function	O
.	O

First	O
,	O
these	O
dynein	O
subunits	O
could	O
be	O
in	O
functional	O
complexes	O
with	O
,	O
and	O
exert	O
negative	O
regulation	O
on	O
,	O
the	O
DHC	O
-	O
1	O
HC	O
(	O
Figure	O
5B	O
)	O
.	O

The	O
suppression	O
mechanism	O
in	O
this	O
case	O
proposes	O
that	O
removal	O
of	O
the	O
suppressing	O
ACs	O
increases	O
residual	O
mutant	O
DHC	O
-	O
1	O
activity	O
.	O

The	O
other	O
,	O
nonsuppressing	O
,	O
accessory	O
subunits	O
might	O
then	O
function	O
in	O
nonmitotic	O
cellular	O
processes	O
such	O
as	O
neuronal	O
transport	O
or	O
organelle	O
positioning	O
.	O

In	O
support	O
of	O
this	O
view	O
,	O
physical	O
removal	O
of	O
the	O
intermediate	O
chains	O
of	O
rat	B
cytoplasmic	O
dynein	O
increased	O
HC	O
ATPase	O
activity	O
by	O
about	O
4	O
-	O
fold	O
(	O
light	O
chains	O
were	O
not	O
monitored	O
in	O
this	O
study	O
but	O
were	O
likely	O
removed	O
as	O
well	O
)	O
[	O
73	O
]	O
.	O

Thus	O
,	O
at	O
least	O
with	O
respect	O
to	O
ATPase	O
activity	O
,	O
some	O
dynein	O
ACs	O
do	O
act	O
as	O
biochemical	O
negative	O
regulators	O
of	O
HC	O
function	O
.	O

An	O
Assortment	O
of	O
Essential	O
and	O
Nonessential	O
Dynein	O
Complexes	O

Alternatively	O
,	O
an	O
assortment	O
of	O
dynein	O
complexes	O
(	O
with	O
different	O
ACs	O
)	O
could	O
coexist	O
within	O
early	O
embryonic	O
cells	O
,	O
with	O
only	O
a	O
subset	O
required	O
for	O
the	O
essential	O
mitotic	O
functions	O
that	O
require	O
DHC	O
-	O
1	O
.	O

In	O
this	O
case	O
,	O
suppression	O
might	O
result	O
from	O
the	O
release	O
of	O
DHC	O
-	O
1	O
HCs	O
from	O
less	O
essential	O
motor	O
complexes	O
,	O
allowing	O
more	O
of	O
the	O
functionally	O
compromised	O
HCs	O
to	O
participate	O
in	O
the	O
essential	O
process	O
of	O
mitosis	O
.	O

We	O
currently	O
disfavor	O
this	O
hypothesis	O
because	O
two	O
of	O
the	O
suppressing	O
light	O
chains	O
(	O
DYLT	O
-	O
1	O
and	O
DYRB	O
-	O
1	O
)	O
can	O
indeed	O
localize	O
to	O
meiotic	O
and	O
mitotic	O
spindles	O
(	O
Figures	O
6	O
and	O
7	O
)	O
,	O
sites	O
where	O
DHC	O
-	O
1	O
has	O
been	O
shown	O
by	O
others	O
to	O
localize	O
and	O
function	O
.	O

Furthermore	O
,	O
the	O
distribution	O
of	O
DYRB	O
-	O
1	O
and	O
DYLT	O
-	O
1	O
closely	O
resembles	O
the	O
distribution	O
of	O
the	O
HC	O
in	O
dhc	O
-	O
1	O
(	O
or195	O
)	O
embryos	O
,	O
suggesting	O
that	O
these	O
two	O
light	O
chains	O
associate	O
with	O
the	O
HC	O
during	O
mitosis	O
(	O
Figure	O
7	O
and	O
[	O
10	O
]	O
)	O
.	O

Finally	O
,	O
dhc	O
-	O
1	O
-	O
like	O
phenotypes	O
result	O
from	O
mutation	O
or	O
RNAi	O
knockdown	O
of	O
three	O
suppressing	O
ACs	O
in	O
otherwise	O
wild	O
-	O
type	O
worms	B
,	O
indicating	O
that	O
they	O
share	O
at	O
least	O
some	O
common	O
and	O
essential	O
requirements	O
.	O

Regardless	O
of	O
the	O
suppression	O
mechanism	O
,	O
our	O
identification	O
of	O
ACs	O
that	O
genetically	O
interact	O
with	O
the	O
DHC	O
-	O
1	O
HC	O
provides	O
a	O
basis	O
for	O
functionally	O
classifying	O
the	O
paralogs	O
of	O
these	O
dynein	O
subunit	O
gene	O
families	O
,	O
and	O
for	O
further	O
investigation	O
of	O
dynein	O
composition	O
and	O
function	O
.	O

Nonessential	O
Dynein	O
Subunits	O
and	O
Negative	O
Regulation	O
of	O
the	O
HC	O

Some	O
ACs	O
are	O
nonessential	O
,	O
supporting	O
the	O
view	O
that	O
some	O
cytoplasmic	O
dynein	O
subunits	O
could	O
function	O
by	O
exerting	O
negative	O
regulation	O
on	O
the	O
HC	O
,	O
rather	O
than	O
positively	O
influencing	O
essential	O
HC	O
function	O
.	O

For	O
example	O
,	O
DYRB	O
-	O
1	O
is	O
not	O
absolutely	O
required	O
for	O
viability	O
because	O
worms	B
lacking	O
this	O
protein	O
can	O
be	O
propagated	O
,	O
although	O
they	O
are	O
extremely	O
sick	O
and	O
do	O
exhibit	O
two	O
dhc	O
-	O
1	O
-	O
like	O
phenotypes	O
(	O
Figure	O
8	O
)	O
.	O

Also	O
,	O
homozygous	O
dylt	O
-	O
1	O
deletion	O
mutants	O
appear	O
fully	O
viable	O
(	O
Figure	O
8	O
)	O
.	O

The	O
two	O
additional	O
Tctex1	O
C	B
.	I
elegans	I
genes	O
could	O
be	O
functionally	O
redundant	O
with	O
DYLT	O
-	O
1	O
,	O
but	O
simultaneously	O
reducing	O
the	O
function	O
of	O
DYLT	O
-	O
2	O
and	O
DYLT	O
-	O
3	O
by	O
RNAi	O
in	O
the	O
dylt	O
-	O
1	O
deletion	O
strain	O
did	O
not	O
cause	O
lethality	O
(	O
unpublished	O
data	O
)	O
.	O

Because	O
RNAi	O
does	O
not	O
always	O
completely	O
reduce	O
function	O
,	O
the	O
question	O
of	O
redundancy	O
in	O
the	O
Tctex1	O
C	B
.	I
elegans	I
gene	O
family	O
remains	O
unresolved	O
.	O

However	O
,	O
Drosophila	B
contains	O
only	O
a	O
single	O
Tctex1	O
gene	O
,	O
Dlc90F	O
[	O
74	O
,	O
75	O
]	O
.	O

A	O
Dlc90F	O
null	O
allele	O
that	O
deletes	O
80	O
%	O
of	O
the	O
open	O
reading	O
frame	O
is	O
essential	O
only	O
for	O
sperm	O
production	O
but	O
not	O
for	O
viability	O
of	O
male	O
or	O
female	O
flies	O
,	O
despite	O
the	O
wild	O
-	O
type	O
protein	O
being	O
incorporated	O
into	O
dynein	O
motors	O
and	O
expressed	O
in	O
various	O
Drosophila	B
tissues	O
[	O
74	O
]	O
.	O

Thus	O
,	O
at	O
least	O
in	O
Drosophila	B
,	O
the	O
Tctex1	O
dynein	O
light	O
chain	O
family	O
is	O
not	O
required	O
for	O
cell	O
division	O
processes	O
like	O
the	O
HC	O
is	O
.	O

Interestingly	O
,	O
budding	O
yeast	B
does	O
not	O
possess	O
genes	O
for	O
the	O
Tctex1	O
or	O
roadblock	O
ACs	O
,	O
indicating	O
that	O
functional	O
cytoplasmic	O
dynein	O
does	O
not	O
require	O
these	O
subunits	O
that	O
are	O
conserved	O
in	O
many	O
other	O
organisms	O
.	O

The	O
AC	O
genes	O
that	O
yeast	B
does	O
posses	O
are	O
not	O
required	O
for	O
HC	O
motility	O
in	O
vitro	O
because	O
dynein	O
purified	O
from	O
yeast	B
with	O
mutations	O
in	O
these	O
genes	O
remains	O
fully	O
active	O
[	O
2	O
]	O
.	O

Thus	O
,	O
dynein	O
function	O
in	O
several	O
contexts	O
does	O
not	O
require	O
AC	O
subunits	O
,	O
and	O
we	O
suggest	O
that	O
in	O
some	O
cases	O
they	O
may	O
have	O
negative	O
regulatory	O
roles	O
.	O

Negative	O
regulation	O
of	O
cytoplasmic	O
dynein	O
may	O
be	O
redundant	O
with	O
other	O
modes	O
of	O
HC	O
regulation	O
or	O
only	O
required	O
during	O
special	O
circumstances	O
.	O

Further	O
studies	O
of	O
subunit	O
localization	O
,	O
and	O
in	O
vitro	O
studies	O
of	O
C	B
.	I
elegans	I
dynein	O
motility	O
,	O
may	O
provide	O
further	O
insight	O
into	O
the	O
modes	O
of	O
AC	O
regulation	O
and	O
function	O
.	O

Materials	O
and	O
Methods	O

C	B
.	I
elegans	I
strains	O
and	O
culture	O
.	O

Strains	O
were	O
cultured	O
according	O
to	O
standard	O
procedures	O
[	O
28	O
]	O
.	O

ts	O
mutants	O
were	O
maintained	O
at	O
15	O
degrees	O
C	O
and	O
GFP	O
-	O
expressing	O
strains	O
in	O
a	O
wild	O
-	O
type	O
background	O
were	O
maintained	O
in	O
a	O
23	O
degrees	O
C	O
incubator	O
.	O

dhc	O
-	O
1	O
(	O
or195	O
)	O
was	O
outcrossed	O
six	O
times	O
to	O
the	O
N2	O
Bristol	O
wild	O
-	O
type	O
strain	O
and	O
the	O
or283	O
and	O
or352	O
dhc	O
-	O
1	O
mutants	O
were	O
each	O
outcrossed	O
four	O
times	O
with	O
N2	O
.	O

For	O
sequencing	O
mutant	O
dhc	O
-	O
1	O
loci	O
,	O
genomic	O
DNA	O
was	O
amplified	O
as	O
overlapping	O
~	O
1	O
-	O
kb	O
fragments	O
from	O
the	O
start	O
codon	O
to	O
the	O
stop	O
codon	O
and	O
sequenced	O
at	O
the	O
University	O
of	O
Oregon	O
DNA	O
sequencing	O
laboratory	O
.	O

For	O
double	O
mutant	O
constructions	O
,	O
the	O
dhc	O
-	O
1	O
(	O
or195	O
)	O
mutation	O
was	O
monitored	O
by	O
sequencing	O
or	O
by	O
assaying	O
a	O
restriction	O
fragment	O
length	O
polymorphism	O
caused	O
by	O
the	O
mutation	O
with	O
Hpy188I	O
(	O
New	O
England	O
Biolabs	O
,	O
http	O
:	O
/	O
/	O
www	O
.	O
neb	O
.	O
com	O
)	O
,	O
following	O
PCR	O
amplification	O
of	O
the	O
mutated	O
region	O
.	O

The	O
dylt	O
-	O
1	O
(	O
ok417	O
)	O
and	O
ufd	O
-	O
2	O
(	O
tm1380	O
)	O
alleles	O
were	O
monitored	O
by	O
PCR	O
amplification	O
of	O
genomic	O
sequence	O
encompassing	O
the	O
deletions	O
and	O
assaying	O
product	O
size	O
by	O
agarose	O
gel	O
electrophoresis	O
.	O

GFP	O
imaging	O
.	O

Visualization	O
of	O
GFP	O
fusion	O
protein	O
localization	O
was	O
accomplished	O
by	O
mounting	O
embryos	O
on	O
M9	O
+	O
3	O
%	O
agarose	O
pads	O
on	O
microscope	O
slides	O
covered	O
with	O
a	O
coverslip	O
.	O

Time	O
-	O
lapse	O
videos	O
were	O
obtained	O
on	O
a	O
spinning	O
disk	O
Nikon	O
Eclipse	O
TE2000	O
-	O
U	O
microscope	O
(	O
Nikon	O
Instruments	O
,	O
http	O
:	O
/	O
/	O
www	O
.	O
nikon	O
.	O
com	O
)	O
fitted	O
with	O
an	O
ORCA	O
-	O
ER	O
digital	O
camera	O
(	O
Hamamatsu	O
Photonics	O
,	O
http	O
:	O
/	O
/	O
www	O
.	O
hamamatsu	O
.	O
com	O
)	O
using	O
a	O
Nikon	O
60	O
x	O
,	O
1	O
.	O
4	O
NA	O
Plan	O
Apo	O
oil	O
objective	O
lens	O
.	O

Videos	O
were	O
adjusted	O
for	O
contrast	O
in	O
ImageJ	O
(	O
National	O
Institutes	O
of	O
Health	O
,	O
http	O
:	O
/	O
/	O
rsb	O
.	O
info	O
.	O
nih	O
.	O
gov	O
/	O
ij	O
/	O
)	O
[	O
76	O
]	O
,	O
images	O
were	O
adjusted	O
for	O
levels	O
in	O
Adobe	O
Photoshop	O
(	O
http	O
:	O
/	O
/	O
www	O
.	O
adobe	O
.	O
com	O
/	O
)	O
.	O

RNAi	O
screening	O
.	O

After	O
obtaining	O
the	O
E	B
.	I
coli	I
RNAi	O
library	O
from	O
the	O
MRC	O
Geneservice	O
(	O
Cambridge	O
,	O
UK	O
)	O
[	O
17	O
,	O
19	O
]	O
,	O
we	O
rearrayed	O
it	O
into	O
a	O
48	O
-	O
well	O
microplate	O
format	O
using	O
a	O
liquid	O
-	O
handling	O
Qiagen	O
BioRobot	O
8000	O
(	O
http	O
:	O
/	O
/	O
www	O
.	O
qiagen	O
.	O
com	O
)	O
.	O

E	B
.	I
coli	I
strains	O
were	O
thawed	O
from	O
-	O
80	O
degrees	O
C	O
storage	O
and	O
inoculated	O
into	O
1	O
ml	O
of	O
LB	O
+	O
100	O
mg	O
/	O
ml	O
ampicillin	O
-	O
containing	O
96	O
-	O
well	O
growth	O
plates	O
(	O
Whatman	O
,	O
http	O
:	O
/	O
/	O
www	O
.	O
whatman	O
.	O
com	O
)	O
and	O
covered	O
with	O
microporous	O
sealing	O
film	O
(	O
USA	O
Scientific	O
,	O
http	O
:	O
/	O
/	O
www	O
.	O
usascientific	O
.	O
com	O
)	O
.	O

Only	O
48	O
wells	O
of	O
the	O
96	O
-	O
well	O
growth	O
plates	O
were	O
filled	O
with	O
media	O
,	O
corresponding	O
to	O
the	O
rearrayed	O
E	B
.	I
coli	I
library	O
.	O

After	O
overnight	O
shaking	O
incubation	O
at	O
37	O
degrees	O
C	O
,	O
20	O
mu	O
l	O
of	O
the	O
cultures	O
were	O
dispensed	O
with	O
a	O
24	O
-	O
channel	O
electronic	O
repeating	O
pipette	O
(	O
Rainin	O
,	O
http	O
:	O
/	O
/	O
www	O
.	O
rainin	O
.	O
com	O
)	O
onto	O
48	O
-	O
well	O
plates	O
(	O
Nunc	O
,	O
http	O
:	O
/	O
/	O
www	O
.	O
nuncbrand	O
.	O
com	O
/	O
)	O
containing	O
NGM	O
agar	O
,	O
100	O
mu	O
g	O
/	O
ml	O
ampicillin	O
,	O
and	O
1	O
mM	O
IPTG	O
and	O
allowed	O
to	O
dry	O
and	O
induce	O
dsRNA	O
at	O
37	O
degrees	O
C	O
overnight	O
.	O

The	O
48	O
-	O
well	O
agar	O
plates	O
were	O
filled	O
with	O
a	O
Wheaton	O
Unispense	O
peristaltic	O
pump	O
(	O
http	O
:	O
/	O
/	O
www	O
.	O
wheaton	O
.	O
com	O
)	O
equipped	O
with	O
a	O
custom	O
-	O
made	O
adaptor	O
(	O
University	O
of	O
Oregon	O
Technical	O
Science	O
Administration	O
)	O
that	O
allowed	O
simultaneous	O
filling	O
of	O
eight	O
wells	O
with	O
the	O
agar	O
solution	O
.	O

Approximately	O
15	O
hypochlorite	O
-	O
synchronized	O
L1	O
mutant	O
larvae	O
were	O
pipetted	O
into	O
each	O
well	O
of	O
the	O
48	O
-	O
well	O
plates	O
with	O
a	O
multichannel	O
pipette	O
and	O
allowed	O
to	O
produce	O
broods	O
.	O

Screening	O
for	O
F1	O
viability	O
was	O
performed	O
by	O
visual	O
examination	O
with	O
a	O
dissecting	O
microscope	O
.	O

Phenotypes	O
were	O
recorded	O
on	O
an	O
Excel	O
spreadsheet	O
(	O
http	O
:	O
/	O
/	O
www	O
.	O
microsoft	O
.	O
com	O
)	O
and	O
organized	O
in	O
a	O
FileMaker	O
Pro	O
(	O
http	O
:	O
/	O
/	O
www	O
.	O
filemaker	O
.	O
com	O
)	O
database	O
.	O

We	O
qualitatively	O
identified	O
295	O
initial	O
positive	O
suppressing	O
E	B
.	I
coli	I
strains	O
,	O
for	O
which	O
we	O
repeated	O
the	O
assay	O
on	O
60	O
-	O
mm	O
plates	O
with	O
E	B
.	I
coli	I
again	O
thawed	O
from	O
the	O
library	O
(	O
not	O
streak	O
purified	O
)	O
.	O

If	O
the	O
observed	O
phenotypes	O
reproduced	O
,	O
the	O
assay	O
was	O
performed	O
with	O
three	O
streak	O
-	O
purified	O
E	B
.	I
coli	I
colonies	O
,	O
and	O
a	O
single	O
isolate	O
that	O
again	O
displayed	O
the	O
interaction	O
was	O
kept	O
for	O
further	O
analysis	O
.	O

Embryonic	O
viability	O
quantitation	O
methods	O
.	O

To	O
quantitate	O
embryonic	O
viability	O
we	O
used	O
the	O
following	O
procedure	O
.	O

Cultures	O
of	O
dsRNA	O
-	O
producing	O
bacteria	O
were	O
grown	O
overnight	O
in	O
LB	O
+	O
100	O
mu	O
g	O
/	O
ml	O
ampicillin	O
.	O

Cultures	O
(	O
0	O
.	O
2	O
ml	O
)	O
were	O
seeded	O
onto	O
60	O
-	O
mm	O
NGM	O
agar	O
plates	O
containing	O
100	O
mu	O
g	O
/	O
ml	O
ampicillin	O
and	O
1	O
mM	O
IPTG	O
and	O
allowed	O
to	O
induce	O
dsRNAs	O
overnight	O
at	O
room	O
temperature	O
.	O

The	O
L4440	O
control	O
vector	O
-	O
containing	O
strain	O
was	O
used	O
as	O
the	O
bacterial	O
lawn	O
for	O
the	O
experiments	O
shown	O
in	O
Figures	O
2A	O
and	O
3B	O
.	O

Approximately	O
80	O
synchronized	O
L1	O
larvae	O
(	O
obtained	O
from	O
hypochlorite	O
-	O
treated	O
worms	B
)	O
were	O
pipetted	O
onto	O
the	O
plates	O
and	O
allowed	O
to	O
grow	O
to	O
young	O
adulthood	O
.	O

Five	O
gravid	O
worms	B
were	O
transferred	O
to	O
prepared	O
NGM	O
agar	O
plates	O
supplemented	O
with	O
100	O
mu	O
g	O
/	O
ml	O
ampicillin	O
and	O
1	O
mM	O
IPTG	O
containing	O
a	O
small	O
RNAi	O
bacterial	O
lawn	O
produced	O
from	O
~	O
5	O
mu	O
l	O
of	O
overnight	O
E	B
.	I
coli	I
culture	O
.	O

After	O
producing	O
broods	O
,	O
the	O
adult	O
worms	B
were	O
removed	O
and	O
the	O
embryos	O
were	O
allowed	O
to	O
develop	O
for	O
at	O
least	O
24	O
h	O
.	O

Embryos	O
and	O
larvae	O
were	O
then	O
counted	O
immediately	O
or	O
after	O
storage	O
at	O
4	O
degrees	O
C	O
.	O

We	O
considered	O
only	O
suppressor	O
dsRNAs	O
that	O
increased	O
embryonic	O
viability	O
greater	O
than	O
3	O
-	O
fold	O
above	O
the	O
background	O
viability	O
observed	O
with	O
the	O
L4440	O
control	O
vector	O
(	O
in	O
the	O
dhc	O
-	O
1	O
(	O
or195	O
)	O
)	O
screen	O
to	O
be	O
significant	O
enough	O
for	O
continued	O
study	O
.	O

Molecular	O
biology	O
.	O

We	O
introduced	O
a	O
polylinker	O
site	O
containing	O
six	O
unique	O
restriction	O
enzyme	O
recognition	O
sites	O
into	O
the	O
pIC26	O
GFP	O
-	O
S	O
protein	O
plasmid	O
by	O
using	O
phosphorylated	O
and	O
PAGE	O
-	O
purified	O
synthetic	O
oligonucleotides	O
[	O
77	O
]	O
.	O

Following	O
ligation	O
,	O
the	O
new	O
plasmid	O
was	O
sequence	O
verified	O
.	O

The	O
modified	O
vector	O
,	O
pSO26	O
,	O
allows	O
the	O
use	O
of	O
additional	O
restriction	O
enzymes	O
and	O
directional	O
cloning	O
for	O
inserting	O
genes	O
of	O
interest	O
(	O
Figure	O
S2	O
)	O
.	O

The	O
SpeI	O
site	O
was	O
recreated	O
at	O
the	O
5	O
'	O
end	O
of	O
the	O
polylinker	O
but	O
not	O
at	O
the	O
3	O
'	O
end	O
.	O

We	O
amplified	O
N2	O
genomic	O
DNA	O
or	O
cDNA	O
(	O
Invitrogen	O
,	O
http	O
:	O
/	O
/	O
www	O
.	O
invitrogen	O
.	O
com	O
)	O
with	O
Pfu	O
Turbo	O
polymerase	O
(	O
Stratagene	O
,	O
http	O
:	O
/	O
/	O
www	O
.	O
stratagene	O
.	O
com	O
)	O
,	O
and	O
cloned	O
A	O
-	O
tailed	O
PCR	O
products	O
into	O
either	O
pGEM	O
-	O
T	O
or	O
pGEM	O
-	O
T	O
-	O
easy	O
shuttle	O
vectors	O
(	O
Promega	O
,	O
http	O
:	O
/	O
/	O
www	O
.	O
promega	O
.	O
com	O
)	O
.	O

Inserted	O
genes	O
were	O
sequence	O
verified	O
at	O
the	O
University	O
of	O
Oregon	O
DNA	O
sequencing	O
laboratory	O
prior	O
to	O
cleavage	O
and	O
ligation	O
to	O
pSO26	O
(	O
see	O
Table	O
S3	O
for	O
restriction	O
sites	O
and	O
primer	O
sequences	O
used	O
)	O
.	O

All	O
of	O
the	O
constructs	O
used	O
in	O
this	O
study	O
were	O
cloned	O
as	O
SpeI	O
-	O
AsiSI	O
or	O
AscI	O
-	O
AsiSI	O
fragments	O
,	O
except	O
for	O
the	O
STAR	O
-	O
2	O
gene	O
,	O
which	O
was	O
amplified	O
as	O
a	O
SpeI	O
fragment	O
and	O
cloned	O
into	O
pIC26	O
.	O

To	O
construct	O
dynein	O
subunit	O
dsRNA	O
-	O
expressing	O
plasmids	O
not	O
available	O
in	O
the	O
RNAi	O
library	O
,	O
gene	O
fragments	O
were	O
amplified	O
from	O
N2	O
genomic	O
DNA	O
with	O
the	O
following	O
primers	O
:	O
F41G4	O
.	O
1	O
:	O
5	O
'	O
-	O
AAGATATCACCCAAAATGGT	O
-	O
3	O
'	O
and	O
5	O
'	O
-	O
CGGATATCTCGACTGAAGCT	O
-	O
3	O
'	O
,	O
xbx	O
-	O
1	O
:	O
5	O
'	O
-	O
AAGATATCTACGACGATGGA	O
-	O
3	O
'	O
and	O
5	O
'	O
-	O
CGGATATCCGTGCCTCTGCA	O
-	O
3	O
'	O
,	O
dlc	O
-	O
3	O
:	O
5	O
'	O
-	O
AAGATATCAATTTCAGGTGG	O
-	O
3	O
'	O
and	O
5	O
'	O
-	O
CGGATATCAGCACACTTGCA	O
-	O
3	O
'	O
.	O

The	O
PCR	O
products	O
were	O
cut	O
with	O
EcoRV	O
,	O
ligated	O
to	O
EcoRV	O
-	O
digested	O
L4440	O
,	O
and	O
sequence	O
verified	O
.	O

Isolation	O
of	O
transgenic	O
worms	B
.	O

GFP	O
fusion	O
plasmids	O
were	O
bombarded	O
into	O
unc	O
-	O
119	O
(	O
ed3	O
)	O
worms	B
as	O
previously	O
described	O
except	O
with	O
the	O
following	O
two	O
changes	O
[	O
78	O
]	O
.	O

Three	O
milligrams	O
of	O
gold	O
particles	O
were	O
used	O
per	O
hepta	O
adaptor	O
bombardment	O
.	O

Also	O
,	O
we	O
briefly	O
sonicated	O
the	O
gold	O
particles	O
(	O
prior	O
to	O
DNA	O
coating	O
and	O
while	O
suspended	O
in	O
50	O
%	O
glycerol	O
)	O
with	O
a	O
Branson	O
sonifier	O
450	O
(	O
http	O
:	O
/	O
/	O
www	O
.	O
sonifier	O
.	O
com	O
/	O
)	O
fitted	O
with	O
a	O
small	O
tip	O
set	O
to	O
power	O
level	O
1	O
,	O
to	O
disrupt	O
gold	O
aggregates	O
.	O

Non	O
-	O
Unc	O
worms	B
were	O
picked	O
to	O
new	O
plates	O
and	O
allowed	O
to	O
produce	O
broods	O
,	O
which	O
were	O
assayed	O
for	O
GFP	O
fluorescence	O
with	O
a	O
Zeiss	O
axioskop	O
microscope	O
(	O
http	O
:	O
/	O
/	O
www	O
.	O
zeiss	O
.	O
com	O
/	O
)	O
fitted	O
with	O
an	O
X	O
-	O
Cite	O
120	O
illumination	O
system	O
(	O
EXFO	O
life	O
sciences	O
,	O
Mississauga	O
,	O
Ontario	O
,	O
Canada	O
)	O
.	O

For	O
each	O
fluorescent	O
line	O
,	O
12	O
GFP	O
-	O
positive	O
worms	B
were	O
singled	O
to	O
new	O
plates	O
to	O
determine	O
if	O
the	O
constructs	O
were	O
integrated	O
or	O
were	O
carried	O
as	O
extrachromosomal	O
arrays	O
.	O

Supporting	O
Information	O

Accession	O
Numbers	O

The	O
National	O
Center	O
for	O
Biotechnology	O
Information	O
(	O
NCBI	O
)	O
database	O
(	O
http	O
:	O
/	O
/	O
www	O
.	O
ncbi	O
.	O
nlm	O
.	O
nih	O
.	O
gov	O
/	O
gquery	O
/	O
gquery	O
.	O
fcgi	O
?	O
itool	O
=	O
toolbar	O
)	O
accession	O
numbers	O
for	O
the	O
dhc	O
-	O
1	O
homologs	O
discussed	O
in	O
this	O
paper	O
are	O
C	B
.	I
elegans	I
,	O
NP	O
_	O
491363	O
;	O
Dictyostelium	B
discoideum	I
,	O
XP	O
_	O
643185	O
;	O
Drosophila	B
melanogaster	I
,	O
AAA60323	O
;	O
Homo	B
sapiens	I
,	O
NP	O
_	O
001367	O
;	O
Mus	B
musculus	I
,	O
NP	O
_	O
084514	O
;	O
Saccharomyces	B
cerevisiae	I
,	O
NP	O
_	O
012980	O
;	O
and	O
Schizosaccharomyces	B
pombe	I
,	O
NP	O
_	O
001018285	O
.	O

The	O
NCBI	O
accession	O
numbers	O
for	O
the	O
Drosophila	B
and	O
human	B
DYLT	O
-	O
1	O
and	O
DYRB	O
-	O
1	O
protein	O
homologues	O
,	O
respectively	O
,	O
are	O
Dlc90F	O
,	O
NP	O
_	O
477356	O
;	O
DYNLT3	O
,	O
NP	O
_	O
006511	O
;	O
DYNLRB1	O
,	O
NP	O
_	O
054902	O
;	O
and	O
robl	O
,	O
NP	O
_	O
523771	O
.	O

Identification	O
of	O
Two	O
Independent	O
Risk	O
Factors	O
for	O
Lupus	O
within	O
the	O
MHC	O
in	O
United	O
Kingdom	O
Families	O

Abstract	O

The	O
association	O
of	O
the	O
major	O
histocompatibility	O
complex	O
(	O
MHC	O
)	O
with	O
SLE	O
is	O
well	O
established	O
yet	O
the	O
causal	O
variants	O
arising	O
from	O
this	O
region	O
remain	O
to	O
be	O
identified	O
,	O
largely	O
due	O
to	O
inadequate	O
study	O
design	O
and	O
the	O
strong	O
linkage	O
disequilibrium	O
demonstrated	O
by	O
genes	O
across	O
this	O
locus	O
.	O

The	O
majority	O
of	O
studies	O
thus	O
far	O
have	O
identified	O
strong	O
association	O
with	O
classical	O
class	O
II	O
alleles	O
,	O
in	O
particular	O
HLA	O
-	O
DRB1	O
*	O
0301	O
and	O
HLA	O
-	O
DRB1	O
*	O
1501	O
.	O

Additional	O
associations	O
have	O
been	O
reported	O
with	O
class	O
III	O
alleles	O
;	O
specifically	O
,	O
complement	O
C4	O
null	O
alleles	O
and	O
a	O
tumor	O
necrosis	O
factor	O
promoter	O
SNP	O
(	O
TNF	O
-	O
308G	O
/	O
A	O
)	O
.	O

However	O
,	O
the	O
relative	O
effects	O
of	O
these	O
class	O
II	O
and	O
class	O
III	O
variants	O
have	O
not	O
been	O
determined	O
.	O

We	O
have	O
thus	O
used	O
a	O
family	O
-	O
based	O
approach	O
to	O
map	O
association	O
signals	O
across	O
the	O
MHC	O
class	O
II	O
and	O
class	O
III	O
regions	O
in	O
a	O
cohort	O
of	O
314	O
complete	O
United	O
Kingdom	O
Caucasian	O
SLE	O
trios	O
by	O
typing	O
tagging	O
SNPs	O
together	O
with	O
classical	O
typing	O
of	O
the	O
HLA	O
-	O
DRB1	O
locus	O
.	O

Using	O
TDT	O
and	O
conditional	O
regression	O
analyses	O
,	O
we	O
have	O
demonstrated	O
the	O
presence	O
of	O
two	O
distinct	O
and	O
independent	O
association	O
signals	O
in	O
SLE	O
:	O
HLA	O
-	O
DRB1	O
*	O
0301	O
(	O
nominal	O
p	O
=	O
4	O
.	O
9	O
x	O
10	O
-	O
8	O
,	O
permuted	O
p	O
<	O
0	O
.	O
0001	O
,	O
OR	O
=	O
2	O
.	O
3	O
)	O
and	O
the	O
T	O
allele	O
of	O
SNP	O
rs419788	O
(	O
nominal	O
p	O
=	O
4	O
.	O
3	O
x	O
10	O
-	O
8	O
,	O
permuted	O
p	O
<	O
0	O
.	O
0001	O
,	O
OR	O
=	O
2	O
.	O
0	O
)	O
in	O
intron	O
6	O
of	O
the	O
class	O
III	O
region	O
gene	O
SKIV2L	O
.	O

Assessment	O
of	O
genotypic	O
risk	O
demonstrates	O
a	O
likely	O
dominant	O
model	O
of	O
inheritance	O
for	O
HLA	O
-	O
DRB1	O
*	O
0301	O
,	O
while	O
rs419788	O
-	O
T	O
confers	O
susceptibility	O
in	O
an	O
additive	O
manner	O
.	O

Furthermore	O
,	O
by	O
comparing	O
transmitted	O
and	O
untransmitted	O
parental	O
chromosomes	O
,	O
we	O
have	O
delimited	O
our	O
class	O
II	O
signal	O
to	O
a	O
180	O
kb	O
region	O
encompassing	O
the	O
alleles	O
HLA	O
-	O
DRB1	O
*	O
0301	O
-	O
HLA	O
-	O
DQA1	O
*	O
0501	O
-	O
HLA	O
-	O
DQB1	O
*	O
0201	O
alone	O
.	O

Our	O
class	O
III	O
signal	O
importantly	O
excludes	O
independent	O
association	O
at	O
the	O
TNF	O
promoter	O
polymorphism	O
,	O
TNF	O
-	O
308G	O
/	O
A	O
,	O
in	O
our	O
SLE	O
cohort	O
and	O
provides	O
a	O
potentially	O
novel	O
locus	O
for	O
future	O
genetic	O
and	O
functional	O
studies	O
.	O

Systemic	O
lupus	O
erythematosus	O
(	O
SLE	O
/	O
lupus	O
)	O
is	O
a	O
complex	O
autoimmune	O
disease	O
in	O
which	O
the	O
body	O
'	O
s	O
immune	O
system	O
attacks	O
its	O
own	O
tissues	O
,	O
causing	O
inflammation	O
in	O
a	O
variety	O
of	O
different	O
organs	O
such	O
as	O
the	O
skin	O
,	O
joints	O
,	O
and	O
kidneys	O
.	O

The	O
cause	O
of	O
lupus	O
is	O
not	O
known	O
,	O
but	O
genes	O
play	O
a	O
significant	O
role	O
in	O
the	O
predisposition	O
to	O
disease	O
.	O

The	O
major	O
histocompatibility	O
complex	O
(	O
MHC	O
)	O
on	O
Chromosome	O
6	O
contains	O
at	O
least	O
100	O
different	O
genes	O
that	O
affect	O
the	O
immune	O
system	O
,	O
including	O
the	O
genes	O
with	O
the	O
strongest	O
effect	O
on	O
lupus	O
susceptibility	O
.	O

Despite	O
the	O
importance	O
of	O
the	O
MHC	O
in	O
SLE	O
,	O
the	O
identity	O
of	O
the	O
actual	O
genes	O
in	O
the	O
MHC	O
region	O
that	O
cause	O
SLE	O
has	O
remained	O
elusive	O
.	O

In	O
the	O
present	O
study	O
,	O
we	O
used	O
the	O
latest	O
set	O
of	O
genetic	O
markers	O
present	O
at	O
the	O
MHC	O
in	O
lupus	O
families	O
to	O
identify	O
the	O
actual	O
genes	O
that	O
affect	O
the	O
disease	O
.	O

To	O
our	O
knowledge	O
,	O
we	O
have	O
shown	O
for	O
the	O
first	O
time	O
that	O
two	O
separate	O
groups	O
of	O
genes	O
are	O
involved	O
in	O
SLE	O
.	O

One	O
group	O
of	O
genes	O
alters	O
how	O
the	O
immune	O
system	O
may	O
inappropriately	O
target	O
its	O
own	O
tissues	O
in	O
the	O
disease	O
.	O

How	O
the	O
second	O
set	O
of	O
genes	O
predisposes	O
to	O
SLE	O
is	O
the	O
subject	O
of	O
ongoing	O
study	O
.	O

Introduction	O

Since	O
the	O
early	O
1970s	O
,	O
the	O
human	B
major	O
histocompatibility	O
complex	O
(	O
MHC	O
)	O
has	O
been	O
shown	O
to	O
be	O
associated	O
with	O
a	O
number	O
of	O
autoimmune	O
,	O
inflammatory	O
,	O
and	O
infectious	O
diseases	O
,	O
and	O
it	O
continues	O
to	O
be	O
the	O
focus	O
of	O
intense	O
research	O
[	O
1	O
]	O
.	O

The	O
recently	O
defined	O
extended	O
MHC	O
(	O
xMHC	O
)	O
encompasses	O
7	O
.	O
6	O
Mb	O
of	O
genome	O
on	O
6p21	O
.	O
3	O
and	O
is	O
divided	O
into	O
five	O
subregions	O
from	O
telomere	O
to	O
centromere	O
:	O
extended	O
class	O
I	O
,	O
classical	O
class	O
I	O
,	O
classical	O
class	O
III	O
,	O
classical	O
class	O
II	O
,	O
and	O
extended	O
class	O
II	O
.	O

In	O
addition	O
,	O
the	O
MHC	O
contains	O
two	O
hypervariable	O
regions	O
,	O
the	O
RCCX	O
module	O
in	O
class	O
III	O
(	O
spanning	O
complement	O
C4	O
)	O
and	O
the	O
HLA	O
-	O
DRB	O
genes	O
in	O
class	O
II	O
,	O
that	O
both	O
exhibit	O
copy	O
number	O
polymorphism	O
.	O

Examination	O
of	O
the	O
sequence	O
across	O
the	O
extended	O
MHC	O
reveals	O
the	O
presence	O
of	O
421	O
genes	O
,	O
and	O
over	O
252	O
(	O
60	O
%	O
)	O
are	O
thought	O
to	O
be	O
expressed	O
[	O
2	O
]	O
.	O

Around	O
40	O
%	O
of	O
genes	O
expressed	O
within	O
the	O
classical	O
MHC	O
encode	O
proteins	O
with	O
putative	O
immunomodulatory	O
function	O
[	O
3	O
]	O
.	O

The	O
classical	O
class	O
I	O
and	O
class	O
II	O
loci	O
encode	O
the	O
human	B
leucocyte	O
antigen	O
(	O
HLA	O
)	O
proteins	O
involved	O
in	O
antigen	O
presentation	O
to	O
T	O
cells	O
,	O
initiating	O
the	O
adaptive	O
immune	O
response	O
.	O

The	O
class	O
III	O
region	O
contains	O
the	O
greatest	O
density	O
of	O
genes	O
in	O
the	O
genome	O
(	O
58	O
expressed	O
genes	O
)	O
,	O
which	O
are	O
often	O
found	O
in	O
functionally	O
related	O
clusters	O
[	O
2	O
]	O
.	O

A	O
major	O
obstacle	O
in	O
the	O
identification	O
of	O
disease	O
-	O
specific	O
causal	O
variants	O
within	O
the	O
MHC	O
has	O
been	O
the	O
strong	O
linkage	O
disequilibrium	O
(	O
LD	O
)	O
exhibited	O
by	O
certain	O
alleles	O
in	O
this	O
region	O
,	O
resulting	O
in	O
the	O
existence	O
of	O
long	O
-	O
range	O
,	O
conserved	O
,	O
extended	O
haplotypes	O
[	O
4	O
]	O
,	O
also	O
known	O
as	O
ancestral	O
haplotypes	O
[	O
5	O
]	O
,	O
sometimes	O
spanning	O
more	O
than	O
2	O
Mb	O
[	O
6	O
]	O
.	O

Thus	O
,	O
for	O
many	O
MHC	O
-	O
associated	O
diseases	O
,	O
it	O
has	O
only	O
been	O
possible	O
to	O
delimit	O
association	O
signals	O
to	O
a	O
particular	O
extended	O
haplotype	O
or	O
segment	O
of	O
one	O
.	O

Systemic	O
lupus	O
erythematosus	O
(	O
SLE	O
/	O
lupus	O
,	O
[	O
Online	O
Mendelian	O
Inheritance	O
in	O
Man	B
152700	O
,	O
http	O
:	O
/	O
/	O
www	O
.	O
ncbi	O
.	O
nlm	O
.	O
nih	O
.	O
gov	O
/	O
sites	O
/	O
entrez	O
?	O
db	O
=	O
OMIM	O
&	O
TabCmd	O
=	O
Limits	O
]	O
)	O
is	O
a	O
chronic	O
,	O
multi	O
-	O
system	O
autoimmune	O
disease	O
affecting	O
young	O
women	B
ten	O
times	O
more	O
commonly	O
than	O
men	B
.	O

The	O
worldwide	O
prevalence	O
of	O
SLE	O
is	O
estimated	O
at	O
between	O
12	O
and	O
124	O
cases	O
per	O
100	O
,	O
000	O
individuals	O
[	O
7	O
]	O
.	O

SLE	O
is	O
characterized	O
by	O
the	O
presence	O
of	O
pathogenic	O
autoantibodies	O
to	O
nuclear	O
and	O
cell	O
-	O
surface	O
antigens	O
that	O
show	O
affinity	O
maturation	O
.	O

The	O
consequent	O
immune	O
complexes	O
deposit	O
in	O
tissues	O
,	O
causing	O
inflammation	O
and	O
damage	O
.	O

It	O
is	O
well	O
established	O
that	O
there	O
is	O
a	O
complex	O
genetic	O
component	O
to	O
lupus	O
aetiology	O
,	O
with	O
hormonal	O
and	O
environmental	O
influences	O
also	O
contributing	O
to	O
disease	O
susceptibility	O
[	O
8	O
,	O
9	O
]	O
.	O

The	O
MHC	O
has	O
been	O
the	O
most	O
consistently	O
confirmed	O
genetic	O
risk	O
factor	O
for	O
SLE	O
,	O
and	O
multiple	O
different	O
genes	O
within	O
the	O
region	O
have	O
been	O
significantly	O
implicated	O
with	O
disease	O
susceptibility	O
.	O

For	O
example	O
,	O
hereditary	O
and	O
acquired	O
deficiencies	O
of	O
the	O
early	O
classical	O
complement	O
component	O
C4	O
,	O
located	O
within	O
the	O
MHC	O
class	O
III	O
locus	O
,	O
leads	O
to	O
a	O
lupus	O
-	O
like	O
syndrome	O
.	O

A	O
role	O
for	O
another	O
class	O
III	O
gene	O
,	O
tumour	O
necrosis	O
factor	O
alpha	O
(	O
TNF	O
)	O
,	O
in	O
SLE	O
was	O
suggested	O
following	O
the	O
observation	O
that	O
the	O
lupus	O
-	O
prone	O
New	O
Zealand	O
F1	O
mouse	B
hybrid	O
exhibits	O
constitutively	O
low	O
TNF	O
expression	O
[	O
10	O
]	O
.	O

Recently	O
,	O
the	O
development	O
of	O
antinuclear	O
antibodies	O
in	O
patients	B
treated	O
with	O
TNF	O
antagonists	O
has	O
also	O
stimulated	O
interest	O
in	O
the	O
possible	O
role	O
of	O
TNF	O
in	O
SLE	O
[	O
11	O
-	O
13	O
]	O
.	O

Murine	O
and	O
human	B
candidate	O
gene	O
studies	O
,	O
together	O
with	O
genome	O
-	O
wide	O
linkage	O
screens	O
,	O
provide	O
further	O
support	O
that	O
multiple	O
genetic	O
loci	O
,	O
including	O
the	O
mouse	B
MHC	O
complex	O
H2	O
and	O
the	O
human	B
MHC	O
locus	O
,	O
contribute	O
to	O
disease	O
susceptibility	O
[	O
14	O
-	O
17	O
]	O
.	O

It	O
should	O
be	O
noted	O
that	O
the	O
human	B
MHC	O
was	O
first	O
associated	O
with	O
SLE	O
in	O
1971	O
,	O
when	O
studies	O
demonstrated	O
that	O
lupus	O
probands	O
were	O
enriched	O
for	O
the	O
class	O
I	O
alleles	O
HL	O
-	O
A8	O
(	O
now	O
known	O
as	O
HLA	O
-	O
B8	O
)	O
and	O
HLA	O
-	O
W15	O
(	O
now	O
known	O
as	O
HLA	O
-	O
B15	O
)	O
when	O
compared	O
with	O
healthy	O
controls	O
[	O
18	O
,	O
19	O
]	O
.	O

Further	O
case	O
control	O
association	O
studies	O
were	O
small	O
,	O
performed	O
in	O
ethnically	O
diverse	O
populations	O
,	O
and	O
tested	O
only	O
a	O
small	O
number	O
of	O
the	O
classical	O
HLA	O
and	O
complement	O
C4	O
alleles	O
.	O

The	O
most	O
consistent	O
findings	O
reported	O
to	O
date	O
are	O
associations	O
with	O
the	O
class	O
II	O
alleles	O
HLA	O
-	O
DR2	O
(	O
DRB1	O
*	O
1501	O
)	O
and	O
HLA	O
-	O
DR3	O
(	O
DRB1	O
*	O
0301	O
)	O
and	O
their	O
respective	O
haplotypes	O
in	O
Caucasian	O
populations	O
.	O

The	O
complement	O
C4A	O
null	O
allele	O
(	O
C4A	O
*	O
Q0	O
)	O
has	O
shown	O
inconsistent	O
association	O
with	O
lupus	O
in	O
a	O
number	O
of	O
studies	O
-	O
-	O
a	O
situation	O
that	O
may	O
reflect	O
genetic	O
heterogeneity	O
in	O
disease	O
susceptibility	O
[	O
20	O
-	O
23	O
]	O
.	O

In	O
addition	O
,	O
a	O
recent	O
study	O
has	O
demonstrated	O
that	O
low	O
C4A	O
copy	O
number	O
is	O
a	O
risk	O
factor	O
for	O
lupus	O
in	O
a	O
European	O
American	O
cohort	O
[	O
24	O
]	O
.	O

However	O
,	O
the	O
C4A	O
null	O
allele	O
lies	O
on	O
the	O
lupus	O
-	O
associated	O
DR3	O
"	O
autoimmune	O
"	O
extended	O
haplotype	O
(	O
AH8	O
.	O
1	O
)	O
,	O
which	O
exhibits	O
extremely	O
strong	O
LD	O
[	O
6	O
]	O
.	O

It	O
therefore	O
remains	O
to	O
be	O
definitively	O
established	O
whether	O
this	O
locus	O
constitutes	O
a	O
distinct	O
susceptibility	O
allele	O
to	O
that	O
of	O
the	O
class	O
II	O
association	O
or	O
is	O
merely	O
in	O
LD	O
with	O
it	O
.	O

Similarly	O
,	O
certain	O
TNF	O
promoter	O
polymorphisms	O
,	O
including	O
the	O
much	O
-	O
studied	O
SNP	O
TNF	O
-	O
308G	O
/	O
A	O
,	O
have	O
shown	O
association	O
with	O
SLE	O
;	O
but	O
again	O
,	O
many	O
of	O
these	O
variants	O
are	O
carried	O
on	O
the	O
highly	O
conserved	O
8	O
.	O
1	O
ancestral	O
haplotype	O
,	O
thus	O
restricting	O
interpretation	O
of	O
these	O
data	O
.	O

In	O
2002	O
,	O
a	O
family	O
-	O
based	O
study	O
employing	O
microsatellites	O
as	O
surrogate	O
markers	O
for	O
HLA	O
-	O
DRB1	O
haplotypes	O
in	O
Caucasian	O
lupus	O
families	O
demonstrated	O
association	O
with	O
DR3	O
-	O
,	O
DR2	O
-	O
,	O
and	O
DR8	O
(	O
DRB1	O
*	O
0801	O
)	O
-	O
containing	O
haplotypes	O
.	O

In	O
that	O
study	O
,	O
Graham	O
and	O
colleagues	O
reported	O
that	O
,	O
taking	O
advantage	O
of	O
recombinant	O
chromosomes	O
,	O
the	O
disease	O
risk	O
region	O
could	O
be	O
limited	O
to	O
a	O
1	O
Mb	O
region	O
encompassing	O
classical	O
class	O
II	O
and	O
class	O
III	O
[	O
25	O
]	O
.	O

We	O
have	O
performed	O
a	O
medium	O
resolution	O
association	O
mapping	O
study	O
of	O
the	O
MHC	O
in	O
lupus	O
families	O
,	O
utilizing	O
a	O
combination	O
of	O
SNPs	O
and	O
four	O
-	O
digit	O
typing	O
at	O
the	O
HLA	O
-	O
DRB1	O
locus	O
in	O
order	O
to	O
anchor	O
haplotypes	O
.	O

Sixty	O
-	O
eight	O
SNPs	O
were	O
successfully	O
genotyped	O
across	O
a	O
2	O
.	O
4	O
Mb	O
region	O
of	O
the	O
MHC	O
,	O
from	O
the	O
class	O
I	O
locus	O
KIAA1949	O
to	O
the	O
class	O
II	O
gene	O
HLA	O
-	O
DPB2	O
,	O
in	O
314	O
UK	O
Caucasian	O
SLE	O
trios	O
.	O

We	O
used	O
these	O
data	O
to	O
perform	O
a	O
family	O
-	O
based	O
association	O
study	O
in	O
an	O
attempt	O
to	O
distinguish	O
the	O
relative	O
effects	O
of	O
the	O
class	O
II	O
and	O
class	O
III	O
regions	O
of	O
the	O
MHC	O
in	O
lupus	O
susceptibility	O
.	O

In	O
addition	O
,	O
we	O
employed	O
the	O
long	O
-	O
range	O
haplotype	O
test	O
to	O
search	O
for	O
the	O
presence	O
of	O
high	O
-	O
frequency	O
,	O
extended	O
haplotypes	O
indicative	O
of	O
recent	O
positive	O
selection	O
[	O
26	O
]	O
.	O

We	O
have	O
also	O
used	O
family	O
-	O
based	O
and	O
case	O
-	O
control	O
strategies	O
to	O
examine	O
genotypic	O
risk	O
at	O
HLA	O
-	O
DRB1	O
and	O
rs419788	O
.	O

Results	O

Association	O
Testing	O
of	O
HLA	O
-	O
DRB1	O
and	O
MHC	O
Region	O
SNPs	O

In	O
order	O
to	O
define	O
the	O
causal	O
variation	O
within	O
the	O
MHC	O
region	O
,	O
we	O
typed	O
314	O
complete	O
SLE	O
trios	O
for	O
the	O
HLA	O
-	O
DRB1	O
gene	O
as	O
well	O
as	O
for	O
86	O
SNPs	O
across	O
a	O
2	O
.	O
4	O
Mb	O
region	O
encompassing	O
the	O
HLA	O
class	O
I	O
locus	O
HLA	O
-	O
B	O
to	O
HLA	O
-	O
DPB2	O
.	O

High	O
-	O
quality	O
genotype	O
data	O
was	O
obtained	O
for	O
HLA	O
-	O
DRB1	O
and	O
68	O
MHC	O
SNPs	O
(	O
see	O
Table	O
S1	O
for	O
quality	O
control	O
data	O
)	O
.	O

Association	O
testing	O
of	O
the	O
HLA	O
-	O
DRB1	O
gene	O
revealed	O
a	O
significant	O
association	O
with	O
HLA	O
-	O
DRB1	O
*	O
0301	O
(	O
nominal	O
p	O
=	O
4	O
.	O
9	O
x	O
10	O
-	O
8	O
,	O
permuted	O
p	O
<	O
0	O
.	O
0001	O
,	O
T	O
:	O
U	O
=	O
129	O
:	O
55	O
)	O
in	O
our	O
lupus	O
cohort	O
(	O
Table	O
1	O
)	O
.	O

There	O
was	O
also	O
a	O
trend	O
for	O
under	O
transmission	O
of	O
the	O
HLA	O
-	O
DRB1	O
*	O
0701	O
allele	O
(	O
nominal	O
p	O
=	O
0	O
.	O
0013	O
,	O
T	O
:	O
U	O
42	O
:	O
77	O
)	O
;	O
however	O
,	O
this	O
association	O
was	O
no	O
longer	O
significant	O
after	O
correction	O
for	O
multiple	O
testing	O
as	O
determined	O
by	O
10	O
,	O
000	O
permutations	O
of	O
the	O
dataset	O
(	O
permuted	O
p	O
=	O
0	O
.	O
09	O
)	O
.	O

Furthermore	O
,	O
we	O
did	O
not	O
find	O
evidence	O
of	O
association	O
with	O
HLA	O
-	O
DRB1	O
*	O
1501	O
(	O
nominal	O
p	O
=	O
1	O
.	O
0	O
,	O
T	O
:	O
U	O
70	O
:	O
70	O
)	O
or	O
HLA	O
-	O
DRB1	O
*	O
0801	O
(	O
nominal	O
p	O
=	O
1	O
.	O
0	O
,	O
T	O
:	O
U	O
=	O
11	O
:	O
11	O
)	O
in	O
our	O
cohort	O
(	O
see	O
Table	O
S2	O
for	O
complete	O
HLA	O
-	O
DRB1	O
association	O
data	O
)	O
;	O
alleles	O
previously	O
suggested	O
by	O
microsatellite	O
typing	O
of	O
a	O
US	O
lupus	O
cohort	O
[	O
25	O
]	O
.	O

Association	O
testing	O
of	O
the	O
MHC	O
region	O
SNPs	O
also	O
identified	O
significant	O
evidence	O
of	O
association	O
to	O
SLE	O
(	O
Table	O
1	O
for	O
associated	O
markers	O
and	O
Table	O
S3	O
for	O
all	O
MHC	O
SNPs	O
)	O
.	O

The	O
SNP	O
with	O
the	O
most	O
significant	O
association	O
,	O
rs419788	O
(	O
nominal	O
p	O
=	O
4	O
.	O
3	O
x	O
10	O
-	O
8	O
,	O
permuted	O
p	O
<	O
0	O
.	O
0001	O
)	O
was	O
of	O
similar	O
strength	O
to	O
that	O
of	O
the	O
HLA	O
-	O
DRB1	O
*	O
0301	O
allele	O
,	O
with	O
odds	O
ratios	O
(	O
ORs	O
)	O
and	O
95	O
%	O
confidence	O
intervals	O
(	O
CIs	O
)	O
of	O
2	O
.	O
0	O
(	O
1	O
.	O
6	O
-	O
2	O
.	O
6	O
)	O
and	O
2	O
.	O
3	O
(	O
1	O
.	O
7	O
-	O
3	O
.	O
2	O
)	O
,	O
respectively	O
.	O

This	O
SNP	O
is	O
located	O
within	O
intron	O
6	O
of	O
the	O
class	O
III	O
gene	O
,	O
superkiller	O
viralicidic	O
activity	O
2	O
-	O
like	O
(	O
Saccharomyces	B
cerevisiae	I
)	O
(	O
SKIV2L	O
)	O
,	O
and	O
is	O
located	O
approximately	O
500	O
kb	O
telomeric	O
to	O
the	O
HLA	O
-	O
DRB1	O
gene	O
.	O

Of	O
the	O
other	O
12	O
SNPs	O
that	O
were	O
significantly	O
associated	O
with	O
SLE	O
(	O
nominal	O
p	O
=	O
4	O
.	O
0	O
x	O
10	O
-	O
4	O
to	O
2	O
.	O
5	O
x	O
10	O
-	O
7	O
;	O
permuted	O
p	O
=	O
0	O
.	O
03	O
to	O
<	O
0	O
.	O
0001	O
)	O
,	O
one	O
was	O
located	O
in	O
the	O
class	O
I	O
region	O
between	O
HLA	O
-	O
B	O
and	O
MICA	O
,	O
seven	O
were	O
located	O
in	O
the	O
class	O
III	O
region	O
,	O
and	O
four	O
were	O
situated	O
in	O
the	O
class	O
II	O
region	O
(	O
Table	O
1	O
;	O
Figure	O
S1	O
)	O
.	O

Specifically	O
,	O
the	O
seven	O
associated	O
class	O
III	O
SNPs	O
were	O
located	O
in	O
or	O
close	O
to	O
the	O
following	O
genes	O
:	O
the	O
TNF	O
promoter	O
,	O
BAT3	O
,	O
SLC44A4	O
,	O
EHMT2	O
,	O
TNXB	O
,	O
GPSM3	O
,	O
and	O
NOTCH4	O
.	O

One	O
of	O
the	O
four	O
class	O
II	O
associated	O
SNPs	O
was	O
close	O
to	O
HLA	O
-	O
DRA	O
,	O
two	O
were	O
between	O
HLA	O
-	O
DRB1	O
and	O
HLA	O
-	O
DQA1	O
and	O
one	O
was	O
in	O
intron	O
1	O
of	O
HLA	O
-	O
DQA1	O
.	O

The	O
correlation	O
between	O
all	O
68	O
SNPs	O
and	O
HLA	O
-	O
DRB1	O
in	O
our	O
UK	O
SLE	O
cohort	O
is	O
illustrated	O
in	O
Figure	O
1	O
.	O

The	O
markers	O
showing	O
significant	O
association	O
are	O
highlighted	O
.	O

Conditional	O
Analyses	O
Identify	O
Two	O
Independent	O
Association	O
Signals	O
in	O
the	O
MHC	O

In	O
order	O
to	O
establish	O
whether	O
the	O
two	O
most	O
associated	O
signals	O
identified	O
in	O
this	O
association	O
-	O
mapping	O
experiment	O
are	O
likely	O
to	O
represent	O
a	O
single	O
causal	O
allele	O
or	O
independent	O
risk	O
factors	O
,	O
we	O
first	O
examined	O
the	O
association	O
data	O
conditioned	O
upon	O
the	O
presence	O
of	O
the	O
HLA	O
-	O
DRB1	O
*	O
0301	O
allele	O
.	O

We	O
found	O
that	O
four	O
of	O
the	O
13	O
associated	O
SNPs	O
showed	O
evidence	O
of	O
signals	O
independent	O
of	O
HLA	O
-	O
DRB1	O
*	O
0301	O
in	O
our	O
dataset	O
,	O
the	O
strongest	O
of	O
which	O
was	O
rs419788	O
(	O
Table	O
1	O
)	O
.	O

We	O
therefore	O
conditioned	O
the	O
three	O
remaining	O
SNPs	O
(	O
rs2523589	O
,	O
rs1052486	O
,	O
and	O
rs605203	O
)	O
on	O
rs419788	O
to	O
assess	O
whether	O
these	O
signals	O
are	O
truly	O
independent	O
of	O
each	O
other	O
or	O
show	O
association	O
due	O
to	O
LD	O
with	O
rs419788	O
.	O

In	O
addition	O
,	O
we	O
included	O
HLA	O
-	O
DRB1	O
in	O
stepwise	O
conditional	O
regression	O
analyses	O
performed	O
on	O
the	O
SNPs	O
showing	O
association	O
independent	O
of	O
HLA	O
-	O
DRB1	O
(	O
unpublished	O
data	O
)	O
.	O

These	O
analyses	O
demonstrated	O
that	O
the	O
observed	O
association	O
signals	O
at	O
rs2523589	O
,	O
rs1052486	O
,	O
and	O
rs605203	O
were	O
predominantly	O
dependent	O
upon	O
the	O
association	O
at	O
rs419788	O
,	O
and	O
suggested	O
that	O
there	O
are	O
two	O
major	O
independent	O
association	O
signals	O
in	O
the	O
MHC	O
in	O
UK	O
SLE	O
:	O
HLA	O
-	O
DRB1	O
and	O
rs419788	O
.	O

The	O
independence	O
of	O
the	O
association	O
signals	O
at	O
HLA	O
-	O
DRB1	O
and	O
rs419788	O
is	O
further	O
supported	O
by	O
the	O
observation	O
that	O
there	O
is	O
only	O
modest	O
LD	O
between	O
these	O
two	O
(	O
r2	O
=	O
0	O
.	O
24	O
)	O
.	O

There	O
was	O
no	O
association	O
with	O
any	O
other	O
HLA	O
-	O
DRB1	O
allele	O
and	O
the	O
four	O
SNPs	O
independent	O
of	O
HLA	O
-	O
DRB1	O
*	O
0301	O
(	O
TRANSMIT	O
,	O
unpublished	O
data	O
)	O
.	O

The	O
association	O
of	O
the	O
tumour	O
necrosis	O
factor	O
gene	O
promoter	O
SNP	O
TNF	O
-	O
308G	O
/	O
A	O
with	O
SLE	O
is	O
lost	O
after	O
conditioning	O
for	O
HLA	O
-	O
DRB1	O
*	O
0301	O
in	O
our	O
cohort	O
.	O

If	O
we	O
perform	O
the	O
reverse	O
analysis	O
and	O
condition	O
HLA	O
-	O
DRB1	O
*	O
0301	O
on	O
the	O
presence	O
of	O
the	O
TNF	O
promoter	O
SNP	O
,	O
we	O
find	O
that	O
the	O
association	O
remains	O
,	O
confirming	O
that	O
our	O
TNF	O
association	O
is	O
secondary	O
to	O
that	O
of	O
HLA	O
-	O
DRB1	O
*	O
0301	O
.	O

Genotypic	O
Risk	O
for	O
Class	O
II	O
and	O
Class	O
III	O
Association	O
Signals	O

Having	O
established	O
independent	O
association	O
at	O
the	O
allelic	O
level	O
with	O
HLA	O
-	O
DRB1	O
*	O
0301	O
and	O
rs419788	O
-	O
T	O
in	O
our	O
UK	O
SLE	O
cohort	O
,	O
we	O
wanted	O
to	O
further	O
determine	O
the	O
genotypic	O
risk	O
conferred	O
by	O
these	O
variants	O
and	O
hence	O
gain	O
insight	O
into	O
their	O
underlying	O
mode	O
of	O
inheritance	O
in	O
lupus	O
.	O

We	O
used	O
case	O
-	O
control	O
and	O
family	O
-	O
based	O
analyses	O
to	O
assess	O
genotypic	O
risk	O
at	O
HLA	O
-	O
DRB1	O
,	O
while	O
the	O
family	O
-	O
based	O
test	O
alone	O
was	O
used	O
for	O
rs419788	O
.	O

Common	O
family	O
-	O
based	O
tests	O
of	O
LD	O
,	O
such	O
as	O
those	O
used	O
in	O
this	O
study	O
(	O
Genehunter	O
)	O
,	O
measure	O
transmission	O
distortion	O
based	O
on	O
allele	O
counts	O
rather	O
than	O
genotype	O
counts	O
;	O
the	O
former	O
has	O
been	O
shown	O
to	O
be	O
more	O
powerful	O
under	O
additive	O
models	O
,	O
while	O
the	O
latter	O
has	O
greater	O
power	O
under	O
recessive	O
or	O
dominant	O
genetic	O
models	O
[	O
27	O
]	O
.	O

The	O
genotype	O
-	O
pedigree	O
disequilibrium	O
test	O
(	O
geno	O
-	O
PDT	O
)	O
determines	O
LD	O
between	O
a	O
locus	O
genotype	O
and	O
disease	O
by	O
comparing	O
genotypes	O
that	O
are	O
transmitted	O
from	O
parent	O
to	O
proband	O
with	O
those	O
that	O
are	O
not	O
[	O
27	O
]	O
.	O

We	O
used	O
the	O
geno	O
-	O
PDT	O
to	O
assess	O
genotypic	O
risk	O
for	O
our	O
class	O
II	O
and	O
class	O
III	O
association	O
signals	O
:	O
HLA	O
-	O
DRB1	O
and	O
the	O
SNP	O
rs419788	O
.	O

In	O
the	O
case	O
-	O
control	O
analysis	O
for	O
HLA	O
-	O
DRB1	O
,	O
ORs	O
with	O
95	O
%	O
CI	O
were	O
calculated	O
and	O
Fisher	O
'	O
s	O
exact	O
test	O
employed	O
to	O
assess	O
statistically	O
significant	O
differences	O
between	O
HLA	O
-	O
DRB1	O
genotypes	O
in	O
lupus	O
probands	O
and	O
healthy	O
controls	O
.	O

For	O
HLA	O
-	O
DRB1	O
,	O
the	O
alleles	O
were	O
coded	O
as	O
follows	O
:	O
HLA	O
-	O
DRB1	O
*	O
0301	O
,	O
HLA	O
-	O
DRB1	O
*	O
1501	O
,	O
HLA	O
-	O
DRB1	O
*	O
X	O
where	O
X	O
represents	O
all	O
HLA	O
-	O
DRB1	O
alleles	O
other	O
than	O
HLA	O
-	O
DRB1	O
*	O
0301	O
,	O
and	O
HLA	O
-	O
DRB1	O
*	O
1501	O
.	O

We	O
included	O
HLA	O
-	O
DRB1	O
*	O
1501	O
in	O
the	O
analysis	O
,	O
even	O
though	O
we	O
find	O
no	O
allelic	O
association	O
in	O
our	O
cohort	O
,	O
because	O
previous	O
studies	O
have	O
shown	O
a	O
greater	O
risk	O
for	O
lupus	O
in	O
individuals	O
who	O
are	O
compound	O
heterozygotes	O
for	O
HLA	O
-	O
DRB1	O
*	O
0301	O
-	O
and	O
HLA	O
-	O
DRB1	O
*	O
1501	O
-	O
containing	O
haplotypes	O
[	O
25	O
,	O
28	O
]	O
.	O

Overall	O
the	O
results	O
are	O
consistent	O
with	O
a	O
dominant	O
effect	O
from	O
HLA	O
-	O
DRB1	O
*	O
0301	O
(	O
Table	O
2	O
)	O
and	O
a	O
dose	O
-	O
dependent	O
(	O
additive	O
)	O
effect	O
from	O
rs419788	O
-	O
T	O
(	O
Table	O
3	O
)	O
.	O

Specifically	O
,	O
both	O
case	O
-	O
control	O
and	O
geno	O
-	O
PDT	O
demonstrate	O
that	O
there	O
is	O
no	O
dose	O
-	O
dependent	O
increase	O
in	O
disease	O
risk	O
for	O
HLA	O
-	O
DRB1	O
*	O
0301	O
.	O

Rather	O
,	O
it	O
appears	O
that	O
the	O
presence	O
of	O
a	O
single	O
copy	O
of	O
HLA	O
-	O
DRB1	O
*	O
0301	O
alone	O
is	O
sufficient	O
to	O
increase	O
susceptibility	O
to	O
disease	O
.	O

Moreover	O
the	O
0301	O
/	O
X	O
genotypes	O
constitute	O
the	O
greatest	O
risk	O
in	O
our	O
cohort	O
rather	O
than	O
the	O
0301	O
/	O
1501	O
heterozygotes	O
.	O

Genotypes	O
containing	O
HLA	O
-	O
DRB1	O
*	O
1501	O
in	O
the	O
absence	O
of	O
HLA	O
-	O
DRB1	O
*	O
0301	O
revealed	O
no	O
significant	O
association	O
in	O
our	O
cohort	O
.	O

All	O
three	O
rs419788	O
genotypes	O
demonstrated	O
significant	O
association	O
in	O
our	O
lupus	O
families	O
(	O
Table	O
3	O
)	O
.	O

The	O
common	O
CC	O
genotype	O
was	O
significantly	O
under	O
transmitted	O
,	O
while	O
the	O
rare	O
T	O
allele	O
displayed	O
dose	O
-	O
dependent	O
over	O
transmission	O
to	O
lupus	O
probands	O
.	O

Characterization	O
of	O
HLA	O
-	O
DRB1	O
*	O
0301	O
Risk	O
Haplotype	O

Next	O
,	O
we	O
wanted	O
to	O
further	O
delimit	O
the	O
MHC	O
class	O
II	O
association	O
signal	O
that	O
we	O
have	O
detected	O
at	O
HLA	O
-	O
DRB1	O
.	O

We	O
used	O
phased	O
parental	O
genotype	O
data	O
to	O
compare	O
the	O
allelic	O
composition	O
of	O
HLA	O
-	O
DRB1	O
*	O
0301	O
-	O
bearing	O
haplotypes	O
that	O
were	O
transmitted	O
(	O
T	O
)	O
to	O
affected	O
probands	O
to	O
those	O
that	O
were	O
not	O
transmitted	O
(	O
or	O
untransmitted	O
,	O
UT	O
)	O
with	O
the	O
aim	O
of	O
identifying	O
differences	O
that	O
could	O
delineate	O
the	O
lupus	O
susceptibility	O
interval	O
(	O
s	O
)	O
arising	O
from	O
this	O
haplotype	O
(	O
summarized	O
in	O
Figures	O
2A	O
,	O
2B	O
,	O
and	O
S2	O
)	O
.	O

We	O
observed	O
a	O
striking	O
difference	O
between	O
transmitted	O
and	O
untransmitted	O
chromosomes	O
within	O
the	O
class	O
II	O
region	O
:	O
nearly	O
all	O
transmitted	O
HLA	O
-	O
DRB1	O
*	O
0301	O
haplotypes	O
(	O
99	O
%	O
)	O
are	O
identical	O
across	O
a	O
180	O
kb	O
region	O
defined	O
by	O
eight	O
SNPs	O
,	O
whereas	O
the	O
corresponding	O
region	O
within	O
untransmitted	O
HLA	O
-	O
DRB1	O
*	O
0301	O
haplotypes	O
exhibits	O
significant	O
recombination	O
.	O

These	O
data	O
strongly	O
suggest	O
the	O
existence	O
of	O
a	O
risk	O
haplotype	O
that	O
,	O
interestingly	O
,	O
contains	O
only	O
three	O
expressed	O
genes	O
:	O
HLA	O
-	O
DRB1	O
,	O
HLA	O
-	O
DQA1	O
,	O
and	O
HLA	O
-	O
DQB1	O
.	O

Furthermore	O
,	O
we	O
can	O
confidently	O
define	O
the	O
allelic	O
composition	O
of	O
this	O
risk	O
haplotype	O
,	O
as	O
these	O
three	O
genes	O
are	O
in	O
strong	O
LD	O
and	O
occur	O
in	O
one	O
common	O
haplotype	O
in	O
Caucasians	O
:	O
HLA	O
-	O
DRB1	O
*	O
0301	O
-	O
HLA	O
-	O
DQA1	O
*	O
0501	O
-	O
HLA	O
-	O
DQB1	O
*	O
0201	O
.	O

Thus	O
,	O
we	O
hypothesize	O
that	O
the	O
specific	O
combination	O
of	O
all	O
three	O
alleles	O
is	O
required	O
to	O
confer	O
disease	O
risk	O
in	O
lupus	O
or	O
that	O
disease	O
susceptibility	O
lies	O
with	O
either	O
HLA	O
-	O
DRB1	O
*	O
0301	O
or	O
the	O
HLA	O
-	O
DQ	O
alleles	O
.	O

We	O
do	O
not	O
have	O
sufficient	O
numbers	O
of	O
recombinant	O
chromosomes	O
in	O
this	O
risk	O
region	O
to	O
further	O
delimit	O
this	O
signal	O
:	O
2	O
/	O
176	O
(	O
1	O
.	O
1	O
%	O
)	O
transmitted	O
HLA	O
-	O
DRB1	O
*	O
0301	O
haplotypes	O
are	O
recombinant	O
at	O
HLA	O
-	O
DQA1	O
-	O
HLA	O
-	O
DQB1	O
;	O
3	O
/	O
178	O
(	O
1	O
.	O
7	O
%	O
)	O
transmitted	O
haplotypes	O
identical	O
across	O
HLA	O
-	O
DQA1	O
-	O
HLA	O
-	O
DQB1	O
do	O
not	O
possess	O
HLA	O
-	O
DRB1	O
*	O
0301	O
.	O

The	O
composite	O
relative	O
extended	O
haplotype	O
homozygosity	O
(	O
REHH	O
)	O
versus	O
frequency	O
plot	O
for	O
UK	O
SLE	O
;	O
Utah	O
residents	O
with	O
ancestry	O
from	O
northern	O
and	O
western	O
Europe	O
(	O
CEPH	O
)	O
;	O
and	O
Yoruba	O
in	O
Ibadan	O
,	O
Nigeria	O
(	O
Yoruba	O
)	O
populations	O
is	O
shown	O
in	O
Figure	O
3A	O
.	O

We	O
can	O
only	O
comment	O
on	O
evidence	O
for	O
positive	O
selection	O
in	O
CEPH	O
individuals	O
,	O
as	O
we	O
have	O
used	O
this	O
population	O
alone	O
to	O
assess	O
background	O
variation	O
on	O
Chromosome	O
6	O
.	O

The	O
SLE	O
and	O
Yoruba	O
cohorts	O
are	O
shown	O
for	O
comparative	O
purposes	O
.	O

We	O
find	O
no	O
evidence	O
of	O
positive	O
selection	O
for	O
HLA	O
-	O
DRB1	O
*	O
0301	O
in	O
the	O
CEPH	O
population	O
.	O

However	O
,	O
this	O
allele	O
is	O
enriched	O
in	O
our	O
lupus	O
cohort	O
(	O
21	O
%	O
of	O
parental	O
chromosomes	O
)	O
and	O
displays	O
greater	O
extended	O
homozygosity	O
when	O
compared	O
with	O
HLA	O
-	O
DRB1	O
*	O
0301	O
-	O
bearing	O
haplotypes	O
in	O
CEPH	O
and	O
Yoruba	O
.	O

Hence	O
,	O
the	O
HLA	O
-	O
DRB1	O
*	O
0301	O
allele	O
in	O
lupus	O
is	O
observed	O
as	O
an	O
outlier	O
on	O
the	O
plot	O
when	O
compared	O
to	O
background	O
variation	O
in	O
CEPH	O
.	O

These	O
data	O
support	O
our	O
previous	O
observations	O
(	O
outlined	O
above	O
)	O
of	O
the	O
highly	O
conserved	O
nature	O
of	O
HLA	O
-	O
DRB1	O
*	O
0301	O
haplotypes	O
in	O
lupus	O
.	O

In	O
addition	O
,	O
the	O
haplotype	O
bifurcation	O
plots	O
centered	O
on	O
HLA	O
-	O
DRB1	O
*	O
0301	O
for	O
UK	O
SLE	O
,	O
CEPH	O
,	O
and	O
Yoruba	O
populations	O
in	O
Figure	O
3B	O
illustrate	O
preservation	O
of	O
the	O
common	O
HLA	O
-	O
DRB1	O
*	O
0301	O
haplotype	O
in	O
CEPH	O
and	O
UK	O
SLE	O
,	O
while	O
that	O
seen	O
in	O
the	O
Yoruba	O
is	O
significantly	O
different	O
.	O

The	O
class	O
II	O
regions	O
of	O
all	O
three	O
populations	O
are	O
essentially	O
identical	O
across	O
our	O
chosen	O
SNPs	O
;	O
the	O
main	O
differences	O
lie	O
in	O
class	O
III	O
.	O

The	O
difference	O
in	O
African	O
populations	O
in	O
the	O
class	O
III	O
region	O
is	O
one	O
possible	O
explanation	O
for	O
the	O
lack	O
of	O
evidence	O
for	O
an	O
association	O
between	O
HLA	O
-	O
DRB1	O
*	O
0301	O
and	O
SLE	O
in	O
African	O
or	O
African	O
American	O
populations	O
.	O

However	O
,	O
HLA	O
-	O
DRB1	O
*	O
0301	O
has	O
a	O
lower	O
frequency	O
(	O
~	O
7	O
%	O
-	O
10	O
%	O
)	O
in	O
African	O
populations	O
compared	O
with	O
Europeans	O
(	O
~	O
13	O
%	O
)	O
,	O
and	O
the	O
number	O
of	O
HLA	O
association	O
studies	O
conducted	O
in	O
African	O
populations	O
is	O
very	O
limited	O
.	O

Characterization	O
of	O
Class	O
III	O
Region	O
Risk	O
Haplotype	O

Our	O
data	O
reveal	O
a	O
second	O
independent	O
signal	O
at	O
the	O
MHC	O
in	O
SLE	O
arising	O
from	O
the	O
T	O
allele	O
of	O
SNP	O
rs419788	O
in	O
intron	O
6	O
of	O
the	O
class	O
III	O
gene	O
,	O
SKIV2L	O
.	O

Further	O
evidence	O
supporting	O
the	O
independence	O
of	O
the	O
rs419788	O
-	O
T	O
and	O
HLA	O
-	O
DRB1	O
*	O
0301	O
alleles	O
is	O
provided	O
by	O
the	O
moderate	O
LD	O
between	O
these	O
two	O
variants	O
(	O
r2	O
=	O
0	O
.	O
24	O
)	O
coupled	O
with	O
our	O
data	O
demonstrating	O
that	O
only	O
47	O
%	O
of	O
rs419788	O
-	O
T	O
allele	O
-	O
bearing	O
haplotypes	O
contain	O
HLA	O
-	O
DRB1	O
*	O
0301	O
.	O

The	O
structure	O
and	O
composition	O
of	O
T	O
and	O
UT	O
haplotypes	O
anchored	O
at	O
rs419788	O
-	O
T	O
were	O
essentially	O
identical	O
(	O
Figures	O
2C	O
,	O
2D	O
,	O
and	O
S2	O
)	O
,	O
and	O
hence	O
not	O
informative	O
in	O
delimiting	O
our	O
class	O
III	O
signal	O
.	O

Therefore	O
,	O
we	O
examined	O
the	O
LD	O
structure	O
around	O
our	O
associated	O
class	O
III	O
SNP	O
to	O
better	O
define	O
our	O
disease	O
risk	O
interval	O
.	O

In	O
our	O
lupus	O
dataset	O
the	O
rs419788	O
-	O
T	O
allele	O
resides	O
on	O
three	O
of	O
seven	O
haplotypes	O
present	O
within	O
a	O
large	O
block	O
of	O
six	O
SNPs	O
exhibiting	O
strong	O
LD	O
.	O

This	O
haplotype	O
block	O
encompasses	O
roughly	O
270	O
kb	O
containing	O
class	O
III	O
genes	O
from	O
SLC44A4	O
to	O
AGER	O
,	O
including	O
the	O
RCCX	O
module	O
.	O

Next	O
,	O
we	O
analyzed	O
the	O
haplotype	O
block	O
structure	O
of	O
this	O
region	O
in	O
CEPH	O
families	O
using	O
SNP	O
data	O
dumped	O
from	O
the	O
International	O
HapMap	O
Project	O
(	O
http	O
:	O
/	O
/	O
www	O
.	O
hapmap	O
.	O
org	O
/	O
)	O
.	O

The	O
greater	O
density	O
of	O
SNP	O
typing	O
available	O
in	O
the	O
HapMap	O
CEPH	O
population	O
compared	O
to	O
our	O
current	O
UK	O
SLE	O
map	O
allowed	O
us	O
to	O
potentially	O
refine	O
our	O
signal	O
by	O
exploring	O
correlations	O
between	O
our	O
associated	O
SNP	O
and	O
those	O
surrounding	O
it	O
.	O

Analysis	O
of	O
these	O
data	O
(	O
Figure	O
4	O
)	O
suggests	O
the	O
presence	O
of	O
short	O
-	O
range	O
LD	O
around	O
our	O
associated	O
variant	O
,	O
rs419788	O
,	O
in	O
CEPH	O
families	O
,	O
encompassing	O
approximately	O
40	O
kb	O
of	O
the	O
genome	O
which	O
includes	O
the	O
five	O
genes	O
:	O
complement	O
factor	O
B	O
(	O
CFB	O
)	O
,	O
RD	O
RNA	O
binding	O
protein	O
(	O
RDBP	O
)	O
,	O
SKIV2L	O
,	O
dom	O
-	O
3	O
homolg	O
Z	O
(	O
C	B
.	I
elegans	I
)	O
(	O
DOM3Z	O
)	O
,	O
and	O
serine	O
/	O
threonine	O
kinase	O
19	O
(	O
STK19	O
)	O
,	O
and	O
does	O
not	O
include	O
the	O
complement	O
C4	O
locus	O
.	O

Furthermore	O
,	O
assessment	O
of	O
marker	O
association	O
in	O
our	O
lupus	O
dataset	O
demonstrates	O
that	O
after	O
conditioning	O
for	O
HLA	O
-	O
DRB1	O
*	O
0301	O
,	O
the	O
only	O
markers	O
that	O
retain	O
association	O
signals	O
are	O
telomeric	O
of	O
SKIV2L	O
,	O
suggesting	O
that	O
complement	O
C4	O
,	O
which	O
is	O
centromeric	O
to	O
this	O
gene	O
,	O
may	O
not	O
be	O
responsible	O
for	O
our	O
independent	O
class	O
III	O
signal	O
.	O

Subphenotype	O
Analysis	O

In	O
order	O
to	O
gain	O
further	O
insight	O
into	O
disease	O
pathogenesis	O
,	O
we	O
examined	O
common	O
lupus	O
subphenotypes	O
.	O

Such	O
subsets	O
are	O
more	O
homogeneous	O
than	O
lupus	O
per	O
se	O
and	O
thus	O
maybe	O
enriched	O
for	O
specific	O
predisposing	O
variants	O
.	O

In	O
addition	O
,	O
one	O
might	O
expect	O
a	O
close	O
association	O
between	O
MHC	O
class	O
II	O
alleles	O
and	O
autoantibody	O
subsets	O
in	O
lupus	O
if	O
these	O
are	O
indeed	O
causal	O
variants	O
,	O
given	O
their	O
role	O
in	O
antigen	O
presentation	O
and	O
subsequent	O
humoral	O
immunity	O
.	O

We	O
therefore	O
tested	O
our	O
two	O
main	O
MHC	O
association	O
signals	O
,	O
HLA	O
-	O
DRB1	O
*	O
0301	O
and	O
rs419788	O
,	O
for	O
association	O
with	O
renal	O
disease	O
and	O
autoantibody	O
subsets	O
in	O
our	O
lupus	O
cohort	O
.	O

We	O
found	O
that	O
HLA	O
-	O
DRB1	O
*	O
0301	O
was	O
associated	O
with	O
the	O
presence	O
of	O
anti	O
-	O
Ro	O
and	O
anti	O
-	O
La	O
antibodies	O
in	O
our	O
UK	O
SLE	O
cohort	O
,	O
with	O
the	O
latter	O
showing	O
the	O
greatest	O
evidence	O
of	O
association	O
(	O
anti	O
-	O
La	O
nominal	O
p	O
<	O
0	O
.	O
001	O
compared	O
with	O
anti	O
-	O
Ro	O
nominal	O
p	O
<	O
0	O
.	O
025	O
)	O
.	O

We	O
found	O
no	O
association	O
of	O
HLA	O
-	O
DRB1	O
*	O
0301	O
with	O
renal	O
disease	O
or	O
any	O
other	O
autoantibody	O
subsets	O
in	O
our	O
dataset	O
(	O
see	O
Table	O
S4	O
for	O
detailed	O
results	O
)	O
.	O

Genotypes	O
of	O
the	O
SNP	O
rs419788	O
were	O
not	O
associated	O
with	O
any	O
of	O
the	O
tested	O
lupus	O
subphenotypes	O
after	O
controlling	O
for	O
the	O
effect	O
of	O
HLA	O
-	O
DRB1	O
*	O
0301	O
(	O
unpublished	O
data	O
)	O
.	O

Discussion	O

We	O
present	O
the	O
first	O
family	O
-	O
based	O
SNP	O
association	O
study	O
of	O
the	O
MHC	O
in	O
SLE	O
.	O

We	O
have	O
genotyped	O
69	O
markers	O
(	O
HLA	O
-	O
DRB1	O
and	O
68	O
SNPs	O
)	O
across	O
2	O
.	O
4	O
Mb	O
of	O
the	O
MHC	O
,	O
encompassing	O
class	O
III	O
and	O
class	O
II	O
,	O
in	O
a	O
cohort	O
of	O
314	O
UK	O
Caucasian	O
SLE	O
trios	O
.	O

Transmission	O
disequilibrium	O
testing	O
of	O
these	O
data	O
has	O
shown	O
predominant	O
association	O
with	O
the	O
alleles	O
HLA	O
-	O
DRB1	O
*	O
0301	O
and	O
rs419788	O
-	O
T	O
,	O
together	O
with	O
12	O
other	O
MHC	O
SNPs	O
.	O

Moreover	O
,	O
using	O
conditional	O
analyses	O
,	O
we	O
have	O
shown	O
that	O
the	O
two	O
primary	O
signals	O
of	O
association	O
at	O
the	O
MHC	O
are	O
independent	O
of	O
each	O
other	O
.	O

Specifically	O
,	O
one	O
signal	O
arises	O
from	O
HLA	O
-	O
DRB1	O
*	O
0301	O
in	O
class	O
II	O
and	O
the	O
other	O
from	O
the	O
T	O
allele	O
of	O
SNP	O
rs419788	O
in	O
the	O
class	O
III	O
gene	O
SKIV2L	O
.	O

Examination	O
of	O
bifurcation	O
plots	O
for	O
T	O
and	O
UT	O
HLA	O
-	O
DRB1	O
*	O
0301	O
-	O
containing	O
haplotypes	O
has	O
enabled	O
delineation	O
of	O
our	O
class	O
II	O
association	O
signal	O
to	O
a	O
180	O
kb	O
region	O
encompassing	O
HLA	O
-	O
DRB1	O
*	O
0301	O
-	O
HLA	O
-	O
DQA1	O
*	O
0501	O
-	O
HLA	O
-	O
DQB1	O
*	O
0201	O
.	O

These	O
data	O
substantially	O
refine	O
that	O
previously	O
published	O
by	O
Graham	O
et	O
al	O
.	O
in	O
2002	O
[	O
25	O
]	O
,	O
where	O
the	O
lupus	O
susceptibility	O
interval	O
within	O
HLA	O
-	O
DRB1	O
*	O
0301	O
-	O
containing	O
haplotypes	O
could	O
only	O
be	O
delimited	O
to	O
a	O
1	O
Mb	O
region	O
encompassing	O
class	O
II	O
and	O
class	O
III	O
.	O

The	O
precise	O
causal	O
variant	O
(	O
s	O
)	O
within	O
this	O
region	O
remains	O
to	O
be	O
determined	O
,	O
as	O
the	O
three	O
implicated	O
alleles	O
exhibit	O
strong	O
LD	O
with	O
few	O
recombination	O
events	O
separating	O
them	O
(	O
two	O
out	O
of	O
176	O
transmitted	O
HLA	O
-	O
DRB1	O
*	O
0301	O
chromosomes	O
in	O
our	O
dataset	O
)	O
.	O

However	O
,	O
all	O
three	O
allelic	O
variants	O
represent	O
attractive	O
functional	O
candidates	O
in	O
lupus	O
susceptibility	O
for	O
their	O
role	O
in	O
antigen	O
presentation	O
and	O
stimulation	O
of	O
the	O
adaptive	O
immune	O
response	O
.	O

Our	O
association	O
of	O
HLA	O
-	O
DRB1	O
*	O
0301	O
with	O
lupus	O
concurs	O
with	O
published	O
data	O
in	O
Caucasian	O
cohorts	O
and	O
is	O
well	O
established	O
[	O
16	O
]	O
.	O

While	O
our	O
lack	O
of	O
association	O
with	O
HLA	O
-	O
DRB1	O
*	O
1501	O
and	O
HLA	O
-	O
DRB1	O
*	O
0801	O
is	O
consistent	O
with	O
previous	O
data	O
from	O
the	O
UK	O
[	O
29	O
]	O
,	O
Spain	O
[	O
30	O
]	O
,	O
the	O
Netherlands	O
[	O
31	O
]	O
,	O
Sweden	O
[	O
32	O
]	O
,	O
Mexico	O
[	O
33	O
]	O
,	O
and	O
the	O
US	O
[	O
34	O
]	O
,	O
it	O
conflicts	O
with	O
that	O
of	O
other	O
US	O
groups	O
[	O
25	O
,	O
35	O
]	O
.	O

Interestingly	O
,	O
we	O
demonstrate	O
a	O
trend	O
,	O
though	O
not	O
statistically	O
significant	O
,	O
for	O
undertransmission	O
of	O
HLA	O
-	O
DRB1	O
*	O
0701	O
-	O
-	O
a	O
result	O
also	O
observed	O
in	O
prior	O
UK	O
and	O
Canadian	O
lupus	O
studies	O
[	O
29	O
,	O
36	O
]	O
.	O

Moreover	O
,	O
a	O
negative	O
association	O
of	O
HLA	O
-	O
DRB1	O
*	O
0701	O
has	O
been	O
reported	O
in	O
other	O
autoimmune	O
diseases	O
including	O
Graves	O
disease	O
[	O
37	O
,	O
38	O
]	O
,	O
type	O
1	O
diabetes	O
[	O
39	O
]	O
,	O
and	O
rheumatoid	O
arthritis	O
[	O
40	O
]	O
.	O

It	O
appears	O
that	O
the	O
conflicting	O
results	O
between	O
UK	O
SLE	O
and	O
previous	O
US	O
(	O
Minnesota	O
[	O
MN	O
]	O
)	O
[	O
25	O
]	O
SLE	O
data	O
stem	O
from	O
differences	O
in	O
HLA	O
-	O
DRB1	O
allele	O
frequency	O
in	O
the	O
probands	O
of	O
each	O
cohort	O
.	O

The	O
reason	O
for	O
this	O
is	O
unclear	O
.	O

A	O
comparison	O
between	O
UK	O
and	O
MN	O
SLE	O
cohorts	O
(	O
Table	O
4	O
)	O
reveals	O
that	O
UK	O
SLE	O
cases	O
are	O
enriched	O
for	O
HLA	O
-	O
DRB1	O
*	O
0301	O
but	O
not	O
HLA	O
-	O
DRB1	O
*	O
0801	O
or	O
HLA	O
-	O
DRB1	O
*	O
1501	O
when	O
compared	O
to	O
a	O
UK	O
control	O
population	O
.	O

In	O
contrast	O
,	O
MN	O
SLE	O
cases	O
are	O
enriched	O
for	O
HLA	O
-	O
DRB1	O
*	O
0301	O
-	O
DQB1	O
*	O
0201	O
,	O
DRB1	O
*	O
0801	O
-	O
DQB1	O
*	O
0402	O
,	O
and	O
DRB1	O
*	O
1501	O
-	O
DQB1	O
*	O
0602	O
inferred	O
haplotypes	O
when	O
compared	O
to	O
MN	O
controls	O
[	O
25	O
]	O
.	O

There	O
is	O
no	O
statistically	O
significant	O
difference	O
in	O
the	O
aforementioned	O
HLA	O
class	O
II	O
alleles	O
/	O
haplotypes	O
between	O
UK	O
and	O
MN	O
control	O
populations	O
that	O
could	O
account	O
for	O
the	O
disparity	O
seen	O
in	O
the	O
respective	O
lupus	O
cohorts	O
.	O

Differences	O
in	O
disease	O
severity	O
and	O
subphenotype	O
frequency	O
between	O
the	O
two	O
populations	O
could	O
account	O
for	O
the	O
observed	O
discrepancy	O
.	O

From	O
the	O
limited	O
data	O
available	O
we	O
found	O
that	O
the	O
presence	O
of	O
renal	O
disease	O
appears	O
to	O
be	O
similar	O
in	O
both	O
cohorts	O
(	O
UK	O
SLE	O
36	O
%	O
compared	O
with	O
MN	O
SLE	O
40	O
%	O
)	O
,	O
while	O
the	O
gender	O
ratios	O
are	O
significantly	O
different	O
(	O
female	O
:	O
male	O
UK	O
SLE	O
11	O
:	O
1	O
compared	O
with	O
MN	O
SLE	O
57	O
:	O
1	O
,	O
Chi	O
square	O
p	O
value	O
<	O
0	O
.	O
001	O
)	O
.	O

We	O
were	O
unable	O
to	O
compare	O
other	O
lupus	O
subphenotypes	O
.	O

Furthermore	O
,	O
closer	O
inspection	O
of	O
these	O
data	O
reveals	O
that	O
microsatellite	O
-	O
inference	O
of	O
HLA	O
-	O
DRB1	O
alleles	O
in	O
the	O
MN	O
SLE	O
dataset	O
may	O
underestimate	O
the	O
frequency	O
of	O
HLA	O
-	O
DRB1	O
*	O
0301	O
and	O
overestimate	O
that	O
of	O
HLA	O
-	O
DRB1	O
*	O
1501	O
,	O
thus	O
diminishing	O
the	O
effect	O
of	O
the	O
former	O
and	O
enhancing	O
that	O
of	O
the	O
latter	O
.	O

It	O
is	O
also	O
possible	O
that	O
the	O
MN	O
SLE	O
cohort	O
shows	O
greater	O
racial	O
heterogeneity	O
in	O
comparison	O
to	O
our	O
UK	O
SLE	O
cohort	O
,	O
despite	O
both	O
being	O
characterized	O
as	O
Caucasian	O
.	O

Previous	O
studies	O
have	O
demonstrated	O
increased	O
risk	O
for	O
lupus	O
in	O
individuals	O
carrying	O
particular	O
combinations	O
of	O
microsatellite	O
-	O
inferred	O
HLA	O
-	O
DRB1	O
-	O
HLA	O
-	O
DQB1	O
haplotypes	O
[	O
25	O
,	O
28	O
]	O
.	O

The	O
highest	O
risk	O
genotype	O
was	O
found	O
to	O
be	O
the	O
compound	O
heterozygote	O
HLA	O
-	O
DRB1	O
*	O
0301	O
-	O
DQB1	O
*	O
0201	O
/	O
HLA	O
-	O
DRB1	O
*	O
1501	O
-	O
DQB1	O
*	O
0602	O
,	O
while	O
HLA	O
-	O
DRB1	O
*	O
0301	O
-	O
DQB1	O
*	O
0201	O
-	O
containing	O
genotypes	O
demonstrated	O
a	O
dose	O
-	O
dependent	O
effect	O
in	O
increasing	O
lupus	O
susceptibility	O
[	O
25	O
,	O
28	O
]	O
.	O

In	O
the	O
present	O
study	O
,	O
we	O
have	O
examined	O
genotypic	O
risk	O
at	O
the	O
classically	O
typed	O
HLA	O
-	O
DRB1	O
locus	O
and	O
in	O
contrast	O
to	O
the	O
aforementioned	O
data	O
of	O
Graham	O
et	O
al	O
.	O

[	O
25	O
,	O
28	O
]	O
we	O
have	O
shown	O
a	O
likely	O
dominant	O
effect	O
of	O
the	O
associated	O
allele	O
,	O
HLA	O
-	O
DRB1	O
*	O
0301	O
.	O

The	O
case	O
-	O
control	O
and	O
family	O
-	O
based	O
analyses	O
for	O
HLA	O
-	O
DRB1	O
also	O
show	O
the	O
greater	O
power	O
of	O
the	O
former	O
to	O
detect	O
significant	O
association	O
(	O
Table	O
2	O
)	O
.	O

Specifically	O
,	O
all	O
genotypes	O
containing	O
HLA	O
-	O
DRB1	O
*	O
0301	O
show	O
increased	O
transmission	O
to	O
lupus	O
probands	O
;	O
however	O
,	O
homozygotes	O
show	O
no	O
greater	O
risk	O
compared	O
with	O
heterozygotes	O
,	O
as	O
would	O
be	O
expected	O
under	O
additive	O
or	O
multiplicative	O
models	O
.	O

Thus	O
,	O
a	O
dominant	O
model	O
of	O
inheritance	O
,	O
requiring	O
the	O
presence	O
of	O
a	O
single	O
copy	O
of	O
the	O
disease	O
-	O
predisposing	O
variant	O
alone	O
,	O
likely	O
underlies	O
the	O
susceptibility	O
conferred	O
by	O
HLA	O
-	O
DRB1	O
*	O
0301	O
in	O
UK	O
SLE	O
.	O

Such	O
a	O
model	O
would	O
fit	O
an	O
antigen	O
presentation	O
hypothesis	O
where	O
susceptible	O
individuals	O
carrying	O
an	O
HLA	O
-	O
DRB1	O
*	O
0301	O
allele	O
are	O
able	O
to	O
present	O
auto	O
-	O
antigens	O
to	O
CD4	O
+	O
lymphocytes	O
,	O
thus	O
stimulating	O
an	O
autoimmune	O
response	O
.	O

The	O
differences	O
between	O
our	O
UK	O
SLE	O
and	O
the	O
previously	O
published	O
US	O
SLE	O
data	O
may	O
reflect	O
disease	O
,	O
ethnic	O
,	O
and	O
haplotypic	O
heterogeneity	O
.	O

Interestingly	O
,	O
analysis	O
of	O
genotypic	O
risk	O
at	O
the	O
associated	O
class	O
III	O
marker	O
,	O
rs419788	O
,	O
suggests	O
an	O
additive	O
(	O
dose	O
-	O
dependent	O
)	O
pattern	O
of	O
inheritance	O
for	O
the	O
rare	O
T	O
allele	O
,	O
where	O
one	O
copy	O
confers	O
a	O
low	O
risk	O
of	O
disease	O
and	O
two	O
copies	O
results	O
in	O
greater	O
susceptibility	O
.	O

The	O
different	O
inheritance	O
patterns	O
for	O
our	O
class	O
II	O
and	O
class	O
III	O
association	O
signals	O
provide	O
further	O
evidence	O
for	O
their	O
independence	O
.	O

A	O
variety	O
of	O
HLA	O
-	O
DR	O
and	O
HLA	O
-	O
DQ	O
alleles	O
have	O
been	O
associated	O
with	O
autoantibody	O
subsets	O
in	O
ethnically	O
diverse	O
populations	O
of	O
lupus	O
.	O

The	O
strongest	O
associations	O
have	O
been	O
demonstrated	O
between	O
anti	O
-	O
Ro	O
and	O
anti	O
-	O
La	O
antibodies	O
and	O
HLA	O
-	O
DR3	O
and	O
HLA	O
-	O
DQ2	O
(	O
HLA	O
-	O
DQB1	O
*	O
0201	O
)	O
,	O
which	O
are	O
in	O
strong	O
LD	O
[	O
41	O
-	O
45	O
]	O
in	O
case	O
-	O
control	O
studies	O
.	O

Here	O
,	O
we	O
confirm	O
the	O
association	O
of	O
HLA	O
-	O
DRB1	O
*	O
0301	O
with	O
anti	O
-	O
Ro	O
and	O
anti	O
-	O
La	O
antibody	O
production	O
in	O
our	O
family	O
-	O
based	O
cohort	O
.	O

Examination	O
of	O
LD	O
structure	O
around	O
our	O
second	O
independent	O
association	O
,	O
rs419788	O
-	O
T	O
in	O
class	O
III	O
,	O
coupled	O
with	O
the	O
results	O
of	O
our	O
conditional	O
analysis	O
,	O
suggests	O
that	O
this	O
signal	O
could	O
also	O
be	O
delimited	O
to	O
a	O
relatively	O
narrow	O
genomic	O
interval	O
of	O
about	O
40	O
kb	O
given	O
further	O
SNP	O
mapping	O
in	O
our	O
cohort	O
.	O

This	O
region	O
includes	O
the	O
genes	O
CFB	O
,	O
RDBP	O
,	O
SKIV2L	O
,	O
DOM3Z	O
,	O
and	O
STK19	O
,	O
but	O
does	O
not	O
include	O
complement	O
C4	O
.	O

Thus	O
,	O
complement	O
C4	O
null	O
alleles	O
,	O
which	O
have	O
been	O
implicated	O
in	O
lupus	O
pathogenesis	O
,	O
may	O
not	O
be	O
responsible	O
for	O
our	O
class	O
III	O
signal	O
.	O

We	O
conclude	O
,	O
therefore	O
,	O
that	O
our	O
family	O
-	O
based	O
mapping	O
study	O
has	O
potentially	O
revealed	O
a	O
hitherto	O
unknown	O
lupus	O
susceptibility	O
interval	O
in	O
the	O
class	O
III	O
region	O
of	O
the	O
MHC	O
.	O

However	O
,	O
we	O
cannot	O
conclusively	O
exclude	O
association	O
at	O
complement	O
C4	O
/	O
RCCX	O
without	O
direct	O
determination	O
of	O
C4	O
polymorphism	O
/	O
copy	O
number	O
in	O
our	O
cohort	O
.	O

With	O
respect	O
to	O
the	O
genes	O
implicated	O
in	O
our	O
study	O
,	O
CFB	O
is	O
a	O
vital	O
component	O
of	O
the	O
alternate	O
complement	O
pathway	O
and	O
disregulation	O
may	O
clearly	O
affect	O
the	O
inflammatory	O
response	O
[	O
46	O
]	O
.	O

RD	O
and	O
Skiv2l	O
are	O
proteins	O
potentially	O
involved	O
in	O
RNA	O
processing	O
.	O

The	O
RD	O
protein	O
forms	O
part	O
of	O
a	O
negative	O
elongation	O
factor	O
(	O
NELF	O
)	O
complex	O
that	O
represses	O
RNA	O
polymerase	O
II	O
transcript	O
elongation	O
,	O
while	O
Skiv2l	O
is	O
a	O
DEAD	O
box	O
protein	O
with	O
possible	O
function	O
as	O
an	O
RNA	O
helicase	O
.	O

The	O
function	O
of	O
Dom3z	O
is	O
currently	O
unknown	O
,	O
although	O
the	O
homologous	O
yeast	B
protein	O
binds	O
nuclear	O
exoribonuclease	O
.	O

Moreover	O
,	O
its	O
ubiquitous	O
expression	O
suggests	O
a	O
housekeeping	O
role	O
.	O

STK19	O
is	O
a	O
protein	O
kinase	O
of	O
unknown	O
function	O
with	O
primary	O
nuclear	O
localization	O
[	O
47	O
]	O
.	O

Interestingly	O
,	O
RDBP	O
and	O
SKIV2L	O
are	O
found	O
to	O
be	O
highly	O
expressed	O
in	O
T	O
lymphocytes	O
,	O
B	O
lymphocytes	O
,	O
and	O
dendritic	O
cells	O
(	O
SymAtlas	O
,	O
http	O
:	O
/	O
/	O
symatlas	O
.	O
gnf	O
.	O
org	O
/	O
SymAtlas	O
/	O
)	O
.	O

A	O
number	O
of	O
studies	O
have	O
demonstrated	O
conflicting	O
evidence	O
for	O
and	O
against	O
association	O
with	O
various	O
TNF	O
locus	O
polymorphisms	O
in	O
SLE	O
[	O
48	O
]	O
.	O

A	O
recent	O
meta	O
-	O
analysis	O
of	O
the	O
TNF	O
-	O
308G	O
/	O
A	O
promoter	O
polymorphism	O
in	O
SLE	O
[	O
48	O
]	O
revealed	O
evidence	O
of	O
association	O
for	O
the	O
minor	O
allele	O
(	O
A	O
)	O
in	O
European	O
populations	O
;	O
however	O
,	O
this	O
study	O
did	O
not	O
account	O
for	O
LD	O
with	O
class	O
II	O
alleles	O
.	O

On	O
conditioning	O
our	O
dataset	O
for	O
HLA	O
-	O
DRB1	O
*	O
0301	O
,	O
we	O
find	O
that	O
the	O
TNF	O
promoter	O
signal	O
is	O
lost	O
,	O
suggesting	O
that	O
this	O
association	O
is	O
not	O
independent	O
and	O
is	O
due	O
to	O
LD	O
with	O
HLA	O
-	O
DRB1	O
*	O
0301	O
(	O
or	O
another	O
variant	O
in	O
LD	O
with	O
HLA	O
-	O
DRB1	O
*	O
0301	O
)	O
.	O

In	O
summary	O
,	O
we	O
have	O
found	O
association	O
with	O
two	O
distinct	O
and	O
independent	O
variants	O
within	O
the	O
class	O
II	O
(	O
HLA	O
-	O
DRB1	O
*	O
0301	O
)	O
and	O
class	O
III	O
(	O
SKIV2L	O
)	O
regions	O
of	O
the	O
MHC	O
in	O
UK	O
SLE	O
trios	O
.	O

We	O
can	O
delimit	O
our	O
class	O
II	O
signal	O
in	O
lupus	O
to	O
three	O
genetic	O
variants	O
(	O
HLA	O
-	O
DRB1	O
*	O
0301	O
-	O
HLA	O
-	O
DQA1	O
*	O
0501	O
-	O
HLA	O
-	O
DQB1	O
*	O
0201	O
)	O
that	O
may	O
confer	O
disease	O
risk	O
in	O
combination	O
or	O
as	O
separate	O
signals	O
.	O

Our	O
class	O
III	O
signal	O
importantly	O
excludes	O
independent	O
association	O
at	O
the	O
TNF	O
promoter	O
polymorphism	O
TNF	O
-	O
308G	O
/	O
A	O
and	O
potentially	O
provides	O
a	O
novel	O
locus	O
for	O
further	O
study	O
.	O

Materials	O
and	O
Methods	O

Study	O
cohorts	O
.	O

SLE	O
families	O
.	O

The	O
cohort	O
comprises	O
314	O
complete	O
SLE	O
trios	O
(	O
that	O
is	O
,	O
mother	O
,	O
father	O
,	O
and	O
affected	O
lupus	O
proband	O
)	O
collected	O
as	O
previously	O
described	O
[	O
49	O
]	O
.	O

All	O
study	O
participants	B
are	O
European	O
Caucasian	O
on	O
the	O
basis	O
of	O
grandparental	O
origin	O
.	O

All	O
314	O
lupus	O
probands	O
(	O
288	O
female	O
,	O
26	O
male	O
)	O
fulfill	O
the	O
revised	O
American	O
College	O
of	O
Rheumatology	O
(	O
ACR	O
)	O
criteria	O
for	O
SLE	O
[	O
50	O
]	O
,	O
36	O
%	O
of	O
whom	O
have	O
a	O
diagnosis	O
of	O
lupus	O
nephritis	O
.	O

Written	O
consent	O
was	O
obtained	O
from	O
all	O
study	O
participants	B
and	O
ethical	O
approval	O
for	O
this	O
study	O
was	O
obtained	O
from	O
the	O
Multi	O
-	O
Centre	O
Research	O
Ethics	O
Committee	O
(	O
MREC	O
2	O
June	O
1998	O
)	O
.	O

Healthy	O
controls	O
.	O

The	O
control	O
population	O
for	O
the	O
HLA	O
-	O
DRB1	O
genotypic	O
risk	O
case	O
-	O
control	O
analysis	O
constitutes	O
1	O
,	O
667	O
healthy	O
males	O
of	O
Northern	O
European	O
origin	O
.	O

The	O
individuals	O
are	O
potential	O
hematopoietic	O
stem	O
cell	O
donors	O
and	O
were	O
typed	O
to	O
four	O
digits	O
for	O
HLA	O
-	O
DRB1	O
at	O
the	O
Anthony	O
Nolan	O
Trust	O
,	O
UK	O
for	O
this	O
purpose	O
.	O

The	O
level	O
of	O
resolution	O
used	O
for	O
the	O
typing	O
of	O
HLA	O
-	O
DRB1	O
*	O
15	O
alleles	O
in	O
these	O
healthy	O
controls	O
resulted	O
in	O
the	O
ambiguous	O
allele	O
string	O
HLA	O
-	O
DRB1	O
*	O
1501	O
/	O
1502	O
/	O
1504	O
/	O
1506	O
.	O

However	O
,	O
it	O
is	O
likely	O
that	O
the	O
great	O
majority	O
are	O
HLA	O
-	O
DRB1	O
*	O
1501	O
.	O

There	O
is	O
no	O
gender	O
bias	O
in	O
HLA	O
-	O
DRB1	O
allele	O
frequencies	O
,	O
so	O
although	O
we	O
have	O
used	O
a	O
male	O
control	O
cohort	O
,	O
the	O
frequencies	O
would	O
be	O
expected	O
to	O
be	O
the	O
same	O
in	O
a	O
similar	O
female	O
cohort	O
(	O
Steven	O
Marsh	O
,	O
personal	O
communication	O
)	O
.	O

SNP	O
genotyping	O
.	O

Eighty	O
-	O
six	O
SNPs	O
were	O
chosen	O
for	O
genotyping	O
in	O
our	O
mapping	O
study	O
.	O

Specifically	O
,	O
we	O
selected	O
40	O
MHC	O
class	O
II	O
and	O
class	O
III	O
haplotype	O
tagging	O
SNPs	O
from	O
a	O
preliminary	O
MHC	O
SNP	O
map	O
[	O
51	O
]	O
that	O
had	O
previously	O
shown	O
robust	O
genotyping	O
efficacy	O
.	O

In	O
addition	O
,	O
we	O
typed	O
36	O
MHC	O
class	O
II	O
tag	O
SNPs	O
from	O
a	O
subsequent	O
high	O
-	O
resolution	O
MHC	O
study	O
[	O
52	O
]	O
.	O

We	O
also	O
included	O
the	O
TNF	O
-	O
308G	O
/	O
A	O
promoter	O
SNP	O
,	O
together	O
with	O
nine	O
further	O
SNPs	O
in	O
the	O
region	O
of	O
HLA	O
-	O
B	O
and	O
MICA	O
obtained	O
from	O
the	O
database	O
,	O
dbSNP	O
(	O
http	O
:	O
/	O
/	O
www	O
.	O
ncbi	O
.	O
nlm	O
.	O
nih	O
.	O
gov	O
/	O
projects	O
/	O
SNP	O
/	O
)	O
.	O

The	O
latter	O
SNPs	O
had	O
not	O
been	O
well	O
characterized	O
.	O

All	O
variants	O
were	O
typed	O
in	O
the	O
entire	O
cohort	O
(	O
n	O
=	O
942	O
)	O
.	O

The	O
SNPs	O
span	O
approximately	O
2	O
.	O
4	O
Mb	O
of	O
the	O
MHC	O
from	O
the	O
class	O
I	O
gene	O
,	O
KIAA1949	O
to	O
the	O
class	O
II	O
pseudogene	O
,	O
HLA	O
-	O
DPB2	O
and	O
thus	O
encompass	O
MHC	O
class	O
III	O
and	O
class	O
II	O
.	O

SNP	O
genotyping	O
was	O
performed	O
at	O
the	O
Broad	O
Institute	O
of	O
MIT	O
and	O
Harvard	O
and	O
at	O
Imperial	O
College	O
London	O
by	O
matrix	O
-	O
assisted	O
laser	O
desorption	O
/	O
ionisation	O
time	O
-	O
of	O
-	O
flight	O
(	O
MALDI	O
-	O
TOF	O
)	O
mass	O
spectrometry	O
using	O
the	O
Sequenom	O
MassARRAY	O
platform	O
as	O
previously	O
described	O
[	O
53	O
]	O
.	O

SNPs	O
that	O
failed	O
Sequenom	O
typing	O
were	O
retyped	O
by	O
KBiosciences	O
(	O
http	O
:	O
/	O
/	O
www	O
.	O
kbioscience	O
.	O
co	O
.	O
uk	O
/	O
)	O
using	O
their	O
in	O
-	O
house	O
SNP	O
genotyping	O
methodology	O
,	O
KASPar	O
(	O
http	O
:	O
/	O
/	O
www	O
.	O
kbioscience	O
.	O
co	O
.	O
uk	O
/	O
genotyping	O
/	O
index	O
.	O
htm	O
)	O
,	O
a	O
competitive	O
allele	O
-	O
specific	O
PCR	O
technique	O
.	O

HLA	O
-	O
DRB1	O
genotyping	O
.	O

HLA	O
-	O
DRB1	O
typing	O
was	O
performed	O
at	O
the	O
Anthony	O
Nolan	O
Trust	O
,	O
UK	O
.	O

All	O
samples	O
(	O
n	O
=	O
942	O
UK	O
SLE	O
trios	O
and	O
n	O
=	O
1	O
,	O
667	O
controls	O
)	O
were	O
genotyped	O
using	O
LABType	O
SSO	O
(	O
sequence	O
-	O
specific	O
oligonucleotide	O
)	O
typing	O
technology	O
according	O
to	O
the	O
manufacturer	O
'	O
s	O
written	O
recommendations	O
(	O
http	O
:	O
/	O
/	O
www	O
.	O
onelambda	O
.	O
com	O
)	O
.	O

Briefly	O
,	O
a	O
locus	O
-	O
specific	O
biotinylated	O
PCR	O
amplicon	O
is	O
produced	O
,	O
denatured	O
,	O
and	O
rehybridized	O
to	O
complementary	O
oligonucleotide	O
probes	O
conjugated	O
to	O
fluorescently	O
coded	O
beads	O
.	O

The	O
bound	O
biotinylated	O
PCR	O
product	O
can	O
be	O
detected	O
using	O
R	O
-	O
phycoerythrin	O
-	O
conjugated	O
streptavidin	O
.	O

A	O
flow	O
analyzer	O
identifies	O
the	O
fluorescent	O
intensity	O
of	O
phycoerythrin	O
on	O
each	O
bead	O
.	O

The	O
assignment	O
of	O
HLA	O
type	O
is	O
based	O
on	O
the	O
reaction	O
pattern	O
compared	O
to	O
patterns	O
associated	O
with	O
known	O
sequences	O
.	O

High	O
resolution	O
testing	O
was	O
performed	O
using	O
the	O
Dynal	O
AllSet	O
+	O
SSP	O
(	O
sequence	O
-	O
specific	O
primers	O
)	O
DRB1	O
assay	O
according	O
to	O
the	O
manufacturer	O
'	O
s	O
protocol	O
(	O
Invitrogen	O
)	O
for	O
SLE	O
families	O
only	O
.	O

The	O
presence	O
or	O
absence	O
of	O
PCR	O
amplification	O
was	O
detected	O
in	O
a	O
gel	O
electrophoresis	O
step	O
using	O
visualization	O
by	O
ethidium	O
bromide	O
incorporation	O
.	O

Genotypes	O
were	O
determined	O
using	O
SSPTool	O
software	O
.	O

Samples	O
that	O
could	O
not	O
be	O
resolved	O
to	O
four	O
digits	O
using	O
SSO	O
and	O
PCR	O
-	O
SSP	O
were	O
analyzed	O
by	O
DNA	O
sequencing	O
of	O
exon	O
2	O
of	O
HLA	O
-	O
DRB1	O
.	O

Primers	O
,	O
reagents	O
,	O
and	O
protocols	O
were	O
provided	O
by	O
The	O
Anthony	O
Nolan	O
Trust	O
,	O
UK	O
(	O
primer	O
sequences	O
are	O
available	O
on	O
request	O
)	O
.	O

Specific	O
HLA	O
-	O
DRB1	O
alleles	O
were	O
assigned	O
by	O
comparing	O
the	O
resultant	O
sequence	O
with	O
reference	O
sequence	O
from	O
the	O
IMGT	O
/	O
HLA	O
Database	O
[	O
54	O
]	O
.	O

Data	O
analysis	O
.	O

Mendelian	O
inconsistencies	O
were	O
removed	O
using	O
PedCheck	O
[	O
55	O
]	O
.	O

Families	O
in	O
which	O
more	O
than	O
eight	O
markers	O
demonstrated	O
Mendel	O
errors	O
were	O
removed	O
from	O
further	O
analysis	O
.	O

Markers	O
with	O
less	O
than	O
80	O
%	O
genotyping	O
efficiency	O
and	O
markers	O
where	O
more	O
than	O
eight	O
families	O
showed	O
Mendel	O
errors	O
were	O
also	O
excluded	O
from	O
analysis	O
.	O

Two	O
markers	O
located	O
within	O
the	O
SLE	O
associated	O
class	O
II	O
region	O
(	O
rs2239802	O
in	O
intron	O
4	O
of	O
HLA	O
-	O
DRA	O
and	O
rs6457594	O
in	O
the	O
region	O
between	O
HLA	O
-	O
DRB9	O
and	O
HLA	O
-	O
DRB5	O
)	O
show	O
deviation	O
from	O
Hardy	O
-	O
Weinberg	O
equilibrium	O
(	O
HWE	O
)	O
,	O
which	O
may	O
reflect	O
an	O
undetected	O
SLE	O
association	O
or	O
systematic	O
genotyping	O
error	O
.	O

HWE	O
was	O
assessed	O
in	O
parental	O
samples	O
in	O
our	O
cohort	O
.	O

There	O
is	O
currently	O
no	O
uniform	O
opinion	O
in	O
the	O
community	O
regarding	O
the	O
inclusion	O
or	O
exclusion	O
of	O
SNPs	O
that	O
show	O
deviation	O
from	O
HWE	O
,	O
hence	O
we	O
elected	O
to	O
include	O
these	O
markers	O
in	O
the	O
final	O
analysis	O
.	O

Sixty	O
-	O
eight	O
out	O
of	O
the	O
total	O
86	O
SNPs	O
passed	O
our	O
quality	O
-	O
control	O
measures	O
(	O
see	O
Table	O
S1	O
for	O
details	O
)	O
.	O

In	O
summary	O
,	O
one	O
SNP	O
was	O
monomorphic	O
in	O
our	O
dataset	O
,	O
four	O
SNPs	O
yielded	O
low	O
genotyping	O
efficiency	O
,	O
and	O
13	O
SNPs	O
were	O
excluded	O
for	O
unacceptable	O
Mendel	O
error	O
rate	O
.	O

The	O
mean	O
call	O
rate	O
for	O
all	O
markers	O
post	O
-	O
quality	O
control	O
was	O
94	O
%	O
(	O
range	O
83	O
%	O
to	O
99	O
%	O
)	O
.	O

Family	O
-	O
based	O
association	O
testing	O
was	O
performed	O
using	O
Genehunter	O
TDT	O
(	O
version	O
2	O
.	O
1	O
)	O
[	O
56	O
]	O
and	O
TRANSMIT	O
(	O
version	O
2	O
.	O
5	O
)	O
[	O
57	O
]	O
.	O

Haplotypes	O
were	O
constructed	O
and	O
permutation	O
testing	O
performed	O
using	O
Haploview	O
(	O
version	O
3	O
.	O
32	O
)	O
[	O
58	O
]	O
.	O

Significance	O
of	O
association	O
signals	O
in	O
all	O
analyses	O
was	O
based	O
on	O
permutation	O
testing	O
(	O
10	O
,	O
000	O
permutations	O
)	O
.	O

The	O
data	O
are	O
represented	O
both	O
as	O
nominal	O
and	O
permuted	O
p	O
values	O
.	O

ORs	O
with	O
95	O
%	O
CI	O
for	O
family	O
-	O
based	O
analyses	O
were	O
calculated	O
in	O
PLINK	O
(	O
http	O
:	O
/	O
/	O
pngu	O
.	O
mgh	O
.	O
harvard	O
.	O
edu	O
/	O
purcell	O
/	O
plink	O
/	O
)	O
[	O
59	O
]	O
.	O

Conditional	O
regression	O
analyses	O
were	O
undertaken	O
using	O
WHAP	O
[	O
60	O
]	O
.	O

The	O
geno	O
-	O
PDT	O
was	O
performed	O
using	O
PDT	O
version	O
5	O
.	O
1	O
with	O
default	O
settings	O
[	O
27	O
]	O
.	O

The	O
HLA	O
-	O
DRB1	O
alleles	O
were	O
coded	O
into	O
three	O
groups	O
for	O
the	O
geno	O
-	O
PDT	O
and	O
the	O
case	O
-	O
control	O
analysis	O
:	O
HLA	O
-	O
DRB1	O
*	O
0301	O
,	O
HLA	O
-	O
DRB1	O
*	O
1501	O
and	O
HLA	O
-	O
DRX	O
where	O
HLA	O
-	O
DRX	O
includes	O
all	O
HLA	O
-	O
DRB1	O
alleles	O
other	O
than	O
HLA	O
-	O
DRB1	O
*	O
0301	O
or	O
HLA	O
-	O
DRB1	O
*	O
1501	O
.	O

The	O
HLA	O
-	O
DRB1	O
*	O
1501	O
code	O
in	O
the	O
healthy	O
controls	O
represents	O
the	O
allele	O
string	O
HLA	O
-	O
DRB1	O
*	O
1501	O
/	O
1502	O
/	O
1504	O
/	O
1506	O
,	O
as	O
described	O
previously	O
.	O

The	O
HLA	O
-	O
DRB1	O
*	O
1501	O
code	O
in	O
the	O
lupus	O
probands	O
represents	O
the	O
alleles	O
HLA	O
-	O
DRB1	O
*	O
1501	O
(	O
84	O
out	O
of	O
91	O
*	O
1501	O
and	O
*	O
1502	O
alleles	O
)	O
and	O
HLA	O
-	O
DRB1	O
*	O
1502	O
(	O
7	O
/	O
91	O
*	O
1501	O
and	O
*	O
1502	O
alleles	O
)	O
,	O
as	O
*	O
1504	O
and	O
*	O
1506	O
were	O
not	O
present	O
in	O
this	O
population	O
.	O

Fisher	O
'	O
s	O
exact	O
test	O
was	O
used	O
to	O
assess	O
significance	O
of	O
association	O
in	O
the	O
case	O
-	O
control	O
analysis	O
.	O

Subphenotype	O
analysis	O
.	O

We	O
looked	O
for	O
association	O
of	O
the	O
HLA	O
-	O
DRB1	O
*	O
0301	O
allele	O
with	O
autoantibody	O
subsets	O
and	O
renal	O
disease	O
in	O
our	O
cohort	O
using	O
the	O
Chi	O
-	O
square	O
test	O
.	O

We	O
compared	O
cases	O
with	O
and	O
without	O
the	O
subphenotype	O
of	O
interest	O
with	O
DRB1	O
*	O
0301	O
homozygosity	O
,	O
heterozygosity	O
,	O
combined	O
homozygosity	O
and	O
heterozygosity	O
,	O
and	O
non	O
-	O
DRB1	O
*	O
0301	O
status	O
.	O

We	O
performed	O
the	O
same	O
analyses	O
for	O
homozygous	O
and	O
heterozygous	O
genotypes	O
of	O
the	O
associated	O
SNP	O
rs419788	O
.	O

The	O
autoantibody	O
subsets	O
compared	O
were	O
anti	O
-	O
C1q	O
,	O
IgG	O
,	O
and	O
IgM	O
anti	O
-	O
cardiolipin	O
antibodies	O
(	O
ACLG	O
and	O
ACLM	O
)	O
,	O
anti	O
-	O
Ro	O
,	O
anti	O
-	O
La	O
,	O
anti	O
-	O
RNP	O
,	O
anti	O
-	O
Sm	O
,	O
and	O
anti	O
-	O
dsDNA	O
.	O

Delineation	O
of	O
associated	O
MHC	O
haplotypes	O
and	O
evidence	O
for	O
positive	O
selection	O
.	O

We	O
looked	O
for	O
positively	O
selected	O
alleles	O
in	O
our	O
dataset	O
using	O
the	O
long	O
-	O
range	O
haplotype	O
test	O
as	O
measured	O
by	O
extended	O
haplotype	O
homozygosity	O
(	O
EHH	O
)	O
,	O
previously	O
described	O
by	O
Sabeti	O
et	O
al	O
.	O

[	O
26	O
]	O
.	O

Essentially	O
,	O
such	O
an	O
analysis	O
allows	O
assessment	O
of	O
positive	O
selection	O
by	O
mining	O
datasets	O
for	O
high	O
frequency	O
extended	O
haplotypes	O
in	O
comparison	O
to	O
the	O
other	O
core	O
haplotypes	O
at	O
a	O
locus	O
.	O

EHH	O
is	O
defined	O
as	O
the	O
probability	O
that	O
two	O
randomly	O
chosen	O
chromosomes	O
carrying	O
the	O
core	O
haplotype	O
of	O
interest	O
will	O
be	O
identical	O
by	O
descent	O
(	O
homozygosity	O
at	O
all	O
SNPs	O
)	O
for	O
the	O
entire	O
interval	O
from	O
the	O
core	O
to	O
a	O
distance	O
x	O
.	O

The	O
REHH	O
is	O
the	O
ratio	O
of	O
the	O
EHH	O
on	O
the	O
tested	O
core	O
haplotype	O
compared	O
with	O
the	O
combined	O
EHH	O
of	O
all	O
the	O
other	O
core	O
haplotypes	O
at	O
the	O
region	O
excluding	O
the	O
tested	O
core	O
;	O
as	O
such	O
,	O
REHH	O
accounts	O
for	O
local	O
variation	O
in	O
recombination	O
rate	O
while	O
EHH	O
does	O
not	O
[	O
26	O
]	O
.	O

The	O
program	O
emphase	O
was	O
employed	O
to	O
assign	O
the	O
phase	O
of	O
parental	O
genotype	O
data	O
and	O
reconstruct	O
missing	O
information	O
.	O

Emphase	O
is	O
a	O
simple	O
phaser	O
similar	O
to	O
the	O
phaser	O
of	O
Excoffier	O
and	O
Slatkin	O
[	O
61	O
]	O
.	O

It	O
is	O
very	O
fast	O
,	O
especially	O
on	O
large	O
datasets	O
,	O
and	O
sufficiently	O
accurate	O
for	O
most	O
genetic	O
applications	O
.	O

EHH	O
analysis	O
was	O
performed	O
on	O
the	O
phased	O
parental	O
data	O
using	O
the	O
software	O
program	O
SWEEP	O
(	O
http	O
:	O
/	O
/	O
www	O
.	O
broad	O
.	O
mit	O
.	O
edu	O
/	O
mpg	O
/	O
sweep	O
/	O
index	O
.	O
html	O
)	O
.	O

Haplotype	O
bifurcation	O
plots	O
.	O

We	O
represent	O
the	O
breakdown	O
of	O
LD	O
on	O
core	O
haplotypes	O
using	O
haplotype	O
bifurcation	O
diagrams	O
generated	O
in	O
the	O
program	O
TREE	O
[	O
62	O
]	O
(	O
also	O
explained	O
in	O
[	O
52	O
]	O
)	O
.	O

REHH	O
versus	O
frequency	O
plots	O
.	O

Fifty	O
-	O
three	O
SNPs	O
(	O
identified	O
in	O
Figure	O
1	O
)	O
are	O
common	O
to	O
our	O
dataset	O
and	O
the	O
CEPH	O
and	O
Yoruba	O
HapMap	O
[	O
63	O
]	O
populations	O
.	O

These	O
three	O
datasets	O
,	O
together	O
with	O
CEPH	O
SNP	O
data	O
for	O
Chromosome	O
6	O
in	O
its	O
entirety	O
,	O
were	O
used	O
to	O
generate	O
separate	O
REHH	O
versus	O
frequency	O
plots	O
in	O
SWEEP	O
.	O

The	O
plots	O
from	O
the	O
four	O
cohorts	O
were	O
combined	O
for	O
visual	O
,	O
not	O
statistical	O
,	O
comparison	O
.	O

Evidence	O
for	O
positive	O
selection	O
was	O
quantitatively	O
assessed	O
in	O
CEPH	O
individuals	O
,	O
as	O
this	O
population	O
alone	O
was	O
used	O
to	O
assess	O
background	O
variation	O
on	O
Chromosome	O
6	O
.	O

The	O
UK	O
SLE	O
and	O
Yoruba	O
cohort	O
data	O
are	O
shown	O
for	O
comparison	O
.	O

The	O
95th	O
percentile	O
based	O
on	O
total	O
CEPH	O
Chromosome	O
6	O
SNP	O
data	O
is	O
shown	O
.	O

Supporting	O
Information	O

Accession	O
Numbers	O

The	O
Online	O
Mendelian	O
Inheritance	O
in	O
Man	B
(	O
OMIM	O
,	O
http	O
:	O
/	O
/	O
www	O
.	O
ncbi	O
.	O
nlm	O
.	O
nih	O
.	O
gov	O
/	O
sites	O
/	O
entrez	O
?	O
db	O
=	O
omim	O
)	O
accession	O
numbers	O
for	O
the	O
genes	O
described	O
in	O
this	O
study	O
are	O
as	O
follows	O
:	O
AGER	O
,	O
600214	O
;	O
BAT3	O
,	O
142590	O
;	O
C4A	O
,	O
120810	O
;	O
C4B	O
,	O
120820	O
;	O
CFB	O
,	O
138470	O
;	O
DOM3Z	O
,	O
605996	O
;	O
DOM3Z	O
,	O
605996	O
;	O
EHMT2	O
,	O
604599	O
;	O
HLA	O
-	O
B	O
,	O
142830	O
;	O
HLA	O
-	O
DPB2	O
,	O
120290	O
;	O
HLA	O
-	O
DQA1	O
,	O
146880	O
;	O
HLA	O
-	O
DQB1	O
,	O
604305	O
;	O
HLA	O
-	O
DRA	O
,	O
142860	O
;	O
HLA	O
-	O
DRB1	O
,	O
142857	O
;	O
KIAA1949	O
,	O
610990	O
;	O
MICA	O
,	O
600169	O
;	O
NOTCH4	O
,	O
164951	O
;	O
RDBP	O
,	O
154040	O
;	O
RDBP	O
,	O
154040	O
;	O
SKIV2L	O
,	O
600478	O
;	O
SLC44A4	O
,	O
606107	O
;	O
STK19	O
,	O
604977	O
;	O
STK19	O
,	O
604977	O
;	O
TNF	O
,	O
191160	O
;	O
and	O
TNXB	O
,	O
600985	O
.	O

SuperCAT	O
:	O
a	O
supertree	O
database	O
for	O
combined	O
and	O
integrative	O
multilocus	O
sequence	O
typing	O
analysis	O
of	O
the	O
Bacillus	B
cereus	I
group	I
of	O
bacteria	O
(	O
including	O
B	B
.	I
cereus	I
,	O
B	B
.	I
anthracis	I
and	O
B	B
.	I
thuringiensis	I
)	O

Abstract	O

The	O
Bacillus	B
cereus	I
group	I
of	O
bacteria	O
is	O
an	O
important	O
group	O
including	O
mammalian	O
and	O
insect	O
pathogens	O
,	O
such	O
as	O
B	B
.	I
anthracis	I
,	O
the	O
anthrax	B
bacterium	O
,	O
B	B
.	I
thuringiensis	I
,	O
used	O
as	O
a	O
biological	O
pesticide	O
and	O
B	B
.	I
cereus	I
,	O
often	O
involved	O
in	O
food	O
poisoning	O
incidents	O
.	O

To	O
characterize	O
the	O
population	O
structure	O
and	O
epidemiology	O
of	O
these	O
bacteria	O
,	O
five	O
separate	O
multilocus	O
sequence	O
typing	O
(	O
MLST	O
)	O
schemes	O
have	O
been	O
developed	O
,	O
which	O
makes	O
results	O
difficult	O
to	O
compare	O
.	O

Therefore	O
,	O
we	O
have	O
developed	O
a	O
database	O
that	O
compiles	O
and	O
integrates	O
MLST	O
data	O
from	O
all	O
five	O
schemes	O
for	O
the	O
B	B
.	I
cereus	I
group	I
,	O
accessible	O
at	O
http	O
:	O
/	O
/	O
mlstoslo	O
.	O
uio	O
.	O
no	O
/	O
.	O

Supertree	O
techniques	O
were	O
used	O
to	O
combine	O
the	O
phylogenetic	O
information	O
from	O
analysis	O
of	O
all	O
schemes	O
and	O
datasets	O
,	O
in	O
order	O
to	O
produce	O
an	O
integrated	O
view	O
of	O
the	O
B	B
.	I
cereus	I
group	I
population	O
.	O

The	O
database	O
currently	O
contains	O
strain	O
information	O
and	O
sequence	O
data	O
for	O
1029	O
isolates	O
and	O
26	O
housekeeping	O
gene	O
fragments	O
,	O
which	O
can	O
be	O
searched	O
by	O
keywords	O
,	O
MLST	O
scheme	O
,	O
or	O
sequence	O
similarity	O
.	O

Supertrees	O
can	O
be	O
browsed	O
according	O
to	O
various	O
criteria	O
such	O
as	O
species	O
,	O
isolate	O
source	O
,	O
or	O
genetic	O
distance	O
,	O
and	O
subtrees	O
containing	O
strains	O
of	O
interest	O
can	O
be	O
extracted	O
.	O

Besides	O
analysis	O
of	O
the	O
available	O
data	O
,	O
the	O
user	O
has	O
the	O
possibility	O
to	O
enter	O
her	O
/	O
his	O
own	O
sequences	O
and	O
compare	O
them	O
to	O
the	O
database	O
and	O
/	O
or	O
include	O
them	O
into	O
the	O
supertree	O
reconstructions	O
.	O

INTRODUCTION	O

Multilocus	O
sequence	O
typing	O
(	O
MLST	O
)	O
is	O
a	O
tool	O
that	O
is	O
widely	O
used	O
for	O
phylogenetic	O
typing	O
of	O
bacteria	O
.	O

MLST	O
is	O
based	O
on	O
polymerase	O
chain	O
reaction	O
(	O
PCR	O
)	O
amplification	O
and	O
sequencing	O
of	O
internal	O
fragments	O
of	O
usually	O
seven	O
essential	O
or	O
housekeeping	O
genes	O
spread	O
around	O
the	O
bacterial	O
chromosome	O
.	O

The	O
genetic	O
relatedness	O
among	O
isolates	O
is	O
then	O
determined	O
by	O
comparison	O
of	O
the	O
nucleotide	O
sequence	O
types	O
(	O
1	O
,	O
2	O
)	O
.	O

MLST	O
is	O
thus	O
a	O
method	O
that	O
is	O
unambiguous	O
and	O
truly	O
portable	O
among	O
laboratories	O
.	O

Since	O
the	O
initial	O
development	O
of	O
this	O
technique	O
for	O
Neisseria	B
meningitidis	I
in	O
1998	O
,	O
MLST	O
schemes	O
have	O
been	O
developed	O
for	O
about	O
30	O
species	O
including	O
some	O
of	O
the	O
most	O
important	O
bacterial	O
pathogens	O
,	O
e	O
.	O
g	O
.	O
Streptococcus	B
pneumoniae	I
,	O
Streptococcus	B
pyogenes	I
,	O
Haemophilus	B
influenzae	I
,	O
Staphylococcus	B
aureus	I
,	O
Campylobacter	B
jejuni	I
,	O
Enterococcus	B
faecium	I
,	O
Burkholderia	B
pseudomallei	I
,	O
Escherichia	B
coli	I
,	O
Salmonella	B
enterica	I
and	O
the	O
Bacillus	B
cereus	I
group	I
(	O
see	O
(	O
1	O
)	O
for	O
a	O
recent	O
review	O
)	O
.	O

These	O
MLST	O
schemes	O
have	O
been	O
used	O
successfully	O
to	O
explore	O
the	O
population	O
structure	O
of	O
bacteria	O
,	O
to	O
study	O
the	O
evolution	O
of	O
their	O
virulence	O
properties	O
,	O
to	O
identify	O
antibiotic	O
-	O
resistant	O
strains	O
and	O
epidemic	O
clones	O
,	O
and	O
for	O
epidemiological	O
surveillance	O
.	O

The	O
B	B
.	I
cereus	I
group	I
includes	O
bacterial	O
species	O
that	O
are	O
of	O
medical	O
and	O
/	O
or	O
economic	O
importance	O
,	O
such	O
as	O
B	B
.	I
anthracis	I
,	O
an	O
obligate	O
mammalian	O
pathogen	O
causing	O
the	O
lethal	O
disease	O
anthrax	B
,	O
B	B
.	I
cereus	I
,	O
an	O
opportunistic	O
human	B
pathogen	O
involved	O
in	O
food	O
-	O
poisoning	O
incidents	O
and	O
contaminations	O
in	O
hospitals	O
,	O
B	B
.	I
thuringiensis	I
,	O
an	O
insect	O
pathogen	O
and	O
one	O
of	O
the	O
world	O
'	O
s	O
most	O
widely	O
used	O
biopesticide	O
and	O
B	B
.	I
weihenstephanensis	I
,	O
a	O
cold	O
-	O
tolerant	O
species	O
known	O
for	O
contaminating	O
dairies	O
.	O

These	O
species	O
are	O
genetically	O
very	O
closely	O
related	O
and	O
may	O
be	O
considered	O
as	O
one	O
species	O
based	O
on	O
genetic	O
and	O
genomic	O
evidence	O
(	O
3	O
-	O
5	O
)	O
.	O

Unlike	O
other	O
bacterial	O
species	O
that	O
are	O
typed	O
using	O
a	O
single	O
MLST	O
scheme	O
,	O
five	O
separate	O
schemes	O
have	O
been	O
developed	O
for	O
the	O
B	B
.	I
cereus	I
group	I
,	O
based	O
on	O
different	O
sets	O
of	O
genes	O
and	O
isolates	O
(	O
5	O
-	O
10	O
)	O
.	O

The	O
Priest	O
scheme	O
(	O
8	O
)	O
is	O
currently	O
the	O
most	O
widely	O
used	O
.	O

Studies	O
with	O
the	O
various	O
schemes	O
have	O
independently	O
indicated	O
that	O
the	O
B	B
.	I
cereus	I
group	I
population	O
is	O
divided	O
into	O
three	O
main	O
phylogenetic	O
clusters	O
and	O
that	O
species	O
are	O
usually	O
intermixed	O
within	O
the	O
groups	O
.	O

One	O
cluster	O
contains	O
the	O
monomorphic	O
B	B
.	I
anthracis	I
isolates	O
and	O
a	O
number	O
of	O
B	B
.	I
cereus	I
and	O
B	B
.	I
thuringiensis	I
strains	O
,	O
many	O
of	O
which	O
are	O
from	O
clinical	O
sources	O
.	O

A	O
second	O
heterogeneous	O
cluster	O
includes	O
B	B
.	I
cereus	I
and	O
B	B
.	I
thuringiensis	I
isolates	O
from	O
various	O
origins	O
,	O
while	O
cold	O
-	O
tolerant	O
B	B
.	I
weihenstephanensis	I
and	O
B	B
.	I
cereus	I
isolates	O
belong	O
to	O
the	O
third	O
group	O
.	O

The	O
separate	O
MLST	O
analyses	O
have	O
also	O
revealed	O
that	O
the	O
B	B
.	I
cereus	I
group	I
population	O
is	O
weakly	O
clonal	O
overall	O
due	O
to	O
numerous	O
clinical	O
and	O
virulent	O
isolates	O
emerging	O
from	O
different	O
phylogenetic	O
positions	O
(	O
5	O
-	O
8	O
,	O
11	O
-	O
14	O
)	O
,	O
with	O
the	O
exception	O
of	O
the	O
'	O
cold	O
-	O
tolerant	O
'	O
cluster	O
that	O
seems	O
to	O
exhibit	O
a	O
panmictic	O
(	O
or	O
sexual	O
)	O
population	O
structure	O
,	O
i	O
.	O
e	O
.	O
with	O
frequent	O
genetic	O
exchanges	O
between	O
strains	O
(	O
9	O
)	O
.	O

Despite	O
the	O
overall	O
congruence	O
between	O
the	O
various	O
MLST	O
studies	O
,	O
the	O
use	O
of	O
separate	O
schemes	O
with	O
no	O
gene	O
overlap	O
and	O
very	O
little	O
strain	O
overlap	O
has	O
produced	O
a	O
confusing	O
situation	O
and	O
makes	O
the	O
results	O
difficult	O
to	O
compare	O
directly	O
.	O

Therefore	O
,	O
we	O
recently	O
proposed	O
a	O
combined	O
scheme	O
based	O
on	O
genes	O
taken	O
from	O
three	O
of	O
the	O
four	O
schemes	O
available	O
by	O
then	O
and	O
for	O
which	O
we	O
created	O
a	O
web	O
-	O
based	O
database	O
accessible	O
at	O
the	O
University	O
of	O
Oslo	O
'	O
s	O
MLST	O
server	O
,	O
http	O
:	O
/	O
/	O
mlstoslo	O
.	O
uio	O
.	O
no	O
/	O
(	O
5	O
)	O
.	O

Here	O
,	O
in	O
order	O
to	O
provide	O
the	O
B	B
.	I
cereus	I
group	I
research	O
community	O
with	O
a	O
common	O
MLST	O
resource	O
,	O
we	O
have	O
developed	O
on	O
the	O
same	O
website	O
a	O
database	O
,	O
SuperCAT	O
,	O
that	O
compiles	O
and	O
integrates	O
MLST	O
data	O
from	O
all	O
the	O
published	O
B	B
.	I
cereus	I
group	I
schemes	O
.	O

In	O
addition	O
,	O
we	O
applied	O
supertree	O
reconstruction	O
methods	O
to	O
build	O
an	O
integrated	O
view	O
of	O
the	O
B	B
.	I
cereus	I
group	I
population	O
and	O
phylogeny	O
.	O

Below	O
we	O
describe	O
the	O
content	O
and	O
main	O
features	O
of	O
the	O
new	O
database	O
as	O
well	O
as	O
the	O
process	O
of	O
supertree	O
building	O
.	O

DATABASE	O
CONTENT	O
AND	O
IMPLEMENTATION	O

The	O
SuperCAT	O
database	O
provides	O
information	O
,	O
sequence	O
and	O
phylogenetic	O
data	O
for	O
all	O
bacterial	O
isolates	O
that	O
have	O
been	O
typed	O
using	O
any	O
of	O
the	O
five	O
published	O
MLST	O
schemes	O
for	O
the	O
B	B
.	I
cereus	I
group	I
(	O
Table	O
1	O
)	O
.	O

Strain	O
information	O
,	O
when	O
known	O
,	O
includes	O
isolate	O
description	O
,	O
source	O
and	O
geographical	O
location	O
of	O
isolation	O
,	O
and	O
the	O
scheme	O
(	O
s	O
)	O
used	O
for	O
typing	O
.	O

The	O
sequence	O
data	O
include	O
the	O
nucleotide	O
sequences	O
of	O
the	O
MLST	O
loci	O
examined	O
in	O
a	O
given	O
strain	O
.	O

SuperCAT	O
also	O
contains	O
the	O
phylogenetic	O
supertree	O
of	O
the	O
B	B
.	I
cereus	I
group	I
reconstructed	O
by	O
combining	O
the	O
sequence	O
data	O
from	O
all	O
five	O
schemes	O
,	O
as	O
well	O
as	O
supertrees	O
built	O
for	O
individual	O
schemes	O
.	O

Information	O
and	O
sequences	O
for	O
isolates	O
typed	O
by	O
the	O
Priest	O
and	O
Tourasse	O
-	O
Helgason	O
schemes	O
were	O
retrieved	O
from	O
the	O
databases	O
devoted	O
to	O
these	O
schemes	O
at	O
http	O
:	O
/	O
/	O
pubmlst	O
.	O
org	O
/	O
bcereus	O
and	O
http	O
:	O
/	O
/	O
mlstoslo	O
.	O
uio	O
.	O
no	O
/	O
,	O
respectively	O
.	O

MLST	O
data	O
for	O
additional	O
strains	O
not	O
available	O
in	O
the	O
pubmlst	O
.	O
org	O
repository	O
(	O
strains	O
from	O
(	O
15	O
)	O
are	O
missing	O
therein	O
)	O
and	O
for	O
the	O
Helgason	O
,	O
Ko	O
,	O
and	O
Candelon	O
-	O
Sorokin	O
schemes	O
were	O
taken	O
from	O
the	O
published	O
literature	O
and	O
the	O
Genbank	O
nucleotide	O
sequence	O
database	O
(	O
Table	O
1	O
)	O
.	O

In	O
addition	O
,	O
sequences	O
of	O
all	O
MLST	O
loci	O
were	O
extracted	O
from	O
the	O
complete	O
genomes	O
of	O
the	O
21	O
sequenced	O
B	B
.	I
cereus	I
group	I
strains	O
available	O
in	O
Genbank	O
.	O

Altogether	O
,	O
SuperCAT	O
currently	O
contains	O
data	O
for	O
1029	O
isolates	O
and	O
26	O
gene	O
fragments	O
from	O
25	O
different	O
genes	O
.	O

However	O
,	O
since	O
most	O
strains	O
have	O
been	O
typed	O
using	O
only	O
6	O
or	O
7	O
of	O
the	O
26	O
loci	O
,	O
about	O
one	O
-	O
third	O
of	O
the	O
complete	O
set	O
of	O
sequences	O
are	O
included	O
.	O

The	O
26	O
loci	O
,	O
only	O
available	O
for	O
the	O
completely	O
sequenced	O
strains	O
,	O
sum	O
up	O
to	O
10	O
619	O
bp	O
.	O

All	O
these	O
genes	O
are	O
located	O
on	O
the	O
chromosome	O
,	O
thus	O
the	O
database	O
provides	O
no	O
information	O
about	O
extrachromosomal	O
plasmids	O
even	O
though	O
most	O
of	O
the	O
strains	O
do	O
carry	O
one	O
or	O
several	O
small	O
and	O
/	O
or	O
large	O
plasmids	O
.	O

Unlike	O
scheme	O
-	O
specific	O
MLST	O
databases	O
,	O
SuperCAT	O
does	O
not	O
contain	O
allele	O
and	O
sequence	O
type	O
(	O
ST	O
)	O
numbers	O
.	O

Since	O
isolates	O
in	O
SuperCAT	O
have	O
been	O
typed	O
by	O
different	O
subsets	O
of	O
loci	O
,	O
complete	O
allelic	O
profiles	O
are	O
unavailable	O
and	O
therefore	O
STs	O
cannot	O
be	O
assigned	O
for	O
most	O
strains	O
,	O
except	O
the	O
fully	O
sequenced	O
ones	O
.	O

Table	O
1	O
.	O
The	O
five	O
MLST	O
schemes	O
designed	O
for	O
typing	O
bacteria	O
of	O
the	O
B	B
.	I
cereus	I
groupSchemeGenesTota	I
sequence	O
length	O
(	O
bp	O
)	O
Total	O
number	O
of	O
isolateseUsed	O
in	O
(	O
references	O
)	O
Helgasonadk	O
,	O
ccpA	O
,	O
ftsA	O
,	O
glpT	O
,	O
pyre	O
,	O
recF	O
and	O
sucC2	O
938120	O
(	O
6	O
,	O
12	O
,	O
46	O
)	O
Candelon	O
-	O
Sorokina	O
,	O
cclpC	O
,	O
dinB	O
,	O
gdpD	O
,	O
panC	O
,	O
purF	O
and	O
yhfL2	O
850149	O
(	O
9	O
,	O
10	O
)	O
Kob	O
,	O
cgyrB	O
,	O
mbl	O
,	O
mdh	O
,	O
mutS	O
,	O
pycA	O
(	O
1	O
)	O
and	O
rpoB2	O
00265	O
(	O
7	O
)	O
Priesta	O
,	O
bglpF	O
,	O
gmk	O
,	O
ilvD	O
,	O
pta	O
,	O
purH	O
,	O
pycA	O
(	O
2	O
)	O
and	O
tpi2	O
829721	O
(	O
8	O
,	O
11	O
,	O
13	O
-	O
15	O
,	O
46	O
-	O
48	O
)	O
Tourasse	O
-	O
Helgasona	O
,	O
b	O
,	O
dadk	O
,	O
ccpA	O
,	O
glpF	O
,	O
glpT	O
,	O
panC	O
,	O
pta	O
and	O
pycA	O
(	O
2	O
)	O
2	O
658172	O
(	O
5	O
)	O
aSpecific	O
databases	O
for	O
the	O
Priest	O
and	O
Tourasse	O
-	O
Helgason	O
schemes	O
are	O
accessible	O
at	O
http	O
:	O
/	O
/	O
pubmlst	O
.	O
org	O
/	O
bcereus	O
/	O
and	O
http	O
:	O
/	O
/	O
mlstoslo	O
.	O
uio	O
.	O
no	O
/	O
,	O
respectively	O
.	O

A	O
BLAST	O
database	O
for	O
the	O
Candelon	O
-	O
Sorokin	O
scheme	O
is	O
available	O
at	O
http	O
:	O
/	O
/	O
spock	O
.	O
jouy	O
.	O
inra	O
.	O
fr	O
/	O
cgi	O
-	O
bin	O
/	O
bacilliMLSopen	O
.	O
cgi	O
.	O
bWhile	O
the	O
Tourasse	O
-	O
Helgason	O
and	O
Priest	O
schemes	O
use	O
the	O
same	O
gene	O
fragment	O
for	O
the	O
pycA	O
gene	O
,	O
the	O
Ko	O
scheme	O
is	O
based	O
on	O
a	O
different	O
and	O
non	O
-	O
overlapping	O
gene	O
region	O
.	O
cThe	O
B	B
.	I
cereus	I
group	I
-	O
specific	O
transcriptional	O
regulator	O
plcR	O
was	O
originally	O
included	O
in	O
the	O
Candelon	O
-	O
Sorokin	O
and	O
Ko	O
schemes	O
.	O

However	O
,	O
plcR	O
follows	O
a	O
phylogeny	O
different	O
from	O
the	O
other	O
MLST	O
loci	O
(	O
7	O
,	O
10	O
)	O
and	O
is	O
no	O
longer	O
used	O
for	O
MLST	O
;	O
therefore	O
,	O
it	O
is	O
not	O
included	O
in	O
SuperCAT	O
.	O
dThe	O
Tourasse	O
-	O
Helgason	O
scheme	O
is	O
a	O
combined	O
scheme	O
based	O
on	O
3	O
genes	O
from	O
the	O
Helgason	O
scheme	O
(	O
adk	O
,	O
ccpA	O
,	O
and	O
glpT	O
)	O
,	O
3	O
genes	O
from	O
the	O
Priest	O
scheme	O
(	O
glpF	O
,	O
pta	O
and	O
pycA	O
(	O
2	O
)	O
)	O
,	O
and	O
the	O
panC	O
gene	O
from	O
the	O
Candelon	O
-	O
Sorokin	O
scheme	O
.	O
eIncluding	O
strains	O
with	O
fully	O
sequenced	O
genomes	O
.	O

SuperCAT	O
is	O
built	O
as	O
a	O
relational	O
database	O
using	O
the	O
PostgreSQL	O
management	O
system	O
,	O
and	O
data	O
are	O
accessible	O
through	O
a	O
graphical	O
web	O
interface	O
.	O

User	O
queries	O
and	O
results	O
pages	O
are	O
processed	O
and	O
created	O
on	O
-	O
the	O
-	O
fly	O
via	O
a	O
highly	O
modified	O
version	O
of	O
the	O
mlstdbNet	O
software	O
(	O
16	O
)	O
written	O
in	O
PERL	O
and	O
based	O
on	O
the	O
DataBase	O
Interface	O
(	O
DBI	O
)	O
and	O
Common	O
Gateway	O
Interface	O
(	O
CGI	O
)	O
modules	O
.	O

The	O
database	O
is	O
implemented	O
on	O
a	O
Linux	O
Apache	O
web	O
server	O
maintained	O
through	O
the	O
facilities	O
and	O
support	O
provided	O
by	O
the	O
Norwegian	O
EMBnet	O
node	O
.	O

Some	O
large	O
supertree	O
computations	O
are	O
run	O
on	O
a	O
Linux	O
supercomputer	O
at	O
the	O
University	O
of	O
Oslo	O
.	O

The	O
ATV	O
(	O
A	O
Tree	O
Viewer	O
)	O
Java	O
applet	O
is	O
used	O
for	O
phylogenetic	O
tree	O
display	O
(	O
17	O
)	O
.	O

ATV	O
notably	O
supports	O
horizontal	O
and	O
vertical	O
zooming	O
capabilities	O
that	O
are	O
suitable	O
for	O
browsing	O
large	O
trees	O
.	O

The	O
Jalview	O
editor	O
Java	O
applet	O
is	O
also	O
implemented	O
in	O
SuperCAT	O
for	O
advanced	O
multiple	O
sequence	O
alignment	O
display	O
(	O
18	O
)	O
.	O

SUPERTREE	O
RECONSTRUCTION	O

Supertree	O
techniques	O
allow	O
to	O
combine	O
the	O
phylogenetic	O
information	O
from	O
different	O
datasets	O
into	O
a	O
common	O
phylogenetic	O
tree	O
and	O
several	O
studies	O
have	O
shown	O
that	O
meaningful	O
supertrees	O
can	O
be	O
obtained	O
even	O
when	O
taxon	O
overlap	O
is	O
very	O
sparse	O
(	O
see	O
(	O
19	O
,	O
20	O
)	O
for	O
reviews	O
)	O
.	O

Supertree	O
analysis	O
has	O
thus	O
become	O
increasingly	O
popular	O
for	O
taking	O
advantage	O
and	O
combining	O
the	O
massive	O
amount	O
of	O
sequence	O
data	O
available	O
in	O
public	O
databases	O
for	O
reconstructing	O
large	O
-	O
scale	O
organismal	O
phylogenies	O
with	O
the	O
ultimate	O
goal	O
of	O
building	O
the	O
tree	O
of	O
life	O
(	O
21	O
-	O
24	O
)	O
.	O

In	O
this	O
study	O
,	O
the	O
21	O
B	B
.	I
cereus	I
group	I
strains	O
that	O
have	O
been	O
completely	O
sequenced	O
,	O
and	O
for	O
which	O
the	O
sequences	O
at	O
all	O
26	O
MLST	O
loci	O
are	O
thus	O
available	O
,	O
can	O
be	O
used	O
to	O
join	O
all	O
five	O
schemes	O
and	O
provide	O
the	O
strain	O
overlap	O
necessary	O
for	O
supertree	O
analysis	O
.	O

The	O
global	O
B	B
.	I
cereus	I
group	I
supertree	O
,	O
containing	O
1029	O
isolates	O
,	O
was	O
reconstructed	O
according	O
to	O
the	O
widely	O
used	O
matrix	O
representation	O
by	O
parsimony	O
(	O
MRP	O
)	O
procedure	O
(	O
Figure	O
1	O
;	O
(	O
19	O
,	O
25	O
,	O
26	O
)	O
)	O
.	O

Scheme	O
-	O
specific	O
supertrees	O
were	O
also	O
reconstructed	O
for	O
each	O
of	O
the	O
five	O
MLST	O
schemes	O
by	O
the	O
same	O
technique	O
.	O

Briefly	O
,	O
a	O
phylogenetic	O
tree	O
is	O
built	O
for	O
every	O
gene	O
separately	O
by	O
the	O
maximum	O
likelihood	O
method	O
with	O
the	O
PHYML	O
_	O
aLRT	O
program	O
(	O
27	O
)	O
.	O

Then	O
,	O
each	O
gene	O
tree	O
is	O
recoded	O
into	O
a	O
binary	O
matrix	O
representing	O
the	O
branching	O
order	O
(	O
i	O
.	O
e	O
.	O
the	O
phylogenetic	O
groupings	O
)	O
following	O
standard	O
MRP	O
coding	O
using	O
the	O
SuperMRP	O
.	O
pl	O
script	O
(	O
28	O
)	O
.	O

All	O
gene	O
tree	O
matrices	O
are	O
concatenated	O
into	O
a	O
supermatrix	O
,	O
in	O
which	O
isolates	O
missing	O
from	O
a	O
particular	O
tree	O
are	O
coded	O
using	O
the	O
'	O
?	O
'	O
character	O
representing	O
unknown	O
data	O
.	O

In	O
this	O
supermatrix	O
,	O
the	O
sequence	O
of	O
0	O
'	O
s	O
,	O
1	O
'	O
s	O
and	O
?	O
'	O
s	O
defines	O
the	O
branching	O
profile	O
of	O
a	O
strain	O
.	O

Closely	O
related	O
strains	O
have	O
similar	O
branching	O
profiles	O
.	O

Supertrees	O
are	O
then	O
generated	O
from	O
the	O
supermatrix	O
by	O
the	O
maximum	O
parsimony	O
technique	O
using	O
the	O
program	O
MIX	O
from	O
the	O
PHYLIP	O
package	O
(	O
29	O
)	O
run	O
with	O
default	O
parameters	O
.	O

The	O
maximum	O
parsimony	O
step	O
infers	O
the	O
trees	O
that	O
would	O
require	O
the	O
minimum	O
number	O
of	O
changes	O
between	O
the	O
branching	O
profiles	O
of	O
all	O
isolates	O
,	O
where	O
the	O
unknown	O
characters	O
can	O
take	O
any	O
of	O
the	O
two	O
possible	O
states	O
0	O
or	O
1	O
(	O
they	O
are	O
not	O
treated	O
as	O
missing	O
gaps	O
)	O
.	O

As	O
many	O
trees	O
were	O
equally	O
parsimonious	O
,	O
the	O
final	O
supertree	O
was	O
taken	O
as	O
the	O
strict	O
consensus	O
of	O
all	O
parsimony	O
trees	O
with	O
the	O
CONSENSE	O
program	O
of	O
PHYLIP	O
.	O

In	O
order	O
to	O
obtain	O
branch	O
lengths	O
that	O
are	O
proportional	O
to	O
the	O
amount	O
of	O
nucleotide	O
changes	O
,	O
we	O
added	O
an	O
additional	O
step	O
in	O
which	O
branch	O
lengths	O
and	O
statistical	O
support	O
for	O
groupings	O
are	O
estimated	O
from	O
the	O
concatenated	O
sequences	O
by	O
the	O
maximum	O
likelihood	O
method	O
employing	O
approximate	O
likelihood	O
-	O
ratio	O
tests	O
(	O
aLRTs	O
)	O
for	O
branches	O
using	O
PHYML	O
_	O
aLRT	O
with	O
Shimodaira	O
-	O
Hasegawa	O
-	O
like	O
support	O
values	O
(	O
27	O
,	O
30	O
)	O
.	O

aLRTs	O
provide	O
a	O
fast	O
way	O
of	O
testing	O
branch	O
support	O
without	O
requirement	O
of	O
multiple	O
replicates	O
like	O
traditional	O
bootstrap	O
procedures	O
.	O

The	O
Felsenstein	O
-	O
1984	O
nucleotide	O
substitution	O
model	O
supplemented	O
with	O
a	O
gamma	O
distribution	O
(	O
F84	O
+	O
Gamma	O
)	O
was	O
used	O
in	O
maximum	O
likelihood	O
computations	O
for	O
individual	O
gene	O
trees	O
and	O
the	O
supertree	O
(	O
31	O
)	O
.	O

This	O
model	O
allows	O
for	O
unequal	O
base	O
frequencies	O
,	O
transition	O
/	O
transversion	O
rate	O
bias	O
,	O
and	O
gamma	O
-	O
distributed	O
substitution	O
rate	O
variation	O
among	O
sites	O
.	O

It	O
was	O
empirically	O
chosen	O
as	O
a	O
consensus	O
from	O
exploratory	O
model	O
testing	O
using	O
ModelTest	O
(	O
32	O
,	O
33	O
)	O
,	O
which	O
indicated	O
that	O
models	O
including	O
these	O
three	O
factors	O
were	O
most	O
appropriate	O
for	O
the	O
MLST	O
loci	O
studied	O
,	O
although	O
models	O
for	O
individual	O
loci	O
differed	O
slightly	O
.	O

Note	O
that	O
the	O
maximum	O
likelihood	O
technique	O
also	O
allows	O
for	O
uneven	O
rates	O
of	O
nucleotide	O
substitution	O
between	O
strains	O
,	O
which	O
allows	O
to	O
accommodate	O
slow	O
-	O
and	O
fast	O
-	O
evolving	O
isolates	O
.	O

To	O
reduce	O
the	O
size	O
of	O
the	O
binary	O
supermatrix	O
and	O
speed	O
up	O
computations	O
,	O
individual	O
gene	O
trees	O
and	O
the	O
supertree	O
were	O
built	O
using	O
only	O
one	O
representative	O
from	O
a	O
set	O
of	O
strains	O
having	O
identical	O
sequences	O
.	O

The	O
remaining	O
identical	O
isolates	O
were	O
graphically	O
added	O
to	O
the	O
tree	O
afterwards	O
when	O
drawing	O
the	O
final	O
supertree	O
.	O

Figure	O
1	O
.	O
Schematic	O
overview	O
of	O
the	O
B	B
.	I
cereus	I
group	I
supertree	O
reconstruction	O
procedure	O
using	O
Matrix	O
Representation	O
by	O
Parsimony	O
(	O
MRP	O
)	O
.	O

See	O
text	O
for	O
details	O
.	O

It	O
should	O
be	O
noted	O
that	O
the	O
global	O
1029	O
-	O
strain	O
supertree	O
retains	O
the	O
phylogenetic	O
signals	O
from	O
the	O
individual	O
schemes	O
and	O
contains	O
the	O
three	O
main	O
clusters	O
of	O
the	O
B	B
.	I
cereus	I
group	I
population	O
described	O
in	O
the	O
section	O
'	O
Introduction	O
'	O
.	O

The	O
integrated	O
SuperCAT	O
system	O
may	O
also	O
allow	O
to	O
infer	O
new	O
relationships	O
between	O
strains	O
that	O
were	O
analyzed	O
with	O
different	O
gene	O
sets	O
.	O

Even	O
though	O
the	O
26	O
loci	O
sequences	O
are	O
available	O
for	O
only	O
21	O
isolates	O
,	O
they	O
apparently	O
provide	O
enough	O
overlap	O
information	O
for	O
building	O
the	O
main	O
branches	O
of	O
the	O
supertree	O
.	O

These	O
21	O
isolates	O
cover	O
all	O
three	O
clusters	O
,	O
although	O
the	O
majority	O
of	O
them	O
are	O
B	B
.	I
anthracis	I
strains	O
or	O
clinical	O
strains	O
closely	O
related	O
to	O
B	B
.	I
anthracis	I
due	O
to	O
the	O
focus	O
of	O
genome	O
sequencing	O
projects	O
,	O
making	O
the	O
part	O
of	O
the	O
supertree	O
containing	O
these	O
isolates	O
likely	O
to	O
be	O
more	O
accurate	O
than	O
the	O
rest	O
of	O
the	O
tree	O
.	O

Furthermore	O
,	O
111	O
other	O
isolates	O
have	O
been	O
typed	O
by	O
10	O
genes	O
or	O
more	O
,	O
providing	O
additional	O
overlap	O
(	O
see	O
the	O
'	O
Gene	O
Distribution	O
'	O
page	O
)	O
.	O

Although	O
about	O
two	O
-	O
thirds	O
of	O
the	O
sequence	O
data	O
are	O
missing	O
overall	O
,	O
it	O
has	O
been	O
shown	O
for	O
other	O
organisms	O
that	O
relevant	O
supertrees	O
could	O
be	O
reconstructed	O
with	O
datasets	O
containing	O
more	O
than	O
90	O
%	O
of	O
missing	O
data	O
,	O
especially	O
when	O
the	O
characters	O
that	O
are	O
present	O
are	O
informative	O
(	O
20	O
,	O
22	O
,	O
23	O
,	O
34	O
)	O
.	O

Empirical	O
and	O
simulation	O
studies	O
have	O
indicated	O
that	O
this	O
behavior	O
may	O
be	O
due	O
to	O
the	O
fact	O
that	O
the	O
characters	O
which	O
are	O
present	O
are	O
more	O
important	O
for	O
the	O
tree	O
-	O
building	O
process	O
than	O
those	O
which	O
are	O
absent	O
(	O
see	O
(	O
20	O
,	O
34	O
)	O
and	O
references	O
therein	O
)	O
.	O

Precise	O
within	O
-	O
cluster	O
groupings	O
may	O
contain	O
more	O
uncertainty	O
,	O
as	O
indicated	O
by	O
the	O
large	O
number	O
of	O
unresolved	O
multifurcations	O
in	O
the	O
B	B
.	I
cereus	I
group	I
supertree	O
.	O

Finally	O
,	O
it	O
is	O
also	O
worth	O
mentioning	O
that	O
the	O
branching	O
orders	O
of	O
the	O
scheme	O
-	O
specific	O
MRP	O
supertrees	O
are	O
highly	O
correlated	O
to	O
those	O
of	O
the	O
published	O
trees	O
built	O
with	O
concatenated	O
sequences	O
and	O
other	O
phylogenetic	O
algorithms	O
.	O

DATA	O
ACCESS	O
AND	O
MANIPULATION	O

The	O
complete	O
list	O
of	O
isolates	O
included	O
in	O
SuperCAT	O
(	O
currently	O
1029	O
)	O
with	O
strain	O
description	O
,	O
source	O
and	O
country	O
of	O
origin	O
is	O
available	O
at	O
the	O
database	O
home	O
page	O
.	O

By	O
default	O
all	O
isolates	O
in	O
the	O
database	O
are	O
used	O
in	O
the	O
analysis	O
tools	O
provided	O
,	O
but	O
the	O
user	O
can	O
select	O
strains	O
of	O
interest	O
by	O
keywords	O
,	O
MLST	O
scheme	O
,	O
entering	O
a	O
list	O
of	O
strain	O
identifiers	O
,	O
or	O
choosing	O
isolates	O
individually	O
via	O
checkboxes	O
.	O

All	O
subsequent	O
analyses	O
will	O
be	O
based	O
on	O
the	O
selected	O
strain	O
subset	O
and	O
their	O
loci	O
.	O

The	O
keyword	O
search	O
will	O
look	O
for	O
matches	O
in	O
any	O
of	O
the	O
strain	O
,	O
description	O
,	O
source	O
,	O
location	O
and	O
scheme	O
fields	O
.	O

Complex	O
keyword	O
queries	O
with	O
several	O
logical	O
operators	O
can	O
be	O
formulated	O
in	O
the	O
'	O
advanced	O
search	O
'	O
page	O
.	O

Note	O
that	O
many	O
isolates	O
were	O
referred	O
by	O
alternative	O
names	O
in	O
different	O
MLST	O
schemes	O
and	O
publications	O
,	O
therefore	O
synonyms	O
have	O
been	O
included	O
in	O
the	O
strain	O
descriptions	O
that	O
allow	O
a	O
particular	O
isolate	O
to	O
be	O
looked	O
up	O
using	O
any	O
of	O
its	O
alternative	O
identifiers	O
.	O

A	O
sequence	O
search	O
is	O
also	O
possible	O
using	O
BLASTN	O
(	O
35	O
)	O
,	O
in	O
order	O
to	O
select	O
isolates	O
that	O
have	O
allele	O
sequences	O
identical	O
to	O
user	O
-	O
entered	O
query	O
sequences	O
.	O

Throughout	O
SuperCAT	O
,	O
clicking	O
on	O
a	O
strain	O
name	O
will	O
pop	O
up	O
an	O
isolate	O
-	O
specific	O
window	O
showing	O
all	O
relevant	O
information	O
and	O
giving	O
access	O
to	O
the	O
nucleotide	O
sequences	O
of	O
individual	O
loci	O
for	O
that	O
isolate	O
.	O

Detailed	O
information	O
about	O
the	O
MLST	O
schemes	O
(	O
e	O
.	O
g	O
.	O
loci	O
names	O
and	O
lengths	O
,	O
genomic	O
coordinates	O
,	O
literature	O
references	O
)	O
and	O
their	O
overlap	O
,	O
the	O
distribution	O
of	O
available	O
loci	O
among	O
the	O
isolates	O
,	O
and	O
the	O
supertree	O
reconstruction	O
procedure	O
can	O
be	O
obtained	O
by	O
clicking	O
the	O
relevant	O
links	O
in	O
the	O
header	O
line	O
present	O
at	O
the	O
top	O
of	O
every	O
page	O
.	O

Apart	O
from	O
the	O
basic	O
functions	O
for	O
selecting	O
and	O
accessing	O
strain	O
information	O
and	O
sequence	O
data	O
for	O
all	O
five	O
B	B
.	I
cereus	I
group	I
MLST	O
schemes	O
,	O
the	O
main	O
features	O
of	O
SuperCAT	O
relate	O
to	O
the	O
manipulation	O
of	O
the	O
supertrees	O
constructed	O
by	O
the	O
MRP	O
approach	O
.	O

The	O
global	O
supertree	O
based	O
on	O
the	O
combination	O
of	O
all	O
five	O
B	B
.	I
cereus	I
group	I
MLST	O
schemes	O
as	O
well	O
as	O
the	O
five	O
scheme	O
-	O
specific	O
supertrees	O
can	O
be	O
browsed	O
according	O
to	O
various	O
user	O
-	O
chosen	O
criteria	O
(	O
Figure	O
2	O
)	O
.	O

Isolates	O
in	O
the	O
supertrees	O
can	O
be	O
colored	O
by	O
species	O
or	O
source	O
of	O
isolation	O
.	O

It	O
is	O
also	O
possible	O
to	O
specifically	O
mark	O
in	O
red	O
the	O
current	O
subset	O
of	O
strains	O
that	O
has	O
been	O
selected	O
by	O
the	O
user	O
and	O
to	O
extract	O
from	O
the	O
supertrees	O
the	O
subtree	O
containing	O
only	O
those	O
isolates	O
.	O

In	O
the	O
case	O
of	O
the	O
multi	O
-	O
scheme	O
supertree	O
highlighting	O
of	O
the	O
strains	O
can	O
be	O
based	O
on	O
genetic	O
distance	O
.	O

With	O
this	O
option	O
the	O
user	O
can	O
mark	O
on	O
and	O
/	O
or	O
extract	O
from	O
the	O
tree	O
the	O
isolates	O
that	O
are	O
genetically	O
closely	O
related	O
to	O
strains	O
of	O
her	O
/	O
his	O
choice	O
.	O

The	O
user	O
can	O
either	O
select	O
strains	O
that	O
share	O
one	O
or	O
several	O
identical	O
allele	O
sequences	O
with	O
her	O
/	O
his	O
query	O
isolate	O
(	O
s	O
)	O
or	O
that	O
are	O
at	O
a	O
specified	O
genetic	O
distance	O
.	O

Distances	O
between	O
isolates	O
are	O
computed	O
by	O
summing	O
up	O
the	O
lengths	O
of	O
the	O
branches	O
(	O
in	O
average	O
number	O
of	O
nucleotide	O
substitutions	O
per	O
site	O
)	O
connecting	O
the	O
isolates	O
in	O
the	O
supertree	O
(	O
known	O
as	O
patristic	O
distances	O
;	O
(	O
36	O
)	O
)	O
.	O

The	O
genetic	O
relatedness	O
search	O
functions	O
are	O
also	O
available	O
in	O
a	O
separate	O
page	O
for	O
the	O
user	O
to	O
find	O
closely	O
related	O
isolates	O
without	O
tree	O
manipulation	O
.	O

SuperCAT	O
allows	O
to	O
compare	O
the	O
scheme	O
-	O
specific	O
MLST	O
supertrees	O
with	O
each	O
other	O
and	O
with	O
the	O
global	O
supertree	O
by	O
using	O
the	O
subset	O
of	O
isolates	O
that	O
are	O
common	O
to	O
all	O
selected	O
schemes	O
.	O

Common	O
isolates	O
can	O
either	O
be	O
highlighted	O
in	O
red	O
or	O
be	O
extracted	O
as	O
subtrees	O
from	O
each	O
supertree	O
,	O
which	O
can	O
be	O
used	O
for	O
comparing	O
the	O
positions	O
of	O
the	O
common	O
strains	O
in	O
the	O
various	O
MLST	O
trees	O
.	O

For	O
all	O
supertree	O
-	O
related	O
options	O
,	O
detailed	O
tree	O
navigation	O
can	O
be	O
achieved	O
using	O
the	O
various	O
functions	O
in	O
the	O
ATV	O
tree	O
window	O
when	O
the	O
trees	O
are	O
displayed	O
(	O
17	O
)	O
.	O

Figure	O
2	O
.	O
Examples	O
of	O
supertree	O
browsing	O
and	O
manipulation	O
in	O
SuperCAT	O
.	O

A	O
,	O
supertree	O
colored	O
by	O
species	O
;	O
B	O
,	O
specific	O
highlighting	O
of	O
user	O
-	O
selected	O
strains	O
(	O
in	O
red	O
)	O
;	O
C	O
,	O
extracted	O
subtree	O
containing	O
only	O
the	O
strains	O
highlighted	O
in	O
B	O
.	O

Trees	O
are	O
displayed	O
using	O
ATV	O
(	O
17	O
)	O
.	O

Besides	O
the	O
manipulation	O
of	O
the	O
precomputed	O
supertrees	O
,	O
SuperCAT	O
offers	O
the	O
user	O
the	O
possibility	O
to	O
compute	O
new	O
supertrees	O
by	O
MRP	O
using	O
any	O
combination	O
of	O
strains	O
,	O
schemes	O
and	O
genes	O
.	O

Supertree	O
computations	O
may	O
be	O
extremely	O
time	O
consuming	O
,	O
ranging	O
from	O
a	O
few	O
minutes	O
to	O
2	O
-	O
3	O
days	O
with	O
the	O
complete	O
database	O
.	O

Users	O
are	O
therefore	O
requested	O
to	O
enter	O
their	O
e	O
-	O
mail	O
addresses	O
and	O
will	O
receive	O
a	O
notification	O
containing	O
a	O
link	O
to	O
the	O
results	O
page	O
when	O
the	O
supertree	O
is	O
ready	O
.	O

Note	O
that	O
when	O
building	O
a	O
supertree	O
for	O
a	O
user	O
-	O
selected	O
subset	O
of	O
strains	O
,	O
the	O
computation	O
will	O
first	O
include	O
all	O
database	O
isolates	O
.	O

A	O
subtree	O
containing	O
only	O
the	O
user	O
-	O
selected	O
isolates	O
will	O
then	O
be	O
extracted	O
from	O
the	O
supertree	O
of	O
all	O
strains	O
.	O

Although	O
more	O
time	O
consuming	O
,	O
this	O
strategy	O
allows	O
:	O
(	O
i	O
)	O
to	O
avoid	O
sampling	O
artefacts	O
as	O
phylogenies	O
built	O
with	O
different	O
isolate	O
sets	O
may	O
vary	O
and	O
(	O
ii	O
)	O
to	O
obtain	O
relationships	O
even	O
if	O
the	O
selected	O
isolates	O
have	O
been	O
typed	O
using	O
non	O
-	O
overlapping	O
gene	O
sets	O
,	O
as	O
the	O
supertree	O
of	O
all	O
isolates	O
can	O
always	O
be	O
built	O
owing	O
to	O
the	O
completely	O
sequenced	O
strains	O
that	O
are	O
common	O
to	O
all	O
schemes	O
.	O

Another	O
main	O
feature	O
of	O
the	O
SuperCAT	O
database	O
is	O
that	O
the	O
user	O
can	O
enter	O
her	O
/	O
his	O
own	O
private	O
sequences	O
and	O
conduct	O
several	O
sequence	O
analyses	O
(	O
Figure	O
3	O
)	O
.	O

These	O
analyses	O
include	O
:	O
(	O
a	O
)	O
building	O
new	O
supertrees	O
containing	O
user	O
isolates	O
and	O
sequences	O
;	O
(	O
b	O
)	O
finding	O
database	O
isolates	O
having	O
sequences	O
most	O
similar	O
to	O
the	O
user	O
'	O
s	O
query	O
sequences	O
using	O
an	O
on	O
-	O
line	O
BLASTN	O
(	O
35	O
)	O
service	O
;	O
and	O
(	O
c	O
)	O
aligning	O
user	O
sequences	O
to	O
database	O
genes	O
using	O
the	O
multiple	O
sequence	O
alignment	O
program	O
CLUSTALW	O
(	O
37	O
)	O
.	O

For	O
the	O
last	O
option	O
,	O
the	O
Jalview	O
editor	O
(	O
18	O
)	O
is	O
provided	O
for	O
advanced	O
multiple	O
alignment	O
display	O
.	O

All	O
user	O
-	O
entered	O
data	O
must	O
be	O
in	O
FASTA	O
format	O
and	O
can	O
be	O
either	O
copied	O
and	O
pasted	O
into	O
the	O
query	O
forms	O
or	O
uploaded	O
from	O
text	O
files	O
stored	O
locally	O
on	O
the	O
user	O
'	O
s	O
computer	O
.	O

Figure	O
3	O
.	O
Examples	O
of	O
query	O
results	O
in	O
SuperCAT	O
.	O

A	O
,	O
multi	O
-	O
scheme	O
BLAST	O
search	O
with	O
sequence	O
alignment	O
;	O
B	O
,	O
multi	O
-	O
scheme	O
genetic	O
search	O
showing	O
the	O
list	O
of	O
isolates	O
sharing	O
one	O
or	O
more	O
sequences	O
with	O
a	O
query	O
strain	O
;	O
C	O
,	O
multiple	O
sequence	O
alignment	O
using	O
Jalview	O
(	O
18	O
)	O
.	O

All	O
strain	O
information	O
data	O
,	O
sequences	O
and	O
phylogenetic	O
trees	O
,	O
including	O
user	O
-	O
made	O
supertrees	O
and	O
extracted	O
subtrees	O
,	O
can	O
be	O
saved	O
and	O
downloaded	O
freely	O
from	O
the	O
database	O
.	O

Users	O
wishing	O
to	O
have	O
their	O
MLST	O
data	O
included	O
as	O
part	O
of	O
the	O
SuperCAT	O
release	O
(	O
and	O
/	O
or	O
the	O
Tourasse	O
-	O
Helgason	O
scheme	O
-	O
specific	O
database	O
)	O
are	O
welcome	O
to	O
contact	O
N	O
.	O
J	O
.	O
T	O
.	O
or	O
A	O
.	O
-	O
B	O
.	O
K	O
.	O
at	O
the	O
e	O
-	O
mail	O
addresses	O
given	O
on	O
the	O
Oslo	O
MLST	O
server	O
front	O
page	O
.	O

DISCUSSION	O
AND	O
FUTURE	O
DEVELOPMENTS	O

SuperCAT	O
is	O
a	O
newly	O
created	O
database	O
devoted	O
to	O
the	O
B	B
.	I
cereus	I
group	I
of	O
bacteria	O
whose	O
main	O
objectives	O
are	O
to	O
provide	O
a	O
common	O
MLST	O
repository	O
and	O
means	O
for	O
building	O
a	O
comprehensive	O
genetic	O
analysis	O
of	O
the	O
group	O
that	O
has	O
been	O
typed	O
by	O
five	O
separate	O
schemes	O
.	O

The	O
database	O
is	O
publicly	O
and	O
freely	O
available	O
at	O
http	O
:	O
/	O
/	O
mlstoslo	O
.	O
uio	O
.	O
no	O
/	O
,	O
along	O
with	O
the	O
database	O
specific	O
for	O
the	O
combined	O
scheme	O
of	O
(	O
5	O
)	O
.	O

We	O
plan	O
to	O
update	O
SuperCAT	O
quarterly	O
.	O

Future	O
developments	O
of	O
the	O
database	O
may	O
deal	O
with	O
refining	O
the	O
supertree	O
-	O
building	O
procedure	O
.	O

In	O
particular	O
,	O
a	O
new	O
improved	O
method	O
has	O
recently	O
been	O
developed	O
for	O
taking	O
into	O
account	O
both	O
nucleotide	O
substitutions	O
and	O
recombination	O
events	O
in	O
phylogenies	O
,	O
as	O
part	O
of	O
the	O
ClonalFrame	O
software	O
,	O
which	O
has	O
been	O
applied	O
to	O
the	O
B	B
.	I
cereus	I
group	I
and	O
the	O
Priest	O
scheme	O
(	O
38	O
)	O
.	O

It	O
would	O
therefore	O
be	O
of	O
interest	O
to	O
examine	O
the	O
suitability	O
of	O
ClonalFrame	O
in	O
the	O
supertree	O
context	O
.	O

It	O
is	O
also	O
tempting	O
to	O
extend	O
the	O
supertree	O
analysis	O
beyond	O
MLST	O
data	O
,	O
by	O
incorporating	O
the	O
phylogenies	O
obtained	O
previously	O
from	O
large	O
-	O
scale	O
multilocus	O
enzyme	O
electrophoresis	O
(	O
MLEE	O
;	O
(	O
3	O
,	O
39	O
-	O
41	O
)	O
)	O
and	O
amplified	O
fragment	O
length	O
polymorphism	O
(	O
AFLP	O
;	O
(	O
42	O
-	O
45	O
)	O
)	O
studies	O
.	O

The	O
MRP	O
framework	O
is	O
ideal	O
since	O
it	O
allows	O
to	O
integrate	O
trees	O
that	O
can	O
be	O
built	O
from	O
different	O
methods	O
and	O
data	O
.	O

As	O
MLEE	O
,	O
AFLP	O
and	O
MLST	O
have	O
different	O
levels	O
of	O
resolution	O
,	O
one	O
can	O
hope	O
that	O
combining	O
them	O
might	O
provide	O
an	O
even	O
more	O
robust	O
supertree	O
for	O
the	O
B	B
.	I
cereus	I
group	I
.	O

Discovery	O
of	O
genes	O
implicated	O
in	O
whirling	O
disease	O
infection	O
and	O
resistance	O
in	O
rainbow	B
trout	I
using	O
genome	O
-	O
wide	O
expression	O
profiling	O

Abstract	O

Background	O

Whirling	O
disease	O
,	O
caused	O
by	O
the	O
pathogen	O
Myxobolus	B
cerebralis	I
,	O
afflicts	O
several	O
salmonid	O
species	O
.	O

Rainbow	B
trout	I
are	O
particularly	O
susceptible	O
and	O
may	O
suffer	O
high	O
mortality	O
rates	O
.	O

The	O
disease	O
is	O
persistent	O
and	O
spreading	O
in	O
hatcheries	O
and	O
natural	O
waters	O
of	O
several	O
countries	O
,	O
including	O
the	O
U	O
.	O
S	O
.	O
A	O
.	O
,	O
and	O
the	O
economic	O
losses	O
attributed	O
to	O
whirling	O
disease	O
are	O
substantial	O
.	O

In	O
this	O
study	O
,	O
genome	O
-	O
wide	O
expression	O
profiling	O
using	O
cDNA	O
microarrays	O
was	O
conducted	O
for	O
resistant	O
Hofer	O
and	O
susceptible	O
Trout	O
Lodge	O
rainbow	B
trout	I
strains	O
following	O
pathogen	O
exposure	O
with	O
the	O
primary	O
objective	O
of	O
identifying	O
specific	O
genes	O
implicated	O
in	O
whirling	O
disease	O
resistance	O
.	O

Results	O

Several	O
genes	O
were	O
significantly	O
up	O
-	O
regulated	O
in	O
skin	O
following	O
pathogen	O
exposure	O
for	O
both	O
the	O
resistant	O
and	O
susceptible	O
rainbow	B
trout	I
strains	O
.	O

For	O
both	O
strains	O
,	O
response	O
to	O
infection	O
appears	O
to	O
be	O
linked	O
with	O
the	O
interferon	O
system	O
.	O

Expression	O
profiles	O
for	O
three	O
genes	O
identified	O
with	O
microarrays	O
were	O
confirmed	O
with	O
qRT	O
-	O
PCR	O
.	O

Ubiquitin	O
-	O
like	O
protein	O
1	O
was	O
up	O
-	O
regulated	O
over	O
100	O
fold	O
and	O
interferon	O
regulating	O
factor	O
1	O
was	O
up	O
-	O
regulated	O
over	O
15	O
fold	O
following	O
pathogen	O
exposure	O
for	O
both	O
strains	O
.	O

Expression	O
of	O
metallothionein	O
B	O
,	O
which	O
has	O
known	O
roles	O
in	O
inflammation	O
and	O
immune	O
response	O
,	O
was	O
up	O
-	O
regulated	O
over	O
5	O
fold	O
in	O
the	O
resistant	O
Hofer	O
strain	O
but	O
was	O
unchanged	O
in	O
the	O
susceptible	O
Trout	O
Lodge	O
strain	O
following	O
pathogen	O
exposure	O
.	O

Conclusion	O

The	O
present	O
study	O
has	O
provided	O
an	O
initial	O
view	O
into	O
the	O
genetic	O
basis	O
underlying	O
immune	O
response	O
and	O
resistance	O
of	O
rainbow	B
trout	I
to	O
the	O
whirling	O
disease	O
parasite	O
.	O

The	O
identified	O
genes	O
have	O
allowed	O
us	O
to	O
gain	O
insight	O
into	O
the	O
molecular	O
mechanisms	O
implicated	O
in	O
salmonid	O
immune	O
response	O
and	O
resistance	O
to	O
whirling	O
disease	O
infection	O
.	O

Background	O

Whirling	O
disease	O
was	O
first	O
described	O
among	O
farmed	O
rainbow	B
trout	I
(	O
Oncorhynchus	B
mykiss	I
)	O
,	O
a	O
native	O
North	O
American	O
salmonid	O
species	O
,	O
introduced	O
to	O
Germany	O
as	O
a	O
food	O
fish	O
in	O
the	O
late	O
1800s	O
[	O
1	O
]	O
.	O

Whirling	O
disease	O
is	O
associated	O
with	O
systemic	O
infections	O
by	O
the	O
myxozoan	O
Myxobolus	B
cerebralis	I
,	O
a	O
parasite	O
with	O
presumed	O
origins	O
among	O
salmonid	O
fish	O
in	O
Eurasia	O
[	O
2	O
,	O
3	O
]	O
.	O

Rainbow	B
trout	I
are	O
highly	O
susceptible	O
to	O
whirling	O
disease	O
and	O
the	O
introduction	O
of	O
the	O
parasite	O
to	O
the	O
U	O
.	O
S	O
.	O
A	O
.	O
in	O
the	O
1950s	O
had	O
immediate	O
economic	O
impacts	O
on	O
salmonid	O
hatcheries	O
in	O
both	O
eastern	O
and	O
western	O
states	O
[	O
2	O
]	O
.	O

The	O
parasite	O
has	O
a	O
broad	O
worldwide	O
distribution	O
and	O
has	O
been	O
identified	O
in	O
25	O
states	O
in	O
the	O
U	O
.	O
S	O
.	O
A	O
.	O
where	O
salmonid	O
fish	O
are	O
present	O
[	O
4	O
]	O
.	O

Salmonid	O
hatcheries	O
throughout	O
the	O
U	O
.	O
S	O
.	O
A	O
have	O
suffered	O
drastic	O
economic	O
losses	O
due	O
to	O
whirling	O
disease	O
outbreaks	O
.	O

The	O
disease	O
has	O
more	O
recently	O
been	O
recognized	O
as	O
the	O
principal	O
cause	O
of	O
major	O
population	O
declines	O
among	O
wild	O
rainbow	B
trout	I
populations	O
in	O
the	O
intermountain	O
region	O
of	O
the	O
U	O
.	O
S	O
.	O
A	O
with	O
serious	O
negative	O
impacts	O
on	O
sportfishing	O
and	O
allied	O
industries	O
[	O
5	O
-	O
7	O
]	O
.	O

Additionally	O
,	O
concerns	O
continue	O
over	O
the	O
potential	O
negative	O
ecologic	O
impacts	O
of	O
whirling	O
disease	O
on	O
wild	O
salmonid	O
populations	O
,	O
particularly	O
threatened	O
or	O
endangered	O
salmonids	O
such	O
as	O
bull	B
trout	I
(	O
Salvelinus	B
confluentus	I
)	O
,	O
cutthroat	B
trout	I
(	O
Oncorhynchus	B
clarki	I
)	O
,	O
and	O
steelhead	B
(	O
Oncorhynchus	B
mykiss	I
)	O
[	O
8	O
,	O
9	O
]	O
.	O

Myxobolus	B
cerebralis	I
has	O
a	O
complex	O
life	O
cycle	O
that	O
includes	O
two	O
alternate	O
hosts	O
,	O
a	O
salmonid	O
fish	O
and	O
an	O
oligochaete	O
worm	O
,	O
Tubifex	B
tubifex	I
[	O
10	O
,	O
11	O
]	O
.	O

Infection	O
in	O
the	O
salmonid	O
host	O
begins	O
when	O
microscopic	O
waterborne	O
actinospore	O
stages	O
of	O
M	B
.	I
cerebralis	I
are	O
released	O
from	O
the	O
worm	O
and	O
contact	O
the	O
skin	O
of	O
the	O
fish	O
host	O
.	O

Actinospores	O
,	O
also	O
referred	O
to	O
as	O
triactinomyxons	O
for	O
M	B
.	I
cerebralis	I
,	O
attach	O
preferentially	O
to	O
fins	O
and	O
the	O
buccal	O
cavity	O
where	O
they	O
release	O
one	O
or	O
more	O
of	O
three	O
coiled	O
polar	O
filaments	O
which	O
penetrate	O
and	O
then	O
anchor	O
them	O
to	O
the	O
epidermis	O
[	O
12	O
]	O
.	O

Within	O
minutes	O
the	O
sporoplasm	O
,	O
which	O
contains	O
64	O
internal	O
cells	O
,	O
migrates	O
from	O
the	O
triactinomxyon	O
to	O
deeper	O
layers	O
of	O
the	O
epidermis	O
,	O
an	O
action	O
that	O
may	O
be	O
facilitated	O
by	O
parasite	O
proteases	O
[	O
13	O
-	O
15	O
]	O
.	O

Aggregates	O
and	O
single	O
cells	O
from	O
the	O
sporoplasm	O
then	O
begin	O
mitotic	O
replication	O
within	O
two	O
h	O
of	O
initial	O
infection	O
,	O
alternating	O
between	O
inter	O
and	O
intracellular	O
locations	O
,	O
a	O
process	O
that	O
may	O
also	O
depend	O
upon	O
parasite	O
coded	O
protease	O
activity	O
[	O
15	O
,	O
16	O
]	O
.	O

Over	O
the	O
next	O
10	O
h	O
at	O
water	O
temperatures	O
of	O
15	O
degrees	O
C	O
,	O
parasites	O
within	O
host	O
epithelial	O
cells	O
further	O
divide	O
by	O
the	O
process	O
of	O
endogeny	O
or	O
cell	O
within	O
cell	O
replication	O
prior	O
to	O
release	O
and	O
then	O
penetration	O
of	O
new	O
host	O
cells	O
.	O

Between	O
12	O
and	O
20	O
h	O
post	O
infection	O
,	O
the	O
number	O
of	O
parasite	O
cells	O
present	O
in	O
the	O
epidermis	O
steadily	O
declines	O
until	O
new	O
stages	O
are	O
observed	O
in	O
the	O
subcutis	O
at	O
48	O
h	O
.	O

Degenerative	O
stages	O
observed	O
in	O
the	O
epidermis	O
between	O
12	O
and	O
20	O
h	O
are	O
suspected	O
to	O
be	O
a	O
result	O
of	O
the	O
action	O
of	O
the	O
host	O
immune	O
response	O
,	O
although	O
the	O
cellular	O
and	O
or	O
humoral	O
factors	O
involved	O
are	O
not	O
currently	O
known	O
.	O

After	O
a	O
brief	O
residence	O
in	O
the	O
subcutis	O
,	O
parasite	O
stages	O
are	O
presumed	O
to	O
migrate	O
to	O
proximal	O
nervous	O
tissues	O
,	O
initially	O
in	O
peripheral	O
and	O
then	O
more	O
central	O
locations	O
[	O
16	O
]	O
.	O

Migration	O
and	O
potential	O
replication	O
of	O
parasite	O
stages	O
in	O
nervous	O
tissue	O
ensues	O
over	O
the	O
next	O
16	O
d	O
with	O
the	O
first	O
parasites	O
exiting	O
to	O
invade	O
cartilage	O
observed	O
at	O
20	O
d	O
post	O
infection	O
[	O
16	O
]	O
.	O

Feeding	O
on	O
cartilage	O
may	O
induce	O
a	O
host	O
inflammatory	O
response	O
that	O
constricts	O
the	O
spinal	O
cord	O
,	O
brain	O
stem	O
,	O
and	O
caudal	O
nerves	O
resulting	O
in	O
the	O
erratic	O
swimming	O
behavior	O
(	O
whirling	O
)	O
and	O
black	O
tail	O
observed	O
among	O
fish	O
with	O
acute	O
whirling	O
disease	O
[	O
17	O
]	O
.	O

An	O
additional	O
impact	O
of	O
cartilage	O
destruction	O
are	O
permanent	O
deformities	O
to	O
the	O
skeletal	O
system	O
that	O
may	O
increase	O
vulnerability	O
to	O
predation	O
and	O
impair	O
ability	O
to	O
forage	O
for	O
food	O
[	O
1	O
]	O
.	O

The	O
final	O
developmental	O
stages	O
of	O
the	O
parasite	O
in	O
the	O
fish	O
are	O
environmentally	O
resistant	O
spore	O
stages	O
(	O
myxospores	O
)	O
which	O
remained	O
trapped	O
in	O
cartilage	O
or	O
bone	O
[	O
18	O
]	O
.	O

Death	O
of	O
infected	O
fish	O
or	O
ingestion	O
by	O
fish	O
or	O
avian	O
predators	O
releases	O
myxospores	O
from	O
the	O
fish	O
tissues	O
and	O
they	O
may	O
be	O
ingested	O
by	O
the	O
second	O
host	O
,	O
the	O
benthic	O
dwelling	O
oligochaete	O
T	B
.	I
tubifex	I
[	O
19	O
]	O
.	O

A	O
second	O
developmental	O
cycle	O
then	O
occurs	O
under	O
the	O
mucosal	O
lining	O
of	O
the	O
intestine	O
that	O
results	O
in	O
the	O
release	O
of	O
thousands	O
of	O
the	O
actinospore	O
(	O
triactinomyxon	O
)	O
stages	O
potentially	O
over	O
the	O
entire	O
lifetime	O
of	O
the	O
individual	O
oligochaete	O
[	O
20	O
]	O
.	O

Susceptibility	O
to	O
whirling	O
disease	O
in	O
U	O
.	O
S	O
.	O
rainbow	B
trout	I
strains	O
is	O
pervasive	O
with	O
only	O
two	O
of	O
the	O
tested	O
native	O
strains	O
displaying	O
any	O
degree	O
of	O
resistance	O
,	O
which	O
may	O
be	O
inconsistent	O
and	O
relatively	O
moderate	O
[	O
21	O
,	O
22	O
]	O
.	O

Hatchery	O
rainbow	B
trout	I
in	O
Germany	O
(	O
Hofer	O
strain	O
)	O
,	O
however	O
,	O
have	O
acquired	O
a	O
degree	O
of	O
resistance	O
to	O
whirling	O
disease	O
that	O
is	O
consistently	O
much	O
higher	O
than	O
any	O
domestic	O
rainbow	O
strains	O
and	O
comparable	O
to	O
that	O
of	O
brown	B
trout	I
(	O
Salmon	B
trutta	I
)	O
,	O
which	O
are	O
native	O
to	O
Europe	O
and	O
typically	O
asymptomatic	O
following	O
infection	O
[	O
23	O
]	O
.	O

Laboratory	O
tests	O
comparing	O
rainbow	B
trout	I
strains	O
under	O
the	O
same	O
environmental	O
conditions	O
and	O
pathogen	O
exposure	O
indicate	O
that	O
the	O
Hofer	O
strain	O
'	O
s	O
ability	O
to	O
combat	O
M	B
.	I
cerebralis	I
infection	O
has	O
a	O
genetic	O
basis	O
.	O

Recently	O
,	O
controlled	O
crosses	O
of	O
the	O
Hofer	O
strain	O
and	O
a	O
susceptible	O
strain	O
(	O
Colorado	O
River	O
rainbow	B
trout	I
[	O
CRR	O
]	O
)	O
demonstrated	O
that	O
resistance	O
to	O
whirling	O
disease	O
was	O
inherited	O
by	O
progeny	O
[	O
24	O
]	O
and	O
heritability	O
estimates	O
are	O
currently	O
underway	O
.	O

The	O
discovery	O
of	O
the	O
resistant	O
Hofer	O
strain	O
allowed	O
us	O
to	O
conduct	O
an	O
intraspecific	O
comparison	O
of	O
susceptible	O
and	O
resistant	O
rainbow	B
trout	I
in	O
order	O
to	O
gain	O
insight	O
into	O
the	O
genetic	O
basis	O
underlying	O
whirling	O
disease	O
susceptibility	O
for	O
this	O
species	O
.	O

Gene	O
expression	O
profiling	O
,	O
through	O
the	O
use	O
of	O
microarrays	O
,	O
is	O
an	O
extremely	O
high	O
-	O
throughput	O
method	O
to	O
discover	O
specific	O
genes	O
and	O
pathways	O
involved	O
in	O
a	O
disease	O
phenotype	O
without	O
the	O
bias	O
of	O
a	O
candidate	O
gene	O
approach	O
.	O

In	O
this	O
study	O
,	O
microarray	O
analysis	O
was	O
used	O
to	O
examine	O
expression	O
changes	O
in	O
a	O
resistant	O
and	O
susceptible	O
strain	O
of	O
rainbow	B
trout	I
following	O
exposure	O
to	O
M	B
.	I
cerebralis	I
,	O
the	O
pathogen	O
causing	O
whirling	O
disease	O
.	O

We	O
have	O
found	O
several	O
genes	O
significantly	O
up	O
-	O
regulated	O
in	O
both	O
the	O
resistant	O
and	O
susceptible	O
strain	O
that	O
appear	O
to	O
be	O
involved	O
in	O
host	O
response	O
to	O
infection	O
.	O

We	O
have	O
also	O
found	O
a	O
gene	O
which	O
is	O
significantly	O
up	O
-	O
regulated	O
in	O
the	O
resistant	O
but	O
remains	O
unchanged	O
in	O
the	O
susceptible	O
rainbow	B
trout	I
strain	O
following	O
pathogen	O
exposure	O
that	O
is	O
a	O
likely	O
candidate	O
gene	O
for	O
involvement	O
in	O
conferring	O
whirling	O
disease	O
resistance	O
.	O

Results	O
and	O
Discussion	O

Quantitative	O
PCR	O
conducted	O
on	O
caudal	O
fin	O
tissues	O
at	O
two	O
hours	O
post	O
exposure	O
to	O
M	B
.	I
cerebralis	I
demonstrated	O
each	O
fish	O
strain	O
had	O
similar	O
initial	O
pathogen	O
loads	O
,	O
although	O
there	O
was	O
substantial	O
variation	O
between	O
individual	O
fish	O
within	O
each	O
strain	O
.	O

The	O
mean	O
parasite	O
copy	O
numbers	O
per	O
host	O
cell	O
were	O
1	O
.	O
20	O
x	O
106	O
(	O
SD	O
1	O
.	O
53	O
x	O
106	O
)	O
for	O
the	O
Hofer	O
and	O
1	O
.	O
04	O
x	O
106	O
(	O
SD	O
0	O
.	O
91	O
x	O
106	O
)	O
for	O
the	O
Trout	O
Lodge	O
.	O

These	O
mean	O
values	O
and	O
standard	O
deviations	O
are	O
similar	O
to	O
those	O
obtained	O
in	O
additional	O
studies	O
of	O
susceptible	O
rainbow	B
trout	I
when	O
examined	O
at	O
early	O
time	O
points	O
post	O
TAM	O
exposure	O
(	O
unpublished	O
data	O
)	O
.	O

In	O
order	O
to	O
study	O
genes	O
involved	O
in	O
whirling	O
disease	O
response	O
,	O
resistant	O
and	O
susceptible	O
rainbow	B
trout	I
strains	O
were	O
exposed	O
to	O
M	B
.	I
cerebralis	I
and	O
RNA	O
from	O
skin	O
tissue	O
was	O
converted	O
to	O
cDNA	O
and	O
hybridized	O
onto	O
microarrays	O
.	O

Relative	O
gene	O
expression	O
for	O
exposed	O
and	O
unexposed	O
controls	O
for	O
each	O
strain	O
was	O
compared	O
and	O
the	O
list	O
of	O
differentially	O
expressed	O
genes	O
for	O
both	O
strains	O
is	O
found	O
in	O
Table	O
1	O
.	O

A	O
combined	O
total	O
of	O
17	O
genes	O
or	O
features	O
(	O
14	O
annotated	O
genes	O
,	O
3	O
unknown	O
features	O
)	O
were	O
differentially	O
expressed	O
in	O
one	O
or	O
both	O
strains	O
following	O
pathogen	O
exposure	O
and	O
are	O
involved	O
with	O
rainbow	B
trout	I
infection	O
response	O
to	O
whirling	O
disease	O
exposure	O
.	O

Several	O
of	O
these	O
genes	O
were	O
found	O
in	O
different	O
locations	O
on	O
the	O
array	O
as	O
unique	O
expressed	O
sequence	O
tag	O
(	O
EST	O
)	O
clones	O
and	O
their	O
repeated	O
presence	O
on	O
the	O
significance	O
gene	O
lists	O
provides	O
additional	O
support	O
for	O
their	O
involvement	O
in	O
the	O
whirling	O
disease	O
phenotype	O
.	O

The	O
small	O
number	O
of	O
genes	O
found	O
potentially	O
indicates	O
that	O
only	O
a	O
few	O
genes	O
contribute	O
to	O
the	O
phenotypic	O
differences	O
found	O
between	O
resistant	O
Hofer	O
and	O
susceptible	O
Trout	O
Lodge	O
,	O
at	O
least	O
in	O
terms	O
of	O
differential	O
gene	O
expression	O
,	O
during	O
early	O
disease	O
progression	O
in	O
the	O
skin	O
.	O

In	O
the	O
microarray	O
statistical	O
analysis	O
,	O
when	O
the	O
delta	O
value	O
was	O
adjusted	O
even	O
slightly	O
lower	O
,	O
the	O
FDR	O
estimate	O
increases	O
from	O
0	O
%	O
to	O
~	O
78	O
%	O
.	O

Since	O
increasing	O
the	O
FDR	O
cut	O
-	O
off	O
to	O
such	O
a	O
high	O
percentage	O
would	O
dramatically	O
reduce	O
power	O
,	O
we	O
chose	O
to	O
leave	O
the	O
gene	O
list	O
small	O
with	O
an	O
estimated	O
FDR	O
of	O
0	O
%	O
.	O

This	O
type	O
of	O
dramatic	O
increase	O
in	O
FDR	O
estimation	O
is	O
additional	O
support	O
that	O
there	O
are	O
not	O
many	O
genes	O
differentially	O
expressed	O
in	O
response	O
to	O
whirling	O
disease	O
infection	O
for	O
our	O
chosen	O
tissue	O
and	O
time	O
points	O
.	O

Different	O
salmonid	O
microarray	O
platforms	O
,	O
such	O
as	O
those	O
available	O
from	O
Oregon	O
State	O
University	O
and	O
Michigan	O
State	O
University	O
,	O
or	O
different	O
tissues	O
and	O
time	O
points	O
may	O
produce	O
additional	O
candidate	O
genes	O
.	O

A	O
recent	O
time	O
course	O
study	O
used	O
a	O
candidate	O
gene	O
approach	O
to	O
identify	O
four	O
genes	O
(	O
TGF	O
-	O
beta	O
,	O
IL	O
-	O
1	O
beta	O
1	O
,	O
IL	O
-	O
1	O
beta	O
2	O
,	O
and	O
COX	O
-	O
2	O
)	O
that	O
were	O
significantly	O
up	O
-	O
regulated	O
by	O
both	O
Hofer	O
and	O
Trout	O
Lodge	O
in	O
response	O
to	O
whirling	O
disease	O
infection	O
[	O
25	O
]	O
.	O

These	O
genes	O
and	O
their	O
downstream	O
effectors	O
were	O
not	O
identified	O
in	O
the	O
current	O
microarray	O
study	O
,	O
likely	O
due	O
to	O
many	O
differences	O
in	O
experimental	O
design	O
between	O
the	O
two	O
studies	O
(	O
e	O
.	O
g	O
.	O
,	O
pathogen	O
exposure	O
levels	O
,	O
tissue	O
types	O
,	O
water	O
temperatures	O
,	O
age	O
of	O
fish	O
at	O
exposure	O
,	O
etc	O
.	O
)	O
.	O

While	O
downstream	O
effectors	O
of	O
these	O
genes	O
were	O
present	O
on	O
the	O
microarray	O
,	O
only	O
one	O
of	O
the	O
four	O
genes	O
(	O
COX	O
-	O
2	O
)	O
was	O
actually	O
present	O
on	O
the	O
microarray	O
.	O

It	O
is	O
our	O
hope	O
that	O
future	O
genome	O
sequencing	O
will	O
enable	O
the	O
construction	O
of	O
more	O
comprehensive	O
microarray	O
platforms	O
for	O
economically	O
important	O
aquaculture	O
species	O
,	O
such	O
as	O
Atlantic	B
salmon	I
and	O
rainbow	B
trout	I
.	O

All	O
significant	O
genes	O
identified	O
by	O
the	O
current	O
microarray	O
study	O
were	O
up	O
-	O
regulated	O
following	O
pathogen	O
exposure	O
for	O
one	O
or	O
both	O
strains	O
.	O

Therefore	O
,	O
it	O
appears	O
that	O
both	O
strains	O
are	O
undergoing	O
transcriptional	O
activation	O
to	O
defend	O
against	O
whirling	O
disease	O
infection	O
and	O
thus	O
,	O
are	O
exclusively	O
employing	O
positive	O
regulation	O
for	O
the	O
genes	O
examined	O
in	O
skin	O
during	O
early	O
disease	O
progression	O
.	O

The	O
normal	O
caveats	O
that	O
apply	O
for	O
microarray	O
studies	O
(	O
gene	O
discovery	O
is	O
limited	O
by	O
transcripts	O
on	O
arrays	O
,	O
differences	O
at	O
transcriptional	O
level	O
may	O
not	O
cause	O
phenotypic	O
differences	O
,	O
results	O
are	O
dependent	O
upon	O
tissue	O
type	O
and	O
time	O
point	O
chosen	O
,	O
etc	O
.	O
)	O
apply	O
for	O
this	O
study	O
.	O

Additionally	O
,	O
the	O
comparison	O
of	O
two	O
rainbow	B
trout	I
strains	O
(	O
i	O
.	O
e	O
.	O
,	O
resistant	O
versus	O
susceptible	O
)	O
added	O
another	O
layer	O
of	O
complexity	O
to	O
the	O
analysis	O
.	O

We	O
chose	O
to	O
not	O
directly	O
compare	O
the	O
two	O
strains	O
because	O
there	O
could	O
be	O
expression	O
differences	O
between	O
them	O
,	O
due	O
to	O
divergence	O
following	O
strain	O
isolation	O
,	O
that	O
are	O
unrelated	O
to	O
the	O
whirling	O
disease	O
phenotype	O
.	O

With	O
that	O
in	O
mind	O
,	O
the	O
two	O
strains	O
were	O
first	O
compared	O
entirely	O
separately	O
from	O
each	O
other	O
to	O
discover	O
expression	O
differences	O
in	O
response	O
to	O
pathogen	O
exposure	O
for	O
each	O
strain	O
.	O

Only	O
the	O
genes	O
responding	O
to	O
infection	O
,	O
and	O
therefore	O
implicated	O
in	O
the	O
whirling	O
disease	O
phenotype	O
,	O
were	O
compared	O
between	O
the	O
two	O
strains	O
for	O
differential	O
gene	O
expression	O
(	O
Figure	O
1	O
)	O
.	O

A	O
limitation	O
of	O
this	O
approach	O
to	O
our	O
study	O
is	O
that	O
constitutively	O
expressed	O
transcripts	O
which	O
are	O
differentially	O
expressed	O
between	O
the	O
two	O
strains	O
that	O
contribute	O
to	O
the	O
whirling	O
disease	O
phenotype	O
cannot	O
be	O
identified	O
.	O

Microarray	O
analysis	O
of	O
genes	O
differentially	O
expressed	O
in	O
the	O
resistant	O
Hofer	O
strain	O
in	O
response	O
to	O
pathogen	O
exposure	O

A	O
total	O
of	O
16	O
genes	O
or	O
features	O
(	O
13	O
annotated	O
genes	O
,	O
3	O
unknown	O
features	O
)	O
were	O
up	O
-	O
regulated	O
in	O
the	O
resistant	O
Hofer	O
strain	O
following	O
pathogen	O
exposure	O
.	O

All	O
13	O
annotated	O
genes	O
have	O
been	O
previously	O
implicated	O
in	O
host	O
immune	O
response	O
for	O
other	O
infectious	O
diseases	O
.	O

Viral	B
Hemorrhagic	I
Septicemia	I
Virus	I
(	O
VHSV	B
)	O
induced	O
protein	O
and	O
neighbor	O
of	O
COX	O
-	O
4	O
are	O
the	O
only	O
annotated	O
genes	O
without	O
known	O
molecular	O
functions	O
.	O

A	O
common	O
link	O
between	O
the	O
majority	O
of	O
annotated	O
genes	O
with	O
known	O
molecular	O
functions	O
is	O
an	O
involvement	O
in	O
the	O
interferon	O
system	O
.	O

The	O
interferon	O
system	O
is	O
one	O
of	O
the	O
first	O
lines	O
of	O
host	O
defense	O
against	O
invading	O
pathogens	O
for	O
vertebrates	O
(	O
for	O
review	O
see	O
[	O
26	O
]	O
)	O
,	O
including	O
teleost	B
fish	I
(	O
for	O
review	O
see	O
[	O
27	O
]	O
)	O
.	O

Other	O
economically	O
important	O
salmonid	O
pathogens	O
,	O
such	O
as	O
infectious	B
pancreatic	I
necrosis	I
virus	I
and	O
infectious	B
salmon	I
anaemia	I
virus	I
have	O
been	O
found	O
to	O
activate	O
both	O
type	O
I	O
and	O
type	O
II	O
interferon	O
(	O
IFN	O
)	O
responses	O
in	O
the	O
Atlantic	B
salmon	I
host	O
following	O
infection	O
[	O
28	O
]	O
.	O

Interferons	O
are	O
cytokine	O
proteins	O
that	O
are	O
secreted	O
following	O
infection	O
and	O
play	O
a	O
critical	O
role	O
in	O
both	O
innate	O
and	O
adaptive	O
immunity	O
.	O

The	O
IFN	O
system	O
has	O
been	O
most	O
widely	O
researched	O
in	O
mammals	O
and	O
studies	O
have	O
found	O
that	O
type	O
I	O
IFN	O
(	O
mammalian	O
IFN	O
-	O
alpha	O
/	O
beta	O
)	O
are	O
secreted	O
by	O
the	O
pathogen	O
-	O
infected	O
cells	O
as	O
part	O
of	O
a	O
rapid	O
initial	O
immune	O
response	O
while	O
Type	O
II	O
IFN	O
(	O
mammalian	O
IFN	O
-	O
gamma	O
)	O
is	O
secreted	O
by	O
natural	O
killer	O
(	O
NK	O
)	O
and	O
T	O
cells	O
and	O
plays	O
a	O
more	O
central	O
role	O
in	O
the	O
second	O
wave	O
of	O
immune	O
response	O
.	O

To	O
cope	O
with	O
the	O
myriad	O
of	O
host	O
infections	O
,	O
the	O
interferon	O
system	O
is	O
highly	O
complex	O
and	O
involves	O
the	O
regulation	O
of	O
hundreds	O
of	O
genes	O
[	O
29	O
,	O
30	O
]	O
.	O

Specifically	O
,	O
type	O
I	O
IFN	O
acts	O
to	O
increase	O
MHC	O
class	O
I	O
expression	O
for	O
antigen	O
presentation	O
[	O
31	O
]	O
,	O
promote	O
T	O
cell	O
survival	O
[	O
32	O
]	O
,	O
inhibit	O
cell	O
proliferation	O
[	O
33	O
]	O
,	O
mediate	O
apoptosis	O
[	O
26	O
]	O
,	O
and	O
increase	O
NK	O
cell	O
activity	O
[	O
34	O
]	O
.	O

Type	O
II	O
IFN	O
acts	O
to	O
increase	O
both	O
MHC	O
class	O
I	O
and	O
II	O
expression	O
for	O
antigen	O
presentation	O
[	O
29	O
]	O
,	O
stimulate	O
macrophages	O
to	O
kill	O
engulfed	O
pathogens	O
[	O
35	O
]	O
,	O
induce	O
apoptosis	O
[	O
36	O
]	O
,	O
and	O
regulate	O
leukocyte	O
-	O
endothelium	O
interactions	O
[	O
37	O
]	O
in	O
addition	O
to	O
many	O
other	O
immune	O
-	O
related	O
activities	O
.	O

It	O
is	O
informative	O
to	O
examine	O
the	O
functional	O
roles	O
of	O
each	O
gene	O
'	O
s	O
encoded	O
protein	O
specifically	O
to	O
better	O
understand	O
the	O
part	O
each	O
plays	O
,	O
both	O
individually	O
and	O
as	O
interconnected	O
components	O
,	O
in	O
host	O
immune	O
response	O
.	O

Expression	O
of	O
the	O
interferon	O
-	O
induced	O
35	O
kDa	O
protein	O
is	O
induced	O
by	O
IFN	O
and	O
it	O
is	O
involved	O
in	O
cytokine	O
signalling	O
[	O
38	O
]	O
.	O

Interferon	O
regulatory	O
factor	O
1	O
(	O
IRF	O
-	O
1	O
)	O
and	O
interferon	O
regulatory	O
factor	O
7	O
(	O
IRF	O
-	O
7	O
)	O
are	O
transcription	O
factors	O
that	O
induce	O
expression	O
of	O
IFN	O
responsive	O
genes	O
[	O
39	O
,	O
40	O
]	O
.	O

Additionally	O
,	O
IRF	O
-	O
1	O
is	O
involved	O
in	O
apoptosis	O
and	O
cell	O
cycle	O
regulation	O
related	O
to	O
tumor	O
suppression	O
[	O
41	O
]	O
.	O

Similarly	O
,	O
cyclin	O
-	O
dependent	O
kinase	O
4	O
inhibitor	O
B	O
(	O
p15	O
-	O
INK4b	O
)	O
plays	O
a	O
role	O
in	O
apoptosis	O
[	O
42	O
]	O
,	O
cell	O
cycle	O
regulation	O
[	O
42	O
]	O
,	O
and	O
tumor	O
suppression	O
[	O
43	O
]	O
and	O
can	O
be	O
induced	O
by	O
the	O
cytokine	O
TGF	O
-	O
beta	O
[	O
44	O
]	O
.	O

Gig2	O
is	O
an	O
interferon	O
-	O
inducible	O
protein	O
that	O
is	O
likely	O
part	O
of	O
the	O
JAK	O
-	O
STAT	O
signal	O
transduction	O
pathway	O
[	O
45	O
]	O
.	O

Ubiquitin	O
and	O
the	O
proteasome	O
subunit	O
beta	O
type	O
8	O
precursor	O
are	O
both	O
members	O
of	O
the	O
ubiquitin	O
-	O
proteasome	O
system	O
(	O
for	O
review	O
see	O
[	O
26	O
]	O
)	O
,	O
which	O
serves	O
to	O
degrade	O
proteins	O
via	O
proteolysis	O
.	O

These	O
degraded	O
proteins	O
can	O
originate	O
from	O
an	O
invading	O
pathogen	O
and	O
are	O
displayed	O
on	O
MHC	O
class	O
I	O
proteins	O
.	O

The	O
beta	O
-	O
2	O
-	O
microglobulin	O
is	O
an	O
integral	O
component	O
of	O
MHC	O
class	O
I	O
proteins	O
and	O
is	O
therefore	O
involved	O
in	O
antigen	O
processing	O
and	O
presentation	O
to	O
cytotoxic	O
T	O
cells	O
[	O
46	O
]	O
.	O

Haptoglobin	O
binds	O
hemoglobin	O
and	O
limits	O
its	O
availability	O
to	O
infectious	O
bacteria	O
,	O
thus	O
preventing	O
bacterial	O
proliferation	O
in	O
a	O
wound	O
[	O
47	O
]	O
.	O

The	O
PPAR	O
-	O
alpha	O
-	O
interacting	O
complex	O
protein	O
285	O
is	O
a	O
transcriptional	O
co	O
-	O
activator	O
with	O
helicase	O
activity	O
[	O
48	O
]	O
and	O
has	O
sequence	O
similarity	O
to	O
a	O
rainbow	B
trout	I
VHSV	B
-	O
induced	O
protein	O
.	O

Gene	O
expression	O
of	O
metallothionein	O
B	O
(	O
MT	O
-	O
B	O
)	O
is	O
induced	O
by	O
several	O
metal	O
ions	O
[	O
49	O
]	O
,	O
cytokines	O
[	O
50	O
-	O
52	O
]	O
,	O
and	O
stress	O
hormones	O
[	O
53	O
-	O
55	O
]	O
.	O

MT	O
proteins	O
are	O
believed	O
to	O
play	O
diverse	O
functional	O
roles	O
in	O
inflammation	O
,	O
immune	O
response	O
,	O
apoptosis	O
,	O
tumor	O
suppression	O
,	O
and	O
detoxification	O
(	O
for	O
reviews	O
see	O
[	O
55	O
,	O
56	O
]	O
)	O
.	O

Microarray	O
analysis	O
of	O
genes	O
differentially	O
expressed	O
in	O
the	O
susceptible	O
Trout	O
Lodge	O
strain	O
in	O
response	O
to	O
pathogen	O
exposure	O

A	O
total	O
of	O
six	O
genes	O
or	O
features	O
(	O
five	O
annotated	O
genes	O
,	O
one	O
unknown	O
feature	O
)	O
were	O
up	O
-	O
regulated	O
in	O
the	O
susceptible	O
Trout	O
Lodge	O
strain	O
following	O
pathogen	O
exposure	O
.	O

Only	O
one	O
of	O
the	O
significant	O
genes	O
for	O
Trout	O
Lodge	O
,	O
which	O
has	O
sequence	O
similarity	O
to	O
CC	O
chemokine	O
SCYA113	O
,	O
was	O
not	O
also	O
differentially	O
expressed	O
in	O
Hofer	O
in	O
response	O
to	O
pathogen	O
exposure	O
.	O

The	O
CC	O
chemokine	O
SCYA113	O
gene	O
is	O
a	O
member	O
of	O
the	O
CC	O
chemokine	O
family	O
,	O
which	O
guides	O
leukocytes	O
to	O
sites	O
of	O
infection	O
and	O
inflammation	O
(	O
for	O
review	O
see	O
[	O
57	O
]	O
)	O
.	O

The	O
fewer	O
number	O
of	O
significant	O
genes	O
found	O
for	O
Trout	O
Lodge	O
relative	O
to	O
Hofer	O
may	O
indicate	O
a	O
decrease	O
in	O
transcriptional	O
activation	O
for	O
this	O
susceptible	O
strain	O
.	O

There	O
is	O
,	O
however	O
,	O
likely	O
some	O
degree	O
of	O
overlap	O
in	O
both	O
strains	O
'	O
response	O
to	O
pathogen	O
exposure	O
due	O
to	O
the	O
fact	O
that	O
several	O
genes	O
were	O
up	O
-	O
regulated	O
in	O
both	O
Hofer	O
and	O
Trout	O
Lodge	O
(	O
i	O
.	O
e	O
.	O
,	O
ubiquitin	O
-	O
like	O
protein	O
1	O
,	O
IRF	O
-	O
1	O
,	O
and	O
PPAR	O
-	O
alpha	O
-	O
interacting	O
protein	O
Gig2	O
)	O
.	O

A	O
critical	O
phase	O
in	O
the	O
early	O
stages	O
of	O
M	B
.	I
cerebralis	I
infection	O
in	O
trout	O
is	O
invasion	O
and	O
intracellular	O
replication	O
,	O
processes	O
that	O
begin	O
as	O
early	O
as	O
one	O
hour	O
post	O
exposure	O
to	O
triactinomyxons	O
[	O
16	O
]	O
.	O

A	O
role	O
for	O
accumulated	O
ubiquinated	O
proteins	O
in	O
the	O
lysosome	O
in	O
the	O
killing	O
of	O
Mycobacterium	B
tuberculosis	I
has	O
recently	O
been	O
described	O
that	O
has	O
implications	O
for	O
a	O
range	O
of	O
intracellular	O
infections	O
[	O
58	O
]	O
and	O
some	O
similar	O
responses	O
to	O
infection	O
may	O
be	O
occurring	O
for	O
both	O
resistant	O
and	O
susceptible	O
strains	O
.	O

Microarray	O
analysis	O
of	O
genes	O
differentially	O
expressed	O
between	O
resistant	O
and	O
susceptible	O
strains	O
in	O
response	O
to	O
pathogen	O
exposure	O

Of	O
the	O
genes	O
differentially	O
expressed	O
in	O
response	O
to	O
pathogen	O
exposure	O
for	O
both	O
strains	O
,	O
only	O
metallothionein	O
B	O
shows	O
a	O
statistically	O
significant	O
difference	O
in	O
expression	O
between	O
the	O
two	O
strains	O
(	O
Table	O
2	O
)	O
.	O

MT	O
-	O
B	O
was	O
found	O
to	O
be	O
up	O
-	O
regulated	O
in	O
the	O
resistant	O
Hofer	O
strain	O
following	O
pathogen	O
exposure	O
but	O
remained	O
unchanged	O
in	O
the	O
susceptible	O
Trout	O
Lodge	O
strain	O
.	O

As	O
previously	O
noted	O
,	O
metallothionein	O
has	O
been	O
implicated	O
in	O
a	O
broad	O
range	O
of	O
functional	O
capacities	O
,	O
including	O
inflammatory	O
and	O
immune	O
responses	O
.	O

Several	O
cytokines	O
can	O
induce	O
metallothionein	O
expression	O
including	O
IFN	O
[	O
59	O
-	O
61	O
]	O
,	O
interleukin	O
-	O
1	O
[	O
50	O
]	O
,	O
interleukin	O
-	O
6	O
[	O
51	O
]	O
,	O
and	O
tumor	O
necrosis	O
factor	O
-	O
alpha	O
[	O
52	O
]	O
.	O

Metallothionein	O
has	O
been	O
shown	O
to	O
mediate	O
leukocyte	O
chemotaxis	O
and	O
has	O
been	O
hypothesized	O
to	O
serve	O
as	O
an	O
early	O
"	O
danger	O
signal	O
"	O
during	O
times	O
of	O
stress	O
or	O
infection	O
to	O
activate	O
an	O
immune	O
response	O
[	O
62	O
]	O
.	O

The	O
functional	O
similarities	O
between	O
metallothionein	O
and	O
CC	O
chemokine	O
SCYA113	O
,	O
at	O
least	O
in	O
terms	O
of	O
leukocyte	O
chemotaxis	O
,	O
are	O
certainly	O
of	O
interest	O
since	O
these	O
genes	O
displayed	O
quite	O
distinct	O
expression	O
profiles	O
.	O

Metallothionein	O
was	O
up	O
-	O
regulated	O
in	O
the	O
resistant	O
Hofer	O
strain	O
and	O
CC	O
chemokine	O
SCYA113	O
was	O
up	O
-	O
regulated	O
in	O
the	O
susceptible	O
Trout	O
Lodge	O
strain	O
(	O
although	O
CC	O
chemokine	O
SCYA113	O
did	O
not	O
pass	O
the	O
significance	O
cut	O
-	O
off	O
to	O
be	O
considered	O
differentially	O
expressed	O
between	O
the	O
two	O
strains	O
)	O
.	O

This	O
distinction	O
between	O
two	O
genes	O
,	O
capable	O
of	O
similar	O
biological	O
roles	O
,	O
may	O
indicate	O
that	O
leukocyte	O
movements	O
to	O
,	O
and	O
their	O
activities	O
once	O
at	O
,	O
the	O
infection	O
site	O
are	O
key	O
factors	O
in	O
determining	O
resistance	O
versus	O
susceptibility	O
to	O
whirling	O
disease	O
.	O

Evaluations	O
by	O
light	O
microscopy	O
and	O
qPCR	O
for	O
M	B
.	I
cerebralis	I
genomic	O
DNA	O
of	O
Hofer	O
and	O
Trout	O
Lodge	O
rainbow	B
trout	I
exposed	O
to	O
triactinomyxons	O
demonstrates	O
Hofer	O
more	O
efficiently	O
eliminates	O
invading	O
parasites	O
in	O
the	O
skin	O
(	O
M	O
.	O
Adkison	O
,	O
pers	O
.	O
comm	O
.	O
)	O
.	O

While	O
the	O
parasite	O
effectively	O
penetrates	O
the	O
epidermis	O
in	O
both	O
strains	O
,	O
significantly	O
fewer	O
parasites	O
survive	O
the	O
migration	O
from	O
the	O
skin	O
to	O
the	O
nerves	O
as	O
evaluated	O
at	O
10	O
d	O
post	O
exposure	O
.	O

A	O
role	O
for	O
host	O
immune	O
factors	O
in	O
the	O
elimination	O
of	O
invading	O
parasites	O
,	O
even	O
in	O
susceptible	O
rainbow	B
trout	I
strains	O
,	O
is	O
suggested	O
by	O
several	O
prior	O
light	O
and	O
electron	O
microscopy	O
studies	O
that	O
demonstrate	O
an	O
increase	O
in	O
degenerative	O
stages	O
in	O
the	O
skin	O
beginning	O
as	O
early	O
as	O
12	O
h	O
and	O
then	O
their	O
elimination	O
by	O
24	O
h	O
post	O
-	O
exposure	O
to	O
triactinomyxons	O
[	O
12	O
,	O
16	O
,	O
63	O
]	O
.	O

The	O
difference	O
in	O
metallothionein	O
expression	O
may	O
be	O
due	O
to	O
an	O
alternative	O
immune	O
response	O
pathway	O
since	O
the	O
protein	O
has	O
known	O
involvement	O
in	O
diverse	O
functional	O
capacities	O
.	O

For	O
instance	O
,	O
metallothionein	O
'	O
s	O
role	O
as	O
a	O
zinc	O
-	O
finger	O
transcriptional	O
regulator	O
[	O
64	O
]	O
may	O
dramatically	O
alter	O
the	O
expression	O
profiles	O
between	O
resistant	O
and	O
susceptible	O
rainbow	B
trout	I
.	O

All	O
biological	O
roles	O
of	O
this	O
diverse	O
protein	O
should	O
be	O
considered	O
when	O
examining	O
the	O
complexities	O
of	O
host	O
immune	O
response	O
.	O

Additionally	O
,	O
upstream	O
regulators	O
of	O
metallothionein	O
expression	O
could	O
be	O
the	O
true	O
underlying	O
cause	O
of	O
the	O
whirling	O
disease	O
phenotype	O
since	O
a	O
gene	O
expression	O
study	O
alone	O
cannot	O
determine	O
if	O
a	O
gene	O
is	O
directly	O
contributing	O
to	O
a	O
phenotype	O
(	O
i	O
.	O
e	O
.	O
,	O
cause	O
versus	O
downstream	O
effect	O
)	O
.	O

Validation	O
of	O
microarray	O
results	O
by	O
qRT	O
-	O
PCR	O

Quantitative	O
RT	O
-	O
PCR	O
(	O
qRT	O
-	O
PCR	O
)	O
confirmed	O
the	O
microarrays	O
results	O
for	O
two	O
of	O
the	O
genes	O
up	O
-	O
regulated	O
in	O
both	O
Hofer	O
and	O
Trout	O
Lodge	O
following	O
infection	O
,	O
ubiquitin	O
and	O
IRF	O
-	O
1	O
,	O
and	O
the	O
metallothionein	O
gene	O
(	O
MT	O
-	O
B	O
)	O
,	O
which	O
was	O
up	O
-	O
regulated	O
in	O
Hofer	O
but	O
remained	O
unchanged	O
in	O
Trout	O
Lodge	O
following	O
infection	O
(	O
Figure	O
2	O
)	O
.	O

The	O
qRT	O
-	O
PCR	O
results	O
for	O
IRF	O
-	O
1	O
and	O
metallothionein	O
were	O
quite	O
similar	O
to	O
the	O
microarray	O
results	O
for	O
each	O
gene	O
,	O
in	O
terms	O
of	O
relative	O
expression	O
changes	O
in	O
response	O
to	O
infection	O
.	O

MT	O
-	O
B	O
was	O
found	O
to	O
once	O
again	O
be	O
significantly	O
up	O
-	O
regulated	O
in	O
the	O
resistant	O
Hofer	O
strain	O
following	O
pathogen	O
exposure	O
but	O
remained	O
unchanged	O
in	O
the	O
susceptible	O
Trout	O
Lodge	O
.	O

This	O
difference	O
in	O
MT	O
-	O
B	O
gene	O
expression	O
between	O
the	O
two	O
strains	O
was	O
statistically	O
significant	O
(	O
P	O
~	O
0	O
.	O
001	O
)	O
.	O

The	O
relative	O
degree	O
of	O
up	O
-	O
regulation	O
for	O
ubiquitin	O
following	O
pathogen	O
exposure	O
was	O
considerably	O
higher	O
in	O
the	O
qRT	O
-	O
PCR	O
(	O
~	O
9	O
-	O
17	O
fold	O
greater	O
up	O
-	O
regulation	O
in	O
qRT	O
-	O
PCR	O
versus	O
microarrays	O
)	O
.	O

Many	O
other	O
studies	O
have	O
also	O
observed	O
this	O
pattern	O
of	O
greater	O
sensitivity	O
in	O
qRT	O
-	O
PCR	O
versus	O
microarray	O
results	O
(	O
for	O
examples	O
see	O
[	O
65	O
,	O
66	O
]	O
,	O
which	O
is	O
often	O
attributed	O
to	O
the	O
more	O
gene	O
-	O
specific	O
optimized	O
conditions	O
of	O
the	O
qRT	O
-	O
PCR	O
approach	O
.	O

Given	O
the	O
high	O
degree	O
of	O
statistical	O
support	O
and	O
biological	O
relevance	O
of	O
the	O
candidate	O
genes	O
,	O
we	O
believe	O
this	O
study	O
provides	O
initial	O
insight	O
into	O
rainbow	B
trout	I
genes	O
and	O
pathways	O
responding	O
to	O
whirling	O
disease	O
infection	O
and	O
identifies	O
the	O
first	O
candidate	O
genes	O
for	O
whirling	O
disease	O
resistance	O
.	O

Potential	O
future	O
studies	O

While	O
the	O
interferon	O
system	O
appears	O
to	O
be	O
a	O
likely	O
candidate	O
system	O
for	O
further	O
study	O
,	O
many	O
of	O
the	O
significant	O
genes	O
are	O
found	O
in	O
alternative	O
pathways	O
and	O
have	O
distinct	O
roles	O
and	O
functions	O
in	O
other	O
systems	O
.	O

Furthermore	O
,	O
it	O
is	O
increasingly	O
apparent	O
that	O
epistatic	O
interactions	O
and	O
the	O
interplay	O
between	O
pathways	O
/	O
networks	O
previously	O
classified	O
as	O
discrete	O
can	O
have	O
enormous	O
phenotypic	O
effects	O
on	O
quantitative	O
traits	O
[	O
67	O
]	O
.	O

Multiple	O
avenues	O
of	O
research	O
should	O
be	O
examined	O
in	O
future	O
studies	O
,	O
using	O
the	O
candidate	O
genes	O
presented	O
here	O
as	O
an	O
initial	O
guide	O
,	O
due	O
to	O
the	O
complex	O
relationships	O
between	O
hosts	O
and	O
pathogens	O
.	O

For	O
instance	O
,	O
the	O
migration	O
of	O
leukocytes	O
and	O
their	O
subsequent	O
activity	O
in	O
the	O
skin	O
are	O
likely	O
a	O
critical	O
part	O
of	O
the	O
early	O
immune	O
and	O
inflammatory	O
host	O
response	O
after	O
pathogen	O
infection	O
.	O

Additionally	O
,	O
it	O
is	O
quite	O
feasible	O
that	O
the	O
difference	O
in	O
metallothionein	O
expression	O
is	O
due	O
to	O
an	O
alternative	O
immune	O
response	O
pathway	O
since	O
the	O
protein	O
has	O
known	O
involvement	O
in	O
diverse	O
functional	O
capacities	O
.	O

For	O
instance	O
,	O
metallothionein	O
'	O
s	O
role	O
as	O
a	O
zinc	O
-	O
finger	O
transcriptional	O
regulator	O
[	O
64	O
]	O
may	O
dramatically	O
alter	O
the	O
expression	O
profiles	O
between	O
resistant	O
and	O
susceptible	O
rainbow	B
trout	I
.	O

All	O
biological	O
roles	O
of	O
this	O
diverse	O
protein	O
should	O
be	O
considered	O
when	O
examining	O
the	O
complexities	O
of	O
host	O
immune	O
response	O
.	O

Finally	O
,	O
upstream	O
regulators	O
of	O
metallothionein	O
expression	O
could	O
be	O
the	O
true	O
underlying	O
cause	O
of	O
the	O
whirling	O
disease	O
phenotype	O
since	O
a	O
gene	O
expression	O
study	O
alone	O
cannot	O
determine	O
if	O
a	O
gene	O
is	O
directly	O
contributing	O
to	O
a	O
phenotype	O
(	O
i	O
.	O
e	O
.	O
,	O
cause	O
versus	O
downstream	O
effect	O
)	O
.	O

The	O
expression	O
profiles	O
of	O
a	O
variety	O
of	O
metallothionein	O
upstream	O
regulators	O
,	O
such	O
as	O
cytokines	O
and	O
metal	O
transcription	O
factor	O
(	O
MTF	O
-	O
1	O
)	O
,	O
could	O
be	O
evaluated	O
in	O
a	O
time	O
course	O
study	O
during	O
early	O
disease	O
progression	O
to	O
identify	O
additional	O
candidate	O
genes	O
.	O

A	O
QTL	O
mapping	O
approach	O
could	O
also	O
be	O
used	O
to	O
identify	O
particular	O
chromosomal	O
regions	O
directly	O
contributing	O
to	O
the	O
disease	O
phenotype	O
.	O

Conclusion	O

The	O
present	O
study	O
has	O
provided	O
the	O
first	O
examination	O
into	O
the	O
genetic	O
basis	O
underlying	O
rainbow	B
trout	I
'	O
s	O
immune	O
response	O
and	O
resistance	O
to	O
the	O
whirling	O
disease	O
pathogen	O
.	O

Several	O
genes	O
were	O
significantly	O
up	O
-	O
regulated	O
in	O
skin	O
following	O
pathogen	O
exposure	O
for	O
both	O
the	O
resistant	O
Hofer	O
and	O
susceptible	O
Trout	O
Lodge	O
rainbow	B
trout	I
strains	O
.	O

For	O
both	O
strains	O
,	O
response	O
to	O
infection	O
appears	O
to	O
be	O
linked	O
with	O
the	O
interferon	O
system	O
.	O

Metallothionein	O
B	O
is	O
differentially	O
expressed	O
between	O
the	O
resistant	O
and	O
susceptible	O
strains	O
and	O
is	O
a	O
good	O
candidate	O
for	O
future	O
whirling	O
disease	O
resistance	O
studies	O
.	O

The	O
identified	O
genes	O
have	O
allowed	O
us	O
to	O
gain	O
initial	O
insight	O
into	O
the	O
molecular	O
mechanisms	O
involved	O
in	O
a	O
salmonid	O
host	O
'	O
s	O
immune	O
response	O
and	O
resistance	O
to	O
whirling	O
disease	O
infection	O
.	O

Methods	O

Animal	O
care	O
,	O
pathogen	O
exposure	O
,	O
and	O
RNA	O
preparation	O

Hofer	O
and	O
Trout	O
Lodge	O
rainbow	B
trout	I
strains	O
were	O
reared	O
in	O
35	O
gallon	O
aquaria	O
with	O
15	O
degrees	O
C	O
flow	O
-	O
through	O
well	O
water	O
for	O
nine	O
weeks	O
post	O
-	O
hatch	O
,	O
with	O
each	O
fish	O
weighing	O
approximately	O
6	O
.	O
5	O
grams	O
prior	O
to	O
pathogen	O
exposure	O
.	O

Individuals	O
from	O
each	O
strain	O
(	O
n	O
=	O
60	O
)	O
were	O
exposed	O
to	O
2	O
,	O
000	O
triactinomyxons	O
(	O
TAMs	O
)	O
per	O
fish	O
for	O
one	O
hour	O
.	O

Additional	O
fish	O
(	O
n	O
=	O
60	O
)	O
from	O
both	O
strains	O
served	O
as	O
unexposed	O
controls	O
,	O
which	O
were	O
treated	O
identically	O
to	O
exposed	O
fish	O
at	O
all	O
experimental	O
stages	O
other	O
than	O
their	O
lack	O
of	O
pathogen	O
exposure	O
.	O

Fish	O
were	O
then	O
kept	O
under	O
standard	O
aquaculture	O
conditions	O
until	O
euthanized	O
.	O

TaqMan	O
PCR	O
for	O
the	O
quantitative	O
evaluation	O
of	O
genomic	O
parasite	O
DNA	O
was	O
employed	O
to	O
confirm	O
that	O
fish	O
in	O
both	O
the	O
Hofer	O
and	O
Trout	O
Lodge	O
groups	O
received	O
equal	O
amounts	O
of	O
parasite	O
exposure	O
.	O

At	O
two	O
hours	O
post	O
TAM	O
exposure	O
,	O
6	O
fish	O
in	O
each	O
exposed	O
group	O
were	O
removed	O
and	O
euthanized	O
with	O
an	O
overdose	O
of	O
benzocaine	O
at	O
a	O
concentration	O
of	O
500	O
mg	O
/	O
L	O
.	O

Caudal	O
fins	O
were	O
removed	O
posterior	O
to	O
the	O
peduncle	O
and	O
used	O
as	O
the	O
tissue	O
for	O
a	O
quantiative	O
TaqMan	O
assay	O
following	O
procedures	O
described	O
by	O
Kelley	O
et	O
al	O
.	O

[	O
68	O
]	O
.	O

Microarray	O
studies	O
examining	O
skin	O
four	O
hours	O
after	O
pathogen	O
exposure	O
did	O
not	O
identify	O
any	O
genes	O
differentially	O
expressed	O
between	O
Trout	O
Lodge	O
and	O
Hofer	O
strains	O
(	O
data	O
not	O
shown	O
)	O
.	O

Therefore	O
,	O
we	O
chose	O
a	O
later	O
time	O
point	O
(	O
24	O
hours	O
after	O
exposure	O
)	O
so	O
that	O
early	O
host	O
immune	O
response	O
was	O
more	O
likely	O
to	O
be	O
fully	O
underway	O
and	O
significant	O
expression	O
changes	O
could	O
be	O
detected	O
.	O

After	O
the	O
24	O
hour	O
incubation	O
period	O
,	O
all	O
fish	O
were	O
euthanized	O
with	O
an	O
overdose	O
of	O
benzocaine	O
at	O
a	O
concentration	O
of	O
500	O
mg	O
/	O
L	O
.	O

Each	O
fish	O
was	O
euthanized	O
individually	O
and	O
the	O
caudal	O
fin	O
(	O
largely	O
comprised	O
of	O
skin	O
tissue	O
)	O
was	O
removed	O
posterior	O
to	O
the	O
peduncle	O
.	O

The	O
fin	O
was	O
immediately	O
placed	O
into	O
2	O
x	O
Nucleic	O
Acid	O
Purification	O
Lysis	O
Solution	O
supplied	O
with	O
ABI	O
'	O
s	O
TransPrep	O
Chemistry	O
kit	O
(	O
Applied	O
Biosystems	O
,	O
Foster	O
City	O
,	O
CA	O
)	O
to	O
stop	O
further	O
gene	O
expression	O
changes	O
.	O

Total	O
RNA	O
was	O
extracted	O
from	O
the	O
fin	O
of	O
each	O
individual	O
using	O
the	O
ABI	O
Prism	O
(	O
TM	O
)	O
TransPrep	O
system	O
with	O
the	O
ABI	O
Prism	O
(	O
TM	O
)	O
6100	O
Nucleic	O
Acid	O
PrepStation	O
according	O
to	O
manufacturer	O
instructions	O
.	O

RNA	O
quality	O
was	O
assessed	O
by	O
agarose	O
gel	O
electrophoresis	O
and	O
RNA	O
concentrations	O
were	O
measured	O
using	O
a	O
ND	O
-	O
1000	O
spectrophotometer	O
(	O
NanoDrop	O
Technologies	O
,	O
Wilmington	O
,	O
DE	O
)	O
.	O

Starting	O
total	O
RNA	O
yields	O
were	O
not	O
sufficient	O
for	O
microarray	O
hybridizations	O
due	O
to	O
the	O
small	O
amount	O
of	O
caudal	O
fin	O
tissue	O
present	O
on	O
these	O
young	O
fish	O
.	O

Therefore	O
,	O
250	O
-	O
1000	O
ng	O
of	O
total	O
RNA	O
was	O
used	O
as	O
the	O
starting	O
material	O
to	O
create	O
amplified	O
RNA	O
(	O
aRNA	O
)	O
indirectly	O
labeled	O
with	O
Cy3	O
or	O
Cy5	O
fluorescent	O
dyes	O
(	O
GE	O
Healthcare	O
,	O
Buckinghamshire	O
,	O
UK	O
)	O
using	O
the	O
Amino	O
Allyl	O
MessageAmp	O
(	O
TM	O
)	O
II	O
aRNA	O
Amplification	O
kit	O
according	O
to	O
manufacturer	O
instructions	O
(	O
Ambion	O
,	O
Austin	O
,	O
TX	O
)	O
.	O

Microarray	O
hybridization	O
and	O
data	O
analysis	O

Salmonid	O
cDNA	O
microarrays	O
(	O
GRASP16k	O
v2	O
.	O
0	O
)	O
were	O
obtained	O
from	O
consortium	O
for	O
Genomic	O
Research	O
on	O
Atlantic	O
Salmon	O
(	O
cGRASP	O
)	O
and	O
details	O
of	O
microarray	O
development	O
and	O
fabrication	O
can	O
be	O
found	O
in	O
von	O
Schalburg	O
et	O
al	O
.	O

[	O
69	O
]	O
.	O

These	O
arrays	O
contain	O
13	O
,	O
421	O
Atlantic	B
salmon	I
and	O
2	O
,	O
576	O
rainbow	B
trout	I
cDNA	O
features	O
and	O
have	O
been	O
successfully	O
used	O
for	O
several	O
previous	O
rainbow	B
trout	I
gene	O
expression	O
studies	O
[	O
70	O
-	O
73	O
]	O
.	O

For	O
each	O
rainbow	B
trout	I
strain	O
,	O
competitive	O
hybridization	O
was	O
conducted	O
on	O
every	O
array	O
using	O
equal	O
amounts	O
(	O
8	O
mu	O
g	O
)	O
of	O
differentially	O
labeled	O
aRNA	O
from	O
one	O
control	O
fish	O
and	O
one	O
exposed	O
fish	O
.	O

Four	O
biological	O
replicates	O
were	O
performed	O
for	O
each	O
experimental	O
condition	O
and	O
dye	O
-	O
sample	O
coupling	O
was	O
swapped	O
between	O
biological	O
replicates	O
in	O
a	O
balanced	O
block	O
design	O
.	O

Prehybridization	O
washes	O
for	O
all	O
microarrays	O
included	O
:	O
2	O
x	O
5	O
min	O
in	O
0	O
.	O
1	O
%	O
SDS	O
,	O
5	O
x	O
1	O
min	O
in	O
NANOpure	O
H2O	O
with	O
0	O
.	O
5	O
mM	O
dithiothreotol	O
,	O
1	O
min	O
in	O
near	O
boiling	O
nanopure	O
H2O	O
,	O
centrifugation	O
for	O
2	O
min	O
at	O
1500	O
RPM	O
.	O

To	O
reduce	O
background	O
,	O
the	O
microarrays	O
were	O
next	O
incubated	O
for	O
90	O
min	O
in	O
5	O
x	O
SSC	O
,	O
0	O
.	O
1	O
%	O
SDS	O
,	O
3	O
%	O
BSA	O
(	O
Fraction	O
V	O
)	O
at	O
49	O
degrees	O
C	O
,	O
washed	O
3	O
x	O
20	O
s	O
in	O
nanopure	O
H2O	O
,	O
and	O
dried	O
by	O
centrifugation	O
for	O
5	O
min	O
at	O
1500	O
RPM	O
.	O

The	O
labeled	O
aRNA	O
samples	O
were	O
competitively	O
hybridized	O
to	O
microarrays	O
prewarmed	O
to	O
49	O
degrees	O
C	O
for	O
16	O
hours	O
in	O
a	O
formamide	O
-	O
based	O
buffer	O
(	O
Genisphere	O
,	O
Hatfield	O
,	O
PA	O
)	O
with	O
LNA	O
dT	O
blocker	O
(	O
Genisphere	O
)	O
.	O

Posthybridization	O
washes	O
for	O
all	O
microarrays	O
included	O
:	O
1	O
x	O
10	O
min	O
in	O
2	O
x	O
SSC	O
,	O
0	O
.	O
1	O
%	O
SDS	O
prewarmed	O
to	O
49	O
degrees	O
C	O
,	O
2	O
x	O
5	O
min	O
in	O
2	O
x	O
SSC	O
,	O
0	O
.	O
1	O
%	O
SDS	O
at	O
room	O
temperature	O
,	O
2	O
x	O
5	O
min	O
1	O
x	O
SSC	O
at	O
room	O
temperature	O
,	O
2	O
x	O
5	O
min	O
0	O
.	O
1	O
x	O
SSC	O
at	O
room	O
temperature	O
.	O

Slides	O
were	O
then	O
dried	O
by	O
centrifugation	O
and	O
immediately	O
scanned	O
using	O
an	O
Agilent	O
G2565BA	O
Microarray	O
Scanner	O
(	O
Agilent	O
Technologies	O
,	O
Santa	O
Clara	O
,	O
CA	O
)	O
.	O

Data	O
underwent	O
local	O
background	O
subtraction	O
and	O
LOWESS	O
normalization	O
using	O
Agilent	O
'	O
s	O
Feature	O
Extraction	O
software	O
.	O

Raw	O
and	O
processed	O
gene	O
expression	O
data	O
have	O
been	O
deposited	O
into	O
the	O
NCBI	O
Gene	O
Expression	O
Omnibus	O
[	O
74	O
]	O
(	O
series	O
GSE8631	O
)	O
and	O
are	O
in	O
compliance	O
with	O
MIAME	O
guidelines	O
.	O

The	O
Significance	O
Analysis	O
of	O
Microarrays	O
(	O
SAM	O
)	O
software	O
package	O
[	O
75	O
]	O
was	O
used	O
to	O
identify	O
differentially	O
expressed	O
genes	O
between	O
exposed	O
and	O
unexposed	O
control	O
fish	O
for	O
each	O
rainbow	B
trout	I
strain	O
.	O

Both	O
a	O
Wilcoxon	O
rank	O
sum	O
and	O
a	O
modified	O
t	O
-	O
test	O
were	O
conducted	O
with	O
1	O
,	O
000	O
permutations	O
and	O
the	O
minimum	O
fold	O
change	O
cut	O
-	O
off	O
was	O
set	O
to	O
2	O
.	O
0	O
up	O
-	O
or	O
down	O
-	O
regulated	O
.	O

A	O
false	O
discovery	O
rate	O
(	O
FDR	O
)	O
of	O
0	O
.	O
00	O
%	O
was	O
estimated	O
for	O
both	O
strains	O
.	O

To	O
determine	O
statistically	O
significant	O
differences	O
between	O
the	O
Hofer	O
and	O
Trout	O
Lodge	O
strains	O
,	O
a	O
Welch	O
'	O
s	O
t	O
-	O
test	O
(	O
P	O
-	O
value	O
<	O
0	O
.	O
01	O
)	O
was	O
implemented	O
in	O
Microsoft	O
Excel	O
between	O
the	O
log	O
ratios	O
(	O
exposed	O
/	O
control	O
)	O
for	O
each	O
strain	O
for	O
all	O
genes	O
that	O
were	O
significant	O
for	O
at	O
least	O
one	O
strain	O
in	O
the	O
SAM	O
program	O
.	O

Quantitative	O
RT	O
-	O
PCR	O

Microarray	O
expression	O
results	O
were	O
validated	O
by	O
qRT	O
-	O
PCR	O
for	O
several	O
identified	O
genes	O
.	O

Prior	O
to	O
qRT	O
-	O
PCR	O
,	O
80	O
ng	O
of	O
total	O
RNA	O
was	O
reverse	O
transcribed	O
from	O
each	O
biological	O
replicate	O
used	O
for	O
the	O
microarray	O
study	O
along	O
with	O
two	O
additional	O
samples	O
(	O
total	O
n	O
=	O
6	O
per	O
experimental	O
condition	O
)	O
using	O
the	O
QuantiScript	O
Reverse	O
Transcriptase	O
kit	O
(	O
Qiagen	O
,	O
Valencia	O
,	O
CA	O
)	O
according	O
to	O
manufacturer	O
instructions	O
.	O

In	O
contrast	O
to	O
the	O
microarray	O
experiments	O
,	O
the	O
template	O
RNA	O
was	O
not	O
amplified	O
before	O
cDNA	O
synthesis	O
.	O

EST	O
clone	O
sequences	O
from	O
the	O
cGRASP	O
microarray	O
were	O
used	O
to	O
design	O
primers	O
for	O
genes	O
undergoing	O
validation	O
,	O
along	O
with	O
a	O
beta	O
-	O
actin	O
reference	O
gene	O
used	O
for	O
normalization	O
,	O
with	O
Primer3	O
software	O
[	O
76	O
]	O
and	O
the	O
sequence	O
for	O
each	O
primer	O
pair	O
is	O
shown	O
in	O
Table	O
3	O
.	O

The	O
Quantitect	O
(	O
TM	O
)	O
SYBR	O
(	O
R	O
)	O
Green	O
RT	O
-	O
PCR	O
kit	O
(	O
Qiagen	O
)	O
was	O
used	O
according	O
to	O
the	O
manufacturer	O
'	O
s	O
instructions	O
except	O
the	O
final	O
PCR	O
volume	O
was	O
reduced	O
to	O
25	O
mu	O
l	O
.	O

The	O
PCR	O
conditions	O
used	O
on	O
a	O
Chromo4	O
Real	O
Time	O
PCR	O
Detection	O
System	O
(	O
Bio	O
-	O
Rad	O
,	O
Hercules	O
,	O
CA	O
)	O
were	O
as	O
follows	O
:	O
HotStarTaq	O
DNA	O
polymerase	O
activation	O
at	O
95	O
degrees	O
C	O
for	O
15	O
min	O
,	O
45	O
cycles	O
of	O
15	O
s	O
denaturation	O
at	O
94	O
degrees	O
C	O
,	O
30	O
s	O
annealing	O
at	O
58	O
degrees	O
C	O
,	O
30	O
s	O
extension	O
at	O
72	O
degrees	O
C	O
,	O
followed	O
by	O
a	O
melting	O
curve	O
to	O
ensure	O
that	O
a	O
single	O
PCR	O
product	O
was	O
produced	O
for	O
each	O
reaction	O
.	O

For	O
each	O
gene	O
,	O
the	O
relative	O
amount	O
of	O
gene	O
expression	O
was	O
calculated	O
using	O
the	O
Delta	O
Delta	O
CT	O
method	O
[	O
77	O
]	O
and	O
significance	O
was	O
determined	O
using	O
a	O
nonparametric	O
Mann	O
-	O
Whitney	O
U	O
test	O
and	O
multiple	O
linear	O
regression	O
in	O
JMP	O
.	O

Authors	O
'	O
contributions	O

MRB	O
participated	O
in	O
study	O
conception	O
and	O
design	O
,	O
conducted	O
gene	O
expression	O
experiments	O
and	O
data	O
analysis	O
,	O
and	O
drafted	O
the	O
manuscript	O
.	O

ABW	O
participated	O
in	O
study	O
design	O
,	O
data	O
analysis	O
,	O
and	O
manuscript	O
revision	O
.	O

RPH	O
and	O
BPM	O
participated	O
in	O
study	O
conception	O
and	O
design	O
,	O
supervision	O
of	O
research	O
activities	O
,	O
and	O
manuscript	O
revision	O
.	O

All	O
authors	O
read	O
and	O
approved	O
the	O
final	O
manuscript	O
.	O

The	O
comparative	O
analysis	O
of	O
statistics	O
,	O
based	O
on	O
the	O
likelihood	O
ratio	O
criterion	O
,	O
in	O
the	O
automated	O
annotation	O
problem	O

Abstract	O

Background	O

This	O
paper	O
discusses	O
the	O
problem	O
of	O
automated	O
annotation	O
.	O

It	O
is	O
a	O
continuation	O
of	O
the	O
previous	O
work	O
on	O
the	O
A4	O
-	O
algorithm	O
(	O
Adaptive	O
algorithm	O
of	O
automated	O
annotation	O
)	O
developed	O
by	O
Leontovich	O
and	O
others	O
.	O

Results	O

A	O
number	O
of	O
new	O
statistics	O
for	O
the	O
automated	O
annotation	O
of	O
biological	O
sequences	O
is	O
introduced	O
.	O

All	O
these	O
statistics	O
are	O
based	O
on	O
the	O
likelihood	O
ratio	O
criterion	O
.	O

Conclusion	O

Some	O
of	O
the	O
statistics	O
yield	O
a	O
prediction	O
quality	O
that	O
is	O
significantly	O
higher	O
(	O
up	O
to	O
1	O
.	O
5	O
times	O
higher	O
)	O
in	O
comparison	O
with	O
the	O
results	O
obtained	O
with	O
the	O
A4	O
-	O
procedure	O
.	O

Background	O

Many	O
biological	O
databanks	O
,	O
both	O
dealing	O
with	O
protein	O
sequences	O
(	O
e	O
.	O
g	O
.	O
,	O
SWISS	O
-	O
PROT	O
)	O
and	O
nucleotide	O
sequences	O
(	O
e	O
.	O
g	O
.	O
,	O
GeneBank	O
)	O
,	O
contain	O
not	O
only	O
primary	O
structures	O
of	O
sequences	O
(	O
i	O
.	O
e	O
.	O
,	O
sequences	O
of	O
letters	O
-	O
amino	O
acids	O
or	O
nucleotides	O
)	O
,	O
but	O
also	O
information	O
about	O
functions	O
and	O
properties	O
of	O
these	O
sequences	O
.	O

This	O
information	O
is	O
stored	O
in	O
so	O
called	O
description	O
fields	O
of	O
the	O
sequences	O
.	O

There	O
exist	O
different	O
types	O
of	O
description	O
fields	O
-	O
KW	O
(	O
KeyWords	O
)	O
,	O
DE	O
(	O
Descriptions	O
)	O
,	O
.	O
.	O
.	O
,	O
FT	O
(	O
Feature	O
Table	O
)	O
,	O
.	O
.	O
.	O
;	O
elements	O
of	O
description	O
fields	O
are	O
referred	O
to	O
as	O
words	O
.	O

Words	O
from	O
KW	O
,	O
DE	O
,	O
.	O
.	O
.	O
fields	O
describe	O
a	O
sequence	O
as	O
a	O
whole	O
,	O
while	O
words	O
from	O
FT	O
fields	O
correspond	O
to	O
certain	O
positions	O
(	O
letters	O
)	O
of	O
a	O
sequence	O
.	O

The	O
automated	O
annotation	O
problem	O
can	O
be	O
described	O
as	O
follows	O
.	O

Consider	O
a	O
biological	O
sequence	O
(	O
referred	O
to	O
as	O
a	O
query	O
sequence	O
)	O
with	O
known	O
primary	O
structure	O
(	O
i	O
.	O
e	O
.	O
letter	O
sequence	O
)	O
but	O
unknown	O
properties	O
and	O
functions	O
(	O
i	O
.	O
e	O
.	O
,	O
description	O
fields	O
)	O
.	O

The	O
task	O
is	O
to	O
determine	O
functions	O
and	O
properties	O
of	O
this	O
sequence	O
(	O
in	O
other	O
words	O
,	O
to	O
restore	O
its	O
description	O
fields	O
)	O
on	O
the	O
basis	O
of	O
the	O
primary	O
structure	O
.	O

The	O
annotation	O
should	O
be	O
fully	O
automated	O
.	O

This	O
is	O
the	O
subject	O
of	O
the	O
current	O
paper	O
.	O

There	O
are	O
two	O
main	O
approaches	O
to	O
the	O
solution	O
of	O
this	O
problem	O
.	O

In	O
the	O
first	O
approach	O
(	O
it	O
can	O
be	O
called	O
a	O
static	O
one	O
)	O
a	O
certain	O
fixed	O
protein	O
classification	O
(	O
grouping	O
proteins	O
according	O
to	O
similarity	O
in	O
structure	O
and	O
/	O
or	O
functions	O
)	O
,	O
specified	O
beforehand	O
,	O
is	O
used	O
:	O
for	O
a	O
query	O
protein	O
the	O
search	O
of	O
a	O
relative	O
group	O
(	O
super	O
family	O
)	O
is	O
performed	O
on	O
the	O
basis	O
of	O
primary	O
structures	O
,	O
and	O
properties	O
/	O
functions	O
of	O
this	O
group	O
are	O
extended	O
to	O
the	O
query	O
protein	O
.	O

An	O
example	O
of	O
this	O
approach	O
is	O
described	O
in	O
the	O
paper	O
by	O
W	O
.	O

Fleischmann	O
et	O
al	O
.	O

[	O
1	O
]	O
,	O
it	O
uses	O
the	O
protein	O
classification	O
(	O
more	O
than	O
1000	O
families	O
)	O
,	O
stored	O
in	O
the	O
Prosite	O
databank	O
.	O

The	O
second	O
approach	O
(	O
it	O
can	O
be	O
called	O
a	O
dynamic	O
or	O
an	O
adaptive	O
one	O
)	O
does	O
not	O
use	O
protein	O
classification	O
.	O

Instead	O
,	O
a	O
"	O
dynamic	O
"	O
collection	O
of	O
bank	O
sequences	O
that	O
are	O
similar	O
to	O
a	O
query	O
sequence	O
is	O
generated	O
,	O
and	O
then	O
common	O
properties	O
/	O
functions	O
of	O
these	O
bank	O
sequences	O
are	O
extended	O
to	O
the	O
query	O
sequence	O
.	O

One	O
of	O
the	O
first	O
examples	O
of	O
this	O
approach	O
was	O
described	O
by	O
M	O
.	O
A	O
.	O

Andrade	O
et	O
al	O
.	O

[	O
2	O
]	O
.	O

In	O
this	O
paper	O
the	O
prediction	O
was	O
based	O
on	O
so	O
called	O
word	O
reliability	O
function	O
-	O
a	O
function	O
depending	O
on	O
the	O
degree	O
of	O
similarity	O
between	O
a	O
query	O
sequence	O
and	O
corresponding	O
bank	O
sequences	O
.	O

In	O
other	O
examples	O
of	O
annotation	O
procedures	O
based	O
on	O
the	O
dynamic	O
approach	O
prediction	O
was	O
performed	O
in	O
a	O
"	O
naive	O
"	O
way	O
-	O
all	O
properties	O
/	O
functions	O
of	O
similar	O
proteins	O
were	O
extended	O
to	O
a	O
query	O
protein	O
,	O
or	O
using	O
stochastic	O
methods	O
-	O
only	O
properties	O
/	O
functions	O
that	O
are	O
most	O
frequent	O
for	O
the	O
collection	O
of	O
similar	O
proteins	O
were	O
extended	O
(	O
see	O
[	O
3	O
,	O
4	O
]	O
)	O
.	O

The	O
current	O
paper	O
uses	O
the	O
dynamic	O
approach	O
.	O

This	O
paper	O
is	O
a	O
sequel	O
to	O
paper	O
[	O
5	O
]	O
that	O
describes	O
the	O
A4	O
algorithm	O
(	O
the	O
Adaptive	O
Algorithm	O
of	O
Automated	O
Annotation	O
)	O
,	O
so	O
results	O
of	O
the	O
paper	O
[	O
5	O
]	O
are	O
constantly	O
used	O
here	O
.	O

The	O
A4	O
algorithm	O
is	O
based	O
on	O
a	O
stochastic	O
approach	O
.	O

More	O
precisely	O
,	O
it	O
is	O
based	O
on	O
the	O
notion	O
of	O
transfer	O
probabilities	O
.	O

Transfer	O
probabilities	O
are	O
the	O
probabilities	O
of	O
word	O
transfer	O
(	O
extension	O
)	O
from	O
description	O
fields	O
of	O
one	O
sequence	O
to	O
description	O
fields	O
of	O
another	O
sequence	O
;	O
they	O
depend	O
on	O
the	O
measure	O
of	O
similarity	O
between	O
sequences	O
.	O

Transfer	O
probabilities	O
are	O
evaluated	O
on	O
the	O
basis	O
of	O
word	O
transfer	O
frequencies	O
in	O
the	O
found	O
collection	O
of	O
sequences	O
similar	O
to	O
a	O
query	O
sequence	O
.	O

For	O
each	O
word	O
from	O
description	O
fields	O
of	O
sequences	O
included	O
in	O
the	O
collection	O
the	O
prediction	O
of	O
the	O
fact	O
that	O
this	O
word	O
belongs	O
(	O
or	O
does	O
not	O
belong	O
)	O
to	O
the	O
description	O
field	O
of	O
a	O
query	O
sequence	O
is	O
performed	O
;	O
this	O
prediction	O
is	O
based	O
on	O
transfer	O
probabilities	O
.	O

In	O
the	O
current	O
paper	O
we	O
introduce	O
and	O
analyze	O
a	O
number	O
of	O
new	O
statistics	O
for	O
the	O
prediction	O
.	O

All	O
of	O
them	O
are	O
based	O
on	O
the	O
likelihood	O
ratio	O
criterion	O
[	O
6	O
]	O
(	O
which	O
is	O
the	O
most	O
powerful	O
criterion	O
)	O
.	O

As	O
in	O
[	O
5	O
]	O
,	O
all	O
these	O
statistics	O
are	O
evaluated	O
using	O
transfer	O
probabilities	O
.	O

Two	O
approaches	O
to	O
statistics	O
definition	O
are	O
introduced	O
:	O
a	O
"	O
discrete	O
"	O
approach	O
and	O
a	O
"	O
continuous	O
"	O
approach	O
.	O

A	O
detailed	O
analysis	O
and	O
comparison	O
of	O
introduced	O
statistics	O
are	O
performed	O
and	O
the	O
best	O
statistics	O
are	O
selected	O
.	O

The	O
emphasis	O
is	O
on	O
a	O
precise	O
description	O
of	O
the	O
way	O
these	O
statistics	O
can	O
be	O
constructed	O
using	O
well	O
-	O
known	O
concepts	O
from	O
statistical	O
decision	O
theory	O
.	O

The	O
current	O
A4	O
algorithm	O
uses	O
SPKW	O
as	O
a	O
language	O
of	O
annotation	O
.	O

Of	O
course	O
,	O
it	O
is	O
possible	O
to	O
use	O
GO	O
terms	O
in	O
A4	O
as	O
well	O
.	O

That	O
would	O
facilitate	O
comparison	O
with	O
other	O
approaches	O
.	O

However	O
,	O
at	O
the	O
current	O
stage	O
of	O
our	O
research	O
we	O
test	O
and	O
choose	O
"	O
the	O
best	O
decision	O
making	O
algorithm	O
"	O
,	O
not	O
"	O
the	O
best	O
annotation	O
terminology	O
"	O
.	O

Obviously	O
,	O
which	O
annotation	O
is	O
used	O
hardly	O
matters	O
for	O
the	O
problem	O
of	O
finding	O
the	O
optimal	O
"	O
decision	O
making	O
algorithm	O
"	O

Results	O

Algorithm	O
description	O

Generation	O
of	O
a	O
collection	O
of	O
similar	O
sequences	O

First	O
,	O
we	O
introduce	O
some	O
notation	O
.	O

For	O
the	O
sake	O
of	O
brevity	O
we	O
write	O
"	O
a	O
word	O
omega	O
belongs	O
to	O
a	O
sequence	O
pi	O
"	O
instead	O
of	O
"	O
a	O
word	O
omega	O
belongs	O
to	O
description	O
fields	O
of	O
a	O
sequence	O
pi	O
"	O
.	O

If	O
omega	O
is	O
a	O
KW	O
-	O
type	O
word	O
(	O
to	O
be	O
definite	O
,	O
further	O
in	O
the	O
paper	O
we	O
consider	O
only	O
amino	O
-	O
acid	O
sequences	O
and	O
KW	O
-	O
type	O
words	O
)	O
,	O
we	O
write	O
omega	O
in	O
KW	O
[	O
pi	O
]	O
.	O

The	O
application	O
of	O
an	O
annotation	O
procedure	O
to	O
an	O
unannotated	O
amino	O
-	O
acid	O
query	O
sequence	O
(	O
i	O
.	O
e	O
.	O
,	O
the	O
prediction	O
of	O
description	O
fields	O
)	O
starts	O
with	O
generating	O
a	O
collection	O
of	O
sequences	O
similar	O
to	O
this	O
query	O
sequence	O
with	O
known	O
description	O
fields	O
.	O

These	O
similar	O
sequences	O
are	O
selected	O
from	O
a	O
certain	O
databank	O
that	O
contains	O
annotated	O
amino	O
-	O
acid	O
sequences	O
,	O
e	O
.	O
g	O
.	O
,	O
SWISS	O
-	O
PROT	O
.	O

There	O
exist	O
different	O
approaches	O
to	O
the	O
generation	O
of	O
a	O
collection	O
of	O
similar	O
sequences	O
(	O
see	O
[	O
7	O
]	O
)	O
.	O

This	O
collections	O
can	O
be	O
generated	O
on	O
the	O
basis	O
of	O
global	O
alignments	O
between	O
a	O
query	O
sequence	O
and	O
bank	O
sequences	O
(	O
global	O
alignments	O
can	O
be	O
constructed	O
,	O
e	O
.	O
g	O
.	O
,	O
by	O
CLUSTAL	O
procedure	O
)	O
using	O
an	O
identity	O
percentage	O
or	O
,	O
more	O
generally	O
,	O
a	O
similarity	O
percentage	O
as	O
a	O
similarity	O
measure	O
.	O

Another	O
variant	O
is	O
to	O
use	O
local	O
alignments	O
(	O
i	O
.	O
e	O
.	O
,	O
alignments	O
of	O
most	O
similar	O
fragments	O
of	O
compared	O
sequences	O
,	O
see	O
[	O
7	O
]	O
)	O
instead	O
of	O
global	O
alignments	O
.	O

Local	O
alignments	O
can	O
be	O
constructed	O
,	O
for	O
example	O
,	O
by	O
a	O
well	O
-	O
known	O
BLAST	O
procedure	O
[	O
7	O
,	O
8	O
]	O
,	O
in	O
which	O
sum	O
of	O
weights	O
or	O
a	O
corresponding	O
e	O
-	O
value	O
serves	O
as	O
a	O
measure	O
of	O
similarity	O
between	O
fragments	O
(	O
and	O
thus	O
between	O
compared	O
sequences	O
)	O
.	O

Other	O
alignment	O
procedures	O
are	O
also	O
acceptable	O
;	O
alignment	O
procedure	O
selection	O
does	O
not	O
play	O
a	O
critical	O
role	O
.	O

Since	O
we	O
build	O
on	O
the	O
A4	O
procedure	O
,	O
we	O
briefly	O
summarize	O
that	O
approach	O
.	O

In	O
the	O
A4	O
procedure	O
a	O
collection	O
of	O
similar	O
sequences	O
is	O
generated	O
on	O
the	O
basis	O
of	O
local	O
alignments	O
of	O
a	O
special	O
type	O
.	O

These	O
alignments	O
are	O
constructed	O
by	O
the	O
DotHelix	O
procedure	O
(	O
[	O
9	O
]	O
)	O
,	O
in	O
which	O
the	O
"	O
power	O
"	O
(	O
sum	O
of	O
weights	O
divided	O
by	O
the	O
root	O
of	O
the	O
length	O
of	O
the	O
local	O
alignment	O
,	O
see	O
[	O
9	O
,	O
10	O
]	O
for	O
details	O
)	O
serves	O
as	O
a	O
similarity	O
measure	O
.	O

Each	O
local	O
alignment	O
constructed	O
by	O
DotHelix	O
procedure	O
is	O
a	O
chain	O
of	O
closely	O
located	O
gapless	O
local	O
alignments	O
.	O

Local	O
alignments	O
that	O
are	O
generated	O
during	O
the	O
construction	O
of	O
a	O
collection	O
of	O
similar	O
sequences	O
are	O
referred	O
to	O
as	O
primary	O
local	O
alignments	O
.	O

Each	O
sequence	O
from	O
a	O
collection	O
of	O
similar	O
sequences	O
pi	O
1	O
,	O
.	O
.	O
.	O
,	O
pi	O
n	O
can	O
have	O
several	O
corresponding	O
primary	O
local	O
alignments	O
,	O
but	O
for	O
the	O
sake	O
of	O
simplicity	O
we	O
assume	O
that	O
each	O
similar	O
sequence	O
pi	O
i	O
has	O
exactly	O
one	O
corresponding	O
primary	O
local	O
alignment	O
,	O
the	O
one	O
with	O
the	O
maximum	O
similarity	O
measure	O
.	O

Let	O
mu	O
i	O
denote	O
the	O
similarity	O
measure	O
(	O
power	O
)	O
of	O
a	O
primary	O
alignment	O
that	O
corresponds	O
to	O
pi	O
i	O
.	O

The	O
value	O
of	O
mu	O
i	O
characterizes	O
the	O
measure	O
of	O
similarity	O
between	O
fragments	O
that	O
constitute	O
this	O
alignment	O
;	O
at	O
the	O
same	O
time	O
mu	O
i	O
can	O
be	O
treated	O
as	O
a	O
measure	O
of	O
similarity	O
between	O
the	O
whole	O
query	O
sequence	O
pi	O
0	O
and	O
the	O
whole	O
similar	O
sequence	O
pi	O
i	O
.	O

We	O
assume	O
that	O
similar	O
sequences	O
are	O
ordered	O
in	O
such	O
a	O
way	O
that	O
mu	O
1	O
>	O
=	O
mu	O
2	O
>	O
=	O
.	O
.	O
.	O
>	O
=	O
mu	O
n	O
.	O

The	O
exact	O
stochastic	O
formulation	O
of	O
the	O
problem	O

Let	O
pi	O
0	O
be	O
an	O
unannotated	O
amino	O
-	O
acid	O
query	O
sequence	O
,	O
pi	O
1	O
,	O
.	O
.	O
.	O
,	O
pi	O
n	O
be	O
a	O
collection	O
of	O
sequences	O
similar	O
to	O
pi	O
0	O
,	O
and	O
omega	O
be	O
a	O
word	O
that	O
belongs	O
to	O
some	O
similar	O
sequences	O
(	O
i	O
.	O
e	O
.	O
,	O
omega	O
in	O
KW	O
[	O
pi	O
i	O
]	O
.	O
for	O
at	O
least	O
one	O
similar	O
sequence	O
pi	O
i	O
)	O
.	O

The	O
task	O
is	O
to	O
predict	O
whether	O
this	O
word	O
omega	O
belongs	O
to	O
the	O
query	O
sequence	O
pi	O
0	O
or	O
not	O
.	O

Let	O
us	O
put	O

xi	O
i	O
=	O
1	O
,	O
if	O
omega	O
in	O
KW	O
[	O
pi	O
i	O
]	O
,	O
and	O
xi	O
i	O
=	O
0	O
,	O
if	O
omega	O
not	O
-	O
in	O
KW	O
[	O
pi	O
i	O
]	O
(	O
i	O
=	O
1	O
,	O
.	O
.	O
.	O
,	O
n	O
)	O
.	O

we	O
also	O
put	O

xi	O
0	O
=	O
1	O
,	O
if	O
omega	O
in	O
KW	O
[	O
pi	O
0	O
]	O
,	O
and	O
xi	O
0	O
=	O
0	O
,	O
if	O
omega	O
not	O
-	O
in	O
KW	O
[	O
pi	O
0	O
]	O
.	O

Variables	O
xi	O
i	O
can	O
be	O
treated	O
as	O
random	O
variates	O
Actually	O
,	O
they	O
depend	O
on	O
omega	O
.	O

For	O
the	O
sake	O
of	O
brevity	O
we	O
write	O
xi	O
i	O
instead	O
of	O
xi	O
i	O
(	O
omega	O
)	O
.	O

In	O
this	O
notation	O
the	O
problem	O
can	O
be	O
stated	O
as	O
follows	O
.	O

Measures	O
of	O
similarity	O
mu	O
i	O
between	O
the	O
query	O
sequence	O
pi	O
0	O
and	O
similar	O
sequences	O
pi	O
i	O
and	O
values	O
of	O
random	O
variates	O
xi	O
i	O
,	O
i	O
=	O
1	O
,	O
.	O
.	O
.	O
,	O
n	O
,	O
are	O
given	O
.	O

The	O
task	O
is	O
to	O
determine	O
whether	O
the	O
word	O
omega	O
belongs	O
to	O
the	O
query	O
sequence	O
pi	O
0	O
or	O
not	O
.	O

In	O
other	O
words	O
,	O
two	O
hypotheses	O
are	O
considered	O
,	O
H1	O
:	O
xi	O
0	O
=	O
1	O
(	O
i	O
.	O
e	O
.	O
,	O
omega	O
in	O
KW	O
[	O
pi	O
0	O
]	O
)	O
,	O
and	O
H0	O
:	O
xi	O
0	O
=	O
0	O
(	O
i	O
.	O
e	O
.	O
,	O
omega	O
not	O
-	O
in	O
KW	O
[	O
pi	O
0	O
]	O
)	O
,	O
and	O
the	O
task	O
is	O
to	O
construct	O
a	O
procedure	O
that	O
allows	O
to	O
decide	O
which	O
hypothesis	O
is	O
true	O
on	O
the	O
basis	O
of	O
xi	O
=	O
(	O
xi	O
1	O
,	O
.	O
.	O
.	O
,	O
xi	O
n	O
)	O
.	O

As	O
announced	O
in	O
the	O
introduction	O
,	O
we	O
base	O
our	O
procedures	O
on	O
the	O
likelihood	O
ratio	O
.	O

Let	O
us	O
recall	O
the	O
famous	O
Bayes	O
'	O
Theorem	O
that	O
can	O
be	O
written	O
as	O

P	O
{	O
H1	O
|	O
xi	O
}	O
P	O
{	O
H0	O
|	O
xi	O
}	O
=	O
P	O
{	O
xi	O
0	O
=	O
1	O
|	O
xi	O
}	O
P	O
{	O
xi	O
0	O
=	O
0	O
|	O
xi	O
}	O
=	O
P	O
{	O
xi	O
0	O
=	O
1	O
,	O
xi	O
}	O
/	O
P	O
{	O
xi	O
}	O
P	O
{	O
xi	O
0	O
=	O
0	O
,	O
xi	O
}	O
/	O
P	O
{	O
xi	O
}	O
=	O
P	O
{	O
xi	O
|	O
xi	O
0	O
=	O
1	O
}	O
P	O
{	O
xi	O
|	O
xi	O
0	O
=	O
0	O
}	O
.	O
P	O
{	O
xi	O
0	O
=	O
1	O
}	O
P	O
{	O
xi	O
0	O
=	O
0	O
}	O
.	O

Here	O
the	O
left	O
part	O
is	O
the	O
posterior	O
odds	O
,	O
that	O
is	O
the	O
ratio	O
of	O
a	O
posteriori	O
probabilities	O
of	O
hypotheses	O
H1	O
and	O
H0	O
(	O
a	O
posteriori	O
means	O
that	O
values	O
xi	O
1	O
,	O
.	O
.	O
.	O
,	O
xi	O
n	O
are	O
known	O
)	O
.	O

It	O
is	O
equal	O
to	O
the	O
product	O
of	O
the	O
likelihood	O
ratio	O
P	O
{	O
xi	O
|	O
xi	O
0	O
=	O
1	O
}	O
P	O
{	O
xi	O
|	O
xi	O
0	O
=	O
0	O
}	O
(	O
i	O
.	O
e	O
.	O
,	O
the	O
ratio	O
of	O
probabilities	O
that	O
the	O
set	O
of	O
values	O
xi	O
=	O
xi	O
(	O
omega	O
)	O
is	O
realized	O
for	O
the	O
word	O
omega	O
given	O
the	O
conditions	O
xi	O
0	O
=	O
1	O
and	O
xi	O
0	O
=	O
0	O
respectively	O
)	O
and	O
the	O
prior	O
odds	O
,	O
that	O
is	O
the	O
ratio	O
of	O
a	O
priori	O
probabilities	O
of	O
hypotheses	O
H1	O
and	O
H0	O
.	O

Statistical	O
decision	O
theory	O
tells	O
us	O
that	O
the	O
optimal	O
prediction	O
procedure	O
should	O
be	O
based	O
on	O
the	O
statistic	O
P	O
{	O
H1	O
|	O
xi	O
}	O
P	O
{	O
H0	O
|	O
xi	O
}	O
or	O
equivalently	O
on	O
the	O
likelihood	O
ratio	O
.	O

For	O
any	O
statistic	O
a	O
threshold	O
value	O
should	O
be	O
specified	O
for	O
the	O
procedure	O
:	O
if	O
the	O
value	O
of	O
the	O
statistic	O
is	O
greater	O
than	O
the	O
threshold	O
,	O
hypothesis	O
H1	O
is	O
accepted	O
,	O
otherwise	O
hypothesis	O
H0	O
is	O
accepted	O
.	O

The	O
threshold	O
value	O
should	O
be	O
selected	O
in	O
such	O
a	O
way	O
that	O
the	O
total	O
number	O
of	O
incorrect	O
predictions	O
(	O
i	O
.	O
e	O
.	O
,	O
the	O
sum	O
of	O
the	O
number	O
of	O
type	O
1	O
errors	O
and	O
the	O
number	O
of	O
type	O
2	O
errors	O
)	O
would	O
be	O
minimal	O
.	O

It	O
is	O
clear	O
that	O
if	O
the	O
prior	O
odds	O
are	O
equal	O
to	O
1	O
,	O
then	O
a	O
threshold	O
value	O
of	O
one	O
should	O
be	O
selected	O
for	O
the	O
likelihood	O
ratio	O
;	O
total	O
number	O
of	O
errors	O
would	O
(	O
theoretically	O
)	O
be	O
minimal	O
for	O
this	O
threshold	O
.	O

Surely	O
,	O
the	O
assumption	O
that	O
the	O
ratio	O
of	O
a	O
priori	O
hypothesis	O
probabilities	O
equals	O
1	O
does	O
not	O
seem	O
to	O
be	O
natural	O
.	O

Indeed	O
,	O
the	O
number	O
of	O
considered	O
words	O
that	O
do	O
not	O
belong	O
to	O
a	O
query	O
sequence	O
is	O
much	O
greater	O
(	O
approximately	O
8	O
times	O
greater	O
)	O
than	O
the	O
number	O
of	O
considered	O
words	O
that	O
belong	O
to	O
a	O
query	O
sequence	O
.	O

But	O
statistics	O
that	O
are	O
obtained	O
from	O
the	O
assumption	O
that	O
this	O
a	O
priori	O
ratio	O
equals	O
1	O
,	O
and	O
the	O
assumption	O
that	O
this	O
a	O
priori	O
ratio	O
does	O
not	O
equal	O
1	O
,	O
but	O
is	O
constant	O
(	O
i	O
.	O
e	O
.	O
,	O
it	O
does	O
not	O
depend	O
on	O
a	O
word	O
omega	O
)	O
are	O
equivalent	O
.	O

Essentially	O
these	O
are	O
the	O
same	O
statistics	O
(	O
only	O
the	O
threshold	O
value	O
should	O
be	O
changed	O
:	O
a	O
value	O
P	O
{	O
xi	O
0	O
=	O
0	O
}	O
P	O
{	O
xi	O
0	O
=	O
1	O
}	O
should	O
be	O
taken	O
instead	O
of	O
1	O
;	O
as	O
it	O
was	O
noted	O
,	O
this	O
value	O
approximately	O
equals	O
8	O
in	O
our	O
data	O
)	O
.	O

Therefore	O
,	O
we	O
assume	O
from	O
now	O
on	O
that	O
the	O
ratio	O
of	O
a	O
priori	O
hypothesis	O
probabilities	O
equals	O
1	O
.	O

Thus	O
all	O
considered	O
statistics	O
are	O
based	O
on	O
the	O
likelihood	O
ratio	O

(	O
1	O
)	O
P	O
{	O
xi	O
|	O
xi	O
0	O
=	O
1	O
}	O
P	O
{	O
xi	O
|	O
xi	O
0	O
=	O
0	O
}	O

Assumption	O
of	O
independence	O
of	O
variables	O
xi	O
i	O
.	O

Transfer	O
probabilities	O

By	O
virtue	O
of	O
equation	O
(	O
1	O
)	O
we	O
need	O
to	O
estimate	O
conditional	O
probabilities	O
P	O
{	O
xi	O
|	O
xi	O
0	O
=	O
epsilon	O
}	O
,	O
where	O
epsilon	O
=	O
1	O
or	O
0	O
in	O
order	O
to	O
calculate	O
the	O
likelihood	O
ratio	O
.	O

Our	O
derivation	O
of	O
these	O
estimates	O
uses	O
the	O
assumption	O
that	O
variables	O
xi	O
i	O
,	O
i	O
=	O
1	O
,	O
.	O
.	O
.	O
,	O
n	O
,	O
are	O
independent	O
in	O
the	O
aggregate	O
.	O

Surely	O
,	O
this	O
assumption	O
is	O
false	O
.	O

In	O
reality	O
variables	O
xi	O
i	O
are	O
dependent	O
,	O
and	O
the	O
dependence	O
is	O
considerably	O
strong	O
.	O

Nevertheless	O
,	O
in	O
our	O
definition	O
of	O
the	O
likelihood	O
ratio	O
statistic	O
(	O
and	O
the	O
statistic	O
that	O
is	O
the	O
logarithm	O
of	O
the	O
likelihood	O
ratio	O
)	O
we	O
use	O
the	O
independence	O
assumption	O
.	O

Since	O
variables	O
xi	O
i	O
are	O
not	O
independent	O
,	O
one	O
can	O
not	O
assert	O
that	O
the	O
obtained	O
statistics	O
are	O
the	O
most	O
powerful	O
,	O
but	O
these	O
statistics	O
can	O
be	O
still	O
quite	O
good	O
.	O

In	O
decision	O
theory	O
,	O
this	O
approach	O
is	O
known	O
as	O
the	O
naive	O
Bayes	O
procedure	O
.	O

The	O
independence	O
of	O
variables	O
xi	O
i	O
implies	O
the	O
equality	O

(	O
2	O
)	O
P	O
{	O
xi	O
|	O
xi	O
0	O
=	O
epsilon	O
}	O
=	O
product	O
i	O
=	O
1nP	O
{	O
xi	O
i	O
|	O
xi	O
0	O
=	O
epsilon	O
}	O
,	O
epsilon	O
=	O
1	O
,	O
0	O

Each	O
variable	O
xi	O
i	O
has	O
exactly	O
two	O
possible	O
values	O
:	O
1	O
and	O
0	O
.	O

Thus	O
,	O
everything	O
is	O
reduced	O
to	O
the	O
following	O
four	O
conditional	O
probabilities	O
:	O

(	O
3	O
)	O
P	O
{	O
xi	O
i	O
=	O
1	O
|	O
xi	O
0	O
=	O
1	O
}	O
,	O
P	O
{	O
xi	O
i	O
=	O
0	O
|	O
xi	O
0	O
=	O
1	O
}	O
,	O
P	O
{	O
xi	O
i	O
=	O
1	O
|	O
xi	O
0	O
=	O
0	O
}	O
,	O
P	O
{	O
xi	O
i	O
=	O
0	O
|	O
xi	O
0	O
=	O
0	O
}	O
.	O

In	O
addition	O
,	O
it	O
is	O
clear	O
that	O

(	O
4	O
)	O
P	O
{	O
xi	O
i	O
=	O
1	O
|	O
xi	O
0	O
=	O
1	O
}	O
+	O
P	O
{	O
xi	O
i	O
=	O
0	O
|	O
xi	O
0	O
=	O
1	O
}	O
=	O
1	O
,	O
P	O
{	O
xi	O
i	O
=	O
1	O
|	O
xi	O
0	O
=	O
0	O
}	O
+	O
P	O
{	O
xi	O
i	O
=	O
0	O
|	O
xi	O
0	O
=	O
0	O
}	O
=	O
1	O
,	O

so	O
actually	O
everything	O
is	O
reduced	O
to	O
two	O
conditional	O
probabilities	O

P	O
{	O
xi	O
i	O
=	O
1	O
|	O
xi	O
0	O
=	O
1	O
}	O
,	O
P	O
{	O
xi	O
i	O
=	O
1	O
|	O
xi	O
0	O
=	O
0	O
}	O
.	O

Conditional	O
probabilities	O
(	O
3	O
)	O
are	O
a	O
special	O
case	O
of	O
conditional	O
probabilities	O
of	O
the	O
type	O

P	O
{	O
xi	O
i	O
=	O
epsilon	O
1	O
|	O
xi	O
j	O
=	O
epsilon	O
2	O
}	O
,	O
where	O
epsilon	O
1	O
,	O
epsilon	O
2	O
=	O
1	O
or	O
0	O
,	O
i	O
,	O
j	O
=	O
0	O
,	O
1	O
,	O
.	O
.	O
.	O
,	O
n	O

(	O
above	O
special	O
case	O
corresponds	O
to	O
j	O
=	O
0	O
)	O
.	O

We	O
call	O
all	O
this	O
conditional	O
probabilities	O
transfer	O
probabilities	O
and	O
denote	O
them	O
by	O

P	O
{	O
xi	O
i	O
=	O
epsilon	O
1	O
|	O
xi	O
j	O
=	O
epsilon	O
2	O
}	O
=	O
p	O
epsilon	O
1	O
|	O
epsilon	O
2	O
.	O

Transfer	O
probabilities	O
depend	O
on	O
i	O
,	O
j	O
(	O
and	O
certainly	O
on	O
the	O
word	O
omega	O
)	O
:	O

p	O
epsilon	O
1	O
|	O
epsilon	O
2	O
=	O
p	O
epsilon	O
1	O
|	O
epsilon	O
2	O
(	O
i	O
,	O
j	O
;	O
omega	O
)	O
.	O

Conditional	O
probabilities	O
play	O
a	O
central	O
role	O
in	O
our	O
procedure	O
.	O

According	O
to	O
equation	O
(	O
4	O
)	O
,	O
it	O
suffices	O
to	O
explain	O
how	O
transfer	O
probabilities	O
p1	O
|	O
1	O
,	O
p1	O
|	O
0	O
are	O
evaluated	O
.	O

We	O
suppose	O
that	O
transfer	O
probabilities	O
satisfy	O
the	O
following	O
assumptions	O
(	O
"	O
axioms	O
"	O
)	O
(	O
the	O
sense	O
of	O
these	O
assumptions	O
is	O
obvious	O
)	O
.	O

Assumption	O
1	O
)	O
For	O
a	O
fixed	O
word	O
omega	O
and	O
for	O
sequences	O
pi	O
0	O
,	O
pi	O
1	O
,	O
.	O
.	O
.	O
,	O
pi	O
n	O
(	O
i	O
.	O
e	O
.	O
,	O
for	O
the	O
sequence	O
pi	O
0	O
and	O
sequences	O
similar	O
to	O
pi	O
0	O
)	O
transfer	O
probabilities	O
depend	O
only	O
on	O
the	O
measure	O
of	O
similarity	O
between	O
sequences	O
.	O

Thus	O
,	O
we	O
have	O
:	O

p1	O
|	O
1	O
=	O
p1	O
|	O
1	O
(	O
i	O
,	O
j	O
;	O
omega	O
)	O
=	O
p1	O
|	O
1	O
(	O
mu	O
ij	O
;	O
omega	O
)	O
=	O
p1	O
|	O
1	O
(	O
mu	O
ij	O
)	O
=	O
1	O
-	O
p0	O
|	O
1	O
(	O
mu	O
ij	O
)	O
,	O

p1	O
|	O
0	O
=	O
p1	O
|	O
0	O
(	O
i	O
,	O
j	O
;	O
omega	O
)	O
=	O
p1	O
|	O
0	O
(	O
mu	O
ij	O
;	O
omega	O
)	O
=	O
p1	O
|	O
0	O
(	O
mu	O
ij	O
)	O
=	O
1	O
-	O
p0	O
|	O
0	O
(	O
mu	O
ij	O
)	O
,	O

where	O
mu	O
ij	O
is	O
the	O
measure	O
of	O
similarity	O
between	O
sequences	O
pi	O
i	O
,	O
pi	O
j	O
(	O
i	O
,	O
j	O
=	O
0	O
,	O
1	O
,	O
.	O
.	O
.	O
,	O
n	O
)	O
.	O

Particularly	O
,	O
if	O
one	O
of	O
these	O
sequences	O
is	O
the	O
query	O
sequence	O
pi	O
0	O
and	O
mu	O
j	O
is	O
the	O
measure	O
of	O
similarity	O
between	O
pi	O
j	O
,	O
pi	O
0	O
,	O
we	O
have	O

(	O
5	O
)	O
P	O
{	O
xi	O
j	O
=	O
1	O
|	O
xi	O
0	O
=	O
1	O
}	O
=	O
p1	O
|	O
1	O
(	O
mu	O
j	O
)	O
,	O
P	O
{	O
xi	O
j	O
=	O
1	O
|	O
xi	O
0	O
=	O
0	O
}	O
=	O
p1	O
|	O
0	O
(	O
mu	O
j	O
)	O
.	O

Assumption	O
2	O
)	O
Transfer	O
probabilities	O
(	O
for	O
an	O
arbitrary	O
fixed	O
word	O
omega	O
)	O
depend	O
on	O
similarity	O
measure	O
mu	O
monotonically	O
:	O
the	O
probability	O
p1	O
|	O
1	O
(	O
mu	O
)	O
increases	O
(	O
does	O
not	O
decrease	O
)	O
and	O
the	O
probability	O
p1	O
|	O
0	O
(	O
mu	O
)	O
decreases	O
(	O
does	O
not	O
increase	O
)	O
as	O
mu	O
increases	O
.	O

Assumption	O
3	O
)	O
The	O
inequality	O

(	O
6	O
)	O
p1	O
|	O
1	O
(	O
mu	O
)	O
>	O
p1	O
|	O
0	O
(	O
mu	O
)	O

always	O
holds	O
(	O
if	O
mu	O
>	O
0	O
)	O
.	O

Transfer	O
probabilities	O
are	O
evaluated	O
on	O
the	O
basis	O
of	O
the	O
measure	O
of	O
similarity	O
between	O
similar	O
sequences	O
for	O
which	O
it	O
is	O
known	O
whether	O
omega	O
in	O
KW	O
[	O
pi	O
i	O
]	O
using	O
the	O
so	O
called	O
isotonic	O
regression	O
procedure	O
(	O
see	O
[	O
11	O
]	O
)	O
.	O

(	O
In	O
[	O
5	O
]	O
this	O
procedure	O
was	O
referred	O
to	O
as	O
monotonization	O
procedure	O
)	O
.	O

Results	O
of	O
this	O
procedure	O
are	O
piecewise	O
-	O
constant	O
monotonous	O
functions	O
of	O
the	O
similarity	O
measure	O
mu	O
that	O
increase	O
(	O
do	O
not	O
decrease	O
)	O
for	O
probabilities	O
p1	O
|	O
1	O
(	O
mu	O
)	O
and	O
decrease	O
(	O
do	O
not	O
increase	O
)	O
for	O
probabilities	O
p1	O
|	O
0	O
(	O
mu	O
)	O
.	O

We	O
briefly	O
recall	O
the	O
isotonic	O
regression	O
problem	O
.	O

Let	O
one	O
have	O
two	O
number	O
sets	O
(	O
i	O
.	O
e	O
.	O
,	O
a	O
set	O
of	O
points	O
in	O
the	O
plain	O
)	O
xi	O
,	O
yi	O
,	O
i	O
=	O
1	O
,	O
.	O
.	O
.	O
,	O
n	O
,	O
for	O
which	O
x1	O
<	O
=	O
x2	O
<	O
=	O
.	O
.	O
.	O
<	O
=	O
xn	O
.	O

The	O
task	O
is	O
to	O
find	O
values	O
z1	O
,	O
z2	O
,	O
.	O
.	O
.	O
,	O
zn	O
,	O
z1	O
<	O
=	O
z2	O
<	O
=	O
.	O
.	O
.	O
<	O
=	O
zn	O
,	O
that	O
minimize	O
the	O
deviation	O
sum	O
i	O
=	O
1n	O
(	O
zi	O
-	O
yi	O
)	O
2	O
.	O

This	O
is	O
the	O
monotone	O
-	O
increasing	O
isotonic	O
regression	O
problem	O
.	O

The	O
monotone	O
-	O
decreasing	O
isotonic	O
regression	O
problem	O
is	O
similar	O
;	O
the	O
only	O
difference	O
is	O
that	O
here	O
z1	O
>	O
=	O
z2	O
>	O
=	O
.	O
.	O
.	O
>	O
=	O
zn	O
.	O

The	O
isotonic	O
regression	O
procedure	O
constructs	O
a	O
monotonic	O
number	O
sequence	O
z1	O
,	O
.	O
.	O
.	O
,	O
zn	O
(	O
while	O
in	O
linear	O
regression	O
values	O
of	O
zi	O
are	O
linearly	O
expressed	O
in	O
terms	O
of	O
xi	O
:	O
zi	O
=	O
alpha	O
xi	O
+	O
beta	O
)	O
.	O

An	O
algorithm	O
for	O
the	O
solution	O
of	O
isotonic	O
regression	O
problem	O
can	O
be	O
easily	O
constructed	O
.	O

We	O
do	O
not	O
describe	O
it	O
here	O
.	O

We	O
only	O
note	O
that	O
each	O
zi	O
is	O
the	O
mean	O
value	O
of	O
{	O
yj	O
}	O
over	O
a	O
window	O
of	O
variable	O
length	O
:	O
Li	O
:	O
zi	O
=	O
(	O
sum	O
j	O
=	O
t	O
(	O
i	O
)	O
t	O
(	O
i	O
)	O
+	O
L	O
(	O
i	O
)	O
-	O
1yi	O
)	O
/	O
Li	O
.	O

For	O
different	O
indices	O
these	O
windows	O
either	O
coincide	O
or	O
do	O
not	O
overlap	O
,	O
and	O
the	O
i	O
-	O
th	O
window	O
contains	O
i	O
.	O

We	O
also	O
note	O
that	O
the	O
values	O
of	O
xi	O
are	O
not	O
essential	O
in	O
the	O
isotonic	O
regression	O
problem	O
,	O
only	O
the	O
order	O
of	O
values	O
of	O
yi	O
is	O
essential	O
.	O

To	O
obtain	O
the	O
transfer	O
probabilities	O
using	O
isotonic	O
regression	O
we	O
proceed	O
as	O
follows	O
.	O

For	O
the	O
evaluation	O
of	O
p1	O
|	O
1	O
we	O
consider	O
pairs	O
of	O
similar	O
sequences	O
pi	O
i	O
,	O
pi	O
j	O
that	O
satisfy	O
the	O
condition	O
omega	O
in	O
KW	O
[	O
pi	O
i	O
]	O
.	O

Let	O
mu	O
ij	O
denote	O
the	O
measure	O
of	O
similarity	O
between	O
sequences	O
pi	O
i	O
,	O
pi	O
j	O
.	O

We	O
put	O
xi	O
ij	O
=	O
1	O
if	O
the	O
word	O
omega	O
belongs	O
to	O
the	O
sequence	O
pi	O
j	O
,	O
and	O
put	O
xi	O
ij	O
=	O
0	O
if	O
omega	O
does	O
not	O
belong	O
to	O
pi	O
j	O
(	O
recall	O
that	O
the	O
word	O
omega	O
belongs	O
to	O
pi	O
i	O
)	O
.	O

Then	O
we	O
apply	O
the	O
monotone	O
-	O
increasing	O
isotonic	O
regression	O
procedure	O
to	O
the	O
collection	O
of	O
points	O
(	O
mu	O
ij	O
,	O
xi	O
ij	O
)	O
,	O
where	O
mu	O
ij	O
are	O
in	O
ascending	O
order	O
.	O

The	O
resulting	O
values	O
are	O
the	O
estimates	O
of	O
the	O
transfer	O
probabilities	O
p1	O
|	O
1	O
(	O
mu	O
ij	O
)	O
.	O

Similarly	O
,	O
applying	O
the	O
monotone	O
-	O
decreasing	O
isotonic	O
regression	O
procedure	O
to	O
the	O
collection	O
of	O
points	O
(	O
mu	O
ij	O
,	O
xi	O
ij	O
)	O
that	O
correspond	O
to	O
pairs	O
of	O
similar	O
sequences	O
pi	O
i	O
,	O
pi	O
j	O
for	O
which	O
omega	O
does	O
not	O
belong	O
to	O
pi	O
i	O
,	O
we	O
obtain	O
values	O
of	O
the	O
transfer	O
probabilities	O
p1	O
|	O
0	O
(	O
mu	O
ij	O
)	O
.	O

As	O
we	O
noted	O
,	O
the	O
probabilities	O
p1	O
|	O
1	O
,	O
p1	O
|	O
0	O
are	O
supposed	O
to	O
satisfy	O
condition	O
(	O
6	O
)	O
.	O

Therefore	O
,	O
if	O
it	O
turns	O
out	O
that	O
functions	O
p1	O
|	O
1	O
(	O
mu	O
)	O
,	O
p1	O
|	O
0	O
(	O
mu	O
)	O
obtained	O
after	O
the	O
application	O
of	O
isotonic	O
regression	O
procedure	O
do	O
not	O
satisfy	O
this	O
condition	O
for	O
some	O
values	O
of	O
mu	O
,	O
then	O
we	O
consider	O
that	O
probabilities	O
p1	O
|	O
1	O
,	O
p1	O
|	O
0	O
are	O
not	O
defined	O
for	O
these	O
values	O
of	O
mu	O
.	O

Hence	O
,	O
it	O
is	O
possible	O
that	O
transfer	O
probabilities	O
are	O
defined	O
only	O
for	O
sufficiently	O
large	O
values	O
of	O
mu	O
,	O
but	O
not	O
for	O
all	O
mu	O
.	O

In	O
particular	O
,	O
it	O
is	O
possible	O
that	O
for	O
some	O
words	O
there	O
are	O
no	O
values	O
of	O
mu	O
such	O
that	O
inequality	O
(	O
6	O
)	O
holds	O
.	O

These	O
words	O
are	O
referred	O
to	O
as	O
degenerate	O
words	O
.	O

Statistics	O
description	O

All	O
statistics	O
considered	O
in	O
this	O
paper	O
are	O
based	O
on	O
the	O
likelihood	O
ratio	O
criterion	O
,	O
that	O
is	O
on	O
formula	O
(	O
1	O
)	O
under	O
the	O
assumption	O
of	O
independence	O
of	O
variables	O
xi	O
i	O
(	O
formula	O
(	O
2	O
)	O
)	O
.	O

Two	O
approaches	O
are	O
used	O
in	O
the	O
definitions	O
of	O
these	O
statistics	O
.	O

One	O
of	O
them	O
can	O
be	O
called	O
a	O
"	O
discrete	O
"	O
approach	O
;	O
the	O
other	O
can	O
be	O
called	O
a	O
"	O
continuous	O
"	O
approach	O
.	O

The	O
discrete	O
approach	O
is	O
based	O
directly	O
on	O
formulae	O
(	O
1	O
)	O
,	O
(	O
2	O
)	O
and	O
the	O
definition	O
of	O
transfer	O
probabilities	O
.	O

It	O
follows	O
from	O
(	O
5	O
)	O
that	O
the	O
following	O
formulae	O
for	O
conditional	O
probabilities	O
hold	O
:	O

P	O
{	O
xi	O
i	O
|	O
xi	O
0	O
=	O
1	O
}	O
=	O
p1	O
|	O
1	O
(	O
mu	O
i	O
)	O
,	O
if	O
xi	O
i	O
=	O
1	O
,	O

P	O
{	O
xi	O
i	O
|	O
xi	O
0	O
=	O
1	O
}	O
=	O
p0	O
|	O
1	O
(	O
mu	O
i	O
)	O
=	O
1	O
-	O
p1	O
|	O
1	O
(	O
mu	O
i	O
)	O
,	O
if	O
xi	O
i	O
=	O
0	O
,	O

and	O
hence	O

(	O
7	O
)	O
P	O
{	O
xi	O
i	O
|	O
xi	O
0	O
=	O
1	O
}	O
=	O
(	O
1	O
-	O
p1	O
|	O
1	O
(	O
mu	O
i	O
)	O
)	O
.	O
(	O
p1	O
|	O
1	O
(	O
mu	O
i	O
)	O
1	O
-	O
p1	O
|	O
1	O
(	O
mu	O
i	O
)	O
)	O
)	O
xi	O
i	O
.	O

Similarly	O
,	O

(	O
8	O
)	O
P	O
{	O
xi	O
i	O
|	O
xi	O
0	O
=	O
0	O
}	O
=	O
(	O
1	O
-	O
p1	O
|	O
0	O
(	O
mu	O
i	O
)	O
)	O
.	O
(	O
p1	O
|	O
0	O
(	O
mu	O
i	O
)	O
1	O
-	O
p1	O
|	O
0	O
(	O
mu	O
i	O
)	O
)	O
xi	O
i	O
.	O

Relations	O
(	O
7	O
)	O
,	O
(	O
8	O
)	O
together	O
with	O
(	O
1	O
)	O
,	O
(	O
2	O
)	O
imply	O
the	O
following	O
formula	O
for	O
the	O
logarithm	O
of	O
the	O
likelihood	O
ratio	O
:	O

(	O
9	O
)	O
T	O
(	O
1	O
)	O
(	O
xi	O
;	O
omega	O
)	O
=	O
T	O
(	O
1	O
)	O
(	O
xi	O
)	O
=	O
ln	O
(	O
product	O
i	O
=	O
1nP	O
{	O
xi	O
i	O
|	O
xi	O
0	O
=	O
1	O
}	O
P	O
{	O
xi	O
i	O
|	O
xi	O
0	O
=	O
0	O
}	O
)	O
=	O
alpha	O
0	O
+	O
sum	O
i	O
=	O
1n	O
alpha	O
i	O
.	O
xi	O
i	O
,	O

where	O

(	O
10	O
)	O
alpha	O
0	O
=	O
sum	O
i	O
=	O
1n	O
alpha	O
0i	O
,	O
alpha	O
0i	O
=	O
ln	O
1	O
-	O
p1	O
|	O
1	O
(	O
mu	O
i	O
)	O
1	O
-	O
p1	O
|	O
0	O
(	O
mu	O
i	O
)	O
<	O
0	O

(	O
11	O
)	O
alpha	O
i	O
=	O
ln	O
p1	O
|	O
1	O
(	O
mu	O
i	O
)	O
(	O
1	O
-	O
p1	O
|	O
0	O
(	O
mu	O
i	O
)	O
)	O
p1	O
|	O
0	O
(	O
mu	O
i	O
)	O
(	O
1	O
-	O
p1	O
|	O
1	O
(	O
mu	O
i	O
)	O
)	O
>	O
0	O
.	O

One	O
can	O
see	O
that	O
the	O
statistic	O
T	O
(	O
1	O
)	O
can	O
be	O
expressed	O
as	O
a	O
linear	O
combination	O
of	O
the	O
xi	O
i	O
.	O

As	O
we	O
noted	O
,	O
theoretically	O
the	O
best	O
threshold	O
value	O
for	O
the	O
statistic	O
T	O
(	O
1	O
)	O
is	O
equal	O
to	O
1n1	O
=	O
0	O
.	O

However	O
,	O
that	O
is	O
only	O
theoretical	O
.	O

As	O
the	O
assumption	O
of	O
independence	O
of	O
variables	O
xi	O
i	O
is	O
incorrect	O
and	O
the	O
statistic	O
T	O
(	O
1	O
)	O
is	O
only	O
a	O
rough	O
estimate	O
of	O
logarithm	O
of	O
the	O
likelihood	O
ratio	O
,	O
the	O
best	O
threshold	O
value	O
is	O
not	O
necessarily	O
equal	O
to	O
zero	O
(	O
and	O
this	O
threshold	O
does	O
not	O
really	O
equal	O
zero	O
in	O
practice	O
)	O
.	O

Let	O
us	O
put	O
eta	O
=	O
eta	O
(	O
omega	O
)	O
=	O
T	O
(	O
1	O
)	O
-	O
alpha	O
0	O
sum	O
i	O
=	O
1n	O
alpha	O
i	O
.	O

From	O
the	O
definition	O
of	O
eta	O
and	O
relations	O
(	O
9	O
)	O
-	O
(	O
11	O
)	O
it	O
follows	O
that	O

(	O
12	O
)	O
eta	O
=	O
sum	O
i	O
=	O
1na	O
^	O
i	O
xi	O
i	O
,	O

where	O

(	O
13	O
)	O
a	O
^	O
i	O
=	O
ln	O
p1	O
|	O
1	O
(	O
mu	O
i	O
)	O
(	O
1	O
-	O
p1	O
|	O
0	O
(	O
mu	O
i	O
)	O
)	O
p1	O
|	O
0	O
(	O
mu	O
i	O
)	O
(	O
1	O
-	O
p1	O
|	O
1	O
(	O
mu	O
i	O
)	O
)	O
sum	O
i	O
=	O
1nln	O
p1	O
|	O
1	O
(	O
mu	O
i	O
)	O
(	O
1	O
-	O
p1	O
|	O
0	O
(	O
mu	O
i	O
)	O
)	O
p1	O
|	O
0	O
(	O
mu	O
i	O
)	O
(	O
1	O
-	O
p1	O
|	O
1	O
(	O
mu	O
i	O
)	O
)	O
>	O
0	O
.	O

We	O
note	O
that	O

(	O
14	O
)	O
sum	O
i	O
=	O
1na	O
^	O
i	O
=	O
1	O
.	O

The	O
variable	O
eta	O
(	O
omega	O
)	O
can	O
be	O
treated	O
as	O
a	O
second	O
statistic	O
.	O

Its	O
values	O
lie	O
between	O
0	O
and	O
1	O
.	O

Statistics	O
T	O
(	O
1	O
)	O
and	O
eta	O
are	O
linearly	O
dependent	O
,	O
and	O
hence	O
for	O
a	O
fixed	O
word	O
omega	O
these	O
statistics	O
are	O
equivalent	O
.	O

However	O
,	O
the	O
coefficients	O
alpha	O
0	O
and	O
alpha	O
i	O
(	O
i	O
=	O
1	O
,	O
.	O
.	O
.	O
,	O
n	O
)	O
are	O
different	O
for	O
different	O
words	O
omega	O
,	O
so	O
the	O
relation	O
between	O
thresholds	O
,	O
used	O
in	O
the	O
prediction	O
,	O
is	O
different	O
for	O
different	O
words	O
;	O
consequently	O
,	O
the	O
statistics	O
T	O
(	O
1	O
)	O
and	O
eta	O
are	O
not	O
equivalent	O
for	O
the	O
whole	O
totality	O
of	O
words	O
(	O
We	O
will	O
see	O
later	O
that	O
if	O
thresholds	O
are	O
well	O
-	O
chosen	O
,	O
then	O
eta	O
leads	O
to	O
better	O
results	O
than	O
T	O
(	O
1	O
)	O
)	O
.	O

The	O
other	O
approach	O
to	O
the	O
definition	O
of	O
statistics	O
,	O
used	O
in	O
the	O
annotation	O
procedure	O
,	O
starts	O
from	O
a	O
linear	O
combination	O
eta	O
=	O
sum	O
i	O
=	O
1nai	O
xi	O
i	O
of	O
the	O
xi	O
i	O
as	O
in	O
formula	O
(	O
12	O
)	O
.	O

Here	O
coefficients	O
alpha	O
i	O
are	O
not	O
necessarily	O
given	O
by	O
(	O
13	O
)	O
,	O
but	O
should	O
be	O
positive	O
and	O
satisfy	O
the	O
relation	O
(	O
14	O
)	O
.	O

This	O
approach	O
uses	O
the	O
assumption	O
that	O
eta	O
has	O
the	O
normal	O
distribution	O
.	O

Certainly	O
this	O
assumption	O
is	O
not	O
correct	O
(	O
at	O
least	O
because	O
the	O
inequality	O
0	O
<	O
=	O
eta	O
<	O
=	O
1	O
always	O
holds	O
)	O
.	O

Nevertheless	O
,	O
we	O
use	O
this	O
assumption	O
(	O
and	O
,	O
similarly	O
to	O
the	O
discrete	O
approach	O
,	O
the	O
assumption	O
of	O
independence	O
of	O
variables	O
xi	O
i	O
(	O
omega	O
)	O
)	O
.	O

(	O
As	O
the	O
normal	O
distribution	O
is	O
continuous	O
,	O
this	O
approach	O
can	O
be	O
called	O
"	O
continuous	O
"	O
)	O
.	O

Thus	O
,	O
we	O
consider	O
a	O
random	O
variable	O

(	O
15	O
)	O
eta	O
=	O
sum	O
i	O
=	O
1nai	O
xi	O
i	O

and	O
assume	O
that	O
it	O
has	O
a	O
normal	O
distribution	O
.	O

Denote	O
by	O

M1	O
eta	O
=	O
M	O
(	O
eta	O
|	O
xi	O
0	O
=	O
1	O
)	O
,	O
D1	O
eta	O
=	O
D	O
(	O
eta	O
|	O
xi	O
0	O
=	O
1	O
)	O
=	O
sigma	O
12	O
,	O
M0	O
eta	O
=	O
M	O
(	O
eta	O
|	O
xi	O
0	O
=	O
0	O
)	O
,	O
D0	O
eta	O
=	O
D	O
(	O
eta	O
|	O
xi	O
0	O
=	O
0	O
)	O
=	O
sigma	O
02	O

the	O
conditional	O
expectations	O
and	O
dispersions	O
of	O
eta	O
given	O
that	O
xi	O
0	O
=	O
1	O
or	O
0	O
respectively	O
.	O

We	O
have	O

M1	O
eta	O
=	O
sum	O
aiM	O
(	O
xi	O
i	O
|	O
xi	O
0	O
=	O
1	O
)	O
=	O
sum	O
aip1	O
|	O
1	O
(	O
mu	O
i	O
)	O
,	O
M0	O
eta	O
=	O
sum	O
aip1	O
|	O
0	O
(	O
mu	O
i	O
)	O
.	O

Further	O
,	O
the	O
assumption	O
of	O
independence	O
of	O
xi	O
i	O
(	O
omega	O
)	O
implies	O
that	O

D1	O
eta	O
=	O
sigma	O
12	O
=	O
sum	O
iai2	O
.	O
p1	O
|	O
1	O
(	O
mu	O
i	O
)	O
.	O
(	O
1	O
-	O
p1	O
|	O
1	O
(	O
mu	O
i	O
)	O
)	O
,	O
D0	O
eta	O
=	O
sigma	O
02	O
=	O
sum	O
iai2	O
.	O
p1	O
|	O
0	O
(	O
mu	O
i	O
)	O
.	O
(	O
1	O
-	O
p1	O
|	O
0	O
(	O
mu	O
i	O
)	O
)	O
.	O

(	O
We	O
note	O
that	O
it	O
is	O
the	O
only	O
place	O
where	O
the	O
independence	O
of	O
xi	O
i	O
is	O
used	O
;	O
therefore	O
,	O
the	O
assumption	O
of	O
independence	O
of	O
xi	O
i	O
is	O
not	O
as	O
essential	O
in	O
this	O
approach	O
as	O
it	O
was	O
in	O
the	O
definition	O
of	O
the	O
statistic	O
T	O
(	O
1	O
)	O
)	O
.	O

It	O
follows	O
from	O
the	O
assumption	O
of	O
a	O
normal	O
distribution	O
that	O
in	O
cases	O
xi	O
0	O
=	O
1	O
and	O
0	O
the	O
variables	O

(	O
16	O
)	O
eta	O
-	O
M1	O
eta	O
sigma	O
1	O
and	O
eta	O
-	O
M0	O
eta	O
sigma	O
0	O
have	O
standard	O
normal	O
distribution	O
N	O
(	O
0	O
,	O
1	O
)	O

As	O
above	O
,	O
we	O
use	O
the	O
logarithm	O
of	O
the	O
likelihood	O
ratio	O
as	O
a	O
statistic	O
and	O
in	O
addition	O
assume	O
that	O
the	O
ratio	O
of	O
a	O
priori	O
hypothesis	O
probabilities	O
is	O
equal	O
to	O
1	O
.	O

Let	O
us	O
denote	O
this	O
statistic	O
by	O
T	O
(	O
2	O
)	O
.	O

Relation	O
(	O
16	O
)	O
implies	O
that	O

T	O
(	O
2	O
)	O
(	O
lambda	O
)	O
=	O
ln	O
P	O
{	O
lambda	O
<	O
=	O
eta	O
<	O
=	O
lambda	O
+	O
d	O
lambda	O
|	O
xi	O
0	O
=	O
1	O
}	O
P	O
{	O
lambda	O
<	O
=	O
eta	O
<	O
=	O
lambda	O
+	O
d	O
lambda	O
|	O
xi	O
0	O
=	O
0	O
}	O
=	O
ln	O
(	O
1	O
/	O
2	O
pi	O
.	O
sigma	O
1	O
)	O
.	O
exp	O
{	O
-	O
12	O
.	O
(	O
(	O
lambda	O
-	O
M1	O
eta	O
)	O
/	O
sigma	O
1	O
)	O
2	O
}	O
(	O
1	O
/	O
2	O
pi	O
.	O
sigma	O
0	O
)	O
.	O
exp	O
{	O
12	O
.	O
(	O
(	O
lambda	O
-	O
M0	O
eta	O
)	O
/	O
sigma	O
0	O
)	O
2	O
}	O
=	O
12	O
.	O
{	O
(	O
(	O
lambda	O
-	O
M0	O
eta	O
)	O
/	O
sigma	O
0	O
)	O
2	O
-	O
(	O
(	O
lambda	O
-	O
M1	O
eta	O
)	O
/	O
sigma	O
1	O
)	O
2	O
}	O
+	O
ln	O
(	O
sigma	O
0	O
/	O
sigma	O
1	O
)	O
.	O

Another	O
variant	O
of	O
this	O
statistic	O
-	O
statistic	O
T	O
^	O
(	O
2	O
)	O
-	O
was	O
used	O
in	O
the	O
paper	O
[	O
5	O
]	O
.	O

The	O
statistic	O
T	O
^	O
(	O
2	O
)	O
is	O
the	O
ratio	O
of	O
type	O
1	O
error	O
to	O
type	O
2	O
error	O
:	O

(	O
17	O
)	O
T	O
^	O
(	O
2	O
)	O
(	O
lambda	O
)	O
=	O
ln	O
P	O
(	O
1	O
)	O
(	O
lambda	O
)	O
P	O
(	O
2	O
)	O
(	O
lambda	O
)	O
=	O
ln	O
Phi	O
(	O
(	O
lambda	O
-	O
M1	O
eta	O
)	O
/	O
sigma	O
1	O
)	O
1	O
-	O
Phi	O
(	O
(	O
lambda	O
-	O
M0	O
eta	O
)	O
/	O
sigma	O
0	O
)	O
,	O

where	O
Phi	O
(	O
x	O
)	O
is	O
the	O
cumulative	O
normal	O
distribution	O
function	O
:	O
Phi	O
(	O
x	O
)	O
=	O
12	O
pi	O
integral	O
-	O
infinity	O
xe	O
-	O
z22dz	O
.	O

The	O
statistics	O
eta	O
and	O
T	O
^	O
(	O
2	O
)	O
are	O
equivalent	O
for	O
an	O
arbitrary	O
fixed	O
word	O
omega	O
(	O
although	O
not	O
equivalent	O
for	O
the	O
whole	O
totality	O
of	O
words	O
)	O
.	O

At	O
the	O
same	O
time	O
,	O
the	O
statistics	O
eta	O
and	O
T	O
(	O
2	O
)	O
are	O
not	O
necessarily	O
equivalent	O
,	O
as	O
the	O
dependence	O
of	O
T	O
(	O
2	O
)	O
on	O
eta	O
may	O
turn	O
out	O
to	O
be	O
not	O
monotonic	O
.	O

Moreover	O
,	O
it	O
is	O
never	O
monotonic	O
for	O
all	O
values	O
of	O
eta	O
.	O

However	O
,	O
we	O
are	O
interested	O
only	O
in	O
values	O
0	O
<	O
=	O
eta	O
<	O
=	O
1	O
,	O
and	O
usually	O
(	O
though	O
not	O
always	O
)	O
the	O
dependence	O
of	O
T	O
(	O
2	O
)	O
on	O
eta	O
is	O
monotonous	O
for	O
these	O
values	O
of	O
eta	O
,	O
and	O
in	O
this	O
case	O
the	O
statistics	O
eta	O
and	O
T	O
(	O
2	O
)	O
are	O
equivalent	O
(	O
for	O
a	O
fixed	O
word	O
omega	O
)	O
.	O

Furthermore	O
,	O
even	O
in	O
the	O
case	O
where	O
the	O
dependence	O
is	O
not	O
monotonic	O
,	O
the	O
monotonicity	O
is	O
violated	O
only	O
for	O
the	O
values	O
of	O
eta	O
close	O
either	O
to	O
0	O
or	O
to	O
1	O
,	O
and	O
the	O
lack	O
of	O
monotonicity	O
can	O
be	O
disregarded	O
.	O

We	O
still	O
have	O
to	O
discuss	O
the	O
question	O
of	O
the	O
choice	O
of	O
coefficients	O
ai	O
in	O
(	O
15	O
)	O
.	O

One	O
of	O
the	O
variants	O
was	O
described	O
above	O
:	O
formula	O
(	O
13	O
)	O
can	O
be	O
applied	O
.	O

Another	O
variant	O
was	O
introduced	O
in	O
[	O
5	O
]	O
.	O

This	O
variant	O
can	O
be	O
described	O
as	O
follows	O
.	O

As	O
above	O
,	O
we	O
assume	O
that	O
the	O
variate	O
eta	O
=	O
sum	O
ai	O
xi	O
i	O
has	O
a	O
normal	O
distribution	O
.	O

Each	O
set	O
of	O
coefficients	O
ai	O
and	O
each	O
threshold	O
value	O
lambda	O
have	O
corresponding	O
theoretical	O
frequencies	O
of	O
type	O
1	O
and	O
type	O
2	O
errors	O
P	O
(	O
1	O
)	O
(	O
lambda	O
)	O
,	O
P	O
(	O
2	O
)	O
(	O
lambda	O
)	O
.	O

The	O
idea	O
is	O
to	O
take	O
the	O
set	O
of	O
coefficients	O
{	O
ai	O
}	O
that	O
gives	O
the	O
minimum	O
sum	O
P	O
(	O
1	O
)	O
(	O
lambda	O
)	O
+	O
P	O
(	O
2	O
)	O
(	O
lambda	O
)	O
,	O
where	O
lambda	O
is	O
the	O
best	O
threshold	O
value	O
for	O
this	O
coefficient	O
set	O
.	O

However	O
,	O
analytically	O
it	O
is	O
very	O
cumbersome	O
,	O
so	O
the	O
following	O
simplification	O
was	O
implemented	O
.	O

For	O
a	O
fixed	O
set	O
of	O
coefficients	O
{	O
ai	O
}	O
we	O
select	O
the	O
threshold	O
value	O
lambda	O
such	O
that	O
the	O
frequency	O
of	O
type	O
1	O
errors	O
is	O
equal	O
to	O
the	O
frequency	O
of	O
type	O
2	O
errors	O
:	O
P	O
(	O
1	O
)	O
(	O
lambda	O
)	O
=	O
P	O
(	O
2	O
)	O
(	O
lambda	O
)	O
.	O

Then	O
we	O
find	O
the	O
set	O
of	O
coefficients	O
that	O
minimizes	O
these	O
frequencies	O
P	O
(	O
1	O
)	O
(	O
lambda	O
)	O
=	O
P	O
(	O
2	O
)	O
(	O
lambda	O
)	O
.	O

Here	O
the	O
search	O
of	O
the	O
coefficient	O
set	O
can	O
be	O
reduced	O
to	O
a	O
conditional	O
extremum	O
problem	O
.	O

The	O
A4	O
algorithm	O
uses	O
an	O
iterated	O
procedure	O
for	O
the	O
solution	O
of	O
this	O
problem	O
(	O
see	O
[	O
5	O
]	O
)	O
.	O

In	O
order	O
to	O
optimize	O
the	O
automated	O
annotation	O
procedure	O
,	O
that	O
is	O
to	O
increase	O
the	O
prediction	O
quality	O
,	O
certain	O
modifications	O
of	O
the	O
procedure	O
were	O
introduced	O
.	O

For	O
each	O
statistic	O
(	O
eta	O
,	O
T	O
(	O
1	O
)	O
,	O
T	O
(	O
2	O
)	O
,	O
T	O
^	O
(	O
2	O
)	O
)	O
many	O
variants	O
(	O
up	O
to	O
36	O
)	O
,	O
including	O
the	O
variant	O
that	O
was	O
described	O
above	O
,	O
were	O
considered	O
-	O
each	O
variant	O
corresponds	O
to	O
a	O
certain	O
combination	O
of	O
these	O
modifications	O
.	O

Some	O
variants	O
really	O
turned	O
out	O
to	O
be	O
better	O
than	O
the	O
variants	O
described	O
above	O
.	O

A	O
simplified	O
scheme	O
of	O
modifications	O
(	O
and	O
thereby	O
of	O
statistic	O
variants	O
)	O
can	O
be	O
described	O
as	O
follows	O
.	O

1	O
)	O
What	O
primary	O
local	O
alignments	O
are	O
considered	O
?	O

In	O
the	O
described	O
variant	O
of	O
statistics	O
only	O
one	O
primary	O
local	O
alignment	O
(	O
the	O
one	O
with	O
the	O
maximum	O
power	O
)	O
was	O
considered	O
.	O

Meanwhile	O
,	O
all	O
constructed	O
local	O
alignments	O
with	O
sufficiently	O
high	O
power	O
can	O
be	O
considered	O
,	O
as	O
it	O
was	O
done	O
in	O
[	O
5	O
]	O
.	O

In	O
this	O
case	O
indices	O
i	O
in	O
(	O
9	O
)	O
,	O
(	O
12	O
)	O
,	O
(	O
15	O
)	O
correspond	O
not	O
to	O
individual	O
similar	O
sequences	O
,	O
but	O
to	O
primary	O
local	O
alignments	O
of	O
this	O
sequences	O
.	O

2	O
)	O
Are	O
the	O
lengths	O
of	O
primary	O
local	O
alignments	O
taken	O
into	O
consideration	O
?	O

In	O
the	O
described	O
variant	O
lengths	O
of	O
primary	O
local	O
alignments	O
were	O
not	O
taken	O
into	O
consideration	O
,	O
but	O
these	O
lengths	O
can	O
be	O
considered	O
as	O
well	O
.	O

In	O
this	O
case	O
indices	O
i	O
in	O
(	O
9	O
)	O
,	O
(	O
12	O
)	O
,	O
(	O
15	O
)	O
correspond	O
not	O
to	O
similar	O
sequences	O
or	O
primary	O
local	O
alignments	O
,	O
but	O
to	O
individual	O
positions	O
of	O
these	O
primary	O
local	O
alignments	O
(	O
as	O
in	O
case	O
of	O
FT	O
-	O
type	O
words	O
)	O
.	O

In	O
this	O
case	O
the	O
total	O
number	O
of	O
variates	O
xi	O
i	O
is	O
equal	O
to	O
the	O
overall	O
length	O
of	O
all	O
primary	O
local	O
alignments	O
.	O

For	O
these	O
variants	O
of	O
statistics	O
long	O
local	O
alignments	O
turn	O
out	O
to	O
be	O
more	O
significant	O
than	O
short	O
local	O
alignments	O
with	O
the	O
same	O
power	O
.	O

3	O
)	O
How	O
are	O
the	O
coefficients	O
ai	O
calculated	O
?	O

The	O
coefficients	O
ai	O
in	O
(	O
15	O
)	O
can	O
be	O
calculated	O
using	O
different	O
methods	O
-	O
either	O
formula	O
(	O
13	O
)	O
can	O
be	O
used	O
,	O
or	O
an	O
iterative	O
method	O
(	O
described	O
in	O
[	O
5	O
]	O
)	O
can	O
be	O
applied	O
.	O

(	O
For	O
the	O
statistic	O
T	O
(	O
1	O
)	O
the	O
coefficients	O
ai	O
are	O
always	O
calculated	O
using	O
formula	O
(	O
13	O
)	O
)	O
.	O

As	O
there	O
are	O
3	O
modifications	O
,	O
the	O
total	O
number	O
of	O
basic	O
variants	O
(	O
in	O
the	O
described	O
simplified	O
scheme	O
)	O
equals	O
23	O
=	O
8	O
(	O
and	O
for	O
the	O
statistic	O
T	O
(	O
1	O
)	O
it	O
equals	O
4	O
)	O
.	O

So	O
,	O
variants	O
of	O
the	O
statistics	O
eta	O
,	O
T	O
(	O
1	O
)	O
,	O
T	O
(	O
2	O
)	O
,	O
T	O
^	O
(	O
2	O
)	O
are	O
considered	O
in	O
this	O
paper	O
.	O

Moreover	O
,	O
for	O
the	O
purpose	O
of	O
comparison	O
(	O
as	O
in	O
the	O
paper	O
[	O
5	O
]	O
)	O
the	O
simple	O
statistic	O

(	O
18	O
)	O
q	O
=	O
q	O
(	O
omega	O
)	O
=	O
sum	O
in	O
xi	O
in	O

(	O
the	O
frequency	O
of	O
occurrence	O
of	O
a	O
word	O
omega	O
in	O
the	O
collection	O
of	O
similar	O
sequences	O
)	O
is	O
also	O
considered	O
.	O

Finally	O
we	O
quote	O
a	O
scheme	O
of	O
the	O
A4	O
algorithm	O
in	O
Figure	O
1	O
(	O
this	O
scheme	O
is	O
essentially	O
taken	O
from	O
[	O
5	O
]	O
)	O
.	O

A	O
short	O
description	O
of	O
each	O
stage	O
can	O
be	O
found	O
in	O
[	O
5	O
]	O
.	O

Here	O
we	O
only	O
note	O
that	O
the	O
most	O
time	O
-	O
consuming	O
stage	O
is	O
the	O
first	O
one	O
-	O
the	O
generation	O
of	O
a	O
collection	O
of	O
similar	O
sequences	O
.	O

We	O
also	O
note	O
that	O
in	O
the	O
current	O
investigation	O
regions	O
were	O
not	O
determined	O
,	O
and	O
the	O
prediction	O
was	O
performed	O
for	O
the	O
whole	O
query	O
sequence	O
.	O

Testing	O
results	O

Testing	O
scheme	O

A	O
collection	O
of	O
518	O
sequences	O
,	O
randomly	O
selected	O
from	O
SWISS	O
-	O
PROT	O
databank	O
,	O
was	O
generated	O
.	O

Note	O
that	O
only	O
initially	O
annotated	O
sequences	O
(	O
i	O
.	O
e	O
.	O
,	O
sequences	O
whose	O
description	O
fields	O
were	O
not	O
obtained	O
by	O
the	O
extension	O
from	O
similar	O
sequences	O
)	O
were	O
selected	O
.	O

The	O
prediction	O
was	O
performed	O
for	O
KW	O
-	O
type	O
words	O
.	O

All	O
selected	O
sequences	O
were	O
divided	O
into	O
two	O
groups	O
.	O

The	O
first	O
group	O
contained	O
210	O
sequences	O
.	O

This	O
group	O
was	O
used	O
during	O
the	O
"	O
learning	O
stage	O
"	O
:	O
the	O
procedure	O
was	O
applied	O
to	O
all	O
sequences	O
from	O
the	O
group	O
,	O
and	O
values	O
of	O
procedure	O
parameters	O
(	O
including	O
optimal	O
threshold	O
values	O
)	O
that	O
minimize	O
the	O
total	O
number	O
of	O
errors	O
for	O
the	O
first	O
group	O
were	O
selected	O
.	O

The	O
remaining	O
308	O
sequences	O
were	O
used	O
for	O
the	O
"	O
main	O
testing	O
"	O
that	O
was	O
performed	O
using	O
parameter	O
values	O
obtained	O
on	O
the	O
basis	O
of	O
"	O
learning	O
"	O
results	O
.	O

A	O
list	O
of	O
all	O
these	O
308	O
sequences	O
is	O
given	O
in	O
Additional	O
file	O
1	O
.	O

The	O
total	O
number	O
of	O
KW	O
-	O
type	O
words	O
in	O
the	O
description	O
fields	O
of	O
308	O
selected	O
sequences	O
,	O
used	O
as	O
query	O
sequences	O
,	O
was	O
equal	O
to	O
1176	O
(	O
the	O
positive	O
prediction	O
was	O
preferable	O
for	O
these	O
words	O
)	O
.	O

As	O
it	O
was	O
noted	O
,	O
a	O
collection	O
of	O
similar	O
sequences	O
was	O
generated	O
for	O
each	O
query	O
sequence	O
;	O
the	O
number	O
of	O
sequences	O
in	O
these	O
collections	O
equaled	O
100	O
.	O

Then	O
the	O
list	O
of	O
all	O
KW	O
-	O
type	O
words	O
from	O
description	O
fields	O
of	O
similar	O
sequences	O
was	O
formed	O
.	O

The	O
majority	O
of	O
these	O
words	O
belonged	O
only	O
to	O
one	O
similar	O
sequence	O
.	O

All	O
such	O
words	O
are	O
degenerate	O
,	O
transfer	O
probabilities	O
are	O
not	O
defined	O
for	O
them	O
.	O

At	O
the	O
same	O
time	O
nearly	O
all	O
these	O
words	O
did	O
not	O
belong	O
to	O
the	O
query	O
sequence	O
.	O

Hence	O
it	O
was	O
sensible	O
to	O
perform	O
prediction	O
only	O
for	O
words	O
that	O
belonged	O
to	O
at	O
least	O
two	O
similar	O
sequences	O
.	O

For	O
all	O
these	O
words	O
transfer	O
probabilities	O
were	O
evaluated	O
,	O
non	O
-	O
degenerate	O
words	O
(	O
i	O
.	O
e	O
.	O
,	O
words	O
with	O
defined	O
transfer	O
probabilities	O
)	O
were	O
determined	O
,	O
and	O
the	O
prediction	O
was	O
performed	O
(	O
for	O
both	O
degenerate	O
and	O
non	O
-	O
degenerate	O
words	O
)	O
.	O

Table	O
1	O
shows	O
certain	O
characteristics	O
of	O
sequences	O
used	O
for	O
the	O
testing	O
.	O

The	O
average	O
number	O
of	O
words	O
considered	O
per	O
query	O
sequence	O
equals	O
30	O
and	O
the	O
entire	O
range	O
was	O
from	O
3	O
to	O
67	O
.	O

Final	O
results	O

Testing	O
results	O
are	O
presented	O
in	O
Table	O
2	O
.	O

The	O
table	O
contains	O
testing	O
results	O
for	O
the	O
basic	O
statistics	O
eta	O
,	O
T	O
(	O
1	O
)	O
,	O
T	O
(	O
2	O
)	O
,	O
T	O
^	O
(	O
2	O
)	O
as	O
well	O
as	O
for	O
the	O
statistics	O
q	O
and	O
SAnd	O
,	O
included	O
into	O
the	O
table	O
for	O
the	O
purpose	O
of	O
comparison	O
(	O
See	O
the	O
Discussion	O
section	O
)	O
.	O

Each	O
line	O
of	O
the	O
table	O
corresponds	O
to	O
a	O
certain	O
variant	O
of	O
studied	O
statistics	O
.	O

The	O
first	O
column	O
shows	O
which	O
statistic	O
and	O
which	O
variant	O
of	O
this	O
statistic	O
corresponds	O
to	O
a	O
line	O
.	O

Variants	O
are	O
given	O
in	O
square	O
brackets	O
:	O
the	O
first	O
number	O
equals	O
0	O
if	O
lengths	O
of	O
primary	O
local	O
alignments	O
are	O
not	O
considered	O
,	O
and	O
1	O
otherwise	O
;	O
the	O
second	O
number	O
equals	O
0	O
if	O
the	O
coefficients	O
ai	O
are	O
calculated	O
using	O
formula	O
(	O
13	O
)	O
,	O
and	O
1	O
if	O
the	O
coefficients	O
ai	O
are	O
calculated	O
using	O
the	O
iterative	O
procedure	O
(	O
for	O
the	O
statistic	O
T	O
(	O
1	O
)	O
the	O
second	O
number	O
is	O
always	O
0	O
)	O
.	O

The	O
second	O
column	O
contains	O
the	O
number	O
N1	O
of	O
type	O
1	O
errors	O
(	O
i	O
.	O
e	O
.	O
,	O
number	O
of	O
cases	O
when	O
the	O
prediction	O
for	O
a	O
word	O
that	O
belongs	O
to	O
description	O
fields	O
of	O
a	O
query	O
sequence	O
is	O
negative	O
)	O
.	O

The	O
third	O
column	O
contains	O
the	O
number	O
N2	O
of	O
type	O
2	O
errors	O
(	O
i	O
.	O
e	O
.	O
,	O
number	O
of	O
cases	O
when	O
the	O
prediction	O
for	O
a	O
word	O
that	O
does	O
not	O
belong	O
to	O
description	O
fields	O
of	O
a	O
query	O
sequence	O
is	O
positive	O
)	O
.	O

The	O
forth	O
column	O
contains	O
the	O
total	O
number	O
of	O
errors	O
Nall	O
=	O
N1	O
+	O
N2	O
.	O

The	O
next	O
columns	O
contain	O
sums	O
P	O
(	O
1	O
)	O
+	O
P	O
(	O
2	O
)	O
and	O
P	O
(	O
1	O
)	O
+	O
P	O
(	O
+	O
)	O
,	O
where	O
P	O
(	O
1	O
)	O
is	O
the	O
proportion	O
of	O
type	O
1	O
errors	O
,	O
P	O
(	O
2	O
)	O
is	O
the	O
proportion	O
of	O
type	O
2	O
errors	O
,	O
and	O
P	O
(	O
+	O
)	O
is	O
the	O
ratio	O
of	O
false	O
positive	O
predictions	O
to	O
the	O
total	O
number	O
of	O
predictions	O
:	O
P	O
(	O
1	O
)	O
=	O
N1nq	O
,	O
P	O
(	O
2	O
)	O
=	O
N2nall	O
-	O
nq	O
,	O
P	O
(	O
+	O
)	O
=	O
N2n	O
+	O
(	O
nall	O
is	O
the	O
total	O
number	O
of	O
words	O
for	O
which	O
the	O
prediction	O
is	O
performed	O
,	O
i	O
.	O
e	O
.	O
,	O
total	O
number	O
of	O
KW	O
-	O
type	O
words	O
in	O
description	O
fields	O
of	O
all	O
sequences	O
,	O
similar	O
to	O
at	O
least	O
one	O
query	O
sequence	O
,	O
nq	O
is	O
the	O
number	O
of	O
words	O
(	O
from	O
the	O
list	O
of	O
these	O
nall	O
words	O
)	O
that	O
belong	O
to	O
query	O
sequences	O
,	O
n	O
+	O
is	O
the	O
total	O
number	O
of	O
words	O
for	O
which	O
the	O
prediction	O
is	O
positive	O
;	O
here	O
nall	O
=	O
9236	O
,	O
nq	O
=	O
1176	O
,	O
nall	O
-	O
nq	O
=	O
8060	O
;	O
the	O
value	O
of	O
n	O
+	O
of	O
depends	O
on	O
the	O
threshold	O
evaluated	O
for	O
the	O
given	O
version	O
of	O
statistic	O
at	O
the	O
"	O
learning	O
stage	O
"	O
)	O
.	O

Lines	O
are	O
ordered	O
according	O
to	O
the	O
prediction	O
quality	O
:	O
higher	O
lines	O
correspond	O
to	O
statistic	O
variants	O
with	O
lower	O
total	O
number	O
of	O
errors	O
.	O

For	O
a	O
fixed	O
statistic	O
,	O
lines	O
that	O
correspond	O
to	O
the	O
best	O
variant	O
of	O
this	O
statistic	O
(	O
i	O
.	O
e	O
.	O
,	O
for	O
the	O
variant	O
that	O
leads	O
to	O
the	O
lowest	O
total	O
number	O
of	O
errors	O
)	O
are	O
marked	O
.	O

Recall	O
that	O
the	O
statistic	O
T	O
^	O
(	O
2	O
)	O
[	O
1	O
,	O
0	O
]	O
is	O
exactly	O
the	O
statistic	O
that	O
was	O
considered	O
in	O
[	O
5	O
]	O
(	O
note	O
that	O
it	O
is	O
the	O
best	O
variant	O
for	O
the	O
statistic	O
T	O
^	O
(	O
2	O
)	O
)	O
.	O

The	O
results	O
could	O
also	O
have	O
been	O
presented	O
as	O
a	O
confusion	O
table	O
as	O
laid	O
out	O
in	O
Table	O
3	O
,	O
but	O
doing	O
so	O
for	O
all	O
variants	O
would	O
take	O
a	O
lot	O
of	O
space	O
.	O

The	O
testing	O
results	O
showed	O
that	O
the	O
first	O
modification	O
(	O
consideration	O
of	O
all	O
primary	O
local	O
alignments	O
or	O
only	O
one	O
primary	O
local	O
alignment	O
with	O
the	O
maximum	O
power	O
)	O
did	O
not	O
significantly	O
affect	O
the	O
prediction	O
quality	O
,	O
so	O
results	O
are	O
only	O
presented	O
for	O
one	O
case	O
(	O
all	O
local	O
alignments	O
are	O
considered	O
,	O
similarly	O
to	O
[	O
5	O
]	O
)	O
.	O

Note	O
that	O
the	O
results	O
presented	O
in	O
the	O
Table	O
correspond	O
to	O
the	O
whole	O
totality	O
of	O
words	O
including	O
degenerate	O
words	O
(	O
though	O
statistics	O
eta	O
,	O
T	O
(	O
1	O
)	O
,	O
T	O
(	O
2	O
)	O
,	O
T	O
^	O
(	O
2	O
)	O
,	O
T	O
(	O
nik	O
)	O
were	O
evaluated	O
only	O
for	O
non	O
-	O
degenerate	O
words	O
,	O
for	O
degenerate	O
words	O
the	O
prediction	O
was	O
performed	O
on	O
the	O
basis	O
of	O
the	O
statistic	O
q	O
,	O
i	O
.	O
e	O
.	O
,	O
on	O
the	O
basis	O
of	O
word	O
frequency	O
)	O
.	O

In	O
particular	O
,	O
the	O
total	O
number	O
of	O
errors	O
includes	O
errors	O
for	O
degenerate	O
words	O
.	O

It	O
is	O
worth	O
noticing	O
that	O
the	O
total	O
number	O
of	O
errors	O
for	O
degenerate	O
words	O
in	O
case	O
of	O
the	O
best	O
choice	O
of	O
threshold	O
q0	O
for	O
the	O
frequency	O
q	O
(	O
omega	O
)	O
turned	O
out	O
to	O
be	O
surprisingly	O
small	O
:	O
only	O
13	O
(	O
whereas	O
the	O
number	O
of	O
errors	O
for	O
the	O
whole	O
totality	O
of	O
words	O
was	O
220	O
)	O
;	O
these	O
errors	O
included	O
twelve	O
type	O
1	O
errors	O
and	O
one	O
type	O
2	O
error	O
(	O
recall	O
that	O
the	O
prediction	O
was	O
performed	O
for	O
2029	O
degenerate	O
words	O
,	O
and	O
the	O
prediction	O
was	O
incorrect	O
only	O
in	O
13	O
cases	O
)	O
.	O

Such	O
a	O
small	O
number	O
of	O
errors	O
can	O
seemingly	O
be	O
explained	O
by	O
the	O
fact	O
that	O
for	O
degenerate	O
words	O
the	O
frequency	O
q	O
(	O
omega	O
)	O
is	O
nearly	O
always	O
close	O
either	O
to	O
1	O
or	O
to	O
0	O
,	O
otherwise	O
in	O
almost	O
all	O
cases	O
transfer	O
probabilities	O
p1	O
|	O
1	O
,	O
p1	O
|	O
0	O
can	O
be	O
defined	O
for	O
at	O
least	O
some	O
values	O
of	O
similarity	O
measure	O
mu	O
and	O
hence	O
a	O
word	O
omega	O
turns	O
out	O
to	O
be	O
non	O
-	O
degenerate	O
.	O

We	O
also	O
note	O
that	O
along	O
with	O
type	O
1	O
and	O
type	O
2	O
errors	O
other	O
errors	O
can	O
occur	O
,	O
as	O
it	O
is	O
possible	O
that	O
some	O
words	O
from	O
description	O
fields	O
of	O
a	O
query	O
sequence	O
do	O
not	O
belong	O
to	O
description	O
fields	O
of	O
similar	O
sequences	O
and	O
hence	O
the	O
prediction	O
is	O
not	O
performed	O
for	O
these	O
words	O
at	O
all	O
.	O

However	O
,	O
we	O
used	O
a	O
large	O
number	O
of	O
similar	O
sequences	O
(	O
100	O
)	O
for	O
the	O
prediction	O
,	O
so	O
such	O
errors	O
were	O
extremely	O
rare	O
(	O
only	O
two	O
words	O
for	O
the	O
whole	O
test	O
set	O
of	O
518	O
sequences	O
,	O
whereas	O
the	O
number	O
of	O
words	O
for	O
which	O
the	O
prediction	O
was	O
performed	O
equaled	O
9236	O
)	O
.	O

Hence	O
,	O
in	O
our	O
case	O
these	O
errors	O
can	O
be	O
disregarded	O
.	O

Statistical	O
analysis	O
showed	O
that	O
the	O
precision	O
of	O
the	O
evaluation	O
of	O
N1	O
,	O
N2	O
,	O
Nall	O
is	O
reasonable	O
:	O
it	O
can	O
be	O
checked	O
that	O
the	O
relative	O
precision	O
of	O
Nall	O
(	O
the	O
standard	O
error	O
of	O
ln	O
(	O
Nall	O
)	O
)	O
is	O
in	O
the	O
order	O
of	O
7	O
-	O
10	O
%	O
which	O
is	O
in	O
line	O
with	O
the	O
relative	O
precision	O
of	O
a	O
Poisson	O
random	O
variable	O
that	O
is	O
given	O
by	O
1	O
/	O
Nall	O
.	O

However	O
,	O
since	O
the	O
"	O
methods	O
"	O
(	O
the	O
statistics	O
and	O
their	O
variants	O
)	O
are	O
compared	O
on	O
the	O
same	O
sequences	O
,	O
the	O
standard	O
error	O
for	O
the	O
comparison	O
between	O
methods	O
is	O
much	O
smaller	O
due	O
to	O
the	O
high	O
correlation	O
of	O
results	O
for	O
the	O
same	O
sequence	O
and	O
is	O
in	O
the	O
order	O
of	O
2	O
-	O
4	O
%	O
.	O

This	O
implies	O
that	O
"	O
methods	O
"	O
for	O
which	O
Nall	O
differ	O
by	O
more	O
than	O
10	O
%	O
can	O
considered	O
to	O
be	O
significantly	O
different	O
.	O

This	O
shows	O
that	O
size	O
of	O
the	O
experiment	O
with	O
210	O
randomly	O
selected	O
sequences	O
in	O
the	O
learning	O
stage	O
and	O
308	O
sequences	O
in	O
the	O
testing	O
stage	O
is	O
large	O
enough	O
to	O
obtain	O
valid	O
statements	O
about	O
the	O
accuracy	O
of	O
the	O
proposed	O
methodology	O
and	O
allows	O
statistical	O
comparisons	O
of	O
different	O
statistics	O
and	O
variants	O
.	O

When	O
the	O
set	O
of	O
tested	O
sequences	O
is	O
fixed	O
,	O
the	O
total	O
number	O
of	O
errors	O
Nall	O
is	O
an	O
objective	O
characteristic	O
of	O
prediction	O
quality	O
,	O
and	O
the	O
optimal	O
threshold	O
values	O
(	O
selected	O
during	O
the	O
"	O
learning	O
stage	O
"	O
)	O
provide	O
exactly	O
the	O
minimum	O
of	O
the	O
total	O
number	O
of	O
errors	O
.	O

However	O
,	O
if	O
different	O
testing	O
results	O
(	O
based	O
on	O
different	O
sets	O
of	O
query	O
sequences	O
)	O
are	O
compared	O
,	O
then	O
absolute	O
numbers	O
of	O
errors	O
can	O
not	O
be	O
treated	O
as	O
a	O
procedure	O
quality	O
measure	O
,	O
and	O
relative	O
quantities	O
(	O
proportions	O
)	O
should	O
be	O
considered	O
instead	O
of	O
absolute	O
quantities	O
.	O

Usually	O
a	O
sum	O
of	O
the	O
proportion	O
of	O
type	O
1	O
errors	O
and	O
the	O
proportion	O
of	O
type	O
2	O
errors	O
P	O
(	O
1	O
)	O
+	O
P	O
(	O
2	O
)	O
is	O
used	O
as	O
a	O
quality	O
measure	O
;	O
values	O
of	O
this	O
sum	O
are	O
presented	O
in	O
the	O
fifth	O
column	O
of	O
Table	O
2	O
.	O

However	O
,	O
in	O
our	O
situation	O
the	O
number	O
of	O
words	O
nall	O
-	O
nq	O
that	O
do	O
not	O
belong	O
to	O
query	O
sequences	O
is	O
much	O
larger	O
than	O
nq	O
,	O
and	O
for	O
the	O
majority	O
of	O
these	O
words	O
it	O
is	O
obvious	O
that	O
they	O
do	O
not	O
belong	O
to	O
a	O
query	O
sequence	O
.	O

Consequently	O
,	O
in	O
case	O
of	O
optimal	O
parameter	O
values	O
the	O
proportion	O
of	O
type	O
2	O
errors	O
P	O
(	O
2	O
)	O
is	O
small	O
,	O
it	O
is	O
considerably	O
smaller	O
than	O
P	O
(	O
1	O
)	O
.	O

Thus	O
the	O
quantity	O
P	O
(	O
1	O
)	O
+	O
P	O
(	O
2	O
)	O
is	O
not	O
representative	O
in	O
our	O
case	O
(	O
see	O
[	O
5	O
]	O
)	O
.	O

The	O
ratio	O
P	O
(	O
+	O
)	O
of	O
the	O
number	O
of	O
wrong	O
positive	O
predictions	O
to	O
the	O
total	O
number	O
of	O
positive	O
predictions	O
is	O
more	O
representative	O
than	O
P	O
(	O
2	O
)	O
.	O

Hence	O
,	O
it	O
is	O
natural	O
to	O
measure	O
procedure	O
quality	O
by	O
the	O
sum	O
P	O
(	O
1	O
)	O
+	O
P	O
(	O
+	O
)	O
.	O

Exactly	O
this	O
procedure	O
quality	O
measure	O
was	O
used	O
in	O
[	O
5	O
]	O
.	O

In	O
medical	O
decision	O
making	O
(	O
diagnostic	O
testing	O
)	O
the	O
terms	O
sensitivity	O
(	O
sens	O
=	O
1	O
-	O
P	O
(	O
1	O
)	O
)	O
and	O
specificity	O
(	O
spec	O
=	O
1	O
-	O
P	O
(	O
2	O
)	O
)	O
are	O
frequently	O
used	O
to	O
quantify	O
the	O
accuracy	O
of	O
a	O
procedure	O
,	O
while	O
the	O
quantity	O
1	O
-	O
P	O
(	O
+	O
)	O
is	O
known	O
as	O
the	O
positive	O
predictive	O
value	O
.	O

Alternative	O
terminology	O
is	O
discussed	O
in	O
[	O
12	O
]	O
.	O

The	O
ROC	O
curve	O
plotting	O
sens	O
against	O
1	O
-	O
spec	O
is	O
a	O
popular	O
way	O
of	O
showing	O
the	O
overall	O
performance	O
of	O
a	O
diagnostic	O
test	O
without	O
specification	O
of	O
a	O
cut	O
off	O
value	O
.	O

It	O
is	O
also	O
used	O
and	O
discussed	O
in	O
[	O
12	O
]	O
,	O
but	O
with	O
different	O
labels	O
for	O
the	O
axes	O
.	O

Figure	O
2	O
contains	O
ROC	O
curves	O
for	O
the	O
best	O
variants	O
of	O
the	O
statistics	O
(	O
i	O
.	O
e	O
.	O
,	O
for	O
variants	O
that	O
were	O
marked	O
in	O
Table	O
2	O
)	O
applied	O
to	O
the	O
non	O
-	O
degenerate	O
words	O
.	O

Discussion	O

Overall	O
comparison	O
of	O
the	O
statistics	O
T	O
(	O
1	O
)	O
,	O
eta	O
,	O
T	O
(	O
2	O
)	O
,	O
T	O
^	O
(	O
2	O
)	O

Mean	O
values	O
of	O
Nall	O
(	O
where	O
averaging	O
is	O
performed	O
over	O
all	O
variants	O
presented	O
in	O
Table	O
2	O
)	O
for	O
different	O
statistics	O
are	O
the	O
following	O
:	O
241	O
for	O
eta	O
,	O
310	O
for	O
T	O
(	O
1	O
)	O
,	O
320	O
for	O
T	O
(	O
2	O
)	O
,	O
and	O
356	O
for	O
T	O
^	O
(	O
2	O
)	O
(	O
recall	O
that	O
differences	O
in	O
the	O
order	O
of	O
10	O
%	O
can	O
be	O
considered	O
to	O
be	O
significant	O
)	O
.	O

These	O
numbers	O
show	O
that	O
the	O
statistics	O
can	O
clearly	O
be	O
ordered	O
with	O
respect	O
to	O
the	O
prediction	O
quality	O
:	O
the	O
best	O
statistic	O
is	O
eta	O
,	O
then	O
comes	O
T	O
(	O
1	O
)	O
,	O
then	O
T	O
(	O
2	O
)	O
,	O
and	O
finally	O
T	O
^	O
(	O
2	O
)	O
.	O

For	O
the	O
comparison	O
of	O
the	O
statistics	O
eta	O
,	O
T	O
(	O
1	O
)	O
,	O
as	O
well	O
as	O
for	O
the	O
comparison	O
of	O
statistics	O
the	O
T	O
(	O
2	O
)	O
,	O
T	O
^	O
(	O
2	O
)	O
this	O
conclusion	O
is	O
obvious	O
.	O

For	O
the	O
comparison	O
of	O
the	O
statistics	O
T	O
(	O
1	O
)	O
,	O
T	O
(	O
2	O
)	O
it	O
seems	O
to	O
be	O
less	O
obvious	O
,	O
but	O
the	O
consideration	O
of	O
variants	O
in	O
which	O
the	O
calculation	O
of	O
coefficients	O
ai	O
is	O
performed	O
using	O
formula	O
(	O
13	O
)	O
(	O
i	O
.	O
e	O
.	O
,	O
variants	O
[	O
0	O
,	O
0	O
]	O
and	O
[	O
1	O
,	O
0	O
]	O
;	O
recall	O
that	O
the	O
statistic	O
T	O
(	O
1	O
)	O
has	O
only	O
such	O
variants	O
)	O
clearly	O
shows	O
that	O
the	O
statistic	O
T	O
(	O
1	O
)	O
is	O
considerably	O
better	O
than	O
T	O
(	O
2	O
)	O
.	O

The	O
same	O
conclusion	O
can	O
be	O
drawn	O
from	O
the	O
comparison	O
of	O
ROC	O
curves	O
presented	O
in	O
Fig	O
.	O

2	O
.	O

Testing	O
results	O
show	O
that	O
the	O
prediction	O
quality	O
for	O
the	O
best	O
variant	O
of	O
the	O
statistic	O
eta	O
(	O
see	O
the	O
first	O
line	O
of	O
Table	O
2	O
)	O
is	O
much	O
higher	O
(	O
higher	O
by	O
50	O
%	O
)	O
in	O
comparison	O
with	O
results	O
of	O
[	O
5	O
]	O
(	O
see	O
the	O
line	O
of	O
Table	O
2	O
that	O
corresponds	O
to	O
T	O
^	O
(	O
2	O
)	O
[	O
0	O
,	O
1	O
]	O
)	O
.	O

That	O
is	O
the	O
most	O
striking	O
finding	O
of	O
the	O
current	O
paper	O
.	O

It	O
is	O
interesting	O
to	O
see	O
that	O
the	O
statistic	O
eta	O
turned	O
out	O
to	O
be	O
better	O
than	O
T	O
(	O
1	O
)	O
:	O
the	O
latter	O
would	O
be	O
expected	O
to	O
be	O
better	O
as	O
it	O
equals	O
the	O
logarithm	O
of	O
the	O
likelihood	O
ratio	O
(	O
in	O
reality	O
,	O
it	O
does	O
not	O
equal	O
this	O
logarithm	O
because	O
the	O
xi	O
i	O
are	O
not	O
independent	O
)	O
.	O

We	O
suppose	O
that	O
this	O
fact	O
can	O
be	O
explained	O
as	O
follows	O
.	O

Recall	O
that	O
T	O
(	O
1	O
)	O
and	O
eta	O
are	O
equivalent	O
for	O
an	O
arbitrary	O
fixed	O
word	O
omega	O
.	O

These	O
statistics	O
turn	O
out	O
to	O
be	O
not	O
equivalent	O
only	O
if	O
they	O
are	O
compared	O
on	O
the	O
whole	O
totality	O
of	O
words	O
.	O

It	O
is	O
worth	O
noting	O
that	O
the	O
variation	O
of	O
the	O
values	O
of	O
the	O
statistic	O
T	O
(	O
1	O
)	O
(	O
i	O
.	O
e	O
.	O
,	O
the	O
difference	O
between	O
values	O
of	O
T	O
(	O
1	O
)	O
in	O
cases	O
xi	O
1	O
=	O
.	O
.	O
.	O
.	O
=	O
xi	O
n	O
=	O
0	O
and	O
xi	O
1	O
=	O
.	O
.	O
.	O
.	O
=	O
xi	O
n	O
=	O
1	O
)	O
significantly	O
depends	O
on	O
a	O
word	O
omega	O
:	O
for	O
some	O
words	O
these	O
values	O
vary	O
from	O
-	O
700	O
to	O
700	O
,	O
for	O
some	O
other	O
from	O
-	O
0	O
.	O
01	O
to	O
0	O
.	O
01	O
.	O

In	O
principle	O
,	O
the	O
optimal	O
threshold	O
value	O
is	O
different	O
for	O
different	O
words	O
.	O

As	O
the	O
ranges	O
of	O
T	O
(	O
1	O
)	O
values	O
essentially	O
vary	O
,	O
then	O
it	O
is	O
probable	O
that	O
optimal	O
thresholds	O
also	O
essentially	O
vary	O
.	O

The	O
optimal	O
threshold	O
for	O
the	O
whole	O
totality	O
of	O
words	O
is	O
a	O
certain	O
mean	O
value	O
of	O
thresholds	O
over	O
individual	O
words	O
omega	O
.	O

Since	O
the	O
optimal	O
thresholds	O
are	O
significantly	O
different	O
for	O
different	O
words	O
,	O
the	O
quality	O
of	O
the	O
mean	O
is	O
low	O
:	O
for	O
certain	O
words	O
(	O
e	O
.	O
g	O
.	O
,	O
words	O
with	O
small	O
variation	O
of	O
T	O
(	O
1	O
)	O
)	O
this	O
mean	O
is	O
completely	O
unrepresentative	O
.	O

In	O
the	O
same	O
time	O
,	O
the	O
range	O
of	O
values	O
of	O
eta	O
is	O
the	O
same	O
for	O
all	O
words	O
(	O
these	O
values	O
lie	O
between	O
0	O
and	O
1	O
)	O
.	O

Consequently	O
,	O
the	O
difference	O
between	O
optimal	O
thresholds	O
for	O
individual	O
words	O
is	O
probably	O
not	O
so	O
significant	O
,	O
and	O
the	O
mean	O
gives	O
better	O
quality	O
for	O
individual	O
words	O
in	O
comparison	O
with	O
T	O
(	O
1	O
)	O
.	O

From	O
the	O
point	O
of	O
view	O
of	O
prediction	O
quality	O
the	O
statistic	O
T	O
(	O
2	O
)	O
turned	O
out	O
to	O
be	O
worse	O
than	O
T	O
(	O
1	O
)	O
.	O

It	O
is	O
not	O
surprising	O
,	O
because	O
during	O
the	O
derivation	O
of	O
the	O
formula	O
for	O
T	O
(	O
2	O
)	O
along	O
with	O
the	O
incorrect	O
assumption	O
of	O
independence	O
of	O
xi	O
i	O
we	O
also	O
made	O
the	O
incorrect	O
assumption	O
of	O
the	O
normal	O
distribution	O
of	O
eta	O
.	O

This	O
consideration	O
is	O
applicable	O
to	O
T	O
^	O
(	O
2	O
)	O
as	O
well	O
.	O

Since	O
the	O
cut	O
-	O
off	O
points	O
for	O
these	O
statistics	O
are	O
determined	O
empirically	O
in	O
the	O
test	O
set	O
and	O
validated	O
in	O
the	O
training	O
set	O
,	O
the	O
violation	O
of	O
the	O
normality	O
assumption	O
does	O
not	O
invalidate	O
the	O
procedures	O
as	O
such	O
,	O
but	O
might	O
affect	O
their	O
performance	O
.	O

Effect	O
of	O
procedure	O
modifications	O

The	O
next	O
issue	O
is	O
the	O
dependence	O
of	O
prediction	O
quality	O
on	O
procedure	O
modifications	O
.	O

One	O
can	O
see	O
that	O
for	O
a	O
fixed	O
statistic	O
the	O
prediction	O
quality	O
significantly	O
depends	O
on	O
the	O
choice	O
of	O
the	O
variant	O
.	O

Thus	O
,	O
the	O
introduction	O
of	O
modifications	O
turned	O
out	O
to	O
be	O
effective	O
.	O

It	O
is	O
interesting	O
that	O
all	O
statistics	O
for	O
which	O
coefficients	O
aj	O
can	O
be	O
calculated	O
in	O
different	O
ways	O
(	O
these	O
are	O
the	O
statistics	O
eta	O
,	O
T	O
(	O
2	O
)	O
T	O
^	O
(	O
2	O
)	O
)	O
prediction	O
quality	O
was	O
better	O
in	O
case	O
when	O
these	O
coefficients	O
were	O
calculated	O
using	O
the	O
iterative	O
procedure	O
.	O

At	O
the	O
same	O
time	O
the	O
dependence	O
of	O
prediction	O
quality	O
on	O
the	O
modification	O
related	O
to	O
the	O
consideration	O
of	O
lengths	O
of	O
primary	O
local	O
alignments	O
is	O
more	O
intricate	O
:	O
for	O
the	O
statistic	O
eta	O
,	O
and	O
to	O
a	O
lesser	O
extent	O
for	O
the	O
statistics	O
T	O
(	O
1	O
)	O
,	O
T	O
(	O
2	O
)	O
,	O
the	O
results	O
are	O
better	O
if	O
lengths	O
of	O
primary	O
local	O
alignments	O
are	O
considered	O
,	O
but	O
for	O
the	O
statistic	O
T	O
^	O
(	O
2	O
)	O
results	O
are	O
better	O
when	O
lengths	O
of	O
primary	O
local	O
alignments	O
are	O
not	O
considered	O
.	O

Currently	O
reasons	O
of	O
this	O
fact	O
are	O
not	O
clear	O
for	O
us	O
.	O

As	O
it	O
was	O
noted	O
,	O
the	O
dependence	O
of	O
results	O
on	O
modifications	O
dealing	O
with	O
the	O
number	O
of	O
considered	O
primary	O
local	O
alignments	O
for	O
similar	O
sequences	O
is	O
not	O
essential	O
.	O

(	O
However	O
,	O
we	O
note	O
that	O
for	O
nearly	O
all	O
variants	O
that	O
were	O
described	O
above	O
as	O
well	O
as	O
variants	O
that	O
were	O
not	O
described	O
,	O
prediction	O
quality	O
is	O
better	O
in	O
case	O
when	O
all	O
primary	O
local	O
alignments	O
are	O
considered	O
)	O
.	O

Comparison	O
with	O
other	O
procedures	O

For	O
the	O
purpose	O
of	O
comparison	O
we	O
compared	O
our	O
findings	O
with	O
the	O
simple	O
statistic	O
q	O
(	O
omega	O
)	O
(	O
the	O
frequency	O
of	O
word	O
occurrence	O
in	O
the	O
list	O
of	O
similar	O
sequences	O
,	O
see	O
(	O
18	O
)	O
)	O
was	O
also	O
considered	O
,	O
using	O
a	O
threshold	O
of	O
q	O
=	O
0	O
.	O
422	O
.	O

As	O
expected	O
,	O
q	O
(	O
omega	O
)	O
gave	O
essentially	O
worse	O
results	O
in	O
comparison	O
with	O
T	O
(	O
1	O
)	O
,	O
eta	O
,	O
T	O
(	O
2	O
)	O
,	O
T	O
^	O
(	O
2	O
)	O
(	O
see	O
Table	O
2	O
)	O
.	O

Furthermore	O
,	O
we	O
compared	O
our	O
results	O
with	O
the	O
results	O
,	O
which	O
predicts	O
all	O
of	O
the	O
words	O
for	O
which	O
there	O
is	O
among	O
similar	O
sequences	O
at	O
least	O
one	O
sequence	O
with	O
a	O
power	O
above	O
a	O
certain	O
threshold	O
.	O

Such	O
an	O
approach	O
was	O
used	O
by	O
Andrade	O
M	O
.	O

et	O
al	O
.	O

[	O
2	O
]	O
.	O

This	O
is	O
the	O
statistics	O
SAnd	O
as	O
already	O
mentioned	O
in	O
Table	O
2	O
.	O

It	O
is	O
defined	O
as	O
SAnd	O
(	O
omega	O
)	O
=	O
max	O
mu	O
j	O
,	O
where	O
mu	O
j	O
is	O
the	O
measure	O
of	O
similarity	O
between	O
sequences	O
pi	O
0	O
,	O
pi	O
j	O
,	O
and	O
the	O
maximum	O
is	O
taken	O
on	O
the	O
j	O
for	O
which	O
xi	O
j	O
(	O
omega	O
)	O
=	O
1	O
(	O
i	O
.	O
e	O
.	O
the	O
word	O
belongs	O
to	O
these	O
sequences	O
)	O
.	O

In	O
our	O
application	O
similarity	O
is	O
measured	O
by	O
the	O
power	O
value	O
(	O
see	O
[	O
9	O
,	O
10	O
]	O
)	O
as	O
used	O
in	O
the	O
other	O
statistics	O
in	O
this	O
paper	O
and	O
mentioned	O
before	O
,	O
while	O
[	O
2	O
]	O
used	O
the	O
E	O
-	O
value	O
.	O

That	O
makse	O
the	O
cut	O
-	O
offs	O
hard	O
to	O
compare	O
.	O

The	O
results	O
for	O
these	O
statistics	O
are	O
given	O
in	O
the	O
same	O
Table	O
2	O
.	O

The	O
results	O
were	O
better	O
than	O
in	O
the	O
statistics	O
q	O
(	O
omega	O
)	O
,	O
but	O
worse	O
than	O
in	O
any	O
of	O
our	O
statistics	O
.	O

Surprisingly	O
,	O
it	O
turned	O
out	O
that	O
the	O
prediction	O
quality	O
is	O
better	O
when	O
only	O
some	O
similar	O
sequences	O
(	O
e	O
.	O
g	O
.	O
,	O
10	O
from	O
100	O
)	O
are	O
used	O
for	O
the	O
evaluation	O
of	O
a	O
statistic	O
(	O
but	O
not	O
for	O
the	O
evaluation	O
of	O
transfer	O
probabilities	O
!	O
)	O
.	O

It	O
means	O
that	O
a	O
large	O
part	O
of	O
similar	O
sequences	O
only	O
leads	O
to	O
an	O
increase	O
of	O
"	O
noise	O
"	O
.	O

(	O
See	O
[	O
13	O
]	O
for	O
details	O
.	O
)	O

We	O
would	O
also	O
like	O
to	O
mention	O
the	O
work	O
[	O
14	O
]	O
on	O
FunCat	O
categories	O
containing	O
a	O
set	O
of	O
about	O
7	O
,	O
500	O
well	O
annotated	O
proteins	O
and	O
providing	O
a	O
benchmarking	O
for	O
different	O
methods	O
of	O
automated	O
annotation	O
.	O

It	O
would	O
be	O
interesting	O
to	O
apply	O
our	O
procedure	O
to	O
this	O
database	O
,	O
but	O
that	O
has	O
not	O
been	O
realized	O
yet	O
.	O

We	O
did	O
not	O
attempt	O
at	O
this	O
stage	O
to	O
apply	O
our	O
approach	O
to	O
the	O
GO	O
annotation	O
.	O

It	O
would	O
be	O
interesting	O
further	O
research	O
to	O
switch	O
to	O
GO	O
data	O
and	O
to	O
compare	O
our	O
approach	O
with	O
other	O
approaches	O
in	O
the	O
literature	O
.	O

There	O
is	O
a	O
similarity	O
with	O
the	O
approach	O
of	O
Kajan	O
et	O
al	O
.	O

[	O
15	O
]	O
.	O

They	O
also	O
base	O
their	O
procedures	O
on	O
the	O
likelihood	O
ratio	O
,	O
but	O
use	O
approximations	O
based	O
on	O
maximal	O
similarity	O
(	O
or	O
minimal	O
distance	O
)	O
,	O
while	O
we	O
attempt	O
to	O
estimate	O
the	O
likelihood	O
ratio	O
from	O
pairwise	O
comparisons	O
within	O
the	O
set	O
of	O
similar	O
sequences	O
.	O

There	O
is	O
also	O
an	O
interesting	O
relation	O
with	O
the	O
GOPET	O
tool	O
presented	O
in	O
[	O
16	O
]	O
based	O
on	O
earlier	O
work	O
by	O
the	O
same	O
authors	O
[	O
17	O
]	O
.	O

These	O
authors	O
use	O
a	O
number	O
of	O
characteristics	O
of	O
the	O
set	O
of	O
found	O
similar	O
sequences	O
for	O
term	O
(	O
word	O
)	O
,	O
such	O
as	O
maximal	O
e	O
-	O
value	O
,	O
frequency	O
of	O
the	O
term	O
etc	O
.	O
,	O
as	O
a	O
coordinates	O
of	O
decision	O
making	O
space	O
.	O

They	O
use	O
more	O
features	O
while	O
we	O
concentrate	O
on	O
the	O
similarity	O
.	O

That	O
might	O
be	O
an	O
advantage	O
for	O
their	O
method	O
.	O

On	O
the	O
other	O
hand	O
we	O
try	O
to	O
use	O
the	O
information	O
from	O
all	O
similar	O
sequences	O
in	O
an	O
optimal	O
way	O
relying	O
on	O
statistical	O
decision	O
theory	O
by	O
means	O
of	O
the	O
use	O
of	O
transfer	O
probabilities	O
and	O
the	O
concept	O
of	O
likelihood	O
ratio	O
.	O

It	O
is	O
an	O
interesting	O
topic	O
of	O
further	O
research	O
to	O
compare	O
the	O
two	O
methods	O
.	O

So	O
far	O
we	O
only	O
predicted	O
the	O
presence	O
of	O
a	O
key	O
word	O
.	O

It	O
is	O
quite	O
a	O
challenge	O
to	O
obtain	O
a	O
true	O
prediction	O
of	O
function	O
.	O

Conclusion	O

The	O
main	O
conclusion	O
of	O
the	O
paper	O
is	O
that	O
the	O
introduction	O
of	O
the	O
concept	O
of	O
likelihood	O
ratio	O
coming	O
from	O
statistical	O
decision	O
theory	O
is	O
very	O
helpful	O
in	O
the	O
development	O
of	O
automated	O
annotation	O
procedures	O
.	O

We	O
obtained	O
a	O
substantial	O
improvement	O
when	O
compared	O
with	O
our	O
previous	O
results	O
.	O

We	O
are	O
sure	O
that	O
there	O
is	O
room	O
for	O
further	O
improvement	O
.	O

Issues	O
for	O
further	O
research	O
are	O
the	O
size	O
of	O
the	O
set	O
of	O
similar	O
sequences	O
and	O
the	O
combination	O
of	O
different	O
statistics	O
into	O
a	O
"	O
super	O
-	O
predictor	O
"	O
.	O

Authors	O
'	O
contributions	O

A	O
.	O
M	O
.	O

Leontovich	O
and	O
H	O
.	O
C	O
.	O
van	O
Houwelingen	O
developed	O
the	O
approach	O
.	O

A	O
.	O
M	O
.	O

Leontovich	O
developed	O
the	O
methodology	O
and	O
the	O
algorithms	O
in	O
cooperation	O
with	O
K	O
.	O
Y	O
.	O

Tokmachev	O
and	O
H	O
.	O
C	O
.	O
van	O
Houwelingen	O
.	O

K	O
.	O
Y	O
.	O

Tokmachev	O
carried	O
out	O
all	O
computations	O
.	O

Supplementary	O
Material	O

Borrelia	B
burgdorferi	I
membranes	O
are	O
the	O
primary	O
targets	O
of	O
reactive	O
oxygen	O
species	O

Abstract	O

Spirochetes	O
living	O
in	O
an	O
oxygen	O
-	O
rich	O
environment	O
or	O
when	O
challenged	O
by	O
host	O
immune	O
cells	O
are	O
exposed	O
to	O
reactive	O
oxygen	O
species	O
(	O
ROS	O
)	O
.	O

These	O
species	O
can	O
harm	O
/	O
destroy	O
cysteinyl	O
residues	O
,	O
iron	O
-	O
sulphur	O
clusters	O
,	O
DNA	O
and	O
polyunsaturated	O
lipids	O
,	O
leading	O
to	O
inhibition	O
of	O
growth	O
or	O
cell	O
death	O
.	O

Because	O
Borrelia	B
burgdorferi	I
contains	O
no	O
intracellular	O
iron	O
,	O
DNA	O
is	O
most	O
likely	O
not	O
a	O
major	O
target	O
for	O
ROS	O
via	O
Fenton	O
reaction	O
.	O

In	O
support	O
of	O
this	O
,	O
growth	O
of	O
B	B
.	I
burgdorferi	I
in	O
the	O
presence	O
of	O
5	O
mM	O
H2O2	O
had	O
no	O
effect	O
on	O
the	O
DNA	O
mutation	O
rate	O
(	O
spontaneous	O
coumermycin	O
A1	O
resistance	O
)	O
,	O
and	O
cells	O
treated	O
with	O
10	O
mM	O
t	O
-	O
butyl	O
hydroperoxide	O
or	O
10	O
mM	O
H2O2	O
show	O
no	O
increase	O
in	O
DNA	O
damage	O
.	O

Unlike	O
most	O
bacteria	O
,	O
B	B
.	I
burgdorferi	I
incorporates	O
ROS	O
-	O
susceptible	O
polyunsaturated	O
fatty	O
acids	O
from	O
the	O
environment	O
into	O
their	O
membranes	O
.	O

Analysis	O
of	O
lipoxidase	O
-	O
treated	O
B	B
.	I
burgdorferi	I
cells	O
by	O
Electron	O
Microscopy	O
showed	O
significant	O
irregularities	O
indicative	O
of	O
membrane	O
damage	O
.	O

Fatty	O
acid	O
analysis	O
of	O
cells	O
treated	O
with	O
lipoxidase	O
indicated	O
that	O
host	O
-	O
derived	O
linoleic	O
acid	O
had	O
been	O
dramatically	O
reduced	O
(	O
50	O
-	O
fold	O
)	O
in	O
these	O
cells	O
,	O
with	O
a	O
corresponding	O
increase	O
in	O
the	O
levels	O
of	O
malondialdehyde	O
by	O
-	O
product	O
(	O
fourfold	O
)	O
.	O

These	O
data	O
suggest	O
that	O
B	B
.	I
burgdorferi	I
membrane	O
lipids	O
are	O
targets	O
for	O
attack	O
by	O
ROS	O
encountered	O
in	O
the	O
various	O
stages	O
of	O
the	O
infective	O
cycle	O
.	O

Introduction	O

Borrelia	B
burgdorferi	I
,	O
the	O
causative	O
agent	O
of	O
Lyme	O
disease	O
,	O
survives	O
and	O
proliferates	O
in	O
distinctly	O
different	O
niches	O
,	O
including	O
its	O
arthropod	O
vector	O
and	O
various	O
mammalian	O
hosts	O
.	O

These	O
'	O
micro	O
'	O
environments	O
provide	O
their	O
own	O
distinct	O
sets	O
of	O
advantages	O
and	O
challenges	O
to	O
B	B
.	I
burgdorferi	I
.	O

For	O
example	O
,	O
during	O
the	O
initial	O
stages	O
of	O
infection	O
of	O
the	O
mammalian	O
host	O
,	O
immune	O
cells	O
attempt	O
to	O
prevent	O
B	B
.	I
burgdorferi	I
from	O
establishing	O
an	O
infection	O
using	O
several	O
systems	O
including	O
those	O
generating	O
bacteriocidal	O
reactive	O
oxygen	O
species	O
(	O
ROS	O
)	O
[	O
e	O
.	O
g	O
.	O
superoxide	O
radicals	O
(	O
O2	O
-	O
)	O
,	O
hydrogen	O
peroxide	O
(	O
H2O2	O
)	O
and	O
hydroxyl	O
radicals	O
(	O
OH	O
)	O
]	O
and	O
reactive	O
nitrogen	O
species	O
(	O
RNS	O
)	O
[	O
e	O
.	O
g	O
.	O
nitric	O
oxide	O
(	O
NO	O
)	O
and	O
peroxynitrite	O
]	O
(	O
Storz	O
and	O
Imlay	O
,	O
1999	O
)	O
.	O

In	O
order	O
for	O
B	B
.	I
burgdorferi	I
to	O
successfully	O
colonize	O
a	O
new	O
host	O
and	O
cause	O
disease	O
,	O
they	O
must	O
overcome	O
the	O
challenges	O
posed	O
by	O
the	O
innate	O
immune	O
system	O
including	O
the	O
deleterious	O
effects	O
of	O
ROS	O
/	O
RNS	O
compounds	O
.	O

The	O
effects	O
of	O
ROS	O
/	O
RNS	O
on	O
cells	O
have	O
been	O
extensively	O
investigated	O
.	O

These	O
highly	O
reactive	O
compounds	O
have	O
been	O
shown	O
to	O
damage	O
cellular	O
macromolecules	O
including	O
DNA	O
,	O
proteins	O
and	O
cellular	O
membranes	O
.	O

The	O
damage	O
to	O
membranes	O
can	O
arise	O
through	O
either	O
lipid	O
or	O
membrane	O
protein	O
damage	O
.	O

In	O
eukaryotes	O
,	O
membrane	O
lipids	O
are	O
a	O
major	O
target	O
of	O
ROS	O
.	O

Free	O
radicals	O
attack	O
polyunsaturated	O
fatty	O
acids	O
in	O
membranes	O
and	O
initiate	O
lipid	O
peroxidation	O
.	O

A	O
primary	O
effect	O
of	O
this	O
is	O
a	O
decrease	O
in	O
membrane	O
fluidity	O
which	O
affects	O
the	O
physical	O
properties	O
of	O
the	O
membrane	O
altering	O
the	O
function	O
of	O
membrane	O
-	O
associated	O
proteins	O
.	O

Once	O
lipid	O
peroxides	O
form	O
,	O
they	O
react	O
with	O
adjacent	O
polyunsaturated	O
lipids	O
causing	O
an	O
amplification	O
of	O
the	O
damage	O
.	O

Lipid	O
peroxides	O
undergo	O
further	O
oxidation	O
to	O
a	O
variety	O
of	O
products	O
,	O
including	O
aldehydes	O
,	O
which	O
subsequently	O
react	O
with	O
and	O
damage	O
membrane	O
proteins	O
.	O

However	O
,	O
in	O
bacteria	O
,	O
it	O
is	O
assumed	O
that	O
lipids	O
are	O
not	O
subject	O
to	O
the	O
oxidative	O
damage	O
observed	O
in	O
eukaryotic	O
cells	O
.	O

Only	O
certain	O
polyunsaturated	O
lipids	O
,	O
such	O
as	O
linoleic	O
acid	O
and	O
linolenic	O
acid	O
,	O
are	O
susceptible	O
to	O
oxidation	O
(	O
Gutteridge	O
and	O
Halliwell	O
,	O
1990	O
)	O
,	O
and	O
it	O
is	O
clear	O
that	O
most	O
bacteria	O
do	O
not	O
synthesize	O
or	O
incorporate	O
these	O
types	O
of	O
lipids	O
in	O
their	O
cell	O
membrane	O
.	O

Two	O
notable	O
exceptions	O
are	O
the	O
photosynthetic	O
bacteria	O
which	O
synthesize	O
and	O
incorporate	O
significant	O
levels	O
of	O
linoleic	O
acid	O
in	O
their	O
membrane	O
(	O
Tasaka	O
et	O
al	O
.	O
,	O
1996	O
)	O
and	O
Helicobacter	B
pylori	I
membranes	O
which	O
contain	O
between	O
0	O
.	O
5	O
%	O
and	O
3	O
%	O
linoleic	O
acid	O
(	O
Ursini	O
and	O
Bindoli	O
,	O
1987	O
)	O
.	O

Instead	O
,	O
it	O
has	O
been	O
shown	O
that	O
the	O
most	O
damaging	O
effects	O
of	O
ROS	O
in	O
bacteria	O
result	O
from	O
the	O
interactions	O
of	O
H2O2	O
with	O
'	O
free	O
'	O
Fe2	O
+	O
(	O
Imlay	O
,	O
2003	O
)	O
,	O
generating	O
very	O
reactive	O
OH	O
(	O
Fenton	O
reaction	O
)	O
.	O

Because	O
of	O
this	O
reactivity	O
,	O
the	O
effect	O
on	O
any	O
given	O
biomolecule	O
will	O
depend	O
largely	O
upon	O
proximity	O
to	O
the	O
target	O
.	O

Because	O
Fe2	O
+	O
localizes	O
along	O
the	O
phosphodiester	O
backbone	O
of	O
nucleic	O
acid	O
,	O
DNA	O
is	O
a	O
major	O
target	O
of	O
OH	O
.	O

This	O
reactive	O
species	O
can	O
pull	O
electrons	O
from	O
either	O
the	O
base	O
or	O
sugar	O
moieties	O
,	O
producing	O
a	O
variety	O
of	O
lesions	O
including	O
single	O
-	O
and	O
double	O
-	O
stranded	O
breaks	O
in	O
the	O
backbone	O
and	O
chemical	O
cross	O
-	O
links	O
to	O
other	O
molecules	O
.	O

These	O
strand	O
breaks	O
and	O
other	O
lesions	O
block	O
DNA	O
replication	O
and	O
contribute	O
to	O
OH	O
toxicity	O
and	O
cell	O
death	O
.	O

Other	O
base	O
damage	O
,	O
which	O
does	O
not	O
hinder	O
replication	O
,	O
may	O
result	O
in	O
a	O
significant	O
increase	O
in	O
mutation	O
rates	O
.	O

The	O
intracellular	O
biochemistry	O
of	O
B	B
.	I
burgdorferi	I
suggests	O
that	O
the	O
primary	O
cellular	O
target	O
of	O
ROS	O
may	O
be	O
distinct	O
from	O
that	O
described	O
in	O
other	O
bacteria	O
such	O
as	O
Escherichia	B
coli	I
.	O

In	O
E	B
.	I
coli	I
,	O
the	O
extent	O
of	O
DNA	O
damage	O
due	O
to	O
H2O2	O
and	O
Fenton	O
chemistry	O
is	O
directly	O
proportional	O
to	O
Fe	O
metabolism	O
and	O
the	O
free	O
Fe	O
concentration	O
within	O
the	O
cell	O
(	O
10	O
micro	O
M	O
)	O
(	O
Keyer	O
and	O
Imlay	O
,	O
1996	O
)	O
.	O

As	O
the	O
intracellular	O
Fe	O
concentrations	O
of	O
B	B
.	I
burgdorferi	I
are	O
estimated	O
to	O
be	O
<	O
10	O
atoms	O
per	O
cell	O
(	O
Posey	O
and	O
Gherardini	O
,	O
2000	O
)	O
,	O
it	O
seems	O
unlikely	O
that	O
DNA	O
is	O
a	O
primary	O
target	O
for	O
ROS	O
.	O

Therefore	O
,	O
the	O
purpose	O
of	O
this	O
study	O
is	O
to	O
determine	O
the	O
biochemical	O
effects	O
of	O
ROS	O
on	O
B	B
.	I
burgdorferi	I
,	O
including	O
growth	O
effects	O
and	O
biological	O
/	O
physical	O
damage	O
.	O

Results	O

Effect	O
of	O
ROS	O
on	O
B	B
.	I
burgdorferi	I
cells	O

In	O
order	O
to	O
determine	O
what	O
the	O
cellular	O
targets	O
of	O
ROS	O
in	O
B	B
.	I
burgdorferi	I
are	O
,	O
we	O
first	O
needed	O
to	O
determine	O
the	O
sensitivity	O
of	O
Borrelia	O
cells	O
to	O
various	O
oxidants	O
.	O

Microaerobic	O
cultures	O
of	O
B	B
.	I
burgdorferi	I
strain	O
B31A3	O
were	O
grown	O
to	O
a	O
cell	O
density	O
of	O
5	O
x	O
107	O
cells	O
ml	O
-	O
1	O
,	O
treated	O
with	O
varying	O
concentrations	O
of	O
H2O2	O
(	O
0	O
-	O
50	O
mM	O
)	O
or	O
t	O
-	O
butyl	O
hydroperoxide	O
(	O
0	O
-	O
50	O
mM	O
)	O
and	O
the	O
number	O
of	O
surviving	O
cells	O
determined	O
by	O
plating	O
.	O

The	O
results	O
are	O
shown	O
in	O
Fig	O
.	O

1	O
.	O

When	O
cells	O
were	O
exposed	O
to	O
10	O
mM	O
t	O
-	O
butyl	O
hydroperoxide	O
,	O
approximately	O
50	O
%	O
of	O
the	O
cells	O
survive	O
(	O
Fig	O
.	O
1A	O
)	O
.	O

In	O
contrast	O
,	O
when	O
E	B
.	I
coli	I
cells	O
were	O
exposed	O
to	O
1	O
mM	O
t	O
-	O
butyl	O
hydroperoxide	O
,	O
approximately	O
1	O
%	O
of	O
the	O
cells	O
survive	O
.	O

B	B
.	I
burgdorferi	I
cells	O
were	O
much	O
more	O
resistant	O
to	O
t	O
-	O
butyl	O
hydroperoxide	O
than	O
E	B
.	I
coli	I
cells	O
,	O
with	O
a	O
survival	O
rate	O
of	O
approximately	O
100	O
%	O
at	O
1	O
mM	O
t	O
-	O
butyl	O
hydroperoxide	O
.	O

This	O
trend	O
was	O
observed	O
when	O
cells	O
were	O
exposed	O
to	O
H2O2	O
.	O

E	B
.	I
coli	I
cells	O
exposed	O
to	O
1	O
mM	O
H2O2	O
have	O
approximately	O
10	O
%	O
survivability	O
,	O
while	O
100	O
%	O
of	O
the	O
B	B
.	I
burgdorferi	I
cells	O
survive	O
at	O
this	O
concentration	O
,	O
and	O
approximately	O
80	O
%	O
survive	O
when	O
exposed	O
to	O
10	O
mM	O
H2O2	O
(	O
Fig	O
.	O
1B	O
)	O
.	O

Similar	O
results	O
were	O
obtained	O
when	O
cells	O
were	O
exposed	O
in	O
HN	O
(	O
Hepes	O
-	O
NaCl	O
)	O
buffer	O
,	O
suggesting	O
that	O
the	O
high	O
-	O
level	O
resistance	O
to	O
ROS	O
was	O
not	O
due	O
to	O
the	O
interaction	O
of	O
ROS	O
with	O
components	O
of	O
Barbour	O
-	O
Stoenner	O
-	O
Kelly	O
(	O
BSK	O
-	O
II	O
)	O
growth	O
medium	O
.	O

Taken	O
together	O
,	O
these	O
data	O
indicated	O
that	O
B	B
.	I
burgdorferi	I
strain	O
B31A3	O
was	O
highly	O
resistant	O
to	O
exposure	O
to	O
both	O
t	O
-	O
butyl	O
peroxide	O
and	O
H2O2	O
.	O

Borrelia	B
burgdorferi	I
DNA	O
is	O
not	O
the	O
primary	O
target	O
of	O
ROS	O

For	O
most	O
bacteria	O
,	O
DNA	O
is	O
the	O
major	O
target	O
of	O
ROS	O
causing	O
a	O
wide	O
variety	O
of	O
DNA	O
lesions	O
.	O

This	O
is	O
in	O
part	O
due	O
to	O
the	O
localization	O
of	O
'	O
free	O
'	O
Fe2	O
+	O
along	O
the	O
phosphodiester	O
backbone	O
of	O
nucleic	O
acids	O
,	O
putting	O
the	O
DNA	O
in	O
close	O
proximity	O
to	O
the	O
active	O
species	O
formed	O
via	O
the	O
Fenton	O
reaction	O
.	O

However	O
,	O
B	B
.	I
burgdorferi	I
has	O
been	O
shown	O
to	O
harbour	O
few	O
genes	O
encoding	O
orthologues	O
of	O
known	O
iron	O
-	O
containing	O
proteins	O
,	O
does	O
not	O
require	O
Fe	O
for	O
growth	O
and	O
has	O
intracellular	O
Fe	O
concentrations	O
estimated	O
to	O
be	O
<	O
10	O
atoms	O
per	O
cell	O
(	O
Posey	O
and	O
Gherardini	O
,	O
2000	O
)	O
.	O

Taken	O
together	O
,	O
these	O
observations	O
strongly	O
suggest	O
that	O
B	B
.	I
burgdorferi	I
DNA	O
is	O
not	O
a	O
major	O
target	O
for	O
ROS	O
.	O

To	O
test	O
this	O
hypothesis	O
,	O
different	O
techniques	O
were	O
used	O
to	O
measure	O
DNA	O
damage	O
in	O
B	B
.	I
burgdorferi	I
cells	O
after	O
exposure	O
to	O
ROS	O
.	O

One	O
reliable	O
indicator	O
of	O
DNA	O
damage	O
by	O
ROS	O
in	O
a	O
cell	O
is	O
an	O
increase	O
in	O
the	O
spontaneous	O
mutation	O
rate	O
.	O

In	O
B	B
.	I
burgdorferi	I
,	O
mutations	O
that	O
confer	O
resistance	O
to	O
coumermycin	O
A1	O
,	O
which	O
targets	O
the	O
beta	O
subunit	O
of	O
DNA	O
gyrase	O
,	O
have	O
been	O
mapped	O
to	O
gyrB	O
,	O
the	O
gene	O
encoding	O
DNA	O
gyrase	O
B	O
(	O
Samuels	O
et	O
al	O
.	O
,	O
1994	O
)	O
.	O

In	O
each	O
case	O
,	O
a	O
single	O
point	O
mutation	O
correlated	O
with	O
this	O
drug	O
resistance	O
.	O

To	O
determine	O
if	O
exposure	O
to	O
oxidants	O
increases	O
DNA	O
damage	O
by	O
increasing	O
point	O
mutations	O
,	O
B	B
.	I
burgdorferi	I
B31A3	O
cells	O
grown	O
under	O
microaerobic	O
conditions	O
were	O
treated	O
with	O
5	O
mM	O
H2O2	O
and	O
plated	O
in	O
the	O
presence	O
and	O
absence	O
of	O
250	O
ng	O
ml	O
-	O
1	O
coumermycin	O
A1	O
.	O

The	O
mutation	O
frequency	O
was	O
calculated	O
as	O
the	O
number	O
of	O
colonies	O
that	O
are	O
CouR	O
per	O
total	O
number	O
of	O
cells	O
plated	O
.	O

The	O
spontaneous	O
resistance	O
frequency	O
of	O
treated	O
cells	O
was	O
approximately	O
equivalent	O
to	O
that	O
of	O
untreated	O
cells	O
,	O
8	O
.	O
8	O
x	O
10	O
-	O
8	O
and	O
1	O
.	O
33	O
x	O
10	O
-	O
7	O
,	O
respectively	O
,	O
indicating	O
no	O
increase	O
in	O
the	O
number	O
of	O
point	O
mutations	O
(	O
Fig	O
.	O
2A	O
)	O
.	O

Also	O
,	O
no	O
increase	O
in	O
point	O
mutations	O
was	O
observed	O
when	O
cells	O
were	O
treated	O
with	O
higher	O
concentrations	O
of	O
H2O2	O
(	O
10	O
mM	O
)	O
or	O
when	O
treated	O
with	O
t	O
-	O
butyl	O
hydroperoxide	O
(	O
5	O
and	O
10	O
mM	O
)	O
(	O
data	O
not	O
shown	O
)	O
.	O

Another	O
effective	O
way	O
to	O
determine	O
DNA	O
damage	O
is	O
by	O
measuring	O
the	O
number	O
of	O
apurinic	O
/	O
apyrimidinic	O
sites	O
(	O
AP	O
)	O
.	O

AP	O
sites	O
in	O
DNA	O
,	O
where	O
the	O
DNA	O
base	O
is	O
lost	O
,	O
can	O
be	O
generated	O
spontaneously	O
under	O
physiological	O
conditions	O
by	O
hydrolysis	O
of	O
the	O
N	O
-	O
glycosylic	O
bond	O
,	O
or	O
can	O
also	O
be	O
formed	O
by	O
DNA	O
-	O
damaging	O
agents	O
(	O
Lindahl	O
and	O
Nyberg	O
,	O
1972	O
)	O
,	O
such	O
as	O
UV	O
,	O
alkylating	O
agents	O
or	O
OH	O
.	O

They	O
are	O
also	O
intermediates	O
in	O
the	O
base	O
excision	O
repair	O
pathway	O
(	O
BER	O
)	O
(	O
Weiss	O
and	O
Grossman	O
,	O
1987	O
;	O
Friedberg	O
and	O
Hanawalt	O
,	O
1988	O
;	O
Wallace	O
,	O
1988	O
)	O
.	O

Thus	O
,	O
the	O
cellular	O
steady	O
state	O
level	O
of	O
AP	O
sites	O
would	O
increase	O
as	O
a	O
consequence	O
of	O
base	O
modifications	O
and	O
their	O
subsequent	O
repair	O
.	O

As	O
AP	O
sites	O
are	O
bypassed	O
inefficiently	O
by	O
DNA	O
polymerase	O
in	O
bacterial	O
cells	O
,	O
DNA	O
lesions	O
can	O
result	O
in	O
a	O
significant	O
block	O
in	O
DNA	O
replication	O
.	O

Therefore	O
,	O
the	O
number	O
of	O
AP	O
sites	O
can	O
serve	O
as	O
a	O
sensitive	O
indicator	O
of	O
DNA	O
damage	O
resulting	O
from	O
oxidative	O
stress	O
(	O
Kubo	O
et	O
al	O
.	O
,	O
1992	O
)	O
.	O

To	O
determine	O
whether	O
ROS	O
can	O
damage	O
B	B
.	I
burgdorferi	I
DNA	O
,	O
strain	O
B31A3	O
cells	O
grown	O
under	O
microaerobic	O
conditions	O
were	O
treated	O
with	O
H2O2	O
(	O
1	O
or	O
10	O
mM	O
)	O
,	O
t	O
-	O
butyl	O
hydroperoxide	O
(	O
1	O
or	O
10	O
mM	O
)	O
or	O
lipoxidase	O
(	O
an	O
enzyme	O
which	O
specifically	O
catalyses	O
the	O
hydroperoxidation	O
of	O
lipids	O
containing	O
a	O
cis	O
,	O
cis	O
-	O
pentadiene	O
structure	O
,	O
such	O
as	O
linoleic	O
acid	O
)	O
.	O

The	O
DNA	O
was	O
isolated	O
and	O
assayed	O
for	O
AP	O
sites	O
.	O

The	O
results	O
are	O
shown	O
in	O
Fig	O
.	O

2B	O
.	O

In	O
all	O
cases	O
,	O
the	O
numbers	O
of	O
AP	O
sites	O
per	O
105	O
bp	O
DNA	O
were	O
equivalent	O
,	O
indicating	O
that	O
the	O
addition	O
of	O
oxidants	O
did	O
not	O
increase	O
the	O
number	O
of	O
DNA	O
base	O
lesions	O
.	O

In	O
contrast	O
,	O
when	O
E	B
.	I
coli	I
strain	O
TA4315	O
cells	O
(	O
ahpCF	O
)	O
(	O
Storz	O
et	O
al	O
.	O
,	O
1989	O
)	O
were	O
treated	O
with	O
100	O
micro	O
M	O
H2O2	O
,	O
the	O
number	O
of	O
AP	O
sites	O
increased	O
~	O
10	O
-	O
fold	O
over	O
untreated	O
cells	O
.	O

These	O
data	O
suggest	O
that	O
B	B
.	I
burgdorferi	I
DNA	O
was	O
not	O
a	O
major	O
target	O
for	O
oxidative	O
damage	O
under	O
these	O
conditions	O
.	O

It	O
is	O
of	O
note	O
to	O
mention	O
that	O
the	O
total	O
number	O
of	O
AP	O
sites	O
per	O
105	O
bp	O
DNA	O
is	O
approximately	O
10	O
-	O
fold	O
higher	O
in	O
untreated	O
Borrelia	O
B31A3	O
DNA	O
than	O
in	O
untreated	O
E	B
.	I
coli	I
DNA	O
.	O

The	O
Borrelia	O
genome	O
consists	O
of	O
a	O
linear	O
chromosome	O
and	O
multiple	O
linear	O
and	O
circular	O
plasmids	O
.	O

Numerous	O
observations	O
indicate	O
that	O
functional	O
telomeres	O
require	O
interaction	O
with	O
DNA	O
damage	O
repair	O
proteins	O
,	O
suggesting	O
that	O
the	O
DNA	O
damage	O
repair	O
machinery	O
,	O
including	O
the	O
BER	O
,	O
is	O
involved	O
in	O
replication	O
of	O
telomeres	O
and	O
protection	O
of	O
functional	O
chromosome	O
ends	O
(	O
Verdun	O
and	O
Karlseder	O
,	O
2007	O
)	O
.	O

An	O
important	O
intermediate	O
in	O
BER	O
is	O
the	O
apurinic	O
or	O
abasic	O
site	O
.	O

Therefore	O
,	O
it	O
was	O
possible	O
that	O
the	O
higher	O
numbers	O
of	O
AP	O
sites	O
in	O
untreated	O
Borrelia	O
DNA	O
was	O
due	O
to	O
the	O
number	O
of	O
telomeres	O
present	O
in	O
the	O
genome	O
.	O

The	O
B	B
.	I
burgdorferi	I
strain	O
B31A3	O
harbours	O
11	O
linear	O
plasmids	O
and	O
a	O
linear	O
chromosome	O
with	O
~	O
100	O
unpaired	O
bases	O
in	O
the	O
telomere	O
loops	O
per	O
genome	O
or	O
10	O
bases	O
per	O
105	O
bp	O
DNA	O
(	O
Hinnebusch	O
and	O
Barbour	O
,	O
1991	O
;	O
Chaconas	O
,	O
2005	O
)	O
.	O

Untreated	O
Borrelia	O
B31A3	O
contains	O
11	O
+	O
/	O
-	O
3	O
.	O
8	O
AP	O
sites	O
per	O
105	O
bp	O
DNA	O
,	O
suggesting	O
that	O
the	O
elevated	O
number	O
of	O
AP	O
sites	O
in	O
Borrelia	O
was	O
due	O
to	O
the	O
number	O
of	O
telomeres	O
.	O

To	O
test	O
this	O
hypothesis	O
,	O
the	O
AP	O
sites	O
were	O
measured	O
in	O
DNA	O
isolated	O
from	O
untreated	O
B	B
.	I
burgdorferi	I
strain	O
B314	O
which	O
harbours	O
no	O
linear	O
plasmids	O
(	O
Sadziene	O
et	O
al	O
.	O
,	O
1993	O
)	O
.	O

The	O
number	O
of	O
unpaired	O
bases	O
in	O
the	O
telomere	O
loops	O
per	O
genome	O
was	O
estimated	O
to	O
be	O
10	O
,	O
which	O
corresponds	O
to	O
1	O
base	O
per	O
105	O
bp	O
DNA	O
,	O
and	O
only	O
3	O
.	O
6	O
+	O
/	O
-	O
0	O
.	O
2	O
AP	O
sites	O
per	O
105	O
bp	O
DNA	O
were	O
detected	O
,	O
supporting	O
the	O
hypothesis	O
that	O
the	O
high	O
number	O
of	O
AP	O
sites	O
in	O
untreated	O
Borrelia	O
DNA	O
was	O
due	O
to	O
the	O
number	O
of	O
unpaired	O
bases	O
in	O
the	O
telomeres	O
.	O

The	O
analyses	O
of	O
the	O
AP	O
sites	O
strongly	O
suggested	O
that	O
B	B
.	I
burgdorferi	I
DNA	O
was	O
not	O
the	O
major	O
target	O
for	O
oxidative	O
damage	O
.	O

In	O
addition	O
to	O
the	O
generation	O
of	O
abasic	O
sites	O
,	O
oxygen	O
radicals	O
often	O
damage	O
DNA	O
through	O
the	O
formation	O
of	O
8	O
-	O
oxoguanine	O
lesions	O
(	O
Nakamura	O
et	O
al	O
.	O
,	O
2000	O
)	O
.	O

8	O
-	O
Oxoguanine	O
,	O
through	O
its	O
ability	O
to	O
mispair	O
with	O
bases	O
other	O
than	O
cytosine	O
,	O
likely	O
plays	O
a	O
role	O
in	O
DNA	O
mutagenesis	O
.	O

Consequently	O
,	O
8	O
-	O
oxoguanine	O
is	O
often	O
used	O
as	O
a	O
marker	O
of	O
oxidized	O
DNA	O
damage	O
.	O

To	O
determine	O
whether	O
ROS	O
can	O
damage	O
B	B
.	I
burgdorferi	I
DNA	O
and	O
cause	O
8	O
-	O
oxoguanine	O
lesions	O
,	O
strain	O
B31A3	O
cells	O
grown	O
under	O
microaerobic	O
conditions	O
were	O
treated	O
with	O
H2O2	O
(	O
5	O
or	O
10	O
mM	O
)	O
,	O
t	O
-	O
butyl	O
hydroperoxide	O
(	O
5	O
or	O
10	O
mM	O
)	O
or	O
lipoxidase	O
.	O

The	O
DNA	O
was	O
isolated	O
and	O
assayed	O
for	O
8	O
-	O
oxoguanine	O
using	O
an	O
Enzyme	O
-	O
Linked	O
ImmunoSorbent	O
Assay	O
.	O

The	O
results	O
are	O
shown	O
in	O
Fig	O
.	O

2C	O
.	O

In	O
all	O
cases	O
,	O
the	O
amount	O
of	O
8	O
-	O
oxoguanine	O
in	O
Borrelia	O
cells	O
was	O
below	O
the	O
detection	O
limit	O
of	O
the	O
assay	O
.	O

In	O
contrast	O
,	O
when	O
a	O
MutM	O
(	O
the	O
specific	O
glycosylase	O
that	O
removes	O
the	O
8	O
-	O
oxoguanine	O
)	O
-	O
deficient	O
E	B
.	I
coli	I
strain	O
was	O
treated	O
with	O
100	O
micro	O
M	O
H2O2	O
,	O
the	O
amount	O
of	O
8	O
-	O
oxoguanine	O
sites	O
increased	O
~	O
fivefold	O
over	O
untreated	O
cells	O
.	O

It	O
is	O
important	O
to	O
point	O
out	O
that	O
no	O
MutM	O
homologue	O
has	O
been	O
identified	O
in	O
the	O
genome	O
of	O
B	B
.	I
burgdorferi	I
.	O

Taken	O
together	O
,	O
these	O
data	O
suggested	O
that	O
B	B
.	I
burgdorferi	I
DNA	O
was	O
not	O
a	O
major	O
target	O
for	O
oxidative	O
damage	O
under	O
these	O
conditions	O
.	O

The	O
membranes	O
of	O
B	B
.	I
burgdorferi	I
are	O
targeted	O
during	O
oxidative	O
stress	O

In	O
eukaryotes	O
,	O
membrane	O
lipids	O
are	O
a	O
major	O
target	O
of	O
ROS	O
.	O

Free	O
radicals	O
can	O
attack	O
polyunsaturated	O
fatty	O
acids	O
,	O
such	O
as	O
linoleic	O
acid	O
and	O
linolenic	O
acid	O
,	O
in	O
membranes	O
and	O
initiate	O
lipid	O
peroxidation	O
.	O

This	O
reaction	O
can	O
cascade	O
throughout	O
the	O
membrane	O
to	O
adjacent	O
polyunsaturated	O
fatty	O
acids	O
,	O
decreasing	O
membrane	O
fluidity	O
and	O
generating	O
more	O
toxic	O
products	O
such	O
as	O
aldehydes	O
(	O
Imlay	O
,	O
2003	O
)	O
.	O

Because	O
most	O
bacterial	O
membranes	O
contain	O
saturated	O
and	O
monounsaturated	O
fatty	O
acids	O
rather	O
than	O
'	O
reactive	O
'	O
polyunsaturated	O
lipids	O
,	O
peroxidation	O
of	O
lipids	O
in	O
bacterial	O
membranes	O
is	O
not	O
considered	O
a	O
problem	O
.	O

As	O
B	B
.	I
burgdorferi	I
cannot	O
synthesize	O
their	O
own	O
lipids	O
,	O
they	O
must	O
instead	O
scavenge	O
them	O
.	O

Therefore	O
,	O
it	O
seems	O
likely	O
that	O
their	O
membrane	O
composition	O
would	O
reflect	O
the	O
host	O
'	O
s	O
lipid	O
profile	O
or	O
that	O
of	O
their	O
growth	O
medium	O
(	O
Barbour	O
,	O
1984	O
;	O
Fraser	O
et	O
al	O
.	O
,	O
1997	O
)	O
and	O
would	O
contain	O
some	O
polyunsaturated	O
fatty	O
acids	O
.	O

To	O
determine	O
if	O
B	B
.	I
burgdorferi	I
contains	O
polyunsaturated	O
lipids	O
,	O
B	B
.	I
burgdorferi	I
strain	O
B31A3	O
was	O
grown	O
under	O
anaerobic	O
conditions	O
and	O
analysed	O
for	O
fatty	O
acid	O
composition	O
by	O
Lipid	O
Technologies	O
(	O
Austin	O
,	O
MN	O
)	O
.	O

The	O
results	O
are	O
shown	O
in	O
Table	O
1	O
and	O
are	O
reported	O
as	O
percentage	O
of	O
total	O
fatty	O
acid	O
content	O
.	O

Linoleic	O
acid	O
comprised	O
~	O
10	O
%	O
of	O
the	O
total	O
lipid	O
content	O
and	O
the	O
linolenic	O
acid	O
content	O
was	O
measured	O
to	O
be	O
~	O
1	O
%	O
,	O
indicating	O
that	O
Borrelia	O
cells	O
do	O
contain	O
lipids	O
that	O
are	O
susceptible	O
to	O
ROS	O
damage	O
.	O

The	O
amount	O
of	O
linoleic	O
acid	O
and	O
linolenic	O
acid	O
present	O
in	O
Borrelia	O
reflected	O
the	O
amount	O
present	O
in	O
the	O
media	O
.	O

Therefore	O
,	O
these	O
results	O
suggested	O
that	O
the	O
amount	O
of	O
these	O
fatty	O
acids	O
in	O
the	O
membranes	O
would	O
vary	O
as	O
availability	O
varies	O
.	O

To	O
determine	O
if	O
Borrelia	O
polyunsaturated	O
lipids	O
can	O
undergo	O
lipid	O
peroxidation	O
,	O
B	B
.	I
burgdorferi	I
B31A3	O
cells	O
grown	O
microaerobically	O
were	O
treated	O
with	O
1	O
mM	O
t	O
-	O
butyl	O
hydroperoxide	O
or	O
250	O
mg	O
of	O
lipoxidase	O
,	O
and	O
the	O
cell	O
pellets	O
were	O
analysed	O
for	O
fatty	O
acid	O
composition	O
(	O
Industrial	O
Laboratory	O
)	O
.	O

The	O
results	O
are	O
shown	O
in	O
Table	O
2	O
and	O
are	O
reported	O
as	O
the	O
percentage	O
of	O
total	O
cell	O
mass	O
.	O

The	O
per	O
cent	O
of	O
linoleic	O
acid	O
in	O
the	O
total	O
cell	O
mass	O
decreased	O
with	O
treatment	O
,	O
while	O
the	O
levels	O
of	O
oleic	O
acid	O
(	O
c18	O
:	O
1n9	O
)	O
and	O
pentadecanoic	O
acid	O
(	O
c15	O
:	O
0	O
)	O
remained	O
relatively	O
constant	O
.	O

Untreated	O
cells	O
contained	O
0	O
.	O
04	O
%	O
linoleic	O
acid	O
,	O
while	O
cells	O
treated	O
with	O
t	O
-	O
butyl	O
hydroperoxide	O
contained	O
10	O
-	O
fold	O
less	O
(	O
0	O
.	O
004	O
%	O
)	O
linoleic	O
acid	O
and	O
cells	O
treated	O
with	O
lipoxidase	O
had	O
no	O
detectable	O
linoleic	O
acid	O
present	O
in	O
the	O
sample	O
.	O

These	O
data	O
indicated	O
that	O
the	O
linoleic	O
acid	O
present	O
in	O
B	B
.	I
burgdorferi	I
membranes	O
can	O
be	O
oxidized	O
by	O
ROS	O
.	O

Malondialdehyde	O
(	O
MDA	O
)	O
is	O
generated	O
as	O
a	O
relatively	O
stable	O
end	O
-	O
product	O
from	O
the	O
oxidative	O
degradation	O
of	O
polyunsaturated	O
fatty	O
acids	O
.	O

MDA	O
has	O
thus	O
been	O
used	O
as	O
an	O
indicator	O
of	O
lipid	O
peroxidation	O
(	O
Gutteridge	O
and	O
Halliwell	O
,	O
1990	O
;	O
Esterbauer	O
et	O
al	O
.	O
,	O
1991	O
)	O
.	O

To	O
further	O
demonstrate	O
that	O
Borrelia	O
lipids	O
can	O
undergo	O
lipid	O
peroxidation	O
,	O
B31A3	O
cells	O
grown	O
microaerobically	O
were	O
treated	O
with	O
5	O
mM	O
AAPH	O
(	O
free	O
radical	O
generator	O
)	O
or	O
250	O
mg	O
of	O
lipoxidase	O
and	O
MDA	O
measured	O
(	O
Seljeskog	O
et	O
al	O
.	O
,	O
2006	O
)	O
.	O

The	O
results	O
are	O
shown	O
in	O
Fig	O
.	O

3	O
.	O

Untreated	O
cells	O
contained	O
~	O
16	O
.	O
5	O
micro	O
M	O
of	O
MDA	O
per	O
mg	O
of	O
protein	O
.	O

When	O
the	O
cells	O
were	O
treated	O
with	O
AAPH	O
or	O
lipoxidase	O
,	O
the	O
amount	O
of	O
MDA	O
increased	O
~	O
1	O
.	O
5	O
-	O
fold	O
(	O
27	O
.	O
3	O
micro	O
M	O
of	O
MDA	O
per	O
mg	O
of	O
protein	O
)	O
and	O
approximately	O
twofold	O
(	O
33	O
micro	O
M	O
of	O
MDA	O
per	O
mg	O
of	O
protein	O
)	O
respectively	O
(	O
Fig	O
.	O
3A	O
)	O
.	O

As	O
a	O
control	O
,	O
eukaryotic	O
cells	O
(	O
mouse	B
myeloma	O
cells	O
SP2	O
)	O
were	O
treated	O
with	O
AAPH	O
and	O
MDA	O
measured	O
(	O
Fig	O
.	O
3B	O
)	O
.	O

Mouse	B
myeloma	O
cells	O
have	O
been	O
used	O
as	O
a	O
model	O
system	O
for	O
the	O
determination	O
of	O
phospholipid	O
hydroperoxides	O
(	O
Chotimarkorn	O
et	O
al	O
.	O
,	O
2005	O
)	O
.	O

In	O
this	O
case	O
,	O
the	O
amount	O
of	O
MDA	O
increased	O
approximately	O
threefold	O
(	O
36	O
.	O
3	O
micro	O
M	O
of	O
MDA	O
per	O
mg	O
of	O
protein	O
)	O
in	O
the	O
treated	O
cells	O
versus	O
untreated	O
cells	O
(	O
11	O
.	O
7	O
micro	O
M	O
of	O
MDA	O
per	O
mg	O
of	O
protein	O
)	O
.	O

Taken	O
together	O
,	O
these	O
data	O
suggested	O
that	O
,	O
like	O
eukaryotic	O
membranes	O
,	O
Borrelia	O
membrane	O
lipids	O
were	O
capable	O
of	O
undergoing	O
lipid	O
peroxidation	O
.	O

As	O
shown	O
in	O
Fig	O
.	O

3A	O
,	O
there	O
is	O
a	O
measurable	O
quantity	O
of	O
MDA	O
present	O
even	O
in	O
untreated	O
cells	O
,	O
suggesting	O
that	O
the	O
membrane	O
lipids	O
are	O
damaged	O
without	O
the	O
addition	O
of	O
exogenous	O
ROS	O
.	O

Oxidative	O
damage	O
is	O
an	O
unavoidable	O
by	O
-	O
product	O
of	O
growth	O
in	O
an	O
oxygen	O
environment	O
because	O
superoxide	O
anions	O
and	O
H2O2	O
are	O
formed	O
whenever	O
molecular	O
oxygen	O
chemically	O
oxidizes	O
electron	O
carriers	O
.	O

To	O
determine	O
if	O
the	O
Borrelia	O
lipids	O
are	O
damaged	O
from	O
growth	O
in	O
an	O
oxygen	O
environment	O
,	O
B	B
.	I
burgdorferi	I
B31A3	O
cells	O
were	O
grown	O
under	O
anaerobic	O
,	O
microaerobic	O
and	O
aerobic	O
conditions	O
and	O
MDA	O
measured	O
.	O

Figure	O
3C	O
demonstrates	O
that	O
as	O
the	O
oxygen	O
concentration	O
increased	O
,	O
the	O
amount	O
of	O
MDA	O
increased	O
.	O

Cells	O
grown	O
under	O
anaerobic	O
conditions	O
contained	O
the	O
lowest	O
amount	O
of	O
MDA	O
(	O
7	O
.	O
6	O
micro	O
M	O
of	O
MDA	O
per	O
mg	O
of	O
protein	O
)	O
,	O
approximately	O
twofold	O
less	O
than	O
the	O
measured	O
amount	O
in	O
microaerobic	O
cells	O
(	O
16	O
.	O
5	O
micro	O
M	O
of	O
MDA	O
per	O
mg	O
of	O
protein	O
)	O
.	O

Aerobically	O
grown	O
cells	O
contained	O
the	O
highest	O
amount	O
of	O
MDA	O
,	O
~	O
1	O
.	O
5	O
-	O
fold	O
greater	O
than	O
that	O
observed	O
in	O
microaerobic	O
cells	O
(	O
28	O
.	O
8	O
micro	O
M	O
of	O
MDA	O
per	O
mg	O
of	O
protein	O
)	O
and	O
~	O
3	O
.	O
7	O
-	O
fold	O
greater	O
than	O
that	O
observed	O
in	O
anaerobically	O
grown	O
cells	O
.	O

These	O
data	O
suggested	O
that	O
Borrelia	O
lipids	O
can	O
be	O
damaged	O
during	O
aerobic	O
growth	O
.	O

Our	O
High	O
Performance	O
Liquid	O
Chromatography	O
analyses	O
of	O
the	O
MDA	O
present	O
in	O
anaerobically	O
grown	O
B	B
.	I
burgdorferi	I
cells	O
showed	O
a	O
small	O
peak	O
with	O
a	O
retention	O
time	O
similar	O
to	O
that	O
of	O
the	O
MDA	O
standard	O
.	O

This	O
was	O
puzzling	O
as	O
little	O
or	O
no	O
lipid	O
peroxidation	O
should	O
occur	O
under	O
these	O
conditions	O
.	O

To	O
further	O
characterize	O
this	O
'	O
MDA	O
'	O
peak	O
,	O
a	O
three	O
-	O
dimensional	O
diode	O
array	O
spectra	O
was	O
generated	O
by	O
scanning	O
each	O
sample	O
during	O
the	O
elution	O
of	O
the	O
peak	O
(	O
Fig	O
.	O
4	O
,	O
lower	O
sections	O
)	O
.	O

An	O
authentic	O
MDA	O
standard	O
was	O
also	O
scanned	O
as	O
a	O
control	O
(	O
Fig	O
.	O
4A	O
,	O
lower	O
section	O
)	O
.	O

In	O
the	O
anaerobically	O
grown	O
cells	O
,	O
the	O
spectrum	O
shows	O
that	O
two	O
compounds	O
with	O
different	O
absorbance	O
maximums	O
(	O
Fig	O
.	O
4B	O
,	O
lower	O
section	O
)	O
comprised	O
the	O
single	O
retention	O
time	O
peak	O
from	O
the	O
HPLC	O
chromatogram	O
(	O
Fig	O
.	O
4B	O
,	O
upper	O
section	O
)	O
.	O

Based	O
on	O
this	O
spectrum	O
,	O
the	O
amount	O
of	O
actual	O
MDA	O
contributed	O
<	O
15	O
%	O
of	O
the	O
total	O
amount	O
of	O
material	O
detected	O
in	O
the	O
HPLC	O
peak	O
while	O
the	O
second	O
contaminating	O
peak	O
contributed	O
>	O
85	O
%	O
.	O

Therefore	O
,	O
the	O
amount	O
of	O
MDA	O
in	O
untreated	O
anaerobically	O
grown	O
cells	O
was	O
considerably	O
less	O
than	O
the	O
7	O
.	O
6	O
micro	O
M	O
of	O
MDA	O
per	O
mg	O
of	O
protein	O
actually	O
measured	O
.	O

However	O
,	O
in	O
cells	O
grown	O
under	O
microaerobic	O
conditions	O
,	O
the	O
MDA	O
peak	O
contributed	O
more	O
to	O
the	O
overall	O
retention	O
time	O
peak	O
when	O
compared	O
with	O
the	O
anaerobic	O
spectrum	O
,	O
while	O
the	O
second	O
contaminating	O
peak	O
stays	O
relatively	O
constant	O
(	O
Fig	O
.	O
4C	O
,	O
lower	O
section	O
)	O
.	O

These	O
spectra	O
demonstrated	O
that	O
the	O
increase	O
in	O
the	O
MDA	O
retention	O
time	O
peak	O
between	O
anaerobically	O
and	O
aerobically	O
grown	O
cells	O
was	O
due	O
to	O
the	O
increase	O
in	O
the	O
amount	O
of	O
authentic	O
MDA	O
present	O
.	O

The	O
fluorescent	O
probe	O
diphenyl	O
-	O
1	O
-	O
pyrenylphophine	O
(	O
DPPP	O
)	O
has	O
been	O
used	O
for	O
detection	O
of	O
lipid	O
hydroperoxides	O
in	O
cell	O
membranes	O
(	O
Okimoto	O
et	O
al	O
.	O
,	O
2000	O
;	O
Takahashi	O
et	O
al	O
.	O
,	O
2001	O
)	O
.	O

In	O
this	O
method	O
,	O
the	O
hydroperoxides	O
are	O
reduced	O
with	O
DPPP	O
,	O
resulting	O
in	O
the	O
formation	O
of	O
the	O
fluorescent	O
arylphosphine	O
oxide	O
.	O

To	O
visualize	O
the	O
lipid	O
hydroperoxides	O
,	O
B	B
.	I
burgdorferi	I
B31A3	O
cells	O
were	O
labelled	O
with	O
DPPP	O
and	O
observed	O
by	O
fluorescence	O
microscopy	O
(	O
Fig	O
.	O
5B	O
)	O
.	O

E	B
.	I
coli	I
Top10	O
cells	O
and	O
mouse	B
myeloma	O
SP2	O
cells	O
were	O
also	O
labelled	O
and	O
visualized	O
to	O
serve	O
as	O
negative	O
and	O
positive	O
controls	O
respectively	O
(	O
Fig	O
.	O
5A	O
and	O
C	O
)	O
.	O

Red	O
Fluorescent	O
dye	O
was	O
used	O
to	O
visualize	O
the	O
cell	O
membranes	O
.	O

A	O
strong	O
fluorescence	O
of	O
DPPP	O
was	O
observed	O
for	O
B31A3	O
cells	O
(	O
Fig	O
.	O
5B	O
)	O
and	O
for	O
the	O
mouse	B
myeloma	O
cells	O
(	O
Fig	O
.	O
5C	O
)	O
,	O
but	O
not	O
for	O
the	O
E	B
.	I
coli	I
cells	O
(	O
Fig	O
.	O
5A	O
)	O
.	O

An	O
overlay	O
of	O
the	O
two	O
dyes	O
demonstrates	O
that	O
the	O
DPPP	O
fluorescence	O
of	O
both	O
the	O
Borrelia	O
and	O
myeloma	O
cells	O
corresponds	O
to	O
the	O
areas	O
of	O
red	O
fluorescence	O
.	O

This	O
indicated	O
that	O
lipid	O
hydroperoxides	O
were	O
present	O
on	O
the	O
Borrelia	O
cell	O
membranes	O
and	O
suggested	O
that	O
the	O
membranes	O
were	O
damaged	O
.	O

To	O
further	O
demonstrate	O
Borrelia	O
membrane	O
damage	O
,	O
B	B
.	I
burgdorferi	I
B31A3	O
cells	O
were	O
grown	O
under	O
anaerobic	O
and	O
microaerobic	O
conditions	O
and	O
visualized	O
by	O
negative	O
stain	O
using	O
an	O
electron	O
microscope	O
.	O

Additionally	O
,	O
cells	O
grown	O
under	O
microaerobic	O
conditions	O
were	O
treated	O
with	O
250	O
mg	O
of	O
lipoxidase	O
and	O
visualized	O
by	O
Electron	O
Microscopy	O
.	O

Intact	O
membranes	O
were	O
observed	O
in	O
cultures	O
of	O
B31A3	O
grown	O
under	O
anaerobic	O
and	O
microaerobic	O
conditions	O
(	O
Fig	O
.	O
6A	O
and	O
B	O
respectively	O
)	O
.	O

However	O
,	O
in	O
cultures	O
treated	O
with	O
lipoxidase	O
(	O
Fig	O
.	O
6C	O
)	O
,	O
a	O
significant	O
number	O
of	O
membrane	O
blebs	O
were	O
seen	O
surrounding	O
the	O
spirochetes	O
,	O
indicating	O
membrane	O
damage	O
.	O

Taken	O
together	O
,	O
these	O
data	O
indicated	O
that	O
Borrelia	O
membranes	O
were	O
a	O
target	O
for	O
oxidative	O
stress	O
.	O

Discussion	O

Most	O
bacterial	O
pathogens	O
are	O
faced	O
with	O
the	O
challenge	O
of	O
overcoming	O
ROS	O
generated	O
by	O
the	O
host	O
immune	O
system	O
.	O

These	O
radicals	O
can	O
cause	O
a	O
great	O
deal	O
of	O
damage	O
to	O
biological	O
molecules	O
both	O
in	O
vitro	O
and	O
in	O
vivo	O
.	O

The	O
potential	O
cellular	O
targets	O
for	O
ROS	O
damage	O
in	O
bacteria	O
include	O
DNA	O
,	O
RNA	O
,	O
proteins	O
and	O
lipids	O
,	O
and	O
extensive	O
work	O
has	O
been	O
done	O
to	O
determine	O
the	O
cellular	O
targets	O
of	O
ROS	O
that	O
affect	O
bacterial	O
survival	O
.	O

To	O
date	O
,	O
the	O
most	O
definitive	O
work	O
has	O
been	O
done	O
on	O
E	B
.	I
coli	I
.	O

It	O
seems	O
clear	O
from	O
several	O
studies	O
that	O
the	O
most	O
physiologically	O
relevant	O
target	O
of	O
ROS	O
in	O
E	B
.	I
coli	I
is	O
DNA	O
.	O

The	O
exposure	O
to	O
micro	O
M	O
concentrations	O
of	O
ROS	O
(	O
i	O
.	O
e	O
.	O
H2O2	O
)	O
is	O
sufficient	O
to	O
cause	O
DNA	O
damage	O
,	O
inhibit	O
DNA	O
replication	O
,	O
increase	O
the	O
mutation	O
rate	O
and	O
often	O
lead	O
to	O
cell	O
death	O
.	O

This	O
process	O
leading	O
to	O
DNA	O
damage	O
begins	O
with	O
formation	O
of	O
O2	O
-	O
and	O
H2O2	O
from	O
the	O
oxidation	O
of	O
flavoproteins	O
and	O
/	O
or	O
the	O
diffusion	O
of	O
these	O
reactive	O
species	O
from	O
the	O
extracellular	O
milieu	O
.	O

The	O
subsequent	O
oxidation	O
of	O
Fe	O
-	O
S	O
proteins	O
by	O
ROS	O
(	O
e	O
.	O
g	O
.	O
O2	O
-	O
)	O
leads	O
to	O
an	O
increase	O
in	O
intracellular	O
'	O
free	O
'	O
Fe2	O
+	O
which	O
triggers	O
the	O
reduction	O
of	O
H2O2	O
to	O
OH	O
(	O
Fenton	O
reaction	O
)	O
.	O

The	O
highly	O
reactive	O
nature	O
of	O
OH	O
limits	O
its	O
diffusion	O
so	O
that	O
it	O
generally	O
reacts	O
with	O
molecules	O
in	O
close	O
proximity	O
to	O
its	O
origin	O
(	O
e	O
.	O
g	O
.	O
the	O
Fe2	O
+	O
associated	O
with	O
DNA	O
)	O
.	O

In	O
DNA	O
,	O
OH	O
oxidizes	O
sugar	O
and	O
base	O
moieties	O
,	O
producing	O
radicals	O
which	O
ultimately	O
generate	O
lesions	O
,	O
including	O
base	O
modifications	O
,	O
strand	O
breaks	O
and	O
chemical	O
cross	O
-	O
links	O
to	O
other	O
molecules	O
.	O

Base	O
modifications	O
lead	O
to	O
mismatching	O
and	O
increased	O
mutation	O
frequencies	O
while	O
more	O
severe	O
damage	O
,	O
such	O
as	O
strand	O
breaks	O
,	O
prevents	O
DNA	O
replication	O
,	O
contributing	O
to	O
OH	O
toxicity	O
and	O
cell	O
death	O
.	O

Critical	O
to	O
this	O
chemical	O
process	O
in	O
vivo	O
is	O
the	O
presence	O
of	O
iron	O
.	O

No	O
other	O
metal	O
or	O
non	O
-	O
metal	O
electron	O
carrier	O
appears	O
to	O
be	O
able	O
to	O
univalently	O
reduce	O
H2O2	O
to	O
OH	O
in	O
vivo	O
(	O
Macomber	O
et	O
al	O
.	O
,	O
2007	O
)	O
.	O

These	O
observations	O
are	O
critical	O
in	O
beginning	O
to	O
understand	O
the	O
oxidative	O
damage	O
/	O
targets	O
in	O
B	B
.	I
burgdorferi	I
.	O

It	O
has	O
been	O
shown	O
in	O
E	B
.	I
coli	I
that	O
the	O
free	O
-	O
iron	O
pool	O
size	O
determines	O
the	O
rate	O
of	O
oxidative	O
DNA	O
damage	O
.	O

For	O
example	O
,	O
in	O
wild	O
-	O
type	O
E	B
.	I
coli	I
,	O
free	O
iron	O
levels	O
are	O
estimated	O
to	O
be	O
10	O
micro	O
M	O
,	O
yet	O
H2O2	O
is	O
only	O
mildly	O
genotoxic	O
(	O
Keyer	O
and	O
Imlay	O
,	O
1996	O
)	O
.	O

However	O
,	O
in	O
E	B
.	I
coli	I
Fur	O
-	O
mutants	O
,	O
intracellular	O
iron	O
concentration	O
increases	O
eightfold	O
while	O
survival	O
is	O
10	O
-	O
fold	O
lower	O
when	O
cells	O
are	O
exposed	O
to	O
H2O2	O
.	O

Because	O
B	B
.	I
burgdorferi	I
cells	O
do	O
not	O
contain	O
detectable	O
levels	O
of	O
intracellular	O
Fe	O
,	O
it	O
seems	O
unlikely	O
that	O
DNA	O
is	O
a	O
major	O
target	O
for	O
damage	O
via	O
the	O
Fenton	O
reaction	O
in	O
this	O
bacterium	O
(	O
Posey	O
and	O
Gherardini	O
,	O
2000	O
)	O
.	O

The	O
experimental	O
data	O
present	O
in	O
this	O
report	O
suggested	O
that	O
this	O
was	O
the	O
case	O
.	O

When	O
B	B
.	I
burgdorferi	I
cells	O
were	O
exposed	O
to	O
high	O
concentrations	O
of	O
ROS	O
(	O
e	O
.	O
g	O
.	O
H2O2	O
)	O
,	O
there	O
was	O
no	O
effect	O
on	O
the	O
spontaneous	O
mutation	O
rate	O
(	O
Fig	O
.	O
2A	O
)	O
or	O
the	O
number	O
of	O
DNA	O
lesions	O
(	O
AP	O
sites	O
or	O
8	O
-	O
oxoguanine	O
)	O
(	O
Fig	O
.	O
2B	O
and	O
C	O
)	O
.	O

It	O
should	O
be	O
noted	O
that	O
in	O
these	O
experiments	O
,	O
a	O
wild	O
-	O
type	O
strain	O
of	O
B	B
.	I
burgdorferi	I
was	O
used	O
and	O
presumably	O
all	O
of	O
the	O
endogenous	O
oxidative	O
stress	O
enzymes	O
were	O
expressed	O
.	O

Therefore	O
,	O
it	O
is	O
possible	O
that	O
no	O
DNA	O
damage	O
was	O
observed	O
because	O
these	O
enzymes	O
are	O
capable	O
of	O
detoxifying	O
the	O
cell	O
and	O
protecting	O
nucleic	O
acids	O
from	O
oxidation	O
via	O
the	O
Fenton	O
reaction	O
.	O

However	O
,	O
we	O
do	O
not	O
believe	O
this	O
to	O
be	O
the	O
case	O
as	O
the	O
concentration	O
of	O
oxidants	O
used	O
in	O
these	O
experiments	O
were	O
significantly	O
higher	O
than	O
concentrations	O
known	O
to	O
cause	O
DNA	O
damage	O
in	O
E	B
.	I
coli	I
and	O
other	O
pathogenic	O
bacteria	O
.	O

The	O
lack	O
of	O
detectable	O
DNA	O
damage	O
in	O
B	B
.	I
burgdorferi	I
cells	O
under	O
the	O
conditions	O
tested	O
could	O
be	O
the	O
result	O
of	O
very	O
efficient	O
DNA	O
repair	O
systems	O
.	O

Bacteria	O
,	O
such	O
as	O
E	B
.	I
coli	I
,	O
harbour	O
genes	O
encoding	O
repair	O
enzymes	O
(	O
i	O
.	O
e	O
.	O
MutM	O
,	O
MutY	O
,	O
Ung	O
,	O
AlkA	O
,	O
MutS	O
,	O
MutL	O
,	O
ExoIII	O
,	O
EndoVIII	O
,	O
PolI	O
,	O
RecJ	O
)	O
.	O

Key	O
enzymes	O
in	O
the	O
repair	O
of	O
8	O
-	O
oxoguanine	O
lesions	O
resulting	O
from	O
the	O
oxidation	O
of	O
DNA	O
are	O
the	O
bifunctional	O
glycosylases	O
,	O
such	O
as	O
MutM	O
,	O
MutY	O
or	O
EndoVIII	O
.	O

The	O
first	O
activity	O
of	O
these	O
enzymes	O
is	O
to	O
remove	O
oxidized	O
or	O
ring	O
-	O
saturated	O
bases	O
while	O
the	O
second	O
activity	O
is	O
to	O
remove	O
the	O
resulting	O
deoxyribose	O
residue	O
,	O
generating	O
a	O
3	O
'	O
-	O
phosphate	O
end	O
(	O
Krwawicz	O
et	O
al	O
.	O
,	O
2007	O
)	O
.	O

This	O
3	O
'	O
-	O
P	O
is	O
converted	O
to	O
a	O
3	O
'	O
-	O
OH	O
by	O
various	O
enzymes	O
/	O
pathways	O
and	O
the	O
lesion	O
is	O
repaired	O
by	O
enzymes	O
(	O
e	O
.	O
g	O
.	O
ExoIII	O
,	O
PolI	O
,	O
LigI	O
etc	O
.	O
)	O
in	O
the	O
short	O
or	O
long	O
BER	O
pathways	O
(	O
S	O
-	O
BER	O
,	O
L	O
-	O
BER	O
)	O
.	O

Interestingly	O
,	O
the	O
B	B
.	I
burgdorferi	I
genome	O
does	O
not	O
contain	O
genes	O
encoding	O
homologues	O
of	O
MutM	O
,	O
MutY	O
or	O
EndoVIII	O
,	O
suggesting	O
that	O
it	O
would	O
be	O
difficult	O
for	O
the	O
cells	O
to	O
efficiently	O
repair	O
8	O
-	O
oxoguanine	O
sites	O
using	O
this	O
pathway	O
.	O

B	B
.	I
burgdorferi	I
does	O
harbour	O
the	O
genes	O
encoding	O
the	O
enzymes	O
Ung	O
(	O
monofunctional	O
gylcosylase	O
,	O
BB0053	O
)	O
,	O
MutS	O
(	O
BB0797	O
,	O
BB0098	O
)	O
,	O
MutL	O
(	O
BB0211	O
)	O
,	O
ExoIII	O
(	O
BB0114	O
)	O
,	O
PolI	O
(	O
BB0548	O
)	O
,	O
LigI	O
(	O
BB0552	O
)	O
and	O
RecJ	O
(	O
BB0254	O
)	O
(	O
Fraser	O
et	O
al	O
.	O
,	O
1997	O
)	O
which	O
are	O
involved	O
in	O
excision	O
and	O
repair	O
,	O
via	O
S	O
-	O
BER	O
or	O
L	O
-	O
BER	O
,	O
of	O
deaminated	O
,	O
alkylated	O
,	O
methylated	O
or	O
mismatched	O
bases	O
.	O

Clearly	O
,	O
these	O
repair	O
systems	O
in	O
B	B
.	I
burgdorferi	I
do	O
not	O
seem	O
as	O
robust	O
at	O
defending	O
against	O
oxidation	O
of	O
DNA	O
as	O
those	O
described	O
in	O
E	B
.	I
coli	I
.	O

The	O
lack	O
of	O
key	O
repair	O
enzymes	O
in	O
this	O
system	O
may	O
indicate	O
that	O
B	B
.	I
burgdorferi	I
DNA	O
is	O
not	O
subjected	O
to	O
the	O
same	O
challenge	O
from	O
ROS	O
as	O
is	O
E	B
.	I
coli	I
.	O

In	O
most	O
bacteria	O
,	O
ROS	O
-	O
mediated	O
damage	O
to	O
lipids	O
(	O
lipid	O
peroxidation	O
)	O
is	O
very	O
unlikely	O
because	O
of	O
the	O
lack	O
of	O
polyunsaturated	O
fatty	O
acids	O
(	O
e	O
.	O
g	O
.	O
linoleic	O
acid	O
)	O
(	O
Imlay	O
,	O
2003	O
)	O
.	O

When	O
it	O
does	O
occur	O
,	O
lipid	O
peroxidation	O
is	O
initiated	O
by	O
the	O
attack	O
of	O
free	O
radicals	O
on	O
polyunsaturated	O
fatty	O
acids	O
which	O
decreases	O
the	O
membrane	O
fluidity	O
and	O
,	O
if	O
these	O
reactions	O
propagate	O
,	O
lipid	O
peroxides	O
and	O
their	O
degradation	O
products	O
(	O
e	O
.	O
g	O
.	O
aldehydes	O
)	O
in	O
turn	O
could	O
damage	O
proteins	O
(	O
Gutteridge	O
and	O
Halliwell	O
,	O
1990	O
)	O
.	O

This	O
would	O
dramatically	O
affect	O
the	O
function	O
of	O
transmembrane	O
proteins	O
and	O
membrane	O
-	O
bound	O
lipoproteins	O
involved	O
in	O
the	O
maintenance	O
of	O
membrane	O
potential	O
and	O
solute	O
transport	O
,	O
decreasing	O
cell	O
survivability	O
.	O

In	O
contrast	O
to	O
most	O
bacteria	O
,	O
B	B
.	I
burgdorferi	I
membranes	O
contained	O
significant	O
levels	O
of	O
unsaturated	O
fatty	O
acids	O
,	O
such	O
as	O
linoleic	O
acid	O
and	O
linolenic	O
acid	O
,	O
which	O
were	O
derived	O
from	O
the	O
growth	O
media	O
(	O
Table	O
1	O
)	O
.	O

Thus	O
,	O
it	O
seemed	O
possible	O
that	O
lipids	O
and	O
/	O
or	O
proteins	O
rather	O
than	O
DNA	O
are	O
the	O
primary	O
targets	O
of	O
ROS	O
in	O
B	B
.	I
burgdorferi	I
.	O

When	O
Borrelia	O
cells	O
are	O
treated	O
with	O
oxidants	O
,	O
the	O
levels	O
of	O
linoleic	O
acid	O
decreased	O
while	O
other	O
fatty	O
acids	O
remain	O
unaffected	O
(	O
Table	O
2	O
)	O
.	O

In	O
addition	O
,	O
HPLC	O
-	O
based	O
assays	O
demonstrated	O
that	O
,	O
as	O
linoleic	O
acid	O
concentrations	O
decrease	O
,	O
MDA	O
(	O
a	O
toxic	O
lipid	O
peroxide	O
intermediate	O
)	O
increased	O
(	O
Fig	O
.	O
3	O
)	O
.	O

When	O
these	O
cells	O
were	O
examined	O
by	O
electron	O
microscopy	O
,	O
damage	O
to	O
the	O
membranes	O
(	O
membrane	O
'	O
blebs	O
'	O
)	O
was	O
observed	O
(	O
Fig	O
.	O
6	O
)	O
.	O

These	O
data	O
indicated	O
that	O
unlike	O
most	O
other	O
bacteria	O
,	O
Borrelia	O
membranes	O
were	O
damaged	O
by	O
oxygen	O
radicals	O
.	O

As	O
B	B
.	I
burgdorferi	I
may	O
be	O
exposed	O
to	O
potentially	O
harmful	O
oxygen	O
species	O
at	O
different	O
stages	O
of	O
the	O
infective	O
cycle	O
,	O
the	O
ability	O
to	O
protect	O
its	O
membrane	O
lipids	O
from	O
ROS	O
should	O
be	O
required	O
for	O
survival	O
in	O
the	O
different	O
host	O
environments	O
.	O

In	O
eukaryotic	O
cells	O
,	O
where	O
lipid	O
peroxidation	O
is	O
a	O
major	O
consequence	O
of	O
oxidative	O
attack	O
,	O
proteins	O
which	O
protect	O
membranes	O
have	O
been	O
well	O
studied	O
.	O

For	O
example	O
,	O
phospholipid	O
hydroperoxide	O
glutathione	O
peroxidase	O
,	O
a	O
member	O
of	O
the	O
glutathione	O
peroxidase	O
family	O
,	O
has	O
been	O
identified	O
in	O
a	O
variety	O
of	O
higher	O
organisms	O
.	O

These	O
enzymes	O
are	O
capable	O
of	O
reducing	O
an	O
assortment	O
of	O
hydroperoxy	O
lipids	O
,	O
including	O
oxidized	O
phospholipids	O
and	O
cholesterol	O
esters	O
(	O
Ursini	O
and	O
Bindoli	O
,	O
1987	O
)	O
,	O
and	O
protect	O
complex	O
membranes	O
from	O
oxidative	O
damage	O
.	O

Much	O
less	O
is	O
known	O
about	O
the	O
enzyme	O
(	O
s	O
)	O
responsible	O
for	O
protecting	O
unsaturated	O
lipids	O
from	O
ROS	O
in	O
prokaryotes	O
.	O

In	O
H	B
.	I
pylori	I
,	O
lipid	O
hydroperoxide	O
levels	O
in	O
ahpC	O
mutants	O
are	O
approximately	O
three	O
times	O
higher	O
than	O
in	O
wild	O
-	O
type	O
cells	O
,	O
suggesting	O
a	O
role	O
for	O
AhpC	O
in	O
reducing	O
organic	O
peroxides	O
(	O
Wang	O
et	O
al	O
.	O
,	O
2006a	O
,	O
b	O
)	O
.	O

In	O
addition	O
,	O
purified	O
AhpC	O
has	O
been	O
shown	O
to	O
reduce	O
linoleic	O
acid	O
hydroperoxide	O
in	O
vitro	O
(	O
Baker	O
et	O
al	O
.	O
,	O
2001	O
)	O
.	O

Because	O
these	O
antioxidant	O
enzymes	O
promote	O
the	O
in	O
vivo	O
survival	O
of	O
cells	O
when	O
challenged	O
with	O
ROS	O
,	O
enzymes	O
for	O
the	O
reduction	O
of	O
lipid	O
peroxides	O
in	O
Borrelia	O
need	O
to	O
be	O
identified	O
.	O

Interestingly	O
,	O
Borrelia	O
cells	O
grown	O
aerobically	O
showed	O
signs	O
of	O
membrane	O
damage	O
similar	O
to	O
those	O
observed	O
in	O
cells	O
exposed	O
to	O
various	O
oxidants	O
.	O

The	O
amount	O
of	O
MDA	O
in	O
untreated	O
aerobically	O
grown	O
cells	O
was	O
equivalent	O
to	O
that	O
observed	O
in	O
treated	O
cells	O
(	O
Fig	O
.	O
3	O
)	O
.	O

Also	O
,	O
EM	O
indicated	O
that	O
cells	O
grown	O
microaerobically	O
or	O
aerobically	O
had	O
significantly	O
more	O
membrane	O
damage	O
than	O
cells	O
grown	O
anaerobically	O
(	O
Fig	O
.	O
6	O
)	O
.	O

This	O
indicated	O
that	O
Borrelia	O
membranes	O
can	O
be	O
damaged	O
simply	O
by	O
exposure	O
to	O
physiologically	O
relevant	O
concentrations	O
of	O
dissolved	O
oxygen	O
.	O

In	O
exponentially	O
growing	O
E	B
.	I
coli	I
,	O
Imlay	O
and	O
Fridovich	O
(	O
1991	O
)	O
have	O
shown	O
that	O
both	O
O2	O
-	O
and	O
H2O2	O
are	O
generated	O
by	O
the	O
autoxidation	O
of	O
components	O
of	O
the	O
respiratory	O
chain	O
during	O
oxygen	O
metabolism	O
.	O

In	O
contrast	O
,	O
B	B
.	I
burgdorferi	I
is	O
very	O
metabolically	O
limited	O
and	O
has	O
no	O
enzymes	O
for	O
the	O
TCA	O
cycle	O
or	O
respiration	O
.	O

Therefore	O
,	O
it	O
seems	O
more	O
likely	O
that	O
sources	O
of	O
ROS	O
are	O
exogenous	O
(	O
e	O
.	O
g	O
.	O
innate	O
immune	O
response	O
in	O
the	O
mammalian	O
host	O
)	O
rather	O
than	O
endogenous	O
.	O

In	O
addition	O
,	O
the	O
current	O
practice	O
of	O
growing	O
B	B
.	I
burgdorferi	I
under	O
atmospheric	O
oxygen	O
could	O
itself	O
be	O
unintentionally	O
compromising	O
cell	O
integrity	O
during	O
in	O
vitro	O
manipulations	O
.	O

Analyses	O
of	O
the	O
B	B
.	I
burgdorferi	I
genome	O
indicates	O
that	O
only	O
a	O
few	O
genes	O
encoding	O
putative	O
oxidative	O
stress	O
/	O
intracellular	O
redox	O
proteins	O
(	O
SodA	O
,	O
NapA	O
,	O
BosR	O
,	O
CoADR	O
,	O
Trx	O
and	O
TrxR	O
)	O
(	O
Fraser	O
et	O
al	O
.	O
,	O
1997	O
)	O
are	O
present	O
,	O
compared	O
with	O
other	O
bacterial	O
pathogens	O
,	O
including	O
other	O
pathogenic	O
spirochetes	O
(	O
e	O
.	O
g	O
.	O
Treponema	O
,	O
Leptospira	O
)	O
.	O

Despite	O
this	O
apparent	O
'	O
deficiency	O
'	O
in	O
the	O
number	O
of	O
ROS	O
-	O
protective	O
enzymes	O
,	O
B	B
.	I
burgdorferi	I
cells	O
appear	O
to	O
be	O
able	O
to	O
cope	O
with	O
physiologically	O
relevant	O
levels	O
of	O
ROS	O
.	O

There	O
are	O
several	O
factors	O
that	O
would	O
contribute	O
to	O
this	O
phenomenon	O
:	O
(	O
i	O
)	O
as	O
B	B
.	I
burgdorferi	I
does	O
not	O
harbour	O
the	O
genes	O
encoding	O
respiratory	O
enzymes	O
nor	O
metabolize	O
oxygen	O
,	O
it	O
seems	O
unlikely	O
that	O
significant	O
levels	O
of	O
ROS	O
are	O
generated	O
via	O
the	O
incomplete	O
reduction	O
of	O
O2	O
during	O
cellular	O
metabolism	O
.	O

This	O
would	O
suggest	O
that	O
potential	O
ROS	O
challenges	O
to	O
B	B
.	I
burgdorferi	I
would	O
come	O
almost	O
completely	O
from	O
extracellular	O
sources	O
with	O
little	O
contribution	O
from	O
intracellularly	O
generated	O
ROS	O
;	O
(	O
ii	O
)	O
owing	O
to	O
a	O
lack	O
of	O
understanding	O
of	O
the	O
physiological	O
conditions	O
in	O
vector	O
and	O
host	O
tissues	O
infected	O
with	O
B	B
.	I
burgdorferi	I
,	O
it	O
is	O
difficult	O
to	O
assess	O
the	O
levels	O
and	O
/	O
or	O
sites	O
of	O
the	O
potential	O
ROS	O
challenge	O
during	O
the	O
infective	O
cycle	O
and	O
(	O
iii	O
)	O
most	O
importantly	O
,	O
analyses	O
of	O
the	O
potential	O
targets	O
for	O
ROS	O
in	O
B	B
.	I
burgdorferi	I
strongly	O
suggested	O
that	O
the	O
major	O
targets	O
of	O
oxidative	O
damage	O
are	O
different	O
and	O
perhaps	O
less	O
extensive	O
in	O
this	O
bacterium	O
than	O
in	O
other	O
bacterial	O
pathogens	O
(	O
e	O
.	O
g	O
.	O
E	B
.	I
coli	I
)	O
.	O

Taken	O
together	O
,	O
this	O
suggests	O
that	O
B	B
.	I
burgdorferi	I
would	O
be	O
innately	O
more	O
resistant	O
to	O
ROS	O
and	O
require	O
a	O
less	O
extensive	O
repertoire	O
of	O
enzymes	O
to	O
protect	O
the	O
cells	O
from	O
oxidative	O
damage	O
.	O

Experimental	O
procedures	O

Strains	O
,	O
growth	O
conditions	O
and	O
reagents	O

Borrelia	B
burgdorferi	I
strain	O
B31A3	O
and	O
strain	O
B314	O
(	O
Sadziene	O
et	O
al	O
.	O
,	O
1993	O
)	O
were	O
grown	O
in	O
modified	O
BSK	O
-	O
II	O
(	O
Barbour	O
,	O
1984	O
)	O
medium	O
at	O
34	O
degrees	O
C	O
under	O
an	O
atmosphere	O
of	O
0	O
-	O
20	O
%	O
O2	O
with	O
5	O
%	O
CO2	O
and	O
the	O
balance	O
N2	O
.	O

Cells	O
density	O
was	O
determined	O
using	O
a	O
dark	O
-	O
field	O
microscope	O
.	O

All	O
reagents	O
were	O
purchased	O
from	O
Sigma	O
Chemicals	O
,	O
St	O
.	O

Louis	O
,	O
MO	O
unless	O
stated	O
otherwise	O
.	O

E	B
.	I
coli	I
strain	O
Top10	O
,	O
strain	O
TA4315	O
(	O
ahpCF	O
)	O
(	O
Storz	O
et	O
al	O
.	O
,	O
1989	O
)	O
and	O
CM1319	O
(	O
mutM	O
)	O
(	O
Bridges	O
et	O
al	O
.	O
,	O
1996	O
)	O
were	O
grown	O
in	O
Luria	O
-	O
Bertani	O
(	O
LB	O
)	O
at	O
37	O
degrees	O
C	O
with	O
shaking	O
.	O

Per	O
cent	O
survivability	O
assays	O

Borrelia	B
burgdorferi	I
strain	O
B31A3	O
was	O
grown	O
to	O
a	O
cell	O
density	O
of	O
5	O
x	O
107	O
cells	O
ml	O
-	O
1	O
in	O
BSK	O
II	O
under	O
microaerobic	O
(	O
3	O
%	O
O2	O
)	O
conditions	O
,	O
the	O
culture	O
split	O
and	O
the	O
cells	O
treated	O
with	O
varying	O
concentrations	O
of	O
oxidants	O
(	O
0	O
-	O
50	O
mM	O
t	O
-	O
butyl	O
hydroperoxide	O
or	O
H2O2	O
)	O
at	O
34	O
degrees	O
C	O
for	O
4	O
h	O
.	O

After	O
the	O
incubation	O
,	O
cells	O
were	O
diluted	O
in	O
fresh	O
BSK	O
II	O
,	O
plated	O
on	O
BSK	O
plates	O
and	O
incubated	O
7	O
-	O
14	O
days	O
at	O
34	O
degrees	O
C	O
.	O

Per	O
cent	O
survivability	O
was	O
calculated	O
as	O
the	O
number	O
of	O
colonies	O
on	O
the	O
treated	O
plates	O
versus	O
the	O
number	O
of	O
colonies	O
on	O
the	O
untreated	O
plates	O
.	O

Determination	O
of	O
the	O
spontaneous	O
mutation	O
rate	O

To	O
determine	O
spontaneous	O
resistance	O
to	O
coumermycin	O
A1	O
,	O
B	B
.	I
burgdorferi	I
B31A3	O
cells	O
were	O
grown	O
under	O
microaerobic	O
conditions	O
to	O
a	O
cell	O
density	O
of	O
5	O
x	O
107	O
cells	O
ml	O
-	O
1	O
and	O
treated	O
with	O
5	O
mM	O
H2O2	O
for	O
1	O
h	O
at	O
34	O
degrees	O
C	O
.	O

The	O
cells	O
were	O
plated	O
on	O
BSK	O
plates	O
containing	O
0	O
or	O
250	O
ng	O
ml	O
-	O
1	O
coumermycin	O
A1	O
and	O
incubated	O
7	O
-	O
14	O
days	O
at	O
34	O
degrees	O
C	O
.	O

The	O
resistance	O
frequency	O
was	O
calculated	O
as	O
the	O
number	O
of	O
colonies	O
that	O
are	O
CouR	O
per	O
total	O
number	O
of	O
cells	O
plated	O
.	O

Measurement	O
of	O
DNA	O
base	O
lesions	O

Borrelia	B
burgdorferi	I
B31A3	O
cells	O
were	O
grown	O
in	O
BSK	O
-	O
II	O
under	O
microaerobic	O
conditions	O
to	O
a	O
cell	O
density	O
of	O
5	O
x	O
107	O
cells	O
ml	O
-	O
1	O
,	O
treated	O
with	O
various	O
oxidants	O
(	O
1	O
or	O
10	O
mM	O
t	O
-	O
butyl	O
hydroperoxide	O
,	O
1	O
or	O
10	O
mM	O
H2O2	O
,	O
10	O
mM	O
paraquat	O
or	O
lipoxidase	O
)	O
for	O
4	O
h	O
and	O
total	O
DNA	O
was	O
isolated	O
using	O
Wizard	O
Genomic	O
DNA	O
Purification	O
Kit	O
(	O
Promega	O
Corp	O
.	O
,	O
Madison	O
,	O
WI	O
)	O
.	O

The	O
number	O
of	O
base	O
lesions	O
was	O
determined	O
using	O
the	O
DNA	O
Damage	O
Quantification	O
Colorimetric	O
Assay	O
kit	O
(	O
Oxford	O
Biomedical	O
Research	O
,	O
Oxford	O
,	O
MI	O
)	O
following	O
the	O
manufacturer	O
'	O
s	O
protocol	O
.	O

Briefly	O
,	O
500	O
ng	O
of	O
DNA	O
was	O
mixed	O
with	O
an	O
equal	O
volume	O
of	O
10	O
mM	O
biotinylated	O
aldehyde	O
reactive	O
probe	O
(	O
ARP	O
)	O
reagent	O
and	O
incubated	O
for	O
1	O
h	O
at	O
37	O
degrees	O
C	O
.	O

The	O
DNA	O
-	O
ARP	O
product	O
was	O
ethanol	O
-	O
precipitated	O
using	O
glycogen	O
as	O
a	O
carrier	O
,	O
washed	O
three	O
times	O
with	O
70	O
%	O
ethanol	O
and	O
resuspended	O
in	O
Tris	O
-	O
EDTA	O
to	O
give	O
a	O
final	O
concentration	O
of	O
0	O
.	O
5	O
micro	O
g	O
ml	O
-	O
1	O
.	O

The	O
DNA	O
-	O
ARP	O
product	O
was	O
allowed	O
to	O
bind	O
to	O
the	O
wells	O
of	O
96	O
-	O
well	O
microplate	O
overnight	O
at	O
37	O
degrees	O
C	O
.	O

After	O
the	O
binding	O
,	O
the	O
wells	O
were	O
washed	O
four	O
times	O
with	O
TPBS	O
(	O
137	O
mM	O
NaCl	O
,	O
2	O
.	O
7	O
mM	O
KCl	O
,	O
10	O
mM	O
Na3HPO4	O
,	O
2	O
mM	O
KH2PO4	O
,	O
0	O
.	O
5	O
%	O
Tween	O
20	O
,	O
pH	O
7	O
.	O
4	O
)	O
.	O

The	O
HRP	O
-	O
streptavidin	O
conjugate	O
was	O
diluted	O
to	O
0	O
.	O
5	O
micro	O
g	O
ml	O
-	O
1	O
in	O
Assay	O
Buffer	O
(	O
0	O
.	O
15	O
M	O
NaCl	O
,	O
10	O
mM	O
NasHPO4	O
,	O
1	O
.	O
5	O
mM	O
KH2PO4	O
,	O
2	O
.	O
5	O
mM	O
KCl	O
,	O
5	O
mg	O
ml	O
-	O
1	O
BSA	O
,	O
0	O
.	O
1	O
%	O
Tween	O
,	O
pH	O
7	O
.	O
5	O
)	O
,	O
100	O
micro	O
l	O
was	O
added	O
to	O
each	O
well	O
and	O
the	O
plate	O
incubated	O
at	O
100	O
r	O
.	O
p	O
.	O
m	O
.	O
for	O
1	O
h	O
at	O
room	O
temperature	O
(	O
RT	O
)	O
.	O

After	O
incubation	O
,	O
the	O
wells	O
were	O
washed	O
four	O
times	O
with	O
TPBS	O
,	O
100	O
micro	O
l	O
of	O
substrate	O
was	O
added	O
to	O
each	O
well	O
and	O
incubated	O
for	O
1	O
h	O
at	O
37	O
degrees	O
C	O
.	O

The	O
reaction	O
was	O
then	O
quenched	O
with	O
100	O
micro	O
l	O
of	O
1	O
M	O
sulphuric	O
acid	O
and	O
the	O
reaction	O
was	O
monitored	O
at	O
450	O
nm	O
.	O

The	O
number	O
of	O
aldehyde	O
reactive	O
probe	O
(	O
DNA	O
base	O
lesions	O
)	O
per	O
105	O
bp	O
DNA	O
was	O
determined	O
using	O
a	O
standard	O
curve	O
.	O

As	O
a	O
control	O
,	O
E	B
.	I
coli	I
TA4315	O
cells	O
were	O
grown	O
in	O
minimal	O
media	O
to	O
OD600	O
of	O
0	O
.	O
4	O
,	O
treated	O
with	O
0	O
or	O
100	O
micro	O
M	O
H2O2	O
for	O
30	O
min	O
and	O
DNA	O
isolated	O
.	O

The	O
number	O
of	O
base	O
lesions	O
was	O
determined	O
as	O
described	O
above	O
.	O

B	B
.	I
burgdorferi	I
strain	O
B314	O
cells	O
were	O
grown	O
under	O
microaerobic	O
conditions	O
and	O
DNA	O
isolated	O
.	O

The	O
number	O
of	O
DNA	O
lesions	O
was	O
determined	O
as	O
described	O
.	O

To	O
determine	O
the	O
amount	O
of	O
8	O
-	O
oxoguanine	O
in	O
B	B
.	I
burgdorferi	I
DNA	O
,	O
cells	O
were	O
grown	O
and	O
treated	O
as	O
described	O
above	O
and	O
DNA	O
isolated	O
.	O

The	O
DNA	O
was	O
converted	O
to	O
single	O
-	O
stranded	O
DNA	O
by	O
boiling	O
the	O
sample	O
for	O
5	O
min	O
followed	O
by	O
rapid	O
chill	O
on	O
ice	O
.	O

The	O
DNA	O
was	O
then	O
digested	O
with	O
nuclease	O
P1	O
for	O
2	O
h	O
and	O
then	O
treated	O
with	O
alkaline	O
phosphatase	O
for	O
1	O
h	O
following	O
manufacturer	O
'	O
s	O
protocols	O
.	O

The	O
resultant	O
mixture	O
was	O
then	O
centrifuged	O
for	O
5	O
min	O
at	O
6000	O
g	O
and	O
the	O
supernatant	O
used	O
for	O
the	O
8	O
-	O
oxoguanine	O
ELISA	O
assay	O
(	O
Oxford	O
Biomedical	O
Research	O
,	O
Oxford	O
,	O
MI	O
)	O
.	O

As	O
a	O
control	O
,	O
E	B
.	I
coli	I
CM1319	O
(	O
mutM	O
)	O
cells	O
were	O
grown	O
in	O
LB	O
to	O
OD600	O
of	O
0	O
.	O
4	O
,	O
treated	O
with	O
0	O
or	O
100	O
micro	O
M	O
H2O2	O
for	O
1	O
h	O
and	O
DNA	O
isolated	O
.	O

The	O
concentration	O
of	O
8	O
-	O
oxoguanine	O
was	O
determined	O
as	O
above	O
.	O

Lipid	O
analyses	O

To	O
determine	O
fatty	O
acid	O
content	O
in	O
B	B
.	I
burgdorferi	I
total	O
membranes	O
,	O
B	B
.	I
burgdorferi	I
strain	O
B31A3	O
was	O
grown	O
under	O
anaerobic	O
conditions	O
to	O
a	O
cell	O
density	O
of	O
5	O
x	O
107	O
cells	O
ml	O
-	O
1	O
,	O
harvested	O
by	O
centrifugation	O
(	O
5000	O
g	O
,	O
15	O
min	O
,	O
4	O
degrees	O
C	O
)	O
and	O
washed	O
two	O
times	O
with	O
HN	O
(	O
20	O
mM	O
NaCl	O
,	O
50	O
mM	O
Hepes	O
,	O
pH	O
7	O
.	O
6	O
)	O
buffer	O
.	O

Cell	O
pellets	O
were	O
analysed	O
for	O
fatty	O
acid	O
composition	O
by	O
fatty	O
acid	O
methyl	O
ester	O
(	O
FAME	O
)	O
gas	O
chromatography	O
(	O
Lipid	O
Technologies	O
,	O
Austin	O
,	O
MN	O
)	O
and	O
results	O
are	O
reported	O
as	O
percentage	O
of	O
total	O
fatty	O
acid	O
content	O
.	O

To	O
determine	O
the	O
effects	O
of	O
oxidants	O
on	O
fatty	O
acid	O
composition	O
,	O
a	O
1	O
.	O
5	O
l	O
culture	O
of	O
B	B
.	I
burgdorferi	I
strain	O
B31A3	O
was	O
grown	O
under	O
microaerobic	O
conditions	O
to	O
a	O
cell	O
density	O
of	O
5	O
x	O
107	O
cells	O
ml	O
-	O
1	O
.	O

The	O
culture	O
was	O
split	O
into	O
500	O
ml	O
aliquots	O
,	O
the	O
first	O
was	O
treated	O
with	O
1	O
mM	O
t	O
-	O
butyl	O
hydroperoxide	O
,	O
the	O
second	O
with	O
0	O
.	O
25	O
mg	O
of	O
lipoxidase	O
(	O
17	O
700	O
units	O
)	O
and	O
the	O
third	O
was	O
untreated	O
.	O

All	O
cultures	O
were	O
incubated	O
for	O
12	O
h	O
at	O
34	O
degrees	O
C	O
.	O

Cells	O
were	O
harvested	O
by	O
centrifugation	O
(	O
5000	O
g	O
,	O
4	O
degrees	O
C	O
,	O
15	O
min	O
)	O
and	O
washed	O
three	O
times	O
with	O
HN	O
buffer	O
.	O

The	O
fatty	O
acids	O
present	O
in	O
the	O
cell	O
pellets	O
were	O
analysed	O
by	O
FAME	O
gas	O
chromatography	O
(	O
Industrial	O
Laboratory	O
,	O
Wheat	O
Ridge	O
,	O
CO	O
)	O
.	O

Fatty	O
acids	O
were	O
reported	O
as	O
percentage	O
of	O
total	O
cell	O
mass	O
.	O

Measurement	O
of	O
MDA	O

Borrelia	B
burgdorferi	I
strain	O
B31A3	O
was	O
grown	O
aerobically	O
,	O
microaerobically	O
and	O
anaerobically	O
as	O
described	O
above	O
to	O
a	O
cell	O
density	O
of	O
5	O
x	O
107	O
cells	O
ml	O
-	O
1	O
.	O

The	O
microaerobic	O
culture	O
was	O
split	O
and	O
treated	O
with	O
either	O
5	O
mM	O
AAPH	O
[	O
2	O
,	O
2	O
'	O
-	O
azobis	O
(	O
2	O
-	O
methylpropionamidine	O
)	O
dihydrochloride	O
]	O
or	O
250	O
mg	O
of	O
lipoxidase	O
for	O
4	O
h	O
at	O
34	O
degrees	O
C	O
.	O

To	O
measure	O
the	O
amount	O
of	O
MDA	O
,	O
the	O
cells	O
were	O
derivatized	O
with	O
thiobarbituric	O
acid	O
and	O
analysed	O
by	O
HPLC	O
as	O
described	O
by	O
Seljeskog	O
et	O
al	O
.	O

(	O
2006	O
)	O
.	O

After	O
the	O
incubation	O
,	O
all	O
cells	O
were	O
harvested	O
by	O
centrifugation	O
(	O
1000	O
g	O
,	O
5	O
min	O
,	O
4	O
degrees	O
C	O
)	O
and	O
washed	O
three	O
times	O
with	O
HN	O
buffer	O
.	O

Each	O
sample	O
was	O
resuspended	O
in	O
50	O
micro	O
l	O
of	O
HN	O
,	O
mixed	O
with	O
150	O
micro	O
l	O
of	O
0	O
.	O
1	O
N	O
perchloric	O
acid	O
,	O
150	O
micro	O
l	O
of	O
40	O
mM	O
thiobarbituric	O
acid	O
and	O
35	O
micro	O
l	O
of	O
20	O
%	O
SDS	O
,	O
vortexed	O
and	O
heated	O
at	O
97	O
degrees	O
C	O
for	O
60	O
min	O
.	O

After	O
cooling	O
at	O
-	O
20	O
degrees	O
C	O
for	O
20	O
min	O
,	O
300	O
micro	O
l	O
of	O
methanol	O
and	O
100	O
micro	O
l	O
of	O
20	O
%	O
trichloroacetic	O
acid	O
was	O
added	O
and	O
the	O
samples	O
were	O
mixed	O
vigorously	O
and	O
centrifuged	O
(	O
13	O
000	O
g	O
,	O
6	O
min	O
)	O
.	O

The	O
samples	O
(	O
10	O
micro	O
l	O
)	O
were	O
then	O
analysed	O
with	O
an	O
Agilent	O
Technologies	O
1200	O
series	O
HPLC	O
system	O
using	O
a	O
C18	O
4	O
.	O
6	O
x	O
150	O
mm	O
column	O
with	O
mobile	O
phase	O
72	O
:	O
17	O
:	O
11	O
(	O
50	O
mM	O
KPO4	O
,	O
pH	O
6	O
.	O
8	O
:	O
methanol	O
:	O
acetonitrile	O
)	O
.	O

Absorbance	O
was	O
monitored	O
at	O
532	O
nm	O
.	O

Pure	O
MDA	O
standards	O
(	O
0	O
-	O
10	O
micro	O
M	O
)	O
were	O
prepared	O
in	O
methanol	O
for	O
comparison	O
.	O

As	O
a	O
negative	O
control	O
,	O
E	B
.	I
coli	I
Top10	O
cells	O
were	O
grown	O
to	O
OD600	O
of	O
0	O
.	O
4	O
,	O
treated	O
with	O
0	O
or	O
5	O
mM	O
AAPH	O
for	O
30	O
min	O
and	O
MDA	O
measured	O
as	O
above	O
.	O

As	O
a	O
positive	O
control	O
,	O
mouse	B
myeloma	O
SP2	O
/	O
O	O
cells	O
were	O
cultured	O
with	O
HYQ	O
-	O
CCM1	O
(	O
HyClone	O
)	O
medium	O
at	O
37	O
degrees	O
C	O
in	O
a	O
humidified	O
5	O
%	O
CO2	O
atmosphere	O
,	O
treated	O
with	O
1	O
mM	O
AAPH	O
at	O
37	O
degrees	O
C	O
for	O
4	O
h	O
(	O
Chotimarkorn	O
et	O
al	O
.	O
,	O
2005	O
)	O
and	O
MDA	O
measured	O
as	O
above	O
.	O

Identification	O
of	O
lipid	O
damage	O
using	O
Diphenyl	O
-	O
1	O
-	O
pyrenylphosphine	O
fluorescent	O
stain	O

Borrelia	B
burgdorferi	I
strain	O
B31A3	O
cells	O
were	O
grown	O
microaerobically	O
as	O
described	O
above	O
until	O
a	O
cell	O
density	O
of	O
5	O
x	O
107	O
cells	O
ml	O
-	O
1	O
was	O
obtained	O
.	O

The	O
culture	O
was	O
divided	O
into	O
two	O
equal	O
aliquots	O
and	O
the	O
cells	O
treated	O
with	O
5	O
mM	O
AAPH	O
for	O
4	O
h	O
at	O
34	O
degrees	O
C	O
.	O

After	O
the	O
incubation	O
,	O
all	O
cells	O
were	O
harvested	O
by	O
centrifugation	O
(	O
1000	O
g	O
,	O
5	O
min	O
,	O
4	O
degrees	O
C	O
)	O
and	O
washed	O
three	O
times	O
with	O
HN	O
buffer	O
.	O

To	O
visualize	O
Borrelia	O
cells	O
,	O
the	O
cells	O
were	O
stained	O
with	O
PKH26	O
Red	O
Fluorescent	O
Cell	O
Linker	O
Dye	O
(	O
Sigma	O
Aldrich	O
)	O
following	O
the	O
manufacturer	O
'	O
s	O
protocol	O
.	O

To	O
visualize	O
the	O
lipid	O
hydroperoxides	O
in	O
the	O
cell	O
membrane	O
,	O
the	O
cells	O
were	O
counterstained	O
with	O
DPPP	O
(	O
Cayman	O
Chemicals	O
,	O
MI	O
)	O
(	O
Okimoto	O
et	O
al	O
.	O
,	O
2000	O
)	O
.	O

Briefly	O
,	O
after	O
cells	O
were	O
stained	O
with	O
the	O
Red	O
Fluorescent	O
dye	O
,	O
2	O
ml	O
of	O
rabbit	B
serum	O
was	O
added	O
to	O
stop	O
the	O
reaction	O
and	O
the	O
mixture	O
incubated	O
for	O
1	O
min	O
at	O
RT	O
.	O

Next	O
,	O
4	O
ml	O
of	O
HN	O
buffer	O
was	O
added	O
,	O
the	O
cells	O
harvested	O
by	O
centrifugation	O
(	O
1000	O
g	O
,	O
10	O
min	O
,	O
RT	O
)	O
and	O
washed	O
three	O
times	O
with	O
HN	O
buffer	O
.	O

The	O
cells	O
were	O
then	O
resuspended	O
in	O
1	O
ml	O
of	O
HN	O
buffer	O
,	O
incubated	O
at	O
34	O
degrees	O
C	O
for	O
5	O
min	O
and	O
30	O
micro	O
l	O
of	O
2	O
.	O
5	O
mM	O
DPPP	O
was	O
added	O
.	O

The	O
incubation	O
was	O
then	O
continued	O
at	O
34	O
degrees	O
C	O
for	O
5	O
min	O
in	O
the	O
dark	O
.	O

After	O
incubation	O
,	O
the	O
mixture	O
was	O
centrifuged	O
(	O
1000	O
g	O
,	O
10	O
min	O
,	O
RT	O
)	O
and	O
the	O
cells	O
washed	O
three	O
times	O
with	O
HN	O
buffer	O
.	O

The	O
cells	O
were	O
then	O
resuspended	O
in	O
100	O
micro	O
l	O
HN	O
buffer	O
and	O
observed	O
by	O
fluorescence	O
microscopy	O
with	O
excitation	O
wavelengths	O
551	O
nm	O
(	O
Red	O
Fluorescent	O
)	O
and	O
351	O
nm	O
(	O
DPPP	O
)	O
,	O
and	O
emission	O
wavelengths	O
567	O
nm	O
(	O
Red	O
Fluorescent	O
)	O
and	O
380	O
nm	O
(	O
DPPP	O
)	O
.	O

As	O
a	O
positive	O
control	O
,	O
mouse	B
myeloma	O
SP2	O
/	O
O	O
cells	O
were	O
cultured	O
with	O
HYQ	O
-	O
CCM1	O
(	O
HyClone	O
)	O
medium	O
at	O
37	O
degrees	O
C	O
in	O
a	O
humidified	O
5	O
%	O
CO2	O
atmosphere	O
,	O
treated	O
with	O
1	O
mM	O
AAPH	O
at	O
37	O
degrees	O
C	O
for	O
4	O
h	O
(	O
Chotimarkorn	O
et	O
al	O
.	O
,	O
2005	O
)	O
and	O
stained	O
as	O
described	O
above	O
.	O

As	O
a	O
negative	O
control	O
,	O
E	B
.	I
coli	I
Top10	O
cells	O
were	O
grown	O
to	O
OD600	O
of	O
0	O
.	O
4	O
,	O
treated	O
with	O
0	O
or	O
5	O
mM	O
AAPH	O
for	O
30	O
min	O
and	O
stained	O
as	O
described	O
above	O
.	O

Electron	O
microscopy	O

Borrelia	B
burgdorferi	I
cells	O
were	O
grown	O
under	O
microaerobic	O
or	O
anaerobic	O
conditions	O
to	O
a	O
cell	O
density	O
of	O
5	O
x	O
107	O
cells	O
ml	O
-	O
1	O
.	O

The	O
microaerobic	O
cultures	O
were	O
split	O
and	O
treated	O
with	O
lipoxidase	O
for	O
4	O
h	O
at	O
34	O
degrees	O
C	O
.	O

Cells	O
were	O
harvested	O
by	O
centrifugation	O
(	O
5000	O
g	O
,	O
10	O
min	O
,	O
4	O
degrees	O
C	O
)	O
,	O
washed	O
and	O
resuspended	O
in	O
HBSS	O
(	O
Lonza	O
Group	O
Ltd	O
,	O
Switzerland	O
)	O
.	O

The	O
cells	O
were	O
fixed	O
with	O
Karnovsky	O
'	O
s	O
phosphate	O
for	O
5	O
min	O
at	O
RT	O
adsorbed	O
to	O
Formvar	O
/	O
carbon	O
-	O
coated	O
grids	O
(	O
Ted	O
Pella	O
,	O
Redding	O
,	O
CA	O
)	O
for	O
5	O
min	O
and	O
washed	O
three	O
times	O
in	O
H2O	O
.	O

The	O
grids	O
were	O
stained	O
with	O
1	O
%	O
ammonium	O
molybdate	O
and	O
allowed	O
to	O
air	O
-	O
dry	O
.	O

Samples	O
were	O
examined	O
using	O
a	O
Hitachi	O
H7500	O
electron	O
microscope	O
(	O
Hitachi	O
High	O
Technologies	O
America	O
,	O
Pleasanton	O
,	O
CA	O
)	O
.	O

Cytotoxic	O
Activity	O
of	O
Silyl	O
-	O
and	O
Germyl	O
-	O
Substituted	O
4	O
,	O
4	O
-	O
Dioxo	O
-	O
3a	O
,	O
6a	O
-	O
Dihydrothieno	O
[	O
2	O
,	O
3	O
-	O
d	O
]	O
isoxazolines	O
-	O
2	O

Abstract	O

The	O
[	O
2	O
+	O
3	O
]	O
dipolar	O
cycloaddition	O
of	O
nitrile	O
oxides	O
to	O
the	O
double	O
C	O
=	O
C	O
bonds	O
of	O
thiophene	O
-	O
1	O
,	O
1	O
-	O
dioxides	O
leads	O
to	O
formation	O
of	O
the	O
fused	O
isoxazolines	O
-	O
2	O
(	O
1	O
,	O
2	O
)	O
.	O

Tumor	O
growth	O
inhibition	O
of	O
these	O
compounds	O
strongly	O
depends	O
on	O
the	O
nature	O
of	O
group	O
IV	O
A	O
element	O
increasing	O
from	O
slightly	O
active	O
tert	O
-	O
butyl	O
derivatives	O
to	O
silicon	O
and	O
germanium	O
containing	O
analogues	O
.	O

The	O
products	O
of	O
benzonitrile	O
oxide	O
cycloaddition	O
have	O
greater	O
cytotoxic	O
effect	O
than	O
the	O
compounds	O
obtained	O
from	O
the	O
cycloaddition	O
reaction	O
of	O
2	O
,	O
5	O
-	O
disubstituted	O
thiophene	O
-	O
1	O
,	O
1	O
-	O
dioxides	O
with	O
acetonitrile	O
oxide	O
.	O

Fused	O
silyl	O
substituted	O
isoxazolines	O
-	O
2	O
are	O
stronger	O
NO	O
-	O
inducers	O
than	O
their	O
germyl	O
and	O
tert	O
-	O
butyl	O
analogues	O
.	O

CYTOTOXIC	O
ACTIVITY	O
OF	O
SILYL	O
-	O
AND	O
GERMYL	O
-	O
SUBSTITUTED	O
4	O
,	O
4	O
-	O
DIOXO	O
-	O
3a	O
,	O
6a	O
-	O
DIHYDROTHIENO	O
[	O
2	O
,	O
3	O
-	O
d	O
]	O
ISOXAZOLINES	O
-	O
2	O

E	O
.	O

Lukevics	O
*	O
,	O
P	O
.	O

Arsenyan	O
,	O
I	O
.	O

Shestakova	O
,	O
O	O
.	O

Zharkova	O
,	O
I	O
.	O

Kanepe	O
,	O
R	O
.	O

Mezapuke	O
,	O
and	O
O	O
.	O

Pudova	O
Latvian	O
Institute	O
of	O
Organic	O
Synthesis	O
,	O
Aizkraukles	O
21	O
,	O
Riga	O
,	O
LV	O
-	O
1006	O
,	O
Latvia	O

ABSTRACT	O
The	O
[	O
2	O
+	O
3	O
]	O
dipolar	O
cycloaddition	O
of	O
nitrile	O
oxides	O
to	O
the	O
double	O
(	O
3	O
=	O
(	O
3	O
bonds	O
of	O
thiophene	O
-	O
l	O
,	O
l	O
-	O
dioides	O
leads	O
to	O
formation	O
of	O
the	O
fused	O
isoxazolines	O
-	O
2	O
(	O
1	O
,	O
2	O
)	O
.	O

Tumor	O
growth	O
inhibition	O
of	O
these	O
compounds	O
strongly	O
depends	O
on	O
the	O
nature	O
of	O
group	O
IV	O
A	O
element	O
increasing	O
from	O
slightly	O
active	O
ert	O
-	O
butyl	O
derivatives	O
to	O
silicon	O
and	O
germanium	O
containing	O
analogues	O
.	O

The	O
products	O
of	O
benzonitdle	O
oxide	O
cycloaddition	O
have	O
greater	O
cytotoic	O
effect	O
than	O
the	O
compounds	O
obtained	O
from	O
he	O
cycloaddition	O
reaction	O
of	O
2	O
,	O
5	O
-	O
disubstituted	O
thiophene	O
-	O
l	O
,	O
l	O
-	O
dioxides	O
with	O
acetonitrile	O
oxide	O
.	O

Fused	O
silyl	O
substituted	O
isoxazolines	O
-	O
2	O
are	O
stronger	O
NO	O
-	O
inducers	O
than	O
their	O
germyl	O
and	O
tert	O
-	O
butyl	O
analogues	O
.	O

INTRODUCTION	O
The	O
interest	O
in	O
silyl	O
substituted	O
thiophene	O
-	O
l	O
,	O
l	O
-	O
dioxides	O
stems	O
from	O
the	O
fact	O
that	O
they	O
are	O
useful	O
synthetic	O
intermediates	O
for	O
the	O
preparation	O
of	O
various	O
types	O
of	O
organic	O
compounds	O
by	O
Diels	O
-	O
Alder	O
cycloaddition	O
[	O
1	O
]	O
,	O
amine	O
induced	O
ring	O
-	O
opening	O
reaction	O
[	O
2	O
]	O
,	O
or	O
coupling	O
of	O
bromothiophene	O
-	O
l	O
,	O
l	O
-	O
dioxides	O
with	O
thienyl	O
stannanes	O
in	O
the	O
presence	O
of	O
a	O
palladium	O
(	O
0	O
)	O
catalyst	O
[	O
3	O
]	O
.	O

It	O
has	O
been	O
shown	O
that	O
unsubstituted	O
thiophene	O
-	O
l	O
,	O
l	O
-	O
dioxide	O
prepared	O
in	O
situ	O
is	O
a	O
quite	O
reactive	O
dipolarophile	O
in	O
the	O
[	O
2	O
+	O
3	O
]	O
cycloaddition	O
reactions	O
with	O
N	O
,	O
o	O
-	O
diphenylnitrone	O
[	O
4	O
]	O
,	O
benzonitrile	O
[	O
4	O
,	O
5	O
]	O
and	O
mesitonitrile	O
[	O
4	O
,	O
5	O
]	O
oxides	O
yielding	O
mono	O
-	O
and	O
diisoxazolines	O
-	O
2	O
and	O
N	O
-	O
substituted	O
isoxazolidines	O
.	O

Moreover	O
,	O
our	O
recent	O
studies	O
indicate	O
that	O
silyl	O
-	O
and	O
germylcontaining	O
isoxazolines	O
have	O
gained	O
a	O
great	O
deal	O
of	O
attention	O
as	O
compounds	O
possessing	O
a	O
wide	O
spectrum	O
of	O
the	O
biological	O
properties	O
.	O

The	O
vasodilating	O
,	O
anticoagulant	O
and	O
cardioprotective	O
activity	O
of	O
5	O
-	O
Si	O
-	O
(	O
Ge	O
)	O
substituted	O
isoxazolines	O
-	O
2	O
has	O
been	O
studied	O
in	O
vitro	O
and	O
in	O
vivo	O
[	O
6	O
,	O
7	O
]	O
.	O

The	O
most	O
active	O
isoxazoline	O
-	O
3	O
-	O
(	O
5	O
"	O
-	O
triethylgermyl	O
-	O
3	O
"	O
-	O
isoxazolino	O
)	O
pyridine	O
hydrochloride	O
protected	O
the	O
heart	O
from	O
rhythm	O
disturbances	O
and	O
lethality	O
during	O
ischemiareperfusion	O
[	O
7	O
]	O
.	O

It	O
has	O
been	O
shown	O
that	O
silylisoxazolines	O
-	O
2	O
are	O
more	O
potent	O
in	O
protection	O
against	O
hypoxia	O
and	O
corazole	O
convulsions	O
than	O
germanium	O
analogues	O
.	O

However	O
,	O
germylisoxazolines	O
-	O
2	O
are	O
stronger	O
tumor	O
growth	O
inhibitors	O
and	O
NO	O
-	O
inducers	O
than	O
their	O
silicon	O
analogue	O
[	O
8	O
]	O
.	O

This	O
work	O
presents	O
the	O
results	O
of	O
cytotoxic	O
activity	O
for	O
fused	O
isoxazolines	O
-	O
2	O
bearing	O
a	O
group	O
14	O
element	O
as	O
substituent	O
(	O
1	O
,	O
2	O
)	O
in	O
function	O
of	O
the	O
nature	O
of	O
the	O
group	O
14	O
element	O
.	O

M	O

e3M	O
.	O
CH3	O
N	O

-	O
0	O
\	O
R	O

O	O
\	O
M	O

e3M	O
S	O

N	O

02	O

02	O
2	O

1	O

MATERIALS	O
AND	O
METHODS	O
CHEMISTRY	O
Seven	O
tert	O
-	O
butyl	O
-	O
,	O
trimethylsilyl	O
-	O
,	O
and	O
trimethylgermyl	O
-	O
substituted	O
4	O
,	O
4	O
-	O
dioxo	O
-	O
3a	O
,	O
6adihydrothieno	O
[	O
2	O
,	O
3	O
-	O
d	O
]	O
isoxazoline	O
-	O
2	O
1	O
and	O
2	O
(	O
Table	O
1	O
)	O
were	O
prepared	O
by	O
the	O
[	O
2	O
+	O
3	O
]	O
dipolar	O
63	O

Vol	O
.	O

7	O
,	O
No	O
.	O
2	O
,	O
2000	O

Cytotoxic	O
Activity	O
ofSilyl	O
-	O
and	O
Germyl	O
-	O
Substituted	O
4	O
,	O
4	O
-	O
dioxo	O
-	O
3a	O
,	O
6a	O
-	O
Dihydrothieno	O
[	O
2	O
,	O
3	O
-	O
d	O
]	O
Isoxazolines	O
-	O
2	O

cycloaddition	O
of	O
aceto	O
-	O
and	O
benzonitrile	O
oxides	O
to	O
2	O
,	O
5	O
-	O
disubstituted	O
thiophene	O
-	O
l	O
,	O
l	O
-	O
dioxides	O
.	O

Their	O
synthesis	O
and	O
characterization	O
are	O
given	O
in	O
ref	O
.	O

[	O
9	O
]	O
.	O

_	O
,	O
,	O
/	O
0	O
\	O
N	O
Me3M	O
M	O
'	O
Me3	O

Me3M	O

02	O
M	O
,	O
M	O
'	O
=	O
C	O
,	O
Si	O
,	O
Ge	O
;	O
R	O
=	O
Me	O
,	O
Ph	O
;	O
R	O
'	O
=	O
H	O
,	O
Me3Ge	O
Table	O
1	O
.	O

Me3C	O
,	O
MeSi	O
,	O
Investigated	O
dihydrothieno	O
[	O
2	O
,	O
3	O
-	O
d	O
]	O
isoxazolines	O
-	O
2	O

02	O
Me3Ge	O
substituted	O

%	O
,	O
\	O
R	O
4	O
,	O
4	O
-	O
dioxo	O
-	O
3a	O
,	O
6a	O

Compound	O

'	O
Type	O
la	O

M	O

R	O
H	O
Me3Ge	O
Me3Ge	O

Yield	O

4	O
,	O
4	O
-	O
dioxo	O
-	O
3	O
methyl	O
"	O
5	O
-	O
tert	O
-	O
butyl	O
-	O
3a	O
,	O
6adihydrothieno	O
[	O
2	O
,	O
3	O
-	O
d	O
]	O
isoxazoline	O
-	O
2	O

(	O
3	O
'	O
C	O
Si	O

(	O
%	O
)	O
80	O

4	O
,	O
4	O
-	O
dioxo	O
-	O
3	O
-	O
methyl	O
-	O
3a	O
-	O
trimethylgermyl	O
-	O
5	O
-	O
tert	O
-	O
butyl3a	O
,	O
6a	O
-	O
d	O
ihyd	O
rothieno	O
[	O
2	O
,	O
3	O
-	O
d	O
]	O
isoxazoli	O
ne	O
-	O
2	O
4	O
,	O
4	O
-	O
dioxo	O
-	O
3	O
-	O
methyl	O
-	O
3a	O
-	O
trimethyigermyl	O
-	O
5tri	O
methylsilyl	O
-	O
3a	O
,	O
6a	O
-	O
d	O
hyd	O
roth	O
ien	O
o	O
[	O
2	O
,	O
3d	O
]	O
isoxazoline	O
-	O
2	O
4	O
,	O
4	O
-	O
d	O
io	O
x	O
o	O
-	O
3	O
-	O
meth	O
y	O
I	O
-	O
3a	O
,	O
5	O
-	O
b	O
s	O
tri	O
m	O
ethy	O
Ig	O
e	O
rmy	O
I	O
)	O
3a	O
,	O
6a	O
-	O
d	O
hyd	O
rothieno	O
[	O
2	O
,	O
3	O
-	O
d	O
]	O
isoxazo	O
ne	O
-	O
2	O
4	O
,	O
4	O
-	O
d	O
ioxo	O
-	O
3	O
-	O
ph	O
en	O
y	O
I	O
-	O
5	O
-	O
tert	O
-	O
b	O
uty	O
I	O
-	O
3a	O
,	O
6adihydrothieno	O
[	O
2	O
,	O
3	O
-	O
d	O
]	O
isoxazoline	O
-	O
2	O
4	O
,	O
4	O
-	O
d	O
ioxo	O
-	O
3	O
-	O
p	O
h	O
e	O
ny	O
I	O
-	O
5	O
-	O
tri	O
meth	O
y	O
si	O
ly	O
I	O
-	O
3a	O
,	O
6adihydrothieno	O
[	O
2	O
,	O
3	O
-	O
d	O
]	O
isoxazoline	O
-	O
2	O
4	O
,	O
4	O
-	O
d	O
ioxo	O
-	O
3	O
-	O
p	O
h	O
e	O
n	O
y	O
I	O
-	O
5	O
-	O
tri	O
methy	O
Ig	O
e	O
rmy	O
I	O
-	O
3a	O
,	O
6adi	O
,	O
hydr0thieno	O
[	O
2	O
,	O
3	O
,	O
d	O
]	O
isoxazoline	O
-	O
2	O

lb	O
lc	O

58	O
45	O
67	O
84	O

ld	O
2a	O
2b	O

Ge	O

Me3Ge	O

C	O
Si	O

77	O
85	O

2c	O

Ge	O

IN	O
VITRO	O
CYTOTOXITY	O
ASSAY	O
Monolayer	O
cells	O
lines	O
were	O
cultivated	O
for	O
72	O
h	O
in	O
DMEM	O
standard	O
medium	O
without	O
an	O
indicator	O
and	O
antibiotics	O
.	O

After	O
the	O
ampoule	O
was	O
defreezed	O
not	O
more	O
than	O
four	O
passa4ges	O
were	O
performed	O
.	O

The	O
control	O
cells	O
and	O
cells	O
with	O
tested	O
substances	O
in	O
the	O
range	O
of	O
2	O
-	O
5	O
10	O
cell	O
/	O
mL	O
concentration	O
(	O
depending	O
on	O
line	O
nature	O
)	O
were	O
placed	O
on	O
a	O
separate	O
96	O
wells	O
plates	O
.	O

Solutions	O
containing	O
test	O
compounds	O
were	O
diluted	O
and	O
added	O
in	O
wells	O
to	O
give	O
the	O
final	O
concentrations	O
of	O
50	O
,	O
25	O
,	O
12	O
.	O
5	O
,	O
and	O
6	O
.	O
25	O
#	O
g	O
/	O
mL	O
Control	O
cells	O
were	O
treated	O
in	O
the	O
same	O
manner	O
only	O
in	O
the	O
absence	O
of	O
test	O
compounds	O
.	O

Plates	O
were	O
cultivated	O
for	O
72	O
h	O
.	O

A	O
quantity	O
of	O
survived	O
cells	O
was	O
determined	O
using	O
crystal	O
violet	O
(	O
CV	O
)	O
or	O
3	O
-	O
(	O
4	O
,	O
5	O
-	O
dimethylthiazol	O
-	O
2	O
-	O
yl	O
)	O
-	O
2	O
,	O
5diphenyltetrazolini	O
bromide	O
(	O
MTT	O
)	O
coloration	O
which	O
was	O
assayed	O
by	O
multiscan	O
spectrofotometer	O
.	O

The	O
quantity	O
of	O
alive	O
cells	O
on	O
control	O
plate	O
was	O
taken	O
in	O
calculations	O
for	O
100	O
%	O
[	O
10	O
,	O
11	O
]	O
.	O

Concentration	O
of	O
NO	O
was	O
determined	O
according	O
to	O
[	O
10	O
]	O
.	O

RESULTS	O
AND	O
DISCUSSION	O
Potential	O
cytotoxic	O
activity	O
of	O
synthesized	O
fused	O
isoxazolines	O
1	O
and	O
2	O
was	O
tested	O
in	O
vitro	O
on	O
four	O
monolayer	O
tumor	O
cell	O
lines	O
:	O
MG	O
-	O
22A	O
(	O
mouse	B
hepatoma	O
)	O
,	O
HT	O
-	O
1080	O
(	O
human	B
fibroblastoma	O
)	O
,	O
B16	O
(	O
mouse	B
melanoma	O
)	O
,	O
Neuro	O
2A	O
(	O
mouse	B
neiroblastoma	O
)	O
.	O

Concentrations	O
providing	O
50	O
%	O
of	O
tumor	O
death	O
effect	O
were	O
determined	O
according	O
to	O
the	O
known	O
procedure	O
[	O
12	O
]	O
using	O
96	O
well	O
plates	O
.	O

The	O
experimental	O
evaluation	O
of	O
cytotoxicity	O
properties	O
is	O
presented	O
in	O
Table	O
2	O
.	O

A	O
preliminary	O
analysis	O
of	O
the	O
structure	O
-	O
activity	O
relationship	O
for	O
the	O
cytotoxic	O
action	O
clearly	O
indicates	O
the	O
strong	O
influence	O
of	O
the	O
MeM	O
(	O
M	O
=	O
C	O
,	O
Si	O
,	O
Ge	O
)	O
group	O
in	O
position	O
5	O
of	O
fused	O
isoxazolines	O
1	O
and	O
2	O
.	O

Derivatives	O
bearing	O
tert	O
-	O
butyl	O
substituent	O
(	O
la	O
,	O
b	O
and	O
2a	O
)	O
have	O
a	O
slight	O
cytotoxic	O
effect	O
(	O
>	O
10	O
#	O
g	O
/	O
mL	O
)	O
.	O

The	O
substitution	O
of	O
the	O
tert	O
-	O
butyl	O
group	O
by	O
trimethylsilyl	O
or	O
64	O

E	O
.	O

Lukevics	O
et	O
al	O
.	O

Metal	O
-	O
Based	O
Drugs	O

A	O

oO	O

{	O
D	O

0	O

0	O

65	O

Vol	O
.	O

7	O
,	O
No	O
.	O
2	O
,	O
2000	O

Cytotoxic	O
Activity	O
ofSilyl	O
-	O
and	O
Germyl	O
-	O
Substituted	O
4	O
,	O
4	O
-	O
dioxo	O
-	O
3a	O
,	O
6a	O
-	O
Dihydrothieno	O
[	O
2	O
,	O
3	O
-	O
d	O
]	O
Isoxazolines	O
-	O
2	O

trimethylgermyl	O
ones	O
leads	O
to	O
considerable	O
increase	O
of	O
cytotoxicity	O
.	O

It	O
must	O
be	O
noted	O
that	O
the	O
activity	O
of	O
silicon	O
-	O
and	O
germanium	O
-	O
containing	O
compounds	O
(	O
1	O
and	O
l	O
d	O
)	O
depends	O
on	O
the	O
tumor	O
type	O
.	O

5	O
-	O
Trimethylsilyl	O
-	O
substituted	O
fused	O
isoxazoline	O
le	O
is	O
more	O
active	O
than	O
the	O
germanium	O
analogue	O
l	O
d	O
in	O
tests	O
on	O
HP	O
-	O
1080	O
and	O
MG	O
-	O
22A	O
cell	O
lines	O
.	O

However	O
,	O
the	O
germanium	O
compound	O
ld	O
has	O
greater	O
cytotoxic	O
effect	O
on	O
Neuro	O
2A	O
and	O
B16	O
cell	O
lines	O
than	O
the	O
silicon	O
derivative	O
lc	O
.	O

Comparison	O
of	O
the	O
tumor	O
growth	O
inhibition	O
for	O
derivatives	O
1	O
and	O
2	O
shows	O
a	O
higher	O
activity	O
of	O
the	O
condensed	O
isoxazolines	O
2	O
containing	O
a	O
phenyl	O
group	O
in	O
position	O
3	O
with	O
respect	O
to	O
4	O
,	O
4	O
-	O
dioxo	O
-	O
3	O
-	O
methyl	O
-	O
3a	O
-	O
trimethylgermyl	O
-	O
5	O
-	O
MeM	O
-	O
3a	O
,	O
6a	O
-	O
dihyd	O
rothieno	O
[	O
2	O
,	O
3d	O
]	O
isoxazolines	O
l	O
b	O
-	O
d	O
.	O

Silyl	O
-	O
and	O
germyl	O
-	O
substituted	O
fused	O
isoxazolines	O
have	O
a	O
medium	O
NOinduction	O
ability	O
,	O
4	O
,	O
4	O
-	O
dioxo	O
-	O
3	O
-	O
phenyl	O
-	O
5	O
-	O
trimethylsilyl	O
-	O
3a	O
,	O
6a	O
-	O
dihydrothieno	O
[	O
2	O
,	O
3	O
-	O
d	O
]	O
isoxazoline	O
-	O
2	O
(	O
2b	O
)	O
being	O
the	O
most	O
active	O
(	O
250	O
%	O
in	O
the	O
MG	O
-	O
22A	O
test	O
)	O
.	O

ACKNOWLEGMENT	O
We	O
are	O
grateful	O
to	O
Latvian	O
Taiho	O
Foundation	O
for	O
financial	O
support	O
.	O

REFERENCES	O
1	O
.	O

A	O
.	O

R	O
.	O

M	O
.	O

Donovan	O
,	O
M	O
.	O

K	O
.	O

Shepherd	O
,	O
Tetrahedron	O
Lett	O
.	O
,	O
35	O
(	O
1994	O
)	O
4425	O
.	O

2	O
.	O

S	O
.	O

Gronowitz	O
,	O
A	O
.	O
-	O
B	O
.	O

H0rnfeldt	O
,	O
E	O
.	O

Lukevics	O
,	O
O	O
.	O

Pudova	O
,	O
Synthesis	O
,	O
(	O
1994	O
)	O
40	O
.	O

3	O
.	O

G	O
.	O

Barbarella	O
,	O
L	O
.	O

Favaretto	O
,	O
G	O
.	O

Sotgiu	O
,	O
M	O
.	O

Zambianchi	O
,	O
L	O
.	O

Antolini	O
,	O
O	O
.	O

Pudova	O
,	O
A	O
.	O

Bongini	O
,	O
J	O
.	O

Org	O
.	O

Chem	O
.	O
,	O
63	O
(	O
1998	O
)	O
5497	O
.	O

4	O
.	O

A	O
.	O

Bened	O
,	O
R	O
.	O

Durand	O
,	O
D	O
.	O

Pioch	O
,	O
P	O
.	O

Geneste	O
,	O
J	O
.	O

P	O
.	O

Declerq	O
,	O
G	O
.	O

Germain	O
,	O
J	O
.	O

Rambaud	O
,	O
R	O
.	O

Roques	O
,	O
J	O
.	O

Org	O
.	O

Chem	O
.	O
,	O
46	O
(	O
1981	O
)	O
3502	O
.	O

5	O
.	O

F	O
.	O

M	O
.	O

Albini	O
,	O
P	O
.	O

Ceva	O
,	O
A	O
.	O

Mascherpa	O
,	O
E	O
.	O

Albini	O
,	O
P	O
.	O

Caramella	O
,	O
Tetrahedron	O
,	O
38	O
(	O
1982	O
)	O

6	O
.	O

7	O
.	O

8	O
.	O

9	O
.	O

10	O
.	O

11	O
.	O

12	O
.	O

3629	O
.	O

E	O
.	O

Lukevics	O
,	O
M	O
.	O

Veveris	O
,	O
V	O
.	O

Dirnens	O
,	O
Appl	O
.	O

Organomet	O
.	O

Chem	O
.	O
,	O
11	O
(	O
1997	O
)	O
805	O
.	O

E	O
.	O

Lukevics	O
,	O
P	O
.	O

Arsenyan	O
,	O
M	O
.	O

Veveris	O
,	O
Metal	O
Based	O
Drugs	O
,	O
5	O
(	O
1998	O
)	O
251	O
.	O

E	O
.	O

Lukevics	O
,	O
P	O
.	O

Arsenyan	O
,	O
S	O
.	O

Germane	O
,	O
I	O
.	O

Shestakova	O
,	O
Applied	O
Organomet	O
.	O

Chem	O
.	O
,	O
13	O
(	O
1999	O
)	O
795	O
.	O

E	O
.	O

Lukevics	O
,	O
P	O
.	O

Arsenyan	O
,	O
S	O
.	O

Belyakov	O
,	O
J	O
.	O

Popelis	O
,	O
O	O
.	O

Pudova	O
,	O
Organometallics	O
,	O
18	O
(	O
1999	O
)	O
3187	O
.	O

D	O
.	O
J	O
.	O

Fast	O
,	O
R	O
.	O
C	O
.	O

Lynch	O
,	O
R	O
.	O
W	O
.	O

Leu	O
,	O
J	O
.	O

Leuckocyt	O
.	O

Biol	O
.	O
,	O
52	O
(	O
1992	O
)	O
255	O
.	O

P	O
.	O
J	O
.	O

Freshney	O
,	O
Culture	O
of	O
Animal	O
Cells	O
(	O
A	O
Manual	O
of	O
Basic	O
Technique	O
)	O
,	O
Wiley	O
-	O
Liss	O
,	O
New	O
York	O
,	O
1994	O
,	O
pp	O
.	O

296	O
-	O
297	O
.	O

R	O
.	O

J	O
.	O

Riddell	O
,	O
R	O
.	O

H	O
.	O

Clothier	O
,	O
M	O
.	O

Fd	O
.	O

Balls	O
,	O
Chem	O
.	O

Toxicol	O
.	O
,	O
24	O
(	O
1986	O
)	O
469	O
.	O

Received	O
:	O
January	O
21	O
,	O
2000	O
Accepted	O
:	O
February	O
1	O
,	O
2000	O
Received	O
in	O
revised	O
camera	O
-	O
ready	O
format	O
"	O
February	O
2	O
,	O
2000	O

66	O

IL	O
-	O
5	O
drives	O
eosinophils	O
from	O
bone	O
marrow	O
to	O
blood	O
and	O
tissues	O
in	O
a	O
guinea	B
-	I
pig	I
model	O
of	O
visceral	O
larva	O
migrans	O
syndrome	O

Abstract	O

This	O
study	O
was	O
undertaken	O
to	O
evaluate	O
the	O
role	O
of	O
IL	O
-	O
5	O
in	O
eosinophil	O
migration	O
and	O
in	O
the	O
maintenance	O
of	O
eosinophilia	O
in	O
a	O
guinea	B
-	I
pig	I
model	O
of	O
visceral	O
larva	O
migrans	O
syndrome	O
.	O

The	O
results	O
show	O
that	O
the	O
infection	O
of	O
animals	O
with	O
Toxocara	B
canis	I
induced	O
an	O
early	O
increase	O
in	O
serum	O
IL	O
-	O
5	O
levels	O
that	O
might	O
be	O
essential	O
for	O
eosinophil	O
differentiation	O
and	O
proliferation	O
and	O
for	O
the	O
development	O
of	O
eosinophilia	O
.	O

When	O
infected	O
guinea	B
-	I
pigs	I
were	O
treated	O
with	O
mAb	O
anti	O
-	O
IL	O
-	O
5	O
(	O
TRFK	O
-	O
5	O
)	O
given	O
at	O
the	O
same	O
time	O
or	O
1	O
or	O
3	O
days	O
after	O
infection	O
,	O
there	O
was	O
a	O
high	O
percentage	O
of	O
reduction	O
of	O
eosinophil	O
counts	O
18	O
days	O
after	O
infection	O
.	O

However	O
,	O
when	O
the	O
mAb	O
was	O
administered	O
during	O
the	O
peak	O
of	O
eosinophilia	O
,	O
there	O
was	O
high	O
inhibition	O
in	O
blood	O
,	O
no	O
inhibition	O
in	O
bronchoalveolar	O
lavage	O
fluid	O
(	O
BALF	O
)	O
or	O
peritoneum	O
and	O
an	O
increase	O
in	O
eosinophil	O
numbers	O
in	O
bone	O
marrow	O
.	O

Thus	O
,	O
a	O
basic	O
level	O
of	O
IL	O
-	O
5	O
may	O
be	O
essential	O
to	O
drive	O
eosinophils	O
from	O
bone	O
marrow	O
to	O
blood	O
and	O
tissues	O
,	O
and	O
for	O
the	O
maintenance	O
of	O
eosinophilia	O
in	O
infected	O
animals	O
.	O

We	O
may	O
also	O
conclude	O
that	O
when	O
eosinophils	O
have	O
already	O
migrated	O
to	O
the	O
lungs	O
,	O
TRFK	O
-	O
5	O
has	O
no	O
power	O
to	O
inhibit	O
eosinophilia	O
,	O
which	O
is	O
also	O
under	O
control	O
of	O
local	O
lung	O
cells	O
producing	O
IL	O
-	O
5	O
.	O

In	O
this	O
way	O
,	O
only	O
one	O
later	O
TRFK	O
-	O
5	O
treatment	O
may	O
not	O
be	O
sufficient	O
to	O
modify	O
the	O
lung	O
parenchyma	O
microenvironment	O
,	O
since	O
T	B
.	I
canis	I
antigens	O
had	O
already	O
stimulated	O
some	O
cell	O
populations	O
to	O
produce	O
IL	O
-	O
5	O
.	O

Research	O
Paper	O
Mediators	O
of	O
Inflammation	O
5	O
,	O
24	O
-	O
31	O
(	O
1996	O
)	O

Tins	O
study	O
was	O
undertaken	O
to	O
evaluate	O
the	O
role	O
of	O
11	O
-	O
5	O
in	O
eosinophil	O
migration	O
and	O
in	O
the	O
maintenance	O
of	O
eosinophilia	O
in	O
a	O
guinea	B
-	I
pig	I
model	O
of	O
visceral	O
larva	O
migrans	O
syndrome	O
.	O

The	O
results	O
show	O
that	O
the	O
infection	O
of	O
animals	O
with	O
Toxocara	B
canis	I
induced	O
an	O
early	O
increase	O
in	O
serum	O
11	O
-	O
5	O
levels	O
that	O
might	O
be	O
essential	O
for	O
eosi	O

IL	O
-	O
5	O
drives	O
eosinophils	O
from	O
bone	O
marrow	O
to	O
blood	O
and	O
tissues	O
in	O
a	O
guinea	B
-	I
pig	I
model	O
of	O
visceral	O
larva	O
migrans	O
syndrome	O
L	O
.	O

H	O
.	O

Faccioli	O
,	O
1	O
"	O
cA	O
V	O
.	O

F	O
.	O

Mokwa	O
,	O
C	O
.	O

L	O
.	O

Silva	O
,	O
G	O
.	O

M	O
.	O

Rocha	O
,	O
J	O
.	O

I	O
.	O

Araujo	O
,	O
M	O
.	O

A	O
.	O

Nahori	O
2	O
and	O
B	O
.	O

B	O
.	O

Vargaftig	O
2	O

nophil	O
differentiation	O
and	O
proliferation	O
and	O
for	O
the	O
development	O
of	O
eosinophilia	O
.	O

When	O
infected	O
guinea	B
-	I
pigs	I
were	O
treated	O
with	O
mAb	O
anti	O
-	O
11	O
-	O
5	O
(	O
TRFK	O
-	O
5	O
)	O
given	O
at	O
the	O
same	O
time	O
or	O
1	O
or	O
3	O
days	O
after	O
infection	O
,	O
there	O
was	O
a	O
high	O
percentage	O
of	O
reduction	O
of	O
eosinophil	O
counts	O
18	O
days	O
after	O
infection	O
.	O

However	O
,	O
when	O
the	O
mAb	O
was	O
administered	O
during	O
the	O
peak	O
of	O
eosinophilia	O
,	O
there	O
was	O
high	O
inhibition	O
in	O
blood	O
,	O
no	O
inhibition	O
in	O
bronchoalveolar	O
lavage	O
fluid	O
(	O
BALF	O
)	O
or	O
peritoneum	O
and	O
an	O
increase	O
in	O
eosinophil	O
numbers	O
in	O
bone	O
marrow	O
.	O

Thus	O
,	O
a	O
basic	O
level	O
of	O
11	O
-	O
5	O
may	O
be	O
essential	O
to	O
drive	O
eosinophils	O
from	O
bone	O
marrow	O
to	O
blood	O
and	O
tissues	O
,	O
and	O
for	O
the	O
maintenance	O
of	O
eosinophilia	O
in	O
infected	O
animals	O
.	O

We	O
may	O
also	O
conclude	O
that	O
when	O
eosinophils	O
have	O
already	O
migrated	O
to	O
the	O
lungs	O
,	O
TRFK	O
-	O
5	O
has	O
no	O
power	O
to	O
inhibit	O
eosinophilia	O
,	O
which	O
is	O
also	O
under	O
control	O
of	O
local	O
lung	O
cells	O
producing	O
11	O
-	O
5	O
.	O

In	O
this	O
way	O
,	O
only	O
one	O
later	O
TRFK	O
-	O
5	O
treatment	O
may	O
not	O
be	O
sufficient	O
to	O
modify	O
the	O
lung	O
parenchyma	O
microenvironment	O
,	O
since	O
T	B
.	I
canis	I
antigens	O
had	O
already	O
stimulated	O
some	O
cell	O
populations	O
to	O
produce	O
11	O
-	O
5	O
.	O

1Department	O
of	O
Parasitology	O
,	O
Microbiology	O
and	O
Immunology	O
,	O
School	O
of	O
Medicine	O
of	O
Ribeir	O
,	O
5o	O
Preto	O
,	O
14049	O
-	O
900	O
,	O
Ribeiro	O
Preto	O
,	O
SP	O
,	O
Brazil	O
.	O

Fax	O
:	O
(	O
+	O
55	O
)	O
16	O
633	O
6631	O
2Unit	O
de	O
Pharmacologie	O
Cellulaire	O
,	O
Unit	O
Associe	O
Institut	O
Pasteur	O
/	O
INSERM	O
n	O
.	O

285	O
,	O
Paris	O
,	O

France	O
.	O

CACorresponding	O
Author	O

Key	O
words	O
:	O
Eosinophil	O
,	O
Eosinophilia	O
by	O
Toxocara	B
canis	I
,	O
IL	O
-	O
5	O
in	O
eosinophilia	O
,	O
Toxocara	B
canis	I

Introduction	O

treatment	O
in	O
mice	B
infected	O
with	O

Eosinophilia	O
has	O
been	O
associated	O
with	O
parasitic	O
diseases	O
,	O
particularly	O
when	O
the	O
parasites	O
invade	O
the	O
tissues	O
or	O
injure	O
the	O
mucosal	O
surfaces	O
.	O

Toxocara	B
canis	I
is	O
an	O
intestinal	O
parasite	O
of	O
dogs	B
,	O
and	O
is	O
the	O
most	O
common	O
aetiologic	O
agent	O
of	O
visceral	O
larva	O
migrans	O
syndrome	O
(	O
VLMS	O
)	O
.	O

In	O
humans	B
,	O
VLMS	O
results	O
from	O
the	O
ingestion	O
of	O
embryonated	O
eggs	O
of	O
T	B
.	I
canis	I
,	O
that	O
eclode	O
in	O
the	O
small	O
intesfine	O
.	O

The	O
infective	O
larvae	O
invade	O
the	O
mucosa	O
,	O
move	O
into	O
the	O
liver	O
via	O
the	O
portal	O
circulation	O
,	O
and	O
from	O
there	O
to	O
the	O
lungs	O
.	O

2	O
Beaver	O
et	O
al	O
.	O
,	O
3	O
who	O
were	O
the	O
first	O
to	O
describe	O
this	O
syndrome	O
,	O
noted	O
the	O
intense	O
eosinophilia	O
which	O
reaches	O
more	O
than	O
90	O
%	O
of	O
total	O
leucocyte	O
counts	O
.	O

However	O
,	O
there	O
are	O
few	O
studies	O
regarding	O
the	O
mechanisms	O
involved	O
in	O
the	O
blood	O
and	O
tissue	O
eosinophilia	O
obseeeed	O
in	O
VLMS	O
.	O

Several	O
investigators	O
have	O
suggested	O
a	O
direct	O
correlation	O
between	O
eosinophilia	O
and	O
interleukin5	O
(	O
IL	O
-	O
5	O
)	O
in	O
human	B
helminth	O
infections4	O
'	O
5	O
and	O
in	O
experimental	O
animal	O
models	O
.	O

67	O
Inhibition	O
of	O
eosinophilia	O
has	O
been	O
demonstrated	O
by	O
anti	O
-	O
IL	O
-	O
5	O
24	O
Mediators	O
of	O
Inflammation	O
Vol	O
5	O

brasiliensis	O
,	O
8	O
$	O
chistosoma	O
mansoni	O
,	O
Toxocara	B
canis7	I
and	O
Heligmosomoidespolyg	B
.	O

1	O
IL	O
-	O
5	O
has	O
also	O
been	O
shown	O
to	O
support	O
the	O
terminal	O
differentiation	O
,	O
proliferation	O
of	O
eosinophil	O
precursors	O
11	O
'	O
12	O
and	O
eosinophil	O
activation	O
.	O

13	O
Although	O
IL	O
-	O
5	O
does	O
not	O
demonstrate	O
eosinophil	O
chemotactic	O
activity	O
in	O
vivo14	O
there	O
is	O
some	O
evidence	O
suggesting	O
that	O
this	O
cytokine	O
may	O
modulate	O
a	O
selective	O
eosinophil	O
accumulation	O
at	O
the	O
site	O
of	O
inflammation	O
.	O

Moreover	O
,	O
Sehmi	O
et	O
a	O
/	O
.	O
15	O
reported	O
that	O
IL	O
-	O
5	O
has	O
a	O
selective	O
priming	O
effect	O
on	O
eosinophil	O
migratory	O
response	O
to	O
nonselective	O
chemoattractant	O
mediators	O
in	O
vitro	O
.	O

Also	O
,	O
Moser	O
et	O
a	O
/	O
.	O

16	O
have	O
demonstrated	O
that	O
in	O
order	O
to	O
acquire	O
the	O
ability	O
to	O
transmigrate	O
,	O
eosinophils	O
must	O
be	O
primed	O
with	O
IL	O
-	O
5	O
,	O
IL	O
-	O
3	O
and	O
GM	O
-	O
CSF	O
.	O

Thus	O
,	O
the	O
involvement	O
of	O
IL	O
-	O
5	O
in	O
eosinophilia	O
is	O
not	O
fully	O
understood	O
.	O

In	O
the	O
present	O
study	O
we	O
have	O
used	O
a	O
guinea	B
-	I
pig	I
model	O
of	O
VLMS	O
to	O
investigate	O
the	O
involvement	O
of	O
IL	O
-	O
5	O
in	O
eosinophil	O
migration	O
and	O
in	O
the	O
maintenance	O
of	O
eosinophilia	O
in	O
blood	O
,	O
bone	O
marrow	O
,	O
lung	O
and	O
peritoneal	O
cavity	O
.	O

(	O
C	O
)	O
1996	O
Rapid	O
Science	O
Publishers	O

Nipostrongylus	O

1996	O

IL	O
-	O
5	O
drives	O
eosinophils	O
in	O
guinea	B
-	I
pig	I

Materials	O
and	O
Methods	O
Animals	O
:	O
Outbred	O
albino	O
weighing	O
300	O
-	O
400g	O
at	O
the	O
ments	O
were	O
obtained	O
from	O
the	O
School	O
of	O
Medicine	O
of	O
versity	O
of	O
So	O
Paulo	O
,	O
Brazil	O
.	O

female	O
guinea	B
-	I
pigs	I
start	O
of	O
the	O
experi	O

were	O
routinely	O
processed	O
,	O
embedded	O
in	O
paraffin	O
,	O
sectioned	O
at	O
4	O
-	O
61	O
.	O
tm	O
,	O
and	O
stained	O
with	O
Chromothope	O
2R	O
and	O
haematoxylin	O
,	O
for	O
examination	O
by	O
light	O
microscopy	O
.	O

Determination	O
oflL	O
-	O
5	O
in	O
serum	O
:	O
The	O
IL	O
-	O
5	O
level	O
in	O
the	O
serum	O
of	O
guinea	B
-	I
pigs	I
was	O
measured	O
using	O
an	O
enzyme	O
-	O
linked	O
immunosorbent	O
assay	O
(	O
ELISA	O
)	O
.	O

Briefly	O
,	O
ELISA	O
plates	O
(	O
96	O
-	O
well	O
Immunoplate	O
MaxiSorp	O
,	O
Nunc	O
,	O
Roskilde	O
,	O
Denmark	O
)	O
were	O
coated	O
with	O
IL	O
-	O
5	O
-	O
specific	O
monoclonal	O
antibody	O
(	O
TRFK	O
-	O
5	O
,	O
5	O
lag	O
/	O
ml	O
in	O
phosphate	O
buffered	O
saline	O
,	O
pH	O
7	O
.	O
4	O
,	O
PBS	O
,	O
100	O
l	O
.	O
tl	O
/	O
well	O
)	O
.	O

After	O
2	O
h	O
of	O
incubation	O
at	O
37C	O
,	O
the	O
wells	O
were	O
washed	O
four	O
times	O
with	O
PBS	O
containing	O
0	O
.	O
1	O
%	O
Tween	O
20	O
(	O
PBS	O
-	O
T	O
)	O
.	O

Then	O
,	O
100	O
btl	O
of	O
samples	O
or	O
recombinant	O
murine	B
IL	O
-	O
5	O
standards	O
(	O
0	O
.	O
15	O
-	O
200ng	O
/	O
ml	O
)	O
in	O
PBS	O
-	O
T	O
and	O
2	O
%	O
BSA	O
(	O
PBSTBSA	O
)	O
were	O
added	O
to	O
each	O
well	O
.	O

After	O
incubation	O
for	O
l	O
h	O
at	O
37C	O
,	O
the	O
wells	O
were	O
washed	O
three	O
times	O
and	O
100	O
l	O
.	O
tl	O
of	O
biotinylated	O
rat	B
anti	O
-	O
murine	B
IL	O
-	O
5	O
(	O
biotinylated	O
-	O
TRFK	O
-	O
5	O
,	O
1	O
lag	O
/	O
ml	O
in	O
PBS	O
-	O
TBSA	O
)	O
was	O
added	O
.	O

After	O
incubation	O
for	O
1	O
h	O
at	O
37C	O
,	O
the	O
wells	O
were	O
washed	O
again	O
three	O
times	O
and	O
100	O
of	O
peroxidase	O
-	O
labelled	O
streptavidin	O
(	O
1	O
/	O
1000	O
,	O
Kirkegaard	O
&	O
Perry	O
Laboratories	O
Inc	O
.	O
,	O
Maryland	O
,	O
USA	O
)	O
were	O
added	O
to	O
each	O
well	O
.	O

Following	O
incubation	O
for	O
l	O
h	O
at	O
37C	O
and	O
further	O
washing	O
,	O
the	O
enzyme	O
was	O
developed	O
using	O
the	O
TMB	O
substrate	O
peroxidase	O
for	O
5	O
min	O
.	O

The	O
reaction	O
was	O
stopped	O
by	O
adding	O
501	O
.	O
tl	O
of	O
2	O
.	O
0	O
N	O
HCl	O
,	O
and	O
the	O
optical	O
densities	O
were	O
read	O
at	O
490nm	O
using	O
an	O
automated	O
plate	O
reader	O
.	O

The	O
sensitivity	O
of	O
the	O
assay	O
was	O
0	O
.	O
15	O
ng	O
/	O
ml	O
and	O
the	O
upper	O
limit	O
100ng	O
/	O
ml	O
.	O

the	O
animal	O
house	O
of	O
Ribeiro	O
Preto	O
,	O
Uni	O

Infection	O
of	O
animals	O
:	O
T	B
.	I
canis	I
eggs	O
were	O
obtained	O
by	O
the	O
methods	O
of	O
Olson	O
and	O
Schulz	O
,	O
17	O
with	O
minor	O
modifications	O
.	O

Briefly	O
,	O
gravid	O
female	O
worms	O
were	O
recovered	O
from	O
dogs	B
,	O
and	O
the	O
eggs	O
were	O
rescued	O
from	O
the	O
uterus	O
,	O
washed	O
and	O
allowed	O
to	O
develop	O
to	O
the	O
infective	O
stage	O
in	O
shallow	O
dishes	O
containing	O
0	O
.	O
5	O
%	O
formalin	O
at	O
37C	O
.	O

Under	O
light	O
ether	O
anaesthesia	O
,	O
the	O
animals	O
were	O
infected	O
with	O
I	O
ml	O
saline	O
containing	O
500	O
T	B
.	I
canis	I
eggs	O
,	O
by	O
gastric	O
intubation	O
using	O
a	O
metal	O
cannula	O
.	O

Blood	O
cell	O
counts	O
:	O
Guinea	B
-	I
pigs	I
were	O
anaesthetized	O
with	O
sodium	O
pentobarbitone	O
(	O
30mg	O
/	O
kg	O
,	O
i	O
.	O
v	O
.	O
)	O
and	O
blood	O
samples	O
were	O
collected	O
by	O
cardiac	O
puncture	O
with	O
10	O
%	O
EDTA	O
.	O

Total	O
cell	O
counts	O
were	O
carried	O
out	O
using	O
diluting	O
fluid	O
in	O
a	O
Neubauer	O
chamber	O
.	O

Differential	O
countings	O
were	O
obtained	O
using	O
Rosenfeld	O
-	O
stained	O
cytocentrifuge	O
preparations	O
,	O

Bronchoalveolar	O
lavage	O
fluid	O
.	O

The	O
guinea	B
-	I
pigs	I
were	O
killed	O
by	O
an	O
overdose	O
of	O
sodium	O
pentobarbitone	O
and	O
5ml	O
of	O
phosphate	O
-	O
buffered	O
saline	O
(	O
PBS	O
)	O
containing	O
0	O
.	O
5	O
%	O
sodium	O
citrate	O
(	O
PBS	O
/	O
SC	O
)	O
,	O
at	O
room	O
temperature	O
,	O
were	O
instilled	O
through	O
a	O
polyethylene	O
cannula	O
introduced	O
into	O
the	O
trachea	O
.	O

The	O
cells	O
present	O
in	O
the	O
bronchoalveolar	O
lavage	O
fluid	O
(	O
BALF	O
)	O
were	O
recovered	O
immediately	O
.	O

The	O
procedure	O
was	O
repeated	O
once	O
.	O

The	O
leucocyte	O
counts	O
in	O
the	O
BAI	O
_	O
were	O
determined	O
as	O
described	O
above	O
,	O
Peritoneal	O
cells	O
:	O
The	O
cells	O
from	O
the	O
peritoneal	O
cavities	O
were	O
harvested	O
by	O
injection	O
of	O
10ml	O
of	O
PBS	O
/	O
SC	O
into	O
the	O
peritoneum	O
.	O

Only	O
5	O
-	O
8	O
ml	O
of	O
the	O

fluid	O
was	O
withdrawn	O
for	O
cell	O
counts	O
,	O
as	O
described	O
above	O
,	O

Monoclonal	O
antibodies	O
:	O
The	O
rat	B
monoclonal	O
antibody	O
TRFK	O
-	O
5	O
was	O
a	O
generous	O
gift	O
from	O
Dr	O
P	O
.	O

Minoprio	O
,	O
Institut	O
Pasteur	O
,	O
Paris	O
.	O

The	O
neutralizing	O
antibody	O
was	O
purified	O
by	O
precipitation	O
with	O
ammonium	O
sulfate	O
(	O
45	O
%	O
)	O
from	O
ascites	O
prepared	O
in	O
CD1	O
nude	B
mice	I
(	O
Charles	O
River	O
,	O
St	O
Aubin	O
les	O
Elbeuf	O
,	O
France	O
)	O
inoculated	O
1	O
week	O
before	O
the	O
injection	O
of	O
hybridoma	O
cells	O
,	O
with	O
I	O
ml	O
of	O
pristane	O
(	O
Sigma	O
)	O
.	O

After	O
precipitation	O
and	O
dialysis	O
of	O
the	O
ascite	O
fluid	O
overnight	O
against	O
PBS	O
,	O
the	O
dialysate	O
was	O
further	O
purified	O
on	O
a	O
Protein	O
G1	O
column	O
(	O
HiTrapTM	O
,	O
Pharmacia	O
Upsala	O
,	O
Sweden	O
)	O
.	O

Bone	O
marrow	O
cells	O
:	O
Bone	O
marrow	O
cells	O
were	O
collected	O
by	O
flushing	O
the	O
contents	O
of	O
the	O
guinea	B
-	I
pig	I
femur	O
with	O
10	O
ml	O
of	O
PBS	O
/	O
SC	O
.	O

Total	O
cell	O
numbers	O
were	O
determined	O
as	O
above	O
.	O

In	O
the	O
differential	O
cell	O
counts	O
the	O
cell	O
populations	O
were	O
divided	O
into	O
mature	O
neutrophils	O
,	O
mature	O
eosinophils	O
and	O
others	O
(	O
mainly	O
precursors	O
and	O
mononuclear	O

cells	O
)	O
,	O
Histopathological	O
studies	O
:	O
Tissues	O
were	O
removed	O
from	O
guinea	B
-	I
pigs	I
at	O
various	O
times	O
post	O
-	O
infection	O
and	O
immediately	O
fixed	O
in	O
10	O
%	O
formalin	O
.	O

Tissues	O

Eosinophil	O
and	O
cytokine	O
depletion	O
:	O
Guinea	B
-	I
pigs	I
were	O
injected	O
i	O
.	O
p	O
.	O
with	O
TRFK	O
-	O
5	O
or	O
with	O
the	O
irrelevant	O
antibody	O
(	O
rat	B
IgG	O
against	O
total	O
anti	O
-	O
human	B
IgG	O
)	O
once	O
,	O
2mg	O
/	O
animal	O
,	O
at	O
the	O
time	O
of	O
infection	O
or	O
at	O
different	O
intervals	O
(	O
1	O
,	O
3	O
,	O
12	O
or	O
17	O
days	O
)	O
thereafter	O
.	O

The	O
animals	O
in	O
this	O
group	O
were	O
sacririced	O
18	O
days	O
after	O
infection	O
.	O
liver	O
:	O
One	O
lobule	O
of	O
was	O
used	O
to	O
determine	O
the	O
larval	O
each	O
liver	O
counts	O
from	O
infected	O
guinea	B
-	I
pigs	I
.	O

Larval	O
recovery	O

Recovery	O

of	O
larvae	O
from	O

Mediators	O
of	O
Inflammation	O
Vol	O
5	O

1996	O

25	O

L	O
.	O

H	O
.	O

Faccioli	O
et	O
al	O
.	O

was	O
evaluated	O
as	O
described	O
by	O
Kayes	O
and	O
Oaks	O
,	O
18	O
with	O
minor	O
modifications	O
.	O

Briefly	O
,	O
the	O
tissue	O
was	O
chopped	O
and	O
digested	O
with	O
pepsin	O
-	O
HC1	O
(	O
pH	O
1	O
.	O
5	O

1	O
.	O
8	O
)	O
for	O
2h	O
at	O
37C	O
.	O

Larval	O
counts	O
for	O
each	O
sample	O
were	O
performed	O
after	O
centrifugation	O
and	O
examination	O
of	O
three	O
100	O
-	O
l	O
.	O
tl	O
samples	O
under	O
the	O
light	O
microscope	O
.	O

Statistical	O
analysis	O
:	O
Data	O
are	O
presented	O
as	O
the	O
mean	O
_	O
+	O
S	O
.	O
E	O
.	O
M	O
.	O
and	O
were	O
analysed	O
statistically	O
using	O
the	O
Mann	O
-	O
Whitney	O
test	O
for	O
unpaired	O
data	O
.	O

A	O
p	O
<	O
0	O
.	O
05	O
value	O
was	O
considered	O
to	O
be	O
statistically	O

significant	O
.	O

Results	O

of	O
eosinophil	O
counts	O
in	O
blood	O
bone	O
marrow	O
,	O
BALF	O
and	O
peritoneum	O
:	O
Guinea	B
-	I
pigs	I
infected	O
with	O
T	B
.	I
canis	I
eggs	O
showed	O
a	O
timedependent	O
blood	O
,	O
bone	O
-	O
marrow	O
,	O
BAUV	O
and	O
peritoneal	O
eosinophilia	O
(	O
Fig	O
.	O
1	O
)	O
.	O

The	O
results	O
represent	O
the	O
mean	O
of	O
nine	O
animals	O
obtained	O
in	O
three	O
different	O
experiments	O
.	O

The	O
eosinophil	O
number	O
Kinetics	O
16	O

increased	O
significantly	O
from	O
0	O
.	O
55	O
+	O
_	O
0	O
.	O
37	O
x	O
105	O
at	O
the	O
beginning	O
of	O
experiment	O
to	O
6	O
.	O
0	O
+	O
_	O
_	O
1	O
.	O
03	O
x	O
105	O
at	O
6	O
days	O
post	O
-	O
infection	O
,	O
peaked	O
at	O
day	O
18	O
(	O
12	O
.	O
0	O
_	O
+	O
2	O
.	O
31	O
x	O
105	O
)	O
,	O
and	O
decreased	O
by	O
day	O
24	O
(	O
8	O
.	O
11	O
2	O
.	O
85	O
x	O
105	O
)	O
(	O
Fig	O
.	O
1A	O
)	O
.	O

A	O
rise	O
in	O
the	O
percentage	O
of	O
mature	O
eosinophils	O
in	O
bone	O
marrow	O
"	O
was	O
observed	O
12	O
days	O
after	O
infection	O
(	O
ranging	O
from	O
6	O
2	O
%	O
to	O
14	O
2	O
%	O
)	O
and	O
peaked	O
at	O
18	O
days	O
(	O
17	O
2	O
%	O
)	O
(	O
Fig	O
.	O
1B	O
)	O
.	O

As	O
in	O
blood	O
,	O
the	O
number	O
of	O
eosinophils	O
in	O
BALF	O
increased	O
significantly	O
from	O
0	O
.	O
14	O
0	O
.	O
06	O
x	O
105	O
to	O
1	O
.	O
37	O
_	O
+	O
0	O
.	O
35	O
x	O
105	O
at	O
6	O
days	O
after	O
infection	O
,	O
reaching	O
a	O
peak	O
at	O
18	O
days	O
(	O
10	O
.	O
23	O
2	O
.	O
62	O
x	O
105	O
)	O
with	O
an	O
increase	O
in	O
relative	O
number	O
of	O
as	O
much	O
as	O
90	O
%	O
in	O
eosinophil	O
counts	O
in	O
relation	O
to	O
controls	O
,	O
and	O
was	O
still	O
elevated	O
at	O
day	O
24	O
(	O
9	O
.	O
07	O
_	O
_	O
_	O
3	O
.	O
47	O
x	O
10	O
s	O
)	O
(	O
Fig	O
.	O
1C	O
)	O
.	O

The	O
remaining	O
cells	O
in	O
the	O
BALF	O
were	O
alveolar	O
macrophages	O
,	O
lymphocytes	O
,	O
mast	O
cells	O
and	O
ciliated	O
cells	O
.	O

In	O
contrast	O
to	O
blood	O
and	O
BALF	O
,	O
the	O
number	O
of	O
eosinophils	O
in	O
the	O
peritoneal	O
cavity	O
increased	O
significantl	O
only	O
at	O
day	O
12	O
post	O
-	O
infection	O
(	O
onset	O
,	O
2	O
.	O
06	O
1	O
.	O
04	O
x	O
105	O
;	O
day	O
6	O
,	O
3	O
.	O
68	O
_	O
+	O
0	O
.	O
82	O
x	O
105	O
;	O
day	O
12	O
,	O
5	O
.	O
77	O
+	O
_	O
1	O
.	O
12	O
x	O
10	O
>	O
;	O
and	O
increased	O
progres	O

_	O
_	O
_	O
_	O
_	O
.	O

(	O
B	O
)	O

(	O
AI	O
Blood	O

24	O
20	O
"	O

Bone	O
Marrow	O

1612	O
8	O

4	O
O0	O

3	O

6	O

9	O

12	O

15	O

111	O

21	O

24	O

16	O

(	O
c	O
)	O
BALF	O

16	O

ID	O
)	O
Peritoneum	O

12	O

_	O
_	O
o	O

12	O

8	O

4	O

0	O
3	O

O6	O
9	O

12	O

15	O

16	O

21	O

24	O

Days	O
postinfoction	O

FIG	O
.	O

1	O
.	O

Number	O
of	O
eosinophils	O
in	O
blood	O
,	O
BALF	O
and	O
peritoneal	O
cavity	O
,	O
and	O
percentage	O
,	O
of	O
eosinophils	O
in	O
bone	O
marrow	O
of	O
T	B
.	I
canisqnfected	I
guinea	B
-	I
pigs	I
.	O

Values	O
are	O
the	O
mean	O
-	O
t	O
-	O
S	O
.	O
E	O
.	O
M	O
.	O

(	O
n	O
=	O
8	O
to	O
9	O
)	O
.	O

Asterisks	O
indicate	O
a	O
significant	O
difference	O
between	O
infected	O
and	O
noninfected	O
animals	O
(	O
n	O
5	O
6	O
)	O
.	O

*	O
p	O
<	O
0	O
.	O
05	O
and	O
*	O
*	O
p	O
<	O
0	O
.	O
01	O
.	O

26	O
Mediators	O
of	O
Inflammation	O
Vol	O
5	O

1996	O

IL	O
-	O
5	O
drives	O
eosinophils	O
in	O
guinea	B
-	I
pig	I

sively	O
until	O
day	O
24	O
,	O
12	O
.	O
44	O
4	O
-	O
2	O
.	O
72	O
x	O
105	O
)	O
(	O
Fig	O
.	O
1D	O
)	O
.	O

The	O
percentage	O
of	O
eosinophils	O
in	O
some	O
animals	O
reached	O
55	O
%	O
at	O
the	O
peak	O
of	O
infection	O
.	O

No	O
increase	O
in	O
the	O
number	O
of	O
mononuclear	O
cells	O
was	O
seen	O
in	O
any	O
compartment	O
analysed	O
.	O

Larval	O
counts	O
:	O
The	O
percentage	O
of	O
inoculated	O
T	B
.	I
canis	I
larvae	O
recovered	O
by	O
peptic	O
digestion	O
of	O
the	O
liver	O
of	O
experimental	O
animals	O
4	O
h	O
and	O
1	O
,	O
2	O
,	O
3	O
,	O
4	O
,	O
9	O
,	O
12	O
and	O
18	O
days	O
after	O
inoculation	O
of	O
500	O
eggs	O
per	O
animal	O
is	O
shown	O
in	O
Fig	O
.	O

2	O
.	O

Most	O
of	O
the	O
larvae	O
were	O
recovered	O
2	O
to	O
4	O
days	O
after	O
infection	O
and	O
10	O
%	O
recovery	O
was	O
also	O
observed	O
on	O
day	O
18	O
in	O
the	O
liver	O
of	O
the	O
animals	O
.	O

150	O

120	O

IL	O
-	O
5	O
level	O
in	O
serum	O
of	O
infected	O
animals	O
:	O
IL	O
-	O
5	O
was	O
measured	O
in	O
the	O
serum	O
of	O
infected	O
and	O
normal	O
guinea	B
-	I
pigs	I
.	O

Each	O
time	O
point	O
in	O
Fig	O
.	O

3	O
represents	O
the	O
mean	O
of	O
results	O
from	O
three	O
to	O
five	O
infected	O
animals	O
,	O
and	O
from	O
six	O
controls	O
.	O

Two	O
peaks	O
of	O
IL5	O
were	O
present	O
in	O
the	O
serum	O
of	O
infected	O
guineapigs	B
1	O
day	O
after	O
infection	O
(	O
102	O
_	O
_	O
+	O
22	O
pg	O
/	O
ml	O
)	O
,	O
and	O
18	O
days	O
later	O
(	O
59	O
7	O
pg	O
/	O
ml	O
)	O
.	O

The	O
level	O
of	O
IL	O
-	O
5	O
in	O
the	O
controls	O
was	O
31	O
4	O
-	O
4	O
pg	O
/	O
ml	O
.	O

Eosinophil	O
numbers	O
in	O
infected	O
animals	O
treated	O
with	O
TRFK	O
-	O
5	O
:	O
When	O
guinea	B
-	I
pigs	I
received	O
an	O
i	O
.	O
p	O
.	O
injection	O
of	O
TRFK	O
-	O
5	O
,	O
the	O
monoclonal	O
antibody	O
against	O
IL	O
-	O
5	O
,	O
at	O
the	O
time	O
of	O
egg	O
administration	O
or	O
1	O
day	O
later	O
,	O
the	O
number	O
of	O
eosinophils	O
in	O
blood	O
,	O
BALF	O
,	O
peritoneal	O
cavity	O
and	O
bone	O
marrow	O
was	O

_	O

30	O

0	O

0	O

3	O

6	O

12	O

18	O

Days	O
postinfection	O

FIG	O
.	O

3	O
.	O

IL	O
-	O
5	O
concentration	O
in	O
serum	O
of	O
T	B
.	I
caniinfected	I
guineapigs	B
(	O
n	O
3	O
-	O
5	O
)	O
.	O

Basal	O
IL	O
-	O
5	O
concentrations	O
were	O
of	O
31	O
4	O
pg	O
/	O
ml	O
(	O
n	O
=	O
12	O
)	O
.	O

_	O

24	O

60	O

50	O

40	O

0	O

"	O
T	O
"	O

1	O
"	O

0	O

3	O

6	O

9	O

12	O

15	O

18	O

21	O

24	O

Days	O
postinfection	O
FIG	O
.	O

2	O
.	O

Percentage	O
of	O
T	B
.	I
canis	I
larvae	O
recovered	O
from	O
liver	O
of	O
guinea	B
-	I
pigs	I
studied	O
at	O
various	O
times	O
post	O
-	O
infection	O
.	O

Data	O
obtained	O
from	O
five	O
animals	O
.	O

drastically	O
reduced	O
,	O
even	O
when	O
determined	O
18	O
days	O
after	O
infection	O
(	O
Table	O
1	O
)	O
.	O

No	O
inhibition	O
of	O
eosinophil	O
counts	O
was	O
observed	O
when	O
the	O
animals	O
were	O
inoculated	O
with	O
the	O
irrelevant	O
antibody	O
at	O
the	O
time	O
of	O
infection	O
(	O
Table	O
1	O
)	O
.	O

Fig	O
.	O

4	O
shows	O
the	O
comparative	O
results	O
of	O
eosinophilia	O
obtained	O
when	O
the	O
antibody	O
was	O
given	O
3	O
days	O
or	O
17	O
days	O
after	O
egg	O
inoculation	O
.	O

The	O
antibody	O
given	O
at	O
3	O
days	O
after	O
infection	O
induced	O
a	O
high	O
percentage	O
of	O
inhibition	O
in	O
eosinophil	O
counts	O
in	O
all	O
the	O
compartments	O
analysed	O
18	O
days	O
after	O
infection	O
(	O
Fig	O
.	O
4A	O
)	O
.	O

However	O
,	O
when	O
TRFK	O
-	O
5	O
was	O
administered	O
to	O
the	O
infected	O
animals	O
on	O
day	O
17	O
post	O
-	O
infection	O
(	O
thus	O
1	O
day	O
before	O
sacrifice	O
)	O
,	O
a	O
significant	O
inhibition	O
in	O
number	O
and	O
percentage	O
of	O
eosinophils	O
was	O
observed	O
only	O
in	O
the	O
blood	O
(	O
p	O
=	O
0	O
.	O
030	O
)	O
(	O
Fig	O
.	O
4B	O
)	O
.	O

A	O
small	O
non	O
-	O
significant	O
decrease	O
was	O
seen	O
in	O
BALF	O
(	O
p	O
0	O
.	O
790	O
)	O
and	O
peritoneum	O
(	O
p	O
=	O
0	O
.	O
222	O
)	O
.	O

Moreover	O
,	O
the	O
number	O
of	O
mature	O
eosinophils	O
in	O
bone	O
marrow	O
increased	O
by	O
140	O
%	O
(	O
p	O
0	O
.	O
038	O
)	O
.	O

As	O
demonstrated	O
in	O
Fig	O
.	O

4B	O
,	O
the	O
behaviour	O
of	O
eosinotShilia	O
in	O
BALF	O
was	O
completely	O
different	O
from	O
that	O
observed	O
in	O
blood	O
.	O

Thus	O
,	O
to	O
better	O
understand	O
the	O
eosinophilia	O
in	O
the	O
lungs	O
of	O
infected	O
animals	O
,	O
we	O
monitored	O
eosinophil	O
numbers	O
in	O
BALF	O
after	O
administration	O
of	O
TRFK	O
-	O
5	O
at	O
the	O
same	O
time	O
,	O
or	O
1	O
,	O
3	O
,	O
12	O
or	O
17	O
days	O
after	O
infection	O
.	O

The	O
animals	O
were	O
sacrificed	O
18	O
days	O
after	O
infection	O
.	O

In	O
another	O
group	O
,	O
TRFK	O
-	O
5	O
was	O
administered	O
18	O
days	O
post	O
-	O
infection	O
and	O
the	O
animals	O
were	O
sacrificed	O
6	O
days	O
later	O
.	O

When	O
the	O
mAb	O
was	O
administered	O
at	O
the	O
same	O
time	O
or	O
1	O
or	O
3	O
days	O
postinfection	O
there	O
was	O
a	O
significant	O
inhibition	O
in	O
the	O
number	O
of	O
eosinophils	O
(	O
Fig	O
.	O
5	O
)	O
.	O

These	O
data	O
show	O
Mediators	O
of	O
Inflammation	O
Vol	O
5	O

1996	O

27	O

L	O
.	O

H	O
.	O

Faccioli	O
et	O
al	O
.	O

Table	O
1	O
.	O

Eosinophils	O
in	O
T	O
.	O
caniinfected	O
guinea	B
-	I
pigs	I
treated	O
or	O
untreated	O
with	O
TRFK	O
-	O
5	O
Compartment	O

Time	O
of	O
sacrifice	O

(	O
days	O
)	O

Non18	O
24	O
18	O
24	O
18	O
24	O
18	O
24	O

treated	O

Blood	O

12	O
.	O
18	O
5	O
.	O
28	O
10	O
.	O
08	O
-	O
t	O
-	O
2	O
.	O
85	O
16	O
.	O
50	O
4	O
.	O
42	O
6	O
.	O
57	O
+	O
_	O
_	O
1	O
.	O
68	O

BALF	O
Peritoneal	O
cavity	O

12	O
.	O
31	O
-	O
I	O
-	O
2	O
.	O
35	O
12	O
.	O
44	O
2	O
.	O
33	O
9	O
6	O

Bone	O
marrow	O

_	O
_	O
_	O
_	O
_	O
_	O
_	O
_	O
_	O
_	O
_	O
_	O
_	O
_	O
_	O
_	O
Days	O
of	O
treatment	O
with	O
TRFK	O
-	O
5	O
after	O
egg	O
administration	O

Irrelevant	O
Ab	O
at	O
the	O
time	O
of	O
infection	O

0	O

3	O

12	O

17	O

18	O

(	O
n	O
6	O
)	O

(	O
n	O
=	O
4	O
)	O

(	O
n	O
=	O
4	O
)	O

(	O
n	O
5	O
)	O

(	O
n	O
5	O
)	O

(	O
n	O
=	O
4	O
)	O

0	O
.	O
14	O
-	O
t	O
-	O
0	O
.	O
14	O
"	O

0	O
.	O
26	O
0	O
.	O
79	O

0	O
.	O
26	O
*	O
0	O
.	O
24	O
*	O

0	O
.	O
17	O
_	O
-	O
t	O
-	O
0	O
.	O
17	O
"	O

0	O
.	O
15	O

0	O
.	O
15	O
"	O

2	O
.	O
59	O

0	O
.	O
80	O
*	O
4	O
.	O
36	O
2	O
.	O
21	O

13	O
.	O
32	O

4	O
.	O
54	O

O	O
.	O

15	O

0	O
.	O
15	O
*	O

0	O
.	O
36	O

0	O
.	O
10	O
"	O

1	O
.	O
22	O
-	O
t	O
-	O
0	O
.	O
50	O
*	O

7	O
.	O
07	O
-	O
t	O
-	O
2	O
.	O
39	O

15	O
.	O
24	O

29	O
.	O
31	O
_	O
+	O
15	O
.	O
90	O
16	O
.	O
09	O

10	O
.	O
33	O
_	O
+	O
4	O
.	O
10	O
3	O
.	O
79	O

1	O
.	O
47	O
-	O
t	O
-	O
0	O
.	O
76	O
*	O
3	O

0	O
.	O
48	O

_	O
+	O
0	O
.	O
35	O
*	O

0	O
.	O
46	O
2	O
.	O
6	O

0	O
.	O
27	O
*	O
1	O
.	O
3	O
"	O

2	O
.	O
89	O

0	O
.	O
94	O
*	O

10	O
.	O
42	O

4	O
.	O
00	O

1	O
.	O
58	O
"	O

-	O
+	O

1	O
"	O

1	O
.	O
25	O
-	O
I	O
-	O
0	O
.	O
25	O
*	O

+	O

5	O

15	O
-	O
t	O
-	O
2	O

9	O
_	O
+	O
1	O

2	O

0	O
.	O
7	O
*	O

In	O
blood	O
BALF	O
and	O
peritoneal	O
cavity	O
the	O
values	O
represent	O
mean	O
-	O
t	O
-	O
_	O
S	O
.	O
E	O
.	O
M	O
.	O

x	O
10	O
eosinophils	O
.	O

*	O
p	O
<	O
0	O
.	O
05	O
.	O

ml	O
-	O
1	O

and	O
in	O
bone	O
marrow	O
mean	O
-	O
t	O
-	O
_	O
S	O
.	O
E	O
.	O
M	O
.	O
of	O
the	O
percentage	O
of	O
mature	O

that	O
the	O
inhibition	O
of	O
the	O
first	O
peak	O
of	O
IL	O
-	O
5	O
which	O
appeared	O
at	O
1	O
to	O
3	O
days	O
after	O
infection	O
as	O
shown	O
in	O
Fig	O
.	O

3	O
,	O
is	O
also	O
very	O
important	O
for	O
the	O
establishment	O
of	O
eosinophilia	O
in	O
the	O
lungs	O
.	O

However	O
,	O
24	O
-	O
(	O
A	O
)	O

when	O
the	O
mAb	O
was	O
administered	O
12	O
,	O
17	O
or	O
18	O
days	O
after	O
infection	O
there	O
was	O
no	O
significant	O
inhibition	O
in	O
the	O
numbers	O
of	O
eosinophils	O
in	O
BALF	O
(	O
Fig	O
.	O
5	O
)	O
,	O
showing	O
that	O
once	O
established	O
,	O
the	O
eosi18	O

15x	O

16	O

12	O

.	O
_	O
.	O

0	O

12	O

o	O

BIo	O
o	O
d	O

BALF	O

P	O
e	O
rit	O
oneum	O

Bone	O
marrow	O

24	O
-	O
(	O
Is	O
)	O

1815	O

E	O
x	O

20	O

16	O

o	O

12	O
/	O
/	O
/	O
.	O

o	O
=	O
o	O

12	O

0	O
Blood	O

O	O
"	O

BALF	O

Peritoneum	O

Bone	O
marrow	O
FIG	O
.	O

4	O
.	O

Number	O
of	O
eosinophils	O
in	O
blood	O
,	O
BALF	O
and	O
peritoneum	O
and	O
percentage	O
of	O
eosinophils	O
in	O
bone	O
marrow	O
of	O
T	B
.	I
caniinfected	I
guinea	B
-	I
pigs	I
submitted	O
or	O
not	O
to	O
treatment	O
with	O
TRFK	O
-	O
5	O
.	O

(	O
A	O
)	O
2	O
mg	O
/	O
animal	O
at	O
3	O
days	O
post	O
-	O
infection	O
;	O
(	O
B	O
)	O
2	O
mg	O
/	O
animal	O
17	O
days	O
post	O
-	O
infection	O
.	O

The	O
treated	O
and	O
control	O
animals	O
were	O
sacrificed	O
18	O
days	O
after	O
infection	O
.	O

Asterisks	O
indicate	O
a	O
significant	O
difference	O
from	O
infected	O
controls	O
(	O
n	O
=	O
5	O
-	O
6	O
)	O
and	O
from	O
animals	O
treated	O
with	O
TRFK	O
-	O
5	O
(	O
n	O
=	O
4	O
-	O
5	O
)	O
.	O

*	O
p	O
<	O
0	O
.	O
05	O
and	O
*	O
*	O
p	O
<	O
0	O
.	O
01	O
.	O

28	O
Mediators	O
of	O
Inflammation	O
Vol	O
5	O

1996	O

IL	O
-	O
5	O
drives	O
eosinophils	O
in	O
guinea	B
-	I
pig	I
24	O

E	O

20	O

heart	O
;	O
data	O
not	O
shown	O
)	O
and	O
muscle	O
,	O
as	O
reported	O
by	O
other	O
investigators	O
,	O
8	O
were	O
infiltrated	O
.	O

The	O
factors	O
responsible	O
for	O
in	O
vivo	O
eosinophil	O
accumulation	O
at	O
inflammatory	O
sites	O
have	O
been	O

0	O

TRFK	O
-	O
5	O
i	O
.	O
p	O
.	O

0	O

3	O

12	O
17	O

A	O

B	O

FIG	O
.	O

5	O
.	O

Number	O
of	O
eosinophils	O
in	O
BALF	O
of	O
T	O
.	O
caniinfected	O
guinea	B
-	I
pigs	I
submitted	O
or	O
not	O
to	O
treatment	O
with	O
TRFK	O
-	O
5	O
.	O

(	O
A	O
)	O
animals	O
were	O
sacrificed	O
18	O
days	O
post	O
-	O
infection	O
and	O
(	O
B	O
)	O
24	O
days	O
after	O
infection	O
.	O

Asterisks	O
indicate	O
a	O
significant	O
difference	O
from	O
infected	O
control	O
and	O
from	O
animals	O
treated	O
with	O
TRFK	O
-	O
5	O
(	O
p	O
<	O
0	O
.	O
01	O
)	O
.	O

nophilia	O
persists	O
in	O
lungs	O
,	O
probably	O
by	O
the	O
secretion	O
of	O
IL	O
-	O
5	O
from	O
cells	O
localized	O
in	O
the	O
lung	O
microenvironment	O
,	O

Histopathological	O
analysis	O
:	O
The	O
treatment	O
of	O
T	B
.	I
canis	I
-	O
infected	O
animals	O
with	O
irrelevant	O
antibody	O
showed	O
a	O
widespread	O
eosinophilic	O
infiltration	O
as	O
in	O
untreated	O
animals	O
(	O
Fig	O
.	O
6A	O
,	O
B	O
)	O
.	O

However	O
,	O
the	O
treatment	O
of	O
animals	O
with	O
TRFK	O
-	O
5	O
at	O
the	O
same	O
time	O
of	O
infection	O
,	O
or	O
1	O
day	O
or	O
3	O
days	O
later	O
ted	O
to	O
a	O
complete	O
inhibition	O
of	O
eosinophil	O
infiltration	O
in	O
the	O
lung	O
parenchyma	O
(	O
Fig	O
.	O
6C	O
)	O
.	O

By	O
contrast	O
,	O
the	O
mononuclear	O
cell	O
infiltration	O
in	O
the	O
lungs	O
was	O
not	O
modified	O
.	O

When	O
the	O
infected	O
guinea	B
-	I
pigs	I
received	O
TRFK	O
-	O
5	O
1	O
day	O
before	O
sacrifice	O
(	O
or	O
17	O
days	O
post	O
-	O
infection	O
)	O
,	O
eosinophil	O
infiltration	O
in	O
the	O
lung	O
parenchyma	O
was	O
also	O
inhibited	O
(	O
Fig	O
.	O
6D	O
)	O
but	O
not	O
to	O
the	O
same	O
extent	O
as	O
observed	O
in	O
the	O
group	O
receiving	O
TRFK	O
-	O
5	O
given	O
at	O
the	O
time	O
of	O
infection	O
or	O
3	O
days	O
later	O
.	O

Thus	O
,	O
the	O
histological	O
determination	O
of	O
eosinophil	O
infiltration	O
in	O
these	O
lungs	O
corroborates	O
a	O
reduction	O
but	O
not	O
a	O
sizeable	O
inhibition	O
of	O
eosinophil	O
numbers	O
as	O
observed	O
in	O
the	O
BALF	O
of	O
the	O
same	O
infected	O
animals	O
,	O

poorly	O
defined	O
,	O
although	O
T	O
lymphocytes	O
and	O
mast	O
cells	O
appear	O
to	O
be	O
involved	O
in	O
eosinophilia	O
.	O

9	O
'	O
2	O
IL	O
-	O
5	O
,	O
a	O
T	O
cell	O
-	O
derived	O
factor	O
that	O
regulates	O
B	O
cell	O
functions	O
,	O
is	O
an	O
eosinophil	O
differentiation	O
factor11	O
as	O
well	O
as	O
a	O
stimulating	O
and	O
survival	O
-	O
prolonging	O
factor	O
specific	O
for	O
eosinophils	O
in	O
vitro	O
.	O

2	O
Also	O
,	O
several	O
investigators	O
have	O
demonstrated	O
that	O
sTstemic	O
eosinophilia	O
in	O
mice	B
infected	O
with	O
parasites	O
is	O
mediated	O
by	O
IL	O
-	O
5	O
produced	O
in	O
response	O
to	O
the	O
infection	O
.	O

2	O
'	O
22	O
In	O
the	O
present	O
study	O
,	O
the	O
i	O
.	O
p	O
.	O
administration	O
of	O
the	O
TRFK	O
-	O
5	O
antibody	O
markedly	O
inhibited	O
the	O
widespread	O
eosinophilia	O
observed	O
in	O
T	B
.	I
canis	I
-	O
infected	O
guinea	B
-	I
pigs	I
,	O
indicating	O
that	O
IL5	O
participated	O
in	O
a	O
guinea	B
-	I
pig	I
model	O
of	O
VLMS	O
eosinophJlia	O
.	O

Most	O
of	O
the	O
T	B
.	I
canis	I
larvae	O
which	O
penetrated	O
the	O
intestinal	O
wall	O
had	O
migrated	O
into	O
the	O
liver	O
within	O
72h	O
after	O
inoculation	O
as	O
demonstrated	O
here	O
and	O
elsewhere	O
.	O

2	O
It	O
is	O
apparently	O
during	O
this	O
interval	O
that	O
the	O
worm	O
provides	O
the	O
signals	O
to	O
cytokine	O
-	O
producing	O
cells	O
,	O
which	O
in	O
turn	O
trigger	O
increased	O
serum	O
levels	O
of	O
specific	O
cytokine	O
as	O
demonstrated	O
here	O
for	O
IL	O
-	O
5	O
,	O
24	O
to	O
72	O
h	O
after	O
infection	O
.	O

The	O
signals	O
may	O
be	O
provided	O
directly	O
by	O
the	O
invading	O
parasite	O
or	O
by	O
cells	O
in	O
response	O
to	O
the	O
parasite	O
.	O

The	O
cytokine	O
pattern	O
that	O
develops	O
at	O
this	O
early	O
stage	O
,	O
probably	O
induced	O
by	O
a	O
T	O
-	O
cell	O
independent	O
pathway	O
,	O
may	O
also	O
influence	O
the	O
pattern	O
of	O
T	O
cell	O
differentiation	O
into	O
a	O
Th2	O
type	O
,	O
which	O
may	O
be	O
responsible	O
for	O
the	O
second	O
peak	O
of	O
IL	O
-	O
5	O
observed	O
in	O
our	O
experimental	O
model	O
(	O
Fig	O
.	O
3	O
)	O
,	O
although	O
a	O
second	O
cycle	O
of	O
larval	O
invasion	O
(	O
Fig	O
.	O
2	O
)	O
with	O
a	O
rapid	O
peak	O
of	O
IL	O
-	O
5	O
liberation	O
cannot	O
be	O
ruled	O
out	O
.	O

Discussion	O
The	O
results	O
of	O
the	O
present	O
study	O
show	O
that	O
in	O
our	O
experimental	O
model	O
widespread	O
eosinophilia	O
follows	O
the	O
infection	O
of	O
guinea	B
-	I
pigs	I
with	O
second	O
stage	O
eggs	O
from	O
T	B
.	I
canis	I
,	O
as	O
also	O
noted	O
in	O
humans	B
and	O
in	O
other	O
experimental	O
animals	O
.	O

7	O
'	O
7	O
T	B
.	I
canis	I
is	O
a	O
potent	O
stimulus	O
for	O
systemic	O
eosinophilia	O
,	O
since	O
blood	O
,	O
BALF	O
,	O
peritoneum	O
and	O
all	O
tissues	O
examined	O
(	O
kidney	O
,	O
eyes	O
,	O
spleen	O
,	O
thymus	O
,	O

Thus	O
,	O
our	O
results	O
suggest	O
that	O
the	O
eosinophilia	O
against	O
helminth	O
larvae	O
may	O
be	O
initiated	O
by	O
the	O
release	O
of	O
IL	O
-	O
5	O
when	O
the	O
parasites	O
migrate	O
from	O
the	O
intestine	O
to	O
the	O
liver	O
by	O
stimulation	O
of	O
specific	O
cell	O
populations	O
.	O

Then	O
,	O
an	O
early	O
release	O
of	O
IL	O
-	O
5	O
quickly	O
induces	O
eosinophil	O
recruitment	O
,	O
probably	O
first	O
from	O
the	O
stored	O
mature	O
eosinophil	O
pool	O
from	O
vascular	O
endothelium	O
or	O
by	O
the	O
mobilization	O
of	O
eosinophils	O
from	O
extravascular	O
sites	O
to	O
the	O
blood	O
.	O

This	O
fact	O
could	O
explain	O
why	O
we	O
found	O
increased	O
eosinophils	O
first	O
in	O
blood	O
and	O
later	O
in	O
other	O
compartments	O
.	O

The	O
early	O
IL	O
-	O
5	O
release	O
may	O
also	O
serve	O
as	O
a	O
signal	O
for	O
eosinophil	O
differentiation	O
and	O
maturation	O
in	O
bone	O
marrow	O
.	O

The	O
time	O

inteeeal	O
observed	O
between	O
the	O
first	O
peak	O
of	O
IL	O
-	O
5	O
release	O
and	O
the	O
increase	O
of	O
eosinophils	O
in	O
blood	O
coincides	O
with	O
that	O
reported	O
to	O
be	O
necessary	O
for	O
eosinophil	O
differentiation	O
and	O
maturation	O
in	O
vitro	O
.	O

12Increased	O
eosinophil	O
production	O
and	O
liberation	O
into	O
blood	O
and	O
other	O
tissues	O
occurs	O
Mediators	O
of	O
Inflammation	O
Vol	O
5	O

1996	O

29	O

L	O
.	O

H	O
.	O

Faccioli	O
et	O
al	O
.	O

FIG	O
.	O

6	O
.	O

(	O
A	O
)	O
photomicrographs	O
of	O
lung	O
parenchyma	O
from	O
guinea	B
-	I
pigs	I
infected	O
for	O
18	O
days	O
with	O
T	B
.	I
cani	I
,	O
,	O
(	O
B	O
)	O
infected	O
animals	O
which	O
were	O
treated	O
with	O
irrelevant	O
antibody	O
at	O
the	O
time	O
of	O
infection	O
;	O
(	O
C	O
)	O
infected	O
animals	O
which	O
were	O
treated	O
with	O
the	O
mAb	O
TRFK	O
-	O
5	O
at	O
3	O
days	O
after	O
infection	O
;	O
(	O
D	O
)	O
mAb	O
administration	O
17	O
days	O
after	O
infection	O
.	O

The	O
animals	O
were	O
sacrificed	O
18	O
days	O
after	O
infection	O
.	O

Note	O
the	O
intense	O
eosinophil	O
infiltration	O
into	O
the	O
lung	O
in	O
A	O
and	O
B	O
,	O
the	O
inhibition	O
of	O
eosinophils	O
in	O
C	O
and	O
the	O
reduction	O
of	O
eosinophils	O
in	O
D	O
.	O

thereafter	O
.	O

Thus	O
,	O
early	O
and	O
later	O
IL	O
-	O
5	O
release	O
provides	O
a	O
necessary	O
level	O
of	O
this	O
cytokine	O
,	O
which	O
is	O
involved	O
in	O
the	O
maintenance	O
of	O
eosinophilia	O
.	O

We	O
may	O
assume	O
that	O
the	O
inhibition	O
of	O
the	O
first	O
peak	O
of	O
IL	O
-	O
5	O
release	O
by	O
TRFK	O
-	O
5	O
does	O
not	O
permit	O
the	O
subsequent	O
T	O
cell	O
stimulation	O
and	O
differentiation	O
.	O

This	O
may	O
explain	O
the	O
long	O
-	O
lasting	O
effect	O
of	O
TRFK5	O
treatment	O
observed	O
here	O
and	O
also	O
reported	O
by	O
others	O
.	O

8	O
In	O
agreement	O
with	O
our	O
results	O
,	O
there	O
is	O
an	O
important	O
observation	O
of	O
Svetic	O
et	O
al	O
.	O

24	O
showing	O
that	O
a	O
specific	O
and	O
highly	O
reproducible	O
IL	O
-	O
5	O
gene	O
expression	O
pattern	O
is	O
detectable	O
in	O
Peyer	O
'	O
s	O
patches	O
by	O
6	O
to	O
12h	O
after	O
Heligmosomoides	B
polygyrus	I
infection	O
.	O

The	O
early	O
increase	O
in	O
IL	O
-	O
5	O
gene	O
expression	O
after	O
infection	O
was	O
probably	O
T	O
cell	O
-	O
independent	O
,	O
inasmuch	O
as	O
it	O
was	O
obseeeed	O
in	O
Peyer	O
'	O
s	O
patches	O
of	O
congenitally	O
athymic	O
mice	B
and	O
of	O
conventional	O
mice	B
treated	O
with	O
anti	O
-	O
CD4	O
30	O
Mediators	O
of	O
Inflammation	O
Vol	O
5	O

and	O
anti	O
-	O
CD8	O
mAb	O
.	O

Moreover	O
,	O
Kusama	O
eta	O
/	O
.	O

25	O
have	O
observed	O
two	O
peaks	O
of	O
eosinophilia	O
in	O
normal	O
and	O
athymic	O
mice	B
,	O
and	O
suggested	O
that	O
IL	O
-	O
5	O
observed	O
in	O
the	O
first	O
peak	O
was	O
produced	O
by	O
cells	O
other	O
than	O
CD4	O
T	O
cells	O
,	O
since	O
anti	O
-	O
CD4	O
and	O
anti	O
-	O
CD3	O
mAb	O
reduced	O
only	O
the	O
second	O
peak	O
of	O
eosinophilia	O
in	O
normal	O
mice	B
and	O
slightly	O
reduced	O
the	O
first	O
peak	O
of	O
eosinophilia	O
in	O
both	O
normal	O
and	O
nu	O
/	O
nu	O
mice	B
.	O

The	O
local	O
lung	O
cells	O
producing	O
IL	O
-	O
5	O
may	O
also	O
help	O
us	O
to	O
explain	O
the	O
reason	O
why	O
12	O
,	O
17	O
or	O
18	O
days	O
post	O
-	O
infection	O
TRFK	O
-	O
5	O
treatment	O
only	O
partially	O
inhibits	O
,	O
or	O
does	O
not	O
inhibit	O
eosinophil	O
infiltration	O
into	O
the	O
lungs	O
,	O
as	O
demonstrated	O
in	O
Figs	O
5	O
and	O
6	O
.	O

We	O
may	O
suggest	O
that	O
when	O
eosinophils	O
have	O
already	O
migrated	O
to	O
the	O
lungs	O
,	O
TRFK	O
-	O
5	O
has	O
no	O
power	O
to	O
inhibit	O
eosinophilia	O
,	O
which	O
is	O
also	O
under	O
control	O
of	O
local	O
lung	O
cells	O
producing	O
IL	O
-	O
5	O
.	O

In	O
this	O
way	O
,	O
only	O
one	O
later	O
TRFK	O

1996	O

IL	O
-	O
5	O
drives	O
eosinophils	O
in	O
guinea	B
-	I
pig	I

5	O
treatment	O
may	O
not	O
be	O
sufficient	O
to	O
modify	O
the	O
lung	O
parenchyma	O
microenvironment	O
,	O
since	O
T	B
.	I
canis	I
antigens	O
have	O
already	O
stimulated	O
some	O
cell	O
populations	O
to	O
produce	O
IL	O
-	O
5	O
,	O
as	O
demonstrated	O
by	O
Kusama	O
et	O
aL25These	O
results	O
suggest	O
that	O
eosinophilia	O
in	O
lungs	O
is	O
under	O
the	O
control	O
of	O
different	O
factors	O
when	O
compared	O
to	O
that	O
observed	O
in	O
blood	O
and	O
the	O
peritoneal	O
cavity	O
.	O

One	O
of	O
the	O
most	O
important	O
results	O
obtained	O
here	O
was	O
the	O
inhibition	O
of	O
circulating	O
eosinophil	O
numbers	O
by	O
the	O
different	O
mAb	O
treatments	O
,	O
even	O
when	O
the	O
antibody	O
was	O
given	O
at	O
the	O
peak	O
of	O
blood	O
eosinophilia	O
,	O
which	O
was	O
accompanied	O
by	O
an	O
increase	O
of	O
mature	O
eosinophils	O
in	O
bone	O
marrow	O
.	O

This	O
suggests	O
that	O
IL	O
-	O
5	O
,	O
apart	O
from	O
being	O
required	O
for	O
the	O
terminal	O
differentiation	O
of	O
eosinophils	O
in	O
bone	O
marrow	O
,	O
26	O
is	O
also	O
likely	O
to	O
drive	O
eosinophils	O
from	O
the	O
bone	O
marrow	O
to	O
the	O
blood	O
and	O
then	O
to	O
the	O
tissues	O
,	O
probably	O
by	O
upregulating	O
VLA	O
-	O
4	O
expression	O
in	O
eosinophils	O
.	O

Moser	O
et	O
aL	O
have	O
demonstrated	O
that	O
in	O
order	O
to	O
acquire	O
the	O
ability	O
to	O
transmigrate	O
,	O
eosinophils	O
must	O
be	O
primed	O
with	O
cytokines	O
such	O
as	O
IL	O
-	O
5	O
,	O
IL	O
-	O
3	O
or	O
GM	O
-	O
CSF	O
for	O
expression	O
of	O
adhesion	O
molecules	O
such	O
as	O
VI	O
-	O
4	O
.	O

Recently	O
,	O
Pretolani	O
et	O
al	O
.	O

27	O
have	O
indeed	O
shown	O
that	O
an	O
anti	O
-	O
VLA	O
-	O
4	O
antibody	O
suppresses	O
eosinophil	O
recruitment	O
to	O
lung	O
in	O
the	O
guinea	B
-	I
pig	I
and	O
,	O
as	O
a	O
consequence	O
,	O
inhibits	O
the	O
accompanying	O
bronchopulmonary	O
hyperresponsiveness	O
.	O

tant	O
in	O
protective	O
immunity	O
to	O
a	O
gastrointestinal	O
nematode	O
infection	O
in	O
mice	B
.	O

Proc	O
Natl	O
Acad	O
Sci	O
USA	O
1991	O
;	O
88	O
=	O
5513	O
-	O
5517	O
.	O

11	O
.	O

Yamaguchi	O
A	O
,	O
Suda	O
T	O
,	O
Suda	O
J	O
,	O
et	O
al	O
.	O

Purified	O
interleukin	O
(	O
IL	O
-	O
5	O
)	O
supports	O
the	O
terminal	O
differentiation	O
and	O
proliferation	O
of	O
murine	B
eosinophilic	O

precursors	O
.	O

J	O
Exp	O
Med	O
1988	O
;	O
16	O
'	O
7	O
:	O
43	O
-	O
56	O
.	O

12	O
.	O

Yamaguchi	O
Y	O
,	O
Hayashi	O
Y	O
,	O
Sugama	O
Y	O
,	O
et	O
al	O
.	O

Highly	O
purified	O
murine	B
interleukin	O
(	O
IL	O
-	O
5	O
)	O
stimulates	O
eosinophil	O
function	O
and	O
prolongs	O
in	O
vitro	O
survival	O
.	O

IL	O
-	O
5	O
as	O
an	O
eosinophil	O
chemotactic	O
factor	O
.	O

J	O
Exp	O
Med	O
1988	O
;	O
16	O
'	O
7	O
:	O
17371752	O
.	O

13	O
.	O

Rothenberg	O
ME	O
,	O
Petersen	O
J	O
,	O
Stevens	O
RL	O
,	O
Silberstein	O
DS	O
,	O
McKenzie	O
DT	O
,	O
Austen	O
KF	O
,	O
Owen	O
WF	O
.	O

IL	O
-	O
5	O
-	O
dependent	O
conversion	O
of	O
normodense	O
human	B
eosinophils	O
to	O
the	O
hypodense	O
phenotype	O
uses	O
3T3	O
fibroblasts	O
for	O
enhanced	O
viability	O
,	O
accelerated	O
hypodensity	O
,	O
and	O
sustained	O
antibodydependent	O
cytotoxicity	O
.	O

J	O
Immuno11989	O
;	O
143	O
;	O
2311	O
-	O
2316	O
.	O

14	O
.	O

Collins	O
PD	O
,	O
Weg	O
VB	O
,	O
Faccioli	O
LH	O
,	O
Watson	O
ML	O
,	O
Moqbel	O
R	O
,	O
Williams	O
TJ	O
.	O

Eosinophil	O
accumulation	O
induced	O
by	O
human	B
interleukin	O
-	O
8	O
in	O
the	O
guinea	B
pig	I
in	O
vivo	O
.	O

Immunology	O
1993	O
;	O
'	O
7	O
}	O
;	O
312	O
-	O
318	O
.	O

15	O
.	O

Sehmi	O
R	O
,	O
Wardlavo	O
AJ	O
,	O
Cromwell	O
O	O
,	O
Kurihara	O
K	O
,	O
Waltmann	O
P	O
,	O
Kay	O
AB	O
.	O

Interleukin	O
-	O
5	O
selectively	O
enhances	O
the	O
chemotactic	O
response	O
of	O
eosinophils	O
obtained	O
from	O
normal	O
but	O
not	O
eosinophilic	O
subjects	O
.	O

Blood	O
1992	O
;	O
'	O
79	O
;	O
2952	O
-	O
2959	O
.	O

16	O
.	O

Moser	O
R	O
,	O
Fehr	O
J	O
,	O
Bruijnzeel	O
PLB	O
.	O

IL	O
-	O
4	O
controls	O
the	O
selective	O
endotheliumdriven	O
transmigration	O
of	O
eosinophils	O
from	O
allergic	O
individuals	O
.	O

J	O
Immunol	O
1992	O
;	O
149	O
:	O
1432	O
-	O
1438	O
.	O

17	O
.	O

Olson	O
LJ	O
,	O
Schulz	O
CW	O
.	O

Nematode	O
induced	O
hypersensitivity	O
reactions	O
in	O
guinea	B
pigs	I
:	O
onset	O
of	O
eosinophilia	O
and	O
positive	O
Schultz	O
-	O
Dale	O
reactions	O
following	O
graded	O
infection	O
with	O
Toxocara	B
canis	I
.	O

Ann	O
N	O
Y	O
Acad	O
Sci	O
1963	O
;	O
113	O
;	O
440	O
-	O
455	O
.	O

18	O
.	O

Kayes	O
SG	O
,	O
Oaks	O

JA	O
.	O

Development	O

of	O
the	O
granulomatous	O
response	O
in	O

murine	B
toxocariasis	O
.	O

I	O
.	O

Initial	O
events	O
.	O

Am	O
J	O
Patho11978	O
;	O
,	O
}	O
3	O
;	O

277	O
-	O
294	O
.	O

19	O
.	O

Basten	O
A	O
,	O
Beeson	O
PB	O
.	O

Mechanisms	O
of	O
eosinophilia	O
.	O

II	O
.	O

Role	O
of	O
the	O
lymphocyte	O
.	O

J	O
Exp	O
Med	O
1970	O
;	O
131	O
;	O
1288	O
-	O
1305	O
.	O

20	O
.	O

Plaut	O
M	O
,	O
Pierce	O
JH	O
,	O
Watson	O
CJ	O
,	O
Hanley	O
-	O
Hyde	O
J	O
,	O
Nordan	O
RP	O
,	O
Paul	O
WE	O
.	O

Mast	O
cell	O
lines	O
produce	O
lymphokines	O
in	O
response	O
to	O
cross	O
-	O
linkage	O
of	O
Fc	O
epsilon	O
RI	O
or	O
to	O
calcium	O
ionophoras	O
.	O

Nature	O
1989	O
;	O
339	O
:	O
64	O
-	O
67	O
.	O

is	O
21	O
.	O

Sher	O
A	O
,	O
Coffman	O
RL	O
,	O
Hieny	O
S	O
,	O
Scott	O
P	O
,	O
Cheever	O
AW	O
.	O

Interleukin	O
required	O
for	O
the	O
blood	O
and	O
tissue	O
eosinophilia	O
but	O
not	O
granuloma	O
formation	O
induced	O
by	O
infection	O
with	O
Schistosoma	B
mansoni	I
.	O

Proc	O
Natl	O
Acad	O
Sci	O
USA	O
1990	O
;	O
8	O
'	O
7	O
;	O
61	O
-	O
65	O
.	O

22	O
.	O

Herndon	O
FJ	O
,	O
Kayes	O
SG	O
.	O

Depletion	O
of	O
eosinophils	O
by	O
anti	O
-	O
IL	O
-	O
5	O
monoclonal	O
antibody	O
treatment	O
of	O
mice	B
infected	O
with	O
Trichinella	B
spiralis	I
does	O
not	O
alter	O
parasite	O
burden	O
or	O
immunologic	O
resistance	O
to	O
reinfection	O
.	O

J	O
Immuno11992	O
;	O
149	O
:	O
3642	O
-	O
3647	O
.	O

23	O
.	O

Oshima	O
T	O
.	O
Standardization	O
of	O
techniques	O
for	O
infecting	O
mice	B
with	O
Tox24	O
.	O
ocara	O
canis	O
and	O
observations	O
on	O
the	O
normal	O
migration	O
routes	O
of	O
the	O
larvae	O
.	O

J	O
Parasito11961	O
;	O
4	O
'	O
7	O
=	O
652	O
.	O

Svetic	O
A	O
,	O
Madden	O
KB	O
,	O
Zhou	O
XD	O
,	O
et	O
al	O
.	O

A	O
primary	O
intestinal	O
helminthic	O
infection	O
rapidly	O
induces	O
a	O
gut	O
-	O
associated	O
elevation	O
of	O
Th2	O
-	O
associated	O
cytokines	O
and	O
IL	O
-	O
3	O
.	O

J	O
Immuno11993	O
;	O
150	O
:	O
3434	O
-	O
3441	O
.	O

Kusama	O
Y	O
,	O
Takamoto	O
M	O
,	O
Kasahara	O
T	O
,	O
Takatsu	O
K	O
,	O
Nariuchi	O
H	O
,	O
Sugane	O
K	O
.	O
Mechanisms	O
of	O
eosinophilia	O
in	O
BALB	O
/	O
c	O
-	O
nu	O
/	O
+	O
and	O
congenitally	O
athymic	O
BALB	O
/	O
c	O
-	O
nu	O
/	O
nu	O
mice	B
infected	O
with	O
Toxocara	B
canis	I
.	O

Immunology	O
1995	O
;	O
84	O
;	O
461	O
-	O
468	O
.	O

Rennick	O
DM	O
,	O
Thompson	O
-	O
Snipes	O
L	O
,	O
Coffman	O
RL	O
,	O
Seymour	O
BWP	O
,	O
Jackson	O
JD	O
,	O
Hudak	O
S	O
.	O

In	O
vivo	O
administration	O
of	O
antibody	O
to	O
interleukin	O
-	O
5	O
inhibits	O
increased	O
generation	O
of	O
eosinophils	O
and	O
their	O
progenitors	O
in	O
bone	O
marrow	O
of	O
parasitized	O
mice	B
.	O

Blood	O
1990	O
;	O
'	O
76	O
:	O
312	O
-	O
316	O
.	O

Petrolani	O
M	O
,	O
Ruffle	O
C	O
,	O
Lapa	O
e	O
Silva	O
JR	O
,	O
Joseph	O
D	O
,	O
Lobb	O
RR	O
,	O
Boris	O
Vargaftig	O
B	O
.	O
Antibody	O
to	O
very	O
late	O
activation	O
antigen	O
4	O
prevents	O
antigen	O
-	O
induced	O
bronchial	O
hyperreactivity	O
and	O
cellular	O
infiltration	O
in	O
guinea	B
pig	I
airways	O
.	O

J	O
Exp	O
Med	O
1994	O
;	O
180	O
=	O
795	O
-	O
805	O
.	O

References	O
25	O
.	O

1	O
.	O

Nutman	O

2	O
.	O

3	O
.	O

4	O
.	O

5	O
.	O

6	O
.	O

7	O
.	O

8	O
.	O

9	O
.	O

TB	O
,	O
Ottesen	O
EA	O
,	O
Cohen	O
SG	O
.	O

The	O
eosinophil	O
,	O
eosinophilia	O
,	O
and	O
eosinophil	O
-	O
related	O
disorders	O
.	O

Allergy	O
Proc	O
1989	O
;	O
10	O
;	O
47	O
-	O
62	O
.	O

Glickman	O
LT	O
,	O
Schantz	O
PM	O
.	O

Epidemiology	O
and	O
pathogenesis	O
of	O
zoonotic	O
toxocariasis	O
.	O

Epidem	O
Rev	O
1981	O
;	O
3	O
=	O
230	O
-	O
250	O
.	O

Beaver	O
P	O
,	O
Snyder	O
H	O
,	O
Carrera	O
G	O
,	O
Dent	O
J	O
,	O
Lafferty	O
J	O
.	O
Chronic	O
eosinophilia	O
due	O
to	O
visceral	O
larva	O
migrans	O
.	O

Pediatrics	O
1952	O
;	O
9	O
:	O
7	O
-	O
19	O
.	O

Limaye	O
AP	O
,	O
Abrams	O
JS	O
,	O
Silver	O
JE	O
,	O
Ottesen	O
EA	O
,	O
Nutman	O
TB	O
.	O

Regulation	O
of	O
parasite	O
-	O
induced	O
eosinophilia	O
:	O
selectively	O
increased	O
interleukin	O
production	O
in	O
helminth	O
-	O
infected	O
patients	B
.	O

J	O
Exp	O
Med	O
1990	O
;	O
l	O
'	O
7	O
:	O
a	O
;	O
399	O
-	O
402	O
.	O

Steel	O
C	O
,	O
Nutman	O
TB	O
.	O

Regulation	O
of	O
IL	O
-	O
5	O
in	O
onchocerciasis	O
:	O
a	O
critical	O
role	O
for	O
IL	O
-	O
2	O
.	O

J	O
Immuno11993	O
;	O
15	O
{	O
}	O
;	O
5511	O
-	O
5518	O
.	O

Yamaguchi	O
Y	O
,	O
Matsui	O
T	O
,	O
Kasahara	O
T	O
,	O
et	O
al	O
.	O

In	O
vivo	O
changes	O
of	O
hemapoietic	O
progenitors	O
and	O
the	O
expression	O
of	O
the	O
interleukin	O
gene	O
in	O
eosinophilic	O
mice	B
infected	O
with	O
Toxocara	B
canis	I
.	O

Exp	O
Hemato11990	O
;	O
18	O
;	O
1152	O
-	O
1157	O
.	O

Parsons	O
JC	O
,	O
Coffman	O
RL	O
,	O
Grieve	O
RB	O
.	O

Antibody	O
to	O
interleukin	O
prevents	O
blood	O
and	O
tissue	O
eosinophilia	O
but	O
not	O
liver	O
trapping	O
in	O
murine	B
larval	O
toxocariasis	O
.	O

Parasite	O
Immuno11993	O
;	O
15	O
:	O
501	O
-	O
508	O
.	O

Coffman	O
RL	O
,	O
Seymour	O
BWP	O
,	O
Hudak	O
S	O
,	O
Jackson	O
J	O
,	O
Rennick	O
D	O
.	O
Antibody	O
to	O
interleukin	O
-	O
5	O
inhibits	O
helminth	O
-	O
induced	O
eosinophilia	O
in	O
mice	B
.	O

Science	O
1989	O
;	O
245	O
;	O
308	O
-	O
310	O
.	O

Sher	O
A	O
,	O
Coffman	O
RL	O
,	O
Hieny	O
S	O
,	O
Cheever	O
AW	O
.	O

Ablation	O
of	O
eosinophil	O
and	O
IgE	O
responses	O
with	O
anti	O
-	O
IL	O
-	O
5	O
or	O
anti	O
-	O
IL	O
-	O
4	O
antibodies	O
fails	O
to	O
affect	O
immunity	O
against	O
Schistosoma	B
mansoni	I
in	O
the	O
mouse	B
.	O

J	O
Immuno11990	O
;	O
145	O
:	O
3911	O

26	O
.	O

27	O
.	O

ACKNOWLEDGEMENTS	O
.	O

This	O
work	O
was	O
funded	O
by	O
grant	O
300652	O
/	O
85	O
-	O
2	O
from	O
Conselho	O
Nacional	O
de	O
Desenvolvimento	O
Cientifico	O
e	O
Tecnol6gico	O
(	O
CNPq	O
)	O
and	O
Grant	O
92	O
/	O
5105	O
-	O
7	O
from	O
Fundago	O
de	O
Amparo	O
ft	O
Pesquisa	O
do	O
Estado	O
de	O
So	O
Paulo	O
(	O
FAPESP	O
)	O
.	O

We	O
wish	O
to	O
thank	O
Mrs	O
M	O
.	O
A	O
.	O

Fernandes	O
for	O
technical	O
assistance	O
,	O
Mrs	O
M	O
.	O
M	O
.	O
O	O
.	O

Rossi	O
for	O
the	O
histological	O
sections	O
,	O
M	O
.	O

Costa	O
Gongalves	O
for	O
the	O
photography	O
artwork	O
,	O
and	O
Dr	O
P	O
.	O

Minoprio	O
,	O
Institut	O
Pasteur	O
,	O
for	O
kindly	O
providing	O
TRFK	O
-	O
5	O
.	O

3916	O
.	O

10	O
.	O

Urban	O

Jr	O
JF	O
,	O

Katona	O
IM	O
,	O
Paul	O
WE	O
,	O
Finkelman	O
FD	O
.	O

Interleukin	O
4	O
is	O
impor	O

Received	O
12	O
October	O
1995	O
;	O
accepted	O
17	O
November	O
1995	O

Mediators	O
of	O
Inflammation	O
Vol	O
5	O

1996	O

31	O

Modeling	O
the	O
effect	O
of	O
PTPN22	O
in	O
rheumatoid	O
arthritis	O

Abstract	O

In	O
order	O
to	O
model	O
the	O
effect	O
of	O
PTPN22	O
on	O
rheumatoid	O
arthritis	O
(	O
RA	O
)	O
,	O
we	O
determined	O
the	O
combination	O
of	O
single	O
-	O
nucleotide	O
-	O
polymorphisms	O
(	O
SNPs	O
)	O
showing	O
the	O
strongest	O
association	O
with	O
RA	O
.	O

Three	O
SNPs	O
(	O
rs2476601	O
-	O
rs12730735	O
-	O
rs11102685	O
)	O
were	O
selected	O
for	O
which	O
we	O
estimated	O
the	O
genotypic	O
relative	O
risks	O
(	O
GRRs	O
)	O
of	O
the	O
corresponding	O
genotypes	O
.	O

On	O
the	O
basis	O
of	O
these	O
GRRs	O
we	O
defined	O
four	O
at	O
-	O
risk	O
genotypic	O
classes	O
.	O

Relative	O
to	O
the	O
class	O
of	O
reference	O
risk	O
,	O
individuals	O
had	O
a	O
risk	O
approximately	O
multiplied	O
by	O
two	O
,	O
three	O
,	O
or	O
four	O
.	O

This	O
classification	O
was	O
confirmed	O
by	O
the	O
excess	O
of	O
identity	O
-	O
by	O
-	O
descent	O
(	O
IBD	O
)	O
sharing	O
(	O
IBD	O
=	O
2	O
)	O
for	O
the	O
sibs	O
of	O
an	O
index	O
in	O
the	O
high	O
-	O
risk	O
class	O
and	O
by	O
excess	O
of	O
non	O
-	O
IBD	O
sharing	O
(	O
IBD	O
=	O
0	O
)	O
when	O
the	O
index	O
belonged	O
to	O
the	O
low	O
-	O
risk	O
class	O
.	O

The	O
observed	O
data	O
could	O
not	O
be	O
explained	O
by	O
the	O
role	O
of	O
a	O
single	O
variant	O
but	O
were	O
compatible	O
either	O
with	O
a	O
joint	O
effect	O
of	O
the	O
three	O
typed	O
SNPs	O
of	O
PTPN22	O
on	O
RA	O
or	O
with	O
the	O
role	O
of	O
two	O
untyped	O
variants	O
.	O

Background	O

The	O
single	O
-	O
nucleotide	O
polymorphism	O
(	O
SNP	O
)	O
R620W	O
,	O
also	O
denoted	O
rs2476601	O
,	O
is	O
located	O
within	O
the	O
hematopoietic	O
-	O
specific	O
protein	O
tyrosine	O
phosphatase	O
gene	O
,	O
PTPN22	O
.	O

This	O
SNP	O
(	O
C	O
/	O
T	O
)	O
codes	O
for	O
an	O
amino	O
-	O
acid	O
change	O
and	O
the	O
frequency	O
of	O
its	O
minor	O
allele	O
T	O
has	O
been	O
recently	O
and	O
repeatedly	O
shown	O
to	O
be	O
increased	O
in	O
patients	B
with	O
rheumatoid	O
arthritis	O
(	O
RA	O
)	O
[	O
1	O
]	O
.	O

The	O
allele	O
T	O
confers	O
1	O
.	O
7	O
-	O
to	O
1	O
.	O
9	O
-	O
fold	O
increased	O
risk	O
to	O
heterozygote	O
and	O
higher	O
risks	O
to	O
homozygote	O
carriers	O
[	O
2	O
]	O
compared	O
to	O
the	O
non	O
-	O
carrier	O
individuals	O
.	O

This	O
variant	O
is	O
also	O
well	O
known	O
to	O
be	O
associated	O
with	O
several	O
other	O
autoimmune	O
diseases	O
[	O
3	O
]	O
,	O
such	O
as	O
systemic	O
lupus	O
erythematosus	O
and	O
type	O
1	O
diabetes	O
.	O

Recently	O
,	O
Carlton	O
et	O
al	O
.	O

[	O
2	O
]	O
studied	O
the	O
PTPN22	O
genetic	O
variations	O
in	O
the	O
North	O
American	O
Rheumatoid	O
Arthritis	O
Consortium	O
(	O
NARAC	O
)	O
data	O
.	O

Using	O
the	O
information	O
on	O
several	O
SNPs	O
typed	O
in	O
PTPN22	O
,	O
they	O
compared	O
the	O
haplotype	O
distributions	O
in	O
NARAC	O
patients	B
and	O
controls	O
.	O

They	O
demonstrated	O
that	O
SNP	O
R620W	O
does	O
not	O
fully	O
explain	O
the	O
association	O
between	O
PTPN22	O
and	O
RA	O
and	O
suggested	O
the	O
effect	O
of	O
at	O
least	O
one	O
additional	O
variant	O
in	O
the	O
PTPN22	O
gene	O
.	O

We	O
propose	O
here	O
to	O
reanalyze	O
the	O
NARAC	O
data	O
using	O
both	O
association	O
and	O
linkage	O
information	O
for	O
modeling	O
the	O
role	O
of	O
PTPN22	O
in	O
RA	O
.	O

Methods	O

Data	O

We	O
selected	O
from	O
the	O
NARAC	O
data	O
the	O
511	O
families	O
with	O
affected	O
sib	O
pairs	O
typed	O
for	O
14	O
SNPs	O
of	O
PTPN22	O
,	O
and	O
1404	O
unrelated	O
controls	O
also	O
typed	O
for	O
all	O
these	O
SNPs	O
.	O

For	O
each	O
affected	O
sib	O
pair	O
we	O
considered	O
the	O
proband	O
as	O
an	O
index	O
RA	O
patient	B
.	O

The	O
R620W	O
SNP	O
is	O
one	O
of	O
the	O
14	O
SNPs	O
in	O
PTPN22	O
.	O

It	O
is	O
located	O
at	O
the	O
ninth	O
position	O
,	O
so	O
it	O
will	O
be	O
subsequently	O
denoted	O
as	O
SNP	O
9	O
.	O

A	O
preliminary	O
study	O
of	O
linkage	O
disequilibrium	O
(	O
LD	O
)	O
among	O
the	O
14	O
SNPs	O
was	O
examined	O
in	O
the	O
1404	O
controls	O
.	O

The	O
LD	O
analysis	O
lead	O
us	O
to	O
exclude	O
3	O
SNPs	O
(	O
SNP	O
2	O
,	O
SNP	O
12	O
,	O
SNP	O
13	O
)	O
,	O
which	O
are	O
in	O
complete	O
LD	O
with	O
one	O
(	O
or	O
more	O
)	O
other	O
SNP	O
(	O
s	O
)	O
.	O

Selection	O
of	O
associated	O
SNPs	O

The	O
combination	O
test	O
[	O
4	O
]	O
was	O
used	O
on	O
the	O
11	O
remaining	O
SNPs	O
to	O
select	O
the	O
subset	O
of	O
SNPs	O
showing	O
a	O
significant	O
difference	O
in	O
the	O
genotypic	O
distribution	O
between	O
RA	O
index	O
patients	B
and	O
controls	O
.	O

Its	O
principle	O
consists	O
in	O
testing	O
all	O
possible	O
combinations	O
of	O
SNPs	O
within	O
a	O
gene	O
.	O

Here	O
,	O
there	O
are	O
(	O
211	O
-	O
1	O
)	O
possible	O
combinations	O
.	O

Such	O
a	O
systematic	O
testing	O
of	O
all	O
SNPs	O
and	O
all	O
SNP	O
combinations	O
raises	O
the	O
problem	O
of	O
multiple	O
and	O
non	O
-	O
independent	O
tests	O
.	O

This	O
problem	O
is	O
generally	O
solved	O
by	O
the	O
implementation	O
of	O
a	O
permutation	O
procedure	O
that	O
allows	O
estimation	O
of	O
corrected	O
p	O
-	O
values	O
.	O

Here	O
,	O
associated	O
combinations	O
are	O
very	O
significant	O
and	O
the	O
number	O
of	O
permutations	O
necessary	O
to	O
discriminate	O
them	O
would	O
be	O
extremely	O
high	O
and	O
almost	O
unreachable	O
.	O

Nevertheless	O
,	O
the	O
chi	O
-	O
square	O
values	O
of	O
the	O
genotypic	O
association	O
test	O
are	O
so	O
high	O
that	O
even	O
the	O
conservative	O
Bonferroni	O
correction	O
can	O
be	O
used	O
.	O

We	O
selected	O
the	O
most	O
associated	O
and	O
parsimonious	O
subset	O
of	O
SNPs	O
by	O
nested	O
chi	O
-	O
square	O
tests	O
(	O
NCST	O
)	O
in	O
a	O
forward	O
procedure	O
.	O

The	O
NCST	O
compares	O
the	O
strength	O
of	O
association	O
between	O
nested	O
significant	O
subsets	O
.	O

Genotypic	O
relative	O
-	O
risk	O
estimation	O

For	O
the	O
selected	O
subset	O
of	O
SNPs	O
,	O
we	O
used	O
the	O
marker	O
association	O
segregation	O
chi	O
-	O
square	O
(	O
MASC	O
)	O
method	O
[	O
5	O
]	O
to	O
compute	O
the	O
genotypic	O
relative	O
risk	O
(	O
GRR	O
)	O
of	O
each	O
genotype	O
.	O

The	O
genotype	O
distributions	O
of	O
index	O
and	O
controls	O
was	O
conditional	O
on	O
the	O
fact	O
that	O
the	O
index	O
has	O
an	O
affected	O
sib	O
.	O

Stratified	O
sib	O
pair	O
IBD	O
estimation	O

Conditional	O
on	O
each	O
marker	O
genotype	O
of	O
the	O
index	O
cases	O
,	O
the	O
number	O
of	O
parental	O
alleles	O
identical	O
by	O
descent	O
(	O
IBD	O
)	O
shared	O
by	O
the	O
index	O
case	O
and	O
one	O
affected	O
sib	O
were	O
estimated	O
on	O
PTPN22	O
with	O
the	O
MERLIN	O
software	O
[	O
6	O
]	O
.	O

MERLIN	O
is	O
able	O
to	O
take	O
into	O
account	O
LD	O
between	O
SNPs	O
during	O
the	O
IBD	O
computation	O
.	O

So	O
the	O
estimated	O
IBD	O
distributions	O
are	O
computed	O
on	O
the	O
overall	O
set	O
of	O
SNPs	O
even	O
if	O
they	O
are	O
in	O
LD	O
.	O

The	O
fit	O
of	O
a	O
model	O
to	O
the	O
IBD	O
distributions	O
stratified	O
on	O
index	O
marker	O
genotypes	O
[	O
7	O
]	O
may	O
then	O
be	O
tested	O
by	O
the	O
MASC	O
method	O
.	O

Modeling	O
PTPN22	O
effect	O

We	O
applied	O
the	O
MASC	O
method	O
[	O
5	O
]	O
to	O
find	O
the	O
most	O
parsimonious	O
model	O
explaining	O
the	O
overall	O
observations	O
,	O
i	O
.	O
e	O
.	O
,	O
the	O
genotype	O
and	O
the	O
stratified	O
sib	O
-	O
pair	O
IBD	O
distributions	O
.	O

To	O
do	O
this	O
,	O
MASC	O
requires	O
the	O
haplotype	O
frequencies	O
in	O
the	O
general	O
population	O
,	O
which	O
were	O
estimated	O
on	O
the	O
unrelated	O
controls	O
by	O
the	O
MERLIN	O
software	O
.	O

The	O
MASC	O
method	O
computes	O
the	O
expected	O
genotype	O
marker	O
distribution	O
and	O
the	O
expected	O
sib	O
-	O
pair	O
IBD	O
distributions	O
stratified	O
on	O
marker	O
genotypes	O
for	O
a	O
given	O
genetic	O
model	O
.	O

Here	O
,	O
the	O
computation	O
of	O
the	O
genotypic	O
distribution	O
is	O
conditioned	O
on	O
the	O
fact	O
that	O
index	O
cases	O
have	O
an	O
affected	O
sib	O
.	O

The	O
global	O
expected	O
likelihood	O
of	O
the	O
genetic	O
model	O
given	O
the	O
observed	O
data	O
is	O
then	O
computed	O
as	O
the	O
product	O
of	O
the	O
likelihoods	O
of	O
each	O
expected	O
distribution	O
,	O
and	O
is	O
maximized	O
on	O
the	O
model	O
parameters	O
.	O

The	O
fit	O
of	O
the	O
model	O
to	O
the	O
observed	O
data	O
is	O
tested	O
by	O
a	O
likelihood	O
ratio	O
test	O
(	O
LRT	O
)	O
between	O
global	O
expected	O
likelihood	O
and	O
the	O
likelihood	O
of	O
the	O
saturated	O
model	O
.	O

Results	O

Selection	O
of	O
associated	O
SNPs	O

Many	O
subsets	O
of	O
SNPs	O
show	O
significant	O
associations	O
.	O

Table	O
1	O
presents	O
a	O
selection	O
of	O
the	O
most	O
associated	O
combinations	O
of	O
one	O
,	O
two	O
,	O
and	O
three	O
SNPs	O
.	O

When	O
considering	O
only	O
the	O
effect	O
of	O
a	O
single	O
SNP	O
,	O
the	O
only	O
significant	O
associated	O
one	O
after	O
correction	O
for	O
multiple	O
testing	O
is	O
SNP	O
9	O
.	O

The	O
combination	O
of	O
SNPs	O
9	O
-	O
10	O
is	O
the	O
one	O
which	O
,	O
among	O
the	O
combination	O
of	O
two	O
SNPs	O
,	O
best	O
improves	O
the	O
association	O
shown	O
by	O
the	O
SNP	O
9	O
alone	O
(	O
p	O
=	O
0	O
.	O
017	O
)	O
.	O

The	O
subset	O
SNPs	O
9	O
-	O
10	O
-	O
11	O
(	O
rs2476601	O
-	O
rs12730735	O
-	O
rs11102685	O
)	O
is	O
the	O
only	O
one	O
that	O
improves	O
significantly	O
the	O
association	O
shown	O
by	O
the	O
SNPs	O
9	O
-	O
10	O
(	O
p	O
=	O
0	O
.	O
038	O
)	O
.	O

Adding	O
another	O
SNP	O
to	O
this	O
subset	O
does	O
not	O
significantly	O
improve	O
the	O
association	O
.	O

Consequently	O
,	O
all	O
the	O
subsequent	O
analyses	O
have	O
been	O
done	O
considering	O
SNPs	O
9	O
-	O
10	O
-	O
11	O
and	O
their	O
ten	O
corresponding	O
genotypes	O
.	O

GRR	O
estimation	O

Table	O
2	O
displays	O
the	O
genotypes	O
and	O
the	O
corresponding	O
GRRs	O
for	O
SNP	O
9	O
taken	O
alone	O
(	O
columns	O
1	O
and	O
2	O
)	O
and	O
for	O
the	O
set	O
of	O
the	O
three	O
SNPs	O
9	O
-	O
10	O
-	O
11	O
(	O
columns	O
3	O
and	O
4	O
)	O
.	O

The	O
GRRs	O
vary	O
from	O
1	O
to	O
2	O
.	O
7	O
when	O
considering	O
only	O
SNP	O
9	O
,	O
whereas	O
the	O
variation	O
ranges	O
from	O
1	O
to	O
4	O
.	O
7	O
when	O
the	O
information	O
on	O
the	O
three	O
SNPs	O
is	O
taken	O
into	O
account	O
.	O

Interestingly	O
,	O
the	O
CC	O
genotype	O
of	O
the	O
SNP	O
9	O
can	O
be	O
subdivided	O
in	O
several	O
genotypes	O
when	O
taking	O
into	O
account	O
the	O
genotypes	O
for	O
SNPs	O
10	O
and	O
11	O
(	O
rows	O
1	O
to	O
6	O
)	O
with	O
GRRs	O
ranging	O
from	O
1	O
(	O
CC	O
-	O
GG	O
-	O
AA	O
)	O
to	O
3	O
.	O
6	O
(	O
CC	O
-	O
AA	O
-	O
GG	O
)	O
.	O

This	O
observation	O
demonstrates	O
the	O
importance	O
of	O
using	O
the	O
additional	O
information	O
on	O
SNPs	O
10	O
-	O
11	O
.	O

Sib	O
pair	O
IBD	O
estimation	O

The	O
proportion	O
of	O
RA	O
sibs	O
sharing	O
0	O
,	O
1	O
,	O
or	O
2	O
parental	O
alleles	O
for	O
PTPN22	O
is	O
0	O
.	O
26	O
(	O
181	O
pairs	O
)	O
,	O
0	O
.	O
51	O
(	O
362	O
pairs	O
)	O
,	O
and	O
0	O
.	O
23	O
(	O
167	O
pairs	O
)	O
,	O
respectively	O
,	O
and	O
does	O
not	O
differ	O
from	O
the	O
IBD	O
distribution	O
0	O
.	O
25	O
;	O
0	O
.	O
5	O
;	O
0	O
.	O
25	O
expected	O
under	O
no	O
linkage	O
.	O

However	O
,	O
if	O
our	O
GRRs	O
correctly	O
reflect	O
the	O
differential	O
risk	O
of	O
RA	O
,	O
we	O
expect	O
to	O
see	O
differences	O
in	O
the	O
IBD	O
vectors	O
stratified	O
on	O
the	O
genotypes	O
of	O
the	O
subset	O
of	O
SNPs	O
9	O
-	O
10	O
-	O
11	O
[	O
7	O
]	O
.	O

To	O
avoid	O
cells	O
with	O
small	O
numbers	O
of	O
individuals	O
we	O
pooled	O
sib	O
pairs	O
with	O
the	O
index	O
genotypes	O
(	O
SNP	O
9	O
-	O
10	O
-	O
11	O
)	O
that	O
have	O
similar	O
risk	O
.	O

We	O
thus	O
defined	O
four	O
arbitrary	O
at	O
risk	O
genotypic	O
classes	O
:	O
the	O
low	O
risk	O
class	O
(	O
L	O
;	O
GRR	O
=	O
1	O
;	O
19	O
pairs	O
)	O
,	O
the	O
intermediate	O
risk	O
class	O
1	O
(	O
I1	O
;	O
1	O
<	O
GRR	O
<	O
=	O
2	O
;	O
295	O
pairs	O
)	O
,	O
the	O
intermediate	O
risk	O
class	O
2	O
(	O
I2	O
;	O
2	O
<	O
GRR	O
<	O
=	O
3	O
;	O
157	O
pairs	O
)	O
,	O
and	O
the	O
high	O
risk	O
class	O
(	O
H	O
;	O
GRR	O
>	O
3	O
;	O
34	O
pairs	O
)	O
.	O

Table	O
3	O
shows	O
that	O
the	O
proportion	O
of	O
IBD	O
=	O
0	O
decreases	O
from	O
0	O
.	O
47	O
to	O
0	O
.	O
09	O
according	O
to	O
the	O
fact	O
that	O
the	O
index	O
belongs	O
to	O
class	O
L	O
or	O
class	O
H	O
and	O
conversely	O
,	O
the	O
proportion	O
of	O
IBD	O
=	O
2	O
increases	O
from	O
0	O
.	O
11	O
to	O
0	O
.	O
26	O
.	O

These	O
stratified	O
IBD	O
distributions	O
are	O
consistent	O
with	O
the	O
risk	O
genotypic	O
classes	O
.	O

In	O
contrast	O
,	O
the	O
IBD	O
sharing	O
distributions	O
stratified	O
only	O
on	O
SNP	O
9	O
genotypes	O
are	O
not	O
consistent	O
with	O
the	O
GRR	O
estimates	O
on	O
this	O
SNP	O
(	O
Table	O
4	O
)	O
.	O

Modeling	O
PTPN22	O
effect	O

We	O
apply	O
the	O
MASC	O
method	O
in	O
using	O
the	O
genotype	O
distribution	O
only	O
on	O
the	O
SNP	O
9	O
and	O
the	O
IBD	O
stratified	O
on	O
the	O
SNP	O
9	O
genotypes	O
.	O

In	O
that	O
case	O
,	O
the	O
single	O
and	O
causal	O
effect	O
of	O
the	O
SNP	O
9	O
is	O
not	O
rejected	O
(	O
p	O
=	O
0	O
.	O
29	O
)	O
.	O

Then	O
,	O
we	O
model	O
the	O
effect	O
of	O
PTPN22	O
using	O
the	O
four	O
genotypic	O
groups	O
of	O
risk	O
defined	O
on	O
the	O
genotypes	O
of	O
the	O
combination	O
of	O
the	O
SNPs	O
9	O
-	O
10	O
-	O
11	O
and	O
the	O
IBD	O
information	O
stratified	O
on	O
them	O
.	O

In	O
this	O
case	O
,	O
we	O
reject	O
the	O
direct	O
effect	O
of	O
SNP	O
9	O
(	O
p	O
=	O
0	O
.	O
005	O
)	O
.	O

We	O
also	O
reject	O
the	O
effect	O
of	O
a	O
single	O
untyped	O
SNP	O
(	O
p	O
=	O
0	O
.	O
04	O
)	O
.	O

However	O
,	O
we	O
do	O
not	O
reject	O
the	O
interactive	O
effect	O
of	O
the	O
3	O
SNPs	O
(	O
p	O
=	O
0	O
.	O
53	O
)	O
or	O
the	O
interactive	O
effect	O
of	O
two	O
untyped	O
SNPs	O
.	O

Discussion	O

The	O
involvement	O
of	O
PTPN22	O
and	O
HLA	O
in	O
RA	O
susceptibility	O
is	O
no	O
longer	O
disputed	O
.	O

However	O
,	O
as	O
shown	O
by	O
Carlton	O
et	O
al	O
.	O
and	O
confirmed	O
in	O
this	O
study	O
,	O
the	O
role	O
of	O
PTPN22	O
cannot	O
be	O
explained	O
only	O
by	O
the	O
R620W	O
SNP	O
.	O

A	O
correct	O
modeling	O
of	O
PTPN22	O
is	O
important	O
and	O
shows	O
that	O
the	O
genotypic	O
risk	O
varies	O
much	O
more	O
(	O
1	O
to	O
4	O
.	O
7	O
)	O
than	O
reported	O
in	O
the	O
literature	O
(	O
1	O
to	O
2	O
.	O
7	O
)	O
[	O
4	O
]	O
.	O

In	O
this	O
study	O
we	O
proposed	O
,	O
for	O
the	O
first	O
time	O
,	O
a	O
model	O
for	O
the	O
effect	O
of	O
PTPN22	O
,	O
taking	O
into	O
account	O
both	O
association	O
and	O
linkage	O
information	O
.	O

Another	O
method	O
,	O
called	O
LAMP	O
[	O
8	O
]	O
was	O
recently	O
proposed	O
for	O
joint	O
modeling	O
of	O
linkage	O
and	O
association	O
[	O
8	O
]	O
.	O

The	O
linkage	O
information	O
used	O
by	O
the	O
LAMP	O
method	O
is	O
the	O
global	O
IBD	O
sharing	O
of	O
affected	O
sib	O
pairs	O
.	O

However	O
,	O
it	O
is	O
very	O
important	O
to	O
note	O
that	O
the	O
power	O
of	O
model	O
discrimination	O
strongly	O
depends	O
on	O
the	O
association	O
and	O
linkage	O
information	O
that	O
is	O
used	O
.	O

As	O
shown	O
here	O
,	O
the	O
information	O
on	O
SNP	O
9	O
alone	O
and	O
on	O
the	O
global	O
IBD	O
is	O
very	O
poor	O
as	O
compared	O
with	O
that	O
of	O
the	O
three	O
SNPs	O
9	O
-	O
10	O
-	O
11	O
and	O
to	O
the	O
stratified	O
IBD	O
distributions	O
on	O
the	O
four	O
at	O
-	O
risk	O
genotype	O
groups	O
.	O

In	O
conclusion	O
,	O
we	O
applied	O
a	O
four	O
-	O
step	O
strategy	O
to	O
model	O
the	O
effect	O
of	O
a	O
candidate	O
gene	O
covered	O
by	O
several	O
SNPs	O
:	O
1	O
)	O
to	O
select	O
the	O
most	O
associated	O
set	O
of	O
SNPs	O
;	O
2	O
)	O
to	O
group	O
the	O
corresponding	O
genotypes	O
according	O
their	O
GRRs	O
;	O
3	O
)	O
to	O
stratify	O
IBD	O
sharing	O
information	O
on	O
the	O
at	O
-	O
risk	O
genotype	O
groups	O
;	O
4	O
)	O
to	O
model	O
the	O
effect	O
of	O
the	O
candidate	O
gene	O
while	O
taking	O
into	O
account	O
both	O
linkage	O
and	O
association	O
information	O
.	O

This	O
strategy	O
allowed	O
better	O
modeling	O
of	O
the	O
effect	O
of	O
PTPN22	O
in	O
RA	O
susceptibility	O
.	O

Recently	O
,	O
du	O
Montcel	O
et	O
al	O
.	O

[	O
9	O
]	O
refined	O
the	O
modeling	O
of	O
HLA	O
in	O
RA	O
susceptibility	O
.	O

A	O
next	O
step	O
will	O
be	O
to	O
use	O
simultaneously	O
the	O
PTPN22	O
and	O
HLA	O
information	O
to	O
evaluate	O
their	O
joint	O
effects	O
while	O
taking	O
into	O
account	O
important	O
covariables	O
such	O
as	O
age	O
and	O
gender	O
.	O

Competing	O
interests	O

The	O
author	O
(	O
s	O
)	O
declare	O
that	O
they	O
have	O
no	O
competing	O
interests	O
.	O

Purinergic	O
signalling	O
in	O
the	O
subretinal	O
space	O
:	O
a	O
role	O
in	O
the	O
communication	O
between	O
the	O
retina	O
and	O
the	O
RPE	O

Abstract	O

The	O
retinal	O
pigment	O
epithelium	O
(	O
RPE	O
)	O
is	O
separated	O
from	O
the	O
photoreceptor	O
outer	O
segments	O
by	O
the	O
subretinal	O
space	O
.	O

While	O
the	O
actual	O
volume	O
of	O
this	O
space	O
is	O
minimal	O
,	O
the	O
communication	O
that	O
occurs	O
across	O
this	O
microenvironment	O
is	O
important	O
to	O
the	O
visual	O
process	O
,	O
and	O
accumulating	O
evidence	O
suggests	O
the	O
purines	O
ATP	O
and	O
adenosine	O
contribute	O
to	O
this	O
communication	O
.	O

P1	O
and	O
P2	O
receptors	O
are	O
localized	O
to	O
membranes	O
on	O
both	O
the	O
photoreceptor	O
outer	O
segments	O
and	O
on	O
the	O
apical	O
membrane	O
of	O
the	O
RPE	O
which	O
border	O
subretinal	O
space	O
.	O

ATP	O
is	O
released	O
across	O
the	O
apical	O
membrane	O
of	O
the	O
RPE	O
into	O
this	O
space	O
in	O
response	O
to	O
various	O
triggers	O
including	O
glutamate	O
and	O
chemical	O
ischemia	O
.	O

This	O
ATP	O
is	O
dephosphorylated	O
into	O
adenosine	O
by	O
a	O
series	O
of	O
ectoenzymes	O
on	O
the	O
RPE	O
apical	O
membrane	O
.	O

Regulation	O
of	O
release	O
and	O
ectoenzyme	O
activity	O
in	O
response	O
to	O
light	O
-	O
sensitive	O
signals	O
can	O
alter	O
the	O
balance	O
of	O
purines	O
in	O
subretinal	O
space	O
,	O
and	O
thus	O
coordinate	O
communication	O
across	O
subretinal	O
space	O
with	O
the	O
visual	O
process	O
.	O

Introduction	O

The	O
retinal	O
pigment	O
epithelium	O
(	O
RPE	O
)	O
lies	O
between	O
the	O
outer	O
segments	O
of	O
the	O
photoreceptors	O
and	O
the	O
choroidal	O
blood	O
supply	O
(	O
Fig	O
.	O
1	O
)	O
.	O

The	O
RPE	O
combines	O
the	O
functions	O
of	O
epithelial	O
and	O
glial	O
cells	O
,	O
providing	O
a	O
barrier	O
while	O
also	O
supporting	O
the	O
neural	O
photoreceptors	O
and	O
modulating	O
their	O
function	O
.	O

Tight	O
communication	O
between	O
photoreceptors	O
and	O
the	O
RPE	O
is	O
critical	O
to	O
coordinate	O
the	O
multiple	O
levels	O
of	O
interaction	O
,	O
and	O
the	O
purinergic	O
contribution	O
to	O
this	O
communication	O
is	O
becoming	O
apparent	O
.	O

The	O
relevance	O
of	O
this	O
purinergic	O
input	O
is	O
emphasized	O
by	O
the	O
many	O
functional	O
effects	O
of	O
P1	O
and	O
P2	O
receptor	O
stimulation	O
and	O
by	O
the	O
multiple	O
mechanisms	O
in	O
place	O
to	O
regulate	O
subretinal	O
levels	O
of	O
purine	O
agonists	O
.	O

As	O
the	O
dynamics	O
of	O
ATP	O
release	O
and	O
extracellular	O
conversion	O
into	O
adenosine	O
will	O
modify	O
agonist	O
availability	O
,	O
the	O
modulation	O
of	O
these	O
processes	O
can	O
exert	O
a	O
temporal	O
control	O
on	O
purinergic	O
signaling	O
.	O

The	O
following	O
review	O
will	O
outline	O
the	O
main	O
interactions	O
between	O
the	O
RPE	O
and	O
photoreceptors	O
,	O
describe	O
the	O
effects	O
of	O
stimulating	O
purinergic	O
receptors	O
on	O
both	O
sides	O
of	O
subretinal	O
space	O
,	O
and	O
summarize	O
how	O
levels	O
of	O
ATP	O
,	O
ADP	O
,	O
and	O
adenosine	O
are	O
manipulated	O
in	O
this	O
microenvironment	O
.	O

Fig	O
.	O
1Schematic	O
illustration	O
of	O
the	O
key	O
components	O
of	O
purinergic	O
signaling	O
in	O
the	O
subretinal	O
microenvironment	O
.	O

Stimulation	O
of	O
P2	O
receptors	O
on	O
the	O
RPE	O
can	O
enhance	O
transepithelial	O
fluid	O
absorption	O
while	O
P1	O
receptors	O
can	O
modulate	O
phagocytosis	O
.	O

ATP	O
released	O
through	O
CFTR	O
and	O
other	O
Cl	O
-	O
channels	O
can	O
stimulate	O
P2	O
receptors	O
or	O
be	O
converted	O
to	O
ADP	O
,	O
AMP	O
,	O
and	O
adenosine	O
(	O
Ado	O
)	O
by	O
a	O
series	O
of	O
ectonucleotidases	O
present	O
on	O
the	O
apical	O
membrane	O
of	O
the	O
RPE	O
.	O

By	O
controlling	O
the	O
balance	O
of	O
extracellular	O
purines	O
available	O
to	O
stimulate	O
these	O
receptors	O
these	O
mechanisms	O
can	O
control	O
levels	O
of	O
endogenous	O
purines	O
available	O
to	O
activate	O
the	O
receptors	O
.	O

While	O
theoretically	O
possible	O
,	O
it	O
remains	O
to	O
be	O
determined	O
whether	O
these	O
subretinal	O
purines	O
can	O
actually	O
stimulate	O
photoreceptors	O

Purines	O
and	O
subretinal	O
space	O

RPE	O
-	O
photoreceptor	O
interactions	O
across	O
the	O
subretinal	O
space	O

The	O
outer	O
segments	O
of	O
the	O
rods	O
and	O
cones	O
are	O
responsible	O
for	O
the	O
initial	O
stages	O
of	O
vision	O
,	O
converting	O
photon	O
energy	O
into	O
a	O
series	O
of	O
enzymatic	O
reactions	O
that	O
close	O
the	O
light	O
-	O
sensitive	O
channels	O
on	O
the	O
photoreceptor	O
plasma	O
membrane	O
,	O
hyperpolarize	O
the	O
cells	O
,	O
and	O
reduce	O
the	O
release	O
of	O
glutamate	O
from	O
the	O
synaptic	O
terminals	O
[	O
1	O
,	O
2	O
]	O
.	O

Efficient	O
photoreceptor	O
function	O
depends	O
upon	O
both	O
short	O
-	O
term	O
and	O
long	O
-	O
term	O
support	O
from	O
the	O
RPE	O
.	O

The	O
critical	O
nature	O
of	O
these	O
interactions	O
is	O
evident	O
from	O
the	O
rapid	O
degeneration	O
of	O
photoreceptors	O
in	O
the	O
absence	O
of	O
a	O
healthy	O
RPE	O
layer	O
and	O
by	O
the	O
RPE	O
localization	O
of	O
defective	O
gene	O
product	O
in	O
some	O
forms	O
of	O
hereditary	O
photoreceptor	O
degeneration	O
[	O
3	O
]	O
.	O

The	O
apical	O
membrane	O
of	O
the	O
RPE	O
is	O
separated	O
from	O
the	O
plasma	O
membrane	O
of	O
the	O
outer	O
segments	O
by	O
an	O
extracellular	O
space	O
of	O
only	O
10	O
-	O
20	O
nm	O
[	O
4	O
]	O
.	O

Although	O
small	O
,	O
this	O
subretinal	O
space	O
contains	O
a	O
highly	O
structured	O
matrix	O
which	O
ensheathes	O
the	O
outer	O
segments	O
and	O
extends	O
to	O
the	O
RPE	O
[	O
5	O
,	O
6	O
]	O
.	O

The	O
presence	O
of	O
enzymes	O
within	O
this	O
interphotoreceptor	O
matrix	O
emphasizes	O
that	O
this	O
extracellular	O
space	O
itself	O
is	O
functionally	O
active	O
[	O
7	O
,	O
8	O
]	O
.	O

This	O
intimate	O
anatomical	O
relationship	O
between	O
photoreceptors	O
and	O
the	O
RPE	O
reflects	O
multiple	O
functional	O
interactions	O
.	O

For	O
example	O
,	O
the	O
RPE	O
accepts	O
,	O
recycles	O
,	O
and	O
exports	O
central	O
components	O
of	O
the	O
phototransduction	O
process	O
[	O
9	O
]	O
.	O

The	O
outer	O
segments	O
are	O
continuously	O
resynthesized	O
,	O
and	O
the	O
phagocytosis	O
,	O
degradation	O
,	O
and	O
processing	O
of	O
shed	O
outer	O
segment	O
tips	O
by	O
the	O
RPE	O
cells	O
is	O
central	O
to	O
this	O
renewal	O
[	O
10	O
]	O
.	O

The	O
ion	O
channels	O
and	O
transporters	O
on	O
the	O
apical	O
membrane	O
of	O
the	O
RPE	O
help	O
regulate	O
the	O
ionic	O
composition	O
of	O
the	O
subretinal	O
space	O
[	O
11	O
]	O
.	O

As	O
extracellular	O
levels	O
of	O
ions	O
can	O
modify	O
the	O
ionic	O
driving	O
forces	O
across	O
the	O
photoreceptor	O
plasma	O
membrane	O
,	O
these	O
RPE	O
transporters	O
can	O
influence	O
the	O
state	O
of	O
neural	O
activity	O
.	O

The	O
transport	O
of	O
fluid	O
and	O
ions	O
from	O
the	O
apical	O
membrane	O
to	O
basolateral	O
membrane	O
of	O
the	O
RPE	O
is	O
also	O
one	O
of	O
the	O
main	O
forces	O
keeping	O
the	O
retina	O
attached	O
[	O
12	O
]	O
.	O

The	O
control	O
of	O
photoreceptor	O
activity	O
by	O
light	O
gives	O
a	O
rapid	O
temporal	O
dependence	O
to	O
some	O
interactions	O
between	O
the	O
photoreceptors	O
and	O
the	O
RPE	O
.	O

The	O
volume	O
of	O
subretinal	O
space	O
increases	O
in	O
response	O
to	O
light	O
[	O
13	O
]	O
,	O
linking	O
small	O
changes	O
in	O
the	O
ionic	O
composition	O
of	O
the	O
subretinal	O
space	O
with	O
activity	O
of	O
the	O
RPE	O
transport	O
mechanisms	O
which	O
maintain	O
this	O
volume	O
[	O
14	O
,	O
15	O
]	O
.	O

Other	O
processes	O
are	O
controlled	O
on	O
a	O
diurnal	O
cycle	O
.	O

The	O
shed	O
tips	O
of	O
the	O
outer	O
segments	O
are	O
phagocytosed	O
by	O
the	O
RPE	O
soon	O
after	O
the	O
onset	O
of	O
light	O
[	O
16	O
,	O
17	O
]	O
.	O

These	O
processes	O
can	O
both	O
be	O
modulated	O
by	O
purine	O
levels	O
in	O
subretinal	O
space	O
,	O
indicating	O
purinergic	O
regulation	O
is	O
important	O
over	O
multiple	O
time	O
scales	O
.	O

Purinergic	O
receptors	O
on	O
photoreceptors	O

A2	O
adenosine	O
receptors	O
were	O
localized	O
to	O
both	O
the	O
inner	O
and	O
outer	O
segments	O
of	O
photoreceptor	O
outer	O
segments	O
over	O
a	O
decade	O
ago	O
by	O
Blazynski	O
and	O
colleagues	O
[	O
18	O
]	O
,	O
with	O
more	O
recent	O
reports	O
emphasizing	O
their	O
functional	O
role	O
.	O

A2	O
agonists	O
inhibit	O
the	O
L	O
-	O
type	O
Ca2	O
+	O
channel	O
on	O
rod	O
outer	O
segments	O
[	O
19	O
]	O
and	O
can	O
inhibit	O
the	O
synaptic	O
release	O
of	O
glutamate	O
from	O
rods	O
,	O
suggesting	O
changes	O
in	O
adenosine	O
levels	O
in	O
subretinal	O
space	O
could	O
modulate	O
light	O
sensitivity	O
[	O
20	O
]	O
.	O

The	O
A2	O
agonist	O
DPMA	O
and	O
the	O
adenosine	O
deaminase	O
inhibitor	O
EHNA	O
reduce	O
mRNA	O
for	O
opsin	O
in	O
rods	O
,	O
suggesting	O
that	O
endogenous	O
levels	O
of	O
adenosine	O
can	O
downregulate	O
opsin	O
message	O
at	O
night	O
[	O
21	O
]	O
.	O

EHNA	O
and	O
the	O
A2A	O
receptor	O
agonist	O
CGS21680	O
also	O
increase	O
the	O
survival	O
of	O
chick	O
embryonic	O
photoreceptors	O
in	O
culture	O
[	O
22	O
]	O
,	O
indicating	O
a	O
long	O
-	O
term	O
neuroprotective	O
role	O
for	O
adenosine	O
.	O

P2	O
receptors	O
are	O
also	O
present	O
in	O
the	O
photoreceptors	O
.	O

mRNA	O
for	O
the	O
P2X2	O
receptor	O
is	O
expressed	O
in	O
the	O
photoreceptor	O
cell	O
bodies	O
,	O
with	O
immunohistochemical	O
localization	O
of	O
the	O
protein	O
to	O
outer	O
segments	O
[	O
23	O
]	O
.	O

In	O
situ	O
hybridization	O
indicates	O
the	O
photoreceptor	O
layer	O
has	O
the	O
highest	O
level	O
of	O
P2Y2	O
receptor	O
of	O
any	O
region	O
in	O
the	O
rabbit	B
retina	O
,	O
although	O
staining	O
was	O
not	O
pronounced	O
in	O
monkey	O
[	O
24	O
]	O
.	O

P2X7	O
receptors	O
have	O
recently	O
been	O
localized	O
to	O
photoreceptor	O
synaptic	O
terminals	O
,	O
with	O
evidence	O
for	O
ecto	O
-	O
ATPase	O
activity	O
in	O
the	O
synapse	O
,	O
and	O
functional	O
evidence	O
suggesting	O
ATP	O
augments	O
transmission	O
of	O
the	O
light	O
response	O
by	O
rods	O
[	O
25	O
]	O
.	O

It	O
was	O
suggested	O
that	O
ATP	O
might	O
be	O
co	O
-	O
released	O
from	O
photoreceptors	O
with	O
glutamate	O
,	O
although	O
this	O
remains	O
to	O
be	O
tested	O
directly	O
.	O

Purinergic	O
receptors	O
on	O
the	O
RPE	O

Stimulation	O
of	O
P1	O
receptors	O
can	O
have	O
a	O
considerable	O
impact	O
on	O
RPE	O
cells	O
.	O

A2	O
receptors	O
have	O
been	O
recognized	O
on	O
cultured	O
and	O
fresh	O
RPE	O
cells	O
for	O
some	O
time	O
[	O
26	O
,	O
27	O
]	O
,	O
with	O
in	O
situ	O
hybridization	O
confirming	O
the	O
presence	O
of	O
A2A	O
receptors	O
in	O
rat	B
RPE	O
[	O
28	O
]	O
.	O

Stimulation	O
of	O
A2	O
receptors	O
reduces	O
the	O
rate	O
of	O
rod	O
outer	O
segment	O
phagocytosis	O
by	O
RPE	O
cells	O
[	O
29	O
]	O
,	O
while	O
application	O
of	O
adenosine	O
to	O
the	O
apical	O
membrane	O
of	O
chick	O
RPE	O
cells	O
increases	O
the	O
basolateral	O
Cl	O
-	O
conductance	O
,	O
the	O
transepithelial	O
potential	O
,	O
and	O
the	O
c	O
-	O
wave	O
,	O
and	O
decreases	O
the	O
hyperpolarization	O
of	O
the	O
basal	O
membrane	O
in	O
response	O
to	O
light	O
[	O
30	O
]	O
.	O

Although	O
adenosine	O
alone	O
does	O
not	O
increase	O
intracellular	O
Ca2	O
+	O
levels	O
[	O
31	O
]	O
,	O
adenosine	O
acts	O
synergistically	O
with	O
ATP	O
to	O
elevate	O
Ca2	O
+	O
levels	O
in	O
human	B
RPE	O
cells	O
by	O
stimulating	O
both	O
A1	O
and	O
A2A	O
receptors	O
[	O
32	O
,	O
33	O
]	O
.	O

Stimulation	O
of	O
A1	O
receptors	O
with	O
high	O
doses	O
of	O
NECA	O
increases	O
the	O
active	O
transport	O
of	O
fluorescein	O
across	O
the	O
RPE	O
,	O
while	O
activation	O
of	O
A2A	O
receptors	O
decreases	O
this	O
transport	O
,	O
and	O
by	O
extension	O
,	O
transport	O
of	O
the	O
ions	O
that	O
underlie	O
fluid	O
movement	O
[	O
34	O
]	O
.	O

Stimulation	O
of	O
A1	O
and	O
A2A	O
receptors	O
produces	O
analogous	O
increases	O
and	O
decreases	O
,	O
respectively	O
,	O
in	O
the	O
absorption	O
of	O
subretinal	O
fluid	O
blebs	O
.	O

This	O
is	O
consistent	O
with	O
the	O
negative	O
coupling	O
of	O
the	O
A1	O
receptor	O
and	O
the	O
positive	O
coupling	O
of	O
the	O
A2	O
receptors	O
to	O
adenylate	O
cyclase	O
,	O
as	O
increasing	O
cAMP	O
inhibits	O
the	O
transport	O
of	O
fluid	O
across	O
the	O
RPE	O
towards	O
the	O
choroid	O
[	O
35	O
-	O
37	O
]	O
.	O

The	O
agonist	O
2	O
-	O
Cl	O
adenosine	O
reverses	O
the	O
deficit	O
in	O
phosphoinositide	O
metabolism	O
found	O
in	O
diabetic	O
RPE	O
cells	O
[	O
38	O
]	O
,	O
suggesting	O
effects	O
on	O
metabolism	O
in	O
addition	O
to	O
transport	O
and	O
phagocytosis	O
.	O

Multiple	O
P2	O
receptors	O
have	O
been	O
localized	O
to	O
the	O
RPE	O
.	O

The	O
P2Y2	O
receptor	O
was	O
initially	O
characterized	O
in	O
cultured	O
human	B
RPE	O
[	O
31	O
]	O
,	O
with	O
subsequent	O
reports	O
localizing	O
transcript	O
for	O
P2Y1	O
,	O
P2Y2	O
,	O
P2Y4	O
,	O
and	O
P2Y6	O
in	O
the	O
rat	B
RPE	O
/	O
choroid	O
[	O
39	O
]	O
and	O
for	O
P2Y1	O
and	O
P2Y12	O
receptors	O
in	O
ARPE	O
-	O
19	O
cells	O
[	O
40	O
]	O
,	O
and	O
functionally	O
identifying	O
a	O
P2X	O
receptor	O
in	O
rat	B
RPE	O
cells	O
[	O
41	O
]	O
.	O

ATP	O
,	O
ADP	O
,	O
and	O
UTP	O
induce	O
numerous	O
effects	O
on	O
RPE	O
physiology	O
[	O
32	O
,	O
33	O
,	O
42	O
,	O
43	O
]	O
.	O

While	O
these	O
effects	O
likely	O
involve	O
multiple	O
different	O
receptor	O
types	O
,	O
the	O
contributions	O
of	O
the	O
P2Y2	O
receptor	O
have	O
been	O
explored	O
in	O
most	O
detail	O
to	O
date	O
.	O

The	O
P2Y2	O
receptor	O
has	O
been	O
specifically	O
localized	O
to	O
the	O
apical	O
membrane	O
of	O
fresh	O
bovine	B
RPE	O
cells	O
,	O
and	O
addition	O
of	O
ATP	O
to	O
this	O
membrane	O
transiently	O
elevates	O
Ca2	O
+	O
,	O
activates	O
a	O
basolateral	O
Cl	O
-	O
conductance	O
,	O
inhibits	O
an	O
apical	O
K	O
+	O
conductance	O
,	O
and	O
increases	O
the	O
apical	O
to	O
basolateral	O
flow	O
of	O
fluid	O
[	O
43	O
]	O
.	O

This	O
increased	O
absorption	O
of	O
fluid	O
from	O
the	O
subretinal	O
space	O
suggests	O
P2Y2	O
receptor	O
stimulation	O
could	O
reduce	O
the	O
excess	O
fluid	O
that	O
accumulates	O
in	O
retinal	O
edemas	O
,	O
and	O
several	O
reports	O
have	O
supported	O
this	O
theory	O
.	O

ATP	O
,	O
UTP	O
,	O
and	O
the	O
P2Y2	O
receptor	O
agonist	O
INS37217	O
decrease	O
the	O
size	O
of	O
subretinal	O
fluid	O
blebs	O
when	O
injected	O
into	O
subretinal	O
space	O
of	O
rats	B
[	O
44	O
]	O
.	O

In	O
both	O
normal	O
and	O
rds	O
+	O
/	O
-	O
mice	B
with	O
experimentally	O
induced	O
detachment	O
,	O
INS31217	O
improves	O
the	O
ERG	O
recovery	O
and	O
decreased	O
cell	O
death	O
[	O
45	O
]	O
.	O

INS37217	O
also	O
reduces	O
subretinal	O
blebs	O
in	O
rabbits	B
[	O
46	O
]	O
.	O

Injection	O
of	O
another	O
P2Y2	O
agonist	O
,	O
INS542	O
,	O
increases	O
the	O
active	O
transport	O
of	O
fluorescein	O
across	O
the	O
RPE	O
,	O
consistent	O
with	O
this	O
upregulation	O
of	O
ion	O
and	O
fluid	O
transport	O
across	O
the	O
tissue	O
[	O
47	O
]	O
.	O

Together	O
these	O
experiments	O
emphasize	O
the	O
clinical	O
potential	O
of	O
treating	O
retinal	O
edema	O
with	O
P2Y2	O
agonists	O
.	O

Regulation	O
of	O
purine	O
levels	O
in	O
subretinal	O
space	O

While	O
synthesized	O
purinergic	O
agonists	O
may	O
prove	O
useful	O
in	O
treating	O
some	O
ocular	O
disorders	O
,	O
the	O
endogenous	O
activation	O
of	O
P1	O
and	O
P2	O
receptors	O
in	O
the	O
subretinal	O
microenvironment	O
will	O
ultimately	O
be	O
determined	O
by	O
availability	O
of	O
agonists	O
.	O

These	O
levels	O
are	O
largely	O
controlled	O
by	O
the	O
release	O
of	O
ATP	O
into	O
the	O
subretinal	O
space	O
,	O
its	O
conversion	O
into	O
other	O
purines	O
including	O
adenosine	O
,	O
and	O
the	O
manipulation	O
of	O
adenosine	O
by	O
enzymes	O
or	O
transporters	O
.	O

Recent	O
work	O
has	O
increased	O
our	O
understanding	O
of	O
both	O
the	O
stimuli	O
that	O
initiate	O
changes	O
in	O
subretinal	O
purine	O
levels	O
and	O
the	O
mechanisms	O
that	O
mediate	O
these	O
changes	O
.	O

Release	O
of	O
ATP	O
by	O
the	O
RPE	O

At	O
least	O
some	O
of	O
the	O
ATP	O
capable	O
of	O
stimulating	O
the	O
purinergic	O
receptors	O
on	O
RPE	O
cells	O
is	O
released	O
from	O
the	O
RPE	O
itself	O
.	O

The	O
resulting	O
autocrine	O
stimulation	O
ensures	O
local	O
delivery	O
,	O
and	O
control	O
,	O
of	O
purines	O
to	O
initiate	O
the	O
physiologic	O
changes	O
in	O
the	O
RPE	O
.	O

The	O
release	O
of	O
ATP	O
by	O
RPE	O
cells	O
is	O
triggered	O
by	O
multiple	O
stimuli	O
including	O
osmotic	O
stress	O
,	O
bFGF	O
,	O
UTP	O
,	O
NMDA	O
,	O
glutamate	O
,	O
and	O
ATP	O
[	O
39	O
,	O
40	O
,	O
48	O
-	O
51	O
]	O
.	O

The	O
ATP	O
release	O
following	O
activation	O
of	O
NMDA	O
receptors	O
by	O
glutamate	O
may	O
have	O
the	O
most	O
interesting	O
implications	O
for	O
communication	O
across	O
subretinal	O
space	O
,	O
given	O
that	O
glutamate	O
confers	O
the	O
light	O
signal	O
from	O
photoreceptors	O
to	O
the	O
rest	O
of	O
the	O
visual	O
system	O
.	O

Glutamate	O
and	O
the	O
specific	O
receptor	O
agonist	O
NMDA	O
triggers	O
ATP	O
release	O
from	O
ARPE	O
-	O
19	O
cells	O
,	O
with	O
the	O
release	O
inhibited	O
by	O
NMDA	O
antagonist	O
MK	O
-	O
801	O
,	O
and	O
by	O
DCKA	O
,	O
which	O
inhibits	O
the	O
glycine	O
B	O
binding	O
site	O
on	O
NMDA	O
receptors	O
[	O
51	O
,	O
52	O
]	O
.	O

Although	O
NMDA	O
raises	O
intracellular	O
Ca2	O
+	O
levels	O
,	O
this	O
increase	O
is	O
prevented	O
by	O
eliminating	O
ATP	O
with	O
apyrase	O
,	O
indicating	O
autostimulation	O
through	O
released	O
ATP	O
is	O
responsible	O
for	O
this	O
Ca2	O
+	O
signal	O
.	O

NMDA	O
also	O
triggers	O
a	O
release	O
of	O
ATP	O
when	O
applied	O
to	O
the	O
intact	O
bovine	B
RPE	O
eyecup	O
[	O
51	O
]	O
.	O

The	O
NMDA	O
receptors	O
and	O
the	O
ATP	O
release	O
sites	O
have	O
been	O
functionally	O
identified	O
to	O
the	O
apical	O
membrane	O
of	O
the	O
bovine	B
RPE	O
,	O
suggesting	O
the	O
neurotransmitter	O
interactions	O
could	O
amplify	O
the	O
signal	O
from	O
any	O
glutamate	O
reaching	O
subretinal	O
space	O
.	O

The	O
ability	O
of	O
both	O
UTP	O
and	O
ATP	O
to	O
stimulate	O
release	O
of	O
ATP	O
from	O
the	O
RPE	O
supports	O
the	O
theory	O
that	O
the	O
system	O
acts	O
to	O
amplify	O
signals	O
.	O

When	O
applied	O
at	O
greater	O
than	O
1	O
mu	O
M	O
,	O
ATP	O
triggers	O
a	O
secondary	O
release	O
of	O
ATP	O
peaking	O
10	O
min	O
after	O
the	O
initial	O
stimuli	O
[	O
40	O
]	O
.	O

UTP	O
also	O
initiates	O
a	O
release	O
in	O
extracellular	O
ATP	O
with	O
a	O
similar	O
delay	O
[	O
48	O
]	O
.	O

The	O
rise	O
in	O
ATP	O
triggered	O
by	O
UTP	O
is	O
inhibited	O
by	O
the	O
Cl	O
-	O
channel	O
blocker	O
NPPB	O
,	O
and	O
UDP	O
is	O
much	O
less	O
effective	O
at	O
triggering	O
release	O
than	O
UTP	O
;	O
both	O
observations	O
suggest	O
the	O
P2Y2	O
receptor	O
contributes	O
to	O
the	O
increase	O
in	O
ATP	O
more	O
than	O
diphosphokinase	O
,	O
although	O
influence	O
from	O
the	O
enzyme	O
cannot	O
be	O
ruled	O
out	O
[	O
53	O
]	O
.	O

Recent	O
evidence	O
suggests	O
that	O
ischemia	O
may	O
lead	O
to	O
the	O
release	O
of	O
ATP	O
from	O
RPE	O
cells	O
.	O

Chemical	O
ischemia	O
triggers	O
a	O
substantial	O
ATP	O
release	O
from	O
cardiac	O
myocytes	O
[	O
54	O
]	O
,	O
while	O
changes	O
in	O
oxygen	O
levels	O
trigger	O
ATP	O
release	O
in	O
central	O
chemoreceptors	O
[	O
55	O
]	O
.	O

We	O
found	O
that	O
exposure	O
to	O
sodium	O
cyanide	O
led	O
to	O
a	O
rapid	O
release	O
of	O
ATP	O
from	O
ARPE	O
-	O
19	O
cells	O
(	O
Fig	O
.	O
2	O
)	O
.	O

As	O
hypoxic	O
and	O
/	O
or	O
ischemic	O
challenge	O
may	O
lead	O
to	O
changes	O
in	O
the	O
expression	O
of	O
growth	O
factors	O
in	O
RPE	O
cells	O
during	O
certain	O
ocular	O
disorders	O
such	O
as	O
macular	O
degeneration	O
[	O
56	O
]	O
,	O
and	O
as	O
purines	O
can	O
induce	O
expression	O
of	O
VEGF	O
in	O
other	O
cells	O
[	O
57	O
]	O
,	O
this	O
ATP	O
release	O
may	O
contribute	O
to	O
growth	O
factor	O
signaling	O
by	O
the	O
diseased	O
RPE	O
.	O

Fig	O
.	O
2Chemical	O
ischemia	O
triggers	O
ATP	O
release	O
from	O
ARPE	O
-	O
19	O
cells	O
.	O

ATP	O
release	O
was	O
measured	O
in	O
the	O
bath	O
directly	O
from	O
cells	O
plated	O
in	O
96	O
-	O
well	O
plates	O
to	O
which	O
the	O
luciferin	O
-	O
luciferase	O
reaction	O
mixture	O
was	O
added	O
[	O
51	O
]	O
.	O

Left	O
Levels	O
of	O
ATP	O
in	O
the	O
bath	O
after	O
addition	O
of	O
5	O
mM	O
NaCN	O
to	O
the	O
cells	O
.	O

Measurement	O
began	O
1	O
min	O
after	O
addition	O
of	O
NaCN	O
or	O
control	O
solution	O
to	O
wells	O
.	O

Right	O
Levels	O
of	O
ATP	O
measured	O
at	O
the	O
peak	O
,	O
3	O
min	O
after	O
addition	O
of	O
NaCN	O
(	O
n	O
=	O
12	O
)	O
.	O

Levels	O
were	O
normalized	O
to	O
concurrent	O
levels	O
in	O
control	O
(	O
n	O
=	O
14	O
)	O
.	O

Symbols	O
and	O
bars	O
represent	O
mean	O
+	O
/	O
-	O
SE	O
,	O
*	O
p	O
<	O
0	O
.	O
001	O

The	O
particular	O
conduit	O
for	O
ATP	O
release	O
varies	O
with	O
the	O
stimuli	O
.	O

The	O
release	O
in	O
response	O
to	O
hypotonic	O
challenge	O
is	O
largely	O
dependent	O
upon	O
CFTR	O
,	O
as	O
it	O
was	O
prevented	O
by	O
the	O
specific	O
CFTR	O
inhibitor	O
CFTR172	O
in	O
addition	O
to	O
the	O
more	O
general	O
blocker	O
glybenclamide	O
[	O
50	O
]	O
.	O

While	O
the	O
precise	O
mechanisms	O
by	O
which	O
CFTR	O
contributes	O
to	O
this	O
release	O
are	O
not	O
yet	O
known	O
,	O
a	O
role	O
for	O
CFTR	O
in	O
ATP	O
release	O
into	O
subretinal	O
space	O
is	O
consistent	O
with	O
the	O
reduction	O
of	O
certain	O
ERG	O
components	O
in	O
cftr	O
-	O
/	O
-	O
mice	B
[	O
58	O
]	O
and	O
with	O
the	O
ability	O
of	O
apical	O
ATP	O
to	O
activate	O
conductances	O
associated	O
with	O
these	O
ERG	O
components	O
[	O
43	O
]	O
.	O

The	O
release	O
of	O
ATP	O
is	O
also	O
largely	O
blocked	O
by	O
the	O
vesicular	O
transport	O
inhibitor	O
brefeldin	O
A	O
,	O
suggesting	O
the	O
two	O
processes	O
occurred	O
in	O
series	O
whereby	O
ATP	O
efflux	O
follows	O
the	O
insertion	O
of	O
vesicles	O
containing	O
CFTR	O
into	O
the	O
plasma	O
membrane	O
.	O

Although	O
the	O
Ca2	O
+	O
chelator	O
BAPTA	O
blocks	O
this	O
ATP	O
release	O
[	O
50	O
]	O
,	O
raising	O
Ca2	O
+	O
alone	O
with	O
ionophore	O
ionomycin	O
does	O
not	O
itself	O
initiate	O
release	O
[	O
48	O
]	O
.	O

This	O
necessary	O
but	O
not	O
sufficient	O
contribution	O
of	O
Ca2	O
+	O
also	O
supports	O
a	O
role	O
for	O
vesicular	O
insertion	O
.	O

In	O
contrast	O
to	O
the	O
release	O
following	O
hypotonic	O
challenge	O
,	O
the	O
ATP	O
release	O
in	O
response	O
to	O
NMDA	O
does	O
not	O
involve	O
CFTR	O
[	O
51	O
]	O
.	O

Release	O
is	O
blocked	O
by	O
NPPB	O
,	O
however	O
,	O
suggesting	O
another	O
type	O
of	O
anion	O
channel	O
could	O
serve	O
as	O
a	O
conduit	O
for	O
ATP	O
release	O
.	O

The	O
presence	O
of	O
parallel	O
mechanisms	O
coexisting	O
on	O
the	O
same	O
cell	O
for	O
ATP	O
release	O
triggered	O
by	O
either	O
agonists	O
or	O
by	O
cell	O
swelling	O
has	O
also	O
been	O
reported	O
in	O
astrocytes	O
[	O
59	O
]	O
and	O
may	O
reflect	O
the	O
multiple	O
roles	O
of	O
purinergic	O
signaling	O
within	O
a	O
given	O
tissue	O
.	O

As	O
both	O
stimuli	O
lead	O
to	O
release	O
across	O
the	O
apical	O
membrane	O
into	O
subretinal	O
space	O
,	O
both	O
are	O
expected	O
to	O
influence	O
signaling	O
in	O
the	O
microenvironment	O
.	O

Interconversion	O
of	O
purines	O
in	O
subretinal	O
space	O

The	O
interconversion	O
of	O
nucleotides	O
and	O
nucleosides	O
each	O
capable	O
of	O
stimulating	O
distinct	O
receptors	O
makes	O
the	O
purinergic	O
signaling	O
system	O
of	O
particular	O
interest	O
in	O
a	O
confined	O
region	O
such	O
as	O
the	O
subretinal	O
space	O
.	O

The	O
main	O
enzymes	O
responsible	O
for	O
dephosphorylating	O
extracellular	O
ATP	O
on	O
the	O
RPE	O
cells	O
have	O
been	O
analyzed	O
and	O
a	O
basic	O
understanding	O
of	O
their	O
regulation	O
has	O
begun	O
.	O

This	O
section	O
first	O
describes	O
the	O
enzymes	O
that	O
act	O
on	O
ATP	O
and	O
ADP	O
,	O
followed	O
by	O
enzymes	O
which	O
convert	O
AMP	O
into	O
adenosine	O
.	O

The	O
dephosphorylation	O
of	O
extracellular	O
ATP	O
by	O
RPE	O
cells	O
involves	O
enzymes	O
from	O
multiple	O
families	O
[	O
40	O
]	O
,	O
as	O
found	O
in	O
airway	O
epithelial	O
cells	O
[	O
60	O
]	O
.	O

Degradation	O
of	O
ATP	O
by	O
the	O
apical	O
membrane	O
of	O
the	O
fresh	O
bovine	B
eyecup	O
and	O
by	O
ARPE	O
-	O
19	O
cells	O
is	O
inhibited	O
by	O
ARL67156	O
or	O
beta	O
gamma	O
mATP	O
.	O

Message	O
for	O
eNPP1	O
,	O
eNPP2	O
,	O
and	O
eNPP3	O
is	O
present	O
in	O
ARPE	O
-	O
19	O
cells	O
,	O
consistent	O
with	O
the	O
preference	O
of	O
beta	O
gamma	O
mATP	O
for	O
members	O
of	O
the	O
eNPP	O
family	O
[	O
61	O
]	O
.	O

The	O
cells	O
also	O
express	O
NTPDase2	O
,	O
and	O
NTPDase3	O
,	O
although	O
the	O
intermittent	O
presence	O
of	O
NTPDase1	O
likely	O
reflects	O
a	O
regulated	O
process	O
[	O
40	O
]	O
.	O

Ecto	O
-	O
alkaline	O
phosphatase	O
has	O
no	O
effect	O
on	O
ATP	O
degradation	O
in	O
RPE	O
cells	O
,	O
in	O
contrast	O
to	O
its	O
considerable	O
contribution	O
in	O
airway	O
epithelium	O
[	O
62	O
]	O
.	O

The	O
putative	O
contribution	O
from	O
diphosphokinases	O
to	O
interconversion	O
of	O
subretinal	O
purines	O
is	O
presently	O
unknown	O
.	O

Extracellular	O
AMP	O
is	O
rapidly	O
dephosphorylated	O
into	O
adenosine	O
in	O
subretinal	O
space	O
.	O

The	O
production	O
of	O
adenosine	O
from	O
ATP	O
at	O
the	O
apical	O
membrane	O
of	O
the	O
bovine	B
RPE	O
eyecup	O
is	O
inhibited	O
by	O
the	O
ecto	O
-	O
5	O
'	O
-	O
nucleotidase	O
inhibitor	O
alpha	O
beta	O
mADP	O
,	O
confirming	O
a	O
role	O
for	O
this	O
enzyme	O
[	O
63	O
]	O
.	O

The	O
enzyme	O
is	O
localized	O
to	O
rat	B
RPE	O
and	O
ARPE	O
-	O
19	O
cells	O
immunohistochemicall	O
.	O

Degradation	O
of	O
5	O
'	O
AMP	O
is	O
highest	O
near	O
the	O
subretinal	O
space	O
of	O
rat	B
retina	O
[	O
63	O
]	O
,	O
although	O
localization	O
in	O
mouse	B
indicated	O
larger	O
amounts	O
of	O
ecto	O
-	O
5	O
'	O
-	O
nucleotidase	O
at	O
the	O
tips	O
of	O
adjacent	O
M	O
u	O
ller	O
cells	O
[	O
64	O
]	O
.	O

Levamisole	O
does	O
not	O
inhibit	O
the	O
dephosphorylation	O
of	O
5	O
'	O
AMP	O
by	O
the	O
RPE	O
,	O
consistent	O
with	O
the	O
absence	O
of	O
substantial	O
ecto	O
-	O
alkaline	O
phosphatase	O
in	O
subretinal	O
space	O
.	O

The	O
presence	O
of	O
light	O
may	O
alter	O
the	O
levels	O
of	O
adenosine	O
in	O
subretinal	O
space	O
.	O

Epinephrine	O
is	O
released	O
at	O
the	O
onset	O
of	O
light	O
[	O
65	O
]	O
and	O
stimulation	O
of	O
the	O
RPE	O
with	O
epinephrine	O
can	O
decrease	O
activity	O
of	O
ecto	O
-	O
5	O
'	O
-	O
nucleotidase	O
[	O
63	O
]	O
.	O

While	O
norepinephrine	O
and	O
phenylephrine	O
lead	O
to	O
similar	O
decreases	O
in	O
enzyme	O
activity	O
,	O
prazosin	O
and	O
corynanthine	O
block	O
the	O
effects	O
of	O
norepinephrine	O
,	O
implicating	O
the	O
alpha	O
1	O
epinephrine	O
receptor	O
in	O
the	O
inhibition	O
of	O
ecto	O
-	O
5	O
'	O
-	O
nucleotidase	O
[	O
63	O
]	O
.	O

The	O
kinetics	O
of	O
inhibition	O
are	O
consistent	O
with	O
cleavage	O
of	O
the	O
nucleotidase	O
from	O
its	O
GPI	O
anchor	O
.	O

The	O
phagocytosis	O
of	O
rod	O
outer	O
segments	O
is	O
maximal	O
shortly	O
after	O
light	O
onset	O
[	O
16	O
]	O
,	O
and	O
this	O
phagocytosis	O
is	O
inhibited	O
by	O
adenosine	O
[	O
29	O
]	O
.	O

The	O
ability	O
of	O
epinephrine	O
released	O
by	O
the	O
illuminated	O
retina	O
to	O
reduce	O
ecto	O
-	O
5	O
'	O
-	O
nucleotidase	O
activity	O
and	O
consequently	O
adenosine	O
levels	O
may	O
relieve	O
this	O
inhibition	O
and	O
enhance	O
the	O
rate	O
of	O
phagocytosis	O
at	O
light	O
onset	O
.	O

Physiologic	O
effects	O
of	O
subretinal	O
purines	O
on	O
the	O
RPE	O
and	O
photoreceptors	O

The	O
number	O
of	O
purinergic	O
receptors	O
on	O
both	O
photoreceptor	O
and	O
RPE	O
membranes	O
suggests	O
purines	O
make	O
multiple	O
contributions	O
to	O
the	O
physiology	O
of	O
the	O
outer	O
retina	O
.	O

Our	O
increased	O
understanding	O
of	O
how	O
agonist	O
levels	O
in	O
subretinal	O
space	O
are	O
controlled	O
has	O
begun	O
to	O
indicate	O
how	O
and	O
when	O
this	O
contribution	O
may	O
occur	O
.	O

Future	O
research	O
will	O
involve	O
applying	O
these	O
findings	O
from	O
isolated	O
systems	O
to	O
intact	O
RPE	O
-	O
photoreceptor	O
models	O
,	O
and	O
pursuing	O
the	O
role	O
of	O
defective	O
purinergic	O
regulation	O
in	O
ocular	O
disease	O
.	O

While	O
it	O
is	O
unlikely	O
that	O
ATP	O
released	O
across	O
the	O
apical	O
membrane	O
of	O
the	O
RPE	O
can	O
diffuse	O
to	O
these	O
P2	O
receptors	O
in	O
the	O
outer	O
plexiform	O
layer	O
given	O
the	O
ecto	O
-	O
ATPase	O
activity	O
in	O
the	O
synaptic	O
clef	O
[	O
25	O
]	O
,	O
stimulation	O
of	O
receptors	O
elsewhere	O
on	O
the	O
photoreceptor	O
membrane	O
is	O
possible	O
.	O

It	O
would	O
be	O
interesting	O
to	O
determine	O
whether	O
ATP	O
released	O
from	O
the	O
RPE	O
and	O
converted	O
to	O
adenosine	O
by	O
ecto	O
-	O
nucleotidases	O
can	O
actually	O
modulate	O
the	O
response	O
to	O
light	O
by	O
stimulating	O
the	O
A2A	O
receptors	O
on	O
photoreceptor	O
outer	O
segments	O
.	O

The	O
impact	O
of	O
purinergic	O
signaling	O
on	O
chronic	O
ocular	O
diseases	O
is	O
also	O
of	O
interest	O
,	O
such	O
as	O
the	O
role	O
of	O
ischemia	O
-	O
driven	O
ATP	O
release	O
in	O
VEGF	O
production	O
.	O

While	O
the	O
small	O
size	O
of	O
subretinal	O
space	O
can	O
complicate	O
pharmacologic	O
manipulation	O
within	O
the	O
intact	O
RPE	O
-	O
photoreceptor	O
complex	O
,	O
molecular	O
approaches	O
may	O
provide	O
new	O
insight	O
into	O
how	O
endogenous	O
purines	O
in	O
subretinal	O
space	O
affect	O
the	O
physiology	O
,	O
and	O
pathophysiology	O
,	O
of	O
both	O
RPE	O
and	O
photoreceptors	O
.	O

Comparative	O
Genome	O
Analysis	O
of	O
Filamentous	O
Fungi	O
Reveals	O
Gene	O
Family	O
Expansions	O
Associated	O
with	O
Fungal	O
Pathogenesis	O

Abstract	O

Fungi	O
and	O
oomycetes	O
are	O
the	O
causal	O
agents	O
of	O
many	O
of	O
the	O
most	O
serious	O
diseases	O
of	O
plants	O
.	O

Here	O
we	O
report	O
a	O
detailed	O
comparative	O
analysis	O
of	O
the	O
genome	O
sequences	O
of	O
thirty	O
-	O
six	O
species	O
of	O
fungi	O
and	O
oomycetes	O
,	O
including	O
seven	O
plant	O
pathogenic	O
species	O
,	O
that	O
aims	O
to	O
explore	O
the	O
common	O
genetic	O
features	O
associated	O
with	O
plant	O
disease	O
-	O
causing	O
species	O
.	O

The	O
predicted	O
translational	O
products	O
of	O
each	O
genome	O
have	O
been	O
clustered	O
into	O
groups	O
of	O
potential	O
orthologues	O
using	O
Markov	O
Chain	O
Clustering	O
and	O
the	O
data	O
integrated	O
into	O
the	O
e	O
-	O
Fungi	O
object	O
-	O
oriented	O
data	O
warehouse	O
(	O
http	O
:	O
/	O
/	O
www	O
.	O
e	O
-	O
fungi	O
.	O
org	O
.	O
uk	O
/	O
)	O
.	O

Analysis	O
of	O
the	O
species	O
distribution	O
of	O
members	O
of	O
these	O
clusters	O
has	O
identified	O
proteins	O
that	O
are	O
specific	O
to	O
filamentous	O
fungal	O
species	O
and	O
a	O
group	O
of	O
proteins	O
found	O
only	O
in	O
plant	O
pathogens	O
.	O

By	O
comparing	O
the	O
gene	O
inventories	O
of	O
filamentous	O
,	O
ascomycetous	O
phytopathogenic	O
and	O
free	O
-	O
living	O
species	O
of	O
fungi	O
,	O
we	O
have	O
identified	O
a	O
set	O
of	O
gene	O
families	O
that	O
appear	O
to	O
have	O
expanded	O
during	O
the	O
evolution	O
of	O
phytopathogens	O
and	O
may	O
therefore	O
serve	O
important	O
roles	O
in	O
plant	O
disease	O
.	O

We	O
have	O
also	O
characterised	O
the	O
predicted	O
set	O
of	O
secreted	O
proteins	O
encoded	O
by	O
each	O
genome	O
and	O
identified	O
a	O
set	O
of	O
protein	O
families	O
which	O
are	O
significantly	O
over	O
-	O
represented	O
in	O
the	O
secretomes	O
of	O
plant	O
pathogenic	O
fungi	O
,	O
including	O
putative	O
effector	O
proteins	O
that	O
might	O
perturb	O
host	O
cell	O
biology	O
during	O
plant	O
infection	O
.	O

The	O
results	O
demonstrate	O
the	O
potential	O
of	O
comparative	O
genome	O
analysis	O
for	O
exploring	O
the	O
evolution	O
of	O
eukaryotic	O
microbial	O
pathogenesis	O
.	O

Introduction	O

Fungi	O
and	O
oomycetes	O
are	O
responsible	O
for	O
many	O
of	O
the	O
world	O
'	O
s	O
most	O
devastating	O
plant	O
diseases	O
including	O
late	O
blight	O
disease	O
of	O
potato	B
,	O
caused	O
by	O
the	O
oomycete	O
pathogen	O
Phytophthora	B
infestans	I
and	O
rice	B
blast	O
disease	O
caused	O
by	O
the	O
ascomycete	O
fungus	O
Magnaporthe	B
grisea	I
,	O
both	O
of	O
which	O
are	O
responsible	O
for	O
very	O
significant	O
harvest	O
losses	O
each	O
year	O
.	O

The	O
enormous	O
diversity	O
of	O
crop	O
diseases	O
caused	O
by	O
these	O
eukaryotic	O
micro	O
-	O
organisms	O
poses	O
a	O
difficult	O
challenge	O
to	O
the	O
development	O
of	O
durable	O
disease	O
control	O
strategies	O
.	O

Identifying	O
common	O
underlying	O
molecular	O
mechanisms	O
necessary	O
for	O
pathogenesis	O
in	O
a	O
wide	O
range	O
of	O
pathogenic	O
species	O
is	O
therefore	O
a	O
major	O
goal	O
of	O
current	O
research	O
.	O

Approximately	O
100	O
,	O
000	O
species	O
of	O
fungi	O
have	O
so	O
far	O
been	O
described	O
,	O
but	O
only	O
a	O
very	O
small	O
proportion	O
of	O
these	O
are	O
pathogenic	O
[	O
1	O
]	O
.	O

Phylogenetic	O
studies	O
have	O
,	O
meanwhile	O
,	O
shown	O
that	O
disease	O
-	O
causing	O
pathogens	O
are	O
not	O
necessarily	O
closely	O
-	O
related	O
to	O
each	O
other	O
,	O
and	O
in	O
fact	O
are	O
spread	O
throughout	O
all	O
taxonomic	O
groups	O
of	O
fungi	O
,	O
often	O
showing	O
a	O
close	O
evolutionary	O
relationship	O
to	O
non	O
-	O
pathogenic	O
species	O
[	O
2	O
]	O
,	O
[	O
3	O
]	O
.	O

It	O
therefore	O
seems	O
likely	O
that	O
phytopathogenicity	O
has	O
evolved	O
as	O
a	O
trait	O
many	O
times	O
during	O
fungal	O
and	O
oomycete	O
evolution	O
[	O
1	O
]	O
and	O
in	O
some	O
groups	O
may	O
be	O
ancestral	O
to	O
the	O
more	O
recent	O
emergence	O
of	O
saprotrophic	O
species	O
.	O

A	O
significant	O
effort	O
has	O
gone	O
into	O
the	O
identification	O
of	O
pathogenicity	O
determinants	O
-	O
individual	O
genes	O
that	O
are	O
essential	O
for	O
a	O
pathogen	O
to	O
invade	O
a	O
host	O
plant	O
successfully	O
,	O
but	O
which	O
are	O
dispensable	O
for	O
saprophytic	O
growth	O
[	O
4	O
]	O
,	O
[	O
5	O
]	O
.	O

However	O
,	O
far	O
from	O
being	O
novel	O
proteins	O
encoded	O
only	O
by	O
the	O
genomes	O
of	O
pathogenic	O
fungi	O
,	O
many	O
of	O
the	O
genes	O
identified	O
so	O
far	O
encode	O
components	O
of	O
conserved	O
signalling	O
pathways	O
that	O
are	O
found	O
in	O
all	O
species	O
of	O
fungi	O
,	O
such	O
as	O
the	O
mitogen	O
activated	O
protein	O
(	O
MAP	O
)	O
kinases	O
[	O
6	O
]	O
,	O
adenylate	O
cyclase	O
[	O
7	O
]	O
and	O
G	O
-	O
protein	O
subunits	O
[	O
8	O
]	O
.	O

The	O
MAP	O
kinase	O
pathways	O
,	O
for	O
example	O
,	O
have	O
been	O
studied	O
extensively	O
in	O
the	O
budding	O
yeast	B
Saccharomyces	B
cerevisiae	I
and	O
trigger	O
morphological	O
and	O
biochemical	O
changes	O
in	O
response	O
to	O
external	O
stimuli	O
such	O
as	O
starvation	O
stress	O
or	O
hyperosmotic	O
conditions	O
[	O
9	O
]	O
.	O

In	O
pathogenic	O
fungi	O
,	O
components	O
of	O
these	O
pathways	O
have	O
evolved	O
instead	O
to	O
regulate	O
the	O
morphological	O
changes	O
associated	O
with	O
plant	O
infection	O
.	O

For	O
example	O
,	O
appressorium	O
formation	O
in	O
the	O
rice	B
blast	I
fungus	I
Magnaporthe	B
grisea	I
,	O
stimulated	O
by	O
hard	O
,	O
hydrophobic	O
surfaces	O
is	O
regulated	O
by	O
a	O
MAP	O
kinase	O
cascade	O
[	O
10	O
]	O
.	O

This	O
pathway	O
deploys	O
novel	O
classes	O
of	O
G	O
-	O
protein	O
coupled	O
receptors	O
not	O
found	O
in	O
the	O
genome	O
of	O
S	B
.	I
cerevisiae	I
[	O
11	O
]	O
,	O
but	O
the	O
inductive	O
signal	O
is	O
transmitted	O
via	O
a	O
MAP	O
kinase	O
,	O
Pmk1	O
,	O
that	O
is	O
a	O
functional	O
homologue	O
of	O
the	O
yeast	B
Fus3	O
MAP	O
kinase	O
where	O
it	O
serves	O
a	O
role	O
in	O
pheromone	O
signalling	O
[	O
10	O
]	O
.	O

Similarly	O
,	O
conserved	O
metabolic	O
pathways	O
such	O
as	O
the	O
glyoxylate	O
cycle	O
and	O
amino	O
acid	O
biosynthesis	O
are	O
also	O
important	O
for	O
pathogenesis	O
[	O
12	O
]	O
-	O
[	O
14	O
]	O
.	O

This	O
may	O
in	O
some	O
cases	O
reflect	O
the	O
nutritional	O
environment	O
the	O
pathogen	O
encounters	O
when	O
growing	O
in	O
the	O
host	O
plant	O
tissue	O
,	O
and	O
in	O
others	O
shows	O
the	O
importance	O
of	O
simple	O
metabolites	O
for	O
pathogenic	O
processes	O
,	O
such	O
as	O
the	O
role	O
of	O
glycerol	O
as	O
a	O
compatible	O
solute	O
for	O
generating	O
turgor	O
pressure	O
in	O
the	O
appressorium	O
of	O
M	B
.	I
grisea	I
[	O
15	O
]	O
.	O

It	O
is	O
undoubtedly	O
the	O
case	O
,	O
however	O
,	O
that	O
identification	O
of	O
such	O
genes	O
has	O
also	O
been	O
a	O
consequence	O
of	O
the	O
manner	O
in	O
which	O
these	O
studies	O
have	O
been	O
carried	O
out	O
,	O
often	O
using	O
yeast	B
as	O
a	O
model	O
organism	O
to	O
test	O
hypotheses	O
concerning	O
the	O
developmental	O
biology	O
and	O
biochemistry	O
of	O
plant	O
pathogenic	O
species	O
.	O

Other	O
pathogenicity	O
factors	O
identified	O
to	O
date	O
have	O
been	O
shown	O
to	O
be	O
involved	O
in	O
functions	O
associated	O
with	O
host	O
infection	O
,	O
such	O
as	O
plant	O
cell	O
wall	O
degradation	O
,	O
toxin	O
biosynthesis	O
and	O
protection	O
against	O
plant	O
defences	O
[	O
reviewed	O
in	O
5	O
]	O
.	O

Identification	O
of	O
a	O
pathogenicity	O
factor	O
generally	O
involves	O
making	O
a	O
mutant	O
fungal	O
strain	O
with	O
a	O
non	O
-	O
functioning	O
version	O
of	O
the	O
gene	O
by	O
targeted	O
gene	O
deletion	O
and	O
assaying	O
the	O
ability	O
of	O
the	O
mutant	O
to	O
cause	O
disease	O
.	O

Therefore	O
,	O
most	O
pathogenicity	O
factors	O
identified	O
so	O
far	O
,	O
have	O
been	O
validated	O
in	O
only	O
a	O
small	O
number	O
of	O
genetically	O
tractable	O
pathogenic	O
fungi	O
,	O
such	O
as	O
M	B
.	I
grisea	I
and	O
the	O
corn	B
smut	O
Ustilago	B
maydis	I
and	O
many	O
of	O
the	O
advances	O
in	O
understanding	O
the	O
developmental	O
biology	O
of	O
plant	O
infection	O
have	O
occurred	O
in	O
these	O
model	O
pathogens	O
[	O
16	O
]	O
,	O
[	O
17	O
]	O
.	O

However	O
,	O
there	O
are	O
severe	O
limitations	O
to	O
studying	O
pathogenicity	O
by	O
mutating	O
one	O
gene	O
at	O
a	O
time	O
and	O
working	O
predominantly	O
with	O
a	O
hypothesis	O
-	O
driven	O
,	O
reverse	O
genetics	O
approach	O
.	O

Many	O
virulence	O
-	O
associated	O
processes	O
,	O
for	O
instance	O
,	O
such	O
as	O
the	O
development	O
of	O
infection	O
structures	O
and	O
haustoria	O
,	O
are	O
likely	O
to	O
involve	O
a	O
large	O
number	O
of	O
gene	O
products	O
and	O
so	O
there	O
is	O
likely	O
to	O
be	O
redundancy	O
in	O
gene	O
function	O
.	O

One	O
example	O
of	O
this	O
is	O
cutinase	O
,	O
a	O
type	O
of	O
methyl	O
esterase	O
that	O
hydrolyses	O
the	O
protective	O
cutin	O
layer	O
present	O
on	O
the	O
outside	O
of	O
the	O
plant	O
epidermis	O
.	O

Cutinase	O
was	O
excluded	O
as	O
a	O
pathogencity	O
factor	O
for	O
M	B
.	I
grisea	I
on	O
the	O
basis	O
that	O
a	O
mutant	O
strain	O
containing	O
a	O
non	O
-	O
functional	O
cutinase	O
-	O
encoding	O
gene	O
was	O
still	O
able	O
to	O
cause	O
rice	B
blast	O
disease	O
[	O
18	O
]	O
.	O

However	O
,	O
sequencing	O
of	O
the	O
M	B
.	I
grisea	I
genome	O
has	O
shown	O
the	O
presence	O
of	O
eight	O
potential	O
cutinase	O
-	O
encoding	O
genes	O
implicated	O
in	O
virulence	O
[	O
19	O
]	O
.	O

Additionally	O
,	O
targeted	O
gene	O
deletion	O
is	O
not	O
feasible	O
in	O
many	O
important	O
pathogens	O
and	O
the	O
normal	O
definition	O
of	O
fungal	O
pathogenicity	O
cannot	O
be	O
applied	O
in	O
the	O
case	O
of	O
obligate	O
biotrophs	O
,	O
such	O
as	O
the	O
powdery	O
mildew	O
fungus	O
Blumeria	B
graminis	I
,	O
which	O
cannot	O
be	O
cultured	O
away	O
from	O
living	O
host	O
plants	O
.	O

Therefore	O
,	O
new	O
approaches	O
are	O
needed	O
to	O
identify	O
genes	O
that	O
are	O
vital	O
for	O
the	O
process	O
of	O
pathogenicity	O
.	O

These	O
include	O
high	O
-	O
throughput	O
methods	O
such	O
as	O
microarray	O
analysis	O
,	O
serial	O
analysis	O
of	O
gene	O
expression	O
(	O
SAGE	O
)	O
,	O
insertional	O
mutagenesis	O
,	O
proteomics	O
and	O
metabolomics	O
[	O
19	O
]	O
,	O
[	O
20	O
]	O
and	O
are	O
dependent	O
on	O
the	O
availability	O
of	O
genome	O
sequence	O
information	O
.	O

After	O
the	O
initial	O
release	O
of	O
the	O
genome	O
of	O
the	O
budding	O
yeast	B
S	B
.	I
cerevisiae	I
in	O
1996	O
[	O
21	O
]	O
,	O
the	O
number	O
of	O
publicly	O
available	O
sequenced	O
fungal	O
genomes	O
has	O
recently	O
risen	O
very	O
quickly	O
.	O

A	O
large	O
number	O
of	O
fungal	O
genome	O
sequences	O
are	O
now	O
publicly	O
available	O
,	O
including	O
those	O
from	O
several	O
phytopathogenic	O
fungi	O
,	O
including	O
M	B
.	I
grisea	I
[	O
22	O
]	O
,	O
Ustilago	B
maydis	I
[	O
23	O
]	O
,	O
Gibberella	B
zeae	I
[	O
24	O
]	O
(	O
the	O
causal	O
agent	O
of	O
head	O
blight	O
of	O
wheat	B
and	O
barley	B
)	O
,	O
Stagonospora	B
nodorum	I
[	O
25	O
]	O
(	O
the	O
causal	O
agent	O
of	O
glume	O
blotch	O
of	O
wheat	B
)	O
,	O
the	O
grey	O
mould	O
fungus	O
Botrytis	B
cinerea	I
and	O
the	O
white	O
mould	O
fungus	O
Sclerotinia	B
sclerotiorum	I
[	O
reviewed	O
in	O
19	O
]	O
.	O

Comparison	O
of	O
gene	O
inventories	O
of	O
pathogenic	O
and	O
non	O
-	O
pathogenic	O
organisms	O
offers	O
the	O
most	O
direct	O
means	O
of	O
providing	O
new	O
information	O
concerning	O
the	O
mechanisms	O
involved	O
in	O
fungal	O
and	O
oomycete	O
pathogenicity	O
.	O

In	O
this	O
report	O
,	O
we	O
have	O
developed	O
and	O
utilized	O
the	O
e	O
-	O
Fungi	O
object	O
-	O
oriented	O
data	O
warehouse	O
[	O
26	O
]	O
,	O
which	O
contains	O
data	O
from	O
36	O
species	O
of	O
fungi	O
and	O
oomycetes	O
and	O
deploys	O
a	O
range	O
of	O
querying	O
tools	O
to	O
allow	O
interrogation	O
of	O
a	O
significant	O
amount	O
of	O
genome	O
data	O
in	O
unparalleled	O
detail	O
.	O

We	O
report	O
the	O
identification	O
of	O
new	O
gene	O
families	O
that	O
are	O
over	O
represented	O
in	O
the	O
genomes	O
of	O
filamentous	O
ascomycete	O
phytopathogens	O
and	O
define	O
gene	O
sets	O
that	O
are	O
specific	O
to	O
diverse	O
fungal	O
pathogen	O
species	O
.	O

We	O
also	O
report	O
the	O
putatively	O
secreted	O
protein	O
sets	O
which	O
are	O
produced	O
by	O
plant	O
pathogenic	O
fungi	O
and	O
which	O
may	O
play	O
significant	O
roles	O
in	O
plant	O
infection	O
.	O

Results	O

Identification	O
of	O
orthologous	O
gene	O
sets	O
from	O
fungal	O
and	O
oomcyete	O
genomes	O

Genome	O
sequences	O
and	O
sets	O
of	O
predicted	O
proteins	O
were	O
analysed	O
from	O
34	O
species	O
of	O
fungi	O
and	O
2	O
species	O
of	O
oomycete	O
(	O
Table	O
1	O
)	O
.	O

In	O
order	O
to	O
compare	O
such	O
a	O
large	O
number	O
of	O
genomes	O
,	O
an	O
object	O
-	O
oriented	O
data	O
warehouse	O
has	O
been	O
constructed	O
known	O
as	O
e	O
-	O
Fungi	O
[	O
26	O
]	O
which	O
integrates	O
genomic	O
data	O
with	O
a	O
variety	O
of	O
functional	O
data	O
and	O
has	O
a	O
powerful	O
set	O
of	O
queries	O
that	O
enables	O
sophisticated	O
,	O
whole	O
-	O
genome	O
comparisons	O
to	O
be	O
performed	O
.	O

To	O
compare	O
genome	O
inventories	O
,	O
the	O
entire	O
set	O
of	O
predicted	O
proteins	O
from	O
the	O
36	O
species	O
(	O
348	O
,	O
787	O
proteins	O
)	O
were	O
clustered	O
using	O
Markov	O
Chain	O
Clustering	O
[	O
27	O
]	O
as	O
described	O
previously	O
[	O
28	O
]	O
,	O
[	O
29	O
]	O
.	O

A	O
total	O
of	O
282	O
,	O
061	O
predicted	O
proteins	O
were	O
grouped	O
into	O
23	O
,	O
724	O
clusters	O
,	O
each	O
cluster	O
representing	O
a	O
group	O
of	O
putative	O
orthologues	O
.	O

The	O
remaining	O
66	O
,	O
934	O
sequences	O
were	O
singletons	O
,	O
the	O
products	O
of	O
unique	O
genes	O
.	O

A	O
total	O
of	O
165	O
clusters	O
contained	O
proteins	O
from	O
all	O
36	O
species	O
used	O
in	O
this	O
study	O
(	O
Table	O
S1	O
)	O
.	O

Not	O
surprisingly	O
,	O
they	O
included	O
many	O
proteins	O
involved	O
in	O
basic	O
cellular	O
processes	O
,	O
such	O
as	O
ribosomal	O
proteins	O
,	O
components	O
of	O
transcription	O
,	O
translation	O
and	O
DNA	O
replication	O
apparatus	O
,	O
cytoskeletal	O
proteins	O
,	O
histones	O
,	O
proteins	O
involved	O
in	O
the	O
secretory	O
pathway	O
,	O
protein	O
folding	O
,	O
protein	O
sorting	O
and	O
ubiquitin	O
-	O
mediated	O
proteolysis	O
and	O
enzymes	O
involved	O
in	O
primary	O
metabolism	O
.	O

Only	O
16	O
clusters	O
contained	O
proteins	O
that	O
were	O
found	O
in	O
all	O
34	O
species	O
of	O
fungi	O
,	O
but	O
which	O
were	O
absent	O
from	O
the	O
two	O
species	O
of	O
oomycete	O
(	O
Table	O
S2	O
)	O
.	O

This	O
number	O
of	O
fungal	O
-	O
specific	O
clusters	O
is	O
surprisingly	O
low	O
considering	O
the	O
phylogenetic	O
distance	O
between	O
the	O
oomycetes	O
and	O
fungi	O
[	O
30	O
]	O
.	O

The	O
list	O
however	O
,	O
is	O
consistent	O
with	O
the	O
fundamental	O
differences	O
in	O
biology	O
between	O
fungi	O
and	O
oomycetes	O
and	O
included	O
proteins	O
involved	O
in	O
fungal	O
septation	O
,	O
glycosylation	O
,	O
transcriptional	O
regulation	O
,	O
cell	O
signalling	O
,	O
as	O
well	O
as	O
two	O
amino	O
-	O
acyl	O
tRNA	O
synthetases	O
.	O

The	O
obligate	O
mammalian	O
pathogen	O
Encephalitozoon	B
cuniculi	I
,	O
a	O
microsporidian	O
fungus	O
,	O
has	O
a	O
reduced	O
genome	O
that	O
codes	O
only	O
for	O
1	O
,	O
997	O
proteins	O
and	O
lacks	O
genes	O
encoding	O
enzymes	O
of	O
many	O
primary	O
metabolic	O
pathways	O
such	O
as	O
the	O
tricarboxylic	O
acid	O
cycle	O
,	O
fatty	O
acid	O
beta	O
-	O
oxidation	O
,	O
biosynthetic	O
enzymes	O
of	O
the	O
vast	O
majority	O
of	O
amino	O
acids	O
,	O
fatty	O
acids	O
and	O
nucleotides	O
,	O
as	O
well	O
as	O
components	O
of	O
the	O
respiratory	O
electron	O
transport	O
chain	O
and	O
F1	O
-	O
F0	O
ATP	O
synthase	O
.	O

It	O
also	O
lacks	O
mitochondria	O
and	O
peroxisomes	O
[	O
31	O
]	O
.	O

Therefore	O
,	O
we	O
reasoned	O
that	O
the	O
inclusion	O
of	O
this	O
species	O
in	O
the	O
analysis	O
of	O
MCL	O
clusters	O
is	O
likely	O
to	O
result	O
in	O
underestimation	O
of	O
the	O
number	O
of	O
groups	O
of	O
conserved	O
proteins	O
.	O

By	O
discarding	O
E	B
.	I
cuniculi	I
,	O
there	O
are	O
377	O
clusters	O
that	O
contained	O
proteins	O
from	O
35	O
species	O
of	O
fungi	O
and	O
oomycetes	O
(	O
Table	O
S3	O
)	O
.	O

This	O
relatively	O
small	O
number	O
of	O
fungal	O
-	O
conserved	O
clusters	O
reflects	O
the	O
large	O
evolutionary	O
distance	O
between	O
members	O
of	O
the	O
fungal	O
kingdom	O
,	O
as	O
well	O
as	O
complex	O
patterns	O
of	O
gene	O
gains	O
and	O
losses	O
during	O
the	O
evolution	O
of	O
fungi	O
.	O

Basidiomycetes	O
and	O
ascomycetes	O
are	O
thought	O
to	O
have	O
diverged	O
nearly	O
1	O
,	O
000	O
million	O
years	O
ago	O
[	O
32	O
]	O
and	O
the	O
Saccharomycotina	O
alone	O
are	O
more	O
evolutionarily	O
diverged	O
than	O
the	O
Chordate	O
phylum	O
of	O
the	O
animal	O
kingdom	O
[	O
33	O
]	O
.	O

Since	O
the	O
divergence	O
of	O
Saccharomycotina	O
(	O
hemiascomycetes	O
)	O
and	O
Pezizomycotina	O
(	O
euascomycetes	O
)	O
,	O
the	O
genomes	O
of	O
the	O
latter	O
have	O
greatly	O
increased	O
in	O
size	O
,	O
partly	O
due	O
to	O
the	O
appearance	O
of	O
novel	O
genes	O
related	O
to	O
the	O
filamentous	O
lifestyle	O
.	O

Lineage	O
-	O
specific	O
gene	O
losses	O
have	O
also	O
been	O
shown	O
in	O
a	O
number	O
of	O
hemiascomycete	O
species	O
[	O
34	O
]	O
.	O

As	O
well	O
as	O
the	O
groups	O
of	O
proteins	O
mentioned	O
above	O
(	O
Table	O
S1	O
)	O
,	O
the	O
fungal	O
-	O
conserved	O
clusters	O
included	O
those	O
containing	O
enzymes	O
from	O
primary	O
metabolic	O
pathways	O
not	O
present	O
in	O
E	B
.	I
cuniculi	I
,	O
such	O
as	O
the	O
tricarboxylic	O
acid	O
cycle	O
,	O
amino	O
acid	O
metabolism	O
,	O
fatty	O
acid	O
biosynthesis	O
,	O
cholesterol	O
biosynthesis	O
and	O
nucleotide	O
metabolism	O
,	O
as	O
well	O
as	O
components	O
of	O
the	O
respiratory	O
electron	O
transport	O
chain	O
and	O
F1	O
-	O
F0	O
ATP	O
synthase	O
.	O

The	O
conserved	O
protein	O
clusters	O
also	O
include	O
a	O
number	O
of	O
transporters	O
(	O
including	O
mitochondrial	O
transporters	O
)	O
,	O
enzymes	O
involved	O
in	O
haem	O
biosynthesis	O
,	O
autophagy	O
-	O
related	O
proteins	O
,	O
those	O
involved	O
in	O
protein	O
targeting	O
to	O
the	O
peroxisome	O
and	O
vacuole	O
and	O
additional	O
groups	O
of	O
proteins	O
involved	O
in	O
signal	O
transduction	O
that	O
are	O
not	O
present	O
in	O
E	B
.	I
cuniculi	I
(	O
including	O
those	O
involved	O
in	O
inosine	O
triphosphate	O
and	O
leukotriene	O
metabolism	O
)	O
.	O

The	O
analysis	O
also	O
showed	O
there	O
were	O
105	O
clusters	O
that	O
contained	O
proteins	O
from	O
33	O
species	O
of	O
fungi	O
(	O
excluding	O
E	B
.	I
cuniculi	I
)	O
,	O
but	O
not	O
from	O
the	O
two	O
species	O
of	O
oomycete	O
(	O
see	O
Table	O
S4	O
)	O
.	O

As	O
well	O
as	O
those	O
mentioned	O
previously	O
(	O
Table	O
S2	O
)	O
,	O
the	O
group	O
includes	O
a	O
number	O
of	O
clusters	O
of	O
transporters	O
that	O
are	O
conserved	O
in	O
fungi	O
but	O
not	O
found	O
in	O
oomycetes	O
,	O
as	O
well	O
as	O
proteins	O
involved	O
in	O
fungal	O
cell	O
wall	O
synthesis	O
,	O
and	O
lipid	O
metabolism	O
.	O

It	O
may	O
be	O
the	O
case	O
that	O
the	O
genomes	O
of	O
oomycete	O
species	O
do	O
not	O
possess	O
orthologues	O
of	O
the	O
fungal	O
genes	O
in	O
these	O
clusters	O
,	O
or	O
alternatively	O
,	O
the	O
large	O
evolutionary	O
distance	O
between	O
the	O
oomycetes	O
and	O
fungi	O
mean	O
that	O
the	O
corresponding	O
orthologues	O
from	O
each	O
Kingdom	O
cluster	O
separately	O
.	O

Comparative	O
analysis	O
of	O
yeasts	O
and	O
filamentous	O
fungi	O

One	O
striking	O
difference	O
in	O
the	O
morphology	O
of	O
species	O
of	O
fungi	O
is	O
between	O
those	O
that	O
have	O
a	O
filamentous	O
,	O
multi	O
-	O
cellular	O
growth	O
habit	O
and	O
those	O
that	O
grow	O
as	O
single	O
yeast	B
cells	O
.	O

There	O
is	O
some	O
overlap	O
between	O
these	O
two	O
groups	O
;	O
because	O
some	O
fungi	O
are	O
dimorphic	O
or	O
even	O
pleiomorphic	O
,	O
switching	O
between	O
different	O
growth	O
forms	O
depending	O
on	O
environmental	O
conditions	O
or	O
the	O
stage	O
of	O
their	O
life	O
cycle	O
.	O

For	O
example	O
,	O
the	O
corn	B
-	O
smut	O
fungus	O
Ustilago	B
maydis	I
can	O
exist	O
saprophytically	O
as	O
haploid	O
yeast	B
-	O
like	O
cells	O
,	O
but	O
needs	O
to	O
form	O
a	O
dikaryotic	O
filamentous	O
growth	O
form	O
in	O
order	O
to	O
infect	O
the	O
host	O
plant	O
[	O
23	O
]	O
.	O

Generally	O
the	O
genomes	O
of	O
the	O
filamentous	O
fungi	O
contain	O
more	O
protein	O
-	O
encoding	O
genes	O
(	O
9	O
,	O
000	O
-	O
17	O
,	O
000	O
)	O
than	O
those	O
from	O
unicellular	O
yeasts	O
(	O
5	O
,	O
000	O
-	O
7	O
,	O
000	O
)	O
,	O
perhaps	O
reflecting	O
their	O
greater	O
morphological	O
complexity	O
and	O
secondary	O
metabolic	O
capacity	O
.	O

U	B
.	I
maydis	I
,	O
however	O
,	O
has	O
6	O
,	O
522	O
protein	O
encoding	O
genes	O
,	O
perhaps	O
reflecting	O
its	O
lack	O
of	O
extensive	O
secondary	O
metabolic	O
pathways	O
and	O
its	O
potential	O
usefulness	O
in	O
defining	O
the	O
minimal	O
gene	O
sets	O
associated	O
with	O
biotrophic	O
growth	O
[	O
23	O
]	O
.	O

The	O
increase	O
in	O
proteome	O
size	O
in	O
filamentous	O
ascomycetes	O
may	O
be	O
due	O
to	O
the	O
expansion	O
of	O
certain	O
gene	O
families	O
or	O
the	O
presence	O
of	O
novel	O
genes	O
that	O
are	O
essential	O
for	O
the	O
filamentous	O
lifestyle	O
.	O

For	O
the	O
purposes	O
of	O
this	O
study	O
,	O
the	O
filamentous	O
fungi	O
were	O
defined	O
as	O
the	O
filamentous	O
ascomycetes	O
(	O
subphylum	O
Pezizomycotina	O
)	O
,	O
basidiomycetes	O
and	O
zygomycetes	O
and	O
the	O
unicellular	O
fungi	O
were	O
defined	O
as	O
the	O
budding	O
yeasts	O
(	O
order	O
Saccharomycetales	O
)	O
,	O
the	O
archiascomycete	O
Schizosaccharomyces	B
pombe	I
and	O
the	O
microsporidian	O
fungus	O
Encephalitozoon	B
cuniculi	I
.	O

A	O
total	O
of	O
37	O
MCL	O
clusters	O
contained	O
proteins	O
from	O
all	O
species	O
of	O
filamentous	O
fungi	O
,	O
but	O
no	O
species	O
of	O
unicellular	O
fungi	O
(	O
Table	O
2	O
)	O
.	O

Interestingly	O
,	O
eight	O
of	O
these	O
clusters	O
also	O
contained	O
proteins	O
from	O
both	O
species	O
of	O
oomycete	O
represented	O
in	O
e	O
-	O
Fungi	O
.	O

The	O
filamentous	O
-	O
fungal	O
specific	O
clusters	O
included	O
a	O
number	O
of	O
proteins	O
that	O
are	O
involved	O
in	O
cytoskeletal	O
rearrangements	O
(	O
dedicator	O
of	O
cytokinesis	O
protein	O
,	O
integrin	O
beta	O
-	O
1	O
-	O
binding	O
protein	O
,	O
dynactin	O
p62	O
family	O
,	O
dynein	O
light	O
intermediate	O
chain	O
2	O
)	O
,	O
it	O
seems	O
likely	O
that	O
these	O
are	O
required	O
for	O
the	O
complex	O
morphological	O
changes	O
that	O
filamentous	O
fungi	O
undergo	O
during	O
their	O
lifecycle	O
and	O
the	O
production	O
of	O
differentiated	O
cells	O
,	O
such	O
as	O
spores	O
,	O
fruiting	O
bodies	O
and	O
infection	O
structures	O
.	O

The	O
results	O
also	O
suggest	O
that	O
filamentous	O
fungal	O
species	O
make	O
a	O
greater	O
use	O
of	O
lipids	O
as	O
signalling	O
molecules	O
than	O
yeast	B
species	O
.	O

For	O
example	O
,	O
the	O
occurrence	O
of	O
filamentous	O
fungal	O
-	O
specific	O
clusters	O
representing	O
two	O
groups	O
of	O
lysophospholipases	O
,	O
as	O
well	O
as	O
ceramidases	O
that	O
are	O
involved	O
in	O
sphingolipid	O
signalling	O
[	O
35	O
]	O
and	O
linoleate	O
diol	O
synthases	O
that	O
can	O
catalyse	O
the	O
formation	O
of	O
leukotrienes	O
[	O
36	O
]	O
.	O

Interestingly	O
,	O
one	O
of	O
the	O
products	O
of	O
linoleate	O
diol	O
synthase	O
has	O
been	O
shown	O
to	O
be	O
a	O
sporulation	O
hormone	O
in	O
Aspergillus	B
nidulans	I
[	O
37	O
]	O
.	O

There	O
is	O
also	O
a	O
cluster	O
that	O
represents	O
homologues	O
of	O
a	O
novel	O
human	B
gene	O
(	O
LRP16	O
)	O
that	O
acts	O
downstream	O
of	O
a	O
steroid	O
receptor	O
and	O
promotes	O
cell	O
proliferation	O
[	O
38	O
]	O
.	O

Two	O
clusters	O
of	O
filamentous	O
fungal	O
-	O
specific	O
proteins	O
represent	O
enzymes	O
involved	O
in	O
molypterin	O
biosynthesis	O
(	O
MCL2420	O
,	O
MCL2581	O
)	O
.	O

Molypterin	O
is	O
a	O
molybdenum	O
-	O
containing	O
co	O
-	O
factor	O
for	O
nitrate	O
reductase	O
,	O
an	O
enzyme	O
that	O
is	O
known	O
to	O
be	O
absent	O
from	O
the	O
species	O
of	O
yeast	B
used	O
in	O
this	O
study	O
[	O
39	O
]	O
.	O

Both	O
these	O
clusters	O
are	O
also	O
found	O
in	O
oomycetes	O
.	O

There	O
are	O
other	O
clusters	O
representing	O
proteins	O
important	O
for	O
activities	O
specific	O
to	O
filamentous	O
fungi	O
,	O
such	O
as	O
homologues	O
of	O
Pro11	O
(	O
striatin	O
)	O
which	O
regulates	O
fruiting	O
body	O
formation	O
in	O
Sordaria	B
macrospora	I
[	O
40	O
]	O
,	O
the	O
vegetatible	O
incompatibility	O
protein	O
HET	O
-	O
E	O
-	O
1	O
,	O
which	O
prevents	O
the	O
formation	O
of	O
heterokaryons	O
between	O
incompatible	O
fungal	O
strains	O
in	O
Podospora	B
anserina	I
[	O
41	O
]	O
,	O
anucleate	O
primary	O
sterigmata	O
protein	O
A	O
from	O
Aspergillus	B
nidulans	I
,	O
which	O
is	O
essential	O
for	O
nuclear	O
migration	O
and	O
conidiophore	O
development	O
[	O
42	O
]	O
and	O
cytochrome	O
P450	O
and	O
polyketide	O
synthase	O
-	O
encoding	O
genes	O
,	O
both	O
of	O
which	O
are	O
involved	O
in	O
a	O
number	O
of	O
secondary	O
metabolic	O
pathways	O
including	O
toxin	O
biosynthesis	O
[	O
43	O
]	O
.	O

Pathogenicity	O
-	O
associated	O
gene	O
functions	O
in	O
fungi	O

As	O
the	O
selected	O
set	O
of	O
fungi	O
includes	O
both	O
saprotrophic	O
and	O
pathogenic	O
species	O
,	O
this	O
allows	O
us	O
to	O
compare	O
the	O
gene	O
inventories	O
of	O
phytopathogenic	O
and	O
closely	O
related	O
non	O
-	O
pathogenic	O
fungi	O
to	O
look	O
for	O
genes	O
that	O
are	O
unique	O
to	O
phytopathogens	O
.	O

Analysis	O
of	O
MCL	O
clusters	O
showed	O
that	O
there	O
were	O
no	O
clusters	O
that	O
contained	O
proteins	O
from	O
all	O
species	O
of	O
fungal	O
phytopathogen	O
in	O
e	O
-	O
Fungi	O
(	O
namely	O
B	B
.	I
cinerea	I
,	O
Eremothecium	B
gossypii	I
,	O
G	B
.	I
zeae	I
,	O
M	B
.	I
grisea	I
,	O
S	B
.	I
sclerotiorum	I
,	O
S	B
.	I
nodorum	I
and	O
U	B
.	I
maydis	I
)	O
but	O
did	O
not	O
contain	O
proteins	O
from	O
non	O
-	O
pathogenic	O
species	O
.	O

There	O
were	O
,	O
however	O
,	O
four	O
clusters	O
that	O
were	O
exclusive	O
to	O
filamentous	O
ascomycete	O
phytopathogens	O
(	O
namely	O
B	B
.	I
cinerea	I
,	O
G	B
.	I
zeae	I
,	O
M	B
.	I
grisea	I
,	O
S	B
.	I
sclerotiorum	I
,	O
S	B
.	I
nodorum	I
as	O
shown	O
in	O
Table	O
3	O
)	O
.	O

Significantly	O
,	O
none	O
of	O
the	O
members	O
of	O
these	O
clusters	O
had	O
homology	O
to	O
any	O
known	O
proteins	O
or	O
contained	O
motifs	O
from	O
the	O
Pfam	O
database	O
[	O
44	O
]	O
,	O
so	O
we	O
were	O
unable	O
to	O
predict	O
their	O
function	O
,	O
although	O
two	O
of	O
the	O
clusters	O
(	O
MCL4854	O
and	O
MCL8229	O
)	O
consisted	O
entirely	O
of	O
proteins	O
that	O
were	O
predicted	O
to	O
be	O
secreted	O
.	O

Taken	O
together	O
,	O
the	O
observations	O
indicate	O
that	O
a	O
battery	O
of	O
completely	O
novel	O
secreted	O
proteins	O
may	O
be	O
associated	O
with	O
ascomycete	O
fungal	O
pathogens	O
.	O

Pathogenicity	O
factors	O
have	O
been	O
defined	O
as	O
genes	O
that	O
are	O
essential	O
for	O
successful	O
completion	O
of	O
the	O
pathogen	O
lifecycle	O
but	O
dispensable	O
for	O
saprophytic	O
growth	O
[	O
4	O
]	O
.	O

This	O
is	O
an	O
experimental	O
definition	O
based	O
on	O
whether	O
null	O
mutations	O
of	O
a	O
given	O
gene	O
reduce	O
the	O
virulence	O
of	O
the	O
pathogen	O
on	O
its	O
host	O
.	O

We	O
wished	O
to	O
ascertain	O
whether	O
homologues	O
of	O
previously	O
characterised	O
and	O
experimentally	O
-	O
validated	O
pathogenicity	O
factors	O
were	O
limited	O
to	O
the	O
genomes	O
of	O
pathogenic	O
species	O
.	O

A	O
search	O
was	O
therefore	O
made	O
for	O
pathogenicity	O
factors	O
that	O
have	O
been	O
identified	O
experimentally	O
for	O
the	O
species	O
of	O
phytopathogens	O
represented	O
in	O
e	O
-	O
Fungi	O
using	O
PHI	O
-	O
base	O
,	O
the	O
plant	O
-	O
host	O
interaction	O
database	O
[	O
45	O
]	O
.	O

The	O
matching	O
locus	O
was	O
identified	O
for	O
each	O
pathogenicity	O
factor	O
in	O
the	O
corresponding	O
genome	O
sequence	O
by	O
comparing	O
a	O
published	O
protein	O
sequence	O
with	O
sets	O
of	O
predicted	O
proteins	O
for	O
each	O
genome	O
using	O
BLASTP	O
.	O

This	O
produced	O
a	O
list	O
of	O
105	O
pathogenicity	O
factors	O
,	O
although	O
corresponding	O
loci	O
could	O
not	O
be	O
found	O
in	O
genome	O
sequences	O
for	O
all	O
the	O
published	O
genes	O
(	O
see	O
Table	O
S5	O
)	O
.	O

MCL	O
clusters	O
containing	O
these	O
proteins	O
were	O
identified	O
(	O
76	O
unique	O
clusters	O
)	O
and	O
the	O
species	O
distribution	O
of	O
members	O
of	O
these	O
clusters	O
analysed	O
.	O

In	O
total	O
,	O
29	O
of	O
the	O
MCL	O
clusters	O
contained	O
pathogenicity	O
factors	O
with	O
members	O
from	O
at	O
least	O
34	O
of	O
the	O
36	O
species	O
represented	O
in	O
e	O
-	O
Fungi	O
(	O
Table	O
4	O
)	O
.	O

Not	O
surprisingly	O
,	O
many	O
of	O
these	O
clusters	O
contain	O
conserved	O
components	O
of	O
signalling	O
pathways	O
such	O
as	O
protein	O
kinases	O
,	O
adenylate	O
cyclases	O
,	O
G	O
-	O
proteins	O
and	O
cell	O
cycle	O
regulators	O
.	O

Cellular	O
morphogenesis	O
is	O
known	O
to	O
be	O
important	O
for	O
infection	O
of	O
the	O
host	O
plant	O
by	O
many	O
phytopathogens	O
,	O
for	O
example	O
,	O
in	O
appressorium	O
formation	O
in	O
Magnaporthe	B
grisea	I
[	O
46	O
]	O
or	O
the	O
switch	O
in	O
the	O
growth	O
form	O
of	O
Ustilago	B
maydis	I
from	O
yeast	B
-	O
like	O
growth	O
to	O
filamentous	O
invasive	O
growth	O
[	O
47	O
]	O
.	O

Links	O
between	O
successful	O
plant	O
infection	O
and	O
cell	O
cycle	O
control	O
have	O
also	O
been	O
demonstrated	O
[	O
48	O
]	O
.	O

It	O
seems	O
likely	O
that	O
conserved	O
signalling	O
pathways	O
that	O
control	O
activities	O
,	O
such	O
as	O
mating	O
and	O
morphogenesis	O
in	O
all	O
fungi	O
,	O
have	O
evolved	O
to	O
control	O
processes	O
essential	O
for	O
pathogencity	O
in	O
phytopathogens	O
.	O

Other	O
conserved	O
pathogenicity	O
factors	O
encode	O
enzymes	O
of	O
metabolic	O
pathways	O
that	O
are	O
present	O
in	O
nearly	O
all	O
fungi	O
,	O
but	O
seem	O
to	O
be	O
important	O
for	O
the	O
life	O
cycle	O
of	O
particular	O
pathogenic	O
species	O
,	O
for	O
example	O
,	O
enzymes	O
involved	O
in	O
beta	O
-	O
oxidation	O
of	O
fatty	O
acids	O
,	O
the	O
glyoxylate	O
shunt	O
,	O
amino	O
acid	O
metabolism	O
and	O
the	O
utilisation	O
of	O
stored	O
sugars	O
.	O

When	O
considered	O
together	O
,	O
this	O
may	O
indicate	O
that	O
nutritional	O
conditions	O
which	O
fungi	O
encounter	O
when	O
invading	O
host	O
plant	O
tissue	O
require	O
mobilisation	O
of	O
stored	O
lipids	O
prior	O
to	O
nutrition	O
being	O
extracted	O
from	O
the	O
host	O
plant	O
.	O

Seventeen	O
of	O
the	O
MCL	O
clusters	O
containing	O
pathogenicity	O
factors	O
were	O
specific	O
to	O
filamentous	O
ascomycetes	O
(	O
Table	O
5	O
)	O
.	O

These	O
include	O
a	O
number	O
of	O
enzymes	O
involved	O
in	O
secondary	O
metabolism	O
,	O
such	O
as	O
those	O
involved	O
in	O
the	O
synthesis	O
of	O
the	O
fungal	O
toxin	O
trichothecene	O
in	O
G	B
.	I
zeae	I
[	O
43	O
]	O
and	O
those	O
involved	O
in	O
melanin	O
biosynthesis	O
[	O
49	O
]	O
,	O
as	O
well	O
as	O
structural	O
proteins	O
,	O
some	O
of	O
which	O
are	O
components	O
of	O
differentiated	O
cell	O
types	O
not	O
seen	O
in	O
yeasts	O
,	O
for	O
example	O
,	O
hydrophobins	O
which	O
are	O
components	O
of	O
aerial	O
structures	O
such	O
as	O
fruiting	O
bodies	O
[	O
50	O
]	O
but	O
are	O
also	O
involved	O
in	O
pathogenicity	O
[	O
16	O
]	O
.	O

There	O
also	O
seems	O
to	O
be	O
a	O
number	O
of	O
filamentous	O
ascomycete	O
specific	O
receptor	O
proteins	O
(	O
transducin	O
beta	O
-	O
subunit	O
,	O
G	O
-	O
protein	O
coupled	O
receptor	O
,	O
tetraspanins	O
)	O
that	O
have	O
evolved	O
in	O
pathogens	O
to	O
be	O
used	O
in	O
sensing	O
environmental	O
cues	O
that	O
are	O
essential	O
for	O
successful	O
infection	O
of	O
the	O
host	O
[	O
51	O
]	O
.	O

The	O
Woronin	O
body	O
is	O
a	O
structure	O
found	O
only	O
in	O
filamentous	O
ascomycetes	O
,	O
and	O
has	O
been	O
shown	O
to	O
be	O
essential	O
for	O
pathogenicity	O
in	O
M	B
.	I
grisea	I
[	O
52	O
]	O
.	O

A	O
major	O
constituent	O
of	O
the	O
woronin	O
body	O
,	O
encoded	O
by	O
MVP1	O
,	O
is	O
a	O
pathogenicity	O
factor	O
for	O
M	B
.	I
grisea	I
,	O
but	O
also	O
has	O
homologues	O
in	O
nearly	O
all	O
species	O
of	O
filamentous	O
ascomycetes	O
.	O

Two	O
proteins	O
that	O
were	O
initially	O
discovered	O
as	O
being	O
highly	O
expressed	O
in	O
the	O
appressoria	O
of	O
M	B
.	I
grisea	I
and	O
essential	O
for	O
pathogenicity	O
(	O
Mas1	O
and	O
Mas3	O
)	O
[	O
53	O
]	O
also	O
have	O
homologues	O
in	O
a	O
number	O
of	O
species	O
of	O
filamentous	O
fungi	O
(	O
Table	O
5	O
)	O
.	O

Thus	O
,	O
many	O
innovations	O
that	O
have	O
allowed	O
filamentous	O
ascomycetes	O
to	O
have	O
a	O
more	O
complex	O
morphology	O
than	O
unicellular	O
yeasts	O
have	O
also	O
evolved	O
to	O
be	O
essential	O
for	O
plant	O
infection	O
by	O
phytopathogenic	O
species	O
.	O

Interestingly	O
,	O
none	O
of	O
the	O
MCL	O
clusters	O
containing	O
known	O
pathogenicity	O
factors	O
contained	O
members	O
only	O
from	O
phytopathogenic	O
fungi	O
,	O
apart	O
from	O
those	O
that	O
were	O
restricted	O
to	O
just	O
one	O
species	O
.	O

These	O
are	O
therefore	O
likely	O
to	O
represent	O
highly	O
-	O
specialised	O
proteins	O
that	O
have	O
evolved	O
for	O
the	O
specific	O
lifecycle	O
of	O
just	O
one	O
species	O
of	O
phytopathogen	O
,	O
for	O
example	O
the	O
Pwl	O
proteins	O
involved	O
in	O
determining	O
host	O
range	O
of	O
different	O
strains	O
of	O
M	B
.	I
grisea	I
[	O
54	O
]	O
.	O

Two	O
of	O
the	O
proteins	O
specific	O
to	O
M	B
.	I
grisea	I
,	O
the	O
metallothionein	O
Mmt1	O
[	O
55	O
]	O
and	O
the	O
hydrophobin	O
Mpg1	O
[	O
56	O
]	O
are	O
small	O
polypeptides	O
and	O
are	O
members	O
of	O
highly	O
divergent	O
gene	O
families	O
,	O
other	O
members	O
of	O
which	O
do	O
not	O
cluster	O
together	O
using	O
BLASTP	O
.	O

Comparative	O
analysis	O
of	O
plant	O
-	O
pathogenic	O
and	O
saprotrophic	O
filamentous	O
ascomycetes	O

Based	O
on	O
the	O
analysis	O
reported	O
,	O
it	O
is	O
likely	O
that	O
in	O
general	O
there	O
are	O
a	O
large	O
number	O
of	O
differences	O
in	O
gene	O
inventories	O
between	O
filamentous	O
and	O
yeast	B
-	O
like	O
fungi	O
.	O

Therefore	O
,	O
in	O
order	O
to	O
compare	O
the	O
genomes	O
of	O
phytopathogens	O
and	O
saprotrophs	O
,	O
we	O
focused	O
on	O
filamentous	O
ascomycetes	O
in	O
order	O
to	O
resolve	O
in	O
greater	O
detail	O
the	O
distinct	O
differences	O
in	O
gene	O
sets	O
between	O
these	O
two	O
ecologically	O
separate	O
groups	O
of	O
fungi	O
.	O

In	O
this	O
way	O
differences	O
due	O
to	O
phylogeny	O
between	O
the	O
species	O
would	O
be	O
minimised	O
.	O

We	O
compared	O
the	O
gene	O
inventories	O
of	O
the	O
phytopathogens	O
B	B
.	I
cinerea	I
,	O
G	B
.	I
zeae	I
,	O
M	B
.	I
grisea	I
,	O
S	B
.	I
sclerotiorum	I
,	O
S	B
.	I
nodorum	I
with	O
the	O
non	O
-	O
pathogens	O
Aspergillus	B
nidulans	I
,	O
Chaetomium	B
globosum	I
,	O
Neurospora	B
crassa	I
and	O
Trichoderma	B
reesei	I
.	O

Phylogenetic	O
analysis	O
suggests	O
that	O
the	O
phytopathogenic	O
species	O
do	O
not	O
form	O
a	O
separate	O
clade	O
from	O
the	O
pathogenic	O
species	O
(	O
Figure	O
1	O
)	O
,	O
[	O
3	O
]	O
and	O
we	O
assumed	O
that	O
differences	O
in	O
gene	O
inventory	O
should	O
therefore	O
reflect	O
lifestyle	O
rather	O
than	O
evolutionary	O
distance	O
.	O

In	O
order	O
for	O
such	O
a	O
comparison	O
to	O
be	O
considered	O
valid	O
,	O
the	O
completeness	O
and	O
quality	O
of	O
the	O
fungal	O
genome	O
sequences	O
used	O
should	O
,	O
however	O
,	O
also	O
be	O
comparable	O
.	O

Table	O
S6	O
summarises	O
the	O
available	O
data	O
about	O
genome	O
sequence	O
coverage	O
,	O
genome	O
size	O
and	O
the	O
number	O
of	O
predicted	O
proteins	O
for	O
each	O
species	O
.	O

This	O
shows	O
that	O
the	O
genome	O
coverage	O
is	O
greater	O
than	O
5x	O
and	O
the	O
number	O
of	O
predicted	O
proteins	O
in	O
the	O
range	O
of	O
10	O
,	O
000	O
-	O
16	O
,	O
000	O
for	O
all	O
genomes	O
used	O
,	O
suggesting	O
a	O
high	O
level	O
of	O
equivalence	O
between	O
species	O
with	O
regard	O
to	O
sequence	O
quality	O
.	O

From	O
our	O
work	O
it	O
seems	O
unlikely	O
that	O
there	O
are	O
pathogenicity	O
factors	O
conserved	O
in	O
,	O
and	O
specific	O
to	O
,	O
all	O
species	O
of	O
phytopathogen	O
.	O

It	O
may	O
,	O
for	O
instance	O
,	O
be	O
the	O
case	O
that	O
differences	O
in	O
the	O
gene	O
inventories	O
are	O
due	O
to	O
the	O
expansion	O
of	O
certain	O
gene	O
families	O
in	O
the	O
genomes	O
of	O
phytopathogenic	O
species	O
associated	O
with	O
functions	O
necessary	O
for	O
pathogenesis	O
.	O

To	O
define	O
protein	O
families	O
,	O
we	O
used	O
the	O
Pfam	O
database	O
which	O
contains	O
protein	O
family	O
models	O
based	O
on	O
Hidden	O
Markov	O
Models	O
[	O
44	O
]	O
,	O
[	O
57	O
]	O
.	O

Sets	O
of	O
predicted	O
proteins	O
for	O
each	O
fungal	O
species	O
in	O
e	O
-	O
Fungi	O
were	O
analysed	O
for	O
the	O
occurrence	O
of	O
Pfam	O
motifs	O
and	O
the	O
number	O
of	O
proteins	O
containing	O
each	O
domain	O
across	O
fungal	O
species	O
ascertained	O
.	O

The	O
sets	O
of	O
predicted	O
protein	O
sequences	O
used	O
in	O
this	O
study	O
have	O
been	O
automatically	O
predicted	O
as	O
part	O
of	O
each	O
individual	O
genome	O
project	O
and	O
are	O
likely	O
to	O
contain	O
a	O
number	O
of	O
artefactual	O
sequences	O
.	O

The	O
use	O
of	O
Pfam	O
motifs	O
to	O
define	O
gene	O
families	O
in	O
this	O
study	O
reduces	O
the	O
likelihood	O
of	O
such	O
sequences	O
affecting	O
the	O
data	O
,	O
since	O
Pfam	O
motifs	O
are	O
based	O
on	O
multiple	O
sequence	O
alignments	O
of	O
well	O
-	O
studied	O
proteins	O
.	O

A	O
small	O
number	O
of	O
Pfam	O
motifs	O
were	O
not	O
found	O
in	O
the	O
proteomes	O
of	O
the	O
filamentous	O
ascomycete	O
non	O
-	O
pathogens	O
,	O
but	O
were	O
found	O
in	O
the	O
proteomes	O
of	O
at	O
least	O
three	O
species	O
of	O
filamentous	O
ascomycete	O
phytopathogens	O
(	O
Table	O
6	O
)	O
.	O

These	O
include	O
the	O
Cas1p	O
-	O
like	O
motif	O
(	O
PF07779	O
)	O
,	O
found	O
in	O
4	O
species	O
of	O
phytopathogen	O
,	O
including	O
five	O
copies	O
in	O
G	B
.	I
zeae	I
,	O
and	O
the	O
Yeast	B
cell	O
wall	O
synthesis	O
protein	O
KRE9	O
/	O
KNH1	O
motif	O
(	O
PF05390	O
)	O
,	O
which	O
was	O
found	O
in	O
three	O
species	O
of	O
phytopathogen	O
.	O

Cas1p	O
is	O
a	O
membrane	O
protein	O
necessary	O
for	O
the	O
O	O
-	O
acetylation	O
of	O
the	O
capsular	O
polysaccharide	O
of	O
the	O
basidiomycete	O
animal	O
pathogen	O
Cryptococcus	B
neoformans	I
[	O
58	O
]	O
.	O

KRE9	O
and	O
KNH1	O
are	O
involved	O
in	O
the	O
synthesis	O
of	O
cell	O
surface	O
polysaccharides	O
in	O
S	B
.	I
cerevisiae	I
[	O
59	O
]	O
.	O

Taken	O
together	O
this	O
suggests	O
that	O
synthesis	O
of	O
cell	O
surface	O
polysaccharides	O
is	O
important	O
for	O
phytopathogens	O
,	O
perhaps	O
helping	O
to	O
shroud	O
the	O
fungus	O
from	O
plant	O
defences	O
.	O

The	O
function	O
of	O
the	O
YDG	O
/	O
SRA	O
domain	O
motif	O
(	O
PF02182	O
)	O
is	O
unknown	O
,	O
but	O
is	O
found	O
in	O
a	O
novel	O
mouse	B
cell	O
proliferation	O
protein	O
Np95	O
,	O
in	O
which	O
the	O
domain	O
is	O
important	O
both	O
for	O
the	O
interaction	O
with	O
histones	O
and	O
for	O
chromatin	O
binding	O
in	O
vivo	O
[	O
60	O
]	O
.	O

As	O
well	O
as	O
domains	O
of	O
unknown	O
function	O
,	O
the	O
list	O
of	O
phytopathogen	O
-	O
specific	O
Pfam	O
motifs	O
includes	O
Allophanate	O
hydrolase	O
(	O
PF02682	O
)	O
which	O
is	O
found	O
in	O
an	O
enzyme	O
involved	O
in	O
the	O
ATP	O
-	O
dependent	O
urea	O
degradation	O
pathway	O
[	O
61	O
]	O
,	O
a	O
peptidase	O
motif	O
,	O
an	O
opioid	O
growth	O
receptor	O
motif	O
(	O
PF04664	O
)	O
and	O
Mnd1	O
(	O
PF03962	O
)	O
,	O
which	O
is	O
involved	O
in	O
recombination	O
and	O
meiotic	O
nuclear	O
division	O
[	O
62	O
]	O
.	O

To	O
detect	O
potential	O
gene	O
family	O
expansion	O
,	O
we	O
decided	O
to	O
identify	O
Pfam	O
motifs	O
that	O
were	O
present	O
in	O
both	O
phytopathogenic	O
and	O
non	O
-	O
pathogenic	O
species	O
of	O
filamentous	O
ascomycetes	O
,	O
but	O
that	O
were	O
more	O
common	O
in	O
the	O
genomes	O
of	O
the	O
former	O
.	O

The	O
Pfam	O
motifs	O
were	O
ranked	O
on	O
the	O
ratio	O
of	O
the	O
mean	O
number	O
of	O
proteins	O
containing	O
each	O
motif	O
in	O
phytopathogens	O
,	O
when	O
compared	O
to	O
non	O
-	O
pathogens	O
(	O
Table	O
7	O
)	O
.	O

The	O
tables	O
only	O
show	O
ratios	O
of	O
greater	O
than	O
or	O
equal	O
to	O
2	O
.	O
5	O
.	O

Pfam	O
motifs	O
that	O
were	O
more	O
common	O
in	O
the	O
proteomes	O
of	O
pathogens	O
,	O
include	O
some	O
found	O
in	O
enzymes	O
involved	O
in	O
secondary	O
metabolic	O
pathways	O
.	O

These	O
include	O
novel	O
enzymes	O
that	O
have	O
only	O
previously	O
been	O
studied	O
in	O
non	O
-	O
fungal	O
species	O
,	O
such	O
as	O
the	O
chalcone	O
synthases	O
;	O
type	O
III	O
polyketide	O
synthases	O
involved	O
in	O
the	O
biosynthesis	O
of	O
flavonoids	O
in	O
plants	O
[	O
63	O
]	O
and	O
lipoxygenases	O
;	O
components	O
of	O
metabolic	O
pathways	O
resulting	O
in	O
the	O
synthesis	O
of	O
physiologically	O
-	O
active	O
compounds	O
such	O
as	O
eicosanoids	O
in	O
mammals	O
[	O
64	O
]	O
and	O
jasmonic	O
acid	O
in	O
plants	O
[	O
65	O
]	O
as	O
well	O
as	O
antibiotic	O
synthesis	O
monooxygenases	O
.	O

It	O
seems	O
likely	O
that	O
secondary	O
metabolism	O
is	O
essential	O
in	O
phytopathogenic	O
species	O
for	O
the	O
synthesis	O
of	O
mycotoxins	O
,	O
antibiotics	O
,	O
siderophores	O
and	O
pigments	O
[	O
66	O
]	O
,	O
but	O
it	O
may	O
also	O
offer	O
fungal	O
pathogens	O
a	O
distinct	O
alternative	O
means	O
of	O
perturbing	O
host	O
metabolism	O
,	O
cell	O
signalling	O
or	O
plant	O
defence	O
,	O
in	O
contrast	O
to	O
bacterial	O
pathogens	O
that	O
rely	O
on	O
protein	O
secretion	O
to	O
achieve	O
this	O
.	O

There	O
also	O
seems	O
to	O
be	O
number	O
of	O
protease	O
and	O
peptidase	O
domains	O
that	O
are	O
more	O
common	O
in	O
the	O
genomes	O
of	O
phytopathogens	O
as	O
well	O
as	O
domains	O
from	O
two	O
classes	O
of	O
cell	O
-	O
wall	O
degrading	O
enzymes	O
:	O
namely	O
cutinase	O
(	O
PF01083	O
)	O
and	O
Glycosyl	O
hydrolase	O
family	O
53	O
(	O
PF07745	O
)	O
which	O
is	O
found	O
in	O
arabinogalactan	O
endo	O
-	O
1	O
,	O
4	O
-	O
beta	O
-	O
galactosidases	O
that	O
hydrolyze	O
the	O
galactan	O
side	O
chains	O
that	O
form	O
part	O
of	O
the	O
complex	O
carbohydrate	O
structure	O
of	O
pectin	O
[	O
67	O
]	O
.	O

Two	O
other	O
domains	O
found	O
in	O
enzymes	O
involved	O
in	O
pectin	O
degradation	O
,	O
pectinesterase	O
(	O
PF01095	O
)	O
and	O
Glycosyl	O
hydrolases	O
family	O
28	O
(	O
PF00295	O
)	O
are	O
both	O
more	O
than	O
twice	O
as	O
common	O
in	O
the	O
genomes	O
of	O
phytopathogens	O
than	O
saprotrophs	O
.	O

In	O
contrast	O
,	O
domains	O
found	O
in	O
cellulases	O
have	O
fairly	O
equal	O
distribution	O
between	O
the	O
proteomes	O
of	O
phytopathogens	O
and	O
non	O
-	O
pathogens	O
(	O
data	O
not	O
shown	O
)	O
.	O

Therefore	O
,	O
for	O
phytopathogens	O
the	O
most	O
essential	O
enzymes	O
for	O
pathogenesis	O
may	O
well	O
be	O
those	O
that	O
allow	O
the	O
fungus	O
to	O
penetrate	O
the	O
protective	O
cutin	O
layer	O
of	O
the	O
plant	O
epidermis	O
and	O
disrupt	O
the	O
pectin	O
matrix	O
of	O
the	O
plant	O
cell	O
wall	O
in	O
which	O
cellulose	O
fibrils	O
are	O
embedded	O
.	O

Pectin	O
-	O
degrading	O
enzymes	O
have	O
already	O
been	O
shown	O
to	O
be	O
pathogenicity	O
factors	O
in	O
a	O
number	O
of	O
fungi	O
[	O
68	O
]	O
.	O

NPP1	O
motifs	O
are	O
characteristic	O
of	O
a	O
group	O
of	O
proteins	O
called	O
NLPs	O
(	O
Nep1	O
-	O
like	O
proteins	O
)	O
that	O
trigger	O
defence	O
responses	O
,	O
necrosis	O
and	O
cell	O
death	O
in	O
plants	O
and	O
may	O
act	O
as	O
virulence	O
factors	O
[	O
69	O
]	O
.	O

The	O
NLPs	O
are	O
more	O
common	O
in	O
the	O
genomes	O
of	O
phytopathogenic	O
,	O
when	O
compared	O
to	O
non	O
-	O
pathogenic	O
ascomycetes	O
,	O
but	O
are	O
even	O
more	O
numerous	O
in	O
the	O
proteomes	O
of	O
the	O
oomycetes	O
(	O
64	O
proteins	O
in	O
Phytophthora	B
ramorum	I
and	O
75	O
in	O
Phytophthora	B
sojae	I
)	O
.	O

Proteins	O
containing	O
the	O
Chitin	O
recognition	O
protein	O
domain	O
(	O
PF00187	O
)	O
are	O
also	O
very	O
common	O
in	O
the	O
proteomes	O
of	O
phytopathogens	O
(	O
18	O
in	O
M	B
.	I
grisea	I
and	O
16	O
in	O
S	B
.	I
nodorum	I
)	O
.	O

A	O
role	O
for	O
chitin	O
-	O
binding	O
proteins	O
has	O
been	O
proposed	O
in	O
protecting	O
the	O
fungal	O
cell	O
wall	O
from	O
chitinases	O
produced	O
by	O
host	O
plants	O
[	O
70	O
]	O
.	O

There	O
are	O
also	O
two	O
other	O
Pfam	O
motifs	O
,	O
which	O
are	O
more	O
common	O
in	O
the	O
proteomes	O
of	O
phytopathogens	O
,	O
that	O
are	O
found	O
in	O
enzymes	O
involved	O
in	O
the	O
catabolism	O
of	O
toxic	O
compounds	O
,	O
namely	O
arylesterase	O
(	O
PF01731	O
)	O
and	O
EthD	O
protein	O
(	O
PF07110	O
)	O
which	O
breakdown	O
organophosphorus	O
esters	O
[	O
71	O
]	O
and	O
ethyl	O
tert	O
-	O
butyl	O
ether	O
[	O
72	O
]	O
,	O
respectively	O
.	O

Comparative	O
secretome	O
analysis	O
of	O
phytopathogenic	O
and	O
saprotrophic	O
filamentous	O
ascomycetes	O

Studies	O
in	O
bacterial	O
pathogens	O
and	O
oomycetes	O
have	O
shown	O
that	O
a	O
range	O
of	O
secreted	O
proteins	O
known	O
as	O
effectors	O
are	O
important	O
for	O
establishing	O
infection	O
of	O
the	O
host	O
plant	O
[	O
73	O
]	O
,	O
[	O
74	O
]	O
.	O

These	O
secreted	O
proteins	O
may	O
disable	O
plant	O
defences	O
and	O
subvert	O
cellular	O
processes	O
to	O
suit	O
the	O
needs	O
of	O
invading	O
pathogens	O
.	O

Therefore	O
,	O
we	O
decided	O
also	O
to	O
compare	O
gene	O
family	O
size	O
in	O
the	O
secretomes	O
of	O
phytopathogens	O
and	O
non	O
-	O
pathogens	O
.	O

There	O
are	O
a	O
number	O
of	O
programs	O
available	O
that	O
predict	O
whether	O
a	O
protein	O
is	O
likely	O
to	O
be	O
secreted	O
,	O
although	O
the	O
predictions	O
they	O
give	O
significantly	O
differ	O
from	O
each	O
other	O
.	O

Therefore	O
we	O
defined	O
the	O
secretome	O
of	O
each	O
fungal	O
species	O
based	O
on	O
those	O
proteins	O
that	O
are	O
predicted	O
to	O
be	O
secreted	O
by	O
two	O
different	O
programs	O
:	O
SignalP	O
3	O
.	O
0	O
[	O
75	O
]	O
and	O
WoLFPSORT	O
[	O
76	O
]	O
.	O

The	O
size	O
of	O
each	O
secretome	O
is	O
summarised	O
in	O
Figure	O
2	O
.	O

Even	O
when	O
using	O
two	O
programs	O
,	O
the	O
sizes	O
of	O
predicted	O
secretomes	O
can	O
vary	O
greatly	O
.	O

For	O
example	O
,	O
a	O
similar	O
analysis	O
for	O
M	B
.	I
grisea	I
using	O
SignalP	O
and	O
ProtComp	O
(	O
www	O
.	O
Softberry	O
.	O
com	O
)	O
predicted	O
only	O
739	O
secreted	O
proteins	O
(	O
out	O
of	O
a	O
proteome	O
of	O
11	O
,	O
109	O
)	O
compared	O
to	O
our	O
prediction	O
of	O
1	O
,	O
546	O
secreted	O
proteins	O
(	O
out	O
of	O
a	O
proteome	O
of	O
12	O
,	O
841	O
)	O
[	O
22	O
]	O
.	O

The	O
size	O
of	O
the	O
secretomes	O
for	O
each	O
species	O
varied	O
from	O
5	O
%	O
-	O
12	O
%	O
of	O
the	O
total	O
proteome	O
.	O

Overall	O
,	O
the	O
size	O
of	O
the	O
secretomes	O
from	O
phytopathogens	O
did	O
not	O
differ	O
greatly	O
from	O
that	O
of	O
non	O
-	O
pathogens	O
.	O

Table	O
8	O
shows	O
a	O
list	O
of	O
Pfam	O
motifs	O
,	O
not	O
found	O
in	O
the	O
secretomes	O
of	O
non	O
-	O
pathogenic	O
filamentous	O
ascomycetes	O
,	O
that	O
were	O
present	O
in	O
at	O
least	O
three	O
phytopathogenic	O
fungal	O
species	O
.	O

The	O
Isochorismatase	O
motif	O
(	O
PF00857	O
)	O
was	O
found	O
in	O
the	O
secretomes	O
of	O
all	O
five	O
species	O
of	O
phytopathogen	O
.	O

Isochorismatase	O
catalyses	O
the	O
conversion	O
of	O
isochorismate	O
to	O
2	O
,	O
3	O
-	O
dihydroxybenzoate	O
and	O
pyruvate	O
.	O

It	O
has	O
been	O
implicated	O
in	O
the	O
synthesis	O
of	O
the	O
anti	O
-	O
microbial	O
compound	O
phenazine	O
by	O
Pseudomonas	B
aeruginosa	I
[	O
77	O
]	O
and	O
the	O
siderophore	O
,	O
enterobactin	O
,	O
by	O
Escherichia	B
coli	I
[	O
78	O
]	O
.	O

The	O
isochorismatase	O
motif	O
is	O
also	O
found	O
in	O
a	O
number	O
of	O
hydrolases	O
,	O
such	O
as	O
nicotinamidase	O
that	O
converts	O
nicotinamide	O
to	O
nicotinic	O
acid	O
[	O
79	O
]	O
.	O

Members	O
of	O
this	O
family	O
are	O
found	O
in	O
all	O
filamentous	O
ascomycetes	O
,	O
but	O
interestingly	O
they	O
are	O
only	O
secreted	O
in	O
phytopathogens	O
.	O

Salicylic	O
acid	O
is	O
synthesised	O
in	O
plants	O
in	O
response	O
to	O
pathogen	O
attack	O
and	O
mediates	O
plant	O
defences	O
.	O

As	O
isochorismate	O
is	O
a	O
precursor	O
of	O
salicyclic	O
acid	O
[	O
80	O
]	O
,	O
it	O
may	O
be	O
worth	O
speculating	O
that	O
isochorismatases	O
secreted	O
by	O
fungi	O
could	O
act	O
to	O
reduce	O
salicylic	O
acid	O
accumulation	O
in	O
response	O
to	O
pathogen	O
attack	O
and	O
thus	O
inhibit	O
plant	O
defence	O
responses	O
.	O

The	O
secreted	O
isochorismatases	O
(	O
apart	O
from	O
one	O
of	O
the	O
proteins	O
from	O
S	B
.	I
nodorum	I
)	O
all	O
show	O
sequence	O
similarity	O
to	O
ycaC	O
from	O
E	B
.	I
coli	I
,	O
an	O
octameric	O
hydrolase	O
of	O
unknown	O
function	O
[	O
81	O
]	O
.	O

Pfam	O
motifs	O
found	O
in	O
the	O
secretomes	O
of	O
at	O
least	O
three	O
species	O
of	O
phytopathogens	O
,	O
but	O
not	O
in	O
any	O
of	O
the	O
non	O
-	O
pathogens	O
also	O
include	O
those	O
found	O
in	O
enzymes	O
potentially	O
involved	O
in	O
detoxification	O
,	O
such	O
as	O
arylesterase	O
and	O
amidohydrolase	O
,	O
and	O
also	O
beta	O
-	O
ketoacyl	O
synthase	O
,	O
which	O
catalyses	O
the	O
condensation	O
of	O
malonyl	O
-	O
ACP	O
with	O
a	O
growing	O
fatty	O
acid	O
chain	O
and	O
is	O
found	O
as	O
a	O
component	O
of	O
a	O
number	O
of	O
enzyme	O
systems	O
,	O
including	O
fatty	O
acid	O
synthases	O
and	O
polyketide	O
synthases	O
[	O
82	O
]	O
,	O
[	O
83	O
]	O
.	O

Table	O
9	O
shows	O
a	O
list	O
of	O
Pfam	O
motifs	O
that	O
are	O
more	O
common	O
in	O
the	O
secretomes	O
of	O
phytopathogens	O
as	O
compared	O
to	O
saprotrophs	O
.	O

These	O
include	O
a	O
number	O
of	O
secreted	O
proteases	O
,	O
transcription	O
factors	O
and	O
components	O
of	O
signal	O
transduction	O
pathways	O
.	O

The	O
Kelch	O
domain	O
(	O
PF01344	O
)	O
shows	O
the	O
most	O
striking	O
difference	O
in	O
distribution	O
between	O
phytopathogenic	O
and	O
non	O
-	O
pathogenic	O
genomes	O
.	O

This	O
50	O
-	O
residue	O
domain	O
is	O
found	O
in	O
a	O
number	O
of	O
actin	O
-	O
binding	O
proteins	O
[	O
84	O
]	O
,	O
as	O
well	O
as	O
enzymes	O
such	O
as	O
galactose	O
oxidase	O
and	O
neuraminidase	O
.	O

The	O
putative	O
function	O
of	O
each	O
secreted	O
Kelch	O
domain	O
-	O
containing	O
protein	O
was	O
ascertained	O
by	O
performing	O
a	O
BLAST	O
search	O
against	O
the	O
NCBI	O
non	O
-	O
redundant	O
protein	O
database	O
(	O
Table	O
10	O
)	O
.	O

A	O
number	O
of	O
these	O
seem	O
to	O
be	O
galactose	O
oxidases	O
,	O
enzymes	O
which	O
catalyse	O
the	O
oxidation	O
of	O
a	O
range	O
of	O
primary	O
alcohols	O
,	O
including	O
galactose	O
,	O
to	O
the	O
corresponding	O
aldehyde	O
with	O
the	O
concomitant	O
reduction	O
of	O
oxygen	O
to	O
hydrogen	O
peroxide	O
(	O
H2O2	O
)	O
[	O
85	O
]	O
.	O

Galactose	O
oxidase	O
shares	O
a	O
copper	O
radical	O
oxidase	O
motif	O
with	O
the	O
hydrogen	O
peroxide	O
-	O
generating	O
glyoxal	O
oxidases	O
involved	O
in	O
lignin	O
-	O
degradation	O
in	O
Phanerochaete	B
chrysosporium	I
[	O
86	O
]	O
.	O

H2O2	O
-	O
producing	O
copper	O
oxidases	O
have	O
been	O
shown	O
to	O
have	O
roles	O
in	O
morphogenesis	O
,	O
in	O
the	O
corn	B
-	O
smut	O
fungus	O
Ustilago	B
maydis	I
for	O
example	O
,	O
a	O
glyoxal	O
oxidase	O
is	O
required	O
for	O
filamentous	O
growth	O
and	O
pathogenicity	O
[	O
87	O
]	O
and	O
a	O
galactose	O
oxidase	O
is	O
involved	O
in	O
fruiting	O
body	O
formation	O
in	O
the	O
gram	O
-	O
negative	O
bacterium	O
Stigmatella	B
aurantiaca	I
[	O
88	O
]	O
.	O

Interestingly	O
,	O
the	O
list	O
of	O
Pfam	O
motifs	O
more	O
common	O
in	O
the	O
secretomes	O
of	O
phytopathogens	O
also	O
includes	O
those	O
found	O
in	O
copper	O
amine	O
oxidases	O
,	O
H2O2	O
-	O
generating	O
enzymes	O
that	O
catalyse	O
the	O
oxidative	O
deamination	O
of	O
primary	O
amines	O
to	O
the	O
corresponding	O
aldehydes	O
[	O
89	O
]	O
and	O
peroxidases	O
,	O
haem	O
-	O
containing	O
enzymes	O
that	O
use	O
hydrogen	O
peroxide	O
as	O
the	O
electron	O
acceptor	O
to	O
catalyse	O
a	O
number	O
of	O
oxidative	O
reactions	O
.	O

Secreted	O
fungal	O
peroxidases	O
include	O
enzymes	O
involved	O
in	O
lignin	O
breakdown	O
by	O
the	O
white	O
rot	O
fungus	O
Phanerochaete	B
chrysosporium	I
[	O
90	O
]	O
,	O
but	O
in	O
plants	O
they	O
generate	O
reactive	O
oxygen	O
species	O
and	O
are	O
involved	O
in	O
defence	O
responses	O
and	O
growth	O
induction	O
[	O
91	O
]	O
.	O

A	O
number	O
of	O
other	O
secreted	O
Kelch	O
domain	O
-	O
containing	O
proteins	O
have	O
similarity	O
to	O
proteins	O
of	O
unknown	O
function	O
from	O
species	O
of	O
the	O
bacterial	O
phytopathogen	O
Xanthomonas	O
.	O

Many	O
Kelch	O
domain	O
-	O
containing	O
proteins	O
are	O
involved	O
in	O
cytoskeletal	O
rearrangement	O
and	O
cell	O
morphology	O
[	O
92	O
]	O
,	O
[	O
93	O
]	O
.	O

It	O
may	O
be	O
worth	O
speculating	O
that	O
secreted	O
Kelch	O
domain	O
-	O
containing	O
proteins	O
could	O
act	O
as	O
effectors	O
,	O
causing	O
changes	O
in	O
the	O
arrangement	O
of	O
the	O
cytoskeleton	O
of	O
infected	O
plants	O
to	O
aid	O
the	O
proliferation	O
of	O
fungal	O
hyphae	O
.	O

It	O
has	O
recently	O
been	O
shown	O
,	O
for	O
example	O
,	O
that	O
M	B
.	I
grisea	I
co	O
-	O
opts	O
plasmodesmata	O
to	O
move	O
from	O
cell	O
to	O
cell	O
in	O
infected	O
rice	B
leaves	O
[	O
94	O
]	O
and	O
would	O
therefore	O
need	O
to	O
peturb	O
cytoskeletal	O
organisation	O
in	O
rice	B
epidermal	O
cells	O
.	O

There	O
are	O
other	O
Pfam	O
domains	O
that	O
are	O
more	O
common	O
in	O
the	O
secretomes	O
of	O
phytopathogens	O
that	O
may	O
potentially	O
be	O
found	O
in	O
effectors	O
such	O
as	O
the	O
PAN	O
domain	O
(	O
PF00024	O
)	O
,	O
that	O
mediates	O
protein	O
-	O
protein	O
and	O
protein	O
-	O
carbohydrate	O
interactions	O
[	O
95	O
]	O
and	O
the	O
F5	O
/	O
8	O
type	O
C	O
domain	O
(	O
PF00754	O
)	O
,	O
found	O
in	O
the	O
discoidin	O
family	O
of	O
proteins	O
involved	O
in	O
cell	O
-	O
adhesion	O
or	O
developmental	O
processes	O
[	O
96	O
]	O
.	O

Discussion	O

One	O
of	O
the	O
most	O
fundamental	O
aims	O
in	O
plant	O
pathology	O
research	O
is	O
to	O
define	O
precisely	O
the	O
difference	O
between	O
pathogenic	O
and	O
non	O
-	O
pathogenic	O
microorganisms	O
.	O

The	O
answer	O
cannot	O
be	O
one	O
of	O
simple	O
phylogeny	O
,	O
because	O
phytopathogenic	O
species	O
are	O
found	O
in	O
all	O
taxonomic	O
divisions	O
of	O
fungi	O
and	O
are	O
often	O
closely	O
related	O
to	O
non	O
-	O
pathogenic	O
species	O
[	O
3	O
]	O
.	O

Before	O
the	O
availability	O
of	O
genomic	O
sequences	O
and	O
high	O
throughput	O
approaches	O
to	O
study	O
gene	O
function	O
[	O
20	O
]	O
,	O
research	O
was	O
concentrated	O
on	O
the	O
search	O
for	O
single	O
pathogenicity	O
factors	O
;	O
genes	O
that	O
are	O
dispensable	O
for	O
saprophytic	O
growth	O
but	O
essential	O
for	O
successful	O
infection	O
of	O
the	O
host	O
plant	O
[	O
4	O
]	O
,	O
[	O
97	O
]	O
.	O

However	O
,	O
rather	O
than	O
encoding	O
novel	O
proteins	O
found	O
only	O
in	O
phytopathogens	O
,	O
the	O
majority	O
of	O
pathogenicity	O
factors	O
discovered	O
in	O
this	O
way	O
have	O
been	O
found	O
to	O
be	O
involved	O
in	O
signalling	O
cascades	O
and	O
metabolic	O
pathways	O
and	O
hence	O
are	O
conserved	O
in	O
most	O
species	O
of	O
fungi	O
[	O
5	O
]	O
.	O

Components	O
of	O
signalling	O
cascades	O
that	O
in	O
the	O
budding	O
yeast	B
S	B
.	I
cerevisiae	I
are	O
responsible	O
for	O
responses	O
to	O
pheromones	O
,	O
nutritional	O
starvation	O
and	O
osmotic	O
stress	O
[	O
9	O
]	O
have	O
in	O
many	O
cases	O
evolved	O
different	O
roles	O
in	O
the	O
life	O
cycle	O
of	O
pathogens	O
,	O
such	O
as	O
controlling	O
appressorium	O
formation	O
,	O
dimorphism	O
and	O
growth	O
[	O
10	O
]	O
.	O

Although	O
the	O
central	O
components	O
of	O
signalling	O
are	O
conserved	O
between	O
phytopathogens	O
and	O
S	B
.	I
cerevisiae	I
,	O
the	O
receptors	O
are	O
often	O
different	O
,	O
reflecting	O
the	O
different	O
environmental	O
cues	O
to	O
which	O
the	O
pathogen	O
needs	O
to	O
respond	O
[	O
11	O
]	O
,	O
[	O
98	O
]	O
.	O

Analysis	O
of	O
all	O
available	O
genome	O
sequences	O
from	O
a	O
wider	O
range	O
of	O
fungal	O
species	O
has	O
for	O
the	O
first	O
time	O
allowed	O
us	O
to	O
address	O
the	O
differences	O
between	O
phytopathogens	O
and	O
non	O
-	O
pathogens	O
at	O
a	O
whole	O
genome	O
level	O
.	O

For	O
this	O
purpose	O
,	O
the	O
e	O
-	O
Fungi	O
data	O
warehouse	O
provides	O
a	O
means	O
to	O
interrogate	O
the	O
vast	O
amounts	O
of	O
genomic	O
and	O
functional	O
data	O
available	O
in	O
a	O
simple	O
integrated	O
manner	O
[	O
26	O
]	O
.	O

Previous	O
research	O
,	O
in	O
which	O
EST	O
datasets	O
were	O
compared	O
with	O
genomic	O
sequences	O
,	O
suggested	O
that	O
the	O
expressed	O
gene	O
inventories	O
of	O
phytopathogenic	O
species	O
were	O
not	O
significantly	O
more	O
similar	O
to	O
one	O
another	O
than	O
to	O
those	O
of	O
saprotrophic	O
filamentous	O
fungi	O
[	O
99	O
]	O
.	O

We	O
clustered	O
sets	O
of	O
predicted	O
proteins	O
from	O
36	O
different	O
species	O
of	O
fungi	O
and	O
oomycetes	O
into	O
groups	O
of	O
potential	O
orthologues	O
and	O
the	O
species	O
distribution	O
of	O
members	O
of	O
each	O
cluster	O
was	O
ascertained	O
.	O

There	O
were	O
no	O
clusters	O
that	O
were	O
completely	O
specific	O
to	O
phytopathogenic	O
species	O
across	O
both	O
fungi	O
and	O
oomycetes	O
,	O
suggesting	O
that	O
the	O
presence	O
of	O
novel	O
,	O
universal	O
pathogenicity	O
factors	O
in	O
the	O
genomes	O
of	O
phytopathogens	O
is	O
unlikely	O
.	O

This	O
was	O
confirmed	O
by	O
looking	O
at	O
clusters	O
containing	O
empirically	O
defined	O
pathogenicity	O
factors	O
,	O
where	O
homologues	O
of	O
many	O
of	O
these	O
were	O
found	O
in	O
all	O
species	O
studied	O
and	O
none	O
were	O
conserved	O
in	O
the	O
genomes	O
only	O
of	O
phytopathogens	O
.	O

A	O
small	O
number	O
were	O
only	O
found	O
in	O
a	O
single	O
species	O
of	O
fungus	O
and	O
probably	O
represented	O
proteins	O
that	O
are	O
highly	O
specialised	O
for	O
a	O
particular	O
role	O
in	O
a	O
specific	O
pathogenic	O
species	O
,	O
for	O
example	O
in	O
host	O
-	O
plant	O
recognition	O
[	O
54	O
]	O
.	O

Previous	O
research	O
also	O
suggested	O
that	O
the	O
gene	O
inventories	O
of	O
filamentous	O
fungi	O
were	O
more	O
similar	O
to	O
each	O
other	O
than	O
to	O
those	O
of	O
unicellular	O
yeasts	O
[	O
99	O
]	O
.	O

Analysis	O
of	O
the	O
clusters	O
of	O
similar	O
proteins	O
show	O
some	O
clusters	O
that	O
are	O
found	O
in	O
all	O
species	O
of	O
filamentous	O
fungi	O
(	O
including	O
ascomycetes	O
,	O
basidiomycetes	O
and	O
zygomycetes	O
)	O
but	O
are	O
not	O
present	O
in	O
the	O
genomes	O
of	O
yeasts	O
,	O
consistent	O
with	O
the	O
original	O
conclusion	O
.	O

These	O
contain	O
a	O
number	O
of	O
proteins	O
that	O
are	O
likely	O
to	O
be	O
involved	O
in	O
morphological	O
changes	O
associated	O
with	O
the	O
more	O
complex	O
filamentous	O
lifestyle	O
,	O
as	O
well	O
those	O
involved	O
in	O
secondary	O
metabolism	O
and	O
signalling	O
cascades	O
that	O
are	O
not	O
found	O
in	O
yeasts	O
.	O

In	O
particular	O
,	O
our	O
results	O
suggest	O
that	O
filamentous	O
fungi	O
use	O
a	O
wider	O
variety	O
of	O
lipid	O
molecules	O
for	O
the	O
purpose	O
of	O
signalling	O
.	O

Some	O
of	O
these	O
may	O
act	O
as	O
pheromones	O
,	O
or	O
hormones	O
-	O
chemical	O
messengers	O
diffusing	O
from	O
one	O
cell	O
to	O
another	O
to	O
elicit	O
a	O
physiological	O
or	O
developmental	O
response	O
[	O
37	O
]	O
.	O

A	O
number	O
of	O
these	O
innovations	O
to	O
the	O
filamentous	O
lifestyle	O
may	O
serve	O
important	O
roles	O
in	O
pathogenesis	O
as	O
well	O
,	O
because	O
homologues	O
of	O
a	O
number	O
of	O
pathogenicity	O
factors	O
are	O
found	O
only	O
in	O
filamentous	O
ascomycetes	O
.	O

The	O
distribution	O
of	O
filamentous	O
fungi	O
-	O
specific	O
proteins	O
,	O
such	O
as	O
involved	O
in	O
those	O
cytoskeletal	O
rearrangements	O
and	O
fruiting	O
body	O
formation	O
,	O
throughout	O
the	O
fungal	O
kingdom	O
(	O
and	O
in	O
some	O
cases	O
in	O
oomycetes	O
as	O
well	O
)	O
,	O
suggests	O
that	O
the	O
last	O
common	O
ancestral	O
fungus	O
may	O
well	O
have	O
been	O
multi	O
-	O
cellular	O
and	O
the	O
evolution	O
of	O
uni	O
-	O
cellular	O
fungi	O
was	O
likely	O
associated	O
with	O
massive	O
gene	O
loss	O
.	O

For	O
example	O
,	O
it	O
has	O
been	O
shown	O
that	O
early	O
in	O
ascomycete	O
evolution	O
there	O
was	O
a	O
proliferation	O
of	O
subtilase	O
-	O
type	O
protease	O
-	O
encoding	O
genes	O
that	O
have	O
been	O
retained	O
in	O
some	O
filamentous	O
ascomycete	O
lineages	O
,	O
but	O
lost	O
in	O
the	O
yeast	B
lineage	O
[	O
100	O
]	O
.	O

It	O
has	O
previously	O
been	O
speculated	O
that	O
the	O
evolution	O
of	O
phytopathogenesis	O
was	O
associated	O
with	O
the	O
expansion	O
of	O
certain	O
gene	O
families	O
[	O
1	O
]	O
.	O

Duplication	O
of	O
an	O
ancestral	O
gene	O
,	O
followed	O
by	O
mutation	O
allows	O
members	O
of	O
the	O
family	O
to	O
take	O
on	O
new	O
functions	O
[	O
101	O
]	O
.	O

For	O
example	O
,	O
genomes	O
of	O
the	O
filamentous	O
ascomycetes	O
studied	O
here	O
have	O
between	O
40	O
and	O
140	O
cytochrome	O
P450	O
-	O
encoding	O
genes	O
(	O
data	O
not	O
shown	O
)	O
that	O
are	O
involved	O
in	O
toxin	O
biosynthesis	O
,	O
lipid	O
metabolism	O
,	O
alkane	O
assimilation	O
and	O
detoxification	O
[	O
102	O
]	O
and	O
which	O
probably	O
arose	O
via	O
gene	O
duplication	O
and	O
functional	O
diversification	O
.	O

In	O
contrast	O
,	O
the	O
genome	O
of	O
the	O
budding	O
yeast	B
S	B
.	I
cerevisiae	I
has	O
only	O
three	O
cytochrome	O
P450	O
-	O
encoding	O
enzymes	O
.	O

We	O
have	O
shown	O
here	O
that	O
there	O
are	O
likely	O
to	O
be	O
large	O
differences	O
in	O
the	O
gene	O
inventories	O
of	O
filamentous	O
fungi	O
compared	O
to	O
unicellular	O
yeasts	O
.	O

To	O
study	O
the	O
differences	O
between	O
phytopathogenic	O
and	O
saprophytic	O
fungi	O
,	O
we	O
concentrated	O
on	O
the	O
filamentous	O
ascomycetes	O
where	O
there	O
are	O
a	O
number	O
of	O
phytopathogenic	O
species	O
genomes	O
have	O
been	O
sequenced	O
along	O
with	O
closely	O
related	O
non	O
-	O
pathogens	O
.	O

Protein	O
families	O
were	O
defined	O
using	O
Pfam	O
motifs	O
[	O
57	O
]	O
and	O
the	O
predicted	O
protein	O
sets	O
for	O
each	O
species	O
analysed	O
in	O
order	O
to	O
identify	O
domains	O
that	O
were	O
specific	O
to	O
or	O
more	O
common	O
in	O
the	O
genomes	O
of	O
phytopathogens	O
.	O

Not	O
surprisingly	O
,	O
many	O
of	O
the	O
protein	O
families	O
we	O
identified	O
are	O
likely	O
to	O
be	O
associated	O
with	O
pathogenic	O
processes	O
such	O
as	O
plant	O
cell	O
wall	O
degradation	O
,	O
toxin	O
biosynthesis	O
,	O
formation	O
of	O
reactive	O
oxygen	O
species	O
and	O
detoxification	O
[	O
5	O
]	O
.	O

Studies	O
of	O
bacterial	O
phytopathogens	O
have	O
shown	O
the	O
importance	O
of	O
effectors	O
,	O
secreted	O
proteins	O
that	O
disable	O
plant	O
defences	O
and	O
subvert	O
metabolic	O
and	O
morphological	O
processes	O
for	O
the	O
benefit	O
of	O
the	O
invading	O
pathogen	O
and	O
which	O
require	O
delivery	O
via	O
a	O
type	O
III	O
secretion	O
system	O
that	O
are	O
often	O
deployed	O
during	O
pathogenesis	O
[	O
73	O
]	O
.	O

Bacterial	O
type	O
III	O
secreted	O
effectors	O
(	O
T3SEs	O
)	O
have	O
been	O
shown	O
to	O
target	O
salicyclic	O
acid	O
and	O
abscisic	O
acid	O
-	O
dependent	O
defences	O
,	O
host	O
vesicle	O
trafficking	O
,	O
transcription	O
and	O
RNA	O
metabolism	O
,	O
and	O
several	O
components	O
of	O
the	O
plant	O
defence	O
signalling	O
networks	O
[	O
103	O
]	O
.	O

Very	O
recently	O
,	O
potential	O
effector	O
-	O
encoding	O
genes	O
have	O
been	O
identified	O
in	O
the	O
genomes	O
of	O
several	O
species	O
of	O
oomycete	O
pathogens	O
and	O
are	O
defined	O
by	O
the	O
presence	O
of	O
a	O
conserved	O
RXLR	O
-	O
EER	O
motif	O
downstream	O
of	O
the	O
signal	O
peptide	O
sequence	O
[	O
74	O
]	O
.	O

The	O
RXLR	O
-	O
EER	O
motif	O
is	O
necessary	O
for	O
delivery	O
of	O
effector	O
proteins	O
into	O
host	O
plant	O
cells	O
and	O
is	O
therefore	O
critical	O
to	O
their	O
biological	O
activity	O
[	O
74	O
]	O
.	O

To	O
identify	O
potential	O
fungal	O
effectors	O
,	O
we	O
compared	O
Pfam	O
motif	O
frequency	O
between	O
the	O
secretomes	O
of	O
phytopathogens	O
and	O
non	O
-	O
pathogens	O
.	O

This	O
analysis	O
identified	O
potential	O
effector	O
-	O
encoding	O
genes	O
,	O
including	O
secreted	O
proteases	O
,	O
transcription	O
factors	O
and	O
proteins	O
that	O
may	O
be	O
involved	O
in	O
cytoskeletal	O
rearrangements	O
(	O
such	O
as	O
Kelch	O
-	O
domain	O
containing	O
proteins	O
)	O
and	O
protein	O
-	O
protein	O
interactions	O
,	O
as	O
well	O
as	O
a	O
group	O
of	O
pathogen	O
-	O
specific	O
secreted	O
isochorisimatases	O
that	O
potentially	O
could	O
suppress	O
salicyclic	O
acid	O
-	O
dependent	O
host	O
plant	O
defences	O
.	O

Bacterial	O
T3SEs	O
are	O
injected	O
directly	O
into	O
the	O
host	O
cytoplasm	O
via	O
the	O
type	O
III	O
secretion	O
injection	O
apparatus	O
[	O
73	O
]	O
.	O

In	O
contrast	O
,	O
the	O
potential	O
fungal	O
effectors	O
identified	O
in	O
this	O
study	O
appear	O
to	O
be	O
secreted	O
by	O
the	O
normal	O
cellular	O
secretory	O
pathway	O
via	O
the	O
endoplasmic	O
reticulum	O
and	O
the	O
mechanism	O
by	O
which	O
fungal	O
effectors	O
might	O
be	O
taken	O
up	O
by	O
plant	O
cells	O
and	O
enter	O
into	O
the	O
host	O
cytoplasm	O
is	O
currently	O
unknown	O
.	O

Although	O
the	O
evolution	O
of	O
phytopathogenicity	O
is	O
likely	O
to	O
have	O
happened	O
several	O
times	O
and	O
the	O
lifestyles	O
of	O
these	O
fungi	O
are	O
diverse	O
,	O
a	O
comparison	O
of	O
gene	O
inventories	O
of	O
a	O
number	O
of	O
species	O
using	O
a	O
powerful	O
resource	O
,	O
such	O
as	O
e	O
-	O
Fungi	O
,	O
has	O
allowed	O
us	O
to	O
pinpoint	O
new	O
gene	O
families	O
that	O
may	O
serve	O
important	O
roles	O
in	O
the	O
virulence	O
of	O
phytopathogens	O
,	O
allowing	O
their	O
selection	O
for	O
gene	O
functional	O
studies	O
,	O
that	O
are	O
currently	O
in	O
progress	O
.	O

The	O
analyses	O
deployed	O
here	O
may	O
also	O
offer	O
a	O
blueprint	O
for	O
the	O
types	O
of	O
larger	O
,	O
more	O
comprehensive	O
studies	O
that	O
will	O
be	O
necessary	O
to	O
interpret	O
the	O
large	O
flow	O
of	O
genetic	O
data	O
that	O
will	O
result	O
from	O
next	O
generation	O
DNA	O
sequence	O
analysis	O
utilizing	O
both	O
a	O
much	O
wider	O
variety	O
of	O
fungal	O
pathogen	O
species	O
and	O
also	O
large	O
sets	O
of	O
individual	O
isolates	O
of	O
existing	O
species	O
.	O

Materials	O
and	O
Methods	O

Clustering	O
of	O
sequences	O

Sets	O
of	O
predicted	O
proteins	O
were	O
downloaded	O
for	O
each	O
of	O
the	O
36	O
genomes	O
from	O
respective	O
sequencing	O
project	O
websites	O
(	O
Table	O
1	O
)	O
.	O

Proteins	O
less	O
than	O
40	O
amino	O
acids	O
in	O
length	O
were	O
not	O
included	O
in	O
this	O
analysis	O
.	O

Proteins	O
were	O
clustered	O
using	O
"	O
all	O
against	O
all	O
"	O
BLASTP	O
[	O
104	O
]	O
followed	O
by	O
Markov	O
Chain	O
Clustering	O
(	O
MCL	O
)	O
[	O
27	O
]	O
with	O
2	O
.	O
5	O
as	O
a	O
moderate	O
inflation	O
value	O
and	O
10	O
-	O
10	O
as	O
an	O
E	O
-	O
value	O
cut	O
-	O
off	O
,	O
as	O
described	O
previously	O
[	O
28	O
]	O
,	O
[	O
29	O
]	O
.	O

Clusters	O
were	O
annotated	O
based	O
on	O
best	O
hit	O
against	O
Swiss	O
-	O
Prot	O
protein	O
database	O
[	O
105	O
]	O
of	O
members	O
of	O
that	O
cluster	O
(	O
e	O
-	O
value	O
<	O
10	O
-	O
20	O
using	O
BLASTP	O
)	O
,	O
or	O
Pfam	O
motifs	O
contained	O
in	O
proteins	O
from	O
the	O
cluster	O
in	O
the	O
absence	O
of	O
Swiss	O
-	O
Prot	O
hits	O
.	O

Identification	O
of	O
Pfam	O
motifs	O

The	O
Pfam	O
-	O
A	O
library	O
from	O
release	O
18	O
.	O
0	O
of	O
the	O
Pfam	O
database	O
was	O
downloaded	O
from	O
the	O
Pfam	O
website	O
(	O
http	O
:	O
/	O
/	O
www	O
.	O
sanger	O
.	O
ac	O
.	O
uk	O
/	O
Software	O
/	O
Pfam	O
/	O
)	O
.	O

This	O
library	O
contains	O
7973	O
protein	O
models	O
constructed	O
from	O
manually	O
curated	O
multiple	O
alignments	O
and	O
covers	O
75	O
%	O
of	O
proteins	O
in	O
UniProt	O
[	O
44	O
]	O
,	O
[	O
57	O
]	O
.	O

This	O
library	O
was	O
used	O
to	O
analyse	O
the	O
sequences	O
of	O
predicted	O
proteins	O
for	O
all	O
36	O
fungal	O
genomes	O
to	O
identify	O
the	O
Pfam	O
motifs	O
that	O
each	O
protein	O
contains	O
.	O

The	O
analysis	O
was	O
performed	O
using	O
the	O
"	O
pfam	O
_	O
scan	O
"	O
perl	O
script	O
(	O
version	O
0	O
.	O
5	O
)	O
downloaded	O
from	O
the	O
Pfam	O
website	O
and	O
HMMER	O
software	O
(	O
downloaded	O
from	O
http	O
:	O
/	O
/	O
hmmer	O
.	O
wustl	O
.	O
edu	O
/	O
)	O
.	O

Default	O
thresholds	O
were	O
used	O
,	O
which	O
are	O
hand	O
-	O
curated	O
for	O
every	O
family	O
and	O
designed	O
to	O
minimise	O
false	O
positives	O
[	O
44	O
]	O
.	O

Identification	O
of	O
secreted	O
proteins	O

The	O
N	O
-	O
terminal	O
sequence	O
of	O
each	O
predicted	O
protein	O
from	O
the	O
36	O
fungal	O
genomes	O
used	O
in	O
this	O
study	O
was	O
analysed	O
for	O
the	O
presence	O
of	O
a	O
signal	O
peptide	O
using	O
SignalP	O
3	O
.	O
0	O
[	O
75	O
]	O
and	O
sub	O
-	O
cellular	O
localisation	O
was	O
predicted	O
using	O
WoLF	O
PSORT	O
[	O
76	O
]	O
.	O

Both	O
these	O
programs	O
were	O
installed	O
locally	O
.	O

SignalP	O
3	O
.	O
0	O
uses	O
two	O
different	O
algorithms	O
to	O
identify	O
signal	O
sequences	O
.	O

The	O
secretome	O
for	O
each	O
fungal	O
species	O
was	O
defined	O
as	O
containing	O
those	O
proteins	O
that	O
were	O
predicted	O
have	O
a	O
signal	O
peptide	O
by	O
both	O
prediction	O
algorithms	O
from	O
SignalP	O
3	O
.	O
0	O
and	O
also	O
predicted	O
to	O
be	O
extracellular	O
by	O
WoLF	O
PSORT	O
.	O

Data	O
analysis	O

All	O
the	O
data	O
produced	O
,	O
as	O
described	O
above	O
,	O
was	O
stored	O
in	O
the	O
e	O
-	O
Fungi	O
data	O
warehouse	O
[	O
26	O
]	O
from	O
which	O
it	O
can	O
be	O
accessed	O
via	O
a	O
web	O
-	O
interface	O
(	O
http	O
:	O
/	O
/	O
www	O
.	O
e	O
-	O
fungi	O
.	O
org	O
.	O
uk	O
/	O
)	O
.	O

Analyses	O
described	O
in	O
this	O
study	O
were	O
performed	O
using	O
the	O
e	O
-	O
Fungi	O
database	O
.	O

Supporting	O
Information	O

Emergence	O
of	O
Delayed	O
Methylmercury	O
Toxicity	O
after	O
Perinatal	O
Exposure	O
in	O
Metallothionein	O
-	O
Null	O
and	O
Wild	O
-	O
Type	O
C57BL	O
Mice	B

Abstract	O

Background	O

Although	O
a	O
long	O
latency	O
period	O
of	O
toxicity	O
after	O
exposure	O
to	O
methylmercury	O
(	O
MeHg	O
)	O
is	O
known	O
to	O
exist	O
in	O
humans	B
,	O
few	O
animal	O
studies	O
have	O
addressed	O
this	O
issue	O
.	O

Substantiation	O
of	O
delayed	O
MeHg	O
toxicity	O
in	O
animals	O
would	O
affect	O
the	O
risk	O
evaluation	O
of	O
MeHg	O
.	O

Objectives	O

Our	O
goal	O
in	O
this	O
study	O
was	O
to	O
demonstrate	O
the	O
existence	O
of	O
a	O
latency	O
period	O
in	O
a	O
rodent	O
model	O
in	O
which	O
the	O
toxicity	O
of	O
perinatal	O
MeHg	O
exposure	O
becomes	O
apparent	O
only	O
later	O
in	O
life	O
.	O

Our	O
study	O
included	O
metallothionein	O
(	O
MT	O
)	O
knockout	O
mice	B
because	O
studies	O
have	O
suggested	O
the	O
potential	O
susceptibility	O
of	O
this	O
strain	O
to	O
the	O
neurodevelopmental	O
toxicity	O
of	O
MeHg	O
.	O

Methods	O

Pregnant	O
MT	O
-	O
null	O
and	O
wild	O
-	O
type	O
C57Bl	O
/	O
6J	O
mice	B
were	O
exposed	O
to	O
MeHg	O
through	O
their	O
diet	O
containing	O
5	O
mu	O
g	O
Hg	O
/	O
g	O
during	O
gestation	O
and	O
early	O
lactation	O
.	O

We	O
examined	O
behavioral	O
functions	O
of	O
the	O
offspring	O
using	O
frequently	O
used	O
paradigms	O
,	O
including	O
open	O
field	O
behavior	O
(	O
OPF	O
)	O
,	O
passive	O
avoidance	O
(	O
PA	O
)	O
,	O
and	O
the	O
Morris	O
water	O
maze	O
(	O
MM	O
)	O
,	O
at	O
ages	O
of	O
12	O
-	O
13	O
and	O
52	O
-	O
53	O
weeks	O
.	O

Results	O

At	O
12	O
weeks	O
of	O
age	O
,	O
behavioral	O
effects	O
of	O
MeHg	O
were	O
not	O
detected	O
,	O
except	O
for	O
OPF	O
performance	O
in	O
MeHg	O
-	O
exposed	O
MT	O
-	O
null	O
females	O
.	O

At	O
52	O
weeks	O
of	O
age	O
,	O
the	O
MeHg	O
-	O
exposed	O
groups	O
showed	O
poorer	O
performance	O
both	O
in	O
PA	O
and	O
MM	O
,	O
and	O
their	O
OPF	O
activity	O
differed	O
from	O
controls	O
.	O

These	O
effects	O
of	O
MeHg	O
appeared	O
exaggerated	O
in	O
the	O
MT	O
-	O
null	O
strain	O
.	O

The	O
brain	O
Hg	O
concentration	O
had	O
leveled	O
off	O
by	O
13	O
weeks	O
of	O
age	O
.	O

Conclusions	O

The	O
results	O
suggest	O
the	O
existence	O
of	O
a	O
long	O
latency	O
period	O
after	O
perinatal	O
exposure	O
to	O
low	O
-	O
level	O
MeHg	O
,	O
in	O
which	O
the	O
behavioral	O
effects	O
emerged	O
long	O
after	O
the	O
leveling	O
-	O
off	O
of	O
brain	O
Hg	O
levels	O
.	O

Hence	O
,	O
the	O
initial	O
toxicologic	O
event	O
responsible	O
for	O
the	O
late	O
effects	O
should	O
have	O
occurred	O
before	O
this	O
leveling	O
-	O
off	O
of	O
brain	O
Hg	O
.	O

Methylmercury	O
(	O
MeHg	O
)	O
poses	O
serious	O
and	O
practical	O
concerns	O
for	O
human	B
populations	O
regarding	O
perinatal	O
exposure	O
.	O

Fish	O
,	O
especially	O
large	O
predator	O
(	O
carnivore	O
)	O
fish	O
species	O
,	O
accumulate	O
high	O
concentrations	O
of	O
MeHg	O
through	O
the	O
marine	O
food	O
chain	O
,	O
and	O
exposure	O
of	O
pregnant	O
women	B
to	O
MeHg	O
through	O
the	O
consumption	O
of	O
fish	O
has	O
evoked	O
widespread	O
concern	O
due	O
to	O
potential	O
effects	O
on	O
offspring	O
.	O

Two	O
large	O
-	O
scale	O
cohort	O
studies	O
in	O
fish	O
-	O
eating	O
populations	O
of	O
Seychelles	O
and	O
Faroe	O
islanders	O
are	O
being	O
conducted	O
;	O
although	O
the	O
former	O
has	O
not	O
found	O
consistent	O
adverse	O
developmental	O
effects	O
of	O
MeHg	O
(	O
Myers	O
et	O
al	O
.	O
2007	O
)	O
,	O
the	O
latter	O
has	O
reported	O
adverse	O
effects	O
(	O
Debes	O
et	O
al	O
.	O
2006	O
)	O
.	O

Fundamental	O
reasons	O
for	O
this	O
discrepancy	O
have	O
not	O
been	O
completely	O
elucidated	O
,	O
and	O
many	O
questions	O
remain	O
regarding	O
the	O
neurotoxicity	O
of	O
MeHg	O
,	O
despite	O
extensive	O
study	O
.	O

Among	O
the	O
unanswered	O
questions	O
is	O
whether	O
there	O
is	O
a	O
long	O
latency	O
period	O
for	O
behavioral	O
manifestations	O
after	O
exposure	O
to	O
MeHg	O
(	O
Clarkson	O
and	O
Magos	O
2006	O
;	O
Landrigan	O
et	O
al	O
.	O
2005	O
;	O
Rice	O
1996	O
;	O
Weiss	O
et	O
al	O
.	O
2005a	O
,	O
2005b	O
)	O
.	O

Typical	O
examples	O
of	O
latent	O
toxicity	O
in	O
humans	B
,	O
including	O
both	O
acute	O
and	O
chronic	O
MeHg	O
exposures	O
,	O
have	O
been	O
described	O
in	O
detail	O
elsewhere	O
(	O
Weiss	O
et	O
al	O
.	O
2005a	O
)	O
.	O

Davidson	O
et	O
al	O
.	O

(	O
2006	O
)	O
recently	O
suggested	O
that	O
effects	O
of	O
perinatal	O
exposure	O
to	O
MeHg	O
may	O
emerge	O
9	O
years	O
after	O
birth	O
in	O
the	O
Seychelles	O
cohort	O
.	O

Consequently	O
,	O
risk	O
assessments	O
of	O
MeHg	O
exposure	O
could	O
be	O
inaccurate	O
because	O
studies	O
(	O
human	B
or	O
animal	O
)	O
usually	O
do	O
not	O
focus	O
on	O
later	O
stages	O
of	O
life	O
and	O
therefore	O
could	O
miss	O
delayed	O
effects	O
.	O

The	O
possibility	O
of	O
delayed	O
toxicity	O
is	O
exemplified	O
by	O
the	O
expanded	O
Barker	O
hypothesis	O
,	O
which	O
posits	O
that	O
the	O
origin	O
of	O
some	O
neurodegenerative	O
diseases	O
such	O
as	O
Parkinson	O
and	O
Alzheimer	O
diseases	O
lies	O
in	O
early	O
exposure	O
to	O
environmental	O
chemicals	O
(	O
Landrigan	O
et	O
al	O
.	O
2005	O
)	O
.	O

Although	O
epidemiologic	O
evidence	O
would	O
be	O
ideal	O
for	O
exploring	O
the	O
possibility	O
of	O
delayed	O
toxicity	O
(	O
and	O
,	O
indeed	O
,	O
data	O
from	O
epidemiologic	O
studies	O
form	O
the	O
basis	O
of	O
current	O
risk	O
assessment	O
for	O
developmental	O
toxicity	O
of	O
MeHg	O
)	O
,	O
considering	O
the	O
complex	O
effects	O
of	O
numerous	O
potential	O
confounders	O
and	O
the	O
existence	O
of	O
multiple	O
exposures	O
in	O
human	B
populations	O
,	O
animal	O
models	O
would	O
likely	O
make	O
important	O
contributions	O
to	O
this	O
field	O
.	O

Although	O
numerous	O
animal	O
studies	O
have	O
described	O
the	O
developmental	O
neurotoxicity	O
of	O
MeHg	O
(	O
Watanabe	O
and	O
Satoh	O
,	O
1996	O
)	O
,	O
few	O
have	O
addressed	O
the	O
latency	O
issue	O
.	O

Few	O
studies	O
have	O
evaluated	O
the	O
neurobehavioral	O
effects	O
in	O
rodents	O
longitudinally	O
beyond	O
6	O
months	O
after	O
perinatal	O
exposure	O
.	O

Spyker	O
(	O
1975	O
)	O
addressed	O
this	O
issue	O
in	O
her	O
pioneering	O
work	O
,	O
reporting	O
the	O
late	O
development	O
of	O
behavioral	O
toxicity	O
in	O
mice	B
prenatally	O
exposed	O
to	O
MeHg	O
;	O
it	O
appeared	O
,	O
however	O
,	O
that	O
the	O
substantial	O
mortality	O
and	O
retarded	O
growth	O
among	O
the	O
exposed	O
mice	B
were	O
apparent	O
before	O
weaning	O
,	O
indicating	O
that	O
the	O
doses	O
used	O
(	O
even	O
though	O
some	O
lower	O
dose	O
levels	O
were	O
included	O
)	O
exerted	O
severe	O
toxicity	O
.	O

Using	O
a	O
relatively	O
complex	O
schedule	O
-	O
controlled	O
operant	O
behavior	O
method	O
,	O
rats	B
whose	O
parents	O
were	O
exposed	O
to	O
MeHg	O
(	O
0	O
.	O
5	O
or	O
6	O
.	O
4	O
mg	O
/	O
L	O
)	O
from	O
4	O
weeks	O
before	O
mating	O
and	O
continuing	O
to	O
postnatal	O
day	O
(	O
PND	O
)	O
16	O
were	O
shown	O
to	O
be	O
less	O
sensitive	O
to	O
a	O
change	O
in	O
the	O
reinforcement	O
schedule	O
than	O
were	O
their	O
nonexposed	O
counterparts	O
at	O
28	O
-	O
32	O
months	O
of	O
age	O
(	O
Newland	O
et	O
al	O
.	O
2004	O
)	O
.	O

Mice	B
that	O
were	O
perinatally	O
exposed	O
to	O
1	O
or	O
3	O
mg	O
/	O
L	O
MeHg	O
in	O
drinking	O
water	O
did	O
not	O
show	O
significant	O
deviation	O
from	O
controls	O
in	O
behavioral	O
performance	O
(	O
motor	O
performance	O
,	O
memory	O
,	O
and	O
learning	O
)	O
at	O
5	O
,	O
15	O
,	O
or	O
26	O
months	O
of	O
age	O
,	O
but	O
the	O
lifetime	O
-	O
exposed	O
groups	O
did	O
show	O
a	O
significant	O
deviation	O
(	O
Weiss	O
et	O
al	O
.	O
2005c	O
)	O
.	O

The	O
existence	O
of	O
a	O
latency	O
period	O
(	O
i	O
.	O
e	O
.	O
,	O
the	O
absence	O
of	O
effects	O
earlier	O
in	O
life	O
followed	O
by	O
the	O
emergence	O
of	O
effects	O
at	O
a	O
later	O
stage	O
of	O
life	O
)	O
has	O
not	O
been	O
demonstrated	O
in	O
any	O
rodent	O
study	O
.	O

In	O
nonhuman	O
primates	O
,	O
delayed	O
emergence	O
of	O
the	O
signs	O
of	O
neurotoxicity	O
was	O
observed	O
several	O
years	O
after	O
the	O
cessation	O
of	O
a	O
7	O
-	O
year	O
postnatal	O
exposure	O
(	O
Rice	O
1996	O
)	O
.	O

Metallothionein	O
(	O
MT	O
)	O
protects	O
against	O
the	O
toxicities	O
of	O
a	O
variety	O
of	O
metals	O
.	O

We	O
examined	O
the	O
neurotoxicity	O
and	O
developmental	O
toxicity	O
of	O
metallic	O
Hg	O
in	O
MT	O
I	O
/	O
II	O
-	O
knockout	O
mice	B
(	O
Yoshida	O
et	O
al	O
.	O
2004	O
)	O
and	O
demonstrated	O
the	O
susceptibility	O
of	O
this	O
genetically	O
manipulated	O
strain	O
to	O
the	O
toxicity	O
of	O
metallic	O
Hg	O
.	O

In	O
contrast	O
to	O
metallic	O
Hg	O
,	O
MeHg	O
does	O
not	O
induce	O
MT	O
,	O
and	O
MT	O
would	O
not	O
substantially	O
influence	O
the	O
kinetics	O
of	O
MeHg	O
(	O
Yasutake	O
et	O
al	O
.	O
1998	O
)	O
.	O

Several	O
reports	O
,	O
however	O
,	O
have	O
demonstrated	O
protective	O
effects	O
of	O
MT	O
against	O
MeHg	O
toxicity	O
,	O
which	O
was	O
ascribed	O
to	O
the	O
radical	O
scavenging	O
effect	O
of	O
MT	O
(	O
Yao	O
et	O
al	O
.	O
2000	O
)	O
.	O

We	O
also	O
showed	O
that	O
perinatal	O
exposure	O
to	O
MeHg	O
results	O
in	O
altered	O
metabolism	O
of	O
thyroid	O
hormones	O
in	O
neonates	O
that	O
was	O
more	O
distinct	O
in	O
MT	O
-	O
null	O
strains	O
than	O
their	O
wild	O
-	O
type	O
counterparts	O
(	O
Mori	O
et	O
al	O
.	O
2006	O
)	O
.	O

The	O
vulnerability	O
of	O
the	O
MT	O
-	O
null	O
strain	O
suggests	O
that	O
delayed	O
neurobehavioral	O
toxicity	O
due	O
to	O
MeHg	O
,	O
if	O
it	O
does	O
exist	O
,	O
might	O
be	O
more	O
distinctive	O
in	O
this	O
strain	O
.	O

By	O
utilizing	O
the	O
MT	O
-	O
null	O
strain	O
,	O
we	O
aimed	O
to	O
answer	O
the	O
following	O
two	O
questions	O
:	O
First	O
,	O
could	O
we	O
generate	O
a	O
model	O
in	O
which	O
the	O
toxicity	O
of	O
MeHg	O
would	O
emerge	O
or	O
at	O
least	O
become	O
exaggerated	O
later	O
in	O
life	O
as	O
opposed	O
to	O
earlier	O
in	O
life	O
(	O
i	O
.	O
e	O
.	O
,	O
at	O
3	O
-	O
6	O
months	O
,	O
which	O
was	O
the	O
timing	O
for	O
most	O
of	O
the	O
earlier	O
studies	O
that	O
used	O
behavioral	O
evaluations	O
)	O
?	O

Second	O
,	O
would	O
the	O
MT	O
-	O
null	O
strain	O
be	O
affected	O
more	O
than	O
its	O
parent	O
C57BL	O
strain	O
?	O

Answering	O
either	O
of	O
these	O
questions	O
not	O
only	O
could	O
influence	O
the	O
risk	O
evaluation	O
of	O
MeHg	O
,	O
but	O
it	O
could	O
also	O
lead	O
to	O
a	O
better	O
understanding	O
of	O
the	O
mechanism	O
of	O
toxicity	O
for	O
perinatal	O
MeHg	O
exposure	O
.	O

To	O
address	O
these	O
issues	O
,	O
we	O
used	O
three	O
behavioral	O
paradigms	O
,	O
the	O
open	O
field	O
(	O
OPF	O
)	O
,	O
passive	O
avoidance	O
(	O
PA	O
)	O
,	O
and	O
Morris	O
(	O
water	O
)	O
maze	O
(	O
MM	O
)	O
tests	O
,	O
which	O
are	O
often	O
used	O
in	O
this	O
field	O
and	O
which	O
we	O
used	O
in	O
our	O
previous	O
studies	O
on	O
the	O
effects	O
of	O
Hg	O
vapor	O
(	O
Yoshida	O
et	O
al	O
.	O
2004	O
,	O
2006	O
)	O
.	O

Performances	O
in	O
the	O
MM	O
and	O
PA	O
are	O
said	O
to	O
be	O
the	O
most	O
sensitive	O
to	O
aging	O
(	O
Gower	O
and	O
Lamberty	O
1993	O
)	O
.	O

We	O
used	O
a	O
dose	O
of	O
5	O
mu	O
g	O
MeHg	O
/	O
g	O
in	O
the	O
diet	O
,	O
which	O
resulted	O
in	O
a	O
brain	O
Hg	O
level	O
relevant	O
to	O
human	B
risk	O
assessment	O
.	O

We	O
evaluated	O
the	O
behavioral	O
end	O
points	O
twice	O
,	O
once	O
around	O
3	O
months	O
of	O
age	O
and	O
the	O
other	O
time	O
around	O
1	O
year	O
;	O
the	O
latter	O
time	O
roughly	O
corresponds	O
to	O
the	O
period	O
when	O
many	O
behavioral	O
performances	O
,	O
including	O
OPF	O
(	O
Acevedoa	O
et	O
al	O
.	O
2006	O
;	O
Carrie	O
et	O
al	O
.	O
1999	O
;	O
Gower	O
and	O
Lamberty	O
1993	O
)	O
,	O
PA	O
(	O
Gower	O
and	O
Lamberty	O
1993	O
)	O
,	O
and	O
MM	O
(	O
Bach	O
et	O
al	O
.	O
1999	O
;	O
Carrie	O
et	O
al	O
.	O
1999	O
)	O
,	O
show	O
alterations	O
in	O
this	O
mouse	B
strain	O
.	O

Materials	O
and	O
Methods	O

Animals	O
and	O
MeHg	O
exposure	O

OLA129	O
/	O
C57BL	O
/	O
6J	O
strain	O
mice	B
(	O
wild	O
type	O
)	O
and	O
MT	O
I	O
/	O
II	O
-	O
knockout	O
mice	B
(	O
MT	O
-	O
null	O
)	O
of	O
this	O
strain	O
were	O
provided	O
by	O
K	O
.	O
H	O
.	O

Choo	O
of	O
the	O
Murdoch	O
Institute	O
,	O
Parkville	O
,	O
Australia	O
(	O
Michalska	O
and	O
Choo	O
1993	O
)	O
and	O
were	O
of	O
a	O
mixed	O
genetic	O
background	O
of	O
129	O
/	O
Ola	O
and	O
C57BL	O
/	O
6	O
strains	O
.	O

F1	O
hybrid	O
mice	B
were	O
mated	O
with	O
C57BL	O
/	O
6	O
mice	B
for	O
six	O
generations	O
at	O
the	O
National	O
Institute	O
for	O
Environmental	O
Studies	O
(	O
Tsukuba	O
,	O
Japan	O
)	O
.	O

At	O
10	O
weeks	O
of	O
age	O
,	O
single	O
male	O
and	O
female	O
mice	B
were	O
allowed	O
to	O
cohabit	O
;	O
every	O
female	O
mouse	B
was	O
checked	O
each	O
morning	O
for	O
the	O
presence	O
of	O
a	O
vaginal	O
plug	O
.	O

When	O
a	O
plug	O
was	O
confirmed	O
,	O
the	O
day	O
was	O
designated	O
as	O
day	O
0	O
of	O
gestation	O
(	O
GD0	O
)	O
.	O

The	O
diet	O
,	O
NIH	O
-	O
07PLD	O
formula	O
(	O
CLEA	O
Japan	O
,	O
Inc	O
.	O
,	O
Tokyo	O
,	O
Japan	O
)	O
,	O
contained	O
vitamins	O
and	O
trace	O
elements	O
as	O
follows	O
(	O
per	O
kilogram	O
diet	O
)	O
:	O
3	O
.	O
2	O
mg	O
CuSO4	O
,	O
88	O
mg	O
FeSO4	O
,	O
149	O
mg	O
MnSO4	O
,	O
25	O
mg	O
ZnCO3	O
,	O
1	O
.	O
6	O
mg	O
Ca	O
(	O
IO3	O
)	O
2	O
,	O
11	O
mg	O
vitamin	O
B1	O
,	O
4	O
.	O
7	O
mg	O
vitamin	O
B2	O
,	O
1	O
.	O
9	O
mg	O
vitamin	O
B6	O
,	O
44	O
mg	O
vitamin	O
E	O
,	O
in	O
addition	O
to	O
5	O
mu	O
g	O
MeHg	O
/	O
g	O
.	O

This	O
diet	O
was	O
fed	O
to	O
the	O
pregnant	O
mice	B
starting	O
from	O
GD0	O
through	O
10	O
days	O
after	O
delivery	O
(	O
i	O
.	O
e	O
.	O
,	O
PND10	O
)	O
.	O

Thereafter	O
,	O
we	O
switched	O
mice	B
to	O
a	O
diet	O
that	O
did	O
not	O
contain	O
MeHg	O
.	O

We	O
chose	O
GD0	O
as	O
the	O
beginning	O
of	O
exposure	O
because	O
exposures	O
that	O
started	O
before	O
conception	O
often	O
resulted	O
in	O
fairly	O
high	O
Hg	O
concentrations	O
in	O
fetal	O
/	O
neonatal	O
brains	O
(	O
Kakita	O
et	O
al	O
.	O
2003	O
)	O
,	O
and	O
we	O
chose	O
PND10	O
to	O
cover	O
the	O
early	O
neonatal	O
period	O
,	O
in	O
which	O
considerable	O
brain	O
growth	O
occurs	O
.	O

In	O
our	O
experimental	O
setting	O
,	O
the	O
neonatal	O
mice	B
started	O
to	O
eat	O
from	O
the	O
diet	O
bucket	O
and	O
drink	O
from	O
the	O
water	O
bottle	O
from	O
PND10	O
onward	O
.	O

Control	O
mice	B
were	O
kept	O
on	O
the	O
same	O
diet	O
but	O
without	O
MeHg	O
(	O
<	O
0	O
.	O
01	O
mu	O
g	O
Hg	O
/	O
g	O
)	O
.	O

On	O
PND1	O
,	O
to	O
avoid	O
the	O
confounding	O
effects	O
due	O
to	O
different	O
litter	O
size	O
,	O
we	O
reduced	O
each	O
litter	O
to	O
six	O
pups	O
(	O
three	O
males	O
and	O
three	O
females	O
when	O
possible	O
)	O
,	O
and	O
on	O
PND10	O
,	O
two	O
males	O
and	O
two	O
females	O
from	O
each	O
litter	O
were	O
killed	O
for	O
chemical	O
analyses	O
.	O

The	O
remaining	O
male	O
and	O
female	O
offspring	O
per	O
litter	O
were	O
weaned	O
on	O
PND28	O
and	O
used	O
for	O
subsequent	O
behavioral	O
analyses	O
(	O
either	O
at	O
12	O
-	O
13	O
weeks	O
or	O
52	O
-	O
53	O
weeks	O
,	O
depending	O
on	O
the	O
litter	O
)	O
as	O
described	O
below	O
.	O

We	O
measured	O
body	O
weights	O
of	O
the	O
weaned	O
mice	B
every	O
2	O
weeks	O
.	O

Thus	O
,	O
four	O
experimental	O
groups	O
were	O
used	O
(	O
with	O
or	O
without	O
MeHg	O
exposure	O
for	O
two	O
strains	O
)	O
,	O
and	O
each	O
group	O
consisted	O
of	O
12	O
-	O
13	O
litters	O
.	O

For	O
half	O
of	O
the	O
litters	O
,	O
the	O
behavioral	O
analyses	O
were	O
conducted	O
at	O
12	O
-	O
13	O
weeks	O
of	O
age	O
,	O
and	O
upon	O
completion	O
of	O
the	O
behavioral	O
analyses	O
,	O
the	O
animals	O
were	O
killed	O
under	O
ether	O
anesthesia	O
.	O

We	O
then	O
dissected	O
the	O
organs	O
(	O
brain	O
,	O
liver	O
,	O
and	O
kidneys	O
)	O
for	O
Hg	O
analyses	O
.	O

For	O
the	O
remaining	O
half	O
of	O
the	O
litters	O
,	O
we	O
conducted	O
the	O
behavioral	O
tests	O
at	O
52	O
-	O
53	O
weeks	O
of	O
age	O
.	O

The	O
mice	B
were	O
treated	O
humanely	O
and	O
with	O
regard	O
to	O
alleviation	O
of	O
suffering	O
according	O
to	O
the	O
National	O
Institute	O
for	O
Environmental	O
Studies	O
'	O
Guidelines	O
for	O
Animal	O
Welfare	O
and	O
the	O
guidelines	O
of	O
St	O
.	O

Marianna	O
University	O
.	O

Behavioral	O
evaluations	O

The	O
details	O
of	O
each	O
behavioral	O
procedure	O
have	O
been	O
described	O
elsewhere	O
(	O
Yoshida	O
et	O
al	O
.	O
2006	O
)	O
.	O

Brief	O
descriptions	O
follow	O
.	O

For	O
the	O
OPF	O
test	O
,	O
we	O
used	O
an	O
OPF	O
apparatus	O
(	O
Ohara	O
Co	O
.	O
,	O
Ltd	O
.	O
,	O
Tokyo	O
,	O
Japan	O
)	O
with	O
a	O
60	O
x	O
60	O
-	O
cm	O
floor	O
surrounded	O
by	O
walls	O
60	O
cm	O
high	O
.	O

The	O
experimental	O
room	O
light	O
was	O
turned	O
off	O
,	O
and	O
a	O
dim	O
light	O
of	O
80	O
lux	O
was	O
lit	O
during	O
the	O
experiment	O
.	O

We	O
placed	O
a	O
mouse	B
in	O
the	O
center	O
of	O
the	O
floor	O
and	O
monitored	O
its	O
behavior	O
for	O
10	O
min	O
using	O
a	O
CCD	O
camera	O
connected	O
to	O
a	O
computer	O
.	O

The	O
position	O
of	O
the	O
center	O
of	O
gravity	O
was	O
calculated	O
by	O
image	O
-	O
analyzing	O
software	O
,	O
which	O
was	O
used	O
to	O
calculate	O
the	O
total	O
distance	O
traveled	O
by	O
the	O
mouse	B
as	O
well	O
as	O
the	O
positional	O
preference	O
(	O
either	O
center	O
or	O
peripheral	O
,	O
where	O
peripheral	O
was	O
defined	O
as	O
the	O
area	O
within	O
10	O
cm	O
from	O
the	O
wall	O
)	O
.	O

We	O
cleaned	O
the	O
OPF	O
apparatus	O
with	O
70	O
%	O
ethanol	O
between	O
trials	O
.	O

The	O
apparatus	O
for	O
the	O
PA	O
test	O
(	O
Ohara	O
Co	O
.	O
Ltd	O
.	O
)	O
consisted	O
of	O
a	O
light	O
compartment	O
that	O
illuminated	O
by	O
a	O
400	O
-	O
lux	O
light	O
and	O
a	O
dark	O
compartment	O
with	O
black	O
opaque	O
walls	O
and	O
lids	O
.	O

The	O
two	O
compartments	O
were	O
separated	O
by	O
a	O
mobile	O
guillotine	O
door	O
.	O

On	O
the	O
first	O
day	O
(	O
training	O
trial	O
)	O
,	O
we	O
placed	O
each	O
mouse	B
in	O
the	O
light	O
compartment	O
facing	O
away	O
from	O
the	O
guillotine	O
door	O
,	O
which	O
was	O
closed	O
.	O

After	O
30	O
sec	O
of	O
introduction	O
,	O
the	O
door	O
was	O
opened	O
;	O
when	O
the	O
mouse	B
entered	O
the	O
dark	O
compartment	O
,	O
a	O
brief	O
electric	O
shock	O
(	O
4	O
mA	O
for	O
2	O
sec	O
)	O
was	O
delivered	O
through	O
the	O
metal	O
grid	O
floor	O
.	O

This	O
would	O
force	O
the	O
mouse	B
back	O
to	O
the	O
light	O
component	O
.	O

The	O
interval	O
between	O
the	O
opening	O
of	O
the	O
door	O
and	O
the	O
entry	O
to	O
the	O
dark	O
room	O
(	O
in	O
seconds	O
)	O
was	O
recorded	O
and	O
defined	O
as	O
the	O
latency	O
.	O

On	O
the	O
next	O
day	O
,	O
the	O
same	O
procedure	O
was	O
repeated	O
,	O
but	O
without	O
the	O
electric	O
shock	O
(	O
retaining	O
trail	O
)	O
.	O

In	O
this	O
PA	O
paradigm	O
,	O
aversive	O
learning	O
was	O
assumed	O
to	O
be	O
established	O
in	O
the	O
training	O
trial	O
,	O
and	O
we	O
used	O
its	O
retention	O
in	O
the	O
retaining	O
trail	O
as	O
the	O
index	O
of	O
learning	O
.	O

Between	O
each	O
individual	O
trial	O
,	O
we	O
cleaned	O
the	O
apparatus	O
with	O
ethanol	O
.	O

The	O
cutoff	O
time	O
of	O
the	O
retention	O
session	O
was	O
300	O
sec	O
.	O

The	O
MM	O
test	O
apparatus	O
(	O
Ohara	O
Co	O
.	O
,	O
Ltd	O
.	O
)	O
was	O
a	O
round	O
-	O
shaped	O
water	O
pool	O
with	O
a	O
diameter	O
of	O
120	O
cm	O
.	O

A	O
small	O
platform	O
was	O
submerged	O
in	O
the	O
water	O
,	O
which	O
provided	O
a	O
place	O
for	O
mice	B
to	O
escape	O
from	O
the	O
water	O
(	O
i	O
.	O
e	O
.	O
,	O
an	O
aversive	O
stimulus	O
,	O
water	O
temperature	O
=	O
23	O
+	O
/	O
-	O
1	O
degrees	O
C	O
)	O
.	O

The	O
water	O
was	O
made	O
opaque	O
by	O
adding	O
white	O
paint	O
so	O
that	O
the	O
mouse	B
could	O
not	O
see	O
the	O
submerged	O
platform	O
.	O

In	O
each	O
trial	O
,	O
we	O
released	O
a	O
mouse	B
into	O
the	O
pool	O
from	O
a	O
determined	O
position	O
along	O
the	O
wall	O
,	O
and	O
the	O
performance	O
of	O
the	O
mouse	B
was	O
monitored	O
by	O
a	O
CCD	O
camera	O
/	O
image	O
analyzer	O
.	O

The	O
time	O
required	O
to	O
reach	O
the	O
platform	O
was	O
recorded	O
.	O

If	O
a	O
mouse	B
could	O
not	O
find	O
the	O
platform	O
within	O
60	O
sec	O
after	O
release	O
,	O
it	O
was	O
led	O
to	O
the	O
platform	O
and	O
placed	O
on	O
it	O
for	O
20	O
sec	O
before	O
being	O
removed	O
.	O

In	O
these	O
cases	O
,	O
a	O
latency	O
of	O
60	O
sec	O
was	O
recorded	O
.	O

We	O
conducted	O
the	O
trial	O
once	O
a	O
day	O
up	O
to	O
the	O
fifth	O
day	O
for	O
each	O
mouse	B
,	O
and	O
the	O
order	O
of	O
each	O
mouse	B
was	O
counterbalanced	O
across	O
the	O
day	O
.	O

On	O
the	O
sixth	O
day	O
,	O
a	O
transfer	O
test	O
(	O
or	O
probe	O
test	O
)	O
,	O
which	O
is	O
a	O
trial	O
without	O
the	O
platform	O
,	O
was	O
conducted	O
;	O
in	O
this	O
procedure	O
,	O
we	O
counted	O
the	O
number	O
of	O
times	O
that	O
the	O
mouse	B
crossed	O
the	O
position	O
where	O
the	O
platform	O
had	O
been	O
.	O

Tissue	O
Hg	O
concentration	O

The	O
tissue	O
samples	O
were	O
homogenized	O
(	O
10	O
%	O
weight	O
/	O
volume	O
)	O
in	O
distilled	O
water	O
using	O
a	O
Polytron	O
homogenizer	O
(	O
Kinematica	O
GmbH	O
,	O
Littau	O
,	O
Switzerland	O
)	O
.	O

We	O
determined	O
Hg	O
levels	O
in	O
the	O
homogenates	O
by	O
the	O
oxygen	O
combustion	O
-	O
gold	O
amalgamation	O
method	O
(	O
Ohkawa	O
et	O
al	O
.	O
1977	O
)	O
using	O
an	O
atomic	O
absorption	O
Hg	O
detector	O
MD	O
-	O
1	O
(	O
Nippon	O
Instruments	O
,	O
Co	O
.	O
Ltd	O
.	O
,	O
Osaka	O
,	O
Japan	O
)	O
.	O

To	O
ensure	O
the	O
accuracy	O
of	O
the	O
measurement	O
,	O
we	O
included	O
reference	O
material	O
from	O
a	O
dogfish	O
(	O
DORM	O
-	O
2	O
;	O
National	O
Research	O
Council	O
of	O
Canada	O
,	O
Ottawa	O
,	O
Ontario	O
,	O
Canada	O
)	O
with	O
a	O
certified	O
value	O
of	O
4	O
.	O
64	O
+	O
/	O
-	O
0	O
.	O
26	O
mu	O
g	O
/	O
g	O
in	O
the	O
analyses	O
;	O
the	O
observed	O
values	O
fell	O
within	O
the	O
certified	O
range	O
.	O

The	O
detection	O
limit	O
of	O
the	O
measurement	O
was	O
0	O
.	O
1	O
ng	O
Hg	O
.	O

Statistics	O

We	O
analyzed	O
behavioral	O
data	O
for	O
OPF	O
and	O
PA	O
by	O
analysis	O
of	O
variance	O
(	O
ANOVA	O
)	O
,	O
taking	O
sex	O
,	O
strain	O
,	O
and	O
MeHg	O
exposure	O
as	O
the	O
factors	O
.	O

All	O
the	O
interactions	O
among	O
these	O
factors	O
were	O
put	O
into	O
the	O
model	O
.	O

When	O
any	O
of	O
the	O
interactions	O
was	O
highly	O
significant	O
,	O
we	O
analyzed	O
the	O
data	O
separately	O
in	O
an	O
appropriate	O
way	O
;	O
for	O
example	O
,	O
if	O
sex	O
x	O
Hg	O
was	O
significant	O
,	O
the	O
data	O
for	O
males	O
and	O
females	O
were	O
separately	O
analyzed	O
for	O
the	O
effects	O
of	O
strain	O
and	O
Hg	O
.	O

Whenever	O
appropriate	O
,	O
ANOVAs	O
were	O
followed	O
by	O
Mann	O
-	O
Whitney	O
U	O
or	O
Student	O
'	O
s	O
t	O
-	O
tests	O
,	O
depending	O
on	O
the	O
nature	O
and	O
distribution	O
of	O
the	O
variables	O
.	O

We	O
analyzed	O
data	O
for	O
the	O
MM	O
by	O
repeated	O
-	O
measures	O
ANOVA	O
,	O
taking	O
the	O
exposure	O
as	O
between	O
-	O
group	O
and	O
trials	O
as	O
within	O
-	O
group	O
variables	O
.	O

The	O
test	O
was	O
performed	O
for	O
each	O
of	O
the	O
four	O
sex	O
and	O
strain	O
combinations	O
separately	O
.	O

The	O
significance	O
level	O
was	O
set	O
at	O
p	O
<	O
0	O
.	O
05	O
.	O

Results	O

Body	O
weight	O

Up	O
to	O
20	O
weeks	O
of	O
age	O
,	O
the	O
body	O
weight	O
values	O
of	O
the	O
control	O
and	O
MeHg	O
-	O
exposed	O
groups	O
were	O
not	O
different	O
,	O
regardless	O
of	O
strain	O
or	O
sex	O
.	O

After	O
28	O
weeks	O
,	O
except	O
for	O
the	O
wild	O
-	O
type	O
female	O
groups	O
,	O
the	O
MeHg	O
-	O
exposed	O
groups	O
weighed	O
significantly	O
less	O
than	O
the	O
controls	O
(	O
Figure	O
1	O
)	O
.	O

OPF	O

At	O
12	O
weeks	O
of	O
age	O
,	O
a	O
three	O
-	O
way	O
ANOVA	O
of	O
the	O
locomotion	O
distance	O
revealed	O
that	O
only	O
strain	O
was	O
a	O
significant	O
factor	O
(	O
p	O
<	O
0	O
.	O
001	O
)	O
,	O
reflecting	O
the	O
longer	O
distance	O
traveled	O
by	O
the	O
MT	O
-	O
null	O
mice	B
(	O
Figure	O
2A	O
)	O
.	O

Strain	O
was	O
also	O
a	O
significant	O
factor	O
for	O
the	O
proportion	O
of	O
the	O
central	O
-	O
area	O
locomotion	O
(	O
Figure	O
3A	O
)	O
,	O
and	O
Hg	O
exposure	O
marginally	O
affected	O
this	O
outcome	O
.	O

In	O
MT	O
-	O
null	O
females	O
,	O
the	O
proportion	O
of	O
central	O
-	O
area	O
locomotion	O
was	O
higher	O
in	O
MeHg	O
-	O
exposed	O
mice	B
than	O
in	O
the	O
controls	O
;	O
this	O
difference	O
was	O
not	O
observed	O
in	O
any	O
other	O
strain	O
-	O
sex	O
combination	O
.	O

At	O
52	O
weeks	O
of	O
age	O
,	O
the	O
strain	O
x	O
Hg	O
interaction	O
was	O
highly	O
significant	O
(	O
p	O
<	O
0	O
.	O
001	O
)	O
in	O
an	O
ANOVA	O
of	O
locomotion	O
distance	O
(	O
Figure	O
2B	O
)	O
;	O
MeHg	O
exposure	O
was	O
associated	O
with	O
decreased	O
locomotion	O
distance	O
in	O
wild	O
-	O
type	O
mice	B
and	O
with	O
increased	O
distance	O
in	O
MT	O
-	O
null	O
mice	B
.	O

A	O
strain	O
-	O
wise	O
two	O
-	O
way	O
ANOVA	O
(	O
with	O
sex	O
and	O
Hg	O
as	O
the	O
factors	O
)	O
revealed	O
that	O
only	O
Hg	O
was	O
significant	O
in	O
both	O
strains	O
(	O
p	O
<	O
0	O
.	O
01	O
)	O
.	O

Regarding	O
the	O
proportion	O
of	O
the	O
central	O
-	O
area	O
locomotion	O
,	O
the	O
effects	O
of	O
MeHg	O
appeared	O
to	O
depend	O
on	O
sex	O
[	O
i	O
.	O
e	O
.	O
,	O
sex	O
x	O
Hg	O
was	O
highly	O
significant	O
(	O
p	O
<	O
0	O
.	O
001	O
)	O
in	O
the	O
three	O
-	O
way	O
ANOVA	O
;	O
Figure	O
3B	O
]	O
.	O

Indeed	O
,	O
a	O
sex	O
-	O
wise	O
two	O
-	O
way	O
ANOVA	O
showed	O
significant	O
effects	O
of	O
Hg	O
only	O
in	O
females	O
(	O
p	O
<	O
0	O
.	O
001	O
)	O
.	O

PA	O

At	O
12	O
weeks	O
of	O
age	O
,	O
all	O
the	O
groups	O
showed	O
prolonged	O
latency	O
in	O
the	O
second	O
(	O
retention	O
)	O
trial	O
,	O
and	O
no	O
consistent	O
effect	O
of	O
MeHg	O
was	O
recognized	O
regardless	O
of	O
strain	O
or	O
sex	O
(	O
Figure	O
4A	O
)	O
.	O

At	O
52	O
weeks	O
of	O
age	O
,	O
a	O
three	O
-	O
way	O
ANOVA	O
revealed	O
a	O
significant	O
interaction	O
between	O
strain	O
and	O
Hg	O
(	O
p	O
<	O
0	O
.	O
05	O
)	O
;	O
strain	O
-	O
wise	O
two	O
-	O
way	O
ANOVAs	O
revealed	O
a	O
significant	O
effect	O
of	O
Hg	O
on	O
learning	O
in	O
MT	O
-	O
null	O
mice	B
of	O
both	O
sexes	O
;	O
these	O
groups	O
of	O
mice	B
showed	O
significantly	O
shorter	O
(	O
less	O
than	O
half	O
)	O
latency	O
times	O
compared	O
to	O
control	O
mice	B
(	O
Figure	O
4B	O
)	O
.	O

A	O
notable	O
difference	O
between	O
the	O
results	O
at	O
52	O
weeks	O
of	O
age	O
and	O
those	O
at	O
12	O
weeks	O
was	O
that	O
many	O
of	O
the	O
tested	O
mice	B
exceeded	O
the	O
cutoff	O
time	O
in	O
the	O
retention	O
trials	O
at	O
52	O
weeks	O
,	O
except	O
for	O
the	O
MT	O
-	O
null	O
groups	O
.	O

MM	O

At	O
13	O
weeks	O
of	O
age	O
,	O
repeated	O
-	O
measures	O
ANOVA	O
did	O
not	O
indicate	O
any	O
effects	O
of	O
MeHg	O
(	O
Figure	O
5A	O
)	O
.	O

At	O
52	O
weeks	O
of	O
age	O
(	O
Figure	O
5B	O
)	O
,	O
wild	O
-	O
type	O
males	O
and	O
MT	O
-	O
null	O
females	O
shared	O
the	O
same	O
statistical	O
results	O
;	O
Hg	O
as	O
well	O
as	O
the	O
Hg	O
x	O
trial	O
interaction	O
were	O
statistically	O
significant	O
.	O

Thus	O
,	O
in	O
both	O
cases	O
,	O
the	O
MeHg	O
groups	O
showed	O
a	O
longer	O
latency	O
,	O
hampering	O
learning	O
performance	O
.	O

Tissue	O
Hg	O
concentration	O

At	O
PND10	O
,	O
which	O
was	O
immediately	O
after	O
the	O
exposure	O
,	O
brain	O
Hg	O
concentrations	O
of	O
the	O
neonatal	O
mice	B
were	O
approximately	O
<	O
=	O
0	O
.	O
5	O
mu	O
g	O
/	O
g	O
(	O
Table	O
1	O
)	O
.	O

Although	O
the	O
MT	O
-	O
null	O
mice	B
and	O
females	O
showed	O
slightly	O
higher	O
brain	O
Hg	O
concentrations	O
than	O
the	O
corresponding	O
wild	O
-	O
type	O
group	O
and	O
males	O
,	O
respectively	O
,	O
neither	O
of	O
these	O
differences	O
was	O
significant	O
.	O

At	O
13	O
weeks	O
,	O
when	O
the	O
behavioral	O
tests	O
were	O
completed	O
,	O
the	O
brain	O
Hg	O
concentration	O
was	O
comparable	O
to	O
the	O
control	O
(	O
nonexposed	O
)	O
level	O
(	O
approximately	O
5	O
ng	O
/	O
g	O
in	O
both	O
the	O
exposed	O
and	O
control	O
brains	O
)	O
.	O

Interestingly	O
,	O
MT	O
-	O
null	O
mice	B
had	O
a	O
significantly	O
lower	O
brain	O
Hg	O
concentration	O
than	O
the	O
corresponding	O
wild	O
-	O
type	O
groups	O
.	O

Discussion	O

Results	O
of	O
the	O
present	O
study	O
demonstrate	O
the	O
delayed	O
emergence	O
of	O
neurobehavioral	O
toxicity	O
due	O
to	O
perinatal	O
MeHg	O
exposure	O
,	O
which	O
presumably	O
developed	O
after	O
brain	O
MeHg	O
concentrations	O
had	O
leveled	O
off	O
.	O

This	O
emergent	O
toxicity	O
was	O
exaggerated	O
in	O
MT	O
-	O
null	O
mice	B
and	O
was	O
more	O
distinct	O
in	O
females	O
.	O

To	O
our	O
knowledge	O
,	O
our	O
findings	O
show	O
the	O
first	O
clear	O
-	O
cut	O
demonstrations	O
of	O
a	O
long	O
latency	O
period	O
of	O
MeHg	O
neurobehavioral	O
toxicity	O
in	O
rodents	O
and	O
possible	O
genetic	O
susceptibility	O
for	O
the	O
emergent	O
toxicity	O
.	O

The	O
exposure	O
level	O
should	O
be	O
considered	O
before	O
discussing	O
the	O
end	O
points	O
.	O

On	O
PND10	O
,	O
immediately	O
after	O
the	O
cessation	O
of	O
MeHg	O
exposure	O
,	O
the	O
brain	O
Hg	O
concentration	O
was	O
approximately	O
0	O
.	O
5	O
mu	O
g	O
/	O
g	O
,	O
regardless	O
of	O
the	O
strain	O
or	O
sex	O
.	O

In	O
a	O
previous	O
study	O
,	O
the	O
brain	O
Hg	O
concentration	O
in	O
mice	B
perinatally	O
exposed	O
to	O
6	O
mg	O
MeHg	O
/	O
L	O
(	O
via	O
water	O
)	O
peaked	O
between	O
PND0	O
and	O
PND4	O
and	O
was	O
approximately	O
three	O
times	O
higher	O
than	O
on	O
PND21	O
(	O
Goulet	O
et	O
al	O
.	O
2003	O
)	O
.	O

Therefore	O
,	O
the	O
peak	O
brain	O
Hg	O
concentration	O
,	O
which	O
is	O
presumably	O
observed	O
around	O
birth	O
,	O
can	O
be	O
estimated	O
as	O
about	O
3	O
-	O
fold	O
higher	O
than	O
that	O
on	O
PND10	O
and	O
would	O
be	O
approximately	O
1	O
.	O
5	O
mu	O
g	O
/	O
g	O
(	O
0	O
.	O
5	O
mu	O
g	O
/	O
g	O
x	O
3	O
)	O
,	O
which	O
is	O
one	O
of	O
the	O
lowest	O
levels	O
among	O
recent	O
rodent	O
studies	O
.	O

As	O
shown	O
by	O
Sakamoto	O
et	O
al	O
.	O

(	O
2002	O
)	O
in	O
their	O
Figure	O
2	O
,	O
prenatal	O
exposure	O
of	O
rats	B
to	O
MeHg	O
showed	O
a	O
peak	O
brain	O
Hg	O
concentration	O
around	O
PND1	O
that	O
was	O
four	O
to	O
five	O
times	O
greater	O
than	O
the	O
level	O
on	O
PND10	O
.	O

Also	O
,	O
Newland	O
and	O
Rasmussen	O
(	O
2000	O
)	O
reported	O
a	O
slight	O
alteration	O
of	O
a	O
complex	O
operant	O
behavior	O
in	O
rats	B
at	O
ages	O
<	O
2	O
years	O
at	O
brain	O
Hg	O
concentrations	O
as	O
low	O
as	O
0	O
.	O
5	O
mu	O
g	O
/	O
g	O
at	O
birth	O
,	O
although	O
statistical	O
significance	O
of	O
this	O
particular	O
effect	O
was	O
not	O
clear	O
.	O

It	O
should	O
be	O
noted	O
that	O
rats	B
have	O
different	O
Hg	O
kinetics	O
(	O
Hirayama	O
and	O
Yasutake	O
1986	O
;	O
Yasutake	O
and	O
Hirayama	O
1990	O
)	O
due	O
to	O
the	O
high	O
affinity	O
of	O
rat	O
hemoglobin	O
for	O
MeHg	O
(	O
Clarkson	O
and	O
Magos	O
2006	O
)	O
.	O

The	O
most	O
important	O
observation	O
of	O
the	O
present	O
study	O
was	O
that	O
the	O
effects	O
of	O
low	O
-	O
level	O
MeHg	O
exposure	O
were	O
detected	O
only	O
at	O
later	O
stages	O
in	O
the	O
lives	O
of	O
the	O
mice	B
.	O

Except	O
for	O
the	O
central	O
-	O
area	O
occupancy	O
in	O
OPF	O
in	O
MT	O
-	O
null	O
females	O
,	O
no	O
statistically	O
significant	O
effects	O
of	O
MeHg	O
were	O
observed	O
in	O
any	O
of	O
the	O
three	O
behavioral	O
tests	O
at	O
12	O
weeks	O
of	O
age	O
.	O

In	O
contrast	O
,	O
significant	O
effects	O
were	O
observed	O
in	O
all	O
three	O
tests	O
at	O
52	O
weeks	O
of	O
age	O
.	O

The	O
brain	O
Hg	O
concentration	O
of	O
the	O
exposed	O
groups	O
had	O
leveled	O
off	O
and	O
was	O
not	O
distinguishable	O
from	O
the	O
non	O
-	O
exposed	O
group	O
at	O
13	O
weeks	O
of	O
age	O
,	O
immediately	O
after	O
the	O
first	O
phase	O
of	O
the	O
behavioral	O
testing	O
.	O

Therefore	O
,	O
in	O
the	O
present	O
study	O
,	O
there	O
was	O
a	O
latency	O
period	O
in	O
which	O
the	O
dose	O
and	O
effects	O
could	O
not	O
be	O
detected	O
,	O
although	O
effects	O
were	O
observed	O
9	O
months	O
later	O
.	O

Another	O
notable	O
observation	O
was	O
that	O
the	O
emergent	O
manifestation	O
of	O
toxicity	O
was	O
also	O
recognized	O
in	O
the	O
suppression	O
of	O
body	O
weight	O
(	O
except	O
for	O
wild	O
-	O
type	O
females	O
)	O
,	O
which	O
only	O
became	O
apparent	O
on	O
or	O
after	O
28	O
weeks	O
of	O
age	O
.	O

The	O
existence	O
of	O
a	O
latency	O
period	O
of	O
as	O
long	O
as	O
several	O
years	O
after	O
chronic	O
(	O
7	O
years	O
from	O
birth	O
)	O
,	O
low	O
-	O
level	O
exposure	O
to	O
MeHg	O
has	O
been	O
described	O
in	O
nonhuman	O
primates	O
(	O
Rice	O
1996	O
)	O
.	O

In	O
that	O
case	O
,	O
however	O
,	O
the	O
Hg	O
concentration	O
in	O
the	O
brain	O
remained	O
elevated	O
,	O
presumably	O
as	O
a	O
result	O
of	O
the	O
long	O
exposure	O
.	O

Indeed	O
,	O
Rice	O
(	O
1996	O
)	O
argued	O
that	O
the	O
minute	O
amount	O
of	O
residual	O
brain	O
Hg	O
could	O
have	O
caused	O
the	O
delayed	O
toxicity	O
.	O

This	O
was	O
clearly	O
not	O
the	O
case	O
in	O
the	O
present	O
study	O
because	O
the	O
Hg	O
concentration	O
leveled	O
off	O
around	O
the	O
time	O
of	O
the	O
first	O
phase	O
of	O
the	O
behavioral	O
study	O
.	O

The	O
absence	O
of	O
behavioral	O
effects	O
at	O
12	O
weeks	O
of	O
age	O
ruled	O
out	O
the	O
possibility	O
that	O
the	O
residual	O
behavioral	O
effects	O
were	O
due	O
to	O
elevated	O
Hg	O
early	O
in	O
life	O
.	O

Therefore	O
,	O
the	O
behavioral	O
toxicity	O
that	O
surfaced	O
at	O
52	O
weeks	O
of	O
age	O
must	O
have	O
had	O
its	O
origin	O
before	O
the	O
brain	O
Hg	O
concentration	O
leveled	O
off	O
(	O
at	O
or	O
before	O
13	O
weeks	O
of	O
age	O
)	O
,	O
although	O
the	O
redistribution	O
of	O
Hg	O
to	O
the	O
brain	O
from	O
other	O
sites	O
of	O
deposition	O
,	O
such	O
as	O
the	O
liver	O
,	O
cannot	O
be	O
completely	O
excluded	O
.	O

The	O
long	O
silent	O
period	O
before	O
the	O
manifestations	O
of	O
toxicity	O
emerged	O
suggests	O
that	O
a	O
slow	O
process	O
plays	O
a	O
role	O
in	O
this	O
latent	O
toxicity	O
.	O

Although	O
an	O
example	O
of	O
a	O
slow	O
process	O
is	O
aging	O
,	O
52	O
weeks	O
of	O
age	O
might	O
not	O
be	O
sufficiently	O
old	O
for	O
a	O
mouse	B
to	O
be	O
considered	O
aged	O
in	O
the	O
physiologic	O
sense	O
because	O
C57BL	O
/	O
6	O
mice	B
have	O
a	O
relatively	O
long	O
life	O
span	O
among	O
mouse	B
strains	O
[	O
median	O
survival	O
of	O
27	O
-	O
31	O
months	O
(	O
Gower	O
and	O
Lamberty	O
1993	O
)	O
]	O
and	O
a	O
survival	O
rate	O
at	O
18	O
-	O
19	O
months	O
as	O
high	O
as	O
90	O
%	O
(	O
Institute	O
on	O
Aging	O
HP	O
)	O
(	O
National	O
Institute	O
on	O
Aging	O
2008	O
)	O
.	O

Nevertheless	O
,	O
various	O
behavioral	O
examinations	O
have	O
shown	O
age	O
-	O
related	O
changes	O
in	O
the	O
performance	O
of	O
mice	B
at	O
approximately	O
1	O
year	O
of	O
age	O
in	O
the	O
OPF	O
(	O
Acevedoa	O
et	O
al	O
.	O
2006	O
;	O
Carrie	O
et	O
al	O
.	O
1999	O
)	O
,	O
MM	O
(	O
Bach	O
et	O
al	O
.	O
1999	O
;	O
Carrie	O
et	O
al	O
.	O
1999	O
)	O
,	O
and	O
PA	O
(	O
Gower	O
and	O
Lamberty	O
1993	O
)	O
tests	O
.	O

The	O
observed	O
effects	O
of	O
MeHg	O
,	O
including	O
the	O
deterioration	O
in	O
the	O
PA	O
and	O
MM	O
and	O
suppression	O
in	O
the	O
OPF	O
(	O
in	O
wild	O
-	O
type	O
mice	B
)	O
,	O
were	O
consistent	O
with	O
these	O
reported	O
effects	O
of	O
aging	O
on	O
behavioral	O
function	O
(	O
in	O
the	O
sense	O
described	O
above	O
)	O
,	O
except	O
for	O
the	O
increased	O
OPF	O
activity	O
in	O
the	O
MT	O
-	O
null	O
mice	B
.	O

Regardless	O
of	O
its	O
neural	O
basis	O
,	O
the	O
basis	O
of	O
neurobehavioral	O
toxicity	O
should	O
be	O
sought	O
in	O
early	O
life	O
stages	O
when	O
the	O
brain	O
Hg	O
concentration	O
is	O
highly	O
elevated	O
(	O
approximately	O
1	O
.	O
5	O
mu	O
g	O
/	O
g	O
at	O
its	O
peak	O
)	O
.	O

Some	O
in	O
vivo	O
experiments	O
have	O
demonstrated	O
several	O
candidate	O
mechanisms	O
of	O
perinatal	O
exposure	O
to	O
MeHg	O
,	O
including	O
abnormal	O
migration	O
of	O
neurons	O
and	O
/	O
or	O
glias	O
(	O
Kakita	O
et	O
al	O
.	O
2003	O
;	O
Rodier	O
et	O
al	O
.	O
1984	O
)	O
,	O
but	O
at	O
higher	O
Hg	O
concentrations	O
.	O

Using	O
exactly	O
the	O
same	O
exposure	O
protocol	O
as	O
the	O
present	O
study	O
,	O
we	O
found	O
suppressed	O
activity	O
of	O
type	O
III	O
iodo	O
-	O
thyronine	O
deiodinase	O
,	O
a	O
thyroid	O
hormone	O
-	O
metabolizing	O
enzyme	O
,	O
in	O
the	O
brains	O
of	O
PND10	O
mouse	B
neonates	O
(	O
Mori	O
et	O
al	O
.	O
2006	O
)	O
,	O
consistent	O
with	O
our	O
previous	O
study	O
of	O
higher	O
MeHg	O
doses	O
(	O
Watanabe	O
et	O
al	O
.	O
1999	O
)	O
.	O

This	O
perturbation	O
could	O
be	O
one	O
of	O
the	O
candidate	O
mechanisms	O
responsible	O
for	O
the	O
later	O
anomalous	O
behaviors	O
because	O
even	O
a	O
transient	O
change	O
in	O
thyroid	O
hormones	O
during	O
the	O
critical	O
period	O
of	O
perinatal	O
life	O
exerts	O
long	O
-	O
term	O
consequences	O
(	O
Auso	O
et	O
al	O
.	O
2004	O
)	O
.	O

The	O
effects	O
of	O
MeHg	O
at	O
52	O
weeks	O
of	O
age	O
were	O
influenced	O
by	O
two	O
potential	O
modifying	O
factors	O
,	O
sex	O
and	O
strain	O
.	O

In	O
the	O
OPF	O
,	O
while	O
the	O
locomotion	O
was	O
affected	O
in	O
both	O
strains	O
(	O
although	O
the	O
direction	O
was	O
opposite	O
)	O
,	O
center	O
occupancy	O
was	O
significantly	O
increased	O
only	O
in	O
the	O
MT	O
-	O
null	O
mice	B
.	O

In	O
addition	O
,	O
the	O
effects	O
on	O
PA	O
were	O
significant	O
only	O
in	O
MT	O
-	O
null	O
mice	B
,	O
whereas	O
MeHg	O
at	O
a	O
higher	O
dose	O
was	O
reported	O
to	O
worsen	O
PA	O
performance	O
in	O
rats	B
(	O
6	O
-	O
8	O
weeks	O
of	O
age	O
;	O
Sakamoto	O
et	O
al	O
.	O
2002	O
)	O
.	O

In	O
addition	O
,	O
body	O
weight	O
gain	O
was	O
suppressed	O
in	O
both	O
male	O
and	O
female	O
MT	O
-	O
null	O
mice	B
,	O
whereas	O
in	O
wild	O
-	O
type	O
mice	B
the	O
suppression	O
was	O
observed	O
only	O
in	O
males	O
.	O

Taken	O
together	O
,	O
the	O
MT	O
-	O
null	O
strain	O
appeared	O
to	O
be	O
slightly	O
more	O
susceptible	O
to	O
the	O
late	O
-	O
emergent	O
effects	O
of	O
MeHg	O
.	O

Several	O
lines	O
of	O
evidence	O
have	O
shown	O
that	O
MT	O
-	O
I	O
,	O
II	O
is	O
protective	O
against	O
the	O
toxicity	O
of	O
MeHg	O
(	O
Leiva	O
-	O
Presa	O
et	O
al	O
.	O
2004	O
;	O
Yao	O
et	O
al	O
.	O
2000	O
)	O
,	O
and	O
the	O
present	O
results	O
were	O
basically	O
consistent	O
with	O
these	O
reports	O
.	O

We	O
have	O
also	O
reported	O
the	O
susceptibility	O
of	O
the	O
MT	O
-	O
null	O
strain	O
to	O
the	O
neurotoxic	O
effects	O
of	O
metallic	O
Hg	O
(	O
Yoshida	O
et	O
al	O
.	O
2004	O
,	O
2006	O
)	O
.	O

The	O
difference	O
in	O
the	O
susceptibility	O
to	O
MeHg	O
between	O
sexes	O
is	O
still	O
debated	O
(	O
Clarkson	O
and	O
Magos	O
2006	O
;	O
National	O
Research	O
Council	O
2000	O
;	O
Vahter	O
2007	O
)	O
.	O

In	O
the	O
present	O
study	O
,	O
some	O
responses	O
to	O
MeHg	O
were	O
different	O
between	O
the	O
sexes	O
,	O
including	O
OPF	O
performance	O
at	O
12	O
and	O
52	O
weeks	O
of	O
age	O
and	O
MM	O
performance	O
at	O
52	O
weeks	O
.	O

The	O
fact	O
that	O
the	O
MT	O
-	O
null	O
female	O
group	O
was	O
the	O
only	O
group	O
affected	O
by	O
MeHg	O
at	O
12	O
weeks	O
may	O
suggest	O
the	O
particular	O
susceptibility	O
of	O
females	O
in	O
this	O
strain	O
.	O

This	O
point	O
needs	O
to	O
be	O
clarified	O
in	O
further	O
experiments	O
.	O

The	O
question	O
remains	O
of	O
why	O
MT	O
-	O
null	O
mice	B
are	O
susceptible	O
to	O
the	O
delayed	O
neurotoxicity	O
of	O
perinatal	O
MeHg	O
.	O

Apparently	O
kinetics	O
play	O
only	O
a	O
minor	O
role	O
because	O
the	O
strain	O
did	O
not	O
show	O
distinct	O
effects	O
on	O
the	O
brain	O
Hg	O
concentration	O
at	O
PND10	O
.	O

The	O
significantly	O
lower	O
brain	O
Hg	O
concentration	O
in	O
MT	O
-	O
null	O
mice	B
compared	O
with	O
corresponding	O
wild	O
-	O
type	O
mice	B
at	O
13	O
weeks	O
of	O
age	O
indicated	O
that	O
MT	O
-	O
I	O
,	O
II	O
might	O
play	O
a	O
significant	O
role	O
in	O
the	O
retention	O
of	O
Hg	O
(	O
or	O
MeHg	O
)	O
.	O

This	O
is	O
consistent	O
with	O
the	O
results	O
of	O
studies	O
of	O
metallic	O
Hg	O
exposure	O
(	O
Yoshida	O
et	O
al	O
.	O
2004	O
,	O
2005	O
)	O
;	O
a	O
lower	O
brain	O
Hg	O
concentration	O
may	O
not	O
guarantee	O
lower	O
toxicity	O
,	O
supporting	O
the	O
protective	O
role	O
of	O
the	O
protein	O
.	O

Earlier	O
studies	O
suggest	O
that	O
brain	O
MT	O
-	O
I	O
,	O
II	O
has	O
an	O
important	O
role	O
both	O
in	O
the	O
response	O
to	O
oxidative	O
injury	O
(	O
Potter	O
et	O
al	O
.	O
2007	O
)	O
and	O
in	O
the	O
process	O
of	O
aging	O
(	O
Kojima	O
et	O
al	O
.	O
1999	O
)	O
.	O

Therefore	O
,	O
the	O
lack	O
of	O
MT	O
can	O
exaggerate	O
the	O
toxicity	O
of	O
MeHg	O
by	O
enhancing	O
the	O
initial	O
effects	O
due	O
to	O
oxygen	O
radicals	O
and	O
/	O
or	O
by	O
accelerating	O
functional	O
aging	O
.	O

Apart	O
from	O
this	O
,	O
an	O
intriguing	O
possibility	O
is	O
that	O
the	O
brain	O
-	O
specific	O
isoform	O
,	O
MT	O
-	O
III	O
,	O
might	O
contribute	O
to	O
the	O
results	O
we	O
obtained	O
because	O
the	O
expression	O
of	O
MT	O
-	O
III	O
,	O
together	O
with	O
MT	O
-	O
I	O
,	O
is	O
increased	O
in	O
the	O
brain	O
of	O
old	O
rats	B
,	O
resulting	O
in	O
the	O
low	O
availability	O
of	O
free	O
zinc	O
for	O
synapses	O
(	O
Mocchegiani	O
et	O
al	O
.	O
2004	O
)	O
.	O

The	O
age	O
-	O
dependent	O
expressions	O
of	O
MT	O
isoforms	O
might	O
be	O
modified	O
in	O
MT	O
-	O
null	O
mice	B
.	O

Results	O
of	O
the	O
present	O
study	O
might	O
allow	O
the	O
possibility	O
of	O
alternative	O
interpretations	O
due	O
to	O
some	O
potentially	O
confounding	O
factors	O
.	O

For	O
example	O
,	O
except	O
for	O
the	O
wild	O
-	O
type	O
females	O
,	O
we	O
observed	O
significant	O
differences	O
in	O
body	O
weight	O
between	O
MeHg	O
-	O
exposed	O
and	O
non	O
-	O
exposed	O
groups	O
.	O

Because	O
these	O
differences	O
only	O
became	O
clear	O
later	O
in	O
life	O
,	O
they	O
might	O
be	O
associated	O
with	O
the	O
toxicity	O
that	O
also	O
emerged	O
later	O
in	O
life	O
.	O

Manipulation	O
of	O
body	O
weight	O
in	O
rodents	O
alters	O
activity	O
levels	O
,	O
although	O
the	O
reported	O
results	O
are	O
not	O
always	O
consistent	O
with	O
each	O
other	O
(	O
Harrison	O
and	O
Archer	O
1987	O
;	O
Samuelsson	O
et	O
al	O
.	O
2008	O
)	O
.	O

Also	O
,	O
the	O
differential	O
performance	O
in	O
PA	O
could	O
be	O
related	O
with	O
the	O
potential	O
effects	O
of	O
MeHg	O
on	O
(	O
electric	O
)	O
shock	O
sensitivity	O
,	O
which	O
we	O
did	O
not	O
examine	O
.	O

At	O
least	O
one	O
high	O
-	O
dose	O
study	O
with	O
adult	O
rats	B
showed	O
reduced	O
electric	O
sensitivity	O
due	O
to	O
mercury	O
exposure	O
(	O
Wu	O
et	O
al	O
.	O
1985	O
)	O
.	O

These	O
possibilities	O
need	O
to	O
be	O
addressed	O
in	O
future	O
studies	O
.	O

To	O
summarize	O
,	O
the	O
present	O
results	O
suggest	O
that	O
an	O
initial	O
(	O
or	O
triggering	O
)	O
toxicologic	O
event	O
occurs	O
before	O
the	O
brain	O
Hg	O
concentration	O
stabilizes	O
and	O
that	O
the	O
nature	O
of	O
this	O
event	O
should	O
be	O
either	O
an	O
acceleration	O
of	O
the	O
aging	O
process	O
or	O
interaction	O
with	O
the	O
aging	O
process	O
.	O

Thus	O
,	O
by	O
identifying	O
the	O
physiologic	O
events	O
associated	O
with	O
the	O
functional	O
aging	O
of	O
the	O
examined	O
behavioral	O
tasks	O
,	O
the	O
fundamental	O
toxicologic	O
scar	O
might	O
be	O
revealed	O
.	O

A	O
Novel	O
Role	O
of	O
the	O
NRF2	O
Transcription	O
Factor	O
in	O
the	O
Regulation	O
of	O
Arsenite	O
-	O
Mediated	O
Keratin	O
16	O
Gene	O
Expression	O
in	O
Human	B
Keratinocytes	O

Abstract	O

Background	O

Inorganic	O
sodium	O
arsenite	O
(	O
iAs	O
)	O
is	O
a	O
ubiquitous	O
environmental	O
contaminant	O
and	O
is	O
associated	O
with	O
an	O
increased	O
risk	O
of	O
skin	O
hyperkeratosis	O
and	O
cancer	O
.	O

Objectives	O

We	O
investigated	O
the	O
molecular	O
mechanisms	O
underlying	O
the	O
regulation	O
of	O
the	O
keratin	O
16	O
(	O
K16	O
)	O
gene	O
by	O
iAs	O
in	O
the	O
human	B
keratinocyte	O
cell	O
line	O
HaCaT	O
.	O

Methods	O

We	O
performed	O
reverse	O
transcriptase	O
polymerase	O
chain	O
reaction	O
,	O
luciferase	O
assays	O
,	O
Western	O
blots	O
,	O
and	O
electrophoretic	O
mobility	O
shift	O
assays	O
to	O
determine	O
the	O
transcriptional	O
regulation	O
of	O
the	O
K16	O
gene	O
by	O
iAs	O
.	O

We	O
used	O
gene	O
overexpression	O
approaches	O
to	O
elucidate	O
the	O
nuclear	O
factor	O
erythroid	O
-	O
derived	O
2	O
related	O
factor	O
2	O
(	O
NRF2	O
)	O
involved	O
in	O
the	O
K16	O
induction	O
.	O

Results	O

iAs	O
induced	O
the	O
mRNA	O
and	O
protein	O
expression	O
of	O
K16	O
.	O

We	O
also	O
found	O
that	O
the	O
expression	O
of	O
K16	O
was	O
transcriptionally	O
induced	O
by	O
iAs	O
through	O
activator	O
protein	O
-	O
1	O
-	O
like	O
sites	O
and	O
an	O
antioxidant	O
response	O
element	O
(	O
ARE	O
)	O
in	O
its	O
gene	O
promoter	O
region	O
.	O

Treatment	O
with	O
iAs	O
also	O
enhanced	O
the	O
production	O
and	O
translocation	O
of	O
the	O
NRF2	O
transcription	O
factor	O
,	O
an	O
ARE	O
-	O
binding	O
protein	O
,	O
into	O
the	O
nucleus	O
without	O
modification	O
of	O
its	O
mRNA	O
expression	O
.	O

In	O
addition	O
,	O
iAs	O
elongated	O
the	O
half	O
-	O
life	O
of	O
the	O
NRF2	O
protein	O
.	O

When	O
overexpressed	O
in	O
HaCaT	O
cells	O
,	O
NRF2	O
was	O
also	O
directly	O
involved	O
in	O
not	O
only	O
the	O
up	O
-	O
regulation	O
of	O
the	O
detoxification	O
gene	O
thioredoxin	O
but	O
also	O
K16	O
gene	O
expression	O
.	O

Conclusions	O

Our	O
data	O
clearly	O
indicate	O
that	O
the	O
K16	O
gene	O
is	O
a	O
novel	O
target	O
of	O
NRF2	O
.	O

Furthermore	O
,	O
our	O
findings	O
also	O
suggest	O
that	O
NRF2	O
has	O
opposing	O
roles	O
in	O
the	O
cell	O
-	O
-	O
in	O
the	O
activation	O
of	O
detoxification	O
pathways	O
and	O
in	O
promoting	O
the	O
development	O
of	O
skin	O
disorders	O
.	O

Inorganic	O
sodium	O
arsenite	O
(	O
iAs	O
)	O
,	O
a	O
ubiquitous	O
element	O
,	O
is	O
one	O
of	O
the	O
most	O
toxic	O
metals	O
present	O
in	O
the	O
natural	O
environment	O
(	O
Bagla	O
and	O
Kaiser	O
1996	O
)	O
.	O

Arsenicals	O
are	O
found	O
as	O
naturally	O
occurring	O
constituents	O
of	O
soil	O
,	O
food	O
,	O
and	O
drinking	O
water	O
(	O
Wu	O
et	O
al	O
.	O
1989	O
;	O
Yoshida	O
et	O
al	O
.	O
2004	O
)	O
,	O
and	O
exposure	O
to	O
iAs	O
has	O
been	O
associated	O
with	O
a	O
variety	O
of	O
disease	O
outcomes	O
,	O
including	O
disorders	O
of	O
the	O
skin	O
,	O
urinary	O
bladder	O
,	O
liver	O
,	O
and	O
lung	O
(	O
Tchounwou	O
et	O
al	O
.	O
2004	O
)	O
.	O

In	O
particular	O
,	O
skin	O
hyperkeratosis	O
is	O
a	O
characteristic	O
dermatologic	O
lesion	O
associated	O
with	O
ingestion	O
of	O
arsenic	O
from	O
contaminated	O
groundwater	O
(	O
McLellan	O
2002	O
;	O
Yoshida	O
et	O
al	O
.	O
2004	O
)	O
.	O

There	O
is	O
also	O
a	O
significant	O
association	O
between	O
hyperkeratosis	O
,	O
nonmelanoma	O
skin	O
cancer	O
(	O
e	O
.	O
g	O
.	O
,	O
basal	O
cell	O
carcinoma	O
and	O
squamous	O
cell	O
carcinoma	O
)	O
,	O
and	O
Bowen	O
disease	O
(	O
Col	O
et	O
al	O
.	O
1999	O
;	O
Rossman	O
et	O
al	O
.	O
2004	O
)	O
.	O

Furthermore	O
,	O
the	O
pathologic	O
features	O
associated	O
with	O
arsenic	O
-	O
induced	O
hyperkeratosis	O
present	O
as	O
typical	O
acanthotic	O
types	O
of	O
psoriasis	O
-	O
like	O
keratosis	O
,	O
characterized	O
by	O
the	O
aberrant	O
proliferation	O
and	O
terminal	O
differentiation	O
of	O
epidermal	O
keratinocytes	O
(	O
Lee	O
et	O
al	O
.	O
2006	O
)	O
.	O

Many	O
epidemiologic	O
studies	O
have	O
shown	O
that	O
hyperkeratoses	O
are	O
the	O
most	O
frequent	O
precursor	O
lesions	O
of	O
some	O
skin	O
cancers	O
(	O
Bagla	O
and	O
Kaiser	O
1996	O
;	O
Col	O
et	O
al	O
.	O
1999	O
)	O
.	O

The	O
keratins	O
are	O
the	O
most	O
prominent	O
cytoskeletal	O
proteins	O
in	O
keratinocytes	O
and	O
comprise	O
a	O
large	O
family	O
of	O
proteins	O
that	O
form	O
intermediate	O
filament	O
networks	O
in	O
all	O
epithelial	O
cell	O
types	O
(	O
Moll	O
et	O
al	O
.	O
1982	O
)	O
.	O

Keratin	O
16	O
(	O
K16	O
)	O
and	O
keratin	O
6	O
(	O
K6	O
)	O
genes	O
are	O
constitutively	O
expressed	O
in	O
a	O
number	O
of	O
stratified	O
epithelial	O
levels	O
,	O
including	O
the	O
palmar	O
and	O
plantar	O
epidermis	O
(	O
Moll	O
et	O
al	O
.	O
1982	O
)	O
.	O

In	O
skin	O
diseases	O
characterized	O
by	O
aberrant	O
proliferation	O
and	O
differentiation	O
,	O
such	O
as	O
psoriasis	O
and	O
cancer	O
,	O
K16	O
is	O
detectable	O
at	O
higher	O
levels	O
compared	O
with	O
normal	O
tissue	O
(	O
Haider	O
et	O
al	O
.	O
2006	O
)	O
.	O

Furthermore	O
,	O
the	O
tissue	O
-	O
specific	O
overexpression	O
of	O
wild	O
-	O
type	O
K16	O
in	O
the	O
epidermis	O
of	O
transgenic	O
mice	B
results	O
in	O
the	O
hyperproliferation	O
of	O
keratinocytes	O
and	O
aberrant	O
keratinization	O
of	O
cornified	O
layers	O
,	O
leading	O
to	O
hyperkeratosis	O
of	O
the	O
skin	O
(	O
Takahashi	O
et	O
al	O
.	O
1994	O
)	O
.	O

Nuclear	O
factor	O
erythoid	O
-	O
derived	O
2	O
related	O
factor	O
2	O
(	O
NRF2	O
)	O
,	O
a	O
"	O
cap	O
'	O
n	O
'	O
collar	O
"	O
basic	O
leucine	O
zipper	O
transcription	O
factor	O
,	O
regulates	O
a	O
transcriptional	O
program	O
that	O
maintains	O
cellular	O
redox	O
homeostasis	O
and	O
protects	O
cells	O
from	O
oxidative	O
stress	O
and	O
xenobiotic	O
agents	O
(	O
Ishii	O
et	O
al	O
.	O
2000	O
;	O
Moi	O
et	O
al	O
.	O
1994	O
)	O
.	O

Several	O
detoxifying	O
and	O
antioxidant	O
genes	O
,	O
including	O
glutathione	O
-	O
S	O
-	O
transferases	O
(	O
GSTs	O
)	O
,	O
heme	O
oxygenase	O
-	O
1	O
(	O
HMOX1	O
)	O
,	O
and	O
thioredoxin	O
(	O
TXN	O
)	O
,	O
are	O
regulated	O
by	O
NRF2	O
through	O
the	O
antioxidant	O
responsive	O
element	O
(	O
ARE	O
)	O
in	O
the	O
respective	O
promoter	O
regions	O
of	O
these	O
genes	O
(	O
McMahon	O
et	O
al	O
.	O
2001	O
;	O
Wakabayashi	O
et	O
al	O
.	O
2004	O
)	O
.	O

NRF2	O
is	O
held	O
in	O
the	O
cytoplasm	O
by	O
a	O
cytoskeletal	O
-	O
associated	O
specific	O
inhibitory	O
protein	O
(	O
kelch	O
-	O
like	O
ECH	O
-	O
associated	O
protein	O
1	O
;	O
KEAP1	O
)	O
under	O
normal	O
cellular	O
redox	O
state	O
conditions	O
,	O
where	O
it	O
is	O
continuously	O
targeted	O
by	O
the	O
proteasomal	O
degradation	O
pathway	O
(	O
McMahon	O
et	O
al	O
.	O
2003	O
)	O
.	O

Upon	O
exposure	O
of	O
the	O
cell	O
to	O
oxidative	O
stress	O
or	O
electrophiles	O
,	O
NRF2	O
can	O
escape	O
this	O
KEAP1	O
-	O
mediated	O
repression	O
,	O
translocate	O
to	O
the	O
nucleus	O
,	O
and	O
activate	O
the	O
expression	O
of	O
its	O
target	O
genes	O
(	O
Dinkova	O
-	O
Kostova	O
et	O
al	O
.	O
2002	O
;	O
McMahon	O
et	O
al	O
.	O
2003	O
)	O
.	O

Recently	O
,	O
studies	O
of	O
Keap1	O
-	O
/	O
-	O
mice	B
have	O
shown	O
that	O
NRF2	O
accumulates	O
in	O
the	O
nucleus	O
and	O
constitutively	O
activates	O
the	O
transcription	O
of	O
its	O
target	O
genes	O
,	O
even	O
in	O
the	O
absence	O
of	O
stress	O
signals	O
(	O
Wakabayashi	O
et	O
al	O
.	O
2003	O
)	O
.	O

Most	O
interestingly	O
,	O
however	O
,	O
the	O
skin	O
,	O
esophagus	O
,	O
and	O
forestomach	O
of	O
Keap1	O
-	O
deficient	O
mice	B
show	O
cornified	O
layer	O
and	O
hyperkeratosis	O
phenotypes	O
.	O

In	O
addition	O
,	O
previous	O
studies	O
have	O
also	O
shown	O
that	O
the	O
expression	O
of	O
NRF2	O
and	O
ARE	O
-	O
controlled	O
genes	O
is	O
induced	O
by	O
iAs	O
in	O
some	O
cell	O
types	O
(	O
Pi	O
et	O
al	O
.	O
2003	O
;	O
Sakurai	O
et	O
al	O
.	O
2005	O
)	O
.	O

Furthermore	O
,	O
histochemical	O
analyses	O
have	O
indicated	O
that	O
the	O
expression	O
of	O
K16	O
is	O
increased	O
in	O
Bowen	O
disease	O
,	O
basal	O
cell	O
carcinoma	O
,	O
and	O
squamous	O
cell	O
carcinoma	O
induced	O
by	O
arsenicals	O
(	O
Yu	O
et	O
al	O
.	O
1993	O
)	O
.	O

However	O
,	O
it	O
remains	O
to	O
be	O
determined	O
whether	O
NRF2	O
can	O
regulate	O
the	O
transcriptional	O
activation	O
of	O
K16	O
upon	O
iAs	O
exposure	O
in	O
human	B
keratinocytes	O
.	O

Hence	O
,	O
these	O
findings	O
prompted	O
us	O
to	O
investigate	O
the	O
molecular	O
mechanisms	O
underlying	O
the	O
regulation	O
of	O
the	O
K16	O
gene	O
by	O
iAs	O
-	O
induced	O
NRF2	O
mediation	O
.	O

Materials	O
and	O
Methods	O

Chemicals	O
and	O
reagents	O

A	O
purified	O
preparation	O
of	O
inorganic	O
sodium	O
arsenite	O
(	O
iAs	O
;	O
NaAsO2	O
;	O
Merck	O
,	O
Darmstadt	O
,	O
Germany	O
)	O
was	O
dissolved	O
in	O
phosphate	O
-	O
buffered	O
saline	O
(	O
PBS	O
)	O
and	O
added	O
directly	O
to	O
the	O
culture	O
medium	O
.	O

A	O
fresh	O
iAs	O
solution	O
was	O
prepared	O
for	O
each	O
new	O
experiment	O
.	O

Cycloheximide	O
(	O
CHX	O
)	O
,	O
dimethyl	O
-	O
sulfoxide	O
(	O
DMSO	O
)	O
,	O
and	O
a	O
protease	O
inhibitor	O
cocktail	O
were	O
purchased	O
from	O
Sigma	O
(	O
St	O
.	O
Louis	O
,	O
MO	O
,	O
USA	O
)	O
.	O

CHX	O
was	O
dissolved	O
in	O
DMSO	O
and	O
stored	O
-	O
20	O
degrees	O
C	O
until	O
use	O
.	O

Cells	O
and	O
culture	O
conditions	O

The	O
human	B
keratinocyte	O
HaCaT	O
cell	O
line	O
was	O
obtained	O
from	O
N	O
.	O
E	O
.	O

Fusenig	O
(	O
German	O
Cancer	O
Research	O
Center	O
,	O
Heidelberg	O
,	O
Germany	O
)	O
.	O

Cells	O
were	O
maintained	O
in	O
monolayer	O
cultures	O
in	O
95	O
%	O
air	O
and	O
5	O
%	O
CO2	O
at	O
37	O
degrees	O
C	O
in	O
Dulbecco	O
'	O
s	O
modified	O
Eagles	O
medium	O
(	O
DMEM	O
)	O
supplemented	O
with	O
10	O
%	O
fetal	O
bovine	O
serum	O
(	O
FBS	O
)	O
,	O
50	O
U	O
/	O
mL	O
penicillin	O
and	O
50	O
mg	O
/	O
mL	O
streptomycin	O
and	O
nonessential	O
amino	O
acids	O
(	O
Gibco	O
BRL	O
,	O
Paisley	O
,	O
UK	O
)	O
.	O

RNA	O
preparation	O
and	O
semiquantitative	O
reverse	O
transcriptase	O
-	O
polymerase	O
chain	O
reaction	O
(	O
RT	O
-	O
PCR	O
)	O
analysis	O

We	O
determined	O
RNA	O
expression	O
levels	O
by	O
semiquantitative	O
RT	O
-	O
PCR	O
analysis	O
as	O
described	O
previously	O
(	O
Sugioka	O
et	O
al	O
.	O
2004	O
)	O
.	O

Total	O
RNA	O
was	O
isolated	O
from	O
HaCaT	O
cells	O
using	O
the	O
GeneElute	O
Mammalian	O
Total	O
RNA	O
Kit	O
(	O
Sigma	O
)	O
.	O

The	O
specific	O
primers	O
used	O
for	O
first	O
-	O
strand	O
cDNA	O
synthesis	O
and	O
PCR	O
were	O
as	O
follows	O
:	O
K16	O
[	O
forward	O
,	O
5	O
'	O
-	O
GAT	O
GCT	O
TGC	O
TCT	O
GAG	O
AGG	O
TC	O
-	O
3	O
'	O
,	O
and	O
reverse	O
,	O
5	O
'	O
-	O
CCA	O
GCA	O
AGA	O
TCT	O
GGT	O
ACT	O
CC	O
-	O
3	O
'	O
;	O
Gene	O
Bank	O
accession	O
no	O
.	O
NM	O
_	O
005557	O
(	O
National	O
Center	O
for	O
Biotechnology	O
Information	O
2007	O
)	O
]	O
;	O
c	O
-	O
Jun	O
(	O
forward	O
,	O
5	O
'	O
-	O
CCT	O
GTT	O
GCG	O
GCC	O
CCG	O
AAA	O
CT	O
-	O
3	O
'	O
,	O
and	O
reverse	O
,	O
5	O
'	O
-	O
ACC	O
ATG	O
CCT	O
GCC	O
CCG	O
TTG	O
AC	O
-	O
3	O
'	O
;	O
NM	O
_	O
002228	O
)	O
;	O
c	O
-	O
Fos	O
(	O
forward	O
,	O
5	O
'	O
-	O
TTT	O
GCC	O
TAA	O
CCG	O
CCA	O
CGA	O
TGA	O
T	O
-	O
3	O
'	O
,	O
and	O
reverse	O
,	O
5	O
'	O
-	O
TTG	O
CCG	O
CTT	O
TCT	O
GCC	O
ACC	O
TC	O
-	O
3	O
'	O
;	O
NM	O
_	O
005252	O
)	O
;	O
NRF2	O
(	O
forward	O
,	O
5	O
'	O
-	O
AGA	O
TTC	O
ACA	O
GGC	O
CTT	O
TCT	O
CG	O
-	O
3	O
'	O
,	O
and	O
reverse	O
,	O
5	O
'	O
-	O
CAG	O
CTC	O
TCC	O
CTA	O
CCG	O
TTG	O
GA	O
-	O
3	O
'	O
;	O
AF323119	O
)	O
;	O
KEAP1	O
(	O
forward	O
,	O
5	O
'	O
-	O
CAG	O
AGG	O
TGG	O
TGG	O
TGT	O
TGC	O
TTA	O
T	O
-	O
3	O
'	O
,	O
and	O
reverse	O
,	O
5	O
'	O
-	O
AGC	O
TCG	O
TTC	O
ATG	O
ATG	O
CCA	O
AAG	O
-	O
3	O
'	O
;	O
NM	O
_	O
012289	O
)	O
;	O
TXN	O
(	O
forward	O
,	O
5	O
'	O
-	O
CAG	O
GGG	O
AAT	O
GAA	O
AGA	O
AAG	O
G	O
-	O
3	O
'	O
,	O
and	O
reverse	O
,	O
5	O
'	O
-	O
CAA	O
GGT	O
GAA	O
GCA	O
GAT	O
CG	O
-	O
3	O
'	O
;	O
NM	O
_	O
003329	O
)	O
,	O
and	O
glyceraldehyde	O
3	O
-	O
phosphate	O
dehydrogenase	O
(	O
GAPDH	O
)	O
as	O
a	O
loading	O
control	O
(	O
forward	O
,	O
5	O
'	O
-	O
ACC	O
ACA	O
GTC	O
CAT	O
GCC	O
ATC	O
AC	O
-	O
3	O
'	O
,	O
and	O
reverse	O
,	O
5	O
'	O
-	O
TCC	O
ACC	O
ACC	O
CTG	O
TTG	O
CTG	O
TA	O
-	O
3	O
'	O
,	O
NM	O
_	O
002046	O
)	O
.	O

PCR	O
products	O
were	O
separated	O
on	O
a	O
1	O
.	O
8	O
%	O
agarose	O
gel	O
and	O
stained	O
with	O
ethidium	O
bromide	O
.	O

Western	O
blot	O
analysis	O

We	O
performed	O
Western	O
blot	O
analysis	O
as	O
described	O
previously	O
(	O
Sugioka	O
et	O
al	O
.	O
2004	O
)	O
.	O

Briefly	O
,	O
nuclear	O
and	O
cytoplasmic	O
proteins	O
were	O
extracted	O
using	O
the	O
NE	O
-	O
PER	O
nuclear	O
and	O
cytoplasmic	O
extraction	O
kit	O
(	O
Pierce	O
,	O
Rockford	O
,	O
IL	O
,	O
USA	O
)	O
according	O
to	O
the	O
manufacturer	O
'	O
s	O
protocol	O
.	O

For	O
protein	O
extraction	O
,	O
the	O
cells	O
were	O
lysed	O
in	O
a	O
buffer	O
containing	O
complete	O
protease	O
inhibitor	O
cocktail	O
.	O

We	O
measured	O
protein	O
concentrations	O
using	O
the	O
DC	O
Protein	O
Assay	O
Kit	O
(	O
Bio	O
-	O
Rad	O
,	O
Richmond	O
,	O
CA	O
,	O
USA	O
)	O
.	O

Equal	O
amounts	O
of	O
protein	O
were	O
then	O
resolved	O
by	O
sodium	O
dodecyl	O
sulfate	O
-	O
polyacrylamide	O
gel	O
electrophoresis	O
(	O
SDS	O
-	O
PAGE	O
)	O
and	O
transferred	O
to	O
a	O
polyvinylidene	O
fluoride	O
membrane	O
(	O
Amersham	O
Biosciences	O
,	O
Bucks	O
,	O
UK	O
)	O
.	O

Immunoblotting	O
was	O
carried	O
out	O
with	O
specific	O
antibodies	O
in	O
Tris	O
-	O
buffered	O
saline	O
with	O
0	O
.	O
05	O
%	O
Tween	O
20	O
.	O

The	O
primary	O
antibodies	O
were	O
as	O
follows	O
:	O
K16	O
(	O
Neomarkers	O
,	O
Fremont	O
,	O
CA	O
,	O
USA	O
)	O
,	O
NRF2	O
and	O
KEAP1	O
(	O
Santa	O
Cruz	O
Biotechnology	O
,	O
Santa	O
Cruz	O
,	O
CA	O
,	O
USA	O
)	O
,	O
c	O
-	O
Jun	O
(	O
Cell	O
Signaling	O
,	O
Beverly	O
,	O
MA	O
,	O
USA	O
)	O
,	O
and	O
beta	O
-	O
actin	O
(	O
Sigma	O
)	O
.	O

After	O
washing	O
,	O
the	O
membranes	O
were	O
probed	O
with	O
horseradish	B
peroxidase	O
-	O
conjugated	O
secondary	O
antibodies	O
and	O
developed	O
by	O
chemiluminescence	O
using	O
the	O
ECL	O
Plus	O
Detection	O
Kit	O
(	O
Amersham	O
Biosciences	O
)	O
.	O

Plasmids	O
,	O
transfections	O
,	O
and	O
luciferase	O
assays	O

Human	B
K16	O
promoter	O
regions	O
of	O
varying	O
lengths	O
(	O
pXK	O
-	O
1	O
,	O
3	O
,	O
4	O
,	O
5	O
-	O
1	O
,	O
and	O
5	O
-	O
2	O
)	O
were	O
provided	O
by	O
Y	O
-	O
N	O
Wang	O
(	O
National	O
Cheng	O
Kung	O
University	O
,	O
Taiwan	O
)	O
.	O

These	O
DNA	O
fragments	O
were	O
prepared	O
from	O
HaCaT	O
cells	O
and	O
were	O
ligated	O
into	O
the	O
pXP	O
-	O
1	O
luciferase	O
vector	O
(	O
Wang	O
and	O
Chang	O
2003	O
)	O
.	O

The	O
p3xARE	O
/	O
Luc	O
vector	O
,	O
harboring	O
three	O
tandem	O
repeats	O
of	O
ARE	O
,	O
was	O
donated	O
by	O
X	O
.	O
L	O
.	O

Chen	O
(	O
Discovery	O
Research	O
,	O
AtheroGenics	O
Inc	O
.	O
,	O
Alpharetta	O
,	O
GA	O
,	O
USA	O
)	O
(	O
Chen	O
et	O
al	O
.	O
2003	O
)	O
.	O

The	O
wild	O
-	O
type	O
NRF2	O
expression	O
vector	O
(	O
WT	O
-	O
NRF2	O
)	O
was	O
a	O
gift	O
from	O
H	O
.	O
S	O
.	O

So	O
(	O
Wonkwang	O
University	O
School	O
of	O
Medicine	O
,	O
Korea	O
)	O
(	O
So	O
et	O
al	O
.	O
2006	O
)	O
.	O

NRF2	O
cDNA	O
was	O
subcloned	O
into	O
a	O
pcDNA3	O
.	O
1	O
(	O
+	O
)	O
vector	O
(	O
Invitrogen	O
,	O
San	O
Diego	O
,	O
CA	O
,	O
USA	O
)	O
.	O

For	O
the	O
transfection	O
of	O
reporter	O
plasmids	O
,	O
we	O
seeded	O
HaCaT	O
cells	O
into	O
six	O
-	O
well	O
plates	O
at	O
a	O
density	O
of	O
80	O
%	O
the	O
previous	O
day	O
.	O

Cells	O
were	O
then	O
transfected	O
with	O
a	O
total	O
of	O
each	O
luciferase	O
reporter	O
construct	O
(	O
2	O
.	O
5	O
mu	O
g	O
)	O
using	O
LipofectAMINE	O
plus	O
(	O
Invitrogen	O
)	O
.	O

To	O
control	O
for	O
the	O
efficiency	O
of	O
transfection	O
,	O
Renilla	O
luciferase	O
gene	O
expression	O
was	O
monitored	O
using	O
either	O
the	O
pRL	O
-	O
CMV	O
or	O
pRL	O
-	O
TK	O
vectors	O
(	O
Promega	O
,	O
Madison	O
,	O
WI	O
,	O
USA	O
)	O
.	O

For	O
overexpression	O
of	O
WT	O
-	O
NRF2	O
,	O
we	O
normalized	O
the	O
total	O
plasmid	O
concentration	O
using	O
the	O
pcDNA3	O
.	O
1	O
(	O
+	O
)	O
empty	O
vector	O
.	O

Thirty	O
-	O
six	O
hours	O
after	O
transfection	O
,	O
the	O
medium	O
was	O
replaced	O
with	O
fresh	O
medium	O
containing	O
either	O
vehicle	O
(	O
PBS	O
)	O
or	O
iAs	O
for	O
6	O
hr	O
.	O

After	O
iAs	O
exposure	O
,	O
we	O
harvested	O
cells	O
and	O
analyzed	O
them	O
for	O
luciferase	O
activity	O
using	O
a	O
Dual	O
-	O
Luciferase	O
Reporter	O
Assay	O
System	O
(	O
Promega	O
)	O
.	O

For	O
the	O
investigation	O
of	O
the	O
role	O
of	O
NRF2	O
in	O
regulating	O
K16	O
gene	O
expression	O
,	O
transfection	O
of	O
an	O
NRF2	O
expression	O
plasmid	O
into	O
HaCaT	O
cells	O
was	O
carried	O
out	O
using	O
LipofectAMINE	O
2000	O
(	O
Invitrogen	O
)	O
.	O

Cells	O
were	O
cultured	O
in	O
100	O
-	O
mm	O
plates	O
24	O
hr	O
before	O
transfection	O
.	O

The	O
expression	O
plasmid	O
WT	O
-	O
NRF2	O
(	O
15	O
mu	O
g	O
)	O
was	O
then	O
transfected	O
into	O
the	O
cells	O
for	O
48	O
-	O
60	O
hr	O
.	O

As	O
a	O
negative	O
control	O
,	O
we	O
used	O
15	O
mu	O
g	O
of	O
the	O
pcDNA3	O
.	O
1	O
(	O
+	O
)	O
empty	O
vector	O
.	O

Electrophoretic	O
mobility	O
-	O
shift	O
assays	O
(	O
EMSA	O
)	O

We	O
extracted	O
and	O
measured	O
nuclear	O
proteins	O
as	O
described	O
above	O
.	O

Nuclear	O
protein	O
/	O
DNA	O
complexes	O
were	O
subjected	O
to	O
electrophoresis	O
in	O
nondenaturing	O
5	O
%	O
polyacrylamide	O
gels	O
containing	O
2	O
%	O
glycerol	O
in	O
0	O
.	O
25	O
%	O
Tris	O
-	O
borate	O
/	O
EDTA	O
buffer	O
and	O
transferred	O
to	O
Hybond	O
-	O
N	O
+	O
nylon	O
transfer	O
membranes	O
(	O
Amersham	O
Biosciences	O
)	O
for	O
detection	O
using	O
the	O
Light	O
-	O
Shift	O
EMSA	O
kit	O
(	O
Pierce	O
)	O
according	O
to	O
the	O
manufacturer	O
'	O
s	O
protocol	O
,	O
with	O
minor	O
modifications	O
.	O

We	O
incubated	O
10	O
-	O
mu	O
g	O
aliquots	O
of	O
nuclear	O
extract	O
with	O
the	O
DNA	O
probe	O
in	O
a	O
binding	O
reaction	O
buffer	O
containing	O
10	O
mM	O
Tris	O
/	O
HCl	O
(	O
pH	O
7	O
.	O
6	O
)	O
,	O
50	O
mM	O
KCl	O
,	O
0	O
.	O
5	O
mM	O
dithiothreitol	O
,	O
0	O
.	O
25	O
mM	O
EDTA	O
,	O
5	O
%	O
glycerol	O
,	O
2	O
.	O
5	O
mM	O
MgCl2	O
,	O
0	O
.	O
05	O
%	O
NP	O
-	O
40	O
detergent	O
,	O
and	O
2	O
mu	O
g	O
of	O
poly	O
(	O
dI	O
-	O
dC	O
)	O
.	O
poly	O
(	O
dI	O
-	O
dC	O
)	O
for	O
30	O
min	O
at	O
room	O
temperature	O
.	O

For	O
supershift	O
assays	O
,	O
2	O
mu	O
g	O
of	O
either	O
a	O
polyclonal	O
anti	O
-	O
NRF2	O
or	O
an	O
anti	O
-	O
c	O
-	O
Jun	O
antibody	O
(	O
Santa	O
Cruz	O
Biotechnology	O
)	O
was	O
added	O
with	O
the	O
nuclear	O
protein	O
for	O
2	O
hr	O
at	O
4	O
degrees	O
C	O
before	O
the	O
labeled	O
oligonucleotide	O
probe	O
was	O
added	O
.	O

Biotin	O
-	O
labeled	O
,	O
double	O
-	O
stranded	O
oligonucleotides	O
WT	O
-	O
K16ARE	O
(	O
-	O
157	O
/	O
-	O
132	O
,	O
5	O
'	O
-	O
GGGGAACCTGGAGTCAGCAG	O
-	O
TAGGA	O
-	O
3	O
'	O
)	O
,	O
containing	O
an	O
ARE	O
site	O
(	O
-	O
148	O
/	O
-	O
140	O
,	O
underlined	O
)	O
in	O
the	O
human	B
K16	O
promoter	O
region	O
,	O
and	O
Mut	O
-	O
K16ARE	O
(	O
5	O
'	O
-	O
GGGGAA	O
-	O
CCTGGAGTCAaaAGTTAGGA	O
-	O
3	O
'	O
,	O
mutated	O
GC	O
box	O
in	O
the	O
ARE	O
)	O
were	O
prepared	O
by	O
Fasmac	O
(	O
Kanagawa	O
,	O
Japan	O
)	O
.	O

A	O
consensus	O
ARE	O
probe	O
was	O
purchased	O
from	O
Panomics	O
,	O
Inc	O
.	O

(	O
Redwood	O
City	O
,	O
CA	O
,	O
USA	O
)	O
.	O

For	O
competition	O
binding	O
of	O
the	O
K16	O
ARE	O
-	O
complexes	O
,	O
we	O
used	O
an	O
unlabeled	O
AP	O
-	O
1	O
consensus	O
oligonucleotide	O
(	O
5	O
'	O
-	O
TATC	O
-	O
GATAAGCTATGAGTCATCCG	O
-	O
3	O
'	O
)	O
.	O

The	O
binding	O
specificity	O
was	O
confirmed	O
in	O
each	O
case	O
by	O
the	O
addition	O
of	O
a	O
100	O
-	O
fold	O
molar	O
excess	O
of	O
unlabeled	O
oligonucleotide	O
.	O

CHX	O
chase	O
experiment	O

We	O
investigated	O
the	O
posttranscriptional	O
regulation	O
of	O
both	O
the	O
steady	O
-	O
state	O
levels	O
and	O
half	O
-	O
life	O
of	O
the	O
NRF2	O
protein	O
by	O
CHX	O
chase	O
analysis	O
.	O

Cells	O
were	O
incubated	O
in	O
serum	O
-	O
free	O
medium	O
in	O
the	O
absence	O
or	O
presence	O
of	O
iAs	O
for	O
6	O
hr	O
.	O

The	O
culture	O
medium	O
was	O
then	O
replaced	O
with	O
serum	O
-	O
free	O
medium	O
containing	O
CHX	O
(	O
100	O
mu	O
g	O
/	O
mL	O
)	O
.	O

We	O
prepared	O
cell	O
lysates	O
at	O
0	O
,	O
10	O
,	O
30	O
,	O
60	O
,	O
120	O
,	O
and	O
240	O
min	O
after	O
iAs	O
treatment	O
.	O

Whole	O
-	O
cell	O
lysates	O
were	O
resolved	O
by	O
SDS	O
-	O
PAGE	O
and	O
immunoblotted	O
with	O
antibodies	O
against	O
NRF2	O
.	O

Statistics	O

All	O
the	O
data	O
generated	O
from	O
at	O
least	O
three	O
independent	O
experiments	O
and	O
expressed	O
as	O
the	O
mean	O
+	O
/	O
-	O
SD	O
were	O
analyzed	O
by	O
the	O
Student	O
'	O
s	O
t	O
-	O
test	O
.	O

Statistical	O
comparisons	O
were	O
made	O
by	O
logarithmic	O
transformation	O
of	O
the	O
normalized	O
values	O
.	O

We	O
considered	O
p	O
-	O
values	O
<	O
0	O
.	O
01	O
to	O
be	O
statistically	O
significant	O
.	O

Results	O

K16	O
expression	O
is	O
induced	O
by	O
iAs	O
in	O
HaCaT	O
cells	O

We	O
wanted	O
to	O
determine	O
whether	O
the	O
K16	O
mRNA	O
is	O
transcriptionally	O
regulated	O
by	O
iAs	O
,	O
and	O
treated	O
HaCaT	O
cells	O
with	O
this	O
compound	O
for	O
various	O
time	O
periods	O
over	O
a	O
range	O
of	O
doses	O
.	O

After	O
treatment	O
of	O
HaCaT	O
cells	O
with	O
1	O
-	O
20	O
mu	O
M	O
iAs	O
,	O
the	O
expression	O
of	O
K16	O
mRNA	O
was	O
increased	O
compared	O
with	O
the	O
control	O
at	O
6	O
hr	O
(	O
Figure	O
1A	O
)	O
but	O
had	O
declined	O
to	O
basal	O
levels	O
at	O
24	O
hr	O
.	O

The	O
increase	O
in	O
the	O
K16	O
protein	O
levels	O
after	O
6	O
hr	O
of	O
iAs	O
exposure	O
was	O
just	O
detectable	O
at	O
10	O
-	O
20	O
mu	O
M	O
,	O
but	O
a	O
dose	O
-	O
dependent	O
increase	O
was	O
more	O
evident	O
at	O
10	O
hr	O
(	O
Figure	O
1B	O
)	O
.	O

This	O
enhancement	O
of	O
K16	O
expression	O
had	O
declined	O
to	O
basal	O
levels	O
at	O
24	O
hr	O
.	O

Identification	O
of	O
the	O
iAs	O
responsive	O
region	O
in	O
the	O
K16	O
gene	O
promoter	O

To	O
investigate	O
the	O
mechanisms	O
underlying	O
the	O
transactivation	O
of	O
the	O
K16	O
gene	O
by	O
iAs	O
,	O
we	O
first	O
examined	O
the	O
response	O
of	O
the	O
K16	O
regulatory	O
region	O
to	O
this	O
compound	O
using	O
a	O
luciferase	O
reporter	O
gene	O
assay	O
.	O

The	O
dose	O
-	O
dependent	O
activation	O
of	O
K16	O
transcription	O
after	O
iAs	O
treatment	O
was	O
observed	O
with	O
a	O
construct	O
containing	O
a	O
515	O
-	O
bp	O
fragment	O
of	O
the	O
K16	O
promoter	O
(	O
Figure	O
2A	O
)	O
.	O

To	O
further	O
elucidate	O
the	O
region	O
containing	O
the	O
iAs	O
responsive	O
element	O
,	O
we	O
examined	O
a	O
series	O
of	O
deletions	O
of	O
the	O
5	O
'	O
-	O
flanking	O
region	O
of	O
K16	O
gene	O
.	O

The	O
ARE	O
sequence	O
in	O
the	O
pXK	O
-	O
5	O
-	O
1	O
vector	O
contains	O
an	O
activator	O
protein	O
-	O
1	O
(	O
AP	O
-	O
1	O
)	O
-	O
like	O
element	O
followed	O
by	O
a	O
GC	O
box	O
.	O

As	O
shown	O
in	O
Figure	O
2B	O
,	O
an	O
enhancement	O
in	O
the	O
reporter	O
activity	O
levels	O
was	O
observed	O
for	O
the	O
promoter	O
constructs	O
,	O
pXK	O
-	O
1	O
,	O
3	O
,	O
4	O
,	O
and	O
5	O
-	O
1	O
,	O
in	O
response	O
to	O
20	O
mu	O
M	O
iAs	O
.	O

A	O
decline	O
in	O
reporter	O
activity	O
,	O
however	O
,	O
depended	O
on	O
the	O
number	O
of	O
AP	O
-	O
1	O
-	O
like	O
sites	O
,	O
and	O
the	O
results	O
for	O
the	O
pXK	O
-	O
5	O
-	O
1	O
construct	O
show	O
also	O
that	O
ARE	O
is	O
activated	O
by	O
iAs	O
.	O

In	O
contrast	O
,	O
no	O
significant	O
activation	O
was	O
observed	O
using	O
a	O
pXK	O
-	O
5	O
-	O
2	O
construct	O
in	O
response	O
to	O
20	O
mu	O
M	O
iAs	O
.	O

Expression	O
of	O
AP	O
-	O
1	O
transcriptions	O
factor	O
and	O
c	O
-	O
Jun	O
production	O
following	O
iAs	O
treatment	O

We	O
examined	O
AP	O
-	O
1	O
transcription	O
factors	O
c	O
-	O
Jun	O
and	O
c	O
-	O
Fos	O
expression	O
in	O
iAs	O
-	O
treated	O
HaCaT	O
cells	O
by	O
semiquantitative	O
RT	O
-	O
PCR	O
.	O

iAs	O
-	O
induced	O
c	O
-	O
Jun	O
expression	O
was	O
observed	O
during	O
the	O
first	O
3	O
hr	O
after	O
treatment	O
(	O
data	O
not	O
shown	O
)	O
.	O

An	O
appreciable	O
induction	O
of	O
c	O
-	O
Jun	O
was	O
also	O
confirmed	O
after	O
6	O
hr	O
,	O
but	O
this	O
was	O
down	O
-	O
regulated	O
by	O
24	O
hr	O
after	O
iAs	O
treatment	O
(	O
Figure	O
3A	O
)	O
.	O

In	O
contrast	O
,	O
the	O
expression	O
of	O
c	O
-	O
Fos	O
was	O
only	O
transiently	O
detectable	O
at	O
3	O
hr	O
(	O
data	O
not	O
shown	O
)	O
but	O
was	O
not	O
observed	O
during	O
the	O
6	O
-	O
24	O
hr	O
period	O
of	O
this	O
experiment	O
.	O

As	O
shown	O
in	O
Figure	O
3B	O
,	O
iAs	O
-	O
enhanced	O
c	O
-	O
Jun	O
production	O
can	O
be	O
observed	O
in	O
a	O
dose	O
-	O
dependent	O
manner	O
at	O
6	O
hr	O
,	O
but	O
it	O
declines	O
from	O
10	O
to	O
24	O
hr	O
.	O

iAs	O
potently	O
induces	O
the	O
translocation	O
of	O
NRF2	O
and	O
activates	O
the	O
ARE	O
of	O
the	O
K16	O
promoter	O

The	O
results	O
of	O
our	O
reporter	O
assays	O
suggested	O
that	O
iAs	O
stimulates	O
not	O
only	O
the	O
AP	O
-	O
1	O
-	O
like	O
sites	O
but	O
also	O
the	O
ARE	O
site	O
within	O
the	O
K16	O
gene	O
promoter	O
in	O
HaCaT	O
cells	O
(	O
Figure	O
3	O
)	O
.	O

In	O
addition	O
,	O
several	O
oxidative	O
stress	O
agents	O
and	O
toxic	O
chemicals	O
,	O
including	O
iAs	O
,	O
have	O
been	O
reported	O
to	O
induce	O
the	O
expression	O
of	O
ARE	O
-	O
dependent	O
genes	O
in	O
several	O
cell	O
types	O
(	O
Pi	O
et	O
al	O
.	O
2003	O
;	O
Sakurai	O
et	O
al	O
.	O
2005	O
)	O
.	O

On	O
the	O
basis	O
of	O
our	O
observations	O
and	O
some	O
recent	O
reports	O
,	O
we	O
thus	O
hypothesized	O
that	O
iAs	O
would	O
have	O
the	O
ability	O
to	O
activate	O
the	O
ARE	O
of	O
the	O
K16	O
gene	O
promoter	O
directly	O
,	O
resulting	O
in	O
the	O
induction	O
of	O
K16	O
expression	O
in	O
HaCaT	O
cells	O
.	O

To	O
confirm	O
that	O
the	O
K16	O
ARE	O
indeed	O
functions	O
as	O
an	O
iAs	O
-	O
responsive	O
transcriptional	O
control	O
element	O
,	O
we	O
performed	O
transient	O
transfections	O
of	O
HaCaT	O
cells	O
with	O
a	O
p3xARE	O
/	O
Luc	O
construct	O
and	O
then	O
subjected	O
these	O
cells	O
to	O
iAs	O
for	O
6	O
hr	O
.	O

As	O
shown	O
in	O
Figure	O
4A	O
,	O
treatment	O
of	O
HaCaT	O
cells	O
with	O
iAs	O
results	O
in	O
a	O
dramatic	O
increase	O
in	O
ARE	O
-	O
driven	O
promoter	O
activity	O
.	O

Likewise	O
,	O
EMSA	O
using	O
a	O
consensus	O
ARE	O
probe	O
show	O
that	O
iAs	O
-	O
induced	O
ARE	O
-	O
binding	O
complexes	O
increase	O
markedly	O
,	O
in	O
a	O
dose	O
-	O
dependent	O
fashion	O
(	O
Figure	O
4B	O
)	O
.	O

These	O
results	O
indicate	O
that	O
iAs	O
has	O
the	O
ability	O
to	O
activate	O
the	O
ARE	O
-	O
driven	O
genes	O
.	O

We	O
performed	O
further	O
EMSA	O
experiments	O
using	O
an	O
ARE	O
probe	O
specific	O
to	O
the	O
K16	O
proximal	O
promoter	O
region	O
(	O
WT	O
-	O
K16ARE	O
)	O
and	O
found	O
that	O
K16ARE	O
-	O
nuclear	O
protein	O
complexes	O
formation	O
is	O
augmented	O
by	O
iAs	O
in	O
a	O
dose	O
-	O
dependent	O
manner	O
(	O
Figure	O
4C	O
)	O
.	O

Moreover	O
,	O
the	O
formation	O
of	O
these	O
complexes	O
is	O
specifically	O
inhibited	O
by	O
the	O
addition	O
of	O
excess	O
unlabeled	O
oligonucleotide	O
competitor	O
(	O
Figure	O
4B	O
,	O
C	O
)	O
,	O
whereas	O
an	O
excess	O
of	O
an	O
unlabeled	O
AP	O
-	O
1	O
probe	O
competes	O
only	O
marginally	O
for	O
K16ARE	O
binding	O
(	O
Figure	O
4C	O
)	O
.	O

The	O
NRF2	O
transcription	O
factor	O
has	O
been	O
shown	O
to	O
bind	O
to	O
AREs	O
upon	O
translocation	O
into	O
the	O
nucleus	O
,	O
resulting	O
in	O
the	O
induction	O
of	O
ARE	O
-	O
mediated	O
genes	O
(	O
Wakabayashi	O
et	O
al	O
.	O
2004	O
)	O
.	O

To	O
examine	O
whether	O
iAs	O
induces	O
and	O
translocates	O
NRF2	O
into	O
the	O
nucleus	O
in	O
HaCaT	O
cells	O
,	O
we	O
treated	O
these	O
cells	O
with	O
iAs	O
for	O
either	O
3	O
or	O
6	O
hr	O
.	O

As	O
shown	O
in	O
Figure	O
4D	O
,	O
a	O
dose	O
-	O
dependent	O
accumulation	O
of	O
NRF2	O
protein	O
was	O
observed	O
in	O
the	O
nucleus	O
upon	O
treatment	O
with	O
iAs	O
for	O
6	O
hr	O
.	O

This	O
was	O
not	O
observed	O
in	O
the	O
parallel	O
experiment	O
performed	O
over	O
the	O
3	O
-	O
hr	O
time	O
course	O
.	O

Supershift	O
EMSA	O
analysis	O
using	O
an	O
NRF2	O
antibody	O
showed	O
that	O
the	O
iAs	O
-	O
induced	O
and	O
iAs	O
-	O
translocated	O
NRF2	O
protein	O
binds	O
to	O
the	O
WT	O
-	O
K16ARE	O
probe	O
containing	O
the	O
ARE	O
sequence	O
of	O
the	O
K16	O
proximal	O
promoter	O
region	O
(	O
5	O
'	O
-	O
GGAGTCAGC	O
-	O
3	O
'	O
)	O
that	O
comprises	O
an	O
AP	O
-	O
1	O
-	O
like	O
site	O
and	O
a	O
GC	O
box	O
,	O
whereas	O
the	O
supershift	O
of	O
c	O
-	O
Jun	O
was	O
not	O
observed	O
(	O
Figure	O
4E	O
)	O
.	O

To	O
identify	O
whether	O
the	O
GC	O
box	O
is	O
dispensable	O
for	O
the	O
iAs	O
-	O
stimulated	O
binding	O
activity	O
of	O
NRF2	O
,	O
we	O
next	O
performed	O
EMSA	O
analyses	O
with	O
either	O
WT	O
-	O
or	O
a	O
Mut	O
-	O
K16ARE	O
probe	O
containing	O
an	O
intact	O
AP	O
-	O
1	O
-	O
like	O
element	O
but	O
a	O
mutated	O
GC	O
box	O
.	O

As	O
shown	O
in	O
Figure	O
4F	O
,	O
the	O
K16ARE	O
-	O
nuclear	O
protein	O
complexes	O
and	O
supershifted	O
bands	O
that	O
were	O
enhanced	O
by	O
iAs	O
treatment	O
were	O
largely	O
abolished	O
by	O
the	O
addition	O
of	O
the	O
Mut	O
-	O
K16ARE	O
probe	O
.	O

iAs	O
stabilizes	O
the	O
NRF2	O
protein	O

We	O
examined	O
the	O
effects	O
of	O
iAs	O
treatment	O
on	O
the	O
function	O
of	O
KEAP1	O
in	O
HaCaT	O
cells	O
.	O

Treatment	O
with	O
iAs	O
did	O
not	O
alter	O
the	O
expression	O
levels	O
of	O
KEAP1	O
mRNA	O
or	O
protein	O
over	O
either	O
a	O
3	O
or	O
6	O
hr	O
time	O
course	O
(	O
Figure	O
5A	O
)	O
.	O

Next	O
,	O
we	O
examined	O
the	O
effects	O
of	O
iAs	O
on	O
the	O
expression	O
of	O
NRF2	O
mRNA	O
in	O
HaCaT	O
cells	O
.	O

Exposure	O
to	O
iAs	O
did	O
not	O
significantly	O
alter	O
the	O
steady	O
-	O
state	O
levels	O
of	O
NRF2	O
mRNA	O
(	O
data	O
not	O
shown	O
)	O
.	O

Production	O
of	O
NRF2	O
protein	O
,	O
however	O
,	O
was	O
observed	O
to	O
increase	O
in	O
both	O
a	O
dose	O
-	O
and	O
time	O
-	O
dependent	O
manner	O
(	O
Figure	O
4D	O
)	O
.	O

To	O
further	O
examine	O
the	O
stabilization	O
of	O
NRF2	O
protein	O
by	O
iAs	O
,	O
we	O
monitored	O
the	O
decay	O
of	O
basal	O
and	O
iAs	O
-	O
induced	O
NRF2	O
proteins	O
after	O
inhibition	O
of	O
protein	O
synthesis	O
by	O
CHX	O
(	O
Figure	O
5B	O
)	O
.	O

The	O
results	O
of	O
this	O
analysis	O
revealed	O
that	O
the	O
NRF2	O
protein	O
levels	O
decrease	O
by	O
approximately	O
50	O
%	O
within	O
30	O
min	O
of	O
treatment	O
with	O
CHX	O
in	O
cells	O
that	O
had	O
not	O
been	O
exposed	O
to	O
iAs	O
.	O

Only	O
trace	O
amounts	O
of	O
NRF2	O
are	O
then	O
detectable	O
after	O
60	O
min	O
of	O
exposure	O
to	O
CHX	O
in	O
these	O
cells	O
.	O

The	O
HaCaT	O
cells	O
were	O
then	O
pretreated	O
with	O
iAs	O
for	O
6	O
hr	O
before	O
their	O
exposure	O
to	O
CHX	O
in	O
a	O
similar	O
timecourse	O
experiment	O
.	O

The	O
levels	O
of	O
NRF2	O
in	O
these	O
iAs	O
-	O
treated	O
cells	O
were	O
again	O
found	O
to	O
decrease	O
by	O
about	O
50	O
%	O
,	O
but	O
only	O
after	O
120	O
min	O
of	O
CHX	O
exposure	O
.	O

NRF2	O
plays	O
a	O
crucial	O
role	O
in	O
the	O
regulation	O
of	O
K16	O
gene	O
expression	O
in	O
HaCaT	O
cells	O

To	O
confirm	O
the	O
functional	O
role	O
of	O
NRF2	O
in	O
the	O
induction	O
of	O
K16	O
gene	O
expression	O
by	O
iAs	O
,	O
we	O
investigated	O
whether	O
the	O
expression	O
of	O
K16	O
mRNA	O
is	O
induced	O
by	O
the	O
overexpression	O
of	O
NRF2	O
(	O
WT	O
-	O
NRF2	O
)	O
in	O
HaCaT	O
cells	O
.	O

We	O
also	O
investigated	O
the	O
expression	O
of	O
the	O
detoxification	O
gene	O
TXN	O
,	O
which	O
is	O
highly	O
induced	O
by	O
a	O
variety	O
of	O
oxidative	O
stimuli	O
through	O
NRF2	O
-	O
mediated	O
ARE	O
transactivation	O
(	O
Kim	O
et	O
al	O
.	O
2001	O
)	O
.	O

The	O
expression	O
of	O
TXN	O
gene	O
in	O
untransfected	O
cells	O
after	O
treatment	O
with	O
iAs	O
was	O
stronger	O
than	O
that	O
of	O
the	O
control	O
cells	O
(	O
Figure	O
6A	O
)	O
.	O

When	O
the	O
cells	O
were	O
transfected	O
with	O
WT	O
-	O
NRF2	O
and	O
then	O
treated	O
with	O
or	O
without	O
iAs	O
,	O
the	O
expression	O
of	O
TXN	O
mRNA	O
was	O
augmented	O
markedly	O
compared	O
with	O
the	O
empty	O
-	O
vector	O
control	O
.	O

Similarly	O
,	O
the	O
expression	O
of	O
K16	O
mRNA	O
was	O
also	O
induced	O
in	O
cells	O
transfected	O
with	O
WT	O
-	O
NRF2	O
in	O
the	O
absence	O
or	O
presence	O
of	O
iAs	O
.	O

We	O
next	O
performed	O
a	O
transient	O
transfection	O
of	O
HaCaT	O
cells	O
with	O
the	O
pXK	O
-	O
5	O
-	O
1	O
luciferase	O
vector	O
together	O
with	O
the	O
WT	O
-	O
NRF2	O
vector	O
.	O

The	O
overexpression	O
of	O
NRF2	O
in	O
increasing	O
concentrations	O
resulted	O
in	O
significant	O
enhancement	O
of	O
the	O
ARE	O
-	O
mediated	O
K16	O
promoter	O
activation	O
(	O
Figure	O
6B	O
)	O
.	O

Discussion	O

In	O
the	O
present	O
study	O
,	O
we	O
showed	O
for	O
the	O
first	O
time	O
that	O
iAs	O
induces	O
the	O
transcriptional	O
activation	O
of	O
K16	O
in	O
the	O
human	B
keratinocyte	O
cell	O
line	O
,	O
HaCaT	O
,	O
through	O
the	O
ARE	O
present	O
in	O
its	O
gene	O
promoter	O
.	O

It	O
has	O
been	O
reported	O
previously	O
that	O
treatment	O
with	O
iAs	O
enhances	O
the	O
production	O
and	O
translocation	O
of	O
NRF2	O
into	O
the	O
nucleus	O
in	O
several	O
cell	O
types	O
.	O

However	O
,	O
until	O
now	O
it	O
has	O
remained	O
uncertain	O
whether	O
the	O
induction	O
of	O
NRF2	O
by	O
iAs	O
mediates	O
the	O
transcriptional	O
activation	O
of	O
the	O
K16	O
gene	O
in	O
keratinocytes	O
.	O

In	O
our	O
current	O
experiments	O
,	O
we	O
demonstrated	O
that	O
iAs	O
elongates	O
the	O
half	O
-	O
life	O
of	O
the	O
NRF2	O
protein	O
,	O
which	O
results	O
in	O
its	O
increased	O
expression	O
levels	O
.	O

Furthermore	O
,	O
this	O
iAs	O
-	O
induced	O
NRF2	O
protein	O
was	O
shown	O
to	O
bind	O
to	O
the	O
ARE	O
sequences	O
in	O
the	O
promoter	O
region	O
of	O
the	O
K16	O
gene	O
.	O

Finally	O
,	O
by	O
overexpressing	O
NRF2	O
,	O
we	O
have	O
clarified	O
that	O
its	O
induction	O
is	O
involved	O
in	O
not	O
only	O
the	O
gene	O
expression	O
of	O
the	O
detoxification	O
gene	O
TXN	O
,	O
but	O
also	O
in	O
the	O
upregulation	O
of	O
K16	O
expression	O
in	O
HaCaT	O
cells	O
through	O
the	O
ARE	O
in	O
the	O
K16	O
gene	O
promoter	O
.	O

These	O
experiments	O
indicate	O
an	O
important	O
and	O
novel	O
function	O
for	O
NRF2	O
in	O
the	O
regulation	O
of	O
K16	O
in	O
keratinocytes	O
and	O
also	O
help	O
to	O
further	O
explain	O
the	O
molecular	O
mechanisms	O
underlying	O
arsenic	O
-	O
mediated	O
epidermal	O
hyperkeratosis	O
.	O

In	O
our	O
present	O
experiments	O
,	O
the	O
expression	O
levels	O
of	O
K16	O
mRNA	O
and	O
protein	O
were	O
indeed	O
found	O
to	O
be	O
enhanced	O
by	O
iAs	O
in	O
a	O
dose	O
-	O
dependent	O
manner	O
(	O
Figure	O
1	O
)	O
.	O

In	O
addition	O
,	O
luciferase	O
assays	O
of	O
the	O
K16	O
promoter	O
revealed	O
that	O
iAs	O
enhances	O
its	O
activity	O
in	O
a	O
dose	O
-	O
dependent	O
fashion	O
,	O
which	O
is	O
stimulated	O
by	O
AP	O
-	O
1	O
-	O
like	O
sites	O
and	O
an	O
ARE	O
(	O
Figure	O
2	O
)	O
.	O

The	O
promoter	O
of	O
the	O
human	B
K16	O
gene	O
was	O
recently	O
cloned	O
and	O
sequenced	O
,	O
and	O
several	O
AP	O
-	O
1	O
-	O
like	O
sites	O
were	O
found	O
within	O
the	O
-	O
515	O
-	O
bp	O
region	O
of	O
the	O
gene	O
(	O
Wang	O
and	O
Chang	O
2003	O
)	O
.	O

AP	O
-	O
1	O
transcription	O
factor	O
can	O
be	O
formed	O
by	O
the	O
dimerization	O
of	O
either	O
Jun	O
or	O
Jun	O
/	O
Fos	O
family	O
members	O
(	O
Eferl	O
and	O
Wagner	O
2003	O
)	O
.	O

In	O
the	O
present	O
study	O
,	O
the	O
increased	O
expression	O
of	O
c	O
-	O
Jun	O
,	O
but	O
not	O
c	O
-	O
Fos	O
was	O
evident	O
in	O
the	O
nuclei	O
of	O
HaCaT	O
cells	O
after	O
iAs	O
treatment	O
(	O
Figure	O
3	O
)	O
.	O

Our	O
findings	O
thus	O
suggest	O
that	O
the	O
activation	O
of	O
c	O
-	O
Jun	O
/	O
AP	O
-	O
1	O
is	O
one	O
of	O
the	O
essential	O
steps	O
in	O
the	O
regulation	O
of	O
K16	O
gene	O
expression	O
by	O
iAs	O
exposure	O
in	O
HaCaT	O
cells	O
.	O

It	O
has	O
been	O
well	O
documented	O
that	O
the	O
ARE	O
core	O
sequence	O
includes	O
an	O
AP	O
-	O
1	O
-	O
like	O
binding	O
site	O
(	O
TGAC	O
/	O
GTCA	O
)	O
,	O
followed	O
by	O
a	O
GC	O
box	O
(	O
Rushmore	O
et	O
al	O
.	O
1991	O
;	O
Xie	O
et	O
al	O
.	O
1995	O
)	O
.	O

We	O
have	O
found	O
in	O
our	O
current	O
analyses	O
that	O
the	O
AP	O
-	O
1	O
-	O
like	O
site	O
within	O
the	O
K16	O
promoter	O
region	O
from	O
-	O
148	O
to	O
-	O
140	O
bp	O
(	O
5	O
'	O
-	O
GGAGTCAGC	O
-	O
3	O
'	O
)	O
resembles	O
a	O
consensus	O
ARE	O
sequence	O
.	O

Recent	O
studies	O
have	O
shown	O
that	O
AREs	O
can	O
be	O
specifically	O
bound	O
by	O
complexes	O
of	O
several	O
basic	O
-	O
leucine	O
zipper	O
transcription	O
factors	O
,	O
including	O
NRF2	O
(	O
Ishii	O
et	O
al	O
.	O
2000	O
;	O
Moi	O
et	O
al	O
.	O
1994	O
)	O
.	O

NRF2	O
heterodimerizes	O
with	O
either	O
AP	O
-	O
1	O
or	O
small	O
MAF	O
(	O
MAFG	O
,	O
MAFK	O
,	O
and	O
MAFF	O
)	O
proteins	O
(	O
MAF	O
,	O
v	O
-	O
maf	O
musculoaponeurotic	O
fibrosarcoma	O
oncogene	O
homolog	O
)	O
and	O
binds	O
to	O
the	O
ARE	O
to	O
induce	O
the	O
transcription	O
of	O
ARE	O
-	O
mediated	O
genes	O
(	O
Motohashi	O
et	O
al	O
.	O
2002	O
)	O
.	O

In	O
the	O
present	O
investigation	O
,	O
EMSA	O
and	O
supershift	O
assays	O
showed	O
that	O
the	O
NRF2	O
proteins	O
in	O
the	O
nuclei	O
bind	O
to	O
the	O
ARE	O
sequences	O
of	O
K16	O
promoter	O
region	O
after	O
iAs	O
exposure	O
.	O

iAs	O
-	O
induced	O
c	O
-	O
Jun	O
,	O
however	O
,	O
does	O
not	O
bind	O
to	O
this	O
ARE	O
(	O
Figure	O
4E	O
)	O
.	O

c	O
-	O
Jun	O
may	O
thus	O
act	O
on	O
other	O
AP	O
-	O
1	O
sites	O
within	O
the	O
K16	O
promoter	O
region	O
.	O

These	O
results	O
also	O
suggest	O
that	O
other	O
heterodimer	O
partners	O
of	O
NRF2	O
are	O
involved	O
in	O
the	O
ARE	O
regulation	O
of	O
K16	O
promoter	O
region	O
underlying	O
iAs	O
-	O
mediated	O
the	O
K16	O
gene	O
expression	O
.	O

Gel	O
shifts	O
with	O
an	O
K16Mut	O
-	O
ARE	O
probe	O
(	O
harboring	O
a	O
mutation	O
in	O
the	O
ARE	O
GC	O
box	O
)	O
clearly	O
show	O
that	O
the	O
ARE	O
sequence	O
in	O
the	O
K16	O
promoter	O
,	O
particularly	O
the	O
terminal	O
GC	O
dinucleotide	O
,	O
is	O
essential	O
for	O
mediating	O
iAs	O
-	O
induced	O
K16	O
transactivation	O
and	O
NRF2	O
binding	O
(	O
Figure	O
4F	O
)	O
.	O

Several	O
investigations	O
have	O
suggested	O
that	O
the	O
GC	O
nucleotides	O
within	O
the	O
ARE	O
are	O
essential	O
for	O
both	O
the	O
basal	O
and	O
oxidative	O
stress	O
-	O
induced	O
activities	O
of	O
the	O
ARE	O
-	O
related	O
genes	O
,	O
NAD	O
(	O
P	O
)	O
H	O
dehydrogenase	O
quinone	O
1	O
(	O
NQO1	O
)	O
and	O
glutamate	O
-	O
cysteine	O
ligase	O
catalytic	O
subunit	O
(	O
GCLC	O
)	O
(	O
Wasserman	O
and	O
Fahl	O
1997	O
;	O
Wild	O
et	O
al	O
.	O
1998	O
)	O
.	O

Our	O
current	O
results	O
are	O
consistent	O
with	O
these	O
earlier	O
studies	O
in	O
showing	O
that	O
the	O
formation	O
of	O
the	O
iAs	O
-	O
responsive	O
NRF2	O
/	O
ARE	O
complexes	O
is	O
reduced	O
by	O
a	O
mutation	O
in	O
the	O
GC	O
box	O
.	O

Collectively	O
,	O
our	O
present	O
observations	O
reveal	O
a	O
new	O
molecular	O
mechanism	O
in	O
which	O
iAs	O
-	O
induced	O
K16	O
gene	O
expression	O
is	O
also	O
regulated	O
by	O
activation	O
NRF2	O
/	O
ARE	O
pathways	O
.	O

It	O
has	O
been	O
widely	O
accepted	O
that	O
oxidative	O
stress	O
disrupts	O
sequestration	O
of	O
NRF2	O
by	O
KEAP1	O
,	O
permits	O
NRF2	O
translocation	O
to	O
the	O
nucleus	O
,	O
and	O
transactivates	O
the	O
expression	O
of	O
various	O
NRF2	O
-	O
mediated	O
genes	O
(	O
Dinkova	O
-	O
Kostova	O
et	O
al	O
.	O
2002	O
;	O
McMahon	O
et	O
al	O
.	O
2003	O
)	O
.	O

Our	O
present	O
study	O
showed	O
that	O
iAs	O
elongates	O
the	O
half	O
-	O
life	O
of	O
the	O
NRF2	O
protein	O
but	O
has	O
no	O
effects	O
upon	O
KEAP1	O
expression	O
(	O
Figure	O
5	O
)	O
.	O

Other	O
studies	O
have	O
also	O
demonstrated	O
that	O
the	O
production	O
of	O
NRF2	O
is	O
increased	O
by	O
various	O
inducers	O
via	O
posttranscriptional	O
control	O
(	O
Nguyen	O
et	O
al	O
.	O
2003	O
;	O
Stewart	O
et	O
al	O
.	O
2003	O
)	O
.	O

Several	O
earlier	O
reports	O
also	O
indicated	O
that	O
either	O
oxidative	O
stress	O
or	O
antioxidant	O
substances	O
stabilize	O
the	O
expression	O
of	O
the	O
NRF2	O
protein	O
,	O
either	O
by	O
directly	O
modifying	O
the	O
cysteine	O
residues	O
on	O
KEAP1	O
to	O
disrupt	O
the	O
NRF2	O
/	O
KEAP1	O
complex	O
(	O
Dinkova	O
-	O
Kostova	O
et	O
al	O
.	O
2002	O
)	O
or	O
by	O
facilitating	O
the	O
release	O
of	O
NRF2	O
through	O
the	O
phosphorylation	O
of	O
the	O
NRF2	O
/	O
KEAP1	O
complex	O
(	O
Bloom	O
and	O
Jaiswal	O
2003	O
)	O
.	O

These	O
findings	O
are	O
largely	O
consistent	O
with	O
our	O
present	O
finding	O
that	O
iAs	O
stabilizes	O
the	O
expression	O
of	O
NRF2	O
in	O
HaCaT	O
cells	O
by	O
elongating	O
the	O
protein	O
half	O
-	O
life	O
.	O

Recently	O
,	O
Wakabayashi	O
et	O
al	O
.	O

(	O
2003	O
)	O
demonstrated	O
that	O
NRF2	O
accumulates	O
in	O
the	O
nucleus	O
at	O
constitutively	O
high	O
levels	O
and	O
produces	O
various	O
cytoprotective	O
genes	O
in	O
embryonic	O
fibroblast	O
-	O
and	O
liver	O
-	O
derived	O
Keap1	O
-	O
null	O
mice	B
.	O

Surprisingly	O
,	O
these	O
Keap1	O
-	O
deficient	O
mice	B
also	O
show	O
a	O
thicker	O
stratum	O
corneum	O
epidermis	O
,	O
abnormal	O
keratinization	O
,	O
and	O
cornification	O
in	O
the	O
esophagus	O
and	O
forestomach	O
(	O
hyperkeratosis	O
)	O
.	O

K6	O
was	O
found	O
to	O
be	O
strongly	O
expressed	O
in	O
the	O
esophageal	O
epithelium	O
of	O
these	O
mice	B
.	O

These	O
results	O
indicate	O
that	O
K6	O
is	O
also	O
a	O
target	O
gene	O
of	O
NRF2	O
.	O

In	O
addition	O
,	O
the	O
promoter	O
of	O
the	O
K6	O
gene	O
bears	O
a	O
remarkable	O
sequence	O
similarity	O
to	O
the	O
K16	O
promoter	O
(	O
Jiang	O
et	O
al	O
.	O
1993	O
)	O
.	O

Therefore	O
,	O
we	O
examined	O
whether	O
K16	O
gene	O
expression	O
is	O
also	O
regulated	O
by	O
NRF2	O
.	O

In	O
the	O
present	O
study	O
,	O
the	O
gene	O
expression	O
and	O
transactivation	O
of	O
K16	O
were	O
dramatically	O
induced	O
by	O
transfection	O
with	O
WT	O
-	O
NRF2	O
via	O
in	O
HaCaT	O
cells	O
,	O
clearly	O
demonstrating	O
that	O
NRF2	O
acts	O
as	O
a	O
direct	O
transcriptional	O
regulator	O
of	O
the	O
K16	O
gene	O
(	O
Figure	O
6	O
)	O
.	O

In	O
addition	O
,	O
we	O
also	O
showed	O
that	O
transfection	O
of	O
HaCaT	O
cells	O
with	O
WT	O
-	O
NRF2	O
induces	O
the	O
expression	O
of	O
detoxification	O
gene	O
TXN	O
(	O
Figure	O
6A	O
)	O
.	O

NRF2	O
may	O
thus	O
have	O
a	O
major	O
role	O
to	O
play	O
in	O
the	O
development	O
of	O
hyperkeratosis	O
,	O
whereas	O
the	O
expression	O
and	O
induction	O
of	O
NRF2	O
is	O
implicated	O
in	O
cell	O
protection	O
against	O
a	O
variety	O
of	O
genotoxic	O
and	O
cytotoxic	O
effects	O
.	O

Hence	O
,	O
based	O
on	O
these	O
results	O
and	O
on	O
the	O
findings	O
from	O
studies	O
of	O
Keap1	O
knockout	O
mice	B
,	O
iAs	O
may	O
both	O
cause	O
hyperkeratosis	O
and	O
induce	O
detoxification	O
enzymes	O
via	O
the	O
modification	O
of	O
NRF2	O
.	O

Given	O
that	O
there	O
are	O
both	O
beneficial	O
and	O
adverse	O
effects	O
of	O
NRF2	O
activity	O
,	O
caution	O
will	O
therefore	O
be	O
needed	O
when	O
using	O
antioxidants	O
for	O
prevention	O
and	O
therapy	O
.	O

Although	O
further	O
investigations	O
are	O
needed	O
,	O
we	O
believe	O
that	O
our	O
findings	O
provide	O
important	O
clues	O
for	O
the	O
design	O
of	O
future	O
therapies	O
for	O
arsenic	O
-	O
mediated	O
hyperkeratosis	O
and	O
for	O
treatments	O
involving	O
the	O
molecular	O
targeting	O
of	O
NRF2	O
.	O

Conclusion	O

Our	O
findings	O
clearly	O
demonstrate	O
that	O
the	O
induction	O
of	O
the	O
K16	O
gene	O
in	O
human	B
keratinocytes	O
by	O
iAs	O
depends	O
on	O
NRF2	O
activation	O
.	O

Our	O
results	O
thus	O
represent	O
a	O
valuable	O
initial	O
effort	O
to	O
elucidate	O
the	O
relationship	O
between	O
the	O
K16	O
gene	O
and	O
the	O
NRF2	O
transcription	O
factor	O
,	O
which	O
may	O
be	O
responsible	O
for	O
hyperkeratosis	O
.	O

Identification	O
and	O
Analysis	O
of	O
Co	O
-	O
Occurrence	O
Networks	O
with	O
NetCutter	O

Abstract	O

Background	O

Co	O
-	O
occurrence	O
analysis	O
is	O
a	O
technique	O
often	O
applied	O
in	O
text	O
mining	O
,	O
comparative	O
genomics	O
,	O
and	O
promoter	O
analysis	O
.	O

The	O
methodologies	O
and	O
statistical	O
models	O
used	O
to	O
evaluate	O
the	O
significance	O
of	O
association	O
between	O
co	O
-	O
occurring	O
entities	O
are	O
quite	O
diverse	O
,	O
however	O
.	O

Methodology	O
/	O
Principal	O
Findings	O

We	O
present	O
a	O
general	O
framework	O
for	O
co	O
-	O
occurrence	O
analysis	O
based	O
on	O
a	O
bipartite	O
graph	O
representation	O
of	O
the	O
data	O
,	O
a	O
novel	O
co	O
-	O
occurrence	O
statistic	O
,	O
and	O
software	O
performing	O
co	O
-	O
occurrence	O
analysis	O
as	O
well	O
as	O
generation	O
and	O
analysis	O
of	O
co	O
-	O
occurrence	O
networks	O
.	O

We	O
show	O
that	O
the	O
overall	O
stringency	O
of	O
co	O
-	O
occurrence	O
analysis	O
depends	O
critically	O
on	O
the	O
choice	O
of	O
the	O
null	O
-	O
model	O
used	O
to	O
evaluate	O
the	O
significance	O
of	O
co	O
-	O
occurrence	O
and	O
find	O
that	O
random	O
sampling	O
from	O
a	O
complete	O
permutation	O
set	O
of	O
the	O
bipartite	O
graph	O
permits	O
co	O
-	O
occurrence	O
analysis	O
with	O
optimal	O
stringency	O
.	O

We	O
show	O
that	O
the	O
Poisson	O
-	O
binomial	O
distribution	O
is	O
the	O
most	O
natural	O
co	O
-	O
occurrence	O
probability	O
distribution	O
when	O
vertex	O
degrees	O
of	O
the	O
bipartite	O
graph	O
are	O
variable	O
,	O
which	O
is	O
usually	O
the	O
case	O
.	O

Calculation	O
of	O
Poisson	O
-	O
binomial	O
P	O
-	O
values	O
is	O
difficult	O
,	O
however	O
.	O

Therefore	O
,	O
we	O
propose	O
a	O
fast	O
bi	O
-	O
binomial	O
approximation	O
for	O
calculation	O
of	O
P	O
-	O
values	O
and	O
show	O
that	O
this	O
statistic	O
is	O
superior	O
to	O
other	O
measures	O
of	O
association	O
such	O
as	O
the	O
Jaccard	O
coefficient	O
and	O
the	O
uncertainty	O
coefficient	O
.	O

Furthermore	O
,	O
co	O
-	O
occurrence	O
analysis	O
of	O
more	O
than	O
two	O
entities	O
can	O
be	O
performed	O
using	O
the	O
same	O
statistical	O
model	O
,	O
which	O
leads	O
to	O
increased	O
signal	O
-	O
to	O
-	O
noise	O
ratios	O
,	O
robustness	O
towards	O
noise	O
,	O
and	O
the	O
identification	O
of	O
implicit	O
relationships	O
between	O
co	O
-	O
occurring	O
entities	O
.	O

Using	O
NetCutter	O
,	O
we	O
identify	O
a	O
novel	O
protein	O
biosynthesis	O
related	O
set	O
of	O
genes	O
that	O
are	O
frequently	O
coordinately	O
deregulated	O
in	O
human	B
cancer	O
related	O
gene	O
expression	O
studies	O
.	O

NetCutter	O
is	O
available	O
at	O
http	O
:	O
/	O
/	O
bio	O
.	O
ifom	O
-	O
ieo	O
-	O
campus	O
.	O
it	O
/	O
NetCutter	O
/	O
)	O
.	O

Conclusion	O

Our	O
approach	O
can	O
be	O
applied	O
to	O
any	O
set	O
of	O
categorical	O
data	O
where	O
co	O
-	O
occurrence	O
analysis	O
might	O
reveal	O
functional	O
relationships	O
such	O
as	O
clinical	O
parameters	O
associated	O
with	O
cancer	O
subtypes	O
or	O
SNPs	O
associated	O
with	O
disease	O
phenotypes	O
.	O

The	O
stringency	O
of	O
our	O
approach	O
is	O
expected	O
to	O
offer	O
an	O
advantage	O
in	O
a	O
variety	O
of	O
applications	O
.	O

Introduction	O

Biological	O
research	O
has	O
experienced	O
a	O
paradigm	O
shift	O
in	O
the	O
last	O
decade	O
catalyzed	O
by	O
the	O
availability	O
of	O
genome	O
sequences	O
and	O
the	O
resulting	O
development	O
of	O
high	O
-	O
throughput	O
technologies	O
.	O

The	O
large	O
data	O
volumes	O
produced	O
by	O
these	O
novel	O
technologies	O
are	O
often	O
published	O
as	O
supplementary	O
material	O
and	O
/	O
or	O
stored	O
in	O
extensive	O
data	O
repositories	O
[	O
1	O
]	O
.	O

Functional	O
interpretation	O
of	O
these	O
data	O
is	O
an	O
ongoing	O
challenge	O
.	O

Co	O
-	O
occurrence	O
analysis	O
,	O
based	O
on	O
the	O
hypothesis	O
that	O
co	O
-	O
occurring	O
entities	O
are	O
functionally	O
linked	O
,	O
is	O
a	O
technique	O
that	O
has	O
been	O
used	O
in	O
three	O
main	O
areas	O
of	O
biological	O
research	O
:	O

Co	O
-	O
occurrence	O
of	O
genes	O
in	O
sequenced	O
genomes	O
relies	O
on	O
the	O
fact	O
that	O
proteins	O
do	O
not	O
function	O
in	O
isolation	O
and	O
are	O
dependent	O
on	O
other	O
proteins	O
,	O
either	O
as	O
direct	O
binding	O
partners	O
,	O
or	O
as	O
catalysts	O
of	O
substrates	O
.	O

Thus	O
,	O
when	O
two	O
proteins	O
significantly	O
co	O
-	O
occur	O
in	O
a	O
large	O
number	O
of	O
genomes	O
or	O
can	O
be	O
observed	O
as	O
fusion	O
proteins	O
in	O
a	O
subset	O
of	O
genomes	O
,	O
they	O
are	O
likely	O
to	O
be	O
binding	O
partners	O
or	O
enzymes	O
needed	O
for	O
a	O
specific	O
metabolic	O
pathway	O
.	O

Examples	O
of	O
those	O
studies	O
have	O
been	O
reported	O
by	O
[	O
2	O
]	O
-	O
[	O
7	O
]	O
.	O

Text	O
mining	O
is	O
a	O
quickly	O
evolving	O
field	O
that	O
aims	O
at	O
developing	O
technologies	O
helping	O
to	O
cope	O
with	O
the	O
functional	O
interpretation	O
of	O
large	O
volumes	O
of	O
publications	O
.	O

Co	O
-	O
occurrence	O
of	O
gene	O
names	O
in	O
publication	O
abstracts	O
,	O
entire	O
publications	O
,	O
or	O
other	O
gene	O
-	O
related	O
databases	O
has	O
been	O
used	O
to	O
derive	O
co	O
-	O
occurrence	O
networks	O
with	O
clear	O
evidence	O
that	O
edges	O
in	O
those	O
networks	O
are	O
reflecting	O
functionally	O
relevant	O
relationships	O
[	O
8	O
]	O
-	O
[	O
11	O
]	O
.	O

Gene	O
names	O
have	O
also	O
been	O
analyzed	O
for	O
co	O
-	O
occurrence	O
with	O
other	O
entities	O
such	O
as	O
mutations	O
[	O
12	O
]	O
,	O
chemical	O
compounds	O
[	O
13	O
]	O
,	O
and	O
disease	O
related	O
keywords	O
[	O
14	O
]	O
.	O

From	O
the	O
resulting	O
networks	O
,	O
hypotheses	O
about	O
candidate	O
genes	O
involved	O
in	O
inherited	O
diseases	O
and	O
drug	O
targets	O
can	O
be	O
derived	O
.	O

Clustering	O
of	O
gene	O
related	O
publications	O
using	O
keywords	O
has	O
been	O
applied	O
to	O
enhance	O
the	O
quality	O
of	O
gene	O
expression	O
clusters	O
[	O
15	O
]	O
,	O
[	O
16	O
]	O
.	O

More	O
general	O
(	O
non	O
gene	O
-	O
centric	O
)	O
approaches	O
try	O
to	O
organize	O
the	O
literature	O
into	O
functional	O
areas	O
based	O
on	O
co	O
-	O
occurrence	O
of	O
MeSH	O
terms	O
,	O
keywords	O
,	O
diseases	O
,	O
phenotypes	O
,	O
chemicals	O
,	O
and	O
similar	O
objects	O
of	O
biomedical	O
research	O
interest	O
[	O
17	O
]	O
-	O
[	O
21	O
]	O
.	O

Co	O
-	O
occurrence	O
analysis	O
of	O
transcription	O
factor	O
binding	O
motifs	O
has	O
been	O
carried	O
out	O
in	O
a	O
variety	O
of	O
slightly	O
differing	O
ways	O
in	O
a	O
wide	O
range	O
of	O
organisms	O
,	O
including	O
humans	B
.	O

[	O
22	O
]	O
-	O
[	O
33	O
]	O
.	O

The	O
underlying	O
hypothesis	O
is	O
that	O
co	O
-	O
regulated	O
genes	O
,	O
identified	O
usually	O
by	O
gene	O
expression	O
studies	O
,	O
should	O
contain	O
specific	O
combinations	O
of	O
transcription	O
factor	O
binding	O
motifs	O
in	O
their	O
upstream	O
regulatory	O
regions	O
,	O
the	O
identification	O
of	O
which	O
would	O
allow	O
the	O
reverse	O
-	O
engineering	O
of	O
transcription	O
regulatory	O
networks	O
[	O
34	O
]	O
.	O

We	O
have	O
recently	O
applied	O
co	O
-	O
occurrence	O
analysis	O
to	O
studying	O
published	O
gene	O
expression	O
signatures	O
and	O
showed	O
that	O
co	O
-	O
occurrence	O
patterns	O
of	O
genes	O
reflect	O
cancer	O
signaling	O
pathways	O
[	O
35	O
]	O
.	O

Although	O
co	O
-	O
occurrence	O
analysis	O
has	O
a	O
respectable	O
history	O
,	O
the	O
methodologies	O
used	O
in	O
the	O
studies	O
mentioned	O
above	O
could	O
not	O
be	O
easily	O
applied	O
to	O
studying	O
gene	O
expression	O
signatures	O
.	O

There	O
are	O
three	O
main	O
reasons	O
that	O
dictated	O
the	O
use	O
of	O
a	O
different	O
approach	O
.	O

First	O
,	O
gene	O
expression	O
signatures	O
can	O
vary	O
in	O
size	O
by	O
orders	O
of	O
magnitude	O
.	O

Obviously	O
,	O
the	O
larger	O
a	O
signature	O
the	O
more	O
likely	O
it	O
is	O
to	O
find	O
two	O
or	O
more	O
genes	O
co	O
-	O
occurring	O
in	O
that	O
signature	O
.	O

Thus	O
,	O
the	O
significance	O
of	O
co	O
-	O
occurrences	O
must	O
be	O
evaluated	O
in	O
the	O
presence	O
of	O
considerable	O
heterogeneity	O
of	O
co	O
-	O
occurrence	O
probabilities	O
among	O
gene	O
lists	O
.	O

As	O
a	O
consequence	O
,	O
the	O
statistics	O
used	O
to	O
evaluate	O
the	O
significance	O
of	O
co	O
-	O
occurrence	O
events	O
must	O
reflect	O
this	O
heterogeneity	O
.	O

In	O
particular	O
,	O
it	O
must	O
be	O
based	O
on	O
list	O
-	O
specific	O
co	O
-	O
occurrence	O
probabilities	O
.	O

Second	O
,	O
in	O
the	O
vast	O
majority	O
of	O
previous	O
studies	O
,	O
co	O
-	O
occurrence	O
is	O
analyzed	O
for	O
pair	O
-	O
wise	O
combinations	O
of	O
co	O
-	O
occurring	O
entities	O
.	O

We	O
found	O
that	O
the	O
resulting	O
stringency	O
of	O
this	O
approach	O
is	O
not	O
adequate	O
for	O
the	O
analysis	O
of	O
published	O
gene	O
expression	O
signatures	O
[	O
35	O
]	O
.	O

Third	O
,	O
the	O
null	O
-	O
model	O
against	O
which	O
the	O
significance	O
of	O
co	O
-	O
occurrences	O
is	O
tested	O
does	O
not	O
work	O
well	O
for	O
gene	O
expression	O
signatures	O
.	O

A	O
common	O
procedure	O
is	O
to	O
use	O
generic	O
randomization	O
of	O
the	O
entire	O
data	O
set	O
under	O
analysis	O
or	O
to	O
select	O
subsets	O
of	O
data	O
entries	O
randomly	O
for	O
comparison	O
purposes	O
.	O

However	O
,	O
gene	O
expression	O
signatures	O
are	O
composed	O
of	O
distinct	O
gene	O
sets	O
and	O
the	O
null	O
-	O
model	O
must	O
maintain	O
this	O
property	O
,	O
which	O
is	O
not	O
guaranteed	O
using	O
these	O
approaches	O
.	O

Furthermore	O
,	O
the	O
list	O
-	O
specific	O
nature	O
of	O
co	O
-	O
occurrence	O
probabilities	O
cannot	O
be	O
dealt	O
with	O
properly	O
.	O

NetCutter	O
was	O
developed	O
to	O
address	O
these	O
challenges	O
and	O
to	O
provide	O
a	O
generic	O
tool	O
for	O
generating	O
and	O
analyzing	O
co	O
-	O
occurrence	O
networks	O
.	O

Although	O
NetCutter	O
has	O
been	O
developed	O
for	O
the	O
analysis	O
of	O
gene	O
expression	O
signatures	O
,	O
it	O
is	O
based	O
on	O
abstract	O
concepts	O
that	O
make	O
it	O
applicable	O
to	O
a	O
wide	O
variety	O
of	O
problems	O
.	O

The	O
input	O
is	O
represented	O
by	O
a	O
bipartite	O
graph	O
that	O
is	O
composed	O
of	O
list	O
-	O
entry	O
pairs	O
,	O
which	O
are	O
stored	O
in	O
tab	O
-	O
separated	O
text	O
format	O
.	O

Co	O
-	O
occurrence	O
of	O
entries	O
in	O
lists	O
is	O
analyzed	O
using	O
pair	O
-	O
wise	O
or	O
higher	O
order	O
combinations	O
of	O
entries	O
.	O

The	O
significance	O
of	O
co	O
-	O
occurrence	O
is	O
tested	O
using	O
a	O
novel	O
bi	O
-	O
binomial	O
approximation	O
of	O
Poisson	O
-	O
binomial	O
statistics	O
(	O
which	O
is	O
a	O
binomial	O
distribution	O
with	O
trial	O
specific	O
probabilities	O
)	O
that	O
handles	O
list	O
-	O
length	O
-	O
heterogeneity	O
properly	O
and	O
provides	O
a	O
novel	O
measure	O
of	O
association	O
that	O
is	O
found	O
to	O
be	O
superior	O
to	O
the	O
Jaccard	O
and	O
the	O
uncertainty	O
coefficients	O
.	O

Occurrence	O
probabilities	O
are	O
obtained	O
from	O
an	O
edge	O
-	O
swapping	O
procedure	O
that	O
maintains	O
vertex	O
degrees	O
in	O
the	O
underlying	O
bipartite	O
graph	O
and	O
distinct	O
sets	O
of	O
entries	O
per	O
list	O
.	O

As	O
we	O
shall	O
see	O
below	O
,	O
this	O
procedure	O
has	O
a	O
number	O
of	O
advantages	O
over	O
other	O
possible	O
null	O
-	O
models	O
and	O
permits	O
co	O
-	O
occurrence	O
analysis	O
with	O
near	O
maximum	O
stringency	O
.	O

Last	O
but	O
not	O
least	O
,	O
NetCutter	O
is	O
equipped	O
with	O
a	O
number	O
of	O
algorithms	O
for	O
the	O
identification	O
of	O
network	O
communities	O
,	O
vertex	O
ranking	O
,	O
and	O
convenience	O
tools	O
needed	O
in	O
the	O
analysis	O
of	O
co	O
-	O
occurrence	O
networks	O
,	O
or	O
any	O
undirected	O
graph	O
.	O

We	O
illustrate	O
the	O
utility	O
of	O
NetCutter	O
in	O
the	O
identification	O
of	O
corresponding	O
clusters	O
of	O
genes	O
and	O
publications	O
from	O
the	O
PubLiME	O
data	O
set	O
.	O

PubLiME	O
(	O
Published	O
Lists	O
of	O
Microarray	O
Experiments	O
)	O
is	O
a	O
repository	O
of	O
published	O
cancer	O
related	O
gene	O
expression	O
signatures	O
(	O
http	O
:	O
/	O
/	O
bio	O
.	O
ifom	O
-	O
ieo	O
-	O
campus	O
.	O
it	O
/	O
Publime	O
)	O
.	O

The	O
concept	O
of	O
cluster	O
correspondence	O
follows	O
from	O
the	O
bipartite	O
graph	O
representation	O
of	O
the	O
data	O
.	O

Reversing	O
the	O
list	O
-	O
entry	O
order	O
in	O
the	O
bipartite	O
graph	O
permits	O
identifying	O
communities	O
of	O
entries	O
as	O
well	O
as	O
communities	O
of	O
lists	O
.	O

We	O
show	O
that	O
communities	O
of	O
publications	O
corresponding	O
to	O
communities	O
of	O
genes	O
in	O
the	O
PubLiME	O
data	O
set	O
can	O
be	O
used	O
to	O
generate	O
hypotheses	O
about	O
the	O
putative	O
function	O
of	O
gene	O
communities	O
.	O

Results	O

The	O
bipartite	O
graph	O
model	O
of	O
co	O
-	O
occurrence	O
analysis	O

Co	O
-	O
occurrence	O
analysis	O
using	O
NetCutter	O
is	O
based	O
on	O
the	O
abstraction	O
of	O
list	O
-	O
entry	O
pairs	O
.	O

Any	O
entity	O
that	O
co	O
-	O
occurs	O
with	O
some	O
other	O
entity	O
must	O
be	O
confined	O
to	O
some	O
sort	O
of	O
container	O
where	O
co	O
-	O
occurrence	O
is	O
observed	O
.	O

For	O
example	O
,	O
in	O
the	O
case	O
of	O
gene	O
name	O
co	O
-	O
occurrence	O
in	O
PubMed	O
abstracts	O
,	O
the	O
abstract	O
is	O
the	O
container	O
and	O
the	O
gene	O
names	O
are	O
the	O
co	O
-	O
occurring	O
entities	O
.	O

Similarly	O
,	O
co	O
-	O
occurrence	O
of	O
transcription	O
factor	O
binding	O
motifs	O
is	O
observed	O
in	O
gene	O
promoters	O
.	O

The	O
promoters	O
are	O
the	O
containers	O
where	O
motif	O
entities	O
co	O
-	O
occur	O
.	O

The	O
containers	O
generally	O
host	O
more	O
than	O
one	O
entity	O
(	O
otherwise	O
co	O
-	O
occurrence	O
would	O
be	O
impossible	O
)	O
and	O
can	O
be	O
conveniently	O
interpreted	O
as	O
lists	O
.	O

The	O
co	O
-	O
occurring	O
entities	O
are	O
the	O
list	O
entries	O
.	O

Lists	O
and	O
entries	O
form	O
a	O
bipartite	O
graph	O
with	O
one	O
part	O
of	O
the	O
graph	O
representing	O
lists	O
and	O
the	O
other	O
part	O
representing	O
entries	O
.	O

The	O
presence	O
of	O
a	O
given	O
entry	O
in	O
a	O
given	O
list	O
is	O
indicated	O
by	O
an	O
edge	O
between	O
the	O
corresponding	O
list	O
and	O
entry	O
vertices	O
.	O

It	O
is	O
required	O
that	O
each	O
entry	O
can	O
be	O
linked	O
to	O
the	O
same	O
list	O
only	O
once	O
.	O

Without	O
loss	O
of	O
generality	O
,	O
let	O
'	O
s	O
consider	O
genes	O
as	O
entries	O
and	O
PubMedID	O
_	O
listIDs	O
as	O
lists	O
in	O
the	O
following	O
,	O
unless	O
otherwise	O
specified	O
(	O
Fig	O
.	O
1A	O
)	O
.	O

This	O
interpretation	O
of	O
lists	O
and	O
entries	O
has	O
been	O
applied	O
in	O
the	O
co	O
-	O
occurrence	O
analysis	O
of	O
published	O
gene	O
expression	O
signatures	O
[	O
35	O
]	O
.	O

Occurrence	O
probabilities	O
and	O
null	O
-	O
models	O

A	O
prerequisite	O
for	O
co	O
-	O
occurrence	O
analysis	O
is	O
the	O
availability	O
of	O
occurrence	O
probabilities	O
of	O
genes	O
per	O
list	O
.	O

The	O
occurrence	O
probabilities	O
can	O
be	O
derived	O
from	O
randomizing	O
the	O
bipartite	O
graph	O
and	O
are	O
dependent	O
on	O
the	O
choice	O
of	O
the	O
null	O
-	O
model	O
.	O

A	O
null	O
-	O
model	O
creates	O
an	O
occurrence	O
probability	O
matrix	O
where	O
the	O
occurrence	O
probability	O
for	O
each	O
list	O
-	O
gene	O
pair	O
is	O
listed	O
.	O

As	O
a	O
general	O
property	O
of	O
this	O
matrix	O
,	O
the	O
sum	O
of	O
all	O
matrix	O
elements	O
must	O
equal	O
the	O
number	O
of	O
edges	O
in	O
the	O
bipartite	O
graph	O
.	O

This	O
is	O
because	O
each	O
edge	O
is	O
linked	O
to	O
either	O
side	O
of	O
the	O
bipartite	O
graph	O
with	O
certainty	O
and	O
therefore	O
the	O
sum	O
of	O
occurrence	O
probabilities	O
over	O
all	O
lists	O
(	O
which	O
can	O
be	O
calculated	O
as	O
the	O
row	O
sum	O
if	O
genes	O
are	O
listed	O
vertically	O
or	O
as	O
the	O
column	O
sum	O
if	O
genes	O
are	O
listed	O
horizontally	O
)	O
followed	O
by	O
summing	O
the	O
results	O
over	O
all	O
genes	O
must	O
be	O
1	O
for	O
every	O
edge	O
.	O

The	O
number	O
of	O
matrix	O
elements	O
is	O
given	O
by	O
#	O
genes	O
*	O
#	O
lists	O
and	O
therefore	O
the	O
average	O
occurrence	O
probability	O
for	O
any	O
null	O
-	O
model	O
must	O
be	O
#	O
edges	O
/	O
(	O
#	O
genes	O
*	O
#	O
lists	O
)	O
.	O

As	O
a	O
consequence	O
,	O
different	O
null	O
-	O
models	O
will	O
only	O
be	O
distinguished	O
by	O
the	O
way	O
they	O
attribute	O
occurrence	O
probabilities	O
to	O
vertices	O
with	O
different	O
vertex	O
degrees	O
but	O
not	O
by	O
the	O
average	O
occurrence	O
probability	O
.	O

We	O
consider	O
six	O
different	O
strategies	O
to	O
randomize	O
the	O
bipartite	O
graph	O
.	O

First	O
,	O
we	O
could	O
reconnect	O
all	O
edges	O
of	O
the	O
graph	O
randomly	O
.	O

The	O
probability	O
of	O
being	O
connected	O
by	O
an	O
edge	O
for	O
a	O
given	O
list	O
-	O
gene	O
pair	O
is	O
given	O
by	O
(	O
1	O
/	O
#	O
genes	O
)	O
*	O
(	O
1	O
/	O
#	O
lists	O
)	O
.	O

Since	O
there	O
are	O
#	O
edges	O
edges	O
to	O
be	O
reconnected	O
,	O
the	O
occurrence	O
probability	O
for	O
a	O
single	O
list	O
-	O
gene	O
pair	O
is	O
#	O
edges	O
/	O
(	O
#	O
genes	O
*	O
#	O
lists	O
)	O
,	O
i	O
.	O
e	O
.	O
equal	O
to	O
the	O
average	O
occurrence	O
probability	O
.	O

Thus	O
,	O
this	O
model	O
provides	O
equal	O
occurrence	O
probabilities	O
for	O
all	O
gene	O
-	O
list	O
pairs	O
and	O
does	O
not	O
consider	O
vertex	O
degrees	O
.	O

We	O
call	O
this	O
model	O
the	O
generic	O
randomization	O
(	O
GR	O
)	O
model	O
in	O
the	O
following	O
.	O

Second	O
,	O
we	O
could	O
disconnect	O
the	O
edges	O
on	O
only	O
the	O
list	O
side	O
of	O
the	O
bipartite	O
graph	O
and	O
reconnect	O
them	O
randomly	O
.	O

The	O
occurrence	O
probability	O
of	O
a	O
gene	O
vertex	O
would	O
be	O
given	O
by	O
(	O
gene	O
vertex	O
degree	O
)	O
/	O
#	O
lists	O
.	O

The	O
sum	O
of	O
these	O
probabilities	O
over	O
all	O
lists	O
is	O
equal	O
to	O
the	O
gene	O
vertex	O
degree	O
and	O
the	O
sum	O
of	O
all	O
gene	O
vertex	O
degrees	O
is	O
equal	O
to	O
the	O
total	O
number	O
of	O
edges	O
.	O

Thus	O
,	O
the	O
sum	O
of	O
all	O
matrix	O
elements	O
is	O
equal	O
to	O
the	O
number	O
of	O
edges	O
,	O
as	O
required	O
.	O

Since	O
this	O
model	O
considers	O
gene	O
vertex	O
degrees	O
,	O
we	O
call	O
it	O
the	O
gene	O
vertex	O
degree	O
(	O
GVD	O
)	O
model	O
.	O

Third	O
,	O
we	O
disconnect	O
the	O
edges	O
on	O
the	O
gene	O
side	O
of	O
the	O
bipartite	O
graph	O
and	O
reconnect	O
them	O
randomly	O
.	O

The	O
probability	O
of	O
a	O
list	O
vertex	O
being	O
connected	O
to	O
a	O
gene	O
would	O
be	O
given	O
by	O
(	O
list	O
vertex	O
degree	O
)	O
/	O
#	O
genes	O
.	O

The	O
sum	O
of	O
these	O
probabilities	O
over	O
all	O
genes	O
is	O
equal	O
to	O
the	O
list	O
vertex	O
degree	O
and	O
the	O
sum	O
of	O
all	O
list	O
vertex	O
degrees	O
is	O
equal	O
to	O
the	O
total	O
number	O
of	O
edges	O
.	O

Again	O
,	O
the	O
sum	O
of	O
all	O
matrix	O
elements	O
is	O
equal	O
to	O
the	O
total	O
number	O
of	O
edges	O
.	O

Since	O
this	O
model	O
considers	O
list	O
vertex	O
degrees	O
,	O
we	O
call	O
it	O
the	O
list	O
vertex	O
degree	O
(	O
LVD	O
)	O
model	O
.	O

In	O
model	O
four	O
and	O
five	O
,	O
we	O
reconnect	O
edges	O
considering	O
both	O
gene	O
and	O
list	O
vertex	O
degrees	O
and	O
allow	O
multiple	O
edges	O
between	O
list	O
-	O
gene	O
pairs	O
.	O

The	O
occurrence	O
probabilities	O
in	O
model	O
four	O
are	O
calculated	O
according	O
to	O
the	O
binomial	O
distribution	O
.	O

We	O
calculate	O
the	O
probability	O
of	O
a	O
list	O
-	O
gene	O
pair	O
for	O
being	O
connected	O
as	O
the	O
cumulative	O
binomial	O
probability	O
of	O
the	O
list	O
-	O
gene	O
pair	O
being	O
chosen	O
at	O
least	O
once	O
in	O
the	O
process	O
of	O
randomly	O
reconnecting	O
the	O
edges	O
.	O

This	O
can	O
be	O
achieved	O
by	O
setting	O
the	O
number	O
of	O
trials	O
equal	O
to	O
the	O
gene	O
vertex	O
degree	O
,	O
the	O
probability	O
of	O
success	O
equal	O
to	O
the	O
list	O
vertex	O
degree	O
divided	O
by	O
the	O
total	O
number	O
of	O
edges	O
,	O
and	O
the	O
number	O
of	O
successes	O
equal	O
to	O
0	O
.	O

The	O
occurrence	O
probability	O
of	O
a	O
list	O
-	O
gene	O
pair	O
is	O
then	O
given	O
by	O
the	O
complement	O
of	O
this	O
probability	O
.	O

This	O
model	O
is	O
called	O
the	O
binomial	O
(	O
BN	O
)	O
model	O
.	O

In	O
model	O
five	O
,	O
we	O
calculate	O
occurrence	O
probabilities	O
according	O
to	O
the	O
hypergeometric	O
distribution	O
.	O

The	O
number	O
of	O
successes	O
in	O
the	O
sample	O
is	O
equal	O
to	O
0	O
,	O
the	O
sample	O
size	O
is	O
equal	O
to	O
the	O
gene	O
vertex	O
degree	O
,	O
the	O
number	O
of	O
successes	O
in	O
the	O
population	O
is	O
set	O
to	O
the	O
list	O
vertex	O
degree	O
,	O
and	O
the	O
population	O
size	O
is	O
the	O
total	O
number	O
of	O
edges	O
.	O

Again	O
,	O
the	O
occurrence	O
probability	O
of	O
a	O
list	O
-	O
gene	O
pair	O
is	O
obtained	O
as	O
the	O
complement	O
of	O
this	O
probability	O
.	O

We	O
call	O
this	O
model	O
the	O
hypergeometric	O
(	O
HG	O
)	O
model	O
.	O

Calculating	O
occurrence	O
probabilities	O
in	O
this	O
manner	O
does	O
not	O
guarantee	O
that	O
the	O
matrix	O
elements	O
add	O
up	O
to	O
the	O
total	O
number	O
of	O
edges	O
.	O

Therefore	O
,	O
the	O
matrices	O
are	O
normalized	O
such	O
that	O
this	O
condition	O
is	O
satisfied	O
by	O
multiplying	O
each	O
matrix	O
element	O
with	O
the	O
factor	O
#	O
edges	O
/	O
(	O
observed	O
matrix	O
sum	O
)	O
,	O
which	O
is	O
generally	O
quite	O
close	O
to	O
1	O
,	O
however	O
.	O

In	O
model	O
six	O
,	O
we	O
again	O
consider	O
vertex	O
degrees	O
,	O
but	O
we	O
require	O
that	O
each	O
list	O
is	O
composed	O
of	O
distinct	O
sets	O
of	O
genes	O
.	O

Thus	O
,	O
multiple	O
edges	O
are	O
forbidden	O
.	O

This	O
condition	O
is	O
satisfied	O
by	O
applying	O
an	O
edge	O
-	O
swapping	O
procedure	O
during	O
graph	O
randomization	O
.	O

Edge	O
-	O
swapping	O
works	O
by	O
randomly	O
choosing	O
two	O
list	O
-	O
gene	O
pairs	O
from	O
the	O
bipartite	O
graph	O
and	O
prior	O
to	O
performing	O
the	O
edge	O
-	O
swap	O
,	O
a	O
test	O
is	O
performed	O
to	O
ensure	O
that	O
the	O
two	O
genes	O
are	O
not	O
already	O
linked	O
to	O
the	O
respective	O
target	O
lists	O
.	O

This	O
procedure	O
is	O
performed	O
a	O
large	O
number	O
of	O
times	O
.	O

To	O
ensure	O
complete	O
randomization	O
of	O
the	O
graph	O
,	O
the	O
number	O
of	O
swaps	O
performed	O
should	O
be	O
significantly	O
larger	O
than	O
the	O
number	O
of	O
edges	O
.	O

After	O
performing	O
R	O
randomizations	O
of	O
the	O
graph	O
and	O
counting	O
the	O
number	O
of	O
times	O
a	O
gene	O
has	O
been	O
linked	O
to	O
a	O
particular	O
list	O
,	O
division	O
of	O
this	O
number	O
by	O
R	O
gives	O
the	O
occurrence	O
probability	O
of	O
a	O
gene	O
in	O
a	O
given	O
list	O
.	O

As	O
will	O
be	O
shown	O
below	O
,	O
edge	O
-	O
swapping	O
produces	O
occurrence	O
probabilities	O
that	O
closely	O
approximate	O
occurrence	O
probabilities	O
obtained	O
by	O
generating	O
a	O
complete	O
permutation	O
set	O
of	O
the	O
bipartite	O
graph	O
,	O
counting	O
the	O
number	O
of	O
times	O
a	O
gene	O
is	O
found	O
part	O
of	O
a	O
list	O
,	O
and	O
dividing	O
this	O
number	O
by	O
the	O
total	O
number	O
of	O
permutations	O
.	O

In	O
the	O
permutation	O
model	O
,	O
the	O
sum	O
of	O
occurrence	O
probabilities	O
of	O
a	O
gene	O
over	O
all	O
lists	O
equals	O
the	O
gene	O
vertex	O
degree	O
(	O
see	O
below	O
)	O
and	O
thus	O
the	O
sum	O
of	O
all	O
matrix	O
elements	O
is	O
the	O
number	O
of	O
edges	O
.	O

Since	O
permutation	O
sets	O
of	O
bipartite	O
graphs	O
are	O
difficult	O
to	O
calculate	O
,	O
we	O
use	O
the	O
edge	O
-	O
swapping	O
procedure	O
as	O
a	O
close	O
approximation	O
and	O
call	O
this	O
model	O
the	O
edge	O
-	O
swapping	O
(	O
ES	O
)	O
model	O
.	O

Fig	O
.	O

1	O
shows	O
the	O
occurrence	O
probabilities	O
of	O
the	O
different	O
null	O
-	O
models	O
for	O
the	O
bipartite	O
graph	O
shown	O
in	O
Fig	O
.	O

1A	O
.	O

The	O
GR	O
model	O
yields	O
identical	O
occurrence	O
probabilities	O
for	O
all	O
list	O
-	O
gene	O
pairs	O
,	O
which	O
is	O
equal	O
to	O
the	O
average	O
occurrence	O
probability	O
in	O
all	O
models	O
.	O

In	O
the	O
other	O
models	O
,	O
the	O
occurrence	O
probabilities	O
deviate	O
to	O
varying	O
extent	O
from	O
the	O
average	O
occurrence	O
probability	O
as	O
a	O
function	O
of	O
vertex	O
degrees	O
.	O

In	O
the	O
GVD	O
model	O
,	O
the	O
deviations	O
are	O
a	O
function	O
of	O
gene	O
vertex	O
degree	O
and	O
in	O
the	O
LVD	O
model	O
the	O
deviations	O
are	O
dependent	O
on	O
list	O
vertex	O
degrees	O
.	O

In	O
the	O
remaining	O
models	O
,	O
the	O
deviations	O
are	O
functions	O
of	O
both	O
the	O
gene	O
and	O
the	O
list	O
vertex	O
degrees	O
.	O

In	O
all	O
cases	O
,	O
larger	O
than	O
average	O
occurrence	O
probabilities	O
are	O
obtained	O
for	O
larger	O
vertex	O
degrees	O
at	O
the	O
expense	O
of	O
smaller	O
than	O
average	O
occurrence	O
probabilities	O
for	O
smaller	O
vertex	O
degrees	O
.	O

From	O
these	O
data	O
,	O
it	O
is	O
difficult	O
to	O
choose	O
the	O
most	O
effective	O
null	O
-	O
model	O
.	O

A	O
hint	O
can	O
be	O
gleaned	O
from	O
gene1	O
,	O
however	O
.	O

Gene1	O
is	O
present	O
in	O
all	O
lists	O
.	O

Therefore	O
,	O
the	O
co	O
-	O
occurrence	O
probability	O
of	O
gene1	O
with	O
other	O
genes	O
,	O
which	O
is	O
calculated	O
by	O
multiplying	O
the	O
occurrence	O
probabilities	O
of	O
gene1	O
and	O
geneX	O
for	O
every	O
list	O
under	O
study	O
,	O
should	O
depend	O
only	O
on	O
the	O
occurrence	O
probability	O
of	O
this	O
other	O
gene	O
.	O

In	O
other	O
words	O
,	O
the	O
occurrence	O
probability	O
of	O
gene1	O
in	O
all	O
lists	O
should	O
be	O
1	O
.	O
0	O
.	O

Only	O
two	O
models	O
satisfy	O
this	O
constraint	O
:	O
The	O
GVD	O
and	O
the	O
ES	O
models	O
.	O

Since	O
the	O
GVD	O
model	O
does	O
not	O
consider	O
list	O
vertex	O
degrees	O
,	O
it	O
seems	O
that	O
the	O
ES	O
model	O
is	O
the	O
preferred	O
null	O
-	O
model	O
.	O

Expected	O
number	O
of	O
co	O
-	O
occurrences	O

As	O
a	O
general	O
criterion	O
for	O
comparing	O
the	O
effectiveness	O
of	O
different	O
null	O
-	O
models	O
,	O
we	O
have	O
to	O
compare	O
them	O
for	O
the	O
number	O
of	O
expected	O
co	O
-	O
occurrences	O
.	O

The	O
most	O
effective	O
null	O
-	O
model	O
will	O
be	O
the	O
one	O
that	O
maximizes	O
the	O
expected	O
number	O
of	O
co	O
-	O
occurrences	O
.	O

If	O
the	O
expected	O
number	O
of	O
co	O
-	O
occurrences	O
is	O
larger	O
,	O
an	O
observed	O
number	O
of	O
co	O
-	O
occurrences	O
in	O
a	O
real	O
bipartite	O
graph	O
will	O
be	O
less	O
significant	O
and	O
thus	O
such	O
a	O
null	O
-	O
model	O
permits	O
co	O
-	O
occurrence	O
analysis	O
with	O
higher	O
stringency	O
.	O

The	O
expected	O
number	O
of	O
co	O
-	O
occurrences	O
depends	O
in	O
an	O
obvious	O
fashion	O
on	O
the	O
list	O
vertex	O
degree	O
.	O

If	O
pair	O
-	O
wise	O
co	O
-	O
occurrences	O
are	O
considered	O
,	O
the	O
number	O
of	O
co	O
-	O
occurrences	O
in	O
a	O
list	O
of	O
vertex	O
degree	O
N	O
is	O
given	O
by	O
the	O
binomial	O
coefficient	O
N	O
over	O
2	O
.	O

Larger	O
lists	O
will	O
give	O
rise	O
to	O
more	O
co	O
-	O
occurrences	O
and	O
the	O
number	O
increases	O
quickly	O
with	O
list	O
vertex	O
degree	O
.	O

The	O
dependency	O
of	O
the	O
expected	O
number	O
of	O
co	O
-	O
occurrences	O
on	O
the	O
gene	O
vertex	O
degree	O
is	O
less	O
obvious	O
and	O
depends	O
strongly	O
on	O
the	O
null	O
-	O
model	O
.	O

A	O
gene	O
that	O
is	O
part	O
of	O
a	O
list	O
with	O
vertex	O
degree	O
N	O
will	O
give	O
rise	O
to	O
N	O
-	O
1	O
co	O
-	O
occurrences	O
in	O
that	O
list	O
.	O

The	O
null	O
-	O
model	O
permits	O
calculating	O
the	O
probability	O
to	O
find	O
this	O
gene	O
in	O
a	O
given	O
list	O
.	O

Thus	O
,	O
the	O
expected	O
number	O
of	O
co	O
-	O
occurrences	O
of	O
a	O
gene	O
is	O
given	O
by	O
the	O
sum	O
of	O
expected	O
co	O
-	O
occurrences	O
in	O
all	O
lists	O
where	O
for	O
a	O
single	O
list	O
the	O
expected	O
co	O
-	O
occurrences	O
are	O
given	O
by	O
(	O
Nl	O
-	O
1	O
)	O
*	O
pl	O
.	O

Nl	O
is	O
the	O
list	O
vertex	O
degree	O
and	O
pl	O
is	O
the	O
occurrence	O
probability	O
of	O
the	O
gene	O
in	O
that	O
list	O
as	O
determined	O
by	O
the	O
null	O
-	O
model	O
.	O

We	O
used	O
the	O
PubLiME	O
data	O
set	O
[	O
35	O
]	O
to	O
calculate	O
the	O
expected	O
number	O
of	O
co	O
-	O
occurrences	O
with	O
different	O
null	O
-	O
models	O
.	O

The	O
results	O
are	O
shown	O
in	O
Fig	O
2A	O
.	O

The	O
expected	O
number	O
of	O
co	O
-	O
occurrences	O
was	O
calculated	O
for	O
all	O
genes	O
in	O
all	O
lists	O
using	O
all	O
null	O
-	O
models	O
and	O
the	O
sum	O
of	O
expected	O
co	O
-	O
occurrences	O
per	O
gene	O
is	O
shown	O
as	O
a	O
scatter	O
plot	O
with	O
the	O
gene	O
vertex	O
degree	O
on	O
the	O
x	O
-	O
axis	O
and	O
the	O
expected	O
number	O
of	O
co	O
-	O
occurrences	O
on	O
the	O
y	O
-	O
axis	O
.	O

The	O
results	O
in	O
Fig	O
.	O

2A	O
suggest	O
the	O
following	O
ranking	O
of	O
null	O
-	O
models	O
:	O
GR	O
<	O
GVD	O
<	O
LVD	O
<	O
BN	O
=	O
HG	O
<	O
ES	O
.	O

The	O
BN	O
and	O
the	O
HG	O
models	O
perform	O
in	O
an	O
essentially	O
identical	O
way	O
.	O

However	O
,	O
the	O
ES	O
model	O
is	O
the	O
model	O
that	O
yields	O
the	O
largest	O
estimates	O
of	O
expected	O
co	O
-	O
occurrences	O
.	O

The	O
results	O
are	O
also	O
in	O
line	O
with	O
the	O
intuitive	O
expectation	O
that	O
genes	O
with	O
higher	O
vertex	O
degree	O
give	O
rise	O
to	O
more	O
co	O
-	O
occurrences	O
.	O

However	O
,	O
it	O
can	O
be	O
seen	O
that	O
this	O
is	O
not	O
true	O
for	O
all	O
null	O
-	O
models	O
.	O

In	O
particular	O
,	O
it	O
is	O
not	O
true	O
for	O
the	O
GR	O
and	O
the	O
LVD	O
models	O
,	O
which	O
do	O
not	O
consider	O
gene	O
vertex	O
degrees	O
.	O

As	O
outlined	O
above	O
,	O
it	O
is	O
expected	O
that	O
the	O
null	O
-	O
model	O
that	O
yields	O
the	O
highest	O
estimates	O
of	O
expected	O
co	O
-	O
occurrences	O
should	O
permit	O
co	O
-	O
occurrence	O
analysis	O
with	O
the	O
highest	O
stringency	O
.	O

In	O
Fig	O
.	O

2B	O
,	O
this	O
hypothesis	O
is	O
tested	O
directly	O
again	O
using	O
the	O
PubLiME	O
data	O
set	O
[	O
35	O
]	O
.	O

For	O
all	O
null	O
-	O
models	O
,	O
co	O
-	O
occurrence	O
analysis	O
was	O
carried	O
out	O
using	O
module	O
size	O
3	O
and	O
support	O
5	O
(	O
co	O
-	O
occurrence	O
modules	O
must	O
be	O
present	O
in	O
at	O
least	O
five	O
publications	O
)	O
.	O

The	O
choice	O
of	O
these	O
parameters	O
has	O
been	O
discussed	O
in	O
[	O
35	O
]	O
.	O

The	O
number	O
of	O
co	O
-	O
occurrence	O
modules	O
was	O
then	O
determined	O
that	O
have	O
a	O
Z	O
-	O
score	O
higher	O
or	O
equal	O
than	O
the	O
cut	O
-	O
off	O
shown	O
in	O
Fig	O
.	O

2B	O
.	O

The	O
Z	O
-	O
score	O
is	O
calculated	O
from	O
the	O
mean	O
and	O
variance	O
of	O
the	O
Poisson	O
-	O
binomial	O
distribution	O
as	O
shown	O
in	O
the	O
Materials	O
and	O
Methods	O
section	O
and	O
published	O
in	O
[	O
35	O
]	O
.	O

More	O
details	O
on	O
the	O
probability	O
distribution	O
will	O
be	O
provided	O
below	O
.	O

The	O
GR	O
and	O
GVD	O
models	O
perform	O
very	O
poorly	O
and	O
identify	O
large	O
numbers	O
of	O
modules	O
with	O
high	O
Z	O
-	O
scores	O
.	O

The	O
LVD	O
model	O
performs	O
a	O
little	O
better	O
and	O
approximates	O
the	O
BN	O
and	O
HG	O
models	O
at	O
higher	O
Z	O
-	O
score	O
cut	O
-	O
offs	O
.	O

The	O
BN	O
and	O
HG	O
models	O
give	O
essentially	O
identical	O
results	O
.	O

However	O
,	O
the	O
ES	O
model	O
is	O
the	O
model	O
that	O
yields	O
the	O
fewest	O
number	O
of	O
significant	O
co	O
-	O
occurrence	O
modules	O
and	O
is	O
thus	O
the	O
most	O
stringent	O
.	O

The	O
increased	O
stringency	O
of	O
the	O
ES	O
model	O
over	O
the	O
BN	O
and	O
HG	O
models	O
is	O
also	O
reflected	O
in	O
a	O
higher	O
signal	O
-	O
to	O
-	O
noise	O
ratio	O
calculated	O
as	O
the	O
number	O
of	O
significant	O
co	O
-	O
occurrence	O
modules	O
in	O
the	O
real	O
bipartite	O
graph	O
divided	O
by	O
the	O
number	O
of	O
modules	O
found	O
in	O
a	O
randomized	O
bipartite	O
graph	O
(	O
Fig	O
.	O
2C	O
)	O
.	O

The	O
reason	O
for	O
the	O
superior	O
stringency	O
of	O
the	O
ES	O
model	O
over	O
all	O
other	O
models	O
can	O
be	O
explained	O
by	O
examining	O
the	O
average	O
occurrence	O
probability	O
per	O
gene	O
and	O
list	O
vertex	O
degree	O
.	O

Fig	O
.	O

2D	O
and	O
E	O
show	O
the	O
average	O
occurrence	O
probability	O
of	O
genes	O
with	O
the	O
same	O
gene	O
vertex	O
degree	O
as	O
a	O
function	O
of	O
the	O
gene	O
vertex	O
degree	O
.	O

It	O
can	O
be	O
seen	O
that	O
the	O
ES	O
model	O
yields	O
higher	O
occurrence	O
probability	O
estimates	O
for	O
genes	O
with	O
higher	O
vertex	O
degrees	O
as	O
compared	O
to	O
the	O
BN	O
and	O
HG	O
models	O
.	O

In	O
GR	O
and	O
LVD	O
models	O
,	O
gene	O
vertex	O
degrees	O
are	O
ignored	O
and	O
occurrence	O
probabilities	O
for	O
genes	O
with	O
large	O
vertex	O
degree	O
are	O
very	O
small	O
,	O
which	O
is	O
compensated	O
by	O
larger	O
occurrence	O
probabilities	O
for	O
genes	O
with	O
small	O
vertex	O
degree	O
.	O

The	O
GVD	O
model	O
is	O
identical	O
to	O
the	O
ES	O
model	O
in	O
this	O
setting	O
.	O

Fig	O
.	O

2E	O
shows	O
the	O
average	O
occurrence	O
probability	O
of	O
all	O
lists	O
with	O
the	O
same	O
vertex	O
degree	O
as	O
a	O
function	O
of	O
list	O
vertex	O
degree	O
.	O

It	O
can	O
be	O
seen	O
that	O
the	O
ES	O
model	O
provides	O
higher	O
occurrence	O
probability	O
estimates	O
for	O
large	O
lists	O
as	O
compared	O
to	O
the	O
BN	O
and	O
HG	O
models	O
.	O

In	O
this	O
setting	O
,	O
the	O
LVD	O
model	O
performs	O
like	O
the	O
ES	O
model	O
while	O
the	O
GR	O
and	O
GVD	O
models	O
yield	O
small	O
occurrence	O
probabilities	O
for	O
large	O
lists	O
.	O

Since	O
it	O
has	O
been	O
shown	O
above	O
that	O
long	O
lists	O
and	O
genes	O
with	O
high	O
vertex	O
degree	O
are	O
responsible	O
for	O
a	O
large	O
part	O
of	O
the	O
total	O
number	O
of	O
co	O
-	O
occurrences	O
for	O
the	O
most	O
stringent	O
null	O
-	O
models	O
,	O
the	O
null	O
-	O
model	O
that	O
provides	O
larger	O
occurrence	O
probability	O
estimates	O
for	O
genes	O
and	O
lists	O
with	O
high	O
vertex	O
degree	O
at	O
the	O
expense	O
of	O
lower	O
estimates	O
for	O
smaller	O
degrees	O
will	O
be	O
the	O
most	O
stringent	O
because	O
large	O
occurrence	O
probabilities	O
make	O
co	O
-	O
occurrence	O
more	O
likely	O
and	O
thus	O
less	O
significant	O
.	O

By	O
these	O
criteria	O
,	O
the	O
ES	O
model	O
is	O
the	O
most	O
stringent	O
of	O
all	O
models	O
tested	O
.	O

The	O
ES	O
model	O
as	O
an	O
approximation	O
of	O
the	O
permutation	O
null	O
-	O
model	O

The	O
data	O
shown	O
above	O
have	O
revealed	O
that	O
the	O
ES	O
model	O
is	O
the	O
best	O
of	O
the	O
models	O
tested	O
.	O

One	O
may	O
wonder	O
,	O
however	O
,	O
whether	O
yet	O
more	O
effective	O
null	O
-	O
models	O
can	O
be	O
found	O
.	O

An	O
obvious	O
choice	O
would	O
be	O
the	O
permutation	O
model	O
.	O

In	O
the	O
permutation	O
model	O
,	O
a	O
complete	O
permutation	O
set	O
of	O
the	O
bipartite	O
graph	O
is	O
created	O
such	O
that	O
each	O
list	O
is	O
composed	O
of	O
distinct	O
sets	O
of	O
genes	O
.	O

The	O
number	O
of	O
graphs	O
where	O
a	O
gene	O
is	O
present	O
in	O
a	O
given	O
list	O
divided	O
by	O
the	O
total	O
number	O
of	O
permutations	O
then	O
provides	O
the	O
occurrence	O
probability	O
estimate	O
.	O

The	O
permutation	O
model	O
is	O
the	O
ideal	O
null	O
-	O
model	O
because	O
it	O
is	O
exhaustive	O
.	O

The	O
problem	O
is	O
that	O
a	O
complete	O
permutation	O
set	O
of	O
bipartite	O
graphs	O
of	O
some	O
complexity	O
is	O
very	O
time	O
consuming	O
to	O
calculate	O
.	O

For	O
example	O
,	O
the	O
simple	O
bipartite	O
graph	O
from	O
Fig	O
.	O

1A	O
is	O
part	O
of	O
a	O
permutation	O
set	O
of	O
455	O
graphs	O
.	O

The	O
number	O
of	O
permutations	O
is	O
increasing	O
quickly	O
as	O
the	O
numbers	O
of	O
genes	O
and	O
lists	O
grow	O
.	O

However	O
,	O
since	O
edge	O
-	O
swapping	O
ensures	O
that	O
gene	O
lists	O
are	O
composed	O
of	O
distinct	O
sets	O
of	O
genes	O
,	O
each	O
edge	O
-	O
swap	O
produces	O
a	O
graph	O
that	O
is	O
part	O
of	O
the	O
permutation	O
set	O
of	O
the	O
bipartite	O
graph	O
.	O

Edge	O
-	O
swapping	O
can	O
thus	O
be	O
viewed	O
as	O
a	O
random	O
sampling	O
procedure	O
from	O
the	O
permutation	O
set	O
of	O
the	O
bipartite	O
graph	O
.	O

Therefore	O
,	O
occurrence	O
probability	O
estimates	O
derived	O
by	O
edge	O
-	O
swapping	O
should	O
approximate	O
those	O
obtained	O
from	O
the	O
permutation	O
model	O
.	O

We	O
generated	O
a	O
complete	O
permutation	O
set	O
of	O
the	O
graph	O
shown	O
in	O
Fig	O
.	O

1A	O
to	O
verify	O
this	O
hypothesis	O
.	O

The	O
results	O
are	O
shown	O
in	O
Fig	O
.	O

3	O
.	O

Fig	O
.	O

3A	O
shows	O
how	O
the	O
number	O
of	O
possible	O
permutations	O
can	O
be	O
calculated	O
.	O

Gene1	O
is	O
present	O
in	O
all	O
lists	O
and	O
does	O
not	O
have	O
an	O
impact	O
on	O
the	O
total	O
number	O
of	O
permutations	O
.	O

Gene2	O
,	O
having	O
vertex	O
degree	O
two	O
,	O
is	O
present	O
in	O
two	O
out	O
of	O
three	O
lists	O
in	O
one	O
out	O
of	O
three	O
possible	O
ways	O
.	O

The	O
remaining	O
genes	O
have	O
vertex	O
degree	O
1	O
and	O
can	O
be	O
freely	O
chosen	O
to	O
fill	O
the	O
empty	O
slots	O
.	O

We	O
can	O
now	O
count	O
exactly	O
how	O
many	O
times	O
a	O
gene	O
is	O
linked	O
to	O
a	O
list	O
and	O
divide	O
these	O
counts	O
by	O
455	O
,	O
the	O
size	O
of	O
the	O
permutation	O
set	O
,	O
to	O
obtain	O
exact	O
occurrence	O
probabilities	O
.	O

These	O
numbers	O
are	O
shown	O
in	O
graphical	O
form	O
in	O
Fig	O
.	O

3B	O
and	O
in	O
numerical	O
form	O
in	O
Fig	O
.	O

3C	O
.	O

Fig	O
.	O

3B	O
also	O
shows	O
the	O
occurrence	O
probability	O
estimates	O
obtained	O
by	O
edge	O
-	O
swapping	O
side	O
-	O
by	O
-	O
side	O
to	O
the	O
exact	O
occurrence	O
probabilities	O
.	O

The	O
graph	O
in	O
Fig	O
.	O

1A	O
was	O
subjected	O
to	O
edge	O
-	O
swapping	O
1000	O
times	O
and	O
the	O
number	O
of	O
times	O
a	O
gene	O
was	O
found	O
present	O
in	O
a	O
list	O
was	O
divided	O
by	O
1000	O
to	O
obtain	O
the	O
occurrence	O
probability	O
.	O

At	O
each	O
run	O
,	O
100	O
random	O
edge	O
swaps	O
were	O
performed	O
to	O
ensure	O
complete	O
randomization	O
of	O
the	O
graph	O
.	O

This	O
procedure	O
was	O
repeated	O
10	O
times	O
and	O
the	O
mean	O
and	O
standard	O
deviation	O
of	O
occurrence	O
probability	O
estimates	O
for	O
each	O
gene	O
in	O
each	O
list	O
are	O
shown	O
.	O

In	O
all	O
cases	O
,	O
the	O
mean	O
differs	O
from	O
the	O
real	O
probability	O
by	O
less	O
than	O
two	O
standard	O
deviations	O
,	O
in	O
most	O
cases	O
by	O
less	O
than	O
one	O
standard	O
deviation	O
.	O

Thus	O
,	O
edge	O
-	O
swapping	O
provides	O
reliable	O
estimates	O
of	O
exact	O
occurrence	O
probabilities	O
as	O
determined	O
from	O
a	O
complete	O
permutation	O
set	O
.	O

As	O
an	O
interesting	O
observation	O
,	O
we	O
provide	O
evidence	O
that	O
occurrence	O
probabilities	O
are	O
non	O
-	O
linear	O
functions	O
of	O
vertex	O
degrees	O
in	O
the	O
edge	O
-	O
swapping	O
model	O
.	O

This	O
is	O
illustrated	O
in	O
Fig	O
.	O

3C	O
.	O

Individual	O
and	O
average	O
occurrence	O
probabilities	O
are	O
shown	O
as	O
a	O
function	O
of	O
gene	O
and	O
list	O
vertex	O
degrees	O
.	O

Non	O
-	O
linearity	O
of	O
individual	O
occurrence	O
probabilities	O
can	O
be	O
verified	O
from	O
the	O
counts	O
table	O
underneath	O
the	O
plots	O
.	O

However	O
,	O
the	O
average	O
occurrence	O
probability	O
is	O
found	O
to	O
depend	O
on	O
vertex	O
degrees	O
in	O
a	O
linear	O
fashion	O
instead	O
.	O

This	O
is	O
a	O
consequence	O
of	O
the	O
fact	O
that	O
occurrence	O
probabilities	O
of	O
a	O
gene	O
over	O
all	O
lists	O
add	O
up	O
to	O
the	O
gene	O
vertex	O
degree	O
and	O
that	O
the	O
occurrence	O
probabilities	O
of	O
all	O
genes	O
for	O
a	O
given	O
list	O
add	O
up	O
to	O
the	O
list	O
vertex	O
degree	O
.	O

At	O
the	O
same	O
time	O
,	O
since	O
the	O
most	O
stringent	O
permutation	O
based	O
null	O
-	O
model	O
predicts	O
non	O
-	O
linear	O
dependencies	O
of	O
individual	O
occurrence	O
probabilities	O
on	O
vertex	O
degrees	O
,	O
assuming	O
such	O
linearity	O
in	O
statistical	O
models	O
of	O
co	O
-	O
occurrence	O
will	O
be	O
linked	O
to	O
loss	O
of	O
stringency	O
.	O

We	O
conclude	O
that	O
the	O
ES	O
null	O
-	O
model	O
is	O
the	O
null	O
-	O
model	O
that	O
permits	O
co	O
-	O
occurrence	O
analysis	O
with	O
the	O
highest	O
stringency	O
among	O
the	O
models	O
tested	O
and	O
that	O
it	O
closely	O
approximates	O
occurrence	O
probabilities	O
derived	O
from	O
an	O
ideal	O
permutation	O
model	O
.	O

The	O
increased	O
stringency	O
of	O
the	O
ES	O
model	O
over	O
other	O
models	O
is	O
a	O
consequence	O
of	O
higher	O
occurrence	O
probabilities	O
for	O
genes	O
and	O
list	O
with	O
high	O
vertex	O
degrees	O
,	O
which	O
are	O
giving	O
rise	O
to	O
a	O
large	O
part	O
of	O
all	O
co	O
-	O
occurrences	O
in	O
the	O
bipartite	O
graph	O
.	O

Since	O
large	O
occurrence	O
probabilities	O
make	O
co	O
-	O
occurrence	O
more	O
likely	O
,	O
the	O
analysis	O
becomes	O
more	O
stringent	O
.	O

Co	O
-	O
occurrence	O
probabilities	O

Co	O
-	O
occurrence	O
analysis	O
can	O
be	O
thought	O
of	O
as	O
a	O
Bernoulli	O
experiment	O
with	O
a	O
binomial	O
outcome	O
(	O
a	O
given	O
combination	O
of	O
entries	O
is	O
either	O
present	O
or	O
not	O
present	O
in	O
a	O
given	O
list	O
)	O
.	O

Thus	O
,	O
the	O
Binomial	O
distribution	O
(	O
BD	O
)	O
is	O
a	O
natural	O
choice	O
for	O
judging	O
the	O
significance	O
of	O
the	O
number	O
of	O
co	O
-	O
occurrences	O
.	O

However	O
,	O
the	O
BD	O
is	O
defined	O
for	O
a	O
probability	O
of	O
success	O
which	O
is	O
equal	O
in	O
all	O
trials	O
.	O

The	O
list	O
-	O
specific	O
nature	O
of	O
occurrence	O
probabilities	O
is	O
not	O
compatible	O
with	O
this	O
condition	O
(	O
analysis	O
of	O
each	O
list	O
represents	O
one	O
trial	O
)	O
,	O
which	O
means	O
that	O
co	O
-	O
occurrence	O
analysis	O
in	O
the	O
presence	O
of	O
list	O
-	O
length	O
-	O
heterogeneity	O
is	O
better	O
described	O
as	O
a	O
series	O
of	O
Poisson	O
trials	O
,	O
where	O
the	O
probability	O
of	O
success	O
varies	O
from	O
trial	O
to	O
trial	O
.	O

Therefore	O
,	O
the	O
significance	O
of	O
co	O
-	O
occurrences	O
must	O
be	O
evaluated	O
using	O
a	O
binomial	O
distribution	O
with	O
trial	O
-	O
specific	O
probabilities	O
,	O
i	O
.	O
e	O
.	O
the	O
Poisson	O
-	O
binomial	O
distribution	O
(	O
PBD	O
)	O
.	O

The	O
probability	O
of	O
success	O
in	O
a	O
single	O
Poisson	O
trial	O
can	O
be	O
calculated	O
by	O
multiplying	O
the	O
list	O
-	O
specific	O
occurrence	O
probabilities	O
for	O
the	O
combination	O
of	O
genes	O
under	O
study	O
.	O

The	O
number	O
of	O
occurrence	O
probabilities	O
that	O
need	O
to	O
be	O
multiplied	O
is	O
equal	O
to	O
the	O
module	O
size	O
,	O
i	O
.	O
e	O
.	O
the	O
number	O
of	O
genes	O
whose	O
combination	O
is	O
studied	O
.	O

An	O
observed	O
number	O
of	O
co	O
-	O
occurrences	O
for	O
a	O
combination	O
of	O
genes	O
can	O
then	O
be	O
evaluated	O
using	O
the	O
PBD	O
,	O
which	O
is	O
given	O
by	O
the	O
formula	O
[	O
36	O
]	O
:	O
(	O
18	O
)	O

The	O
structure	O
of	O
this	O
formula	O
is	O
very	O
similar	O
to	O
the	O
structure	O
of	O
the	O
formula	O
used	O
to	O
calculate	O
the	O
binomial	O
distribution	O
,	O
except	O
that	O
multiplication	O
with	O
a	O
binomial	O
coefficient	O
is	O
replaced	O
by	O
summation	O
over	O
individual	O
terms	O
,	O
which	O
makes	O
calculation	O
of	O
P	O
-	O
values	O
using	O
(	O
18	O
)	O
inefficient	O
(	O
note	O
that	O
equation	O
numbering	O
starts	O
in	O
the	O
Materials	O
and	O
Methods	O
section	O
)	O
.	O

Here	O
,	O
Ak	O
denotes	O
the	O
kth	O
set	O
of	O
indices	O
of	O
the	O
i	O
lists	O
where	O
genes	O
are	O
co	O
-	O
occurring	O
(	O
"	O
success	O
"	O
)	O
.	O

There	O
are	O
possible	O
sets	O
and	O
summation	O
is	O
carried	O
out	O
accordingly	O
.	O
denotes	O
the	O
set	O
of	O
indices	O
of	O
N	O
-	O
i	O
lists	O
where	O
genes	O
are	O
not	O
co	O
-	O
occurring	O
(	O
"	O
failure	O
"	O
)	O
.	O

[	O
36	O
]	O
have	O
reported	O
two	O
fast	O
procedures	O
for	O
calculating	O
exact	O
PBD	O
P	O
-	O
values	O
.	O

However	O
,	O
both	O
procedures	O
work	O
with	O
probability	O
ratios	O
and	O
suffer	O
from	O
numerical	O
overflow	O
/	O
underflow	O
problems	O
for	O
large	O
numbers	O
of	O
trials	O
.	O

NetCutter	O
uses	O
two	O
workarounds	O
to	O
circumvent	O
this	O
problem	O
.	O

One	O
is	O
based	O
on	O
using	O
Poisson	O
-	O
binomial	O
Z	O
-	O
scores	O
,	O
which	O
can	O
be	O
calculated	O
very	O
easily	O
instead	O
(	O
see	O
below	O
)	O
.	O

The	O
other	O
relies	O
on	O
a	O
fast	O
approximation	O
procedure	O
for	O
calculating	O
Poisson	O
-	O
binomial	O
P	O
-	O
values	O
,	O
which	O
we	O
call	O
bi	O
-	O
binomial	O
approximation	O
(	O
BBA	O
)	O
or	O
bi	O
-	O
binomial	O
distribution	O
(	O
BBD	O
)	O
.	O

Z	O
-	O
scores	O
and	O
P	O
-	O
values	O
of	O
BBD	O

Given	O
the	O
mean	O
mu	O
(	O
1	O
)	O
and	O
variance	O
sigma	O
2	O
(	O
2	O
)	O
of	O
PBD	O
(	O
see	O
Materials	O
and	O
Methods	O
)	O
,	O
the	O
Z	O
-	O
score	O
associated	O
with	O
a	O
given	O
number	O
of	O
co	O
-	O
occurrences	O
x	O
is	O
obtained	O
as	O
:	O
(	O
19	O
)	O

Considering	O
the	O
structure	O
of	O
formulae	O
(	O
1	O
)	O
and	O
(	O
2	O
)	O
(	O
Materials	O
and	O
Methods	O
section	O
)	O
,	O
PBD	O
Z	O
-	O
scores	O
can	O
be	O
calculated	O
very	O
easily	O
and	O
provide	O
a	O
simple	O
estimate	O
of	O
the	O
significance	O
of	O
co	O
-	O
occurrence	O
modules	O
.	O

However	O
,	O
in	O
contrast	O
to	O
normally	O
distributed	O
Z	O
-	O
scores	O
,	O
binomial	O
and	O
Poisson	O
-	O
binomial	O
Z	O
-	O
scores	O
do	O
not	O
correspond	O
to	O
the	O
same	O
P	O
-	O
value	O
for	O
different	O
sets	O
of	O
probabilities	O
of	O
success	O
.	O

To	O
see	O
this	O
,	O
calculate	O
for	O
example	O
the	O
probability	O
of	O
success	O
in	O
a	O
series	O
of	O
100	O
Bernoulli	O
trials	O
with	O
success	O
probability	O
0	O
.	O
1	O
and	O
0	O
.	O
9	O
for	O
the	O
expectation	O
of	O
10	O
and	O
90	O
successes	O
,	O
respectively	O
.	O

The	O
Z	O
-	O
score	O
will	O
be	O
0	O
in	O
both	O
cases	O
but	O
the	O
corresponding	O
cumulative	O
P	O
-	O
values	O
are	O
0	O
.	O
5832	O
and	O
0	O
.	O
5487	O
.	O

Therefore	O
,	O
exact	O
levels	O
of	O
significance	O
cannot	O
be	O
derived	O
from	O
Z	O
-	O
scores	O
alone	O
.	O

Thus	O
,	O
a	O
fast	O
and	O
reliable	O
procedure	O
for	O
calculating	O
Poisson	O
-	O
binomial	O
P	O
-	O
values	O
is	O
needed	O
.	O

The	O
BBD	O
approximation	O
was	O
developed	O
to	O
solve	O
this	O
problem	O
.	O

The	O
BBD	O
approximation	O
of	O
PBD	O
P	O
-	O
values	O
follows	O
from	O
the	O
relationship	O
between	O
the	O
variance	O
of	O
PBD	O
and	O
the	O
population	O
variance	O
of	O
trial	O
-	O
specific	O
probabilities	O
of	O
success	O
.	O

This	O
relationship	O
is	O
shown	O
in	O
Materials	O
and	O
Methods	O
to	O
be	O
described	O
by	O
(	O
4	O
)	O
:	O
(	O
4	O
)	O

This	O
equation	O
shows	O
that	O
there	O
is	O
an	O
inverse	O
linear	O
relationship	O
between	O
the	O
population	O
variance	O
S2	O
of	O
the	O
N	O
trial	O
probabilities	O
and	O
the	O
variance	O
of	O
PBD	O
sigma	O
2	O
,	O
which	O
means	O
that	O
PBD	O
becomes	O
increasingly	O
narrow	O
as	O
the	O
variance	O
of	O
trial	O
probabilities	O
grows	O
.	O

It	O
also	O
shows	O
that	O
,	O
for	O
constant	O
mean	O
mu	O
and	O
number	O
of	O
trials	O
N	O
,	O
the	O
shape	O
of	O
PBD	O
depends	O
only	O
on	O
the	O
variance	O
of	O
trial	O
probabilities	O
.	O

Therefore	O
,	O
relationship	O
(	O
4	O
)	O
suggests	O
an	O
easy	O
way	O
to	O
approximate	O
PBD	O
P	O
-	O
values	O
.	O

The	O
P	O
-	O
value	O
can	O
be	O
obtained	O
by	O
constructing	O
a	O
set	O
of	O
trial	O
probabilities	O
with	O
equal	O
variance	O
as	O
the	O
original	O
set	O
of	O
trial	O
probabilities	O
,	O
which	O
,	O
however	O
,	O
are	O
not	O
all	O
different	O
.	O

In	O
other	O
words	O
,	O
the	O
series	O
of	O
Poisson	O
trials	O
can	O
be	O
replaced	O
by	O
two	O
sets	O
of	O
Bernoulli	O
trials	O
with	O
trial	O
probabilities	O
p1	O
and	O
p2	O
constructed	O
such	O
that	O
the	O
variance	O
is	O
equal	O
to	O
the	O
original	O
set	O
of	O
trial	O
probabilities	O
.	O

This	O
strategy	O
is	O
illustrated	O
in	O
Fig	O
.	O

4	O
and	O
explains	O
why	O
this	O
approximation	O
is	O
called	O
bi	O
-	O
binomial	O
.	O

The	O
details	O
on	O
how	O
to	O
obtain	O
the	O
values	O
of	O
the	O
two	O
sets	O
of	O
Bernoulli	O
trial	O
probabilities	O
and	O
the	O
number	O
of	O
trials	O
with	O
p1	O
and	O
p2	O
as	O
probabilities	O
of	O
success	O
are	O
provided	O
in	O
the	O
Materials	O
and	O
Methods	O
section	O
.	O

The	O
precision	O
of	O
the	O
BBD	O
approximation	O
is	O
discussed	O
in	O
supplementary	O
material	O
Simulation	O
S1	O
.	O

In	O
order	O
to	O
evaluate	O
whether	O
BBD	O
P	O
-	O
values	O
as	O
a	O
significance	O
measure	O
of	O
co	O
-	O
occurrence	O
offer	O
an	O
advantage	O
over	O
other	O
measures	O
such	O
as	O
the	O
Jaccard	O
coefficient	O
or	O
the	O
uncertainty	O
coefficient	O
,	O
pair	O
-	O
wise	O
co	O
-	O
occurrence	O
of	O
two	O
genes	O
in	O
200	O
lists	O
with	O
and	O
without	O
list	O
-	O
length	O
-	O
heterogeneity	O
was	O
studied	O
(	O
Fig	O
.	O
5	O
)	O
.	O

Each	O
gene	O
is	O
assumed	O
to	O
occur	O
in	O
100	O
lists	O
.	O

Therefore	O
,	O
the	O
occurrence	O
probabilities	O
of	O
both	O
genes	O
over	O
all	O
200	O
lists	O
must	O
add	O
up	O
to	O
100	O
,	O
regardless	O
of	O
list	O
-	O
length	O
-	O
heterogeneity	O
.	O

For	O
simplicity	O
,	O
occurrence	O
probabilities	O
of	O
both	O
genes	O
are	O
assumed	O
to	O
be	O
equal	O
in	O
any	O
particular	O
list	O
.	O

The	O
co	O
-	O
occurrence	O
probability	O
in	O
a	O
list	O
is	O
then	O
given	O
by	O
the	O
square	O
of	O
the	O
occurrence	O
probability	O
in	O
that	O
list	O
.	O

For	O
all	O
possible	O
co	O
-	O
occurrences	O
from	O
0	O
to	O
100	O
,	O
the	O
Jaccard	O
and	O
uncertainty	O
coefficients	O
were	O
calculated	O
as	O
detailed	O
in	O
the	O
Materials	O
and	O
Methods	O
section	O
.	O

In	O
addition	O
,	O
cumulative	O
BBD	O
P	O
-	O
values	O
were	O
calculated	O
using	O
the	O
co	O
-	O
occurrence	O
probabilities	O
as	O
trial	O
probabilities	O
.	O

To	O
illustrate	O
the	O
advantage	O
of	O
BBD	O
over	O
BD	O
as	O
co	O
-	O
occurrence	O
probability	O
distribution	O
,	O
cumulative	O
BD	O
P	O
-	O
values	O
of	O
a	O
BD	O
with	O
the	O
same	O
mean	O
as	O
BBD	O
but	O
constant	O
trial	O
probabilities	O
is	O
shown	O
.	O

These	O
trial	O
probabilities	O
can	O
be	O
obtained	O
by	O
dividing	O
the	O
mean	O
of	O
BBD	O
by	O
the	O
number	O
of	O
lists	O
.	O

Three	O
different	O
cases	O
of	O
list	O
-	O
length	O
-	O
heterogeneity	O
are	O
considered	O
in	O
Fig	O
.	O

5	O
:	O
No	O
heterogeneity	O
(	O
standard	O
deviation	O
0	O
)	O
,	O
heterogeneity	O
with	O
standard	O
deviation	O
0	O
.	O
283	O
and	O
heterogeneity	O
with	O
standard	O
deviation	O
0	O
.	O
401	O
in	O
the	O
occurrence	O
probabilities	O
.	O

The	O
Jaccard	O
and	O
uncertainty	O
coefficients	O
are	O
by	O
definition	O
insensitive	O
to	O
list	O
-	O
length	O
-	O
heterogeneity	O
because	O
differences	O
in	O
co	O
-	O
occurrence	O
probabilities	O
in	O
a	O
given	O
list	O
cannot	O
be	O
considered	O
in	O
their	O
calculation	O
.	O

This	O
is	O
because	O
both	O
coefficients	O
are	O
defined	O
by	O
the	O
counts	O
of	O
the	O
four	O
list	O
classes	O
:	O
both	O
genes	O
absent	O
,	O
both	O
genes	O
present	O
,	O
first	O
gene	O
absent	O
second	O
gene	O
present	O
,	O
and	O
first	O
gene	O
present	O
second	O
gene	O
absent	O
,	O
i	O
.	O
e	O
.	O
by	O
the	O
corresponding	O
contingency	O
table	O
,	O
which	O
does	O
not	O
change	O
with	O
different	O
list	O
-	O
length	O
-	O
heterogeneity	O
.	O

In	O
the	O
absence	O
of	O
list	O
-	O
length	O
-	O
heterogeneity	O
,	O
the	O
cumulative	O
P	O
-	O
values	O
of	O
BD	O
and	O
BBD	O
(	O
which	O
are	O
perfectly	O
overlapping	O
as	O
expected	O
)	O
assume	O
0	O
.	O
5	O
at	O
50	O
co	O
-	O
occurrences	O
,	O
which	O
corresponds	O
to	O
the	O
expected	O
number	O
of	O
co	O
-	O
occurrences	O
calculated	O
as	O
(	O
50	O
=	O
100	O
occurrences	O
per	O
gene	O
/	O
200	O
lists	O
)	O
^	O
2	O
*	O
200	O
lists	O
.	O

The	O
uncertainty	O
coefficient	O
is	O
found	O
to	O
be	O
0	O
and	O
the	O
Jaccard	O
coefficient	O
is	O
0	O
.	O
33333	O
at	O
that	O
point	O
.	O

When	O
there	O
is	O
modest	O
list	O
-	O
length	O
-	O
heterogeneity	O
(	O
standard	O
deviation	O
0	O
.	O
283	O
)	O
,	O
the	O
mean	O
of	O
BBD	O
is	O
shifting	O
to	O
the	O
right	O
.	O

This	O
is	O
because	O
the	O
sum	O
of	O
squares	O
of	O
varying	O
occurrence	O
probabilities	O
(	O
i	O
.	O
e	O
.	O
the	O
sum	O
of	O
co	O
-	O
occurrence	O
probabilities	O
used	O
as	O
trial	O
probabilities	O
,	O
which	O
is	O
equal	O
to	O
the	O
mean	O
of	O
BBD	O
)	O
is	O
always	O
larger	O
than	O
the	O
sum	O
of	O
squares	O
of	O
constant	O
occurrence	O
probabilities	O
with	O
the	O
same	O
average	O
occurrence	O
probability	O
(	O
0	O
.	O
5	O
)	O
.	O

The	O
corresponding	O
BD	O
in	O
the	O
presence	O
of	O
list	O
-	O
length	O
-	O
heterogeneity	O
is	O
obtained	O
by	O
dividing	O
the	O
expected	O
number	O
of	O
co	O
-	O
occurrences	O
by	O
the	O
total	O
number	O
of	O
lists	O
,	O
which	O
means	O
assuming	O
equal	O
co	O
-	O
occurrences	O
in	O
all	O
lists	O
.	O

This	O
visualization	O
is	O
shown	O
to	O
illustrate	O
how	O
BBD	O
(	O
which	O
is	O
narrower	O
than	O
the	O
corresponding	O
BD	O
)	O
gives	O
rise	O
to	O
a	O
steeper	O
cumulative	O
distribution	O
of	O
P	O
-	O
values	O
and	O
as	O
a	O
consequence	O
to	O
more	O
significant	O
P	O
-	O
values	O
for	O
numbers	O
of	O
co	O
-	O
occurrence	O
that	O
are	O
far	O
from	O
the	O
expectation	O
.	O

As	O
the	O
level	O
of	O
list	O
-	O
length	O
-	O
heterogeneity	O
grows	O
(	O
standard	O
deviation	O
of	O
occurrence	O
probabilities	O
0	O
.	O
401	O
)	O
,	O
the	O
mean	O
of	O
BBD	O
is	O
shifted	O
even	O
further	O
to	O
the	O
right	O
and	O
BBD	O
P	O
-	O
values	O
are	O
distributed	O
in	O
a	O
still	O
steeper	O
fashion	O
as	O
compared	O
to	O
corresponding	O
BD	O
P	O
-	O
values	O
and	O
the	O
interval	O
of	O
non	O
-	O
significant	O
co	O
-	O
occurrences	O
is	O
shrinking	O
further	O
.	O

With	O
modest	O
list	O
-	O
length	O
-	O
heterogeneity	O
,	O
the	O
expected	O
number	O
of	O
co	O
-	O
occurrences	O
is	O
66	O
,	O
which	O
is	O
associated	O
with	O
a	O
Jaccard	O
coefficient	O
of	O
0	O
.	O
49	O
and	O
an	O
uncertainty	O
coefficient	O
of	O
0	O
.	O
075	O
.	O

In	O
the	O
case	O
of	O
large	O
list	O
-	O
length	O
-	O
heterogeneity	O
,	O
the	O
expected	O
number	O
of	O
co	O
-	O
occurrences	O
is	O
82	O
with	O
J	O
=	O
0	O
.	O
69	O
and	O
UC	O
=	O
0	O
.	O
32	O
.	O

Taken	O
together	O
,	O
these	O
data	O
show	O
that	O
the	O
expected	O
number	O
of	O
co	O
-	O
occurrences	O
varies	O
strongly	O
with	O
the	O
level	O
of	O
list	O
-	O
length	O
-	O
heterogeneity	O
and	O
that	O
the	O
expected	O
number	O
of	O
co	O
-	O
occurrences	O
is	O
associated	O
with	O
different	O
values	O
of	O
UC	O
and	O
J	O
.	O

To	O
complicate	O
matters	O
further	O
,	O
66	O
co	O
-	O
occurrences	O
(	O
J	O
=	O
0	O
.	O
49	O
,	O
UC	O
=	O
0	O
.	O
075	O
)	O
represent	O
significant	O
positive	O
association	O
(	O
PBBD	O
=	O
0	O
.	O
996	O
)	O
with	O
equal	O
list	O
lengths	O
,	O
no	O
significant	O
association	O
with	O
modest	O
differences	O
in	O
list	O
length	O
(	O
PBBD	O
=	O
0	O
.	O
536	O
)	O
and	O
strongly	O
negative	O
association	O
(	O
meaning	O
one	O
gene	O
excludes	O
the	O
other	O
)	O
with	O
strong	O
list	O
-	O
length	O
-	O
heterogeneity	O
(	O
PBBD	O
=	O
0	O
.	O
00016	O
)	O
.	O

Thus	O
,	O
the	O
same	O
J	O
and	O
UC	O
association	O
measure	O
is	O
obtained	O
for	O
positive	O
,	O
negative	O
,	O
and	O
absence	O
of	O
association	O
.	O

Therefore	O
,	O
the	O
meaning	O
of	O
these	O
measures	O
cannot	O
be	O
interpreted	O
properly	O
in	O
the	O
absence	O
of	O
knowledge	O
about	O
the	O
occurrence	O
probabilities	O
of	O
the	O
co	O
-	O
occurring	O
entities	O
.	O

Furthermore	O
,	O
the	O
data	O
in	O
Fig	O
.	O

5	O
also	O
show	O
that	O
neither	O
J	O
nor	O
UC	O
can	O
distinguish	O
between	O
positive	O
and	O
negative	O
association	O
while	O
this	O
is	O
easy	O
with	O
cumulative	O
BBD	O
P	O
-	O
values	O
:	O
Large	O
P	O
-	O
values	O
mean	O
positive	O
association	O
and	O
low	O
P	O
-	O
values	O
mean	O
negative	O
association	O
.	O

In	O
summary	O
,	O
we	O
conclude	O
that	O
BBD	O
provides	O
a	O
novel	O
association	O
measure	O
that	O
offers	O
a	O
number	O
of	O
advantages	O
over	O
the	O
existing	O
contingency	O
table	O
based	O
association	O
measures	O
Jaccard	O
coefficient	O
and	O
uncertainty	O
coefficient	O
.	O

The	O
results	O
in	O
Fig	O
.	O

5	O
also	O
show	O
that	O
significance	O
of	O
association	O
depends	O
critically	O
on	O
the	O
specific	O
distribution	O
of	O
co	O
-	O
occurring	O
entities	O
over	O
lists	O
of	O
varying	O
length	O
(	O
because	O
this	O
distribution	O
determines	O
the	O
occurrence	O
probabilities	O
)	O
and	O
that	O
contingency	O
table	O
based	O
methods	O
(	O
which	O
cannot	O
capture	O
this	O
distribution	O
)	O
should	O
be	O
avoided	O
in	O
the	O
presence	O
of	O
significant	O
list	O
-	O
length	O
-	O
heterogeneity	O
.	O

Generation	O
of	O
co	O
-	O
occurrence	O
networks	O
and	O
the	O
identification	O
of	O
communities	O

The	O
procedures	O
outlined	O
above	O
allow	O
the	O
identification	O
of	O
significant	O
co	O
-	O
occurrence	O
modules	O
in	O
any	O
type	O
of	O
bipartite	O
graph	O
.	O

Three	O
user	O
defined	O
parameters	O
have	O
an	O
impact	O
on	O
the	O
stringency	O
of	O
co	O
-	O
occurrence	O
analysis	O
:	O
The	O
module	O
size	O
,	O
the	O
support	O
,	O
and	O
the	O
Z	O
-	O
score	O
/	O
P	O
-	O
value	O
cutoff	O
.	O

The	O
module	O
size	O
determines	O
how	O
many	O
entries	O
will	O
be	O
tested	O
for	O
co	O
-	O
occurrence	O
,	O
the	O
support	O
sets	O
a	O
lower	O
boundary	O
on	O
the	O
required	O
number	O
of	O
co	O
-	O
occurrences	O
,	O
and	O
the	O
Z	O
-	O
score	O
/	O
P	O
-	O
value	O
cutoff	O
sets	O
the	O
significance	O
threshold	O
.	O

In	O
general	O
,	O
higher	O
module	O
size	O
leads	O
to	O
more	O
stringent	O
co	O
-	O
occurrence	O
analysis	O
at	O
the	O
cost	O
of	O
computational	O
complexity	O
.	O

The	O
support	O
parameter	O
allows	O
limiting	O
this	O
complexity	O
by	O
filtering	O
out	O
co	O
-	O
occurrence	O
modules	O
which	O
co	O
-	O
occur	O
less	O
frequently	O
than	O
required	O
by	O
the	O
support	O
.	O

The	O
significance	O
cutoff	O
permits	O
adjusting	O
the	O
signal	O
-	O
to	O
-	O
noise	O
ratio	O
,	O
which	O
is	O
calculated	O
as	O
the	O
number	O
of	O
co	O
-	O
occurrence	O
modules	O
observed	O
in	O
the	O
real	O
versus	O
a	O
randomized	O
bipartite	O
graph	O
.	O

The	O
impact	O
of	O
these	O
parameters	O
on	O
the	O
stringency	O
of	O
co	O
-	O
occurrence	O
analysis	O
has	O
been	O
reported	O
previously	O
for	O
the	O
PubLiME	O
data	O
set	O
[	O
35	O
]	O
and	O
is	O
illustrated	O
in	O
a	O
simulation	O
study	O
provided	O
as	O
supplementary	O
material	O
Simulation	O
S1	O
.	O

From	O
the	O
set	O
of	O
significant	O
co	O
-	O
occurrence	O
modules	O
,	O
a	O
co	O
-	O
occurrence	O
network	O
is	O
generated	O
by	O
considering	O
each	O
entry	O
a	O
vertex	O
and	O
drawing	O
an	O
edge	O
between	O
any	O
two	O
vertices	O
,	O
which	O
have	O
been	O
part	O
of	O
the	O
same	O
significant	O
co	O
-	O
occurrence	O
module	O
[	O
35	O
]	O
.	O

An	O
important	O
question	O
in	O
the	O
analysis	O
of	O
co	O
-	O
occurrence	O
networks	O
regards	O
the	O
presence	O
of	O
network	O
communities	O
.	O

Communities	O
can	O
be	O
understood	O
as	O
groups	O
of	O
vertices	O
with	O
the	O
property	O
that	O
the	O
number	O
of	O
edges	O
running	O
within	O
groups	O
is	O
larger	O
than	O
expected	O
by	O
chance	O
and	O
that	O
the	O
number	O
of	O
edges	O
running	O
between	O
groups	O
is	O
lower	O
than	O
expected	O
by	O
chance	O
[	O
37	O
]	O
.	O

This	O
problem	O
of	O
partitioning	O
a	O
graph	O
is	O
often	O
referred	O
to	O
as	O
the	O
graph	O
-	O
cut	O
problem	O
(	O
hence	O
the	O
name	O
NetCutter	O
)	O
.	O

NetCutter	O
is	O
built	O
on	O
the	O
Java	O
Universal	O
Network	O
and	O
Graph	O
framework	O
(	O
JUNG	O
)	O
software	O
package	O
(	O
http	O
:	O
/	O
/	O
jung	O
.	O
sourceforge	O
.	O
net	O
)	O
,	O
which	O
provides	O
algorithms	O
for	O
solving	O
this	O
problem	O
.	O

In	O
particular	O
,	O
NetCutter	O
implements	O
the	O
Bicomponent	O
clustering	O
algorithm	O
[	O
38	O
]	O
,	O
the	O
Edge	O
-	O
Betweenness	O
clustering	O
algorithm	O
[	O
39	O
]	O
,	O
and	O
the	O
Exact	O
Flow	O
Community	O
algorithm	O
[	O
40	O
]	O
.	O

Furthermore	O
,	O
there	O
is	O
a	O
clustering	O
tool	O
that	O
is	O
not	O
part	O
of	O
the	O
JUNG	O
package	O
,	O
namely	O
an	O
algorithm	O
identifying	O
communities	O
using	O
eigenvectors	O
of	O
the	O
modularity	O
matrix	O
[	O
37	O
]	O
.	O

The	O
code	O
for	O
this	O
algorithm	O
was	O
kindly	O
provided	O
by	O
Mark	O
Newman	O
in	O
C	O
+	O
+	O
and	O
ported	O
to	O
Java	O
.	O

In	O
addition	O
to	O
these	O
tools	O
,	O
NetCutter	O
provides	O
a	O
number	O
of	O
convenience	O
functions	O
for	O
the	O
analysis	O
of	O
co	O
-	O
occurrence	O
networks	O
,	O
such	O
as	O
testing	O
the	O
significance	O
of	O
lists	O
reporting	O
a	O
set	O
of	O
entries	O
making	O
up	O
a	O
network	O
community	O
,	O
ranking	O
of	O
vertices	O
,	O
random	O
graph	O
generators	O
for	O
topological	O
analysis	O
of	O
co	O
-	O
occurrence	O
networks	O
,	O
and	O
others	O
.	O

Details	O
on	O
all	O
functions	O
are	O
provided	O
in	O
the	O
NetCutter	O
software	O
documentation	O
.	O

One	O
of	O
the	O
possible	O
applications	O
of	O
NetCutter	O
is	O
illustrated	O
below	O
.	O

This	O
application	O
is	O
tightly	O
linked	O
to	O
the	O
bipartite	O
graph	O
representation	O
of	O
the	O
data	O
.	O

Namely	O
,	O
NetCutter	O
can	O
be	O
used	O
to	O
perform	O
co	O
-	O
occurrence	O
analysis	O
of	O
genes	O
or	O
list	O
derived	O
from	O
the	O
same	O
bipartite	O
graph	O
.	O

The	O
network	O
communities	O
identified	O
in	O
each	O
both	O
reflect	O
the	O
same	O
underlying	O
structure	O
of	O
the	O
bipartite	O
graph	O
.	O

In	O
the	O
case	O
of	O
gene	O
expression	O
signatures	O
stored	O
in	O
PubLiME	O
,	O
clusters	O
of	O
genes	O
correspond	O
to	O
clusters	O
of	O
publications	O
,	O
which	O
can	O
reveal	O
possible	O
functions	O
of	O
gene	O
clusters	O
.	O

Cluster	O
correspondence	O
and	O
association	O
studies	O

The	O
co	O
-	O
occurrence	O
analysis	O
of	O
the	O
PubLiME	O
data	O
set	O
published	O
previously	O
[	O
35	O
]	O
identified	O
5	O
major	O
network	O
communities	O
of	O
genes	O
with	O
consistent	O
functional	O
annotations	O
that	O
are	O
deregulated	O
in	O
cancer	O
related	O
gene	O
expression	O
signatures	O
.	O

This	O
analysis	O
was	O
performed	O
by	O
considering	O
all	O
genes	O
mentioned	O
in	O
a	O
particular	O
publication	O
as	O
a	O
single	O
signature	O
,	O
even	O
though	O
they	O
might	O
have	O
been	O
part	O
of	O
different	O
tables	O
and	O
cluster	O
analyses	O
.	O

Here	O
we	O
present	O
an	O
advanced	O
analysis	O
of	O
the	O
PubLiME	O
data	O
set	O
where	O
each	O
table	O
and	O
/	O
or	O
cluster	O
identified	O
in	O
a	O
given	O
publication	O
is	O
considered	O
as	O
a	O
separate	O
signature	O
.	O

This	O
brings	O
the	O
total	O
number	O
of	O
signatures	O
to	O
be	O
analyzed	O
to	O
1015	O
comprising	O
a	O
total	O
of	O
7358	O
differentially	O
regulated	O
genes	O
derived	O
from	O
233	O
publications	O
reporting	O
cancer	O
related	O
signatures	O
derived	O
from	O
human	B
samples	O
.	O

We	O
use	O
this	O
analysis	O
to	O
illustrate	O
three	O
major	O
points	O
:	O
First	O
,	O
the	O
set	O
of	O
communities	O
reported	O
previously	O
is	O
reproduced	O
by	O
this	O
more	O
fine	O
-	O
grained	O
analysis	O
.	O

Second	O
,	O
the	O
set	O
of	O
gene	O
communities	O
corresponds	O
to	O
a	O
set	O
of	O
publication	O
communities	O
.	O

Third	O
,	O
associations	O
between	O
publications	O
and	O
gene	O
communities	O
can	O
be	O
calculated	O
with	O
higher	O
stringency	O
using	O
the	O
edge	O
-	O
swapping	O
null	O
-	O
model	O
in	O
conjunction	O
with	O
bi	O
-	O
binomial	O
P	O
-	O
values	O
as	O
compared	O
to	O
binomial	O
or	O
hypergeometric	O
statistics	O
.	O

The	O
bipartite	O
graph	O
to	O
be	O
analyzed	O
is	O
composed	O
of	O
PubMedID	O
_	O
listID	O
-	O
gene	O
pairs	O
(	O
see	O
supplementary	O
material	O
Table	O
S1	O
)	O
.	O

Co	O
-	O
occurrence	O
analysis	O
was	O
carried	O
out	O
in	O
two	O
ways	O
:	O
First	O
,	O
gene	O
co	O
-	O
occurrence	O
was	O
analyzed	O
and	O
communities	O
of	O
co	O
-	O
occurring	O
genes	O
were	O
defined	O
by	O
edge	O
-	O
betweenness	O
clustering	O
as	O
described	O
in	O
Materials	O
and	O
Methods	O
.	O

Second	O
,	O
co	O
-	O
occurrence	O
of	O
PubMedID	O
_	O
listIDs	O
was	O
analyzed	O
.	O

To	O
this	O
end	O
,	O
the	O
order	O
of	O
PubMedID	O
_	O
listID	O
-	O
gene	O
pairs	O
was	O
reversed	O
to	O
form	O
GENE	O
-	O
PUBMEDID	O
_	O
LISTID	O
pairs	O
.	O

Thus	O
,	O
the	O
lists	O
in	O
the	O
resulting	O
bipartite	O
graph	O
are	O
formed	O
by	O
genes	O
and	O
the	O
entries	O
are	O
the	O
PubMedID	O
_	O
listIDs	O
where	O
the	O
genes	O
are	O
reported	O
as	O
differentially	O
regulated	O
.	O

Occurrence	O
probabilities	O
for	O
the	O
reversed	O
bipartite	O
graph	O
can	O
be	O
obtained	O
by	O
transposing	O
the	O
occurrence	O
probability	O
matrix	O
of	O
the	O
original	O
bipartite	O
graph	O
.	O

Since	O
the	O
gene	O
communities	O
identified	O
in	O
gene	O
co	O
-	O
occurrence	O
analysis	O
reflect	O
the	O
structure	O
inherent	O
in	O
the	O
bipartite	O
graph	O
(	O
which	O
is	O
not	O
affected	O
by	O
reversing	O
the	O
list	O
-	O
entry	O
order	O
)	O
,	O
co	O
-	O
occurrence	O
analysis	O
of	O
the	O
reversed	O
bipartite	O
graph	O
will	O
result	O
in	O
PubMedID	O
_	O
listID	O
communities	O
that	O
reflect	O
the	O
same	O
underlying	O
structure	O
in	O
the	O
bipartite	O
graph	O
.	O

In	O
other	O
words	O
,	O
PubMedID	O
_	O
listID	O
communities	O
correspond	O
to	O
gene	O
communities	O
.	O

In	O
less	O
abstract	O
terms	O
,	O
the	O
PubMedID	O
_	O
listID	O
communities	O
should	O
correspond	O
to	O
sets	O
of	O
publications	O
that	O
report	O
similar	O
sets	O
of	O
genes	O
as	O
differentially	O
regulated	O
.	O

The	O
identification	O
of	O
communities	O
of	O
publications	O
can	O
help	O
the	O
researcher	O
to	O
easily	O
identify	O
publications	O
studying	O
genes	O
in	O
a	O
gene	O
community	O
that	O
is	O
of	O
interest	O
to	O
the	O
researcher	O
.	O

The	O
results	O
of	O
both	O
types	O
of	O
co	O
-	O
occurrence	O
analysis	O
are	O
displayed	O
in	O
Fig	O
.	O

6	O
.	O

Fig	O
.	O

6A	O
shows	O
the	O
gene	O
clusters	O
identified	O
.	O

The	O
clusters	O
are	O
named	O
after	O
significant	O
enrichments	O
of	O
gene	O
categories	O
as	O
determined	O
by	O
functional	O
category	O
enrichment	O
using	O
DAVID	O
[	O
41	O
]	O
.	O

The	O
P	O
-	O
values	O
shown	O
are	O
Benjamini	O
corrected	O
for	O
multiple	O
testing	O
as	O
reported	O
by	O
DAVID	O
.	O

The	O
clusters	O
are	O
very	O
similar	O
to	O
the	O
clusters	O
published	O
previously	O
[	O
35	O
]	O
.	O

There	O
is	O
one	O
new	O
cluster	O
that	O
is	O
strongly	O
enriched	O
for	O
ribosomal	O
proteins	O
(	O
"	O
protein	O
biosynthesis	O
"	O
cluster	O
)	O
,	O
which	O
has	O
not	O
reached	O
significance	O
in	O
our	O
previous	O
analysis	O
.	O

The	O
"	O
surface	O
antigen	O
"	O
cluster	O
contains	O
many	O
genes	O
that	O
had	O
been	O
reported	O
as	O
part	O
of	O
the	O
"	O
signal	O
transduction	O
"	O
cluster	O
.	O

Altogether	O
,	O
however	O
,	O
these	O
results	O
strongly	O
support	O
the	O
notion	O
that	O
the	O
gene	O
clusters	O
in	O
the	O
PubLiME	O
data	O
set	O
can	O
be	O
reproduced	O
by	O
the	O
more	O
fine	O
-	O
grained	O
analysis	O
that	O
considers	O
sublists	O
in	O
each	O
publication	O
as	O
separate	O
signatures	O
.	O

The	O
corresponding	O
clusters	O
of	O
PubMedID	O
_	O
listIDs	O
are	O
shown	O
in	O
Fig	O
.	O

6B	O
.	O

There	O
are	O
five	O
clusters	O
,	O
which	O
have	O
been	O
named	O
after	O
their	O
corresponding	O
gene	O
cluster	O
.	O

Only	O
one	O
cluster	O
(	O
the	O
"	O
extracellular	O
matrix	O
-	O
immune	O
response	O
cluster	O
"	O
)	O
cannot	O
be	O
separated	O
by	O
edge	O
-	O
betweenness	O
clustering	O
at	O
the	O
point	O
of	O
maximal	O
graph	O
modularity	O
.	O

To	O
see	O
that	O
this	O
naming	O
is	O
indeed	O
justified	O
,	O
we	O
needed	O
to	O
investigate	O
how	O
strongly	O
a	O
given	O
PubMedID	O
_	O
listID	O
is	O
associated	O
with	O
a	O
given	O
gene	O
cluster	O
,	O
i	O
.	O
e	O
.	O
how	O
significant	O
is	O
the	O
overlap	O
of	O
the	O
genes	O
reported	O
in	O
a	O
gene	O
cluster	O
and	O
the	O
genes	O
reported	O
in	O
a	O
PubMedID	O
_	O
listID	O
.	O

Binomial	O
or	O
hypergemetric	O
statistics	O
are	O
generally	O
used	O
to	O
calculate	O
this	O
significance	O
.	O

However	O
,	O
the	O
bipartite	O
graph	O
model	O
in	O
conjunction	O
with	O
the	O
edge	O
-	O
swapping	O
null	O
-	O
model	O
offers	O
a	O
more	O
fine	O
-	O
grained	O
approach	O
based	O
on	O
bi	O
-	O
binomial	O
statistics	O
.	O

The	O
edge	O
-	O
swapping	O
null	O
-	O
model	O
determines	O
occurrence	O
probabilities	O
in	O
such	O
a	O
way	O
that	O
the	O
number	O
of	O
genes	O
in	O
a	O
given	O
PubMedID	O
_	O
listID	O
is	O
associated	O
with	O
insignificant	O
P	O
-	O
values	O
in	O
the	O
context	O
of	O
the	O
complete	O
bipartite	O
graph	O
.	O

However	O
,	O
when	O
a	O
subset	O
of	O
genes	O
is	O
analyzed	O
,	O
e	O
.	O
g	O
.	O
all	O
the	O
genes	O
that	O
are	O
reported	O
in	O
a	O
particular	O
list	O
,	O
the	O
P	O
-	O
value	O
associated	O
with	O
the	O
number	O
of	O
genes	O
contained	O
in	O
this	O
list	O
will	O
likely	O
be	O
highly	O
significant	O
according	O
to	O
how	O
unlikely	O
it	O
is	O
to	O
obtain	O
all	O
the	O
genes	O
contained	O
in	O
a	O
given	O
list	O
in	O
a	O
random	O
draw	O
from	O
all	O
genes	O
present	O
in	O
the	O
bipartite	O
graph	O
.	O

Thus	O
,	O
PubMedID	O
_	O
listID	O
association	O
with	O
a	O
set	O
of	O
genes	O
in	O
the	O
bipartite	O
graph	O
model	O
can	O
be	O
calculated	O
in	O
the	O
following	O
way	O
:	O
The	O
set	O
of	O
genes	O
that	O
is	O
used	O
to	O
analyze	O
association	O
is	O
used	O
to	O
extract	O
a	O
subgraph	O
from	O
the	O
original	O
bipartite	O
graph	O
where	O
occurrence	O
probabilities	O
for	O
each	O
gene	O
-	O
PubMedID	O
_	O
listID	O
pair	O
are	O
identical	O
to	O
those	O
in	O
the	O
original	O
bipartite	O
graph	O
(	O
i	O
.	O
e	O
.	O
they	O
are	O
not	O
recalculated	O
by	O
edge	O
-	O
swapping	O
)	O
.	O

The	O
vertex	O
degree	O
of	O
the	O
PubMedID	O
_	O
listID	O
vertices	O
in	O
the	O
subgraph	O
indicates	O
the	O
number	O
of	O
genes	O
contained	O
in	O
each	O
PubMedID	O
_	O
listID	O
overlapping	O
with	O
the	O
set	O
of	O
genes	O
used	O
to	O
extract	O
the	O
subgraph	O
.	O

From	O
the	O
occurrence	O
probabilities	O
of	O
the	O
genes	O
in	O
a	O
given	O
PubMedID	O
_	O
listID	O
,	O
the	O
bi	O
-	O
binomial	O
P	O
-	O
value	O
can	O
then	O
be	O
calculated	O
for	O
every	O
list	O
vertex	O
degree	O
observed	O
in	O
the	O
subgraph	O
.	O

In	O
Fig	O
.	O

7	O
,	O
the	O
significance	O
of	O
association	O
of	O
the	O
PubMedID	O
_	O
listIDs	O
(	O
see	O
Fig	O
.	O
6B	O
)	O
with	O
the	O
cell	O
cycle	O
cluster	O
of	O
genes	O
(	O
Fig	O
.	O
6A	O
)	O
is	O
calculated	O
.	O

For	O
comparison	O
,	O
binomial	O
and	O
hypergeometric	O
P	O
-	O
values	O
are	O
also	O
shown	O
.	O

It	O
can	O
be	O
seen	O
that	O
the	O
bi	O
-	O
binomial	O
P	O
-	O
value	O
is	O
larger	O
than	O
the	O
binomial	O
and	O
hypergeometric	O
P	O
-	O
values	O
,	O
which	O
means	O
that	O
the	O
strength	O
of	O
association	O
is	O
evaluated	O
in	O
a	O
more	O
stringent	O
manner	O
using	O
BBD	O
statistics	O
(	O
see	O
Discussion	O
for	O
an	O
explanation	O
of	O
this	O
observation	O
)	O
.	O

The	O
analysis	O
of	O
significant	O
associations	O
between	O
PubMedID	O
_	O
listIDs	O
and	O
gene	O
clusters	O
now	O
permit	O
answering	O
the	O
question	O
whether	O
there	O
is	O
correspondence	O
between	O
gene	O
clusters	O
and	O
PubMedID	O
_	O
listID	O
clusters	O
.	O

The	O
naming	O
of	O
PubMedID	O
_	O
listID	O
clusters	O
shown	O
in	O
Fig	O
.	O

6B	O
is	O
based	O
on	O
the	O
number	O
of	O
PubMedID	O
_	O
listID	O
that	O
are	O
significantly	O
associated	O
with	O
gene	O
clusters	O
shown	O
in	O
Fig	O
.	O

6A	O
.	O

First	O
,	O
for	O
each	O
gene	O
cluster	O
,	O
all	O
the	O
PubMedID	O
_	O
listIDs	O
that	O
are	O
associated	O
with	O
that	O
cluster	O
with	O
more	O
than	O
95	O
%	O
confidence	O
(	O
i	O
.	O
e	O
.	O
cumulative	O
bi	O
-	O
binomial	O
P	O
-	O
values	O
>	O
=	O
0	O
.	O
95	O
)	O
were	O
identified	O
.	O

Second	O
,	O
the	O
number	O
of	O
significant	O
PubMedID	O
_	O
listIDs	O
in	O
each	O
PubMedID	O
_	O
listID	O
cluster	O
was	O
counted	O
for	O
every	O
gene	O
cluster	O
.	O

The	O
significance	O
of	O
this	O
number	O
was	O
then	O
calculated	O
using	O
binomial	O
statistics	O
.	O

The	O
results	O
of	O
this	O
analysis	O
are	O
shown	O
in	O
Table	O
1	O
.	O

Negative	O
decadic	O
logarithms	O
of	O
the	O
binomial	O
P	O
-	O
value	O
are	O
displayed	O
.	O

It	O
is	O
apparent	O
that	O
each	O
PubMedID	O
_	O
listID	O
cluster	O
is	O
strongly	O
associated	O
with	O
at	O
least	O
one	O
gene	O
cluster	O
,	O
except	O
for	O
the	O
"	O
extracellular	O
matrix	O
-	O
immune	O
response	O
"	O
cluster	O
,	O
which	O
is	O
associated	O
with	O
two	O
gene	O
clusters	O
.	O

The	O
strength	O
of	O
these	O
associations	O
suggests	O
that	O
the	O
PubMedID	O
_	O
listID	O
clusters	O
are	O
indeed	O
corresponding	O
to	O
the	O
gene	O
clusters	O
and	O
that	O
both	O
the	O
gene	O
and	O
the	O
PubMedID	O
_	O
listID	O
clusters	O
reflect	O
the	O
structure	O
of	O
the	O
bipartite	O
graph	O
representing	O
the	O
PubLiME	O
data	O
set	O
.	O

Details	O
about	O
all	O
the	O
lists	O
analyzed	O
are	O
attached	O
as	O
supplementary	O
material	O
Table	O
S2	O
.	O

Looking	O
at	O
these	O
lists	O
,	O
some	O
general	O
conclusions	O
about	O
the	O
gene	O
clusters	O
can	O
be	O
drawn	O
.	O

Cell	O
cycle	O
cluster	O
genes	O
have	O
been	O
found	O
deregulated	O
in	O
a	O
wide	O
variety	O
of	O
tumor	O
types	O
such	O
as	O
colon	O
cancer	O
,	O
breast	O
cancer	O
,	O
in	O
biliary	O
tract	O
cancer	O
,	O
pancreatic	O
cancer	O
,	O
gastric	O
cancer	O
,	O
prostate	O
cancer	O
,	O
T	O
-	O
cell	O
leukemia	O
,	O
glioma	O
,	O
acute	O
lymphoblastic	O
and	O
myeloblastic	O
leukemias	O
,	O
soft	O
tissue	O
sarcoma	O
,	O
neuroblastoma	O
,	O
as	O
well	O
as	O
in	O
a	O
number	O
of	O
cellular	O
model	O
systems	O
in	O
response	O
to	O
different	O
stimuli	O
.	O

Thus	O
,	O
the	O
cell	O
cycle	O
cluster	O
seems	O
to	O
consist	O
of	O
genes	O
with	O
a	O
general	O
role	O
in	O
oncogenesis	O
.	O

The	O
surface	O
antigen	O
cluster	O
instead	O
seems	O
to	O
be	O
derived	O
preferentially	O
from	O
studies	O
on	O
leukemia	O
.	O

The	O
interferon	O
cluster	O
genes	O
are	O
found	O
deregulated	O
in	O
virus	O
induced	O
pathologies	O
such	O
as	O
papilloma	O
virus	O
induced	O
cervical	O
cancer	O
,	O
and	O
viral	O
hepatitis	O
.	O

Immune	O
response	O
cluster	O
genes	O
were	O
reported	O
as	O
differentially	O
regulated	O
in	O
inflammatory	O
conditions	O
such	O
as	O
ulcerative	O
colitis	O
,	O
Crohn	O
'	O
s	O
disease	O
,	O
and	O
Helicobacter	B
pylori	I
infections	O
.	O

Genes	O
of	O
the	O
extracellular	O
matrix	O
cluster	O
seem	O
to	O
be	O
associated	O
with	O
cancer	O
progression	O
studies	O
and	O
metastatic	O
potential	O
.	O

For	O
the	O
protein	O
biosynthesis	O
cluster	O
,	O
there	O
are	O
15	O
signatures	O
that	O
are	O
significantly	O
enriched	O
for	O
those	O
genes	O
.	O

The	O
cancers	O
studied	O
comprise	O
medulloblastoma	O
,	O
glioblastoma	O
,	O
pancreatic	O
cancer	O
,	O
soft	O
tissue	O
sarcoma	O
,	O
lung	O
carcinoma	O
,	O
breast	O
carcinoma	O
,	O
prostate	O
carcinoma	O
,	O
multiple	O
myeloma	O
,	O
and	O
lymphocytic	O
leukemia	O
.	O

The	O
genes	O
are	O
also	O
found	O
deregulated	O
in	O
response	O
to	O
DNA	O
damage	O
.	O

Although	O
the	O
number	O
of	O
signatures	O
is	O
limited	O
,	O
the	O
variation	O
in	O
conditions	O
where	O
the	O
genes	O
are	O
deregulated	O
is	O
compatible	O
with	O
the	O
hypothesis	O
that	O
protein	O
biosynthesis	O
genes	O
,	O
as	O
cell	O
cycle	O
genes	O
,	O
are	O
deregulated	O
in	O
many	O
cancer	O
types	O
,	O
which	O
might	O
reflect	O
the	O
general	O
property	O
of	O
cancer	O
cells	O
to	O
divide	O
and	O
grow	O
in	O
an	O
uncontrolled	O
fashion	O
.	O

Discussion	O

Here	O
we	O
have	O
investigated	O
basic	O
aspects	O
of	O
co	O
-	O
occurrence	O
analysis	O
and	O
present	O
a	O
software	O
tool	O
,	O
NetCutter	O
,	O
which	O
can	O
be	O
used	O
to	O
identify	O
and	O
analyze	O
generic	O
co	O
-	O
occurrence	O
networks	O
.	O

In	O
NetCutter	O
,	O
a	O
co	O
-	O
occurrence	O
data	O
set	O
is	O
represented	O
as	O
a	O
bipartite	O
graph	O
with	O
one	O
part	O
representing	O
lists	O
and	O
the	O
other	O
part	O
list	O
entries	O
whose	O
co	O
-	O
occurrence	O
patterns	O
are	O
studied	O
.	O

The	O
bipartite	O
graph	O
representation	O
of	O
co	O
-	O
occurrence	O
data	O
sets	O
allows	O
the	O
efficacy	O
of	O
different	O
null	O
-	O
models	O
to	O
be	O
tested	O
systematically	O
.	O

We	O
have	O
shown	O
that	O
an	O
edge	O
-	O
swapping	O
procedure	O
used	O
to	O
randomize	O
the	O
bipartite	O
graph	O
generates	O
a	O
null	O
-	O
model	O
that	O
allows	O
co	O
-	O
occurrence	O
analysis	O
with	O
the	O
highest	O
stringency	O
.	O

The	O
other	O
null	O
-	O
models	O
tested	O
here	O
tend	O
to	O
underestimate	O
occurrence	O
probabilities	O
of	O
entries	O
per	O
list	O
for	O
lists	O
and	O
genes	O
with	O
high	O
vertex	O
degrees	O
,	O
i	O
.	O
e	O
.	O
for	O
lists	O
and	O
genes	O
where	O
most	O
co	O
-	O
occurrences	O
are	O
observed	O
.	O

As	O
a	O
result	O
,	O
co	O
-	O
occurrences	O
are	O
judged	O
more	O
significant	O
than	O
they	O
really	O
are	O
.	O

Co	O
-	O
occurrence	O
data	O
sets	O
with	O
exactly	O
equal	O
lists	O
lengths	O
are	O
likely	O
to	O
be	O
the	O
exception	O
from	O
the	O
rule	O
.	O

It	O
can	O
be	O
assumed	O
that	O
some	O
list	O
-	O
length	O
-	O
heterogeneity	O
will	O
be	O
present	O
in	O
most	O
circumstances	O
.	O

An	O
important	O
consequence	O
of	O
list	O
-	O
length	O
-	O
heterogeneity	O
regards	O
the	O
co	O
-	O
occurrence	O
probability	O
distribution	O
used	O
to	O
evaluate	O
the	O
significance	O
of	O
the	O
observed	O
number	O
of	O
co	O
-	O
occurrences	O
.	O

Co	O
-	O
occurrence	O
analysis	O
in	O
the	O
presence	O
of	O
list	O
-	O
length	O
-	O
heterogeneity	O
is	O
best	O
performed	O
using	O
the	O
Poisson	O
-	O
binomial	O
distribution	O
(	O
a	O
binomial	O
distribution	O
with	O
trial	O
specific	O
probabilities	O
)	O
.	O

However	O
,	O
calculating	O
Poisson	O
-	O
binomial	O
P	O
-	O
values	O
for	O
large	O
numbers	O
of	O
lists	O
is	O
difficult	O
using	O
existing	O
procedures	O
[	O
36	O
]	O
.	O

We	O
have	O
presented	O
an	O
approximation	O
to	O
the	O
Poisson	O
-	O
binomial	O
distribution	O
,	O
called	O
bi	O
-	O
binomial	O
distribution	O
,	O
which	O
is	O
based	O
on	O
replacing	O
the	O
set	O
of	O
Poisson	O
trials	O
by	O
two	O
sets	O
of	O
Bernoulli	O
trials	O
.	O

The	O
resulting	O
distribution	O
reproduces	O
the	O
Poisson	O
-	O
binomial	O
distribution	O
nearly	O
exactly	O
and	O
its	O
P	O
-	O
values	O
can	O
be	O
calculated	O
with	O
ease	O
even	O
for	O
thousands	O
of	O
lists	O
(	O
see	O
also	O
supplementary	O
material	O
Simulation	O
S1	O
for	O
details	O
on	O
the	O
precision	O
of	O
BBD	O
)	O
.	O

Importantly	O
,	O
BBD	O
provides	O
a	O
novel	O
measure	O
of	O
association	O
,	O
which	O
is	O
shown	O
to	O
be	O
superior	O
to	O
existing	O
measures	O
such	O
as	O
the	O
Jaccard	O
coefficient	O
and	O
the	O
uncertainty	O
coefficient	O
,	O
whose	O
values	O
cannot	O
be	O
interpreted	O
properly	O
in	O
the	O
absence	O
of	O
knowledge	O
about	O
the	O
occurrence	O
probabilities	O
of	O
co	O
-	O
occurring	O
entities	O
.	O

It	O
is	O
worth	O
noting	O
that	O
Poisson	O
-	O
binomial	O
Z	O
-	O
scores	O
are	O
distinguished	O
from	O
Gaussian	O
Z	O
-	O
scores	O
by	O
the	O
fact	O
that	O
they	O
do	O
not	O
correspond	O
to	O
the	O
same	O
P	O
-	O
value	O
for	O
different	O
PBDs	O
,	O
BBDs	O
,	O
and	O
even	O
BDs	O
.	O

This	O
is	O
because	O
the	O
Z	O
-	O
score	O
is	O
an	O
explicit	O
part	O
of	O
the	O
function	O
defining	O
the	O
normal	O
probability	O
density	O
while	O
it	O
is	O
not	O
part	O
of	O
the	O
definitions	O
of	O
BD	O
,	O
PBD	O
,	O
and	O
BBD	O
densities	O
.	O

As	O
a	O
consequence	O
,	O
the	O
simple	O
Poisson	O
-	O
binomial	O
Z	O
-	O
score	O
based	O
approach	O
to	O
evaluating	O
significance	O
of	O
co	O
-	O
occurrence	O
must	O
be	O
complemented	O
with	O
the	O
BBD	O
to	O
approximate	O
Poisson	O
-	O
binomial	O
P	O
-	O
values	O
in	O
order	O
to	O
enable	O
multiple	O
testing	O
corrections	O
and	O
to	O
allow	O
calculation	O
of	O
confidence	O
levels	O
in	O
association	O
studies	O
precisely	O
.	O

However	O
,	O
NetCutter	O
is	O
equipped	O
with	O
a	O
bipartite	O
graph	O
randomization	O
tool	O
that	O
permits	O
measuring	O
the	O
number	O
of	O
false	O
positives	O
due	O
to	O
multiple	O
testing	O
directly	O
by	O
comparing	O
the	O
number	O
of	O
significant	O
co	O
-	O
occurrence	O
modules	O
in	O
the	O
real	O
bipartite	O
graph	O
to	O
the	O
corresponding	O
number	O
in	O
a	O
randomized	O
version	O
thereof	O
.	O

Randomization	O
is	O
performed	O
by	O
edge	O
-	O
swapping	O
in	O
order	O
to	O
preserve	O
vertex	O
degrees	O
.	O

The	O
resulting	O
signal	O
-	O
to	O
-	O
noise	O
ratios	O
that	O
are	O
plotted	O
for	O
each	O
Z	O
-	O
score	O
/	O
P	O
-	O
value	O
cutoff	O
provide	O
a	O
highly	O
reliable	O
and	O
visually	O
intuitive	O
defense	O
mechanism	O
against	O
false	O
positives	O
(	O
see	O
also	O
supplementary	O
material	O
Simulation	O
S1	O
)	O
.	O

In	O
the	O
vast	O
majority	O
of	O
co	O
-	O
occurrence	O
studies	O
,	O
pair	O
-	O
wise	O
co	O
-	O
occurrences	O
have	O
been	O
analyzed	O
using	O
different	O
statistical	O
models	O
.	O

We	O
have	O
observed	O
that	O
the	O
stringency	O
of	O
pair	O
-	O
wise	O
co	O
-	O
occurrence	O
analysis	O
is	O
far	O
below	O
the	O
stringency	O
of	O
co	O
-	O
occurrence	O
analysis	O
using	O
higher	O
order	O
combinations	O
of	O
co	O
-	O
occurring	O
entities	O
[	O
35	O
]	O
.	O

In	O
NetCutter	O
,	O
co	O
-	O
occurrence	O
analysis	O
is	O
preceded	O
by	O
occurrence	O
analysis	O
,	O
i	O
.	O
e	O
.	O
the	O
occurrence	O
probability	O
of	O
each	O
entry	O
in	O
each	O
list	O
is	O
determined	O
.	O

Starting	O
from	O
occurrence	O
probabilities	O
,	O
co	O
-	O
occurrence	O
probabilities	O
for	O
any	O
size	O
of	O
co	O
-	O
occurrence	O
modules	O
under	O
study	O
can	O
be	O
obtained	O
by	O
multiplying	O
the	O
respective	O
list	O
-	O
specific	O
occurrence	O
probabilities	O
.	O

Given	O
the	O
list	O
-	O
specific	O
co	O
-	O
occurrence	O
probabilities	O
,	O
bi	O
-	O
binomial	O
P	O
-	O
values	O
are	O
then	O
calculated	O
in	O
exactly	O
the	O
same	O
way	O
for	O
any	O
module	O
size	O
.	O

As	O
a	O
consequence	O
,	O
NetCutter	O
can	O
perform	O
co	O
-	O
occurrence	O
analysis	O
for	O
higher	O
order	O
combinations	O
of	O
co	O
-	O
occurring	O
entries	O
(	O
i	O
.	O
e	O
.	O
larger	O
module	O
sizes	O
)	O
using	O
the	O
same	O
statistical	O
model	O
.	O

One	O
of	O
the	O
benefits	O
of	O
using	O
higher	O
module	O
sizes	O
is	O
robustness	O
of	O
the	O
analyses	O
in	O
the	O
presence	O
of	O
noise	O
.	O

This	O
is	O
because	O
each	O
edge	O
in	O
the	O
resulting	O
co	O
-	O
occurrence	O
network	O
is	O
evaluated	O
many	O
times	O
since	O
every	O
pair	O
of	O
co	O
-	O
occurring	O
entries	O
can	O
be	O
part	O
of	O
many	O
higher	O
order	O
co	O
-	O
occurrence	O
modules	O
[	O
35	O
]	O
.	O

Another	O
advantage	O
is	O
that	O
implicit	O
relationships	O
between	O
entries	O
,	O
which	O
have	O
never	O
occurred	O
together	O
[	O
18	O
]	O
,	O
can	O
be	O
derived	O
as	O
a	O
natural	O
by	O
-	O
product	O
of	O
using	O
module	O
sizes	O
larger	O
than	O
2	O
.	O

As	O
shown	O
in	O
a	O
simulation	O
study	O
(	O
supplementary	O
material	O
Simulation	O
S1	O
)	O
,	O
the	O
result	O
is	O
a	O
dramatic	O
reduction	O
of	O
misclassifications	O
at	O
higher	O
module	O
sizes	O
.	O

NetCutter	O
can	O
be	O
used	O
to	O
calculate	O
the	O
strength	O
of	O
association	O
between	O
a	O
subset	O
of	O
entries	O
and	O
lists	O
reporting	O
those	O
entries	O
.	O

In	O
this	O
case	O
,	O
the	O
analysis	O
is	O
performed	O
on	O
a	O
subgraph	O
of	O
the	O
original	O
bipartite	O
graph	O
.	O

The	O
subgraph	O
can	O
correspond	O
to	O
communities	O
of	O
entries	O
in	O
the	O
co	O
-	O
occurrence	O
network	O
,	O
or	O
any	O
set	O
of	O
entries	O
of	O
interest	O
.	O

NetCutter	O
will	O
then	O
calculate	O
the	O
significance	O
of	O
observing	O
a	O
given	O
number	O
of	O
occurrences	O
of	O
an	O
entry	O
in	O
the	O
user	O
defined	O
subset	O
of	O
lists	O
using	O
bi	O
-	O
binomal	O
statistics	O
.	O

This	O
analysis	O
mode	O
corresponds	O
to	O
association	O
studies	O
with	O
the	O
advantage	O
that	O
the	O
structure	O
of	O
the	O
underlying	O
bipartite	O
graph	O
(	O
i	O
.	O
e	O
.	O
list	O
length	O
heterogeneity	O
)	O
is	O
considered	O
and	O
handled	O
appropriately	O
using	O
the	O
bi	O
-	O
binomial	O
distribution	O
.	O

As	O
a	O
consequence	O
,	O
association	O
studies	O
can	O
be	O
performed	O
with	O
higher	O
stringency	O
.	O

This	O
result	O
can	O
be	O
understood	O
by	O
examining	O
the	O
occurrence	O
probability	O
matrix	O
that	O
is	O
implicitly	O
assumed	O
in	O
performing	O
binomial	O
or	O
hypergeometric	O
tests	O
for	O
the	O
significance	O
of	O
overlaps	O
.	O

In	O
both	O
tests	O
,	O
a	O
gene	O
is	O
assumed	O
to	O
have	O
an	O
equal	O
opportunity	O
to	O
be	O
present	O
in	O
a	O
list	O
.	O

Therefore	O
,	O
the	O
probability	O
of	O
success	O
for	O
a	O
gene	O
to	O
be	O
part	O
of	O
a	O
list	O
is	O
given	O
by	O
the	O
list	O
vertex	O
degree	O
divided	O
by	O
the	O
total	O
number	O
of	O
genes	O
.	O

In	O
other	O
words	O
,	O
both	O
tests	O
are	O
implicitly	O
based	O
on	O
the	O
list	O
vertex	O
degree	O
model	O
,	O
which	O
has	O
been	O
shown	O
previously	O
to	O
underestimate	O
the	O
occurrence	O
probability	O
and	O
the	O
expected	O
number	O
of	O
co	O
-	O
occurrences	O
for	O
genes	O
with	O
high	O
vertex	O
degree	O
(	O
see	O
Fig	O
.	O
2A	O
)	O
.	O

Since	O
the	O
BBD	O
P	O
-	O
values	O
are	O
calculated	O
from	O
the	O
ES	O
-	O
model	O
,	O
which	O
assigns	O
higher	O
occurrence	O
probabilities	O
to	O
genes	O
with	O
higher	O
vertex	O
degree	O
and	O
more	O
expected	O
co	O
-	O
occurrences	O
,	O
the	O
observed	O
number	O
of	O
overlaps	O
between	O
a	O
set	O
of	O
genes	O
of	O
interest	O
and	O
the	O
content	O
of	O
a	O
given	O
list	O
(	O
which	O
can	O
be	O
viewed	O
as	O
co	O
-	O
occurrence	O
of	O
the	O
overlapping	O
genes	O
in	O
that	O
list	O
)	O
will	O
be	O
judged	O
less	O
significant	O
when	O
the	O
overlapping	O
genes	O
are	O
of	O
high	O
vertex	O
degree	O
(	O
and	O
vice	O
versa	O
when	O
the	O
overlapping	O
genes	O
are	O
of	O
low	O
vertex	O
degree	O
)	O
as	O
compared	O
to	O
binomial	O
or	O
hypergeometric	O
tests	O
.	O

Since	O
the	O
BBD	O
P	O
-	O
values	O
are	O
derived	O
from	O
the	O
most	O
stringent	O
ES	O
null	O
-	O
model	O
,	O
BBD	O
P	O
-	O
values	O
provide	O
a	O
more	O
reliable	O
estimate	O
for	O
the	O
significance	O
of	O
overlap	O
.	O

Co	O
-	O
occurrence	O
analysis	O
of	O
data	O
represented	O
as	O
bipartite	O
graphs	O
permits	O
visualizing	O
the	O
structure	O
of	O
the	O
bipartite	O
graph	O
either	O
as	O
communities	O
of	O
list	O
entries	O
(	O
genes	O
)	O
or	O
as	O
communities	O
of	O
lists	O
(	O
PubMedID	O
_	O
ListID	O
)	O
in	O
co	O
-	O
occurrence	O
networks	O
.	O

We	O
have	O
analyzed	O
the	O
PubLiME	O
data	O
set	O
for	O
the	O
presence	O
of	O
corresponding	O
gene	O
and	O
list	O
clusters	O
.	O

In	O
addition	O
to	O
previously	O
published	O
clusters	O
of	O
genes	O
,	O
we	O
describe	O
a	O
novel	O
gene	O
cluster	O
that	O
is	O
composed	O
of	O
protein	O
biosynthesis	O
associated	O
genes	O
[	O
35	O
]	O
.	O

We	O
found	O
that	O
the	O
corresponding	O
clusters	O
of	O
PubMedID	O
_	O
ListID	O
(	O
gene	O
expression	O
signatures	O
)	O
are	O
in	O
general	O
strongly	O
enriched	O
for	O
genes	O
reported	O
in	O
the	O
corresponding	O
gene	O
cluster	O
and	O
that	O
interrogation	O
of	O
corresponding	O
clusters	O
can	O
be	O
used	O
to	O
deduct	O
hypotheses	O
about	O
the	O
putative	O
function	O
of	O
gene	O
clusters	O
.	O

In	O
addition	O
to	O
co	O
-	O
occurrence	O
analysis	O
,	O
NetCutter	O
offers	O
a	O
number	O
of	O
tools	O
for	O
the	O
analysis	O
of	O
co	O
-	O
occurrence	O
networks	O
,	O
or	O
any	O
undirected	O
graph	O
.	O

In	O
particular	O
,	O
community	O
identification	O
is	O
supported	O
by	O
four	O
different	O
community	O
identification	O
algorithms	O
.	O

NetCutter	O
also	O
offers	O
a	O
range	O
of	O
convenience	O
functions	O
that	O
are	O
of	O
help	O
in	O
network	O
analysis	O
.	O

Worthy	O
of	O
mentioning	O
are	O
the	O
random	O
graph	O
generators	O
that	O
can	O
provide	O
control	O
graphs	O
for	O
topological	O
studies	O
.	O

The	O
complete	O
set	O
of	O
options	O
is	O
described	O
in	O
the	O
software	O
documentation	O
.	O

In	O
summary	O
,	O
we	O
present	O
a	O
general	O
framework	O
for	O
co	O
-	O
occurrence	O
analysis	O
with	O
many	O
potential	O
applications	O
.	O

We	O
illustrate	O
a	O
number	O
of	O
advantages	O
of	O
using	O
the	O
bipartite	O
graph	O
representation	O
of	O
data	O
and	O
the	O
associated	O
statistics	O
.	O

In	O
particular	O
,	O
the	O
identification	O
of	O
corresponding	O
clusters	O
permits	O
the	O
identification	O
of	O
functional	O
subunits	O
such	O
as	O
gene	O
clusters	O
on	O
the	O
one	O
hand	O
,	O
and	O
the	O
generation	O
of	O
hypotheses	O
about	O
the	O
function	O
of	O
those	O
units	O
by	O
analyzing	O
the	O
corresponding	O
list	O
clusters	O
on	O
the	O
other	O
hand	O
.	O

Future	O
developments	O
will	O
be	O
directed	O
towards	O
the	O
analysis	O
of	O
data	O
sets	O
that	O
are	O
considerably	O
larger	O
than	O
the	O
data	O
sets	O
analyzed	O
so	O
far	O
.	O

For	O
example	O
,	O
co	O
-	O
occurrence	O
analysis	O
might	O
be	O
of	O
interest	O
for	O
the	O
analysis	O
of	O
single	O
nucleotide	O
polymorphism	O
(	O
SNP	O
)	O
data	O
sets	O
and	O
association	O
studies	O
of	O
genome	O
variability	O
with	O
disease	O
.	O

Each	O
patient	B
is	O
characterized	O
by	O
a	O
specific	O
range	O
of	O
SNPs	O
.	O

Co	O
-	O
occurrence	O
patterns	O
of	O
patients	B
according	O
to	O
their	O
SNPs	O
could	O
be	O
compared	O
to	O
clinical	O
parameters	O
with	O
the	O
aim	O
of	O
identifying	O
genomic	O
regions	O
associated	O
with	O
disease	O
.	O

The	O
increased	O
stringency	O
of	O
association	O
studies	O
offered	O
by	O
NetCutter	O
may	O
be	O
of	O
use	O
in	O
the	O
analysis	O
of	O
polygenic	O
diseases	O
where	O
conventional	O
methods	O
fail	O
.	O

For	O
being	O
useful	O
in	O
this	O
setting	O
,	O
NetCutter	O
must	O
be	O
capable	O
of	O
analyzing	O
bipartite	O
graphs	O
with	O
millions	O
instead	O
of	O
thousands	O
of	O
vertices	O
.	O

Materials	O
and	O
Methods	O

Implementation	O
of	O
NetCutter	O

NetCutter	O
is	O
written	O
in	O
Java	O
using	O
NetBeans6	O
software	O
(	O
http	O
:	O
/	O
/	O
www	O
.	O
netbeans	O
.	O
info	O
/	O
)	O
and	O
tested	O
on	O
the	O
Java	O
Runtime	O
environment	O
1	O
.	O
6	O
.	O
0	O
.	O
0	O
.	O
on	O
a	O
Windows	O
XP	O
Professional	O
computer	O
.	O

The	O
Java	O
Runtime	O
environment	O
,	O
which	O
can	O
be	O
downloaded	O
from	O
http	O
:	O
/	O
/	O
java	O
.	O
sun	O
.	O
com	O
/	O
,	O
must	O
be	O
installed	O
on	O
a	O
computer	O
that	O
is	O
intended	O
to	O
run	O
NetCutter	O
.	O

NetCutter	O
is	O
provided	O
as	O
a	O
single	O
jar	O
file	O
and	O
should	O
run	O
by	O
double	O
clicking	O
the	O
jar	O
file	O
,	O
provided	O
that	O
the	O
Java	O
runtime	O
environment	O
is	O
properly	O
installed	O
.	O

NetCutter	O
makes	O
use	O
of	O
the	O
following	O
software	O
packages	O
and	O
classes	O
:	O
JUNG	O
version	O
1	O
.	O
3	O
(	O
http	O
:	O
/	O
/	O
jung	O
.	O
sourceforge	O
.	O
net	O
/	O
download	O
.	O
html	O
)	O
,	O
Apache	O
Jakarta	O
Commons	O
Collections	O
3	O
.	O
1	O
(	O
http	O
:	O
/	O
/	O
jakarta	O
.	O
apache	O
.	O
org	O
/	O
commons	O
/	O
collections	O
/	O
)	O
,	O
Cern	O
Colt	O
Scientific	O
Library	O
1	O
.	O
2	O
.	O
0	O
(	O
http	O
:	O
/	O
/	O
dsd	O
.	O
lbl	O
.	O
gov	O
/	O
hoschek	O
/	O
colt	O
/	O
)	O
,	O
Xerces	O
(	O
http	O
:	O
/	O
/	O
xerces	O
.	O
apache	O
.	O
org	O
/	O
xerces2	O
-	O
j	O
/	O
index	O
.	O
html	O
)	O
,	O
Jama	O
(	O
http	O
:	O
/	O
/	O
math	O
.	O
nist	O
.	O
gov	O
/	O
javanumerics	O
/	O
jama	O
/	O
)	O
,	O
Netlib	O
Java	O
LAPACK	O
(	O
http	O
:	O
/	O
/	O
www	O
.	O
netlib	O
.	O
org	O
/	O
lapack	O
/	O
)	O
,	O
JFreeChart	O
(	O
http	O
:	O
/	O
/	O
www	O
.	O
jfree	O
.	O
org	O
/	O
jfreechart	O
/	O
)	O
,	O
partition	O
.	O
java	O
(	O
http	O
:	O
/	O
/	O
astro	O
.	O
u	O
-	O
strasbg	O
.	O
fr	O
/	O
fmurtagh	O
/	O
mda	O
-	O
sw	O
/	O
java	O
/	O
partition	O
.	O
java	O
)	O
.	O

Bi	O
-	O
binomial	O
approximation	O
of	O
Poisson	O
-	O
binomial	O
distribution	O

The	O
Poisson	O
-	O
binomial	O
distribution	O
(	O
binomial	O
distribution	O
with	O
trial	O
specific	O
probabilities	O
)	O
has	O
recently	O
been	O
proposed	O
as	O
a	O
statistic	O
that	O
properly	O
handles	O
largely	O
differing	O
sizes	O
of	O
gene	O
expression	O
signatures	O
in	O
meta	O
-	O
analysis	O
of	O
gene	O
expression	O
data	O
[	O
35	O
]	O
.	O

Z	O
-	O
scores	O
have	O
been	O
used	O
to	O
estimate	O
the	O
significance	O
of	O
co	O
-	O
occurrence	O
because	O
P	O
-	O
value	O
calculation	O
is	O
cumbersome	O
and	O
error	O
prone	O
.	O

Two	O
methods	O
reported	O
by	O
[	O
36	O
]	O
suffer	O
from	O
numerical	O
overflow	O
/	O
underflow	O
problems	O
when	O
large	O
numbers	O
of	O
Poisson	O
trials	O
with	O
probabilities	O
deviating	O
significantly	O
from	O
0	O
.	O
5	O
are	O
being	O
analyzed	O
.	O

Therefore	O
,	O
we	O
propose	O
a	O
fast	O
approximation	O
of	O
P	O
-	O
values	O
based	O
on	O
a	O
bi	O
-	O
binomial	O
distribution	O
.	O

The	O
bi	O
-	O
binomial	O
distribution	O
is	O
a	O
special	O
case	O
of	O
the	O
Poisson	O
-	O
binomial	O
distribution	O
where	O
the	O
probability	O
of	O
success	O
can	O
assume	O
only	O
two	O
values	O
.	O

In	O
order	O
to	O
achieve	O
a	O
good	O
approximation	O
of	O
the	O
underlying	O
Poisson	O
-	O
binomial	O
distribution	O
,	O
the	O
values	O
of	O
these	O
two	O
probabilities	O
and	O
the	O
number	O
of	O
trials	O
where	O
they	O
are	O
assumed	O
must	O
be	O
determined	O
carefully	O
.	O

As	O
is	O
shown	O
in	O
the	O
following	O
,	O
the	O
values	O
of	O
the	O
two	O
trial	O
probabilities	O
and	O
their	O
number	O
of	O
occurrences	O
follow	O
from	O
the	O
formula	O
used	O
to	O
calculate	O
the	O
variance	O
of	O
the	O
Poisson	O
-	O
binomial	O
distribution	O
and	O
from	O
the	O
formula	O
yielding	O
the	O
population	O
variance	O
of	O
trial	O
probabilities	O
of	O
the	O
Poisson	O
-	O
binomial	O
distribution	O
to	O
be	O
approximated	O
.	O

The	O
mean	O
mu	O
and	O
the	O
variance	O
sigma	O
2	O
of	O
the	O
Poisson	O
-	O
binomial	O
distribution	O
are	O
given	O
by	O
equation	O
(	O
1	O
)	O
and	O
(	O
2	O
)	O
,	O
respectively	O
.	O
(	O
1	O
)	O
(	O
2	O
)	O
pi	O
is	O
the	O
trial	O
-	O
specific	O
probability	O
of	O
success	O
and	O
N	O
is	O
the	O
total	O
number	O
of	O
trials	O
.	O

For	O
the	O
sake	O
of	O
completeness	O
,	O
a	O
formal	O
proof	O
of	O
equation	O
(	O
1	O
)	O
is	O
reported	O
as	O
supplementary	O
material	O
Proof	O
S1	O
and	O
the	O
proof	O
of	O
equation	O
(	O
2	O
)	O
can	O
be	O
obtained	O
in	O
an	O
analogous	O
fashion	O
.	O

The	O
population	O
variance	O
S2	O
of	O
trial	O
probabilities	O
pi	O
is	O
given	O
by	O
equation	O
(	O
3	O
)	O
.	O
(	O
3	O
)	O

Rearranging	O
equation	O
(	O
3	O
)	O
considering	O
(	O
1	O
)	O
and	O
(	O
2	O
)	O
leads	O
to	O
(	O
4	O
)	O
and	O
(	O
5	O
)	O
,	O
where	O
pa	O
denotes	O
the	O
average	O
trial	O
probability	O
of	O
success	O
and	O
qa	O
its	O
complement	O
.	O
(	O
4	O
)	O
(	O
5	O
)	O
Now	O
let	O
'	O
s	O
define	O
two	O
trial	O
probabilities	O
p1	O
and	O
p2	O
,	O
which	O
are	O
used	O
N1	O
and	O
N2	O
times	O
during	O
the	O
Poisson	O
trials	O
,	O
respectively	O
.	O

Thus	O
,	O
N1	O
and	O
N2	O
add	O
up	O
to	O
N	O
.	O
(	O
6	O
)	O

Considering	O
(	O
1	O
)	O
,	O
the	O
average	O
trial	O
probability	O
pa	O
can	O
then	O
be	O
obtained	O
from	O
(	O
7	O
)	O
.	O
(	O
7	O
)	O

Using	O
(	O
7	O
)	O
,	O
p1	O
can	O
thus	O
be	O
calculated	O
as	O
(	O
8	O
)	O
.	O
(	O
8	O
)	O

Similarly	O
,	O
considering	O
(	O
2	O
)	O
,	O
the	O
variance	O
sigma	O
2	O
is	O
given	O
by	O
(	O
9	O
)	O
.	O
(	O
9	O
)	O

Substituting	O
p1	O
in	O
(	O
9	O
)	O
using	O
(	O
8	O
)	O
followed	O
by	O
substituting	O
sigma	O
2	O
in	O
(	O
5	O
)	O
by	O
(	O
9	O
)	O
leads	O
to	O
a	O
quadratic	O
equation	O
for	O
p2	O
as	O
a	O
function	O
of	O
pa	O
,	O
N	O
,	O
and	O
S2	O
,	O
as	O
shown	O
in	O
equation	O
(	O
10	O
)	O
.	O
(	O
10	O
)	O

The	O
solution	O
to	O
(	O
10	O
)	O
is	O
given	O
by	O
(	O
11	O
)	O
.	O
(	O
11	O
)	O

Setting	O
p2	O
to	O
(	O
12	O
)	O
p1	O
can	O
be	O
obtained	O
from	O
(	O
8	O
)	O
and	O
shown	O
to	O
be	O
given	O
by	O
formula	O
(	O
13	O
)	O
:	O
(	O
13	O
)	O
Choosing	O
p2	O
as	O
(	O
12a	O
)	O
leads	O
to	O
p1	O
(	O
13a	O
)	O

Comparing	O
(	O
13a	O
)	O
to	O
(	O
12	O
)	O
and	O
(	O
12a	O
)	O
to	O
(	O
13	O
)	O
,	O
it	O
can	O
be	O
seen	O
that	O
the	O
formulae	O
are	O
identical	O
except	O
for	O
the	O
fact	O
that	O
N1	O
and	O
N2	O
are	O
reversed	O
.	O

Since	O
the	O
assignment	O
of	O
which	O
set	O
of	O
trials	O
is	O
called	O
N1	O
and	O
which	O
set	O
of	O
trials	O
is	O
called	O
N2	O
is	O
completely	O
arbitrary	O
,	O
we	O
can	O
limit	O
the	O
remaining	O
analysis	O
on	O
(	O
12	O
)	O
and	O
(	O
13	O
)	O
without	O
loss	O
of	O
generality	O
.	O

Note	O
that	O
(	O
12	O
)	O
and	O
(	O
13	O
)	O
do	O
not	O
guarantee	O
that	O
p1	O
and	O
p2	O
are	O
always	O
confined	O
between	O
0	O
and	O
1	O
for	O
any	O
combination	O
of	O
N1	O
and	O
N2	O
.	O

While	O
probabilities	O
smaller	O
than	O
0	O
or	O
bigger	O
than	O
1	O
would	O
still	O
result	O
in	O
a	O
distribution	O
with	O
the	O
same	O
overall	O
variance	O
as	O
the	O
original	O
distribution	O
,	O
P	O
-	O
value	O
calculation	O
will	O
be	O
imprecise	O
because	O
the	O
tails	O
of	O
the	O
distribution	O
will	O
deviate	O
significantly	O
from	O
the	O
original	O
distribution	O
.	O

Thus	O
,	O
we	O
need	O
to	O
define	O
the	O
values	O
N1	O
and	O
N2	O
in	O
such	O
a	O
way	O
that	O
p2	O
<	O
=	O
1	O
and	O
p1	O
>	O
=	O
0	O
.	O

This	O
can	O
be	O
achieved	O
by	O
evaluating	O
(	O
12	O
)	O
and	O
(	O
13	O
)	O
.	O

Evaluating	O
(	O
12	O
)	O
for	O
the	O
condition	O
that	O
p2	O
<	O
=	O
1	O
,	O
solving	O
the	O
resulting	O
inequality	O
for	O
N2	O
,	O
and	O
considering	O
(	O
5	O
)	O
,	O
which	O
relates	O
S2	O
and	O
sigma	O
2	O
,	O
we	O
obtain	O
(	O
14	O
)	O
.	O
(	O
14	O
)	O

Similarly	O
,	O
evaluating	O
(	O
13	O
)	O
for	O
the	O
condition	O
p1	O
>	O
=	O
0	O
,	O
solving	O
the	O
resulting	O
inequality	O
for	O
N2	O
,	O
considering	O
(	O
5	O
)	O
,	O
which	O
relates	O
S2	O
and	O
sigma	O
2	O
,	O
and	O
defining	O
mu	O
f	O
the	O
expected	O
number	O
of	O
failures	O
as	O
N	O
*	O
(	O
1	O
-	O
pa	O
)	O
(	O
15	O
)	O
,	O
(	O
15	O
)	O
we	O
obtain	O
(	O
16	O
)	O
(	O
16	O
)	O

The	O
meaning	O
of	O
these	O
boundaries	O
is	O
best	O
illustrated	O
by	O
considering	O
a	O
Poisson	O
-	O
binomial	O
distribution	O
whose	O
variance	O
is	O
0	O
,	O
i	O
.	O
e	O
.	O
that	O
assumes	O
1	O
at	O
X	O
=	O
mu	O
and	O
0	O
otherwise	O
.	O

In	O
this	O
case	O
(	O
14	O
)	O
requires	O
N2	O
<	O
=	O
mu	O
while	O
(	O
16	O
)	O
requires	O
N2	O
>	O
=	O
mu	O
.	O

These	O
conditions	O
can	O
only	O
be	O
fulfilled	O
contemporaneously	O
when	O
N2	O
is	O
set	O
to	O
mu	O
.	O

Intuitively	O
,	O
this	O
means	O
that	O
there	O
are	O
mu	O
trials	O
with	O
probability	O
of	O
success	O
1	O
and	O
N	O
-	O
mu	O
trials	O
with	O
probability	O
of	O
0	O
,	O
resulting	O
in	O
a	O
Poisson	O
-	O
binomial	O
distribution	O
with	O
variance	O
sigma	O
2	O
=	O
0	O
and	O
mean	O
mu	O
.	O

When	O
sigma	O
2	O
is	O
larger	O
than	O
0	O
,	O
the	O
choice	O
of	O
N1	O
and	O
N2	O
is	O
more	O
flexible	O
.	O

However	O
,	O
since	O
the	O
choice	O
of	O
N2	O
=	O
mu	O
is	O
valid	O
for	O
all	O
possible	O
values	O
of	O
sigma	O
2	O
,	O
this	O
is	O
how	O
NetCutter	O
determines	O
N1	O
and	O
N2	O
.	O

When	O
mu	O
is	O
not	O
an	O
integer	O
,	O
N2	O
is	O
set	O
to	O
the	O
integer	O
closest	O
to	O
mu	O
.	O

Having	O
determined	O
p2	O
(	O
12	O
)	O
and	O
p1	O
(	O
13	O
)	O
as	O
well	O
a	O
N1	O
and	O
N2	O
(	O
14	O
,	O
16	O
,	O
6	O
)	O
,	O
we	O
can	O
now	O
calculate	O
the	O
bi	O
-	O
binomial	O
approximation	O
of	O
the	O
Poisson	O
-	O
binomial	O
distribution	O
in	O
a	O
fashion	O
that	O
is	O
very	O
similar	O
to	O
calculate	O
the	O
binomial	O
P	O
-	O
value	O
.	O

With	O
q1	O
=	O
1	O
-	O
p1	O
and	O
q2	O
=	O
1	O
-	O
p2	O
we	O
obtain	O
:	O
(	O
17	O
)	O

The	O
summation	O
is	O
necessary	O
because	O
i	O
successes	O
can	O
be	O
obtained	O
from	O
any	O
combination	O
of	O
j	O
p1	O
and	O
i	O
-	O
j	O
p2	O
trials	O
,	O
where	O
j	O
can	O
assume	O
any	O
value	O
from	O
0	O
to	O
i	O
.	O

Calculating	O
Jaccard	O
and	O
uncertainty	O
coefficients	O

For	O
the	O
purpose	O
of	O
comparing	O
the	O
efficacy	O
of	O
the	O
bi	O
-	O
binomial	O
distribution	O
as	O
a	O
significance	O
measure	O
of	O
co	O
-	O
occurrence	O
,	O
Jaccard	O
and	O
uncertainty	O
coefficients	O
(	O
which	O
are	O
also	O
called	O
measures	O
of	O
association	O
)	O
were	O
calculated	O
using	O
the	O
formulae	O
:	O

The	O
Jaccard	O
coefficient	O
J	O
is	O
calculated	O
as	O
the	O
number	O
of	O
times	O
A	O
and	O
B	O
occur	O
together	O
divided	O
by	O
the	O
number	O
of	O
times	O
A	O
occurs	O
without	O
B	O
plus	O
the	O
number	O
of	O
times	O
B	O
occurs	O
without	O
A	O
plus	O
the	O
number	O
of	O
times	O
A	O
and	O
B	O
occur	O
together	O
[	O
42	O
]	O
.	O

The	O
uncertainty	O
coefficient	O
[	O
42	O
]	O
is	O
calculated	O
as	O
:	O
H	O
is	O
the	O
entropy	O
associated	O
with	O
A	O
,	O
B	O
,	O
and	O
AB	O
.	O

For	O
A	O
,	O
the	O
entropy	O
is	O
calculated	O
from	O
the	O
probabilities	O
of	O
A	O
occurring	O
in	O
n1	O
out	O
of	O
N	O
lists	O
(	O
n1	O
/	O
N	O
)	O
and	O
A	O
not	O
occurring	O
in	O
n2	O
out	O
of	O
N	O
lists	O
(	O
n2	O
/	O
N	O
)	O
.	O

Analogous	O
calculations	O
lead	O
to	O
the	O
entropy	O
associated	O
with	O
B	O
.	O

For	O
H	O
(	O
A	O
,	O
B	O
)	O
,	O
the	O
probabilities	O
of	O
A	O
occurring	O
without	O
B	O
,	O
B	O
occurring	O
without	O
A	O
,	O
A	O
and	O
B	O
occurring	O
together	O
,	O
and	O
neither	O
A	O
nor	O
B	O
occurring	O
in	O
the	O
lists	O
are	O
used	O
.	O

Co	O
-	O
occurrence	O
analysis	O
of	O
the	O
PubLiME	O
data	O
set	O

The	O
bipartite	O
graph	O
to	O
be	O
analyzed	O
is	O
composed	O
of	O
27619	O
PubMedID	O
_	O
listID	O
-	O
gene	O
pairs	O
(	O
see	O
supplementary	O
material	O
Table	O
S1	O
)	O
.	O

Edge	O
-	O
swapping	O
(	O
1000	O
simulations	O
,	O
see	O
above	O
)	O
was	O
used	O
to	O
determine	O
occurrence	O
probabilities	O
and	O
gene	O
co	O
-	O
occurrence	O
was	O
analyzed	O
using	O
module	O
size	O
3	O
(	O
co	O
-	O
occurrence	O
of	O
three	O
genes	O
)	O
,	O
bi	O
-	O
binomial	O
Z	O
-	O
score	O
cutoff	O
6	O
,	O
bi	O
-	O
binomial	O
P	O
-	O
value	O
cutoff	O
1	O
.	O
0E	O
-	O
5	O
,	O
and	O
support	O
5	O
.	O

Supplementary	O
material	O
Simulation	O
S1	O
provides	O
details	O
on	O
why	O
module	O
size	O
3	O
is	O
chosen	O
.	O

The	O
support	O
parameter	O
ensures	O
that	O
each	O
3	O
-	O
gene	O
co	O
-	O
occurrence	O
module	O
is	O
present	O
in	O
at	O
least	O
5	O
signatures	O
.	O

We	O
identified	O
1654	O
significant	O
modules	O
in	O
the	O
test	O
data	O
compared	O
to	O
5	O
modules	O
in	O
a	O
randomized	O
bipartite	O
graph	O
,	O
corresponding	O
to	O
a	O
signal	O
-	O
to	O
-	O
noise	O
ratio	O
of	O
331	O
.	O

The	O
co	O
-	O
occurrence	O
network	O
was	O
generated	O
from	O
the	O
significant	O
co	O
-	O
occurrence	O
modules	O
by	O
drawing	O
an	O
edge	O
between	O
each	O
pair	O
wise	O
combination	O
of	O
genes	O
that	O
are	O
part	O
of	O
the	O
same	O
co	O
-	O
occurrence	O
module	O
.	O

Gene	O
communities	O
were	O
identified	O
in	O
this	O
network	O
by	O
edge	O
-	O
betweenness	O
clustering	O
removing	O
4	O
edges	O
,	O
which	O
resulted	O
in	O
a	O
maximal	O
network	O
modularity	O
of	O
0	O
.	O
63	O
.	O

Modularity	O
is	O
calculated	O
as	O
described	O
by	O
[	O
43	O
]	O
.	O

For	O
the	O
identification	O
of	O
PubMedID	O
_	O
listID	O
clusters	O
,	O
the	O
PubMedID	O
_	O
listID	O
-	O
gene	O
pairs	O
in	O
the	O
original	O
bipartite	O
graph	O
were	O
reversed	O
to	O
form	O
gene	O
-	O
PubMedID	O
_	O
listID	O
pairs	O
.	O

Occurrence	O
probabilities	O
were	O
obtained	O
by	O
transposing	O
the	O
original	O
occurrence	O
probability	O
matrix	O
determined	O
by	O
edge	O
-	O
swapping	O
as	O
described	O
above	O
.	O

PubMedID	O
_	O
listID	O
co	O
-	O
occurrence	O
was	O
analyzed	O
using	O
module	O
size	O
5	O
,	O
Z	O
-	O
score	O
cutoff	O
6	O
,	O
bi	O
-	O
binomial	O
P	O
-	O
value	O
cutoff	O
1	O
.	O
0E	O
-	O
5	O
,	O
and	O
support	O
3	O
.	O

Please	O
note	O
that	O
the	O
choice	O
of	O
these	O
parameters	O
is	O
dictated	O
by	O
the	O
parameters	O
used	O
in	O
gene	O
co	O
-	O
occurrence	O
analysis	O
.	O

The	O
reversal	O
of	O
the	O
bipartite	O
graph	O
necessitates	O
the	O
support	O
parameter	O
used	O
in	O
gene	O
co	O
-	O
occurrence	O
analysis	O
(	O
5	O
)	O
to	O
be	O
used	O
as	O
module	O
size	O
in	O
PubMedID	O
_	O
listID	O
co	O
-	O
occurrence	O
analysis	O
and	O
the	O
module	O
size	O
used	O
in	O
gene	O
co	O
-	O
occurrence	O
analysis	O
(	O
3	O
)	O
to	O
be	O
used	O
as	O
the	O
support	O
parameter	O
in	O
PubMedID	O
_	O
listID	O
co	O
-	O
occurrence	O
analysis	O
if	O
the	O
scope	O
of	O
the	O
analysis	O
is	O
the	O
identification	O
of	O
PubMedID	O
_	O
listID	O
clusters	O
that	O
correspond	O
to	O
gene	O
clusters	O
identified	O
before	O
.	O

The	O
significance	O
cutoffs	O
remain	O
unchanged	O
.	O

PubMedID	O
_	O
listID	O
co	O
-	O
occurrence	O
analysis	O
revealed	O
448	O
significant	O
co	O
-	O
occurrence	O
modules	O
in	O
the	O
real	O
bipartite	O
graph	O
and	O
6	O
significant	O
co	O
-	O
occurrence	O
modules	O
in	O
the	O
randomized	O
bipartite	O
graph	O
with	O
a	O
signal	O
-	O
to	O
-	O
noise	O
ratio	O
of	O
75	O
.	O

Communities	O
in	O
the	O
resulting	O
co	O
-	O
occurrence	O
network	O
were	O
identified	O
by	O
edge	O
-	O
betweenness	O
clustering	O
removing	O
130	O
edges	O
.	O

The	O
resulting	O
maximal	O
network	O
modularity	O
was	O
found	O
to	O
be	O
0	O
.	O
47	O
.	O

Supporting	O
Information	O

Personal	O
and	O
environmental	O
correlates	O
of	O
active	O
travel	O
and	O
physical	O
activity	O
in	O
a	O
deprived	O
urban	O
population	O

Abstract	O

Background	O

Environmental	O
characteristics	O
may	O
be	O
associated	O
with	O
patterns	O
of	O
physical	O
activity	O
in	O
general	O
or	O
with	O
particular	O
types	O
of	O
physical	O
activity	O
such	O
as	O
active	O
travel	O
(	O
walking	O
or	O
cycling	O
for	O
transport	O
)	O
.	O

However	O
,	O
most	O
studies	O
in	O
this	O
field	O
have	O
been	O
conducted	O
in	O
North	O
America	O
and	O
Australia	O
,	O
and	O
hypotheses	O
about	O
putative	O
correlates	O
should	O
be	O
tested	O
in	O
a	O
wider	O
range	O
of	O
sociospatial	O
contexts	O
.	O

We	O
therefore	O
examined	O
the	O
contribution	O
of	O
putative	O
personal	O
and	O
environmental	O
correlates	O
of	O
active	O
travel	O
and	O
overall	O
physical	O
activity	O
in	O
deprived	O
urban	O
neighbourhoods	O
in	O
Glasgow	O
,	O
Scotland	O
as	O
part	O
of	O
the	O
baseline	O
for	O
a	O
longitudinal	O
study	O
of	O
the	O
effects	O
of	O
opening	O
a	O
new	O
urban	O
motorway	O
(	O
freeway	O
)	O
.	O

Methods	O

We	O
conducted	O
a	O
postal	O
survey	O
of	O
a	O
random	O
sample	O
of	O
residents	O
(	O
n	O
=	O
1322	O
)	O
,	O
collecting	O
data	O
on	O
socioeconomic	O
status	O
,	O
perceptions	O
of	O
the	O
local	O
environment	O
,	O
travel	O
behaviour	O
,	O
physical	O
activity	O
and	O
general	O
health	O
and	O
wellbeing	O
using	O
a	O
new	O
14	O
-	O
item	O
neighbourhood	O
rating	O
scale	O
,	O
a	O
travel	O
diary	O
,	O
the	O
short	O
form	O
of	O
the	O
International	O
Physical	O
Activity	O
Questionnaire	O
(	O
IPAQ	O
)	O
and	O
the	O
SF	O
-	O
8	O
.	O

We	O
analysed	O
the	O
correlates	O
of	O
active	O
travel	O
and	O
overall	O
physical	O
activity	O
using	O
multivariate	O
logistic	O
regression	O
,	O
first	O
building	O
models	O
using	O
personal	O
(	O
individual	O
and	O
household	O
)	O
explanatory	O
variables	O
and	O
then	O
adding	O
environmental	O
variables	O
.	O

Results	O

Active	O
travel	O
was	O
associated	O
with	O
being	O
younger	O
,	O
living	O
in	O
owner	O
-	O
occupied	O
accommodation	O
,	O
not	O
having	O
to	O
travel	O
a	O
long	O
distance	O
to	O
work	O
and	O
not	O
having	O
access	O
to	O
a	O
car	O
,	O
whereas	O
overall	O
physical	O
activity	O
was	O
associated	O
with	O
living	O
in	O
social	O
rented	O
accommodation	O
and	O
not	O
being	O
overweight	O
.	O

After	O
adjusting	O
for	O
personal	O
characteristics	O
,	O
neither	O
perceptions	O
of	O
the	O
local	O
environment	O
nor	O
the	O
objective	O
proximity	O
of	O
respondents	O
'	O
homes	O
to	O
motorway	O
or	O
major	O
road	O
infrastructure	O
explained	O
much	O
of	O
the	O
variance	O
in	O
active	O
travel	O
or	O
overall	O
physical	O
activity	O
,	O
although	O
we	O
did	O
identify	O
a	O
significant	O
positive	O
association	O
between	O
active	O
travel	O
and	O
perceived	O
proximity	O
to	O
shops	O
.	O

Conclusion	O

Apart	O
from	O
access	O
to	O
local	O
amenities	O
,	O
environmental	O
characteristics	O
may	O
have	O
limited	O
influence	O
on	O
active	O
travel	O
in	O
deprived	O
urban	O
populations	O
characterised	O
by	O
a	O
low	O
level	O
of	O
car	O
ownership	O
,	O
in	O
which	O
people	B
may	O
have	O
less	O
capacity	O
for	O
making	O
discretionary	O
travel	O
choices	O
than	O
the	O
populations	O
studied	O
in	O
most	O
published	O
research	O
on	O
the	O
environmental	O
correlates	O
of	O
physical	O
activity	O
.	O

Background	O

Until	O
recently	O
,	O
research	O
on	O
correlates	O
of	O
physical	O
activity	O
was	O
dominated	O
by	O
studies	O
of	O
individual	O
demographic	O
and	O
psychosocial	O
characteristics	O
[	O
1	O
]	O
.	O

This	O
reflected	O
an	O
emphasis	O
on	O
promoting	O
sport	O
,	O
recreation	O
or	O
health	O
-	O
directed	O
exercise	O
using	O
techniques	O
to	O
encourage	O
individual	O
behaviour	O
change	O
[	O
2	O
]	O
.	O

However	O
,	O
there	O
is	O
little	O
evidence	O
that	O
such	O
approaches	O
are	O
effective	O
in	O
increasing	O
physical	O
activity	O
in	O
the	O
medium	O
-	O
to	O
-	O
long	O
term	O
[	O
3	O
]	O
.	O

If	O
habitual	O
patterns	O
of	O
behaviour	O
are	O
environmentally	O
cued	O
,	O
sustained	O
change	O
is	O
likely	O
to	O
require	O
a	O
supportive	O
environment	O
in	O
which	O
people	B
can	O
be	O
active	O
[	O
4	O
,	O
5	O
]	O
.	O

There	O
is	O
therefore	O
increasing	O
interest	O
in	O
the	O
influence	O
of	O
the	O
social	O
and	O
physical	O
environment	O
on	O
physical	O
activity	O
.	O

With	O
respect	O
to	O
the	O
physical	O
(	O
natural	O
or	O
built	O
)	O
environment	O
,	O
a	O
growing	O
body	O
of	O
evidence	O
suggests	O
that	O
certain	O
environmental	O
characteristics	O
may	O
be	O
associated	O
with	O
patterns	O
of	O
physical	O
activity	O
in	O
general	O
or	O
with	O
particular	O
types	O
of	O
physical	O
activity	O
such	O
as	O
walking	O
or	O
cycling	O
as	O
modes	O
of	O
transport	O
[	O
4	O
-	O
10	O
]	O
.	O

Among	O
the	O
correlates	O
most	O
frequently	O
identified	O
in	O
such	O
reviews	O
-	O
some	O
ascertained	O
using	O
'	O
objective	O
'	O
measures	O
,	O
and	O
others	O
in	O
terms	O
of	O
people	B
'	O
s	O
perceptions	O
-	O
are	O
the	O
aesthetic	O
quality	O
of	O
the	O
surroundings	O
,	O
the	O
presence	O
of	O
pavements	O
(	O
sidewalks	O
)	O
,	O
the	O
convenience	O
of	O
facilities	O
for	O
being	O
active	O
,	O
the	O
availability	O
of	O
green	O
space	O
,	O
access	O
to	O
amenities	O
(	O
destinations	O
)	O
within	O
walking	O
or	O
cycling	O
distance	O
,	O
safety	O
from	O
traffic	O
and	O
personal	O
attack	O
,	O
and	O
the	O
lack	O
of	O
heavy	O
traffic	O
.	O

Some	O
of	O
these	O
local	O
characteristics	O
reflect	O
higher	O
-	O
order	O
aspects	O
of	O
urban	O
design	O
and	O
spatial	O
policy	O
such	O
as	O
population	O
density	O
,	O
connectivity	O
and	O
mixed	O
land	O
use	O
[	O
6	O
,	O
8	O
]	O
.	O

Importantly	O
,	O
different	O
characteristics	O
may	O
be	O
associated	O
with	O
different	O
types	O
of	O
physical	O
activity	O
;	O
for	O
example	O
,	O
Owen	O
and	O
colleagues	O
found	O
that	O
the	O
aesthetic	O
quality	O
of	O
the	O
surroundings	O
was	O
associated	O
with	O
walking	O
for	O
exercise	O
or	O
recreation	O
and	O
with	O
walking	O
in	O
general	O
,	O
but	O
not	O
with	O
walking	O
for	O
transport	O
,	O
whereas	O
perceptions	O
of	O
traffic	O
were	O
associated	O
with	O
walking	O
for	O
transport	O
and	O
walking	O
in	O
general	O
,	O
but	O
not	O
with	O
walking	O
for	O
exercise	O
or	O
recreation	O
[	O
5	O
]	O
.	O

Despite	O
the	O
growing	O
volume	O
of	O
published	O
studies	O
in	O
this	O
field	O
,	O
many	O
authors	O
remain	O
circumspect	O
in	O
their	O
interpretation	O
of	O
the	O
available	O
evidence	O
.	O

Giles	O
-	O
Corti	O
and	O
Donovan	O
have	O
described	O
access	O
to	O
a	O
supportive	O
physical	O
environment	O
as	O
a	O
necessary	O
,	O
but	O
insufficient	O
,	O
condition	O
for	O
an	O
increase	O
in	O
physical	O
activity	O
in	O
the	O
population	O
[	O
11	O
]	O
,	O
while	O
Handy	O
found	O
'	O
convincing	O
'	O
evidence	O
of	O
an	O
association	O
between	O
physical	O
activity	O
and	O
the	O
built	O
environment	O
in	O
general	O
but	O
'	O
less	O
convincing	O
'	O
evidence	O
as	O
to	O
which	O
specific	O
environmental	O
characteristics	O
were	O
most	O
strongly	O
associated	O
[	O
7	O
]	O
.	O

One	O
limitation	O
of	O
the	O
available	O
evidence	O
is	O
that	O
most	O
research	O
has	O
been	O
conducted	O
in	O
North	O
America	O
and	O
Australia	O
[	O
9	O
,	O
12	O
]	O
,	O
and	O
it	O
is	O
not	O
clear	O
whether	O
associations	O
observed	O
in	O
those	O
countries	O
are	O
generalisable	O
to	O
other	O
settings	O
with	O
different	O
aggregate	O
socioeconomic	O
characteristics	O
(	O
e	O
.	O
g	O
.	O
wealth	O
or	O
access	O
to	O
private	O
cars	O
)	O
or	O
environmental	O
characteristics	O
(	O
e	O
.	O
g	O
.	O
climate	O
,	O
patterns	O
of	O
land	O
use	O
,	O
or	O
availability	O
of	O
public	O
transport	O
)	O
.	O

For	O
example	O
,	O
North	O
American	O
researchers	O
are	O
often	O
interested	O
in	O
the	O
presence	O
or	O
absence	O
of	O
pavements	O
(	O
sidewalks	O
)	O
,	O
but	O
it	O
is	O
unusual	O
for	O
streets	O
in	O
the	O
United	O
Kingdom	O
(	O
UK	O
)	O
not	O
to	O
have	O
a	O
pavement	O
or	O
footpath	O
beside	O
them	O
.	O

Hypotheses	O
about	O
putative	O
environmental	O
correlates	O
of	O
physical	O
activity	O
therefore	O
need	O
to	O
be	O
tested	O
in	O
a	O
wider	O
range	O
of	O
settings	O
.	O

A	O
more	O
profound	O
limitation	O
of	O
the	O
available	O
evidence	O
is	O
that	O
identifying	O
a	O
relationship	O
between	O
,	O
for	O
example	O
,	O
urban	O
form	O
and	O
walking	O
for	O
transport	O
is	O
not	O
the	O
same	O
thing	O
as	O
showing	O
that	O
changing	O
the	O
built	O
environment	O
will	O
lead	O
to	O
a	O
change	O
in	O
behaviour	O
[	O
13	O
]	O
.	O

Few	O
researchers	O
have	O
taken	O
up	O
the	O
opportunity	O
(	O
or	O
challenge	O
)	O
presented	O
by	O
'	O
natural	O
experiments	O
'	O
to	O
investigate	O
the	O
effects	O
of	O
environmental	O
interventions	O
on	O
physical	O
activity	O
[	O
14	O
]	O
.	O

We	O
therefore	O
established	O
a	O
longitudinal	O
study	O
to	O
examine	O
changes	O
associated	O
with	O
the	O
opening	O
of	O
a	O
new	O
urban	O
section	O
of	O
the	O
M74	O
motorway	O
(	O
freeway	O
)	O
currently	O
under	O
construction	O
in	O
Glasgow	O
,	O
Scotland	O
.	O

The	O
rationale	O
and	O
design	O
for	O
this	O
study	O
have	O
been	O
described	O
previously	O
[	O
15	O
]	O
.	O

It	O
is	O
claimed	O
that	O
the	O
new	O
motorway	O
,	O
which	O
will	O
mostly	O
pass	O
through	O
or	O
close	O
to	O
densely	O
-	O
populated	O
urban	O
neighbourhoods	O
,	O
will	O
contribute	O
to	O
the	O
regeneration	O
of	O
a	O
region	O
which	O
includes	O
some	O
of	O
the	O
most	O
deprived	O
and	O
least	O
healthy	O
working	O
-	O
class	O
communities	O
in	O
Europe	O
[	O
16	O
]	O
.	O

It	O
is	O
also	O
claimed	O
that	O
the	O
new	O
motorway	O
will	O
divert	O
traffic	O
from	O
local	O
streets	O
,	O
reduce	O
traffic	O
noise	O
and	O
bring	O
new	O
local	O
employment	O
opportunities	O
,	O
thereby	O
improving	O
characteristics	O
of	O
the	O
local	O
environment	O
held	O
to	O
be	O
associated	O
with	O
active	O
travel	O
.	O

Others	O
claim	O
that	O
the	O
new	O
motorway	O
will	O
encourage	O
car	O
use	O
,	O
degrade	O
the	O
aesthetic	O
quality	O
of	O
the	O
surroundings	O
and	O
reduce	O
the	O
safety	O
and	O
attractiveness	O
of	O
routes	O
for	O
pedestrians	O
and	O
cyclists	O
across	O
the	O
line	O
of	O
the	O
motorway	O
-	O
all	O
changes	O
which	O
may	O
be	O
expected	O
to	O
discourage	O
active	O
travel	O
[	O
15	O
]	O
.	O

The	O
eventual	O
aim	O
of	O
the	O
M74	O
study	O
will	O
be	O
to	O
assess	O
the	O
effects	O
of	O
this	O
major	O
modification	O
to	O
the	O
urban	O
built	O
environment	O
and	O
transport	O
infrastructure	O
on	O
perceptions	O
of	O
the	O
local	O
environment	O
and	O
on	O
population	O
health	O
and	O
health	O
-	O
related	O
behaviour	O
,	O
the	O
primary	O
outcome	O
of	O
interest	O
being	O
a	O
change	O
in	O
the	O
quantity	O
of	O
'	O
active	O
travel	O
'	O
(	O
walking	O
and	O
cycling	O
for	O
transport	O
)	O
.	O

In	O
this	O
paper	O
,	O
we	O
report	O
findings	O
from	O
the	O
cross	O
-	O
sectional	O
(	O
baseline	O
)	O
phase	O
of	O
the	O
study	O
which	O
contribute	O
evidence	O
on	O
the	O
environmental	O
correlates	O
of	O
physical	O
activity	O
in	O
this	O
comparatively	O
deprived	O
urban	O
population	O
.	O

We	O
focus	O
on	O
two	O
specific	O
hypotheses	O
:	O
first	O
,	O
that	O
levels	O
of	O
active	O
travel	O
and	O
overall	O
physical	O
activity	O
vary	O
with	O
demographic	O
and	O
socioeconomic	O
characteristics	O
,	O
but	O
not	O
necessarily	O
in	O
the	O
same	O
way	O
;	O
second	O
,	O
that	O
these	O
relationships	O
may	O
be	O
partly	O
explained	O
by	O
the	O
perceived	O
characteristics	O
of	O
the	O
local	O
environment	O
in	O
which	O
people	B
live	O
and	O
by	O
their	O
objectively	O
-	O
assessed	O
proximity	O
to	O
motorway	O
and	O
major	O
road	O
infrastructure	O
.	O

Methods	O

Delineation	O
of	O
study	O
areas	O

We	O
used	O
spatially	O
referenced	O
census	O
and	O
transport	O
infrastructure	O
data	O
held	O
and	O
analysed	O
in	O
a	O
geographical	O
information	O
system	O
(	O
GIS	O
)	O
,	O
combined	O
with	O
field	O
visits	O
,	O
to	O
delineate	O
three	O
study	O
areas	O
in	O
Glasgow	O
with	O
similar	O
aggregate	O
socioeconomic	O
characteristics	O
and	O
broadly	O
similar	O
topographical	O
characteristics	O
apart	O
from	O
their	O
proximity	O
to	O
urban	O
motorway	O
infrastructure	O
(	O
Table	O
1	O
,	O
Figure	O
1	O
)	O
.	O

All	O
three	O
study	O
areas	O
extended	O
from	O
inner	O
mixed	O
-	O
use	O
districts	O
close	O
to	O
the	O
city	O
centre	O
to	O
residential	O
suburbs	O
,	O
contained	O
major	O
arterial	O
roads	O
other	O
than	O
motorways	O
,	O
and	O
contained	O
a	O
mixture	O
of	O
housing	O
stock	O
including	O
traditional	O
high	O
-	O
density	O
tenements	O
,	O
high	O
-	O
rise	O
flats	O
and	O
new	O
housing	O
developments	O
(	O
Figure	O
2	O
)	O
.	O

Sampling	O
and	O
survey	O
administration	O

We	O
used	O
the	O
Royal	O
Mail	O
Postcode	O
Address	O
File	O
(	O
PAF	O
)	O
(	O
version	O
2005	O
.	O
3	O
)	O
to	O
identify	O
all	O
residential	O
addresses	O
whose	O
unit	O
postcode	O
(	O
zip	O
code	O
)	O
was	O
within	O
one	O
of	O
the	O
study	O
areas	O
(	O
total	O
n	O
=	O
35601	O
)	O
and	O
drew	O
a	O
random	O
sample	O
of	O
3000	O
households	O
from	O
each	O
area	O
.	O

Unit	O
postcodes	O
(	O
e	O
.	O
g	O
.	O
G12	O
8RZ	O
)	O
are	O
the	O
smallest	O
available	O
unit	O
of	O
postal	O
geography	O
in	O
the	O
UK	O
;	O
residential	O
unit	O
postcodes	O
cover	O
about	O
15	O
addresses	O
on	O
average	O
.	O

We	O
sent	O
the	O
survey	O
to	O
all	O
households	O
(	O
total	O
n	O
=	O
9000	O
)	O
between	O
28	O
September	O
and	O
4	O
October	O
2005	O
and	O
resent	O
the	O
survey	O
to	O
all	O
non	O
-	O
responding	O
households	O
between	O
26	O
and	O
31	O
October	O
2005	O
.	O

We	O
alerted	O
households	O
to	O
the	O
survey	O
by	O
means	O
of	O
a	O
postcard	O
sent	O
a	O
few	O
days	O
in	O
advance	O
,	O
used	O
coloured	O
paper	O
for	O
some	O
of	O
the	O
survey	O
materials	O
,	O
and	O
posted	O
survey	O
packs	O
in	O
white	O
envelopes	O
printed	O
with	O
the	O
university	O
crest	O
;	O
these	O
techniques	O
have	O
been	O
shown	O
in	O
a	O
meta	O
-	O
analysis	O
to	O
be	O
associated	O
with	O
increased	O
response	O
rates	O
to	O
postal	O
surveys	O
[	O
17	O
]	O
.	O

We	O
asked	O
householders	O
to	O
ensure	O
that	O
the	O
questionnaire	O
was	O
completed	O
by	O
a	O
resident	O
aged	O
16	O
or	O
over	O
;	O
if	O
more	O
than	O
one	O
resident	O
was	O
eligible	O
,	O
we	O
asked	O
householders	O
to	O
select	O
the	O
person	B
with	O
the	O
most	O
recent	O
birthday	O
.	O

Respondents	O
who	O
consented	O
to	O
follow	O
-	O
up	O
were	O
entered	O
into	O
a	O
prize	O
draw	O
to	O
win	O
a	O
pound	O
50	O
(	O
euro	O
63	O
;	O
US	O
$	O
92	O
)	O
gift	O
voucher	O
.	O

Responses	O
received	O
more	O
than	O
three	O
months	O
after	O
the	O
first	O
mailing	O
wave	O
were	O
disregarded	O
in	O
analysis	O
.	O

Data	O
collection	O

The	O
questionnaire	O
included	O
items	O
on	O
demographic	O
and	O
socioeconomic	O
characteristics	O
,	O
health	O
and	O
wellbeing	O
(	O
including	O
the	O
the	O
SF	O
-	O
8	O
scale	O
)	O
,	O
perceptions	O
of	O
the	O
local	O
environment	O
,	O
travel	O
behaviour	O
and	O
the	O
short	O
form	O
of	O
the	O
International	O
Physical	O
Activity	O
Questionnaire	O
(	O
IPAQ	O
)	O
(	O
Additional	O
file	O
1	O
)	O
.	O

We	O
developed	O
a	O
new	O
'	O
neighbourhood	O
scale	O
'	O
to	O
assess	O
perceptions	O
of	O
relevant	O
characteristics	O
of	O
the	O
local	O
environment	O
(	O
aesthetics	O
,	O
green	O
space	O
,	O
access	O
to	O
amenities	O
,	O
convenience	O
of	O
routes	O
,	O
traffic	O
,	O
road	O
safety	O
and	O
personal	O
safety	O
)	O
.	O

The	O
development	O
,	O
principal	O
components	O
analysis	O
and	O
reliability	O
of	O
the	O
items	O
in	O
this	O
scale	O
and	O
the	O
derivation	O
and	O
reliability	O
of	O
summary	O
variables	O
are	O
reported	O
in	O
an	O
accompanying	O
paper	O
[	O
18	O
]	O
.	O

Data	O
cleaning	O
and	O
derivation	O
of	O
variables	O

Demographic	O
and	O
socioeconomic	O
characteristics	O

We	O
excluded	O
from	O
analysis	O
all	O
respondents	O
who	O
failed	O
to	O
enter	O
their	O
age	O
or	O
sex	O
.	O

We	O
then	O
examined	O
the	O
distributions	O
of	O
all	O
raw	O
variables	O
and	O
carried	O
out	O
range	O
and	O
consistency	O
checks	O
to	O
identify	O
any	O
anomalous	O
values	O
or	O
variables	O
with	O
a	O
high	O
proportion	O
of	O
missing	O
responses	O
.	O

As	O
a	O
consequence	O
,	O
we	O
collapsed	O
responses	O
on	O
distance	O
to	O
place	O
of	O
work	O
or	O
study	O
,	O
housing	O
tenure	O
,	O
car	O
access	O
and	O
working	O
situation	O
into	O
fewer	O
categories	O
by	O
merging	O
categories	O
with	O
small	O
numbers	O
of	O
responses	O
;	O
we	O
also	O
disregarded	O
household	O
composition	O
and	O
working	O
situation	O
of	O
spouse	O
or	O
partner	O
in	O
analysis	O
because	O
of	O
the	O
large	O
numbers	O
of	O
missing	O
values	O
for	O
these	O
variables	O
.	O

Health	O
and	O
wellbeing	O

We	O
calculated	O
body	O
mass	O
index	O
(	O
BMI	O
)	O
by	O
converting	O
,	O
where	O
necessary	O
,	O
self	O
-	O
reported	O
heights	O
and	O
weights	O
from	O
imperial	O
to	O
metric	O
units	O
and	O
dividing	O
the	O
height	O
in	O
metres	O
by	O
the	O
square	O
of	O
the	O
weight	O
in	O
kilograms	O
;	O
we	O
also	O
categorised	O
respondents	O
into	O
quintiles	O
of	O
BMI	O
.	O

We	O
calculated	O
physical	O
(	O
PCS	O
-	O
8	O
)	O
and	O
mental	O
(	O
MCS	O
-	O
8	O
)	O
health	O
summary	O
scores	O
from	O
the	O
SF	O
-	O
8	O
data	O
and	O
scaled	O
these	O
to	O
population	O
norms	O
using	O
the	O
method	O
and	O
coefficients	O
given	O
in	O
the	O
SF	O
-	O
8	O
manual	O
[	O
19	O
]	O
.	O

Objective	O
environmental	O
characteristics	O

We	O
linked	O
each	O
record	O
to	O
the	O
unit	O
postcode	O
of	O
residence	O
.	O

We	O
then	O
constructed	O
concentric	O
buffers	O
at	O
100	O
-	O
metre	O
intervals	O
up	O
to	O
500	O
metres	O
around	O
the	O
routes	O
and	O
access	O
points	O
of	O
existing	O
and	O
planned	O
motorways	O
and	O
around	O
the	O
network	O
of	O
other	O
major	O
(	O
A	O
-	O
and	O
B	O
-	O
class	O
)	O
roads	O
,	O
and	O
assigned	O
each	O
respondent	O
to	O
a	O
category	O
of	O
proximity	O
to	O
each	O
type	O
of	O
road	O
infrastructure	O
(	O
within	O
100	O
metres	O
,	O
101	O
-	O
200	O
metres	O
,	O
etc	O
.	O
)	O
based	O
on	O
the	O
location	O
of	O
the	O
centroid	O
of	O
their	O
unit	O
postcode	O
.	O

Travel	O
behaviour	O

For	O
travel	O
time	O
analysis	O
we	O
included	O
travel	O
diaries	O
which	O
recorded	O
no	O
travel	O
at	O
all	O
,	O
but	O
we	O
disregarded	O
travel	O
data	O
from	O
respondents	O
who	O
had	O
not	O
been	O
at	O
home	O
on	O
the	O
day	O
of	O
the	O
travel	O
diary	O
,	O
whose	O
questionnaire	O
had	O
been	O
misprinted	O
such	O
that	O
the	O
travel	O
diary	O
pages	O
were	O
unusable	O
,	O
who	O
had	O
recorded	O
journeys	O
without	O
reporting	O
valid	O
quantitative	O
data	O
on	O
the	O
durations	O
of	O
those	O
journeys	O
,	O
or	O
whose	O
completed	O
travel	O
diary	O
appeared	O
implausible	O
.	O

We	O
also	O
disregarded	O
journeys	O
whose	O
purpose	O
was	O
not	O
stated	O
or	O
was	O
beyond	O
the	O
scope	O
of	O
the	O
travel	O
diary	O
(	O
Additional	O
file	O
1	O
,	O
page	O
8	O
)	O
.	O

We	O
summed	O
the	O
reported	O
travel	O
time	O
for	O
each	O
mode	O
of	O
transport	O
,	O
calculated	O
a	O
total	O
travel	O
time	O
by	O
active	O
modes	O
(	O
walking	O
plus	O
cycling	O
)	O
and	O
by	O
all	O
modes	O
combined	O
,	O
and	O
calculated	O
the	O
proportion	O
of	O
total	O
travel	O
time	O
contributed	O
by	O
each	O
mode	O
of	O
transport	O
.	O

Physical	O
activity	O

We	O
cleaned	O
and	O
analysed	O
IPAQ	O
data	O
in	O
accordance	O
with	O
the	O
IPAQ	O
scoring	O
protocol	O
.	O

We	O
therefore	O
disregarded	O
physical	O
activity	O
data	O
from	O
respondents	O
who	O
had	O
reported	O
more	O
than	O
16	O
hours	O
of	O
physical	O
activity	O
per	O
day	O
or	O
who	O
had	O
missing	O
or	O
internally	O
inconsistent	O
data	O
on	O
the	O
frequency	O
or	O
duration	O
of	O
any	O
of	O
the	O
three	O
categories	O
of	O
physical	O
activity	O
(	O
walking	O
,	O
moderate	O
-	O
intensity	O
activity	O
or	O
vigorous	O
activity	O
)	O
.	O

We	O
also	O
recoded	O
reported	O
durations	O
of	O
activity	O
of	O
less	O
than	O
ten	O
minutes	O
to	O
zero	O
,	O
and	O
of	O
greater	O
than	O
180	O
minutes	O
to	O
180	O
minutes	O
.	O

We	O
calculated	O
the	O
estimated	O
total	O
physical	O
activity	O
energy	O
expenditure	O
for	O
each	O
respondent	O
(	O
MET	O
-	O
min	O
/	O
week	O
)	O
and	O
used	O
a	O
combination	O
of	O
frequency	O
,	O
duration	O
and	O
total	O
energy	O
expenditure	O
to	O
assign	O
each	O
respondent	O
to	O
a	O
'	O
high	O
'	O
,	O
'	O
moderate	O
'	O
or	O
'	O
low	O
'	O
category	O
of	O
overall	O
physical	O
activity	O
in	O
accordance	O
with	O
the	O
prescribed	O
IPAQ	O
algorithm	O
.	O

The	O
'	O
high	O
'	O
category	O
corresponds	O
to	O
a	O
sufficient	O
level	O
of	O
physical	O
activity	O
to	O
meet	O
current	O
public	O
health	O
recommendations	O
for	O
adults	O
[	O
20	O
]	O
.	O

Analysis	O

We	O
considered	O
it	O
unlikely	O
that	O
the	O
statistical	O
assumptions	O
required	O
for	O
linear	O
regression	O
could	O
be	O
met	O
because	O
the	O
distributions	O
of	O
time	O
spent	O
walking	O
and	O
cycling	O
and	O
of	O
estimated	O
total	O
physical	O
activity	O
energy	O
expenditure	O
were	O
both	O
strongly	O
positively	O
skewed	O
and	O
dominated	O
by	O
a	O
large	O
number	O
of	O
zero	O
values	O
which	O
meant	O
that	O
the	O
data	O
were	O
not	O
amenable	O
to	O
log	O
-	O
transformation	O
.	O

We	O
therefore	O
modelled	O
the	O
correlates	O
of	O
active	O
travel	O
and	O
physical	O
activity	O
using	O
multivariate	O
logistic	O
regression	O
.	O

We	O
defined	O
'	O
active	O
travel	O
'	O
as	O
a	O
binary	O
condition	O
achieved	O
by	O
any	O
respondent	O
who	O
had	O
reported	O
at	O
least	O
30	O
minutes	O
of	O
travel	O
by	O
walking	O
,	O
cycling	O
or	O
both	O
in	O
their	O
travel	O
diary	O
,	O
reflecting	O
the	O
current	O
recommendation	O
that	O
adults	O
should	O
accumulate	O
at	O
least	O
30	O
minutes	O
of	O
moderate	O
-	O
intensity	O
physical	O
activity	O
on	O
most	O
days	O
of	O
the	O
week	O
[	O
20	O
]	O
,	O
and	O
we	O
defined	O
'	O
physical	O
activity	O
'	O
as	O
a	O
binary	O
condition	O
achieved	O
by	O
any	O
respondent	O
whose	O
overall	O
physical	O
activity	O
was	O
categorised	O
as	O
'	O
high	O
'	O
using	O
IPAQ	O
.	O

We	O
then	O
built	O
separate	O
multivariate	O
models	O
for	O
active	O
travel	O
and	O
physical	O
activity	O
following	O
the	O
method	O
of	O
Hosmer	O
and	O
Lemeshow	O
[	O
21	O
]	O
,	O
first	O
including	O
only	O
'	O
personal	O
'	O
(	O
individual	O
or	O
household	O
)	O
variables	O
and	O
then	O
adding	O
'	O
environmental	O
'	O
variables	O
(	O
Additional	O
file	O
2	O
)	O
.	O

Results	O

Response	O

We	O
received	O
1345	O
completed	O
questionnaires	O
.	O

After	O
subtracting	O
from	O
the	O
numerator	O
23	O
completed	O
questionnaires	O
with	O
missing	O
critical	O
demographic	O
data	O
(	O
age	O
or	O
sex	O
)	O
,	O
and	O
after	O
subtracting	O
from	O
the	O
denominator	O
676	O
addresses	O
from	O
which	O
survey	O
packs	O
were	O
returned	O
as	O
undeliverable	O
,	O
this	O
left	O
1322	O
valid	O
responses	O
to	O
be	O
entered	O
into	O
analysis	O
-	O
a	O
response	O
rate	O
of	O
1322	O
/	O
(	O
9000	O
-	O
676	O
)	O
=	O
15	O
.	O
9	O
%	O
.	O

Characteristics	O
of	O
study	O
participants	B

Demographic	O
and	O
socioeconomic	O
characteristics	O

Respondents	O
were	O
aged	O
between	O
16	O
and	O
89	O
years	O
(	O
median	O
age	O
48	O
years	O
)	O
.	O

804	O
(	O
61	O
%	O
)	O
were	O
women	B
.	O

Only	O
136	O
(	O
26	O
%	O
)	O
of	O
the	O
men	B
and	O
145	O
(	O
18	O
%	O
)	O
of	O
the	O
women	B
reported	O
having	O
access	O
to	O
a	O
bicycle	O
.	O

For	O
those	O
who	O
usually	O
travelled	O
to	O
a	O
place	O
of	O
work	O
or	O
study	O
,	O
the	O
median	O
reported	O
distance	O
was	O
3	O
.	O
5	O
miles	O
(	O
about	O
5	O
.	O
5	O
kilometres	O
)	O
.	O

Other	O
characteristics	O
of	O
study	O
participants	B
are	O
summarised	O
in	O
Table	O
2	O
.	O

Health	O
and	O
wellbeing	O

25	O
%	O
of	O
respondents	O
reported	O
difficulty	O
walking	O
for	O
a	O
quarter	O
of	O
a	O
mile	O
,	O
39	O
%	O
reported	O
a	O
long	O
-	O
term	O
health	O
problem	O
or	O
disability	O
,	O
and	O
50	O
%	O
were	O
overweight	O
(	O
median	O
BMI	O
25	O
.	O
1	O
kg	O
/	O
m2	O
)	O
.	O

The	O
median	O
mental	O
health	O
summary	O
score	O
(	O
MCS	O
-	O
8	O
)	O
was	O
significantly	O
lower	O
(	O
i	O
.	O
e	O
.	O
poorer	O
)	O
than	O
the	O
population	O
norm	O
(	O
median	O
47	O
.	O
3	O
,	O
95	O
%	O
CI	O
46	O
.	O
4	O
to	O
48	O
.	O
1	O
)	O
;	O
the	O
median	O
physical	O
health	O
summary	O
score	O
(	O
PCS	O
-	O
8	O
)	O
was	O
not	O
significantly	O
different	O
from	O
the	O
population	O
norm	O
(	O
median	O
50	O
.	O
9	O
,	O
95	O
%	O
CI	O
49	O
.	O
6	O
to	O
51	O
.	O
7	O
)	O
.	O

Descriptive	O
data	O
on	O
travel	O
behaviour	O
and	O
physical	O
activity	O

Travel	O
behaviour	O

1099	O
travel	O
diaries	O
were	O
suitable	O
for	O
travel	O
time	O
analysis	O
.	O

Men	B
and	O
women	B
were	O
equally	O
likely	O
to	O
have	O
returned	O
usable	O
travel	O
time	O
data	O
,	O
but	O
respondents	O
who	O
were	O
older	O
,	O
retired	O
,	O
or	O
living	O
in	O
social	O
rented	O
accommodation	O
or	O
who	O
did	O
not	O
have	O
access	O
to	O
a	O
car	O
were	O
less	O
likely	O
to	O
have	O
returned	O
usable	O
data	O
.	O

On	O
average	O
,	O
respondents	O
recorded	O
about	O
an	O
hour	O
'	O
s	O
travel	O
per	O
day	O
(	O
mean	O
61	O
.	O
5	O
minutes	O
,	O
median	O
50	O
.	O
0	O
minutes	O
)	O
,	O
of	O
which	O
a	O
minority	O
was	O
spent	O
using	O
active	O
modes	O
of	O
transport	O
(	O
walking	O
or	O
cycling	O
:	O
mean	O
20	O
.	O
0	O
minutes	O
,	O
median	O
10	O
.	O
0	O
minutes	O
)	O
(	O
Table	O
3	O
)	O
.	O

304	O
respondents	O
(	O
28	O
%	O
)	O
recorded	O
at	O
least	O
30	O
minutes	O
of	O
active	O
travel	O
,	O
of	O
whom	O
294	O
(	O
97	O
%	O
)	O
recorded	O
at	O
least	O
30	O
minutes	O
of	O
walking	O
.	O

Physical	O
activity	O

833	O
respondents	O
returned	O
complete	O
physical	O
activity	O
data	O
suitable	O
for	O
analysis	O
.	O

Women	B
and	O
respondents	O
who	O
were	O
older	O
,	O
retired	O
,	O
or	O
living	O
in	O
social	O
rented	O
accommodation	O
or	O
who	O
did	O
not	O
have	O
access	O
to	O
a	O
car	O
were	O
less	O
likely	O
to	O
have	O
returned	O
usable	O
data	O
.	O

Respondents	O
reported	O
a	O
mean	O
of	O
318	O
minutes	O
'	O
walking	O
per	O
week	O
and	O
a	O
mean	O
estimated	O
total	O
physical	O
activity	O
energy	O
expenditure	O
of	O
3000	O
MET	O
-	O
minutes	O
per	O
week	O
(	O
Table	O
4	O
)	O
.	O

Only	O
316	O
respondents	O
(	O
38	O
%	O
)	O
were	O
categorised	O
as	O
having	O
achieved	O
a	O
'	O
high	O
'	O
(	O
i	O
.	O
e	O
.	O
sufficient	O
)	O
level	O
of	O
physical	O
activity	O
.	O

Correlates	O
of	O
active	O
travel	O

Active	O
travel	O
was	O
significantly	O
associated	O
with	O
being	O
younger	O
,	O
living	O
in	O
owner	O
-	O
occupied	O
accommodation	O
,	O
not	O
having	O
to	O
travel	O
more	O
than	O
four	O
miles	O
to	O
work	O
,	O
having	O
access	O
to	O
a	O
bicycle	O
,	O
not	O
having	O
access	O
to	O
a	O
car	O
,	O
and	O
the	O
absence	O
of	O
any	O
difficulty	O
walking	O
.	O

The	O
final	O
best	O
model	O
of	O
the	O
'	O
personal	O
'	O
correlates	O
of	O
active	O
travel	O
provided	O
satisfactory	O
goodness	O
-	O
of	O
-	O
fit	O
(	O
Hosmer	O
and	O
Lemeshow	O
test	O
:	O
chi	O
2	O
=	O
13	O
.	O
04	O
,	O
df	O
=	O
8	O
;	O
P	O
=	O
0	O
.	O
11	O
)	O
and	O
explained	O
nearly	O
one	O
-	O
fifth	O
of	O
the	O
total	O
variance	O
in	O
active	O
travel	O
(	O
Nagelkerke	O
'	O
s	O
R2	O
=	O
18	O
.	O
7	O
%	O
)	O
(	O
Table	O
5	O
)	O
.	O

Adding	O
'	O
environmental	O
'	O
variables	O
to	O
the	O
model	O
showed	O
an	O
additional	O
significant	O
positive	O
association	O
between	O
active	O
travel	O
and	O
perceived	O
proximity	O
to	O
shops	O
,	O
and	O
an	O
additional	O
significant	O
negative	O
association	O
between	O
active	O
travel	O
and	O
perceived	O
road	O
safety	O
for	O
cyclists	O
.	O

The	O
final	O
best	O
model	O
of	O
the	O
personal	O
and	O
environmental	O
correlates	O
of	O
active	O
travel	O
also	O
provided	O
satisfactory	O
goodness	O
-	O
of	O
-	O
fit	O
(	O
Hosmer	O
and	O
Lemeshow	O
test	O
:	O
chi	O
2	O
=	O
10	O
.	O
61	O
,	O
df	O
=	O
8	O
;	O
P	O
=	O
0	O
.	O
23	O
)	O
and	O
explained	O
slightly	O
more	O
of	O
the	O
total	O
variance	O
in	O
active	O
travel	O
than	O
did	O
the	O
personal	O
model	O
alone	O
(	O
Nagelkerke	O
'	O
s	O
R2	O
=	O
20	O
.	O
1	O
%	O
)	O
(	O
Figure	O
3	O
)	O
.	O

In	O
order	O
to	O
aid	O
interpretation	O
,	O
we	O
also	O
partitioned	O
the	O
dataset	O
into	O
two	O
strata	O
(	O
'	O
No	O
car	O
available	O
'	O
and	O
'	O
Car	O
available	O
'	O
)	O
and	O
refitted	O
the	O
final	O
model	O
separately	O
to	O
each	O
stratum	O
of	O
the	O
dataset	O
(	O
Table	O
6	O
)	O
.	O

This	O
showed	O
that	O
the	O
subset	O
of	O
respondents	O
with	O
no	O
access	O
to	O
a	O
car	O
accounted	O
for	O
the	O
significant	O
overall	O
relationship	O
between	O
active	O
travel	O
and	O
access	O
to	O
a	O
bicycle	O
,	O
whereas	O
those	O
with	O
access	O
to	O
a	O
car	O
accounted	O
for	O
the	O
significant	O
overall	O
relationships	O
with	O
distance	O
to	O
place	O
of	O
work	O
or	O
study	O
and	O
perceptions	O
of	O
the	O
local	O
environment	O
.	O

The	O
relationship	O
with	O
difficulty	O
walking	O
was	O
also	O
stronger	O
in	O
this	O
group	O
than	O
in	O
those	O
without	O
access	O
to	O
a	O
car	O
.	O

Correlates	O
of	O
physical	O
activity	O

Physical	O
activity	O
was	O
significantly	O
associated	O
with	O
living	O
in	O
social	O
-	O
rented	O
accommodation	O
,	O
not	O
being	O
overweight	O
,	O
and	O
the	O
absence	O
of	O
any	O
difficulty	O
walking	O
.	O

The	O
final	O
best	O
model	O
of	O
the	O
'	O
personal	O
'	O
correlates	O
of	O
physical	O
activity	O
provided	O
satisfactory	O
goodness	O
-	O
of	O
-	O
fit	O
(	O
Hosmer	O
and	O
Lemeshow	O
test	O
:	O
chi	O
2	O
=	O
3	O
.	O
89	O
,	O
df	O
=	O
7	O
;	O
P	O
=	O
0	O
.	O
89	O
)	O
and	O
explained	O
about	O
one	O
-	O
sixth	O
of	O
the	O
total	O
variance	O
in	O
physical	O
activity	O
(	O
Nagelkerke	O
'	O
s	O
R2	O
=	O
15	O
.	O
9	O
%	O
)	O
(	O
Table	O
7	O
)	O
.	O

Adding	O
'	O
environmental	O
'	O
variables	O
to	O
the	O
model	O
showed	O
an	O
additional	O
significant	O
negative	O
association	O
between	O
physical	O
activity	O
and	O
perception	O
of	O
traffic	O
volume	O
(	O
i	O
.	O
e	O
.	O
respondents	O
who	O
perceived	O
there	O
to	O
be	O
a	O
higher	O
volume	O
of	O
traffic	O
were	O
more	O
likely	O
to	O
report	O
physical	O
activity	O
)	O
.	O

The	O
final	O
best	O
model	O
of	O
the	O
personal	O
and	O
environmental	O
correlates	O
of	O
physical	O
activity	O
also	O
provided	O
satisfactory	O
goodness	O
-	O
of	O
-	O
fit	O
(	O
Hosmer	O
and	O
Lemeshow	O
test	O
:	O
chi	O
2	O
=	O
3	O
.	O
86	O
,	O
df	O
=	O
8	O
;	O
P	O
=	O
0	O
.	O
87	O
)	O
and	O
explained	O
slightly	O
more	O
of	O
the	O
total	O
variance	O
in	O
physical	O
activity	O
than	O
did	O
the	O
personal	O
model	O
alone	O
(	O
Nagelkerke	O
'	O
s	O
16	O
.	O
6	O
%	O
)	O
(	O
Figure	O
3	O
)	O
.	O

Discussion	O

Principal	O
findings	O

In	O
this	O
deprived	O
urban	O
population	O
,	O
the	O
likelihood	O
of	O
reporting	O
active	O
travel	O
was	O
associated	O
with	O
being	O
younger	O
,	O
living	O
in	O
owner	O
-	O
occupied	O
accommodation	O
,	O
not	O
having	O
to	O
travel	O
a	O
long	O
distance	O
to	O
work	O
and	O
not	O
having	O
access	O
to	O
a	O
car	O
,	O
whereas	O
overall	O
physical	O
activity	O
was	O
associated	O
with	O
living	O
in	O
social	O
-	O
rented	O
accommodation	O
and	O
not	O
being	O
overweight	O
.	O

After	O
adjusting	O
for	O
individual	O
and	O
household	O
characteristics	O
,	O
neither	O
perceptions	O
of	O
the	O
local	O
environment	O
nor	O
the	O
objective	O
proximity	O
of	O
respondents	O
'	O
homes	O
to	O
motorway	O
or	O
major	O
road	O
infrastructure	O
appeared	O
to	O
explain	O
much	O
of	O
the	O
variance	O
in	O
active	O
travel	O
or	O
overall	O
physical	O
activity	O
,	O
although	O
we	O
did	O
find	O
a	O
significant	O
positive	O
association	O
between	O
active	O
travel	O
and	O
perceived	O
proximity	O
to	O
shops	O
.	O

Representativeness	O
and	O
completeness	O
of	O
survey	O
data	O

Our	O
difficulty	O
in	O
obtaining	O
a	O
representative	O
sample	O
of	O
the	O
resident	O
population	O
is	O
not	O
unique	O
to	O
our	O
study	O
.	O

Although	O
our	O
final	O
response	O
rate	O
was	O
low	O
,	O
it	O
was	O
almost	O
identical	O
to	O
that	O
achieved	O
in	O
a	O
recent	O
population	O
-	O
based	O
intervention	O
study	O
elsewhere	O
in	O
Glasgow	O
[	O
22	O
]	O
.	O

Some	O
of	O
the	O
challenges	O
of	O
recruiting	O
research	O
participants	B
in	O
areas	O
of	O
deprivation	O
have	O
been	O
described	O
elsewhere	O
[	O
23	O
]	O
;	O
these	O
are	O
superimposed	O
on	O
a	O
downward	O
trend	O
in	O
participation	O
in	O
even	O
the	O
best	O
-	O
resourced	O
national	O
population	O
surveys	O
[	O
24	O
]	O
and	O
an	O
upward	O
(	O
and	O
socially	O
biased	O
)	O
trend	O
in	O
opt	O
-	O
outs	O
from	O
the	O
main	O
alternative	O
sampling	O
frame	O
,	O
the	O
edited	O
electoral	O
register	O
[	O
25	O
]	O
.	O

Although	O
our	O
achieved	O
sample	O
contained	O
a	O
higher	O
proportion	O
of	O
respondents	O
from	O
owner	O
-	O
occupied	O
and	O
car	O
-	O
owning	O
households	O
than	O
predicted	O
from	O
2001	O
census	O
data	O
for	O
the	O
same	O
census	O
output	O
areas	O
,	O
these	O
differences	O
may	O
be	O
partly	O
accounted	O
for	O
by	O
an	O
upward	O
background	O
trend	O
in	O
owner	O
occupation	O
and	O
car	O
access	O
between	O
2001	O
and	O
2005	O
.	O

Our	O
achieved	O
sample	O
is	O
still	O
clearly	O
disadvantaged	O
overall	O
,	O
in	O
terms	O
of	O
socioeconomic	O
and	O
health	O
status	O
,	O
compared	O
with	O
the	O
country	O
as	O
a	O
whole	O
.	O

It	O
also	O
contains	O
sufficient	O
heterogeneity	O
to	O
enable	O
us	O
to	O
examine	O
,	O
in	O
time	O
,	O
how	O
the	O
effects	O
of	O
the	O
intervention	O
are	O
distributed	O
between	O
socioeconomic	O
groups	O
.	O

We	O
therefore	O
consider	O
our	O
achieved	O
sample	O
fit	O
for	O
purpose	O
.	O

We	O
had	O
to	O
disregard	O
a	O
substantial	O
proportion	O
of	O
cases	O
in	O
analysis	O
because	O
respondents	O
had	O
returned	O
unusable	O
travel	O
time	O
data	O
or	O
had	O
returned	O
physical	O
activity	O
data	O
that	O
were	O
incomplete	O
,	O
internally	O
inconsistent	O
or	O
included	O
a	O
'	O
Don	O
'	O
t	O
know	O
'	O
response	O
and	O
were	O
therefore	O
unacceptable	O
according	O
to	O
the	O
IPAQ	O
scoring	O
protocol	O
.	O

Most	O
published	O
studies	O
using	O
the	O
same	O
,	O
short	O
form	O
of	O
IPAQ	O
have	O
either	O
not	O
reported	O
the	O
distribution	O
of	O
the	O
continuous	O
summary	O
measures	O
or	O
have	O
not	O
reported	O
data	O
for	O
the	O
UK	O
separately	O
from	O
those	O
for	O
other	O
countries	O
where	O
higher	O
levels	O
of	O
physical	O
activity	O
are	O
reported	O
.	O

Despite	O
the	O
high	O
proportion	O
of	O
missing	O
physical	O
activity	O
data	O
in	O
our	O
dataset	O
,	O
however	O
,	O
the	O
aggregate	O
continuous	O
data	O
we	O
obtained	O
were	O
broadly	O
comparable	O
to	O
those	O
reported	O
in	O
R	O
u	O
tten	O
and	O
colleagues	O
'	O
study	O
of	O
a	O
random	O
sample	O
of	O
UK	O
adults	O
[	O
26	O
]	O
.	O

We	O
could	O
have	O
included	O
more	O
cases	O
in	O
physical	O
activity	O
analysis	O
by	O
,	O
for	O
example	O
,	O
imputing	O
missing	O
values	O
,	O
but	O
the	O
results	O
would	O
not	O
have	O
been	O
comparable	O
with	O
others	O
'	O
owing	O
to	O
the	O
substantial	O
deviations	O
from	O
the	O
scoring	O
protocol	O
which	O
would	O
have	O
been	O
required	O
.	O

The	O
frequency	O
of	O
unusable	O
responses	O
was	O
not	O
reported	O
in	O
the	O
international	O
multi	O
-	O
centre	O
study	O
which	O
originally	O
established	O
the	O
validity	O
and	O
reliability	O
of	O
IPAQ	O
[	O
27	O
]	O
.	O

It	O
is	O
possible	O
that	O
offering	O
a	O
'	O
Don	O
'	O
t	O
know	O
'	O
option	O
in	O
the	O
self	O
-	O
completed	O
IPAQ	O
questionnaire	O
encourages	O
respondents	O
to	O
select	O
this	O
rather	O
than	O
to	O
enter	O
what	O
may	O
be	O
a	O
reasonably	O
precise	O
estimate	O
of	O
the	O
actual	O
time	O
spent	O
in	O
physical	O
activity	O
;	O
the	O
respondent	O
has	O
no	O
way	O
of	O
knowing	O
that	O
a	O
single	O
'	O
Don	O
'	O
t	O
know	O
'	O
response	O
will	O
result	O
in	O
all	O
of	O
their	O
physical	O
activity	O
data	O
being	O
disregarded	O
in	O
analysis	O
.	O

This	O
should	O
be	O
considered	O
in	O
any	O
future	O
revision	O
of	O
the	O
IPAQ	O
questionnaire	O
and	O
scoring	O
protocol	O
.	O

Contribution	O
of	O
active	O
travel	O
to	O
overall	O
physical	O
activity	O

The	O
explanatory	O
variables	O
that	O
were	O
significantly	O
associated	O
with	O
active	O
travel	O
but	O
not	O
with	O
physical	O
activity	O
(	O
distance	O
to	O
place	O
of	O
work	O
or	O
study	O
,	O
access	O
to	O
a	O
bicycle	O
,	O
access	O
to	O
a	O
car	O
,	O
perceived	O
proximity	O
to	O
shops	O
,	O
and	O
perceived	O
road	O
safety	O
for	O
cyclists	O
)	O
all	O
have	O
an	O
obvious	O
intuitive	O
relationship	O
with	O
the	O
use	O
of	O
walking	O
or	O
cycling	O
as	O
modes	O
of	O
transport	O
.	O

That	O
they	O
were	O
not	O
significantly	O
associated	O
with	O
overall	O
physical	O
activity	O
suggests	O
either	O
that	O
active	O
travel	O
contributes	O
only	O
a	O
minority	O
of	O
respondents	O
'	O
overall	O
physical	O
activity	O
or	O
that	O
other	O
factors	O
not	O
measured	O
in	O
this	O
study	O
are	O
more	O
important	O
correlates	O
of	O
overall	O
physical	O
activity	O
than	O
those	O
which	O
determine	O
active	O
travel	O
.	O

A	O
crude	O
comparision	O
of	O
the	O
quantity	O
of	O
active	O
travel	O
reported	O
in	O
the	O
one	O
-	O
day	O
travel	O
diaries	O
with	O
the	O
quantities	O
of	O
physical	O
activity	O
reported	O
using	O
IPAQ	O
suggests	O
that	O
on	O
average	O
,	O
active	O
travel	O
may	O
indeed	O
make	O
only	O
a	O
small	O
(	O
~	O
15	O
%	O
)	O
contribution	O
to	O
overall	O
physical	O
activity	O
in	O
this	O
study	O
population	O
.	O

However	O
,	O
the	O
real	O
contribution	O
may	O
be	O
substantially	O
greater	O
than	O
this	O
if	O
,	O
as	O
has	O
been	O
shown	O
previously	O
,	O
respondents	O
tend	O
to	O
over	O
-	O
report	O
their	O
physical	O
activity	O
using	O
IPAQ	O
[	O
28	O
]	O
.	O

There	O
can	O
be	O
little	O
doubt	O
that	O
active	O
travel	O
makes	O
a	O
substantial	O
contribution	O
to	O
the	O
total	O
quantity	O
of	O
walking	O
reported	O
in	O
this	O
study	O
population	O
.	O

Irrespective	O
of	O
the	O
true	O
contribution	O
of	O
active	O
travel	O
to	O
overall	O
physical	O
activity	O
,	O
however	O
,	O
it	O
remains	O
likely	O
that	O
other	O
unmeasured	O
personal	O
and	O
social	O
factors	O
beyond	O
the	O
scope	O
of	O
this	O
study	O
may	O
be	O
more	O
important	O
correlates	O
of	O
overall	O
physical	O
activity	O
.	O

Socio	O
-	O
spatial	O
patterning	O
of	O
active	O
travel	O
and	O
overall	O
physical	O
activity	O

Respondents	O
living	O
in	O
owner	O
-	O
occupied	O
households	O
were	O
more	O
likely	O
to	O
report	O
active	O
travel	O
than	O
those	O
living	O
in	O
social	O
-	O
rented	O
accommodation	O
,	O
but	O
less	O
likely	O
to	O
report	O
sufficient	O
overall	O
physical	O
activity	O
.	O

Since	O
neither	O
working	O
situation	O
nor	O
perceived	O
financial	O
situation	O
emerged	O
as	O
significantly	O
associated	O
with	O
active	O
travel	O
or	O
overall	O
physical	O
activity	O
,	O
housing	O
tenure	O
and	O
car	O
access	O
are	O
the	O
remaining	O
explanatory	O
variables	O
in	O
this	O
dataset	O
which	O
can	O
be	O
interpreted	O
as	O
markers	O
of	O
socioeconomic	O
status	O
.	O

Although	O
having	O
access	O
to	O
a	O
car	O
clearly	O
reflects	O
the	O
possession	O
of	O
a	O
material	O
asset	O
,	O
it	O
has	O
been	O
argued	O
that	O
this	O
is	O
a	O
less	O
direct	O
marker	O
of	O
socioeconomic	O
status	O
than	O
some	O
other	O
markers	O
because	O
,	O
in	O
Scotland	O
at	O
least	O
,	O
access	O
to	O
a	O
car	O
is	O
a	O
more	O
-	O
or	O
-	O
less	O
essential	O
requirement	O
for	O
living	O
in	O
many	O
rural	O
areas	O
,	O
whereas	O
it	O
is	O
possible	O
to	O
live	O
in	O
a	O
dense	O
urban	O
settlement	O
such	O
as	O
Glasgow	O
without	O
using	O
a	O
car	O
.	O

In	O
the	O
final	O
models	O
in	O
this	O
study	O
,	O
therefore	O
,	O
housing	O
tenure	O
may	O
be	O
regarded	O
as	O
the	O
primary	O
marker	O
of	O
socioeconomic	O
status	O
.	O

The	O
findings	O
consequently	O
suggest	O
conflicting	O
socioeconomic	O
gradients	O
in	O
prevalence	O
:	O
more	O
advantaged	O
respondents	O
were	O
more	O
likely	O
to	O
report	O
active	O
travel	O
,	O
but	O
more	O
disadvantaged	O
respondents	O
were	O
more	O
likely	O
to	O
report	O
sufficient	O
overall	O
physical	O
activity	O
.	O

The	O
higher	O
prevalence	O
of	O
sufficient	O
overall	O
physical	O
activity	O
among	O
the	O
more	O
disadvantaged	O
despite	O
their	O
lower	O
propensity	O
for	O
active	O
travel	O
is	O
likely	O
to	O
reflect	O
higher	O
quantities	O
of	O
physical	O
activity	O
in	O
other	O
domains	O
,	O
particularly	O
occupational	O
and	O
domestic	O
activities	O
,	O
since	O
leisure	O
-	O
time	O
physical	O
activity	O
tends	O
to	O
be	O
higher	O
among	O
more	O
advantaged	O
groups	O
[	O
29	O
]	O
.	O

Environmental	O
characteristics	O
:	O
paradoxical	O
,	O
unmeasured	O
,	O
or	O
irrelevant	O
?	O

The	O
two	O
environmental	O
variables	O
that	O
emerged	O
as	O
significantly	O
associated	O
with	O
active	O
travel	O
,	O
particularly	O
among	O
those	O
without	O
access	O
to	O
a	O
car	O
,	O
were	O
perceived	O
proximity	O
to	O
shops	O
and	O
perceived	O
road	O
safety	O
for	O
cyclists	O
.	O

The	O
positive	O
association	O
with	O
perceived	O
proximity	O
to	O
shops	O
suggests	O
that	O
for	O
active	O
travel	O
to	O
be	O
undertaken	O
in	O
this	O
population	O
,	O
it	O
may	O
be	O
more	O
important	O
that	O
people	B
live	O
close	O
to	O
the	O
amenities	O
they	O
need	O
than	O
that	O
they	O
live	O
in	O
an	O
environment	O
with	O
more	O
favourable	O
subjective	O
or	O
discretionary	O
considerations	O
such	O
as	O
attractiveness	O
or	O
noise	O
.	O

This	O
would	O
be	O
consistent	O
with	O
an	O
understanding	O
that	O
walking	O
as	O
a	O
mode	O
of	O
transport	O
is	O
primarily	O
a	O
way	O
of	O
undertaking	O
journeys	O
which	O
have	O
to	O
be	O
made	O
anyway	O
,	O
as	O
opposed	O
to	O
more	O
discretionary	O
(	O
recreational	O
)	O
forms	O
of	O
walking	O
which	O
may	O
be	O
more	O
susceptible	O
to	O
the	O
influence	O
of	O
less	O
-	O
structural	O
characteristics	O
.	O

Although	O
the	O
negative	O
association	O
with	O
perceived	O
road	O
safety	O
for	O
cyclists	O
appears	O
counter	O
-	O
intuitive	O
,	O
similar	O
'	O
paradoxical	O
inverse	O
relationships	O
'	O
have	O
been	O
reported	O
elsewhere	O
,	O
for	O
example	O
by	O
Titze	O
and	O
colleagues	O
in	O
a	O
study	O
of	O
the	O
correlates	O
of	O
cycling	O
among	O
students	O
[	O
30	O
]	O
and	O
by	O
Humpel	O
and	O
colleagues	O
in	O
a	O
study	O
of	O
correlates	O
of	O
walking	O
for	O
pleasure	O
[	O
31	O
]	O
.	O

Titze	O
and	O
colleagues	O
suggest	O
that	O
respondents	O
who	O
cycle	O
regularly	O
are	O
more	O
likely	O
to	O
be	O
aware	O
of	O
,	O
and	O
report	O
,	O
the	O
danger	O
posed	O
by	O
traffic	O
than	O
non	O
-	O
cyclists	O
or	O
infrequent	O
cyclists	O
.	O

A	O
similar	O
phenomenon	O
could	O
explain	O
the	O
negative	O
association	O
between	O
physical	O
activity	O
and	O
perception	O
of	O
traffic	O
volume	O
.	O

Overall	O
,	O
the	O
influence	O
of	O
the	O
putative	O
environmental	O
characteristics	O
examined	O
in	O
this	O
study	O
on	O
active	O
travel	O
and	O
physical	O
activity	O
appeared	O
small	O
compared	O
with	O
that	O
of	O
the	O
personal	O
characteristics	O
found	O
to	O
be	O
significant	O
,	O
and	O
including	O
environmental	O
characteristics	O
in	O
the	O
models	O
did	O
not	O
substantially	O
modify	O
the	O
influence	O
of	O
personal	O
characteristics	O
.	O

On	O
the	O
one	O
hand	O
,	O
this	O
could	O
reflect	O
an	O
artefact	O
of	O
the	O
research	O
methods	O
(	O
a	O
false	O
negative	O
error	O
)	O
,	O
which	O
could	O
have	O
arisen	O
in	O
various	O
ways	O
.	O

In	O
particular	O
,	O
the	O
'	O
wrong	O
'	O
environmental	O
exposure	O
may	O
have	O
been	O
measured	O
,	O
in	O
that	O
the	O
environmental	O
characteristics	O
examined	O
were	O
those	O
of	O
the	O
immediate	O
surroundings	O
of	O
respondents	O
'	O
homes	O
,	O
whereas	O
the	O
propensity	O
to	O
choose	O
active	O
modes	O
of	O
transport	O
may	O
be	O
more	O
strongly	O
influenced	O
by	O
the	O
characteristics	O
of	O
the	O
environment	O
elsewhere	O
on	O
their	O
routes	O
[	O
30	O
]	O
,	O
for	O
example	O
the	O
perceived	O
danger	O
of	O
cycling	O
in	O
the	O
city	O
centre	O
-	O
an	O
association	O
which	O
may	O
be	O
absent	O
,	O
or	O
at	O
least	O
diluted	O
,	O
when	O
the	O
'	O
exposure	O
'	O
examined	O
is	O
limited	O
to	O
the	O
residential	O
environment	O
.	O

It	O
could	O
also	O
be	O
argued	O
that	O
the	O
apparently	O
weak	O
influence	O
of	O
environmental	O
characteristics	O
in	O
this	O
study	O
reflects	O
a	O
reliance	O
on	O
respondents	O
'	O
perceptions	O
which	O
have	O
not	O
been	O
objectively	O
verified	O
and	O
may	O
therefore	O
be	O
a	O
weak	O
proxy	O
for	O
the	O
'	O
true	O
'	O
objectively	O
-	O
measured	O
characteristics	O
of	O
their	O
surroundings	O
.	O

However	O
,	O
as	O
recent	O
reviews	O
have	O
pointed	O
out	O
,	O
the	O
current	O
weight	O
of	O
evidence	O
for	O
objective	O
environmental	O
correlates	O
of	O
walking	O
is	O
no	O
greater	O
than	O
that	O
for	O
subjective	O
environmental	O
correlates	O
[	O
5	O
]	O
and	O
it	O
is	O
entirely	O
plausible	O
that	O
people	B
'	O
s	O
perceptions	O
of	O
their	O
environment	O
may	O
be	O
at	O
least	O
as	O
important	O
as	O
their	O
objective	O
conditions	O
in	O
influencing	O
their	O
behaviour	O
[	O
6	O
]	O
.	O

On	O
the	O
other	O
hand	O
,	O
we	O
may	O
have	O
demonstrated	O
a	O
real	O
absence	O
of	O
any	O
major	O
association	O
.	O

Although	O
at	O
first	O
sight	O
this	O
appears	O
at	O
odds	O
with	O
the	O
growing	O
body	O
of	O
review	O
-	O
level	O
evidence	O
for	O
environmental	O
correlates	O
of	O
physical	O
activity	O
,	O
Wendel	O
-	O
Vos	O
and	O
colleagues	O
noted	O
that	O
of	O
all	O
the	O
environmental	O
factors	O
examined	O
in	O
all	O
the	O
studies	O
included	O
in	O
their	O
review	O
,	O
analysis	O
showed	O
a	O
'	O
null	O
association	O
'	O
in	O
76	O
%	O
of	O
cases	O
[	O
9	O
]	O
,	O
and	O
our	O
finding	O
that	O
personal	O
factors	O
account	O
for	O
a	O
much	O
larger	O
proportion	O
of	O
the	O
variance	O
in	O
active	O
travel	O
or	O
physical	O
activity	O
than	O
is	O
accounted	O
for	O
by	O
environmental	O
factors	O
is	O
consistent	O
with	O
those	O
of	O
some	O
other	O
European	O
studies	O
[	O
32	O
,	O
33	O
]	O
.	O

In	O
the	O
particular	O
context	O
of	O
this	O
study	O
,	O
residents	O
may	O
simply	O
have	O
adapted	O
to	O
adverse	O
conditions	O
in	O
their	O
local	O
environment	O
in	O
the	O
ways	O
identified	O
by	O
Hedges	O
in	O
a	O
qualitative	O
study	O
of	O
people	B
living	O
close	O
to	O
new	O
roads	O
built	O
in	O
the	O
UK	O
in	O
the	O
1970s	O
[	O
34	O
]	O
-	O
particularly	O
by	O
attitudinal	O
adaptation	O
,	O
which	O
Hedges	O
characterises	O
as	O
developing	O
an	O
attitude	O
that	O
it	O
is	O
futile	O
to	O
resist	O
.	O

One	O
can	O
imagine	O
that	O
in	O
the	O
most	O
deprived	O
areas	O
of	O
Glasgow	O
,	O
people	B
may	O
have	O
become	O
resigned	O
to	O
the	O
nature	O
of	O
their	O
surroundings	O
,	O
seeing	O
them	O
as	O
inevitable	O
and	O
not	O
amenable	O
to	O
change	O
either	O
through	O
environmental	O
improvement	O
or	O
through	O
their	O
moving	O
to	O
another	O
area	O
.	O

Conclusion	O

After	O
demographic	O
and	O
socioeconomic	O
characteristics	O
were	O
taken	O
into	O
account	O
,	O
neither	O
perceptions	O
of	O
the	O
local	O
environment	O
nor	O
objective	O
proximity	O
to	O
major	O
road	O
infrastructure	O
appeared	O
to	O
explain	O
much	O
of	O
the	O
variance	O
in	O
active	O
travel	O
or	O
overall	O
physical	O
activity	O
in	O
this	O
study	O
.	O

Our	O
study	O
population	O
may	O
be	O
both	O
objectively	O
constrained	O
by	O
their	O
socioeconomic	O
circumstances	O
(	O
including	O
comparatively	O
limited	O
access	O
to	O
private	O
cars	O
)	O
and	O
adapted	O
to	O
living	O
in	O
conditions	O
which	O
others	O
would	O
consider	O
to	O
pose	O
a	O
barrier	O
to	O
active	O
travel	O
.	O

Under	O
these	O
circumstances	O
,	O
environmental	O
characteristics	O
which	O
have	O
been	O
found	O
to	O
influence	O
discretionary	O
active	O
travel	O
in	O
studies	O
in	O
other	O
,	O
more	O
affluent	O
populations	O
may	O
simply	O
be	O
irrelevant	O
in	O
a	O
population	O
which	O
is	O
more	O
captive	O
in	O
its	O
travel	O
choices	O
.	O

Environmental	O
correlates	O
of	O
active	O
travel	O
should	O
not	O
be	O
assumed	O
to	O
be	O
generalisable	O
between	O
populations	O
;	O
researchers	O
should	O
continue	O
to	O
test	O
hypotheses	O
about	O
putative	O
environmental	O
correlates	O
in	O
different	O
settings	O
,	O
and	O
policymakers	O
should	O
recognise	O
that	O
the	O
effects	O
of	O
interventions	O
to	O
change	O
the	O
environment	O
are	O
likely	O
to	O
vary	O
between	O
populations	O
and	O
between	O
socioeconomic	O
groups	O
within	O
populations	O
.	O

Competing	O
interests	O

This	O
paper	O
is	O
based	O
on	O
material	O
contained	O
in	O
the	O
first	O
author	O
'	O
s	O
PhD	O
thesis	O
.	O

Authors	O
'	O
contributions	O

DO	O
had	O
the	O
original	O
idea	O
for	O
the	O
study	O
,	O
designed	O
the	O
study	O
and	O
the	O
survey	O
materials	O
,	O
applied	O
for	O
ethical	O
approval	O
,	O
cleaned	O
and	O
coded	O
the	O
survey	O
data	O
,	O
carried	O
out	O
all	O
the	O
geographical	O
and	O
statistical	O
analyses	O
and	O
wrote	O
the	O
paper	O
.	O

MP	O
was	O
DO	O
'	O
s	O
PhD	O
supervisor	O
.	O

RM	O
,	O
NM	O
,	O
MP	O
and	O
SP	O
constituted	O
the	O
steering	O
group	O
for	O
the	O
study	O
,	O
contributed	O
to	O
and	O
advised	O
on	O
the	O
design	O
of	O
the	O
study	O
and	O
the	O
interpretation	O
of	O
the	O
emerging	O
findings	O
,	O
and	O
contributed	O
to	O
the	O
critical	O
revision	O
of	O
the	O
paper	O
.	O

All	O
authors	O
read	O
and	O
approved	O
the	O
final	O
manuscript	O
.	O

Supplementary	O
Material	O

Foamy	O
Macrophages	O
from	O
Tuberculous	O
Patients	B
'	O
Granulomas	O
Constitute	O
a	O
Nutrient	O
-	O
Rich	O
Reservoir	O
for	O
M	B
.	I
tuberculosis	I
Persistence	O

Abstract	O

Tuberculosis	O
(	O
TB	O
)	O
is	O
characterized	O
by	O
a	O
tight	O
interplay	O
between	O
Mycobacterium	B
tuberculosis	I
and	O
host	O
cells	O
within	O
granulomas	O
.	O

These	O
cellular	O
aggregates	O
restrict	O
bacterial	O
spreading	O
,	O
but	O
do	O
not	O
kill	O
all	O
the	O
bacilli	O
,	O
which	O
can	O
persist	O
for	O
years	O
.	O

In	O
-	O
depth	O
investigation	O
of	O
M	B
.	I
tuberculosis	I
interactions	O
with	O
granuloma	O
-	O
specific	O
cell	O
populations	O
are	O
needed	O
to	O
gain	O
insight	O
into	O
mycobacterial	O
persistence	O
,	O
and	O
to	O
better	O
understand	O
the	O
physiopathology	O
of	O
the	O
disease	O
.	O

We	O
have	O
analyzed	O
the	O
formation	O
of	O
foamy	O
macrophages	O
(	O
FMs	O
)	O
,	O
a	O
granuloma	O
-	O
specific	O
cell	O
population	O
characterized	O
by	O
its	O
high	O
lipid	O
content	O
,	O
and	O
studied	O
their	O
interaction	O
with	O
the	O
tubercle	O
bacillus	O
.	O

Within	O
our	O
in	O
vitro	O
human	B
granuloma	O
model	O
,	O
M	B
.	I
tuberculosis	I
long	O
chain	O
fatty	O
acids	O
,	O
namely	O
oxygenated	O
mycolic	O
acids	O
(	O
MA	O
)	O
,	O
triggered	O
the	O
differentiation	O
of	O
human	B
monocyte	O
-	O
derived	O
macrophages	O
into	O
FMs	O
.	O

In	O
these	O
cells	O
,	O
mycobacteria	O
no	O
longer	O
replicated	O
and	O
switched	O
to	O
a	O
dormant	O
non	O
-	O
replicative	O
state	O
.	O

Electron	O
microscopy	O
observation	O
of	O
M	B
.	I
tuberculosis	I
-	O
infected	O
FMs	O
showed	O
that	O
the	O
mycobacteria	O
-	O
containing	O
phagosomes	O
migrate	O
towards	O
host	O
cell	O
lipid	O
bodies	O
(	O
LB	O
)	O
,	O
a	O
process	O
which	O
culminates	O
with	O
the	O
engulfment	O
of	O
the	O
bacillus	O
into	O
the	O
lipid	O
droplets	O
and	O
with	O
the	O
accumulation	O
of	O
lipids	O
within	O
the	O
microbe	O
.	O

Altogether	O
,	O
our	O
results	O
suggest	O
that	O
oxygenated	O
mycolic	O
acids	O
from	O
M	B
.	I
tuberculosis	I
play	O
a	O
crucial	O
role	O
in	O
the	O
differentiation	O
of	O
macrophages	O
into	O
FMs	O
.	O

These	O
cells	O
might	O
constitute	O
a	O
reservoir	O
used	O
by	O
the	O
tubercle	O
bacillus	O
for	O
long	O
-	O
term	O
persistence	O
within	O
its	O
human	B
host	O
,	O
and	O
could	O
provide	O
a	O
relevant	O
model	O
for	O
the	O
screening	O
of	O
new	O
antimicrobials	O
against	O
non	O
-	O
replicating	O
persistent	O
mycobacteria	O
.	O

Introduction	O

Tuberculosis	O
caused	O
by	O
Mycobacterium	B
tuberculosis	I
(	O
M	B
.	I
tb	I
)	O
remains	O
one	O
of	O
the	O
leading	O
causes	O
of	O
mortality	O
in	O
the	O
world	O
,	O
with	O
around	O
2	O
million	O
deaths	O
each	O
year	O
[	O
1	O
]	O
.	O

Most	O
individuals	O
remain	O
asymptomatic	O
after	O
the	O
primary	O
infection	O
with	O
only	O
10	O
%	O
at	O
risk	O
of	O
developing	O
an	O
active	O
disease	O
during	O
their	O
life	O
[	O
2	O
]	O
.	O

In	O
asymptomatic	O
individuals	O
,	O
the	O
bacilli	O
are	O
not	O
cleared	O
but	O
rather	O
persist	O
in	O
a	O
dormant	O
state	O
,	O
from	O
which	O
they	O
may	O
reactivate	O
and	O
induce	O
clinical	O
disease	O
at	O
later	O
stages	O
[	O
3	O
]	O
.	O

The	O
prognosis	O
of	O
the	O
disease	O
depends	O
on	O
the	O
host	O
'	O
s	O
efficiency	O
to	O
constrain	O
the	O
bacilli	O
at	O
the	O
site	O
of	O
infection	O
.	O

When	O
inhaled	O
M	B
.	I
tb	I
reach	O
the	O
lungs	O
,	O
they	O
are	O
internalized	O
by	O
lung	O
macrophages	O
.	O

The	O
latter	O
trigger	O
the	O
accumulation	O
at	O
the	O
infectious	O
site	O
of	O
macrophages	O
,	O
lymphocytes	O
and	O
dendritic	O
cells	O
,	O
to	O
form	O
a	O
granuloma	O
,	O
which	O
is	O
a	O
major	O
histo	O
-	O
pathological	O
feature	O
of	O
TB	O
.	O

Within	O
granulomas	O
,	O
macrophages	O
differentiate	O
into	O
epithelio	O
i	O
d	O
cells	O
(	O
differentiated	O
macrophages	O
)	O
,	O
and	O
/	O
or	O
fuse	O
to	O
form	O
multinucleated	O
giant	O
cells	O
(	O
MGC	O
)	O
.	O

Macrophages	O
with	O
large	O
numbers	O
of	O
lipid	O
-	O
free	O
vacuoles	O
,	O
as	O
well	O
as	O
macrophages	O
filled	O
with	O
lipid	O
-	O
containing	O
bodies	O
,	O
also	O
called	O
foamy	O
macrophages	O
(	O
FM	O
)	O
are	O
also	O
found	O
within	O
granulomatous	O
structures	O
in	O
both	O
experimental	O
animal	O
models	O
and	O
human	B
disease	O
[	O
4	O
]	O
,	O
[	O
5	O
]	O
.	O

The	O
above	O
cells	O
are	O
surrounded	O
by	O
a	O
rim	O
of	O
lymphocytes	O
,	O
and	O
at	O
later	O
stages	O
,	O
a	O
tight	O
coat	O
of	O
fibroblasts	O
encloses	O
the	O
structure	O
[	O
6	O
]	O
.	O

Although	O
the	O
structure	O
and	O
cell	O
composition	O
of	O
granulomas	O
are	O
well	O
known	O
,	O
the	O
biology	O
of	O
these	O
inflammatory	O
structures	O
and	O
,	O
more	O
specifically	O
,	O
the	O
role	O
of	O
granuloma	O
-	O
specific	O
cell	O
types	O
,	O
remain	O
largely	O
unknown	O
.	O

We	O
have	O
previously	O
developed	O
an	O
in	O
vitro	O
model	O
of	O
human	B
tuberculous	O
granulomas	O
to	O
gain	O
insight	O
into	O
the	O
survival	O
strategies	O
of	O
the	O
tubercle	O
bacillus	O
within	O
its	O
human	B
host	O
.	O

This	O
model	O
now	O
enables	O
the	O
characterization	O
of	O
granuloma	O
-	O
specific	O
cell	O
types	O
,	O
and	O
their	O
modulation	O
by	O
M	B
.	I
tb	I
[	O
7	O
]	O
.	O

The	O
main	O
advantage	O
of	O
this	O
model	O
over	O
in	O
vivo	O
animal	O
models	O
or	O
ex	O
vivo	O
human	B
biopsy	O
samples	O
,	O
is	O
the	O
availability	O
of	O
live	O
granuloma	O
cells	O
which	O
facilitates	O
analysis	O
of	O
their	O
cell	O
biology	O
.	O

Using	O
this	O
model	O
we	O
have	O
recently	O
shown	O
that	O
,	O
within	O
granulomas	O
,	O
large	O
multinucleated	O
giant	O
cells	O
,	O
also	O
known	O
as	O
Langhans	O
giant	O
cells	O
,	O
result	O
from	O
the	O
induction	O
of	O
granuloma	O
macrophage	O
fusion	O
by	O
M	B
.	I
tb	I
glycolipids	O
[	O
8	O
]	O
.	O

We	O
have	O
shown	O
that	O
these	O
cells	O
have	O
lost	O
the	O
ability	O
to	O
mediate	O
bacterial	O
uptake	O
upon	O
maturation	O
,	O
but	O
have	O
conserved	O
their	O
ability	O
to	O
mediate	O
antigen	O
presentation	O
[	O
9	O
]	O
.	O

The	O
differentiation	O
of	O
macrophages	O
into	O
FMs	O
has	O
been	O
particularly	O
well	O
described	O
in	O
individuals	O
developing	O
a	O
postprimary	O
,	O
also	O
known	O
as	O
secondary	O
or	O
adult	O
,	O
TB	O
.	O

These	O
postprimary	O
infections	O
are	O
considered	O
to	O
be	O
the	O
result	O
of	O
re	O
-	O
infection	O
or	O
reactivation	O
of	O
a	O
primary	O
TB	O
[	O
10	O
]	O
.	O

FMs	O
have	O
been	O
described	O
in	O
leprosy	O
patients	B
or	O
M	B
.	I
avium	I
-	O
infected	O
AIDS	O
(	O
Acquired	O
ImmunoDeficiency	O
Syndrome	O
)	O
patients	B
,	O
and	O
in	O
chronic	O
stages	O
of	O
M	B
.	I
tb	I
infection	O
in	O
mice	B
[	O
4	O
]	O
,	O
[	O
11	O
]	O
,	O
[	O
12	O
]	O
.	O

The	O
foamy	O
aspect	O
of	O
these	O
macrophages	O
is	O
the	O
result	O
of	O
intracellular	O
lipid	O
accumulation	O
within	O
lipid	O
bodies	O
,	O
also	O
called	O
lipid	O
droplets	O
or	O
lipid	O
vacuoles	O
[	O
13	O
]	O
,	O
[	O
14	O
]	O
,	O
[	O
15	O
]	O
.	O

In	O
an	O
experimental	O
model	O
of	O
leukocyte	O
infection	O
,	O
it	O
was	O
recently	O
suggested	O
that	O
BCG	O
(	O
Bacille	O
Calmette	O
Guerin	O
)	O
infection	O
can	O
induce	O
,	O
in	O
a	O
TLR2	O
-	O
dependent	O
fashion	O
,	O
the	O
rapid	O
formation	O
of	O
lipid	O
bodies	O
carrying	O
out	O
part	O
of	O
the	O
eicosano	O
i	O
d	O
biosynthesis	O
that	O
usually	O
accompanies	O
the	O
infection	O
,	O
thus	O
pointing	O
to	O
an	O
active	O
role	O
for	O
lipid	O
bodies	O
during	O
the	O
course	O
of	O
infection	O
[	O
16	O
]	O
.	O

However	O
,	O
the	O
mechanisms	O
regulating	O
this	O
lipid	O
accumulation	O
during	O
mycobacterial	O
infection	O
and	O
their	O
significance	O
in	O
the	O
physiopathology	O
of	O
tuberculosis	O
are	O
not	O
understood	O
.	O

Most	O
of	O
the	O
studies	O
on	O
TB	O
granulomas	O
have	O
focused	O
on	O
the	O
contribution	O
of	O
host	O
components	O
,	O
but	O
very	O
little	O
is	O
known	O
about	O
the	O
role	O
played	O
by	O
bacterial	O
constituents	O
in	O
terms	O
of	O
granuloma	O
formation	O
and	O
progression	O
.	O

The	O
present	O
work	O
was	O
aimed	O
at	O
deciphering	O
the	O
role	O
of	O
FMs	O
in	O
M	B
.	I
tb	I
survival	O
within	O
human	B
granulomas	O
.	O

To	O
test	O
our	O
working	O
hypothesis	O
according	O
to	O
which	O
FMs	O
constitute	O
a	O
nutrient	O
-	O
rich	O
reservoir	O
for	O
M	B
.	I
tb	I
persistence	O
,	O
we	O
used	O
our	O
in	O
vitro	O
model	O
of	O
human	B
granulomas	O
to	O
analyze	O
the	O
formation	O
of	O
FMs	O
and	O
their	O
role	O
during	O
M	B
.	I
tb	I
infection	O
.	O

We	O
showed	O
that	O
only	O
highly	O
virulent	O
mycobacteria	O
(	O
M	B
.	I
tb	I
,	O
M	B
.	I
avium	I
)	O
and	O
not	O
saprophytic	O
ones	O
(	O
M	B
.	I
smegmatis	I
)	O
could	O
induce	O
the	O
formation	O
of	O
FMs	O
in	O
mature	O
granulomas	O
.	O

Moreover	O
,	O
we	O
demonstrated	O
that	O
oxygenated	O
mycolic	O
acids	O
specifically	O
produced	O
by	O
the	O
above	O
pathogenic	O
species	O
were	O
responsible	O
for	O
FMs	O
formation	O
.	O

Once	O
differentiated	O
,	O
FMs	O
were	O
unable	O
to	O
mediate	O
phagocytosis	O
of	O
new	O
bacilli	O
and	O
their	O
microbicidal	O
activity	O
was	O
reduced	O
.	O

M	B
.	I
tb	I
was	O
not	O
killed	O
in	O
FMs	O
but	O
instead	O
persisted	O
in	O
a	O
non	O
-	O
replicating	O
state	O
,	O
and	O
over	O
-	O
expressed	O
dormancy	O
genes	O
.	O

Noteworthy	O
,	O
in	O
foamy	O
macrophages	O
,	O
M	B
.	I
tb	I
-	O
containing	O
phagosomes	O
were	O
shown	O
to	O
migrate	O
towards	O
lipid	O
bodies	O
which	O
they	O
progressively	O
surrounded	O
and	O
engulfed	O
.	O

As	O
a	O
result	O
,	O
bacteria	O
were	O
freed	O
into	O
lipid	O
bodies	O
,	O
thus	O
favoring	O
the	O
bacilli	O
'	O
s	O
access	O
to	O
nutrients	O
.	O

From	O
these	O
data	O
,	O
we	O
propose	O
that	O
FMs	O
could	O
form	O
a	O
secure	O
reservoir	O
for	O
the	O
tubercle	O
bacilli	O
.	O

Methods	O

Human	B
samples	O

Human	B
blood	O
samples	O
,	O
purchased	O
from	O
the	O
French	O
National	O
Blood	O
provider	O
of	O
Toulouse	O
,	O
were	O
collected	O
from	O
fully	O
anonymized	O
non	O
-	O
tuberculous	O
control	O
donors	O
,	O
an	O
ethical	O
committee	O
approval	O
was	O
,	O
therefore	O
,	O
not	O
necessary	O
.	O

This	O
study	O
was	O
conducted	O
according	O
to	O
the	O
principles	O
expressed	O
in	O
the	O
Helsinki	O
Declaration	O
,	O
with	O
informed	O
consent	O
obtained	O
from	O
each	O
donor	O
.	O

We	O
chose	O
to	O
work	O
on	O
lymph	O
node	O
samples	O
rather	O
than	O
lung	O
biopsies	O
,	O
which	O
are	O
usually	O
only	O
paraffin	O
-	O
embedded	O
,	O
because	O
staining	O
for	O
lipids	O
can	O
only	O
be	O
performed	O
on	O
frozen	O
samples	O
.	O

Lymph	O
node	O
biopsies	O
were	O
taken	O
for	O
diagnosis	O
purposes	O
,	O
in	O
ten	O
non	O
-	O
HIV	B
patients	B
.	O

For	O
each	O
biopsy	O
,	O
a	O
fragment	O
was	O
sent	O
to	O
the	O
microbiology	O
laboratory	O
,	O
another	O
was	O
frozen	O
in	O
liquid	O
nitrogen	O
and	O
the	O
main	O
part	O
was	O
fixed	O
in	O
formalin	O
and	O
paraffin	O
-	O
embedded	O
for	O
histological	O
examination	O
.	O

M	B
.	I
tb	I
was	O
identified	O
in	O
9	O
lymph	O
node	O
biopsies	O
and	O
from	O
the	O
lung	O
aspiration	O
in	O
the	O
last	O
patient	B
.	O

This	O
latter	O
case	O
showed	O
no	O
signs	O
of	O
necrosis	O
,	O
and	O
no	O
FMs	O
were	O
found	O
in	O
the	O
lymph	O
node	O
biopsy	O
.	O

This	O
study	O
complies	O
with	O
the	O
guidelines	O
of	O
the	O
declaration	O
of	O
Helsinki	O
.	O

Bacterial	O
strains	O
and	O
culture	O
conditions	O

Wild	O
-	O
type	O
M	B
.	I
smegmatis	I
and	O
M	B
.	I
smegmatis	I
/	O
hma	O
strains	O
were	O
previously	O
described	O
[	O
17	O
]	O
,	O
M	B
.	I
tuberculosis	I
-	O
GFP	O
were	O
a	O
kind	O
gift	O
from	O
Dr	O
.	O
C	O
.	O

Guilhot	O
(	O
CNRS	O
-	O
IPBS	O
,	O
Toulouse	O
France	O
)	O
.	O

Bacilli	O
were	O
grown	O
in	O
Middlebrook	O
7H9	O
medium	O
(	O
Difco	O
)	O
supplemented	O
with	O
10	O
%	O
albumin	O
-	O
dextrose	O
-	O
catalase	O
(	O
Difco	O
)	O
.	O

Fluorescent	O
M	B
.	I
smegmatis	I
and	O
M	B
.	I
smegmatis	I
/	O
hma	O
were	O
obtained	O
by	O
FITC	O
labelling	O
as	O
described	O
in	O
[	O
18	O
]	O
.	O

Isolation	O
of	O
RNA	O
from	O
intraphagosomal	O
M	B
.	I
tb	I

Six	O
and	O
12	O
days	O
post	O
-	O
infection	O
(	O
MOI	O
10	O
)	O
,	O
macrophages	O
and	O
FMs	O
(	O
5	O
x	O
106	O
)	O
were	O
washed	O
twice	O
with	O
PBS	O
,	O
scraped	O
off	O
the	O
cell	O
dishes	O
and	O
recovered	O
by	O
centrifugation	O
.	O

The	O
cell	O
pellets	O
were	O
lysed	O
with	O
lysis	O
buffer	O
(	O
RNEasy	O
mini	O
kit	O
,	O
Quiagen	O
)	O
and	O
transferred	O
to	O
2	O
ml	O
Eppendorf	O
-	O
tubes	O
containing	O
a	O
0	O
.	O
5	O
ml	O
suspension	O
of	O
0	O
.	O
1	O
mm	O
-	O
diameter	O
glass	O
beads	O
(	O
Biospec	O
)	O
.	O

Mycobacteria	O
were	O
disrupted	O
using	O
a	O
bead	O
beater	O
(	O
Retsch	O
)	O
followed	O
by	O
a	O
5	O
min	O
centrifugation	O
at	O
14	O
000g	O
.	O

RNA	O
contained	O
in	O
the	O
supernatant	O
was	O
then	O
column	O
-	O
purified	O
according	O
to	O
the	O
manufacturer	O
'	O
s	O
conditions	O
using	O
the	O
RNEasy	O
mini	O
kit	O
(	O
Qiagen	O
)	O
and	O
quantified	O
.	O

Quantitative	O
Real	O
-	O
Time	O
RT	O
-	O
PCR	O

In	O
RNA	O
samples	O
DNA	O
contamination	O
was	O
excluded	O
by	O
DNAse	O
I	O
treatment	O
(	O
Ambion	O
)	O
.	O

1	O
micro	O
g	O
total	O
RNA	O
was	O
reverse	O
-	O
transcribed	O
using	O
random	O
hexamer	O
primers	O
(	O
Ambion	O
)	O
and	O
Superscript	O
III	O
reverse	O
transcriptase	O
(	O
Invitrogen	O
)	O
.	O

Real	O
-	O
time	O
PCR	O
was	O
performed	O
on	O
cDNA	O
using	O
the	O
SYBR	O
green	O
essay	O
(	O
Applied	O
Biosystems	O
)	O
.	O

Reverse	O
and	O
forward	O
primers	O
used	O
are	O
listed	O
below	O
in	O
Table	O
1	O
.	O

Fluorescence	O
was	O
measured	O
by	O
ABIPrism	O
7300	O
(	O
Applied	O
Biosystems	O
)	O
.	O

The	O
calculated	O
threshold	O
cycle	O
(	O
Ct	O
)	O
value	O
for	O
each	O
gene	O
of	O
interest	O
was	O
normalized	O
to	O
the	O
Ct	O
value	O
for	O
16S	O
and	O
the	O
fold	O
expression	O
was	O
calculated	O
using	O
the	O
formula	O
:	O
fold	O
change	O
=	O
2	O
-	O
Delta	O
.	O
(	O
Delta	O
Ct	O
)	O
[	O
19	O
]	O
.	O

Real	O
-	O
time	O
PCR	O
conditions	O
include	O
initial	O
activation	O
at	O
94	O
degrees	O
C	O
for	O
5	O
min	O
,	O
followed	O
by	O
40	O
cycles	O
of	O
denaturation	O
at	O
94	O
degrees	O
C	O
for	O
30	O
sec	O
,	O
annealing	O
and	O
extension	O
at	O
65	O
degrees	O
C	O
for	O
1	O
min	O
.	O

The	O
gene	O
induction	O
ratios	O
were	O
obtained	O
by	O
comparing	O
gene	O
expression	O
levels	O
in	O
intracellular	O
bacilli	O
with	O
those	O
of	O
log	O
-	O
phase	O
in	O
vitro	O
-	O
grown	O
bacilli	O
.	O

RNAs	O
were	O
isolated	O
from	O
two	O
independent	O
macrophage	O
infections	O
.	O

In	O
vitro	O
human	B
granuloma	O
formation	O

In	O
vitro	O
granulomas	O
were	O
obtained	O
as	O
previously	O
described	O
[	O
7	O
]	O
.	O

Briefly	O
,	O
1	O
x	O
106	O
freshly	O
isolated	O
Peripheral	O
Blood	O
Mononuclear	O
Cells	O
(	O
PBMCs	O
)	O
were	O
incubated	O
with	O
1	O
x	O
104	O
viable	O
M	B
.	I
tb	I
,	O
or	O
1	O
x	O
103	O
viable	O
M	B
.	I
smegmatis	I
or	O
M	B
.	I
smegmatis	I
/	O
hma	O
.	O

The	O
culture	O
medium	O
was	O
RPMI	O
-	O
1640	O
+	O
Glutamax	O
(	O
Difco	O
)	O
,	O
containing	O
7	O
.	O
5	O
%	O
human	B
AB	O
serum	O
(	O
Sigma	O
-	O
Aldrich	O
)	O
.	O

Macrophage	O
differentiation	O

2	O
.	O
5	O
x	O
106	O
PBMCs	O
prepared	O
in	O
RPMI	O
-	O
1640	O
+	O
Glutamax	O
(	O
Difco	O
)	O
were	O
plated	O
over	O
coverslips	O
in	O
24	O
-	O
well	O
plates	O
.	O

After	O
2	O
h	O
culture	O
at	O
37	O
degrees	O
C	O
,	O
cells	O
were	O
washed	O
3	O
times	O
with	O
PBS	O
and	O
then	O
refed	O
with	O
RPMI	O
-	O
1640	O
+	O
Glutamax	O
(	O
Difco	O
)	O
,	O
containing	O
7	O
.	O
5	O
%	O
human	B
AB	O
serum	O
.	O

After	O
6	O
days	O
of	O
culturing	O
,	O
macrophages	O
were	O
differentiated	O
.	O

Respiratory	O
burst	O
assay	O
with	O
Nitroblue	O
tetrazolium	O
(	O
NBT	O
)	O

Human	B
monocyte	O
derived	O
macrophages	O
were	O
stimulated	O
with	O
M	B
.	I
smegmatis	I
/	O
hma	O
for	O
2	O
h	O
at	O
37	O
degrees	O
C	O
,	O
washed	O
and	O
reincubated	O
in	O
mycobacterium	O
-	O
free	O
medium	O
.	O

After	O
2	O
days	O
of	O
differentiation	O
into	O
FMs	O
,	O
macrophages	O
were	O
co	O
-	O
stained	O
with	O
NBT	O
(	O
2	O
mg	O
/	O
ml	O
Sigma	O
-	O
Aldrich	O
)	O
and	O
Nile	O
red	O
(	O
Sigma	O
-	O
Aldrich	O
)	O
for	O
30	O
min	O
at	O
37	O
degrees	O
C	O
.	O

Stained	O
cells	O
were	O
fixed	O
and	O
then	O
analysed	O
with	O
an	O
inverted	O
microscope	O
(	O
Nikon	O
TE	O
300	O
)	O
.	O

Phagocytosis	O
and	O
Survival	O
test	O

For	O
phagocytosis	O
assays	O
,	O
differentiated	O
macrophages	O
were	O
incubated	O
with	O
M	B
.	I
smegmatis	I
/	O
hma	O
mycolic	O
acids	O
for	O
2	O
days	O
and	O
then	O
infected	O
with	O
1	O
x	O
108	O
labeled	O
mycobacteria	O
per	O
well	O
for	O
90	O
min	O
,	O
washed	O
3	O
times	O
with	O
PBS	O
and	O
chased	O
for	O
3	O
h	O
in	O
fresh	O
culture	O
medium	O
.	O

For	O
survival	O
experiments	O
,	O
macrophages	O
were	O
infected	O
with	O
M	B
.	I
tuberculosis	I
-	O
GFP	O
(	O
10	O
bacteria	O
/	O
cell	O
)	O
,	O
washed	O
3	O
times	O
with	O
PBS	O
(	O
Gibco	O
)	O
and	O
re	O
-	O
incubated	O
in	O
fresh	O
culture	O
medium	O
.	O

At	O
selected	O
time	O
points	O
thereafter	O
(	O
1	O
,	O
3	O
,	O
6	O
,	O
10	O
and	O
14	O
days	O
)	O
cells	O
were	O
labeled	O
with	O
Nile	O
red	O
(	O
Sigma	O
-	O
Aldrich	O
)	O
,	O
fixed	O
and	O
observed	O
under	O
a	O
confocal	O
microscope	O
.	O

The	O
amount	O
of	O
mycobacteria	O
per	O
cells	O
was	O
evaluated	O
.	O

(	O
100	O
cells	O
were	O
analyzed	O
for	O
each	O
time	O
point	O
)	O
.	O

Lipid	O
body	O
staining	O
and	O
immunostaining	O

Granuloma	O
cells	O
were	O
collected	O
and	O
plated	O
onto	O
glass	O
coverslips	O
with	O
a	O
cytospin	O
(	O
Thermo	O
Shandon	O
)	O
fixed	O
for	O
30	O
min	O
in	O
PBS	O
-	O
PFA	O
4	O
%	O
and	O
stained	O
with	O
Oil	O
red	O
-	O
O	O
(	O
Sigma	O
-	O
Aldrich	O
)	O
as	O
described	O
[	O
20	O
]	O
.	O

The	O
slides	O
were	O
then	O
counterstained	O
with	O
haematoxylin	O
(	O
Dako	O
Cytomation	O
)	O
and	O
observed	O
under	O
an	O
inverted	O
microscope	O
(	O
Nikon	O
TE	O
300	O
)	O
.	O

For	O
fluorescence	O
analysis	O
,	O
granuloma	O
cells	O
or	O
macrophages	O
were	O
collected	O
in	O
PBS	O
,	O
lipid	O
bodies	O
were	O
stained	O
with	O
Nile	O
red	O
(	O
Sigma	O
-	O
Aldrich	O
,	O
0	O
.	O
1	O
micro	O
g	O
/	O
ml	O
,	O
from	O
a	O
stock	O
solution	O
in	O
methanol	O
)	O
for	O
15	O
min	O
washed	O
with	O
PBS	O
,	O
fixed	O
for	O
30	O
min	O
in	O
PBS	O
-	O
PFA	O
4	O
%	O
,	O
mounted	O
with	O
the	O
fluorescent	O
mounting	O
medium	O
(	O
Dako	O
Cytomation	O
)	O
and	O
observed	O
under	O
a	O
confocal	O
microscope	O
.	O

In	O
order	O
to	O
distinguish	O
the	O
lipids	O
contained	O
within	O
lipid	O
bodies	O
,	O
from	O
those	O
of	O
the	O
cell	O
membrane	O
,	O
we	O
used	O
the	O
fluorescent	O
emission	O
spectrum	O
properties	O
of	O
Nile	O
red	O
which	O
depend	O
upon	O
the	O
kind	O
of	O
lipid	O
associated	O
with	O
Nile	O
red	O
,	O
i	O
.	O
e	O
.	O
for	O
triacylglycerol	O
:	O
lambda	O
max	O
em	O
=	O
590	O
nm	O
,	O
for	O
phospholipids	O
:	O
lambda	O
max	O
em	O
=	O
640	O
nm	O
(	O
Molecular	O
Probes	O
handbook	O
)	O
.	O

On	O
confocal	O
microscopy	O
pictures	O
,	O
the	O
phospholipid	O
background	O
of	O
both	O
macrophages	O
and	O
FM	O
appears	O
in	O
red	O
and	O
the	O
triacylglycerol	O
-	O
rich	O
lipid	O
bodies	O
appear	O
in	O
white	O
.	O

Cells	O
were	O
considered	O
to	O
be	O
positive	O
for	O
Nile	O
red	O
staining	O
when	O
more	O
than	O
50	O
%	O
of	O
the	O
cell	O
surface	O
was	O
stained	O
(	O
see	O
Figure	O
S2	O
)	O
.	O

Mycolic	O
acid	O
isolation	O

Bacterial	O
residues	O
obtained	O
after	O
lipid	O
extraction	O
with	O
organic	O
solvents	O
[	O
17	O
]	O
were	O
saponified	O
with	O
a	O
mixture	O
of	O
40	O
%	O
KOH	O
aqueous	O
solution	O
and	O
methoxyethanol	O
(	O
1	O
:	O
7	O
,	O
v	O
/	O
v	O
)	O
at	O
110	O
degrees	O
C	O
for	O
3	O
hours	O
in	O
a	O
screw	O
-	O
capped	O
tube	O
.	O

After	O
acidification	O
,	O
fatty	O
acids	O
were	O
extracted	O
with	O
diethylether	O
,	O
derivatised	O
into	O
methyl	O
esters	O
with	O
diazomethane	O
and	O
analyzed	O
by	O
analytical	O
thin	O
-	O
layer	O
chromatography	O
on	O
silica	O
Gel	O
60	O
(	O
Silica	O
Gel	O
60	O
Macherey	O
-	O
Nagel	O
)	O
using	O
either	O
dicholoromethane	O
or	O
petroleum	O
ether	O
/	O
diethylether	O
(	O
9	O
:	O
1	O
,	O
v	O
/	O
v	O
,	O
five	O
runs	O
)	O
.	O

Visualization	O
of	O
lipid	O
spots	O
was	O
performed	O
by	O
spraying	O
the	O
plates	O
with	O
molybdophosphoric	O
acid	O
(	O
10	O
%	O
in	O
ethanol	O
)	O
,	O
followed	O
by	O
charring	O
.	O

Processing	O
for	O
electron	O
microscopy	O

Granulomas	O
were	O
fixed	O
for	O
1	O
hour	O
at	O
room	O
temperature	O
with	O
2	O
.	O
5	O
%	O
glutaraldehyde	O
in	O
0	O
.	O
1	O
M	O
cacodylate	O
buffer	O
,	O
pH	O
7	O
.	O
2	O
,	O
containing	O
0	O
.	O
1	O
M	O
sucrose	O
,	O
5	O
mM	O
CaCl2	O
and	O
5	O
mM	O
MgCl2	O
.	O

After	O
two	O
successive	O
15	O
-	O
min	O
washes	O
with	O
the	O
same	O
buffer	O
,	O
the	O
granulomas	O
were	O
postfixed	O
for	O
1	O
hour	O
at	O
RT	O
with	O
1	O
%	O
osmium	O
tetroxide	O
(	O
Electron	O
Microscopy	O
Science	O
)	O
in	O
the	O
same	O
buffer	O
devoid	O
of	O
sucrose	O
.	O

The	O
granulomas	O
were	O
scraped	O
off	O
the	O
culture	O
dishes	O
with	O
a	O
rubber	O
policeman	O
and	O
concentrated	O
in	O
1	O
%	O
agarose	O
in	O
the	O
same	O
buffer	O
.	O

After	O
a	O
one	O
hour	O
treatment	O
at	O
room	O
temperature	O
with	O
1	O
%	O
uranyl	O
acetate	O
in	O
Veronal	O
buffer	O
,	O
the	O
samples	O
were	O
dehydrated	O
in	O
a	O
graded	O
series	O
of	O
ethanol	O
and	O
embedded	O
in	O
Spurr	O
resin	O
.	O

Thin	O
sections	O
were	O
stained	O
with	O
uranyl	O
acetate	O
and	O
lead	O
citrate	O
.	O

Image	O
acquisition	O
in	O
confocal	O
microscopy	O

The	O
images	O
were	O
obtained	O
using	O
a	O
Leica	O
confocal	O
fluorescence	O
microscope	O
(	O
SP2	O
)	O
equipped	O
with	O
a	O
Plan	O
Apo	O
40	O
x	O
1	O
.	O
4	O
Ph	O
6	O
objective	O
(	O
Olympus	O
Optical	O
)	O
and	O
CoolSNAP	O
-	O
Pro	O
CF	O
digital	O
camera	O
in	O
conjunction	O
with	O
Image	O
-	O
Pro	O
Plus	O
version	O
4	O
.	O
5	O
.	O
1	O
.	O
3	O
software	O
(	O
Media	O
Cybernetics	O
)	O
.	O

The	O
images	O
were	O
edited	O
using	O
Adobe	O
Photoshop	O
CS2	O
9	O
software	O
(	O
Adobe	O
Systems	O
)	O
.	O

Results	O

Foamy	O
macrophages	O
are	O
strongly	O
associated	O
with	O
necrotic	O
lesions	O
and	O
often	O
contain	O
M	B
.	I
tuberculosis	I

We	O
analyzed	O
lymph	O
node	O
biopsies	O
from	O
10	O
tuberculous	O
patients	B
as	O
a	O
first	O
step	O
for	O
evaluating	O
the	O
role	O
of	O
FMs	O
within	O
tuberculous	O
granulomas	O
.	O

A	O
section	O
through	O
a	O
representative	O
biopsy	O
is	O
shown	O
in	O
Figure	O
1	O
.	O

Well	O
-	O
circumscribed	O
and	O
-	O
differentiated	O
granulomatous	O
structures	O
were	O
observed	O
in	O
all	O
the	O
samples	O
(	O
Figure	O
1A	O
)	O
.	O

Classically	O
,	O
lesions	O
display	O
a	O
necrotic	O
center	O
(	O
N	O
)	O
,	O
an	O
interface	O
area	O
between	O
the	O
necrotic	O
center	O
and	O
the	O
histiocytes	O
(	O
I	O
)	O
,	O
and	O
some	O
peripheral	O
granulomas	O
(	O
G	O
)	O
.	O

Only	O
seven	O
out	O
of	O
ten	O
patients	B
presented	O
lesions	O
displaying	O
central	O
necrosis	O
(	O
Table	O
2	O
)	O
.	O

Staining	O
of	O
the	O
histology	O
samples	O
with	O
Oil	O
red	O
-	O
O	O
,	O
a	O
classic	O
lipid	O
stain	O
,	O
confirmed	O
the	O
presence	O
of	O
FMs	O
within	O
the	O
granulomatous	O
structures	O
in	O
six	O
out	O
of	O
seven	O
samples	O
presenting	O
necrosis	O
(	O
Figure	O
1B	O
)	O
,	O
whereas	O
no	O
FMs	O
were	O
found	O
in	O
the	O
three	O
non	O
-	O
necrotic	O
lesions	O
(	O
Table	O
2	O
)	O
.	O

Noteworthy	O
,	O
in	O
samples	O
with	O
necrotic	O
areas	O
,	O
FMs	O
were	O
always	O
found	O
in	O
the	O
interface	O
region	O
flanking	O
the	O
central	O
necrosis	O
(	O
Figure	O
1B	O
)	O
.	O

These	O
observations	O
firstly	O
confirmed	O
the	O
presence	O
of	O
FMs	O
in	O
most	O
TB	O
patients	B
'	O
lesions	O
thereby	O
suggesting	O
that	O
these	O
cells	O
play	O
an	O
important	O
role	O
in	O
the	O
formation	O
/	O
maintenance	O
of	O
such	O
lesions	O
.	O

Second	O
,	O
FMs	O
seem	O
to	O
be	O
associated	O
with	O
necrosis	O
,	O
which	O
is	O
a	O
hallmark	O
of	O
TB	O
lesions	O
,	O
since	O
they	O
were	O
observed	O
only	O
in	O
lesions	O
with	O
a	O
necrotic	O
center	O
and	O
preferentially	O
located	O
around	O
the	O
necrotic	O
area	O
.	O

Interestingly	O
,	O
staining	O
,	O
in	O
parallel	O
,	O
of	O
serial	O
thin	O
sections	O
from	O
a	O
patient	B
'	O
s	O
lesion	O
biopsy	O
with	O
Oil	O
red	O
-	O
O	O
(	O
Figure	O
1C	O
)	O
and	O
Ziehl	O
Nielsen	O
(	O
Figure	O
1D	O
)	O
,	O
showed	O
that	O
most	O
of	O
the	O
bacilli	O
(	O
arrow	O
)	O
were	O
located	O
in	O
the	O
same	O
area	O
as	O
FMs	O
,	O
thus	O
suggesting	O
a	O
strong	O
association	O
between	O
the	O
persisting	O
tubercle	O
bacilli	O
and	O
FMs	O
within	O
granulomas	O
.	O

M	B
.	I
tuberculosis	I
induces	O
the	O
formation	O
of	O
FMs	O
within	O
in	O
vitro	O
human	B
tuberculous	O
granulomas	O

To	O
further	O
characterize	O
the	O
role	O
of	O
FMs	O
in	O
the	O
granulomatous	O
response	O
,	O
we	O
assessed	O
whether	O
FM	O
formation	O
in	O
granulomatous	O
structures	O
was	O
triggered	O
only	O
by	O
pathogenic	O
mycobacterial	O
species	O
(	O
M	B
.	I
tb	I
)	O
,	O
or	O
by	O
low	O
virulent	O
ones	O
(	O
M	B
.	I
smegmatis	I
)	O
as	O
well	O
.	O

PBMCs	O
from	O
non	O
-	O
tuberculous	O
control	O
individuals	O
were	O
infected	O
with	O
M	B
.	I
tb	I
or	O
M	B
.	I
smegmatis	I
,	O
following	O
the	O
procedure	O
previously	O
described	O
for	O
the	O
induction	O
of	O
granulomatous	O
structures	O
(	O
[	O
7	O
]	O
,	O
[	O
9	O
]	O
and	O
Figure	O
S1	O
)	O
.	O

Granuloma	O
cells	O
collected	O
at	O
days	O
3	O
and	O
11	O
were	O
stained	O
with	O
Oil	O
red	O
-	O
O	O
to	O
visualize	O
the	O
lipid	O
droplets	O
within	O
FMs	O
under	O
the	O
light	O
microscope	O
(	O
Figure	O
2	O
)	O
.	O

At	O
day	O
3	O
,	O
several	O
M	B
.	I
tb	I
-	O
induced	O
granuloma	O
cells	O
already	O
showed	O
lipid	O
bodies	O
(	O
Figure	O
2A	O
)	O
.	O

In	O
contrast	O
,	O
the	O
cells	O
collected	O
from	O
M	B
.	I
smegmatis	I
-	O
induced	O
granulomas	O
were	O
seldom	O
(	O
5	O
%	O
)	O
positively	O
stained	O
(	O
Figure	O
2B	O
)	O
.	O

Interestingly	O
,	O
M	B
.	I
avium	I
induced	O
FM	O
formation	O
in	O
a	O
similar	O
way	O
to	O
M	B
.	I
tb	I
(	O
not	O
shown	O
)	O
.	O

By	O
day	O
11	O
,	O
the	O
amount	O
of	O
positively	O
stained	O
cells	O
had	O
increased	O
in	O
M	B
.	I
tb	I
-	O
induced	O
granulomas	O
,	O
but	O
not	O
in	O
M	B
.	I
smegmatis	I
-	O
induced	O
ones	O
.	O

In	O
addition	O
,	O
the	O
number	O
of	O
lipid	O
bodies	O
per	O
cell	O
increased	O
dramatically	O
with	O
time	O
,	O
as	O
depited	O
in	O
the	O
enlarged	O
views	O
(	O
Figures	O
2A	O
,	O
C	O
)	O
.	O

The	O
quantitative	O
evaluation	O
of	O
the	O
percentage	O
of	O
FMs	O
within	O
granulomas	O
induced	O
by	O
both	O
strains	O
confirmed	O
the	O
differences	O
observed	O
under	O
the	O
light	O
microscope	O
,	O
and	O
showed	O
a	O
seven	O
-	O
fold	O
difference	O
(	O
44	O
%	O
vs	O
6	O
%	O
respectively	O
)	O
between	O
M	B
.	I
tb	I
and	O
M	B
.	I
smegmatis	I
in	O
terms	O
of	O
their	O
ability	O
to	O
induce	O
FM	O
formation	O
(	O
Figure	O
2D	O
)	O
.	O

Our	O
results	O
therefore	O
show	O
that	O
virulent	O
species	O
such	O
as	O
M	B
.	I
tb	I
and	O
M	B
.	I
avium	I
,	O
contrary	O
to	O
poorly	O
or	O
avirulent	O
ones	O
such	O
as	O
M	B
.	I
smegmatis	I
,	O
are	O
able	O
to	O
induce	O
the	O
formation	O
of	O
FMs	O
within	O
our	O
experimental	O
model	O
.	O

Oxygenated	O
mycolic	O
acids	O
induce	O
the	O
maturation	O
of	O
macrophages	O
into	O
FMs	O

Mycolic	O
acids	O
from	O
M	B
.	I
tb	I
incorporated	O
into	O
liposomes	O
were	O
recently	O
shown	O
to	O
trigger	O
the	O
differentiation	O
of	O
mice	B
peritoneal	O
macrophages	O
into	O
foamy	O
-	O
like	O
cells	O
[	O
21	O
]	O
.	O

Interestingly	O
,	O
both	O
M	B
.	I
tb	I
and	O
M	B
.	I
avium	I
,	O
which	O
induce	O
FM	O
formation	O
,	O
express	O
a	O
family	O
of	O
oxygenated	O
mycolic	O
acids	O
,	O
especially	O
ketomycolic	O
acids	O
,	O
which	O
are	O
not	O
produced	O
by	O
M	B
.	I
smegmatis	I
(	O
Figure	O
3A	O
)	O
.	O

In	O
this	O
context	O
,	O
inactivation	O
of	O
the	O
M	B
.	I
tb	I
hma	O
gene	O
(	O
mmaA4	O
-	O
Rv0642c	O
)	O
was	O
shown	O
to	O
abolish	O
the	O
synthesis	O
of	O
oxygenated	O
keto	O
-	O
and	O
hydroxyl	O
-	O
mycolic	O
acid	O
in	O
the	O
mutant	O
strain	O
[	O
17	O
]	O
.	O

Conversely	O
,	O
transforming	O
M	B
.	I
smegmatis	I
with	O
the	O
hma	O
gene	O
induced	O
the	O
production	O
of	O
both	O
keto	O
-	O
and	O
hydroxyl	O
-	O
mycolic	O
acids	O
[	O
22	O
]	O
,	O
(	O
Figures	O
3B	O
,	O
C	O
)	O
.	O

In	O
the	O
light	O
of	O
both	O
data	O
,	O
we	O
anticipated	O
that	O
oxygenated	O
mycolic	O
acids	O
specifically	O
produced	O
by	O
M	B
.	I
tb	I
and	O
M	B
.	I
avium	I
,	O
under	O
the	O
control	O
of	O
hma	O
,	O
are	O
responsible	O
for	O
FM	O
formation	O
within	O
human	B
granulomas	O
.	O

To	O
test	O
this	O
hypothesis	O
,	O
we	O
compared	O
FM	O
formation	O
after	O
infection	O
of	O
PBMCs	O
with	O
either	O
the	O
wild	O
-	O
type	O
,	O
or	O
the	O
hma	O
-	O
expressing	O
M	B
.	I
smegmatis	I
strain	O
(	O
M	B
.	I
smegmatis	I
/	O
hma	O
)	O
.	O

Granulomas	O
cells	O
were	O
collected	O
3	O
days	O
later	O
and	O
stained	O
with	O
Oil	O
red	O
-	O
O	O
to	O
visualize	O
lipid	O
bodies	O
.	O

Wild	O
-	O
type	O
M	B
.	I
smegmatis	I
-	O
induced	O
granulomas	O
displayed	O
only	O
5	O
.	O
5	O
%	O
of	O
FM	O
,	O
whereas	O
the	O
hma	O
gene	O
-	O
expressing	O
strain	O
induced	O
granulomas	O
bearing	O
a	O
majority	O
(	O
67	O
%	O
)	O
of	O
brightly	O
stained	O
Oil	O
red	O
-	O
O	O
positive	O
cells	O
(	O
Figures	O
4A	O
,	O
B	O
,	O
C	O
)	O
.	O

Induction	O
of	O
FM	O
formation	O
was	O
even	O
greater	O
if	O
isolated	O
macrophages	O
were	O
directly	O
infected	O
with	O
either	O
strain	O
.	O

After	O
only	O
4	O
hours	O
of	O
infection	O
,	O
M	B
.	I
smegmatis	I
/	O
hma	O
had	O
already	O
transformed	O
64	O
%	O
of	O
the	O
infected	O
macrophages	O
into	O
lipid	O
body	O
-	O
positive	O
cells	O
(	O
see	O
Figure	O
S2	O
for	O
Nile	O
red	O
positive	O
cells	O
)	O
,	O
whereas	O
only	O
9	O
%	O
of	O
the	O
cells	O
contained	O
lipid	O
bodies	O
after	O
infection	O
with	O
the	O
wild	O
-	O
type	O
strain	O
(	O
Figures	O
4D	O
,	O
E	O
,	O
F	O
)	O
.	O

To	O
confirm	O
the	O
specific	O
role	O
of	O
hma	O
-	O
dependent	O
oxygenated	O
mycolic	O
acids	O
in	O
FM	O
formation	O
,	O
and	O
to	O
rule	O
out	O
a	O
possible	O
combined	O
effect	O
of	O
oxygenated	O
mycolic	O
-	O
acids	O
with	O
other	O
mycobacterial	O
components	O
,	O
mycolic	O
acids	O
isolated	O
from	O
wild	O
-	O
type	O
M	B
.	I
smegmatis	I
or	O
M	B
.	I
smegmatis	I
/	O
hma	O
were	O
incubated	O
with	O
isolated	O
macrophages	O
.	O

With	O
mycolic	O
acids	O
isolated	O
from	O
the	O
wild	O
-	O
type	O
strain	O
,	O
only	O
13	O
%	O
of	O
the	O
macrophages	O
were	O
transformed	O
into	O
FM	O
whereas	O
66	O
%	O
of	O
the	O
macrophages	O
incubated	O
with	O
mycolic	O
acids	O
isolated	O
from	O
M	B
.	I
smegmatis	I
/	O
hma	O
were	O
strongly	O
stained	O
for	O
lipid	O
bodies	O
(	O
Figures	O
4G	O
,	O
H	O
,	O
I	O
)	O
.	O

These	O
results	O
therefore	O
indicate	O
that	O
oxygenated	O
mycolic	O
acids	O
play	O
a	O
leading	O
role	O
in	O
M	B
.	I
tb	I
-	O
induced	O
FM	O
formation	O
.	O

The	O
phagocytic	O
and	O
bactericidal	O
activities	O
are	O
arrested	O
in	O
FMs	O

To	O
assess	O
the	O
function	O
of	O
granuloma	O
FM	O
,	O
we	O
first	O
evaluated	O
the	O
ability	O
of	O
such	O
cells	O
to	O
mediate	O
phagocytosis	O
.	O

For	O
this	O
purpose	O
,	O
macrophages	O
isolated	O
from	O
PBMCs	O
were	O
exposed	O
to	O
M	B
.	I
smegmatis	I
/	O
hma	O
-	O
derived	O
mycolic	O
acids	O
to	O
induce	O
FM	O
formation	O
.	O

Two	O
days	O
later	O
,	O
the	O
cell	O
population	O
contained	O
a	O
mixture	O
of	O
FM	O
(	O
50	O
-	O
70	O
%	O
)	O
and	O
macrophages	O
(	O
30	O
-	O
50	O
%	O
)	O
,	O
as	O
assessed	O
by	O
Nile	O
red	O
staining	O
(	O
not	O
shown	O
)	O
.	O

The	O
mixed	O
cell	O
population	O
was	O
infected	O
with	O
FITC	O
-	O
labelled	O
M	B
.	I
smegmatis	I
.	O

Intracellular	O
bacilli	O
were	O
found	O
only	O
within	O
Nile	O
red	O
-	O
negative	O
macrophages	O
thereby	O
indicating	O
that	O
FMs	O
are	O
unable	O
to	O
ingest	O
bacteria	O
(	O
Figure	O
5A	O
)	O
.	O

This	O
result	O
was	O
reproduced	O
using	O
other	O
mycobacterial	O
strains	O
,	O
such	O
as	O
M	B
.	I
tb	I
and	O
M	B
.	I
bovis	I
BCG	I
,	O
for	O
infection	O
(	O
not	O
shown	O
)	O
.	O

These	O
results	O
further	O
suggest	O
that	O
the	O
bacilli	O
found	O
in	O
granuloma	O
FMs	O
were	O
internalized	O
by	O
macrophages	O
prior	O
to	O
their	O
transformation	O
into	O
FMs	O
.	O

To	O
assess	O
whether	O
FMs	O
are	O
able	O
to	O
develop	O
a	O
respiratory	O
burst	O
,	O
which	O
is	O
a	O
major	O
intracellular	O
bactericidal	O
activity	O
,	O
the	O
ability	O
of	O
Nile	O
red	O
positive	O
cells	O
(	O
i	O
.	O
e	O
.	O
FMs	O
)	O
to	O
mediate	O
NBT	O
reduction	O
was	O
determined	O
.	O

As	O
shown	O
in	O
Figure	O
5D	O
,	O
only	O
8	O
%	O
of	O
the	O
NBT	O
-	O
positive	O
cells	O
(	O
Figure	O
5B	O
)	O
were	O
Nile	O
red	O
positive	O
FMs	O
(	O
Figure	O
5C	O
)	O
.	O

This	O
strongly	O
suggests	O
that	O
once	O
macrophages	O
have	O
differentiated	O
into	O
FMs	O
,	O
they	O
lose	O
the	O
ability	O
to	O
mediate	O
intracellular	O
bactericidal	O
activity	O
.	O

We	O
postulate	O
that	O
FMs	O
could	O
,	O
therefore	O
,	O
form	O
a	O
secure	O
reservoir	O
for	O
the	O
tubercle	O
bacilli	O
.	O

M	B
.	I
tuberculosis	I
persists	O
in	O
a	O
dormant	O
non	O
-	O
replicative	O
state	O
in	O
FMs	O

To	O
evaluate	O
the	O
validity	O
of	O
the	O
above	O
hypothesis	O
,	O
we	O
analyzed	O
the	O
ability	O
of	O
M	B
.	I
tb	I
to	O
replicate	O
within	O
FMs	O
.	O

For	O
this	O
purpose	O
,	O
isolated	O
macrophages	O
were	O
infected	O
with	O
M	B
.	I
tb	I
.	O

At	O
selected	O
intervals	O
post	O
-	O
infection	O
,	O
the	O
amount	O
of	O
bacilli	O
per	O
cell	O
was	O
compared	O
in	O
both	O
non	O
-	O
differentiated	O
macrophages	O
and	O
FMs	O
(	O
Figure	O
5E	O
)	O
.	O

Until	O
day	O
6	O
,	O
M	B
.	I
tb	I
replicated	O
in	O
a	O
similar	O
fashion	O
in	O
both	O
cell	O
types	O
.	O

In	O
contrast	O
,	O
after	O
day	O
6	O
post	O
-	O
infection	O
,	O
the	O
amount	O
of	O
bacilli	O
remained	O
stationary	O
in	O
FMs	O
,	O
whereas	O
it	O
continued	O
to	O
increase	O
in	O
macrophages	O
.	O

It	O
is	O
interesting	O
to	O
note	O
that	O
arrest	O
of	O
bacterial	O
replication	O
coincided	O
with	O
completion	O
of	O
macrophage	O
differentiation	O
into	O
FM	O
,	O
i	O
.	O
e	O
.	O
starting	O
from	O
day	O
3	O
post	O
-	O
infection	O
.	O

Our	O
data	O
suggest	O
,	O
that	O
the	O
bacilli	O
found	O
in	O
granuloma	O
FMs	O
were	O
internalized	O
by	O
macrophages	O
prior	O
to	O
their	O
differentiation	O
into	O
FMs	O
and	O
also	O
that	O
bacilli	O
can	O
terminate	O
their	O
replication	O
cycle	O
while	O
macrophages	O
are	O
being	O
transformed	O
into	O
FM	O
,	O
but	O
that	O
replication	O
comes	O
to	O
a	O
halt	O
as	O
soon	O
as	O
the	O
maturation	O
process	O
is	O
complete	O
.	O

We	O
next	O
determined	O
whether	O
the	O
non	O
-	O
replicative	O
bacilli	O
observed	O
in	O
FMs	O
were	O
still	O
alive	O
.	O

For	O
this	O
purpose	O
,	O
we	O
analyzed	O
the	O
expression	O
of	O
a	O
series	O
of	O
genes	O
known	O
to	O
be	O
up	O
-	O
regulated	O
when	O
bacilli	O
are	O
in	O
a	O
persistent	O
non	O
-	O
replicating	O
state	O
[	O
23	O
]	O
,	O
[	O
24	O
]	O
.	O

RNA	O
was	O
,	O
therefore	O
,	O
prepared	O
from	O
both	O
in	O
vitro	O
-	O
grown	O
M	B
.	I
tb	I
and	O
intracellular	O
bacilli	O
at	O
day	O
6	O
and	O
12	O
post	O
-	O
infection	O
.	O

The	O
respective	O
amounts	O
of	O
RNA	O
corresponding	O
to	O
isocitrate	O
lyase	O
,	O
alpha	O
-	O
cristallin	O
,	O
a	O
very	O
hypothetical	O
7	O
.	O
6	O
kDa	O
protein	O
,	O
CHP	O
and	O
DosR	O
proteins	O
were	O
then	O
quantified	O
by	O
RT	O
-	O
PCR	O
.	O

As	O
shown	O
in	O
Table	O
3	O
,	O
the	O
dormancy	O
genes	O
were	O
all	O
strongly	O
up	O
-	O
regulated	O
in	O
intracellular	O
bacilli	O
at	O
day	O
12	O
post	O
-	O
infection	O
.	O

These	O
results	O
further	O
demonstrate	O
that	O
the	O
bacilli	O
are	O
not	O
killed	O
in	O
FMs	O
,	O
but	O
rather	O
persist	O
in	O
a	O
dormant	O
,	O
and	O
therefore	O
non	O
-	O
replicative	O
stage	O
[	O
25	O
]	O
.	O

Interestingly	O
,	O
the	O
dormancy	O
genes	O
were	O
not	O
as	O
strongly	O
expressed	O
at	O
day	O
6	O
,	O
time	O
at	O
which	O
bacteria	O
were	O
still	O
able	O
to	O
replicate	O
in	O
macrophages	O
undergoing	O
differentiation	O
into	O
FMs	O
.	O

Characterization	O
of	O
M	B
.	I
tb	I
survival	O
within	O
FMs	O
and	O
interaction	O
with	O
lipid	O
bodies	O

To	O
gain	O
further	O
insight	O
into	O
the	O
morphological	O
appearance	O
of	O
M	B
.	I
tb	I
within	O
FM	O
and	O
into	O
the	O
interactions	O
between	O
FM	O
lipid	O
bodies	O
(	O
LB	O
)	O
and	O
M	B
.	I
tb	I
-	O
containing	O
phagosomes	O
,	O
granulomas	O
were	O
fixed	O
and	O
processed	O
for	O
conventional	O
electron	O
microscopy	O
at	O
days	O
3	O
and	O
11	O
post	O
-	O
infection	O
.	O

Whatever	O
the	O
time	O
point	O
at	O
which	O
granuloma	O
cells	O
were	O
observed	O
,	O
bacteria	O
were	O
all	O
enclosed	O
in	O
phagosomes	O
,	O
most	O
of	O
which	O
contained	O
a	O
single	O
bacterium	O
.	O

None	O
of	O
them	O
(	O
over	O
a	O
thousand	O
which	O
were	O
examined	O
under	O
the	O
electron	O
microscope	O
)	O
were	O
free	O
in	O
the	O
cytoplasm	O
and	O
only	O
one	O
was	O
enclosed	O
in	O
a	O
classical	O
autophagic	O
vacuole	O
.	O

At	O
day	O
3	O
post	O
-	O
infection	O
,	O
FMs	O
profiles	O
(	O
thin	O
sections	O
)	O
were	O
scarce	O
,	O
representing	O
at	O
most	O
9	O
%	O
of	O
the	O
total	O
population	O
of	O
macrophage	O
profiles	O
observed	O
under	O
the	O
electron	O
microscope	O
(	O
Figure	O
6A	O
)	O
.	O

In	O
addition	O
,	O
86	O
%	O
of	O
the	O
FM	O
profiles	O
displayed	O
at	O
most	O
5	O
small	O
LBs	O
(	O
Figure	O
6B	O
)	O
.	O

At	O
this	O
stage	O
of	O
granuloma	O
formation	O
,	O
bacteria	O
were	O
infrequent	O
in	O
FM	O
,	O
but	O
were	O
found	O
in	O
other	O
types	O
of	O
macrophages	O
.	O

One	O
of	O
these	O
displayed	O
large	O
numbers	O
of	O
vacuoles	O
containing	O
flocculent	O
material	O
and	O
often	O
one	O
or	O
two	O
LBs	O
.	O

Over	O
95	O
%	O
of	O
the	O
bacteria	O
located	O
in	O
the	O
different	O
granuloma	O
macrophages	O
were	O
morphologically	O
intact	O
,	O
and	O
therefore	O
alive	O
[	O
26	O
]	O
.	O

Intact	O
bacteria	O
present	O
no	O
breaks	O
in	O
the	O
cell	O
wall	O
or	O
cytoplasmic	O
membrane	O
and	O
their	O
cytoplasm	O
has	O
preserved	O
its	O
ultrastructural	O
organization	O
and	O
electron	O
opacity	O
.	O

Furthermore	O
,	O
they	O
display	O
no	O
electron	O
translucent	O
intracytoplasmic	O
lipid	O
inclusions	O
(	O
ILI	O
)	O
.	O

Bacteria	O
were	O
also	O
observed	O
in	O
between	O
cells	O
,	O
probably	O
as	O
a	O
result	O
of	O
cell	O
lysis	O
within	O
granulomas	O
.	O

These	O
bacteria	O
were	O
also	O
morphologically	O
intact	O
and	O
devoid	O
of	O
ILI	O
(	O
not	O
shown	O
)	O
.	O

At	O
day	O
11	O
post	O
-	O
infection	O
,	O
M	B
.	I
tb	I
-	O
containing	O
macrophages	O
displaying	O
large	O
numbers	O
of	O
vacuoles	O
with	O
flocculent	O
material	O
were	O
less	O
frequently	O
observed	O
.	O

Interestingly	O
,	O
the	O
amount	O
of	O
such	O
vacuoles	O
had	O
strongly	O
decreased	O
in	O
most	O
of	O
these	O
cells	O
while	O
the	O
number	O
of	O
LBs	O
had	O
increased	O
.	O

The	O
percentage	O
of	O
FM	O
had	O
increased	O
to	O
reach	O
41	O
%	O
of	O
the	O
total	O
population	O
of	O
macrophage	O
profiles	O
within	O
the	O
granulomas	O
(	O
Figure	O
6A	O
)	O
.	O

From	O
these	O
observations	O
,	O
it	O
is	O
tempting	O
to	O
assume	O
that	O
the	O
highly	O
vesiculated	O
macrophages	O
give	O
rise	O
to	O
FMs	O
.	O

Within	O
FMs	O
,	O
the	O
size	O
and	O
amount	O
of	O
LBs	O
had	O
also	O
increased	O
with	O
time	O
since	O
48	O
%	O
of	O
the	O
FM	O
profiles	O
now	O
displayed	O
more	O
than	O
5	O
LB	O
per	O
FM	O
thin	O
section	O
(	O
Figure	O
6B	O
)	O
,	O
randomly	O
distributed	O
within	O
the	O
cells	O
(	O
Figure	O
6C	O
)	O
.	O

About	O
30	O
%	O
of	O
the	O
FM	O
profiles	O
displayed	O
between	O
1	O
and	O
20	O
bacteria	O
,	O
which	O
were	O
morphologically	O
intact	O
and	O
enclosed	O
within	O
phagosomes	O
(	O
Figure	O
6C	O
,	O
enlarged	O
view	O
)	O
.	O

The	O
interaction	O
between	O
these	O
bacteria	O
and	O
the	O
cellular	O
LBs	O
was	O
next	O
examined	O
at	O
day	O
11	O
.	O

Sixty	O
percent	O
of	O
the	O
bacilli	O
were	O
scattered	O
throughout	O
the	O
FMs	O
and	O
displayed	O
no	O
obvious	O
signs	O
of	O
interaction	O
with	O
the	O
cellular	O
LBs	O
.	O

A	O
small	O
fraction	O
of	O
the	O
bacteria	O
(	O
21	O
%	O
)	O
,	O
however	O
,	O
were	O
observed	O
in	O
the	O
close	O
vicinity	O
of	O
cellular	O
LBs	O
.	O

The	O
membrane	O
of	O
the	O
phagosomes	O
in	O
which	O
they	O
were	O
enclosed	O
clearly	O
interacted	O
with	O
cellular	O
LBs	O
(	O
Figures	O
6C	O
,	O
7A	O
,	O
7B	O
,	O
arrows	O
)	O
and	O
became	O
tightly	O
apposed	O
to	O
an	O
increasingly	O
larger	O
surface	O
area	O
of	O
the	O
LB	O
.	O

As	O
a	O
result	O
,	O
the	O
phagosomes	O
started	O
to	O
surround	O
LBs	O
in	O
a	O
zippering	O
fashion	O
(	O
Figures	O
7E	O
,	O
F	O
)	O
.	O

Ultimately	O
,	O
bacilli	O
(	O
19	O
%	O
)	O
were	O
translocated	O
to	O
cellular	O
LBs	O
(	O
Figure	O
7C	O
)	O
.	O

From	O
these	O
observations	O
,	O
it	O
is	O
tempting	O
to	O
assume	O
that	O
M	B
.	I
tb	I
-	O
containing	O
phagosomes	O
engulf	O
cellular	O
LBs	O
rather	O
than	O
fusing	O
with	O
them	O
.	O

This	O
process	O
,	O
which	O
is	O
reminiscent	O
of	O
autophagy	O
,	O
resulted	O
in	O
the	O
transfer	O
of	O
free	O
bacteria	O
into	O
the	O
lumen	O
of	O
cellular	O
LBs	O
(	O
Figure	O
7C	O
)	O
,	O
some	O
of	O
which	O
displayed	O
up	O
to	O
21	O
bacteria	O
(	O
Figure	O
7G	O
)	O
.	O

Interestingly	O
,	O
only	O
altered	O
M	B
.	I
tb	I
found	O
within	O
FM	O
lipid	O
bodies	O
exhibited	O
electron	O
translucent	O
ILIs	O
(	O
Figures	O
7D	O
,	O
G	O
)	O
,	O
thereby	O
suggesting	O
that	O
they	O
are	O
able	O
to	O
accumulate	O
host	O
cell	O
lipids	O
.	O

In	O
previous	O
work	O
,	O
the	O
term	O
altered	O
bacteria	O
had	O
been	O
used	O
to	O
define	O
live	O
bacteria	O
that	O
had	O
acquired	O
ILIs	O
[	O
26	O
]	O
.	O

Since	O
the	O
presence	O
of	O
ILIs	O
within	O
the	O
cytoplasm	O
of	O
M	B
.	I
tb	I
is	O
typical	O
for	O
non	O
-	O
replicating	O
bacteria	O
in	O
a	O
state	O
of	O
dormancy	O
[	O
27	O
]	O
,	O
this	O
further	O
confirms	O
that	O
these	O
bacteria	O
are	O
dormant	O
.	O

Discussion	O

Studies	O
carried	O
out	O
several	O
decades	O
ago	O
suggested	O
that	O
postprimary	O
tuberculosis	O
starts	O
as	O
a	O
lipid	O
pneumonia	O
[	O
28	O
]	O
,	O
[	O
29	O
]	O
.	O

Indeed	O
,	O
following	O
a	O
first	O
inflammatory	O
process	O
leading	O
to	O
exudates	O
of	O
mononuclear	O
cells	O
within	O
alveolar	O
spaces	O
,	O
early	O
pathologists	O
observed	O
an	O
accumulation	O
of	O
lipid	O
droplets	O
in	O
alveolar	O
macrophages	O
of	O
TB	O
patients	B
.	O

Tubercle	O
bacilli	O
were	O
shown	O
to	O
reside	O
in	O
these	O
lipid	O
-	O
rich	O
macrophages	O
which	O
were	O
named	O
foamy	O
macrophages	O
(	O
FMs	O
)	O
[	O
30	O
]	O
.	O

Recently	O
,	O
histo	O
-	O
pathological	O
analysis	O
of	O
biopsies	O
from	O
patients	B
with	O
untreated	O
tuberculosis	O
confirmed	O
the	O
century	O
-	O
old	O
histological	O
descriptions	O
of	O
postprimary	O
tuberculosis	O
[	O
10	O
]	O
.	O

In	O
this	O
study	O
,	O
Hunter	O
et	O
al	O
showed	O
that	O
postprimary	O
tuberculosis	O
begins	O
as	O
a	O
lipid	O
pneumonia	O
with	O
the	O
accumulation	O
of	O
large	O
amounts	O
of	O
lipid	O
-	O
rich	O
FMs	O
,	O
accompanied	O
by	O
bronchial	O
obstruction	O
.	O

It	O
was	O
also	O
shown	O
that	O
in	O
alveolar	O
foamy	O
macrophages	O
,	O
the	O
bacilli	O
were	O
mainly	O
found	O
within	O
lipid	O
droplets	O
.	O

All	O
these	O
observations	O
underline	O
the	O
important	O
,	O
yet	O
often	O
neglected	O
,	O
role	O
of	O
lipid	O
accumulation	O
,	O
and	O
more	O
precisely	O
FM	O
formation	O
,	O
at	O
the	O
infectious	O
site	O
in	O
the	O
physiopathology	O
of	O
TB	O
.	O

In	O
murine	O
experimental	O
models	O
,	O
FMs	O
accumulate	O
within	O
the	O
outermost	O
layer	O
of	O
granulomatous	O
structures	O
occupying	O
the	O
alveolar	O
spaces	O
during	O
the	O
chronic	O
phase	O
of	O
infection	O
.	O

This	O
strongly	O
suggests	O
that	O
FMs	O
could	O
be	O
involved	O
in	O
lesion	O
cleaning	O
via	O
phagocytic	O
uptake	O
of	O
cellular	O
debris	O
generated	O
by	O
the	O
local	O
inflammatory	O
response	O
.	O

Once	O
filled	O
with	O
debris	O
,	O
FMs	O
would	O
leave	O
the	O
parenchyma	O
through	O
the	O
alveolar	O
spaces	O
up	O
to	O
the	O
superior	O
bronchial	O
tree	O
,	O
to	O
be	O
finally	O
swallowed	O
and	O
digested	O
in	O
the	O
stomach	O
[	O
31	O
]	O
.	O

In	O
fact	O
,	O
this	O
process	O
is	O
very	O
well	O
known	O
,	O
and	O
is	O
a	O
crucial	O
factor	O
for	O
TB	O
diagnosis	O
in	O
children	B
.	O

As	O
infants	B
do	O
not	O
usually	O
generate	O
cavitary	O
lesions	O
,	O
and	O
because	O
it	O
is	O
difficult	O
to	O
detect	O
bacilli	O
in	O
the	O
sputum	O
,	O
the	O
diagnosis	O
is	O
linked	O
to	O
the	O
detection	O
of	O
bacilli	O
in	O
the	O
gastrointestinal	O
lavage	O
[	O
32	O
]	O
.	O

We	O
show	O
that	O
M	B
.	I
tb	I
-	O
induced	O
the	O
transformation	O
of	O
in	O
vitro	O
-	O
grown	O
human	B
granuloma	O
macrophages	O
into	O
FMs	O
within	O
6	O
days	O
,	O
and	O
even	O
more	O
rapidly	O
(	O
3	O
-	O
4	O
hours	O
)	O
in	O
cultured	O
macrophages	O
.	O

Although	O
this	O
event	O
occurs	O
more	O
quickly	O
than	O
in	O
vivo	O
,	O
or	O
in	O
animal	O
models	O
,	O
our	O
data	O
are	O
consistent	O
with	O
the	O
above	O
in	O
vivo	O
observations	O
.	O

Within	O
FMs	O
,	O
bacilli	O
and	O
LBs	O
were	O
often	O
tightly	O
linked	O
,	O
to	O
the	O
point	O
that	O
a	O
non	O
-	O
negligible	O
amount	O
of	O
bacteria	O
were	O
ultimately	O
observed	O
within	O
LBs	O
.	O

Interestingly	O
,	O
some	O
of	O
the	O
bacilli	O
transferred	O
into	O
lipid	O
bodies	O
displayed	O
their	O
own	O
intracytoplasmic	O
lipid	O
inclusions	O
,	O
which	O
are	O
considered	O
to	O
be	O
one	O
of	O
the	O
hallmarks	O
of	O
non	O
-	O
replicating	O
(	O
dormant	O
)	O
M	B
.	I
tb	I
[	O
27	O
]	O
.	O

The	O
recent	O
observation	O
of	O
persistent	O
ILI	O
-	O
containing	O
tubercle	O
bacilli	O
within	O
adipocyte	O
LBs	O
[	O
33	O
]	O
is	O
in	O
good	O
agreement	O
with	O
our	O
observations	O
.	O

Since	O
bacilli	O
residing	O
in	O
phagosomes	O
that	O
do	O
not	O
interact	O
with	O
cellular	O
lipid	O
bodies	O
do	O
not	O
display	O
ILIs	O
,	O
it	O
is	O
tempting	O
to	O
assume	O
that	O
lipids	O
within	O
ILIs	O
are	O
of	O
cellular	O
origin	O
.	O

The	O
accumulation	O
of	O
lipids	O
within	O
bacilli	O
[	O
47	O
]	O
,	O
via	O
interaction	O
with	O
FM	O
lipid	O
bodies	O
could	O
,	O
therefore	O
,	O
be	O
crucial	O
to	O
M	B
.	I
tb	I
persistence	O
.	O

It	O
is	O
indeed	O
known	O
that	O
M	B
.	I
tb	I
accumulates	O
lipids	O
,	O
and	O
more	O
precisely	O
triacylglycerols	O
,	O
during	O
dormancy	O
[	O
34	O
]	O
,	O
[	O
35	O
]	O
from	O
which	O
it	O
derives	O
both	O
carbon	O
and	O
energy	O
for	O
its	O
own	O
metabolism	O
.	O

Intracellular	O
persistence	O
of	O
M	B
.	I
tb	I
is	O
also	O
critically	O
linked	O
to	O
the	O
acquisition	O
of	O
host	O
cholesterol	O
through	O
the	O
Mce4	O
transporter	O
system	O
[	O
36	O
]	O
.	O

The	O
question	O
that	O
arises	O
is	O
how	O
do	O
bacteria	O
gain	O
access	O
to	O
lipids	O
from	O
LB	O
?	O

Direct	O
fusion	O
of	O
phagosomes	O
with	O
FM	O
lipid	O
bodies	O
seems	O
unlikely	O
as	O
the	O
membranes	O
of	O
both	O
structures	O
are	O
quite	O
different	O
from	O
one	O
another	O
.	O

Our	O
observations	O
suggest	O
instead	O
that	O
once	O
M	B
.	I
tb	I
-	O
containing	O
phagosomes	O
have	O
established	O
close	O
contact	O
with	O
a	O
lipid	O
body	O
,	O
they	O
surround	O
and	O
engulf	O
the	O
latter	O
by	O
a	O
process	O
that	O
remains	O
to	O
be	O
deciphered	O
.	O

This	O
phenomenon	O
is	O
somewhat	O
reminiscent	O
of	O
autophagy	O
,	O
as	O
observed	O
under	O
conditions	O
of	O
cholesterol	O
depletion	O
in	O
macrophages	O
infected	O
with	O
M	B
.	I
avium	I
[	O
37	O
]	O
.	O

After	O
degradation	O
of	O
the	O
resulting	O
inner	O
membrane	O
,	O
bacteria	O
would	O
be	O
freed	O
within	O
the	O
lipids	O
of	O
the	O
engulfed	O
LB	O
,	O
and	O
therefore	O
be	O
in	O
direct	O
contact	O
with	O
cellular	O
lipids	O
.	O

How	O
bacilli	O
translocate	O
the	O
cellular	O
lipids	O
to	O
their	O
own	O
cytoplasm	O
remains	O
to	O
be	O
established	O
.	O

Another	O
important	O
phenomenon	O
underlined	O
by	O
our	O
study	O
is	O
the	O
strong	O
correlation	O
between	O
the	O
presence	O
of	O
FMs	O
in	O
the	O
granulomatous	O
structures	O
and	O
the	O
development	O
of	O
necrosis	O
within	O
the	O
lesion	O
,	O
as	O
suggested	O
by	O
Pagel	O
over	O
80	O
years	O
ago	O
[	O
29	O
]	O
.	O

Interestingly	O
,	O
FMs	O
were	O
systematically	O
located	O
at	O
the	O
interface	O
region	O
between	O
the	O
histiocytes	O
and	O
the	O
central	O
necrosis	O
area	O
of	O
the	O
biopsied	O
lesions	O
.	O

Although	O
necrosis	O
formation	O
could	O
depend	O
on	O
an	O
indirect	O
effect	O
of	O
the	O
global	O
immune	O
response	O
,	O
our	O
data	O
indicate	O
that	O
the	O
formation	O
of	O
FMs	O
is	O
an	O
important	O
factor	O
favoring	O
the	O
appearance	O
of	O
necrosis	O
.	O

Analysis	O
of	O
larger	O
series	O
of	O
biopsy	O
samples	O
are	O
,	O
however	O
,	O
needed	O
to	O
definitely	O
demonstrate	O
our	O
actual	O
hypothesis	O
according	O
to	O
which	O
FMs	O
play	O
a	O
direct	O
and	O
unique	O
role	O
in	O
necrosis	O
formation	O
.	O

Consistent	O
with	O
this	O
hypothesis	O
,	O
we	O
observed	O
that	O
FMs	O
induced	O
from	O
M	B
.	I
tb	I
-	O
infected	O
macrophages	O
displayed	O
permanent	O
TNF	O
-	O
alpha	O
secretion	O
,	O
a	O
potent	O
pro	O
-	O
necrotic	O
factor	O
,	O
whereas	O
M	B
.	I
smegmatis	I
-	O
infected	O
macrophages	O
were	O
poor	O
producers	O
of	O
TNF	O
-	O
alpha	O
.	O

At	O
day	O
4	O
post	O
-	O
infection	O
,	O
TNF	O
-	O
alpha	O
secretion	O
was	O
indeed	O
twofold	O
higher	O
in	O
macrophages	O
(	O
of	O
which	O
70	O
%	O
had	O
differentiated	O
into	O
FMs	O
)	O
infected	O
with	O
M	B
.	I
tb	I
than	O
in	O
those	O
infected	O
with	O
M	B
.	I
smegmatis	I
,	O
as	O
measured	O
both	O
by	O
ELISA	O
and	O
RNA	O
quantification	O
(	O
Peyron	O
,	O
unpublished	O
observations	O
)	O
.	O

However	O
,	O
one	O
must	O
keep	O
in	O
mind	O
that	O
the	O
association	O
of	O
FMs	O
and	O
necrosis	O
may	O
be	O
the	O
consequence	O
of	O
the	O
FM	O
cleaning	O
process	O
of	O
lipoproteins	O
released	O
into	O
the	O
necrotic	O
tissue	O
,	O
as	O
observed	O
in	O
atherosclerosis	O
lesions	O
[	O
38	O
]	O
.	O

It	O
is	O
thus	O
tempting	O
to	O
propose	O
that	O
M	B
.	I
tb	I
mycolic	O
acids	O
may	O
be	O
responsible	O
for	O
the	O
development	O
of	O
necrotic	O
lesions	O
,	O
due	O
to	O
their	O
ability	O
to	O
induce	O
TNF	O
-	O
alpha	O
production	O
by	O
FMs	O
.	O

Whether	O
mycolic	O
acids	O
are	O
directly	O
involved	O
in	O
TNF	O
-	O
alpha	O
production	O
,	O
or	O
only	O
indirectly	O
by	O
inducing	O
FM	O
formation	O
,	O
remains	O
a	O
matter	O
of	O
debate	O
currently	O
under	O
study	O
.	O

Our	O
observations	O
are	O
strikingly	O
similar	O
to	O
the	O
phenomena	O
described	O
for	O
postprimary	O
tuberculosis	O
,	O
that	O
seems	O
to	O
begin	O
as	O
localized	O
foci	O
of	O
pneumonia	O
followed	O
by	O
massive	O
necrosis	O
leading	O
to	O
the	O
formation	O
of	O
pulmonary	O
cavities	O
[	O
10	O
]	O
.	O

If	O
this	O
proves	O
to	O
be	O
the	O
case	O
,	O
then	O
the	O
traditionally	O
admitted	O
phenomenon	O
of	O
cavitation	O
arising	O
from	O
the	O
erosion	O
of	O
caseating	O
granulomatous	O
structures	O
from	O
bronchi	O
can	O
be	O
ruled	O
out	O
[	O
39	O
]	O
.	O

In	O
our	O
study	O
,	O
we	O
successfully	O
induced	O
FM	O
formation	O
from	O
isolated	O
macrophages	O
infected	O
with	O
M	B
.	I
tb	I
,	O
i	O
.	O
e	O
.	O
outside	O
a	O
granulomatous	O
structure	O
,	O
which	O
is	O
consistent	O
with	O
Hunter	O
'	O
s	O
recent	O
proposal	O
.	O

Until	O
now	O
,	O
mycolic	O
acids	O
have	O
been	O
considered	O
to	O
be	O
indirectly	O
involved	O
in	O
virulence	O
mechanisms	O
as	O
being	O
part	O
of	O
complex	O
molecules	O
of	O
the	O
mycobacterial	O
envelope	O
.	O

The	O
most	O
widely	O
studied	O
mycolic	O
acid	O
-	O
containing	O
mycobacterial	O
compound	O
trehalose	O
6	O
,	O
6	O
'	O
dimycolate	O
(	O
TDM	O
)	O
,	O
has	O
been	O
extensively	O
analyzed	O
for	O
its	O
role	O
in	O
virulence	O
since	O
the	O
mid	O
-	O
fifties	O
[	O
40	O
]	O
.	O

Recently	O
,	O
it	O
was	O
shown	O
to	O
interfere	O
with	O
the	O
host	O
granulomatous	O
response	O
[	O
41	O
]	O
.	O

Overall	O
,	O
TDM	O
was	O
mainly	O
shown	O
to	O
mediate	O
macrophage	O
activation	O
and	O
a	O
Th1	O
-	O
type	O
response	O
to	O
M	B
.	I
tb	I
infection	O
(	O
for	O
review	O
,	O
see	O
[	O
25	O
]	O
)	O
.	O

Our	O
results	O
demonstrate	O
a	O
direct	O
role	O
of	O
oxygenated	O
mycolic	O
acids	O
for	O
FM	O
formation	O
,	O
independently	O
from	O
the	O
appearance	O
and	O
stage	O
of	O
the	O
disease	O
.	O

M	B
.	I
tb	I
-	O
specific	O
mycolic	O
acids	O
indeed	O
trigger	O
the	O
transformation	O
of	O
both	O
isolated	O
and	O
granuloma	O
macrophages	O
,	O
into	O
FM	O
.	O

Given	O
the	O
absence	O
of	O
FM	O
formation	O
in	O
M	B
.	I
smegmatis	I
-	O
induced	O
granulomas	O
,	O
despite	O
the	O
induction	O
of	O
a	O
comparative	O
inflammatory	O
response	O
,	O
ascertained	O
by	O
the	O
similar	O
induction	O
of	O
granulomas	O
,	O
this	O
phenomenon	O
clearly	O
depends	O
upon	O
a	O
direct	O
contact	O
with	O
the	O
bacilli	O
,	O
and	O
not	O
to	O
the	O
inflammatory	O
response	O
.	O

Mycolic	O
acids	O
are	O
major	O
and	O
hallmark	O
components	O
of	O
the	O
mycobacterial	O
cell	O
wall	O
.	O

They	O
constitute	O
40	O
-	O
60	O
%	O
of	O
dry	O
weight	O
of	O
the	O
envelope	O
[	O
42	O
]	O
.	O

All	O
members	O
of	O
the	O
complex	O
(	O
e	O
.	O
g	O
.	O
M	B
.	I
tb	I
,	O
Mycobacterium	B
africanum	I
,	O
Mycobacterium	B
bovis	I
and	O
Mycobacterium	B
microti	I
)	O
are	O
able	O
to	O
synthesize	O
the	O
same	O
combination	O
of	O
mycolic	O
acids	O
,	O
i	O
.	O
e	O
.	O
cyclopropanated	O
alpha	O
-	O
mycolic	O
acids	O
,	O
ketomycolic	O
and	O
methoxymycolic	O
acids	O
[	O
17	O
]	O
,	O
which	O
are	O
not	O
synthesized	O
by	O
non	O
-	O
pathogenic	O
mycobacterial	O
species	O
[	O
43	O
]	O
.	O

These	O
structural	O
specificities	O
probably	O
account	O
for	O
part	O
of	O
the	O
pathogenicity	O
of	O
these	O
species	O
,	O
as	O
shown	O
by	O
the	O
impaired	O
virulence	O
of	O
mutant	O
strains	O
deprived	O
of	O
keto	O
and	O
methoxyl	O
groups	O
in	O
experimental	O
infections	O
[	O
17	O
]	O
,	O
[	O
44	O
]	O
,	O
[	O
45	O
]	O
.	O

Our	O
study	O
,	O
therefore	O
,	O
gives	O
the	O
first	O
proof	O
of	O
a	O
direct	O
role	O
of	O
isolated	O
mycolic	O
acids	O
in	O
the	O
interplay	O
between	O
M	B
.	I
tb	I
and	O
host	O
cells	O
.	O

Interestingly	O
,	O
this	O
effect	O
is	O
expressed	O
both	O
by	O
whole	O
bacilli	O
and	O
isolated	O
lipids	O
,	O
suggesting	O
that	O
oxygenated	O
mycolic	O
acids	O
are	O
either	O
secreted	O
by	O
the	O
bacilli	O
,	O
or	O
exposed	O
at	O
the	O
cell	O
wall	O
surface	O
in	O
a	O
manner	O
enabling	O
their	O
bioactivity	O
.	O

According	O
to	O
our	O
results	O
,	O
mycolic	O
acids	O
trigger	O
the	O
formation	O
,	O
within	O
granulomas	O
,	O
of	O
FMs	O
in	O
which	O
bacilli	O
can	O
hide	O
and	O
survive	O
.	O

Oxygenated	O
mycolic	O
acids	O
,	O
either	O
free	O
,	O
as	O
constituents	O
of	O
TDM	O
[	O
44	O
]	O
,	O
or	O
linked	O
to	O
the	O
cell	O
wall	O
arabinogalactan	O
[	O
46	O
]	O
,	O
[	O
47	O
]	O
,	O
should	O
,	O
therefore	O
,	O
be	O
considered	O
as	O
major	O
virulence	O
factors	O
enabling	O
M	B
.	I
tb	I
survival	O
for	O
long	O
periods	O
of	O
time	O
in	O
a	O
persistent	O
state	O
.	O

Being	O
an	O
inducer	O
of	O
host	O
lipid	O
accumulation	O
,	O
and	O
FM	O
formation	O
at	O
the	O
site	O
of	O
infection	O
,	O
these	O
oxygenated	O
mycolic	O
acids	O
could	O
,	O
therefore	O
,	O
also	O
be	O
responsible	O
for	O
the	O
induction	O
of	O
necrosis	O
within	O
lesions	O
,	O
thus	O
favoring	O
M	B
.	I
tb	I
dissemination	O
.	O

Interestingly	O
,	O
deletion	O
of	O
the	O
mmaA4	O
(	O
Rv0642c	O
)	O
gene	O
also	O
drastically	O
decreased	O
the	O
ability	O
of	O
M	B
.	I
tb	I
to	O
induce	O
the	O
differentiation	O
of	O
macrophages	O
into	O
FMs	O
(	O
data	O
not	O
shown	O
)	O
.	O

However	O
,	O
the	O
residual	O
ability	O
of	O
this	O
mutant	O
to	O
induce	O
FMs	O
suggests	O
that	O
other	O
mycobacterial	O
factors	O
might	O
partially	O
trigger	O
the	O
formation	O
of	O
FM	O
.	O

With	O
regard	O
to	O
the	O
mycolic	O
acid	O
methyltransferases	O
,	O
given	O
that	O
(	O
i	O
)	O
mmaA2	O
(	O
Rv0644c	O
)	O
and	O
mmaA3	O
(	O
Rv0643c	O
)	O
are	O
pseudogenes	O
in	O
M	B
.	I
leprae	I
and	O
(	O
ii	O
)	O
mmaA4	O
KO	O
present	O
no	O
trans	O
cyclopropanation	O
[	O
45	O
]	O
,	O
thus	O
excluding	O
the	O
involvement	O
of	O
the	O
cmaA2	O
(	O
Rv0503c	O
)	O
gene	O
,	O
we	O
expect	O
that	O
at	O
least	O
pcaA	O
(	O
Rv0470c	O
)	O
,	O
which	O
introduces	O
cis	O
-	O
cyclopropane	O
,	O
may	O
play	O
the	O
same	O
role	O
.	O

Consistent	O
with	O
this	O
hypothesis	O
,	O
a	O
pcaA	O
null	O
mutant	O
is	O
unable	O
to	O
persist	O
within	O
infected	O
mice	B
[	O
46	O
]	O
,	O
thus	O
demonstrating	O
the	O
role	O
of	O
a	O
mycolic	O
acid	O
methyltransferase	O
in	O
the	O
chronic	O
stage	O
of	O
infection	O
.	O

Overall	O
,	O
our	O
study	O
has	O
shed	O
light	O
on	O
a	O
previously	O
uncharacterized	O
cell	O
population	O
participating	O
in	O
human	B
tuberculous	O
granulomas	O
,	O
namely	O
foamy	O
macrophages	O
.	O

We	O
propose	O
that	O
the	O
specific	O
induction	O
of	O
FM	O
by	O
M	B
.	I
tb	I
would	O
create	O
a	O
favourable	O
environment	O
for	O
persistent	O
bacteria	O
.	O

In	O
our	O
opinion	O
,	O
FMs	O
could	O
be	O
a	O
safe	O
shelter	O
because	O
they	O
preserve	O
bacilli	O
from	O
a	O
direct	O
contact	O
with	O
granuloma	O
lymphocytes	O
and	O
histiocytes	O
,	O
they	O
lose	O
one	O
of	O
the	O
major	O
macrophage	O
bactericidal	O
activities	O
and	O
they	O
constitute	O
an	O
important	O
source	O
of	O
nutrients	O
for	O
the	O
bacilli	O
thanks	O
to	O
the	O
fatty	O
acids	O
accumulated	O
in	O
their	O
lipid	O
granules	O
.	O

Supporting	O
Information	O

A	O
Case	O
-	O
Control	O
Study	O
to	O
Assess	O
the	O
Relationship	O
between	O
Poverty	O
and	O
Visual	O
Impairment	O
from	O
Cataract	O
in	O
Kenya	O
,	O
the	O
Philippines	O
,	O
and	O
Bangladesh	O

Abstract	O

Background	O

The	O
link	O
between	O
poverty	O
and	O
health	O
is	O
central	O
to	O
the	O
Millennium	O
Development	O
Goals	O
(	O
MDGs	O
)	O
.	O

Poverty	O
can	O
be	O
both	O
a	O
cause	O
and	O
consequence	O
of	O
poor	O
health	O
,	O
but	O
there	O
are	O
few	O
epidemiological	O
studies	O
exploring	O
this	O
complex	O
relationship	O
.	O

The	O
aim	O
of	O
this	O
study	O
was	O
to	O
examine	O
the	O
association	O
between	O
visual	O
impairment	O
from	O
cataract	O
and	O
poverty	O
in	O
adults	O
in	O
Kenya	O
,	O
Bangladesh	O
,	O
and	O
the	O
Philippines	O
.	O

Methods	O
and	O
Findings	O

A	O
population	O
-	O
based	O
case	O
-	O
control	O
study	O
was	O
conducted	O
in	O
three	O
countries	O
during	O
2005	O
-	O
2006	O
.	O

Cases	O
were	O
persons	B
aged	O
50	O
y	O
or	O
older	O
and	O
visually	O
impaired	O
due	O
to	O
cataract	O
(	O
visual	O
acuity	O
<	O
6	O
/	O
24	O
in	O
the	O
better	O
eye	O
)	O
.	O

Controls	O
were	O
persons	B
age	O
-	O
and	O
sex	O
-	O
matched	O
to	O
the	O
case	O
participants	B
with	O
normal	O
vision	O
selected	O
from	O
the	O
same	O
cluster	O
.	O

Household	O
expenditure	O
was	O
assessed	O
through	O
the	O
collection	O
of	O
detailed	O
consumption	O
data	O
,	O
and	O
asset	O
ownership	O
and	O
self	O
-	O
rated	O
wealth	O
were	O
also	O
measured	O
.	O

In	O
total	O
,	O
596	O
cases	O
and	O
535	O
controls	O
were	O
included	O
in	O
these	O
analyses	O
(	O
Kenya	O
142	O
cases	O
,	O
75	O
controls	O
;	O
Bangladesh	O
216	O
cases	O
,	O
279	O
controls	O
;	O
Philippines	O
238	O
cases	O
,	O
180	O
controls	O
)	O
.	O

Case	O
participants	B
were	O
more	O
likely	O
to	O
be	O
in	O
the	O
lowest	O
quartile	O
of	O
per	O
capita	O
expenditure	O
(	O
PCE	O
)	O
compared	O
to	O
controls	O
in	O
Kenya	O
(	O
odds	O
ratio	O
=	O
2	O
.	O
3	O
,	O
95	O
%	O
confidence	O
interval	O
0	O
.	O
9	O
-	O
5	O
.	O
5	O
)	O
,	O
Bangladesh	O
(	O
1	O
.	O
9	O
,	O
1	O
.	O
1	O
-	O
3	O
.	O
2	O
)	O
,	O
and	O
the	O
Philippines	O
(	O
3	O
.	O
1	O
,	O
1	O
.	O
7	O
-	O
5	O
.	O
7	O
)	O
,	O
and	O
there	O
was	O
significant	O
dose	O
-	O
response	O
relationship	O
across	O
quartiles	O
of	O
PCE	O
.	O

These	O
associations	O
persisted	O
after	O
adjustment	O
for	O
self	O
-	O
rated	O
health	O
and	O
social	O
support	O
indicators	O
.	O

A	O
similar	O
pattern	O
was	O
observed	O
for	O
the	O
relationship	O
between	O
cataract	O
visual	O
impairment	O
with	O
asset	O
ownership	O
and	O
self	O
-	O
rated	O
wealth	O
.	O

There	O
was	O
no	O
consistent	O
pattern	O
of	O
association	O
between	O
PCE	O
and	O
level	O
of	O
visual	O
impairment	O
due	O
to	O
cataract	O
,	O
sex	O
,	O
or	O
age	O
among	O
the	O
three	O
countries	O
.	O

Conclusions	O

Our	O
data	O
show	O
that	O
people	B
with	O
visual	O
impairment	O
due	O
to	O
cataract	O
were	O
poorer	O
than	O
those	O
with	O
normal	O
sight	O
in	O
all	O
three	O
low	O
-	O
income	O
countries	O
studied	O
.	O

The	O
MDGs	O
are	O
committed	O
to	O
the	O
eradication	O
of	O
extreme	O
poverty	O
and	O
provision	O
of	O
health	O
care	O
to	O
poor	O
people	B
,	O
and	O
this	O
study	O
highlights	O
the	O
need	O
for	O
increased	O
provision	O
of	O
cataract	O
surgery	O
to	O
poor	O
people	B
,	O
as	O
they	O
are	O
particularly	O
vulnerable	O
to	O
visual	O
impairment	O
from	O
cataract	O
.	O

Background	O
.	O

Globally	O
,	O
about	O
45	O
million	O
people	B
are	O
blind	O
.	O

As	O
with	O
many	O
other	O
conditions	O
,	O
avoidable	O
blindness	O
(	O
preventable	O
or	O
curable	O
blindness	O
)	O
is	O
a	O
particular	O
problem	O
for	O
people	B
in	O
developing	O
countries	O
-	O
-	O
90	O
%	O
of	O
blind	O
people	B
live	O
in	O
poor	O
regions	O
of	O
the	O
world	O
.	O

Although	O
various	O
infections	O
and	O
disorders	O
can	O
cause	O
blindness	O
,	O
cataract	O
is	O
the	O
most	O
common	O
cause	O
.	O

In	O
cataract	O
,	O
which	O
is	O
responsible	O
for	O
half	O
of	O
all	O
cases	O
of	O
blindness	O
in	O
the	O
world	O
,	O
the	O
lens	O
of	O
the	O
eye	O
gradually	O
becomes	O
cloudy	O
.	O

Because	O
the	O
lens	O
focuses	O
light	O
to	O
produce	O
clear	O
,	O
sharp	O
images	O
,	O
as	O
cataract	O
develops	O
,	O
vision	O
becomes	O
increasingly	O
foggy	O
or	O
fuzzy	O
,	O
colors	O
become	O
less	O
intense	O
,	O
and	O
the	O
ability	O
to	O
see	O
shapes	O
against	O
a	O
background	O
declines	O
.	O

Eventually	O
,	O
vision	O
may	O
be	O
lost	O
completely	O
.	O

Cataract	O
can	O
be	O
treated	O
with	O
an	O
inexpensive	O
,	O
simple	O
operation	O
in	O
which	O
the	O
cloudy	O
lens	O
is	O
surgically	O
removed	O
and	O
an	O
artificial	O
lens	O
is	O
inserted	O
into	O
the	O
eye	O
to	O
restore	O
vision	O
.	O

In	O
developed	O
countries	O
,	O
this	O
operation	O
is	O
common	O
and	O
easily	O
accessible	O
but	O
many	O
poor	O
countries	O
lack	O
the	O
resources	O
to	O
provide	O
the	O
operation	O
to	O
everyone	O
who	O
needs	O
it	O
.	O

In	O
addition	O
,	O
blind	O
people	B
often	O
cannot	O
afford	O
to	O
travel	O
to	O
the	O
hospitals	O
where	O
the	O
operation	O
,	O
which	O
also	O
may	O
come	O
with	O
a	O
fee	O
,	O
is	O
done	O
.	O

Why	O
Was	O
This	O
Study	O
Done	O
?	O

Because	O
blindness	O
may	O
reduce	O
earning	O
potential	O
,	O
many	O
experts	O
believe	O
that	O
poverty	O
and	O
blindness	O
(	O
and	O
,	O
more	O
generally	O
,	O
poor	O
health	O
)	O
are	O
inextricably	O
linked	O
.	O

People	B
become	O
ill	O
more	O
often	O
in	O
poor	O
countries	O
than	O
in	O
wealthy	O
countries	O
because	O
they	O
have	O
insufficient	O
food	O
,	O
live	O
in	O
substandard	O
housing	O
,	O
and	O
have	O
limited	O
access	O
to	O
health	O
care	O
,	O
education	O
,	O
water	O
,	O
and	O
sanitation	O
.	O

Once	O
they	O
are	O
ill	O
,	O
their	O
ability	O
to	O
earn	O
money	O
may	O
be	O
reduced	O
,	O
which	O
increases	O
their	O
personal	O
poverty	O
and	O
slows	O
the	O
economic	O
development	O
of	O
the	O
whole	O
country	O
.	O

Because	O
of	O
this	O
potential	O
link	O
between	O
health	O
and	O
poverty	O
,	O
improvements	O
in	O
health	O
are	O
at	O
the	O
heart	O
of	O
the	O
United	O
Nations	O
Millennium	O
Development	O
Goals	O
,	O
a	O
set	O
of	O
eight	O
goals	O
established	O
in	O
2000	O
with	O
the	O
primary	O
aim	O
of	O
reducing	O
world	O
poverty	O
.	O

However	O
,	O
few	O
studies	O
have	O
actually	O
investigated	O
the	O
complex	O
relationship	O
between	O
poverty	O
and	O
health	O
.	O

Here	O
,	O
the	O
researchers	O
investigate	O
the	O
association	O
between	O
visual	O
impairment	O
from	O
cataract	O
and	O
poverty	O
among	O
adults	O
living	O
in	O
three	O
low	O
-	O
income	O
countries	O
.	O

What	O
Did	O
the	O
Researchers	O
Do	O
and	O
Find	O
?	O

The	O
researchers	O
identified	O
nearly	O
600	O
people	B
aged	O
50	O
y	O
or	O
more	O
with	O
severe	O
cataract	O
-	O
induced	O
visual	O
impairment	O
(	O
"	O
cases	O
"	O
)	O
primarily	O
through	O
a	O
survey	O
of	O
the	O
population	O
in	O
Kenya	O
,	O
Bangladesh	O
,	O
and	O
the	O
Philippines	O
.	O

They	O
matched	O
each	O
case	O
to	O
a	O
normally	O
sighted	O
(	O
"	O
control	O
"	O
)	O
person	B
of	O
similar	O
age	O
and	O
sex	O
living	O
nearby	O
.	O

They	O
then	O
assessed	O
a	O
proxy	O
for	O
the	O
income	O
level	O
,	O
measured	O
as	O
"	O
per	O
capita	O
expenditure	O
"	O
(	O
PCE	O
)	O
,	O
of	O
all	O
the	O
study	O
participants	B
(	O
people	B
with	O
cataracts	O
and	O
controls	O
)	O
by	O
collecting	O
information	O
about	O
what	O
their	O
households	O
consumed	O
.	O

The	O
participants	B
'	O
housing	O
conditions	O
and	O
other	O
assets	O
and	O
their	O
self	O
-	O
rated	O
wealth	O
were	O
also	O
measured	O
.	O

In	O
all	O
three	O
countries	O
,	O
cases	O
were	O
more	O
likely	O
to	O
be	O
in	O
the	O
lowest	O
quarter	O
(	O
quartile	O
)	O
of	O
the	O
range	O
of	O
PCEs	O
for	O
that	O
country	O
than	O
controls	O
.	O

In	O
the	O
Philippines	O
,	O
for	O
example	O
,	O
people	B
with	O
cataract	O
-	O
affected	O
vision	O
were	O
three	O
times	O
more	O
likely	O
than	O
normally	O
sighted	O
controls	O
to	O
have	O
a	O
PCE	O
in	O
the	O
lowest	O
quartile	O
than	O
in	O
the	O
highest	O
quartile	O
.	O

The	O
risk	O
of	O
cataract	O
-	O
related	O
visual	O
impairment	O
increased	O
as	O
PCE	O
decreased	O
in	O
all	O
three	O
countries	O
.	O

Similarly	O
,	O
severe	O
cataract	O
-	O
induced	O
visual	O
impairment	O
was	O
more	O
common	O
in	O
those	O
who	O
owned	O
fewer	O
assets	O
and	O
those	O
with	O
lower	O
self	O
-	O
rated	O
wealth	O
.	O

However	O
,	O
there	O
was	O
no	O
consistent	O
association	O
between	O
PCE	O
and	O
the	O
level	O
of	O
cataract	O
-	O
induced	O
visual	O
impairment	O
.	O

What	O
Do	O
These	O
Findings	O
Mean	O
?	O

These	O
findings	O
show	O
that	O
there	O
is	O
an	O
association	O
between	O
visual	O
impairment	O
caused	O
by	O
cataract	O
and	O
poverty	O
in	O
Kenya	O
,	O
Bangladesh	O
,	O
and	O
the	O
Philippines	O
.	O

However	O
,	O
because	O
the	O
financial	O
circumstances	O
of	O
the	O
people	B
in	O
this	O
study	O
were	O
assessed	O
after	O
cataracts	O
had	O
impaired	O
their	O
sight	O
,	O
this	O
study	O
does	O
not	O
prove	O
that	O
poverty	O
is	O
a	O
cause	O
of	O
visual	O
impairment	O
.	O

A	O
causal	O
connection	O
between	O
poverty	O
and	O
cataract	O
can	O
only	O
be	O
shown	O
by	O
determining	O
the	O
PCEs	O
of	O
normally	O
sighted	O
people	B
and	O
following	O
them	O
for	O
several	O
years	O
to	O
see	O
who	O
develops	O
cataract	O
.	O

Nevertheless	O
,	O
by	O
confirming	O
an	O
association	O
between	O
poverty	O
and	O
blindness	O
,	O
these	O
findings	O
highlight	O
the	O
need	O
for	O
increased	O
provision	O
of	O
cataract	O
surgery	O
to	O
poor	O
people	B
,	O
particularly	O
since	O
cataract	O
surgery	O
has	O
the	O
potential	O
to	O
improve	O
the	O
quality	O
of	O
life	O
for	O
many	O
people	B
in	O
developing	O
countries	O
at	O
a	O
relatively	O
low	O
cost	O
.	O

Additional	O
Information	O
.	O

Please	O
access	O
these	O
Web	O
sites	O
via	O
the	O
online	O
version	O
of	O
this	O
summary	O
at	O
http	O
:	O
/	O
/	O
dx	O
.	O
doi	O
.	O
org	O
/	O
10	O
.	O
1371	O
/	O
journal	O
.	O
pmed	O
.	O
0050244	O
.	O

Introduction	O

Improvements	O
in	O
health	O
are	O
at	O
the	O
heart	O
of	O
the	O
Millennium	O
Development	O
Goals	O
,	O
with	O
the	O
recognition	O
that	O
better	O
health	O
is	O
central	O
to	O
the	O
primary	O
aim	O
of	O
reducing	O
poverty	O
as	O
well	O
as	O
important	O
in	O
its	O
own	O
right	O
.	O

Empirical	O
data	O
are	O
needed	O
to	O
back	O
up	O
this	O
claim	O
.	O

Unravelling	O
the	O
relationship	O
between	O
blindness	O
and	O
poverty	O
therefore	O
has	O
important	O
implications	O
,	O
and	O
may	O
also	O
be	O
informative	O
for	O
the	O
association	O
between	O
poverty	O
and	O
other	O
disabilities	O
.	O

Blindness	O
is	O
a	O
common	O
condition	O
globally	O
,	O
affecting	O
approximately	O
45	O
million	O
people	B
,	O
and	O
more	O
than	O
a	O
third	O
of	O
blindness	O
is	O
caused	O
by	O
cataract	O
[	O
1	O
,	O
2	O
]	O
.	O

Globally	O
,	O
the	O
prevalence	O
of	O
blindness	O
is	O
five	O
-	O
fold	O
higher	O
in	O
poor	O
than	O
rich	O
countries	O
[	O
2	O
]	O
.	O

Limited	O
data	O
show	O
that	O
within	O
countries	O
the	O
poor	O
are	O
also	O
more	O
likely	O
to	O
be	O
blind	O
[	O
3	O
,	O
4	O
]	O
.	O

It	O
is	O
frequently	O
asserted	O
that	O
blindness	O
is	O
both	O
a	O
cause	O
and	O
consequence	O
of	O
poverty	O
,	O
but	O
there	O
are	O
few	O
empirical	O
data	O
to	O
support	O
this	O
claim	O
.	O

Poverty	O
may	O
cause	O
cataract	O
blindness	O
,	O
because	O
access	O
to	O
cataract	O
surgery	O
is	O
limited	O
in	O
low	O
-	O
income	O
countries	O
[	O
5	O
]	O
.	O

Furthermore	O
,	O
within	O
poor	O
countries	O
some	O
evidence	O
suggests	O
that	O
lack	O
of	O
money	O
is	O
a	O
major	O
barrier	O
to	O
uptake	O
of	O
cataract	O
surgery	O
by	O
individuals	O
[	O
6	O
-	O
8	O
]	O
.	O

Blindness	O
may	O
also	O
cause	O
poverty	O
,	O
as	O
the	O
blind	O
individual	O
,	O
or	O
the	O
household	O
members	O
who	O
care	O
for	O
them	O
,	O
have	O
a	O
reduced	O
earning	O
potential	O
[	O
4	O
,	O
9	O
]	O
.	O

This	O
complex	O
problem	O
could	O
have	O
serious	O
implications	O
;	O
estimates	O
from	O
The	O
Gambia	O
suggest	O
that	O
there	O
is	O
a	O
substantial	O
economic	O
burden	O
from	O
lost	O
productivity	O
among	O
blind	O
people	B
[	O
10	O
]	O
.	O

Therefore	O
,	O
blindness	O
prevention	O
may	O
ultimately	O
be	O
cost	O
saving	O
[	O
11	O
]	O
.	O

Extrapolations	O
on	O
a	O
global	O
level	O
indicate	O
that	O
a	O
successful	O
eye	O
care	O
programme	O
could	O
prevent	O
more	O
than	O
100	O
million	O
cases	O
of	O
blindness	O
between	O
2000	O
and	O
2020	O
,	O
and	O
consequently	O
save	O
at	O
least	O
US	O
$	O
102	O
billion	O
,	O
which	O
would	O
otherwise	O
be	O
lost	O
to	O
reductions	O
in	O
productivity	O
associated	O
with	O
blindness	O
[	O
12	O
]	O
.	O

However	O
,	O
these	O
estimates	O
are	O
based	O
on	O
extrapolations	O
from	O
limited	O
data	O
and	O
were	O
not	O
based	O
on	O
individual	O
-	O
level	O
data	O
.	O

It	O
is	O
also	O
difficult	O
to	O
identify	O
the	O
component	O
of	O
productivity	O
loss	O
that	O
is	O
due	O
to	O
blindness	O
,	O
as	O
this	O
condition	O
mainly	O
affects	O
older	O
people	B
,	O
who	O
may	O
suffer	O
from	O
other	O
comorbidities	O
that	O
restrict	O
their	O
employment	O
opportunities	O
or	O
make	O
them	O
dependent	O
on	O
the	O
care	O
of	O
others	O
.	O

The	O
Cataract	O
Impact	O
Study	O
was	O
undertaken	O
to	O
assess	O
the	O
relationship	O
between	O
cataract	O
visual	O
impairment	O
and	O
"	O
economic	O
poverty	O
"	O
and	O
quality	O
of	O
life	O
,	O
and	O
to	O
estimate	O
the	O
impact	O
of	O
cataract	O
surgery	O
on	O
these	O
factors	O
in	O
three	O
low	O
-	O
income	O
countries	O
.	O

The	O
aim	O
of	O
the	O
current	O
paper	O
is	O
to	O
assess	O
the	O
association	O
at	O
baseline	O
between	O
visual	O
impairment	O
from	O
cataract	O
and	O
household	O
poverty	O
(	O
measured	O
through	O
consumption	O
,	O
asset	O
ownership	O
,	O
and	O
self	O
-	O
rated	O
wealth	O
)	O
in	O
a	O
population	O
-	O
based	O
case	O
-	O
control	O
study	O
in	O
Kenya	O
,	O
the	O
Philippines	O
,	O
and	O
Bangladesh	O
.	O

Methods	O

Setting	O

Case	O
and	O
control	O
participants	B
were	O
recruited	O
from	O
Nakuru	O
district	O
,	O
Kenya	O
(	O
January	O
-	O
February	O
,	O
2005	O
)	O
;	O
Negros	O
island	O
(	O
May	O
-	O
June	O
,	O
2005	O
)	O
and	O
Antique	O
district	O
(	O
April	O
-	O
May	O
,	O
2006	O
)	O
,	O
Philippines	O
;	O
and	O
Satkhira	O
district	O
,	O
Bangladesh	O
(	O
November	O
-	O
December	O
,	O
2005	O
)	O
.	O

Selection	O
of	O
Cases	O
and	O
Controls	O

Persons	B
with	O
cataract	O
visual	O
impairment	O
(	O
cases	O
)	O
and	O
persons	B
without	O
(	O
controls	O
)	O
were	O
primarily	O
recruited	O
through	O
a	O
population	O
-	O
based	O
survey	O
of	O
adults	O
aged	O
>	O
=	O
50	O
y	O
[	O
6	O
-	O
8	O
]	O
.	O

Clusters	O
of	O
50	O
people	B
(	O
regardless	O
of	O
visual	O
impairment	O
)	O
aged	O
>	O
=	O
50	O
y	O
were	O
selected	O
through	O
probability	O
-	O
proportionate	O
to	O
size	O
sampling	O
,	O
using	O
either	O
the	O
census	O
(	O
Philippines	O
and	O
Bangladesh	O
)	O
or	O
electoral	O
role	O
(	O
Kenya	O
)	O
as	O
the	O
sampling	O
frame	O
.	O

Households	O
within	O
clusters	O
were	O
selected	O
through	O
a	O
modification	O
of	O
compact	O
segment	O
sampling	O
,	O
whereby	O
a	O
map	O
was	O
drawn	O
of	O
the	O
enumeration	O
area	O
that	O
was	O
divided	O
into	O
segments	O
,	O
each	O
including	O
approximately	O
50	O
people	B
aged	O
>	O
=	O
50	O
y	O
,	O
and	O
one	O
segment	O
was	O
chosen	O
at	O
random	O
[	O
13	O
]	O
.	O

Households	O
in	O
the	O
segment	O
were	O
included	O
sequentially	O
until	O
50	O
people	B
aged	O
>	O
=	O
50	O
y	O
were	O
identified	O
.	O

The	O
surveys	O
included	O
3	O
,	O
503	O
(	O
93	O
%	O
response	O
rate	O
)	O
people	B
aged	O
>	O
=	O
50	O
y	O
in	O
Kenya	O
,	O
4	O
,	O
868	O
(	O
92	O
%	O
)	O
in	O
Bangladesh	O
,	O
2	O
,	O
774	O
(	O
76	O
%	O
)	O
in	O
Negros	O
,	O
and	O
3	O
,	O
177	O
(	O
83	O
%	O
)	O
in	O
Antique	O
.	O

All	O
people	B
in	O
the	O
survey	O
aged	O
>	O
=	O
50	O
y	O
underwent	O
visual	O
acuity	O
(	O
VA	O
)	O
testing	O
and	O
ophthalmic	O
examination	O
.	O

VA	O
was	O
measured	O
in	O
full	O
daylight	O
with	O
available	O
spectacle	O
correction	O
with	O
a	O
Snellen	O
tumbling	O
"	O
E	O
"	O
chart	O
using	O
optotype	O
size	O
6	O
/	O
18	O
(	O
20	O
/	O
60	O
)	O
on	O
one	O
side	O
and	O
size	O
6	O
/	O
60	O
(	O
20	O
/	O
200	O
)	O
on	O
the	O
other	O
side	O
at	O
6	O
or	O
3	O
metres	O
.	O

If	O
the	O
VA	O
was	O
<	O
6	O
/	O
18	O
in	O
either	O
eye	O
then	O
pinhole	O
vision	O
was	O
also	O
measured	O
.	O

Participants	B
with	O
pinhole	O
vision	O
<	O
6	O
/	O
18	O
but	O
>	O
6	O
/	O
60	O
in	O
the	O
better	O
eye	O
due	O
to	O
age	O
-	O
related	O
cataract	O
were	O
given	O
a	O
second	O
VA	O
test	O
using	O
an	O
"	O
E	O
"	O
of	O
size	O
6	O
/	O
24	O
.	O

The	O
ophthalmologist	O
examined	O
all	O
eyes	O
with	O
a	O
presenting	O
VA	O
<	O
6	O
/	O
18	O
with	O
a	O
torch	O
(	O
i	O
.	O
e	O
.	O
,	O
flashlight	O
)	O
,	O
direct	O
ophthalmoscope	O
,	O
and	O
/	O
or	O
portable	O
slit	O
lamp	O
.	O

The	O
principal	O
cause	O
of	O
blindness	O
or	O
visual	O
impairment	O
was	O
recorded	O
,	O
according	O
to	O
the	O
WHO	O
convention	O
in	O
which	O
the	O
major	O
cause	O
is	O
assigned	O
to	O
the	O
primary	O
disorder	O
or	O
,	O
if	O
there	O
are	O
two	O
existing	O
primary	O
disorders	O
,	O
to	O
the	O
one	O
that	O
is	O
easiest	O
to	O
treat	O
[	O
14	O
]	O
.	O

Survey	O
participants	B
were	O
eligible	O
for	O
inclusion	O
as	O
cases	O
if	O
they	O
were	O
aged	O
>	O
=	O
50	O
y	O
with	O
best	O
corrected	O
visual	O
acuity	O
<	O
6	O
/	O
24	O
in	O
the	O
better	O
eye	O
due	O
to	O
cataract	O
,	O
as	O
diagnosed	O
by	O
an	O
ophthalmologist	O
.	O

All	O
eligible	O
cases	O
identified	O
from	O
these	O
surveys	O
were	O
invited	O
to	O
participate	O
in	O
the	O
study	O
.	O

Participants	B
were	O
eligible	O
to	O
be	O
controls	O
if	O
they	O
were	O
aged	O
>	O
=	O
50	O
y	O
,	O
did	O
not	O
have	O
VA	O
<	O
6	O
/	O
24	O
in	O
the	O
better	O
eye	O
due	O
to	O
cataract	O
and	O
did	O
not	O
live	O
in	O
the	O
same	O
household	O
as	O
a	O
case	O
.	O

During	O
the	O
survey	O
a	O
list	O
was	O
maintained	O
of	O
all	O
eligible	O
controls	O
,	O
by	O
age	O
group	O
(	O
50	O
-	O
54	O
,	O
55	O
-	O
59	O
,	O
60	O
-	O
64	O
,	O
65	O
-	O
69	O
,	O
and	O
>	O
70	O
)	O
and	O
sex	O
.	O

Whenever	O
a	O
case	O
was	O
identified	O
,	O
one	O
age	O
-	O
and	O
sex	O
-	O
matched	O
control	O
was	O
randomly	O
selected	O
from	O
the	O
list	O
for	O
inclusion	O
(	O
or	O
up	O
to	O
two	O
controls	O
in	O
Bangladesh	O
)	O
.	O

If	O
no	O
matching	O
eligible	O
controls	O
had	O
been	O
identified	O
in	O
that	O
cluster	O
at	O
that	O
stage	O
of	O
the	O
survey	O
,	O
then	O
the	O
next	O
eligible	O
control	O
in	O
the	O
cluster	O
was	O
recruited	O
.	O

Because	O
of	O
logistical	O
and	O
time	O
constraints	O
,	O
additional	O
cases	O
were	O
also	O
included	O
through	O
community	O
-	O
based	O
case	O
detection	O
.	O

In	O
Kenya	O
and	O
Negros	O
(	O
Philippines	O
)	O
,	O
clusters	O
were	O
randomly	O
selected	O
through	O
probability	O
proportionate	O
to	O
size	O
using	O
the	O
same	O
cluster	O
sampling	O
procedure	O
after	O
completion	O
of	O
the	O
population	O
-	O
based	O
survey	O
.	O

Clusters	O
were	O
visited	O
in	O
advance	O
and	O
asked	O
that	O
all	O
people	B
>	O
=	O
50	O
y	O
with	O
vision	O
problems	O
come	O
to	O
a	O
central	O
point	O
on	O
a	O
specified	O
day	O
,	O
and	O
that	O
a	O
list	O
be	O
made	O
of	O
people	B
unable	O
to	O
attend	O
(	O
e	O
.	O
g	O
.	O
,	O
due	O
to	O
blindness	O
or	O
other	O
physical	O
disability	O
)	O
.	O

After	O
examining	O
patients	B
at	O
the	O
central	O
point	O
,	O
the	O
survey	O
team	O
then	O
visited	O
those	O
unable	O
to	O
leave	O
their	O
houses	O
.	O

Any	O
identified	O
eligible	O
cases	O
that	O
agreed	O
to	O
be	O
part	O
of	O
the	O
study	O
were	O
interviewed	O
in	O
their	O
homes	O
.	O

In	O
Bangladesh	O
and	O
Antique	O
(	O
Philippines	O
)	O
,	O
community	O
case	O
detection	O
was	O
carried	O
out	O
simultaneously	O
with	O
the	O
survey	O
by	O
two	O
of	O
the	O
four	O
teams	O
,	O
so	O
that	O
controls	O
were	O
included	O
for	O
these	O
cases	O
.	O

Within	O
each	O
cluster	O
from	O
the	O
survey	O
,	O
one	O
interviewer	O
was	O
asked	O
to	O
be	O
taken	O
to	O
two	O
community	O
members	O
aged	O
>	O
=	O
50	O
y	O
with	O
eye	O
problems	O
,	O
living	O
within	O
the	O
cluster	O
boundaries	O
but	O
not	O
from	O
the	O
segments	O
selected	O
for	O
the	O
survey	O
.	O

If	O
VA	O
was	O
<	O
6	O
/	O
24	O
with	O
pinhole	O
in	O
the	O
better	O
eye	O
,	O
the	O
ophthalmologist	O
was	O
called	O
to	O
carry	O
out	O
the	O
full	O
eye	O
examination	O
,	O
and	O
eligible	O
cases	O
were	O
included	O
in	O
the	O
study	O
.	O

For	O
the	O
purposes	O
of	O
the	O
present	O
analyses	O
,	O
control	O
individuals	O
with	O
any	O
visual	O
impairment	O
(	O
VA	O
<	O
6	O
/	O
18	O
in	O
the	O
better	O
eye	O
)	O
were	O
excluded	O
(	O
n	O
=	O
14	O
in	O
Kenya	O
,	O
n	O
=	O
53	O
in	O
Bangladesh	O
,	O
n	O
=	O
24	O
in	O
the	O
Philippines	O
)	O
.	O

Case	O
and	O
control	O
participants	B
who	O
were	O
significantly	O
communication	O
impaired	O
(	O
e	O
.	O
g	O
.	O
deafness	O
,	O
dementia	O
,	O
or	O
psychiatric	O
disease	O
)	O
were	O
excluded	O
(	O
fewer	O
than	O
five	O
per	O
country	O
)	O
,	O
and	O
one	O
case	O
was	O
excluded	O
in	O
the	O
Philippines	O
because	O
of	O
missing	O
age	O
data	O
.	O

One	O
household	O
had	O
two	O
eligible	O
cases	O
(	O
Kenya	O
)	O
,	O
and	O
one	O
of	O
these	O
participants	B
was	O
excluded	O
for	O
the	O
poverty	O
analyses	O
as	O
poverty	O
was	O
assessed	O
through	O
household	O
level	O
indicators	O
(	O
see	O
below	O
)	O
.	O

In	O
total	O
,	O
147	O
cases	O
(	O
82	O
from	O
the	O
survey	O
and	O
65	O
from	O
case	O
detection	O
)	O
and	O
79	O
controls	O
were	O
included	O
in	O
Kenya	O
;	O
217	O
cases	O
(	O
162	O
from	O
survey	O
and	O
55	O
from	O
case	O
detection	O
)	O
and	O
280	O
controls	O
in	O
Bangladesh	O
;	O
and	O
238	O
cases	O
(	O
146	O
survey	O
and	O
92	O
case	O
detection	O
)	O
and	O
180	O
controls	O
in	O
the	O
Philippines	O
.	O

Data	O
Collection	O

All	O
case	O
and	O
control	O
participants	B
were	O
interviewed	O
in	O
their	O
homes	O
by	O
trained	O
interviewers	O
in	O
the	O
local	O
language	O
.	O

Each	O
interview	O
lasted	O
approximately	O
1	O
h	O
.	O

Measures	O
of	O
poverty	O
.	O

Poverty	O
was	O
measured	O
through	O
(	O
a	O
)	O
monthly	O
per	O
capita	O
expenditure	O
(	O
PCE	O
)	O
to	O
indicate	O
consumption	O
,	O
(	O
b	O
)	O
asset	O
ownership	O
,	O
and	O
(	O
c	O
)	O
self	O
-	O
rated	O
wealth	O
.	O

The	O
economic	O
part	O
of	O
the	O
questionnaires	O
was	O
adapted	O
through	O
interviews	O
,	O
focus	O
group	O
discussions	O
,	O
and	O
pilot	O
testing	O
in	O
each	O
country	O
to	O
ensure	O
local	O
relevance	O
.	O

The	O
person	B
primarily	O
responsible	O
for	O
household	O
finances	O
(	O
which	O
may	O
have	O
been	O
the	O
case	O
/	O
control	O
or	O
another	O
household	O
member	O
)	O
was	O
interviewed	O
to	O
assess	O
PCE	O
and	O
assets	O
.	O

PCE	O
was	O
measured	O
using	O
methods	O
based	O
on	O
the	O
World	O
Bank	O
'	O
s	O
Living	O
Standards	O
Measurement	O
Study	O
[	O
15	O
]	O
.	O

Items	O
were	O
included	O
on	O
food	O
(	O
42	O
-	O
52	O
items	O
per	O
country	O
)	O
,	O
education	O
(	O
three	O
items	O
)	O
,	O
health	O
(	O
five	O
items	O
)	O
,	O
household	O
expenses	O
(	O
nine	O
items	O
)	O
,	O
and	O
personal	O
expenses	O
(	O
21	O
or	O
22	O
items	O
)	O
.	O

In	O
total	O
,	O
85	O
items	O
were	O
included	O
in	O
the	O
questionnaire	O
in	O
Kenya	O
,	O
90	O
in	O
the	O
Philippines	O
,	O
and	O
79	O
in	O
Bangladesh	O
.	O

The	O
informant	O
was	O
asked	O
to	O
recall	O
the	O
monetary	O
value	O
of	O
food	O
that	O
was	O
purchased	O
,	O
consumed	O
from	O
home	O
production	O
,	O
or	O
received	O
as	O
payment	O
in	O
kind	O
or	O
as	O
gifts	O
.	O

Consumption	O
was	O
assessed	O
over	O
a	O
1	O
-	O
wk	O
period	O
for	O
frequently	O
consumed	O
items	O
,	O
and	O
this	O
was	O
scaled	O
up	O
to	O
estimate	O
monthly	O
consumption	O
.	O

The	O
amount	O
consumed	O
monthly	O
was	O
assessed	O
for	O
items	O
that	O
were	O
consumed	O
more	O
rarely	O
.	O

Monthly	O
rent	O
was	O
recorded	O
among	O
households	O
who	O
rented	O
,	O
and	O
households	O
who	O
owned	O
their	O
property	O
were	O
asked	O
to	O
estimate	O
the	O
amount	O
that	O
they	O
could	O
charge	O
in	O
rent	O
per	O
month	O
.	O

The	O
consumption	O
on	O
all	O
items	O
was	O
summed	O
to	O
calculate	O
total	O
monthly	O
household	O
consumption	O
,	O
and	O
this	O
was	O
converted	O
to	O
United	O
States	O
dollars	O
(	O
US	O
$	O
)	O
at	O
the	O
2005	O
exchange	O
rate	O
(	O
$	O
1	O
=	O
76	O
Kenya	O
shillings	O
,	O
64	O
Bangladesh	O
taka	O
,	O
55	O
Philippine	O
pesos	O
)	O
.	O

Total	O
monthly	O
household	O
consumption	O
was	O
divided	O
by	O
the	O
number	O
of	O
household	O
members	O
to	O
calculate	O
monthly	O
PCE	O
for	O
the	O
household	O
.	O

The	O
household	O
informant	O
was	O
also	O
asked	O
about	O
the	O
number	O
and	O
type	O
of	O
context	O
-	O
specific	O
assets	O
owned	O
by	O
the	O
household	O
,	O
including	O
different	O
types	O
of	O
furniture	O
,	O
electrical	O
equipment	O
,	O
cattle	B
,	O
and	O
vehicles	O
.	O

Information	O
was	O
collected	O
on	O
household	O
characteristics	O
,	O
including	O
the	O
building	O
material	O
of	O
the	O
floor	O
,	O
roof	O
,	O
and	O
walls	O
;	O
type	O
of	O
toilet	O
;	O
and	O
the	O
number	O
of	O
rooms	O
.	O

Self	O
-	O
rated	O
wealth	O
was	O
assessed	O
by	O
asking	O
the	O
household	O
informant	O
to	O
rank	O
the	O
household	O
'	O
s	O
wealth	O
relative	O
to	O
others	O
in	O
the	O
community	O
on	O
a	O
scale	O
from	O
1	O
(	O
poorest	O
)	O
to	O
10	O
(	O
richest	O
)	O
.	O

Covariates	O
.	O

Case	O
and	O
control	O
individuals	O
were	O
interviewed	O
about	O
standard	O
sociodemographic	O
indicators	O
,	O
including	O
household	O
composition	O
,	O
education	O
,	O
and	O
employment	O
.	O

Information	O
was	O
collected	O
on	O
vision	O
-	O
related	O
quality	O
of	O
life	O
using	O
the	O
World	O
Health	O
Organization	O
Prevention	O
of	O
Blindness	O
and	O
Deafness	O
20	O
-	O
item	O
Visual	O
Functioning	O
Questionnaire	O
[	O
16	O
,	O
17	O
]	O
,	O
and	O
health	O
-	O
related	O
quality	O
of	O
life	O
was	O
assessed	O
using	O
items	O
from	O
the	O
European	O
Quality	O
of	O
Life	O
Questionnaire	O
[	O
18	O
]	O
.	O

Detailed	O
time	O
-	O
use	O
data	O
were	O
collected	O
using	O
methods	O
based	O
on	O
the	O
World	O
Bank	O
'	O
s	O
Living	O
Standards	O
Measurement	O
Study	O
[	O
15	O
]	O
.	O

Training	O
and	O
Fieldwork	O

Interviewers	O
were	O
trained	O
for	O
1	O
wk	O
,	O
including	O
2	O
d	O
of	O
pilot	O
testing	O
.	O

Attempts	O
were	O
made	O
to	O
minimise	O
measurement	O
bias	O
by	O
emphasising	O
the	O
need	O
for	O
consistency	O
in	O
data	O
collection	O
among	O
cases	O
and	O
controls	O
.	O

The	O
questionnaires	O
were	O
translated	O
into	O
the	O
local	O
languages	O
(	O
three	O
in	O
Kenya	O
,	O
three	O
in	O
the	O
Philippines	O
,	O
and	O
one	O
in	O
Bangladesh	O
)	O
and	O
back	O
-	O
translated	O
by	O
independent	O
translators	O
(	O
one	O
for	O
each	O
language	O
)	O
who	O
were	O
also	O
asked	O
to	O
comment	O
on	O
appropriateness	O
of	O
language	O
used	O
for	O
the	O
target	O
population	O
.	O

A	O
review	O
was	O
held	O
to	O
discuss	O
differences	O
in	O
translation	O
and	O
modify	O
accordingly	O
.	O

The	O
questionnaire	O
was	O
piloted	O
in	O
each	O
setting	O
and	O
small	O
modifications	O
to	O
wording	O
of	O
some	O
items	O
were	O
made	O
,	O
where	O
appropriate	O
,	O
to	O
ensure	O
local	O
understanding	O
.	O

Teams	O
were	O
accompanied	O
by	O
a	O
field	O
supervisor	O
at	O
least	O
1	O
d	O
per	O
wk	O
to	O
ensure	O
that	O
high	O
quality	O
was	O
maintained	O
and	O
interviews	O
were	O
observed	O
randomly	O
throughout	O
the	O
study	O
.	O

Statistical	O
Analysis	O

Microsoft	O
Access	O
was	O
used	O
for	O
data	O
entry	O
,	O
and	O
all	O
data	O
were	O
double	O
entered	O
and	O
validated	O
.	O

Analyses	O
were	O
undertaken	O
in	O
SAS	O
version	O
8	O
.	O
2	O
.	O

The	O
mean	O
and	O
range	O
of	O
each	O
expenditure	O
item	O
was	O
calculated	O
to	O
assess	O
whether	O
answers	O
were	O
plausible	O
,	O
and	O
to	O
identify	O
and	O
exclude	O
gross	O
outliers	O
(	O
none	O
identified	O
)	O
.	O

Rental	O
equivalents	O
were	O
imputed	O
based	O
on	O
household	O
characteristics	O
and	O
non	O
-	O
rent	O
expenditure	O
for	O
households	O
where	O
these	O
estimates	O
were	O
missing	O
or	O
unreasonably	O
low	O
(	O
<	O
$	O
1	O
per	O
mo	O
)	O
(	O
four	O
in	O
Kenya	O
,	O
three	O
in	O
Bangladesh	O
,	O
18	O
in	O
the	O
Philippines	O
)	O
.	O

Total	O
monthly	O
household	O
consumption	O
was	O
divided	O
by	O
the	O
number	O
of	O
household	O
members	O
to	O
calculate	O
per	O
capita	O
household	O
expenditure	O
.	O

Per	O
capita	O
household	O
expenditure	O
was	O
divided	O
into	O
quartiles	O
,	O
separately	O
for	O
each	O
country	O
,	O
based	O
on	O
the	O
distribution	O
of	O
the	O
data	O
for	O
the	O
case	O
and	O
control	O
participants	B
combined	O
.	O

Households	O
with	O
incomplete	O
expenditure	O
data	O
were	O
excluded	O
from	O
analyses	O
(	O
five	O
cases	O
and	O
four	O
controls	O
in	O
Kenya	O
;	O
one	O
case	O
and	O
one	O
control	O
in	O
Bangladesh	O
)	O
.	O

A	O
relative	O
index	O
of	O
household	O
assets	O
was	O
derived	O
using	O
principal	O
components	O
analysis	O
(	O
PCA	O
)	O
to	O
determine	O
weights	O
for	O
a	O
list	O
of	O
assets	O
and	O
wealth	O
indicators	O
[	O
19	O
]	O
.	O

Variables	O
entered	O
into	O
the	O
PCA	O
included	O
building	O
materials	O
of	O
the	O
house	O
,	O
ownership	O
of	O
ten	O
household	O
assets	O
,	O
animal	O
ownership	O
,	O
and	O
education	O
of	O
the	O
head	O
of	O
the	O
household	O
.	O

The	O
derived	O
index	O
was	O
divided	O
into	O
quartiles	O
from	O
poorest	O
(	O
lowest	O
socioeconomic	O
status	O
[	O
SES	O
]	O
index	O
)	O
to	O
least	O
poor	O
(	O
highest	O
SES	O
index	O
)	O
.	O

PCA	O
analyses	O
were	O
undertaken	O
separately	O
for	O
each	O
country	O
.	O

The	O
means	O
of	O
the	O
poverty	O
variables	O
were	O
first	O
compared	O
for	O
cases	O
recruited	O
through	O
the	O
two	O
different	O
methods	O
,	O
and	O
then	O
from	O
cases	O
and	O
controls	O
using	O
t	O
-	O
tests	O
for	O
continuous	O
variables	O
(	O
e	O
.	O
g	O
.	O
,	O
PCE	O
and	O
assets	O
)	O
.	O

For	O
categorical	O
variables	O
(	O
e	O
.	O
g	O
.	O
,	O
household	O
rank	O
)	O
we	O
used	O
the	O
Mann	O
-	O
Whitney	O
test	O
and	O
presented	O
medians	O
and	O
interquartile	O
ranges	O
.	O

PCE	O
was	O
highly	O
skewed	O
and	O
therefore	O
was	O
log	O
transformed	O
for	O
the	O
t	O
-	O
tests	O
.	O

The	O
two	O
-	O
way	O
correlations	O
were	O
calculated	O
between	O
PCE	O
,	O
assets	O
,	O
and	O
household	O
rank	O
,	O
in	O
turn	O
.	O

Logistic	O
regression	O
analyses	O
were	O
undertaken	O
separately	O
for	O
each	O
country	O
,	O
assessing	O
the	O
association	O
between	O
case	O
/	O
control	O
status	O
and	O
sociodemographic	O
and	O
poverty	O
variables	O
.	O

Conditional	O
logistic	O
regression	O
was	O
not	O
undertaken	O
,	O
since	O
the	O
matching	O
was	O
incomplete	O
,	O
so	O
all	O
analyses	O
were	O
adjusted	O
for	O
the	O
matching	O
variables	O
(	O
age	O
,	O
sex	O
,	O
and	O
rural	O
/	O
urban	O
location	O
)	O
.	O

Likelihood	O
ratio	O
tests	O
were	O
undertaken	O
to	O
assess	O
the	O
significance	O
of	O
adding	O
covariates	O
with	O
more	O
than	O
two	O
levels	O
(	O
e	O
.	O
g	O
.	O
,	O
age	O
groups	O
,	O
self	O
-	O
rated	O
health	O
groups	O
)	O
to	O
the	O
model	O
.	O

Tests	O
for	O
trend	O
were	O
undertaken	O
across	O
quartiles	O
of	O
the	O
poverty	O
variables	O
and	O
assessed	O
using	O
the	O
p	O
-	O
value	O
for	O
trend	O
.	O

Analyses	O
were	O
also	O
conducted	O
adjusting	O
for	O
the	O
logistic	O
regression	O
analyses	O
for	O
poverty	O
by	O
social	O
support	O
indicators	O
(	O
marital	O
status	O
and	O
household	O
size	O
)	O
and	O
self	O
-	O
rated	O
health	O
,	O
since	O
these	O
variables	O
may	O
confound	O
the	O
association	O
between	O
cataract	O
visual	O
impairment	O
and	O
poverty	O
.	O

Analyses	O
from	O
the	O
Philippines	O
were	O
also	O
adjusted	O
for	O
study	O
site	O
,	O
since	O
data	O
were	O
obtained	O
from	O
two	O
settings	O
(	O
Negros	O
and	O
Antique	O
)	O
.	O

An	O
attempt	O
was	O
made	O
to	O
disentangle	O
the	O
relationship	O
between	O
poverty	O
and	O
cataract	O
by	O
stratifying	O
the	O
analyses	O
by	O
age	O
,	O
sex	O
,	O
and	O
level	O
of	O
visual	O
impairment	O
among	O
the	O
cases	O
.	O

Ethical	O
Approval	O

Informed	O
signed	O
or	O
thumb	O
-	O
printed	O
consent	O
was	O
obtained	O
from	O
all	O
cases	O
and	O
controls	O
.	O

In	O
Kenya	O
and	O
Bangladesh	O
all	O
cases	O
were	O
offered	O
free	O
cataract	O
surgery	O
at	O
the	O
local	O
hospital	O
,	O
with	O
free	O
transport	O
.	O

In	O
the	O
Philippines	O
,	O
patients	B
were	O
referred	O
for	O
surgery	O
,	O
which	O
was	O
subsidised	O
for	O
patients	B
who	O
could	O
not	O
afford	O
the	O
fee	O
.	O

Ethical	O
approval	O
for	O
this	O
study	O
was	O
obtained	O
from	O
the	O
ethics	O
committees	O
of	O
the	O
London	O
School	O
of	O
Hygiene	O
&	O
Tropical	O
Medicine	O
,	O
the	O
Kenya	O
Medical	O
Research	O
Institute	O
,	O
the	O
Bangladesh	O
Medical	O
Research	O
Council	O
,	O
and	O
the	O
University	O
of	O
St	O
.	O

La	O
Salle	O
,	O
Bacolod	O
,	O
Philippines	O
.	O

This	O
study	O
complied	O
with	O
the	O
guidelines	O
of	O
the	O
Declaration	O
of	O
Helsinki	O
.	O

Results	O

Sociodemographic	O
Characteristics	O
of	O
Cases	O
and	O
Controls	O

Case	O
and	O
control	O
participants	B
were	O
matched	O
reasonably	O
closely	O
by	O
sex	O
and	O
location	O
.	O

However	O
,	O
within	O
the	O
age	O
category	O
>	O
=	O
70	O
y	O
,	O
cases	O
tended	O
to	O
be	O
older	O
than	O
the	O
controls	O
,	O
so	O
that	O
cases	O
were	O
over	O
-	O
represented	O
in	O
the	O
oldest	O
age	O
groups	O
(	O
75	O
-	O
79	O
and	O
>	O
=	O
80	O
y	O
)	O
compared	O
to	O
controls	O
(	O
Table	O
1	O
)	O
.	O

Cases	O
were	O
less	O
likely	O
to	O
be	O
married	O
than	O
controls	O
,	O
in	O
Kenya	O
(	O
OR	O
0	O
.	O
6	O
,	O
95	O
%	O
CI	O
0	O
.	O
3	O
-	O
1	O
.	O
1	O
)	O
,	O
Bangladesh	O
(	O
0	O
.	O
6	O
,	O
0	O
.	O
4	O
-	O
1	O
.	O
0	O
)	O
,	O
and	O
the	O
Philippines	O
(	O
0	O
.	O
7	O
,	O
0	O
.	O
4	O
-	O
1	O
.	O
0	O
)	O
,	O
although	O
this	O
only	O
reached	O
statistical	O
significance	O
in	O
Bangladesh	O
(	O
p	O
=	O
0	O
.	O
03	O
)	O
.	O

There	O
was	O
a	O
strong	O
protective	O
effect	O
of	O
literacy	O
and	O
education	O
on	O
cataract	O
in	O
Bangladesh	O
and	O
Kenya	O
that	O
was	O
not	O
evident	O
in	O
the	O
Philippines	O
.	O

Cases	O
were	O
substantially	O
less	O
likely	O
to	O
have	O
a	O
job	O
other	O
than	O
working	O
in	O
the	O
field	O
compared	O
to	O
controls	O
in	O
all	O
three	O
countries	O
.	O

Cases	O
reported	O
significantly	O
poorer	O
self	O
-	O
rated	O
health	O
than	O
controls	O
-	O
-	O
this	O
pattern	O
was	O
particularly	O
evident	O
in	O
the	O
Philippines	O
(	O
OR	O
for	O
lowest	O
versus	O
highest	O
quartile	O
of	O
self	O
-	O
rated	O
health	O
=	O
5	O
.	O
7	O
,	O
95	O
%	O
CI	O
3	O
.	O
0	O
-	O
10	O
.	O
7	O
)	O
but	O
also	O
apparent	O
in	O
Kenya	O
(	O
2	O
.	O
6	O
,	O
1	O
.	O
1	O
-	O
6	O
.	O
2	O
)	O
and	O
Bangladesh	O
(	O
3	O
.	O
3	O
,	O
2	O
.	O
1	O
-	O
5	O
.	O
3	O
)	O
.	O

Summary	O
Wealth	O
Measures	O

All	O
three	O
settings	O
were	O
poor	O
.	O

The	O
mean	O
PCE	O
was	O
less	O
than	O
US	O
$	O
1	O
per	O
person	B
per	O
day	O
in	O
all	O
three	O
settings	O
:	O
US	O
$	O
26	O
.	O
4	O
(	O
standard	O
deviation	O
[	O
SD	O
]	O
=	O
US	O
$	O
34	O
.	O
9	O
)	O
in	O
Kenya	O
,	O
US	O
$	O
21	O
.	O
7	O
(	O
US	O
$	O
48	O
.	O
0	O
)	O
in	O
Bangladesh	O
and	O
US	O
$	O
26	O
.	O
1	O
(	O
US	O
$	O
23	O
.	O
5	O
)	O
in	O
the	O
Philippines	O
.	O

The	O
biggest	O
expense	O
was	O
food	O
in	O
all	O
three	O
settings	O
,	O
making	O
up	O
55	O
%	O
of	O
PCE	O
in	O
Kenya	O
,	O
47	O
%	O
in	O
Bangladesh	O
,	O
and	O
64	O
%	O
in	O
the	O
Philippines	O
,	O
followed	O
by	O
household	O
expenses	O
including	O
rent	O
(	O
21	O
%	O
in	O
Kenya	O
,	O
28	O
%	O
Bangladesh	O
,	O
and	O
22	O
%	O
Philippines	O
)	O
(	O
Figure	O
1	O
)	O
.	O

The	O
majority	O
of	O
food	O
consumption	O
was	O
from	O
direct	O
purchase	O
(	O
70	O
%	O
in	O
Kenya	O
,	O
75	O
%	O
in	O
Bangladesh	O
,	O
and	O
77	O
%	O
in	O
the	O
Philippines	O
)	O
or	O
home	O
-	O
grown	O
production	O
(	O
24	O
%	O
in	O
Kenya	O
,	O
22	O
%	O
in	O
Bangladesh	O
,	O
and	O
17	O
%	O
in	O
the	O
Philippines	O
)	O
,	O
and	O
little	O
was	O
from	O
gifts	O
or	O
payments	O
.	O

An	O
asset	O
score	O
was	O
created	O
through	O
PCA	O
in	O
the	O
three	O
settings	O
.	O

The	O
first	O
principal	O
component	O
explained	O
22	O
%	O
of	O
the	O
variability	O
in	O
asset	O
variables	O
in	O
Kenya	O
,	O
25	O
%	O
in	O
Bangladesh	O
,	O
and	O
24	O
%	O
in	O
the	O
Philippines	O
.	O

Self	O
-	O
perceived	O
wealth	O
of	O
the	O
household	O
clustered	O
around	O
the	O
average	O
with	O
a	O
large	O
proportion	O
of	O
households	O
in	O
Kenya	O
(	O
48	O
%	O
)	O
,	O
Bangladesh	O
(	O
43	O
%	O
)	O
,	O
and	O
the	O
Philippines	O
(	O
64	O
%	O
)	O
;	O
households	O
stating	O
that	O
they	O
were	O
ranked	O
between	O
4	O
and	O
6	O
,	O
on	O
a	O
scale	O
from	O
1	O
to	O
10	O
,	O
in	O
terms	O
of	O
wealth	O
in	O
their	O
community	O
.	O

The	O
three	O
measures	O
of	O
poverty	O
were	O
highly	O
correlated	O
,	O
each	O
showing	O
significant	O
correlation	O
(	O
p	O
<	O
0	O
.	O
001	O
)	O
with	O
the	O
other	O
measure	O
.	O

Economic	O
and	O
Household	O
Characteristics	O
of	O
Cases	O
and	O
Controls	O

There	O
were	O
no	O
significant	O
differences	O
in	O
PCE	O
,	O
assets	O
,	O
or	O
household	O
rank	O
between	O
cases	O
recruited	O
through	O
the	O
population	O
-	O
based	O
survey	O
and	O
those	O
recruited	O
through	O
case	O
detection	O
,	O
with	O
the	O
exception	O
that	O
the	O
case	O
-	O
detection	O
cases	O
had	O
lower	O
household	O
rank	O
in	O
Kenya	O
(	O
mean	O
=	O
3	O
.	O
7	O
versus	O
3	O
.	O
1	O
,	O
p	O
=	O
0	O
.	O
02	O
)	O
.	O

Consequently	O
,	O
cases	O
recruited	O
through	O
the	O
two	O
methods	O
were	O
combined	O
in	O
the	O
subsequent	O
analyses	O
.	O

Cases	O
were	O
poorer	O
than	O
controls	O
,	O
in	O
all	O
three	O
settings	O
according	O
to	O
all	O
three	O
poverty	O
measurements	O
(	O
Table	O
2	O
)	O
.	O

The	O
mean	O
PCE	O
was	O
20	O
%	O
-	O
28	O
%	O
lower	O
for	O
members	O
of	O
households	O
with	O
a	O
case	O
than	O
for	O
control	O
households	O
,	O
and	O
this	O
difference	O
was	O
highly	O
significant	O
in	O
Bangladesh	O
and	O
the	O
Philippines	O
;	O
for	O
Kenya	O
it	O
was	O
lower	O
but	O
did	O
not	O
reach	O
significance	O
(	O
p	O
=	O
0	O
.	O
07	O
)	O
.	O

The	O
PCA	O
score	O
for	O
assets	O
was	O
significantly	O
lower	O
among	O
cases	O
than	O
controls	O
in	O
Kenya	O
and	O
Bangladesh	O
,	O
and	O
it	O
was	O
lower	O
in	O
the	O
Philippines	O
although	O
it	O
did	O
not	O
reach	O
significance	O
(	O
p	O
=	O
0	O
.	O
06	O
)	O
.	O

Self	O
-	O
perceived	O
wealth	O
was	O
significantly	O
lower	O
for	O
households	O
with	O
a	O
case	O
compared	O
to	O
control	O
households	O
in	O
Kenya	O
(	O
3	O
.	O
4	O
versus	O
4	O
.	O
5	O
)	O
and	O
Bangladesh	O
(	O
3	O
.	O
9	O
versus	O
4	O
.	O
6	O
)	O
,	O
though	O
not	O
in	O
the	O
Philippines	O
(	O
4	O
.	O
1	O
versus	O
4	O
.	O
3	O
)	O
.	O

There	O
was	O
no	O
difference	O
in	O
the	O
size	O
of	O
the	O
households	O
of	O
cases	O
and	O
controls	O
in	O
any	O
of	O
the	O
three	O
settings	O
.	O

The	O
ratio	O
of	O
dependents	O
(	O
i	O
.	O
e	O
.	O
,	O
household	O
member	O
aged	O
<	O
15	O
or	O
>	O
=	O
50	O
y	O
)	O
to	O
independents	O
(	O
i	O
.	O
e	O
.	O
,	O
household	O
member	O
aged	O
15	O
-	O
50	O
y	O
)	O
was	O
similar	O
between	O
cases	O
and	O
controls	O
in	O
Bangladesh	O
(	O
1	O
.	O
4	O
versus	O
1	O
.	O
4	O
)	O
,	O
but	O
the	O
dependency	O
ratio	O
was	O
higher	O
for	O
controls	O
than	O
cases	O
in	O
Kenya	O
(	O
2	O
.	O
1	O
versus	O
1	O
.	O
6	O
)	O
and	O
the	O
Philippines	O
(	O
1	O
.	O
7	O
versus	O
1	O
.	O
3	O
)	O
,	O
due	O
to	O
the	O
smaller	O
number	O
of	O
people	B
of	O
working	O
age	O
.	O

Patterns	O
of	O
Expenditure	O
in	O
Cases	O
and	O
Controls	O

Figure	O
1	O
shows	O
the	O
total	O
PCE	O
and	O
the	O
allocation	O
of	O
expenditure	O
within	O
quartiles	O
of	O
PCE	O
for	O
cases	O
and	O
controls	O
.	O

Monthly	O
PCE	O
was	O
similar	O
for	O
cases	O
and	O
controls	O
within	O
each	O
of	O
the	O
quartiles	O
of	O
expenditure	O
.	O

There	O
was	O
a	O
gradual	O
increase	O
in	O
PCE	O
between	O
the	O
first	O
three	O
quartiles	O
,	O
and	O
then	O
a	O
rapid	O
increase	O
between	O
the	O
third	O
and	O
the	O
richest	O
quartile	O
.	O

Within	O
the	O
first	O
three	O
quartiles	O
of	O
PCE	O
the	O
majority	O
of	O
expenditure	O
was	O
on	O
food	O
.	O

Substantial	O
expenditure	O
on	O
non	O
-	O
food	O
items	O
was	O
observed	O
only	O
in	O
the	O
highest	O
quartile	O
of	O
expenditure	O
,	O
where	O
about	O
half	O
of	O
expenditure	O
was	O
on	O
non	O
-	O
food	O
items	O
.	O

Similar	O
patterns	O
of	O
PCE	O
were	O
observed	O
for	O
cases	O
and	O
controls	O
in	O
Kenya	O
,	O
Bangladesh	O
,	O
and	O
the	O
Philippines	O
within	O
each	O
quartile	O
of	O
expenditure	O
.	O

These	O
results	O
demonstrate	O
that	O
cataract	O
visual	O
impairment	O
was	O
related	O
to	O
reduced	O
PCE	O
,	O
but	O
not	O
allocation	O
of	O
expenditure	O
.	O

Multivariate	O
Analyses	O
of	O
Poverty	O
and	O
Cataract	O
Visual	O
Impairment	O

Multivariate	O
analyses	O
showed	O
that	O
case	O
participants	B
were	O
consistently	O
poorer	O
than	O
controls	O
in	O
Kenya	O
,	O
Bangladesh	O
,	O
and	O
the	O
Philippines	O
,	O
using	O
three	O
different	O
measures	O
of	O
poverty	O
(	O
Table	O
3	O
)	O
.	O

Cases	O
were	O
more	O
likely	O
than	O
controls	O
to	O
be	O
in	O
the	O
lowest	O
quartile	O
of	O
PCE	O
rather	O
than	O
the	O
highest	O
quartile	O
in	O
Kenya	O
(	O
OR	O
2	O
.	O
3	O
,	O
95	O
%	O
CI	O
0	O
.	O
9	O
-	O
5	O
.	O
5	O
)	O
,	O
Bangladesh	O
(	O
1	O
.	O
9	O
,	O
1	O
.	O
1	O
-	O
3	O
.	O
2	O
)	O
and	O
the	O
Philippines	O
(	O
3	O
.	O
1	O
,	O
1	O
.	O
7	O
-	O
5	O
.	O
7	O
)	O
.	O

In	O
all	O
three	O
settings	O
these	O
associations	O
showed	O
significant	O
dose	O
-	O
response	O
as	O
assessed	O
by	O
the	O
p	O
-	O
value	O
for	O
trend	O
across	O
the	O
quartiles	O
,	O
with	O
decreasing	O
PCE	O
related	O
to	O
case	O
status	O
and	O
these	O
relationships	O
persisted	O
after	O
adjustment	O
for	O
self	O
-	O
rated	O
health	O
and	O
social	O
support	O
indicators	O
.	O

A	O
similar	O
pattern	O
was	O
observed	O
for	O
the	O
relationship	O
between	O
case	O
-	O
control	O
status	O
and	O
asset	O
ownership	O
.	O

Cases	O
were	O
significantly	O
more	O
likely	O
to	O
be	O
in	O
the	O
lowest	O
quartile	O
of	O
asset	O
ownership	O
rather	O
than	O
the	O
highest	O
quartile	O
compared	O
to	O
controls	O
in	O
Kenya	O
(	O
3	O
.	O
7	O
,	O
1	O
.	O
4	O
-	O
9	O
.	O
6	O
)	O
,	O
Bangladesh	O
(	O
2	O
.	O
6	O
,	O
1	O
.	O
5	O
-	O
4	O
.	O
4	O
)	O
,	O
and	O
the	O
Philippines	O
(	O
2	O
.	O
1	O
,	O
1	O
.	O
1	O
-	O
3	O
.	O
8	O
)	O
.	O

Cases	O
were	O
also	O
significantly	O
more	O
likely	O
to	O
be	O
in	O
the	O
lowest	O
quartile	O
of	O
household	O
rank	O
rather	O
than	O
the	O
highest	O
,	O
compared	O
to	O
controls	O
in	O
Kenya	O
(	O
3	O
.	O
5	O
,	O
1	O
.	O
5	O
-	O
8	O
.	O
0	O
)	O
,	O
Bangladesh	O
(	O
2	O
.	O
7	O
,	O
1	O
.	O
6	O
-	O
4	O
.	O
7	O
)	O
and	O
the	O
Philippines	O
(	O
2	O
.	O
3	O
,	O
1	O
.	O
1	O
-	O
4	O
.	O
8	O
)	O
.	O

The	O
associations	O
with	O
assets	O
and	O
household	O
rank	O
also	O
showed	O
a	O
significant	O
dose	O
-	O
response	O
relationship	O
,	O
and	O
the	O
associations	O
were	O
largely	O
unchanged	O
after	O
adjustment	O
for	O
self	O
-	O
rated	O
health	O
and	O
social	O
support	O
indicators	O
.	O

In	O
Kenya	O
and	O
Bangladesh	O
the	O
relationship	O
between	O
PCE	O
and	O
case	O
status	O
was	O
somewhat	O
weaker	O
than	O
for	O
the	O
other	O
measures	O
of	O
poverty	O
,	O
while	O
the	O
reverse	O
was	O
true	O
in	O
the	O
Philippines	O
.	O

Stratifying	O
the	O
association	O
between	O
PCE	O
and	O
cataract	O
visual	O
impairment	O
by	O
level	O
of	O
visual	O
impairment	O
showed	O
an	O
inconsistent	O
pattern	O
(	O
Table	O
4	O
)	O
.	O

In	O
Kenya	O
,	O
the	O
association	O
with	O
low	O
PCE	O
was	O
somewhat	O
stronger	O
comparing	O
cataract	O
blind	O
cases	O
to	O
controls	O
(	O
OR	O
3	O
.	O
1	O
,	O
95	O
%	O
CI	O
0	O
.	O
9	O
-	O
10	O
.	O
8	O
)	O
than	O
comparing	O
moderate	O
visually	O
impaired	O
cases	O
to	O
controls	O
(	O
1	O
.	O
8	O
,	O
0	O
.	O
6	O
-	O
5	O
.	O
4	O
)	O
,	O
while	O
this	O
pattern	O
was	O
reversed	O
in	O
Bangladesh	O
(	O
blind	O
cases	O
versus	O
controls	O
:	O
1	O
.	O
8	O
,	O
1	O
.	O
0	O
-	O
3	O
.	O
4	O
;	O
moderately	O
visually	O
impaired	O
cases	O
versus	O
controls	O
:	O
3	O
.	O
1	O
,	O
1	O
.	O
3	O
-	O
7	O
.	O
2	O
)	O
.	O

In	O
the	O
Philippines	O
the	O
association	O
with	O
low	O
PCE	O
was	O
strongest	O
comparing	O
severely	O
visually	O
impaired	O
cases	O
to	O
controls	O
(	O
5	O
.	O
9	O
,	O
2	O
.	O
0	O
-	O
17	O
.	O
6	O
)	O
.	O

The	O
association	O
between	O
cataract	O
visual	O
impairment	O
and	O
PCE	O
was	O
stronger	O
among	O
men	B
than	O
women	B
in	O
Bangladesh	O
and	O
the	O
Philippines	O
,	O
while	O
the	O
reverse	O
was	O
true	O
in	O
Kenya	O
(	O
Table	O
5	O
)	O
.	O

In	O
Kenya	O
and	O
the	O
Philippines	O
the	O
strongest	O
association	O
between	O
cataract	O
and	O
PCE	O
was	O
among	O
people	B
aged	O
70	O
-	O
79	O
y	O
,	O
while	O
in	O
Bangladesh	O
the	O
strongest	O
effect	O
was	O
in	O
people	B
aged	O
over	O
80	O
y	O
.	O

Stratifying	O
the	O
association	O
between	O
assets	O
and	O
household	O
rank	O
with	O
cataract	O
by	O
level	O
of	O
visual	O
impairment	O
,	O
sex	O
,	O
or	O
age	O
broadly	O
repeated	O
these	O
findings	O
,	O
and	O
generally	O
supported	O
the	O
lack	O
of	O
consistent	O
pattern	O
(	O
unpublished	O
data	O
)	O
.	O

Discussion	O

This	O
large	O
,	O
multicentre	O
population	O
-	O
based	O
case	O
-	O
control	O
study	O
provides	O
evidence	O
that	O
people	B
with	O
visual	O
impairment	O
from	O
cataract	O
are	O
poorer	O
than	O
control	O
participants	B
with	O
normal	O
vision	O
matched	O
for	O
age	O
and	O
sex	O
.	O

This	O
pattern	O
was	O
evident	O
whether	O
poverty	O
was	O
measured	O
in	O
terms	O
of	O
PCE	O
,	O
assets	O
,	O
or	O
self	O
-	O
rated	O
wealth	O
.	O

Marital	O
status	O
seemed	O
to	O
be	O
protective	O
for	O
cataract	O
visual	O
impairment	O
,	O
possibly	O
indicating	O
the	O
role	O
of	O
social	O
support	O
in	O
health	O
-	O
seeking	O
behaviour	O
.	O

Reduced	O
self	O
-	O
rated	O
health	O
was	O
also	O
strongly	O
related	O
to	O
cataract	O
visual	O
impairment	O
.	O

This	O
demonstrates	O
the	O
impact	O
of	O
poor	O
vision	O
on	O
overall	O
assessments	O
of	O
health	O
and	O
supports	O
our	O
previous	O
finding	O
of	O
a	O
relationship	O
between	O
cataract	O
and	O
quality	O
of	O
life	O
[	O
17	O
]	O
.	O

Adjustment	O
for	O
marital	O
status	O
and	O
self	O
-	O
rated	O
health	O
did	O
not	O
entirely	O
explain	O
the	O
association	O
between	O
poverty	O
and	O
cataract	O
visual	O
impairment	O
,	O
suggesting	O
that	O
it	O
operated	O
through	O
other	O
pathways	O
.	O

Visual	O
impairment	O
could	O
cause	O
poverty	O
through	O
reduced	O
employment	O
opportunities	O
.	O

We	O
might	O
therefore	O
expect	O
to	O
see	O
a	O
stronger	O
relationship	O
between	O
cataract	O
and	O
poverty	O
among	O
the	O
blind	O
case	O
participants	B
who	O
may	O
have	O
fewer	O
employment	O
opportunities	O
than	O
among	O
those	O
less	O
impaired	O
(	O
i	O
.	O
e	O
.	O
,	O
moderate	O
visual	O
impairment	O
)	O
.	O

Poverty	O
may	O
also	O
cause	O
visual	O
impairment	O
through	O
restricted	O
access	O
to	O
cataract	O
surgery	O
.	O

In	O
this	O
case	O
we	O
would	O
expect	O
to	O
see	O
a	O
stronger	O
relationship	O
between	O
poverty	O
and	O
less	O
severely	O
affected	O
cases	O
(	O
i	O
.	O
e	O
.	O
,	O
moderate	O
visual	O
impairment	O
)	O
,	O
as	O
poor	O
families	O
may	O
allocate	O
money	O
for	O
surgery	O
on	O
members	O
who	O
are	O
blind	O
from	O
cataract	O
,	O
so	O
that	O
poverty	O
mainly	O
restricts	O
access	O
to	O
surgery	O
among	O
people	B
who	O
are	O
moderately	O
visually	O
impaired	O
.	O

The	O
relationships	O
that	O
we	O
observed	O
between	O
level	O
of	O
visual	O
impairment	O
and	O
cataract	O
were	O
inconsistent	O
across	O
the	O
three	O
settings	O
.	O

Perhaps	O
this	O
shows	O
that	O
both	O
pathways	O
were	O
operating	O
or	O
that	O
the	O
dynamics	O
of	O
the	O
relationship	O
between	O
poverty	O
and	O
blindness	O
vary	O
in	O
different	O
settings	O
.	O

Levels	O
of	O
literacy	O
and	O
education	O
were	O
lower	O
among	O
cases	O
than	O
controls	O
.	O

These	O
long	O
-	O
term	O
indicators	O
of	O
disadvantage	O
are	O
unlikely	O
to	O
have	O
changed	O
after	O
the	O
onset	O
of	O
cataract	O
.	O

This	O
observation	O
provides	O
some	O
evidence	O
that	O
poverty	O
preceded	O
blindness	O
in	O
our	O
study	O
participants	B
.	O

It	O
is	O
frequently	O
asserted	O
that	O
blindness	O
is	O
both	O
a	O
cause	O
and	O
consequence	O
of	O
poverty	O
,	O
but	O
there	O
are	O
few	O
empirical	O
data	O
to	O
support	O
this	O
claim	O
.	O

Globally	O
,	O
the	O
prevalence	O
of	O
blindness	O
is	O
five	O
-	O
fold	O
higher	O
in	O
poor	O
than	O
rich	O
countries	O
[	O
2	O
]	O
,	O
and	O
data	O
from	O
Pakistan	O
and	O
India	O
suggest	O
that	O
within	O
countries	O
the	O
poor	O
are	O
more	O
likely	O
to	O
be	O
blind	O
[	O
3	O
,	O
4	O
]	O
.	O

Some	O
blinding	O
conditions	O
are	O
a	O
direct	O
consequence	O
of	O
poverty	O
,	O
notably	O
trachoma	O
,	O
which	O
thrives	O
in	O
poor	O
areas	O
lacking	O
water	O
and	O
sanitation	O
[	O
20	O
]	O
.	O

Other	O
blinding	O
diseases	O
clearly	O
contribute	O
to	O
poverty	O
,	O
such	O
as	O
onchocerciasis	O
,	O
which	O
results	O
in	O
the	O
abandonment	O
of	O
the	O
fertile	O
areas	O
near	O
to	O
the	O
rivers	O
where	O
the	O
disease	O
vector	O
thrives	O
[	O
9	O
]	O
.	O

A	O
larger	O
literature	O
shows	O
that	O
poor	O
people	B
are	O
more	O
likely	O
to	O
be	O
ill	O
or	O
disabled	O
than	O
their	O
richer	O
compatriots	O
,	O
ranging	O
from	O
general	O
disability	O
in	O
India	O
,	O
Bulgaria	O
,	O
and	O
Ghana	O
[	O
21	O
]	O
;	O
common	O
mental	O
disorders	O
in	O
Brazil	O
,	O
Chile	O
,	O
India	O
,	O
and	O
Zimbabwe	O
[	O
22	O
]	O
;	O
deafness	O
in	O
Brazil	O
[	O
23	O
]	O
;	O
and	O
tuberculosis	O
in	O
China	O
[	O
24	O
]	O
.	O

There	O
are	O
also	O
some	O
exceptions	O
such	O
as	O
a	O
case	O
-	O
control	O
study	O
in	O
Rwanda	O
which	O
failed	O
to	O
show	O
an	O
association	O
between	O
PCE	O
and	O
musculoskeletal	O
impairment	O
,	O
perhaps	O
because	O
the	O
population	O
was	O
almost	O
universally	O
poor	O
[	O
25	O
]	O
.	O

Poverty	O
may	O
increase	O
the	O
incidence	O
of	O
disease	O
,	O
particularly	O
preventable	O
diseases	O
such	O
as	O
tuberculosis	O
.	O

Poverty	O
may	O
also	O
restrict	O
access	O
to	O
appropriate	O
health	O
care	O
and	O
so	O
prolong	O
the	O
duration	O
of	O
disease	O
.	O

A	O
study	O
in	O
rural	O
Tanzania	O
showed	O
that	O
care	O
-	O
seeking	O
behaviour	O
for	O
childhood	O
illness	O
is	O
worse	O
among	O
poorer	O
families	O
than	O
among	O
the	O
relatively	O
rich	O
families	O
[	O
26	O
]	O
.	O

Another	O
Tanzanian	O
study	O
found	O
that	O
people	B
with	O
higher	O
levels	O
of	O
asset	O
ownership	O
were	O
more	O
likely	O
to	O
obtain	O
antimalarials	O
even	O
though	O
they	O
were	O
less	O
likely	O
to	O
be	O
parasitaemic	O
[	O
27	O
]	O
.	O

With	O
respect	O
to	O
cataract	O
,	O
there	O
is	O
little	O
evidence	O
that	O
prevention	O
is	O
possible	O
,	O
and	O
so	O
the	O
main	O
pathway	O
from	O
poverty	O
to	O
blindness	O
is	O
likely	O
to	O
be	O
through	O
reduced	O
access	O
to	O
cataract	O
surgical	O
services	O
.	O

High	O
health	O
care	O
costs	O
may	O
also	O
exacerbate	O
poverty	O
.	O

A	O
study	O
in	O
rural	O
China	O
showed	O
that	O
ill	O
health	O
increases	O
medical	O
expenditure	O
significantly	O
,	O
which	O
detracts	O
from	O
expenditure	O
on	O
food	O
,	O
education	O
,	O
investment	O
in	O
farming	O
,	O
and	O
participation	O
in	O
social	O
activities	O
[	O
28	O
]	O
.	O

Inability	O
to	O
afford	O
cataract	O
surgery	O
is	O
cited	O
as	O
the	O
major	O
barrier	O
to	O
the	O
uptake	O
of	O
surgery	O
in	O
the	O
surveys	O
conducted	O
in	O
Kenya	O
,	O
the	O
Philippines	O
,	O
and	O
Bangladesh	O
[	O
6	O
-	O
8	O
]	O
.	O

This	O
indicates	O
that	O
the	O
cost	O
of	O
surgery	O
is	O
perceived	O
as	O
substantial	O
by	O
many	O
households	O
,	O
notwithstanding	O
the	O
problems	O
of	O
assessing	O
the	O
complex	O
issue	O
of	O
barriers	O
in	O
the	O
absence	O
of	O
in	O
-	O
depth	O
qualitative	O
interviews	O
.	O

Consequently	O
,	O
there	O
are	O
lower	O
rates	O
of	O
cataract	O
surgery	O
among	O
the	O
poor	O
[	O
3	O
]	O
.	O

Poverty	O
may	O
also	O
limit	O
the	O
employment	O
opportunities	O
of	O
the	O
person	B
with	O
disability	O
or	O
their	O
household	O
members	O
.	O

This	O
pattern	O
has	O
been	O
demonstrated	O
for	O
people	B
with	O
HIV	B
in	O
South	O
Africa	O
[	O
29	O
]	O
,	O
tuberculosis	O
in	O
China	O
[	O
24	O
]	O
,	O
or	O
disability	O
in	O
Sri	O
Lanka	O
[	O
22	O
]	O
.	O

An	O
impact	O
of	O
blindness	O
on	O
reduced	O
employment	O
or	O
income	O
has	O
been	O
observed	O
in	O
Guinea	O
[	O
9	O
]	O
and	O
India	O
[	O
4	O
]	O
.	O

A	O
belief	O
that	O
blindness	O
reduces	O
the	O
employment	O
opportunities	O
of	O
household	O
members	O
is	O
widespread	O
,	O
but	O
so	O
far	O
there	O
is	O
limited	O
supportive	O
evidence	O
.	O

There	O
is	O
a	O
further	O
complication	O
to	O
investigations	O
of	O
the	O
relationship	O
between	O
cataract	O
and	O
poverty	O
,	O
as	O
the	O
individuals	O
with	O
cataract	O
are	O
likely	O
to	O
be	O
elderly	O
and	O
facing	O
multiple	O
disabilities	O
.	O

Our	O
study	O
took	O
account	O
of	O
the	O
potential	O
impact	O
of	O
multiple	O
disabilities	O
,	O
as	O
we	O
adjusted	O
for	O
self	O
-	O
rated	O
health	O
,	O
which	O
is	O
closely	O
related	O
to	O
overall	O
health	O
,	O
and	O
this	O
adjustment	O
had	O
no	O
overall	O
impact	O
on	O
our	O
results	O
[	O
30	O
]	O
.	O

Study	O
Strengths	O

This	O
was	O
a	O
large	O
population	O
-	O
based	O
case	O
-	O
control	O
study	O
,	O
conducted	O
in	O
three	O
countries	O
,	O
allowing	O
international	O
comparisons	O
.	O

This	O
was	O
the	O
first	O
study	O
,	O
to	O
our	O
knowledge	O
,	O
to	O
relate	O
PCE	O
to	O
visual	O
impairment	O
.	O

We	O
also	O
measured	O
assets	O
,	O
which	O
reflects	O
long	O
-	O
term	O
access	O
to	O
resources	O
,	O
and	O
self	O
-	O
rated	O
wealth	O
.	O

We	O
used	O
expenditure	O
as	O
a	O
proxy	O
for	O
income	O
,	O
which	O
has	O
aided	O
both	O
academic	O
and	O
nonacademic	O
investigations	O
.	O

As	O
one	O
example	O
,	O
the	O
notorious	O
Chicago	O
gangster	O
Al	O
Capone	O
managed	O
to	O
escape	O
prosecution	O
for	O
smuggling	O
,	O
gambling	O
,	O
bootlegging	O
,	O
and	O
murder	O
for	O
years	O
,	O
but	O
was	O
eventually	O
convicted	O
of	O
tax	O
evasion	O
,	O
because	O
the	O
jury	O
was	O
convinced	O
that	O
his	O
exorbitant	O
expenses	O
on	O
clothes	O
,	O
furnishing	O
,	O
foods	O
,	O
and	O
gifts	O
were	O
inconsistent	O
with	O
his	O
claim	O
that	O
he	O
had	O
no	O
income	O
.	O

Expenditure	O
often	O
provides	O
a	O
better	O
measure	O
of	O
poverty	O
than	O
income	O
for	O
a	O
number	O
of	O
reasons	O
.	O

Income	O
may	O
be	O
variable	O
by	O
season	O
,	O
whereas	O
households	O
attempt	O
to	O
smooth	O
expenditure	O
over	O
the	O
year	O
.	O

People	B
are	O
more	O
comfortable	O
sharing	O
information	O
about	O
expenditure	O
than	O
income	O
,	O
and	O
it	O
may	O
be	O
a	O
more	O
meaningful	O
measure	O
than	O
income	O
in	O
an	O
agrarian	O
society	O
as	O
it	O
reflects	O
what	O
the	O
household	O
is	O
able	O
to	O
command	O
based	O
on	O
its	O
current	O
income	O
,	O
borrowing	O
ability	O
,	O
or	O
household	O
savings	O
[	O
31	O
]	O
.	O

PCE	O
also	O
has	O
advantages	O
over	O
assets	O
,	O
as	O
it	O
may	O
be	O
more	O
responsive	O
to	O
change	O
,	O
which	O
will	O
be	O
important	O
for	O
the	O
follow	O
-	O
up	O
analyses	O
of	O
the	O
study	O
participants	B
after	O
they	O
have	O
undergone	O
cataract	O
surgery	O
.	O

Study	O
Limitations	O

There	O
are	O
a	O
number	O
of	O
limitations	O
relating	O
to	O
the	O
measurement	O
of	O
poverty	O
in	O
this	O
study	O
.	O

Our	O
analyses	O
focus	O
on	O
monetary	O
indicators	O
of	O
poverty	O
,	O
while	O
we	O
acknowledge	O
that	O
health	O
,	O
education	O
,	O
and	O
housing	O
are	O
also	O
important	O
.	O

We	O
concede	O
that	O
it	O
is	O
difficult	O
to	O
measure	O
expenditure	O
accurately	O
[	O
32	O
,	O
33	O
]	O
,	O
but	O
this	O
also	O
true	O
for	O
the	O
measurement	O
of	O
diet	O
and	O
other	O
variables	O
,	O
which	O
is	O
standard	O
practise	O
in	O
many	O
epidemiological	O
studies	O
.	O

Furthermore	O
,	O
a	O
large	O
number	O
of	O
items	O
were	O
included	O
in	O
our	O
measure	O
of	O
expenditure	O
so	O
that	O
the	O
measure	O
was	O
comprehensive	O
[	O
33	O
]	O
.	O

Expenditure	O
data	O
were	O
not	O
validated	O
through	O
diaries	O
or	O
other	O
means	O
,	O
although	O
assets	O
and	O
self	O
-	O
rated	O
wealth	O
correlated	O
highly	O
with	O
PCE	O
.	O

Other	O
recent	O
estimates	O
of	O
expenditure	O
are	O
not	O
available	O
from	O
surveys	O
conducted	O
in	O
these	O
countries	O
to	O
allow	O
comparison	O
.	O

The	O
per	O
capita	O
estimates	O
of	O
monthly	O
gross	O
national	O
income	O
from	O
the	O
World	O
Development	O
Indicators	O
database	O
show	O
somewhat	O
higher	O
estimates	O
in	O
Kenya	O
(	O
US	O
$	O
48	O
)	O
and	O
Bangladesh	O
(	O
US	O
$	O
40	O
)	O
than	O
our	O
PCE	O
derived	O
estimates	O
,	O
and	O
far	O
higher	O
estimates	O
for	O
the	O
Philippines	O
(	O
US	O
$	O
108	O
)	O
.	O

This	O
discrepancy	O
may	O
be	O
reasonable	O
,	O
as	O
the	O
World	O
Development	O
Indicators	O
reflect	O
national	O
averages	O
,	O
while	O
we	O
sampled	O
the	O
households	O
with	O
elderly	O
people	B
in	O
poor	O
regions	O
of	O
the	O
country	O
,	O
many	O
of	O
whom	O
were	O
visually	O
impaired	O
from	O
cataract	O
.	O

PCE	O
was	O
calculated	O
simply	O
by	O
dividing	O
the	O
total	O
household	O
expenditure	O
by	O
the	O
number	O
of	O
household	O
members	O
,	O
without	O
inclusion	O
of	O
economies	O
of	O
scale	O
or	O
equivalence	O
scales	O
.	O

There	O
is	O
no	O
widely	O
accepted	O
alternative	O
to	O
the	O
simple	O
equal	O
-	O
sharing	O
convention	O
,	O
and	O
the	O
majority	O
of	O
expenditure	O
was	O
on	O
food	O
which	O
does	O
not	O
allow	O
for	O
economies	O
of	O
scale	O
.	O

Furthermore	O
,	O
there	O
were	O
slightly	O
fewer	O
people	B
of	O
working	O
age	O
in	O
the	O
control	O
households	O
in	O
Kenya	O
and	O
the	O
Philippines	O
,	O
so	O
adjustment	O
for	O
equivalence	O
scores	O
would	O
be	O
unlikely	O
to	O
explain	O
the	O
higher	O
poverty	O
among	O
cases	O
.	O

The	O
case	O
and	O
control	O
households	O
were	O
of	O
similar	O
sizes	O
in	O
the	O
three	O
settings	O
,	O
so	O
economies	O
of	O
scales	O
are	O
unlikely	O
to	O
have	O
explained	O
the	O
differences	O
.	O

There	O
were	O
a	O
number	O
of	O
limitations	O
relating	O
to	O
study	O
design	O
.	O

Unfortunately	O
,	O
we	O
did	O
not	O
record	O
the	O
exact	O
numbers	O
of	O
cases	O
and	O
controls	O
who	O
refused	O
to	O
participate	O
or	O
were	O
unable	O
to	O
communicate	O
(	O
believed	O
to	O
be	O
fewer	O
than	O
five	O
in	O
each	O
country	O
)	O
,	O
so	O
the	O
response	O
rate	O
is	O
unknown	O
,	O
but	O
was	O
believed	O
to	O
be	O
high	O
.	O

A	O
variety	O
of	O
methods	O
were	O
used	O
for	O
case	O
recruitment	O
,	O
as	O
we	O
were	O
not	O
able	O
to	O
obtain	O
enough	O
cases	O
through	O
the	O
survey	O
alone	O
.	O

However	O
,	O
cases	O
recruited	O
through	O
the	O
population	O
-	O
based	O
survey	O
and	O
through	O
case	O
detection	O
had	O
similar	O
poverty	O
characteristics	O
.	O

Conclusions	O

Our	O
data	O
show	O
that	O
people	B
with	O
visual	O
impairment	O
due	O
to	O
cataract	O
were	O
poorer	O
than	O
controls	O
in	O
three	O
low	O
income	O
countries	O
,	O
Bangladesh	O
,	O
Kenya	O
,	O
and	O
the	O
Philippines	O
.	O

The	O
Millennium	O
Development	O
Goals	O
are	O
committed	O
to	O
the	O
eradication	O
of	O
extreme	O
poverty	O
and	O
provision	O
of	O
health	O
care	O
to	O
poor	O
people	B
.	O

This	O
study	O
confirms	O
an	O
association	O
between	O
poverty	O
and	O
blindness	O
and	O
highlights	O
the	O
need	O
for	O
increased	O
provision	O
of	O
cataract	O
surgery	O
to	O
poor	O
people	B
,	O
particularly	O
since	O
cataract	O
surgery	O
is	O
a	O
highly	O
cost	O
-	O
effective	O
intervention	O
in	O
these	O
settings	O
[	O
34	O
]	O
.	O

Human	B
genetic	O
selection	O
on	O
the	O
MTHFR	O
677C	O
>	O
T	O
polymorphism	O

Abstract	O

Background	O

The	O
prevalence	O
of	O
genotypes	O
of	O
the	O
677C	O
>	O
T	O
polymorphism	O
for	O
the	O
MTHFR	O
gene	O
varies	O
among	O
humans	B
.	O

In	O
previous	O
studies	O
,	O
we	O
found	O
changes	O
in	O
the	O
genotypic	O
frequencies	O
of	O
this	O
polymorphism	O
in	O
populations	O
of	O
different	O
ages	O
,	O
suggesting	O
that	O
this	O
could	O
be	O
caused	O
by	O
an	O
increase	O
in	O
the	O
intake	O
of	O
folate	O
and	O
multivitamins	O
by	O
women	B
during	O
the	O
periconceptional	O
period	O
.	O

The	O
aim	O
was	O
to	O
analyze	O
changes	O
in	O
the	O
allelic	O
frequencies	O
of	O
this	O
polymorphism	O
in	O
a	O
Spanish	O
population	O
,	O
including	O
samples	O
from	O
spontaneous	O
abortions	O
(	O
SA	O
)	O
.	O

Methods	O

A	O
total	O
of	O
1305	O
subjects	O
born	O
in	O
the	O
20th	O
century	O
were	O
genotyped	O
for	O
the	O
677C	O
>	O
T	O
polymorphism	O
using	O
allele	O
specific	O
real	O
-	O
time	O
PCR	O
with	O
Taqman	O
(	O
R	O
)	O
probes	O
.	O

A	O
section	O
of	O
our	O
population	O
(	O
n	O
=	O
276	O
)	O
born	O
in	O
1980	O
-	O
1989	O
was	O
compared	O
with	O
fetal	O
samples	O
(	O
n	O
=	O
344	O
)	O
from	O
SA	O
of	O
unknown	O
etiology	O
from	O
the	O
same	O
period	O
.	O

Results	O

An	O
increase	O
in	O
the	O
frequency	O
of	O
the	O
T	O
allele	O
(	O
0	O
.	O
38	O
vs	O
0	O
.	O
47	O
;	O
p	O
<	O
0	O
.	O
001	O
)	O
and	O
of	O
the	O
TT	O
genotype	O
(	O
0	O
.	O
14	O
vs	O
0	O
.	O
24	O
;	O
p	O
<	O
0	O
.	O
001	O
)	O
in	O
subjects	O
born	O
in	O
the	O
last	O
quarter	O
of	O
the	O
century	O
was	O
observed	O
.	O

In	O
the	O
1980	O
-	O
1989	O
period	O
,	O
the	O
results	O
show	O
that	O
the	O
frequency	O
of	O
the	O
wild	O
type	O
genotype	O
(	O
CC	O
)	O
is	O
about	O
tenfold	O
lower	O
in	O
the	O
SA	O
samples	O
than	O
in	O
the	O
controls	O
(	O
0	O
.	O
03	O
vs	O
0	O
.	O
33	O
;	O
p	O
<	O
0	O
.	O
001	O
)	O
and	O
that	O
the	O
frequency	O
of	O
the	O
TT	O
genotype	O
increases	O
in	O
the	O
controls	O
(	O
0	O
.	O
19	O
to	O
0	O
.	O
27	O
)	O
and	O
in	O
the	O
SA	O
samples	O
(	O
0	O
.	O
20	O
to	O
0	O
.	O
33	O
(	O
p	O
<	O
0	O
.	O
01	O
)	O
)	O
;	O
r	O
=	O
0	O
.	O
98	O
.	O

Conclusion	O

Selection	O
in	O
favor	O
of	O
the	O
T	O
allele	O
has	O
been	O
detected	O
.	O

This	O
selection	O
could	O
be	O
due	O
to	O
the	O
increased	O
fetal	O
viability	O
in	O
early	O
stages	O
of	O
embryonic	O
development	O
,	O
as	O
is	O
deduced	O
by	O
the	O
increase	O
of	O
mutants	O
in	O
both	O
living	O
and	O
SA	O
populations	O
.	O

Background	O

The	O
methylenetetrahydrof	O
reductase	O
enzyme	O
(	O
MTHFR	O
)	O
catalyzes	O
a	O
reaction	O
that	O
produces	O
5	O
-	O
methyltetrahydrofola	O
(	O
5	O
-	O
methylTHF	O
)	O
,	O
the	O
methyl	O
donor	O
for	O
homocysteine	O
in	O
the	O
synthesis	O
of	O
methionine	O
.	O

The	O
677C	O
>	O
T	O
mutation	O
of	O
the	O
MTHFR	O
gene	O
has	O
been	O
associated	O
with	O
a	O
thermolabile	O
enzyme	O
with	O
decreased	O
activity	O
that	O
may	O
cause	O
an	O
increase	O
in	O
plasma	O
homocysteine	O
concentrations	O
[	O
1	O
]	O
when	O
folate	O
status	O
is	O
poor	O
.	O

This	O
polymorphism	O
is	O
one	O
of	O
the	O
most	O
widely	O
studied	O
clinically	O
relevant	O
polymorphisms	O
in	O
humans	B
,	O
as	O
it	O
is	O
related	O
to	O
cardiovascular	O
disease	O
[	O
2	O
]	O
and	O
neural	O
tube	O
defects	O
(	O
NTD	O
;	O
601634	O
)	O
[	O
3	O
]	O
.	O

A	O
large	O
number	O
of	O
studies	O
have	O
provided	O
a	O
broad	O
overview	O
of	O
the	O
prevalence	O
of	O
the	O
677C	O
>	O
T	O
polymorphism	O
in	O
different	O
human	B
populations	O
,	O
showing	O
that	O
the	O
distribution	O
of	O
frequencies	O
is	O
diverse	O
[	O
4	O
]	O
.	O

These	O
differences	O
have	O
been	O
also	O
observed	O
between	O
groups	O
of	O
different	O
ages	O
in	O
the	O
same	O
Spanish	O
population	O
(	O
older	O
and	O
younger	O
than	O
24	O
years	O
)	O
[	O
5	O
]	O
and	O
in	O
a	O
Swiss	O
population	O
(	O
older	O
and	O
younger	O
than	O
60	O
years	O
)	O
[	O
6	O
]	O
,	O
as	O
well	O
as	O
in	O
a	O
Japanese	O
population	O
[	O
7	O
]	O
.	O

In	O
some	O
populations	O
,	O
such	O
the	O
Toscanians	O
in	O
Italy	O
[	O
8	O
]	O
and	O
Mexicans	O
[	O
9	O
]	O
,	O
the	O
homozygous	O
mutated	O
genotype	O
(	O
TT	O
)	O
has	O
reached	O
frequencies	O
greater	O
than	O
30	O
%	O
.	O

On	O
the	O
other	O
hand	O
,	O
in	O
Africans	O
the	O
frequency	O
of	O
the	O
TT	O
genotype	O
is	O
very	O
low	O
(	O
less	O
than	O
1	O
%	O
)	O
[	O
10	O
,	O
11	O
]	O
,	O
but	O
,	O
in	O
African	O
-	O
Americans	O
,	O
it	O
has	O
already	O
reached	O
2	O
%	O
[	O
12	O
]	O
.	O

Studies	O
based	O
on	O
the	O
distribution	O
of	O
genotypic	O
and	O
allelic	O
frequencies	O
of	O
the	O
677C	O
>	O
T	O
polymorphism	O
and	O
the	O
1298A	O
>	O
C	O
polymorphism	O
in	O
the	O
MTHFR	O
gene	O
in	O
Israeli	O
,	O
Japanese	O
and	O
Ghanaian	O
Africans	O
populations	O
[	O
13	O
]	O
concluded	O
that	O
the	O
677T	O
mutation	O
in	O
the	O
MTHFR	O
gene	O
emerged	O
as	O
a	O
founder	O
haplotype	O
with	O
some	O
selective	O
advantage	O
.	O

Recently	O
,	O
preliminary	O
evidence	O
of	O
genetic	O
selection	O
of	O
this	O
polymorphism	O
related	O
to	O
folate	O
intake	O
has	O
been	O
reported	O
[	O
14	O
]	O
.	O

The	O
aim	O
of	O
the	O
present	O
study	O
is	O
to	O
analyze	O
the	O
changes	O
in	O
frequencies	O
of	O
the	O
677C	O
>	O
T	O
polymorphism	O
during	O
the	O
20th	O
century	O
and	O
particularly	O
the	O
evolution	O
of	O
the	O
frequencies	O
during	O
the	O
decade	O
of	O
1980	O
-	O
1989	O
,	O
by	O
comparing	O
the	O
genotype	O
frequencies	O
between	O
living	O
subjects	O
born	O
in	O
this	O
period	O
versus	O
samples	O
of	O
spontaneous	O
abortions	O
(	O
SA	O
)	O
that	O
occurred	O
during	O
in	O
the	O
same	O
time	O
period	O
.	O

Methods	O

Subjects	O

This	O
study	O
was	O
approved	O
by	O
the	O
Ethics	O
Committee	O
at	O
the	O
University	O
Hospital	O
"	O
Virgen	O
de	O
la	O
Victoria	O
"	O
(	O
M	O
a	O
laga	O
)	O
.	O

One	O
of	O
the	O
study	O
groups	O
consisted	O
of	O
344	O
fetal	O
tissue	O
samples	O
from	O
SA	O
,	O
obtained	O
from	O
the	O
Department	O
of	O
Pathology	O
of	O
the	O
University	O
Hospital	O
Carlos	O
Haya	O
(	O
M	O
a	O
laga	O
)	O
.	O

These	O
samples	O
were	O
selected	O
after	O
checking	O
the	O
clinical	O
history	O
and	O
by	O
the	O
inclusion	O
criteria	O
of	O
containing	O
histologically	O
confirmed	O
fetal	O
tissue	O
collected	O
in	O
the	O
1980s	O
from	O
SA	O
at	O
less	O
than	O
3	O
months	O
(	O
11	O
+	O
/	O
-	O
1	O
.	O
70	O
week	O
)	O
and	O
of	O
unknown	O
etiology	O
.	O

These	O
fetal	O
samples	O
were	O
compared	O
with	O
a	O
control	O
population	O
of	O
276	O
subjects	O
born	O
in	O
the	O
1980s	O
with	O
an	O
average	O
age	O
of	O
22	O
+	O
/	O
-	O
4	O
.	O
58	O
.	O

Another	O
population	O
of	O
subjects	O
born	O
in	O
the	O
south	O
of	O
Spain	O
in	O
the	O
20th	O
century	O
were	O
genotyped	O
(	O
1305	O
subjects	O
,	O
697	O
women	B
and	O
608	O
men	B
)	O
and	O
divided	O
into	O
four	O
groups	O
according	O
to	O
birth	O
date	O
:	O
1900	O
to	O
1925	O
(	O
n	O
=	O
206	O
)	O
;	O
1926	O
to	O
1950	O
(	O
n	O
=	O
320	O
)	O
,	O
1951	O
to	O
1975	O
(	O
n	O
=	O
408	O
)	O
,	O
1976	O
to	O
2000	O
(	O
n	O
=	O
371	O
)	O
.	O

Individuals	O
were	O
selected	O
randomly	O
from	O
different	O
areas	O
of	O
the	O
province	O
of	O
Malaga	O
,	O
in	O
southern	O
Spain	O
,	O
and	O
from	O
different	O
social	O
statuses	O
to	O
avoid	O
a	O
selection	O
bias	O
.	O

All	O
the	O
selected	O
individuals	O
were	O
Caucasian	O
and	O
residents	O
of	O
the	O
study	O
area	O
.	O

The	O
parents	O
of	O
all	O
subjects	O
included	O
in	O
the	O
study	O
were	O
also	O
Caucasian	O
and	O
born	O
in	O
Spain	O
.	O

The	O
possibility	O
of	O
a	O
founder	O
effect	O
or	O
genetic	O
drift	O
was	O
investigated	O
and	O
rejected	O
.	O

All	O
the	O
selected	O
individuals	O
were	O
also	O
genotyped	O
for	O
an	O
insertion	O
/	O
deletion	O
polymorphism	O
in	O
the	O
angiotensin	O
converting	O
enzyme	O
(	O
ACE	O
)	O
gene	O
and	O
/	O
or	O
the	O
2756A	O
>	O
G	O
polymorphism	O
in	O
the	O
methionine	O
synthase	O
gene	O
(	O
MTR	O
)	O
,	O
in	O
order	O
to	O
determine	O
whether	O
or	O
not	O
our	O
adult	O
and	O
young	O
populations	O
were	O
genetically	O
homogeneous	O
.	O

No	O
significant	O
differences	O
were	O
observed	O
in	O
allelic	O
or	O
genotypic	O
frequencies	O
for	O
these	O
genes	O
between	O
the	O
different	O
groups	O
.	O

The	O
population	O
studied	O
was	O
randomly	O
selected	O
according	O
to	O
age	O
.	O

Subjects	O
0	O
-	O
12	O
years	O
old	O
were	O
selected	O
from	O
dried	O
blood	O
spots	O
from	O
neonatal	O
screening	O
papers	O
;	O
subjects	O
10	O
-	O
24	O
years	O
old	O
were	O
recruited	O
from	O
students	O
in	O
primary	O
and	O
secondary	O
schools	O
and	O
in	O
university	O
;	O
subjects	O
25	O
-	O
50	O
years	O
old	O
and	O
>	O
51	O
years	O
old	O
were	O
recruited	O
using	O
their	O
Andalusia	O
Health	O
Service	O
identity	O
cards	O
.	O

After	O
approval	O
by	O
the	O
University	O
Hospital	O
Ethical	O
Committee	O
,	O
all	O
the	O
subjects	O
were	O
contacted	O
,	O
and	O
,	O
from	O
those	O
whose	O
written	O
consent	O
was	O
obtained	O
,	O
10	O
ml	O
of	O
blood	O
was	O
taken	O
.	O

The	O
investigation	O
in	O
this	O
study	O
conforms	O
to	O
the	O
principles	O
outlined	O
in	O
the	O
Declaration	O
of	O
Helsinki	O
.	O

Genetic	O
analysis	O

The	O
fetal	O
samples	O
were	O
extracted	O
from	O
the	O
archived	O
formalin	O
-	O
fixed	O
,	O
paraffin	O
-	O
embedded	O
tissue	O
sections	O
.	O

Genomic	O
DNA	O
was	O
extracted	O
from	O
fetal	O
tissue	O
using	O
the	O
method	O
described	O
by	O
Coombs	O
et	O
al	O
.	O

(	O
1999	O
)	O
[	O
15	O
]	O
.	O

Genomic	O
DNA	O
of	O
the	O
second	O
and	O
third	O
groups	O
was	O
extracted	O
from	O
peripheral	O
leukocytes	O
using	O
the	O
AquaPure	O
Genomic	O
DNA	O
Blood	O
Kit	O
(	O
Bio	O
-	O
Rad	O
)	O
.	O

Genotyping	O
was	O
performed	O
using	O
Real	O
Time	O
PCR	O
with	O
allele	O
specific	O
Taqman	O
(	O
R	O
)	O
probes	O
and	O
primers	O
described	O
by	O
Ulvik	O
et	O
al	O
.	O

(	O
2001	O
)	O
[	O
16	O
]	O
and	O
the	O
following	O
optimized	O
protocol	O
for	O
45	O
cycles	O
:	O
10	O
s	O
-	O
94	O
degrees	O
C	O
,	O
40	O
s	O
-	O
54	O
degrees	O
C	O
,	O
15	O
s	O
-	O
72	O
degrees	O
C	O
.	O

The	O
PCR	O
mix	O
(	O
25	O
mu	O
l	O
total	O
volume	O
)	O
consisted	O
of	O
5	O
mu	O
l	O
of	O
genomic	O
DNA	O
,	O
0	O
.	O
5	O
mu	O
l	O
of	O
sense	O
primer	O
,	O
0	O
.	O
62	O
mu	O
l	O
of	O
anti	O
-	O
sense	O
primer	O
,	O
0	O
.	O
85	O
mu	O
l	O
Taqman	O
(	O
R	O
)	O
probe	O
FAM	O
,	O
0	O
.	O
43	O
mu	O
l	O
Taqman	O
(	O
R	O
)	O
probe	O
TET	O
,	O
20	O
mu	O
l	O
PCR	O
-	O
buffer	O
iQ	O
-	O
SupermixTM	O
(	O
Bio	O
-	O
Rad	O
)	O
(	O
containing	O
100	O
mM	O
KCl	O
,	O
40	O
mM	O
Tris	O
-	O
HCl	O
,	O
(	O
pH	O
8	O
.	O
4	O
)	O
1	O
.	O
6	O
mM	O
dNTP	O
(	O
dATP	O
,	O
dCTP	O
,	O
dGTP	O
and	O
dTTP	O
)	O
,	O
iTaq	O
(	O
R	O
)	O
polymerase	O
(	O
50	O
units	O
/	O
mL	O
)	O
and	O
6	O
mM	O
MgCl2	O
)	O
and	O
17	O
.	O
75	O
mu	O
l	O
H2O	O
.	O

Statistical	O
and	O
mathematical	O
analysis	O

All	O
samples	O
were	O
genotyped	O
,	O
and	O
the	O
allelic	O
and	O
genotypic	O
frequencies	O
were	O
compared	O
.	O

Differences	O
were	O
analyzed	O
statistically	O
using	O
the	O
chi	O
-	O
square	O
test	O
or	O
Fisher	O
'	O
s	O
exact	O
test	O
.	O

Correlations	O
are	O
expressed	O
using	O
Pearson	O
'	O
s	O
coefficient	O
(	O
r	O
)	O
.	O

Compliance	O
of	O
genotype	O
distributions	O
with	O
Hardy	O
-	O
Weinberg	O
(	O
HW	O
)	O
equilibrium	O
was	O
evaluated	O
by	O
chi	O
-	O
square	O
analysis	O
.	O

For	O
all	O
tests	O
,	O
a	O
p	O
-	O
value	O
<	O
0	O
.	O
05	O
was	O
considered	O
to	O
be	O
statistically	O
significant	O
.	O

Values	O
are	O
expressed	O
as	O
the	O
mean	O
+	O
/	O
-	O
SD	O
.	O

The	O
genetic	O
selection	O
model	O
was	O
calculated	O
for	O
the	O
evolution	O
of	O
the	O
677C	O
>	O
T	O
genotypes	O
.	O

The	O
genetic	O
selection	O
could	O
be	O
classified	O
as	O
codominant	O
or	O
incompletely	O
dominant	O
and	O
directional	O
with	O
the	O
heterozygous	O
genotype	O
having	O
an	O
intermediate	O
fitness	O
.	O

For	O
this	O
kind	O
of	O
selection	O
,	O
the	O
most	O
appropriate	O
mathematical	O
model	O
is	O
dq	O
=	O
[	O
spq	O
(	O
2hp	O
+	O
q	O
-	O
h	O
)	O
]	O
/	O
[	O
p2	O
+	O
2pq	O
(	O
1	O
-	O
hs	O
)	O
+	O
q2	O
x	O
(	O
1	O
-	O
s	O
)	O
]	O
,	O
where	O
dq	O
is	O
the	O
change	O
of	O
frequency	O
of	O
the	O
allele	O
with	O
lower	O
fitness	O
,	O
s	O
is	O
the	O
fraction	O
of	O
that	O
genotype	O
lost	O
to	O
selection	O
,	O
h	O
is	O
the	O
degree	O
of	O
dominance	O
(	O
between	O
0	O
,	O
for	O
no	O
dominance	O
and	O
1	O
,	O
for	O
complete	O
dominance	O
)	O
,	O
and	O
p	O
is	O
the	O
frequency	O
of	O
the	O
allele	O
with	O
higher	O
fitness	O
.	O

Results	O

We	O
analyzed	O
the	O
genotype	O
frequencies	O
of	O
the	O
677C	O
>	O
T	O
polymorphism	O
in	O
a	O
population	O
born	O
during	O
the	O
20th	O
century	O
.	O

A	O
total	O
of	O
1305	O
subjects	O
were	O
divided	O
into	O
four	O
groups	O
of	O
25	O
years	O
according	O
to	O
birth	O
date	O
.	O

The	O
genotype	O
frequencies	O
were	O
compared	O
between	O
the	O
four	O
quarters	O
of	O
the	O
century	O
and	O
showed	O
very	O
significant	O
changes	O
(	O
p	O
<	O
0	O
.	O
001	O
)	O
in	O
the	O
group	O
born	O
in	O
the	O
last	O
quarter	O
of	O
the	O
20th	O
century	O
(	O
1976	O
-	O
2000	O
)	O
,	O
when	O
compared	O
to	O
any	O
of	O
the	O
other	O
groups	O
.	O

The	O
changes	O
show	O
a	O
decrease	O
of	O
the	O
CC	O
genotype	O
and	O
an	O
increase	O
of	O
the	O
TT	O
genotype	O
in	O
the	O
last	O
25	O
years	O
of	O
the	O
20th	O
century	O
.	O

(	O
Table	O
1	O
)	O

Considering	O
that	O
each	O
25	O
year	O
period	O
corresponds	O
to	O
a	O
generation	O
,	O
allelic	O
frequencies	O
did	O
not	O
change	O
during	O
the	O
first	O
75	O
years	O
of	O
the	O
century	O
(	O
HW	O
equilibrium	O
)	O
.	O

However	O
,	O
we	O
found	O
that	O
allelic	O
and	O
genotypic	O
frequencies	O
for	O
the	O
677C	O
>	O
T	O
polymorphism	O
in	O
the	O
last	O
quarter	O
of	O
the	O
century	O
are	O
significantly	O
different	O
compared	O
to	O
the	O
previous	O
generation	O
(	O
1951	O
-	O
1975	O
)	O
.	O

The	O
genotype	O
frequencies	O
in	O
the	O
last	O
quarter	O
of	O
the	O
century	O
are	O
not	O
the	O
expected	O
by	O
a	O
HW	O
calculation	O
using	O
the	O
allelic	O
frequencies	O
of	O
the	O
previous	O
generation	O
.	O

This	O
could	O
be	O
described	O
as	O
a	O
consequence	O
of	O
genetic	O
selection	O
found	O
in	O
this	O
population	O
,	O
in	O
the	O
absence	O
of	O
other	O
causes	O
.	O

Applying	O
the	O
mathematical	O
model	O
described	O
above	O
to	O
our	O
population	O
,	O
the	O
calculated	O
fitness	O
(	O
s	O
)	O
is	O
0	O
.	O
5	O
,	O
and	O
it	O
can	O
be	O
predicted	O
that	O
both	O
alleles	O
will	O
be	O
approximately	O
at	O
a	O
frequency	O
of	O
50	O
%	O
in	O
the	O
next	O
generation	O
and	O
allele	O
T	O
will	O
be	O
at	O
90	O
%	O
after	O
seven	O
generations	O
(	O
Figure	O
1A	O
)	O
.	O

Another	O
possibility	O
is	O
that	O
a	O
scenario	O
could	O
be	O
predicted	O
in	O
which	O
both	O
alleles	O
will	O
have	O
frequencies	O
of	O
about	O
50	O
%	O
in	O
the	O
next	O
generation	O
and	O
that	O
they	O
will	O
maintain	O
this	O
stability	O
while	O
conditions	O
remain	O
unchanged	O
.	O

(	O
Figure	O
1B	O
)	O

The	O
comparison	O
of	O
the	O
genotype	O
frequencies	O
between	O
a	O
group	O
of	O
fetal	O
samples	O
from	O
SA	O
that	O
occurred	O
during	O
the	O
1980	O
-	O
1989	O
decade	O
and	O
living	O
subjects	O
born	O
in	O
the	O
same	O
decade	O
showed	O
significant	O
differences	O
in	O
genotype	O
frequencies	O
(	O
p	O
<	O
0	O
.	O
001	O
)	O
.	O

CC	O
genotypes	O
were	O
almost	O
absent	O
in	O
abortion	O
samples	O
compared	O
to	O
living	O
subjects	O
(	O
0	O
.	O
03	O
vs	O
0	O
.	O
33	O
)	O
,	O
while	O
CT	O
and	O
TT	O
genotypes	O
were	O
overrepresented	O
in	O
the	O
same	O
group	O
.	O

When	O
3	O
-	O
year	O
periods	O
are	O
studied	O
in	O
the	O
decade	O
,	O
we	O
detected	O
a	O
significant	O
increase	O
of	O
the	O
mutated	O
subjects	O
during	O
the	O
decade	O
(	O
CT	O
p	O
<	O
0	O
.	O
05	O
;	O
TT	O
p	O
<	O
0	O
.	O
01	O
)	O
.	O

Allele	O
frequencies	O
showed	O
the	O
same	O
pattern	O
(	O
p	O
<	O
0	O
.	O
05	O
)	O
.	O

Controls	O
showed	O
the	O
same	O
tendency	O
but	O
without	O
statistical	O
significance	O
.	O

(	O
Table	O
2	O
)	O

The	O
evolution	O
of	O
genotype	O
frequencies	O
during	O
the	O
1980	O
-	O
1989	O
decade	O
of	O
the	O
TT	O
genotypes	O
correlates	O
well	O
in	O
both	O
living	O
populations	O
as	O
well	O
as	O
fetal	O
samples	O
r	O
=	O
0	O
.	O
98	O
(	O
p	O
=	O
0	O
.	O
11	O
)	O
.	O

Discussion	O

Different	O
reports	O
show	O
that	O
the	O
prevalence	O
of	O
the	O
677C	O
>	O
T	O
polymorphism	O
of	O
the	O
MTHFR	O
gene	O
differs	O
dramatically	O
among	O
human	B
populations	O
.	O

Evidence	O
of	O
this	O
dynamism	O
can	O
be	O
observed	O
in	O
many	O
reports	O
:	O
frequency	O
variations	O
between	O
populations	O
that	O
are	O
geographically	O
very	O
close	O
,	O
even	O
in	O
the	O
same	O
country	O
[	O
8	O
]	O
;	O
changes	O
found	O
in	O
the	O
same	O
race	O
or	O
ethnic	O
group	O
such	O
as	O
Africans	O
[	O
10	O
,	O
11	O
]	O
and	O
African	O
-	O
Americans	O
[	O
12	O
]	O
;	O
the	O
high	O
prevalence	O
of	O
the	O
677C	O
>	O
T	O
poymorphism	O
in	O
populations	O
with	O
special	O
nutritional	O
features	O
such	O
as	O
Mexicans	O
[	O
9	O
]	O
and	O
Japanese	O
[	O
13	O
]	O
;	O
and	O
changes	O
in	O
frequencies	O
between	O
generations	O
of	O
the	O
same	O
population	O
,	O
as	O
has	O
been	O
observed	O
in	O
Spain	O
[	O
5	O
]	O
,	O
Switzerland	O
[	O
6	O
]	O
and	O
Japan	O
[	O
7	O
]	O
.	O

There	O
are	O
numerous	O
interpretations	O
of	O
this	O
great	O
diversity	O
,	O
and	O
most	O
tend	O
to	O
be	O
related	O
to	O
adaptation	O
to	O
external	O
conditions	O
such	O
as	O
climate	O
or	O
nutritional	O
status	O
.	O

Dependence	O
of	O
folate	O
degradation	O
on	O
skin	O
pigmentation	O
[	O
17	O
]	O
,	O
nutritional	O
habits	O
or	O
human	B
intervention	O
periconceptional	O
periods	O
could	O
explain	O
this	O
genetic	O
variation	O
.	O

Definitely	O
,	O
external	O
factors	O
in	O
combination	O
with	O
different	O
levels	O
of	O
MTHFR	O
enzyme	O
activity	O
,	O
conditioned	O
by	O
polymorphisms	O
,	O
could	O
influence	O
the	O
fetal	O
viability	O
of	O
certain	O
genotypes	O
.	O

In	O
1998	O
,	O
we	O
suggested	O
the	O
possibility	O
of	O
genetic	O
selection	O
in	O
Spain	O
in	O
favor	O
of	O
the	O
mutants	O
of	O
the	O
677C	O
>	O
T	O
polymorphism	O
in	O
the	O
MTHFR	O
gene	O
based	O
on	O
the	O
fact	O
that	O
treatment	O
with	O
vitamins	O
and	O
folates	O
during	O
pregnancy	O
increased	O
the	O
viability	O
of	O
fetuses	O
with	O
the	O
TT	O
homozygous	O
genotype	O
.	O

This	O
hypothesis	O
was	O
based	O
on	O
the	O
increase	O
in	O
the	O
number	O
of	O
mutated	O
individuals	O
found	O
in	O
our	O
population	O
since	O
the	O
mid	O
-	O
1970s	O
[	O
5	O
]	O
and	O
the	O
coincident	O
increased	O
intake	O
of	O
vitamins	O
and	O
folate	O
by	O
pregnant	O
women	B
in	O
Spain	O
[	O
18	O
,	O
19	O
]	O
.	O

In	O
2002	O
,	O
a	O
new	O
study	O
found	O
changes	O
in	O
genotype	O
frequencies	O
for	O
the	O
677C	O
>	O
T	O
and	O
1298A	O
>	O
C	O
polymorphisms	O
in	O
different	O
age	O
groups	O
.	O

Total	O
homocysteine	O
(	O
tHcy	O
)	O
levels	O
in	O
plasma	O
were	O
also	O
analyzed	O
according	O
to	O
the	O
different	O
genotype	O
interactions	O
[	O
20	O
]	O
.	O

That	O
study	O
hypothesized	O
about	O
fetal	O
viability	O
and	O
about	O
a	O
genetic	O
selection	O
model	O
on	O
the	O
basis	O
of	O
non	O
-	O
linkage	O
disequilibrium	O
between	O
both	O
polymorphisms	O
.	O

Recently	O
,	O
a	O
study	O
with	O
fetal	O
and	O
control	O
populations	O
showed	O
the	O
strong	O
influence	O
of	O
these	O
polymorphisms	O
,	O
though	O
mainly	O
of	O
the	O
677C	O
>	O
T	O
polymorphism	O
,	O
on	O
spontaneous	O
early	O
abortion	O
[	O
21	O
]	O
.	O

In	O
the	O
present	O
study	O
,	O
significant	O
changes	O
in	O
allelic	O
and	O
genotypic	O
frequencies	O
are	O
detected	O
,	O
as	O
is	O
Hardy	O
-	O
Weinberg	O
disequilibrium	O
,	O
at	O
the	O
677C	O
>	O
T	O
polymorphism	O
.	O

We	O
hypothesize	O
that	O
there	O
is	O
a	O
dynamic	O
process	O
of	O
genetic	O
selection	O
that	O
favors	O
the	O
T	O
allele	O
.	O

This	O
process	O
of	O
selection	O
started	O
during	O
the	O
last	O
quarter	O
of	O
the	O
20th	O
century	O
,	O
during	O
which	O
the	O
frequency	O
for	O
mutant	O
homozygous	O
(	O
TT	O
)	O
rose	O
significantly	O
from	O
14	O
%	O
to	O
24	O
%	O
.	O

We	O
propose	O
that	O
this	O
increase	O
in	O
mutants	O
is	O
due	O
to	O
the	O
inclusion	O
of	O
an	O
external	O
factor	O
that	O
enhances	O
mutant	O
fetal	O
viability	O
.	O

If	O
we	O
apply	O
the	O
mathematical	O
model	O
for	O
dynamic	O
selection	O
developed	O
for	O
diploid	O
organisms	O
with	O
sexual	O
reproduction	O
,	O
the	O
T	O
allele	O
could	O
reach	O
to	O
90	O
%	O
in	O
seven	O
generations	O
in	O
our	O
population	O
(	O
Figure	O
1A	O
)	O
.	O

However	O
,	O
this	O
model	O
assumes	O
selection	O
in	O
a	O
constant	O
environment	O
that	O
applies	O
to	O
all	O
individuals	O
in	O
the	O
population	O
studied	O
.	O

In	O
our	O
case	O
,	O
we	O
suggest	O
that	O
the	O
external	O
factor	O
is	O
related	O
to	O
an	O
increase	O
in	O
folate	O
and	O
vitamin	O
intake	O
in	O
women	B
in	O
periconceptional	O
period	O
and	O
does	O
not	O
affect	O
to	O
all	O
individuals	O
[	O
18	O
,	O
19	O
]	O
.	O

We	O
assume	O
that	O
prediction	O
of	O
a	O
classic	O
selection	O
model	O
in	O
this	O
case	O
is	O
only	O
theoretical	O
.	O

On	O
the	O
basis	O
of	O
a	O
competition	O
between	O
alleles	O
in	O
which	O
an	O
environmental	O
factor	O
favors	O
one	O
allele	O
versus	O
the	O
other	O
,	O
the	O
final	O
result	O
would	O
be	O
that	O
predicted	O
by	O
the	O
previous	O
mathematical	O
model	O
.	O

However	O
in	O
this	O
case	O
,	O
the	O
environment	O
is	O
not	O
selecting	O
against	O
the	O
wild	O
type	O
allele	O
but	O
rather	O
allowing	O
the	O
survival	O
of	O
more	O
mutated	O
alleles	O
.	O

Therefore	O
,	O
the	O
expected	O
result	O
would	O
be	O
not	O
a	O
systematic	O
increase	O
of	O
the	O
mutated	O
allele	O
but	O
the	O
creation	O
of	O
an	O
allelic	O
balance	O
dependent	O
on	O
vitamin	O
and	O
folate	O
abundance	O
conditions	O
.	O

In	O
this	O
case	O
,	O
the	O
mutation	O
would	O
have	O
a	O
lower	O
influence	O
on	O
fetal	O
viability	O
(	O
Figure	O
1B	O
)	O
.	O

The	O
results	O
showed	O
an	O
increase	O
in	O
mutated	O
genotypes	O
(	O
CT	O
and	O
TT	O
)	O
and	O
a	O
strong	O
protection	O
against	O
abortion	O
by	O
the	O
wild	O
type	O
genotype	O
(	O
CC	O
)	O
,	O
which	O
is	O
practically	O
non	O
-	O
existent	O
in	O
the	O
SA	O
group	O
.	O

The	O
frequency	O
of	O
the	O
CC	O
genotype	O
shows	O
no	O
change	O
over	O
the	O
decade	O
studied	O
(	O
1980	O
-	O
1989	O
)	O
,	O
which	O
indicates	O
that	O
folate	O
does	O
not	O
exert	O
a	O
visible	O
effect	O
on	O
this	O
genotype	O
.	O

However	O
,	O
the	O
frequency	O
of	O
the	O
mutated	O
allele	O
increases	O
during	O
this	O
decade	O
,	O
especially	O
in	O
fetuses	O
from	O
abortions	O
,	O
and	O
this	O
increase	O
correlated	O
with	O
the	O
increase	O
of	O
the	O
T	O
allele	O
in	O
the	O
control	O
population	O
.	O

This	O
finding	O
suggests	O
that	O
the	O
effect	O
of	O
folate	O
is	O
crucial	O
to	O
viability	O
during	O
the	O
early	O
stages	O
of	O
embryonic	O
development	O
,	O
but	O
,	O
even	O
with	O
folate	O
,	O
not	O
all	O
embryos	O
will	O
survive	O
until	O
birth	O
.	O

In	O
this	O
population	O
,	O
the	O
mutant	O
allele	O
with	O
lower	O
enzymatic	O
activity	O
has	O
higher	O
fitness	O
than	O
the	O
wild	O
type	O
.	O

In	O
the	O
folate	O
cycle	O
,	O
it	O
can	O
be	O
observed	O
that	O
5	O
,	O
10	O
-	O
methyleneTHF	O
availability	O
may	O
be	O
important	O
.	O

5	O
,	O
10	O
-	O
methyleneTHF	O
is	O
the	O
substrate	O
for	O
several	O
reactions	O
in	O
the	O
cycle	O
,	O
but	O
two	O
of	O
them	O
(	O
5	O
-	O
methylTHF	O
and	O
thymidilate	O
synthesis	O
)	O
might	O
be	O
essential	O
for	O
embryo	O
development	O
in	O
folate	O
deficiency	O
conditions	O
.	O

In	O
both	O
cases	O
,	O
complete	O
or	O
limited	O
MTHFR	O
activity	O
will	O
produce	O
higher	O
or	O
lower	O
5	O
,	O
10	O
-	O
methyleneTHF	O
availability	O
,	O
which	O
might	O
be	O
an	O
essential	O
factor	O
for	O
embryo	O
development	O
,	O
such	O
that	O
a	O
greater	O
folate	O
levels	O
can	O
compensate	O
the	O
lower	O
enzymatic	O
activity	O
of	O
the	O
mutant	O
.	O

The	O
implications	O
of	O
this	O
polymorphism	O
in	O
nucleotide	O
synthesis	O
have	O
not	O
yet	O
been	O
determined	O
,	O
but	O
certain	O
data	O
,	O
such	O
as	O
high	O
levels	O
of	O
uric	O
acid	O
found	O
in	O
mutated	O
subjects	O
[	O
22	O
,	O
23	O
]	O
,	O
suggest	O
that	O
there	O
are	O
different	O
turnover	O
rates	O
associated	O
with	O
different	O
polymorphisms	O
.	O

Conclusion	O

We	O
suggest	O
that	O
there	O
is	O
genetic	O
selection	O
in	O
our	O
population	O
for	O
the	O
T	O
allele	O
of	O
the	O
MTHFR	O
-	O
677C	O
>	O
T	O
polymorphism	O
,	O
whose	O
origin	O
could	O
be	O
an	O
increase	O
in	O
fetal	O
viability	O
during	O
the	O
early	O
stages	O
of	O
embryonic	O
development	O
because	O
of	O
an	O
increase	O
in	O
folate	O
and	O
vitamin	O
intake	O
by	O
women	B
in	O
the	O
periconceptional	O
period	O
that	O
began	O
to	O
be	O
established	O
in	O
Spain	O
in	O
the	O
last	O
quarter	O
of	O
the	O
20th	O
century	O
[	O
18	O
,	O
19	O
]	O
.	O

Higher	O
frequencies	O
for	O
the	O
T	O
allele	O
and	O
TT	O
genotype	O
in	O
our	O
population	O
are	O
observed	O
in	O
the	O
living	O
and	O
SA	O
populations	O
.	O

Competing	O
interests	O

The	O
authors	O
declare	O
that	O
they	O
have	O
no	O
competing	O
interests	O
.	O

Authors	O
'	O
contributions	O

AMO	O
performed	O
the	O
statistical	O
analysis	O
,	O
helped	O
to	O
draft	O
the	O
manuscript	O
and	O
revised	O
it	O
for	O
publication	O
.	O

GC	O
is	O
the	O
corresponding	O
author	O
,	O
participated	O
in	O
the	O
acquisition	O
of	O
samples	O
and	O
carried	O
out	O
the	O
genotyping	O
.	O

ARP	O
carried	O
out	O
the	O
bibliographic	O
search	O
and	O
helped	O
to	O
draft	O
the	O
manuscript	O
.	O

AJJ	O
participated	O
in	O
the	O
selection	O
and	O
the	O
processing	O
of	O
samples	O
.	O

MJG	O
coordinated	O
the	O
laboratory	O
work	O
and	O
selected	O
the	O
genotyping	O
method	O
.	O

AR	O
selected	O
the	O
control	O
subjects	O
and	O
designed	O
the	O
consent	O
form	O
.	O

MR	O
helped	O
in	O
the	O
interpretation	O
of	O
data	O
and	O
tables	O
performance	O
.	O

ARE	O
conceived	O
the	O
study	O
and	O
is	O
the	O
guarantor	O
of	O
this	O
work	O
and	O
the	O
general	O
coordinator	O
.	O

All	O
authors	O
read	O
and	O
approved	O
the	O
final	O
manuscript	O
.	O

Pre	O
-	O
publication	O
history	O

The	O
pre	O
-	O
publication	O
history	O
for	O
this	O
paper	O
can	O
be	O
accessed	O
here	O
:	O

Protein	O
subfamily	O
assignment	O
using	O
the	O
Conserved	O
Domain	O
Database	O

Abstract	O

Background	O

Domains	O
,	O
evolutionarily	O
conserved	O
units	O
of	O
proteins	O
,	O
are	O
widely	O
used	O
to	O
classify	O
protein	O
sequences	O
and	O
infer	O
protein	O
function	O
.	O

Often	O
,	O
two	O
or	O
more	O
overlapping	O
domain	O
models	O
match	O
a	O
region	O
of	O
a	O
protein	O
sequence	O
.	O

Therefore	O
,	O
procedures	O
are	O
required	O
to	O
choose	O
appropriate	O
domain	O
annotations	O
for	O
the	O
protein	O
.	O

Here	O
,	O
we	O
propose	O
a	O
method	O
for	O
assigning	O
NCBI	O
-	O
curated	O
domains	O
from	O
the	O
Curated	O
Domain	O
Database	O
(	O
CDD	O
)	O
that	O
takes	O
into	O
account	O
the	O
organization	O
of	O
the	O
domains	O
into	O
hierarchies	O
of	O
homologous	O
domain	O
models	O
.	O

Findings	O

Our	O
analysis	O
of	O
alignment	O
scores	O
from	O
NCBI	O
-	O
curated	O
domain	O
assignments	O
suggests	O
that	O
identifying	O
the	O
correct	O
model	O
among	O
closely	O
related	O
models	O
is	O
more	O
difficult	O
than	O
choosing	O
between	O
non	O
-	O
overlapping	O
domain	O
models	O
.	O

We	O
find	O
that	O
simple	O
heuristics	O
based	O
on	O
sorting	O
scores	O
and	O
domain	O
-	O
specific	O
thresholds	O
are	O
effective	O
at	O
reducing	O
classification	O
error	O
.	O

In	O
fact	O
,	O
in	O
our	O
test	O
set	O
,	O
the	O
heuristics	O
result	O
in	O
almost	O
90	O
%	O
of	O
current	O
misclassifications	O
due	O
to	O
missing	O
domain	O
subfamilies	O
being	O
replaced	O
by	O
more	O
generic	O
domain	O
assignments	O
,	O
thereby	O
eliminating	O
a	O
significant	O
amount	O
of	O
error	O
within	O
the	O
database	O
.	O

Conclusion	O

Our	O
proposed	O
domain	O
subfamily	O
assignment	O
rule	O
has	O
been	O
incorporated	O
into	O
the	O
CD	O
-	O
Search	O
software	O
for	O
assigning	O
CDD	O
domains	O
to	O
query	O
protein	O
sequences	O
and	O
has	O
significantly	O
improved	O
pre	O
-	O
calculated	O
domain	O
annotations	O
on	O
protein	O
sequences	O
in	O
NCBI	O
'	O
s	O
Entrez	O
resource	O
.	O

Background	O

A	O
major	O
goal	O
in	O
the	O
post	O
-	O
genomic	O
world	O
is	O
to	O
infer	O
protein	O
function	O
from	O
sequence	O
information	O
.	O

One	O
popular	O
approach	O
is	O
to	O
classify	O
protein	O
families	O
or	O
domains	O
by	O
grouping	O
homologous	O
sequences	O
and	O
annotating	O
the	O
groups	O
with	O
properties	O
such	O
as	O
general	O
function	O
,	O
intracellular	O
location	O
,	O
three	O
-	O
dimensional	O
structure	O
,	O
conserved	O
sequence	O
patterns	O
or	O
motifs	O
,	O
evolutionary	O
origin	O
,	O
and	O
binding	O
and	O
active	O
sites	O
.	O

Novel	O
proteins	O
can	O
be	O
characterized	O
quickly	O
by	O
assigning	O
a	O
group	O
via	O
profile	O
search	O
methods	O
.	O

However	O
,	O
more	O
than	O
one	O
family	O
or	O
subfamily	O
may	O
exhibit	O
similarity	O
to	O
overlapping	O
sequence	O
intervals	O
and	O
to	O
a	O
degree	O
that	O
seems	O
convincing	O
(	O
Figure	O
1	O
)	O
.	O

Assigning	O
the	O
protein	O
to	O
the	O
correct	O
group	O
not	O
only	O
yields	O
the	O
correct	O
annotations	O
,	O
but	O
may	O
also	O
help	O
to	O
avoid	O
propagating	O
annotation	O
errors	O
and	O
alleviate	O
current	O
issues	O
with	O
mislabelling	O
in	O
protein	O
sequence	O
databases	O
[	O
1	O
,	O
2	O
]	O
.	O

Here	O
,	O
we	O
examine	O
the	O
problem	O
of	O
making	O
correct	O
domain	O
assignments	O
from	O
the	O
Conserved	O
Domain	O
Database	O
[	O
3	O
,	O
4	O
]	O
.	O

Domains	O
are	O
evolutionarily	O
conserved	O
units	O
in	O
proteins	O
and	O
frequently	O
correspond	O
to	O
recurrent	O
structural	O
and	O
functional	O
units	O
.	O

The	O
particular	O
function	O
of	O
a	O
protein	O
depends	O
on	O
its	O
combination	O
of	O
domains	O
;	O
two	O
-	O
thirds	O
of	O
prokaryotic	O
proteins	O
and	O
80	O
%	O
of	O
eukaryotic	O
proteins	O
have	O
more	O
than	O
one	O
domain	O
.	O

To	O
create	O
new	O
protein	O
functions	O
,	O
novel	O
domain	O
architectures	O
arise	O
through	O
domain	O
rearrangement	O
and	O
recombination	O
,	O
frequently	O
through	O
gene	O
duplication	O
and	O
fission	O
or	O
fusion	O
events	O
[	O
5	O
,	O
6	O
]	O
.	O

A	O
domain	O
may	O
be	O
represented	O
as	O
a	O
multiple	O
sequence	O
alignment	O
(	O
MSA	O
)	O
of	O
homologous	O
sequence	O
fragments	O
.	O

To	O
identify	O
the	O
domains	O
in	O
a	O
query	O
protein	O
sequence	O
,	O
the	O
MSAs	O
are	O
converted	O
into	O
scoring	O
models	O
such	O
as	O
hidden	O
Markov	O
model	O
or	O
position	O
-	O
specific	O
scoring	O
matrix	O
for	O
use	O
with	O
database	O
search	O
algorithms	O
such	O
HMMER	O
[	O
7	O
]	O
and	O
RPS	O
-	O
BLAST	O
[	O
8	O
]	O
.	O

To	O
refine	O
protein	O
annotation	O
,	O
domains	O
models	O
may	O
be	O
subdivided	O
to	O
represent	O
more	O
specific	O
functions	O
or	O
conserved	O
features	O
.	O

CDD	O
curators	O
apply	O
phylogenetic	O
and	O
structural	O
analysis	O
to	O
construct	O
hierarchies	O
of	O
homologous	O
domain	O
models	O
,	O
related	O
by	O
common	O
descent	O
,	O
to	O
reflect	O
aspects	O
of	O
their	O
evolutionary	O
histories	O
[	O
3	O
,	O
4	O
]	O
.	O

Curation	O
follows	O
an	O
iterative	O
procedure	O
to	O
split	O
domain	O
models	O
into	O
subfamilies	O
that	O
redistributes	O
sequences	O
into	O
more	O
narrowly	O
defined	O
models	O
.	O

In	O
the	O
hierarchy	O
tree	O
structure	O
,	O
the	O
leaf	O
domains	O
represent	O
highly	O
conserved	O
and	O
often	O
orthologous	O
protein	O
subgroups	O
.	O

Their	O
precursor	O
(	O
internal	O
)	O
domains	O
,	O
on	O
the	O
other	O
hand	O
,	O
reflect	O
ancient	O
gene	O
duplication	O
events	O
,	O
as	O
CDD	O
aims	O
to	O
categorize	O
ancient	O
conserved	O
domain	O
families	O
.	O

It	O
may	O
seem	O
natural	O
that	O
once	O
the	O
profiles	O
have	O
been	O
defined	O
,	O
the	O
most	O
significant	O
match	O
to	O
a	O
query	O
sequence	O
is	O
the	O
correct	O
one	O
.	O

Indeed	O
,	O
domains	O
from	O
Pfam	O
[	O
9	O
,	O
10	O
]	O
and	O
SMART	O
[	O
11	O
]	O
are	O
assigned	O
following	O
the	O
lowest	O
alignment	O
E	O
-	O
value	O
that	O
exceeds	O
a	O
family	O
-	O
specific	O
cutoff	O
[	O
12	O
,	O
13	O
]	O
.	O

This	O
straightforward	O
approach	O
works	O
well	O
when	O
the	O
candidate	O
domains	O
are	O
disjoint	O
.	O

Domain	O
subfamilies	O
may	O
be	O
obtained	O
through	O
automated	O
methods	O
such	O
as	O
the	O
SCI	O
-	O
PHY	O
algorithm	O
for	O
identifying	O
functional	O
subtypes	O
of	O
known	O
domain	O
families	O
[	O
14	O
,	O
15	O
]	O
or	O
by	O
mirroring	O
other	O
hierarchical	O
domain	O
classifications	O
such	O
as	O
SCOP	O
[	O
16	O
]	O
and	O
CATH	O
[	O
17	O
]	O
.	O

However	O
,	O
subfamily	O
assignment	O
methods	O
generally	O
attempt	O
to	O
classify	O
a	O
member	O
of	O
a	O
family	O
at	O
the	O
subfamily	O
level	O
given	O
that	O
the	O
family	O
is	O
known	O
,	O
as	O
in	O
a	O
statistical	O
pairwise	O
/	O
profile	O
method	O
proposed	O
for	O
SUPERFAMILY	O
[	O
18	O
-	O
20	O
]	O
.	O

The	O
systematic	O
arrangement	O
of	O
CDD	O
domains	O
requires	O
identifying	O
the	O
most	O
suitable	O
level	O
of	O
resolution	O
among	O
domain	O
models	O
that	O
offer	O
more	O
or	O
less	O
fine	O
-	O
grained	O
descriptions	O
of	O
a	O
protein	O
.	O

We	O
take	O
the	O
viewpoint	O
that	O
if	O
a	O
protein	O
cannot	O
be	O
associated	O
unambiguously	O
with	O
a	O
specific	O
subgroup	O
or	O
may	O
be	O
a	O
member	O
of	O
a	O
subgroup	O
that	O
has	O
not	O
been	O
defined	O
,	O
the	O
protein	O
can	O
be	O
assigned	O
a	O
more	O
generic	O
domain	O
model	O
or	O
the	O
superfamily	O
in	O
general	O
.	O

Consequently	O
the	O
ideal	O
domain	O
assignment	O
to	O
a	O
query	O
sequence	O
will	O
be	O
the	O
most	O
specific	O
domain	O
,	O
within	O
a	O
candidate	O
hierarchy	O
,	O
with	O
a	O
strong	O
match	O
to	O
the	O
sequence	O
.	O

Here	O
,	O
we	O
analyze	O
a	O
set	O
of	O
correct	O
domain	O
assignments	O
from	O
CDD	O
to	O
establish	O
an	O
improved	O
method	O
for	O
assigning	O
domains	O
to	O
query	O
sequences	O
.	O

The	O
effectiveness	O
of	O
a	O
traditional	O
alignment	O
score	O
and	O
domain	O
-	O
specific	O
threshold	O
is	O
of	O
particular	O
interest	O
,	O
as	O
this	O
method	O
is	O
efficient	O
and	O
makes	O
use	O
of	O
alignment	O
information	O
that	O
is	O
already	O
computed	O
for	O
CDD	O
.	O

Constructing	O
a	O
benchmark	O
set	O
of	O
correct	O
domain	O
assignments	O

To	O
benchmark	O
domain	O
assignment	O
heuristics	O
,	O
a	O
reference	O
set	O
of	O
domain	O
assignments	O
is	O
constructed	O
from	O
the	O
NCBI	O
-	O
curated	O
portion	O
of	O
CDD	O
v	O
.	O

2	O
.	O
12	O
.	O

This	O
set	O
contains	O
every	O
sequence	O
fragment	O
present	O
among	O
the	O
MSAs	O
and	O
its	O
domain	O
assignment	O
.	O

The	O
NCBI	O
-	O
curated	O
domains	O
have	O
undergone	O
rigorous	O
testing	O
to	O
optimize	O
the	O
MSAs	O
and	O
distributions	O
of	O
representative	O
sequence	O
fragments	O
.	O

The	O
correct	O
or	O
most	O
specific	O
domain	O
for	O
each	O
sequence	O
in	O
a	O
hierarchy	O
is	O
defined	O
as	O
the	O
domain	O
having	O
no	O
descendant	O
that	O
contains	O
an	O
overlapping	O
sequence	O
interval	O
.	O

Two	O
sequence	O
intervals	O
from	O
one	O
protein	O
are	O
said	O
to	O
overlap	O
if	O
one	O
sequence	O
interval	O
contains	O
at	O
least	O
30	O
%	O
of	O
the	O
positions	O
of	O
the	O
other	O
.	O

While	O
each	O
sequence	O
has	O
been	O
placed	O
in	O
the	O
most	O
specific	O
domain	O
model	O
that	O
characterizes	O
it	O
,	O
this	O
step	O
is	O
required	O
as	O
parent	O
and	O
child	O
domains	O
share	O
overlapping	O
sequences	O
(	O
Figure	O
1	O
)	O
.	O

Sequences	O
with	O
overlapping	O
regions	O
from	O
more	O
than	O
one	O
hierarchy	O
are	O
counted	O
once	O
for	O
each	O
hierarchy	O
.	O

Non	O
-	O
overlapping	O
regions	O
of	O
a	O
protein	O
are	O
treated	O
independently	O
.	O

Alignments	O
between	O
all	O
NCBI	O
-	O
curated	O
domains	O
and	O
proteins	O
present	O
in	O
the	O
public	O
Entrez	O
protein	O
set	O
at	O
time	O
of	O
analysis	O
(	O
September	O
2007	O
)	O
[	O
21	O
]	O
have	O
been	O
pre	O
-	O
computed	O
using	O
RPS	O
-	O
BLAST	O
.	O

In	O
this	O
analysis	O
,	O
the	O
alignment	O
score	O
refers	O
to	O
the	O
bitscore	O
,	O
a	O
normalized	O
version	O
of	O
the	O
raw	O
alignment	O
score	O
between	O
the	O
query	O
sequence	O
and	O
the	O
PSSM	O
,	O
which	O
allows	O
alignments	O
from	O
different	O
searches	O
to	O
be	O
compared	O
.	O

The	O
bitscore	O
corresponds	O
roughly	O
to	O
the	O
alignment	O
E	O
-	O
value	O
and	O
is	O
used	O
instead	O
to	O
avoid	O
real	O
value	O
rounding	O
issues	O
.	O

A	O
significant	O
PSSM	O
-	O
sequence	O
alignment	O
is	O
called	O
a	O
hit	O
,	O
for	O
brevity	O
.	O

We	O
call	O
a	O
match	O
between	O
a	O
sequence	O
region	O
and	O
its	O
correct	O
domain	O
a	O
self	O
hit	O
to	O
distinguish	O
it	O
from	O
other	O
hits	O
to	O
overlapping	O
sequence	O
regions	O
.	O

Other	O
hits	O
to	O
the	O
sequences	O
in	O
the	O
reference	O
dataset	O
serve	O
as	O
examples	O
of	O
incorrect	O
domain	O
assignments	O
.	O

CDD	O
v	O
2	O
.	O
12	O
contains	O
3078	O
NCBI	O
-	O
curated	O
domains	O
in	O
495	O
hierarchies	O
,	O
including	O
298	O
single	O
-	O
domain	O
"	O
hierarchies	O
"	O
and	O
197	O
trees	O
with	O
2357	O
leaf	O
and	O
423	O
internal	O
domains	O
.	O

Many	O
sequence	O
fragments	O
used	O
to	O
construct	O
the	O
NCBI	O
-	O
curated	O
domain	O
profiles	O
come	O
from	O
proteins	O
that	O
have	O
been	O
replaced	O
with	O
newer	O
versions	O
or	O
declared	O
obsolete	O
.	O

Among	O
the	O
109186	O
representative	O
sequences	O
in	O
NCBI	O
-	O
curated	O
domain	O
hierarchies	O
,	O
over	O
21	O
%	O
have	O
no	O
hits	O
and	O
more	O
than	O
90	O
%	O
of	O
those	O
sequences	O
are	O
no	O
longer	O
present	O
in	O
Entrez	O
.	O

This	O
analysis	O
excludes	O
the	O
149	O
curated	O
domains	O
without	O
corresponding	O
live	O
data	O
in	O
Entrez	O
,	O
leaving	O
2929	O
domains	O
.	O

Performance	O
of	O
a	O
simple	O
high	O
-	O
score	O
assignment	O
method	O

We	O
begin	O
by	O
assessing	O
the	O
performance	O
of	O
the	O
previous	O
method	O
for	O
assigning	O
NCBI	O
-	O
curated	O
domains	O
from	O
CDD	O
.	O

The	O
NCBI	O
CD	O
-	O
Search	O
tool	O
[	O
22	O
]	O
has	O
historically	O
relied	O
on	O
alignment	O
E	O
-	O
value	O
and	O
properties	O
such	O
as	O
the	O
source	O
domain	O
database	O
to	O
highlight	O
one	O
or	O
a	O
few	O
most	O
likely	O
domain	O
assignments	O
,	O
without	O
claiming	O
to	O
pinpoint	O
the	O
correct	O
domain	O
assignment	O
.	O

Analysis	O
of	O
all	O
hits	O
to	O
the	O
sequences	O
in	O
the	O
benchmark	O
set	O
reveals	O
that	O
assigning	O
domains	O
by	O
high	O
alignment	O
score	O
alone	O
achieves	O
96	O
%	O
accuracy	O
over	O
all	O
sequences	O
and	O
100	O
%	O
accuracy	O
over	O
the	O
representative	O
sequences	O
for	O
91	O
.	O
5	O
%	O
of	O
domain	O
models	O
.	O

Further	O
,	O
categorizing	O
non	O
-	O
self	O
hits	O
by	O
their	O
hierarchical	O
relationships	O
to	O
the	O
correct	O
domain	O
reveals	O
that	O
assigning	O
to	O
a	O
subclass	O
of	O
the	O
correct	O
domain	O
is	O
the	O
most	O
common	O
type	O
of	O
error	O
when	O
a	O
sequence	O
matches	O
the	O
correct	O
domain	O
and	O
other	O
domains	O
(	O
Table	O
1	O
)	O
.	O

For	O
simplicity	O
,	O
all	O
non	O
-	O
self	O
hits	O
are	O
labelled	O
as	O
incorrect	O
hits	O
in	O
the	O
tables	O
although	O
some	O
child	O
/	O
descendant	O
and	O
parent	O
/	O
ancestor	O
assignments	O
may	O
not	O
be	O
regarded	O
as	O
actual	O
classification	O
errors	O
.	O

Child	O
/	O
descendant	O
domains	O
score	O
higher	O
than	O
the	O
self	O
hit	O
for	O
21	O
.	O
8	O
%	O
of	O
sequences	O
with	O
both	O
types	O
of	O
hits	O
.	O

These	O
higher	O
scores	O
may	O
reflect	O
computational	O
bias	O
from	O
longer	O
profiles	O
,	O
overly	O
cautious	O
assignment	O
of	O
a	O
sequence	O
to	O
a	O
more	O
generic	O
domain	O
,	O
or	O
missing	O
subfamilies	O
.	O

In	O
contrast	O
,	O
higher	O
scores	O
from	O
parent	O
/	O
ancestor	O
domains	O
or	O
domains	O
from	O
other	O
branches	O
of	O
a	O
hierarchy	O
are	O
rarely	O
observed	O
.	O

For	O
additional	O
data	O
and	O
discussion	O
of	O
all	O
analyses	O
described	O
in	O
this	O
document	O
,	O
see	O
[	O
Additional	O
file	O
1	O
]	O
.	O

We	O
define	O
a	O
score	O
threshold	O
for	O
each	O
domain	O
to	O
be	O
the	O
lowest	O
self	O
-	O
hit	O
score	O
to	O
that	O
domain	O
among	O
all	O
of	O
its	O
sequences	O
in	O
the	O
benchmark	O
set	O
.	O

This	O
additional	O
heuristic	O
,	O
in	O
particular	O
,	O
reduces	O
incorrect	O
assignments	O
to	O
subclasses	O
as	O
only	O
9	O
.	O
1	O
%	O
of	O
hits	O
to	O
subclasses	O
score	O
above	O
the	O
thresholds	O
for	O
those	O
subclasses	O
(	O
Table	O
2	O
)	O
.	O

The	O
threshold	O
definition	O
works	O
around	O
the	O
issue	O
of	O
small	O
data	O
size	O
-	O
over	O
60	O
%	O
of	O
domains	O
have	O
20	O
or	O
fewer	O
self	O
hits	O
-	O
and	O
addresses	O
variances	O
in	O
scores	O
between	O
domains	O
due	O
to	O
properties	O
such	O
as	O
length	O
and	O
residue	O
composition	O
,	O
or	O
practical	O
issues	O
such	O
as	O
incomplete	O
local	O
alignments	O
,	O
which	O
are	O
not	O
considered	O
by	O
simple	O
high	O
-	O
score	O
heuristics	O
.	O

The	O
definition	O
is	O
more	O
restrictive	O
than	O
its	O
Pfam	O
counterpart	O
,	O
the	O
minimum	O
alignment	O
score	O
among	O
all	O
sequences	O
in	O
the	O
automated	O
"	O
full	O
alignment	O
"	O
,	O
as	O
NCBI	O
-	O
curated	O
hierarchies	O
in	O
CDD	O
tend	O
to	O
present	O
a	O
finer	O
-	O
grained	O
classification	O
of	O
a	O
protein	O
domain	O
family	O
.	O

Proposed	O
rule	O
for	O
specific	O
domain	O
assignment	O

We	O
propose	O
to	O
label	O
a	O
single	O
domain	O
as	O
correct	O
or	O
specific	O
for	O
a	O
protein	O
sequence	O
region	O
if	O
its	O
alignment	O
score	O
is	O
highest	O
among	O
all	O
domains	O
that	O
align	O
to	O
overlapping	O
regions	O
of	O
the	O
protein	O
sequence	O
and	O
the	O
score	O
exceeds	O
a	O
pre	O
-	O
calculated	O
threshold	O
for	O
the	O
domain	O
,	O
defined	O
as	O
the	O
minimum	O
alignment	O
score	O
among	O
confirmed	O
members	O
of	O
the	O
domain	O
.	O

Sequence	O
intervals	O
that	O
are	O
difficult	O
to	O
group	O
with	O
a	O
specific	O
subclass	O
with	O
high	O
confidence	O
following	O
this	O
rule	O
may	O
receive	O
only	O
generic	O
domain	O
assignments	O
.	O

Assuming	O
that	O
the	O
set	O
of	O
overlapping	O
domains	O
represents	O
an	O
ancient	O
domain	O
superfamily	O
,	O
such	O
a	O
generic	O
assignment	O
would	O
be	O
characterized	O
as	O
membership	O
with	O
the	O
respective	O
superfamily	O
.	O

Reducing	O
misclassifications	O
and	O
errors	O
due	O
to	O
missing	O
subfamilies	O

A	O
more	O
concrete	O
picture	O
of	O
the	O
effect	O
of	O
the	O
proposed	O
rule	O
may	O
be	O
gleaned	O
by	O
quantifying	O
misclassifications	O
,	O
defined	O
to	O
be	O
either	O
descendants	O
of	O
the	O
correct	O
domain	O
or	O
domains	O
that	O
lie	O
in	O
other	O
branches	O
of	O
the	O
correct	O
hierarchy	O
.	O

Averaged	O
over	O
domains	O
in	O
multi	O
-	O
domain	O
hierarchies	O
and	O
counting	O
only	O
sequences	O
with	O
self	O
hits	O
,	O
the	O
misclassification	O
rate	O
using	O
high	O
scores	O
only	O
is	O
2	O
.	O
6	O
%	O
.	O

Incorporating	O
score	O
thresholds	O
to	O
eliminate	O
low	O
-	O
scoring	O
best	O
hits	O
reduces	O
the	O
misclassification	O
rate	O
to	O
0	O
.	O
85	O
%	O
.	O

Misclassifications	O
may	O
also	O
be	O
used	O
to	O
estimate	O
error	O
due	O
to	O
missing	O
subfamilies	O
.	O

Not	O
all	O
subclasses	O
in	O
a	O
domain	O
hierarchy	O
may	O
have	O
been	O
identified	O
as	O
the	O
available	O
sequence	O
databases	O
only	O
provide	O
a	O
terse	O
snapshot	O
of	O
protein	O
domain	O
diversity	O
.	O

We	O
simulate	O
a	O
cross	O
-	O
validation	O
experiment	O
to	O
ask	O
,	O
if	O
an	O
existing	O
domain	O
model	O
were	O
missing	O
from	O
a	O
hierarchy	O
,	O
what	O
fraction	O
of	O
its	O
sequence	O
intervals	O
have	O
best	O
hits	O
to	O
other	O
models	O
in	O
the	O
hierarchy	O
that	O
are	O
not	O
ancestors	O
of	O
the	O
correct	O
model	O
?	O

Averaged	O
over	O
leaf	O
domains	O
,	O
50	O
.	O
9	O
%	O
of	O
domain	O
assignments	O
made	O
from	O
high	O
alignment	O
score	O
alone	O
are	O
misclassifications	O
,	O
compared	O
to	O
6	O
.	O
0	O
%	O
of	O
domain	O
assignments	O
after	O
thresholds	O
are	O
used	O
to	O
screen	O
hits	O
.	O

Function	O
and	O
classification	O
through	O
specific	O
domain	O
assignments	O
:	O
Glycyl	O
radical	O
enzymes	O

To	O
illustrate	O
the	O
effect	O
of	O
our	O
proposed	O
method	O
,	O
we	O
examine	O
domain	O
assignments	O
from	O
the	O
glycyl	O
radical	O
enzymes	O
(	O
RNR	O
_	O
PFL	O
hierarchy	O
)	O
.	O

Its	O
subgroups	O
have	O
distinct	O
and	O
important	O
functions	O
,	O
including	O
ribonucleotide	O
reductases	O
(	O
RNRs	O
)	O
,	O
which	O
synthesize	O
deoxyribonucleotides	O
,	O
and	O
pyruvate	O
-	O
formate	O
lysases	O
(	O
PFLs	O
)	O
,	O
a	O
family	O
of	O
catabolic	O
enzymes	O
.	O

The	O
proposed	O
method	O
places	O
the	O
sequence	O
[	O
Entrez	O
:	O
CAA42118	O
]	O
into	O
RNR	O
class	O
1	O
and	O
places	O
[	O
Entrez	O
:	O
AAZ61477	O
]	O
into	O
RNR	O
class	O
-	O
1	O
-	O
like	O
domain	O
.	O

The	O
functions	O
of	O
these	O
proteins	O
are	O
inferred	O
by	O
their	O
subclass	O
.	O

Other	O
proteins	O
receive	O
generic	O
assignments	O
to	O
this	O
family	O
.	O

For	O
example	O
,	O
PFL2	O
(	O
cd01677	O
)	O
is	O
the	O
best	O
match	O
to	O
[	O
Entrez	O
:	O
ABX41552	O
]	O
and	O
[	O
Entrez	O
:	O
EDQ26237	O
]	O
with	O
alignment	O
scores	O
that	O
fall	O
short	O
of	O
the	O
PFL2	O
threshold	O
.	O

The	O
first	O
alignment	O
includes	O
a	O
long	O
insertion	O
(	O
gap	O
)	O
,	O
and	O
the	O
latter	O
exhibits	O
weak	O
sequence	O
similarity	O
;	O
in	O
both	O
of	O
these	O
scenarios	O
the	O
transfer	O
of	O
functional	O
annotation	O
may	O
not	O
be	O
straightforward	O
.	O

Domain	O
assignments	O
also	O
help	O
to	O
make	O
biological	O
insights	O
.	O

RNRs	O
fall	O
into	O
classes	O
that	O
use	O
different	O
mechanisms	O
and	O
/	O
or	O
cofactors	O
.	O

Class	O
1	O
is	O
oxygen	O
dependent	O
and	O
class	O
3	O
is	O
used	O
by	O
strictly	O
or	O
facultative	O
anaerobic	O
organisms	O
.	O

RNR	O
_	O
1	O
_	O
like	O
has	O
a	O
similar	O
active	O
site	O
to	O
class	O
1	O
and	O
at	O
the	O
time	O
of	O
curation	O
,	O
no	O
specific	O
literature	O
was	O
available	O
about	O
this	O
subclass	O
.	O

We	O
observed	O
that	O
the	O
strictly	O
anaerobic	O
organism	O
Chlorobium	B
limicola	I
DSM	O
24	O
has	O
RNR	O
_	O
3	O
proteins	O
(	O
e	O
.	O
g	O
.	O
[	O
Entrez	O
:	O
ZP	O
_	O
00512827	O
]	O
)	O
as	O
well	O
as	O
an	O
enzyme	O
(	O
[	O
Entrez	O
:	O
ZP	O
_	O
00512727	O
]	O
)	O
that	O
matches	O
RNR	O
_	O
1	O
_	O
like	O
,	O
suggesting	O
that	O
RNR	O
_	O
1	O
_	O
like	O
,	O
a	O
subfamily	O
lacking	O
experimental	O
characterization	O
,	O
may	O
contain	O
non	O
-	O
oxygen	O
dependent	O
versions	O
of	O
RNR	O
_	O
1	O
.	O

Discussion	O

While	O
many	O
sequences	O
can	O
be	O
classified	O
by	O
sequence	O
similarity	O
,	O
profiles	O
of	O
protein	O
domain	O
families	O
make	O
it	O
possible	O
to	O
quickly	O
classify	O
more	O
distant	O
homologs	O
[	O
23	O
]	O
and	O
can	O
better	O
handle	O
multi	O
-	O
domain	O
proteins	O
.	O

An	O
important	O
step	O
in	O
transferring	O
annotations	O
from	O
known	O
protein	O
families	O
is	O
identifying	O
the	O
subclass	O
that	O
provides	O
the	O
best	O
characterization	O
for	O
the	O
protein	O
.	O

Here	O
,	O
we	O
conducted	O
the	O
first	O
focused	O
analysis	O
of	O
domain	O
assignments	O
from	O
CDD	O
in	O
order	O
to	O
assess	O
existing	O
methods	O
for	O
domain	O
and	O
domain	O
subfamily	O
assignment	O
and	O
identify	O
ways	O
to	O
improve	O
the	O
quality	O
of	O
assignments	O
.	O

We	O
find	O
that	O
best	O
-	O
scoring	O
hits	O
are	O
sometimes	O
too	O
specific	O
,	O
causing	O
a	O
sequence	O
to	O
be	O
mislabelled	O
by	O
a	O
subfamily	O
of	O
the	O
correct	O
domain	O
.	O

We	O
propose	O
a	O
subclass	O
assignment	O
procedure	O
that	O
enables	O
concrete	O
assignments	O
,	O
computed	O
quickly	O
using	O
existing	O
data	O
,	O
and	O
demonstrate	O
that	O
this	O
procedure	O
largely	O
avoids	O
over	O
-	O
predictions	O
or	O
false	O
positive	O
assignments	O
and	O
is	O
robust	O
enough	O
to	O
deal	O
with	O
situations	O
such	O
as	O
incomplete	O
hierarchies	O
in	O
which	O
not	O
all	O
subfamilies	O
have	O
been	O
identified	O
.	O

We	O
elected	O
to	O
not	O
employ	O
standard	O
jack	O
-	O
knife	O
or	O
cross	O
-	O
validation	O
testing	O
for	O
a	O
sequence	O
against	O
its	O
correct	O
domain	O
,	O
as	O
the	O
task	O
is	O
to	O
classify	O
sequence	O
fragments	O
that	O
are	O
very	O
similar	O
to	O
a	O
subfamily	O
,	O
where	O
the	O
subfamily	O
model	O
is	O
also	O
constructed	O
from	O
very	O
similar	O
sequences	O
.	O

Although	O
the	O
sequence	O
and	O
domain	O
databases	O
evolve	O
rapidly	O
,	O
we	O
expect	O
our	O
findings	O
to	O
provide	O
an	O
accurate	O
snapshot	O
for	O
some	O
time	O
.	O

A	O
version	O
of	O
our	O
proposed	O
method	O
has	O
been	O
incorporated	O
into	O
the	O
current	O
version	O
of	O
the	O
CD	O
-	O
Search	O
program	O
and	O
the	O
pre	O
-	O
calculated	O
annotation	O
of	O
proteins	O
with	O
domains	O
in	O
NCBI	O
'	O
s	O
Entrez	O
system	O
.	O

Domain	O
assignments	O
to	O
specific	O
orthologous	O
subfamilies	O
or	O
ancient	O
subfamilies	O
are	O
distinguished	O
from	O
non	O
-	O
specific	O
assignments	O
to	O
a	O
domain	O
superfamily	O
.	O

High	O
-	O
confidence	O
annotation	O
of	O
functional	O
sites	O
is	O
also	O
provided	O
following	O
these	O
results	O
.	O

We	O
hope	O
the	O
improved	O
ability	O
to	O
quickly	O
and	O
accurately	O
classify	O
proteins	O
will	O
be	O
a	O
valuable	O
step	O
toward	O
simplifying	O
protein	O
sequence	O
analysis	O
and	O
the	O
computational	O
annotation	O
of	O
genomes	O
.	O

Competing	O
interests	O

The	O
authors	O
declare	O
that	O
they	O
have	O
no	O
competing	O
interests	O
.	O

Authors	O
'	O
contributions	O

JF	O
carried	O
out	O
the	O
experiments	O
and	O
drafted	O
the	O
manuscript	O
.	O

AMB	O
conceived	O
the	O
study	O
,	O
participated	O
in	O
its	O
design	O
,	O
and	O
helped	O
to	O
draft	O
the	O
manuscript	O
.	O

Supplementary	O
Material	O

Identification	O
of	O
recruitment	O
and	O
retention	O
strategies	O
for	O
rehabilitation	O
professionals	O
in	O
Ontario	O
,	O
Canada	O
:	O
results	O
from	O
expert	O
panels	O

Abstract	O

Background	O

Demand	O
for	O
rehabilitation	O
services	O
is	O
expected	O
to	O
increase	O
due	O
to	O
factors	O
such	O
as	O
an	O
aging	O
population	O
,	O
workforce	O
pressures	O
,	O
rise	O
in	O
chronic	O
and	O
complex	O
multi	O
-	O
system	O
disorders	O
,	O
advances	O
in	O
technology	O
,	O
and	O
changes	O
in	O
interprofessional	O
health	O
service	O
delivery	O
models	O
.	O

However	O
,	O
health	O
human	B
resource	O
(	O
HHR	O
)	O
strategies	O
for	O
Canadian	O
rehabilitation	O
professionals	O
are	O
lagging	O
behind	O
other	O
professional	O
groups	O
such	O
as	O
physicians	O
and	O
nurses	O
.	O

The	O
objectives	O
of	O
this	O
study	O
were	O
:	O
1	O
)	O
to	O
identify	O
recruitment	O
and	O
retention	O
strategies	O
of	O
rehabilitation	O
professionals	O
including	O
occupational	O
therapists	O
,	O
physical	O
therapists	O
and	O
speech	O
language	O
pathologists	O
from	O
the	O
literature	O
;	O
and	O
2	O
)	O
to	O
investigate	O
both	O
the	O
importance	O
and	O
feasibility	O
of	O
the	O
identified	O
strategies	O
using	O
expert	O
panels	O
amongst	O
HHR	O
and	O
education	O
experts	O
.	O

Methods	O

A	O
review	O
of	O
the	O
literature	O
was	O
conducted	O
to	O
identify	O
recruitment	O
and	O
retention	O
strategies	O
for	O
rehabilitation	O
professionals	O
.	O

Two	O
expert	O
panels	O
,	O
one	O
on	O
Recruitment	O
and	O
Retention	O
and	O
the	O
other	O
on	O
Education	O
were	O
convened	O
to	O
determine	O
the	O
importance	O
and	O
feasibility	O
of	O
the	O
identified	O
strategies	O
.	O

A	O
modified	O
-	O
delphi	O
process	O
was	O
used	O
to	O
gain	O
consensus	O
and	O
to	O
rate	O
the	O
identified	O
strategies	O
along	O
these	O
two	O
dimensions	O
.	O

Results	O

A	O
total	O
of	O
34	O
strategies	O
were	O
identified	O
by	O
the	O
Recruitment	O
and	O
Retention	O
and	O
Education	O
expert	O
panels	O
as	O
being	O
important	O
and	O
feasible	O
for	O
the	O
development	O
of	O
a	O
HHR	O
plan	O
for	O
recruitment	O
and	O
retention	O
of	O
rehabilitation	O
professionals	O
.	O

Seven	O
were	O
categorized	O
under	O
the	O
Quality	O
of	O
Worklife	O
and	O
Work	O
Environment	O
theme	O
,	O
another	O
seven	O
in	O
Financial	O
Incentives	O
and	O
Marketing	O
,	O
two	O
in	O
Workload	O
and	O
Skill	O
Mix	O
,	O
thirteen	O
in	O
Professional	O
Development	O
and	O
five	O
in	O
Education	O
and	O
Training	O
.	O

Conclusion	O

Based	O
on	O
the	O
results	O
from	O
the	O
expert	O
panels	O
,	O
the	O
three	O
major	O
areas	O
of	O
focus	O
for	O
HHR	O
planning	O
in	O
the	O
rehabilitation	O
sector	O
should	O
include	O
strategies	O
addressing	O
Quality	O
of	O
Worklife	O
and	O
Work	O
Environment	O
,	O
Financial	O
Incentives	O
and	O
Marketing	O
and	O
Professional	O
Development	O
.	O

Background	O

Demand	O
for	O
rehabilitation	O
services	O
is	O
expected	O
to	O
increase	O
within	O
the	O
next	O
decade	O
primarily	O
due	O
to	O
factors	O
such	O
as	O
an	O
aging	O
population	O
,	O
workforce	O
pressures	O
,	O
rise	O
in	O
chronic	O
and	O
complex	O
multi	O
-	O
system	O
disorders	O
,	O
advances	O
in	O
technology	O
,	O
and	O
changes	O
in	O
health	O
service	O
delivery	O
models	O
[	O
1	O
-	O
4	O
]	O
.	O

In	O
Canada	O
,	O
rehabilitation	O
personnel	O
constitute	O
the	O
third	O
largest	O
health	O
professional	O
group	O
after	O
nurses	O
and	O
physicians	O
.	O

Despite	O
the	O
size	O
of	O
this	O
workforce	O
,	O
studies	O
have	O
consistently	O
reported	O
ongoing	O
shortages	O
of	O
physiotherapists	O
(	O
PTs	O
)	O
,	O
occupational	O
therapists	O
(	O
OTs	O
)	O
and	O
speech	O
-	O
language	O
pathologists	O
(	O
SLPs	O
)	O
across	O
all	O
jurisdictions	O
[	O
5	O
-	O
7	O
]	O
.	O

Similarly	O
,	O
recruitment	O
and	O
retention	O
of	O
rehabilitation	O
professionals	O
has	O
been	O
considered	O
a	O
challenge	O
internationally	O
,	O
nationally	O
and	O
provincially	O
.	O

At	O
the	O
international	O
level	O
,	O
the	O
literature	O
reports	O
recruitment	O
and	O
retention	O
difficulties	O
of	O
rehabilitation	O
therapists	O
in	O
countries	O
such	O
as	O
Australia	O
,	O
New	O
Zealand	O
,	O
United	O
Kingdom	O
and	O
the	O
United	O
States	O
[	O
8	O
-	O
13	O
]	O
.	O

Provinces	O
across	O
Canada	O
face	O
similar	O
issues	O
;	O
with	O
Ontario	O
projected	O
to	O
face	O
the	O
most	O
difficulty	O
due	O
to	O
its	O
population	O
growth	O
rate	O
[	O
14	O
]	O
.	O

Based	O
on	O
the	O
Canadian	O
Institute	O
for	O
Health	O
Information	O
'	O
s	O
Health	O
Personnel	O
Trends	O
in	O
Canada	O
from	O
1993	O
to	O
2002	O
report	O
,	O
numerous	O
factors	O
have	O
been	O
suggested	O
to	O
influence	O
demand	O
for	O
physiotherapy	O
and	O
occupational	O
therapy	O
services	O
.	O

Factors	O
that	O
may	O
influence	O
increase	O
demand	O
for	O
physiotherapy	O
include	O
:	O
shift	O
in	O
health	O
service	O
delivery	O
models	O
from	O
hospital	O
to	O
community	O
care	O
;	O
earlier	O
patient	B
discharge	O
;	O
increased	O
expectations	O
from	O
aging	O
Canadians	O
concerning	O
more	O
active	O
lifestyles	O
;	O
growing	O
private	O
practice	O
sector	O
and	O
continued	O
shortages	O
for	O
PTs	O
in	O
both	O
private	O
and	O
public	O
sectors	O
in	O
rural	O
,	O
remote	O
and	O
urban	O
settings	O
across	O
Canada	O
[	O
2	O
]	O
.	O

In	O
1993	O
,	O
an	O
Ontario	O
study	O
stated	O
that	O
in	O
order	O
to	O
meet	O
demands	O
of	O
changing	O
health	O
care	O
policy	O
,	O
medical	O
technology	O
and	O
demographic	O
changes	O
in	O
the	O
population	O
,	O
the	O
PT	O
profession	O
required	O
an	O
annual	O
growth	O
rate	O
of	O
4	O
.	O
4	O
%	O
until	O
the	O
year	O
2000	O
[	O
5	O
]	O
.	O

However	O
,	O
the	O
national	O
health	O
personnel	O
databases	O
revealed	O
that	O
the	O
actual	O
average	O
annual	O
growth	O
rate	O
of	O
active	O
PTs	O
in	O
Canada	O
from	O
1995	O
to	O
2004	O
was	O
only	O
2	O
.	O
5	O
%	O
,	O
approximately	O
half	O
of	O
the	O
projected	O
requirement	O
suggested	O
to	O
meet	O
demand	O
[	O
15	O
]	O
.	O

Similarly	O
,	O
in	O
Ontario	O
in	O
the	O
early	O
1990s	O
an	O
increase	O
in	O
demand	O
for	O
OTs	O
was	O
projected	O
because	O
of	O
the	O
reported	O
shortage	O
in	O
OTs	O
and	O
high	O
attrition	O
rate	O
[	O
16	O
]	O
.	O

The	O
shortage	O
of	O
OTs	O
was	O
explained	O
by	O
another	O
Ontario	O
study	O
to	O
be	O
the	O
result	O
of	O
the	O
changing	O
philosophies	O
of	O
care	O
and	O
management	O
for	O
the	O
disabled	O
,	O
and	O
a	O
clearer	O
understanding	O
of	O
the	O
role	O
of	O
OT	O
in	O
the	O
physical	O
and	O
mental	O
well	O
-	O
being	O
of	O
the	O
disabled	O
[	O
17	O
]	O
.	O

In	O
terms	O
of	O
actual	O
shortages	O
,	O
some	O
authors	O
have	O
reported	O
ongoing	O
vacancies	O
and	O
recruitment	O
difficulties	O
for	O
OTs	O
[	O
11	O
,	O
18	O
]	O
while	O
others	O
have	O
reported	O
an	O
increase	O
in	O
demand	O
for	O
both	O
PTs	O
[	O
19	O
]	O
and	O
OTs	O
[	O
20	O
]	O
.	O

Speech	O
language	O
pathology	O
is	O
facing	O
similar	O
service	O
demands	O
.	O

A	O
report	O
released	O
in	O
March	O
2003	O
by	O
the	O
College	O
of	O
Audiologists	O
and	O
Speech	O
-	O
Language	O
Pathologists	O
of	O
Ontario	O
(	O
CASLPO	O
)	O
concluded	O
that	O
based	O
on	O
prevalence	O
rates	O
for	O
Ontario	O
residents	O
with	O
speech	O
,	O
language	O
and	O
related	O
disorders	O
,	O
the	O
demand	O
for	O
service	O
would	O
increase	O
by	O
13	O
%	O
while	O
the	O
number	O
of	O
SLPs	O
would	O
decrease	O
by	O
4	O
%	O
resulting	O
in	O
an	O
overall	O
reduction	O
in	O
service	O
of	O
15	O
%	O
[	O
21	O
]	O
.	O

The	O
American	O
Speech	O
-	O
Language	O
-	O
Hearing	O
Association	O
(	O
ASHA	O
)	O
has	O
been	O
tracking	O
SLP	O
vacancies	O
.	O

In	O
their	O
2005	O
ASHA	O
Speech	O
-	O
Language	O
Pathology	O
Health	O
Care	O
survey	O
,	O
48	O
%	O
of	O
respondents	O
indicated	O
that	O
they	O
had	O
funded	O
unfilled	O
positions	O
for	O
SLPS	O
in	O
their	O
agency	O
[	O
22	O
]	O
.	O

The	O
same	O
survey	O
also	O
reported	O
that	O
65	O
%	O
of	O
respondents	O
in	O
home	O
care	O
indicated	O
that	O
job	O
openings	O
were	O
more	O
numerous	O
than	O
job	O
seekers	O
in	O
their	O
geographic	O
area	O
.	O

While	O
labour	O
market	O
demand	O
and	O
supply	O
are	O
influential	O
factors	O
on	O
recruitment	O
and	O
retention	O
decisions	O
,	O
the	O
development	O
of	O
strategies	O
requires	O
an	O
understanding	O
of	O
conceptual	O
frameworks	O
or	O
theories	O
to	O
categorise	O
and	O
explain	O
how	O
other	O
underlying	O
factors	O
impact	O
health	O
worker	O
'	O
s	O
mobility	O
.	O

For	O
example	O
,	O
Lehmann	O
et	O
al	O
.	O
'	O
s	O
model	O
described	O
that	O
health	O
worker	O
'	O
s	O
decisions	O
to	O
accept	O
and	O
stay	O
in	O
remote	O
areas	O
in	O
the	O
public	O
sector	O
depends	O
on	O
two	O
interrelated	O
aspects	O
:	O
the	O
impact	O
of	O
the	O
different	O
environments	O
(	O
i	O
.	O
e	O
.	O
individual	O
,	O
local	O
,	O
work	O
,	O
national	O
and	O
international	O
)	O
and	O
the	O
location	O
of	O
decision	O
-	O
makers	O
(	O
i	O
.	O
e	O
.	O
local	O
government	O
,	O
Ministry	O
of	O
Health	O
,	O
HR	O
directorate	O
,	O
public	O
service	O
and	O
other	O
ministries	O
)	O
[	O
23	O
]	O
.	O

Behavioural	O
and	O
social	O
science	O
theories	O
,	O
such	O
as	O
those	O
explained	O
by	O
Tett	O
and	O
Meyer	O
,	O
found	O
that	O
job	O
satisfaction	O
and	O
organizational	O
commitment	O
each	O
contribute	O
independently	O
to	O
the	O
prediction	O
of	O
the	O
intention	O
to	O
resign	O
(	O
turnover	O
)	O
,	O
however	O
job	O
satisfaction	O
was	O
a	O
stronger	O
predictor	O
than	O
organizational	O
commitment	O
[	O
24	O
]	O
.	O

Based	O
on	O
this	O
notion	O
,	O
considerable	O
research	O
has	O
been	O
devoted	O
to	O
identifying	O
factors	O
that	O
affect	O
job	O
satisfaction	O
among	O
rehabilitation	O
professionals	O
.	O

While	O
there	O
is	O
no	O
single	O
,	O
agreed	O
upon	O
model	O
of	O
job	O
satisfaction	O
,	O
a	O
variety	O
of	O
theoretical	O
models	O
have	O
been	O
studied	O
to	O
explain	O
concepts	O
and	O
relationships	O
associated	O
with	O
overall	O
job	O
satisfaction	O
.	O

The	O
two	O
most	O
commonly	O
used	O
theories	O
of	O
job	O
satisfaction	O
for	O
rehabilitation	O
professionals	O
are	O
the	O
Herzberg	O
'	O
s	O
Motivation	O
-	O
Hygiene	O
Theory	O
[	O
25	O
]	O
and	O
Mottaz	O
'	O
s	O
concepts	O
of	O
work	O
values	O
and	O
work	O
rewards	O
[	O
26	O
]	O
.	O

A	O
number	O
of	O
rehabilitation	O
studies	O
have	O
used	O
the	O
Herzberg	O
'	O
s	O
Motivation	O
-	O
Hygiene	O
Theory	O
,	O
also	O
known	O
as	O
the	O
two	O
-	O
factor	O
theory	O
of	O
motivation	O
to	O
explain	O
associations	O
between	O
motivation	O
,	O
job	O
satisfaction	O
and	O
retention	O
factors	O
among	O
OTs	O
,	O
PTs	O
and	O
SLPs	O
[	O
27	O
-	O
31	O
]	O
.	O

Frederick	O
Herzberg	O
et	O
al	O
.	O
explained	O
that	O
there	O
were	O
two	O
independent	O
incidents	O
occurring	O
at	O
peoples	B
'	O
jobs	O
:	O
one	O
that	O
made	O
them	O
feel	O
good	O
or	O
satisfied	O
,	O
and	O
another	O
that	O
made	O
them	O
feel	O
bad	O
or	O
dissatisfied	O
at	O
work	O
[	O
25	O
]	O
.	O

Intrinsic	O
factors	O
that	O
motivate	O
people	B
such	O
as	O
achievement	O
,	O
recognition	O
,	O
work	O
itself	O
,	O
responsibility	O
,	O
advancement	O
and	O
personal	O
growth	O
were	O
called	O
the	O
"	O
motivators	O
"	O
which	O
lead	O
to	O
feelings	O
of	O
satisfaction	O
.	O

Extrinsic	O
factors	O
such	O
as	O
work	O
conditions	O
,	O
company	O
policies	O
,	O
supervision	O
,	O
interpersonal	O
work	O
relations	O
,	O
salary	O
and	O
job	O
security	O
,	O
known	O
as	O
"	O
hygiene	O
"	O
factors	O
,	O
were	O
claimed	O
to	O
prevent	O
dissatisfaction	O
.	O

"	O
Motivators	O
"	O
directly	O
affect	O
a	O
person	B
'	O
s	O
motivational	O
drive	O
to	O
do	O
a	O
good	O
job	O
,	O
therefore	O
they	O
are	O
believed	O
to	O
be	O
more	O
important	O
than	O
hygiene	O
factors	O
.	O

Mottaz	O
on	O
the	O
other	O
hand	O
,	O
accounted	O
for	O
individual	O
differences	O
in	O
job	O
satisfaction	O
among	O
workers	O
and	O
based	O
his	O
study	O
on	O
two	O
dimensions	O
:	O
"	O
work	O
rewards	O
"	O
and	O
"	O
work	O
values	O
"	O
[	O
26	O
]	O
.	O

"	O
Work	O
rewards	O
"	O
are	O
perceived	O
characteristics	O
of	O
the	O
job	O
and	O
have	O
three	O
conceptual	O
clusters	O
which	O
include	O
task	O
,	O
social	O
and	O
organizational	O
rewards	O
[	O
26	O
]	O
.	O

Mottaz	O
describes	O
"	O
task	O
rewards	O
"	O
(	O
intrinsic	O
)	O
as	O
having	O
five	O
independent	O
characteristics	O
including	O
:	O
skill	O
variety	O
,	O
task	O
identity	O
,	O
task	O
significance	O
,	O
autonomy	O
and	O
feedback	O
.	O

Examples	O
include	O
interesting	O
and	O
challenging	O
work	O
,	O
self	O
-	O
direction	O
and	O
responsibility	O
,	O
creativity	O
,	O
opportunities	O
to	O
use	O
one	O
'	O
s	O
skills	O
and	O
feedback	O
.	O

In	O
the	O
same	O
study	O
,	O
Mottaz	O
stated	O
that	O
"	O
social	O
rewards	O
"	O
(	O
extrinsic	O
)	O
are	O
derived	O
from	O
the	O
interpersonal	O
relationships	O
established	O
with	O
others	O
at	O
work	O
.	O

Having	O
supportive	O
colleagues	O
and	O
supervisors	O
is	O
an	O
example	O
of	O
this	O
dimension	O
.	O

Lastly	O
,	O
"	O
organizational	O
rewards	O
"	O
(	O
extrinsic	O
)	O
are	O
tangible	O
rewards	O
that	O
are	O
provided	O
by	O
the	O
employer	O
/	O
organization	O
to	O
facilitate	O
performance	O
.	O

Such	O
factors	O
include	O
working	O
conditions	O
,	O
pay	O
and	O
fringe	O
benefits	O
,	O
career	O
advancement	O
and	O
security	O
.	O

The	O
second	O
dimension	O
of	O
job	O
satisfaction	O
is	O
based	O
on	O
"	O
work	O
values	O
"	O
,	O
which	O
is	O
the	O
importance	O
that	O
individuals	O
place	O
on	O
their	O
work	O
rewards	O
[	O
26	O
]	O
.	O

For	O
example	O
,	O
some	O
rehabilitation	O
therapists	O
may	O
value	O
extrinsic	O
rewards	O
such	O
as	O
pay	O
and	O
benefits	O
as	O
more	O
important	O
than	O
intrinsic	O
factors	O
like	O
clinical	O
autonomy	O
and	O
challenging	O
work	O
.	O

Although	O
the	O
Herzberg	O
and	O
Mottaz	O
conceptual	O
frameworks	O
are	O
organized	O
differently	O
,	O
their	O
job	O
satisfaction	O
variables	O
are	O
very	O
similar	O
(	O
i	O
.	O
e	O
.	O
work	O
conditions	O
,	O
pay	O
,	O
interpersonal	O
relationships	O
,	O
etc	O
.	O
)	O
and	O
they	O
both	O
classify	O
these	O
factors	O
as	O
having	O
intrinsic	O
or	O
extrinsic	O
elements	O
.	O

Despite	O
the	O
growing	O
body	O
of	O
literature	O
on	O
recruitment	O
and	O
retention	O
factors	O
in	O
various	O
industries	O
,	O
there	O
is	O
a	O
minimal	O
amount	O
of	O
research	O
studying	O
these	O
factors	O
specifically	O
among	O
rehabilitation	O
professionals	O
.	O

One	O
published	O
study	O
however	O
,	O
did	O
look	O
at	O
extrinsic	O
and	O
intrinsic	O
job	O
satisfaction	O
factors	O
on	O
recruitment	O
and	O
retention	O
of	O
rehabilitation	O
professionals	O
(	O
OTs	O
,	O
PTs	O
and	O
SLPs	O
)	O
[	O
32	O
]	O
.	O

Results	O
from	O
this	O
study	O
showed	O
that	O
intrinsic	O
factors	O
such	O
as	O
professional	O
growth	O
and	O
having	O
a	O
work	O
environment	O
in	O
line	O
with	O
personal	O
values	O
are	O
more	O
significant	O
in	O
predicting	O
career	O
satisfaction	O
than	O
extrinsic	O
factors	O
such	O
as	O
pay	O
and	O
continuing	O
education	O
.	O

These	O
same	O
intrinsic	O
factors	O
are	O
also	O
significant	O
in	O
predicting	O
retention	O
in	O
rehabilitation	O
professionals	O
.	O

Another	O
study	O
looking	O
at	O
recruitment	O
and	O
retention	O
of	O
allied	O
health	O
professionals	O
in	O
the	O
rural	O
areas	O
in	O
New	O
South	O
Wales	O
identified	O
that	O
the	O
main	O
reasons	O
why	O
people	B
liked	O
working	O
in	O
rural	O
areas	O
were	O
because	O
of	O
the	O
attractive	O
environment	O
and	O
helpful	O
team	O
members	O
[	O
33	O
]	O
.	O

However	O
82	O
%	O
of	O
employees	O
reported	O
that	O
having	O
their	O
partner	O
move	O
away	O
was	O
the	O
number	O
one	O
reason	O
for	O
leaving	O
a	O
rural	O
job	O
.	O

A	O
similar	O
study	O
was	O
conducted	O
among	O
OTs	O
and	O
PTs	O
in	O
Northwestern	O
Ontario	O
[	O
34	O
]	O
.	O

Findings	O
from	O
this	O
study	O
indicated	O
that	O
factors	O
contributing	O
to	O
initial	O
decision	O
on	O
location	O
of	O
practice	O
include	O
availability	O
of	O
leisure	O
/	O
recreation	O
activities	O
,	O
proximity	O
of	O
family	O
origin	O
and	O
influences	O
of	O
spouse	O
/	O
partners	O
.	O

Study	O
results	O
also	O
showed	O
that	O
the	O
main	O
reasons	O
therapists	O
left	O
their	O
job	O
were	O
to	O
be	O
closer	O
to	O
their	O
family	O
,	O
lack	O
of	O
job	O
opportunity	O
and	O
spousal	O
influence	O
.	O

Solely	O
understanding	O
factors	O
that	O
influence	O
recruitment	O
and	O
retention	O
decisions	O
is	O
not	O
sufficient	O
in	O
the	O
development	O
of	O
a	O
HHR	O
plan	O
for	O
rehabilitation	O
professionals	O
.	O

In	O
order	O
for	O
the	O
plan	O
to	O
be	O
effective	O
and	O
sustainable	O
in	O
addressing	O
these	O
factors	O
,	O
the	O
most	O
important	O
and	O
feasible	O
workforce	O
strategies	O
needs	O
to	O
be	O
identified	O
.	O

There	O
have	O
been	O
a	O
number	O
of	O
reports	O
on	O
health	O
human	B
resources	O
(	O
HHR	O
)	O
planning	O
,	O
recruitment	O
and	O
retention	O
strategies	O
for	O
physicians	O
[	O
35	O
,	O
36	O
]	O
and	O
nurses	O
[	O
37	O
]	O
,	O
however	O
information	O
regarding	O
rehabilitation	O
professionals	O
is	O
lacking	O
.	O

Canadian	O
reports	O
indicate	O
that	O
the	O
main	O
reason	O
for	O
significant	O
gaps	O
in	O
this	O
field	O
is	O
the	O
absence	O
of	O
current	O
and	O
reliable	O
data	O
available	O
on	O
supply	O
,	O
demand	O
and	O
labour	O
force	O
participation	O
trends	O
for	O
rehabilitation	O
therapists	O
[	O
38	O
-	O
40	O
]	O
.	O

There	O
is	O
some	O
research	O
that	O
has	O
investigated	O
theoretical	O
models	O
of	O
job	O
satisfaction	O
on	O
recruitment	O
and	O
retention	O
[	O
28	O
,	O
32	O
]	O
;	O
however	O
few	O
studies	O
have	O
looked	O
at	O
how	O
these	O
models	O
have	O
been	O
implemented	O
.	O

Other	O
studies	O
have	O
examined	O
the	O
relationship	O
of	O
gender	O
,	O
workplace	O
setting	O
(	O
i	O
.	O
e	O
.	O
hospital	O
,	O
ambulatory	O
,	O
rehabilitation	O
,	O
acute	O
and	O
long	O
-	O
term	O
care	O
)	O
and	O
geographical	O
location	O
(	O
i	O
.	O
e	O
.	O
rural	O
or	O
urban	O
)	O
on	O
job	O
satisfaction	O
and	O
retention	O
among	O
rehabilitation	O
professionals	O
[	O
41	O
-	O
43	O
]	O
.	O

Furthermore	O
,	O
no	O
empirical	O
studies	O
have	O
examined	O
conceptual	O
frameworks	O
for	O
organizing	O
recruitment	O
and	O
retention	O
strategies	O
for	O
rehabilitation	O
therapists	O
.	O

To	O
address	O
this	O
gap	O
,	O
this	O
research	O
identified	O
recruitment	O
and	O
retention	O
strategies	O
from	O
the	O
literature	O
for	O
rehabilitation	O
professionals	O
and	O
determined	O
their	O
importance	O
and	O
feasibility	O
using	O
expert	O
panels	O
.	O

Methods	O

Phase	O
1	O
:	O
Literature	O
Review	O

Identification	O
of	O
recruitment	O
and	O
retention	O
strategies	O

A	O
review	O
of	O
the	O
literature	O
was	O
conducted	O
to	O
identify	O
recruitment	O
and	O
retention	O
strategies	O
for	O
rehabilitation	O
therapists	O
.	O

In	O
this	O
study	O
,	O
rehabilitation	O
professionals	O
were	O
defined	O
as	O
physical	O
therapists	O
(	O
PTs	O
)	O
,	O
occupational	O
therapists	O
(	O
OTs	O
)	O
and	O
speech	O
-	O
language	O
pathologists	O
(	O
SLPs	O
)	O
.	O

Both	O
published	O
and	O
non	O
-	O
empirical	O
literature	O
was	O
accessed	O
in	O
this	O
review	O
.	O

Keywords	O
used	O
to	O
search	O
for	O
relevant	O
published	O
studies	O
in	O
the	O
Consolidated	O
International	O
Nursing	O
and	O
Allied	O
Health	O
Sciences	O
Library	O
(	O
CINAHL	O
)	O
(	O
1982	O
to	O
2005	O
)	O
and	O
Medline	O
(	O
1996	O
to	O
2005	O
)	O
included	O
:	O
"	O
health	O
human	B
resources	O
or	O
health	O
manpower	O
"	O
,	O
"	O
rehabilitation	O
or	O
rehabilitation	O
professionals	O
or	O
vocational	O
"	O
,	O
"	O
allied	O
health	O
professionals	O
or	O
personnel	O
"	O
,	O
"	O
recruitment	O
strategies	O
"	O
,	O
"	O
retention	O
strategies	O
"	O
,	O
"	O
physical	O
therapist	O
or	O
physiotherapist	O
"	O
,	O
"	O
occupational	O
therapy	O
or	O
occupational	O
therapist	O
"	O
,	O
"	O
speech	O
-	O
language	O
pathologist	O
or	O
speech	O
-	O
language	O
pathology	O
"	O
.	O

Non	O
-	O
empirical	O
literature	O
searches	O
were	O
made	O
on	O
international	O
and	O
national	O
on	O
-	O
line	O
catalogues	O
and	O
publications	O
from	O
health	O
organizations	O
,	O
professional	O
associations	O
,	O
and	O
hospital	O
and	O
home	O
care	O
organizations	O
.	O

International	O
reports	O
were	O
limited	O
to	O
developed	O
countries	O
since	O
the	O
purpose	O
of	O
this	O
study	O
was	O
to	O
identify	O
strategies	O
appropriate	O
to	O
the	O
Ontario	O
setting	O
.	O

Organization	O
and	O
consolidation	O
of	O
strategies	O

There	O
was	O
a	O
paucity	O
of	O
peer	O
-	O
reviewed	O
studies	O
obtained	O
exploring	O
rehabilitation	O
HHR	O
strategies	O
,	O
therefore	O
the	O
majority	O
of	O
strategies	O
were	O
selected	O
from	O
grey	O
literature	O
reports	O
from	O
international	O
,	O
national	O
and	O
provincial	O
health	O
organizations	O
.	O

From	O
the	O
literature	O
review	O
,	O
107	O
potential	O
strategies	O
were	O
identified	O
according	O
to	O
their	O
relevance	O
to	O
HHR	O
issues	O
for	O
rehabilitation	O
in	O
Ontario	O
.	O

These	O
strategies	O
were	O
then	O
categorized	O
into	O
two	O
broad	O
groups	O
:	O
A	O
)	O
Recruitment	O
and	O
Retention	O
(	O
n	O
=	O
73	O
)	O
,	O
and	O
B	O
)	O
Education	O
(	O
n	O
=	O
34	O
)	O
.	O

The	O
majority	O
of	O
strategies	O
were	O
not	O
specific	O
to	O
rehabilitation	O
professionals	O
and	O
they	O
were	O
reviewed	O
by	O
a	O
group	O
of	O
three	O
individuals	O
collectively	O
(	O
rehabilitation	O
researcher	O
,	O
manager	O
,	O
and	O
clinician	O
)	O
for	O
duplication	O
,	O
clarity	O
,	O
action	O
focused	O
properties	O
and	O
appropriateness	O
to	O
the	O
Canadian	O
or	O
Ontario	O
setting	O
.	O

When	O
necessary	O
,	O
a	O
small	O
number	O
of	O
strategies	O
were	O
re	O
-	O
worded	O
to	O
be	O
relevant	O
to	O
a	O
rehabilitation	O
context	O
.	O

This	O
analysis	O
resulted	O
in	O
the	O
selection	O
of	O
40	O
Recruitment	O
and	O
Retention	O
and	O
24	O
Education	O
strategies	O
.	O

Only	O
14	O
recruitment	O
and	O
retention	O
and	O
six	O
education	O
strategies	O
were	O
obtained	O
from	O
peer	O
-	O
reviewed	O
articles	O
.	O

Since	O
the	O
majority	O
of	O
strategies	O
were	O
identified	O
from	O
the	O
grey	O
literature	O
,	O
it	O
was	O
not	O
surprising	O
that	O
there	O
was	O
no	O
apriori	O
peer	O
-	O
reviewed	O
conceptual	O
framework	O
that	O
reflected	O
the	O
breadth	O
of	O
the	O
strategies	O
obtained	O
from	O
the	O
literature	O
review	O
.	O

As	O
a	O
result	O
,	O
the	O
themes	O
used	O
by	O
the	O
Health	O
and	O
Community	O
Services	O
Human	B
Resources	O
Sector	O
Study	O
in	O
Newfoundland	O
and	O
Labrador	O
[	O
44	O
]	O
formed	O
the	O
basis	O
for	O
the	O
organizational	O
framework	O
for	O
this	O
study	O
since	O
they	O
aligned	O
with	O
the	O
identified	O
strategies	O
.	O

Each	O
group	O
was	O
further	O
categorized	O
into	O
the	O
five	O
themes	O
(	O
three	O
for	O
Recruitment	O
and	O
Retention	O
and	O
two	O
for	O
Education	O
)	O
.	O

The	O
three	O
Recruitment	O
and	O
Retention	O
strategy	O
themes	O
were	O
:	O
(	O
1	O
)	O
Quality	O
of	O
Worklife	O
and	O
Work	O
Environment	O
[	O
n	O
=	O
19	O
]	O
;	O
(	O
2	O
)	O
Workload	O
and	O
Skill	O
Mix	O
[	O
n	O
=	O
6	O
]	O
;	O
and	O
(	O
3	O
)	O
Financial	O
Incentives	O
and	O
Marketing	O
[	O
n	O
=	O
15	O
]	O
.	O

The	O
two	O
Education	O
strategy	O
themes	O
were	O
:	O
(	O
1	O
)	O
Education	O
and	O
Training	O
[	O
n	O
=	O
11	O
]	O
and	O
(	O
2	O
)	O
Professional	O
Development	O
(	O
n	O
=	O
13	O
)	O
.	O

Phase	O
2	O
:	O
Expert	O
Panel	O

Participant	B
Selection	O

Once	O
this	O
study	O
was	O
approved	O
by	O
the	O
Research	O
Ethics	O
Board	O
at	O
the	O
University	O
of	O
Toronto	O
,	O
key	O
informants	O
who	O
participated	O
in	O
a	O
previous	O
study	O
regarding	O
rehabilitation	O
supply	O
and	O
demand	O
at	O
the	O
University	O
of	O
Toronto	O
[	O
21	O
]	O
were	O
asked	O
to	O
nominate	O
potential	O
participants	B
for	O
the	O
panels	O
.	O

The	O
selection	O
criteria	O
considered	O
were	O
acknowledged	O
leadership	O
in	O
the	O
panel	O
member	O
'	O
s	O
specialty	O
,	O
expertise	O
in	O
recruitment	O
and	O
retention	O
or	O
education	O
and	O
training	O
of	O
rehabilitation	O
professionals	O
.	O

Absence	O
of	O
conflicts	O
of	O
interest	O
,	O
geographic	O
diversity	O
,	O
and	O
diversity	O
of	O
practice	O
setting	O
were	O
also	O
considered	O
.	O

After	O
purposefully	O
selecting	O
the	O
initial	O
list	O
of	O
candidates	O
from	O
among	O
the	O
nominations	O
,	O
each	O
nominee	O
was	O
contacted	O
to	O
establish	O
their	O
interest	O
and	O
availability	O
.	O

Those	O
who	O
expressed	O
an	O
interest	O
in	O
participating	O
were	O
asked	O
to	O
send	O
their	O
curriculum	O
vitae	O
to	O
help	O
the	O
research	O
team	O
evaluate	O
their	O
contributions	O
to	O
their	O
field	O
of	O
expertise	O
.	O

Once	O
candidate	O
panelists	O
were	O
selected	O
,	O
each	O
received	O
a	O
letter	O
explaining	O
the	O
expert	O
panel	O
process	O
and	O
consent	O
form	O
.	O

Two	O
separate	O
panels	O
were	O
constructed	O
:	O
one	O
for	O
Recruitment	O
and	O
Retention	O
(	O
n	O
=	O
8	O
)	O
and	O
the	O
other	O
for	O
Education	O
(	O
n	O
=	O
9	O
)	O
(	O
Table	O
1	O
)	O
.	O

The	O
size	O
of	O
the	O
panel	O
was	O
large	O
enough	O
to	O
permit	O
diversity	O
of	O
representation	O
while	O
still	O
being	O
small	O
enough	O
to	O
allow	O
all	O
participants	B
to	O
be	O
involved	O
in	O
the	O
group	O
discussion	O
[	O
45	O
]	O
.	O

Expert	O
Panel	O
Process	O
:	O
Round	O
1	O
Survey	O

A	O
modified	O
-	O
delphi	O
technique	O
was	O
then	O
used	O
for	O
the	O
expert	O
panel	O
process	O
,	O
[	O
46	O
,	O
47	O
]	O
based	O
on	O
the	O
RAND	O
/	O
UCLA	O
appropriateness	O
method	O
[	O
45	O
]	O
.	O

In	O
round	O
1	O
,	O
members	O
of	O
the	O
Recruitment	O
and	O
Retention	O
panel	O
were	O
sent	O
an	O
electronic	O
survey	O
containing	O
the	O
40	O
strategies	O
identified	O
from	O
the	O
literature	O
review	O
and	O
the	O
Education	O
panelists	O
were	O
also	O
sent	O
an	O
electronic	O
survey	O
with	O
24	O
strategies	O
.	O

For	O
Round	O
1	O
,	O
each	O
panel	O
was	O
asked	O
to	O
rate	O
the	O
strategies	O
using	O
a	O
nine	O
-	O
point	O
Likert	O
-	O
type	O
rating	O
scale	O
that	O
ranged	O
from	O
"	O
none	O
"	O
(	O
1	O
)	O
to	O
"	O
maximum	O
"	O
(	O
9	O
)	O
,	O
on	O
two	O
key	O
dimensions	O
:	O
Feasibility	O
and	O
Importance	O
.	O

Feasibility	O
was	O
defined	O
as	O
the	O
practicality	O
and	O
cost	O
implications	O
of	O
the	O
strategy	O
and	O
was	O
rated	O
from	O
the	O
respondents	O
'	O
perspective	O
.	O

Importance	O
was	O
defined	O
as	O
how	O
valuable	O
,	O
appropriate	O
and	O
useful	O
the	O
strategy	O
could	O
be	O
for	O
rehabilitation	O
HHR	O
planning	O
in	O
Ontario	O
.	O

At	O
the	O
end	O
of	O
the	O
survey	O
,	O
panelists	O
were	O
given	O
the	O
opportunity	O
to	O
suggest	O
additional	O
strategies	O
that	O
they	O
felt	O
were	O
appropriate	O
to	O
consider	O
.	O

Once	O
completed	O
,	O
panelists	O
were	O
asked	O
to	O
return	O
the	O
survey	O
to	O
the	O
study	O
office	O
by	O
email	O
or	O
fax	O
prior	O
to	O
the	O
expert	O
panel	O
meeting	O
in	O
Round	O
2	O
.	O

Data	O
from	O
each	O
questionnaire	O
were	O
entered	O
into	O
a	O
spreadsheet	O
and	O
tabulated	O
.	O

Descriptive	O
statistics	O
were	O
calculated	O
for	O
each	O
strategy	O
using	O
frequency	O
distributions	O
and	O
proportional	O
percentages	O
of	O
respondents	O
.	O

Importance	O
and	O
feasibility	O
rankings	O
were	O
based	O
on	O
the	O
percentage	O
of	O
expert	O
panelists	O
'	O
low	O
,	O
medium	O
and	O
high	O
ratings	O
.	O

Expert	O
Panel	O
Process	O
Round	O
2	O
:	O
Expert	O
Panel	O
one	O
-	O
day	O
meeting	O

After	O
the	O
independent	O
completion	O
of	O
the	O
survey	O
,	O
each	O
panel	O
was	O
convened	O
separately	O
for	O
a	O
one	O
-	O
day	O
meeting	O
for	O
final	O
discussions	O
,	O
debates	O
and	O
consensus	O
voting	O
to	O
decide	O
on	O
strategies	O
[	O
48	O
]	O
.	O

A	O
strategy	O
that	O
had	O
been	O
scored	O
7	O
,	O
8	O
or	O
9	O
for	O
both	O
feasibility	O
and	O
importance	O
by	O
two	O
-	O
thirds	O
of	O
the	O
panel	O
was	O
considered	O
a	O
high	O
rating	O
.	O

Strategies	O
that	O
had	O
a	O
combination	O
of	O
medium	O
and	O
high	O
scores	O
between	O
4	O
and	O
9	O
in	O
either	O
of	O
the	O
two	O
dimensions	O
were	O
considered	O
medium	O
rated	O
strategies	O
,	O
while	O
low	O
rated	O
strategies	O
had	O
scores	O
between	O
1	O
and	O
3	O
for	O
both	O
dimensions	O
.	O

On	O
the	O
day	O
of	O
the	O
meeting	O
,	O
the	O
panelists	O
were	O
given	O
a	O
copy	O
of	O
the	O
aggregated	O
survey	O
results	O
indicating	O
the	O
ratings	O
of	O
all	O
of	O
the	O
strategies	O
.	O

High	O
and	O
low	O
rated	O
strategies	O
were	O
not	O
discussed	O
as	O
there	O
was	O
already	O
consensus	O
,	O
whereas	O
all	O
medium	O
rated	O
strategies	O
were	O
subject	O
to	O
discussion	O
.	O

Using	O
a	O
nominal	O
group	O
process	O
[	O
47	O
]	O
,	O
each	O
strategy	O
was	O
discussed	O
in	O
turn	O
,	O
and	O
panelists	O
were	O
given	O
an	O
opportunity	O
to	O
raise	O
any	O
issues	O
or	O
concerns	O
regarding	O
the	O
clarity	O
and	O
wording	O
of	O
each	O
strategy	O
.	O

Each	O
of	O
the	O
strategies	O
discussed	O
were	O
then	O
individually	O
rated	O
a	O
second	O
time	O
by	O
each	O
panelist	O
in	O
an	O
attempt	O
to	O
reach	O
further	O
consensus	O
.	O

Results	O

Selection	O
of	O
strategies	O
for	O
Round	O
1	O
:	O
Modified	O
Delphi	O
process	O

Following	O
Round	O
1	O
rating	O
of	O
the	O
40	O
identified	O
strategies	O
,	O
the	O
Recruitment	O
and	O
Retention	O
panel	O
reached	O
consensus	O
on	O
12	O
strategies	O
.	O

However	O
,	O
14	O
had	O
a	O
combination	O
of	O
high	O
/	O
medium	O
importance	O
and	O
feasibility	O
ratings	O
and	O
14	O
had	O
medium	O
ratings	O
on	O
both	O
dimensions	O
,	O
therefore	O
it	O
required	O
further	O
discussion	O
.	O

An	O
additional	O
strategy	O
regarding	O
family	O
relocation	O
programs	O
was	O
added	O
by	O
this	O
panel	O
.	O

The	O
Education	O
Panel	O
ranked	O
16	O
of	O
24	O
strategies	O
with	O
high	O
importance	O
and	O
feasibility	O
after	O
Round	O
1	O
.	O

Since	O
there	O
were	O
only	O
eight	O
strategies	O
with	O
medium	O
ratings	O
,	O
this	O
expert	O
panel	O
decided	O
to	O
review	O
all	O
the	O
strategies	O
at	O
the	O
face	O
-	O
to	O
-	O
face	O
meeting	O
to	O
discuss	O
the	O
rationale	O
that	O
would	O
explain	O
why	O
some	O
of	O
the	O
highly	O
rated	O
strategies	O
were	O
not	O
already	O
implemented	O
and	O
to	O
come	O
to	O
a	O
consensus	O
on	O
the	O
other	O
eight	O
medium	O
rated	O
strategies	O
.	O

They	O
also	O
added	O
an	O
additional	O
strategy	O
for	O
career	O
paths	O
.	O

Selection	O
of	O
strategies	O
for	O
Round	O
2	O
:	O
Face	O
-	O
to	O
-	O
face	O
meeting	O

A	O
total	O
of	O
34	O
strategies	O
were	O
identified	O
by	O
both	O
the	O
Recruitment	O
and	O
Retention	O
and	O
Education	O
expert	O
panels	O
as	O
being	O
important	O
and	O
feasible	O
for	O
the	O
development	O
of	O
a	O
HHR	O
plan	O
for	O
recruitment	O
and	O
retention	O
of	O
rehabilitation	O
professionals	O
.	O

Under	O
the	O
Recruitment	O
and	O
Retention	O
theme	O
,	O
seven	O
were	O
categorized	O
as	O
Quality	O
of	O
Worklife	O
and	O
Work	O
Environment	O
;	O
two	O
were	O
Workload	O
and	O
Skill	O
Mix	O
,	O
and	O
another	O
seven	O
were	O
Financial	O
Incentives	O
and	O
Marketing	O
.	O

As	O
for	O
the	O
Education	O
panel	O
,	O
five	O
were	O
categorized	O
as	O
Education	O
and	O
Training	O
strategies	O
while	O
the	O
other	O
thirteen	O
were	O
related	O
to	O
Professional	O
Development	O
.	O

As	O
indicated	O
in	O
Table	O
2	O
,	O
at	O
the	O
end	O
of	O
the	O
second	O
round	O
of	O
voting	O
,	O
the	O
Recruitment	O
and	O
Retention	O
panel	O
had	O
a	O
total	O
of	O
16	O
highly	O
important	O
and	O
feasible	O
strategies	O
,	O
8	O
high	O
/	O
medium	O
importance	O
and	O
feasibility	O
,	O
8	O
medium	O
and	O
9	O
low	O
ratings	O
for	O
both	O
dimensions	O
.	O

The	O
Education	O
panel	O
on	O
the	O
other	O
hand	O
had	O
a	O
total	O
of	O
18	O
high	O
,	O
1	O
high	O
/	O
medium	O
,	O
3	O
medium	O
and	O
3	O
low	O
rating	O
strategies	O
.	O

Recruitment	O
and	O
Retention	O
Strategy	O
Rankings	O

Table	O
3	O
provides	O
a	O
detailed	O
description	O
and	O
ranking	O
of	O
each	O
of	O
the	O
recruitment	O
and	O
retention	O
strategies	O
that	O
were	O
rated	O
highly	O
important	O
and	O
feasible	O
.	O

The	O
importance	O
and	O
feasibility	O
rankings	O
were	O
based	O
on	O
the	O
largest	O
proportion	O
of	O
panel	O
members	O
rating	O
a	O
strategy	O
a	O
7	O
,	O
8	O
or	O
9	O
.	O

The	O
overall	O
combined	O
ranking	O
was	O
based	O
on	O
the	O
average	O
of	O
the	O
proportion	O
of	O
these	O
two	O
dimensions	O
.	O

Among	O
these	O
selected	O
strategies	O
,	O
the	O
majority	O
were	O
classified	O
under	O
Quality	O
of	O
Worklife	O
and	O
Work	O
Environment	O
(	O
44	O
%	O
)	O
and	O
Financial	O
Incentives	O
and	O
Marketing	O
(	O
44	O
%	O
)	O
,	O
followed	O
by	O
Workload	O
and	O
Skill	O
Mix	O
(	O
12	O
%	O
)	O
.	O

It	O
should	O
be	O
noted	O
that	O
some	O
strategies	O
had	O
equal	O
rankings	O
;	O
therefore	O
the	O
total	O
number	O
of	O
rankings	O
did	O
not	O
equal	O
the	O
total	O
number	O
of	O
strategies	O
.	O

Recruitment	O
and	O
retention	O
strategies	O
that	O
had	O
a	O
combination	O
of	O
high	O
and	O
medium	O
ratings	O
in	O
either	O
of	O
the	O
two	O
dimensions	O
included	O
:	O
sense	O
of	O
empowerment	O
in	O
promoting	O
healthy	O
work	O
environments	O
;	O
team	O
-	O
building	O
exercises	O
;	O
developing	O
participatory	O
decision	O
-	O
making	O
systems	O
;	O
improving	O
rural	O
working	O
conditions	O
;	O
recognizing	O
work	O
-	O
life	O
balance	O
;	O
creating	O
an	O
environment	O
where	O
staff	O
are	O
valued	O
;	O
optimizing	O
scope	O
of	O
practice	O
and	O
work	O
-	O
management	O
autonomy	O
.	O

Strategies	O
that	O
had	O
medium	O
importance	O
and	O
feasibility	O
ratings	O
included	O
:	O
resolving	O
concerns	O
about	O
liability	O
and	O
accountability	O
in	O
collaborative	O
practice	O
;	O
recruiting	O
international	O
trained	O
therapists	O
;	O
opportunity	O
to	O
work	O
in	O
different	O
settings	O
;	O
interprofessional	O
payment	O
schemes	O
;	O
family	O
leave	O
;	O
staff	O
recognition	O
and	O
creating	O
a	O
position	O
for	O
a	O
provincial	O
health	O
professional	O
recruiter	O
.	O

Low	O
importance	O
and	O
feasibility	O
strategies	O
included	O
:	O
word	O
of	O
mouth	O
references	O
;	O
bursaries	O
and	O
retention	O
bonuses	O
;	O
exchange	O
employment	O
opportunities	O
;	O
health	O
promotion	O
;	O
retention	O
workshop	O
;	O
80	O
-	O
20	O
staffing	O
model	O
(	O
80	O
%	O
clinical	O
and	O
20	O
%	O
learning	O
new	O
skills	O
or	O
training	O
others	O
)	O
;	O
using	O
recruitment	O
agencies	O
and	O
providing	O
recruitment	O
bonuses	O
(	O
Table	O
4	O
)	O
.	O

Education	O
Strategy	O
Rankings	O

Education	O
strategies	O
that	O
were	O
rated	O
highly	O
important	O
and	O
feasible	O
are	O
described	O
in	O
Table	O
5	O
.	O

The	O
majority	O
of	O
strategies	O
in	O
this	O
group	O
tend	O
to	O
be	O
in	O
the	O
area	O
of	O
Professional	O
Development	O
(	O
72	O
%	O
)	O
,	O
more	O
so	O
than	O
Education	O
and	O
Training	O
(	O
28	O
%	O
)	O
.	O

The	O
medium	O
rated	O
education	O
strategies	O
included	O
:	O
expand	O
interprofessional	O
education	O
;	O
provide	O
incentives	O
for	O
students	O
interested	O
in	O
rural	O
practice	O
;	O
summer	O
mentorship	O
programs	O
for	O
high	O
school	O
students	O
;	O
and	O
aboriginal	O
student	O
support	O
program	O
.	O

The	O
strategies	O
that	O
were	O
considered	O
neither	O
feasible	O
nor	O
important	O
included	O
:	O
using	O
return	O
of	O
service	O
contracts	O
after	O
professional	O
development	O
;	O
create	O
a	O
tiered	O
pathway	O
approach	O
through	O
modular	O
education	O
and	O
laddered	O
credentialing	O
and	O
in	O
accreditation	O
standards	O
allow	O
greater	O
use	O
of	O
rural	O
practice	O
sites	O
(	O
Table	O
6	O
)	O
.	O

Since	O
the	O
purpose	O
of	O
the	O
panel	O
was	O
to	O
identify	O
recruitment	O
and	O
retention	O
and	O
education	O
strategies	O
that	O
could	O
inform	O
the	O
development	O
of	O
a	O
HHR	O
plan	O
for	O
rehabilitation	O
professionals	O
,	O
there	O
was	O
also	O
discussion	O
about	O
contextual	O
factors	O
that	O
would	O
influence	O
a	O
plan	O
.	O

Panelists	O
commented	O
that	O
key	O
factors	O
to	O
consider	O
prior	O
to	O
implementation	O
of	O
these	O
strategies	O
should	O
include	O
workplace	O
setting	O
,	O
geographical	O
location	O
(	O
i	O
.	O
e	O
.	O
urban	O
and	O
rural	O
)	O
and	O
gender	O
issues	O
.	O

Discussion	O

The	O
purpose	O
of	O
this	O
study	O
was	O
to	O
identify	O
recruitment	O
and	O
retention	O
strategies	O
to	O
inform	O
the	O
development	O
of	O
HHR	O
planning	O
for	O
rehabilitation	O
professionals	O
in	O
Ontario	O
.	O

This	O
study	O
highlights	O
that	O
Quality	O
of	O
Worklife	O
and	O
Work	O
Environment	O
,	O
Financial	O
Incentives	O
and	O
Marketing	O
and	O
Professional	O
Development	O
are	O
the	O
three	O
major	O
areas	O
of	O
focus	O
when	O
developing	O
a	O
competitive	O
HR	O
plan	O
in	O
the	O
rehabilitation	O
sector	O
.	O

Quality	O
of	O
Worklife	O
and	O
Work	O
Environment	O

Quality	O
of	O
Worklife	O
and	O
Work	O
Environment	O
strategies	O
ranked	O
among	O
the	O
top	O
category	O
for	O
recruitment	O
and	O
retention	O
of	O
rehabilitation	O
therapists	O
.	O

This	O
has	O
also	O
been	O
found	O
among	O
nurses	O
[	O
44	O
]	O
where	O
it	O
was	O
reported	O
that	O
addressing	O
such	O
factors	O
can	O
affect	O
the	O
overall	O
success	O
of	O
the	O
program	O
[	O
49	O
]	O
.	O

Specifically	O
,	O
our	O
findings	O
showed	O
that	O
the	O
top	O
ranked	O
strategy	O
for	O
both	O
importance	O
and	O
feasibility	O
was	O
improving	O
and	O
maintaining	O
the	O
safety	O
of	O
rehabilitation	O
professionals	O
in	O
the	O
workplace	O
.	O

Specific	O
strategies	O
that	O
could	O
reduce	O
aggression	O
,	O
abuse	O
and	O
violence	O
in	O
the	O
workplace	O
include	O
:	O
zero	O
tolerance	O
policies	O
,	O
access	O
to	O
employee	O
support	O
programs	O
and	O
providing	O
assistance	O
to	O
rehabilitation	O
professionals	O
who	O
work	O
alone	O
(	O
i	O
.	O
e	O
.	O
home	O
care	O
and	O
rural	O
and	O
remote	O
areas	O
)	O
.	O

Since	O
there	O
is	O
less	O
control	O
over	O
the	O
environment	O
in	O
the	O
home	O
care	O
setting	O
,	O
safety	O
may	O
become	O
a	O
greater	O
concern	O
in	O
one	O
practice	O
setting	O
over	O
another	O
.	O

This	O
might	O
suggest	O
that	O
because	O
there	O
is	O
less	O
control	O
in	O
environments	O
such	O
as	O
home	O
care	O
,	O
remote	O
areas	O
,	O
and	O
psychiatric	O
settings	O
,	O
maintaining	O
safety	O
will	O
be	O
more	O
difficult	O
and	O
that	O
solutions	O
will	O
need	O
to	O
be	O
tailored	O
to	O
these	O
settings	O
in	O
order	O
to	O
ensure	O
retention	O
of	O
providers	O
.	O

Although	O
no	O
studies	O
have	O
looked	O
at	O
implementing	O
personal	O
safety	O
strategies	O
for	O
home	O
care	O
therapists	O
,	O
written	O
policies	O
and	O
procedures	O
for	O
home	O
care	O
nurses	O
during	O
inclement	O
weather	O
and	O
for	O
dealing	O
with	O
abusive	O
or	O
dangerous	O
patients	B
,	O
families	O
and	O
neighbourhoods	O
have	O
been	O
reported	O
[	O
50	O
]	O
.	O

In	O
addition	O
to	O
the	O
above	O
,	O
ensuring	O
open	O
and	O
timely	O
communication	O
between	O
employer	O
and	O
worker	O
was	O
also	O
ranked	O
highly	O
among	O
the	O
recruitment	O
and	O
retention	O
strategies	O
.	O

Examples	O
of	O
strategies	O
include	O
:	O
open	O
door	O
policies	O
,	O
employee	O
advisory	O
committees	O
and	O
regular	O
staff	O
meetings	O
and	O
evaluations	O
.	O

Although	O
these	O
strategies	O
were	O
reported	O
to	O
be	O
used	O
among	O
organizations	O
providing	O
services	O
to	O
persons	B
with	O
developmental	O
disabilities	O
in	O
Alberta	O
,	O
there	O
was	O
no	O
description	O
of	O
the	O
organizations	O
,	O
sample	O
size	O
or	O
methodology	O
[	O
51	O
]	O
.	O

Similar	O
findings	O
were	O
found	O
in	O
a	O
qualitative	O
study	O
among	O
16	O
nurses	O
working	O
from	O
diverse	O
practice	O
settings	O
(	O
acute	O
,	O
long	O
-	O
term	O
care	O
,	O
rehabilitation	O
and	O
community	O
;	O
from	O
both	O
urban	O
and	O
rural	O
areas	O
)	O
in	O
a	O
health	O
region	O
in	O
western	O
Canada	O
.	O

From	O
the	O
semi	O
-	O
structured	O
interviews	O
,	O
study	O
participants	B
expressed	O
a	O
desire	O
for	O
improved	O
consultation	O
and	O
communication	O
with	O
nurses	O
regarding	O
changes	O
to	O
the	O
health	O
care	O
system	O
[	O
52	O
]	O
.	O

Financial	O
Incentives	O
and	O
Marketing	O

Another	O
area	O
that	O
was	O
ranked	O
highly	O
was	O
marketing	O
strategies	O
to	O
increase	O
high	O
school	O
student	O
and	O
public	O
awareness	O
of	O
rehabilitation	O
careers	O
.	O

These	O
specific	O
strategies	O
were	O
also	O
recommended	O
by	O
the	O
Ontario	O
Hospital	O
Association	O
(	O
OHA	O
)	O
in	O
order	O
to	O
establish	O
a	O
competitive	O
position	O
for	O
Ontario	O
hospitals	O
in	O
respect	O
of	O
recruitment	O
and	O
retention	O
of	O
health	O
care	O
professionals	O
[	O
53	O
]	O
.	O

Similar	O
strategies	O
have	O
been	O
developed	O
by	O
the	O
American	O
Physical	O
Therapy	O
Association	O
(	O
APTA	O
)	O
in	O
response	O
to	O
the	O
declining	O
number	O
of	O
students	O
applying	O
to	O
Physical	O
Therapy	O
Education	O
Programs	O
[	O
54	O
]	O
.	O

To	O
address	O
this	O
trend	O
,	O
APTA	O
developed	O
a	O
campaign	O
to	O
promote	O
Physical	O
Therapy	O
as	O
the	O
profession	O
of	O
choice	O
to	O
high	O
school	O
and	O
college	O
students	O
across	O
the	O
United	O
States	O
.	O

The	O
potential	O
components	O
of	O
their	O
plan	O
included	O
:	O
developing	O
a	O
"	O
Recruiting	O
Kit	O
"	O
for	O
educators	O
,	O
students	O
and	O
various	O
APTA	O
members	O
to	O
be	O
used	O
in	O
the	O
high	O
school	O
and	O
college	O
settings	O
to	O
introduce	O
Physical	O
Therapy	O
as	O
a	O
career	O
;	O
establishing	O
public	O
relations	O
initiatives	O
that	O
demonstrate	O
the	O
role	O
of	O
Physical	O
Therapy	O
in	O
the	O
public	O
arena	O
targeting	O
minority	O
groups	O
that	O
are	O
underrepresented	O
in	O
the	O
profession	O
;	O
and	O
creating	O
alliances	O
with	O
professional	O
associations	O
of	O
high	O
school	O
guidance	O
counsellors	O
and	O
educators	O
.	O

Based	O
on	O
our	O
finding	O
,	O
the	O
APTA	O
model	O
may	O
have	O
applicability	O
in	O
Ontario	O
.	O

Workload	O
and	O
Skill	O
Mix	O

Of	O
the	O
six	O
Workload	O
and	O
Skill	O
Mix	O
strategies	O
only	O
two	O
were	O
highly	O
rated	O
:	O
implementing	O
a	O
caseload	O
management	O
database	O
and	O
using	O
support	O
personnel	O
.	O

Caseload	O
management	O
has	O
been	O
identified	O
in	O
the	O
literature	O
as	O
an	O
issue	O
affecting	O
all	O
three	O
rehabilitation	O
professions	O
.	O

For	O
example	O
,	O
in	O
physiotherapy	O
,	O
Christie	O
'	O
s	O
study	O
[	O
55	O
]	O
found	O
that	O
caseload	O
expectations	O
tended	O
to	O
be	O
significantly	O
higher	O
than	O
the	O
reality	O
and	O
that	O
caseload	O
varies	O
across	O
different	O
programs	O
.	O

Similarly	O
,	O
the	O
Canadian	O
Association	O
of	O
Speech	O
-	O
Language	O
Pathologists	O
and	O
Audiologists	O
(	O
CASPLA	O
)	O
survey	O
indicated	O
that	O
factors	O
affecting	O
the	O
workload	O
of	O
SLPs	O
include	O
delivery	O
models	O
,	O
client	O
disorder	O
,	O
severity	O
and	O
work	O
setting	O
[	O
56	O
]	O
.	O

A	O
literature	O
review	O
and	O
environmental	O
scan	O
undertaken	O
by	O
the	O
Canadian	O
Association	O
of	O
Occupational	O
Therapists	O
(	O
CAOT	O
)	O
proposed	O
that	O
guiding	O
principles	O
for	O
caseload	O
management	O
should	O
include	O
:	O
evidence	O
-	O
based	O
occupational	O
therapy	O
,	O
cost	O
-	O
effectiveness	O
,	O
accountability	O
,	O
professional	O
leadership	O
and	O
expert	O
judgment	O
,	O
comprehensiveness	O
and	O
flexibility	O
[	O
57	O
]	O
.	O

Therefore	O
,	O
upon	O
implementation	O
of	O
a	O
caseload	O
management	O
database	O
for	O
rehabilitation	O
,	O
key	O
factors	O
to	O
consider	O
include	O
workplace	O
setting	O
and	O
client	O
service	O
delivery	O
models	O
.	O

The	O
other	O
highly	O
rated	O
Workload	O
and	O
Skill	O
Mix	O
strategy	O
was	O
the	O
use	O
of	O
support	O
personnel	O
(	O
i	O
.	O
e	O
.	O
physiotherapy	O
assistants	O
or	O
exercise	O
therapists	O
)	O
to	O
increase	O
efficiency	O
of	O
utilization	O
of	O
scarcer	O
and	O
higher	O
order	O
rehabilitation	O
competencies	O
.	O

Considerations	O
for	O
implementing	O
this	O
strategy	O
include	O
addressing	O
key	O
issues	O
such	O
supply	O
,	O
standards	O
of	O
education	O
,	O
standards	O
of	O
practice	O
and	O
accreditation	O
.	O

These	O
are	O
highlighted	O
in	O
an	O
article	O
by	O
Salvatori	O
[	O
58	O
]	O
who	O
reported	O
that	O
the	O
actual	O
number	O
of	O
OT	O
personnel	O
delivering	O
OT	O
services	O
in	O
Canada	O
remains	O
unknown	O
and	O
that	O
there	O
are	O
no	O
national	O
standards	O
of	O
education	O
nor	O
accreditation	O
process	O
for	O
OT	O
assistants	O
.	O

CAOT	O
believes	O
that	O
in	O
order	O
to	O
utilize	O
support	O
personnel	O
appropriately	O
,	O
studies	O
on	O
human	B
resource	O
needs	O
for	O
occupational	O
therapy	O
and	O
support	O
personnel	O
are	O
first	O
needed	O
with	O
input	O
from	O
OTs	O
,	O
stakeholders	O
,	O
funders	O
,	O
decision	O
makers	O
and	O
health	O
policy	O
planners	O
[	O
59	O
]	O
.	O

Since	O
there	O
is	O
a	O
lack	O
of	O
competency	O
profiles	O
related	O
to	O
the	O
role	O
,	O
responsibilities	O
,	O
and	O
supervision	O
of	O
assistants	O
,	O
particularly	O
with	O
regards	O
to	O
delivering	O
services	O
in	O
unsupervised	O
community	O
-	O
based	O
settings	O
,	O
the	O
type	O
of	O
workplace	O
setting	O
where	O
this	O
strategy	O
may	O
be	O
implemented	O
should	O
be	O
considered	O
[	O
58	O
]	O
.	O

Education	O
and	O
Training	O

Given	O
that	O
60	O
%	O
of	O
highly	O
rated	O
Education	O
and	O
Training	O
strategies	O
targeted	O
rural	O
and	O
remote	O
practices	O
underscores	O
the	O
importance	O
of	O
specific	O
strategies	O
for	O
rural	O
and	O
remote	O
areas	O
in	O
the	O
development	O
of	O
a	O
HHR	O
plan	O
.	O

The	O
need	O
to	O
build	O
on	O
existing	O
mechanisms	O
to	O
expand	O
the	O
availability	O
of	O
rural	O
and	O
remote	O
clinical	O
placements	O
by	O
providing	O
financial	O
and	O
accommodation	O
support	O
was	O
ranked	O
among	O
the	O
top	O
two	O
most	O
important	O
and	O
feasible	O
education	O
strategies	O
for	O
rehabilitation	O
professionals	O
.	O

Not	O
only	O
has	O
this	O
strategy	O
been	O
used	O
as	O
a	O
recruitment	O
tool	O
for	O
rehabilitation	O
students	O
,	O
it	O
has	O
also	O
been	O
reported	O
by	O
Solomon	O
et	O
al	O
.	O

[	O
34	O
]	O
to	O
be	O
effective	O
in	O
retaining	O
OTs	O
and	O
PTs	O
in	O
underserviced	O
Northwestern	O
Ontario	O
communities	O
.	O

Respondents	O
from	O
Solomon	O
et	O
al	O
.	O
'	O
s	O
study	O
reported	O
that	O
the	O
top	O
three	O
benefits	O
of	O
supervising	O
students	O
were	O
that	O
it	O
stimulates	O
thinking	O
,	O
it	O
provides	O
opportunity	O
to	O
contribute	O
to	O
the	O
profession	O
and	O
that	O
it	O
provides	O
access	O
to	O
current	O
information	O
.	O

The	O
reported	O
disadvantages	O
however	O
was	O
that	O
it	O
was	O
time	O
-	O
consuming	O
and	O
students	O
contributed	O
stress	O
to	O
the	O
working	O
environment	O
.	O

Similarly	O
,	O
a	O
two	O
-	O
part	O
study	O
found	O
substantial	O
gaps	O
between	O
financial	O
incentives	O
students	O
deem	O
important	O
in	O
the	O
creation	O
of	O
an	O
appealing	O
clinical	O
placement	O
opportunity	O
and	O
the	O
actual	O
provisions	O
offered	O
to	O
them	O
by	O
Southeastern	O
Ontario	O
communities	O
[	O
60	O
,	O
61	O
]	O
.	O

Although	O
OT	O
and	O
PT	O
students	O
reported	O
that	O
they	O
were	O
more	O
willing	O
to	O
complete	O
a	O
clinical	O
placement	O
in	O
an	O
underserviced	O
community	O
if	O
provided	O
travel	O
stipends	O
,	O
rent	O
-	O
free	O
housing	O
and	O
interprofessional	O
education	O
opportunities	O
,	O
the	O
majority	O
of	O
these	O
incentives	O
were	O
only	O
available	O
to	O
medical	O
students	O
.	O

In	O
addition	O
to	O
training	O
students	O
for	O
rural	O
and	O
remote	O
practice	O
,	O
a	O
longitudinal	O
study	O
reported	O
that	O
perceived	O
opportunity	O
for	O
career	O
development	O
was	O
the	O
most	O
significant	O
factor	O
related	O
to	O
job	O
turnover	O
and	O
regional	O
attrition	O
among	O
physiotherapists	O
working	O
in	O
Northern	O
Ontario	O
[	O
5	O
]	O
.	O

Therefore	O
developing	O
workforce	O
strategies	O
for	O
rehabilitation	O
therapists	O
working	O
in	O
these	O
areas	O
should	O
be	O
among	O
one	O
of	O
the	O
priority	O
areas	O
in	O
HHR	O
planning	O
.	O

Professional	O
Development	O

Our	O
findings	O
indicate	O
that	O
the	O
theme	O
with	O
the	O
largest	O
number	O
of	O
strategies	O
that	O
were	O
considered	O
important	O
and	O
feasible	O
to	O
implement	O
as	O
part	O
of	O
HHR	O
planning	O
was	O
professional	O
development	O
.	O

Many	O
were	O
specific	O
to	O
rural	O
and	O
remote	O
areas	O
.	O

Although	O
the	O
importance	O
of	O
continuous	O
professional	O
development	O
(	O
CPD	O
)	O
in	O
recruitment	O
and	O
retention	O
is	O
well	O
recognized	O
,	O
a	O
Canadian	O
study	O
reported	O
several	O
barriers	O
to	O
its	O
implementation	O
[	O
62	O
]	O
.	O

In	O
the	O
case	O
of	O
OTs	O
employed	O
in	O
public	O
settings	O
in	O
Nova	O
Scotia	O
,	O
Townsend	O
et	O
al	O
.	O

(	O
2006	O
)	O
found	O
that	O
the	O
most	O
powerful	O
deterrent	O
for	O
CPD	O
was	O
the	O
lack	O
of	O
support	O
from	O
workplace	O
policies	O
.	O

Based	O
on	O
their	O
study	O
results	O
,	O
the	O
use	O
of	O
CPD	O
as	O
a	O
recruitment	O
and	O
retention	O
strategy	O
was	O
highly	O
influenced	O
by	O
gender	O
issues	O
,	O
work	O
-	O
life	O
balance	O
,	O
career	O
advancement	O
,	O
working	O
conditions	O
,	O
geographical	O
location	O
,	O
professional	O
versus	O
employer	O
responsibility	O
,	O
and	O
employee	O
benefits	O
.	O

Although	O
occupational	O
therapy	O
is	O
a	O
female	O
-	O
dominated	O
profession	O
,	O
workplace	O
policies	O
did	O
not	O
address	O
issues	O
of	O
gender	O
.	O

For	O
example	O
,	O
therapists	O
in	O
this	O
study	O
indicated	O
that	O
CPD	O
competes	O
with	O
family	O
commitments	O
,	O
therefore	O
these	O
activities	O
are	O
"	O
done	O
largely	O
during	O
personal	O
time	O
,	O
mainly	O
at	O
their	O
own	O
cost	O
,	O
and	O
on	O
top	O
of	O
childcare	O
,	O
eldercare	O
,	O
homemaking	O
and	O
other	O
family	O
responsibilities	O
"	O
[	O
62	O
]	O
.	O

In	O
addition	O
,	O
heavy	O
workloads	O
,	O
lack	O
of	O
salary	O
and	O
career	O
incentives	O
,	O
and	O
lack	O
of	O
policy	O
and	O
funding	O
support	O
are	O
all	O
barriers	O
to	O
CPD	O
.	O

These	O
issues	O
become	O
more	O
pronounced	O
in	O
rural	O
and	O
remote	O
settings	O
because	O
smaller	O
communities	O
often	O
only	O
have	O
one	O
therapist	O
;	O
hence	O
the	O
systemic	O
pressure	O
of	O
workload	O
demands	O
makes	O
it	O
difficult	O
for	O
the	O
therapist	O
to	O
leave	O
patient	B
care	O
.	O

OTs	O
from	O
this	O
study	O
also	O
questioned	O
who	O
was	O
responsible	O
for	O
CPD	O
.	O

Some	O
felt	O
that	O
it	O
was	O
the	O
professional	O
'	O
s	O
responsibility	O
while	O
others	O
felt	O
that	O
it	O
was	O
the	O
responsibility	O
of	O
the	O
employer	O
to	O
provide	O
CPD	O
opportunities	O
.	O

The	O
primary	O
limitation	O
employers	O
faced	O
was	O
the	O
lack	O
of	O
financial	O
resources	O
,	O
however	O
giving	O
employees	O
time	O
off	O
without	O
pay	O
was	O
an	O
alternative	O
strategy	O
utilized	O
instead	O
of	O
funding	O
professional	O
development	O
activities	O
.	O

Although	O
there	O
are	O
professional	O
and	O
provincial	O
variations	O
in	O
funding	O
for	O
CPD	O
across	O
Canada	O
,	O
these	O
results	O
are	O
informative	O
in	O
that	O
it	O
highlights	O
the	O
need	O
for	O
employers	O
to	O
consider	O
how	O
workplace	O
policies	O
can	O
affect	O
recruitment	O
and	O
retention	O
strategies	O
.	O

Limitations	O
of	O
this	O
study	O
should	O
be	O
noted	O
.	O

First	O
,	O
the	O
majority	O
of	O
the	O
strategies	O
were	O
obtained	O
from	O
the	O
grey	O
literature	O
that	O
is	O
not	O
subject	O
to	O
the	O
same	O
scrutiny	O
as	O
the	O
peer	O
-	O
reviewed	O
literature	O
.	O

Second	O
,	O
almost	O
none	O
of	O
the	O
strategies	O
were	O
specifically	O
developed	O
for	O
rehabilitation	O
professionals	O
and	O
in	O
many	O
cases	O
had	O
to	O
be	O
re	O
-	O
worded	O
to	O
fit	O
the	O
rehabilitation	O
context	O
.	O

There	O
is	O
a	O
lack	O
of	O
research	O
on	O
rehabilitation	O
clinicians	O
'	O
perspectives	O
on	O
recruitment	O
and	O
retention	O
strategies	O
;	O
therefore	O
future	O
research	O
should	O
focus	O
on	O
investigating	O
this	O
area	O
.	O

Third	O
,	O
during	O
the	O
face	O
-	O
to	O
-	O
face	O
meeting	O
,	O
bias	O
could	O
have	O
resulted	O
from	O
panelists	O
whose	O
opinion	O
may	O
have	O
influenced	O
others	O
significantly	O
,	O
especially	O
if	O
members	O
came	O
from	O
similar	O
workplace	O
settings	O
.	O

The	O
facilitator	O
of	O
the	O
expert	O
panels	O
however	O
,	O
followed	O
a	O
strict	O
process	O
for	O
managing	O
the	O
discussion	O
and	O
ensured	O
that	O
all	O
panelists	O
were	O
given	O
the	O
opportunity	O
to	O
express	O
their	O
opinions	O
.	O

Finally	O
,	O
although	O
some	O
strategies	O
such	O
as	O
competitive	O
wage	O
packages	O
,	O
training	O
/	O
growth	O
opportunities	O
and	O
professional	O
development	O
are	O
viewed	O
as	O
both	O
a	O
recruitment	O
and	O
retention	O
incentive	O
,	O
other	O
strategies	O
do	O
not	O
overlap	O
and	O
are	O
appropriate	O
for	O
only	O
one	O
of	O
the	O
two	O
tasks	O
.	O

For	O
example	O
,	O
increasing	O
public	O
awareness	O
of	O
rehabilitation	O
careers	O
,	O
providing	O
rural	O
and	O
remote	O
orientation	O
packages	O
and	O
family	O
relocation	O
programs	O
are	O
only	O
appropriate	O
for	O
attracting	O
a	O
worker	O
while	O
ensuring	O
open	O
and	O
timely	O
communication	O
may	O
be	O
seen	O
as	O
a	O
strategy	O
only	O
for	O
retention	O
.	O

Future	O
research	O
should	O
therefore	O
consider	O
studying	O
recruitment	O
and	O
retention	O
strategies	O
separately	O
so	O
that	O
a	O
distinction	O
between	O
the	O
two	O
can	O
be	O
made	O
.	O

Conclusion	O

This	O
study	O
identified	O
34	O
strategies	O
that	O
should	O
be	O
considered	O
as	O
important	O
and	O
feasible	O
for	O
implementation	O
as	O
part	O
of	O
HHR	O
planning	O
for	O
rehabilitation	O
professionals	O
.	O

Although	O
the	O
highest	O
ranked	O
strategies	O
focused	O
on	O
areas	O
of	O
Quality	O
of	O
Worklife	O
and	O
Work	O
Environment	O
,	O
Financial	O
Incentives	O
and	O
Marketing	O
and	O
Professional	O
Development	O
,	O
key	O
factors	O
that	O
need	O
to	O
be	O
considered	O
in	O
the	O
context	O
of	O
implementation	O
include	O
:	O
workplace	O
setting	O
,	O
geographical	O
location	O
and	O
gender	O
issues	O
.	O

While	O
this	O
is	O
the	O
first	O
study	O
to	O
our	O
knowledge	O
that	O
provides	O
a	O
comprehensive	O
list	O
of	O
recruitment	O
and	O
retention	O
strategies	O
relevant	O
to	O
rehabilitation	O
professionals	O
,	O
more	O
information	O
is	O
needed	O
for	O
the	O
development	O
of	O
a	O
HHR	O
plan	O
.	O

Information	O
on	O
trends	O
in	O
labour	O
force	O
participation	O
as	O
well	O
as	O
knowledge	O
regarding	O
the	O
use	O
and	O
effectiveness	O
of	O
recruitment	O
and	O
retention	O
strategies	O
for	O
rehabilitation	O
professionals	O
is	O
needed	O
.	O

More	O
importantly	O
,	O
the	O
success	O
of	O
implementing	O
and	O
sustaining	O
such	O
strategies	O
requires	O
future	O
research	O
to	O
validate	O
these	O
strategies	O
from	O
the	O
perspective	O
of	O
rehabilitation	O
clinicians	O
and	O
human	B
resource	O
decisions	O
makers	O
(	O
i	O
.	O
e	O
.	O
local	O
government	O
,	O
stakeholders	O
,	O
etc	O
.	O
)	O
so	O
that	O
specific	O
barriers	O
and	O
challenges	O
can	O
be	O
identified	O
.	O

Competing	O
interests	O

The	O
authors	O
declare	O
that	O
they	O
have	O
no	O
competing	O
interests	O
.	O

Authors	O
'	O
contributions	O

DT	O
participated	O
in	O
the	O
design	O
of	O
the	O
study	O
,	O
conducted	O
the	O
literature	O
review	O
,	O
analyzed	O
and	O
interpreted	O
the	O
results	O
and	O
drafted	O
the	O
manuscript	O
.	O

LMH	O
,	O
AD	O
,	O
DB	O
and	O
KB	O
were	O
involved	O
in	O
providing	O
feedback	O
and	O
editing	O
the	O
content	O
of	O
the	O
manuscript	O
.	O

MDL	O
recommended	O
participants	B
for	O
the	O
expert	O
panel	O
and	O
was	O
involved	O
in	O
providing	O
feedback	O
and	O
editing	O
the	O
content	O
of	O
the	O
manuscript	O
.	O

SJ	O
participated	O
in	O
the	O
design	O
of	O
the	O
study	O
,	O
recommended	O
participants	B
for	O
the	O
expert	O
panel	O
,	O
organized	O
and	O
consolidated	O
strategies	O
,	O
interpreted	O
the	O
data	O
and	O
edited	O
the	O
content	O
of	O
the	O
manuscript	O
.	O

Pre	O
-	O
publication	O
history	O

The	O
pre	O
-	O
publication	O
history	O
for	O
this	O
paper	O
can	O
be	O
accessed	O
here	O
:	O

A	O
life	O
threatening	O
uterine	O
inversion	O
and	O
massive	O
post	O
partum	O
hemorrhage	O
caused	O
by	O
placenta	O
accrete	O
during	O
Caesarean	O
section	O
in	O
a	O
primigravida	O
:	O
a	O
case	O
report	O

Abstract	O

Background	O

A	O
32	O
-	O
year	O
-	O
old	O
Caucasian	O
primigravida	O
was	O
admitted	O
for	O
elective	O
Caesarean	O
Section	O
at	O
36	O
weeks	O
and	O
6	O
days	O
with	O
the	O
diagnosis	O
of	O
preeclampsia	O
.	O

Case	O
presentation	O

Traction	O
of	O
the	O
umbilical	O
cord	O
after	O
delivery	O
of	O
a	O
healthy	O
baby	O
resulted	O
in	O
uterine	O
inversion	O
.	O

The	O
placenta	O
was	O
found	O
to	O
be	O
densely	O
adherent	O
to	O
the	O
posterior	O
uterine	O
wall	O
.	O

Piecemeal	O
excision	O
of	O
the	O
placenta	O
as	O
close	O
as	O
possible	O
to	O
the	O
uterine	O
lining	O
was	O
then	O
performed	O
.	O

Conclusion	O

In	O
this	O
way	O
we	O
were	O
able	O
to	O
control	O
a	O
massive	O
post	O
partum	O
hemorrhage	O
and	O
preserve	O
the	O
fertility	O
of	O
the	O
patient	B
.	O

Background	O

Placenta	O
accreta	O
is	O
defined	O
as	O
abnormal	O
adherence	O
,	O
either	O
in	O
whole	O
or	O
in	O
part	O
of	O
the	O
afterbirth	O
to	O
the	O
underlying	O
uterine	O
wall	O
.	O

Placenta	O
accreta	O
and	O
other	O
pathological	O
placentations	O
(	O
such	O
as	O
increta	O
,	O
percreta	O
)	O
are	O
rare	O
complications	O
of	O
pregnancy	O
with	O
potential	O
life	O
threatening	O
and	O
fertility	O
threatening	O
consequences	O
.	O

The	O
incidence	O
of	O
placenta	O
accreta	O
has	O
increased	O
ten	O
times	O
over	O
the	O
last	O
fifteen	O
years	O
,	O
which	O
reflects	O
the	O
increase	O
in	O
the	O
rate	O
of	O
Caesarean	O
Sections	O
(	O
CS	O
)	O
[	O
1	O
]	O
.	O

Placenta	O
accreta	O
has	O
become	O
the	O
most	O
important	O
cause	O
of	O
peripartum	O
hysterectomy	O
.	O

A	O
life	O
threatening	O
acute	O
uterine	O
inversion	O
and	O
massive	O
PPH	O
can	O
be	O
caused	O
by	O
placenta	O
accreta	O
during	O
CS	O
but	O
seldom	O
in	O
a	O
primigravida	O
(	O
Figure	O
1	O
)	O
.	O

Case	O
presentation	O

A	O
32	O
year	O
old	O
,	O
primigravida	O
,	O
was	O
admitted	O
in	O
a	O
District	O
General	O
Hospital	O
for	O
elective	O
Caesarean	O
section	O
at	O
36	O
weeks	O
and	O
6	O
days	O
with	O
the	O
diagnosis	O
of	O
preeclampsia	O
.	O

She	O
had	O
two	O
antenatal	O
ultrasound	O
examinations	O
showing	O
a	O
healthy	O
fetus	O
and	O
posterior	O
fundal	O
placenta	O
.	O

The	O
patient	B
had	O
lower	O
segment	O
CS	O
of	O
a	O
healthy	O
male	O
infant	B
under	O
spinal	O
anesthesia	O
.	O

The	O
placenta	O
was	O
found	O
to	O
be	O
densely	O
adherent	O
to	O
the	O
posterior	O
uterine	O
wall	O
.	O

Traction	O
of	O
the	O
umbilical	O
cord	O
was	O
applied	O
and	O
subsequently	O
resulted	O
in	O
uterine	O
inversion	O
.	O

The	O
placenta	O
was	O
removed	O
by	O
'	O
piecemeal	O
'	O
excising	O
as	O
close	O
as	O
possible	O
to	O
the	O
uterine	O
lining	O
.	O

About	O
80	O
%	O
of	O
the	O
placental	O
tissue	O
was	O
removed	O
until	O
the	O
uterine	O
inversion	O
was	O
corrected	O
.	O

The	O
uterus	O
was	O
closed	O
in	O
two	O
layers	O
.	O

Two	O
intra	O
-	O
abdominal	O
drains	O
were	O
sited	O
.	O

The	O
estimated	O
blood	O
loss	O
was	O
2	O
.	O
5	O
litres	O
and	O
five	O
units	O
of	O
blood	O
were	O
transfused	O
together	O
with	O
2	O
units	O
of	O
FFP	O
during	O
intra	O
-	O
operative	O
and	O
post	O
-	O
operative	O
period	O
.	O

In	O
addition	O
,	O
the	O
patient	B
was	O
treated	O
with	O
intravenous	O
oxytocin	O
infusion	O
,	O
pr	O
misoprostol	O
and	O
antibiotics	O
.	O

On	O
the	O
second	O
post	O
partum	O
day	O
,	O
vaginal	O
Doppler	O
ultrasound	O
scan	O
showed	O
significant	O
amount	O
of	O
placental	O
tissues	O
with	O
increased	O
vascularity	O
measuring	O
2	O
.	O
7	O
x	O
6	O
.	O
6	O
x	O
6	O
.	O
8	O
cms	O
within	O
the	O
endometrial	O
cavity	O
(	O
Figure	O
2	O
)	O
.	O

The	O
patient	B
was	O
discharged	O
on	O
the	O
fifth	O
post	O
-	O
operative	O
day	O
with	O
a	O
conservative	O
management	O
.	O

A	O
follow	O
up	O
Ultrasound	O
scan	O
after	O
two	O
weeks	O
showed	O
reduction	O
of	O
placental	O
mass	O
(	O
Figure	O
3	O
)	O
.	O

In	O
addition	O
,	O
there	O
was	O
significant	O
decrease	O
in	O
serum	O
beta	O
HCG	O
levels	O
from	O
2300	O
u	O
/	O
L	O
on	O
day	O
1	O
to	O
13	O
u	O
/	O
L	O
at	O
four	O
weeks	O
post	O
operatively	O
.	O

The	O
patient	B
remained	O
with	O
minimal	O
vaginal	O
bleeding	O
without	O
abdominal	O
pain	O
.	O

She	O
had	O
two	O
normal	O
periods	O
after	O
stopping	O
breastfeeding	O
and	O
was	O
feeling	O
well	O
.	O

She	O
was	O
discharged	O
from	O
the	O
early	O
pregnancy	O
unit	O
.	O

Discussion	O

A	O
life	O
-	O
threatening	O
uterine	O
inversion	O
can	O
be	O
rarely	O
caused	O
by	O
placenta	O
accreta	O
[	O
2	O
]	O
.	O

Placenta	O
accreta	O
classically	O
presents	O
with	O
retained	O
placenta	O
and	O
hemorrhage	O
.	O

The	O
association	O
between	O
uterine	O
inversion	O
and	O
placenta	O
accreta	O
is	O
unclear	O
,	O
however	O
,	O
strong	O
traction	O
on	O
the	O
umbilical	O
cord	O
with	O
fundal	O
placenta	O
,	O
excessive	O
fundal	O
pressure	O
,	O
relaxed	O
uterus	O
,	O
short	O
umbilical	O
cord	O
,	O
uterine	O
anomalies	O
and	O
antepartum	O
use	O
of	O
magnesium	O
sulphate	O
are	O
known	O
associated	O
factors	O
[	O
2	O
]	O
.	O

Uterine	O
inversion	O
and	O
retain	O
placenta	O
accreta	O
can	O
both	O
be	O
fatal	O
complications	O
[	O
3	O
]	O
.	O

In	O
the	O
case	O
described	O
the	O
placenta	O
accreta	O
was	O
complicated	O
by	O
uterine	O
inversion	O
and	O
subsequent	O
massive	O
post	O
partum	O
hemorrhage	O
,	O
significantly	O
increasing	O
the	O
risk	O
of	O
maternal	O
mortality	O
.	O

Massive	O
post	O
partum	O
hemorrhage	O
is	O
a	O
major	O
cause	O
of	O
maternal	O
mortality	O
in	O
the	O
United	O
Kingdom	O
(	O
why	O
women	B
die	O
latest	O
report	O
)	O
[	O
4	O
]	O
.	O

In	O
this	O
case	O
,	O
the	O
placenta	O
was	O
clamped	O
as	O
close	O
to	O
the	O
uterine	O
cavity	O
as	O
possible	O
and	O
cut	O
.	O

The	O
base	O
of	O
the	O
placenta	O
was	O
overrun	O
with	O
haemostatic	O
sutures	O
and	O
this	O
was	O
repeated	O
until	O
as	O
much	O
of	O
the	O
placenta	O
as	O
possible	O
was	O
removed	O
(	O
Figure	O
4	O
)	O
.	O

Placental	O
removal	O
enabled	O
correction	O
of	O
uterine	O
inversion	O
.	O

Despite	O
the	O
many	O
conditions	O
associated	O
with	O
uterine	O
inversion	O
risk	O
assessment	O
is	O
often	O
lacking	O
making	O
the	O
condition	O
usually	O
unexpected	O
at	O
the	O
time	O
of	O
presentation	O
.	O

The	O
association	O
between	O
abnormal	O
placentation	O
such	O
as	O
placenta	O
accreta	O
and	O
uterine	O
inversion	O
is	O
well	O
supported	O
[	O
2	O
]	O
.	O

Therefore	O
,	O
we	O
advocate	O
antenatal	O
evaluation	O
and	O
risk	O
assessment	O
for	O
placenta	O
accreta	O
[	O
5	O
]	O
.	O

Prenatal	O
Ultrasound	O
reported	O
sensitivity	O
of	O
94	O
%	O
and	O
specificity	O
of	O
79	O
%	O
for	O
placenta	O
accreta	O
,	O
but	O
offer	O
no	O
more	O
than	O
provisional	O
diagnostic	O
probability	O
statement	O
[	O
6	O
]	O
.	O

Moreover	O
,	O
because	O
45	O
%	O
of	O
placenta	O
accreta	O
cases	O
were	O
not	O
detected	O
by	O
ultrasound	O
,	O
it	O
is	O
important	O
to	O
consider	O
avoiding	O
manual	O
removal	O
of	O
placenta	O
if	O
there	O
were	O
intraoperative	O
signs	O
of	O
accreta	O
[	O
6	O
]	O
.	O

If	O
clinically	O
or	O
sonographically	O
the	O
patient	B
is	O
suspected	O
antenatally	O
to	O
be	O
at	O
risk	O
of	O
placenta	O
accreta	O
,	O
appropriate	O
management	O
options	O
should	O
be	O
considered	O
,	O
such	O
as	O
attempted	O
conservative	O
management	O
or	O
hysterectomy	O
and	O
counseling	O
provided	O
about	O
potential	O
sequelae	O
[	O
6	O
]	O
.	O

The	O
traditional	O
management	O
is	O
abdominal	O
hysterectomy	O
,	O
but	O
this	O
operation	O
terminates	O
fertility	O
and	O
may	O
have	O
devastating	O
psychological	O
effects	O
.	O

However	O
,	O
in	O
correct	O
circumstances	O
,	O
a	O
conservative	O
approach	O
may	O
be	O
suitable	O
.	O

Conservative	O
management	O
of	O
abnormally	O
invasive	O
placentation	O
can	O
be	O
effective	O
and	O
fertility	O
can	O
be	O
preserved	O
.	O

It	O
should	O
be	O
only	O
considered	O
in	O
highly	O
selected	O
cases	O
when	O
blood	O
loss	O
is	O
minimal	O
and	O
there	O
is	O
wish	O
for	O
fertility	O
preservation	O
[	O
7	O
]	O
.	O

For	O
women	B
who	O
want	O
to	O
preserve	O
their	O
fertility	O
the	O
placenta	O
should	O
be	O
left	O
intact	O
if	O
possible	O
after	O
caesarean	O
delivery	O
as	O
this	O
approach	O
lowers	O
the	O
risk	O
of	O
subsequent	O
hysterectomy	O
from	O
85	O
%	O
to	O
15	O
%	O
.	O

For	O
women	B
who	O
have	O
completed	O
their	O
family	O
,	O
hysterectomy	O
with	O
placenta	O
left	O
in	O
situ	O
is	O
preferable	O
to	O
lower	O
the	O
maternal	O
morbidity	O
rates	O
[	O
6	O
]	O
.	O

This	O
case	O
report	O
involved	O
conservative	O
management	O
.	O

Peripartum	O
hysterectomy	O
was	O
avoided	O
and	O
the	O
aim	O
was	O
to	O
preserve	O
fertility	O
.	O

Prophylactic	O
antibiotics	O
,	O
post	O
partum	O
oxytocics	O
and	O
the	O
use	O
of	O
misoprostol	O
post	O
operatively	O
helped	O
to	O
prevent	O
further	O
post	O
partum	O
hemorrhage	O
.	O

When	O
a	O
patient	B
isinitially	O
opted	O
for	O
conservative	O
management	O
,	O
the	O
possibility	O
of	O
recurrence	O
should	O
be	O
discussed	O
[	O
8	O
]	O
.	O

Furthermore	O
,	O
placentation	O
should	O
be	O
carefully	O
monitored	O
for	O
recurrence	O
in	O
any	O
subsequent	O
pregnancy	O
,	O
particularly	O
if	O
the	O
placenta	O
is	O
located	O
at	O
the	O
same	O
site	O
as	O
the	O
previous	O
placenta	O
accreta	O
.	O

Conservative	O
treatment	O
for	O
placenta	O
accreta	O
may	O
be	O
an	O
alternative	O
procedure	O
in	O
some	O
selected	O
cases	O
.	O

Conclusion	O

We	O
suggest	O
an	O
alternative	O
approach	O
for	O
managing	O
uterine	O
inversion	O
caused	O
by	O
placenta	O
accreta	O
that	O
involved	O
conservative	O
management	O
.	O

This	O
way	O
hysterectomy	O
was	O
avoided	O
and	O
fertility	O
was	O
preserved	O
.	O

Abbreviations	O

CS	O
:	O
Caesarean	O
Section	O
;	O
FFP	O
:	O
Fresh	O
Frozen	O
Plasma	O

Consent	O

Written	O
informed	O
consent	O
was	O
obtained	O
from	O
the	O
patient	B
for	O
publication	O
of	O
this	O
case	O
report	O
and	O
accompanying	O
images	O
.	O

A	O
copy	O
of	O
the	O
written	O
consent	O
is	O
available	O
for	O
review	O
by	O
the	O
Editor	O
-	O
in	O
Chief	O
of	O
this	O
journal	O
.	O

Competing	O
interests	O

The	O
authors	O
declare	O
that	O
they	O
have	O
no	O
competing	O
interests	O
.	O

Authors	O
'	O
contributions	O

All	O
authors	O
have	O
made	O
substantial	O
contribution	O
to	O
concept	O
this	O
case	O
report	O
.	O

Neurogenin2	O
Directs	O
Granule	O
Neuroblast	O
Production	O
and	O
Amplification	O
while	O
NeuroD1	O
Specifies	O
Neuronal	O
Fate	O
during	O
Hippocampal	O
Neurogenesis	O

Abstract	O

The	O
specification	O
and	O
differentiation	O
of	O
dentate	O
gyrus	O
granule	O
neurons	O
in	O
the	O
hippocampus	O
require	O
temporally	O
and	O
spatially	O
coordinated	O
actions	O
of	O
both	O
intrinsic	O
and	O
extrinsic	O
molecules	O
.	O

The	O
basic	O
helix	O
-	O
loop	O
-	O
helix	O
transcription	O
factor	O
Neurogenin2	O
(	O
Ngn2	O
)	O
and	O
NeuroD1	O
are	O
key	O
regulators	O
in	O
these	O
processes	O
.	O

Based	O
on	O
existing	O
classification	O
,	O
we	O
analyzed	O
the	O
molecular	O
events	O
occurring	O
during	O
hippocampal	O
neurogenesis	O
,	O
primarily	O
focusing	O
on	O
juvenile	O
animals	O
.	O

We	O
found	O
that	O
Ngn2	O
is	O
transiently	O
expressed	O
by	O
late	O
type	O
-	O
2a	O
amplifying	O
progenitors	O
.	O

The	O
Ngn2	O
progenies	O
mature	O
into	O
hippocampal	O
granule	O
neurons	O
.	O

Interestingly	O
,	O
the	O
loss	O
of	O
Ngn2	O
at	O
early	O
stages	O
of	O
development	O
leads	O
to	O
a	O
robust	O
reduction	O
in	O
neurogenesis	O
,	O
but	O
does	O
not	O
disturb	O
granule	O
neuron	O
maturation	O
per	O
se	O
.	O

We	O
found	O
that	O
the	O
role	O
of	O
Ngn2	O
is	O
to	O
maintain	O
progenitors	O
in	O
an	O
undifferentiated	O
state	O
,	O
allowing	O
them	O
to	O
amplify	O
prior	O
to	O
their	O
maturation	O
into	O
granule	O
neurons	O
upon	O
NeuroD1	O
induction	O
.	O

When	O
we	O
overexpressed	O
Ngn2	O
and	O
NeuroD1	O
in	O
vivo	O
,	O
we	O
found	O
NeuroD1	O
to	O
exhibit	O
a	O
more	O
pronounced	O
neuron	O
-	O
inductive	O
effect	O
,	O
leading	O
to	O
granule	O
neuron	O
commitment	O
,	O
than	O
that	O
displayed	O
by	O
Ngn2	O
.	O

Finally	O
,	O
we	O
observed	O
that	O
all	O
markers	O
expressed	O
during	O
the	O
transcriptional	O
control	O
of	O
hippocampal	O
neurogenesis	O
in	O
rodents	O
are	O
also	O
present	O
in	O
the	O
human	B
hippocampus	O
.	O

Taken	O
together	O
,	O
we	O
demonstrate	O
a	O
critical	O
role	O
of	O
for	O
Ngn2	O
and	O
NeuroD1	O
in	O
controlling	O
neuronal	O
commitment	O
and	O
hippocampal	O
granule	O
neuroblast	O
formation	O
,	O
both	O
during	O
embryonic	O
development	O
and	O
in	O
post	O
-	O
natal	O
hippocampal	O
granule	O
neurogenesis	O
.	O

Introduction	O

Neurons	O
are	O
born	O
not	O
only	O
during	O
development	O
of	O
the	O
central	O
nervous	O
system	O
,	O
but	O
neurogenesis	O
also	O
continues	O
into	O
adulthood	O
.	O

In	O
both	O
rodent	B
and	O
human	B
adult	O
brain	O
,	O
neurogenesis	O
is	O
active	O
in	O
two	O
distinct	O
zones	O
of	O
the	O
forebrain	O
:	O
the	O
subventricular	O
zone	O
(	O
SVZ	O
)	O
of	O
the	O
lateral	O
ventricle	O
and	O
the	O
subgranular	O
zone	O
(	O
SGZ	O
)	O
of	O
the	O
hippocampal	O
dentate	O
gyrus	O
(	O
DG	O
)	O
[	O
1	O
]	O
-	O
[	O
5	O
]	O
.	O

The	O
molecular	O
mechanism	O
underlying	O
neurogenesis	O
in	O
the	O
DG	O
is	O
not	O
fully	O
understood	O
.	O

Clearly	O
,	O
a	O
cascade	O
of	O
transcriptional	O
events	O
controls	O
the	O
specification	O
of	O
neuronal	O
identity	O
in	O
the	O
DG	O
[	O
3	O
]	O
,	O
[	O
6	O
]	O
-	O
[	O
8	O
]	O
,	O
but	O
details	O
of	O
the	O
expression	O
pattern	O
and	O
function	O
of	O
each	O
transcription	O
factor	O
remain	O
elusive	O
.	O

The	O
paired	O
-	O
box	O
homeodomain	O
transcription	O
factor	O
Pax6	O
and	O
the	O
bHLH	O
transcription	O
factors	O
Ngn2	O
and	O
NeuroD1	O
are	O
important	O
when	O
cells	O
acquire	O
a	O
pan	O
-	O
neuronal	O
character	O
and	O
a	O
specific	O
neuronal	O
subtype	O
[	O
9	O
]	O
,	O
[	O
10	O
]	O
.	O

In	O
the	O
developing	O
neocortex	O
,	O
Pax6	O
is	O
expressed	O
in	O
dividing	O
radial	O
glial	O
cells	O
at	O
the	O
ventricular	O
surface	O
[	O
9	O
]	O
.	O

In	O
the	O
adult	O
hippocampus	O
,	O
Pax6	O
is	O
expressed	O
in	O
astrocytes	O
in	O
the	O
SGZ	O
and	O
are	O
considered	O
to	O
be	O
the	O
true	O
stem	O
cells	O
[	O
9	O
]	O
,	O
[	O
11	O
]	O
.	O

Loss	O
-	O
and	O
gain	O
-	O
of	O
-	O
function	O
studies	O
indicate	O
that	O
Pax6	O
is	O
involved	O
in	O
regulating	O
the	O
proliferation	O
of	O
neocortical	O
and	O
hippocampal	O
progenitors	O
[	O
9	O
]	O
,	O
[	O
12	O
]	O
-	O
[	O
16	O
]	O
.	O

During	O
neocorticogenesis	O
,	O
high	O
concentrations	O
of	O
Pax6	O
induce	O
the	O
expression	O
of	O
the	O
bHLH	O
transcription	O
factor	O
Neurogenin2	O
(	O
Ngn2	O
)	O
[	O
17	O
]	O
.	O

In	O
turn	O
,	O
Ngn2	O
causes	O
cell	O
cycle	O
exit	O
[	O
18	O
]	O
,	O
an	O
event	O
that	O
takes	O
place	O
when	O
NeuroD1	O
starts	O
to	O
be	O
expressed	O
[	O
19	O
]	O
.	O

In	O
the	O
developing	O
hippocampus	O
,	O
the	O
absence	O
of	O
Ngn2	O
leads	O
to	O
a	O
reduced	O
number	O
of	O
granule	O
neurons	O
[	O
20	O
]	O
.	O

NeuroD1	O
,	O
on	O
the	O
other	O
hand	O
,	O
is	O
essential	O
for	O
the	O
differentiation	O
and	O
survival	O
of	O
hippocampal	O
granule	O
neurons	O
[	O
10	O
]	O
.	O

Interestingly	O
,	O
in	O
the	O
absence	O
of	O
Ngn2	O
,	O
NeuroD1	O
can	O
still	O
be	O
activated	O
and	O
neuronal	O
differentiation	O
can	O
still	O
take	O
place	O
[	O
20	O
]	O
.	O

This	O
has	O
led	O
to	O
the	O
idea	O
that	O
the	O
primary	O
role	O
of	O
Ngn2	O
is	O
not	O
to	O
direct	O
neuronal	O
differentiation	O
.	O

Only	O
a	O
small	O
number	O
of	O
studies	O
have	O
addressed	O
the	O
role	O
of	O
Ngn2	O
and	O
NeuroD1	O
in	O
hippocampal	O
neurogenesis	O
[	O
10	O
]	O
,	O
[	O
20	O
]	O
,	O
[	O
21	O
]	O
.	O

Therefore	O
,	O
we	O
now	O
re	O
-	O
examine	O
their	O
roles	O
in	O
hippocampal	O
neurogenesis	O
in	O
detail	O
,	O
using	O
gain	O
-	O
and	O
loss	O
-	O
of	O
-	O
function	O
experiments	O
.	O

We	O
first	O
establish	O
a	O
hierarchy	O
of	O
transcriptional	O
events	O
that	O
occur	O
during	O
neurogenesis	O
in	O
the	O
DG	O
and	O
then	O
define	O
the	O
place	O
that	O
Ngn2	O
,	O
NeuroD1	O
and	O
other	O
transcription	O
factors	O
have	O
in	O
this	O
cascade	O
.	O

We	O
find	O
that	O
a	O
lack	O
of	O
Ngn2	O
expression	O
result	O
in	O
a	O
markedly	O
smaller	O
hippocampus	O
and	O
an	O
almost	O
complete	O
absence	O
of	O
the	O
DG	O
.	O

We	O
show	O
that	O
Ngn2	O
is	O
required	O
for	O
granule	O
neuroblasts	O
production	O
/	O
amplification	O
.	O

Gain	O
-	O
of	O
-	O
function	O
of	O
NeuroD1	O
during	O
development	O
of	O
the	O
DG	O
results	O
in	O
an	O
efficient	O
generation	O
of	O
granule	O
neuroblasts	O
,	O
an	O
effect	O
that	O
we	O
do	O
not	O
observe	O
when	O
we	O
overexpress	O
Ngn2	O
.	O

Finally	O
,	O
we	O
demonstrate	O
that	O
the	O
same	O
transcription	O
factors	O
and	O
cellular	O
markers	O
seen	O
in	O
mouse	B
and	O
rat	B
tissue	O
are	O
also	O
present	O
in	O
the	O
human	B
hippocampus	O
.	O

Results	O

Expression	O
of	O
transcription	O
factors	O
and	O
cellular	O
markers	O
define	O
different	O
phases	O
of	O
postnatal	O
hippocampal	O
granule	O
neuron	O
maturation	O

We	O
first	O
analyzed	O
in	O
detail	O
the	O
chronology	O
of	O
expression	O
of	O
different	O
transcription	O
factors	O
and	O
cell	O
-	O
specific	O
markers	O
during	O
DG	O
granule	O
neuron	O
formation	O
and	O
correlated	O
our	O
findings	O
to	O
the	O
previously	O
established	O
classification	O
of	O
adult	O
hippocampal	O
neurogenesis	O
[	O
3	O
]	O
.	O

The	O
current	O
classification	O
describes	O
hippocampal	O
stem	O
cells	O
and	O
progenies	O
into	O
three	O
categories	O
(	O
type	O
-	O
1	O
,	O
-	O
2	O
and	O
-	O
3	O
cells	O
)	O
depending	O
on	O
the	O
markers	O
they	O
express	O
as	O
they	O
mature	O
.	O

In	O
the	O
adult	O
mouse	B
DG	O
,	O
only	O
a	O
very	O
small	O
proportion	O
of	O
cells	O
undergo	O
mitosis	O
at	O
any	O
one	O
given	O
time	O
[	O
22	O
]	O
.	O

Consequently	O
,	O
in	O
adult	O
animals	O
it	O
is	O
difficult	O
to	O
analyze	O
which	O
transcription	O
factors	O
are	O
involved	O
in	O
the	O
transition	O
phase	O
from	O
one	O
cell	O
category	O
to	O
the	O
next	O
.	O

Therefore	O
,	O
we	O
studied	O
2	O
week	O
-	O
old	O
rodents	O
which	O
have	O
higher	O
numbers	O
of	O
maturing	O
granule	O
neurons	O
in	O
the	O
DG	O
.	O

We	O
performed	O
triple	O
immunohistochemistry	O
for	O
all	O
markers	O
of	O
interest	O
and	O
compared	O
results	O
from	O
2	O
week	O
-	O
and	O
2	O
month	O
-	O
old	O
mice	B
(	O
Figure	O
1	O
and	O
figure	O
S1	O
)	O
.	O

We	O
first	O
confirmed	O
that	O
stem	O
cells	O
in	O
the	O
SGZ	O
exhibit	O
characteristics	O
of	O
radial	O
glia	O
[	O
3	O
]	O
,	O
[	O
11	O
]	O
,	O
[	O
16	O
]	O
.	O

They	O
extend	O
radial	O
processes	O
from	O
the	O
SGZ	O
to	O
the	O
apex	O
of	O
the	O
subgranular	O
layer	O
(	O
SGL	O
)	O
and	O
the	O
basal	O
molecular	O
layer	O
.	O

Moreover	O
,	O
they	O
express	O
the	O
intermediate	O
filament	O
protein	O
nestin	O
,	O
glial	O
fibrillary	O
acidic	O
protein	O
(	O
GFAP	O
)	O
and	O
glial	O
glutamate	O
transporter	O
(	O
GLAST	O
)	O
[	O
16	O
]	O
(	O
Figure	O
1A	O
and	O
B	O
and	O
figure	O
S1A	O
and	O
S1B	O
)	O
.	O

The	O
GFAP	O
-	O
and	O
GLAST	O
+	O
cells	O
are	O
defined	O
as	O
type	O
-	O
1	O
cells	O
[	O
3	O
]	O
.	O

They	O
also	O
express	O
the	O
paired	O
-	O
homeodomain	O
transcription	O
factor	O
Pax6	O
(	O
Figure	O
1B	O
)	O
.	O

These	O
radial	O
glia	O
-	O
like	O
stem	O
cells	O
divide	O
relatively	O
infrequently	O
,	O
and	O
are	O
believed	O
to	O
undergo	O
symmetric	O
division	O
(	O
giving	O
rise	O
to	O
two	O
identical	O
stem	O
cells	O
)	O
under	O
some	O
conditions	O
.	O

They	O
can	O
also	O
divide	O
asymmetrically	O
and	O
give	O
rise	O
to	O
a	O
new	O
stem	O
cell	O
and	O
one	O
neuronal	O
progenitor	O
,	O
which	O
usually	O
is	O
defined	O
as	O
a	O
type	O
-	O
2	O
cell	O
(	O
Figure	O
2B	O
)	O
[	O
3	O
]	O
.	O

Type	O
-	O
2	O
cells	O
are	O
divided	O
into	O
two	O
different	O
populations	O
:	O
type	O
-	O
2a	O
expressing	O
nestin	O
and	O
type	O
-	O
2b	O
co	O
-	O
expressing	O
nestin	O
and	O
doublecortin	O
(	O
Dcx	O
)	O
[	O
23	O
]	O
.	O

Based	O
on	O
a	O
previous	O
report	O
[	O
24	O
]	O
,	O
we	O
examined	O
the	O
expression	O
pattern	O
of	O
the	O
T	O
-	O
domain	O
transcription	O
factors	O
Tbr1	O
and	O
Tbr2	O
.	O

We	O
found	O
that	O
Tbr2	O
is	O
expressed	O
in	O
type	O
-	O
2a	O
cells	O
,	O
in	O
agreement	O
with	O
a	O
recent	O
report	O
[	O
25	O
]	O
.	O

In	O
the	O
SGZ	O
of	O
2	O
week	O
-	O
old	O
mice	B
,	O
we	O
found	O
an	O
average	O
of	O
50	O
-	O
70	O
Tbr2	O
+	O
cells	O
per	O
30	O
micro	O
m	O
-	O
thick	O
section	O
throughout	O
the	O
rostro	O
-	O
caudal	O
axis	O
of	O
the	O
dorsal	O
hippocampus	O
.	O

This	O
number	O
was	O
reduced	O
by	O
35	O
%	O
in	O
2	O
month	O
-	O
old	O
mice	B
(	O
Figure	O
1C	O
with	O
figure	O
S1C	O
and	O
data	O
not	O
shown	O
)	O
.	O

As	O
opposed	O
to	O
Tbr1	O
(	O
Figure	O
1D	O
and	O
figure	O
S1D	O
)	O
,	O
Tbr2	O
+	O
cells	O
did	O
not	O
co	O
-	O
express	O
Dcx	O
or	O
PSA	O
-	O
NCAM	O
(	O
Figure	O
1C	O
and	O
figure	O
S1C	O
)	O
.	O

We	O
observed	O
that	O
Tbr1	O
-	O
immuoreactivity	O
gradually	O
decreased	O
as	O
neurons	O
matured	O
and	O
started	O
to	O
express	O
NeuN	O
(	O
Figure	O
1H	O
and	O
figure	O
S1H	O
)	O
.	O

Thus	O
,	O
Tbr2	O
labels	O
type	O
-	O
2	O
cells	O
,	O
while	O
Tbr1	O
is	O
expressed	O
by	O
immature	O
granule	O
neurons	O
.	O

We	O
then	O
examined	O
the	O
molecular	O
phenotype	O
of	O
type	O
-	O
3	O
cells	O
,	O
a	O
cell	O
type	O
that	O
transiently	O
expresses	O
Calretinin	O
[	O
26	O
]	O
.	O

We	O
hypothesized	O
that	O
hippocampal	O
type	O
-	O
3	O
cells	O
might	O
also	O
express	O
the	O
bHLH	O
transcription	O
factor	O
NeuroD1	O
,	O
known	O
to	O
partially	O
overlap	O
with	O
Tbr2	O
and	O
Tbr1	O
in	O
different	O
brain	O
regions	O
[	O
24	O
]	O
.	O

We	O
found	O
that	O
NeuroD1	O
expression	O
in	O
the	O
hippocampus	O
starts	O
in	O
Tbr2	O
+	O
cells	O
and	O
extends	O
to	O
post	O
-	O
mitotic	O
Tbr1	O
+	O
cells	O
,	O
which	O
also	O
express	O
the	O
hippocampal	O
granule	O
identity	O
transcription	O
factor	O
Prox1	O
(	O
Figure	O
1G	O
and	O
1I	O
and	O
figure	O
S1G	O
and	O
S1I	O
)	O
.	O

While	O
Tbr1	O
expression	O
ceases	O
during	O
granule	O
maturation	O
,	O
that	O
of	O
NeuroD1	O
is	O
weakly	O
maintained	O
when	O
NeuN	O
expression	O
starts	O
(	O
Figure	O
1G	O
and	O
1H	O
and	O
figure	O
S1G	O
and	O
S1H	O
)	O
.	O

We	O
found	O
that	O
calretinin	O
expression	O
decreased	O
during	O
granule	O
neuron	O
maturation	O
,	O
before	O
NeuroD1	O
was	O
reduced	O
(	O
Figure	O
1F	O
)	O
.	O

Thus	O
NeuroD1	O
is	O
expressed	O
in	O
type	O
-	O
2b	O
and	O
type	O
-	O
3	O
cells	O
,	O
as	O
well	O
as	O
immature	O
granule	O
neurons	O
.	O

Finally	O
,	O
we	O
found	O
that	O
NeuroD2	O
starts	O
to	O
be	O
expressed	O
just	O
after	O
NeuroD1	O
and	O
,	O
unlike	O
NeuroD1	O
,	O
continues	O
to	O
be	O
highly	O
expressed	O
in	O
mature	O
neurons	O
(	O
Figure	O
1J	O
and	O
data	O
not	O
shown	O
)	O
.	O

Mash1	O
and	O
Ngn2	O
define	O
the	O
early	O
versus	O
late	O
type	O
-	O
2a	O
stage	O
in	O
2	O
weeks	O
old	O
mice	B

Having	O
established	O
the	O
hierarchy	O
of	O
transcription	O
factors	O
and	O
cellular	O
markers	O
appearing	O
during	O
hippocampal	O
neurogenesis	O
,	O
we	O
set	O
out	O
to	O
clarify	O
the	O
position	O
of	O
the	O
two	O
bHLH	O
transcription	O
factors	O
Ngn2	O
and	O
Mash1	O
,	O
in	O
this	O
process	O
.	O

We	O
found	O
that	O
more	O
than	O
90	O
%	O
of	O
Ngn2	O
-	O
immunoreactive	O
cells	O
are	O
Pax6	O
positive	O
(	O
Figure	O
2A	O
)	O
,	O
and	O
almost	O
all	O
co	O
-	O
express	O
Tbr2	O
(	O
Figure	O
2B	O
)	O
.	O

Thus	O
,	O
Ngn2	O
appears	O
to	O
be	O
expressed	O
by	O
type	O
-	O
2a	O
cells	O
.	O

As	O
our	O
antibodies	O
against	O
Ngn2	O
and	O
NeuroD1	O
were	O
made	O
in	O
the	O
same	O
species	O
,	O
we	O
could	O
not	O
determine	O
if	O
there	O
was	O
an	O
overlap	O
between	O
these	O
two	O
proteins	O
.	O

However	O
,	O
by	O
comparing	O
their	O
overlapping	O
expression	O
pattern	O
with	O
that	O
of	O
Tbr2	O
,	O
we	O
propose	O
that	O
some	O
Ngn2	O
+	O
cells	O
co	O
-	O
express	O
NeuroD1	O
,	O
and	O
that	O
they	O
appear	O
at	O
the	O
onset	O
of	O
NeuroD1	O
expression	O
and	O
downregulation	O
of	O
Ngn2	O
.	O

We	O
base	O
this	O
assumption	O
on	O
the	O
facts	O
that	O
more	O
than	O
50	O
%	O
of	O
the	O
Tbr2	O
+	O
cells	O
are	O
Ngn2	O
+	O
and	O
more	O
than	O
50	O
%	O
of	O
Tbr2	O
+	O
cells	O
also	O
express	O
NeuroD1	O
.	O

The	O
expression	O
of	O
Ngn2	O
in	O
adult	O
hippocampus	O
was	O
hard	O
to	O
detect	O
using	O
immunohistochemistry	O
due	O
to	O
the	O
low	O
expression	O
of	O
the	O
protein	O
(	O
data	O
not	O
shown	O
)	O
.	O

However	O
,	O
it	O
is	O
present	O
,	O
as	O
previously	O
described	O
using	O
reporter	O
mice	B
and	O
as	O
revealed	O
by	O
in	O
situ	O
hybridization	O
[	O
21	O
]	O
.	O

We	O
next	O
examined	O
the	O
expression	O
of	O
Mash1	O
and	O
compared	O
it	O
with	O
that	O
of	O
Ngn2	O
,	O
Pax6	O
and	O
Tbr2	O
.	O

We	O
found	O
some	O
Mash1	O
+	O
cells	O
(	O
10	O
-	O
20	O
cells	O
per	O
section	O
)	O
in	O
the	O
dorsal	O
hippocampus	O
.	O

Almost	O
all	O
of	O
them	O
co	O
-	O
expressed	O
Pax6	O
(	O
Figure	O
2C	O
)	O
.	O

Only	O
few	O
cells	O
co	O
-	O
expressed	O
Tbr2	O
(	O
Figure	O
2D	O
)	O
or	O
Ngn2	O
(	O
Figure	O
2E	O
)	O
,	O
suggesting	O
that	O
Mash1	O
is	O
downregulated	O
when	O
these	O
two	O
proteins	O
are	O
expressed	O
.	O

None	O
of	O
the	O
Mash1	O
-	O
expressing	O
cells	O
were	O
positive	O
for	O
NeuroD1	O
(	O
Figure	O
2F	O
)	O
.	O

Mash1	O
+	O
cells	O
were	O
still	O
undergoing	O
mitosis	O
(	O
Figure	O
2C	O
)	O
and	O
consequently	O
over	O
90	O
%	O
of	O
them	O
co	O
-	O
labeled	O
with	O
the	O
cell	O
-	O
cycle	O
marker	O
Ki67	O
(	O
Figure	O
S1J	O
)	O
.	O

Taken	O
together	O
,	O
we	O
show	O
that	O
Mash1	O
and	O
Ngn2	O
are	O
expressed	O
in	O
early	O
and	O
late	O
stages	O
of	O
maturation	O
of	O
type2a	O
progenitors	O
,	O
respectively	O
,	O
and	O
that	O
both	O
transcription	O
factors	O
are	O
co	O
-	O
expressed	O
briefly	O
when	O
cells	O
transit	O
from	O
early	O
to	O
late	O
phase	O
type2a	O
cells	O
.	O

Ngn2	O
progenies	O
become	O
hippocampal	O
granule	O
neurons	O

Previous	O
work	O
has	O
shown	O
that	O
in	O
Mash1	O
null	O
mutant	O
mice	B
hippocampal	O
neurogenesis	O
is	O
not	O
reduced	O
and	O
the	O
hippocampus	O
is	O
not	O
malformed	O
[	O
20	O
]	O
.	O

Therefore	O
we	O
focused	O
our	O
initial	O
analysis	O
on	O
the	O
role	O
of	O
Ngn2	O
in	O
hippocampal	O
neurogenesis	O
.	O

We	O
characterized	O
the	O
fate	O
of	O
Ngn2	O
-	O
expressing	O
cells	O
using	O
Ngn2	O
Knock	O
-	O
in	O
green	O
fluorescent	O
protein	O
(	O
GFP	O
)	O
mice	B
(	O
Ngn2	O
+	O
/	O
GFP	O
)	O
[	O
27	O
]	O
.	O

In	O
the	O
SGZ	O
of	O
2	O
week	O
-	O
old	O
hippocampi	O
,	O
we	O
found	O
bright	O
GFP	O
-	O
expressing	O
cells	O
that	O
were	O
positive	O
for	O
Tbr2	O
(	O
Figure	O
2H	O
)	O
,	O
the	O
immature	O
neuronal	O
marker	O
PSA	O
-	O
NCAM	O
(	O
Figure	O
2I	O
)	O
and	O
NeuroD1	O
(	O
Figure	O
2J	O
)	O
.	O

Furthermore	O
,	O
Prox1	O
+	O
,	O
NeuroD2	O
+	O
and	O
calretinin	O
+	O
cells	O
were	O
also	O
weakly	O
positive	O
for	O
GFP	O
.	O

We	O
made	O
similar	O
observations	O
in	O
2	O
month	O
-	O
old	O
mice	B
(	O
data	O
not	O
shown	O
)	O
confirming	O
earlier	O
published	O
results	O
[	O
21	O
]	O
)	O
.	O

We	O
did	O
not	O
observe	O
Mash1	O
+	O
/	O
GFP	O
+	O
and	O
NeuN	O
+	O
/	O
GFP	O
+	O
cells	O
(	O
Figure	O
2G	O
)	O
.	O

These	O
data	O
from	O
Ngn2	O
+	O
/	O
GFP	O
mice	B
are	O
entirely	O
consistent	O
with	O
our	O
earlier	O
observations	O
using	O
immunocytochemistry	O
to	O
label	O
Ngn2	O
-	O
expressing	O
cells	O
and	O
with	O
GFP	O
undergoing	O
slow	O
degradation	O
after	O
the	O
expression	O
of	O
Ngn2	O
has	O
ceased	O
.	O

Importantly	O
,	O
none	O
of	O
the	O
GFP	O
-	O
expressing	O
cells	O
,	O
including	O
those	O
only	O
weakly	O
fluorescent	O
,	O
residing	O
in	O
the	O
SGL	O
expressed	O
the	O
astrocytic	O
marker	O
GFAP	O
or	O
the	O
oligodendrocytic	O
markers	O
CNPase	O
(	O
data	O
not	O
shown	O
)	O
.	O

Taken	O
together	O
,	O
the	O
data	O
show	O
that	O
Ngn2	O
progenies	O
become	O
neurons	O
and	O
never	O
generate	O
astrocytes	O
or	O
oligodendrocytes	O
.	O

Marked	O
reduction	O
of	O
hippocampal	O
granule	O
neurons	O
in	O
absence	O
of	O
Ngn2	O

To	O
determine	O
the	O
role	O
of	O
Ngn2	O
during	O
the	O
initiation	O
of	O
hippocampal	O
granule	O
neurogenesis	O
,	O
we	O
analyzed	O
the	O
hippocampus	O
of	O
mice	B
lacking	O
Ngn2	O
(	O
Ngn2GFP	O
/	O
GFP	O
)	O
.	O

In	O
contrast	O
to	O
the	O
mice	B
use	O
by	O
Galichet	O
and	O
coworkers	O
,	O
our	O
mice	B
have	O
a	O
lifespan	O
of	O
only	O
2	O
weeks	O
after	O
birth	O
.	O

Therefore	O
,	O
we	O
analyzed	O
2	O
week	O
-	O
old	O
and	O
younger	O
mice	B
.	O

Consistent	O
with	O
previous	O
observations	O
[	O
20	O
]	O
,	O
the	O
hippocampus	O
in	O
Ngn2GFP	O
/	O
GFP	O
mutants	O
is	O
clearly	O
malformed	O
(	O
Figure	O
3A	O
)	O
.	O

In	O
two	O
week	O
-	O
old	O
Ngn2GFP	O
/	O
GFP	O
mice	B
,	O
the	O
ventral	O
blade	O
of	O
the	O
DG	O
is	O
completely	O
absent	O
.	O

Already	O
on	O
postnatal	O
day	O
1	O
-	O
2	O
,	O
the	O
ventral	O
blade	O
of	O
the	O
DG	O
is	O
malformed	O
along	O
its	O
whole	O
rostro	O
-	O
caudal	O
axis	O
(	O
Figure	O
3B	O
)	O
.	O

As	O
neither	O
migration	O
defects	O
nor	O
cell	O
death	O
cause	O
the	O
reduced	O
number	O
of	O
hippocampal	O
neurons	O
in	O
Ngn2	O
null	O
mice	B
[	O
20	O
]	O
,	O
we	O
asked	O
if	O
Ngn2	O
is	O
necessary	O
for	O
production	O
of	O
hippocampal	O
granule	O
neuroblasts	O
.	O

We	O
first	O
injected	O
2	O
day	O
-	O
old	O
mouse	B
pups	O
with	O
BrdU	O
2	O
hours	O
prior	O
to	O
sacrifice	O
,	O
allowing	O
us	O
to	O
evaluate	O
cell	O
proliferation	O
and	O
ongoing	O
neurogenesis	O
.	O

We	O
also	O
injected	O
BrdU	O
into	O
female	O
mice	B
on	O
their	O
final	O
day	O
of	O
pregnancy	O
and	O
examined	O
the	O
brains	O
of	O
their	O
pups	O
48	O
hours	O
later	O
(	O
corresponding	O
to	O
P1	O
-	O
P2	O
old	O
pups	O
)	O
.	O

This	O
allowed	O
us	O
to	O
assess	O
the	O
number	O
of	O
neurons	O
derived	O
from	O
the	O
last	O
day	O
of	O
intrauterine	O
development	O
.	O

Regardless	O
of	O
whether	O
the	O
mice	B
were	O
WT	O
or	O
hetero	O
/	O
homozygous	O
mutant	O
pups	O
,	O
we	O
found	O
cells	O
that	O
had	O
incorporated	O
BrdU	O
in	O
the	O
hippocampal	O
subventricular	O
zone	O
(	O
hSVZ	O
)	O
,	O
fimbria	O
and	O
the	O
DG	O
(	O
Figure	O
4A	O
and	O
B	O
;	O
[	O
28	O
]	O
)	O
,	O
suggesting	O
that	O
progenitors	O
originating	O
in	O
the	O
hSVZ	O
divide	O
while	O
migrating	O
towards	O
the	O
DG	O
.	O

Most	O
of	O
them	O
were	O
organized	O
in	O
chains	O
typical	O
of	O
migrating	O
cells	O
(	O
Figure	O
4A	O
and	O
B	O
and	O
figure	O
S2	O
)	O
.	O

In	O
Ngn2GFP	O
/	O
GFP	O
mutant	O
mice	B
injected	O
with	O
BrdU	O
2	O
hours	O
prior	O
to	O
sacrifice	O
,	O
we	O
observed	O
a	O
decrease	O
in	O
the	O
number	O
of	O
BrdU	O
+	O
cells	O
compared	O
to	O
heterozygous	O
littermates	O
.	O

Thus	O
,	O
the	O
numbers	O
of	O
newborn	O
cells	O
were	O
reduced	O
in	O
the	O
hSVZ	O
/	O
fimbria	O
(	O
133	O
.	O
3	O
+	O
/	O
-	O
7	O
.	O
5	O
for	O
Ngn2	O
+	O
/	O
GFP	O
vs	O
69	O
.	O
7	O
+	O
/	O
-	O
5	O
.	O
0	O
for	O
Ngn2GFP	O
/	O
GFP	O
)	O
and	O
DG	O
(	O
132	O
.	O
0	O
+	O
/	O
-	O
9	O
.	O
1	O
for	O
Ngn2	O
+	O
/	O
GFP	O
vs	O
42	O
.	O
6	O
+	O
/	O
-	O
2	O
.	O
2	O
for	O
Ngn2GFP	O
/	O
GFP	O
)	O
(	O
Figure	O
4C	O
and	O
D	O
)	O
.	O

We	O
also	O
examined	O
the	O
number	O
of	O
newborn	O
cells	O
differentiating	O
into	O
neurons	O
,	O
and	O
identified	O
them	O
by	O
the	O
co	O
-	O
expression	O
of	O
BrdU	O
and	O
NeuroD1	O
.	O

As	O
expected	O
,	O
they	O
were	O
relatively	O
few	O
in	O
numbers	O
because	O
the	O
short	O
delay	O
(	O
2	O
hours	O
)	O
between	O
BrdU	O
administration	O
and	O
sacrifice	O
in	O
this	O
first	O
experimental	O
paradigm	O
.	O

In	O
Ngn2GFP	O
/	O
GFP	O
null	O
mutants	O
,	O
we	O
found	O
the	O
number	O
of	O
cells	O
differentiating	O
into	O
neurons	O
to	O
be	O
reduced	O
by	O
60	O
%	O
and	O
71	O
%	O
in	O
the	O
hSVZ	O
/	O
fimbria	O
(	O
8	O
.	O
6	O
+	O
/	O
-	O
1	O
.	O
4	O
for	O
Ngn2	O
+	O
/	O
GFP	O
vs	O
3	O
.	O
4	O
+	O
/	O
-	O
0	O
.	O
5	O
for	O
Ngn2GFP	O
/	O
GFP	O
)	O
and	O
DG	O
(	O
9	O
.	O
7	O
+	O
/	O
-	O
1	O
.	O
1	O
for	O
Ngn2	O
+	O
/	O
GFP	O
vs	O
2	O
.	O
8	O
+	O
/	O
-	O
0	O
.	O
6	O
for	O
Ngn2GFP	O
/	O
GFP	O
)	O
,	O
respectively	O
,	O
(	O
Figure	O
4E	O
and	O
F	O
)	O
.	O

As	O
a	O
result	O
,	O
the	O
number	O
of	O
NeuroD1	O
+	O
cells	O
in	O
the	O
DG	O
was	O
reduced	O
by	O
80	O
%	O
(	O
580	O
.	O
3	O
+	O
/	O
-	O
27	O
.	O
7	O
for	O
Ngn2	O
+	O
/	O
GFP	O
vs	O
116	O
.	O
2	O
+	O
/	O
-	O
7	O
.	O
3	O
for	O
Ngn2GFP	O
/	O
GFP	O
;	O
Figure	O
4G	O
)	O
.	O

We	O
obtained	O
similar	O
results	O
in	O
the	O
second	O
paradigm	O
,	O
i	O
.	O
e	O
.	O
in	O
mice	B
that	O
we	O
sacrificed	O
48	O
hours	O
after	O
BrdU	O
administration	O
and	O
in	O
which	O
a	O
larger	O
number	O
of	O
the	O
newborn	O
cells	O
had	O
time	O
to	O
mature	O
into	O
neurons	O
.	O

In	O
this	O
case	O
,	O
the	O
number	O
of	O
BrdU	O
+	O
/	O
NeuroD1	O
+	O
cells	O
in	O
the	O
DG	O
was	O
reduced	O
by	O
73	O
%	O
of	O
Ngn2GFP	O
/	O
GFP	O
mutant	O
animals	O
(	O
91	O
.	O
5	O
+	O
/	O
-	O
24	O
.	O
1	O
for	O
Ngn2	O
+	O
/	O
GFP	O
vs	O
26	O
.	O
4	O
+	O
/	O
-	O
3	O
.	O
3	O
for	O
Ngn2GFP	O
/	O
GFP	O
)	O
(	O
Figure	O
4J	O
)	O
.	O

We	O
found	O
no	O
differences	O
in	O
the	O
proportion	O
of	O
BrdU	O
+	O
cells	O
that	O
expressed	O
NeuroD1	O
in	O
Ngn2	O
+	O
/	O
GFP	O
and	O
Ngn2GFP	O
/	O
GFP	O
mice	B
(	O
14	O
.	O
2	O
+	O
/	O
-	O
1	O
.	O
0	O
%	O
and	O
17	O
.	O
4	O
+	O
/	O
-	O
1	O
.	O
8	O
%	O
respectively	O
;	O
Figure	O
4K	O
)	O
.	O

This	O
shows	O
that	O
the	O
few	O
cells	O
that	O
manage	O
to	O
proliferate	O
in	O
the	O
Ngn2	O
null	O
mice	B
have	O
the	O
same	O
ability	O
to	O
differentiate	O
into	O
neurons	O
as	O
those	O
in	O
mice	B
with	O
one	O
Ngn2	O
allele	O
.	O

Interestingly	O
,	O
the	O
absence	O
of	O
Ngn2	O
did	O
not	O
alter	O
the	O
identity	O
of	O
neurons	O
in	O
the	O
DG	O
granule	O
layer	O
in	O
2	O
week	O
-	O
old	O
Ngn2	O
null	O
mice	B
.	O

The	O
maturing	O
granule	O
progenitors	O
sequentially	O
expressed	O
Pax6	O
,	O
Tbr2	O
(	O
Figure	O
S3A	O
and	O
S3B	O
)	O
,	O
NeuroD1	O
and	O
Calretinin	O
(	O
Figure	O
4L	O
)	O
,	O
PSA	O
-	O
NCAM	O
(	O
Figure	O
4N	O
)	O
,	O
Tbr1	O
(	O
data	O
not	O
shown	O
)	O
and	O
Prox1	O
(	O
Figure	O
4M	O
)	O
.	O

We	O
confirmed	O
that	O
the	O
same	O
transcriptional	O
cascade	O
is	O
active	O
in	O
the	O
20	O
%	O
(	O
compared	O
to	O
mice	B
with	O
one	O
Ngn2	O
allele	O
)	O
residual	O
granule	O
neurons	O
that	O
are	O
formed	O
two	O
day	O
-	O
old	O
in	O
Ngn2GFP	O
/	O
GFP	O
mice	B
(	O
Figure	O
S3D	O
-	O
G	O
and	O
data	O
not	O
shown	O
)	O
.	O

We	O
next	O
investigated	O
if	O
the	O
cells	O
that	O
failed	O
to	O
develop	O
into	O
neurons	O
in	O
Ngn2GFP	O
/	O
GFP	O
mutant	O
mice	B
,	O
became	O
glial	O
cells	O
.	O

We	O
found	O
that	O
cells	O
expressing	O
GFP	O
never	O
co	O
-	O
labeled	O
with	O
the	O
astrocyte	O
marker	O
GFAP	O
(	O
Figure	O
4N	O
)	O
or	O
the	O
oligodendrocyte	O
marker	O
CNPase	O
(	O
data	O
not	O
shown	O
)	O
.	O

Altogether	O
,	O
our	O
results	O
show	O
that	O
Ngn2	O
plays	O
an	O
important	O
role	O
during	O
the	O
production	O
/	O
amplification	O
of	O
hippocampal	O
granule	O
neuroblasts	O
,	O
but	O
not	O
the	O
acquisition	O
of	O
the	O
granule	O
neuron	O
identity	O
(	O
Figure	O
S7	O
)	O
.	O

Ngn2	O
controls	O
the	O
amplification	O
of	O
granule	O
neuron	O
progenitors	O

We	O
next	O
monitored	O
the	O
mitogenic	O
activity	O
of	O
Ngn2	O
+	O
cells	O
in	O
the	O
DG	O
of	O
2	O
week	O
-	O
old	O
WT	O
mice	B
.	O

We	O
observed	O
that	O
over	O
50	O
%	O
of	O
Ngn2	O
+	O
cells	O
in	O
the	O
DG	O
of	O
WT	O
mice	B
co	O
-	O
expressed	O
the	O
mitosis	O
marker	O
Ki67	O
(	O
Figure	O
5A	O
)	O
.	O

Inspired	O
by	O
this	O
finding	O
,	O
we	O
injected	O
BrdU	O
into	O
2	O
week	O
-	O
old	O
WT	O
and	O
Ngn2GFP	O
/	O
GFP	O
mice	B
and	O
compared	O
cell	O
proliferation	O
in	O
the	O
DG	O
.	O

We	O
observed	O
92	O
%	O
reduction	O
in	O
number	O
of	O
proliferating	O
cells	O
in	O
the	O
SGZ	O
of	O
Ngn2	O
null	O
mutant	O
mice	B
(	O
6	O
.	O
7	O
+	O
/	O
-	O
0	O
.	O
5	O
)	O
compared	O
to	O
WT	O
(	O
83	O
.	O
6	O
+	O
/	O
-	O
1	O
.	O
2	O
)	O
and	O
heterozygotic	O
(	O
data	O
not	O
shown	O
)	O
littermates	O
(	O
Figure	O
5B	O
-	O
C	O
)	O
.	O

This	O
data	O
confirm	O
the	O
importance	O
of	O
Ngn2	O
during	O
the	O
amplification	O
of	O
granule	O
progenitor	O
.	O
s	O
.	O

To	O
further	O
explore	O
whether	O
Ngn2	O
+	O
cells	O
become	O
post	O
-	O
mitotic	O
or	O
still	O
proliferate	O
after	O
Ngn2	O
is	O
downregulated	O
,	O
we	O
performed	O
immunohistochemistry	O
on	O
sections	O
through	O
the	O
DG	O
of	O
Ngn2	O
+	O
/	O
GFP	O
mice	B
.	O

We	O
stained	O
them	O
with	O
the	O
mitosis	O
marker	O
Phospho	O
-	O
histone	O
3	O
(	O
PH3	O
)	O
and	O
NeuroD1	O
,	O
which	O
is	O
downstream	O
of	O
Ngn2	O
in	O
the	O
transcriptional	O
cascade	O
controlling	O
neurogenesis	O
.	O

Thus	O
,	O
in	O
the	O
same	O
sections	O
we	O
could	O
identify	O
whether	O
cells	O
that	O
had	O
initiated	O
Ngn2	O
expression	O
(	O
GFP	O
labeled	O
)	O
,	O
continued	O
to	O
divide	O
(	O
PH3	O
+	O
)	O
or	O
committed	O
to	O
neuronal	O
differentiation	O
(	O
NeuroD1	O
+	O
)	O
.	O

We	O
observed	O
some	O
GFP	O
+	O
cells	O
that	O
co	O
-	O
expressed	O
PH3	O
.	O

They	O
all	O
exhibited	O
morphological	O
characteristics	O
of	O
one	O
of	O
the	O
five	O
mitotic	O
phases	O
:	O
prophase	O
,	O
metaphase	O
,	O
anaphase	O
,	O
telophase	O
and	O
cytokinesis	O
(	O
Figure	O
5D	O
and	O
data	O
not	O
shown	O
)	O
.	O

Unexpectedly	O
,	O
cells	O
that	O
colabeled	O
for	O
GFP	O
,	O
PH3	O
and	O
NeuroD1	O
(	O
Figure	O
5E	O
and	O
figure	O
S4A	O
and	O
S4B	O
)	O
were	O
rare	O
.	O

This	O
indicates	O
that	O
Ngn2	O
+	O
cells	O
undergo	O
division	O
/	O
amplification	O
and	O
that	O
they	O
mature	O
into	O
post	O
-	O
mitotic	O
neurons	O
upon	O
NeuroD1	O
expression	O
.	O

In	O
mice	B
lacking	O
Ngn2	O
,	O
we	O
found	O
the	O
cells	O
expressing	O
GFP	O
localized	O
to	O
the	O
malformed	O
ventral	O
blade	O
of	O
the	O
DG	O
(	O
Figure	O
5F	O
and	O
G	O
)	O
.	O

All	O
of	O
these	O
cells	O
were	O
Ki67	O
+	O
and	O
they	O
only	O
very	O
rarely	O
expressed	O
PH3	O
(	O
Figure	O
5F	O
and	O
G	O
,	O
and	O
figure	O
S4C	O
)	O
in	O
the	O
absence	O
of	O
Ngn2	O
most	O
of	O
the	O
cells	O
are	O
arrested	O
in	O
the	O
cell	O
cycle	O
prior	O
to	O
entering	O
the	O
M	O
phase	O
and	O
their	O
mitosis	O
is	O
impaired	O
.	O

These	O
data	O
suggest	O
that	O
the	O
mechanism	O
of	O
action	O
of	O
Ngn2	O
is	O
conserved	O
from	O
development	O
of	O
the	O
DG	O
to	O
postnatal	O
hippocampal	O
neurogenesis	O
.	O

Our	O
findings	O
suggest	O
that	O
Ngn2	O
regulates	O
amplification	O
and	O
cell	O
cycle	O
exit	O
of	O
DG	O
granule	O
progenitors	O
.	O

To	O
examine	O
this	O
hypothesis	O
,	O
we	O
compared	O
the	O
effects	O
of	O
Ngn2	O
and	O
NeuroD1	O
on	O
mitotic	O
activity	O
in	O
embryonic	O
cortico	O
-	O
hippocampal	O
neurosphere	O
-	O
derived	O
progenitors	O
,	O
5	O
days	O
upon	O
transduction	O
,	O
in	O
vitro	O
.	O

In	O
cultures	O
transduced	O
with	O
Ngn2	O
retrovirus	O
,	O
we	O
found	O
that	O
27	O
.	O
2	O
%	O
(	O
+	O
/	O
-	O
4	O
.	O
1	O
%	O
)	O
of	O
the	O
PH3	O
+	O
cells	O
had	O
been	O
transduced	O
(	O
Figure	O
I1	O
-	O
J	O
)	O
.	O

These	O
cells	O
were	O
immunopositive	O
for	O
MAP2	O
(	O
Figure	O
5I1	O
and	O
I2	O
)	O
and	O
therefore	O
represented	O
dividing	O
neuroblasts	O
.	O

By	O
contrast	O
,	O
in	O
NeuroD1	O
transduced	O
cultures	O
,	O
only	O
7	O
.	O
3	O
%	O
of	O
PH3	O
+	O
cells	O
were	O
GFP	O
+	O
(	O
Figure	O
5H1	O
,	O
H2	O
and	O
J	O
)	O
.	O

All	O
of	O
the	O
NeuroD1	O
-	O
transduced	O
cells	O
became	O
MAP2	O
+	O
(	O
Figure	O
5H	O
)	O
.	O

To	O
confirm	O
this	O
data	O
we	O
pulse	O
-	O
labeled	O
transduced	O
cultures	O
with	O
chlorodeoxyuridine	O
(	O
CldU	O
)	O
for	O
48	O
hours	O
,	O
five	O
days	O
after	O
differentiation	O
.	O

In	O
contrast	O
to	O
NeuroD1	O
-	O
transduced	O
cultures	O
,	O
we	O
observed	O
dividing	O
cells	O
transduced	O
with	O
Ngn2	O
retrovirus	O
that	O
were	O
positive	O
for	O
PH3	O
and	O
that	O
had	O
incorporated	O
CldU	O
(	O
Figure	O
5K	O
-	O
L2	O
)	O
.	O

As	O
the	O
number	O
of	O
cells	O
PH3	O
+	O
/	O
CldU	O
+	O
/	O
GFP	O
+	O
we	O
observed	O
was	O
low	O
,	O
we	O
did	O
not	O
quantify	O
this	O
finding	O
.	O

Collectively	O
,	O
we	O
have	O
shown	O
that	O
Ngn2	O
is	O
required	O
for	O
granule	O
neuroblast	O
production	O
and	O
amplification	O
and	O
that	O
in	O
the	O
absence	O
of	O
Ngn2	O
the	O
progenitors	O
arrest	O
in	O
the	O
cell	O
cycle	O
.	O

NeuroD1	O
,	O
on	O
the	O
other	O
hand	O
,	O
induces	O
cell	O
cycle	O
exit	O
and	O
promotes	O
rapid	O
neuronal	O
maturation	O
.	O

NeuroD1	O
directs	O
neuronal	O
differentiation	O
and	O
maturation	O

Based	O
on	O
our	O
previous	O
observations	O
we	O
proposed	O
that	O
Ngn2	O
primarily	O
controls	O
amplification	O
of	O
granule	O
neuroblasts	O
and	O
NeuroD1	O
directs	O
neuronal	O
differentiation	O
.	O

To	O
test	O
this	O
hypothesis	O
,	O
we	O
overexpressed	O
Ngn2	O
or	O
NeuroD1	O
in	O
E14	O
.	O
5	O
cortico	O
-	O
hippocampal	O
neurospheres	O
and	O
compared	O
their	O
effects	O
after	O
5	O
days	O
of	O
differentiation	O
of	O
the	O
progenitors	O
.	O

All	O
cortico	O
-	O
hippocampal	O
progenitors	O
expressed	O
Pax6	O
prior	O
to	O
differentiation	O
(	O
Figure	O
S5	O
)	O
.	O

After	O
5	O
days	O
,	O
both	O
factors	O
suppressed	O
Pax6	O
and	O
Sox2	O
(	O
Figure	O
S5	O
,	O
figure	O
6C	O
)	O
and	O
induced	O
expression	O
of	O
Tbr1	O
,	O
Map2	O
,	O
NeuroD1	O
and	O
PSA	O
-	O
NCAM	O
(	O
Figure	O
6D	O
and	O
E	O
)	O
.	O

Interestingly	O
,	O
all	O
Ngn2	O
-	O
overexpressing	O
cells	O
co	O
-	O
expressed	O
NeuroD1	O
.	O

Based	O
on	O
these	O
findings	O
,	O
we	O
next	O
explored	O
whether	O
Ngn2	O
overexpression	O
induces	O
NeuroD1	O
expression	O
,	O
and	O
if	O
NeuroD1	O
in	O
turn	O
directs	O
neuronal	O
differentiation	O
.	O

We	O
compared	O
the	O
effects	O
of	O
both	O
transcription	O
factors	O
in	O
progenitors	O
that	O
either	O
do	O
or	O
do	O
not	O
normally	O
express	O
them	O
.	O

Thus	O
,	O
we	O
expressed	O
Ngn2	O
in	O
E14	O
.	O
5	O
neural	O
progenitors	O
isolated	O
from	O
three	O
different	O
brain	O
regions	O
:	O
cortex	O
/	O
hippocampus	O
,	O
lateral	O
ganglionic	O
eminence	O
(	O
LGE	O
)	O
and	O
ventral	O
mesencephalon	O
(	O
VM	O
)	O
.	O

Ngn2	O
expression	O
in	O
the	O
developing	O
forebrain	O
is	O
normally	O
limited	O
to	O
the	O
neocortex	O
,	O
and	O
it	O
does	O
not	O
appear	O
in	O
LGE	O
tissue	O
[	O
29	O
]	O
.	O

In	O
the	O
developing	O
VM	O
,	O
both	O
Ngn2	O
and	O
NeuroD1	O
are	O
expressed	O
,	O
but	O
not	O
when	O
neural	O
progenitors	O
from	O
this	O
region	O
are	O
cultured	O
in	O
vitro	O
[	O
30	O
]	O
,	O
[	O
31	O
]	O
.	O

In	O
our	O
experiments	O
,	O
cortico	O
-	O
hippocampal	O
progenitors	O
could	O
differentiate	O
into	O
neurons	O
,	O
although	O
they	O
did	O
not	O
normally	O
express	O
NeuroD1	O
(	O
Figure	O
6E	O
)	O
.	O

When	O
we	O
overexpressed	O
Ngn2	O
in	O
VM	O
and	O
LGE	O
progenitors	O
,	O
the	O
cells	O
started	O
to	O
express	O
both	O
NeuroD1	O
and	O
PSA	O
-	O
NCAM	O
(	O
Figure	O
6F	O
and	O
G	O
)	O
.	O

We	O
then	O
overexpressed	O
NeuroD1	O
in	O
the	O
same	O
types	O
of	O
cultured	O
progenitors	O
and	O
found	O
that	O
the	O
cells	O
became	O
immunoreactive	O
for	O
PSA	O
-	O
NCAM	O
(	O
Figure	O
6G	O
and	O
data	O
not	O
shown	O
)	O
.	O

Thus	O
,	O
NeuroD1	O
is	O
sufficient	O
to	O
direct	O
neuronal	O
differentiation	O
in	O
cortico	O
-	O
hippocampal	O
-	O
,	O
LGE	O
-	O
and	O
VM	O
-	O
derived	O
progenitors	O
.	O

Our	O
results	O
from	O
in	O
vitro	O
cultures	O
and	O
the	O
analysis	O
of	O
the	O
DG	O
of	O
Ngn2	O
mutant	O
animals	O
collectively	O
show	O
the	O
neuron	O
-	O
inducing	O
effect	O
of	O
NeuroD1	O
in	O
hippocampal	O
granule	O
cell	O
progenitors	O
[	O
32	O
]	O
.	O

NeuroD1	O
directs	O
exclusive	O
neuronal	O
differentiation	O
of	O
hippocampal	O
granule	O
neuron	O
progenitors	O

As	O
the	O
next	O
step	O
,	O
we	O
tested	O
the	O
effects	O
of	O
NeuroD1	O
in	O
vivo	O
and	O
compared	O
them	O
with	O
those	O
of	O
Ngn2	O
.	O

We	O
injected	O
retroviruses	O
carrying	O
the	O
gene	O
for	O
either	O
Ngn2	O
[	O
33	O
]	O
or	O
NeuroD1	O
,	O
and	O
the	O
reporter	O
gene	O
eGFP	O
into	O
the	O
ventricles	O
E15	O
.	O
5	O
rat	B
embryos	O
,	O
in	O
utero	O
(	O
Figure	O
7A	O
)	O
.	O

Three	O
weeks	O
later	O
,	O
when	O
the	O
rats	B
were	O
about	O
two	O
weeks	O
old	O
,	O
we	O
examined	O
their	O
hippocampi	O
and	O
analyzed	O
the	O
eGFP	O
+	O
cells	O
.	O

The	O
rats	B
injected	O
with	O
control	O
vector	O
exhibited	O
eGFP	O
+	O
cells	O
within	O
the	O
hippocampus	O
that	O
were	O
either	O
star	O
-	O
shaped	O
,	O
progenitor	O
/	O
glial	O
-	O
like	O
cells	O
(	O
14	O
.	O
8	O
+	O
/	O
-	O
3	O
.	O
4	O
%	O
)	O
or	O
neuron	O
-	O
like	O
cells	O
with	O
long	O
neurites	O
(	O
85	O
.	O
3	O
+	O
/	O
-	O
3	O
.	O
4	O
%	O
)	O
(	O
Figure	O
7B	O
)	O
.	O

In	O
rats	B
that	O
we	O
had	O
injected	O
with	O
the	O
vector	O
encoding	O
Ngn2	O
,	O
the	O
eGFP	O
-	O
labeled	O
,	O
the	O
transduced	O
hippocampal	O
cells	O
were	O
composed	O
of	O
31	O
.	O
9	O
%	O
(	O
+	O
/	O
-	O
5	O
.	O
7	O
%	O
)	O
progenitor	O
/	O
glia	O
-	O
like	O
cells	O
and	O
69	O
.	O
4	O
%	O
(	O
+	O
/	O
-	O
6	O
.	O
1	O
%	O
)	O
neuron	O
-	O
like	O
cells	O
(	O
Figure	O
7B	O
)	O
.	O

The	O
glia	O
-	O
like	O
subpopulation	O
was	O
immunopositive	O
for	O
the	O
astrocytic	O
marker	O
GFAP	O
(	O
Figure	O
7C	O
-	O
D	O
)	O
.	O

In	O
contrast	O
,	O
virtually	O
all	O
of	O
the	O
transduced	O
cells	O
in	O
rats	B
injected	O
with	O
the	O
NeuroD1	O
vector	O
became	O
neuron	O
-	O
like	O
cells	O
(	O
99	O
.	O
9	O
%	O
+	O
/	O
-	O
0	O
.	O
1	O
;	O
Figure	O
7B	O
)	O
.	O

None	O
of	O
these	O
cells	O
stained	O
for	O
GFAP	O
(	O
Figure	O
7E	O
and	O
F	O
)	O
.	O

They	O
were	O
positioned	O
in	O
the	O
external	O
layers	O
of	O
both	O
the	O
ventral	O
and	O
dorsal	O
blades	O
of	O
the	O
DG	O
(	O
Figure	O
7B3	O
,	O
E	O
and	O
I	O
and	O
figure	O
S6A	O
)	O
.	O

When	O
we	O
examined	O
neuronal	O
maturation	O
of	O
Ngn2	O
-	O
and	O
NeuroD1	O
-	O
transduced	O
cells	O
,	O
we	O
observed	O
that	O
only	O
a	O
few	O
of	O
those	O
transduced	O
with	O
the	O
NeuroD1	O
vector	O
expressed	O
the	O
early	O
mature	O
neuronal	O
marker	O
Tbr1	O
(	O
3	O
.	O
1	O
+	O
/	O
-	O
1	O
.	O
4	O
%	O
;	O
Figure	O
7I	O
and	O
J	O
)	O
.	O

They	O
were	O
located	O
within	O
the	O
basal	O
layers	O
,	O
near	O
the	O
SGL	O
,	O
of	O
the	O
ventral	O
and	O
dorsal	O
blades	O
of	O
the	O
DG	O
.	O

In	O
contrast	O
,	O
a	O
greater	O
proportion	O
of	O
the	O
cells	O
transduced	O
with	O
Ngn2	O
still	O
expressed	O
Tbr1	O
(	O
19	O
.	O
6	O
%	O
+	O
/	O
-	O
3	O
.	O
3	O
%	O
;	O
Figure	O
7H	O
and	O
J	O
)	O
,	O
indicating	O
that	O
they	O
were	O
less	O
mature	O
than	O
the	O
vast	O
majority	O
of	O
the	O
NeuroD1	O
-	O
transduced	O
cells	O
.	O

Immunohistochemistry	O
for	O
NeuN	O
confirmed	O
these	O
data	O
(	O
Figure	O
7M	O
and	O
O	O
,	O
and	O
figure	O
S6A	O
)	O
.	O

Indeed	O
,	O
when	O
we	O
overexpressed	O
Ngn2	O
the	O
proportion	O
of	O
hippocampal	O
progenitors	O
that	O
became	O
NeuN	O
+	O
was	O
no	O
greater	O
than	O
in	O
rats	B
transduced	O
with	O
the	O
control	O
virus	O
(	O
Figure	O
7F	O
)	O
.	O

As	O
a	O
whole	O
,	O
our	O
in	O
utero	O
injection	O
experiments	O
confirm	O
that	O
NeuroD1	O
has	O
a	O
stronger	O
neuron	O
-	O
inducing	O
effect	O
than	O
Ngn2	O
when	O
overexpressed	O
in	O
hippocampal	O
progenitors	O
.	O

Involvement	O
of	O
Mash1	O
,	O
Ngn2	O
,	O
Tbr	O
and	O
NeuroD	O
proteins	O
during	O
human	B
hippocampal	O
neurogenesis	O

Finally	O
,	O
we	O
examined	O
whether	O
the	O
transcription	O
factors	O
and	O
cellular	O
markers	O
that	O
are	O
expressed	O
in	O
rodents	O
are	O
also	O
expressed	O
in	O
human	B
hippocampus	O
.	O

We	O
performed	O
immunohistochemistry	O
on	O
aged	O
human	B
hippocampal	O
DG	O
and	O
found	O
GFAP	O
-	O
,	O
Sox2	O
-	O
,	O
Pax6	O
-	O
,	O
Nestin	O
-	O
,	O
Prox1	O
-	O
and	O
NeuN	O
-	O
immunopositive	O
cells	O
.	O

This	O
indicates	O
that	O
radial	O
glia	O
-	O
like	O
stem	O
cells	O
,	O
neural	O
progenitors	O
and	O
mature	O
granule	O
neurons	O
are	O
present	O
in	O
the	O
aged	O
human	B
hippocampus	O
(	O
Figure	O
8A	O
-	O
E	O
)	O
.	O

While	O
Prox1	O
is	O
found	O
mainly	O
in	O
granule	O
neurons	O
,	O
Sox2	O
and	O
Pax6	O
are	O
exclusively	O
localized	O
to	O
cells	O
in	O
the	O
SGZ	O
(	O
Figure	O
8D	O
and	O
E	O
)	O
.	O

As	O
for	O
aged	O
rodents	O
,	O
we	O
did	O
not	O
observe	O
the	O
presence	O
of	O
Mash1	O
,	O
Ngn2	O
,	O
Tbr2	O
,	O
Tbr1	O
and	O
NeuroD1	O
proteins	O
in	O
aged	O
human	B
hippocampus	O
,	O
using	O
immunohistochemistry	O
.	O

However	O
,	O
we	O
could	O
identify	O
the	O
presence	O
of	O
the	O
transcripts	O
,	O
using	O
RT	O
-	O
PCR	O
(	O
Figure	O
8F	O
)	O
.	O

In	O
addition	O
,	O
we	O
detected	O
mRNA	O
for	O
Prox1	O
,	O
Calbindin1	O
and	O
Calbindin2	O
/	O
Calretinin	O
(	O
Figure	O
8F	O
)	O
.	O

Interestingly	O
,	O
we	O
also	O
observed	O
Sonic	O
Hedgehog	O
and	O
Wnt	O
-	O
3A	O
transcripts	O
,	O
indicating	O
that	O
they	O
are	O
present	O
in	O
the	O
human	B
DG	O
and	O
supporting	O
previous	O
claims	O
that	O
they	O
are	O
important	O
for	O
the	O
regulation	O
of	O
adult	O
hippocampal	O
neurogenesis	O
(	O
Figure	O
8F	O
;	O
[	O
34	O
]	O
,	O
[	O
35	O
]	O
)	O
.	O

Finally	O
,	O
we	O
also	O
found	O
mRNA	O
for	O
GLAST	O
,	O
Pax6	O
and	O
GFAP	O
which	O
suggests	O
that	O
radial	O
glia	O
-	O
like	O
stem	O
cells	O
are	O
present	O
in	O
the	O
adult	O
human	B
hippocampus	O
,	O
and	O
may	O
play	O
a	O
role	O
in	O
adult	O
human	B
hippocampal	O
neurogenesis	O
(	O
Figure	O
8F	O
;	O
[	O
8	O
]	O
)	O
.	O

Overall	O
,	O
our	O
data	O
show	O
that	O
different	O
proteins	O
known	O
to	O
play	O
key	O
roles	O
in	O
rodent	B
hippocampal	O
granule	O
neurogenesis	O
are	O
present	O
in	O
the	O
adult	O
human	B
hippocampus	O
.	O

Discussion	O

In	O
this	O
study	O
we	O
determine	O
the	O
functions	O
of	O
Ngn2	O
and	O
NeuroD1	O
during	O
hippocampal	O
neurogenesis	O
.	O

First	O
,	O
we	O
map	O
the	O
hierarchy	O
of	O
molecular	O
markers	O
of	O
neurogenesis	O
in	O
the	O
DG	O
.	O

Second	O
,	O
we	O
describe	O
that	O
Ngn2	O
is	O
necessary	O
for	O
granule	O
progenitor	O
production	O
/	O
amplification	O
.	O

Third	O
,	O
we	O
demonstrate	O
that	O
NeuroD1	O
directs	O
neuronal	O
differentiation	O
of	O
granule	O
progenitors	O
.	O

Finally	O
,	O
we	O
show	O
that	O
different	O
cellular	O
markers	O
expressed	O
during	O
hippocampal	O
neurogenesis	O
in	O
rodents	O
are	O
present	O
in	O
human	B
.	O

Sequential	O
expression	O
of	O
different	O
transcription	O
factors	O
and	O
cellular	O
markers	O
during	O
hippocampal	O
neurogenesis	O

We	O
clarified	O
the	O
pattern	O
of	O
expression	O
of	O
various	O
markers	O
expressed	O
during	O
postnatal	O
and	O
adult	O
hippocampal	O
granule	O
neurogenesis	O
in	O
detail	O
.	O

We	O
found	O
that	O
the	O
transcription	O
factor	O
Pax6	O
is	O
initially	O
expressed	O
by	O
both	O
radial	O
glia	O
stem	O
cells	O
(	O
type	O
-	O
1	O
)	O
and	O
early	O
amplifying	O
progenitors	O
(	O
type	O
-	O
2a	O
)	O
.	O

The	O
next	O
transcription	O
factor	O
to	O
appear	O
in	O
chronology	O
is	O
Mash1	O
.	O

Mash1	O
expression	O
characterizes	O
the	O
early	O
stage	O
of	O
hippocampal	O
progenitor	O
amplification	O
(	O
early	O
type	O
-	O
2a	O
)	O
.	O

The	O
role	O
of	O
Mash1	O
during	O
hippocampal	O
granule	O
neurogenesis	O
is	O
still	O
unclear	O
.	O

Mash1	O
null	O
mutant	O
mice	B
do	O
not	O
display	O
any	O
clear	O
malformation	O
of	O
the	O
DG	O
[	O
20	O
]	O
.	O

However	O
,	O
overexpression	O
of	O
Mash1	O
alone	O
in	O
the	O
DG	O
leads	O
to	O
the	O
generation	O
of	O
oligodendrocytes	O
[	O
36	O
]	O
.	O

Based	O
on	O
these	O
observations	O
,	O
we	O
hypothesize	O
that	O
Mash1	O
-	O
expressing	O
cells	O
are	O
not	O
yet	O
committed	O
towards	O
a	O
granule	O
cell	O
fate	O
.	O

They	O
may	O
still	O
have	O
the	O
potential	O
to	O
generate	O
both	O
neurons	O
and	O
oligodendrocytes	O
,	O
as	O
is	O
the	O
case	O
in	O
the	O
SVZ	O
[	O
37	O
]	O
.	O

In	O
agreement	O
with	O
different	O
developing	O
brain	O
regions	O
,	O
we	O
found	O
that	O
Ngn2	O
starts	O
to	O
be	O
expressed	O
in	O
Mash1	O
-	O
positive	O
transiently	O
amplifying	O
progenitors	O
,	O
i	O
.	O
e	O
.	O
"	O
late	O
type	O
-	O
2a	O
cells	O
"	O
according	O
to	O
the	O
classification	O
we	O
propose	O
.	O

We	O
observed	O
that	O
Pax6	O
expression	O
persisted	O
longer	O
than	O
that	O
of	O
Mash1	O
,	O
in	O
Ngn2	O
-	O
expressing	O
cells	O
(	O
late	O
type	O
-	O
2a	O
cells	O
)	O
,	O
in	O
juvenile	O
but	O
not	O
adult	O
DG	O
(	O
Fig	O
.	O
1	O
and	O
figure	O
S1	O
)	O
.	O

Later	O
on	O
,	O
Ngn2	O
is	O
downregulated	O
,	O
whilst	O
Tbr2	O
expression	O
persists	O
(	O
type	O
-	O
2b	O
cells	O
)	O
.	O

The	O
transition	O
from	O
amplifying	O
progenitor	O
to	O
neuroblast	O
is	O
defined	O
by	O
the	O
expression	O
of	O
NeuroD1	O
.	O

Thus	O
,	O
Ngn2	O
is	O
expressed	O
at	O
the	O
beginning	O
of	O
the	O
transiently	O
amplifying	O
progenitor	O
phase	O
while	O
NeuroD1	O
marks	O
the	O
end	O
of	O
that	O
period	O
.	O

This	O
applies	O
both	O
to	O
the	O
juvenile	O
and	O
adult	O
rat	B
brain	O
[	O
21	O
]	O
,	O
[	O
25	O
]	O
.	O

After	O
NeuroD1	O
is	O
turned	O
on	O
the	O
progenitors	O
leave	O
the	O
cell	O
cycle	O
,	O
gradually	O
mature	O
,	O
express	O
PSA	O
-	O
NCAM	O
,	O
NeuroD2	O
,	O
Calretinin	O
,	O
Prox1	O
,	O
Tbr1	O
and	O
,	O
finally	O
,	O
NeuN	O
.	O

NeuroD1	O
expression	O
persists	O
at	O
low	O
levels	O
in	O
mature	O
neurons	O
(	O
Figure	O
9	O
;	O
[	O
10	O
]	O
)	O
.	O

We	O
found	O
the	O
sequential	O
expression	O
of	O
these	O
markers	O
conserved	O
in	O
juvenile	O
(	O
P2	O
and	O
2	O
weeks	O
)	O
and	O
adult	O
rodent	B
brains	O
.	O

Importantly	O
,	O
we	O
observed	O
that	O
the	O
same	O
transcription	O
factors	O
and	O
neuronal	O
markers	O
are	O
also	O
present	O
in	O
the	O
adult	O
human	B
hippocampus	O
and	O
arranged	O
spatially	O
in	O
a	O
manner	O
reminiscent	O
with	O
what	O
we	O
saw	O
in	O
rodents	O
.	O

It	O
is	O
possible	O
,	O
however	O
,	O
that	O
some	O
of	O
these	O
markers	O
are	O
expressed	O
for	O
longer	O
or	O
shorter	O
periods	O
at	O
postnatal	O
and	O
adult	O
stages	O
of	O
hippocampal	O
progenitor	O
maturation	O
.	O

Moreover	O
,	O
one	O
can	O
ask	O
to	O
which	O
extent	O
the	O
number	O
of	O
divisions	O
occurring	O
during	O
neuroblasts	O
maturation	O
is	O
conserved	O
at	O
postnatal	O
and	O
adult	O
stages	O
of	O
neurogenesis	O
.	O

A	O
new	O
function	O
for	O
Ngn2	O
in	O
maintenance	O
of	O
a	O
progenitor	O
state	O
for	O
granule	O
neuron	O
production	O
/	O
amplification	O
during	O
embryonic	O
and	O
postnatal	O
hippocampal	O
neurogenesis	O

In	O
agreement	O
with	O
earlier	O
work	O
,	O
we	O
confirm	O
that	O
Ngn2	O
is	O
indispensable	O
for	O
hippocampal	O
development	O
and	O
plays	O
a	O
vital	O
role	O
in	O
postnatal	O
hippocampal	O
granule	O
neurogenesis	O
.	O

Ngn2	O
null	O
mutant	O
animals	O
display	O
a	O
reduced	O
size	O
of	O
the	O
cornu	O
ammonis	O
and	O
a	O
malformed	O
DG	O
(	O
Figure	O
3	O
and	O
4	O
;	O
[	O
20	O
]	O
)	O
.	O

We	O
show	O
that	O
the	O
number	O
of	O
newborn	O
neurons	O
(	O
incorporated	O
BrdU	O
)	O
is	O
decreased	O
in	O
absence	O
of	O
Ngn2	O
,	O
but	O
hippocampal	O
granule	O
neuron	O
subtype	O
specification	O
is	O
not	O
affected	O
,	O
post	O
-	O
nataly	O
.	O

Likewise	O
,	O
neurons	O
from	O
other	O
brain	O
regions	O
,	O
e	O
.	O
g	O
.	O
ventral	O
midbrain	O
dopamine	O
neurons	O
,	O
can	O
be	O
generated	O
in	O
the	O
absence	O
of	O
Ngn2	O
[	O
30	O
]	O
,	O
[	O
31	O
]	O
.	O

The	O
reduced	O
numbers	O
of	O
mature	O
neurons	O
in	O
the	O
hippocampus	O
and	O
ventral	O
midbrain	O
of	O
Ngn2	O
null	O
mutant	O
animals	O
does	O
not	O
appear	O
to	O
be	O
due	O
to	O
cell	O
death	O
or	O
migration	O
defects	O
[	O
20	O
]	O
,	O
[	O
31	O
]	O
.	O

Instead	O
it	O
may	O
be	O
due	O
to	O
a	O
defect	O
in	O
the	O
generation	O
and	O
/	O
or	O
amplification	O
of	O
neuronal	O
progenitors	O
.	O

Indeed	O
,	O
in	O
the	O
hippocampus	O
of	O
postnatal	O
animals	O
,	O
we	O
observed	O
that	O
cells	O
lacking	O
Ngn2	O
arrest	O
in	O
the	O
cell	O
cycle	O
,	O
maintain	O
Pax6	O
expression	O
and	O
cease	O
to	O
proliferate	O
.	O

When	O
overexpressed	O
in	O
neural	O
progenitors	O
in	O
vitro	O
,	O
Ngn2	O
lead	O
to	O
up	O
-	O
regulation	O
of	O
NeuroD1	O
and	O
caused	O
neuronal	O
differentiation	O
(	O
Figure	O
6	O
)	O
,	O
which	O
was	O
not	O
always	O
the	O
case	O
when	O
we	O
overexpressed	O
the	O
same	O
factor	O
in	O
vivo	O
(	O
Figure	O
7L	O
,	O
N	O
and	O
O	O
)	O
.	O

We	O
also	O
saw	O
that	O
Ngn2	O
does	O
not	O
always	O
efficiently	O
induce	O
cell	O
cycle	O
exit	O
.	O

Typically	O
some	O
mitotically	O
active	O
eGFP	O
+	O
cells	O
were	O
present	O
in	O
the	O
DG	O
of	O
rats	B
injected	O
with	O
the	O
Ngn2	O
retrovirus	O
(	O
Figure	O
7P	O
)	O
,	O
and	O
we	O
observed	O
that	O
cultured	O
Ngn2	O
-	O
transduced	O
cells	O
are	O
still	O
capable	O
of	O
dividing	O
.	O

Thus	O
,	O
Ngn2	O
does	O
not	O
always	O
promote	O
cell	O
cycle	O
exit	O
and	O
neuronal	O
commitment	O
,	O
but	O
depending	O
on	O
the	O
state	O
of	O
the	O
cells	O
,	O
Ngn2	O
may	O
instead	O
promote	O
alternate	O
cellular	O
fates	O
[	O
38	O
]	O
-	O
[	O
40	O
]	O
.	O

Indeed	O
,	O
an	O
earlier	O
study	O
has	O
shown	O
that	O
Ngn2	O
-	O
overexpressing	O
progenitors	O
generate	O
oligodendrocytes	O
when	O
grafted	O
to	O
the	O
adult	O
spinal	O
cord	O
[	O
40	O
]	O
.	O

We	O
have	O
also	O
seen	O
that	O
Ngn2	O
-	O
overexpressing	O
neural	O
progenitors	O
from	O
the	O
embryonic	O
midbrain	O
form	O
astrocytes	O
when	O
grafted	O
to	O
the	O
striatum	O
(	O
unpublished	O
observations	O
)	O
.	O

Probably	O
,	O
Ngn2	O
cannot	O
influence	O
already	O
committed	O
cells	O
,	O
but	O
rather	O
would	O
control	O
neuroblasts	O
production	O
.	O

One	O
could	O
speculate	O
that	O
Ngn2	O
oscillates	O
during	O
granule	O
neuron	O
formation	O
,	O
as	O
recently	O
demonstrated	O
during	O
neocorticogenesis	O
[	O
41	O
]	O
,	O
[	O
42	O
]	O
.	O

NeuroD1	O
,	O
but	O
not	O
Ngn2	O
,	O
is	O
obligatory	O
for	O
granule	O
neuron	O
progenitor	O
differentiation	O

Hippocampal	O
granule	O
progenitors	O
can	O
mature	O
and	O
express	O
Tbr1	O
and	O
Prox1	O
,	O
both	O
during	O
the	O
development	O
and	O
postnatally	O
,	O
even	O
in	O
the	O
absence	O
of	O
Ngn2	O
.	O

Because	O
neuronal	O
differentiation	O
still	O
occurs	O
in	O
Ngn2	O
null	O
mice	B
,	O
it	O
is	O
clear	O
that	O
compensatory	O
,	O
Ngn2	O
-	O
independent	O
mechanisms	O
induce	O
NeuroD1	O
expression	O
.	O

One	O
candidate	O
is	O
Ngn1	O
,	O
which	O
is	O
expressed	O
during	O
neocorticogenesis	O
,	O
the	O
specification	O
of	O
olfactory	O
sensory	O
neurons	O
and	O
during	O
embryonic	O
rat	B
hippocampal	O
development	O
[	O
43	O
]	O
-	O
[	O
47	O
]	O
.	O

Both	O
Ngn1	O
and	O
Ngn2	O
regulate	O
NeuroD1	O
[	O
19	O
]	O
,	O
[	O
48	O
]	O
.	O

The	O
introduction	O
of	O
two	O
mutant	O
forms	O
of	O
Ngn1	O
,	O
a	O
deletion	O
of	O
the	O
basic	O
region	O
of	O
Ngn1	O
and	O
a	O
substitution	O
of	O
two	O
amino	O
acids	O
in	O
the	O
C	O
-	O
terminal	O
basic	O
region	O
,	O
prevents	O
NeuroD1	O
expression	O
and	O
neuronal	O
differentiation	O
[	O
48	O
]	O
.	O

The	O
double	O
null	O
Ngn1	O
/	O
Ngn2	O
mutant	O
displays	O
a	O
more	O
severe	O
phenotype	O
than	O
single	O
gene	O
(	O
Ngn1	O
or	O
Ngn2	O
)	O
mutant	O
mice	B
.	O

For	O
example	O
,	O
the	O
total	O
brain	O
size	O
of	O
the	O
double	O
mutants	O
is	O
much	O
smaller	O
[	O
10	O
]	O
,	O
[	O
32	O
]	O
.	O

If	O
the	O
role	O
of	O
Ngn1	O
during	O
hippocampal	O
neurogenesis	O
is	O
to	O
activate	O
NeuroD1	O
and	O
that	O
of	O
Ngn2	O
is	O
to	O
control	O
granule	O
neuroblasts	O
production	O
/	O
amplification	O
,	O
the	O
DG	O
of	O
double	O
Ngn1	O
/	O
Ngn2	O
knockout	O
mice	B
should	O
resemble	O
that	O
of	O
NeuroD1	O
null	O
mutant	O
mice	B
.	O

We	O
demonstrated	O
that	O
NeuroD1	O
directs	O
neuronal	O
differentiation	O
both	O
in	O
vitro	O
and	O
in	O
vivo	O
.	O

In	O
progenitors	O
isolated	O
from	O
different	O
embryonic	O
brain	O
regions	O
and	O
cultured	O
in	O
vitro	O
,	O
we	O
found	O
that	O
overexpression	O
of	O
NeuroD1	O
induced	O
neuronal	O
differentiation	O
.	O

The	O
neurons	O
generated	O
expressed	O
PSA	O
-	O
NCAM	O
,	O
Dcx	O
and	O
MAP2	O
.	O

After	O
in	O
utero	O
retroviral	O
vector	O
-	O
mediated	O
gene	O
delivery	O
,	O
virtually	O
all	O
cells	O
transduced	O
with	O
NeuroD1	O
became	O
neurons	O
.	O

In	O
contrast	O
,	O
progenitors	O
transduced	O
with	O
Ngn2	O
or	O
control	O
retroviruses	O
adopted	O
a	O
neuron	O
-	O
like	O
morphology	O
in	O
only	O
70	O
-	O
85	O
%	O
of	O
cases	O
.	O

Under	O
in	O
vitro	O
cell	O
culture	O
conditions	O
,	O
when	O
we	O
overexpressed	O
Ngn2	O
in	O
progenitors	O
derived	O
from	O
the	O
LGE	O
we	O
observed	O
robust	O
expression	O
of	O
NeuroD1	O
and	O
neuronal	O
differentiation	O
.	O

These	O
in	O
vitro	O
results	O
differ	O
from	O
those	O
we	O
obtained	O
when	O
we	O
transduced	O
the	O
embryonic	O
brain	O
with	O
a	O
viral	O
vector	O
expressing	O
Ngn2	O
.	O

In	O
this	O
latter	O
case	O
,	O
Ngn2	O
did	O
not	O
induce	O
neurons	O
and	O
the	O
transduced	O
cells	O
did	O
not	O
express	O
NeuroD1	O
.	O

Therefore	O
,	O
Ngn2	O
appears	O
to	O
direct	O
non	O
-	O
neuronal	O
cell	O
type	O
specification	O
in	O
vivo	O
[	O
38	O
]	O
-	O
[	O
40	O
]	O
.	O

Taken	O
together	O
,	O
we	O
have	O
confirmed	O
that	O
NeuroD1	O
plays	O
a	O
key	O
role	O
in	O
neuronal	O
differentiation	O
in	O
the	O
hippocampus	O
,	O
both	O
during	O
development	O
and	O
in	O
the	O
adult	O
brain	O
.	O

Concluding	O
remark	O

We	O
present	O
a	O
detailed	O
classification	O
of	O
different	O
stages	O
in	O
hippocampal	O
neurogenesis	O
.	O

Our	O
detailed	O
molecular	O
mapping	O
of	O
hippocampal	O
neurogenesis	O
allows	O
for	O
a	O
more	O
accurate	O
analysis	O
of	O
how	O
new	O
factors	O
stimulate	O
neurogenesis	O
at	O
different	O
steps	O
in	O
the	O
development	O
of	O
granule	O
neurons	O
.	O

Thereby	O
we	O
hope	O
to	O
facilitate	O
the	O
development	O
of	O
new	O
agents	O
,	O
which	O
stimulate	O
endogenous	O
progenitors	O
in	O
the	O
treatment	O
of	O
diseases	O
.	O

Materials	O
and	O
Methods	O

Animal	O
tissue	O
preparation	O

The	O
creation	O
of	O
the	O
Ngn2	O
transgenic	O
mice	B
was	O
reported	O
elsewhere	O
(	O
ref	O
guillemot	O
)	O
.	O

Heterozygote	O
male	O
and	O
female	O
mice	B
were	O
crossed	O
to	O
obtain	O
WT	O
,	O
heterozygote	O
(	O
Ngn2	O
+	O
/	O
GFP	O
)	O
and	O
null	O
mutant	O
(	O
Ngn2GFP	O
/	O
GFP	O
)	O
animals	O
.	O

Tails	O
of	O
the	O
Ngn2	O
offspring	O
were	O
used	O
to	O
obtain	O
DNA	O
for	O
determination	O
of	O
the	O
genotype	O
using	O
a	O
polymerase	O
chain	O
reaction	O
(	O
PCR	O
)	O
assay	O
as	O
previously	O
reported	O
[	O
31	O
]	O
.	O

As	O
null	O
mutant	O
Ngn2GFP	O
/	O
GFP	O
do	O
not	O
survive	O
longer	O
than	O
2	O
.	O
5	O
-	O
3	O
weeks	O
after	O
birth	O
,	O
Ngn2GFP	O
/	O
GFP	O
and	O
their	O
littermates	O
were	O
sacrificed	O
at	O
the	O
postnatal	O
ages	O
of	O
two	O
days	O
(	O
P2	O
)	O
or	O
two	O
weeks	O
for	O
this	O
study	O
.	O

Neurogenesis	O
was	O
assessed	O
in	O
two	O
weeks	O
or	O
two	O
months	O
old	O
WT	O
mice	B
.	O

Sprague	O
Dawley	O
pregnant	O
rats	B
were	O
ordered	O
from	O
B	O
&	O
K	O
Universal	O
Ltd	O
,	O
Sollentuna	O
,	O
Sweden	O
(	O
hppt	O
:	O
/	O
/	O
www	O
.	O
bku	O
.	O
com	O
)	O
.	O

All	O
animals	O
were	O
housed	O
in	O
groups	O
with	O
ad	O
libitum	O
access	O
to	O
food	O
and	O
water	O
at	O
a	O
12	O
-	O
h	O
light	O
/	O
dark	O
cycle	O
.	O

All	O
experimental	O
procedures	O
conducted	O
in	O
this	O
study	O
had	O
been	O
approved	O
by	O
the	O
Ethical	O
Committee	O
at	O
Lund	O
University	O
.	O

For	O
immunohistochemical	O
analysis	O
,	O
mice	B
(	O
from	O
two	O
weeks	O
old	O
and	O
adult	O
stage	O
)	O
and	O
juvenile	O
rats	B
were	O
sacrificed	O
by	O
transcardial	O
perfusion	O
with	O
saline	O
for	O
5	O
-	O
10	O
minutes	O
,	O
followed	O
by	O
4	O
%	O
paraformaldehyde	O
(	O
PFA	O
)	O
for	O
10	O
minutes	O
.	O

Brains	O
were	O
kept	O
in	O
PFA	O
overnight	O
at	O
4	O
degrees	O
C	O
and	O
subsequently	O
cryopreserved	O
in	O
a	O
20	O
-	O
30	O
%	O
sucrose	O
/	O
0	O
.	O
1	O
M	O
phosphate	O
buffer	O
solution	O
until	O
sectioning	O
on	O
a	O
microtome	O
apparatus	O
(	O
30	O
micro	O
m	O
thickness	O
sections	O
,	O
Microm	O
Zeiss	O
)	O
.	O

Seven	O
series	O
of	O
coronal	O
sections	O
were	O
cut	O
throughout	O
the	O
brain	O
.	O

Free	O
-	O
floating	O
sections	O
were	O
preserved	O
in	O
antifreeze	O
solution	O
until	O
immunohistochemistry	O
was	O
performed	O
.	O

Heads	O
of	O
postanatal	O
two	O
days	O
old	O
mice	B
were	O
decapitated	O
and	O
soaked	O
in	O
PFA	O
4	O
%	O
for	O
24	O
hours	O
,	O
at	O
4	O
degrees	O
C	O
and	O
transferred	O
into	O
sucrose	O
solution	O
until	O
sectioning	O
on	O
cryostat	O
apparatus	O
(	O
16	O
micro	O
m	O
thickness	O
;	O
Leica	O
CM3000	O
)	O
.	O

Sections	O
were	O
mounted	O
on	O
Superfrost	O
glass	O
slides	O
and	O
stored	O
at	O
-	O
80	O
degrees	O
C	O
until	O
immunohistochemistry	O
was	O
performed	O
.	O

Cloning	O
,	O
subcloning	O
,	O
virus	O
production	O
and	O
titer	O
measurement	O

The	O
Moloney	O
leukemia	O
-	O
derived	O
retroviral	O
vectors	O
used	O
in	O
this	O
study	O
,	O
pCMMP	O
-	O
IRES2eGFP	O
-	O
WPRE	O
and	O
pCMMP	O
-	O
Ngn2	O
-	O
IRES2eGFP	O
-	O
WPRE	O
were	O
previously	O
described	O
[	O
40	O
]	O
,	O
[	O
49	O
]	O
.	O

To	O
generate	O
the	O
construct	O
pCMMP	O
-	O
NeuroD1	O
-	O
IRES2eGFP	O
-	O
WPRE	O
,	O
mouse	B
NeuroD1	O
cDNA	O
was	O
amplified	O
from	O
a	O
pCS2	O
+	O
mtNeuroD1	O
plasmid	O
(	O
kindly	O
provided	O
by	O
Professor	O
Jackie	O
Lee	O
,	O
Denver	O
university	O
,	O
Boulder	O
,	O
USA	O
)	O
by	O
PCR	O
to	O
introduce	O
the	O
restriction	O
sites	O
PmeI	O
in	O
5	O
'	O
and	O
XhoI	O
in	O
3	O
'	O
.	O

Amplification	O
of	O
cDNA	O
was	O
performed	O
as	O
previously	O
described	O
[	O
49	O
]	O
.	O

The	O
construction	O
was	O
verified	O
by	O
enzymatic	O
restriction	O
and	O
by	O
DNA	O
sequencing	O
using	O
BigDye	O
3	O
.	O
1	O
(	O
ABI	O
)	O
.	O

All	O
infectious	O
particles	O
were	O
produced	O
using	O
the	O
producer	O
cell	O
line	O
293VSV	O
-	O
G	O
and	O
as	O
previously	O
described	O
[	O
49	O
]	O
.	O

The	O
titer	O
of	O
each	O
retrovirus	O
was	O
measured	O
by	O
flow	O
-	O
cytometry	O
based	O
on	O
eGFP	O
expression	O
,	O
four	O
days	O
following	O
infection	O
of	O
HT1080	O
cells	O
and	O
ranged	O
from	O
0	O
.	O
5	O
x	O
109	O
-	O
2	O
.	O
1	O
x	O
109	O
TU	O
/	O
ml	O
(	O
All	O
details	O
on	O
how	O
to	O
produce	O
infectious	O
particles	O
can	O
be	O
provided	O
upon	O
request	O
)	O
.	O

Neurosphere	O
generation	O
,	O
transduction	O
and	O
differentiation	O

Pregnant	O
female	O
Sprague	B
-	I
Dawley	I
rats	I
(	O
B	O
&	O
K	O
Universal	O
,	O
Sollentuna	O
,	O
Sweden	O
)	O
were	O
terminally	O
anesthetized	O
by	O
an	O
overdose	O
of	O
sodium	O
pentobarbital	O
(	O
i	O
.	O
p	O
.	O
,	O
60	O
ng	O
/	O
ml	O
)	O
.	O

Embryos	O
at	O
stage	O
embryonic	O
day	O
E14	O
.	O
5	O
(	O
Plug	O
day	O
as	O
day	O
0	O
)	O
were	O
collected	O
and	O
cortical	O
-	O
hippocampal	O
neurospheres	O
were	O
generated	O
following	O
dissection	O
of	O
the	O
dorso	O
-	O
posterior	O
part	O
of	O
the	O
cortical	O
tissue	O
,	O
and	O
generated	O
as	O
previously	O
described	O
[	O
49	O
]	O
.	O

In	O
this	O
study	O
,	O
second	O
passage	O
(	O
P2	O
)	O
neurospheres	O
were	O
used	O
to	O
study	O
the	O
effect	O
of	O
the	O
overexpression	O
of	O
Ngn2	O
and	O
NeuroD1	O
on	O
neuronal	O
differentiation	O
.	O

Each	O
well	O
,	O
containing	O
an	O
equal	O
starting	O
population	O
of	O
200	O
,	O
000	O
cells	O
/	O
ml	O
,	O
corresponding	O
to	O
15	O
-	O
25	O
neurospheres	O
,	O
was	O
transduced	O
independently	O
with	O
each	O
retrovirus	O
at	O
a	O
multiplicity	O
of	O
infection	O
(	O
MOI	O
)	O
of	O
1	O
,	O
in	O
proliferation	O
medium	O
supplemented	O
by	O
protamine	O
-	O
sulfate	O
(	O
4	O
mg	O
/	O
ml	O
,	O
Sigma	O
)	O
.	O

To	O
induce	O
differentiation	O
,	O
the	O
medium	O
was	O
replaced	O
with	O
normal	O
basic	O
differentiation	O
medium	O
two	O
days	O
post	O
-	O
transduction	O
and	O
subsequently	O
changed	O
every	O
other	O
day	O
until	O
fixation	O
.	O

Immunocytochemistry	O
,	O
immunohistochemistry	O
and	O
microscopy	O

The	O
antibodies	O
used	O
in	O
this	O
study	O
are	O
:	O
rabbit	B
anti	O
-	O
GFAP	O
(	O
1	O
:	O
1000	O
;	O
DAKO	O
)	O
,	O
mouse	B
anti	O
-	O
Nestin	O
(	O
1	O
:	O
100	O
;	O
BD	O
PharMingen	O
)	O
,	O
guinea	B
pig	I
anti	O
-	O
Glast	O
(	O
1	O
:	O
500	O
;	O
Chemicon	O
)	O
,	O
rabbit	B
anti	O
-	O
Prox1	O
(	O
1	O
:	O
1000	O
;	O
Covance	O
)	O
,	O
goat	B
anti	O
-	O
Ngn2	O
(	O
1	O
:	O
20	O
;	O
Santa	O
Cruz	O
)	O
,	O
goat	B
anti	O
-	O
NeuroD1	O
(	O
1	O
:	O
200	O
;	O
Santa	O
Cruz	O
)	O
,	O
rabbit	B
anti	O
-	O
Pax6	O
(	O
1	O
:	O
150	O
;	O
Covance	O
)	O
,	O
rabbit	B
anti	O
-	O
Trb2	O
(	O
1	O
:	O
500	O
;	O
Chemicon	O
)	O
,	O
rabbit	B
anti	O
-	O
Trb1	O
:	O
(	O
1	O
:	O
1000	O
;	O
Chemicon	O
)	O
,	O
goat	B
anti	O
-	O
Dcx	O
:	O
(	O
1	O
:	O
500	O
;	O
Santa	O
Cruz	O
)	O
,	O
mouse	B
anti	O
-	O
PSA	O
-	O
NCAM	O
:	O
(	O
1	O
:	O
500	O
;	O
Chemicon	O
)	O
,	O
mouse	B
anti	O
-	O
NeuN	O
(	O
1	O
:	O
300	O
;	O
Chemicon	O
)	O
,	O
rabbit	B
anti	O
-	O
Calretinin	O
(	O
1	O
:	O
500	O
;	O
Swant	O
)	O
;	O
mouse	B
anti	O
-	O
Sox2	O
(	O
1	O
:	O
100	O
;	O
R	O
&	O
D	O
systems	O
)	O
,	O
mouse	B
anti	O
-	O
Mash1	O
(	O
1	O
:	O
100	O
;	O
BD	O
PharMingen	O
)	O
,	O
rabbit	B
anti	O
-	O
NeuroD2	O
(	O
1	O
:	O
300	O
;	O
ABCAM	O
)	O
,	O
mouse	B
anti	O
-	O
MAP2	O
(	O
1	O
:	O
500	O
;	O
Sigma	O
)	O
,	O
rabbit	B
anti	O
-	O
Ki67	O
(	O
1	O
:	O
150	O
;	O
NovaCastra	O
)	O
and	O
rabbit	B
anti	O
-	O
phospho	O
-	O
Histone	O
H3	O
.	O

The	O
secondary	O
antibodies	O
(	O
1	O
:	O
200	O
)	O
Cy2	O
,	O
FITC	O
,	O
Cy3	O
and	O
Cy5	O
were	O
from	O
Jackson	O
IR	O
laboratories	O
,	O
Alexa	O
-	O
fluor	O
488	O
,	O
568	O
,	O
595	O
and	O
647	O
from	O
Invitrogen	O
-	O
Molecular	O
Probes	O
.	O

DAPI	O
(	O
1	O
:	O
1000	O
)	O
was	O
purchased	O
from	O
Sigma	O
.	O

For	O
immunocytochemistry	O
,	O
cultures	O
were	O
fixed	O
in	O
4	O
%	O
paraformaldehyde	O
at	O
day	O
five	O
,	O
rinsed	O
with	O
PBS	O
three	O
times	O
prior	O
to	O
pre	O
-	O
incubation	O
with	O
a	O
blocking	O
solution	O
(	O
10	O
%	O
donkey	B
serum	O
,	O
0	O
.	O
25	O
%	O
TritonX100	O
in	O
PBS	O
)	O
for	O
1	O
hour	O
.	O

The	O
remainder	O
of	O
the	O
procedure	O
was	O
performed	O
as	O
previously	O
described	O
[	O
49	O
]	O
.	O

Specimen	O
analyses	O
were	O
performed	O
using	O
a	O
Leica	O
confocal	O
microscope	O
(	O
Leica	O
software	O
,	O
equipped	O
with	O
a	O
GreNe	O
and	O
a	O
HeNe	O
laser	O
,	O
using	O
the	O
following	O
lines	O
of	O
excitation	O
:	O
488	O
nm	O
,	O
594	O
nm	O
and	O
647	O
nm	O
)	O
.	O

Samples	O
were	O
analyzed	O
using	O
20	O
x	O
,	O
40	O
x	O
and	O
63	O
x	O
objectives	O
,	O
sometimes	O
zoomed	O
.	O

Figures	O
were	O
composed	O
in	O
CANVAS	O
-	O
X	O
software	O
.	O

Bromo	O
-	O
deoxyuridine	O
(	O
BrdU	O
)	O
and	O
Cloro	O
-	O
deoxyuridine	O
(	O
CldU	O
)	O
pulse	O
labeling	O
and	O
immunohisto	O
-	O
and	O
immunocyto	O
-	O
chemistry	O

To	O
assess	O
cell	O
proliferation	O
and	O
ongoing	O
neurogenesis	O
in	O
vivo	O
,	O
animals	O
were	O
injected	O
with	O
BrdU	O
(	O
100	O
mg	O
/	O
kg	O
,	O
Sigma	O
)	O
,	O
two	O
hours	O
prior	O
to	O
sacrifice	O
(	O
for	O
both	O
P2	O
and	O
two	O
weeks	O
old	O
Ngn2	O
mice	B
)	O
.	O

To	O
assess	O
neurogenesis	O
,	O
BrdU	O
(	O
100	O
mg	O
/	O
kg	O
)	O
was	O
injected	O
48	O
hours	O
prior	O
to	O
sacrifice	O
(	O
for	O
P2	O
animals	O
,	O
BrdU	O
was	O
injected	O
in	O
pregnant	O
dams	O
half	O
day	O
prior	O
to	O
give	O
birth	O
)	O
.	O

Immunohistochemistry	O
was	O
carried	O
on	O
as	O
described	O
above	O
using	O
a	O
rat	B
anti	O
-	O
CldU	O
/	O
BrdU	O
primary	O
antibody	O
(	O
1	O
:	O
200	O
,	O
monoclonal	O
,	O
Immunologicalsdirect	O
,	O
Oxfordshire	O
,	O
UK	O
)	O
,	O
with	O
an	O
additional	O
denaturation	O
in	O
1	O
M	O
HCl	O
for	O
30	O
minutes	O
prior	O
to	O
pre	O
-	O
incubation	O
with	O
serum	O
.	O

To	O
assess	O
the	O
neuronal	O
-	O
inducing	O
activity	O
of	O
Ngn2	O
and	O
NeuroD1	O
,	O
transduced	O
cultures	O
were	O
incubated	O
with	O
CldU	O
(	O
20	O
micro	O
M	O
,	O
Sigma	O
)	O
for	O
2	O
days	O
,	O
after	O
a	O
period	O
of	O
differentiation	O
of	O
five	O
days	O
.	O

For	O
immunocytochemistry	O
,	O
cultures	O
were	O
fixed	O
with	O
4	O
%	O
paraformaldehyde	O
at	O
day	O
7	O
,	O
rinsed	O
with	O
PBS	O
three	O
times	O
,	O
treated	O
with	O
1	O
M	O
HCl	O
at	O
65	O
degrees	O
C	O
for	O
5	O
-	O
10	O
min	O
,	O
pre	O
-	O
incubated	O
and	O
then	O
incubated	O
with	O
a	O
rat	B
anti	O
-	O
CldU	O
/	O
BrdU	O
antibody	O
and	O
other	O
primary	O
antibodies	O
.	O

The	O
remainder	O
of	O
the	O
procedure	O
was	O
performed	O
according	O
to	O
the	O
protocol	O
for	O
immunohistochemistry	O
already	O
mentioned	O
.	O

In	O
utero	O
surgery	O

Timed	O
pregnant	O
female	O
Sprague	B
Dawley	I
rats	I
with	O
embryos	O
at	O
gestational	O
age	O
E15	O
.	O
5	O
were	O
anesthetized	O
with	O
halothane	O
.	O

The	O
mother	O
was	O
placed	O
in	O
the	O
lower	O
level	O
of	O
a	O
two	O
-	O
level	O
wooden	O
stage	O
.	O

The	O
abdomen	O
was	O
shaved	O
with	O
an	O
electric	O
razor	O
and	O
then	O
cleaned	O
with	O
70	O
%	O
alcohol	O
.	O

A	O
2	O
-	O
3	O
cm	O
midline	O
laparotomy	O
was	O
performed	O
.	O

Each	O
uterine	O
horn	O
was	O
carefully	O
taken	O
out	O
individually	O
and	O
the	O
number	O
of	O
embryos	O
recorded	O
.	O

One	O
horn	O
was	O
then	O
placed	O
back	O
inside	O
the	O
mother	O
,	O
whilst	O
the	O
other	O
horn	O
was	O
prepared	O
for	O
injection	O
.	O

The	O
embryos	O
were	O
kept	O
moist	O
with	O
constant	O
application	O
of	O
warm	O
saline	O
to	O
prevent	O
dehydration	O
.	O

Approximately	O
2	O
micro	O
l	O
of	O
viral	O
suspension	O
(	O
1	O
x	O
10	O
^	O
9TU	O
/	O
ml	O
)	O
was	O
injected	O
into	O
the	O
lateral	O
ventricle	O
of	O
each	O
embryo	O
,	O
except	O
for	O
the	O
embryo	O
closest	O
to	O
the	O
vagina	O
.	O

After	O
the	O
injections	O
,	O
the	O
uterine	O
horns	O
were	O
placed	O
back	O
into	O
the	O
abdomen	O
.	O

The	O
abdominal	O
wall	O
and	O
the	O
overlying	O
skin	O
were	O
then	O
sutured	O
.	O

Care	O
was	O
taken	O
not	O
to	O
damage	O
abdominal	O
muscles	O
so	O
that	O
normal	O
delivery	O
of	O
the	O
pups	O
was	O
possible	O
at	O
term	O
.	O

The	O
entire	O
surgery	O
generally	O
took	O
about	O
45	O
minutes	O
to	O
one	O
hour	O
.	O

Each	O
mother	O
was	O
allowed	O
to	O
recover	O
in	O
her	O
cage	O
before	O
being	O
returned	O
to	O
the	O
animal	O
stable	O
.	O

Shredded	O
paper	O
was	O
added	O
to	O
each	O
cage	O
to	O
encourage	O
nesting	O
and	O
special	O
care	O
was	O
taken	O
not	O
to	O
stress	O
the	O
mothers	O
.	O

Following	O
normal	O
delivery	O
,	O
the	O
pups	O
were	O
allowed	O
to	O
develop	O
to	O
adulthood	O
up	O
to	O
two	O
weeks	O
.	O

Quantification	O

For	O
the	O
in	O
vivo	O
experiment	O
,	O
manual	O
cell	O
counting	O
was	O
performed	O
on	O
18	O
and	O
30	O
micro	O
m	O
thick	O
brain	O
sections	O
for	O
two	O
days	O
and	O
two	O
weeks	O
old	O
animals	O
,	O
respectively	O
.	O

The	O
brain	O
of	O
P2	O
animals	O
was	O
cut	O
into	O
10	O
series	O
of	O
coronal	O
sections	O
;	O
the	O
brain	O
of	O
two	O
-	O
weeks	O
old	O
animals	O
was	O
cut	O
into	O
7	O
-	O
8	O
series	O
of	O
coronal	O
sections	O
.	O

For	O
each	O
staining	O
,	O
one	O
-	O
two	O
series	O
from	O
three	O
to	O
five	O
different	O
individuals	O
were	O
analyzed	O
per	O
genotype	O
using	O
a	O
confocal	O
microscope	O
with	O
1	O
,	O
2	O
or	O
3	O
lines	O
of	O
excitation	O
,	O
in	O
sequential	O
scanning	O
in	O
order	O
to	O
avoid	O
false	O
positives	O
.	O

When	O
two	O
series	O
were	O
analyzed	O
,	O
only	O
one	O
series	O
was	O
counted	O
.	O

The	O
mean	O
number	O
of	O
cells	O
per	O
hippocampus	O
expressing	O
the	O
markers	O
of	O
interest	O
,	O
was	O
calculated	O
for	O
each	O
brain	O
,	O
based	O
on	O
the	O
analysis	O
of	O
6	O
-	O
8	O
consecutive	O
dorsal	O
hippocampal	O
sections	O
.	O

The	O
final	O
mean	O
number	O
of	O
cells	O
per	O
section	O
was	O
calculated	O
by	O
adding	O
the	O
mean	O
number	O
from	O
each	O
individual	O
.	O

We	O
expressed	O
the	O
data	O
as	O
the	O
mean	O
number	O
of	O
positive	O
cells	O
+	O
/	O
-	O
standard	O
error	O
of	O
the	O
mean	O
(	O
SEM	O
)	O
.	O

In	O
this	O
study	O
,	O
more	O
than	O
25	O
Ngn2	O
null	O
,	O
>	O
45	O
Ngn2	O
heterozygotes	O
,	O
and	O
>	O
60	O
WT	O
individuals	O
(	O
including	O
rats	B
injected	O
with	O
retroviruses	O
)	O
were	O
analyzed	O
,	O
in	O
total	O
.	O

Statistical	O
comparison	O
was	O
performed	O
using	O
one	O
-	O
factor	O
analysis	O
of	O
variance	O
(	O
ANOVA	O
)	O
with	O
transcription	O
factor	O
,	O
cellular	O
marker	O
,	O
genotype	O
or	O
time	O
as	O
variables	O
,	O
followed	O
by	O
post	O
-	O
hoc	O
analysis	O
when	O
significant	O
differences	O
were	O
observed	O
,	O
using	O
Statview	O
5	O
.	O
0	O
software	O
(	O
SAS	O
institute	O
Inc	O
.	O
)	O
.	O

For	O
cell	O
culture	O
experiments	O
,	O
three	O
independent	O
experiments	O
were	O
performed	O
,	O
each	O
in	O
duplicate	O
.	O

The	O
counting	O
was	O
based	O
on	O
seven	O
randomly	O
chosen	O
different	O
fields	O
of	O
view	O
.	O

For	O
each	O
diagram	O
,	O
the	O
level	O
of	O
significance	O
(	O
p	O
-	O
value	O
)	O
is	O
represented	O
as	O
follows	O
:	O
P	O
<	O
0	O
.	O
05	O
=	O
*	O
;	O
P	O
<	O
0	O
.	O
001	O
=	O
*	O
*	O
;	O
P	O
<	O
0	O
.	O
0001	O
=	O
*	O
*	O
*	O
.	O

All	O
data	O
are	O
expressed	O
as	O
+	O
/	O
-	O
standard	O
error	O
of	O
the	O
mean	O
(	O
SEM	O
)	O
.	O

Human	B
sample	O
and	O
RT	O
-	O
PCR	O

The	O
brain	O
from	O
a	O
64	O
year	O
-	O
old	O
male	O
was	O
provided	O
by	O
the	O
Harvard	O
Brain	O
Tissue	O
Resource	O
Center	O
.	O

The	O
individual	O
whose	O
brain	O
tissue	O
was	O
being	O
analyzed	O
gave	O
written	O
consent	O
for	O
storage	O
and	O
use	O
of	O
his	O
tissue	O
for	O
research	O
.	O

Five	O
millimeters	O
thick	O
fresh	O
human	B
hippocampal	O
tissue	O
sample	O
was	O
snap	O
frozen	O
.	O

The	O
frozen	O
tissue	O
block	O
was	O
cut	O
into	O
20	O
series	O
of	O
coronal	O
sections	O
,	O
using	O
a	O
cryostat	O
.	O

Every	O
10	O
sections	O
,	O
one	O
section	O
was	O
placed	O
in	O
an	O
Eppendorf	O
tube	O
,	O
on	O
dry	O
ice	O
.	O

Pooled	O
sections	O
were	O
used	O
for	O
RT	O
-	O
PCR	O
.	O

Total	O
RNA	O
was	O
prepared	O
using	O
Trizol	O
and	O
RNAeasy	O
,	O
supplemented	O
with	O
RNAGuard	O
as	O
previously	O
described	O
[	O
49	O
]	O
.	O

The	O
RNA	O
was	O
digested	O
with	O
shrimp	O
DNAse	O
before	O
cDNA	O
synthesis	O
,	O
which	O
was	O
performed	O
using	O
a	O
mix	O
of	O
oligo	O
-	O
dT	O
and	O
random	O
hexamer	O
primers	O
and	O
SuperscriptII	O
reverse	O
transcriptase	O
.	O

Advantage2	O
polymerase	O
mix	O
(	O
Clontech	O
/	O
BRL	O
)	O
was	O
used	O
for	O
PCR	O
,	O
with	O
the	O
following	O
cycling	O
conditions	O
:	O
10	O
cycles	O
of	O
94	O
degrees	O
C	O
for	O
30	O
seconds	O
,	O
68	O
degrees	O
C	O
for	O
2	O
minutes	O
,	O
30	O
cycles	O
of	O
94	O
degrees	O
C	O
for	O
30	O
seconds	O
,	O
60	O
degrees	O
C	O
for	O
1	O
minute	O
,	O
68	O
degrees	O
C	O
for	O
1	O
minute	O
and	O
30	O
seconds	O
,	O
one	O
cycle	O
of	O
68	O
degrees	O
C	O
for	O
2	O
minutes	O
,	O
soak	O
at	O
16	O
degrees	O
C	O
.	O

Primers	O
marked	O
*	O
were	O
designed	O
by	O
PrimerBank	O
.	O

hRPS18	O
(	O
sense	O
)	O
5	O
'	O
-	O
GCCTTTGCCATCACTGCCAT	O
and	O
hRPS18	O
(	O
antisense	O
)	O
5	O
'	O
-	O
GCCAGTGGTCTTGGTGTGCT	O
,	O
hPAX6	O
(	O
sense	O
)	O
5	O
'	O
-	O
GCCCTGGAGAAAGAGTTTGA	O
hPAX6	O
(	O
antisense	O
)	O
5	O
'	O
-	O
GGGGAAATGAGTCCTGTTGA	O
,	O
hTBR1	O
(	O
sense	O
)	O
5	O
'	O
-	O
GCGGACACCAATGTGCAAGG	O
and	O
hTBR1	O
(	O
antisense	O
)	O
5	O
'	O
-	O
CGAGGGGGTCAGGCGGTCCA	O
,	O
hTBR2	O
(	O
sense	O
)	O
5	O
'	O
-	O
GACCTGTGGCAAAGCCGACA	O
and	O
hTBR2	O
(	O
antisense	O
)	O
5	O
'	O
-	O
GGGGGTGTCTCTATCCAAGA	O
,	O
hPDHX	O
(	O
=	O
PROX1	O
)	O
(	O
sense	O
)	O
5	O
'	O
-	O
GGGACACTACGGTTCCGTTT	O
and	O
hPDHX	O
(	O
antisense	O
)	O
5	O
'	O
-	O
CTCTCCATCCCAGCTTACAT	O
,	O
hNGN2	O
(	O
sense	O
)	O
*	O
5	O
'	O
-	O
CATCAAGAAGACCCGTAGAC	O
and	O
hNGN2	O
(	O
antisense	O
)	O
*	O
5	O
'	O
-	O
CAACACTGCCTCGGAGAAG	O
,	O
hMASH1	O
(	O
sense	O
)	O
5	O
'	O
-	O
CCTGGATCCGCATGGAAAGC	O
and	O
hMASH1	O
(	O
antisense	O
)	O
5	O
'	O
-	O
CCTGGATCCCCCCTCAGAAC	O
,	O
hNEUROD1	O
(	O
sense	O
)	O
5	O
'	O
-	O
GCTCAGGACCTACTAACAAC	O
and	O
hNEUROD1	O
(	O
antisense	O
)	O
5	O
'	O
-	O
CAAAGCGTCTGAACGAAGGA	O
,	O
hGLAST	O
(	O
sense	O
)	O
5	O
'	O
-	O
CATCAGGGAAGATGGGAATG	O
and	O
hGLAST	O
(	O
antisense	O
)	O
5	O
'	O
-	O
CCACGGGGGCATACCACATT	O
,	O
hNEST	O
(	O
sense	O
)	O
5	O
'	O
-	O
CAGGAGCGGCTGCGGGCTAC	O
and	O
hNEST	O
(	O
antisense	O
)	O
5	O
'	O
-	O
CAGGGCTGAGGGGTGGTGCC	O
,	O
hGFAP	O
(	O
sense	O
)	O
5	O
'	O
-	O
CCACGAGGAGGAGGTTCGGG	O
and	O
hGFAP	O
(	O
antisense	O
)	O
5	O
-	O
GGAATGGTGATCCGGTTCTC	O
,	O
hCALB2	O
(	O
=	O
Calretinin	O
)	O
(	O
sense	O
)	O
5	O
'	O
-	O
GGCTCTGGCATGATGTCAAA	O
and	O
hCALB2	O
(	O
antisense	O
)	O
5	O
'	O
-	O
GGGCATCCAGCTCATGCTCG	O
,	O
hCALB1	O
(	O
sense	O
)	O
5	O
'	O
-	O
GCGAAAGAAGGCTGGATTGG	O
and	O
hCALB1	O
(	O
antisense	O
)	O
5	O
'	O
-	O
CCCTCCATCCGACAAAGCCA	O
,	O
hSOX2	O
(	O
sense	O
)	O
5	O
'	O
-	O
GGAGAACCCCAAGATGCACA	O
and	O
hSOX2	O
(	O
antisense	O
)	O
5	O
'	O
-	O
GAGGAAGAGGTAACCACAGG	O
,	O
hWNT3A	O
(	O
sense	O
)	O
5	O
'	O
-	O
CCGAGGGCATCAAGATTGGC	O
and	O
hWNT3A	O
(	O
antisense	O
)	O
5	O
'	O
-	O
TCGGGTTGCGACCACCAGCA	O
,	O
hSHH	O
*	O
(	O
sense	O
)	O
5	O
'	O
-	O
ACTCCGAGCGATTTAAGGAA	O
and	O
hSHH	O
*	O
(	O
antisense	O
)	O
5	O
'	O
-	O
CAGACGTGGTGATGTCCACT	O
.	O

Supporting	O
Information	O

A	O
novel	O
DNA	O
-	O
binding	O
protein	O
modulating	O
methicillin	O
resistance	O
in	O
Staphylococcus	B
aureus	I

Abstract	O

Background	O

Methicillin	O
resistance	O
in	O
Staphylococcus	B
aureus	I
is	O
conferred	O
by	O
the	O
mecA	O
-	O
encoded	O
penicillin	O
-	O
binding	O
protein	O
PBP2a	O
.	O

Additional	O
genomic	O
factors	O
are	O
also	O
known	O
to	O
influence	O
resistance	O
levels	O
in	O
strain	O
specific	O
ways	O
,	O
although	O
little	O
is	O
known	O
about	O
their	O
contribution	O
to	O
resistance	O
phenotypes	O
in	O
clinical	O
isolates	O
.	O

Here	O
we	O
searched	O
for	O
novel	O
proteins	O
binding	O
to	O
the	O
mec	O
operator	O
,	O
in	O
an	O
attempt	O
to	O
identify	O
new	O
factor	O
(	O
s	O
)	O
controlling	O
methicillin	O
resistance	O
phenotypes	O
.	O

Results	O

Analysis	O
of	O
proteins	O
binding	O
to	O
a	O
DNA	O
fragment	O
containing	O
the	O
mec	O
operator	O
region	O
identified	O
a	O
novel	O
,	O
putative	O
helix	O
-	O
turn	O
-	O
helix	O
DNA	O
-	O
binding	O
protein	O
,	O
SA1665	O
.	O

Nonpolar	O
deletion	O
of	O
SA1665	O
,	O
in	O
heterogeneously	O
methicillin	O
resistant	O
S	B
.	I
aureus	I
(	O
MRSA	B
)	O
of	O
different	O
genetic	O
backgrounds	O
,	O
increased	O
methicillin	O
resistance	O
levels	O
in	O
a	O
strain	O
dependent	O
manner	O
.	O

This	O
phenotype	O
could	O
be	O
fully	O
complemented	O
by	O
reintroducing	O
SA1665	O
in	O
trans	O
.	O

Northern	O
and	O
Western	O
blot	O
analyses	O
,	O
however	O
,	O
revealed	O
that	O
SA1665	O
had	O
no	O
visible	O
influence	O
on	O
mecA	O
transcription	O
or	O
amounts	O
of	O
PBP2a	O
produced	O
.	O

Conclusion	O

SA1665	O
is	O
a	O
new	O
chromosomal	O
factor	O
which	O
influences	O
methicillin	O
resistance	O
in	O
MRSA	B
.	O

Although	O
SA1665	O
bound	O
to	O
the	O
mecA	O
promoter	O
region	O
,	O
it	O
had	O
no	O
apparent	O
influence	O
on	O
mecA	O
transcription	O
or	O
translation	O
,	O
suggesting	O
that	O
this	O
predicted	O
DNA	O
-	O
binding	O
protein	O
modulates	O
resistance	O
indirectly	O
,	O
most	O
likely	O
through	O
the	O
control	O
of	O
other	O
genomic	O
factors	O
which	O
contribute	O
to	O
resistance	O
.	O

Background	O

Methicillin	O
resistant	O
S	B
.	I
aureus	I
(	O
MRSA	B
)	O
are	O
an	O
ever	O
increasing	O
threat	O
,	O
both	O
in	O
clinical	O
settings	O
and	O
more	O
recently	O
as	O
an	O
emerging	O
community	O
acquired	O
pathogen	O
.	O

Their	O
invasiveness	O
and	O
pathogenesis	O
relies	O
on	O
a	O
variable	O
arsenal	O
of	O
virulence	O
factors	O
,	O
paired	O
with	O
resistance	O
to	O
virtually	O
all	O
beta	O
-	O
lactams	O
and	O
their	O
derivatives	O
.	O

Their	O
ability	O
to	O
rapidly	O
generate	O
resistance	O
to	O
other	O
unrelated	O
classes	O
of	O
antibiotics	O
,	O
or	O
to	O
take	O
up	O
additional	O
resistance	O
determinants	O
,	O
severely	O
hampers	O
therapy	O
and	O
eradication	O
.	O

In	O
S	B
.	I
aureus	I
,	O
methicillin	O
resistance	O
is	O
conferred	O
by	O
an	O
acquired	O
,	O
beta	O
-	O
lactam	O
-	O
insensitive	O
penicillin	O
-	O
binding	O
protein	O
(	O
PBP	O
)	O
,	O
PBP2a	O
[	O
1	O
-	O
4	O
]	O
.	O

PBP2a	O
is	O
encoded	O
by	O
mecA	O
,	O
which	O
is	O
divergently	O
transcribed	O
from	O
its	O
cognate	O
regulators	O
,	O
mecR1	O
(	O
sensor	O
/	O
signal	O
transducer	O
)	O
and	O
mecI	O
(	O
repressor	O
)	O
.	O

If	O
mecR1	O
-	O
mecI	O
are	O
absent	O
or	O
truncated	O
,	O
transcriptional	O
control	O
of	O
mecA	O
is	O
taken	O
over	O
by	O
the	O
structurally	O
similar	O
blaZ	O
(	O
penicillinase	O
)	O
regulatory	O
elements	O
blaR1	O
/	O
blaI	O
,	O
if	O
present	O
.	O

In	O
the	O
absence	O
of	O
both	O
regulatory	O
loci	O
,	O
mecA	O
is	O
constitutively	O
transcribed	O
[	O
5	O
,	O
6	O
]	O
.	O

In	O
the	O
presence	O
of	O
beta	O
-	O
lactams	O
,	O
the	O
transmembrane	O
sensor	O
/	O
signal	O
transducers	O
BlaR1	O
/	O
MecR1	O
,	O
undergo	O
a	O
conformational	O
change	O
,	O
followed	O
by	O
autoproteolytic	O
cleavage	O
of	O
the	O
n	O
-	O
terminal	O
cytoplasmic	O
domain	O
,	O
leading	O
to	O
the	O
activation	O
of	O
the	O
cytoplasmic	O
peptidase	O
and	O
subsequent	O
dissociation	O
of	O
the	O
repressor	O
due	O
to	O
proteolytic	O
degradation	O
[	O
7	O
-	O
9	O
]	O
.	O

However	O
,	O
the	O
signal	O
transduction	O
cascade	O
of	O
this	O
regulatory	O
system	O
has	O
still	O
not	O
been	O
completely	O
elucidated	O
.	O

Oxacillin	O
resistance	O
levels	O
conferred	O
by	O
mecA	O
are	O
strain	O
specific	O
and	O
can	O
vary	O
greatly	O
,	O
with	O
oxacillin	O
minimal	O
inhibitory	O
concentrations	O
(	O
MICs	O
)	O
of	O
different	O
strains	O
ranging	O
from	O
phenotypically	O
susceptible	O
levels	O
,	O
as	O
low	O
as	O
1	O
mu	O
g	O
/	O
ml	O
up	O
to	O
extremely	O
high	O
values	O
of	O
>	O
500	O
mu	O
g	O
/	O
ml	O
.	O

Methicillin	O
resistance	O
is	O
also	O
generally	O
expressed	O
heterogeneously	O
.	O

Heterogeneously	O
resistant	O
MRSA	B
,	O
when	O
exposed	O
to	O
beta	O
-	O
lactam	O
antibiotics	O
,	O
segregate	O
highly	O
resistant	O
subpopulations	O
,	O
which	O
are	O
much	O
more	O
resistant	O
than	O
the	O
majority	O
of	O
the	O
cells	O
[	O
10	O
]	O
.	O

The	O
frequency	O
of	O
highly	O
resistant	O
subclones	O
generated	O
is	O
often	O
well	O
above	O
the	O
spontaneous	O
mutation	O
frequency	O
,	O
and	O
once	O
selected	O
high	O
level	O
resistance	O
often	O
remains	O
stable	O
,	O
even	O
in	O
the	O
absence	O
of	O
selective	O
pressure	O
.	O

There	O
is	O
currently	O
no	O
satisfactory	O
genetic	O
model	O
which	O
explains	O
how	O
these	O
higher	O
resistance	O
levels	O
are	O
triggered	O
or	O
selected	O
and	O
exactly	O
what	O
factors	O
are	O
functionally	O
responsible	O
for	O
the	O
increased	O
resistance	O
in	O
clinical	O
isolates	O
.	O

Methicillin	O
resistance	O
levels	O
are	O
known	O
to	O
not	O
directly	O
correlate	O
with	O
mecA	O
transcription	O
or	O
levels	O
of	O
PBP2a	O
produced	O
[	O
11	O
,	O
12	O
]	O
.	O

However	O
,	O
resistance	O
levels	O
can	O
be	O
manipulated	O
by	O
environmental	O
conditions	O
,	O
such	O
as	O
temperature	O
,	O
pH	O
,	O
osmolarity	O
,	O
and	O
medium	O
composition	O
[	O
13	O
,	O
14	O
]	O
.	O

It	O
has	O
been	O
shown	O
experimentally	O
,	O
that	O
in	O
addition	O
to	O
mecA	O
,	O
methicillin	O
resistance	O
depends	O
on	O
the	O
correct	O
interplay	O
of	O
a	O
multitude	O
of	O
genomic	O
factors	O
,	O
termed	O
fem	O
/	O
aux	O
factors	O
,	O
including	O
genes	O
involved	O
in	O
peptidoglycan	O
precursor	O
formation	O
,	O
composition	O
and	O
turnover	O
;	O
teichoic	O
acid	O
synthesis	O
;	O
and	O
genes	O
of	O
unknown	O
or	O
poorly	O
characterised	O
functions	O
[	O
15	O
-	O
18	O
]	O
.	O

In	O
addition	O
to	O
structural	O
genes	O
,	O
many	O
regulatory	O
loci	O
have	O
also	O
been	O
shown	O
to	O
influence	O
resistance	O
levels	O
,	O
including	O
global	O
regulators	O
of	O
virulence	O
factor	O
production	O
such	O
as	O
the	O
quorum	O
sensing	O
agr	O
system	O
,	O
the	O
staphylococcal	O
accessory	O
regulator	O
SarA	O
and	O
the	O
alternate	O
sigma	O
factor	O
sigma	O
B	O
[	O
19	O
,	O
20	O
]	O
;	O
regulators	O
of	O
metabolism	O
,	O
such	O
as	O
the	O
catabolite	O
control	O
protein	O
A	O
(	O
CcpA	O
)	O
[	O
21	O
]	O
;	O
and	O
the	O
VraSR	O
two	O
-	O
component	O
sensor	O
transducer	O
,	O
which	O
induces	O
the	O
cell	O
wall	O
stress	O
stimulon	O
in	O
response	O
to	O
cell	O
wall	O
active	O
antibiotic	O
challenge	O
[	O
22	O
]	O
.	O

The	O
vast	O
MIC	O
differences	O
between	O
MRSA	B
strains	O
,	O
the	O
population	O
heterogeneity	O
within	O
single	O
strains	O
and	O
the	O
dependence	O
of	O
resistance	O
levels	O
on	O
external	O
factors	O
are	O
reflected	O
in	O
these	O
many	O
structural	O
genes	O
and	O
global	O
regulators	O
,	O
which	O
can	O
influence	O
resistance	O
levels	O
.	O

While	O
typically	O
considered	O
nosocomial	O
pathogens	O
,	O
new	O
faster	O
growing	O
and	O
apparently	O
more	O
virulent	O
MRSA	B
have	O
begun	O
spreading	O
in	O
the	O
community	O
.	O

Interestingly	O
,	O
these	O
emerging	O
strains	O
often	O
express	O
very	O
low	O
methicillin	O
resistance	O
,	O
e	O
.	O
g	O
.	O
the	O
MRSA	B
clone	O
spreading	O
amongst	O
intravenous	O
drug	O
users	O
in	O
the	O
Zurich	O
area	O
,	O
which	O
has	O
an	O
in	O
vitro	O
doubling	O
time	O
of	O
25	O
min	O
,	O
but	O
oxacillin	O
MICs	O
of	O
only	O
0	O
.	O
5	O
to	O
4	O
mu	O
g	O
/	O
ml	O
[	O
23	O
]	O
.	O

This	O
particular	O
clone	O
'	O
s	O
low	O
-	O
level	O
resistance	O
is	O
partially	O
due	O
to	O
a	O
promoter	O
mutation	O
,	O
leading	O
to	O
tight	O
repression	O
of	O
mecA	O
,	O
but	O
resistance	O
levels	O
appear	O
to	O
be	O
mainly	O
restricted	O
by	O
unknown	O
factors	O
within	O
its	O
genomic	O
background	O
[	O
12	O
]	O
.	O

To	O
identify	O
potential	O
factors	O
involved	O
in	O
mecA	O
regulation	O
or	O
methicillin	O
resistance	O
levels	O
in	O
such	O
an	O
extremely	O
low	O
level	O
resistant	O
MRSA	B
,	O
we	O
performed	O
DNA	O
-	O
binding	O
protein	O
purification	O
assays	O
,	O
using	O
the	O
mecA	O
operator	O
region	O
as	O
bait	O
.	O

A	O
novel	O
,	O
uncharacterized	O
protein	O
,	O
SA1665	O
,	O
was	O
found	O
to	O
bind	O
to	O
this	O
DNA	O
fragment	O
,	O
and	O
shown	O
to	O
increase	O
methicillin	O
resistance	O
levels	O
when	O
deleted	O
.	O

Results	O

Identification	O
of	O
SA1665	O

MRSA	B
strain	O
CHE482	O
is	O
the	O
type	O
strain	O
for	O
the	O
so	O
-	O
called	O
"	O
drug	O
clone	O
"	O
spreading	O
amongst	O
intravenous	O
drug	O
users	O
in	O
the	O
Zurich	O
area	O
[	O
12	O
,	O
23	O
]	O
.	O

This	O
strain	O
carries	O
mecA	O
and	O
expresses	O
PBP2a	O
,	O
but	O
appears	O
phenotypically	O
methicillin	O
susceptible	O
by	O
conventional	O
phenotypic	O
tests	O
.	O

However	O
,	O
like	O
most	O
other	O
low	O
-	O
level	O
resistant	O
MRSA	B
,	O
it	O
can	O
segregate	O
a	O
small	O
proportion	O
of	O
higher	O
resistant	O
subclones	O
in	O
the	O
presence	O
of	O
beta	O
-	O
lactams	O
.	O

We	O
hypothesized	O
that	O
regulation	O
of	O
methicillin	O
resistance	O
in	O
such	O
low	O
-	O
level	O
resistant	O
clonal	O
lineages	O
may	O
differ	O
qualitatively	O
from	O
classical	O
heterogeneously	O
-	O
or	O
highly	O
-	O
resistant	O
MRSA	B
.	O

A	O
DNA	O
-	O
binding	O
protein	O
purification	O
assay	O
was	O
performed	O
to	O
identify	O
new	O
potential	O
factors	O
involved	O
in	O
the	O
regulation	O
of	O
mecA	O
/	O
PBP2a	O
.	O

The	O
mecA	O
/	O
mecR1	O
intergenic	O
DNA	O
region	O
,	O
including	O
the	O
5	O
'	O
9	O
bp	O
of	O
mecR1	O
and	O
the	O
first	O
52	O
bp	O
of	O
mecA	O
,	O
was	O
used	O
as	O
bait	O
against	O
crude	O
protein	O
extract	O
from	O
strain	O
CHE482	O
.	O

Proteins	O
binding	O
to	O
this	O
DNA	O
fragment	O
were	O
analysed	O
by	O
SDS	O
-	O
PAGE	O
.	O

Even	O
though	O
CHE482	O
contained	O
BlaI	O
,	O
which	O
is	O
known	O
to	O
bind	O
to	O
the	O
mec	O
operator	O
,	O
this	O
band	O
could	O
not	O
be	O
identified	O
on	O
gels	O
due	O
to	O
co	O
-	O
migrating	O
,	O
non	O
-	O
specific	O
bands	O
the	O
same	O
size	O
as	O
BlaI	O
(	O
14	O
.	O
9	O
KDa	O
)	O
that	O
bound	O
to	O
both	O
the	O
DNA	O
-	O
coated	O
and	O
uncoated	O
control	O
beads	O
.	O

The	O
most	O
prominent	O
protein	O
band	O
of	O
~	O
16	O
-	O
20	O
kDa	O
,	O
isolated	O
from	O
DNA	O
-	O
labelled	O
but	O
not	O
from	O
control	O
beads	O
,	O
was	O
identified	O
as	O
the	O
hypothetical	O
protein	O
SA1665	O
(	O
N315	O
genome	O
annotation	O
[	O
BA000018	O
]	O
)	O
(	O
Figure	O
1A	O
)	O
.	O

SA1665	O
encodes	O
a	O
predicted	O
17	O
-	O
kDa	O
protein	O
with	O
an	O
n	O
-	O
terminal	O
helix	O
-	O
turn	O
-	O
helix	O
(	O
HTH	O
)	O
motif	O
characteristic	O
of	O
DNA	O
-	O
binding	O
transcriptional	O
regulators	O
.	O

The	O
amino	O
acid	O
sequence	O
of	O
SA1665	O
showed	O
100	O
%	O
identity	O
amongst	O
S	B
.	I
aureus	I
database	O
sequences	O
and	O
97	O
-	O
98	O
%	O
identity	O
amongst	O
other	O
staphylococci	O
,	O
including	O
S	B
.	I
haemolyticus	I
,	O
S	B
.	I
epidermidis	I
and	O
S	B
.	I
saprophyticus	I
,	O
indicating	O
that	O
SA1665	O
is	O
highly	O
conserved	O
.	O

Conversely	O
,	O
there	O
were	O
no	O
orfs	O
highly	O
similar	O
to	O
SA1665	O
found	O
in	O
other	O
bacterial	O
species	O
,	O
with	O
the	O
most	O
similar	O
sequences	O
found	O
in	O
Bacillus	B
licheniformis	I
DSM13	O
and	O
Desulfitobacterium	B
hafniense	I
Y51	I
,	O
which	O
shared	O
only	O
64	O
%	O
and	O
59	O
%	O
similarity	O
,	O
respectively	O
.	O

Electro	O
mobility	O
shift	O
assays	O
(	O
EMSA	O
)	O

EMSA	O
was	O
used	O
to	O
confirm	O
binding	O
of	O
SA1665	O
to	O
the	O
mec	O
operator	O
region	O
.	O

Crude	O
protein	O
extracts	O
of	O
E	B
.	I
coli	I
strain	I
BL21	I
,	O
carrying	O
the	O
empty	O
plasmid	O
(	O
pET28nHis6	O
)	O
or	O
pME20	O
(	O
pET28nHis6	O
-	O
SA1665	O
)	O
which	O
expressed	O
nHis6	O
-	O
SA1665	O
upon	O
induction	O
with	O
IPTG	O
,	O
were	O
incubated	O
with	O
the	O
161	O
-	O
bp	O
biotinylated	O
-	O
DNA	O
fragment	O
previously	O
used	O
as	O
bait	O
in	O
the	O
DNA	O
-	O
binding	O
protein	O
assay	O
.	O

A	O
band	O
shift	O
was	O
observed	O
with	O
extracts	O
from	O
the	O
strain	O
expressing	O
recombinant	O
nHis6	O
-	O
SA1665	O
but	O
not	O
from	O
the	O
control	O
strain	O
carrying	O
the	O
empty	O
plasmid	O
.	O

Several	O
bands	O
resulted	O
from	O
the	O
shift	O
,	O
which	O
is	O
most	O
likely	O
due	O
to	O
protein	O
oligomerisation	O
(	O
Figure	O
2A	O
)	O
.	O

The	O
specificity	O
of	O
the	O
gel	O
shift	O
was	O
also	O
demonstrated	O
by	O
the	O
addition	O
of	O
increasing	O
concentrations	O
of	O
purified	O
nHis6	O
-	O
SA1665	O
protein	O
to	O
the	O
biotinylated	O
-	O
DNA	O
fragment	O
(	O
Figure	O
2B	O
)	O
.	O

Band	O
-	O
shift	O
of	O
the	O
biotinylated	O
DNA	O
was	O
inhibited	O
in	O
the	O
presence	O
of	O
specific	O
competitor	O
DNA	O
but	O
not	O
by	O
the	O
presence	O
of	O
the	O
non	O
-	O
specific	O
competitor	O
DNA	O
,	O
confirming	O
that	O
nHis6	O
-	O
SA1665	O
had	O
a	O
specific	O
binding	O
affinity	O
for	O
the	O
161	O
-	O
bp	O
DNA	O
fragment	O
.	O

Effect	O
of	O
SA1665	O
deletion	O
on	O
beta	O
-	O
lactam	O
resistance	O

To	O
analyse	O
the	O
effect	O
of	O
SA1665	O
inactivation	O
on	O
methicillin	O
resistance	O
,	O
nonpolar	O
markerless	O
deletions	O
of	O
SA1665	O
(	O
Figure	O
1B	O
)	O
were	O
constructed	O
in	O
a	O
selection	O
of	O
clinical	O
MRSA	B
isolates	O
,	O
which	O
varied	O
in	O
their	O
genetic	O
background	O
,	O
SCCmec	O
type	O
,	O
and	O
mecA	O
regulation	O
[	O
24	O
]	O
.	O

Strain	O
CHE482	O
,	O
belongs	O
to	O
clonal	O
complex	O
CC45	O
and	O
sequence	O
type	O
ST45	O
,	O
and	O
contains	O
a	O
novel	O
SCCmec	O
(	O
SCCmecN1	O
[	O
23	O
]	O
)	O
;	O
while	O
strains	O
ZH37	O
(	O
CC45	O
/	O
ST45	O
)	O
and	O
ZH73	O
(	O
CC22	O
/	O
ST22	O
)	O
contain	O
type	O
IV	O
SCCmecs	O
.	O

All	O
three	O
of	O
these	O
strains	O
have	O
truncated	O
mecI	O
/	O
mecR1	O
regulatory	O
loci	O
but	O
intact	O
BlaI	O
/	O
BlaR1	O
loci	O
controlling	O
mecA	O
expression	O
.	O

Strain	O
ZH44	O
(	O
CCT8	O
/	O
ST8	O
)	O
contained	O
a	O
type	O
A	O
mec	O
complex	O
(	O
mecI	O
-	O
mecR1	O
-	O
mecA	O
)	O
within	O
a	O
type	O
II	O
SCCmec	O
,	O
and	O
had	O
no	O
beta	O
-	O
lactamase	O
locus	O
;	O
so	O
mecA	O
was	O
only	O
under	O
the	O
control	O
of	O
its	O
cognate	O
regulators	O
MecI	O
/	O
MecR1	O
.	O

Deletion	O
of	O
SA1665	O
increased	O
oxacillin	O
resistance	O
in	O
all	O
mutants	O
compared	O
to	O
their	O
corresponding	O
parent	O
strains	O
,	O
as	O
demonstrated	O
on	O
oxacillin	O
gradient	O
plates	O
(	O
Figure	O
3A	O
)	O
;	O
with	O
mutants	O
Delta	O
CHE482	O
and	O
Delta	O
ZH37	O
approximately	O
doubling	O
in	O
resistance	O
and	O
Delta	O
ZH44	O
and	O
Delta	O
ZH73	O
expressing	O
considerably	O
higher	O
resistance	O
.	O

Population	O
analysis	O
resistance	O
profiles	O
of	O
the	O
mutants	O
showed	O
a	O
distinct	O
shift	O
at	O
the	O
top	O
of	O
the	O
curve	O
,	O
indicating	O
that	O
the	O
higher	O
resistance	O
was	O
due	O
to	O
increased	O
basal	O
oxacillin	O
resistance	O
levels	O
(	O
Figure	O
3B	O
)	O
.	O

Strains	O
CHE482	O
/	O
Delta	O
CHE482	O
and	O
ZH37	O
/	O
Delta	O
ZH37	O
had	O
very	O
similar	O
resistance	O
profiles	O
,	O
despite	O
having	O
different	O
SCCmec	O
elements	O
,	O
suggesting	O
that	O
it	O
was	O
their	O
common	O
clonal	O
background	O
(	O
CC45	O
)	O
that	O
determined	O
their	O
resistance	O
levels	O
and	O
the	O
extent	O
of	O
resistance	O
increase	O
upon	O
SA1665	O
deletion	O
.	O

Growth	O
curve	O
analyses	O
showed	O
that	O
deletion	O
of	O
SA1665	O
slightly	O
reduced	O
the	O
growth	O
rate	O
of	O
all	O
strains	O
tested	O
(	O
Figure	O
3C	O
)	O
.	O

Wild	O
type	O
growth	O
rates	O
were	O
restored	O
upon	O
complementation	O
(	O
data	O
not	O
shown	O
)	O
.	O

Resistance	O
complementation	O

Plasmids	O
pME26	O
and	O
pME27	O
were	O
constructed	O
for	O
complementation	O
of	O
the	O
deletion	O
mutants	O
.	O

Both	O
plasmids	O
contained	O
the	O
SA1665	O
orf	O
along	O
with	O
its	O
own	O
promoter	O
and	O
transcriptional	O
terminator	O
.	O

Strains	O
Delta	O
CHE482	O
,	O
Delta	O
ZH37	O
,	O
and	O
Delta	O
ZH73	O
were	O
complemented	O
with	O
pME26	O
,	O
and	O
intrinsically	O
kanamycin	O
resistant	O
strain	O
Delta	O
ZH44	O
was	O
complemented	O
with	O
pME27	O
.	O

Wild	O
type	O
-	O
like	O
resistance	O
levels	O
were	O
restored	O
in	O
all	O
mutants	O
by	O
introduction	O
of	O
the	O
complementing	O
plasmids	O
,	O
as	O
shown	O
by	O
gradient	O
plates	O
(	O
Figure	O
3A	O
)	O
.	O

Transcriptional	O
analyses	O

Primer	O
extension	O
,	O
using	O
the	O
5	O
'	O
-	O
biotinylated	O
primer	O
me97	O
,	O
identified	O
two	O
potential	O
SA1665	O
transcriptional	O
start	O
sites	O
(	O
TSS	O
)	O
,	O
76	O
-	O
nt	O
and	O
139	O
-	O
nt	O
upstream	O
of	O
the	O
SA1665	O
ATG	O
start	O
codon	O
(	O
Figure	O
4A	O
)	O
.	O

Predicted	O
sigma	O
A	O
promoter	O
consensus	O
-	O
10	O
/	O
-	O
35	O
box	O
sequences	O
were	O
located	O
upstream	O
of	O
both	O
TSS	O
(	O
Figure	O
4B	O
)	O
.	O

Identical	O
TSS	O
were	O
also	O
identified	O
using	O
the	O
downstream	O
primer	O
me98	O
(	O
data	O
not	O
shown	O
)	O
.	O

Northern	O
blot	O
analysis	O
was	O
used	O
to	O
investigate	O
SA1665	O
expression	O
and	O
the	O
influence	O
of	O
SA1665	O
deletion	O
on	O
mecA	O
and	O
mecR1	O
transcription	O
.	O

RNA	O
samples	O
taken	O
from	O
different	O
time	O
points	O
over	O
the	O
growth	O
curve	O
of	O
CHE482	O
showed	O
that	O
SA1665	O
was	O
expressed	O
strongly	O
in	O
early	O
exponential	O
phase	O
at	O
OD600	O
nm	O
0	O
.	O
25	O
and	O
0	O
.	O
5	O
,	O
then	O
transcript	O
levels	O
decreased	O
and	O
were	O
almost	O
undetectable	O
in	O
early	O
stationary	O
phase	O
at	O
OD600	O
nm	O
4	O
.	O
0	O
(	O
Figure	O
5A	O
)	O
.	O

In	O
addition	O
to	O
the	O
main	O
transcript	O
of	O
~	O
0	O
.	O
46	O
kb	O
,	O
a	O
weaker	O
,	O
larger	O
transcript	O
of	O
~	O
0	O
.	O
6	O
kb	O
was	O
also	O
visible	O
,	O
especially	O
at	O
later	O
growth	O
stages	O
.	O

Figure	O
5B	O
shows	O
the	O
transcriptional	O
behaviour	O
of	O
SA1665	O
when	O
CHE482	O
cells	O
were	O
challenged	O
with	O
sub	O
-	O
inhibitory	O
(	O
4	O
mu	O
g	O
/	O
ml	O
)	O
and	O
inhibitory	O
(	O
120	O
mu	O
g	O
/	O
ml	O
)	O
concentrations	O
of	O
cefoxitin	O
.	O

These	O
results	O
showed	O
that	O
low	O
levels	O
of	O
cefoxitin	O
,	O
such	O
as	O
those	O
used	O
to	O
induce	O
mecA	O
/	O
mecR1	O
transcription	O
,	O
appeared	O
to	O
slightly	O
decrease	O
SA1665	O
transcription	O
after	O
30	O
min	O
exposure	O
,	O
while	O
larger	O
,	O
inhibitory	O
concentrations	O
caused	O
even	O
more	O
significant	O
alterations	O
in	O
the	O
SA1665	O
transcriptional	O
profile	O
,	O
making	O
it	O
similar	O
to	O
that	O
normally	O
seen	O
in	O
stationary	O
phase	O
growth	O
.	O

These	O
results	O
indicate	O
that	O
transcription	O
of	O
SA1665	O
may	O
respond	O
in	O
some	O
way	O
to	O
cell	O
wall	O
stress	O
,	O
rather	O
than	O
in	O
direct	O
response	O
to	O
the	O
presence	O
of	O
beta	O
-	O
lactams	O
.	O

This	O
observation	O
is	O
based	O
on	O
relatively	O
subtle	O
changes	O
in	O
SA1665	O
transcription	O
,	O
especially	O
at	O
low	O
concentrations	O
of	O
cefoxitin	O
such	O
as	O
those	O
required	O
for	O
mecA	O
/	O
mecR1	O
induction	O
.	O

Since	O
deletion	O
of	O
SA1665	O
has	O
been	O
shown	O
to	O
increase	O
beta	O
-	O
lactam	O
resistance	O
,	O
reduced	O
SA1665	O
transcription	O
in	O
the	O
presence	O
of	O
beta	O
-	O
lactams	O
may	O
also	O
provide	O
some	O
protection	O
against	O
beta	O
-	O
lactam	O
exposure	O
.	O

Northerns	O
also	O
showed	O
that	O
,	O
as	O
expected	O
,	O
the	O
SA1665	O
transcripts	O
were	O
absent	O
from	O
the	O
deletion	O
mutant	O
(	O
Figure	O
5C	O
)	O
,	O
and	O
additional	O
experiments	O
demonstrated	O
that	O
wild	O
type	O
SA1665	O
transcription	O
patterns	O
were	O
restored	O
by	O
complementation	O
of	O
Delta	O
CHE482	O
with	O
pME26	O
(	O
data	O
not	O
shown	O
)	O
.	O

The	O
effects	O
of	O
SA1665	O
deletion	O
on	O
directly	O
up	O
-	O
and	O
down	O
-	O
stream	O
genes	O
were	O
also	O
investigated	O
.	O

Northern	O
blots	O
of	O
the	O
neighbouring	O
genes	O
SA1664	O
,	O
SA1666	O
and	O
SA1667	O
,	O
showed	O
that	O
expression	O
of	O
all	O
three	O
genes	O
was	O
very	O
weak	O
compared	O
to	O
that	O
of	O
SA1665	O
.	O

A	O
weak	O
transcript	O
of	O
about	O
3	O
kb	O
was	O
present	O
in	O
hybridizations	O
probed	O
with	O
orfs	O
SA1665	O
-	O
SA1667	O
.	O

This	O
band	O
decreased	O
in	O
size	O
in	O
the	O
SA1665	O
mutant	O
when	O
probed	O
with	O
SA1666	O
and	O
SA1667	O
.	O

One	O
of	O
the	O
transcripts	O
hybridising	O
to	O
the	O
SA1664	O
probe	O
also	O
decreased	O
in	O
size	O
by	O
~	O
0	O
.	O
5	O
kb	O
in	O
the	O
SA1665	O
mutant	O
,	O
suggesting	O
that	O
SA1665	O
was	O
present	O
on	O
several	O
transcripts	O
of	O
different	O
lengths	O
,	O
including	O
a	O
high	O
abundance	O
monocistronic	O
transcript	O
and	O
low	O
abundance	O
polycistronic	O
transcripts	O
(	O
Figure	O
5C	O
)	O
.	O

Transcript	O
abundance	O
of	O
both	O
the	O
upstream	O
SA1666	O
-	O
SA1667	O
operon	O
and	O
the	O
downstream	O
SA1664	O
-	O
specific	O
transcript	O
all	O
appeared	O
to	O
increase	O
slightly	O
in	O
Delta	O
CHE482	O
.	O

The	O
significance	O
of	O
these	O
subtle	O
increases	O
in	O
transcription	O
are	O
unknown	O
,	O
however	O
,	O
polar	O
effects	O
from	O
SA1665	O
deletion	O
seem	O
unlikely	O
,	O
based	O
on	O
the	O
facts	O
that	O
all	O
genes	O
were	O
still	O
transcribed	O
,	O
their	O
transcription	O
levels	O
all	O
remained	O
extremely	O
low	O
and	O
the	O
transcriptional	O
terminator	O
of	O
SA1665	O
remained	O
intact	O
in	O
the	O
deletion	O
mutant	O
(	O
Figure	O
1B	O
)	O
.	O

Expression	O
of	O
mecR1	O
and	O
mecA	O
were	O
analysed	O
from	O
RNA	O
of	O
uninduced	O
and	O
induced	O
cultures	O
of	O
CHE482	O
and	O
Delta	O
CHE482	O
.	O

Cells	O
were	O
induced	O
at	O
OD600	O
nm	O
0	O
.	O
25	O
(	O
Figure	O
5D	O
)	O
and	O
1	O
.	O
0	O
(	O
data	O
not	O
shown	O
)	O
with	O
sub	O
-	O
inhibitory	O
concentrations	O
of	O
cefoxitin	O
,	O
to	O
relieve	O
BlaI	O
-	O
repression	O
of	O
mecA	O
.	O

mecR1	O
,	O
although	O
truncated	O
in	O
CHE482	O
,	O
was	O
still	O
transcribed	O
and	O
had	O
the	O
same	O
expression	O
pattern	O
as	O
mecA	O
,	O
as	O
both	O
became	O
derepressed	O
over	O
time	O
and	O
had	O
the	O
highest	O
transcript	O
levels	O
after	O
30	O
min	O
of	O
induction	O
.	O

In	O
the	O
mutant	O
Delta	O
CHE482	O
,	O
transcripts	O
of	O
both	O
mecA	O
and	O
mecR1	O
'	O
were	O
unaffected	O
by	O
SA1665	O
deletion	O
,	O
indicating	O
that	O
SA1665	O
had	O
no	O
influence	O
on	O
their	O
expression	O
at	O
either	O
OD	O
0	O
.	O
25	O
(	O
Figure	O
5D	O
)	O
or	O
OD	O
1	O
.	O
0	O
(	O
data	O
not	O
shown	O
)	O
.	O

SA1665	O
deletion	O
also	O
had	O
no	O
effect	O
on	O
mecA	O
transcription	O
or	O
induction	O
in	O
strains	O
ZH37	O
,	O
ZH44	O
and	O
ZH73	O
(	O
data	O
not	O
shown	O
)	O
.	O

Western	O
blot	O
analysis	O

Mutants	O
of	O
CHE482	O
and	O
of	O
ZH44	O
and	O
ZH73	O
,	O
which	O
had	O
the	O
largest	O
differences	O
in	O
oxacillin	O
resistance	O
levels	O
,	O
were	O
analysed	O
by	O
Western	O
blot	O
analysis	O
to	O
determine	O
if	O
SA1665	O
affected	O
production	O
of	O
PBP2a	O
from	O
mecA	O
.	O

As	O
shown	O
in	O
Figure	O
5E	O
,	O
all	O
pairs	O
of	O
wild	O
type	O
and	O
mutant	O
strains	O
had	O
similar	O
amounts	O
of	O
PBP2a	O
present	O
both	O
before	O
and	O
after	O
induction	O
with	O
cefoxitin	O
,	O
indicating	O
that	O
SA1665	O
deletion	O
did	O
not	O
alter	O
amounts	O
of	O
PBP2a	O
produced	O
.	O

Therefore	O
it	O
seems	O
that	O
SA1665	O
exerts	O
no	O
direct	O
control	O
over	O
mecA	O
or	O
PBP2a	O
expression	O
.	O

Discussion	O

Methicillin	O
resistance	O
in	O
MRSA	B
is	O
primarily	O
dependent	O
on	O
the	O
presence	O
of	O
the	O
mecA	O
gene	O
,	O
however	O
,	O
resistance	O
levels	O
are	O
generally	O
governed	O
by	O
strain	O
-	O
specific	O
factors	O
including	O
mecA	O
regulatory	O
elements	O
and	O
other	O
chromosomal	O
fem	O
/	O
aux	O
factors	O
which	O
either	O
enhance	O
or	O
repress	O
the	O
expression	O
of	O
resistance	O
.	O

For	O
instance	O
,	O
the	O
very	O
low	O
-	O
level	O
methicillin	O
resistance	O
of	O
the	O
Zurich	O
drug	O
clone	O
CHE482	O
,	O
was	O
shown	O
to	O
be	O
controlled	O
by	O
its	O
genetic	O
background	O
[	O
12	O
]	O
suggesting	O
that	O
it	O
either	O
contained	O
or	O
lacked	O
certain	O
fem	O
/	O
aux	O
factors	O
involved	O
in	O
controlling	O
resistance	O
expression	O
.	O

Many	O
of	O
the	O
currently	O
known	O
fem	O
/	O
aux	O
factors	O
are	O
directly	O
or	O
indirectly	O
involved	O
in	O
cell	O
wall	O
synthesis	O
and	O
turnover	O
,	O
or	O
envelope	O
biogenesis	O
,	O
however	O
there	O
still	O
remain	O
factors	O
of	O
unknown	O
function	O
.	O

Most	O
of	O
the	O
currently	O
known	O
fem	O
/	O
aux	O
factors	O
reduce	O
methicillin	O
resistance	O
levels	O
when	O
inactivated	O
.	O

A	O
few	O
genes	O
,	O
such	O
as	O
lytH	O
,	O
dlt	O
,	O
norG	O
,	O
sarV	O
and	O
cidA	O
increase	O
resistance	O
levels	O
upon	O
inactivation	O
or	O
mutation	O
.	O

All	O
of	O
these	O
genes	O
,	O
except	O
norG	O
,	O
which	O
is	O
an	O
efflux	O
pump	O
regulator	O
,	O
play	O
a	O
role	O
in	O
either	O
autolysis	O
or	O
are	O
important	O
for	O
cell	O
physiology	O
and	O
growth	O
[	O
25	O
-	O
30	O
]	O
.	O

Other	O
genes	O
increase	O
beta	O
-	O
lactam	O
resistance	O
upon	O
overexpression	O
,	O
such	O
as	O
hmrA	O
coding	O
for	O
a	O
putative	O
amidohydrolase	O
,	O
hmrB	O
coding	O
for	O
a	O
putative	O
acyl	O
carrier	O
protein	O
[	O
31	O
]	O
,	O
or	O
the	O
NorG	O
-	O
controlled	O
abcA	O
multidrug	O
efflux	O
pump	O
[	O
28	O
]	O
.	O

SA1665	O
,	O
a	O
predicted	O
DNA	O
-	O
binding	O
transcriptional	O
regulator	O
,	O
was	O
found	O
to	O
bind	O
to	O
a	O
DNA	O
fragment	O
containing	O
the	O
mecA	O
promoter	O
region	O
.	O

However	O
,	O
although	O
this	O
protein	O
shifted	O
the	O
mecA	O
operator	O
/	O
5	O
'	O
coding	O
sequence	O
,	O
it	O
did	O
not	O
appear	O
to	O
directly	O
control	O
mecA	O
or	O
mecR1	O
transcription	O
or	O
PBP2a	O
production	O
.	O

Therefore	O
its	O
binding	O
to	O
the	O
mecA	O
region	O
may	O
have	O
no	O
specific	O
regulatory	O
function	O
.	O

Such	O
interactions	O
have	O
been	O
noted	O
before	O
,	O
such	O
as	O
the	O
HTH	O
protein	O
NorG	O
,	O
which	O
was	O
shown	O
to	O
bind	O
specifically	O
to	O
norA	O
,	O
norB	O
and	O
norC	O
promoters	O
,	O
but	O
only	O
transcription	O
of	O
norB	O
was	O
increased	O
when	O
NorG	O
was	O
overexpressed	O
[	O
28	O
]	O
.	O

We	O
have	O
to	O
postulate	O
therefore	O
that	O
SA1665	O
may	O
modulate	O
beta	O
-	O
lactam	O
resistance	O
in	O
a	O
mecA	O
-	O
independent	O
manner	O
,	O
by	O
controlling	O
cellular	O
functions	O
affecting	O
resistance	O
levels	O
.	O

Experiments	O
to	O
determine	O
the	O
SA1665	O
regulon	O
are	O
ongoing	O
.	O

The	O
impact	O
of	O
deleting	O
SA1665	O
in	O
MRSA	B
was	O
extremely	O
strain	O
specific	O
,	O
underlining	O
the	O
importance	O
of	O
the	O
genetic	O
background	O
in	O
governing	O
the	O
final	O
methicillin	O
resistance	O
levels	O
of	O
MRSA	B
,	O
and	O
demonstrating	O
the	O
large	O
genomic	O
variability	O
between	O
different	O
strain	O
lineages	O
.	O

Conclusion	O

SA1665	O
is	O
a	O
previously	O
uncharacterised	O
DNA	O
-	O
binding	O
protein	O
that	O
has	O
a	O
negative	O
effect	O
on	O
beta	O
-	O
lactam	O
resistance	O
in	O
MRSA	B
.	O

The	O
SA1665	O
protein	O
was	O
identified	O
in	O
a	O
DNA	O
-	O
binding	O
protein	O
purification	O
assay	O
,	O
in	O
which	O
it	O
bound	O
to	O
a	O
DNA	O
fragment	O
covering	O
the	O
mec	O
operator	O
region	O
.	O

However	O
,	O
while	O
nonpolar	O
deletion	O
of	O
SA1665	O
was	O
shown	O
to	O
increase	O
oxacillin	O
resistance	O
levels	O
in	O
several	O
heterogeneously	O
resistant	O
MRSA	B
,	O
its	O
deletion	O
had	O
no	O
effect	O
on	O
mecA	O
transcription	O
or	O
PBP2a	O
production	O
.	O

Therefore	O
the	O
negative	O
impact	O
of	O
SA1665	O
on	O
methicillin	O
resistance	O
is	O
most	O
likely	O
to	O
be	O
through	O
the	O
regulation	O
of	O
other	O
chromosomal	O
factors	O
or	O
cellular	O
functions	O
required	O
for	O
methicllin	O
resistance	O
.	O

Methods	O

Strains	O
and	O
growth	O
conditions	O

Strains	O
and	O
plasmids	O
used	O
in	O
this	O
study	O
are	O
listed	O
in	O
Table	O
1	O
.	O

Clinical	O
isolates	O
are	O
from	O
the	O
IMM	O
collection	O
in	O
Zurich	O
,	O
Switzerland	O
.	O

Strains	O
were	O
grown	O
at	O
37	O
degrees	O
C	O
in	O
Luria	O
Bertani	O
(	O
LB	O
)	O
broth	O
,	O
shaking	O
at	O
180	O
rpm	O
,	O
or	O
on	O
LB	O
agar	O
.	O

Media	O
were	O
supplemented	O
with	O
the	O
following	O
antibiotics	O
when	O
appropriate	O
:	O
25	O
or	O
50	O
mu	O
g	O
/	O
ml	O
kanamycin	O
,	O
10	O
mu	O
g	O
/	O
ml	O
chloramphenicol	O
,	O
5	O
or	O
10	O
mu	O
g	O
/	O
ml	O
tetracycline	O
,	O
100	O
mu	O
g	O
/	O
ml	O
ampicillin	O
.	O

Concentrations	O
of	O
cefoxitin	O
used	O
for	O
transcriptional	O
induction	O
were	O
either	O
sub	O
-	O
inhibitory	O
(	O
4	O
mu	O
g	O
/	O
ml	O
)	O
or	O
inhibitory	O
(	O
120	O
mu	O
g	O
/	O
ml	O
)	O
.	O

Susceptibility	O
testing	O

Oxacillin	O
resistance	O
levels	O
were	O
compared	O
by	O
swabbing	O
0	O
.	O
5	O
McFarland	O
cell	O
suspensions	O
across	O
agar	O
plates	O
containing	O
appropriate	O
concentration	O
gradients	O
of	O
oxacillin	O
.	O

For	O
population	O
analysis	O
profiles	O
,	O
appropriate	O
dilutions	O
of	O
an	O
overnight	O
culture	O
,	O
ranging	O
from	O
100	O
to	O
108	O
,	O
were	O
plated	O
on	O
increasing	O
concentrations	O
of	O
oxacillin	O
.	O

Plates	O
were	O
incubated	O
at	O
35	O
degrees	O
C	O
and	O
colony	O
forming	O
units	O
per	O
ml	O
(	O
cfu	O
/	O
ml	O
)	O
were	O
determined	O
after	O
48	O
h	O
.	O

Binding	O
-	O
protein	O
purification	O

Crude	O
protein	O
extracts	O
were	O
isolated	O
from	O
CHE482	O
,	O
grown	O
under	O
normal	O
culture	O
conditions	O
until	O
OD600	O
nm	O
1	O
.	O
5	O
.	O

Cells	O
were	O
harvested	O
,	O
resuspended	O
in	O
PBS	O
(	O
pH	O
7	O
.	O
4	O
)	O
and	O
mechanically	O
lysed	O
using	O
Lysing	O
Matrix	O
B	O
(	O
BIO	O
101	O
Systems	O
)	O
tubes	O
and	O
a	O
FastPrep	O
FP120	O
(	O
BIO	O
101	O
Systems	O
)	O
.	O

Suspensions	O
were	O
clarified	O
by	O
centrifugation	O
and	O
supernatants	O
,	O
containing	O
soluble	O
cytoplasmic	O
proteins	O
,	O
were	O
transferred	O
to	O
Amicon	O
Ultra	O
centrifugal	O
filter	O
devices	O
(	O
Millipore	O
)	O
with	O
a	O
pore	O
cut	O
-	O
off	O
size	O
of	O
10	O
kDa	O
.	O

Proteins	O
were	O
then	O
washed	O
and	O
concentrated	O
in	O
1	O
x	O
binding	O
buffer	O
(	O
10	O
mM	O
Tris	O
-	O
HCl	O
,	O
pH	O
7	O
.	O
5	O
,	O
1	O
mM	O
EDTA	O
,	O
and	O
1	O
mM	O
DTT	O
,	O
0	O
.	O
5	O
M	O
NaCl	O
)	O
.	O

Protein	O
concentrations	O
were	O
measured	O
by	O
Bradford	O
assay	O
(	O
BioRad	O
Laboratories	O
GmbH	O
)	O
[	O
32	O
]	O
.	O

Primer	O
pair	O
me36F	O
/	O
me36Rbiot	O
(	O
Table	O
2	O
)	O
were	O
used	O
to	O
amplify	O
a	O
biotinylated	O
mecA	O
promoter	O
/	O
operator	O
fragment	O
,	O
which	O
was	O
bound	O
to	O
streptavidin	O
coated	O
magnetic	O
beads	O
(	O
Dynabeads	O
M	O
-	O
280	O
Streptavidin	O
,	O
DYNAL	O
BIOTECH	O
)	O
according	O
to	O
the	O
manufacturer	O
'	O
s	O
instructions	O
.	O

Binding	O
reactions	O
,	O
containing	O
DNA	O
-	O
coated	O
beads	O
mixed	O
with	O
100	O
mu	O
g	O
of	O
crude	O
protein	O
extract	O
in	O
1	O
x	O
protein	O
binding	O
buffer	O
(	O
20	O
mM	O
Hepes	O
,	O
pH	O
7	O
.	O
6	O
,	O
1	O
mM	O
EDTA	O
,	O
10	O
mM	O
(	O
NH4	O
)	O
2SO4	O
,	O
1	O
mM	O
DTT	O
,	O
0	O
.	O
2	O
%	O
Tween	O
20	O
(	O
w	O
/	O
v	O
)	O
,	O
30	O
mM	O
KCl	O
)	O
,	O
0	O
.	O
02	O
mu	O
g	O
/	O
mu	O
l	O
poly	O
d	O
(	O
I	O
-	O
C	O
)	O
and	O
2	O
ng	O
/	O
mu	O
l	O
poly	O
L	O
-	O
lysine	O
,	O
were	O
incubated	O
at	O
room	O
temperature	O
for	O
30	O
min	O
with	O
constant	O
rotation	O
.	O

Beads	O
were	O
then	O
washed	O
and	O
binding	O
-	O
proteins	O
eluted	O
in	O
elution	O
buffer	O
(	O
1	O
x	O
protein	O
binding	O
buffer	O
containing	O
2	O
M	O
KCl	O
)	O
.	O

Eluted	O
proteins	O
were	O
dialysed	O
against	O
water	O
,	O
concentrated	O
by	O
evaporation	O
,	O
and	O
run	O
on	O
15	O
%	O
SDS	O
polyacrylamide	O
gels	O
.	O

Gels	O
were	O
silver	O
stained	O
using	O
the	O
Protein	O
Silver	O
Staining	O
kit	O
(	O
Amersham	O
Biosciences	O
AB	O
)	O
without	O
the	O
addition	O
of	O
glutaraldehyde	O
.	O

Protein	O
bands	O
were	O
excised	O
from	O
gels	O
and	O
analysed	O
by	O
mass	O
spectrometry	O
(	O
LC	O
/	O
ESI	O
/	O
MS	O
/	O
MS	O
)	O
at	O
the	O
Functional	O
Genomics	O
Centre	O
,	O
Zurich	O
.	O

The	O
SA1665	O
protein	O
sequence	O
[	O
BAB42933	O
]	O
was	O
analysed	O
by	O
Blast	O
search	O
and	O
motif	O
scan	O
.	O

Expression	O
of	O
recombinant	O
SA1665	O
protein	O

SA1665	O
was	O
amplified	O
using	O
primer	O
pair	O
me65BamHI	O
/	O
me65XhoI	O
(	O
Table	O
2	O
)	O
and	O
cloned	O
in	O
-	O
frame	O
into	O
pET28nHis6	O
(	O
unpublished	O
,	O
D	O
.	O
Frey	O
)	O
.	O

The	O
resulting	O
plasmid	O
,	O
pME20	O
,	O
was	O
transformed	O
into	O
E	B
.	I
coli	I
BL21	I
for	O
expression	O
of	O
recombinant	O
nHis6	O
-	O
SA1665	O
protein	O
.	O

To	O
maximise	O
the	O
abundance	O
of	O
soluble	O
protein	O
produced	O
,	O
cultures	O
were	O
grown	O
in	O
osmotic	O
shock	O
medium	O
at	O
37	O
degrees	O
C	O
(	O
1	O
g	O
/	O
l	O
NaCl	O
,	O
16	O
g	O
/	O
l	O
tryptone	O
,	O
10	O
g	O
/	O
l	O
yeast	B
,	O
1	O
M	O
sorbitol	O
,	O
10	O
mM	O
betaine	O
,	O
modified	O
from	O
[	O
33	O
]	O
)	O
to	O
an	O
OD600	O
nm	O
of	O
0	O
.	O
5	O
,	O
cooled	O
briefly	O
on	O
ice	O
,	O
then	O
induced	O
by	O
adding	O
100	O
mu	O
M	O
IPTG	O
and	O
growing	O
overnight	O
at	O
22	O
degrees	O
C	O
.	O

Crude	O
soluble	O
proteins	O
were	O
extracted	O
using	O
CelLyticB	O
2	O
x	O
cell	O
lysis	O
reagent	O
(	O
SIGMA	O
)	O
.	O

HIS	O
-	O
Select	O
Cobalt	O
Affinity	O
Gel	O
(	O
SIGMA	O
)	O
was	O
used	O
to	O
purify	O
recombinant	O
nHis6	O
-	O
SA1665	O
according	O
to	O
the	O
manufacturer	O
'	O
s	O
instructions	O
.	O

Electro	O
mobility	O
shift	O
assay	O

For	O
gel	O
shift	O
assays	O
,	O
6	O
ng	O
aliquots	O
of	O
the	O
biotinylated	O
-	O
DNA	O
fragment	O
used	O
for	O
binding	O
-	O
protein	O
purification	O
were	O
incubated	O
with	O
0	O
-	O
250	O
ng	O
of	O
purified	O
nHis6	O
-	O
SA1665	O
protein	O
in	O
1	O
x	O
binding	O
buffer	O
(	O
20	O
mM	O
Hepes	O
pH	O
7	O
.	O
6	O
,	O
1	O
mM	O
EDTA	O
,	O
10	O
mM	O
(	O
NH4	O
)	O
2SO4	O
,	O
1	O
mM	O
DTT	O
,	O
0	O
.	O
2	O
%	O
Tween	O
20	O
(	O
w	O
/	O
v	O
)	O
,	O
30	O
mM	O
KCl	O
)	O
containing	O
0	O
.	O
05	O
mu	O
g	O
/	O
mu	O
l	O
poly	O
d	O
(	O
I	O
-	O
C	O
)	O
(	O
Roche	O
)	O
and	O
5	O
ng	O
/	O
mu	O
l	O
poly	O
L	O
-	O
lysine	O
(	O
Roche	O
)	O
.	O

For	O
control	O
binding	O
reactions	O
,	O
130	O
x	O
unlabelled	O
mec	O
operator	O
DNA	O
(	O
amplified	O
using	O
primers	O
me36F	O
/	O
me36R	O
,	O
Table	O
2	O
)	O
was	O
used	O
as	O
a	O
specific	O
binding	O
competitor	O
and	O
6	O
ng	O
of	O
herring	O
sperm	O
DNA	O
was	O
used	O
as	O
unspecific	O
competitor	O
DNA	O
.	O

Binding	O
was	O
carried	O
out	O
at	O
22	O
degrees	O
C	O
for	O
30	O
min	O
.	O

Samples	O
were	O
run	O
on	O
6	O
%	O
native	O
polyacrylamide	O
gels	O
,	O
contact	O
blotted	O
onto	O
positively	O
charged	O
nylon	O
membrane	O
and	O
detected	O
with	O
the	O
Biotin	O
Chromogenic	O
Detection	O
Kit	O
(	O
Fermentas	O
)	O
.	O

Primer	O
extension	O

RNA	O
was	O
extracted	O
from	O
CHE482	O
cultures	O
that	O
were	O
grown	O
to	O
OD600	O
nm	O
0	O
.	O
5	O
,	O
as	O
previously	O
described	O
[	O
12	O
]	O
.	O

Primer	O
extension	O
reactions	O
were	O
performed	O
using	O
20	O
mu	O
g	O
of	O
total	O
RNA	O
and	O
3	O
pmol	O
of	O
the	O
5	O
'	O
-	O
biotin	O
-	O
labelled	O
primers	O
me97	O
and	O
me98	O
(	O
Table	O
2	O
)	O
using	O
Superscript	O
II	O
reverse	O
transcriptase	O
(	O
Invitrogen	O
)	O
,	O
according	O
to	O
the	O
manufacturers	O
instructions	O
.	O

Sequencing	O
reactions	O
were	O
performed	O
using	O
the	O
Thermo	O
Sequenase	O
cycle	O
sequencing	O
kit	O
(	O
U	O
.	O
S	O
.	O
Biochemicals	O
)	O
.	O

The	O
Biotin	O
Chromogenic	O
Detection	O
Kit	O
(	O
Fermentas	O
)	O
was	O
used	O
for	O
biotin	O
detection	O
.	O

Markerless	O
deletion	O
of	O
SA1665	O

In	O
frame	O
markerless	O
deletions	O
of	O
SA1665	O
,	O
from	O
the	O
chromosomes	O
of	O
CHE482	O
,	O
ZH37	O
,	O
ZH44	O
,	O
and	O
ZH73	O
,	O
were	O
constructed	O
using	O
the	O
pKOR1	O
allelic	O
replacement	O
system	O
,	O
as	O
described	O
by	O
Bae	O
et	O
al	O
.	O

[	O
34	O
]	O
.	O

Primer	O
pairs	O
used	O
to	O
amplify	O
the	O
DNA	O
fragments	O
flanking	O
SA1665	O
,	O
for	O
recombination	O
into	O
pKOR1	O
were	O
:	O
me62attB1	O
/	O
me51BamHI	O
and	O
me62BamHI	O
/	O
me62attB2	O
(	O
Table	O
2	O
)	O
.	O

All	O
deletion	O
mutants	O
were	O
confirmed	O
by	O
nucleotide	O
sequencing	O
over	O
the	O
deleted	O
region	O
,	O
as	O
well	O
as	O
by	O
Southern	O
blot	O
analysis	O
[	O
35	O
]	O
and	O
pulsed	O
field	O
gel	O
electrophoresis	O
(	O
PFGE	O
)	O
[	O
36	O
]	O
.	O

Cloning	O
of	O
SA1665	O
for	O
complementation	O

A	O
1533	O
-	O
bp	O
DNA	O
fragment	O
,	O
containing	O
SA1665	O
together	O
with	O
690	O
-	O
bp	O
of	O
upstream	O
and	O
379	O
-	O
bp	O
of	O
downstream	O
DNA	O
,	O
was	O
amplified	O
from	O
strain	O
CHE482	O
using	O
primers	O
me94BamHI	O
/	O
me94Asp718	O
(	O
Table	O
2	O
)	O
and	O
cloned	O
into	O
the	O
E	B
.	I
coli	I
/	O
S	B
.	I
aureus	I
shuttle	O
vectors	O
pAW17	O
and	O
pBUS1	O
[	O
37	O
]	O
,	O
creating	O
the	O
complementing	O
plasmids	O
pME26	O
and	O
pME27	O
,	O
respectively	O
.	O

Plasmids	O
were	O
electroporated	O
into	O
RN4220	O
[	O
38	O
]	O
and	O
then	O
transduced	O
into	O
different	O
strains	O
using	O
phage	O
80	O
alpha	O
.	O

Northern	O
blot	O
analysis	O

Strains	O
were	O
grown	O
overnight	O
in	O
LB	O
(	O
Difco	O
)	O
,	O
diluted	O
1	O
:	O
200	O
and	O
grown	O
for	O
another	O
3	O
h	O
.	O

This	O
preculture	O
was	O
used	O
to	O
inoculate	O
150	O
ml	O
(	O
1	O
:	O
1000	O
)	O
of	O
fresh	O
prewarmed	O
LB	O
.	O

Cells	O
were	O
then	O
grown	O
to	O
OD600	O
nm	O
0	O
.	O
25	O
or	O
1	O
.	O
0	O
and	O
either	O
left	O
uninduced	O
or	O
induced	O
with	O
cefoxitin	O
4	O
or	O
120	O
mu	O
g	O
/	O
ml	O
.	O

Cultures	O
were	O
sampled	O
from	O
both	O
uninduced	O
and	O
induced	O
cells	O
at	O
time	O
point	O
0	O
'	O
before	O
induction	O
and	O
at	O
10	O
'	O
and	O
30	O
'	O
(	O
min	O
)	O
after	O
induction	O
.	O

To	O
monitor	O
SA1665	O
expression	O
over	O
growth	O
,	O
separate	O
cultures	O
were	O
also	O
sampled	O
at	O
different	O
growth	O
stages	O
corresponding	O
to	O
OD600	O
nm	O
0	O
.	O
25	O
,	O
0	O
.	O
5	O
,	O
1	O
,	O
2	O
,	O
and	O
4	O
.	O

Total	O
RNA	O
was	O
extracted	O
as	O
described	O
by	O
Cheung	O
et	O
al	O
.	O

[	O
39	O
]	O
.	O

RNA	O
samples	O
(	O
10	O
mu	O
g	O
)	O
were	O
separated	O
in	O
a	O
1	O
.	O
5	O
%	O
agarose	O
-	O
20	O
mM	O
guanidine	O
thiocyanate	O
gel	O
in	O
1	O
x	O
TBE	O
running	O
buffer	O
[	O
40	O
]	O
,	O
then	O
transferred	O
and	O
detected	O
as	O
described	O
previously	O
[	O
41	O
]	O
.	O

Digoxigenin	O
(	O
DIG	O
)	O
labelled	O
-	O
probes	O
were	O
amplified	O
using	O
the	O
PCR	O
DIG	O
Probe	O
synthesis	O
kit	O
(	O
Roche	O
)	O
.	O

Table	O
2	O
contains	O
the	O
list	O
of	O
primer	O
pairs	O
used	O
for	O
the	O
amplification	O
of	O
SA1664	O
,	O
SA1665	O
,	O
SA1666	O
,	O
SA1667	O
,	O
mecR1	O
and	O
mecA	O
[	O
42	O
]	O
probes	O
.	O

All	O
Northern	O
'	O
s	O
were	O
repeated	O
at	O
least	O
two	O
times	O
,	O
using	O
independently	O
isolated	O
RNA	O
samples	O
.	O

Western	O
blot	O
analysis	O

Cells	O
were	O
cultured	O
,	O
as	O
described	O
for	O
Northern	O
blot	O
analysis	O
,	O
to	O
OD600	O
nm	O
1	O
.	O
0	O
,	O
then	O
induced	O
with	O
cefoxitin	O
4	O
mu	O
g	O
/	O
ml	O
.	O

Samples	O
were	O
collected	O
at	O
time	O
0	O
(	O
before	O
induction	O
)	O
,	O
10	O
and	O
30	O
min	O
(	O
after	O
induction	O
)	O
.	O

Cells	O
were	O
harvested	O
by	O
centrifugation	O
,	O
resuspended	O
in	O
PBS	O
pH	O
7	O
.	O
4	O
containing	O
DNase	O
,	O
lysostaphin	O
and	O
lysozyme	O
(	O
150	O
mu	O
g	O
/	O
ml	O
of	O
each	O
)	O
and	O
incubated	O
for	O
1	O
h	O
at	O
37	O
degrees	O
C	O
.	O

Suspensions	O
were	O
then	O
sonicated	O
and	O
protein	O
aliquots	O
(	O
15	O
mu	O
g	O
)	O
were	O
separated	O
on	O
7	O
.	O
5	O
%	O
SDS	O
-	O
polyacrylamide	O
gels	O
,	O
blotted	O
onto	O
nitrocellulose	O
membranes	O
(	O
Hybond	O
)	O
and	O
stained	O
with	O
Ponceau	O
to	O
confirm	O
equal	O
protein	O
loading	O
.	O

PBP2a	O
detection	O
was	O
performed	O
using	O
monoclonal	O
PBP2a	O
antibody	O
(	O
1	O
:	O
20000	O
)	O
from	O
the	O
MRSA	B
-	O
screen	O
kit	O
(	O
Denka	O
Seiken	O
)	O
.	O

Authors	O
'	O
contributions	O

ME	O
carried	O
out	O
molecular	O
genetic	O
and	O
microbiological	O
studies	O
and	O
drafted	O
the	O
manuscript	O
.	O

BB	O
participated	O
in	O
the	O
design	O
of	O
the	O
study	O
and	O
helped	O
to	O
draft	O
the	O
manuscript	O
.	O

NM	O
participated	O
in	O
the	O
design	O
and	O
coordination	O
of	O
the	O
study	O
,	O
carried	O
out	O
molecular	O
biological	O
studies	O
and	O
helped	O
to	O
draft	O
the	O
manuscript	O
.	O

All	O
authors	O
read	O
and	O
approved	O
the	O
final	O
manuscript	O
.	O

Organization	O
and	O
structure	O
of	O
the	O
mouse	B
interleukin	O
-	O
2	O
gene	O
.	O

Abstract	O

We	O
have	O
cloned	O
a	O
chromosomal	O
DNA	O
segment	O
which	O
covers	O
the	O
entire	O
sequence	O
for	O
the	O
murine	B
interleukin	O
-	O
2	O
gene	O
and	O
analysed	O
the	O
structure	O
of	O
the	O
gene	O
.	O

The	O
coding	O
regions	O
are	O
separated	O
into	O
four	O
blocks	O
by	O
three	O
introns	O
each	O
of	O
which	O
is	O
located	O
similarly	O
to	O
the	O
corresponding	O
human	B
gene	O
.	O

The	O
exon	O
sequences	O
can	O
be	O
aligned	O
perfectly	O
with	O
the	O
previously	O
cloned	O
cDNA	O
sequence	O
.	O

Of	O
particular	O
interests	O
is	O
the	O
presence	O
of	O
sequences	O
within	O
the	O
5	O
'	O
-	O
flanking	O
region	O
which	O
are	O
highly	O
conserved	O
between	O
mouse	B
and	O
man	B
.	O

The	O
conserved	O
region	O
which	O
spans	O
more	O
than	O
400	O
base	O
pairs	O
may	O
play	O
a	O
role	O
in	O
the	O
regulation	O
of	O
IL	O
-	O
2	O
gene	O
expression	O
.	O
Images	O

Volume	O
12	O
Number	O
24	O
1984	O
Nucleic	O
Acids	O
Research	O

Organization	O
and	O
structure	O
of	O
the	O
mouse	B
interleukin	O
-	O
2	O
gene	O

Akira	O
Fuse	O
*	O
,	O
Takashi	O
Fujita	O
,	O
Hidetaro	O
Yasumitsu	O
,	O
Nobukazu	O
Kashima	O
+	O
,	O
Katsushige	O
Hasegawa	O
and	O
Tadatsugu	O
Taniguchi	O
?	O

Department	O
of	O
Biochemistry	O
,	O
Cancer	O
Institute	O
,	O
Japanese	O
Foundation	O
for	O
Cancer	O
Research	O
,	O
Toshimaku	O
,	O
Tokyo	O
170	O
and	O
Institute	O
for	O
Molecular	O
and	O
Cellular	O
Biology	O
,	O
Osaka	O
University	O
,	O
Suita	O
-	O
shi	O
,	O
Osaka	O
565	O
,	O
Japan	O

Received	O
10	O
October	O
1984	O
;	O
Revised	O
and	O
Accepted	O
20	O
November	O
1984	O

ABSTRACT	O

We	O
have	O
cloned	O
a	O
chromosomal	O
DNA	O
segment	O
which	O
covers	O
the	O
entire	O
sequence	O
for	O
the	O
murine	B
interleukin	O
-	O
2	O
gene	O
and	O
analysed	O
the	O
structure	O
of	O
the	O
gene	O
.	O

The	O
coding	O
regions	O
are	O
separated	O
into	O
four	O
blocks	O
by	O
three	O
introns	O
each	O
of	O
which	O
is	O
located	O
similarly	O
to	O
the	O
corresponding	O
human	B
gene	O
.	O

The	O
exon	O
sequences	O
can	O
be	O
aligned	O
perfectly	O
with	O
the	O
previously	O
cloned	O
cDNA	O
sequence	O
.	O

Of	O
particular	O
interests	O
is	O
the	O
presence	O
of	O
sequences	O
within	O
the	O
5	O
'	O
flanking	O
region	O
which	O
are	O
highly	O
conserved	O
between	O
mouse	B
and	O
man	B
.	O

The	O
conserved	O
region	O
which	O
spans	O
more	O
than	O
400	O
base	O
pairs	O
may	O
play	O
a	O
role	O
in	O
the	O
regulation	O
of	O
IL	O
-	O
2	O
gene	O
expression	O
.	O

INTRODUCTION	O

Interleukin	O
-	O
2	O
(	O
IL	O
-	O
2	O
)	O
is	O
a	O
lymphokine	O
produced	O
by	O
T	O
cells	O
upon	O
antigenic	O
or	O
mitogenic	O
stimulation	O
and	O
is	O
required	O
for	O
the	O
proliferation	O
of	O
T	O
cells	O
(	O
1	O
,	O
2	O
)	O
.	O

Several	O
other	O
biological	O
activities	O
of	O
IL	O
-	O
2	O
which	O
appear	O
to	O
be	O
crucial	O
in	O
the	O
immune	O
regulation	O
have	O
also	O
been	O
reported	O
(	O
3	O
,	O
4	O
.	O
5	O
.	O
6	O
.	O
7	O
.	O
)	O
.	O

We	O
previously	O
reported	O
isolation	O
and	O
sequence	O
analysis	O
of	O
the	O
cDNA	O
for	O
human	B
IL	O
-	O
2	O
(	O
8	O
)	O
,	O
as	O
well	O
as	O
the	O
chromosomal	O
gene	O
(	O
9	O
)	O
.	O

More	O
recently	O
,	O
we	O
have	O
isolated	O
a	O
cDNA	O
which	O
encodes	O
murine	B
IL	O
-	O
2	O
(	O
Kashima	O
et	O
al	O
.	O
,	O
submitted	O
for	O
publication	O
)	O
.	O

The	O
cDNA	O
contains	O
a	O
unique	O
tandem	O
repeat	O
of	O
CAG	O
sequence	O
which	O
would	O
encode	O
12	O
consecutive	O
glutamine	O
residues	O
in	O
the	O
active	O
IL	O
-	O
2	O
molecule	O
.	O

In	O
order	O
to	O
study	O
the	O
structure	O
of	O
the	O
murine	B
IL	O
-	O
2	O
chromosomal	O
gene	O
and	O
its	O
controlling	O
region	O
,	O
we	O
isolated	O
and	O
analysed	O
a	O
A	O
phage	O
clone	O
containing	O
the	O
gene	O
and	O
its	O
flanking	O
sequences	O
.	O

MATERIALS	O
AND	O
METHODS	O

Southern	O
blotting	O
of	O
total	O
mouse	B
DNA	O

Mouse	B
chromosomal	O
DNA	O
was	O
extracted	O
from	O
liver	O
of	O
BALB	O
/	O
c6	O

?	O
I	O
R	O
L	O
Press	O
Limited	O
,	O
Oxford	O
,	O
England	O
.	O

Nucleic	O
Acids	O
Research	O

Volume	O
12	O
Number	O
24	O
1984	O

9323	O

Nucleic	O
Acids	O
Research	O

mouse	B
as	O
described	O
before	O
(	O
10	O
)	O
.	O

High	O
molecular	O
genomic	O
DNA	O
was	O
digested	O
with	O
various	O
restriction	O
enzymes	O
and	O
electrophoresed	O
on	O
0	O
.	O
8	O
%	O
agarose	O
gel	O
.	O

Blotting	O
analysis	O
of	O
DNA	O
was	O
carried	O
out	O
by	O
the	O
method	O
of	O
Southern	O
(	O
11	O
)	O
.	O

Hybridization	O
was	O
carried	O
out	O
as	O
described	O
previously	O
and	O
filters	O
were	O
washed	O
either	O
in	O
3	O
x	O
SSC	O
at	O
650C	O
(	O
lower	O
stringent	O
condition	O
)	O
or	O
in	O
0	O
.	O
1	O
x	O
SSC	O
at	O
650C	O
(	O
higher	O
stringent	O
condition	O
)	O
.	O

Screening	O
of	O
genomic	O
DNA	O
library	O

A	O
bacteriophage	O
XCharon	O
4A	O
/	O
mouse	B
genomic	O
DNA	O
library	O
prepared	O
with	O
partial	O
EcoRI	O
digests	O
of	O
mouse	B
DNA	O
from	O
MPC	O
11	O
plasmacytoma	O
cells	O
was	O
kindly	O
provided	O
by	O
Dr	O
.	O
T	O
.	O

Honjo	O
.	O

Mouse	B
IL	O
-	O
2	O
-	O
specific	O
clones	O
were	O
screened	O
by	O
the	O
method	O
of	O
Benton	O
and	O
Davis	O
(	O
12	O
)	O
,	O
using	O
700	O
bp	O
PstI	O
-	O
AccI	O
fragment	O
of	O
a	O
cDNA	O
clone	O
,	O
pMIL2	O
-	O
45	O
as	O
the	O
probe	O
(	O
Kashima	O
et	O
al	O
.	O
,	O
submitted	O
for	O
publication	O
)	O
.	O

Hybridization	O
was	O
performed	O
as	O
described	O
previously	O
(	O
13	O
)	O
.	O

Positive	O
clones	O
were	O
rescreened	O
at	O
least	O
twice	O
.	O

Subcloninq	O
and	O
sequencing	O
of	O
the	O
mouse	B
IL	O
-	O
2	O
gene	O

Two	O
EcoRI	O
fragments	O
of	O
3	O
.	O
3	O
Kbp	O
and	O
2	O
.	O
8	O
Kbp	O
from	O
the	O
positive	O
recombinant	O
X	O
phage	O
were	O
subcloned	O
into	O
EcoRI	O
site	O
of	O
plasmid	O
pBR322	O
.	O

DNA	O
segments	O
derived	O
from	O
subcloned	O
3	O
.	O
3	O
Kbp	O
and	O
2	O
.	O
8	O
Kbp	O
fragments	O
were	O
labelled	O
at	O
either	O
3	O
'	O
end	O
or	O
5	O
'	O
end	O
,	O
and	O
subjected	O
to	O
sequence	O
analysis	O
by	O
the	O
chemical	O
degradation	O
method	O
(	O
14	O
)	O
.	O

The	O
0	O
.	O
8	O
Kbp	O
EcoRI	O
fragment	O
from	O
the	O
same	O
X	O
phage	O
clone	O
was	O
directly	O
subjected	O
to	O
sequence	O
analysis	O
by	O
the	O
dideoxy	O
chain	O
termination	O
method	O
(	O
15	O
)	O
.	O

RESULTS	O

Total	O
DNA	O
blotting	O
analysis	O

In	O
order	O
to	O
study	O
structural	O
organization	O
of	O
the	O
mouse	B
IL	O
-	O
2	O
gene	O
,	O
we	O
first	O
subjected	O
total	O
mouse	B
DNA	O
to	O
the	O
blotting	O
analysis	O
by	O
using	O
various	O
probes	O
specific	O
for	O
IL	O
-	O
2	O
gene	O
.	O

When	O
mouse	B
DNA	O
was	O
digested	O
with	O
various	O
restriction	O
endonucleases	O
and	O
then	O
probed	O
with	O
a	O
7	O
kb	O
human	B
chromosomal	O
DNA	O
segment	O
which	O
contains	O
the	O
human	B
IL	O
-	O
2	O
gene	O
and	O
its	O
flanking	O
region	O
(	O
Fig	O
.	O
1	O
lane	O
1	O
-	O
8	O
,	O
ref	O
.	O
9	O
.	O
)	O
,	O
single	O
positive	O
band	O
appeared	O
at	O
lower	O
but	O
not	O
at	O
higher	O
stringent	O
condition	O
for	O
washing	O
the	O
filters	O
(	O
see	O
Figure	O
legend	O
)	O
.	O

Additional	O
bands	O
corresponding	O
to	O
those	O
observed	O
by	O
using	O
mouse	B
IL	O
-	O
2	O
cDNA	O
probes	O
(	O
lane	O
13	O
-	O
17	O
)	O
also	O
appeared	O
by	O
longer	O

9324	O

Nucleic	O
Acids	O
Research	O

M	O
1	O
2	O
3	O
4	O
M	O
5	O
6	O
7	O
8	O
M	O
9	O
101112	O
M	O
13	O
141516	O
17	O

a	O
~	O
~	O
3	O
.	O
.	O

I	O
pMIL2	O
-	O
45	O
SacI	O
Acc	O
I	O

CZI	O
~	O
~	O
1	O
1t	O
L2	O
-	O
20	O

Acc	O
I	O

1	O
00	O
tp	O
lX	O
i	O

Fig	O
.	O

1	O
.	O

Blot	O
hybridization	O
analysis	O
of	O
mouse	B
chromosomal	O
DNA	O
.	O

High	O
molecular	O
DNA	O
prepared	O
from	O
Liver	O
BALB	O
/	O
C6	O
mouse	B
was	O
digested	O
with	O
various	O
restriction	O
endonucleases	O
(	O
BamHI	O
for	O
lanes	O
1	O
,	O
5	O
,	O
9	O
,	O
13	O
;	O
EcoRI	O
for	O
lanes	O
2	O
,	O
6	O
,	O
10	O
,	O
14	O
,	O
17	O
;	O
HindIII	O
for	O
lanes	O
3	O
,	O
7	O
,	O
11	O
,	O
15	O
;	O
XbaI	O
for	O
lanes	O
4	O
,	O
8	O
,	O
12	O
,	O
16	O
)	O
.	O

The	O
resulting	O
digests	O
were	O
fractionated	O
on	O
0	O
.	O
8	O
%	O
agarose	O
gel	O
and	O
transferred	O
to	O
a	O
nitrocellulose	O
filter	O
.	O

Filters	O
were	O
hybridized	O
by	O
the	O
published	O
procedure	O
(	O
13	O
)	O
either	O
with	O
the	O
nick	O
-	O
translated	O
chromosomal	O
DNA	O
containing	O
human	B
IL	O
-	O
2	O
gene	O
and	O
its	O
flanking	O
region	O
(	O
total	O
length	O
,	O
7	O
.	O
0	O
kb	O
,	O
ref	O
.	O
9	O
)	O
(	O
lane	O
1	O
-	O
8	O
)	O
or	O
with	O
the	O
nick	O
-	O
translated	O
cDNA	O
for	O
mouse	B
IL	O
-	O
2	O
(	O
see	O
figure	O
)	O
.	O

Filters	O
were	O
then	O
washed	O
either	O
in	O
3	O
x	O
SSC	O
at	O
65	O
%	O
(	O
lower	O
stringent	O
condition	O
)	O
(	O
lane	O
1	O
-	O
4	O
,	O
9	O
-	O
12	O
)	O
or	O
0	O
.	O
1	O
x	O
SSC	O
at	O
65	O
OC	O
(	O
higher	O
stringent	O
condition	O
)	O
(	O
lane	O
5	O
-	O
8	O
,	O
13	O
-	O
17	O
)	O
.	O

Lane	O
M	O
each	O
contains	O
7	O
size	O
markers	O
with	O
their	O
size	O
being	O
23	O
.	O
7	O
kb	O
,	O
9	O
.	O
5	O
kb	O
,	O
6	O
.	O
7	O
kb	O
,	O
4	O
.	O
3	O
kb	O
,	O
2	O
.	O
3	O
kb	O
,	O
2	O
.	O
0	O
kb	O
and	O
0	O
.	O
6	O
kb	O
,	O
respectively	O
.	O

Brief	O
restriction	O
endonuclease	O
cleavage	O
map	O
for	O
the	O
mouse	B
IL	O
-	O
2	O
cDNAs	O
is	O
presented	O
in	O
the	O
lower	O
part	O
of	O
the	O
figure	O
.	O

exposure	O
of	O
the	O
film	O
(	O
data	O
not	O
shown	O
)	O
.	O

Those	O
results	O
suggest	O
the	O
presence	O
of	O
highly	O
conserved	O
sequences	O
between	O
human	B
and	O
mouse	B
DNA	O
either	O
in	O
the	O
flanking	O
regions	O
or	O
in	O
the	O
introns	O
of	O
the	O
IL	O
-	O
2	O
gene	O
,	O
since	O
the	O
coding	O
regions	O
apparently	O
show	O
lower	O
degree	O
of	O
sequence	O
homology	O
as	O
evidenced	O
in	O
this	O
series	O
of	O
blotting	O
analysis	O
(	O
see	O
below	O
)	O
.	O

When	O
the	O
PstI	O
insert	O
of	O
a	O
mouse	B
IL	O
-	O
2	O
cDNA	O
clone	O
,	O
pMIL2	O
-	O
20	O
,	O
was	O
used	O
as	O
the	O
probe	O
,	O
a	O
simple	O
pattern	O
was	O

9325	O

Nucleic	O
Acids	O
Research	O

obtained	O
at	O
higher	O
stringent	O
condition	O
(	O
lane	O
13	O
-	O
17	O
)	O
.	O

While	O
the	O
EcoRI	O
-	O
digested	O
DNA	O
gave	O
rise	O
to	O
two	O
positive	O
bands	O
(	O
2	O
.	O
8	O
kb	O
and	O
0	O
.	O
8	O
kb	O
)	O
(	O
Fig	O
.	O
1	O
,	O
lane	O
14	O
)	O
by	O
this	O
analysis	O
,	O
one	O
additional	O
band	O
of	O
3	O
.	O
3	O
kb	O
also	O
appeared	O
when	O
the	O
same	O
DNA	O
was	O
probed	O
with	O
a	O
longer	O
cDNA	O
insert	O
from	O
another	O
clone	O
,	O
pMIL2	O
-	O
45	O
(	O
Fig	O
.	O
1	O
,	O
lane	O
17	O
)	O
.	O

The	O
3	O
.	O
3	O
kb	O
band	O
was	O
similar	O
in	O
its	O
size	O
with	O
the	O
positive	O
band	O
which	O
became	O
detectable	O
by	O
probing	O
the	O
same	O
DNA	O
with	O
the	O
7	O
.	O
0	O
kb	O
human	B
DNA	O
probe	O
(	O
Fig	O
.	O
1	O
,	O
lane	O
2	O
)	O
.	O

Since	O
this	O
band	O
appeared	O
with	O
the	O
cDNA	O
probe	O
extending	O
further	O
upstream	O
,	O
it	O
is	O
likely	O
that	O
the	O
5	O
'	O
region	O
of	O
the	O
gene	O
is	O
located	O
within	O
this	O
DNA	O
segment	O
(	O
see	O
below	O
)	O
.	O

Indeed	O
,	O
this	O
3	O
.	O
3	O
kb	O
band	O
did	O
not	O
appear	O
even	O
after	O
longer	O
exposure	O
of	O
lane	O
14	O
(	O
result	O
not	O
shown	O
)	O
.	O

BamHI	O
digest	O
of	O
the	O
mouse	B
DNA	O
(	O
Fig	O
.	O
1	O
,	O
lane	O
1	O
,	O
13	O
)	O
constantly	O
gave	O
a	O
very	O
faint	O
signal	O
which	O
would	O
correspond	O
to	O
a	O
DNA	O
larger	O
than	O
15	O
kb	O
.	O

Taken	O
together	O
,	O
the	O
results	O
suggested	O
the	O
presence	O
of	O
a	O
single	O
copy	O
gene	O
for	O
murine	B
IL	O
-	O
2	O
.	O

On	O
the	O
other	O
hand	O
appearance	O
of	O
the	O
multiple	O
positive	O
bands	O
at	O
lower	O
stringent	O
washing	O
condition	O
(	O
lane	O
9	O
-	O
12	O
)	O
indicates	O
the	O
presence	O
of	O
IL	O
-	O
2	O
related	O
sequences	O
within	O
the	O
mouse	B
genome	O
.	O

Screening	O
of	O
recombinant	O
phaqe	O
libraries	O

We	O
next	O
screened	O
a	O
gene	O
library	O
from	O
partial	O
EcoRIdigested	O
DNA	O
from	O
MPC	O
11	O
cells	O
and	O
by	O
using	O
0	O
.	O
8	O
Kbp	O
SacI	O
-	O
AccI	O
cDNA	O
fragment	O
as	O
the	O
probe	O
and	O
isolated	O
14	O
positive	O
clones	O
containing	O
sequences	O
specific	O
to	O
the	O
mouse	B
IL	O
-	O
2	O
gene	O
.	O

Three	O
of	O
the	O
clones	O
analysed	O
all	O
contained	O
three	O
EcoRI	O
fragments	O
whose	O
size	O
is	O
in	O
agreement	O
with	O
the	O
result	O
of	O
blotting	O
analysis	O
of	O
the	O
chromosomal	O
DNA	O
as	O
shown	O
in	O
Fig	O
.	O

1	O
(	O
lane	O
17	O
)	O
.	O

One	O
of	O
these	O
is	O
designated	O
MIL	O
-	O
2G70	O
.	O

Nucleotide	O
sequence	O
analysis	O

Two	O
DNA	O
fragments	O
of	O
3	O
.	O
3	O
Kbp	O
and	O
2	O
.	O
8	O
Kbp	O
were	O
excised	O
from	O
the	O
phage	O
clone	O
MIL	O
-	O
2G70	O
by	O
EcoRI	O
digestion	O
and	O
they	O
were	O
subcloned	O
into	O
pBR322	O
.	O

DNA	O
sequences	O
were	O
determined	O
for	O
selected	O
regions	O
of	O
both	O
inserts	O
and	O
compared	O
to	O
the	O
known	O
cDNA	O
sequences	O
(	O
Kashima	O
et	O
al	O
.	O
,	O
submitted	O
for	O
publication	O
)	O
.	O

The	O
strategy	O
used	O
for	O
sequence	O
analysis	O
of	O
the	O
genomic	O
DNA	O
is	O
presented	O
in	O
Fig	O
.	O

2	O
.	O

Comparison	O
of	O
the	O
mouse	B
genomic	O
IL	O
-	O
2	O
sequence	O
with	O
mouse	B
IL	O
-	O
2	O
cDNA	O
sequence	O
revealed	O
that	O
,	O
like	O
the	O
human	B
gene	O
,	O
the	O
gene	O
is	O
divided	O
into	O
four	O
exons	O
.	O

A	O
putative	O

9326	O

Nucleic	O
Acids	O
Research	O

E	O
E	O
E	O
E	O
E	O

500bp	O
s	O
7S	O
P	O
HBH	O
H	O
\	O
A	O

200	O
bp	O
*	O
,	O
-	O
4	O

I	O
4	O
-	O
4	O
-	O
-	O
-	O
-	O
*	O
*	O
-	O
-	O
-	O
4	O

Fig	O
.	O

2	O
.	O

Restriction	O
map	O
and	O
sequencing	O
strategy	O
of	O
mouse	B
IL	O
-	O
2	O
gene	O
.	O

Horizontal	O
lines	O
indicate	O
the	O
length	O
of	O
mouse	B
DNA	O
inserted	O
into	O
the	O
X	O
phage	O
Charon	O
4A	O
or	O
plasmid	O
subclones	O
.	O

Filled	O
blocks	O
,	O
dashed	O
blocks	O
and	O
open	O
blocks	O
indicate	O
protein	O
coding	O
regions	O
,	O
untranslated	O
regions	O
and	O
introns	O
,	O
respectively	O
.	O

Horizontal	O
arrows	O
indicate	O
the	O
direction	O
and	O
extent	O
of	O
sequence	O
determination	O
without	O
ambiguity	O
.	O

Dashed	O
arrows	O
:	O
determination	O
was	O
done	O
by	O
the	O
chain	O
termination	O
method	O
(	O
15	O
)	O
after	O
subcloning	O
the	O
0	O
.	O
8	O
kb	O
fragment	O
into	O
M13	O
.	O

Rest	O
of	O
the	O
sequence	O
determination	O
was	O
carried	O
out	O
by	O
the	O
method	O
of	O
Maxam	O
and	O
Gilbert	O
(	O
14	O
)	O
.	O

A	O
AccI	O
site	O
,	O
B	O
;	O
BamHI	O
site	O
,	O
E	O
;	O
EcoRI	O
site	O
,	O
H	O
;	O
HindIII	O
site	O
,	O
P	O
;	O
PstI	O
site	O
,	O
S	O
;	O
SacI	O
site	O
.	O

capping	O
site	O
or	O
the	O
transcription	O
initiation	O
site	O
was	O
located	O
32	O
bp	O
downstream	O
from	O
a	O
TATAAA	O
consensus	O
promotor	O
sequence	O
(	O
Fig	O
.	O

3	O
)	O
.	O
The	O
first	O
ATG	O
triplet	O
was	O
located	O
79	O
bp	O
downstream	O
from	O
the	O
TATA	O
box	O
.	O

As	O
seen	O
also	O
in	O
the	O
murine	B
IL	O
-	O
2	O
cDNA	O
,	O
there	O
is	O
an	O
unusual	O
repeat	O
of	O
CAG	O
triplet	O
coding	O
for	O
12	O
glutamine	O
residues	O
in	O
a	O
row	O
in	O
the	O
first	O
exon	O
.	O

The	O
second	O
exon	O
(	O
60	O
bp	O
)	O
is	O
separated	O
from	O
the	O
first	O
exon	O
by	O
a	O
short	O
intron	O
consisting	O
of	O
97	O
bp	O
.	O

The	O
second	O
,	O
the	O
third	O
and	O
the	O
fourth	O
exons	O
are	O
interrupted	O
by	O
longer	O
introns	O
whose	O
size	O
is	O
about	O
2	O
.	O
3	O
Kbp	O
and	O
1	O
.	O
6	O
Kbp	O
,	O
respectively	O
.	O

As	O
far	O
as	O
the	O
available	O
sequence	O
data	O
are	O
concerned	O
,	O
it	O
seems	O
that	O
,	O
despite	O
their	O
identical	O
location	O
,	O
intron	O
sequences	O
are	O
distinctly	O
dissimilar	O
except	O
for	O
the	O
junction	O
regions	O
between	O
the	O
human	B
and	O
mouse	B
IL	O
-	O
2	O
genes	O
.	O

There	O
are	O
two	O
potential	O
poly	O
(	O
A	O
)	O
addition	O
signals	O
within	O
the	O
mouse	B
gene	O
(	O
nucleotide	O
positions	O
793	O
-	O
798	O
and	O
924	O
-	O
929	O
in	O
Fig	O
.	O
3	O
)	O
and	O
,	O
based	O
on	O
our	O
sequence	O
data	O
for	O
various	O
cDNA	O
clones	O
,	O
both	O
signals	O
seem	O
to	O
function	O
and	O
give	O
rise	O
to	O
heterogeneous	O
termini	O
of	O
the	O
mRNA	O
in	O
the	O
LBRM	O
-	O
33	O
cells	O
(	O
16	O
)	O
.	O

We	O
have	O
also	O
determined	O
the	O
sequence	O
of	O
about	O
500	O
bp	O
of	O
5	O
'	O
-	O
flanking	O
region	O
of	O
mouse	B
IL	O
-	O
2	O
gene	O
,	O
since	O
(	O
i	O
)	O
promoter	O
/	O
regulatory	O
sequences	O
are	O
located	O
in	O
this	O
region	O
in	O
many	O
other	O
genes	O
of	O
eukaryotes	O
and	O
(	O
ii	O
)	O
this	O
region	O
appeared	O
to	O
contain	O
sequences	O
which	O
show	O
strongest	O
cross	O
-	O
hybridization	O
between	O
human	B
and	O
mouse	B
DNA	O
around	O
the	O
IL	O
-	O
2	O
gene	O
(	O
Fig	O
.	O
1	O
)	O
.	O

Comparison	O
of	O
the	O
nucleotide	O
sequences	O
for	O
the	O
5	O
'	O
flanking	O
region	O

9327	O

Nucleic	O
Acids	O
Research	O

-	O
4	O
.	O
0	O

TAGGAGGTAAACCATCTCGA	O
-	O
400	O
-	O
350	O

GATTTATTCTTTTCATCTAT	O

-	O
300	O
-	O
250	O

CATGAGTTACTTTTGTGTCT	O

-	O
200	O
-	O
150	O

TGGGCTAACCCGACCAAGAG	O

-	O
100	O
-	O
50	O

AAACAAAGGTAATACTTTCT	O
CAGCATTAACAGTATAAATT	O
TCACCCTTGCTAATCACTCC	O

50	O
100	O

ATG	O
TAC	O
AGC	O
ATG	O
CAG	O
CTC	O
GCA	O
TCC	O
TGT	O
GTC	O
ACA	O
TTG	O
ACA	O
CTT	O
GTG	O
CTC	O
CTT	O
GTC	O
AAC	O
AGC	O
GCA	O
CCC	O
ACT	O
Met	O
Tyr	O
Ser	O
Met	O
Gln	O
Leu	O
Ala	O
Ser	O
Cys	O
Val	O
Thr	O
Leu	O
Thr	O
Leu	O
Val	O
Leu	O
Leu	O
Val	O
Asn	O
Ser	O
Ala	O
Pro	O
Thr	O

150	O

TCA	O
AGC	O
TCC	O
ACT	O
TCA	O
AGC	O
TCT	O
ACA	O
GCG	O
GAA	O
GCA	O
CAG	O
CAG	O
CAG	O
CAG	O
CAG	O
CAG	O
CAG	O
CAG	O
CAG	O
CAG	O
CAG	O
CAG	O
Ser	O
Ser	O
Ser	O
Thr	O
Ser	O
Ser	O
Ser	O
Thr	O
Ala	O
Glu	O
Ala	O
Gln	O
Gln	O
Gln	O
Gln	O
Gln	O
Gln	O
Gln	O
Gln	O
Gln	O
Gln	O
Gln	O
Gln	O

200	O

CAC	O
CTG	O
GAG	O
CAG	O
CTG	O
TTG	O
ATG	O
GAC	O
CTA	O
CAG	O
GAG	O
CTC	O
CTG	O
AGC	O
AGG	O
ATG	O
GAG	O
GTAAGTGCACAGCCATCCCA	O
His	O
Leu	O
Glu	O
Gln	O
Leu	O
Leu	O
Met	O
Asp	O
Leu	O
Gln	O
Glu	O
Leu	O
Leu	O
Ser	O
Arg	O
Met	O
Glu	O

TATAGGCAATACCTTTAGCT	O
AAT	O
TAC	O
AGG	O
AAC	O

lAsn	O
Tyr	O
Arg	O
Asn	O
250	O

CTG	O
AAA	O
CTC	O
CCC	O
AGG	O
ATG	O
CTC	O
ACC	O
TTC	O
AAA	O
TTT	O
TAC	O
TTG	O
CCC	O
AAG	O
CAG	O
GTGAGTGAGTTTCTGTTTAA	O
Leu	O
Lys	O
Leu	O
Pro	O
Arg	O
Met	O
Leu	O
Thr	O
Phe	O
Lys	O
Phe	O
Tyr	O
Leu	O
Pro	O
Lys	O
Gln	O

TCTAATG	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
_	O
_	O

?	O
_	O
_	O
_	O
_	O
_	O
_	O
_	O
_	O
_	O
_	O
_	O
_	O
_	O
_	O
_	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
2000	O
bp	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
?	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
AATGTGAACCTTGTAGTTTC	O
TATGCATTGGTAGAGAAACA	O
TGGTTGTGAGCTCTTGCTCT	O
CCTTCTCTTGATTAGAGAGA	O

300	O
350	O

GCC	O
ACA	O
GAA	O
TTG	O
AAA	O
GAT	O
CTT	O
CAG	O
TGC	O
CTA	O
GAA	O
GAT	O
GAA	O
CTT	O
GGA	O
CCT	O
CTG	O
CGG	O
CAT	O
GTT	O
CTG	O
GAT	O
TTG	O
Ala	O
Thr	O
Glu	O
Leu	O
Lys	O
Asp	O
Leu	O
Gln	O
Cys	O
Leu	O
Glu	O
Asp	O
Glu	O
Leu	O
Gly	O
Pro	O
Leu	O
Arg	O
His	O
Val	O
Leu	O
Asp	O
Leu	O

490	O

ACT	O
CAA	O
AGC	O
AAA	O
AGC	O
TTT	O
CAA	O
TTG	O
GAA	O
GAT	O
GCT	O
GAG	O
AAT	O
TTC	O
ATC	O
AGC	O
AAT	O
ATC	O
AGA	O
GTA	O
ACT	O
GTT	O
GTA	O
Thr	O
Gln	O
Ser	O
Lys	O
Ser	O
Phe	O
Gln	O
Leu	O
Glu	O
Asp	O
Ala	O
Glu	O
Asn	O
Phe	O
Ile	O
Ser	O
Asn	O
Ile	O
Arg	O
Val	O
Thr	O
Val	O
Val	O
AAA	O
CTA	O
AAG	O
GTAAGGTGTTGCTTTATTTG	O
Lys	O
Leu	O
Lys	O

CTTTGATGGGTTCTGTGCAT	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
1000	O
bp	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
GAATTCTACAGAAGTGTTCA	O
TATTTTTTATGCTTTACCAT	O

CAGTGTTAAAATAAATGCCT	O

450	O
500	O

GGC	O
TCT	O
GAC	O
AAC	O
ACA	O
TTT	O
GAG	O
TGC	O
CAA	O
TTC	O
GAT	O
GAT	O
GAG	O
TCA	O
GCA	O
ACT	O
GTG	O
GTG	O
GAC	O
TTT	O
CTG	O
AGG	O
AGA	O
Gly	O
Ser	O
Asp	O
Asn	O
Thr	O
Phe	O
Glu	O
Cys	O
Gln	O
Phe	O
Asp	O
Asp	O
GlU	O
Ser	O
Ala	O
Thr	O
Val	O
Val	O
Asp	O
Phe	O
Leu	O
Arg	O
Arg	O

550	O

TGG	O
ATA	O
GCC	O
TTC	O
TGT	O
CAA	O
AGC	O
ATC	O
ATC	O
TCA	O
ACA	O
AGC	O
CCT	O
CAA	O
TAACTATGTACCTCCTGCTT	O
Trp	O
Ile	O
Ala	O
Phe	O
Cys	O
Gln	O
Ser	O
Ile	O
Ile	O
Ser	O
Thr	O
Ser	O
Pro	O
Gln	O

600	O
650	O

TCTCTATTTAT4TAAATATT	O

700	O
750	O

GATCTTTAAAGATTCTTTTT	O
+	O
ATTATATTGAATTGTTAAAT	O

<	O
4	O
>	O
800	O
850	O

ATCATGTGTAGGTAGACTcA	O
TAAAAGTAmAGATGATTCAA	O

900	O
0	O
"	O

TAAGCGCTAAAATAACTTCT	O
AAA	O
GATGGCTTGTGGGAAAAGAT	O

Fig	O
.	O

3	O
.	O

Nucleotide	O
sequence	O
of	O
mouse	B
IL	O
-	O
2	O
gene	O
.	O

Four	O
exons	O
are	O
framed	O
.	O

Numbers	O
refer	O
to	O
nucleotide	O
positions	O
of	O
exons	O
from	O
the	O
presumed	O
cap	O
site	O
.	O

Dots	O
and	O
open	O
circles	O
indicate	O
TATA	O
box	O
and	O
poly	O
A	O
additional	O
signals	O
,	O
respectively	O
.	O

9328	O

Nucleic	O
Acids	O
Research	O

-	O
4	O
5	O
0	O
-	O
400	O

TAGGAGGT	O
AAACCA	O
T	O
CTCGAAAC	O
GGAAACCAATATCCTTCCTG	O

.	O
0	O
*	O
.	O
0	O
.	O
-	O
*	O
.	O

*	O
.	O
.	O
*	O
-	O
-	O
.	O

-	O
-	O
.	O
*	O
-	O
@	O
.	O
.	O
.	O
.	O
.	O
.	O
.	O
.	O
.	O
.	O
.	O
.	O
.	O
.	O

-	O
-	O
-	O
*	O
-	O
*	O
*	O

TAAAAAGGTAAAACCAGTTC	O
GAAACAGGAAACCAATACAC	O
CATTTATTCTTTTCATCTGT	O

-	O
350	O
-	O
300	O

TCTTGCGCCCGTCCACCACA	O
T	O
ACAGGTTCAGGATGGTTTTG	O
TCTTGCTCTTGTTCACCACA	O
TGCTATTCACATGTTCAGTG	O
TGAGTTACTTTTGTATCCC	O

-	O
250	O

CA	O
CCCC	O
AAAG	O
AGGAAAATTTGTTTCATACG	O
CCACCTAAGAGTGGGCTAAC	O

*	O
~	O
~	O
~	O
~	O
~	O
.	O
.	O
.	O
.	O
.	O

*	O
.	O
-	O
-	O
*	O
.	O
.	O
-	O
*	O
.	O
-	O
-	O
.	O
*	O
*	O
.	O

*	O
-	O
.	O

-	O
-	O
.	O

*	O
-	O
*	O
-	O
-	O
-	O
*	O
-	O
0	O
@	O
*	O
-	O
-	O
0	O
.	O
.	O

.	O

CACCCCCTTAAAGAAAGGAG	O

-	O
200	O
-	O
150	O

CCAAGAGGGATTTCACCTAA	O
GGGGTTTAAACAAATTCCAG	O
CAAAGAGGGATTTCACCTAC	O
AAATTCCAAAGAGTCATCAG	O

-	O
100	O
-	O
50	O

TACTTTCTGCCACACAGGTA	O
TGTTTTTT	O
CAGACAGGTAAAGTC	O
TTTGAAAATATGTGTAATAT	O
ATAAGCCTCCCATGCTGAAG	O
Mouse	B
rTATGCATCTCTTGTTCAAG	O
Human	B

Fig	O
.	O

4	O
.	O

Comparison	O
of	O
5	O
'	O
-	O
flanking	O
regions	O
of	O
mouse	B
and	O
human	B
IL	O
-	O
2	O
genes	O
.	O

In	O
aligning	O
the	O
sequences	O
for	O
both	O
genes	O
,	O
gaps	O
were	O
introduced	O
to	O
maximize	O
homology	O
.	O

Dots	O
indicate	O
identical	O
nucleotide	O
sequences	O
.	O

Number	O
1	O
indicates	O
putative	O
transcription	O
initiation	O
site	O
.	O

Inverted	O
repeats	O
are	O
indicated	O
by	O
bars	O
and	O
dashed	O
lines	O
.	O

TATA	O
box	O
is	O
framed	O
.	O

of	O
both	O
genes	O
is	O
illustrated	O
in	O
Fig	O
.	O

4	O
.	O

The	O
nucleotide	O
sequence	O
homology	O
from	O
the	O
TATA	O
box	O
to	O
-	O
470	O
is	O
85	O
%	O
.	O

The	O
highest	O
region	O
of	O
homology	O
was	O
observed	O
between	O
the	O
TATA	O
box	O
and	O
position	O
-	O
97	O
(	O
60	O
bp	O
matches	O
out	O
of	O
64	O
bp	O
)	O
of	O
both	O
genes	O
.	O

DISCUSSION	O

We	O
have	O
isolated	O
recombinant	O
clones	O
for	O
mouse	B
IL	O
-	O
2	O
gene	O
from	O
a	O
phage	O
Charon	O
4A	O
/	O
mouse	B
genomic	O
DNA	O
library	O
and	O
determined	O
the	O
entire	O
sequence	O
of	O
the	O
gene	O
except	O
for	O
the	O
sequence	O
of	O
the	O
internal	O
portion	O
of	O
the	O
second	O
and	O
third	O
introns	O
.	O

The	O
mouse	B
IL	O
-	O
2	O
cDNA	O
sequence	O
was	O
aligned	O
with	O
the	O
genomic	O
sequence	O
and	O
both	O
sequences	O
matched	O
completely	O
each	O
other	O
.	O

The	O
unusual	O
CAG	O
repeats	O
encoding	O
12	O
glutamines	O
which	O
was	O
found	O
previously	O
in	O
the	O
cloned	O
cDNA	O
was	O
shown	O
to	O
be	O
present	O
also	O
in	O
the	O
chromosomal	O
gene	O
.	O

This	O
finding	O
further	O
excludes	O
the	O
possibility	O
that	O
the	O
unique	O
repeat	O
is	O
generated	O
by	O
artifacts	O
during	O
the	O
cDNA	O
cloning	O
process	O
.	O

Although	O
we	O
can	O
not	O
rule	O
out	O
the	O
possibility	O
for	O
the	O
deletion	O
of	O
this	O
sequence	O
in	O
the	O
human	B
IL	O
-	O
2	O
gene	O
,	O
it	O
is	O
more	O
likely	O
that	O
the	O
CAG	O
repeat	O
has	O
been	O
generated	O
in	O
the	O
mouse	B
genome	O
rather	O
recently	O
.	O

The	O
repeat	O
could	O
have	O
been	O
generated	O
either	O
by	O
a	O
direct	O
insertion	O
of	O
the	O
sequence	O
or	O
by	O
the	O
duplication	O
after	O
insertion	O
of	O
a	O
unit	O
sequence	O
.	O

9329	O

Nucleic	O
Acids	O
Research	O

Organization	O
of	O
the	O
mouse	B
IL	O
-	O
2	O
gene	O
resembles	O
to	O
that	O
of	O
the	O
human	B
gene	O
(	O
Fig	O
.	O
2	O
.	O
,	O
ref	O
.	O
9	O
)	O
.	O

There	O
seems	O
to	O
be	O
little	O
sequence	O
homology	O
between	O
corresponding	O
introns	O
of	O
mouse	B
and	O
human	B
IL	O
-	O
2	O
genes	O
,	O
except	O
for	O
the	O
intron	O
-	O
exon	O
junctions	O
part	O
of	O
which	O
is	O
thought	O
to	O
be	O
necessary	O
for	O
the	O
RNA	O
splicing	O
(	O
17	O
,	O
18	O
)	O
.	O

Dissimilarity	O
of	O
the	O
intron	O
sequences	O
among	O
the	O
genes	O
which	O
are	O
derived	O
from	O
a	O
common	O
ancestor	O
has	O
been	O
reported	O
in	O
other	O
genes	O
(	O
19	O
,	O
20	O
)	O
.	O

In	O
spite	O
of	O
the	O
divergence	O
in	O
sequence	O
of	O
introns	O
,	O
the	O
size	O
and	O
position	O
of	O
the	O
introns	O
are	O
very	O
similar	O
between	O
the	O
murine	B
and	O
human	B
IL	O
-	O
2	O
genes	O
.	O

Of	O
particular	O
interests	O
is	O
the	O
presence	O
of	O
highly	O
conserved	O
sequences	O
in	O
the	O
5	O
'	O
-	O
flanking	O
region	O
of	O
the	O
human	B
and	O
mouse	B
IL	O
-	O
2	O
gene	O
(	O
Fig	O
.	O
4	O
)	O
.	O

Whereas	O
the	O
coding	O
region	O
shows	O
nucleotide	O
sequence	O
homology	O
of	O
72	O
%	O
between	O
the	O
two	O
genes	O
,	O
the	O
5	O
'	O
upstream	O
region	O
spanning	O
about	O
500	O
bp	O
(	O
Fig	O
.	O
4	O
)	O
shows	O
85	O
%	O
homology	O
which	O
was	O
readily	O
detectable	O
by	O
the	O
blotting	O
analysis	O
(	O
Fig	O
.	O
1	O
,	O
lane	O
1	O
-	O
4	O
)	O
.	O

Since	O
we	O
have	O
not	O
yet	O
determined	O
the	O
nucleotide	O
sequence	O
further	O
upstream	O
of	O
the	O
mouse	B
gene	O
,	O
we	O
do	O
not	O
know	O
whether	O
or	O
not	O
this	O
similarity	O
extends	O
further	O
.	O

It	O
is	O
likely	O
that	O
such	O
sequences	O
are	O
involved	O
in	O
the	O
controlled	O
expression	O
of	O
the	O
IL	O
-	O
2	O
genes	O
in	O
activated	O
T	O
-	O
lymphocytes	O
.	O

Work	O
is	O
in	O
progress	O
to	O
identify	O
such	O
DNA	O
sequences	O
by	O
introducing	O
the	O
cloned	O
genes	O
into	O
various	O
lymphocytic	O
cell	O
lines	O
.	O

Our	O
preliminary	O
results	O
indicate	O
that	O
the	O
5	O
'	O
-	O
flanking	O
sequence	O
of	O
the	O
human	B
IL	O
-	O
2	O
gene	O
mediates	O
mitogen	O
induced	O
expression	O
of	O
the	O
gene	O
in	O
T	O
-	O
lymphocytic	O
cells	O
(	O
Fujita	O
&	O
Taniguchi	O
,	O
unpublished	O
observation	O
)	O
.	O

ACKNOWLEDGEMENTS	O

We	O
thank	O
Dr	O
.	O
T	O
.	O

Honjo	O
for	O
mouse	B
gene	O
library	O
.	O

We	O
are	O
also	O
indepted	O
to	O
Ms	O
.	O
M	O
.	O

Nagatsuka	O
for	O
typing	O
the	O
manuscript	O
.	O

This	O
work	O
was	O
supported	O
in	O
part	O
by	O
Grant	O
-	O
in	O
-	O
Aid	O
for	O
Special	O
Project	O
Research	O
,	O
Cancer	O
-	O
Bioscience	O
from	O
the	O
Ministry	O
of	O
Education	O
,	O
Science	O
and	O
Culture	O
,	O
Japan	O
.	O

?	O
To	O
whom	O
correspondence	O
should	O
be	O
addressed	O

*	O
Present	O
address	O
:	O
Department	O
of	O
Microbiology	O
,	O
School	O
of	O
Medicine	O
,	O
Chiba	O
University	O
,	O
Chiba	O
280	O
,	O
Japan	O

+	O
Present	O
address	O
:	O
Central	O
Research	O
Laboratory	O
,	O
Ajinomoto	O
Co	O
.	O
Inc	O
.	O
,	O
Totsuka	O
-	O
ku	O
,	O
Yokohama	O
244	O
,	O
Japan	O

9330	O

Nucleic	O
Acids	O
Research	O

REFERENCES	O

1	O
.	O

Morgan	O
,	O
D	O
.	O

A	O
.	O
,	O
Ruscetti	O
,	O
F	O
.	O

W	O
.	O
and	O
Gallo	O
,	O
R	O
.	O

(	O
1976	O
)	O
Science	O
,	O

193	O
,	O
1007	O
-	O
1008	O
.	O

2	O
.	O

Gil	O
lis	O
,	O
S	O
.	O

Ferm	O
,	O
M	O
.	O

M	O
.	O
,	O
Ou	O
,	O
W	O
.	O
and	O
Smith	O
,	O
K	O
.	O

(	O
1	O
978	O
)	O
J	O
.	O

Immunol	O
.	O
,	O
120	O
,	O
2023	O
-	O
2027	O
.	O

3	O
.	O

Chen	O
,	O
B	O
.	O

M	O
.	O
and	O
Di	O
Sabato	O
,	O
G	O
.	O

(	O
1976	O
)	O
Cell	O
.	O

Immunol	O
.	O
,	O
22	O
,	O
211	O

224	O
.	O

4	O
.	O

Henney	O
,	O
C	O
.	O

S	O
.	O
,	O
Kuribayashi	O
,	O
K	O
.	O
,	O
Kern	O
,	O
D	O
.	O

E	O
.	O
and	O
Gillis	O
,	O
S	O
.	O

(	O
1981	O
)	O
Nature	O
,	O
291	O
,	O
335	O
-	O
338	O
.	O

5	O
.	O

Wagner	O
,	O
H	O
.	O
,	O
Hardt	O
,	O
C	O
.	O
,	O
Heeg	O
,	O
K	O
.	O
,	O
Rollinghoff	O
,	O
M	O
.	O
and	O

Pfizenmaier	O
,	O
K	O
.	O

(	O
1980	O
)	O
Nature	O
,	O
284	O
,	O
278	O
-	O
280	O
.	O

6	O
.	O

Farrar	O
,	O
J	O
.	O

J	O
.	O
,	O
Benjamin	O
,	O
W	O
.	O

R	O
.	O
,	O
Hilfikr	O
M	O
.	O

L	O
.	O
,	O
Howard	O
,	O
M	O
.	O
,	O

Farrar	O
,	O
W	O
.	O

L	O
.	O
and	O
Fuller	O
-	O
Farrar	O
,	O
J	O
.	O

(	O
1982	O
)	O
Immunol	O
.	O

Rev	O
.	O

63	O
,	O
129	O
-	O
166	O
.	O

7	O
.	O

Pearlstein	O
,	O
K	O
.	O
,	O
Palladino	O
,	O
M	O
.	O

A	O
.	O
,	O
Welte	O
,	O
K	O
.	O
and	O
Vilcek	O
,	O
J	O
.	O

(	O
1983	O
)	O
Cell	O
.	O

Immunol	O
.	O
,	O
80	O
,	O
1	O
-	O
9	O
.	O

8	O
.	O

Taniguchi	O
,	O
T	O
.	O
,	O
Matsui	O
,	O
H	O
.	O
,	O
Fujita	O
,	O
T	O
.	O
,	O
Takaoka	O
,	O
C	O
.	O
,	O
Kashima	O
,	O

N	O
.	O
,	O
Yoshimoto	O
,	O
R	O
.	O
and	O
Hamuro	O
,	O
J	O
.	O

(	O
1983	O
)	O
Nature	O
302	O
,	O
305	O
-	O
310	O
.	O

9	O
.	O

Fujita	O
,	O
T	O
.	O
,	O
Takaoka	O
,	O
C	O
.	O
,	O
Matsui	O
,	O
H	O
.	O
and	O
Taniguchi	O
T	O
.	O

(	O
1983	O
)	O

Proc	O
.	O

Natl	O
.	O

Acad	O
.	O

Sci	O
.	O

USA	O
80	O
,	O
7437	O
-	O
7411	O
.	O

10	O
.	O

Ohno	O
,	O
S	O
.	O
and	O
Taniguchi	O
,	O
T	O
.	O

(	O
1982	O
)	O
Nucleic	O
Acids	O
Res	O
.	O

10	O
,	O
967	O

977	O
.	O

11	O
.	O

Southern	O
,	O
E	O
.	O

M	O
.	O

(	O
1975	O
)	O
J	O
.	O

Mol	O
.	O

Biol	O
.	O

98	O
,	O
503	O
-	O
517	O
.	O

12	O
.	O

Benton	O
,	O
W	O
.	O

D	O
.	O
and	O
Davis	O
,	O
R	O
.	O

W	O
.	O

(	O
1977	O
)	O
Science	O
196	O
,	O
180	O
-	O
182	O
.	O

13	O
.	O

Ohno	O
,	O
S	O
.	O
and	O
Taniguchi	O
,	O
T	O
.	O

(	O
1981	O
)	O
Proc	O
.	O

Natl	O
.	O

Acad	O
.	O

Sci	O
.	O

USA	O

78	O
,	O
5305	O
-	O
5309	O
.	O

14	O
.	O

Maxam	O
,	O
A	O
.	O

M	O
.	O
and	O
Gilbert	O
,	O
W	O
.	O

(	O
1980	O
)	O
Meth	O
.	O

Enzymol	O
.	O

65	O
,	O
560	O

580	O
.	O

15	O
.	O

Sanger	O
,	O
F	O
.	O
,	O
Nicklen	O
,	O
S	O
.	O
and	O
Coulson	O
,	O
A	O
.	O

R	O
.	O

(	O
1977	O
)	O
Proc	O
.	O

Natl	O
.	O

Acad	O
.	O

Sci	O
.	O

USA	O
,	O
74	O
,	O
5463	O
-	O
5467	O
.	O

16	O
.	O

Gillis	O
,	O
S	O
.	O
,	O
Scheid	O
,	O
M	O
.	O
and	O
Watson	O
,	O
J	O
.	O

D	O
.	O
(	O
1980	O
)	O
J	O
.	O

Immunol	O
.	O

,	O
125	O
,	O
2570	O
-	O
2580	O
.	O

17	O
.	O

Breathnach	O
,	O
R	O
.	O
,	O
Benoist	O
,	O
C	O
.	O
,	O
O	O
'	O
Hare	O
,	O
K	O
.	O
,	O
Gannon	O
,	O
F	O
.	O
and	O

Chambon	O
,	O
P	O
.	O
(	O
1978	O
)	O
Proc	O
.	O

Natl	O
.	O

Acad	O
.	O

Sci	O
.	O

USA	O
,	O
75	O
,	O
4853	O
-	O
4857	O
.	O

18	O
.	O

Lerner	O
,	O
M	O
.	O

R	O
.	O
,	O
Boyle	O
,	O
J	O
.	O

A	O
.	O
,	O
Mount	O
,	O
S	O
.	O

M	O
.	O
,	O
Wolin	O
,	O
S	O
.	O

L	O
.	O
and	O

Steitz	O
,	O
J	O
.	O

A	O
.	O

(	O
1980	O
)	O
Nature	O
,	O
283	O
,	O
220	O
-	O
224	O
.	O

19	O
.	O

Van	O
Ooyen	O
,	O
A	O
.	O
,	O
Van	O
den	O
Berg	O
,	O
J	O
.	O
,	O
Mantei	O
,	O
N	O
.	O
and	O
Weissmann	O
,	O

C	O
.	O
(	O
1979	O
)	O
Science	O
,	O
206	O
,	O
337	O
-	O
344	O
.	O

20	O
.	O

Searle	O
,	O
P	O
.	O

F	O
.	O
,	O
Davison	O
,	O
B	O
.	O

L	O
.	O
,	O
Stuart	O
,	O
G	O
.	O

W	O
.	O
,	O
Wilkie	O
,	O
T	O
.	O

M	O
.	O
,	O

Norstedt	O
,	O
G	O
.	O
and	O
Palmiter	O
,	O
R	O
.	O

D	O
.	O

(	O
1984	O
)	O
Mol	O
.	O

Cell	O
.	O

Biol	O
.	O

4	O
,	O
1221	O
-	O
1230	O
.	O

9331	O

Preparation	O
of	O
oligodeoxyribonucleo	O
methylphosphonates	O
on	O
a	O
polystyrene	O
support	O
.	O

Abstract	O

An	O
efficient	O
procedure	O
is	O
described	O
for	O
synthesizing	O
deoxyribonucleoside	O
methylphosphonates	O
on	O
polystyrene	O
polymer	O
supports	O
which	O
involves	O
condensing	O
5	O
'	O
-	O
dimethoxytrityldeoxy	O
3	O
'	O
-	O
methylphosphonates	O
.	O

The	O
oligomers	O
are	O
removed	O
from	O
the	O
support	O
and	O
the	O
base	O
protecting	O
groups	O
hydrolyzed	O
by	O
treatment	O
with	O
ethylenediamine	O
in	O
ethanol	O
,	O
which	O
avoids	O
hydrolysis	O
of	O
the	O
methylphosphonate	O
linkages	O
.	O

Two	O
types	O
of	O
oligomers	O
were	O
synthesized	O
:	O
those	O
containing	O
only	O
methylphosphonate	O
linkages	O
,	O
d	O
-	O
Np	O
(	O
Np	O
)	O
nN	O
,	O
and	O
those	O
which	O
terminate	O
with	O
a	O
5	O
'	O
nucleotide	O
residue	O
,	O
dNp	O
(	O
Np	O
)	O
nN	O
.	O

The	O
latter	O
oligomers	O
can	O
be	O
phosphorylated	O
by	O
polynucleotide	O
kinase	O
,	O
and	O
are	O
separated	O
by	O
polyacrylamide	O
gel	O
electrophoresis	O
according	O
to	O
their	O
chain	O
length	O
.	O

Piperdine	O
randomly	O
cleaves	O
the	O
oligomer	O
methylphosphonate	O
linkages	O
and	O
generates	O
a	O
series	O
of	O
shorter	O
oligomers	O
whose	O
number	O
corresponds	O
to	O
the	O
length	O
of	O
the	O
original	O
oligomer	O
.	O

Apurinic	O
sites	O
introduced	O
by	O
acid	O
treatment	O
spontaneously	O
hydrolyze	O
to	O
give	O
oligomers	O
which	O
terminate	O
with	O
free	O
3	O
'	O
and	O
5	O
'	O
OH	O
groups	O
.	O

These	O
reactions	O
may	O
be	O
used	O
to	O
characterize	O
the	O
oligomers	O
.	O
Images	O

Vlue1Nubr1193NcecAis	O

Preparation	O
of	O
oligodeoxyribonucleo	O
methylphosphonates	O
on	O
a	O
polystyrene	O
support	O
P	O
.	O
S	O
.	O
Miller	O
,	O
C	O
.	O
H	O
.	O
Agris	O
,	O
A	O
.	O
Murakami	O
,	O
P	O
.	O
M	O
.	O
Reddy	O
,	O
S	O
.	O
A	O
.	O
Spitz	O
and	O
P	O
.	O
O	O
.	O
P	O
.	O
Ts	O
'	O
o	O

Division	O
of	O
Biophysics	O
,	O
Johns	O
Hopkins	O
University	O
,	O
School	O
of	O
Hygiene	O
and	O
Public	O
Health	O
,	O
Baltimore	O
,	O
MD	O
21205	O
,	O
USA	O

Received	O
26	O
July	O
1983	O
;	O
Accepted	O
5	O
September	O
1983	O

ABSTRACT	O

An	O
efficient	O
procedure	O
is	O
described	O
for	O
synthesizing	O
deoxyribonucleoside	O
methylphosphonates	O
on	O
polystyrene	O
polyner	O
supports	O
which	O
involves	O
condensing	O
5	O
'	O
-	O
dimethoxytrityldeoxy	O
3	O
'	O
-	O
methylphosphonates	O
.	O

The	O
oligomers	O
are	O
removed	O
from	O
the	O
support	O
and	O
the	O
base	O
protecting	O
groups	O
hydrolyzed	O
by	O

treatment	O
with	O
ethylenediamine	O
in	O
ethanol	O
,	O
which	O
avoids	O
hydrolysis	O
of	O
the	O

methylphosphonate	O
linkages	O
.	O

Two	O
types	O
of	O
oligomers	O
were	O
synthesized	O
:	O
those	O
containing	O
only	O
methylphosphonate	O
linkages	O
,	O
d	O
-	O
Np	O
(	O
Np	O
)	O
N	O
,	O
and	O
those	O
which	O

terminate	O
with	O
a	O
5	O
'	O
nucleotide	O
residue	O
,	O
dNp	O
(	O
Np	O
)	O
N	O
.	O
-	O
J	O
he	O
latter	O
oligomers	O
can	O
be	O
phosphorylated	O
by	O
polynucleotide	O
kinase	O
,	O
and	O
are	O
separated	O
by	O

polyacrylamide	O
gel	O
electrophoresis	O
according	O
to	O
their	O
chain	O
length	O
.	O

Piperdine	O
randomly	O
cleaves	O
the	O
oligomer	O
methylphosphonate	O
linkages	O
and	O
generates	O
a	O

series	O
of	O
shorter	O
oligomers	O
whose	O
number	O
corresponds	O
to	O
the	O
length	O
of	O
the	O

original	O
oligomer	O
.	O

Apurinic	O
sites	O
introduced	O
by	O
acid	O
treatment	O
spontaneously	O
hydrolyze	O
to	O
give	O
oligomers	O
which	O
terminate	O
with	O
free	O
3	O
'	O
and	O
5	O
'	O
OH	O
groups	O
.	O

These	O
reactions	O
may	O
be	O
used	O
to	O
characterize	O
the	O
oligomers	O
.	O

INTRODUCTION	O

Oligonucleoside	O
methylphosphonates	O
have	O
been	O
used	O
to	O
st	O
-	O
udy	O
the	O
function	O
of	O
specific	O
RNA	O
sequences	O
in	O
biochemical	O
and	O
intact	O
cellular	O
systems	O
(	O
1	O
,	O
2	O
)	O
.	O

Since	O
these	O
nonionic	O
nucleic	O
acid	O
analogs	O
can	O
be	O
taken	O
up	O
intact	O
by	O
mammalian	O
cells	O
and	O
certain	O
bacterial	O
cells	O
in	O
culture	O
,	O
these	O
compounds	O
promise	O
to	O
be	O
useful	O
reagents	O
for	O
exploring	O
and	O
regulating	O
the	O
function	O
of	O
nucleic	O
acids	O
within	O
living	O
cells	O
.	O

In	O
order	O
to	O
carry	O
out	O
more	O
extensive	O
biochemical	O
and	O
biological	O
studies	O
,	O
an	O
efficient	O
method	O
for	O
synthesis	O
of	O
oligonucleoside	O
methylphosphonates	O
of	O
defined	O
sequence	O
is	O
needed	O
.	O

Previously	O
we	O
described	O
the	O
synthesis	O
of	O

methylphosphonate	O
analogs	O
on	O
a	O
silica	O
gel	O
support	O
(	O
3	O
)	O
.	O

Protected	O
nucleoside	O
3	O
'	O
-	O
methylphosphonic	O
chlorides	O
or	O
tetrazolides	O
were	O
used	O
as	O
synthetic	O

intermediates	O
.	O

While	O
oligothymidine	O
methylphosphonates	O
could	O
be	O
efficiently	O
synthesized	O
by	O
this	O
procedure	O
,	O
low	O
yields	O
were	O
encountered	O
when	O
other	O

nucleosides	O
,	O
particularly	O
d	O
-	O
[	O
(	O
MeO	O
)	O
2Tr	O
]	O
ibuG	O
were	O
used	O
.	O

Recently	O
Sinha	O
et	O
al	O
.	O

?	O
)	O
I	O
RL	O
Press	O
Limited	O
,	O
Oxford	O
,	O
England	O
.	O

Nucleic	O
Acids	O
Research	O

Volume	O
1	O
1	O
Number	O
18	O
1983	O

6225	O

Nucleic	O
Acids	O
Research	O

described	O
the	O
preparation	O
of	O
oligonucleoside	O
methylphosphophonate	O
on	O
a	O
glass	O
support	O
using	O
nucleoside	O
3	O
'	O
-	O
methylphosphine	O
chlorides	O
as	O
reactive	O
intermediates	O
(	O
4	O
)	O
.	O

In	O
this	O
paper	O
we	O
describe	O
a	O
set	O
of	O
useful	O
methods	O
for	O
the	O
synthesis	O
and	O
analysis	O
of	O
these	O
analogs	O
.	O

The	O
synthesis	O
involves	O
condensation	O
of	O
protected	O
nucleoside	O
3	O
'	O
-	O
methylphosphonate	O
triethylammonium	O
salts	O
with	O
nucleosides	O
or	O

oligomers	O
linked	O
to	O
a	O
polystyrene	O
support	O
.	O

This	O
method	O
has	O
proven	O
to	O
be	O
easy	O
to	O
use	O
and	O
allows	O
relatively	O
rapid	O
synthesis	O
of	O
oligomers	O
of	O
defined	O
sequence	O
up	O
to	O
nine	O
nucleosides	O
in	O
length	O
.	O

We	O
have	O
also	O
developed	O
conditions	O
for	O
the	O

efficient	O
removal	O
of	O
base	O
protecting	O
groups	O
and	O
subsequent	O
purification	O
of	O
the	O
oligomers	O
.	O

A	O
novel	O
hydrolysis	O
reaction	O
which	O
can	O
be	O
used	O
as	O
a	O
basis	O
for	O

characterizing	O
and	O
sequencing	O
these	O
oligonucleotide	O
analogs	O
occurs	O
at	O
apurinic	O
sites	O
created	O
by	O
acid	O
treatment	O
of	O
the	O
oligomers	O
.	O

EXPERIMENTAL	O

Materials	O
and	O
Methods	O

Protected	O
nucleosides	O
,	O
d	O
-	O
[	O
(	O
MeO	O
)	O
2Tr	O
]	O
N	O
,	O
were	O
purchased	O
from	O
P	O
.	O
L	O
.	O

Biochemicals	O
and	O
were	O
used	O
without	O
further	O
purification	O
.	O

Protected	O
nucleoside	O
3	O
'	O
-	O
methylphosphonate	O
triethylammoni	O
um	O
salts	O
,	O
d	O
-	O
[	O
(	O
MeO	O
)	O
2Tr	O
]	O
Np	O
*	O
Et3NH	O
,	O
were	O

prepared	O
as	O
previously	O
described	O
(	O
3	O
)	O
.	O

5	O
-	O
Dimethoxytrityl	O
protected	O
nucleosides	O
esterified	O
to	O
1	O
%	O
or	O
2	O
%	O
crosslinked	O
polystyrene	O
were	O
purchased	O
from	O
Chem	O
Genes	O
Inc	O
.	O

The	O
nucleoside	O
loading	O
level	O
was	O
40	O
to	O
120	O
pmol	O
of	O

nucleoside	O
/	O
g	O
of	O
support	O
.	O

Mesitylenesulfonyl	O
-	O
3	O
-	O
nitrotriazole	O
(	O
MSNT	O
)	O
was	O
purchased	O
from	O
Vega	O
Biochemicals	O
.	O

Anhydrous	O
pyridine	O
was	O
prepared	O
by	O

refluxing	O
previously	O
purified	O
pyridine	O
(	O
5	O
)	O
over	O
calcium	O
hydride	O
chips	O
for	O
several	O
hours	O
followed	O
by	O
distillation	O
onto	O
calcium	O
hydride	O
chips	O
in	O
5	O
ml	O
V	O
-	O
vials	O
fitted	O
with	O
Teflon	O
-	O
lined	O
septum	O
caps	O
(	O
Wheaton	O
Scientific	O
)	O
.	O

Lyophilized	O
spleen	O
phosphodiesterase	O
was	O
obtained	O
from	O
P	O
.	O
L	O
.	O

Biochemicals	O
.	O

T	O
-	O
4	O
polynucleotide	O
kinase	O
and	O
[	O
y	O
-	O
32P	O
]	O
-	O
ATP	O
were	O
obtained	O
from	O
New	O
England	O
Nuclear	O
.	O

Reversed	O
phase	O
high	O
performance	O
liquid	O
chromatography	O
(	O
HPLC	O
)	O
was	O
carried	O
out	O
on	O
Whatman	O
Inc	O
.	O

C	O
-	O
18	O
(	O
ODS	O
-	O
3	O
)	O
columns	O
(	O
0	O
.	O
4	O
x	O
25	O
cm	O
)	O
.	O

Analytical	O
columns	O
were	O

eluted	O
with	O
50	O
ml	O
linear	O
gradients	O
of	O
acetonitrile	O
in	O
water	O
or	O
acetonitrile	O
in	O
0	O
.	O
1	O
M	O
ammonium	O
acetate	O
(	O
pH	O
5	O
.	O
8	O
)	O
at	O
a	O
flow	O
rate	O
of	O
2	O
.	O
5	O
ml	O
/	O
min	O
.	O

The	O
eluate	O
was	O

monitored	O
at	O
254	O
nm	O
.	O

The	O
following	O
molar	O
extinction	O
coefficients	O
were	O
used	O
at	O
254	O
nm	O
:	O
d	O
-	O
T	O
7	O
,	O
250	O
,	O
dA	O
13	O
,	O
270	O
,	O
dC	O
6	O
,	O
260	O
,	O
dG	O
13	O
,	O
700	O
.	O

Unless	O
otherwise	O
noted	O
,	O
all	O
reactions	O
and	O
operations	O
were	O
carried	O
out	O
at	O
room	O
temperature	O
.	O

General	O
Procedure	O
for	O
Preparing	O
Oligonucleoside	O
Methylphosphonates	O
.	O

The	O

following	O
procedure	O
represents	O
the	O
current	O
method	O
used	O
in	O
our	O
laboratory	O
to	O

6226	O

Nucleic	O
Acids	O
Research	O

synthesize	O
methylphosphonate	O
oligomers	O
.	O

Table	O
I	O
lists	O
some	O
of	O
the	O
oligomers	O
which	O
have	O
been	O
synthesized	O
on	O
polystyrene	O
supports	O
.	O

Oligomers	O
7	O
,	O
8	O
,	O
and	O
10	O
were	O
synthesized	O
as	O
described	O
below	O
.	O

The	O
other	O
oligomers	O
were	O
synthesized	O
in	O
essentially	O
the	O
same	O
manner	O
except	O
the	O
condensation	O
reactions	O
were	O
run	O
in	O
1	O
ml	O
V	O
-	O
vials	O
or	O
in	O
glass	O
reaction	O
columns	O
purchased	O
from	O
Bachem	O
Inc	O
.	O

When	O
the	O

reactions	O
were	O
run	O
in	O
V	O
-	O
vials	O
,	O
the	O
support	O
was	O
dried	O
by	O
several	O
evaporations	O

with	O
anhydrous	O
pyridine	O
in	O
the	O
V	O
-	O
vial	O
(	O
3	O
)	O
.	O

When	O
the	O
reactions	O
were	O
run	O
in	O
the	O
glass	O
reaction	O
column	O
,	O
the	O
support	O
was	O
dried	O
by	O
a	O
single	O
evaporation	O
with	O
anhydrous	O
pyridine	O
overnight	O
at	O
room	O
temperature	O
.	O

Synthesis	O
of	O
Protected	O
Oligonucleoside	O
Methylphosphonates	O
.	O

The	O
synthetic	O

reactions	O
are	O
most	O
conveniently	O
carried	O
out	O
in	O
a	O
polypropylene	O
col	O
umn	O
(	O
Bio	O
Rad	O
Econo	O
column	O
)	O
fitted	O
with	O
a	O
Teflon	O
3	O
-	O
way	O
valve	O
(	O
Bio	O
Rad	O
)	O
and	O
a	O
rubber	O
septum	O
cap	O
(	O
Wheaton	O
Scientific	O
)	O
.	O

During	O
washing	O
operations	O
,	O
the	O
septum	O
cap	O
is	O
removed	O
and	O
the	O
3	O
-	O
way	O
valve	O
is	O
connected	O
to	O
a	O
filter	O
flask	O
via	O
a	O
Luerer	O

adaptor	O
and	O
tubing	O
set	O
(	O
Bio	O
Rad	O
)	O
.	O

Generally	O
vacuum	O
is	O
not	O
required	O
to	O
wash	O

the	O
support	O
.	O

During	O
the	O
drying	O
step	O
,	O
one	O
port	O
of	O
the	O
3	O
-	O
way	O
valve	O
is	O
connected	O
to	O
a	O
cold	O
trap	O
and	O
vacuum	O
pump	O
via	O
the	O
barrel	O
of	O
a	O
1	O
ml	O
plastic	O
syringe	O
.	O

The	O
other	O
port	O
is	O
connected	O
to	O
a	O
Drierite	O
column	O
filled	O
with	O
dry	O
argon	O
.	O

A	O
reaction	O
cycle	O
consists	O
of	O
the	O
following	O
10	O
steps	O
:	O
1	O
)	O
The	O
support	O
(	O
60	O
mg	O
,	O
1	O
%	O
crosslinked	O
)	O
in	O
the	O
column	O
is	O
washed	O
with	O
three	O
2	O
ml	O
portions	O
of	O

methylene	O
chloride	O
/	O
isopropanol	O
(	O
85	O
:	O
15	O
,	O
v	O
/	O
v	O
)	O
.	O

2	O
)	O
The	O
support	O
is	O
treated	O
with	O
2	O
ml	O
of	O
1	O
M	O
zinc	O
bromide	O
in	O
methylene	O
chloride	O
/	O
isopropanol	O
solution	O
.	O

Two	O
fiveminute	O
treatments	O
are	O
used	O
when	O
the	O
support	O
-	O
bound	O
nucleoside	O
is	O

d	O
-	O
[	O
(	O
MeO	O
)	O
2Tr	O
]	O
bzA	O
or	O
d	O
-	O
[	O
(	O
MeO	O
)	O
2Tr	O
]	O
ibuG	O
,	O
while	O
four	O
treatments	O
are	O
used	O
when	O
the	O
nucleoside	O
is	O
d	O
-	O
[	O
(	O
MeO	O
)	O
2Tr	O
]	O
T	O
or	O
d	O
-	O
[	O
(	O
MeO	O
)	O
2Tr	O
]	O
bzC	O
.	O

After	O
each	O
treatment	O
the	O

orange	O
solution	O
is	O
collected	O
in	O
a	O
clean	O
flask	O
.	O

3	O
)	O
The	O
support	O
is	O
washed	O
with	O
two	O
2	O
ml	O
portions	O
of	O
methylene	O
chloride	O
/	O
isopropanol	O
and	O
the	O
washings	O
are	O

collected	O
in	O
same	O
flask	O
used	O
in	O
step	O
2	O
)	O
.	O

The	O
solution	O
is	O
diluted	O
to	O
50	O
ml	O
and	O
a	O
0	O
.	O
20	O
ml	O
aliquot	O
is	O
dissolved	O
in	O
0	O
.	O
80	O
ml	O
of	O
perchloric	O
acid	O
/	O
ethanol	O
(	O
3	O
:	O
2	O
,	O

v	O
/	O
v	O
)	O
.	O

The	O
absorbance	O
is	O
determined	O
at	O
500	O
nm	O
and	O
the	O
amount	O
of	O
trityl	O
cation	O
is	O
determined	O
using	O
a	O
molar	O
extinction	O
coefficient	O
of	O
89	O
,	O
000	O
.	O

4	O
)	O
The	O
column	O
is	O
attached	O
to	O
a	O
waste	O
flask	O
and	O
the	O
support	O
is	O
washed	O
with	O
three	O
2	O
ml	O

portions	O
of	O
0	O
.	O
5	O
M	O
triethylammonium	O
acetate	O
in	O
dimethylformamide	O
;	O
three	O
2	O
ml	O

portions	O
of	O
anhydrous	O
pyridine	O
and	O
three	O
2	O
ml	O
portions	O
of	O
diethyl	O
ether	O
.	O

5	O
)	O
The	O
column	O
is	O
fitted	O
with	O
the	O
septum	O
cap	O
and	O
set	O
up	O
in	O
the	O
drying	O
mode	O
under	O

house	O
vacuum	O
for	O
at	O
least	O
5	O
min	O
.	O

6	O
)	O
The	O
support	O
is	O
dried	O
by	O
adding	O
300	O
jl	O
of	O
anhydrous	O
pyridine	O
via	O
a	O
gas	O
tight	O
syringe	O
(	O
Hamilton	O
)	O
.	O

After	O
the	O
support	O
has	O
swollen	O
,	O
the	O
vacuum	O
(	O
oil	O
pump	O
)	O
is	O
applied	O
and	O
the	O
support	O
is	O
warmed	O
with	O
a	O

6227	O

Nucleic	O
Acids	O
Research	O

stream	O
of	O
air	O
from	O
a	O
hair	O
dryer	O
.	O

Evaporation	O
is	O
continued	O
for	O
10	O
min	O
.	O

Dry	O
argon	O
is	O
then	O
admitted	O
and	O
the	O
drying	O
operation	O
is	O
repeated	O
two	O
more	O
times	O
.	O

7	O
)	O
The	O
coupling	O
mixture	O
is	O
prepared	O
by	O
dissolving	O
0	O
.	O
20	O
mmol	O
of	O
MSNT	O
in	O
320	O
pl	O
of	O
anhydrous	O
pyridine	O
.	O

The	O
solution	O
is	O
then	O
transferred	O
to	O
the	O
vial	O

containing	O
0	O
.	O
06	O
mmol	O
of	O
d	O
-	O
[	O
(	O
MeO	O
)	O
2Tr	O
]	O
Np	O
-	O
Et3NH	O
.	O

The	O
nucleotide	O
is	O
dissolved	O
by	O
vortexing	O
and	O
the	O
coupling	O
solution	O
is	O
then	O
added	O
dropwise	O
to	O
the	O
support	O
.	O

It	O
is	O
important	O
to	O
add	O
the	O
solution	O
slowly	O
and	O
to	O
allow	O
the	O
support	O
to	O
swell	O
.	O

Trapped	O
gas	O
bubbles	O
may	O
be	O
removed	O
by	O
gently	O
tapping	O
the	O
column	O
.	O

This	O
entire	O
operation	O
is	O
carried	O
out	O
using	O
one	O
predried	O
syringe	O
.	O

The	O
syringe	O
is	O
left	O
in	O

the	O
V	O
-	O
vial	O
while	O
the	O
reagents	O
are	O
being	O
dissolved	O
.	O

8	O
)	O
The	O
reaction	O
mixture	O
is	O
kept	O
at	O
room	O
temperature	O
for	O
two	O
hrs	O
.	O

9	O
)	O
The	O
column	O
is	O
set	O
up	O
in	O
the	O

washing	O
mode	O
and	O
the	O
support	O
is	O
washed	O
with	O
three	O
2	O
ml	O
portions	O
of	O
anhydrous	O
pyridine	O
.	O

The	O
solution	O
,	O
which	O
contains	O
unreacted	O
nucleoside	O

3	O
'	O
-	O
methylphosphonate	O
and	O
MSNT	O
,	O
is	O
collected	O
in	O
a	O
separate	O
flask	O
.	O

A	O
50	O
%	O

aqueous	O
pyridine	O
solution	O
(	O
1	O
ml	O
)	O
is	O
added	O
and	O
the	O
solution	O
is	O
kept	O
at	O
40C	O
for	O

later	O
purification	O
and	O
recovery	O
of	O
d	O
-	O
[	O
(	O
MeO	O
)	O
2Tr	O
]	O
Np	O
.	O

10	O
)	O
The	O
support	O
is	O
treated	O
with	O
a	O
solution	O
containing	O
2	O
ml	O
of	O
anhydrous	O
pyridine	O
,	O
1	O
ml	O
of	O
acetic	O

anhydride	O
and	O
20	O
mg	O
of	O
dimethylaminopyridin	O
for	O
30	O
min	O
.	O

(	O
This	O
step	O
was	O
not	O
included	O
for	O
the	O
synthesis	O
of	O
oligomer	O
10	O
)	O
.	O

11	O
)	O
Return	O
to	O
step	O
1	O
,	O
for	O
the	O
next	O
cycle	O
.	O

Removal	O
of	O
Base	O
Protecting	O
Groups	O
.	O

The	O
following	O
general	O
procedure	O
was	O
found	O
to	O
be	O
the	O
most	O
effective	O
method	O
for	O
cleaving	O
the	O
oligonucleotide	O
from	O
the	O
1	O
%	O
crosslinked	O
support	O
and	O
for	O
removing	O
the	O
base	O
protecting	O
groups	O
with	O
minimal	O
hydrolysis	O
of	O
the	O
phosphonate	O
backbone	O
.	O

The	O
following	O
steps	O
were	O
used	O
for	O

deprotecting	O
oligomers	O
7	O
,	O
8	O
and	O
10	O
.	O

Oligomer	O
9	O
was	O
deprotected	O
in	O
a	O
similar	O

fashion	O
except	O
step	O
4	O
)	O
was	O
carried	O
out	O
at	O
650C	O
for	O
3	O
hrs	O
.	O

For	O
oligomers	O
1	O
-	O
6	O
,	O
step	O
3	O
)	O
was	O
not	O
included	O
and	O
step	O
4	O
)	O
was	O
carried	O
out	O
at	O
650	O
for	O
3	O
hrs	O
.	O

1	O
)	O
After	O
the	O
final	O
condensation	O
step	O
the	O
support	O
(	O
60	O
mg	O
)	O
is	O
washed	O
with	O
three	O
2	O
ml	O
portions	O
of	O
anhydrous	O
pyridine	O
;	O
three	O
2	O
ml	O
portions	O
of	O
methylene	O

chloride	O
/	O
isopropanol	O
and	O
three	O
2	O
ml	O
portions	O
of	O
diethyl	O
ether	O
.	O

The	O
support	O
is	O
then	O
dried	O
under	O
house	O
vacuum	O
.	O

2	O
)	O
The	O
support	O
is	O
swollen	O
by	O
addition	O
of	O
2	O
ml	O
of	O
pyridine	O
and	O
the	O
excess	O
is	O
removed	O
under	O
house	O
vacuum	O
.	O

3	O
)	O
The	O
support	O
is	O
treated	O
with	O
3	O
ml	O
of	O
0	O
.	O
017	O
M	O
tetra	O
-	O
n	O
-	O
butylammonium	O
fluoride	O
in	O

tetrahydrofuran	O
/	O
pyridine	O
/	O
water	O
(	O
8	O
:	O
1	O
:	O
1	O
,	O
v	O
/	O
v	O
)	O
for	O
40	O
hrs	O
at	O
room	O
temperature	O
.	O

No	O
shaking	O
is	O
required	O
.	O

The	O
support	O
is	O
then	O
washed	O
with	O
three	O
2	O
ml	O
portions	O
of	O
50	O
%	O
pyridine	O
/	O
water	O
;	O
three	O
2	O
ml	O
portions	O
of	O
pyridine	O
;	O
and	O
three	O
2	O
ml	O

portions	O
of	O
methylene	O
chloride	O
/	O
isopropanol	O
.	O

4	O
)	O
The	O
support	O
is	O
treated	O
with	O
3	O
ml	O
of	O
ethylenediamine	O
/	O
ethanol	O
(	O
1	O
:	O
1	O
,	O
v	O
/	O
v	O
)	O
for	O
7	O
hrs	O
at	O
room	O
temperature	O

6228	O

Nucleic	O
Acids	O
Research	O

without	O
shaking	O
.	O

The	O
solution	O
is	O
collected	O
and	O
the	O
support	O
is	O
washed	O
with	O

four	O
2	O
ml	O
portions	O
of	O
pyridine	O
/	O
ethanol	O
(	O
1	O
:	O
1	O
,	O
v	O
/	O
v	O
)	O
and	O
four	O
2	O
ml	O
portions	O
of	O
N	O
,	O
N	O
-	O
dimethylformamide	O
.	O

The	O
combined	O
eluate	O
and	O
washings	O
are	O
evaporated	O
at	O
250C	O
and	O
the	O
oily	O
residue	O
is	O
co	O
-	O
evaporated	O
several	O
time	O
with	O
50	O
%	O
aqueous	O
ethanol	O
.	O

Purification	O
of	O
Oligonucleoside	O
Methylphosphonates	O
.	O

For	O
oligomers	O
which	O

contain	O
only	O
methylphosphonate	O
linkages	O
(	O
1	O
-	O
6	O
)	O
,	O
the	O
residue	O
from	O
step	O
4	O
)	O
of	O
the	O
previous	O
section	O
is	O
dissolved	O
in	O
a	O
small	O
volume	O
of	O
50	O
%	O
aqueous	O
ethanol	O
.	O

The	O
solution	O
is	O
chromatographed	O
on	O
a	O
C	O
-	O
18	O
reversed	O
phase	O
column	O
(	O
0	O
.	O
46	O
cm	O
x	O
25	O
cm	O

for	O
100	O
A254	O
units	O
or	O
less	O
;	O
0	O
.	O
9	O
cm	O
x	O
50	O
cm	O
for	O
more	O
than	O
100	O
A254	O
units	O
)	O
using	O
a	O
linear	O
gradient	O
of	O
0	O
%	O
to	O
25	O
%	O
(	O
8	O
-	O
mer	O
or	O
less	O
)	O
or	O
0	O
%	O
to	O
35	O
%	O
(	O
9	O
mer	O
)	O

acetonitrile	O
in	O
water	O
to	O
remove	O
non	O
-	O
tritylated	O
oligomers	O
.	O

The	O
desired	O

tritylated	O
oligomer	O
is	O
eluted	O
with	O
50	O
%	O
acetonitrile	O
in	O
water	O
.	O

The	O
solvents	O
are	O
evaporated	O
and	O
the	O
residue	O
is	O
treated	O
with	O
1	O
ml	O
of	O
80	O
%	O
acetic	O
acid	O
in	O
water	O
for	O
1	O
hr	O
at	O
room	O
temperature	O
.	O

The	O
solvents	O
are	O
evaporated	O
and	O
the	O

residue	O
is	O
repeatedly	O
evaporated	O
with	O
ethanol	O
to	O
ensure	O
complete	O
removal	O
of	O

acetic	O
acid	O
.	O

The	O
oligomer	O
is	O
then	O
purified	O
by	O
C	O
-	O
18	O
reversed	O
phase	O
HPLC	O
using	O
a	O
0	O
%	O
to	O
25	O
%	O
or	O
30	O
%	O
acetonitrile	O
in	O
water	O
gradient	O
.	O

For	O
oligomers	O
which	O
terminate	O
with	O
a	O
5	O
'	O
-	O
nucleoside	O
phosphodiester	O
linkage	O
(	O
7	O
-	O
10	O
)	O
the	O
residue	O
from	O
step	O
4	O
)	O
described	O
in	O
the	O
preceeding	O
section	O
is	O
treated	O
with	O
80	O
%	O
acetic	O
acid	O
in	O
water	O
for	O
15	O
min	O
at	O
room	O
temperature	O
.	O

After	O
removal	O
of	O
the	O
acetic	O
acid	O
by	O
evaporation	O
,	O
the	O
residue	O
is	O
dissolved	O
in	O
20	O
ml	O
of	O
50	O
%	O
aqueous	O
ethanol	O
and	O
the	O
solution	O
is	O
passed	O
through	O
a	O
DEAE	O
cellulose	O
column	O
(	O
2	O
.	O
5	O
x	O
8	O
cm	O
,	O
bicarbonate	O
form	O
)	O
which	O
has	O
been	O
previously	O
washed	O
with	O
50	O
%	O
aqueous	O
ethanol	O
.	O

The	O
column	O
is	O
monitored	O
at	O
254	O
nm	O
and	O
washed	O
with	O
50	O
%	O

aqueous	O
ethanol	O
until	O
the	O
pen	O
returns	O
to	O
the	O
baseline	O
.	O

The	O
desired	O
oligomer	O
is	O
then	O
eluted	O
with	O
0	O
.	O
15	O
M	O
triethylammonium	O
bicarbonate	O
in	O
50	O
%	O
aqueous	O

ethanol	O
.	O

The	O
buffer	O
is	O
removed	O
by	O
evaporation	O
and	O
co	O
-	O
evaporated	O
with	O
50	O
%	O

aqueous	O
ethanol	O
.	O

The	O
oligomer	O
is	O
then	O
further	O
purified	O
by	O
C	O
-	O
18	O
reversed	O
phase	O
HPLC	O
using	O
a	O
0	O
%	O
to	O
30	O
%	O
acetonitrile	O
in	O
0	O
.	O
10	O
M	O
ammonium	O
acetate	O
(	O
pH	O
5	O
.	O
8	O
)	O

gradient	O
.	O

The	O
oligomer	O
is	O
freed	O
of	O
ammonium	O
acetate	O
by	O
desalting	O
on	O
a	O
Bio	O
-	O
Gel	O
P	O
-	O
2	O
column	O
(	O
1	O
.	O
5	O
x	O
20	O
cm	O
)	O
.	O

Removal	O
of	O
the	O
5	O
'	O
-	O
Terminal	O
Nucleotide	O
Unit	O
.	O

Oligomers	O
which	O
terminate	O
with	O
a	O
5	O
'	O
-	O
nucleotide	O
phosphodiester	O
may	O
be	O
converted	O
to	O
the	O
oligonucleoside	O

methylphosphonate	O
by	O
the	O
following	O
procedure	O
.	O

The	O
oligomer	O
(	O
3	O
A254	O
units	O
)	O
is	O
dissolved	O
in	O
40	O
pl	O
of	O
water	O
and	O
treated	O
at	O
370C	O
for	O
2	O
hrs	O
with	O
10	O
PI	O
(	O
1	O
-	O
2	O

units	O
)	O
of	O
spleen	O
phosphodiesterase	O
dissolved	O
in	O
water	O
.	O

The	O
completeness	O
of	O
the	O
reaction	O
is	O
determined	O
by	O
reversed	O
phase	O
HPLC	O
.	O

The	O
solution	O
is	O
then	O

6229	O

Nucleic	O
Acids	O
Research	O

diluted	O
with	O
50	O
ul	O
of	O
water	O
and	O
passed	O
through	O
a	O
DEAE	O
cellulose	O
column	O
(	O
0	O
.	O
5	O
x	O
1	O
cm	O
)	O
.	O

The	O
column	O
is	O
washed	O
with	O
500	O
Pl	O
of	O
water	O
and	O
the	O
oligomer	O
is	O
recovered	O
by	O
lyophilization	O
.	O

Recovery	O
of	O
Protected	O
Nucleoside	O
3	O
'	O
-	O
Methylphosphonates	O
.	O

The	O
aqueous	O
pyridine	O
solution	O
from	O
step	O
9	O
)	O
described	O
in	O
General	O
Procedure	O
for	O
Preparing	O

Oligonucleoside	O
Methylphosphonates	O
,	O
is	O
evaporated	O
after	O
addition	O
of	O
0	O
.	O
1	O
ml	O
of	O
triethylamine	O
.	O

The	O
residue	O
is	O
dissolved	O
in	O
50	O
ml	O
of	O
chloroform	O
and	O
the	O

solution	O
is	O
extracted	O
twice	O
with	O
50	O
ml	O
of	O
1	O
M	O
ammonium	O
bicarbonate	O
.	O

The	O

chloroform	O
layer	O
is	O
dried	O
over	O
anhydrous	O
sodium	O
sulfate	O
.	O

Several	O
drops	O
of	O
triethylamine	O
are	O
added	O
to	O
clarify	O
the	O
solution	O
.	O

After	O
filtration	O
the	O

solvents	O
are	O
evaporated	O
and	O
the	O
residue	O
is	O
evaporated	O
with	O
three	O
2	O
ml	O
portions	O
of	O
anhydrous	O
pyridine	O
on	O
an	O
oil	O
pump	O
.	O

The	O
foamy	O
residue	O
is	O
dissolved	O
in	O
2	O
ml	O
of	O
dry	O
methylene	O
chloride	O
and	O
the	O
solution	O
is	O
added	O
dropwise	O
to	O
a	O
stirred	O
solution	O
of	O
1	O
%	O
triethylamine	O
in	O
hexane	O
.	O

The	O
resulting	O
precipitate	O
is	O

collected	O
via	O
filtration	O
on	O
a	O
sintered	O
glass	O
filter	O
,	O
washed	O
with	O
hexane	O
and	O
dried	O
in	O
a	O
vacuum	O
desiccator	O
.	O

Removal	O
of	O
Base	O
Protecting	O
Groups	O
with	O
Ethylenediamine	O
.	O

Several	O
mg	O
of	O

d	O
-	O
I	O
[	O
(	O
MeO	O
)	O
2Tr	O
]	O
bzA	O
,	O
d	O
-	O
[	O
(	O
MeO	O
)	O
2Tr	O
]	O
bzC	O
and	O
d	O
-	O
[	O
(	O
MeO	O
)	O
2Tr	O
]	O
ibu	O
G	O
were	O
each	O
dissolved	O
in	O
250	O
pl	O
of	O
ethylenediamine	O
/	O
ethanol	O
(	O
1	O
:	O
1	O
,	O
v	O
/	O
v	O
)	O
.	O

The	O
solutions	O
were	O
incubated	O
at	O
room	O
temperature	O
.	O

At	O
various	O
times	O
aliquots	O
were	O
chromatographed	O
on	O
silica	O
gel	O
TLC	O
plates	O
which	O
were	O
eluted	O
with	O
10	O
%	O
methanol	O
in	O
chloroform	O
.	O

The	O
spots	O
corresponding	O
to	O
the	O
starting	O
material	O
and	O
the	O
product	O
were	O
cut	O
out	O
and	O

treated	O
with	O
1	O
.	O
5	O
ml	O
of	O
perchloric	O
acid	O
/	O
ethanol	O
(	O
3	O
:	O
2	O
,	O
v	O
/	O
v	O
)	O
for	O
30	O
min	O
.	O

The	O

absorbance	O
of	O
each	O
solution	O
was	O
measured	O
at	O
500	O
nm	O
and	O
the	O
percent	O
reaction	O
was	O
determined	O
.	O

The	O
half	O
-	O
lives	O
of	O
the	O
reactions	O
are	O
given	O
in	O
Table	O
II	O
.	O

Removal	O
of	O
Protected	O
-	O
Nucleosides	O
from	O
Polystyrene	O
Support	O
.	O

Five	O
mg	O
of	O
d	O
-	O
[	O
(	O
MeO	O
)	O
2Tr	O
]	O
T	O
(	O
ED	O
(	O
1	O
%	O
crosslinked	O
)	O
,	O
d	O
-	O
[	O
(	O
MeO	O
)	O
2Tr	O
]	O
bzA	O
O	O
?	O
(	O
1	O
%	O
crosslinked	O
)	O
,	O

d	O
-	O
[	O
(	O
MeO	O
)	O
2Tr	O
]	O
bzC	O
(	O
?	O
)	O
(	O
1	O
%	O
and	O
2	O
%	O
crosslinked	O
)	O
and	O
d	O
-	O
[	O
(	O
MeO	O
)	O
2Tr	O
]	O
ibuGcD	O
(	O
1	O
%	O
and	O
2	O
%	O
crosslinked	O
)	O
were	O
each	O
treated	O
with	O
500	O
ul	O
of	O
ethylenediamine	O
/	O
ethanol	O
(	O
1	O
:	O
1	O
,	O
v	O
/	O
v	O
)	O
solution	O
at	O
room	O
temperature	O
.	O

At	O
various	O
times	O
,	O
10	O
pl	O
aliquots	O
were	O

removed	O
,	O
the	O
solvent	O
was	O
evaporated	O
and	O
the	O
residue	O
was	O
dissolved	O
in	O
1	O
ml	O
of	O
perchloric	O
acid	O
/	O
ethanol	O
solution	O
(	O
3	O
:	O
2	O
,	O
v	O
/	O
v	O
)	O
.	O

The	O
amount	O
of	O
dimethoxytrityl	O
cation	O
and	O
hence	O
the	O
amount	O
of	O
nucleoside	O
cleaved	O
from	O
the	O
support	O
was	O

determined	O
by	O
measuring	O
the	O
absorbance	O
at	O
500	O
nm	O
.	O

The	O
half	O
lives	O
of	O
the	O
cleavage	O
reactions	O
are	O
given	O
in	O
Table	O
II	O
.	O

Hydrolysis	O
of	O
the	O
Methylphosphonate	O
Linkage	O
by	O
Ethylenediamine	O
.	O

Oligonucleoside	O
methylphosphonates	O
(	O
1	O
.	O
25	O
A254	O
units	O
each	O
)	O
were	O
treated	O
with	O
50	O
il	O
of	O
ethylenediamine	O
/	O
ethanol	O
(	O
1	O
:	O
1	O
,	O
v	O
/	O
v	O
)	O
at	O
room	O
temperature	O
.	O

Aliquots	O

6230	O

Nucleic	O
Acids	O
Research	O

(	O
10	O
pl	O
)	O
were	O
withdrawn	O
at	O
various	O
times	O
and	O
the	O
solvents	O
were	O
evaporated	O
.	O

The	O
residue	O
was	O
dissolved	O
in	O
20	O
PI	O
of	O
50	O
%	O
aqueous	O
ethanol	O
and	O
the	O
solution	O

examined	O
by	O
C	O
-	O
18	O
reversed	O
phase	O
HPLC	O
using	O
a	O
0	O
%	O
to	O
25	O
%	O
acetonitrile	O
in	O
water	O
gradient	O
.	O

The	O
mole	O
percent	O
of	O
starting	O
oligomer	O
remaining	O
after	O
100	O
hrs	O
of	O
treatment	O
is	O
given	O
in	O
Table	O
III	O
.	O

Hydrolysis	O
of	O
Oligonucleoside	O
Methylphosphonates	O
in	O
Acid	O
.	O

Six	O
A254	O
units	O
of	O
oligomer	O
were	O
dissolved	O
in	O
100	O
pl	O
of	O
0	O
.	O
01	O
M	O
hydrochloric	O
acid	O
solution	O
.	O

The	O

solution	O
was	O
heated	O
at	O
either	O
450	O
or	O
650C	O
.	O

Aliquots	O
(	O
10	O
Pil	O
)	O
were	O
withdrawn	O
at	O
various	O
times	O
and	O
added	O
to	O
10	O
pl	O
of	O
0	O
.	O
015	O
M	O
ammonium	O
hydroxide	O
at	O
0	O
?	O
C	O
.	O

The	O
samples	O
were	O
then	O
injected	O
directly	O
onto	O
a	O
C	O
-	O
18	O
reversed	O
phase	O
column	O
which	O

was	O
eluted	O
with	O
50	O
ml	O
of	O
a	O
linear	O
gradient	O
of	O
0	O
%	O
to	O
25	O
%	O
acetonitrile	O
in	O
water	O

at	O
a	O
flow	O
rate	O
of	O
2	O
.	O
5	O
ml	O
/	O
min	O
.	O

The	O
products	O
of	O
the	O
reaction	O
were	O
determined	O
by	O
comparison	O
with	O
authentic	O
samples	O
.	O

Labeling	O
5	O
'	O
-	O
End	O
of	O
Oligonucleoside	O
Methylphosphonates	O
with	O
T4	O
-	O
Polynucleotide	O
Kinase	O
.	O

Oligonucleoside	O
methylphosphonates	O
(	O
2	O
nmol	O
)	O
were	O
dissolved	O
in	O
a	O
buffer	O
solution	O
containing	O
50	O
mM	O
Tris	O
-	O
HC1	O
(	O
pH	O
9	O
.	O
0	O
)	O
,	O
10	O
mM	O
MgCl2	O
,	O
5	O
mM	O
dithiothreitol	O
,	O
20	O
pM	O
spermidine	O
,	O
and	O
[	O
y	O
-	O
32P	O
]	O
ATP	O
(	O
8	O
ljCi	O
,	O
4Ci	O
/	O
mmol	O
)	O
.	O

T4	O
-	O
polynucleotide	O
kinase	O
(	O
4	O
units	O
)	O
was	O
added	O
to	O
the	O
solution	O
,	O
which	O
was	O
made	O
up	O
to	O
50	O
ul	O
by	O
adding	O
water	O
.	O

The	O
solutions	O
were	O
incubated	O
at	O
370C	O
for	O
2	O
hrs	O
.	O

The	O
reaction	O
was	O
checked	O
by	O
PEI	O
-	O
cellulose	O
TLC	O
.	O

The	O
PEI	O
-	O
cellulose	O
plate	O

(	O
12x2Ocm	O
,	O
Merck	O
)	O
was	O
preactivated	O
by	O
elution	O
with	O
1	O
.	O
2	O
M	O
pyridinium	O
formate	O
(	O
pH	O
3	O
.	O
5	O
)	O
.	O

Small	O
aliquots	O
(	O
0	O
.	O
1	O
pl	O
)	O
of	O
PNK	O
reaction	O
solutions	O
were	O
applied	O
and	O

developed	O
with	O
1	O
.	O
5	O
M	O
pyridinium	O
formate	O
(	O
pH	O
3	O
.	O
5	O
)	O
.	O

The	O
TLC	O
plate	O
was	O
dried	O
and	O
autoradiographed	O
using	O
an	O
intensifying	O
screen	O
at	O
room	O
temperature	O
.	O

Gel	O
Electrophoresis	O
of	O
5	O
'	O
-	O
Labeled	O
Oligonucleoside	O
Methylphosphonates	O
.	O

Polyacrylamide	O
gels	O
were	O
prepared	O
by	O
polymerizing	O
a	O
solution	O
containing	O
18	O
%	O
(	O
w	O
/	O
v	O
)	O
acrylamide	O
,	O
0	O
.	O
8	O
%	O
(	O
w	O
/	O
v	O
)	O
N	O
,	O
N	O
'	O
-	O
methylenebisacrylami	O
.	O

7M	O
urea	O
,	O
89	O
mM	O
Tris	O
-	O
borate	O
(	O
pH	O
8	O
.	O
2	O
)	O
,	O
2	O
mM	O
EDTA	O
,	O
0	O
.	O
07	O
%	O
(	O
w	O
/	O
v	O
)	O
ammonium	O
persulfate	O
,	O
in	O
the	O

presence	O
of	O
N	O
,	O
N	O
,	O
N	O
'	O
,	O
N	O
'	O
-	O
tetramethylethylened	O
(	O
20	O
Pil	O
/	O
20	O
ml	O
solution	O
)	O
.	O

The	O

solution	O
was	O
poured	O
into	O
a	O
0	O
.	O
75	O
x	O
140	O
x	O
150	O
mm	O
mold	O
and	O
allowed	O
to	O
polymerize	O
for	O
2	O
hrs	O
at	O
room	O
temperature	O
.	O

5	O
'	O
-	O
Labeled	O
oligonucleoside	O
methylphosphonates	O
were	O
dissolved	O
in	O
10	O
%	O
aqueous	O
glycerol	O
solution	O
containing	O
0	O
.	O
04	O
%	O
bromophenol	O
blue	O
and	O
applied	O
to	O
the	O
gel	O
.	O

The	O
electrophoresis	O
was	O
run	O
using	O
89	O
mM	O

Tris	O
-	O
Borate	O
buffer	O
containing	O
10	O
mM	O
EDTA	O
.	O

After	O
electrophoresis	O
the	O
gel	O
was	O
dried	O
using	O
a	O
gel	O
-	O
dryer	O
and	O
autoradiographed	O
using	O
intensifying	O
screens	O
at	O
room	O
temperature	O
.	O

Pa	O
rti	O
al	O
Cl	O
eavage	O
of	O
01	O
i	O
gonucl	O
eosi	O
de	O
Methyl	O
phosphonates	O
wi	O
th	O
Hydrochl	O
ori	O
c	O
Aci	O
d	O
or	O
Piperidine	O
.	O

Aliquots	O
(	O
1	O
,	O
jl	O
)	O
from	O
the	O
polynucleotide	O
kinase	O
reaction	O

6231	O

Nucleic	O
Acids	O
Research	O

mixture	O
were	O
incubated	O
with	O
1	O
il	O
of	O
1	O
M	O
hydrochloric	O
acid	O
at	O
37	O
?	O
C	O
for	O
30	O
min	O
.	O

After	O
incubation	O
the	O
solution	O
was	O
neutralized	O
with	O
1	O
Pl	O
of	O
1	O
M	O
ammonium	O

hydroxide	O
and	O
then	O
allowed	O
to	O
stand	O
at	O
room	O
temperature	O
for	O
10	O
min	O
before	O
cooling	O
to	O
00	O
.	O

Alternatively	O
,	O
aliquots	O
(	O
1	O
pl	O
)	O
from	O
the	O
phosphorylation	O

reaction	O
were	O
incubated	O
with	O
1	O
ul	O
of	O
1	O
M	O
aqueous	O
piperidine	O
at	O
370C	O
for	O
10	O
min	O
after	O
which	O
the	O
solution	O
was	O
cooled	O
to	O
0	O
?	O
and	O
evaporated	O
.	O

The	O
treated	O

samples	O
were	O
then	O
subjected	O
to	O
polyacrylamide	O
gel	O
electrophoresis	O
as	O
described	O
above	O
without	O
further	O
purification	O
.	O

RESULTS	O
AND	O
DISCUSSION	O

Synthesis	O
of	O
Protected	O
Oligonucleoside	O
Methylphosphonates	O
.	O

Table	O
I	O
shows	O
some	O
of	O
the	O
protected	O
oligonucleoside	O
methylphosphonates	O
which	O
have	O
been	O

synthesized	O
on	O
aminomethyl	O
succinyl	O
-	O
derivatized	O
polystyrene	O
supports	O
.	O

The	O
basic	O
synthetic	O
steps	O
which	O
are	O
shown	O
in	O
Figure	O
1	O
are	O
described	O
in	O
detail	O
in	O
the	O
Experimental	O
section	O
.	O

These	O
steps	O
are	O
:	O
(	O
1	O
)	O
removal	O
of	O
the	O

dimethoxytrityl	O
group	O
with	O
1	O
M	O
zinc	O
bromide	O
solution	O
;	O
(	O
2	O
)	O
drying	O
the	O
support	O

via	O
co	O
-	O
evaporation	O
with	O
anhydrous	O
pyridine	O
;	O
(	O
3	O
)	O
reaction	O
of	O
the	O
support	O
-	O
bound	O

nucleoside	O
or	O
oligonucleotide	O
with	O
a	O
coupling	O
mixture	O
containing	O
0	O
.	O
15	O
to	O
0	O
.	O
2	O
M	O
d	O
-	O
[	O
(	O
MeO	O
)	O
2Tr	O
)	O
-	O
NpjEt3NH	O
and	O
0	O
.	O
3	O
to	O
0	O
.	O
6	O
M	O
mesitylenesulfonyl	O
-	O
3	O
-	O
nitrotriazole	O
in	O
anhydrous	O
pyridine	O
and	O
(	O
4	O
)	O
acetylation	O
of	O
unreacted	O
5	O
'	O
-	O
OH	O
groups	O
with	O
acetic	O

anhydride	O
.	O

The	O
reactions	O
and	O
washing	O
steps	O
were	O
most	O
conveniently	O
carried	O
out	O
in	O
a	O
polypropylene	O
Econo	O
Column	O
fitted	O
with	O
a	O
septum	O
cap	O
and	O
a	O
3	O
-	O
way	O
Teflon	O

DMTrO	O
,	O
O	O
Figure	O
1	O
:	O
Preparation	O
of	O
Protected	O

Oligonucleoside	O
Methylphosphonates	O
on	O
a	O
1	O
T	O
o	O
w	O
Polystyrene	O
Support	O

0	O

H	O
BFvON	O
DlDTrOjO4B	O

U	O
)	O
I	O
CH3	O
-	O
gd	O
-	O
OEt	O
3NH	O

0	O

6232	O

Nucleic	O
Acids	O
Research	O

stopcock	O
.	O

Thus	O
no	O
transfers	O
of	O
the	O
support	O
are	O
required	O
using	O
this	O
apparatus	O
.	O

The	O
synthetic	O
procedure	O
is	O
analogous	O
to	O
the	O
phosphotriester	O
approach	O
used	O
to	O
prepared	O
protected	O
oligonucleotide	O
phosphotriesters	O
on	O
polystyrene	O
supports	O
(	O
6	O
)	O
.	O

However	O
,	O
we	O
found	O
the	O
methylphosrhonate	O
coupling	O
reaction	O
to	O
be	O

extremely	O
sensitive	O
to	O
moisture	O
.	O

Drying	O
procedures	O
such	O
as	O
washing	O
with	O

anhydrous	O
solvent	O
or	O
blowing	O
dry	O
nitrogen	O
gas	O
through	O
the	O
support	O
which	O
are	O
satisfactory	O
for	O
phosphotriester	O
synthesis	O
resulted	O
in	O
low	O
yields	O
of	O
the	O
methylphosphonates	O
.	O

The	O
best	O
yields	O
were	O
obtained	O
when	O
the	O
support	O
was	O

co	O
-	O
evaporated	O
with	O
anhydrous	O
pyridine	O
by	O
directly	O
attaching	O
the	O
reaction	O

column	O
to	O
a	O
vacuum	O
pump	O
and	O
dry	O
-	O
ice	O
trap	O
.	O

Three	O
10	O
min	O
co	O
-	O
evaporations	O
were	O
sufficient	O
to	O
render	O
the	O
support	O
anhydrous	O
.	O

The	O
protected	O
nucleoside	O
3	O
'	O
-	O
methylphosphonate	O
triethylammonium	O
salts	O
used	O
in	O
the	O
coupling	O
reactions	O
were	O
prepared	O
from	O
their	O
cyanoethyl	O
ester	O

derivatives	O
(	O
3	O
)	O
.	O

These	O
monomers	O
were	O
recovered	O
after	O
each	O
coupling	O
step	O
and	O

were	O
freed	O
of	O
unreacted	O
MSNT	O
by	O
a	O
simple	O
extraction	O
step	O
.	O

After	O
precipitation	O
and	O
drying	O
,	O
the	O
monomers	O
could	O
be	O
reused	O
for	O
other	O
syntheses	O
.	O

The	O
ability	O
to	O
recover	O
the	O
unreacted	O
monomers	O
is	O
particularly	O
important	O
for	O
large	O
scale	O

synthesis	O
since	O
large	O
excesses	O
of	O
these	O
materials	O
are	O
employed	O
in	O
the	O
coupling	O
step	O
.	O

This	O
recovery	O
step	O
represents	O
a	O
potential	O
advantage	O
over	O
the	O
phosphine	O
synthetic	O
method	O
(	O
4	O
)	O
,	O
since	O
it	O
is	O
not	O
clear	O
that	O
nucleoside	O
3	O
'	O
-	O
methylphosphine	O
chlorides	O
can	O
be	O
recovered	O
after	O
reaction	O
.	O

Two	O
types	O
of	O
methylphosphonate	O
oligomers	O
were	O
prepared	O
;	O
those	O
which	O
contain	O
only	O
methylphosphonate	O
linkages	O
,	O
oligomers	O
1	O
-	O
6	O
,	O
and	O
those	O
which	O
terminate	O
with	O
a	O
5	O
'	O
-	O
nucleoside	O
3	O
'	O
-	O
p	O
-	O
chlorophenyl	O
phosphotriester	O
moiety	O
,	O

oligomers	O
7	O
-	O
10	O
.	O

Oligomers	O
were	O
synthesized	O
on	O
both	O
1	O
%	O
and	O
2	O
%	O
crosslinked	O

supports	O
.	O

As	O
shown	O
in	O
Table	O
I	O
,	O
the	O
average	O
yield	O
per	O
coupling	O
step	O
which	O
was	O
determined	O
by	O
trityl	O
group	O
analysis	O
was	O
approximately	O
82	O
%	O
,	O
for	O
both	O
types	O
of	O

support	O
.	O

This	O
yield	O
is	O
adequate	O
to	O
allow	O
preparation	O
of	O
protected	O
octamers	O
or	O
nonamers	O
in	O
25	O
%	O
and	O
20	O
%	O
overall	O
yield	O
,	O
respectively	O
.	O

Deprotection	O
.	O

Our	O
previous	O
studies	O
(	O
1	O
)	O
and	O
those	O
of	O
Sinha	O
et	O
al	O
.	O

(	O
4	O
)	O
show	O

that	O
methylphosphonate	O
linkages	O
are	O
cleaved	O
by	O
base	O
.	O

We	O
found	O
this	O
hydrolysis	O
reaction	O
to	O
depend	O
to	O
some	O
extent	O
upon	O
the	O
nucleoside	O
sequence	O
of	O
the	O

oligomer	O
.	O

Hydrolysis	O
of	O
methylphosphonate	O
linkages	O
by	O
concentrated	O
ammonium	O
hydroxide	O
in	O
pyridine	O
(	O
1	O
:	O
1	O
v	O
/	O
v	O
)	O
,	O
the	O
reagent	O
commonly	O
used	O
to	O
remove	O

oligonucleotide	O
base	O
protecting	O
groups	O
,	O
can	O
be	O
largely	O
suppressed	O
if	O
the	O

reactions	O
are	O
run	O
at	O
0	O
?	O
C	O
(	O
1	O
)	O
.	O

However	O
,	O
these	O
conditions	O
are	O
unsatisfactory	O
for	O
removal	O
of	O
oligonucleoside	O
methylphosphonates	O
from	O
the	O
polystyrene	O

6233	O

Nucleic	O
Acids	O
Research	O

Table	O
I	O
.	O
Syntheses	O
of	O
Protected	O
Oligonucleoside	O
Methylphosphonates	O
on	O

Polystyrene	O
Supports	O

Support	O
Average	O
cross	O
-	O
yield	O
Protected	O
oligomer	O
(	O
a	O
)	O
linking	O
per	O

(	O
%	O
)	O
coupling	O

step	O
(	O
%	O
)	O

1	O
d	O
-	O
[	O
(	O
MeO	O
)	O
2Tr	O
]	O
bzCpbzCpbzApT	O
-	O
O	O
1	O
81	O
2	O
d	O
-	O
[	O
(	O
MeO	O
)	O
2Tr	O
]	O
ibuGpbzCpbzCpbzApT	O
-	O
1	O
82	O
3	O
d	O
-	O
[	O
(	O
MeO	O
)	O
2Tr	O
]	O
bzCpbzApi	O
buGpi	O
buGpTpbzApbzA	O
-	O
G1i	O
2	O
83	O
4	O
d	O
-	O
[	O
(	O
MeO	O
)	O
2Tr	O
]	O
bzCLpTpT	O
bzApbzCpbzCpTpibuG	O
-	O
?	O

2	O
85	O
5	O
d	O
-	O
[	O
(	O
MeO	O
)	O
2Tr	O
]	O
TpbzCpbzCpTpbzCpbzCp	O
-	O
(	O
?	O

2	O
86	O
6	O
d	O
-	O
[	O
(	O
MeO	O
)	O
2Tr	O
]	O
TpTpTpbzApbzCpbzCpTp	O
-	O
?	O

1	O
83	O
7	O
d	O
-	O
[	O
(	O
MeO	O
)	O
2Tr	O
]	O
bzApbzApbzA	O
-	O
?	O

1	O
83	O
8	O
d	O
-	O
[	O
(	O
MeO	O
)	O
2Tr	O
]	O
bzA4bzCpbzCpbzApT	O
-	O
?	O

1	O
81	O
9	O
d	O
-	O
[	O
(	O
MeO	O
)	O
2Tr	O
]	O
bzApibuGpbzCpbzApbzA	O
-	O
(	O
2	O
74	O
10	O
d	O
-	O
[	O
(	O
MeO	O
)	O
2Tr	O
]	O
bzApbzApbzApbzApibuG	O
-	O
(	O
Q	O
1	O
86	O

(	O
a	O
)	O
p	O
=	O
methylphosphonate	O
linkage	O

T	O
=	O
p	O
-	O
chlorophenyl	O
phosphotriester	O
linkage	O
(	O
Q	O
=	O
polystyrene	O
support	O

(	O
b	O
)	O
Determined	O
by	O
analysis	O
of	O
the	O
dimethoxytrityl	O
group	O
after	O
each	O

coupling	O
step	O
.	O

support	O
.	O

We	O
therefore	O
examined	O
other	O
deprotection	O
procedures	O
.	O

Recently	O
Barnett	O
and	O
Letsinger	O
described	O
removal	O
of	O
base	O
protecting	O
groups	O
from	O
oligonucleotide	O
B	O
,	O
B	O
,	O
0	O
-	O
trichloroethylphosph	O
using	O
a	O

mixture	O
of	O
ethylenediamine	O
in	O
phenol	O
(	O
7	O
)	O
.	O

We	O
have	O
found	O
ethylenediamine	O
in	O
ethanol	O
(	O
1	O
:	O
1	O
,	O
v	O
/	O
v	O
)	O
rapidly	O
and	O
cleanly	O
removes	O
benzoyl	O
and	O
isobutyryl	O
protecting	O
groups	O
from	O
dA	O
,	O
dC	O
and	O
dG	O
nucleosides	O
.	O

This	O
reagent	O
is	O

particularly	O
attractive	O
since	O
it	O
can	O
be	O
easily	O
removed	O
by	O
evaporation	O
.	O

In	O
our	O
initial	O
investigations	O
,	O
ol	O
igonucleoside	O
methylphosphonates	O
were	O

cleaved	O
from	O
the	O
support	O
and	O
base	O
protecting	O
groups	O
were	O
removed	O
by	O
treatment	O
with	O
ethylenediamine	O
/	O
ethanol	O
(	O
1	O
:	O
1	O
,	O
v	O
/	O
v	O
)	O
at	O
65	O
?	O
C	O
for	O
3	O
hrs	O
.	O

Although	O

preliminary	O
results	O
indicated	O
the	O
methylphosphonate	O
linkages	O
of	O
several	O
dimers	O
were	O
stable	O
to	O
these	O
conditions	O
,	O
we	O
later	O
found	O
that	O
the	O
linkages	O
of	O
onger	O

6234	O

Nucleic	O
Acids	O
Research	O

Table	O
II	O
.	O

Hydrolysis	O
of	O
Protected	O
Nucleosides	O
by	O
Ethylenediamine	O
at	O
220C	O

Protected	O
Time	O
required	O
to	O
Time	O
required	O
to	O
nucleoside	O
remove	O
50	O
%	O
of	O
the	O
cleave	O
50	O
%	O
of	O
the	O

base	O
protecting	O
nucleoside	O
from	O
the	O
groups	O
(	O
min	O
)	O
1	O
%	O
crosslinked	O

support	O
(	O
min	O
)	O

d	O
-	O
[	O
(	O
MeO	O
)	O
2Tr	O
)	O
bzA	O
10	O
105	O
d	O
-	O
[	O
(	O
MeO	O
)	O
2Tr	O
bzC	O
20	O
105	O
d	O
-	O
[	O
(	O
MeO	O
)	O
2Tr	O
]	O
i	O
buG	O
40	O
54	O
d	O
-	O
[	O
(	O
MeO	O
)	O
2Tr	O
]	O
T	O
_	O
105	O

oligomers	O
were	O
hydrolyzed	O
to	O
various	O
extents	O
by	O
this	O
procedure	O
.	O

This	O
of	O

course	O
resulted	O
in	O
loss	O
of	O
product	O
as	O
was	O
evidenced	O
by	O
the	O
presence	O
of	O
shorter	O
oligomers	O
in	O
amounts	O
greater	O
than	O
expected	O
based	O
upon	O
the	O
coupling	O
yields	O
.	O

To	O
circumvent	O
this	O
problem	O
we	O
examined	O
the	O
deprotection	O
reactions	O
at	O
lower	O
temperatures	O
and	O
found	O
they	O
could	O
be	O
run	O
effectively	O
at	O
room	O

temperature	O
.	O

Table	O
II	O
shows	O
the	O
half	O
-	O
lives	O
for	O
removing	O
the	O
base	O
protecting	O
groups	O
from	O
nucleosides	O
at	O
room	O
temperature	O
.	O

While	O
the	O
isobutryl	O
protecting	O
group	O
is	O
removed	O
at	O
the	O
slowest	O
rate	O
,	O
all	O
the	O
groups	O
are	O
completely	O
removed	O
within	O
240	O
min	O
.	O

The	O
sole	O
product	O
of	O
each	O
reaction	O
is	O
the	O
5	O
'	O
-	O
O	O
-	O
dimethoxytritylnucle	O
as	O
shown	O
by	O
TLC	O
.	O

Table	O
II	O
also	O
shows	O
the	O
half	O
-	O
lives	O
for	O
cleavage	O
of	O
protected	O
nucleosides	O
from	O
the	O
1	O
%	O
crosslinked	O
support	O
.	O

The	O
deoxyguanosine	O
nucleoside	O
is	O
cleaved	O

most	O
rapidly	O
while	O
the	O
other	O
three	O
nucleosides	O
have	O
essentially	O
the	O
same	O
rates	O
of	O
hydrolysis	O
.	O

All	O
the	O
nucleosides	O
are	O
completely	O
removed	O
from	O
the	O
support	O
within	O
7	O
hrs	O
.	O

In	O
contrast	O
,	O
very	O
different	O
rates	O
were	O
observed	O
for	O
the	O
2	O
%	O

crosslinked	O
supports	O
.	O

In	O
these	O
cases	O
,	O
very	O
little	O
cleavage	O
occurred	O
during	O
the	O
first	O
4	O
hrs	O
of	O
incubation	O
after	O
which	O
increasing	O
amounts	O
of	O
nucleoside	O
were	O
released	O
over	O
a	O
24	O
hr	O
period	O
.	O

This	O
effect	O
may	O
be	O
due	O
to	O
the	O
slower	O
swelling	O
rate	O
of	O
the	O
2	O
%	O
crosslinked	O
support	O
versus	O
the	O
1	O
%	O
support	O
.	O

The	O

results	O
of	O
these	O
experiments	O
suggest	O
that	O
,	O
although	O
condensation	O
reactions	O

occur	O
with	O
equal	O
efficiencies	O
on	O
both	O
the	O
1	O
%	O
and	O
2	O
%	O
crosslinked	O
supports	O
,	O
the	O
1	O
%	O
support	O
is	O
preferred	O
for	O
syntheses	O
since	O
the	O
oligomers	O
can	O
be	O
removed	O
more	O
readily	O
under	O
mild	O
conditions	O
.	O

The	O
stability	O
of	O
the	O
methylphosphonate	O
linkage	O
in	O
a	O
number	O
of	O
oligomers	O

of	O
varying	O
chain	O
length	O
and	O
base	O
composition	O
was	O
examined	O
following	O
prolonged	O
exposure	O
to	O
ethylenediamine	O
/	O
ethanol	O
at	O
room	O
temperature	O
.	O

As	O
shown	O
in	O
Table	O
III	O
,	O
some	O
of	O
these	O
oligomers	O
,	O
most	O
notably	O
the	O
dimer	O
and	O
d	O
-	O
GpGpT	O
,	O
were	O

6235	O

Nucleic	O
Acids	O
Research	O

Table	O
III	O
.	O

Hydrolysis	O
of	O
Oligonucleoside	O
Methylphosphonates	O
by	O

Ethylenediamine	O
at	O
22	O
?	O
C	O

|	O
Oligomer	O
Mole	O
percent	O
of	O
oligomer	O
remaining	O
after	O
treatment	O
for	O

24	O
hrs	O
48	O
hrs	O
96	O
hrs	O

d	O
-	O
T	O
A	O
100	O
100	O
100	O
d	O
-	O
A5r	O
100	O
100	O
100	O
d	O
-	O
TpT	O
100	O
100	O
100	O
d	O
-	O
l	O
pT	O
95	O
97	O
91	O
d	O
-	O
qgG	O
{	O
T	O
100	O
100	O
100	O
d	O
-	O
ApApA	O
93	O
87	O
75	O
d	O
-	O
C	O
pC	O
ApT	O
92	O
83	O
67	O

completely	O
stable	O
over	O
a	O
96	O
hr	O
period	O
.	O

The	O
maximum	O
rate	O
of	O
hydrolysis	O
for	O
a	O
methylphosphonate	O
linkage	O
in	O
those	O
oligomers	O
which	O
were	O
hydrolyzed	O
is	O

estimated	O
to	O
be	O
0	O
.	O
13	O
mole	O
%	O
/	O
hr	O
.	O

The	O
results	O
of	O
these	O
studies	O
show	O
that	O
the	O
oligonucleoside	O
methylphosphonates	O
could	O
be	O
cleaved	O
from	O
the	O
1	O
%	O
crosslinked	O
support	O
and	O
completely	O
freed	O
of	O
base	O
protecting	O
groups	O
with	O
little	O
or	O
no	O
hydrolysis	O
of	O
the	O
methylphosphonate	O
linkage	O
by	O
treatment	O
with	O

ethylenediamine	O
/	O
ethanol	O
(	O
1	O
:	O
1	O
,	O
v	O
/	O
v	O
)	O
at	O
room	O
temperature	O
for	O
7	O
hrs	O
.	O

These	O
conditions	O
were	O
subsequently	O
adopted	O
for	O
the	O
deprotection	O
step	O
.	O

Purification	O
of	O
Oligonucleoside	O
Methylphosphonates	O
.	O

Two	O
methods	O
were	O
employed	O
to	O
purify	O
oligomers	O
following	O
cleavage	O
from	O
the	O
support	O
.	O

For	O
oligomers	O
which	O
contain	O
only	O
methylphosphonate	O
linkages	O
,	O
the	O
tritylated	O
oligomer	O
was	O
isolated	O

by	O
preparative	O
reversed	O
phase	O
HPLC	O
.	O

This	O
separation	O
is	O
based	O
upon	O
the	O
greater	O
affinity	O
of	O
the	O
tritylated	O
oligomer	O
for	O
the	O
hydrophobic	O
C	O
-	O
18	O
matrix	O
of	O
the	O

column	O
.	O

Shorter	O
,	O
non	O
-	O
tritylated	O
oligomers	O
were	O
first	O
eluted	O
with	O
a	O
0	O
%	O
to	O
25	O
%	O
or	O
0	O
%	O
to	O
30	O
%	O
acetonitrile	O
in	O
water	O
gradient	O
.	O

The	O
tritylated	O
product	O
was	O
then	O
eluted	O
with	O
a	O
step	O
gradient	O
of	O
50	O
%	O
acetonitrile	O
in	O
water	O
.	O

The	O
dimethoxytrityl	O
group	O
was	O
removed	O
from	O
the	O
material	O
in	O
the	O
50	O
%	O

acetonitrile	O
fraction	O
by	O
treatment	O
with	O
80	O
%	O
acetic	O
acid	O
at	O
room	O
temperature	O
.	O

Because	O
these	O
oligomers	O
were	O
originally	O
cleaved	O
from	O
the	O
support	O
by	O

ethylenediamine	O
/	O
ethanol	O
(	O
1	O
:	O
1	O
,	O
v	O
/	O
v	O
)	O
at	O
65	O
?	O
C	O
,	O
we	O
usually	O
found	O
that	O
the	O

tritylated	O
oligomer	O
fraction	O
contained	O
shorter	O
oligomers	O
in	O
addition	O
to	O
the	O
desired	O
product	O
.	O

These	O
were	O
easily	O
separated	O
by	O
preparative	O
reversed	O
phase	O
HPLC	O
.	O

While	O
this	O
purification	O
procedure	O
is	O
qualitatively	O
satisfactory	O
,	O

recoveries	O
from	O
the	O
reversed	O
phase	O
columns	O
varied	O
from	O
50	O
%	O
to	O
90	O
%	O
.	O

These	O

losses	O
which	O
appeared	O
to	O
be	O
due	O
to	O
irreverisble	O
absorption	O
of	O
the	O
oligomers	O
to	O
the	O
column	O
varied	O
depending	O
on	O
the	O
base	O
composition	O
of	O
the	O
oligomers	O
.	O

6236	O

Nucleic	O
Acids	O
Research	O

Figure	O
2	O
:	O
Purification	O
of	O

d	O
-	O
ApApApApGpCpApApG	O
.	O

(	O
a	O
)	O
Ol	O
igomers	O
obtained	O
after	O
treatment	O
of	O
support	O
wi	O
th	O
ethylenediamine	O
/	O
ethanol	O
(	O
1	O
:	O
1	O
,	O

v	O
/	O
v	O
)	O
.	O

(	O
b	O
)	O
Ol	O
igomers	O
obtained	O
after	O
treatment	O
of	O
the	O
mixture	O
in	O
(	O
a	O
)	O
with	O
80	O
%	O
acetic	O
acid	O
.	O

(	O
c	O
)	O
Oligomers	O
eluted	O
from	O
DEAE	O
cellulose	O
column	O
with	O

0	O
.	O
15	O
M	O
triethylammonium	O
bicarbonate	O
.	O

(	O
d	O
)	O
Nonamer	O
obtained	O
after	O
preparative	O
reversed	O
phase	O
HPLC	O
.	O

Peaks	O
marked	O

with	O
the	O
symbol	O
(	O
X	O
)	O
are	O
derived	O
from	O
impurities	O
in	O
the	O
solvents	O
used	O
to	O
elute	O
the	O
oligomer	O
from	O
the	O
polystyrene	O
support	O
.	O

d	O
"	O
AAAGCAAGc	O

O	O
I	O
t10	O
15	O
20	O
25	O

Time	O
(	O
min	O
)	O

For	O
the	O
oligomers	O
which	O
terminate	O
with	O
a	O
5	O
'	O
-	O
nucleoside	O
phosphotriester	O
group	O
,	O
the	O
support	O
was	O
first	O
treated	O
for	O
40	O
hrs	O
with	O
tetra	O
-	O
n	O
-	O
butylammonium	O

fluoride	O
(	O
8	O
)	O
to	O
remove	O
the	O
p	O
-	O
chlorophenyl	O
protecting	O
group	O
.	O

These	O
oligomers	O

6237	O

b	O

Nucleic	O
Acids	O
Research	O

were	O
then	O
cleaved	O
from	O
the	O
support	O
and	O
the	O
base	O
protecting	O
groups	O
were	O
removed	O
by	O
treatment	O
with	O
ethylenediamine	O
/	O
ethanol	O
(	O
1	O
:	O
1	O
,	O
v	O
/	O
v	O
)	O
for	O
7	O
hrs	O
at	O
room	O
temperature	O
.	O

For	O
example	O
,	O
the	O
reversed	O
phase	O
HPLC	O
profile	O
for	O
products	O

obtained	O
after	O
cleavage	O
of	O
the	O
nonamer	O
,	O
d	O
-	O
[	O
(	O
MeO	O
)	O
2Tr	O
]	O
ApAjApApGpCpApApG	O
,	O
is	O
shown	O
in	O
Figure	O
2a	O
.	O

The	O
peaks	O
marked	O
with	O
(	O
X	O
)	O
are	O
from	O
impurities	O
in	O
the	O

solvents	O
used	O
to	O
elute	O
the	O
oligomer	O
from	O
the	O
support	O
.	O

The	O
tritylated	O
nonamer	O
appears	O
at	O
22	O
min	O
in	O
the	O
chromatogram	O
and	O
is	O
eluted	O
with	O
50	O
%	O
aqueous	O

acetonitrile	O
.	O

After	O
removal	O
of	O
the	O
dimethoxytrityl	O
group	O
,	O
the	O
nonamer	O
elutes	O
at	O
15	O
.	O
2	O
min	O
(	O
Figure	O
2b	O
)	O
.	O

The	O
peaks	O
which	O
appear	O
between	O
19	O
and	O
25	O
min	O
are	O
shorter	O
oligomers	O
which	O
contain	O
a	O
5	O
'	O
-	O
mesitylenesulfonate	O
group	O
.	O

At	O
this	O
stage	O
,	O
the	O
nonamer	O
was	O
partially	O
purified	O
by	O
ion	O
exchange	O

chromatography	O
on	O
a	O
DEAE	O
cellulose	O
column	O
.	O

This	O
step	O
,	O
which	O
resulted	O
in	O
84	O
%	O
recovery	O
of	O
material	O
loaded	O
onto	O
the	O
column	O
,	O
removed	O
most	O
of	O
the	O
shorter	O

oligomers	O
as	O
shown	O
in	O
Figure	O
2c	O
.	O

After	O
removal	O
of	O
the	O
buffer	O
,	O
the	O
nonamer	O
was	O
purified	O
by	O
preparative	O
reversed	O
phase	O
HPLC	O
using	O
a	O
0	O
%	O
to	O
30	O
%	O
acetonitrile	O
in	O
0	O
.	O
1	O
M	O
ammonium	O
acetate	O
gradient	O
.	O

The	O
recovery	O
of	O
material	O
from	O
the	O
column	O

(	O
84	O
%	O
)	O
appears	O
to	O
be	O
higher	O
when	O
ammonium	O
acetate	O
is	O
used	O
.	O

The	O
pure	O
nonamer	O

(	O
Figure	O
2d	O
)	O
was	O
obtained	O
in	O
10	O
%	O
overall	O
yield	O
based	O
on	O
the	O
amount	O
of	O
d	O
-	O
[	O
(	O
MeO	O
)	O
2	O
Tr	O
]	O
ibuG	O
originally	O
bound	O
to	O
the	O
polystyrene	O
support	O
.	O

The	O
oligomer	O
was	O
desalted	O
on	O
a	O
Bio	O
-	O
Gel	O
P	O
-	O
2	O
gel	O
filtration	O
column	O
.	O

Similar	O
results	O
were	O

obtained	O
for	O
the	O
other	O
oligomers	O
purified	O
by	O
this	O
method	O
.	O

Thus	O
,	O
for	O
example	O
dApApA	O
and	O
d	O
-	O
ApCpCpApT	O
were	O
obtained	O
in	O
44	O
%	O
and	O
22	O
%	O
isolated	O
yields	O
respectively	O
based	O
upon	O
the	O
amount	O
of	O
d	O
-	O
[	O
(	O
MeO	O
)	O
2Tr	O
]	O
N	O
.	O

The	O
5	O
'	O
-	O
terminal	O
nucleotide	O
may	O
be	O
removed	O
enzynatically	O
to	O
give	O
an	O

oligomer	O
which	O
contains	O
only	O
methylphosphonate	O
linkages	O
.	O

Thus	O
treatment	O
of	O

the	O
nonamer	O
,	O
d	O
-	O
ApApApApGpCpApApG	O
,	O
with	O
spleen	O
phosphodiesterase	O
gave	O
d	O
-	O
Ap	O
and	O

the	O
octamer	O
d	O
-	O
ApApApGpCpApApG	O
whose	O
retention	O
time	O
is	O
16	O
.	O
4	O
min	O
on	O
the	O
reversed	O
phase	O
column	O
.	O

The	O
noncharged	O
octamer	O
was	O
freed	O
of	O
d	O
-	O
Ap	O
and	O
enzyne	O
by	O
simply	O
passing	O
it	O
through	O
a	O
small	O
DEAE	O
cellulose	O
column	O
.	O

Characterization	O
.	O

Methylphosphonate	O
linkages	O
are	O
cleaved	O
by	O
base	O
.	O

We	O
have	O
found	O
piperdine	O
is	O
particularly	O
effective	O
.	O

The	O
cleavage	O
occurs	O
in	O
a	O
random	O
manner	O
giving	O
nucleosides	O
,	O
nucleoside	O
3	O
'	O
-	O
or	O
5	O
'	O
-	O
methylphosphonates	O
and	O

nucleoside	O
3	O
'	O
,	O
5	O
'	O
-	O
bis	O
-	O
methylphosphonates	O
.	O

This	O
hydrolysis	O
reaction	O
may	O
be	O
used	O
to	O
characterize	O
dimers	O
,	O
since	O
the	O
identity	O
and	O
ratio	O
of	O
the	O
products	O
formed	O
are	O
easily	O
determined	O
by	O
reversed	O
phase	O
HPLC	O
.	O

However	O
,	O
the	O
method	O
becomes	O
less	O
satisfactory	O
for	O
longer	O
oligomers	O
.	O

Purine	O
-	O
containing	O
oligonucleoside	O
methylphosphonates	O
may	O
be	O
depurinated	O
by	O
treatment	O
with	O
hydrochloric	O
acid	O
at	O
650	O
.	O

The	O
methylphosphonate	O
linkage	O
is	O

6238	O

Nucleic	O
Acids	O
Research	O

9	O
0	O
OH	O
cH3P	O
:	O
O	O
cH	O
CH3P	O

9	O
9	O

CH	O
-	O
P	O
:	O
O	O
C	O
cH	O
:	O
0pO	O

O	O
~	O
~	O
~	O
j4	O
HO	O
OP	O
3	O
0	O
H	O
0	O
0OH0	O

9	O
S	O
S	O

Figure	O
3	O
:	O
Hydrolysis	O
of	O
the	O
internucleoside	O
methylphsophonate	O
linkages	O
at	O
an	O

apurinic	O
site	O
produced	O
by	O
treatment	O
of	O
the	O
oligomer	O
with	O
hydrochloric	O
acid	O
at	O
pH	O
2	O
.	O

resistant	O
to	O
hydrolysis	O
by	O
these	O
conditions	O
as	O
shown	O
by	O
the	O
stability	O
of	O
d	O
-	O
TpT	O
and	O
d	O
-	O
TpTpT	O
.	O

On	O
the	O
other	O
hand	O
,	O
dimers	O
or	O
trimers	O
containing	O
purine	O
bases	O

such	O
as	O
d	O
-	O
ApA	O
,	O
dApT	O
,	O
dTpA	O
or	O
d	O
-	O
ApApA	O
have	O
half	O
-	O
lives	O
between	O
92	O
and	O
144	O
min	O
in	O
0	O
.	O
01	O
M	O
hydrochloric	O
acid	O
.	O

Following	O
neutralization	O
with	O
ammonium	O
hydroxide	O
,	O
the	O
products	O
of	O
these	O
reactions	O
were	O
characterized	O
by	O
reversed	O
phase	O
HPLC	O
.	O

d	O
-	O
ApA	O
gave	O
adenine	O
,	O
while	O
both	O
d	O
-	O
ApT	O
and	O
d	O
-	O
TpA	O
gave	O
adenine	O
and	O
thymidine	O
as	O
the	O
sole	O
products	O
of	O
the	O
reaction	O
.	O

Adenine	O
and	O
d	O
-	O
ApA	O
were	O
the	O
only	O
products	O

observed	O
when	O
d	O
-	O
ApApA	O
was	O
partially	O
hydrolyzed	O
.	O

When	O
d	O
-	O
CpCpApT	O
was	O
completely	O
hydrolyzed	O
in	O
acid	O
three	O
products	O
,	O
d	O
-	O
CpC	O
,	O
adenine	O
and	O
thynidine	O
,	O
were	O
observed	O
in	O
a	O
molar	O
ratio	O
of	O
1	O
:	O
1	O
:	O
1	O
.	O

In	O
contrast	O
to	O
the	O
base	O
hydrolysis	O
of	O
the	O
methylphosphonate	O
group	O
,	O
apurinic	O
sites	O
produced	O
by	O
acid	O
treatment	O
are	O
further	O
hydrolyzed	O
to	O

nucleosides	O
or	O
oligomers	O
with	O
free	O
5	O
'	O
-	O
and	O
3	O
'	O
-	O
OH	O
groups	O
.	O

The	O
absence	O
of	O

terminal	O
phosphonate	O
residues	O
suggests	O
hydrolysis	O
occurs	O
as	O
shown	O
in	O
Figure	O
3	O
.	O

The	O
OH	O
group	O
on	O
the	O
4	O
'	O
-	O
carbon	O
generated	O
by	O
opening	O
the	O
ribose	O
at	O
the	O
apurinic	O
site	O
may	O
participate	O
in	O
an	O
intramolecular	O
attack	O
on	O
the	O
adjacent	O
phosphonate	O
linkages	O
which	O
results	O
in	O
removal	O
of	O
the	O
phosphonate	O
residues	O
from	O
the	O
neighboring	O
nucleoside	O
hydroxyls	O
.	O

Previous	O
studies	O
by	O
Agarwal	O
and	O
Riftina	O
indicated	O
dithymidine	O
methyl	O
-	O
or	O
phenylphosphonates	O
can	O
be	O
phosphorylated	O
by	O
polynucleotide	O
kinase	O
(	O
9	O
)	O
.	O

Sinha	O
et	O
al	O
.	O
reported	O
that	O
dimers	O
but	O
not	O
trimers	O
or	O
tetramers	O
served	O
as	O

substrates	O
for	O
this	O
enzyme	O
(	O
4	O
)	O
.	O

We	O
were	O
unable	O
to	O
phosphorylate	O
tetramers	O
or	O
longer	O
oligomers	O
which	O
contain	O
only	O
methylphosphonate	O
linkages	O
.	O

However	O
,	O
those	O
oligomers	O
which	O
terminate	O
with	O
a	O
5	O
'	O
-	O
dAp	O
-	O
residue	O
are	O
readily	O

6239	O

Nucleic	O
Acids	O
Research	O

a	O

ATP	O
1	O

1	O
2	O
3	O
4	O

b	O

6	O
mer	O
Mik	O

6	O
mer	O
go	O

3mer	O
a	O
a	O
a	O
X	O
2mer	O
do	O
ATP	O
411	O

12	O
w	O
34	O

1	O
2	O
3	O
4	O
5	O
6	O

Figure	O
4	O
:	O
(	O
a	O
)	O
PEI	O
-	O
cellulose	O
TLC	O
of	O
T4	O
polynucleotide	O
kinase	O
reactions	O
.	O

1	O
)	O
[	O
y	O
-	O
32p	O
]	O
ATP	O
;	O
2	O
)	O
d	O
-	O
ApApA	O
reaction	O
mixture	O
;	O
3	O
)	O
d	O
-	O
ApGpCpApApG	O

reaction	O
mixture	O
;	O
4	O
)	O
d	O
-	O
ApApApApG	O
_	O
pCpApAeG	O
reaction	O
mixture	O
.	O

The	O
chromatogram	O
was	O
eluted	O
wi	O
th1	O
.	O
5	O
M	O
pyridinium	O
formate	O
,	O
pH	O
3	O
.	O
5	O
.	O

(	O
b	O
)	O
Polyacrylamide	O
gel	O
electrophoresis	O
of	O
phosphoryljted	O

olihonucleoside	O
methylghosphonates	O
.	O

1	O
)	O
markers	O
:	O
d	O
-	O
pTpT	O
(	O
2	O
mer	O
)	O
;	O
d	O
-	O
,	O
3pApApA	O
(	O
3	O
mer	O
)	O
;	O
d	O
-	O
2pApGpCpApApG	O
(	O
6	O
mer	O
)	O
;	O

d	O
-	O
32pApApApApGpCpApApG	O
(	O
9	O
mer	O
.	O

Lanes	O
2	O
-	O
4	O
:	O
products	O
obtained	O

after	O
partTaT	O
fy	O
?	O
rlysis	O
of	O
dl2pApApA	O
(	O
2	O
)	O
;	O
d	O
-	O
2pApGpCpApApG	O
(	O
3	O
)	O
and	O
d	O
-	O
32pApARApApGpCpAZARG	O
;	O
(	O
4	O
)	O
with	O
0	O
.	O
5	O
M	O
piperidine	O
at	O
377C	O
for	O
10	O
min	O
Lanel	O
t	O
:	O
products	O
obtained	O
Wfter	O
partial	O
hydrolysis	O
of	O
d	O
-	O
3Kp	O
-	O
ApGRCpApApG	O
(	O
5	O
)	O
and	O
d	O
-	O
32p	O
-	O
ApApAppGpjCppAjG	O
(	O
6	O
)	O
with	O
0	O
.	O
5	O
M	O
HC1	O
at	O
371C	O
fCor30	O
min	O
.	O

Electrophoresis	O
was	O
carried	O
out	O
at	O

constant	O
voltage	O
(	O
800	O
v	O
)	O
until	O
the	O
bromphenol	O
blue	O
marker	O
dye	O
had	O
migrated	O
halfway	O
down	O
the	O
gel	O
.	O

phosphorylated	O
by	O
polynucleotide	O
kinase	O
.	O

The	O
phosphorylation	O
reaction	O
is	O
easily	O
followed	O
by	O
PEI	O
-	O
cellulose	O
TLC	O
.	O

As	O
shown	O
in	O
Figure	O
4a	O
,	O
the	O
phosphorylated	O
oligomers	O
have	O
a	O
higher	O
Rf	O
values	O
than	O
does	O
d	O
-	O
ATP	O
.	O

The	O
phosphorylated	O
methylphosphonate	O
oligomers	O
can	O
be	O
separated	O
according	O
to	O
their	O
chain	O
lengths	O
by	O
polyacrylamide	O
gel	O
electrophoresis	O
on	O
an	O
18	O
%	O
gel	O

containing	O
7	O
M	O
urea	O
as	O
shown	O
in	O
Figure	O
4	O
(	O
b	O
)	O
.	O

Lane	O
1	O
shows	O
the	O
separation	O
of	O
a	O
trimer	O
,	O
hexamer	O
and	O
nonamer	O
.	O

The	O
band	O
which	O
appears	O
directly	O
below	O
the	O

nonamer	O
may	O
arise	O
from	O
traces	O
of	O
contaminating	O
octamer	O
which	O
were	O
not	O
removed	O
during	O
the	O
purification	O
of	O
d	O
-	O
ApApApApGpCpApApG	O
.	O

6240	O

Nucleic	O
Acids	O
Research	O

When	O
the	O
oligomers	O
were	O
partially	O
hydrolyzed	O
with	O
piperidine	O
,	O
a	O
series	O
of	O
new	O
bands	O
appears	O
corresponding	O
to	O
shorter	O
oligomers	O
produced	O
via	O
hydrolysis	O
of	O
the	O
methylphosphonate	O
linkages	O
(	O
Lanes	O
2	O
-	O
4	O
)	O
.	O

Because	O
of	O
the	O
random	O
nature	O
of	O
this	O
cleavage	O
reaction	O
,	O
the	O
oligomers	O
should	O
terminate	O
with	O
either	O
a	O
3	O
'	O
-	O
OH	O
or	O
a	O
3	O
'	O
-	O
methylphosphonate	O
group	O
.	O

In	O
the	O
case	O
of	O
the	O
trimer	O
,	O
32pApApA	O
,	O

hydrolysis	O
gives	O
two	O
bands	O
which	O
correspond	O
to	O
d	O
-	O
32pApA	O
and	O
d	O
-	O
32pApAp	O
(	O
Lane	O
2	O
)	O
.	O

The	O
same	O
products	O
are	O
observed	O
for	O
hydrolysis	O
of	O
the	O
nonamer	O
,	O

d	O
-	O
32pApApApApGpCpApApG	O
(	O
Lane	O
4	O
)	O
.	O

A	O
similar	O
situation	O
is	O
observed	O
for	O

d32pApGpCpApApG	O
although	O
the	O
dimers	O
d	O
-	O
32pApG	O
and	O
d	O
-	O
32pApGp	O
have	O
somewhat	O

different	O
mobilities	O
(	O
Lane	O
3	O
)	O
.	O

These	O
dimers	O
cannot	O
be	O
separated	O
when	O
the	O
gel	O
is	O
run	O
in	O
the	O
absence	O
of	O
urea	O
.	O

It	O
is	O
possible	O
to	O
determine	O
the	O
chain	O
lengths	O
of	O
the	O
original	O
oligomers	O

by	O
counting	O
the	O
number	O
of	O
oligomers	O
produced	O
by	O
partial	O
piperidine	O
hydrolysis	O
.	O

For	O
example	O
,	O
starting	O
with	O
the	O
trimer	O
band	O
,	O
one	O
can	O
observe	O
3	O
bands	O

corresponding	O
to	O
tetramer	O
,	O
pentamer	O
and	O
hexamer	O
for	O
the	O
hydrolysis	O
products	O
of	O
d	O
-	O
32pApGpCpApApG	O
(	O
Lane	O
3	O
)	O
and	O
6	O
bands	O
corresponding	O
to	O
tetramer	O
,	O
pentamer	O
,	O
hexamer	O
,	O
heptamer	O
,	O
octamer	O
and	O
nonamer	O
for	O
the	O
hydrolysis	O
products	O
of	O

32pApApApApGpCpApApG	O
(	O
Lane	O
4	O
)	O
.	O

The	O
positions	O
of	O
the	O
oligomers	O
of	O
the	O
same	O

chain	O
length	O
appear	O
to	O
be	O
very	O
similar	O
which	O
suggests	O
that	O
the	O
mobilities	O
are	O
not	O
greatly	O
affected	O
by	O
base	O
composition	O
on	O
the	O
urea	O
-	O
containing	O
gel	O
.	O

This	O

procedure	O
thus	O
provides	O
a	O
rapid	O
and	O
convenient	O
method	O
for	O
characterizing	O
the	O
methyl	O
phosphonate	O
ol	O
i	O
gomers	O
.	O

Treatment	O
of	O
the	O
phosphorylated	O
oligomers	O
with	O
acid	O
produces	O
shorter	O

oligomers	O
which	O
result	O
from	O
chain	O
cleavage	O
at	O
apurinic	O
sites	O
.	O

In	O
this	O
case	O
the	O
oligomers	O
terminate	O
with	O
a	O
3	O
'	O
-	O
OH	O
group	O
.	O

Treatment	O
of	O
32pApGpCpApALpG	O

produces	O
an	O
intense	O
band	O
corresponding	O
to	O
the	O
pentamer	O
,	O
d	O
-	O
32pApGjCpAjA	O
(	O
Lane	O
5	O
)	O
while	O
treatment	O
of	O
32pApApApApGpCpApApG	O
produces	O
an	O
intense	O
band	O
corresponding	O
to	O
the	O
octamer	O
d	O
-	O
32pApApAPApGpCpApA	O
and	O
fainter	O
bands	O

corresponding	O
to	O
the	O
heptamer	O
,	O
hexamer	O
,	O
tetramer	O
and	O
trimer	O
.	O

These	O
results	O
suggest	O
that	O
under	O
the	O
conditions	O
of	O
the	O
experiment	O
,	O
hydrolysis	O
occurs	O
preferentially	O
at	O
the	O
3	O
'	O
-	O
terminal	O
G	O
residue	O
of	O
both	O
oligomers	O
.	O

It	O
should	O
be	O
possible	O
to	O
extend	O
this	O
methodology	O
to	O
other	O
base	O
specific	O

depurination	O
or	O
depyrimidination	O
reactions	O
similar	O
to	O
those	O
employed	O
in	O
the	O
Maxam	O
-	O
Gilbert	O
sequencing	O
method	O
(	O
10	O
)	O
.	O

Experiments	O
directed	O
toward	O
this	O
goal	O
are	O
currently	O
in	O
progress	O
and	O
will	O
be	O
reported	O
in	O
a	O
future	O
communication	O
.	O

ACKNOWLEDGEMENT	O
:	O
This	O
work	O
was	O
supported	O
in	O
part	O
by	O
the	O
following	O
grants	O
from	O
the	O
National	O
Institutes	O
of	O
Health	O
:	O
GM	O
16066	O
(	O
P	O
.	O
O	O
.	O
P	O
.	O
T	O
.	O
)	O
and	O
GM	O
31927	O

6241	O

Nucleic	O
Acids	O
Research	O

(	O
P	O
.	O
S	O
.	O
M	O
.	O
)	O
,	O
and	O
from	O
a	O
grant	O
from	O
Association	O
for	O
International	O
Cancer	O
Research	O
.	O

REFERENCES	O
:	O

1	O
.	O

MTTITr	O
,	O
P	O
.	O
S	O
.	O
,	O
McParland	O
,	O
K	O
.	O
B	O
.	O
,	O
Jayaraman	O
,	O
K	O
.	O
and	O
Ts	O
'	O
o	O
,	O
P	O
.	O
O	O
.	O
P	O
.	O

(	O
1981	O
)	O

Biochemistry	O
20	O
,	O
1874	O
-	O
1880	O
.	O

2	O
.	O

Jayaraman	O
,	O
K	O
.	O
,	O
McParland	O
,	O
K	O
.	O
B	O
.	O
,	O
Miller	O
,	O
P	O
.	O
S	O
.	O
and	O
Ts	O
'	O
o	O
,	O
P	O
.	O
O	O
.	O
P	O
.	O

(	O
1981	O
)	O

Proc	O
.	O

Natl	O
.	O

Acad	O
.	O

Sci	O
.	O

78	O
,	O
1537	O
-	O
1541	O
.	O

3	O
.	O

Miller	O
,	O
P	O
.	O
S	O
.	O
,	O
Agris	O
,	O
C	O
.	O
H	O
.	O
,	O
Blandin	O
,	O
M	O
.	O
,	O
Murakami	O
,	O
A	O
.	O
,	O
Reddy	O
,	O
P	O
.	O
M	O
.	O
,	O

Spitz	O
,	O
S	O
.	O
A	O
.	O
and	O
Ts	O
'	O
o	O
,	O
P	O
.	O
O	O
.	O
P	O
.	O

(	O
1983	O
)	O
Nucleic	O
Acids	O
Res	O
.	O
,	O
submitted	O
for	O
publ	O
ication	O
.	O

4	O
.	O

Sinha	O
,	O
N	O
.	O
D	O
.	O

Grossbruchaus	O
,	O
V	O
.	O
and	O
Koester	O
,	O
H	O
.	O

(	O
1983	O
)	O
Tetrahedron	O
Letters	O

24	O
,	O
877	O
-	O
880	O
.	O

5	O
.	O

Miller	O
,	O
P	O
.	O
S	O
.	O
,	O
Cheng	O
,	O
D	O
.	O
M	O
.	O
,	O
Dreon	O
,	O
N	O
.	O
,	O
Jayaraman	O
,	O
K	O
.	O
,	O
Kan	O
,	O
L	O
.	O
-	O
S	O
.	O
,	O

Leutzinger	O
,	O
E	O
.	O
E	O
.	O
,	O
Pulford	O
,	O
S	O
.	O
M	O
.	O
and	O
Ts	O
'	O
o	O
,	O
P	O
.	O
O	O
.	O
P	O
.	O

(	O
1980	O
)	O
Biochemistry	O
19	O
,	O
4688	O
-	O
4698	O
.	O

6	O
.	O

Ito	O
,	O
H	O
.	O
,	O
Ike	O
,	O
Y	O
.	O
,	O
Ikuta	O
,	O
S	O
.	O
and	O
Itakura	O
,	O
K	O
.	O
,	O
(	O
1982	O
)	O
Nucleic	O
Acids	O
Res	O

10	O
,	O
1755	O
-	O
1769	O
.	O

7	O
.	O

Barnett	O
,	O
R	O
.	O
W	O
.	O
and	O
Letsinger	O
,	O
R	O
.	O
L	O
.	O

(	O
1981	O
)	O
Tetrahedron	O
Letters	O
22	O
,	O

991	O
-	O
994	O
.	O

6242	O

Further	O
studies	O
on	O
partially	O
purified	O
calf	B
thymus	O
DNA	O
polymerase	O
a	O
.	O

Abstract	O

Attempts	O
to	O
prevent	O
the	O
urea	O
conversion	O
of	O
a	O
200	O
-	O
230	O
,	O
000	O
molecular	O
weight	O
DNA	O
polymerase	O
alpha	O
to	O
a	O
150	O
-	O
170	O
,	O
000	O
molecular	O
weight	O
form	O
by	O
the	O
inclusion	O
of	O
protease	O
inhibitors	O
have	O
not	O
been	O
successful	O
.	O

No	O
other	O
method	O
has	O
been	O
found	O
capable	O
of	O
dissociating	O
a	O
50	O
-	O
70	O
,	O
000	O
fragment	O
or	O
subunit	O
from	O
the	O
DNA	O
polymerase	O
subunit	O
.	O

Addition	O
of	O
this	O
50	O
-	O
70	O
,	O
000	O
subunit	O
to	O
the	O
polymerase	O
subunit	O
does	O
not	O
aid	O
the	O
binding	O
of	O
the	O
enzyme	O
to	O
DNA	O
,	O
but	O
does	O
have	O
an	O
effect	O
on	O
the	O
utilisation	O
of	O
synthetic	O
template	O
-	O
initiator	O
complexes	O
by	O
the	O
polymerase	O
subunit	O
.	O

Volume	O
6	O
Number	O
10	O
1979	O

Nucleic	O
Acids	O
Research	O

Further	O
studies	O
on	O
partially	O
purified	O
calf	B
thymus	O
DNA	O
polymerase	O
a	O
Keith	O
McKune	O
and	O
Andrew	O
M	O
.	O
Holmes	O
*	O

Biochemistry	O
Department	O
,	O
Strathclyde	O
University	O
,	O
The	O
Todd	O
Centre	O
,	O
31	O
Taylor	O
Street	O
,	O
Glasgow	O
,	O
G4	O
ONR	O
,	O
UK	O

Received	O
I	O
June	O
1979	O
ABSTRACT	O

Attempts	O
to	O
prevent	O
the	O
urea	O
conversion	O
of	O
a	O
200	O
-	O
230	O
,	O
000	O
molecular	O
weight	O
DNA	O
polymerase	O
a	O
to	O
a	O
150	O
-	O
170	O
,	O
000	O
molecular	O
weight	O
form	O
by	O
the	O

inclusion	O
of	O
protease	O
inhibitors	O
have	O
not	O
been	O
successful	O
.	O

No	O
other	O
method	O
has	O
been	O
found	O
capable	O
of	O
dissociating	O
a	O
50	O
-	O
70	O
,	O
000	O
fragment	O
or	O
subunit	O
from	O
the	O
DNA	O
polymerase	O
subunit	O
.	O

Addition	O
of	O
this	O
50	O
-	O
70	O
,	O
000	O
subunit	O
to	O
the	O
polymerase	O
subunit	O
does	O
not	O
aid	O
the	O
binding	O
of	O
the	O
enzyme	O
to	O
DNA	O
,	O
but	O
does	O
have	O
an	O
effect	O
on	O
the	O
utilisation	O
of	O
synthetic	O
template	O
-	O
initiator	O
complexes	O
by	O
the	O
polymerase	O
subunit	O
.	O

INTRODUCTION	O

In	O
mammals	O
DNA	O
polymerase	O
a	O
is	O
thought	O
to	O
be	O
the	O
replicative	O

enzyme	O
,	O
but	O
due	O
to	O
low	O
levels	O
of	O
activity	O
,	O
even	O
in	O
tissues	O
actively	O
making	O
DNA	O
,	O
and	O
to	O
enzyme	O
heterogeneity	O
it	O
has	O
been	O
found	O
difficult	O
to	O
purify	O

However	O
,	O
small	O
samples	O
of	O
DNA	O
polymerase	O
a	O
have	O
been	O
highly	O
purified	O

2	O
,	O
3	O
,	O
4	O
,	O
5	O
from	O
several	O
sources	O
and	O
partially	O
characterised	O

Heterogeneity	O
has	O
been	O
observed	O
in	O
DNA	O
polymerase	O
a	O
from	O
a	O
var	O

6	O
7	O

iety	O
of	O
sources	O
,	O
including	O
rat	B
liver	O
and	O
spleen	O
,	O
Hela	O
cells	O
,	O
baby	O
hamster	O

8	O
9	O
,	O
10	O
11	O

kidney	O
cells	O
,	O
mouse	B
myeloma	O
,	O
Drosophila	B
embryos	O
and	O
calf	B
thymus	O

1	O
,	O
6	O
,	O
12	O
,	O
13	O
.	O

We	O
have	O
previously	O
observed	O
several	O
species	O
of	O
calf	B
thymus	O

DNA	O
polymerase	O
a	O
differing	O
in	O
size	O
and	O
charge	O
.	O

In	O
order	O
of	O
elution	O
from	O
DEAE	O
cellulose	O
they	O
are	O
enzyme	O
A1	O
(	O
200	O
-	O
230	O
,	O
000	O
molecular	O
weight	O
)	O
,	O
A2	O
(	O
200	O
-	O
230	O
,	O
000	O
)	O
,	O
B	O
(	O
100	O
-	O
110	O
,	O
000	O
)	O
and	O
C	O
(	O
150	O
-	O
170	O
,	O
000	O
)	O
.	O

A	O
poly	O
(	O
dA	O
)	O
.	O
oligo	O

(	O
dT	O
)	O
10	O
preferring	O
enzyme	O
,	O
enzyrrme	O
D	O
(	O
140	O
-	O
150	O
,	O
000	O
molecular	O
weight	O
)	O
elutes	O
just	O
after	O
enzyme	O
B	O
.	O

The	O
A	O
enzymes	O
seem	O
identical	O
in	O
all	O
properties	O
except	O
their	O
charge	O
.	O

5	O
.	O
0	O
-	O
5	O
.	O

5S	O
enzymes	O
,	O
analagous	O
to	O
B	O
,	O
have	O
been	O
observed	O
to	O

C	O
Information	O
Retrieval	O
Limited	O
1	O
Falconberg	O
Court	O
London	O
Wl	O
V	O
5FG	O
England	O

3341	O

Nucleic	O
Acids	O
Research	O

arise	O
as	O
the	O
result	O
of	O
proteolytic	O
action	O
'	O
,	O
similarly	O
the	O
B	O
enzyme	O
above	O
14	O

,	O
but	O
the	O
relationship	O
of	O
the	O
other	O
observed	O
species	O
is	O
not	O
clear	O
,	O
nor	O
is	O

the	O
problem	O
of	O
which	O
,	O
if	O
any	O
,	O
of	O
these	O
species	O
is	O
the	O
replicative	O
enzyme	O
,	O

although	O
circumstantial	O
evidence	O
has	O
implicated	O
a	O
DNA	O
polymerase	O
a	O
to	O
be	O

15	O
the	O
replicative	O
enzyme	O
in	O
adenovirus	B
infected	O
KB	O
cells	O

We	O
have	O
previously	O
shown	O
that	O
several	O
of	O
these	O
enzymes	O
are	O
inter	O

16	O

convertible	O
.	O

In	O
particular	O
,	O
mild	O
urea	O
treatment	O
can	O
convert	O
both	O
A	O

enzymes	O
to	O
C	O
enzyme	O
,	O
with	O
the	O
loss	O
of	O
a	O
subunit	O
or	O
fragment	O
of	O
50	O
-	O
70	O
,	O
000	O
molecular	O
weight	O
.	O

The	O
C	O
enzyme	O
retains	O
DNA	O
polymerase	O
activity	O
,	O
but	O

does	O
show	O
differences	O
compared	O
to	O
A	O
enzyme	O
in	O
heat	O
sensitivity	O
and	O
sensitivity	O
to	O
N	O
-	O
ethylmaleimide	O
.	O

Highly	O
purified	O
samples	O
of	O
A	O
and	O
C	O
enzymes	O
when	O
subjected	O
to	O
sodium	O
dodecyl	O
sulphate	O
polyacrylamide	O
gel	O
electrophoresis	O
have	O
shown	O
a	O
corre	O

lation	O
of	O
DNA	O
polymerase	O
activity	O
with	O
a	O
polypeptide	O
band	O
155	O
,	O
000	O
molecular	O
weight	O
.	O

Contaminating	O
material	O
of	O
50	O
-	O
70	O
,	O
000	O
molecular	O
weight	O
appeared	O

to	O
obscure	O
the	O
putative	O
50	O
-	O
70	O
,	O
000	O
subunit	O
in	O
gels	O
of	O
A	O
enzyme	O
.	O

The	O
conclusions	O
drawn	O
were	O
that	O
DNA	O
polymerase	O
a	O
is	O
a	O
155	O
,	O
000	O
molecular	O
weight	O

polypeptide	O
(	O
C	O
enzyrrme	O
)	O
which	O
can	O
and	O
does	O
associated	O
with	O
material	O
of	O
50	O

70	O
,	O
000	O
molecular	O
weight	O
to	O
give	O
A	O
enzyme	O
,	O
and	O
that	O
enzyme	O
B	O
is	O
a	O
proteol	O

14	O

ytic	O
degradation	O
product	O
.	O

The	O
relationship	O
of	O
enzyme	O
D	O
to	O
the	O
others	O
is	O

not	O
clear	O
.	O

It	O
is	O
possible	O
that	O
during	O
the	O
enzyme	O
isolation	O
procedure	O
proteolytic	O
action	O
may	O
have	O
taken	O
place	O
on	O
a	O
200	O
-	O
230	O
,	O
000	O
molecular	O
weight	O
enzyme	O
releasing	O
155	O
,	O
000	O
and	O
50	O
-	O
70	O
,	O
000	O
fragments	O
which	O
remain	O
in	O
association	O

until	O
urea	O
treatment	O
separates	O
them	O
.	O

It	O
is	O
also	O
possible	O
that	O
urea	O
treatment	O
itself	O
renders	O
the	O
enzyme	O
susceptible	O
to	O
contaminating	O
proteases	O
.	O

Further	O
experiments	O
to	O
ascertain	O
whether	O
or	O
not	O
this	O
is	O
the	O
case	O
and	O
,	O
if	O
so	O
,	O
to	O
prevent	O
it	O
,	O
have	O
been	O
carried	O
out	O
.	O

A	O
enzyme	O
can	O
be	O
reconstituted	O
from	O
C	O
enzyme	O
formed	O
by	O
the	O
action	O

of	O
urea	O
on	O
A	O
enzyme	O
by	O
concentrating	O
it	O
with	O
the	O
50	O
-	O
70	O
,	O
000	O
molecular	O
weight	O
material	O
.	O

The	O
A	O
enzyrme	O
obtained	O
in	O
this	O
manner	O
is	O
highly	O
purified	O
,	O
as	O
is	O

the	O
C	O
enzyme	O
formed	O
by	O
the	O
urea	O
treatment	O
,	O
and	O
has	O
been	O
used	O
in	O
attempts	O
to	O
show	O
differences	O
in	O
synthetic	O
template	O
-	O
initiator	O
complex	O
utilisation	O

3342	O

Nucleic	O
Acids	O
Research	O

b	O
y	O
the	O
se	O
two	O
enzyme	O
s	O
.	O

MATERIALS	O
AND	O
METHODS	O

Calf	B
thymus	O
was	O
obtained	O
from	O
10	O
-	O
16	O
week	O
old	O
calves	B
and	O
frozen	O
at	O

-	O
20	O
?	O
C	O
until	O
required	O
.	O

Chromatographic	O
media	O
and	O
chemicals	O
were	O
obtained	O

6	O

from	O
sources	O
previously	O
referred	O
to	O
.	O

Radioactive	O
deoxynucleoside	O
tri	O

phosphates	O
were	O
obtained	O
from	O
the	O
Radiochemical	O
Centre	O
,	O
Amersham	O
,	O
Bucks	O
.	O

Synthetic	O
oligo	O
and	O
polynucleotides	O
were	O
obtained	O
from	O
P	O
.	O

L	O
.	O

Biochemicals	O

Inc	O
.	O
,	O
except	O
for	O
poly	O
(	O
dC	O
)	O
which	O
was	O
a	O
gift	O
from	O
Dr	O
.	O
I	O
.	O
R	O
.	O

Johnston	O
and	O
pre	O

17	O

pared	O
from	O
oligo	O
d	O
(	O
C	O
)	O
5	O
as	O
described	O
.	O

N	O
-	O
a	O
-	O
p	O
Tosyl	O
-	O
L	O
-	O
lysine	O
chloromethy	O

lketone	O
HCl	O
and	O
phenylmethylsulphony	O
were	O
obtained	O
from	O
Sigma	O
and	O
Trasylol	O
from	O
Bayer	O
.	O

Except	O
where	O
indicated	O
all	O
buffers	O
contained	O
20	O
%	O
w	O
/	O
v	O
glycerol	O
and	O

1	O
mM	O
dithiothreitol	O
.	O

Standard	O
linear	O
phosphate	O
gradients	O
were	O
run	O
between	O
0	O
.	O
03	O
M	O
and	O
0	O
.	O
25	O
M	O
potassium	O
phosphate	O
,	O
pH	O
7	O
.	O
8	O
.	O

Gradient	O
salt	O
concentr	O

2	O

ations	O
were	O
measured	O
using	O
a	O
conductivity	O
meter	O
as	O
described	O
.	O

Urea	O
was	O

prepared	O
as	O
a	O
4	O
.	O

8	O
M	O
solution	O
in	O
20	O
%	O
w	O
/	O
v	O
glycerol	O
,	O
stirred	O
with	O
Amberlite	O

MB3	O
and	O
filtered	O
.	O

Dithiothreitol	O
was	O
added	O
to	O
a	O
final	O
concentration	O
of	O
1	O
mM	O
before	O
use	O
.	O

6	O
DNA	O
polymerase	O
was	O
assayed	O
using	O
activated	O
DNA	O
as	O
described	O

except	O
that	O
the	O
buffer	O
was	O
50	O
mM	O
tris	O
HC1	O
,	O
pH	O
7	O
.	O
8	O
.	O

One	O
unit	O
of	O
DNA	O
polymerase	O
activity	O
incorporates	O
ln	O
mol	O
[	O
H	O
]	O
dTMP	O
into	O
an	O
acid	O
insoluble	O
form	O
in	O
one	O
hour	O
at	O
370C	O
.	O

Assays	O
using	O
synthetic	O
template	O
-	O
initiator	O
complexes	O
were	O
carried	O
out	O
at	O
30	O
?	O
C	O
in	O
0	O
.	O

12	O
ml	O
.	O

The	O
template	O
-	O
initiator	O
complexes	O

6	O

were	O
prepared	O
and	O
assays	O
processed	O
as	O
described	O
.	O

All	O
assays	O
contained	O

1	O
mM	O
dithiothreitol	O
,	O
62	O
.	O

5	O
p	O
.	O
g	O
bovine	B
serum	O
albumin	O
,	O
1	O
,	O
ug	O
template	O
-	O
initiator	O
complex	O
,	O
enzyme	O
protein	O
and	O
the	O
relevant	O
[	O
H	O
]	O
deoxynucleoside	O
triphosphate	O
at	O
0	O
.	O
1	O
mM	O
and	O
12	O
-	O
15	O
cpm	O
/	O
pmol	O
.	O

These	O
assays	O
were	O
carried	O
out	O
at	O
either	O
pH	O
6	O
.	O
4	O
in	O
20	O
mM	O
sodium	O
-	O
potassium	O
phosphate	O
,	O
or	O
at	O
pH	O
7	O
.	O
8	O
in	O
50	O
mM	O
tris	O
HCl	O
and	O
contained	O
either	O
10	O
mM	O
MgCl2	O
or	O
1	O
mM	O
MnCl2	O
as	O
indicated	O
.	O

Preliminary	O
purification	O
of	O
DNA	O
polymerase	O
a	O
to	O
Fraction	O
IV	O
was	O
as	O

6	O

described	O
,	O
the	O
purification	O
steps	O
being	O
phosphocellulose	O
chromatography	O
,	O

ammonium	O
sulphate	O
precipitation	O
and	O
gel	O
filtration	O
on	O
Sepharose	O
6B	O
.	O

3343	O

Nucleic	O
Acids	O
Research	O

Enzyme	O
obtained	O
from	O
the	O
DEAE	O
cellulose	O
step	O
is	O
referred	O
to	O
as	O
Fraction	O

V	O
enzyme	O
.	O

Samples	O
were	O
prepared	O
for	O
sodium	O
dodecyl	O
sulphate	O
polyacrylamide	O
gel	O
electrophoresis	O
and	O
scanned	O
as	O
previously	O
described2	O

RESULTS	O
AND	O
DISCUSSION	O

(	O
a	O
)	O
Interconversion	O
Studies	O

A	O
enzyme	O
was	O
routinely	O
converted	O
to	O
C	O
enzyme	O
by	O
incubating	O
200500	O
units	O
/	O
ml	O
of	O
Fraction	O
V	O
A	O
enzyme	O
in	O
2	O
.	O
4	O
M	O
urea	O
in	O
0	O
.	O

02	O
M	O
potassium	O

phosphate	O
,	O
pH	O
7	O
.	O
8	O
,	O
for	O
60	O
minutes	O
at	O
0	O
?	O
C	O
.	O

The	O
mixture	O
was	O
then	O
loaded	O
on	O
to	O
a	O
DEAE	O
cellulose	O
,	O
washed	O
with	O
0	O
.	O

03	O
M	O
potassium	O
phosphate	O
pH	O
7	O
.	O

8	O
,	O
and	O
enzyrme	O
eluted	O
either	O
with	O
the	O
standard	O
phosphate	O
gradient	O
or	O
batchwise	O
.	O

Under	O
these	O
conditions	O
usually	O
about	O
50	O
-	O
60	O
%	O
of	O
recovered	O
activity	O
was	O

enzyme	O
C	O
(	O
Fig	O
1	O
a	O
)	O
.	O

Overall	O
recovery	O
was	O
70	O
-	O
80	O
%	O
.	O

A	O
enzyme	O
was	O
recon	O

14	O

stituted	O
essentially	O
as	O
described	O
.	O

The	O
flow	O
through	O
material	O
from	O
the	O

DEAE	O
cellulose	O
column	O
after	O
the	O
urea	O
treatment	O
was	O
loaded	O
on	O
to	O
a	O
1	O
x	O
0	O
.	O

8	O
cm	O
phosphocellulose	O
column	O
,	O
washed	O
with	O
0	O
.	O
03	O
M	O
potassium	O
phosphate	O
,	O
pH	O
7	O
.	O
8	O
,	O
and	O
the	O
protein	O
eluted	O
with	O
0	O
.	O
25	O
M	O
potassium	O
phosphate	O
,	O
pH	O
7	O
.	O

8	O
.	O

This	O
material	O
,	O
the	O
putative	O
subunit	O
,	O
was	O
vacuum	O
dialysed	O
with	O
the	O
C	O
enzyme	O
produced	O
by	O
the	O
urea	O
treatment	O
,	O
rechromatographed	O
on	O
DEAE	O
cellulose	O
and	O
enzyme	O
eluted	O
batchwise	O
(	O
Fig	O
1	O
b	O
)	O
.	O

Recovery	O
from	O
this	O
procedure	O
was	O

usually	O
50	O
-	O
70	O
%	O
A	O
enzyme	O
.	O

Overall	O
recovery	O
was	O
30	O
-	O
40	O
%	O
of	O
the	O
C	O
enzyme	O
dialysed	O
.	O

If	O
the	O
material	O
eluted	O
from	O
the	O
phosphocellulose	O
by	O
the	O
0	O
.	O

25	O
M	O
potassium	O
phosphate	O
was	O
heated	O
to	O
90	O
?	O
C	O
for	O
5	O
minutes	O
prior	O
to	O
vacuum	O

dialysis	O
with	O
the	O
C	O
enzyme	O
the	O
recovery	O
from	O
the	O
DEAE	O
cellulose	O
column	O

was	O
significantly	O
higher	O
(	O
60	O
-	O
70	O
%	O
of	O
the	O
original	O
C	O
enzyme	O
activity	O
)	O
,	O
but	O
all	O
recoverable	O
DNA	O
polymerase	O
activity	O
was	O
C	O
enzyme	O
.	O

This	O
,	O
together	O
with	O
the	O
fact	O
that	O
the	O
60	O
minute	O
treatment	O
with	O
urea	O
has	O
,	O
on	O
occasions	O
,	O
given	O

rise	O
to	O
a	O
50	O
%	O
increase	O
in	O
DNA	O
polymerase	O
activity	O
prior	O
to	O
loading	O
on	O
to	O
the	O
DEAE	O
cellulose	O
column	O
,	O
would	O
indicate	O
that	O
A	O
enzyme	O
is	O
less	O
active	O
on	O

activated	O
DNA	O
than	O
is	O
C	O
enzyme	O
.	O

If	O
the	O
DEAE	O
cellulose	O
flow	O
through	O
material	O
came	O
from	O
urea	O
treatment	O
of	O
A2	O
enzyme	O
then	O
A2	O
was	O
produced	O
on	O
reconstitution	O
;	O
if	O
from	O
A1	O
then	O
A1	O
was	O
produced	O
.	O

Although	O
the	O
mild	O
urea	O
treatment	O
of	O
A	O
has	O
been	O
used	O
to	O
prepare	O
C	O
of	O

3344	O

Nucleic	O
Acids	O
Research	O

b	O

120	O
180	O
C	O

I	O
I	O
^	O

Figure	O
la	O
DEAE	O
cellulose	O
chromatography	O
after	O
2	O
.	O
4	O
M	O
urea	O
treatment	O
.	O

4	O
,	O
5000	O
units	O
,	O
4	O
.	O
4	O
mg	O
of	O
Fraction	O
II	O
A2	O
enzyme	O
were	O
incubated	O
with	O
urea	O
at	O
a	O
final	O
concentration	O
of	O
2	O
.	O
4	O
M	O
for	O
60	O
minutes	O
at	O
0	O
?	O
C	O
,	O
loaded	O
on	O
to	O
a	O
5	O
x	O
1	O
.	O
4	O
cm	O
DEAE	O
cellulose	O
column	O
,	O
the	O
column	O
was	O
washed	O
with	O
0	O
.	O

03	O
M	O
potassium	O
phosphate	O
,	O
pH	O
7	O
.	O
8	O
and	O
a	O
200	O
ml	O
standard	O
phosphate	O
gradient	O
applied	O
.	O

2	O
.	O
3	O
ml	O
fractions	O
were	O
collected	O
and	O
10	O
Rl	O
assayed	O
for	O
5	O
minutes	O
.	O

(	O
o	O
-	O
o	O
)	O
no	O

phenylmethylsulphony	O
(	O
*	O
-	O
*	O
)	O
3	O
mM	O
phenylmethylsulphony	O
(	O
-	O
)	O
phosphate	O
gradient	O
.	O

Figure	O
lb	O
The	O
reconstitution	O
of	O
A2	O
enzyme	O
.	O

3000	O
units	O
for	O
C	O
enzyme	O

derived	O
by	O
urea	O
treatment	O
of	O
A2	O
were	O
vacuum	O
dialysed	O
with	O
the	O
DEAE	O
cellulose	O
flow	O
through	O
material	O
after	O
phosphocellulose	O
chromatography	O
and	O

chromatographed	O
on	O
a	O
2	O
x	O
1	O
.	O

2	O
cm	O
DEAE	O
cellulose	O
column	O
.	O

After	O
washing	O
with	O
0	O
.	O
03	O
M	O
potassium	O
phosphate	O
,	O
pH	O
7	O
.	O
7	O
,	O
the	O
enzymes	O
were	O
eluted	O
batchwise	O
with	O
the	O
above	O
concentrations	O
of	O
potassium	O
phosphate	O
,	O
pH	O
7	O
.	O
8	O
.	O

1	O
ml	O
fractions	O
were	O
collected	O
and	O
10	O
.	O
l	O
assayed	O
for	O
10	O
minutes	O
.	O

3345	O

Nucleic	O
Acids	O
Research	O

high	O
specific	O
activity	O
it	O
is	O
possible	O
that	O
conversion	O
of	O
the	O
200	O
-	O
230	O
,	O
000	O
molecular	O
weight	O
enzymes	O
to	O
a	O
155	O
-	O
170	O
,	O
000	O
species	O
maybe	O
due	O
to	O
unfolding	O
of	O
the	O
molecule	O
to	O
allow	O
limited	O
attack	O
by	O
contaminating	O
proteases	O
.	O

Accord	O

ingly	O
the	O
urea	O
conversion	O
of	O
A	O
to	O
C	O
was	O
investigated	O
in	O
the	O
presence	O
of	O
certain	O
protease	O
inhibitors	O
.	O

The	O
presence	O
of	O
the	O
serine	O
protease	O
inhibitor	O

phenylmethylsulphony	O
-	O
fluoride	O
in	O
the	O
incubation	O
and	O
chromatography	O
buffers	O
did	O
not	O
affect	O
the	O
conversion	O
of	O
A2to	O
C	O
(	O
Fig	O
1	O
a	O
)	O
.	O

Likewise	O
trasylol	O
and	O
Na	O
-	O
p	O
Tosyl	O
-	O
L	O
-	O
lysine	O
chloromethylketone	O
HC1	O
had	O
no	O
effect	O
.	O

However	O
,	O
protease	O
action	O
could	O
have	O
occurred	O
earlier	O
in	O
the	O
purification	O
procedure	O
and	O
the	O
urea	O
could	O
be	O
separating	O
two	O
fragments	O
.	O

Usually	O
the	O
DEAE	O
cellulose	O
profile	O
shows	O
that	O
the	O
majority	O
of	O
the	O
enzyme	O
activity	O
is	O
present	O
as	O
A	O

enzyme	O
(	O
Fig	O
2	O
)	O
.	O

In	O
this	O
instance	O
A1	O
and	O
A2	O
have	O
not	O
been	O
separated	O
.	O

When	O
the	O
temperature	O
of	O
the	O
material	O
in	O
the	O
original	O
blending	O
procedure	O
was	O
kept	O
below	O
0	O
?	O
C	O
or	O
phenylmethylsulphony	O
,	O
N	O
-	O
a	O
-	O
p	O
Tosyl	O
-	O
L	O
-	O
lysine	O
chloromethylketone	O
HCl	O
or	O
trasylol	O
was	O
included	O
in	O
the	O
isolation	O
buffers	O
the	O
DEAE	O
cellulose	O
profile	O
was	O
similar	O
.	O

The	O
A	O
enzymes	O
were	O
still	O
capable	O
of	O
conversion	O
by	O
mild	O
urea	O
treatment	O
to	O
C	O
enzyme	O
,	O
indicating	O
that	O
if	O
protease	O
activity	O
is	O
involved	O
then	O
it	O
is	O
not	O
susceptible	O
to	O
these	O
inhibitors	O
.	O

When	O
the	O
calf	B

20FI	O
:	O
Now	O
~	O
~	O
~	O
20	O
20Fr	O
Na	O
06	O

Figure	O
2	O
DEAE	O
cellulose	O
elution	O
profile	O
of	O
calf	B
thymus	O
DNA	O
polymerase	O
a	O
.	O

47	O
,	O
000	O
units	O
,	O
97	O
mg	O
of	O
Fraction	O
IV	O
enzyme	O
prepared	O
from	O
415	O
g	O
of	O
calf	B

thymus	O
were	O
loaded	O
on	O
to	O
a	O
10	O
x	O
1	O
.	O
8	O
cm	O
DEAE	O
cellulose	O
column	O
,	O
after	O
washing	O
with	O
0	O
.	O

03	O
M	O
potassium	O
phosphate	O
,	O
pH	O
7	O
.	O

8	O
a	O
400	O
ml	O
standard	O
phosphate	O
gradient	O
was	O
applied	O
.	O

5	O
ml	O
fractions	O
were	O
collected	O
and	O
10	O
,	O
ul	O
assayed	O
for	O
5	O
minutes	O
.	O

3346	O

Nucleic	O
Acids	O
Research	O

thymus	O
was	O
allowed	O
to	O
warm	O
up	O
during	O
the	O
blending	O
procedure	O
,	O
or	O
the	O
supernatant	O
prior	O
to	O
phosphocellulose	O
chromatography	O
was	O
heated	O
to	O
37	O
?	O
C	O
for	O
30	O
minutes	O
,	O
there	O
was	O
a	O
marked	O
decrease	O
in	O
the	O
amount	O
of	O
A	O
enzyme	O
with	O
a	O
concomitant	O
increase	O
in	O
the	O
amount	O
of	O
B	O
and	O
C	O
(	O
unpublished	O
observation	O
)	O
.	O

The	O
presence	O
of	O
phenylmethylsulphony	O
,	O
N	O
-	O
a	O
-	O
p	O
T	O
osyl	O
-	O
L	O
-	O
lysine	O

chloromethylketone	O
HCl	O
or	O
trasylol	O
under	O
these	O
conditions	O
only	O
had	O
a	O
marginal	O
effect	O
on	O
the	O
appearance	O
of	O
C	O
enzyme	O
,	O
but	O
did	O
reduce	O
the	O
amount	O
of	O
B	O

enzyme	O
.	O

Heating	O
the	O
enzyme	O
to	O
37	O
?	O
C	O
after	O
the	O
phosphocellulose	O
step	O
had	O
no	O
effect	O
on	O
the	O
DEAE	O
cellulose	O
elution	O
profile	O
.	O

Attempts	O
to	O
convert	O
A	O
enzyme	O
to	O
C	O
using	O
trypsin	O
have	O
not	O
been	O
successful	O
.	O

A	O
enzyme	O
activity	O
is	O
lost	O
without	O
the	O
appearance	O
of	O
any	O
other	O
species	O
(	O
unpublished	O
observation	O
)	O
,	O
although	O

14	O
the	O
action	O
of	O
trypsin	O
on	O
C	O
enzyme	O
can	O
give	O
rise	O
to	O
small	O
amounts	O
of	O
B	O

Although	O
the	O
conversion	O
of	O
A	O
enzyme	O
to	O
C	O
does	O
not	O
appear	O
to	O
be	O
the	O
result	O
of	O
serine	O
protease	O
action	O
,	O
proteases	O
other	O
than	O
serine	O
proteases	O

18	O

could	O
have	O
been	O
responsible	O
.	O

Also	O
,	O
the	O
fact	O
that	O
A	O
enzyme	O
can	O
be	O
recon	O

stituted	O
from	O
C	O
plus	O
the	O
flow	O
through	O
material	O
from	O
the	O
DEAE	O
cellulose	O
after	O
urea	O
treatment	O
does	O
not	O
necessarily	O
mean	O
we	O
are	O
dealing	O
with	O
two	O
subunits	O
as	O
fragments	O
produced	O
by	O
proteases	O
mray	O
be	O
reassembled	O
to	O
give	O
active	O

enzyme	O
9	O
.	O

However	O
,	O
the	O
fact	O
that	O
a	O
200	O
-	O
230	O
,	O
000	O
molecular	O
weight	O
polypeptide	O
band	O
has	O
never	O
been	O
observed	O
in	O
sodium	O
dodecylsulphate	O
polyacrylamride	O
gels	O
of	O
highly	O
purified	O
A	O
enzyme	O
,	O
or	O
even	O
cruder	O
fractions	O
of	O
A	O

enzyrre	O
(	O
unpublished	O
observation	O
)	O
,	O
may	O
be	O
significant	O
.	O

One	O
might	O
expect	O

some	O
of	O
the	O
enzyme	O
not	O
to	O
have	O
been	O
attacked	O
by	O
whatever	O
is	O
responsible	O
for	O
cleaving	O
the	O
molecule	O
,	O
if	O
,	O
indeed	O
,	O
this	O
does	O
happen	O
.	O

It	O
would	O
appear	O
,	O
therefore	O
,	O
that	O
the	O
A	O
enzyme	O
consists	O
of	O
subunits	O
of	O
155	O
,	O
000	O
and	O
50	O
-	O
70	O
,	O
000	O
molecular	O
weight	O
with	O
the	O
small	O
subunit	O
having	O
a	O
slightly	O
different	O
charge	O
in	O
the	O

case	O
of	O
A	O
and	O
A2	O
.	O

It	O
has	O
also	O
been	O
concluded	O
that	O
the	O
heterogeneity	O
in	O
the	O

1	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
3	O
mouse	B
myeloma	O
DNA	O
polymerase	O
a	O
fraction	O
is	O
not	O
due	O
to	O
proteolysis	O
.	O

However	O
,	O
the	O
50	O
-	O
70	O
,	O
000	O
molecular	O
weight	O
subunit	O
has	O
not	O
yet	O
been	O
identified	O
.	O

Sodiurrm	O
dodecylsulphate	O
polyacrylamide	O
gels	O
of	O
reconstituted	O
A	O
enzyme	O
have	O
shown	O
polypeptide	O
bands	O
at	O
150	O
-	O
160	O
,	O
000	O
and	O
50	O
-	O
70	O
,	O
000	O
molecular	O
weight	O

(	O
Fig	O
.	O
3	O
)	O
,	O
but	O
the	O
ratio	O
of	O
staining	O
intensity	O
of	O
the	O
bands	O
does	O
not	O
correspond	O
to	O
a	O
1	O
:	O
1	O
relationship	O
.	O

The	O
ratio	O
of	O
the	O
two	O
bands	O
is	O
variable	O
but	O
is	O
usually	O
between	O
1	O
:	O
2	O
and	O
1	O
:	O
3	O
,	O
indicating	O
,	O
perhaps	O
,	O
that	O
more	O
than	O
one	O
subunit	O
of	O
50	O

3347	O

Nucleic	O
Acids	O
Research	O

TOP	O
123	O
4	O
5	O
6	O

Figure	O
3	O
Scan	O
of	O
a	O
5	O
%	O
sodium	O
dodecyl	O
sulphate	O
polyacrylamide	O
gel	O
of	O

reconstituted	O
A2	O
enzyme	O
.	O

1500	O
units	O
of	O
reconstituted	O
A2	O
enzyme	O
were	O
subjected	O
to	O
polyacrylamide	O
gel	O
electrophoresis	O
under	O
non	O
-	O
denaturing	O
conditions	O
.	O

The	O
gels	O
were	O
sliced	O
,	O
enzyme	O
extracted	O
and	O
assayed	O
and	O
the	O
peak	O

fraction	O
of	O
DNA	O
polymerase	O
activity	O
from	O
three	O
gels	O
were	O
pooled	O
,	O
subjected	O
to	O
sodium	O
dodecyl	O
sulphate	O
polyacrylamide	O
gel	O
electrophoresis	O
on	O
a	O
single	O

gel	O
,	O
stained	O
and	O
scanned	O
at	O
2	O
volt	O
sensitivity	O
as	O
described2	O
.	O

The	O
molecular	O
weight	O
standards	O
were	O
:	O
(	O
1	O
)	O
bovine	B
serum	O
albumin	O
dimer	O
(	O
134	O
,	O
000	O
)	O
,	O
(	O
2	O
)	O
,	O
3	O
galactosidase	O
(	O
130	O
,	O
000	O
)	O
,	O
(	O
3	O
)	O
phosphorylase	O
a	O
(	O
94	O
,	O
000	O
)	O
,	O
(	O
4	O
)	O
bovine	B
serum	O

albumin	O
(	O
68	O
,	O
000	O
)	O
,	O
(	O
5	O
)	O
pyruvate	O
kinase	O
(	O
57	O
,	O
000	O
)	O
and	O
(	O
6	O
)	O
lactate	O
dehydrogenase	O
(	O
35	O
,	O
000	O
)	O
.	O

70	O
,	O
000	O
molecular	O
weight	O
can	O
associate	O
with	O
the	O
155	O
,	O
000	O
subunit	O
.	O

The	O
proportion	O
of	O
the	O
lower	O
molecular	O
weight	O
polypeptide	O
band	O
is	O
higher	O
in	O
the	O
reconstituted	O
A	O
enzyrrme	O
than	O
in	O
the	O
C	O
enzyme	O
preparation	O
from	O
which	O
it	O
was	O
formed	O
,	O
but	O
even	O
the	O
C	O
enzyme	O
contained	O
some	O
material	O
in	O
the	O
region	O
.	O

Breakdown	O
of	O
material	O
from	O
155	O
,	O
000	O
to	O
50	O
-	O
70	O
,	O
000	O
may	O
be	O
partly	O
responsible	O
for	O
the	O
contamination	O
,	O
but	O
the	O
presence	O
of	O
phenylmethylsulphony	O
in	O
samples	O
in	O
preparation	O
for	O
sodium	O
dodecylsulphate	O
polyacrylamide	O
gel	O
electrophoresis	O
has	O
not	O
been	O
successful	O
in	O
preventing	O
it	O
.	O

The	O
human	B
KB	O
cell	O

DNA	O
polymerase	O
a	O
,	O
equivalent	O
to	O
the	O
C	O
enzyme	O
,	O
has	O
been	O
reported	O
to	O
consist	O

4	O

of	O
subunits	O
of	O
76	O
,	O
000	O
and	O
66	O
,	O
000	O
molecular	O
weight	O
,	O
but	O
at	O
no	O
time	O
have	O
we	O

observed	O
polypeptide	O
bands	O
at	O
76	O
,	O
000	O
and	O
66	O
,	O
000	O
rising	O
and	O
falling	O
with	O

enzyme	O
activity	O
in	O
any	O
gels	O
of	O
calf	B
thyrrmus	O
enzymes	O
A1	O
,	O
A	O
and	O
C	O
(	O
and	O

2	O
unpublished	O
observations	O
)	O
.	O

(	O
b	O
)	O
Template	O
Studies	O

Use	O
has	O
been	O
made	O
of	O
the	O
urea	O
conversion	O
of	O
A	O
to	O
C	O
and	O
of	O
the	O
reconstitution	O
of	O
A	O
enzyme	O
to	O
obtain	O
samples	O
of	O
highly	O
purified	O
DNA	O
polymerase	O
,	O

specific	O
activity	O
in	O
excess	O
of	O
50	O
,	O
000	O
units	O
/	O
mg	O
,	O
in	O
order	O
to	O
study	O
the	O
effect	O
of	O
this	O
50	O
-	O
70	O
,	O
000	O
molecular	O
weight	O
subunit	O
on	O
the	O
DNA	O
polymerase	O
subunit	O
.	O

Previous	O
results	O
have	O
indicated	O
that	O
A	O
enzyrrme	O
is	O
stabler	O
to	O
heat	O
and	O
less	O

3348	O

Nucleic	O
Acids	O
Research	O

14	O
,	O
21	O

susceptible	O
to	O
N	O
-	O
ethylmaleimide	O
than	O
C	O
enzyme	O
.	O

It	O
has	O
been	O
reported	O

that	O
highly	O
purified	O
DNA	O
polymerase	O
a	O
can	O
be	O
associated	O
with	O
a	O
protein	O
capable	O
of	O
binding	O
to	O
DNA	O
containing	O
no	O
3	O
'	O
OH	O
ends	O
and	O
capable	O
of	O
being	O
released	O
during	O
the	O
DNA	O
polymerase	O
assay	O
.	O

Attempts	O
to	O
dissociate	O
the	O
50	O

70	O
,	O
000	O
molecular	O
weight	O
subunit	O
from	O
the	O
polymerase	O
subunit	O
by	O
incubating	O
A2	O
with	O
DNA	O
polymerase	O
reaction	O
mixes	O
containing	O
activated	O
DNA	O
,	O
poly	O

(	O
dA	O
-	O
T	O
)	O
and	O
poly	O
(	O
dT	O
)	O
.	O
oligo	O
(	O
A	O
)	O
10	O
followed	O
by	O
ultracentrifugation	O
in	O
high	O
salt	O
have	O
been	O
unsuccessful	O
.	O

Similarly	O
A	O
absorbed	O
and	O
eluted	O
from	O
either	O
native	O
or	O
denatured	O
DNA	O
cellulose	O
remained	O
A	O
enzyme	O
.	O

Both	O
A	O
and	O
C	O
enzymes	O

were	O
eluted	O
from	O
the	O
DNA	O
celluloses	O
by	O
less	O
than	O
0	O
.	O

1	O
M	O
NaCl	O
so	O
it	O
does	O
not	O
appear	O
that	O
the	O
subunit	O
enhances	O
the	O
binding	O
of	O
the	O
DNA	O
polymerase	O
subunit	O
to	O
DNA	O
.	O

However	O
,	O
there	O
are	O
differences	O
in	O
the	O
response	O
of	O
A	O
and	O
C	O

enzymes	O
to	O
synthetic	O
template	O
-	O
initiator	O
complexes	O
(	O
Table	O
1	O
)	O
.	O

Even	O
if	O
one	O
takes	O
into	O
account	O
the	O
fact	O
that	O
A	O
enzyme	O
is	O
less	O
active	O
on	O
activated	O
DNA	O

than	O
C	O
enzyme	O
(	O
the	O
addition	O
of	O
the	O
50	O
-	O
70	O
,	O
000	O
subunit	O
to	O
the	O
polymerase	O
subunit	O
appears	O
to	O
result	O
in	O
a	O
decrease	O
of	O
about	O
30	O
%	O
of	O
polymerase	O
activity	O
on	O
activated	O
DNA	O
)	O
the	O
A	O
enzyme	O
is	O
still	O
more	O
active	O
on	O
these	O
templates	O
.	O

Although	O
there	O
is	O
a	O
variation	O
in	O
activity	O
on	O
these	O
template	O
-	O
initiator	O
comp	O

lexes	O
each	O
time	O
assays	O
are	O
carried	O
out	O
on	O
them	O
depending	O
on	O
the	O
method	O
of	O
preparing	O
the	O
complexes	O
and	O
the	O
base	O
ratio	O
of	O
template	O
to	O
initiator	O
,	O
A	O
enzyme	O
always	O
seems	O
to	O
be	O
significantly	O
more	O
active	O
than	O
C	O
.	O

The	O
A2	O

enzyme	O
at	O
pH	O
7	O
.	O
8	O
,	O
with	O
extra	O
subunit	O
(	O
s	O
)	O
is	O
clearly	O
more	O
effective	O
on	O
the	O

oligoribonucleotide	O
initiator	O
,	O
oligo	O
(	O
A	O
)	O
10	O
than	O
is	O
enzyme	O
C	O
.	O

In	O
view	O
of	O
the	O
proposed	O
RNA	O
initiation	O
of	O
Okazaki	O
pieces	O
this	O
may	O
indicate	O
a	O
role	O
of	O
this	O
subunit	O
in	O
Okazaki	O
piece	O
synthesis	O
,	O
in	O
that	O
it	O
may	O
aid	O
the	O
DNA	O
polymerase	O
to	O
'	O
take	O
over	O
'	O
from	O
the	O
RNA	O
polymerase	O
.	O

Using	O
poly	O
(	O
dA	O
)	O
.	O
oligo	O
(	O
dT	O
)	O
10	O

(	O
A	O
:	O
T	O
=	O
20	O
:	O
1	O
)	O
and	O
following	O
the	O
incorporation	O
of	O
[	O
H	O
]	O
dTMP	O
as	O
a	O
function	O
of	O
time	O
a	O
short	O
lag	O
was	O
observed	O
for	O
C	O
enzyme	O
,	O
but	O
not	O
for	O
A2	O
(	O
Fig	O
.	O
4	O
)	O
.	O

Similar	O
re	O
sult	O
s	O
we	O
re	O
obtained	O
when	O
poly	O
(	O
dC	O
)	O
.	O
oligo	O
(	O
dG	O
)	O
1	O
0	O
(	O
C	O
:	O
G	O
=	O
5	O
:	O
1	O
)	O
wa	O
s	O

used	O
as	O
temrrplate	O
-	O
initiator	O
,	O
but	O
not	O
when	O
poly	O
(	O
dT	O
)	O
.	O
oligo	O
(	O
A	O
)	O
10	O
(	O
T	O
:	O
A	O
=	O
1	O
:	O
1	O
)	O
was	O
used	O
.	O

Neither	O
enzyme	O
showed	O
a	O
lag	O
on	O
this	O
template	O
-	O
initiator	O
complex	O
or	O
on	O
activated	O
DNA	O
.	O

Incorporation	O
versus	O
enzyme	O
concentration	O
also	O
showed	O
this	O
lag	O
for	O
C	O
enzyme	O
on	O
poly	O
(	O
dA	O
)	O
.	O
oligo	O
(	O
dT	O
)	O
10	O
.	O

It	O
is	O
not	O
certain	O
what	O
causes	O

3349	O

Nucleic	O
Acids	O
Research	O

TABLE	O
1	O
Template	O
utilisation	O
by	O
reconstituted	O
A	O
and	O
C	O
derived	O
from	O
A	O
.	O

3H	O
]	O
dNTP	O
Divalent	O
cation	O
A2	O
at	O
pH	O
C	O
at	O
pH	O

Template	O
_	O
6	O
.	O
4	O
7	O
.	O
8	O
6	O
.	O
4	O
7	O
.	O
8	O
Activated	O
DNA	O
dTTP	O
Mg	O
+	O
+	O
100	O
100	O
Activated	O
DNA	O
dATP	O
Mg	O
+	O
+	O
91	O
85	O
Activated	O
DNA	O
dGTP	O
Mg	O
+	O
+	O
85	O
82	O
poly	O
(	O
dA	O
)	O
.	O
oligo	O
(	O
dT	O
)	O
10	O
dTTP	O
Mg	O
66	O
.	O
0	O
4	O
.	O
0	O
20	O
91	O

(	O
A	O
:	O
T	O
=	O
20	O
:	O
1	O
)	O

poly	O
(	O
dA	O
)	O
.	O

oligo	O
(	O
dT	O
)	O
dTTP	O
Mu	O
19	O
.	O
0	O
4	O
.	O

5	O
6	O
.	O

5	O
2	O
.	O
5	O

poly	O
(	O
dA	O
.	O

oig	O
~	O
10	O
(	O
A	O
:	O
T	O
=	O
20	O
:	O
1	O
)	O

poly	O
(	O
dT	O
)	O
.	O

oligo	O
(	O
dA	O
)	O
10	O
dATP	O
Mg	O
2	O
.	O
5	O
<	O
1	O
(	O
1	O
(	O
1	O

(	O
T	O
:	O
A	O
=	O
5	O
:	O
1	O
)	O

poly	O
(	O
dT	O
)	O
.	O
oligo	O
(	O
dA	O
)	O
1	O
dATP	O
Mn	O
+	O
+	O
15	O
.	O
5	O
23	O
.	O
0	O
9	O
.	O

0	O
3	O
.	O

0	O

poly	O
(	O
dT	O
)	O
.	O

oligo	O
(	O
A	O
)	O
10	O
dATP	O
Mg	O
15	O
.	O
0	O
230	O
.	O
0	O
10	O
.	O
0	O
77	O
.	O

5	O

(	O
T	O
:	O
A	O
=	O
1	O
:	O
1	O
)	O

poly	O
(	O
dT	O
)	O
*	O
oligo	O
(	O
A	O
)	O
10	O
dATP	O
Mn	O
41	O
.	O
5	O
75	O
.	O

5	O
19	O
.	O
5	O
21	O
.	O
5	O

(	O
T	O
:	O
A	O
=	O
1	O
:	O
1	O
)	O

poly	O
(	O
dC	O
)	O
.	O

oligo	O
(	O
dG	O
)	O
dGTP	O
Mg	O
+	O
+	O
6	O
.	O

0	O
15	O
.	O
5	O
4	O
.	O

5	O
7	O
.	O

5	O

(	O
C	O
:	O
G	O
=	O
5	O
:	O
1	O
)	O
10	O

poly	O
(	O
dC	O
)	O
.	O

oligo	O
(	O
dG	O
)	O
10	O
dGTP	O
Mn	O
+	O
6	O
.	O

0	O
29	O
.	O
5	O
5	O
.	O

0	O
6	O
.	O

5	O

(	O
C	O
:	O
G	O
=	O
5	O
:	O
1	O
)	O
.	O

.	O

Values	O
given	O
are	O
relative	O
to	O
incorporation	O
of	O
[	O
H	O
]	O
dTMP	O
at	O
pH	O
7	O
.	O

8	O
on	O
activated	O
DNA	O
.	O

For	O
A2	O
this	O
was	O
176	O
.	O
5	O
pmol	O
,	O
for	O
C	O
232	O
pmol	O
.	O

dATP	O
,	O
dCTP	O
,	O
dGTP	O
and	O
dTTP	O
were	O
included	O
for	O
assays	O
using	O
activated	O
DNA	O
,	O
only	O
the	O
deoxynucleoside	O
triphosphate	O
stated	O
was	O
used	O
in	O
the	O
synthetic	O
template	O

initiator	O
complex	O
assays	O
.	O

Assays	O
were	O
for	O
10	O
minutes	O
.	O

The	O
buffers	O
and	O
concentrations	O
of	O
the	O
divalent	O
cations	O
were	O
as	O
in	O
Materials	O
and	O
Methods	O
.	O

this	O
lag	O
,	O
but	O
the	O
annealing	O
of	O
template	O
to	O
initiator	O
is	O
only	O
transient	O
'	O
and	O
the	O
DNA	O
polymerase	O
subunit	O
may	O
have	O
difficulty	O
in	O
stabilising	O
the	O
complex	O
and	O
the	O
50	O
-	O
70	O
,	O
000	O
molecular	O
weight	O
subunit	O
may	O
be	O
able	O
to	O
help	O
the	O
poly	O

merase	O
subunit	O
to	O
overcome	O
this	O
.	O

Addition	O
of	O
the	O
50	O
-	O
70	O
,	O
000	O
subunit	O
to	O
the	O
polymerase	O
subunit	O
prior	O
to	O
assaying	O
with	O
these	O
templates	O
had	O
no	O
effect	O
on	O
activity	O
and	O
it	O
may	O
be	O
that	O
a	O
preincubation	O
period	O
is	O
required	O
before	O
the	O
two	O
3350	O

Nucleic	O
Acids	O
Research	O

Figure	O
4	O
Activity	O
of	O
A2	O
and	O
C	O
enzymes	O
on	O
poly	O
(	O
dA	O
)	O
.	O
oligo	O
(	O
dT	O
)	O
jO	O
(	O
A	O
:	O
T	O
=	O

20	O
:	O
1	O
)	O
as	O
a	O
function	O
of	O
time	O
.	O

50	O
,	O
ul	O
samples	O
were	O
withdrawn	O
at	O
various	O
times	O
from	O
a	O
0	O
.	O

6	O
inl	O
incubation	O
mix	O
at	O
30	O
?	O
C	O
and	O
added	O
to	O
0	O
.	O

5	O
ml	O
0	O
.	O

1	O
M	O
sodium	O

pyrophosphate	O
containing	O
100	O
,	O
ug	O
/	O
ml	O
native	O
calf	B
thymus	O
DNA	O
and	O
processed	O
for	O
counting	O
in	O
the	O
usual	O
manner6	O
.	O

The	O
mix	O
contained	O
1	O
mM	O
dithiothreitol	O
,	O
50	O
mM	O
tris	O
HC1	O
,	O
pH	O
7	O
.	O
8	O
10	O
mM	O
MgC12	O
,	O
0	O
.	O

1	O
mM	O
[	O
3H	O
]	O
dTTP	O
(	O
15	O
cpm	O
/	O
pmol	O
)	O
,	O
312	O
.	O
5	O
,	O
ug	O
bovine	B
serum	O
albumin	O
,	O
5	O
Fg	O
poly	O
(	O
dA	O
)	O
.	O
oligo	O
(	O
dT	O
)	O
(	O
A	O
:	O
T	O
=	O
20	O
:	O
1	O
)	O
and	O
enzyme	O
protein	O
(	O
*	O
-	O
*	O
)	O
3	O
.	O
3	O
units	O
reconstituted	O
A2	O
,	O
(	O
o	O
-	O
o	O
)	O
16	O
.	O

0	O
units	O
urea	O
derived	O
C	O
enzyme	O
.	O

subunits	O
become	O
fully	O
associated	O
.	O

After	O
the	O
lag	O
phase	O
is	O
over	O
the	O
C	O
enzyme	O
is	O
still	O
less	O
active	O
on	O
these	O
template	O
-	O
initiators	O
than	O
A	O
enzyme	O
.	O

That	O
is	O
the	O
A	O
enzyme	O
seems	O
capable	O
of	O
elongating	O
the	O
initiator	O
faster	O
than	O
the	O
C	O
enzyme	O
.	O

Experiments	O
to	O
determine	O
whether	O
the	O
differences	O
in	O
rates	O
of	O
elongation	O
of	O
these	O
template	O
-	O
initiator	O
complexes	O
are	O
differences	O
in	O
processivity	O
of	O
the	O

enzymes	O
under	O
the	O
different	O
pH	O
and	O
divalent	O
cation	O
conditions	O
are	O
under	O
way	O
.	O

ACKNOWLEDGEMENTS	O

We	O
thank	O
the	O
Medical	O
Research	O
Council	O
for	O
a	O
research	O
grant	O
.	O

Communications	O
concerning	O
the	O
paper	O
should	O
be	O
sent	O
to	O
:	O

Dr	O
.	O
A	O
.	O

M	O
.	O

Holmes	O
,	O
Department	O
of	O
Biochemistry	O
,	O
University	O
of	O
Strathclyde	O
,	O
The	O
Todd	O
Centre	O
,	O
31	O
Taylor	O
Street	O
,	O
Glasgow	O
G4	O
ONR	O
,	O
U	O
.	O
K	O
.	O

3351	O

Nucleic	O
Acids	O
Research	O

REFERENCES	O

(	O
1	O
)	O
Bollum	O
,	O
F	O
.	O
J	O
.	O

(	O
1975	O
)	O
.	O

Prog	O
.	O

Nucleic	O
Acid	O
Res	O
.	O

Mol	O
.	O

Biol	O
.	O

15	O
,	O

109	O
-	O
144	O
.	O

(	O
2	O
)	O
Holmes	O
,	O
A	O
.	O
M	O
.	O
,	O
Hesslewood	O
,	O
I	O
.	O
P	O
.	O
and	O
Johnston	O
,	O
I	O
.	O
R	O
.	O

(	O
1976	O
)	O
.	O

Eur	O
.	O

J	O
.	O

Biochem	O
.	O

62	O
,	O
229	O
-	O
235	O
.	O

(	O
3	O
)	O
Matsukage	O
,	O
A	O
.	O
,	O
Sivarajan	O
,	O
M	O
.	O
and	O
Wilson	O
,	O
S	O
.	O
H	O
.	O

(	O
1976	O
)	O
.	O

Biochem	O

istry	O
15	O
,	O
5305	O
-	O
5314	O
.	O

(	O
4	O
)	O
Fisher	O
,	O
P	O
.	O
A	O
.	O
and	O
Korn	O
,	O
D	O
.	O

(	O
1977	O
)	O
.	O

J	O
.	O

Biol	O
.	O

Chem	O
.	O

252	O
,	O
6528	O

6535	O
.	O

(	O
5	O
)	O
Fichot	O
,	O
O	O
.	O
,	O
Pascal	O
,	O
M	O
.	O
,	O
Mechali	O
,	O
M	O
.	O
and	O
De	O
Recondo	O
,	O
A	O
,	O
-	O
M	O
.	O

(	O
1979	O
)	O
.	O

Biochim	O
.	O

Biophys	O
.	O

Acta	O
,	O
561	O
,	O
28	O
-	O
41	O
.	O

(	O
6	O
)	O
Holmes	O
,	O
A	O
.	O
M	O
.	O
,	O
Hesslewood	O
,	O
I	O
.	O
R	O
.	O
and	O
Johnston	O
,	O
I	O
.	O
R	O
.	O

(	O
1974	O
)	O
.	O

Eur	O
.	O

J	O
.	O

Biochemn	O
.	O

43	O
,	O
487	O
-	O
499	O
.	O

(	O
7	O
)	O
Noy	O
,	O
G	O
.	O
P	O
.	O
and	O
Weissbach	O
,	O
A	O
.	O

(	O
1977	O
)	O
.	O

Biochim	O
.	O

Biophys	O
.	O

Acta	O
,	O

447	O
,	O
70	O
-	O
83	O
.	O

(	O
8	O
)	O
Craig	O
,	O
R	O
.	O
K	O
.	O
and	O
Keir	O
,	O
H	O
.	O

M	O
.	O

(	O
1975	O
)	O
.	O

Biochem	O
.	O

J	O
.	O

145	O
,	O
225	O
-	O
232	O
.	O

(	O
9	O
)	O
Matsukage	O
,	O
A	O
.	O
,	O
Bohn	O
,	O
E	O
.	O
W	O
.	O
and	O
Wilson	O
,	O
S	O
.	O
H	O
.	O

(	O
1974	O
)	O
.	O

Proc	O
.	O

Natl	O
.	O

Acad	O
.	O

Sci	O
.	O

U	O
.	O
S	O
.	O
A	O
.	O

71	O
,	O
578	O
-	O
582	O
.	O

110	O
)	O
Hachmann	O
,	O
H	O
.	O
J	O
.	O
and	O
Lezius	O
,	O
A	O
.	O
G	O
.	O

(	O
1975	O
)	O
.	O

Eur	O
.	O

J	O
.	O

Biochem	O
.	O

50	O
,	O

357	O
-	O
366	O
.	O

(	O
11	O
)	O
Brakel	O
,	O
C	O
.	O
L	O
.	O
and	O
Blumenthal	O
,	O
A	O
.	O
B	O
.	O

(	O
1977	O
)	O
.	O

Biochemistry	O
,	O
16	O
,	O

3137	O
-	O
3143	O
.	O

(	O
12	O
)	O
Momparler	O
,	O
R	O
.	O
L	O
.	O
,	O
Rossi	O
,	O
M	O
.	O
and	O
Labitan	O
,	O
A	O
.	O

(	O
1973	O
)	O
.	O

J	O
.	O

Biol	O
.	O

Chem	O
.	O

248	O
,	O
285	O
-	O
293	O
.	O

(	O
13	O
)	O
Yoshida	O
,	O
S	O
.	O
,	O
Konda	O
,	O
T	O
.	O
and	O
Ando	O
,	O
T	O
.	O

(	O
1974	O
)	O
.	O

Biochim	O
.	O

Biophys	O
.	O

Acta	O
,	O
353	O
,	O
463	O
-	O
474	O
.	O

(	O
14	O
)	O
Holmes	O
,	O
A	O
.	O
M	O
.	O
,	O
Hesslewood	O
,	O
I	O
.	O
P	O
.	O
,	O
Wickremasinghe	O
,	O
R	O
.	O
G	O
.	O
and	O

Johnston	O
,	O
I	O
.	O
R	O
.	O

(	O
1977	O
)	O
.	O

Biochem	O
.	O

Soc	O
.	O

Symp	O
.	O

42	O
,	O
17	O
-	O
36	O
.	O

(	O
15	O
)	O
De	O
Jong	O
,	O
A	O
.	O
,	O
Van	O
der	O
Vliet	O
,	O
P	O
.	O
and	O
Jansz	O
,	O
H	O
.	O
S	O
.	O

(	O
1977	O
)	O
.	O

Biochim	O
.	O

Biophys	O
.	O

Acta	O
,	O
476	O
,	O
156	O
-	O
165	O
.	O

(	O
16	O
)	O
Holmes	O
,	O
A	O
.	O
M	O
.	O
,	O
Hesslewood	O
,	O
I	O
.	O
P	O
.	O
and	O
Johnston	O
,	O
I	O
.	O
R	O
.	O

(	O
1975	O
)	O
.	O

Nature	O
(	O
London	O
)	O
255	O
,	O
420	O
-	O
422	O
.	O

(	O
17	O
)	O
Bollum	O
,	O
F	O
.	O

J	O
.	O

(	O
1966	O
)	O
.	O

Procedures	O
in	O
Nucleic	O
Acid	O
Research	O

(	O
Cantoni	O
,	O
G	O
.	O
L	O
.	O
and	O
Davis	O
,	O
D	O
.	O
R	O
.	O
eds	O
)	O
.	O

pp	O
577	O
-	O
583	O
,	O
Harper	O
and	O
Row	O
,	O
New	O
York	O
.	O

(	O
18	O
)	O
Barrett	O
,	O
A	O
.	O
J	O
.	O

(	O
1975	O
)	O
.	O

Proteases	O
and	O
Biological	O
Control	O
pp	O
467	O
-	O
482	O
,	O

Cold	O
Spring	O
Harbor	O
Laboratory	O
,	O
Cold	O
Spring	O
Harbor	O
.	O

(	O
19	O
)	O
Richards	O
,	O
F	O
.	O

M	O
.	O
and	O
Vithayathil	O
,	O
P	O
.	O
J	O
.	O

(	O
1960	O
)	O
.	O

Brookhaven	O
Symp	O
.	O

Biol	O
.	O

13	O
,	O
115	O
-	O
134	O
.	O

(	O
20	O
)	O
Lowe	O
,	O
P	O
.	O
A	O
.	O
,	O
and	O
Malcolm	O
,	O
A	O
.	O
B	O
.	O
D	O
.	O

(	O
1976	O
)	O
.	O

Eur	O
.	O

J	O
.	O

Biochem	O
.	O

64	O
,	O

177	O
-	O
188	O
.	O

(	O
21	O
)	O
Hesslewood	O
,	O
I	O
.	O
P	O
.	O
,	O
Holmes	O
,	O
A	O
.	O
M	O
.	O
,	O
Wakeling	O
,	O
W	O
.	O
F	O
.	O
and	O
Johnston	O
,	O

I	O
.	O
R	O
.	O

(	O
1978	O
)	O
.	O

Eur	O
.	O

J	O
.	O

Biochenr	O
.	O
.	O

84	O
,	O
123	O
-	O
131	O
.	O

(	O
22	O
)	O
Mechali	O
,	O
M	O
.	O
and	O
De	O
Recondo	O
,	O
A	O
.	O

-	O
M	O
.	O

(	O
1978	O
)	O
.	O

Biochim	O
.	O

Biophys	O
.	O

Res	O
.	O

Comm	O
,	O
82	O
,	O
255	O
-	O
264	O
.	O

(	O
23	O
)	O
Chang	O
,	O
L	O
.	O
M	O
.	O
S	O
.	O
,	O
Cassani	O
,	O
G	O
.	O
R	O
.	O
and	O
Bollum	O
,	O
F	O
.	O
J	O
.	O

(	O
1972	O
)	O
.	O

J	O
.	O

Biol	O
.	O

Che	O
.	O

247	O
,	O
7718	O
-	O
7723	O
.	O

(	O
24	O
)	O
Wickremasinghe	O
,	O
R	O
.	O
G	O
.	O
and	O
Johnston	O
,	O
I	O
.	O
R	O
.	O

(	O
1974	O
)	O
.	O

Biochim	O
.	O

Biophys	O
.	O

Acta	O
,	O
361	O
,	O
37	O
-	O
52	O
.	O

3352	O

Primitive	O
Neuroectodermal	O
Tumor	O
(	O
PNET	O
)	O
of	O
the	O
kidney	O
:	O
a	O
case	O
report	O

Abstract	O

Background	O

A	O
case	O
of	O
Primitive	O
Neuroectodermal	O
Tumor	O
(	O
PNET	O
)	O
of	O
the	O
kidney	O
in	O
a	O
27	O
-	O
year	O
-	O
old	O
woman	B
is	O
presented	O
.	O

Few	O
cases	O
are	O
reported	O
in	O
the	O
literature	O
with	O
a	O
variable	O
,	O
nonspecific	O
presentation	O
and	O
an	O
aggressive	O
behaviour	O
.	O

In	O
our	O
case	O
,	O
a	O
radical	O
nephrectomy	O
with	O
lymphadenectomy	O
was	O
performed	O
and	O
there	O
was	O
no	O
residual	O
or	O
recurrent	O
tumour	O
at	O
24	O
-	O
month	O
follow	O
-	O
up	O
.	O

Methods	O

The	O
surgical	O
specimens	O
were	O
formalin	O
-	O
fixed	O
and	O
paraffin	O
embedded	O
.	O

The	O
sections	O
were	O
stained	O
with	O
routinary	O
H	O
&	O
E	O
.	O

Immunohistochemistry	O
was	O
performed	O
.	O

Results	O

The	O
immunohistochemical	O
evaluation	O
revealed	O
a	O
diffuse	O
CD99	O
positivity	O
in	O
the	O
cytoplasm	O
of	O
the	O
neoplastic	O
cells	O
.	O

Pankeratin	O
,	O
cytokeratin	O
AE1	O
/	O
AE3	O
,	O
vimentin	O
,	O
desmin	O
,	O
S100	O
,	O
cromogranin	O
were	O
negative	O
.	O

The	O
clinical	O
presentation	O
and	O
the	O
macroscopic	O
aspect	O
,	O
together	O
with	O
the	O
histological	O
pattern	O
,	O
the	O
cytological	O
characteristic	O
and	O
the	O
cellular	O
immunophenotype	O
addressed	O
the	O
diagnosis	O
towards	O
primary	O
PNET	O
of	O
kidney	O
.	O

Conclusions	O

Since	O
sometimes	O
it	O
is	O
difficult	O
to	O
discriminate	O
between	O
PNET	O
and	O
Ewing	O
'	O
s	O
tumour	O
,	O
we	O
reviewed	O
the	O
difficulties	O
in	O
differential	O
diagnosis	O
.	O

These	O
tumors	O
have	O
a	O
common	O
precursor	O
but	O
the	O
stage	O
of	O
differentiation	O
in	O
which	O
it	O
is	O
blocked	O
is	O
probably	O
different	O
.	O

This	O
could	O
also	O
explain	O
their	O
different	O
biological	O
behaviour	O
and	O
prognosis	O
.	O

Background	O

The	O
peripheral	O
Primitive	O
Neuroectodermal	O
Tumor	O
(	O
PNET	O
)	O
,	O
firstly	O
recognized	O
by	O
Arthur	O
Purdy	O
Stout	O
in	O
1918	O
,	O
is	O
a	O
member	O
of	O
the	O
family	O
of	O
"	O
small	O
round	O
-	O
cell	O
tumors	O
"	O
.	O

Primitive	O
renal	O
localization	O
is	O
very	O
rare	O
.	O

There	O
are	O
almost	O
50	O
cases	O
reported	O
in	O
the	O
literature	O
,	O
although	O
it	O
is	O
difficult	O
to	O
estimate	O
the	O
exact	O
number	O
since	O
often	O
it	O
has	O
not	O
been	O
differentiated	O
from	O
Ewing	O
'	O
s	O
Sarcoma	O
[	O
1	O
-	O
13	O
]	O
.	O

Renal	O
PNET	O
is	O
more	O
aggressive	O
than	O
in	O
the	O
other	O
sites	O
.	O

It	O
frequently	O
arises	O
during	O
childhood	O
or	O
adolescence	O
,	O
having	O
an	O
aggressive	O
clinical	O
course	O
towards	O
metastatic	O
disease	O
and	O
death	O
.	O

It	O
often	O
recurs	O
locally	O
and	O
metastasises	O
early	O
to	O
regional	O
lymph	O
nodes	O
,	O
lungs	O
,	O
liver	O
,	O
bone	O
and	O
bone	O
marrow	O
,	O
resulting	O
in	O
a	O
poor	O
prognosis	O
.	O

The	O
5	O
-	O
year	O
disease	O
-	O
free	O
survival	O
rate	O
,	O
for	O
patients	B
presenting	O
well	O
confined	O
extra	O
-	O
skeletal	O
PNET	O
,	O
is	O
around	O
45	O
-	O
55	O
%	O
and	O
cases	O
with	O
advanced	O
disease	O
at	O
presentation	O
have	O
a	O
median	O
relapse	O
-	O
free	O
survival	O
of	O
only	O
2	O
years	O
[	O
1	O
]	O
.	O

Case	O
presentation	O

A	O
27	O
-	O
year	O
-	O
old	O
woman	B
was	O
referred	O
because	O
of	O
a	O
mild	O
left	O
flank	O
pain	O
and	O
haematuria	O
.	O

Ultrasonography	O
identified	O
a	O
left	O
renal	O
mass	O
homogeneously	O
hyperechogenic	O
in	O
comparison	O
with	O
renal	O
parenchyma	O
.	O

CT	O
scan	O
showed	O
a	O
11	O
mm	O
x	O
8	O
mm	O
x	O
6	O
mm	O
tumor	O
replacing	O
the	O
upper	O
half	O
of	O
the	O
left	O
kidney	O
with	O
extension	O
into	O
the	O
renal	O
vein	O
.	O

Chest	O
x	O
-	O
ray	O
was	O
negative	O
.	O

Pathological	O
stage	O
after	O
radical	O
nephrectomy	O
was	O
T3aN0Mx	O
.	O

The	O
surgical	O
specimens	O
were	O
formalin	O
-	O
fixed	O
and	O
paraffin	O
embedded	O
.	O

The	O
sections	O
were	O
stained	O
with	O
routinary	O
H	O
&	O
E	O
.	O

Immunohistochemistry	O
was	O
performed	O
using	O
avidin	O
biotin	O
complex	O
technique	O
and	O
diaminobenzidine	O
as	O
chromogen	O
.	O

The	O
antibodies	O
used	O
included	O
CD99	O
(	O
Dako	O
,	O
M3601	O
)	O
,	O
pankeratin	O
(	O
Dako	O
,	O
M0821	O
)	O
,	O
cytokeratin	O
AE1	O
/	O
AE3	O
(	O
Dako	O
,	O
M3515	O
)	O
,	O
vimentin	O
(	O
Dako	O
,	O
M7010	O
)	O
,	O
desmin	O
(	O
Dako	O
,	O
M0760	O
)	O
,	O
S100	O
(	O
Dako	O
,	O
Z0311	O
)	O
,	O
and	O
chromogranin	O
A	O
(	O
Dako	O
,	O
M0869	O
)	O
,	O
at	O
suggested	O
dilution	O
.	O

We	O
performed	O
also	O
appropriate	O
routinely	O
positive	O
and	O
negative	O
controls	O
.	O

The	O
tumor	O
was	O
multilobular	O
,	O
grey	O
,	O
glistening	O
,	O
focally	O
hemorrhagic	O
,	O
surrounded	O
by	O
a	O
capsule	O
and	O
with	O
a	O
sharp	O
demarcation	O
from	O
the	O
uninvolved	O
kidney	O
.	O

Histologically	O
,	O
the	O
tumor	O
consisted	O
of	O
small	O
round	O
cells	O
with	O
round	O
nuclei	O
and	O
scant	O
cytoplasm	O
.	O

It	O
presented	O
different	O
patterns	O
,	O
with	O
cohesive	O
lobules	O
or	O
rosettes	O
and	O
perivascular	O
pseudo	O
-	O
rosettes	O
or	O
,	O
in	O
some	O
areas	O
,	O
spindle	O
cellular	O
elements	O
(	O
fig	O
.	O
1	O
)	O
.	O

The	O
immunohistochemical	O
evaluation	O
revealed	O
a	O
diffuse	O
CD99	O
positivity	O
in	O
the	O
cytoplasm	O
of	O
the	O
neoplastic	O
cells	O
(	O
fig	O
.	O
2	O
)	O
;	O
tumoral	O
cells	O
were	O
also	O
visible	O
in	O
the	O
vascular	O
lumens	O
(	O
fig	O
.	O
3	O
)	O
.	O

By	O
contrast	O
,	O
pankeratin	O
,	O
cytokeratin	O
AE1	O
/	O
AE3	O
,	O
vimentin	O
,	O
desmin	O
,	O
S100	O
,	O
cromogranin	O
were	O
negative	O
.	O

The	O
clinical	O
presentation	O
and	O
the	O
macroscopic	O
aspect	O
,	O
together	O
with	O
the	O
histological	O
pattern	O
,	O
the	O
cytological	O
characteristic	O
and	O
the	O
cellular	O
immunophenotype	O
addressed	O
the	O
diagnosis	O
towards	O
primary	O
PNET	O
of	O
kidney	O
.	O

A	O
bone	O
scan	O
did	O
not	O
reveal	O
positive	O
areas	O
.	O

Eight	O
cycles	O
of	O
chemotherapy	O
with	O
Vincristine	O
,	O
Ifosfamide	O
and	O
Adriamycin	O
,	O
four	O
cycles	O
of	O
Ifosfamide	O
and	O
VP16	O
and	O
eight	O
sittings	O
of	O
local	O
radiotherapy	O
were	O
sequentially	O
performed	O
.	O

Follow	O
-	O
up	O
examinations	O
with	O
CT	O
and	O
bone	O
scan	O
failed	O
to	O
show	O
residual	O
or	O
recurrent	O
tumor	O
after	O
24	O
months	O
.	O

Conclusions	O

Primitive	O
Neuroectodermal	O
Tumor	O
of	O
the	O
kidney	O
is	O
a	O
rare	O
entity	O
.	O

The	O
few	O
cases	O
reported	O
revealed	O
a	O
variable	O
presentation	O
and	O
an	O
aggressive	O
behaviour	O
.	O

The	O
distinction	O
from	O
other	O
primary	O
malignancies	O
of	O
the	O
kidneys	O
is	O
crucial	O
for	O
prognosis	O
.	O

The	O
differential	O
diagnosis	O
includes	O
extra	O
-	O
osseous	O
Ewing	O
'	O
s	O
sarcoma	O
,	O
rhabdomyosarcoma	O
,	O
Wilm	O
'	O
s	O
tumor	O
,	O
carcinoid	O
,	O
neuroblastoma	O
,	O
clear	O
cell	O
sarcoma	O
of	O
the	O
kidney	O
,	O
lymphoma	O
,	O
the	O
small	O
cell	O
variant	O
of	O
osteosarcoma	O
,	O
desmoplastic	O
small	O
round	O
cell	O
tumor	O
and	O
nephroblastoma	O
[	O
5	O
]	O
.	O

The	O
Homer	O
-	O
Wright	O
type	O
rosettes	O
,	O
commonly	O
scarce	O
of	O
number	O
or	O
less	O
defined	O
in	O
extra	O
skeletal	O
Ewing	O
'	O
s	O
sarcoma	O
(	O
ES	O
)	O
,	O
are	O
a	O
typical	O
histological	O
feature	O
for	O
PNET	O
and	O
can	O
address	O
the	O
diagnosis	O
although	O
they	O
can	O
be	O
found	O
also	O
in	O
neuroblastoma	O
[	O
5	O
]	O
.	O

To	O
better	O
address	O
the	O
diagnosis	O
,	O
an	O
immunohistochemical	O
analysis	O
is	O
necessary	O
.	O

In	O
our	O
case	O
the	O
presence	O
of	O
MIC	O
-	O
2	O
gene	O
products	O
,	O
known	O
also	O
as	O
CD99	O
,	O
12E7	O
,	O
E2	O
,	O
013	O
and	O
HBA71	O
,	O
suggested	O
a	O
PNET	O
diagnosis	O
.	O

Primitive	O
neuroectodermal	O
tumors	O
only	O
immunorreactive	O
to	O
CD99	O
,	O
even	O
if	O
uncommon	O
,	O
are	O
reported	O
in	O
the	O
literature	O
[	O
13	O
]	O
.	O

The	O
reactivity	O
to	O
vimentin	O
,	O
NSE	O
and	O
S	O
-	O
100	O
may	O
facilitate	O
the	O
diagnosis	O
but	O
is	O
not	O
patognomonic	O
,	O
while	O
CD	O
99	O
positivity	O
is	O
nowadays	O
a	O
clue	O
for	O
the	O
diagnosis	O
.	O

Moreover	O
cytogenetic	O
studies	O
(	O
not	O
performed	O
in	O
our	O
case	O
)	O
demonstrated	O
that	O
PNET	O
and	O
Ewing	O
'	O
s	O
sarcoma	O
can	O
both	O
be	O
associated	O
to	O
a	O
translocation	O
of	O
the	O
long	O
arms	O
of	O
chromosome	O
11	O
and	O
22	O
,	O
t	O
(	O
11	O
;	O
22	O
)	O
(	O
q22	O
;	O
q12	O
)	O
[	O
5	O
]	O
.	O

Despite	O
their	O
genetic	O
and	O
antigenic	O
similarity	O
,	O
many	O
authors	O
currently	O
recognize	O
PNET	O
and	O
extra	O
-	O
skeletal	O
Ewing	O
'	O
s	O
sarcoma	O
of	O
the	O
kidney	O
as	O
separate	O
entities	O
.	O

It	O
is	O
also	O
important	O
to	O
keep	O
separate	O
renal	O
PNET	O
and	O
malignant	O
rhabdomyosarcoma	O
tumor	O
(	O
MRT	O
)	O
.	O

Weeks	O
et	O
al	O
reported	O
8	O
cases	O
suggestive	O
for	O
PNET	O
but	O
mimicking	O
MRT	O
[	O
14	O
]	O
.	O

Although	O
renal	O
PNET	O
and	O
MRT	O
show	O
similar	O
clinico	O
-	O
pathological	O
features	O
,	O
the	O
latter	O
usually	O
occurs	O
in	O
very	O
young	O
children	O
,	O
having	O
a	O
more	O
aggressive	O
prognosis	O
.	O

Rodriguez	O
et	O
al	O
postulated	O
that	O
these	O
two	O
renal	O
neoplasms	O
share	O
a	O
common	O
undifferentiated	O
precursor	O
to	O
explain	O
their	O
similarity	O
and	O
we	O
agree	O
with	O
these	O
Authors	O
[	O
12	O
]	O
.	O

Indeed	O
,	O
the	O
hypothesis	O
that	O
tumors	O
arise	O
from	O
stem	O
cells	O
(	O
SCs	O
)	O
as	O
a	O
consequence	O
of	O
a	O
maturative	O
arrest	O
is	O
now	O
growing	O
[	O
15	O
]	O
.	O

SCs	O
are	O
present	O
in	O
almost	O
all	O
tissues	O
and	O
may	O
originate	O
different	O
cellular	O
lineages	O
by	O
the	O
multi	O
-	O
step	O
process	O
named	O
"	O
differentiation	O
"	O
.	O

The	O
role	O
of	O
SCs	O
in	O
tumorigenesis	O
was	O
clearly	O
demonstrated	O
in	O
a	O
number	O
of	O
carcinogenic	O
models	O
showing	O
that	O
solid	O
and	O
haematopoietic	O
cancers	O
could	O
arise	O
from	O
tissue	O
-	O
specific	O
SCs	O
[	O
16	O
-	O
19	O
]	O
.	O

In	O
agreement	O
with	O
Sell	O
and	O
Pierce	O
,	O
we	O
retain	O
that	O
the	O
degree	O
of	O
malignancy	O
of	O
a	O
carcinoma	O
depends	O
by	O
the	O
stage	O
in	O
which	O
SCs	O
differentiation	O
stopped	O
during	O
carcinogenesis	O
[	O
19	O
]	O
.	O

In	O
particular	O
,	O
since	O
PNET	O
,	O
Ewing	O
'	O
s	O
tumour	O
and	O
MRT	O
have	O
a	O
similar	O
morphology	O
,	O
our	O
hypothesis	O
is	O
that	O
the	O
mesenchimal	O
stem	O
precursor	O
of	O
these	O
tumors	O
is	O
the	O
same	O
,	O
but	O
the	O
stage	O
of	O
differentiation	O
in	O
which	O
it	O
is	O
blocked	O
is	O
different	O
.	O

This	O
could	O
explain	O
why	O
sometimes	O
it	O
is	O
difficult	O
to	O
discriminate	O
between	O
these	O
tumors	O
,	O
notwithstanding	O
they	O
present	O
a	O
different	O
biological	O
behaviour	O
.	O

Competing	O
interests	O

None	O
declared	O
.	O

Authors	O
'	O
contribution	O

All	O
authors	O
contributed	O
.	O

Pre	O
-	O
publication	O
history	O

The	O
pre	O
-	O
publication	O
history	O
for	O
this	O
paper	O
can	O
be	O
accessed	O
here	O
:	O

The	O
c1	O
genes	O
of	O
P1	O
and	O
P7	O
.	O

Abstract	O

The	O
c1	O
genes	O
of	O
the	O
heteroimmune	O
phages	O
P1	O
and	O
P7	O
were	O
sequenced	O
and	O
their	O
products	O
were	O
compared	O
.	O

P7c1	O
expression	O
was	O
correlated	O
with	O
the	O
translation	O
in	O
vitro	O
of	O
a	O
protein	O
whose	O
predicted	O
molecular	O
weight	O
(	O
33	O
,	O
000	O
daltons	O
)	O
is	O
indistinguishable	O
from	O
that	O
of	O
the	O
P1c1	O
repressor	O
.	O

The	O
c1	O
regions	O
from	O
both	O
P1	O
and	O
P7	O
were	O
found	O
to	O
contain	O
open	O
reading	O
frames	O
capable	O
of	O
coding	O
for	O
a	O
283	O
-	O
amino	O
acid	O
protein	O
whose	O
predicted	O
secondary	O
structure	O
lacks	O
the	O
helix	O
-	O
turn	O
-	O
helix	O
motif	O
commonly	O
associated	O
with	O
repressor	O
proteins	O
.	O

Two	O
P1c1	O
amber	O
mutations	O
were	O
localized	O
to	O
the	O
283	O
-	O
amino	O
acid	O
open	O
reading	O
frame	O
.	O

The	O
P1c1	O
and	O
P7c1	O
sequences	O
were	O
found	O
to	O
differ	O
at	O
only	O
18	O
positions	O
,	O
all	O
but	O
two	O
of	O
which	O
alter	O
the	O
third	O
position	O
of	O
the	O
affected	O
codon	O
and	O
do	O
not	O
alter	O
the	O
amino	O
acid	O
sequence	O
of	O
the	O
protein	O
.	O

Plasmids	O
expressing	O
the	O
c1	O
gene	O
from	O
either	O
phage	O
cause	O
the	O
repression	O
of	O
transcription	O
from	O
a	O
cloned	O
promoter	O
situated	O
upstream	O
of	O
P1c1	O
.	O
Images	O

Volme	O
7	O
Nmbe	O
19198	O
Nulei	O
Acds	O
eserc	O

The	O
cl	O
genes	O
of	O
P1	O
and	O
P7	O

Francis	O
A	O
.	O
Osborne	O
,	O
Sonja	O
R	O
.	O
Stovall	O
and	O
Barbara	O
R	O
.	O
Baumstark	O
*	O

Department	O
of	O
Biology	O
,	O
Georgia	O
State	O
University	O
,	O
Atlanta	O
,	O
GA	O
30303	O
,	O
USA	O

Received	O
July	O
11	O
,	O
1989	O
;	O
Revised	O
and	O
Accepted	O
August	O
29	O
,	O
1989	O
EMBL	O
accession	O
nos	O
X16005	O
,	O
X16006	O

ABSTRACT	O

The	O
cl	O
genes	O
of	O
the	O
heteroimmune	O
phages	O
P1	O
and	O
P7	O
were	O
sequenced	O
and	O
their	O
products	O
were	O
compared	O
.	O

P7cl	O
expression	O
was	O
correlated	O
with	O
the	O
translation	O
in	O
vitro	O
of	O
a	O
protein	O
whose	O
predicted	O
molecular	O
weight	O
(	O
33	O
,	O
000	O
daltons	O
)	O
is	O
indistinguishable	O
from	O
that	O
of	O
the	O
Plcl	O
repressor	O
.	O

The	O
cl	O
regions	O
from	O
both	O
P1	O
and	O
P7	O
were	O
found	O
to	O
contain	O
open	O
reading	O
frames	O
capable	O
of	O
coding	O
for	O
a	O
283	O
-	O
amino	O
acid	O
protein	O
whose	O
predicted	O
secondary	O
structure	O
lacks	O
the	O
helix	O
-	O
tum	O
-	O
helix	O
motif	O
commonly	O
associated	O
with	O
repressor	O
proteins	O
.	O

Two	O
Plcl	O
amber	O
mutations	O
were	O
localized	O
to	O
the	O
283	O
-	O
amino	O
acid	O
open	O
reading	O
frame	O
.	O

The	O
Plcl	O
and	O
P7cl	O
sequences	O
were	O
found	O
to	O
differ	O
at	O
only	O
18	O
positions	O
,	O
all	O
but	O
two	O
of	O
which	O
alter	O
the	O
third	O
position	O
of	O
the	O
affected	O
codon	O
and	O
do	O
not	O
alter	O
the	O
amino	O
acid	O
sequence	O
of	O
the	O
protein	O
.	O

Plasmids	O
expressing	O
the	O
cI	O
gene	O
from	O
either	O
phage	O
cause	O
the	O
repression	O
of	O
transcription	O
from	O
a	O
cloned	O
promoter	O
situated	O
upstream	O
of	O
Plcl	O
.	O

INTRODUCTION	O

The	O
cl	O
genes	O
of	O
the	O
plasmid	O
prophages	O
P1	O
and	O
P7	O
code	O
for	O
repressor	O
proteins	O
that	O
are	O
required	O
for	O
the	O
establishment	O
and	O
maintenance	O
of	O
lysogeny	O
(	O
reviewed	O
in	O
1	O
)	O
.	O

A	O
protein	O
corresponding	O
to	O
the	O
Plcl	O
repressor	O
has	O
been	O
isolated	O
and	O
shown	O
to	O
be	O
a	O
sequence	O
-	O
specific	O
DNA	O
binding	O
protein	O
that	O
recognizes	O
several	O
widely	O
dispersed	O
sites	O
on	O
the	O
phage	O
DNA	O
(	O
2	O
-	O
7	O
)	O
.	O

The	O
consensus	O
DNA	O
sequence	O
recognized	O
by	O
the	O
Plcl	O
repressor	O
(	O
ATTTATTAGAGCA	O
[	O
A	O
/	O
T	O
]	O
T	O
)	O
contains	O
no	O
discernable	O
bilateral	O
symmetry	O
,	O
a	O
feature	O
that	O
is	O
highly	O
unusual	O
among	O
prokaryotic	O
operator	O
sites	O
.	O

P1	O
and	O
P7	O
are	O
heteroimmune	O
;	O
that	O
is	O
,	O
each	O
phage	O
is	O
able	O
to	O
establish	O
a	O
lytic	O
infection	O
on	O
a	O
lysogen	O
of	O
the	O
other	O
phage	O
.	O

In	O
this	O
sense	O
,	O
their	O
relationship	O
is	O
analogous	O
to	O
that	O
of	O
phage	O
X	O
and	O
434	O
,	O
which	O
differ	O
in	O
the	O
DNA	O
specificity	O
of	O
their	O
cI	O
repressor	O
proteins	O
(	O
8	O
)	O
.	O

However	O
,	O
genetic	O
studies	O
indicate	O
that	O
Plcl	O
and	O
P7cl	O
can	O
be	O
crossed	O
into	O
the	O
heterologous	O
phage	O
without	O
affecting	O
the	O
immunity	O
specificity	O
of	O
the	O
recipient	O
(	O
9	O
)	O
.	O

The	O
basis	O
for	O
P1	O
/	O
P7	O
heteroimmunity	O
has	O
been	O
localized	O
to	O
a	O
second	O
regulatory	O
gene	O
,	O
c4	O
,	O
that	O
is	O
unlinked	O
to	O
cl	O
.	O

The	O
c4	O
gene	O
products	O
prevent	O
the	O
expression	O
of	O
antireb	O
,	O
a	O
closely	O
linked	O
gene	O
that	O
interferes	O
with	O
cl	O
-	O
mediated	O
repression	O
(	O
10	O
,	O
11	O
)	O
.	O

According	O
to	O
current	O
models	O
,	O
P1	O
/	O
P7	O
heteroimmunity	O
results	O
from	O
the	O
inability	O
of	O
the	O
c4	O
repressor	O
of	O
one	O
phage	O
to	O
prevent	O
antireb	O
expression	O
from	O
the	O
heteroimmune	O
phage	O
genome	O
(	O
10	O
,	O
11	O
)	O
.	O

Because	O
the	O
cl	O
genes	O
of	O
P1	O
and	O
P7	O
are	O
genetically	O
interchangeable	O
,	O
it	O
is	O
anticipated	O
that	O
the	O
two	O
gene	O
products	O
carry	O
out	O
similar	O
or	O
identical	O
regulatory	O
functions	O
.	O

The	O
studies	O
presented	O
in	O
this	O
paper	O
were	O
undertaken	O
to	O
investigate	O
the	O
biochemical	O
basis	O
for	O
the	O
apparent	O
genetic	O
identity	O
of	O
the	O
two	O
cl	O
genes	O
.	O

In	O
this	O
paper	O
,	O
we	O
present	O
the	O
DNA	O
sequence	O
of	O
the	O
cl	O
genes	O
of	O
P1	O
and	O
P7	O
and	O
the	O
predicted	O
amino	O
acid	O
sequence	O
of	O
the	O
cl	O
repressor	O
proteins	O
.	O

We	O
report	O
that	O
Plcl	O
and	O
P7cl	O
code	O
for	O
proteins	O
of	O
identical	O
size	O
(	O
283	O
amino	O
acids	O
)	O
and	O

Nucleic	O
Acids	O
Research	O

Volume	O
17	O
Number	O
19	O
1989	O

767	O
1	O

(	O
r	O
IRL	O
Press	O

Nucleic	O
Acids	O
Research	O

nearly	O
identical	O
sequence	O
.	O

We	O
report	O
further	O
that	O
both	O
repressors	O
prevent	O
the	O
expression	O
of	O
a	O
promoter	O
located	O
immediately	O
upstream	O
of	O
the	O
Plc	O
1	O
open	O
reading	O
frame	O
,	O
an	O
observation	O
that	O
confirms	O
their	O
functional	O
similarity	O
and	O
suggests	O
an	O
autoregulatory	O
role	O
for	O
the	O
two	O
proteins	O
.	O

Analysis	O
of	O
the	O
secondary	O
structure	O
predicted	O
by	O
the	O
open	O
reading	O
frames	O
does	O
not	O
reveal	O
the	O
characteristic	O
helix	O
-	O
turn	O
-	O
helix	O
(	O
12	O
)	O
or	O
other	O
motifs	O
commonly	O
associated	O
with	O
DNA	O
binding	O
proteins	O
.	O

MATERIALS	O
AND	O
METHODS	O
Bacterial	O
and	O
phage	O
strains	O
.	O

E	B
.	I
coli	I
K336	O
is	O
a	O
SuO	O
derivative	O
of	O
K140	O
(	O
13	O
)	O
.	O

E	B
.	I
coli	I
CB454	O
is	O
a	O
recA	O
-	O
,	O
lacZderivative	O
of	O
K	O
-	O
12	O
(	O
14	O
)	O
.	O

P1	O
+	O
is	O
described	O
by	O
Scott	O
(	O
13	O
)	O
.	O

P7	O
+	O
is	O
the	O
strain	O
of	O
Smith	O
(	O
15	O
)	O
,	O
as	O
described	O
by	O
Scott	O
(	O
16	O
)	O
.	O

P7cl	O
.	O

1	O
contains	O
a	O
missense	O
mutation	O
in	O
the	O
cl	O
gene	O
(	O
17	O
)	O
.	O

The	O
P7	O
phage	O
strains	O
and	O
the	O
cl	O
amber	O
mutant	O
phage	O
strains	O
PIci	O
.	O
245Cm	O
,	O
Plc1	O
.	O

169	O
and	O
P	O
Ic	O
.	O
55	O
(	O
11	O
)	O
were	O
generously	O
provided	O
by	O
June	O
Scott	O
.	O

Enzymes	O
and	O
reagents	O
.	O

Restriction	O
enzymes	O
,	O
T4	O
DNA	O
ligase	O
and	O
polymerase	O
,	O
and	O
the	O
Klenow	O
fragment	O
of	O
E	B
.	I
coli	I
DNA	O
polymerase	O
were	O
purchased	O
from	O
Boehringer	O
Biochemicals	O
or	O
New	O
England	O
Biolabs	O
and	O
reactions	O
were	O
carried	O
out	O
according	O
to	O
the	O
manufacturers	O
'	O
instructions	O
.	O

DNA	O
sequencing	O
kits	O
and	O
in	O
vitro	O
transcription	O
-	O
translation	O
kits	O
were	O
purchased	O
from	O
Bethesda	O
Research	O
Laboratories	O
and	O
Amersham	O
Corporation	O
,	O
respectively	O
.	O

Synthetic	O
oligonucleotides	O
to	O
be	O
used	O
as	O
sequencing	O
primers	O
were	O
prepared	O
on	O
an	O
Applied	O
Biosystems	O
DNA	O
synthesizer	O
.	O

Plasmid	O
construction	O
.	O

pBRB7	O
.	O
2	O
.	O

pBRB7	O
.	O
2	O
(	O
2	O
)	O
contains	O
a	O
3	O
.	O
2	O
kb	O
EcoRI	O
/	O
PvuII	O
fragment	O
from	O
the	O
cl	O
region	O
of	O
P1	O
(	O
Figure	O
1	O
)	O
inserted	O
into	O
the	O
2	O
.	O
3	O
kb	O
EcoRIlPvuII	O
fragment	O
of	O
pBR322	O
that	O
contains	O
the	O
origin	O
of	O
replication	O
and	O
the	O
f3	O
-	O
lactamase	O
gene	O
.	O

pFA02	O
.	O

P7	O
plasmid	O
DNA	O
was	O
digested	O
with	O
PvuII	O
,	O
ligated	O
to	O
similarly	O
digested	O
pBR322	O
,	O
and	O
transformed	O
into	O
E	B
.	I
coli	I
K336	O
.	O

Ampicillin	O
-	O
resistant	O
colonies	O
were	O
screened	O
for	O
cl	O
activity	O
by	O
cross	O
-	O
streak	O
complementation	O
analysis	O
against	O
P7cl	O
.	O
1	O
(	O
18	O
)	O
.	O

pFAO2	O
contains	O
a	O
3	O
.	O
5	O
kb	O
insert	O
of	O
P7	O
DNA	O
.	O

The	O
fragment	O
was	O
localized	O
to	O
the	O
cl	O
region	O
of	O
the	O
P7	O
genome	O
by	O
Southern	O
hybridization	O
against	O
P1	O
and	O
P7	O
DNA	O
that	O
had	O
been	O
digested	O
with	O
BamHI	O
and	O
BglII	O
(	O
data	O
not	O
shown	O
)	O
.	O

pBRBJ69	O
.	O

1	O
and	O
pBRB55	O
.	O

1	O
.	O

The	O
PI	O
cI	O
open	O
reading	O
frame	O
was	O
previously	O
localized	O
to	O
a	O
2	O
.	O
6	O
kb	O
EcoRlIBamHI	O
fragment	O
derived	O
from	O
PlEcoRI	O
-	O
7	O
(	O
2	O
)	O
.	O

This	O
fragment	O
also	O
contains	O
the	O
wildtype	O
allele	O
for	O
the	O
conditional	O
lethal	O
mutation	O
am43	O
(	O
19	O
,	O
20	O
)	O
.	O

To	O
clone	O
the	O
cl	O
reading	O
frame	O
from	O
the	O
amber	O
mutant	O
phage	O
Plc1	O
.	O
169	O
and	O
P	O
Ic	O
.	O
55	O
,	O
we	O
digested	O
phage	O
DNA	O
with	O
EcoRI	O
and	O
BamHI	O
,	O
ligated	O
the	O
digestion	O
products	O
into	O
similarly	O
digested	O
pBR322	O
,	O
and	O
transformed	O
the	O
ligation	O
mixture	O
into	O
E	B
.	I
coli	I
K336	O
.	O

Ampicillin	O
-	O
resistant	O
,	O
tetracyclinesensitiv	O
colonies	O
were	O
screened	O
by	O
cross	O
-	O
streak	O
complementation	O
analysis	O
for	O
their	O
ability	O
to	O
support	O
the	O
growth	O
of	O
Plam43	O
.	O

Plasmid	O
DNA	O
isolated	O
from	O
complementation	O
-	O
positive	O
cells	O
was	O
shown	O
by	O
agarose	O
gel	O
electrophoresis	O
to	O
carry	O
plasmids	O
containing	O
the	O
2	O
.	O
6	O
kb	O
EcoRIlBamHI	O
fragment	O
from	O
the	O
cl	O
region	O
.	O

The	O
cl	O
mutant	O
open	O
reading	O
frames	O
were	O
placed	O
under	O
the	O
control	O
of	O
normal	O
regulatory	O
signals	O
present	O
in	O
the	O
cI	O
region	O
by	O
digesting	O
the	O
cl	O
.	O
55	O
and	O
cl	O
.	O

169	O
-	O
containing	O
plasmids	O
with	O
BamHI	O
and	O
PvuII	O
and	O
inserting	O
a	O
601	O
bp	O
BamHI	O
/	O
PvuH	O
fragment	O
containing	O
the	O
cl	O
promoter	O
region	O
(	O
2	O
)	O
.	O

The	O
resulting	O
plasmids	O
,	O
pBRB55	O
.	O
1	O
and	O
pBRB169	O
.	O
1	O
,	O
respectively	O
,	O
contain	O
the	O
3	O
.	O
2	O
kb	O
EcoRllPvuIl	O
fragment	O
analogous	O
to	O
that	O
present	O
in	O
pBRB7	O
.	O
2	O
(	O
Figure	O
1	O
)	O
.	O

pBCB2	O
.	O

13	O
-	O
2	O
.	O
18	O
.	O

To	O
identify	O
cl	O
-	O
repressible	O
promoters	O
,	O
we	O
introduced	O
selected	O
fragments	O

7672	O

Nucleic	O
Acids	O
Research	O

4	O
f	O
-	O
-	O
+	O

I	O
4	O
P1	O
4	O
-	O
4	O
-	O
4	O

ECAR	O
H	O
C	O
B	O
R	O
P	O

4	O
4	O
.	O
4	O
,	O
~	O
4	O
,	O
1	O
1	O
4	O
.	O

I	O
4	O
,	O
I	O
11	O

t	O
t	O
t	O
t	O
t	O
E	O
G	O
R	O
N	O
E	O
B	O
R	O
P	O

4	O
4	O
-	O

4	O

1	O
'	O
'	O
110z	O
I	O
I	O
I	O
I	O
I	O
I	O
1	O

3	O
.	O
2	O
1	O
.	O
5	O
1	O
.	O
0	O
0	O
.	O
5	O
0	O

P7	O

pBRB7	O
.	O
2	O

-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
cl1	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O
-	O

r	O
~	O
/	O
>	O
'	O
pFAO2	O

*	O
-	O
lacZ	O
pBCB2	O
.	O
13	O

<	O
-	O
lacZ	O
Z	O
pBCB2	O
.	O
16	O
<	O
-	O
lacZX	O
pBCB2	O
.	O
18	O

Fig	O
.	O

1	O
.	O

The	O
cl	O
regions	O
of	O
P1	O
and	O
P7	O
.	O

A	O
restriction	O
map	O
is	O
indicated	O
by	O
the	O
solid	O
line	O
in	O
the	O
upper	O
part	O
of	O
the	O
figure	O
.	O

Sites	O
for	O
EcoRI	O
(	O
E	O
)	O
,	O
Pvul	O
(	O
P	O
)	O
,	O
NnrI	O
(	O
N	O
)	O
,	O
Bgll	O
(	O
G	O
)	O
,	O
BamHI	O
(	O
B	O
)	O
,	O
and	O
EcoRV	O
(	O
R	O
)	O
are	O
shown	O
.	O

The	O
sequencing	O
strategy	O
is	O
indicated	O
by	O
the	O
horizontal	O
arrows	O
.	O

Letters	O
and	O
arrows	O
above	O
and	O
below	O
the	O
map	O
refer	O
to	O
sites	O
and	O
sequence	O
analysis	O
for	O
P1	O
and	O
P7	O
,	O
respectively	O
.	O

The	O
size	O
of	O
this	O
region	O
(	O
in	O
kilobase	O
pairs	O
)	O
is	O
indicated	O
below	O
the	O
map	O
.	O

The	O
DNA	O
fragments	O
present	O
in	O
selected	O
plasmids	O
are	O
illustrated	O
by	O
boxes	O
at	O
the	O
bottom	O
of	O
the	O
figure	O
.	O

The	O
dashed	O
line	O
reveals	O
the	O
approximate	O
position	O
of	O
the	O
cl	O
gene	O
(	O
2	O
)	O
.	O

The	O
sites	O
of	O
the	O
-	O
yb	O
mutations	O
introduced	O
into	O
pFA02	O
are	O
indicated	O
by	O
asterisks	O
.	O

pFA02	O
.	O
16	O
and	O
pFA02	O
.	O
26	O
contain	O
insertions	O
located	O
0	O
.	O
9	O
kb	O
and	O
1	O
.	O
4	O
kb	O
,	O
respectively	O
,	O
from	O
the	O
PvuIl	O
site	O
at	O
the	O
left	O
side	O
of	O
the	O
map	O
.	O

The	O
direction	O
of	O
the	O
lacZ	O
open	O
reading	O
frame	O
in	O
pBCB2	O
.	O
13	O
-	O
18	O
is	O
indicated	O
by	O
the	O
adjacent	O
arrow	O
.	O

from	O
the	O
cI	O
region	O
of	O
P1	O
into	O
pCB192	O
,	O
a	O
promoter	O
-	O
probe	O
vector	O
containing	O
promoterless	O
copies	O
of	O
lacZ	O
and	O
galK	O
extending	O
in	O
opposite	O
directions	O
from	O
a	O
multiple	O
cloning	O
site	O
(	O
21	O
)	O
.	O

The	O
source	O
of	O
P1	O
DNA	O
for	O
these	O
constructions	O
was	O
pZHA3	O
,	O
a	O
derivative	O
of	O
pBRB7	O
.	O
2	O
that	O
contains	O
a	O
HindIlI	O
linker	O
at	O
the	O
single	O
EcoRV	O
site	O
located	O
about	O
200	O
bps	O
upstream	O
of	O
the	O
cl	O
open	O
reading	O
frame	O
(	O
Figure	O
1	O
)	O
.	O

pBCB2	O
.	O
13	O
contains	O
a	O
460	O
bp	O
fragment	O
of	O
P1	O
DNA	O
extending	O
from	O
the	O
EcoRV	O
site	O
to	O
a	O
Bgll	O
site	O
within	O
the	O
cI	O
open	O
reading	O
frame	O
.	O

pBCB2	O
.	O

16	O
contains	O
a	O
130	O
bp	O
fragment	O
extending	O
from	O
the	O
EcoRV	O
site	O
to	O
a	O
BamHI	O
site	O
located	O
about	O
100	O
bps	O
upstream	O
of	O
the	O
cl	O
open	O
reading	O
frame	O
,	O
while	O
pBCB2	O
.	O
18	O
contains	O
the	O
region	O
extending	O
from	O
this	O
BamHI	O
site	O
to	O
the	O
Bglll	O
site	O
within	O
the	O
open	O
reading	O
frame	O
(	O
Figure	O
1	O
)	O
.	O

The	O
orientation	O
of	O
the	O
P1	O
DNA	O
fragments	O
within	O
these	O
plasmids	O
was	O
confirmed	O
by	O
restriction	O
mapping	O
and	O
DNA	O
sequencing	O
.	O

To	O
test	O
for	O
the	O
regulation	O
of	O
promoter	O
expression	O
by	O
cl	O
,	O
we	O
transformed	O
pBCB2	O
.	O
13	O
and	O
its	O
derivatives	O
into	O
CB454	O
(	O
pBRB7	O
.	O
152	O
)	O
and	O
CB454	O
(	O
pFAO2	O
.	O
152	O
)	O
,	O
two	O
strains	O
that	O
express	O
P7cl	O
and	O
Pll	O
,	O
respectively	O
,	O
from	O
the	O
pCB192	O
-	O
compatible	O
kanamycin	O
-	O
resistant	O
vector	O
pDPT152	O
(	O
22	O
)	O
.	O

Cells	O
harboring	O
both	O
plasmids	O
were	O
selected	O
by	O
their	O
resistance	O
to	O
both	O
ampicillin	O
and	O
kanamycin	O
.	O

lacZ	O
expression	O
was	O
measured	O
by	O
the	O
procedure	O
of	O
Miller	O
(	O
23	O
)	O
.	O

pBRB7	O
.	O
152	O
was	O
generated	O
by	O
introducing	O
PlEcoRI	O
-	O
7	O
into	O
pDPT152	O
.	O

pBRB7	O
.	O
152	O
has	O
sustained	O
a	O
spontaneous	O
deletion	O
within	O
the	O
EcoRI	O
-	O
7	O
fragment	O
that	O
results	O
in	O
the	O
loss	O
of	O
2	O
.	O
5	O
kb	O
of	O
P1	O
DNA	O
from	O
the	O
far	O
left	O
side	O
of	O
the	O
P1	O
genetic	O
map	O
,	O
but	O
retains	O
the	O
3	O
.	O
2	O
kb	O
PvuHlEcoRI	O
fragment	O
required	O
for	O
cl	O
expression	O
that	O
is	O
present	O
in	O
pBRB7	O
.	O
2	O
(	O
Figure	O
1	O
)	O
.	O

7673	O

z	O

I	O
011Z	O
I	O

e	O
.	O
,	O

Nucleic	O
Acids	O
Research	O

Table	O
1	O
.	O

Complementation	O
of	O
PIci	O
.	O
245	O
by	O
plasmids	O
that	O
contain	O
cI	O
genes	O
.	O

Phenotype	O
Efficiency	O
Relative	O

of	O
of	O
Efficiency	O
of	O
Plasmid	O
cI	O
gene	O
Lysogeny	O
Lysogeny	O
pBR322	O
1	O
.	O
5x	O
10	O
-	O
6	O
6	O
.	O
0x	O
10	O
-	O
6	O
pBRB7	O
.	O
2	O
Plcl	O
+	O
2	O
.	O
5	O
x	O
10	O
-	O
'	O
1	O
.	O
0	O

pBRB55	O
.	O
1	O
Plcl	O
-	O
am	O
1	O
.	O
4	O
x	O
10	O
-	O
6	O
5	O
.	O
6	O
x	O
10	O
-	O
6	O
pBRB169	O
.	O
1	O
PlCl	O
-	O
am	O
2	O
.	O
1	O
x	O
10	O
-	O
6	O
8	O
.	O
4	O
x	O
10	O
-	O
6	O
pFAO2	O
P7cl	O
+	O
8	O
.	O
7	O
x	O
10	O
-	O
2	O
0	O
.	O
35	O

pFAO2	O
.	O
16	O
P7c	O
I	O
-	O
,	O
4	O
.	O
7	O
x	O
10	O
-	O
6	O
1	O
.	O
9	O
X	O
10	O
-	O
5	O
pFAO2	O
.	O
26	O
P7cI	O
-	O
1	O
3	O
.	O
1	O
x	O
10	O
-	O
6	O
1	O
.	O
2	O
x	O
10	O
-	O
5	O

Complementation	O
for	O
lysogeny	O
was	O
carried	O
out	O
as	O
described	O
by	O
Devlin	O
et	O
al	O
.	O

(	O
26	O
)	O
.	O

The	O
plasmids	O
were	O
carried	O
by	O
E	B
.	I
coli	I
K336	O
.	O

Cells	O
were	O
grown	O
to	O
mid	O
-	O
log	O
phase	O
at	O
370	O
in	O
LB	O
containing	O
50	O
tig	O
/	O
m1	O
sodium	O
ampicillin	O
and	O
infected	O
with	O
Plcl	O
.	O
245	O
at	O
a	O
multiplicity	O
of	O
infection	O
of	O
5	O
in	O
the	O
presence	O
of	O
50	O
mM	O
CaC12	O
.	O

After	O
10	O
minutes	O
,	O
non	O
-	O
absorbed	O
phage	O
were	O
removed	O
by	O
centrifugation	O
and	O
the	O
infection	O
was	O
allowed	O
to	O
proceed	O
for	O
2	O
hours	O
at	O
370	O
.	O

The	O
infected	O
cells	O
were	O
plated	O
on	O
LB	O
plates	O
containing	O
50	O
pLg	O
/	O
ml	O
sodium	O
ampicillin	O
,	O
50	O
pLg	O
/	O
ml	O
chloramphenicol	O
,	O
and	O
40	O
mM	O
sodium	O
citrate	O
.	O

The	O
efficiency	O
of	O
lysogeny	O
is	O
defined	O
as	O
the	O
number	O
of	O
ApRCmR	O
cells	O
at	O
the	O
end	O
of	O
infection	O
divided	O
by	O
the	O
number	O
of	O
ApR	O
cells	O
present	O
at	O
the	O
start	O
of	O
the	O
infection	O
.	O

To	O
construct	O
pFA02	O
.	O
152	O
,	O
we	O
introduced	O
a	O
2	O
.	O
8	O
kb	O
EcoRV	O
fragment	O
of	O
P7	O
DNA	O
containing	O
the	O
cl	O
gene	O
(	O
Figure	O
1	O
)	O
into	O
the	O
single	O
EcoRI	O
site	O
of	O
pDPT152	O
after	O
it	O
had	O
been	O
rendered	O
blunt	O
-	O
ended	O
by	O
extension	O
with	O
T4	O
DNA	O
polymerase	O
.	O

cl	O
expression	O
by	O
cells	O
harboring	O
either	O
pBRB7	O
.	O
152	O
or	O
pFA02	O
.	O
152	O
was	O
confirmed	O
by	O
measuring	O
their	O
ability	O
to	O
form	O
chloramphenicol	O
-	O
resistant	O
lysogens	O
when	O
infected	O
with	O
Plcl	O
.	O
245Cm	O
.	O

,	O
yb	O
insertional	O
mutagenesis	O
.	O

Insertional	O
mutagenesis	O
of	O
P7cl	O
was	O
carried	O
out	O
using	O
the	O
'	O
yb	O
transposon	O
of	O
F	O
(	O
24	O
)	O
as	O
described	O
by	O
Devlin	O
et	O
al	O
.	O

(	O
25	O
)	O
.	O

E	B
.	I
coli	I
W1485	O
(	O
pFA02	O
)	O
was	O
mated	O
with	O
the	O
F	O
-	O
strain	O
MX648	O
and	O
subsequently	O
plated	O
on	O
ampicillin	O
(	O
to	O
select	O
for	O
the	O
plasmid	O
)	O
and	O
streptomycin	O
sulfate	O
(	O
to	O
select	O
for	O
the	O
recipient	O
strain	O
)	O
.	O

Transconjugants	O
which	O
could	O
support	O
only	O
lytic	O
growth	O
upon	O
infection	O
by	O
P7cl	O
.	O
1	O
(	O
as	O
scored	O
by	O
cross	O
-	O
streak	O
analysis	O
;	O
18	O
)	O
were	O
assumed	O
to	O
have	O
lost	O
cl	O
-	O
complementing	O
activity	O
and	O
were	O
characterized	O
further	O
.	O

The	O
positions	O
of	O
two	O
cl	O
-	O
insertional	O
mutations	O
,	O
carried	O
by	O
pFA02	O
.	O
16	O
and	O
pFA02	O
.	O
26	O
,	O
were	O
identified	O
by	O
restriction	O
mapping	O
(	O
Figure	O
1	O
)	O
.	O

DNA	O
sequencing	O
.	O

DNA	O
sequence	O
analysis	O
was	O
carried	O
out	O
using	O
the	O
M13	O
-	O
dideoxy	O
technique	O
of	O
Sanger	O
et	O
al	O
.	O

(	O
26	O
)	O
.	O

Selected	O
DNA	O
fragments	O
containing	O
the	O
cl	O
wildtype	O
or	O
mutant	O
genes	O
were	O
introduced	O
into	O
M13	O
mp8	O
or	O
mp9	O
.	O

18	O
-	O
nucleotide	O
oligomers	O
complementary	O
to	O
defined	O
sequences	O
within	O
the	O
cl	O
gene	O
were	O
extended	O
using	O
the	O
Klenow	O
fragment	O
of	O
DNA	O
polymerase	O
in	O
the	O
presence	O
of	O
dideoxynucleotide	O
triphosphates	O
and	O
analyzed	O
by	O
polyacrylamide	O
-	O
urea	O
gel	O
electrophoresis	O
.	O

The	O
sequencing	O
strategy	O
is	O
shown	O
in	O
Figure	O
1	O
.	O

RESULTS	O

Localization	O
of	O
the	O
P7cJ	O
gene	O
.	O

Initial	O
localization	O
of	O
the	O
P7cl	O
gene	O
was	O
undertaken	O
by	O
subjecting	O
pFA02	O
to	O
'	O
yb	O
mutagenesis	O
and	O
determining	O
the	O
map	O
position	O
of	O
inserts	O
which	O
destroy	O
the	O
ability	O
of	O
the	O
plasmids	O
to	O
complement	O
a	O
P7cl	O
-	O
mutation	O
(	O
as	O
determined	O
by	O
cross	O
-	O
streak	O
analysis	O
)	O
.	O

pFA02	O
and	O
the	O
-	O
yb	O
insertion	O
mutants	O
were	O
tested	O
further	O
by	O
comparing	O
their	O
ability	O
to	O
complement	O
a	O
PIcI	O
amber	O
mutation	O
with	O
the	O
complementation	O
activity	O
of	O
plasmids	O
containing	O
cl	O
genes	O
isolated	O

7674	O

Nucleic	O
Acids	O
Research	O

B	O
C	O
D	O
E	O
F	O
G	O

*	O
.	O
4	O

68	O

43	O

29	O
-	O
_	O
-	O
=	O
I	O
=	O
Am	O
~	O
W	O
_	O

18	O

14	O
p	O

Fig	O
.	O

2	O
.	O

In	O
vitro	O
transcription	O
-	O
translation	O
of	O
plasmids	O
carrying	O
the	O
cl	O
region	O
of	O
P1	O
and	O
P7	O
.	O

Proteins	O
encoded	O
by	O
selected	O
plasmids	O
were	O
labeled	O
with	O
35S	O
methionine	O
according	O
to	O
the	O
procedure	O
of	O
DeVries	O
and	O
Zubay	O
(	O
27	O
)	O
,	O
using	O
a	O
commercial	O
in	O
vitro	O
transcription	O
/	O
tramnslation	O
kit	O
from	O
Amersham	O
Corporation	O
.	O

The	O
reaction	O
mixtures	O
were	O
subjected	O
to	O
electrophoresis	O
on	O
a	O
12	O
.	O
5	O
%	O
SDS	O
-	O
polyacrylamide	O
gel	O
and	O
the	O
labeled	O
proteins	O
were	O
visualized	O
by	O
autoradiography	O
.	O

The	O
migration	O
of	O
14C	O
-	O
labeled	O
protein	O
molecular	O
weight	O
standards	O
(	O
Bethesda	O
Research	O
Laboratories	O
)	O
is	O
indicated	O
at	O
the	O
left	O
side	O
of	O
the	O
figure	O
.	O

Plasmids	O
present	O
in	O
each	O
lane	O
are	O
:	O
A	O
.	O

pBRB55	O
.	O
1	O
;	O
B	O
.	O

pBRB169	O
.	O
1	O
;	O
C	O
.	O

pBRB7	O
.	O
2	O
;	O
D	O
.	O

pFAO2	O
;	O
E	O
.	O

pFAO2	O
.	O
16	O
;	O
F	O
.	O

pFAO2	O
.	O
26	O
;	O
G	O
.	O

pBR322	O
.	O

from	O
P1	O
wildtype	O
and	O
amber	O
mutants	O
.	O

Lysogeny	O
by	O
cells	O
infected	O
with	O
Plcl	O
.	O
245Cm	O
was	O
scored	O
as	O
the	O
growth	O
of	O
infected	O
cells	O
on	O
ampicillin	O
(	O
to	O
select	O
for	O
the	O
resident	O
plasmid	O
)	O
and	O
chloramphenicol	O
(	O
to	O
select	O
for	O
the	O
phage	O
genome	O
)	O
.	O

The	O
values	O
observed	O
for	O
the	O
two	O
plasmids	O
containing	O
Plcl	O
and	O
P7cl	O
(	O
pBRB7	O
.	O
2	O
and	O
pFA02	O
,	O
respectively	O
)	O
are	O
very	O
similar	O
and	O
significantly	O
higher	O
than	O
those	O
obtained	O
for	O
pBR322	O
or	O
for	O
any	O
of	O
the	O
plasmids	O
carrying	O

Table	O
2	O
.	O

Assay	O
for	O
lacZ	O
expression	O
from	O
plasmids	O
containing	O
P1	O
DNA	O
fragments	O
.	O

,	O
3	O
-	O
galactosidase	O
activity	O
(	O
units	O
)	O

minus	O
cI	O
plus	O
Pici	O
plus	O
P7cl	O
relative	O
activity	O

(	O
pDPT152	O
)	O
(	O
pBB7	O
.	O
152	O
)	O
(	O
pFA02	O
.	O
152	O
)	O
+	O
PICJ	O
+	O
P7cJ	O

pCB192	O
0	O
.	O
58	O
0	O
.	O
55	O
0	O
.	O
54	O
0	O
.	O
95	O
0	O
.	O
93	O
pBCB2	O
.	O
13	O
154	O
15	O
.	O
2	O
13	O
.	O
6	O
0	O
.	O
10	O
0	O
.	O
09	O
pBCB2	O
.	O
16	O
1	O
.	O
1	O
1	O
.	O
2	O
1	O
.	O
1	O
1	O
.	O
1	O
1	O
.	O
0	O
pBCB2	O
.	O
18	O
4	O
.	O
0	O
3	O
.	O
4	O
3	O
.	O
9	O
0	O
.	O
9	O
1	O
.	O
0	O

Cells	O
containing	O
derivatives	O
of	O
the	O
ApR	O
promoter	O
-	O
probe	O
plasmid	O
pCB192	O
and	O
the	O
compatible	O
KnR	O
plasmid	O
pDPT152	O
were	O
grown	O
in	O
LB	O
at	O
37	O
?	O
.	O

When	O
they	O
reached	O
mid	O
-	O
log	O
phase	O
,	O
the	O
cells	O
were	O
chilled	O
,	O
lysed	O
,	O
and	O
assayed	O
for	O
(	O
3	O
-	O
galactosidase	O
activity	O
according	O
to	O
the	O
procedure	O
of	O
Miller	O
(	O
23	O
)	O
.	O

Plasmids	O
derived	O
from	O
pCB192	O
are	O
indicated	O
at	O
the	O
left	O
side	O
of	O
the	O
Table	O
.	O

Plasmids	O
derived	O
from	O
pDPT152	O
are	O
indicated	O
in	O
parentheses	O
across	O
the	O
top	O
of	O
the	O
Table	O
.	O

The	O
values	O
reported	O
are	O
the	O
average	O
of	O
two	O
independent	O
experiments	O
.	O

Relative	O
activity	O
is	O
defined	O
as	O
the	O
f3	O
-	O
galactosidase	O
activity	O
measured	O
in	O
cells	O
harboring	O
plasmids	O
expressing	O
cl	O
divided	O
by	O
the	O
activity	O
measured	O
in	O
cells	O
carrying	O
only	O
pDPT152	O
.	O

7675	O

Nucleic	O
Acids	O
Research	O

GATATCCAATCAGGAGTACC	O
GCATCACCCAAGACGACCTG	O
GATGATCTCACTGACACAAT	O
CGAATATCTCATGGCCACTA	O
ACCAGCCAGACTCACAATAA	O
105	O
v	O
-	O
-	O

TtgAca	O
TATAATG	O

CTAATAAATCTATTATTTTC	O
GTTGGATCCTTCTATAATGG	O
TGGCCAACAACTCCCAGTGT	O
AATCCGCTGTGAGTTGTTGG	O
CCATGTCAATTCTGGAGGAG	O
210	O

b	O
-	O
-	O
-	O
-	O
-	O
I	O
I	O
GGAGGtG	O

ATG	O
ATA	O
AAT	O
TAT	O
GTC	O
TAC	O
GGC	O
GAA	O
CAA	O
CTG	O
TAC	O
CAG	O
GAG	O
TTC	O
GTC	O
AGC	O
TTC	O
AGG	O
GAT	O
CTC	O
TTT	O
CTA	O
AAA	O
AAA	O
GCT	O
GTT	O
GCA	O
CGC	O
GCC	O
CAA	O
300	O
MET	O
lIe	O
Asn	O
Tyr	O
Vat	O
Tyr	O
Gly	O
Glu	O
Gin	O
Leu	O
Tyr	O
Gin	O
Gtu	O
Phe	O
Vat	O
Ser	O
Phe	O
Arg	O
Asp	O
Leu	O
Phe	O
Leu	O
Lys	O
Lys	O
Ala	O
Val	O
Ala	O
Arg	O
Ala	O
Gtn	O

tag	O
(	O
cl	O
.	O
55	O
)	O

CAC	O
GTT	O
GAT	O
GCC	O
GCC	O
AGC	O
GAC	O
GGT	O
CGT	O
CCT	O
GTT	O
CGC	O
CCG	O
GTT	O
GTC	O
GTT	O
CTG	O
CCG	O
TTC	O
AM	O
GM	O
ACG	O
GAC	O
AGC	O
ATT	O
CAG	O
GCT	O
GMA	O
ATT	O
GAT	O
390	O
His	O
Val	O
Asp	O
Ala	O
Ala	O
Ser	O
Asp	O
Gly	O
Arg	O
Pro	O
Vat	O
Arg	O
Pro	O
Vat	O
Vat	O
Vat	O
Leu	O
Pro	O
Phe	O
Lys	O
Glu	O
Thr	O
Asp	O
Ser	O
lIe	O
Gin	O
Ala	O
Glu	O
lie	O
Asp	O

T	O
A	O
C	O
A	O
G	O

AAA	O
TGG	O
ACA	O
TTA	O
ATG	O
GCG	O
CGG	O
GAA	O
CTG	O
GAG	O
CAG	O
TAC	O
CCA	O
GAT	O
CTC	O
MT	O
ATC	O
CCA	O
MG	O
ACT	O
ATT	O
TTA	O
TAT	O
CCT	O
GTA	O
CCT	O
AAC	O
ATC	O
CTT	O
CGC	O
480	O

9	O

Lys	O
Trp	O
Thr	O
Leu	O
MET	O
Ala	O
Arg	O
Glu	O
Leu	O
Gtu	O
Gin	O
Tyr	O
Pro	O
Asp	O
Leu	O
Asn	O
lIe	O
Pro	O
Lys	O
Thr	O
lie	O
Leu	O
Tyr	O
Pro	O
Vat	O
Pro	O
Asn	O
lIe	O
Leu	O
Arg	O

A	O
T	O
C	O

GGT	O
GTG	O
CGT	O
AAG	O
GTT	O
ACG	O
ACT	O
TAT	O
CAG	O
ACA	O
GAA	O
GCA	O
GTG	O
MC	O
AGC	O
GTC	O
AAT	O
ATG	O
ACC	O
GCT	O
GGC	O
CGC	O
ATT	O
ATT	O
CAT	O
CTG	O
ATT	O
GAT	O
AAG	O
GAC	O
570	O
Gly	O
Vat	O
Arg	O
Lys	O
Vat	O
Thr	O
Thr	O
Tyr	O
Gin	O
Thr	O
Glu	O
Ala	O
Vat	O
Asn	O
Ser	O
Vat	O
Asn	O
MET	O
Thr	O
Ala	O
Gly	O
Arg	O
lIe	O
lIe	O
His	O
Leu	O
lIe	O
Asp	O
Lys	O
Asp	O

G	O

ATT	O
CGC	O
ATC	O
CAA	O
AM	O
AGC	O
GCG	O
GGG	O
ATC	O
MT	O
GAG	O
CAC	O
AGT	O
GCG	O
AAA	O
TAC	O
ATA	O
GAG	O
MC	O
CTG	O
GAA	O
GCA	O
ACA	O
AM	O
GAG	O
CTA	O
ATG	O
AAG	O
CAG	O
TAC	O
660	O
lle	O
Arg	O
lIe	O
Gin	O
Lys	O
Ser	O
Ala	O
Gly	O
lIe	O
Asn	O
Gtu	O
His	O
Ser	O
Ala	O
Lys	O
Tyr	O
lIe	O
Gtu	O
Asn	O
Leu	O
Gtu	O
Ala	O
Thr	O
Lys	O
Gtu	O
Leu	O
MET	O
Lys	O
Gin	O
Tyr	O

T	O
T	O

CCG	O
GAG	O
GAT	O
GAA	O
AAA	O
TTC	O
CGT	O
ATG	O
CGC	O
GTA	O
CAC	O
GGC	O
TTT	O
AGC	O
GAA	O
ACA	O
ATG	O
CTG	O
CGC	O
GTC	O
CAT	O
TAC	O
ATT	O
TCC	O
AGT	O
AGC	O
CCT	O
AAC	O
TAC	O
AAT	O
750	O
Pro	O
Glu	O
Asp	O
Glu	O
Lys	O
Phe	O
Arg	O
MET	O
Arg	O
Vat	O
His	O
Gly	O
Phe	O
Ser	O
Gtu	O
Thr	O
MET	O
Leu	O
Arg	O
Vat	O
His	O
Tyr	O
lie	O
Ser	O
Ser	O
Ser	O
Pro	O
Asn	O
Tyr	O
Asn	O

Phe	O

T	O
C	O
G	O
T	O
T	O

I	O
~	O
~	O
~	O
I	O
I	O
II	O

GAT	O
GGC	O
MA	O
TCA	O
GTT	O
AGT	O
TAC	O
CAT	O
GTG	O
CTG	O
CTA	O
TGT	O
GGC	O
GTG	O
TTT	O
ATC	O
TGC	O
GAT	O
GM	O
ACT	O
CTC	O
CGA	O
GAT	O
GGA	O
ATC	O
ATC	O
ATC	O
AAC	O
GGT	O
GAA	O
840	O

e	O
.	O
.	O

Asp	O
Gly	O
Lys	O
Ser	O
Vat	O
Ser	O
Tyr	O
His	O
Vat	O
Leu	O
Leu	O
Cys	O
Gly	O
Vat	O
Phe	O
lie	O
Cys	O
Asp	O
Glu	O
Thr	O
Leu	O
Arg	O
Asp	O
Gly	O
lIe	O
lie	O
lIe	O
Asn	O
Gly	O
Gtu	O

Pro	O

C	O
tag	O
(	O
cl	O
.	O
169	O
)	O

TTT	O
GAG	O
AM	O
GCA	O
AAA	O
TTT	O
AGC	O
CTT	O
TAT	O
GAC	O
TCT	O
ATA	O
GM	O
CCG	O
ATC	O
ATC	O
TGC	O
GAC	O
CGC	O
TGG	O
CCG	O
CAG	O
GCA	O
AM	O
ATA	O
TAT	O
CGC	O
CTG	O
GCA	O
GAT	O
930	O
Phe	O
Gtu	O
Lys	O
Ala	O
Lys	O
Phe	O
Ser	O
Leu	O
Tyr	O
Asp	O
Ser	O
lIe	O
Glu	O
Pro	O
lie	O
lie	O
Cys	O
Asp	O
Arg	O
Trp	O
Pro	O
Gin	O
Ala	O
Lys	O
lIe	O
Tyr	O
Arg	O
Leu	O
Ala	O
Asp	O

T	O

ATT	O
GM	O
MT	O
GTA	O
AM	O
AM	O
CM	O
ATT	O
GCC	O
ATC	O
ACT	O
CGC	O
GM	O
GAG	O
AAA	O
G	O
GTC	O
AM	O
TCA	O
GCC	O
GCA	O
TCA	O
GTT	O
ACG	O
CGC	O
AGC	O
CGC	O
AAA	O
ACT	O
AAG	O
1020	O

n	O
-	O
-	O
-	O
-	O
-	O

lie	O
Glu	O
Asn	O
Vat	O
Lys	O
Lys	O
Gin	O
lIe	O
Ala	O
lie	O
Thr	O
Arg	O
Glu	O
Glu	O
Lys	O
Lys	O
Vat	O
Lys	O
Ser	O
Ala	O
Ala	O
Ser	O
Vat	O
Thr	O
Arg	O
Ser	O
Arg	O
Lys	O
Thr	O
Lys	O

AAG	O
GGG	O
CAG	O
CCA	O
GTA	O
AAC	O
GAC	O
MC	O
CCC	O
GAA	O
AGC	O
GCG	O
CM	O
TAG	O
Lys	O
Gly	O
Gin	O
Pro	O
Val	O
Asn	O
Asp	O
Asn	O
Pro	O
Glu	O
Ser	O
Ala	O
Gin	O
ter	O

Fig	O
.	O

3	O
.	O

DNA	O
sequence	O
of	O
PIcI	O
and	O
P7cl	O
.	O

The	O
DNA	O
sequence	O
of	O
PIcI	O
is	O
indicated	O
.	O

Positions	O
where	O
the	O
sequence	O
of	O
P7cl	O
differs	O
from	O
that	O
of	O
Plcl	O
are	O
indicated	O
above	O
the	O
P1	O
sequence	O
.	O

The	O
amino	O
acid	O
sequence	O
predicted	O
by	O
the	O
open	O
reading	O
frame	O
is	O
given	O
below	O
the	O
sequence	O
.	O

The	O
two	O
amino	O
acid	O
substitutions	O
present	O
in	O
P7cl	O
are	O
shown	O
below	O
the	O
open	O
reading	O
frame	O
.	O

The	O
locations	O
of	O
the	O
amber	O
mutant	O
codons	O
in	O
cl	O
.	O
55	O
and	O
ci	O
.	O

169	O
are	O
indicated	O
by	O
small	O
letters	O
above	O
the	O
sequence	O
.	O

Sites	O
for	O
selected	O
restriction	O
enzymes	O
(	O
EcoRV	O
[	O
v	O
]	O
;	O
BamHI	O
[	O
b	O
]	O
;	O
Bgll	O
[	O
g	O
]	O
;	O
EcoRP	O
[	O
e	O
]	O
;	O
and	O
NruI	O
[	O
n	O
]	O
)	O
are	O
illustrated	O
by	O
dashed	O
lines	O
beneath	O
the	O
sequence	O
.	O

The	O
cl	O
repressor	O
binding	O
site	O
is	O
underlined	O
.	O

Inverted	O
arrows	O
beneath	O
the	O
sequence	O
illustrate	O
the	O
inverted	O
repeat	O
sequence	O
upstream	O
of	O
the	O
open	O
reading	O
frame	O
.	O

Predicted	O
promoter	O
ribosome	O
binding	O
sites	O
are	O
indicated	O
by	O
the	O
presence	O
of	O
the	O
consensus	O
sequences	O
above	O
and	O
below	O
the	O
line	O
,	O
respectively	O
.	O

The	O
DNA	O
sequences	O
of	O
Plcl	O
from	O
bp	O
1	O
-	O
134	O
and	O
bp	O
1	O
-	O
434	O
were	O
reported	O
previously	O
(	O
2	O
,	O
5	O
)	O
.	O

mutant	O
cl	O
genes	O
from	O
either	O
P1	O
or	O
P7	O
(	O
Table	O
1	O
)	O
.	O

The	O
efficiency	O
with	O
which	O
a	O
cloned	O
P7cl	O
gene	O
complements	O
a	O
PlcI	O
mutation	O
confirms	O
previous	O
genetic	O
studies	O
indicating	O
that	O
these	O
two	O
genes	O
are	O
functionally	O
interchangeable	O
(	O
9	O
)	O
.	O

The	O
location	O
of	O
the	O
'	O
y6	O
mutations	O
that	O
destroy	O
cl	O
-	O
complementing	O
activity	O
suggests	O
that	O
the	O
P7cl	O
open	O
reading	O
frame	O
occupies	O
a	O
map	O
position	O
similar	O
to	O
that	O
of	O
the	O
P1	O
open	O
reading	O
frame	O
(	O
Figure	O
1	O
)	O
.	O

7676	O

Nucleic	O
Acids	O
Research	O

Proteins	O
produced	O
by	O
fragments	O
containing	O
Plcl	O
.	O

As	O
an	O
initial	O
step	O
in	O
the	O
comparison	O
of	O
the	O
P1	O
and	O
P7	O
repressors	O
,	O
we	O
analyzed	O
the	O
gene	O
products	O
expressed	O
from	O
the	O
cloned	O
cl	O
regions	O
.	O

In	O
an	O
in	O
vitro	O
transcription	O
-	O
translation	O
reaction	O
,	O
plasmids	O
coding	O
for	O
the	O
wildtpe	O
alleles	O
of	O
either	O
PIcI	O
or	O
P7cl	O
direct	O
the	O
production	O
of	O
a	O
protein	O
with	O
an	O
estimated	O
molecular	O
weight	O
of	O
33	O
,	O
000	O
daltons	O
(	O
Figure	O
2	O
,	O
Lanes	O
C	O
and	O
D	O
)	O
,	O
a	O
size	O
that	O
agrees	O
closely	O
with	O
the	O
predicted	O
molecular	O
weight	O
of	O
the	O
PIcI	O
repressor	O
reported	O
previously	O
(	O
3	O
,	O
28	O
)	O
.	O

The	O
loss	O
of	O
the	O
33	O
,	O
000	O
dalton	O
protein	O
in	O
the	O
cl	O
-	O
'	O
ya	O
-	O
induced	O
P7	O
mutant	O
plasmids	O
(	O
Figure	O
2	O
,	O
Lanes	O
E	O
and	O
F	O
)	O
is	O
consistent	O
with	O
its	O
designation	O
as	O
the	O
P7cl	O
repressor	O
.	O

As	O
expected	O
,	O
the	O
33	O
,	O
000	O
dalton	O
protein	O
is	O
not	O
observed	O
when	O
reaction	O
mixtures	O
contain	O
DNA	O
from	O
Plcl	O
amber	O
mutants	O
(	O
Figure	O
2	O
,	O
Lanes	O
A	O
and	O
B	O
)	O
.	O

DNA	O
sequence	O
analysis	O
of	O
the	O
cl	O
genes	O
.	O

To	O
make	O
a	O
direct	O
comparison	O
between	O
the	O
Plcl	O
and	O
P7cl	O
DNA	O
sequences	O
and	O
to	O
predict	O
the	O
amino	O
acid	O
sequences	O
of	O
the	O
repressor	O
proteins	O
,	O
we	O
carried	O
out	O
M	O
13	O
-	O
dideoxy	O
sequence	O
analysis	O
of	O
cloned	O
fragments	O
carrying	O
the	O
cl	O
genes	O
.	O

The	O
sequences	O
of	O
about	O
1	O
kb	O
of	O
P1	O
and	O
P7	O
DNA	O
were	O
determined	O
starting	O
from	O
a	O
common	O
EcoRV	O
site	O
predicted	O
to	O
lie	O
approximately	O
200	O
bps	O
upstream	O
of	O
the	O
cl	O
genes	O
.	O

The	O
P1	O
and	O
P7	O
sequences	O
(	O
Figure	O
3	O
)	O
both	O
contain	O
an	O
ATG	O
initiation	O
codon	O
preceded	O
by	O
a	O
putative	O
ribosome	O
binding	O
sequence	O
(	O
29	O
)	O
situated	O
211	O
bps	O
downstream	O
of	O
the	O
EcoRV	O
site	O
.	O

In	O
each	O
case	O
,	O
the	O
initiation	O
codon	O
is	O
followed	O
by	O
an	O
open	O
reading	O
reading	O
frame	O
extending	O
for	O
283	O
codons	O
.	O

The	O
P1	O
and	O
P7	O
open	O
reading	O
frames	O
code	O
for	O
proteins	O
with	O
predicted	O
molecular	O
weights	O
(	O
32	O
,	O
515	O
and	O
32	O
,	O
499	O
daltons	O
,	O
respectively	O
)	O
that	O
agree	O
closely	O
with	O
the	O
values	O
of	O
the	O
proteins	O
expressed	O
from	O
the	O
cloned	O
DNA	O
fragments	O
(	O
Figure	O
2	O
)	O
and	O
with	O
results	O
predicted	O
independently	O
for	O
the	O
purified	O
PIcI	O
repressor	O
(	O
3	O
-	O
4	O
)	O
.	O

The	O
localization	O
of	O
two	O
PIcI	O
amber	O
mutations	O
to	O
the	O
P1	O
open	O
reading	O
frame	O
confirms	O
its	O
identification	O
as	O
the	O
cI	O
coding	O
sequence	O
.	O

cI	O
.	O

169	O
contains	O
an	O
amber	O
mutation	O
that	O
would	O
result	O
in	O
a	O
protein	O
fragment	O
of	O
26	O
,	O
680	O
daltons	O
,	O
a	O
value	O
that	O
agrees	O
well	O
with	O
the	O
size	O
of	O
a	O
protein	O
fragment	O
observed	O
under	O
the	O
in	O
vitro	O
transcription	O
/	O
translation	O
reaction	O
conditions	O
(	O
Figure	O
2	O
,	O
Lane	O
B	O
)	O
.	O

The	O
cl	O
.	O
55	O
amber	O
mutation	O
lies	O
close	O
to	O
the	O
N	O
-	O
terminal	O
region	O
of	O
the	O
protein	O
,	O
resulting	O
in	O
the	O
production	O
of	O
a	O
fragment	O
of	O
55	O
amino	O
acids	O
that	O
is	O
apparently	O
too	O
small	O
to	O
resolve	O
under	O
the	O
electrophoretic	O
conditions	O
used	O
for	O
separation	O
of	O
the	O
proteins	O
.	O

Over	O
60	O
%	O
of	O
the	O
amino	O
acid	O
sequence	O
predicted	O
for	O
the	O
PIcI	O
open	O
reading	O
frame	O
has	O
been	O
verified	O
by	O
amino	O
acid	O
sequence	O
analysis	O
of	O
peptide	O
fragments	O
isolated	O
from	O
the	O
purified	O
repressor	O
protein	O
(	O
see	O
accompanying	O
paper	O
,	O
reference	O
3	O
)	O
.	O

The	O
DNA	O
sequences	O
of	O
P1	O
and	O
P7	O
are	O
identical	O
for	O
a	O
399	O
-	O
bp	O
region	O
that	O
extends	O
from	O
the	O
EcoRV	O
site	O
at	O
the	O
5	O
'	O
side	O
of	O
the	O
cl	O
gene	O
to	O
a	O
point	O
188	O
bps	O
within	O
the	O
open	O
reading	O
frame	O
.	O

The	O
sequences	O
within	O
the	O
Plcl	O
and	O
the	O
P7cl	O
open	O
reading	O
frames	O
differ	O
at	O
only	O
18	O
positions	O
,	O
all	O
but	O
two	O
of	O
which	O
occur	O
in	O
the	O
wobble	O
position	O
of	O
the	O
predicted	O
codon	O
.	O

From	O
these	O
results	O
,	O
we	O
conclude	O
that	O
the	O
functional	O
identity	O
of	O
the	O
P1	O
and	O
P7	O
cl	O
genes	O
is	O
a	O
consequence	O
of	O
their	O
nearly	O
identical	O
amino	O
acid	O
sequence	O
.	O

Analysis	O
of	O
promoters	O
upstream	O
of	O
the	O
cl	O
open	O
reading	O
frame	O
.	O

Expression	O
of	O
Plcl	O
was	O
shown	O
previously	O
to	O
require	O
sequences	O
on	O
the	O
distal	O
side	O
of	O
a	O
BamHI	O
site	O
(	O
2	O
,	O
5	O
)	O
located	O
about	O
100	O
bps	O
upstream	O
of	O
the	O
open	O
reading	O
frame	O
(	O
Figure	O
3	O
)	O
.	O

A	O
binding	O
site	O
for	O
the	O
cl	O
repressor	O
has	O
also	O
been	O
shown	O
to	O
exist	O
close	O
to	O
this	O
BamHI	O
site	O
(	O
2	O
,	O
5	O
,	O
6	O
)	O
.	O

To	O
determine	O
whether	O
this	O
region	O
contains	O
a	O
promoter	O
that	O
is	O
detectable	O
in	O
vivo	O
and	O
,	O
further	O
,	O
to	O
determine	O
whether	O
this	O
promoter	O
can	O
be	O
regulated	O
by	O
cl	O
repressor	O
proteins	O
from	O
either	O
P1	O
or	O
P7	O
,	O
we	O
introduced	O
several	O
DNA	O
fragments	O
from	O
this	O
region	O
into	O
the	O
promoter	O
probe	O
vector	O
pCB192	O
,	O
screened	O
for	O
promoter	O
activity	O
(	O
as	O
monitored	O
by	O
lacZ	O
expression	O
)	O
and	O
checked	O
for	O
repression	O
of	O
this	O
activity	O
in	O
the	O
presence	O
of	O
a	O
compatible	O

7677	O

Nucleic	O
Acids	O
Research	O

plasmid	O
expressing	O
Plcl	O
or	O
P7cl	O
.	O

Cells	O
harboring	O
pBCB2	O
.	O
13	O
(	O
a	O
plasmid	O
which	O
carries	O
a	O
460	O
bp	O
fragment	O
of	O
P1	O
DNA	O
that	O
extends	O
across	O
the	O
BamHI	O
site	O
upstream	O
of	O
cl	O
into	O
the	O
open	O
reading	O
frame	O
)	O
are	O
dark	O
blue	O
in	O
the	O
presence	O
of	O
Xgal	O
and	O
produce	O
significant	O
levels	O
of	O
3	O
-	O
galactosidase	O
(	O
Table	O
2	O
)	O
.	O

In	O
contrast	O
,	O
pBCB2	O
.	O
16	O
and	O
pBCB2	O
.	O
18	O
(	O
which	O
each	O
contain	O
DNA	O
from	O
only	O
one	O
side	O
of	O
the	O
BamHI	O
site	O
located	O
in	O
pBCB2	O
.	O
13	O
)	O
do	O
not	O
confer	O
a	O
blue	O
color	O
on	O
their	O
host	O
cell	O
in	O
the	O
presence	O
of	O
X	O
-	O
Gal	O
and	O
express	O
negligible	O
amounts	O
of	O
3	O
-	O
galactosidase	O
(	O
Table	O
2	O
)	O
.	O

These	O
observations	O
suggest	O
that	O
expression	O
from	O
the	O
promoter	O
identified	O
here	O
requires	O
sequences	O
that	O
span	O
the	O
BamHI	O
site	O
upstream	O
of	O
cl	O
.	O

Expression	O
of	O
cl	O
from	O
a	O
compatible	O
plasmid	O
in	O
the	O
presence	O
of	O
pBCB2	O
.	O

13	O
results	O
in	O
a	O
90	O
%	O
reduction	O
in	O
promoter	O
strength	O
(	O
Table	O
2	O
)	O
.	O

This	O
reduction	O
is	O
seen	O
in	O
the	O
presence	O
of	O
either	O
Plcl	O
or	O
P7cl	O
,	O
indicating	O
that	O
the	O
two	O
repressor	O
proteins	O
are	O
both	O
capable	O
of	O
repressing	O
expression	O
from	O
this	O
promoter	O
.	O

DISCUSSION	O
.	O

The	O
DNA	O
sequences	O
of	O
Plcl	O
and	O
P7cl	O
differ	O
at	O
only	O
18	O
sites	O
,	O
all	O
but	O
two	O
of	O
which	O
occur	O
at	O
the	O
third	O
position	O
of	O
the	O
affected	O
codon	O
.	O

This	O
observation	O
provides	O
biochemical	O
confirmation	O
of	O
the	O
functional	O
identity	O
predicted	O
on	O
the	O
basis	O
of	O
previous	O
genetic	O
analysis	O
(	O
9	O
)	O
.	O

A	O
number	O
of	O
DNA	O
binding	O
proteins	O
exhibit	O
a	O
common	O
structural	O
motif	O
in	O
which	O
two	O
helices	O
are	O
separated	O
by	O
a	O
glycine	O
residue	O
(	O
12	O
)	O
.	O

This	O
motif	O
is	O
not	O
observed	O
in	O
the	O
predicted	O
secondary	O
structures	O
(	O
30	O
)	O
of	O
the	O
Plcl	O
and	O
P7cl	O
amino	O
acid	O
sequences	O
.	O

A	O
sequence	O
with	O
some	O
similarity	O
to	O
the	O
XCro	O
helix	O
-	O
turn	O
-	O
helix	O
region	O
was	O
previously	O
reported	O
near	O
the	O
Nterminus	O
of	O
the	O
PIcI	O
protein	O
(	O
5	O
)	O
;	O
however	O
,	O
it	O
was	O
noted	O
that	O
the	O
potential	O
for	O
helix	O
formation	O
is	O
disrupted	O
by	O
the	O
presence	O
of	O
several	O
prolines	O
within	O
the	O
region	O
.	O

The	O
secondary	O
structure	O
predicted	O
for	O
the	O
Plcl	O
and	O
P7cl	O
repressor	O
proteins	O
(	O
30	O
)	O
does	O
not	O
reveal	O
other	O
structural	O
characteristics	O
(	O
e	O
.	O
g	O
.	O
,	O
Zn	O
fingers	O
(	O
31	O
)	O
,	O
leucine	O
zippers	O
(	O
32	O
)	O
,	O
or	O
helix	O
-	O
loop	O
-	O
helix	O
motifs	O
(	O
33	O
)	O
)	O
that	O
have	O
been	O
associated	O
with	O
DNA	O
binding	O
activity	O
in	O
other	O
systems	O
.	O

A	O
search	O
of	O
the	O
GenBank	O
and	O
EMBL	O
databases	O
does	O
not	O
reveal	O
any	O
other	O
known	O
regulatory	O
proteins	O
with	O
significant	O
amino	O
acid	O
similarity	O
to	O
the	O
Plcl	O
or	O
the	O
P7cl	O
repressor	O
sequences	O
.	O

Since	O
the	O
Plcl	O
repressor	O
differs	O
from	O
most	O
other	O
repressors	O
in	O
DNA	O
binding	O
specificity	O
(	O
i	O
.	O
e	O
.	O
,	O
in	O
its	O
recognition	O
of	O
an	O
asymmetric	O
operator	O
sequence	O
)	O
,	O
it	O
is	O
not	O
unexpected	O
to	O
find	O
that	O
the	O
protein	O
does	O
not	O
exhibit	O
common	O
structural	O
motifs	O
at	O
the	O
amino	O
acid	O
level	O
.	O

The	O
cl	O
-	O
repressible	O
promoter	O
described	O
in	O
this	O
report	O
is	O
located	O
in	O
a	O
region	O
just	O
upstream	O
of	O
the	O
cl	O
open	O
reading	O
frame	O
and	O
is	O
oriented	O
in	O
the	O
direction	O
of	O
cl	O
.	O

Because	O
the	O
promoter	O
is	O
present	O
on	O
a	O
multicopy	O
plasmid	O
,	O
it	O
is	O
not	O
possible	O
to	O
make	O
a	O
direct	O
calculation	O
of	O
promoter	O
strength	O
;	O
however	O
,	O
the	O
values	O
observed	O
are	O
about	O
five	O
-	O
fold	O
lower	O
than	O
the	O
levels	O
produced	O
by	O
a	O
derivative	O
of	O
pCB192	O
that	O
contains	O
the	O
plac	O
promoter	O
from	O
pUC19	O
(	O
34	O
)	O
.	O

Because	O
sequences	O
on	O
both	O
sides	O
of	O
the	O
BamHI	O
site	O
located	O
upstream	O
of	O
cl	O
are	O
required	O
for	O
promoter	O
activity	O
(	O
Table	O
2	O
)	O
,	O
we	O
suggest	O
that	O
the	O
promoter	O
spans	O
this	O
site	O
.	O

Less	O
than	O
10	O
bps	O
downstream	O
of	O
this	O
BamHI	O
site	O
is	O
a	O
heptanucleotide	O
sequence	O
(	O
TATAATG	O
)	O
that	O
is	O
identical	O
to	O
the	O
-	O
10	O
consensus	O
sequence	O
for	O
RNA	O
polymerase	O
(	O
35	O
)	O
.	O

If	O
this	O
sequence	O
does	O
indeed	O
correspond	O
to	O
the	O
-	O
10	O
region	O
of	O
the	O
promoter	O
,	O
the	O
-	O
35	O
region	O
would	O
be	O
predicted	O
to	O
lie	O
on	O
the	O
other	O
side	O
of	O
the	O
BamHI	O
site	O
in	O
a	O
region	O
that	O
overlaps	O
a	O
known	O
cI	O
repressor	O
binding	O
site	O
(	O
2	O
-	O
5	O
)	O
.	O

Analysis	O
of	O
this	O
region	O
does	O
not	O
reveal	O
any	O
sequences	O
with	O
significant	O
similarity	O
to	O
the	O
-	O
35	O
consensus	O
sequence	O
.	O

The	O
best	O
fit	O
is	O
the	O
sequence	O
TCTATT	O
(	O
Figure	O
3	O
)	O
,	O
which	O
matches	O
only	O
two	O
positions	O
of	O
the	O
-	O
35	O
consensus	O
(	O
TTGACA	O
)	O
.	O

The	O
lack	O
of	O
a	O
strong	O
-	O
35	O
region	O
is	O
often	O
observed	O
with	O
genes	O
that	O
require	O
an	O
activator	O
.	O

Although	O
a	O
pentanucleotide	O
sequence	O
corresponding	O
to	O
the	O
conserved	O
portion	O
of	O
the	O
CRP	O
protein	O
consensus	O
binding	O
site	O
(	O
36	O
)	O

7678	O

Nucleic	O
Acids	O
Research	O

is	O
located	O
just	O
upstream	O
of	O
the	O
predicted	O
-	O
35	O
region	O
(	O
at	O
position	O
91	O
;	O
Figure	O
3	O
)	O
,	O
a	O
role	O
for	O
CRP	O
-	O
mediated	O
activation	O
in	O
cl	O
expression	O
has	O
not	O
previously	O
been	O
described	O
.	O

The	O
orientation	O
of	O
the	O
promoter	O
and	O
its	O
cl	O
-	O
repressible	O
character	O
raise	O
the	O
possibility	O
that	O
cl	O
expression	O
is	O
autoregulatory	O
.	O

If	O
this	O
is	O
so	O
,	O
one	O
potential	O
activator	O
would	O
be	O
the	O
cl	O
repressor	O
itself	O
.	O

Expression	O
cannot	O
be	O
absolutely	O
dependent	O
on	O
cl	O
-	O
mediated	O
activation	O
,	O
however	O
,	O
because	O
the	O
cloned	O
promoter	O
exhibits	O
significant	O
activity	O
in	O
the	O
absence	O
of	O
the	O
cl	O
gene	O
(	O
Table	O
2	O
)	O
.	O

Under	O
the	O
conditions	O
reported	O
here	O
,	O
the	O
presence	O
of	O
the	O
cl	O
gene	O
results	O
in	O
a	O
decrease	O
rather	O
than	O
an	O
increase	O
in	O
lacZ	O
expression	O
;	O
however	O
,	O
these	O
observations	O
do	O
not	O
rule	O
out	O
a	O
potential	O
activator	O
role	O
for	O
the	O
cl	O
protein	O
,	O
since	O
the	O
ratios	O
of	O
repressor	O
and	O
operator	O
provided	O
by	O
the	O
multicopy	O
plasmids	O
may	O
not	O
be	O
optimal	O
for	O
activation	O
.	O

Physiologically	O
,	O
the	O
role	O
of	O
additional	O
repressor	O
binding	O
sites	O
in	O
regulating	O
cl	O
expression	O
also	O
cannot	O
be	O
discounted	O
.	O

Three	O
potential	O
operator	O
sites	O
have	O
been	O
identified	O
several	O
hundred	O
bps	O
upstream	O
of	O
the	O
cI	O
open	O
reading	O
frame	O
(	O
2	O
-	O
5	O
)	O
;	O
one	O
or	O
more	O
of	O
these	O
could	O
be	O
involved	O
(	O
possibly	O
through	O
a	O
DNA	O
looping	O
mechanism	O
;	O
37	O
)	O
in	O
the	O
activation	O
or	O
repression	O
of	O
cl	O
expression	O
during	O
phage	O
growth	O
.	O

A	O
cl	O
-	O
repressible	O
promoter	O
oriented	O
in	O
the	O
direction	O
of	O
cl	O
was	O
previously	O
reported	O
(	O
38	O
)	O
to	O
be	O
located	O
entirely	O
within	O
PlBamHI	O
-	O
9	O
,	O
a	O
fragment	O
located	O
upstream	O
of	O
cl	O
which	O
is	O
bracketed	O
by	O
the	O
BamHI	O
site	O
within	O
pBCB2	O
.	O

13	O
.	O

Because	O
sequences	O
on	O
both	O
sides	O
of	O
this	O
BamHI	O
site	O
are	O
required	O
for	O
the	O
activity	O
of	O
the	O
promoter	O
in	O
pBCB2	O
.	O
13	O
,	O
we	O
suggest	O
that	O
the	O
previously	O
identified	O
promoter	O
is	O
distinct	O
from	O
the	O
one	O
reported	O
here	O
.	O

The	O
promoter	O
from	O
BamHI	O
-	O
9	O
could	O
correspond	O
to	O
a	O
consensus	O
promoter	O
sequence	O
that	O
is	O
situated	O
about	O
500	O
bps	O
upstream	O
of	O
cl	O
and	O
overlaps	O
a	O
cl	O
repressor	O
binding	O
site	O
(	O
2	O
)	O
.	O

If	O
so	O
,	O
cl	O
expression	O
is	O
likely	O
to	O
be	O
controlled	O
by	O
more	O
than	O
one	O
promoter	O
.	O

Located	O
between	O
this	O
promoter	O
sequence	O
and	O
the	O
promoter	O
encoded	O
on	O
pBCB2	O
.	O

13	O
is	O
an	O
open	O
reading	O
frame	O
whose	O
product	O
(	O
termed	O
coi	O
,	O
or	O
c	O
-	O
one	O
inactivator	O
)	O
has	O
been	O
implicated	O
in	O
the	O
establishment	O
of	O
lytic	O
growth	O
(	O
1	O
,	O
39	O
;	O
B	O
.	O
R	O
.	O
Baumstark	O
,	O
unpublished	O
results	O
)	O
.	O

It	O
has	O
been	O
suggested	O
(	O
2	O
)	O
that	O
the	O
decision	O
to	O
enter	O
lytic	O
or	O
lysogenic	O
growth	O
is	O
influenced	O
by	O
the	O
level	O
of	O
transcription	O
initiated	O
from	O
the	O
distal	O
promoter	O
(	O
which	O
would	O
transcribe	O
coi	O
prior	O
to	O
the	O
transcription	O
of	O
cl	O
)	O
relative	O
to	O
that	O
of	O
the	O
promoter	O
located	O
immediately	O
upstream	O
of	O
the	O
cl	O
gene	O
(	O
which	O
would	O
transcribe	O
only	O
ci	O
)	O
.	O

A	O
32	O
-	O
nucleotide	O
hyphenated	O
inverted	O
repeat	O
sequence	O
is	O
located	O
just	O
upstream	O
of	O
the	O
cl	O
open	O
reading	O
frame	O
(	O
positions	O
146	O
-	O
188	O
;	O
Figure	O
3	O
)	O
.	O

It	O
is	O
not	O
currently	O
known	O
whether	O
this	O
sequence	O
has	O
any	O
regulatory	O
effect	O
on	O
cl	O
expression	O
.	O

Conceivably	O
,	O
the	O
sequence	O
could	O
serve	O
as	O
a	O
recognition	O
site	O
for	O
an	O
as	O
-	O
yet	O
-	O
unidentified	O
regulatory	O
protein	O
.	O

Alternatively	O
,	O
it	O
may	O
affect	O
the	O
secondary	O
structure	O
of	O
the	O
messenger	O
RNA	O
.	O

A	O
transcript	O
extending	O
from	O
a	O
promoter	O
located	O
upstream	O
of	O
the	O
putative	O
coi	O
open	O
reading	O
frame	O
would	O
be	O
capable	O
of	O
forming	O
a	O
stable	O
stem	O
-	O
loop	O
structure	O
containing	O
16	O
bps	O
with	O
a	O
single	O
bp	O
mismatch	O
(	O
AG	O
=	O
-	O
33	O
.	O
6	O
Kcal	O
)	O
of	O
this	O
inverted	O
repeat	O
sequence	O
.	O

Such	O
a	O
structure	O
could	O
potentially	O
serve	O
as	O
a	O
recognition	O
site	O
for	O
a	O
regulatory	O
factor	O
or	O
,	O
alternatively	O
,	O
could	O
mask	O
such	O
a	O
site	O
.	O

On	O
the	O
other	O
hand	O
,	O
transcription	O
originating	O
from	O
the	O
promoter	O
spanning	O
the	O
BamHI	O
site	O
just	O
upstream	O
of	O
cl	O
would	O
start	O
at	O
a	O
site	O
within	O
the	O
inverted	O
repeat	O
sequence	O
,	O
forming	O
a	O
comparatively	O
less	O
stable	O
stem	O
-	O
loop	O
structure	O
of	O
about	O
8	O
bps	O
.	O

The	O
role	O
of	O
the	O
inverted	O
repeat	O
region	O
in	O
the	O
regulation	O
of	O
cl	O
expression	O
is	O
currently	O
under	O
investigation	O
.	O

ACKNOWLEDGEMENTS	O

We	O
thank	O
Heinz	O
Schuster	O
for	O
his	O
review	O
of	O
the	O
manuscript	O
.	O

This	O
work	O
was	O
supported	O
by	O
National	O
Science	O
Foundation	O
grant	O
DMB	O
-	O
8704146	O
.	O

7679	O

Nucleic	O
Acids	O
Research	O

Abbreviations	O
:	O
bp	O
,	O
basepairs	O
;	O
kb	O
,	O
kilobase	O
pairs	O
;	O
X	O
-	O
Gal	O
,	O
5	O
-	O
Bromo	O
-	O
4	O
-	O
Chloro	O
-	O
3	O
-	O
indolylbeta	O
-	O
D	O
-	O
galactopyranoside	O
.	O

*	O
To	O
whom	O
correspondence	O
should	O
be	O
addressed	O

REFERENCES	O

1	O
.	O

Yarmolinsky	O
,	O
M	O
.	O
B	O
.	O
,	O
and	O
Steinberg	O
,	O
N	O
.	O

(	O
1988	O
)	O
.	O

In	O
Calendar	O
,	O
R	O
.	O
,	O
(	O
ed	O
.	O
)	O
,	O
The	O
Bacteriophages	O
,	O
Plenum	O
Publishing	O

Corp	O
.	O
,	O
NY	O
,	O
Vol	O
.	O

1	O
,	O
pp	O
.	O

291	O
-	O
438	O
.	O

2	O
.	O

Baumstark	O
,	O
B	O
.	O
R	O
.	O
,	O
Stovall	O
,	O
S	O
.	O
R	O
.	O
,	O
and	O
Ashkar	O
,	O
S	O
.	O

(	O
1987	O
)	O
.	O

Virology	O
156	O
,	O
404	O
-	O
413	O
.	O

3	O
.	O

Dreiseikelmann	O
,	O
B	O
.	O
,	O
Velleman	O
,	O
M	O
.	O
,	O
and	O
Schuster	O
,	O
H	O
.	O

(	O
1988	O
)	O
.	O

J	O
.	O

Biol	O
.	O

Chem	O
.	O

263	O
,	O
1391	O
-	O
1397	O
.	O

4	O
.	O

Heinrich	O
,	O
J	O
.	O
,	O
Riedel	O
,	O
H	O
.	O
-	O
D	O
.	O
,	O
Baumstark	O
,	O
B	O
.	O
R	O
.	O
,	O
Kimura	O
,	O
M	O
.	O
,	O
and	O
Schuster	O
,	O
H	O
.	O

(	O
1989	O
)	O
.	O

Nucleic	O
Acids	O
Res	O
,	O

this	O
volume	O
.	O

5	O
.	O

Eliason	O
,	O
J	O
.	O
L	O
.	O
,	O
and	O
Stemnberg	O
,	O
N	O
.	O

(	O
1987	O
)	O
.	O

J	O
.	O

Mol	O
.	O

Biol	O
.	O

198	O
,	O
281	O
-	O
293	O
.	O

6	O
.	O

Velleman	O
,	O
M	O
.	O
,	O
Dreiseikelmann	O
,	O
B	O
.	O
,	O
and	O
Schuster	O
,	O
H	O
.	O

(	O
1987	O
)	O
.	O

Proc	O
.	O

Natl	O
.	O

Acad	O
.	O

Sci	O
.	O

USA	O
84	O
,	O
5570	O
-	O
5574	O
.	O

7	O
.	O

Citron	O
,	O
M	O
.	O
,	O
Velleman	O
,	O
M	O
.	O
,	O
and	O
Schuster	O
,	O
H	O
.	O

(	O
1988	O
)	O
.	O

J	O
.	O

Biol	O
.	O

Chem	O
.	O

264	O
,	O
3611	O
-	O
3617	O
.	O

8	O
.	O

Chadwick	O
,	O
P	O
.	O
,	O
Pirotta	O
,	O
V	O
.	O
,	O
Steinberg	O
,	O
R	O
.	O
,	O
Hopkins	O
,	O
N	O
.	O
,	O
and	O
Ptashne	O
,	O
M	O
.	O

(	O
1970	O
)	O
.	O

Cold	O
Spring	O
Harbor	O
Symp	O
.	O

Quant	O
.	O

Biol	O
.	O

35	O
,	O
283	O
-	O
294	O
.	O

9	O
.	O

Chesney	O
,	O
R	O
.	O
H	O
.	O
,	O
and	O
Scott	O
,	O
J	O
.	O
R	O
.	O

(	O
1975	O
)	O
.	O

Virology	O
67	O
,	O
375	O
-	O
384	O
.	O

10	O
.	O

Wandersman	O
,	O
C	O
.	O
,	O
and	O
Yarmolinsky	O
,	O
M	O
.	O

(	O
1977	O
)	O
.	O

Virology	O
78	O
,	O
267	O
-	O
276	O
.	O

11	O
.	O

Scott	O
,	O
J	O
.	O
R	O
.	O
,	O
West	O
,	O
B	O
.	O
W	O
.	O
,	O
and	O
Laping	O
,	O
J	O
.	O
L	O
.	O

(	O
1978	O
)	O
.	O

Virology	O
85	O
,	O
587	O
-	O
600	O
.	O

12	O
.	O

Pabo	O
,	O
C	O
.	O
O	O
.	O
,	O
and	O
Sauer	O
,	O
R	O
.	O

A	O
.	O

(	O
1984	O
)	O
.	O

Ann	O
.	O

Rev	O
.	O

Biochem	O
.	O

53	O
,	O
293	O
-	O
321	O
.	O

13	O
.	O

Scott	O
,	O
J	O
.	O
R	O
.	O

(	O
1974	O
)	O
.	O

Virology	O
62	O
,	O
344	O
-	O
349	O
.	O

14	O
.	O

Schneider	O
,	O
K	O
.	O
,	O
and	O
Beck	O
,	O
C	O
.	O
F	O
.	O

(	O
1987	O
)	O
.	O

Methods	O
in	O
Enzymol	O
.	O

153	O
,	O
452	O
-	O
461	O
.	O

15	O
.	O

Smith	O
,	O
H	O
.	O
W	O
.	O

(	O
1972	O
)	O
.	O

Nature	O
New	O
Biol	O
.	O

238	O
,	O
205	O
-	O
206	O
.	O

16	O
.	O

Scott	O
,	O
J	O
.	O
R	O
.	O

(	O
1975	O
)	O
.	O

Virology	O
65	O
,	O
173	O
-	O
178	O
.	O

17	O
.	O

Scott	O
,	O
J	O
.	O
R	O
.	O
,	O
Kropf	O
,	O
M	O
.	O
M	O
.	O
,	O
and	O
Mendelson	O
,	O
L	O
.	O

(	O
1977	O
)	O
.	O

Virology	O
76	O
,	O
39	O
-	O
46	O
.	O

18	O
.	O

Scott	O
,	O
J	O
.	O
R	O
.	O

(	O
1968	O
)	O
.	O

Virology	O
36	O
,	O
564	O
-	O
574	O
.	O

19	O
.	O

Walker	O
,	O
D	O
.	O
H	O
.	O
,	O
Jr	O
.	O
,	O
and	O
Walker	O
,	O
J	O
.	O
T	O
.	O

(	O
1976	O
)	O
.	O

J	O
.	O

Virol	O
.	O

20	O
,	O
177	O
-	O
187	O
.	O

20	O
.	O

Stemnberg	O
,	O
N	O
.	O

(	O
1979	O
)	O
.	O

Virology	O
96	O
,	O
129	O
-	O
142	O
.	O

21	O
.	O

Schneider	O
,	O
K	O
.	O
,	O
and	O
Beck	O
,	O
C	O
.	O
F	O
.	O

(	O
1986	O
)	O
.	O

Gene	O
42	O
,	O
37	O
-	O
48	O
.	O

22	O
.	O

Taylor	O
,	O
D	O
.	O
P	O
.	O
,	O
and	O
Cohen	O
,	O
S	O
.	O
N	O
.	O

(	O
1979	O
)	O
.	O

J	O
.	O

Bacteriol	O
.	O

137	O
,	O
92	O
-	O
104	O
.	O

23	O
.	O

Miller	O
,	O
J	O
.	O
H	O
.	O

(	O
1972	O
)	O
.	O

In	O
Experiments	O
in	O
Molecular	O
Genetics	O
,	O
Cold	O
Spring	O
Harbor	O
Laboratory	O
,	O
Cold	O
Spring	O

Harbor	O
,	O
N	O
.	O
Y	O
.	O

352	O
-	O
355	O
.	O

24	O
.	O

Guyer	O
,	O
R	O
.	O
S	O
.	O

(	O
1978	O
)	O
.	O

J	O
.	O

Mol	O
.	O

Biol	O
.	O

126	O
,	O
347	O
-	O
365	O
.	O

25	O
.	O

Devlin	O
,	O
B	O
.	O
H	O
.	O
,	O
Baumstark	O
,	O
B	O
.	O
R	O
.	O
,	O
and	O
Scott	O
,	O
J	O
.	O
R	O
.	O

(	O
1982	O
)	O
.	O

Virology	O
120	O
,	O
360	O
-	O
375	O
.	O

26	O
.	O

Sanger	O
,	O
F	O
.	O
,	O
Nicklen	O
,	O
S	O
.	O
,	O
and	O
Coulson	O
,	O
A	O
.	O
R	O
.	O

(	O
1977	O
)	O
.	O

Proc	O
.	O

Natl	O
.	O

Acad	O
.	O

Sci	O
.	O

USA	O
74	O
,	O
5463	O
-	O
5467	O
.	O

27	O
.	O

DeVries	O
,	O
J	O
.	O
K	O
.	O
,	O
and	O
Zubay	O
,	O
G	O
.	O

(	O
1967	O
)	O
.	O

Proc	O
.	O

Natl	O
.	O

Acad	O
.	O

Sci	O
.	O

USA	O
57	O
,	O
1010	O
-	O
1012	O
.	O

28	O
.	O

Heilmann	O
,	O
H	O
.	O
,	O
Reeve	O
,	O
J	O
.	O
R	O
.	O
,	O
and	O
Puhler	O
,	O
A	O
.	O

(	O
1980	O
)	O
.	O

Mol	O
.	O

Gen	O
.	O

Genet	O
.	O

178	O
,	O
149	O
-	O
154	O
.	O

29	O
.	O

Shine	O
,	O
J	O
.	O
,	O
and	O
Dalgarno	O
,	O
L	O
.	O

(	O
1974	O
)	O
.	O

Proc	O
.	O

Natl	O
.	O

Acad	O
.	O

Sci	O
.	O

USA	O
71	O
,	O
1342	O
-	O
1346	O
.	O

30	O
.	O

Chou	O
,	O
P	O
.	O
Y	O
.	O
,	O
and	O
Fasman	O
,	O
G	O
.	O
D	O
.	O

(	O
1978	O
)	O
.	O

Adv	O
.	O

Enzymol	O
.	O

47	O
,	O
45	O
-	O
148	O
.	O

31	O
.	O

Berg	O
,	O
J	O
.	O
M	O
.	O

(	O
1986	O
)	O
.	O

Nature	O
319	O
,	O
264	O
-	O
265	O
.	O

32	O
.	O

Landschultz	O
,	O
W	O
.	O
H	O
.	O
,	O
Johnson	O
,	O
P	O
.	O
F	O
.	O
,	O
and	O
McKnight	O
,	O
S	O
.	O
L	O
.	O

(	O
1988	O
)	O
.	O

Science	O
240	O
,	O
1759	O
-	O
1764	O
.	O

33	O
.	O

Murre	O
,	O
C	O
.	O
,	O
McCaw	O
,	O
P	O
.	O
,	O
and	O
Baltimore	O
,	O
D	O
.	O

Cell	O
56	O
,	O
777	O
-	O
783	O
.	O

34	O
.	O

Anderson	O
,	O
B	O
.	O
E	O
.	O
,	O
Baumstark	O
,	O
B	O
.	O
R	O
.	O
,	O
and	O
Bellini	O
,	O
W	O
.	O
J	O
.	O

(	O
1988	O
)	O
.	O

J	O
.	O

Bacteriol	O
.	O

170	O
,	O
4493	O
-	O
4500	O
.	O

35	O
.	O

Rosenberg	O
,	O
M	O
.	O
,	O
and	O
Court	O
,	O
D	O
.	O

(	O
1979	O
)	O
.	O

Annu	O
.	O

Rev	O
.	O

Genet	O
.	O

13	O
,	O
319	O
-	O
353	O
.	O

36	O
.	O

Ebright	O
,	O
R	O
.	O
H	O
.	O
,	O
Cossart	O
,	O
P	O
.	O
,	O
Gicquel	O
-	O
Sanzey	O
,	O
B	O
.	O
,	O
and	O
Beckwith	O
,	O
J	O
.	O

(	O
1984	O
)	O
.	O

Nature	O
311	O
,	O
232	O
-	O
235	O
.	O

37	O
.	O

Ptashne	O
,	O
M	O
.	O

(	O
1986	O
)	O
.	O

Nature	O
322	O
,	O
697	O
-	O
701	O
.	O

38	O
.	O

Stemnberg	O
,	O
N	O
.	O
,	O
and	O
Hoess	O
,	O
R	O
.	O

(	O
1983	O
)	O
.	O

Annu	O
.	O

Rev	O
.	O

Genet	O
.	O

17	O
,	O
123	O
-	O
154	O
.	O

39	O
.	O

Scott	O
,	O
J	O
.	O
R	O
.	O

(	O
1980	O
)	O
.	O

Curr	O
.	O

Top	O
.	O

Microbiol	O
.	O

Immunol	O
.	O

90	O
,	O
49	O
-	O
65	O
.	O

7680	O

This	O
article	O
,	O
submitted	O
on	O
disc	O
,	O
has	O
been	O
automatically	O

converted	O
into	O
this	O
typeset	O
format	O
by	O
the	O
publisher	O
.	O

Down	O
-	O
regulation	O
of	O
the	O
M6P	O
/	O
IGF	O
-	O
II	O
receptor	O
increases	O
cell	O
proliferation	O
and	O
reduces	O
apoptosis	O
in	O
neonatal	O
rat	B
cardiac	O
myocytes	O

Abstract	O

Background	O

The	O
mannose	O
6	O
-	O
phosphate	O
/	O
insulin	O
-	O
like	O
growth	O
factor	O
-	O
II	O
receptor	O
(	O
M6P	O
/	O
IGF2R	O
)	O
is	O
a	O
multi	O
-	O
functional	O
protein	O
that	O
has	O
been	O
implicated	O
in	O
regulation	O
of	O
cell	O
growth	O
and	O
apoptosis	O
.	O

Cardiac	O
myocytes	O
express	O
relatively	O
high	O
levels	O
of	O
M6P	O
/	O
IGF2R	O
,	O
and	O
cardiomyocyte	O
apoptosis	O
has	O
been	O
identified	O
in	O
a	O
variety	O
of	O
cardiovascular	O
disorders	O
,	O
such	O
as	O
myocardial	O
infarction	O
and	O
heart	O
failure	O
.	O

However	O
,	O
involvement	O
of	O
M6P	O
/	O
IGF2R	O
in	O
the	O
pathogenesis	O
of	O
these	O
conditions	O
has	O
not	O
been	O
determined	O
.	O

Thus	O
,	O
the	O
objective	O
of	O
this	O
study	O
was	O
to	O
determine	O
the	O
role	O
of	O
M6P	O
/	O
IGF2R	O
in	O
regulation	O
of	O
cardiac	O
myocyte	O
growth	O
and	O
apoptosis	O
.	O

Results	O

We	O
down	O
-	O
regulated	O
the	O
expression	O
of	O
M6P	O
/	O
IGF2R	O
in	O
neonatal	O
rat	B
cardiac	O
myocytes	O
and	O
examined	O
the	O
effect	O
on	O
cell	O
proliferation	O
and	O
apoptosis	O
.	O

Infection	O
of	O
neonatal	O
cardiomyocytes	O
with	O
an	O
adenovirus	O
expressing	O
a	O
ribozyme	O
targeted	O
against	O
the	O
M6P	O
/	O
IGF2R	O
significantly	O
reduced	O
the	O
level	O
of	O
M6P	O
/	O
IGF2R	O
mRNA	O
,	O
as	O
determined	O
by	O
RT	O
-	O
PCR	O
and	O
Ribonuclease	O
Protection	O
Assay	O
(	O
RPA	O
)	O
.	O

M6P	O
-	O
containing	O
protein	O
binding	O
and	O
endocytosis	O
as	O
well	O
as	O
the	O
M6P	O
/	O
IGF2R	O
-	O
mediated	O
internalization	O
of	O
125I	O
-	O
IGF	O
-	O
II	O
were	O
lower	O
in	O
the	O
ribozyme	O
-	O
treated	O
cells	O
than	O
the	O
control	O
myocytes	O
,	O
indicating	O
that	O
the	O
number	O
of	O
functional	O
M6P	O
/	O
IGF2R	O
in	O
the	O
ribozyme	O
treated	O
cells	O
was	O
reduced	O
.	O

Accordingly	O
,	O
a	O
marked	O
increase	O
in	O
cell	O
proliferation	O
and	O
a	O
reduced	O
cell	O
susceptibility	O
to	O
hypoxia	O
-	O
and	O
TNF	O
-	O
induced	O
apoptosis	O
were	O
observed	O
in	O
the	O
ribozyme	O
-	O
treated	O
cells	O
.	O

Conclusions	O

These	O
findings	O
suggest	O
that	O
M6P	O
/	O
IGF2R	O
may	O
play	O
a	O
role	O
in	O
regulation	O
of	O
cardiac	O
myocyte	O
growth	O
and	O
apoptosis	O
.	O

Down	O
regulation	O
of	O
this	O
gene	O
in	O
cardiac	O
tissues	O
might	O
be	O
a	O
new	O
approach	O
to	O
prevention	O
of	O
cell	O
death	O
or	O
promotion	O
of	O
mitogenesis	O
for	O
certain	O
heart	O
diseases	O
.	O

Background	O

The	O
mannose	O
6	O
-	O
phosphate	O
/	O
insulin	O
-	O
like	O
growth	O
factor	O
-	O
II	O
receptor	O
(	O
M6P	O
/	O
IGF2R	O
)	O
is	O
a	O
unique	O
protein	O
that	O
interacts	O
with	O
multiple	O
ligands	O
,	O
some	O
of	O
which	O
are	O
important	O
growth	O
regulatory	O
factors	O
[	O
1	O
]	O
.	O

The	O
M6P	O
/	O
IGF2R	O
participates	O
in	O
internalization	O
and	O
lysosomal	O
degradation	O
of	O
IGF	O
-	O
II	O
,	O
a	O
mitogen	O
normally	O
acting	O
through	O
the	O
IGF	O
-	O
I	O
receptor	O
to	O
stimulate	O
cell	O
proliferation	O
[	O
2	O
]	O
.	O

The	O
M6P	O
/	O
IGF2	O
receptor	O
is	O
required	O
for	O
the	O
activation	O
of	O
TGF	O
-	O
beta	O
[	O
3	O
]	O
,	O
a	O
potent	O
growth	O
inhibitor	O
for	O
many	O
cell	O
types	O
.	O

This	O
receptor	O
is	O
also	O
involved	O
in	O
the	O
binding	O
,	O
transport	O
and	O
activation	O
of	O
newly	O
-	O
synthesized	O
lysosomal	O
enzymes	O
,	O
such	O
as	O
cathepsins	O
[	O
4	O
,	O
5	O
]	O
,	O
which	O
have	O
been	O
recently	O
implicated	O
in	O
the	O
induction	O
of	O
apoptosis	O
[	O
6	O
]	O
.	O

On	O
the	O
basis	O
of	O
these	O
functions	O
,	O
the	O
M6P	O
/	O
IGF2R	O
has	O
been	O
proposed	O
to	O
play	O
a	O
significant	O
role	O
in	O
regulation	O
of	O
cell	O
growth	O
and	O
apoptosis	O
[	O
7	O
]	O
.	O

Apoptosis	O
,	O
or	O
programmed	O
cell	O
death	O
,	O
is	O
a	O
tightly	O
regulated	O
process	O
used	O
to	O
remove	O
excess	O
,	O
hazardous	O
or	O
damaged	O
somatic	O
cells	O
,	O
and	O
is	O
crucial	O
for	O
the	O
development	O
,	O
maintenance	O
and	O
survival	O
of	O
an	O
organism	O
.	O

However	O
,	O
alterations	O
in	O
the	O
control	O
of	O
apoptosis	O
have	O
also	O
been	O
shown	O
to	O
contribute	O
to	O
human	B
diseases	O
.	O

In	O
fact	O
,	O
morphological	O
and	O
biochemical	O
markers	O
of	O
apoptosis	O
have	O
been	O
identified	O
in	O
a	O
wide	O
variety	O
of	O
cardiovascular	O
disorders	O
,	O
including	O
myocardial	O
infarction	O
and	O
heart	O
failure	O
.	O

This	O
suggests	O
that	O
activation	O
of	O
apoptotic	O
pathways	O
contributes	O
to	O
cardiomyocyte	O
loss	O
and	O
subsequent	O
cardiac	O
dysfunction	O
in	O
these	O
conditions	O
.	O

A	O
number	O
of	O
factors	O
involved	O
in	O
cardiomyocyte	O
apoptosis	O
are	O
currently	O
known	O
and	O
include	O
insulin	O
-	O
like	O
growth	O
factor	O
-	O
I	O
(	O
IGF	O
-	O
I	O
)	O
,	O
stress	O
-	O
activated	O
protein	O
kinases	O
(	O
SAPKs	O
)	O
and	O
the	O
anti	O
-	O
apoptotic	O
Bcl	O
-	O
2	O
family	O
[	O
8	O
]	O
.	O

There	O
are	O
indications	O
that	O
other	O
factors	O
may	O
be	O
involved	O
in	O
induction	O
and	O
regulation	O
of	O
cardiac	O
apoptosis	O
.	O

However	O
,	O
these	O
potential	O
factors	O
and	O
their	O
corresponding	O
mechanisms	O
have	O
not	O
been	O
identified	O
.	O

Several	O
lines	O
of	O
evidence	O
point	O
to	O
the	O
potential	O
involvement	O
of	O
M6P	O
/	O
IGF2R	O
in	O
cardiac	O
myocyte	O
proliferation	O
and	O
apoptosis	O
.	O

Cardiac	O
myocytes	O
express	O
relatively	O
high	O
levels	O
of	O
M6P	O
/	O
IGF2R	O
and	O
transgenic	O
mice	B
containing	O
a	O
homologous	O
deletion	O
of	O
the	O
M6P	O
/	O
IGF2R	O
gene	O
manifest	O
ventricular	O
hyperplasia	O
due	O
to	O
an	O
increase	O
in	O
cell	O
number	O
[	O
9	O
,	O
10	O
]	O
,	O
suggesting	O
that	O
the	O
M6P	O
/	O
IGF2R	O
normally	O
acts	O
to	O
suppress	O
cardiac	O
myocyte	O
cell	O
growth	O
.	O

It	O
has	O
also	O
been	O
shown	O
that	O
TGF	O
-	O
beta	O
,	O
a	O
potent	O
growth	O
suppressor	O
whose	O
activation	O
requires	O
the	O
binding	O
of	O
latent	O
TGF	O
-	O
beta	O
to	O
M6P	O
/	O
IGF2R	O
[	O
3	O
]	O
,	O
is	O
commonly	O
upregulated	O
in	O
chronic	O
heart	O
failure	O
[	O
11	O
]	O
.	O

Additional	O
evidence	O
for	O
the	O
involvement	O
of	O
M6P	O
/	O
IGF2R	O
in	O
regulation	O
of	O
apoptosis	O
comes	O
from	O
studies	O
of	O
tumorigenesis	O
.	O

It	O
has	O
been	O
shown	O
that	O
M6P	O
/	O
IGF2R	O
expression	O
is	O
significantly	O
reduced	O
in	O
a	O
variety	O
of	O
tumors	O
and	O
loss	O
of	O
heterozygocity	O
(	O
LOH	O
)	O
at	O
the	O
M6P	O
/	O
IGF2R	O
gene	O
locus	O
6q26	O
have	O
been	O
found	O
in	O
breast	O
,	O
liver	O
cancers	O
and	O
squamous	O
cell	O
carcinoma	O
of	O
the	O
lung	O
[	O
12	O
-	O
15	O
]	O
.	O

Although	O
several	O
studies	O
have	O
examined	O
the	O
effect	O
of	O
M6P	O
/	O
IGF2R	O
over	O
-	O
expression	O
on	O
cell	O
growth	O
[	O
7	O
]	O
,	O
it	O
is	O
not	O
known	O
whether	O
down	O
-	O
regulation	O
of	O
this	O
receptor	O
protein	O
leads	O
to	O
cellular	O
protection	O
against	O
apoptosis	O
.	O

Ribozymes	O
are	O
catalytic	O
RNA	O
molecules	O
that	O
cleave	O
a	O
complementary	O
mRNA	O
sequence	O
[	O
16	O
]	O
,	O
thereby	O
inactivating	O
specific	O
mRNAs	O
and	O
suppressing	O
gene	O
expression	O
in	O
vitro	O
and	O
in	O
vivo	O
[	O
17	O
,	O
18	O
]	O
.	O

Ribozymes	O
have	O
been	O
shown	O
to	O
be	O
highly	O
specific	O
,	O
efficient	O
and	O
stable	O
.	O

They	O
can	O
be	O
packaged	O
into	O
viral	O
vectors	O
to	O
enhance	O
transfer	O
into	O
cells	O
and	O
to	O
achieve	O
longer	O
expression	O
compared	O
with	O
naked	O
oligonucleotides	O
.	O

In	O
the	O
present	O
study	O
,	O
we	O
employed	O
ribozyme	O
technology	O
to	O
study	O
the	O
role	O
of	O
M6P	O
/	O
IGF2R	O
in	O
regulation	O
of	O
cardiac	O
myocyte	O
cell	O
growth	O
.	O

A	O
hammerhead	O
ribozyme	O
against	O
the	O
M6P	O
/	O
IGF2R	O
mRNA	O
was	O
constructed	O
and	O
packaged	O
in	O
an	O
adenoviral	O
vector	O
.	O

We	O
then	O
examined	O
the	O
effect	O
of	O
ribozyme	O
-	O
mediated	O
down	O
-	O
regulation	O
of	O
M6P	O
/	O
IGF2R	O
expression	O
on	O
cell	O
growth	O
and	O
hypoxia	O
-	O
and	O
TNF	O
-	O
induced	O
apoptosis	O
.	O

Results	O

Cleavage	O
reaction	O
of	O
the	O
ribozyme	O
in	O
vitro	O

The	O
M6P	O
/	O
IGF2R	O
ribozyme	O
we	O
constructed	O
has	O
13	O
-	O
bp	O
binding	O
arms	O
complementary	O
to	O
the	O
target	O
site	O
of	O
M6P	O
/	O
IGF2R	O
mRNA	O
,	O
and	O
a	O
catalytic	O
core	O
(	O
Fig	O
.	O
1A	O
)	O
.	O

To	O
evaluate	O
the	O
bioactivity	O
of	O
the	O
ribozyme	O
and	O
the	O
accessibility	O
of	O
the	O
target	O
site	O
,	O
a	O
cleavage	O
reaction	O
was	O
performed	O
in	O
vitro	O
.	O

The	O
substrates	O
,	O
[	O
alpha	O
-	O
32P	O
]	O
labeled	O
RNA	O
transcripts	O
containing	O
45	O
bp	O
of	O
M6P	O
/	O
IGF2R	O
mRNA	O
or	O
an	O
unmatched	O
sequence	O
,	O
were	O
incubated	O
with	O
the	O
ribozyme	O
as	O
described	O
(	O
see	O
Materials	O
and	O
Methods	O
)	O
.	O

The	O
ribozyme	O
cleaved	O
only	O
the	O
specific	O
M6P	O
/	O
IGF2R	O
mRNA	O
into	O
the	O
expected	O
products	O
.	O

In	O
the	O
assay	O
of	O
time	O
course	O
,	O
the	O
hammerhead	O
ribozyme	O
was	O
able	O
to	O
cleave	O
24	O
.	O
2	O
%	O
of	O
the	O
M6P	O
/	O
IGF2R	O
target	O
within	O
10	O
minutes	O
of	O
incubation	O
,	O
50	O
.	O
3	O
%	O
of	O
the	O
M6P	O
/	O
IGF2R	O
target	O
within	O
40	O
minutes	O
of	O
incubation	O
,	O
and	O
by	O
640	O
minutes	O
,	O
80	O
.	O
8	O
%	O
of	O
the	O
M6P	O
/	O
IGF2R	O
target	O
was	O
converted	O
to	O
the	O
expected	O
products	O
(	O
Fig	O
.	O
1B	O
)	O
.	O

This	O
ribozyme	O
did	O
not	O
digest	O
the	O
unmatched	O
sequence	O
(	O
Fig	O
.	O
1B	O
)	O
.	O

These	O
results	O
indicate	O
a	O
high	O
efficiency	O
and	O
specificity	O
of	O
the	O
ribozyme	O
in	O
vitro	O
.	O

Ribozymes	O
down	O
-	O
regulate	O
M6P	O
/	O
IGF2R	O
expression	O
in	O
cardiac	O
myocytes	O

To	O
examine	O
the	O
ability	O
of	O
the	O
ribozyme	O
to	O
reduce	O
levels	O
of	O
M6P	O
/	O
IGF2R	O
mRNA	O
in	O
cultured	O
cardiac	O
myocytes	O
,	O
total	O
RNA	O
was	O
extracted	O
from	O
cells	O
infected	O
with	O
Ad	O
-	O
GFP	O
/	O
IGF2R	O
-	O
Rz	O
or	O
Ad	O
-	O
GFP	O
,	O
and	O
subjected	O
to	O
RT	O
-	O
PCR	O
using	O
M6P	O
/	O
IGF2R	O
-	O
specific	O
primers	O
.	O

Primers	O
specific	O
for	O
beta	O
-	O
actin	O
were	O
added	O
to	O
a	O
parallel	O
reaction	O
to	O
serve	O
as	O
an	O
internal	O
standard	O
.	O

Cells	O
were	O
used	O
4	O
days	O
after	O
infection	O
,	O
with	O
average	O
infection	O
efficiency	O
of	O
70	O
-	O
80	O
%	O
(	O
for	O
which	O
a	O
viral	O
dose	O
used	O
had	O
minimal	O
cytotoxicity	O
)	O
.	O

The	O
RT	O
-	O
PCR	O
product	O
of	O
M6P	O
/	O
IGF2R	O
was	O
856	O
bp	O
,	O
and	O
the	O
beta	O
-	O
actin	O
product	O
was	O
285	O
bp	O
.	O

As	O
shown	O
in	O
Fig	O
.	O

2A	O
,	O
the	O
Ad	O
-	O
GFP	O
/	O
IGF2R	O
-	O
Rz	O
-	O
infected	O
cells	O
exhibited	O
a	O
significantly	O
lower	O
level	O
of	O
M6P	O
/	O
IGF2R	O
mRNA	O
than	O
Ad	O
-	O
GFP	O
-	O
infected	O
cells	O
,	O
with	O
a	O
reduction	O
of	O
about	O
50	O
%	O
.	O

This	O
result	O
was	O
confirmed	O
by	O
ribonuclease	O
protection	O
assay	O
(	O
RPA	O
)	O
,	O
in	O
which	O
GAPDH	O
was	O
used	O
as	O
a	O
control	O
(	O
Fig	O
.	O
2C	O
&	O
2D	O
)	O
.	O

There	O
was	O
no	O
significant	O
difference	O
in	O
the	O
level	O
of	O
M6P	O
/	O
IGF2R	O
mRNA	O
between	O
Ad	O
-	O
GFP	O
-	O
infected	O
cells	O
and	O
uninfected	O
cells	O
(	O
data	O
not	O
shown	O
)	O
,	O
indicating	O
that	O
infection	O
with	O
the	O
adenovirus	O
itself	O
did	O
not	O
alter	O
the	O
endogenous	O
M6P	O
/	O
IGF2R	O
mRNA	O
level	O
.	O

The	O
results	O
demonstrated	O
that	O
the	O
ribozyme	O
was	O
highly	O
effective	O
in	O
suppressing	O
M6P	O
/	O
IGF2R	O
expression	O
in	O
cultured	O
cardiac	O
myocytes	O
.	O

Effect	O
of	O
ribozyme	O
expression	O
on	O
the	O
functional	O
activity	O
of	O
M6P	O
/	O
IGF2R	O

To	O
determine	O
the	O
effect	O
of	O
the	O
ribozyme	O
on	O
the	O
functional	O
activity	O
of	O
M6P	O
/	O
IGF2R	O
,	O
binding	O
and	O
internalization	O
of	O
exogenous	O
125I	O
-	O
IGF	O
-	O
II	O
was	O
measured	O
in	O
cells	O
infected	O
with	O
Ad	O
-	O
GFP	O
/	O
IGF2R	O
-	O
Rz	O
.	O

As	O
shown	O
in	O
Fig	O
.	O

3A	O
,	O
cells	O
infected	O
with	O
Ad	O
-	O
GFP	O
/	O
IGF2R	O
-	O
Rz	O
showed	O
a	O
54	O
%	O
reduction	O
in	O
125I	O
-	O
IGF	O
-	O
II	O
internalization	O
when	O
compared	O
with	O
the	O
control	O
cells	O
(	O
infected	O
with	O
Ad	O
-	O
GFP	O
)	O
.	O

We	O
also	O
examined	O
the	O
effect	O
of	O
the	O
ribozyme	O
on	O
the	O
M6P	O
-	O
binding	O
activity	O
of	O
the	O
M6P	O
/	O
IGF2R	O
using	O
the	O
M6P	O
-	O
bearing	O
lysosomal	O
enzyme	O
,	O
beta	O
-	O
glucuronidase	O
,	O
as	O
a	O
probe	O
.	O

The	O
results	O
showed	O
that	O
the	O
maximal	O
M6P	O
-	O
binding	O
capacity	O
of	O
cells	O
treated	O
with	O
the	O
ribozyme	O
was	O
about	O
50	O
%	O
less	O
than	O
that	O
of	O
controls	O
(	O
Fig	O
.	O
3B	O
)	O
.	O

Furthermore	O
,	O
we	O
assessed	O
the	O
ability	O
of	O
cells	O
to	O
internalize	O
exogenous	O
beta	O
-	O
glucuronidase	O
after	O
treatment	O
with	O
ribozyme	O
.	O

Similarly	O
,	O
the	O
M6P	O
-	O
inhibitable	O
endocytosis	O
of	O
beta	O
-	O
glucuronidase	O
by	O
ribozyme	O
-	O
treated	O
cells	O
was	O
about	O
52	O
%	O
less	O
than	O
that	O
of	O
control	O
cells	O
(	O
Fig	O
.	O
3C	O
)	O
.	O

These	O
results	O
confirm	O
that	O
the	O
number	O
of	O
functional	O
M6P	O
/	O
IGF2R	O
in	O
ribozyme	O
-	O
treated	O
cells	O
was	O
reduced	O
.	O

Adenoviral	O
delivery	O
of	O
ribozymes	O
increases	O
the	O
proliferation	O
of	O
cardiac	O
myocytes	O

We	O
examined	O
the	O
effects	O
of	O
the	O
ribozyme	O
on	O
the	O
growth	O
of	O
cultured	O
neonatal	O
rat	B
cardiac	O
myocytes	O
.	O

Morphological	O
evaluation	O
showed	O
a	O
remarkable	O
difference	O
in	O
growth	O
pattern	O
between	O
Ad	O
-	O
GFP	O
/	O
IGF2R	O
-	O
Rz	O
-	O
infected	O
cells	O
and	O
the	O
control	O
cells	O
:	O
the	O
ribozyme	O
-	O
expressing	O
cells	O
formed	O
larger	O
and	O
more	O
spread	O
colonies	O
(	O
Fig	O
.	O
4	O
)	O
.	O

Assessment	O
of	O
cell	O
proliferative	O
activity	O
by	O
the	O
MTT	O
assay	O
and	O
counts	O
of	O
viable	O
cells	O
showed	O
that	O
the	O
number	O
of	O
cardiac	O
myocytes	O
in	O
ribozyme	O
-	O
expressing	O
cultures	O
was	O
significantly	O
higher	O
than	O
in	O
control	O
cultures	O
(	O
Fig	O
.	O
5	O
)	O
.	O

These	O
results	O
indicate	O
that	O
treatment	O
with	O
M6P	O
/	O
IGF2R	O
-	O
ribozyme	O
can	O
promote	O
cardiac	O
myocyte	O
proliferation	O
.	O

Effect	O
of	O
M6P	O
/	O
IGF2R	O
-	O
ribozyme	O
expression	O
on	O
apoptosis	O
of	O
cardiac	O
myocytes	O

We	O
examined	O
the	O
effects	O
of	O
ribozyme	O
expression	O
on	O
TNF	O
-	O
alpha	O
and	O
hypoxia	O
-	O
induced	O
apoptosis	O
of	O
cultured	O
cardiac	O
myocytes	O
.	O

After	O
a	O
24	O
hr	O
challenge	O
with	O
hypoxia	O
,	O
the	O
number	O
of	O
apoptotic	O
cells	O
in	O
M6P	O
/	O
IGF2R	O
-	O
Rz	O
expressing	O
cultures	O
was	O
38	O
%	O
lower	O
than	O
in	O
control	O
cultures	O
as	O
determined	O
by	O
Hoechst	O
staining	O
(	O
which	O
highlights	O
the	O
nuclei	O
of	O
apoptotic	O
cells	O
)	O
and	O
ELISA	O
(	O
Fig	O
.	O
6A	O
,	O
7A	O
)	O
.	O

MTT	O
analysis	O
showed	O
that	O
the	O
number	O
of	O
viable	O
cells	O
in	O
ribozyme	O
-	O
treated	O
cultures	O
was	O
40	O
%	O
higher	O
than	O
in	O
control	O
cultures	O
(	O
Fig	O
.	O
7A	O
)	O
.	O

After	O
treatment	O
with	O
TNF	O
-	O
alpha	O
,	O
as	O
shown	O
in	O
Fig	O
.	O

6B	O
,	O
a	O
large	O
number	O
of	O
control	O
cells	O
underwent	O
apoptosis	O
,	O
as	O
indicated	O
by	O
morphological	O
changes	O
(	O
small	O
round	O
shape	O
)	O
and	O
bright	O
blue	O
nuclear	O
staining	O
.	O

There	O
were	O
significantly	O
more	O
apoptotic	O
cells	O
in	O
control	O
cultures	O
than	O
in	O
cultures	O
expressing	O
the	O
Ad	O
-	O
GFP	O
/	O
IGF2R	O
-	O
Rz	O
.	O

The	O
number	O
of	O
apoptotic	O
cells	O
,	O
as	O
measured	O
by	O
the	O
cell	O
death	O
ELISA	O
assay	O
,	O
in	O
cultures	O
infected	O
with	O
Ad	O
-	O
GFP	O
/	O
IGF2R	O
-	O
Rz	O
was	O
significantly	O
(	O
about	O
40	O
%	O
)	O
lower	O
than	O
in	O
cultures	O
infected	O
with	O
Ad	O
-	O
GFP	O
(	O
Fig	O
.	O
7B	O
)	O
.	O

Accordingly	O
,	O
the	O
number	O
of	O
viable	O
cells	O
,	O
as	O
measured	O
by	O
MTT	O
analysis	O
,	O
in	O
cultures	O
infected	O
with	O
Ad	O
-	O
GFP	O
/	O
IGF2R	O
-	O
Rz	O
was	O
significantly	O
(	O
about	O
45	O
%	O
)	O
higher	O
than	O
in	O
cultures	O
infected	O
with	O
Ad	O
-	O
GFP	O
(	O
Fig	O
.	O
7B	O
)	O
.	O

These	O
results	O
are	O
consistent	O
with	O
the	O
hypothesis	O
that	O
decreasing	O
M6P	O
/	O
IGF2R	O
expression	O
by	O
ribozyme	O
treatment	O
can	O
reduce	O
cell	O
apoptosis	O
.	O

Discussion	O

Some	O
62	O
,	O
000	O
,	O
000	O
Americans	O
have	O
one	O
or	O
more	O
types	O
of	O
cardiovascular	O
disease	O
(	O
CVD	O
)	O
and	O
CVD	O
is	O
the	O
leading	O
cause	O
(	O
40	O
.	O
1	O
%	O
)	O
of	O
death	O
in	O
the	O
United	O
States	O
.	O

Myocardial	O
infarction	O
and	O
heart	O
failure	O
,	O
conditions	O
accompanied	O
by	O
cardiac	O
myocyte	O
apoptosis	O
,	O
represent	O
23	O
%	O
of	O
all	O
CVDs	O
and	O
are	O
a	O
growing	O
clinical	O
challenge	O
in	O
need	O
of	O
novel	O
therapeutic	O
strategies	O
.	O

In	O
this	O
study	O
,	O
we	O
investigated	O
the	O
M6P	O
/	O
IGF2R	O
as	O
a	O
potential	O
new	O
therapeutic	O
target	O
for	O
reduction	O
of	O
cardiac	O
apoptosis	O
and	O
cardiac	O
injury	O
in	O
these	O
conditions	O
.	O

Using	O
ribozyme	O
technology	O
we	O
down	O
-	O
regulated	O
the	O
expression	O
of	O
the	O
M6P	O
/	O
IGF2R	O
in	O
neonatal	O
cardiac	O
myocytes	O
.	O

We	O
then	O
examined	O
cell	O
proliferation	O
and	O
apoptosis	O
under	O
normal	O
conditions	O
and	O
post	O
challenge	O
with	O
either	O
hypoxia	O
,	O
a	O
model	O
of	O
ischemia	O
-	O
reperfusion	O
,	O
or	O
TNF	O
-	O
alpha	O
,	O
a	O
cytokine	O
implicated	O
in	O
the	O
pathogenesis	O
of	O
chronic	O
heart	O
failure	O
[	O
19	O
]	O
.	O

Our	O
results	O
demonstrate	O
an	O
association	O
of	O
a	O
decrease	O
in	O
the	O
expression	O
and	O
function	O
of	O
the	O
M6P	O
/	O
IGF2R	O
with	O
increased	O
cell	O
proliferation	O
and	O
decreased	O
cell	O
susceptibility	O
to	O
hypoxia	O
-	O
and	O
TNF	O
-	O
induced	O
apoptosis	O
.	O

Expression	O
of	O
the	O
ribozyme	O
targeted	O
against	O
the	O
M6P	O
/	O
IGF2R	O
in	O
cardiomyocytes	O
resulted	O
in	O
down	O
-	O
regulation	O
of	O
M6P	O
/	O
IGF2R	O
expression	O
,	O
as	O
measured	O
by	O
RT	O
-	O
PCR	O
and	O
RPA	O
,	O
and	O
of	O
M6P	O
/	O
IGF2R	O
function	O
,	O
as	O
indicated	O
by	O
a	O
decrease	O
in	O
internalization	O
of	O
125I	O
-	O
IGF	O
-	O
II	O
,	O
and	O
beta	O
-	O
glucuronidase	O
binding	O
and	O
endocytosis	O
.	O

MTT	O
analysis	O
and	O
viable	O
cell	O
counts	O
showed	O
that	O
ribozyme	O
-	O
mediated	O
down	O
-	O
regulation	O
of	O
M6P	O
/	O
IGF2R	O
resulted	O
in	O
a	O
marked	O
increase	O
in	O
cell	O
proliferation	O
of	O
cardiomyocytes	O
,	O
which	O
normally	O
express	O
high	O
levels	O
of	O
M6P	O
/	O
IGF2R	O
[	O
20	O
]	O
and	O
have	O
limited	O
proliferative	O
capabilities	O
[	O
21	O
]	O
.	O

These	O
results	O
are	O
consistent	O
with	O
the	O
findings	O
of	O
previous	O
knockout	O
studies	O
[	O
9	O
,	O
10	O
]	O
.	O

Since	O
the	O
M6P	O
/	O
IGF2R	O
has	O
multiple	O
actions	O
on	O
cell	O
growth	O
,	O
its	O
proliferative	O
effect	O
on	O
the	O
heart	O
cells	O
observed	O
in	O
this	O
study	O
might	O
involve	O
multiple	O
mechanisms	O
.	O

However	O
,	O
it	O
is	O
likely	O
that	O
unchecked	O
IGF	O
-	O
II	O
stimulation	O
plays	O
a	O
key	O
role	O
in	O
the	O
effect	O
.	O

Because	O
the	O
M6P	O
/	O
IGF2R	O
is	O
believed	O
to	O
sequester	O
and	O
degrade	O
IGF	O
-	O
II	O
[	O
2	O
]	O
,	O
a	O
decrease	O
in	O
M6P	O
/	O
IGF2R	O
expression	O
and	O
function	O
could	O
result	O
in	O
decreased	O
degradation	O
and	O
hence	O
increased	O
bioavailability	O
of	O
IGF	O
-	O
II	O
to	O
the	O
IGF	O
-	O
I	O
receptor	O
,	O
which	O
mediates	O
the	O
growth	O
-	O
promoting	O
effect	O
of	O
IGF	O
-	O
II	O
.	O

Supporting	O
evidence	O
for	O
the	O
involvement	O
of	O
IGF	O
-	O
II	O
in	O
the	O
proliferative	O
effect	O
resulting	O
from	O
loss	O
of	O
M6P	O
/	O
IGF2R	O
function	O
comes	O
from	O
studies	O
of	O
M6P	O
/	O
IGF2R	O
knock	O
-	O
out	O
mice	B
.	O

M6P	O
/	O
IGF2R	O
-	O
null	O
mice	B
display	O
global	O
hyperplasia	O
that	O
coincides	O
with	O
elevated	O
levels	O
of	O
IGF	O
-	O
II	O
.	O

Most	O
importantly	O
,	O
however	O
,	O
the	O
lethal	O
nature	O
of	O
an	O
M6P	O
/	O
IGF2R	O
-	O
null	O
phenotype	O
is	O
reversed	O
in	O
an	O
IGF	O
-	O
II	O
-	O
null	O
background	O
[	O
9	O
]	O
.	O

Our	O
results	O
showing	O
that	O
ribozyme	O
-	O
mediated	O
down	O
-	O
regulation	O
of	O
M6P	O
/	O
IGF2R	O
lead	O
to	O
a	O
decrease	O
in	O
IGF	O
-	O
II	O
internalization	O
support	O
the	O
above	O
possibility	O
.	O

However	O
,	O
further	O
investigation	O
to	O
confirm	O
this	O
mechanism	O
is	O
warranted	O
.	O

More	O
importantly	O
,	O
our	O
results	O
also	O
showed	O
that	O
M6P	O
/	O
IGF2R	O
down	O
-	O
regulation	O
resulted	O
in	O
decreased	O
sensitivity	O
of	O
cardiomyocytes	O
to	O
hypoxia	O
-	O
and	O
TNF	O
-	O
induced	O
apoptosis	O
.	O

There	O
is	O
evidence	O
that	O
lysosomal	O
enzymes	O
,	O
such	O
as	O
cathepsins	O
B	O
and	O
D	O
contribute	O
to	O
hypoxia	O
-	O
and	O
TNF	O
-	O
induced	O
apoptosis	O
in	O
vitro	O
[	O
22	O
-	O
25	O
]	O
and	O
in	O
vivo	O
[	O
26	O
,	O
27	O
]	O
.	O

The	O
M6P	O
/	O
IGF2R	O
has	O
been	O
shown	O
to	O
be	O
involved	O
in	O
binding	O
,	O
transport	O
and	O
activation	O
of	O
lysosomal	O
enzymes	O
,	O
including	O
cathepsins	O
[	O
4	O
,	O
5	O
]	O
.	O

Therefore	O
,	O
it	O
is	O
possible	O
that	O
down	O
-	O
regulation	O
of	O
the	O
M6P	O
/	O
IGF2R	O
results	O
in	O
improper	O
trafficking	O
and	O
activation	O
of	O
cathepsins	O
.	O

This	O
,	O
in	O
turn	O
would	O
eliminate	O
the	O
apoptotic	O
cascades	O
triggered	O
by	O
these	O
enzymes	O
under	O
hypoxia	O
and	O
TNF	O
stimulation	O
and	O
result	O
in	O
decreased	O
sensitivity	O
of	O
cardiomyocytes	O
to	O
apoptosis	O
.	O

It	O
has	O
also	O
been	O
shown	O
that	O
TNF	O
stimulation	O
involves	O
the	O
activation	O
of	O
TGF	O
-	O
beta	O
[	O
28	O
-	O
30	O
]	O
,	O
a	O
ligand	O
of	O
M6P	O
/	O
IGF2R	O
that	O
has	O
been	O
implicated	O
in	O
the	O
progression	O
of	O
chronic	O
heart	O
failure	O
[	O
11	O
,	O
31	O
]	O
.	O

Therefore	O
,	O
down	O
-	O
regulation	O
of	O
M6P	O
/	O
IGF2R	O
expression	O
could	O
also	O
lead	O
to	O
a	O
decreased	O
bioavailability	O
of	O
activated	O
TGF	O
-	O
beta	O
,	O
thereby	O
decreasing	O
the	O
sensitivity	O
of	O
cardiomyocytes	O
to	O
the	O
TNF	O
/	O
TGF	O
-	O
beta	O
apoptotic	O
pathway	O
.	O

The	O
detailed	O
mechanism	O
of	O
the	O
observed	O
effects	O
is	O
unknown	O
and	O
requires	O
further	O
investigation	O
.	O

Conclusions	O

The	O
present	O
study	O
demonstrates	O
that	O
ribozyme	O
-	O
mediated	O
down	O
-	O
regulation	O
of	O
expression	O
and	O
functional	O
activity	O
of	O
the	O
M6P	O
/	O
IGF2R	O
results	O
in	O
a	O
decrease	O
in	O
the	O
susceptibility	O
of	O
cardiac	O
myocytes	O
to	O
apoptotic	O
stimuli	O
.	O

These	O
findings	O
suggest	O
that	O
this	O
receptor	O
might	O
be	O
involved	O
in	O
cardiac	O
cell	O
growth	O
and	O
apoptosis	O
.	O

The	O
ability	O
of	O
the	O
M6P	O
/	O
IGF2R	O
ribozyme	O
to	O
reduce	O
M6P	O
/	O
IGF2R	O
expression	O
and	O
function	O
in	O
transfected	O
cells	O
verifies	O
the	O
utility	O
of	O
the	O
ribozyme	O
in	O
studying	O
the	O
role	O
of	O
M6P	O
/	O
IGF2R	O
in	O
cardiomyocyte	O
growth	O
and	O
apoptosis	O
.	O

In	O
addition	O
to	O
its	O
utility	O
as	O
a	O
research	O
tool	O
,	O
the	O
ribozyme	O
,	O
with	O
further	O
exploration	O
and	O
development	O
,	O
might	O
have	O
potential	O
application	O
as	O
a	O
therapeutic	O
agent	O
to	O
prevent	O
cell	O
death	O
or	O
promote	O
mitogenesis	O
for	O
certain	O
clinical	O
conditions	O
,	O
such	O
as	O
,	O
myocardial	O
infarction	O
and	O
chronic	O
heart	O
failure	O
.	O

Methods	O

Construction	O
of	O
recombinant	O
M6P	O
/	O
IGF2R	O
-	O
RZ	O
adenoviral	O
vector	O

The	O
nucleotide	O
numbers	O
of	O
the	O
rat	B
M6P	O
/	O
IGF2R	O
sequence	O
targeted	O
by	O
the	O
hammerhead	O
ribozyme	O
is	O
1147	O
-	O
1160	O
after	O
coding	O
site	O
(	O
exon	O
9	O
)	O
.	O

The	O
structure	O
of	O
the	O
M6P	O
/	O
IGF2R	O
hammerhead	O
ribozyme	O
is	O
shown	O
in	O
Fig	O
.	O

1	O
.	O

A	O
49	O
bp	O
M6P	O
/	O
IGF2R	O
ribozyme	O
oligonucleotide	O
,	O
5	O
'	O
-	O
GAATTCCCC	O
ACACTG	O
ATGAGCCGCTTCGGCGGCGA	O
GCGT	O
-	O
3	O
'	O
and	O
the	O
corresponding	O
reverse	O
complementary	O
strand	O
were	O
synthesized	O
.	O

The	O
fragments	O
were	O
subcloned	O
to	O
produce	O
a	O
plasmid	O
containing	O
a	O
ribozyme	O
against	O
M6P	O
/	O
IGF2R	O
.	O

For	O
construction	O
of	O
the	O
recombinant	O
adenovirus	O
containing	O
the	O
M6P	O
/	O
IGF2R	O
-	O
ribozyme	O
(	O
pAd	O
-	O
GFP	O
/	O
IGF2R	O
-	O
Rz	O
)	O
,	O
the	O
segments	O
containing	O
the	O
ribozymes	O
were	O
amplified	O
by	O
PCR	O
and	O
cloned	O
into	O
a	O
pAdTrack	O
-	O
CMV	O
vector	O
and	O
then	O
recombined	O
homologously	O
with	O
an	O
adenoviral	O
backbone	O
pAdEasy	O
1	O
vector	O
to	O
generate	O
(	O
pAd	O
-	O
GFP	O
/	O
IGF2R	O
-	O
Rz	O
)	O
,	O
following	O
the	O
protocol	O
described	O
by	O
He	O
et	O
al	O
.	O

[	O
32	O
]	O
.	O

The	O
pAd	O
-	O
GFP	O
/	O
IGF2R	O
-	O
Rz	O
carries	O
both	O
the	O
IGF2R	O
-	O
Rz	O
and	O
GFP	O
(	O
as	O
reporter	O
)	O
genes	O
,	O
each	O
under	O
the	O
control	O
of	O
separate	O
cytomegalovirus	O
(	O
CMV	O
)	O
promoters	O
.	O

Another	O
viral	O
vector	O
,	O
pAd	O
-	O
GFP	O
,	O
which	O
carries	O
the	O
GFP	O
gene	O
only	O
under	O
the	O
control	O
of	O
the	O
CMV	O
promoter	O
,	O
was	O
generated	O
and	O
used	O
as	O
a	O
control	O
vector	O
.	O

The	O
adenoviral	O
vector	O
DNA	O
were	O
linerized	O
with	O
Pac	O
I	O
and	O
transfected	O
into	O
the	O
replication	O
-	O
permissive	O
293	O
cells	O
(	O
E1A	O
transcomplementing	O
cell	O
line	O
)	O
by	O
using	O
Lipofectamine	O
(	O
Life	O
Technologies	O
)	O
to	O
produce	O
E1	O
-	O
deleted	O
,	O
replication	O
-	O
defective	O
recombinant	O
adenovirus	O
as	O
described	O
previously	O
[	O
33	O
]	O
.	O

Large	O
-	O
scale	O
amplification	O
of	O
recombinant	O
adenovirus	O
in	O
293	O
cells	O
was	O
followed	O
by	O
purification	O
using	O
a	O
discontinuous	O
CsCl	O
gradient	O
.	O

The	O
constructs	O
were	O
confirmed	O
by	O
enzymatic	O
digestion	O
and	O
DNA	O
sequencing	O
.	O

Transcription	O
and	O
cleavage	O
reaction	O
of	O
ribozyme	O
in	O
vitro	O

Plasmids	O
containing	O
the	O
ribozyme	O
or	O
the	O
substrate	O
(	O
either	O
45	O
bp	O
of	O
M6P	O
/	O
IGF2R	O
mRNA	O
or	O
an	O
unmatched	O
sequence	O
5	O
'	O
-	O
GTGCTGTCTGTATG	O
-	O
3	O
'	O
)	O
were	O
linearized	O
with	O
MluI	O
,	O
respectively	O
.	O

All	O
transcripts	O
were	O
generated	O
with	O
T7	O
RNA	O
polymerase	O
(	O
Promega	O
)	O
.	O

Substrate	O
transcripts	O
were	O
labeled	O
by	O
incorporation	O
of	O
[	O
alpha	O
-	O
32P	O
]	O
UTP	O
(	O
NEN	O
Life	O
Science	O
Products	O
,	O
Inc	O
.	O
)	O
.	O

Specific	O
activity	O
of	O
the	O
[	O
alpha	O
-	O
32P	O
]	O
UTP	O
(	O
10	O
mu	O
Ci	O
/	O
mu	O
l	O
)	O
and	O
the	O
base	O
composition	O
of	O
each	O
substrate	O
molecule	O
were	O
used	O
to	O
calculate	O
the	O
substrate	O
concentration	O
.	O

Ribozyme	O
transcripts	O
were	O
quantified	O
spectrophotometrical	O
.	O

(	O
The	O
half	O
-	O
life	O
of	O
the	O
M6P	O
/	O
IGF2R	O
target	O
is	O
about	O
280	O
minutes	O
)	O
.	O

Cleavage	O
reaction	O
mixture	O
contained	O
substrate	O
RNA	O
(	O
40	O
nM	O
)	O
,	O
increasing	O
amounts	O
of	O
ribozyme	O
(	O
60	O
nM	O
)	O
,	O
20	O
mM	O
MgCl2	O
and	O
20	O
mM	O
Tris	O
-	O
HCl	O
,	O
pH8	O
.	O
0	O
,	O
in	O
a	O
final	O
volume	O
of	O
10	O
mu	O
l	O
.	O

The	O
mixture	O
was	O
incubated	O
at	O
37	O
degrees	O
C	O
for	O
a	O
time	O
-	O
course	O
of	O
cleavage	O
reaction	O
from	O
0	O
,	O
5	O
,	O
10	O
,	O
20	O
,	O
40	O
,	O
80	O
,	O
160	O
,	O
320	O
,	O
to	O
640	O
minutes	O
and	O
the	O
cleavage	O
reaction	O
was	O
stopped	O
by	O
addition	O
of	O
loading	O
buffer	O
(	O
80	O
%	O
formamide	O
,	O
10	O
mM	O
Na2EDTA	O
,	O
pH	O
8	O
.	O
0	O
,	O
and	O
1	O
mg	O
/	O
ml	O
each	O
bromophenol	O
blue	O
and	O
xylene	O
cyanol	O
)	O
.	O

Cleavage	O
products	O
were	O
analyzed	O
on	O
a	O
15	O
%	O
polyacrylamide	O
and	O
8M	O
urea	O
gel	O
.	O

Product	O
and	O
substrate	O
fragments	O
were	O
quantitated	O
by	O
using	O
NIH	O
Imager	O
.	O

Cell	O
cultures	O
and	O
infection	O
with	O
Ad	O
-	O
GFP	O
/	O
Rz	O
-	O
IGF2R	O
and	O
Ad	O
-	O
GFP	O

Cardiac	O
myocytes	O
were	O
isolated	O
from	O
1	O
-	O
day	O
-	O
old	O
newborn	O
rats	B
using	O
the	O
Neonatal	O
Cardiomyocyte	O
Isolation	O
System	O
(	O
Worthington	O
)	O
.	O

The	O
isolated	O
cells	O
were	O
plated	O
in	O
6	O
-	O
well	O
plates	O
and	O
cultured	O
in	O
F	O
-	O
10	O
medium	O
containing	O
5	O
%	O
(	O
vol	O
/	O
vol	O
)	O
FBS	O
and	O
10	O
%	O
(	O
vol	O
/	O
vol	O
)	O
horse	B
serum	O
at	O
37	O
degrees	O
C	O
in	O
a	O
tissue	O
culture	O
incubator	O
with	O
5	O
%	O
CO2	O
and	O
98	O
%	O
relative	O
humidity	O
.	O

Cells	O
were	O
used	O
for	O
experiments	O
after	O
2	O
-	O
3	O
days	O
of	O
culture	O
.	O

Viral	O
infections	O
were	O
carried	O
out	O
by	O
adding	O
viral	O
particles	O
at	O
various	O
concentrations	O
(	O
usually	O
,	O
2	O
x	O
108	O
virus	O
particles	O
/	O
ml	O
)	O
to	O
culture	O
medium	O
containing	O
2	O
%	O
(	O
vol	O
/	O
vol	O
)	O
FBS	O
.	O

Initially	O
,	O
optimal	O
viral	O
concentration	O
was	O
determined	O
by	O
using	O
Ad	O
-	O
GFP	O
to	O
achieve	O
an	O
optimal	O
balance	O
of	O
high	O
gene	O
expression	O
and	O
low	O
viral	O
titer	O
to	O
minimize	O
cytotoxicity	O
.	O

After	O
24	O
hours	O
of	O
incubation	O
,	O
the	O
infection	O
medium	O
was	O
replaced	O
with	O
normal	O
(	O
15	O
%	O
vol	O
/	O
vol	O
serum	O
)	O
culture	O
medium	O
.	O

For	O
treatment	O
with	O
IGF	O
-	O
II	O
,	O
cells	O
were	O
incubated	O
with	O
50	O
ng	O
/	O
ml	O
IGF	O
-	O
II	O
after	O
24	O
hours	O
infection	O
with	O
Ad	O
-	O
GFP	O
/	O
IGF2R	O
-	O
Rz	O
or	O
Ad	O
-	O
GFP	O
.	O

Four	O
days	O
after	O
infection	O
,	O
cells	O
were	O
used	O
for	O
analysis	O
of	O
gene	O
expression	O
of	O
M6P	O
/	O
IGF2R	O
and	O
its	O
effect	O
on	O
cell	O
growth	O
and	O
apoptosis	O
.	O

Analysis	O
of	O
gene	O
expression	O
in	O
cardiac	O
myocytes	O

The	O
M6P	O
/	O
IGF2R	O
transcripts	O
were	O
determined	O
by	O
both	O
RT	O
-	O
PCR	O
and	O
Ribonuclease	O
Protection	O
Assay	O
(	O
RPA	O
)	O
.	O

RT	O
-	O
PCR	O
was	O
performed	O
using	O
the	O
GeneAmp	O
EZ	O
rTth	O
RNA	O
PCR	O
kit	O
(	O
Roche	O
)	O
.	O

Total	O
RNA	O
was	O
extracted	O
from	O
cultured	O
cells	O
using	O
an	O
RNA	O
isolation	O
kit	O
(	O
Qiagen	O
,	O
)	O
,	O
according	O
to	O
the	O
manufacturer	O
'	O
s	O
protocol	O
.	O

M6P	O
/	O
IGF2R	O
transcripts	O
were	O
amplified	O
using	O
the	O
primers	O
(	O
5	O
'	O
-	O
GACAGGCTCGTTCTGACTTA	O
-	O
3	O
'	O
)	O
and	O
(	O
5	O
'	O
-	O
CTTCCACTCTTATCCACAGC	O
-	O
3	O
'	O
)	O
specific	O
to	O
the	O
M6P	O
/	O
IGF2R	O
.	O

Each	O
RT	O
-	O
PCR	O
assay	O
was	O
performed	O
in	O
triplicate	O
and	O
product	O
levels	O
varied	O
by	O
less	O
than	O
3	O
.	O
2	O
%	O
for	O
each	O
RNA	O
sample	O
.	O

Primers	O
specific	O
for	O
beta	O
-	O
actin	O
cDNA	O
were	O
added	O
to	O
a	O
parallel	O
reaction	O
to	O
standardize	O
for	O
variations	O
in	O
PCR	O
between	O
samples	O
.	O

PCR	O
products	O
were	O
resolved	O
on	O
a	O
1	O
.	O
0	O
%	O
agarose	O
gel	O
,	O
visualized	O
under	O
UV	O
light	O
and	O
quantitated	O
using	O
NIH	O
Imager	O
.	O

RPA	O
was	O
performed	O
using	O
the	O
RPA	O
III	O
kit	O
(	O
Ambion	O
,	O
Austin	O
,	O
TX	O
)	O
.	O

Briefly	O
,	O
total	O
RNA	O
was	O
extracted	O
from	O
cultured	O
cells	O
using	O
a	O
total	O
RNA	O
isolation	O
reagent	O
(	O
TRIzol	O
,	O
Gibco	O
BRL	O
)	O
according	O
to	O
the	O
manufacturer	O
'	O
s	O
protocol	O
.	O

The	O
plasmid	O
containing	O
the	O
rat	B
M6P	O
/	O
IGF2R	O
gene	O
was	O
linearized	O
and	O
used	O
as	O
a	O
transcription	O
template	O
.	O

Antisense	O
RNA	O
probes	O
were	O
transcribed	O
in	O
vitro	O
using	O
[	O
33P	O
]	O
-	O
UTP	O
,	O
T7	O
polymerase	O
(	O
Riboprobea	O
System	O
T7	O
kit	O
,	O
Promega	O
)	O
,	O
hybridized	O
with	O
the	O
total	O
RNA	O
extracted	O
from	O
the	O
rat	B
cardiomyocytes	O
,	O
and	O
digested	O
with	O
ribonuclease	O
to	O
remove	O
non	O
-	O
hybridized	O
RNA	O
and	O
probe	O
.	O

The	O
protected	O
RNA	O
.	O
RNA	O
was	O
resolved	O
on	O
a	O
denaturing	O
5	O
%	O
sequence	O
gel	O
and	O
subjected	O
to	O
autoradiography	O
.	O

A	O
probe	O
targeting	O
the	O
GAPDH	O
gene	O
was	O
used	O
as	O
an	O
internal	O
control	O
.	O

Measurement	O
of	O
125I	O
-	O
IGF	O
-	O
II	O
internalization	O

Cells	O
were	O
incubated	O
at	O
37	O
degrees	O
C	O
for	O
2	O
hrs	O
in	O
serum	O
-	O
free	O
F	O
-	O
10	O
culture	O
medium	O
containing	O
125I	O
-	O
labeled	O
IGF	O
-	O
II	O
(	O
0	O
.	O
5	O
ng	O
/	O
ml	O
)	O
with	O
or	O
without	O
excess	O
unlabeled	O
IGF	O
-	O
II	O
(	O
2	O
mu	O
g	O
/	O
ml	O
)	O
.	O

Following	O
the	O
incubation	O
,	O
the	O
cells	O
were	O
washed	O
three	O
times	O
with	O
ice	O
-	O
cold	O
PBS	O
,	O
and	O
cell	O
-	O
associated	O
radioactivity	O
was	O
determined	O
by	O
a	O
gamma	O
counter	O
.	O

Specific	O
internalized	O
125I	O
-	O
IGF	O
-	O
II	O
was	O
calculated	O
by	O
subtracting	O
the	O
count	O
of	O
samples	O
with	O
excessive	O
unlabeled	O
IGF	O
-	O
II	O
from	O
that	O
without	O
unlabeled	O
IGF	O
-	O
II	O
,	O
and	O
normalized	O
to	O
protein	O
contents	O
.	O

Beta	O
-	O
glucuronidase	O
binding	O
assay	O

Binding	O
of	O
beta	O
-	O
glucuronidase	O
was	O
assayed	O
as	O
described	O
previously	O
[	O
34	O
,	O
35	O
]	O
.	O

Briefly	O
,	O
cells	O
were	O
permeabilized	O
with	O
0	O
.	O
25	O
%	O
saponin	O
in	O
50	O
mM	O
Hepes	O
(	O
pH	O
7	O
.	O
0	O
)	O
,	O
150	O
mM	O
NaCl	O
,	O
5	O
mM	O
beta	O
-	O
glycerophosphate	O
,	O
0	O
.	O
5	O
%	O
human	B
serum	O
albumin	O
,	O
and	O
10	O
mM	O
mannose	O
-	O
6	O
-	O
phosphate	O
(	O
M6P	O
)	O
for	O
30	O
minutes	O
on	O
ice	O
.	O

The	O
cells	O
were	O
washed	O
three	O
times	O
with	O
ice	O
-	O
cold	O
PBS	O
containing	O
0	O
.	O
05	O
%	O
saponin	O
.	O

They	O
were	O
incubated	O
with	O
20	O
,	O
000	O
units	O
/	O
ml	O
beta	O
-	O
glucuronidase	O
from	O
bovine	B
liver	O
(	O
Sigma	O
)	O
in	O
50	O
mM	O
Hepes	O
(	O
pH	O
7	O
.	O
5	O
)	O
containing	O
150	O
mM	O
NaCl	O
,	O
5	O
mM	O
beta	O
-	O
glycerophosphate	O
,	O
0	O
.	O
5	O
%	O
human	B
serum	O
albumin	O
,	O
0	O
.	O
5	O
%	O
saponin	O
with	O
or	O
without	O
10	O
mM	O
M6P	O
overnight	O
on	O
ice	O
.	O

Cells	O
were	O
washed	O
five	O
times	O
with	O
ice	O
-	O
cold	O
PBS	O
containing	O
0	O
.	O
05	O
%	O
saponin	O
and	O
sonicated	O
in	O
100	O
mM	O
sodium	O
acetate	O
(	O
pH	O
4	O
.	O
6	O
)	O
.	O

The	O
protein	O
concentration	O
of	O
solubilized	O
cell	O
extract	O
was	O
measured	O
and	O
enzyme	O
activity	O
was	O
assayed	O
as	O
follows	O
:	O
for	O
each	O
reaction	O
50	O
ul	O
cell	O
extract	O
were	O
added	O
to	O
500	O
ul	O
of	O
100	O
mM	O
sodium	O
acetate	O
(	O
pH	O
4	O
.	O
0	O
)	O
containing	O
1	O
mM	O
paranitrophenyl	O
(	O
PNP	O
)	O
-	O
beta	O
-	O
glucuronide	O
(	O
Sigma	O
)	O
as	O
substrate	O
.	O

After	O
an	O
incubation	O
period	O
of	O
3	O
hours	O
at	O
37	O
degrees	O
C	O
,	O
500	O
ul	O
1	O
M	O
Na2CO3	O
were	O
added	O
to	O
each	O
reaction	O
and	O
the	O
absorbance	O
was	O
measured	O
at	O
400	O
nm	O
.	O

Experimental	O
values	O
were	O
compared	O
to	O
a	O
standard	O
curve	O
that	O
was	O
constructed	O
using	O
1	O
-	O
100	O
nM	O
solutions	O
of	O
PNP	O
(	O
Sigma	O
)	O
in	O
500	O
ul	O
100	O
mM	O
sodium	O
acetate	O
and	O
500	O
u1	O
1	O
M	O
Na2CO3	O
.	O

Specific	O
activity	O
was	O
calculated	O
as	O
nM	O
of	O
PNP	O
produced	O
/	O
hour	O
/	O
mg	O
of	O
protein	O
.	O

Beta	O
-	O
glucuronidase	O
endocytosis	O
assay	O

Beta	O
-	O
glucuronidase	O
endocytosis	O
assay	O
was	O
carried	O
out	O
as	O
described	O
previously	O
[	O
36	O
]	O
.	O

Briefly	O
,	O
confluent	O
cell	O
cultures	O
were	O
washed	O
twice	O
with	O
pre	O
-	O
warmed	O
serum	O
-	O
free	O
DMEM	O
followed	O
by	O
incubation	O
with	O
DMEM	O
containing	O
5	O
mg	O
/	O
ml	O
human	B
serum	O
albumin	O
and	O
10	O
mM	O
M6P	O
for	O
20	O
minutes	O
.	O

Following	O
incubation	O
cells	O
were	O
washed	O
3	O
times	O
with	O
pre	O
-	O
warmed	O
DMEM	O
.	O

Cells	O
were	O
then	O
incubated	O
in	O
DMEM	O
containing	O
5	O
mg	O
/	O
ml	O
human	B
serum	O
albumin	O
alone	O
or	O
4000	O
units	O
beta	O
-	O
glucuronidase	O
with	O
or	O
without	O
10	O
mM	O
M6P	O
for	O
2	O
hours	O
at	O
37	O
degrees	O
C	O
.	O

Following	O
the	O
incubation	O
,	O
the	O
cells	O
were	O
washed	O
5	O
times	O
with	O
ice	O
-	O
cold	O
PBS	O
and	O
subjected	O
to	O
enzyme	O
activity	O
assay	O
as	O
described	O
above	O
.	O

Cell	O
proliferation	O
assay	O
(	O
MTT	O
assay	O
and	O
cell	O
counts	O
)	O

Cardiac	O
myocytes	O
were	O
grown	O
in	O
culture	O
plates	O
(	O
tissue	O
culture	O
grade	O
,	O
12	O
wells	O
,	O
flat	O
bottom	O
)	O
in	O
a	O
final	O
volume	O
of	O
1	O
ml	O
serum	O
-	O
containing	O
culture	O
medium	O
per	O
well	O
,	O
in	O
a	O
humidified	O
atmosphere	O
(	O
37	O
degrees	O
C	O
and	O
5	O
%	O
C02	O
)	O
for	O
3	O
days	O
.	O

After	O
infection	O
with	O
Ad	O
-	O
GFP	O
/	O
IGF2R	O
-	O
Rz	O
or	O
Ad	O
-	O
GFP	O
,	O
cells	O
were	O
incubated	O
with	O
or	O
without	O
50	O
ng	O
/	O
ml	O
IGF	O
-	O
II	O
for	O
4	O
days	O
.	O

Following	O
supplementation	O
with	O
IGF	O
-	O
II	O
,	O
100	O
mu	O
l	O
MTT	O
labeling	O
reagent	O
(	O
Roche	O
)	O
were	O
added	O
to	O
each	O
well	O
and	O
cells	O
were	O
incubated	O
for	O
4	O
hours	O
,	O
followed	O
by	O
addition	O
of	O
1	O
ml	O
solubilization	O
solution	O
into	O
each	O
well	O
.	O

The	O
plate	O
was	O
placed	O
in	O
an	O
incubator	O
at	O
37	O
degrees	O
C	O
overnight	O
.	O

Spectrophotometrical	O
absorbency	O
of	O
the	O
samples	O
was	O
measured	O
using	O
an	O
UV	O
-	O
visible	O
Recording	O
Spectrophotometer	O
with	O
wavelength	O
of	O
550	O
-	O
690	O
nm	O
.	O

In	O
addition	O
,	O
the	O
total	O
number	O
of	O
viable	O
cells	O
in	O
each	O
treatment	O
was	O
counted	O
by	O
trypan	O
blue	O
exclusion	O
method	O
using	O
a	O
hemocytometer	O
.	O

Induction	O
and	O
analysis	O
of	O
cell	O
apoptosis	O

Cells	O
were	O
infected	O
with	O
Ad	O
-	O
GFP	O
or	O
Ad	O
-	O
GFP	O
/	O
IGF2R	O
-	O
Rz	O
.	O

Seventy	O
-	O
two	O
hours	O
post	O
infection	O
,	O
cells	O
were	O
treated	O
with	O
TNF	O
(	O
0	O
.	O
1	O
ng	O
/	O
ml	O
)	O
for	O
24	O
hrs	O
or	O
subjected	O
to	O
hypoxia	O
.	O

For	O
induction	O
of	O
apoptosis	O
by	O
hypoxia	O
,	O
cell	O
culture	O
medium	O
was	O
changed	O
to	O
serum	O
-	O
free	O
F	O
-	O
10	O
saturated	O
with	O
95	O
%	O
N2	O
/	O
5	O
%	O
CO2	O
and	O
cells	O
were	O
placed	O
in	O
a	O
37	O
degrees	O
C	O
airtight	O
box	O
saturated	O
with	O
95	O
%	O
N2	O
/	O
5	O
%	O
CO2	O
for	O
24	O
hrs	O
.	O

For	O
normoxic	O
controls	O
,	O
culture	O
medium	O
was	O
changed	O
to	O
F	O
-	O
10	O
/	O
5	O
%	O
F	O
BS	O
/	O
10	O
%	O
HS	O
and	O
cells	O
were	O
placed	O
in	O
a	O
37	O
degrees	O
C	O
/	O
5	O
%	O
CO2	O
incubator	O
for	O
24	O
hrs	O
before	O
analysis	O
.	O

Apoptotic	O
cells	O
were	O
identified	O
by	O
Hoechst	O
staining	O
using	O
the	O
Vybrant	O
(	O
TM	O
)	O
Apoptosis	O
Kit	O
#	O
5	O
(	O
Molecular	O
Probes	O
)	O
according	O
to	O
the	O
manufacturer	O
'	O
s	O
protocol	O
.	O

In	O
addition	O
,	O
after	O
infection	O
with	O
Ad	O
-	O
GFP	O
or	O
Ad	O
-	O
GFP	O
/	O
IGF2R	O
-	O
Rz	O
and	O
challenge	O
with	O
either	O
TNF	O
or	O
hypoxia	O
,	O
cell	O
viability	O
was	O
assessed	O
using	O
the	O
MTT	O
assay	O
Kit	O
(	O
Roche	O
Molecular	O
Biochemicals	O
)	O
and	O
cell	O
apoptosis	O
was	O
determined	O
using	O
the	O
Cell	O
Death	O
Detection	O
ELISA	O
Kit	O
assay	O
(	O
Roche	O
Molecular	O
Biochemicals	O
)	O
according	O
to	O
the	O
manufacturer	O
'	O
s	O
protocol	O
.	O

Statistical	O
analysis	O

Students	O
'	O
t	O
-	O
test	O
was	O
used	O
to	O
evaluate	O
the	O
difference	O
between	O
two	O
values	O
.	O

Each	O
experiment	O
was	O
repeated	O
at	O
least	O
three	O
times	O
.	O

Statistical	O
significance	O
was	O
accepted	O
at	O
the	O
level	O
of	O
p	O
<	O
0	O
.	O
05	O
.	O

List	O
of	O
abbreviations	O
used	O

Ad	O
-	O
GFP	O
,	O
adenovirus	O
carrying	O
GFP	O
gene	O
;	O
Ad	O
-	O
GFP	O
/	O
IGF2R	O
-	O
Rz	O
,	O
adenovirus	O
carrying	O
both	O
the	O
ribozyme	O
against	O
M6P	O
/	O
IGF2R	O
and	O
the	O
GFP	O
gene	O
;	O
GFP	O
,	O
green	O
fluorescent	O
protein	O
;	O
IGF	O
-	O
II	O
,	O
insulin	O
-	O
like	O
growth	O
factor	O
II	O
;	O
M6P	O
/	O
IGF2R	O
,	O
mannose	O
6	O
-	O
phosphate	O
/	O
insulin	O
-	O
like	O
growth	O
factor	O
II	O
receptor	O
;	O
Rz	O
,	O
ribozyme	O
.	O

Authors	O
'	O
contributions	O

ZC	O
carried	O
out	O
construction	O
of	O
the	O
ribozyme	O
,	O
production	O
of	O
the	O
viruses	O
,	O
cellular	O
experiments	O
,	O
biochemical	O
assays	O
and	O
data	O
analysis	O
.	O

YG	O
carried	O
out	O
the	O
RPA	O
assay	O
and	O
participated	O
in	O
the	O
molecular	O
biological	O
studies	O
.	O

JXK	O
conceived	O
of	O
the	O
study	O
,	O
participated	O
in	O
its	O
design	O
and	O
coordination	O
,	O
and	O
drafted	O
the	O
manuscript	O
.	O

SledgeHMMER	O
:	O
a	O
web	O
server	O
for	O
batch	O
searching	O
the	O
Pfam	O
database	O

Abstract	O

The	O
SledgeHMMER	O
web	O
server	O
is	O
intended	O
for	O
genome	O
-	O
scale	O
searching	O
of	O
the	O
Pfam	O
database	O
without	O
having	O
to	O
install	O
this	O
database	O
and	O
the	O
HMMER	O
software	O
locally	O
.	O

The	O
server	O
implements	O
a	O
parallelized	O
version	O
of	O
hmmpfam	O
,	O
the	O
program	O
used	O
for	O
searching	O
the	O
Pfam	O
HMM	O
database	O
.	O

Pfam	O
search	O
results	O
have	O
been	O
calculated	O
for	O
the	O
entire	O
Swiss	O
-	O
Prot	O
and	O
TrEmbl	O
database	O
sequences	O
(	O
~	O
1	O
.	O
2	O
million	O
)	O
on	O
256	O
processors	O
of	O
IA64	O
-	O
based	O
teragrid	O
machines	O
.	O

The	O
Pfam	O
database	O
can	O
be	O
searched	O
in	O
local	O
,	O
glocal	O
or	O
merged	O
mode	O
,	O
using	O
either	O
gathering	O
or	O
E	O
-	O
value	O
thresholds	O
.	O

Query	O
sequences	O
are	O
first	O
matched	O
against	O
the	O
pre	O
-	O
calculated	O
entries	O
to	O
retrieve	O
results	O
,	O
and	O
those	O
without	O
matches	O
are	O
processed	O
through	O
a	O
new	O
search	O
process	O
.	O

Results	O
are	O
emailed	O
in	O
a	O
space	O
-	O
delimited	O
tabular	O
format	O
upon	O
completion	O
of	O
the	O
search	O
.	O

While	O
most	O
other	O
Pfam	O
-	O
searching	O
web	O
servers	O
set	O
a	O
limit	O
of	O
one	O
sequence	O
per	O
query	O
,	O
this	O
server	O
processes	O
batch	O
sequences	O
with	O
no	O
limit	O
on	O
the	O
number	O
of	O
input	O
sequences	O
.	O

The	O
web	O
server	O
and	O
downloadable	O
data	O
are	O
accessible	O
from	O
http	O
:	O
/	O
/	O
SledgeHmmer	O
.	O
sdsc	O
.	O
edu	O
.	O

INTRODUCTION	O

Searching	O
for	O
conserved	O
domains	O
has	O
become	O
an	O
integral	O
part	O
of	O
several	O
bioinformatics	O
data	O
analysis	O
pipelines	O
.	O

The	O
Pfam	O
protein	O
families	O
database	O
[	O
(	O
1	O
)	O
;	O
http	O
:	O
/	O
/	O
pfam	O
.	O
wustl	O
.	O
edu	O
]	O
contains	O
the	O
single	O
largest	O
public	O
collection	O
of	O
conserved	O
functional	O
domains	O
and	O
hence	O
is	O
integrated	O
into	O
many	O
bioinformatics	O
resources	O
.	O

The	O
current	O
version	O
(	O
release	O
12	O
)	O
of	O
the	O
Pfam	O
-	O
A	O
database	O
contains	O
7316	O
HMM	O
domains	O
,	O
making	O
it	O
an	O
indispensable	O
resource	O
for	O
protein	O
functional	O
annotation	O
(	O
2	O
)	O
.	O

However	O
,	O
the	O
size	O
of	O
the	O
Pfam	O
database	O
is	O
quite	O
large	O
(	O
~	O
600	O
MB	O
)	O
and	O
genome	O
-	O
scale	O
searching	O
of	O
protein	O
sequences	O
against	O
this	O
database	O
is	O
a	O
highly	O
compute	O
-	O
intensive	O
task	O
.	O

Hence	O
,	O
with	O
the	O
exception	O
of	O
the	O
Sanger	O
Center	O
web	O
server	O
(	O
http	O
:	O
/	O
/	O
www	O
.	O
sanger	O
.	O
ac	O
.	O
uk	O
/	O
Software	O
/	O
Pfam	O
)	O
,	O
all	O
other	O
Pfam	O
-	O
searching	O
servers	O
permit	O
submission	O
of	O
only	O
one	O
protein	O
sequence	O
at	O
a	O
time	O
(	O
http	O
:	O
/	O
/	O
pfam	O
.	O
wustl	O
.	O
edu	O
,	O
http	O
:	O
/	O
/	O
pfam	O
.	O
jouy	O
.	O
inra	O
.	O
fr	O
,	O
http	O
:	O
/	O
/	O
pfam	O
.	O
cgb	O
.	O
ki	O
.	O
se	O
)	O
.	O

Currently	O
,	O
the	O
Sanger	O
Center	O
web	O
server	O
limits	O
batch	O
submission	O
to	O
1000	O
sequences	O
at	O
a	O
time	O
.	O

Other	O
than	O
this	O
,	O
for	O
batch	O
searching	O
,	O
users	O
are	O
required	O
to	O
install	O
the	O
Pfam	O
database	O
and	O
the	O
HMMER	O
software	O
[	O
(	O
3	O
)	O
;	O
http	O
:	O
/	O
/	O
hmmer	O
.	O
wustl	O
.	O
edu	O
)	O
locally	O
.	O

Given	O
the	O
size	O
and	O
dynamic	O
nature	O
of	O
this	O
database	O
(	O
14	O
updates	O
in	O
the	O
last	O
two	O
years	O
)	O
,	O
it	O
is	O
not	O
convenient	O
to	O
maintain	O
the	O
latest	O
versions	O
of	O
these	O
tools	O
locally	O
.	O

Moreover	O
,	O
the	O
hmmpfam	O
program	O
used	O
for	O
searching	O
the	O
Pfam	O
database	O
is	O
very	O
slow	O
and	O
memory	O
intensive	O
(	O
on	O
Solaris	O
machines	O
,	O
the	O
processing	O
speed	O
is	O
about	O
10	O
sequences	O
per	O
1	O
h	O
of	O
CPU	O
time	O
)	O
,	O
making	O
this	O
process	O
a	O
bottleneck	O
in	O
several	O
data	O
analysis	O
pipelines	O
.	O

Web	O
servers	O
that	O
enable	O
batch	O
searching	O
of	O
the	O
Pfam	O
database	O
are	O
extremely	O
beneficial	O
to	O
the	O
user	O
community	O
,	O
especially	O
to	O
those	O
without	O
local	O
access	O
to	O
high	O
-	O
end	O
computational	O
power	O
,	O
memory	O
and	O
disk	O
space	O
.	O

To	O
this	O
end	O
we	O
have	O
developed	O
a	O
parallelized	O
version	O
,	O
as	O
well	O
as	O
an	O
optimized	O
single	O
-	O
processor	O
version	O
,	O
of	O
hmmpfam	O
from	O
release	O
2	O
.	O
3	O
.	O
2	O
of	O
the	O
HMMER	O
software	O
,	O
as	O
described	O
in	O
the	O
next	O
section	O
.	O

Using	O
these	O
programs	O
,	O
we	O
present	O
the	O
SledgeHMMER	O
web	O
server	O
(	O
http	O
:	O
/	O
/	O
SledgeHmmer	O
.	O
sdsc	O
.	O
edu	O
)	O
,	O
which	O
is	O
capable	O
of	O
batch	O
searching	O
a	O
large	O
number	O
of	O
protein	O
sequences	O
concurrently	O
.	O

DESIGN	O
AND	O
IMPLEMENTATION	O

The	O
current	O
web	O
service	O
is	O
mainly	O
intended	O
for	O
genome	O
-	O
scale	O
searching	O
of	O
the	O
Pfam	O
-	O
A	O
database	O
.	O

Searches	O
are	O
possible	O
for	O
different	O
Pfam	O
-	O
searching	O
modes	O
such	O
as	O
local	O
,	O
glocal	O
and	O
merged	O
,	O
using	O
either	O
gathering	O
or	O
E	O
-	O
value	O
thresholds	O
.	O

To	O
expedite	O
the	O
response	O
time	O
,	O
we	O
developed	O
a	O
database	O
containing	O
pre	O
-	O
calculated	O
Pfam	O
search	O
results	O
.	O

Query	O
sequences	O
are	O
matched	O
against	O
the	O
pre	O
-	O
calculated	O
entries	O
using	O
hexadecimal	O
hashing	O
methods	O
from	O
the	O
MD5	O
Perl	O
module	O
,	O
and	O
those	O
without	O
matches	O
are	O
separated	O
out	O
.	O

Results	O
for	O
matching	O
sequences	O
are	O
retrieved	O
from	O
the	O
pre	O
-	O
calculated	O
database	O
while	O
,	O
for	O
other	O
sequences	O
,	O
a	O
new	O
search	O
process	O
is	O
initiated	O
using	O
our	O
improved	O
hmmpfam	O
program	O
.	O

Results	O
are	O
emailed	O
in	O
a	O
space	O
-	O
delimited	O
tabular	O
format	O
upon	O
completion	O
of	O
the	O
search	O
.	O

Parallelizing	O
the	O
hmmpfam	O
algorithm	O

Computing	O
batch	O
searches	O
against	O
the	O
Pfam	O
database	O
is	O
a	O
two	O
-	O
dimensional	O
(	O
2D	O
)	O
problem	O
,	O
i	O
.	O
e	O
.	O
searching	O
N	O
query	O
sequences	O
against	O
M	O
Pfam	O
HMMs	O
.	O

Thus	O
,	O
this	O
problem	O
can	O
be	O
parallelized	O
across	O
any	O
dimension	O
or	O
across	O
both	O
dimensions	O
.	O

A	O
minor	O
disadvantage	O
of	O
parallelizing	O
across	O
the	O
M	O
dimension	O
is	O
that	O
a	O
global	O
gather	O
needs	O
to	O
be	O
performed	O
at	O
the	O
end	O
of	O
the	O
computation	O
to	O
identify	O
the	O
best	O
matched	O
HMM	O
models	O
.	O

Along	O
the	O
N	O
dimension	O
the	O
computation	O
is	O
completely	O
independent	O
,	O
however	O
;	O
due	O
to	O
the	O
variation	O
in	O
the	O
query	O
sequence	O
lengths	O
,	O
the	O
traditional	O
message	O
passing	O
interface	O
(	O
MPI	O
)	O
technique	O
of	O
splitting	O
the	O
file	O
into	O
equal	O
numbers	O
of	O
sequences	O
may	O
result	O
in	O
load	O
imbalance	O
.	O

Hence	O
,	O
the	O
best	O
way	O
to	O
parallelize	O
code	O
along	O
the	O
N	O
dimension	O
is	O
to	O
stripmine	O
the	O
query	O
sequences	O
as	O
the	O
processors	O
finish	O
working	O
on	O
their	O
previous	O
ones	O
.	O

This	O
can	O
be	O
achieved	O
using	O
an	O
MPI	O
technique	O
in	O
which	O
one	O
processor	O
reads	O
the	O
query	O
sequence	O
file	O
and	O
sends	O
the	O
sequences	O
to	O
all	O
others	O
.	O

Here	O
,	O
we	O
have	O
parallelized	O
the	O
HMMER	O
code	O
along	O
the	O
N	O
dimension	O
(	O
query	O
sequences	O
)	O
using	O
a	O
Unix	O
-	O
based	O
file	O
-	O
locking	O
technique	O
.	O

This	O
implementation	O
requires	O
all	O
the	O
processors	O
,	O
nodes	O
and	O
computers	O
working	O
on	O
a	O
single	O
problem	O
to	O
have	O
access	O
to	O
a	O
file	O
system	O
that	O
honors	O
Unix	O
file	O
locking	O
.	O

So	O
far	O
,	O
we	O
have	O
tested	O
the	O
implementation	O
on	O
AIX	O
,	O
Linux	O
,	O
NFS	O
and	O
GPFS	O
file	O
systems	O
and	O
found	O
our	O
program	O
to	O
work	O
correctly	O
.	O

The	O
advantages	O
of	O
parallelizing	O
with	O
file	O
locking	O
are	O
that	O
(	O
i	O
)	O
new	O
processes	O
can	O
join	O
or	O
leave	O
the	O
process	O
pool	O
in	O
the	O
middle	O
of	O
computing	O
;	O
(	O
ii	O
)	O
almost	O
perfect	O
load	O
balancing	O
can	O
be	O
achieved	O
;	O
(	O
iii	O
)	O
processors	O
with	O
different	O
clock	O
speeds	O
running	O
different	O
operating	O
systems	O
can	O
be	O
part	O
of	O
the	O
same	O
pool	O
;	O
and	O
(	O
iv	O
)	O
systems	O
do	O
not	O
need	O
to	O
have	O
MPI	O
or	O
parallel	O
virtual	O
machine	O
(	O
PVM	O
)	O
installed	O
.	O

Since	O
the	O
parallelized	O
subroutines	O
are	O
written	O
in	O
a	O
separate	O
file	O
as	O
function	O
calls	O
,	O
very	O
little	O
change	O
is	O
needed	O
to	O
the	O
original	O
HMMER	O
code	O
.	O

These	O
parallel	O
routines	O
are	O
generic	O
and	O
,	O
hence	O
,	O
can	O
be	O
used	O
to	O
parallelize	O
other	O
programs	O
with	O
similar	O
computational	O
requirements	O
,	O
such	O
as	O
the	O
BLAST	O
suite	O
of	O
programs	O
.	O

A	O
brief	O
description	O
of	O
the	O
parallel	O
function	O
calls	O
is	O
provided	O
below	O
.	O

All	O
the	O
processes	O
joining	O
the	O
work	O
pool	O
will	O
call	O

The	O
first	O
process	O
that	O
calls	O
this	O
subroutine	O
will	O
create	O
the	O
lockFile	O
and	O
write	O
the	O
starting	O
index	O
.	O

This	O
is	O
the	O
index	O
from	O
which	O
sequence	O
stripmining	O
happens	O
.	O

The	O
rest	O
of	O
the	O
processes	O
open	O
the	O
file	O
stream	O
to	O
the	O
lockFile	O
.	O

Then	O
,	O
inside	O
the	O
main	O
work	O
loop	O
,	O
every	O
process	O
calls	O

resulting	O
in	O
every	O
process	O
getting	O
a	O
unique	O
next	O
available	O
job	O
(	O
index	O
)	O
.	O

Each	O
process	O
computes	O
the	O
homology	O
search	O
for	O
the	O
sequence	O
index	O
matching	O
the	O
unique	O
index	O
obtained	O
.	O

These	O
steps	O
are	O
iterated	O
until	O
no	O
more	O
sequences	O
are	O
left	O
in	O
the	O
query	O
sequence	O
file	O
.	O

Outside	O
the	O
work	O
loop	O
at	O
the	O
end	O
,	O
all	O
the	O
processes	O
call	O

which	O
will	O
close	O
the	O
lockFile	O
.	O

The	O
user	O
has	O
to	O
ensure	O
a	O
unique	O
lockFile	O
for	O
each	O
new	O
query	O
sequence	O
file	O
.	O

If	O
for	O
some	O
reason	O
the	O
work	O
pool	O
is	O
stopped	O
in	O
the	O
middle	O
of	O
a	O
query	O
sequence	O
file	O
,	O
it	O
can	O
continue	O
from	O
the	O
same	O
point	O
by	O
using	O
the	O
same	O
lockFile	O
.	O

In	O
this	O
version	O
of	O
the	O
hmmpfam	O
program	O
,	O
all	O
processes	O
write	O
search	O
results	O
to	O
a	O
single	O
output	O
file	O
.	O

To	O
minimize	O
synchronization	O
overheads	O
,	O
each	O
process	O
writes	O
the	O
output	O
into	O
a	O
temporary	O
buffer	O
and	O
writes	O
once	O
per	O
sequence	O
into	O
the	O
output	O
file	O
.	O

For	O
the	O
sake	O
of	O
convenience	O
,	O
additional	O
synchronization	O
routines	O
are	O
provided	O
for	O
locking	O
and	O
unlocking	O
.	O

This	O
parallel	O
algorithm	O
has	O
been	O
tested	O
on	O
several	O
platforms	O
and	O
file	O
systems	O
including	O
Intel	O
IA32	O
,	O
IA64	O
Linux	O
platforms	O
,	O
power3	O
and	O
power4	O
-	O
based	O
AIX	O
platforms	O
and	O
Sparc4	O
-	O
based	O
Solaris	O
platforms	O
.	O

The	O
code	O
was	O
run	O
on	O
800	O
processors	O
of	O
power4	O
-	O
based	O
datastar	O
machines	O
and	O
256	O
processors	O
of	O
IA64	O
-	O
based	O
teragrid	O
machines	O
located	O
at	O
the	O
San	O
Diego	O
Supercomputer	O
Center	O
(	O
SDSC	O
)	O
to	O
test	O
scalability	O
issues	O
.	O

Single	O
-	O
processor	O
optimization	O
of	O
hmmpfam	O

Initially	O
,	O
we	O
utilized	O
version	O
2	O
.	O
2g	O
of	O
HMMER	O
.	O

Performance	O
analysis	O
revealed	O
that	O
the	O
main	O
computational	O
kernel	O
was	O
accessing	O
the	O
2D	O
arrays	O
with	O
a	O
wrong	O
stride	O
.	O

Correcting	O
this	O
resulted	O
in	O
doubling	O
of	O
the	O
performance	O
;	O
however	O
,	O
the	O
HMMER	O
developer	O
has	O
rectified	O
this	O
issue	O
in	O
release	O
2	O
.	O
3	O
.	O
2	O
.	O

In	O
addition	O
,	O
HMMER	O
reads	O
the	O
database	O
file	O
from	O
disk	O
for	O
every	O
sequence	O
it	O
searches	O
.	O

This	O
is	O
extremely	O
inefficient	O
for	O
batch	O
searches	O
.	O

We	O
have	O
corrected	O
this	O
by	O
reading	O
the	O
whole	O
database	O
into	O
memory	O
once	O
and	O
conducting	O
searches	O
from	O
memory	O
.	O

Performance	O
testing	O

We	O
compared	O
our	O
improved	O
IA64	O
single	O
-	O
processor	O
hmmpfam	O
with	O
the	O
equivalent	O
program	O
from	O
the	O
original	O
HMMER	O
2	O
.	O
3	O
.	O
2	O
release	O
on	O
an	O
Itanium	O
II	O
IA64	O
processor	O
(	O
Figure	O
1	O
)	O
.	O

As	O
expected	O
,	O
the	O
per	O
sequence	O
CPU	O
time	O
for	O
our	O
program	O
is	O
reduced	O
up	O
to	O
10	O
-	O
fold	O
in	O
batch	O
searches	O
,	O
while	O
in	O
the	O
case	O
of	O
the	O
original	O
2	O
.	O
3	O
.	O
2	O
release	O
,	O
it	O
is	O
linear	O
to	O
the	O
number	O
of	O
sequences	O
.	O

Performance	O
difference	O
in	O
single	O
-	O
sequence	O
processing	O
could	O
be	O
attributed	O
to	O
compilation	O
differences	O
.	O

Performance	O
differences	O
resulting	O
in	O
the	O
slope	O
difference	O
of	O
the	O
two	O
plots	O
may	O
be	O
due	O
to	O
the	O
elimination	O
of	O
the	O
need	O
to	O
reload	O
the	O
Pfam	O
database	O
from	O
disk	O
for	O
every	O
sequence	O
in	O
our	O
case	O
.	O

Processing	O
data	O
from	O
disk	O
can	O
be	O
an	O
order	O
of	O
magnitude	O
slower	O
than	O
processing	O
in	O
memory	O
.	O

Scaling	O
tests	O
were	O
conducted	O
on	O
a	O
128	O
-	O
node	O
Itanium	O
II	O
IA64	O
cluster	O
.	O

We	O
used	O
a	O
fixed	O
set	O
of	O
500	O
sequences	O
as	O
the	O
test	O
set	O
and	O
ran	O
on	O
1	O
-	O
32	O
processors	O
.	O

As	O
expected	O
,	O
the	O
time	O
required	O
to	O
process	O
a	O
given	O
set	O
of	O
sequences	O
reduces	O
linearly	O
with	O
the	O
number	O
of	O
processors	O
(	O
data	O
not	O
shown	O
)	O
.	O

This	O
also	O
indicates	O
that	O
the	O
parallelization	O
overheads	O
using	O
our	O
method	O
are	O
minimal	O
.	O

However	O
,	O
as	O
the	O
ratio	O
of	O
the	O
number	O
of	O
sequences	O
to	O
the	O
number	O
of	O
processors	O
reduces	O
to	O
one	O
,	O
load	O
imbalances	O
due	O
to	O
the	O
processing	O
time	O
differences	O
between	O
different	O
sequences	O
start	O
to	O
dominate	O
,	O
reducing	O
parallel	O
efficiency	O
.	O

Pre	O
-	O
calculated	O
results	O

We	O
have	O
generated	O
pre	O
-	O
calculated	O
Pfam	O
search	O
results	O
for	O
the	O
entire	O
Swiss	O
-	O
Prot	O
and	O
TrEmbl	O
protein	O
sequences	O
(	O
~	O
1	O
.	O
2	O
million	O
)	O
,	O
using	O
our	O
parallelized	O
'	O
hmmpfam	O
'	O
on	O
256	O
processors	O
of	O
IA64	O
-	O
based	O
teragrid	O
machines	O
located	O
at	O
the	O
SDSC	O
.	O

Pfam	O
searches	O
have	O
been	O
performed	O
separately	O
,	O
using	O
either	O
gathering	O
thresholds	O
or	O
E	O
-	O
value	O
cutoffs	O
against	O
glocal	O
(	O
Pfam	O
_	O
ls	O
)	O
or	O
local	O
(	O
Pfam	O
_	O
fs	O
)	O
alignment	O
models	O
.	O

Glocal	O
and	O
local	O
search	O
results	O
were	O
parsed	O
and	O
merged	O
by	O
removing	O
all	O
local	O
search	O
hits	O
that	O
are	O
completely	O
overlapped	O
by	O
glocal	O
search	O
hits	O
.	O

Input	O
and	O
output	O
formats	O

The	O
program	O
takes	O
only	O
FASTA	O
-	O
formatted	O
sequences	O
as	O
input	O
and	O
searches	O
can	O
be	O
done	O
in	O
any	O
search	O
mode	O
,	O
i	O
.	O
e	O
.	O
local	O
,	O
glocal	O
or	O
merged	O
.	O

The	O
maximum	O
E	O
-	O
value	O
allowed	O
for	O
searches	O
is	O
10	O
.	O

SledgeHMMER	O
results	O
are	O
emailed	O
to	O
the	O
user	O
in	O
a	O
space	O
-	O
delimited	O
,	O
one	O
hit	O
per	O
line	O
tabular	O
format	O
(	O
Figure	O
2	O
)	O
.	O

The	O
response	O
time	O
for	O
receiving	O
results	O
depends	O
on	O
the	O
number	O
of	O
query	O
sequences	O
and	O
the	O
fraction	O
of	O
these	O
existing	O
in	O
the	O
pre	O
-	O
calculated	O
entries	O
.	O

DISCUSSION	O

The	O
SledgeHMMER	O
server	O
provides	O
a	O
unique	O
service	O
to	O
the	O
scientific	O
community	O
wishing	O
to	O
batch	O
search	O
the	O
Pfam	O
database	O
on	O
the	O
web	O
.	O

To	O
the	O
best	O
of	O
our	O
knowledge	O
,	O
this	O
is	O
the	O
only	O
such	O
server	O
that	O
has	O
no	O
limit	O
on	O
the	O
number	O
of	O
input	O
sequences	O
.	O

The	O
current	O
pre	O
-	O
calculated	O
database	O
covers	O
~	O
70	O
%	O
of	O
the	O
available	O
non	O
-	O
redundant	O
protein	O
sequence	O
space	O
,	O
and	O
we	O
plan	O
to	O
add	O
additional	O
new	O
sequences	O
from	O
other	O
resources	O
such	O
as	O
the	O
NR	O
database	O
from	O
GenBank	O
and	O
SEQRES	O
from	O
the	O
PDB	O
(	O
Protein	O
Data	O
Bank	O
)	O
in	O
the	O
future	O
.	O

Our	O
pre	O
-	O
calculated	O
database	O
is	O
updated	O
for	O
every	O
new	O
release	O
of	O
the	O
Pfam	O
database	O
or	O
SPTr	O
databases	O
(	O
Swiss	O
-	O
Prot	O
+	O
TrEMBL	O
)	O
in	O
order	O
to	O
provide	O
access	O
to	O
the	O
most	O
current	O
data	O
.	O

Single	O
-	O
processor	O
optimized	O
hmmpfam	O
binaries	O
and	O
the	O
source	O
code	O
can	O
be	O
downloaded	O
from	O
the	O
current	O
web	O
server	O
.	O

In	O
the	O
future	O
,	O
we	O
intend	O
to	O
make	O
such	O
binaries	O
available	O
for	O
many	O
additional	O
operating	O
systems	O
and	O
propagate	O
these	O
modifications	O
to	O
other	O
HMMER	O
programs	O
as	O
well	O
.	O

Medicinal	O
herb	O
use	O
among	O
asthmatic	O
patients	B
attending	O
a	O
specialty	O
care	O
facility	O
in	O
Trinidad	O

Abstract	O

Background	O

There	O
is	O
an	O
increasing	O
prevalence	O
of	O
asthma	O
in	O
the	O
Caribbean	O
and	O
patients	B
remain	O
non	O
-	O
compliant	O
to	O
therapy	O
despite	O
the	O
development	O
of	O
guidelines	O
for	O
management	O
and	O
prevention	O
.	O

Some	O
patients	B
may	O
self	O
-	O
medicate	O
with	O
medicinal	O
herbs	O
for	O
symptomatic	O
relief	O
,	O
as	O
there	O
is	O
a	O
long	O
tradition	O
of	O
use	O
for	O
a	O
variety	O
of	O
ailments	O
.	O

The	O
study	O
assessed	O
the	O
prevalence	O
of	O
use	O
and	O
the	O
factors	O
affecting	O
the	O
decision	O
to	O
use	O
herbs	O
in	O
asthmatic	O
patients	B
attending	O
a	O
public	O
specialty	O
care	O
clinic	O
in	O
Trinidad	O
.	O

Methods	O

A	O
descriptive	O
,	O
cross	O
-	O
sectional	O
study	O
was	O
conducted	O
at	O
the	O
Chest	O
Clinic	O
in	O
Trinidad	O
using	O
a	O
de	O
novo	O
,	O
pilot	O
-	O
tested	O
,	O
researcher	O
-	O
administered	O
questionnaire	O
between	O
June	O
and	O
July	O
2003	O
.	O

Results	O

Fifty	O
-	O
eight	O
out	O
of	O
191	O
patients	B
(	O
30	O
.	O
4	O
%	O
)	O
reported	O
using	O
herbal	O
remedies	O
for	O
symptomatic	O
relief	O
.	O

Gender	O
,	O
age	O
,	O
ethnicity	O
,	O
and	O
asthma	O
severity	O
did	O
not	O
influence	O
the	O
decision	O
to	O
use	O
herbs	O
;	O
however	O
,	O
62	O
.	O
5	O
%	O
of	O
patients	B
with	O
tertiary	O
level	O
schooling	O
used	O
herbs	O
,	O
p	O
=	O
0	O
.	O
025	O
.	O

Thirty	O
-	O
four	O
of	O
these	O
58	O
patients	B
(	O
58	O
.	O
6	O
%	O
)	O
obtained	O
herbs	O
from	O
their	O
backyards	O
or	O
the	O
supermarket	O
;	O
only	O
14	O
patients	B
(	O
24	O
.	O
1	O
%	O
)	O
obtained	O
herbs	O
from	O
an	O
herbalist	O
,	O
herbal	O
shop	O
or	O
pharmacy	O
.	O

Relatives	O
and	O
friends	O
were	O
the	O
sole	O
source	O
of	O
information	O
for	O
most	O
patients	B
(	O
70	O
.	O
7	O
%	O
)	O
,	O
and	O
only	O
10	O
.	O
3	O
%	O
consulted	O
an	O
herbalist	O
.	O

Ginger	B
,	O
garlic	B
,	O
aloes	O
,	O
shandileer	B
,	O
wild	O
onion	B
,	O
pepper	O
and	O
black	B
sage	I
were	O
the	O
most	O
commonly	O
used	O
herbs	O
.	O

Conclusions	O

Among	O
patients	B
attending	O
the	O
Chest	O
Clinic	O
in	O
Trinidad	O
the	O
use	O
of	O
herbal	O
remedies	O
in	O
asthma	O
is	O
relatively	O
common	O
on	O
the	O
advice	O
of	O
relatives	O
and	O
friends	O
.	O

It	O
is	O
therefore	O
becoming	O
imperative	O
for	O
healthcare	O
providers	O
to	O
become	O
more	O
knowledgeable	O
on	O
this	O
modality	O
and	O
to	O
keep	O
abreast	O
with	O
the	O
latest	O
developments	O
.	O

Background	O

Recent	O
reports	O
from	O
the	O
Caribbean	O
suggest	O
that	O
the	O
incidence	O
of	O
asthma	O
is	O
following	O
the	O
global	O
trend	O
of	O
increasing	O
prevalence	O
.	O

In	O
Jamaica	O
,	O
a	O
prevalence	O
of	O
20	O
.	O
8	O
%	O
for	O
exercise	O
-	O
induced	O
asthma	O
was	O
estimated	O
in	O
a	O
cross	O
-	O
sectional	O
study	O
in	O
schoolchildren	B
[	O
1	O
]	O
.	O

About	O
one	O
in	O
ten	O
patients	B
attending	O
an	O
Accident	O
and	O
Emergency	O
Department	O
in	O
Trinidad	O
were	O
treated	O
for	O
acute	O
severe	O
asthma	O
[	O
2	O
]	O
and	O
over	O
15	O
,	O
000	O
patients	B
attended	O
four	O
A	O
&	O
E	O
departments	O
throughout	O
the	O
island	O
over	O
a	O
12	O
-	O
month	O
period	O
[	O
3	O
]	O
.	O

Inhaled	O
corticosteroids	O
as	O
prophylaxis	O
and	O
'	O
as	O
required	O
'	O
bronchodilator	O
for	O
symptomatic	O
relief	O
are	O
established	O
modalities	O
for	O
asthma	O
management	O
and	O
prevention	O
and	O
the	O
Commonwealth	O
Caribbean	O
Medical	O
Research	O
Council	O
/	O
Global	O
Initiative	O
for	O
Asthma	O
guidelines	O
were	O
adopted	O
in	O
the	O
Caribbean	O
in	O
1997	O
[	O
4	O
]	O
.	O

It	O
has	O
been	O
noted	O
that	O
inefficient	O
management	O
predisposes	O
patients	B
to	O
frequent	O
hospitalization	O
and	O
reduced	O
quality	O
of	O
life	O
.	O

In	O
Trinidad	O
,	O
non	O
-	O
compliance	O
and	O
inadequate	O
inhaler	O
technique	O
negatively	O
impact	O
on	O
effective	O
disease	O
management	O
[	O
5	O
,	O
6	O
]	O
.	O

The	O
frequent	O
unavailability	O
of	O
medication	O
at	O
public	O
health	O
facilities	O
and	O
the	O
prohibitive	O
cost	O
at	O
private	O
pharmacies	O
are	O
significantly	O
associated	O
with	O
non	O
-	O
compliance	O
and	O
consequently	O
poor	O
disease	O
control	O
.	O

In	O
these	O
studies	O
,	O
some	O
patients	B
indicated	O
their	O
use	O
of	O
herbal	O
remedies	O
as	O
an	O
alternative	O
to	O
conventional	O
medicines	O
.	O

Over	O
the	O
last	O
few	O
decades	O
,	O
a	O
global	O
resurgence	O
in	O
the	O
use	O
of	O
herbal	O
remedies	O
has	O
fuelled	O
the	O
growing	O
multi	O
-	O
billion	O
dollar	O
international	O
trade	O
of	O
botanical	O
products	O
.	O

Many	O
patients	B
,	O
dissatisfied	O
with	O
conventional	O
medicines	O
because	O
they	O
expect	O
permanent	O
cures	O
,	O
believe	O
that	O
herbal	O
remedies	O
are	O
'	O
natural	O
'	O
and	O
sometimes	O
self	O
-	O
medicate	O
without	O
informing	O
their	O
attending	O
physician	O
.	O

Although	O
there	O
is	O
a	O
long	O
history	O
of	O
traditional	O
use	O
of	O
medicinal	O
herbs	O
throughout	O
the	O
Caribbean	O
[	O
7	O
,	O
8	O
]	O
few	O
studies	O
were	O
done	O
to	O
assess	O
the	O
prevalence	O
of	O
use	O
.	O

Surveys	O
in	O
Jamaica	O
reported	O
an	O
almost	O
100	O
%	O
use	O
of	O
herbal	O
teas	O
and	O
remedies	O
by	O
respondents	O
throughout	O
the	O
island	O
[	O
9	O
]	O
and	O
71	O
%	O
in	O
paediatrics	O
inpatients	O
at	O
the	O
University	O
Hospital	O
[	O
10	O
]	O
.	O

These	O
studies	O
,	O
however	O
,	O
assessed	O
only	O
the	O
lifetime	O
use	O
of	O
medicinal	O
herbs	O
and	O
did	O
not	O
identify	O
their	O
use	O
for	O
any	O
particular	O
disease	O
.	O

In	O
Trinidad	O
and	O
Tobago	O
,	O
the	O
use	O
of	O
'	O
bush	O
medicine	O
'	O
in	O
diabetic	O
patients	B
attending	O
primary	O
healthcare	O
facilities	O
throughout	O
the	O
island	O
was	O
assessed	O
and	O
although	O
42	O
%	O
reportedly	O
used	O
herbs	O
,	O
only	O
24	O
%	O
used	O
this	O
healthcare	O
modality	O
for	O
self	O
-	O
management	O
of	O
diabetes	O
[	O
11	O
]	O
.	O

Another	O
survey	O
conducted	O
at	O
an	O
outpatient	O
surgical	O
facility	O
in	O
Trinidad	O
indicated	O
a	O
lifetime	O
prevalence	O
of	O
86	O
%	O
among	O
patients	B
[	O
12	O
]	O
for	O
any	O
healthcare	O
issue	O
.	O

This	O
study	O
was	O
undertaken	O
to	O
assess	O
the	O
extent	O
of	O
use	O
of	O
herbal	O
remedies	O
by	O
asthmatic	O
patients	B
attending	O
a	O
specialty	O
chest	O
clinic	O
in	O
Trinidad	O
for	O
symptomatic	O
relief	O
and	O
to	O
determine	O
the	O
factors	O
influencing	O
the	O
patient	B
'	O
s	O
decision	O
to	O
use	O
herbs	O
.	O

Methods	O

The	O
study	O
was	O
approved	O
by	O
the	O
Ethics	O
Committee	O
of	O
the	O
Faculty	O
of	O
Medical	O
Sciences	O
,	O
University	O
of	O
the	O
West	O
Indies	O
,	O
St	O
.	O

Augustine	O
campus	O
and	O
permission	O
to	O
interview	O
patients	B
was	O
granted	O
by	O
the	O
Director	O
of	O
the	O
Chest	O
Clinic	O
of	O
the	O
Ministry	O
of	O
Health	O
,	O
Trinidad	O
and	O
Tobago	O
.	O

The	O
study	O
was	O
conducted	O
over	O
the	O
two	O
-	O
month	O
period	O
June	O
to	O
July	O
2003	O
.	O

Sample	O
and	O
setting	O

The	O
Chest	O
Clinic	O
was	O
chosen	O
as	O
the	O
source	O
of	O
subjects	O
as	O
this	O
is	O
the	O
only	O
national	O
tertiary	O
level	O
health	O
facility	O
specializing	O
in	O
the	O
management	O
of	O
respiratory	O
diseases	O
.	O

Patients	B
entering	O
the	O
study	O
were	O
physician	O
-	O
diagnosed	O
asthmatics	O
based	O
on	O
self	O
-	O
reporting	O
symptoms	O
of	O
wheezing	O
,	O
chest	O
tightness	O
and	O
nocturnal	O
coughing	O
in	O
the	O
previous	O
year	O
.	O

Patients	B
were	O
recruited	O
by	O
consecutive	O
sampling	O
and	O
the	O
nature	O
and	O
purpose	O
of	O
the	O
study	O
were	O
explained	O
on	O
an	O
individual	O
basis	O
.	O

Those	O
confirming	O
their	O
willingness	O
to	O
participate	O
signed	O
their	O
informed	O
consent	O
and	O
were	O
interviewed	O
using	O
a	O
de	O
novo	O
,	O
pilot	O
-	O
tested	O
,	O
researcher	O
-	O
administered	O
questionnaire	O
.	O

Interview	O
instrument	O

The	O
questionnaire	O
assessed	O
demographic	O
data	O
such	O
as	O
age	O
,	O
gender	O
,	O
ethnicity	O
,	O
residential	O
district	O
,	O
education	O
,	O
employment	O
and	O
socioeconomic	O
status	O
.	O

Subjects	O
reported	O
their	O
disease	O
severity	O
as	O
intermittent	O
,	O
moderate	O
or	O
severe	O
as	O
determined	O
by	O
the	O
Global	O
Initiative	O
for	O
Asthma	O
(	O
GINA	O
)	O
guidelines	O
with	O
respect	O
to	O
symptom	O
frequency	O
[	O
4	O
]	O
.	O

Patients	B
also	O
reported	O
their	O
use	O
of	O
herbal	O
remedies	O
,	O
identified	O
the	O
herbs	O
used	O
,	O
the	O
frequency	O
of	O
use	O
,	O
source	O
of	O
herbal	O
medicines	O
and	O
the	O
reasons	O
for	O
the	O
use	O
of	O
herbs	O
.	O

Statistical	O
analysis	O

The	O
sample	O
size	O
was	O
calculated	O
as	O
185	O
patients	B
assuming	O
a	O
prevalence	O
of	O
86	O
%	O
[	O
13	O
]	O
with	O
a	O
confidence	O
level	O
of	O
95	O
%	O
.	O

Since	O
all	O
variables	O
were	O
categorical	O
,	O
chi	O
2	O
tests	O
were	O
performed	O
to	O
determine	O
whether	O
there	O
were	O
statistically	O
significant	O
associations	O
between	O
the	O
use	O
of	O
herbs	O
and	O
these	O
variables	O
.	O

The	O
p	O
value	O
was	O
set	O
at	O
<	O
0	O
.	O
05	O
for	O
statistical	O
significance	O
.	O

The	O
data	O
was	O
analyzed	O
using	O
SPSS	O
for	O
Windows	O
(	O
Version	O
9	O
.	O
0	O
,	O
Chicago	O
,	O
IL	O
)	O
.	O

Results	O

Demography	O

During	O
the	O
study	O
period	O
one	O
hundred	O
and	O
ninety	O
one	O
patients	B
consented	O
to	O
participate	O
.	O

The	O
demographic	O
details	O
of	O
the	O
sample	O
are	O
given	O
in	O
Table	O
1	O
.	O

Patients	B
between	O
35	O
and	O
64	O
years	O
of	O
age	O
formed	O
the	O
largest	O
portion	O
of	O
the	O
sample	O
(	O
62	O
.	O
3	O
%	O
)	O
.	O

There	O
was	O
a	O
significant	O
gender	O
difference	O
with	O
females	O
outnumbering	O
males	O
by	O
a	O
2	O
:	O
1	O
ratio	O
,	O
p	O
<	O
0	O
.	O
01	O
.	O

Most	O
patients	B
were	O
of	O
Asian	O
Indian	O
origin	O
(	O
58	O
.	O
1	O
%	O
)	O
and	O
resided	O
in	O
suburban	O
areas	O
(	O
60	O
.	O
2	O
%	O
)	O
.	O

There	O
was	O
a	O
high	O
level	O
of	O
unemployment	O
(	O
30	O
.	O
4	O
%	O
)	O
;	O
this	O
could	O
be	O
correlated	O
to	O
primary	O
schooling	O
(	O
seven	O
or	O
less	O
years	O
of	O
formal	O
education	O
)	O
being	O
the	O
highest	O
educational	O
level	O
attained	O
in	O
52	O
.	O
9	O
%	O
and	O
no	O
formal	O
schooling	O
in	O
5	O
.	O
2	O
%	O
of	O
the	O
sample	O
population	O
.	O

Income	O
was	O
low	O
,	O
with	O
42	O
.	O
9	O
%	O
of	O
the	O
sample	O
population	O
earning	O
below	O
US	O
$	O
4	O
,	O
000	O
per	O
year	O
.	O

Antiasthmatic	O
drug	O
use	O

The	O
GINA	O
guidelines	O
were	O
recently	O
adopted	O
in	O
the	O
Caribbean	O
and	O
asthmatic	O
patients	B
are	O
currently	O
treated	O
according	O
to	O
their	O
symptom	O
severity	O
.	O

In	O
our	O
sample	O
population	O
,	O
particularly	O
in	O
patients	B
with	O
moderate	O
and	O
severe	O
symptoms	O
,	O
corticosteroids	O
(	O
controllers	O
)	O
and	O
beta	O
2	O
-	O
agonists	O
(	O
relievers	O
)	O
were	O
prescribed	O
at	O
very	O
high	O
rates	O
,	O
Table	O
2	O
.	O

Almost	O
90	O
%	O
of	O
all	O
patients	B
with	O
moderate	O
symptoms	O
were	O
prescribed	O
drugs	O
in	O
these	O
classes	O
.	O

Almost	O
all	O
patients	B
with	O
severe	O
symptoms	O
were	O
prescribed	O
beta	O
2	O
-	O
agonists	O
.	O

This	O
high	O
level	O
of	O
prescription	O
and	O
use	O
of	O
beta	O
2	O
-	O
agonists	O
suggest	O
a	O
lack	O
of	O
symptomatic	O
control	O
in	O
our	O
sample	O
population	O
.	O

Theophylline	O
and	O
anticholinergics	O
were	O
prescribed	O
in	O
both	O
categories	O
of	O
patients	B
,	O
but	O
to	O
a	O
lesser	O
extent	O
.	O

Factors	O
influencing	O
the	O
use	O
of	O
herbal	O
remedies	O

Gender	O
,	O
age	O
,	O
ethnicity	O
,	O
residential	O
district	O
,	O
employment	O
status	O
,	O
income	O
and	O
asthma	O
severity	O
had	O
no	O
statistically	O
significant	O
effect	O
on	O
the	O
use	O
of	O
herbal	O
remedies	O
within	O
the	O
sample	O
population	O
,	O
Table	O
3	O
.	O

However	O
,	O
almost	O
two	O
-	O
thirds	O
(	O
62	O
.	O
5	O
%	O
)	O
of	O
patients	B
with	O
tertiary	O
education	O
used	O
herbal	O
remedies	O
for	O
asthma	O
,	O
p	O
=	O
0	O
.	O
025	O
.	O

Characteristics	O
of	O
patients	B
using	O
herbal	O
remedies	O

Most	O
patients	B
(	O
70	O
.	O
7	O
%	O
)	O
using	O
herbs	O
were	O
advised	O
by	O
a	O
relative	O
or	O
friend	O
and	O
only	O
10	O
.	O
3	O
%	O
sought	O
the	O
advice	O
of	O
an	O
herbalist	O
,	O
Table	O
4	O
.	O

A	O
cultural	O
/	O
traditional	O
basis	O
was	O
the	O
reason	O
for	O
herbal	O
remedy	O
usage	O
in	O
twenty	O
-	O
one	O
(	O
36	O
.	O
2	O
%	O
)	O
patients	B
and	O
another	O
twelve	O
(	O
20	O
.	O
7	O
%	O
)	O
patients	B
used	O
herbs	O
because	O
they	O
felt	O
that	O
were	O
either	O
'	O
natural	O
'	O
or	O
'	O
healthy	O
'	O
.	O

Twelve	O
(	O
20	O
.	O
7	O
%	O
)	O
patients	B
used	O
herbs	O
because	O
they	O
believed	O
that	O
their	O
physician	O
-	O
prescribed	O
allopathic	O
medicines	O
were	O
not	O
working	O
.	O

Most	O
patients	B
(	O
58	O
.	O
6	O
%	O
)	O
obtained	O
their	O
herbs	O
or	O
medicinal	O
plants	O
from	O
either	O
their	O
backyards	O
or	O
the	O
supermarket	O
.	O

Only	O
fourteen	O
(	O
24	O
.	O
1	O
%	O
)	O
obtained	O
their	O
herbal	O
supplies	O
from	O
an	O
herbalist	O
,	O
herbal	O
shop	O
or	O
pharmacy	O
.	O

Seventeen	O
(	O
29	O
.	O
3	O
%	O
)	O
of	O
these	O
patients	B
reported	O
using	O
herbs	O
within	O
the	O
last	O
week	O
and	O
most	O
these	O
patients	B
(	O
60	O
.	O
3	O
%	O
)	O
used	O
herbs	O
within	O
the	O
last	O
six	O
months	O
.	O

Many	O
of	O
these	O
patients	B
were	O
using	O
both	O
physician	O
-	O
prescribed	O
antiasthmatic	O
drugs	O
and	O
herbal	O
remedies	O
,	O
Table	O
5	O
.	O

No	O
patient	B
with	O
either	O
moderate	O
or	O
severe	O
symptoms	O
indicated	O
that	O
herbal	O
remedies	O
alone	O
were	O
sufficient	O
to	O
relieve	O
symptomatic	O
episodes	O
.	O

It	O
is	O
interesting	O
to	O
note	O
that	O
most	O
patients	B
with	O
moderate	O
symptoms	O
(	O
57	O
.	O
1	O
%	O
)	O
believed	O
that	O
concurrent	O
use	O
of	O
conventional	O
medications	O
and	O
herbs	O
gave	O
better	O
symptomatic	O
relieve	O
.	O

One	O
the	O
other	O
hand	O
,	O
most	O
patients	B
with	O
severe	O
symptoms	O
(	O
53	O
.	O
8	O
%	O
)	O
believed	O
that	O
physician	O
-	O
prescribed	O
medications	O
worked	O
better	O
than	O
herbal	O
remedies	O
,	O
while	O
23	O
.	O
1	O
%	O
believed	O
that	O
neither	O
relieved	O
their	O
symptoms	O
.	O

Herbs	O
used	O
in	O
asthma	O

Most	O
patients	B
in	O
the	O
sample	O
used	O
more	O
than	O
one	O
medicinal	O
herb	O
simultaneously	O
,	O
which	O
were	O
usually	O
prepared	O
and	O
administered	O
as	O
mixtures	O
in	O
teas	O
.	O

Almost	O
one	O
in	O
four	O
patients	B
using	O
medicinal	O
herbs	O
(	O
22	O
.	O
5	O
%	O
)	O
used	O
either	O
garlic	B
(	O
Allium	B
sativum	I
)	O
or	O
ginger	B
(	O
Zingiber	B
officinale	I
)	O
for	O
symptomatic	O
relief	O
of	O
asthma	O
,	O
Table	O
6	O
.	O

Aloes	O
(	O
Aloe	B
vera	I
)	O
shandileer	B
(	O
Leonotis	B
nepetifolia	I
)	O
,	O
wild	O
onion	B
(	O
Hymenocallis	B
tubiflora	I
)	O
,	O
pepper	O
(	O
Capsicum	O
spp	O
.	O
)	O
tulsi	B
(	O
Ocimum	B
gratissimum	I
)	O
,	O
black	B
sage	I
(	O
Cordia	B
curassavica	I
)	O
,	O
shadon	B
beni	I
(	O
Eryngium	B
foetidium	I
)	O
,	O
lemongrass	B
(	O
Cymbopogon	B
citratus	I
)	O
and	O
nutmeg	B
(	O
Myristica	B
fragrans	I
)	O
were	O
the	O
more	O
popular	O
traditional	O
indigenous	O
West	O
Indian	O
medicinal	O
plants	O
used	O
.	O

Two	O
patients	B
reported	O
using	O
marijuana	O
(	O
leaves	O
and	O
roots	O
)	O
.	O

Herbs	O
of	O
European	O
and	O
North	O
American	O
origin	O
,	O
identified	O
as	O
Echinacea	O
(	O
Echinacea	B
purpurea	I
)	O
,	O
Golden	B
Seal	I
(	O
Hydrastis	B
canadensis	I
)	O
and	O
Chamomile	B
(	O
Matricaria	B
chamomilla	I
)	O
were	O
less	O
frequently	O
used	O
.	O

Five	O
patients	B
reported	O
using	O
trade	O
name	O
imported	O
tablets	O
for	O
asthma	O
.	O

Effect	O
of	O
income	O
and	O
education	O
on	O
the	O
use	O
of	O
herbs	O

Patients	B
using	O
easily	O
accessible	O
herbs	O
such	O
as	O
ginger	B
(	O
Zingiber	B
officinale	I
)	O
and	O
aloes	O
(	O
Aloe	B
vera	I
)	O
,	O
and	O
traditional	O
indigenous	O
medicinal	O
herbs	O
such	O
as	O
shandileer	B
(	O
Leonotis	B
nepetifolia	I
)	O
and	O
tulsi	B
(	O
Ocimum	B
gratissimum	I
)	O
were	O
more	O
likely	O
to	O
be	O
earning	O
less	O
than	O
US	O
$	O
12	O
,	O
000	O
,	O
Table	O
7	O
.	O

Herbs	O
of	O
European	O
or	O
North	O
American	O
origin	O
(	O
Echinacea	B
purpurea	I
and	O
Matricaria	B
chamomilla	I
)	O
were	O
more	O
likely	O
to	O
be	O
used	O
by	O
patients	B
earning	O
in	O
excess	O
of	O
US	O
$	O
12	O
,	O
000	O
per	O
annum	O
.	O

Income	O
did	O
not	O
affect	O
the	O
use	O
of	O
either	O
garlic	B
or	O
cocoa	O
onion	B
.	O

Aloes	O
(	O
Aloe	B
vera	I
)	O
,	O
tulsi	B
(	O
Ocimum	B
gratissimum	I
)	O
and	O
golden	O
seal	O
were	O
preferred	O
in	O
patients	B
with	O
at	O
least	O
twelve	O
years	O
of	O
formal	O
education	O
,	O
Table	O
7	O
.	O

Garlic	B
and	O
Echinacea	B
were	O
the	O
preferred	O
herbal	O
medicines	O
in	O
patients	B
with	O
more	O
than	O
twelve	O
years	O
formal	O
education	O
.	O

Educational	O
level	O
did	O
not	O
affect	O
the	O
patients	B
'	O
decision	O
to	O
use	O
shandileer	B
(	O
Leonotis	B
nepetifolia	I
)	O
,	O
wild	O
onion	B
(	O
Hymenocallis	B
tubiflora	I
)	O
or	O
ginger	B
(	O
Zingibe	B
officinale	I
)	O
.	O

Discussion	O

This	O
is	O
the	O
first	O
study	O
of	O
its	O
kind	O
in	O
the	O
Caribbean	O
to	O
assess	O
the	O
use	O
of	O
medicinal	O
herbs	O
by	O
asthmatic	O
patients	B
attending	O
a	O
specialty	O
care	O
clinic	O
.	O

The	O
findings	O
of	O
this	O
study	O
are	O
instructive	O
as	O
the	O
use	O
of	O
medicinal	O
herbs	O
for	O
self	O
-	O
medication	O
in	O
disease	O
management	O
has	O
far	O
reaching	O
implications	O
on	O
the	O
quality	O
of	O
healthcare	O
delivery	O
[	O
14	O
]	O
.	O

We	O
report	O
a	O
prevalence	O
of	O
30	O
.	O
4	O
%	O
in	O
our	O
patient	B
sample	O
,	O
which	O
is	O
significantly	O
higher	O
than	O
that	O
in	O
the	O
UK	O
,	O
Denmark	O
,	O
Singapore	O
and	O
in	O
the	O
US	O
[	O
15	O
-	O
18	O
]	O
.	O

Most	O
patients	B
using	O
medicinal	O
herbs	O
relied	O
on	O
the	O
advice	O
of	O
relatives	O
and	O
friends	O
as	O
their	O
sole	O
source	O
of	O
information	O
,	O
as	O
were	O
caregivers	O
of	O
children	O
in	O
a	O
US	O
study	O
[	O
19	O
]	O
.	O

We	O
suggest	O
that	O
this	O
information	O
on	O
the	O
use	O
of	O
medicinal	O
plants	O
could	O
have	O
come	O
from	O
traditional	O
/	O
cultural	O
knowledge	O
,	O
anecdotal	O
evidence	O
or	O
from	O
the	O
greater	O
public	O
awareness	O
through	O
information	O
networks	O
such	O
as	O
the	O
internet	O
on	O
the	O
potential	O
medicinal	O
benefits	O
of	O
herbs	O
.	O

Asthma	O
is	O
an	O
emerging	O
chronic	O
disease	O
in	O
the	O
Caribbean	O
and	O
we	O
suggest	O
that	O
the	O
traditional	O
knowledge	O
in	O
this	O
area	O
may	O
be	O
relatively	O
'	O
new	O
'	O
and	O
exist	O
in	O
relation	O
to	O
other	O
diseases	O
affecting	O
the	O
respiratory	O
tract	O
,	O
such	O
as	O
cough	O
,	O
the	O
common	O
cold	O
and	O
the	O
flu	O
.	O

This	O
may	O
be	O
one	O
of	O
the	O
reasons	O
for	O
the	O
low	O
prevalence	O
of	O
use	O
of	O
herbs	O
in	O
elderly	O
asthmatic	O
patients	B
,	O
as	O
a	O
strong	O
traditional	O
knowledge	O
may	O
not	O
have	O
existed	O
.	O

We	O
expected	O
a	O
higher	O
prevalence	O
of	O
herbal	O
use	O
in	O
individuals	O
living	O
in	O
rural	O
areas	O
as	O
these	O
districts	O
are	O
depots	O
for	O
traditional	O
knowledge	O
as	O
was	O
reported	O
in	O
Jamaica	O
where	O
rural	O
respondents	O
used	O
a	O
larger	O
variety	O
of	O
herbs	O
than	O
those	O
living	O
in	O
urban	O
areas	O
[	O
10	O
]	O
.	O

As	O
suggested	O
earlier	O
,	O
we	O
suspect	O
that	O
due	O
to	O
the	O
recent	O
emergence	O
of	O
asthma	O
as	O
a	O
chronic	O
disease	O
in	O
the	O
Caribbean	O
it	O
is	O
reasonable	O
to	O
expect	O
that	O
traditional	O
knowledge	O
in	O
the	O
management	O
of	O
this	O
disease	O
is	O
not	O
strong	O
and	O
our	O
results	O
are	O
indicative	O
of	O
this	O
.	O

We	O
suspected	O
that	O
employment	O
status	O
could	O
have	O
predicted	O
the	O
use	O
of	O
herbs	O
,	O
however	O
,	O
this	O
was	O
not	O
the	O
case	O
in	O
our	O
study	O
sample	O
.	O

Unemployed	O
patients	B
did	O
not	O
improvise	O
more	O
in	O
their	O
use	O
of	O
herbal	O
remedies	O
than	O
those	O
in	O
other	O
income	O
groups	O
,	O
even	O
though	O
most	O
of	O
the	O
herbs	O
used	O
were	O
relatively	O
common	O
,	O
readily	O
available	O
and	O
cheap	O
.	O

The	O
low	O
socioeconomic	O
status	O
of	O
the	O
majority	O
of	O
the	O
sample	O
may	O
have	O
prohibited	O
both	O
consultation	O
with	O
qualified	O
herbalists	O
and	O
the	O
purchase	O
of	O
imported	O
,	O
processed	O
herbs	O
that	O
would	O
have	O
incurred	O
additional	O
out	O
-	O
of	O
-	O
pocket	O
expense	O
to	O
the	O
patient	B
.	O

What	O
we	O
noted	O
was	O
that	O
there	O
was	O
no	O
difference	O
in	O
the	O
use	O
of	O
herbs	O
across	O
the	O
income	O
ranges	O
and	O
that	O
in	O
fact	O
,	O
patients	B
earning	O
relatively	O
modest	O
annual	O
incomes	O
between	O
$	O
US12	O
,	O
000	O
and	O
$	O
US19	O
,	O
999	O
were	O
most	O
likely	O
to	O
use	O
herbs	O
,	O
although	O
this	O
did	O
not	O
reach	O
statistical	O
significance	O
.	O

Attaining	O
a	O
higher	O
education	O
positively	O
influence	O
the	O
decision	O
to	O
use	O
herbs	O
.	O

We	O
suggest	O
that	O
in	O
the	O
absence	O
of	O
traditional	O
knowledge	O
regarding	O
the	O
medicinal	O
use	O
of	O
herbs	O
for	O
asthma	O
,	O
a	O
higher	O
educational	O
level	O
may	O
predispose	O
an	O
individual	O
to	O
greater	O
access	O
to	O
general	O
knowledge	O
,	O
especially	O
with	O
greater	O
exposure	O
to	O
the	O
internet	O
and	O
other	O
sources	O
of	O
information	O
,	O
and	O
this	O
could	O
be	O
a	O
factor	O
in	O
positively	O
influencing	O
the	O
individual	O
'	O
s	O
decision	O
to	O
use	O
medicinal	O
herbs	O
.	O

The	O
availability	O
of	O
scientific	O
evidence	O
-	O
based	O
information	O
on	O
the	O
efficacy	O
of	O
herbs	O
for	O
diverse	O
healthcare	O
problems	O
may	O
be	O
particularly	O
significant	O
in	O
patients	B
with	O
the	O
resources	O
to	O
avail	O
themselves	O
to	O
such	O
information	O
,	O
particularly	O
those	O
with	O
higher	O
educational	O
and	O
income	O
levels	O
.	O

This	O
is	O
particularly	O
true	O
for	O
garlic	B
and	O
Echinacea	B
,	O
which	O
have	O
been	O
extensively	O
researched	O
and	O
furthermore	O
patients	B
with	O
higher	O
educational	O
and	O
income	O
levels	O
would	O
be	O
more	O
likely	O
be	O
at	O
an	O
advantage	O
to	O
access	O
information	O
via	O
literature	O
or	O
on	O
the	O
world	O
wide	O
web	O
regarding	O
the	O
use	O
of	O
these	O
medicinal	O
plants	O
.	O

Patients	B
using	O
imported	O
,	O
processed	O
,	O
and	O
obviously	O
more	O
expensive	O
herbal	O
medications	O
were	O
on	O
the	O
higher	O
end	O
of	O
the	O
socioeconomic	O
scale	O
and	O
were	O
more	O
likely	O
to	O
afford	O
these	O
medications	O
.	O

It	O
was	O
also	O
observed	O
that	O
garlic	B
and	O
Echinacea	B
were	O
the	O
herbs	O
of	O
choice	O
in	O
patients	B
with	O
higher	O
educational	O
levels	O
.	O

These	O
herbs	O
have	O
a	O
long	O
tradition	O
of	O
use	O
and	O
are	O
widely	O
researched	O
in	O
Europe	O
and	O
North	O
America	O
.	O

The	O
traditional	O
use	O
and	O
strong	O
scientific	O
evidence	O
to	O
support	O
their	O
therapeutic	O
efficacy	O
could	O
be	O
important	O
factors	O
influencing	O
the	O
patient	B
'	O
s	O
decision	O
.	O

It	O
has	O
been	O
suggested	O
elsewhere	O
that	O
patients	B
with	O
higher	O
educational	O
levels	O
also	O
tend	O
be	O
more	O
involved	O
in	O
the	O
management	O
of	O
their	O
health	O
;	O
they	O
tend	O
to	O
self	O
-	O
medicate	O
or	O
even	O
suggest	O
to	O
their	O
physicians	O
the	O
course	O
of	O
therapy	O
.	O

Although	O
one	O
in	O
five	O
patients	B
using	O
medicinal	O
herbs	O
stated	O
that	O
"	O
conventional	O
medicines	O
were	O
not	O
working	O
"	O
as	O
the	O
reason	O
for	O
using	O
this	O
alternative	O
healthcare	O
modality	O
,	O
we	O
noted	O
that	O
asthma	O
severity	O
does	O
not	O
affect	O
the	O
decision	O
to	O
use	O
herbs	O
.	O

In	O
previous	O
studies	O
,	O
poor	O
management	O
was	O
associated	O
with	O
non	O
-	O
compliance	O
with	O
prescribed	O
pharmacotherapy	O
and	O
poor	O
inhaler	O
technique	O
[	O
5	O
,	O
6	O
]	O
.	O

The	O
backyard	O
and	O
home	O
garden	O
were	O
major	O
sources	O
of	O
readily	O
available	O
herbs	O
such	O
as	O
aloes	O
,	O
shadon	B
beni	I
and	O
lemongrass	B
.	O

Wild	O
growing	O
'	O
weeds	O
'	O
such	O
as	O
shandileer	B
,	O
tulsi	B
,	O
cocoa	O
onion	B
and	O
black	B
sage	I
were	O
also	O
identified	O
.	O

The	O
supermarket	O
was	O
a	O
major	O
source	O
of	O
inexpensive	O
common	O
medicinal	O
herbs	O
such	O
as	O
garlic	B
,	O
ginger	B
and	O
nutmeg	B
.	O

The	O
identification	O
of	O
these	O
medicinal	O
herbs	O
provides	O
an	O
opportunity	O
to	O
investigate	O
West	O
Indian	O
plants	O
used	O
to	O
treat	O
asthma	O
to	O
determine	O
whether	O
they	O
possess	O
pharmacological	O
properties	O
.	O

Scientific	O
investigations	O
have	O
shown	O
that	O
some	O
of	O
these	O
herbs	O
possess	O
pharmacological	O
and	O
anti	O
-	O
inflammatory	O
properties	O
,	O
and	O
these	O
may	O
be	O
useful	O
in	O
suppressing	O
the	O
characteristic	O
exaggerated	O
immune	O
response	O
in	O
asthma	O
[	O
20	O
-	O
24	O
]	O
.	O

Pepper	O
and	O
bayleaf	B
have	O
also	O
been	O
shown	O
to	O
exhibit	O
anti	O
-	O
inflammatory	O
properties	O
[	O
[	O
25	O
,	O
26	O
]	O
27	O
]	O
.	O

There	O
is	O
an	O
imperative	O
to	O
commence	O
scientific	O
investigations	O
on	O
traditional	O
West	O
Indian	O
medicinal	O
plants	O
to	O
determine	O
their	O
therapeutic	O
efficacy	O
and	O
safety	O
.	O

The	O
survey	O
instrument	O
specifically	O
asked	O
questions	O
on	O
the	O
use	O
of	O
medicinal	O
herbs	O
in	O
asthma	O
and	O
did	O
not	O
inquire	O
about	O
the	O
use	O
of	O
herbs	O
as	O
customary	O
teas	O
or	O
tonics	O
.	O

We	O
therefore	O
did	O
not	O
determine	O
lifetime	O
prevalence	O
for	O
the	O
use	O
of	O
herbs	O
in	O
our	O
patient	B
sample	O
,	O
but	O
we	O
suppose	O
that	O
had	O
this	O
been	O
included	O
that	O
there	O
might	O
have	O
been	O
a	O
prevalence	O
similar	O
to	O
those	O
reported	O
in	O
the	O
Jamaica	O
[	O
10	O
,	O
11	O
]	O
and	O
Trinidad	O
[	O
13	O
]	O
surveys	O
.	O

The	O
survey	O
was	O
also	O
limited	O
in	O
that	O
by	O
electing	O
to	O
conduct	O
the	O
study	O
at	O
a	O
public	O
health	O
facility	O
we	O
obviously	O
had	O
a	O
bias	O
towards	O
patients	B
at	O
the	O
lower	O
rung	O
of	O
the	O
socioeconomic	O
ladder	O
,	O
with	O
lower	O
income	O
and	O
educational	O
status	O
.	O

As	O
a	O
consequence	O
,	O
the	O
results	O
reflected	O
patients	B
from	O
this	O
demographic	O
background	O
.	O

We	O
may	O
have	O
expected	O
a	O
different	O
outcome	O
in	O
asthmatic	O
patients	B
attending	O
private	O
institutions	O
,	O
where	O
their	O
characteristics	O
would	O
have	O
been	O
slightly	O
different	O
,	O
as	O
we	O
noted	O
that	O
even	O
in	O
our	O
sample	O
the	O
small	O
number	O
of	O
persons	O
with	O
higher	O
income	O
and	O
educational	O
status	O
tended	O
to	O
use	O
more	O
medicinal	O
herbs	O
for	O
symptomatic	O
relief	O
.	O

We	O
did	O
not	O
assess	O
whether	O
patients	B
informed	O
their	O
attending	O
physician	O
at	O
the	O
clinic	O
about	O
their	O
use	O
of	O
herbs	O
or	O
determined	O
whether	O
the	O
knowledge	O
or	O
attitudes	O
of	O
these	O
physicians	O
regarding	O
the	O
use	O
of	O
herbs	O
influenced	O
the	O
patients	B
'	O
decision	O
to	O
use	O
herbs	O
.	O

The	O
study	O
was	O
also	O
limited	O
in	O
that	O
we	O
did	O
not	O
ascertain	O
the	O
out	O
-	O
of	O
-	O
pocket	O
expense	O
for	O
herbal	O
remedies	O
by	O
patients	B
,	O
although	O
most	O
stated	O
that	O
herbal	O
medicines	O
(	O
which	O
we	O
supposed	O
were	O
processed	O
,	O
imported	O
products	O
)	O
were	O
more	O
expensive	O
than	O
conventional	O
medicines	O
.	O

We	O
assumed	O
that	O
an	O
additional	O
expense	O
would	O
have	O
only	O
been	O
incurred	O
by	O
those	O
patients	B
purchasing	O
processed	O
,	O
imported	O
herbs	O
obtained	O
from	O
a	O
herbalist	O
,	O
herbal	O
shop	O
or	O
pharmacy	O
(	O
24	O
.	O
1	O
%	O
)	O
and	O
who	O
actually	O
consulted	O
a	O
herbalist	O
(	O
10	O
.	O
3	O
%	O
)	O
.	O

We	O
also	O
reasoned	O
that	O
since	O
all	O
the	O
other	O
herbs	O
used	O
were	O
inexpensive	O
and	O
available	O
from	O
either	O
the	O
backyard	O
garden	O
or	O
supermarket	O
(	O
58	O
.	O
6	O
%	O
)	O
that	O
the	O
cost	O
to	O
patients	B
selecting	O
these	O
remedies	O
was	O
minimal	O
.	O

Conclusions	O

The	O
findings	O
of	O
this	O
study	O
are	O
important	O
in	O
that	O
local	O
medicinal	O
plants	O
in	O
Trinidad	O
have	O
been	O
identified	O
in	O
the	O
self	O
-	O
management	O
of	O
asthma	O
in	O
a	O
significant	O
number	O
of	O
patients	B
attending	O
the	O
specialty	O
clinic	O
.	O

These	O
identified	O
herbs	O
can	O
now	O
be	O
targeted	O
for	O
scientific	O
investigation	O
to	O
determine	O
whether	O
their	O
pharmacological	O
efficacy	O
will	O
assist	O
in	O
the	O
development	O
of	O
viable	O
healthcare	O
alternatives	O
in	O
a	O
developing	O
country	O
.	O

These	O
findings	O
are	O
also	O
important	O
for	O
policymakers	O
in	O
the	O
health	O
sector	O
who	O
are	O
given	O
the	O
mandate	O
to	O
regulate	O
issues	O
pertaining	O
to	O
the	O
public	O
'	O
s	O
health	O
.	O

We	O
are	O
also	O
becoming	O
more	O
aware	O
of	O
the	O
potential	O
for	O
critical	O
interplay	O
between	O
herbs	O
and	O
drugs	O
when	O
taken	O
concomitantly	O
to	O
produce	O
life	O
-	O
threatening	O
interactions	O
.	O

Since	O
herbs	O
are	O
here	O
to	O
stay	O
and	O
patients	B
will	O
continue	O
to	O
self	O
-	O
medicate	O
with	O
increasing	O
frequency	O
,	O
it	O
is	O
imperative	O
that	O
healthcare	O
providers	O
become	O
more	O
knowledgeable	O
on	O
this	O
modality	O
and	O
keep	O
abreast	O
with	O
the	O
latest	O
developments	O
in	O
herbal	O
therapy	O
.	O

Competing	O
interests	O

The	O
author	O
(	O
s	O
)	O
declare	O
that	O
they	O
have	O
no	O
competing	O
interests	O
.	O

Authors	O
'	O
contributions	O

YNC	O
was	O
the	O
P	O
.	O
I	O
.	O
in	O
this	O
study	O
.	O

He	O
was	O
responsible	O
for	O
the	O
study	O
concept	O
,	O
development	O
of	O
methodology	O
,	O
coordinating	O
the	O
research	O
activities	O
,	O
analyzing	O
the	O
data	O
,	O
and	O
writing	O
the	O
manuscript	O
.	O

AFW	O
was	O
responsible	O
for	O
data	O
input	O
and	O
analysis	O
.	O

DA	O
was	O
involved	O
in	O
methodological	O
development	O
,	O
data	O
collection	O
,	O
data	O
input	O
and	O
analysis	O
and	O
presentation	O
at	O
regional	O
conference	O
.	O

RC	O
was	O
involved	O
in	O
methodological	O
development	O
,	O
data	O
collection	O
,	O
data	O
input	O
and	O
analysis	O
.	O

NW	O
was	O
involved	O
in	O
methodological	O
development	O
,	O
data	O
collection	O
and	O
input	O
.	O

RM	O
was	O
involved	O
in	O
methodological	O
development	O
,	O
data	O
collection	O
and	O
input	O
.	O

OS	O
was	O
involved	O
in	O
methodological	O
development	O
,	O
data	O
collection	O
and	O
input	O
.	O

DW	O
was	O
involved	O
in	O
methodological	O
development	O
,	O
data	O
collection	O
and	O
input	O
.	O

All	O
authors	O
read	O
and	O
approved	O
the	O
final	O
manuscript	O
.	O

Pre	O
-	O
publication	O
history	O

The	O
pre	O
-	O
publication	O
history	O
for	O
this	O
paper	O
can	O
be	O
accessed	O
here	O
:	O